Peptide amide linker resin

EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD N-Ethyl-N - [ 3 - (dimethy lamino)propy 1] -c arbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9 -Fluoreny lme thoxy c arbony 1 Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin w-Chloroperbenzoic acid Methoxy polyethylene glycol /V-Carboxv a-aminoacid anhydride /V - M e t h v 1 pyrrol i do n e Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate. 

For syntheses of peptides as their C-terminal amides in Fmoc-SPPS, the most common linker is a benzhydryl-type handle, the Rink amide linker. Most commonly used resins are available with a Rink amide linker preinstalled. The PAL [46, 47] ( peptide amide linker ) handle, which has a trisalkoxybenzyl structure, is also very suitable for Fmoc-SPPS of peptide amides. 

FIGURE 5.18 Resins and linkers for synthesis of peptide amides using Fmoc/tBu chemistry. Chain assembly is effected after removal of the Fmoc group. Treatment with CF3C02H releases a peptide amide by cleavage at the NH-CH/CH2 bond. 

Two approaches for solid-phase chemical ligation have been described. Canne et al. have developed an elegant system that utilizes an oxime forming ligation to attach the first peptide to the resin, a selectively cleavable ester link to remove the peptide from the resin as a C-terminal carboxylic acid, and the Acm group to protect the N-terminal cysteine residue)311 A complementary approach has been developed by Brik et al. that utilizes native chemical ligation to attach the first peptide to the solid support, a safety-catch acid labile linker to remove the final polypeptide from the support as a C-terminal amide and either Acm or Msc group for N-terminal cysteine protection)32 ... 

Solid-phase synthesis (SPS) of peptides containing at their C-termini the usual carboxylic acid or carboxamide functionalities is a well-established process the peptide is traditionally attached to the resin through the a-carboxyl group of the C-terminal residue, and synthesis proceeds in the C A direction (1,2). However, synthetic peptides containing modifications at the C-termini are often desired because of their potential therapeutic properties and/or synthetic significance as intermediates in peptide and protein chemistry. Therefore, effective solid-phase methods are needed for the preparation of these peptide targets (3). The present chapter describes backbone amide linker (BAL) strategies (4)... 

A wide range of benzhydryl-based linkers bearing additional electron-donating functionalities has also been developed for Fmoc SPPS of peptide amides, the most popular of which are the eponymous Rink amide (7) [13] and Knorr linkers 24 [65]. Primary amides prepared on this resin can be cleaved with TFA in the same manner as previously described for the PAL linker. 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

Several linkers have been developed that rely on the formation of highly stabilized aromatic carbocations. The most frequently used are the eponymous Sieber amide linker 36 [3] and Barany s 3-XAL linker 6 [4]. Both are based on a 3-methoxyxanthine scaffold, which owing to the highly stabilized nature of the xan-thenium ion can provide primary amides on treatment with 1% TFA in DCM, making them excellent tools for the synthesis of protected peptide carboxamides. The Sieber amide resin has also been used to prepare secondary amides via reductive alkylation of the amino group, acylation of the resultant amine and cleavage with dilute TFA [88]. Brill et al. [67] have effected transamination of trifluoroacety-lated Sieber amide resin in good yield. This approach offers considerable potential for the immobilization of amines on this support. 

To obtain head-to-tail cyclic peptides on the solid-phase, the N- and C-termini must be free and not linked to the resin. Two strategies are commonly used (i) a side-chain anchoring approach and (ii) a backbone amide linker. 

The polyalkoxyaminobenzyi and alkoxydiphenyiamino resins (Table 7) have been used for some time to prepare peptide amides and can be cleaved under milder acidic conditions than those used for the BHA and related resins. The most widely used linkers for peptide amide synthesis are 5-(4-aminomethyl-... 

A much wider generalization of the side-chain anchoring principle was reported by Jensen et al. [31]. The growing peptide is linked to the resin through a backbone amide nitrogen using an appropriate handle called a backbone amide linker (BAL) (Scheme 2C). This approach is compatible... 

---