Exploiting Unconventional Building Blocks in Chemical Synthesis

项目总结/摘要 本申请的中心目标是利用非常规的合成 开发新的、可靠的和有效的方法的基础。 这些方法旨在能够构建立体化学上丰富的 支架，包括那些在自然发生的小分子和药物中看到的。 复杂小分子合成新方法的发展 仍然是重要的研究领域。市场上的大多数药剂都是 通过有机合成制备的，包括绝大多数具有 在过去的三十年里变得可用。新药的化学结构 实体变得越来越复杂，现在通常带有sp3中心，而不是 “扁平”结构。这导致化学家越来越需要开发新的 可以可靠地建造复杂结构的方法。 我们在建议中寻求利用的两个非传统构建模块 研究的是酰胺和张力环炔和联烯。关于酰胺，C-N 酰胺键长期以来被认为是稳定的，因此， 依赖于C-N键断裂仍然有限。我们寻求开发方法， 利用镍催化来利用酰胺官能团作为配体。我们建议 组装具有确定的立体中心的重要连接，包括四元 立体中心，使用催化和化学酶的方法。这些努力提供了 新的机会，在该领域的强键活化镍催化，沿着 通过C-N键断裂操作酰胺的新工具。关于 紧张的环炔和联烯，我们试图拦截这些短暂的，高活性的， 物种来有效地构建复杂的分子支架。这些方法应考虑到 建立了具有两个新键和三个SP3中心的支架。 将靶向对映体特异性和催化对映体选择性变体。我们 方法将在几个合成努力的背景下进行评估。的 我们的研究结果应该导致强大的新战略和工具， 各种重要分子，包括天然产物和药物。

Project Summary/Abstract The central objective of this application is to harness unconventional synthetic building blocks for the development of new, reliable, and efficient, methodologies. These methodologies are intended to enable the construction of stereochemically rich scaffolds, including those seen in naturally occurring small molecules and medicines. The development of new methods and the syntheses of complex small molecules continues to be vital areas of research. 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. The chemical structures of new drug entities are becoming increasingly complex, now often bearing sp3 centers rather than “flat” structures. This has led to an increased need for chemists to develop new methods that can reliably build intricate structures. The two unconventional building blocks we seek to harness in the proposed studies are amides and strained cyclic alkynes and allenes. Regarding amides, the C–N bond of amides has long been viewed as stable, such that synthetic methodologies that rely on C–N bond cleavage have remained limited. We seek to develop methods that utilize nickel catalysis to harness amide functional groups as synthons. We propose to assemble important linkages with defined stereocenters, including quaternary stereocenters, using catalysis and chemoenzymatic methods. These efforts provide new opportunities in the area of strong bond activation by nickel catalysis, along with new tools for the manipulation of amides via C–N bond cleavage. With regard to strained cyclic alkynes and allenes, we seek to intercept these transient, highly reactive species to efficiently build complex molecular scaffolds. Such methods should allow for the establishment of scaffolds bearing two new bonds and three sp3 centers. Enantiospecific and catalytic enantioselective variants will be targeted. Our methodologies will be evaluated in the context of several synthetic endeavors. The results of our studies should lead to powerful new strategies and tools for accessing various molecules of importance, including natural products and medicines.