Two (Chemo)-Enzymatic Cascades for the Production of Opposite Enantiomers of Chiral Azidoalcohols

Elia Calderini,Anett Schallmey,Frank Hollmann,Rainer Wardenga,Philipp Süss

doi:10.3390/catal11080982

Abstract

Multi-step cascade reactions have gained increasing attention in the biocatalysis field in recent years. In particular, multi-enzymatic cascades can achieve high molecular complexity without workup of reaction intermediates thanks to the enzymes’ intrinsic selectivity; and where enzymes fall short, organo- or metal catalysts can further expand the range of possible synthetic routes. Here, we present two enantiocomplementary (chemo)-enzymatic cascades composed of either a styrene monooxygenase (StyAB) or the Shi epoxidation catalyst for enantioselective alkene epoxidation in the first step, coupled with a halohydrin dehalogenase (HHDH)-catalysed regioselective epoxide ring opening in the second step for the synthesis of chiral aliphatic non-terminal azidoalcohols. Through the controlled formation of two new stereocenters, corresponding azidoalcohol products could be obtained with high regioselectivity and excellent enantioselectivity (99% ee) in the StyAB-HHDH cascade, while product enantiomeric excesses in the Shi-HHDH cascade ranged between 56 and 61%.

Highlights

Biocatalytic and chemo-enzymatic cascade reactions have gained a lot of attention in recent years due to their environmental benefits and the ability to achieve high product yields and enantiomeric excesses over multi-step synthetic routes [1]
ST-10, the unspecific peroxygenase from A. aegerita, the Shi epodixation diketal catalyst, and both (R,R)- and (S,S)-enantiomers of the Jacobsen catalyst were tested on an analytical scale (1 mL) for the conversion of 5 mM substrate using the respective optimal conditions described in the literature
We have demonstrated that this strategy can be extended to linear non-terminal alkene substrates, giving access to a broader range of possible azidoalcohol products

Summary

Introduction

Biocatalytic and chemo-enzymatic cascade reactions have gained a lot of attention in recent years due to their environmental benefits and the ability to achieve high product yields and enantiomeric excesses over multi-step synthetic routes [1]. Their main advantages are (i) the avoidance of intermediate workup steps and (ii) the possibility to include unstable intermediates that are directly converted further in the (bio)catalytic step [1,2,3]. Compounds containing an azido group have a particular synthetic importance, and they caught the attention of organic chemists already in the previous century. They are key intermediates for the synthesis of aminoalcohols [4,5,6], lactams [7], amino sugars [8], oxazolines [9], and are important in the synthesis of carbohydrates and nucleosides [10,11]

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