Facile Stereoselective Reduction of Prochiral Ketones by using an F₄₂₀‐dependent Alcohol Dehydrogenase

Abstract

Effective procedures for the synthesis of optically pure alcohols are highly valuable. A commonly employed method involves the biocatalytic reduction of prochiral ketones. This is typically achieved by using nicotinamide cofactor-dependent reductases. In this work, we demonstrate that a rather unexplored class of enzymes can also be used for this. We used an F 420-dependent alcohol dehydrogenase (ADF) from Methanoculleus thermophilicus that was found to reduce various ketones to enantiopure alcohols. The respective (S) alcohols were obtained in excellent enantiopurity (> 99 % ee). Furthermore, we discovered that the deazaflavoenzyme can be used as a self-sufficient system by merely using a sacrificial cosubstrate (isopropanol) and a catalytic amount of cofactor F 420 or the unnatural cofactor FOP to achieve full conversion. This study reveals that deazaflavoenzymes complement the biocatalytic toolbox for enantioselective ketone reductions.

A Tailor-Made Deazaflavin-Mediated Recycling System for Artificial Nicotinamide Cofactor Biomimetics

“…For industrial applications other cheaper and more accessible electron donors might be used, such as isopropanol, formate, or hydrogen gas in combination with F 420 -dependent alcohol dehydrogenases or formate dehydrogenases or hydrogenases, respectively. 47 − 52 The use of these electron donors could make this an inexpensive and scalable recycling system.…”

“…arvum (FSD-Cryar) were used as recycling enzymes in the conversion experiments as a proof of concept, which use the somewhat expensive sacrificial electron donor glucose-6-phosphate. For industrial applications other cheaper and more accessible electron donors might be used, such as isopropanol, formate, or hydrogen gas in combination with F 420 -dependent alcohol dehydrogenases or formate dehydrogenases or hydrogenases, respectively. − The use of these electron donors could make this an inexpensive and scalable recycling system.…”

Diversification by CofC and Control by CofD Govern Biosynthesis and Evolution of Coenzyme F 420 and Its Derivative 3PG-F 420

“…In streptomycetes, F 420 H 2 is used for reduction steps during the biosynthesis of antibiotics like thiopeptins ( 10 ), lanthipeptides ( 11 ), or oxytetracycline ( 12 , 13 ). Increasing interest in F 420 is also driven by the utilization of F 420 H 2 -dependent reductases in biocatalysis, for example, for asymmetric ene reductions ( 14 – 18 ).…”

Diversification by CofC and control by CofD govern biosynthesis and evolution of coenzyme F420 and its derivative 3PG-F420

“…In streptomycetes, F 420 H 2 is used for reduction steps during the biosynthesis of antibiotics like thiopeptins (10), lanthipeptides (11), or oxytetracycline (12,13). Increasing interest in F 420 is also driven by the utilization of F 420 H 2 -dependent reductases in biocatalysis, e.g., for asymmetric ene reductions (14)(15)(16)(17)(18).…”

“…In streptomycetes, F 420 H 2 is used for reduction steps during the biosynthesis of antibiotics like thiopeptins (10), lanthipeptides (11), or oxytetracycline (12,13). Increasing interest in F 420 is also driven by the utilization of F 420 H 2 -dependent reductases in biocatalysis, e.g., for asymmetric ene reductions (14)(15)(16)(17)(18). Intriguingly, F also occurs in a few Gram-negative bacteria where it has been acquired most likely by horizontal transfer of its biosynthetic genes from actinobacteria (19,20).…”