Cycloisomerization reactions of enamides and related compounds using platinum(II), gold(I), and silver(I) salts to form complex ring systems : the total synthesis of (+)-fawcettidine

This dissertation presents investigations of enamides as π-nucleophiles within the context of electrophilic platinum(II) and gold(I) salt catalyzed cycloisomerization reactions. Chapter 1 provides a brief overview of electrophilic metal salt catalyzed cycloisomerization reactions with a primary focus on platinum, gold, and silver salts. Chapter 2 describes the first total synthesis of Lycopodium alkaloid (+)-fawcettidine (2.5), completed in sixteen synthetic operations from (R)-(+)-pulegone (2.56). The feature reaction in the sequence was a platinum(II)-catalyzed annulation of highly functionalized bicyclic enamide 2.124 to give tricycle 2.125. This annulation reaction installed the quaternary stereocenter, placed the double bond of the enamine in the correct position, and formed an exocyclic alkene which was amenable to further manipulation. A thiolate anion addition to an enone and a Ramberg-Backlund reaction were other noteworthy steps for the completion of the synthesis of (+)-fawcettidine. Chapter 3 describes the platinum(II)- and gold(I)-catalyzed cyclorearrangement of 1,2,3,4-tetrahydropyridine derivatives containing an aromatic substituted alkyne moiety tethered at the 3-position of the ring. The reactions proceeded by a tandem cycloisomerization/Friedel-Crafts addition process resulting from an initial 6-endo-dig cyclization, forming nitrogen-containing tetracyclic scaffolds featuring a quaternary carbon center. The 5-exo-dig mode of cyclization was observed to be a minor pathway. Platinum(II)-catalyzed cycloisomerization reactions formed the products in 51-98% yield. Gold(I)-catalyzed cycloisomerization reactions were lower yielding. An unexpected azocine derivative was observed when an enamide substrate was treated with 20 mol% of silverhexafluoroantimonate(V). Chapter 4 describes the platinum(II)- and gold(I)-catalyzed cycloisomerization/Friedel-Crafts tandem process of acyclic enamine derivatives featuring 1-arylalkynes. Four tricyclic products were observed: two products were formed by initial 6-endo-dig (major pathway) or 5-exo-dig (minor pathway) cyclization. The alkene of the 6-endo product frequently isomerized under the reaction conditions to form a 1-aza-substituted indene derivative, and the 5-exo product often eliminated to form substituted naphthalene derivatives. Catalysis with a platinum(II) salt, a gold(I) species derived from the mixture of triphenylphosphine gold(I) chloride and silver hexafluoroantimonate(V), or [(2-biphenyl-bis-tbutylphosphine)Au(I)・NCCH₃]⁺SbF₆⁺⁻(1.70) gave mixtures of products in 21-100% yield. Gold(I) catalyst 1.70 was the most effective of the catalysts tested.Science, Faculty ofChemistry, Department ofGraduat