Amides safety-catch linkers

Backes BJ, EUman JA (1999) An alkanesulfon-amide safety-catch linker for solid-phase synthesis. J Org Chem 64 2322-2330... 

Resin-bound amides generally need to be activated to make them susceptible to saponification under acceptably mild reaction conditions [114] (Table 3.5). Particularly elegant are those linkers that allow this activation to be realized as the final synthetic step before cleavage (safety-catch linkers [115-117]). The activation of some amide-based safety-catch linkers is outlined in Figure 3.9. 

Figure 3.9. Activation and nucleophilic cleavage of amide-based safety-catch linkers [118,119].

Amides are generally very resistant towards nucleophilic cleavage. Safety-catch linkers, such as those described in Section 3.1.2.3, can, however, be cleaved by amines to yield amides (Entries 1 and 2, Table 3.15). Entry 4 in Table 3.15 is an example of a... 

Arylhydrazides can serve as safety-catch linkers for C-terminal carboxylic acids, amides, or esters. Cleavage proceeds via oxidation with copper(II) salts and subsequent cleavage of the diazenyl moiety by means of a nucleophile [39] (Scheme 6.1.8). 

Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening. 

Finally, a safety-catch linker utilizing the acidic lability of the indole core was reported by Ley and colleagues (Scheme 1.7). Substrates attached to solid supports through the tosyl-protected indole (17) were stable in acidic conditions. However, deprotection of the tosyl group using TBAF provided activated intermediate 18. Treatment of the activated linker with 50% TFA in DCM was then sufficient to release the target amides 19. 

Two other safety-catch linkers should be mentioned because of their options in multifimctional cleavage. The first one published by Abell et aL in 1999 offers the possibility to release carboxylic acids, carboxylic esters and amides (Scheme 25) [179]. 

Linkers cleavable by nucleophiles include the safety-catch linker [13, 14], hydrazino benzoyl linker [15, 16] and 4-hydroxymethylbenzoic acid (HMBA) [14, 17] (Table 1). All three linkers can provide fully protected peptides, and as the HMBA and hydrazinobenzoyl linkers are acid-stable, the peptide side-chains can be deprotected prior to release of the peptide. The HMBA linker is a versatile but less often used linker for Fmoc-SPPS. Varying the nucleophile employed in the cleavage cocktail a wide range of C-terminal modified peptides can be obtained primary amide (NH3 in methanol) [18,19], hydrazides (5 % NH2NH2 in DMF) [20], acids (0.1 M aqueous NaOH) [21], and methyl esters (5 % DIEA, 5 % MeOH in DMF at 50 °C) [22] (Fig. 1). 

This chapter provides two protocols for the solid-phase synthesis of peptide thioesters using N -Fmoc-protected amino acids. The first protocol is based on a so-called safety-catch linker, while the second relies on a backbone amide linker. 

Key words Thioesters, Safety-catch linker. Backbone amide linker, BAL... 

In the following section, two strategies for peptide thioester synthesis will be described (1) the safety-catch linker (SCL) strategy and (2) the backbone amide linker (BAL) strategy using tri-thioortho ester building blocks. 

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 ... 

Resins/linkers used Safety Catch, Rink amide, Wang, Sasrin, THP, traceless. 

SCAL, safety catch acid-labile linker or safety catch amide linker. 

FIGURE 2.10 A solid-phase total synthesis of kahalalide A. The Kenner safety-catch sulfonamide linker was employed for backbone amide attachment. After assembly of the hnear peptide, safety-catch activation resulted in macrocyclative cleavage from the resin. 

Scheme 10 Safety-catch ester linker for amide synthesis...

Fmoc-based solid-phase glycopeptide synthesis is compatible with the standard linkers (handles) widely used in peptide synthesis, such as Rink amide, Wang, SASRIN (mild acid cleavage), 2-chlorotrityl chloride (protected peptide acid), and Sieber (protected peptide amides). For combinatorial one-bead one-compound studies, both the safety-catch amide linker (SCAL, stable to both acid and base until sulfone reduction) [24] and the photocleavable linker 4-[4-(l-aminoethyl)-2-methoxy-5-nitrophenoxy] butyric acid [25 ] have been successfully applied. These linkers are suitable for displaying the frilly deprotected glycopeptides on bead while allowing their nondestructive recovery after bead assay. Concerning... 

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