Cleavage safety-catch linkers

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. 

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... 

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. 

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). 

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

Entry 9 in Table 3.13 is an example of a safety-catch linker, which requires activation by TFA-mediated cleavage of a tert-butyl ether. The unactivated 2-(tm-butoxyj-phenyl esters are cleaved by amines 700 times more slowly than the corresponding 2-hydroxyphenyl esters [289]. A similar linker has been described [290], in which a benzyl ether is used instead of a ferf-butyl ether. Activation of this linker by debenzy-lation was achieved by treatment with HF or HBr/TFA [290]. 

Table 3.26 lists illustrative examples of cleavage reactions of support-bound N-aryl-carbamates, anilides, and /V-arylsulfonamidcs. /V-Arylcarbamatcs are more susceptible to attack by nucleophiles than /V-alkylcarbamates, and, if strong bases or nucleophiles are to be used in a reaction sequence, it might be a better choice to link the aniline to the support as an /V-bcnzyl derivative. Entry 7 (Table 3.26) is an example of a safety-catch linker for anilines, in which activation is achieved by enzymatic hydrolysis of a phenylacetamide to liberate a primary amine, which then cleaves the anilide. 

Multidirectional cleavage strategies,93,97 98 which offer the possibility to liberate several different functional groups or elements of diversity. Safety-catch linker strategies97,99,100 have been of special interest in this context. 

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). 

Sulfur has been used in linkers such as thioethers, sulfoxides, sulfones, sulfonic acids and their corresponding derivatives. A safety-catch linker for amines is based on 2-(thiobenzyl)ethylcarbamates [44]. Linkage is performed with preformed handles containing ethenyloxycarbonyl-protected amines 37. Attachment to thiomethyl-ated polystyrene 38 is performed under conditions involving radicals. Cleavage was performed with an oxidizing agent, which forms the retro Michael substrate (Scheme 6.1.11). 

Figure 12 A solid-phase total synthesis of the antimycobacterial cyclodepsipeptide kaha-lalide A. The synthesis relies on the Kenner safety-catch linker for attachment to the peptide backbone, followed by macrocyclative cleavage of the linear depsipeptide...

In principle, linker 96 can be regarded as a safety-catch linker. Prior to activation by alkylation it is completely stable towards the coupling conditions, while after alkylation 97 undergoes efficient cleavage. The principle has been used to synthesize a small library of biarylmethanes 98 [115]. A disadvantage is the observed formation of homocoupling products. Pure products were only obtained after chromatography on silica gel. 

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. 

A further safety-catch linker is based on a difhiane-protected benzoin (173). It can be activated for cleavage by photolysis according to Scheme 79, after removal of the dithiane protection [194]. It can be applied to the attachment and subsequent release of alcohols and carboxylic acids. A disadvantage is that if activation is performed with a Hg(II) salt, then this must be removed completely in order to avoid problems in assays using proteins as biological targets. 

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. 

Since safety-catch means the activation of the linker prior to cleavage, such a system can be applied for monodirectional, such as traceless linkers, or multifunctional linkers [9] as well as for cleavage-cyclization strategies. Table 16.1 gives an overview of the safety-catch linker types known to date. Slight differences... 

Scheme 16.6 Activation and subsequent cleavage by 13-elimination on Wade s safety-catch linker.

Camarero et al. [108] used the hydrazine safety-catch linker to prepare peptide thioesters. After assembling the peptide using standard Fmoc protocols, the fully protected peptide resin was activated by mild oxidation with N-bromosuc-cinimide (NB S) in the presence of pyridine, forming a reactive acyl diazene that was then deaved with an a-amino add S-alkyl thioester such as H-AA-SEt, where AA is Gly or Ala. After TFA deprotection, peptide thioesters were obtained in good yields. Although the oxidation step did produce racemization, and other sensitive amino acids such as Tyr(tBu) and Trp(Boc) were not affected, Met and Cys presented some problems. Met was completely oxidized, and a reductive cleavage was required. For Cys, the Cys(Trt) derivative should be avoided and use of Cys(Npys) or Cys(S-StBu) is recommended instead. 

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... 

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