Total syntheses of anti-HIV natural product daurichromenic acid, rhododaurichromanic acids A and B; syntheses of anticancer natural products OSW-1 and its analogs; and studies toward the total synthesis of anticancer natural products superstolide A.

摘要

Daurichromenic acid and its two novel chromane derivatives rhododaurichromanic acids A & B were isolated from the leaves and twigs of Rhododendron dauricum. These compounds exhibit potent anti-HIV activity and are considered to be potential new leads for the development of anti-HIV agents. Employing our newly developed synthesis of 2H -benzopyrans via microwave-assisted tandem condensation followed by intramolecular SN2' cyclization, we have completed the total syntheses of these three compounds. Our total synthesis of daurichromenic acid consists of only 5 linear operations with 51% overall yield, which will enable us to prepare multigrams materials for further biological studies.; OSW-1 is a natural saponin and its anticancer activities are 10- to 100-fold more potent than many well-known anticancer agents in clinical use. Its cytotoxicity profile suggests that it may have a unique mode of action that is different from other well-known anticancer agents. However, its mechanism still remains as a mystery after years of study. Employing the synthetic approach (total 33 steps) developed in our laboratory more than 250 mg of OSW-1 have been prepared that is used in the biological studies. Experiments have shown that mitochondria are involved in OSW-1's action. To identify its exact cellular target(s) and determine its novel mechanism of action, the synthesis of biotinylated-OSW-1 has been successfully completed (total 42 steps). In addition, several analogs of OSW-1 for the study of its SAR have also been prepared. These analogs are being tested in Prof. Huang's laboratory at MD Anderson Cancer Center.; Superstolide A is a potent anticancer marine natural product. The complex molecular structure provides formidable synthetic challenge, and no total synthesis has yet been reported. To supply sufficient quantities of the target material for future biological studies, a highly efficient synthesis of this complex molecule (11 stereocenters, 6 double bonds, 3 rings, and 5 different functionalities) is required. Since the construction of the 16-membered macrolactone is critical in our synthetic strategy, it is necessary to conduct a model study for its feasibility. Currently we are working on the model study for the investigation of three crucial carbon-carbon bond-forming reactions.