Oxygen Promoted Pd(II) Catalysis for Medicinal Chemistry

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DESCRIPTION (provided by applicant): As drug candidates, there are numerous bioactive natural products and synthetic compounds, which contain conjugated aryl and/or alkenyl moieties in their structures. To facilitate syntheses, we have embarked on the development of a new synthetic methodology to efficiently prepare such functional groups. This projected study extends our current synthetic protocol to a wide array of systems, to generate aryl-aryl, aryl-alkenyl, alkenyl-alkenyl, alkenyl-alkynyl bonds expeditiously. Since these functionalities are common in biologically active natural products and synthetic drug leads, our methodology will benefit synthetic and medicinal chemists by providing useful methods as well as crucial synthetic scaffolds. In this proposed project, we will study oxygen promoted Pd(ll) catalysis, reminiscent of the Heck reaction, to provide a complimentary method of preparing the aforementioned systems. While Heck chemistry utilizes oxidative addition to halides, our proposed protocol employs transmetallation of an aryl or alkenyl boronic acid. Due to the difference in mechanistic pathways, our conditions are mild and facile, offering an efficient alternative to the existing C-C bond forming tools. These transformations are achieved under base-free conditions, which are effective at room temperature with most substrates. Should the development of the current methodology become successful, this research will facilitate a lot of syntheses for drug discovery and process development. Besides, the oxidative Pd(ll) catalysis is an emerging field, and our successful development of the proposed methodology will strengthen this new field in organic chemistry. Additionally, the developed procedures are environmentally benign, thus the oxygen promoted catalysis can drastically reduce clean-up costs and avoid side reactions caused by metal salts and their by-products. As a result, this methodology will be applicable to large scale manufacturing, aiding in the drug development. We believe our novel technology will help to advance organic synthesis, process chemistry, and medicinal chemistry, culminating in drug discovery.