Total syntheses of fastigiatine and the hibarimicin aglycons

Part one of this two-part thesis describes my efforts toward the total syntheses of the complex polycyclic alkaloids (--)-himeradine A and (+)-fastigiatine, which are members of the Lycopodium family of natural products. A cascade reaction sequence featuring a biosynthesis-inspired transannular Mannich reaction was planned to construct the strained and densely functionalized pentacyclic cores of the molecules from acyclic starting materials. After difficulties were encountered in a first-generation synthesis plan toward (--)-himeradine A, a second-generation synthesis plan was eventually successful in accomplishing the first total synthesis of (+)-fastigiatine via a formal [3+3]-cycloaddition reaction and a retro-aldol tandem transannular Mannich reaction sequence.;In part two of this thesis, syntheses of the hibarimicin aglycons, including HMP-Y1, atrop-HMP-Y1, hibarimicinone, atrop-hibarimicinone, and HMP-P1, are reported. These natural products are amongst the largest and most complex type-II polyketides isolated. A novel benzylic fluoride Michael-Claisen reaction sequence was developed to construct the complete carbon skeleton of HMP-Y1 and atrop-HMP-Y1 via a symmetrical bidirectional double annulation reaction. Through efforts to convert HMP-Y1 derivatives to hibarimicinone and HMP-P1, a biomimetic mono-oxidation to desymmetrize protected HMP-Y1 was realized. A bidirectional unsymmetrical double annulation and biomimetic etherification were developed to construct the polycyclic and highly-oxidized skeleton of hibarimicinone, atrop-hibarimicinone, and HMP-P1. Lastly, a pH-dependent rotational barrier about the C2-C2' bond of hibarimicinone was discovered, which provides valuable information for achieving the syntheses of the glycosylated congeners of hibarimicinone.