Synthèse de buténolides naturels et développement d'une nouvelle réaction en cascade pour l'élaboration de furo (2,3-b) chromones

Authors: Muddala, Ramesh
Advisor: Boukouvalas, John
Abstract: This thesis describes the development of new synthetic methods and the establishment of streamlined total syntheses of densely functionalized oxacyclic natural products of biological and medicinal interest. In particular, we describe the first synthesis of the structurally unique antitumor antibiotic basidalin (Chapter 2). Originally isolated from a terrestrial fungus in 1983, basidalin is the first and only natural product known thus far to possess a tetronamide motif. In addition, basidalin displays significant antitumor activity in vitro and in vivo. These attributes have captured the interests of the synthetic and medicinal chemistry communities for over three decades. Notwithstanding the several approaches reported in the literature, none of them were successful in delivering even traces of basidalin. To overcome this challenge, advantage of previously conveyed technology by the Boukouvalas group was taken to judiciously design a strategy that proved highly effective. Indeed, we were able to synthesize basidalin in 39% overall yield after 5 steps and only 3 purifications by chromatography. Chapter 3 concerns the development of a new, iron-catalyzed process for installing carbon substituents onto the –position of the butenolide ring and its application to the first synthesis of the marine myxobacterial antibiotic enhygrolide A. Specifically, we have shown that the hitherto unexplored butenolide pivalates are superior to triflates as electrophilic partners in iron-catalyzed sp2-sp3 cross-coupling with Grignard reagents. This discovery, combined with a tactically sound synthesis plan, enabled enhygrolide A to be prepared with high overall efficiency (54%) in 5 steps from commercial chemicals. In Chapter 4 we describe a new methodology for constructing a rare type of antitumor annonaceous acetogenins, characterized by an –(2-hydroxyalkyl)––hydroxybutenolide motify. The power of this methodology was demonstrated by the first synthesis of such an acetogenin, namely donnaienin A. Our route is convergent (24 steps in total, longest linear route: 15 steps, 6.5% yield) offering considerable synthetic flexibility for future applications. Finally, we have developed a new and efficient tandem reaction sequence for the synthesis of furo[2,3-b]chromones. This process involves regiocontrolled oxazole−ynone Diels−Alder cycloaddition/cycloreversion followed by in situ oxa-Michael addition/elimination to deliver furo[2,3-b]chromones in generally high yields. Its utility was demonstrated by the first synthesis of a furo[2,3-b]chromone natural product (bothriofuran A), accomplished in 5 steps (27% overall).
Document Type: Thèse de doctorat
Issue Date: 2018
Open Access Date: 21 December 2019
Grantor: Université Laval
Collection:Thèses et mémoires

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