Method Development for the Stereoselective Synthesis of Medium-Sized Cyclic Ethers and Application to Natural Product Synthesis: Part I. Organocatalytic Oxa-Conjugate Addition for α,α´-trans-Oxepanes Part II. Gold(I)-Catalyzed Alkoxylation for α,α´-cis-Oxocenes Part III. Studies toward the Synthesis

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2015

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Lanier, Megan

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Hong, Jiyong

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Abstract

Medium-sized cyclic ethers are challenging synthetic targets due to enthalpic and entropic barriers. Methods for the stereoselective synthesis of α,α΄-disubstituted medium-sized cyclic ethers began to appear with the discovery of naturally-occurring, ladder-shaped polycyclic ethers, such as brevetoxin B, and monocyclic ethers, such as (+)-laurencin. Despite the progress made in this field, limitations remain including competing formation of smaller ring sizes and scarcity of catalytic methods. Our aim has been to develop stereoselective syntheses for 7- and 8-membered cyclic ethers which have potential for application in natural product synthesis. The C-O bond disconnection was selected for the methods described within because cyclization and stereoinduction could be achieved simultaneously. In the case of 7-membered cyclic ethers, an organocatalytic oxa-conjugate addition reaction promoted by the gem-disubstituent (Thorpe−Ingold) effect has been developed to stereoselectively provide α,α′-trans-oxepanes. A gold(I)-catalyzed alkoxylation reaction has also allowed access to α,α′-cis-oxocenes. This method has been probed for feasibility in the stereoselective synthesis of (+)-intricenyne, an 8-membered cyclic ether belonging to the C15 nonterpenoid acetogenin natural product class. These methods have the potential to become general and efficient routes to highly functionalized oxepanes and oxocenes.

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Lanier, Megan (2015). Method Development for the Stereoselective Synthesis of Medium-Sized Cyclic Ethers and Application to Natural Product Synthesis: Part I. Organocatalytic Oxa-Conjugate Addition for α,α´-trans-Oxepanes Part II. Gold(I)-Catalyzed Alkoxylation for α,α´-cis-Oxocenes Part III. Studies toward the Synthesis. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/9941.

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