Enantioselective total synthesis of the potent anti-HIV agent neotripterifordin. Reassignment of stereochemistry at C(16)
Enantioselective total synthesis of the potent anti-HIV agent neotripterifordin. Reassignment of stereochemistry at C(16)
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DOI：
10.1021/ja972549c
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发表时间：
1997-10-15
影响因子：
15
通讯作者：
Liu, K
中科院分区：
文献类型：
--
作者：
Corey, EJ;Liu, K
中药雷公藤（雷藤科）的提取物具有抗肿瘤、抗炎和免疫抑制活性1,2和许多生物活性化合物，包括抗肿瘤二萜雷公藤甲素和雷公藤二烯醚3和有效的HIV复制抑制剂新雷公藤甲素（EC50 25 nM）。由于其五环拓扑结构、立体化学和功能的复杂性，先前被指定为结构1,5的新雷公藤藿苷也作为一个具有挑战性的合成目标而受到关注。在本文中，我们描述了一个对映选择性全合成的新雷公藤甲素，它决定了结构从1到2的修正。通过对映选择性催化环氧化反应和氧烷引发的阳离子-烯烃聚环反应，合成的新雷公藤甲苷的绝对立体化学性质得以确立。将不饱和酮3与酰基膦46（1.1当量）偶联，在20:1 THF-HMPA下-78℃下反应1 h，然后在23℃下反应5 h，以82%的收率立体特异地合成了z -烯烃5。通过以下步骤，5以85%的产率转化为三烯6:(1)THP（四氢吡喃基）裂解（0.1等量的tosylate吡啶在55℃乙醇中裂解4小时）；(2)丙烯醇（MnO2）在23℃的正己烷中氧化1h；(3) 23℃时THF中Ph3PdCH2的Wittig甲基化；(4)脱硅（Bu4NF， THF, 23℃，4 h）。Katsuki-Sharpless epoxidation8的烯丙基醇单元6(0.09枚(-)酒石酸二乙酯,Ti (Oi-Pr) 4日0.075枚3枚t-BuOOH, 4 A分子筛,以结构,23 C 2 h和12 C 15 h)给相应的(R) - R,β环氧甲醇的94%的收益率96%的ee O-benzylated(1.15枚不,1.1枚的溴化苄,0.1枚n-Bu4NI在四氢呋喃在23 C 6 h)形成手性环氧二烯醚7 94%的收益率。用1.2等量的TiCl4在CH2Cl2 at-94 C中处理10分钟，产生了非常干净和立体选择性的双环
The Chinese medicinal plant Tripterygium wilfordii Hook (Celastraceae) has provided extracts with antitumor, antiinflammatory, and immunosuppressive activities1, 2 and a number of bioactive compounds, including the antitumor diterpenoids triptolide and tripdiolide3 and the potent inhibitor of HIV replication, neotripterifordin (EC50 25 nM). 4, 5 Neotripterifordin, which had previously been assigned structure 1, 5 is also of interest as a challenging target for synthesis because of the combined complexity of pentacyclic topology, stereochemistry, and functionality. In this paper, we describe an enantioselective total synthesis of neotripterifordin which dictates revision of structure from 1 to 2. The absolute stereochemistry of the synthetic neotripterifordin was set in place by a combination of enantioselective catalytic epoxidation and oxirane-initiated cation-olefin polyannulation.Wittig coupling of unsaturated ketone 3 with phosphonium ylide 46 (1.1 equiv) in 20: 1 THF-HMPA at-78 C for 1 h and then at 23 C for 5 h produced the Z-olefin 5 stereospecifically in 82% yield. 7 Conversion of 5 to the triene 6 was accomplished in 85% yield by the following sequence:(1) THP (tetrahydropyranyl) cleavage (0.1 equiv of pyridinium tosylate in ethanol at 55 C for 4 h);(2) oxidation of the allylic alcohol (MnO2 in hexane at 23 C for 1 h);(3) Wittig methylenation (Ph3PdCH2 in THF at 23 C); and (4) desilylation (Bu4NF, THF, 23 C, 4 h). Katsuki-Sharpless epoxidation8 of the allylic alcohol subunit of 6 (0.09 equiv of (-)-diethyl tartrate, 0.075 equiv of Ti (Oi-Pr) 4, 3 equiv of t-BuOOH, 4 Å molecular sieves, CH2Cl2, at-23 C for 2 h and-12 C for 15 h) gave the corresponding (R)-R, β-epoxy carbinol of 96% ee in 94% yield which was O-benzylated (1.15 equiv of NaH, 1.1 equiv of benzyl bromide, 0.1 equiv of n-Bu4NI in THF at 23 C for 6 h) to form the chiral epoxy diene ether 7 in 94% yield. Treatment of 7 with 1.2 equiv of TiCl4 in CH2Cl2 at-94 C for 10 min effected a remarkably clean and stereoselective double-annu-