A thermal 6pi electrocyclization strategy towards taiwaniaquinoids. First enantiospecific synthesis of (-)-taiwaniaquinone G.

The first route towards taiwaniaquinoid terpenes bearing an A/B trans-configuration has been developed through a sequence which includes a thermal 6pi electrocyclization.

A very efficient route toward the 4a-methyltetrahydrofluorene skeleton: short synthesis of (+/-)-dichroanone and (+/-)-taiwaniaquinone H.

A very expedient and efficient new route toward taiwaniaquinoids, bearing the 4a-methyltetrahydrofluorene skeleton, is reported. Key steps are the intramolecular Friedel-Crafts alkylation of an aryldiene and the degradative oxidation of a methylenedioxy group; the latter process could also be utilized for building the 2-hydroxy-1,4-benzoquinone unit, which is frequently found in natural products. Utilizing this new methodology, (+/-)-dichroanone (7) (three steps, 77% overall yield) and (+/-)-taiwaniaquinone H (6) (four steps, 70% overall yield) have been synthesized from commercial alpha- (11a) or beta-cyclocitral (11b).

An enantiospecific route towards taiwaniaquinoids. First synthesis of (-)-taiwaniaquinone H and (-)-dichroanone.

A new methodology for the enantiospecific synthesis of taiwaniaquinoids, based on a thermal 6pi electrocyclization, is reported. Under this procedure, 4a-methylhexahydrofluorene terpenoids bearing an A/B trans-configuration has been prepared for the first time. This methodology also makes it feasible to synthesize taiwaniaquinoids with an A/B cis-configuration and 4a-methyltetrahydrofluorene terpenoids. Accordingly, the first synthesis of (-)-taiwaniaquinone G, (-)-taiwaniaquinone H and (-)-dichroanone has been achieved.

Taiwaniaquinoid and abietane quinone derivatives with trypanocidal activity against T. cruzi and Leishmania spp.

The in vitro leishmanicidal (Leishmania infantum and Leishmania braziliensis) and trypanocidal (Trypanosoma cruzi) activities of different compounds were evaluated. These compounds, of vegetal origin but synthesised in our laboratory, included five taiwaniaquinoid derivatives (S-567; S-569; S-589; S-602 and A-246) and one abietane quinone (P-1). The in vitro activity of the compounds on extracellular and intracellular forms of the two Leishmania species and T. cruzi was assayed. Infectivity and cytotoxicity tests for the Leishmania species were conducted on J774.2 macrophage cells using Glucantime as the reference drug. From all the compounds assayed, the derivatives P-1>S-567 were more active and less toxic than Glucantime. Infection rates and amastigote means indicated that these two compounds were the most active in both Leishmania species. In the case of T. cruzi, the best derivatives were P-1 and S-567, at the same levels as for the Leishmania species. These compounds exhibited the most potent anti-proliferative activity against the extracellular vector form (the epimastigote), the extracellular host form (the trypomastigote), and the intracellular host form (the amastigote), with lower toxicity than that of the reference drug Benznidazole. Metabolite excretion studies showed that alterations mainly at the level of the mitochondria may explain observed metabolic changes in succinate and acetate production, perhaps due to the disturbance of enzymes involved in sugar metabolism within the mitochondrion. The in vivo studies for T. cruzi provided results consistent with those found in vitro. No signs of toxicity were detected in mice treated with the compounds tested, and the parasitic charge was slightly lower than in the control. The effects of these two compounds were also demonstrated with the change in the anti-T. cruzi antibody levels during the chronic stage.