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：在本更新申请中，主要研究者 FDA最近的规定可能会增加 介绍新的手性药物，这项研究计划的目的是 开发低成本的替代品来合成潜在的药物 对映体纯形式的中间体和试剂。 一个主要的努力是针对使用结晶- 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 单官能的手性有机硼酸酯络合物和 使用AT制备双官能底物。 配置 通过结晶平衡混合物来控制硼的含量 立体异构体。 应注意，随后可进行随后的接合形成工艺 在立体硼原子的控制下， 将应用于合成含有 季碳，从氨基酸和羟基酸开始。 新的手性有机硼刘易斯酸将被制备用于不对称 转化和催化。 这些试剂将用于 活化非手性亚胺和硫化物以形成对映选择性键 反应. 长期目标据说包括概念上相关的 羰基化合物和醚的活化。 首席研究员指出，该计划的另一个主要部分 涉及手性羰基化合物的合成， 烯醇化物的质子化。 他报告说，一种高效的不对称 已发现酰胺烯醇化物的质子供体， 化合物是手性苯胺。 他指出， 以制备更简单的类似物， 当这一目标实现时，该技术将应用于 酯通过烯醇化物的去外消旋化。 它还指出， 将探索二醇二酯的顺序去外消旋化作为一种方法， 实现高对映体过量。 还可使用各种其它基材。 包括α-烷氧基和α-氨基的衍生物 内酰胺、内酯、酯和酮烯醇化物。 最后，该技术的机械方面将使用 光谱技术