Aminomethyl resin

The allylic HYCRAM derivative was subsequently modified by insertion of a standard amino acid between the aminomethyl resin and the hydroxy butenoic acid moiety. Using this allylic anchor, the resin-linked, glycosylated HIV peptide T-derivative 164 was synthesized by application of Fmoc amino protection and sidechain protection with lert-butyl groups. The lac-tosamine peptide T (165) could be released from the resin by application of the palladium(0)-catalyzed allyl-transfer reaction to V-methyl aniline as the allyl acceptor. 

FIGURE 5.17 Resins and linkers for synthesis of peptides using Fmoc/tBu chemistry. The linkers are secured to supports by reaction with aminomethyl resins. A protected amino acid is anchored to the support as an ester by reaction with a hydroxyl or chloro group (italicized). The alkoxy and phenyl substituents render the benzyl esters sensitive to the cleavage reagents. 

The synthetic approach used in this work is shown in Scheme 9. Two known solution pathways were used to convert shikimic acid to an epoxide intermediate. In fact, both the (-)35 and the (+)36 enantiomers were formed. After minor synthetic transformations, these epoxides were linked to Ten-tagel S aminomethyl resin with an o-nitrophenyl-derived photocleavable linker 7437 via amide bond formation to give intermediate 75. The first point of variation was added via various iodo-benzyl nitrone carboxylic acids 76 via 1,3-dipolar addition/esterification reactions. Highly constrained resin-bound tetracyclic hydrooxazoles 77 were thereby produced. 

C-Terminal peptide carbamates are prepared by reaction of the mixed succinimidyl carbonate of the N -protected amino alcohol (e.g., Fmoc-Phe-o-CO-OSu) obtained from the N -protected amino alcohol with DSC in the presence of DMAP, without isolation, with an aminomethyl resin (e.g., H-PAL-Nle-PEG-PSty).f l Standard Fmoc/tBu assembly of the remaining sequence is subsequently performed. Cleavage of the resin with TFA/H2O (19 1) affords the peptide carbamates with good purity. Use of isolated and purified 4-nitrophenyl carbonate monomers has also been described for the same purpose.f l... 

ChloroallyKc Aminomethyl Resin 4 Preparation and Attachment of the C-Terminal Amino Acid ... 

In order to immobilize the linker, the hydroxy group is either treated directly with a carboxy functionalized resin or is coupled to a dicarboxyl-ic acid spacer on aminomethyl resin. 

Deprotection-protection Aminomethyl resin Chloromethyl resin Wang resin 2-Chlorotrityl resin Benzoic acid resin HMPB-MBHA resin TentaGel... 

Hydroxyethylene resin HMPA resin Chloromethyl resin Hydroxymethyl resin Tritylchloride resin Rink amide resin Wang resin REM resin Aminomethyl resin Chloromethyl resin Wang resin Rink amide resin PAL amide resin MBHA resin Chloromethyl resin Chlorotrityl resin Wang resin PAM resin Polystyrene resin Chloromethyl resin Chlorotrityl resin Wang resin Rink amide resin Sasrin resin Polystyrene resin Chloromethyl resin Benzoic acid resin Wang resin Trityl resin 2-Chlorotrityl resin PAL resin Rink amide resin MBHA resin REM resin Hydroxymethyl resin Polystyrene Aminomethyl resin Chloromethyl resin 2-Chlorotrityl resin Hydroxyethyl resin Rink amide resin Wang resin MBHA resin Sieber resin... 

Cleavage, nonstandard Aminomethyl resin Chloromethyl resin Benzoic acid resin Hydroxymethyl resin Rink amide resin Wang resin PAL amide resin MBHA resin Kaiser oxime resin REM resin TentaGel S OH TentaGel S PHB Spheron Ara 1000 ... 

The oxidation-reduction method, developed initially by Mukaiyama et al. [133] and related to the previously described organophosphorus methods, has permitted a variety of important solid-phase applications. The mechanism of the activation is complex and involves the oxidation of the triaryl/ alkyl-phosphine to the oxide as well as reduction of the disulfide to the mercapto derivative. However, different active species, such as 81 (Fig. 11), the 2-pyridyl thioester, or even the symmetrical anhydride, have been postulated to form. For the intermediate 81, the peptide bond formation may proceed through a (cyclic transition state. The method has been used for conventional stepwise synthesis [134], acylation of the first protected amino acid to a hydroxymethyl resin, and to achieve segment condensation on a solid support in the opposite direction (N C) [135,136]. Lastly, it has been used for efficient grafting of a polyethylene glycol (molecular weight 2000) derivative to an aminomethyl resin to prepare PEG-PS resins [137]. 

Very recently a rapid method for the preparation of effective polymer-supported isocyanate resins has been reported [31]. Gel-type isocyanate resins tvere generated from aminomethyl resins and inexpensive substrates as alternatives to the commercially available, expensive macroporous polystyrene isocyanate supports. Several isocyanates have been investigated phenyl diisocyanate (PDI) tvas found to be the most efficient. Aminomethyl resin was pre-swollen in NMP, mixed with 2 equiv. PDI, and irradiated at 100 °C for 5 min (Scheme 16.7). Filtration, washing with NMP and DCM and drying under vacuum furnished the corresponding isocyanate resin. The reactivity of this novel gel-type resin was better than that of commercially available methyl isocyanate resins and it was successfully used for purification of a small amide library [31]. 

Scheme 16.7. Preparation of gel-type isocyanate resin from aminomethyl resin.

Reagents and conditions i) 2-nitrobenzyl bromide, DMF, 70°C ii) a) Na2S20<, EtOH, reflux, b) HBr, MeOH, dioxane Hi) PMB chloride, py, CHsCIs iv) methyl 4-formylbenzoate, NaOMe, MeOH, reflux v) aminomethyl resin, AcOH, MeOH/dioxane vi) NaOMe, MeOH, reflux vii) toluene, DMF, distillation viii) KOtBu, reflux. 

Abbreviations used for amino acids and the designations of peptides follow the rules of the lUPAC-IUB Commision of Biochemical Nomenclature in J. Biol. Chem., 247 (1972) 977-983. The following additional abbreviations are used AGP, acyl carrier protein AM, aminomethyl (resin) Boc, tert.-butyloxycarbonyl BOP, benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexa-fluorophosphate Bu, -butyl DCC, N,N -di-cyclohexylcarbodiimide DEAE, diethyl-aminoethyl DIEA, N,N-diisopropylethyl-amine DIPCDI, N,N -diisopropylcarbodi-imide DMAP, 4-dimethylaminopyridine DMF, N,N-dimethylformamide Dts, dithia-succinoyl EtOAc, ethyl acetate EtOH, ethanol Fmoc, 9-fluorenylmethyloxycarbon-yl HOBt, 1-hydroxybenzotriazole HPLC, high-performance liquid chromatography IR, infrared IRAA, internal reference amino acid MBHA, 4-methylbenzhydrylamine (resin) Nle, norleucine NMR, nuclear mag-... 

CVclic Peptides. Polymer supp s aid in the synthesis of cyclic peptides (1.10.131. A recent example is the synthesis of cyc/o-(Gly-His)3 2% crude chromatographic yield in a 1% cross-linked, 0.20 mmol/g aminomethyl resin by a bidirectional method (1401. The actual yield of die cyclization step (Scheme 13) is unknown, because the ovoall yield includes the yields of initial attachrnent, five deprotection-coupling steps, and cleavage from the resin. Most importantly, the cyclic hexapeptide contained no detectable amounts of linear or oligomoic cyclic peptides. 

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