2-Ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline, peptide

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. 

PEPTIDE-BOND FORMATION FROM 1-ETHOXYCARBONYL-2-ETHOXY-1,2-DIHYDROQUINOLINE-MEDIATED REACTIONS OF /V-ALKOXYCARBONYLAMINO ACIDS... 

Peptide synthesis /-Amyl chloroformate. Bis-(2,4-dinitrophenyl)carbonate. Bis-o-phenylene pyrophosphite. i-Butyl chloroformate. sec-Butyl chloroformate. /-Butyl chloroformate. /-Butyl 2,4,5-trichlorophenyl carbonate. CopoIy(ethylene-N-hydroxymaleimide). N,N-Diethyl-I-propynylamine. Di-(p-nitrophenyl)sulfate. Ethoxyacetylene. N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline. N-Ethylbenzisoxazolium fluoroborate. Ethyl chloroformate. N-Ethyl-5-phenylisoxazolium-3 -sulfonate. N-Hydroxysuccinimide trifluoroacetate. Methyl-morpholine. 4-Methylthiophenol. p-Nitrophenol. Oxalylchloride. Pentachlorophenol. Pentamethylbenzyl chloride. /-Pentyl chloroformate. Phenacyl bromide. Polyhexamethylene carbodiimide. Tetraethyl pyrophosphite. 1,2,4-Triazole. 

PEPTIDE SYNTHESIS r-Amyl chloro-formate. f-Butyl azidoformate. Diethyl methyleneraalonate. N-Ethoxycarbonyl-2-ethoxy-l,3-dihydroquinoline. Hexamethylphosphoric triamide. 1-Hydroxybenzo triazole. Triphenylphosphine—2,2 -Dipyridyl disulfide. Triphenyl phosphite. 

At the University of Ottawa the work of L. Benoiton and his students, especially F.M.F. Chen, gained major importance in the study of racemization during peptide synthesis. The loss of chiral purity in activated AT-methylamino acids is one of their numerous contributions. l-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ), the coupling reagent mentioned on page 91 was introduced in 1968 by B. Belleau and Malek at Ottawa. 

Brown and Williams (1971) and Williams et al. (1972) described the preparation of the polymeric reagent based on EEDQ (2-ethoxy-1-ethoxycarbonyl-l,2-dihydroquinoline) (Scheme 12-21) and used it to couple peptides. It was found to give clean products in high yields, and the reactions proceeded with little racemization. The recent was also regenerable. 

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