Angiogenesis inhibitors are promising drugs for the treatment of angiogenesis-related diseases including cancer. We have recently reported the isolation and structural determination of unique pentaketide dimers, epoxyquinols A (1) and B (2), which show anti-angiogenic activity, but have different structural properties from the known angiogenesis inhibitors. To facilitate elucidation of the mechanism of action of epoxyquinols A (1) and B (2), the development of a method for their total synthesis and derivatization is highly desirable. Though structurally epoxyquinols A and B have a highly functionalized and complicated heptacyclic ring system containing 12 stereo-centers, biosynthetically it is proposed they are formed via an unusual oxidative dimerization of the much simpler epoxycyclohexenone 3. The synthesis starts from the Diels-Alder reaction between furan and chiral dienophile, planned to establish the correct stereochemistry and introduce all the carbon atoms except those in the side chain. The combination of HfCl_4 and the chiral acrylate ester of Corey's auxiliary enables the highly diastereoselective Diels-Alder reaction of furan, which established the correct stereochemistry. All 12 chiral centers of epoxyquinols A (1) and B (2) are controlled by the highly diastereoselective reactions in the route from the initial Diels-Alder product. Iodolactonization followed by hydrolysis and epoxidation gave the endo epoxide 3 in high yield. The stereoselective epoxidation of the homoallylic alcohol and α-iodination of the cyclohexenone were key steps to form the monomer 3. Practical synthetic route of the monomer 3 was also developed: Column chromatography-free synthesis of iodolactone 6 from furan and acryloyl chloride, and lipase-catalyzed kinetic resolution of racemic cyclohexenol (±)-8 enabled the multi-gram synthesis of both enantiomers of the monomer 3. Epoxyquinols A (1) and B (2) were synthesized from the monomer 3 by the biomimetic oxidative dimerization; MnO_2 oxidation of the primary hydroxy group of the monomer 3 without protection of the secondary hydroxy group affords aldehyde 17. The subsequent 6π-electrocyclization proceeds smoothly, providing dienone derivative 18a and 18b, which dimerize to give epoxyquinols A (1) and B (2) in 40% and 25% yield, respectively.
