L-ethoxycarbonyl-2-

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. 

FIGURE 2.15 Peptide-bond formation from l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquino-line-mediated reactions of A-alkoxycarbonylamino acids.46 The intermediate is the mixed anhydride that is slowly generated in the presence of the attacking nucleophile without a tertiary amine having been added. 

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. 

Coupling the substituents to the polyacid core is a key step. The reaction must have a high yield to limit purification problems and show high selectivity between the amines and alcohols present to limit side reactions. The amidifica-tion reaction chosen is a coupling reaction used in peptide chemistry. The reaction is carried out at room temperature in the presence of a coupling reagent such as NjAT -dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcar-bodiimide or l-ethoxycarbonyl-2-ethoxyl-l,2-dihydroquinoline, possibly in the presence of an activator such as hydroxybenzotriazole or N-hydroxysuccimide (Fig. 8). 

Two other azepine syntheses involving the interconversion of valence isomers are worthy of note, namely the isomerization of the novel 7-azatetracycloheptane (261), prepared from benzvalene as indicated in Scheme 34, to 1-phenyl-Iff-azepine (79TL1553) and the rearrangement of the syn isomer of the 2-azatricycloheptane (70 H in place of D), which at 120 °C yields l-ethoxycarbonyl-2,3-dihydro-Iff-azepine by a [w2s+ 4,] concerted process. As expected, the anti isomer, for which a concerted process would require a geometrically unfavoured [ 2a + w4a] process, rearranges only at 350 °C, and then by a non-concerted polar reaction (73JA7320). 

Equimolar amounts of nitroalkene, CaO and ethyl[(4-nitrobenzenesulfonyl)oxy]-carbamate were ground in a mortar. After 20 min petroleum ether was added to precipitate the salt. After filtration, the crude mixture was concentrated in vacuo and the l-(ethoxycarbonyl)-2-nitroaziridines were purified by flash chromatography on silica gel (hexane-ethyl acetate, 8 2). 

Azepine, resonance energy, 56, 364, 378 Azepine, 1-t-butyliminomethyl-1,2,3,4-tetrahydro-, lithiation, 56, 273 l//-Azepine, l-ethoxycarbonyl-2,3,4,5,6,7-hexafluoro-, formation, photolysis,... 

Dithiocarboxy- E5, 906 (Ar—CC13 + H2S) l-(l-Ethoxycarbonyl-2-al keny 1 iden)-E14b, 122 (1-Alkyl-pyridinium-Salz + En-X)... 

Triazan l-Ethoxycarbonyl-2-isopropyl-3-isopropyliden-EI4b,719 [R — N = N — R + R00C-NH-0-S02-R)... 

Dithian 2-(l-Ethoxycarbonyl-2-oxo-propyl)- E14a/3, 466 [2-(2-Oxo— 1-COOR —propyli-den)—1,3-dithian + Mg R-SOjH]... 

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