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Issue 13, 2005
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The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation

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Abstract

The antimitotic marine macrolide altohyrtin A/spongistatin 1 (1) has been synthesised in a highly convergent and stereocontrolled manner, thus contributing to the replenishment of the largely exhausted material from the initial isolation work. Coupling of the AB- and CD-spiroacetal subunits by a stereoselective aldol reaction was achieved by using either a lithium (67 : 33 dr) or boron enolate (90 : 10 dr). A highly (Z)-selective Wittig coupling was used to unite the northern hemisphere aldehyde 2 with the southern hemisphere phosphonium salt 3. Deprotection and subsequent regioselective macrolactonisation on a triol seco-acid completed the synthesis of altohyrtin A. Two structural analogues were also prepared and evaluated as growth inhibitory agents against a range of human tumour cell lines, including Taxol-resistant strains, alongside altohyrtin A and paclitaxel (Taxol), revealing that dehydration in the E-ring is tolerated and results in enhanced cytotoxicity (at the low picomolar level), whereas the presence of the full C44–C51 side-chain appears to be crucial for biological activity.

Graphical abstract: The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation

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Publication details

The article was received on 22 Mar 2005, accepted on 03 May 2005 and first published on 24 May 2005


Article type: Paper
DOI: 10.1039/B504151A
Citation: Org. Biomol. Chem., 2005,3, 2431-2440
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    The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation

    I. Paterson, D. Y.-K. Chen, M. J. Coster, J. L. Aceña, J. Bach and D. J. Wallace, Org. Biomol. Chem., 2005, 3, 2431
    DOI: 10.1039/B504151A

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