哈利斯塔丁1和2的总合成
Vemula Praveen Kumar1, Yoshito Kishi1
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Journal of the American Chemical Society
|August 14, 2020
概括
通过使用介导的合反应实现了素1和2的首次全合成. 溶剂的选择显著影响了螺旋催化体的立体选择性,有利于天然的合素序列.
科学领域:
- 有机化学
- 合成化学
- 医学化学
背景情况:
- 哈利斯塔丁是一种复杂的天然产品,具有潜在的抗癌特性.
- 之前的合成努力因构建核心结构的挑战而受到限制.
研究的目的:
- 实现第一个全合成的哈利斯塔丁1和2.
- 开发使用介导合反应的新合成方法.
- 在关键的结合形成步骤和螺旋化中研究立体化学控制.
主要方法:
- 用于α-四元和乙烯酸联接 (C11/C12键) 的固体测量Ni/Cr介导联接.
- 采用催化,不对称的Co/Cr介导的化,用于立体选择性C17-C19片段的整合.
- 应用非对称的Ni/Cr介导合用于C19/C20键形成.
- 使用p-toluenesulfonic acid (PTSA) 对[5,5]-spiroketalization的立体选择性进行了研究.
主要成果:
- 已经成功合成了哈利斯塔丁1和2.
- 使用各种Cr介导合物实现了高效的C11/C12,C17/C19和C19/C20键形成.
- 证明溶剂成分对螺旋催化体的立体选择性有重大影响,甲醇与水的混合物在自然序列中具有> 20:1的选择性.
- 表明1: 1的甲醇水中的PTSA可以将C38-epi- Halichondrins同质化为天然的 Halichondrins.
结论:
- 开发的合成策略为类药物和相关类型提供了可行的途径.
- 这项研究强调了在复杂分子合成过程中控制立体化学的溶剂选择的重要性.
- 这些发现为基于基的化合物的合成和潜在的表皮化提供了见解.
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