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Static to inducibly dynamic stereocontrol: The convergent use of racemic β-substituted ketones

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Science  28 Aug 2020:
Vol. 369, Issue 6507, pp. 1113-1118
DOI: 10.1126/science.abc9909

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Expanding the kinetic resolution purview

Dynamic kinetic resolution (DKR) is a powerful method to transform a pair of mirror-image reactants into just one of the two possible mirror-image products. The key is to find a means of rapidly interconverting the reactants while one of them is being more efficiently funneled to product. DeHovitz et al. report cooperative application of organocatalysis, photoredox catalysis, and enzymatic catalysis to achieve DKR of β-substituted ketones into chiral alcohols. This β position has typically been considered too configurationally stable for a DKR approach.

Science, this issue p. 1113

Abstract

The synthesis of stereochemically complex molecules in the pharmaceutical and agrochemical industries requires precise control over each distinct stereocenter, a feat that can be challenging and time consuming using traditional asymmetric synthesis. Although stereoconvergent processes have the potential to streamline and simplify synthetic routes, they are currently limited by a narrow scope of inducibly dynamic stereocenters that can be readily epimerized. Here, we report the use of photoredox catalysis to enable the racemization of traditionally static, unreactive stereocenters through the intermediacy of prochiral radical species. This technology was applied in conjunction with biocatalysts such as ketoreductases and aminotransferases to realize stereoconvergent syntheses of stereodefined γ-substituted alcohols and amines from β-substituted ketones.

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