Derived from Phenylalanine

Several metabolites in which phenylalanine participates as a component of the diketopiperazine ring have been isolated from Aspergillus species. Other possible components of the diketopiperazine skeleton are serine (gliotoxin), phenylalanine (aranotin and emestrin), and glycine (aspirochlorine). It is interesting that all of these metabolites possess two-four sulfur atoms in the molecule. These inhibit bacterial growth and are rather toxic to mammalian cells. 

In 1980 bisdethiobis(methylthio)gliotoxin (62) was isolated from Gliocladium deliquescens (yield, 6% of gliotoxin). Obtained as amorphous, it was characterized via the crystalline, bis-4-bromobenzoate of the didehydro derivative and identified by synthesis from gliotoxin by reduction and methylation 125). 

DL-[l- C]Phenylalanine is incorporated into gliotoxin (61) in 4.2% yield, and degradation of labeled gliotoxin shows that essentially all of the radioactivity (82%) resides at position 1, suggesting the intact incorporation of phenyl- 

Bisdethiobis(methylthio)gliotoxin (63) is formed irreversibly from gliotoxin 

Acetylation of aranotin (65), C2oHigN207S2, mp 198-200°C, affords another metabolite, acetylaranotin (66), C22H2oN20sS2 201-215°C, which has a 

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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). 

The benzoic acid, the acid moiety found in cocaine (98), is also derived from phenylalanine (141). Feeding of [4-3H]phenylalanine to E. coca led to the benzoyl moiety, where 96% of the 3H was located at the para position (138). The intermediacy of cinnamic, 3-hydroxy-3-phenylpropionic, and benzoylacetic acid in the formation of benzoic acid has been suggested (138). 

Glucosinolates can also be derived from phenylalanine. Wittstock and Halkier36 have identified CYP79A2 from Arabidopsis and shown that it catalyzes the conversion of phenylalanine to phenylacteladoxime with the subsequent accumulation ofbenzylglucosinolate. 

Tyrosine is structurally related to and derived from phenylalanine. It is the metabolic precursor to dopamine, an important neurotransmitter. Tyrosine is also the precursor to the hormones epinephrine and norepinephrine and to melanin, the pigment of skin. 

As early as 1981, Inoue and Oku [17] had introduced a cyclic dipeptide organocatalyst derived from phenylalanine and histidine that could mimic the hydroxy-... 

Essential amino acids. f Derived from phenylalanine in mammals. 

Phenylalanine, tyrosine, and tryptophan are converted to a variety of important compounds in plants. The rigid polymer lignin, derived from phenylalanine and tyrosine, is second only to cellulose in abundance in plant tissues. The structure of the lignin polymer is complex and not well understood. Tryptophan is also the precursor of the plant growth hormone indole-3-acetate, or auxin (Fig. 22-28a), which has been implicated in the regulation of a wide range of biological processes in plants. 

Aqueous surfactants are another class of catalysts. Substantial rate enhancement is seen in the reaction occurring at the micellar hydrocarbon-water interface, which is ascribed to a concentration of the reactant in the micellar pseudo-phase. Chiral p-nitrophenyl esters derived from phenylalanine are hydrolyzed by a histidine-containing dipeptide at a micellar interphase, at which a very high enantiomer discrimination, kR/ks up to 30.4 at 0°C, is observed (49). As shown in Scheme 20, the enantioselectivity is expressed at the stage at which a transient, zwitter-ionic tetrahedral intermediate leading to the acylimidazole is formed,... 

Carboxy terminal thiols are abbreviated as Xaa[CH2SH] to indicate replacement of the amino acid carboxy group (or peptide bond) with CH2SH. Thus, Phe[CH2SH] would be used to abbreviate +NH3CH(Bzl)CH2SH, derived from phenylalanine. 

Gerona-Navarro and coworkers in 2004 have reported the synthesis and the evaluation of a series of new 2-azetidinones (Fig. 50), derived from phenylalanine [281], which were designed on the basis of the structure of the reported (3-lactam inhibitors [367] and the residues implicated in the active site of the HCMV protease [417]. These compounds have been evaluated against HCMV in human embryonic lung cells [418], and the results compared to those obtained for the reference compounds, which were the model (3-lactam la of Fig. 49, the viral DNA polymerase inhibitors DHPG (ganciclovir), and HPMPC (cidofovir). 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

The Edman degradation removes the N-terminal amino acid, which is identified as a phenylthiohy-dantoin derivative. The first Edman degradation of Val-Phe-Gly-Ala gives the phenylthiohydantoin derived from valine the second gives the phenylthiohydantoin derived from phenylalanine. 

Streptonigrin.—Details of a study of the biosynthesis of streptonigrin (139) that had earlier been published in preliminary form (cf. Vol. 9, p. 24 Vol. 10, p. 23) are now available in full papers.51 52 In essence, the new results are that labelled anthranilic acid was not incorporated into streptonigrin (139),51 that l-rather than D-tryptophan was a precursor, and that label from C-7a in tryptophan (94) appeared, it was deduced, at C-8 in (139).52 The exclusive labelling of C-8 by tryptophan indicates that rings A and B do not derive from this amino-acid. These rings do not derive from phenylalanine and tyrosine, and negative results have been obtained with shikimic acid due, at the least, to poor cellular uptake.51... 

Several biogenetic schemes have been suggested to account for the origin of biphenyl and biphenyl ether lactonic alkaloids (52, 62, 83, 84). The proposals differ in the mode of biogenesis of the phenylquinolizidine moiety. Steps common to all the proposals are the reduction of oxo group in the phenylquinolizidone (130) followed by esterification with of / -coumaric acid (C6 C3) unit derived from phenylalanine via cinnamic acid. 

This body of evidence led to the conclusion that two intact C6-C3 units derived from phenylalanine are incorporated into lactonic Lythraceae alkaloids. One unit is the precursor of the phenylpropanoid part of the alkaloids (C-l 1 to C-19) and the other gives rise to the C-3 to C-l, C-20 to C-25 segment of the phenylquinolizidine part ... 

Cephalotaxus Alkaloids.—Preliminary results indicate that the homo-Erythrina alkaloid schelhammeridine (52) derives from phenylalanine and tyrosine by way of a phenethylisoquinoline precursor [as (53)].52 Previous evidence for the biosynthesis of the related alkaloid cephalotaxine (54), obtained with tyrosine labelled in the side-chain, has indicated a different pathway which involves two molecules of this amino-acid.53 Recently, however, tyrosine labelled in the aromatic ring was examined as a cephalotaxine precursor and was found54 to label ring A of (54) almost exclusively, i.e. only one unit of tyrosine is used for biosynthesis. This is obviously inconsistent with the previous evidence and the early incorporations are... 

In reactions with acyclic dienes, the stereoselection with the (S)-valinol-derived cro-tonate imides is only about 3 1, but diastereoselection is high with N-acyl oxazolidines derived from phenylalanine. The chiral auxiliary is cleaved by transesterification with lithium benzyloxide in 85-95% yield. ... 

Feeding deterrent in bees Alkaloids derived from phenylalanine/tyrosine 0.008% 152... 

Vincristine ilkaloids derived from phenylalanine and tyrosine Mouse... 

Alkaloids derived from phenylalanine Sanguinarine Papaver bracteatum Fungal elicitor CC 466.467... 

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