Safety-catch anchor

For safety-catch anchors, two independent, separate reactions are required in order to liberate the product from the solid-phase carrier.The first reaction is like a switch, in that it converts the anchor into a cleavable form the second results in the release of the product. 

Arylsulfide Cleavage 1. Oxidation 2. Amine Product after cleavage Aromatic amine [277] 

Ar Carrier Thiolfunctionalized PEG/PS - The product is cleaved by nucleophile aromatic substitution. Chemical reactions Mitsunobu reaction, reduction.  

Benzamide-PS/DVB [278] Cleavage 1) (Boc)20 2) MeONa Product after cleavage Methylestcr 

5-Dimethyl-4-methylsulfinylphenyl)-4- Cleavage Product after cleavage  

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Patek M, Lebl M, Safety-catch anchoring linkage for synthesis of peptide amides by Boc/Fmoc strategy, Tetrahedron Lett., 32 3891-3894, 1991. 

Depending on the chemical structure of the anchor and chemistry of its attachment to the resin, the product can be cleaved at the end of the synthesis either with acid, base or nucleophilic cleavage reagents, hydrogenolysis, enzymatic, palladium-catalyzed or photochemical, oxidative and reductive cleavage methods. In addition, the safety-catch anchors can be chemically modified at the end of the synthesis to provide a structure which is subsequently cleavable. 

Isonitrile solid support 8j functions as a safety-catch anchor for acyl-aminoamides formed by a Ugi 4CC reaction [356]. Boc derivatization of the secondary amide anchoring site causes activation toward nucleophilic attack, and thus products could be cleaved by reaction with alkoxide ion. 

An anchor for traceless linking might also have a safety-catch function or be suitable for multifunctional cleavage. Linker systems enable the introduction of certain atoms or molecule fragments and will play an important role in the development of diverse organic substance libraries. It is important to point out that the final diversity is achieved on cleavage, and not in an additional solution phase re-... 

However, the chromophore in the DMB linker proved to be too sensitive to light, so a dithiane-protected structure, introduced by Chan [35] and Balasubramanian, was used to employ a safety-catch strategy. Using this strategy, peptides could be anchored to the linker by a C-terminal ester bond [36] or by an N-terminal carbamate bond [37] (Scheme 17.10). In a Fmoc-alanine releasing test, the dithiane was deprotected using methyl triflate or periodic acid, and photocleavage resulted in a 92% yield of Fmoc-Ala after 2 h. 

An application of a related resin involves the synthesis of oligonucleotides via photolabile carbonate and carbamate anchors [230]. Photocleavable al-koxylbenzyl safety-catch solid supports Sr (Table 5) have been prepared [231,232]. Carboxylic acids were esterified by reaction with the secondary alcohol function of 5r and alcohols and amines could be attached via carbonate and carbamate derivatives, respectively. Unlike many previously reported photolabile linkers, these anchors were stable to irradiation with sunlight. In each case, product release was effected by treatment with mercuric chloride to remove the safety catch followed by irradiation with light of wavelength 350 nm, which leaves a benzofuran by-product tethered to the resin. 

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... 

Scheme 8.84 The Heck reaction of an iodoarene anchored to an enzyme-labile safety catch linker [592].

Heidler P, Link A (2005) N-Acyl-N-alkyl-sulfonamide anchors derived from Kenner s safety-catch linker powerfid tools in bioor-ganic and medicinal chemistry. Bioorg Med Chem 13 585-599... 

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