Carbene Catalysis Strategies for Organic Synthesis

 描述（由申请人提供）：新的选择性化学反应是推进生物学和医学的重要组成部分。最强大和有效的化学反应通常使用催化剂来控制反应性和选择性。新催化剂概念的发现具有超越既定反应性的广泛用途，可以通过提供具有生物活性的化合物的非常规和有效途径来极大地影响生物医学研究。我们催化研究的长期目标是开发新的刘易斯碱催化转化，直接应用于生物活性分子的合成和研究。我们开发的N-杂环卡宾（NHC）作为催化剂将继续发现新的方法，并产生重要的有机催化新概念。我们的中心假设是，在“卡宾催化”领域的新发现将显着推进化学合成，生物有机化学和医学。本研究的具体目标是：（1）开发新型的卡宾协同催化过程。已发现N-杂环卡宾（刘易斯碱）与刘易斯酸相容以增强选择性和反应性。刘易斯酸、氢键给体或过渡金属配合物与NHC的结合将为化学合成提供新的机会;（2）探索基于偶氮唑的取代反应活化;（3）探索卡宾催化驱动的全合成。虽然已经出现了新的NHC催化反应的爆炸，很少有目标合成采用任何这些新的反应作为一个关键步骤。我们将使用NHC催化的分子内Michael反应作为合成氨基酸和相关天然产物的关键步骤。此外，反式环NHC催化的内酯形成将被追求作为主要途径来合成repin，一种有效的细胞毒素。我们的研究在使用有机催化产生新的反应性将建立新的方法，为有效的合成分子。本研究也将为亲核试剂催化的极性反转反应和协同催化提供重要的知识。这些发现将最终导致发展的立体选择性和相关的策略，是有用的医学相关的合成，从而进一步的NIGMS的使命的强大的集合。

 DESCRIPTION (provided by applicant): New selective chemical reactions are essential components to advance biology and medicine. The most powerful and efficient chemical reactions commonly use catalysis to control reactivity and selectivity. The discovery of new catalyst concepts with broad utility beyond established reactivity can greatly impact biomedical research by providing unconventional and efficient access to compounds with biological activity. The long-term goal of our catalysis research is to develop new Lewis base-catalyzed transformations with direct application to the syntheses and investigation of bioactive molecules. Our development of N-heterocyclic carbenes (NHCs) as catalysts will continue to uncover new approaches and generate important new concepts of organocatalysis. Our central hypothesis is that new discoveries in the field of "carbene catalysis" will significantly advance chemical synthesis, bioorganic chemistry and medicine. The specific goals of this proposal are: (1) Develop new cooperative carbene catalysis processes. N-heterocyclic carbenes (Lewis bases) have been discovered to be compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acids, hydrogen bond donors or transition metal complexes with NHCs will provide new opportunities for chemical synthesis; (2) explore azolium-based activation for substitution reactions; (3) investigate carbene catalysis-driven total syntheses. While there has been an explosion of new NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed intramolecular Michael reaction as the key step in the synthesis of arnamial and related natural products. In addition, a trans-annular NHC-catalyzed lactone formation will be pursued as the main approach to synthesize repin, a potent cytotoxin. 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 and cooperative catalysis. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for medically relevant synthesis and thus further the mission of NIGMS.