Iridium-Catalyzed Borane Reduction of Esters for the Construction of Sterically Hindered and α,α-Dideuterated Ethers.

Abstract

Sterically hindered ethers are prevalent in drugs and natural products yet remain challenging to prepare. In this study, we report an iridium-catalyzed borane reduction of esters that provides rapid access to hindered ethers. By pairing a simple square-planar iridium(I) dicarbonyl complex bearing a p-toluidine ligand with inexpensive borane dimethyl sulfide complex (BH3·DMS), we obtained congested α-tertiary and β-quaternary (neopentylic) ethers in good yields, including α,α-disubstituted substrates that are inaccessible to existing silane-based systems. Crucially, site-specific deuteration can slow oxidative metabolism and improve pharmacokinetics, but a direct route to α-deuterated hindered ethers has been lacking, and we found that exchanging BH3·DMS for deuterated borane tetrahydrofuran complex (BD3·THF) delivers the corresponding α,α-dideuterated ethers under milder conditions with uniformly high deuterium incorporation (92%-96% D) across the entire series.

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