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Article

Atroposelective Formal [2 + 5] Macrocyclization Synthesis for a Novel All-Hydrocarbon Cyclo[7] Meta-Benzene Macrocycle

by
Chao Gao
1,*,
Hongchen Li
2,
Jing Zhao
1,
Lulu Bu
1,
Mei Sun
1,
Jingrui Wang
1,
Gang Tao
1,
Longde Wang
1,
Li Li
1,
Guilin Wen
1 and
Yunhu Hu
1,*
1
School of Chemistry and Materials Engineering, Huainan Normal University, Huainan 232038, China
2
CNOOC Institute of Chemicals & Advanced Materials, Beijing 102209, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(14), 3363; https://doi.org/10.3390/molecules29143363
Submission received: 17 June 2024 / Revised: 8 July 2024 / Accepted: 15 July 2024 / Published: 17 July 2024
(This article belongs to the Section Organic Chemistry)
Browse Figures
Review Reports Versions Notes

Abstract

:
A novel axially chiral all-hydrocarbon cyclo[7] (1,3-(4,6-dimethyl)benzene (CDMB-7) was designed and synthesized using atroposelective[2 + 5] cyclization through Suzuki–Miyaura coupling. CDMB-7 adopts an irregular bowl-like shape with C2 symmetry and exhibits two diastereoisomers in its crystallographic structure. The conformational isomers of CDMB-7 racemates remain stable at high temperatures (393 K). High-performance liquid chromatography (HPLC) confirmed that a single chiral isomer will spontaneously undergo racemization within 30 min at room temperature. This finding opens up possibilities for achieving adaptive chirality in all-hydrocarbon cyclo[7] m-benzene macrocycles.

1. Introduction

Atropisomerism is widely observed in pharmaceutical molecules [1,2,3], chiral natural products [4,5,6], chiral ligands [7,8,9], and specific macrocyclic molecules [10]. The phenomenon primarily arises from restricted rotation around a molecular axis (single bond) [11,12], facilitating the chiral separation of individual enantiomers [13]. Such separation presents opportunities for creating novel chiral drugs and functional materials. However, delving into the intricacies of isomerization within supramolecular chemistry remains a formidable challenge. The macrocycles highlighted in various studies, including crown ethers [14,15], carbon nanobelts [16,17], nanorings [18,19,20], cuppyrroles [21], triptycene derivatives [22], calixarenes [23,24,25], cyclobenzenes [26,27,28,29,30], superhelicenes [31,32,33], etc., exhibit considerable intrinsic or potential isomerization values, which have a profound impact on their synthesis and functional applications. Given this, it is essential to harness the diverse performance of these macrocycles in chiral self-recognition, detection, characterization, and fluorescence [34,35,36].
Cyclo-meta-phenylenes (CMPs), characterized by a representative macrocycle [37,38], have attracted widespread interest due to their simple composition and unique structure. So far, due to the lack of involved synthesis and modification strategies, few all-hydrocarbon as-prepared CMPs and related derivatives CDMB-8 [39] (Figure 1A) have been reported. Herein, we build a new, all-hydrocarbon cyclo[7] (1,3-(4,6-dimethyl)benzene) (CDMB-7) that exists in C2 symmetry. Two non-enantiomeric isomers of CDMB-7 can be generated simultaneously, and still maintain the stability of the configuration at high-temperatures (393 K), without causing conversion due to external stimuli.

2. Results

The synthesis of CDMB-7 is shown in Figure 1B. Briefly, the Suzuki–Miyaura coupling “[2 + 5]” cyclization between boronylated dimer 1 [40] and dibrominated pentamer 2 afforded the target macrocycle CDMB-7 in a yield of 26%. Dibrominated pentamer 2 was generated from the reported work [39]; then, with the varieties of chiral ligands involved and through controlling the process of asymmetric cyclization [41,42,43], unfortunately, the obtained pure products are still racemic mixtures. Its structure was subsequently confirmed by single crystal X-ray diffraction.
The [Pd], base, and solvent effects in the cyclization from 1, 2, and 3 are explored for the reaction optimization (Table 1). The highest 26% yield is achieved using Cs2CO3 under Ar and PhMe (Note: the reaction solvents are all analytical reagents (ARs)).
The structures of 3 are fully characterized via (1H, 13C, COSY, NOESY, ROESY) NMR, high-resolution mass spectra (HMRS, MALDI-FTICR), and further confirmed by single crystal X-ray diffraction analysis. In particular, only 3 showed racemates containing two diastereoisomers, which implied that the [2 + 5] cyclization is a highly diastereoselective reaction.
It is applied to preliminary single chiral isomer exploration by adding additional chiral ligands under the optimized condition. This showed that using (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl or (S)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl, the yields are 43% and 40%, respectively (Table 2, entry 1, 2). However, the addition of other chiral phosphine ligands did not have a significant promotional effect on the yield, as shown in Table 2. Hence, it suggests that the (S)-binaphthyl ligands positively influence the enhancement of the reaction yield by generating a bidentate coordination reaction intermediate in the same orientation as 2. Thus, both (R)-BINAP and (S)-BINAP can produce the racemic form of CDMB-7 with a high yield.
Moreover, the HPLC-confirmed target macrocycles, obtained after the reaction of all chiral ligands involved, were found to be racemic. It indicates that the introduction of chiral ligands did not effectively regulate the chirality of products. The rigidity of fragments 1, 2 was probably the main factor in generating the single chiral isomer.

3. Discussion

The 1H NMR spectrum of CDMB-7 (produced through the above synthetic process) recorded at 273 K in tetrachloroethane-d2 (TCE-d2) is characterized by six signals for the benzene ring protons that appear in a 1:4:3:2:2:2 ratio (Figure 2a). Seven groups of signals are seen (appearing as three overlapping peaks) corresponding to the meso-methyl groups. In addition, 21 signals are also seen in the 13C NMR spectrum (Figure S10, ESI). The findings mentioned above help us prove that CDMB-7 adopts a fixed structure with C2 symmetry in TCE-d2.
More evidence for the macrocycle formation with C2-symmetry came from crystal diffraction analysis [44,45,46,47,48]. The crystal was grown via slow evaporation in DCM/CH3CN (1:2, v/v). The crystal structure showed that C2-CDMB-7 has a foldable curved irregular “bowl-like” conformation with the seven meso-dimethyl benzene units. And the diameter of CDMB-7 in different views is 6.762 Å to 9.250 Å (Figure S3, ESI). Interestingly, two non-enantiomeric isomers coexist as racemates in the crystal (Figure 3b).
According to the analysis of NMR, the two-dimensional spectrum revealed that the benzene ring interactions between adjacent hydrogen–hydrogen and remote hydrogen–hydrogen in the macrocyclic molecule CDMB-7 are relatively weak (Figure 2b). The HSQC and HMBC two-dimensional spectrum have not been detected. Thus, it confirmed that there is almost no interaction between the inside carbon and hydrogen atoms of CDMB-7 macrocycle, also explaining the macrocycle structure’s existence as individual units. The variable temperature 1H NMR showed some shifts in specific signals seen upon heating at 283–393 K temperature range, the whole spectroscopic peak of the NMR recorded at 283 K was retained (Figure 2c). It indicates that the conformer of C2-CDMB-7 exists in a de-symmetrization shape-persistent nature at high temperatures.

4. Materials and Methods

We have achieved the separation of the single chiral isomer with diastereoselectvity of CDMB-7, generating peaks with an area ratio of 1:1 in chromatographic analysis column AD-H (mainly filled with silica surface covalently bonded cellulose-tri (3,5-dimethylphenylcarbamoyl) and the factor of chiral separation reaches 2 in HPLC (Figure 3a). Then, it successfully separated two single conformational isomers of the diastereoselective C2-CDMB-7 (separate yield < 5%, ee: 85%, 83%) using n-hexane and methanol (99/1, v/v) as the mobile phase through AD chromatographic preparation column at 30 °C.
However, it was further investigated when the two diastereoselective separated chiral isomer solutions were allowed to stand at room temperature for 30 min; the respective samples were injected again, and the signals of the two sets of chromatographic peaks showed consistency with the determination results of the racemic mixture in HPLC.
The initial crystallographic data obtained through chiral mode X-ray diffraction analysis (Figure 3b) showed two diastereoselective isomers of CDMB-7 rapidly reaching racemization in solution. It is postulated that the absence of strong polar or bulky substituents, other than the methyl group, in the molecular structure of CDMB-7 contributes to this conversion. This construction results in a shallow energy barrier for the configurational interconversion of its chiral isomers. Solvent interaction further facilitates this process, allowing the molecules to attain an energetic equilibrium easily.
Consequently, the single chiral species transform into their enantioselective images (mirror isomer), culminating in forming a stable racemic mixture in CDMB-7 solid phase. The findings of this research suggest that the nature of the functional group substitutions in CDMB-7, as well the selection of solvent, are likely the primary determinants influencing its enantioselective reactivity. On the other hand, the meso-dimethyl multi-aromatic ring units of C2-CDMB-7 and its irregular twisted conformation have the characteristic of available enantiomerization for racemization.
This study establishes a foundation for further investigation of the self-adaptive chirality of C2-CDMB-7. C2-CDMB-7 can responsively alter its chiral conformation in reaction to diverse external stimuli, such as pressure, solvents, and guest molecules. This adaptive shift in chiral configuration or conformation elicits distinctive chiral responses. Furthermore, we try to synthesize a novel chiral pharmaceutical derived from the CDMB-7 scaffold, tailored to interact with the humors, blood, or additional biological mediators within the organism. This interaction aims to effectuate a conformational shift in the target drug molecule, enhancing its lesion-specific therapeutic potency, thereby, eradicating associated pathologies. Moreover, we strive to attain the precise modulation of CDMB-7 analog adaptive chiral entities to guarantee their conformational transition is exclusive to particular solvent systems. Such specificity would enable these molecules to discriminate selectively against distinct ions, chiral diminutive molecules, or chiral moieties in a solution, thus augmenting the enantioselectivity of chiral recognition.

5. Conclusions

In conclusion, we have demonstrated a novel axially chiral cyclo[7] (1,3-(4,6-dimethyl)benzene (CDMB-7), synthesized through atroposelective Suzuki–Miyaura [2 + 5] cyclization in 43% yield. This protocol offers an economical and straightforward approach for directly synthesizing all-hydrocarbon odd-numbered multi-aromatic macrocycles. Analytical studies, including X-ray, NMR, and HPLC, identified that the atroposelectivity primarily originates from the rigidity of the as-prepared fragments, and the conformation of C2-CDMB-7 can undergo spontaneous “racemization”. These insights pave the way for further investigations into the self-adaptive chirality of C2-CDMB-7 and its potential application in dynamic chiral recognition, detection, and luminescence.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29143363/s1, The detailed synthetic procedures of new compounds, experimental figures, UV-vis and fluorescence spectra, X-ray crystal structure, and analytical data (PDF).

Author Contributions

Conceptualization, C.G. and H.L.; writing—original draft preparation: J.Z., L.B., L.W., L.L. and G.W.; writing—review and editing: M.S., J.W., G.T. and Y.H. All authors have read and agreed to the published version of the manuscript.

Funding

The authors thank the key Natural Science Foundation of Anhui Province 2023AH040210 (L.L.), 2023AH051535 (C.G.), 2023AH051536 (G.-L.W.) and Science and Technology Planning Project of Huainan 2021047 (G.-L.W.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

CCDC 2330139 accessed on 1 February 2024 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

Conflicts of Interest

The authors declare no competing financial interests.

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Molecules 29 03363 g001
Figure 1. (A) Previous examples of CDMB-8 [39] synthesis; (B) Suzuki–Miyaura coupling [2 + 5] cyclization for C2-CDMB-7 synthesis (this work).
Figure 1. (A) Previous examples of CDMB-8 [39] synthesis; (B) Suzuki–Miyaura coupling [2 + 5] cyclization for C2-CDMB-7 synthesis (this work).
Molecules 29 03363 g001
Molecules 29 03363 g002
Figure 2. (a) 1H NMR (273 K, 500 MHz) of benzene ring protons in CDMB-7 (5.00 mM); (b) expansion of the temperature dependent 1H MR (500 MHz) spectra of C2-CDMB-7 (5.00 mM) in TCE-d2; (c) COSY, NOESY, or ROESY two-dimensional spectra of C2-CDMB-7 (5.00 mM).
Figure 2. (a) 1H NMR (273 K, 500 MHz) of benzene ring protons in CDMB-7 (5.00 mM); (b) expansion of the temperature dependent 1H MR (500 MHz) spectra of C2-CDMB-7 (5.00 mM) in TCE-d2; (c) COSY, NOESY, or ROESY two-dimensional spectra of C2-CDMB-7 (5.00 mM).
Molecules 29 03363 g002
Molecules 29 03363 g003
Figure 3. (a) HPLC peaks of C2-CDMB-7 in chromatographic column AD-H (2.0 × 10−4 M, n-hexane/isopropanol, 95/5, v/v, 25 °C); (b) C2-CDMB-7 original crystal racemates under the chiral mode of X-ray crystal diffraction.
Figure 3. (a) HPLC peaks of C2-CDMB-7 in chromatographic column AD-H (2.0 × 10−4 M, n-hexane/isopropanol, 95/5, v/v, 25 °C); (b) C2-CDMB-7 original crystal racemates under the chiral mode of X-ray crystal diffraction.
Molecules 29 03363 g003
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 29 03363 i001
Entry[Pd]BaseSolventYield(%) b
1Pd2(dba)3Cs2CO3PhMe26
2Pd(dppf)2Cl2Cs2CO3PhMe25
3Pd[(PPh3)]4Cs2CO3PhMeND c
4Pd(OAc)2Cs2CO3PhMe<5
5PdCl2Cs2CO3PhMeND
6Pd2(dba)3Cs2CO3DMFND
7Pd2(dba)3Cs2CO3DMSO<5
8Pd2(dba)3Cs2CO3CH3CNMess d
9Pd2(dba)3Cs2CO3THF18
10Pd2(dba)3Cs2CO3DMAND
11Pd2(dba)3K2CO3PhMe15
12Pd2(dba)3CH3COOKPhMe22
13Pd2(dba)3NaOHPhMeMess
14Pd2(dba)3CsFPhMeMess
15Pd2(dba)3tBuONaPhMeND
a Reaction conditions: 1, 2 (0.15 mmol, 0.075 M, 1 equiv.), [Pd] (5 mmol %, 3.75 × 10−3 M), base (0.75 mmol, 0.375 M, 5 equiv.), solvent (2.0 mL), 100 °C, Ar, 12 h. b Isolated yields. c Not detected. d Mess: an inseparable mixture.
Table 2. Exploration of chiral phosphine ligand a.
Table 2. Exploration of chiral phosphine ligand a.
EntryLigand aYield(%) b
1(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl40
2(S)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl43
3(R)-(+)-TolBINAP18
4(R)-(+)-SEGPHOS15
5(R)-(R)-JOSIPHOS12
6(R)-Ph-Garphos<5
7(S)-(R)-JOSIPHOS23
8(S)-DM-SEGPHOS30
9(S)-2,2′-Bis(di-3,5-xylylphosphino)-1,1′-binaphthyl35
10(R)-(+)-MOP22
a Reaction conditions: 1, 2 (0.15 mmol, 0.075 M, 1 equiv.), [Pd] (5 mmol %, 3.75 × 10−3 M), base (0.75 mmol, 0.375 M, 5 equiv.), ligand (15 mmol %, 1.12 × 10−2 M), solvent (2.00 mL), 100 °C, Ar, 12 h. b Isolated yields.
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MDPI and ACS Style

Gao, C.; Li, H.; Zhao, J.; Bu, L.; Sun, M.; Wang, J.; Tao, G.; Wang, L.; Li, L.; Wen, G.; et al. Atroposelective Formal [2 + 5] Macrocyclization Synthesis for a Novel All-Hydrocarbon Cyclo[7] Meta-Benzene Macrocycle. Molecules 2024, 29, 3363. https://doi.org/10.3390/molecules29143363

AMA Style

Gao C, Li H, Zhao J, Bu L, Sun M, Wang J, Tao G, Wang L, Li L, Wen G, et al. Atroposelective Formal [2 + 5] Macrocyclization Synthesis for a Novel All-Hydrocarbon Cyclo[7] Meta-Benzene Macrocycle. Molecules. 2024; 29(14):3363. https://doi.org/10.3390/molecules29143363

Chicago/Turabian Style

Gao, Chao, Hongchen Li, Jing Zhao, Lulu Bu, Mei Sun, Jingrui Wang, Gang Tao, Longde Wang, Li Li, Guilin Wen, and et al. 2024. "Atroposelective Formal [2 + 5] Macrocyclization Synthesis for a Novel All-Hydrocarbon Cyclo[7] Meta-Benzene Macrocycle" Molecules 29, no. 14: 3363. https://doi.org/10.3390/molecules29143363

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