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Desymmetrization of Prochiral Cyclobutanones via Nitrogen Insertion: A Concise Route to Chiral γ-Lactams.

ABSTRACT: Asymmetric access to γ-lactams is achieved via a cyclobutanone ring expansion using widely available (1S,2R)-1-amino-2-indanol for chiral induction. Mechanistic analysis of the key N,O-ketal rearrangement reveals a Curtin-Hammett scenario, which enables a downstream stereoinduction (up to 88:12 dr) and is corroborated by spectroscopic, crystallographic, and computational studies. In combination with an easy deprotection protocol, this operationally simple sequence allows the synthesis of a range of optically pure γ-lactams, including those bearing all-carbon quaternary stereocenters. In addition, the formal synthesis of drug molecules baclofen, brivaracetam, and pregabalin further demonstrates the synthetic utility and highlights the general applicability of the presented method.

SUBMITTER: Sietmann J

PROVIDER: S-EPMC8252468 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Desymmetrization of Prochiral Cyclobutanones via Nitrogen Insertion: A Concise Route to Chiral γ-Lactams.

Sietmann Jan J Ong Mike M Mück-Lichtenfeld Christian C Daniliuc Constantin G CG Wahl Johannes M JM

Angewandte Chemie (International ed. in English) 20210310 17

Asymmetric access to γ-lactams is achieved via a cyclobutanone ring expansion using widely available (1S,2R)-1-amino-2-indanol for chiral induction. Mechanistic analysis of the key N,O-ketal rearrangement reveals a Curtin-Hammett scenario, which enables a downstream stereoinduction (up to 88:12 dr) and is corroborated by spectroscopic, crystallographic, and computational studies. In combination with an easy deprotection protocol, this operationally simple sequence allows the synthesis of a range ...[more]

PMID: 33538070

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