Generation of Z-Olefins via formic acid-mediated, metal-catalyzed additions to dienes

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The pharmaceutical, agrochemical, and fine-chemical sectors are under increasing pressure to prepare complex small molecules in an efficient manner while minimizing associated costs and waste outputs. The Z-olefin unit is a key structural feature found in drug molecules, fragrances and perfumes, and insecticides, while also serving as a linchpin unit in chemical synthesis. As Z-olefins are generally less thermodynamically stable than the corresponding E-isomers, their construction in the context of functional molecule synthesis remains challenging. ****We have developed a new method for the preparation of Z-olefins from dienes via the selective transfer of hydrogen from formic acid. The Rh-catalyzed process provides access to products with high chemo-, stereo-, and regioselectivity. The reduction pathway can be interrupted in the presence of electrophiles to form coupled products that contain the Z-olefin fragment. The use of formic acid as the hydride source is key to the methodology and provides significant advantages over protocols that use high pressures of hydrogen gas or inorganic/organometallic reducing agents. In order to ensure uptake of the process by commercial partners and to expand our IP landscape we aim to: 1) expand the scope of targets that can undergo Z-selective reduction and reductive coupling to strengthen the platform of reactivity; 2) identify new metal/ligand combinations that promote improved reactivity and scope at reduced metal-loadings for each class of reaction; 3) further develop collaboration and licensing relationships with partners in the pharmaceutical/custom synthesis/chemical manufacturing sectors. These studies will enable the generation of a suite of synthetic manifolds and catalysts to prepare both simple and complex molecules bearing Z-olefin units under conditions that are attractive to employ in both discovery and production contexts.******************