1 -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

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

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. 

S.P. solid-phase technique L.P. liquid-phase technique OPTcp pentachlorophenyl ester TEEP tetraethyl pyrophosphit OTCp trichlorophenyl ester ONp p-nitrophenyl ester ONSu N-hydroxysuccinimido ester OPFp pentafluorophenyl ester OQu 8-hydroxyquinyl ester OPy 3-hydroxy-pyridyl ester ODnp 2,4-dinitrophenyl ester DCC dicyclohexylcarbodiimide HOBn 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazin Opi JV-hy-droxypiperidine EEDQ 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline Tos p-toluenesulfonyl PTC propanetricarboxylic acid OBu tm-butyl ester Nva norvaline Aha aminohexanoic acid Om ornithine... 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) and IIDQ (2-isobutyloxy-l-isobutyloxycarbo-nyl-1,2-dihydroquinoline) are agents which produce mixed anhydrides. EEDQ is a selective and efficient coupling reagent. 

To further exploit the potential usefiilness of this new family of clusters, monoadduct 54 was saponified into 55 (0.05 M NaOH, quant) and condensed to L-lysine methyl ester using 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ) to give extended dimer 56 in 50 % yield together with monoadduct in 15 % yield [75]. Additionally, tert-butyl thioethers 52 could be transformed into thiols by a two step process involving 2-nitrobenzenesulfenyl chloride (2-N02-PhSCl, HOAc, r.t, 3h, 84%) followed by disulfide reduction with 2-mercaptoethanol (60%). Curiously, attempts to directly obtain these thiolated telomers by reaction with thioacetic acid f ed. These telomers were slightly better ligands then lactose in inhibition of binding of peanut lectin to a polymeric lactoside [76]. 

In addition to the typical cyclization procedures described above, methods involving the use of other mild, cyclodehydrating agents have been published. For example, cyanuric chloride in the presence of triethylamine, 2-ethoxy-A-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ) or 2-isobutoxy-A-isobutoxy-carbonyl-1,2-dihydroquinoline (IIDQ), ° A,A-dimethylchlorosulfitemethanimi-... 

C were suspended in toluene/CH2Cl2 (40 mL, 50/50 v/v%) and 3-aminopropyltriethoxysilane (0.88 mL, 0.00379 mol) was added. The mixture was heated overnight at reflux, cooled, and filtered to recover the aminopropyl-APMS, which were then washed with toluene and MeOH. These were then reacted with R-(-)-3,5-dinitrobenzoyl-a-phenylglycine (2.657 g, 0 0075 mol) in toluene/CH2Cl2 (40 mL, 50/50 v/v%) to which N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (0.875 g, 0 0075 mol) had been added to catalyze the reaction. After stirring overnight, the solid was recovered by filtration and washed with toluene and MeOH to afford the product as a yellow powder (2 792 g). 

The synthesis of CMDBSSu involves the random carboxymethylation of hydroxyl groups on the glucose units, the benzylamidation of some of the carboxylic groups with benzylamine in the presence of N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ) to carboxymethyl dextran benzylamide (CMDB), the sulfonation of phenyl rings and sulfation of remaining hydroxyl groups at the polymer backbone (Fig. 39, [108,222]). 

TV-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), only one nucleoside product was formed. A comparison to authentic casimiroedine showed it to be identical (137). The cis analog of the alkaloid was obtained similarly from 82 and m-cinnamic acid. Cytostatic activity of casimiroedine has been reported (137). 

AMIDES N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ). Silicon tetrachloride. Sodium hydride-Dimethylsulf-oxide. Triphenyl phosphite. 

Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) activates acids via a mixed anhydride and generates quinoline, ethanol, and carbon dioxide as by-products. As with EDCI, the by-product quinoline of the reaction can be extracted into an aqueous acidic medium. 

An ethyl carbonate, prepared and cleaved by conditions similar to those described for a methyl carbonate, was used to protect a hydroxyl group in glucose. Ethyl chlo-roformate in pyridine or CH2CI2/TEA is the most common method of preparation for this carbonate. The carbonate may be prepared by exchange with diethyl carbonate in the presence of a MgLa mixed oxide catalyst. The carbonates of 2-hydroxycar-boxylic acids may also be prepared by the reaction of 2-ethoxy-l-(ethoxycarbonyl)-1,2-dihydroquinoline (EEDQ). These carbonates can also be cleaved enzymatically with Lipase B from Candida antarctica (phosphate buffer, pH 7, 30-60°C)." ... 

RCO2H, desired alcohol as solvent, 2-ethoxy-l-ethoxy-l-(ethoxycarbonyl)-l, 2-dihydroquinoline (EEDQ), 5h to overnight, rt, reflux, 56-95% yield. Amino acids are not racemized. ... 

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. 

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