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.

A 13-step total synthesis of the fungal meroterpenoid berkeleyone A is reported. The molecular skeleton is formed using the first examples of two critical construction reactions: (1) an epoxide-initiated, β-ketoester-terminated polycyclization, and (2) an isomerization-cyclization cascade to generate the remaining bicyclo[3.3.1]nonane framework. The resulting 6-step synthesis of the carbocyclic core of the berkeleyone natural products has been used to access protoaustinoid A and berkeleyone A, and will aid future biosynthetic investigations into the origin of related natural products.

The synthesis of natural products increasingly uses computational chemistry approaches to model and understand molecular phenomena. Calculations are employed to rationalize reaction outcomes, predict how a new system will perform, and inform synthetic design. As a result, new insights into the interactions of fundamental chemical forces have emerged that advance the field of complex small molecule synthesis. This review presents ten examples of computational techniques used in the synthesis of natural products, and discusses the unique perspectives afforded by these quantitative analyses.