5.6- Dihydroxyphenylalanin

Chira.lHydrogena.tion, Biological reactions are stereoselective, and numerous dmgs must be pure optical isomers. Metal complex catalysts have been found that give very high yields of chiral products, and some have industrial appHcation (17,18). The hydrogenation of the methyl ester of acetamidocinnamic acid has been carried out to give a precusor of L-dopa, ie, 3,4-dihydroxyphenylalanine, a dmg used in the treatment of Parkinson s disease. 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

Robinson (1934) has elaborated this into a scheme embracing hydrastine, berberine, epicryptopine, corydaline, sanguinarine and homochelidonine, though he points out that dihydroxyphenylalanine is labile and too easily convertible into indole derivatives to be capable of... 

Monsanto s commercial route to the Parkinson s drug, L-DOPA (3,4-dihydroxyphenylalanine), utilizes an Erlenmeyer azlactone prepared from vanillin. The pioneering research in catalytic asymmetric hydrogenation by William Knowles as exemplified by his reduction of 24 to 25 in 95% ee with the DiPAMP diphosphine ligand was recognized with a Nobel Prize in Chemistry in 2001. ... 

The dl-a-methYl-3,4-dihYdroxYphenylalanine may be made as described in U.S. Patent 2,868,818. Five-tenths of a gram of 3-hYdroxY-4-methoxYphenylalanine was dissolved in 20 ml of concentrated hydrochloric acid, the solution saturated with hydrogen chloride and heated in a sealed tube at 150°C for 2 hours. The dark reaction mixture was concentrated to dryness in vacuo, excess acid removed by flushing several times with ethanol. On dissolving the dark residue in a minimum amount of water and adjusting the clarified solution to pH 6.5 with ammonium hydroxide the compound separated in fine crystals which were filtered, washed with alcohoi and ether. The crystalline product had a MP of 299.5° to 300°C with decomposition. 

Then, as described in U.S. Patent 3,158,648, the optical isomers may be resolved as follows. 37 g of racemic a-methYl-3,4-dihYdroxYphenylalanine are slurried at 35°C in 100 cc of 1.0 N hydrochloric acid. The excess solids are filtered leaving a saturated solution containing 34.6 g of racemic amino acid of which about 61% is present as the hydrochloride. The solution Is then seeded at 35°C with 7 g of hydrated L-o -methYl-3,4-dihYdroxYphenYlalanine (6.2 g of anhydrous material). The mixture is then cooled to 20°C in 30 minutes and aged one hour at 20°C. The separated material Is isolated by filtration, washed twice with 10 cc of cold water and dried in vacuo. The yield of product is 14.1 g of L-a-methYl-3,4-di-hydroxyphenylalanine in the form of a sesquihydrate of 100% purity as determined by the rotation of the copper complex. 

The nigrostriatal system is predominantly involved in motor control, which is particularly evident in Parkinson s disease (PD), where a progressive loss of these neurons results in loss of motor function. In the early stages of the disorder, the motor impairment can be reversed by the administration of the dopamine precursor l-DOPA (L-3,4-dihydroxyphenylalanine), which bypasses the need for TH in dopamine... 

L-Dihydroxyphenylalanine 4-Dihydroxyphenylethylamine Dimeric Transcription Factors Dioxins Dipeptidase Dipeptidylpeptidase Dipeptidylpeptidase IV Direct Thrombin Inhibitors Discharge of Neurons... 

It is noteworthy that, as early as 1929, Shibata and Tsuchida reported a kinetic resolution of rac-3,4-dihydroxyphenylalanine by selective oxidation of one enantiomer using a chiral cobalt complex [Co(en)3NH3Cl]Br2 as a catalyst [46,47]. Figure 12 shows a highly enantioselective addition of diisopropy-Izinc to 2-(ferf-butylethynyl)pyrimidine-5-carbaldehyde via an autocatalytic process in the presence of a chiral octahedral cobalt complex with ethylenedi-... 

Tyrosine is the immediate precursor of catecholamines, and tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis. Tyrosine hydroxylase is found in both soluble and particle-bound forms only in tissues that synthesize catecholamines it functions as an oxidoreductase, with tetrahydropteridine as a cofactor, to convert L-tyrosine to L-dihydroxyphenylalanine (L-dopa). 

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

Figure 8.5 The synthetic pathway for noradrenaline. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-P-hydroxylase (DpH) after uptake of dopamine into the vesicles from the cell cytosol...

Some work has been completed on reaction of proteins with nitrite followed by hydrolysis and analysis for amino acids It has been shown that 3-nitrotyrosine and 3,4-dihydroxyphenylalanine are formed from bovine serum albumin when nitrosation occurs under conditions similar to those found in the human stomach (36), Direct demonstration that nitrite reacts with protein has been made by using NaN02 with bovine serum albumin (pH 5.5, 20 C and 200 ppm nitrite). A 60% loss of the originally added nitrite was observed in one week and nearly half of the nitrite (labelled %) could be recovered from the protein. Similar work with myosin revealed that 10-20% of the incorporated label was present as 3-nitrotyro-sine (J7). 

Allomelanins — These are structurally different compounds containing little or no nitrogen. They are considered polymers of phenolic compounds like catechol. Fnngi prodnce melanin pigments, predominantly dihydroxyphenylalanine (DOPA)-melanin and dihydroxynaphthalene (DHN)-melanin. ... 

Oliveira, J. C., Silva, D. M., Amorim, H. V, Teixeira AA Effect of the combination of crude coffee bean extracts with high and low polyphenoloxidase activity on 3,4-dihydroxyphenylalanine, Cientifica, 3, 332, 1975. (CA84 178461y)... 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Figure 1. The biosynthetic pathway from tyrosine to melanin (according to Hearing and Tsukamoto, 1991 Tsukamoto et al., 1992). Tyrosinase catalyzes three different reactions in this pathway (1, 2, 3). The reaction catalyzed by the product of TRP-2, DOPAchrome tautomerase, is indicated by 4. DOPA = 3,4-dihydroxyphenylalanine DHICA = 5,6-dihydroxyin-dole-2-carboxylic acid DHI = 5,6-dihydroxyindole.

In the context of synthesis and exchange reactions of biodegradable drug-binding matrices, starch trisuccinic acid was loaded via imidazolides with amines such as n-butylamine, morpholine, 4-aminobenzoic acid, or 3,4-dihydroxyphenylalanine to prepare the respective amides in high yields [160] an example is presented below. 

Recently, chloromethylated benzocoumarin 11c, hydroxylmethylated benzocou-marin 12, and chloromethylated coumarin 13 were used in the efficient preparation of several fluorescent ester conjugates of /V-benzyloxycarbonyl-neurotransmitter amino acids, such as p-alanine, tyrosine, 3,4-dihydroxyphenylalanine (DOPA), glutamic acid, and y-aminobutyric acid (GABA) [39, 40],... 

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