The conformationally controlled reactions of macrolides 42, 43, 72 and 74 were investigated. Treatment of these 14-membered lactones with hydride reducing agents and organocopper reagents led to diastereoselective product formation. The product distributions could be rationalized using low energy starting material or product conformations. A detailed conformational analysis involving MM2/MMP2 calculations and X-ray crystallographic studies led to a simple model for determining these low energy conformations. In order to simplify the identification of ring conformations, an improved procedure for the generation of polar maps was developed. With the aid of polar maps, a previously unknown low energy conformation for 14-membered rings was discovered. The discovery of this new conformation led to an improved nomenclature system for large rings, which considers the number of bonds separating both corner and pseudo corner atoms. Under this proposed nomenclature, the newly discovered conformation is designated the [34'3'4'] conformation. The work described in this thesis also led to a useful method for assigning the stereochemistry of trimethylsilyl enol ethers. Nuclear Overhauser effect difference spectroscopy (NOEDS) was used to unambiguously distinguish between E and Z trimethylsilyl enol ethers. One advantage of this technique over the widely used ¹³C NMR method is that only one isomer is required to accurately assign the E or Z geometry. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

The goal of this project was to synthesize a fluorinated disaccharide as a substrate or inhibitor for a glycosidase enzyme. A substrate analogue with only one strategically positioned fluorine atom could be used to probe such a complex interaction by using ¹⁹F NMR to monitor any changes in chemical shift, line width, and p coupling constants which arise when the analogue binds to the enzyme. Such changes would be more easily observed by using ¹⁹F NMR to monitor the perturbations around the single F nucleus than by monitoring the ¹H NMR because the spectrum in the latter case is much more complex due to the number of protons inherent in both the natural substrate and the enzyme. The compounds 3,4,6-tri-0-acetyl-2-deoxy-2-fluoro-α-D-glucopyranosyl bromide [5] and 2,3-di-0-acetyl-l,6-anhydro-β-D-glucose [2] were synthesized as appropriate starting materials and then coupled in diethyl ether in the presence of Ag₂CO₃, using AgSO₃CF₃ as a catalyst; these are the simple conditions of the well-known Koenigs-Knorr reaction. The coupling of a halosugar bearing a non-participating group at C-2 with an alcohol in low concentration has been shown by many other workers to result in a mixture of a- and 3-linked products, with the former being predominant. In this study, only the a-linked disaccharide 2,3-di-0-acetyl-l,6-anhydro-4-0-(3,4,6-tri-0-acetyl-2-deoxy-2-fluoro-α-D-glycopyranosyl)-B-D-glucopyranose [12] was obtained, the corresponding β-linked disaccharide was not observed in the reaction mixture. This fact suggests that some factor in either the reaction conditions employed or in the nature of the two sugars involved in the coupling was responsible for the exclusive production of only one type of linkage. The α-linked disaccharide [12] was deprotected to give the free sugar 2'-deoxy-2'-fluoro-maltose (4-0-(2-deoxy-2-fluoro-α-D-glucopyranosyl)-D-glucopyranose [14]) which is the C-2' fluorinated analogue of maltose. This compound should be a suitable probe for enzyme systems such as Maltase or α-glycosidase. The proton decoupled ¹⁹F NMR of [14] displayed two distinct resonances separated by 0.1 ppm which could be due to the α and β anomeric forms of that compound. The optical rotations values and the α/β anomeric ratios deduced from the ¹H NMR spectra for maltose and [14] were comparable, suggesting that this may indeed be the case. The synthesis of 4-0-(2-deoxy-2-fluoro-α-D-galacto-pyranosyl)-D-glucopyranose [17] was initiated with the view of using such a compound to study an α-galactosidase system; the partial synthesis of this molecule is also included herein. The conformational aspects of all the sugars synthesized in this work were deduced from ¹H NMR and then confirmed by ¹⁹F NMR and optical rotation. The ¹⁹F NMR spectra of the disaccharides were simple and were shown to provide sufficient information for the deduction of the conformational and configurational aspects of these sugars in the region of interest. This indicated that changes in the region about the fluorine could be monitored using ¹⁹F NMR and that these sugars could thus prove to be valuable probes for the elucidation of enzyme mechanisms. / Science, Faculty of / Chemistry, Department of / Graduate

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This study consists of four major areas of research. First, the relationship between and was extended to Lrl nil homoallylic couplings and was used to determine the relative degree of puckering in a series of dihydroaromatic carboxylic acids. Second, the effect of coupling contributions transmitted through space were examined by theoretical calculations of the intermediate neglect of differential overlap finite perturbation theory type (INDO-FPT) including selective overlap reduction experiments to determine the sign and magnitude of the major through-space contributions and the effect of the orientation of the substituent upon the vicinal carbon3 carbon coupling. Third, the dependence of the J upon substituent orientation in norbornanes was empirically investigated by the synthesis of a series of lactones and cyclic ethers whose conformation was rigid and known. Fourth, a large number of norbornanes substituted with methyls in the 1, 3, and 7 position and a carbon-13 labeled substituent in the 2 position were synthesized and studied in order to obtain a variety of vicinal C-C couplings; all the NMR parameters for this series of compounds were determined while the carbon13 labeled substituent was varied from methyl to methylene to carbinol to aldehyde and to carboxylic acid.

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Thesis (Ph.D.)--Drexel University, 2010. / Includes abstract and vita. Includes bibliographical references (leaves 192-215).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 217-223).

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