Resins linkers used

Resins/linkers used Benzoic acid PS. TentaGel S OH, PEG-resin, Kaiser oxime and Wang. 

O-o-V"1 gA° R X.H.C R 0 NH2 [52] Amides of different types are produced to form peptido-mimetics and/or peptoids. Not only condensation reactions but also alkylation and substitution reactions are described. Resins/linkers used Wang, Rink amide, Knorr TenlaGel. Phosphoramides were prepared on Pore glass, 3 split-pool libraries. [21] [50-57]... 

OMe / R 0 OMe y oMe 0jry. 0j h2 [59] Intramolecular cyclizalion is a common approach to lactams, e.g. benzodiazepines. Resins/linkers used Rink amide and Wang. [58] [59]... 

Resins/linkers used Safety Catch, Rink amide, Wang, Sasrin, THP, traceless. 

Resins/linkers used Wang, Rink, NpSSM, THP, trityl. 

Resins/linkers used hydroxymethylene. High yields. 

Via Heck reactions Resins/ linkers used Rink amide, Wang and Tentagel S-OH Several Pd catalysts investigated. 

Ms CN O DBU [56J thiophene Resins/linkers used Wang resin. Moderate to high yields. 4-thiazolidinone, thiazole thiazolidine thiazanone Tentagel or Sasrin resin one-pot reaction good yields [56] [241] [200] [204] [205] [242]... 

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). 

Zheng A, Shan D, Shi X, Wang B. A model resin linker for solid-phase peptide synthesis which can be cleaved using two sequential mild reactions. J Org Chem 1999 64 7459-7466. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

After isolating the product of a solid phase synthesis, the support (resin + linker) is usually discarded as waste, although successful examples of its reuse in further synthetic cycles are known with trityl type linkers (Frechet and Haque 1975). To reduce both volume of operation and amount of waste, the loading of the resin (quantified as millimoles of functionality per gram) has to be increased. Besides theoretical limitations (for polystyrene this is reached when every phenyl ring is substituted by the linker), there may be practical boundaries for using highly loaded resins in solid-phase supported synthesis. This issue was studied... 

Scheme 27 Synthesis of a palmitoylated and farnesylated N-Ras peptide with the hydrazine linker using the resin llpidatlon approach.

Typically lightly cross-linked gel-type resins are prepared in the absence of any solvent or porogen. However it is possible to include relatively large volumes of thermodynamically compatible solvent in the polymerization without inducing any phase separation at the low levels of cross-linker used in gel-type resin synthesis. 

A key element in the original Merriheld procedure of solid-phase synthesis is the solid support system. That system consists of two parts a resin head and a. linker, an organic compound used to join the hrst amino acid to the resin head. The resin beads used by Merriheld are small spherical objects made of cross-linked polystyrene. This material consists primarily of the polymer polystyrene whose linear molecules are linked to each other at various positions by the addition of divinylhenzene (CH2 = CHCgH jCH =CH2). The hnal cross-linked material is relatively rigid, with enough hexihility to permit... 

Although several routes have been published for the preparation of hydroxamic acids on solid phase, these generally involve the preparation of a special linker to which hydrox-ylamine is attached. Dankwardt s approach obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated in Scheme 86. CarboxyUc-acid-ester-linked, polymer-supported, Cbz-protected amino acids 195 (formed from 194) were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids 196. 

The two main resin linkers developed so far are shown in Scheme 18, i.e. tris(alk-oxy)benzylamide- 412 and 4-alkoxybenzylamide-type linkers)341 the former being TFA labile and thus fully compatible with Fmoc/tBu and the latter strongly acid labile and correspondingly compatible with Boc/Bzl chemistry. As shown in the case of the tris(alk-oxy)benzaldehyde handle such handles may be introduced into the C-terminal amino acid ester by reductive amination, and after suitable N -protection coupled to amino-functionalized resins (see Scheme 18). Alternatively, the tris(alkoxy)benzaldehyde-functionalized resin, BAL resin, (see Scheme 14) is used to link the C-terminal amino acid ester by reductive amination. To overcome the difficult acylation of the V -arylamino acid ester derivative on resin (best results with 10 equivalent symmetrical anhydrides), synthesis in solution of the C-terminal dipeptide building block containing the amide handle followed by its attachment to the resin has been proposed)341 ... 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

D. Stones, D. J. Miller, M. W. Beaton, T. J. Rutherford and D. Gani, A method for the quantification of resin loading using 19F gel phase NMR spectroscopy and a new method for benzyl ether linker cleavage in solid phase chemistry, Tet. Lett, 1998, 39, 4875 1878. 

In a parallel study, Wipf and Fritch11041 have shown that also urethane-protected (Boc), and even amino acid segments, are tolerated as acyl compounds on the aziridine nitrogen. The best results were obtained with alkylcopper reagents derived from CuCN and an alkyl-lithium in the presence of boron trifluoride-diethyl ether complex. Some 6-alkylated compounds (11-15%) were isolated as well. This work was extended to a solid-phase procedure that resulted in resin-bound alkene isosteres that could immediately be used in further peptide synthesis.11051 For this purpose, the 2-nitrophenylsulfonyl (oNbs) group was used for nitrogen protection and aziridine activation. It could be readily cleaved with benzenethio-late, which was compatible with the acid-sensitive Wang linker used. 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

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