Biocatalytic Enantioselective Oxidation of Sec-Allylic Alcohols with Flavin-Dependent Oxidases.

Somayyeh Gandomkar,Mathias Pickl,Bastian Daniel,Peter Macheroux,Wolfgang Kroutil,Alexander Swoboda,Wael Elaily,Doris Loidolt,Marco W Fraaije,Etta Jost

doi:10.1002/adsc.201900921

Abstract

The oxidation of allylic alcohols is challenging to perform in a chemo‐ as well as stereo‐selective fashion at the expense of molecular oxygen using conventional chemical protocols. Here, we report the identification of a library of flavin‐dependent oxidases including variants of the berberine bridge enzyme (BBE) analogue from Arabidopsis thaliana (AtBBE15) and the 5‐(hydroxymethyl)furfural oxidase (HMFO) and its variants (V465T, V465S, V465T/W466H and V367R/W466F) for the enantioselective oxidation of sec‐allylic alcohols. While primary and benzylic alcohols as well as certain sugars are well known to be transformed by flavin‐dependent oxidases, sec‐allylic alcohols have not been studied yet except in a single report. The model substrates investigated were oxidized enantioselectively in a kinetic resolution with an E‐value of up to >200. For instance HMFO V465S/T oxidized the (S)‐enantiomer of (E)‐oct‐3‐en‐2‐ol (1 a) and (E)‐4‐phenylbut‐3‐en‐2‐ol with E>200 giving the remaining (R)‐alcohol with ee>99% at 50% conversion. The enantioselectivity could be decreased if required by medium engineering by the addition of cosolvents (e. g. dimethyl sulfoxide).

Highlights

The oxidation of alcohols to the corresponding carbonyl compounds at the expense of molecular oxygen still belongs to the challenges in chemistry, as discussed in various recent reports and reviews using e. g
We report the identification of a library of flavin-dependent oxidases including variants of the berberine bridge enzyme (BBE) analogue from Arabidopsis thaliana (AtBBE15) and the 5(hydroxymethyl)furfural oxidase (HMFO) and its variants (V465T, V465S, V465T/W466H and V367R/W466F) for the enantioselective oxidation of sec-allylic alcohols
Since alcohol dehydrogenases require another enzyme for cofactor [NAD (P)+] recycling, oxidases using molecular oxygen as the direct oxidant would be preferred from a practical point of view.[6c,7]

Summary

Introduction

The oxidation of alcohols to the corresponding carbonyl compounds at the expense of molecular oxygen still belongs to the challenges in chemistry, as discussed in various recent reports and reviews using e. g. The oxidation of alcohols to the corresponding carbonyl compounds at the expense of molecular oxygen still belongs to the challenges in chemistry, as discussed in various recent reports and reviews using e. G. Ru-catalysts,[1] oxovanadium complexes,[2] colloidal[3] or metallic gold.[4] to the challenge of activating molecular oxygen as oxidant, the chemoselectivity is still poorly addressed. Allylic alcohols are prone to various side reactions such as epoxidation, 1,3H-shifts followed by tautomerization or polymerization.[5] An alternative to the metal-based oxidation, may be the biocatalytic oxidation of alcohols, including the use of alcohol dehydrogenases and oxidases.[6] Since alcohol dehydrogenases require another enzyme for cofactor [NAD (P)+] recycling, oxidases using molecular oxygen as the direct oxidant would be preferred from a practical point of view.[6c,7]

Methods

Results

Conclusion