Various metal-ligand catalyst systems were screened in order to determine if enantioselective oxidations were suitable as potential transformations for Competing Enantioselective Conversion (CEC) analysis. Optimization of CEC conditions allowed for analysis in the common solvent CDCl3, which minimized analysis time by avoiding a workup step. Increasing the equivalents of oxidant from 1 to 5 afforded greater difference in selectivity over a 16.5 hour time frame of the analysis, which allows for more accurate determination of absolute configuration. Synthesis of enantioenriched sulfoxides for substrate testing began using the Senanayake protocol. Initial CEC results indicated a lack of selectivity or a mismatch in selectivity that prompted the investigation of the Uemura system. The Uemura system was unreliable in our hands, and the project was ultimately abandoned.

Using the kinetic resolution data reported by the Krasnov group, a suitable pseudoenantiomeric acyl chloride bearing substitution along the aromatic ring was synthesized as a potential CEC reagent. Multi-step synthesis of heterocyclic amine substrates bearing varying substitution at the chiral center or aromatic ring was conducted to assess the scope of CEC reactivity. Initial investigations into the CEC reactions displayed mixed results, with a few substrates displaying predicted selectivity and one other displaying the opposite selectivity. Several other substrates did not display any relevant mass peaks (starting material or product) after repeated trials. A base screen showed that the inclusion of tertiary amine bases to the CEC reaction did not influence the selectivity in an appreciable manner.

Abstract 1:Synthetic routes to a heterobifunctional cysteine-lysine linker (MSSO) and an alkyne-bearing photo-inducible non-specific cross-linker (DzYSO) were developed and executed to provide collision-induced dissociation (CID) cleavable cross-linkers to probe protein structural dynamics. Additionally, an alkynylated acid-cleavable cross-linker (Alkyne-A-DIA) was designed and synthesized to evaluate potential for use of a ketal in selectively releasing biotinylated cross-linked fragments. The three linkers will be used for in vitro and in vivo protein interaction elucidation studies analyzed through liquid chromatography tandem mass spectrometry. Abstract 2: p53 is an enzyme that is responsible for facilitating cell cycle arrest, DNA repair, and apoptosis. It has been linked extensively to the development of cancer upon the introduction of missense mutations to structurally integral amino acids. Benzoimidazolylphenylpropenones and indolylphenylpropenones have shown promise in the restoration of native structure and function to mutant forms of p53 (R175, Y220C, R248W, R273H, G245S and R280Q) resulting in cytotoxic activity against cancerous cell lines possessing these mutations. These substrates were synthesized to reactivate p53 and photo-label the binding site targeted by these compounds. Abstract 3: The synthesis of intermediates toward ent-kaurane diterpenoid crokonoid A is discussed. In this discussion, the logic behind our approach and the optimization of several steps in the sequence are explored. Preliminary experiments to probe how to effectively set and maintain the stereocenter at C-14 are reported, without much success thus far.

The first chapter of this thesis focuses on the development of the competing enantioselective conversion method (CEC) for the assignment of the absolute configuration of amines. This method utilizes Bode’s hydroxamic esters as the source of chirality. The optimization and control studies for this method are discussed in detail. Many examples, including complex drugs and natural products, are examined and a preliminary mnemonic was developed.

The second chapter focuses on the efforts toward the synthesis of the western fragment of phainanoid F. Background is given on the previous failed routes in our laboratory and how they led to the new synthetic route. Three different approaches toward the fragment are discussed, one which failed, and the other two that are not yet complete. If efforts are placed in these approaches, it seems likely that one will afford the western fragment in due time.

The third chapter will provide details on the synthesis of kujounins A1 and A2 in our laboratory. Kujounin A2 was synthesized in 7 steps from L-ascorbic acid based on a biomimetic approach. A new biosynthetic pathway is presented that seems likely to produce the kujounins. A key Tsuji-Trost reaction followed by an ozonolysis afforded the core of the natural product in just two steps. The sensitive disulfide moiety was more difficult to install but was accomplished in a few steps. Biological activity studies are pending.

The last chapter discusses the total synthesis of the proposed structure of (–)-himeradine A. An overview of background and previous work accomplished on himeradine A in our lab is provided. The total synthesis was completed in just 17 longest linear steps and only 10 of those steps required column chromatography. This synthesis features a key tartaric acid salt resolution of a piperidine, a B-alkyl Suzuki of two complex fragments, a photoredox conjugate addition, and a transannular Mannich reaction that forms 5 bonds in 1 step. The spectral data was consistent with Shair’s synthetic sample and had some discrepancies with the isolated natural product. Epimers of himeradine A will be synthesized in our laboratory in due time.

The first chapter of this dissertation focus on the history and syntheses of the bioactive steroidal alkaloid (–) batrachotoxin. Several notable partial syntheses are discussed, as well as two total synthesis. Previous efforts by the Rychnovsky group, as well as our current route towards batrachotoxin are described in Chapter 2. The successful synthesis of fully elaborated AB and DE steroidal fragments are disclosed, as well as the key reductive fragment coupling and Heck cyclization to form the steroidal core.

Chapters 3 provides a concise introduction to the Lycopodium family of natural products, while Chapters 4 and 5 describe our recent efforts towards the total synthesis of two Lycopodium alkaloids, (+)-fastigiatine and (–)-himeradine A. Following the successful first-generation synthesis of fastigiatine, we chose to pursue a modified second-generation route that was inspired by computationally modeling. Highlights of the synthesis include a diastereoselective reduction-ketalization, an optimized dibromocarbene mediated ring-expansion, and utilization of photoredox catalysis to perform a radical aminomethylene conjugate addition. In Chapter 5, our efforts towards the total synthesis of himeradine A are disclosed. A highly efficient racemic synthesis of an advanced tri substituted piperidine was achieved, and several methods to perform a late-stage resolution are discussed. A proof-of-concept Suzuki coupling between the quinolizidine precursor and pentacyclic core precursor was successful. Elaboration of the coupled intermediate through the remainder of the synthesis was accomplished, confirming the validity of our approach towards the synthesis of himeradine A.

Finally, several strategies towards the synthesis of the 4,5-spirocyclic fragment of phainanoid F are presented in Chapter 6. While initial efforts on a model system were unsuccessful due to unexpected carbocation rearrangements, a route involving the photochemical Wolff ring contraction proved to be an efficient method to access the cyclobutane moiety found in the natural product. This approach is currently being applied towards the enantioselective synthesis of the western fragment of phainanoid F.

The first part of the dissertation describes the characterization of lithium 4,4’-di-tert-butylbiphenylide (LiDBB). The rates of formation and degradation of LiDBB were investigated and decomposition products identified. Stored LiDBB was found to give equivalent yields of a [4.5] spirocycle over 16 weeks.

The second part of the dissertation details the preparation of substituted spiropyrrolidines and spiropiperidines by double alkylation of α-aminonitriles, followed by stereoselective reductive lithiation and cyclization. In all cases, cyclization occurred with high diastereoselectivity.

The third part of the dissertation investigated the use of LiDBB in flow reactors. Direct ring opening of an epoxide, instead of its thiophenyl derivative, was examined. Non-cryogenic flow conditions substantially increased the yield of spiropyrrolidines and a spiropiperidine. A substituted [4.5] spirocycle also was formed in higher yield and diastereoselectivity as compared to batch conditions.

Abstract 1:Progress towards enantioselective synthesis of the meroterpenoid rhodatin and the synthesis of the related terpenoid rhodocorane L, both with unique oxidized acorane-type core structures, will be discussed. The spiro[4.5] bicyclic acorane core of each will be formed using asymmetric gold-catalyzed dearomative spirocyclization. This work towards rhodatin explores synthesis and reactivity of ene-diketones, which are rare understudied motifs, towards carbon nucleophiles. Abstract 2: The transcription factor p53 is an important medicinal chemistry target, as mutations of the corresponding TP53 gene are found in most human cancers. Restoration of the native tumor-suppressing function of mutant p53 via binding of a small molecule drug to the L1/S3 pocket on the p53 protein has been previously achieved using benzoimidazolylphenylpropenones. Building off this scaffold, 59 compounds were synthesized and tested to further explore the structure-activity relationship through non-covalent and covalent interactions with the L1/S3 binding pocket. A 10-fold improvement in IC50 resulted from addition of an acrylamide to achieve covalent binding or by replacement of the arene with pyridine, improving the non-covalent binding. Abstract 3: Synthesis of a mass spectrometry cleavable crosslinker, tBu-P-DSBSO, is described. This linker contains a combination of features not yet seen in the literature: a t-butyl protected phosphonic acid enrichment handle, sulfoxides as mass spectrometry cleavable groups, and N-hydroxysuccinimide esters as reactive ends. Crosslinking studies using this linker are still ongoing. Progress towards the analogous crosslinker without the t-butyl protecting groups, P-DSBSO, is described.

The first chapter outlines our early optimization work on the conversion of thioesters into alkynes in three steps or less to reduce the step count in the synthesis of the eastern fragment of the natural product strasseriolide B. Three different synthetic routes were attempted to achieve this goal. The first route required formation of an enol triflate followed by reductive lithiation and methylation. However, the reactions generally led to decomposition. The second route employed the formation of β-ketothioesters prior to enol triflate formation, followed by a decarboxylation/elimination sequence. Poor yields and lack of selectivity when forming the enol triflate resulted in rerouting. The final route used a palladium-catalyzed deallylation of allyl β-ketoesters to perform the same decarboxylation/elimination sequence. Although feasible, four steps were required, rendering the project goal unsuccessful.

The first chapter additionally describes our progress towards the total synthesis of strasseriolide D via a convergent synthesis. Strasseriolides A–D were isolated in 2020 from the fungal strain Strasseria geniculate. We recently reported the first total syntheses of A and B with LLSs of 16 and 17 steps, respectively. Strasseriolides B and D showed potent antimalarial activity against drug-sensitive and drug-resistant P. falciparum parasites. Later in vivo studies evaluated the treatment of strasseriolides A, B, and D in mice and found strasseriolide B to be acutely toxic while strasseriolide D displayed no cytotoxicity and significant inhibitory activity. We investigated a synthetic strategy to provide material for further investigation of strasseriolide D’s antimalarial activity. A summary of the synthesis of the eastern fragment and a thorough description of the western fragment will be presented. The eastern and western fragments were envisioned to couple through an esterification and the synthesis will be completed via an NHK macrocyclization.

Chapter Two outlines a project I joined shortly after concluding the thioester to alkyne methodology project. It describes our group’s previous methodology that demonstrated osmium tetroxide and TMEDA generate stable crystalline adducts with alkenes that facilitate X-ray analyses and structure assignments. Alternatively, osmate esters can be prepared from diols, potassium osmate, and TMEDA·2TsOH in a non-oxidative condensation reaction. This new approach provides a convenient route to form stable, crystalline osmate (VI) esters for X-ray analysis. Because it is redox neutral, it works with a variety of diol substrates, including 1,3-diols, that cannot be prepared from alkenes. α-Hydroxy acids also form stable osmate esters in reasonable yield and readily crystallize. An alternative ligand screen was performed to assess improved crystallinity from substituted TMEDA analogues. The enhanced crystallinity of osmate esters and the incorporation of a heavy atom make reliable determination of structure and absolute configuration routine.

The third chapter describes the progress towards a total synthesis of populusene A, a cembranoid-type diterpene isolated from the tree resin of Populus euphratica by Liu et al. Populusene A contains a structurally uncommon bridgehead alkene in a bicyclo[8.4.1]pentadecane core. NMR methods assigned the structure and relative configurations, and its absolute configuration was proposed based on ECD calculations. The natural product displays sub-micromolar activity against the expression of pro-inflammatory proteins and transcription factors responsible for the regulation of inflammatory cytokines. We are investigating a biomimetic synthetic strategy to confirm its structure and provide material for further investigation of its anti-inflammatory properties.

The final chapter discusses a chemical education project under the advisement of Dr. Renée Link. We describe the creation, implementation, and evaluation of Quick Reference (QR) instructional videos in an undergraduate organic chemistry laboratory (OCL) setting for non-chemistry majors. The QR videos were designed to address specific, recurring questions about equipment, procedure, and concepts that students in our OCL courses find continually challenging. Quick-response barcodes for each video were located close to related glassware, equipment, and chemicals during the teaching laboratory, which could be scanned by a mobile device. Students indicated in survey responses that the QR videos were easily accessible, increased their confidence in the chosen technique, and answered questions that they would otherwise have asked their TA. We found that students engaged the most with video sections relating directly to hands-on procedures ("how"), but disengaged during conceptual explanations ("why"). This study offers useful insights into how chemistry students utilize instructional videos in a laboratory setting.

The following document describes the synthesis and preliminary testing of three novel CID-cleavable crosslinking agents for the study of protein-protein interactions. These crosslinkers contain a sulfoxide group that can be cleaved inside of the mass spectrometer at a lower energy than the peptide backbone, allowing for a series of tandem experiments to identify peptide fragments. Three crosslinkers of varying length containing a lysine-reactive N-hydroxysuccinimide ester and a photoreactive diazirine ring were developed. One crosslinker was functionalized with an alkyne to allow for affinity purification with biotin. Two of the crosslinkers have been found to successfully form crosslinks within synthetic peptides and bovine serum albumin, and experiments are currently ongoing with the third crosslinking agent.

The first chapter of this thesis details our development of a methodology to control π-facial selectivity in intramolecular Diels–Alder cyclizations using a silacycle directing group. The genesis of this project, stemming from a recent total synthesis project in our lab, is discussed. A panel of substrates is synthesized and tested, providing insight into the capabilities and, more importantly, the limits of the methodology. Deeper mechanistic insight is gained through a deuterium-labelling study, the details of which are discussed. Finally, a selection of products delivered using this methodology are shown to be apt for further synthetic derivatization. The second chapter of the thesis presents our ongoing synthetic approach to a pair of Artemisia sesquiterpenoids, artatrovirenols A and B. The isolation and characterization of these natural products is discussed as well as the isolation chemists’ proposed biosynthetic pathway. We discuss the logic of our synthetic approach, which incorporates an intramolecular Diels–Alder cyclization proposed by the isolation chemists as the key step. An initial synthetic route is investigated and discussed, but ultimately abandoned as a key Nazarov cyclization proved to be impractical. A revised synthetic route is devised and discussed, using α-santonin as the starting material. Some preliminary experiments to probe the viability of the key Diels–Alder connection are reported, without success thus far.

The dissertation describes the efforts towards synthesizing new collision-induced dissociation-cleavable protein cross-linkers (CID-XLs). Chapter one describes the background of CID-XLs and the various fragmentation pathways molecules undergo during collision-induced dissociation. Chapter two details the design and synthesis of new lysine-reactive, cysteine- reactive, and carboxylic acid-reactive sulfoxide-containing cross-linkers. A mechanism for fragmentation during tandem mass spectroscopy is proposed, and the limits of the sulfoxide functional group prompted investigation into a different CID-XL functional group. Chapter three investigates the trioxane core as a novel cleavable functional group, and two trioxane-containing CID-XLs were synthesized. Chapter four focuses on appending affinity purification to both a sulfoxide-containing and trioxane-containing CID-XL.