This dissertation describes the development and applications of a radical bicyclization reaction that is initiated via hydrogen-atom-transfer (HAT) to 1,1-disubstituted alkenes. In the first chapter, biomimetic radical polyene cyclizations and HAT-mediated C-C bond forming reactions are reviewed. Mechanistic and strategic aspects pertaining to radical-polar crossover are emphasized throughout, highlighting unique possibilities offered by oxidative or reductive termination.The second chapter details the development of a novel cobalt(II)‐catalyzed bicyclization. The process is presumably initiated by metal‐catalyzed hydrogen‐atom transfer (MHAT) to 1,1‐disubstituted or monosubstituted alkenes. Notably, electron‐rich methyl or electron‐deficient nitrile substituted internal alkenes are tolerated. Electron‐rich aromatic terminators are required in both cases. Terpenoid scaffolds with different substitution patterns are obtained with excellent diastereoselectivities, and the bioactive C20‐oxidized abietane diterpenoid carnosaldehyde was made to showcase the utility of the nitrile‐bearing products. Also provided are the results of several mechanistic experiments that suggest the process features an MHAT‐induced radical bicyclization with late‐stage oxidation to regenerate the aromatic terminator. The third chapter details our studies in applying cobalt(II)‐catalyzed bicyclizations to the synthesis of oxygenated terpenoid scaffolds. A systematic evaluation of substrates bearing different oxygenation patterns was conducted to assess the practicality of using preoxidized bicyclization precursors. The degree of stereoselectivity was often high, but varied with oxygenation locus, with free hydroxy groups performing well in most contexts. The stereochemical outcomes of cyclizations of dioxygenated polyenes were dictated by aliphatic chain oxygenation closest to the initiating 1,1-disubstituted alkene. Simple analyses of non-bonding interactions in the putative cyclization transition states were sufficient to rationalize stereochemical outcomes in most cases. Intramolecular hydrogen bonding directed regioselectivity was observed in one substrate class. To further validate the use of preoxidized polycyclization precursors in bioactive diterpenoid synthesis, we completed the first total syntheses of (+)-2-O-deacteyl plebedipene A, (±)-plebedipene B, and (+)-2-O-deacetyl plebedipene C. Lastly, experiments aimed at expanding the scope of cobalt(II)‐catalyzed polycyclizations are proposed.

Described herein is a compilation of studies in both methodology development and total synthesis in organic chemistry. Chapter 1 describes in detail notable discoveries in the field of dyotropic rearrangements, highlighting computational investigations, methodological analyses, and application to the total synthesis of natural products. Chapter 2 summarizes the formal dyotropic rearrangement observed initially by Gerhard Himbert, and discusses the scope, limitations, and applications of this unique bicyclic rearrangement. Chapter 3 discusses our collaborative computational and experimental investigation into the formal dyotropic shift of arene-allene cycloadducts. Notable contributions include the discovery of Lewis acid-promoted dyotropic rearrangement conditions and isolation of a “trapped intermediate”, strongly supporting a proposed two-step polar mechanism.

Chapter 4 discusses in detail the isocyanoterpene natural products, including their proposed biogenesis, their observed bioactivity, and synthetic strategies by which they can be obtained in a laboratory setting. Chapter 5 elaborates specifically on the kalihinane family of natural products, highlighting their isolation, and summarizing total syntheses targeting their complex structures. Chapter 6 summarizes our progress toward the synthesis of kalihinanes that contain a tetrahydropyran ring. Notable contributions include a convergent sequence that procures an acyclic precursor to the kalihinane core and several methods by which this acyclic precursor can be cyclized to form the tetrahydropyran ring.

Chapter 7 describes in detail the isolation of (+)-7,20-diisocyanoadociane and summarizes the total synthesis efforts toward the completed natural product. Chapter 8 highlights our improvements to our previously published formal synthesis of DICA, which lowers the step count from 24 steps to 17 steps, increases the overall yield significantly, and targets an intermediate from which the natural product can be obtained with high diastereoselectivity.

Chapter 9 provides a short summary of the field of cobalt(III)-carbene radical catalysis, including both mechanistic studies and applications to small molecule synthesis. Chapter 10 details our application of this unique reactivity to a rapid and efficient synthesis of indolines. The discovery and optimization of this methodology is described in detail, accompanied by an investigation into both scope and mechanism.

ABSTRACT OF THE DISSERTATION

Studies of Halogenated Lipids and

Progress Toward the Synthesis of Crotogoudin

By

Dmitriy Igorovich Uchenik

Doctor of Philosophy in Chemistry

University of California, Irvine, 2017

Professor Christopher D. Vanderwal, Chair

This dissertation describes three separate projects which range from work toward the

development of new chemical methods to the synthesis of natural products. Chapter one

introduces the intricacies involved in bimolecular elimination reactions and reports my

efforts to elucidate the source of the highly diastereoselective dehydrohalogenation of

b-dichloro sulfates. Our group has previously found that exposure of b,b,-dichloro

sulfates to LDA provided exclusively the (E)-vinyl sulfate while the same elimination

conducted with t-BuOK gave a 1:5 ratio of (E)- to (Z)- alkene diastereomers. Experiments

exploring the effects of base strength, different countercations, and substrate substitution

were carried out to attempt to elucidate the source of this surprising diastereocontrol.

Early elimination experiments performed on 2,2-dichlorohexyl sulfate supported an

initial hypothesis of diastereocontrol based on competing cation chelation, but further

experimentation demonstrated that the trend did not extend to other b-chloro sulfates.

Chapter two describes synthetic explorations toward the synthesis of the sponge derived

natural product mollenyne A. Synthetic efforts focused on the synthesis of the

dibromochlorohydrin stereo-triad demonstrated the challenge associated with the

regioselective synthesis of a trisubstituted (E)-alkenyl bromide. Failing to install the alkenyl bromide via hydrometalation, a ring-closing metathesis strategy was proposed to

set the alkene geometry. While a 1,1-disubstituted alkenyl bromide was synthesized, we

were unable to achieve the desired metathesis.

Chapter 3 focuses on my efforts toward the total synthesis of the seco-atisane diterpene

crotogoudin. A variety of methods for the installation of bicyclo-[2.2.2]-octanes are

discussed in the context of various natural product syntheses and the two previous

syntheses of crotogoudin by the Carreira and Liu groups are presented. Work toward

improving the synthetic approach designed by Dr. Peter Mai led to the discovery of an

unprecedented, oxygen-dependent copper catalyzed conjugate reduction. An expansion

of Snyder’s manganese(III) mediated free radical enolate cyclization is presented as a

novel method for forming bicyclo-[2.2.2]-octanes.

The thesis describes two desymmetrization approaches to two different natural products. The first chapter contains background on the salvileucalins and the Buchner reaction along with the work done towards the synthesis of salvileucalin B. This includes the synthesis of the diazo substrates for the Buchner reaction and the results of experimentation on a key Buchner reaction step in the sequence. The second chapter contains background on emetine and the work done towards its synthesis. This includes the synthesis of the dihydropyridine intermediate, the results of experimentation on the key step of acidic hydrolysis of the dihydropyridine to facilitate a double Pictet–Spengler reaction, exploration of an oxidative cleavage strategy, and the results on a model system to find conditions for a successful Pictet–Spengler reaction. Future directions of the project are also discussed, which include a Mukaiyama hydration strategy and modulation of the groups on the dihydropyridine nitrogen.

The research described herein focuses on the development of novel methods and synthetic sequences to solve problems in organic synthesis. Chapter 1 details our work on an operationally simple method to synthesize furans and pyrroles in high yield from keto-oxetanes, a non-obvious, easily accessible 1,4-dicarbonyl surrogate.Chapter 2 moves away from synthetic methodologies and is focused on the dihydro-β- agarofuran family of sesquiterpenoid natural products. This chapter begins by detailing the structural features that make this family unique and the diverse array of biological activity that has generated considerable interest in their study. It concludes by discussing the significant amount of synthetic efforts towards the agarofurans, focusing mainly on the most recent examples. Chapter 3 details four strategies towards the synthesis of an easily diversifiable core that could be used to synthesize several agarofurans and related analogs. Key contributions include the first use of an ester chiral auxiliary in a diastereoselective Birch reduction/alkylation reaction of substituted benzenes, an expedient route towards a fully oxidized A-ring fragment, and the synthesis of the AB-core of the agarofurans using an intramolecular 1,3-dipolar cycloaddition reaction. Chapter 4 describes the history of the diastereoselective Birch reduction/alkylation reaction and its use in the synthesis of natural products. Chapter 5 details the development of using ester chiral auxiliaries to effect a diastereoselective Birch reduction/alkylation reaction. This method generates quaternary carbons directly from salicylic acid derivatives with good diastereoselectivity using an easily removable (−)-8-phenylmenthol chiral auxiliary.

Chapter 1 provides an overview of lissoclimide natural products and previous synthetic efforts. The isolation of lissoclimides and their anticancer properties against various cell lines are detailed. Subsequently, the mechanism of protein translation inhibition by chlorolissoclimide is discussed. Our group's previous synthetic endeavors, including the semi-synthesis of chlorolissoclimide, analogue-oriented synthesis of lissoclimide derivatives, and Lewis acid-catalyzed bicyclization to access a related natural product, are presented. In collaboration with the Yusupov, Blanchard, Furche, and Horne groups, we explored novel halogen-π dispersive interactions of chlorolissoclimide within the tRNA E-site pocket. Additionally, the anticancer activities of synthetic lissoclimides were evaluated.Chapter 2 describes the conversion of sclareolide into fluorolissoclimide and methyllissoclimide. Selective C–H functionalization of sclareolide was achieved using an Alexanian hydroxyamide reagent to introduce fluorine and methyl groups with the desired stereochemistry at the C2 position. The mechanism underlying C–H fluorination and the structural basis for selective radical C–H modification of sclareolide were elucidated. Methylsclareolide was subsequently synthesized through methylation of the corresponding iodinated derivative. The syntheses of fluorolissoclimide and methyllissoclimide were completed in concise 9-10 step sequences. Finally, the halogen-π interactions of these compounds, along with bromolissoclimide, chlorolissoclimide, and haterumaimide Q, were investigated within the 80S ribosomal pocket. Chapter 3 commences with a description of. the isolation and structural characterization of brasilicardin A, along with its biological activities and proposed biosynthetic pathway. The complex trans/syn/trans-perhydrophenanthrene core of brasilicardin A has posed significant synthetic challenges, with previous total syntheses relying on Diels–Alder cyclization and intramolecular Michael addition strategies. Our group developed a novel cobalt-catalyzed MHAT-induced polycyclization approach to efficiently construct the tricyclic core of a brasilicardin analogue. Structure-activity relationship studies using SARS models highlighted the critical roles of the disaccharide, amino acid side chain, and diterpenoid core in the biological activity of brasilicardin A. Chapter 4 details the synthesis of brasilicardin A via a polyene cyclization strategy inspired by the biosynthetic pathway. A retrosynthetic analysis identified directed hydrogenation as a key step to construct the desired perhydrophenanthrene core. Epoxypolyene intermediates were prepared via a crucial B-alkyl Suzuki–Miyaura cross-coupling reaction. Both cationic and radical cyclization pathways were explored. Cyclization of a diene-containing epoxypolyene afforded the tricyclic core of brasilicardin A. Investigation of C2 hydroxyl protection revealed that a free alcohol facilitated the desired 6-endo-trig cyclization of an enone-terminated polyene. Future work will focus on optimizing polyene substrate synthesis.

This dissertation describes four research aims involving natural products total synthesis or synthetic methods development. Chapter 1 reviews the isolation, proposed biosynthesis, biological activity, and prior syntheses of pyrroloiminoquinone (PIQ) alkaloids. Chapter 2 describes our efforts towards a synthesis of aleutianamine, a PIQ alkaloid that is structurally distinct from other PIQs and possesses selective anticancer properties. While an aleutianamine synthesis has yet to be accomplished in our laboratory after several synthesis approaches (discussed herein), we discovered novel reactivity of PIQ intermediates en route to aleutianamine, which will aid in our ongoing synthesis efforts. Chapter 3 describes syntheses of numerous simpler PIQ alkaloids, fueled by an efficient synthesis of a versatile PIQ building block en route to aleutianamine. These studies were motivated by a preliminary discovery that some simpler PIQs possess antimalarial properties. By collaborating with the Ben Mamoun and Le Roch groups at Yale and UC Riverside, respectively, we discovered that many of our synthetic PIQs are promising inhibitors of human disease-causing parasites Plasmodium falciparum and Babesia divergens. Chapter 4 describes our synthesis of a monoterpene indole alkaloid alstonlarsine A from alstolucines B and F, which are all isolated from plants of genus Alstonia. The success of our synthesis supports the chemical feasibility of a new biosynthetic proposal for alstonlarsine A. Chapter 5 describes our development of a novel cascade annulation reaction inspired by a bicyclization reaction discovered previously in our lab. In this work, we use similar conditions to react allylbenzenes and electron-deficient alkenes to make functionalized tetralin products.