A Combined Allylic Azide Rearrangement and Intramolecular Schmidt Reaction - Discovery, Development, and Application

Abstract

The research presented herein describes synthetic applications of an allylic azide rearrangement, mainly focusing on its combination with the intramolecular Schmidt reaction to afford vinyl-substituted bicyclic lactams. Undesired stereochemistry was obtained in the initial synthetic route to an advanced intermediate of natural product pinnaic acid, in which a home-made electrochemistry apparatus was involved in the key step to modify the tricyclic lactam. The combination of allylic azide rearrangement and intramolecular Schmidt reaction afforded the target with desired stereochemistry, and the synthesis of the cyclobutanone was achieved by an asymmetric [2+2] cycloaddition. Prior to its combination with the intramolecular Schmidt reaction, the rearrangement of allylic azides was studied from different perspectives such as substrate, time, temperature, and Lewis acid. Next, the combined reaction was studied with the cyclohexanone-based allylic azide, whose stereochemical outcomes were rationalized by the conformational analysis and computational calculations. Different substituents on the cyclic ketone ring system were found to have different impacts on the diastereoselectivity. During this process, a chloro-Prins reaction was found as the major side-reaction, and carbocation-mediated allylic azide rearrangement was confirmed. Dihedral angle was utilized to explain why and in which cases the six-membered intermediate proceeds through chair or boat conformation for fused bicyclic system. This reaction was also utilized to produce twisted amides via cation-π interaction, along with the use of other by-products from different Lewis acids. The utilization of this methodology to finish the total synthesis of alkaloid 205B is underway. Initial studies of the combination of allylic azide rearrangement and alkyne-azide cycloaddition were conducted. Also the reorganization of allylic azides was utilized to generate 2-azadiene species, which may undergo Diels-Alder reactions or electrocyclizations.