Asymmetric synthesis of chiral pyrrolizine-based triheterocycles by organocatalytic cascade aza-Michael-aldol reactions

New, chiral pyrrolizine-based triheterocycles were obtained by the organocatalytic asymmetric cascade aza-Michael-aldol reaction of α-branched α,β-unsaturated aldehydes with 2-(trifluoroacetyl) pyrroles. High enantioselectivities (90-95 % ee) and excellent diastereoselectivities (dr up to >20:1) were achieved by employing this synthetic strategy. The highly functionalized, trifluoromethyl-substituted cascade products have three consecutive stereogenic centers that include two chiral quaternary centers. The chemoselective stepwise Suzuki cross-coupling reaction of the cascade products with two different arylboronic acids provided chiral pyrrolizine-based triheterocycles that contain two distinct aryl substituents in good yields. The organocatalytic asymmetric synthesis of unique and highly functionalized chiral pyrrolizine-based triheterocycles has been achieved by the cascade aza-Michael-aldol reaction of α-branched α,β-unsaturated aldehydes with 2-(trifluoroacetyl)pyrroles as the N-centered heteroaromatic nucleophiles.