Sokolowska Katarzyna, Carballa Diego, Seoane Samuel, Pérez-Fernández Román, Mouriño Antonio, Sicinski Rafal R
†Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
‡Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
J Org Chem. 2015 Jan 2;80(1):165-73. doi: 10.1021/jo502243r. Epub 2014 Nov 25.
Two novel vitamin D analogues of the hormone 1α,25-(OH)2D3 modified at C-7, namely, 7-methyl-1α,25-(OH)2D3 (12) and 7-methyl-1α,25-(OH)2-19-nor-D3 (26), were synthesized and biologically evaluated to gain further insights into the structure-function relationships of vitamin D. Key steps in the synthesis of 12 include the functionalization at C-7 by an efficient regioselective hydrostannylation of an allene precursor, and the construction of the triene framework by a palladium-catalyzed intramolecular cyclization-Suzuki-Miyaura coupling cascade. Since the calcitriol analogue 12 was prone to conversion into its previtamin D form by thermal equilibration, the corresponding 19-nor-compound 26 was also synthesized. The diene moiety of compound 26 was constructed by a modified Julia coupling. UV data as well as X-ray analysis indicate that introduction of the methyl group at C-7 results in a significant deviation from planarity of the 5,7-diene moiety. The new vitamin D analogues 12 and 26 retained good VDR binding ability.
合成了两种在C-7位修饰的新型激素1α,25-(OH)2D3的维生素D类似物，即7-甲基-1α,25-(OH)2D3（12）和7-甲基-1α,25-(OH)2-19-去甲-D3（26），并对其进行了生物学评估，以进一步深入了解维生素D的结构-功能关系。12合成中的关键步骤包括通过丙二烯前体的高效区域选择性氢化锡化反应在C-7位进行官能化，以及通过钯催化的分子内环化-铃木-宫浦偶联级联反应构建三烯骨架。由于骨化三醇类似物12易于通过热平衡转化为其前维生素D形式，因此也合成了相应的19-去甲化合物26。化合物26的二烯部分通过改良的朱利亚偶联反应构建。紫外数据以及X射线分析表明，在C-7位引入甲基会导致5,7-二烯部分的平面度出现显著偏差。新型维生素D类似物12和26保留了良好的维生素D受体结合能力。
