LAUSR

Abstract Density functional theory (DFT) calculations were used to explore the Au(I)-catalyzed selective [4 + 1] annulations of cyclopropyl- and H-substituted 1,4-diyn-3-ols with isoxazole. The results indicated that after the N-nucleophilic attack of isoxazole, instead of obtaining the α–hydroxy gold carbene intermediate proposed experimentally, a concerted three-step forward product by isoxazole O N cleavage, 1,2-phenylalkyne shift and the hydroxyl H shift was identified as the key intermediate, for the reaction proceeding either via an Au-assisted C C double-bond rotation to produce the Z-isomeric enone or via two different Au-assisted C C rotations to furnish the E-configured enone depending on the substituents used. Further theoretical investigations indicated that the chemoselective step is the nucleophilic cyclization but not the C C double-bond rotation. The chemoselective preference for the Z-configured product using the cyclopropyl substitutent was attributed to two factors: i) the additional O H N hydrogen bonding interaction stabilizes the rate-determining cyclization TS leading to the Z-product, and ii) further Z-E product-isomerization is blocked due to significant structural deformation being involved. In contrast, using the H substituent results in a reversed chemoselectivity with exclusive formation of the E-configured enone, which is closely related to the smaller entropy effects involved.