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

Taro Matsuyama; Ko Togashi; Moe Nakano; Hajime Sato; Masanobu Uchiyama

doi:10.1021/jacsau.3c00039

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

JACS Au. 2023 May 15;3(6):1596-1603. doi: 10.1021/jacsau.3c00039. eCollection 2023 Jun 26.

Authors

Taro Matsuyama¹, Ko Togashi¹, Moe Nakano², Hajime Sato², Masanobu Uchiyama^{1

3}

Affiliations

¹ Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
² Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 4-4-37 Takeda, Kofu, Yamanashi 400-8510, Japan.
³ Research Initiative for Supra-Materials (RISM), Shinshu University, 3-15-1 Tokida, Ueda, Nagano 386-8567, Japan.

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.