Enamine Ltd, Chervonotkatska Street 78, Kyiv 02094, Ukraine.
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine.
Org Biomol Chem. 2022 Apr 13;20(15):3183-3200. doi: 10.1039/d2ob00146b.
A practical divergent synthetic approach is reported for the library of regio- and stereoisomers of glutamic acid analogs built on the spiro[3.3]heptane scaffold. Formation of the spirocyclic scaffold was achieved starting from a common precursor - an -silylated 2-(hydroxymethyl)cyclobutanone derivative. Its olefination required using the titanium-based Tebbe protocol since the standard Wittig reaction did not work with this particular substrate. The construction of the second cyclobutane ring of the spirocyclic system was achieved through either subsequent dichloroketene addition or Meinwald oxirane rearrangement as the key synthetic steps, depending on the substitution patterns in the target compounds (1,6- or 1,5-, respectively). Further modified Strecker reaction of the resulting racemic spirocyclic ketones with the Ellman's sulfinamide as a chiral auxiliary had low to moderate diastereoselectivity; nevertheless, all stereoisomers were isolated in pure form chromatographic separation, and their absolute configuration was confirmed by X-ray crystallography. Members of the library were tested for the inhibitory activity against glutamate racemase.
报道了一种实用的发散合成方法，用于构建基于螺[3.3]庚烷支架的谷氨酸类似物的区域和立体异构体文库。该螺环骨架的形成是从一个共同的前体 - α-硅基化的 2-（羟甲基）环丁酮衍生物开始的。由于标准的 Wittig 反应不适用于该特定底物，因此需要使用基于钛的 Tebbe 协议进行烯烃化。螺环系统的第二个环丁烷环的构建是通过随后的二氯代亚酮加成或 Meinwald 环氧乙烷重排作为关键的合成步骤来实现的，具体取决于目标化合物的取代模式（分别为 1,6-或 1,5-）。用 Ellman 的亚磺酰胺作为手性辅助试剂对得到的外消旋螺环酮进行进一步修饰的Strecker 反应具有低至中等的非对映选择性；然而，所有立体异构体都通过色谱分离以纯形式分离出来，并通过 X 射线晶体学确定了它们的绝对构型。对文库成员进行了抑制谷氨酸消旋酶活性的测试。
