Revision of the Peniroquesine Biosynthetic Pathway by Retro-Biosynthetic Theoretical Analysis: Ring Strain Controls the Unique Carbocation Rearrangement Cascade

[Image: see text] 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.