Biocatalytic approaches for a more sustainable synthesis of sandalwood fragrances

The synthesis of campholenic-based fragrances requires the preservation of specific structural elements to capture the desired sandalwood scent. The most critical step of their preparation is the reduction of α,β-unsaturated carbonyl precursors while preserving the campholenic unsaturation. Classical reductions, especially hydrogenations, often lack complete chemoselectivity, leading to the formation of over-reduced byproducts. In addition, the stereochemistry plays a key role in the olfactory perception of these chiral fragrances. However, none of the current industrial syntheses are stereoselective, resulting in wasteful production of non-contributory isomers. Herein, we explore the untapped potential of biocatalytic reductions using ene-reductases (ERs) and alcohol dehydrogenases (ADHs) to enhance the sustainability of four commercial sandalwood fragrances (Brahmanol®, Firsantol®, Sandalore®, and Ebanol®), focusing on the stereoselective synthesis of their most odorant isomers. A comparison of green metrics, including E-factors and EcoScale, between bio- and chemo-based reductions is presented. Higher safety and sustainability is achieved by replacing hydrogenation with enzymatic reduction in the stereoselective preparation of sandalwood fragrances.