Stereodefined Fluorinated Tetrasubstituted Olefins by Catalytic Cross-Metathesis

Practical strategies that provide facile access to tetrasubstituted olefins bearing a fluorine atom and/or a polyfluoroalkyl moiety are crucial to drug discovery and development and are therefore in high demand. Equally important and sought-after are reliable and stereocontrolled methods for modifying such alkenes.

Nonetheless, such methods are scarce, and those available are severely limited in scope.

In this context, catalytic olefin metathesis offers a unique disconnection to access modifiable tetrasubstituted alkenes in either stereoisomeric form.

Still, there are no more than a handful of such reactions, with all ring-closing metathesis (RCM) processes affording a cyclic alkene bearing two methyl groups.

There is only a single reported example of a cross-metathesis (CM) reaction that affords a tetrasubstituted olefin as a stereoisomeric mixture.Inspired by recent progress by the host group, we will develop new cyclic alkylidene catalysts that are designed to promote formation of stereodefined tetrasubstituted fluoro-alkenes by stereoretentive CM.

The substrates will be readily available trisubstituted olefins and commercially available F/F3C-substituted alkenes.

The products will be value-added tetrasubstituted olefins bearing a F/F3C moiety as well as a modifiable C–Cl or C–Br bond.

The method will be applied to the synthesis of fluorinated analogues of natural products such as fluoro-pateamine A.Another key aspect will be application to the modification of important drugs.

Our goal will be to utilize the new catalytic chemistry to generate analogues that might exhibit superior bioactivity, or be active in a different disease area.

We will transform entecavir or barmumycin to their polyhalogenated analogues, which will be tested for in vitro bioactivity through collaboration with experts.

The conversion of readily accessible olefins into their polyfluorinated, tetrasubstituted analogs holds considerable and as-of-yet untapped promise for drug discovery.