Significant attention from the medicinal and pharmaceutical communities has been pushed towards the design and development of natural products for defence against many forms of illnesses. The Amaryllidaceae plant family has shown their prevalence over time aiding towards our needs and becoming viable sources of alkaloids due to their wide variety of bioactivities presented. The low availability towards these often-complex structures with at times comprising up to six contiguous chiral centers have made practical testing scarce. More dominantly the isocarbostyrils are well recognized, being hydroxylated phenanthridones providing increased activities making them model targets to test and develop new synthetic strategies towards. These compounds represent a subset of the Amaryllidaceae alkaloids that lack a basic nitrogen center.
This thesis describes the total synthesis of four derivatives of the antiviral natural product (+)-trans-dihydronarciclasine from α-azidoacetone and m-anisaldehyde. Herein we demonstrate constructive routes towards ring-A modified, fully functionalized rings-B/C derivatives synthesized via asymmetric chemical syntheses providing further insight into SAR studies. This thesis expands on the organocatalytic [3+3]-cycloaddition sequence to produce aminocyclitol cores providing effective routes towards the development of five stereogenic centers in all targeted ring-C structures. Such studies were attributed to the enal adducts isolated from the Wittig reaction towards four natural product derivatives gaining knowledge related to the targeted molecules mode of action. One additional (+)-transdihydrolycoricidine analogue will be communicated, that enables the imaging while inside live cells with use of alkyne-tag Raman imaging.
Limitations of the alkaloids include the toxicity that accompanies these agents and the poor aqueous solubilities they provide, eliciting an increased need for new antiviral agents. The syntheses communicated provide effective routes towards unnatural alkaloids and can be pushed towards alternative chiral aminocyclitol targets for future studies. All
compounds have been sent away for screening including against coronavirus at Johns Hopkins. / Thesis / Bachelor of Science (BSc) / This thesis is primarily driven towards the development of four antiviral lycorane structural type alkaloids, and an analogue synthesized via a copper-cocatalyzed Sonogashira reaction, utilizing a labile phenol-derived sulfonated hydroxyl group in its coupling towards an alkyne tagged structure. This method provides easy access for a variety of compounds without a fluorescent tag, taking steps forward in elucidating how the
Amaryllidaceae alkaloids are delivering their biological effects.
The densely substituted ring-C was obtained via an asymmetric organocatalytic [3+3] sequence for the assembly of the aminocyclitol core and is described. This sequence has provided effective regio, diastereo, and enantioselective access to five unnatural products. Preparation of the precursors were prepared using a Wittig methodology previous reported by the McNulty group that has been used in many syntheses for various
Amaryllidaceae alkaloids
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26289 |
| Date | January 2021 |
| Creators | Scattolon, Jon |
| Contributors | McNulty, Jim, Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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