Modular Enzymatic Cascade Synthesis of Vitamin B5 and Its Derivatives

Access to vitamin B-5 ((R)-pantothenic acid] and both diastereoisomers of alpha-methyl-substituted vitamin B-5 [(R)- and (S)-3-((R)-2,4-dihydroxy-3,3-dimethylbutanamido)-2-methylpropanoic acid) was achieved using a modular three-step biocatalytic cascade involving beta-methylaspartate ammonia lyase (MAL), aspartate-alpha-decarboxylase (ADC), beta-methylaspartate-alpha-decarboxylase (CrpG) or glutamate decarboxylase (GAD), and pantothenate synthetase (PS) enzymes. Starting from simple non-chiral dicarboxylic acids (either fumaric acid or mesaconic acid), vitamin B-5 and both diastereoisomers of alpha-methyl-substituted vitamin B-5, which are valuable precursors for promising antimicrobials against Plasmodium falciparum and multidrugresistant Staphylococcus aureus, can be generated in good yields (up to 70%) and excellent enantiopurity (> 99% ee). This newly developed cascade process may be tailored and used for the biocatalytic production of various vitamin B-5, derivatives by modifying the pantoyl or beta-alanine moiety.