The Laulimalide Family: Total Synthesis and Biological Evaluation of Neolaulimalide, Isolaulimalide, Laulimalide and a Nonnatural Analogue

Abstract

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.

Formal Synthesis of Dictyostatin and Synthesis of Two Dictyostatin Analogues

“…Although the acetylide condensation/stereoselective reduction sequence of reactions to chemoselectively install a Z double bond appears to be challenging, Mulzer et al. were recently able to apply this sequence of reactions successfully in their synthesis of laulimalide and two synthetic analogues 14…”

Modernization of traditional Chinese medicine

“…From the sponge Fasciospongia rimosa, a third isomer named neolaulimalide as well as laulimalide and isolaulimalide were isolated in 1996. Further studies led to the isolation of six additional fijianolides (D -I) from Cacospongia mycofijiensis [70]. Laulimalides are microtubule stabilizers.…”

The Medicinal Potential of Promising Marine Macrolides with Anticancer Activity

“…[47] In 1996, the structure of laulimalide and its absolute configuration was confirmed by Higa and co-workers in X-ray diffraction studies. [46,49] [50] In addition, from cytotoxicity tests with laulimalide and isolaulimalide, laulimalide shows significantly more potent activity against the KB cell line (5 ng mL À1 ) than isolaulimalide (> 200 ng mL À1 ). Furthermore, laulimalide contains a trans-disubstituted epoxide at the C16 and C17 positions and a 2,3-(Z)-enoate.…”

“…[50] Because acid lability is identified as a major drawback in developing laulimalide as an anticancer drug, [55] the equally active isomer neolaulimalide, with improved stability, should be considered a promising alternative lead compound. [50] Because acid lability is identified as a major drawback in developing laulimalide as an anticancer drug, [55] the equally active isomer neolaulimalide, with improved stability, should be considered a promising alternative lead compound.…”

“…[50] Because acid lability is identified as a major drawback in developing laulimalide as an anticancer drug, [55] the equally active isomer neolaulimalide, with improved stability, should be considered a promising alternative lead compound. [50,53] Recently, the total synthesis of its congeners isolaulimalide and neolaulimalide have been reported as well. Most scientists therefore decided to develop the total synthesis of laulimalide instead of neolaulimalide.…”