Total syntheses of (+)-P-3A, epi-(-)-P-3A, and (-)-desacetamido P-3A

Article abstract of DOI:10.1021/ja00080a010

Full details of the first total syntheses of (+)-P-3A (1), epi-(-)-P-3A (2), and (-)-desacetamido P-3A (3) are disclosed. Key strategic elements of the approach include the implementation of an inverse electron demand [4 + 2] cycloaddition reaction of 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine with in situ generated 1,1-diaminoethene for one-step preparation of an appropriately functionalized pyrimidine core and the subsequent use of a diastereoselective N-acyloxazolidinone enolate-imine addition reaction for stereocontrolled introduction of the pyrimidine C2-acetamido side chain. The demonstration and comparison of the functional cleavage of duplex DNA by Fe(II)-1-3 are described. The Fe(II) complex of (+)-P-3A proved to be only 0.8-0.5 times less effective than Fe(II)-deglycobleomycin A₂ at producing cleavage of duplex DNA. Like Fe(II)-bleomycin A₂ or deglycobleomycin A₂, Fe(II)-1-3 produced both single- and double-strand cleavage, although with a decreased propensity for double-stranded cleavage. Unlike bleomycin A₂ or deglycobleomycin A₂, Fe(II)-1-3 or Fe(III)-1-3 were found to cleave duplex DNA with no discernable sequence selectivity, indicating that the metal chelation subunit alone may be insufficient for observation of the characteristic bleomycin A₂ DNA cleavage selectivity. In addition, Fe(II)-1 proved to be 3-5 times more efficient than Fe(II)-2 and Fe(II)-3 at producing DNA cleavage, indicating that the pyrimidine C2-acetamido side chain significantly affects cleavage efficiency although it is not intimately involved in the metal chelation.