Safety-catch principle

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

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

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. 

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... 

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-... 

Besides the halo-subsituted Z derivatives, the Msz group, a group that is based on the safety-catch principle, is of potential interest for particular synthetic tasks as it is stable toward acidic and basic reaction conditions, but it is readily cleaved in a one-pot procedure with silicon tetrachloride/TFA in the presence of scavengers such as anisole, phenols, sulfides, selenides, and thiols. 

Af-Acyl-4-polystyrenesulfonamides, readily available from amino acid active esters and resin-bound sulfonamides were successfully introduced into SPPS by KennerJ A -Acyl-sul-fonamides are stable to alkaline hydrolysis and conditions present during acidolysis of Z or Boc groups. According to the safety-catch principle, they are rapidly cleaved under mild basic conditions (0.5 M NaOH) after conversion into the A -methyl derivatives by reaction with diazomethane. 

A further development of this safety-catch principle led to A -[2-hydroxybenzyl-4-methoxy-5-(methylsulfinyl)] (SiMB) derivatives (Scheme 4) where the acylation potency of the intermediate 8-methoxy-4,5-dihydro-l,4-benzoxazepin-2(3//)-one derivatives (Scheme 2) is significantly enhanced and similarly the rate of intramolecular O N acyl migration. The related Fmoc-protected amino acid derivatives are readily prepared and cleavage is achieved by reductive acidolysis (SiCl4/TFA/anisole/ethandithiol 5 90 2.5 2.5, 2h at room temperature). 

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. 

Another example of the safety-catch principle, in which the cleavage step is used to introduce further diversity, is ouftined in Scheme 76. Arninopyrirnidines of type 167 were synthesized by this approach [187, 188]. 

Figure 15.15 Sulfone-based resins. Resins 25-27 are used as alternatives to REM linkers. Resin 28 is based on the safety-catch principle while resins 29 and 30 were used to synthesize peptides.

A safety-catch linker is defined as a linker which is cleaved by performing two different reactions instead of the normal single step, thus providing better control over the timing of compound release [8]. The safety-catch principle consists of a linker system that is inert throughout all operations of the synthesis and has to be converted before the cleavage step from its stable form into an activated one that is labile towards the cleavage conditions. 

In another application of microwave-assisted resin cleavage, N-benzoylated alanine attached to 4-sulfamylbutyryl resin was cleaved (after activation of the linker with bromoacetonitrile by using Kenner s safety catch principle) with a variety of... 

Scheme 16.38. Solid-supported amide synthesis employing the "safety catch" principle.

Activation of the linker group prior to cleavage ( safety catch principle)... 

The safety catch principle generally leads to multidirectional resin cleavage which allows multiplication of the final library members both in terms of structural and functional diversity. 

A novel safety-catch principle for the multidirectional cleavage of pyrimidines and related heterocycles was first developed by Obrecht et (Figure 1.7.7, entry f). Thus, polymer-... 

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