Harnessing Strained Intermediates to Access Complex Molecules

项目摘要/摘要 本应用程序的中心目标是：(A)开发新的、可靠的和 能够构建具有丰富立体化学成分的支架的高效方法 和(B)实现自然产生的小分子化合物的简明化学合成 具有复杂化学结构的分子。小分子络合物的合成 分子仍然是一个重要的研究领域。事实上，大多数药物上的药物 市场上的药物都是通过有机合成来制备的，包括绝大多数的新药 在过去的三十年里已经可以使用了。此外，它应该是 强调天然产品是最终发现的宝贵线索 新药，除了对开发新的合成策略的启发 和方法。然而，我们现在面临的关键挑战之一是发现可靠的 意味着构建更复杂的架构，但效率和 可预测性。 这项提案的重点是制定方法，以便 化学家利用瞬时产生的紧张中间体，如芳烃， 杂环炔和杂环烯，以便有效地构建络合物 分子支架。更具体地说，我们提出了烯胺芳基化/烯基化反应。 反应建立四元立体中心，除三组分外 联结，这应该允许形成最多两个新的键和两个SP3 中锋。其次，使用不常见和高活性的杂环烯来 通过引入最多两个新绑定来组装复杂的架构 描述了三个SP3中心。初步结果表明，该方案是可行的。 建议的方法。在最后的部分，我们提出了一个简明而雄心勃勃的总数 山竹内酯的合成，它是甘露糖胺生物碱家族中的一员，具有 还有待于合成。我们的研究结果应该会产生强有力的新战略 以及用于获取各种重要分子的工具，包括天然产品和 药物。

Project Summary/Abstract The central objectives of this application are: (a) to develop new, reliable, and efficient, methodologies that enable the construction of stereochemically rich scaffolds and (b) to achieve the concise chemical syntheses of naturally occurring small molecules that possess intricate chemical structures. The synthesis of complex small molecules continues to be a vital area of research. In fact, most medicinal agents on the market are prepared by organic synthesis, including the large majority of all new drugs that have become available over the past three decades. Additionally, it should be emphasized that natural products serve as valuable leads for the ultimate discovery of new medicines, in addition to inspiration for the development of new synthetic strategies and methods. However, one of the key challenges we now face is uncovering reliable means to construct ever more complex architectures, but with increased efficiency and predictability. This proposal is focused on the development of methodology that will allow chemists to harness transiently generated strained intermediates, such as arynes, heterocyclic alkynes, and heterocyclic allenes, in order to efficiently build complex molecular scaffolds. More specifically, we propose an enamine arylation/alkenylation reaction to establish quaternary stereocenters, in addition to three component couplings, which should allow for the formation of up to two new bonds and two sp3 centers. Next, the use of uncommon and highly reactive heterocyclic allenes to assemble complex architectures through the introduction of up to two new bonds and three sp3 centers is described. Preliminary results demonstrate the feasibility of the proposed methodologies. In the final section, we propose a concise and ambitious total synthesis of acantholactone, a member of the manzamine family of alkaloids that has yet to be synthesized. The results of our studies should lead to powerful new strategies and tools for accessing various molecules of importance, including natural products and medicines.