Progress towards the Syntheses of Ambruticin and Its Putative Biosynthetic Intermediate

The ambruticins are a class of polyketide natural products that were isolated in 1977 which have been shown to be completely non-toxic with low oral and intravenous LD50 values. In addition to their biological activity, they displayed a very novel architectural framework embodying a 1,2,3-trisubstituted divinyl cyclopropane and two highly oxygenated pyran rings. The different strategies implemented towards the total synthesis of these classes of polyketide natural products are described in this thesis. The key aspect of this program was the application of the cyclopropane ring formation methodologies via a homoallylic cation rearrangement that have been developed in the Taylor group in recent years. The key 1,2,3-trisubstituted cyclopropane unit was efficiently synthesized in large scale either via activation of homoallylsilane allylic alcohol, or cyclopropanation of homoaldol precursors. Methyl ketone fragment A was constructed in six steps from readily available starting materials and relied on a pivotal tandem three component silyl-modified Sakurai/ring closing metathesis reactions. A Prins reaction followed by a series of oxidation and reduction sequence successfully afforded highly oxygenated hydropyran fragment A. The subsequent coupling via Julia or modified-Julia olefination failed possibly due to the acidity of the methyl ketone coupling partner. This thesis also highlights the progress towards the synthesis of ambruticin J, a putative biosynthetic intermediate recently proposed by Reeves following the characterization of the PKS gene cluster responsible for the biosynthesis of ambruticin. In light of the limited amount of ambruticin J available biosynthetically, its large scale preparation via organic synthesis was implemented in order to investigate the role of the epoxidase, AmbJ during the post-PKS modifications leading to the production of ambruticins and their analogues.The strategy relied on pivotal HWE and metathesis couplings which efficiently provided the advanced divinylcyclopropane intermediates that were suitable for further epoxidation and cyclization studies.