Hydrolase‐Catalysed Preparation of Chiral α,α‐Disubstituted Cyanohydrin Acetates

Abstract

The enzymatic hydrolysis of esters of tertiary alcohols has long been a challenge. In particular their kinetic resolutions have virtually not been addressed. Here we describe the successful kinetic resolution of a,a-disubstituted cyanohydrin acetates, a type of protected tertiary alcohols that form particularly interesting building blocks in organic synthesis. Utilising Subtilisin A the hydrolysis reaction was (S)-selective, while Candida rugosa lipase was (R)-selective. With these commercially available enzymes both enantiomers of the a,a-disubstituted cyanohydrin acetates are now accessible.

A Continuous‐Flow Cascade Reactor System for Subtilisin A‐ Catalyzed Dynamic Kinetic Resolution of N‐tert‐Butyloxycarbonylphenylalanine Ethyl Thioester with Benzylamine

“…[27][28][29][30][31][32] Thev ast majority of biocatalytic reactions,h owever, have been performed so far in batch mode and often the operational parameters seem to be rather suboptimal. [16][17][18][20][21][22][23][24][25][26][33][34][35] Therefore,t op romote faster transfer of biocatalytic processes to an industrial scale,t here is stillm uch room for optimization. Continuous processeso ffer several advantageso vert he batch mode:f acile automation, reproducibility, relatively easy optimization and up-scaling as well as economy of scale in production.…”

An Enzymatic Toolbox for the Kinetic Resolution of 2‐(Pyridin‐x‐yl)but‐3‐yn‐2‐ols and Tertiary Cyanohydrins

“…The absolute configurations of the cyanohydrins 1f-h were recently determined and the configurations of 1i and 1j were assigned on the basis of their elution order in chiral GC analysis. [15,18] The acetates were subjected to analytical-scale kinetic resolution using nine esterases and variants thereof. The reactions were carried out at pH 7.5 and 37°C in the presence of an appropriate cosolvent (Scheme 1).…”

“…Therefore no racemization is needed in the kinetic resolution. Previous attempts with commercially available lipases, proteases, [15] and whole-cell catalysts [16][17][18] have met only moderate success so far or have been limited to aliphatic tertiary cyanohydrins.…”

“…The enantioselective hydrolysis of their esters by carboxyl esterases is a promising alternative to the addition of HCN to ketones as the starting compounds are easy to prepare. [14,15] When a neutral pH is used in the reaction, the cyanohydrin formed decomposes into the corresponding ketone and HCN. The resulting ketones can be reused for the synthesis of the corresponding racemic esters.…”

“…[8,15,19,20] In particular, the esterase-catalyzed hydrolysis of esters of tertiary alcohols is a highly enantioselective route to optically pure building blocks. [8,15] Only a very few commercially available enzymes, however, convert these sterically very demanding substrates. We have identified a series of esterases with confirmed activity towards tertiary alcohols, some of them showing excellent enantioselectivity towards a range of compounds.…”