N-alkenyl aziridines are a unique class of molecules that do not behave as typical enamines as a result of the inability of the nitrogen atom lone-pair of electrons to delocalize. The attenuated nucleophilicity of these enamines presents opportunities for selective functionalization and reactivity not available to classical enamines. An operationally simple and mild copper-mediated coupling has been developed that facilitates the preparation of a broad range of N-alkenyl aziridines not available through existing methods. The preparation and reactivity of highly functionalized N-alkenyl aziridines are reported. Also reported is the application of the chemoselective amine/aldehyde/alkyne (A3) multicomponent coupling involving amphoteric aziridine aldehydes as the aldehyde component. This coupling allows access to propargyl amines with pendent aziridine functionality.

The central theme of the research described in this thesis involves taking advantage of the reversible covalent interactions of organoboron species with diols, and exploiting them as catalyst-substrate interactions. Using this philosophy, novel catalytic transformations have been developed to form carbon-carbon and carbon-oxygen bonds. Chapter 1 describes a method that uses organoboron species to activate pyruvic acids in the direct aldol reaction with aldehydes. Formation of an anionic tetracoordinate boron adduct was the key step in the proposed mechanism. A wide range of aldehydes may be employed, delivering useful isotetronic acid products in high yields. The efficient synthesis of oligosaccharides requires methods for regioselective manipulation of hydroxyl groups in monosaccharides. Catalysis represents a potentially general solution to this problem, and recently, the development of catalyst-controlled methods towards this goal has intensified. Chapter 2 highlights the range of catalysts that may be exploited to alter the reactivity of hydroxyl groups in carbohydrates. Chapter 3 describes a novel diphenylborinic acid-catalyzed protocol, which enables the site-selective functionalization of carbohydrate derivatives and non-carbohydrate-derived 1,2- and 1,3-diols with a wide diversity of electrophiles. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics and catalyst structure-activity relationships. These studies are consistent with reaction of a tetracoordinate borinate complex with the electrophilic species in the turnover-limiting step of the catalytic cycle. Chapter 4 further explores the utility of borinic acid activation in the first small-molecule-catalyzed glycosylation reaction of unprotected or minimally protected glycosyl acceptors. High levels of selectivity for the equatorial hydroxyl group of cis-1,2-diol motifs are demonstrated in reactions of several glycosyl acceptors using a variety of glycosyl halide donors. Chapter 5 describes a novel mode of catalysis using a boronic acid/Lewis base co-catalyst system. The proposed mode of activation involves the formation of a tetracoordinate adduct that displays enhanced nucleophilicity at the boron-bound alkoxide groups. This concept was applied to the regioselective silylation of carbohydrate derivatives as well as the desymmetrization of diols. Finally, Chapter 6 summarizes the work described in this thesis, discusses the challenges encountered in the development of the methodologies, and speculates on future directions that can be taken.

The central theme of the research described in this thesis involves taking advantage of the reversible covalent interactions of organoboron species with diols, and exploiting them as catalyst-substrate interactions. Using this philosophy, novel catalytic transformations have been developed to form carbon-carbon and carbon-oxygen bonds. Chapter 1 describes a method that uses organoboron species to activate pyruvic acids in the direct aldol reaction with aldehydes. Formation of an anionic tetracoordinate boron adduct was the key step in the proposed mechanism. A wide range of aldehydes may be employed, delivering useful isotetronic acid products in high yields. The efficient synthesis of oligosaccharides requires methods for regioselective manipulation of hydroxyl groups in monosaccharides. Catalysis represents a potentially general solution to this problem, and recently, the development of catalyst-controlled methods towards this goal has intensified. Chapter 2 highlights the range of catalysts that may be exploited to alter the reactivity of hydroxyl groups in carbohydrates. Chapter 3 describes a novel diphenylborinic acid-catalyzed protocol, which enables the site-selective functionalization of carbohydrate derivatives and non-carbohydrate-derived 1,2- and 1,3-diols with a wide diversity of electrophiles. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics and catalyst structure-activity relationships. These studies are consistent with reaction of a tetracoordinate borinate complex with the electrophilic species in the turnover-limiting step of the catalytic cycle. Chapter 4 further explores the utility of borinic acid activation in the first small-molecule-catalyzed glycosylation reaction of unprotected or minimally protected glycosyl acceptors. High levels of selectivity for the equatorial hydroxyl group of cis-1,2-diol motifs are demonstrated in reactions of several glycosyl acceptors using a variety of glycosyl halide donors. Chapter 5 describes a novel mode of catalysis using a boronic acid/Lewis base co-catalyst system. The proposed mode of activation involves the formation of a tetracoordinate adduct that displays enhanced nucleophilicity at the boron-bound alkoxide groups. This concept was applied to the regioselective silylation of carbohydrate derivatives as well as the desymmetrization of diols. Finally, Chapter 6 summarizes the work described in this thesis, discusses the challenges encountered in the development of the methodologies, and speculates on future directions that can be taken.

N-alkenyl aziridines are a unique class of molecules that do not behave as typical enamines as a result of the inability of the nitrogen atom lone-pair of electrons to delocalize. The attenuated nucleophilicity of these enamines presents opportunities for selective functionalization and reactivity not available to classical enamines. An operationally simple and mild copper-mediated coupling has been developed that facilitates the preparation of a broad range of N-alkenyl aziridines not available through existing methods. The preparation and reactivity of highly functionalized N-alkenyl aziridines are reported. Also reported is the application of the chemoselective amine/aldehyde/alkyne (A3) multicomponent coupling involving amphoteric aziridine aldehydes as the aldehyde component. This coupling allows access to propargyl amines with pendent aziridine functionality.

Amino aldehydes are important building blocks in organic synthesis. However, due to the innate propensity for condensation to occur upon combination of aldehydes and amines, uprotected amino aldehydes are unstable. One exception to this is the existence of dimeric aziridine aldehydes. We have shown that the enhanced stability observed with these unprotected aziridine aldehydes is due to their dimeric nature. In addition, we have shown that reversible dimer dissociation plays a key role in the kinetics and stereoselectivity of subsequent reactions. Reductive amination with the unprotected amino aldehyde dimers occurs without double addition or epimerization. The resulting aziridine conjugates were used towards a convergent synthesis of aminomethylene peptidomimetics, by aziridine ring opening with C-terminal peptide thioacids. We have shown that we can also utilize the aziridine aldehydes towards the assembly of branched peptides.

The development of dimetallic metal complexes into functional and selective recognition agents for monophosphorylated peptides is described. The development of dimetallic metal complexes into functional and selective phosphopeptide recognition agents is described. Scaffold functionalization was conducted to assess whether binding affinity for phosphate monoesters could be modulated. A protocol for the facile synthesis of symmetric and asymmetric pyridine-functionalized bis-dipicolylamine (BDPA) scaffolds was thus first optimized. Zn(II) complexes were screened for the ability to bind to various phosphate monoesters of biological relevance using isothermal titration calorimetry (ITC). An expanded family of compounds was then screened using a variety of biophysicial and biological techniques for the ability to bind to disrupt Stat3 dimer both in biophysical assays and in whole cells. Several compounds displayed the ability to potently disrupt Stat3 dimer formation at low micromolar doses. Moreover, one compound emerged as having potent anti-cancer activity against MDA468, a solid breast cancer tumor line. Efforts were subsequently redirected towards the development of Zn(II)-BDPA receptors which mimicked the pY, pY+X recognition motif displayed by human SH2 domains. A family of ditopic biphenyl-based receptors, computationally predicted to adopt this binding mode, were synthesized and screened against a family of high-profile pY-containing phosphopeptides. The reported family of mimetics displayed a wide variance in cytotoxicity against common cancer cell lines, supporting our structure-activity hypothesis. Selectivity observed in our fluorescence intensity assay did not hold in a cellular context. We next pursued the development of selective receptors for phosphopeptides containing pS instead of pY. A diverse family of Zn(II)-BDPA receptors featuring a 2’ substituted benzothiazole core were synthesized, and their binding affinities toward model phosphopeptides assessed. A central conclusion of this project is that development of potent, selective receptors for anionic and hydrophobic peptides will likely be possible only by using receptors with cationic or hydrophobic pendants, and by maximizing phosphopeptide-specific interactions. Lastly, investigations into the use of bowl-type receptors as phosphopeptide recognition agents are presented. Synthesis of a prototype bowl receptor and early efforts to characterize the receptor’s binding preferences using ITC are reported. Progress-to-date in the development of a FRET system, which will be used to measure the receptor’s affinity for different dephosphorylation motifs, is also reported.

The development of dimetallic metal complexes into functional and selective recognition agents for monophosphorylated peptides is described. The development of dimetallic metal complexes into functional and selective phosphopeptide recognition agents is described. Scaffold functionalization was conducted to assess whether binding affinity for phosphate monoesters could be modulated. A protocol for the facile synthesis of symmetric and asymmetric pyridine-functionalized bis-dipicolylamine (BDPA) scaffolds was thus first optimized. Zn(II) complexes were screened for the ability to bind to various phosphate monoesters of biological relevance using isothermal titration calorimetry (ITC). An expanded family of compounds was then screened using a variety of biophysicial and biological techniques for the ability to bind to disrupt Stat3 dimer both in biophysical assays and in whole cells. Several compounds displayed the ability to potently disrupt Stat3 dimer formation at low micromolar doses. Moreover, one compound emerged as having potent anti-cancer activity against MDA468, a solid breast cancer tumor line. Efforts were subsequently redirected towards the development of Zn(II)-BDPA receptors which mimicked the pY, pY+X recognition motif displayed by human SH2 domains. A family of ditopic biphenyl-based receptors, computationally predicted to adopt this binding mode, were synthesized and screened against a family of high-profile pY-containing phosphopeptides. The reported family of mimetics displayed a wide variance in cytotoxicity against common cancer cell lines, supporting our structure-activity hypothesis. Selectivity observed in our fluorescence intensity assay did not hold in a cellular context. We next pursued the development of selective receptors for phosphopeptides containing pS instead of pY. A diverse family of Zn(II)-BDPA receptors featuring a 2’ substituted benzothiazole core were synthesized, and their binding affinities toward model phosphopeptides assessed. A central conclusion of this project is that development of potent, selective receptors for anionic and hydrophobic peptides will likely be possible only by using receptors with cationic or hydrophobic pendants, and by maximizing phosphopeptide-specific interactions. Lastly, investigations into the use of bowl-type receptors as phosphopeptide recognition agents are presented. Synthesis of a prototype bowl receptor and early efforts to characterize the receptor’s binding preferences using ITC are reported. Progress-to-date in the development of a FRET system, which will be used to measure the receptor’s affinity for different dephosphorylation motifs, is also reported.

Reaction of unsymmetrical allylic electrophiles with amines gives rise to regioisomeric allylamines. It was found that linear products result from the thermodynamically controlled isomerization of the corresponding branched products, which form initially. The isomerization was found to be promoted by the presence of acid and active palladium catalyst. The use of base shut down the isomerization pathway and allowed for the preparation and isolation of branched allylamines. This methodology provides a powerful control element, which allows for the installation of quaternary and chiral centres next to nitrogen. Later, the isomerization was combined with ring-closing metathesis to afford the synthesis of exocyclic allylamines from their thermodynamically less-stable endocyclic precursors. This rearrangement became feasible as a result of the electrophilic nature of a C – N bond in allylamines. When compared to the conventional intramolecular allylic amination, such approach escapes chemoselectivity issues, which makes it attractive attractive for late-stage synthetic modifications.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / (+)-Myriceric acid A, [(+)-1.1], is a natural product isolated in 0.01% yield from the southern bayberry, myrica cerifera twigs. It is a specific ETA receptor antagonist because it selectively inhibits the endothelin-1 (ET-1) induced increase in [Ca2+] (IC50 = 11 + 2 nM) and antagonizes the binding of ET-1 (Ki = 66 + 15 nM), in rat aortic smooth muscle cells. ET-1 is a potent vasoconstrictor peptide released by the vascular endothelial cell. Over production of this peptide causes vasospasm, which may lead to heart attack, stroke, pulmonary hypertension, and congestive heart failure. My research involved the development of a total synthesis of (+)-myriceric acid A. This is a triterpenoid compound that has five six-member rings, seven stereo-centers, a carboxylic acid group, and a trans-caffeoyl ester side chain. The synthesis was planned to be accomplished by adding the D and E rings to the known ABC ring compound (4a'S,4b'R,8a'R)-1',1',4a',8a'-tetramethyldecahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-8'(3'H)-one [(-)-2.1]. Many model studies, both convergent and linear syntheses, were conducted to determine the best approach to construct the D and E rings. From these studies it was determined that a linear synthesis was best. After the ABCD ring compound (4aR,4bR,6aR,10bR)-1,1,4a,10b-tetramethyl-4,4a,4b,5,6,6a,7,8,10b,11,12,12a-dodecahydro-1H-spiro[chrysene-2,2'-[1,3]dioxolan]-9(3H)-one [(-)-3.41a] was synthesized, several approaches were investigated for the functionalization of the D ring. The best method turned out to be one in which the C14 position of 3.41a was functionalized by a Michael addition of a nitrile group. Conversion of the nitrile to the aldehyde proved to be problematic, but was overcome by the formation of an interesting cyclic hemiiminal which hydrolyzed cleanly to the aldehyde (4aR,4bR,6aR,10aS,10bR,12aR)-1,1,4a,10b-tetramethyl-9-oxohexadecahydro-1H-spiro[chrysene-2,2'-[1,3]dioxolane]-10a-carbaldehyde (4.22) when treated with acid. Herein, the studies that led to the tetra-cyclic aldehyde 4.22, a key intermediate for the synthesis of (+)-myriceric acid A, will be discussed.

Doctor of Philosophy / Department of Chemistry / Stefan Kraft / In the present study, the rescorcin[4]arenes decorated with an alternating arrangement of pyridinium and sulfonate moieties were synthesized to establish a molecular quadrupole. These rescorcin[4]arenes are capable of undergoing conformational changes from a ‘collapsed’ to ‘open’ state. The stability of the two state are controlled by the polarity of the solvent environment. The electrostatic interactions between pyridinium and sulfonates enforced a ‘quadrupolar collapse’ in solvents such as chloroform. While these interactions are disrupted in dimethylsulfoxide. A major synthetic challenge was functionalizing the resorcin[4]arene in a positive/negative/positve/negative pattern was successfully addressed. Comparison to dipolar resorcin[4]arene were undertaken to establish a quantitative measurement of the quadrupolar forces and to address the question of cooperatively provided addition attraction beyond two dipoles. A,C-functionalized-bis sulfonate resorcin[4]arenes and A,C function bis-pyridinium resocin[4]arenes were synthesized independently. Combining these dicationic and dianionic moieties provided an interdigitating dimeric unit with overall quadrupolar charge distribution. Disruption of the quadrupolar salt bridges in CDCl[subscript]3 was accomplished through the addition of DMSO or through dilution. DeltaG[superscript]o, DeltaH[superscript]o, and DeltaS[superscript]o have been determined for the dimer formation. Addition of pyridinium salts led to a disruption of the dimeric capsule. Host-guest binding studies established attractive binding to CS[superscript]2. Larger guests such as toluene, diiodobenzene, dicynanobenzene could not be encapsulated.