Peptide synthesis, coupling reagents

Peptide synthesis. The reagent effects coupling of an N-protected amino acid with an amino acid ester or peptide in yields usually -90% and with low racemization. 

Asymmetric Peptide Synthesis. The reagent activates amino acids through 1,3-Dicyclohexylcarbodiimide (DCC) coupling to the N-hydroximide for subsequent coupling with chiral amino acids. The asymmetric center induces preferential reaction with L-amino acids and high optical purities of L-L-dipeptides can be achieved (eq 2). Enantioselectivity is improved if the 5-methyl group is replaced by isobutyl. ... 

Peptide synthesis. The reagent effects coupling of acylamino acids with amino acid esters in DMF and triethylamine at -10 to 0° in 80-97% yields. Racemization according to the test of Young is less than 3%. The condensation involves the intermediate formation of an acyl azide, which has been isolated... 

Peptide synthesis. The reagent (1) is obtained from the corresponding chloro derivative by treatment with excess anhydrous KF in MeCN. It is nonhygroscopic and ideal for solid-phase coupling. Peptides of high purity are obtained in good yields. 

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

Triisopropylbenzenesulfonyl)-3-nitro-1,2,4-triazole in the presence of 4-rtiorpholine pyridine-1-oxide was used with advantage as a coupling reagent for a solid-phase (p-alkoxybenzyl ester type resin) synthesis of peptides such as Leu-AIa-Gly-Val-OH or Leu-enkephalinamide (Tyr-Gly-Gly-Phe-Leu-NHs). The overall yield in the latter case was 70%, the purity of the peptide was 85-90%, and racemization was virtually zero.[38]... 

Y Kiso, H Yajima. 2-Isobutoxy-l-isobutoxycarbonyl-l,2-dihydro-quinoline as a coupling reagent in peptide synthesis. J Chem Soc Chem Commun 942, 1972. 

S Chen, J Xu. A new coupling reagent for peptide synthesis. Benzotriazol-yl-bis(pyr-rolidino)-carbonium hexafluorophosphate (BCC). Tetrahedron Lett 33, 647, 1992. 

NL Benoiton, Y Lee, FMF Chen. Isopropyl chloroformate as a superior reagent for mixed anhydride generation and couplings in peptide synthesis. Int J Pept Prot Res 31, 577, 1988. 

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