Stereoselective Reactions for the Chemical Synthesis of Bioactive Compounds

生物活性化合物化学合成的立体选择性反应

基本信息

批准号：
8961080
负责人：
Michael Kevin Brown
金额：
$ 29万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The invention of new methods for the stereoselective chemical synthesis of chiral organic molecules is a critical objective in modern organic chemistry because it is essential for the efficient manufacture of pharmaceutical agents. Despite substantial progress in the field of enantioselective chemical synthesis, many significant challenges remain unsolved. In particular, there is a lack of generally effective methods for the enantioselective chemical synthesis of chiral cyclobutanes. In the absence of efficient strategies for the synthesis of these important molecules, their accessibility as biologically active syntheti targets and, more generally, their utility as synthons for chemical synthesis, have been hindered. The long-term goals of our research program are to introduce general and efficient strategies for the stereoselective synthesis of difficult- to-access cyclic and polycyclic molecula frameworks found in important bioactive molecules. Toward this end, the studies described in this application seek to invent efficient catalytic enantioselective [2+2] cycloadditions of alkene with electron deficient allenes that lead to chiral cyclobutanes. Our rationale for the development of these cycloadditions is that they combine readily available starting materials in a complexity building and atom economical transformation that leads to formation of strained four-membered rings with up to three new stereogenic centers. The rings generated by these transformations are either directly found in bioactive molecules or can be subject to a wide variety of chemical reactions to quickly establish complex structures. Therefore, successful implementation of these methods will greatly facilitate the synthesis of a wide range of complex molecules that are difficult or impossible to access with current technologies. Preliminary studies gathered in our lab are extremely encouraging for success in our proposed studies. Specifically, these investigations will lead to: 1) catalytic enantioselective [2+2] cycloadditions of prochiral alleni esters, 2) catalytic dynamic enantioselective [2+2] cycloaddition with racemic allenic esters, and 3) catalytic enantioselective synthesis of allenic ketones and chirality transfer [2+2] cycloadditions. These methods will be useful for the synthesis of several families of biologically active natural products and for the synthesis of scaffolds for drug discovery. The proposed research in this application is innovative because it outlines a new and significantly different approach to the enantioselective synthesis of chiral cyclobutanes, specifically catalytic enantioselective allene-alkene [2+2] cycloadditions. Furthermore, this exercise in reaction development will introduce new concepts and strategies in chemical synthesis by exploring methods to promote reactions with allenes.

描述（由适用提供）：针对手性有机分子的立体选择化学合成的新方法在现代有机化学中是一个关键目标，因为它对于有效地生产了药物的制剂至关重要。尽管在对映选择性化学合成领域取得了重大进展，但仍未解决许多重大挑战。特别是，缺乏用于手性环形对照化学合成的通常有效的方法。在没有有效的策略来合成这些重要分子的情况下，它们作为生物活性合成靶标的可访问性，更普遍地是它们作为化学合成合成的实用性受到阻碍。我们的研究计划的长期目标是引入一般有效的策略，以实现在重要生物活性分子中发现的难以访问的环状和多环分子框架的立体选择合成。为此，本申请中描述的研究旨在发明有效的催化对映选择性[2+2]烯烃的环加成，并具有导致手性环形剂的电子不足艾伦斯。我们的发展理由在这些环加成的是，它们结合了复杂性建筑和原子经济转变中，可随时可用的起始物质，从而形成了紧张的四元环，最多三个新的立体源性中心。这些转换产生的环要么直接在生物活性分子中发现，要么可能受到多种化学反应的影响，以快速建立复杂的结构。因此，这些方法的成功实施将极大地促进合成各种复杂分子，而这些分子很难或无法使用当前技术访问。在我们的实验室中收集的初步研究在我们提出的研究中取得成功非常令人鼓舞。具体而言，这些研究将导致：1）催化对映体选择性[2+2]的抗病毒抗抗毒剂酯的环节，2）用外星抗抗酸酯的催化动态对映体选择性[2+2]环载酯和3）催化对映射的酮酮酮和奇数转移[2+2] 2+2+2+2+2+2+2）。这些方法将有助于合成几个生物活性天然产物家族，以及用于药物发现的脚手架的合成。该应用程序中提出的研究具有创新性，因为它概述了手性旋转型对照式合成的一种新的且显着不同的方法，特别是催化的对映射的Allene-Alkene [2+2]环加成。此外，这种反应发展中的练习将通过探索促进与艾伦反应的方法来引入化学合成中的新概念和策略。