The Stereocontrolled Total Synthesis of Altohyrtin A/Spongistatin 1: Fragment Couplings, Completion of the Synthesis, Analogue Generation and Biological Evaluation
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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.
Organic & Biomolecular Chemistry