New Strategies for Bioactive Molecule Synthesis

描述(申请人提供)：我们最近发现了一种新颖的分子内串联苯炔形成/捕获过程，在该过程中1，3-二炔环与单炔加成生成环状苯类化合物。我们将苯炔形成阶段称为六氢Diels-Alder(HDDA)反应，整个过程称为HDDA级联反应。我们展示了许多令人兴奋和高效的例子，这些例子证明了这种转变的相当多的多功能性和力量。这种热反应不需要催化剂和试剂，具有高度的聚集性和原子经济性。它允许获得高度复杂的苯并中间体，这些中间体即使不是不可能，也是很难通过任何传统的苯并合成来制备的。这一发现将通过一项全新的研究产生重大影响--这在当代合成化学中是一个难得的机会。最畅销的药物中有很大一部分(70%)含有苯环。在其中近一半中，芳烃与一个或多个额外的环(本质上通常是杂环)融合在一起，构成一个多环单元。目前只有几种苯类化合物从头合成的策略存在，而且没有一种是高度通用的。HDDA级联策略适用于合成一系列与药物相关的苯并稠合杂环。我们在两个目标下组织了这个项目，这两个目标平行于生成苯并(第一阶段)和诱捕(第二阶段)事件。子目标a)和b)分别进一步将研究分为分子内反应和分子间反应两类。这项研究将产生两类重大成果：(1)将出现合成类药物分子的使能技术，包括在药物发现和药物制造(工艺)活动中都有价值的新范例；(2)将出现对苯基因反应性的新的基本见解和理解，以及全新的反应类别。HDDA-CASCADE进程代表着几乎未被探索的领域。这项研究将使化学家能够以新的方式思考、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.