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

Ryo Minamikawa; Keisuke Fukaya; Akihiro Kobayashi; Yukinori Komiya; Shio Yamamoto; Daisuke Urabe; Noritaka Chida; Takaaki Sato

doi:10.1055/a-1561-7815

Synthesis, Table of Contents

Synthesis 2021; 53(24): 4621-4635
DOI: 10.1055/a-1561-7815

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

Ryo Minamikawa

^aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

,

Keisuke Fukaya

^bBiotechnology Research Center and Department of Biotechnology,Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan

,

Akihiro Kobayashi

^aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

,

Yukinori Komiya

^aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

,

Shio Yamamoto

^aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

,

Daisuke Urabe

^bBiotechnology Research Center and Department of Biotechnology,Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan

,

Noritaka Chida

^aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

,

Takaaki Sato ∗

^aDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

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Abstract

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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

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References

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