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

Catalytic methods for asymmetric functionalization of unactivated propargylic C-H bonds are scarce. Now, the design of a special ligand for cooperative gold catalysis enables the intramolecular, enantioselective addition of propargylic C-H bonds to aldehyde groups providing chiral cyclopentane/cyclohexane-fused homopropargylic alcohols. 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) approximate to 10) of the ligand in the presence of much more acidic aldehydic alpha-hydrogens (pK(a) approximate to 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.