This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polar rearrangements of peroxides are the only synthetically useful carbon-to-oxygen migrations available for synthesis. While these transformations are potentially powerful, the peroxide starting materials are often hazardous to work with and not readily available. Herein we propose to develop a novel carbon-to-oxygen rearrangement applicable to tertiary alcohols and benzylic or allylic secondary alcohols. This will be achieved by tuning sulfur-oxygen linkages to provide electrophilic oxygen species with a good leaving group on oxygen. Specifically, we propose that carefully designed alkoxysulfonium ions will display the same rearrangement reactivity profile as peroxides. These transformations are predicted to provide an oxocarbenium ion intermediate, which opens the possibility of performing tandem reactions to produce complex oxygen-containing polycyclic products from simple alcohol starting materials. This methodology would find utility in the synthesis of a wide variety of oxygen-containing heterocycles found in both non-natural medicinal agents and natural products. It would also provide a solution to the current lack of general methodology available for the construction of medium- and large-size cyclic ethers and functionalized pyrans and furans, and would be particularly useful for the synthesis of complex unnatural monosaccharides. This methodology would represent a significant advance in the synthesis of oxycycles and in general would fill a void in polar rearrangement methodology. It is likely to be as synthetically useful as the analogous carbon-to-nitrogen rearrangements.
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