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. 2025 Jul 4;90(26):9291-9294.
doi: 10.1021/acs.joc.5c00886. Epub 2025 Jun 18.

Synthetic Study of Kosinostatin Aglycon: Synthesis of the ABCDEFG Ring Skeleton

Yutaro Shimizu  1 , Shuhei Takahashi  1 , Takumi Iwata  1 , Hirokazu Shimooka  1 , Tatsuo Okauchi  1 , Mitsuru Kitamura  1
Affiliations

Synthetic Study of Kosinostatin Aglycon: Synthesis of the ABCDEFG Ring Skeleton

Yutaro Shimizu et al. J Org Chem. .

Abstract

A synthetic method for the CDEFG substructure of kosinostatin was developed using the cyclization of the di-para-nosyl 3-(2-hydroxyethyl)pyrrolidin-2-imine derivative. The key to the success of this cyclization was the choice of the para-nosyloxy (p-NsO) group as the leaving group. This selection enabled the cyclization to proceed under mild reaction conditions, leading to the first construction of a kosinostatin-type scaffold. The method was further applied to the synthesis of the ABCDEFG ring of kosinostatin aglycon.

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Figures

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1
Quinocycline/isoquinocycline antibiotics.
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1. Koert’s Synthesis of Isoquinocyclinone (3)
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2. Koert’s Model Study on the Synthesis of CDEFG Rings of Isoquinocyclinone (3)
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3. Construction of Isoquinocycline/Kosinostatin CDEFG Rings from N,O-Dinosyl Compounds 15a and 15b
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Chemical shifts (1H NMR) of vinyl protons for isoquinocyclinone (3) and kosinostatin aglycon 2 (in DMSO-d 6), and 15a, 15b, 16a, and 16b (in CDCl3). NOE for 16b.
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4. Synthesis of ABCDEFG Ring of Kosinostatin
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