3.4- Dihydroxyphenylalanine derivatives

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... 

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. 

Vitamin Ba (pyridoxine, pyridoxal, pyridoxamine) like nicotinic acid is a pyridine derivative. Its phosphorylated form is the coenzyme in enzymes that decarboxylate amino acids, e.g., tyrosine, arginine, glycine, glutamic acid, and dihydroxyphenylalanine. Vitamin B participates as coenzyme in various transaminations. It also functions in the conversion of tryptophan to nicotinic acid and amide. It is generally concerned with protein metabolism, e.g., the vitamin B8 requirement is increased in rats during increased protein intake. Vitamin B6 is also involved in the formation of unsaturated fatty acids. 

Dopamine is the decarboxylation product of DOPA, dihydroxyphenylalanine, and is formed in a reaction catalysed by DOPA decarboxylase. This enzyme is sometimes referred to as aromatic amino acid decarboxylase, since it is relatively non-specific in its action and can catalyse decarboxylation of other aromatic amino acids, e.g. tryptophan and histidine. DOPA is itself derived by aromatic hydroxylation of tyrosine, using tetrahydrobiopterin (a pteridine derivative see Section 11.9.2) as cofactor. 

The biosynthesis of aristolochic acids is considered to begin with 1-ben-zyltetrahydroisoquinoline precursors and to proceed via aporphine intermediates (5). In radioactive labeling studies, Spenser and Tiwari infused d/-tyrosine-2- C into the stem of A. sipho. The C-labeled aristolochic acid I formed lost more than 60% of its radioactivity when it was decarboxylated to the corresponding nitro phenanthrene derivative. Administration of d/-dihydroxyphenylalanine-2- C re-... 

A combination of decarboxylation and hydroxyla-tion of the ring of tyrosine produces derivatives of o-dihydroxybenzene (catechol), which play important roles as neurotransmitters and are also precursors to melanin, the black pigment of skin and hair. Catecholamines may be formed by decarboxylation of tyrosine into tyramine (step e, Fig. 25-5) and subsequent oxidation. However, the quantitatively more important route is hydroxylation by the reduced pterin-dependent tyrosine hydroxylase (Chapter 18) to 3,4-dihydroxyphenylalanine, better known as dopa. The latter is decarboxylated to dopamine.1313 Hydroxylation of dopamine by an ascorbic acid and... 

One of the first mentions of an imprinted sol-gel-derived silica thin film that was able to discriminate against enantiomers was that of Marx and Liron, who created a chiral cavity for propranolol.66 In a note added to the proof, the authors reported on data that showed a cavity templated with the pure enantiomer, 5-propranolol, that discriminated between it and the R-enantiomer.66 In a later publication, more details were provided on this method and two additional systems (R)- and (5)-2,2,2-trifluoro-1 -(9-anthryl) ethanol and d- and L-3,4-dihydroxyphenylalanine.67... 

Melanin granules are secreted by melanocytes in the hair papilla and distributed to keratin in the hair cortex and inner layers of the hair sheath during normal development. Melanogenesis is subject to hormonal control and has been the focus of intensive genetic studies. Two main forms of melanin exist in human skin—eumelanin and phaeomelanin, both of which are derived from tyrosine through the action of tyrosinase (a cupro-enzyme) and possibly other key enzymes (with nickel, chromium, iron, and manganese as cofactors). Tyrosine is converted to dihydroxyphenylalanine and, via a series of intermediate steps, to indole-5,6-quinone, which polymerizes to eumelanin. Phaeomelanins are produced by a similar mechanism but with the incorporation of sulfur (as cysteine) by a nonenzymatic step in the oxidation process. 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

An asymmetric synthesis of ( —)-(i )-Iaudanosine has been accomplished, proceeding from L-3,4-dihydroxyphenylalanine via the norlaudanosine derivatives (18 R1 = H, R2 = C02Me), (18 R1 = CH2Ph, R2 = CONH2), and (18 R1 = CH2Ph, R2 = CN), which was then converted into norlaudanosine (18 R1 = R2 = H). The nor-base was then jV-formylated and the N-formyl derivative reduced with sodium borohydride. The C-l epimer of the ester (18 R1 = H, R2 = C02Me) was also obtained, and it isomerized to the trans-ester when mixed with sodium methoxide in methanol.28... 

These properties, combined with the fact that the second methoxyl group is not attached to the benzene ring and must, therefore, be derived from the dihydroxyphenylalanine (or prephenic acid) precursor, suggest the presence in rhynchophylline of a /3-methoxyacrylic ester residue. Convincing support for this conclusion is provided by a comparison of the UV- and IR-spectra of rhynchophylline with those of appropriate model compounds. Thus, the UV-spectrum of rhynchophylline is identical with the summation spectrum of 3-ethyloxindole and ethyl jS-ethoxy-a-methylacrylate (74), and it is also closely similar to that of formosanine. The IR-absorption of rhynchophylline in the carbonyl region also resembles that of formosanine, except that rhynchophylline exhibits an additional band, of medium intensity, at 1645 cm-1 this band, however, is also present in the spectrum of ethyl jS-ethoxy-a-methylacrylate. 

The catecholamines - dopamine, norepinephrine, and epinephrine are successively derived from tyrosine. S m-thesis occurs in the nerve terminals and in the adrenal gland. Tyrosine hydroxylase catalyzes the first step (Figure 10.2a) and is the major site of regulation (inhibition by dopamine and noradrenaline, activation by cAMP). This step gives rise to 3,4-dihydroxyphenylalanine (L-DOPA), which in turn is a substrate for L-aromatic acid decarboxylase. De-... 

Aromatic amino acids that originate from the shikimate pathway also act as precursors to many alkaloids. Alkaloids that contain a phenylethylamine moiety are derived from L-tyrosine or its oxidation product L-dihydroxyphenylalanine (L-DOPA). Mescaline (N7) originating from the latter amino acid is known to occur in several cacti and is responsible for the hallucinogenic activity of peyote (Lophophora williamsii, Cactaceae). Lophocerine is a tetrahydroisoquinoline alkaloid derived from L-dopamine and found to occur in a different Lophophora species, L. schotti. 

Luse and M(iLaren (1963) have reviewed published research on the photolysis products and quantum yields tor the destruction of amino acids and have attributed the photochemical inactivation of the enzymes chymo-trypsin, lysozyme, ribonuclease, and trypsin by UV light at 254 m i primarily to destruction of the cystyl and tryptophyl residues. The destruction of these residues in proteins was suggested to be a function of the product of the number of residues present, the molecular extinction coefficient, and the quantum yield for destruction of each residue. Cysteine and tryptamine were identified among the irradiation products from cystine and tryptophan, respectively. Tyrosine, histidine, and phenylalanine were also shown to be degraded by UV, histidine yielding histamine, urocanic acid, and other imidazole derivatives, and phenylalanine yielding tyrosine and dihydroxyphenylalanine. Destruction of these three amino acids was not considered to contribute appreciably to the enzyme inactivation. 

The most attractive detailed hypotheses (Fig. 11) suggest the formation of the erythrinane skeleton by oxidation of LXXXVIII, a symmetrical intermediate derived from two molecules of tyrosine or dihydroxyphenylalanine. The two additional bonds necessary might be formed in either order. In one hypothesis (1, 57) oxidation of one aromatic ring to the o-quinone (LXXXIX) is followed by nucleophilic addition of the amino group and further oxidation to XC (or the related o-quinone). This sequence is exactly analogous to the in vitro oxidation of dihydroxyphenylalanine itself to the quinone dopachrome (3S). Nucleophilic or radical addition of the second phenolic ring to the quinoid system would complete the spiro skeleton of XCI. 

Figure 14.5 Electrophilic 18F-fluorination of an organomercurial derivative of dihydroxyphe-nylalanine as a route to synthesis of6-[18F]fluoro-3,4-dihydroxyphenylalanine (6-[18F]fluoroDOF>A/ FDOPA). Reaction is stereospecific and regioselective but requires a step for deprotection of functional groups.

L-dihydroxyphenylalanine. (L-dopa). An amino acid used in treating Parkinson s disease, manganese poisoning, and muscular dystonia. Derived from several types of beans including vanilla also made synthetically. 

The conversion of tyrosine to 3,4-dihydroxyphenylalanine occurs both in vivo in man (590) and in vitro by the action of tissue tyrosinase (205, 688). Mammals can decarboxylate both tyrosine (402,407) and dihydroxyphenyl-alanine (406), tyrosine decarboxylase and dihydroxyphenylalanine (dopa) decarboxylases being quite distinct and separable (405), though both are dependent on pyridoxal phosphate (73, 758, and review 72). In mammals dihydroxyphenylalanine is the most readily decarboxylated of all amino acids, and it is therefore not unreasonable to assume that this is the substrate normally decarboxylated in adrenaline biosynthesis cf. 74, 75). Support for this concept derives from the fact that both the substrate and the product of the reaction (3,4-dihydroxyphenylethylamine diagram 11) can or do occur in the adrenal (298, 299, 802), and the amine is moreover, like adrenaline and noradrenaline, a normal urinary excretion product (245, 404). 

Decarboxylation of amino acids is a typical feature of the bacterial decomposition of proteins. Both phenylethylamine and tyramine were isolated from putrid meat by Barger and Walpole (30), who considered it extremely probable that they were derived from phenylalanine and tyrosine, respectively. No cell-free preparation of phenylalanine decarboxylase appears to have been reported, but decarboxylation by a crude Streptococcus faecalis preparation provides a valuable method of phenylalanine assay (887). Bacterial tyrosine decarboxylase has been studied in detail (495), especially by Gale and co-workers (summarized in 284). It requires pyridoxal phosphate as coenzyme (26, 326, 327) and, unlike mammalian tyrosine decarboxylase, also attacks dihydroxyphenylalanine. Decarboxylation normally only occurs in acid media and is considered primarily to be a protective mechanism tending to restore the pH to neu-... 

Diagram 28. Derivation of two typical quinine alkaloids from, utlimately, tryptophan and dihydroxyphenylalanine. 

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