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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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References

    1. Martin, J. H. ; Shay, A. J. ; Pruess, L. M. ; Porter, J. N. ; Mowat, J. H. ; Bohonos, N. . Paper-chromatographic studies of antibiotics produced by a Streptomyces aureofaciens. Antibiot. Annu. 1954, 1020.
    2. Celmer W. D., Murai K., Rao K. V., Tanner F. W. Jr., Marsh W. S.. The quinocycline complex. I. Isolation and characterization. Antibiot. Annu. 1957;5:484. - PubMed
    3. McBride T. J., English A. R.. The quinocycline complex. II. Biological studies. Antibiot. Annu. 1957;5:493. - PubMed
    4. Cosulich D. B., Mowat J. H., Broschard R. W., Patrick J. B., Meyer W. E.. Partial structure of the antibiotic isoquinocycline B. Tetrahedron Lett. 1963;4:453–458. doi: 10.1016/S0040-4039(01)90655-0. - DOI

    5. Erratum Tetrahedron. Lett. 1964 750

    6. Tulinsky A.. The Structure of Isoquinocycline A. An X-Ray Crystallographic Determination. J. Am. Chem. Soc. 1964;86:5368. doi: 10.1021/ja01077a089. - DOI
    1. Furumai T., Igarashi Y., Higuchi H., Saito N., Oki T.. Kosinostatin, a quinocycline antibiotic with antitumor activity from Micromonospora sp. TP-A0468. J. Antibiot. 2002;55:128. doi: 10.7164/antibiotics.55.128. - DOI - PubMed
    2. Igarashi Y., Higuchi H., Oki T., Furumai T.. NMR analysis of quinocycline antibiotics: structure determination of kosinostatin, an antitumor substance from Micromonospora sp. TP-A0468. J. Antibiot. 2002;55:134. doi: 10.7164/antibiotics.55.134. - DOI - PubMed
    3. El-Naggar M. Y.. Kosinostatin, a major secondary metabolite isolated from the culture filtrate of Streptomyces violaceusniger strain HAL64. J. Microbiol. 2007;45:262. - PubMed
    1. Cordes J., Harms K., Koert U.. Synthesis of the isoquinocycline-pyrrolopyrrole substructure. Org. Lett. 2010;12:3808. doi: 10.1021/ol101500k. - DOI - PubMed
    2. Breuning M. A., Harms K., Koert U.. The imidato-alkenyllithium route for the synthesis of the isoquinocycline-pyrrolopyrrole substructure. Org. Lett. 2011;13:1402. doi: 10.1021/ol200085g. - DOI - PubMed
    3. Dischmann M., Frassetto T., Breuning M. A., Koert U.. Total synthesis of isoquinocyclinone. Chem.Eur. J. 2014;20:11300. doi: 10.1002/chem.201403880. - DOI - PubMed
    4. Kitamura M., Kubo K., Yoshinaga S., Matsuzaki H., Ezaki K., Matsuura T., Matsuura D., Fukuzumi N., Araki K., Narasaki M.. Synthetic study of kosinostatin aglycone: synthesis of BCDE rings using alkoxycarbonylmethylation of diazonaphthoquinone. Tetrahedron Lett. 2014;55:1653. doi: 10.1016/j.tetlet.2014.01.082. - DOI
    5. Kitamura M., Fukuzumi N., Shinagawa M., Araki K., Shimizu Y., Takahashi S., Iwata T., Shimooka H., Okauchi T.. Formal synthesis of isoquinocyclinone using ortho-alkoxycarbonylmethylation of anthranol via diazoquinone. Tetrahedron Lett. 2023;125:154618. doi: 10.1016/j.tetlet.2023.154618. - DOI
    1. König C. M., Harms K., Koert U.. Stereoselective synthesis of methyl 7-dihydro-trioxacarcinoside B. Org. Lett. 2007;9:4777. doi: 10.1021/ol702078t. - DOI - PubMed
    1. Wuts, P. G. Greene’s Protective Groups in Organic Synthesis, 5th Ed.; John Wiley & Sons, 2014.

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