New Strategies for Bioactive Molecule Synthesis

描述（由申请人提供）：我们最近发现了一种新颖的，分子内，串联苯形成/捕获工艺，其中1,3-二炔环添加到单体上以产生环状苯。我们称苯形成阶段为六脱水Diels-Alder （HDDA）反应，整个过程为HDDA级联反应。我们展示了许多令人兴奋和高效的示例，用于演示这种转换的相当多功能性和强大功能。这种热反应在无催化剂和试剂的情况下进行，具有高度收敛性和原子经济性。它允许获得高度复杂的苯中间体，这将是困难的，如果不是不可能的，任何传统的苯合成制备。这一发现将通过一个全新的研究体系产生重大影响，这在当代合成化学中是一个难得的机会。很大一部分（约70%）最畅销的药物都含有苯环。其中近一半的芳烃与一个或多个附加环（通常是杂环）融合，构成一个多环单元。目前只有少数几种苯类化合物的重新合成方法，而且没有一种是非常普遍的。HDDA级联策略适用于合成一系列具有药学意义的苯并杂环化合物。我们在两个目标下组织了这个项目，它们平行于苯形成（阶段I）和捕获（阶段II）事件。每个子目的a)和b)进一步将研究分别划分为分子内反应和分子间反应。这项研究将导致两类重要成果：(1)合成类药物分子的使能技术，包括在药物发现和药物制造（过程）活动中有价值的新范例，将会出现；(2)对苯的反应性有了新的基本认识和认识，将出现全新的反应类别。hdd级联过程实际上代表了尚未开发的领域。这项研究将允许化学家以新的方式思考、计划和执行芳烃合成。

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.