The Synthesis of 3-Vinylindolines by the Palladium-Catalyzed Intramolecular Allylic Alkylation of Cinnamyl Acetates and the Synthesis of Polyphenolic 4-Aryl-3,4-dihydrocoumarins by Domino Friedel-Crafts Reactions

Abstract

Historically, the alkylation of allylic acetates with non-stabilized C(sp3) nucleophiles has been challenging. The metal-catalyzed alkylation of allylic acetates and carbonates with organotin and organoboron reagents has significantly increased the scope of nucleophiles available to participate in such reactions; however, the generation of C(sp3)-C(sp3) bonds in this manner remains difficult. We therefore designed a substrate in order to explore the intramolecular transition metal-catalyzed alkylation of an allylic acetate with a C(sp3) organotin nucleophile. From this substrate we were able to successfully synthesize a number of 3-vinylindolines in modest to good yields in as little as seven steps through the palladium-catalyzed intramolecular allylic alkylation of cinnamyl acetates with tethered organotin nucleophiles. To the best of our knowledge this represents the first example of such a transformation, resulting in the formation of novel C(sp3)-C(sp3) bonds.

It has been shown that polyphenolic procyandins, members of the flavonoid class of compounds, possess moderate affinity for a synthetic model of a proline rich region of the microtubule associated protein tau. The phosphorylation of this region of tau is thought to be correlated with the development of intraneuronal protein deposits, a hallmark of Alzheimer’s disease physiopathology. In the second part of this thesis, we set out to utilize the domino Friedel-Crafts alkylation/acylation of benzylidene Meldrum’s acids with phenols previously developed in our group for the synthesis of a number of polyphenolic 4-aryl-3,4-dihydrocoumarins, members of the neoflavonoid class of compounds. By synthesizing a library of polyphenolic neoflavonoids in this manner, which possessed variation in the number and position of hydroxyl groups about the aromatic rings, a systematic survey of the structure-activity relationship was to be conducted. This would allow us gain a better understanding of potential therapeutic agents that may be able to attenuate the formation of these intraneuronal protein deposits in the treatment of Alzheimer’s disease.