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One-pot Tandem Diels-Alder/Nazarov Reactions to Generate Advanced Tricyclic Intermediates
AuthorCarmichael, Rachael A.
AdvisorChalifoux, Wesley A.
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One-pot multi-component reactions represent efficacious strategies to rapidly obtain complex intermediates applicable in the synthesis of therapeutically germane compounds. Nazarov reactions of aryl vinyl ketones are viewed as important steps in total synthesis and contribute to expanding the chemist’s synthetic toolbox. Currently, activated substrates or photochemical means are necessary to effect this transformation because the energy barrier is predicted to be relatively high. The stabilizing effect of silyl substituents beta to a carbocation intermediate has been well documented. a) We hypothesized that incorporation of a silyl group into the ynone starting materials may stabilize the reactive intermediates, enabling the aryl Nazarov reaction to proceed even with unactivated substrates. The use of aryl silyl ynones proved successful and as a consequence our group developed a tandem process utilizing the Diels-Alder and Nazarov reactions of aryl ynones to generate carbo- and heterocyclic fused ring systems in good yields. The tandem reactions proceed under Lewis acidic conditions to generate three new carbon-carbon bonds, a quaternary carbon and two stereogenic centers. In order to access a wider range of pharmaceutically important compounds through concise routes, a more versatile technology is needed. The use of diynones as relatively high energy starting materials facilitates multiple carbon-carbon bond formations in a one-pot reaction. With respect to unsymmetrical diynones, regiocontrol of the double bond is accomplished through silane elimination rather than loss of hydrogen, ensuring the formation of one major product. Furthermore, the Diels-Alder cycloaddition occurs preferentially on the silyl substituted alkyne at low temperatures, allowing for a “timed” double Diels-Alder reaction in which two different dienes can be added, generating a highly asymmetric product. Such molecular control permits a significant amount of versatility within the method. b) Our lab has designed and successfully executed a highly modifiable multicomponent reaction, initiating from a double Diels-Alder cycloaddition followed by a Nazarov reaction to furnish the [6-5-6] backbone. This method produces three fused rings evolving from the construction of five new carbon-carbon bonds, quaternary or vicinal quaternary carbons, and stereogenic centers in a one-pot reaction. A diverse array of drug-like scaffolds can be rapidly synthesized through these tandem processes providing a high level of stereo- and regiocontrol in the products.