Enantioselective Total Syntheses of Plectosphaeroic Acids B and C

摘要

Evolution of the synthetic strategy that culminated in the first total syntheses of the structurally unique plectosphaeroic acids B (>2) and C (>3) is described. The successful enantioselective route to (+)->2 and (+)->3 proceeds in 6 and 11 steps from the known hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione >39, which in turn are available in enantiomerically pure form by chemical synthesis. The central challenge in this synthesis endeavor was uniting the hexahydro-2H-pyrazinopyrrolo[2,3-b]indole-1,4-dione and cinnabarinic acid fragments of these marine alkaloids. Critical for achieving this successful C–N bond formation was the use of an iodocinnabarinic acid diester in which the amino group was masked with two Boc substituents, a Cu(I) carboxylate complex, and the weak base KOAc. The highly congested C–N bond generated in this coupling, in conjunction with the delicate nature of the densely functionalized coupling partners, provide striking testament to the power of modern copper-mediated amination methods. Two approaches, one stereoselective, for introducing the methylthio substituents of (+)-plectosphaeroic acid B were developed. The epitrisulfide ring of (+)-plectosphaeroic acid C was formed by ring expansion of an epidisulfide precursor.