Sequential cascade reaction toward the synthesis of (S)-3-hydroxy-3-phenylpropanamide

Carrying out one-pot multistep cascades reactions eliminates the need of intermediates purification and helps to maximize the overall yield, minimize the use of reagents, catalysts and solvents, yielding a more sustainable process1. Optically active (S)-3-hydroxy-3-phenylpropanamide (4) is an important building block for the synthesis of active pharmaceutical ingredients2. In order to synthesize (4) it was envisioned two approaches. Firstly, we performed a simultaneous cascade reaction (Scheme 1). Unfortunately, in this strategy the beta-ketoamide (2) was the only afforded product due to the distinct kinetics of both evaluated enzymes. The KRED used herein is not able to catalyze the transformation of 3-oxo-3-phenylpropanamide (2) into (4), but it can catalyze the transformation of benzoylacetonitrile (1) to 3-hydroxy-3-phenylpropanonitrile (3). On the other hand, (4) was obtained through sequential cascade reaction (Scheme 2), starting from 1 and the same previously evaluated enzymes with 99% conversion and enantiomeric excess >99% in both steps.