The Design and Implementation of Asymmetric Organocatalysis in Synthesis

描述(申请人提供)：拟议研究的目的是开发用于合成的不对称有机催化方法。这一领域的最新进展突出了有机小分子在以有效和选择性的方式促进合成转化方面的效用。有机催化领域的持续进展将为获得以前无法获得的富含对映体的新型、高度功能化的手性构建块提供途径。本方案中的项目将集中于识别和探索手性Bronsted酸催化和手性碱催化，以开发适用于合成新型手性构筑块的新的有机催化方法。我们发展了第一个由一个小的手性分子催化的烯酮和醛的高对映选择性的Morita-Baylis-Hillman(MBH)反应。该反应通过氢键在有机催化剂上实现了高水平的对映选择性。机理研究使我们能够应用我们所学到的关于MBH反应的知识来扩大反应的范围和用途。这笔赠款中的项目将开发用于合成复杂天然产品的反应，例如海绵级的天然产物--有效的抗增殖剂，其作用模式未知，可在纳摩尔浓度下抑制小细胞肺癌的生长。我们还将继续开发不对称MBH反应来合成吡喃多酚，这是一种口服生物利用的天然产物，具有克服2型糖尿病症状的独特模式。这些天然产物不同于其他已知的治疗2型糖尿病的方法，将被用于识别分子靶点。我们还成功地开发了由天然产物金鸡纳生物碱类有机催化剂催化的β-酮酯不对称Mannich反应生成酰亚胺。通过进一步的研究，我们将扩大反应的范围，生产出可用于药物的高度功能化的积木，如黑色素浓缩激素受体拮抗剂SNAP-7941和巴采利定的天然产品。我们还首次开发了一种简单的有机化合物催化的含酮化合物的不对称烯丙基硼加成反应。不对称反应将在天然产物曼扎西丁A的合成中得到突出的体现。

DESCRIPTION (provided by applicant): The aims of the proposed research are to develop asymmetric organocatalytic methods for use in synthesis. Recent advances in this area highlight the utility of small organic molecules for promoting synthetic transformations in an efficient and selective manner. Continued progress in the field of organocatalysis will provide access to novel, highly functionalized chiral building blocks in enantioenriched form that have been previously unavailable. The projects in this proposal will concentrate on identifying and exploring chiral Bronsted acid catalysis and chiral base catalysis in order to develop new organocatalytic methods applicable to the synthesis of novel chiral building blocks. We have developed the first highly enantioselective Morita-Baylis-Hillman (MBH) reaction involving enones and aldehydes catalyzed by a small chiral molecule. The reaction achieves high levels of enantioselectivity from an organic catalyst through hydrogen bonding. Mechanistic investigations allow us to apply what we have learned about the MBH reaction to expand the scope and utility of the reaction. Projects in this grant will develop the reaction for use in the synthesis of complex natural products such as the asmarine class of clerodane natural products, potent antiproliferative agents with unknown modes of action which inhibit small cell lung carcinoma growth in nanomolar concentrations. We will also continue to develop the asymmetric MBH reaction for the synthesis of the pycnanthuquinones, orally bioavailable natural products with a unique mode of overcoming the symptoms of type 2 diabetes mellitus. These natural products are unlike other known treatments of type 2 diabetes and will be used to identify the molecular target. We have also successfully developed the asymmetric Mannich reaction of ?-keto esters to acyl imines catalyzed by the cinchona alkaloid class of natural product organocatalysts. Through further investigations, we will expand the scope of the reaction to produce highly functionalized building blocks that can be used for Pharmaceuticals such as the melanin concentrating hormone receptor antagonist SNAP-7941 and the batzellidine natural products. We have also developed the first asymmetric allylboration of carbonyl containing compounds catalyzed by a simple organic compound. The asymmetric reaction will be highlighted in the synthesis of the natural product manzacidin A.