Organocatalytic Asymmetric Synthesis of Propargylamines with Two Adjacent Stereocenters: Mannich-Type Reactions of In Situ Generated C-Alkynyl Imines with β-Keto Esters

摘要

Propargylamines are important synthetic intermediates for the preparation of polyfunctional amine derivatives as well as biologically active compounds. The standard method of preparing chiral propargylamines (1; Scheme 1) involves the asymmetric alkynylation of imines, thereby creating one new stereogenic center in the bond-forming reaction, and a number of the catalytic variants of this transformation have also been reported (Scheme 1, path a).In contrast, there are only a few cases of the catalytic asymmetric addition of carbon nucleophiles (R2) to C-alkynyl imines, thus giving chiral propargylamines (Scheme 1, path b), and the reactions with prochiral nucleophiles to create two adjacent stereogenic centers are scarce, despite the high synthetic utility.Accordingly, we were interested in the chiral phosphoric acid catalyzed reaction of in situ generated C-alkynyl imines, from the aminals 2, with β-keto esters as nucleophiles. The reaction between C-alkynyl imines and α-substituted β-keto esters would give polyfunctional chiral propargylamines having an alkynyl group and adjacent quaternary and tertiary stereocenters, which cannot be prepared by the frequently employed alkynylation of imines. Herein we report our results on this subject.