Merrifield synthesis peptides

Birr, C. Aspects of the Merrifield Peptide Synthesis, Springer Verlag, Berlin 1978... 

Birr, C. (1978) Automatization of the Merrifield peptide synthesis. n Aspects of the Merrifield Peptide Synthesis (Birr, C., ed.). Springer-Verlag, Berlin New York, pp. 72-80. 

For recent reviews on solid-phase synthesis, see Erickson, B. W., Menified, R. B. Proteins, 3rd Ed. 2 (1976) Blossey, E. C., Neckers, D. C, (Editors) Benchmarks in chemistry -solid phase synthesis, Dowden, Hutchinson Ross, Penn., 1975 Birr, Ch. A ects of the Merrifield Peptide Synthesis, Springer-Verlag, Heidelberg 1979... 

R. Bruce Merrifield was honored with the Nobel Prize in Chemistry in 1984 for invention of peptide synthesis in polymer supports. Merrifield peptide synthesis is now used in scores of laboratories to produce natural peptides and, perhaps more importantly, analogs of natural peptides that are vital for the correlation of structures of peptides with their biological activity. 

Merrifield peptide synthesis is the most highly developed method of synthesis with solid supports. Every step of the synthesis is carried out in the same polymer. Polymer-supported species also have been used as reagents and catalysts for single step synthetic transformations. Useful single step syntheses should be much easier to achieve than multi-step syntheses in polymer supports because they do not require >99% yield to be valuable. This book emphasizes one step processes in the synthesis of low molecular weight organic compounds carried out with polymer-supported reagents and catalysts. 

Merrifield peptide synthesis was first disclosed in late 1962. It has been used widely in research laboratories to prepare both natural and synthetic peptides. The meth is automated. But only two peptides are synthesized commercially by the Merrifield method (33V Lower yield solution coupling methods are used more widely. 

The histories of phase transfer catalysis, Merrifield peptide synthesis, and supported enzymes suggest that synthetic processes using polymeric catalysts may be adopted in commercial production, but that methods for multistep syntheses are less likely. The reasons for this prediction follow. 

Birr, C. "Aspects of the Merrifield Peptide Synthesis", Springer-Verlag Berlin, 1978. 

Barany, G., Merrifield, R. B. Solid Phase Peptide Synthesis, in The Peptides Vol. 2, Gross, E., Meienhofer, J., eds. pp. 1-284, Academic Press, New York 1980 Birr, C. Aspects of the Merrifield Peptide Synthesis, Springer Verlag, Berlin 1978 Stewart, J. M., Young, J. D. Solid Phase Peptide Synthesis, 2nd ed.. Pierce Chemical Co., Rockford, Illinois 1984... 

Fig. 2. Three examples of the solid anchoring of amino acids and peptides in polymer phase, nonreactive during chain elongation in the Merrifield peptide synthesis [type a) benzhydryl amine, b) benzyl ester and c) phenacetyl ester]...

Fig. 6. The cyclic sequence of operations in the Merrifield peptide synthesis...

Fig. 15. The schematic description of truncated and failure sequences in the Merrifield peptide synthesis characterizing the product composition...

Nevertheless, such reactive functions from pre-stages on a modified support may interfere later on with steps of the Merrifield peptide synthesis causing unforeseen troubles. From this shortly depicted complex of problems of subsequent modification of polystyrene supports, the following consequences may be deduced ... 

As the functional sites introduced in this way are located in positions which even in the shrunken state of the support are easily accessible, this type of chloromethylated polystyrene exhibits excellent properties for further transformations in the Merrifield peptide synthesis. Nevertheless, we should retain that this type of reactive polymer may only contain its chloromethyl functions in a relatively dense filling in the shell zone of the polystyrene particles. 

The aspects discussed in the preceding section elucidated the part of work to be finished in batches before starting — more or less automatically — a Merrifield peptide synthesis with its returning cycles of operations on each stage of the process. 

Fig. 59. Different types of reactors used in the Merrifield peptide synthesis, (a) Agitation mode (c) External circulation (d) Drain line (i) Reagents inlet (m) Magnetic clutch (v) Vent line (x) gas stirring...

Besides this fundamental reason one has to realize that the result of even a most accurate multistep synthesis on polymer can be questioned by the chemical reaction necessary to release the final product from its support. Parts of the target sequence can be destroyed and desired protecting groups on side functions may be cleaved. These facts furthermore multiply the possibility for contaminations. Therefore, the overall success of any Merrifield peptide synthesis is inherently related also to the quality of isolation and purification procedures (see for example [168]). 

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