Borane-catalyzed stereoselective synthesis of cyclic ethers via reductive cycloetherification of diketones

Cyclic ethers, particularly α,α’-disubstituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), are prevalent motifs in bioactive compounds. However, efficient stereoselective methods to access these motifs remain limited. Herein, we report a direct, catalytic approach to cis-2,5- and cis-2,6-disubstituted THFs and THPs via reductive cycloetherification of 1,4- and 1,5-diketones. This metal-free transformation is enabled by a simple triarylborane catalyst and employs molecular hydrogen as the reductant, producing water as the sole byproduct. A broad range of products were obtained in high yields (up to 94%) and cis-selectivity (up to >20:1 dr). The method was applied to the concise synthesis of pharmaceutically relevant THFs, offering shorter routes with improved yields, and was scalable to gram quantities. Mechanistic studies support oxocarbenium ion reduction as the key stereodetermining step. DFT calculations suggest that favorable non-covalent interactions between the catalyst and substrate underpin the observed diastereoselectivity. This work introduces a new strategy for hydrogenative cycloetherification and provides a blueprint for the efficient, sustainable synthesis of stereodefined oxacycles.