Stereoselective Synthesis of Isoquinuclidines through an Aza-[4 + 2] Cycloaddition of Chiral Cyclic 2‑Amidodienes

ABSTRACT: A highly stereoselective aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes with N-sulfonyl aldimines is described. While this Lewis acid promoted heterocycloaddition provides an efficient strategy for constructing optically enriched isoquinucli-dines, it is mechanistically intriguing. The cycloaddition favored the endo-II pathway in the absence of a viable bidentate coordination. This represents an unexpected switch from the anticipated endo-I selectivity obtained in the all-carbon cycloaddition. The isoquinuclidine [or 2-azabicyclo[2.2.2]octane] core is aprevalent motif among biologically active natural prod-ucts.1 Catharanthine, an iboga-alkaloid, is a biosynthetic precursor of dimeric vinca alkaloids such as vinblastin and vincristine, which are being used as antitumor agents for treatment of a number of human cancers (Figure 1).2 Moreover, Daphniphyllum alkaloids such as caldaphnidine D have shown a variety of pharmacological activities such a