Biocatalytic desymmetrization for synthesis of chiral enones using flavoenzymes

Abstract

Efficient methods for achieving desaturation of carbonyl compounds are highly sought after in organic chemistry. In contrast to synthetic approaches, enzymatic desaturation systems offer the potential to enhance sustainability and selectivity but have remained elusive. Here we report the development of an enzymatic desaturation system based on flavin-dependent ene-reductases for desymmetrizing cyclohexanones. This platform facilitates the synthesis of a wide array of chiral cyclohexenones bearing quaternary stereocentres—structural motifs commonly present in bioactive molecules—with excellent yields and enantioselectivities. Experimental and computational mechanistic studies reveal the roles of key active-site residues that enable the formation and stabilization of an enolate intermediate in the desaturation event. Additionally, by leveraging these insights, we have devised a biocatalytic strategy for the synthesis of enones by reductively desymmetrizing cyclohexadienones. This method yields the opposite enantiomer compared to our desaturation system, underscoring the enantiodivergence and broad applicability of our flavin-based desymmetrization approaches. Biocatalytic methods for the synthesis of chiral cyclohexenones bearing quaternary stereocentres through oxidation and reduction reactions are reported. Mechanistic studies reveal the role of active-site residues in the oxidation process and inform the development of the enzymatic reduction reaction.