ASYMMETRIC SYNTHESIS AND ITS APPLICATIONS

不对称合成及其应用

• 批准号: 3289244
• 负责人: SATORU MASAMUNE
• 金额: $ 25.15万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3289244
• 关键词: Diels Alder reaction; aldehydes; antibiotics; boranes; drug design /synthesis /production; enolate; erythromycin; monensin; rifamycins; silanes; stereochemistry

Many organic compounds of biological and chemical interest such as medicines, hormones, and vitamins are chiral, and asymmetric catalytic (AC) processes provide a highly efficient means of synthesizing enantiometrically pure substrates. This proposal is aimed mainly at the design and development of such AC processes for four fundamental organic reactions, as itemized below. Part I. The AC Aldol Reaction. Two types of AC processes will be explored. (a) It has been found recently that Sn(IV) (O-t-Bu)4 and related achiral species efficiently catalyze the Mukaiyama-type aldol reaction that involves an aldehyde and a vinyloxysilane to provide the corresponding aldol product. Sn(IV) catalysts with a chiral ligand will be examined. (b) Many boron-mediated aldol reactions proceed stereoselectively to afford the boron aldolate products. Efforts will be made to render some of these reactions catalytic by generating the boron-enolates from the boron aldolates through transesterification or transmetallation. Part II. AC Allyl- and (E)- and (Z)-Crotylmetallation. Two strategies will be explored. (a) The complex (dppeRhC1)2 has just been found to catalyze allylstannation of benzaldehyde with allytributylstannane. This exciting discovery, the first of this kind, will be followed by an extensive search for an optimum set of catalytic metal, ligand, and reagent. (b) The use of a chiral bifunctional catalyst has been highly successful in the Itsuno-Corey reduction of a ketone with diborane and Oguni-Soai-Noyori alkylation of an aldehyde with diethylzinc. This device has now been applied to allylboration with moderate success. The work should and will be continued to enhance the degree of asymmetric induction. Part III. The AC Conjugate Addition of Organometallic Reagents to the alpha,beta-unsaturated Carbonyl System. Our major efforts in this area will concern the design and synthesis of chiral ligands for (a) the cuprate and (b) zincate catalysts. In addition, (c) an exploratory search will be made to discover catalysts capable of effecting conjugate addition of relatively unreactive alkylmetals exemplified by (RO)2BR,R2Zn,R4Ge and R4Sn. Part IV. Design of Chiral Ligands for Transition Metal Catalysts Which Are Used in Hydrogenation, Ketone Reduction, and Hydrosilylation. New types of ligands have been designed to enhance the interaction between the chiral moiety and an incoming reactant and will be examined for their efficiency in the AC processes. In addition to the above AC processes, the synthesis of new chiral boron reagents of high diastereofacial selectivity is included in Part I as Part Ic. The reagents are in high demand for stereochemical control of the aldol-type assembly of two chiral fragments, a process often encountered in convergent natural product syntheses.

许多具有生物和化学意义的有机化合物，例如 药物、激素和维生素具有手性和不对称催化 (AC) 过程提供了一种高效的合成方法 对映体纯的底物。 该提案主要针对 为四种基本有机物设计和开发此类 AC 工艺 反应，如下逐项列出。 第一部分：AC 羟醛反应。 两种类型的 AC 过程将是 探索过。 (a) 最近发现 Sn(IV) (O-t-Bu)4 及相关 非手性物种有效催化 Mukaiyama 型羟醛反应 涉及醛和乙烯基氧基硅烷以提供相应的 醇醛产物。 将研究具有手性配体的 Sn(IV) 催化剂。 (b) 许多硼介导的羟醛反应立体选择性地进行 硼醛酸产品。 将努力使其中一些 通过从硼生成硼烯醇化物来催化反应 通过酯交换或金属转移进行醛缩。 第二部分。 AC烯丙基-和(E)-和(Z)-巴豆基金属化。 两种策略 将被探索。 (a) 配合物 (dppeRhC1)2 刚刚被发现 用烯丙基三丁基锡催化苯甲醛的烯丙基锡化。 这 令人兴奋的发现，这是此类的第一个，随后将是 广泛寻找一组最佳的催化金属、配体和 试剂。 (b) 手性双功能催化剂的使用已得到高度重视 成功地用乙硼烷进行酮的 Itsuno-Corey 还原 醛与二乙基锌的 Oguni-Soai-Noyori 烷基化。 这个装置 现已应用于烯丙基硼化反应并取得了一定的成功。 工作 应该而且将会继续加强不对称诱导的程度。 第三部分。 AC 共轭添加有机金属试剂 α，β-不饱和羰基系统。 我们在这方面的主要努力 将涉及（a）铜酸盐的手性配体的设计和合成 (b)锌酸盐催化剂。 此外，(c) 将进行探索性搜索 发现能够实现共轭加成的催化剂 相对不活泼的烷基金属，例如 (RO)2BR、R2Zn、R4Ge 和 R4Sn。 第四部分。 过渡金属催化剂手性配体的设计 用于氢化、酮还原和氢化硅烷化。 新型的 配体被设计来增强手性之间的相互作用 部分和传入的反应物，并将检查其效率 在交流过程中。 除了上述AC工艺外，新型手性硼的合成 高非立体面选择性试剂包含在第一部分中作为部分 我知道了。 该试剂对于立体化学控制有很高的需求 两个手性片段的羟醛型组装，这是一个经常遇到的过程 聚合天然产物合成。