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Design and Applications of Unconventional Borylation Reactions

Mid-Term Report Summary - DAUBOR (Design and Applications of Unconventional Borylation Reactions)

Traditionally, the methods to form carbon-boron bonds have mostly been based on the electrophilic nature of boron due to its empty p-orbital. Changing the electrophilic nature of boron, by developing methods to generate and use nucleophilic or radical boron species, would open new ways to introduce boron atoms into organic molecules. This concept has been the driving force of my research during the first half of the project. Inspired by unsolved problems found in the synthesis of bioactive molecules, we have searched for unconventional ways to activate boron compounds to efficiently prepare valuable synthetic intermediates. Our primary tool during this first half has been the use of catalytic amounts of copper to generate nucleophilic boron species in situ from commercially available compounds. The lower price and toxicity of copper versus other transition metals and the unique reactivity of the boryl-copper intermediates make these processes particularly attractive. We have invested particular effort in the synthesis of chiral molecules containing sp3 carbon-boron stereocenters, which are difficult to access by known methods. The use of catalytic amounts of copper and chiral ligands has allowed us to obtain high enantioselectivities in these reactions. Using this strategy, we have successfully developed new stereoselective methods for the preparation of fragments that are present in bioactive natural products or drugs such as cyclopropanes (achievement 1), cyclobutanes (achievement 2), benzylic derivatives (achievements 3 and 7), allylic alcohols (achievement 5), allenes (achievement 6), and -aminoboronates (achievement 8). In most cases, we have prepared novel boron-containing molecules that were not accessible using conventional borylation reactions. In doing so, we are not only providing new tools for the preparation of valuable synthetic intermediates but we also increasing the chemical space for potential biological applications.