Stereochemical Control in the Still-Wittig Rearrangement Synthesis of Cyclohexyl (Z)-Alkene Inhibitors of Pin1.
Stereochemical Control in the Still-Wittig Rearrangement Synthesis of Cyclohexyl (Z)-Alkene Inhibitors of Pin1.
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DOI：
10.1371/journal.pone.0139543
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Etzkorn FA
中科院分区：
文献类型：
--
作者：
Chen XR;Fan SA;Ware RI;Etzkorn FA
通过13步反应合成了Pin 1的3个立体异构体抑制剂：（2 R，5S）-、（2S，5 R）-和（2S，5S）-Ac-pSer-N-[（Z）CH = C]-哌啶基（Pip）-2-（2-萘基）乙胺1，分别模拟L-pSer-D-Pro、D-pSer-L-Pro和D-pSer-D-Pro酰胺。在哌啶环中新形成的立体异构中心通过Lucche还原引入，然后通过立体特异性Still-Wittig重排。重排中的（Z）-烯烃与（E）-烯烃的比率始终为5.5比1。原始Ser α-碳的立体化学控制了Luche还原的立体化学，但它不影响重排的立体化学结果，重排始终得到（Z）-烯烃。差向异构化副产物（2S，5S）-10（由（2S，5 R）-9的Na/NH3脱苄基后的后处理产生）被转化为（2S，5S）-1异构体。从Luche还原副产物（2 R，3R）-3再合成化合物（2S，5S）-10，并通过比较旋光度证实其立体化学。（2 R，5S）-1、（2S，5 R）-1和（2S，5S）-1 Pin 1抑制的IC 50值分别为：52、85和140 μM。
Three stereoisomeric inhibitors of Pin1: (2R,5S)-, (2S,5R)- and (2S,5S)-Ac–pSer–Ψ[(Z)CH = C]–pipecolyl(Pip)–2-(2-naphthyl)ethylamine 1, that mimic L-pSer–D-Pro, D-pSer–L-Pro, and D-pSer–D-Pro amides respectively, were synthesized by a 13-step route. The newly formed stereogenic centers in the pipecolyl ring were introduced by Luche reduction, followed by stereospecific -Still-Wittig rearrangement. The (Z)- to (E)-alkene ratio in the rearrangements were consistently 5.5 to 1. The stereochemistry at the original Ser α-carbon controlled the stereochemistry of the Luche reduction, but it did not affect the stereochemical outcome of the rearrangement, which consistently gave the (Z)-alkene. The epimerized by-product, (2S,5S)-10, resulting from the work-up after Na/NH3 debenzylation of (2S,5R)-9, was carried on to the (2S,5S)-1 isomer. Compound (2S,5S)-10 was resynthesized from the Luche reduction by-product, (2R,3R)-3, and the stereochemistry was confirmed by comparison of the optical rotations. The IC50 values for (2R,5S)-1, (2S,5R)-1 and (2S,5S)-1 Pin1 inhibition were: 52, 85, and 140 μM, respectively.