Total Synthesis of Cytotoxic ent-Kauranoid Natural Products

细胞毒性对映贝壳杉素天然产物的全合成

• 批准号: 7908295
• 负责人: DAVID JOHN MICHAELIS
• 金额: $ 4.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908295
• 关键词: Alcohols; Aldehydes; Antineoplastic Agents; Attention; Biological Factors; Cells; Chronic Myeloid Leukemia; Complex; Development; Economics; Family; Human; K-562; Malignant Neoplasms; Molecular Structure; Process; Property; Reaction; Research; Source; Transition Elements; Vanadium; anticancer activity; antitumor agent; cancer therapy; catalyst; chemical reaction; chemotherapeutic agent; cytotoxic; diene; flexibility; novel; oxidation; public health relevance; scaffold

DESCRIPTION (provided by applicant): The complex molecular structure of medicinally important natural products has stimulated the development of new chemical reactions that quickly generate structural complexity from simple starting materials. Transition metal-catalyzed reactions are uniquely suited for this purpose because the chemoselectivity and stereoselectivity of a given process is quite often predictable and reliable. Vanadium catalysts have found widespread application in synthesis, most notably as catalysts for isomerization and asymmetric oxidation reactions. This research plan will focus on the development of a novel vanadium-catalyzed cascade reaction between propargylic alcohols and cyclopropyl aldehydes that generates highly functionalized 1,3-dienes. This tandem process represents a single pot, atom economic construction of highly functionalized dienes that are powerful, flexible intermediates towards more complex targets. After exploring the substrate scope of this cascade reaction, the utility of the 1,3-diene as an intermediate in synthesis will be demonstrated by performing selective inter- and intramolecular transformations to generate important natural product scaffolds. The vanadium-catalyzed cascade will then be used to carry out a concise total synthesis of nodosin and sculponin B of the ent-kauranoid family of natural products. Nodosin and other ent-kauranoids have recently received significant attention due to their potent anticancer activity. Nodosin in particular has shown potent inhibitory activity against K562 human chronic myelogenous leukemia cells. The synthesis of nodosin will represent a general strategy for accessing many of the ent-kauranoids, facilitating further development of this important class of compounds as cancer chemotherapeutic agents. PUBLIC HEALTH RELEVANCE: Natural products have historically been an important source of new chemotherapeutic agents for the treatment of cancer. The ent-kauranoid family of natural products has recently shown large potential for use as anticancer drugs due to their cytotoxic and antitumor properties. This proposal provides a general strategy for rapidly synthesizing the ent-kauranoids and their derivatives, making possible further development of this important class of natural products as anticancer agents

描述(申请人提供)：具有重要药用价值的天然产物的复杂分子结构刺激了新化学反应的发展，这些化学反应迅速从简单的起始材料产生结构复杂性。过渡金属催化的反应特别适合于这一目的，因为给定过程的化学选择性和立体选择性往往是可预测和可靠的。钒催化剂在合成中得到了广泛的应用，尤其是作为异构化和不对称氧化反应的催化剂。这项研究计划将致力于开发一种新型的钒催化的丙叉醇和环丙醛的级联反应，生成高官能化的1，3-二烯。这一串联过程代表了高度官能化的双烯的单锅、原子经济结构，这些双烯是朝着更复杂的目标方向发展的强大、灵活的中间体。在探索了这种级联反应的底物范围之后，将通过进行选择性的分子间和分子内转化来生成重要的天然产物支架来展示1，3-二烯作为中间体在合成中的用途。然后，钒催化的级联将被用来进行一种简明的全合成，即对端-金龙烷类天然产物中的节蛋白和苦参素B进行全合成。由于具有很强的抗癌活性，结蛋白和其他对角叉菜素类化合物最近受到了极大的关注。尤其是结节菌素对K562人慢性粒细胞白血病细胞具有很强的抑制活性。结节蛋白的合成将代表一种通用的策略，用于获得许多对位角叉草苷，促进这类重要化合物作为癌症化疗药物的进一步发展。 公共卫生相关性：历史上，天然产品一直是治疗癌症的新化疗药物的重要来源。由于其细胞毒性和抗肿瘤特性，Ent-kauranid类天然产物最近显示出作为抗癌药物的巨大潜力。该方案为快速合成胡萝卜素及其衍生物提供了一般策略，为进一步开发这类重要的天然产物作为抗癌药物提供了可能。