Asymmetric Total Synthesis of Norzoanthamine

• Published in: Angewandte Chemie 2021-06, Vol.133 (23), p.12917-12922
• Main Authors: Xin, Zhengyuan, Wang, Hui, He, Haibing, Zhao, Xiaoli, Gao, Shuanhu
• Format: Article
• Language: English
• Subjects: Aquatic birds; Asymmetry; Chemistry; metal-catalyzed HAT reaction; norzoanthamine; quaternary centers; radical reactions; Stereochemistry; total synthesis
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202102643

We report herein the asymmetric total synthesis of norzoanthamine using radical reactions as key steps for rapid access to the congested carbocyclic core, which is the major synthetic challenge for most zoanthamine alkaloids. (1) The Ueno–Stork radical cyclization was applied to construct the adjacent quaternary centers at the C‐9 and C‐22 positions; (2) a Co‐catalyzed HAT radical reaction was successfully applied to construct the quaternary center at C‐12 via Csp3‐Csp2 bond formation; (3) a Mn‐catalyzed HAT radical reaction was used to stereospecifically reduce the tetra‐substituted olefin (C13=C18) and install the contiguous stereocenters in proximity to the quaternary center. A one‐pot bio‐inspired cyclization step was finally applied to forge the unstable bis‐amino acetal skeleton. Our approach can precisely control the stereochemistry of seven vicinal stereocenters and effectively construct the highly congested heptacyclic skeleton. We report herein an asymmetric total synthesis of norzoanthamine, a complex marine zoanthamine alkaloid, via radical and bio‐inspired cyclizations comprising the following key steps: 1) the Ueno–Stork radical cyclization; 2) a unique Co‐catalyzed HAT radical reaction; 3) a Mn‐catalyzed HAT radical reaction; and 4) a one‐pot bio‐inspired bis‐aminoacetalization