Enantioselective Total Syntheses of Plectosphaeroic Acids B and C

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 is 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, provided a 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.