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

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.