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智科眼: 双语看懂新科研
首页 中国TOP论文 Nature Science JACS AngewChem PRL AdvMater Lancet Cell EnglMed JAMA
Quaternary-centre-guided synthesis of complex polycyclic terpenes
第四纪中心引导合成 of 复杂多环萜烯
Pengfei Hu; Hyung Min Chi; Kenneth C. DeBacker; Xu Gong; Jonathan H. Keim; Ian Tingyung Hsu; Scott A. Snyder
  • Nature vol: issue: (2019) [全文下载] 扫码分享
  • 影响因子: 41.6 点击(434) 收藏(0) 评分(0)
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  • 综合科学
  • 在任何给定分子中存在季铵中心 - 与其键合的四个其他碳的碳 - 可以具有显着的化学和生物学影响。在许多情况下,正如Thorpe-Ingold效应一样,它可以在环化反应中产生大的速率增强,包括在具有适度生物利用度的分子的药物递送中的应用.1类似地,向候选药物中添加季中心当存在于手性配体中时,3种催化剂,4种助剂和5种助剂,5种季中心可以指导对改进的和独特的区域,立体和/或对映选择性的反应。然而,它们的形成往往是一个障碍,因为它们独特的空间拥塞和构象限制只能通过少量化学转化来可靠地处理.6,7对于特别具有挑战性的情况,如邻近的全碳,8氧杂和氮杂四元印楝素,10,11 scopadulcic acid A12,13和acutumine等分子中的中心9,通常需要开发靶特异性方法以及多功能组和氧化还原操作。鉴于这种明显的二分法,应该存在第四方中心积极影响和指导综合规划的其他方法。在这里,我们展示如果设计综合使得每个四元中心被有意地利用以简化下一个的构造,无论是通过速率加速还是阻塞效应,都可以产生高效,可扩展和模块化的合成。这种方法在此使用萜烯的conidiogenone家族作为代表性案例来举例说明,但是该框架提供了适用于包含多个四元中心的类似合成复杂性的其他目标的独特计划逻辑。
  • 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 is enabling, as in the Thorpe–Ingold effect, which gives rise to large rate enhancements in cyclization reactions, including applications in drug delivery for molecules with modest bioavailability.1 Similarly, the addition of quaternary centres to a drug candidate can enhance both activity and metabolic stability.2 When present in chiral ligands,3 catalysts,4 and auxiliaries,5 quaternary centres can guide reactions to both improved and unique regio-, stereo- and/or enantioselectivity. Yet their formation is often a handicap, because their distinct steric congestion and conformational restriction is reliably handled by only a few chemical transformations.6,7 For particularly challenging cases, as in the vicinal all-carbon,8 oxa-, and aza-quaternary centres9 in molecules such as azadirachtin,10,11 scopadulcic acid A12,13 and acutumine,14 the development of target-specific approaches along with multiple functional-group and redox manipulations is often necessary. Given this apparent dichotomy, other ways for quaternary centres to positively affect and guide synthetic planning should exist. 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, highly efficient, scalable and modular syntheses can result. This approach is exemplified here using the conidiogenone family of terpenes as a representative case, but this framework provides a distinct planning logic applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.
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