Esters solid phase peptide synthesis

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. 

Macke recently introduced a monoreactive DOTA prochelator (4,7,10-tricarboxymethyl-tert-butyl ester A, A, A", A "-tetraazacyclododecane-1 -acetate), which was coupled to Tyr3—Lys5 (BOQ-octreotide via solid-phase peptide synthesis. A one-step deprotection reaction generated the bioactive compound DOTATOC in about 65% yield.142 The 90Y and 177Lu DOTATOC complexes have shown promise for the treatment of neuroendocrine tumors in early clinical trials.143,444... 

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] ... 

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. 

E Atherton, JL Holder, MMeldal, RC Sheppard, RM Valerio. 3,4-Dihydro-4-oxo-l,2,3-benzotriazin-3-yl esters of fluorenylmethoxycarbonyl amino acids as self-indicating reagents for solid phase peptide synthesis. J Chem Soc Perkin Trans 1 2887, 1988. 

PolyHIPE has found a successful application in the field of solid phase peptide synthesis (SPPS), where the highly porous microstructure acts as a support material for a polyamide gel [134]. The polystyrene matrix is functionalised to give vinyl groups on its internal surfaces, and is then impregnated with a DMF solution of N, JV -dimethylacrylamide, acryloylsarcosine methyl ester, crosslinker and initiator. Polymerisation grafts the soft gel onto the rigid support, giving a novel composite material (Fig. 16). 

In 1970, Bayer and coworkers investigated the synthesis of peptides on silica gel [191]. The first amino acid was attached to the support as the ester of l,4-bis(hydroxy-methyl)benzene (Figure 2.8) loadings of 0.006-0.06 mmol/g were attained. Although higher coupling rates than those on polystyrene were reported [191], silica gel never became an established support for solid-phase peptide synthesis. 

Esters of the PAM linker are slightly more resistant towards acids than the corresponding 4-alkylbenzyl esters [5,25-27] (Table 3.1). The PAM linker is particularly well suited for solid-phase peptide synthesis using A-Boc amino acids because less than 0.02% cleavage of the peptide from the support occurs during the acidolytic deprotection steps [27], Esters of both the 4-alkylbenzyl alcohol and PAM linkers can also be cleaved by nucleophiles (see Sections 3.1.2 and 3.3.3). 

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

This new approach involved alkylation of methyl 4-hydroxybenzoate with (354) using caesium bicarbonate as the acid scavenger [174]. The resulting amide ester (356) was sequentially deprotected and saponified to produce (357). Incorporation of the glutamic acid moiety was best accomplished using solid-phase peptide synthesis techniques and gave consistently better overall yields of (358) [102, 177]. 

Atherton, E. and Sheppard, R.C. (1989) 7.2. Activated esters of Fmoc-amino acids. In Solid Phase Peptide Synthesis—A Practical Approach, pp.76-78. Oxford IRE press at Oxford University Press. 

Positional scanning was repeatedly used by Houghten and coworkers [38] in solid-phase peptide synthesis, but few examples of its application to small molecule libraries have been reported. Smith et al. [39] deconvoluted a solid-phase library of 1600 esters/amides, Andrus et al. [40] deconvoluted a solid-phase library of non-natural polyenes, Leone-Bay et al. [41] deconvoluted the activity of an indexed library in an in vivo assay, while Pirrung et al. reported both a solution phase 54-member carbamate library [42] and a solution-phase 72-member tetrahydroacridine library [43]. 

The 9-fluorenylmethoxycarbonyl group is another distinguished contribution from the Carpino laboratory198199 to the solution-phase synthesis of peptides and latterly it has been adapted to solid-phase peptide synthesis too.200 The Fmoc group is exceptionally stable towards acid thus, carboxylic acids can be converted to acid chlorides with thionyl chloride201 or terf-butyl esters using sulfuric acid and isobutene.202 Furthermore, Fmoc groups are unscathed by HBr in... 

Transport peptides can be synthesized using either t-Boc or Fmoc solid phase peptide synthesis strategies with a synthesizer or manually. We routinely synthesize CPPs in a stepwise manner on solid support using an Applied Biosystems Model 431A peptide synthesizer. tert-Butyloxycarbonyl amino acids are coupled as 1-hydroxybenzotriazole (HOBt) esters to a p-methylbenzylhydryl-amine (MBHA) resin (65). C-terminally amidated CPPs are less prone to degradation and show higher internalization efficiency than carboxylic acid derivatives. 

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