Computational Study of the Rh/phanephos-Catalyzed Enantioselective [2+2+2] Cyclization of Enediyne, Affording Lactone-Fused Cyclohexadiene Bearing a Quaternary Bridgehead Carbon

Abstract

Abstract The mechanism of the Rh/phanephos-catalyzed enantioselective [2+2+2] cyclization of an ester-tethered enediyne, which produces a lactone-fused cyclohexadiene bearing an all-carbon quaternary bridgehead carbon, was computationally analyzed using density functional theory (DFT) calculations. This study suggests that the initial oxidative coupling occurs with the 1,6-diyne moiety rather than the 1,6-enyne moiety of the enediyne substrate, and the subsequent insertion of the pendant alkene into the resultant rhodacyclopentadiene intermediate is the enantioselectivity determining step. Further, it is suggested that the experimentally favored enantiomer should be produced through endo-mode alkene insertion followed by two-step reductive elimination. Moreover, DFT calculations show that the Rh/2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) catalyst enables the [2+2+2] cyclization of an enediyne bearing a methyl substituent at the propiolate terminus, which is not feasible using the Rh/phanephos catalyst.