Carboxylic acid pentafluorophenyl

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. 

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. 

Fig. 13. Acylation via activation of a resin-bound carboxylic acid, (a) Pentafluorophenyl trifluoroacetate (6 equiv.) in Py/DMF (1 10), 1 h (b) amine (6 equiv.) CH2C12/DMF (c) TFA/ DCM (1 1) 1 h.

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 develop an EOF based system. Watts et al. have conducted an extensive study on peptide synthesis, where they prepared a library of peptide derivatives within a computer-controlled microreactor system operating under EOF [25-28]. The authors demonstrated that dipeptides could be prepared from pre-activated carboxylic acids. They optimized the reaction using the pentafluorophenyl (PFP) ester of Fmoc- 3-alanine 4 with amine 5 to give dipeptide 6 quantitatively in 20 min (Scheme 14.2). This represented a significant increase in yield compared with the traditional batch synthesis, where only a 50% yield was obtained in 24 h. 

PNA was originally prepared with a pentafluorophenyl (Pfp) ester of the f-Boc-T monomer [2]. Consequent studies employed in situ activation of the corresponding carboxylic acids (Fig. 3). A variety of coupling agents were investigated and ultimately concluded that A-[(dimethylamino)-lH-1,2,3-lriazol[4,5- ]pyridin-1 -ylmethylene]-A-methylmethanaminium hexafluoro-phosphate. A-oxide (HATU) provided the highest overall efficiency [20]. Activation of the monomers with HATU requires a base component to de-protonate the carboxylic acid moiety of the monomer. A mixture of strong... 

Pentafluorophenyl iodosotrifluoroacetate Carboxylic acids from acetylene derivs. Oxidative cleavage under mild conditions... 

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