Novel Ways to Generate Polypropionates for the Synthesis of Polyketide Natural Products by Matthew Edward Calder Doctor of Philosophy in Chemistry Stony Brook University 2012 Polyketide natural products are desirable targets due to their interesting biological and pharmacological properties. Polyketides contain synthetically challenging propionate subunits, which are comprised of alternating methyl and hydroxyl stereogenic centers. The synthesis of polypropionate subunits is the central theme of this work. The first project focused on employing the stereopentad and stereotetrad of the broad-spectrum antibiotic oleandomycin for the total synthesis of the polyketide natural product discodermolide. Our strategy involved a deconstruction/reconstruction process to access the polypropionate fragments that could then be modified to known discodermolide intermediates. Unfortunately, the unavailability of oleandomycin made completing this project difficult. The second project focused on developing a new methodology employing cyclic hydroboration for the stereoselective synthesis of stereopentad fragments. Cyclic hydroboration has been a little used technique in organic synthesis. However, it has been shown to be an effective method for generating simple acyclic compounds that contain remote stereogenic centers in a single step. To date, the cyclic hydroboration of 1,5-dienes has not been employed to synthesize stereopentad subunits. Utilizing work done on model systems in our group and literature precedents, we designed and synthesized a series of structurally complex acyclic dienes. Cyclic hydroboration of the complex dienes afforded stereopentads in moderate to high yields and diastereoselectivity. The reaction installs three of the five contiguous stereocenters in a single step. This work demonstrates that cyclic hydroboration can be an effective way to generate stereopentads. The synthesis, optimization and potential application of this methodology for the synthesis of polyketide natural products are discussed.