Total Synthesis of Cytotoxic ent-Kauranoid Natural Products

描述（由申请人提供）：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，这些反应可从简单的起始材料快速产生结构复杂性。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通常是可预测和可靠的。钒催化剂在合成中有广泛的应用，特别是作为异构化和不对称氧化反应的催化剂。本研究计划将致力于开发一种新型的钒催化炔丙醇和环丙基醛之间的级联反应，生成高度官能化的1，3-二烯。这种串联过程代表了高度官能化的二烯的单锅、原子经济的构造，所述高度官能化的二烯是朝向更复杂目标的强大、灵活的中间体。在探索了这种级联反应的底物范围后，将通过进行选择性的分子间和分子内转化以产生重要的天然产物支架来证明1，3-二烯作为合成中间体的效用。钒催化的级联然后将用于进行对映贝壳杉烷类天然产物家族的nodosin和sculponin B的简明全合成。由于其强有力的抗癌活性，最近受到了极大的关注。特别是Nodosin已经显示出对K562人慢性骨髓性白血病细胞的有效抑制活性。nodosin的合成将代表用于获得许多对映贝壳杉烷类化合物的一般策略，促进这类重要化合物作为癌症化疗剂的进一步开发。 公共卫生相关性：天然产品历来是治疗癌症的新化疗药物的重要来源。对映贝壳杉烷类天然产物家族由于其细胞毒性和抗肿瘤特性，最近显示出用作抗癌药物的巨大潜力。这一建议为快速合成对映贝壳杉烷酸及其衍生物提供了一种通用策略，使得这类重要的天然产物作为抗癌剂的进一步开发成为可能

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