Total Synthesis of Mollanol A

Abstract

Mollanol A is the first isolated member of the mollane-type grayanoids which possesses an unprecedented C-nor-D-homograyanane carbon skeleton and an 5,8-epoxide. Due to its transcriptional activation effects on the Xbp1 upstream promoters in different cell types, it has a potential therapeutic effect on inflammatory bowel disease. Here we report the first total synthesis of mollanol A, which constitutes a 15-step synthesis from commercially available materials via a convergent strategy. The synthesis involves an InCl3-catalyzed Conia-ene cyclization reaction to construct the bicyclo[3.2.1]­octane moiety and a vinylogous aldol reaction/intramolecular oxa-Michael addition sequence to rapidly assemble the oxa-bicyclo[3.2.1] core.

Enantioselective Total Syntheses of Grayanane Diterpenoids and (+)-Kalmanol: Evolution of the Bridgehead Carbocation-Based Cyclization and Late-Stage Functional Group Manipulation Strategies

“…12 In 2022, Yang and co-workers reported a convergent synthesis of mollanol A (8), a mollane-type grayanoid possessing the unique C-nor-D-homograyanane carbon framwork. 13 Most recently, Jia's group finished a total synthesis of (−)-principinol C (9). 14 In addition, Borrelly and Paquette have pioneered the synthetic studies toward kalmanol (10), 15 a B-homo-C-nor grayanoid affecting the systolic tension in atrium of guinea pig and displaying antinociceptive activity, 16 and Williams and coworkers have constructed the grayanoid core of pierisformoside C, 17 but the corresponding total syntheses have yet to be finished.…”

Total Synthesis of (–)-Principinol C

“…它们具有良好的生物活 性, 例如可以作为钠离子通道阻滞剂来使用, 并且具有 镇痛、 镇静作用, 此外还具有 PTP1B 磷酸酶的抑制活性. 由于木藜芦烷型二萜天然产物独特的化学结构引起了 合成化学工作者的浓厚兴趣, 我国合成化学家在此领域 做出了卓越的贡献 [4][5][6] .…”

Total Synthesis of (−)-Principinol C

“…6 Very recently, Yang's group achieved the first total synthesis of mollanol A. 7 In 2014, Hou and co-workers isolated two unprecedented grayanane diterpenoids, principinols A and C (3), from the aerial parts of Rhododendron principis (Scheme 1). 9 They are the first two compounds with C9-α-H in grayanane diterpenoids, and to date, no total synthesis of them has been reported.…”

“…In 2022, the group of Luo reported the total syntheses of (−)-grayanotoxin III, (+)-principinol E, and (−)-rhodomollein XX . Very recently, Yang’s group achieved the first total synthesis of mollanol A …”

“…Their intriguing and complex molecular scaffold makes them attractive targets for total synthesis. However, only eight total syntheses of grayanane diterpenoids have been accomplished, and the major breakthroughs were achieved after 2019. − In 1976, Matsumoto’s group disclosed a relay total synthesis of grayanotoxin II in 40 steps . In 1994, Shirahama’s group reported the total synthesis of (−)-grayanotoxin III in 38 steps .…”