Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline

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. 

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. 

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]). 

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

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. 

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. 

Reagents i, MeCHClCOjMe-Na/K alloy ii, HO ill, MeCHCOaBn-A -ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline iv, hydrolysis... 

The reaction is usually carried out with one equivalent of a tertiary base (EtsN or N-methylmorpholine) in dichloromethane. As a rule, the activation time is not high (from 25 min to 2 h), though this process occurs at a low temperature (—15°C—0°C). Generally, the duration of the second step is 12 h and the yields of the pure amides 109—119 are 53—88%. The mixed ethyl carbonic anhydrides can also be generated by the reaction of carboxylic acids with EEDQ (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) in the presence of the amines (99). This approach allows amides 121 and 122 to be obtained in high yields (Scheme 24.14, Table 24.5) (74). 

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