A general straightforward synthetic approach for the enantioselective construction of medium and large ring cyclopropyl ketones via diastereoselective Simmons-Smith cyclopropanation is discussed. Medium and large 2-cycloalkenone 1,4Di-O-benzyl-L-threitol ketals undergo efficient and diastereoselective cyclopropanation when treated with an excess of the Simmons-Smith reagent. The cyclopropyl ketals are obtained in 80-94% with >23:1-8:1 diastereoselectivity. The first enantioselective synthesis of (-)-modhephene, a natural product possessing the carbocyclic (3.3.3) propellane skeleton, by the use of diastereoselective cyclopropanation methodology is described.

Natural products represent a large and diverse array of molecules. Natural products and their derivatives play important roles in the human sphere, serving as pharmaceuticals, biofuels, and more. However, the structural complexity of many promising natural products prohibits industrial production sufficient to make full use of their capabilities. The challenge posed by natural products has spurred many advances in multiple fields. Despite these achievements, ignorance of the native metabolic pathways and inefficiencies in manipulating the genes involved has slowed the ability of science to capitalize on the enormous potential of natural products. In Chapter 1, we begin by surveying the fields concerned with the production or variation of natural products. This begins with organic synthesis, continues with in vivo and in vitro biocatalytic methods, and concludes with the “combination” techniques that seek to unite the strengths of biocatalysis and organic chemistry: precursor-driven biosynthesis, mutasynthesis and semi-synthesis. After examining the advantages and disadvantages of the extant technologies, in Chapter 2 we describe a novel strategy to develop semi-synthetic routes to underexplored classes of natural products. While it employs features of existing techniques, our strategy originates from a fundamentally different conception of natural product production, which looks away from the native precursors of a single target, and towards versatile precursors amenable to multiple forms of chemical modification. We then carry out a demonstration of this strategy by first biosynthetically producing 2Z,7E-farnesol from heterologously expressed Mycobacterium tuberculosis synthetases, and subsequently derivatizing this unnatural precursor into a set of novel Ambrox© analogs. Complex biocatalytic applications rely on DNA manipulation technologies to rapidly construct and diversify metabolic pathways. When components of the targeted pathway are unknown or poorly understood, the creation of large libraries of variant pathways can be employed to circumvent these limitations and rapidly develop the desired phenotype. In Chapter 3, we harness our existing library building technology, Reiterative Recombination, to the yeast sexual reproduction cycle for the purpose of combining separately constructed library strains via simple mating and chromosome segregation into an exponentially larger combinatorial library. This chapter describes the design, construction, and initial validation of this system, termed Reiterative Segregation. Finally, in Chapter 4, we explore possible elaborations of the Reiterative Segregation design, and work towards combining libraries of alternative sugar metabolic pathways as an application relevant to biofuel production.

We have successfully using the exocyclic double bond of tricarbonyliron triene complexes to undergo (2+1) and (4+2) cycloaddition for the rapid construction of spiro[2.5]octane and spiro[5.5]undecane system. These cycloaddition reactions were chemo-, regio-, and stereoselective. Synthetic studies toward Upenamide, Manzamine A and Manzamine J by using 1-cyano-2,4-cyclohexadiene tricarbonyliron complexes were also discussed.

published_or_final_version / Chemistry / Master / Master of Philosophy

Chamuvarinin (22) is a unique annoanceaeous acetogenin isolated from the roots of Senegalese medicinal plant Uvaria chamae by Laurens and co-workers in 2004. It displays highly potent cytotoxicity towards the cervical cancer cell lines (KB 3-1, IC₅₀= 0.8 nM). Structurally, chamuvarinin is the first reported acetogenin to contain an adjacently linked bis-THF-THP ring system spanning the C15-C28 carbon backbone. However, initial efforts to assign the relative and absolute configuration within this stereochemical array, on the basis of ¹H and ¹³C NMR analysis, provided only partial information pertaining to the relative configuration of C15-C19 region. As a consequence, 32 diastereomeric structural possibilities exist for the highly unusual structure of chamuvarinin; an unrealistic target for total synthesis. The synthesis of the central core tricyclic (BCD) intermediate represents the most challenging aspect in the entire synthesis, which in turn will aid ultimate structural proof. At the outset of the project the stereochemical configuration of C15-C28 (BCD) of chamuvarinin was uncertain and a library approach was proposed to enable structure elucidation (Scheme A-1). Chapter 2 and Chapter 3 detail the synthesis of possible diastereomers of the C9-C21 (51) and C22-C34 fragments (52). Chapter 4 details the intial strategy to couple the key diastereomeric fragments in a series of model studies. Chapter 5 describes the successful coupling strategy via an revised synthetic approach to reach the advanced C9-C34 intermediate 251 (Scheme A-2).

Chapter 1. Ring-Opening Knoevenagel Strategy for the Synthesis of Alpha-Carboalkoxy Cyclopentenones and Their Use in the Diels-Alder Cycloaddition. The Diels-Alder reaction has enabled the synthesis of hundreds of natural products efficiently and with high levels of stereocontrol. Despite over eight decades of development, this reaction is incapable of forming hydrindane ring junctions from alphahydro beta-alkyl cyclopentenones. As such, we used alpha-carboalkoxy cyclopentenones as synergistic dienophiles, but exposed a lack of synthetic tools for assembling strained bicyclic cyclopentenones. We addressed this paucity by developing a ring-opening Knoevenagel reaction for synthesizing these synergistic dienophiles with varying degrees of substitution. The 6 step protecting group free total synthesis of a structurally similar natural product merrekentrone D was achieved to demonstrate the utility of the new method. In addition, the Diels-Alder cycloaddition with these molecules with the Danishefsky-Kitahara diene were studied. The variability of the ring-opening Knoevenagel reaction also led to the development of a decarboxylative Diels-Alder cycloaddition which is degenerate with the alpha-hydro beta-alkyl cyclopentenone Diels- Alder reaction. The hydrindane structures are referred to as iso-Hajos-Parrish ketones which we subsequently demonstrate as powerful building blocks for natural product total synthesis. Chapter 2. Synthetic Studies Towards the Shizukaol Family of Oligomeric Sesquiterpene Natural Products The shizukaol family of oligomeric natural products are one of three oligomeric sesquiterpene families. Three different generations of synthetic strategies towards the unstable and dimeric precursor lindenatriene were studied. The use of the iso-Hajos-Parrish ketone enabled a 10 step, protecting group free, total synthesis of the intermediate. In addition the formation of unnatural dimers was achieved as well as several unexpected results which led to the generalization of our strategy to other natural product families. Chapter 3. Iso-Hajos-Parrish Ketones: Common Intermediates for Sesquiterpene Total Syntheses The three step synthesis of the cyclopropane substituted iso-Hajos-Parrish ketone enabled rapid access to other sesquiterpene families. Through reductase phases the total synthesis of sarcandralactone was achieved in 10 steps without the use of any protecting groups. Studies were also conducted towards achieving the trans-hydrindane ring as a synthetic equivalent to a trans-Diels-Alder paradigm, which was not realized. Additionally, cyclopropane opening of the iso-Hajos-Parrish ketone led to highly oxidized eudesmane skeletons. Our attempts to hydrogenate these molecules in the reductase phase inspired a 6 step total synthesis of des-methyl pinguisone with a strikingly different sesquiterpene framework. Finally, an analysis of redox conservation in total synthesis and the generality of this chemistry to the total synthesis of sesquiterpene natural products will be presented.

PART I Controllable Synthesis of Complex Members of the Resveratrol Oligomer Family Chapter 1. Synthesis and Biological Evaluation of Resveratrol Family Oligomeric Natural Products This introductory chapter traces the history of resveratrol, highlighting the substantial interest in elucidating its potential pharmacological benefits and the ensuing impact on the synthetic community. A plethora of research groups have sought to investigate strategies towards accessing higher order oligomers within the resveratrol family, and these approaches provide context for our own endeavors. Chapter 2. Uniquely Functionalized Resveratrol Dimers: Total Syntheses of Hopeanol and Hopeahainol A In this chapter, we expand upon the utility of a divergent strategy, which has enabled the synthesis of multiple oligomeric, resveratrol-based natural products from a common intermediate. We demonstrate applicability to two exceptional dimeric natural products of the resveratrol family, further developing the truly robust nature of this particular synthetic approach. Chapter 3. Harnessing Redox Reactivity: The Total Synthesis of (±)-Vaticanol A In the final installment of this section, we incorporate distinct methodology into the established chemical toolkit for accessing resveratrol oligomers. Targeting a formidable trimeric resveratrol-based natural product, this work takes advantage of several key insights generated from previous endeavors, particularly selective functionalization techniques. PART II Unexploited Paradigms for Chemical Probe Design, Focusing on Cancer Biology Chapter 1. Introduction to the Drug Discovery Landscape The introduction to Part II presents current approaches to the development of small molecule therapeutics and chemical probes, while concurrently obviating their limitations and the necessity to embrace underappreciated paradigms. Such endeavors could be capable of providing access to many elusive molecular targets. Chapter 2. Small Molecule Inhibitors of GPX4: Attempts at Targeted Covalent Inhibition This chapter discusses a recently validated protein target and our efforts to establish a platform for the development of highly selective, irreversible inhibitors. A unique mechanism of enzymatic activity informs a novel approach towards evaluating the capacity to target specific amino acid residues. Chapter 3. In Silico Design of Protein-Protein Interaction Inhibitors Targeted at the RAS Family of GTPases The final chapter embraces in silico inhibitor design as a strategy towards effectively modulating one of the most challenging protein targets of contemporary drug discovery efforts. As a caveat to traditional in silico approaches, this work sought to validate a multivalent ligand approach towards abrogating key protein-protein interactions.

Graduation date: 2001

Graduation date: 1997

In 2006, the secondary metabolite leiodolide A was isolated from a newly discovered deep-sea sponge of the genus Leiodermatium. The 19-membered macrolide represented a new class of mixed polyketide, nonribosomal, peptide synthetase natural products. A total synthesis of leiodolide A is yet to be achieved and is of specific interest, not only for its complex structure and undefined stereochemistry, but also the potent cytotoxic properties it possesses, particularly towards leukaemia, non-small cell lung and ovarian cancers. A synthetic strategy for leiodolide A must be flexible to overcome the currently unresolved stereochemistry and a convergent route towards the synthesis of the molecule required three subunits. Following the earlier synthesis of the C21-C25 vinyl stannane fragment, this work describes the synthesis of the C1-C10 subunit in the both possible diastereomeric forms. The synthesis of the two required C13 epimers of the C11-C20 subunit is also detailed accompanied by an investigation into potential fragment coupling, in preparation for total synthesis.