An efficient approach to angular tricyclic molecular architecture via Nazarov-like cyclization and double ring-expansion cascade

Yun-Peng Wang; Kun Fang; Yong-Qiang Tu; Jun-Jie Yin; Qi Zhao; Tian Ke

doi:10.1038/s41467-022-29947-5

An efficient approach to angular tricyclic molecular architecture via Nazarov-like cyclization and double ring-expansion cascade

Nat Commun. 2022 Apr 28;13(1):2335. doi: 10.1038/s41467-022-29947-5.

Authors

Yun-Peng Wang^#¹, Kun Fang^#², Yong-Qiang Tu^{3

4}, Jun-Jie Yin^{1

5}, Qi Zhao¹, Tian Ke¹

Affiliations

¹ School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai, 200240, China.
² State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
³ School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai, 200240, China. tuyq@lzu.edu.cn.
⁴ State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China. tuyq@lzu.edu.cn.
⁵ A training graduate student from Harbin Institute of Technology, Shenzhen, 518055, China.

^# Contributed equally.

Abstract

A modular and efficient method for constructing angular tri-carbocyclic architectures containing quaternary carbon center(s) from 1,3-dicycloalkylidenyl ketones is established, which involves an unconventional synergistic cascade of a Nazarov cyclization and two ring expansions. It features high selectivity, mild conditions and convenient operation, wide scope and easy availability of substrate. Substitution with R¹ and R² at the 4πe-system with electron-donating group favors this reaction, while that with electron-withdrawing group or proton disfavors. The electron-donating group as R¹ directs the initial ring expansion at its own site, while the p-π- or n-π- associated substituent as R² favors selectively the later ring expansion near its location because of the beneficial maintenance of an original conjugated system. The stereoselectivity has proved to be governed by either the steric effect of R³ and R⁴ at the expanded rings, or the migration ability of the migrating atom. Density Functional Theory calculation suggests the initial Nazarov cyclization would be the rate-determining step. A racemic total synthesis of the natural (±)-waihoensene is realized in 18 steps by use of this methodology.