Development of Chiral N-Alkoxyamide Strategy and Application to 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 to an amide nitrogen changes the original reactivity of the amide, enabling two key transformations: aza-spirocyclization and the reductive Strecker reaction. In the aza-spirocyclization, DFT calculations indicate that pyramidalization of the alkoxyamide nitrogen is crucial to control the reactivity. 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 diastereoselectivity.