Trityl resins

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

Phenylfluoren-9-yl polystyrene (Phfl) based resin 49 was applied in the solid-phase synthesis of hydroxyl and amino functions [57,58]. This resin has higher acid stability compared to the structurally similar trityl resin. Final release of the product is accomplished with TFA in high purity (Scheme 19). 

Typically, the resin is washed with a mixture of dichloro-methane and methanol (2 1 5 x 10 mL, shaking for 0.5 min each time), with a mixture of dichloromethane (9mL) and methylamine (1 mL, 30% solution in ethanol), with 1,2-dichlo-ropropane (10 mL) over night, with a mixture of dichloromethane (9 mL) and acetic acid (1 mL trityl resin-bound products should not be washed with diluted acetic acid), with a mixture of dichloromethane and methanol (2 1 3 x 10 mL, shaking for 0.5 min each time), and finally with dichloromethane (10 mL). Shorter washing protocols can lead to significant amounts of residual DBU in the final products. 

The immobilization of nucleophilic substrates such as acids, alcohols, thiols and amines is realized by the Trityl resin (16), which is reasonably acid sensitive [28-30]. 

Fmoc-Tyr(S03Na)-OH (3 equiv) DIC (3 equiv)/ HOBt (3 equiv) 2-chloro- trityl-resin AcOH/TFE/CH2C12 (1 1 3), 20 °C, 20 min /V-acetyl-sulfated Leu-enkephalin n.r. [149]... 

Fmoc-Tyr-(S03NBu4)-0H (3 equiv) a n.r. = not reported. HBTU (3 equiv)/HOBt (3 equiv) trityl-resin HFIP/CH2C12 (1 4) oligo- tyrosine- O-sulfate peptides 18 [1521... 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

A slightly modified version of the bis(trichloromethyl) carbonate method 30 has been used for the total SPPS of cyclosporin O 29 (Scheme 1) and omphalotin A 40 (Scheme 37). Since in this case an acid sensitive trityl resin was used, excess DIPEA was added to the resin. 

Amino acids suitable for side-chain attachment to supports that have been used to prepare cyclic peptides on insoluble supports include tyrosine (etherified with Wang resin [60]), histidine (N-alkylated with trityl resin [79]), aspartic acid [66,67,80], asparagine [80], glutamic acid [80,81], lysine [65], and serine [65],... 

Scheme 11 Synthesis of Succinyl Hydroxamic Acids with a Hydroxylamine-Linked Trityl Resin 53 ...

Radical fragmentation of 2-nitrophenyl-azo-trityl resin was studied in the presence of various radical acceptor solvents to elucidate possible radical reaction pathways. When using benzene as solvent, only 2-nitro-bi-phenyl was formed as the product of radical substitution reaction (SNR) in 67% yield. Hydrogen-radical abstraction from the polymer backbone (e.g., from the benzylic units of polystyrene) was completely suppressed. When toluene was used as solvent, a mixture of the following products was obtained nitrobenzene, 4-methyl-2 -nitrobisphenyl, 2-methyl-2 -nitro-bisphenyl, and 3-methyl-2 -nitrobisphenyl (9 9 1 1). In the case of toluene, the nitro-aryl radicals undergo H-abstraction with radical substitution as a competing reaction pathway. These results indicate that H-abstraction... 

At first the Fmoc-Cys-CI-trityl-resin was prepared. The incorporation of the Fmoc-Cys(trt)-OH residue upon 2CI-Trt resin is accomplished with an excess of 1 eq. of Fmoc-Cys(Trt) and 2.5 eq. of N,N -diisopropylethylamine (DIEA). 

The incorporation of the amino acids for obtaining of Boc-D-Phe-Cys-(Trt)-D-Trp-Lys(Boc)-Thr(tBu)-Cys(Trt)-2-CI-trityl-resin is carried out following a synthesis program such as that described below, using an excess of 2.5 equivalents of Fmoc-amino acid, N-hydroxybenzotriazol (HOBt) and diisopropylcarbodiimide (DIPCDI). Later the Fmoc group is deprotected with 20% of piperidine/DMF for 1 min + 5 min. 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

A 9-phenylfluoren-9-yl polystyrene-based resin has been described for the attachment of nitrogen and oxygen nucleophiles. Greater acid stability compared to the standard trityl resins that are widely used in solid-phase peptide synthesis make this solid support an interesting alternative in solid-phase organic synthesis. This resin can be used in Suzuki coupling reactions to furnish biaryls in good yields [100]. 

Reactivation of trityl resins After swelling and washing the resin with toluene (five times), place the resin in a round-bottom flask and cover with toluene. Add freshly distilled acetyl chloride (1 mL/g resin) and fit a reflux condenser on the flask. Heat the reaction mixture at 60°C for 3 h. Allow to cool to room temperature, filter the resin on a frit, and wash six times with DCM. Load it immediately as described in Protocol 4. 

The C-terminal steroid modified heptapeptides, corresponding to the C-terminus of Hedgehog proteins, were synthesized in a combined solid-phase/solntion approach (41). The synthesis built on the dipeptide Fmoc-SG-OAU that was connected to the trityl resin via the free hydroxyl fnnctionality of the serine. The C -terminal allyl ester was cleaved by noble-metal-mediated... 

The solvent was removed from the soln of the crude linear peptide obtained by cleavage of H-As-p(OtBu)-D-Phe-Lys(Boc)-Arg(Pbf)-Gly-trityl-resin (loading 17.60 mmol) with ACOH/TFE/CH2Q2 (1 1 3 250 mL) at rt for 1 h and the obtained acetate salt dissolved in CH2CI2 (200 mL) was added slowly to a soln of 50% T3P (3) in EtOAc (54.24 mL), TEA (63.2 mL), and DMAP (200mg) in CH2Q2 (8L). After 12 h, the mixture was concentrated and purified by flash chromatography (MeOH/EtOAc, 1 10) yield 17.23 g (97%). 

A 320-member library of cell-permeable molecules, with a tetrahydroox-azepine (THOX) core has been synthesized on a trityl resin by using RCM as the cyclative step [224]. These compounds have been tested in the search of candidate heterodimerizers. 

Alanine methyl ester (92 mg, 0.66 mmol) in toluene (2 mb) was added to a slurry of maleimide supported on trityl resin (200 mg, ca. 0.22 mmol),... 

HN-tBu 0 fNH fN o tBu-N=C=0 zv-° o oVy n, KJ n3 [25] Both isocyanates and thioiso-cyanates are used on various resins to prepare (thio)ureas. Aromatic and aliphatic amines are suitable for condensation. N-alkoxy ureas are prepared on trityl resin in 82% yield. [3] [14] [17] [25-39]... 

ResinsAinkers used 2-chloro-trityl resin, CMPP (chloro-methylphenyl pentyl polystyrene), Merrifield or Wang. 

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