Gold-catalysed asymmetric net addition of unactivated propargylic C–H bonds to tethered aldehydes

Abstract

The asymmetric one-step net addition of unactivated propargylic C–H bonds to aldehydes leads to an atom-economic construction of versatile chiral homopropargylic alcohols, but has not yet been realized. Here we show its implementation in an intramolecular manner under mild reaction conditions. This chemistry—via cooperative gold catalysis enabled by a chiral bifunctional phosphine ligand—achieves asymmetric catalytic deprotonation of propargylic C–H (pK_a > 30) by a tertiary amine group (pK_a ≈ 10) of the ligand in the presence of much more acidic aldehydic α-hydrogens (pK_a ≈ 17). The reaction exhibits a broad scope and readily accommodates various functional groups. The cyclopentane/cyclohexane-fused homopropargylic alcohol products are formed with excellent enantiomeric excesses and high trans-selectivities with or without a preexisting substrate chiral centre. Density functional theory studies of the reaction support the conceived reaction mechanism and the calculated energetics corroborate the observed stereoselectivity and confirm additional metal–ligand cooperation.