2-Amino ketene S,S-acetals as α-amino acid homoenolate equivalents. Synthesis of 3-substituted prolines and molecular structure of 2-(N-pivaloylpyrrolidin-2-ylidene)-1,3-dithiane

Abstract

Allylic deprotonation of the heterocyclic 2-amino ketene S,S-acetal 8a, followed by regioselective γ-alkylation reaction of the resulting organolithium 10(a proline homoenolate equivalent) with electrophiles, leads to adduct 11. Controlled hydrolytic cleavage of 11 gives a series of 3-substituted prolines, including the conformationally-constrained aspartate and glutamate derivatives, 14e and 14f respectively. The bicyclic thiolactam 18 has been prepared in an attempt to provide an asymmetric variant of organolithium 10 but efforts to generate the requisite ketene N,S-acetal 19 were unsuccessful. Extension of the ketene S,S-acetal chemistry to other ring sizes has been examined within the context of substituted azetidine-2-carboxylates. Condensation of the protected amino ester 20 with AIMe3–HS(CH2)3SH was complicated, however, by the reactivity of the four-membered ring and led to the ring-opened adduct 24, with none of the required ketene S,S-acetal 22 being observed.