Merrifield’s approach

Despite the breakthrough associated with Merrifield s approach, there are several limitations such as the discontinuous nature of the reaction, the need for large excesses of reagent and the mechanical instability of the polymer matrix. An early solution to the restrictions imposed by Merrifield s polystyrene supported batch process was the use of commercially available benzyl alcohol-functionalized silica (used for H PLC columns). This was initially derivatized with the first member of the peptide chain to be propagated. The synthesis of a tetrapeptide in flow was completed in half the time required for the equivalent batch mode assembly and required significantly smaller excesses of the solution-phase reagent [92],... 

In this way, it is possible to synthesize peptides with the desired sequence of amino acids. Although the process has been completely automated, this approach is only used to prepare peptides of relatively low molar mass. Merrifield s approach, called solid-phase synthesis, has been expanded as a more general tool for synthesizing a wide range of organic compounds. 

Opposite to Merrifield s approach (in which the peptide is built while anchored to the insoluble matrix and the building blocks, i.e. the protected AAs, are in solution and allowed to react with the polymer-bound growing peptide), in our method the growing peptide is in solution and its unprotected amino terminus is allowed to cleave a polymer-bound AA active ester. 

Fig. 2. Merrifield s approach to solid phase peptide synthesis...

The traditional and established way of conducting chemical transformations employs one reaction vessel for each compound synthesized. To prepare 50 different acetamides, 50 reaction vessels are needed, one for each amide. When synthesis of 50 amides is performed at the same time, this approach is referred to as a parallel synthesis. It is, of course, always desirable to simplify the process by reducing the number of vessels used in the synthesis. However, it is not feasible just to mix 50 amines into one reaction vessel and acetylate the mixture of amines because the isolation of 50 amides from the resultant reaction mixture could be complicated and time consuming. Simple separation of individual components was made possible by Merrifield s solid-phase synthesis.1 Solid support-bound substrates can... 

A frequently investigated approach is based on Merrifield s resin, which is a polystyrene polymer [6]. 

Merrifield introduced his solid-phase peptide synthesis (SPPS) methodology in 1963 t l this has since become the preferred method of peptide synthesis. Two decades later, Fur-kaP5,56] extended Merrifield s techniques to the synthesis of libraries of peptides used for the screening of new, desirable pharmaceutical products. Because peptides do not necessarily represent the ideal candidates for therapeutics, more recent attention has focused on other libraries of compounds that can be prepared by solid-phase multistep procedures. Among the approaches used for such purposes, the HO-3CR and the U-4CR, and their combination with other reactions, are finding increasing applications. 

Merrifield s solid phase peptide synthesis presented a new approach to the chemical synthesis ofbiological macromolecules and the solid phase approach was quickly adapted to other fields. Solid phase oligonucleotide synthesis (SPONS) is another vital development in chemical... 

Except for the synthesis of peptides and ohgonucleic acids, Uttle attention has been spent on the question of how synthesis can be carried out in an environment of sophisticated technologies which includes improved hardware. While peptides and oligonucleotides are conveniently prepared by Merrifield s solid phase technique, solution phase synthesis of most other synthetic targets have not been substantially replaced by this solid phase approach. Without discussing this aspect in detail it is obvious that today a renaissance of sophisticated solution phase synthesis can be noted. Immobilization of reagents and particularly catalysts, an old concept indeed, recently returned back onto the stage and this is addressed in this volume of Topics in Current Chemistry in a broader sense. 

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