New convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling between A-ring and C,D-ring parts.
New convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling between A-ring and C,D-ring parts.
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通过 A 环和 C,D 环部分之间的 Suzuki-Miyaura 偶联，新聚合合成 1α,25-二羟基维生素 D3 及其类似物。
DOI：
10.1021/jo0353435
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
F. Sato
中科院分区：
文献类型：
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作者：
T. Hanazawa;A. Koyama;K. Nakata;S. Okamoto;F. Sato
以环氧氯丙烷（4）为起始原料，通过Suzuki-Miyaura偶联反应，有效地制备了A环1a部分（Z）-（3S，5 R）-1-溴亚甲基-3，5-双（叔丁基二甲基硅氧基）-2-亚甲基环己烷，并合成了1 α，25-二羟基维生素D（3）及其类似物。因此，（R）-4通过10步反应序列以49%的总产率转化为（3S，5 R）-5-（叔丁基二甲基甲硅烷基氧基）-8-（三甲基甲硅烷基）-辛-1-烯-7-炔-3-醇（3a）。将由此获得的化合物3a用Ti（O-i-Pr）（4）/2 i-PrMgCl试剂处理，然后用NBS处理，以51%的产率得到（Z）-（1 S，2S，5 R）-2-溴甲基-3-[溴（三甲基甲硅烷基）亚甲基]-5-（叔丁基二甲基甲硅烷基氧基）环己醇（10a），通过用TBSCl/咪唑、DBU和Cs（2）CO（3）依次处理，以87%的产率从其获得1a。在PdCl（2）（dppf）催化剂存在下，使所得A环中间体1a与链烯基硼酸酯12反应，在脱甲硅烷基化后以82%产率得到1 α，25-二羟基维生素D（3）。类似地，制备了A-环部分1b、1c和1d的所有其他三种可能的立体异构体，通过与12偶联，分别以优异的产率合成了1-表-、3-表-和1，3-二-表-1 α，25-二羟基维生素D（3）。以1a和1c为原料，分别合成了脱-C，D-1 α，25-二羟基维生素D（3）类似物瑞替菲罗13及其3-表位衍生物。
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.