The exploitation of resident stereogenic centers to construct new stereogenic centers is a powerful strategy employed in the synthesis of complex organic molecules. Although the influence of both α- and β-stereogenic centers on the diastereoselective addition of nucleophiles to aldehydes has been thoroughly studied, analogous studies of α- and β-substituted imines are sparse. This dissertation describes the comprehensive study of how inherent asymmetry impacts diastereoselective nucleophilic additions to α- and β-chiral N-sulfonyl imines. Chapter one discusses the development of stereodivergent Lewis acid-mediated nucleophilic additions to α-chiral N-sulfonyl imines. From this study, two sets of optimized and generalizable conditions were developed, allowing access to either syn or anti diastereomeric outcomes in >95:5 diastereomeric ratios. Chapter two discusses the diastereoselective Lewis acid-mediated nucleophilic additions to β-chiral N-sulfonyl imines. These reactions typically proceed through a six-membered chelate and result in anti-products. Experimental and computational evidence lead to the construction of a generalizable stereoelectronic model that predicts for the magnitude of selectivity observed based on conformational preferences of the substrate-Lewis acid chelate. These two chapters together constitute a complete study of how 1,2 and 1,3 asymmetric induction affect diastereoselective nucleophilic additions to chiral N-sulfonyl imines.

This dissertation describes four synthetic organic chemistry projects and two computational organic chemistry efforts centered on the Castagnoli-Cushman reaction (CCR) of imines with anhydrides and their derivatives. Chapter one includes a literature review and detailed background on the current state of the CCR, including mechanistic hypotheses and recent catalytic examples. Chapter two details the development of conjugate addition reactions of imines with cyclic enolizable anhydrides to afford β-enaminoketone products. Chapter three describes efforts toward an acid-catalyzed Mukaiyama-type CCR reaction of 2,5-bis(trimethylsilyloxy) furan, including a stereochemical proof by computational NMR. Chapter four describes progress toward the synthesis of the elusive bis-?-lactam natural product bisavenanthramide B-1 by way of the Mukaiyama CCR. Finally, chapter five discusses the mechanistic investigation of the multicomponent variants of the CCR, leading to a new mechanistic proposal for reactions of these type.

The allylation reaction is an ambiphilic reaction depending on the nature of the allylic substituent. Depending on the allylic substituent the allyl can either be nucleophilic or electrophilic. This dissertation describes the nucleophilic crotylation of a-chiral alkoxy imines in high diastereoselectivity and the electrophilic enantioselective allylation of a prochiral heterocyclic sulfonimidamide in high enantioselectivity and yield. Chapter 1 describes the Lewis acid promoted addition of prochiral E and Z allyl nucleophiles to chiral a-alkoxy N-tosyl imines is described. Alkene geometry is selectively transferred to the newly formed carbon-carbon bond, resulting in stereochemical control of carbons 2 and 3, resulting in 2-alkoxy-3-N-tosyl-4-alkyl-5-hexene products. A computational analysis to elucidate the high selectivity is also presented. This methodology was employed in the synthesis of two naturally occurring isomers of clausenamide. Chapter 2 describes the enantioselective allylation of prochiral sulfonimidamides via a Tsuji-Trost Asymmetric Allylation reaction. Sulfonimidamides undergo prototropic tautomerization in solution. In the case where both nitrogen substituents of a disubstituted sulfonimidamide are the same, the two tautomers are also enantiomers, allowing deprotonation to generate a prochiral anion. Herein we report the first transition metal catalyzed approach to the desymmetrization of sulfonimidamides relying on commercially available palladium catalysts and ligands. The reaction leads to functionalized, enantioenriched products in high yields.

The creation of new carbon–carbon bonds with a high degree of stereocontrol is a powerful strategy employed in targeted synthesis of complex organic molecules. Chiral benzene-fused 5-membered rings represent a significant portion of medicinally relevant molecules. This dissertation describes the construction of benzodihydrofurans, indanes and indolines by C–H insertion reactions of donor/donor carbenes. Chapter one discusses the development of a stereochemcially predicative model for insertion reactions to form benzodihydrofurans. From this study, a predictive model for diastereoselecitivty was established. Chapter two discusses methodology development for insertion reactions to make indolines and indanes. These cores were produced in high yields, with a high degree of stereocontrol and functional group tolerance.

Described herein are three projects in the field of organic chemistry pertaining to the asymmetric synthesis of isochromans and isochroman-based natural products by C–H insertion reactions with donor/donor carbenes. The first chapter details the development of a methodology to stereoselectively synthesize isochromans. This work expands on our previous reports by accommodating six-membered ring substrates, notably with perfect diastereoselectivity in all cases and without observation of Stevens rearrangement byproducts. The second chapter employs this methodology towards the asymmetric total synthesis of panowamycin A, panowamycin B, TM-135, and veramycin F. The synthesis of the proposed structure of panowamycin A revealed a stereochemical misassignment. Computational NMR was used to predict the isomer most likely to be the natural substance; the synthesis of this compound was completed and the spectral data were consistent with the reported natural product, therefore confirming the structure to be correct. The third chapter involves the synthesis of tetrasubstituted geminal acyl/alkoxy allenes, which was incidentally discovered while exploring the substrate scope for isochroman formation. With support from byproduct identification and control experiments, the mechanism of formation for these novel compounds is proposed. This new class of allenes was then explored as a reagent in subsequent transformations, where they demonstrated unique reactivity.

Herein is described a method for the diastereoselective synthesis of highly-substituted β-enamino ketones from anhydrides and ketone-derived imines. Cyclic, enolizable anhydrides undergo a base-promoted conjugate addition reaction with ⍺,β-unsaturated N-tosyl ketimines, followed by an intramolecular acylation to give formal [4+2] cycloaddition products. The carboxylic acid-containing products are formed in modest selectivity for the cis-diastereomer and can be fully epimerized to the trans-diastereomer upon esterification.

This dissertation describes two projects in the organic chemistry field centering around the stereoselective synthesis of trisubstituted benzodihydrofurans and related natural products through C–H insertion of donor/donor carbenes into stereogenic centers. The first chapter reports the development of a stereoselective methodology to make 2,2,3-trisubstituted benzodihydrofurans. The method expands intramolecular C–H insertion reactions with donor/donor carbenes to stereogenic insertion centers, thereby enabling benzodihydrofuran formation in high diastereoselectivity and enantioselectivity. Computational studies on the system illuminate the origins of divergent stereochemical outcomes for different substrate classes. The second chapter applies this methodology to the asymmetric synthesis of two dihydrobenzoxanthone natural products, cycloartobiloxanthone and artoindonesianin Z-2. First, an introduction to the natural product subclass outlines structural variations and biosynthetic pathways for the isolated natural products found in the family and their reported biological activities. Progress towards the synthesis of these two natural products is split into three main stages. The first stage reports a first-generation route and its related benzylic oxidation roadblock. The second stage details numerous route-scouting endeavors. The third stage outlines a second-generation route and future work toward completing the asymmetric synthesis of cycloartobiloxanthone and artoindonesianin Z-2.