A short and concise asymmetric synthesis of hamigeran B
A short and concise asymmetric synthesis of hamigeran B
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DOI：
10.1002/chem.200400558
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发表时间：
2005-01-21
影响因子：
4.3
通讯作者：
Chen, I
中科院分区：
文献类型：
--
作者：
Trost, BM;Pissot-Soldermann, C;Chen, I
其中hamigerans B是对宿主细胞具有低细胞毒性的有效抗病毒剂的hamigerans的令人感兴趣的生物学性质使得这些看似简单的结构具有挑战性的合成靶标。一种策略，以hamiglitazone B演变，其中三个连续的立体中心最终建立从钯催化的不对称烯丙基烷基化（AAA）。后者涉及不稳定酮烯醇化物的不对称烯丙基化，产率为77%，ee为93%。通过使用该工艺，可以通过四步从2-甲基环戊酮获得（S）-5-烯丙基-2-异丙基-5-甲基-1-三氟甲磺酰氧环戊烯。通过交叉偶联引入芳基单元在分子间进行，但在分子内失败。另一方面，三氟甲磺酸酯的还原性去除允许Heck反应以实现芳环的分子内引入。这种分子结构的不寻常的构象特性是由Heck反应中β-氢消除的区域选择性和建立异丙基碳立体化学的还原的非对映选择性揭示的。成功的路线由2-甲基环戊酮和二甲基苔黑酚的15个步骤组成，说明了基于Pd AAA的路线的效率。
The interesting biological properties of the hamigerans wherein hamigeran B is a potent antiviral agent with low cytotoxicity to host cells make these deceptively simple looking structures challenging synthetic targets. A strategy to hamigeran B evolved wherein the three contiguous stereo-centers are established ultimately from a Pd catalyzed asymmetric allylic alkylation (AAA). The latter involves an asymmetric allylation of a non-stabilized ketone enolate in 77 % yield and 93 % ee. By using this process, (S)-5- allyl-2-isopropyl-5-methyl-1-trifluoromethanesulfonyloxycyclopentene becomes available in four steps from 2-methylcyclopentanone. Introduction of the aryl unit by cross-coupling proceeded intermolecularly but failed intramolecularly. On the other hand, reductive removal of the triflate permitted a Heck reaction to effect intramolecular introduction of the aryl ring. The unusual conformational properties of this molecular architecture are revealed by the regioselectivity of the beta-hydrogen elimination in the Heck reaction and the diastereoselectivity of the reduction establishing the stereochemistry of the carbon bearing the isopropyl group. The successful route consists of 15 steps from 2-methylcyclopentanone and dimethylorcinol illustrating the efficiency of the route based upon the Pd AAA.