Work

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

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 (4 R )-limonene oxides catalyzed by aluminum isopropylate in toluene and subsequent allylic rearrangement of the intermediates by S N 2′ 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.

Source: Organic Process Research & Development

DOI: 10.1021/acs.oprd.5c00340