Peptide esters

There are two basic strategies for enzyme-catalyzed peptide synthesis equiUbrium- and kineticaHy controlled synthesis. The former is the direct reversal of proteolysis and involves the condensation of an amino component with unactivated carboxyl component. The latter proceeds by the aminolysis of an activated peptide ester. 

Enniatin A [11113-62-5] M 681.9, m 122-122.5", [a]Jj -92 (c 0.9, CHCI3). A cyclic peptidic ester antibiotic which is recrystd from EtOH/water but is deactivated in alkaline soln. [Ovchinnikov and Ivanov in The Proteins (Neurath and Hill eds) Academic Press, NY, Vol V pp. 365 and 516 7952.]... 

A general step ahead in polycondensation was achieved by the application of the active ester method by DeTar et al.19) and Kovacs et al.291 Very soon, the nitrophenyl ester, the pentachlorophenyl ester, or the hydroxysucdnimido ester were used exclusively. The esters of the protected tripeptides could be purified by crystallization, then the N-protecting group was split off and the free peptide esters were purified again. Addition of base starts the polycondensation, resulting quickly in the formation of a viscous solution at low temperature. 

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine to N-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment of carboxylic acids with oxalyl chloride, react with HMDS 2 at 24°C in CH2CI2 to give Me3SiCl 14 and primary amides in 50-92% yield [12]. Free amino acids such as L-phenylalanine or /5-alanine are silylated by Me2SiCl2 48 in pyridine to 0,N-protected and activated cyclic intermediates, which are not isolated but reacted in situ with three equivalents of benzylamine to give, after 16 h and subsequent chro-... 

An analogous synthesis of Z-protected peptide esters is described in reference [47]. The reaction conditions were heating for several hours in anhydrous xylene at 140 °C. 

Acyl azides (see Section 2.13) The acyl-azide method of coupling is unique for two reasons. First, it is the only case in which the immediate precursor of the activated form of the peptide is not the parent acid. The starting material is the peptide ester that is obtained from the amino acid ester by usual chain assembly (Figure 2.25, path A). Second, it is the only method that just about guarantees production of a peptide that is enantiomerically pure, provided scrupulous attention is paid to details of procedure. There is no danger for loss of chirality during conversion of the ester to the hydrazide and then the azide, but care must be taken to avoid contact of... 

S-S Wang, BF Gisin, DP Winter, R Makofske, ID Kulesha, C Tzougraki, J Meienhofer. Facile synthesis of amino acid and peptide esters under mild conditions via cesium salts. J Org Chem 42, 1286, 1977. 

K Ananda, VV Suresh Babu. Deprotonation of chloride salts of amino acid esters and peptide esters using commercial zinc dust. J Pept Res 57, 223, 2001. 

FIGURE 6.1 Constitutional factors affecting the reactivity of functional groups. (A) The reactivity of W depends on the location of the residue. (B) The amino group of a dipeptide ester reacts with the ester carbonyl to form a cyclic dipeptide amino groups of other peptide esters do not react in this manner. (C, D) Reactions between residues of identical configuration do not occur at the same rates as reactions between residues of opposite configuration. 

JA Maclaren. Amino acids and peptides. V. The alkaline saponification of A-benzy-loxycarbonyl peptide esters. Aust J Chem 11, 360, 1958. 

Aminoethyl)piperidine (16) is a base and nucleophile employed for removal of fluorenylmethyl-based protectors during synthesis in solution. The adduct formed with the released moiety can be separated from the peptide ester by extraction into a pH 7.4 phosphate buffer (see Section 7.11). 

The first successful synthesis of a biologically active cyclic peptide, gramicidin S, was accomplished by Schwyzer and Sieber[6,7l via the 4-nitrophenyl ester. The fact that -protected peptide esters can be deprotected to give the peptide active ester salts has made this approach popular not only in the synthesis of sequential polypeptides but also of cyclic peptides. Among the various active esters examined for this purpose, the pentafluorophenyl esters have emerged as the most reactive ones, although a high risk of epimerization is encountered when C-terminal chiral amino acids are involved. 

Methods of Chemical Synthesis of Amino Acid and Peptide Esters of Nucleosides, Nucleotides, and Oligonucleotides T. L. Tsilevich, A. A. Kraevskii and B. P. Gottikh, Russ. Chem. Rev. (Engl. Transl.), 1972, 41, 822-832. 

The protected O-glycosyl amino acid ester or O-glycosyl peptide ester (1 mmol) is stirred in morpholine (10 mL) or morpholine-dichloromethane (1 1) for 30 min. After addition of dichloromethane (100 mL), the solution is washed with diluted aqueous acid (citric acid or HC1 pH 4, 50 mL) and with water (4 x 50 mL), dried with NajSO, and concentrated in vacuo. The crude product is dissolved in 2-5 mL of ethyl acetate. During chromatography on silica gel (50 g) with petrolum ether ethyl-acetate (2 1), W-(9-fluorenylmethyl)morpho-line is eluted. Subsequently, the deblocked amino acid or peptide ester is eluted with methanol. 0-(2,3,4-Tri-0-benzoyl-(3-D- xylopyranosyl)-L-serine benzyl ester 14 yield, 0.63 g (98%) mp 55°C [a]D —41.4 (c 0.5, CH3OH). IV-(L-Asparaginyl-L-leucyl-)-0-(2,3,4,-0-benzoyl-(3-D-xylopyranosyl)-L-serine benzyl ester 17 yield, 0.85 g (98%) amorphous [a]D —42.3° (c 0.5 CH3OH). 

Peach et al. developed a general, racemization free, and high yield procedure for the synthesis of O-desyl peptide esters from the poorly nucleophilic benzoin.1261 Employing the cesium salt of the model dipeptide Z-Gly-Phe-OH in acetone the intramolecular hydantoin formation obtained in polar aprotic solvents, such as DMF and DMSO, can be suppressed and a high yield of Z-Gly-Phe-O-desyl with ee >90% can be generated. 261 ... 

The amino acid chloromethyi ketone (l.Ommol) was dissolved in DMF (4-7mL mmol-1) and Nal (1.1 mmol) was added. The mixture was stirred for 15 min. The peptide ester salt (1.1 mmol) in DMF (2-5 mL mmol 1) was added, followed by NaHC03 (2.1 mmol), and the reaction left to stir for 12-18 h at rt. The soln was then diluted with EtOAc (50-70 mL) and washed with H20. The aqueous layer was extracted (x 2) with EtOAc and the combined extracts were washed with H20 and brine before drying (Na2S04). The resulting (oxomethyleneamino) peptide was of good purity silica gel chromatography, carried out to remove trace impurities, may contribute to epimerization at the chiral center a to the ketone carbonyl. 

Preparation of the thioacids and their esters via SPPS is mainly restricted to the Boc methodology. The popular Fmoc approach is limited by aminolysis of the thioester bond during removal of the Fmoc group by piperidine. However, a modified Fmoc-deprotecting mixture (1-methyl pyrrolidine/hexamethyleneimine/HOBt/DMSO/NMP 25 2 2 35.5 35.5) gave the final desired peptide ester with 24% yield J24 ... 

Scheme 1 Reduction of Peptide Esters to Peptide Aldehydes with Diisobutylaluminum Hydride...

Amino acid and peptide aldehydes with one to three residues have been prepared successfully using diisobutylaluminum hydride. Z-Protected amino aldehydes such as Z-Leu-H, Z-Phe-H, Z-Cys(Bzl)-H, Z-Pro-H have been synthesized with little or no racemization (Table l). 5 The diisobutylaluminum hydride reduction can be used with both peptide esters and Z amino acid esters. However, the Boc protecting group is less stable when refluxed with diisobutylaluminum hydride, thus resulting in its loss while reducing Boc-Ala-OMe or Boc-Ser(OBzl)-OMe. 13 ... 

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