Organocatalytic Asymmetric Formal Aza-[3 + 2] Cycloaddition via Domino Michael/Acetalization: Stereoselective Access to 3,4- cis -Disubstituted Pyrrolidines and Pot-Economical Total Syntheses of (−)-Kain

Abstract

An asymmetric catalytic formal aza-[3 + 2] cycloaddition (domino Michael/acetalization reaction) between aldehydes and benzyl N-(3-nitro-2-propen-1-yl)carbamate catalyzed by a diphenylprolinol silyl ether has been developed, affording 3,4-cis-disubstituted pyrrolidines with excellent diastereo- and enantioselectivity. The transformation proceeds via a domino sequence comprising a Michael addition followed by hemiacetalization. This reaction exhibits broad substrate scope and high functional-group tolerance, enabling concise access to densely functionalized pyrrolidine scaffolds. The method was further applied to the asymmetric total syntheses of (−)-kainic acid and (−)-domoic acid, neuroexcitatory marine natural products bearing highly substituted pyrrolidine cores. These syntheses highlight the versatility of the formal aza-[3 + 2] cycloaddition adduct as a chiral building block, featuring efficient one-pot transformations, Nef oxidation, and olefination to assemble complex pyrrolidines. Overall, this work establishes a unified asymmetric strategy for the rapid and stereocontrolled construction of biologically active pyrrolidine natural products.