The laulimalide family: total synthesis and biological evaluation of neolaulimalide, isolaulimalide, laulimalide and a nonnatural analogue.
We herein describe in full detail the first total synthesis of the antitumor agents neolaulimalide and isolaulimalide as well as a highly efficient route to laulimalide. A Kulinkovich reaction followed by a cyclopropyl-allyl rearrangement is used to install the exo-methylene group. The C(2)-C(16) aldehyde fragment is coupled with the C(17)-C(28) sulfone fragments by a highly (E)-selective Julia-Lythgoe-Kocienski olefination to deliver the key intermediates of all three syntheses. Various conditions for the Yamaguchi macrolactonization are applied to close the individual macrocycles. Finally a carefully elaborated endgame was developed to solve the problem of acyl migration in the case of neolaulimalide. All compounds were tested against several cell lines. The cytotoxicity of neolaulimalide could be confirmed for the first time since its original isolation and it could be shown that it induces tubulin polymerization as efficiently as laulimalide.
Gollner
Andreas
A
University of Vienna, Institute of Organic Chemistry, Währingerstrasse 38, 1090 Vienna, Austria. andreas.gollner@univie.ac.at
Altmann
Karl-Heinz
KH
Gertsch
Jürg
J
Mulzer
Johann
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001688:Biological Products; D002855:Chromatography, Thin Layer; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism; D043823:Taxoids / Q000138:chemical synthesis* / Q000494:pharmacology; D050257:Tubulin Modulators / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001688:Biological Products; D018942:Macrolides; D043823:Taxoids; D050257:Tubulin Modulators; C117306:isolaulimalide; C117305:laulimalide; C533382:neolaulimalide