Total Synthesis of Talatisamine: Exploration of Convergent Synthetic Strategies

Talatisamine (1) is a highly oxygenated C19-diterpenoid alkaloid with K+ channel inhibitory, antiarrhythmic, and neuroprotective activities. Its intricately fused 6/7/5/6/6/5-membered hexacyclic structure (ABCDEF-ring) possesses one nitrogen functionality, five oxygen functionalities, and 12 contiguously aligned stereocenters. This account describes the development of convergent strategies to efficiently assemble this synthetically challenging natural product. First, we explored two radical-based strategies. Treatment of the AE-ring with Et3B and O2 generated a highly reactive C11-bridgehead radical, which sequentially added to the C-ring and the aldehyde via a radical-polar crossover mechanism to afford ACE-ring substructure 6 in a single step. Alternatively, after coupling of the AE-ring and C-ring, the C11-bridgehead radical was utilized to cyclize the central 7-membered B-ring. The 6-membered D-ring was then forged by selenium-induced 6-endo cyclization to furnish ABCDE-ring 3. Second, we pursued a skeletal rearrangement strategy, which culminated in the total synthesis of 1. The D-ring was coupled with the AE-ring as the aromatic ring. Oxidative dearomatization, followed by Diels-Alder reaction, led to the 6/6-membered ring system, which was transformed into the 7/5-membered BC-ring through a stereospecific Wagner-Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza-Prins cyclization to form the remaining 5-membered F-ring, thereby completing the chemical construction of 1.