Synthesis of a Macrocyclic Conjugate of the Diterpenoid Isosteviol and Glucuronic Acid

Abstract

A macrocyclic conjugate of the natural diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) and glucuronic acid was synthesized for the first time. The conjugate contained two molecules of dihydroisosteviol E-D-glucuronoside joined by 1, 8-octanedicarboxylate and 1,8-octanedicarbazoyl spacers. We recently reported the synthesis of the first conjugate of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) and glucuronic acid [1] in which two molecules of the isosteviol derivative dihydroisosteviol (16-hydroxy-ent-beyeran-19-oic acid) functionalized at the carboxyls by E-D-glucopyranuronoyl residues were connected by a 1,6-hexanedicarboxylate spacer. In continuation of research on the synthesis of macrocyclic glycoterpenoids [2], herein we present results for the synthesis of a macrocyclic conjugate of isosteviol and glucuronic acid. We used the methodology for synthesizing macrocyclic isosteviol derivatives [3,4] in which two dihydroisosteviol molecules were first bound through the hydroxyls by reacting them with carboxylic acid chlorides. The resulting diacids (e.g., diacid 4 in Scheme 1) were converted to macrocycles by reacting their carboxylic acid chlorides with diols.The starting carbohydrate component was D-(+)-glucurono-3,6-lactone (1), which was easily converted to methyl-1,2,3,4-tetra-O-acetyl-E-D-glucopyranuronate (2) as before [5]. The methyl-1-deoxy-1-bromo-2,3,4-tri-O-acetyl-E-Dglucopyranuronate 3 that was obtained from it by the literature method [6] was then reacted with diacid 4 in refluxing CH 2 Cl 2 in the presence of tetrabutylammonium bromide (TBAB) and potash. Bisglucuronide 5 was obtained in 56% yield. Its anomeric protons appeared in the PMR spectrum as a single doublet at 5.73 ppm with vicinal SSCC 8.02 Hz. This indicated convincingly that the glycoside bonds had the E-orientation.In fact, the anomeric proton of methyl 1,2,3,4-tetra-O-acetyl-E-D-glucopyranuronate 2 resonated as a doublet at 5.73 ppm with vicinal SSCC 7.8 Hz [6] whereas the anomeric proton of the corresponding D-D-glucopyranuronate was found as a doublet at 6.34 ppm with SSCC 3.7 Hz [5]. Then, bisglucuronoside 5 was reacted at room temperature with hydrazine hydrate as before [7]. The PMR spectrum of the product, which was obtained in 90% yield, lacked the strong singlets corresponding to acetate resonances at 1.96, 1.98, and 1.99 ppm and the ester methyls of the glucopyranuronates at 3.68 ppm, which were observed in the spectrum of 5. A multiplet that was characteristic of the hydrazide NH proton appeared at 7.69-7.73 ppm. All these data combined with MALDI mass spectral data indicated that dihydrazide 6 had formed. The reaction did not affect the carbohydrate anomeric centers. Therefore, the glycoside bonds in 6 retained the E-orientation. Its glucuronate anomeric protons resonated as a single doublet at 3.78 ppm with SSCC 9.63 Hz, which agreed with the literature for various E-glycosides of non-acylated glucuronic acid methyl ester (e.g., G 4.26 ppm and 3 J = 9.4 Hz [8]) and with previous work [9] in whic...

Last Step towards Macrocyclic Glycoterpenoids Having Isosteviol and Glucosamine Moieties

“…One can see that the interaction of deprotected amino groups of glucosamine residues of diglycosides 14, 15, 18, 19 with bielectrophilic reagents will lead to their macrocyclization, and macrocyclic glycoterpenoids analogous to already known macrocycles [4][5][6][7] will be obtained. These reactions are currently being studied and will be reported soon.…”

“…Recently the first syntheses of open chain and macrocyclic glycoterpenoids having one or several diterpenoid moieties bonded with various carbohydrate residues, namely D-glucopyranose [1,2] , glucuronic acid [3][4][5] or trehalose [6,7] have been reported. In continuation of these investigations 2-deoxy-2-amino-D-glucopyranose (glucosamine) was chosen as the next carbohydrate block for macrocyclic glycoterpenoids.…”

The First Macrocyclic Glycoterpenoid Having Glucosamine and Isosteviol Moieties

“…[1][2][3][4] It was found that these macrocycles inhibited the in vitro growth of H37Rv strain of M. Tuberculosis at the minimal inhibition concentration (MIC) value of 12.5 mg/mL that is comparable to the activity of antitubercular drug pyrazinamide. [3,4] Herein, the synthesis of the first macrocyclic glycoterpenoid having isosteviol and glucosamine residues is reported.…”

“…[3,4] Herein, the synthesis of the first macrocyclic glycoterpenoid having isosteviol and glucosamine residues is reported. We followed the previously proposed approach [1] according to which the terminal reactive groups of binuclear isosteviol derivative are functionalized with carbohydrate residues, and these ones then are coupled by any linker. The diol 1 [4] was used as a starting compound in which two isosteviol molecules were bonded to each other with an octamethylene linker attached to their C(16) atoms, while carboxyl groups of these isosteviol moieties were functionalized by 6-hydroxyhexyl chains.…”