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

In this work, a new chemo-enzymatic synthesis of (<i>R</i>)-perillaldehyde ((<i>R</i>)-<b>1</b>, 98% ee) was developed by progressively improving the sustainability of the reaction steps. The key transformation is the oxidation of (<i>R</i>)-perillyl alcohol ((<i>R</i>)-<b>2</b>), catalyzed by a recombinant alcohol dehydrogenase from <i>Geobacillus stearothermophilus</i> (ADH-hT), used as cell-free extract (CFE), in the presence of acetone as a sacrificial substrate. Alcohol (<i>R</i>)-<b>2</b> is obtained in a mixture (44% by NMR analysis) with secondary alcohols <b>4</b> and <b>5</b> in a two-step sequence starting from the rearrangement of (4<i>R</i>)-limonene oxides catalyzed by aluminum isopropylate in toluene and subsequent allylic rearrangement of the intermediates by S_N2' displacement in aqueous acetone. Perillyl alcohol is recovered by column chromatography and oxidized with ADH-hT as a catalyst to afford (<i>R</i>)-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 <b>4</b> and <b>5</b> as side products, complete chemoselectivity toward the oxidation of the primary alcohol is observed. Thus, we also describe the chemoselective oxidation of alcohol <b>2</b> 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.