Convergent Total Synthesis of (-)-Methyl Gummiferolate Enabled by Pattern Recognition and Radical Cyclization.

Authors

Weizhao Zhao, Jingsong Zhen, Mingji Dai

Published in

Journal of the American Chemical Society. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

We report herein an enantioselective total synthesis of (-)-methyl gummiferolate, a complex diterpene natural product with a tetracyclic ent-atisane core including a bicyclo[2.2.2]octane subunit and three all-carbon quaternary centers. Gummiferolic acid has demonstrated potent plant growth-regulatory activity similar or superior to gibberellic acid. Using pattern recognition analysis, the tetracyclic ent-atisane core of (-)-methyl gummiferolate was retrosynthetically traced back to chiral pool molecule (S)-perillaldehyde and a six-membered ring containing starting material which can be accessed using an enantioselective Diels-Alder reaction with the Rawal diene. Our forward synthesis features a substrate-controlled stereoselective MHAT-initiated Baran reductive olefin cross coupling (BROC), a powerful radical cyclization approach, to close the six-membered B ring and an intramolecular alkylation to build the bicyclo[2.2.2]octane subunit. The BROC precursor was assembled in a convergent manner using a 1,2-addition of an alkyl lithium to a Weinreb amide derived from (S)-perillaldehyde. The alkyl lithium precursor was prepared from a known cyclohexenone (12) using key steps including CBS reduction, 2,3-Wittig-Still rearrangement, and Appel iodination. Overall, (-)-methyl gummiferolate was prepared in 18 steps from 12.

PMID:
42804746
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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