Carboxylic acid pentafluorophenyl peptides

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. 

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 ... 

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. 

Using 1-amino-1-deoxy saccharides, Vetter and coworkers constructed a small V-linked glycopeptide library (23 members) [35,36]. The carboxylic acid group of glutamic acid or aspartic acid residues of polymer bound peptides were activated by preparation of the pentafluorophenyl (Pfp) ester derivative. Eigh-... 

Although peptides normally are assembled by in situ activation, i.e., by activation of the carboxylic acid immediately prior to coupling or (Figs. 7, 8, and 9) in the presence of the free amine, preactivated amino acid building blocks are also a viable possibility. Thus, pentafluorophenyl (Pfp) [34] esters of some Fmoc-amino acids are commercially available or can be prepared easily. For these couplings, an auxfliary nucleophile such as HOBt is added, which... 

---