Stereodivergent Synthesis of γ-Functionalized Primary Alcohols via Relay-Synergistic Ir/Amine/Ni Catalysis

Abstract

Primary alcohols bearing chiral motifs constitute a class of highly valuable organic compounds that are widely prevalent in natural products and pharmaceutical molecules. Although impressive progress has been made in α- and β-functionalization of primary alcohols, the development of efficient methods for the synthesis of the γ-functionalized primary alcohols─particularly in an asymmetric fashion─remains a significant challenge. Here we report a relay-synergistic Ir/amine/Ni catalytic manifold that converts primary allylic alcohols into γ-functionalized primary alcohols bearing adjacent γ,δ-stereocenters with full catalyst-controlled stereodivergence. The reaction proceeds sequentially through iridium-catalyzed borrowing hydrogen to oxidize the primary allylic alcohol, followed by a stereodetermining Michael addition cooperatively catalyzed by a chiral amine and a chiral nickel catalyst, and concludes with iridium-hydride-mediated reduction. A series of primary alcohols bearing adjacent γ,δ-stereocenters could be easily synthesized in moderate to excellent yields and with good to excellent stereoselectivities (up to 94% yield, >20:1 dr, >99% ee). By permuting the configurations of the amine and nickel catalysts, all four stereoisomers can be accessed. Remarkably, control experiments indicate that the relay-synergistic strategy suppresses retro-Michael addition by rapidly reducing the unstable Michael adduct, thereby maintaining high diastereoselectivity. Kinetic isotope experiments identify the borrowing-hydrogen oxidation of the primary allylic alcohol as the rate-determining step.