*Review* **Chiral Heterocycle-Based Receptors for Enantioselective Recognition**

**Vaibhav N. Khose 1, Marina E. John 1, Anita D. Pandey 1, Victor Borovkov 2,\* and Anil V. Karnik 1,\***


Received: 27 December 2017; Accepted: 12 January 2018; Published: 24 January 2018

**Abstract:** The majority of biomolecules found in living beings are chiral, therefore chiral molecular recognition in living systems is crucial to life. Following Cram's seminal work on the crown-based chiral recognition, prominent research groups have reported innumerable chiral receptors with distinctly different geometrical features and asymmetry elements. Main applications of such chiral receptors are found in chiral chromatography, as for analytical purposes and for bulk separation of racemates.Incorporation of heterocyclic rings in these recognition systems added a new dimension to the existing group of receptors. Heterocycles have additional features such as availability of unshared electron pairs, pronounced conformational features, introduction of hydrogen bonding and presence of permanent dipoles as well as specific spectral properties in certain cases. These features are found to enhance binding properties of the receptors and the selectivity factors between opposite enantiomers, allowing them to be effectively separated. The review presents the synthetic approaches towards these heterocyclic receptors and their distinctly different behavior vis-à-vis carbocyclic receptors.

**Keywords:** heterocycle; receptors; enantioselective recognition; hydrogen bonding; conformational rigidity; configuration; diastereomeric interactions; macrocycle size; pyridine; dipolar interactions

#### **1. Introduction**

Chiral Analytical techniques have become indispensable tools in pharmaceutical and fragrance industries. Qualitative and quantitative analyses of the enantiomerically pure or enriched compounds used in these industries are essential in the view of criteria set by regulating authorities [1,2]. Most of these techniques are based on the non-bonded diastereomeric interactions between a host and enantiomeric guests. Such diastereomeric interactions are the genesis of the chiral manifestations in natural and man-made systems.

Indeed, chiral molecular recognition remains one of the most expanding research fields in organic chemistry [3]. Various biological phenomena such as enzyme-substrate, antibody-antigen and drug-biomolecule interactions are a manifestation of the importance of enantiospecific supramolecular processes in living organisms [4]. The importance of chirality in the fields of medicine [5,6], asymmetric synthesis, [7,8] catalysis [9], flavor [10], fragrances [11], biochemistry [12] and material science chemistry [13] has already been well established. While the area of asymmetric synthesis has witnessed a tremendous growth, the practicality of preparing homochiral compounds still remains a challenge.Thus, the stimulus for interest in the separation of racemic mixtures exploiting host-guest chemistry has gained popularity over the years.

The earliest studies on enantiomeric recognition of chiral organic ammonium salts by chiral crown ethers were carried out by Cram and coworkers [14]. Since then, the importance of furnishing chiral macrocyclic ligands has been realized. Some of these ligands include amino acid units [15], sugar molecules [16], diaza-crown moieties [17], and crown ethers containing a pyridine sub-cyclic fragment [18]. In the last few decades, strategies and methods for synthesizing simpler organic compounds that mimic the biological receptors havebeen the prime focus in this research area [19–21]. Thus, the artificial receptors having diverse chiral backbones with different elements of chirality [22–25], incorporating aromatic/heteroaromatic alicyclic rings [26–28] in the core structural motif with multiple functionalities [29] have been reported. The receptors containing heteroaromatic ring/heteroalicyclic rings have attracted widespread interest due to their excellent chiral discriminating ability [30]. The receptors with five/six membered heterocycles offer additional advantages while binding the chiral guests through several non-covalent interactions such as hydrogen bonding, electrostatic interactions, hydrophobic binding, cation-π interactions, π-π stacking, steric complementarity, etc. in the enantioselective recognition processes [31]. Analytical techniques such as NMR, UV-Vis, circular dichroism, and fluorescence spectroscopy are commonly used to study chiral recognition, among which the fluorescence approach providesthe highest sensitivity and real-time measurement.

Till date, there is no comprehensive review emphasizing heterocycle-based chiral receptors in enantioselective processes. The present review article presents a detailed account of the recent developments in the design and synthesis of various chiral receptors with heterocyclic motif such as pyridine [18], chromene [32,33], imidazole [34], benzimidazole [35,36], furan [37], thiophene [38], oxazole [22–25] etc. and its application in the enantioselective recognition of different classes of chiral analytes [39,40].

#### **2. Components of Chiral Molecular Recognition**

#### *2.1. Different Types of Forces*

Various non-covalent and covalent interactions are the key elementary factors involved in the host-guest molecular recognition phenomena. Much effort in recent years have moved to more keen understanding for the basis of molecular recognition and the physical principles governing this phenomenon have been the focus of many researchers for centuries. Besides, a wide range of the controlled separation and chemical transformation processes in the drug design, scientific and engineering fields relies on the host-guest chemistry. This section comprehensively addresses the different types of interaction forces in detail.

#### *2.2. Non-Covalent Interactions*

Non-bonded interactions are susceptible to thermal fluctuations and other external factors unlike covalent linkages. Weak forces by themselves are able to form strong intra and intermolecular significant interactions only upon working together or in combination with a covalent binding. They are most ubiquitous in nature and are crucial in determining the three-dimensional structures adopted by proteins and nucleic bases.

Depending upon the origin, non-covalent interactions are divided into the following sub classes; Electrostatic Interactions, Hydrogen Bonding, π-electronic effects, Van der Waals forces and Hydrophobic binding, which are summarized briefly below.

#### 2.2.1. Electrostatic Interactions

Electrostatic or Ionic interactions [41] are strong coulombic attractive forces between opposite charges, observed in the case of several receptors, such as cations and anions, binding effectively to the corresponding guest in place. This type of interaction is non-directional, whilst for the ion-dipole interactions the dipole must be suitably aligned for optimal binding efficiency. The high strength of electrostatic interactions has made them an invaluable tool amongst supramolecular chemists for achieving strong binding. Ionic interactions are basically of two types; the classic ionic bond which is a non-directional attractive force, for example between a positively charged metal ion and negatively charged non-metal, and the salt bridge wherein there is a balance of the electrostaticforces between three or more atoms with partial charges. Such strong attractive interactions stabilize the host guest complex extensively.

#### Hydrogen Bonding Interaction

Hydrogen bonding [41,42] is attractive electrostatic interaction between the hydrogen atom, bearing a partial positive charge, covalently attached to an electronegative atom and another electronegative atom which has a partial negative charge developed on it. Hydrogen bonding is the most widely employed dipole-dipole interaction in the field of supramolecular chiral discrimination. Most receptors have electronegative heteroatoms such as Nitrogen, Oxygen as binding sites involved in hydrogen bonding.

#### 2.2.2. π-Electronic Interactions

#### *π*-*π* Interaction

π-π Interactions [43] are rather weak bindings occurring in the face-to-face or edge-to-faceor edge-to-edge manners, which play a major role in many aspects of biological, solid-state and host-guest supramolecular chemistry. The quadrupole–quadrupole forces are responsible for the *π*-*π* stacking of aromatic rings. Aromatic rings such as benzene, naphthalene, pyridine, imidazole, triazole, indole etc. are often incorporated into the chiral macrocycle for increasing the capacity for chiral recognition to a greater extent owing to the π-π stacking interaction of the host and guest systems.

#### Cation–*π* Interaction

The interaction between a cation and delocalized *π*-electron cloud of the aromatic system exemplifies the cation-*π* interaction [44]. The simplest view of this non-bonding interaction is in the gas phase. In this case, there is no solvent and stabilization of the system is entirely dependent on the cation and *π* system of interest. The cation-πinteractions between the hydrogen-bonded ammonium ion and the aromatic ring of host, exemplifies the chiral recognition of organic ammonium ions by various chiral receptors.

#### 2.2.3. Van der Waals Forces

Van der Waals forces [45] are an attractive noncovalent type of interactions between the fixed dipole in one molecule and induced instantaneous oscillating dipole in another molecule via the corresponding distortion of electron clouds. These forces though underappreciated, are of immense importance to the supramolecular properties of all molecules. However, it is difficult to rationally design the receptors specifically, as this type of interactions is very common to most molecules. The binding of guest into the hydrophobic cavity of host is driven by an enthalpy stabilization. Therefore, even small molecules can make a large number of the Van der Waals contacts and each of them add in a synergistic manner.

Additionally, there is one specific subclass in this category called the "London dispersion forces" and attributed to two induced dipoles.

#### 2.2.4. Hydrophobic Interactions

Hydrophobic interactions [46] are a result of the nonpolar side chains (aromatic rings and hydrocarbon groups) holding tightly in polar solvents, especially water. In this case, there is no sharing of electrons between any groups, therefore it does not produce a true bond. The hydrophobicity of receptors can be manipulated by introducing long side chains. On binding of a guest, the water molecules around a polar surface of the hydrophobic cavity of the host are released into the bulk solvent, which in turn leads to enhancement of its hydrogen bonding capabilities simultaneously increasing the entropy of the system. The hydrophobic interactions are comparatively stronger than Van der Waalsforces or Hydrogen bonding. For example, cyclophanes and cyclodextrins being macrocyclic itself possess inbuilt hydrophobicity contributing to the host-guest affinity and are well-designed to encapsulate guest molecules from an aqueous solution.

#### **3. Analytical Tool for Chiral Recognition**

For efficient enantioselective discrimination, the chiral host-guest interactions should result in certain chemical-physical changes that can be read out by various analytical techniques. Depending on spectral properties of the host-guest complexes, analytical techniques such as fluorescence, UV-visible absorption, circular dichroism, NMR, HPLC, electrochemistry, IR, and mass spectrometry could be used as effective tools to measure the chiral recognition phenomenon. The detailed description of each technique is presented below.

#### *3.1. Fluorescence*

Fluorescence spectroscopic technique received considerable attention because it is able to provide special advantages which include simplicity, low cost, high sensitivity, adaptation to automation and real-time analysis, diverse signal output modes and small quantity of host and guest. This technique allows multiple detection modes such as emission, excitation and lifetime measurements.

For chiral analysis/recognition fluorophores (fluorescent chromophoric systems) should be either intrinsically chiral or made chiral by attaching an enantiopure moiety. The corresponding diastereomeric interactions with the concerned chiral analyte give different fluorescence responses; i.e., the recognition. Such sensors generally respond via the fluorescence enhancement or quenching. The fluorescence quenching is observed due to loss of the energy of the excited state by a non-radiative decay. Such systems are commonly studied by the Stern-Volmer equation [47] (see below).

$$\mathcal{F}\_0/\mathcal{F} = 1 + \mathcal{K}\text{sv [Q]}$$

where

F0 = Initial emission intensity of the host

F = Intensity of the host after addition of analyte (Guest)

*K*sv = Stern-Volmer constant/Stability constant for the complex

[Q] = Concentration of the analyte (Guest)

The Stern-Volmer plot of fluorescence intensity ratio, F0/F vs. [Q], concentration of guest enantiomers would exhibit the linear relationship with host and from the graph, Stern-Volmer constant can be calculated.

However, when complexation results in the enhancement of fluorescence, the system is studied by using the Benesi-Hildebrand equation [48] (see below).

$$\text{Io}/(\text{I}-\text{I}0) = \text{[b}/(\text{a}-\text{b})]\left[1/(\text{K[M]})+1\right]$$

where

I0 = Initial emission intensity of the host

I = Intensity of the host after addition of analyte (Guest)

*K* = Stability constant for the complex

a, b = Constants terms

[M] = Concentration of the analyte (Guest)

The [b/(a − b)] can be found out by plotting the I0/(I − I0) against the inverse of the concentration of analyte, M*−***1**.

The Benesi-Hildebrand equation is similar to equation for straight line, y = mx + C. The intercept of the graph gives the [b/(a − b)]; the I0 and I are found out experimentally and hence *K* can then be calculated.

#### *3.2. UV-Vis Absorption*

UV-vis spectroscopy is one of the widely used methods for chiral recognition as it provides high sensitivity and simplicity to the host-guest binding study. In this case, the host molecule should contain a chromophoric system with the absorption band in the UV-Vis range, while the host-guest complex generally has a different absorption band.The difference in the absorbance of host and corresponding host-guest complex is used for determination of the extent and strength of binding in a quantitative manner.

The association constants related to binding process of the opposite guest enantiomers with the chiral host can be calculated by using the modified Benesie–Hildebrand equation [35] as follows.

$$[H]\_0[G]\_0 = \frac{1}{K\_\text{a} \Delta \varepsilon} + \frac{[G]\_0}{\Delta \varepsilon}$$

Further modified equation, where a double reciprocal plot can be made with 1/Δ*A* as a function of 1/[*G*]0. {where [*G*]0 >>> [*H*]0}.

$$\frac{1}{\Delta A} = \frac{1}{\text{Ka } \Delta \varepsilon [H]\_0 [G]\_0} + \frac{1}{\Delta \varepsilon [G]\_0}$$

where,

[*H*]0 and [*G*]0 are total concentrations of host and guest, respectively,

Δ*ε* is the change of molar extinction coefficient between the free and complexed host,

Δ*A* represents the absorption change of host upon the addition of opposite guest enantiomers.

The plots of 1/Δ*A* against 1/[*G*]0 values, usually give an excellent linear relationship, indicating the corresponding binding process between the host and guest enantiomers. The Δ*ε* value can be derived from the intercept, while *K*<sup>a</sup> (association constant) can be calculated from the slope. The binding constants, K(*R*) or K(*S*) and associated free energy change (Δ*G*0) for the host molecule upon the complexation are obtained by the curve fitting analysis of observed absorbance changes.

#### *3.3. Circular Dichroism (CD)*

Circular dichroism (CD) spectroscopic technique responds to the spatial asymmetry change in conformation and/or configuration, and hence is effectively used for investigating the chiroptical properties of chiral hosts and their complexes with enantiomeric guests. It enables probing the discrimination efficiency of supramolecular hosts and determination of complex stoichiometry and stability.

In general, two or more electronic transitions of the chromophoric units around a chiral center excitonically couple with each other generating bisignate CD signals. It allows the reliable determination of enantiomeric preference by comparing the corresponding amplitudes of exciton couplets from exciton-coupled circular dichroism (ECCD) spectra of the resulting complexes. The sign of the Cotton effect can be used to assign the absolute configuration or relative conformation [3].

#### *3.4. Nuclear Magnetic Resonance (NMR) Analysis*

Enantioselective recognition can be readily studied by using NMR spectroscopy as the diastereomeric interaction between a chiral host and enantiopure guest that is usually accompanied by significant chemical shift changes. This technique is useful for both liquid and solid compounds, while only milligram quantities of samples are required. The recognition process via NMR can be carried out by two main approaches: the use of chiral solvating agents (CSA) and enantiopure

chiral derivatizing agents (CDA). In the case of CSA [49] based on non-covalent interactions, the corresponding diastereomeric complexes are formed between a solute and chiral solvent and the resultant NMR signals deduce the chirality of molecule of interest. A sub-class of CSA is chiral shift reagents (CSR), where a paramagnetic metal ligated to chiral ligands. In the case of CDA [50], the covalent bonded diastereomeric derivatives are formed and their NMR pattern helps in assignment of the configuration of the target compound. Determination of the enantiomeric purity of the samples with certain enantiomeric excess is also possible by using NMR [51]. Furthermore, the variable-temperature 1H NMR measurements are useful in estimating a kinetically more stable complex and exhibit the enantiomeric recognition effect.

Presence of aromatic moieties in the host as well as in the guest generally gives better results due to the magnetic anisotropic effect. It is expected that the protons present in the vicinity of chiral center are affected by the shielding or deshielding effect during the formation of diastereomeric complexes. It results in better separation of the peaks for these protons in both the diastereomers; hence enhancing the chiral recognition.

#### *3.5. High Performance Liquid Chromatography (HPLC)*

Chiral HPLC [52] serves as the most extensively used analytical method for resolving enantiomers of the chiral samples. A stationary phase of the chiral HPLC columns contains an enantiomeric form of the chiral materials such as cellulose or cyclodextrin. Two opposite enantiomers of the analyte are distinct in affinity to the chiral stationary phase (CSP), and therefore show different retention times.

The chiral compounds synthesized in laboratory in a racemic form or enantio-enriched form via asymmetric synthesis are commonly analyzed by chiral HPLC. The separation of enantiomers on chiral HPLC column is based on the diastereomeric binding via three point interactions with a chiral coating present in the column. The difference in the retention time of enantiomers is an example of chiral molecular recognition between the chiral column packing materials and the enantiomers. The most popular chiral columns are Chiralcel OD and Chiralpak AD. Chiralcel OD has the tris(3,5-dimethylphenyl carbamate)s derivative of cellulose as CSP, whereas Chiralpak AD has the same derivative but of amylose (Figure 1). These polysaccharide-based chiral columns are nearly universal with the capability to resolve chiral compounds being almost 80–90% as reported so far using hexane-alcohol as eluents. Most commercially available chiral HPLC columns are carbohydrate-based such as Chiralcel OD and Chiralpak AD, crown ether-based column includes crown pack CR, crown pack CR (+), crown pack CR (−) etc. Thus, re-emphasizing the role of heterocycles in chiral supramolecular chemistry.

**Figure 1.** Chiral column packing materials, of cellulose carbamate andamylose carbamate.

#### *3.6. Mass Spectrometry*

Mass spectrometry [23,53] is the ubiquitous powerful analytical tool for the chiral molecular recognition. The chiral recognition using fast atom bombardment mass spectrometry (FAB-MS) and electrospray ionization mass spectrometry (ESI-MS) are the most significant ways to quantify the recognition phenomena. The methodology working on the basis of isotopic labeling of one of the guest (G+) enantiomers is carried out followed by comparing the peak intensities of 1:1 mixture of the unlabeled (G*R*+) and labeled enantiomer guests (G*<sup>S</sup>*−*d*<sup>n</sup> +). Chiral recognition of the given host is simply measured by using the following equation.

'IRIS' value was defined to be peak intensity ratio, *<sup>I</sup>* [(H + G*R*+)]/*<sup>I</sup>* [(H + G*S*−*d*<sup>n</sup> +)] = I*R*/I*S*-*d*n*IRIS*,


#### *3.7. Electrochemical Methods*

Electrochemical methods have attracted much attention due to their high sensitivity, operational simplicity, and cost efficiency.

Electrochemical methodssuch asion-selective electrodes (ISEs) for pH and cyclic voltammetry (CV) enable the qualitative as well as quantitative determination of the target analyte along with the elucidation of thermodynamics and kinetics of the electron transfer reactions. These techniques convert the chemical and/or physical information of analyte into the electrical signal of either potential or current or both, which is then processed to reveal the accurate chemical information.

The chemical or physical change may be induced directly by the target analyte interacting with the electrode, thereby generating the electric signals monitored as a potential, or current change, or both. Detection based on each of these signals is termed *potentiometry*, *amperometry* (including *coulometry*), and *voltammetry*, respectively.

Electrochemical detection has been applied mainly to the redox-active targets that are charged, that are, ions, and/or capable of undergoing the redox reactions on an electrode leading to either oxidation or reduction of the target.

#### Cyclic Voltammetry

Simultaneous recording and analyzing the potential and current variations with time are the merits of voltammetry [54]. In particular, to make the control and analysis easier, the change of potential can be made linear against five times. The corresponding voltammetry is called *linearsweep voltammetry*. Further, the potential can be linearly increased and then decreased in a cyclic manner, and such a method is called *cyclic voltammetry*. Upon combining with the three-electrode cell it becomes the widely used electrochemical technique for either fundamental studies or detection applications. The most important result from such a measurement is the cyclic *voltammogram*, or simply CV, which plots the variation of current iagainst the linearly changing electrode potential *E*.

CV is nowadays conventionally performed on a computer-controlled potentiostat as commercially supplied. The user needs to input at least three parameters into the potentiostat: the initial and final potentials *E*i and *E*f of the potential scan, and the potential scan rate d*E*/d*t*. The equations below describe the relationships between these parameters:

$$\mathbf{d}E/\mathbf{d}t = (E\mathbf{f} - E\mathbf{i})/(t\mathbf{f} - t\mathbf{i})$$

$$E = E\mathbf{i} + t \times \mathbf{d}E/\mathbf{d}t$$

where *t* is the variable time. In this equation, the start (*t*i) and final (*t*f) times of potential scan are used here to explain the relationship, but are not independent because they are determined by *E*i, *E*f, and d*E*/d*t*. Also, it is of note that the scan rate d*E*/d*t* is positive when *E*f *> E*i and negative when *E*f *< E*i.

The electrode reaction potential and kinetics of redox active molecule are well reflected by the peak potentials and the shape of CV. In general, for a one-electron reaction that converts a molecule in the reduced state R to the oxidized state O, the reaction proceeds as follows:

$$\text{R} \overset{k\_{\text{Fe}}}{\Leftrightarrow} \text{O} + e^-$$

$$k^{\text{e}}\_{\text{f}}$$

where *k*<sup>e</sup> <sup>f</sup> and *kb* <sup>e</sup> are the rate constants for the forward and backward electron transfer reactions, respectively. If *k*<sup>e</sup> <sup>f</sup> ≈ *<sup>k</sup>*<sup>e</sup> <sup>b</sup> and both are sufficiently large, the reaction represents a reversible electrode process. If *k*<sup>e</sup> <sup>f</sup> >> *k*<sup>e</sup> b, the reaction is electrochemically irreversible, even though it may be chemically reversed given a sufficiently long time. Between these two-edged points, the reaction is regarded as quasi-reversible. These situations can be mathematically processed, giving rise to useful conclusions in relation to CVs, particularly for electrochemical detection.

#### **4. Special Features of Heterocyclic Receptors for Enantioselective Recognition**

Chiral molecular recognition is dependent on several parameters. To facilitate and exploit these parameters, the design of chiral receptors is the most crucial factor. The research community continuously broadens the scope of chiral receptors containing the aromatic/heteroaromatic/aliphatic rings. The present review covers a variety of hosts containing one or more heterocyclic rings as a vital part for enantiodiscrimination. Thus, these heterocyclic rings can be of different sizes and structure, for example aromatic rings such as imidazole, benzimidazole, furan, thiophene, pyrrole, triazole, pyridine, quinoline, isoquinoline, etc. or aliphatic rings such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, oxazolidine, etc. A plethora of the heterocyclic receptors synthesized so far has different elements of chirality and possesses special characteristic features to influence the stability of host-guest complex and enantioselective sensing. The key features of these hosts are summarized as follows:


#### **5. Chiral Hosts with Six Member Heterocycle/s**

Six-membered cyclic structures are most abundant in nature. One of the primary reasons being conformational and hence such stuctures are thermodynamically stable. Aromatic rings have advantage of presence of ring current which very strongly influence the NMR signals of the analyte. Pyridine ring has found wide-spread use in the reported receptors so far.

#### *5.1. Nitrogen Containing Six Member Heterocycle/s*

#### Pyridine Ring

Pyridine is one of the six membered aromatic heterocycles which has been extensively used in chiral organocatalysis [55], chiral metal-based catalysis [56], chiral resolving agents [57,58] etc. Reports reveal that inclusion of symmetrical, 2,6-disubstituted pyridine motifs in the host architecture, offers enanhanced binding properties to it.The strikingly common unit found in pyridine containing hosts are the presence of one or more 2,6-disubstituted pyridines, with pyridine nitrogen pointing inwardly, in the structural construct of the macrocycle or the molecular cleft.(Chart 1, part A). Another class of pyridine containing receptors include one or more 4,4-bipyridine motif giving rise to rigid molecular clefts or cyclophanes (Chart 1, part B).

**Chart 1.** 2,6-disustituted pyridine (**A**) and 4,4'-Bipyridine (**B**) containing hosts.

Incorporation of a pyridine unit provides proton acceptors at the pyridyl nitrogens which are important for the tripod hydrogen bonding, while the aromatic system contributes via π-π stacking interaction, along with imparting increased rigidity to form thermodynamically stable complexes with guest molecules. Owing to the aforementioned special features of the pyridine ring, Izatt and group have designed various macrocyclic hosts, particularly chiral crowns ethers containing pyridine units [18], which enable these hosts to recognize specific guests such as chiral organic ammonium salts. It was one of the first extensive recognition studies using chiralmacrocycles (Figure 2) and enantiopure alkylammonium salts. Several experimental techniques such as temperature-dependent 1H NMR spectroscopy, titration calorimetry, Fourier transform ion cyclotron resonance mass spectrometry, and selective crystallization have been employed to establish the corresponding host-guest chiral recognition in the given systems and to report the *K*, ΔH, and ΔS values for the interactions, thus quantitating the binding processes. Additionally, the X-ray crystallographic results provided a structural basis for the recognition.

The parameters and supramolecular interactions that are involved in these chiral systems have been studied exhaustively and several [18,59,60] reviews on this and similar works have been summarized by the group. Their systematic investigations revealed the effect of substituents on the crown ether, guest type and solvent on the extent of enantiomeric recognition.

In continuation of the research on chiral recognition, the authors [61] have developed a gas-phase ion-molecule host-guest system, based on (*S*,*S*)-dimethyldiketopyridino-18-crown-6 (*S*,*S*-**8**) macrocycle for the enantioselective recognition of *R* and *S*enantiomers of α*-*(l-naphthy1)ethylammonium (NapEt+) cation (Figure 3) using mass spectrometry (Reaction 1). It was demonstrated that the *S*,*S*-**8**.*R*-NapEt+ complex was more stable than the *S*,*S-***8**.*S*-NapEt+ complex with the equilibrium constant K obtained for *S*-NapEt<sup>+</sup> being larger than that for *R*-NapEP<sup>+</sup> by a factor of 4. These results confirmed considerable recognition, which was measured by using the FT-ICR/MS techniques. However, no recognition was observed for the same host-guest interaction in the solution phase, indicating that the stabilization of

the complex formed is entirely dependent on the cation-πinteractions between the hydrogen-bonded ammonium ion and aromatic ring of the host.

**Figure 2.** Chiral pyridine containing crown ether ligands.

**Figure 3.** (*S*,*S*)-dimethyldiketopyridino-18-crown-6 (*S*,*S*-**8**) and α-(l-naphthy1)ethylammonium (NapEt+).

*S,S*-8 (*R* or *S*)-NapEt<sup>+</sup> + 18C6 -S,S-8 + 18C6 (*R* or *S*)-NapEt+

In their continuing efforts, same group then synthesized two chiral macrobicyclic cleft compounds containing a pyridine ring [62] as it possesses a three-dimensional cavity which might be useful for the recognition process. Treatment of pyridine-bridged tetrabromide **9** with the respective chiral glycols, chiral methyl-substituted diethylene glycol, (1*S*,5*S*)-3-oxapentane-1,5-diol or the (2*R*,4*R*)-pentanediol furnished the chiral tetramethyl-substituted macrobicycle **10** and macrocycle **11**, respectively (Scheme 1). 1H NMR spectroscopy has been used to determine the chiral recognition behavior of the synthesized compounds **10** and **11**. Indeed, (*S*,*S*,*S*,*S*)-**10**, as a chiral host demonstrateda high degree of the enantiomeric discrimination for(*S*)-enantiomers of α-(1-naphthyl)-ethylammonium perchlorate (NapEt) and phenyl ethyl ammonium perchlorate (PhEt) over their (*R*)-forms. However, a reverse sequence of the recognition was observed for the (*S*,*S*)-**8** host wherein it recognizes the corresponding(*R*) forms of NapEt and PhEt over their (*S*) forms. This high recognition ability of cleft compound was observed owing to its increased molecular rigidity after introduction of a second macro ring on the monocyclic pyridine-crown ligand. The chiral discrimination behavior was studied using binary solvent system, lower enantiomeric recognition was observed for MeOH/CHCl3 in comparison with Ethanol:Dichoroethane (2:8) which revealed the effect of solvent.

Stoddart et al. [63] have developed new axially-chiral tetracationic cyclophanes, (*R*)-**14**.4PF6 and (*R*,*R*)-**16**.4PF6 (Scheme 2). Tetracationic cyclophane, (*R*)-**14**.4PF6 was obtained by the reaction of (*R*)-**12** and **13**.2PF6 and similarly D2 symmetric tetracationic cyclophane, (*R*,*R*)-**16**.4PF6 was synthesized using the treatment of (*R*)-**12** and (*R*)-**15**.2PF6. These tetracationic cyclophane receptors were found to be effective for the chiral recognition in the case of several chiral amino acids, such as L- and

D-enantiomers of phenylalanine (Phe), tyrosine (Tyr), and tryptophane (Trp) as free forms, or methyl esters, or *N*-acetyls in H2O and organic solvents, as determined by using UV-Vis titration. The binding constant and free energies of 1:1 host-guest complexation are provided in Table 1. As one can see, the enantioselective recognition ability decreases from *N-*acetyl-Trp to *N-*acetyl-Tyr (Table 1, entries 7 and 8) and further to less π-electron-rich *N-*acetyl-Phe (Table 1, entries 9 and 10). These results revealed a greater extent of the secondary stereoelectronic interactions between the functional groups of π-electron rich guest and bulky optically-active binaphthol spacer(s) of cyclophane(s), which can be attributed to the π-electron rich nature of guest (primary mode of binding).

**Scheme 1.** Synthesis of macrobicyclic cleft compounds **10** and **11.**

**Scheme 2.** *Cont*.

**Scheme 2.** Synthesis of axially-chiral tetracationic cyclophanes (*R*)-**14**.4PF6 and (*R*,*R*)-**16**.4PF6.

**Table 1.** Binding constants (*K*a) and free energies of complexation (−Δ*G*0) for the 1:1 complexes between cyclophanes (*R*).14.X (X = PF6 or Cl) and (*R*,*R*)-16.4 PF6 and π-electron-rich amino acids a.


<sup>a</sup> All binding constants were determined by UV/vis titration at 25 ◦C. <sup>b</sup> ΔΔ*G*<sup>0</sup> <sup>=</sup> <sup>Δ</sup>*G*<sup>0</sup> (L) − <sup>Δ</sup>*G*0. <sup>c</sup> In H2O as solvent. <sup>d</sup> Not determined. <sup>e</sup> Solvent mixture A: MeCN 90% DMF 10%; solvent mixture B: MeCN 90% DMSO 10%.

Hollosi et al. [64] have established the applicability of CD spectroscopy as an effective tool for the enantioselective discrimination of aryl alkyl ammonium salts **19**–**21** by pyridine-18-crown-6 type ligands, **17** and **18** (Figure 4). Furthermore, the stoichiometry and relative stability of host-guest complexes have been determined. Intriguingly, the study revealed that the heterochiral complexation of (*R*,*R*)-**17** with (*S*)-aralkyl ammonium salts **19** and **20** or (*S*,*S*)-**18** with (*R*)-salts **19** and **20** exhibited additional spectral effects in the spectral region 1Lb and 1La in the form of high amplitude of CD than homochiral complexation.

Mallouk et al. [65] have synthesized the(*S*)-valine-leucine-alanine cyclophane, **26** (Scheme 3). The bipyridine fragment, **23** of **26** was prepared by the reaction of 4, 4'-bipyridine with 4-(chloromethyl)benzoic acid followed by the treatment with 4-(bromomethyl)benzylamine hydrobromide. The standard solid phase synthesis was employed to produce the N-*t*-BOC-protected tripeptide unit, **24**. Finally, the bipyridine and N-*t*-BOC-protected tripeptide units **24** were coupled to obtain the required (*S*)-valine-leucine-alanine cyclophane, **26**. 1H NMR titration for the complexation of chiral cyclophane host **26** in an aqueous media with diverse pharmaceutically interesting chiral

and racemic π-donor guest molecules, such as Non-steroidal Anti-inflammatory Drugs (NSAIDS), *β*-blockers, amino acids, and amino acid derivatives were performed confirming weak binding abilities in the range of 1–39 M−<sup>1</sup> (Table 2). Out of the studied guest molecules, racemic nandalol and DOPA exhibited the substantial binding with **26**. Interestingly, the (*R*)/(*S*) enantioselectivity ratio of 13 ± 5 was found for dihydroxyphenylalanine (DOPA), indicating a strong π-electron donor cationic guest. Two-dimensional NOESY 1H NMR spectra revealed the corresponding multiple intermolecular NOE's signals for (*R*)-DOPA and the host, **26** in the host-guest complex. This result unambiguously confirmed a strong and enantioselective binding of (*R*)-DOPA inside the cavity of **26**, while no measurable interaction was detected for (*S*)-DOPA under the same conditions.

**Figure 4.** Pyridine-18-crown-6 (**17**, **18**) type ligands host for enantioselective recognition of aryl alkyl ammonium salts **19**–**21**.

Hua et al. [30] reported the synthesis of five pyridine-based macrocyclic receptors, **29a**–**e** (Schemes 4 and 5) by simple acylation of the chiral diamine dihydrobromide intermediates, **28a**–**c** with 2,6-pyridinedicarbonyl dichloride in a highly diluted solution. However, the acylation of chiral diamine dihydrobromides, **28a**–**b** with 2,6-pyridinedicarbonyl dichloride simultaneously afforded the [1 + 1] cyclization products, **29a**–**b** and [2 + 2] cyclization products **29c**–**d**. More importantly, under similar reaction condition, the acylation reaction of **28c** and 2,6-pyridinedicarbonyl dichloride, afforded the only [1 + 1] product **29e**,while the [2 + 2] product was not formed. The enantioselective interaction of synthesized chiral macrocyclic receptors, **29a**–**e** with D- and L-amino acid methyl ester hydrochlorides was evaluated by using fluorescence spectroscopy and the difference of fluorescence intensity confirmed significant chiral molecular recognition (Table 3).

As seen in Table 3, macrocycles, **29c**,**e** exhibit the better enantiomeric recognition for D- and L-Ala methyl ester hydrochlorides as compared to other chiral macrocycles, **29a**,**b**,**d**. Chiral macrocycles, **29a**,**c**,**e** all show excellent chiral discrimination for Phe methyl ester hydrochloride, whereas **29b**,**d** do not. In the case of D- and L-His methyl ester dihydrochloride, only **29b** displayed recognition.

Suh et al. [53] synthesized new pyridine-based chiral crown ether, **34** (Scheme 6) as follows. Diol, **30** obtained from the known five step methodology, was coupled with diiodide, **37** prepared from chelidamic acid (**35**) to furnish **32**. The reduction of cyano group of **32**, followed by the treatment

with ethyl isocyanate provided the required chiral host, **34**. The authors also synthesized chiral bis-pyridino-18-crown-6, **31** with the diphenyl substituent by similar methodology in order to compare it with the chiral host, **34**. These hosts exhibited chiral molecular recognition for the enantiomers of methyl ester hydrochlorides of Leu, Gly(Ph), and Phe, which was determined by enantiomer labeled (EL) guest method using fast atom bombardment mass spectrometry (FAB-MS).For host, **34** the IRIS values obtained are in the range of 1.12 to 1.44 indicating that the (*R*)-enantiomer of amino acids showed binding preference over the (*S*)-enantiomer. However, for the host, **31** the IRIS values for chiral recognition were found to be lower than for the chiral host, **34**.

**Scheme 3.** Synthetic of (*S*)-valine-leucine-alanine cyclophane, **26**.

**Table 2.** Results of NMR titrations using the dibromide salt of **26**. Association constants (*K*a) represent the average of two or more proton chemical shifts.


**Table 2.** *Cont.*

**Scheme 4.** Preparation of chiral macrocycles **29a**–**d**.

**Scheme 5.** Preparation of Chiral Macrocycle **29e**.


**Table 3.** Chiral recognition data determined by fluorescence spectra for the interactions of pyridine-containing chiral ligands with enantiomers of amino acid methyl ester hydrochlorides.

**Table 3.** *Cont.*


**Scheme 6.** Synthesis of chiral macrocycles, **31** and **34**.

The same group [23] has prepared *C*2-symmetric chiral bis-pyridino-18-crown-6, (*R*,*R*,*R*,*R*)-**42** and **43** (Scheme 7) with tetraethyl tetracarboxylate and tetramethyl tetracarboxamide groups as chiral barriers in 2008. The synthesis was carried out by a simple alkylation of diethyl-*L*-tartarate (**38**) or *N*,*N*,*N'*,*N'*-tetramethyl tartaramide (**38**) with 2,6-bis(iodomethyl)pyridine (**40**).

**Scheme 7.** Synthetic routes for chiral bis-pyridino-18-crown-6 ethers **42** and **43**.

In this case, the authors used electrospray ionization mass spectrometry (ESI-MS) as a detection tool to evaluate the enantiomeric recognition of amino acid methyl ester hydrochlorides, **44**–**53** (Figure 5) by macrocycles, (*R*,*R*,*R*,*R*)-**42** and **43**. The *IRIS* values obtained by ESI-MS (Table 4) for the (*R*,*R*,*R*,*R*)-**42** with the chiral amino acid methyl ester hydrochlorides guest in the range from 1.30 to 7.66, revealed more stable complexes with the (*R*)-enantiomer preference. However, *IRIS* values for chiral recognition of (*R*,*R*,*R*,*R*)-**43** found in the range of 0.22 to 2.31 demonstrated the inconsistent preference in comparison with (*R*,*R*,*R*,*R*)-**42**.

**Figure 5.** The chemical structures of amino acid methyl ester hydrochlorides (CH3 and CD3 esters) (**44**–**53**) used for the chiral recognition.


Xie et al. [66] developed the first examples of bis-macrocyclic oxo-polyamine type molecular tweezers as the corresponding chiral recognition hosts (Scheme 8). The tweezers, **55**–**57** were prepared through a simple condensation of pyridine ring containing macrocyclic polyamide **54** with 2,6-bis(chlorocarbonyl)pyridine, α, α'-dibromo-*m*-xylene and α, α'-dibromo-*p*-xylene respectively.

These tweezer-like receptors, **54**–**57** showed significant chiral molecular recognition for amino acid esters as determined by using the differential UV spectrometry. The association constants, free energy changes and enantioselectivities, KL/KD are shown in Table 5. It was revealed that the extent of enantioselective recognition for the amino acid derivatives depends on diverse parameters such as the tweezers' shape, steric effects, structural rigidity, hydrogen bond, and π-π stacking between the aromatic groups.

**Scheme 8.** Synthesis of bis-macrocyclic oxo-polyamine type molecular tweezers (**55**–**57**).

**Table 5.** Binding constants (*K*a), the Gibbs free energy changes (−Δ*G*0), enantioselectivities*K*L/*K*<sup>D</sup> and ΔΔ*G*<sup>0</sup> calculated from −Δ*G*<sup>0</sup> for the complexation of L/D-amino acid esters with the chiral receptors –**57** in CHCl3 at 25 ◦C a.


<sup>a</sup> The concentration of the receptors: 2.0 × <sup>10</sup>−<sup>4</sup> mol dm−3. <sup>b</sup> Ala-OMe: alanine methyl ester: Leu-OMe: leucine methyl ester: Phe-OMe: phenylalanine methyl ester: Trp-OMe: tryptophane methyl ester. <sup>c</sup> ΔΔ*G*<sup>0</sup> <sup>=</sup> <sup>Δ</sup>*G*<sup>0</sup> − <sup>Δ</sup>*G*0.

Hua et al. [67] prepared seven *C*2-symmetrical pyridyl unit containing macrocycles. The tosylamine, **58** was reacted with 2,6-bis(bromomethyl)pyridine to afford compound, **59**. Further detosylation gave 2,6-bis(*N*-picolylaminomethyl)-pyridine, **60** followed by condensation with *Z*-protected Val to furnish **61**, while subsequent deprotection yielded **62**. Finally, all three chiral macrocycles, **63**, **64** and **65** were synthesized by acylation of the chiral diamine dihydrobromide intermediate,**62** with 2,6-pyridinedicarbonyl dichloride at high dilution (Scheme 9). These macrocycles,**63**, **64** and **65** were obtained by the [1 + 1], [2 + 2] and [3 + 3] cyclization in 15.6%, 5.1% and 3.7% yields, respectively. By following a similar methodology, the macrocycles, **66**, **67**, **68** and **69** (Figure 6) were synthesized from the respective acids. Macrocycle, **63** was investigated for the chiral molecular recognition of amino acid derivatives by using several spectroscopic techniques such as IR, FAB-MS, fluorescence and UV–vis. Macrocycle **63** showed significant enantiomeric discrimination by IR spectroscopy, wherein the IR frequency shift values of D-amino acid methyl esterhydrochlorides were greater than that of L-isomers. Furthermore, the FAB-MS data showed host-guest 1 + 1 molecular ion peaks for macrocycles **63** and **69** with benzene ring containing amino acid methyl ester hydrochlorides owing to π-π interactions with pyridine ring of the macrocycles showed excellent enantioselective binding. The fluorescence data demonstrated that the when macrocycles **63** and **66** mixed with guest amino acids, Ala-OMe and Ph-OMe, the fluorescence intensity increases. However, in the case of macrocycles **67** and **69** fluorescence intensity decreases probably because nitrogen in the pyridine ring as a binding site interacts with proton by static force.

Sakai et al. [68] designed and synthesized a series of the pyridine incorporated chiral bifunctional macrocyclic hosts, **70**–**74** (Figure 7) using two 2,6-diacylaminopyridine as binding units, chiral BINOL to provide an anisotropic ring-current effect, and amides giving rise to a V-shaped arrangement in **70**–**72**, while a parallel alignment in **73**. Out ofthe five chiral receptors, **70** was evaluated for the chiral discrimination ability using 1H or 19F NMR and was found to be an excellent versatile chiral solvating agent for a wide range of the chiral compounds (Figure 8) having the following functionalities: carboxylic acid, oxazolidinone, lactone, alcohol, sulfoxide, sulfoximine, isocyanate, or epoxide. In particular, **70**, having the NO2 group, influenced the binding capacity as well as the degree of enantioselectivity and further host exhibited special characteristic features such as versatility, signal sharpness, high splitting ability, high sensitivity, wide detection window, and easy synthetic accessibility.

Wilhelm et al. [69] synthesized a series of the (−)-nicotine-based chiral ionic liquid as follows. (Schemes 10–12). (−)-Nicotine, **75** was treated with one equivalent of methyl iodide to furnish **79**, (Scheme 10) subsequently the anion metathesis was carried out and iodide was replaced by PF6, BF4, and NTf2, respectively to obtain the chiral ionic liquids (Scheme 11). In order to produce the desired salt, **78**, **75** was reacted with ethyl bromide, however, the product, **83a** was isolated instead of **78**. As **83b** was not suitable, a different anion was then converted to *N*-ethyl nicotinium bromide **83a**, which upon the anion metathesis resulted in the chiral ionic liquids, **83b**–**d** (Scheme 12). The newly developed enantiopure ionic liquids were evaluated as chiral solvating agents using 19F NMR spectroscopy. In the case of **79b** the best result was observed with Mosher's acid in the 19F NMR and with mandelic acid in the 1H NMR (Table 6, entry 3).

**Scheme 9.** Preparation of macrocycles **63**–**65**.

**Figure 6.** Macrocycle **66**–**69**.

**Figure 7.** Chiral solvating agents, **70**–**74**.

**Figure 8.** Chiral guests used for chiral recognition by (**R**)-**70**.

**Scheme 10.** Synthesis of Ionic liquid **76**–**82**.

**Scheme 11.** Synthesis of Ionic liquid **79a**–**c**.

**Scheme 12.** Synthesis of Ionic liquid **83b**–**d**.

Zhang et al. [70] developed a chiral shift reagent, macrocyclic compound, **85** (Scheme 13) by the simple alkylation of *C*2-symmetric aminonaphthol, **84** with pyridyl chloride in a high yield. Enantiomeric acids gave large nonequivalent chemical shifts (upto 0.80 ppm) in the presence of **85** in 1H NMR (500 MHz) spectra. The quantitative analysis of mandelic acid with a different enantiomeric purity showed that the host, **85** is an excellent chemical shift reagent for chiral carboxylic acids. Indeed, **85** exhibited an excellent ability to discriminate (Table 7) the enantiomers of a broad variety of carboxylic acids (Figure 9) by 1H NMR spectroscopy.

**Scheme 13.** Synthesis of **85**.


**6.**19FNMRchemicalshifts(δ)ofMosher'sacidmandelicacidinandresolutionofΔδvaluesinHz(282MHz19FNMR),(500MHz



0.5 equiv.


**Table 7.** Measurements of 1H Chemical Shift Inequivalencies ΔΔ δ of **86a** and **88b** in the presence of **85** by 1H NMR Spectroscopy (500 MHz) in different solvents at 25 ◦C.

**Figure 9.** Structures of the guests studied.

Pu et al. [71] reported the first example of enantioselective gel collapsing as a new means of the visual chiral sensing (Figure 10). The BINOL-terpyridine-Cu(II) complex, (*R*)-**91** was obtained as a green solid by reaction between the terpyridine conjugate, (*R*)-**90** and CuCl2·2H2O. The enantioselective sensing of gel, (*R*)-**91** was studied upon interaction with chiral amino alcohols. It was observed that (*R*)-**91** in chloroformwhenmixed with (*R*)-phenylglycinol remained stable, whereas when mixed with (*S*)-phenylglycinol collapsed. This confirmed the enantioselective nature of gel towards chiral amino alcohols. This result was compared to the fluorescence response of (*R*)-**91** towards (*R*)- and (*S*)-phenyl glycinol in solution. Intriguingly, enhancement in the fluorescence intensity was observed when (*R*)-**91** was treated with an excess of (*S*)-phenylglycinol.In contrast, weaker fluorescence was observed in the case of (*R*)-phenylglycinol. This difference is due to displacement of the Cu(II) ion in (*R*)-**91** by the chiral amino alcohol, which is enantioselective. Indeed, the reaction of (*R*)-**91** with (*S*)-phenylglycinol is more favorable than that with (*R*)-phenylglycinol. Moreover, other chiral amino alcohols including prolinol, valinol, phenylalaninol, leucinol, and 1-amino-2-propanol also exhibited significant fluorescent enhancement in the presence of (*R*)-**91**.

**Figure 10.** First example of enantioselective gel, **91** and its precursor, **90**.

Togrul et al. [27] synthesized a series of pyridine-macrocycles bearing amino alcohol subunits. A tetra-bromide building block, **93** was prepared for the macrocycle synthesis (Scheme 14) starting from 4-methylphenol, which was converted to 2,5-dihydroxymethyl-4-methylphenol followed by the reaction with pyridine ditosylate to give **92** and final bromination using PBr3. The chiral macrocycles, (*S*,*S*,*S*)-**94**, (*S*,*S*,*S*)-**95** and (*S*,*S*,*S*)-**96** (Scheme 15) were obtained by the treatment of **93** with respective amino alcohols and their enantiomeric recognition properties towards alkyl ammonium salts were investigated by UV-vis spectroscopy (Figure 11). The association constants are summarized in Table 8, demonstrated that the complex host bearing phenyl, (*S*,*S*,*S*)-**94** and isobutyl, (*S*,*S*,*S*)-**94** are more stable with an (*S*)-configuration of the enantiomer of guests of both **98** and **97**; over the (*R*)-configuration because the phenyl and cyclohexyl groups in the (*S*)-enantiomers are placed opposite to the isobutyl and phenyl side chains in the cavity of the host, whereas in opposite enantiomers, these groups are located in the same face, causing unfavorable steric interactions.

**Scheme 14.** Synthesis of compound, **93**.

**Scheme 15.** Synthesis of compound, **94**.

**Figure 11.** Ammonium hydrochloride salts used as guests.


**Table 8.** Binding constant (*K*a), the Gibbs free energy changes (−Δ*G*0), enantioselectivities *K*S/*K*<sup>R</sup> or ΔΔ*G*<sup>0</sup> for including the *R*/*S* guest with the chiral host macrocycles in CHCl3 at 25 ◦C.

The same group [72] has developed a series of the *C*2*-*symmetric, pyridine and diamide–diester groups containing lactone type macrocycles (**102**, **103**) with different side arms by reacting chiral bis(aminoalcohol)oxalamides with acyl pyridine (Schemes 16 and 17).

**Scheme 16.** Synthesis of bis(aminoalcohol)oxalamides.

**Scheme 17.** Synthesis of pyridine-15-crown-5 type macrocycles.

The standard 1H NMR titration experiments were carried out in order to investigate the chiral discrimination ability and complex stability of **102** and **103** with enantiomeric perchlorate salts **98** and **99**. The detailed results are summarized in Table 9. The host 102 formed stable complexes with (*S*)-enantiomers of **98** and **99** whereas host **103** formed the stables complexes with (*R*)-enantiomers of guest as host **103** contains the inverted stereogenic center compare to host **102**. Interestingly, replacing the phenyl group with benzyl ring in the host **102b**, reversed discrimination observed and formed the more stable complexes with (*R*)-enantiomers of **98** and **99**.

**Table 9.** Binding constant (*K*a), the Gibbs free energy changes (Δ*G*0), enantioselectivities *K*R/*K*<sup>S</sup> or ΔΔ*G*<sup>0</sup> for including the *R*/*S* guest with the chiral host macrocycles in DMSO-d6 at 25 ◦C.


<sup>a</sup> **98**: α-phenylethylammonium perchlorate salts; **99**: α-(1-naphthyl)ethylammonium perchlorate salts. <sup>b</sup> The binding constants between the hosts and the guests observed by 1H NMR titration. <sup>c</sup> The ratios of binding constants for each enantiomer. <sup>d</sup> The binding free energy change for the complexes, calculated by <sup>Δ</sup>G0 <sup>=</sup> <sup>−</sup>RTln *<sup>K</sup>*a. <sup>e</sup> ΔΔG0 <sup>=</sup> <sup>−</sup>(ΔG0(R) <sup>−</sup> <sup>Δ</sup>G0(S)). <sup>f</sup> Enantiomeric discrimination factor. <sup>g</sup> Not determined.

Yilmaz Turgut et al. [73] synthesized four *C*2-symmetric chiral pyridine containing 18-crown-6 macrocycles, each containing pairs of the following substituents: ethyl (**107**), isopropyl (**108**), phenyl (**109**), and benzyl (**110**). The synthetic strategy adopted was as follows: firstly, as a chiral source, D-Val, D-Phgly and D-Phe were reduced to the corresponding amino alcohols, D-valinol, **104b**, D-Phenyl glycinol **104c** and D-phenylalaninol, **104d**. The compound, **104a** and the reduced products, **104b**–**d** were reacted with benzaldehyde to give imines, which subsequently were converted to the corresponding N-benzyl derivatives, **105a**, **105b**, and **105c** (Scheme 18) followed by the treatment with 2,6-bis(bromomethyl) pyridine to afford **106a**–**d**. The pyridine containing *C*2-symmetric **106a**–**d** having ethyl-, isopropyl-, phenyl-, and benzyl-moieties in their side arms were cyclized in a 1:1 ratio with 2,6-bis(bromomethyl)pyridine to the desired chiral macrocycles, **107**, **108**, **109** and **110** possessing the dipyridine units (Scheme 18). The chiral recognition of macrocyles towards the D-, L-amino acid methyl ester derivatives was determined by the 1H NMR titration method (Table 10). The compounds, **107** and **108** with the ethyl and isopropyl substituents at the stereogenic center, respectively, demonstrated the highest enantioselectivity and stable complexes, whereas the compounds, **109** and **110** with the corresponding phenyl and benzyl substituents possess a low-to-medium level of these properties. This inefficiency is a result of the fact that the phenyl and benzyl moieties prevent the guest cations from approaching the host.

**Scheme 18.** Synthesis of chiral amino alcohols and chiral macrocycles.

Kumaresh Ghosh et al. [74] prepared a series of pyridinium-based chiral compounds, **112**–**114**, **119** and **122**. The synthesis proceeds (Schemes 19 and 20) with the reaction of Boc-protected L-amino acids like Val (**111a**), Ala (**111b**) and Phgly (**111c**) and 3-aminopyridine to furnish the coupled products, **112a**–**c**, respectively. Further removal of the Boc-groups in **112a**–**c** yielded the corresponding amines, **113a**–**c**, which upon reaction with 1-naphthyl isocyanate afforded the respective urea derivatives, **114a**–**c**. The compounds, **114a**–**c** reacted with the corresponding chloroamides, **119a**–**c** to produce the chloride salts. Further, the anion exchange reactions with NH4PF6 yielded the desired compounds, **115**, **116** and **117**. On the other hand, reaction of **114a** with benzyl bromide followed by the Br− exchange with PF6 − gave **118**.


**Table 10.** Association constant (*K*a), the Gibbs free energy changes (−Δ*G*0),enantioselectivities *K*D/*K*<sup>L</sup> for the complexation of D-/L-guest with the **107**, **108**, **109**, and **110** in CDCl3 with 0.25% CD3OD.

The treatment of 3-aminopyridine with 1-naphthylamine and phosgene afforded the urea, **120**, (Scheme 20) followed by the reaction with the chloroamide, **119a**, to give the chloride salt, **121**. Then the chloride exchange of **121** by using NH4PF6 gave the desired compound, **122**. Next, the amine, **113a** was coupled with 1-naphthylacetyl chloride to obtain the amide derivative, **123**, which, subsequently reacted with **119a** to yield the chloride salt, **124** followed by the ion exchange with NH4PF6to furnish the desired compound, **122**. Among the synthesized compounds, **115**–**117**, **122**, and **125**, the structures, **115** and **125** have been established as effective fluorescent chiral receptors for the selective enantiorecognition of D-lactate over L-lactate.

Bedekar et al. [75] synthesized two diastereomers of the optically active N, O-containing macrocycles, **129** and **130**. First, the ring opening reaction of cyclohexene oxide, **126** with (*S*)-2-phenylethyl amine afforded two diastereomers of aminocyclohexanol, **127a**,**b**, (Scheme 21) which after separation and subsequent condensation with m-xylene dibromide furnished the respective diols, **128a**,**b** (Scheme 22). The final transesterification with dimethyl 2, 6-pyridinedicarboxylate afforded the desired eighteen membered macrocycles, (*S*,*S*,*S*)-**129** and (*R*,*R*,*S*)-**130**. Using 31P NMR as a detection tool, the macrocycles (*S*,*S*,*S*)-**129** and (*R*,*R*,*S*)-**130** were tested for the chiral discrimination of chiral BINOL-based phosphoric acid derivatives by measuring the corresponding chemical shifts (Table 11). The macrocycle, (*R*,*R*,*S*)-**130** showed better discrimination, while (*S*,*S*,*S*)-**129** was found to be ineffective. Further, the discrimination of chiral phorsphoric acid **131a** was corroborated by fluorescence, where the quenching was observed with the interaction of chiral host molecules **129** and **130**. The fluorescence quenching efficiency, ratio of *K*R-131asv /*K*S-131asv was observed to be 1.05 and 1.40 respectively for **129** and **130**.

Interestingly, for the same set of macrocyclic chiral solvating agents (CSAs) **129** and **130**, interaction with the second group of analytes, such as α-substituted phosphonic acids (**132** to **136**) gave a reverse trend (Table 12). The authors proposed that these analytes being smaller in size were better accommodated in the partially closed cavity of macrocycle (*S*,*S*,*S*)-**129**. The formation of H-bond between the phosphonic acid analyte and H-bond acceptor sites of macrocyclic CSA is apparently favored by the partially closed cavity of (*S*,*S*,*S*)-**129**.

**Scheme 19.** (**i**) 3-Aminopyridine, DCC, CH2Cl2, 20 h; (**ii**) TFA, CH2Cl2, 3 h; (**iii**) 1-naphthylamine, triphosgene, Et3N, CH2Cl2, 16 h; (**iv**) (a) **119a**–**c**, CH3CN, reflux, 4 days; (b) NH4PF6, CH3OH-H2O; (**v**) (a) benzyl bromide, CH3CN, reflux, 18 h; (b) NH4PF6, CH3OH-H2O.

**Scheme 20.** (a) (**i**) 1-Naphthylamine, triphosgene, Et3N, CH2Cl2, 18 h; (**ii**) **119a**, CH3CN, reflux, 4 days; (**iii**) NH4PF6, CH3OH-H2O; (**iv**) (b) (**iv**) 1-naphthylacetyl chloride, CH2Cl2, Et3N, 12 h; (**v**) **119a** CH3CN, reflux, 3 days; (**vi**) NH4PF6, CH3OH-H2O.

**Scheme 21.** Preparation of amino alcohols from cyclohexeneoxide.

**Scheme 22.** Synthesis of macrocycles, **129** and **130**.


**Table 11.** Discrimination of binaphthyl phosphoric acids **131** a.

<sup>a</sup> In CDCl3 (20 mM), 162 MHz (<sup>31</sup> P NMR), ratio of 5:1 (2:1). \_b Not resolved.


**Table 12.** Discrimination of monomethyl esters of substituted phosphoric acids **132** to **136** a.

#### *5.2. Oxygen Containing Six Member Heterocycle*

Oxygen containing six member heterocycles is another class of motif found as structural core in several natural and synthetic compounds. Oxygen atom in the heterocyclic ring has two unshared pairs of electrons and hence can effectively participate in many types of the non-bonded interactions mentioned above. Six-membered carbohydrate unit has been very widely used in commercially popular chiral chromatographic columns. It is also a harder Lewis base than nitrogen and consequently different types of ligands can be probed with these heterocycle containing receptors. The particularly chromene heterocycle is a well-known significant core unit in the molecular recognition [32]. Chromenone core has exclusively placed oxygen atoms in 1,4-arrangement in conjugation with a double bond which facilitates brisk electron movement upon change in the electronic environment and hence quick detection under spectroscopic techniques, while studying host-guest interactions (Chart 2). Henece chromeneone becomes a molecule of choice for receptor construction.The general design of chromenone based hosts discussed here, contain one or more chromenone motifs present in the receptor backbone, of molecular cleft or macrocycles.

Moran et al. [33] for the first time synthesized the chromenone and Spiro-bifluorene containing chiral macrocyclic receptor, **141** by reaction of the bis-aminomethylspirobifluorene unit **137** with nitrochromenone 2-carboxylic acid chloride, subsequent reduction of the nitro groups, treatment with phosgene, and slow hydrolysis of the intermediate isocyanates (Scheme 23). Significant chiral recognition of hydroxycarboxylates such as lactic or mandelic acids has been achieved with the macrocyclic receptor, **141** by using 1H NMR. Thus, the receptors **141** showed a good association of the carboxylate group owing to four efficient hydrogen bonds for the syn- and anti-lone pairs of oxo-anion. The resolution of racemic receptor, **141** was achieved on a TLC plate by taking the advantage of its complexing properties with (*R*)-mandelic acid tetramethylammonium salt.

<sup>a</sup> In CD3OD (5%), in CDCl3 (20 mM), 162 MHz (<sup>31</sup> P NMR), ratio of A to 10:4 (2:1). \_b Not resolved.

**Chart 2.** General design of chromenone containing hosts.

**Scheme 23.** Preparation of Receptor **141**.

*Symmetry* **2018**, *10*, 34

With the excellent recognition ability of bischromenylurea skeleton-based receptor **141** for chiral acids, this strategy was further extended [76]. Hence, bischromenylurea and α,α'-(o,o'-dialkyl)diphenyl-*p*-xylylenediamine spacer-based receptors (**145**, **146**) (Scheme 24) were prepared by a simple synthetic approach involving the hydrolysis of ethoxy carbonyl amino chromenone, **144** to give a dicarboxylic acid, which was subsequently coupled with the diamine, **142** or **143** (Scheme 25).

The chiral recognition behavior of racemic receptors, **145** and **146** has been tested with the enantiomers of naproxen by using 1H NMR. However, only a slight chiral discrimination (ratio 1.2:1) was observed for the receptor **145** and (*S*)-naproxen. Intriguingly, high enantioselectivity of 7.2:1 was obtained for the racemic receptor, **146** and (*S*)-naproxen. Apparently this is because **146** possesses a rigid and hindered cavity, where the host-guest binding takes place without disturbing the required complementary geometry.

**Scheme 24.** Synthesis of receptors, **145** and **146.**

**Scheme 25.** Synthesis of diamines, **142** and **143**.

#### **6. Five Member Heterocycles Containing Receptors**

Five member heterocycles such as imidazole, thiophene, furan, oxazole and oxazoline-based chiral compounds have attracted a widespread interest in the asymmetric synthesis and molecular recognition of metal ion, anion and chiral guests, owing to their striking structural features discussed in the Section 4. In the contemporary days several chiral receptors with five membered heterocycles have been developed and explored for the selective detection of chiral acids, chiral alcohols, chiral diamines and chiral amines. However, further chiral recognition using such receptors is used for the determination of concentration and enantiomeric excess of chiral analytes by high throughput methods. In this section, the recent developments in the receptor with five member heterocycles for chiral discrimination processes are presented.

#### *6.1. Imidazole Ring Containing Receptors*

Imidazole core has profound existance in nature, undoubtedly the synthetic community is inspired to construct receptors containing imidazole motifs. Imidazole moiety is bestowed with unique properties like basicity, nucleophilicity, and coordination ability.Acidity of the NH proton present in the imidazole ring can be tuned by changing the electronic properties of the imidazole substituents which is useful in anion binding. On the other hand, the presence of a donor pyridine-like nitrogen atom within the ring enables the imidazole ring towards selectivity in binding cationic species, thus making imidazole derivatives excellent metal ion sensors. The general receptor design of imidazole containing receptors discussed here, contain one or more imidazole motifs either separated by a chiral spacer to form a molecular cleft or 2,2'-linked bisimidazole motif as spacer itself with suitably placed terminal chiral arms (Chart 3).

Xie et al. [34] synthesized the chiral imidazole containing cyclophanes, **149**–**152** by highly selective *N*-alkylation of the imidazolyl 1N-position of **148** with the corresponding dibromides (Scheme 26).

**Chart 3.** General design of imidazole containing hosts.

**Scheme 26.** Synthesis of chiral imidazole cyclophanes, **149**–**152**.

On the basis of differential UV spectroscopic studies, the association constants (*K*a) of inclusion complexes of the chiral imidazole cyclophane receptors with amino acid esters along with the free energy change (*G*0) were determined (Table 13). The *K*<sup>D</sup> values of **149** and **152** for D-Phe-OMe with the –(CH2)4- moiety were found to be 1063 and 208 dm<sup>3</sup> mol−1, respectively, which corresponds to the D/L-selectivity (*K*D/*K*L) of 3.33 and 1.40. The enantioselective recognition ability of **149** with α-amino acid esters and their hydrochlorides gave *K*D/*K*<sup>L</sup> in the range of 1.45–3.52 and *G*<sup>0</sup> from 20.93 to 23.11 kJ mol<sup>−</sup>1. However, **149** gave fairly poor recognition ability for amino acid esters with the aliphatic side chain (Table 13, entries 3–8) due to absence of π-π stacking interactions with receptor.

**Table 13.** Association constants (*K*a), the Gibbs free energy changes (−Δ*G*0), enantioselectivities *K*D/*K*<sup>L</sup> or ΔΔ*G*<sup>0</sup> calculated from −Δ*G*<sup>0</sup> for the including complexation of L/D-amino acid esters with **148**–**152** in CHCl3 at 25 ◦C a.


<sup>a</sup> The concentration of the receptors: 2.0 × <sup>10</sup>−<sup>4</sup> mol dm−3. <sup>b</sup> Ala-OMe: alanine methyl ester; Val-OMe: valine methyl ester; Leu-OMe: leucine methyl ester; Phe-OMe: phenylalanine methyl ester; Trp-OMe: tryptophan methyl ester; Ala-OMe. HCl: alanine methyl ester hydrochloride; Leu-OMe.HCl: leucine methyl ester hydrochloride.

Allen et al. [77] prepared chiral 4,4 -diamido-2,2 -biimidazoles, **156a**,**b** (Scheme 27) by the treatment of acid chloride, **153** with (*S*)-α-methylbenzylamine and (*R*)-tetrahydrofurfurylamine to afford **154a**,**b**, followed by the corresponding iodination and coupling. The macromolecules, **156a**,**b** were found to be beneficial for the chiral recognition of *N*-protected amino acids as revealed by the NMR titration methods. In particular, **156a** discriminates the enantiomers of *N*-Boc-Phe, while **156b** discriminates the enantiomers of *N*-Boc-Ser (Table 14).

**Table 14.** Binding constants *K*<sup>a</sup> (M<sup>−</sup>1) <sup>a</sup> for chiral biimidazoles with amino acid derivatives in CDCl3 at 23 ◦C.


<sup>a</sup> Values represent averages of at least two replicate titrations, rounded to the nearest ±5 M<sup>−</sup>1. Errors in individual fits were ≤15%.

**Scheme 27.** Synthesis of chiral 4,4'-diamido-2,2'-biimidazoles, **156a**,**b**.

Later Xie and coworkers [78,79] synthesized the imidazole-based chiral molecular tweezers (Scheme 28) spaced by 2,6-di(bromomethyl)-4-chlorophenol, 1,3-phenylenebis(methylene) and 2,6-pyridylenebis(methylene). The dibromide salts, **158a**–**c.2Br***−* and **159a**–**c.2Br***−* were obtained by the direct quaternization of **157a**–**c** with 2,6-di(bromomethyl)-4-chlorophenol or 1,3-bis(bromomethyl)benzene or 2,6-bis(bromomethyl)pyridine while the hexafluorophosphate salts **158a**–**c.2PF6** *−* and **159a**–**c.2PF6** *−* were prepared by the treatment with a saturated aqueous solution of NH4PF6. The chiral discrimination of chiral molecular tweezers for amino acids or their derivatives (Tables 15 and 16) were evaluated by the UV-vis titration method.

**Scheme 28.** Synthesis of chiral molecular tweezers.

**Table 15.** Binding constants (*K*a), Gibbs free energy changes (−Δ*G*0), enantioselectivities *K*L/*K*<sup>D</sup> or ΔΔ*G* calculated from −Δ*G* for the including complexation of L/D-amino acids or their derivatives with hosts at 27 ◦C in water or acetonitrile.



**Table 15.** *Cont.*

<sup>a</sup> **158a–c.2Br***<sup>−</sup>* and **159a–c2Br***<sup>−</sup>* in water, **158a–c.2PF6** *−* and **159a2PF6** *<sup>−</sup>* in acetonitrile. <sup>b</sup> the concentration of hosts 5.0 × <sup>10</sup>−<sup>5</sup> mol dm−3.

**Table 16.** Binding constants (*K*a), Gibbs free energy changes (−Δ*G*0), enantioselectivities *K*L/*K*<sup>D</sup> or ΔΔ*G* calculated from −Δ*G* for the complexation of L/D-amino acids or their methyl esters with **158a**–**159b** at 27 ± 0.1 ◦C in water or acetonitrile.



**Table 16.** *Cont.*

<sup>a</sup> **158a**,**<sup>b</sup>** in water; **159a**,**<sup>b</sup>** in acetonitrile. <sup>b</sup> the concentration of hosts 5.0 × <sup>10</sup>−<sup>5</sup> mol dm<sup>−</sup>3; <sup>c</sup> Phe-OMe: phenylalanine methyl ester; BOC-Phe-OMe: BOC-phenylalanine methyl ester; BOC-Ala-OMe: BOC-alanine methyl ester; BOC-His-OMe: BOC-Histidine methyl ester. <sup>d</sup> ΔΔ*G*<sup>0</sup> <sup>=</sup> −(Δ*G*0(L) − <sup>Δ</sup>*G*0(D)).

Yu et al. [29] designed and synthesized the imidazolium-functionalized BINOLs, (*R*)**-160**, (*S*)**-161** and (*S*)**-162** (Figure 12). These hosts were evaluated for chiral recognition with various amino acid derivatives, tetrabutylammonium salts of *t*-Boc-amino acids, such as Ala, Ser, Leu, and Phe. However, *R***-160** exhibited a noteworthy binding ability only for *t*-BOC alanine anion with the high enantioselectivity (*K*D/*K*L) of 4.5, while (*S*)-**161**, bearing imidazolium rings attached to a flexible methylene linker, showed the higher association constant but furnished moderate enantioselectivity, *K*L/*K*<sup>D</sup> value of 2.9 for the same chiral guest. This is a result of the reduction of the steric factor between the BINOL unit and imidazolium due to the flexible methylene linker.

**Figure 12.** Imidazolium-functionalized anion-binding receptors.

Yu et al. [24] developed the imidazolium/benzimidazolium-containing receptors, (*R*)-**168**, (*R*)-**169**, (*R*)-1**70**, (*R*)-**173**, and (*R*)-**176**. At first, MOM-protected boronic acid ester, (*R*)-**164** upon the *N*-arylation with imidazole derivative or benzimidazole yielded the respective coupled products (**165**–**167**) followed by methylation to give the desired hosts, **168**–**170** (Scheme 29). Further, (*R*)-**171** and (*R*)-**174** (Schemes 30 and 31) were converted to (*R*)-**173** and (*R*)-**176**, respectively. The synthesized compounds were then evaluated for the chiral discrimination of amino acid derivatives, such as Ala, Ser, Leu, and Phe, and tetrabutylammonium salts of *t*-Boc-amino acids studied by using fluorescence spectroscopy. The association constants of (*R*)-**<sup>178</sup>** with L- and D-Boc alanine were found to be 4.55 × 105 and

1.02 × 105 L mol−1, respectively, with the *<sup>K</sup>*L/*K*<sup>D</sup> value of 4.5. While (*R*)-**<sup>176</sup>** displayed larger association constants with both L- and D- *t*-Boc alanines, the enantioselectivity was very similar (*KL*/*KD* = 4.1). However, when (*R*)-**173** containing only one 3-imidazolium substituent was tested with two enantiomers of *t*-Boc-alanine, the enantioselectivity was as low as 1.1. Thus, the *C*<sup>2</sup> symmetric sensors, (*R*)-**168** and (*R*)-**176** were more efficient than the *C*<sup>1</sup> symmetric (*R*)-**173** in the chiral recognition.

**Scheme 29.** Synthesis of receptors, (*R*)-**168**, (*R*)-**169** and (*R*)-**170**.

**Scheme 30.** Synthesis of the mono-imidazolium substituted receptor, (*R*)-**173**.

Iyer et al. [80] developed the BINOL-imidazole-based fluorescent sensor, **180** (Scheme 32). It was synthesized by the first formylation of MOM-protected BINOL, **177** followed by the deprotection of MOM and treatment with benzil in the presence of iodine to afford the desire product. This compound was found to be useful as a fluorescent sensor for Cu(II). Furthermore, the in situ generated complex, Cu(II)-**180** was studied for the fluorescent enantioselective recognition of unmodified amino acids (Table 17). L-ala displayed a large enhancement in the fluorescence intensity; whereas D-enantiomer has a small influence under the similar experimental conditions with an enantiomeric fluorescence difference ratio [ef = IL − I0/ID − I0] of 1.52 at the 1:50 molar ratio.

**Scheme 32.** Synthesis procedure of the sensor, **180**.

**5**

#### *6.2. Benzimidazole Ring Containing Receptors*

Benzimidazole is a member of benzo-fused heterocycles. It has received more attention compared to the other members of the same class is possibly because generation of chiral benzimidazoles by easy synthetic protocol. A chiral center can be easily incorporated in the heterocycle and this has led to use of these molecules as a chiral organo-catalyst or as a metal atom containing catalysts [9]. Several such reports have appeared periodically. The use of this molecule in chiral molecular recognition has not received the attention it deserved. Endowed with aromatic electron cloud and almost rigid conformation for the small sized macrocycles can be good structural features for use of chiral benzimidazoles in chiral molecular recognition. Due to the synthetic ease and freedom in

structural tuning that benzimidazole core offers, it is a popular structural motif to be included in chiral ligand design. Our group has been exploring the benzimidazole core in an effective manner for over two decades and very recently we were successful in using it as a chiral host for enantiomeric guests. The Chart 4 ahead, depicts the various manners in which 2-substituted chiral benzimidazole cores can be included in ligand design. Several open chained molecular clefts with benzimidazole motif as end groups can be created using the general receptor design. Using the benzimidazole core, we have successfully synthesized few unsymmetrical macrocycles. Symmetrical macrocycles can aslo be prepared using various spacer (Chart 4).

**Table 17.** Amino acids employed in enantioselective sensing studies and their respective enantiomeric fluorescent difference ratio.


<sup>a</sup> Methionine (Met), Proline (Pro).

**Chart 4.** General design of benzimidazole containing hosts.

Recently, our group [36] has synthesized the chiral benzimidazole-based receptors (Figure 13), mono aza-15-crown-5 **181**, monoaza-[18]crown-6 (*S*,*R*)-**182**,(*S*,*S*)-**183**, and [18]crown-6-sized aza-crown **184**.

**Figure 13.** Chiral benzimidazole-based receptors **181**–**184.**

Supramolecular interactions between the aza-crown host, **181** and enantiomerically pure amine guests in the ionic and neutral forms displayed the enantio-discrimination ability for phenylethyl amine and naphthylethyl amine. However, the reversed enantioselective binding was observed for [18]crown-6, aza-crowns (*S*,*R*)-**182**, (*S*,*S*)-**183** and (*S*)-**184**.

This was the first report which revealed the opposite steric preferences in chiral supramolecular systems. The experimental study was supported by single-crystal XRD data (Figures 14 and 15) and DFT studies. Size-dependent pre-organization effects leading to the corresponding molecular models was invoked to explain the origins of size-dependent enantioselective binding in aza-crowns (*S*,*R*)-**182**, (*S*,*S*)-**183** and (*S*)-**184** and (*S*)-**181**. It was established that these effects influence the preferences for guests with the opposite absolute configuration. Numerous known components, in particular nonbonding interactions responsible for the effective enantioselective binding are known, such as ligating size, hydrogen bonding, dipole-dipole interaction, pi-stacking etc. With these findings, an additional component of size-dependent pre-organization effects for the effective binding of enantiomeric guests was introduced.

**Figure 14.** ORTEP representation of the X-ray crystal structure of **181**.

**Figure 15.** ORTEP diagram of the Cd2+ complex of (*S*,*R*)-**182**. Ellipsoids are given at the 50% probability level.

Ghosh et al. [81] prepared the L-Valine derived benzimidazole-based bis-ureas, **185** and **186**, according to the procedure illustrated in Scheme 33. Alkylation of the ring nitrogen of chiral benzimidazole, **187** yielded **188** and subsequent deportation afforded the **189**. Coupling of **189** with 1,3-diisocyanatobenzene furnished the desired compound, **185**, whereas deprotection of 1**87** gave **190** followed by the treatment with 1,3-diisocyanatobenzene to obtain compound **186**.

**Scheme 33.** Reagents and conditions (**i**) *o*-phenylenediamine, DCC, DMAP, stirred in CH2Cl2 for 19 h; (**ii**) AcOH, heat, 2 h; (**iii**) NaH, THF, *n*-octyl bromide, heat 4 h; (**iv**) 50% TFA in CH2Cl2, stirred for 3 h; (**v**) 1,3-dicyanatobenzene, *N*,*N*-diisopropyl ethylamine stirred in CH2Cl2 for 9 h.

The fluorescence titration of **185** was performed with the tetrabutylammonium salts of tartaric and mandelic acids. The receptor, **185** exhibited clear fluorometric discrimination for D and L tartarates, while a low level of discrimination was found for mandelates. Interestingly, the compound, **186** exhibited a small preference for D-tartrate with the enantiomeric fluorescence difference ratio (ef) of 1.44, which signifies the steric crowding around the binding zone in **185** as the key feature for its enantioselective sensing of tartrate.

Katagiri et al. [82] reported a new achiral host on the basis of Cu(II) complex of pyridine-benzimidazole, **192**, [Cu(bmb-bpy)(H2O)(OTf)2] where (bmb-bpy = 6,6 -bis[((1-methylbenzimidazol-2-yl)thio)methyl]-2,2 -bipyridine) (Figure 16) for the enantioselective and chemoselective recognition of chiral carboxylic acids. Hence, the binding of chiral carboxylic acids, 2-phenylbutyric acid (PBA), 2-phenylpropionic acid (PPA), 2-bromopropionic acid (BPA) and *N*-boc-2-piperidinecarboxylic acid (PCA) to [Cu(bmb–bpy)(H2O)(OTf)2] produced an exciton-coupled circular dichroism signal. The (*R*)-PBA, (*R*)-PPA, (*R*)-PCA gave the positive first Cotton effect and negative second Cotton effect, while (*R*)-showed the negative first Cotton effect and positive second Cotton effect. Further, the opposite (*S*) enantiomers exhibited the mirror image relationship. The linear discriminant analysis (LDA) allowed the assignment of the absolute configuration, the five replicates for the each enantiomers of each carboxylic acids were analyzed at four different wavelength (333, 313, 295, and 285 nm). The LDA plot of chiral carboxylic acids with a positive first Cotton effect appear at a negative position on F1-axis, whereas the plots of the negative first Cotton effect appear at a positive

position. A stronger CD intensity shows a larger absolute value of F1, whereas a weaker CD intensity shows a smaller absolute value. F2-axis shows a small difference in the CD profile for each sample. Furthermore, enantiomeric excess of chiral carboxylic acids, have established using the eight unknown samples in the range of −100% (*S*) to +100% (*R*) plotted on the calibration line with linear regression.

**Figure 16.** Pyridine-benzimidazole-based host **191**, **192**.

#### *6.3. Triazole Ring Containing Receptors*

Triazole has both pyridine and pyrrole type of nitrogens and satisfactory basic character. The chiral center can be easily attached by N-alkylation or N-acylation reactions. Presence of multiple ligating centers and aromatic nature were good enough reasons to attract attention of chiral chemists. Triazole linked hosts are considered to be better chelators for chiralguests for itselectron rich nature due to the presence of three nitrogen atoms adjacent to each other. As per reports, the orientation of nitrogen atom at the third position is important for chiral discrimination of amino acids [69]. The general structural design existing in the triazole based receptors discussed in this report, incorporates one or more triazole motifs at terminal ends separated by a chiral spacer to form a molecular cleft. Triazoles could be further attached to chiral arms which function as chiral discriminators. Few macrocyclic receptors are also prepared in which triazoles are placed in macrocyclic cavity, with nitrogen atoms facing inwards to enable participation during recognition events. (Chart 5).

**Chart 5.** General design of triazole containing hosts.

Sato et al. [83] synthesized the new triazole linked hosts, (**193**, **194**) (Figure 17) by versatile, rapid and high yield copper catalyzed Huisgen-1,3-dipolar cycloaddition (Click Chemistry) of linker azide with saccharide alkyne. These two compounds, **193**, **194** then were investigated for the chiral

recognition ability. It was established that the orientation of nitrogen atoms at the 3-position of triazole rings was the most important factor for the enantiodiscrimination of amino acid esters. Thus, UV titrations revealed the triazole linked host **193** exhibited the chiral recognition preference for (*R*)-alanine isopropyl ester with *K*R/*K*<sup>S</sup> = 2.13 and for host **194** the strong complexes were formed with both the enantiomers of alanine isopropyl ester but no enantioselectivity observed. Further, the similar recognition ability of alanine isopropyl ester by the host **193** and **194** corroborated by the Fast Atom Bombardment Mass spectroscopy method.

**Figure 17.** Triazole linked host compounds, **193** and **194**.

Li et al. [84] synthesized the fluorescent calix-[4]arene bearing a chiral 1,1 -bi-2-naphthol unit-based receptor, **195** (Scheme 34). The in situ generated complex Cu(II)\_**195** were evaluated for the chiral discrimination of performance of the, (*R*)- and (*S*)-Mandelic acid using fluorimeter. The fluorescent intensity of Cu(II)\_**195** complex upon addition of (*R*)-Mandelic acid increased 6.35 fold and with (*S*)-Mandelic acid increased up to 4.87 fold. Thus, the enantiomeric fluorescence difference was found to be 1.69. The tartaric acid and malic acid were also investigated and showed the increased in the fluorescence intensity for *R* enantiomers over the *S* enantiomers. Further, by using the dynamic light scattering, for mandelic acid a remarkable 100-fold detection sensitivity was increased with the detection limit of 2.0 × <sup>10</sup>−<sup>7</sup> M as compared to fluorescent method.

**Scheme 34.** Synthesis of calix-[4]arene, **195** bearing a chiral 1,1 -bi-2-naphthol and its Cu complex.

Ju et al. [85] synthesized **197** (Cyclic Deoxycholate-Triazole-BINOL conjugate) (Scheme 35) from azido-deoxycholic acid ester **196** and BINOL-2yne via the "CuAAC" click reaction. This macrocycle is able to serve as a fluorescent turn-off sensor for Hg2+ ion due to the 1,2,3-triazole motif, which has an outstanding binding ability to transition metal ions. Furthermore, the corresponding [**197**·Hg2+] complex exhibited recognition ability for amino acids with certain enantioselectivity (Table 18). Hence, L-amino acids showed larger *<sup>K</sup>*<sup>a</sup> as compared to D-amino acids. The stronger interaction of [**197**·Hg2+] complex with L-amino acids than with D-amino acids is a result of the chiral spatial structure provided by the deoxycholic acid scaffold.

**Scheme 35.** (**a**) Synthesis of **197**; (**b**) Sturcture of control molecules **198** and **199**.

**Table 18.** Association constants between [**197**-Hg2+] or [**199**-Hg2+] complex and amino acids.


#### *6.4. Benzo-Fused Furan Heterocycles Containing Receptors*

Benzo-fused furans are electron rich units and hence are expected to exhibit anisotropic effects due to the presence of ring current. There are innumerable heterocycles containing benzo-fused furans. The use of this heterocyclic unit in stereo-discrimination reactions are very few. One solution to this situation was to incorporate this unit in receptors with different elements of chirality, such as the presence of chiral axis.

The benzofuran containing hosts are bestowed with excellent fluorscence properties and hence are ideal substrates for development of fluorescent sensor. Our group has designed and synthesized several interesting receptors with benzofuran motifs. The receptors discussed here originate from synthetically simple benzofuran motif which are axially linked or helically linked benzofuran rings (Chart 6). Benzofuran units can be used as a synthon to prepare crowded binols and the free hydroxyl groups of the furo fused binols can be exploited to synthesize macrocycles.

**Chart 6.** General design of benzofuran containing hosts.

Our group [86–89] synthesized several furan ring incorporated chiral receptors. In 2007 [37] the synthesis of chiral furo fused BINOL-based crown ether, (*R*)-**203** has been reported (Scheme 36). Parent furo fused BINOL, **200** was alkylated with ethyl chloroacetate followed by the corresponding reduction and treatment with triethylene glycol tosylate to yield (*R*)-**203**.

The furo-fused BINOL derivative (*R*)-**203** has the following special features: *C*<sup>2</sup> symmetry, a sufficiently enlarged dihedral angle for better stereo-discrimination and modified electronic properties as compared to BINOL. This macrocycle (*R*)-**203** was useful as an enantioselective chiral sensor for phenylethylamine and ethyl ester of valine. Fusion of furan to BINOL resulted in a highly stereodiscriminating backbone for the chiral crown moiety. This receptor, (*R*)-**203** exhibited fluorescence enhancement differences of 2.97 and 2.55 times between two enantiomers of phenylethylamine and ethyl ester of valine, correspondingly. The ratio of association constants for two diastereomeric complexes on the basis of two enantiomers of these guests was found to be 11.30 and 7.02, respectively.

Further in 2016 [25] the *C*s-symmetric rigid organophosphoric acid host, **205** (Scheme 37) was developed by the treatment of helicene diol [72], **204** with phosphoryl chloride and explored for the supramolecular induced circular dichroism sensing of chiral amino alcohol. The study revealed that the rigidity of tautomers, **205A** (Figure 18) or **205B** (Figure 19) and bulkiness of chiral amino alcohols were responsible for the resultant ICD signals (Table 19).

**Scheme 36.** Synthesis of furo fused BINOL-based crown ether.

**Scheme 37.** Synthesis of **205**.

**Figure 18.** Proposed exciton coupling model for amino alcohols, **206**–**209** having small R group, binding with tautomer, **205A**.

In the case of amino alcohols, **206**–**209** (Figure 18) with small substituents such as –CH3, –C2H5, or –CH2CH(CH3)2 present at the stereogenic center, the tautomer **205A** of achiral phosphoric acid **205 is** preferred. This could be possible due to cooperative hydrogen bonding, amino group of guest accepts the acidic hydrogen P−O−H of **205A**, occupying a pseudoaxial position, whereas the alcohol part of the chiral guest acts as a hydrogen bond donor to P=O of the PA group, with a pseudoequatorial position on the H ring. The resultant nine membered spirocyclic hydrogen-bonded **S** ring is able to transfer the information on the *R*/*S* configuration at the stereogenic center of guest to host via H ring, directly attached to the chromophores, exhibited the corresponding ICD signal (negative exciton coupling). The *R*-enantiomers of chiral amino alcohol gave the negative sign in the ICD spectrum while *S*-enantiomer exhibited the mirror image.

Intriguingly, the chiral amino alcohols, **210**–**213** (Figure 19) with bulky substituent at the stereogenic center on interaction with the achiral phosphoric acid preferred the 189B tautomer to result into reversed induced CD pattern to the amino alcohols with small substituent at stereogenic center. This is attributed owing to the amino group of guest hydrogen bonded with an acidic P−O−H group, occupies a pseudoequatorial position. Simultaneously, the–OH group acts as hydrogen bond donor to the P=O group of **205B** and occupies a pseudoaxial position to the rigid, conformationally locked H ring, the newly formed. Resulted complex of host and guest able to transfer the chiral information of guest by the S-ring to H ring and to the chromophore of the host to induced the signals in the CD. Thus, this mechanistic demonstration exemplified the binding mode of the host dependent on the bulk of the substituent present at stereogenic center of guest chiral amino alcohols.

**Figure 19.** Proposed exciton coupling model for amino alcohols, **210**–**213** having bulky R group, binding with tautomer, **205B**.

Complexation of host pophoric acid, **205A** mode, with guest, **206** (2-AP) gave the highest Δ ε value at 498.65 cm<sup>−</sup>1M−1. Similarly, the 205B mode resulted in highest Δ ε value of 641.13 cm−<sup>1</sup> M−<sup>1</sup> for 211 (2-AMB) (Table 19).


**Table 19.** ICD Results for Amino Alcohols, **206**–**213** with **205**.

Subsequently in 2017, [48] Hasan et al. developed the dioxa[6]helicenes-based supramolecular chirogenic system (**214**) for chiral recognition of enantiopure trans-1,2-cyclohexanediamine (Figure 20). The host, **214** was obtained using the reaction of dioxa[6]helicenes and (1*S*)-camphanic chloride and the enantioselective fluorescence study revealed that **214** serves as a turn-on fluorescent sensor for *trans*-cyclohexyl diamine with the excellent enantioselective factor, α = *K*SS/*K*RR = 6.3 in benzene as a solvent.

**Figure 20.** Helicene camphanate.

#### *6.5. Receptors with Nitrogen and Oxygen Containing Five Membered Heterocycles*

Chiral Oxazolines and oxazolidinones have played one of the most noticeable roles [90,91] in chiral processes, by providing Evans' chiral auxiliaeris, chiral organo-catalysts and chiral metal-basedcatalysts. The use of these molecules in the chiral receptors has received some attention. Oxazoline coordinates to a wide range of transition metals. Stereochemical outcome of the metal catalyzed reaction is strongly goverened by the favorable placement of stereogenic centre, the chelating nitrogen atom of oxazoline ligand and the metal ion.

The oxazoline based *C*3-symmetric receptors discussed in this report have tripod like structures with terminal oxazolines or in another case, the free arms of the tripod linked to benzene motif, forming a molecular cage (Chart 7). The types of interactions which are observed in such hosts are *π*-*π* interactions due to aromatic oxazoline rings and tripodal hydrogen bonding interactions due to the flexible arms conataining oxazolines.

**Chart 7.** General design of oxazoline containing receptors.

In 2003, Ahn et al. [22] [developed the benzene-based tripodal *C*3-symmetric oxazoline receptors, **215a**–**c** (Figure 21) for the chiral molecular recognition of α-chiral primary ammonium ions (Table 20). Surprisingly, a good level of the enantioselectivity was observed by one of the receptors **215a**, as it provides the *C*<sup>3</sup> symmetric chiral environment on guest binding. The general results of chiral discrimination for α-substituted guests revealed that the π-π interaction is an important factor. Binding studies using NMR and isothermal titration colorimetry confirmed the host guest complexes formation influenced by the enthalpy changes and minor negative contribution of entropy changes.

**Figure 21.** *C*3-symmetric oxazoline receptors, **215a**–**c**.

The same group [92] later established the use of *C*<sup>3</sup> symmetric receptor, **215a** for the enantioselectivity of *β*-chiralprimary ammonium ions by utilizing a bifurcated H-bonding. Further, the extraction experiments confirmed that this interaction plays a crucial role in the chiral discrimination between the host and guest. The X-ray data proved the existence of such H-bonding. Hence, this article demonstrated that this type of binding is suitable for the chiral molecular recognition with *C*3-symmetric tripodal oxazoline receptors and further extended toward ammonium ions of α-, *β*-, and α, β-chiralprimary amines Tables 21 and 22.

**Table 20.** Enantioselective binding of Tris(oxazoline), **215a** toward Racemic Ammonium Salts.


<sup>a</sup> Enantioselectivity of the ammonium ion extracted from excess racemic salts (RNH3 +Cl−, 10 M equivalent, 0.5 M in D2O; 0.6 M NaPF6) by tris(oxazoline) **215a** (0.05 M in CDCl3) at 25 ◦C. <sup>b</sup> Percentage of the ammonium salts extracted into CDCl3 with respect to tris(oxazoline) 1a. <sup>c</sup> Extraction at 45 ◦C.

**Table 21.** Selective binding of **215a** toward racemic ammonium salts of β-chiral amines, **216**–**224**.

<sup>a</sup> Enantiomeric ratio of the extracted guest from excess racemic salts (10 M equiv., 0.5 M in D2O) by PhBTO **215a** (0.05 M in CDCl3) at 25 ◦C. <sup>b</sup> Percentage of the ammonium salt extracted into CDCl3 with respect to PhBTO **215a**. <sup>c</sup> Major: (*R*)- isomer.

7 **222** 71:29 <5 8 **223** 61:39 10 9 **224** 83:17 <5

Removing the *β*-OH group from **225**, as in **226** or **227**, (Figure 22) results in low enantioselectivities, hence indicating that the secondary H-bond interaction is critical to secure the necessary environment for chiral discrimination as confirmed by the crystallographic structure of the corresponding **215**–**225** complex.

**Table 22.** Selective Binding of **215** toward Racemic Ammonium Salts of α-alkyl-substituted Chiral Amine.

<sup>a</sup> Enantiomeric ratio of the extracted guest from excess racemic salts (10 M equiv., 0.5 M in D2O) by **215** (0.05 M in CDCl3) at 25 ◦C. <sup>b</sup> Percentage of the ammonium salt extracted into CDCl3 with respect to **215**. <sup>c</sup> Major: (*S*)-isomer.

**Figure 22.** Chiral ammonium analytes, **225**–**227**.

In the next article [93] the development of a benzene-based tripodal oxazoline receptor with *C*1-symmetry, **234** upon changing the symmetry of chiral environment from *C*<sup>3</sup> to *C*<sup>1</sup> was reported (Scheme 38). The synthetic strategy was based on the coupling of tris-(cyanomethyl)mesitylene with (*S*)-phenylglycinol in the presence of 5 mol % Cd(OAc)2 to furnish (*S*,*S*)-bis(oxazoline), **233** and subsequent treatment with (*R*)-phenylglycinol under the similar reaction conditions afforded (*S*,*S*,*R*)-**234** in 28% isolated yield.

**Scheme 38.** Synthesis of (*S*,*S*,*R*)-**234**.

Subsequently, **234**–**237** were explored for the chiral discrimination by using extraction experiment. The tripodal receptors with two phenylglycinol-derived oxazolines displayed significant enantioselectivity for racemic α-chiral ammonium ions (Table 23, entries 1–8). It was revealed that the changing receptor's symmetry, from *C*<sup>3</sup> to *C*1, causes intense improvement in the binding mode and chiral recognition. Table 24 shows that **234** was more enantioselective than other hosts, but less selective than **235**. However, **234** gave significantly lower values of the % extraction than other receptors. Furthermore, the receptor **236** and **237** (Figure 23) extracted (*S*)-α-phenylethylammonium ion preferentially over the (*R*)-guest demonstrated the reverse sense of the chiral discrimination in comparison with that of **234**.


**Table 23.** Enantioselective Extraction Experiments Using **234**–**237** towards α-Chiral Organoammonium Guests.



<sup>a</sup> Percentage of receptor-guest adduct with respect to unbound guest, calculated for 1 equiv. of receptor.

Further this group [94] reported the preparation of chiral cage-like receptors, **240a** and **240b** (Scheme 39) via the reaction of corresponding 3-hydroxyphenyl-substituted tripodal oxazolines, **238** with capping molecules, **239**. The chiral recognition behavior of **240a** and **240** was studied for two typical chiral guests; α-phenylethylammonium **98** and alanine methyl ester as α-aryl- and α-alkyl substitutedamines by using 1H NMR (Table 24). However, **240** preferentially binds to (*R*)-**98** with a lower enantioselectivity as compared to **202**. Furthermore, **240** is able to recognize alanine methyl ester with excellent enantioselectivity (7:3), but chiral discrimination is not effective in the case of 235. The degree of chiral discrimination with the cage-like receptors is distinctive from the open sensors, attributed to narrowed space offered for the guest.

**Scheme 39.** Synthesis of cage-like receptors, (*S*,*S*,*S*)-**240a** and (*S*,*S*,*S*)-**240b**.

#### **7. Miscellaneous Heterocyclic Receptors**

Apart from the heterocycles mentioned above, there exists a group of heterocyclic receptors which have a few but significant experimental findings. Given below is the group of such group used in chiral recognition receptors. Hegner et al. [28] described the synthesis of chiral amphiphilic calix[4]resorcinarene, tetrakis(*N*-methylprolyl)tetraundecylcalix-[4]resorcinarene, **242** (Scheme 40), bearing four L-prolyl moieties at the macrocyclic upper rim and four undecyl chains at the lower rim. The methodology consists of the Mannich-type reaction of tetraundecylcalix[4]resorcinarene, **241**, L-proline, and formaldehyde to yield the desired product. The supramolecular complex of calixresorcinarene and Cu(II) displayed the enantioselective recognition properties for phenylalanine with the stronger binding for D-phenylalanine.

Moran et al. [95] synthesized the *cis*-tetrahydrobenzoxanthene receptors, **243**, **244** by following the synthetic route given in Scheme 41. The binding properties of **243** have been evaluated by 1H NMR titration with decanoic acid and Cbz-glycine (Cbz = benzyloxycarbonyl) to give *<sup>K</sup>*a = 1.2 × <sup>10</sup>**<sup>4</sup>** <sup>M</sup>−<sup>1</sup> and 1.5 × 104 <sup>M</sup>−1, respectively. However, the titration of a racemic mixture of **<sup>243</sup>** with the amino acid derivatives, such as Cbz-phenylglycine, exhibited the association (*K*a= 2.3 × <sup>10</sup>**<sup>4</sup>** <sup>M</sup><sup>−</sup>1) but neither splitting of the 1HNMR signals of host nor chiral discrimination were observed. Further, the receptor, **243** was converted to **244** by treatment with the lithium salt of *m*-phenylenediamine, followed by the

reaction with trifluoromethanesulfonic anhydride. The titrations of racemic host carried out with enantiomeric pure guests (amino acid derivatives, Table 25), resulted in splitting of the 1H-NMR signals of **244**, owing to the chiral discrimination, and confirming significant enantioselectivity for **244**. The racemic receptor, **244** then was treated with ethoxycarbonyl-L-leucine and two corresponding enantiomers of the host have been separated on preparative TLC.

**Scheme 40.** Synthetic route to L-RA-Pro, **242.**

**Scheme 41.** *cis*-tetrahydrobenzoxanthene receptors **243**, **244.**

**Table 25.** Enantioselective discrimination for receptor, **244** with different guests in CDCl3 at 20 ◦C.


Roussel et al. [96] reported the non-racemic atropisomeric 1-(2-(4-methyl-2-thioxothiazol-3(2*H*)-yl)phenyl)-3-(hetero)aryl(thio)ureas, **247a**–**h** (Scheme 42). The synthesis was carried out on the basis of parent enantiopure amino-thiazoline-2-thione, **245**, which was converted into the corresponding isothiocyanate, **246** followed by the reaction with the desired aniline derivatives. These thioureas were investigated as neutral anion receptors for the chiral recognition of some amino-acids derivatives using NMR showing moderate binding affinities and discrimination (Table 26). It was exemplified that the intramolecular H-bonding apparently play a noticeable role in the fine tuning of binding and lead to the activation or deactivation depending upon the interaction site.

**Scheme 42.** Synthesis of thiourea, **247a**–**h** from amino-2-thiazoline, **245**.

Periasamy et al. [97] synthesized the Troger's base, **248** (Scheme 43) by reported synthetic methodology via the reaction of *p*-anisidine with paraformaldehyde in the presence of AlCl3 and followed by the enentioseparation with *O*,*O* -dibenzoyl-L-tartaric acid as a resolving agent. Further, the amino alcohol, **249** was prepared from the chiral methoxy Troger's base, **248** by using a standard procedure for the α-alkylation of tertiary amines. These chiral compounds, **248** and **249** demonstrated a good chiral recognition behavior for several carboxylic acids as determined by NMR (Table 27).

**Table 26.** Binding constant (Ka) for the 1:1 complexes formed between thioureas, **247a**,**c**,**g** and urea **247i** and tetrabutylammonium salts of some *N-*Acetyl amino-acid or naproxen in CD3CN at 20 ◦C ( 1H NMR titration).




<sup>a</sup> Ratio less than 1.3 are under the limit of confidence.

**Scheme 43.** Synthetic methodology for Troger's base, **248** and its amino alcohol derivative, **249**.


**Table 27.** Chemical Shift changes (Δ δ) and chemical shift non-equivalence (ΔΔ δ) observed in 1H NMR spectra of guest acids in the presence of hosts, **248** and **249.**

The chiral recognition study (Table 27) established that the chiral methoxy Troger's base **248** exhibited better enantiodiscrimination towards the *C*2-symmetric acids such as 2,3-diphenylsuccinic acid, *o*,*o* -dibenzoyl tartaric acid, and *o*,*o* -ditoluoyl tartaric acid. Whereas, the *C*1-symmetric **249** was showed better discrimination towards unsymmetrical acids mandelic acid and 1,1 -binaphthyl-2,2 -diylphosphoric acid.

Haberhauer et al. [98] synthesized the *C*3-symmetric imidazole-containing macrocyclic peptide receptors, (**251**–**253**) (Scheme 44) with different binding arms. The simple using *N*-alkylation of known scaffold, **250** with the corresponding halogenomethylcompounds afforded the desired receptors.

These hosts were employed as chiral scaffolds for the enantioselective recognition of chiral primary organoammonium ions by using the 1H NMR titration techniques. The arms of receptors, nitrogen-containing aromatic heterocycles were selected as simple units due to their rigidity, bulkiness, and ability to transfer the chiral information of the scaffold to the active binding site, thereby making the enantioselective discrimination possible. The results obtained for the chiral discrimination with several guests are summarized in Tables 28 and 29. The binding constant of receptors **251**–**253** with perchlorate salts of (*R*)-**PEA** and (*S*)-**PEA** were determined Table 28. The benzimdazole receptor, **251** on interaction with the (*R*)-**PEA** and (*S*)-**PEA** influenced the protons towards upfield around 0.10 ppm. The titration curve obtained demonstrated the pseudo linear progression, and found smaller binding constants less than 1 M−<sup>1</sup> owing to receptor, **251** could not orient basic nitrogens of benzimidazole in such a way to form the stable complex. For the quinoline receptor **252**, obtained the quite low value of binding constant as 200 M–1 for (*R*)-**PEA** and 480 M–1 for (*S*)-**PEA** respectively for both enantiomers with maximum 0.03 ppm and 0.06 ppm chemical shift. In the case of isoquinoline receptor, **253** large

chemical shift around 0.3 ppm observed with binding constants, 4500 M–1 for (*S*)-**PEA** and 30,000 M–1 for (*R*)-**PEA**.

**Scheme 44.** Synthesis of *C*3-symmetric imidazole-containing macrocyclic peptides receptor (**251**–**253**).

**Table 28.** Binding constants *K*<sup>a</sup> (M−1) for the formation of 1:1 complexes of **218**–**220** with the perchlorates of (*R*)- and (*S*)-α-phenylethylamine in CDCl3 at 298 K a.


<sup>a</sup> The association constants Ka (M<sup>−</sup>1) for the formation of 1:1 complexes were measured using 1H NMR spectroscopic titrations. <sup>b</sup> A host concentration of 2.5 × <sup>10</sup> <sup>−</sup><sup>4</sup> M was used for titration studies, because of the high binding constant.

For the titration of quinoline receptor **252** with other guests (Table 29) revealed the maximum chemical shift observed in the range of 0.01 ppm and 0.05 ppm and binding constants for the complexes were more similar for (*R*)-**PEA** and (*S*)-**PEA**. Further, quite small binding constant were obtained for **251**\*(*R*)-**AH** and **251**\*(*S*)-**AH** with the respective values of 360 M–1 and 100 M–1. More interestingly, high enantioselectivities were furnished for the complexes of **252** with (*R*)-**BA** vs. (*S*)-**BA** and for the complexes of **252** with (*R*)-**PAM** vs. (*S*)-**PAM**. Intriguingly, the binding constant values of isoquinoline receptor **253** with the both the enantiomers of guests were found to be ten times larger than that of quinolone receptor **252**. In general comparison of receptors **252** and **253** exemplified the high sensitivity to small change in the guest molecules.

Zhao et al. [38] prepared the chiral fluorescent bisboronic acid sensors, **258**, **263** with 3,6-dithiophen-2-yl-9H-carbazole as a fluorophore (Scheme 45). The thiophene units were used to extend the π-conjugation of carbazole and to enhance the electron-donating ability of fluorophore. The synthetic strategy was based on the first iodination of carbazole core and subsequent attachment of 2-formyl-5-thiopheneboronic acid to the carbazole moiety by Pd(0)-catalyzed Suzuki cross-coupling. The chirogenic center was introduced by reductive amination with α benzylamine. Finally, the boronic acid units were attached by a simple *N*-alkylation with 2-(2-bromomethylphenyl)-1,3,2-dioxaborinane. The monoboronic acid sensor, **230** was also prepared from mono iodinate carbazole in the similar manner and used for comparison in the binding studies.


**Table 29.** Binding constants *K*<sup>a</sup> (M<sup>−</sup>1), maximum observed chemical shifts (Δ δmax), Gibbs free energy changes (−Δ*G*0), selectivity coefficients, and differences of the Gibbs free energy changes (ΔΔ*G*0) above) for the formation of 1:1 complexes of **219** and **220** with different salts of α-chiral primary organoammonium ions in CDCl3 at 298 K.

The host containing diboronic acid, **258** exhibited the enantioselective recognition of tartaric acid at acidic pH, and the enantioselectivity was found to be 3.3. The L-tartaric acid showed 5 fold enhancements in the fluorescence while for D-tartaric acid exhibited 3 fold enhancement in the fluorescence. Thus, fluorescence enhancement factor (IF Sample/IF Blank) for **258** upon interaction with tartaric acid was 3.5-fold at pH 3.0. Further, **258** was useful for the enantioselective recognition of D-and L-mandelic acid, whereas **263** containing monoboronic acid failed to display the corresponding chiral recognition of these guests.

Pu and coworkers [99] developed the H8-BINOL-aminemolecules, (*S*)-**264**\_(*S*)-**267** as a promising new class of the enantioselective fluorescent sensors by using their recently developed one-step reaction of H8BINOL with in situ generated aminomethanol (Scheme 46). The NMR studies revealed that the difference between the fluorescence spectra of (*S*)-**264**\_(*S*)-**267** apparently arises from the different capability of their nitrogen atoms to form intramolecular hydrogen bonds. When (*S*)-**267** was treated with enantiomer (*R*)-MA result into the substantial fluorescent enhancement with I*R*/I0 = 3.2. This was anticipated that the involvement of nitrogen of (*S*)-**267** in the complexation with (*R*)-MA to form a structurally more rigid fluorophore. However, for (*S*)-MA, the fluorescence enhancement was smaller with I*R*/I0 = 2.1. This indicates that (*S*)-**267** is a promising candidate for the enantioselective fluorescent recognition of MA in the shorter emission wavelength. Greater fluorescence enhancement at the short wavelength (λem = 330 nm) was observed upon the interaction of (*S*)-**268** (Figure 24) with (*R*)-MA, whereas (*S*)-MA gave smaller enhancement at the same wavelength. Thus, a good enantioselective fluorescent response was observed in this case with ef = 3.5. This study demonstrated that the H8BINOL-based molecules are promising as a new class of the enantioselective fluorescent sensors.

**Scheme 45.** Synthesis of bisboronic acid sensors, **258**, **263** bearing 3,6-dithiophen-2-yl-9H-carbazole as a fluorophore.

Jurczak et al. [31] prepared the tweezer-type compound, **271** by functionalization of 7,7 -diamino 2,2 -diindolylmethane, **269** with peracetylated D-glucuronic acid (**270**) (Figure 25), as a source of chirality, to form the corresponding amide linkage. Similarly, the reference receptor, **272** was synthesized from 7-aminoindole.

**Scheme 46.** Synthesis of the H8BINOL-amine compounds, (*S*)-**264**-(*S*)-**267**.

**Figure 24.** H8BINOL-amino alcohol, (*S*)-**268**.

**Figure 25.** Structures of 7,7 -diamino-2,2 -dindolylmethane (**269**), peracetylated D-glucuronic acid, **270**, and chiral anion receptors **271** and **272**.

The enantioselective recognition of **271** and **272** were studied by 1H NMR titrations for model chiral anionic guests; *S-*(+)-mandelate or *R*(−)-mandelate. It was found that the association constant of (*R*)-MA is larger than that of (*S*)-MA. ROESY spectrum of the host-guest system between **271** and (*R*)-MA shows the corresponding correlations between the aromatic protons of guest and sugar protons (H3 and H5) of host. For weaker bounded (*S*)-MA, additional cross peaks were also found indicating a deeper penetration of the anion into the receptor cavity. This was also confirmed by different ROESY signals arising from the (*R*)*-*mandelate protons and sugar moiety protons of host.

The same group [100] developed the chromenone- and indole−urea-based*C*2-symmetrical receptors, **276** and **280** functionalized with easily accessible 1,3,4,6-tetra-*O*-acetyl-D-glucosamine, starting from amines **273** and **277** (Scheme 47). Subsequently, the condensation with phosgene resulted in **274** and **278** followed by the hydrolysis of ester groups to yield **275** and **279**. These acid compounds were then coupled with the D-glucosamine derivative to furnish the desired products, **276** and **280**.

**Scheme 47.** Synthesis of receptors **276** and **280**.

The receptors, **276** and **280** were evaluated for their binding properties with various anions derived from chiral acids and having a stereogenic center in the α position. It was observed that **276** binds the *S* enantiomers of anions more strongly than the *R* enantiomers in all cases, with the enantioselectivities in the range of 1.2−2.0. A similar trend but with weaker preference for binding the *S* enantiomers was observed for **280** in the most cases. Also, **276** recognizes the chiral guests by steric interaction with the sugar moieties. This hypothesis was further supported by the relative stability constants (*K*S/*K*R) in the mandalate anion series. Hence, reducing the steric hindrance on the α carbon in the anion by substituting Ph with PhCH2 results in increasing the overall stability constants and decreasing the *K*S/*K*<sup>R</sup> value, whereas enhancing this steric hindrance by replacing the hydrogen atom

with the CF3 group significantly decreases both the stability constants and the *K*S/*K*<sup>R</sup> value. In the case of **280** the sugar parts do not interact with the side chain of anions during the complexation, which was explained by the weak enantiodiscrimination.

Yasuda et al. [101] prepared the cage-shaped borate, **285** starting from readily available (*R*)-BINOL, which was converted to methoxybinaphthyl, **281** followed by lithiation at the ortho-position and subsequent condensation with ethyl chloroformate to yield tris(2-methoxybinaphthyl)methanol, **282** (Scheme 48). Further reduction of **282** with a Me2SiHCl/InCl3 system and deprotection of the methoxy groups afforded tris(2-hydroxybinaphthyl) methane, **284** with the axial chirality at all three binaphthyl moieties. Finally, mixing **284** with BH3·THF generated the cage shaped borate, **285**, which was subsequently converted to **285**·PyBr2.

**Scheme 48.** Synthesis of homochiral cage-shaped borate, **285** with *C*3-symmetry.

The chiral recognition of a mixture of the excess amount of racemic phenyl ethyl amine **98** with **<sup>285</sup>**·THF in CD2Cl2 have been studied by 1H NMR measurement. The ratio between the *<sup>R</sup>* and *<sup>S</sup>* enantiomers of phenyl ethyl amine, 1-(2-naphthyl)ethylamine and adducts with **285** found to be 18:1, 23:1 respectively (entry 1, 2 in Table 30), showing the highly enantiorecognition. Further, the *R* and *S* enantiomers ratio for the racemic methyl phenyl sulfoxide with host **285**, was observed to be 7:1 owing to low Lewis basicity of the sulfoxide as compared to amines.

**Table 30.** Recognition of chiral substrates by complexation with **285**.THF.

<sup>a</sup> The ratios and absolute configurations except entry 3 were determined by 1H NMR measurement; <sup>b</sup> heating for 43 h at 80 ◦C; <sup>c</sup> heating for 216 h at 80 ◦C; <sup>d</sup> the absolute configuration was not determined.

#### **8. Summary**

Chiral molecular recognition is a crucial branch of modern chemistry facilitating the qualitative and quantitative analysis of chiral molecules. It is also a basis of the industrially relevant chromatographic technique for bulk separation of racemates. There exists a huge global market for chiral separation technology for qualitative and quantitative estimations of chiral analytes. This review focuses on chiral supramolecular systems with the presence of heterocyclic ring(s) in the host structures. The hosts with the pyridine ring(s) form the major group in both the macrocyclic structures and the open chain tweezers. So far, different spectral and analytical techniques to detect and to estimate the binding between the host and the guest with a noticeable difference in the association constants of two enantiomeric guests have been employed. The fluorescence and NMR spectroscopic methods have been more commonly used for the chiral recognition purpose. Different types of intermolecular interactions between the corresponding hosts and guests involved in each supramolecular system have been proposed and discussed. An additional method on the basis of induced chirality detected by CD has been included in the review, though strictly speaking it is amplification of chirality of the guests based on supramolecular interactions between achiral host and chiral guests. Hosts with presence of different chiral elements have been employed. So far the incorporation of heterocyclic units in chiral hosts seems to be driven by ease of access, presence of aromatic ring and presence of multiple ligating centers. Though crowns and macrocycles of different sizes have been employed for chiral recognition studies, size-dependent enantio-discrimination factor has been noticed only in the last few years. Given the importance of chiral analysis, this branch is poised to achieve momentum in the coming decade.

**Acknowledgments:** Authors thank Mohammed Hasan and Sushil Khot for critical reading and suggestions. Vaibhav N. Khose thanks UGC-NET for the JRF and SRF awards. Victor Borovkov acknowledges funding from the European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration under Grant Agreement no. 621364 (TUTIC-Green).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

## *Review* **Helicene-Based Chiral Auxiliaries and Chirogenesis**

#### **Mohammed Hasan and Victor Borovkov \***

Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia; mhasanfive@gmail.com

**\*** Correspondence: victor.borovkov@ttu.ee; Tel.: +372-620-4382

Received: 7 December 2017; Accepted: 26 December 2017; Published: 29 December 2017

**Abstract:** Helicenes are unique helical chromophores possessing advanced and well-controlled spectral and chemical properties owing to their diverse functionalization and defined structures. Specific modification of these molecules by introducing aromatic rings of differing nature and different functional groups results in special chiroptical properties, making them effective chiral auxiliaries and supramolecular chirogenic hosts. This review aims to highlight these distinct structural features of helicenes; the different synthetic and supramolecular approaches responsible for their efficient chirality control; and their employment in the chirogenic systems, which are still not fully explored. It further covers the limitation, scope, and future prospects of helicene chromophores in chiral chemistry.

**Keywords:** helicene; chiral auxiliaries; supramolecular chirogenesis; chirality

#### **1. Introduction**

Aromatic characteristics in organic compounds are very interesting due to the resonance electronic features, stability, and inter- and intramolecular π-π interactions along with the specific geometric properties and reactivity, making it an important topic for researchers. Among the diverse aromatic compounds, there is a class of the molecules carrying *ortho*-annulated polyaromatic structures, classified as helicenes. In order to understand their unique structural features, helicenes should be compared with the conventional aromatic molecules (Figure 1).

Benzene **1**, naphthalene **2**, and phenanthrene **3** are spatially flat aromatic structures (Figure 1); hence, they are not helicenes. As the number of *ortho*-fused aromatic rings is increased beyond three units, such as in **4**–**6** (Figure 1), the space constraint in the molecule is also enhanced, forcing it to adopt a nonplanar helical arrangement. These types of aromatic structures are called helicenes. As a consequence, the electron resonance ability is restricted throughout the molecule. Similar to

conventional aromatics, helicenes can be functionalized by various synthetic protocols to further enhance their spectral and chemical properties. However, the diversity of helical aromatic structures makes helicenes into unique and advanced chromophoric systems with tunable electronic and steric properties for corresponding applications in all types of stereochemical processes, including chiral auxiliaries and supramolecular chirogenesis. It is of note that, whilst there is a great variety of aromatic structures used in different chiral fields [1], helicenes still lag behind, despite their attractive properties discussed below.

#### **2. Overview of Latest Reviews**

Firstly, the existing reviews on helicenes from within the last five years should be briefly analyzed. Indeed, the chemistry of helicenes has existed for more than a century. However, this topic has been reviewed only recently to a rather limited extent [2–11]. Furthermore, these reviews mainly focused on the synthesis of helicenes and much less on their applications. One of the most comprehensive reviews was published in 2012 by Chen et al., describing helicene synthesis and applications [2]. In 2013, Gingras accumulated three sets of reviews targeting only carbohelicenes and covering the topics of its non-stereoselective [3] and stereoselective synthesis, chiral separation [4], and applications, along with the corresponding properties [5]. Yet, in 2014, three small review articles appeared on the topics of photochemical methods of helicene synthesis [6], helicene-based transition metal complexes [7], and helicene-like chiral auxiliaries [8]. Further, in 2015, Virieux [9] summarized the synthesis and application of helical phosphorus derivatives, where the helicene-based phosphorus ligands were also described. Thus, it is clear that—despite several consecutive reviews and monographs—this field is not fully covered, especially from the point of view of chiral applications. Further, the helicenes, being polyaromatic compounds, have been discussed in several chapters of a few books devoted to polyaromatic compounds and material chemistry [10]. Very recently, in 2017, a book on helicene chemistry [11] was published, covering most of the topic as it had appeared in previous reviews and presenting the progress up until the period of 2015.

Despite these recent efforts described above, a general tutorial and critical summary devoted to the design and tuning of helicene structures for suitable general and specific applications in the areas of chiral auxiliaries and chirogenesis is not yet available. Hence, the present review aims to fill in this gap, with a specific focus on the potential applicability and usefulness of helicene chemistry in these chirality fields—including the latest updates.

#### **3. Classification and Nomenclature**

#### *3.1. Structural Diversity*

In order to understand the structure and type of helicene molecules, a brief introduction into the classification and nomenclature should be made. As a part of classical organic chemistry, helicenes can be structurally divided into two major groups: carbohelicenes and heterohelicenes.

#### 3.1.1. Carbohelicenes

Carbohelicenes are all benzenoid (aromatic) *ortho*-fused systems and named as [n]helicenes, where n represents the number of rings forming a helix in the *ortho*-fused fashion. Thus, the structures **4** [12], **5** [13,14], and **6** [15,16], are [4]helicene, [5]helicene, and [6]helicene, respectively (Figure 1). However, any fused ring which is not present in the *ortho*-fused manner is not included in the n counting. For example, structures **7** [17], **8** [18], and **9** [19] are all [5]helicenes, but not [6]helicenes, despite the presence of six aromatic rings in total (Figure 2). The functionalized helicenes such as **10** [20], **11** [21], and **12** [22] (Figure 2) which have a heteroatom as a substituent on the aromatic ring, as in the case of amino, hydroxyl (phenolic or alcoholic), thiol, or phosphorus-containing groups, are still carbohelicenes but not heterohelicenes. In order to specify the position of functional group(s), a numbering system is used, as shown in the structure **10**. The numbering starts from the

innermost position at one end and goes to another end via the outer helical core in such a way that the functional group has the minimal number. Secondly, only unfused carbons (with hydrogen or other groups as substituents) are counted sequentially (shown in blue), whereas fused carbon atoms (of the helicene core) have the previous number with the corresponding a, b, c suffixes based on the sequence order of fused 1, 2, 3 atoms, and so on (shown in red). Thus, the structure **10** can be named as 2-acetoxy[5]helicene.

In the case of nonsymmetric heterohelicene, the numbering should be started from the peripheral ring which will give the least number to the heteroatomic ring core. In the case of more than one substituent, a general nomenclature rule of numbering should be applied. Yet, in both the cases mentioned, one should always follow the sequential numbering of the helicene core (starting from one innermost atom to another innermost atom of the two peripheral rings).

**Figure 2.** Examples of carbohelicenes: [5]carbohelicenes **7**–**9** with additional fused rings and functionalized [5]-**10**, [6]-**11**, and [7]-**12** carbohelicenes.

#### 3.1.2. Heterohelicenes

Another class of helicenes is the heterohelicenes, in which one or more benzenoid ring is substituted with a heteroatomic ring (Figure 3). Heterohelicenes are generally based on five-membered rings such as thiophene, pyrrole, furan, etc., and six-membered rings mostly containing pyridine. Additionally, they can be fused and functionalized.

The corresponding heteroatom must be a part of the ring present in the fused *ortho* fashion but not as the substituent either in a functional group or in a heteroatomic ring. In the latter, whilst the overall molecule is heterocyclic, the helicene core is not. Further, depending on the heteroatom nature, the helicene structures are named aza[5]helicenes (**13** [23], **14** [24]), oxa[5]helicenes (**15** [25]), and thia[7]helicenes (**16** [26]). If there is more than one heteroaromatic ring or heteroatom, the helicene names are simplified as hetero[n]helicenes, [n]heterohelicenes, or simply [n]helicenes. For two or three similar heteroatomic rings, the prefixes "di", "tri", etc., are added with or without indicating the exact position. For example, the structure **17** [27] is called 7,8-dioxa[6]helicene or simply dioxa[6]helicene. Heterohelicenes containing phosphorus **18** [28], silicon **19** [29], and boron **20** [30] atoms are relatively rare and their chiral properties have not been well studied so far; therefore, they are excluded from this review.

**Figure 3.** Examples of heterohelicenes, **13**–**20**.

#### 3.1.3. Charged Helicenes

Helicenes can also be categorized into neutral and charged helicene molecules. Most of the above examples are neutral helicene molecules, where the charge of the aromatic moiety is zero. However, if there is a charge on the helicene structure, a counter ion should be presented to balance the overall charge, hence resulting in different properties and applications. In such helicenes, exchanging the counter ion can easily enhance a number of the corresponding derivatives, controlling the solubility and pH effect. This counter ion exchange can sometimes offer a new approach towards optical resolution by changing an achiral counter ion to a chiral one in the case of thermodynamically stable structures. For example, quarternized azahelicene **21** [31] and cationic helicene **22** [32] stabilized by electron resonance/conjugation represent typical charged helicenes (Figure 4).

**Figure 4.** Charged helicenes, **21**–**22**.

#### 3.1.4. Special Structural Type of Helicene-Like Molecules

Besides the traditional definition of helicene molecules, there are several special cases which belong to this structural category but are not associated with the above-described major groups of carbo- and heterohelicenes; these are discussed below. Naphthalene **2** and phenanthrene **3** are the simplest *ortho*-fused flat molecules without any steric constraint and, hence, are not helicenes, whilst four fused aromatic rings induce a certain steric hindrance at the innermost peripheral hydrogen atoms, setting up the first member of helicene family. Thus, in [n]helicenes, n should be >3 to be classified as a helicene molecule. However, there are some exceptions to this general rule. Interestingly, phenanthroline-*N,N*-dioxide **23** [33] (Figure 5) is also classified as a helicene in the literature, despite the fact that n = 3. This is due to the fact that the *N,N*-dioxide functionalities at the peri positions in the bay area of the phenanthroline are able to introduce the corresponding spatial constraint to force the molecule to adopt a configurationally stable helical conformation.

**Figure 5.** Special structural types of helicene **23** and helicene-like molecules **24**–**25**.

Besides the well-defined helicene molecules, there also exist helical structures, such as **24** [34] and **25** [35], called helicene-like molecules or helicenoids (Figure 5). Helicenoids usually contain at least one saturated atom as a part of the ring system in the helicene-type core system. Thus, the saturated ring is not able to adopt a flat structure, resulting in the enhancement of helicity. For example, a series of 1,1 -Bi-2-naphthol (BINOL)-based helical systems, sometimes referred to as oxahelicenoids, have been reported so far as configurationally stable structures [34,35]. Other types of saturated hydrocarbon-containing helicenoids, which are actually dihydrohelicenes, are also well documented in literature as precursors for helicene synthesis.

#### *3.2. Spatial Diversity*

Besides the structural diversity described above, helicenes can also be categorized, based on their stereochemistry, into four different categories: achiral (flat structures), stereodynamically labile (when *P* and *M* spatial conformations are in fast equilibrium; for the *P* and *M* definitions, see Section 3.2.1), chiral (enantiomerically stable structures), and *meso* helicenes (helical structure with some symmetry elements). This categorization is highly important for their applications in chiral auxiliaries and for chirogenic systems.

#### 3.2.1. Chiral (Configurationally Stable) Helicenes

In order to understand the helicene spatial structures and this classification, the term "in-plane turn angle" needs to be introduced. Due to the *ortho* fusion mode, each aromatic ring contributes to the overall helicity of the molecule via an in-plane turn angle (Figure 6a). When the sum of the in-plane angles of the contributing rings becomes 360◦ or more, the helicene is forced to adopt a helically chiral structure caused by the corresponding steric clashes between the terminal/peripheral rings. Conventional six-membered (hexagon) aromatic rings such as benzene and pyridine have an in-plane turn angle of 60◦ [36]. However, in the case of five-membered heteroaromatic (pentagon) rings, the value is considerably smaller at 45◦ (thiophene), 35◦ (pyrrole), and 32◦ (furan) [36] due to the different geometric properties of aromatic rings as a result of the variable atomic sizes of heteroatoms and bond length of C–X bond (X = heteroatom S, N, O in the five-member aromatic rings, correspondingly). Therefore, the helicenes with at least one five-membered heteroaromatic ring need n > 6 to become intrinsically chiral, whereas for the helicenes containing all six-membered carbo/hetero aromatic rings, n = 6 is sufficient to make them helically chiral.

**Figure 6.** Schematic representation of (**a**) in-plane turn angle and (**b**) helicity and enantiomers of [6]helicene.

In general, a chiral helicene molecule exists in two enantiomeric forms. The right-handed helical structure (moving from up to down) is assigned the name (*P*)-enantiomer, whereas the left-handed helical structure (moving from up to down) is designated the (*M*)-enantiomer, according to the Cahn–Ingold–Prelog rule (Figure 6b). This type of helicene tends to give configurationally stable enantiomers as the racemization process is expected to go through the highly energetic, strained *Cs*-symmetrical transition state [37]. Along with this thermodynamic stability of enantiomers, helicenes also exhibit notable enhanced (chir)optical properties, making them suitable candidates for chiral auxiliaries and other chirogenic processes. Interestingly, in general, (*P*)-carbohelicenes are observed as dextrorotatory, whereas (*M*)-enantiomers display a levorotatory nature [38].

#### 3.2.2. Achiral Helicenes

Another type of helicene is the achiral flat molecules; for example, *ortho*-condensed polyaromatic molecules consisting of four rings with at least one ring being a five-membered (pentagon) heteroaromatic ring, as in [4]heterohelicenes. Whilst these structures are less interesting from the viewpoint of chirality, they possess enhanced conjugation, electron transfer, and emission properties, making them suitable candidates for various material chemistry applications.

#### 3.2.3. Stereodynamic Helicenes

Holding an intermediate position between the chiral and achiral helicenes are the stereodynamic helicene structures. The geometry of these molecules is close to flat, whilst the van der Waals radii of the innermost hydrogens touch each other, making the structure stereodynamic and nonresolvable in solution, owing to the low (*P*)–(*M*) interconversion energy barrier. These include helicenes consisting of five benzenoid (hexagon) rings or [6]heterohelicenes with two five-membered (pentagon) heteroaromatic rings. However, in a solid state, these structures are able to adopt a chiral helical conformation. The dioxa[6]helicene **16** [27] is a typical example of such a system.

Stereodynamic helicenes are also highly fluorescent in nature due to the extended conjugation, whilst lacking any intrinsic chiroptical properties in solution. Yet, applying host–guest chemistry with suitable enantiopure guests, the corresponding chiroptical properties can be induced and controlled in this type of helicene. Additionally, the stereodynamic helicenes can be made helically chiral by introducing a bulky substitution at the innermost (C1) carbon atom. Computational analysis confirmed that attachment of just one methyl group at the innermost position results in the same steric strength as introduction of one additional *ortho*-fused benzene ring. Thus, [5]helicene with a methyl group at the innermost position has a structure more helical than that of [6]helicene, thus increasing the racemization barrier for the former [37].

#### 3.2.4. *Meso* Helicenes

*Meso* helicenes are achiral, yet need to be classified separately. Two helicene fragments in one molecule, with the presence of a plane of symmetry, produce an achiral *meso* helicene. Each equivalent helical part of this molecule possesses the opposite helical sense, whilst the whole molecule is symmetrical. Potentially, it can be suitably desymmetrized by a covalent bond or supramolecular interaction, making it chiroptically active and, hence, usable in various chirogenic processes. However, this area has not been well investigated yet, as selective modification of only one helicene moiety out of two is an arduous task; this is due to the fact that both the helicene parts are chemically equivalent. For example, carbocyclic helicene **26** [39] and heterocyclic helicene **27**–**28** [40] are *meso* double helicenes (Figure 7). It should be noted that the double helicenes have three stereoisomers, out of which two are optically active ((*P*,*P*) and (*M*,*M*)) and one is optically inactive ((*P*,*M*) or (*M,P*)), defined as a *meso* structure.

**Figure 7.** Examples of *meso* double helicenes **26**–**28**.

#### **4. General Description and Main Synthetic Approaches toward Helicene-Based Chirogenic Systems**

The early pioneering work on helicene synthesis, resolution, and chiroptical properties has been performed by Newman [15,16,41]**,** Wynberg [36,38], Martin [42], and Katz [26]. In general, classical methods of helicene synthesis include the following approaches: oxidative photocyclization, Diels–Alder reactions, and various aromatic and metal-catalyzed coupling reactions [2–6,11]. The synthesis of helicenes is always a challenging task for organic chemistry due to the steric factors involved and difficulty in controlling the regioselectivity of reactions. The same factors are also responsible for the unique reactivity of the helicene skeleton.

The current advances in synthetic chemistry, resolution, and chiral separation are essentially helpful in designing and obtaining novel enantiopure helicene molecules in sufficient quantities to be used for various applications. As BINOL, (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) (BINAP), and related biaryl systems have been successfully applied as ligands, catalysts, and hosts in stereodiscriminating processes [43–45], it is theoretically possible to thoroughly design helicene-based helical systems possessing advantageous chiral properties. Progress in this area is highlighted below with several selected examples.

Let us look closely at a general structure of (*M*)-[6]helicene **6** (Figure 8a), where the benzene rings at the beginning and at the end of the helical arrangement are called the terminal or peripheral rings. It can be clearly seen that the helix experiences steric clashes towards the inner sides (interior), called the helicene's inner core. This structural organization results in a helical chiral cavity. The restricted space available between and around the two peripheral rings can be explored effectively for various chiral discriminating processes. In general, the introduction of suitable functional groups at the peripheral rings can act as a binding site to hold the reactant or guest molecules to facilitate the enantioselectivity, where the chiral cavity space of the helicene is able to influence the corresponding (diastereomeric) transition state and/or complexation mode. In contrast, the opposite outer skeleton of the helicene, termed as the helicene outer core (exterior), can be functionalized and used to covalently link these molecules on surfaces and for other applications.

The tailor-made design of helicenes for a suitable application can be of two types; first, where the functionalization at one peripheral ring is sufficient (monodentate), and second, where functionalization on both the terminal rings is required (bidentate) (Figure 8b). The bidentate helicenes can be *C*2-symmetric (R = R') or nonsymmetric (R = R') molecules. In accordance with the structural

features and substituent patterns of helicenes, their efficiency in chirogenic processes is observed, as demonstrated throughout this review.

**Figure 8.** (**a**) General explanation of terms used for helicene structures and chiral cavity (shaded area); (**b**) representative [6]- and [7]helicenes (R = R' or R = R') with mono- or di-functionalized peripheral rings.

However, since the majority of recently published reviews [2–6] have focused on helicene synthetic chemistry, there is no need to describe this topic here in detail. Alternatively, this review addresses the structural design and stereochemical aspects of helicene chromophores suitable for various applications in chiral processes, whilst synthesis of these molecules will only be highlighted in brief upon necessity to emphasize their spatial and chiral properties.

#### **5. Helicenes as Chiral Auxiliary/Reagent or Additive**

Due to the difficulties associated with the synthesis of helicenes and obtaining the corresponding enantiopure forms in sufficient amounts, their application as a chiral auxiliary in stoichiometric reactions is limited. However, one of the first results on the use of helicenes as chiral auxiliaries in few diastereoselective reactions was reported in 1985–1987 by Martin et al. with racemic 2-substituted-[7]helicene [46–50]. Hence, racemic **29** was employed as an inbuilt chiral auxiliary for the diastereoselective reaction of the carbonyl group of α-keto esters upon reduction with NaBH4, yielding **30** (99% yield; 100% *de)* [46], and on the nucleophilic addition of Grignard reagent to give **31** (95% yield; 100% *de*) [47] (Scheme 1).

**Scheme 1.** Diastereoselective reaction using racemic [7]helicene **29** as a chiral auxiliary.

Although high diastereoselectivity (100%) was observed, the overall process requires attaching (protection) and detaching (deprotection) the helicene auxiliary, thereby making it difficult to scale up. Similarly, [7]helicene-attached unsaturated ester **32** was also utilized for the highly diastereoselective ene reaction with cyclohexene **33** in the presence of SnCl4 to afford **34** with high yield (86%) and 100% *de* [48] (Scheme 2).

**Scheme 2.** Diastereoselective ene reaction using racemic [7]helicene **32** as a chiral auxiliary.

Further, hydroxyamination of E-stilbene **35** under the Sharpless condition by using helicene **36** as a chiral auxiliary resulted in **37** with 32% yield with 100% *de* [49] (Scheme 3).

**Scheme 3.** Diastereoselective hydroxyamination of stilbene reaction using racemic [7]helicene **33** as a chiral auxiliary.

Another example is based on enantioenriched 2-cyano-[7]helicene **38** employed as a stoichiometric chiral additive (reagent) for the epoxidation of alkenes **35** and **39** using H2O2 as an oxidant to give enantiopure epoxides **40** (92%, 99% *ee*) and **41** (84%, 97% *ee*), respectively [50] (Scheme 4). The mechanism includes the initial reaction between enantiopure 2-cyano-[7]helicene **37** and H2O2 to generate in situ the corresponding chiral hydroperoxyimine, which serves as a chiral oxidizing reagent for the subsequent epoxidation of alkenes **35** and **39**, whilst itself converting finally to [7]helicene-2-carboxamide **42**.

These examples (Schemes 1–4) [46–50] are the first cases of helicenes being used as chiral auxiliaries resulting in a high asymmetric conversion (*de* or *ee*), yet noncatalytic in nature. These excellent results were due to the judicious selection of [7]helicene with corresponding functionalization at the 2-position (monodentate) (refer, Figure 8), which locates inside the helical chiral cavity with sufficient accessibility to the reactants. Besides this, a geometric feature of [7]helicenes is that the two peripheral rings are located one above another, hence inducing steric hindrance to one of the reacting prochiral faces and generating high selectivity via the stereospecific approach.

It is of note that most of the helicene-based catalytic research is focused on the use of [6]helicene and substituted [5]helicene-based systems. In cases where functionalization at both the rings is needed, substituted [5]helicenes and [6]helicenes are more suitable due to possibility of the geometrical accessibility of these groups (refer, Figure 8b). These groups are located on the same side; hence, they are capable of coordinating or bonding together with the reactive partners. However, this situation is difficult to obtain in [7]helicenes, as seven benzenoid rings give the in-plane turn angle of 420◦ (7 × 60◦), forcing the functional groups present on the terminal rings to exist in opposite directions, thus unable to work co-operatively (refer, Figure 8b). Yet, when only one of the peripheral rings is functionalized and acts as an active catalytic site, the [7]helicene-based systems have an additional advantage over substituted [5]- and [6]helicenes. This is owing to the same in-plane turn angle property allowing another peripheral ring to block one of the prochiral faces of the reactant. Nevertheless, surprisingly, asymmetric catalysis with [7]helicenes is not well explored in comparison with that with [5]- and [6]helicenes.

**Scheme 4.** Enantioselective epoxidation of alkenes **35** and **39** using enantioenriched [7]helicene **38** as a chiral additive.

#### **6. Helicenes as Chiral Catalysts**

Since various helicene-based phosphine-related ligands have been reviewed [2,5,7–9], only recent selected examples capable of delivering exceptionally high *ee* values are summarized here.

In 2016, the [5]carbohelicene-based phosphine ligands **43** and **44** were rationally designed for application in Pd-catalyzed asymmetric synthesis [51]. Both the systems were prepared from corresponding *rac*-bromo substituted **45** via lithiation and subsequent reaction with chlorodiphenylphosphine followed by oxidation with hydrogen peroxide to afford *rac*-phosphine oxide **46** with 63% yield. It was successfully resolved by using spiro-TADDOL (α,α,α,α-tetraphenyl-1,3-dioxolane-4,5-dimethanol) **47** as a resolving agent to form the insoluble diastereomer **48** with (*P*)-**46**, which in turn gave pure (*P*)-**46** with greater than 99% *ee* on subsequent treatment. Then, (*P*)-**46** was aromatized to **49** quantitatively by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Both the phosphine oxides **48** and **49** were reduced to the corresponding phosphines, **43** and **44,** with trichlorosilane and P(OEt)3 with 70–72% yield and 99% *ee* (Scheme 5) [51].

In general, unsubstituted [5]helicenes are configurationally unstable and tend to racemize easily. However, introduction of the diphenylphosphine group at the 1-position results in the configurational stability of **43** and **44**. Of these two structures, the 7,8-dihydro-derivative **43** tends to be more helical due to the saturated ethane unit, which has greater conformational flexibility. From X-ray analysis, it was confirmed that the helical pitch diameter of dihydrohelicene **43** is 3.54–3.50 Å, which is larger than that of fully aromatic **44**, found to be 3.39–3.34 Å. This rationally changed spatial arrangement has a noticeable influence on its application as a ligand owing to the favorable geometry and distance, which was clearly demonstrated by the metal–ligand and arene interaction. Hence, the double bond (C8a–C14b) is coordinated with the palladium metal center of ligand **44** in a side-on (η 2) fashion,

which is not possible in the case of dihydrohelicene **43**. This difference in geometric features controls the outcome of Pd-catalyzed reactions. For example, the alkylation of *rac*-1,3-diphenylallyl acetate **50** with dimethyl malonate **51** by using (*M*)-dihydrohelicene **43** as a chiral ligand was highly efficient, resulting in the corresponding (*S*)-enantiomer **52** with 99% yield and 94% *ee* (Scheme 6) [51]. In contrast, the fully aromatic (*M*)-helicene **44**, whilst affording the same configuration of the product **52**, gave similar yield, but only 71% *ee* (Scheme 6). This clearly demonstrates that the ligands' geometry allowed them to opt for different transition states.

**Scheme 5.** Synthesis and resolution of enantiopure phosphine ligands **43** and **44**.

**Scheme 6.** Pd-catalyzed asymmetric alkylation of *rac*-1,3-diphenylallyl acetate **50** using helical phosphine ligands **43** and **44**.

Similar types of C1 position substituted phosphinite ligands, helicenoid **53** [52] and helicene **54** [52] (Figure 9), were also prepared and successfully explored for the Pd-catalyzed asymmetric allylic alkylation between **50** and **51** (see Scheme 5). In both cases, the high yields and *ee* of **52** were obtained as with **53** (96%, 90% *ee*) and with **54** (97%, 99% *ee*) [52]. It is of note that this kinetic resolution reaction using helicene ligand **55** [53] was firstly reported in 2000 with 100% conversion and 81% *ee* (Figure 9). Although the results from using **55** are comparatively worse in terms of *ee*, the reaction requires less catalyst loading and proceeds faster compared with other ligands. Interestingly, **55**, whilst being a bidentate ligand, still acts as a monophosphine (monodentate) ligand during the catalytic process owing to the large distance (6.481 Å) between the two phosphorus atoms; this was the subject of pioneering work by Reetz et al. [53]. Thus, one can see that all phosphine (**43**, **44**) and phosphinite (**53**, **54**) ligands prepared later, possess only a mono phosphorus atom and are suitable for application as monodentate ligands in this reaction.

**Figure 9.** Other helicene-based phosphorus-containing ligands **53**–**55** used for Pd-catalyzed allylic substitution reaction of **50** and subsequent kinetic resolution.

The corresponding enantiopure **53** and **54** were synthesized using the Ni-catalyzed [2 + 2 + 2] cycloaddition reaction of alkyne **56** to give **57** (97%), and the subsequent demethylation and esterification as (1*S*)-camphanate to yield the corresponding diastereomers, **58** and **59**. Further, the separated diastereomers were hydrolyzed with alkali to quantitatively produce the enantiomer **60**, which, on subsequent reaction with chlorodiphenylphosphine in the presence of sodium hydride, resulted in the tetrahydro phosphinite ligand, (*P*)-**53**. For **54**, an additional step of dehydrogenation using triphenylmethylium tetrafluoroborate (Ph3CBF4) was required to obtain the diastereomer **61** (92%), which upon hydrolysis gave [6]helicen-1-ol **62**, which was finally converted to phosphinite **54** with 74% yield (Scheme 7) [52].

**Scheme 7.** Synthesis and optical resolution of **53** and **54** by using the Ni-catalyzed [2 + 2 + 2] cycloaddition reaction as a key step.

Inspired by the difference in the catalytic performance of **43** (94% *ee*) and **44** (71% *ee*) (Scheme 6) in Pd-catalyzed asymmetric allylic alkylation, the same group also applied these ligands in other

Pd-catalyzed reactions. Thus, in further investigation, the dihydrohelicene ligand **43** was found to be highly useful in the asymmetric allylation of indoles **63** with 1,3-diphenylallyl acetate **50** to give the 3-alkylated indole product **64** in up to 99% *ee*, and in the etherification with alcohols **65** to yield **66** in up to 94% *ee* (Scheme 8) [51].

**Scheme 8.** Pd-catalyzed asymmetric allylic substitution reactions of **50** by using (*M*)-helicenoid phosphine ligand **43** (**a**) with indole **63** and (**b**) with alcohols **65**.

In the case of fully aromatic helicene **44**, the ligand was highly effective in the stereocontrol of helical chirality in the Suzuki–Miyaura coupling reaction between bromide derivative **67** and boronic acid **68**, resulting in up to 99% *ee* for chiral biaryl products **69** of (*P*)-helicity (Scheme 9) [51].

**Scheme 9.** Pd-catalyzed asymmetric Suzuki–Miyaura coupling between **67** and **68** using (*P*)-**44** as the helicene phosphine ligand.

These examples (**43** and **44**) clearly show that the helicity and space available in the helical groove suitable for a specific transition state play a vital role in the stereoselective control of the reaction pathway. The DFT-based calculation at the B3PW91/6-31G\* level (LANL2DZ for the Pd atoms) revealed that the transition state with minimum steric repulsions between the helicene backbone and the reactant group is responsible for the (*S*)-configuration products (**52**, **64**, and **66**) and *P*-configuration product (**69**) obtained with high *ee* [51].

Helicene-based ligands have been also successfully investigated for the rhodium-catalyzed asymmetric hydrogenation of alkenes. In fact, the first enantioselective catalysis using helical diphosphane **55** was the asymmetric reduction of itaconate **70** as a model compound under mild conditions using in situ generated (*M*)-**55** and [Rh(cod)2] +BF4 −. This results in the corresponding diester (*S*)-**71** with 54% yield and 39% *ee* product, as reported by Reetz et al. [54] (Scheme 10). The synthesis of **55** is based on photochemical cyclization with subsequent conversion of the corresponding helicenedibromide derivative to phosphine **55**, followed by preparative chiral HPLC

separation of the enantiomers [54]. Yamaguchi et al. improved the yield (up to 100%) and enantioselectivity up to 96% *ee* for (*S*)-**71** using the (*M,M,S,l*)-configuration of the bis-helicenic phosphite ligand **72** [55] (Scheme 10). The excellent output in this reaction obtained with **72** was attributed to the matched (suitable) pair of asymmetries, i.e., two (*M*)-helical and one (*S*)-axial chirality. However, the central chirality derived from the *l*-menthyl part does not have much effect on the reaction *ee* outcome.

**Scheme 10.** Comparative Rh-catalyzed asymmetric hydrogenation of itaconate ester **70** using helicene-based ligands **55** and **72**.

Another approach adopted was to design a helicene with the fused phosphole heterocyclic unit at one of the terminal rings where the phosphorus atom has an additional point chirality, denoted as *SP* or *RP*. A key synthetic step includes the diastereoselective photochemical cyclization reaction of a suitable (*SP* or *RP*) enantiopure phosphole-bearing stilbene derivative **73**. The resulting regioisomeric [6]helicene phosphine oxide **74** and phospha[7]helicene **75** were chromatographically separated with 32% and 28% yield, respectively [56] (Scheme 11).

**Scheme 11.** *Cont.*

**Scheme 11.** Photochemical diastereoselective synthesis of [6]helicene phosphine oxide **74** and phospha[7]helicene **75**.

Subsequently, enantiopure **74** was reduced and in situ reacted with gold(I) salts to generate the phospha-substituted helicene–gold complexes, **76** (*endo*) and **77** (*exo*). In *endo*-**76**, the gold atom occupies the internal chiral cavity space, approaching towards the opposite terminal ring, whereas in *exo-***77**, the gold atom is situated at the external face, being away from the helical moiety. Thus, chromatographically separated *endo*-**76** effectively catalyzes the enantioselective cycloisomerization of N-tethered 1,6-enyne **78** to give bicyclo[4.1.0]heptane **79** with 95% yield and 81% *ee*, whilst *exo*-**77** remained almost inactive [56] (Scheme 12). Meanwhile, various phosphole-containing ligands were also prepared and screened in similar reactions with success [8,9,57].

**Scheme 12.** (**a**) Synthesis of *endo* (*SP*,*P*)-**76** and (**b**) its application as a catalyst for the enantioselective cycloisomerization of N-tethered enyne **78**.

However, at present, the scope of the use of helicenes containing phosphorus functionality appears to be limited towards the metal-catalyzed reactions, as described above. A few other attempted asymmetric reactions such as ketoimine reduction (22% *ee*), addition of thioester to benzaldehyde (22% *ee*), and reductive aldol reaction afforded quite low *ee* values, with tetrathia[6]helicene diphosphine oxides as a Lewis base catalyst [58].

Besides these phosphorus-containing helicenes, heterohelicenes with a nitrogen atom at the innermost 1- or 2-position are also able to provide a chiral cavity suitable for various asymmetric organocatalytic processes, where the nitrogen atom plays a crucial role as a Lewis base or hydrogen-bonding auxiliary. The classical synthetic approach for azahelicenes having a nitrogen atom at the peripheral ring as the pyridine subunit is based on the preparation of the corresponding stilbene derivative followed by the photocyclization reaction.

The first use of a pyridine-based helicene as a chiral organocatalyst for promoting the enantioselective acyl group transfer reaction and kinetic resolution of racemic phenylethanol **80** was reported by Stary et al. in 2009 [59]. The preparation of helicenes **81** and **82** [60] involves the [2 + 2 + 2] cyclotrimerization of regioisomeric aromatic triynes **83** and **84** using a Co(I)-catalyzed reaction as the major synthetic step to obtain tetrahydrohelicenes **85** (82%) and **86** (89%), respectively (Scheme 13). Finally, the MnO2-based oxidation resulted in *rac* aza[6]helicene **81** (65%) and **82** (53%). The optical resolution of helicene **81** was carried out through the diastereomeric salt formation with optically pure (+)-*O*,*O* -dibenzoyl-D-tartaric acid, whereas enantiopure **82** was obtained by separation of the corresponding racemic mixture with chiral HPLC (Scheme 13) [60].

It was found that (+)-(*P*)-1-aza[6]helicene **81** is an ineffective catalyst for this process with <5% yield, as the nitrogen atom at the most sterically congested position has very limited accessibility for the reactant. However, the isomeric (−)-(*M*)-2-aza[6]helicene **82**, due to the easily accessible nitrogen atom position, considerably improved the catalytic performance with 46.9% conversion to **87** and 53.1% *ee* for the unreacted starting alcohol **80** (*R*-configuration) with a selectivity factor of 7 for the corresponding (*S*)-enantiomer (Scheme 14) [59].

**Scheme 13.** Synthesis of azahelicenes **81** and **82** via Co+1-catalyzed [2 + 2 + 2] cyclotrimerization reaction.

**Scheme 14.** Kinetic resolution of *rac*-phenylethanol **80** by (*M*)-**81** and (*M*)-**82**.

This example clearly demonstrates how the suitably tailor-made design of azahelicenes can provide a useful chiral pyridine-based nucleophilic organocatalyst comparable to other enantiopure amine-containing catalysts, whilst possessing different elements of asymmetry. In comparison to pyridine, dimethylaminopyridine (DMAP) and DMAP-containing compounds **88**-**90** [61–64] (Figure 10) are better nucleophilic catalysts for acylation of alcohols due to the enhanced nucleophilicity provided by the electron donating nature of the dimethylamino group at the para position. Thus, (*P*)-helicenoids **88** containing a *p*-dialkyl amino substituent turned out to be a more effective enantiodifferentiating catalyst for the resolution of the (*S*)-enantiomer of racemic **80** with the selectivity factor of 17, in 5 h, as compared to 48 h with a selectivity factor of 7 using (*M*)-**82** as the catalyst.

The helicenoidal DMAP **88** has a nitrogen atom at the 2-position and saturated N-alkyl group, whilst the helicenoid core ensures two additional advantages. Firstly, it enhances the nucleophilicity of the pyridine nitrogen at the 2-position by its electron donating ability (+I effect), and secondly, it increases the conformational flexibility to accommodate reactants inside the helical chiral cavity for efficient enantiodifferentiating processes. The attached ethyl substituents at the central ring of the helical outer core were responsible for increasing the lipophilic character and, thus, the solubility in organic solvents for better performance [61]. The helicenoid DMAP **88** displayed a comparatively higher selectivity factor of 17–116, depending on the structure of the racemic aromatic ethanol. In comparison to **88**, the axially chiral DMAP catalyst **89** [62,63] showed selectivity factors of 12–52 (in ether) [62] and 32–95 (in *t*-amyl alcohol) [63] for enantioresolution of different racemic aromatic ethanols. However, the planar chiral DMAP catalyst **90** [64] displayed the smaller selectivity factor of 8.9–29. It is of note that, with planar chiral DMAP **89**, the acylating agent was acetic anhydride, whereas, in other cases, bulkier isobutyric anhydride was used. Thus, the helical DMAP **88** appears to be highly superior to **90** under similar experimental conditions.

**Figure 10.** Structures of simple dimethylaminopyridine (DMAP) and helically, axially, and planar chiral DMAP catalysts **88**–**90**, respectively.

Indeed, the first use of unsubstituted aza[6]helicene **81** and **82** as an organocatalyst for the kinetic resolution of alcohols rationalized the corresponding steric constraint imposed at the 1-position for a bulky acyl moiety and its subsequent group transfer reaction to *rac*-alcohols. However, the additionally functionalized 1-aza[6]helicene was found to be an effective asymmetric catalyst for various reactions [65,66], probably due to the facile access to reactants in the chiral cavity in the transition state, as demonstrated in the following examples.

The azahelicene-based systems were converted to the corresponding *N*-oxides and investigated for the asymmetric ring opening of epoxides with chloride as a nucleophile. For example, 1-aza[6]helicene-*N*-oxide derivatives **91**–**93** (Schemes 15 and 16) [67] were prepared in the racemic form using a general three-step synthetic methodology, and their enantiomers were resolved over chiral HPLC [67]. The representative synthesis of **93** starts from the benzoquinoline aldehyde unit **94** and corresponding bromo-substituted phosphonium salt **95** in three steps, where the initial step involves the Z-selective Wittig condensation followed by the palladium-catalyzed Stille–Kelly coupling reaction to result in azahelicene **96**. Finally, oxidation with *meta*-chloroperbenzoic acid gave the desired helicene-*N*-oxide **93** with 32–49% yield (Scheme 15).

**Scheme 15.** Representative general synthetic scheme for 1-azahelicene-*N*-oxide **93** using Stille–Kelly coupling reaction.

Then, the enantiopure (*P*)-helical ligands **91**–**93** were screened for the desymmetrization of *meso* epoxide **97** with chloride as a nucleophile to obtain **98** with satisfactory yields and *ee* (Scheme 16) [67].

Similarly, enantiopure helical 2,2 -bipyridine-*N*-monoxide **99** was prepared in two steps from enantiopure **93** with 95% yield (Scheme 17a) and applied as a Lewis base type catalyst for the highly enantioselective reaction between aldehyde, **100**, and allenyltrichlorosilane **101** to obtain enantiomerically enriched homopropargylic alcohol **102** [68]. The reaction displayed high conversion (78–97%) and 74–96% *ee* for various *ortho-* and *para*-substituted aromatic aldehyde derivatives, with 18 examples in total (Scheme 17b). Further, the catalyst **99** can be recovered (~80%) without any loss of activity and selectivity after the reaction, making it highly attractive for industrial application.

**Scheme 16.** Desymmetrization of *meso* epoxide **97** using 1-azahelicene-*N*-oxide **91**–**93** as catalysts.

**Scheme 17.** (**a**) Two-step synthesis of helicene (*P*)-**99** from (*P*)-**93** and (**b**) asymmetric synthesis of (*S*)-propargylic alcohols **102** from aldehyde **100** and allenyltrichlorosilane **101** by using (*P*)-**99** as a catalyst.

The (*S*)-alcohol **102** was the major product with (*P*)-helicene **99** as a catalyst. It was also observed that *ortho*-substituted aldehydes **100** always provided higher *ee* than the corresponding *para*-substituted derivatives, regardless of the functional group attached. This key experimental observation indicated that, out of two possible transition states (Figure 11a,b), in one of them, the hydrogen or substituent at the *ortho* position of aldehyde **100** results in steric clash with catalyst **99**, which is responsible for the stereoselectivity. Thus, the suggested transition state model showed preference for the *Si*-face addition with π-π stacking between the bound aldehyde **100** and the bezofused helicene framework of **99** (Figure 11a), whereas the *Re*-face approach is disfavored due to the steric hindrance in the transition state (Figure 11b), where the reactants **100** and **101** and catalyst **99** are coordinated through the silicon atom. A separate DFT-based computational study also supported this mechanism [69].

**Figure 11.** Proposed transition state models showing preference for (**a**) favorable *Si*-face attack and (**b**) unfavorable *Re*-face attack, with (*P*)-**99** catalyst. The bottom and top parts of the transition state models are marked in blue and black, respectively, whilst the coordinated SiCl2 group with the corresponding bonds are marked in magenta.

Azahelicenes have also been investigated as hydrogen bond donor chiral catalysts. The asymmetric addition of azole nucleophiles to nitroalkenes using various hydrogen bond catalysts is known. In this respect, aminopyridinium salts are also capable of activating nitroalkenes through the hydrogen bond donating ability to the nitro group. For this purpose, aza[6]helicene derivatives **103** and **104**, having a 2-aminopyridinium ring at the peripheral position, have been prepared [70]. Hence, the asymmetric addition of 4,7-dihydroindole **105** to nitrostyrene **106** using chiral (*P*)-helicenes **103** and **104** as catalysts, followed by oxidative aromatization, afforded exclusively β-nitro-indol-2-yl **107** with relatively high yield and *ee* (Scheme 18).

It was observed that the increased bulkiness of the amino group gives a higher *ee*. Thus, the results of (*P*)-**104** in terms of *ee* ratio were as follows for the corresponding R: H (69:31) = Bn (69:31) < *t*-Bu (92:8) = 1-adamantyl (92:8). Further, the yields were noticeably improved from 79% (for the *t*-Bu derivative) to 88% (for the adamantyl derivative) under similar conditions; hence, adamantyl-containing (*P*)-**104** is the optimal organocatalyst for this reaction (see the corresponding results summarized in Scheme 18). Further, the enhanced effectiveness of **104** in comparison with **103** indicates that the benzofused helicene framework affects the *ee* value by covering the space beneath the two hydrogen bonds [70], and is thus similar to the case shown in Figure 11.

Another example of the activation of nitroalkenes via the hydrogen bonding donor characteristics was demonstrated by using aminopyridinium-based (*M*)-[6]helicene **108** in the asymmetric Diels–Alder reaction between cyclopentadienes **109** and nitroethylene **110** to give the cycloadduct product **111** in moderate 30–40% *ee* [71]. A traditional hydrogen bonded catalyst generally requires the complementary donor–acceptor units in both reactants to orient specifically for asymmetric induction in the addition reaction. However, here is a case where one counterpart is a nonfunctionalized cyclopentadiene **109**, unsuitable for hydrogen bonding. Therefore, the (*M*)-helicene catalyst **108** used has a aminopyridinium

peripheral ring which only binds to nitroethylene **110** (dienophile) through the corresponding hydrogen bonding. The stereospecificity of this reaction was achieved in the following manner: the helical backbone of (*M*)-**108** blocks one of the faces of **110**, leaving another face accessible to **109** (diene), hence making the whole reaction enantioselective in nature (Scheme 19).

Most of the successful examples of azahelicenes (**91**–**93**, **99**, **103**, **104**, **108**) as organocatalysts described here have a nitrogen atom at the 1-position of the innermost part of the helicene with additional substituents at the 1- or 2-position to modify the reactivity as well as the helicity (chiral cavity space), to facilitate accessibility of the reactant in a stereospecific manner, and to enhance asymmetric output.

**Scheme 18.** Asymmetric addition reaction between 4,7-dihydroindole **105** and nitrostyrene **106** using chiral (*P*)-helicenes **103** and **104** as hydrogen bond donor catalysts.

**Scheme 19.** (*M*)-helicene **108** as a hydrogen bond catalyst for asymmetric Diels–Alder reaction between cyclopentadiene **109** and nitroethylene **110**.

Carbohelicenes **5** and **6** and heterohelicene **112**, devoid of any functional group, are also able to act as chirality inducers in selected asymmetric reactions. Soai et al. have successfully used electron-rich nonfunctionalized carbohelicenes **5** and **6** [72] and heterohelicene **112** [73] for the nucleophilic addition of diisopropylzinc to electron-deficient pyrimidine-5-carbaldehyde **113**. In this case, the chirality induction was a result of two main reasons. Firstly, the formation of a charge transfer complex between helicenes **5**, **6**, and **112** and the carbonyl group of **113** results in the blocking of one reactive face while another face is left to react. Secondly, the final alcohol product **114** obtained can catalyze this reaction by itself, leading to overall chirality amplification to yield up to 95–99% *ee* (Scheme 20). In all these cases, the use of (*P*)-enantiomers of **5**, **6**, and **112** as catalysts resulted in the (*S*)-configuration of **114**, whereas the (*M*)-enantiomer produced the corresponding *R*-configuration. Further, even carbohelicenes **5** and **6** with a very low *ee* such as 0.13% and 0.54% were also able to act as chiral inducers, ensuring considerable stereospecificity and affording 56% and 60% *ee* of **114**, respectively, as a result of chirality amplification by asymmetric autocatalysis [72].

This is an interesting example where chiral inducers with a very low *ee* generate significantly enhanced *ee* of the product. This type of chiral amplification is a "soldiers-and-sergeant" principle and often observable in the field of supramolecular chirogenesis [1]. However, this scope appears to be limited in the case of asymmetric autocatalysis.

Indeed, the asymmetric nucleophilic addition of an organozinc compound to the carbonyl group has been mainly investigated with the use of biaryl-based systems such as BINOL and 2,2 -Diphenyl-(4-biphenanthrol)—axially chiral diol systems capable of coordinating to Lewis acids. Inspired by this, Katz et al. developed the bis[5]helicene-based diol system ([5]HELOL) **115**, which contains two identical units of (*P*)-[5]helicene-1-ol **116** connected by a single biaryl bond at the 2-position. Interestingly, the hydroxyl group is attached at the 1-position (the innermost position of [5]helicene), which makes **116** configurationally stable, and hence provides increased steric hindrance for racemization. The HELOL **115** was synthesized in a total of eight steps on the multigram scale with an overall 44% yield (Scheme 21a) [74]. The helicene backbone **117** was synthesized by Diels–Alder reaction between protected enol ether **118** and quinone **119**. The enantiopure (*P*)-[5]helicene-1-ol **116** was oxidatively coupled using Ag2O, to selectively give (*P*,*P*)-[5]HELOL **115**, with only ~2% of the *meso* isomer. The energy barrier for the racemization of **<sup>115</sup>** (ΔH‡ = 106 ± 3 kJ mol−<sup>1</sup> and <sup>Δ</sup>S‡ <sup>=</sup> −10.0 ± 0.1 J mol−<sup>1</sup> <sup>K</sup>−1) as determined by 1H NMR was found to be even higher than that of (*P*)-[5]helicene **<sup>116</sup>** (ΔH‡ = 95.8 kJ mol−<sup>1</sup> and <sup>Δ</sup>S‡ <sup>=</sup> −17.2 J mol−<sup>1</sup> <sup>K</sup>−1) [74] with the optical rotation value of +2580 in acetonitrile (*c* = 0.01 M). Further, the thermal racemization at 45 ◦C did not occur in 72 h as indicated by circular dichroism (CD) spectroscopy. Additionally, in degassed acetonitrile solution, it was configurationally stable for six days at room temperature as also analyzed by CD measurement. The enantiomeric stability toward conversion to the *meso* isomer and racemization made it a suitable candidate for screening in asymmetric catalysis.

The catalyst **115** was screened for diethylzinc addition to a series of aromatic aldehydes **100**. However, for appreciable catalytic activity, catalyst loading as high as 50 mol% was needed to obtain moderate to good *ee* values of the alcohol products (*S*)-**119** (Scheme 21b). Under similar conditions, the (*R*)-(+)-BINOL gave lower yield (56%) and *ee* (34%) for (*R*)-**119** in comparison to (*P,P*)-(+)-HELOL **115** giving (*S*)-**119** (93% yield, 81% *ee*). This high and opposite stereospecificity is apparently due to a greater steric hindrance of HELOL **115** in comparison to BINOL upon chelation of the zinc atom of the reactant diethyl zinc. Additionally, this crowding in **115** is also able to prevent the phenomenon of zinc–oxygen coordination-based aggregation, responsible for catalyst deactivation, making **115** comparatively more reactive than BINOL [74]. Further, the opposite stereochemical outcome of alcohol products **119** obtained with (*P*,*P*)-(+)-[5]HELOL **115** as a catalyst and (*R*)-(+)-BINOL as catalyst is in accordance with the stereochemistry of the biaryl bond present in HELOL **115**, which appears to be of (*S*)-configuration (see structure **115** in Scheme 21a).

Whilst unsubstituted [4]helicene **4** is a planar and achiral structure, the introduction of two methyl groups on both the peripheral rings at the innermost positions gives rise to a helical structure with configurational stability. In this respect, Yamaguchi et al. have extensively explored the synthetic chemistry and applications of functionalized dimethyl[4]helicene in different fields [75]. Thus, (*P,P*)-[4]helicene cycloamides **120**–**122** were prepared from well-known *rac*-diketone **123** via dicyanohelicene **124**, which was converted to helicene diacid **125** by alkaline hydrolysis. Then, helicene diaicid **125** was resolved by using the chiral base quinine through diastereomeric salt formation. Finally, (*P*)-**125** was converted to acid chloride and then coupled with a suitable diamine linker **126** to obtain cycloamides dimer **120** (24%), trimer **121** (23%), and tetramer **122** (19%) (Scheme 22) [76].

**Scheme 20.** Asymmetric autocatalysis initiated by carbohelicenes (*P*)-**5**, (*P*)-**6**, and heterohelicene (*P*)-**112**.

**Scheme 21.** (**a**) Synthesis of (*P*,*P*)-HELOL **115** and (**b**) its application in asymmetric diethyl zinc addition to benzaldehydes **100**.

**Scheme 22.** Synthesis of (*P,P*)-helicene cycloamides **120**–**122** from diketone **123**.

Interestingly, in this example, the functionalized amino groups are present at the outer core of the helicene but not at the helical chiral cavity as in previous examples; this makes it remarkably different. Yet, when it is dimerized with a suitable linker such as cycloamide **120**, the chirality of the helicene is transferred to a macrocycloamide, which essentially provides a chiral pocket for the asymmetric catalytic transformations. Macrocycloamides such as (*P*,*P*)-**120** have been applied for the asymmetric nucleophilic addition of diethyl zinc to aromatic aldehydes **100** with good yields (51–88%) and moderate enantioselectivities (27–50% *ee*) upon use of up to 5 mol % catalyst (Scheme 23) [76].

**Scheme 23.** (*P,P*)-helicene cycloamide dimer **120** catalyzed asymmetric diethyl zinc addition to aromatic aldehydes **100**.

It has been clearly demonstrated that helicene-based asymmetric organocatalysis is a highly promising and exciting field in terms of the enantioselectivity obtained with the lowest catalyst loading. Thus, this area of chemistry has exciting prospects to explore other well-known asymmetric reactions by using helicenes as organocatalysts, with foreseen advances in terms of the *ee* values in comparison

to conventional organocatalysts. For the most asymmetric organocatalysts, it is possible to design and develop helicene-based helical counterparts which are expected to give improved reactivity and stereoselectivity. However, the design of smart catalysts and their multigram synthesis in the enantiopure form still remain a major challenge to further investigations.

#### **7. Helicene in Supramolecular Chirogenesis**

Besides asymmetric catalysis, helicenes are efficiently used in a modern branch of chiral science called supramolecular chirogenesis, which covers all aspects of asymmetry induction, transfer, amplification, and modulation through noncovalent interactions. In numerous chromophoric systems [1] available to date, helicenes are also successfully employed. Indeed, helicenes have turned out to be one of the most attractive chromophores, which are suitable for several chirogenic applications including chiral recognition, sensors, and self-assembly, and are applicable to various areas ranging from classical solution chemistry, nanoparticles, and polymers, up to the sensing of biologically relevant molecules. Owing to their conjugated aromaticity, these chromophoric systems can be conveniently studied by diverse spectroscopic methods, such as UV, fluorescence, NMR, CD, etc., which are described below with selected examples.

#### *7.1. Helicene-Based Chiral Recognition of Small Molecules*

Since chirality is an essential part of life on Earth, its recognition and sensing play a vital role in such important fields of human activity as scientific research and modern technologies. Therefore, various methods of obtaining enantiopure molecules by optical resolution and by asymmetric synthesis are attractive areas of chemical research. Besides preparation, the analysis of all types of chiral molecules is also an equally important part of physical–organic chemistry. So far, existing analytical methods are based on the enantiodifferentiation procedure conventionally performed by using chiral HPLC, NMR, fluorescence, and CD techniques. In this respect, chiral helicenes are highly prospective host molecules to serve as specific chirality sensors.

One of the first reports of such an application was published in 2001 by Reetz et al. [77]. To this end, 2,5-dihydroxy[6]helicene **127** (HELIXOL) was prepared for chiral recognition of amines **128**–**131** and amino alcohols **132**–**135** by using fluorescence as a detection tool (Scheme 24). The synthetic strategy includes classical Wittig olefination and photochemical cyclization steps. The condensation of **136** with **137** gives cyclic **138**, ether linkage of which ensures structural control during the double photocyclization reaction to obtain helicene cyclophane **139**. The chiral HPLC separation of racemic **139**, followed by the deprotection of the ether group using BBr3, affords enantiopure HELIXOL **127** (Scheme 24).

It was found that the host **127** served as an excellent fluorescent sensor, able to display enantioselective quenching by several amines and amino alcohols through the hydrogen bonding interactions. The best results were obtained for alaninol **133** with enantioselective factor α = K*R*/K*<sup>S</sup>* = 2.1 upon using the levorotary (*M*)-**127**. Although the results obtained with **127** for chirality sensing are moderate, this work is a pioneering contribution for the use of helicenes for the purpose of chirality sensing. Further studies have demonstrated that this new, emerging area is challenging and highly prospective in chemical sciences.

Meanwhile, HELIXOL **127** is a bidentate compound with two hydrogen bonding units (phenolic groups) in the chiral space cavity, which can be used for stereodiscriminating recognition (Figure 8). Thus, it was assumed that amino alcohols may form the corresponding 1:1 host–guest complex, resulting in stronger fluorescence quenching than amines. Indeed, the best result among amines and amino alcohols was obtained for alaninol **133** due to the optimal steric matching in the chiral space available, while displaying the strongest fluorescence quenching output.

Another approach was demonstrated by the application of crown ether-based systems, which are known to bind various cations ranging from metal ions to organic ammonium ions. Hence, the helicene-based crown ethers **140** and **141** were firstly prepared in 1983 by using 1,14-dimethyl pentahelicene and heptahelicene backbones [78,79]. The synthesis was performed by a classical strategy via Wittig condensation followed by photochemical cyclization. Finally, the construction of crown ethers and subsequent resolution of enantiomers using a chiral column packed with (+)-poly-(triphenylmethyl methacrylate) with methanol as an eluting solvent resulted in enantiomers of **140** and **141**. Then, enantiopure **140** and **141** were investigated towards application in the chiral discrimination of racemic amine salts **142**–**144** (Figure 12). This process was based on the selective differential transports of recognizable enantiomers from an aqueous solution to the corresponding organic solvent (CHCl3) by a liquid–liquid extraction procedure. The 1H NMR analysis of the extracted organic layer displayed two distinct –CO2Me signals of the representing diastereoisomeric complexes with the guest, **142**. Finally, the amount of transported guest was analyzed by a reverse extraction back to an aqueous acidic phase followed by the measurement of its UV absorption.

**Scheme 24.** (**a**) Synthesis and resolution of HELIXOL host, **127**; (**b**) Structures of chiral guest amines **128**–**131** and amino alcohols **132**–**135** used for enantioselective recognition studies.

**Figure 12.** [5]helicene- and [6]helicene-bearing crown ethers **140** and **141** capable of enantioselective extraction of chiral amine salts **142**–**144** from aqueous to organic layer.

It was observed that the [5]helicene-based crown ether **140** showed higher enantioselective extracting ability than the [6]helicene-based crown ether **141**. For example, (*M*)-**140** was able to transport 6% of (*S*)-**142**, with optical purity of 75% in 6 h, comparatively better than (*M*)-**141** with 2% transport of 26% optical purity of opposite enantiomer (*R*)-**142** in the same time. The observed opposite enantioselectivity extraction using helicenes **140** and **141** with the same helical sense was rationalized by the phenomenon of changing the crown ether conformation [80]; this is evident in their CPK models. Additionally, the inner methyl groups also assist in the chiral recognition process, as suggested by the same models [78,79].

Another approach to chiral recognition was undertaken by Katz et al. via developing the helicenebased biaryl diol compound named (*M,M*)-[5]HELOL, **115** [81], which was based on enantiopure 1-hydroxy substituted [5]helicene (see **116** in Scheme 20). The in situ generated chloro phosphite derivative **145** was used as a chiral NMR derivatizing agent to discriminate alcohols or amines serving as nucleophilic guests. From the 31P NMR analysis of diastereomeric mixture **146**, the enantiomeric excess of guests (alcohols or amines) was easily determined. An interesting feature of this sensor is its ability to sense a remote chirality, which locates far away from the phosphite group. This is related to the fact that the combined inner cavity formed by individual helicene units and the biaryl bond yields an extended chiral space in **115**. For example, this chiral space is able to recognize the asymmetric centers of 8-phenylnonanol **147** (as far as up to seven methylene units) and vitamin E **148** (Scheme 25). Additionally, the recognition ability of this sensor was related to 100% abundance of phosphorus as NMR active nuclei with high sensitivity and accuracy in measurement; thus, the enantiomeric excess of up to 3% can be easily analyzed [81]. The scope of this HELOL host and its structural analogue were further extended towards other nucleophiles such as alcohols, phenols, amines, and carboxylic acids, also containing a remote chirality, under similar methodology to the 31P NMR-based enantiodiscrimination [82].

**Scheme 25.** (**a**) 31P based diastereomeric NMR sensing of alcohols and amines using (*M,M*)-HELOL **115** and (**b**) examples of remote chirality sensing with molecules **147** and **148**.

A new chiral application as a chiroptical switch along with chiral recognition properties was demonstrated using enantiomerically pure [6]helicene *o*-quinone **149**. The synthesis was carried out by using the Nickel-catalyzed [2 + 2 + 2] cyclotrimerization reaction of triyne **150**, followed by the deprotection of the methoxy group in **151** to result in helicene diol **152** in a racemic form. The enantiomers of **152** were separated on chiral HPLC, followed by the silver oxide-mediated oxidation, to give the quinone **149** in quantitative yield (Scheme 26) [83].

In general, quinones are electrochemically redox active molecules which undergo reduction as diol anions and re-oxidation back to quinone, with the corresponding measurable structural transformations in chromophoric absorption (Figure 13a). Therefore, the helicene-based quinone **149** was also tested for the same, with an additional possibility of chiroptical switching as observed by CD measurement. Both the enantiomers of **149** exhibited a one-electron reduction process to form the semiquinone radical anions, **<sup>149</sup>** <sup>−</sup>, as evident from cyclic voltammetry studies with E1/2 <sup>=</sup> −1.00 V (vs Fc+/0, <sup>Δ</sup>Ep = 0.07 V) in acetonitrile, with a reversible electrochemical behavior. Since **149** − is a stable species, its UV and CD measurements were performed by using an optically transparent thin layer electrochemical cell. It was observed that the helicene quinone **149** is able to be reversibly reduced to the radical anion **149** − and re-oxidized over several cycles, and is an example of chiroptical switching to be conveniently monitored with CD spectroscopy at different wavelengths (Figure 13b) owing to the distinguishable spectral profiles of **149** and **149** −. However, as there is no change in the (*P*) or (*M*) helicity of the chromophore upon electrochemical transformations, the Cotton effect (CE) signs of **149** and **149** − remained the same.

Besides electrochemical switching, **149** − was tested for chiral recognition against 2,2 bis(diphenylphosphanyl)-1,1 -binaphthyldioxide (BINAPO) using electron paramagnetic resonance and electron–nuclear double resonance (ENDOR) spectroscopy. The diastereomeric species formed by coordinated lithiated semiquinone radical anions [Li+{(±)-**149** <sup>−</sup>}] and enantiomers of BINAPO generated noticeable changes of the lithium and proton hyperfine coupling measured by ENDOR spectroscopy. The diastereoisomeric complex **153** exhibits a hyperfine coupling constant (A) value for 7Li at −1.62 MHz, in comparison to −1.76 MHz for another diastereomeric complex **<sup>154</sup>**, indicating the appreciable difference between the diastereomers (Figure 14). It is of note that the racemic sample gives an average value of −1.69 MHz.

**Scheme 26.** Synthesis and resolution of helicene quinone **149** from triyne **150** using the nickel-catalyzed [2 + 2 + 2] cyclotrimerization reaction as a key step.

**Figure 13.** (**a**) Mechanism of reversible electrochemical switching of helicene quinone **149** to helicene semiquinone radical anions **149** −; (**b**) observed reversible chiroptical switching between **149** and **149** −; monitored by CD spectroscopy in acetonitrile. Reversible electrochemical switching for several cycles is shown for the (*M*)-(−) enantiomer at two different wavelengths (top right) along with the corresponding CD spectra. (Figure 13b) reprinted from [83]. © 2014, American Chemical Society.

**Figure 14.** ENDOR spectra of diastereomeric species, **153** (black) and **154** (red) in THF at 210 K, only the low-frequency region is shown. Reprinted from [83]. © 2014, American Chemical Society.

The previously described examples, **127** [77] and **115** [81], represent the inbuilt chiral helicene chromophoric hosts for the chiral recognition of a general class of chiral molecules using some selected analytical techniques such as fluorescence and NMR spectroscopy. An essentially different approach has been recently developed by Karnik et al. on the basis of a new supramolecular chirogenic system, **155**, the key element of which was a stereodynamic dioxa[6]helicene diol **156** chromophore. This system was applied as a specific sensor, suitable for chirality sensing of *trans*-1,2-cyclohexanediamine **157** and monitored by various spectroscopic methods [84]. The helicene **156** was synthesized from 2,7-dihydroxynaphthalene **158** [85]. The first step involved acid-catalyzed condensation between two molecules of **158** and glyoxal to obtain dihydrofurofuran **159** (>95%), followed by the protection of phenolic groups to give acetate **160** (95%). Then, one-pot benzylic bromination and dehydrobromination (aromatization) of **160** using *N*-bromosuccinamide led to **161** (45%), followed by basic hydrolysis resulting in dioxa[6]helicene diol **156** (96%). Finally, selective mono esterification with chiral (1*S*)-camphanic chloride in acetone afforded the desired host, **155**, with 90% yield (Scheme 27) [85].

**Scheme 27.** Multistep synthesis of helicene camphanate **155** from 2,7-dihydroxynaphthalene **158**.

Indeed, the parent dioxa[6]helicene diol **156** is almost a flat stereodynamic-type fluorescent compound, which was selectively modified with a chiral (1*S*)-camphanate group to give **155**, leaving one of the (phenolic) hydroxyl groups free. This inherently free phenolic group and (1*S*)-camphanate chiral handle on the opposite peripheral ring provided a suitable *sui generis* chiral space for guest **157**. In particular, this perfect stereospecific matching results in an effective turn-on fluorescent sensor for the (*S,S*)-enantiomer of **157** with a relatively high enantioselective factor, α = K*SS*/K*RR* = 6.3 (in benzene). The favorable hydrogen-bonding interactions in nonpolar media (benzene and toluene) are responsible for the efficient chiral recognition observed by fluorescence spectroscopy (Figure 15a,b). In nonpolar media, the donor–acceptor type cooperative hydrogen bonding between host **155** and guest **157** (Figure 15c) resulted in a high turn-on enantioselective fluorescence response. The enantiodiscrimination behavior was found to be solvent-dependent as the polarity of solvent can influence the extent of hydrogen bonding between the host and guest. In turn, this induces a unidirectional switch in the helical conformation of the helicene chromophore, resulting in reverse selectivity for the (*R,R*)-enantiomer of **157** in acetonitrile, THF, and chloroform [84].

Further, the NMR studies performed in deuterated chloroform exhibited the chiral camphanate group transfer reaction (Scheme 28a) with the reaction rate of 5.83 × <sup>10</sup>−<sup>6</sup> and 5.97 × <sup>10</sup>−<sup>7</sup> mol dm−<sup>3</sup> <sup>s</sup>−<sup>1</sup> for (*R,R*)-**157** and (*S,S*)-**157**, respectively, as monitored by 1H NMR (Figure 15d). This tenfold increase of the reaction rate for the (*R,R*)-enantiomer allowed the host **155** to behave as a kinetic resolving agent for (*R,R*)-**157**, with up to 68% *de* at room temperature within 4 h (Figure 15d) [84].

**Figure 15.** Fluorescence response of helicene camphanate **155** for *trans*-1,2-cyclohexanediamine **157** (**a**) in benzene and (**b**) in toluene solvent; (**c**) Schematic representation of the donor–acceptor hydrogen bonding between **155** and **157** in nonpolar solvent with turn-on fluorescence response; (**d**) Time-dependent changes observed in 1H NMR spectra of host **155** with 1:1 (*R,R*)-**157** in CDCl3. Reprinted from [84]. Source: http://pubs.acs.org/doi/abs/10.1021/acsomega.6b00522.

Indeed, this is a rare example of the *sui generic* host–guest pair as evident from the fact that diamine **157**, upon supramolecular interaction with the parent stereodynamic helicene diol **156** (Scheme 28b) is able to induce a specific helicity and shift the stereodynamic equilibrium of **156**, as monitored by CD spectroscopy in the region of helicene chromophore absorption.

Further, the same group also developed *Cs*-symmetric rigid achiral organophosphoric acid **163** in two steps, starting from dihyrofurofuran helicene **159** as a supramolecular chirogenic system for the absolute configuration determination of 1,2-amino alcohols by induced CD (ICD) studies [86]. The two-step synthesis includes the reaction of dihyrofurofuran helicene **159** with formaldehyde to form an additionally bridged diol, **164**, and subsequent reaction with POCl3 to obtain the target, **163** (Scheme 29).

**Scheme 28.** (**a**) Chiral group transfer reaction between **155** and (*R,R*)-**157** in chloroform and (**b**) proposed shift in conformational dynamic equilibrium of **156** in the presence of (*R,R*)-**157** in chloroform.

**Scheme 29.** Synthesis of **163** from dihyrofurofuran helicene **159**.

Interestingly, due to the *Cs*-symmetric nature of phosphoric acid, **163** has two tautomeric structures. This structural feature of **163**, in combination with the substituent bulkiness of the guest amino alcohols, together decide the preferred mode of two-point hydrogen bonding on equilibration, which gave a resultant ICD signal correlating with the absolute configuration of the guest [86].

#### *7.2. Polymeric Helicene-Based Chiral Recognition*

Polymer chains can also serve as suitable carriers for chiral helicenes, especially in the case of prospective applications. Thus, using 2-acetylene-[6]helicene **165**, Yashima et al. prepared a series of polymeric helicene pendants, poly-1-**166**, via the rhodium-catalyzed polymerization reaction (Scheme 30) [87]. This polymerization reaction gave stereoregular (*cis-transoidal*) polyacetylenes bearing the corresponding helicene pendants **166** with (*P*)- and (*M*)-polymeric chains with average molecular weight *<sup>M</sup>*<sup>n</sup> = 2.6 × <sup>10</sup>3. However, the formation of a precipitate during the reaction makes it difficult to reproduce. The careful analysis of the CD spectra of monomer **165** and polymers **166**, and their corresponding differential CD spectra, suggests that the helical polyacetylenes with the optically active pendant group exist as a single-handed structure, apparently due to the attractive intramolecular π-π interactions.

**Scheme 30.** (**a**) One step synthesis of polymeric helicene **166** and (**b**) its application against enantioselective adsorption of racemic guests **165**, **167**, and **168**.

The chiral recognition abilities of these polymers were studied in the context of the enantioselective adsorption of three racemic guests, namely, parent helicene **165**, BINOL **167**, and 2,2 -dibromo-binaphthalene **168**. The enantiomers were adsorbed by the polymer in methanol solution and desorbed in a mixture of methanol/THF [1:1, *v*/*v*] followed by chiral HPLC analysis. The poly-1-(*P*)-**166** preferentially adsorbed (*P*)-helicene **165** with 3.6% *ee*; both have similar configurations. As expected, in the case of **166** with opposite absolute configuration, the adsorption preference was observed for (*M*)-helicene **165** with a similar 3.7% *ee*. However, interesting results were obtained for binaphthyl derivatives **167** and **168**, where poly-1-(*P*)-**166** selectively adsorbed the opposite (*S*)-enantiomers with up to 36% *ee*, whilst poly-1-(*M*)-**166** showed similar selectivity towards the (*R*)-enantiomers of **167** and **168**. The calculated separation factor was sufficiently high (1.71–2.18), indicating that these polymers can be used as a stationary phase for the practical separation of racemic mixtures.

#### *7.3. Helicene-Based Chiral Recognition via Nanoparticles*

Another prospective approach for chiral recognition by helicene structures is based on nanomaterials. In this respect, individually racemic, (*P*)-, and (*M*)-helicene thiols **169** were grafted onto gold nanoparticles of 5–22 nm [88] in a mixture of ethanol/water (1:3, *v/v*) under sonication to form the corresponding Au-(*P*/*M*)-, (*P*)-, and (*M*)-**169**-nanoparticles (helicene-grafted nanoparticles) (Figure 16). These helicene-based nanoparticles show chirality-based inter(nano)molecular attractive interaction, resulting in the corresponding aggregation phenomenon followed by a time-dependent precipitation process, as analyzed by UV spectroscopy. All three types of nanoparticles dispersed in DMF gave a stable solution for a period of one week. The addition of the DMF solutions to an aromatic solvent such as benzonitrile resulted in different colors due to the surface plasmonic bands of the gold nanoparticles, as studied by UV–vis spectroscopy and a dynamic light scattering technique. Additionally, the time-dependent aggregates were of different sizes, based on the type of helicene nanoparticles present. The observed chiral recognition induced by the homo- (Au-(*P*/*M*)-**169** nanoparticle : Au-(*P*/*M*)-**169** nanoparticle, Au-(*P*)-**169** nanoparticle : Au-(*P*)-**169** nanoparticle, and Au-(*M*)-**169** nanoparticle : Au-(*M*)-**169** nanoparticle) and hetero self-aggregation (Au-(*M*)-**169** nanoparticle : Au-(*P*)-**169** nanoparticle) of the helicene nanoparticles was found to be enhanced according to the following sequence: Au-(*P*/*M*)-**169** nanoparticle : Au-(*P*/*M*)-**169** nanoparticle < Au-(*M*)-**169** nanoparticle : Au-(*M*)-**169** nanoparticle = Au-(*P*)-**169** nanoparticle : Au-(*P*)-**169** nanoparticle < Au-(*P*)-**169** nanoparticle : Au-(*M*)-**169** nanoparticle. This tendency relates to the interaction strength between the corresponding nanoparticles, which is controlled by stereochemical matching.

Another example of optically active nanoparticles **170** with 70 nm diameter size was obtained by grafting (*P*)-1,12-dimethyl-8-methoxycarbonylbenzo[c]phenanthrene-5-carboxyamide on 3-aminopropylated silica (Figure 17) [89,90]. These nanoparticles were prepared by reacting 3-aminopropylated silica nanoparticles with the corresponding (*P*)-helicene carboxylic acid chloride by refluxing in isopropyl ether for 4 hours using ethyldiisopropylamine as a base.

**Figure 16.** Enantiomeric structures of helicene thiol **169** and representations of the gold nanoparticles formed from **169**. Modified and reprinted, with permission from [88] © 2012, Royal Society of Chemistry.

It was found that these nanoparticles enantioselectively precipitated at a faster speed with (*S*)-configuration of aryl alcohols **80** (47% *ee*) and **171** (61% *ee*) [89] in *m*-bis(trifluoromethyl)benzene (Figure 17). To elucidate the corresponding *ee* values, the precipitate was centrifuged and separated, followed by mixing in 2-propanol. Then, the insoluble material (nanoparticles) was removed and the organic layer was concentrated and analyzed with chiral HPLC, indicating the optical resolution of up to 29–61% *ee* for various aromatic alcohols for the (*S*)-configuration [89]. The mechanism of this stereoselectivity was related to chiral recognition on the basis of the electrostatic aggregation phenomenon. This nanoparticle-based kinetic resolution requires a relatively smaller amount (10 mol %) of **-**nanoparticles **170** as the resolving agent compared with the requirement of conventional 0.5 equivalence, with providing additional possibility for resolving noncrystalline substances, making it an attractive and greener method of choice.

Further, the helicene-based nanoparticles **170** were able to recognize the shape of (*P*)-ethynylhelicene oligomers **172** in solution [90]. It preferentially forms the precipitate with a double helix of the oligomeric structure of **172** in comparison to its random coil structure in trifluoromethylbenzene (Figure 17). The analysis was carried out by CD spectroscopy, where the double helix oligomer shows a strong positive CE followed by a negative one, whilst in the case of the random coil oligomer, a weak CE of opposite sign was observed. This phenomenon was related to the chiral shape recognition on the surface of the nanoparticle by stereospecific absorption, resulting in the visualized selective aggregation-based precipitation, which is useful for the separation of the double helix structure of **172** from its random coil conformation [90]. These examples clearly show the potential of helicene-based chiral nanomaterials for applications in the resolution of chiral molecules ranging from a simple alcohol to complex polymeric structures.

**Figure 17.** Helicene silica nanoparticle **170** and its ability towards chiral recognition and resolution of aromatic alcohol **80** and **171** and double helix oligomer **172**.

#### *7.4. Helicene-Based Chiral Recognition Involving Biologically Relevant Molecules*

The stereodynamic helicenes are also effectively employed for the induced CD-based sensing, where a chiral guest can induce a specific helicity via covalent or supramolecular interactions, thus generating the corresponding CD signals in the helicene absorption region. The guests range from simple organic molecules (Scheme 28b) to complicated biological molecules, as described here.

Thus, Yamada's group explored hydroxymethyl trithia[5]helicene **173** [91–96], which is a stereodynamic compound. Both the (*P*)- and (*M*)-enantiomeric structures are configurationally labile, nonresolvable, and exist in a fast equilibrium. However, due to the presence of an electron-rich aromatic chromophore and polar hydroxymethyl group capable of hydrogen bonding, suitable complexation of the chiral guest (such as biomolecules) [91,93–96] is able to shift the equilibria to one of unidirectional helicity, which, in turn, can be monitored by CD spectroscopy (Figure 18).

**Figure 18.** Stereodynamic hydroxymethyl trithia[5]helicene **173** and a principle of its use as an induced CD host.

The corresponding host–guest studies were successfully implemented with serum albumin [91], (*R*)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy)propionic acid (TAPA) [92], alkyl b-D-pyranoside [93], and bilayered phosphatidylcholine vesicles [94–96] using CD spectroscopy as a major tool. As the extent of helicity induced in **173** by these guest molecules is small, the resultant CD signals are also small. Yet, as CD is a highly sensitive technique, even with a small signal, it can be applied for understanding molecular behavior and chirality in solution.

Tanaka et al. synthesized bis(hydroxymethyl)thia[7]helicene **174** to study its further synthetic chemistry and corresponding applications in the chirality recognition of biological molecules [97–100]. Hence, the helicene **174** was synthesized in a total of nine steps with an overall 33% yield, where the

photochemical cyclization of alkene **175** was a key step to give silyl group protected *rac*-**176**. Further, deprotected racemic **174** was optically separated using the lipase-based enzymatic kinetic resolution method. For example, with the use of *Pseudomonas cepacia* enzyme, (*P*)-**174** (44%, 98% *ee*) was obtained as a slow reactive isomer with simultaneous formation of the corresponding mono- and diacetates, (*M*)-**177** and (*M*)-**178**. Similarly, the use of *Candida antarctica* enzyme resolved opposite (*M*)-**174** (44%, 92% *ee*) with the formation of mono- and diacetates, (*P*)-**177** and (*P*)-**178** (Scheme 31) [97].

**Scheme 31.** Photochemical synthesis and enzymatic resolution of helicene **174**; (**a**) *hv*, I2, propylene oxide, benzene, room temperature; (**b**) tetra-*n*-butylammonium fluoride, THF, 0 ◦C; (**c**) *Pseudomonas cepacia*, CH2Cl2, vinyl acetate, room temprature, 25 h; (**d**) *Candida antarctica*, CH2Cl2, vinyl acetate, 28–29 ◦C, 9.5 h.

Further, enantiopure alcohol **174** was converted to its dichloride **179**, which was converted to **180** [98] and cyclic thia ethers **181**–**183** [99] using suitable synthetic procedures (Scheme 32). These helicene molecules were explored in terms of possible chiral recognition of biologically relevant molecules such as DNA [98,100].

It is well known that, under physiological conditions, a DNA duplex exists as a mixture of the right-handed B-DNA and left-handed Z-DNA forms. The supramolecular association of chiral *C2*-symmetrical **180** with DNA revealed that the (*P*)-enantiomer of **180** displays chiral selection for binding Z-DNA over B-DNA [98]. The corresponding binding constants were found to be (8.0 ± 0.5) × <sup>10</sup><sup>4</sup> <sup>M</sup>−<sup>1</sup> and (1.4 ± 0.3) × 104 <sup>M</sup>−<sup>1</sup> for Z- and B-DNA, as measured by fluorescence titration. Besides, this interaction can be clearly monitored with CD spectroscopy, where, upon binding Z-DNA, there is a considerable decrease in the signal intensity of (*P*)-**180** of up to 70% at 330 nm at neutral pH. Under similar conditions, B-DNA failed to show any significant change in the CD spectra of (*P*)-**180**, indicating (*P*)-helicity-based recognition of Z-DNA. In contrast, although the (*M*)-**180** also showed a 20% reduction, it was observed upon binding both B- and Z-DNA, thus indicating the lack of its discrimination ability.

**Scheme 32.** Synthesis of functionalized helicene **180** and thiaethers **181**–**183** from [7]helicene **174**.

Additionally, it was observed that the (*P*)-**180** not only selectively binds Z-DNA but is also able to force B-DNA to adopt an opposite left-handed helical form, like Z-DNA. Apparently, the methylene-*N*,*N*-dimethylamine functionality in (*P*)-**180** plays a crucial role in this behavior, as the same helicene backbone but with hydroxy methyl substituents, as in the case of **174**, did not show any binding response towards B- and Z-DNA. It is likely that the protonated form of amino substituents in **180** becomes a crucial site for binding DNA, whilst the helicene chirality is an important factor in the enantioselective recognition of left-handed helical Z-DNA.

Further extending the chiral recognition research of biologically important molecules resulted in the development of cyclic helicenes with thiaether linkage, **181**–**183** (Scheme 32) [99,100]. The (*M*)-enantiomers of **181**–**183** turned out to be potential inhibitors against telomerase enzyme activity based on the chiral and steric matching, while binding to the G-quadruplex superhelix structure. The recognition phenomenon is based on the chiral space available at the cleft-pocket and the presence of Z-DNA assisting this helicene binding. Initially, **180** was studied and exhibited no chiral selectivity. This result led to the assumption that the dihedral angle in helicene chromophores plays a key role in the interaction efficiency. On this basis, three different cyclic helicene thiaethers, **181**–**183**, having different length of linkers, were designed to yield the dihedral angles of 22◦, 53◦, and 58◦, respectively.

It was shown that the (*M*)-enantiomer of **181** with the smallest interplanar angle was able to inhibit the telomerase enzyme activity efficiently, presumably as a result of the chiral and steric matching. However, the exact binding mode of this helicene to the G-quadruplexes is not fully understood yet. Here, again, the binding studies relied on CD and fluorescence spectroscopy [100].

In 2013, chiral [5]helicene **184**, containing methyl groups at the innermost positions, was suitably connected with the spermine moiety **185** at the outer sphere of the helicene backbone to act as a host capable of recognizing the DNA conformation [101]. This host was synthesized by the Suzuki–Miyaura coupling of 8-methylnaphthalene-2-boronic acid **186** with dibromo-maleimide **187** to obtain **188**, followed by photocyclization to result in racemic **189** with 92% yield. The enantiomers of **189** were separated on a chiral column followed by further transformation to **190** and, finally, to the target enantiopure **184** (Scheme 33) [101].

**Scheme 33.** Synthesis of helicene-spermine **184**.

The designing concept was such that the cationic spermine unit is able to provide the corresponding electrostatic interactions with the DNA's phosphate backbone of the minor groove, whereas the chiral helicene is expected to form end-stacking mode complexes, altogether resulting in a strong chiral recognition. Indeed, it was demonstrated that (*P*)-**184** binds preferentially to B-DNA over Z-DNA. The opposite trend was observed with (*M*)-**184**, which displayed strong binding for Z-DNA over B-DNA, as studied by performing CD, UV melting temperature, surface plasmon resonance measurements, and isothermal titration calorimetry. From the examples of **180** [98] and **184** [101], it appears that the cationic functional groups assist in binding with DNA through electrostatic interactions; along with this, the chiral helicity-based steric fit allows selectivity. The (*P*)-**180** prefers Z-DNA, whereas in the case of **184**, the (*M*)-enantiomer binds strongly to Z-DNA. As structures, tetrathia[7]helicene **180** having functional groups on the terminal rings (in chiral cavity space) and 1,14-dimethyl[5]helicene **184,** where spermine **185** is situated at the helicene outer core, are completely different in terms of the functional groups and their positions, therefore the exact mode of binding with DNA cannot be generalized and is still not completely understood.

Chiral cationic [4]helicenes **191** (Figure 19), having methoxy substituents at the innermost position, were also able to bind with DNA molecules, as evident from a noticeable change in absorption, fluorescence, and CD spectra obtained during the corresponding host–guest studies [102]. It was concluded that the molecular plane of the helicene dye lies essentially parallel to the DNA bases, implying intercalation mode rather than groove binding. Further, the chiral selectivity based on association constant evaluation indicates that the (*M*)-enantiomer of **191** interacts more strongly with DNA than the corresponding (*P*)-enantiomer of **191**.

**Figure 19.** Structure of (*M*)-enantiomers of **191**.

Yang et al. developed chiral 3-aza[6]helicene-modified β-cyclodextrin **192** by reacting 6-deoxy-6-iodo-β-cyclodextrin **193** with (*P*)/(*M*)-helicene **194**, resulting in two water soluble cationic charged diastereomeric species—(*P*)-**192**/β-cyclodextrin, and (*M*)-**192**/β-cyclodextrin (Scheme 34)—with different fluorescence behavior [103]. The concept was to use water-insoluble 3-aza[6]helicene **194** in aqueous media in combination with the β-cyclodextrin asymmetry for the chiral recognition of amino acids in water.

**Scheme 34.** Synthesis of 3-aza[6]helicene modified β-cyclodextrin **192** as a water-soluble amino acid sensor.

In polar solvents such as methanol, ethanol, and water, the helicene chromophore occupies the β-cyclodextrin cavity to a different extent in two diastereomers: (*P*)-**192**/**-** and (*M*)-**192**/ β-cyclodextrin—favoring monomeric forms rather than self-aggregated species. Both the diastereomers were investigated for complexation towards proteinogenic amino acids by using the fluorescence technique in an aqueous buffer of pH 7.3. It turned out that hydrophobic interactions appeared to be a dominant binding mode with additional electrostatic forces between the cationic charge of helicene and carboxylate anion of corresponding amino acids; besides this, π-π interaction may also contribute in the case of aromatic guests. The chiral discrimination abilities were also found to be highly dependent on pH. A relatively high L/D selectivity of amino acids, up to 12.4, was observed as a consequence of the synergetic effects of the helicene auxiliary and β-cyclodextrin cavity [103].

#### *7.5. Helicene-Based Chiral Recognition via Self-Assembly*

A new approach for chiral recognition via self-assembly was applied by Yamaguchi et al. on the basis of functionalized chiral [4]carbohelicene. The overall studies demonstrated that the helicenes exhibit a noncovalent chiral recognition behavior via different functions, such as charge transfer complexation, crystallization, homocoupling reaction, layer structure formation, self-aggregation, and even upon double helix formation [75]. Their observations indicated that the right-handed helix structure favors the same helicity of its counterpart, which is not generally observed in the case of point chirality (i.e., an (*R*)- or (*S*)-host does not always prefer a guest of the same absolute configuration). Out of several examples, the following one is sufficient to understand this helicity matching phenomenon.

Tetranitro, dicyano-substituted [4]helicene **195**, being an electron-deficient system, strongly interacts with diamino-substituted [4]helicene **196** via a charge transfer complex [104], the formation of which was monitored by UV and NMR techniques. Particularly, in the UV spectrum, a charge transfer band was observed at 500–800 nm in THF. The association constant of the complex with the same configuration—(*M*)-**195** and (*M*)-**196**—was found to be 12.2 M−1; this was noticeably higher than the constant 10.2 M−<sup>1</sup> observed for the opposite configuration—(*P*)-**195** and (*M*)-**196** (Figure 20). Further, the NMR-based NOE experiments revealed that the face-to-face *syn*-conformation of two 1,12-dimethyl groups was preferred over the *anti*-orientation in the corresponding charged transfer complexes [104].

**Figure 20.** Helical discrimination upon supramolecular charge transfer complexation between electron-deficient helicene **195** and electron-rich helicene **196**.

In related studies, a series of racemic [7]helicene derivatives, **197**–**199**, containing pyridinone rings at both the terminals, were prepared using a classical methodology of Wittig olefination and photochemical cyclization, and were characterized both in solution and in solid state [105]. Despite a variety of self-assembly modes according to the stereochemical and topological relationships, these helicenes formed only enantiomerically pure dimers held together by two pairs of the cooperative hydrogen bonds. The self-assembly process was found to be enantiospecific in solution and diastereoselective in solid crystal (Figure 21).

The terminal pyridinone rings were capable of hydrogen bonding via the corresponding amidic N–H functionalities. The solution-phase NMR studies indicated that the helicenes exist as enantiomeric dimers. For example, the NH proton in 2-quinolinone **200** (10<sup>−</sup>4–10−<sup>2</sup> M), as a reference, appeared at 12.9 ppm, whilst the position of this proton in **198** was downfield-shifted by 1 ppm in dilute solution (>10−<sup>5</sup> M), clearly indicating the cooperative hydrogen bonding and self-assembly phenomenon. In turn, the chemical shift was found to be concentration-independent in CDCl3 and THF. In pyridine, as expected, it was concentration-dependent, as pyridine itself is able to compete for the hydrogen bonding. Additionally, the dimeric binding model was confirmed by dilution experiments with the association constant of 207 M−1. The molecular modelling studies also indicated that each dimer is preferably constructed from a monomeric species of the same helicity.

The X-ray crystallographic structure of **199** showed only homochiral dimers; where the R-group (acetyl) is present in the *cis*-orientation to ensure the diastereoselective recognition process during crystallization. These enantiopure dimers are held together by four strong intermolecular hydrogen bonds between two terminal pyridinones.

**Figure 21.** Hydrogen bonding-based self-assembly in pyridinone-containing helicenes **197**–**199** and 2-quinolinone **200**, as a NMR refrence.

#### **8. Enantiopure Helicenes: Enantioselective Synthesis, Chiral Separation, and Racemization**

The chiroptical properties and applications discussed above prompted the development of efficient synthetic procedures to obtain enantiopure helicenes in sufficient quantities required for these investigations [2,4]. Although this topic is not directly related to the category of helicene applications, it is an important background for the whole helicene chemistry; hence, a brief description should be included as a special section. The major methods of obtaining enantiopure helicenes from a racemic mixture are based on optical resolution by chiral HPLC [60,77,78,83,101], diastereomeric salt formation [51,60,76] (for representative resolving agents, see Figure 22), chromatographic separation of diastereomers [52,56,74], and enzymatic-based approaches [97].

**Figure 22.** Selected examples of chiral reagents for helicene optical resolution.

For example, racemic nonfunctionalized helicenes were successfully resolved through charge transfer complexation with electron-deficient molecules, such as TAPA [15,16] or HPLC-based separation with the use of silica coated with TAPA [106]. In the case of functionalized helicenecontaining phenolic groups at the terminal ring, (1*S*)-camphanic chloride acts as the best resolving agent for chromatographically separable diastereomers obtained. Furthermore, their absolute configuration determination was carried out by the 2D ROESY NMR technique [52,74,107]. Particularly, it was observed that in 19 examples of helicenes studied, (*M,S*)-diastereomers were less polar, whilst (*P,S*)-diastereomers were more polar, hence eluting as the first and second fractions, correspondingly, upon the chromatographic separation on silica gel [107]. Another resolving agent, which is also frequently employed for optical resolution, is an *l*-menthyl derivative [4,56]. This approach has a distinct advantage of attaching and detaching a chiral auxiliary before and after the diastereomeric separation, making the whole procedure recyclable and highly efficient. Interestingly, in the case of azahelicene **201** containing the chloro group as a substituent on the outer peripheral pyridine ring, the use of Pd-catalyzed Buchwald–Hartwig coupling with (*S*)-phenylethyl amine gave chromatographically separable diastereomers **202** and **203** (Scheme 35) [108,109]. However, the absolute configuration of the 2-ethylhexyl alkyl chain was not discussed in the paper [108].

**Scheme 35.** Synthesis of chromatographically separable diastereomers **202** and **203** obtained by Pd-catalyzed reaction between *rac*-azahelicene **201** and (*S*)-phenylethylamine.

Besides the optical resolution of racemates, another approach to enantiopure helicenes is based on the stereospecific synthesis, where the originally chiral precursors or reagents are converted into the corresponding helicenes with unidirectional helicity [110]. In particular, the asymmetric synthesis of helicene can be performed by using various synthetic methods, such as photocyclization, Diels–Alder reaction, or metal-catalyzed annulation, in the presence of chiral auxiliaries attached to the reactant(s). These topics have been comprehensively covered in previous reviews [2,4]. Therefore, only a few of those recently published examples of asymmetric helicene synthesis are highlighted below.

In 2016, Sako et al. successfully used the modified BINOL-based vanadium(V) complex **204**, capable of functioning both as redox and Lewis acid catalysts, for the enantioselective synthesis of oxa[9]helicenes **205** starting from polycyclic phenols **206**. The reaction proceeds via oxidative coupling at first, followed by intramolecular cyclization. This results in the one-step enantioselective synthesis of oxa[9]helicenes in good yields with up to 94% *ee* [111] (Scheme 36).

**Scheme 36.** Modified BINOL-based vanadium complex **204**, catalyzed asymmetric synthesis of oxa[9]helicenes **205** from polycyclic phenols **206**.

In 2015, a new general asymmetric synthetic methodology was successfully developed for [5]-, [6]-, and [7]helicenes with ultimate enantioselectivity (*ee* >99) based on the controlled transfer of reactant point chirality to the product with unidirectional helicity [112]. At first, triyne**207**, having inbuilt point chirality, was converted into tetrahydrohelicene diastereomers **208** and **209**, being in the thermodynamic equilibrium, by cobalt-catalyzed tandem [2 + 2 + 2] cycloisomerization. The (*M*)-conformational helicity results in the 1,3-allylic strain, hence making **208** a highly energetic diastereomer in comparison to **209**, the (*P*)-conformational helicity of which gives relief from this strain, when the point chirality is of (*R*)-configuration at the 9-position. Subsequently, the favored diastereomer under acidic conditions yielded fully aromatic helicenes **210** with greater than 99% *ee* (Scheme 37). Thus, (*P*)- and (*M*)-helicenes can be readily prepared starting from the (*R*)- and (*S*) absolute configurations at the 9-position of the precursor, correspondingly.

**Scheme 37.** Asymmetric synthesis of helicenes **210** based on the principle of point-to-helical chirality conversion.

One of the most important points of chiral helicenes is their configurational stability, which can be analyzed by using CD spectroscopy and chiral HPLC in combination with other techniques. Evidently, understanding the mechanism of racemization helps in designing more stable helicene structures. Recently, detailed theoretical racemization studies have been performed on [n]helicenes where n = 4–24 [113]. Consequently, it was found that n = 4–7 involves the one-step concerted mechanism of racemization. The smallest member of the carbohelicene family, [4]helicene has a *C2V* symmetric transition state (TS) with an energy barrier of 4.0 kcal mol-1. However, the TS of n = 5–7 possesses a *Cs*-geometry with the energy barriers of 24.4, 36.9, and 42.0 kcal mol<sup>−</sup>1, respectively. This is a result of the steric hindrance, which accounts for the high TS energies of racemization. For n ≥ 8, besides the steric hindrance, an additional factor of the π-π interaction starts to contribute to the overall structural stability, making the racemization process a multistep process and thus further increasing the energy barrier. For example, when n = 8,9, or 10, helicenes displayed 2, 4, and 6 intermediates for the racemization process, respectively. Thus, in general, when n = 8–24, helicenes involve (2n-14) consecutive displacements, traversing intermediates in the molecule during the racemization process for corresponding carbohelicenes. These theoretical results should be taken into account to control the desired properties of helicene structures in future research.

#### **9. Conclusions**

Helicenes are versatile compounds existing in achiral, stereodynamic, meso, and chiral forms. Additionally, they could be neutral, charged, carbocyclic, heterocyclic, or polymeric in nature, with electron-rich or -deficient characteristics. These conjugated molecules exhibit unique physical properties such as fluorescence and strong chiroptical features, making them exclusively useful for the chirogenesis processes, including chiral recognition using both fluorescence and circular dichroism spectroscopies. Their polyaromatic helical structures are also suitable for providing shielding and deshielding effects, making them potentially applicable as chiral NMR sensors.

The high configurational stability and facile functionalization of the helicene structures open intriguing prospects in the fields of chiral catalysts and auxiliaries for various asymmetric reactions. In the last three decades, there has been much research effort focusing on newer, simpler, and

multigram synthetic procedures including different asymmetric methodologies for obtaining sufficient quantities of enantiopure helicenes for various practical applications, including chirogenesis. It has been established that modified helicene molecules with important properties can be developed by merging the helical structure with other (central, axial, and planar) chirality elements for specific applications. The helicity control may be conveniently achieved by means of the intramolecular cyclization of terminal rings, resulting in a decrease in the helicity. Alternatively, the introduction of functional groups on the terminal rings or presence of saturated bond(s) inside the molecule (helicenoid) increases the helicity. These modifications also govern the helicene chiral cavity space properties, and may thus be adopted for desired applications.

Besides chiral auxiliaries and chirogenesis, the helicene structures are good candidates for material chemistry and nanotechnology. We believe that there is still a large and diverse scope for helicene chemistry and application to be studied in the upcoming future, which will result in novel and interesting discoveries. We are yet to fully explore the real potential of helicene and related molecules.

**Acknowledgments:** M.H. and V.B. acknowledge funding from the European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration under Grant Agreement No. 621364 (TUTIC-Green).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

## *Review* **Chiral Buckybowl Molecules**

**Kuppusamy Kanagaraj 1,†, Kangjie Lin 1,†, Wanhua Wu 1, Guowei Gao 1, Zhihui Zhong 2, Dan Su <sup>2</sup> and Cheng Yang 1,\***


Received: 27 July 2017; Accepted: 21 August 2017; Published: 30 August 2017

**Abstract:** Buckybowls are polynuclear aromatic hydrocarbons that have a curved aromatic surface and are considered fragments of buckminsterfullerenes. The curved aromatic surface led to the loss of planar symmetry of the normal aromatic plane and may cause unique inherent chirality, so-called bowl chirality, which it is possible to thermally racemize through a bowl-to-bowl inversion process. In this short review, we summarize the studies concerning the special field of bowl chirality, focusing on recent practical aspects of attaining diastereo/enantioenriched chiral buckybowls through asymmetric synthesis, chiral optical resolution, selective chiral metal complexation, and chiral assembly formation.

**Keywords:** buckybowl; corannulene; sumanene; bowl chirality; bowl inversion; asymmetric synthesis; chiral resolution

#### **1. Introduction**

Studies on the physical and chemical characteristics of buckybowls have attracted significant interest owing to their direct structural correlation with fullerenes and potential applications in the realm of material science (Figure 1) [1–3]. Corannulene **1** and sumanene **2**, two prototypical buckybowls, are both highly curved π-conjugated aromatic molecules representing the substructures of fullerene. The smallest *C*3v-symmetric fragment **2** comprises a central six-membered ring surrounded by three five- and three six-membered rings fused in an alternating fashion (Figure 1), whereas the smallest *C*5-symmetric fragment **1** contains a central five-membered ring surrounded by five six-membered rings (Figure 1). Regioselective allocation of the five- or six-membered ring subunits around the centroid pentagon or hexagon, respectively, gave the curved bowl-shaped structures. Certain buckybowls are inherently chiral and difficult to separate from the racemates due to their rapid bowl inversion [4]. Controlling the bowl chirality of these π-conjugates and obtaining enantioenriched buckybowls are challenging tasks for chemists, while buckybowls application in chiral materials is highly promising [5–14]. Further extension of the π-conjugation of these chiral enantioenriched buckybowls leads to homochiral carbon nanotubes, and these chiral carbon materials create new perspectives in chiral catalysis, chiral sensing, chiral separation sciences, etc. [15–27]. A better understanding of bowl chirality will help researchers find a good way to control the chiral self-assembly of carbon nanotubes (CNTs) or fullerenes, which have already exhibited exciting potential as next-generation functional materials [28–38].

**Figure 1.** Chemical structures and bowl-shaped fragments of **1** (**left**) and **2** (**right**) as rim hydrogenated subunits of spherical buckminsterfullerene C60.

While several buckybowl-related reviews have been published in recent years [6,39–44], most of them focused on the synthetic strategy and derivation method. Only a few publications involve the stereochemistry or chirality of the buckybowls. In this short review, we summarize recent progress on the stereochemistry of buckybowls and their derivatives. It covers recent developments in the asymmetric synthesis and optical resolution of buckybowls from their racemates, and application of the enantioenriched buckybowls in the chiral aggregate formation and homochiral CNT syntheses [45,46]. These structurally well-defined single-chiral CNTs exploit truly exciting applications ranging from space elevator to armchair quantum wire and bio-related applications [47]. Chiral buckybowls that possess a stable concave or convex shape are suitable for the construction of chiral molecular recognition sites [48]. They may also coordinate metals by virtue of their electron-rich/-deficient properties and thus have the potential for enantioselective organocatalysis [49,50]. Chiral buckybowls, acting as chiral building blocks, can also be used for constructing helical assemblies and preparing homochiral crystalline organic materials.

#### **2. Classification of Bowl Chirality**

Bowl-shaped carbon-based π-conjugated aromatic compounds, so-called "buckybowls", are the partial structure of fullerenes or CNTs (Figure 1). These three-dimensional (3D) curved π-electron systems may possess inherent chirality and present many similarities to chiral fullerenes and CNTs, which is often defined as "bowl chirality" for convenience. The bowl-shaped polyaromatic hydrocarbon chiral buckybowl molecules can be broadly classified into three categories (Figure 2) based on the origin of their chirality. The conjugated bowl structure itself possesses the chirality, such as π-extended buckybowls, e.g., hemifullerene **3**; bowl chirality caused by introduction of one or more substituents on the rim of the buckybowl, e.g., trimethylsumanene **4**; and bowl chirality originated from the introduction of heteroatom into the π-bowl carbon skeleton, e.g., triazasumanene **5**.

**Figure 2.** Classification of chiral buckybowl molecules.

Unlike common aromatic compounds, which often have a symmetry plane along the aromatic ring, buckybowls loss the cross-ring symmetry plane due to the curved shape. Unsubstituted buckybowls **1** and **2** are not chiral due to the presence of the reflection symmetry with respect to the mirror planes containing the rotational axis to show *C*5v and *C*3v symmetry, respectively. Introducing the addends may break the reflection symmetry to cause chirality, and alter their properties, such as bowl-to-bowl inversion [12–22], chirality [12,17,19,23], bowl depth [14,19,20], crystal structure [19,24,25], molecular recognition [2,26,27,51] and supramolecular assembly [3,28–30,52,53] behavior, metal complexation [23,31–36], electronic conductivity [19,37,38], and so on. Although the chirality is an important element in three-dimensional curved π-electron systems, thus far there have been no reports of the enantioselective synthetic control of the bowl chirality.

#### **3. Stereodescriptor System of Buckybowls**

Until now, the absolute configuration of bowl chirality of chiral buckybowl molecules was followed by two independent stereodescriptor systems: The stereodescriptor *C* or *A* based on fullerene nomenclature [17,54] and the another stereodescriptor *P* or *M* based on the Cahn–Ingold–Prelog (CIP) sequence rule [32]. The numbering system of fullerenes follows in general a helical numbering path, starting from the lowest set of numbers for substituents. To assign a descriptor in the chiral fullerene system, the viewer looks from the outside of the fullerene cage at the polygon to start the numbering and trace the path of numbering C(1)–C(6) (Figure 3a) [54]. The chirality of buckybowls is assigned in the same way, and a viewer looks from the convex face and traces the path of numbering from atom C(1) to C(6) (Figure 3b) [17]. If the numbering path describes a clockwise direction/travel, the configuration of the chiral bowl is designated as *C*. In contrast, if the path describes a counterclockwise direction/travel, the configuration of the chiral bowl is designated as *A*.

**Figure 3.** (**a**) Three-dimensional diagram of C60 with the subunit of sumanene including enantiomeric travel numbering schemes and the related stereodescriptor systems *C* and *A*; (**b**) The stereodescriptor system of some *C*<sup>3</sup> symmetric chiral buckybowls.

ᬅ ᬆᬅ ᬅ ᬆ Another stereodescriptor system *P* or *M* for chiral buckybowls uses the CIP sequence rule [32]. Based on the CIP priority rule [55], the "non-fusion peripheral atoms" of buckybowl molecules are compared, and one atom with the highest CIP priority is chosen as the first priority (point of origin, **<sup>1</sup>** , Figure 4) [17,18]. Furthermore, for the next highest CIP priority atom **<sup>2</sup>** versus **<sup>1</sup>** , compare the two neighboring rim atoms attached to this original point, and subsequent atoms attached thereto. For a viewer looking from the concave face of the buckybowl molecule, i.e., looking "into" the cavity of the bowl, the path of CIP priority numbering is from the original point atom to the neighboring atom with higher priority ( **<sup>1</sup>** → **<sup>2</sup>** ). If the path of CIP priority numbering direction describes clockwise travel, the configuration of the chiral bowl is designated as *P*. Otherwise, if the path of CIP priority numbering travels in a counterclockwise direction, the descriptor is *M*. The numbering to specify the positions of substituents follows the nomenclature of fused ring systems.

**Figure 4.** The *P* and *M* stereodescriptor system for some *C*<sup>3</sup> symmetric chiral buckybowl molecules based on the CIP priority rule.

#### **4. Bowl Inversion/Racemization of Chiral Buckybowls**

A unique property of buckybowls lies in that these molecules can thermally flip their curvature in solution via bowl-to-bowl inversion or concave–convex transition. During the bowl inversion process, the inherent bowl chirality inverts; this process is also called racemization (Figure 5a) [12,17–19]. The nonpolar polyaromatic small bowl molecules, like **1** and **2** can thermally flip through a planar transition state and the required energy to cross this transition barrier is defined as bowl inversion energy (Δ*E*) (Figure 5b) [20]. In the solid state, buckybowl molecules exist in a stack structure and show excellent physical properties, such as electron conductivity [24].

The thermally driven bowl-to-bowl inversion is of interest to basic science and can find various applications in functional materials for sensors, chemical machines, or ferroelectric memories. The lifetime of enantiopure chiral buckybowls is controlled by the bowl inversion energy (Δ*E*). The enantiopure chiral buckybowls are expected to contribute to a variety of applications such as asymmetric molecular recognition, homochiral crystal organic materials, chiral self-assembly, and chiral organometallic catalysis [6,7,9].

The introduction of substituents or heteroatoms in the carbon skeleton of buckybowls changes the bowl inversion energy within the range of 20–40 kcal/mol, and therefore could change the lifetimes of chiral buckybowls considerably. Furthermore, the nature, position, number of substituents, and stereoelectronic effects also significantly influence the bowl shape, depth (*x*), lifetime of keeping chirality, electron-deficient/-rich nature, and other physicochemical properties [56]. The bowl-inversion energy of corannulene derivatives was first determined by Scott and co-workers [13]. The interesting dynamic behavior of various buckybowl molecules has been extensively studied by Scott [57], Siegel [14,16], Hirao [15,35], Sakurai [12,17–20], and others. In particular, Sakurai and co-workers studied the effect of the substituent R at the benzylic position of sumanene **11**, which possesses two different conformers, *endo*-R and *exo*-R, differing in the direction of the aromatic bowl shape, concave or convex (Figures 6 and 7) [56].

**Figure 5.** (**a**) Racemization of chiral **2** through bowl-to-bowl inversion/racemization; (**b**) the double-well potential energy profile. Reprinted from [20]. © 2014 Pure & Applied Chemistry.

**Figure 6.** The *endo*-R and *exo*-R conformers of monosubstituted-sumanene **11** as determined by DFT calculations and the involved stereoelectronic effects. Reprinted from [56]. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

**Figure 7.** (**a**) Monosubstituted sumanene derivatives **11**; (**b**) Its graphical representation bowl depth and cone angle.

Introduction of substituents will influence the geometries/conformations of buckybowls and bowl inversion energies as well. The effect of substituents in corannulene has been studied by Siegel and co-workers [14,16]. They demonstrated that introducing the acyclic substituents in corannulene usually decreases the bowl depth and increases the bowl inversion energy. Based on the results of the experimental and theoretical study, they proposed a quantitative equation for bowl inversion energy, which relates the bowl depth to the bowl inversion energy (Figure 7) [14,16]. Steric and electronic factors of substituents also affect the bowl structure and bowl inversion energy of sumanene. Recently, Sakurai and co-workers found that sumanene **2** attached with a mono-iodo substituent induces a slightly deeper bowl depth and a higher bowl inversion energy compared with other sumanene derivatives because of its steric effect, whereas the electronic effects caused by formyl and nitro substituents induced a shallower bowl depth and a lower bowl inversion energy [20].

Siegel and co-workers studied the bowl-to-bowl inversion of corannulene **1** and ethylcorannulene derivatives mediated by extended tetracationic cyclophane (Figure 8) [22,30]. This synthetic host forms a supramolecular complex with **1** and ethylcorannulene via induced fit, and the bowl-to-bowl inversion process was accelerated by a factor of 10 at room temperature. Upon host–guest complexation, the transition state of the guest is stabilized through the stereoelectronic reorganization of the host, which switched from a strained conformation to an energetically favored conformation. Further, the experimental and DFT calculations for bowl-to-bowl inversion process of the host-guest complexion of **1** demonstrates the decrease of bowl-to-bowl inversion energy barrier of corannulene (Figure 8).

**Figure 8.** Comparison of energy profile of bowl-to-bowl inversion of corannulene **1** (black) and tetracationic cyclophane: **1**, complex (green) in Me2CO; absolute contributions of ground-state (GS) destabilization (0.5 kcal mol<sup>−</sup>1) and transition-state (TS) stabilization (2.0 kcal mol−1) to the overall energy-barrier decrease (ΔΔ*G*‡ catalysis) of the bowl-to-bowl inversion process of **1** inside the tetracationic cyclophane calculated by DFT (B97D/Def2-TZVPP). Reprinted from [22]. © 2014 Nature Publishing Group.

#### **5. Heterobuckybowls**

Doping of heteroatoms to the carbon frameworks of bowl-shaped aromatic compounds drastically modulates their geometrical structure and physical and chemical properties. After the successful synthesis of corannulene and sumanene derivatives, researchers began to try to synthesize hetero atom-doped buckybowl molecules, so-called "heterobuckybowls". The introduction of heteroatoms into the carbon skeleton is expected to yield altered electronic properties of basic carbon skeleton buckybowls, especially electron-deficient or -rich in nature. Notably, the substitution of a hetero atom in its carbon skeleton also causes the geometrical change, especially the depth of the bowl. As a result of the change in depth of the bowl, the activation energy for the bowl-to-bowl inversion energy is also altered. The higher the bowl inversion energy is, the more stable the chiral conformer will be. Several heterobuckybowls have been reported in the literature, some of them chiral (Figure 9) [12,58–66].

**Figure 9.** Heterobuckybowls with their bowl depth.

The heteroatoms embedded in the reported heterobuckybowls are mainly the group 14, 15, and 16 elements, such as nitrogen (second row), silicon, phosphorus and sulfur (third row), germanium and selenium (fourth row), and tin and tellurium (fifth row) (Figure 9). Introduction of heteroatoms in the periphery of buckybowls usually resulted in a decrease of the bowl depth of heterobuckybowls, because the bond lengths of carbon–heteroatom increased with the atomic size (Figure 9). The bowl depths of trithiasumane **16** (0.79 Å) and triselenasumane **18** (0.47 Å) [64] have a shallower bowl depth than that of normal sumanene **2** (1.11 Å) [24]. Trisilicasumanene **12** [59,63] and tritellurasumanene **19** have a plane structure, whereas triazasumanene **10** has a deeper bowl depth of 1.30 Å because the C–N bond length (1.47 Å) is shorter than the C–C bond length (1.54 Å) [12]. The high reactivity of nitrogen facilitates the formation of the highly strained triazasumanene derivative with higher bowl-to-bowl inversion energy. More recently, Saito and co-workers prepared a triphosphasumanene trisulfide **13** derivative with a large dipole moment (12.0 D) [67]. The bowl depth of *syn*-isomer **13** is 0.46 Å, which is identical to triselenasumane **18** (0.47 Å) [64] and shallower than sumanene [24], whereas the *anti*-isomer of triphosphasumanene trisulfide **13** exists in an almost plane structure [67].

#### **6. Asymmetric Synthesis of Buckybowl and Azabuckybowl**

Synthesis of buckybowls was a highly challenging task for chemists. The first synthesis of the pristine corannulene was accomplished in 1966 by applying a long synthetic route [68]. The synthetic investigation was postponed until Scott et al. [69] and Siegel et al. [70] reinitiated the synthesis of corannulene with a succinct synthetic route by using the flash vacuum pyrolysis (FVP) method in the early 1990s. In the FVP method, the planar π-conjugated precursors are directly converted into buckybowls under high temperature to yield a racemic mixture [71]. Many buckybowls were thus synthesized using this FVP method, whereas FVP method was unsuccessful for the synthesis of **2** [72]. In 1996, Siegel and co-workers developed the first solution phase synthesis of **1** [73]. Adopting this simple and short solution phase strategy, another pristine buckybowl **2** was obtained by Sakurai and co-workers [74].

In 2008, Sakurai and co-workers reported the first asymmetric synthesis of trimethylsumanene **4** using stepwise conversion strategy under milder reaction conditions [17]. The synthetic strategy is described in Scheme 1.

**Scheme 1.** Strategy for the asymmetric synthesis of chiral (*C*)-trimethylsumanene **4**.

In this strategy, chiral norbornene possessing stereogenic carbon center was used as the precursor, which was converted into planar nonconjugated bowl by Pd catalyzed *syn*-selective cyclotrimerization [75,76], and the *sp3* chirality was thus transmitted to the bowl chirality of **4**. The key concern of this strategy is the rate of racemization, which is directly correlated to the inversion barrier of buckybowls. Many buckybowls have a low bowl-to-bowl inversion barrier at room temperature and are unable to separate their enantiomers. For example, most corannulene derivatives are not able to enantiomerically isolate because of their bowl inversion energy of ca. 11.5 kcal/mol (bowl-bowl-inversion is >20,000 times per second at room temperature) [14]. In contrast, the bowl inversion energy of **2** and **4** is around 20.3 kcal/mol (one time per 143 s) [15,19] and 21.6 kcal/mol [19], respectively. Since the half-life of the bowl inversion of **4** are 2 h at 0 ◦C and 23 min at 20 ◦C [17], the isolation of an enantiomer would be possible if the last aromatization step is carried out at a low temperature.

Thus, the aromatization step, converting the nonconjugated bowl into a conjugated bowl, was carried out using excess DDQ in a very short reaction time (1 min) at 0 ◦C, and the resulting (*C*)-**4** quickly purified at <−20 ◦C. The isolated (*C*)-**4** was stored at −80 ◦C. The chirality of (*C*)-**4** was analyzed by the circular dichroism (CD) spectra at −40 ◦C, which show two positive Cotton effect curves at 247 nm and 284 nm, respectively (Figure 10a). In contrast, the intensity of CD signals gradually decreased at 10 ◦C (Figure 10b), indicating the racemization of (*C*)-**4** through bowl inversion. The experimentally observed bowl inversion energy is 21.6 kcal/mol, which is close to the calculated value (21 kcal/mol). The chiral (*C*)-**4** was converted into (*C*)-**7** (Scheme 2) using (*S*)-MTPA as a derivatization reagent [17]. The bowl inversion energy barrier of (*C*)-**7** is further increased and the *de* values can be determined using NMR or HPLC analysis.

**Figure 10.** (**a**) CD spectra of (*C*)-**4** in CH3CN at −40 ◦C (red line) and UV spectra of (*C*)-**4** in CH3CN at room temperature (blue line); (**b**) Decay of CD spectra of (*C*)-**4** in CH3CN at 10 ◦C for 3 h. Reprinted from [17]. © 2008 American Chemical Society.

**Scheme 2.** Derivatization of (*C*)-**4** using chiral derivatizing reagent for the determination of *ee*.

It has been proven that the bowl inversion energy of buckybowls increased with bowl depth [14]. Theoretical studies suggested that doping of nitrogen will lead to deeper and curved bowl depth compared to the all-carbon counterparts [77]. Sakurai and co-workers reported the first chiral nitrogen-doped buckybowl (Scheme 3) [12]. Pure chiral (*C*)-(−) and (*A*)-(+)-tris(methylthio)triazasumanene **9** was synthesized from corresponding enantiopure nonconjugated simple precursors, which was further converted into corresponding chiral sulfone derivative **10** by oxidation using *meta-*chloroperoxybenzoic acid (*m*-CPBA). From the single crystal analysis, the bowl depth of compound **10** is 1.30 Å, which is deeper than that of **2** (1.11 Å), indicating a higher bowl inversion barrier than the pristine **2**. The bowl inversion energy of triazasumanene is calculated to be 39.9 kcal/mol by DFT method at the B3LYP/6-311 + G(d,p) level. In contrast, the calculated values for **2** and **4** are 18.3 and 19.2 kcal/mol, respectively. This means that chiral triazasumanene **10** takes 1.1 billion years to racemize at 20 ◦C.

Both chiral derivatives of **9** and **10** exhibit the opposite Cotton effect curves (Figure 11), which are a mirror image of the corresponding enantiomers. The CD spectra of **9** and **10** demonstrated the existence of bowl chirality and remained intensive even after a week, indicative of a chiral memory effect. To measure the rate constant and bowl inversion energy of **9**, a racemization experiment was carried out at 488 K and analyzed by chiral HPLC. The racemization rate and energy of **9** were determined to be 1.24 × <sup>10</sup>−<sup>6</sup> <sup>s</sup>−<sup>1</sup> (488 K) and 42.2 kcal/mol, respectively [12].

**Scheme 3.** Strategy for the asymmetric synthesis of chiral triazasumanene **9** and **10**; Insert: X-ray crystal ORTEP drawing structure of **10**; all hydrogen atoms omitted for clarity: (**A**) top view (with thermal ellipsoids set at 50% probability); (**B**) side view with bowl depth. Reprinted from [12]. © 2012 Nature Publishing Group.

**Figure 11.** CD and ultraviolet/visible spectra of (**a**) compound **<sup>9</sup>** in CH2Cl2 solution (1.2 <sup>×</sup> <sup>10</sup>−<sup>5</sup> M). The blue line and red line are CD spectra of (*C*)-(−)-**9** and (*A*)-(+)-**9**, respectively; (**b**) Compound **10** in CH2Cl2 (5.0 <sup>×</sup> <sup>10</sup>−<sup>5</sup> M). The green line is an ultraviolet/visible spectrum. Reprinted from [12]. © <sup>2012</sup> Nature Publishing Group.

The above-discussed solution phase enantioselective synthesis of trimethylsumanene **4** and triazasumanene **9** and **10** represents a useful and versatile strategy for the construction of other homochiral curved π-electron systems from non-conjugated precursors. The chiral transmission from sp3 stereogenic chirality to bowl chirality creates a new dimension for chiral-controlled 3D carbon materials like fullerene and CNTs.

#### **7. Chiral Resolution of Buckybowls**

The optical resolution of racemic chiral buckybowls has also been accomplished using derivatization method [13,71,78–81]. Derivatization at the outer rim of the buckybowl results in a deeper bowl with high bowl inversion energy and makes it resolvable from its racemates using chiral HPLC [12,17,18]. The purity of enantio-enriched chiral buckybowls and its bowl chirality is mainly analyzed using CD spectroscopy, NMR, and chiral HPLC methods [82–87].

As shown above, **2** has less bowl inversion energy than **4**, and it undergoes much slower racemization at 0 ◦C (*t*1/2 = 2 h) [17]. Based on this, Sakurai et al. reported the first asymmetric synthesis of chiral **4** [17], and the enantiomeric excess (*ee*) of **4** is determined by measuring the 1H-NMR spectrum of **7**, which was derivatized from **4** using Mosher's acid chloride (Scheme 2) [17,18]. Upon introducing stereogenic centers at the *sp*<sup>3</sup> carbons at the benzylic positions, it became more stable and could be stored for a long time. The enantioselectivity of **6** was determined to be 89% *ee*, which matches the 1H-NMR analysis of chiral derivatized compound **4** (90% *ee*). The chiral (*A*)-**6** buckybowl was eluted first with a retention time (*t*R) of 38 min and another chiral buckybowl (*C*)-**6** was eluted later with a retention time of 42 min (Figure 12a). The separated enantiomers of buckybowl **6** were analyzed using CD spectroscopy, which showed the mirror image Cotton effect curves generated from its inherent bowl chirality (Figure 12b).

**Figure 12.** Synthesis of racemic (±)-**6** and (±)-**21** derivatives from racemic (±)-**4**. (**a**) Optical resolution of (±)-**6** by chiral HPLC (DAICEL CHIRALPAK IA, 2-propanol, retention time (*t*R); 38 min for (*A*)-**6**, 42 min for (*C*)-**6**); (**b**) CD spectra of each enantiomers **6** in CHCl3; (**c**) Optical resolution of (±)-**21** by chiral HPLC (DAICEL CHIRALPAK IA, hexane/2-propanol = 60/40, 9 ◦C, retention time (*t*R); 17 min for (*A*)-**21**, 18 min for (*C*)-**21**); (**d**) CD spectra of enantioenriched **21** in CH3CN at 27 ◦C. Blue line: CD spectra of (*A*)-**6** and (*A*)-**21**, respectively. Red line: CD spectra of (*C*)-**6** and (*C*)-**21**, respectively. Reprinted from [18]. © 2010 The Chemical Society of Japan.

Racemic (±)-**21** was prepared by aerobic oxidation of racemic (±)-**4** (Figure 12) [18]. The estimated bowl inversion energy of **21** was 23.5 kcal/mol, which corresponds to ca. 44 h half-life at 10 ◦C. Racemic (±)-**21** was optically resolved using a chiral HPLC (Figure 12c). The absolute configuration of each enantiomer was assigned based on the CD spectrum of the enantioenriched (*C*)-**21** prepared from (*C*)-**4**. The bowl chirality of the optically resolved enantioenriched buckybowls (*A*)- and (*C*)-**21** was analyzed using CD spectroscopy, which is shown in Figure 12d. In addition, the bowl inversion barrier of enantio-riched **21** was estimated to be 23.4 and 23.3 kcal/mol in CH3CN and CH2Cl2, respectively, by measuring the time-dependent decay of the intensity of CD spectra at 255 nm at 30 ◦C [18]. These results led to the elucidation of the substituent effect and the correlation between bowl structure and bowl inversion energy [19].

Azasumanene **10** had a deeper bowl depth (1.30 Å) than **2** (1.10 Å) and showed extremely stable bowl chirality (*t*1/2 = 54 billion years at 20 ◦C) because of its high bowl inversion energy (Δ*E* = 42.2 kcal/mol) [12]. Similarly, *C*<sup>3</sup> symmetric chiral **8** was prepared by a Pd-catalyzed cross-coupling reaction between chiral **9** and (*p*-trifluoromethyl)phenyl boronic acid (Figure 13) [88]. The chirality of the obtained **8** was confirmed by chiral HPLC at 25 ◦C using a Daicel Chiralpak® IA column (Figure 13a,b). The CD and UV spectra were measured in a CH2Cl2 solution of enantioenriched **8** derivatives (Figure 13c), which shows the CD signals of the mirror image, indicating that the compounds are of opposite bowl chirality.

**Figure 13.** Strategy for the asymmetric synthesis of chiral **8** from chiral **9**: (**a**) HPLC chart of (*C*)-(−)-**8**; *t*<sup>R</sup> = 5.31 min (UV) and 5.84 min (CD); (**b**) HPLC chart of (*A*)-(+)-**8**; *t*<sup>R</sup> = 8.21 min (UV) and 8.76 min (CD). HPLC analysis was performed at 25 ◦C on a Daicel Chiralpak® IA column with hexane/CH2Cl2 = 50/50. Flow rate: 1 mL/min, detector wavelength: UV, 254 nm; CD, 270 nm; (**c**) CD and UV spectra of compound **<sup>8</sup>** in CH2Cl2 solution (1.5 <sup>×</sup> <sup>10</sup>−<sup>5</sup> M). Blue and red lines: CD spectra of (*A*)-(+)-**<sup>8</sup>** and (*C*)-(−)-**8**, respectively. Green line: UV spectrum of **8**. Reprinted from [88]. © 2017 The Chemical Society of Japan.

Recently, Yang and co-workers prepared azonia[*6*]helicene tethered with supramolecular host *β*-cyclodextrin, and used a chirality sensing probe for underivatized amino acids in water [89–94]. Indeed, tethered azonia[*6*]helicene acts as a conformationally robust chiral auxiliary to improve the chiral recognition ability of native cyclodextrins. Scott and co-workers successfully synthesized the first corannulene-[*n*]helicenes hybrids **22**–**25** by combining two classical nonplanar conjugated systems: the chiral bowl-shaped π-system, corannulene, and the helically chiral helicene (Figure 14). These compounds show unique molecular dynamics in their enantiomerization processes, including inversion motions of both the bowl and the helix [95].

Helix inversion renders *P* and *M* isomers, while corannulene bowl inversion results in concave and convex isomers, so it is predicted to have four isomers (convex-*P*, concave-*P*, convex-*M*, and concave-*M*) in equilibrium. Among the different conformers of corannulene-[*n*]helicenes, the conformer with a terminal helicene ring facing the convex surface of the bowl is more stable than the terminal ring facing the concave bowl surface, as the two forms display different degrees of steric congestion. For **22** and **23**, the energy barriers for bowl-to-bowl inversions were calculated to be 10.6 kcal/mol and 10.1 kcal/mol, respectively, and the helix inversions were 20.9 kcal/mol and 34.6 kcal/mol, respectively.

The enantiomers of corannulene-[*n*]helicenes hybrid were successfully resolved using a chiral-stationary-phase HPLC. The kinetics of thermal racemization of obtained conformers with the *ee* of >99% was studied under different temperature, and the helix inversion barrier value of Δ*G*‡ = 33.5 kcal/mol obtained experimentally is in consensus with the calculated one (34.6 kcal/mol) (Figure 14b). This hybrid system indicates that the chirality mainly arises from the rigid [6]helicene unit, and the non-rigid corannulene unit undergoes a rapid bowl-to-bowl inversion under ambient conditions.

The authors also synthesized **24** and **25** to study the different magnetic shielding effects of the convex and concave faces. The results show that the ring-current effect from the concave face of corannulene led to 1H-NMR signal upfield shifts of 2 ppm to 5 ppm. However, the *t*-Bu group of **24** is shifted upfield by only 0.65 ppm compared to the *t*-Bu group in **25**, which is away from the convex face. This comparison demonstrates that the magnetic shielding of the concave face is much greater than that of the convex face. Similarly, various stereodynamic (non-rigid/fluctuating) systems **26**–**29** based on a corannulene bowl that possesses more than one stereogenic unit were synthesized and their selected diastereomeric conformers were studied via bowl-to-bowl inversion (Figure 14c) [57,96–98].

**Figure 14.** (**a**) Chemical structure of different chiral corannulene-[*n*]helicenes **22**–**25**; (**b**) Theoretical study of interconversion pathways of **23**. Relative Gibbs free energies (Δ*G*) were calculated at the B3LYP/6-31G(d) level at 298.15 K; (**c**) Structures of multiple corannulene derivatives **26**–**29**. (**b**) is reprinted from [95]. © 2016 American Chemical Society.

The enantiopure or enriched chiral buckybowls could be obtained by asymmetric synthesis or optical resolution of racemates using chiral HPLC. The enantiopure buckybowls with inherent chirality are expected to be applicable not only for asymmetric molecular recognition, novel chiral organic materials creation [15,24,39,99], and chiral ligands for transition metals, but also for precursors of chiral fullerenes and CNTs in chemical synthesis. Methods and approaches that control the bowl chirality can potentially be applied to the related chiral fullerenes and CNTs as well.

#### **8. Chiral Metal Complexes of Buckybowls**

In general, metals binding to π-conjugated compounds can be represented by the symbol η<sup>n</sup> (n is the number of coordinating atoms). Fullerene and CNT and their derivatives form a coordination complex with various metal ion through their π-surfaces to form *exo-* as well as *endo-*hedral complexes, which have been used as a potential material in various fields such as molecular electronics and magnetic resonance imaging studies [100–102]. Interestingly, π-curved conjugated fragment **1** (bowl depth = 0.87 Å) preferentially coordinates with various metal ions in the convex surface in the η1, η2, and η<sup>6</sup> modes [23,31,32,39,103–106]. Some corannulene derivatives form concave as well as convex face η6-coordination complexes with ruthenium(II) [31,39,104]. Similarly, another *C*3v symmetric, curved π-conjugated bowl, **2**, forms coordination complexes through the η1, η2, η4, η5, and η<sup>6</sup> modes with limited transition metal ions [107].

In 2007, Hirao and co-workers reported the first selective concave-binding of CpFe+ (Cp = C5H5) to **2** (Figure 15) [33]. The metalation of **2** was carried out in solvent-free conditions using ferrocene at 120 ◦C. Under the ligand exchange method with excesses of CpFe+, the monometalated concave complex **30** was selectively afforded with a η<sup>6</sup> coordination (Figure 15a). In order to study the substituent effect, a methyl group was introduced into the cyclopentadiene ring, resulting in the concave selective complex **31** (Figure 15b). The bowl depth of **2** was not affected upon selective concave complexation of CpFe+ (1.07–1.13 Å), whereas in MeCpFe+ complexation the coordinatized side is flatted to 0.98 Å and the noncoordinated side was not affected (1.13 Å) (Figure 15a,b). Introduction of a chiral substituent *sec*-Bu to the Cp ring causes the target compound **32** as chiral (Figure 15c). The peaks of Ha split in 1H-NMR due to the presence of a chiral *sec*-butyl group. Meanwhile, the concave-selective complexation was confirmed by the split of Hb endo. Furthermore, the chirality of complex **32** was proved by CD spectral analysis, which shows positive CD peaks at 272, 303, and 517 nm, respectively [34].

**Figure 15.** Synthetic strategy for the concave selective coordination complex formation of [RCpFe(sumanene)]PF6. (**a**) Crystal structure of the cation of **30** with thermal ellipsoids set at 50% probability; side view with bowl depth; (**b**) Crystal structure of the cation of **31** with thermal ellipsoids set at 40% probability (the PF6 ion and acetone are omitted for clarity), side view with bowl depth; (**c**) Schematic illustration of chiral concave-face selective coordination of sumanene. (**a**) is reprinted from [33], © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim; (**b**) is reprinted from [34], © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Four years later, the first chiral selective convex-face complex based on pentasubstituted *C*5-symmetric bowl corannulene was reported by Siegel and co-workers [36]. Four kinds of compounds were synthesized to investigate the effect of different substituents in bicyclo[2.2.1]hepta-2,5-diene (nbd) and corannulene derivatives (R = H, Me and *t*-Bu). The crystal structure of **34** is given in Figure 16a. From the stereochemical analysis, **35** and **36** were predicted to have diastereomers **35a**/**35b** pair and **36a**/**36b** pair, respectively, arising from the rotation of chiral nbd ligand (Figure 16b). The complex is more likely to yield a static form with the steric repulsion between nbd ligand and corannulene. The calculated energy gaps between **35a**/**35b** pair and **36a**/**36b** pair are 1.88 kcal/mol and 3.54 kcal/mol, respectively. However, **35a**/**35b** was observed with a ratio of 2.5:1, while only **36a** was detected in the latter pair. These phenomena confirmed the hypothesis that the complex tends to exist in the static form with the steric hindrance.

The Cotton effects of **33** and **36** were observed in the CD spectra and confirmed the steric repulsion hypothesis. The distinct bathochromic shift of **33** and **36** compared to the free chiral nbd ligand was ascribed to the electron transfer from nbd ligand to the corannulene. This kind of curved π-bowl chiral complexation has the potential to function as a catalyst in asymmetrical organometallic chemistry and promote the understanding of selective π-bowl coordination.

**Figure 16.** Synthesis route of selective *C*5-symmetric corannulene-based convex-face complexes **33**–**36**: (**a**) X-ray crystal structure of **34**; (**b**) schematic illustration of diastereomers due to steric repulsion from rotation of the fragment. (**a**) is reprinted from [36], © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

#### **9. Chiral Assembly of Buckybowls**

Generally, various cyclic systems have inherent chirality because of their conformational stability and rigidity, which make them useful as chiroptical sensing probes [108–110]. Their preorganized binding sites can recognize optically active molecular species selectively via noncovalent interactions and gave a conformationally stable chiral organic structures. Furthermore, essential molecular chiral components amplify to form 3D supramolecularly assembled architectures and oriented nanoscale assemblies [111,112]. The nanoscale chirality of these 3D chiral supramolecular assemblies has potential application in functional soft materials.

Curved π-conjugated buckybowl corannulenes mainly form noncolumnar structures through a CH–π interaction rather than a π–π stacking interaction [28–30]. *C*5-Symmetric corannulene undergoes rapid bowl-to-bowl inversion/racemization at ambient or even low temperatures, and is unable to resolve into their enantiomers. Aida and co-workers reported a *C*5v-symmetric decasubstituted liquid crystalline (LC) corannulene derivative tethered with thioalkyl-amide-tribranched paraffinic side chains that forms self-assembled hexagonal columnar LC structures [3]. The nonpolar corannulene derivative can align homeotropically to the electrode surface with an applied electric field, and the alignment of corannulene was memorized for a long time. Hydrogen bond formation among the amide groups plays a key role in the formation of LC.

In order to resolve their enantiomers, the substituents were appended at the outer rim of corannulene viz. thioalkyl chains and amide groups (Figure 17A) [21]. *C*5-symmetric corannulene-based chiral initiators and monomers carrying amide-appended thioalkyl side chains were synthesized from 1,3,5,7,9-pentachlorocorannulene according to methods analogous to those reported by Scott and co-workers [113]. The amide derivatives form a unimolecular closed cage through "intramolecular" H-bonding interactions, which represents the first unimolecular host that is responsive to the chiral hydrocarbon solvent and obeys the majority rule in a chiral environment.

Non-amide derivative **37** does not show chiroptical activity even in chiral limonene, and no CD signal could be seen for **38***R* despite a chiral center in the side chain, whereas amide derivative **40M** showed chiroptical activity in the presence of chiral limonene. Compounds **41M***R* and **41M***S***,** in which amide linkers at the periphery of corannulene are attached to a chiral side chain, show chiroptical activity even in the achiral solvents. The computational simulation studies suggested that the formed stereoisomeric unimolecular closed cages exist in four equilibrated structures (Figure 17B). These amide derivatives form four kinds of "intramolecular" closed cages, and its cyclic amide H-bonded networks take clockwise and anticlockwise geometries. The corannulene bowl chirality axis and the direction of the intramolecular H-bonding (C=O ... H-N) network rotate in the same clockwise or anticlockwise directions (denoted as AA and CC); **39AA** and **39CC** structures are more stable and energetically favored than different directions (denoted as AC and CA; **39AC** and **39CA**).

**Figure 17.** (**A**) Chemical structures of *C*5-symmetric corannulene derivatives **37**–**41** bearing chiral or achiral side chains; (**B**) Schematic representations of the bowl inversion equilibrium using simplified molecular model **39** for *C*5-symmetric corannulenes carrying thioalkyl side chains featuring intramolecularly H-bonded amide units. Blue- and red-colored arc-shaped arrows represent the directions of H→SR and H-bonded N-H→O=C arrays, respectively, along the corannulene periphery. Subscripts C and A for **39** denote the clockwise and anticlockwise directions (tentatively defined), respectively. Four possible stereoisomers were energy minimized at the SCS-MP2/def2-TZVPP//DFT-D3-TPSS/defTZVP level. (**B**) is reprinted from [21]. © 2014 American Chemical Society.

The compound **40M** exhibited opposite Cotton effect curves in chiral solvents (*S*)-limonene and (*R*)-limonene, respectively. Likewise, chiral **41MR**/**41MS** showed chiroptical activity even in an achiral solvent such as methylcyclohexane, displaying mutually mirror-imaged CD spectra (Figure 18a). However, upon addition of a protonic solvent like ethanol, which is known to deteriorate the H-bonding, the **41MR**/**41MS** became CD-silent due to the breaking of the intramolecular H-bonding network. In methylcyclohexane, the CD spectral change of **40M** was monitored in a wide temperature range from −40 to 40 ◦C. When the temperature is lowered to −40 ◦C, the %*de* of **40M** is increased to 45%. At 20 ◦C, %*de* of **41MR** is enhanced to 80% when (*R*)-limonene was used as the solvent, whereas

**41MR** becomes CD-silent when (*S*)-limonene is used as the solvent (Figure 18b). A similar trend is followed by **41MS** (Figure 18b), which indicates that the chiral side-chain of **40M** could cooperate with the chiral solvent, either positively or negatively, in desymmetrizing the bowl inversion equilibrium of the corannulene core. A sigmoidal signal was observed in the CD spectra which demonstrated that the majority rule works in the unimolecular system [21].

**Figure 18.** Circular dichroism (CD) spectra at 20 ◦C of **40M** (green), **41MR** (blue), and **41MS** (red) (20 μM) in (**a**) methylcyclohexane and (**b**) (*R*)- (solid curves) and (*S*)-limonene (dashed curves). Reprinted from [21]. © 2014 American Chemical Society.

Inspired by the metastable property of corannulene derivative **40M**, Aida and co-workers came up with an ingenious strategy to achieve the first example of chiral chain-growth supramolecular polymerization [8]. To break the intramolecular H-bonding network of **40M**, they replaced the H atom connected in N with a methyl group and used **40I** as an initiator of supramolecular polymerization. The carbonyl group of the initiator can function as an H-bonding acceptor, thus attacking the monomer via H-bonding. Subsequently, the self-opening monomer can act as an initiator using its own free C=O, resulting in an oligomer **I-[M]2** with the free C=O end capped as well (Figure 19). As the oligomer elongates, the first chain-growth supramolecular polymerization is realized. Surprisingly, the chiral chain-growth polymerization can also be achieved via chiral initiator **41IR**/**41IS**. When chiral initiator **41IS** was added with racemic monomers **41MR** and **41MS**, chiral helical assemblies were achieved from the analysis of size-exclusion chromatography (SEC), meaning that only **41MS** can polymerize. As a result, chiral resolution of **41MR** and **41MS** was also realized successfully in the same way [8].

Differing from the classical chiral assembly formation in a macroscopic organic system, chiral microscopic assemblies of buckybowl hemifullerene at the surface of inorganic crystal were achieved by Fasel and co-workers [114]. They discovered how chiral bowl-shape hemifullerenes, derivatives of sumanene (Figure 20A), restructure on the copper surface atoms into chiral structures such as chiral nanowires and chiral islands. Unlike other researchers using polar molecules with carbonyl groups as chiral surface modifiers [115,116], Fasel et al. [114] turned their attention to metal-aromatic coordination bonds and found hemifullerenes suitable to induce chirality on a copper surface. Surprisingly, *<sup>M</sup>* enantiomers of hemifullerenes align along the [\_ 33 \_ 4] direction, creating R kinks, while *<sup>P</sup>* counterparts align along the [\_ 334] direction, forming S kinks, which differs from the previously reported arrangement of C60/corannulene along the Cu[110] direction [2]. This phenomenon is observed via scanning tunneling microscopy (STM) at 50 K and X-ray photoelectron diffraction (XPD) at room temperature. The optimized adsorption configuration was simulated by DFT, revealing that the creation of chiral kink creation can be explained by a three-point contact model, which is three *η*1-coordinated Cu–C bonds at this point.

**Figure 19.** Schematic representations of the chiral chain-growth supramolecular polymerization of chiral pentasubstituted corannulene derivative. Reprinted from [8]. © 2015 Science American Association for the Advancement of Science (AAAS).

**Figure 20.** (**A**) Chemical structure of hemifullerene **3** enantiomers; (**B**) a. Structural model of the observed step edge with alternating [\_ 33 \_ 4] and [\_ 334] segments and the formation of chiral kink sites; b. structural model of R kinks decorated by *M* enantiomers and S kinks decorated by *P* enantiomers; c. structural model of a chiral island stabilized by hemifullerene enantiomers; d. structural model of a chiral Cu nanowire stabilized by *<sup>M</sup>*-hemifullerene along the [\_ 33 \_ 4] direction. Reprinted from [114]. © 2010 Nature Publishing Group.

Furthermore, the chiral island and nanowire (Figure 20B) were found to form with different alignments of hemifullerenes. The results indicate the emergence of a chiral shape on Cu surface is of great importance to help investigate the elementary mechanism of chiral recognition or induction occurring on an achiral crystal surface. Unfortunately, efforts to separate the enantiomers adsorbed on the Cu surface were not successful [114].

Tethering the various alkyl chains with different length, number, substitution position, and nature of chiral carbons to the outer rim π-conjugated buckybowls is an effective way to tune the chiral assembly formation, the function of the system and their soft materialization. Extension of π-conjugation through the outer rim of the corannulene provided a single chiral CNT [114].

#### **10. Conclusions and Outlook**

In conclusion, this review summarizes the recent progress of studies on the bowl chirality, focusing on the two kinds of buckybowl compounds, corannulenes and sumanenes. These buckybowls possess curved aromatic rings, and introducing substituents on their aromatic periphery results in the loss of planar symmetry to generate a unique kind of chirality, so-called bowl chirality. The curved aromatic surface is possibly flipped, and such a bowl-to-bowl inversion causes switching of the bowl chirality. The size and shape of the substituents, a doped heteroatom in the aromatic bowl, and introducing a metal complex on the surface of buckybowls will significantly influence the bowl-to-bowl inversion energy as well as the racemization rate. Enantio-/diastereo- pure/enriched chiral buckybowls could be obtained by chiral resolution or chiral synthesis. The introduction of a chiral chain to the rim of the buckybowl dominated the asymmetric synthesis of chiral buckybowls. Sumanene **2** usually has higher bowl-to-bowl inversion energy than corannulene **1**, and asymmetric synthesis of chiral trimethylsumanene **4** and triazasumanene **9** and **10** has been realized using chiral non-conjugated precursors. The selective chiral assemblies of buckybowls with unique chemical and electronic properties may contribute to the development of the field of electronic devices and energy storage. In addition, the synthesis of homochiral CNTs continuously attracts scientists and chiral buckybowls may open up new opportunities in this area. The chiral assemblies of buckybowls are attractive, in relation to topics such as chiral amplification, chiral induction, and chiral memory. There is no doubt that the study of chiral buckybowls is still immature yet highly promising; further investigation will provide more insight into this particular area and lead to applications in various fields such as materials, electronics, and photonics.

**Acknowledgments:** We acknowledge the National Natural Science Foundation of China (Nos. 21572142, 21402129, 21372165, 31370735, and 21321061), the National Key Research and Development Program of China (grant No. 2017YFA0505900), and the State Key Laboratory of Fine Chemicals (KF 1508) and Sichuan Province Science Foundation for Youths (No. 2015JQ0029) for financial support.

**Author Contributions:** Kuppusamy Kanagaraj, Kangjie Lin, Wanhua Wu, Guowei Gao, Zhihui Zhong, Dan Su and Cheng Yang collected and analyzed the references and data and wrote the paper.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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