Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization

Longhui Yu; Hiroshige Ogawa; Shangzhao Li; Tsoh Lam Cheung; Wenchao Liu; Dexiu Yan; Yudai Matsuda; Yusuke Kobayashi; Zhihong Guo; Kotaro Ikeda; Trevor A. Hamlin; Ken Yamazaki; Pei Yuan Qian; Hugh Nakamura

doi:10.1002/anie.202414295

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization

Longhui Yu
, Hiroshige Ogawa
, Shangzhao Li
, Tsoh Lam Cheung
, Wenchao Liu
, Dexiu Yan
, Yudai Matsuda
, Yusuke Kobayashi
, Zhihong Guo
, Kotaro Ikeda
, Trevor A. Hamlin
, Ken Yamazaki^*
, Pei Yuan Qian^*
, Hugh Nakamura^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2-bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

Original language	English
Article number	e202414295
Pages (from-to)	1-11
Number of pages	11
Journal	Angewandte Chemie - International Edition
Volume	64
Issue number	2
Early online date	31 Aug 2024
DOIs	https://doi.org/10.1002/anie.202414295
Publication status	Published - 10 Jan 2025

Bibliographical note

Publisher Copyright:
© 2024 Wiley-VCH GmbH.

© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Funding

Financial support for this work was provided by a grant from the RGC of the Hong Kong SAR, China (ECS, HKUST 26302024), and start-up funds from HKUST (Project No. R9820) to H.N.; the National Key Research and Development Program of China (2018YFA0903200), PI Project of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) [2021HJ01, SMSEGL20SC01], UGC and RGC of the Hong Kong SAR government (16100722, C6026-19G−A, and T11-104/22R) to P.Y.Q.; JSPS KAKENHI (grants numbers JP24 K17682) and JP24H01861 (Green Catalysis Science) to K.Y. The computation was performed using Research Center for Computational Science, Okazaki, Japan (Project: 24-IMS−C118 to K.Y.).

Funders	Funder number
Green Catalysis Science	24-IMS−C118
Hong Kong University of Science and Technology	R9820
RGC	HKUST 26302024
National Key Research and Development Program of China	2018YFA0903200
University Grants Committee	T11‐104/22R, 16100722
Japan Society for the Promotion of Science	JP24 K17682, JP24H01861
Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)	2021HJ01, SMSEGL20SC01

Keywords

chemoenzymatic synthesis
dimerization
natural product synthesis
Zr catalysis

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Yu, L., Ogawa, H., Li, S., Lam Cheung, T., Liu, W., Yan, D., Matsuda, Y., Kobayashi, Y., Guo, Z., Ikeda, K., Hamlin, T. A., Yamazaki, K., Qian, P. Y., & Nakamura, H. (2025). Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization. Angewandte Chemie - International Edition, 64(2), 1-11. Article e202414295. https://doi.org/10.1002/anie.202414295

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abstract = "A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2-bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.",

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author = "Longhui Yu and Hiroshige Ogawa and Shangzhao Li and \{Lam Cheung\}, Tsoh and Wenchao Liu and Dexiu Yan and Yudai Matsuda and Yusuke Kobayashi and Zhihong Guo and Kotaro Ikeda and Hamlin, \{Trevor A.\} and Ken Yamazaki and Qian, \{Pei Yuan\} and Hugh Nakamura",

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AU - Yu, Longhui

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AU - Liu, Wenchao

AU - Yan, Dexiu

AU - Matsuda, Yudai

AU - Kobayashi, Yusuke

AU - Guo, Zhihong

AU - Ikeda, Kotaro

AU - Hamlin, Trevor A.

AU - Yamazaki, Ken

AU - Qian, Pei Yuan

AU - Nakamura, Hugh

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N2 - A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2-bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

AB - A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2-bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

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Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization

Abstract

Bibliographical note

Funding

Keywords

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