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Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine A, and (+)-iso-Pestalazine A. Structure Revision of (+)-Pestalazine A

Loach, Richard P., Fenton, Owen S., Movassaghi, Mohammad
Journal of the American Chemical Society 2016 v.138 no.3 pp. 1057-1064
alkaloids, chemical bonding, diketopiperazines, enantiomers
The concise, enantioselective total syntheses of (+)-asperazine (1), (+)-iso-pestalazine A (2), and (+)-pestalazine A (3) have been achieved by the development of a late-stage C3–C8′ Friedel–Crafts union of polycyclic diketopiperazines. Our modular strategy enables the union of complex polycyclic diketopiperazines in virtually their final forms, thus providing rapid and highly convergent assembly at the challenging quaternary stereocenter of these dimeric alkaloids. The significance of this carbon–carbon bond formation can be gauged by the manifold constraints that were efficiently overcome, namely the substantial steric crowding at both reactive sites, the nucleophilic addition of C8′ over N1′ to the C3 carbocation, and the multitude of reactivity posed by the use of complex diketopiperazine fragments in the coupling event. The success of the indoline π-nucleophile that evolved through our studies is notable given the paucity of competing reaction pathways observed in the presence of the highly reactive C3 carbocation generated. This first total synthesis of (+)-pestalazine A also allowed us to revise the molecular structure for this natural alkaloid.