Exploiting Unconventional Building Blocks in Chemical Synthesis

项目摘要/摘要 这一应用的中心目标是利用非传统的合成 构建开发新的、可靠和高效的方法的基础。 这些方法旨在使立体化学富集物的构建成为可能 支架，包括那些自然产生的小分子和药物中的支架。 新方法的发展与复杂小分子的合成 仍然是重要的研究领域。市场上的大多数药物都是 由有机合成制成，包括绝大多数具有 在过去的三十年里可以使用。新药的化学结构 实体正变得越来越复杂，现在通常带有SP3中心，而不是 “扁平”结构。这导致了对化学家开发新的 可以可靠地构建复杂结构的方法。 我们希望在拟议的 研究的是酰胺和张力环炔和烯。关于酰胺，C-N 长期以来，酰胺键一直被认为是稳定的，因此合成方法 依赖C-N键裂解的情况仍然有限。我们寻求开发出方法， 利用镍催化来利用酰胺官能团作为合成子。我们建议 通过定义的立体中心(包括第四级)组装重要的链接 立体中心，使用催化和化学酶方法。这些努力提供了 镍催化强键活化领域的新机遇，以及 通过C-N键裂解来操纵酰胺的新工具。关于…… 张力环炔和烯，我们试图截获这些瞬变的，高活性的 物种高效地构建复杂的分子支架。这种方法应该允许 建立了承载两个新键和三个SP3中心的支架。 对映异构体和催化对映体选择性变异体将成为靶标。我们的 方法论将在几项综合努力的背景下进行评估。这个 我们的研究结果应该会带来强大的新战略和工具，以获取 各种重要的分子，包括天然产品和药物。

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.