A platform for the discovery of new macrolide antibiotics.

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture

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

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

Total Syntheses of (−)-Majucin and (−)-Jiadifenoxolane A, Complex Majucin-Type <i>Illicium</i> Sesquiterpenes

We report the first chemical syntheses of both (−)-majucin and (−)-jiadifenoxolane A via 10 net oxidations from the ubiquitous terpene (+)-cedrol. Additionally, this approach allows for access to other majucin-type sesquiterpenes, like (−)-jiadifenolide, (−)-jiadifenin, and (−)-(1<i>R</i>,10<i>S</i>)-2-oxo-3,4-dehydroxyneomajucin (ODNM) along the synthetic pathway. Site-selective aliphatic C­(sp³)-H bond oxidation reactions serve as the cornerstone of this work which offers access to highly oxidized natural products from an abundant and renewable terpene feedstock

Total Syntheses of (−)-Majucin and (−)-Jiadifenoxolane A, Complex Majucin-Type <i>Illicium</i> Sesquiterpenes

We report the first chemical syntheses of both (−)-majucin and (−)-jiadifenoxolane A via 10 net oxidations from the ubiquitous terpene (+)-cedrol. Additionally, this approach allows for access to other majucin-type sesquiterpenes, like (−)-jiadifenolide, (−)-jiadifenin, and (−)-(1<i>R</i>,10<i>S</i>)-2-oxo-3,4-dehydroxyneomajucin (ODNM) along the synthetic pathway. Site-selective aliphatic C­(sp³)-H bond oxidation reactions serve as the cornerstone of this work which offers access to highly oxidized natural products from an abundant and renewable terpene feedstock

Oxidative Entry into the <i>Illicium</i> Sesquiterpenes: Enantiospecific Synthesis of (+)-Pseudoanisatin

Illicium sesquiterpenes have been the subject of numerous synthetic efforts due to their ornate and highly oxidized structures as well as significant biological activities. Herein we report the first chemical synthesis of (+)-pseudoanisatin from the abundant feedstock chemical cedrol (∼$50 USD/kg) in 12 steps using extensive site-selective C­(sp³)–H bond functionalization. Significantly, this work represents a novel oxidative strategic template for future approaches to these natural products and their analogs

A platform for the discovery of new macrolide antibiotics.

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture