Epoxides 2,2-disubstituted, kinetic resolution

Jacobsen also showed that 2,2-disubstituted epoxides underwent kinetic resolution catalyzed by (salen)Cr-N3 complex 3 under conditions virtually identical to those employed with monosubstituted epoxides (Scheme 7.34) [64]. Several epoxides in this difficult substrate class were obtained with high ees and in good yields, as were the associated ring-opened products. The kinetic resolution of TBS-... 

In the realm of hydrolytic reactions, Jacobsen has applied his work with chiral salen complexes to advantage for the kinetic resolution of racemic epoxides. For example, the cobalt salen catalyst 59 gave the chiral bromohydrin 61 in excellent ee (>99%) and good yield (74%) from the racemic bromo-epoxide 60. The higher than 50% yield, unusual for a kinetic resolution, is attributed to a bromide-induced dynamic equilibrium with the dibromo alcohol 62, which allows for conversion of unused substrate into the active enantiomer <99JA6086>. Even the recalcitrant 2,2-disubstituted epoxides e.g., 64) succumbed to smooth kinetic resolution upon treatment with... 

Three different principles of selectivity are required to achieve this result. First, the difference in rate of epoxidation by the catalyst of a disubstituted versus a monosubstituted olefin must be such that the propenyl group is epoxidized in complete preference to the vinyl group. The effect of this selectivity is to reduce the choice of olefinic faces to four of the two propenyl groups. Second, the inherent enantiofacial selectivity of the catalyst as represented in Figure 6A.1 will narrow the choice of propenyl faces from four to two. Finally, the steric factor responsible for kinetic resolution of 1-substituted allylic alcohols (Fig. 6A.2) will determine the final choice between the propenyl groups in the enantiomers of 80. The net result is the formation of epoxy alcohol 81 and enrichment of the unreacted allylic alcohol in the (35)-enantiomer. 

The rationale that explains the kinetic resolution of the 1-monosubstituted allylic alcohols predicts that a 1,1-disubstituted allylic alcohol will be difficult to epoxidize with the Ti-tartrate catalyst. In practice, the epoxidation of 1,1-dimethylallyl alcohol (88) with a stoichiometric quantity of the Ti-tartrate complex is very slow, and no epoxy alcohol is isolated... 

Figure 18.22. Dynamic kinetic resolution of 2,2-disubstituted epoxides 63 by epoxide hydrolase.

One especially interesting kinetic resolution/asymmetric epoxidation substrate is (/ .5)-2,4-hexadien-3-ol (80). The racemic diene has eight different alkene faces at which epoxidation can occur and thereby presents an interesting challenge to the selectivity of the epoxidation catalyst. The selectivity can be tested by using slightly less than 0.5 equiv. of oxidant (because the substrate is a racemate, the maximum yield of any one product is 50%). When the reaction was run under these conditions, the only product that was formed was the (l/ ,2/ ,3/ )-epoxy alcohol (81). Three different principles of selectivity are required to achieve this result. First, the difference in rate of epoxidation by the catalyst of a disubstituted... 

To illustrate the utility of the metal salen complexes, several reactions are outlined in Scheme 1. They include the asymmetric epoxidation of unfimctionalized cw-disubstituted and trisubstituted olefins, which are promoted by (salen)Mn complexes." In the case of trani-disubstituted olefins, the simple (salen)Mn complexes do not exhibit the same levels of enantioselectivity as they do with the cis- and trisubstituted derivatives. Promising alternatives include more elaborate (salen)Mn complexes based on the binaphthyl imit, (salen)Cr complexes,and (salen)Ru-based catalysts. Catalysts based on (salen)Co moiety have exhibited amazing levels of selectivity in the hydrolytic kinetic resolution (HKR) of terminal epoxides. The HKR allows access to terminal epoxides and diols with very high enantioselectivities. 

The Cr(salen) catalyst was shown to catalyze the resolution of 2,2-disubstitut-ed epoxides, in which a methylene and a methyl group were distinguished by the chiral catalyst. The ARO of this difficult substrate class demonstrated a useful feature of kinetic resolution, in that the enantiopurity of the unreacted epoxide could be improved through higher substrate conversion (Scheme 17). Alternatively, allowing the reaction to proceed to only 40% conversion allowed production of the tertiary alcohol in 74% yield and 94% ee [36,37,38]. 

In 2004, Umani-Ronchi et al. discovered that chiral (RJi)-[Cr(salen)]Y complexes (Jacobsen catalysts 70/71) could effectively undergo asymmetric F-C alkylation via kinetic resolution of racemic disubstituted epoxides. Treatment of 2-methylindole 74 with 3 equiv trans-1,2-disubstituted epoxides (72a-d) and 3.5 mol % of (/ ,/ )-[Cr(salen)]SbF6 catalyst (71) provided excellent yields (82-99%) of the corresponding chiral P-indolyl alcohols (73a-d) with good optical purity (72-91% ee). With this catalyst, only the (5 iS)-isomer of 72a-d reacts to form the (J ,S)-isomer of 73a-d, respectively. 

TABLE 8.4 Selected Kinetic Resolutions of Some gem-Disubstituted Alkyl Epoxides ... 

Disubstituted aliphatic oxiranes have been reported to be hydrolyzed by EHs from fungi [131], yeast, and bacteria. The most interesting results were observed with yeast and bacterial EHs. As far as kinetic resolution is concerned, it was shown by Weijers [116] that R. glutinis catalyzed the enantioselective hydrolysis of cis-2,3- and trans-2,3-epoxypentane, resulting in residual (2R)-epoxides with yields that approached the theoretical maximum of 50%. More interestingly, biocatalytic transformations of racemic 2,3-disubstituted oxiranes to vicinal diols with high ees at... 

The transition state model suggests that certain racemic olefins might be able to be kinetically resolved. Studies showed that a number of 1,6 and 1,3-disubstituted cyclohexenes could indeed efficiently be resolved with ketone 39 (Scheme 3.36) [61]. A rationalization for the kinetic resolution of 1,6-disubstituted cyclohexene using ketone 39 is shown in Scheme 3.37. Spiro C and D represent the major transition states for the epoxidation of each enantiomer of the racemic olefin. The destabilizing steric interaction between R2 and one of the dioxirane oxygens in spiro D disfavors this transition state, thus the epoxidation of the corresponding enantiomer proceeds at a lower rate. This kinetic resolution not only provides a valuable route to preparing certain chiral intermediates but also further validates the transition state model. 

Sharpless early investigations of epoxidation reactions of secondary allylic alcohols were accompanied by an intriguing observation the enantiomeric alcohols display substantial rate differences in the epoxidation event. This allowed a kinetic resolution process to be considered [78, 79]. As showcased in Equation 12, the racemic substrate 56 features four diastereotopic olefin faces and its epoxidation represents a particularly interesting case [79]. As anticipated, the more nucleophilic, disubstituted olefin displays greater reactivity in the epoxidation to give 58 in > 95 % ee. As is generally the trend for metal-catalyzed epoxidation of allylic alcohols, the anti epoxy alcohol 58 is preferentially formed. Kinetic studies have shown that the use of bulkier tartrate esters, such as diisopropyl tartrate (57), generally further enhances the rate differences between two enantiomeric allylic alcohols [19]. 

---