Quaternary-centre-guided synthesis of complex polycyclic terpenes
Quaternary-centre-guided synthesis of complex polycyclic terpenes
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DOI：
10.1038/s41586-019-1179-2
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发表时间：
2019-05-30
期刊：
影响因子：
64.8
通讯作者：
Snyder, Scott A.
中科院分区：
文献类型：
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作者：
Hu, Pengfei;Chi, Hyung Min;Snyder, Scott A.
在任何给定的分子中，四元中心（一个碳与四个其他碳键合）的存在都会产生重大的化学和生物影响。在许多情况下，它可以实现原本具有挑战性的化学反应。例如，四元中心可大幅提高环化反应的速率（称为索普-英戈尔德效应），该效应可用于生物利用度适中的分子的药物输送 (1)。同样，向候选药物添加四级中心可以增强其活性和代谢稳定性(2)。当存在于手性配体 (3)、催化剂 (4) 和助剂 (5) 中时，四级中心可以引导反应朝着改进的和独特的区域选择性、立体选择性和/或对映选择性方向发展。然而，由于其独特的空间拥挤和构象限制，四级中心的形成只需少量化学转化即可可靠地实现(6,7)。对于特别具有挑战性的情况 - 例如，印楝素 (10,11)、scopadulcic Acid A (12,13) 和 acutumine (14) 等分子中的邻位全碳 (8)、氧杂和氮杂四元中心 (9) - 开发特定靶标的方法以及多官能团和氧化还原操作通常是必要的。因此，需要建立第四纪中心能够积极影响和指导综合规划的替代方式。在这里，我们表明，如果设计合成时，有意利用每个四元中心来简化下一个四元中心的构造（通过速率加速或阻塞效应），那么就可以产生高效、可扩展和模块化的合成。使用萜烯的分生孢子酮家族作为代表性案例来说明这种方法；然而，该框架提供了独特的规划逻辑，适用于包含多个第四纪中心的类似综合复杂性的其他目标。
The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability(1). Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability(2). When present in chiral ligands(3), catalysts(4) and auxiliaries(5), quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations(6,7). For particularly challenging cases-for example, the vicinal all-carbon(8), oxa- and aza-quaternary centres(9) in molecules such as azadirachtin(10,11), scopadulcic acid A(12,13) and acutumine(14)-the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.