Efficient access to molecular complexity and diversity is important for the development of small-molecule screening libraries designed to identify highly specific modulators of disease relevant macromolecular interactions. We envisioned the use of iteratively synthesized bis-vinyl ether substrates for cascade-type transformations to gain rapid access to several different classes of stereochemically rich, linear or polycyclic scaffolds. To evaluate their utility in this context, mechanistic investigations were undertaken to understand the chemical reactivity of bis-vinyl ethers in radical cyclization reactions and [3,3]-sigmatropic rearrangements.
Radical cyclization across bis-vinyl ethers proceeded through an apparent 6-endo-trig/5-exo-trig ring closure to afford functionalized hexahydro-2H-furo[3,4-b]pyrans in good yield, with high diastereoselectivity and excellent regiocontrol. Combination of two electron-withdrawing substituents on the bis-vinyl ether backbone resulted in the trapping of a 5-exo-trig/β-scission product, prompting us to investigate the mechanism for cyclization. Formation of the hexahydrofuropyrans was found to be the result of a 5-exo-trig/3-exo-trig/retro-3-exo-trig pathway to afford a “formal” 6-endo pyranosyl radical that could participate in a second 5-exo-trig cyclization to secure the two ring system.
From this earlier study, we found certain combinations of substituents on the bis-vinyl ether backbone increased the propensity for these substrates to undergo Claisen rearrangement at remarkably low temperatures. Kinetic investigations of the substituent effects influencing bis-vinyl ether stability found that electron-releasing substituents on the γ-allyloxy fragment increased the rate of rearrangement as a result of stabilization of a cationic allyl fragment in the transition state. Thermochemical data derived from the earlier kinetic investigations also indicated that the Claisen rearrangement of bis-vinyl ether substrates occured through a dissociative mechanism, characterised by an ΔS‡ of +2.3 cal K-1 mol-1.
A palladium-catalyzed auxiliary-controlled diastereoselective Claisen rearrangement of bis-vinyl ethers to access aldol-type products is currently under development. Preliminary results indicate that a modest degree of diastereoselectivity can be achieved in this reaction, provided that the steric burden at the stereogenic element is close enough to the pericyclic framework to exert an influence on facial selectivity. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/5730 |
| Date | 20 November 2014 |
| Creators | O'Rourke, Natasha Felicia |
| Contributors | Wulff, Jeremy Earle |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Rights | Available to the World Wide Web |
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