Indolizinone and Quinolizinone via Asymmetric [2+2+2] Cycloaddition

Significance

A highly regio- and enantioselective synthesis of the indolizinone framework by Rh-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates with a variety of internal alkynes is reported. Among tested phosphoramidites, TADDOL-derived ligands show high activity and enantioselectivity. Two regioisomers A and B are formed in this reaction depending on the steric and electronic properties of R. While the electron-rich aryl R groups favor the CO-migrated product B, the sterically less hindered aliphatic R render A as the major product. The utility of this methodology is demonstrated by the efficient synthesis of (+)-lasubine II. The isolation of pyridinone C as a byproduct in this synthesis constitutes evidence for the incorporation of the alkene as the last 2π fragment.