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

Authors:
Open Access
Publisher website
Google Scholar
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.
Funding Information
  • National Institute of General Medical Sciences (GM128570)

This publication has 84 references indexed in Scilit: