Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):29-33. doi: 10.1016/j.jsbmb.2010.02.008. Epub 2010 Feb 12.
Among more than 3000 analogs of 1alpha,25-dihydroxyvitamin D3 synthesized to date, only a few were characterized by structural modifications in the seco-B-ring. The compounds alkylated at C-6 seemed to be interesting targets for synthetic efforts. Such vitamin D analogs easily undergo thermal conversion to their previtamin forms. The results of molecular modeling indicate that significant deviation from planarity must be present in their molecules associated with the interaction of the 6-alkyl substituent and hydrogens from the C-ring. The synthesis of the analog of 1alpha,25-(OH)2D3, being characterized by the presence of the 6-methyl group, is reported here, together with the results of preliminary testing of its biological potency. This 6-alkylated compound was efficiently prepared using a novel stereoconvergent strategy in which the ring A and the triene unit of the vitamin D skeleton are constructed by a one-pot Pd-catalyzed tandem cyclization-Negishi coupling process.
迄今为止，已合成了超过 3000 种 1α,25-二羟维生素 D3 的类似物，其中只有少数是通过对 seco-B-环进行结构修饰得到的。在 C-6 位被烷基化的化合物似乎是合成工作的有趣目标。这类维生素 D 类似物很容易受热转化为其前维生素形式。分子建模的结果表明，它们的分子中必须存在显著的偏离平面，这与 6-烷基取代基与 C 环上氢原子的相互作用有关。本文报道了具有 6-甲基的 1α,25-(OH)2D3 类似物的合成，并对其生物效价进行了初步测试。该 6-烷基化化合物是通过一种新的立体转化策略高效制备的，其中维生素 D 骨架的 A 环和三烯单元通过一锅 Pd 催化的串联环化-Negishi 偶联过程构建。
