Stereoretentive decarbonylative C(sp³)-C(sp³) cross-coupling.

Abstract

While C(sp³)-C(sp³) bond-forming cross-coupling methods have become more common, stereocontrolled bond-formation remains a challenge,¹ despite its importance for drug discovery, where there is a emerging demand for molecules with increased sp3 character.^2-4 Enantiospecific cross-coupling approaches would complement advances in enantioselective coupling,^5-8 but have been limited to specialized substrates with lower availability^5,9 because stereospecific oxidative addition of more abundant chiral alkyl electrophiles is unknown.¹⁰ Inspired by the classic, stereoretentive Curtius rearrangement,¹¹ herein we disclose a catalytic strategy that proceeds by an analogous stereoretentive decarbonylation step to form a versatile chiral alkylnickel intermediate from easily-available chiral amino-acid and α-hydroxy-acid derivatives. The chiral alkylnickel intermediates decompose and/or racemize on the order of minutes, but are sufficiently stable to enable stereoretentive cross-electrophile coupling¹² with alkyl radicals (derived from alkyl iodides) at relatively low temperature (22-40 °C). This mechanistic strategy provides a straightforward approach to stereocontrolled C(sp³)-C(sp³) bond formation, including diastereomers that are inaccessible by stereoselective radical mechanisms. The "metallo-Curtius" strategy described in this study lays a mechanistic foundation for the development many new stereospecific cross-coupling reactions.