Peniroquesine, a sesterterpenoid featuring a unique 5/6/5/6/5 fused pentacyclic ring system, has been known for a long time, but its biosynthetic pathway/mechanism remains elusive. Based on isotopic labeling experiments, a plausible biosynthetic pathway to peniroquesines A–C and their derivatives was recently proposed, in which the characteristic peniroquesine-type 5/6/5/6/5 pentacyclic skeleton is synthesized from geranyl–farnesyl pyrophosphate (GFPP) via a complex concerted A/B/C-ring formation, repeated reverse-Wagner–Meerwein alkyl shifts, three successive secondary (2°) carbocation intermediates, and a highly distorted trans-fused bicyclo[4.2.1]­nonane intermediate. However, our density functional theory calculations do not support this mechanism. By applying a retro-biosynthetic theoretical analysis strategy, we were able to find a preferred pathway for peniroquesine biosynthesis, involving a multistep carbocation cascade including triple skeletal rearrangements, trans-cis isomerization, and 1,3-H shift. This pathway/mechanism is in good agreement with all of the reported isotope-labeling results.

Bisorbibutenolide and bisorbicillinolide are polyketide compounds with complex skeletons that are formed by the dimerization of sorbicillin. These compounds have long been of interest, with several reports of their biosynthesis,...

Salmahyritisol A, similan A, and hippospongide A, which are scalarane‐type sesterterpenoids, feature 6/6/5/7/5 pentacyclic skeletons. Although their biosyntheses have been previously proposed to involve a unique skeletal rearrangement reaction, the detailed reaction mechanism remains unclear as none of the corresponding biosynthetic enzymes for this reaction have been reported. Herein, this skeletal rearrangement reaction was investigated using computational techniques, which revealed the following four key features: (i) the distal 24‐Me substituent controls both the concertedness and activation energy of this transformation, (ii) enzymes are not responsible for the observed regioselectivity of C12−C20 bond formation, (iii) stereoselectivity is enzyme‐regulated, and (iv) protonation is a key step in this skeletal rearrangement process. These new findings provide insight into the C‐ring‐contraction and D‐ring‐expansion mechanisms in scalarane‐type sesterterpenoid biosyntheses.