CHIRAL HETEROELEMENT REAGENTS IN ASYMMETRIC SYNTHESIS

不对称合成中的手性杂元素试剂

• 批准号: 6031275
• 负责人: EDWIN VEDEJS
• 金额: $ 13.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6031275
• 关键词: boron; carbonyl compound; catalyst; chemical synthesis; crystallization; cyclic compound; enolate; imines; organometallic compounds; protonation; stereochemistry; stereoisomer; sulfides

DESCRIPTION: In this renewal application, the principal investigator states that recent FDA regulations are likely to increase the cost of introducing new chiral drugs and that this research program is designed to develop low cost alternatives for the synthesis of potential drug intermediates and reagents in enantiomerically pure form. A major effort is to be directed toward the use of crystallization- assisted asymmetric transformation (AT) as a way to upgrade kinetic stereoselectivity. Chiral organoboronate complexes of monofunctional and difunctional substrates are to be prepared using AT. The configuration at boron is to be controlled by crystallizing an equilibrating mixture of stereoisomers. It is noted that subsequent bond forming processes can then take place under the control of the stereogenic boron atom and that this approach will be applied to the synthesis of chiral building blocks containing quaternary carbon, starting from amino and hydroxy acids. New chiral organoboron Lewis acids are to be made for use in asymmetric transformation and also in catalysis. These reagents are to be used to activate achiral imines and sulfides for enantioselective bond forming reactions. Long range goals are said to include the conceptually related activation of carbonyl compounds and ethers. The principal investigator notes that another major part of this program involves the synthesis of chiral carbonyl compound by the asymmetric protonation of enolates. He reports that a highly effective asymmetric proton donor has been found for amide enolates and that the lead compound is a chiral aniline. He notes that efforts will be initiated to prepare simpler analogs that can be modified for increased acidity and that when this is achieved, the technique will be applied to the deracemization of esters via the enolates. It is also stated that the sequential deracemization of diol diesters will be explored as a way to achieve high enantiomer excess. A variety of other substrates are also to be studied, including derivatives of alpha-alkoxy and alpha-amino lactam, lactone, ester, and ketone enolates. Finally, the mechanistic aspects of the technique are to be probed using spectroscopic techniques.

描述：在此续签应用中，首席调查员 指出最近的FDA法规可能会增加 引入新的手性药物，该研究计划的设计 开发低成本替代品以合成潜在药物 中间和试剂以对映体纯形形式。 一个主要的努力是针对结晶的使用 - 辅助不对称转化（AT）作为升级动力学的一种方式 立体选择性。 手性有机碳酸酯络合物的单功能和 可以使用AT制备使用义务底物。 配置 在硼中，应通过结晶的平衡混合物来​​控制 立体异构体。 注意，随后可以进行随后的债券形成过程 在立体生成硼原子的控制下，这种方法 将应用于手性构建块的合成 第四纪碳，从氨基和羟基酸开始。 新的手性有机牛肉刘易斯酸将用于不对称 转化以及催化。 这些试剂应习惯 激活Achiral aimines和硫化物以形成对映选择性键 反应。 据说远距离目标包括与概念相关的 羰基化合物和醚的激活。 主要调查员指出，该计划的另一个主要部分 涉及非对称性手性羰基化合物的合成 烯醇的质子化。 他报告说高效的不对称 已经发现蛋白体供体用于酰胺烯烯烃，并且是领先者 化合物是手性苯胺。 他指出，将开始努力 准备更简单的类似物，可以修改以增加酸度 而且，当实现这一目标时，该技术将应用于 通过烯醇对酯的散囊化。 还指出 将探索Diol Diesters的顺序取代 实现高对映异构体的过量。 其他各种基材也是 被研究，包括α-烷氧基和α-氨基的衍生物 LACTAM，LACTONE，酯和酮烯醇。 最后，该技术的机械方面应使用 光谱技术。