Total Synthesis of the Ristocetin Aglycon

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• 作者：Brendan M. Crowley ; Yoshiki Mori ; Casey C. McComas ; Datong Tang ; and Dale L. Boger
• 刊名：Journal of the American Chemical Society
• 出版年：2004
• 出版时间：April 7, 2004
• 年：2004
• 卷：126
• 期：13
• 页码：4310 - 4317
• 全文大小：256K
• 年卷期：v.126,no.13(April 7, 2004)
• ISSN：1520-5126

文摘

The first total synthesis of the ristocetin aglycon is described employing a modular and highlyconvergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its aminoacid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formationof 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 stereochemistrycan be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-memberedAB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system4 was implemented employing a room-temperature intermolecular S_NAr reaction of an o-fluoronitroaromaticfor formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amidelinking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-memberedDE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15steps, 8% overall) enlisting an unusually facile (25 C, 8 h, DMF, 95%) and diastereoselective (15:1)aromatic nucleophilic substitution reaction that benefits from substrate preorganization.