Emulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine Interactions.
Emulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine Interactions.
复制标题
DOI：
10.1002/chem.201604632
复制
发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Felix Scheidt;Philipp Selter;Nico Santschi;M. C. Holland;Dmytro V. Dudenko;C. Daniliuc;Christian Mück‐Lichtenfeld;M. Hansen;R. Gilmour
中科院分区：
文献类型：
--
作者：
Felix Scheidt;Philipp Selter;Nico Santschi;M. C. Holland;Dmytro V. Dudenko;C. Daniliuc;Christian Mück‐Lichtenfeld;M. Hansen;R. Gilmour
丙烷单元在自然界中普遍存在，是许多生物活性分子的重要组成部分。这些范围从非环状系统，如神经递质γ-氨基丁酸，到各种色满和二氢苯并呋喃的双环核。在后一种情况下，通过环醚形成的环化确保了高度预组织的结构，而线性支架显示出由围绕两个内部C（sp3）-C（sp3）键的旋转引起的更动态的构象行为。在这项研究中，取代-[CH 2]-单位-[CHF]-中心的评价作为一种策略，以实现无环构象控制，通过阻碍这些内部旋转。强化，非共价氟相互作用被验证为强大的设计功能，导致可编程的构象行为：这些是由每个中心的相对配置编码。通过利用多邻位氟烷烃中的协同相邻立体电子效应，可以用无环模拟物模拟在各种天然产物中发现的二氢苯并呋喃支架的整体构象。这被描述为在链末端的两个键矢量的函数，并通过结合理论，晶体学和光谱分析进行验证。鉴于与氟引入相关的有利的物理化学性质，这种生物活性支架设计的方法可能被证明是可扩展的。
Pervasive in Nature, the propane unit is an essential component of numerous bioactive molecules. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclisation via cyclic ether formation ensures a highly pre-organised structure, whilst linear scaffolds display more dynamic conformational behaviour resulting from rotation about the two internal C(sp3 )-C(sp3 ) bonds. In this study, the replacement of -[CH2 ]- units by -[CHF]- centres is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviours: These are encoded by the relative configuration of each centre. By exploiting cooperative neighbouring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theoretical, crystallographic and spectroscopic analyses. In view of the favourable physicochemical properties associated with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.