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Exploring Enantioselective and Multicomponent One-Pot Reactions Utilizing Alkynes as Linchpins Toward Biologically Active Molecules
AuthorHorton, Jade A.
AdvisorChalifoux, Wesley A.
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Robust synthetic methodology to make complex small molecules that are of biological importance is a highly investigated area. Utilizing fundamental bond-making reactions, like the Diels-Alder reaction and the Nazarov cyclization, in new efficient one-pot methodologies can help to expand the scope of reactions available to make such molecules. Using proprochiral and high energy starting materials like alkynes can afford reactive intermediates that can then undergo further transformations in one pot. The Diels-Alder (DA) reaction is a powerful synthetic tool that organic chemists have relied on for forming six-membered rings with good predictability for nearly a century. While there have been many reports of novel DA reactions and DA reactions in total syntheses, a void still exists in fully utilizing alkynyl dienophiles. There are very few enantioselective DA reactions that utilize alkynyl dienophiles, and none to date that utilize oxygen functionalized dienes. Herein we report a new BINOL-Al-Cl catalyst preparation that is robust enough to catalyze such a reaction with great success both in terms of yield and enantiomeric ratios. The products, 1,4-cyclohexadienes, have two regiochemically different alkenes, which can serve as functional handles that can be further elaborated to furnish molecules of biological interest. While expanding the scope of the enantioselective alkyne DA, alkynyl aldehydes were found to undergo a Hetero-Diels-Alder (HDA) reaction when reacted with oxygen functionalized dienes in the presence of aluminum Lewis acids. There is only one report for the development of an enantioselective HDA reaction utilizing an alkynyl aldehyde. Due to the highly reactive 1,4-cyclohexadiene produced by an alkyne DA reaction, this intermediate is poised to undergo a second, tandem DA reaction. From this tandem DA, a cis-decalin is produced. There are many biologically active terpenoids that contain the cis-decalin structural motif. This two-fold DA reaction proved to be a good method for rapid generation of cis-decalin molecules possessing biological activity. The highly reactive 1,4-cyclohexadiene intermediate formed from an alkyne DA reaction also proved to be poised to undergo a tandem Nazarov cyclization (NC). The reported tandem DA/NC is a reliable way to rapidly generate a library of [6-5-6] tricyclic molecules. In this report one compound contains a nitrogen-containing ring, which opens the door to utilizing heteroatom-containing starting materials. Using indole substituted alkynyl ketones in this reaction would produce even larger [6-5-5-6] tetracyclic molecules. Such polycyclic, heteroatom containing molecules are of high interest due to their abundance not only in nature, but in their use as pharmaceutical drugs.