Fuse Shinichiro, Ishikawa Hiroki, Kitamura Hiroshi, Masui Hisashi, Takahashi Takashi
Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan.
Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
Nat Commun. 2024 Jul 19;15(1):6087. doi: 10.1038/s41467-024-49935-1.
Fenestranes, in which four rings share one carbon atom, have garnered much attention because of their flattened quaternary carbon centers. In addition, the rigid and nonplanar structures of heteroatom-containing fenestranes are attractive scaffolds for pharmaceutical applications. We report one-step syntheses of diaza-dioxa-fenestranes via the sequential (3 + 2) cycloadditions. Our synthesis employs readily synthesizable, nonbranched acyclic allenyl precursors that facilitate sequential cycloaddition reactions. We report the synthesis of 22 heteroatom-containing and differently substituted fenestranes with rings of varying sizes. The prepared diaza-dioxa-fenestranes are subjected to X-ray crystallography and DFT calculations, which suggest that replacing the carbon atoms at the non-bridgehead positions in the fenestrane skeleton with nitrogen and oxygen atoms results in a slight flattening of the quaternary carbon center. Moreover, one of our synthesized c,c-[5.5.5.5]fenestranes containing two isoxazoline rings possesses the flattest quaternary carbon center among previously synthesized heteroatom-containing fenestrane versions.
四联苯，其中四个环共享一个碳原子，由于其扁平的季碳中心而备受关注。此外，含杂原子的四联苯的刚性和非平面结构是药物应用中具有吸引力的骨架。我们报道了通过顺序（3 + 2）环加成一步合成二氮杂二氧杂四联苯。我们的合成使用易于合成的、无支链的非环状烯丙基前体，这有利于顺序环加成反应。我们报道了22种含杂原子且具有不同取代基、环大小各异的四联苯的合成。所制备的二氮杂二氧杂四联苯经过X射线晶体学和密度泛函理论计算，结果表明用氮原子和氧原子取代四联苯骨架中非桥头位置的碳原子会导致季碳中心略有扁平。此外，我们合成的一种含有两个异恶唑啉环的c,c-[5.5.5.5]四联苯在先前合成的含杂原子四联苯版本中具有最扁平的季碳中心。
