SYNTHESIS OF LEUCONOLIDE VIA BORONIC ESTERS

通过硼酯合成亮酮酸内酯

• 批准号: 3295878
• 负责人: DONALD S MATTESON
• 金额: $ 12.17万
• 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/3295878
• 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的不对称合成方法 酯化学将被应用于明串珠菌肽的合成， 大环内酯类抗生素柱晶白霉素的糖苷配基。 所有七个手性中心 可以通过手性二醇的硼酸酯 与（二卤甲基）锂，其将CHX基团插入碳- 绝对构型控制>99%的硼键。 硼有助于 通过各种亲核试剂置换相邻的卤化物， 在此过程中的动力学拆分提供了额外的改进 已经很好的非对映选择性。 计划中的合成构建 分子分为三个主要部分，其中两个将通过一个 卤代硼酸酯与烷氧基锂立体定向偶联 衍生自另一种硼酸酯的试剂。 剩下的部分将是 通过一端酯化和卤乙烯的铃木偶联连接 转化为硼酸酯以提供二烯。 酯化 已经被认为是大环内酯类药物的一种封闭手段。 Suzuki二烯合成 也将作为环闭合的一种手段进行测试。 这种新的化学物质提供了 一个重要的机会，有效控制合成复杂的 手性结构如明串珠菌肽或其它大环内酯或离子载体 抗生素