Modular enzymatic cascade synthesis of vitamin B5 and its derivatives

Access to vitamin B5 [(R)‐pantothenic acid] and both diastereoisomers of α‐methyl‐substituted vitamin B5 [(R)‐ and (S)‐3‐((R)‐2,4‐dihydroxy‐3,3‐dimethylbutanamido)‐2‐methylpropanoic acid] has been achieved using a modular three‐step biocatalytic cascade involving 3‐methylaspartate ammonia lyase (MAL), aspartate‐α‐decarboxylase (ADC), β‐methylaspartate‐α‐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 B5 and both diastereoisomers of α‐methyl‐substituted vitamin B5, which are valuable precursors for promising antimicrobials against Plasmodium falciparum and multidrug‐resistant Staphylococcus aureus, can be generated in good yields (up to 70%) and excellent enantiopurity (>99% ee). This newly developed cascade process might be tailored and used for the biocatalytic production of various vitamin B5 derivatives by modifying the pantoyl or β‐alanine moiety.