Total Synthesis of Talatisamine.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry

Background:

• Talatisamine (1) is a C19-diterpenoid alkaloid.
• It exhibits K+ channel inhibitory and antiarrhythmic activities.
• The molecule possesses a complex hexacyclic 6/7/5/6/6/5-membered-ring structure (ABCDEF-ring) with 12 contiguous stereocenters, presenting a significant synthetic challenge.

Purpose of the Study:

• To develop an efficient synthetic route for talatisamine (1).
• To overcome the synthetic challenges posed by its complex structure.

Main Methods:

• Assembly of two fragments: a chiral 6/6-membered AE-ring (7) and an aromatic 6-membered D-ring (6).
• AE-ring 7 was synthesized from 2-cyclohexenone (8) via a double Mannich reaction.
• Key reactions included oxidative dearomatization/Diels-Alder reaction, Wagner-Meerwein rearrangement, and oxidative aza-Prins cyclization.

Main Results:

• An efficient synthetic route to talatisamine (1) was established.
• The synthesis involved 33 transformations starting from 2-cyclohexenone (8).
• The strategy successfully constructed the intricate hexacyclic core and installed the required stereochemistry.

Conclusions:

• The total synthesis of talatisamine (1) was successfully accomplished.
• This work provides a viable pathway for accessing complex diterpenoid alkaloids.
• The developed synthetic strategy highlights efficient methods for constructing highly fused ring systems.