Total Synthesis and Anti-inflammatory Activity of Stemoamide-Type Alkaloids Including Totally Substituted Butenolides and Pyrroles

Yasuki Soda; Yasukazu Sugiyama; Shunsei Sato; Kana Shibuya; Junya Saegusa; Tomoe Matagawa; Sayaka Kawano; Makoto Yoritate; Keisuke Fukaya; Daisuke Urabe; Takeshi Oishi; Kento Mori; Siro Simizu; Noritaka Chida; Takaaki Sato

doi:10.1055/a-1941-8680

Synthesis, Inhaltsverzeichnis

Synthesis 2023; 55(04): 617-636
DOI: 10.1055/a-1941-8680

paper

Total Synthesis and Anti-inflammatory Activity of Stemoamide-Type Alkaloids Including Totally Substituted Butenolides and Pyrroles

Yasuki Soda

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

,

Yasukazu Sugiyama

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

,

Shunsei Sato

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

,

Kana Shibuya

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

,

Junya Saegusa

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

,

Tomoe Matagawa

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

,

Sayaka Kawano

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

,

Makoto Yoritate

^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

,

Daisuke Urabe

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

,

Takeshi Oishi

^cSchool of Medicine, Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan

,

Kento Mori

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

,

Siro Simizu

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

Totally substituted butenolide including two tetrasubstituted olefins is a distinct structural motif seen in Stemona alkaloids, but efficient methods for its synthesis are not well developed. As an ongoing program aimed at the collective total synthesis of the stemoamide group, we report a stereodivergent method to give either (E)- or (Z)-totally substituted butenolide from the same intermediate. While AgOTf-mediated elimination via an E1-type mechanism results in the formation of the kinetic (Z)-tetrasubstituted olefin, subsequent TfOH-mediated isomerization gives the thermodynamic (E)-tetrasubstituted olefin. The pyrrole ring is another important structure found in Stemona alkaloids. The direct oxidation of pyrrolidine rings with MnO₂ and careful purification gives the pyrrole groups without isomerization of the stereocenter in the lactone group. These two methods enabled us to synthesize a series of stemoamide-type alkaloids including tricyclic, tetracyclic, and pentacyclic frameworks. The anti-inflammatory activities by inhibition of iNOS expression in macrophage cell line RAW264.7 indicate that the most potent anti-inflammatory compounds without cytotoxicity are protostemonines, which consist of pentacyclic frameworks including the totally substituted butenolide.

Key words

amides - anti-inflammatory agents - butenolides - DFT calculations - iNOS - pyrroles - Stemona alkaloids - total synthesis

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Referenzen

References
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Zusatzmaterial

Supporting Information