Synthesis of 2,5-Disubstituted Pyrrolidine Alkaloids via A One-Pot Cascade Using Transaminase and Reductive Aminase Biocatalysts

A multi-enzymatic cascade process involving transaminases (TAs) and reductive aminases (RedAms) to produce enantiomerically pure 2,5-disubstituted pyrrolidine alkaloids from their respective 1,4-diketones is reported. Several TAs were screened and the best results for diketone monoamination were obtained with an R-selective TA from Mycobacterium chlorophenicum and with an S-selective TA from Bacillus megaterium. Pyrroline reduction was best performed by a reductive aminase from Ajellomyces dermatitidis (AdRedAm). Finally, a biocatalytic one-pot cascade was implemented using the aforementioned enzymes and a variety of 2-methyl-5-alkylpyrrolidines were produced with high (>99%) conversion, diastereomeric and enantiomeric excess values.