NEW METHODS FOR STEREOSELECTIVE ADDITIONS TO CARBONYLS

羰基立体选择性加成的新方法

• 批准号: 2185973
• 负责人: TAREK SAMMAKIA
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2185973
• 关键词: Diels Alder reaction; carbonyl compound; catalyst; chemical addition; chemical synthesis; ferrocene; inhibitor /antagonist; lipid biosynthesis; saturated /unsaturated bonds; stereochemistry

The long term objectives of this project are to develop new methods of asymmetric synthesis by gaining an understanding of the stereocontrol elements in existing methods, and applying what we have learned to the design of new reactions. We are primarily interested in reactions that form C-C bonds enantioselectively. Our approach focuses on the generation of chiral oxocarbenium ions, which can be considered activated ketones or aldehydes. these compounds may then undergo diastereoselective addition reactions, or Diels Alder reactions if the oxocarbenium ion is alpha-beta unsaturated, where the asymmetric induction is derived from the chirality of the oxocarbenium ion. In the first part of the proposal, we have unequivocally shown by a deuterium labeling experiment that the chiral acetal addition reactions discovered by W.S. Johnson proceed by way of an oxocarbenium ion. These reactions can display exceptional levels of diastereoselectivity, >300:1 in many cases, thus providing evidence that chiral oxocarbenium ions can provide high levels of asymmetric induction in addition reactions. We are extending our deuterated acetal studies to probe the mechanism of addition to acyclic acetals. We are also examining the activation of alpha-beta unsaturated carbonyl derivatives by their conversion to oxocarbenium ions. formation of the oxocarbenium ions in the Diels Alder reaction, allowing for new opportunities for controlling remote stereochemistry. We have proposed a short synthesis of the cholesterol biosynthesis inhibitor dihydrocompactin using this method, and are examining its scope. We also propose a catalytic variant where a chiral TMS ether is used in catalytic amounts to control the absolute stereochemistry in the Diels Alder reaction. Finally, we describe a chiral alpha-ferrocenyl cation which we hope will serve as an enantioselective catalyst for a variety of reactions. This reagent is similar to the trityl cation which has been shown to be an effective Lewis acid catalyst for numerous reactions including the aldol reaction, reduction of ketones with trialkylsilanes, 1,4 addition of silyl nucleophiles to alpha-beta unsaturated ketones and ester equivalents, and Diels Alder reactions. We describe an enantioselective synthesis of the catalyst precursor and have just begun to examine its reactivity as an asymmetric catalyst. The methods we discover can be used to synthesize a variety of molecules of medicinal interest.

该项目的长期目标是开发新的方法， 通过了解立体控制的不对称合成 现有方法中的元素，并将我们学到的知识应用于 设计新的反应。 我们主要感兴趣的反应， 对映选择性地形成C-C键。 我们的方法侧重于 生成手性氧碳正离子，其可被认为是活化的 酮或醛。 然后这些化合物可以经历 非对映选择性加成反应，或Diels桤木反应，如果 氧碳正离子是α-β不饱和的，其中不对称碳正离子是α-β不饱和的， 诱导源自氧碳正离子的手性。 在 第一部分的建议，我们已经明确表示，由氘 标记实验，手性缩醛加成反应发现， 关于W. S约翰逊通过氧碳正离子进行。 这些反应 可以显示出异常水平的非对映选择性，在许多情况下>300：1， 例，从而提供证据表明，手性氧碳正离子可以提供 加成反应中高水平的不对称诱导。 我们 扩展我们的氘代缩醛研究，以探索 添加到无环缩醛中。 我们也在研究 α-β不饱和羰基衍生物，通过将其转化为 氧碳正离子。 第尔斯桤木中氧碳正离子的形成 反应，允许新的机会，控制远程 立体化学 我们已经提出了一个简短的合成胆固醇 生物合成抑制剂二氢康帕汀，并 检查其范围。 我们还提出了一种催化变体，其中手性 TMS醚以催化量使用以控制绝对浓度。 Diels桤木反应中的立体化学。 最后，我们描述了一个 手性α-二茂铁基阳离子，我们希望它能作为一种 对映选择性催化剂用于各种反应。 该试剂 类似于三苯甲基阳离子， 刘易斯酸催化剂用于许多反应，包括羟醛缩合反应， 用三烷基硅烷还原酮，甲硅烷基的1，4加成 亲核试剂转化为α-β不饱和酮和酯等价物，和 Diels桤木反应。 我们描述了对映选择性合成的 催化剂前体，并刚刚开始检查其反应性， 不对称催化剂 我们发现的方法可以用来合成 各种各样的药用分子