Total Synthesis of Cytotoxic ent-Kauranoid Natural Products

描述（由申请人提供）：药用重要天然产物的复杂分子结构刺激了新的化学反应的发展，这些化学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，主要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的钒催化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。这个串联过程代表了一个单一的锅，高功能化二烯的原子经济结构，是强大的，灵活的中间体，更复杂的目标。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来产生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，钒催化的级联将用于进行天然产物中ent-kauranoid家族的nodosin和sculponin B的简明全合成。近年来，Nodosin和其他类山核桃素因其强大的抗癌活性而受到广泛关注。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的合成将代表获得许多正核核素类化合物的一般策略，促进这类重要化合物作为癌症化疗药物的进一步发展。

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