Enahtioselective Formal Total Syntheses of Didehydrostemofoline and Isodidehydrostemofoline through a Catalytic Dipolar Cycloaddition Cascade

摘要

Plants of the Stemonacea family, which are indigenous to a number of areas in Southeast Asia, have long been used in traditional oriental medicine for treating a variety of ailments. Extraction of the roots and leaves of these plants have yielded a number of biologically active alkaloids that have been targets of many synthetic investigations.'21 Arguably the most complex members of the Stemona alkaloids are those belonging to the stemofoline family, which are characterized by a densely functionalized, caged hexacyclic architecture and differ in the geometry of the C1-C12 double bond and the oxidation state of the butyl side chain at C3 (Figure 1). These alkaloids, which were first reported by Irie and co-workers in 1970 and later isolated from other Stemona species, exhibit strong insecticidal activity because they act as insect acetylcholine receptor antagonists. Didehydrostemofoline (1) is not only the most potent acetylcholine receptor antagonist, but it also exhibits in vivo anti-oxytocin activity as well as antitumor activity against gastric carcinoma. A recent study has shown that stemofoline (2) increases the sensitivity of anticancer drugs such as vinblastine, paclitaxel, and doxorubicin by reversal of P-glycoprotein mediated multi-drug resistance. A number of semisynthetic analogs of these alkaloids have been prepared and found to exhibit acetylcholinesterase inhibitory activity.