Organocatalytic Site-Selective C-H Bond Functionalization

项目摘要/摘要 脂肪族C-H键的位置选择性官能化为生物活性化合物的合成提供了捷径 分子，包括那些不能用其他合成方法可行或实际制造的分子。vt.给出 批准的药物中含氮和含氧官能团的流行率， 开发脂肪族C-H胺化和羟基化的通用方法得到了广泛的认可。 尽管脂肪族C-H选择性分子间羟基化和定向C-H羟基化的催化方法 键已经被成功地开发出来，但由于缺乏官能团，它们的通用性受到很大限制 兼容性和超越衬底选择性控制的能力有限。脂肪族也面临着类似的挑战 C-H胺化，而且它们的量相对较大，因为只有少数几种位点选择方法还没有 已经上报了。因此，选择性脂肪族C-H羟基化和胺化的新催化方法是 更能容忍范围广泛的官能团，并能顺应控制现场的新策略 选择性将极大地提高这种综合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线索的能力。我们提出了一个新的， 统一催化策略，实现定点选择性脂肪族羟基化和胺化反应。战略特征 使用我们实验室开发的IM盐有机催化剂，我们发现它克服了功能 其他催化方法固有的基团兼容性问题。目标1的目标是开发金属镍 与乙醇官能团相容的盐催化分子间位置选择性羟化反应 基团，包括对酒精产品具有选择性的亚甲基C-H键的羟基化。目标是 目标2的目的是开发分子间亚胺盐催化的酰胺化反应，该反应对以下一种具有选择性 多个SP3C-H键。最后，目标3的目标是将这些有机催化方法应用于定向 脂肪族C-H羟基化和胺化以实现醛和酮的远程官能化 现有催化方法未涉及的底物。拟议的研究将产生新的 获取生物活性分子共同合成子的方法和晚期的新方法 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.