Fmoc-His

Fmoc-His(Trt)-OH, PfPyU, DIEA, sym-collidine, HOAt, NMP Ac20, pyridine. 

K Barlos, O Chatzi, D Gatos, G Stavropoulos, T Tsegenidis. Fmoc-His(Mmt)-OH and Fmoc-His(Mtt)-OH. Two new histidine derivatives N""-protected with highly acid-sensitive groups. Preparation, properties and use in peptide synthesis, (dimeth-ylsilyldichloride) Tetrahedron Lett 32, 475, 1991. 

Fmoc-amino acids used as building blocks of testing compounds are as follows Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Met-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Ile-OH, Fmoc-His(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Trp(Boc)-OH, Fmoc-D-Ala-OH, Fmoc-D-Arg(Pmc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Glu(OtBu)-OH, Fmoc-D-His(Trt)-OH, Fmoc-D-Gln(Trt)-OH, Fmoc-D-Leu-OH, Fmoc-D-Met-OH, Fmoc-D-Pro-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Lys(Boc)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-D-Asn(Trt)-OH, Fmoc-3-(4-pyridyl)alanine, Fmoc-D-3-(3-pyridyl)alanine, Fmoc-4-tert-butoxyproline, Fmoc-3-chlorophenylalanine, Fmoc-norleucine, Fmoc-2-cyclohexylglycine, Fmoc-2-aminoisobutyric acid, Fmoc-tranexamic acid, Fmoc-(i ,S)-3-amino-3-(2-furyl)propionic acid, Fmoc-(i ,S)-(6,7-di-methoxy)-l,2,3,4-tetrahydroquinoline-3-carboxylic acid, Fmoc- (R, S)-3-amino-3-(4-hydroxyphenyl)propionic acid, Fmoc-(i ,S)-3-aminovaleric acid, Fmoc-(i ,5 )-3-amino-3-(3,4-dichlorophenyl)propionic acid, Fmoc-isonipecotic acid, Fmoc-(i ,S)-3-amino-3-(3,4-methylenedioxyphenyl)... 

Hydroxybenzotriasole Boc-Arg(HCI)-OH Diisopropylcarbodiimide Fmoc-D-Ser(But)-OH Fmoc-Tyr(BrZ)-OH Fmoc-His(Fmoc)-OFI Pyr-OH (pyroglutamic acid) Boc-Pro-OBzi-polystyrene resin 1% cross-linked with divinylbenzene... 

Peptide synthesis reagents and materials Use NovaSyn TGR resin (Novabiochem) for C-terminal amide synthesis and Fmoc amino acid monomers (Novabiochem) including Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Finoc-Glu(OfBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Trp(Boc)-OH. Other peptide synthesis reagents are as for PNA (above) with the addition of 1,2-ethanedithiol (EDT, >98%, Fluka). A Phenomenex Jupiter C-18 column (analytical and semi-preparative) may be used for reversed-phase HPLC. 

Fmoc-His(Boc)-ODhbt was crystallized by adding a soln in THF/Et20 (1 4) to 5 vols of petroleum ether (bp 40-60 °C) with stirring. Fmoc-Arg(Mtr)-ODhbt was obtained free from lactam (Scheme 5) if the solvent was THF, the reaction temperature was — 25°C for Ih followed by 4 h at ice-salt temperature, and crystallization was at —15 °C. In soln Fmoc-Arg(Mtr)-ODhbt was gradually converted into the lactam, with a half-life of 10 h in DMF and 15 min in CH2Q2. Fmoc-Asp(OtBu)-ODhbt was optically stable over 3.5 h in DMF, but generated 20% of the D-isomer in the presence of 1% DIEA. 

Mixed anhydrides produced from the commercially available 2,6-dichlorobenzoyl chloride (5, see Table 1) and Fmoc-protected amino acids have proven to be convenient reagents for acylating Wang-type resins.P Reaction takes place with good yields and nninimal racennization, except for the case of Fmoc-Cys(Trt)-OH (4% D-isomer) and Fmoc-His(Trt)-OH (27% D-isomer). In the latter case, the use of Trt-His(Trt)-OH (<1.0% d-isomer) circumvents the problem. 

The racemization of His as discussed in Section 4.3.2.2.2 is promoted by its own internal base, the jt-nitrogen of the imidazole ring. Histidine is usually protected at the x-nitrogen, but is commercially available protected at the jt-nitrogen as Fmoc-His(Bum)-OH. However, the less-expensive alternatives protected by Boc or Trt at the x-position can be used effectively if the acidity of the acylating mixture is maintained by the addition of HOBt. 

The tert-butoxymethyl (Bum) protecting group protects the 7r-nitrogen of the imidazole ring and prevents epimerization in Fmoc SPPS [136]. Okada et al. [137,138] have suggested the iVT-l-adamantyloxymethylhisti-dine (A -1-Adorn) derivative for Fmoc chemistry. This derivative is more soluble than Fmoc-His(Bum)-OH and can be obtained in better synthetic yields [137,138]. 

The preparation of head-to-tail cyclic tetra- and hexapeptides has been achieved by Sabatino et al. [32] on a solid support after side-chain attachment of an Fmoc-His-OAl residue to the resin via a trityl spacer. 

Although a variety of solvents have been reported for peptide synthesis, we use highly purified DMF for all coupling reactions Protocol 7). V ere Fmoc-protected amino acids require acid-labile side-chain protection, we recommend Arg(Pbf), Asp(OtBu), Cys(Trt), Glu(OfBu), His(Boc), Lys(Boc), Ser( u), Thr(rBu), Trp(Boc), and T3n-(tBu). Although Fmoc-His(Boc)-OH is thermally labile and must be stored at -20 C, we have found that it couples more efficiently than either Fmoc-His(Trt)-OH or Fmoc-His(Bum)-OH. Fmoc-Asn(Trt)-OH and Fmoc-Gln(Trt)-OH are generally used with HBTU, HATU, or BOP activation the non-side-chain protected derivatives of Asn and Gin can be used with DIC/HOBt activation in short peptides or at the N-terminal coupling (47). 

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