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

• Published in: Organic & biomolecular chemistry Vol. 3; no. 13; p. 2431
• Main Authors: Paterson, Ian, Chen, David Y-K, Coster, Mark J, Aceña, José L, Bach, Jordi, Wallace, Debra J
• Format: Journal Article
• Language: English
• Published: England 07-07-2005
• Subjects: Acetals - chemical synthesis; Alcohols - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Boron - chemistry; Cell Division - drug effects; Drug Resistance, Neoplasm; Humans; Lithium - chemistry; Macrolides - chemical synthesis; Macrolides - pharmacology; Molecular Structure; Pyrans - chemistry; Spiro Compounds - chemical synthesis; Stereoisomerism; Tumor Cells, Cultured
• ISSN: 1477-0520
• DOI: 10.1039/b504151a

The antimitotic marine macrolide altohyrtin A/spongistatin 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 with the southern hemisphere phosphonium salt . 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.