First safety-catch linker

The first safety-catch linker (166) was developed for peptide chemistry [181] and later adapted to combinatorial approaches [182]. The linker is compatible with a number of reaction conditions. The activation for the release step proceeds via an alkylation of fhe imide nitrogen. Nucleophilic attack then leads to fhe desired cleavage according to Scheme 75. 

Felder ER, Petriella P, Schneider P, Synthesis of a photolabile safety catch linker of the 3 -methoxybenzoin type, Proc. of the First Int. Electr. Conf. on Synth. Org. Chem. (ECSOC-1), www.mdpi.org/ecsoc/, September 1-30, 1997. Poster http //www.unibas.ch/mdpi/ecsoc/b0003.html997. 

ER Felder, P Petriella, P Schneider. Synthesis of a photolabile safety catch linker of the 3 -methoxybenzoin type. First International Electronic Conference on Syn-... 

Safety-catch linker, a linker moiety handle) that is stable under the conditions of peptide synthesis, but must be activated for cleavage. The two chemical states of safety-catch linkers differ either by real orthogonality or by the kinetics of the cleavage reaction. The most popular safety-catch linkers are based on sulfonamides, where the first amino acid is anchored in the form of an N-acyl sulfonamide, which is stable towards acidic and basic reaction conditions. Upon N-alkylation of the N-acyl sulfonamide with either diazomethane or iodomethane, a secondary N-acyl... 

In such linkers, the latent bond requires activation before cleavage can occur. Many of the linker units discussed elsewhere in this chapter could be considered safety-catch linker units. For example, photolytic activation described in Section 1.2.4 and cyclorelease discussed in Section 1.2.2 are essentially safety-catch strategies. This section, however, will concentrate on synthetic activation. The first example of such an approach was a sulfonamide linker reported by Kenner et al. in 1971. The sulfonamide 7 is stable to both acidic and basic conditions, making it synthetically valuable. However, alkylation of the nitrogen with, for example, diazomethane or iodoacetonitrile, gave 8, from which substrates (e.g., carboxylic acids 9) could be cleaved under nucleophilic conditions (Scheme 1.4). 

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]. 

Dithianes are known as protecting groups for safety-catch linkers [66] but they can also be used as Unker systems for the synthesis of either carbonyl-containing or aliphatic compounds. Bertini et al. [280] synthesized the first... 

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. 

Loading of the First Amino Acid to the Safety-Catch Linker... 

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 ... 

The safety catch principle for the solid-phase preparation of C-ternninal modified peptides requires the bond between the handle and the first residue to be stable to the normal conditions of SPPS. However, at the end of the synthesis, a chennical transformation of the linker substituent makes the key bond labile to nucleophiles. The 4-sulfanylphenol 44b ti and the sulfonamide 45 (Kenner) resins are two examples of safety catch resins. Thus, in the first case, which is only compatible with the Boc/Bzl strategy, once the peptide chain is elongated, treatment of the peptide-resin with hydrogen peroxide converts the sulfide into the corresponding sulfone, which makes the bond labile to nucleophiles. In the second case, N-methylation with diazomethane leads to an N-methylated peptidyl-sulfonannide-resin, from which peptides can also be cleaved by nucleophiles. 

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