An efficient and sustainable chemoenzymatic synthesis of ethambutol

The anti-tuberculosis drug ethambutol remains in high demand, and hence there is a drive to improve the efficiency and sustainability of its production. Critical intermediates in its synthesis potentially include alkyl ( S )-2-aminobutyrate esters. Taking advantage of the high enantioselectivity of enzymes, we applied ω-amino transaminases (ATAs) for the enantioselective transamination of two α-keto ester substrates, using isopropylamine as the amine donor, to produce the corresponding α-amino esters in enantiomeric excesses ranging between 94-99% and to obtain the desired products in isolated yields of 15-73%, depending on the enzyme variant and reaction conditions. The isopropyl ( i Pr) ester substrate gave rise to greater enzyme activity compared to the corresponding ethyl (Et) ester substrate. Hence, it was shown that isopropyl ( S )-2-aminobutyrate could be synthesised in a good and preparative isolated yield (73%) and in excellent enantiomeric excess (>99%). A novel and potentially industrially feasible synthetic route to ( S , S )-ethambutol was subsequently developed, starting from isopropyl ( S )-2-aminobutyrate. Oxamidation using oxalyl chloride, followed by a novel borane mediated global reduction protocol, furnished ( S , S )-ethambutol as a single stereoisomer in a good albeit unoptimised overall yield.