L-DOPA derivative

Shen H, Kannari K, Yamato H, et al. Effects of benser-azide on L-DOPA-derived extracellular dopamine levels and aromatic L-amino acid decarboxylase activity in the striatum of 6-hydroxydopamine-lesioned rats. Tohoku J Exp Med. 2003 199 149-159. 

M.E. Jung and co-workers have developed a synthesis of selectively protected L-Dopa derivatives from L-tyrosine via a Reimer-Tiemann reaction followed by the modified Dakin oxidation. The formyl group introduced by the Reimer-Tlemann reaction had to be converted to the corresponding phenol. After trying many sets of conditions, the Syper process was chosen, which uses arylselenium compounds as activators for the oxidation. Treatment of the aromatic aldehyde with 2.5 equivalents of 30% hydrogen peroxide in the presence of 4% diphenyl diselenide in dichloromethane for 18h gave the aryl formate in excellent yield. This ester was cleaved by treatment with methanolic ammonia for 1h to afford the desired phenol in good yield. 

Jung, M. E., Lazarova, T. I. Efficient Synthesis of Selectively Protected L-Dopa Derivatives from L-Tyrosine via Reimer-Tiemann and Dakin Reactions. J. Org. Chem. 1997, 62, 1553-1555. 

L-DOPA-derived melanins are synthesized in melanocytes and are responsible for the dark pigmentation of skin and hair of animals and humans. They protect... 

Ishihara and Fushimi designed an interesting Cu(I I) catalyst prepared in situ from Cu(OTf)2 and an L-DOPA-derived monopeptide (270) as a small-molecule artificial metalloenzyme (Scheme 17.61) [87]. The catalyst provides Diels-Alder cycloadducts (271) with excellent diastereo- and enantioselectivities for cycloadditions between a variety of dienes and a,P-unsaturated l-acyl-3,5-dimethylpyrazoles (269). Results for cycloaddition of cyclopentadiene with a, P-unsaturated l-acyl-3,5-dimethylpyrazoles bearing a variety of P-substituents are illustrated in Scheme 17.61. The authors... 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

L-Dopa and Trimethoprim are two other dmgs that can be made from vanillin. u-Dopa is used for the treatment of Parkinson s disease Trimethoprim is an antiinfective agent used mainly for urinary tract infections and certain venereal diseases. Also, Mebeverine, an antispasmodic agent, and Verazide, a generic antitubercular agent, are dmgs that can be made from vanillin or its 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). 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

Acetyl hypofluorite gas is used in a reaction with an arylmercunc acetate to produce a derivative of L-DOPA [56] (equauon 30). 

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. 

I. Ester derivatives L-Dopa Carboxyl ester, e.g., methyl catechol mono-o-pivaloyl. 4-6,8-10... 

Tamai, I., et al. Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepTl. J. Pharm. Sci. 1998, 87, 1542-1546. 

NMR evidence for intermediate dihydrides of cationic Rh catalysts remained elusive for a long time, ever since the first demonstrations [33] of effective enan-tioselective catalysis, for example in the homogeneous hydrogenation of dehydroamino acid derivatives for the synthesis of L-DOPA. 

Perhaps the one major drawback with DIPAMP is the long synthetic sequence required for its preparation, though shorter and cheaper methods are now available [12]. The ligand continues to be a player for the synthesis of amino acid derivatives at scale, including L-Dopa, as mentioned above [12, 25, 27-29]. Its continued use is a testament to the power of the initial discoveries, as well as showing that a chemical catalyst can achieve selectivities only previously seen with enzymes. 

There is little doubt that the hydrogenation of dehydro a-amino acids is the best-studied enantioselective catalytic reaction. This was initiated by the successful development of the L-dopa process by Knowles (see below) and for many years, acetylated aminocinnamic acid derivatives were the model substrates to test most newly developed ligands. As can be seen below, this is the transformation most often used for the stereoselective synthesis of a variety of pharma and... 

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

The selective electrophilic aromatic substitution carried out by displacement of a metallic substituent (Hg, Sn) ( F-fluorodemetallation) using [ F]p2 or [ F]AcOF remains a method of choice to introduce a fluorine atom on a specific position. In the early preparations of [6- F]fluoro-L-DOPA, the reaction of a 6-substituted mercuric derivative with [ F]acetyl hypofluorite yielded the expected compound in 11 % yield [73,74]. Reaction of a mercuric precursor, free or on a modified polystyrene support P-CH2-COOHg(DOPA precursor) allows the preparation of [ F]fluoro-L-DOPA in an overall yield up to 23 %. The polymer supports are easily prepared, require no special treatment for storage and are convenient to use in automated production [75]. 

Employing similar reaction procedures and conditions, the corresponding benzo-15-crown-5 derivatives l-166 and 167 have been derived from L-Dopa... 

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