New processes that leads to formation of new carbon-carbon bond (the Michael reaction, the Mannich reaction and alkylation reaction) or carbon-heteroatom bond (á-halogenation, á-hydroxylation and á-amination) on bridged bicyclic ketones such as tropinone and TBON were investigated, utilizing LDA in the deprotonation step. All reactions, in which new carbon-heteroatom bond is formed, were not successful either due to low selectivity and/or yields. In case of new carbon-carbon bond forming processes, careful choice of electrophile (electrophile having the ester group in á-position to leaving group), allows for alkylation of tropinone with moderate yield and good selectivity. Application of new conditions to the aldol reaction of TBON and tropinone (e.g. MgI2 catalyzed aldol reaction), gave new aldol products that were not detected from the lithium enolate chemistry of these ketones. Modification of reaction conditions in case of MgI2 catalyzed aldol reaction provides, in a one pot process, bis-aldol product from TBON in good yield and high selectivity, as a single diastereoisomer. Finally, TBON is used as a suitable scaffold for the synthesis of thiacocaine. The first known synthesis of racemic thiacocaine is presented, via deprotonation of TBON with LDA, as a key step.

<p>Density Functional Theory is used in order to shed light on the reaction mechanisms and the origins of stereoselectivity in enantioselective organocatalytic reactions. The reactions investigated are the dipeptide-catalyzed aldol reaction, the cinchona thiourea-catalyzed nitroaldol reaction and the prolinol derivative-catalyzed hydrophosphination reaction. We can justify the stereoselectivity in the reactions from the energies arising from different interactions in the transition states. The major contributions to the energy differences are found to be hydrogen bond-type attractions and steric repulsions. This knowledge will be useful in the design of improved catalysts as well as general understanding of the basis of selection in other reactions</p>

The research presented herein explores three aspects of asymmetric catalysis: (1) the development of new catalytic enantioselective reactions, (2) the application of stereoselective catalysis to natural product total synthesis, and (3) the design and synthesis of new chiral catalysts. / Chemistry and Chemical Biology

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

The Whelk-O1 chiral stationary phase is widely used in liquid and supercritical chromatography for the separation of enantiomers. The enantioselective mechanism of the Whelk-O1 chiral stationary phase is the main focus of this thesis. Semi-flexible models are developed based on ab initio calculations for the Whelk-O1 selector and a series of chiral analytes. Extensive molecular dynamics simulations are then applied to study the solvation, selectivity and in silico optimization of the chiral stationary phase. The solvation of the Whelk-O1 chiral stationary phase has been explored in a normal phase n-hexane/2-propanol solvent, a reversed phase water/methanol solvent, and a supercritical CO2/methanol solvent. We found that, in all three solvents, the Whelk-O1 selectors are open to the bulk, indicating readiness for docking of analyte. Significant solvent partitioning at the interfaces was noticed, which generates a polarity gradient between the stationary phase and the bulk, and may encourage a high analyte concentration at the interface. Hydrogen bonding activities on the amide hydrogen, amide oxygen, and nitro oxygen of the Whelk selector have also been analyzed. The selectivity of the Whelk selector was studied by molecular dynamics simulations of analyte docking on the chiral stationary phase. The elution orders and the separation factors for a series of analytes were predicted successfully. We found that hydrogen bonding and π-π stacking interactions are essential for the enantioselectivity as they are strong and specific, and they hold analytes to the cleft region of the Whelk selector. Other interactions, both stabilizing interactions such as the CH-π interaction and the edge-to-face π-π interaction, and destabilizing interactions such as steric hindrance and unfavorable conformational changes also contribute to the enantioselectivity. We identified a dominant docking arrangement for the most retained enantiomers. Other docking arrangements were found to be more frequent for the least retained enantiomers and these involve interactions with alternative selector sites. Based on the identified enantioselective mechanism obtained from the study, an optimization of the Whelk-O1 chiral stationary phase was undertaken and in silico evaluation of the modified chiral stationary phases was carried out. It was demonstrated that restriction of the alternative docking arrangements for the least retained enantiomers could possibly improve the enantioselectivity of the chiral stationary phase. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-10-08 11:54:20.249

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

In the Ward Group, stereoselective aldol reactions of thiopyran derived templates play an important role in polypropionate natural product syntheses. Central to this approach is the diastereo- and enantioselective synthesis of all possible aldol adducts 3 arising from tetrahydro-4H-thiopyran-4-one (1) and 1,4-dioxa-8-thiaspiro[4.5] decane-6- carboxaldehyde (2). There are four possible diastereomers of 3 indicated by the relative configurations at positions 3 and 1’ (syn or anti) and positions 1’ and 6’ (syn or anti). Up to date, the asymmetric aldol reaction of 1 with 2 catalyzed by L-proline or its tetrazole analogue 12 provides efficient access to 3,1’-anti-1’,6’-syn-3 (3-AS) without need for chromatography (>40 g scale; 75% yield, >98% ee) and 3,1’-syn-1’,6’-syn-3(3-SS) (via isomerization of 3-AS; >75% yield, 2 cycles); however, the preparation of enantiopure 3,1’-anti-1’,6’-anti-3 (3-AA) and 3,1’-anti-1’,6’-syn-3 (3-SA) still requires the use of enantiopure aldehyde 2 in a diastereoselective synthesis. Without a simple and scalable route, access to enantioenriched iterative aldol adducts and polypropionate natural products that are based on 3-AA and 3-SA skeletons are hindered. It was observed that conducting the asymmetric aldol synthesis of 3-AS on large scale gave enantioenriched 3-AA as a very minor product. This observation triggered the hypothesis of using L-proline to resolve racemic 3-AA via a retro-aldol reaction.In this thesis, the development, optimization, and application of an unprecedented L-proline catalyzed enantioselective retro-aldol reaction is described. Interesting mechanistic insights were uncovered. An unexpected isomerization process between 3-AA and 3-SA occurs in parallel with the retro-aldol process. The method was demonstrated to be a robust, flexible, and readily scalable process to access highly enantioenriched 3-AA (ee > 95%) and 3-SA (ee > 95%). To the best of our knowledge, this reaction represents the only reported enantioselective retro-aldol reaction catalyzed by L-proline.

Thesis (Ph. D.)--University of Chicago, Department of Chemistry, August 2002. / Includes bibliographical references. Also available on the Internet.

This thesis describes two new phase-transfer catalysed processes, in which asymmetry is mediated via ion-pairing with a chiral cation. In the first chapter, an enantioselective method for N functionalization of pyrroles is described and a phase-transfer catalysed approach to axial chirality via a cation-directed SNAr reaction is discussed in Chapters 3, 4 and 5.

This thesis presents the application and development of H-bond donor organocatalysts. Chapter 2 presents an intramolecular Michael addition of &beta;-dicarbonyls onto &alpha;,&beta;-unsaturated esters catalyzed by tertiary amine/H-bond donor bifunctional catalysts, achieving up to 88&percnt; ee. Chapter 3 outlines the design and synthesis of a new family of cinchona-derived H-bond donor/ammonium salt phase-transfer catalysts. The ability of these asymmetric phase-transfer catalysts to activate less reactive substrates than their tertiary amine analogues and to induce higher levels of enantiocontrol than commercially available phase-transfer catalysts was demonstrated in an intramolecular Michael addition. Chapter 4 details the highly successful application of these new H-bond donor/ammonium salt phase-transfer catalysts to the enantio- and diastereoselective nitro-Mannich reaction of &alpha;-amido sulfones with nitroalkanes. Preliminary investigations into a novel phase-transfer catalyzed asymmetric ketimine reduction demonstrate the ability of these catalysts to provide access to new methods.