Desymmetrization of meso-Pyrrolidines via Oxoammonium-Catalyzed Enantioselective Hydride Transfer

TL;DR

A new catalytic method enables the efficient and selective conversion of symmetrical pyrrolidines into chiral compounds useful for drug development.

Contribution

A novel oxoammonium-catalyzed enantioselective hydride transfer method for desymmetrizing meso-pyrrolidines with high enantiomeric excess.

Findings

An oxoammonium–peptide conjugate catalyst achieved over 90% enantiomeric excess in hydride transfer reactions.

Key catalytic intermediates were isolated, revealing the mechanism of stereochemical induction.

A tight hydrogen bond between the urea group and the peptide was identified as directing asymmetric hydride transfer.

Abstract

We report the oxidative desymmetrization of urea-protected
pyrrolidines
via site-selective hydride transfer from enantiotopic C–H bonds.
The optimal oxoammonium–peptide conjugate catalyst provided
over 90% ee across all tested pyrrolidines, providing
products that can readily undergo subsequent N-deprotection and other
derivatization reactions to form medicinally relevant compounds. We
isolated key on-cycle catalytic intermediates, which allowed us to
elucidate both the mechanism of catalytic activation and the origin
of stereochemical induction in detail. In particular, a stereochemical
model for asymmetric induction emerged from analyzing a covalent catalyst–substrate
adduct, which served as an isolable analog of the enantiodetermining
transition state. In this model, a tight hydrogen bond between the
urea protecting group and the peptide directs the asymmetric hydride
transfer.

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