Enzymatic Synthesis of (S‐(−)‐3‐(3,4‐Dihydroxyphenyl)lactic Acid

Abstract

The first enzymatic synthesis of (S)-(-)-3-(3,4-dihydroxyphenyl)lactic spectrum of pharmacological activities, is described. L-Hydroxyisocaproate dehydrogenase was used as enzyme.Enzymatische Synthese von S-(-)-3-(3,4-Dihydroxyphenyl)-milchsiiur re, cines Dopa-Metaboliten sowie cines nativen Wirkstoffes mit einem breiten Spektrum pharmakologischer Wirkungen, unter Verwendung von acid, a metabolite and naturally Occurring with a broad Die enzymatische Synthese S-(-)-3-(3,4-Dihydroxyphenyl).milchs~u.L-Hydroxyisocaproat-Dehydrogenase wird erstmals beschrieben.3-(3,4-dihydroxyphenyl)lactic acid (1) was first suggested by Smith2) to be a minor metabolite of 3,4-dihydroxyphenylalanine (DOPA) (2), an amino acid formed during the biosynthesis of noradrenaline and adrenaline and widely used in its levo-form in the treatment ofPurkinson's disease. Its formation in meal worms following administration of adrenaline was reported much earlier3) and it has also been identified as a metabolite of safrole epoxide in rats and guinea pigs4). Its R(+)-form has been identified as a water-soluble constituent of the roots of the Chinese medicinal herb Salviu miltiarrhizu (Dan Shen SU)~). It has also been identified very recently in the Ceptidis rhizome6). The pharmacological properties of 1 have been the subject of extensive investigations by Russian and Chinese workers. The following actions have been attributed to 1: hypothermia and decrease in exploratory behaviour7); competitive inhibition of aromatic amino acid pyridoxal decarboxylase8s 9); enhancement of the central effects of L-DOPAIO); marked vasodilatory action on isolated swine coronary artery preparations"); increase in the tolerance of mice to hypoxia**); antagonization of the constrictor response to morphine and propanolol13) and, anticoagulation effects in vitro14). Its actions have also been investigated to understand the underlying mechanisms in the pathogenesis of extrapyramidal disordersIs).The synthesis of 1 was first claimed in a patent by Nagoya et aI.l6). According to them, sodium 3-(3,4-dibenzyloxyphenyl)glycidate can be reduced catalytically by hydrogen to give the sodium salt in 82 % yield. Xue et al. have reported the synthesis of the sodium salt starting from 3,4-dihydroxybenzaldehyde in 37 % overall yield using the azlactone route and subsequent Clemmensen reduction17). Both methods, however, lead to racem. 1.Probably the enantiomers of 1 might possess different pharmacological actions. Besides, the enantiomers could serve as starting materials for the synthesis of other naturally occurring polyphenolic acids such as rosmarinic acid (3). Therefore, it was desirable to develop a new route to synthesize the enantiomers of 1 in good yields. Preliminary experi-~ ~~ Arch. Pharm. (Weinheim) 321,179-180 (1988) 0 VCH Verlagsgesellschafi mbH, 0-6940 Weinheim. I988 0365-6233/88/0303-0179 $OZ.SO/O a) Present adress: Institut fur Biotechnologie, Kernforschungsanlage, D-5 170 Jiilich (FRG)ments using classical routes to 2-hydroxy acids such as oxidative deamination of th...