New Strategies for Bioactive Molecule Synthesis

描述（由申请人提供）：我们最近发现了一种新的分子内串联的苯炔形成/捕获过程，其中1，3-二炔环加成到单炔上以产生环状苯型。我们称苯炔形成阶段为六位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例子，以展示这种转变的相当多的功能和力量。该热反应以无催化剂和试剂的方式进行，并且是高度收敛和原子经济的。它允许获得高度复杂的苯炔中间体，这将是困难的，如果不是不可能的，通过任何常规的苯炔合成制备。这一发现将通过一个全新的研究机构产生重大影响，这在当代合成化学中是一个难得的机会。很大一部分（>70%）最畅销的药物含有苯环。在这些中的近一半中，芳烃与一个或多个额外的环（通常是杂环性质的）稠合，构成多环单元。只有几个策略从头合成的benzophosphate存在，没有一个是高度通用的。HDDA级联策略适用于合成多种药学相关的苯并稠合杂环。我们组织了两个目标下的项目，平行的苯炔形成（第一阶段）和捕获（第二阶段）的事件。子目标a）和B）分别将研究进一步分为分子内和分子间反应类别。这项研究将导致两类重要成果：（1）将出现用于合成药物样分子的技术，包括在药物发现和药物制造（过程）活动中有价值的新范例;（2）将出现对苯炔反应性和全新反应类别的新的基本见解和理解。HDDA级联过程实际上是一个尚未探索的领域。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.