SYNTHESIS OF NAPHTHOQUINONE ANTIBIOTICS BY INTRAMOLECULAR ALKYNE CYCLOADDITION TO CARBENE-CHROMIUM COMPLEXES

Article abstract of DOI:10.1016/S0040-4020(01)91420-6

The reaction of carbene-chromium complexes with alkynes provides a direct route to naphthoquinone derivatives and is the key step in a new approach to the isochromanone antibiotics exemplified by deoxyfrenolicin (1) and nanaomycin A (2).While the regioselectivity of intermolecular addition of the appropriate unsymmetrical disubstituted alkyne is unfavourable, two successful approaches have been developed.Allylacetylene reacts with methoxy-(o-methoxyphenyl)methylidene-Cr(CO)5 with high regioselectivity.Bromination, lithiation, and reaction with acetaldehyde produced the desired precursor.Alkoxypalladation led to pyran ring formation and introduction of the acetate side chain.Following earlier procedures, nanaomycin A (2) was produced.A more convergent alternative involved intramolecular cycloaddition of an alkyne with the alkylidene-chromium unit.A series of model cyclizations established the tether to hold the alkyne in place for cyclization and allows easy removal at a later stage.Deoxyfrenolicin (1) was produced in a highly convergent and efficient process.