Department of Biotechnology and Life Science, Graduate School of Technology , Tokyo University of Agriculture and Technology , 2-24-16, Naka-cho , Koganei City 184-8588 , Tokyo, Japan.
Department of Chemistry, Faculty of Science , Rikkyo University , 3-34-1 Nishi-Ikebukuro , Toshima-ku 171-8501 , Tokyo, Japan.
J Org Chem. 2019 Jun 21;84(12):7630-7641. doi: 10.1021/acs.joc.9b00403. Epub 2019 Apr 24.
(23 S,25 R)-Calcitriol lactone is a major metabolite of vitamin D, but its synthesis has been far less well investigated than that of 1α,25(OH) vitamin D, the active form of vitamin D, even though the lactone is present at a significant level in serum. This paper describes stereoselective syntheses of natural calcitriol lactone and its diastereomers at C23 and C25. This work features (i) the diastereoselective Reformatsky-type crotylation of aldehyde 25 in the presence of chiral ligand L2 to construct the stereochemistry at C23 and (ii) the diastereoselective epoxidation of homoallylic-allylic alcohol 31 to control the stereochemistry at C25. These key reactions allowed us to synthesize CD-ring synthon 30 with all four stereoisomers, and these were further converted into calcitriol lactones 3a-3d by reaction with ene-yne-type A-rings 33 in the presence of a palladium (0) catalyst.
(23S,25R)-钙三醇内酯是维生素 D 的主要代谢物，但与维生素 D 的活性形式 1α,25(OH)维生素 D 相比，其合成的研究要少得多，尽管内酯在血清中以相当高的水平存在。本文描述了天然钙三醇内酯及其在 C23 和 C25 处的非对映异构体的立体选择性合成。这项工作的特点是：（i）在手性配体 L2 的存在下，醛 25 的立体选择性 Reformatsky 型丙炔基化反应，以构建 C23 的立体化学；（ii）高烯丙基-烯丙醇 31 的立体选择性环氧化反应，以控制 C25 的立体化学。这些关键反应使我们能够合成具有所有四个立体异构体的 CD-环合成子 30，并且通过在钯 (0) 催化剂的存在下，将这些合成子与烯炔型 A-环 33 反应，进一步转化为钙三醇内酯 3a-3d。
