Document Type

Dissertation

Date of Degree

Summer 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Gregory K. Friestad

Abstract

Chiral amine functionality is abundant in the world of natural products. In the past, many research groups have made use of the addition of carbanions to imine derivatives in order to achieve such functionality. Nucleophilic addition, however, can prove to be difficult when utilizing complex starting materials since many functional groups are not orthogonal to this approach. Radical addition to imine derivatives is an alternative strategy. There is a broader range of functional group tolerance with this method due to the mild nature and chemoselectivity of radical reactions. Further, secondary functionality may be included in either the radical precursor or acceptor, leading to subsequent formation of nitrogen heterocycles through a radical-polar crossover reaction.

We have found that photolysis of alkyl iodides in the presence of Mn2(CO)10 leads to chemoselective iodine atom abstraction and radical addition to N-acylhydrazones without affecting alky chloride functionality. Using radical precursors or acceptors bearing a suitably positioned alkyl chloride, the radical addition is followed by further bond construction enabled by radical-polar crossover. After the alkyl radical adds to the imine bond, the resulting N-nucleophile displaces the alkyl chloride leaving group via 5-exo-tet or 6-exo-tet cyclizations, furnishing either pyrrolidine or piperidine functionality, respectively. When both 5-exo-tet and 6-exo-tet pathways are available, the 5-exo-tet cyclization is preferred. Isolation of the intermediate radical adduct, still bearing the alkyl chloride functionality, confirms the order of events in this radical-polar crossover annulation. A chiral oxazolidinone stereocontrol element in the N-acylhydrazones provides excellent stereocontol in these reactions.

In the past, the Mn-mediated radical addition to N-acylhydrazones methodology was applied to the synthesis of γ-amino esters and synthetic studies of the tubulysin family of natural products. Throughout this work, it became apparent that there exists a need for a versatile, general approach to the installation of N,O-acetal functionality at peptide bonds. Initial results suggest that such a structure can be synthesized in a latent form, and later oxidized to reveal the N,O-acetal moiety.

Public Abstract

Numerous pharmaceuticals currently in use find their origins in nature. Biologically active compounds found in plants and insects are known as natural products. It is important to be able to synthesize such compounds in a laboratory setting in order to decrease the destruction of nature, and often in order to gain a significant amount of the compound for use in industry.

Chiral amines, specifically chiral pyrrolidines and piperidines, are substructures that occur often in natural products. Throughout my studies in graduate school, I have developed a new method for the synthesis of these substructures. The methodology, termed a Radical-Polar Crossover approach, incorporates two types of intermediates in one reaction, and so facilitates a wide scope of application. Compounds are traditionally constructed one bond at a time, but with the use of Radical-Polar Crossover reactions, the construction of multiple bonds can be achieved in one reaction. The omission of reactions in a synthetic scheme eliminates time consuming workup and purification steps, and this saves time, money, and offers a more “green” approach to synthesis. This methodology will add to the field of medicinal chemistry, hopefully allowing for numerous discoveries in natural product research.

Keywords

publicabstract

Pages

xiv, 127 pages

Bibliography

Includes bibliographical references (pages 114-126).

Copyright

Copyright 2015 Kara Anne Slater

Included in

Chemistry Commons

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