PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .4. SYNTHESIS OF (+--)-2,3,4,5,6,6A-HEXAHYDRO-3-METHYL-8-HYDROXY-1H-4,11B-METHANOBENZOFURO[3,2-D]AZOCINE, AN OXIDE-BRIDGED 5-(META-HYDROXYPHENYL)MORPHAN
PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .4. SYNTHESIS OF (+--)-2,3,4,5,6,6A-HEXAHYDRO-3-METHYL-8-HYDROXY-1H-4,11B-METHANOBENZOFURO[3,2-D]AZOCINE, AN OXIDE-BRIDGED 5-(META-HYDROXYPHENYL)MORPHAN
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DOI：
10.1021/jo00180a019
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发表时间：
1984-01-01
影响因子：
3.6
通讯作者：
RICE, KC
中科院分区：
文献类型：
--
作者：
BURKE, TR;JACOBSON, AE;RICE, KC
描述了外消旋 2,3,4,5,6,6a-六氢-3-甲基-3-羟基-1H-4,11b-甲基苯并呋喃并[3,2-d]偶氮辛 (2) 的合成。该路线利用了芳氧基烯酮到六氢二苯并呋喃的关键光化学转化，从而建立了2的氧化物桥和甲醇桥的相对立体化学。氮与α，β-不饱和化合物的β-碳的1，4-迈克尔型加成建立了第四个也是最后一个环。标题化合物 2 代表有效的 5-(间羟基苯基)吗啡类阿片类镇痛药的氧化物桥衍生物。与具有自由旋转苯基的5-(间羟基苯基)莫芬不同，2的苯环构象受限于86°角。通过X射线分析确定相对于哌啶环的原子1、2、4和12。与母体5-(间羟基苯基)吗啡烷相比，2在小鼠中缺乏体内激动剂或拮抗剂活性，这表明苯环扭转角不适合与阿片受体系统结合。
The synthesis of racemic 2,3,4,5,6,6a-hexahydro-3-methyl-3-hydroxy-1H-4,11b-methanobenzofuro[3,2-d]azocine (2) is described. The route utilized a key photochemical conversion of the aryloxy enone to the hexahydrodibenzofuran, which established the relative stereochemistry of the oxide and methano bridges of 2. A 1,4-Michael-type addition of nitrogen to the .beta.-carbon of the .alpha.,.beta.-unsaturated compound established the 4th and final ring. The title compound 2 represents an oxide-bridged derivative of the potent 5-(m-hydroxyphenyl)morphan class of opioid analgesics. Unlike the 5-(m-hydroxyphenyl)mophans, which have a freely rotating phenyl group, 2 has the phenyl ring conformationally restricted at an angle of 86.degree. relative to atoms 1, 2, 4 and 12 of the piperidine ring as determined by X-ray analysis. The lack of in vivo agonist or antagonist activity of 2 in mice in contrast to the parent 5-(m-hydroxyphenyl)morphan suggests that the phenyl ring torsion angle is unsuitable for binding to the opioid receptor system.