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Part I. Oxidative Syntheses of the Illicium Sesquiterpenes Part II. Three-Step Synthesis of the Quassinoid Core Architecture

  • Author(s): Condakes, Matthew L.
  • Advisor(s): Maimone, Thomas J
  • et al.
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In this two-part dissertation, strategic and tactical advances are disclosed in service of the total syntheses of complex natural products. The first part (Chapters 1-3) chronicles the development of oxidative strategies toward the synthesis of the Illicium sesquiterpenes – advances that have led to total and formal syntheses of a dozen natural products. Beginning with an introduction (Chapter 1) of prior art in the field, from structural elucidations and biological studies to previous synthetic works, we seek to contextualize the notion of an oxidative synthesis and argue that it not only represents a significant departure from that precedent but also stands as an inherently logical approach to these natural products. In Chapter 2, the path to the first successful iteration of this strategy is traced for the synthesis of the moderately-oxidized pseudoanisatinoids from the terpene feedstock chemical, cedrol. Multiple interesting oxidative transformations discussed in detail along the way. In particular, a novel copper(II) bromide-mediated oxidative lactonization is developed and its mechanism studied. Additionally, an exceptionally challenging directed non-heme mononuclear iron(oxo)-catalyzed oxidation of an unactivated C(sp3)–H bond is discussed in detail. The chapter concludes with the successful synthesis of multiple pseudoanisatinoids. Chapter 3 addresses the shortcomings of the work described in Chapter 2 and extends the notion of an oxidative synthesis to the more highly oxidized majucinoid Illicium sesquiterpenes. Through multiple directed and non-directed C(sp3)–H oxidations, the majucinoid core is assembled rapidly, leading to the total and formal syntheses of over a half dozen more natural products. The chapter concludes with a unification of the majucinoid and pseudoanisatinoid routes, providing a persuasive argument for the rational extension of oxidative strategies in complex natural product synthesis.

The second part (Chapter 4) describes burgeoning efforts in the synthesis of quassinoids, degraded triterpene lactone natural products. In this sole chapter, a background on quassinoids is given first, including a history of these compounds’ structures, biological activities, and prior syntheses. That discussion then leads into our synthetic work in the area. Drawing on those lessons, we envision a strategy leveraging elements of hidden symmetry in the natural products’ structures. In order to execute this strategy, a novel copper-catalyzed double-coupling of epoxy ketones is designed. The strengths and limits of this highly regio- and diastereoselective transformation are explored. Finally, the chapter concludes with an application of this methodology to a three-step synthesis of the full quassinoid ring system, creating a solid foundation for future work in this area.

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This item is under embargo until March 29, 2023.