The Design and Implementation of Asymmetric Organocatalysis in Synthesis

合成中不对称有机催化的设计与实现

• 批准号: 7779425
• 负责人: Scott Edward Schaus
• 金额: $ 30.24万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7779425
• 关键词: Acids; Aldehydes; Anxiety; Area; BINOL; Bioavailable; Biological Factors; Catalysis; Cinchona Alkaloids; Complex; Development; Diterpenes; Esters; Glycols; Grant; Growth; Hydrogen Bonding; Hypoglycemic Agents; Imines; Investigation; Ketones; Learning; Mental Depression; Methods; Molecular Target; Non-Insulin-Dependent Diabetes Mellitus; Organic Synthesis; Pharmacologic Substance; Reaction; Research; Research Personnel; SNAP7941; Symptoms; antiproliferative agents; base; catalyst; chiral molecule; clerodane; cyclopentenone; design; lung small cell carcinoma; manzacidin A; melanin-concentrating hormone receptor; novel; obesity treatment; organic base; programs; promoter; pycnanthuquinone A

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.

描述（由申请人提供）：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促进合成转化方面的有效性和选择性。有机催化领域的持续进步将提供新的、高度功能化的手性对映体富集形式的构建模块，这些模块以前是不可用的。本项目将集中于鉴定和探索手性Bronsted酸催化和手性碱催化，以开发新的有机催化方法，适用于合成新的手性构件。我们开发了第一个高对映选择性的Morita-Baylis-Hillman （MBH）反应，涉及烯酮和醛，由一个小手性分子催化。该反应通过氢键从有机催化剂中获得高水平的对映选择性。机械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效用。这项资助的项目将开发用于合成复杂天然产物的反应，如asmarine类克罗丹天然产物，这是一种具有未知作用模式的强效抗增殖剂，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，用于合成pynnanthuquinones，这是一种口服生物可利用的天然产物，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2型糖尿病治疗方法，将用于确定分子靶点。我们还成功地开发了不对称曼尼希反应？金鸡纳生物碱类天然产物有机催化剂催化-酮酯制酰基亚胺。通过进一步的研究，我们将扩大该反应的范围，以生产可用于药物的高功能化构建块，如黑色素浓缩激素受体拮抗剂SNAP-7941和batzelline天然产物。我们还开发了第一个由简单有机化合物催化的含羰基化合物的不对称烯丙基硼化反应。不对称反应将在天然产物曼扎酸苷A的合成中得到重点介绍。