The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: fragment couplings, completion of the synthesis, analogue generation and biological evaluation.
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.
University Chemical Laboratory, Lensfield Road, University of Cambridge, Cambridge, UKCB2 1EW. ip100@cam.ac.uk
Ian
I
Paterson
David Y-K
DY
Chen
Mark J
MJ
Coster
José L
JL
Aceña
Jordi
J
Bach
Debra J
DJ
Wallace
D000080:Acetals / Q000138:chemical synthesis; D000438:Alcohols / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001895:Boron / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008094:Lithium / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D000095702:Polyether Toxins
D000080:Acetals; D000438:Alcohols; D000970:Antineoplastic Agents; D001895:Boron; D008094:Lithium; D018942:Macrolides; D011714:Pyrans; D013141:Spiro Compounds; C083856:spongistatin 1; D000095702:Polyether Toxins