Synthesis Merrifield

Such biosyntheses were models for the Merrifield-synthesis [8] (Fig. 3), which culminated in the development of fully automated peptide synthesizers [9]. In a repeated reaction cycle a N-terminal protected amino acid, which is attached with its C-terminal end to an insoluble solid support, is deprotected, activated and lengthened by a second protected amino acid unit. The deprotect -ing and coupling steps can be repeated until the entire peptide is assembled. 

Iterative procedures hold the potential of automated production as employed reliably and frequently in the case of the Merrifield synthesis. Furthermore, the specific isolation of intermediates and the precise insertion of substituents compensates the enhanced preparative effort compared to polymer syntheses. 

A series of enantiomerically pure stereoisomeric nitronates (5a) and 5a was successfully prepared by varying the reaction conditions (the nature of the group X, the catalyst, etc.) and using the solid-phase Merrifield synthesis (68). 

The cleavage of resin-bound peptides, produced in the Merrifield synthesis, is aided by the addition of quaternary ammonium salts to the basic medium [17, 18]. In many cases, cleavage is 100% effective and rarely less than 70%. 

Graft copolymers of nylon, protein, cellulose, starch, copolymers, or vinyl alcohol have been prepared by the reaction of ethylene oxide with these polymers. Graft copolymers are also produced when styrene is polymerized by Lewis acids in the presence of poly-p-methoxystyrene. The Merrifield synthesis of polypeptides is also based on graft copolymers formed from chloromethaylated PS. Thus, the variety of graft copolymers is great. 

The Merrifield synthesis is not without limitations since anything less than quantitative conversion in each chemical step with the complete absence of side reactions and the complete removal of reagents prior to the next chemical step would yield an impure polypeptide compared to the naturally occurring biological macromolecule. Thus, for the synthesis of a... 

NHCH2COH, which in oxytocin has been modified so that it appears as —NHCH2CNH2. Therefore, attach glycine to the solid support in the first step of the Merrifield synthesis. The carboxyl group can be modified to the required amide after all the amino acid residues have been added and the completed peptide is removed from the solid support. 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this prupose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. Combinatorial chemistry had its beginning with the Merrifield synthesis, particularly when applied to peptide synthesis, and continues as an important part of modem organic chemistry. ... 

Figure 3-2 Merrifield synthesis on a polymer bead support. The growing peptide chain is attached to a polymer support, usually in the form of small beads. The next amino acid (bearing R2) IS attached, and its protecting group (BOO is removed with acid ase treatment. flOC. butyl-oxycarbonyl, DCC, dicyclohexyl-carbodiimide.

An alternative method for the production of polypeptites involves the reation of an amino acid with a reactive amino acid derivative such as N-carboxylanhydride (NCA) in solution. The resulting product is then capable of further reaction with other NCA molecules. This process is far simpler than the Merrifield synthesis, but is not widely used due to poor yields and product impurities. 

The excess of reagents (coupling reagents and N protected amino acids) is very low (10 to 20 %, compared with the excess used (400 to 600 %) in solid phase synthesis (Merrifield synthesis)). 

In an effort to exert more control over the spatial arrangement of the various sensitizer and acceptor groups, Meyer s group have turned to solid-state peptide (Merrifield) synthesis. The amino acid selected was proline, which has a secondary amine and a cyclic structure, forcing polyprolines to adopt a rigid, helical conformation. This means that the distance between substituents on the chain is much more well defined than in polystyrene. As described for the polystyrene-based systems, it is possible to set up a Donor-Ru-Acceptor assembly on a polyproline backbone that is capable of storing redox equivalents (Fig. 7.4). The distance dependence of back electron transfer between Ru-bpy and the oxidized donor (PTZ +) was measured and shown to occur via through-space interactions [23]. 

Figure 9.1.1 Combinatorial peptide libraries as obtained by Merrifield synthesis of peptides on membrane-covered gold particles allow not only investigations of recognition processes between the surface receptors and water-soluble substrates. Systematic changes of the environment of the receptor also become feasible (see Secs. 9.3.2 and 9.6.10). Steps I, III, and V are coupling reactions steps II, IV, and VI are deprotection reactions. About 50 thiolate molecules, including dodecyl sulfide and three peptides, have been deposited on a single gold cluster in statistical distributions and arrangements. (From Templeton et al., 1998.)...

Merrifield synthesis, an alternative name for solid-phase peptide synthesis (SPPS) in honor of the inventor of this ingenious concept [R. B. Merrifield,/. Am. Chem. Soc. 1963, 85, 2149]. 

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