Carbene Catalysis Strategies for Organic Synthesis

描述(由申请人提供)：新的化学转化能够有效地构建对生物医学研究至关重要的重要分子。最强大和最有效的化学反应使用催化来控制反应性和选择性。在过去的25年里，催化方法学的发展主要集中在已建立的反应模式上，如羰基加成、环加成、氧化和还原。这些反应中的许多都遵循电负性概念预测的原理。Umpolung反应逆转了官能团的正常反应性，从而促进了非传统合成策略。贫电子物种(亲电性)向富电子反应物(亲核性)的转变通常是使用化学计量试剂完成的。尽管Umpolung反应在有机合成中很重要，但催化的极性反转反应范围很广，数量有限。我们的中心假设是，使用N-杂环卡宾(NHCS)进行催化的新方法可以显著推动化学方法学和与健康相关的化学合成领域的发展。这一提议的具体目标是：(1)探索新的卡宾催化的高烯酸盐类等价反应。创新的形式环加成、硅烷化和烷基化反应的发展将提供直接获得大量生物活性结构的途径。(2)开发协同卡宾催化新工艺。我们发现卡宾(Lewis碱)与Lewis酸相容，以提高选择性和反应活性。路易斯酸或过渡金属络合物与NHCS的结合将为化学合成提供新的机会。(3)卡宾催化全合成研究。虽然NHC催化的反应数量激增，但很少有目标合成将这些新反应中的任何一个作为关键步骤。我们将使用NHC催化的去对称化作为合成塞科洛宁的关键步骤，塞科环烯醚是一种关键的天然产物。此外，我们还将利用NHC催化的分子内Michael反应合成芳香醛。我们利用有机催化产生新的反应性的研究将为有效地合成分子建立新的方法。这项研究还将为亲核催化的极性反转反应提供重要的知识。这些发现最终将导致开发一系列对合成有用的立体选择性和相关策略的强大集合。

DESCRIPTION (provided by applicant): New chemical transformations enable the efficient construction of important molecules that are essential for biomedical research. The most powerful and efficient chemical reactions use catalysis to control reactivity and selectivity. The developments in catalytic methodology over the last quarter century have focused primarily on established reactivity patterns, such as carbonyl additions, cycloadditions, oxidations, and reductions. Many of these reactions follow principles predicted by electronegativity concepts. Umpolung reactions invert the normal reactivity of functional groups, thereby facilitating unconventional synthetic strategies. This transformation of an electron-poor species (electrophile) into an electron-rich reactant (nucleophile) is typically accomplished using stoichiometric reagents. Even though Umpolung reactions are important in organic synthesis, there are limited catalytic polarity reversal transformations with broad scope. Our central hypothesis is new approaches to catalysis using N-heterocyclic carbenes (NHCs) can significantly advance the field of chemical methodology and health relevant chemical synthesis. The specific goals of this proposal are: (1) Explore new carbene-catalyzed homoenolate equivalent reactions. The development of innovative formal cycloadditions, silylations, and alkylations will provide direct access to a large array of bioactive structures. (2) Develop new cooperative carbene catalysis processes. We have discovered that carbenes (Lewis bases) are compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acid or transition metal complexes with NHCs should provide new opportunities for chemical synthesis. (3) Investigate carbene catalysis-driven total syntheses. While there has been an explosion of NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed desymmetrization as the key step in the synthesis of secologanin, a key secoiridoid natural product. Additionally, we will pursue a synthesis of arnamial using our NHC-catalyzed intramolecular Michael reaction. Our research in generating new reactivity using organocatalysis will establish new approaches for the efficient synthesis of molecules. This research will also provide important knowledge about nucleophile-catalyzed polarity reversal reactions. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for synthesis.