Amino acid esters peptide synthesis

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

The acidity of 19d and the O-nucleophilic character of its anion are regarded as crucial for active ester formation and suppression of racemization of acylated a-amino acids in peptide synthesis <1970CB2024> see Section 9.01.12.3. 

Kisfaludy L, Schon 1 (1983) Preparation and applications of pentafluorophenyl esters of 9-fluorenyknethyloxycarbonyl amino acids for peptide. Synthesis 325-327... 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

The imidazolide group at the amino end of an amino acid is as reactive toward nucleophiles as the imidazolide group at the carboxylic end of an amino acid. If an N-protected amino acid is selected as nucleophile, this method can also be used for peptide synthesis. The amino-activated amino acids, for example N-( 1 -imidazolylcarbonyl)-amino acid esters, are prepared from a-isocyanatocarboxylic acids and imidazole. 

The reaction conditions for this peptide synthesis are equimolar amounts of the reagents, five to eight hours, and 75-85 °C.[44J Use of a-isothiocyanatocarboxylic acids caused the yields of peptides to be lower. Instead of A-( 1 -imidazolylcarbonyl)amino acid esters, the corresponding triazolides were also utilized in the peptide synthesis. 

Co(III)-chelated amino acid ester reactant and/or peptide product (Scheme 1). This basic difficulty was quickly pointed out (5), and has subsequently been examined and commented upon by others (6, 7). Such criticisms are well-founded since epimerization (or racemization) is a common problem, at least to some degree, in all chemical methods of synthesis where acyl-activation is employed. As a result, metal-activation methods have received little attention. However, since 1981 we have refined the Co(III) method such that very fast, clean, couplings can now be carried out using A-[Co(en)2((S)-AAOMe)]3+ reagents, which involve minimal (<2%) epimerization/racemization provided experimental conditions are strictly adhered to. 

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. 

GW Anderson, FM Callahan. 1-Butyl esters of amino acids and peptides and their use in peptide synthesis. J Am Chem Soc 82, 3359, 1960. 

M Jaouadi, C Selve, JR Dormoy, B Castro, J Martinez. Isopropenyl chloroformate in the chemistry of amino acids and peptides. III. Synthesis of active esters of A-protected amino acids. Tetrahedron Lett 26, 1721, 1985. 

G Galavema, R Corradini, A Dossena, R Marchelli. Diaminomethane dihydrochloride, a novel reagent for the synthesis of primary amides of amino acids and peptides from active esters. Int J Pept Prot Res 42, 53, 1993. 

J Kovacs. Racemization and coupling rates of N -protected amino acids and peptide active esters predictive potential, in The Peptides Analysis, Synthesis, Biology, Vol. 2, pp 485-539. Academic Press, New York, 1979. 

The polymer-bound p-nitrobenzophenone oxime (71d) has been found to be a suitable support for stepwise peptide synthesis. Protected peptides can be assembled on 70d by coupling and deprotection steps similar to those employed in the usual Merrifield solid-phase procedures (Scheme 39). Cleavage of peptides from 71d can be accomplished with hydrazine and amino acid esters under mild conditions, which do not affect benzyl ester side-chain protecting groups. 

Active esters peptide synthesis. The reagent in combination with N(C2Hs)j converts N-protected amino acids into active esters (— 85% yield). It can also be used with a tertiary amine to effecl peptide formation between an N-protcctcd amino acid and an amino acid ethyl ester. CBZ-Val-Gly-OC2IIs was prepared in this way in 89% yield. 

Sutton, P. A., and D. A. Buckingham, Cobalt(III)-promoted hydrolysis of amino acid esters and peptides and the synthesis of small peptides , Acc. Chem. Res., 20, 357-364 (1987). 

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. 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

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