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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9300975
• 关键词: Acids; Affect; Agrochemicals; Alkenes; Antifungal Agents; Biological; Chemicals; Complex; Cyclobutanes; Data; Development; Electrons; Esters; Evaluation; Exercise; Family; Foundations; Goals; Health; Human; Investigation; Ketones; Laboratories; Lead; Medicine; Methods; Modernization; Molecular; Natural Products; Organic Chemistry; Outcome; Periodicity; Pharmacologic Substance; Preparation; Reaction; Research; Role; Scheme; Structure; Technology; catalyst; chemical reaction; chemical synthesis; cycloaddition; drug discovery; inhibitor/antagonist; innovation; invention; programs; propadiene; public health relevance; racemization; rapid technique; scaffold; success

 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）：发明手性有机分子的立体选择性化学合成的新方法是现代有机化学中的关键目标，因为它对于有效生产药物制剂至关重要。尽管在对映选择性化学合成领域取得了实质性进展，但许多重大挑战仍未解决。特别地，缺乏用于手性环丁烷的对映选择性化学合成的普遍有效的方法。在缺乏用于合成这些重要分子的有效策略的情况下，它们作为生物活性合成靶标的可及性，以及更一般地，它们作为化学合成的配体的效用，已经受到阻碍。我们的研究计划的长期目标是引入通用和有效的策略，用于立体选择性合成在重要生物活性分子中发现的难以获得的环状和多环分子框架。为此，本申请中描述的研究试图发明烯烃与缺电子联烯的有效催化对映选择性[2+2]环加成，其导致手性环丁烷。我们发展的理由 这些环加成的一个重要特征是它们以复杂的结构和原子经济的转化将容易获得的原料联合收割机结合，导致形成具有至多三个新的立体中心的应变四元环。这些转化产生的环要么直接存在于生物活性分子中，要么可以通过各种化学反应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用当前技术难以或不可能获得的各种复杂分子的合成。在我们实验室收集的初步研究是非常令人鼓舞的成功，在我们提出的研究。具体而言，这些研究将导致：1）前手性丙二烯酯的催化对映选择性[2+2]环加成，2）外消旋丙二烯酯的催化动态对映选择性[2+2]环加成，3）丙二烯酮的催化对映选择性合成和手性转移[2+2]环加成。这些方法将是有用的几个家庭的生物活性的天然产物的合成和药物发现的支架的合成。本申请中提出的研究是创新的，因为它概述了一种新的和显着不同的方法来手性环丁烷的对映选择性合成，特别是催化对映选择性联烯-烯烃[2+2]环加成。此外，在反应发展的这个练习将介绍新的概念和化学合成的策略，探索方法，以促进与联烯反应。