Activation, 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. 

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. 

SCHEME 113 Synthesis of glycopeptide-athioesters by (a) using safety-catch linker and (b) thioesterification of activated C-terminal carboxylic acids. Boc, ferf-butoxycarbonyl. 

Backes BJ, Virgilio AA, Ellman JA, Activation method to prepare a highly reactive acylsulfonamide safety-catch linker for solid-phase synthesis, J. Am. Chem. Soc., 118 3055-3056, 1996. 

The most problematic issue using the catechol safety-catch linker is the activation/ deprotection steps. Although best results are obtained with HF, for large libraries in our laboratory this was not possible. Therefore we tend to use TFMSA/DCM as the activation mixture. 

To overcome the problems associated with these reaction conditions, Backes et al. developed an alkanesulfonamide safety-catch linker for solid-phase s)rnthesis [34]. In this method, acylation of a sulfonamide support affords a support-bound iV-acylsulfonamide that is able to withstand the basic and strongly nucleophilic reaction conditions required for Fmoc-based SPPS. On completion of the solid-phase synthesis sequence, iodoacetonitrile treatment yields iV-cyanomethyl derivatives that can be cleaved under mild nucleophilic reaction conditions to afford the target compounds. Coupling conditions of alkanesulfonamide resin with Boc- and Fmoc-amino acids were developed to minimize the racemization. Using this method, a short synthesis sequence, followed by iodoacetonitrile activation and nucleophilic displacement is able to form dipeptide products from a number of support-bound amino acids incorporating diverse side-chain functionalities. 

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. 

An interesting safety-catch linker is based on solid-phase-bound 1,2-dihydroqui-noline [192]. The principle is outhned in Scheme 77. The acylated form of the 1,2-dihydroquinoline on the support (167) is stable under basic and acidic conditions as well as towards mild reducing agents. Oxidation leads to aromatization and hence to the activated quinolinium derivative 168, which is prone to nucleophilic displacement, leading to the target compounds 169. 

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. 

An elegant safety-catch linker fhat is activated by derivatization of a benzamide with a Boc group has been reported. The compounds can then be released by various nucleophiles, which, in turn, lead to different heterocyclic systems [195]. This linker was developed in connection with an Ugi four-component condensation, for which the starting isonitrile was formed directly on the sohd support 174 (Scheme 80). 

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.

Scheme 16.12 Activation by dehydration on Wieland s safety-catch linker.

Another instance for this linker class is the safety-catch linker by Lyttle, which was developed for the synthesis of nucleic acids on solid supports [62]. Starting from a resin carrying an Alloc-protected amino group fragment, conventional phosphoramidite chemistry was carried out to build up the desired immobilized nucleotide 57. Removal of the Alloc group via palladium catalysis under neutral conditions produces a polymer-bound intermediate 58 with a free amino functionality that can intramolecularly attack activated phosphonates and liberate the nucleotide 59 from the solid support (Scheme 16.14). More examples of safety-catch linkers that use the deprotection of an N-functionality as the activation step are listed in Table 16.1 (resins 61-65) [63-68]. 

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. 

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