Tryptophan peptides, syntheses

The Dim ester was developed for the protection of the carboxyl function during peptide synthesis. It is prepared by transesterification of amino acid methyl esters with 2-(hydroxymethyl)-l,3-dithiane and Al(/-PrO)3 (reflux, 4 h, 75°, 12 torr, 75% yield). It is removed by oxidation [H2O2, (NH4)2Mo04 pH 8, H2O, 60 min, 83% yield]. Since it must be removed by oxidation it is not compatible with.sulfur-containing amino acids such as cysteine and methionine. Its suitability for other, easily oxidized amino acids (e.g., tyrosine and tryptophan) must also be questioned. It is stable to CF3CO2H and HCl/ether. - ... 

The Doc group, introduced with the chloroformate and either DMAP or /-BuOK, is quite acid stable, but can be cleaved with TFMSA-thioanisole-EDT-TFA (10 min, rt) or with / -cresol-HF (1 h, 0°). The Doc group was found to be suitable for tryptophan protection in /-Bu-based peptide synthesis, since no /-butylation of tryptophan was observed during acid deprotection. 

The Hoc group was developed for tryptophan protection to minimize alkylation during BOC-mediated peptide synthesis. It is introduced with the chloroformate (NaOH, CH2CI2, Bu4N HS04 ) and can be cleaved with HF without the need to include thiols in the cleavage mixture. 

C.G. Fields, G.B. Fields, Minimization of tryptophan alkylation following 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis, Tetrahedron Letters 34(1993)6661-6664. 

M Low, L Kisfaludy, P Sohar. terf-Butylation of the indole ring of tryptophan during removal of the fert-butyloxycarbonyl group in peptide synthesis. Hoppe Seyler s Z Physiol Chem 359, 1643, 1978. 

B. Rzeszotarska u. E. Masuikiewicz, Arginine, Histidine and Tryptophane in Peptide Synthesis. The Imidazole Function of Histidine, Org. Prep. Proced. Int. 21, 393-450 (1989). 

Protection of tryptophan. The Boc group can also be used to protect the indole in tryptophan. The mt thyl ester of di-Boc-Trp can be prepared in almost quantitative yield and used for peptide synthesis. Both Boc groups are cleaved with TFA in a reasonable yield. The N -Boc group can be cleaved selectively with 2.7 M HCl in dioxane at 25". 

Diketopiperazine formation has long been described as a side reaction in peptide synthesis. It occurs after deprotection or neutralization of the oc-amino group at the dipeptide stage and reduces the overall yield of the synthesis. However, diketopiperazine structures have also been found in natural products with therapeutic properties and hence they have been used as a scaffolds to design new potential drugs [38, 91, 92]. A typical example would be the synthesis of indolyl diketopiperazine alkaloids. Access to these compounds may be achieved by Pictet-Spengler reaction of L-tryptophan bound to hydroxymethylpolystyrene resin with aldehydes. Fmoc amino acids were then coupled and final Fmoc deprotection resulted in cyclative release to yield alkaloids in 50-99% yields (Figure 15.9) [93, 94],... 

Uses of Phosphonic and Phosphinic Acid Derivatives -Analogues of Lawesson s reagent have been employed in the preparation of thiopeptides and the diphenylphosphinothioyl group protects tryptophane during peptide synthesis.Diphenylphosphinic chloride assists in the formation of 3-lactams from 249... 

DMF. The silyl acid support (SAC) 51 [217] has been used for peptide synthesis with cleavage being effected with either TEA or fluoride ion. It was shown that when using support 51 diketopiperazine formation and tryptophan alkylation are suppressed compared with construction of the same sequence of PAC resin. 

Indole protection, temporary blocking of the side-chain group of tryptophan in peptide synthesis. When applying Boc/Bzl tactics, a popular choice for protecting the Trp indole group is the formyl (For) group, as this is removable by treatment with a... 

Dialkyl H-phosphonates are used not only for the preparation of N-protected amino acids, but also as active coupling agents in the peptide synthesis [89,115,116], Among a wide variety of methods for the synthesis of peptides, the procedure via mixed carboxylic-phosphoric anhydride-type intermediate has so far attracted attention because this compound plays an important role in the biosynthesis of proteins and peptides [117]. Zhao et al. [89] offer the following reaction scheme for the synthesis of peptides. Phenylalanine and tryptophane are nsed as amino acids. 

Many other difficulties arise in specific cases of solid-phase peptide synthesis, e.g., destruction of the tryptophan residue during acidolytic cleavage of resin-peptide bond, pyroglutamyl derivative formation, chain termination by acetylation with acetic acid leaching from teflon components, and formation of y-glutamyl peptides. Solutions to these problems provide the basis for much of the continuing work in the field. 

Crown ethers as catalysts of fluoride-anion-mediated reactions in peptide synthesis. Part 1. Protection of tryptophan by benzyloxycarbonyl and 2,4-dichlorobenzyloxy-carbonylgroups. Y. S. Klausner and M. Chorev, J. C. S. Perkin I, 627 (1977)... 

Group 1 includes, in addition to serotonin and acetylcholine, histamine" and the catecholamine transmitters dopamine and norepinephrine. Each of these compounds is synthesised from a circulating precursor. The synthesis of each is catalysed by an enzyme (e.g. tryptophan hydroxylase for serotonin choline acetyltransferase for acetylcholine) that has a relatively low affinity for its substrate, and which thus normally operates at less-than-maximal efficiency (i.e. because it virtually never is fully saturated with the tryptophan or choline). Group 2 includes the various peptides that have been found in brain neurons which are thought by many scientists to function as neurotransmitters, largely because of their presence in neurons, and their ability to modify ionic fluxes when applied to brain neurons. These compounds almost certainly are synthesised not by enzymes but by polyribosomes (i.e. strands of messenger RNA attached to ribosomes). The concentrations of amino acids needed to allow polysome-directed peptide synthesis to occur at maximal rates in brain apparently are quite low hence, it doesn t seem likely that... 

In the reaction with Boc20/DMAP, A"-Boc-tryptophan methyl ester affords the A/ ,A -di-Boc derivative in almost quantitative yield. This product has been used in peptide synthesis. Moreover, selective cleavage of the A"-Boc group is possible in the presence of the A "-Boc function by using 2.7 N HCl in dioxane. ... 

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