This report describes a three-component, Ni-catalyzed reductive coupling that enables the convergent synthesis of tertiary benzhydryl amines, which are challenging to access by traditional reductive amination methodologies. The reaction makes use of minium ions generated in situ from the condensation of secondary N-trimethylsilyl amines with benzaldehydes, and these species undergo reaction with several distinct classes of organic electrophiles. The synthetic value of this process is demonstrated by a single-step synthesis of antimigraine drug flunarizine (Sibelium) and high yielding derivatization of paroxetine (Paxil) and metoprolol (Lopressor). Mechanistic investigations support a sequential oxidative addition mechanism rather than a pathway proceeding via a-amino radical formation. Accordingly, application of catalytic conditions to an intramolecular reductive coupling is demonstrated for the synthesis of endo- and exocyclic benzhydryl amines.

The Cu-catalyzed synthesis of skipped 1,4-dienes from allylic acetates and vinyl-Grignard reagents is key to bidirectional modifications of acyclic terpene acetates. As a result, trisubstituted double bond containing subunits can be readily transferred into complex polyketides from inexpensive bulk terpenes.

Fijiolide A is a secondary metabolite isolated from a marine-derived actinomycete and displays inhibitory activity against TNF-α-induced activation of NFκB, an important transcription factor and a potential target for the treatment of different cancers and inflammation related diseases. Fijiolide A is a glycosylated complex paracyclophane, which is structurally closely related to the Bergman-aromatization product of enediyne C-1027. We report an enantioselective synthesis of fijiolide A demonstrating the power of fully intermolecular ruthenium-catalyzed [2 + 2 + 2]-cyclotrimerizations with three different alkynes to assemble the heavily substituted central arene core. The characteristic strained [2.6]paracyclophane structure is accessed by a templated atropselective macroetherification reaction.

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Fijiolide A is a secondary metabolite isolated from a marine-derived actinomycete of the genus Nocardiopsis. It was found to significantly reduce the TNF-α induced activity of the transcription factor NFκB, which is considered a promising target for the treatment of cancer and inflammation-related diseases. We disclose an enantioselective synthesis of fijiolide A enabled by a fully intermolecular, yet regioselective cyclotrimerization of three unsymmetrical alkynes to construct its tetra-substituted arene core. An atropselective macroetherification enables the assembly of the strained [2.6]paracyclophane motif. A late-stage glycosylation of the macrocyclic aglycone at its tertiary alcohol position allowed for the first total synthesis of fijiolide A.