The scope of the indium-mediated allylations in aqueous media has been successfully expanded and an improved understanding of the synthetic utility of the reaction has been developed. The range of useful functionalities that can be efficiently produced by the methodology has been increased and the concise construction of naturally occurring and/or biologically significant substrates has been undertaken. / We have demonstrated how N-acylimidazoles could be allylated under controlled temperature conditions, in aqueous media furnishing predominantly 4-alkyl-1,6-heptadien-4-ols. The intermediate alpha-alkyl-beta,gamma-unsaturated ketones were present in significant amounts only when the bulk of the acyl or alpha substituents were such that it interfered with a subsequent allylation. An investigation into the efficient production of the homo allylic ketone, independent of bulk was also performed. Success in this light was effected with the introduction of infrequently used, N-acylpyrazoles in a unique Wienreb-amide type role. These substrates also proved useful for the generation of beta-keto esters in a direct manner via a indium-mediated Reformatsky-type reaction in THF. / A successful extension of the methodology into the realms of intramolecular carbocylizations proved to be high yielding and exclusive in terms of gamma-regio and cis-diastereoselectivity. The high utility of the reaction was shown with the synthesis of oxygen heterocyles fused with alpha-methylene-gamma-butyrolactones, substrates, which were revealed to be cytotoxic against several cancer cell lines. An easy incorporation of chiral auxiliaries to the cyclization reactions was also introduced, and a path to possibly produce these important compounds in an enantioselective manner, revealed. / Indium-mediated allylations in aqueous media also proved useful as a tool for the general construction of paraconic acids, which are naturally occurring, densely functionalized and biologically active 5-membered lactones. A facile route free of labor-intensive tasks was designed and utilized in the production of naturally occurring methylenolactocin and protolichesterinic acid. A further extension to include the synthesis of a related bis -fused lactone, canadensolide, encountered serious problems. Here it was discovered that the reaction of an enolizable allylic indium species with water occurred more quickly than the intended reaction of this species with an aldehyde in an intramolecular cyclization. This, coupled with other results observed throughout our research, revealed that though very useful, the indium-mediated allylation is negatively affected by the presence of gamma-carboxylate groups. While the C-In bond appears to have a low propensity to react with the aqueous media and react quantitatively with appropriate electrophiles, the presence of a gamma-carboxylate group offers the possibility of enol formation leading to the generation of an O-In species that is rapidly protonated. We were therefore able to successfully use the methodology in this circumstance, only for the production of a deoxy analog while canadensolide remained illusive.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.36555 |
| Date | January 1999 |
| Creators | Bryan, Vernal Jermaine. |
| Contributors | Chan, Tak-Hang (advisor) |
| 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 | Doctor of Philosophy (Department of Chemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001746355, proquestno: NQ64525, Theses scanned by UMI/ProQuest. |
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