Studies directed toward the total synthesis of ingenol: A photocycloaddition/Pauson-Khand approach to the construction of the ingenane skelton

The complex structure of ingenol, 1, namely the C-8/C-10 "inside-outside" intrabridgehead stereochemistry of the B/C bicycle has made it a challenging synthetic target for over 20 years. Recently, our group achieved the first total synthesis of (+/-) ingenol, 1. This dissertation describes a second generation approach to the synthesis of 1, focusing on A-ring formation via Pauson-Khand [2+2+1] cycloaddition.*; The first approach presented herein outlines the construction of the ingenane skelelton by way of a [2+2] dioxenone photocycloaddition followed by Pauson-Khand cyclization and then retro-aldol fragmentation. Based on previous results, it was determined that a trans-bicyclo[5.2.0]nonane from the photoaddition would be necessary to assemble the desired "in-out" intrabridgehead stereochemistry of 1. During our application of this sequence, we discovered that the intramolecular [2+2] photoaddition of dioxenones with alkynes affords unexpected secondary photoproducts that are dependent upon alkynyl substitution. Most interestingly, when trimethylsilyl acetylenic alkynes are irradiated, a unique tetracyclic bridged structure is produced. A brief investigation into the scope and mechanism of this transformation is also described.; Continued investigation into the photoaddition/Pauson-Khand cyclization sequence toward 1 highlights the elusive nature of the desired transbicyclo[5.2.0]nonane. In this study, efforts were directed toward the diastereocontrol of the [2+2] photoaddition through asymmetric induction of substituents on the hydrocarbon tether.; Ultimately, in the final section of this dissertation, a modified Pauson-Khand substrate is developed to eliminate the necessity of a diastereoselective [2+2] photocycloaddition. This substrate is proposed to give the desired trans-intrabridgehead stereochemistry of the ingenane skeleton through modeling studies. The synthetic sequence to contruct this substrate and the Pauson-Khand cyclization trials are described.; *Please refer to dissertation for diagrams.