PHYLLANTHOSIDE PHYLLANTHOSTATIN SYNTHETIC STUDIES .7. TOTAL SYNTHESIS OF (+)-PHYLLANTHOCIN AND (+)-PHYLLANTHOCINDIOL

A stereochemically linear total synthesis of (+)-phyllanthocin (5a), the aglycon methyl ester of the antineoplastic glycoside (+)-phyllanthoside (1), is described. The synthesis proceeds in 23 steps (4.5% overall yield) and affords (+)-phyllanthocin in high enantiomeric purity. The central features of the strategy include: (a) construction of aldehyde 8 via a stereoselective, intramolecular ene reaction; (b) elaboration of the spiroketal unit by a two-step tactic involving addition of a functionalized dihydropyran anion (i.e., 9) to 8, followed by a highly stereoselective spiroketalization; and (c) chemo- and stereoselective methylenation of the C(7) carbonyl group. In addition, a second-generation approach is presented, wherein an augmented spiroketalization maneuver not only establishes the C(8) spirocenter but also permits the regio- and stereocontrolled introduction of the C(11) methyl group. The latter sequence furnishes (+)-phyllanthocin in 21 steps (5.6% overall yield). Finally, the advanced phyllanthocin intermediate (+)-49 is converted in five steps (42% overall yield) to (+)-phyllanthocindiol (5b), the aglycon of phyllanthostatin 3.