Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstrasse 36, 48149, Münster, Germany.
Department Chemie, Johannes Gutenberg-Universität, Duesbergweg 10-14, 55128, Mainz, Germany.
Angew Chem Int Ed Engl. 2021 Apr 19;60(17):9719-9723. doi: 10.1002/anie.202100642. Epub 2021 Mar 10.
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.
通过使用广泛可用的(1S,2R)-1-氨基-2-茚醇进行环丁酮环扩张，实现了γ-内酰胺的不对称访问。对关键的 N,O-缩酮重排的机理分析揭示了 Curtin-Hammett 情景，这使得下游的立体诱导（高达 88:12 dr）成为可能，并得到了光谱学、晶体学和计算研究的证实。结合易于脱保护的方案，该操作简单的序列允许合成一系列光学纯的γ-内酰胺，包括那些带有全碳季立体中心的化合物。此外，药物分子巴氯芬、布瓦西坦和普瑞巴林的形式合成进一步证明了所提出方法的合成实用性，并强调了其普遍适用性。
