Stereospecific molecular rearrangement via nucleophilic substitution at quaternary stereocentres in acyclic systems.

Abstract

Nucleophilic substitution at tetravalent (sp³) carbon is a fundamental transformation in organic synthesis, essential for creating carbon-carbon and carbon-heteroatom bonds. While the mechanism of the S_N2 reaction is well understood, achieving stereochemical control in S_N1-type reactions remains extremely challenging due to the complexity of successive carbocation intermediates. Here we present a strategy for preparing complex molecular skeletons via stereospecific S_N1 at a quaternary stereocentre in acyclic systems. By leveraging neighbouring group participation, we facilitate the selective formation of a unique cyclopropylcarbinyl cation intermediate that undergoes selective nucleophilic substitution with high diastereoselectivity and complete inversion of configuration at a distant position from the original carbocation via molecular rearrangement. This methodology has been applied to generate homoallylic tertiary fluorides, bromides, chlorides, ethers, thiocyanates and azides, demonstrating its applicability in accessing diverse functional groups with exceptional diastereoselectivities. This transformation opens new avenues for constructing complex molecular architectures through precise stereocontrol of C-C bond cleavage at a quaternary stereocentre in acyclic systems.