TOTAL SYNTHESES OF (+)-P-3A, EPI-(-)-P-3A, AND (-)-DESACETAMIDO P-3A

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 pyrimdine 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)-l-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.