An efficient and expedient synthetic method was developed for the preparation of chiral poly-substituted morpholine and oxazepine derivatives. The method was designed in the objective of applying the synthesis to the preparation of Cyclophilin A inhibitors. / The stereo- and regioselective method involves the reaction of enantiopure beta-amino alcohols with alpha,beta-unsaturated aldehydes. The synthesis proceeds through three steps; i) Reductive amination, ii) N-alkylation/ N-tosylation and iii) intramolecular-haloetherification. Stereoselectivity of this last step was controlled by N-alkyl/ N-tosyl groups and substitution across the double bond, and was enhanced by the addition of Bronsted acids. Substitution across the double bond of the starting material controlled the regioselectivity of the method. Morpholines were obtained through 6- exo cyclization and oxazepines were obtained through 7-endo cyclization. / A small library of morpholine-based derivatives was designed in-silico. Affinity and binding modes to the Cyclophilin A were investigated through a docking-based virtual screening study.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111575 |
| Date | January 2008 |
| Creators | Bilbeisi, Rana A., 1983- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Chemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 003135024, proquestno: AAIMR66877, Theses scanned by UMI/ProQuest. |
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