Total synthesis of the ristocetin aglycon
Total synthesis of the ristocetin aglycon
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DOI：
10.1021/ja039795a
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发表时间：
2004-04-07
影响因子：
15
通讯作者：
Boger, DL
中科院分区：
文献类型：
--
作者：
Crowley, BM;Mori, Y;Boger, DL
采用模块化和高度收敛的策略，第一次全合成的ristoclavidoglycon。有效的12步ABCD环系统3从其氨基酸亚基的合成（总共12%）依次以分子内芳族亲核取代反应为特征，用于形成二芳基醚和闭合16元CD环系统（65%），分别是非对映选择性的，（三：1.86%）Suzuki偶联，用于安装AB联芳基键，阻转异构体的立体化学可在其上进一步热调节，和有效的大环内酰胺化（51%），用于闭合12元AB环系统。采用邻氟硝基芳族化合物的室温分子间SNAr反应形成FG二芳基醚（69%）和关键的大环内酰胺化（92%）形成酰胺连接残基1和2，实施14元EFG环系统4的类似有效的13步（14%总）合成。将两个关键片段3和4偶联，并通过二芳基醚形成闭合剩余的16元DE环系统，以提供瑞斯托烷四环系统（15步，总共8%），该系统获得异常容易（25 ℃，8小时，DMF，大于或等于95%）和非对映选择性（大于或等于15：1）的芳香亲核取代反应，该反应受益于底物预组织。
The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular SNAr reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degreesC, 8 h, DMF, greater than or equal to95%) and diastereoselective (greater than or equal to15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.