Synthesis and Methodology Enabled by Regioselective Functionalization of Enones

Bioactive natural compounds are of strategic importance in modern medicine. In a period from 1981 to 2014 U.S. Food and Drug Administration approved over 1300 new molecular entities to treat diverse spectrum of conditions, and among these substances unmodified natural products and their direct analogs represent 43% of registered compounds. While inspecting chemical composition of such molecules one can quickly identify enones and their derivatives to be common structural motif. Our research goals were shaped around contribution of synthetic knowledge regarding total chemical synthesis of enone-based biologically active natural products of low abundance, along with development of new synthetic tools that allow transformation of enones into other functional groups, critical in preparation of even broader class of medicinal targets. We successfully demonstrated that enone-derived vinylogous esters can be converted into twelve different phenolic natural compounds of medicinal interest in a very short and highly efficient manner. We also showed that halogenated nature of thus-created aromatic fragments can be incorporated into further synthetic sequence by performing coupling reactions between aryl halide and alkenes as their side tethers. Furthermore, developed oxidative aromatization conditions can be applied to hydrogen-deficient enone systems, and resulting polyhalogenated enones can be used in a preparation of corresponding natural products. Regioselective functionalization of enones also allowed us to explore new synthetic technologies available in this area. Specifically, we successfully developed three Ni-catalyzed transformations on electron-rich anilines that allowed us to convert single universal intermediate into corresponding de-functionalized anilines and indoles of medicinal importance. Finally, we were also able to investigate variety of enantioselective remote functionalization reaction of enones. We showed the possibility of γ-arylation of enone-derived dienol sylil ethers with phenyl bromide into enantioenriched arylated enones under Ni-catalyzed reaction conditions.