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

Abstract

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.

Transition Metal-Catalyzed Tandem Reactions of Ynamides for Divergent N-Heterocycle Synthesis

“…Furthermore, the relevant intramolecular alkoxylation of ynamides initiated stereospecific Claisen rearrangement, and intramolecular hydroalkoxylation of ynamide-initiated stereospecific [1,3]-sigmatropic rearrangement was realized by our group by Brønsted acid catalysis, enabling practical and atom-economical assembly of a range of indole-fused bridged [4.2.1]­lactones and another type of medium-sized lactams, respectively.…”

Efficient and Divergent Synthesis of Medium‐Sized Lactams through Zinc‐Catalyzed Oxidative Cyclization of Indoly Ynamides†

“…Inspired by these results and our recent work on the catalytic construction of medium‐sized lactams, we envisioned that the synthesis of indole‐fused medium‐sized lactams might be achieved through non‐noble metal‐catalyzed ynamide oxidation/C—H functionalization of indoly ynamides (Scheme 1b). Herein, we describe the realization of such a zinc‐catalyzed oxidative cyclization of indoly ynamides, leading to the rapid and practical construction of a diverse range of valuable medium‐sized lactams in mostly good to excellent yields with broad substrate scope.…”

Nitrative bicyclization of 1,7-diynes for accessing skeletally diverse tricyclic pyrroles

“…Nitrogen-containing heterocycles widely appear in an array of natural products, 1 pharmaceutical agents, and functional materials, 2 in which those incorporating five-membered ring skeletons are by far the most prevalent. 3 Indubitably, tricyclic pyrroles are privileged aza-heterocycles that highlight structural complexities and diversities and demonstrate a broad spectrum of biological activities.…”