Grant: Discovery Grants Program - Individual

With discoveries like pharmaceutical drugs, insecticides, polymers, and food additives, organic synthesis stands as a powerful science that helped our modern society enjoy a dramatic increase in life expectancy and standard of living in the past century. Contributing to this chemical revolution are boronic acids, a class of stable and relatively non-toxic boron-containing organic compounds that have undergone huge developments and were applied successfully in various areas of science in the past 25 years. Continued growth in their synthetic and biological applications will occur only if supported by a judicious exploration of their fundamental properties and reactivity. With this view, this program will address several problems and needs of modern pharmaceutical research with the following directions: 1) Synthetic methodology development, with a focus on the development of milder and safer methods to prepare heteroatom-functionalized chiral (non-symmetrical) alkylboronates, a class of boron compounds of great utility for the preparation of pharmaceutical intermediates. To this end, we will develop an unprecedented disproportionation approach to reactive boron intermediates, simpler and more practical, without using cryogens and pyrophoric organolithium reagents. Likewise, we will develop catalytic strategies to activate alkenylboronates in photochemical [2+2] cycloadditions affording cyclobutane products of interest as drug scaffolds, and we will prepare 3-fluoro allylboronates enabling the stereoselective formation of C-F containing molecules of great importance in drug optimization. 2) New catalytic processes where boronic acids are employed as mild and 'green' catalysts, activated with light to effect direct substitutions of readily available alcohols, thus bypassing the use of toxic alkyl halides in these important classes of reactions to address many green chemistry "priority areas" of the pharmaceutical industry. In the same line, a "one-pot" cyclopentanone-to-piperidine ring hop will be developed based on our earlier discovery of a boronic acid-catalyzed Beckmann rearrangement, allowing a unique, streamlined and less wasteful access to piperidines, the most common heterocyclic structural element in drugs. 3) An approach to borosugars, unprecedented carbohydrate mimetics that take advantage of boron's unique ability to act as a mild Lewis acid and form reversible tetracoordinated intermediates, with potential uses in enzyme inhibition and as a tracer in PET imaging. While training several highly qualified young scientists with highly desired skills, this ambitious program will generate groundbreaking new knowledge and concepts impacting daily practices in the pharmaceutical and biological research fields.