Dihydroxyphenylalanine synthesis

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). 

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... 

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. 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

In 1997, Steglich reported (Scheme 7) the synthesis [29] of lamellarin G trimethyl ether (36) based on the biosynthetic proposal that such compounds arise from 3,4-dihydroxyphenylalanine (DOPA) secondary metabolites. 

Figure 11.17 Supplementation of diet with y-linolenic acid to overcome a deficiency of A desaturase Supplementation of a diet with DOPA to overcome a deficiency of monooxygenase in Parkinson s disease. A desaturase is a rate-limiting enzyme in the synthesis of arachidonic acid. Supplementation of diet with y-linolenic acid bypasses this enzyme. Damage to neurones in the brain that use dopamine as a neurotransmitter causes a deficiency of rate-limiting a supplement - enzyme, tyrosine monooxygenase, which is bypassed by a supplement, DOPA (dihydroxyphenylalanine). DOPA (usually, described as L-DOPA) is considered by the medical profession as a drug but, in reality, it is a dietary supplement.

Synthesis of norepinephrine begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, sometimes termed dopa-decarboxylase. The dopamine is actively transported into storage vesicles, where it is converted to norepinephrine (the transmitter) by dopamine (3-hydroxylase, an enzyme within the storage vesicle. 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

These also presumably lead to a transient quinonoid-carbanionic intermediate. Addition of a proton at the original site of decarboxylation followed by breakup of the Schiff base completes the sequence. Decarboxylation of amino acids is nearly irreversible and frequently appears as a final step in synthesis of amino compounds. For example, in the brain glutamic acid is decarboxy-lated to y-aminobutyric acid (Gaba),193 196b while 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxy-... 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Noradrenergic neurons. The noradrenergic neuron uses NE for its neurotransmitter. Monoamine neurotransmitters are synthesized by means of enzymes, which assemble neurotransmitters in the cell body or nerve terminal. For the noradrenergic neuron, this process starts with tyrosine, the amino acid precursor of NE, which is transported into the nervous system from the blood by means of an active transport pump (Fig. 5 — 17). Once inside the neuron, the tyrosine is acted on by three enzymes in sequence, the first of which is tyrosine hydroxylase (TOH), the rate-limiting and most important enzyme in the regulation of NE synthesis. Tyrosine hydroxylase converts the amino acid tyrosine into dihydroxyphenylalanine (DOPA). The second enzyme DOPA decarboxylase (DDC), then acts, converting DOPA into dopamine (DA), which itself is a neurotransmitter in some neurons. However, for NE neurons, DA is just a precursor of NE. In fact, the third and final NE synthetic enzyme, dopamine beta-hydroxylase (DBH), converts DA into NE. The NE is then stored in synaptic packages called vesicles until released by a nerve impulse (Fig. 5—17). 

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. 

In a similar context, 6-18F-3,4-dihydroxyphenylalanine (6-18F-DOPA) was synthesized by direct fluorination of L-3-(3-hydroxy-4-pivaloxyphenyl)alanine (ra-P-DOPA) with Ac018F in acetic acid resulting in the 2- and 5-18F isomers. Hydrolysis of the reaction mixture in hydrochloric acid followed by HPLC separation gave 6-18F-DOPA (equation 23)44. Another application of Ac018F was reported in the synthesis of a trimethyl tin precursor of 2-oxoquazepam, 7-chloro-1 -(2,2,2-trifluoroethyl)-1,3--dihydro-5-(2-fluorophenyl)-2//-l,4-benzodiazepin-2-one, a benzodiazepine agonist, and its conversion to [18F]-2-oxoquazepam by reaction with AcQ18F (equation 24)45. 

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... 

Synthesis of norepinephrine Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase1. This is the rate-limiting step in the formation of norepinephrine. DOPA is decarboxylated to form dopamine. 

In the mid-1960s, it was discovered that L-DOPA was useful in treating Parkinson s disease. L-DOPA is the common name for the amino acid (S)-3,4-dihydroxyphenylalanine, which is the biologically active enantiomer. Its industrial synthesis was formerly achieved by resolution of a racemic intermediate which, in turn, was prepared by heterogeneous hydrogenation of an enamide according to Figure 11a. 

Carboni E, Tanda G, Di Chiara G (1992) Extracellular striatal concentrations of endogenous 3,4-dihydroxyphenylalanine in the absence of a decarboxylase inhibitor—A dynamic index of dopamine synthesis in vivo. / Neurochem 59 2230-2236. 

Ty initiates melanin synthesis by the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (Dopa) and the oxidation of dopa to dopaquinone. In the presence of L-cysteine, dopaquinone rapidly combines with the thiol group to form cysteinyldopas, which undergo nonen-zymatic conversion and polymerization to pheomelanin via benzothiazine intermediates. In the absence of thiol groups, dopaquinone very rapidly undergoes conversion to dopachrome, which is transformed to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) by dopachrome tautomerase. Alternatively, dopachrome is converted nonenzymatically to 5,6-dihydroxyindole (DHI). Oxidation of DHICA and DHI to the corresponding quinones and subsequent polymerization leads to eumelanins. It is still questionable if Ty is involved in this step. 

Thus, peroxidase is capable of catalyzing the synthesis of three important drugs, L-3,4-dihydroxyphenylalanine (XII) (Scheme VII), d-(-)-3,4-dihydroxyphenylglycine and L-epinephrine with yields up to 70 % [90]. 

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