Total Synthesis of Pleurotin via Carbonylative Carbopalladation of Benzyl Halides

卤代烷羰基化碳钯化全合成侧耳素

• 批准号: 7753586
• 负责人: David C Ebner
• 金额: $ 4.43万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753586
• 关键词: Alkenes; Alkynes; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Biological; Complex; Development; Drug resistance; Enzymes; Evaluation; Goals; Lead; Malignant Neoplasms; Medical Research; Methods; Pharmaceutical Preparations; Process; Production; Public Health; Quinones; Route; System; angiogenesis; antitumor agent; cancer therapy; chemical reaction; chemical synthesis; effective therapy; inhibitor/antagonist; novel; pleurotin; thioredoxin reductase; treatment strategy; tumor

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.

项目摘要 有效抗肿瘤药物的化学合成对于开发有效的治疗方法至关重要 癌症的策略。侧耳素是一种具有抗菌作用的醌类真菌代谢产物， 已知的硫氧还蛋白还原酶，一种与血管生成相关的酶， 肿瘤中的增殖、耐药性和细胞凋亡抑制。然而，供应不足， 阻碍了医学研究。一种经由非对映选择性苄基卤合成pleurotin的方法， 引发的碳钯化/羰基化级联。初步研究将涉及制定 一种实现苄基卤的羰基化碳钯化的催化体系。这一过程将涉及 将Pd（0）氧化加成到苄基卤中，随后使烯烃或炔烃碳钯化，和 然后羰基化得到的有机钯物质以制备所需产物。延长 非对映选择性级联过程的方法将允许构建复杂的碳环化合物， 框架。这种新型级联序列的效用将通过一个简洁的对映选择性 侧耳素的全合成。 与公共卫生的相关性 该提案描述了抗癌剂pleurotin的合成路线。通过开发一种新的化学物质 反应，分子将被迅速构建，允许产生大量的 侧耳素获得这种分子将允许进一步的医学研究，并可能导致新的药物， 癌症的治疗