Free Phenylacetic Acid Research Articles

Ligand‐Enabled Auxiliary‐Free meta‐C−H Arylation of Phenylacetic Acids

AbstractThe meta‐C−H arylation of free phenylacetic acid was realized using 2‐carbomethoxynorbornene (NBE‐CO2Me) as a transient mediator. Both the modified norbornene and the mono‐protected 3‐amino‐2‐hydroxypyridine type ligand are crucial for this auxiliary‐free meta‐C−H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta‐arylated products in high yields.

Ligand-Enabled Auxiliary-Free meta-C-H Arylation of Phenylacetic Acids.

The meta-C-H arylation of free phenylacetic acid was realized using 2-carbomethoxynorbornene (NBE-CO2 Me) as a transient mediator. Both the modified norbornene and the mono-protected 3-amino-2-hydroxypyridine type ligand are crucial for this auxiliary-free meta-C-H arylation reaction. A series of phenylacetic acids, including mandelic acid and phenylglycine, react smoothly with various aryl iodides to provide the meta-arylated products in high yields.

The biosynthesis of hyoscyamine: the process by which littorine rearranges to hyoscyamine

The incorporation of isotope from specifically-labelled 3-phenyllactic acid 4 or littorine 7 into 3α-phenylacetoxytropane 10, 3α-phenylacetoxy-6β,7β-epoxytropane and 3α-(2′-hydroxyacetoxy)-tropane 9 has been demonstrated. Transformed root cultures of Datura stramonium or Brugmansia (Datura) Candida x B. aurea incorporated fed (RS)-3-phenyl[1,3-13C2]lactic acid 4 into 3α-phenylacetoxytropane 10 and 3α-phenylacetoxy-6β,7β-epoxytropane wild the efficient retention of both 13C nuclei. In contrast, no label was incorporated into these two compounds from (RS)-3-pheny[2-13C2-2H]lactate 4. From this evidence it can be deduced that 3-phenyllactic acid 4 is not incorporated into 3α-phenylacetoxytropane 10via free phenylacetic acid 6, a route which would result in the loss of the C-1 of 3-phenyllactic acid 4. Furthermore, (RS)-(3′-phenyl[1′,3′-13C2]lactoyl)[methyl-2H3]tropine (littorine 7) was incorporated into 3α-phenylacetoxytropane 10, at up to 4% specific incorporation, with the retention of all the 13C and 2H nuclei. Label was also incorporated into 3α-(2′-hydroxyacetoxy)tropane 9 from (RS)-3-phenyl[1,3-13C2]lactic acid 4 and (RS)-(3′-phenyl[1′,3′-l3C2]lactoyl)[methyl-2H3]tropine 7. We propose, on the basis of these observations, a putative process for the rearrangement of littorine 7 to hyoscyamine 8 and suggest that both 3α-phenylacetoxytropane 10 and 3α-(2′-hydroxyacetoxy)tropane 9 arise as by-products of the rearrangement process.

Direct determination of free phenylacetic acid in human plasma and urine by column-switching high performance liquid chromatography with fluorescence detection.

A simple and highly sensitive column-switching high performance liquid chromatographic method with fluorescence detection for the determination of free phenylacetic acid (PAA) in human plasma and urine is described. The method is based on the direct derivatization of plasma and urine PAA with 6,7-dimethoxy-1-methyl-2(1H)-quinoxalinone-3-propionylcarboxylic acid hydrazide (DMEQ-hydrazide). The derivatization reaction proceeds in aqueous solution in the presence of pyridine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide at 37 degrees C. The resulting DMEQ derivative of PAA is separated from endogenous interfering substances by a column-switching chromatographic system consisting of a precolumn (YMC-Pack C4) for sample clean-up and an analytical column (L-Column ODS) for the complete separation of the derivative. The derivative is detected fluorimetrically at 445 nm with excitation at 367 nm. The detection limits (signal to noise ratio = 3) for PAA is 10 fmol in a 10 microL injection volume. The recoveries from plasma and urine are 75 and 96%, respectively. The present method is highly sensitive and simple compared to conventional liquid-liquid extraction procedures. The sensitivity allows the direct determination of free PAA in an extremely small amount (5 microL) of plasma and urine.

Conjugation of phenylacetic acid and m- and p-hydroxyphenylacetic acids in the rat striatum

Two factors that might regulate the levels of the trace acids, phenylacetic acid (PAA), m-hydroxyphenylacetic acid (mHPAA) and p-hydroxyphenylacetic acid (pHPAA) in the rat striatum were investigated: first, formation of conjugates of these acids and second, transport out of the brain by a probenecid-sensitive system. The presence of conjugates of these acids was investigated by subjecting homogenates of rat striatum to hydrolysis. The concentrations of PAA were increased ten-fold by hydrolysis, pHPAA increased two-fold, and mHPAA was unaffected. These findings coupled with the failure of pargyline to decrease free or total PAA levels suggest that conjugation of PAA is an important factor regulating free PAA levels. The transport inhibitor, probenecid, increased the concentrations of free mHPAA, free pHPAA and the total concentrations of all three acids indicating that all three trace acids can be removed from the rat brain by a transport system.

Phenylethylamine and phenylacetic acid in CSF of schizophrenics and healthy controls.

Phenylethylamine (PEA) is an endogenous substance with amphetamine-like stimulant properties. On the basis of this ability an abnormal brain PEA metabolism has been proposed as an etiological factor in some forms of schizophrenia. In the present study 28 schizophrenic patients and 15 healthy controls were investigated. No significant difference from control values was found in PEA concentration in cerebrospinal fluid (CSF) of either untreated of neuroleptic-treated schizophrenics. However, 2 schizophrenics with highest BPRS scores had extremely high PES concentrations. Free phenylacetic acid (PAA), the major metabolite of PEA, was significantly decreased in ummedicated but not in drug-treated schizophrenics. Because of the assumed neuromodulatory properties of PEA, it is suggested that lowered PAA concentrations and the tendency for PEA to be elevated may imply that altered central neurotransmission occurs in certain forms of schizophrenia.

Kinetics of the enzymatic synthesis of benzylpenicillin

The kinetics of the enzymatic synthesis of benzylpenicillin catalysed by penicillin amidase (EC 3.5.1.11) from Escherichia coli have been studied. Both free phenylacetic acid (PAA) and its activated derivative, phenylacetylglycine (PAG), were used in the synthesis as acylating agents for 6-aminopenicillanic acid (6-APA). The catalytic rate constants for synthesis carried out at pH 6.0 were 11.2 and 25.2 s −1, respectively, i.e. they are close and have high absolute values. The main feature of the enzymatic synthesis of benzylpenicillin from phenylacetylglycine, compared with the synthesis from phenylacetic acid, is the shape of the progress curve of antibiotic accumulation. In the former case, benzylpenicillin gradually accumulates until equilibrium is reached. Thus, if the reaction is carried out at the thermodynamically optimum pH of synthesis (low pH), penicillin can be obtained in high yield. In the case of phenylacetylglycine, the kinetic curves are more complex and are characterized by a clear-cut maximum. The presence of the maximum, its value and position on the time axis depend on reagent concentration and on the pH used. A kinetic scheme is proposed which describes well the experimental dependencies. The possibility of using activated acid derivatives in synthesis and the advantages of using computer calculations for process optimization are discussed.

Phenylacetic acid excretion in man

A rapid, reliable, sensitive, and highly specific mass fragmentographic method for the quantification of phenylacetic acid (PAA) in urine is described. The method was used to determine total, conjugated, and free PAA simultaneously in normal urine. The mean ± SE excretion of total, conjugated, and free PAA in urine of 24 normal adult volunteers were, respectively, 137.4 ± 15.8, 128.8 ± 15.0, 8.49 ± 0.99 mg/24 h. Free PAA constitutes less than 10% of the total (free plus conjugated) urine excretion of PAA.

Decreased cerebrospinal fluid concentration of free phenylacetic acid in depressive illness

Cerebrospinal fluid free phenylacetic acid concentration in a series of depressive patients was significantly lower than values in control subjects. This acid derives from phenylethylamine and the findings may reflect a decrease in its brain formation. Such a deficit may be related to other recent observations of a decrease in urinary output of the major metabolites of the “trace amines”, octopamine and tyramine: phenylethylamine is thought to be the precursor of these “trace amines”.