Hanazawa Takeshi, Koyama Akiko, Nakata Kunio, Okamoto Sentaro, Sato Fumie
Graduate school of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
J Org Chem. 2003 Dec 12;68(25):9767-72. doi: 10.1021/jo0353435.
A new convergent method for the synthesis of 1alpha,25-dihydroxyvitamin D(3) and its analogues has been developed that involves efficient preparation of the A-ring part 1a, (Z)-(3S,5R)-1-bromomethylene-3,5-bis(tert-butyldimethylsilyloxy)-2-methylenecyclohexane, starting from epichlorohydrin (4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-1-en-7-yn-3-ol (3a) through a ten-step reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-Pr)(4)/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo(trimethylsilyl)methylene]-5-(tert-butyldimethylsilyloxy)cyclohexanol (10a) in 51% yield, from which 1a was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs(2)CO(3). The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a PdCl(2)(dppf) catalyst to furnish 1alpha,25-dihydroxyvitamin D(3) in 82% yield after protodesilylation. Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared, from which 1-epi-, 3-epi-, and 1,3-di-epi-1alpha,25-dihydroxyvitamin D(3) were synthesized by coupling with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1alpha,25-dihydroxyvitamin D(3) analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.
已开发出一种合成1α,25 - 二羟基维生素D(3)及其类似物的新收敛方法，该方法涉及高效制备A环部分1a，即(Z)-(3S,5R)-1 - 溴亚甲基 - 3,5 - 双(叔丁基二甲基硅氧基)-2 - 亚甲基环己烷，从环氧氯丙烷(4)开始，以及其与C、D环部分12的铃木 - 宫浦偶联反应。因此，(R)-4通过十步反应序列转化为(3S,5R)-5-(叔丁基二甲基硅氧基)-8-(三甲基硅基)-辛 - 1 - 烯 - 7 - 炔 - 3 - 醇(3a)，总收率为49%。将由此得到的化合物3a用Ti(O-i-Pr)(4)/2 i-PrMgCl试剂处理，然后用NBS处理，以51%的收率得到(Z)-(1S,2S,5R)-2 - 溴甲基 - 3 - [溴(三甲基硅基)亚甲基]-5-(叔丁基二甲基硅氧基)环己醇(10a)，通过依次用TBSCl/咪唑、DBU和Cs(2)CO(3)处理，从其以87%的收率得到1a。所得的A环中间体1a在PdCl(二(二苯基膦)催化剂存在下与烯基硼酸酯12反应，在去硅基化后以82%的收率提供1α,25 - 二羟基维生素D(3)。类似地，制备了A环部分lb、lc和ld的所有其他三种可能的立体异构体，通过与12偶联分别以优异的收率合成了1 - 表 -、3 - 表 - 和1,3 - 二表 - 1α,25 - 二羟基维生素D(3)。分别从1a和1c出发，还制备了去C、D环的1α,25 - 二羟基维生素D(3)类似物、视黄醇13及其3 - 表衍生物。
