With this CAREER Award, the Organic and Macromolecular Chemistry program is supporting the research of Professor Martin D. Burke of the University of Illinois. This project will develop a new strategy for small molecule synthesis, analogous to peptide coupling, involving the iterative cross coupling of B-protected haloboronic acid building blocks. In this approach, bifunctional building blocks having all of the required functional groups preinstalled in the correct oxidation state and with the desired stereochemical relationships are brought together utilizing one mild reaction. The proposed research will define the scope, limitations, and potential of this novel reaction and will allow the simple and flexible construction of a broad range of complex natural products with important biological activities. The ultimate goal of this project is to make complex small molecule synthesis as simple and widely applicable as possible, thereby making the power of synthesis maximally accessible, even to the non-chemist.
Professor Burke will also initiate pioneering a new outreach program entitled Lab Partners, which is designed to expose high school students from nearby rural communities to the excitement and power of organic synthesis. In collaboration with students, educational colleagues at UIUC, and teachers at rural high schools, a mini-curriculum in organic chemistry will be developed which will bring high school students to the UIUC campus for a day of laboratory exercises. This initial pilot program will be expanded to a partnership between high school science teachers and nearby research universities and results will be disseminated via the Internet. It is anticipated that these activities will demystify the college experience and encourage students from underprivileged rural communities to consider a college education in the chemical sciences.
Our group has developed a powerful new platform for making the synthesis of medicines, materials, and biological active natural products as simple, efficient, and broadly accessible as possible. Analogous to the way peptides are now routinely assembled by non-specialists, this strategy uses only one reaction iteratively to join together a collection of building blocks having all of the required functionality pre-installed. Enabling this approach, we discovered that complexing a boronic acid with a very cheap and environmentally friendly ligand, N-methyliminodiacetic acid (MIDA), reversibly attenuates the reactivity of this functional group, thereby facilitating the iterative coupling of building blocks in a precisely controlled manner. Our MIDA boronate building blocks are also exceptionally stable to benchtop storage, silica gel chromatography, and most common reagents, making it possible to readily prepare advanced boronate building blocks from simple boron-containing starting materials. We have also discovered that MIDA boronates can serve as highly effective surrogates for even the most notoriously unstable boronic acids via a "slow-release cross-coupling" strategy. This work resulted in many air-stable 2-heterocyclic, alkenyl, alkynyl, and cyclopropyl building blocks. We also developed a chiral version of the MIDA ligand, dubbed PIDA, which enables many new building blocks to be prepared in stereochemically pure form. We further discovered a novel rearrangement of epoxy PIDA boronates that generates alpha-boryl aldehydes, a new class of intermediates which have proven to be powerful vehicles for generating Csp3 boronates in highly enantioenriched form. Harnessing these new building blocks and methods, we have completed total syntheses of a series of biologically active natural products, including ratanhine, retinal, parinaric acid, crocacin C, peridinin, synechoxanthin, C35-deoxy amphotericin B, several medicines under investigation for the treatment of cancer, asthma, and diabetes, and a range of materials being studied for applications in solar cells and light-emitting diodes. Other leading academic groups have now also begun extensively utilizing MIDA boronates in syntheses of small molecules and/or the development of new methodologies. This platform is ultimately poised to deliver the power of small molecule synthesis to the non-specialist and help shift the rate-limiting step in small molecule science from synthesis to function. This MIDA boronate platform is already having a substantial impact in the chemistry community worldwide. More than 140 MIDA boronates are now commercially-available from Sigma-Aldrich (www.aldrich.com/mida), Boropharm, and AllyChem. These building blocks are now being used to expedite the discovery of new medicines by more than 70 different pharmaceutical companies throughout the U.S., Canada, Europe, India, and Asia, and at least one of our building blocks is already being used on the process scale to prepare a new medicine that is being studied in phase II clinical trials in human patients. In recognition of this rapid and widespread utilization, this work has been highlighted in many different news magazines and journals, been the subject a Chemical and Engineering News Worldwide Webinar presentations (http://pubs.acs.org/cen/webinar/webinar-sigma.html), and "Burke boronates" are now included in the book of Name Reactions (4th ed. Springer-Verlag Berlin Heidelberg). Finally, our work in this area has been recognized by many honors and awards, including three national awards from the American Chemical Society: The Arthur C. Cope Scholar Award, The Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator, and The Kavli Foundation Emerging Leader in Chemistry Lectureship, which will be delivered at the National ACS Meeting in Indianapolis (9/9/13, 4-5pm).
