Polymers peptide synthesis

To illustrate the specific operations involved, the scheme below shows the first steps and the final detachment reaction of a peptide synthesis starting from the carboxyl terminal. N-Boc-glycine is attached to chloromethylated styrene-divinylbenzene copolymer resin. This polymer swells in organic solvents but is completely insoluble. ) Treatment with HCl in acetic acid removes the fert-butoxycarbonyl (Boc) group as isobutene and carbon dioxide. The resulting amine hydrochloride is neutralized with triethylamine in DMF. 

The major disadvantage of solid-phase peptide synthesis is the fact that ail the by-products attached to the resin can only be removed at the final stages of synthesis. Another problem is the relatively low local concentration of peptide which can be obtained on the polymer, and this limits the turnover of all other educts. Preparation of large quantities (> 1 g) is therefore difficult. Thirdly, the racemization-safe methods for acid activation, e.g. with azides, are too mild (= slow) for solid-phase synthesis. For these reasons the convenient Menifield procedures are quite generally used for syntheses of small peptides, whereas for larger polypeptides many research groups adhere to classic solution methods and purification after each condensation step (F.M. Finn, 1976). 

The actual process of solid phase peptide synthesis outlined m Figure 27 15 begins with the attachment of the C terminal ammo acid to the chloromethylated polymer m step 1 Nucleophilic substitution by the carboxylate anion of an N Boc protected C terminal... 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information for this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful... 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

The structures of these ylide polymers were determined and confirmed by IR and NMR spectra. These were the first stable sulfonium ylide polymers reported in the literature. They are very important for such industrial uses as ion-exchange resins, polymer supports, peptide synthesis, polymeric reagent, and polyelectrolytes. Also in 1977, Hass and Moreau [60] found that when poly(4-vinylpyridine) was quaternized with bromomalonamide, two polymeric quaternary salts resulted. These polyelectrolyte products were subjected to thermal decyana-tion at 7200°C to give isocyanic acid or its isomer, cyanic acid. The addition of base to the solution of polyelectro-lyte in water gave a yellow polymeric ylide. 

When the polymer was prepared by the suspension polymerization technique, the product was crosslinked beads of unusually uniform size (see Fig. 16 for SEM picture of the beads) with hydrophobic surface characteristics. This shows that cardanyl acrylate/methacry-late can be used as comonomers-cum-cross-linking agents in vinyl polymerizations. This further gives rise to more opportunities to prepare polymer supports for synthesis particularly for experiments in solid-state peptide synthesis. Polymer supports based on activated acrylates have recently been reported to be useful in supported organic reactions, metal ion separation, etc. [198,199]. Copolymers are expected to give better performance and, hence, coplymers of CA and CM A with methyl methacrylate (MMA), styrene (St), and acrylonitrile (AN) were prepared and characterized [196,197]. 

Murakami, Y. Functionaiited Cyclophanes as Catalysts and Enzyme Models. 115, 103-151 (1983). Mutter, M., and Pillai, V. N. R. New Perspectives in Polymer-Supported Peptide Synthesis. 106, 119-175 (1982). 

ELPs can be produced via chemical synthesis and biosynthetically. For chemical synthesis via solid phase peptide synthesis, the attainable polymer length is limited, and if long polymers with a defined length are required then the biosynthetic approach is more appropriate. An advantage of chemical synthesis is, however, that it enables the facile introduction of functional residues in the polypeptide [27]. 

DMAP has been found to improve the coupling reaction in solid phase peptide synthesis (4). Polypeptides synthesized via the DMAP-DCC method were found to be of higher purity compared to other methods of synthesis. In polymer chemistry, DMAP has been used for hardening of resins and in the synthesis of polyurethanes, (5) polycarbonates, (6) and polyphenyleneoxides (7) ... 

Moser et al. (1968) (one of the co-authors was Clifford Matthews) reported a peptide synthesis using the HCN trimer aminomalonitrile, after pre-treatment in the form of a mild hydrolysis. IR spectra showed the typical nitrile bands (2,200 cm ) and imino-keto bands (1,650 cm ). Acid hydrolysis gave only glycine, while alkaline cleavage of the polymer afforded other amino acids, such as arginine, aspartic acid, threonine etc. The formation of the polymer could have occurred according to the scheme shown in Fig. 4.9. 

The novel concept of synthesizing a molecule while attached to a swollen cross-linked resin bead was introduced and demonstrated by R. B. Merrifield with the solid-phase peptide synthesis method about 20 years ago (1,2). The procedure involves the covalent attachment of an amino-acid residue to the polymer bead followed by the addition of subsequent amino-acid units in a stepwise manner under conditions that do not disrupt the attachment to the support. At the completion of the assembly of the peptide, the product is cleaved from the resin and recovered. The macro-scopically insoluble support provides convenient containment of the desired product so that isolation and purification from soluble co-products in the synthesis can be achieved by simple... 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

The synthesis of some multiblock copolymers was attempted by successive polymerization using this iniferter technique. However, pure tri- or tetrablock copolymers free from homopolymers were not isolated by solvent extraction because no suitable solvent was found for the separation. In 1963, Merrifield reported a brilliant solid-phase peptide synthesis using a reagent attached to the polymer support. If a similar idea can be applied to the iniferter technique, pure block copolymer could be synthesized by radical polymerization. The DC group attached to a polystyrene gel (PSG) through a hydrolyzable ester spacer was prepared and used as a PSG photoiniferter (Eq. 53) [186] ... 

VK Sarin, SBH Kent, RB Merrifield. Properties of swollen polymer networks. Solvation and swelling of peptide-containing resins in solid-phase peptide synthesis. JAm Chem Soc 102, 5463, 1980. 

E Atherton, E Brown, RC Sheppard. A physically supported gel polymer for low pressure, continuous flow solid phase reactions. Applications to solid phase peptide synthesis. J Chem Soc Chem Commun 1151, 1981. 

S Zalpsky, JL Chang, F Albericio, G Barany. Preparation and applications of polyethylene glycol-polystyrene graft resin supports for solid-phase peptide synthesis. Reactive Polymers 22, 243, 1994. 

PG Pietta, PF Cavallo, K Takahashi, GR Marshall. Preparation and use of benzhydrylamine polymers in peptide synthesis. II. Syntheses of thyrotropin releasing hormone, thyrocalcitonin 26-32, and eledoisin. J Org Chem 39, 44, 1974. 

WF DeGrado, ET Kaiser. Polymer-bound oxime esters as supports for solid-phase peptide synthesis. Preparation of protected fragments. J Org Chem 45, 1295, 1980. 

Preparative applications of these reactions have included work on peptide synthesis from amino-acids (suitably protected) using triphenyl phosphine (120)10 7 >108 or a polymer-bound aryldiphenylphosphine (128).109 Coupling is generally very efficient,107 but racemization problems occur in some reactions.108 109 A typical coupling reaction using (128) is outlined in Scheme 9. 

The solid-phase synthesis of dendritic polyamides was explored by Frechet et al. [49]. Inspired by the technique used by Merrifield for peptide synthesis, the same strategy was used to build hyperbranched polyamides onto a polymeric support. The idea was to ensure the preservation of the focal point and to ease the purification between successive steps. The resulting polymers were cleaved from the solid support, allowing ordinary polymer characterization. The reaction was found to be extremely sluggish beyond the fourth generation. 

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