Diastereoselective Synthesis of <i>cis</i> -α,α′-Disubstituted Cyclic Ethers via Borane-Catalyzed Reductive Cyclization of Diketones

Cyclic ethers, particularly <i>cis</i>-α,α'-disubstituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), are prevalent motifs in bioactive compounds. However, efficient stereoselective methods for accessing such motifs remain limited. Herein, we report a direct catalytic approach to <i>cis</i>-2,5- and <i>cis</i>-2,6-disubstituted THFs and THPs via reductive cycloetherification of 1,4- and 1,5-diketones. The transformation uses a simple triarylborane catalyst and dihydrogen as a clean reductant, producing water as the sole byproduct. A broad range of products were obtained in high yields (up to 97%) and with high <i>cis</i>-selectivity (up to >20:1 dr). The method enabled streamlined access to medicinally relevant scaffolds and was scalable to gram quantities. Mechanistic studies support oxocarbenium ion reduction as the stereodetermining step, while density functional theory calculations suggest that weak, noncovalent interactions between the catalyst and substrate contribute to the observed diastereoselectivity. This work introduces a borane-catalyzed hydrogenative cyclization strategy that may inspire future metal-free syntheses of stereodefined heterocycles.