Linkers, safety-catch

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 

Deprotection of the silyl groups from 161 161 (1 g, 0.28-0.29 mmol) was suspended in THF (4mL) and (HFjs-NEts (1 mL) was added. After 24 h, the resin was washed with THF and CH2CI2 and dried to yield 1.01 g of the support ready for the attachment of the aromatic carboxylic acid. 

To a suspension of the hnker as prepared above (200 mg, 58 pmol) were added 4-iodobenzoic acid (2 equiv.), DMAP (0.2 equiv), and DIC (1.2 equiv.), and the mixture was shaken for 18 h at rt. Washing (THF and CH CL) and drying afforded 162. 

Suzuki coupling with resin 162 To a degassed suspension of resin 162 (100 mg, 28 pmol) in DMF were added PhB(OH)2 (14 mg, 112 pmol), [PdCL (dppf)] (4 mg, 6 pmol), and NEI3 (39 pL, 0.28 pmol). After 18 h at 65 °C, the reaction mixture was washed with DMF and CH2CI2 and the resin was dried in readiness for the photolysis. 

Photolysis Photolyses were conducted in quartz cells (1 cm path length, equipped with stirrer bar) with 2-8 mg of resin suspended in 3 mL of solvent in the beam of a 500 W high-pressure Hg lamp fitted with a 280-400 nm dichroic mirror and a 320 nm cut-off filter. The power level was adjusted between 50 and 1000 mW cm by means of a collimating lens. The cells were maintained at 20 °C and irradiated horizontally with gentle mixing of the beads by means of a magnetic stirrer. After photolysis, the supernatant was analyzed by UV spectroscopy and reversed-phase HPLC. Alternatively, the photolysis can also be performed directly in microtiter plates. 

Photochemical cleavage of 165 leads to the release of the corresponding alcohol. The reaction is performed under slightly acidic conditions. 

Among the successful linker strategies that are being developed specifically for the solid-supported 

Thereby, a linker molecule is activated in the very last step before cleavage. 

Regents and conditions i) CHjNj or ICHjCN, DBU ii) Nu (amines or alcohoiates) iii) m-CPBA. GHjCt iv) R3-X, DMF v) DIEA, DMF vi) base vii) R -CHO viii) TFA ix) TfjO, 2,6-di-ferf-butyl-4-methylpyridine CH2CI2, -60 to -30°C X) HglOCOCFa), CH2CI2, HjO, r.t. 

Polymer-bound phosphonium salts 9 form after activation with base the intermediate ylides 10 which can be multidirectionally cleaved by reaction with aldehydes R -CHO to form products of type 11.356 

Another powerful sulfur-based safety-catch linker was developed by Kahne et foj- the 

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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. 

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

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

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). 

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... 

Backes, B. J. Ellman, J. A. Carbon-Carbon Bond Forming Methods on Solid Support. Utilisation of Kenner s Safety-Catch Linker, J. Am. Chem. Soc. 1994,776, 11171-11172. 

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]. 

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... 

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. 

Peptides can also be cyclized through their side-chain functionalities (e.g. using lysine, cysteine, glutamic acid, or aspartic acid [68-71]), or with the aid of synthetic spacers ([72] see also Table 8.5). Examples have been reported of the preparation of cyclic peptides using safety-catch linkers (e.g. (4-alkylmercapto)phenol [62], sulfonamide [73], or hydrazide [74]), 2-nitrophenyl ester attachment [61], or oxime ester... 

Scheme 7.34 Microwave-promoted synthesis of urea-derivatives on solid-support (purity based on crude 1H NMR purified yields on initial loading (0.73 mmol g-1)of alkyl safety-catch linker).

Our interest in diamino acid building blocks or scaffolds is connected with the studies of a new type of safety-catch linkers based on a dia-mino acid residue that we have carried out. Safety-catch linkers for... 

The use of resin-bound convertible isocyanides such as the universal Rink isocyanide-resin [18], the safety-catch linker isocyanide-resin [8b, 19] the cyclo-hexenyl isocyanide-resin [8b], and the carbonate convertible isocyanide-resin [20] has found interesting applications in solid-phase Ugi-4CR and post-condensation transformations [21] (Scheme 2.9). 

Universal Rink Isocyanide-resin Safety Catch Linker Isocyanide-resin... 

The Hulme group also developed an interesting resin-bound isocyanide, the safety-catch linker (Scheme 2.9), which was employed in the synthesis of sev-... 

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). 

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