Synthesis and anti-tuberculous activity of diesters based on isosteviol and dicarboxylic acids

Abstract

Diesters based on isosteviol and dicarboxylic acids were synthesized and tested for antituberculous activity. Isosteviol and some of its derivatives exhibit appreciable tuberculostatic properties in vitro, the activity being dependent on the length of the polymethylene spacer connecting two ent-beyeran fragments.The mechanism of the antituberculous action of isosteviol derivatives are discussed. 473 0091-150X/06/4009-0473

Novel Macrocyclic Derivatives of Diterpenoid Isosteviol

“…Initiating the synthesis of bi-and tetranuclear macrocyclic isosteviol derivatives we considered that exactly binuc-lear isosteviol derivatives 3 (Figure 3) obtained by interaction of dihydroisosteviol 4 with dicarboxylic acids chlorides [9] can be used as suitable starting compounds. The reason is that molecular structures of diacids 3 depend on the length of diester linker bonding two isosteviol fragments (Figure 3).…”

“…We also were sure that a reaction of diacid having unfolded structure 3b (Figure 3) with a binucleophile having the length which is much less than the distance between the COOH groups of diacid should lead exclusively to a tetranuclear macrocycle of 2d kind ( Figure 2). To examine this hypothesis we carried out the reactions of diacid 5 [9] which, according to X-ray data, [10] has unfolded structure 3b with ditosylates of 1,8-n-octanediol, 1,6-nhexanediol, and ethylene glycol (Scheme 1). To obtain diacid 5, firstly isosteviol 1 was converted to the dihydroisosteviol 4 by the reaction with NaBH 4 in CH 3 OH, [8] and compound 4 was obtained in the form of 16(R)-epimer as in many other cases.…”

“…[7,8,11a-c] Then dihydroisosteviol 4 was subjected to interaction with suberoyl chloride. In contrast with the known protocol [9] the reaction was carried out in CH 2 Cl 2 in the presence of pyridine and DMAP that allowed to increase the yield of diacid 5 up to 50 %. The reaction of diacid 5 with diols ditosylates was carried out following similar procedure as the synthesis of isosteviol esters [12] in CH 3 CN in the presence of K 2 CO 3 under reflux for 30-35 h. Surprisingly, in all cases, even in the reaction of diacid 5 with ethylene glycol ditosylate, binuclear macrocycles 7-9 appeared to be the main reaction products.…”

Synthesis of Optically Pure Macroheterocycle with Ester and Hydrazide Fragments on the Basis of l-Menthol

“…[2] Reesterification of cyclic ether 1 with methanol in presence of H 2 SO 4 gave methyl-(3R,6S)-6-hydroxy-3,7-dimethyl octanoate (2), [2+1]-condensation of which with absolute glutaric acid chloranhydride resulted in bis[(1S,4R)-1-isopropyl-6-methoxy-4-methyl-6-oxyhexyl]pentane dioate (4).…”

“…An alternative attempt to synthesize the macrocycle 5 via [2+1]-condensation of methyl-(3R,6S)-6-hydroxy-3,7-dimethyl octanoate (2) with hydrazine hydrate followed by [1+1]-condensation of the resulting 1,2-bis((3R,6S)-6-hydroxy-3,7-dimethyl-1-oxooctyl)hydrazine (3) with glutaric acid chloranhydride failed at the second stage, even with another solvent (CCl 4 was changed for 1,4-dioxane) plus the CoCl 2 catalyst previously used in [4] . The structures of the resulting acyclic compounds 3, 4 and macrolide 5 were established by IR, 1 Н and 13 С NMR spectroscopic techniques; the molecular mass was measured using chromatic mass spectrometry.…”