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.

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.

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 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.

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 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.

The first part of this thesis illustrates the application of kinetic resolution reagents for the determination of absolute configuration. A dual-catalytic approach based on ion pair recognition was explored using the combined action of 4-(N,N-dimethylamino)pyridine (DMAP) and a chiral thiourea receptor co-catalyst. After difficulties were encountered with a dual-catalytic mode, an alternative approach using enantioselective acyl transfer reagents was investigated. The new strategy led to a successful development of a new and efficient method to rapidly establish the absolute configuration of primary amines using mass spectrometry. Part two of this thesis describes the development of a modular approach toward the synthesis of the Lycopodium alkaloids. A highly concise six-step total synthesis of the complex alkaloid (+)-fastigiatine was accomplished using a transannular Mannich reaction that generated two quaternary carbons at a late stage. The modular approach to fastigiatine will be expanded to other members of the family including himeradine A and lyconadin A.

Part I of this dissertation presents the efforts directed towards the total synthesis of batrachotoxin. The general approach focuses on the construction of the C ring of the steroid backbone through two carbon-carbon bond forming reactions. This approach breaks the complex natural product into two more approachable pieces. The AB ring system was accessed from the Hajos-Parish ketone and was coupled to the elaborated D ring by a conjugate addition/Claisen rearrangement sequence to form one of the desired carbon-carbon bonds. Extensive effort has been made in an attempt to cyclize the C ring.

Part II describes the development of a new approach to the synthesis of substituted pyridines. The method aims to provide a reliable synthesis of a diverse scope of substituted pyridines through a concise three step procedure. Readily available enones are first converted into 1,5-dicarbonyls through a two-step Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method.

The first chapter details the development of a method for determining the absolute configuration of β-chiral primary alcohols that bear a π or heteroatom substituent on the stereocenter. The method relies on the rate differences of acylation using Birman’s homobenzotetramisole acylation catalyst. An empirical relationship between the faster reacting catalyst system and absolute configuration of the substrate was developed. The method is applicable to primary carbinols appended to tertiary stereocenters that bear a directing group; directing groups include arenes, heteroarenes, enones, and halides.

The second chapter details the extension of the competing enantioselective conversion method to assign the absolute configuration of secondary alcohols bearing electron-withdrawing groups such as halides and other heteroatoms. The level of selectivity is modest to good and is sufficient for determining configuration. A mathematical analysis identifies conditions for achieving maximum differences in conversion and, consequently, assigning configuration with greater confidence. The new method is effective for halohydrins and secondary−tertiary 1,2-diols and was used to confirm the configuration of two inoterpene natural products.

The third chapter details the completion of the first synthesis of (±)-illisimonin A. Notable steps in the route include a 1,3-dioxa-2-silacyclohexene templated Diels–Alder cycloaddition and type-3 semipinacol rearrangement to generate the trans-pentalene. The final step is an iron-catalyzed C-H oxidation. The synthetic route is robust, with 94 mg of racemic material prepared in a single pass. Classical resolution of a late stage intermediate enabled the synthesis of natural (–)-illisimonin A. The absolute configuration of (–)-illisimonin A was revised to 1S,4S,5S,6S,7R,9R,10R based on the X-ray structure of an heavy-atom analogue.

The fourth chapter details the use of osmium tetroxide and TMEDA to form stable crystalline adducts with alkenes. Osmate derivatization converted many liquid alkenes into solid crystalline compounds, enabling structure determination through X-ray analysis. Osmium, a heavy atom, facilitates the crystallographic analysis and the determination of the absolute configuration using common Mo X-ray sources. The utility of this method for assigning structures and absolute configurations was demonstrated on a number of unsaturated substrates that include simple alkenes, enones, enol ethers, and silyl enol ethers.