4-aryl phenylalanine

Synthesis of unprotected 4-aryl phenylalanine by Suzuki cross-coupling reactions. 

An interesting application of the Suzuki reaction was the direct synthesis of unprotected 4-aryl phenylalanines under microwave irradiation. In addition to the excellent... 

Scheme 2.7 Direct synthesis of unprotected 4-aryl phenylalanines.

Gong, Y. and He, W., Direct synthesis of unprotected 4-aryl phenylalanines via the Suzuki reaction under... 

Isolates from Indian tobacco Q obelia inflata L.), as a cmde mixture of bases, have been recognized as expectorants. The same (or similar) fractions were also used both in the treatment of asthma and as emetics. The principal alkaloid in T. inflata is lobeline (49), an optically active tertiary amine which, unusual among alkaloids, is reported to readily undergo mutarotation, a process normally associated with sugars. Interestingly, it appears that the aryl-bearing side chains in (49) are derived from phenylalanine (25, R = H) (40). 

This is the branch-poiat differentiatiag phenylalanine (25, R = H) from tyrosiae (25, R = OH). Both phenylalanine and tyrosiae contain an aryl ring, a three-carbon side chain (a Cg—Cg fragment), and a nitrogen. Decarboxylation yields a two-carbon side chain (a Cg—Cg fragment), eg, 2-phenethylamine (59, R = H) from phenylalanine and tyramine (59, R = OH) from tyrosiae, although it is not certain that ia all cases decarboxylation must precede use ia alkaloid constmction. 

Partial hydrolysis of a peptide can be carried out either chemically with aqueous acid or enzymatically. Acidic hydrolysis is unselective and leads to a more or less random mixture of small fragments, but enzymatic hydrolysis is quite specific. The enzyme trypsin, for instance, catalyzes hydrolysis of peptides only at the carboxyl side of the basic amino acids arginine and lysine chymotrypsin cleaves only at the carboxyl side of the aryl-substituted amino acids phenylalanine, tyrosine, and tryptophan. 

As the introduction of polar aryl groups into phenylalanine analogues afforded improvements in DPP-4 potency and selectivity, alternative locations to introduce polarity into this series were examined. Replacement of the [3-methyl group with a... 

More specific evidence came from affinity labeling with molecules which could react with specific amino acid group sat or adjacent to the substrate site. These labels were substrate analogues and competitive inhibitors. Substituted aryl alkyl ketones were used. TV-p-toluene-sulphonyl-L-phenylalanine chloromethyl ketone (TPCK) blocked the activity of chymotrypsin. Subsequent sequence analysis identified histidine 57 as its site of binding (see Hess, 1971, p 213, The Enzymes, 3rd ed.). Trypsin, with its preference for basic rather than aromatic residues adjacent to the peptide bond, was not blocked by TPCK but was susceptible to iV-p-toluenesulphonyl-L-lysine chloromethyl ketone (TLCK) (Keil, ibid, p249). 

Alkyl aryl sulfides were anodically oxidized to the corresponding chiral sulfoxides by using poly(amino acid[-coated electrodes. Partially very high enantioselec-tivities (93% ee) were reported [374, 375] however, the reproducibility depended strongly on the lot of the poly(amino acid) used [376]. Earlier, with a similar approach, by using an edge surface graphite anode that was chemically modified with (.S )-phenylalanine, an enantioselectivity of 0.5 to 2.5% was found in the oxidation of methylp-tolyl sulfide to the sulfoxide [377]. 

The HOPG (highly oriented pyrolytic graphite) carbon electrode chemically modified with (5[-phenylalanine at the basal surface led to 2% ee in the reduction of 4-acetylpyridine [377]. A cathode modified with a chiral poly(pyrrole) reduced 4-methylbenzophenone or acetophenone in DMF/LiBr and phenol as proton donor to 1-phenylethanol with up to 17% ee [382]. Alkyl aryl ketones have been reduced to the corresponding alcohols at a Hg cathode in DMF/water in the presence of (1R,2S)-A,A-dimethylephedrinium tetrafluorobo-rate (DET), producing (5 )-l-phenylethanol with 55% ee from acetophenone. Cyclovoltammetry supports an enantioselective protonation of the intermediate (PhCOH(CH3)) [383]. 

Racemic mixtures of underivatized amino acids N-alkyl- and N-aryl-substitued derivates of amino acids (phenylalanine and proline) on graphitic carbon 0.001 M Cu(acetate)2 aqueous solution 229, 230... 

The starting diazoacetamide is prepared by N-arylation of /-phenylalanine methyl ester (DMP, 5.5 M 4-fluoronitrobenzene, 110°C, lOh, 30%), acetoa-cetylation (2,2,6-triraethyl-4/7-l,3-dioxin-4-one, toluene, 110 °C, 4h, 71%) and diazo group transfer (tosyl azide, triethylamine, acetonitrile, 20 °C, 1.5 h, 90%). 

Aryl side chain containing L-a-amino acids, such as phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are derived through the shikimate pathway. The enzymatic transformation of phosphoenolpyr-uvate (PEP) and erythro-4-phosphate, through a series of reactions, yields shikimate (Scheme 2). Although shikimate is an important biosynthetic intermediate for a number of secondary metabolites, this chapter only describes the conversion of shikimate to amino acids containing aryl side chains. In the second part of the biosynthesis, shikimate is converted into chorismate by the addition of PEP to the hydroxyl group at the C5 position. Chorismate is then transformed into prephenate by the enzyme chorismate mutase (Scheme 3). 

Sie sind Vorstufen auch Fur stereoselektive3 Synthesen von a-Amino-/l-hydroxy-car-bonsauren2 (s. Bd. E5, S. 581). 4-Alkoxycarbonyl-5-aryl-4,5-dihydro-l,3-oxazole IV (R3 oder R4 = Aryl) ergeben bei der katalytischen Hydrierung N-Formyl-phenylalanin-ester z.B.3 ... 

Such a rearrangement is not observed with glycine, alanine, 2-aminobutanoic acid or 2-amino-3-cyclohexylpropanoic acid, occurs partially with valine and isoleucine, but is complete with phenylalanine, tyrosine and threonine. By analogy with previous dediazoniation studies on 2-amino acids in acidic media,309 this rearrangement has been explained by the anchimeric assistance of alkyl (Val, lie), aryl (f he, Tyr) or hydroxy (Thr) groups during the dediazoniation process 306 for example, in the case of phenylalanine (4). 

DNBLeu (covalent).5 Chiral phases S-Asp-artyl-S-phenylalanine methyl ester, N.N- Di-propyl-S-alanine cupric acetate. Phosphonates, aryl-sulphoxides, nitrogen heterocycles, di-B-naphthols. 

Lapadatescu C, Ginies C, Le Quere J-L, Bonnarme P (2000) Novel Scheme for Biosynthesis of Aryl Metabolites from L-Phenylalanine in the Fungus Bjerkandera adusta. Appl Environ Microbiol 66 1517... 

In cases where the natural amino acid side chains of enzymes are insufficient to carry out a desired reaction, the enzyme frequently uses coenzymes. A coenzyme is bound by the enzyme along with the substrate, and the enzyme catalyses the bimolecular reaction between the coenzyme and the substrate (cf. Section 2.6.3). A simple model for a-amino acid synthesis by transamination was developed by substituting /I-cyclodextrin with pyridoxamine. Pyridoxamine is able to carry out the transformation of a-keto acids to a-amino acids even without the presence of the cyclodextrin, but with the cyclodextrin cavity as well, the enzyme model proves to be more selective and transaminates substrates with aryl rings bound strongly by the cyclodextrin much more rapidly than those having little affinity for the cyclodextrin. Thus (p-le/f-butylphenyl) pyruvic acid and phenylpyruvic acid are transaminated respectively 15 000 and 100 times faster then pyruvic acid itself, to give (p-le/f-butylphenyl) alanine and phenylalanine (Scheme 12.5). 

Aryl azides are rather bulky groups to append to a ligand, particularly to a small organic molecule, but it has proved possible in many cases to build the reactive group into the structure of a molecule, for instance 8-azido-cAMP and 4-azido-phenylalanine (Fig. 3.2). 

Standard peptide coupling chemistry is performed (Box 25). The acid component is transformed to an activated ester derivative and then treated with the amine [17-19]. This procedure is repeated twice. In the final step the ligands la-le-H4 are deprotected by aryl ether cleavage with BBr3. By use of this simple reaction sequence derivatives with glycine, alanine, phenylalanine, valine, leucine, and other amino acids as spacers were obtained [16]. 

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