d,l- And meso-isochrysohermidin: Total synthesis and interstrand DNA cross-linking

Article abstract of DOI:10.1021/ja00077a046

A concise total synthesis of isochrysohermidin (5) is detailed based on a novel application of the sym-tetrarine → 1,2-diazine → pyrrole Diels-Alder strategy. Two consecutive LUMO_diene-controIled Diels-Alder reactions of 1,1,4,4-tetramethoxy-l,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 C5/C5′ methoxycarbonyl groups, a regioselective oxidative decarboxylation reaction of the cyclic endoperoxides derived from singlet oxygen [4 + 2] cycloaddition to each pyrrole of 12 provided d,l- and maro-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.