Preparative regio- and stereoselective α-hydroxylation of medium chain mono- and dicarboxylic fatty acids

Abstract

Regio- and stereoselective functionalisation reactions like C–H oxidation are of high importance for instance for the valorization of renewables like fatty acids by α-hydroxylation. Here, peroxygenases were envisioned to be of high interest as they require common hydrogen peroxide as the only oxidant generating water as the sole side product. As the unspecific peroxygenase from Hypoxylon sp. (HspUPO) turned out to be not selective for α-hydroxylation, various bacterial peroxygenases from the CYP152 family were tested for the stereoselective α-hydroxylation of medium chain fatty acids (C6, C8, C10). The enzyme P450_Exα proved to be highly suitable for the conversion of caproic acid (C6) (95% conv.) and showed high regioselectivity to give the α-hydroxylated product (α : β-selectivity = 14 : 1). Additionally, P450_Exα successfully converted the dicarboxylic acids azelaic acid (C9) and sebacic acid (C10) exclusively to the corresponding α-monohydroxylated product (up to >99% conversion). P450_Spα hydroxylated the fatty acids C6, C8 and C10 preferentially in α-position giving the optically pure or optically enriched (S)-enantiomer [ee 95–>99% (S)] with up to 99% conversion. Both enzymes were used for preparative synthesis of α-hydroxylated fatty acids at up to 150 mM substrate concentration on 50 mL scale giving for instance 2-hydroxyoctanoic acid with 87% yield on gram scale (1260 mg) reaching TONs up to 42 000.