As the need for developing environmentally friendly chemistry continues to become more apparent, catalytic asymmetric hydrogenation has risen to the forefront as a reliable and eco-friendly method for enantioselective synthesis. We herein describe our progress toward the synthesis of valuable structural motifs via hydrogenation: chiral 1,2-diamines, 1,3-diamines and substituted cyclohexanes. We propose a strategy whereby protected 1,2-diimine and 1,3-diimine surrogates can be hydrogenated selectively and deprotected to furnish the desired chiral amines. Using this strategy, it was demonstrated that imidazolone precursors could be hydrogenated with >20:1 diastereoselectivity to give latent 1,2-diamines, albeit with no enantiomeric excess. We further propose that substituted benzene rings linked to an oxazolidinone chiral-auxiliary can be diastereoselectively hydrogenated using a heterogeneous metal catalyst. Following hydrogenation, the chiral cyclohexanes could be obtained in up to quantitative yield and 99% diastereomeric excess.

Master of Science / Department of Chemistry / Sundeep Rayat / Compounds containing the tetrazole scaffold have wide variety of applications in medicine, food industry, automobile industry, photography, agriculture. As a result, the structure and reactivity of these compounds have been studied. However, the related tetrazolethione scaffold has not been studied well. In our work presented in Chapter-1 (part-1), the synthesis, photochemical properties and reactivities of 1,4-disubstituted tetrazolethione analogs 20a-d are described. The solvent effects on the photochemistry of compounds are discussed and; the rates and quantum yields for the photodecomposition of compounds are documented. The photodecomposition products for the photolysis of 20a-d were analyzed by LCMS, GCMS and NMR spectroscopy; the results pertaining to their identification are also reported. Further, the multiphoton excitation of THF solution of 1-methyl-4-(4-nitrophenyl)-1H-tetrazol-5(4H)-thione 20d with Ti: Sapphire laser was also performed; however, the experiment was not successful. In Chapter-2 (part-1), the cytoxicity of the 1-methyl-4-(4-chlorophenyl)-1H-tetrazol-5(4H)-thione 20c against human breast cancer cell is documented. MTT assays were performed for a time dependent study of the cytoxicity. In part-2 which consists of Chapter-3, the synthesis of 2-(2-phenylimino)vinyl)benzonitirle is described. This was as a step towards our laboratory's goal of synthesizing a series of mono-, di- and tri- azaenyne-allenes and studying their Myers-Saito and Schmittel cyclizations. In future, if our cyclization studies are successful, these cyclizations could be employed for synthesis of heteroaromatic rings found in many compounds of biological importance.

This thesis focuses on the development of carbon-carbon/carbon-heteroatom bond forming reactions using strained ring systems under transition metal catalysis. The first chapter describes the use of bifunctional organoboron reagents with a rhodium catalyst to synthesize carbocycles through a cascade sequence. The reaction of norbornene derivatives gives vinylcyclopropane and cyclopentene products in moderate to good yield. The mechanistic proposal and insights into the reaction mechanism are presented. Preliminary results from studies toward an enantioselective sequential addition/cyclization process are described. The methodology is subsequently applied in the synthesis of a variety of polycyclic heteroaromatics using bifunctional heteroaryl boronate esters. The second chapter describes studies toward the formation of carbon-heteroatom bonds using cyclopropane derivatives. Under a recently developed Pd(OAc)2/PhI(OAc)2 catalytic system, methylenecyclopropanes are isomerized to substituted pyridines via a sequential fragmentation/cyclization process. Under same reaction conditions, allylic acetate products are obtained from the isomerization of cyclopropanes through a similar process.

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.

Chapter 1 details our investigation into the Diels-Alder reaction between arynes and chiral furans and pyrroles for the synthesis of unsymmetrical [2.2.1] oxabicyclic and azabicyclic scaffolds as single enantiomers. It was discovered that the diastereoselectivity of the aryne Diels-Alder reaction was sensitive to conformational effects that could be exploited to obtain both high yields and dr. Stereoselective synthesis using arynes is an overlooked field, and this contribution represents one of only three such examples in the literature. The desymmetrization of meso [2.2.1] oxabicyclic systems by intramolecular cyclization/ring- opening was studied, and a cationic Rh/t-Bu-Josiphos catalyst was developed that delivered polyclic dihydronaphthalene products in excellent yield and ee. These catalyst conditions were used for the ring-opening of an enantiomerically pure unsymmetrical oxabicyclic alkene, which led to the discovery that ring-opening proceeded with complete reagent control. A regiodivergent resolution was designed that gave pairs of enantiomerically enriched dihydronaphthalenes from unsymmetrical racemic starting materials. In chapter 3, the scope of the regiodivergent resolution was expanded to include the ring-opening of remotely-substituted oxabicyclic alkenes and furan-hetaryne Diels-Alder adducts. The utility ii of the method was demonstrated by using it to synthesize two important API molecules from a single racemic precursor. Finally, chapter 4 describes our lab’s efforts toward the total synthesis of the natural products phorbol and prostratin that features the ring-opening of an unsymmetrical [3.2.1] oxabicycle as the key step. Advanced intermediates (requiring >30 linear steps) were synthesized on gram- scale. The entire carbon framework was successfully installed, and our efforts to complete the synthesis are discussed.

This thesis focuses on the development of carbon-carbon/carbon-heteroatom bond forming reactions using strained ring systems under transition metal catalysis. The first chapter describes the use of bifunctional organoboron reagents with a rhodium catalyst to synthesize carbocycles through a cascade sequence. The reaction of norbornene derivatives gives vinylcyclopropane and cyclopentene products in moderate to good yield. The mechanistic proposal and insights into the reaction mechanism are presented. Preliminary results from studies toward an enantioselective sequential addition/cyclization process are described. The methodology is subsequently applied in the synthesis of a variety of polycyclic heteroaromatics using bifunctional heteroaryl boronate esters. The second chapter describes studies toward the formation of carbon-heteroatom bonds using cyclopropane derivatives. Under a recently developed Pd(OAc)2/PhI(OAc)2 catalytic system, methylenecyclopropanes are isomerized to substituted pyridines via a sequential fragmentation/cyclization process. Under same reaction conditions, allylic acetate products are obtained from the isomerization of cyclopropanes through a similar process.

Chapter 1 details our investigation into the Diels-Alder reaction between arynes and chiral furans and pyrroles for the synthesis of unsymmetrical [2.2.1] oxabicyclic and azabicyclic scaffolds as single enantiomers. It was discovered that the diastereoselectivity of the aryne Diels-Alder reaction was sensitive to conformational effects that could be exploited to obtain both high yields and dr. Stereoselective synthesis using arynes is an overlooked field, and this contribution represents one of only three such examples in the literature. The desymmetrization of meso [2.2.1] oxabicyclic systems by intramolecular cyclization/ring- opening was studied, and a cationic Rh/t-Bu-Josiphos catalyst was developed that delivered polyclic dihydronaphthalene products in excellent yield and ee. These catalyst conditions were used for the ring-opening of an enantiomerically pure unsymmetrical oxabicyclic alkene, which led to the discovery that ring-opening proceeded with complete reagent control. A regiodivergent resolution was designed that gave pairs of enantiomerically enriched dihydronaphthalenes from unsymmetrical racemic starting materials. In chapter 3, the scope of the regiodivergent resolution was expanded to include the ring-opening of remotely-substituted oxabicyclic alkenes and furan-hetaryne Diels-Alder adducts. The utility ii of the method was demonstrated by using it to synthesize two important API molecules from a single racemic precursor. Finally, chapter 4 describes our lab’s efforts toward the total synthesis of the natural products phorbol and prostratin that features the ring-opening of an unsymmetrical [3.2.1] oxabicycle as the key step. Advanced intermediates (requiring >30 linear steps) were synthesized on gram- scale. The entire carbon framework was successfully installed, and our efforts to complete the synthesis are discussed.

Noncovalent and reversible covalent interactions have long been exploited in catalysis and supramolecular chemistry. Examples of such noncovalent interactions include hydrogen bonding, halogen bonding and CH-π and π-π interactions. Reversible covalent interactions that have been employed towards these ends comprise the formation of imines, acetals, ketals and boronate esters. This thesis describes the investigation of various noncovalent and reversible covalent interactions, and their possible applications in catalysis and novel reaction development. Chapter 1 describes the investigation of anion receptors composed of hydrogen- and halogen- bond donor groups. Binding studies of these molecules have indicated that they are capable of interacting with an anion simultaneously through hydrogen and halogen bonding. Receptor design was found to have a profound effect on the strength of the halogen bonding interaction. Receptors containing halogen-bond donors showed selectivity for halide anions over oxyanions. In Chapter 2, potential halogen bonding catalysts were synthesized and screened in a series of reactions. Incorporating halogen-bond donors into the catalysts appeared to have no beneficial effect in terms of reactivity. Explanations for these observations are discussed along with suggestions for designing future catalysts that could exploit halogen bonding interactions. Chapter 3 discusses attempts to use hydrogen-bond donor catalysts to effect catalyst-controlled stereoselective additions to 2-nitroglycals. While stereoselective additions were observed in some cases, they were not catalyst-controlled. The results from these experiments suggested that catalysts and reactions developed for simple nitroalkenes could not be easily adapted to 2-nitroglycal substrates. A review of interactions between boron containing compounds and saccharides is presented in Chapter 4. Their applications in drug delivery systems, cellular imaging and the sensing and separation of carbohydrates are discussed, in addition to their uses as protecting and activating groups in oligosaccharide synthesis. Finally in Chapter 5, the development of a regioselective boronic acid-mediated glycosylation reaction is described. This methodology was applied in the synthesis of two key intermediates used in the synthesis of a pentasaccharide derivative isolated from the plant Spergularia ramosa.

Noncovalent and reversible covalent interactions have long been exploited in catalysis and supramolecular chemistry. Examples of such noncovalent interactions include hydrogen bonding, halogen bonding and CH-π and π-π interactions. Reversible covalent interactions that have been employed towards these ends comprise the formation of imines, acetals, ketals and boronate esters. This thesis describes the investigation of various noncovalent and reversible covalent interactions, and their possible applications in catalysis and novel reaction development. Chapter 1 describes the investigation of anion receptors composed of hydrogen- and halogen- bond donor groups. Binding studies of these molecules have indicated that they are capable of interacting with an anion simultaneously through hydrogen and halogen bonding. Receptor design was found to have a profound effect on the strength of the halogen bonding interaction. Receptors containing halogen-bond donors showed selectivity for halide anions over oxyanions. In Chapter 2, potential halogen bonding catalysts were synthesized and screened in a series of reactions. Incorporating halogen-bond donors into the catalysts appeared to have no beneficial effect in terms of reactivity. Explanations for these observations are discussed along with suggestions for designing future catalysts that could exploit halogen bonding interactions. Chapter 3 discusses attempts to use hydrogen-bond donor catalysts to effect catalyst-controlled stereoselective additions to 2-nitroglycals. While stereoselective additions were observed in some cases, they were not catalyst-controlled. The results from these experiments suggested that catalysts and reactions developed for simple nitroalkenes could not be easily adapted to 2-nitroglycal substrates. A review of interactions between boron containing compounds and saccharides is presented in Chapter 4. Their applications in drug delivery systems, cellular imaging and the sensing and separation of carbohydrates are discussed, in addition to their uses as protecting and activating groups in oligosaccharide synthesis. Finally in Chapter 5, the development of a regioselective boronic acid-mediated glycosylation reaction is described. This methodology was applied in the synthesis of two key intermediates used in the synthesis of a pentasaccharide derivative isolated from the plant Spergularia ramosa.

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.