Center for Drug Discovery , Baylor College of Medicine , One Baylor Plaza , Houston , Texas 77030 , United States.
Department of Pharmacology and Chemical Biology , Baylor College of Medicine , One Baylor Plaza , Houston , Texas 77030 , United States.
J Org Chem. 2019 May 17;84(10):6040-6064. doi: 10.1021/acs.joc.9b00148. Epub 2019 Apr 29.
The piperazine heterocycle is housed within a large number of FDA-approved drugs and biological probe compounds. Structurally, however, these compounds are mostly confined to substitutions on the two ring nitrogen atoms, rationalizing the expansion of piperazine chemical diversity through carbon substitutions. On the basis of the concept of systematic chemical diversity, a divergent six-step synthesis was developed in which chiral amino acids were transformed, with high diastereoselectivity, into either cis or trans 5-substituted piperazine-2-acetic acid esters that could be chromatographically rendered diastereomerically homogeneous. Starting from six commercially available amino acids or their respective amino alcohols (both antipodes), we obtained a complete set of 24 protected chiral 2,5-disubstituted piperazines, as single stereoisomers in multigram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as starting materials for parallel library synthesis and as intermediates for the targeted production of more complex C-substituted piperazine compounds.
哌嗪杂环包含在大量获得 FDA 批准的药物和生物探针化合物中。然而，从结构上看，这些化合物大多局限于两个环氮原子上的取代基，因此可以通过碳取代来扩展哌嗪的化学多样性。基于系统化学多样性的概念，开发了一种发散的六步合成方法，其中手性氨基酸以高非对映选择性转化为顺式或反式 5-取代哌嗪-2-乙酸酯，可通过色谱法将其立体异构体均匀化。从六种商业上可获得的氨基酸或其相应的氨基醇（均为对映异构体）开始，我们以多克数量获得了一套完整的 24 个受保护的手性 2,5-取代哌嗪，作为单一立体异构体。这些多样且通用的哌嗪可以在任一个氮原子上进行官能化，从而可以将它们用作平行文库合成的起始材料，以及用于靶向生产更复杂的 C 取代哌嗪化合物的中间体。
