Synthesis of novel retinoid X receptor-selective retinoids
Synthesis of novel retinoid X receptor-selective retinoids
复制标题
DOI：
10.1021/jo0103064
复制
发表时间：
2001-08-24
影响因子：
3.6
通讯作者：
Winneroski, LL
中科院分区：
文献类型：
--
作者：
Faul, MM;Ratz, AM;Winneroski, LL
维甲酸1-5已被确定为有效的RXR激动剂，用于评估非胰岛素依赖型(II)糖尿病(NIDDM)的治疗。已开发出高度收敛的1-5的合成方法。在AlCl3催化下(0.03当量)甲苯与2，5-二氯-2，5-二甲基己烷6进行Friedel-Craft烷基化反应，以98%的产率合成了用于合成1和2的核心四氢萘7。以68%的产率合成了硝基甲烷催化的7与氯甲基烟酸酯9的Fridel-Craft酰化反应。以螯合控制的方式将MeMgCl加到10上，然后脱水得到烯烃11，产率为65%。以三甲基亚砜叶立德为原料，经环丙烷化、皂化等反应，以33%的产率完成了5步合成1，2，4，4，6，6，6，6，6-三甲基亚砜的反应。FeCl3催化的(0.05当量)Friedel-Craft酰化反应以81%的产率得到了酮15。15经皂化后，与50%的NH_2OH在乙酸乙酯中反应，得到顺式和反式的9：1的混合物，从而以43%的产率得到了所需的顺式-2-肟基酮。通过Shapiro反应制备了合成3-5所需的核心溴-二氢萘29。29的易金属化和与Weinreb酰胺30b或36反应得到酮32和37，使用类似于四氢萘系列的化学方法将其转化为3-5。Suzuki将硼酸41和42与三氟乙烯43偶联，为合成这类化合物提供了一种替代方法。
Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of noninsulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl3-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl3-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethyl-tereplithalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH2OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.