A Streamlined Chemoenzymatic One-Pot Process for the Enantioselective Total Synthesis of Tenuipesone A/B

Biocatalysis is a branch of catalysis that has allowed the development of a diverse range of sophisticated synthetic methodologies that target geometrically demanding structures such as pharmaceuticals, natural products, and their analogues. The routes are often more efficient due to enzymes innately high degree of chemo-, regio- and stereoselectivity, while making the overall process more sustainable when compared to their chemical equivalent, as enzymes are naturally biodegradable and operate under physiological conditions. Herein, we demonstrate the power of this catalytic approach via the development of a chemoenzymatic one-pot process that allowed access to the fungal metabolites tenuipesones A and B, along with their enantiomeric counterparts, in good yields (60-72 %) and excellent enantioselectivity (>99 % ee). The stereochemical outcome of the products was controlled through careful selection of the biocatalysts, enabling control of the configuration of the key C7 chiral center. This novel chemoenzymatic cascade process allowed access to all four possible stereoisomers, with their absolute stereochemistry being evaluated to confirm the true configuration of the natural isolates.