The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Am Chem Soc. 2012 Feb 1;134(4):2127-38. doi: 10.1021/ja208503y. Epub 2012 Jan 23.
The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered drug-like cyclophane macrocycles, representing an unusual region of chemical space that can be difficult to access synthetically. The ratio of macrocycle to dimer, generated via a copper catalyzed azide-alkyne cycloaddition macrocyclization in flow at elevated temperature, could be rationalized in terms of the strain energy in the macrocyclic product. The progressive increase in strain resulting from reduction in macrocycle ring size, or the introduction of additional conformational constraints, results in marked deviations from typical geometries. These strained cyclophane macrocyclic systems provide access to spatial orientations of functionality that would not be readily available in unstrained or acyclic analogs. The most strained system prepared represents the first report of an 11-membered cyclophane containing a 1,4-disubstituted 1,2,3-triazole ring and establishes a limit to the ring strain that can be generated using this macrocycle synthesis methodology.
报告了一系列 11-14 元的类似药物的环芳大环的合成、X 射线晶体结构和计算应变能，这些大环代表了一个通常难以通过合成获得的化学空间的不寻常区域。通过在高温下的铜催化叠氮-炔环加成环化在流动中生成的大环与二聚体的比例，可以根据大环产物中的应变能来合理推断。大环环尺寸减小或引入额外的构象限制会导致应变逐渐增加，从而导致明显偏离典型的几何形状。这些应变的环芳大环系统提供了对功能的空间取向的访问，而这些在无应变或非环类似物中是不容易获得的。所制备的最紧张的系统代表了第一个含有 1,4-取代的 1,2,3-三唑环的 11 元环芳大环的报告，并确定了可以使用这种大环合成方法生成的环应变的极限。
