# Introducing Small Rings into Farnesyl Pyrophosphates Paves the Way for the Enzymatic Generation of Unnatural Sesquiterpene Scaffolds

## TL;DR

By modifying farnesyl pyrophosphate with small strained rings, researchers created new sesquiterpene structures using enzymes, leading to 17 new compounds with unique carbon backbones.

## Contribution

Introducing small strained rings into FPP to generate new sesquiterpene scaffolds via enzymatic reactions.

## Key findings

- 17 new terpenoids were synthesized, 11 with previously unknown carbon skeletons.
- Oxetane ring oxygen participated in initial cyclization, influencing product formation.
- Molecular modeling showed alternative enzyme binding poses leading to diverse cyclization pathways.

## Abstract

New sesquiterpene skeletons are accessible when the geminal
dimethyl
group in farnesyl pyrophosphate (FPP) is exchanged by small strained
rings, specifically cyclopropane, cyclobutane, and oxetane. When these
new FPP derivatives are exposed to sesquiterpene synthases, the additional
chemical reactivity installed in the strained rings can interact in
a unique way with the carbocation intermediates in the active centers
of sesquiterpene synthases BcBOT2, PenA, Omp7, and Cop4, which are
known to be substrate promiscuous. As such, they can induce rearrangements
and ring enlargements, which can yield completely new, previously
unknown sesquiterpene carbon skeletons with additional carbon atoms
embedded in the (oligo)­cyclic backbones. A total of 17 new terpenoids
are reported and structurally elucidated, 11 of which have so far
unknown unnatural terpene backbones. Besides rearrangements of the
small rings, we report on the nucleophilic involvement of the oxygen
atom in the oxetane ring during the initial cyclization step. As an
additional finding, the oxetane analogues of the two known sesquiterpenes
africanene and pentalenene were isolated. Molecular modeling studies
revealed that the FPP derivatives are optimally oriented for catalysis
within the enzymes’ active sites. The simulations unveiled
alternative binding poses that facilitate divergent cyclization cascades,
ultimately leading to the formation of previously uncharacterized
molecular frameworks of sesquiterpenes.