Copper-Carbene Mediated 1,2-Cis Furanosylation Reactions

Alber, Adam

Copper-Carbene Mediated 1,2-Cis Furanosylation Reactions

dc.contributor.advisor	Sharma, Indrajeet
dc.contributor.author	Alber, Adam
dc.contributor.committeeMember	Fornelli, Luca
dc.contributor.committeeMember	Shao, Yihan
dc.contributor.committeeMember	Masly, John
dc.date.accessioned	2024-07-26T19:23:08Z
dc.date.available	2024-07-26T19:23:08Z
dc.date.issued	2024-08-01
dc.date.manuscript	2024-06
dc.description.abstract	Carbohydrates are essential biomolecules and are found in a majority of newly discovered natural products. When the fact that around 50% of novel drug molecules are either natural products or molecules based on natural products is taken into account, one would think that a large percentage of novel drug molecules contain carbohydrates. However, carbohydrates remain one of the most underrepresented moieties in drug molecules today. This underrepresentation comes from several factors. Firstly, carbohydrates are compounds that are notoriously difficult to work with, requiring numerous fine manipulations and the hands of a skilled chemist to produce the desired results. Secondly, glycosylation methods often require stoichiometric amounts of harsh reagents or the use of expensive rare-earth promoter. These problems are often further exacerbated as there exist three main forms of glycoside: pyranosides, furanosides, and sialic acids. Pyranosides are the easiest to work with as their propensity to undergo SN2-type reactions means that stereocontrol of the anomeric position is relatively facile. This means that a majority of protocols that are developed for glycosylations are developed for pyranosides. However, due to their difference in reactivity, pyranosylation strategies are often unable to induce effective glycosylation in either furanosides or sialic acids, meaning that these methods translate poorly to furanosylation or sialylation. As a result, efficient methods of furanosylation are few and far between. Taking these factors into account, we notice that while glycosides in general are widely underrepresented in drug molecules approved by the FDA, furanosides are even less represented. On top of that, due to a plethora of reasons, the formation of 1,2-cis furanosides is of a particular challenge and while these species are essential for many organisms and they can be potent therapeutics, are far and beyond the most underrepresented moiety in drug molecules. We sought to tackle this challenge head on by developing novel furanosylation strategies aimed at making furanosylation reactions more approachable to industrial entities. For this, we set out with a particular set of goals in mind. Firstly, we wished to develop furanoside donors that could be readily synthesized in a facile manner at a low cost. Secondly, our strategies must be selective for the challenging 1,2-cis linkages that remain largely underrepresented for pharmaceutical applications. And thirdly, we wanted our donors to be activatable by inexpensive, mild, earth-abundant conditions, namely copper catalysis. These goals have converged in the development of novel approaches to 1,2-cis furanosylation, each of which promoted by mild copper catalysis, featuring benchtop stable donors bearing a carbene precursor moiety. The reactions are high yielding and diastereoselective and represent an excellent potential strategy for the generation of novel therapeutics containing 1,2-cis furanosides which should increase the accessibility of these molecules in the pharmaceutical industry.	en_US
dc.identifier.uri	https://hdl.handle.net/11244/340513
dc.language	en_US	en_US
dc.subject	Copper catalysis	en_US
dc.subject	furanosylation	en_US
dc.subject	1,2-cis glycosylation	en_US
dc.subject	carbene-mediated synthesis	en_US
dc.thesis.degree	Ph.D.	en_US
dc.title	Copper-Carbene Mediated 1,2-Cis Furanosylation Reactions	en_US
ou.group	Dodge Family College of Arts and Sciences::Department of Chemistry and Biochemistry	en_US