The pursuit of biologically active natural products affords numerous avenues of study, all of which strive for a common goal: enhancing activity of and access to potential lead compounds of therapeutic interest. The systems of particular interest to this research are polyketides synthase derived natural products and, in particular, the epothilones and peloruside A. Toward the design of novel methodologies, this project has focused on development of 1,3-diols and their related monoethers with high diastereoselectivity. The method has focused on the intramolecular delivery of an oxygen nucleophile in the form of a methyl ether. The delivery of the oxygen atom to a carbocation via multiple activation schemes was explored, with both iodide activation and alcohol triflation providing the desired diol-monoether in high yield and with high diastereoselectivity. The delivered oxygen nucleophile has also been demonstrated to be synthetically variable, affording both stable and labile ether products. The synthesis of natural product analogues has also been addressed in the course of this research. Specifically, the total synthesis of a hybrid analogue of the epothilones has been undertaken affording two analogues containing both a C14 methyl group and a C9ÌâåÂ-C10 olefin, both designed to impact the conformation of the macrocycle. In the course of the synthesis, a new methodology was employed to install the C14Ìâå methyl group, employing the magnesium-catalyzed anti-aldol chemistry developed by Evans. This reaction provided a simple and highly selective method to install the C14 and C15 stereocenters in a single and high-yielding step. A final and novel project in our efforts toward polyketides is the design of analogues based on analysis of solution conformation. This research has provided an advanced spreadsheet-based method to process data generated by a strategy of molecular modeling and dihedral determination into polar coordinate maps suitable for analysis of large amounts of conformational data. In addition, comparisons of molecular modeling of peloruside A has been accomplished by an array of diverse force fields using the conformational search routines of the MacroModel software. This analysis has revealed interesting conformational preferences of the C9-C15 region of peloruside, which may be exploited in the design of novel analogues based on molecular conformation.  Supplemental data not included in the dissertation:   NicholsonC_Data_MM2.zip (151 MB)  NicholsonC_Data_MM3.zip (154 MB)  NicholsonC_Data_OPLS.zip (19.1 MB)