Date of Completion

1-19-2015

Embargo Period

1-19-2015

Major Advisor

Dennis L. Wright

Associate Advisor

Amy C. Anderson

Associate Advisor

Mark W. Peczuh

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Since the initial report by Diels and Alder in 1928, the [4+2] cycloaddition remains one of the most powerful and most frequently employed methods for the construction of six membered ring systems, generating a high degree of structural complexity in a single synthetic transformation. This cycloaddition process not only generates two new σ-bonds, but also establishes up to four new contiguous stereocenters in the process, owing to the high regio- and stereoselectivities displayed by this pericyclic reaction. In the decades following its discovery, Tobey and Law would report on the intriguing reaction of furan, substituted furans, and cyclopentadiene with both tetrachloro- and tetrabromocyclopropene. The two unsaturated systems reacted smoothly to directly produce cycloheptanoid systems, the products of a formal [4+3] cycloaddition reaction. The authors proposed in their early manuscripts that the tetrahalocyclopropenes under-went an initial thermal Diels-Alder cycloaddition to produce the cyclopropyl norbornene derivatives. However, these workers were unable to isolate or characterize the primary cycloadducts and instead observed a product which had spontaneously rearrange by way of a halogen atom migration to yield the bicyclo[3.2.1]octadiene nucleus.

The majority of my research has been directed toward the application of this Diels-Alder reaction in the direct cycloaddition of furans and perhalocyclopropenes, for the synthesis of polycyclic natural products and their analogs. Of particular importance to our work was the early finding that the oxabicylco[3.2.1]octane adducts could be readily converted into a versatile dibromoenone building block through a high yielding, silver-mediated hydrolysis.

These building blocks serve as rigidified cycloheptenones with functional handles at each of the seven unique carbons of the ring that allows for excellent regio- and stereochemical control during subsequent synthetic elaboration of the core. The ability to effect cleavage, annulation, nucleophilic addition and rearrangement of has allowed the development of synthetic routes to a variety of natural products. Thusly, we have worked to make this reaction a central feature in the synthesis of a variety of natural product targets. Herein, we detail the asymmetric syntheses of terpenoid natural product frondosin A and the synthesis of novel platensimycin analogous compounds, where this formal cycloaddition process was employed to prepare an integral cycloheptane ring system embedded in the polycyclic frameworks.

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