Abstract
This is a full account of our synthetic endeavor on the total synthesis of bis-anthraquinone
antibiotic BE-43472B, an unusual octacyclic aromatic polyketide with a bis-anthraquinone
scaffold. Three key steps enabled a facile access to the anthraquinone unit corresponding
to the ABCF rings; (1) cyclo-condensation or -addition of benzonitrile oxides with
cyclic enone derivatives, (2) benzoin cyclization for the stereoselective ring fusion
with an angular hydroxy group, and (3) pinacol rearrangement for stereoselective installation
of the angular aryl group. Other keys for the success include, (4) diastereoselective
methylation of a lactol derivative, and (5) late-stage installation of the C3 hydroxy
group through stereoselective oxirane ring formation via halohydrin derivatives. Whereas
oxidation of the double bond in the enone with an adjacent 1,3-diketone moiety failed,
the projected oxidation was achieved with the alkene keeping the isoxazole moiety
intact as a 1,3-diketone equivalent. In the racemic total synthesis, X-ray crystal
structure analysis of the target was achieved, proving the three-dimensional architecture
for the first time. The asymmetric total synthesis was also achieved by exploiting
a cycloadduct of the nitrile oxide and the enantiomerically pure cyclohexenone, which
was convertible to the common intermediate via dehydrogenation followed by alkoxycarbonylation.
Key words
antibiotics - bis-anthraquinone - isoxazole - natural products - total synthesis
