# Chemo-enzymatic Approach to (R)‑Perillaldehyde: Improving the Sustainability of the Reaction Steps with the Principles of Green Chemistry

## TL;DR

This paper presents a sustainable chemo-enzymatic method to produce (R)-perillaldehyde using green chemistry principles and an enzyme from a heat-resistant bacterium.

## Contribution

The novel use of a recombinant alcohol dehydrogenase from Geobacillus stearothermophilus in a sustainable, chemoselective oxidation process.

## Key findings

- (R)-Perillaldehyde was synthesized with 98% enantiomeric excess using a recombinant alcohol dehydrogenase as a catalyst.
- The oxidation of (R)-perillyl alcohol in a mixture with secondary alcohols showed complete chemoselectivity toward the primary alcohol.
- The process achieved a 22% isolated yield from limonene oxides using a two-step sequence with green chemistry principles.

## Abstract

In this work, a new chemo-enzymatic synthesis of (R)-perillaldehyde ((R)-1,
98% ee) was
developed by progressively improving the sustainability of the reaction
steps. The key transformation is the oxidation of (R)-perillyl alcohol ((R)-2), catalyzed
by a recombinant alcohol dehydrogenase from Geobacillus
stearothermophilus (ADH-hT), used as cell-free extract
(CFE), in the presence of acetone as a sacrificial substrate. Alcohol
(R)-2 is obtained in a mixture (44%
by NMR analysis) with secondary alcohols 4 and 5 in a two-step sequence starting from the rearrangement of
(4R)-limonene oxides catalyzed by aluminum isopropylate
in toluene and subsequent allylic rearrangement of the intermediates
by SN2′ displacement in aqueous acetone. Perillyl
alcohol is recovered by column chromatography and oxidized with ADH-hT
as a catalyst to afford (R)-perillaldehyde (98% ee),
which is isolated in pure form by distillation under reduced pressure
(22% isolated yield from limonene oxides). When the reaction is performed
on the crude mixture containing perillyl alcohol together with the
secondary alcohols 4 and 5 as side products,
complete chemoselectivity toward the oxidation of the primary alcohol
is observed. Thus, we also describe the chemoselective oxidation of
alcohol 2 in this mixture (44% by NMR analysis) by means
of ADH-hT and subsequent isolation of the corresponding aldehyde by
formation of the Bertagnini adduct. A comparison between these two
routes and those described in the literature is herein discussed.