Acid anhydrides peptide synthesis

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

Intermediate anhydride formation by means of TV-trifluoroacetylimidazole has been employed in the preparation of /7-nitrophenylesters of TV-protected amino acids, which are important in peptide synthesis. 31... 

Fig. 5.2 Peptide synthesis using Leuchs anhydrides amino acid 1 (with residue Ri) is reacted with phosgene to give the Leuchs anhydride. This reacts with amino acid 2 (residue R2) to give the peptide carbamate. The dipeptide is obtained after cleavage of C02...

EJ Heimer, C Chang, T Lambros, J Meienhofer. Stable isolated symmetrical anhydrides of (Va-9-fluorenylmethyloxycarbonylamino acids in solid-phase peptide synthesis. hit J Pept Prot Res 18, 237, 1981. 

M Crisma, V Moretto, G Valle, F Formaggio, C Toniolo. First characterization at atomic resolution of the C-activating groups in a peptide synthesis acid chloride, acid azide and carboxylic-carboxylic mixed anhydride. Int J Pept Prot Res 42, 378, 1993. 

WJ Le Quesne, GT Young. Amino acids and peptides. Part I. An examination of the use of carbobenzoxyglutamic anhydride in the synthesis of glutamyl peptides. J Chem Soc 1954, 1950. 

WD Fuller, MP Cohen, M Shabankareh, RK Blair, M Goodman, FR Naider. Urethane-protected amino acid A-carboxy anhydrides and their use in peptide synthesis. J Am Chem Soc 112, 7414, 1990. 

M Zaoral. Amino acids and peptides. XXXVI. Pivaloyl chloride as a reagent in the mixed anhydride synthesis of peptides. Coll Czech Chem Commun 27, 1273, 1962. 

WD Fuller, M Goodman, FR Naider, Y-F Zhu. Urethane-protected a-amino acid N-carboxy-anhydrides and peptide synthesis. Biopolymers (Pept Sci) 40, 183-205, 1996. 

Chirality derived from the readily accessible a-amino acids has been incorporated into the side chains of aza and diaza macrocyclic polyethers. A number of procedures suitable for peptide synthesis have proved (178) to be unsuitable for acylating the relatively unreactive secondary amine groups of aza crown ethers. Eventually, it was discovered that mixed anhydrides of diphenylphos-phinic acid and alkoxycarbonyl-L-alanine derivatives do yield amides, which can be reduced to the corresponding amines, e.g., l-172. By contrast, the corresponding bisamides of diaza-15-crown-S derivatives could not be reduced and so an alternative approach, involving the use of chiral A-chloroacetamido alcohols derived from a-amino acids, has been employed (178) in the synthesis of chiral receptors, such as ll-173 to ll-175, based on this constitution. 

Peptide synthesis. The anhydride effects peptide synthesis as shown in equation (I). Free acid groups arc buffered with a tertiary amine such as N-elhylmorpholine. The reaction is complete after 24 hours at room temperature. No raccmization is detected in the Anderson-Young test. The resulting alkylphosphonic acid derivative is soluble in water and easily removed. 

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 ... 

As mentioned above, thiazolidine-4-carboxylic acid is characterized by an anomalously low basicity and thus difficult acylation in peptide synthesis. 189 Therefore, the incorporation of this amino acid residue into a growing peptide chain is preferentially preformed via dipeptide derivatives. 139 Suitably N-protected amino acids are coupled directly to the thiazolidine-4-carboxylic acid by the acid fluoride 139 or iV-carboxyan hydride 1392111 methods. The resulting dipeptides are used as building blocks without risk of racemization 139 and standard coupling procedures are applied as pentachlorophenyl esters prepared by the mixed anhydride procedure 121 or PyBOP. 171 ... 

Goodman and Chorev 75 found that the required a-aminoacyl azides 14 are best prepared by reaction of the mixed anhydride of the amino acid with sodium azide. This method led to slightly better yields than the nitrosylation of TV-formylaminoacyl hydrazide. Curtius rearrangement of the a-aminoacyl azide 14 yielded the isocyanate 16, which was subsequently trapped as 17 or 18 as shown in Scheme 2. Comparable yields were obtained by nitrosylation with tert-butyl nitrite. 76 Other methods of acyl azide formation have rarely been employed for PMRI-peptide synthesis. Only Fincham et al. 11 reported the use of trimethylsilyl azide to synthesize an acyl azide en route to a PMRI-peptide. 

V-Carboxy- ,p-didehydroamino acid anhydrides 76 have been employed with success in the synthesis of peptides177-83 (Scheme 25). The ANCA formed from the reaction of (Z)-DHAwith thionyl chloride does not form the desired peptides on direct opening with amines... 

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]. 

Only one method has been used to prepare various peptidyl diazomethyl ketones. A protected amino acid or peptide acid is activated as the mixed anhydride and reacted with ethereal diazomethane at low temperature. Generally a peptide with the desired sequence is prepared first and then converted into the diazomethyl ketone in the final step of the synthesis. Since the diazomethyl ketone functional group is stable to alkali but unstable to acid, acidic conditions used to deprotect many peptide protecting groups must be avoided. 

Although some investigators consider free 1-aminoalkylphosphonic adds as poor substrates for the synthesis of peptides with a C-terminal 1-aminoalkylphosphonic acid moiety, successful procedures are reported in the literature with yields higher than 80% J6 7 The competitive formation of a mixed anhydride between the 1-aminoalkylphosphonic acid and the acylating agent (e.g., N-protected active ester of an amino acid) followed by its fast hydrolysis could be minimized in some solvent systems. The free 1-aminoalkylphosphonic acids could also be N-protected and esterified to provide various esters suitable for the peptide synthesis. 

Ring opening of p-lactams at C2-C3 with application in peptide synthesis was first reported on a-keto p-lactams 126 ([116] for applications of a-keto p-lactams, see [117]), Scheme 42. These p-lactams, readily available via oxidation of 3-hydroxy p-lactams 125, undergoes a Baeyer-Villiger reaction upon exposure to m-CPBA and affords /V-carboxy a-amino acid anhydrides (NCAs) 127 [118]. Shortly after, it was discovered that a more direct, one pot route to these NCAs is feasible by treatment of 3-hydroxy p-lactams with a solution of commercial bleach... 

Peptide synthesis.3 Salts of N-protected amino acids react with 1 (0.5 equiv.) to form a mixed anhydride (2). On addition of triethylamine (2 equiv.) and the salt of an umino acid ester, the protected dipeptide (3) is formed in 80-95% yield. Kiiccmization is slight ( < 0.7%), if any. 

Several systems based on the potentialities of amino acid-phosphoric acid mixed anhydrides have been devised to check the idea that the genetic code developed from an early pathway of RNA-dependent peptide synthesis in an RNA world [168]. RNA sequences have thus been selected that are capable of self-aminoacylation using amino acid adenylates, catalyzing a reaction chemically similar to the aminoacylation of fRNA by the protein aminoacyl fRNA synthetases [169]. 

Weber [61,62] has developed in the context of prebiotic chemistry an original pathway for a-aminothioester synthesis [180], which can start from hydroxyaldehydes 30 intermediates in the formose reaction (a likely prebiotic pathway to carbohydrates). Obviously, thioesters themselves are not observed as products because of their fast hydrolysis in the medium, but they could be converted into peptide bonds in the presence of amino acids or peptide free amino groups, and into mixed anhydride with phosphoric acid in the presence of inorganic phosphate. The reaction involves two key-steps the condensation of ammonia and of the mercaptan on a-keto aldehyde 31... 

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