Part I: Total synthesis of the furanosteroid viridin. Part II: Development of a palladium-catalyzed aminoacetoxylation of alkenes

Reactive natural products that possess the ability to alkylate nucleophilic residues in an enzyme active site can yield insights into the cellular functions of key enzymes. Viridin is the parent member of a family of natural products that includes wortmannin, viridiol, and demethoxyviridin, each of which covalently inhibits protein function. These natural products are distinguished by an unusual structural feature: an electron deficient furan ring fused between C-4 and C-6 of the steroid framework. The doubly-activated carbon of this heterocycle predisposes these compounds to react efficiently with a range of amines including the active site lysine of phosphatidylinositol 3-kinase. A total synthesis of (+/-)-viridin is described. Our strategy features an efficient rhodium-catalyzed alkyne cyclotrimerization, a high-yielding thermal electrocyclic rearrangement, and a late-stage Donohoe dihydroxylation.; Following our synthesis of viridin, we studied new methods for alkene difunctionalization that would facilitate a synthesis of the cytotoxic bisguanidine alkaloid palau'amine. These efforts resulted in the development of a mild, palladium(II)-catalyzed ring-forming aminoacetoxylation of alkenes. Treatment of a range of nitrogen nucleophiles with catalytic palladium(II) in the presence of iodobenzene diacetate as oxidant resulted in alkene aminoacetoxylation, affording a variety of nitrogen-containing heterocycles. Our studies indicate that high levels of reaction regio- and stereocontrol may be possible. It appears that this is a stereoselective trans alkene difunctionalization and thus is a useful alternative to related cis-selective, metal-catalyzed alkene aminohydroxylation processes.