Active esters polymeric

In the course of the active ester polymerization, some nitrile hydrolysis apparently occurs. While clearly present, the nitrile stretching band in the infrared spectrum of the polymer is diminished in intensity. The diminution of the nitrile band could be due to a change in the environment of the nitrile upon pol3mierization or a decrease in the concentration of the group because of some side reaction such as hydrolysis. A reasonable fit to the combustion analysis data for the polymer can be made if a water molecule is included in the calculation. The presence of water in the polymer could be the result of hydration of the hydrophilic functional groups in the molecule or the result of hydrolysis of the some of the nitrile groups to amide groups or a mixture of both. 

So far, various dicarboxylic acid derivatives, dicarboxylic acids, their activated and non-activated esters, cyclic acid anhydrides, and polyanhydrides have been polymerized with glycols through lipase catalysis to give polyesters. 

A modular and flexible approach to polythiophene sensors based on the polymerization of a thiophene-activated ester has been reported (Bernier et al. 2002). Subsequent reaction of the pol5mierized NHS ester with a variety of diamines permits the synthesis of sensors for different analytes from a common platform. For example, reaction of the NHS polymer with an aminomethyl-modified 15-crown-5 derivative yielded a polymer that underwent color changes in the presence of alkah cations (Fig. 12.14). 

A reactive surfactant shown next (RS) was used as a comonomer in a seeded polymerization. RS was easily adsorbed on seed particles due to their amphiphilicity. If dialkyl fumarate was preabsorbed in the particle, the polymerization proceeded quickly and resulted in the formation of skin layer of RS-fumarate copolymer. Because the vinyl group in RS is an allyl type, RS in aqueous phase hardly polymerizes and no water-soluble homopolymer was formed. The active ester group of RS on the skin layer was used for the preparation of functional microspheres (18). 

MI11100. The primary purpose of these studies was to prepare polymeric active esters... 

Because O-glycosylation can also be accomplished with active esters (e.g., penta-fluorophenyl esters) [11] of Fmoc serine and threonine, the Fmoc technique provides a general method for the synthesis of glycopeptides. Thomsen-Friedenreich antigen glycopeptides and neoglycoproteins have been obtained by this method in preparative amounts [12], In combination with acid-labile polymeric benzyl ester anchors, this Fmoc technique was applied to solid-phase syntheses of glycopeptides [11,13,14]. 

Unfortunately, no polymerization of such type has been carried out up to now the only case of this type described in literature is the polymerization of an optically active ester of sorbic acid carried out in the presence of anionic catalysts, which however did not give unequivocal experimental evidence of the above theoretical possibility. 

Similar features may be achieved with organic polymeric materials. Template imprinting of complementary cavities containing appropriate functional groups yields models of enzyme active sites [7.34, 7.35, 7.75]. They perform the synthesis of amino acids with enantioselectivity [7.76] or the esterolysis of activated esters by TSA imprinting [7.77]. 

Except for lactam n-acyl derivatives, compounds such as esters, anhydrides and halogen anhydrides of carboxylic acids, which can activate lactam polymerization, can also be used as activators (promoters). 

The possibility of reaching high polymerization degrees (of ca. 10 in solution but which can increase to approximately 55 upon adsorption on mineral surfaces [ 129]) is an important difference with many other peptide monomers 18 involving a free amino group such as amino acid activated esters (X = OR ). These precursors are subject to the side-reaction yielding diketopiperazine 19 so that polymerization can be interrupted at the dipeptide stage. 

A considerable extension of the duration of activity together with a strongly reduced toxicity has been found (79) for a preparation with morphine-antagonistic activity [7 7 the place of its action being localized also in the central nervous system. Hie possibility of cleavage is in this case attributed to the activated ester, bound between the polymeric chain and the active substance. Besides the above-mentioned derivative of acrylic acid a derivative of vinyl carbamate has also been applied. 

In a polymeric active ester, the acyl component A is bound covalently via an active ester link to the polymeric carrier . Such reagents, —A, readily react with the nucleophile B — in peptide synthesis, the amino component — to give the product A—B. In order to obtain high yields of the peptide A—B, an excess of —A, which cah be later removed from the reaction mixture by filtration or centrifugation, is used. 

For further elongation of the peptide chain, successive coupling reactions with other polymeric active esters may be carried out until the desired sequence is obtained. The polymeric active esters are prepared by the attachment of the N-protected amino acids or peptides to a suitable insoluble polymer. Potentially useful polymeric supports in this case should carry a free hydroxyl function to which the carboxyl group of the amino acid derivatives may be coupled. Crosslinked poly(4-hydroxy-3-... 

The utilization of the polymeric active esters in the step-by-step peptide synthesis is illustrated in scheme 3 with a typical example of the polymer-bound o-nitrophenol. 

Fridkin ascribes several features as prerequisites for ideal polymeric active esters for use in peptide synthesis 98)... 

Mechanization and automation are possible in the synthesis of peptides using solid polymeric active esters also. By passing a solution of the amine component in a suitable solvent through a column packed with the solid polymeric activated carboxyl component, mechanization could be effected. The product, the protected peptide, which is in the eluent, is then N-deprotected, and the product in solution is passed... 

The polymeric active ester method has been used successfully for the preparation of several small- to medium-sized peptides in very pure form the potentiality of the method has also been illustrated by the synthesis of a number of biologically active protein sequences like bradykinin 106), thyrotropin-releasing hormone 107), ACTH sequences 105), and LH—RH 108> in good overall yields. 

Another important application of the polymer reagent method is in the synthesis of cyclic peptides. In this approach, the amino-protected linear peptide (7(5) is converted into the corresponding polymeric active ester (17) by coupling it to a cross-linked hydroxyl function containing polymer (eg. 12) on deprotection of the amino group and subsequent neutralization, the cyclic peptide (18) is obtained in good yields 109 110> ... 

Thus, in this method the stepwise synthesis proceeds on the soluble polymer, as in the liquid phase method the only difference is in the coupling step where the carboxyl component is an insoluble polymeric active ester. The use of the solubilizing C-terminal macromolecular protecting group overcomes the limitations encountered in the original application of the polymer reagent method of peptide synthesis. However, due to the steric limitations characteristic of the polymer-polymer interactions, the attainment of quantitative coupling in each step of the synthesis can be difficult in this method. 

Carboxyl groups may be introduced into block copolymers via direct polymerizations of free-acid monomers or protection—deprotection procedures. Block copolymers of styrene and nitrophenyl methacrylate (B-40) are used for the latter method, where the activated ester pendant is effectively converted into methacrylic acid or acrylamide under mild conditions.166 A homogeneous aqueous system with copper catalysts gives block copolymers with benzoate groups (B-41) via sequential block copolymerization of the two water-soluble monomers.247... 

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