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

TL;DR

A new method for making cis-α,α′-disubstituted cyclic ethers using borane catalysis and hydrogen, offering high yields and selectivity for drug-like molecules.

Contribution

A borane-catalyzed reductive cyclization method for efficient and stereoselective synthesis of medicinally relevant cyclic ethers.

Findings

High yields (up to 97%) and cis-selectivity (>20:1 dr) achieved for THFs and THPs.

Gram-scale synthesis of medicinally relevant scaffolds demonstrated.

Mechanistic studies suggest oxocarbenium ion reduction as the stereodetermining step.

Abstract

Cyclic ethers, particularly cis-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 cis-2,5- and cis-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 cis-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.

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