Polymer-bound active esters

Cohen, B. J. Karoly-Hafeli, H. Patchomik, A. Active Ester of Polymer-Bound 4-Hydroxy-3-nilrobenzophenone as Useful Acylating Reagents. Application to Peptide Synthesis, J. Org. Chem. 1984,49,922. 

Alternatively polymer-bound sodium selenide 6 served as the starting point for an acylat-ing protocol (Scheme 3) [12]. Transformation into selenol ester 9 afforded an active polymer-bound intermediate which was cleaved in the presence of an alkinylcopper species to generate a,/ -alkinyl ketones 10 while the copper selenide can be reacylated using acyl chlorides. 

In 2003, Devocelle and colleagues reported a convenient two-step procedure for the parallel synthesis of hydroxamic acids (or O-protected hydroxamic acids 207) from carboxylic acids and hydroxylamine. It involves the formation of a polymer-bound HOBt active ester 206 from 204 and the acid 205 and subsequent reaction with O-protected or free hydroxylamine (Scheme 89). The use of free hydroxylamine leads to increased yields while maintaining high purities. Recycling of the exhausted resin 204 to prodnce the same or a different hydroxamic acid has been achieved by a three-step protocol, which is easily amenable to automation and cost-economical. 

The direct electrochemical oxidation of aliphatic alcohols occurs at potentials which are much more positive than 2.0 V w. SCE. Therefore, the indirect electrolysis plays a very important role in this case. Using KI or NaBr as redox catalysts those oxidations can be performed already at 0.6 V vs. SCE. Primary alcohols are transformed to esters while secondary alcohols yield ketones In the case of KI, the iodo cation is supposed to be the active species. Using the polymer bound mediator poly-4-vinyl-pyridine hydrobromide, it is possible to oxidize secondary hydroxyl groups selectively in the presence of primary ones (Table 4, No. 40) The double mediator system RuOJCU, already mentioned above (Eq. (29)), can also be used effectively Another double mediator system... 

Several polymeric acyl-transfer reactants have been used to give am-ide/ester products in the solution phase. The excess polymer-bound acyl-transfer reactants and polymer-bound nucleofuge byproducts are easily removed after completion of the reactions. One such application involved the activated nitrophenyl esters 25 (reaction 8).40 A mixture of 10 acid chlorides was converted to an equimolar mixture of 10 amide products a potent preemergent herbicide was discovered using this parallel synthetic approach.41... 

Polymer-bound active esters 26 were prepared from a 1-hydroxyben-zotriazole (HOBt) functionalized polymer and carboxylic acids in the presence of tripyrrolidinyl-bromophosphonium hexafluorophosphate (Py-... 

Parlow, J. J. Normansell, J. E. Discovery of a Herbicidal Lead Using Polymer-Bound Activated Esters in Generating a Combinatorial Library of Amides and Esters, Molecular Diversity, 1996, /, 217. 

A rather unusual Fe(III) species for catalysis is [Cp2Fe]+, ferrocenium. A polymer-bound ferrocenium catalyst was obtained by oxidizing a poly(vinylferrocene-folock-isoprene)copolymer with AgOTf. The activity of this catalyst was tested with the reaction of P-oxo ester 24a and MVK (41a) (cf. Scheme 8.27) [93]. 

Then another N-protected amino acid is coupled to the free amino group of the polymer-bound substrate using the dicyclohexylcarbodiimide activation or the active ester method. The N-deblocking and coupling steps are repeated until the desired sequence is formed. Finally the resin-peptide bond is split by a suitable acid cleavage reaction with HBr—AcOH, trifluoroacetic acid or HF. This results in a simultaneous N-deblocking and deprotection of most of the side-chain functionalities. 

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. 

As an alternative, the strategy outlined in Scheme 5 could also be used. Reaction of the activated linker unit 7 with the amine yielded an amine-linker conjugate 8, which, after selective hydrolysis of the ester function, was attached to the sohd support via an ester or an amide bond to yield polymer-bound amine 9 [20]. 

In 1963 Merrifield introduced solid-state synthesis for the synthesis of peptides. This technique involves chemical functionalization of a polystyrene bead that reacts with the carboxylic acid portion of a N-protected amino acid to give a polymer-bound amino ester such as 284. When 284 is treated with a reagent to deprotect the amine, it can react with another N-protected amino acid, activated at the carbonyl, to give a dipeptide. This procedure can be repeated to generate the desired polypeptide, and when the target has been attained a reagent is added to cleave the polypeptide from the bead (usually by hydrolysis). This solid-state synthesis can be applied to other types of chemical transformations. ... 

An interesting example of intra-polymeric catalysis is provided by the effect of polymer side chains on the aminolysis of polymer-bound nitrophenyl ester [41a], as illustrated in Fig. 10. Thus, apparent reactivity of the polymer-bound carbonyl groups is substantially increased by changing the polymer side chains from phenyl to methoxycarbonyl, and to dimethylamide. This type of intra-polymeric catalysis (shown schematically by species 9 in Fig. 11) assumes special significance in crosslinked polymers and solid phase synthesis. An important implication of this catalytic effect for polymer synthesis is that when an activated polymer intermediate (8) is not sufficiently reactive towards a given nucleophile, polymer reactivity can be enhanced by partial aminolysis with dimethyl-amine [25]. 

Chemical modification of polymer-bound active ester groups is also subject to strong solvent effects. In copolyfAOTcp-styrere), both aminolysis and transesterification with primary alcohols are positively influenced by solvents in the order of dimethylformamide (DMF) > dioxan > diloroform > chlorobenzene > dimethylsulfoxide (DMSO). However, trans-esterification with phenols proceeds in dioxan, but not in DMF. The last-nan d solvent effect is probably related to inactivation of the phenolate ion in DMF, as observed ako for the acylation of polymer-bound phenolic groups by soluble trichlorophenyl esters [64]. 

Fig. 16. Schematic presentation ofpeptide synthesis by inverse solid phase method based on the use of polymer-bound amino acid active esters (coupling reagent) and polymer-bound jnperazine (deprotecting reagent)...

Merrifield succeeded in doing exactly what he described. The basic steps are in Scheme 1 (i) 1) An N-protected amino acid is attached as an ester to a cross-linked polystyrene support. 2) The protecting group is removed. 3) An N-protected, activated amino acid is coupled to the amino group of the polymer-bound amino acid. Steps 2 and 3 are repeated with different amino acids to produce the desired peptide sequence. 4) The completed peptide is cleaved from the polymer, deprotected, and purified. 

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