Total synthesis of bleomycin A2 and related agents. 2. Synthesis of (-)-pyrimidoblamic acid, epi-(+)pyrimidoblamic acid, (+)-desacetamidopyrimidoblamic acid, and (-)-descarboxamidopyrimidoblamic acid

Article abstract of DOI:10.1021/ja00092a012

Full details of concise syntheses of (-)-pyrimidoblamic acid (1), the authentic heterocyclic core of the bleomycin A₂ metal binding domain, as well as the key substructure analogs epi-(+)-pyrimidoblamic acid (2), (+)-desacetamidopyrimidoblamic acid (3), and (-)-descarboxamidopyrimidoblamic acid (4) are described. Key to the approach is the implementation of an inverse electron demand [4+2] cycloaddition reaction of 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine with 1-(dibenzylamino)-1-propyne or in situ generated 1,1-diaminopropene for the one-step preparation of an appropriately functionalized pyrimidine nucleus. The development and subsequent implementation of a diastereoselective imine addition reaction of optically active N-acyloxazolidinone enolates provided a stereocontrolled introduction of the pyrimidoblamic acid C2 acetamido side chain. Chemical studies which unambiguously establish and confirm the absolute configuration of the C2 acetamido side chain are detailed, and their extension to the synthesis of (-)-descarboxamidopyrimidoblamic acid (4) is described.