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

Abstract

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 diastereoselectivity.

Key words

amides - DFT calculations - fasicularin - heteroatom–heteroatom bonds - nucleophilic addition - remote stereocontrol - total synthesis

Publikationsverlauf

Eingereicht: 30. Juni 2021

Angenommen nach Revision: 29. Juli 2021

Accepted Manuscript online:
29. Juli 2021

Artikel online veröffentlicht:
17. September 2021

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