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

Medium-sized cyclic ethers are challenging synthetic targets due to enthalpic and entropic barriers. Methods for the stereoselective synthesis of ¿,¿¿-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 ¿,¿¿-trans-oxepanes. A gold(I)-catalyzed alkoxylation reaction has also allowed access to ¿,¿¿-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.