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amphotericin B N-(D)-methoxytryptophanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.85%
With diphenyl phosphoryl azide; triethylamine; In N,N-dimethyl acetamide; at 20℃;
Example 7 Synthesis of Amide 7: N-(D)-tryptophanamide of AmB In another preferred embodiment the invention provides the AmB analogue denominated amide 7: N-(D)-tryptophanamide of AmB, represented by formula VII; using D-tryptophan as the starting amine. Fort this derivative the same structural aspects of the synthesis of amide 6 were taken into account and it was observed in its synthesis the possible effect on the antibiotic activity that has the change in the stereochemistry of this derivative regarding amide 6. For L-tryptophan and D-tryptophan, before the amide synthesis, it was necessary to perform the sterification reaction of the carboxylic acid to protect it in form of hydrochloride of the methyl ester of tryptophan. This synthesis was performed by reacting 1 equivalent of the amino acid L-tryptophan or D-tryptophan (L-Trp or D-Trp) with excess MeOH and 2 equivalents of Me3SiCl to procure the white precipitate of the hydrochloride of the methyl ester of L-tryptophan or D-tryptophan. Scheme 6 shows the reaction mechanism proposed for this synthesis. The first step in the reaction consists of the nucleophilic addition of the tryptophan carboxyl function (E) on the Si of Me3SiCl (F) inducing the displacement of the Cl- ion. The silicon esters (intermediates G and H) are in an equilibrium in which it is proposed that the deprotonated form is more susceptible to the nucleophilic addition of MeOH. This will form the hydrochloride of the methyl ester tryptophan with trymethylsilanol as a byproduct of the reaction. The hydrochloride of the tryptophan methyl ester is used for the synthesis of the amides of AmB incorporating only an excess of Et3N as basic reagent in the method of Jarzebski. This liberates the form of the methyl ester of the tryptophan to act as amine in the reaction. It is reported that by incorporating the tryptophan structure in AmB polyene molecules they fluoresce under UV light. The tryptophan methyl ester was used for the synthesis of AmB amides as a means to procure amides that fluoresce under UV light. This is a desirable characteristic for experiments of electrophysiology in unit channel as because of this, the channels would present this type of fluorescence. Characterization of Amide N-(D)-tryptophanamide of AmB. The IR spectrum of the product is almost identical to that of amide 6, showing only slight differences in the intensity of the signals. The derivative had a value of Rf=0.62 for which it is qualitatively considered that this product is non-polar regarding AmB. These two results help confirm that amide 7 has the same structure of amide 6, and its epimer. During the process of purification of amide 7 two products were isolated: amide 7a and amide 7b. The IR spectra of both amides have a similar difference to that of amide 2a and amide 2b in the absorption band of the polyhydroxylated chain. Here the difference in the intensity of the bands is not too large. Because of this it is believed that this is the same structure, and it is supposed that the solvation with ether (of the purification) occurred in the polyhydroxylated chain for the amide 7b. Moreover, it is likely that the antibiotic behavior is diminished because the actual concentration of the derivative could be less than that contemplated in the preparation of the amide solution. It is noteworthy that the rest of the spectra of both products are the same. Here, being the epimer (D) of the N-(L)-tryptophanamide, the same values of the derivative 6 are contemplated. Therefore, this synthesis is to determine whether the difference the epimers (L)-(D) stereochemistry will affect the antibiotic activity.
Chemistry
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