Carboxylic pentafluorophenyl esters

A key step in the synthesis of 13-membered meta ansa and 14-membered para ansa peptide alkaloids involves catalytic hydrogenolysis of carbobenzyl-oxypeptide pentafluorophenyl esters. The most suitable solvent is dioxane with addition of a catalytic amount of pyrrolidinopyridine and 2% ethanol. Temperature should not exceed 90°C. The authors believe that after deblocking, the amino function remains on the surface until ring formation with the activated carboxylic function is accomplished (/5/). 

OS 25] [R 4] [P 17] For dipeptide formation from the pentafluorophenyl ester of (J )-2-phenylbutyric acid and (S)-a-methylbenzylamine an extent of racemization of 4.2% was found [86]. At higher concentration (0.5 instead of 0.1 M), a higher degree of racemization was found (7.8%). This experiment also served to demonstrate monitoring of the racemization of a simple carboxylic acid used in peptide synthesis. 

M Meldal, B Klaus. Pentafluorophenyl esters for temporary carboxyl group protection in solid phase synthesis of A-linked glycopeptides. Tetrahedron Lett 48, 6987, 1990. 

Because of the strong nucleophilicity of the amino group, weak activation of the carboxylic acid is often sufficient to effect macrocyclization. For example, the pentacyclic core of the manzamines was constructed by connection of a secondary amine and a pentafluorophenyl ester [36]. 

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

The crude carboxylic acid 55 was dissolved in DMF and cooled to 0°C. Pentafluorophenol (1.1 equiv) and EDC (1.5 equiv) were added and the resulting mixture was stirred at rt for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CHC13 and washed successively with 1M HC1 and H20. The organic phase was dried (MgS04) and concentrated. The resulting pentafluorophenyl ester 56 was used without further purification. 

Uronium salts can be used to convert carboxylates into HOBt or related esters [5], into pentafluorophenyl esters [95], or into acyl halides [10] in the presence of amines (Figure 13.6). A highly reactive O-acylisouronium salt is formed initially. This inter-... 

A number of C-6 carboxamide analogues were prepared in which the stereo-chemically complex glycerol side-chain of Zanamivir or 4-amino-4-deoxy-Neu5Ac2en was replaced entirely by secondary or tertiary amides with the general structure of 94 or 95.95,96 These series of compounds were prepared from the C-6 carboxylate 92 (prepared by periodate oxidation of the glycerol side-chain of 91) by amide couling via the activated pentafluorophenyl ester 93 (Scheme 3). 

Fig. 6.15. Carboxylic acid activation with DCC. [1,3] means the intramolecular substitution of the oxygen atom 01 by the N atom "3" via a cyclic four-membered tetrahedral intermediate. From the point of view of the heteroatoms, this SN reaction corresponds to a migration of the acyl group R-C=0 from the oxygen to the nitrogen. (Examples for amino acid activations in the form of the pentafluorophenyl ester C or the benzotriazolyl ester D are given in Figure 6.32 (oligopeptide synthesis) and Figure 6.31 (dipeptide synthesis), respectively.

In a related approach, pentafluorophenyl esters of Fmoc amino acids 61 (see Table 14) were prepared from a mixture of acid 59 and pentafluorophenyl trifluoroacetate in dimeth-ylformamide in the presence of pyridine,which is a transesterification method developed by Sakakibara (Scheme The reaction involves formation of mixed carboxylic acid... 

To avoid hydrolysis of the no-carrier-added F-labeled active esters in aqueous buffered solution, the acylation route can be inverted, i.e., radiolabeled amines are prepared and coupled with activated carboxyls at the peptide (O Table 42.9, amidation). Oxytocin was successfully coupled with 2-[ F]fluoroethylamine in yields >90% hy both preactivation (NHS, 4-nitrophenyl and pentafluorophenyl esters) and in situ activation of the C-terminus (TBTU) (Jelinski et al. 2002). 

Fig. 2.14 Examples of functionalized polymer films bearing reactive groups for covalent anchoring of biomolecules. (A) amines (PANI), (B) carboxyls (PTh), (C) N-hydroxysuccinimide esters (PPy), (D) pentafluorophenyl esters (PPy), (E) N-hydroxy-phthalimide esters (PPy), (F) aldehydes (PTh) (Reprinted from Ref. [144] with the permission of Royal Society of Chemistry)...

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