Stereoselective synthesis of medium lactams enabled by metal-free hydroalkoxylation/stereospecific [1,3]-rearrangement

• Published in: Nature communications Vol. 10; no. 1; pp. 3234 - 11
• Main Authors: Zhou, Bo, Zhang, Ying-Qi, Zhang, Kairui, Yang, Ming-Yang, Chen, Yang-Bo, Li, You, Peng, Qian, Zhu, Shou-Fei, Zhou, Qi-Lin, Ye, Long-Wu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.07.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 140/131; 639/638/403/933; 639/638/403/934; Acids; Alkenes - chemistry; Alkynes - chemistry; Anticancer properties; Antitumor agents; Atom economy; Biological activity; Breast cancer; Catalysis; Cyclization; Economics; Efficiency; Esophageal cancer; Esophagus; Humanities and Social Sciences; Investigations; Kinetics; Laboratories; Lactams - chemical synthesis; Lactams - chemistry; Melanoma; Metals - chemistry; Models, Chemical; Molecular Structure; multidisciplinary; NMR; Nuclear magnetic resonance; Organic chemistry; Science; Science (multidisciplinary); Stereoisomerism; Stereoselectivity; Substrates
• DOI: 10.1038/s41467-019-11245-2
• ISSN: 2041-1723

Rearrangement reactions have attracted considerable interest over the past decades due to their high bond-forming efficiency and atom economy in the construction of complex organic architectures. In contrast to the well-established [3,3]-rearrangement, [1,3] O-to-C rearrangement has been far less vigorously investigated, and stereospecific [1,3]-rearrangement is extremely rare. Here, we report a metal-free intramolecular hydroalkoxylation/[1,3]-rearrangement, leading to the practical and atom-economical assembly of various valuable medium-sized lactams with wide substrate scope and excellent diastereoselectivity. Moreover, such an asymmetric cascade cyclization has also been realized by chiral Brønsted acid-catalyzed kinetic resolution. In addition, biological tests reveal that some of these medium-sized lactams displayed their bioactivity as antitumor agents against melanoma cells, esophageal cancer cells and breast cancer cells. A mechanistic rationale for the reaction is further supported by control experiments and theoretical calculations. Stereospecific [1,3]-rearrangements are rarely reported method to efficiently build complex organic architectures. Here, the authors describe a metal-free intramolecular hydroalkoxylation/[1,3]-rearrangement sequence affording medium-sized lactams with wide scope, also in an asymmetric fashion.