Probes for narcotic receptor-mediated phenomena.: 33.: Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine.: Synthesis of the penultimate oxide-bridged phenylmorphans
Probes for narcotic receptor-mediated phenomena.: 33.: Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine.: Synthesis of the penultimate oxide-bridged phenylmorphans
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DOI：
10.1021/jo040159k
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发表时间：
2004-08-06
影响因子：
3.6
通讯作者：
Rice, KC
中科院分区：
文献类型：
--
作者：
Hashimoto, A;Przybyl, AK;Rice, KC
通过外消旋-5-（2-氟-5-硝基苯基）-2-甲基-2-氮杂双环[3.3.1]壬-9 β-醇（（+/-）-10）（一种含有芳香硝基活化的氟原子的中间体）完成了氧化物桥连的5-苯基吗啉系列刚性四环化合物中的邻位和对位异构体的合成。氟原子被用作形成外消旋-（1 α，4aalpha，9aalpha）-1，3，4，9a-四氢-2-甲基-6-硝基-2H-1，4a-丙苯并呋喃并[2，3-c]吡啶（（+/-）-11）中的应变四环反式稠合5，6-环系统的离去基团，尽管在三环四氢和六氢二苯并呋喃的形成过程中优选顺式环稠合已被充分证明。对所需的对位异构体（（+/-）-2）及其合成中的两个中间体进行了单晶X射线晶体学研究，确保了正确的结构。E-异构体是12种氧化物桥连的5-苯基吗啉中最后合成的。我们设想这些刚性的四环化合物的合成，以确定三维模式的配体，这将使与阿片受体作为激动剂或拮抗剂的相互作用。
The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2azabicyclo[3.3.1]nonan-9beta-ol ((+/-)-10), an intermediate containing an aromatic nitro-activated fluorine atom. The fluorine atom was used as the leaving group for the formation of the strained tetracyclic trans-fused 5,6-ring system in rac-(1alpha,4aalpha,9aalpha)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-2H-1,4a-propanobenzofuro[2,3-c]pyridine ((+/-)-11), although preference for cis ring fusion during the formation of tricyclic tetra- and hexahydrodibenzofurans has been well-documented. Single-crystal X-ray crystallographic study of the desired para-e isomer ((+/-)-2), as well as of two intermediates in its synthesis, provided assurance of the correct structures. The e-isomers are among the last of the 12 oxide-bridged 5-phenylmorphans to be synthesized. We envisioned the syntheses of these rigid, tetracyclic compounds in order to determine the three-dimensional pattern of a ligand that would enable interaction with opioid receptors as agonists or antagonists.