Method of peptide synthesis

M. Bodansky, Peptide Synthesis, 2nd ed., John Wiley Sons, Inc., New York, 1976 J. Meinhofer in Ref. 1, Chapt. 9, p. 297 G. R. Pettit, Synthetic Peptides, Vols. 1—4, Van Nostrand Reinhold, New York, 1980, Vols. 5, 6, Elsevier New York, 1982 E. Shroeder and K. Luebke, The Peptide, Vol. 1, Methods of Peptide Synthesis, Academic Press, New York, 1965 N. Izumiya and co-workers. Fundamentals and Experiments of Peptide Synthesis (in Japanese), Mamzen, Tokyo, Japan, 1987 R. B. Merriheld,/ Mm. Chem. Soc. 85, 2149 (1963) G. Barany and R. B. Merriheld in E. Gross andj. Meinenhofer, eds.. The Peptides Mnalysis, Synthesis, Biology, Vol. 2, Academic Press, New York, 1980, pp. 1—284 G. R. Marshall, Peptides Chemistry and Biology, Escom, Leiden, The Netherlands, 1988. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Merrifield was awarded the 1984 Nobel Prize in chemistry for developing the solid-phase method of peptide synthesis. 

Describe the synthesis of the dipeptide Lys-Ala by Merrifield s solid phase chemical method of peptide synthesis. What pitfalls might be encountered if yon attempted to add a leucine residue to Lys-Ala to make a tripeptide ... 

A clever new method of peptide synthesis involves formation of an amide bond by reaction of an cv-keto acid with an N-alkylhydroxylamine ... 

Since there are a number of excellent and extensive reviews of peptide chemistry,6-9 no attempt will be made here to describe the known methods of peptide synthesis. Absolute comparisons of the procedure presented herein with other methods of peptide synthesis are impossible... 

Pillai, V.N.R., and Mutter, M. (1980) New, easily removable polyethylene glycol supports for liquid phase method of peptide synthesis./. Org. Chem. 45, 5364-5367. 

GW Anderson, JE Zimmerman, FM Callahan. A reinvestigation of the mixed carbonic anhydride method of peptide synthesis. J Am Chem Soc 89, 5012, 1967. 

RA Boissonnas. A new method of peptide synthesis. Helv Chim Acta 34, 874, 1951. 

J Meienhofer. The mixed carbonic anhydride method of peptide synthesis, in E Gross, J Meienhofer, eds. The Peptides Analysis, Synthesis, Biology, Academic, New York, 1979, Vol 1, pp 263-314. 

M Bergmann, L Zervas. On a general method of peptide synthesis. Ber Deutsch Chem Ges 65, 1192, 1932. 

S Sakakibara, N Inukai. The trifluoroacetate method of peptide synthesis. 1. The synthesis and use of trifluoroacetate reagents. Bull Chem Soc Jpn 38, 1979, 1965. 

Use of Proteases in Peptide Synthesis. Typically peptides are synthesized the standard solid or liquid phase methodologies (56, 57). However, both of these techniques require harsh chemical reactions which are detrimental to certain amino acids. Furthermore, in practical terms most peptide syntheses are limited to the range of 30 to 50 amino acid residues. Hence, peptide synthesis is still somewhat problematic in many cases. In certain situations, the alternative method of peptide synthesis using proteases is an attractive choice. With this form of synthesis, one can avoid the use of the noxious and hazardous chemicals used in solid or liquid phase peptide synthesis. Since the reactions are enzyme catalyzed, racemization of the peptide bond does not occur. This technique has been used with success in the synthesis and semisynthesis of several important peptides including human insulin (55,59). 

The Merriheld method of peptide synthesis is deceptively simple. As shown in the diagram below, it begins with some means of solid support for the synthesis, resin beads in Merriheld s original work, to which is attached a single molecule that can serve as the basis (the monomer) for a far more complex molecule. In Merriheld s original research, the molecule attached to the resin head was an amino acid molecule. 

In general, solid-phase synthesis, rather than solution-phase synthesis, can be the preferred method for the generation of combinatorial libraries because of the greater abihty to automate a solid-phase protocol, primarily due to the use of excess reagents in solution to effect cleaner reactions and to the ease of workup by simple filtration. The solid-phase method of peptide synthesis has had many notable successes. However, the preparation of peptides containing more than 20 amino acids in length using the solid-phase technique often causes major problems in that very extensive purification of the final product is needed. 

The methods of peptidic synthesis, in the liquid phase as well as in the solid phase, have led to the preparation of numerous polypeptides that contain a fluorinated amino acid. Most of the examples concern peptidic hormones and neuropeptides, with replacement of either (1) a phenylalanine (or of a tyrosine) by an analogue containing a... 

Maeji, N. J. Valerio, R. M. Bray, A. M. Campbell, R. A. Geysen, H. M. Grafted Supports Used with the Multipin Method of Peptide Synthesis, Reactive Polymers 1994, 22, 203. 

Modern methods of peptide synthesis began with the solid-phase method introduced by Merrifield299 in 1962 (Fig. 3-15). To begin the synthesis a suitably protected amino acid is covalently linked to a polystyrene bead. The blocking f-butoxycarbonyl (Boc) group is removed as isobutene by an elimination reaction to give a bound amino acid with a free amino group. 

Shenderovich, M., Biopolymers, (1997) 43,219. 01 Schroder, E. Lubke, K., The Peptides Methods of Peptide Synthesis The Peptides Synthesis, Occurrence, and Action of Biologically Active Polypeptides, Academic New York, (1966) Vol. II. 

The first total synthesis of a phallotoxin was that of norphalloin, the norvaline analogue of phalloidin.16 This synthesis, outlined in Scheme 2, initially involves the synthesis of two building blocks followed by their covalent binding via a tryptathionine moiety. Subsequent deprotection and coupling steps using classical methods of peptide synthesis results in the formation of norphalloin, which has proved to be even more toxic than the natural toxins. Since the synthesis of norphalloin, a number of synthetic analogues have been synthesized in order to obtain information on structure-activity relationships.[7 8]... 

Another possibility of generating C-terminal azaglycine amides is given by coupling the C-terminal amino acid of a peptide chain with semicarbazide by the conventional methods of peptide synthesis.142 ... 

Ten years ago Kawamura (1 ) published a brief historical review on this reaction in memory of the sixtieth anniversay of its first report by Louis-Camille Maillard (2. The first Maillard paper was presented on January 8, 1912, by Armand Emile Justin Gautier (1837-1920) in a session of the Academy of Sciences in Paris. Six weeks earlier (November 27, 1911) a remarkable study was reported by Maillard (3) on the condensation of amino acids by use of glycerol. The method of peptide synthesis by Emil Hermann Fischer (1835-1919) was known to him. However, Maillard searched for milder conditions. 

The preparation of glutathion by methods of peptide synthesis is expansive and gives 20-30% yield of GHS. For the first time synthetic glutathion was prepared by M. Bergmann et al. 

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