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

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.