Enantioselective, Catalytic HFL Reaction to Access Chiral 2,5-Pyrrolidines

Significance

Numerous drugs, natural products, ligands, and catalysts feature chiral pyrrolidines, making quick, enantioselective access to this scaffold very desirable. Synthetic approaches generally rely on chiral pool starting materials or lengthy routes. The Nagib lab here introduces the synthesis of chiral 2,5-pyrrolidines through an enantioselective copper-catalyzed Hofmann–Löffler–Freytag (HFL) reaction starting from readily accessible oximes.

Comment

This approach relies on the intramolecular γ C–H imination of the starting oximes. After the classic 1,5-hydrogen atom transfer in HLF reactions, the resulting radical is intercepted by the pre-formed chiral Cu(II) catalyst, which then undergoes an enantiodetermining reductive elimination yielding chiral pyrrolines. Electronically and sterically diverse aryl and even alkyl substituents are tolerated in the 2-position, as are aryl and alkenyl substituents in the 5-position. The authors then demonstrated that the pyrrolidines are suitable for further reduction or nucleophilic addition to access 2,5-pyrrolidines. Notably, α-tertiary amines can be synthesized in this fashion. When the nucleophile is cyanide, the resulting nitriles can be hydrolyzed to amino acid analogues.

Publication History

Article published online:
20 December 2024

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