Methods for the synthesis of peptides

W Konig, R Geiger. A new method for the synthesis of peptides activation of the carboxyl group with dicyclohexylcarbodiimide and 1-hydroxybenzotriazoles. Chem Ber 103, 788, 1970. 

HC Beyerman, EWB De Leer, J Floor. On the repetitive excess mixed anhydride method for the synthesis of peptides. Synthesis of the sequence 1-10 of human growth hormone. Rec Trav Chim Pays-Bas 92, 481, 1973. 

The closely related o-iodylbenzoic acid (IBX) and Dess-Martin oxidations have proved to be effective methods for the synthesis of peptide aldehydes (Table 7, Scheme 6) 9 38 39] 2-Iodobenzoic acid is oxidized by potassium bromate to form 2-iodylbenzoic acid (IBX), which can be used directly for IBX oxidation. IBX can be further treated with acetic anhydride and TosOH at 100 °C for 40 minutes to form the more stable Dess-Martin periodinane reagent 45 46]... 

Alternative methods for the synthesis of peptide aldehydes include reduction of acid halides, phenyl esters, thioesters, and anhydrides prepared from corresponding acids, isoxazolidides, and the hydrolysis of thiazolidine peptides 17,54-56 Enzymes such as thermolysin, subtilisin, and pronase E have proven valuable as effective semisynthetic alternatives 40,57 5 62 ... 

Fluoromethyl ketones are one of the most widely used classes of peptidyl a-fluoroalkyl ketones, second only to trifluoromethyl ketones. Peptidyl fluoromethyl ketones are very effective as irreversible inhibitors of cysteine proteases the first reported use of a fluoromethyl ketone compound was the use of Z-Phe-Ala-CH2F as an irreversible inhibitor of cathepsin BJ2,31 Today, many lysine and arginine derivatives have been synthesized as potential inhibitors for trypsin and trypsin-like enzymesJ3 There are four basic methods for the synthesis of peptide fluoromethyl ketones (1) the reaction of HF with peptide diazomethyl ketones (Section 15.1.4.1.1), (2) a halogen-exchange reaction with a chloro-, bromo-, or iodomethyl ketone (Section 15.1.4.1.2), (3) a Henry nitro-aldol condensation reaction (Section 15.1.4.1.3), and (4) a modified Dakin-West acylation reaction (Section 15.1.4.1.4). 

For the synthesis of peptides, the phosphonic moiety in most cases should be masked as a diester. Diesters of 1-aminoalkylphosphonic acids can be synthesized directly or by esterification of 1-aminoalkylphosphonic acids. If peptides with the free phosphonic moiety are the desired products, then methods are available for the selective removal of both ester groups. Peptides with a free C-terminal phosphonic acid functionality can be synthesized directly from the free 1-aminoalkylphosphonic acids. In addition, methods for synthesis of the peptides with C-terminal phosphonates directly from the peptides are also available. In general, most methods for the synthesis of peptide bonds work well for the synthesis of peptides with C-terminal phosphonates if diesters of 1-aminoalkylphosphonic acids are used. Bulky diaryl esters give yields similar to the diethyl esters. Therefore, the most challenging step in the synthesis of peptide phosphonates is the synthesis of 1-aminoalkylphosphonic acids and/or their esters. It is not possible in this section to review all of the literature data and only examples of several general methods are included. This will still provide a variety of methods for the efficient synthesis 1-aminoalkylphosphonic acids, their esters, and related peptide derivatives. 

The observation that carboxyl ate ions react at a much faster rate than amines with nitrilium ions and that they give Z-O-acylisoamides only, has led to the development of a new method for the synthesis of peptides (13). Imide halide 4 on dissolution in a polar solvent undergoes rapid unimolecular ionization to the nitrilium ion 42 which reacts with the carboxylate ion to give the Z-O-acylisoamide 43 which in turn reacts with the amine to give the amide product 44. The formation of the amide (or peptide) can be carried out by adding the halide 41 to a solution containing both the amine and the carboxylic acid. The initial reaction (41 42 43) is best carried out at pH=6 and when the pH is adjusted to =8, formation of the amide (43 44)... 

Koenig W, Geiger R, New methods for the synthesis of peptides Activation of the carboxyl group with dicyclohexylcarbodiimide by using 1 -hydroxybenzo-triazoles as additives, Chem. Ber., 103 788-798, 1970. 

The foregoing typical results clearly illustrate another very important application of the polyethyleneglycol support method for the synthesis of peptides and protein sequences. The unique suitability of this linear, soluble macromolecular support with optimum hydrophilicity-hydrophobicity balance for the conformational analysis of the bound peptides originates from the peculiar conformational properties of the polymer chain. 

Joseph M, Nagaraj R. A convenient method for the synthesis of peptides acylated with palmitic acid specifically at cysteine thiol. Bioorg. Med. Chem. Lett. 1993 3 1025-1028. 

Scheme 11 The Bailey Method for the Synthesis of Peptides from Ai-Carboxyanhydrides at Low Tempera-...

Ojima, I., Sun, C. M. and Park, Y. H. (1994) New and efficient coupling method for the synthesis of peptides bearing norstatine residue and their analogs. Journal of Organic Chemistry, 59, 1249-1250. 

Reynhout et al. [52] recently published a completely solid phase method for the synthesis of peptide-based triblock copolymers. Amine-functionalized polystyrene was first coupled to an aldehyde-modified resin to give a polystyrene functionalized secondary amine on the resin, which could then be coupled to the next amino acid (Fig. 11). Then the sequence Gly - Ala - Asn -Pro - Asn - Ala - Ala - Gly (GANPNAAG)—a known -hairpin folding peptide found in the CS protein of the Malaria parasite plasmodium falciparum— was synthesized, using standard Fmoc peptide chemistry. After removing the final Fmoc group from the peptide, a carboxylic acid-functionalized polystyrene was coupled to the terminal amine. 

Outline the steps of the solid-phase method for the synthesis of peptides. 

Li et al. developed an efficient method for the synthesis of peptides and proteins. In this method, an 0-salicylaldehyde ester at the C-terminus reacts with N-terminal serine or threonine to realize peptide ligations via an O- to A-acyl transfer (Scheme 10) [81]. 

This paper is a progress report on our continued effort to develop new reagents and methods for the synthesis of peptides, S-lactams and oligonucleotides (ref. 1-4). 

Dialkyl H-phosphonates are used not only for the preparation of N-protected amino acids, but also as active coupling agents in the peptide synthesis [89,115,116], Among a wide variety of methods for the synthesis of peptides, the procedure via mixed carboxylic-phosphoric anhydride-type intermediate has so far attracted attention because this compound plays an important role in the biosynthesis of proteins and peptides [117]. Zhao et al. [89] offer the following reaction scheme for the synthesis of peptides. Phenylalanine and tryptophane are nsed as amino acids. 

It was left to the ingenuity of R. Bruce Merrifield, an organic chemist at the Rockefeller University, to develop an innovative solution to this problem that totally revolutionized the field of peptide synthesis. His plan was to assemble the peptide chain in a stepwise manner by adding new amino acids at the A terminus while the Oterminal end was attached to a solid polymeric support of chloromethylated polystyrene, which is now referred to as the Merrifield. In this fashion, all of the excess reagents, impurities, and by-products could be easily removed by washing the resin after each operation, and the pure polypeptide could be cleaved from the solid support as the last step in the synthesis. Merrifield was awarded the Nobel Prize in Chemistry in 1984 in recognition of his contributions to the invention and development of the solid-phase method for the synthesis of peptides. 

Scheme 12.76. An abbreviated outline of the Menifield method for the synthesis of peptides. The details of the processes in each step are the same as those in a sequence of individual steps to be considered snbsequently. The method can be mechanized and automatic peptide...

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