The antimitotic marine macrolide altohyrtin A/spongistatin 1 has been synthesized 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, I and II, resp., 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 III with the southern hemisphere phosphonium salt IV. Deprotection and subsequent regioselective macrolactonization on a triol seco-acid completed the synthesis of altohyrtin A. Two structural analogs were also prepd. and evaluated as growth inhibitory agents against a range of human tumor 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 biol. activity.