An alcohol dehydrogenase from Clostridium acetobutylicum (CaADH) recently reported by our lab (Chem Comm 2011  , 47, 2420), and deployed in the stereoselective reduction of ?-ketoesters to medicinally relevant chiral synthons, has now been applied to the reduction of  a,a-difluoro-�-ketophosphonates bearing ?, d-unsaturation.  To our knowledge, these represent the first examples of a dehydrogenase-based entry into valuable enantio-enriched  a,a-difluorinated phosphonate building blocks.  The enzymatic reductions proceed in both high yield and ee, and D-glucose/glucose DH serve to regenerate the NADPH cofactor.  Importantly, the resulting phosphonate-bearing, chiral allylic alcohols are found to undergo an exceptionally facile thia-Claisen rearrangement (RR) when derivatized with the appropriate thiono-ester functionality.  In fact, a remarkable SAR is observed for the dependence of rate upon thiono-ester structure in this thia-Claisen RR chemistry, with more than three orders of magnitude separating the observed rate constants for the slowest and fastest thiono-esters.  Indeed, the most favorable RR proceeds with a half-time of 3 min at rt, and proceeds with complete conservation of ee, within experimental error.  The scope, limitations and a detailed kinetic study of this new thia-Claisen RR chemistry will be presented, as will its application to the enantioselective synthesis of a suite of richly functionalized  a,a-difluorinated phosphonate building blocks.

Coupling asymmetric enzymatic carbonyl reduction with an exceptionally facile [3,3]-sigmatropic rearrangement: Rapid access to scalemic, densely functionalized α,α-difluorinated phosphonates

244th National Meeting (2012)

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