Applicability of the Merrifield Synthesis

In this final chapter it is not the author s intention to add to the existing excellent and very comprehensive reviews of [33, 35] applications of gel phase peptide synthesis another less complete one. Instead, from a very personal view, some points are selected for discussion on the applicability of the Merrifield principle, which is of indubitable wealth, not at all only in peptide chemistry. 

One of the most used resins in solid-phase combinatorial organic synthesis, which has found a myriad of applications, is the Merrifield resin (17).61 This resin is also the building block for a tremendous amount of novel resins being developed in combinatorial chemistry with applications in both solid-phase as well as solid-phase-assisted solution-phase combinatorial chemistry. A recent, useful, and novel example is the report of its being employed as a triphenylphosphine scavenging resin.76 During the conversion of azidomethylbenzene (51) into benzylamine, excess triphenyl-phosphine is allowed to react with Merrifield resin (17) in the presence of sodium iodide in acetone. A phosphonium-substituted resin (52) is thus formed. Upon simple filtration, pure benzylamine is isolated as shown in Fig. 22. 

The formahon of hydantoins represents an early application of the cyclahve cleavage strategy. The group of Hobbs DeWitt presented a synthesis starhng from Merrifield resin-bound amino acid derivahves 1 (Scheme 1). These were N-deprotected and subsequently converted to ureas 2 by reachon with an isocyanate. Treatment with 6 M HCl (83-100 °C, 2 h) gave hydantoins 3 in yields of 4-81%, with two dimensions of diversity [1]. 

In addition to ion exchange resins, polymer reagents also include what are called redox or oxidation-reduction polymers which also represent electron transfer agents. Polymer reagents are also used in the Merrifield synthesis of peptides and proteins (see Chapter 30). Other polymer reagents, together with their applications, are... 

For that reason, the applicability of the other strategy introduced by R. L. Letsinger and M. J. Kornet in 1963 [42] is in contrast to the Merrifield procedure limited. In the second method the stepwise peptide synthesis starts from the opposite direction, beginning from the N-terminal amino acid bound by its amino function to an insoluble support. The peptide is elongated by activations of the solid phase carboxyl component on each... 

Myers pseudoephedrine-based enolate alkylation was more recently applied in total syntheses of (-)-platensimycin [19] and brasilinolides [20]. By linking pseudoephedrine through the alcoholic moiety to a Merrifield resin, a polymer-bound version of Myers reagent was developed [21]. A twofold application of the pseudoephedrine-based enolate alkylation in a synthesis of Novartis orally active renin inhibitor CGP60536B demonstrates the value of this method in pharmaceutical chemistry [22]. 

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

Polymer-Supported Synthesis. The passage of time, the publication of thousands of papers, several books,55 and many commercial successes, especially in small-scale applications of Merrifield-type polymers in the peptide field, have led to the realization that harnessing polymer supports for large-scale synthesis work has many hurdles to overcome to become more widely accepted for use in practical large-scale synthesis. 

Cesium salts of iV-protected amino acids were introduced by Gisin [15] for the synthesis of ester bonds under mild reaction conditions in the solid phase synthesis according to Merrifield [48]. Cesium salts of short chained carboxylic acids like cesium propionate found broad application for the selective inversion of the stereochemistry of secondary alcohols which could be performed with cesium salts under careful reaction conditions [49, 50]. 

The application of ultrasound in solid-phase synthesis has been shown to be useful in several cases such as carboxylic acid attachment to Merrifield resin,condensation... 

The breakthrough in peptide chemistry, which opened up applications in biochemistry and molecular biology, was the development of solid phase synthesis by Merrifield in 1963. This formed the basis of automated synthetic procedures in which the nascent peptide chain was covalently linked to a solid support such as a styrene-divinylbenzene copolymer the complex isolation and purification procedures needed to separate reactants and products at the end of each reaction cycle, which characterised previous solution methods of peptide synthesis, were replaced by a simple washing step. With modern automated methods of peptide synthesis, the time for an Fmoc reaction cycle has been reduced to 20 min, so that a 50-residue peptide can be synthesised in a day (Chan and White 2000). 

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