Development of a Chiral N-Alkoxyamide Strategy and Application to the Asymmetric Total Synthesis of Fasicularin

The asymmetric total synthesis of fasicularin by a chiral N-alkoxyamide strategy is reported. Incorporation of the chiral alkoxy group onto an amide nitrogen changes the original reactivity of the amide, enabling two key transformations: aza-spirocyclization and the reductive Strecker reaction. DFT calculations indicate that pyramidalization of the N-alkoxyamide nitrogen is crucial to produce a cyclic hemiaminal in equilibrium, which undergoes aza-spirocyclization. The chiral alkoxy group is also used as a stereocontrol element to establish two consecutive stereocenters. The iridium-catalyzed reductive Strecker reaction of the N-alkoxylactam provides the aminonitrile with high diaste-reoselectivity.

Automated summary

The asymmetric total synthesis of fasicularin was achieved using a chiral N-alkoxyamide strategy, which changed the reactivity of the amide by incorporating a chiral alkoxy group onto an amide nitrogen. DFT calculations highlighted the importance of pyramidalization of the N-alkoxyamide nitrogen for the aza-spirocyclization reaction. The chiral alkoxy group was also utilized for stereocontrol to establish consecutive stereocenters with high diaste-reoselectivity in the iridium-catalyzed reductive Strecker reaction.