Revisiting alcohol dehydrogenases: Self-sufficient regio- and enantio- selective formation of bi- and tri-cyclic lactones

Conference Dates

September 15-19, 2019


The field of biocatalysis has witnessed over the past few years a renewed interest in the design of synthetic routes with high atom-economy, particularly of those employing redox enzymes. For long, the implementation of efficient recycling systems for cofactors (typically nicotinamide) essential to these enzymes was considered attractive for economical reasons, since the use of co-substrate and co-enzyme approaches [1] usually implied co-conversion of a cheap auxiliary substrate (e.g., glucose, ethanol, acetone, formate). In line with growing awareness for sustainable technologies and the desire to reduce the environmental footprint of synthetic processes, strategies that bypass the need for stoichiometric amounts of co-subtrate or reagents are now being considered. For redox enzymes, this translates for instance into the enlargement of the scope of intramolecular hydride transfer, which allows biotransformations to run in closed loop. Exemplary are redox isomerization reactions applied to allylic alcohols or recently cyclic hydroxy-ketones [2]. In both cases, no new bond is created, and the hydride shift is responsible for a switch of functionality.

Owing to the dual redox reactivity of aldehydes and complementary activity of alcohol dehydrogenases (ADHs) on the aldehyde functionality (oxidation/reduction), a formal intramolecular biocatalytic hydride shift can be considered with dialdehyde molecules. Following our work on the disproporationation of aldehydes and the establishment of a biocatalytic Cannizzaro-type reaction using ADHs [3], we are now disclosing a broadly applicable enzymatic platform for the synthesis of bi- and tri-cyclic lactones starting from dialdehydes (Scheme 1). An intramolecular bio-Tishchenko reaction was developed with particular attention to redox economy. High turn-over numbers for the nicotinamide cofactor (up to 1.6x103 half-reactions) along with efficient 1,4-, 1,5- and 1,6-hydride shift on dialdehydes (1:1 ratio enzyme/cofactor) could be demonstrated, following reduction-oxidation sequence through lactol intermediate. Noteworthy, regio- and enantioselectivity were observed with a range of wild-type and engineered ADHs and preparative scale synthesis allowed isolation of several lactone products, with no concomitant waste generation [4]. Application of these lactones in (cross-)polymerization reactions is currently being investigated.

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