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：
9300975
负责人：
Michael Kevin Brown
金额：
$ 29.07万
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（由申请人提供）：尽管对映选择性化学领域取得了实质性进展，但手性有机分子立体选择性化学合成的新方法的发明是现代有机化学的一个关键目标，因为它对于药物制剂的有效制造至关重要。合成中，许多重大挑战仍未解决，特别是，由于缺乏合成这些重要分子的有效策略，因此缺乏普遍有效的手性环丁烷的对映选择性化学合成方法。作为生物活性合成靶标的可及性，更普遍的是，它们作为化学合成合成子的实用性受到阻碍。我们研究计划的长期目标是引入通用且有效的策略来立体选择性合成难以接近的环状化合物。为此，本申请中描述的研究寻求发明缺电子烯烃的有效催化对映选择性[2+2]环加成。我们开发手性环丁烷的理由。这些环加成的一个特点是，它们在复杂的构建和原子经济转化中结合了容易获得的起始材料，从而形成具有多达三个新立体中心的应变四元环。这些转化产生的环要么直接在生物活性分子中发现。或可以进行各种化学反应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现有技术难以或不可能获得的各种复杂分子的合成。在我们的实验室具体来说，这些研究将导致：1）前手性联烯酸酯的催化对映选择性[2+2]环加成，2）与种族联烯酸酯的催化动态对映选择性[2+2]环加成，以及3) 催化对映选择性合成联烯酮和手性转移[2+2]这些方法将可用于合成几个具有生物活性的天然产物家族以及用于药物发现的支架的合成，该申请中提出的研究具有创新性，因为它概述了一种新的且显着不同的对映选择性合成方法。手性环丁烷，特别是催化对映选择性丙二烯-烯烃[2+2]环加成反应。此外，该反应开发练习将通过探索促进反应的方法，在化学合成中引入新的概念和策略。与联烯。