Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




Nancy I. Totah


2-Methylenetetrahydropyran, Carbonyl-Ene, Exocyclic Enol Ether, Pyrans, Three Component Coupling, trioxadispiroketal

Subject Categories



Reactions with 2-methylenetetrahydropyrans are underutilized in the literature, especially with respect to general methods demonstrating their nucleophilic nature. This work provides three general methods toward the synthesis of 2-β-oxygenated pyranyl substrates, which are key structural components of many biologically active polyketides and natural products.

The use of exocyclic enol ethers as nucleophiles was first demonstrated as a general process in three-component coupling reactions with secondary nucleophiles. The 2-β-hydroxy tetrahydropyran products were obtained in good to excellent yields through promotion with stoichiometric levels of titanium(IV) chloride at reduced temperatures. Only activated aldehydes or ketones worked as efficient coupling partners for this method. The point at which the secondary nucleophile was added to the reaction in progress was governed by the level of electrophile activation and in turn the amount of oxonium ion present for immediate capture. NOE studies determined that cis-tetrahydropyran products are solely formed with C6-substituted enol ether substrates.

The carbonyl-ene reaction of exocyclic enol ethers provides 2-β hydroxy dihydropyrans in excellent yields at room temperature. This process only requires catalytic levels of zinc chloride, and both activated and non-activated carbonyl-enophiles act as appropriate coupling partners. These mild reaction conditions produce dihydropyranyl substrates, which are equipped for further functionalization through the newly formed olefin. 2-Methylenetetrahydropyrans, bearing either mono- or di-substitution about the tetrahydropyran ring, were synthesized to determine if any chiral influence could be channeled to the dihydropyranyl products. The diastereomeric ratios of resulting products showed that exocyclic enol ethers with C3 mono- substitution or 2-methylenetetrahydropyrans with di-substitution, where at least one group is held axial, produced moderate levels of selectivity. Alternatively, the other substrates studied in this project demonstrated only low levels of chirality induction.

The carbonyl-ene reaction of exocyclic enol ethers has been applied bi-directionally to iodomethyl-2-methylenetetrahydropyrans to provide bis-β-hydroxypyrans. Good to excellent yields were obtained for the initial carbonyl-ene coupling and subsequent iodine elimination. The second carbonyl-ene coupling of 2-methylenedihydropyran was only effected with highly activated enophile components with zinc(II) chloride as the promoter. This reaction with ethyl glyoxylate proceeded in good to excellent yield with catalytic zinc(II) chloride. Only moderate yields of the pyranyl products were obtained with p-nitrobenzaldehyde and equimolar levels of zinc chloride. The bis-β-hydroxypyran products manufactured from this process are theoretically furnished for further functionalization into trioxadispiroketal systems. Attempted cyclization of these substrates under a number of acidic conditions failed to provide the desired bis-spiroketal systems. Therefore a step-wise approach to their manufacture was attempted, although this too failed to produce the bis-spirocyclic system due to difficulties experienced with iodide elimination.


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