- 1-Ethyl 2-halopyridinium salts, highly efficient coupling reagents for hindered peptide synthesis both in solution and the solid-phase
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1-Ethyl-2-halopyridinium salts, BEP, FEP, BEPH and FEPH, were synthesized and proved to be very effective for the synthesis of hindered peptides containing N-methylated or C(α),C(α)-dialkylated amino acid residues. HPLC monitoring of model reactions indicated that these pyridinium salts demonstrated higher reactivities, lower racemization than the commonly used halogenated uronium and phosphonium salts. The efficiency of these pyridinium type coupling reagents was further proved by the synthesis of a series of hindered oligopeptides and active esters with good yields and convenient workup. The 8-11 tetrapeptide fragment of Cyclosporin A (CsA) and the pentapeptide moiety of Dolastatin 15 were also successfully synthesized using these pyridinium salts. The efficiency of these pyridinium type coupling reagents for SPPS was also demonstrated by the solid-phase synthesis of the extremely hindered 8-11 peptide segment of CsA and the linear undecapeptide of CsO. The mechanism of the pyridinium salt mediated coupling reactions was also studied by 1H NMR, IR and HPLC. It was proposed that the major reactive intermediates were the corresponding acyl halide and acyloxypyridinium salts of the N-protected amino acid or peptide. (C) 2000 Elsevier Science Ltd.
- Li, Peng,Xu, Jie-Cheng
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p. 8119 - 8131
(2007/10/03)
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- Highly efficient synthesis of sterically hindered peptides containing N-methylated amino acid residues using a novel 1H-benzimidazolium salt
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Novel 1H-benzimidazolium type peptide coupling reagent, CMBI, was designed, synthesized, and shown to be efficient in the promotion of the formation of sterically hindered amide and ester bonds. Its high efficiency was proved by model reaction tests and the successful synthesis of various hindered oligopeptides and peptide segments containing N-methyl amino acid residues with fast reaction speeds, low racemization and excellent yields. A mechanism for amide bond formation mediated by the reagent was proposed. (C) 2000 Elsevier Science Ltd.
- Li, Peng,Xu, Jie Cheng
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p. 9949 - 9955
(2007/10/03)
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- 2-Bromo-1-ethyl pyridinium tetrafluoroborate (BEP): A powerful coupling reagent for N-methylated peptide synthesis
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2-Bromo-1-ethyl pyridinium tetrafluoroborate (BEP) was firstly utilized to the synthesis of peptides containing N-methyl amino acid residues both in solution and solid phase, and demonstrated high reactivity, low racemization and excellent yields, which w
- Li, Peng,Xu, Jie Cheng
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p. 204 - 205
(2007/10/03)
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- Total synthesis of cyclosporin O both in solution and in the solid phase using novel thiazolium-, immonium-, and pyridinium-type coupling reagents: BEMT, BDMP, and BEP
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Cyclosporin O (1), an extensively N-methylated immunosuppressive cyclic undecapeptide isolated from Tolypocladium inflatum Gams, was synthesized in 20-23% overall yield via 4 + 7 segment condensation and cyclization by the combined utilization of novel thiazolium- and immonium-type peptide coupling reagents 2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate (BEMT) and 5- (1H-benzotriazol-1-yloxy)-3,4-dihydro-1-methyl 2H-pyrrolium hexachloroantimonate (BDMP) as well as compound 2-bromo-1-ethyl pyridinium tetrafluoroborate (BEP). BEMT and BEP, which have been proven to be very efficient for the coupling of peptide segments containing N-alkylated amino acid residues with respect to the fast reaction speed, low racemization, and high yields, were used to construct hindered amide bonds in CsO with the addition of HOAt, whereas the most efficient HOBt-derived immonium type reagent, BDMP, was used to perform the coupling of coded amino acids in CsO. Thus, the highly hindered protected 8-11 tetrapeptide 25 was successfully synthesized using BEMT in 65% yield, and the 1-7 heptapeptide 21 was obtained in 52-55% yield by the rationally combined utilization of BDMP, BEMT, and BEP. The synthesis of the linear undecapeptide 27 of CsO in the solid phase using BEMT and BEP was accomplished for the further evaluation of the effectiveness of these reagents.
- Li, Peng,Xu, Jie Cheng
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p. 2951 - 2958
(2007/10/03)
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- A novel thiazolium type peptide coupling reagent for hindered amino acids
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A highly efficient coupling reagent, 2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate (BEMT), was designed, synthesized and successfully applied to the synthesis of oligopeptides containing N-alkyl or α-C-dialkyl amino acids. Its efficiency was evaluated by HPLC and 1H NMR methods, and demonstrated by synthesis of a number of N-methyl-rich peptide segments with good yields and negligible racemization. The mechanism of coupling was studied by HPLC, 1H NMR and IR monitoring; it is proposed that labile (acyloxy)thiazolium salts and N-protected amino acid bromides were the major active intermediates with concomitant formation of N-ethyl-4-methyl thiazolidones and a small amount of oxazolones and N-protected amino acid anhydrides.
- Li, Peng,Jie, Cheng Xu
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p. 8301 - 8304
(2007/10/03)
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- CF3-NO2-PyBOP: A New and Highly Efficient Coupling reagent for N-Methyl Amino Acids
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1-hydroxy-4-nitro-6-(trifluoromethyl)benzotriazole-containing phosphonium salt CF3-NO2-PyBOP (1h) proved to be a powerful reagent for in situ coupling of N-methylated amino acids.
- Wijkmans, J.C.H.M.,Blok, F.A.A.,Marel, G.A. van der,Boom, J.H. van,Bloemhoff, W.
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p. 4643 - 4646
(2007/10/02)
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- Coupling N-Methylated Amino Acids Using PyBroP and PyCloP Halogenophosphonium Salts: Mechanism and Fields of Application
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PyBroP (1) and PyCloP (2), two halotripyrrolidinophosphonium hexafluorophosphates, are peptidecoupling reagents highly efficient for coupling N-methylated amino esters, in contrast with PyBOP (3), the hydroxybenzotriazolyl analogue.These halogenophosphonium salts 1 and 2 are convenient (one-pot reactions) stable solids soluble in conventional solvents.Use of them gave an excellent peptide yield with essentially no epimerization.Activation with these reagents probably involves the formation of an (acyloxy)phosphonium, as shown in the case of 2,4,6-trimethylbenzoic acid activation.In the case of reagents 1 and 2, oxazolone and/or a symmetrical anhydride were intermediates which were rapidly aminolyzed.In contrast, the benzotriazolyl ester intermediate which was formed with PyBOP (3) was poorly reactive with N-methylated amino esters.PyBroP (1) and PyCloP (2) were less efficient in the coupling of some Boc-amino acids because of N-carboxyanhydride formation; this was particularly the case when Boc-Val-OH or Boc-MeVal-OH was coupled with MeVal-OMe.
- Coste, Jacques,Frerot, Eric,Jouin, Patrick
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p. 2437 - 2446
(2007/10/02)
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- N-methyl N-carboxyanhydride: An unexpected by-product when coupling boc-n-methyl amino acids
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Activation of Boc-amino acids and Boc-N-methyl amino acids leads to the corresponding NCA. This side reaction explains the low yields obtained when coupling N-methyl amino acids. It was not observed with the Z-or Fmoc-protective groups.
- Frerot, Eric,Coste, Jacques,Poncet, Joel,Jouin, Patrick,Castro, Bertrand
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p. 2815 - 2816
(2007/10/02)
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- Oxybenzotriazole free peptide coupling reagents for N-methylated amino acids
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The main product of N-methylated amino acid coupling, when oxybenzotriazole is present in the reagent (BOP, PyBOP, HBPyU) or as an additive (DCC/HOBt), is the weakly reactive benzotriazolyl ester. On the other hand, the corresponding new halogenated reage
- Coste, Jacques,Frerot, Eric,Jouin, Patrick,Castro, Bertrand
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p. 1967 - 1970
(2007/10/02)
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- BroP: A new reagent for coupling N-methylated amino acids
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BroP (bromo tris(dimethylamino) phosphonium hexafluorophosphate) is a particularly suitable reagent for coupling N-methylated amino acids. It is stable and gives very high yields in short reaction times. Dipeptides are obtained without appreciable epimeri
- Coste,Dufour,Pantaloni,Castro
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p. 669 - 672
(2007/10/02)
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