Chemo‐ and Enantioselective Photoenzymatic Ketone Reductions Using a Promiscuous Flavin‐dependent Nitroreductase

Abstract

Flavoenzymes are oxidoreductases that catalyze an extensive range of different types of reactions.An advanced and powerful approach to achieving transformations that are normally outside the realm of flavoenzymes is the synergistic combination of photocatalysis and biocatalysis. Here we report the identification of a promiscuous flavin-dependent nitroreductase, BaNTR1, that is able to promote enantioselective photobiocatalytic reductions of a broad range of structurally diverse ketones to yield the corresponding alcohols with high conversion (up to >99%) and outstanding enantiopurity (up to >99:1 e.r). Noteworthy, BaNTR1 was able to promote the photoenzymatic reduction of various α,ßunsaturated ketones to give the corresponding optically pure alcohols without reducing the C=C or C≡C bond, illustrating its remarkably high chemoselectivity. Our results highlight the usefulness of photocatalysis for expanding the catalytic repertoire of nitroreductases to include highly enantio-and chemoselective reductions of non-native ketone substrates to produce optically pure alcohols. This includes difficult to prepare allyl alcohols that are not accessible via photoenzymatic conversions using ene-reductases.

Photobiocatalytic Strategies for Organic Synthesis

“…Poelarends demonstrated that similar reactivity could be achieved using nitroreductases, a flavin-dependent oxidoreductase (Figure 45B and C). 137 They found that the nitroreductase from B. amyloliquefaciens could catalyze the reduction of acetophenone and cinnamyl methyl ketone in excellent yield and enantioselectivity. In contrast to the work by Hyster, carbonyl reduction outcompetes alkene reduction for cinnamyl ketones.…”

Design of a gold nanoparticles site in an engineered lipase: an artificial metalloenzyme with enantioselective reductase-like activity

“…Gold metalloenzymes have been shown to be interesting and effective in arylation and hydroamination reactions. 27 Indeed, asymmetric reduction of ketones (to synthesize optically pure alcohols) 28 is a crucial step in the synthesis of many pharmaceuticals, agrochemicals, fragrances, and other small organic molecules. 29 In this way, innovative systems such as these newly synthesised gold metalloenzymes, exploiting the biocatalytic environment, the robustness of the enzyme and the efficiency of the gold nanoparticles, have been tested in the asymmetric reduction of acetophenone to 1-phenylethanol (Fig.…”

“…Gold metalloenzymes have been shown to be interesting and effective in arylation and hydroamination reactions. 27 Indeed, asymmetric reduction of ketones (to synthesize optically pure alcohols) 28 is a crucial step in the synthesis of many pharmaceuticals, agrochemicals, fragrances, and other small organic molecules. 29…”

Preparation of artificial gold metalloenzymes with enantioselective reductase-like activity by combining genetic engineering and protein chemistry

“…A common way to obtain enantioenriched alcohols is by the asymmetric reduction of ketones. [21] Thus, new metalloenzymes have been developed in the field of metalloenzyme production.…”