# Dynamic Enantioconvergent Desaturation of 4,5-Disubstituted γ‑Lactones in Whole Cells of Rhodococcus erythropolis

## TL;DR

Scientists used bacteria to efficiently convert multiple forms of a chemical into a single desired product with high precision and sustainability.

## Contribution

A novel biocatalytic method using Rhodococcus erythropolis cells for dynamic enantioconvergent desaturation of γ-lactones.

## Key findings

- Whole cells of Rhodococcus erythropolis convert four stereoisomers of γ-butyrolactones into a single (R)-configured product with up to 99% enantiomeric excess.
- The process involves a network of enzymes including esterases, alcohol dehydrogenases, ene-reductases, and ketoreductases.
- The method was successfully applied to synthesize a key intermediate for forskolin, demonstrating its potential in sustainable chemistry.

## Abstract

The α,β-desaturation of esters is one of
the most challenging
transformations in organic synthesis. While transition-metal-catalyzed
methods have significantly advanced in the last decades, they often
require high catalyst loading and nongreen solvents and rarely enable
stereoselective transformations. Here we show that whole cells of Rhodococcus erythropolis enable a dynamic enantioconvergent
desaturation of 4,5-disubstituted γ-butyrolactones (Quercus-like lactones), funneling all four initial stereoisomers
into a single (R)-configured product with excellent
enantioselectivity (up to ee 99%). Mechanistic investigations
with deuterium-labeled substrates reveal a highly complex pathway
involving multiple transformations catalyzed by a network of enzymes.
The process includes lactone ring-opening by esterases, stereoselective
oxidation of secondary alcohols by alcohol dehydrogenases (ADHs),
desaturation of carboxylates by ene-reductases (ERs), and stereoselective
reductive steps mediated by ERs and ketoreductases (KRs). The final
stereochemical outcome arises from the combination of two stereoediting
transformations: (i) a site-selective de-epimerization
catalyzed by ADH/KR, and (ii) an ER-mediated E → Z isomerization coupled to the irreversible lactonization
(thermodynamic sink). Finally, this dynamic enantioconvergent biocatalytic
desaturation was applied to the preparation of a key intermediate
used in the total synthesis of forskolin, showcasing the potential
of biocatalytic desaturations as a greener and more stereoselective
alternative to traditional chemical methods with broad implications
for asymmetric synthesis and sustainable chemistry.