A Modular Synthesis of Annonaceous Acetogenins
journal contributionposted on 2003-02-08, 00:00 authored by James A. Marshall, Arnaud Piettre, Mikell A. Paige, Frederick Valeriote
A synthesis of four Annonaceous acetogenins, asiminocin, asimicin, asimin, and bullanin, by a modular approach from seven fundamental subunits, A−G, is described. The approach employs a central core aldehyde segment, C, to which are appended an aliphatic terminus, A or B, a spacer subunit, D or E, and a butenolide terminus, F or G. Coupling of the A, B, D, and E segments to the core aldehyde unit is effected by highly diastereoselective additions of enantiopure allylic indium or tin reagents. The butenolide termini are attached to the ACD, BCE, or BCD intermediates by means of a Sonogashira coupling. The design of the core, spacer, and termini subunits is such that any of the C30, C10, or C4 natural acetogenins or stereoisomers thereof could be prepared. IC50 values for the four aforementioned acetogenins against H-116 human colon cancer cells were found to be in the 10-3 to 10-4 μM range. The IC90 activities were ca. 10-3 μM for asimicin and asimin but only 0.1−1 μM for bullanin and asiminocin.
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diastereoselective additionsAnnonaceous Acetogeninstin reagentsAnnonaceous acetogeninscolon cancer cellsasiminaliphatic terminusasimicinasiminocinenantiopure allylic indiumIC 50 valuesapproachspacer subunitcore aldehyde segmentbutenolide terminuscore aldehyde unitACDBCEtermini subunitsE segmentsC 4butenolide terminiBCD intermediatesbullaninModular SynthesisIC 90 activities