UCLA

We have charted a symmetry-based approach to complex, dimeric members of the pyrrole–imidazole family of alkaloids; palau'amine, axinellamines, massadines and ageliferin. New methods to prepare and manipulate bis-guanidine containing intermediates in this context are discussed. These efforts culminated in the synthesis of a partially halogenated variant of the complete (±)-axinellamine A ring system and the total synthesis of (±)-ageliferin from a common spirocyclopentane intermediate. A novel N-amidinyliminium ion rearrangement was examined for the requisite ring-expansion to provide the 2-aminotetrahydrobenzimidazole core of ageliferin directly. This method was applied to epimeric intermediates to obtain structurally novel tetracycles coined ‘iso’axinellamines.

We proposed access to (±)-axinellamine A via controlled oxidation and subsequent ring-contraction of (±)-ageliferin. This led us to examine oxidative methods for the transformation of 2-aminotetrahydrobenzimidazoles. Progress toward the synthesis of (−)-ageliferin via the oxidative desymmetrization of symmetric 2-aminotetrahydrobenzimidazole intermediates is discussed. Additionally, we report synthetic access to functionalized 3,3'-bipyrrolidines, coined ‘dispacamide dimer precursors’, for the synthesis of complex pyrrole−imidazole dimers. The dimeric framework was obtained by a diastereoselective, nickel-catalyzed reductive homocoupling of an unactivated secondary bromide derived from trans-4-hydroxy-L-proline. Dimeric precursors were desymmetrized by an auto-oxidative process. The method involves a cascading sequence of indiscrete oxidation and guanidine incorporation events followed by desymmetrization.