The Strategy of Peptide Synthesis

The Strategy of Peptide Synthesis 1147 Amino Group Protection 1148 Carboxyl Group Protection 1151 Peptide Bond Formation 1151 Solid-Phase Peptide Synthesis ... 

Solid-phase methodology was established in 1963 in pioneering work conducted by Merrifield in the area of peptide synthesis [19]. Interest in this synthetic strategy continues unabated to this day, particularly in connection with the production of new active components for drugs, since the repetitive amide bond formation performed in automated synthesisers lends itself ideally to the construction of extensive substance libraries by combinatorial chemistry [20]. 

In the reaction vessel of a Beckman 990 Peptide Synthesizer was placed 0.8 g (0.8 mmol) of benzhydrylamino-polystyrene-divinylbenzene resin (Lab Systems, Inc.) as described by Rivaille, supra. Amino acids were added sequentially to this resin by means of the usual methods of Boc-strategy of peptide synthesis on above copolymer. 

These findings can be of considerable impact for the conventional strategies of peptide synthesis. The segment condensation of medium-sized peptides with low solubility to larger peptide chains may result in the increased solubility of the reaction product due to conformational transitions. Whenever it is possible, amino acid residues with low tendencies for p-strueture formation should be inserted towards the middle of the peptide segments. In this respect, the prediction of secondary structures can be a useful tool in establishing the most efficient path for peptide synthesis. To this end, experimental elucidation of the conformational preferences of side-chain-protected trifunctional amino acids is of much relevance 250). 

The strategy of this synthesis is different from that for the examples described above. Heathcock assembles a peptide chain of the S-protected 2-methylcysteines and closes all four thiazoline rings simultaneously at the end. The synthesis of the peptide (Scheme 16) starts with the coupling of the 2-methylcysteine compounds ent-25 and 26. 

The peptide synthesis consists of stepwise-condensation and segment-condensation procedures. In both procedures, it is possible to purify the reaction product at each reaction step. Therefore, protected peptides with a high degree of purity can be obtained from a solution method. The choice of the reagents used in the final deprotection step determines the main strategy of peptide synthesis. The final deprotection procedures are mainly (1) catalytic hydrogenolysis in the presence of palladium,(2) sodium treatment in liquid ammonia for 10 to 15 seconds, repetitively over 30 minutes,(3) TFA treatment at room temperature for 1 hour,t l (4) HF treatment at 0°C for 1 hour,t l or (5) hard-soft acid-base procedure.0 ... 

Contents Introduction. - Activation and Coupling. - Reversible Blocking of Amino and Carboxyl Groups. - Semipermanent Protection of Side Chain Functions. - Side Reactions in Peptide Synthesis. - Tactics and Strategy in Peptide Synthesis. - Techniques for the Facilitation of Peptide Synthesis. - Recent Developments and Perspectives. - Author Index. - Subject Index. 

THE STRATEGY OF PEPTIDE BOND SYNTHESIS N-PROTEaiON AND C-ACTIVATION... 

The Strategy of Peptide Bond Synthesis N-Protection and C-Activation 1077... 

The general scheme that outlines the strategy of Boc synthesis is shown in Fig. 2, which is principally similar to the scheme for Fmoc synthesis (Chapter 2). Prior to the synthesis, the appropriate resins and linkers (Table 3), as well as appropriately protected building blocks (Table 2), should be selected. Generally, two resins, the chloromethyl (or Merrifield) [1] or phenylacetamido-methyl (PAM) [9] resin, are used to generate peptide carboxylates, whereas 4-methylbenzhydrylamine (MHBA) [10] resin is the principal resin for making peptide carboxamides. Boc synthesis is particularly attractive for the synthesis of peptide thioester. 

Developments of protection strategies in peptide synthesis have led to the introduction of a wider variety of protecting groups for different functionalities and provide orthogonal protection to specific side chains (Table 1). 

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