Enantioselective Trans Dihydroxylation of Nonactivated C−C Double Bonds of Aliphatic Heterocycles withSphingomonassp. HXN-200

Abstract

The bacterial strain Sphingomonas sp. HXN-200 was used to catalyze the trans dihydroxylation ofN-substituted 1,2,5,6-tetrahydropyridines 1 and 3-pyrrolines 4 giving the corresponding 3,4-dihydroxypiperidines 3 and 3,4-dihydroxypyrrolidines 6, respectively, with high enantioselectivity and high activity. The trans dihydroxylation was sequentially catalyzed by a monooxygenase and an epoxide hydrolase in the strain with epoxide as intermediate. While both epoxidation and hydrolysis steps contributed to the overall enantioselectivity in trans dihydroxylation of 1, the enantioselectivity in trans dihydroxylation of the symmetric substrate 4 was generated only in the hydrolysis of meso-epoxide 5. The absolute configuration for the bioproducts (+)-3 and (+)-6 was established as (3R,4R) by chemical correlations. Preparative trans dihydroxylation of 1a and 4b with frozen/thawed cells of Sphingomonas sp. HXN-200 afforded the corresponding (+)-(3R,4R)-3,4-dihydroxypiperidine 3a and (+)-(3R,4R)-3,4-dihydroxy pyrrolidine 6b in 96% ee both and in 60% and 80% yield, respectively. These results represent first examples of enantioselective trans dihydroxylation with nonterpene substrates and with bacterial catalyst, thus significantly extending this methodology in practical synthesis of valuable and useful trans diols. Enantioselective hydrolysis of racemic epoxide 2a with Sphingomonas sp. HXN-200 gave 34% of (-)-2a in >99% ee, which is a versatile chiral building block. Further hydrolysis of (-)-2a with the same strain afforded (-)-(3S,4S)-3a in 96% ee and 92% yield. Thus, both enantiomers of 3a can be prepared by biotransformation with Sphingomonas sp. HXN-200.

Biocatalytic preparation of enantioenriched 3,4-dihydroxypiperidines and theoretical study of Candida antarctica lipase B enantioselectivity

“…6 Both routes require a large number of steps to afford the desired compound in low overall yields. Recently, Chang et al 9 have reported the preparation of the optically pure trans-isomers using enantioselective transdihydroxylations or epoxidations of N-substituted 1,2,5,6-tetrahydropyridines, catalyzed by the bacterial strain Sphingomonas sp. HXN-200.…”

Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope

“…The three fused P450cam-RhFRed variants were screened against a panel of substrates, which were selected on the basis of the potential application of their oxidation products. For instance, the terpenes α- and β-ionone and their derivatives have been widely used for the synthesis of carotenoids or in the fragrance industry [23–26], and functionalized aliphatic heterocycles are versatile building blocks for further elaboration, e.g., by biocatalytic means [27]. …”

Vicinal anti‐Dioxygenation of Alkenes

“…HXN‐200, affording the corresponding trans ‐diols 34 and 35 with high enantioselectivities. This cascade reaction is sequentially catalyzed by a monooxygenase and an epoxide hydrolase (Scheme ) …”