Cyathane diterpenes possess an angularly fused unusual 5-6-7 tricyclic framework (cyathane skeleton (1), Scheme 1) with 1, 4-anti stereogenic quaternary carbon centers at the ring junctures. Most compounds in this large family show strong antibiotic activity, and more importantly, erinacines and scabronines exhibit significant stimulating activity in nerve growth factor (NGF) synthesis. Moreover, erinacine E, one of the most complex members in this family, was reported not only as a compound showing potent stimulating activity in NGF synthesis but also as a selective agonist of κ-opioid receptor. For the enantioselective total syntheses of cyathanes, we have developed a convergent synthetic approach using two devised chiral fragments, Fragments A and B. Fragment A was prepared via the catalytic asymmetric intramolecular cyclopropanation of the α-diazo-β-keto sulfone developed by us (Scheme 2). Fragment B was derived from the optically pure building block originally prepared by the baker's yeast-mediated asymmetric reduction of the prochiral cyclohexan-1, 3-dione (Scheme 3). We prepared enantiopure 8 via the coupling reaction of Fragment A and B, followed by ring-closure via the intramolecular aldol reaction. Further transformations from 8 via ring expansion completed the first total synthesis of (+)-allocyathin B_2 (Scheme 4). The trans-fused B, C ring juncture in cyathanes was stereoselectively constructed via the SmI_2 mediated conjugate reduction of enone 9 utilizing the β-oriented C14 hydroxy group as a proton source. Through the key steps, that is, SmI_2 mediated ring expansion, stereoselective vanadium-catalyzed epoxidation, and regioselective cleavage of the epoxide, total syntheses of (-)-erinacine I and (-)-cyathin A_3 were successfully achieved (Scheme 5). Glycosylation reactions of aglycon 18 with several xylose derivatives were extensively surveyed and, finally, we found that MeOTf mediated glycosylation of 18 with 19 stereoselectively provided the desired product to accomplish the first total syntheses of (-)-erinacine B and C (Scheme 6). Further synthetic studies on (-)-erinacine E, (-)-scabronine A, and (-)-cyanthiwigin F are now in progress, and the results obtained till the symposium will be discussed in the presentation.
