*3.1. With Azides*

Jacobsen and coworkers reported the azidolytic KR of terminal epoxides catalyzed by Cr–salen complex **2** (Scheme 4) [92]. The reactions were run under solvent-free conditions at 0–2 ◦C. By using 0.5 equivalents of TMSN3, the ring-opened products could be obtained in 40–49% yield and 89–97% *ee*. The reaction exhibited good functional group tolerance (Scheme 30). One of the investigated reactions, the azidolytic KR of epichlorohydrin, was further investigated, as it was discovered that the unreacted epoxide underwent racemization under the reaction conditions. This enabled the dynamic kinetic resolution (DKR) of epichlorohydrin, where, by adding TMSN3 in portions over time, the desired ring-opened product was obtained in 76% yield and 97% *ee* (Scheme 31) [93].

The same protocol was also extended to include 2,2-disubstituted epoxides, using in situ formed HN3 (formed from TMSN3 and isopropanol) as the nucleophile [94]. Performing the reaction in TBME afforded both ring-opened products and unreacted epoxides in high yields and enantioselectivities (Scheme 32). This methodology was successfully used for the enantioselective preparation of a key intermediate in a synthesis of the natural product taurospongin A [95].

**Scheme 30.** The azidolytic kinetic resolution terminal epoxides catalyzed by Cr–salen complex **2** (Scheme 4).

**Scheme 31.** The dynamic kinetic resolution of epichlorohydrin with TMSN3 catalyzed by Cr–salen complex **53**.

**Scheme 32.** The azidolytic kinetic resolution of 2,2-disubstituted epoxides catalyzed by Cr–salen complex **2** (Scheme 4).

Jacobs and coworkers used Cr–salen complex **1** (Scheme 4) for the KR of terpene epoxides with TMSN3 [96]. This constitutes a rare example of the kinetic resolution of trisubstituted epoxides. The reaction gave enantioenriched epoxides and ring-opened products in good yields and high diastereomeric excess. Initial experiments revealed that both enantiomers of the Cr–salen complex, (*R*,*<sup>R</sup>*)-complex **1** (Scheme 4) and (*S*,*S*)-complex **46** (Scheme 18), exhibited similar reactivity and selectivity. It was therefore hypothesized that the observed stereoselectivity of the reaction was induced by the C4 substituent (Scheme 33) and that the Cr–salen complex served only as an activating agen<sup>t</sup> for the azide-transfer. As such, later experiments were performed with the Cr–salen complex **1**(**46**) as a racemic mixture (Scheme 33). For all investigated substrates, the *cis*-diastereomers were selectively transformed and the *trans*-epoxides remained unreacted (*cis* and *trans* refers to the relative stereochemistry of the methyl group and the C4 substituent). Jacobs and coworkers also investigated the effect of micro-wave irradiation on the Cr–salen-catalyzed KR of terminal epoxides, as well as the ARO of *meso*-epoxides. It was found that the reaction rate could be increased by up to three orders of magnitude without any significant loss of enantioselectivity under micro-wave irradiation [97].

**Scheme 33.** The kinetic resolution of (-)-limonene-1,2-epoxide with TMSN3 catalyzed by Cr–salen complex **1**(**46**) (Schemes 4 and 18, respectively) as a racemic mixture.

Similar to the ARO of *meso*-epoxides with azides, most examples of metal–salen-catalyzed KRs of epoxides with azides are based on chromium-salen complexes. One example of a di fferent metal–salen complex was published by Kim and coworkers, who used binuclear Co(II)salen complexes bearing Lewis acids of group 13 metals (Scheme 34) [98]. The presence of a group 13 Lewis acid was necessary for catalytic activity, and the dimeric complexes showed enhanced reactivity and enantioselectivity compared to their monomeric analogues. The system allowed for low catalyst loading, where 0.5 mol% of complex **54** catalyzed the azidolytic KR of a number of terminal epoxides, a ffording ring-opened products in excellent yields and with high enantioselectivity (Scheme 34).

**Scheme 34.** The azidolytic kinetic resolution of terminal epoxides with catalyzed by dimeric Co(II)salen complexes formed by group 13 metal activation.

For the development of heterogeneous catalysts for the KR of epoxides, the same strategies as for the ARO of *meso*-epoxides have been employed. Early examples of polymer-supported Cr–salen complexes only induced low enantioselectivities in the ring-opened products, but exhibited good stability and recyclability [40]. Jacobs and coworkers have published extensive work on the impregnation of Cr–salen complexes on silica and silica-supported ionic liquids. Both monomeric complex **1** (Scheme 4) and dimeric complex **23** (Figure 7) were separately physiosorbed on silica and evaluated as catalysts in the KR of 1,2-epoxyhexane and 1,2-epoxyoctane, achieving quantitative conversions and high enantioselectivities (up to 98% *ee* for ring-opened products). The dimeric complexes showed improved enantioselectivity compared to the monomeric analogues. Using the catalyst in a continuous flow reactor decreased the deterioration of the solid support and resulted in quantitative yields and high enantioselectivities for both the ring-opened products and unreacted epoxides (up to 99 and 85% *ee*, respectively) [44,45]. Immobilizing the dimeric complex in a silica-supported ionic liquid further improved the reactivity and enantioselectivity, and both the catalyst and the ionic liquid could be recovered by Soxhlet extraction with acetone [46].

Liu and coworkers investigated the macrocyclic oligomer-supported Cr–salen catalysts **29**–**31** (Figure 10) in the KR of 1,2-epoxyhexane and propylene oxide [49]. The same trend as in the ARO of *meso*-epoxides was found, where a shorter linker between the Cr–salen complex and the macrocycle increased the reaction rate and gave the highest yield (45–48%), while a longer linker gave better enantioselectivity (83–84% *ee*) for the ring-opened product.

Yang and Li constructed an e fficient solid nanoreactor by encapsulating Cr–salen complex **1** (Scheme 4) and pyridine inside a mesoporous silica nanocage [99]. The addition of pyridine led

to a pronounced increase in TOF and enantioselectivity, which was attributed to the increased nucleophilicity of the Cr–salen complex after coordination to pyridine. The system was investigated in the KR of 1,2-epoxyhexane with TMSN3 under solvent-free conditions and at very low catalyst loading (0.002 mol%), affording both ring-opened product and unreacted epoxide in close to quantitative yield and with high enantioselectivity (91% *ee* and 92% *ee*respectively). The nanoreactor showed high stability and could be recovered and recycled nine times with maintained reactivity and enantioselectivity.

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

Bartoli and Melchiorre investigated different metal–salen catalysts for the KR of epoxides with different nitrogen-based nucleophiles. Cr–salen complex **1** (Scheme 4) was used for the KR of a variety of *trans*-disubstituted aromatic epoxides with aniline and anisidine (Scheme 35). Complete regioand diastereoselectivity was observed, and the vicinal *anti*-amino alcohol products were obtained in reasonable yields and enantioselectivities (77–99% *ee*). The study also included a rare example of the KR of a trisubstituted epoxide, where applying the protocol on *trans*-2-methyl-2,3-diphenyl oxirane afforded the ring-opened products in 18% yield and 81% *ee* [54].

**Scheme 35.** The aminolytic kinetic resolution of internal *trans*-epoxides catalyzed by Cr–salen complex **1** (Scheme 4).

The same group also investigated the KR of terminal epoxides using *tert*-butyl arbamate as the nucleophile. Co(II)salen complex **45** (Figure 20) was used as a pre-catalyst and oxidized in situ to the corresponding Co(III)salen complex by addition of *p*-nitrobenzoic acid, affording enantiopure (*ee* ≥ 99%) *<sup>N</sup>*-protected vicinal amino alcohols in high yields and with complete regioselectivity, while the unreacted epoxides could also be isolated with high *ee* values (Scheme 36). The protocol was effective for both linear and relatively hindered aliphatic epoxides, as well as epoxides containing different functional groups [100].

**Scheme 36.** The carbamolytic kinetic resolution of terminal epoxides employing Co(II)salen complex **45** as a pre-catalyst (Figure 20).

The use of ionic liquids as the reaction medium is considered an environmentally friendly alternative to traditional organic solvents [101]. This was exploited by Kureshy and coworkers in several studies on the KR of epoxides. In one such study, the protocol presented in Scheme 36 was further improved by the use of ionic liquids as reaction medium [102]. Performing the reaction in [bmim][PF6] afforded both ring-opened products and unreacted epoxides in excellent yields and enantioselectivities for a number of glycidyl ethers and terminal alkyl epoxides (Scheme 37). The reactions were completed in 5–10 h and the catalyst and ionic liquid could be recycled six times with maintained enantioselectivity and reactivity. The choice of nucleophile could be extended to urethane and benzyl carbamate with equally excellent yield and enantioselectivity.

**Scheme 37.** The carbamolytic kinetic resolution of terminal epoxides in ionic liquid, employing Co(II)salen complex **45** (Figure 20) as the pre-catalyst.

In another study, Kureshy and coworkers investigated the KR of *trans*-stilbene oxide and *trans*-β-methyl styrene oxide with different anilines catalyzed by Cr–salen complex **53** (Scheme 31) [103]. Performing the reaction in [bmim][PF6] (Figure 11) afforded ring-opened products in 40–49% yield and 63–99% *ee*. The unreacted epoxides could be recovered in quantitative yield and in 60–97% *ee*. The use of ionic liquids had several advantages, including easy product separation (extraction with *n*-hexane), efficient recyclability of the catalyst and the ionic liquid, and significantly reduced reaction times compared to reactions run in conventional organic solvent.

In another effort to improve the recyclability of the catalyst, Kureshy and coworkers employed the enantiomerically pure polymeric Cr–salen complex **57** (Figure 22) in the KR of *trans*-stilbene oxide and *trans*-β-methyl styrene oxide with anilines as nucleophiles [104]. The reactions were performed in dichloromethane. The desired vicinal amino alcohols were obtained in good to excellent yield (35–49%) and high enantiomeric excess (up to 100% *ee* after a single recrystallization). The unreacted epoxide could be recovered in excellent yield (48–51%) and good to high enantiomeric excess (70–98% *ee*). The catalyst could be easily recovered by precipitation with *n*-hexane and recycled up to four times with maintained enantioselectivity. In a separate study, the same reaction was carried out with dimeric and polymeric Cr–salen complexes under microwave irradiation in a CH2Cl2/MeOH mixture (1:1), which allowed for very short reaction times (2 min) [105]. The best results were achieved with dimeric complex **23** (Figure 7) in the KR of *trans*-stilbene oxide with different anilines. The ring-opened products were obtained in 45–49% yield and 88–94% *ee* and the unreacted epoxides were isolated in 47–48% yield and 80–92% *ee*. Both dimeric catalyst **23** and polymeric catalyst **57** could be recycled five times without loss of reactivity or enantioselectivity.

**Figure 22.** Polymeric Cr–salen complex **57**.

The same group also developed a series of Cr–salen complexes with cationic side groups (catalyst **58**–**60**, Figure 23), which were used in the KR of *trans*-epoxides with different anilines [106]. The best results were obtained with catalyst **60** (Figure 23) in the KR of *trans*-stilbene oxide in dichloromethane, where the ring-opened products were obtained in excellent yields (41–49%) and with high enantioselectivities (86–99% *ee*) and the unreacted epoxides were recovered in quantitative

yield and 89–99% *ee*. The catalyst could be recycled up to six times without loss of reactivity or enantioselectivity.

**Figure 23.** Cr–salen complexes with cationic side chains.

Kureshy and coworkers investigated macrocyclic Cr–salen complex **35** (Figure 14) in the KR of *trans*-epoxides with anilines The ring-opened products were obtained in excellent yields (46–49%) and with high enantioselectivities (up to > 99% *ee*), with concomitant recovery of the unreacted epoxides in quantitative yields and with high enantioselectivities (up to > 99% *ee*) [56]. The reactions were performed in a CH2Cl2/MeOH mixture and the catalyst showed excellent recyclability. The same group also developed another set of macrocyclic Cr–salen complexes [107]. Complex **61** (Figure 24) was used as a catalyst for the synthesis of pharmaceutically important β-amino-α-hydroxyl ester derivatives by the KR of aromatic ester epoxides with anilines. The ring-opened products were obtained in high yields and with high diastereoselectivities and enantioselectivities (Scheme 38). The catalyst showed good stability and good recyclability.

**Figure 24.** Macrocyclic Cr–salen complex **61**.

**Scheme 38.** The aminolytic kinetic resolution of aromatic ester epoxides catalyzed by macrocyclic Cr–salen complex **61** (Figure 24).

For the KR of epoxides with carbamates as nucleophiles, Kureshy and coworkers developed a number of chiral polymeric Co–salen complexes with chiral and achiral linkers. The complexes were evaluated as catalysts in the KR of a number of glycidyl ethers and terminal alkyl epoxides with different carbamates [108]. The reaction with 1 mol% of catalyst **62** (Figure 25) in dichloromethane afforded both epoxides and *<sup>N</sup>*-protected vicinal amino alcohols in quantitative yield and with excellent enantioselectivity (>99% *ee*) in 16 h. The catalyst could be precipitated with *n*-hexane and reused up to six times with complete retention of enantioselectivity.

**Figure 25.** Polymeric Co–salen complex **62**.

Jacobsen and coworkers showed that their oligomeric Co–salen complex **35** (Scheme 10) could be used in the KR of 1,2-epoxyhexane with *tert*-butyl carbamate, where a low catalyst loading (0.2 mol%) was enough to obtain the ring-opened product in high yield and enantioselectivity (Scheme 39) [58].

**Scheme 39.** The carbamolytic kinetic resolution of 1,2-epoxyhexane catalyzed by oligomeric Co–salen complex **35** (Scheme 10).

#### *3.3. With Water (Hydrolytic Kinetic Resolution)*

Since the first report by Jacobsen in 1997, the hydrolytic kinetic resolution (HKR) of terminal epoxides has been one of the most researched applications of metal–salen catalysts. The use of water as an inexpensive and environmentally friendly nucleophile also makes it an attractive method for the enantioenrichment of epoxides otherwise difficult to obtain. The protocols have mainly used Co(III)salen catalysts and the reactions are characterized by excellent yields and enantioselectivities. Hence, instead of only focusing on obtaining high yields and enantioselectivity, much effort has been focused on increasing cooperativity and reaction kinetics, decreasing catalyst loading, as well as developing heterogeneous systems and new catalytic methodologies in general.

In their original paper, Jacobsen and coworkers found that Co(III)salen complex **63** (Scheme 40), formed in situ from the corresponding Co(II)salen complex, worked very well in the HKR of several terminal alkyl, alkenyl, and aryl epoxides, resulting in unreacted (*S*)-terminal epoxides and (*R*)-1,2-diols with excellent yields (up to 46% and 50%, respectively) and *ee* values (up to 99% and 98%, respectively) [109]. The catalyst could be easily regenerated by treatment with acetic acid in air and reused in two cycles without loss of reactivity or enantioselectivity. Later, the scope was extended to a broad group of epoxides with different steric and electronic environments [110]. In almost all cases, the unreacted epoxides could be obtained in > 99% *ee* (Scheme 40a). Furthermore, by tuning the equivalents of water and catalyst loading, most of the 1,2-diols could be obtained with excellent enantioselectivities (94–99% *ee*) (Scheme 40b).

**Scheme 40.** The hydrolytic kinetic resolution of terminal epoxides catalyzed by Co–salen complex **63**. The displayed reaction conditions are optimized for enantioenrichment of (**a**) (*S*)-epoxides; (**b**) (*R*)-1,2-diols.

For cases where the diol was required in very high enantiomeric excess, a strategy called "double resolution" was suggested and employed in the synthesis of (*S*)-3-chloropropane-1,2-diol (Scheme 41). Epichlorohydrin was first subjected to HKR with (*R*,*R*)-salen complex **64** as the catalyst (Figure 26). The enantioenriched unreacted epoxide was then separated and subjected to another HKR with the opposite enantiomer of the catalyst, (*S*,*S*)-salen complex **63** (Scheme 40), which resulted in enantiopure (*S*)-3-chloropropane-1,2-diol in 41% overall yield.

**Scheme 41.** Preparation of enantiopure (*S*)-3-chloropropane-1,2-diol using a "double resolution" strategy employing catalyst **63** (Scheme 40) and **64** (Figure 26).

**64**

**Figure 26.** Co–salen complex **64**.

The high reactivity and excellent enantioselectivity of complex **63** and **64** in the HKR of a broad range of terminal epoxides set a high standard for catalysts for these reactions. Subsequent studies have largely focused on improving other aspects of the catalysis, including reducing reaction times (average reaction time for catalyst **63** was 12–18 h, sometimes up to 72 h), reducing catalyst loading and enabling solvent-free reactions. Another important issue is catalyst recycling. For instance, homogenous catalyst **63** was recycled as a solid residue by distilling off the diols and unreacted epoxides during work up, a method which is time-consuming and only applicable for sufficiently volatile products. In addition, catalyst **63** needed to be regenerated with acetic acid in air before it could be recycled.
