Lipase Catalyzed Enzymatic Resolution Of Ethyl 8-Chloro-6-Hydroxy Octanoate In Non-aqueous Medium

a-Lipoic acid, an excellent antioxidant frequently used in pharmaceuticals, health products and skin conditioners, has been recognized as a B-vitamin involved in the biochemical decarboxylation of a-keto acids and as a growth factor for certain microorganisms. Despite general commercialization as racemates, the anti-oxidation activity of a-lipoic acid was evidenced to reside in its (R)-enantiomer which occurs naturally in mitochondrial complexes. (R)-a-Lipoic acid has been widely used to treat diabetes, liver diseases and radiation injuries and has been recommended as a "neuroprotective agent". Since the first isolation and identification of a-lipoic acid from natural sources, several routes for its synthesis by chemical methods have been developed e.g. from adipate, cyclohexanone and their derivatives. In this study, ethyl 8-chloro-6-hydroxy octanoate (ECHO), a key chlorohydrin precursor for a-lipoic acid was enzymatically resolved, to form an intermediate for the industrial synthesis of (R)-a-lipoic.First, commercial available lipase Novozym 435 was identified for its relatively high activity and enantioselectivity toward the target substrate, ethyl 8-chloro-6-hydroxy octanoate. And then, optimization on various parameters of lipase-catalyzed kinetic resolution was carried out, including acyl donor, temperature, solvent, water activity, substrate loading and enzyme loading. Based on the optimized conditions, an enzymatic transacylation resolution system with relatively high efficiency and selectivity was established, resulting in 47% conversion and 90% eep (enantiomeric excess of product) at 6 h, and a volumetric productivity of 471 g-L-1·d-1. However, the immobilized lipase Novozym 435 could not be reused in the repeated reaction. Temperature, acyl donor and substrate were proven to be the pernicious factors. After those parameters were reoptimized, the catalyst could be reused for 10 batches with high activity and selectivity, affording over 40% yields and about 92=96% eep of (R)-O-acetylated ECHO. The space-time yield of (R)-O-acetylated ECHO was 38 g·L-1·d-1 with 94% eep while the gram-scale preparative reaction was performed.