Enantioselective Synthesis of Axially Chiral Alkylidenecyclobutanes via Palladium-Catalyzed N-Tosylhydrazone-Based Carbene Coupling.

Abstract

The synthesis of axially chiral alkylidenecyclobutanes remains challenging due to the requirement of both an efficient asymmetric catalytic system and preservation of its inherent strained ring structure. We herein disclose an enantioselective carbene cross-coupling reaction of cyclobutanecarbaldehyde-derived N-tosylhydrazones with aryl bromides, enabled by palladium catalysis in combination with an elaborately modified sulfinamide phosphine ligand (Sadphos). This method demonstrates the feasibility of constructing axial chirality on a strained metal carbene intermediate precisely through a sequential process of enantiodetermined migratory insertion followed by central-to-axial-chirality-transfer β-H elimination. The reaction provides access to diverse alkylidenecyclobutanes featuring a heteroatom-substituted, tertiary and all-carbon quaternary stereocenter with excellent yields (up to 95%) and high enantioselectivities (up to 95% ee). Moreover, both enantiomers can be selectively obtained by choosing either cis- or trans-cyclobutane substrates in a stereospecific manner.