Modified nucleosides form an important class of antiviral and anticancer agents, and nucleic acids bearing modified nucleosides hold great promise as therapeutic agents. Oxepane nucleosides and nucleic acids are members of this important class of compounds. Oxepane nucleosides have a seven-membered carbohydrate ring instead of the canonical five-membered pentafuranose ring. This thesis describes work in the development of new synthetic approaches and routes in the synthesis of oxepane nucleosides. In chapter 2, the synthesis of oxepane nucleosides based on the ring expansion approach is described. Building on previous work in the Damha lab, studies in the synthesis of oxepane nucleosides by a ring expansion approach were carried out. In particular, oxepane nucleosides were synthesized using thioglycoside derivatives. Routes in the modification of the oxepane scaffold were explored, but later abandoned in favor of new synthetic approaches to oxepane nucleosides. In chapter 3, work towards the development of new routes in the synthesis of oxepane nucleosides by ring-closing metathesis is described. This new approach to the synthesis of oxepane nucleosides allows for the use of commercially-available nucleosides and circumvents the difficulties observed in glycosylation reaction employed in the previous approach. In chapter 3, various synthetic routes are examined, and work towards the development of viable routes is described. In particular, the direct addition of Grigard reagents to nucleosides dialdehydes, followed by Grubbs II mediated ring closing metathesis serves as a proof-of-principle of the synthesis of oxepane nucleosides by a ring closing route. / Les nucléosides modifiés sont des agents thérapeutiques très efficaces contre le cancer et contre des virus. Les oxepanes font partie de ce groupe important. Au lieu d'avoir un cycle de 5 atomes, les oxepanes ont un cycle modifié de 7 atomes. Cette thèse décrit la recherche sur le développement de nouvelles méthodes pour la synthèse des oxepanes. Dans le deuxième chapitre, la synthèse des oxepanes par la méthode d'expansion de cycle est traitée. Notamment, la synthèse des oxepanes par le biais des hétérosides contenant des thiols est décrite. Dans le troisième chapitre, de nouvelles méthodes pour la synthèse des oxepanes sont étudiées. Toutes ces approches ont pour but ultime d'utiliser la métathèse d'alcènes comme l'étape clé. Notamment, l'addition directe des réactifs de Grignard à des nucléosides contenant deux aldéhydes, suivi d'une métathèse d'alcène, constitue une démonstration de faisabilité de cette approche synthétique.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103473 |
| Date | January 2011 |
| Creators | Gallant, Pascal |
| Contributors | Masad J Damha (Internal/Supervisor) |
| 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 | French |
| 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 | Electronically-submitted theses. |
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