A DFT Guided/Experimental Approach to Asymmetric Allylation and Phase-Transfer Catalysis

The Dudding group is interested in the application of Density Functional Theory (DFT) in developing asymmetric methodologies, and thus the focus of this dissertation will be on the integration of these approaches. Several interrelated subsets of computer aided design and implementation in catalysis have been addressed during the course of these studies. The first of the aims rested upon the advancement of methodologies for the synthesis of biological active C(1)-chiral 3-methylene-indan-1-ols, which in practice lead to the use of a sequential asymmetric Yamamoto-Sakurai-Hosomi allylation/Mizoroki Heck reaction sequence. An important aspect of this work was the utilization of ortho-substituted arylaldehyde reagents which are known to be a problematic class of substrates for existing asymmetric allylation approaches. The second phase of my research program lead to the further development of asymmetric allylation methods using o-arylaldehyde substrates for synthesis of chiral C(3)-substituted phthalides. Apart from the de novo design of these chemistries in silico, which notably utilized water-tolerant, inexpensive, and relatively environmental benign indium metal, this work represented the first computational study of a stereoselective indium-mediated process. Following from these discoveries was the advent of a related, yet catalytic, Ag(I)-catalyzed approach for preparing C(3)-substituted phthalides that from a practical standpoint was complementary in many ways. Not only did this new methodology build upon my earlier work with the integrated (experimental/computational) use of the Ag(I)-catalyzed asymmetric methods in synthesis, it provided fundamental insight arrived at through DFT calculations, regarding the Yamamoto-Sakurai-Hosomi allylation. The development of ligands for unprecedented asymmetric Lewis base catalysis, especially asymmetric allylations using silver and indium metals, followed as a natural extension from these earlier discoveries. To this end, forthcoming as well was the advancement of a family of disubstituted (N-cyclopropenium guanidine/N-imidazoliumyl substituted cyclopropenylimine) nitrogen adducts that has provided fundamental insight into chemical bonding and offered an unprecedented class of phase transfer catalysts (PTC) having far-reaching potential. Salient features of these disubstituted nitrogen species is unprecedented finding of a cyclopropenium based C-H•••πaryl interaction, as well, the presence of a highly dissociated anion projected them to serve as a catalyst promoting fluorination reactions. Attracted by the timely development of these disubstituted nitrogen adducts my last studies as a PhD scholar has addressed the utility of one of the synthesized disubstituted nitrogen adducts as a valuable catalyst for benzylation of the Schiff base N-diphenyl methylene glycine ethyl ester. Additionally, the catalyst was applied for benzylic fluorination, emerging from this exploration was successful fluorination of benzyl bromide and its derivatives in high yields. A notable feature of this protocol is column-free purification of the product and recovery of the catalyst to use in a further reaction sequence.

Design and synthesis of new monoterpenoid derived ligands for asymmetric catalysis /

The work to be presented herein illustrates several important facts. First, the synthesis of BIBOL (19), a 1,4-diol derived from the monoterpene camphor has allowed us to demonstrate that oxidative dimerizations of enolates can, and do proceed with nearly complete diastereoselectivity under kinetically controlled conditions. The yield of BIBOL is now 50% on average, with a 10% yield of a second diastereomer, which is likely the result of a non-kinetic hydride reduction, thereby affording the epimeric alcohol, 20, coupled on the exo face of camphor. This implies the production of 60% of a single coupling diastereomer. No other diastereomers from the reduction were observed. The utility of BEBOL has been illustrated in early asymmetric additions of diethylzinc to aryl aldehydes, with e.e.'s as high as 25-30%. '^' To further the oxidative coupling work, the same methodology which gave rise to BIBOL was applied to the chiral pool ketone, menthone. Interestingly, this gave an excellent yield of the a-halohydrin (31), which is the result of a chlorination of menthone. This result clearly indicates the high stereoselectivity of the process regardless of the outcome, and has illustrated an interesting dichotomy between camphor and menthone. The utility of the chlorination product as a precursor other chiral ligands is currently being investigated. > ' Finally, a new series of 1,3-diols as well as a new aminoalcohol have successfully been synthesized from highly diastereoselective aldol/mannich reactions. Early studies have indicated their potential in asymmetric catalysis, while employing pi-stack interactions as a means of controlling enantioselective aldol reactions.

Aryl hydroxamic acid analogues as potential therapeutic agents /

A new synthetic pathway to analogues of the aglucones of naturally occurring cyclic hydroxamic acids (2,4-dihydroxy-l,4-benzoxazin-3-ones) has been developed. The new pathway involves the coupling of substituted nitrophenols wdth /-propyl-abromo- O-methoxymethylglycolate. These materials were reductively cyclised to reveal the hydroxamic acid functionality. Removal of the C-2 0-methoxymethyl protecting group was achieved chemoselectively using boron trichloride. The analogue 7-methoxy-2,4-dihydroxy-l,4-benzoxazin-3-one (DIMBOA) was assayed with papain and a semilog plot of activity of papain in the presence of excess DIMBOA was found to be linear. A single exponential equation was suggested as the model for kinetic analysis. '^ Nuclear magnetic resonance (NMR) spectra of a couple of hydroxamates were acquired as reference standards for future mechanistic studies of these compounds as thiol protease inhibitors. A 10% '^-labeled sample ofDIMBOA was also prepared for future mechanistic studies using NMR techniques.

Comparing ESL electronic and face-to-face pre-writing conferences and first drafts : discourse, participation, and idea transfer /

This study was a comparative investigation of face-toface (i.e., proximate) and computer-mediated written (i.e., graphic) pre-writing conferences. The participants in this study were advanced English as a second language students. The 2 types of conferences were compared in terms of textual features, participation, and the . degree to which they were on topic. Moreover, drafts written after the 2 types of conferences were compared in terms of textual features, and the degree to which they were related to the conferences. Students produced an equivalent amount of discourse in an equivalent amount of time in the 2 types of conferences. The discourse in graphic conferences displayed greater lexical range, and some evidence suggests that it was less on-topic. Both these results likely occurred because the graphic conferences contained more discourse demonstrating interactive competence. Participation in graphic conferences was found to be as balanced or more balanced among students, and among students and the group leader combined. Overall, the drafts produced after the 2 types of conferences were of equivalent length and topical range, but some evidence suggests that drafts written after proximate conferences were more related to the conferences.

Far infrared reflectance and optical properties of organic superconductor (TMTSF)2ClO4 /

Polarized reflectance measurements of the quasi I-D charge-transfer salt (TMTSFh CI04 were carried out using a Martin-Puplett-type polarizing interferometer and a 3He refrigerator cryostat, at several temperatures between 0.45 K and 26 K, in the far infrared, in the 10 to 70 cm- 1 frequency range. Bis-tetramethyl-tetraselena-fulvalene perchlorate crystals, grown electrochemically and supplied by K. Behnia, of dimensions 2 to 4 by 0.4 by 0.2 mm, were assembled on a flat surface to form a mosaic of 1.5 by 3 mm. The needle shaped crystals were positioned parallel to each other along their long axis, which is the stacking direction of the planar TMTSF cations, exposing the ab plane face (parallel to which the sheets of CI04 anions are positioned). Reflectance measurements were performed with radiation polarized along the stacking direction in the sample. Measurements were carried out following either a fast (15-20 K per minute) or slow (0.1 K per minute) cooling of the sample. Slow cooling permits the anions to order near 24 K, and the sample is expected to be superconducting below 1.2 K, while fast cooling yields an insulating state at low temperatures. Upon the slow cooling the reflectance shows dependence with temperature and exhibits the 28 cm- 1 feature reported previously [1]. Thermoreflectance for both the 'slow' and 'fast' cooling of the sample calculated relative to the 26 K reflectance data indicates that the reflectance is temperature dependent, for the slow cooling case only. A low frequency edge in the absolute reflectance is assigned an electronic origin given its strong temperature dependence in the relaxed state. We attribute the peak in the absolute reflectance near 30 cm-1 to a phonon coupled to the electronic background. Both the low frequency edge and the 30 cm-1 feature are noted te shift towards higher frequcncy, upon cntering the superconducting state, by an amount of the order of the expected superconducting energy gap. Kramers-Kronig analysis was carried out to determine the optical conductivity for the slowly cooled sample from the measured reflectance. In order to do so the low frequency data was extrapolated to zero frequency using a Hagen-Ru bens behaviour, and the high frequency data was extended with the data of Cao et al. [2], and Kikuchi et al. [3]. The real part of the optical conductivity exhibits an asymmetric peak at 35 cm-1, and its background at lower frequencies seems to be losing spectral weight with lowering of the temperature, leading us to presume that a narrow peak is forming at even lower frequencies.

Using classroom meetings to transfer conflict resolution skills /

This study examined whether daily classroom meetings resulted in the positive transfer of conflict resolution information and skills beyond the formal classroom setting and into the classroom. A control group of sixteen Grade five students received three weeks of conflict resolution training and an experimental group of nineteen Grade five students fi-om the same school received three weeks of conflict resolution training followed by three additional weeks of class meetings. Pretest measures were taken via a scaled questionnaire and short answer questions before the conflict resolution lessons began for the following skills: knowledge of conflict resolution; conflict resolution behaviour; and attitude about using conflict resolution to resolve problems with other people. Posttest measures examined conflict resolution skills following involvement in the study. Students chosen randomly and both teachers were interviewed following the study. The teachers were again interviewed three months after the study. Teacher journal notes rounded out the data. The results of the study indicated that the Grade five boys who participated in three weeks of conflict resolution training did not increase their conflict resolution skills in any of the areas examined. Girls who participated in three weeks of conflict resolution training did not improve in two areas (i.e., behaviour, knowledge) and became less positive about using verbal mediation to resolve conflicts. The Grade five students who participated in three weeks of training and three weeks of class meetings obtained different results. The boys improved significantly in their ability to use verbal mediation to resolve conflicts and were more positive about verbal mediation. They did not become more knowledgeable about verbal mediation. The girls who participated in three weeks of training and three weeks of class meetings were more knowledgeable of conflict resolution and used conflict resolution to solve problems with other people. However, they were significantly less positive about using these skills to resolve problems.

Investigation of the mechanism of transfer of a-tocopherol by the human a-tocopherol transfer protein (H-a-TTP) /

The human a-tocopherol transfer protein (h-a-TTP) is understood to be the entity responsible for the specific retention of a-tocopherol (a-toc) in human tissues over all other forms of vitamin E obtained from the diet. a-Tocopherol is the most biologically active form of vitamin E, and to date has been studied extensively with regard to its antioxidant properties and its role of terminating membrane lipid peroxidation chain reactions. However, information surrounding the distribution of a-tocopherol, specifically its delivery to intracellular membranes by a-TTP, is still unclear and the molecular factors influencing transfer remain elusive. To investigate the mechanism of ligand transfer by the h-a-TTP, a fluorescent analogue of a-toc has been used in the development of a fluorescence resonance energy transfer (FRET) assay. (/?)-2,5,7,8-tetramethyl-2-[9-(7-nitro-benzo[l,2,5]oxdiazol-4-ylamino)-nonyl]- chroman-6-ol (NBD-toc) has allowed for the development of the FRET-based ligand transfer assay. This ligand has been utilized in a series of experiments where changes were made to acceptor lipid membrane concentration and composition, as well as to the ionic strength and viscosity of the buffer medium. Such changes have yielded evidence supporting a collisional mechanism of ligand transfer by a-TTP, and have brought to light a new line of inquiry pertaining to the nature of the forces governing the collisional transfer interaction. Through elucidation of the transfer mechanism type, a deeper understanding of the transfer event and the in vivo fate of a-tocopherol have been obtained. Furthermore, the results presented here allow for a deeper investigation of the forces controlling the collisional protein-membrane interaction and their effect on the transfer of a-toc to membranes. Future investigation in this direction will raise the possibility of a complete understanding of the molecular events surrounding the distribution of a-toc within the cell and to the body's tissues.

Synthesis of fluorescent analogues of a-tocopherol as ligands for the human a-tocopherol transfer protein (a-TTP) /

To further understand in vivo localization and trafficking of a-tocopherol (a-Toe), the most biologically active form of vitamin E, between lipid environments, tocopherols are required that can be followed by teclu1iques such as confocal microscopy and fluorescence resonance energy transfer (FRET) assays. To this end, sixteen fluorescent analogues of a-tocopherol (la-d [(1)anthroy loxy -a-tocopherols, A O-a-Toes], 2a-d [w-nitro benzoxadiazole-a-tocopherols, NBD-aToes], 3a-d [w-dansyl-a-tocopherols, DAN-a-Toes], and 4a-d [w-N-methylanthranilamide-atocopherols, NMA-a-TocsD were prepared by substituting fluorescent labels at the terminus of w-functionalized alkyl chains extending from C-2 of the chroman ring while retaining key binding features of the natural ligand. These compounds were prepared starting from (S)-Trolox® acid VIa esterification, protection, and reduction producing the silyl-protected (S)-Trolox aldehyde that was coupled using Wittig chemistry to different w-hydroxyalkylphosphonium bromides. Reduction of the alkene generated the w-hydroxy functionalized 2-n-alkyl intermediates 9a-d having the necessary 2R stereochemistry. A series of functional group manipulations including mesylation, substitution with azide, and hydride reduction provided w-amino functionalized intermediates 12a-d as well. Coupling intermediates 9a-d and 12a-d with the selected fluorophores (9- anthracene carboxylic acid, 4-chloro-7-nitrobenz-2-oxa-l,3-diazole, 5- dimethylaminonapthalene-l-sulfonyl chloride, and I-methyl-2H-3,1-benzoxazine-2,4(1H)dione), followed by deprotection of the phenolic silyl group, gave the desired fluorescent ligands la-d, 2a-d, 3a-d and 4a-d in good yield. Assessment of their binding affinities with recombinant human a-tocopherol transfer protein (ha-TTP) utilizing fluorescent titration binding assays identified competent ligands for further use in protein studies. Compounds Id (C9-AO-a-Toc) and 2d (C9-NBD-a-Toc) both having nonyl alkyl chain extensions between the chromanol and fluorophore were shown to bind specifically to ha-TTP with dissociation constants (KdS) of approximately 280 nM and 55 nM respectively, as compared to 25 nM for the natural ligand 2R,4'R,^'R-a-tocophQxoL.

Synthesis of chiral homoallylic alcohols and phthalans through the asymmetric allylation of carbonyl compounds /

The implementation of chiral centres within biologically active compounds has been a perplexing yet motivational force in chemistry. This work presents the attempted formation of a concurrent or sequential tandem catalyzed methodology of enantioselective nucleophilic addition and electrophilic cyclization. The 2'- arylalkynyl- aldehyde, ketone, and imine substrates used within were adeptly chosen with a dually activated structure; 1) for nucleophilic addition to the electrophilic substituents; and 2) for carbophilic activation of the alkyne substituent to undergo cyclization. To accomplish the nucleophilic addition, two distinct allylation methodologies were pursued: (/?)-BINOL catalyzed-allylboration and (5)- BINAP-AgF catalyzed-allylsilylation. BINAP catalyzed enantioselective allylation of 2'-arylalkynyl-aldehydes, to form chiral homoallylic alcohols, was successful. Homoallylic alcohols were isolated with high enantio-purity (>80%), which then underwent sequential cyclization to form chiral allylic phthalans, in moderate yields. An application of this methodology towards the construction of biologically active compounds was included with the partial synthesis of the natural product and H. pylori inhibitor, (+)-Spirolaxine methyl ether.

Acquisition and transfer of experiential learning from rock climbing to the corporate workplace

There were three purposes to this study. The first purpose was to determine how learning can be influenced by various factors i~ the rock climbing experience. The second purpose was to examine what people can learn from the rock climbing experience. The third purpose was to investigate whether that learning can transfer from the rock climbing experience to the subjects' real life in the workplace. Ninety employees from a financial corporation in the Niagara Region volunteered for this study. All subjects were surveyed throughout a one-day treatment. Ten were purposefully selected one month later for interviews. Ten themes emerged from the subjects in terms of what was learned. Inspiration, motivation, and determination, preparation, goals and limitations, perceptions and expectations, confidence and risk taking, trust and support, teamwork, feedback and encouragement, learning from failure, and finally, skills and flow. All participants were able to transfer what was learned back to the workplace. The results of this study suggested that subjects' learning was influenced by their ability to: take risks in a safe environment, fail without penalty, support each other, plan without time constraints, and enjoy the company of fellow workers that they wouldn't normally associate with. Future directions for research should include different types of treatments such as white water rafting, sky diving, tall ship sailing, or caving.

Attemped asymmetric dehydration with chiral carbodiimides /|nMin-jen Shiao. -- 260 0 St. Catharines [Ont. : s. n.],

This research work has been planned with the intention of synthesizing optically active bicyclo[3,l,0]-hexan-2-one using chiral carbodiimides. Several carbodiimides have been prepared for practice and for attempts at asymmetric induction. The total synthesis of dibenzo[e,g]- (l:3)diazonine and the partial synthesis of l:13-dimethyldibenzo[e,g]- (l:3)diazonine are reported. Attempts to resolve 6,6f-dimethyl-2,2t-diphenic acid were not successful. The NMR spectra of carbodiimides and the related thioureas are compared. The reaction transition state of the 4-hydroxycyclohexanone with optically pure R,R(+)-di(a-phenylethyl)-carbodiimide has been considered. The ORD application to chiral cyclohexanones is discussed.

Attempted asymmetric synthesis of Lactobacillic acid / |nFawzy F. Z. Georges. -- 260 St. Catharines, Ont. : [s. n.],

This research work has been planned with the intention of proving the absolute configuration of lactobacillc acid. During the course of this work, attempts have been made to synthesize cis-2-carboxycyclopropane- l-.acetic acid as,v,a suitable resolvable material. As the results were not satisfactory, the synthesis of ci,s-2-carboxycyclopropane-l-propionic acid has been alternatively attempted by ring opening of bicyclo- [4.1.~-heptan-2-onewithout much success. Attempts to resolve or prepare bicyclo[ 4.1.~-hePtan-2-one optically active are also reported. On the other hand, a complete scheme is described for the possible synthesis of optically active lactobacillic acid. If only bicyclo- ~.1.~ -heptan-2-one can be resolved or prepared optically active, this described scheme can be applied smoothly to the synthesis of enant~omeric lactobacillic acid.

Transfection of newt blastema mesenchyme using the techniques of lipofection and direct gene transfer

The regenerating amphibian limb provides a useful system for studying genes involved in the establishment of positional information. While a number of candidate genes that may playa role in pattern formation have been identified, their function in vivo is unknown in this system. To better ascertain the role of these genes, it would be useful to be able to alter their normal patterns of expression in vivo and to assess the effects of this misexpression on limb pattern. In order to achieve this, a method of introducing a plasmid containing the eDNA of a gene of interest into a newt blastema (a growth zone of mesenchymal progenitor cells) is needed. Unfortunately, most commonly used transfection techniques cannot be used with newt blastema cells. In this study, I have used the techniques of lipofection and direct gene transfer to introduce plasmid DNA containing reporter genes into the cells of a regenerating newt limb. The technique of lipofection was most effective when the blastema cells were transfected in vitro. The optimal ratio for transfection was shown to be 1:3 DNA:Lipofectin (W/w) , and an increase in the amount of DNA present in the mixture (1:3 ratio maintained) resulted in a corresponding increase in gene expression. The technique of direct gene transfer was used to transfect newt blastema cells with and without prior complex formation with Lipofectin. Injection of plasmid DNA alone provided the most 3 promising results. It was possible to introduce plasmid DNA containing the reporter gene ~-galactosidase and achieve significant gene expression in cells associated with the injection site. In the future, it would be interesting to use this technique to inject plasmid DNA containing a gene which may have a role in pattern formation into specific areas of the newt blastema and to analyze the resulting limb pattern that emerges.

Asymmetric cyclopropanation via catalysts incorporating the 1,4-diol ligands and the newly designed dioxaborolane /

The development of new methodology for the asymmetric synthesis of chiral organic compounds is a major focus in modem organic chemistry. The use of chiral catalysts is replacing chiral auxiliaries as a new tool for synthetic chemists. An efficient chiral catalyst allows for large quantities of optically active product to be obtained on use of relatively small amount of enantiopure material, without the need for the removal and recovery of a chiral auxiliary. Furthermore, the most practical catalytic methods utilize an inexpensive and readily available chiral ligand that can provide high and predictable enantioselectivity across a wide range of substrates. In our project, two type of versatile, upgraded chiral ligands have been designed and synthesized. Their application in Simmons-Smith type cyclopropanation is investigated, and the pleasing results suggest that they are the potential catalytic enantioselective candidates to build C-C bonds.