Enantioselective Synthesis of α-Chiral Bicyclo[1.1.1]pentanes via Multicomponent Asymmetric Allylic Alkylation.

Bicyclo[1.1.1]pentanes (BCPs) have emerged as important structural motifs in drug design. However, asymmetric transformations that provide chiral BCPs bearing an adjacent stereocenter are still scarce. Here, we report a catalytic methodology for the enantioselective synthesis of α-chiral 1,3-difunctionalized BCPs from a three-component coupling of [1.1.1]propellane, a Grignard reagent, and an allylic phosphate. The reaction proceeds via the addition of the Grignard reagent to [1.1.1]propellane followed by an asymmetric N-heterocyclic carbene (NHC)-catalyzed allylic substitution of the resulting BCP-Grignard, providing a broad range of α-chiral BCPs with excellent levels of regioselectivity and enantioselectivity.

Enantioselective synthesis of chiral BCPs.

Bicyclo[1.1.1]pentanes (BCPs) have emerged as an interesting scaffold in drug design. These strained molecules can act as bioisosteres of para-substituted phenyl rings, tert-butyl groups or internal alkynes, leading to drug analogues with enhanced pharmacokinetic and physicochemical properties. Thus, catalytic methodologies for the synthesis of BCPs represent a major goal in modern organic synthesis. In particular, asymmetric transformations that provide chiral BCPs bearing an adjacent stereocenter are particularly valuable to expand the chemical space of this important scaffold. In this article, we discuss the available methodologies for the asymmetric synthesis of α-chiral BCPs, their key mechanistic features and their application in bioisosteric replacements in drug design.