An exceptionally facile [3,3]-sigmatropic rearrangement (RR) of the thiono-Claisen-type has been identified in these laboratories.  Allylic thionocarbonates bearing a,a-difluoromethyl phosphonate esters were found to undergo a rapid thiono-Claisen rearrangement. Depending upon the type of thionocarbonate ester, the half-time for the RR ranges over three orders of magnitude, with the most facile variant yet discovered proceeding at room temperature in a matter of minutes. Eyring analysis was performed on three different classes of thionocarbonate RR and indicates that both enthalpic and entropic contributions underlie the rather spectacular rate enhancement observed for the most favorable variant. Moreover, this new thiono-Claisen RR is stereo-retentive.  Thus, starting from enzymatically-generated, highly optically enriched allylic alcohols, a stereo-retentive process is observed, wherein the enantiopurity at the original �-C-O center in the educt is preserved in the d-C-S center of the product.  This rearrangement is quite general and tolerates additional functionality in the substrate, included aromatic, heterocyclic, ether and protected carboxylate groups.    Furthermore, the resulting d-thio-a,a-difluoro-phosphonates map onto a useful scaffold for the development of zinc aminopeptidase inhibitors.

Unusually facile and stereo-retentive [3,3]-sigmatropic rearrangement of the thiono-Claisen variety: Enthalpic and entropic underpinnings

248th National Meeting (2014)

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