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The Laulimalide Family: Total Synthesis and Biological Evaluation of Neolaulimalide, Isolaulimalide, Laulimalide and a Nonnatural Analogue
Author(s) -
Gollner Andreas,
Altmann KarlHeinz,
Gertsch Jürg,
Mulzer Johann
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802605
Subject(s) - computer science
Abstract A sensitive family : The first total synthesis of the antitumor agents neolaulimalide and isolaulimalide as well as a highly efficient route to laulimalide is described. A Kulinkovich reaction followed by a cyclopropyl–allyl rearrangement is used to install the exo ‐methylene group. 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.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.