Development of Azomethine Ylide Cycloadditions and Synthesis of Daphniyunnine D

偶氮甲碱叶立德环加成反应的进展及瑞香碱 D 的合成

• 批准号: 7467277
• 负责人: Steven Michael Mennen
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-18 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467277
• 关键词: Alkaloids; Carbon; Chemicals; Class; Complex; Condition; Cyclization; Development; Inhibitory Concentration 50; Left; Methodology; Methods; Molecular; Pharmacologic Substance; Plants; Process; Pyrrolidines; Reaction; Reagent; Research; Secure; Skeleton; System; Technology; Therapeutic; Tumor Cell Line; Weight; cycloaddition; design; pyrrolidine; stem; ylide

DESCRIPTION (provided by applicant): Complex molecule synthesis offers an unparalleled opportunity to develop and demonstrate new synthetic chemical technologies. Fundamental studies into a new reaction or expansion of an existing molecular transformation can increase the efficiency of the synthesis of a target molecule. Specifically, this proposal is focused on developing rapid and efficient access to complex pyrrolidine heterocycles. A research criterion is to exclude acutely toxic reagents, which will allow for straightforward application to the manufacturing of modern Pharmaceuticals in accord with the FDA's current Good Manufacturing Practices (cGMP). Daphniyunnine D was recently isolated from the stems and leaves of Daphniphyllum yunnanense and constitutes 0.0035% of the dry weight plant mass. This alkaloid shows activity against two tumor cell lines, P-388 and A-549, with IC50 values of 3.0 and 0.6 ?M, respectively. In order to secure sufficient quantities and fully determine the therapeutic potential of daphniyunnine D, a synthetic effort is required. A primary objective of this proposal will be the development of a new class of intramolecular azomethine ylide cyclizations and the demonstration of this reaction in the total synthesis of the complex hexacyclic alkaloid daphniyunnine D. The method for generating the requisite azomethine ylide requires a judicious choice. This choice will be discussed in detail along with the development of this Type III intramolecular azomethine ylide cyclization. Different reaction conditions designed to obtain the necessary reactivity without compromising the stability of the azomethine ylide will be discussed. This high complexity-generating step will allow access to complex derivatives of the coveted pyrrolidine heterocycle and complete the molecular skeleton of daphniyunnine D. Finally, this synthesis of daphniyunnine D will investigate a rational approach for controlling diastereoselectivity in the Pauson-Khand cyclization.

描述（由申请人提供）：复杂分子合成为开发和展示新的合成化学技术提供了无与伦比的机会。对新反应的基础研究或现有分子转化的扩展可以提高靶分子合成的效率。具体地说，该提案的重点是开发快速和有效地获得复杂的吡咯烷杂环。研究标准是排除急性毒性试剂，这将允许直接应用于雅阁FDA现行药品生产质量管理规范（cGMP）的现代药品生产。从云南虎皮楠（Daphniphyllum yunnanense）的茎和叶中分离得到一种名为Daphniyunnine D的化合物，占植物干重的0.0035%。该生物碱对两种肿瘤细胞系P-388和A-549显示活性，IC 50值分别为3.0和0.6？M，分别。为了确保足够的数量和充分确定daphniyunnine D的治疗潜力，需要进行合成努力。该建议的主要目标是开发一类新的分子内甲亚胺叶立德环化反应，并在复杂的六环生物碱daphniyunnine D的全合成中演示该反应。生成必要的甲亚胺叶立德的方法需要明智的选择。这种选择将详细讨论沿着与这种III型分子内甲亚胺叶立德环化的发展。不同的反应条件，旨在获得必要的反应性，而不损害的稳定性的甲亚胺叶立德将进行讨论。这一高度复杂的生成步骤将允许获得令人垂涎的吡咯烷杂环的复杂衍生物，并完成daphniyunnine D的分子骨架。最后，本合成daphniyunnine D将探讨一个合理的方法来控制非对映选择性的Pauson-Khand环化。

项目成果

General approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors: enantioselective total syntheses of (+)- and (-)-gliocladine C, (+)-leptosin D, (+)-T988C, (+)-bionectin A, and (+)-gliocladin A.

• DOI: 10.1021/ja400315y
• 发表时间: 2013-03-13
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: DeLorbe, John E.;Horne, David;Jove, Richard;Mennen, Steven M.;Nam, Sangkil;Zhang, Fang-Li;Overman, Larry E.
• 通讯作者: Overman, Larry E.