Rhodium-Catalyzed Enantioselective Cycloaddition Route to Indolizidines

Significance

Described herein is a synthesis of indolizidines by an asymmetric Rh(I)-catalyzed [2+2+2] cycloaddition of 1,1-disubstituted alkenyl isocyanates to terminal alkynes. The reaction proceeds in moderate to high yields with a high level of enantio- and regioselectivity in the presence of the phosphoramidite ligands. Aliphatic alkynes gave lactams A as major products whereas vinylogous amides B predominated with aryl alkynes. The formation of 2-pyridones E as the major byproduct was suppressed under high dilution reaction conditions (typically 0.04 M). The isolated yields were low with sterically demanding substituents (e.g., R¹ = i-Pr, Cy) and in such reactions an increase in the 2-pyridone byproduct was observed, presumably due to a slow rate of coordination-insertion of the alkene with Rh.