Dyotropic Rearrangement of β‐Lactams: Reaction Development, Mechanistic Study, and Application to the Total Syntheses of Tricyclic Marine Alkaloids

• Published in: Angewandte Chemie International Edition Vol. 64; no. 2; pp. e202414985 - n/a
• Main Authors: Li, Yunshan, Zhang, Jingyang, Chen, Yi, Pang, Jiahua, Chen, Yuejie, Tang, Yefeng
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 10.01.2025; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkaloids; Alkaloids - chemical synthesis; Alkaloids - chemistry; beta-Lactams - chemical synthesis; beta-Lactams - chemistry; Chemistry; Chemistry, Multidisciplinary; lactams; Lactones; Molecular Structure; natural products; Physical Sciences; rearrangement; Science & Technology; Stereoisomerism; Synthesis; total synthesis; SYMMETRY CONTROLLED REACTIONS; RING EXPANSION; CYLINDRICINES; alkaloids; STEREOSPECIFIC SYNTHESIS; lactams; natural products; LACTONES; BUTENOLIDES; ZETA VALENCE QUALITY; FUSED BUTYROLACTONES; BASIS-SETS; total synthesis; rearrangement; LEPADIFORMINE
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202414985

An unprecedented dyotropic rearrangement of β‐lactams has been developed, which provides an enabling tool for the synthesis of structurally diverse γ‐butyrolactams. Unlike the well‐established dyotropic rearrangements of β‐lactones, the present reaction probably proceeds through a dual‐activation mode, and thus displays unusual reactivity and chemoselectivity. The combined computational and experimental results suggest that the dyotropic rearrangement of β‐lactams may proceed through different mechanisms depending on the nature of migrating groups (H, alkyl, or aryl). Hinging on a chemoselective H‐migration dyotropic rearrangement of β‐lactams, we have completed the divergent synthesis of tricyclic marine alkaloids (−)‐lepadiformine A, (+)‐cylindricine C, and (−)‐fasicularin within 11–12 longest linear steps. An unprecedented dyotropic rearrangement of β‐lactams has been developed, which provides an enabling tool for the synthesis of multi‐substituted γ‐butyrolactams. The reactions display several appealing features including excellent efficiency, high stereospecificity, and predictable chemoselectivity. Leveraging the newly developed methods, three tricyclic marine alkaloids have been synthesized in a concise and efficient manner.