Bicyclo[1.1.1]pentanes (BCPs) are highly strained carbocycles with an inherently fascinating molecular structure and the ability to serve as bioisosteres which can successfully replace phenyl, <i>tert</i>-butyl, and alkyne groups in pharmaceutical targets. The Davies group has developed an enantioselective rhodium(II)-catalyzed C–H functionalization of BCPs using donor/acceptor carbenes in which C–H insertion occurs exclusively at the highly strained tertiary carbon of the BCP, rather than the secondary carbons around the periphery of the BCP. This work applies state-of-the-art density functional theory computations to explain this striking regioselectivity. In particular, computations reveal that the preference for C–H insertion at the tertiary site of the BCP is driven by the development of substantial carbocation character in the transition states. Although the tertiary BCP carbocation is constrained by the bicyclic ring system to be nonplanar, it is unusually stable owing to favorable orbital interactions that delocalize the positive charge over the entire ring system. The underlying stability of the nonplanar tertiary BCP carbocation, coupled with the development of substantial carbocation character in the C–H insertion transition states, explains the striking regioselective preference for C–H insertion at the tertiary site of the BCP.

Explaining the regioselectivity of rhodium(II)-catalyzed C–H functionalization of strained bicyclo[1.1.1]pentanes

2019 Fall National Meeting

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