Semeno Volodymyr V, Vasylchenko Vadym O, Fesun Ihor M, Ruzhylo Liudmyla Yu, Kipriianov Mykhailo O, Melnykov Kostiantyn P, Skreminskyi Artem, Iminov Rustam, Mykhailiuk Pavel, Vashchenko Bohdan V, Grygorenko Oleksandr O
Enamine Ltd., Chervonotkatska Street 78, Kyїv, 02094, Ukraine.
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyїv, 01601, Ukraine.
Chemistry. 2024 Feb 26;30(12):e202303859. doi: 10.1002/chem.202303859. Epub 2024 Jan 11.
Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pK , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.
采用亲电双键官能化-分子内烯醇盐烷基化序列来获得一系列桥连和稠合的双环[m.n.k]烷衍生物（即双环[4.1.1]辛烷、双环[2.2.1]庚烷、双环[3.2.1]辛烷、双环[3.1.0]己烷和双环[4.2.0]庚烷）。确定了该方法的适用范围和局限性，并说明了其在目标双环化合物多克规模合成中的适用性。使用所开发的方案，制备了50多种与药物化学相关的单官能和双官能构建块。合成的化合物是苯环和环烷烃环有前景的电子等排体，这通过它们的物理化学和结构表征（pK、LogP和出口向量参数（EVP））得到证实。提出了即将进行的电子等排体替代研究的“经验法则”。
