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Synthesis 2024; 56(09): 1460-1464
DOI: 10.1055/a-2236-0413
paper

An Improved and Scalable Synthesis of the Potent SREBP Inhibitor KK-052 via [3+2] Cycloaddition

Fumihiro Kawagoe
a   Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
,
Sayuri Mototani
a   Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
,
Yasushi Takemoto
b   Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan
,
Motonari Uesugi
b   Institute for Chemical Research and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan
c   School of Pharmacy, Fudan University, Shanghai 201203, P. R. of China
,
Atsushi Kittaka∗
a   Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
› InstitutsangabenThis work was supported in part by Grants-in-Aid from the Japan Society for the Promotion of Science (No. 22K14688 to F.K. and No. 23K06029 to A.K.).
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Abstract

KK-052 is a novel vitamin-D-based selective sterol regulatory element-binding protein (SREBP) suppressor that lacks vitamin D genomic activity mediated through the vitamin D receptor in both in vitro and in vivo settings. In our initial synthetic effort, KK-052 was produced as one of the structural isomers obtained via the Mitsunobu reaction involving a CD-ring allyl alcohol and 5-phenyl-1H-tetrazole. In this work, we present a refined methodology for enhancing the selective synthesis of KK-052 through a [3+2] cycloaddition between a CD-ring benzimidoyl chloride and sodium azide, a technique that proved amenable to gram-scale production. Additionally, this synthetic method permitted the production of a more potent m-methyl analogue of KK-052.

Key words

SREBP - vitamin D3 - KK-052 - [3+2] cycloaddition

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2236-0413.
  • Supporting Information


Publikationsverlauf

Eingereicht: 04. Dezember 2023

Angenommen nach Revision: 28. Dezember 2023

Accepted Manuscript online:
28. Dezember 2023

Artikel online veröffentlicht:
07. Februar 2024

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