New Strategies for Bioactive Molecule Synthesis

生物活性分子合成新策略

• 批准号: 8850869
• 负责人: THOMAS R. HOYE
• 金额: $ 27.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850869
• 关键词: Alder plant; Alkynes; Aromatic Compounds; Boxing; Categories; Chemistry; Complex; Cyclization; Development; Diels Alder reaction; Electronics; Environment; Event; Generic Drugs; Goals; Grant; Health; Heterocyclic Compounds; Lead; Left; Length; Methods; Molecular; Nature; Outcome; Outcomes Research; Pharmaceutical Preparations; Pharmacologic Substance; Process; Property; Reaction; Reagent; Research; Staging; Structure; Synthesis Chemistry; Technology; Variant; catalyst; cycloaddition; drug discovery; drug synthesis; fascinate; innovation; insight; interest; manufacturing process; novel; programs

DESCRIPTION (provided by applicant): We have recently uncovered a novel, intramolecular, tandem benzyne-forming/trapping process in which a 1,3-diyne cycloadds to a monoyne to produce an annulated benzenoid. We call the benzyne-forming stage a hexa-dehydro Diels-Alder (HDDA) reaction and the overall process an HDDA cascade. We show many exciting and highly efficient examples that serve to demonstrate the considerable versatility and power of this transformation. This thermal reaction proceeds in a catalyst- and reagent-free manner and is highly convergent and atom economical. It allows access to highly complex benzyne intermediates that would be difficult, if not impossible, to prepare by any conventional benzyne synthesis. This discovery will lead to a major impact through a fundamentally new body of research-a rare opportunity in contemporary synthetic chemistry. A very large portion (>70%) of top-selling drugs contain a benzenoid ring. In nearly half of these, the arene is fused to one or more additional rings (often heterocyclic in nature), comprising a polycyclic unit. Only a few strategies for de novo synthesis of benzenoids exist, and none is highly general. The HDDA cascade strategy is amenable to the synthesis of a wide array of pharmaceutically relevant, benzo-fused heterocycles. We have organized the project under two Aims, which parallel the benzyne-forming (Stage I) and -trapping (Stage II) events. SubAims a) and b) in each further segregate the studies into the categories of intra- vs. inter- molecular reactions, respectively. This research will lead to two categories of significant outcomes: (1) Enabling technology for synthesis of drug-like molecules, encompassing new paradigms valuable in both drug discovery and drug manufacturing (process) activities, will have emerged; (2) New fundamental insights and understanding of benzyne reactivity and altogether new reaction classes will have emerged. The HDDA-cascade process represents virtually unexplored territory. This research will allow chemists to think about, plan, and perform arene synthesis in new ways.

描述（由申请人提供）：我们最近发现了一种新型的，分子内的，串联的苯甲苯甲酸/诱捕过程，其中1,3-Diyne Cycloadds到monoyne中产生了一个环状的苯苯二酚。我们称苯季形成阶段为Hexa-Dehydro Diels-Alder（HDDA）反应，整体过程为HDDA Cascade。我们展示了许多令人兴奋且高效的例子，这些例子有助于证明这种转变的相当多的多功能性和力量。这种热反应以无催化剂和无试剂的方式进行，并且是高度收敛性和原子经济性的。它允许访问高度复杂的Benzyne中间体，即使不是不可能，任何常规的Benzyne合成都将很难（即使不是不可能）准备。这一发现将通过从根本上进行新的研究体系产生重大影响，这是当代合成化学中的罕见机会。最大的销售药物中有很大的（> 70％）包含一个苯环。在其中近一半的一半中，芳烃被融合到一个或多个额外的环（通常本质上是杂环），包括一个多环形单元。只有少数从头合成苯苯二甲酸酯的策略，没有一个高度笼统的。 HDDA级联策略可以合成各种各样的药物相关的苯并融合杂环。我们已经以两个目标组织了该项目，这与苯甲型形成（I阶段）和 - 诱捕（II阶段）事件相似。 subiaims a）和b）在每个中，分别将研究分别分别为内部和分子间反应的类别。这项研究将导致两类重要的结果：（1）促进类似药物样分子的技术，涵盖在药物发现和药物制造（过程）活动中有价值的新范式，将出现； （2）将出现新的基本见解和对苯甲反应性和完全新反应类别的理解。 HDDA-Cascade过程几乎代表未开发的领域。这项研究将使化学家以新的方式思考，计划和执行芳香综合。