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

Abstract

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.

Mechanistic Investigation of the Degradation Pathways of α–β/α–α Bridged Epipolythiodioxopiperazines (ETPs)

“…All calculations were carried out at the M06-2X level using Gaussian and GRRM programs. M06-2X was selected because of its accuracy in calculating reaction energies for organic polysulfide compounds and its proven track record in reaction mechanism analysis of natural products. − Our initial calculations strongly suggested that the spontaneous desulfurization reaction of 3 does not occur kinetically under neutral conditions. However, under basic conditions, the Path 1-type multistep degradation of the disulfide moiety proceeds smoothly at ambient temperature with reasonable activation energies and large overall exothermicity: deprotonation of phenolic OH of 3 initiates a multistep anion-relay cascade leading to 4 .…”

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

“…Single-point energies were calculated at the mPW1PW91/6-31+G(d,p) level based on the optimized structure by using the M06-2X method. The utility of relative Gibbs free energies (G rel ) based on single-point energy at the mPW1PW91 level has been previously validated for a wide variety of terpene-forming reactions [ 22 , 41 , 53 ].…”

Naturally Occurring Norsteroids and Their Design and Pharmaceutical Application

“…Lastly, three nortriterpenes from the roots of Ziziphus mauritiana, zizimauritic acids A (120), B (121), and C (122), with a unique A-nor-E-seco spiro-lactone ceanothane-type triterpene skeleton, were identified. These compounds displayed cytotoxicity, with IC 50 values ranging from 5.05 to 11.94 µg/mL, and compounds 120 and 122 inhibited the growth of Staphylococcus aureus, with IC 50 values of 2.17 and 12.79 µg/mL, respectively [86].…”

“…Roquefornine A (177), a sesterterpenoid featuring an unprecedented 5/6/5/5/6-mem- Roquefornine A (177), a sesterterpenoid featuring an unprecedented 5/6/5/5/6membered pentacyclic system, was characterized from the fungus Penicillium roqueforti YJ-14 [119]. Additionally, other sesterterpenes, peniroquesines A-C (178-180), with a unique 5-6-5-6-5-fused pentacyclic ring system, were isolated from the same fungus through solid fermentation [120,121].…”