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|All Authors / Contributors:||
Michaël De Paolis; Jieping Zhu; Université Paris-Sud.
|Description:||283 p. : ill. ; 30 cm.|
|Responsibility:||Michaël de Paolis ; sous la dir. de Jieping Zhu.|
The ecteinascidins, a family of tetrahydroisoquinoline alkaloids isolated from the Carribean tunicate Ecteinascidia turbinate, possess potent cytotoxic activity against a variety of tumor cell lines in vitro and against several rodent tumors and human tumor xenografts in vivo. One of its members, the ecteinascidine 743 is currently in phase II/III clinical trials as an anticancer agent. The potent antitumor activities in conjunction with the molecular - complexity and the lack of availability have made Et 743 an attractive synthetic target. In this context, we have been investigated a short and convergent approach to the total synthesis of Et 743. We have developed an efficient route to the central tetrahydroisoquinoline containing a 1,4-bridged 10-membered macrolactone by using phenolic aldol reaction, subsequent Pictet-Spengler cyclization under newly developed conditions. The right fragment of Et 743 derived of L-DOPA was prepared by an asymmetric alkylation using cinchonidium salts as a chiral phase transfert catalyst. The coupling between the two fragments was made by a modified Strecker reaction and after few steps including acid initiated macrocyclization on benzylic position, an advanced intermediate of Et 743 is obtained. N-carbamate-assisted stereoselective synthesis of chiral vicinal amino sulfides is also described.