With this EAGER award, the Chemical Synthesis Program is funding Professor K.C. Nicolaou of Rice University to attempt to develop the first viable catalytic, asymmetric olefin dichlorination. Though clearly of high risk, success across any of the olefin classes to be investigated in this study, would represent high reward, with a likely impact on natural product, medicinal, process and combinatorial chemistry endeavors. The Nicolaou group will explore complementary organocatalytic and organometallic avenues toward the title transformation, with cinchona alkaloids among the chiral scaffolds expected to impart asymmetry, and with both relatively non-polarized alkenes and polarized alkenes of the alpha,beta-unsaturated carbonyl variety to be explored.
If successful, a catalytic asymmetric dichlorination tranformation is expected to have broad scientific impact, across both academic and industrial settings. Given the diverse array of organic, inorganic and organometallic chemistries to be explored, students are expected to benefit from this broad synthetic training. The PI plans to work to include women and chemists from traditionally underrepresented groups in this research team undertaking.
Chirality, an asymmetric characteristic of molecules, is a key trait in all life. With control of a diverse array of proteins nature can easily control chirality of molecules but organic chemists lack such broad tools. There have been great strides over the last decades in discovering methods to control the chirality of molecules produced in a reaction, a process termed enantioselectivity. Our project focused on developing a synthetically useful and robust enantioselective olefin dichlorination reaction, a transformation that has eluded chemists previously. Many natural products, some of which have potential to become therapeutic medicines, would be expediently synthesized by such a reaction. Our previous efforts on this subject provided a lead on what types of catalysts may succeed and we expanded upon that work. We synthesized a library of catalysts, tested them on various substrates and evaluated the enantiomeric enrichment of the products. This allowed us to gain greater insight into the catalyst requirements of the reaction, the limitations of the system we devised and possible improvements in catalyst design. With our experience in asymmetric olefin chlorination, we also explored other mechanistically-distinct chlorination reactions that could be useful to chemists. Work is still ongoing to expand this reaction to a larger substrate scope and improve the enatioselectivity, but with the key knowledge gained from these NSF funded studies we are closer to developing a broadly applicable enantioselective dichlorination reaction.
