SYNTHESIS OF LEUCONOLIDE VIA BORONIC ESTERS

通过硼酯合成亮酮酸内酯

• 批准号: 3295876
• 负责人: DONALD S MATTESON
• 金额: $ 11.64万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3295876
• 关键词: boron; diene; diol; drug design /synthesis /production; esters; halocarbon compound; ionophores; lithium; macrolide antibiotics; molecular asymmetry; stereoisomer

Our recently discovered method of asymmetric synthesis based on boronic ester chemistry will be applied to the synthesis of leuconolide, the aglycone of the macrolide antibiotic leucomycin. All seven chiral centers can be constructed via the reaction of a boronic ester of a chiral diol with a (dihalomethyl)lithium, which inserts a CHX group into the carbon- boron bond with >99% control of absolute configuration. Boron facilitates the displacement of the neighboring halide by a variety of nucleophiles, and kinetic resolution during this process provides additional improvement of the already excellent diastereoselection. The planned synthesis builds the molecule in three major segments, and two of these will be joined by a stereospecific coupling of halo boronic ester with an alkoxy lithium reagent derived from another boronic ester. The remaining segment will be connected via esterification at one end and Suzuki coupling of vinyl halide to boronic ester to provide the diene at the other. The esterification is already known as a means of macrolide closure. The Suzuki diene synthesis will also be tested as a means of ring closure. This new chemistry offers a major opportunity for the efficient controlled synthesis of intricate chiral structures such as leuconolide or other macrolide or ionophore antibiotics.

我们最近发现的基于硼酸的非对称合成方法 酯化学将应用于亮酮的合成， 大环内酯类抗生素白霉素的aglycone。 所有七个手性中心 可以通过手性二醇的硼酸酯的反应来构建 用（二甲甲基）锂，将CHX组插入碳 - 硼键> 99％的绝对配置控制。 硼促进 通过多种亲核试剂的相邻卤化物的位移， 在此过程中的动力学分辨率可提供额外的改进 已经出色的非映选择。 计划的合成构建 三个主要段中的分子，其中两个将与 霍洛硼酯与烷基锂的立体特异性耦合 试剂源自另一种硼烯酯。 其余部分将是 通过酯在一端连接和铃木卤化物的铃木耦合 向硼烯酯提供另一个二烯。 酯是 已经被称为大环内酯类封闭的手段。 铃木狄内合成 也将作为环闭环的手段进行测试。 这种新的化学提供了 有效控制复杂的有效控制的主要机会 手性结构，例如紫糖苷或其他大环内酯类或离子载体 抗生素。