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: 8059704
• 负责人: DAVID JOHN MICHAELIS
• 金额: $ 4.84万
• 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/8059704
• 关键词: Address; Alcohols; Aldehydes; Antineoplastic Agents; Attention; Biological Factors; Cells; Chronic Myeloid Leukemia; Clinical; Complex; DNA Sequence Rearrangement; Development; Economics; Family; Human; Investigation; K-562; Malignant Neoplasms; Medicine; Molecular Structure; Phase; Physical condensation; Process; Property; Reaction; Research; Research Proposals; Scheme; Source; Structure; Transition Elements; Vanadium; anticancer activity; antitumor agent; cancer therapy; catalyst; chemical reaction; chemical synthesis; chemotherapeutic agent; cytotoxic; diene; flexibility; member; method development; novel; oxidation; scaffold; tool

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.

描述（由申请人提供）：具有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，这些反应可以从简单的起始材料快速产生结构复杂性。过渡金属催化反应特别适合此目的，因为给定过程的化学选择性和立体选择性通常是可预测且可靠的。钒催化剂在合成中有着广泛的应用，最引人注目的是作为异构化和不对称氧化反应的催化剂。该研究计划将重点开发一种新型钒催化的炔丙醇和环丙醛之间的级联反应，生成高度功能化的 1,3-二烯。这种串联工艺代表了高功能化二烯的单锅、原子经济结构，这些二烯是针对更复杂目标的强大、灵活的中间体。在探索了该级联反应的底物范围后，将通过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，从而证明 1,3-二烯作为合成中间体的效用。然后，钒催化级联将用于对天然产物 ent-kauranoid 家族的 nodosin 和 sculponin B 进行简明全合成。 Nodosin 和其他 ent-kauranoid 最近因其有效的抗癌活性而受到广泛关注。 Nodosin 尤其显示出对 K562 人类慢性粒细胞白血病细胞的有效抑制活性。 nodosin 的合成将代表获得许多对映贝壳杉烷类化合物的一般策略，促进这一类重要化合物作为癌症化疗药物的进一步开发。