2,3-disubstituted oxiranes

The patterns of regio- and stereoselectivities become more complex in disubstituted oxiranes. Beginning with 2,2-disubstituted oxiranes, attack is always at the accessible C-atom. In terms of substrate enantioselectivity, it was found that 2-butyl-2-methyloxirane (2-methyl-1,2-epoxyhexane, 10.43, R = Bu) was hydrolyzed with a preference for the (5)-enantiomer. This substrate enantioselectivity was lost for branched analogues, namely 2-(/er/-bu-tyl)-2-methyloxirane (10.43, R = /-Bu) and 2-(2,2-dimethylpropyl)-2-meth-yloxirane (10.43, R = (CH3)3CCH2) [124], Thus, it appears that the introduction of a geminal Me group suppresses the enantioselectivity seen with branched monoalkyloxiranes, and reverses it for straight-chain alkyloxiranes. 

We also note that some 2,2-disubstituted oxiranes have toxicological significance, as exemplified by 2,2-dimethyloxirane (2-methyl-l, 2-epoxypropane, 10.43, R = Me). This compound is the toxic metabolite of 2-methyl-prop-1-ene (isobutene), a gaseous alkene widely used as a monomer in the industrial production of adhesives, plastics, and other polymers. Interestingly, detoxification of this epoxide catalyzed by liver epoxide hydrolase was high in the human, intermediate in the rat, and low in the mouse [125], These activities were inversely correlated with the epoxide levels measured in vitro in liver tissue of these species. 

Orru, R.V.A., Mayer, S.F., Kroutil, W. and Faher, K., Tetrahedron, Chemoenzymatic deracemi-sationof (+)-2,2-disubstituted oxiranes. 1998, 54, 859. Steinreiber, A., Hellstrdm, H., Mayer, S.F., Orru, R.V.A., Faber, K., Chemo-enzymatic enantio-convergent synthesis of C4-huilding blocks containing a fully substituted chiral carbon center using bacterial epoxide hydrolases. Synlett, 2001, 111. 

Table 2. Selectivities from the resolution of 2,2-disubstituted oxiranes by bacterial cells (substrate structures are given in Chart 1)...

Scheme 10. Resolution-inversion sequence for the deracemization of 2,2-disubstituted oxiranes...

Faber, K. Chemoenzymatic deracemization of ( )-2,2-disubstituted oxiranes. Tetrahedron 1998, 54, 859-874. 

Figure 11.2-8. Resolution of 2,2-disubstituted oxiranes by bacterial cells.

Among the sterically more demanding substrates, 2,2-disubstituted oxiranes were hydrolyzed in virtually complete enantioselectivities using enzymes from bacterial sources (E > 200), in particular Mycobacterium NCIMB 10420, Rhodococcus (NCIMB 1216, DSM 43338, IFO 3730) and closely related Nocardia spp. (Scheme 2.93) [608, 609]. All bacterial epoxide hydrolases exhibited a preference for the (S)-enantiomer. In those cases where the regioselectivity was determined, attack was found to exclusively occur at the unsubstituted oxirane carbon atom. 

For 2,2-disubstituted oxiranes, this technique was not applicable because an enzyme to perform a highly unfavored nucleophilic attack on a fuUy substituted carbon atom would be required. In this case, a two-step sequence consisting of combined bio- and chemocatalysis was successful (Scheme 2.96) [616]. In the first step, 2,2-disubstituted oxiranes were kinetically resolved by using bacterial epoxide hydrolases in excellent selectivity. The biohydrolysis proceeds exclusively via attack at the unsubstituted carbon atom with complete retention at the stereogenic center. By... 

Scheme 2.96 Deracemization of 2,2-disubstituted oxiranes using combined bio- and chemocatalysis...

Hellstrom, H., Steinreiber, A., Mayer, S.R and Faber, K. (2001) Bacterial epoxide hydrolase-catalyzed resolution of a 2,2-disubstituted oxirane optimization and upscaling. Biotechnol. Lett., 23,169-173. 

Only limited data are available on the biohydrolysis of 2,2-disubstituted oxiranes (Fig. 3, Table 3) employing mammalian and yeast epoxide hydrolases. For instance, the presence of a geminal dimetbyl group in 2.1 resulted in complete enantioselectivity when mEH was used as a catalyst. Thus, epoxide 2.1 was resolved to yield the corresponding (/f)-diol and the remaining (5)-epoxide 2.1 both in more than 95% e.e. at 50% conversion. On the other hand, a simple 2-methyl-2-alkyl oxirane such as 2.2 could not be resolved with high efficiency employing mEH. For this substrate pattern, bacterial epoxide hydrolases proved to be extremely useful. 

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