A concise total synthesis of isochrysohermidin (5) is detailed based on a novel application of the sym-tetrazine --* 1,2-diazine + pyrrole Diels-Alder strategy. Two consecutive LUMOdio-controlled Diels-Alder reactions of 1,1,4,4tetramethoxy-1,3-butadiene (6) with 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine (7) followed by a double reductive ring contraction reaction of the symmetrical 4,4'-bi-1,2-diazine 8 provided 9 in a two-step reaction sequence that constitutes an effective new and general approach to functionalized 3,3'-bipyrroles. Following an efficient three-step reaction sequence for differentiation of the C2/C2' and CS/CS' methoxycarbonyl groups, a regioselective oxidative decarboxylation reaction of the cyclic endoperoxides derived from singlet oxygen [4 + 21 cycloaddition to each pyrrole of 12 provided d.1-and meso-isochrysohermidin (5). In agreement with expectations, both d,l-and meso-5 proved to be effective interstrand DNA cross-linking agents, and the preliminary characterization of their interaction with duplex DNA is described.Autoxidation of the colorless chromogen hermidin (1) isolated from Mercurialisperennis L.2 sequentially provides the transient blue radical anion cyanohermidin (2),3 hermidin dimer (3),l and chrysohermidin ( 4 ) '~~ and may precede rearrangement to isochrysohermidin (5): a 2-oxo-3-pyrrolinedimer first isolated from Mercurialis leiocarpa and recently shown to be related to 4 through a sodium methoxide-promoted rearrangement" (Scheme I). This latter work also led to the demonstration that both d,l-5,5a a racemate, and meso-Sb are present in the samples derived from natural sources, and the d,l-diastereomer was unambiguously identified in X-ray crystallographic studies.5a Our examination of the unusual structure of 5 containing two symmetrical carbinolamides positioned orthogonally at the end of the 3,3'bis-2-oxo-3-pyrroline skeleton suggested it may represent an ideal candidate for interstrand DNA cross-linking through reversible acetal exchange with duplex DNA nucleophilic sites. This interest, the unique structure of 5 and the current lack of naturally derived material, and the intriguing prospect that 5 may be biogenetically derived from l o 2 addition to an appropriate 3,3'bipyrrole precursor provided the incentive for the studies detailed herein.Herein we provide full details6 of a concise total synthesis of isochrysohermidin (5) based on the implementation of two consecutive heteroaromatic azadiene Diels-Alder reactions' of 1,1,4,4-tetramethoxy-1,3-butadiene with 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine8 (6 + 7 -8) and a subsequent double reductive ring contraction reaction9JO of the 4,4'-bi-1 ,Zdiazine 8 (8 -9) representing a new and general approach to such 3,3'bipyrroles and their derivatives. Consistent with the prospect