Deracemization is an attractive approach for the synthesis of optically active alcohols and amines. It represents an optimum alternative to the well know kinetic resolution approach, which suffers from the intrinsic drawback of being limited to 50% yield with high enantiopurity. We developed a deracemization strategy and its implementation in deracemization of secondary alcohols. This approach relies on the use of non-stereospecific oxidation step and a stereoselective reduction step using two mutants of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH) that exhibit various extents of stereoselectivities. The use of orthogonal cofactor regeneration systems allowed for the spontaneous operation of two mutants of TeSADH in deracemization of alcohols. This approach was further improved into a deracemization strategy via stereoinversion that relies on the used of an (R)-selective TeSADH-catalyzed oxidation and (S)-selective TeSADH-catalyzed reduction of the resultant ketone intermediates to the corresponding (S)-configured alcohols. Both approaches were implemented in deracemization of phenyl-ring-containing alcohols to produce their corresponding (S)-configured alcohols in up to 99% ee.

Deracemization of alcohols using orthogonal biocatalytic oxidation and reduction reactions

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ACS Fall 2022

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