O-Methyl-mandelic acid

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

COMT = Catechol-O-Methyl transferase MAO = Monoamine Oxidase HMMA = Hydroxy Methoxy Mandelic Acid... 

The enol form of mandelic acid (101) has been generated by flash photolysis of phenyldiazoacetic acid in aqueous solution.101 The enol forms by hydration of the intermediate carbene (102). The reaction of chloramine-T (TsNClNa O) with methyl p-tolyl sulfide to give the corresponding sulfimide (103) appears to proceed via a nitrene-transfer mechanism in the presence of copper(I) and a second nitrogen ligand (such as acetonitrile).102... 

Catecholamines can be variously oxidized or methylated. Extracellular epinephrine is O-methylated [via liver catechol-O-methyltransferase (COMT)] to 3-methoxyepinephrine (metanephrine) which can thence be oxidized [via monoamine oxidase (MAO)] to 3-methoxy-4-hydroxy-mandelic aldehyde and thence to 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxy-mandelic. acid (VMA). Similarly, extracellular norepinephrine is O-methylated [via liver COMT] to 3-methoxynorepinephrine (normetanephrine) which can be oxidized [via MAO] to 3-methoxy-4-hydroxy-mandelic... 

FIG. 12. The / -mandelic acid (in gold)-based chiral auxiliary at 0-2 can form a more-stable 6-membered dioxolenium ion, frans-decalm-like (32.9 kJ mol-1 relative to its BO), whereas its epimer can lead to a cw-decalin type of dioxolenium ion (72.8 kJ mol-1), ADF-DFT (DPZ frozen core). The trans-decalin leads to a glycosides, whereas the cw-decalin leads to / glycosides. Both 6-membered-ring dioxolenium ions are more stable then any dioxolenium ion based on participation from 0-3 (R 43.9 kJ mol-1 and 5 46.7 kJ mol-1). If R = allyl, then it is hypothesized that non-facially selective glycosylation takes place through the oxacarbenium ion (BO or Bl). Note that the experiment used O-benzyl and not the O-methyl, which was used for the calculation to avoid complications of multiple minima. 

O-Methylation of mandelic acid leads to the enantiomers of a-methoxy-M-phcnylacetic acid (10), which are also commercially available. This methylation without noticeable racemiza-tion was achieved with diazomethane, using aluminum tris(tert-butanoate) as catalyst8. Alternatively, dimethyl sulfate/ sodium hydroxide has been used15, as described in detail for the racemic compound10. The acids have been used for the construction of quite sophisticated chiral auxiliaries, e.g., a rhodium cyclopentadienyl complex (Section 7.2.2.), and for chiral dienes applied in both normal and inverse Diels-Alder reactions (Section D.1.6.1.1.1.). Chiral dienes, e.g., 1, for normal Diels -Alder reactions were prepared by pyrolysis (460 C) of a tricyclic precursor cstcrified with (S)-O-methylmandeloyl chloride or with the free acid and dicyclohexylcarbodiimide/4-dimethylaminopyridine11 -13. 

Chiral heterodienes, e.g., 12, for inverse Diels-Alder reactions were obtained from a-mer-capto ketones as shown14,15,37. In one case, the chiral heterodiene not only included the O-methyl-L-mandelic acid subunit as chiral auxiliary, but also a chiral C4-unit derived from ascorbic acid or tartaric acid, respectively, which is incorporated in the final product (deoxy-ga/octo-heptose)15. 

Norepinephrine (NE) is taken up into the nerve terminus of the adrenergic neuron by neuronal reuptake mechanisms ( pumps ). It is then degraded intracellularly, by monoamine oxidase (MAO) (primarily MAOa, a mitochondrial enzyme) to form dihydroxymandelic acid. This is further inactivated by the tissue enzyme catechol-O-methyl transferase (COMT). Transmitter remaining in the synaptic cleft is rapidly degraded, first by COMT, located on postsynaptic membranes, to form normetanephrine. This in turn is taken into the neuron and converted to 3-methoxy, 4-hydroxy mandelic acid (VMA) through the actions of MAO (see Figure, top of next page). 

Phenylthioglycolic acid C8H8O3 Allyl 2-furoate o-Anisic acid p-Anisic acid Mandelic acid Methylparaben Methyl salicylate Phenoxyacetic acid Resorcinol acetate Tetrahydrophthalic anhydride Vanillin C8H8O3 K... 

Catechol-O-methyltransferase from rat liver requires S-adeno-sylmethionine as a methyl donor and can methylate catechol but not monohydroxy derivatives of phenylethylamine. In vivo, O-methylation occurs exclusively in the meta position to the carbon side chain, but with purified preparations of the enzyme in vitro methylation can lead to both meta and para methylation. The ratio of products is susceptible. to both the polarity of the substrate and the pH of the medium . In man 3-methoxy-4-hydroxy-mandelic acid (18) comprises about 40 per cent of the total urinary metabolites produced from the catecholamines whilst in other pecies 3-methoxy-4-hydroxyphenylglycol (19), isolated as a sulphate ester, is the predominant breakdown product . A typical metabolic grid which indicates the possible types of pathway leading from noradrenalin (17) to both of these metabolites is shown in Figure 4.4 analogous metabolic schemes may be drawn up for both adrenalin and dopamine. 

MAO within adrenergic nerves is apparently involved in the control of the steady-state concentration of NA, both in the CNS and in sympathetic nerves. Inhibition of MAO may increase the NA content of tissues to several times that found under normal conditions. Intraneuronal MAO is also responsible for the degradation of catecholamines released from storage vesicles by reserpine, as described in Paragraph 5.2.4. There is some evidence that catechol deaminated metabolites, such as 3,4-dihydroxy mandelic acid, are formed primarily by the action of MAO within adrenergic nerves. On the other hand, extraneuronal MAO oxidatively deaminates only compounds which have previously been O-methylated. 

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