Kilogram-scale Stereoselective Synthesis of an N-methylprolinol Derivative by Enzymatic Transformation

A scalable method for the manufacture of (S)-1-((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)ethan-1-ol, a key intermediate for KRAS inhibitor candidates, was established. This method simplifies the process by performing the decarboxylation of the β-keto ester and the stereoselective reduction of the resulting ketone in a one-pot enzymatic reaction. Furthermore, the direct methylation via Boc group reduction using lithium aluminum hydride was replaced with the safer Eschweiler-Clarke reaction. The resulting prolinol derivative was isolated as its tartrate salt, yielding a high-quality target compound.