The Adaptive Nature of Palladium Reactivity in Synthesis

Citation

Caspi, Daniel David (2008) The Adaptive Nature of Palladium Reactivity in Synthesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/N37A-5970. https://resolver.caltech.edu/CaltechETD:etd-02212008-145524

Abstract

Both Pd(0) and Pd(II) have had, and continue to have, far-reaching impacts on organic synthesis. The versatile nature of palladium, in conjunction with the mechanistic understanding and predictive models that have been elucidated, has permitted a wealth of exploration into the seemingly endless potential of this metal. The utility of palladium is described in the context of the syntheses of the pharmaceutical agents Prozac®, and Singulair®, as well as the natural products dragmacidin F and telomestatin.

First, the palladium-catalyzed aerobic oxidative kinetic resolution for the enantioselective preparation of a variety of pharmaceutical substances, including Prozac®, and Singulair® is described. In this regard, the versatility of this resolution is further demonstrated by the diversity of the substrates chosen for this study, and for the first time this work extends the utility of the resolution to include amino alcohol derivatives and highly functionalized benzylic alcohols.

Secondly, an enantiodivergent strategy for the total chemical synthesis of both (+)- and (–)-dragmacidin F from a single enantiomer of quinic acid has been developed and successfully implemented. Although unique, the synthetic routes to these antipodes share a number of key features, including novel Pd(0) reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective Suzuki couplings, and high-yielding late-stage Neber rearrangements.

Finally, progress toward the total synthesis of the potent telomerase inhibitor telomestatin is described. Palladium-mediated cross-coupling reactions are employed to assemble oligooxazole intermediates from oxazole building blocks. Additionally, this strategy utilizes a minimum number of protecting groups, and proposes a unique aryl–aryl macrocyclization as the last step of the synthesis. In addition to the biological relevance of the desired target, a successful total synthesis of telomestatin would also enable rapid access to the preparation of telomestatin analogs. This would allow for the investigation of key interactions between telomestatin and the G-quadruplex.

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