Organocatalytic Site-Selective C-H Bond Functionalization

项目总结/摘要 脂肪族C-H键的位点选择性功能化可以为生物活性化合物的合成提供捷径 分子，包括使用其他合成方法不可行或实际上不能制备的那些。给定 批准药物中含氮和含氧官能团的普遍性， 特别是开发用于脂族C-H胺化和羟基化的通用方法得到了广泛认可。 虽然用于脂肪族C-H的选择性分子间和定向C-H羟基化的催化方法 虽然已经成功地开发了键，但是它们的通用性由于缺乏官能团而受到很大限制 相容性和超越选择性的衬底控制的有限能力。对于脂肪族， C-H胺化，它们相对更大，因为只有少数位点选择性方法还没有 被举报。因此，用于选择性脂族C-H羟基化和胺化的新催化方法， 更耐受广泛的官能团，并且适合于新的策略来控制位点 选择性将极大地提高该合成方法的通用性和范围。反过来，这些新方法 将提高合成化学家有效合成治疗先导物的能力。我们提出一个新的， 统一的催化策略，以实现脂肪族的位点选择性羟基化和胺化。战略特点 使用亚胺盐有机催化剂在我们的实验室开发，我们已经发现克服功能 其它催化方法固有的基团相容性问题。目标1的目标是开发亚胺 盐催化的分子间位点选择性羟基化反应， 基团，包括对醇产物具有选择性的亚甲基C-H键的羟基化。客观 目的2的目的之一是开发分子间亚胺鎓盐催化的酰胺化反应，其对以下之一具有选择性： 许多sp3 C-H键。最后，目标3的目的是将这些有机催化方法应用于定向的 脂肪族C-H羟基化和胺化以实现醛和酮的远程官能化 现有的催化方法不能处理的底物。这项研究将产生新的 用于获得生物活性分子共有的外显子的方法和用于后期的新方法 治疗线索的多样化。

Project Summary/Abstract Site-selective functionalization of aliphatic C–H bonds can provide shortcuts to the synthesis of bioactive molecules, including those that cannot be feasibly or practically made using other synthetic approaches. Given the prevalence of nitrogen- and oxygen-containing functional groups in approved drugs, the importance of developing general methods for aliphatic C–H amination and hydroxylation in particular is widely recognized. Although catalytic methods for both selective intermolecular and directed C–H hydroxylations of aliphatic C–H bonds have been successfully developed, their generality is greatly limited by a lack of functional group compatibility and limited ability to override substrate control of selectivity. Similar challenges exist for aliphatic C–H amination, and they are comparatively greater given that only a handful of site-selective methods have yet been reported. As such, new catalytic methods for selective aliphatic C–H hydroxylation and amination that are more tolerant of a wide range of functional groups and that are amenable to new strategies to control site selectivity will greatly improve the generality and scope of this synthetic approach. In turn, these new methods will improve the ability of synthetic chemists to efficiently synthesize therapeutic leads. We propose a new, unified catalytic strategy to achieve site-selective aliphatic hydroxylation and amination. The strategy features the use of iminium salt organocatalysts developed in our lab, that we have discovered overcome functional group compatibility issues inherent to other catalytic methods. The objective of Aim 1 is to develop iminium salt-catalyzed intermolecular site-selective hydroxylation reactions that are compatible with alcohol functional groups, including hydroxylations of methylene C–H bonds that are selective for alcohol products. The objective of Aim 2 is to develop intermolecular iminium salt-catalyzed amidation reactions that are selective for one of many sp3 C–H bonds. Finally, the objective of Aim 3 is to apply these organocatalytic methods to directed aliphatic C–H hydroxylations and aminations to achieve remote functionalizations of aldehyde and ketone substrates that are not addressed by existing catalytic methods. The proposed research will result in new methods for accessing synthons common to bioactive molecules and new methods for the late-stage diversification of therapeutic leads.