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Michael A. Calter




This thesis is focused on the synthesis of the class of potent anticancer natural products known as Rocaglates, or Rocs, through the development of novel asymmetric organocatalytic IFB reactions.

The scope of the IFB reaction was expanded with the use of the linear tertiary bromide electrophiles and cyclohexadione for the construction of the two adjacent stereocenters of the Rocaglate core. By varying the electronic nature of the p-substituents on the electrophile, we were able to exert control over the products formed, as dictated by a U-shaped Hammett correlation.

A new class of IFB-like reactions was developed, characterized by the aldol addition of carbanion nucleophiles to cyclic triketones, followed by hemiacetal formation. The use of highly reactive cyclic electrophiles and aromatic nucleophiles drastically shortened the synthetic route by regio- and diastereoselectively building most of the Rocaglate core in one step, including the two adjacent quaternary stereocenters. We have developed an efficient and highly convergent asymmetric synthetic route to the core of Rocaglates that is also amenable to creating a diverse series of analogs.

While many naturally occurring and synthetic rocaglate derivatives have been shown to exhibit potent anticancer activities, no studies have yet investigated the biological activity of analogs in which the p-anisyl moiety is replaced with alkoxy groups. Seeking to study this novel class of rocaglate analogs, we developed a method for the selective alkylation of the anomeric hydroxyl group of the IFB-like adduct and completed the syntheses of several new potentially active alkoxy Rocaglaol analogs.

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