Selective methods for the synthesis of azole-containing natural products

Over the years, many natural products displaying important biological properties have been considered as lead candidates for development of new drugs and medicines. Amongst these, compounds possessing antibiotic, antifungal and cytotoxic properties are of extreme importance. Importantly, total synthesis has become a leading approach to access appreciable quantities of natural products whose amounts are limited due to a lack of natural sources or suffer from laborious extraction/isolation process. Therefore, the development and implementation of highly chemo-, stereo- and regioselective methodologies which establish a desired stereochemistry or install molecular diversity is a highly investigated field as alteration of natural congeners can lead to synthetic analogues that are of greater pharmacological value than their natural counterparts.;The goal of this research was the examination and application of two synthetic methodologies that would allow formation of two key structural motifs belonging to three natural products which posses cytotoxic, antifungal and antibiotic properties: ulapualide A, mycalolide A and myxothiazole Z. These motifs include a methyl bearing stereogenic center of (S)-configuration positioned adjacent to either a thiazole or oxazole heteroromatic cycle and a vinyl substituted thiazole or oxazole unit attached to a polypropionate chain through a double bond of (S)-configuration. The methodologies investigated include a conjugate reduction of thiazole and oxazole-containing beta,beta'-disubstituted-alpha,beta-unsaturated aldehydes using chiral imidazolidinone amine bases as organocatalysts and dihydropyridine NADH analogues as hydride donors. This method was examined in order to provide a more efficient route than previously reported efforts towards these natural products. Secondly, a ruthenium-catalyzed cross-metathesis involving vinyl-functionalized oxazole substrates and the pertinent olefinic coupling partners was undertaken. In the synthesis of the previously mentioned natural products, the installation of this structural motif was long and involved several functional group transformations. Using a cross-metathesis to install this motif would provide a mild straight-forward route that would be tolerant of neighboring functional groups.;This work showed that a ruthenium-catalyzed cross-metathesis reaction readily coupled vinyl-functionalized oxazole motifs with the corresponding olefinic coupling partners in good yield (up to 92%) and selectivity ( E/Z up to >20/1). Additionally, organocatalytic hydride transfer conjugatively reduces thiazole and oxazole-containing beta,beta'-disubstituted-alpha,beta-unsaturated aldehydes in good yield (up to 84%) and selectivity (er up to 97/3). Ultimately, a protecting group free synthesis of myxothiazole Z was realized in 4% yield (unoptimized) over 8 steps from the longest linear sequence utilizing this process. Additionally, a key intermediate for the synthesis of ulapulalide A was reduced in this fashion in 62% yield ( dr = 85/15).