Safety catches

A polymer-supported sulfonamide, prepared from an amino acid activated ester and a polystyrene-sulfonamide, is stable to acidic hydrolysis (CF3COOH HBr/ HOAc). It is cleaved by the safety-catch method shown below. ... 

Serpins inhibit serine proteinases with a spring-loaded safety catch mechanism... 

In viw PAI and antithrombin are stabilized in their active forms by binding to vitronectin and heparin, respectively. These two serpins seem to have evolved what Max Perutz has called "a spring-loaded safety catch" mechanism that makes them revert to their latent, stable, inactive form unless the catch is kept in a loaded position by another molecule. Only when the safety catch is in the loaded position is the flexible loop of these serpins exposed and ready for action otherwise it snaps back and is buried inside the protein. This remarkable biological control mechanism is achieved by the flexibility that is inherent in protein structures. 

The investigation of minor groove-binding polyamides was greatly accelerated by the implementation of solid-phase synthesis [48]. Originally demonstrated on Boc-y9-Ala-PAM resin with Boc-protected monomers, it was also shown that Fmoc chemistry could be employed with suitably protected monomers and Fmoc-y9-Ala-Wang resin (Fig. 3.8) [49]. Recently, Pessi and coworkers used a sulfonamide-based safety-catch resin to prepare derivatives of hairpin polyamides [50]. Upon activation of the linker, resin-bound polyamides were readily cleaved with stoichiometric quantities of nucleophile to provide thioesters or peptide conjugates. 

Eattori, D., O. Kinzel, P. Ingallinella, E. Bianchi, and A. Pessi. A practical approach to the synthesis of hairpin polyamide-peptide conjugates through the use of a safety-catch linker. Bioorg. Med. Chem. Lett. 2002, 12, 1143-1147. 

As an extension to thep-carboxybenzenesulfonamide safety-catch linker [43,44], alkanesulfonamide handle 37 was developed [45]. This linker tethers carboxylic acids to the solid support to give an acylated sulfonamide which is stable to both basic and acidic conditions (Scheme 12). Products were released by treatment with iodoacetonitrile followed by the addition of a nucleophile. 

Routledge A, Abell C, Balasubramanian S. The use of a dithiane-protected benzoin photolabile safety catch linker for solid-phase synthesis. Tetrahedron Lett 1997 38 1227-1230. 

Kenner GW, McDermott JR, Sheppard RC. The safety catch principle in solid-phase peptide synthesis. J Chem Soc Chem Comm 1971 636-637. 

Backes BJ, Ellman JA. Carbon-carbon bond-forming methods on solid support. Utilization of Kenner s safety-catch linker. J Am Chem Soc 1994 116 11171-11172. 

Scheme 7.46 Solid-supported amide synthesis employingthe safety-catch principle.

Scheme 12.10 Microwave-assisted aminolysis (Kenner safety-catch linker).

Safety-Catch Linker for Solid-Phase Synthesis , J. Am Chem. Soc. 1996,118, 3055-3056. 

Backes, B.J., Dragoli, D.R. and Ellman, J.A., Chiral A-acyl-tert-butanesulfinamides the safety-catch principle applied to diastereoselective enolate alkylations. J. Org. Chem., 1999, 64, 5472-5478. 

The proper choice of a suitable linker is a therefore a key consideration in the design of a solid-phase chemical route. Linkers have to be developed in order to be stable in the presence of reagents and to permit orthogonal cleavage under mild conditions. Often, cleavage conditions dictate the requirements for work-up and purification steps of the released compound. Different cleavage strategies have been developed such as photocleavable, safety catch and traceless linkers as mentioned in Section 3.2.2 [20]. 

The development of sulfone linkers, the exploration of sulfone based chemical transformations and cleavage strategies are an important objective in soHd-phase organic synthesis. This kind of Hnker (Tab. 3.7) has been used with thioethers [108], sulfoxides [109], sulfones [110], sulfonic acids and their corresponding derivatives [111]. Because carbon-sulfur bonds can be cleaved under very mild conditions, some Hnkers have been based on this effect. They can be cleaved under reductive conditions ]112, 113], photolytic conditions [114, 115] or with strong bases [116]. Various safety catch Hnkers have been developed based on the fact that thiols can be oxidized to sulfoxides and sulfones [112, 113]. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

Among the successful linker strategies that are being developed specifically for solid-supported synthesis of small organic molecules, the safety catch principle has become one of the most important approaches. Safety catch linker strategies... 

I 3 Organic Synthesis on Polymeric Supports Tab. 3.12 Safety catch linkers. 

Scheme 10.11 Principle of the enzyme-labile safety catch linker.

Waldmann et al. developed a second exo-linker following a new approach [43-44] which makes use of a safety-catch linker. It is based on the enzymatic cleavage of a functional group embodied in the linker. In this way an intermediate is generated, which subsequently cyclizes intramolecularly according to the principle of assisted removal [54—58] and thereby releases the desired target compounds (Scheme 10.11). 

According to the safety-catch principle, the separation of the desired products proceeds in a two-step process. First, penicillin G acylase hydrolyses the phenyl-... 

Gilley CB, Kobayashi Y (2008) 2-nitrophenyl isocyanide as a versatile convertible isocyanide rapid access to a fused y-lactam (3-lactone bicycle. J Org Chem 73 4198 204 Chen JJ, Golebiowski A, Klopfenstein SR, West L (2002) The universal Rink-isonitrile resin applications in Ugi reactions. Tetrahedron Lett 43 4083 085 Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/Cyclization (UDC) strategy to access carboxylic acids, 1, 4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroqui-noxalinones. Tetrahedron Lett 39 7227-7230... 

Chemical ligation methods for peptide synthesis using thioester chemistry in solution have been previously documented (see Vol. E 22a, Section 4.1.5). Generalized procedures for solid-phase ligation have been developed that simplify the overall procedure. One method uses a safety-catch acid labile linker at the C-terminus and was used for the synthesis of a 71-amino acid chemokine, vMIP I (Section 5.3.2.1). Another procedure uses a selectively cleavable glycolate ester linkage (Section 5.3.2.2). 

Scheme 4 Safety-Catch Backbone Protection Groups 17-241...

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 ... 

Using the Safety-Catch Acid Labile Linker... 

Scheme 6 Strategy for Solid-Phase Synthesis of vMIP I Protein Using a Safety-Catch Linked32 ...

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