Total synthesis of (-)-gambierol
Total synthesis of (-)-gambierol
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DOI：
10.1021/ja028167a
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发表时间：
2002-12-18
影响因子：
15
通讯作者：
Sasaki, M
中科院分区：
文献类型：
--
作者：
Fuwa, H;Kainuma, N;Sasaki, M
海洋多环醚毒素（-）-甘比罗尔（1）的首次全合成已经完成。成功合成的关键特征包括：（1）通过我们开发的B - 烷基铃木 - 宫浦交叉偶联策略，将ABC和EFGH环片段（分别为5和6）汇聚结合，得到八环多醚核心4；（2）利用Pd(PPh₃)₄/CuCl/LiCl促进的施蒂勒偶联在后期引入敏感的三烯侧链。ABC环片段5以线性方式合成（B - AB - ABC），其中A环通过分子内杂迈克尔反应形成，C环通过羟基环氧化物7的6 - 内型环化构建。还描述了一种改进的合成EFGH环片段6的方法，其中将SmI₂诱导的还原环化方法应用于F环和H环的立体选择性构建，以显著的总效率得到6。5的立体选择性硼氢化以及随后与6的铃木 - 宫浦偶联以高产率提供了内环烯醇醚45，其随后被转化为八环多醚核心4。仔细选择全局脱保护阶段是全合成成功的关键因素。H环的官能化和全局脱硅基化得到（Z）- 乙烯基溴化物2。最后，在科里的Pd(PPh₃)₄/CuCl/LiCl促进的施蒂勒条件下，2与（Z）- 乙烯基锡烷3的交叉偶联完成了（-）- 甘比罗尔（1）的全合成。
The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh3)(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B - AB - ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which Sml(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh3)(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).