Strategies for the Controlled Synthesis of Oligomeric Natural Products

1 - Total Syntheses of Helicterin B, Helisorin, and Helisterculin A - The total synthesis of three members of the helicterin family of natural products, helicterin B, helisorin and helisterculin A, was completed from a common, non-biomimetic intermediate. This work featured the development of a complex retro Diels-Alder/Diels-Alder sequence, a Friedel-Crafts ring closure resulting in a highly strained ring-system, an acid-catalyzed hydroxyketone rearrangement, a Lewis acid-promoted dimerization of a bicyclooctene monomer, and the use of a novel phenol protecting group. 2 - Synthetic Studies of an Alternative Diels-Alder Approach Towards the Helicterin and the Yunnaneic Acid Families of Natural Products - Efforts towards the development of an enantioselective synthesis of the helicterin natural products are presented. Given the failure of known methods to achieve this goal, a novel Diels-Alder approach based on a revised biosynthetic proposal was explored. This method achieved a bicyclooctene framework with good stereoselectivity, but its conversion to the natural product core proved challenging. Additionally, a Diels-Alder approach to the core of the yunnaneic acids was developed, one in which the effective reversal of the regiochemical preference of the reaction was achieved. 3 - Small Molecule Inhibitors of Cell Death in a Huntington's Disease Model - A compound based on the core of the helicterin natural products with the ability to prevent cell death in a Huntington's Disease model system was identified. Although its mechanism of action is unknown, its cellular target appears to be distinct from that of prior inhibitors. A number of analogs based on this initial hit were synthesized, and structure-activity relationships were explored. 4 - Synthetic Studies Towards a Biomimetic Approach to the Myrmicarin Alkaloids - The shortest and highest yielding synthesis of the monomeric myrmicarin alkaloids to date has been completed, and the stereochemical complexity of the upper half of the dimeric myrmicarin 430A has been achieved for the first time. Although the dienamine building blocks readily afforded the monomeric natural products under presumed biological conditions, the results of synthetic and theoretical experiments suggest that their dimers are either non-biomimetic or that enzymes are required in the biosynthesis of the higher-order myrmicarins. 5 - Studies on The Mechanism of the Knorr Pyrrole Cyclization - A mechanistic study of the Knorr pyrrole cyclization of an indolizidine-based dienamine to myrmicarin 215B was completed. This cyclization was found to occur exclusively in polar protic solvents, and two solvent molecules were required in the rate-determining step. A revised mechanism for this cyclization is proposed, in which a slow ketone protonation step precedes the cyclization and dehydration steps.