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.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-5962 |
| Date | 01 July 2015 |
| Creators | Slater, Kara Anne |
| Contributors | Friestad, Gregory K. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright 2015 Kara Anne Slater |
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