Traversing Biosynthetic Carbocation Landscapes in the Total Synthesis of Andrastin and Terretonin Meroterpenes

Abstract

Meroterpenes derived from dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate have attracted much biosynthetic attention, yet only recently have synthetic solutions to any family members appeared. A key point of divergence in DMOA-derived meroterpene biosynthesis is the protoaustinoid A carbocation which can be diverted to either the berkeleyone, andrastin, or terretonin structural classes via cyclase-controlled rearrangement pathways. Herein we show that the protoaustinoid bicyclo[3.3.1]nonane nucleus can be reverted to either andrastin or terretonin ring systems under abiotic reaction conditions. The first total syntheses of members of these natural product families are reported as their racemates.

Programmable meroterpene synthesis

“…Cyclopentanones with varying C-5, C-7, and C-8 substitution patterns (see products 26-29) were tolerated, highlighting how different inputs can be easily inserted into our PPAP synthetic blueprint. Sterically congested polycycle 30 was also formed in 30% and forms the basis for a DMOA-derived meroterpene synthetic program 13,14 . Diketones 31 and 32, which contain a gem-dimethyl group in close proximity to either an isopropyl or phenyl substituent also highlight the ability of this method to forge highly hindered C-C linkages.…”

“…Not surprisingly, DMOA-derived meroterpenes [12][13][14] , and especially the PPAPs , have proven to be popular targets for total synthesis, and a wide range of creative synthetic approaches have been developed for this purpose to date. Herein, we solidify a broad strategy for bicyclo[3.3.1]nonane-containing meroterpene construction, which in the case of PPAPs, offers 10-step entry into synthetically challenging and biologically active type A members in a modular and predictable fashion.…”

Computational and Synthetic Investigation of Cationic Rearrangement in the Putative Biosynthesis of Justicane Triterpenoids

“…This report further highlights the synergistic relationships between organic synthesis, mechanistic analysis, and computational chemistry, with similar investigations ongoing in our laboratory. [26] …”

Synform Issue 2020/02

“…A detailed previous mechanistic study had suggest ed that this photoinduced skeletal rearrangement possibly occurred via 1,3acyl migration involving a cage radical pair or a biradical intermediate. 4 Professor Lei remarked: "The in terconversion between dihydrokauradienone and (-)junger mannenone C also occurred smoothly promoted by sunlight, which indicated that entkauranetype and jungermanne nonetype diterpenoids are biosynthetically interrelated via this photoinduced radical rearrangement, which was previ ously thought to be a carbocation rearrangement. We there fore speculate that dihydrokauradienone is most likely a na tural product.…”