Total Synthesis of Pleurotin via Carbonylative Carbopalladation of Benzyl Halides

项目摘要 有效抗肿瘤药物的化学合成对开发有效的治疗方法至关重要。 治疗癌症的策略。侧耳素是一种抗菌醌真菌代谢物，最近被发现是 已知最有效的硫氧还蛋白还原酶抑制剂，硫氧还蛋白还原酶是一种与血管生成相关的酶， 肿瘤中的增殖、耐药和抑制细胞凋亡。然而，供应不足已经 阻碍了医学研究。介绍了一种通过非对映选择性卤代苄基化合物合成侧柏素的方法。 提出了引发碳分配/羰基化级联反应的设想。初步研究将涉及制定 一种催化体系催化卤代苄烷的碳化碳加成反应。这一过程将涉及 将Pd(0)氧化加成到卤化苯中，随后进行烯烃或炔烃的碳钯加成反应，以及 然后，将生成的有机钯物种进行羰化反应，生成所需的产品。展期 非对映选择性级联过程的方法将允许构建复杂的碳环 框架。这种新的级联序列的实用性将通过一个简明的对映选择性来证明 胸苷的全合成。 与公共卫生的相关性 本提案描述了一种合成抗癌剂胸苷的方法。通过开发一种新的化学品 反应，分子将被快速构建，从而允许生产大量的 胸腺肽。对这种分子的接触将使进一步的医学研究成为可能，并有可能导致治疗 癌症的治疗。

Project Summary The chemical synthesis of potent antitumor agents is vital to the development of effective treatment strategies for cancer. Pleurotin, an antibacterial quinone fungal metabolite, was found recently to be one of the most potent known inhibitors of thioredoxin reductase, an enzyme associated with angiogenesis, proliferation, drug resistance, and suppression of apoptosis in tumors. However, insufficient supply has hampered medical research. A method for the synthesis of pleurotin via a diastereoselective benzyl halide- initiated carbopalladation / carbonylation cascade is proposed. Initial studies will involve the development of a catalytic system to effect carbonylative carbopalladation of benzyl halides. This process will involve oxidative addition of Pd(0) into a benzyl halide, subsequent carbopalladation of an alkene or alkyne, and then carbonylation of the resulting organopalladium species to produce the desired product. Extension of the method to a diastereoselective cascade process will allow the construction of complex carbocyclic frameworks. The utility of this novel cascade sequence will be demonstrated by a concise enantioselective total synthesis of pleurotin. Relevance to Public Health This proposal describes a synthetic route to the anticancer agent pleurotin. By developing a new chemical reaction, the molecule will be constructed rapidly, allowing the production of substantial quantities of pleurotin. Access to this molecule will allow further medical research and potentially lead to new drugs for the treatment of cancer.