Studies in enantioselective microbial deuteration

Abstract

This study reports methods for reductive microbial deuteration with a high degree of isotopic labelling, focusing on economical approaches using various yeast strains and inexpensive carbon sources. A strategy of α-hydrogen exchange followed by deuterative microbial reduction gave >95% backbone perdeuteration for crucial chiral building blocks for medicinal and analytical applications, without loss of the enantioselectivity demonstrated in the corresponding protiative processes. Under an air atmosphere, Saccharomyces cerevisiae strain MBG5177 outperformed baker's yeast in the synthesis of (2-²H₁)solketal, while Pichia pastoris strain X-33 provided >95% deuteration in the synthesis of the two studied building blocks using methanol-d₄ as an affordable carbon source. These findings emphasise the potential of microbial strains not traditionally employed by synthetic organic chemists for isotope labelling. Finally, molecular rotational resonance spectroscopy (MRR) was employed as an analytical tool. MRR was shown to provide accurate measurement of site-specific deuteration levels and enantiopurity, validating its utility for simplifying process evaluation in deuterium-labelling chemistry. This work underscores the value of diverse microbial resources and advanced spectroscopic methods in advancing isotope labelling and biocatalysis, with implications for both research and industrial applications.