Solid linker

There is a large range of resins available for SPOS. These resins are derivatised polymer supports with a range of linkers. The roles of linkers are (i) to provide point(s) of attachment for the tethered molecule, akin to a solid supported protecting group(s), (ii) to provide distance from the polymeric backbone in order to minimise interactions with the backbone, (iii) to enable cleavage of product molecules under conditions compatible with the stability of the molecules and the reaction conditions employed for chemical transformations. Hence in order to... 

K. Gordon and S. Balasubramanian, Solid phase synthesis - designer linkers for combinatorial chemistry A review J Chem Technol Biotechnol 74 835-851 7999. 

F. Guillier, D. Grain and M. Bradley, Linkers and Cleavage Strategies in Solid-phase Organic Synthesis and Combinatorial Chemistry, Chem Rev 100 2091-2157 2000. 

W. James, Linkers for solid phase organic synthesis. Tetrahedron 55 4855-4946 7999. 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

A new solid phase method to synthesize libraries of compounds based on 1,2,5-thiadiazolidine heterocycle was developed (00TL(41)3161). Starting from the coupling of the protected aminoacid to the resine functionalized with p-alkoxybenzylalcohol as the linker, a series of sulfahydantoins 251 could be obtained. The method is applicable to aminoacids with a basic side chain, aliphatic aldehydes or aldehydes with basic functionalities. 

Organic Synthesis on Solid Phase. Supports, Linkers, Reactions... 

A chiral separation medium is a complex system. Ideally, interactions that lead to enantioseparation are maximized while nonspecific interactions should be completely suppressed. Typically, a medium for chromatographic separations involves the solid support, the selector, and the linker connecting the two, as shown in scheme 3-1. 

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

For the solid-phase experiments [115], the commercially available Wang and HMPB-AM resins were chosen due their stability under the applied reaction conditions and an easy cleavage with TFA/DCM mixtures. Moreover, a novel, tailor-made and readily available linker, derived from inexpensive syringaldehyde was designed and proven to be superior to both standard Wang and HMPB-AM resins. For an initial study, as a proof of concept , the Wang linker was mimicked with a 4-methoxybenzyl group at N-1 position of a pyrazinone, and the sequence was evaluated in solution (Scheme 41). 

To perform the cycloaddition on solid-phase, N-l-unprotected pyrazi-nones were coupled with the solid support by treatment of the brominated linker in DMF for 6h at ambient temperature, using CS2CO3 as a base (Scheme 43). The reaction time for complete loading could be dramatically shortened to only 5 min under microwave irradiation at a pre-selected maximum temperature of 70 °C. 

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. 

The synthesis of aldehydes and ketoamides was performed on solid phase as well as in solution (Scheme 2.2). A semicarbazone linker (6) was employed for the assembly of the aldehydes on solid phase whereas the corresponding aminoalcohol was coupled in solution to the tripeptide and oxidized to the aldehyde, which produced epimeric mixtures [137]. For the synthesis of the ketoamides, hydroxyester THP resins were used as solid support ((7), Scheme 2.2) [138]. In solution the peptide bond was formed using an aminohydroxycarboxylic acid building block [138, 147]. Oxidation of the free hydroxyl group yielded the final inhibitors ((8), Scheme 2.2). 

Polar polyoxyethylene-polyoxypropylene (POEPOP) resin, deriva-tized with a 4-hydroxymethyl phenoxy linker, was used as a solid support for lanthanide triflate-catalyzed Mukaiyama-type solid-phase aldol reactions.282 The use of an aqueous solvent was found to be crucial. The reactions on an N-terminal peptide aldehyde substrate proceeded in very high yields. 

Jung N, Wiehn M, Brase S (2007) Multifunctional Linkers for Combinatorial Solid Phase Synthesis. 278 1-88... 

An alkylamine linker is incorporated into either the 5 or 3 end of the capture probe and the probe is activated with ethylene glycol bis-succinimidylsuccinate. The activated capture probe is bound to polystyrene microtiter wells precoated with poly(Lys-HBr, Phe). Nearly all of the solid-phase probe coupled to the polystyrene by this procedure is available for hybridization (Running and Urdea, 1990). 

Linkers and Resins for Solid-Phase Synthesis 1997-1999 Pan Li, Elaine K. Kolaczkowski, and Steven A. Kates... 

Backes I, Ellman JA. Solid support linker strategies. Curr Opin Chem Biol 1997 1 86. 

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