*2.1. With Azides*

The enantioselective ring-opening of epoxides with azides is a very important reaction due to the facile conversion of the products into valuable vicinal amino alcohols of very high optical purity (Scheme 3) [16–19]. The first report of a metal–salen catalyst used for an ARO reaction came from Jacobsen and coworkers [20] in 1995 with the use of Cr(III)salen complex **1** for the ARO of epoxides with trimethylsilylazide (TMSN3) as nucleophile (Scheme 4). Since then, considerable efforts have been invested into improving this catalytic system, including developing multi-metallic catalysts and employing different heterogenization strategies. The Cr(III)salen complexes remain the most investigated catalysts for the ARO of epoxides with azides as nucleophile, and only a few less efficient salen complexes based on other metals can be found in the literature [21–23].

**Scheme 3.** The asymmetric ring-opening of cyclohexene oxide with TMSN3 followed by reduction to synthesize the corresponding *trans*-1,2-amino alcohol with high enantioselectivity.

**Scheme 4.** The asymmetric azidolysis of *meso*-epoxides catalyzed by Cr–salen complexes.

The seminal work of Jacobsen and coworkers on chiral Cr–salen complexes for the asymmetric catalysis of the azidolysis of *meso*-epoxides have yielded invaluable insight in the development of catalysts for the ARO of epoxides. Drawing on knowledge gained in their previous work on the asymmetric epoxidation of alkenes [24–26], they found that by using the same salen ligand and exchanging the manganese(III) for chromium(III) (complex **1**), the ARO of cyclic *meso*-epoxides with TMSN3 as nucleophile could be catalyzed in high yields and with high enantioselectivities (up to 99% yield and 97% *ee*, Scheme 4). The reactions could be conducted either in ethereal solution or under solvent-free conditions with similar yields and enantioselectivities [20,27].

The stability of the catalyst under the reaction conditions facilitated the mechanistic studies, which showed that the active catalyst was the Cr–salen azide complex **2** (Scheme 4). This complex could

be isolated from the reaction mixture and recycled up to 10 times at 1 mol% loading with maintained reactivity and enantioselectivity. Kinetic studies revealed a second-order dependence of the reaction rate on the catalyst, suggesting that the catalyst played a dual role in the mechanism: activating both the electrophile and the nucleophile in a bimetallic rate-determining step (Scheme 5) [28]. The proposed mechanism was also supported by the observation of significant non-linear effects of the enantiomeric composition of the catalyst on the enantioselectivity of the reaction [29]. Studies also showed that TMSN3 was not directly involved in the catalytic cycle but rather served as a source of HN3 in the presence of trace amounts of water [28].

**Scheme 5.** The mechanism for the ARO of cyclopentene oxide with TMSN3 catalyzed by Cr–salen complexes as proposed by Jacobsen et al. [28].

The proposal of a bimetallic rate-determining step led to the synthesis and application of dimeric catalysts, both in order to gain further mechanistic insights and in the hope that enforcing the cooperativity would lead to improved catalytic activity and enantioselectivity. Jacobsen and coworkers [30] designed and synthesized a number of covalently linked dimeric complexes with different position and length of the linker (Figure 1), which were evaluated as catalysts for the solvent-free ARO of cyclopentene oxide with TMSN3. The positioning of the linker was based on two limiting geometries envisioned for the transition state of the ARO of *meso*-epoxides catalyzed by monomeric complex **2**: "head-to-head" and "head-to-tail" (Figure 2). Complex **3** was designed to evaluate the "head-to-head" geometry and complexes **4**–**10** were designed to evaluate the "head-to-tail" geometry.

**Figure 1.** Bimetallic catalysts designed to evaluate the "head-to-head" geometry (catalyst **3**) and the "head-to-tail" geometry (catalyst **4**–**10**) of the bimolecular catalysis.

**Figure 2.** The two limiting geometries for the enantioselectivity-determining transition state of the asymmetric ring-opening of *meso*-epoxides catalyzed by Cr–salen complex **2** as proposed by Jacobsen et al. [30].

All of the investigated dimeric complexes could be used under solvent-free conditions and gave increased reaction rates in the ARO of cyclopentene oxide with TMSN3 compared to monomeric analogues. While the complex based on the "head-to-head" alignment (complex **3**) gave very low enantioselectivity (8% *ee*), the "head-to-tail" aligned complexes **4**–**10** gave enantioselectivities similar to those obtained with monomeric analogues (90–94% *ee*). Complexes **4**–**10** also performed efficient catalysis at concentrations one order of magnitude below the lower limit of reactivity for the monomeric analogues. Kinetic studies showed the participation of both inter- and intramolecular pathways in the ARO, with complex **6** (*n* = 5) demonstrating the highest rate constants for both the inter- and intramolecular pathways out of the investigated dimeric catalysts (**4**–**10**). The intramolecular cooperative catalysis could also be observed by the decreasing non-linear effects in the ARO of cyclopentene oxide with TMSN3 with decreasing concentration of the dimeric catalyst [29,30].

Inspired by Jacobsen's dimeric Cr–salen complexes (Figure 1), Wärnmark and coworkers designed and synthesized several heterobimetallic dimeric complexes, based on the idea that some metal–salen complexes might be more efficient at activating the epoxide and others might be better at activating the nucleophile. This was supported by the initial screening of different 1:1 combinations of monometallic salen complexes with different metal ions as catalysts in the ARO of cyclohexene oxide with TMSN3, where synergistic effects in terms of reactivity and enantioselectivity were observed when Cr–monosalen complexes were combined with Mn– or Co–monosalen complexes. The design of the dimeric complexes included a novel design principle, where *C*2- and *C*s-symmetric ligands are desymmetrized by the insertion of two different metal ions, giving catalysts of pseudo-*C*2 [31] and pseudo-*C*s [32] symmetry, respectively (Figure 3). The catalysts were applied in the ARO of a number of *meso*-epoxides with TMSN3. The pseudo-*C*2 catalysts, Cr(III)-Co(III) catalyst **12** gave the best results; the reaction could be performed under solvent-free conditions and with very low catalyst loading (0.01 mol%). The ring-opened products were obtained in excellent yields and enantioselectivities (up to 99% yield and 94% *ee*). The Cr(III)–Co(III) catalyst **12** (Figure 3) exhibited higher enantioselectivity than monomeric analogue **1** (Scheme 4) and dimeric homobimetallic complex **6** (Figure 1) in the ARO of cyclohexene oxide under the same reaction conditions. Cr(III)–Mn(III) catalyst **11** (Figure 3) displayed the highest reactivity, with a turnover frequency (TOF) fifty times higher than monomeric **1** and five times higher than homometallic complex **6** (Figure 1) under the same reaction conditions. The study also included a number of dimeric catalysts with different diamine backbones, although the best results were obtained for the catalysts shown in Figure 3 with *trans*-1,2-diaminocyclohexyl backbones. For the pseudo-*C*s

catalysts **13** and **14** (Figure 3), the ligand itself is achiral, and the chirality is induced only by the coordination of two different metal ions. Even so, this weak source of chirality was enough to induce enantioselectivity and the complexes were found to catalyze the ARO of cyclopentene oxide with TMSN3 under solvent-free conditions, giving the ring-opened product in >99% yield and 63–76% *ee*.

**Figure 3.** Pseudo-*C*2 and pseudo-*C*s-symmetric heterobimetallic bissalen complexes.

Another way of exploiting the cooperative mechanism is by designing catalysts where metal–salen complexes are brought into close proximity by non-covalent interactions. Hence, Mirkin and coworkers [33] developed an allosteric supramolecular catalyst by synthesizing a Cr–salen complex with a 2-diphenylphosphanylethylsulfanyl linker at each end of the salen ligand. The dimeric allosteric catalyst was formed by connecting two Cr–salen complexes through coordination to Rh(I) at each end (Figure 4). The distance between the two Cr–salen units (changing between the closed and open forms) could be allosterically controlled by the reversible binding of a CO molecule and a chloride ion to each Rh(I) center (Figure 4). The catalytic properties were investigated in the ARO of cyclohexene oxide with TMSN3. Using the closed form of the catalyst (complex **15**) gave 68% *ee* and a 20-fold rate enhancement compared to the monomeric catalyst **1** under the same conditions. The open form of the catalyst (complex **16**) generated a further doubling of the reaction rate. However, no *ee* values of the product were reported from the catalysis performed with the open form of the catalyst. Due to the poor solubility of the catalyst, all reactions were performed in benzonitrile.

The same research group also developed catalytically active molecular tweezers based on the same design principle with a single Rh(I) center acting as the hinge [34]. This complex allowed for reactions to be run in THF instead of benzonitrile. Using the catalyst in the ARO of cyclohexene oxide with TMSN3 yielded products with up to 80% *ee*, compared to 26% *ee* obtained with complex **1** under the same reaction conditions. The closed form of the catalyst maintained a high enantioselectivity over a range of concentrations, while the open (linear) form exhibited significantly decreased enantioselectivity at lower concentrations.

Wärnmark and coworkers [35,36] explored hydrogen-bonded supramolecular catalysts, designing Cr–salen complexes capable of forming heterodimers through complementary hydrogen-bonding motifs (complexes **17** and **18** in Figure 5). In addition, complexes containing an alkyl strap were also synthesized (complexes **19** and **20** in Figure 5) in order to force the hydrogen-bonding moieties of the monomers into a favorable conformation to assist the aggregation of the desired cyclic heterodimer. The ARO of cyclohexene oxide and cyclopentene oxide with TMSN3 in toluene was used to evaluate the supramolecular systems. Kinetic studies showed that the supramolecular systems **17** + **18** and **19** + **20**, respectively, gave higher reaction rates than monosalen catalyst **1** (Scheme 4) with the strapped systems showing the highest catalytic efficacy. The effect was most pronounced at lower catalyst concentrations. As an example, at 5 mM catalyst concentration in toluene, the strapped system **19** + **20** gave eight times higher initial rate than monosalen catalyst **1** for the ARO of cyclohexene oxide. Studies also indicated that more than one reaction mechanism may be involved in the catalysis involving these systems. The induced enantioselectivity was, however, significantly lower (<10% *ee*) than what was obtained with catalyst **1**. Equilibrium studies on similar studies by the Wärnmark group [37] showed that only a fraction of the supramolecular assemblies contained the cyclic dimeric structure in solution. Hence, the catalysis was, instead, most likely conducted by a mixture of open, linearly aggregated species.

**Figure 4.** An allosteric supramolecular bissalen catalyst; closed form (top, **15**) and open form (bottom, **16**). PPNCl = bis(triphenylphosphoranylidene)ammonium chloride.

**Figure 5.** Monomeric catalysts **17**–**20**, drawn as hydrogen-bonded cyclic dimeric aggregates.

One area of interest has been the development of heterogeneous metal–salen catalysts, as this potentially allows for an easier product separation and catalyst recovery [14,15,38]. Several different strategies have been explored for the immobilization of metal–salen complexes on different solid supporting materials [39]. In addition to the reactivity and enantioselectivity, the heterogeneous catalysts also need to be evaluated in terms of stability, leaching, and recyclability.

Early examples include polymer-supported chiral Cr–salen complexes [40] and cationic chiral Cr–salen complexes incorporated into the cavities of zeolites and the interlamellar region of montmorillonite [41]. Both of these strategies gave low enantioselectivities in the ARO of cyclic *meso*-epoxides with TMSN3. The decreased enantioselectivities compared to homogeneous catalysts were attributed to a changed steric environment around the complex [40,41] and loss of the cooperative catalytic effect [41].

Garcia and co-workers [42] developed heterogeneous catalysts by binding chiral Cr–salen complexes to solid silicates. The complexes were anchored on functionalized silicates through aminopropyl tethers, either by complexation with the metal (complex **21**, Figure 6) or by covalent linkage to the ligand (complex **22**, Figure 6). The complexes anchored to the solid through coordination to the chromium catalyzed the ARO of cyclohexene oxide with TMSN3 with high yield (93–99%) and up to 70% *ee* but were found to undergo extensive leaching of the complex into the diethyl ether solution. In contrast, the covalently linked complexes showed no leaching but generated only moderate yields and low enantiomeric excesses in the ring-opening of cyclohexene oxide (43–66% yield and 8–18% *ee*). The decreased enantioselectivity compared to homogeneous catalysts was attributed to a likely change in the reaction mechanism.

**Figure 6.** Cr–salen complexes anchored to functionalized silicates SiO2, ITQ-2 and MCM-41.

Jacobs and coworkers [43] conducted further investigations of heterogeneous catalyst **21** (Figure 6) in the ARO of *meso*-epoxides. They found that the level of Cr–salen complex leaching is largely dependent on the choice of solvent. While homogeneously catalyzed ARO reactions of epoxides are usually performed in ethereal solvents, in heterogeneous catalysis, these solvents greatly enhanced the leaching by facilitating ligand exchange processes. Using apolar non-coordinating solvents like hexane gave leaching of <1% in the ARO of cyclohexene oxide and cyclopentene oxide with TMSN3 as nucleophile, while maintaining excellent yields and good enantioselectivities (up to 77% *ee*). Recycling experiments showed that the catalyst could be recycled up to 10 times without loss of reactivity and enantioselectivity, although the reaction time had to be increased after each run.

Jacobs and coworkers also explored monomeric complex **1** (Scheme 4) and dimeric complex **23** (Figure 7) impregnated on unfunctionalized silica [44,45]. The heterogeneous catalysts were used in the ARO of cyclopentene oxide and cyclohexene oxide with TMSN3. All reactions were performed in hexane. The catalyst based on monomeric complexes exhibited moderate reactivity and enantioselectivity (47–98% yield and 30–45% *ee*), and while leaching was limited, the silica support suffered some deterioration after repeated experiment [45]. The catalyst based on dimeric complex **23** (Figure 7) gave higher yields (74–98%) and improved, although still moderate, enantioselectivities (50–68% *ee*). Using the catalyst in a continuous-flow reactor reduced the deterioration of the support, although these experiments were only performed for the KR of 1,2-epoxyhexane with TMSN3 [44]. In later studies, the dimeric Cr–salen complex was also immobilized in a silica-supported ionic liquid, using ionic liquid [bmim][PF6] (bmim = 1-butyl-3-methylimidazolium) [46]. This type of heterogenization resulted in both increased reactivity and enantioselectivity compared to the dimeric catalyst impregnated on silica (93% yield and 75% *ee* in the ARO of cyclohexene oxide with TMSN3), as the catalyst in the supported ionic liquid phase was more accessible for reaction than when adsorbed on a silica surface. The catalyst and the ionic liquid could be recovered by Soxhlet extraction with acetone and recycled without loss of enantioselectivity. As reported for the catalysts impregnated on silica, the support shows some deterioration over time, but this could again be improved by using a continuous-flow reactor.

**Figure 7.** Dimeric Cr–salen complex **23**.

Another approach to the heterogenization of Cr–salen complexes is to use dendritic structures as a soluble support. Hence, Keilitz and Haag [47] developed catalysts based on Cr–salen complexes immobilized on hyperbranched polyglycerol (complexes **24**–**27**, Figure 8). The catalysts consist of Cr–salen analogues with a pyrrolidine backbone, which are linked to the support by linkers of di fferent lengths. The catalysts were used in the ARO of cyclopentene oxide and cyclohexene oxide with TMSN3, using diethyl ether as solvent. The dendrimeric catalysts displayed significant rate enhancements compared to a monomeric analogue, but decreased enantioselectivity. By increasing the length of the linker, the enantioselectivity was improved (from 16% to 64% *ee* for the ARO of cyclopentene oxide). The best results were obtained with a C10 linker (catalyst **26**) which gave the ring-opened products with *ee* values of 48% (for the product from cyclohexene oxide) and 64% (for the product from cyclopentene oxide). Full conversions were reported for all reactions.

**Figure 8.** Cr–salen complexes immobilized on hyperbranched polyglycerol (hPG).

Schulz and coworkers [38] synthesized a chiral calixsalen-type chromium complex that was employed as a heterogeneous catalyst in the ARO of cyclohexene oxide and 3,4-epoxytetrahydrofuran with TMSN3. The macrocyclic catalyst **28** contains 2–5 repeating thiophene-salen units and was used as an oligomeric mixture (Figure 9). The reaction was performed under heterogeneous conditions in *tert*-butyl methyl ether (TBME), and the catalyst could be recovered by filtration and recycled several times. The products were obtained in good yields (62–90%) and moderate enantioselectivities (42–62% *ee*).

**Figure 9.** Macrocyclic calixsalen catalyst **28**.

Inspired by Weck's [48] work on hydrolytic kinetic resolution (HKR) of terminal epoxides, Liu and coworkers [49] studied the catalytic properties of macrocyclic oligomer-supported Cr–salen catalysts in the ARO of cyclohexene oxide with TMSN3. Catalysts with different linker lengths between the salen complex and the oligomers were synthesized and compared (catalysts **29**–**31**, Figure 10). The catalysts were obtained as mixtures of different ring sizes (dimers to decamers) and used as such in the catalytic studies. Reactions carried out with 0.2 mol% catalyst loading in diethyl ether gave significantly higher catalytic activity, enantioselectivity and reaction rates than for the monomeric catalyst **1** (Scheme 4) under the same conditions. The catalyst with the shortest linker (catalyst **29**) showed the highest reaction rate (17 times higher initial TOF than monomeric catalyst **1**) and the catalyst with the longest linker (catalyst **31**) gave the highest enantioselectivity (82% *ee*), demonstrating the importance of distance and relative orientation of the Cr–salen complexes in multi-metallic catalysts. The catalysts could be recovered by precipitation with acetone and recycled up to five times with maintained reactivity and enantioselectivity.

**Figure 10.** Macrocyclic oligomer-supported Cr–salen catalysts.

In an effort to improve catalyst recycling, Song and coworkers [50] investigated the use of ionic liquids based on 1-butyl-3-methylimidazolium salts ([bmim][X], Figure 11) as reaction medium in the ARO of cyclic *meso*-epoxides with TMSN3 catalyzed by Cr–salen complex **1** (Scheme 4). By performing the reactions in ionic liquids, the products could be extracted with hexane, while the catalyst remained in the ionic liquid phase. The recovered catalyst could be recycled several times without loss of reactivity or enantioselectivity. The study also found that the nature of the anionic counter ion has a large influence on the reaction, where reactions performed in [bmim][PF6] gave high yields and enantioselectivies (Scheme 6), comparable to those obtained under homogeneous conditions [20], while reactions carried out in more hydrophilic ionic liquids like [bmim][OTf] hardly gave any product.

**Scheme 6.** The asymmetric azidolysis of cyclopentene oxide catalyzed by Cr–salen complex **1** (Scheme 4) in [bmim][PF6].

Cui and coworkers [51] prepared chiral coordination cages with metal–salen linkers. The so formed supramolecular nanoreactors consisted of six dicarboxylate linkers based on metal–salen complexes (Mn(III)-, Cr(III)-, and Fe(III)salen complexes) and four Cp3Zr3 cluster vertices, giving a tetrahedral cage with a hydrophobic cavity (Figure 12). Remarkably, the mixed-linker cage containing both Mn–salen and Cr–salen linkers was able to catalyze the sequential asymmetric epoxidation/ring-opening of 2,2-dimethyl-2*H*-chromene, giving the product with high yield and enantioselectivity (Scheme 7). The cage catalyst also allowed for very low catalyst loadings and remained active at 0.005−0.01 mol%. The reactions were performed under homogeneous conditions, but the catalyst could be recovered by precipitation by the addition of diethyl ether and recycled up to five times with only a slight decrease of enantioselectivity. The same group also explored metal-organic frameworks (MOFs) containing metal–salen linkers prepared by post-synthetic exchange of ligands. The mixed Cr–Mn MOFs catalyzed the sequential alkene epoxidation/ring-opening of 2,2-dimethyl-2*H*-chromene in good yield and enantioselectivity [52].

Yang and coworkers [53] used Cr–salen complex **1** (Scheme 4) to catalyze the ARO of *meso*-epoxides with TMSN3 as an example reaction to investigate the efficiency of their liquid-solid hybrid catalysts. The hybrid catalysts were designed to bridge homogeneous and heterogeneous catalysis and consisted of a catalyst-containing ionic liquid hosted in a porous solid outer crust (Figure 13). The ionic liquid phase consisted of [bmim][PF6] mixed with 20% [bmim][BF4] and a small amount of water, and the silica porous crust was prepared from tetramethoxysilane (TMOS). The catalytic particles were successfully packed into fixed-bed reactors for continuous flow reactions. During the reaction, the reactants could pass through the porous crust to the liquid pool where the "homogeneous" reaction occurred. When used in a continuous flow system with *n*-octane as the mobile phase, the hybrid catalyst demonstrated high catalytic efficiency for the ARO of cyclopentene oxide, cyclohexene oxide and *cis*-2,3-epoxybutane. The products were obtained with excellent yields (>99%) and up to 93% *ee*

(for the product from cyclopentene oxide). The reactivity and enantioselectivity could be maintained over 600 h.

**Figure 12.** Single crystal X-ray structure of Mn–salen linked coordination cage. The yellow sphere highlights the hydrophobic cavity. Reprinted with permission from Reference [51]. Copyright 2018 American Chemical Society.

**Scheme 7.** The sequential asymmetric epoxidation/ring-opening of 2,2-dimethyl-2*H*-chromenes catalyzed by the mixed Mn–Cr coordination cage shown in Figure 12.

**Figure 13.** A liquid-solid hybrid catalyst. Adapted with permission from Reference [53]. Copyright 2019 American Chemical Society.

#### *2.2. With Anilines, Amines, and Carbamates*

An alternative, seemingly more straightforward method for obtaining enantiopure vicinal amino alcohols than first forming the azido alcohol and then reducing it, is to use amines as nucleophiles in the ARO of *meso*-epoxides. However, this approach suffers from an inherent compatibility problem, as the Lewis acidic metal–salen catalyst can be deactivated by complexation with the Lewis basic amine. Nevertheless, there are several examples of successful strategies for overcoming these issues and achieving highly active and enantioselective catalysis of the aminolysis of *meso*-epoxides.

Bartoli and Melchiorre [54] employed Cr–salen complex **1** (Scheme 4) in the ARO of *meso*-stilbene oxide with anilines as nucleophiles. Reactions carried out in dichloromethane with 10 mol% catalyst loading afforded the corresponding amino alcohols with high yields, complete diastereocontrol (only the *syn*-isomer was observed) and high enantioselectivity (Scheme 8). The use of a catalytic amount of Et3N as an additive was found to give a significantly enhancement of the enantioselectivity (from 76% to 90% *ee* for reaction with aniline) but caused a moderate loss of reactivity.

**Scheme 8.** The asymmetric aminolysis of *meso*-stilbene catalyzed by Cr–salen complex **1** (Scheme 4).

Kureshy and coworkers [55,56] investigated several different approaches to achieve the enantioselective synthesis of vicinal amino alcohols by the ARO of *meso*-epoxides. One such approach is the use of in situ generated monomeric and polymeric Ti(IV)salen complexes from ligands **32** and **33** (Scheme 9) [55]. In order to achieve an efficient asymmetric catalysis, high catalyst loading (20 mol%) and the addition of additives was required. For the ARO of *meso*-stilbene oxide with aniline, the best results were obtained with the enantiopure imine additive **A** (Scheme 9). Under optimized conditions, the ring-opened product was obtained in excellent yield and enantioselectivity (99% yield and >99% *ee*). Noticeably, the use of the opposite enantiomer of the additive resulted in significantly lower enantioselectivity (75% *ee*). The authors suggested that this could indicate synergistic effects between the catalyst and the additive but did not investigate it further. For the ARO of cyclic epoxides, triphenylphosphine was found to be the best additive, although yields and *ee* values were significantly lower than those found for *meso*-stilbene oxide. The monomeric and polymeric catalyst gave comparable yields and enantioselectivities, but the polymeric catalyst generated from ligand **33** showed higher reactivity. In addition, the polymeric catalyst could be precipitated out from the reaction mixture by the addition of *n*-hexane and recycled several times without loss of enantioselectivity.

**Scheme 9.** The asymmetric aminolysis of *meso*-stilbene oxide catalyzed by in situ formed Ti–salen complexes using ligands **32** and **33**.

The same group also synthesized and evaluated a series of enantiopure macrocyclic Cr–salen complexes with different counter ions [56]. After the screening of different reaction conditions, optimal results were obtained for reactions performed in CH2Cl2/MeOH (9:1 *v*/*v*) with 0.5 mol% catalyst loading using catalyst **34** (Figure 14). These conditions were used for the ARO of a limited number of cyclic and acyclic *meso*-epoxides with aniline, giving the products in excellent yields (98–99%) and high enantioselectivities (up to 91% *ee*). The catalyst could be recycled up to four times without loss of reactivity or enantioselectivity.

**Figure 14.** Macrocyclic Cr–salen complex **34**.

Jacobsen and coworkers [57,58] used cyclic Co–salen catalyst **35** as a mixture of oligomers in the ARO of cyclic *meso*-epoxides with phenyl carbamate, resulting in the asymmetric synthesis of *<sup>N</sup>*-protected *trans*-1,2-amino alcohols in high yields and with excellent enantioselectivities (Scheme 10). For six-membered ring epoxides, the addition of the nucleophile was followed by intramolecular cyclization, resulting in *trans*-4,5-disubstituted oxazolidinone products. The ARO of five-membered ring epoxides also proceeded smoothly, although the products did not undergo cyclization, most likely due to the unfavorable strain in *trans*-fused 5-5 ring systems. The products could be deprotected by hydrolysis under basic conditions, and the method could be scaled-up to prepare multigram quantities of the products (Scheme 11).

**Scheme 10.** The asymmetric carbamolysis of *meso*-epoxides catalyzed by cyclic oligomeric Co–salen complex **35**.

**Scheme 11.** A multigram synthesis of *trans*-2-aminocyclohexanol hydrochloride using oligomeric catalyst **35** (Scheme 10).

Peddinti and coworkers [59] used Co(III)salen complexes to catalyze the ARO of cyclohexene oxide with secondary aliphatic amines, enabling the highly enantioselective synthesis of biologically important molecules such as vesamicol. Screening of reaction conditions revealed that the solvent had a large impact on the reaction rate and the enantioselectivity. The counter ion was also shown to affect both the catalytic activity of the catalyst and the enantioselectivity of the reaction. For the ARO of cyclohexene oxide with 4-arylpiperidines, the reaction performed with catalyst **36** in *tert*-butyl methyl ether (TBME) gave products with good yields and good to excellent enantioselectivities (Scheme 12).

**Scheme 12.** The asymmetric aminolysis of cyclohexene oxide catalyzed by Co–salen complex **36**.

In the area of heterogeneous catalysis, Islam and coworkers developed catalysts based on a series of metal–salen complexes supported on functionalized mesoporous silica materials. A chiral Fe(III)salen complex was covalently immobilized on mesoporous silica SBA-15 through an aminopropyl linker (Figure 15) [60]. The so-formed heterogeneous catalyst **37** was used in the ARO of cyclohexene oxide with different anilines, giving the products in high yields (85–96%) and with excellent enantioselectivities (96–99% *ee*). Notably, the reactions could be performed under solvent-free conditions and reached complete conversions in just 2–3 h at room temperature. The catalyst could be recycled up to five times with maintained reactivity and enantioselectivity.

**Figure 15.** A Fe–salen complex immobilized on mesoporous silica SBA-15.

Islam and coworkers [61] also immobilized Co–salen complexes on mesoporous silica. The Co–salen complexes were grafted on the material through non-covalent interactions between quaternary amine groups on the salen units and carboxylate units on the functionalized silica (catalyst **38**, Figure 16). The material showed excellent catalytic activities for the ARO of cyclohexene oxide with a number of aromatic and cyclic amines under solvent-free conditions, with short reaction times (1–2.5 h), high yields and high enantioselectivities (87–97% yield and 77–99% *ee*). After the reaction, the catalyst could be recovered by precipitation and centrifugation and then recycled without loss of reactivity or enantioselectivity and with no detectable metal leaching.

**Figure 16.** A Co–salen complex immobilized on mesoporous silica SBA-15.

Tu and coworkers [62] developed two-dimensional self-supported (i.e., immobilized without the use of an external support) chiral catalysts based on titanium. The catalytic systems consisted of coordination assemblies consisting of heteroditopic ligands containing enantiopure 1,1'-bi-2-naphthol (BINOL) and salen derivatives, where the oxygen bridge in dimeric Ti(IV)salen complexes was used as a crosslinker (Figure 17). Due to the fact of their insolubility in most organic solvents and water, the assemblies were used as heterogeneous catalysts in the ARO of cyclic and acyclic *meso*-epoxides with benzylic and aliphatic amines as nucleophiles. The reactions were performed in toluene and the products were obtained in high yields and enantioselectivities (83–99% yield and 83–98% *ee*). Furthermore, saturated analogues of the metal–salen complexes were also investigated, and the salan-based catalyst **39** was successfully used for the one-pot sequential asymmetric epoxidation/ring-opening of 2,2-dimethyl-4,7-dihydro-1,3-dioxepine, giving the product with high yield and enantioselectivity (Scheme 13). The self-supported catalysts demonstrated very high stability and could be reused up to 20 times without significant loss in yield or enantioselectivity.

Cui and coworkers [63] developed heterogeneous catalysts based on MOFs and coordination cages with metal–salen linkers. The Cr/VO-salen mixed MOF catalysts were fabricated via solvent-assisted linker exchange and used in the ARO of *meso*-stilbene oxide with aniline as nucleophile. The reaction performed in CH2Cl2 with 5 mol% catalyst loading gave the product in 87% yield and 76% *ee*. The same group also designed coordination cages with mixed Mn–salen and Cr–salen linkers which were able to catalyze the sequential asymmetric epoxidation/ring-opening of 2,2-dimethyl-2*H*-chromene with anilines, affording the products in good yield (60–82%) and with excellent enantioselectivity (up to 99.9% *ee*) (Scheme 7) [51].

**Figure 17.** (**a**) A schematic representation of 2D titanium metal–organic coordination assemblies. (**b**) A self-supported chiral Ti–salen catalyst with different linkers and diamine substituents.

**Scheme 13.** The sequential asymmetric epoxidation/ring-opening of 2,2-dimethyl-4,7-dihydro-1,3- dioxepine catalyzed by self-supported Ti-salan catalyst **39**.

### *2.3. With Oxygen-Containing Nucleophiles*

The hydrolytic asymmetric ring opening of cyclic *meso*-epoxides provides a pathway towards enantioenriched vicinal *trans-*diols and is a valuable complement to other methods such as the catalytic asymmetric dihydroxylation of cyclic alkenes which selectively produce *cis*-diols [64]. Several of the catalysts that have proven effective for the HKR of terminal epoxides have also been investigated in the ARO of *meso*-epoxides [65–68]. While many of the HKR catalysts failed to exhibit high reactivity and enantioselectivity in the ARO of *meso*-epoxides, there are a few examples where the use of Co(III)salen complexes afforded enantioenriched vicinal *trans*-diols in high yields and enantioselectivities.

In 2001, Jacobsen and coworkers [69] reported a mixture of macrocyclic oligosalen complexes (catalyst **40**, Figure 18) as a catalyst for the HKR of terminal epoxides. This catalyst was also proven to be effective in the hydrolytic ARO of cyclohexene oxide. Using this catalyst, *trans*-1,2-cyclohexane diol was synthesized with 98% yield and 94% *ee* (Scheme 14).

**Figure 18.** Macrocyclic oligosalen mixtures **40** and **35** and monomeric analogue **41**.

**Scheme 14.** The asymmetric hydrolysis of cyclohexene oxide catalyzed by cyclic oligomeric Co–salen complex **40** (Figure 18).

Kinetic studies demonstrated that oligosalen catalyst **40** was much more reactive and enantioselective in the hydrolysis of cyclohexene oxide than monomeric analogue **41** (Figure 18). Despite its excellent reactivity, the application of catalyst **40** was limited by its low solubility in the reaction mixture. In addition, reproducibility problems were observed when applying **40** from different batches in the same reaction [69]. To resolve these issues, the same group reported a new generation of oligomeric salen complexes (catalyst **35** in Figure 18) which could be prepared on a multigram scale with 60–66% overall yield [58]. The mixture was found to consist mainly of dimer (*n* = 1), with a small amount of trimer (*n* = 2). The catalyst showed improved reactivity and enantioselectivity compared to monosalen complex **41** and oligomeric mixture **40** in the hydrolysis of *meso*-epoxides. The catalyst tolerated a broad scope of substrates and gave the ring-opened products in high yields and enantioselectivities for five- and six-membered cyclic *meso*-epoxides (Scheme 15). The enhanced reactivity of these oligomeric salen complexes compared to monosalen analogues was attributed to the cooperative intramolecular interactions between two salen moieties, which was further supported by the observed first-order kinetic dependence on catalyst concentration.

$$\begin{array}{ccccc} \text{HO}\_{\cdot,\cdot,\cdot} \text{O} & \xrightarrow{\text{O}^{2-}} & \text{O}^{2-} & \text{O}^{2-} & \text{O}^{2-} & \text{O}^{2-} \\ \text{O}^{2-} & & & & \text{O}^{2-} & \text{O}^{2-} & \text{O}^{2-} \\ \text{O}^{2-} & & & & \text{O}^{2-} & \text{O}^{2-} \\ \text{O}^{2-} & & & & \text{O}^{2-} & \\ \text{O}^{2-} & & & & \text{O}^{2-} & \\ \end{array}$$

**Scheme 15.** The asymmetric hydrolysis of cyclic *meso*-epoxides catalyzed by cyclic oligomeric Co–salen complex **35** (Figure 18).

The cooperative mechanism was also exploited by Liu and coworkers in the design of bimetallic catalyst **42** (Figure 19) [70]. Complex **42** is capable of self-assembling into a dimer by aromatic donor-acceptor interactions between naphthalenediimide and pyrene. The catalyst displayed excellent reactivities in HKR reactions of several terminal epoxides as well as in the hydrolytic ARO of cyclohexene oxide, the latter detailed in Scheme 16. In addition, it was found that performing the reactions with a 1:1 mixture of analogues **43** and **44** (Figure 19) gave similar or better results than complex **42**. Using only one of the analogues (either **43** or **44**) required significantly longer reaction times to reach full conversions. This further supported that the aromatic donor-acceptor interactions played an important role for the reactivities of these catalysts.

**Figure 19.** Self-assembling cooperative Co–salen catalysts **42**–**44** (blue = aromatic acceptor, red = aromatic donor).

**Scheme 16.** The asymmetric hydrolysis of cyclohexene oxide catalyzed by cooperative Co–salen complexes **42** or **43** + **44** (Figure 19).

The ARO of *meso*-epoxides with carboxylic acids is of interest owing to its possibility to access monoesters of vicinal diols in high yield and with high enantio- and diastereoselectivity, something which is difficult to achieve with other synthetic methods. Jacobsen's group investigated this type of reaction with various monosalen catalysts, finding that a Co(III)salen complex, generated in situ by stirring Co(II)salen complex **45** (Figure 20) in carboxylic acid in air, was the most effective in catalyzing the reaction [71]. With the addition of diisopropylethylamine, complex **45** catalyzed the reactions between *meso*-epoxides and benzoic acid, affording the corresponding mono-benzoate esters in good to excellent yields and *ee* values (Scheme 17). The substrate scope included cyclic and acyclic *meso*-epoxides with aliphatic and aromatic substituents. The use of one equivalent of weakly coordinating base was necessary to achieve a high rate, enantioselectivity and yield. The authors hypothesized that the beneficial effects might stem from the fact that amines significantly increase the solubility of benzoic acid in TBME. The crystallinity of the mono-benzoate esters also meant that for reactions with moderate *ee* values, the enantiomeric excess could easily be further improved by recrystallization. This methodology was successfully applied to the ARO of *meso*-epoxides with benzoic acid and benzoic acid derivatives as nucleophiles. Using other acids, such as acetic acid or pivalic acid, resulted in lower enantioselectivity and reactivity and was not pursued further.

**Figure 20.** Co(II)salen complex **45**.

**Scheme 17.** The asymmetric ring-opening of *meso*-epoxides with benzoic acid catalyzed by Co–salen complex **45** (Figure 20) to generate monoesters.
