Asymmetric Synthesis of Nitrogen Heterocycles

首席调查员/项目主任(最后、第一、中间)：ROVIS，Tomislav 含氮杂环的不对称合成 摘要 氮普遍存在于生物活性分子和药物中，是第四大 继碳、氢和氧之后的常见元素。它的存在会影响与生物靶标的相互作用， 药代动力学和药效学，以及无数的物理性质。鉴于增加的 饱和的重要性在类药物分子中，碳-氮键越来越具有立体效应，因此， 采用氮肥的方法同样应解决以立体控制的方式这样做。我们有很长的时间 我感兴趣的是从常见的原料中构建饱和氮杂环 解决与最常见的环，如哌啶和吡咯烷有关的合成挑战。 通过这次竞争性更新，我们寻求支持以解决与无环氮相关的问题 含有分子的。 在这里，我们提出了一种多管齐下的方法来合成含氮的复杂结构 从简单的前体进行替换。我们专注于使用最常见的起始材料，例如 烯烃和双烯，并与适度活化的氮偶联伙伴形成联盟。后者中的理想选择 是二恶唑酮部分，由羧酸、羟胺和光气简单组装而成 等价物。重要的是，在C-N键形成后，产物是酰胺，从而避免了随后的 衍生化。我们进一步说明，这一联盟可以在极其复杂的环境中进行。 PHS 398/2590(09/04版)页面续格式页面

Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav Asymmetric Synthesis of Nitrogen Heterocycles Abstract Nitrogen is ubiquitously found in biologically active molecules and pharmaceuticals, the fourth most common element after carbon, hydrogen and oxygen. Its presence impacts interactions with biological targets, pharmacokinetics and pharmacodynamics, as well as myriad physical properties. Given the increased importance of saturation in drug-like molecules, carbon-nitrogen bonds are increasingly stereogenic and thus, methods to incorporate nitrogen should likewise address doing so in stereocontrolled fashion. We have long been interested in constructing saturated nitrogen heterocycles from commonly available feedstocks to address synthetic challenges associates with the most common rings such as piperidines and pyrrolidines. With this competitive renewal, we seek support to address problems associated with acyclic nitrogen containing molecules. Herein we propose a multi-pronged approach to synthesize complex structures containing nitrogen substitution from simple precursors. We focus on using the most commonly available starting materials such as alkenes and dienes, and forge a union to a modestly activated nitrogen coupling partner. Ideal among the latter is the dioxazolone moiety, trivially assembled from carboxylic acids, hydroxylamine and a phosgene equivalent. Importantly, after C-N bond formation, the product is the amide, thereby avoiding subsequent derivatization. We further illustrate that this union can be conducted in an exceedingly complex setting. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page