General Organization. This thesis contains a brief introduction to the area of $\beta$-lactam antibiotics and four other Chapters dealing with the syntheses of various 6-methoxy $\beta$-lactams. Due to the tremendous level of activity in this area the introductory literature material is presented in an illustrative approach rather than a comprehensive approach. Literature surveys were carried out using Chemical Abstracts from 1982 to February 1992. Experimental details are given at the end of each Chapter. Compounds in the schemes which did not lead to desired conclusion were not completely characterized; $\sp1$H NMR and other spectral data whenever available are given in the Experimental section. IR was not recorded in most of these cases. Elemental analyses were not performed at all, since the data from such experiments do not always represent the purity of product. Chapter 1. This section describes the development of various $\beta$-lactam antibiotics, major representative structures, mode of action and overall objectives of the research undertaken. Chapter 2. 7-Methoxy-7-ethyl and 7-methoxy-7-hydroxyethylisocephem analogs were prepared from 4-cinnamyl-3-methoxyazetidinone which was prepared in a multigram scale. This precursor can be purified simply by trituration with ether. The transformation of this monocyclic starting material to the cyclization precursor involved introduction of an additional side-chain at C-3 via. generation of anion using lithium diisopropylamide and quenching of the anion with either ethyl iodide or acetaldehyde. In the case of the hydroxyethyl side-chain oxidation with pyridinium chlorochromate, reduction with L-Selectride and silylation with tert-butyldimethylsilyl triflate was required before carrying out further manipulations. The cinnamyl group was converted to a methylene bearing a leaving group and the p-methoxyphenyl moiety on nitrogen was cleaved and a suitable acetate side-chain was introduced. The anionic annulation with CS$\sb2$ gave the desired bicyclic compounds. An optically active isocephem having a thienamycin type side-chain at C-7 and and a racemic isocephem having a methoxy group at C-7 were prepared by similar method. Chapter 3. 7-Ethyl-7-methoxycarbacephem was prepared using a rhodium carbenoid reaction starting from 4-cinnamyl-3-methoxyazetidinone. A similar method was applied to prepare an advanced intermediate for 7-hydroxyethyl-7-methoxycarbacephem. Chapter 4. 6-Methoxy-PS 5 synthesis was attempted which was found to be unstable. The cyclization was carried out applying the rhodium carbenoid methodology. The cyclization precursor was obtained using nitroaldol condensation starting from an aldehyde which was prepared from 4-cinnamyl-3-methoxyazetidinone. Chapter 5. Syntheses of 6-methoxy-1-methyl-PS 5 analogs were attempted starting from 3-ethyl-3-methoxy-4-methylcinnamylazetidinone. The introduction of 1-methyl group involved the reduction of a suitable $\alpha,\beta$-unsaturated ester obtained via. palladium catalyzed carbonylation reaction.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/7571 |
| Date | January 1992 |
| Creators | Shakya, Sagar Raj. |
| Contributors | Durst, T., |
| Publisher | University of Ottawa (Canada) |
| Source Sets | Université d’Ottawa |
| Detected Language | English |
| Type | Thesis |
| Format | 219 p. |
Page generated in 0.0025 seconds