Pyrroles and pyrrolidines are heterocyclic compounds that are particularly useful for medicinal purposes. They can be found in an assortment of biological contexts, such as cofactors and secondary metabolites, and are present in a range of drugs that treat everything from cardiovascular disease to cancer. Engineering these compounds can be accomplished through a multitude of ways, but a 1,3-dipolar [3+2] cycloaddition may prove to be beneficial in producing lucrative pyrroles or pyrrolidines. This researchWe aims to expand the scope of the known oxazolium salt/4-oxazoline/azomethine ylide route to these important investigate the assembly of five member heterocycles. via azomethine ylide formation through a nucleophile-mediated opening of an oxazolium salt. This methodology generates the reactive Formation of the azomethine ylide under mild conditions that allow in this manner is milder, allowing sensitive functional groups to be preserved. However, only . The 5-substituted and 2,5-disubstituted oxazoles are known to undergo this transformation.ring-open under these conditions Further, only substrates with the di with tethered and un-tethered dipolarophiles. However, Dipolarophile tethered at the five position have been shown to undergo an intramolecular cyclization. Thus, we are focusing our efforts on varying the position of the dipolarophile tether to the position two carbon and position three nitrogen. To tether at position 2, we have used DCC and EDC coupling reactions to prepare keto-amides from the appropriate carboxylic acids and alpha-amino-ketones (e.g., from a protected 4-hydroxy butyric acid and 2-amino-acetophenone). These compounds were then subjected to typical oxazole-forming conditions, using reagents such as triphenylphosphine. From here, the alcohol is deprotected, converted to the aldehyde, and treated with a lithiated alkyne to install the tethered dipolarophile that is ready for the [3+2] cycloaddition sequence. To tether the dipolarophile at position 3, 6- and 7-iodo-2-alkynoates have been prepared that are being used to alkylate the oxazole nitrogen, thus forming the oxazolium salt that is employed in the cycloaddition sequence. Preparation of all intermediates and progress to date will be reported.

Intramolecular oxazolium salt/azomethine ylide cycloaddition reactions with varying dipolarophile tether position

249th National Meeting (2015)

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