ABSTRACT
[structure: see text] The total synthesis of the potent microtubule-stabilizing anticancer agent (-)-laulimalide has been achieved in 27 steps and 2.9% overall yield. Notable features are the use of Jacobsen HDA chemistry for the enantioselective construction of the side chain dihydropyran, a diastereoselective aldol coupling using chiral boron enolate methodology, a Mitsunobu macrolactonization, and a Sharpless AE to introduce the epoxide onto des-epoxy-laulimalide.
Subject(s)
Antineoplastic Agents/chemical synthesis , Paclitaxel/analogs & derivatives , Paclitaxel/chemical synthesis , Taxoids , Antineoplastic Agents/pharmacology , Macrolides , Microtubules/drug effects , Paclitaxel/pharmacology , StereoisomerismABSTRACT
[figure: see text] A stereoselective synthesis of 3, corresponding to the fully functionalized macrocyclic core of the novel microtubule-stabilizing agent, laulimalide, has been completed. Efficient macrolactonization was achieved by a Mitsunobu reaction, installing the sensitive (Z)-enoate, and macrocyclic stereocontrol was then exploited to introduce the methyl group and trans-epoxide.
