Tse, Hon Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 87-89). / Abstracts in English and Chinese. / Acknowledgment --- p.I / Table of Contents --- p.II / Abstract --- p.III / Abstract (Chinese Version) --- p.IV / Abbreviation --- p.V / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Calstegine --- p.1 / Chapter 1.2 --- "1,3-Dipolar Cycloaddition" --- p.5 / Chapter 1.3 --- Intramolecular Nitrone-alkene Cycloaddition (INAC) --- p.7 / Chapter 2. --- Results and Discussion --- p.14 / Chapter 2.1 --- Introduction --- p.14 / Chapter 2.2 --- INAC of Unbranched Hept-6-enoses derived form D-xylose --- p.15 / Chapter 2.2.1 --- "Hept-6-enose derived from 1,3-Diol 80" --- p.19 / Chapter 2.2.2 --- "Hept-6-enose derived from l,3-Diol 82" --- p.21 / Chapter 2.2.3 --- "Hept-6-enose derived from 1,2-Diol 81" --- p.23 / Chapter 2.2.4 --- "Hept-6-enose derived from 1,2-Diol 83" --- p.27 / Chapter 2.2.5 --- Hept-6-enose derived from 93 --- p.30 / Chapter 2.3 --- INAC of Unbranched Hept-6-enoses derived form L-arabinose --- p.33 / Chapter 3. --- Conclusion --- p.39 / Chapter 4. --- Experimental --- p.42 / Chapter 5. --- References --- p.87 / Appendix-Data of X-ray crystallography / Appendix-NMR Spectra

Thesis (D. Med. Scs.)--University of Tartu, 2006. / Vita. Includes bibliographical references.

The development of new methodologies for the asymmetric synthesis of homotropinone and tropane alkaloids using enantiopure sulfinimines [RS(O)N=CR1R²] is the primary objective of this thesis. In one study a four-step intramolecular Mannich cyclization cascade reaction was devised for the asymmetric synthesis of substituted homotropinone alkaloids from enantiopure sulfinimine-derived N-sulfinyl ß-amino ketone ketals. These amino ketone ketal chiral building blocks were prepared in 67-71% yields and high dr (25-14:1) by addition of the Weinreb amide enolate of N-methoxy-Nmethylacetamide to masked oxo sulfinimines (N-sulfinyl imines). Treatment of these Weinreb amides with Grignard reagents gave the N-sulfinyl ß-amino ketone ketals in 93- 95% yields without epimerization. Heating the acyclic ß-amino ketone ketals with the buffer solution NH4OAc:HOAc resulted in a one-pot 4 step intramolecular Mannich cyclization cascade reaction to give substituted homotropinones including (–)- euphococcinine and (–)-adaline in 82-90% yields. In another study a sulfinimine-derived α,ß-unsaturated pyrrolidine nitrone was utilized in the development of a Lewis acid catalyzed [3+2] nitrone cycloaddition reaction for the asymmetric synthesis of the tropane alkaloid (+)-cocaine. The masked oxo sulfinimine was treated with an excess of the sodium enolate of methyl acetate to give N-sulfinyl ß-amino ester in 87% yield and high dr (97:3). Reduction of the ester to aldehyde followed by a Horner-Wadsworth-Emmons olefination reaction afforded the α,ß-unsaturated N-sulfinyl amino acetal. Hydrolysis of the unsaturated amino acetal gave a pyrrolidine, which was selectively oxidized to the pyrrolidine nitrone. The nitrone on heating with the Lewis acid Al(O-t-Bu)3 for 96 h underwent an intramolecular [3+2] cycloaddition to give a tricyclic isoxazolidine, which was transformed into (+)-cocaine in three steps 25% overall yield. This 9 step, 25% overall yield synthesis of (S)-(+)-cocaine from the masked oxo sulfinimine is the most efficient enantioselective route to cocaine from acyclic starting materials. This new methodology is adaptable to the preparation of various cocaine analogs including the first cocaine C-1 analogs. In other studies conformationally constrained novel pyrrolidine analogs (methanopyrrolidines) were synthesized stereoselectively to study the substituent (H, OH, or F) effect on amide conformational preferences. A nucleophilic displacement synthetic route was devised to prepare highly functionalized 5(6)-anti-substituted-methanopyrrolidines from N-benzyl-2-azabicyclo[2.1.1]hexylbromide(s) intermediates with the aid of neighboring group participation. These methanopyrrolidines were then transformed to constrained proline analogs (methanoprolines) to evaluate the impact of proline ring pucker on amide conformations. An α-methoxycarbonyl group was introduced in methanopyrrolidines by treating tert-butoxycarbonyl protected methanopyrrolidines with s-BuLi and quenching with various electrophiles such as CO2, DMF or ClCO2Me. Amide trans-cis conformational preferences (Ktrans/cis) of N-acetyl-methanopyrrolidines and N-acetyl-methanoprolines were determined in various solvents such as CDCl3 and D2O using NMR techniques, including NOE. The small trans amide preference for substituted fluoro- and hydroxy-methanopyrrolidines shows that it is the interaction of the !-methyl ester group and the amide moiety of the methanoprolines that plays a major role in determining amide conformational preferences. The gamma-substituent effect is primarily related to ring pucker and a resultant enhancement of the interaction between the amide carbonyl oxygen and ester carbonyl carbon. The results are relevant to the conformational stability of collagen and protein engineering. / Chemistry

Nous avons détermine le cours stérique préférentiel de la quaternisation des tropanes, dans le but de faciliter l'étude des effets physiologiques des sels quaternaires , étant donné la relation stéréochimie-activité pharmacologique. La corrélation chimique entre les produits majeurs de N- alcoxycarbonylméthylation du tropane, de la tropine, de la pseudo -tropine et de la tropinone et ceux du dihydroxy-3α , 6 β tropane de géométrie sans équivoque, a montré le cours stérique préférentiel équatorial pour toutes ces quaternisations. La conversion du bromure de Nb-éthoxycarbonylmêthyl tropinium en bromure de Nb-éthyl méthyl nortropinium de structure déterminée par analyses aux rayons X, a confirmé le cours stérique préférentiel équatorial pour l 'éthylation, l 'hydroxyéthylation, la chloroéthylation et l'alcoxycarbonylméthylation dans toutes les séries des tropanes . Une revue critique de la corrélation entre les signaux N-mëthyles dans la RMN et la stéréochimie a été présentée, appuyée par une corrélation entre les produits majeurs de la deutérométhylation de la tropine et du dihydroxy-3α , 6 β tropane et ceux de méthoxycarbonylméthylation des deux mêmes amines tertiaires. Nous avons étudié l'influence de la compression stérique sur le cours stérique de la quaternisation, par l'introduction de substituants places en C₂ (ecgoninol et tropanol-2β) sur le cycle piperidine ou en C₆ et C₇(trihy- droxy-3α, 6β, 7β tropane) sur le cycle pyrrolidine . Le cours stérique préférentiel équatorial a été confirmé par les analyses aux rayons X de l’oxyde de la scopolamine, du sel de sodium du bromure de Nb-carboxyméthyl pseudo- tropinium, où nous avons obtenu préférentiellement la stéréochimie Nb des substituants de quaternisation. Nous avons également découvert une épimérisation sur l'atome d'azote des sels quaternaires de la tropinone, jamais rencontrée dans le domaine des tropânes ; celle-ci semble procéder par un mécanisme du type élimination d'HOFMANN suivie d'une addition de MICHAEL. Le principe de CURTIN-HAMMETT offre l'explication la plus vraisemblable de nos résultats, quant à la sélectivité et à la facilité de la quaternisation. / Montréal Trigonix inc. 2018