Oxygen Promoted Pd(II) Catalysis for Medicinal Chemistry

说明(申请人提供)：作为候选药物，有许多具有生物活性的天然产物和合成化合物，它们的结构中含有共轭芳基和/或烯基基团。为了便于合成，我们已经着手开发一种新的合成方法来有效地制备这些官能团。这项计划的研究将我们目前的合成方案扩展到广泛的体系，以快速生成芳基-芳基、芳基-烯基、烯基-烯基、烯基-炔基键。由于这些功能在生物活性天然产物和合成药物先导中很常见，我们的方法将提供有用的方法和关键的合成支架，从而使合成和药物化学家受益。 在这个拟议的项目中，我们将研究氧促进的Pd(11)催化，使人想起Heck反应，以提供一种制备上述体系的补充方法。虽然Heck化学使用卤化物的氧化加成，但我们建议的协议使用芳基或烯基硼酸的跨金属作用。由于机械途径的不同，我们的条件是温和和容易的，为现有的C-C键形成工具提供了一个有效的选择。这些转化是在无碱条件下实现的，这对大多数底物在室温下都是有效的。如果目前方法学的发展取得成功，这项研究将为药物发现和工艺开发提供大量的合成便利。此外，氧化钯催化是一个新兴的领域，我们所提出的方法学的成功发展将加强有机化学中这一新领域的研究。 此外，开发的方法对环境无害，因此氧气促进的催化可以极大地降低清理成本，并避免金属盐及其副产物引起的副反应。因此，该方法学将适用于大规模生产，有助于药物开发。我们相信，我们的新技术将有助于推动有机合成、过程化学和药物化学的发展，最终实现药物发现。

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.