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Automated solution-phase multiplicative synthesis of complex glycans up to a 1,080-mer

Nature Synthesis volume 1, pages 854–863 (2022)Cite this article

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Abstract

Carbohydrates play essential roles in nature, such as in cell–cell communication, cell growth and immunoresponse. However, the synthesis of structurally well-defined carbohydrates, especially large-sized glycans, is a challenging task. Here we report an automated solution-phase multiplicative synthesis of complex glycans enabled by preactivation-based, multicomponent, one-pot glycosylation and continuous multiplying amplification. This was achieved by making a dual-mode automated solution-phase glycan synthesizer. Using this synthesizer, a library of oligosaccharides covering various glycoforms and glycosidic linkages was assembled rapidly, either in a general promoter-activation mode or in a light-induced-activation mode. The automated synthesis of a fully protected fondaparinux pentasaccharide (an anticoagulant) was realized on the gram scale. Furthermore, automated ten-component tandem reactions were performed, allowing the assembly of arabinans up to a 1,080-mer using this automated multiplicative synthesis strategy.

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Fig. 1: Automated glycan synthesis by a preactivation-based, one-pot, multicomponent and continuous multiplicative synthesis strategy.
Fig. 2: The solution-phase synthesizer.
Fig. 3: Automated synthesis of bioactive oligosaccharides in general activation mode.
Fig. 4: Automated synthesis of bioactive oligosaccharides in light-induced activation mode.
Fig. 5: Gram-scale synthesis of a protected fondaparinux pentasaccharide.
Fig. 6: Automated multicomponent synthesis of arabinans.
Fig. 7: Automated multiplicative synthesis of linear 1,080-mer polyarabinosides (1 × 6 × 5 × 4 × 3 × 3 = 1,080) from monosaccharide building blocks.

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The data reported in this paper are available in the main text or the Supplementary Information.

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Acknowledgements

We thank R. Ma, J. Dong, Y. Yin, Y. Xu, L. Yu and L. Chen at WuXi AppTec Co., Ltd. for their help in making the synthesizer. We thank S. Song, Q. Li and F. Liu at Peking University for their help in making the synthesizer and the NMR spectroscopy measurements. This work was financially supported by grants from the National Key Research and Development Program of China (2018YFA0507602), the National Natural Science Foundation of China (21738001, 81821004) and the Beijing Outstanding Young Scientist Program (BJJWZYJH01201910001001).

Author information

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing, China

    Wenlong Yao, De-Cai Xiong, Feifei Li, Bo-Han Li, Xianjin Qin, Li-Na Wang, Wan-Ying Xue, Nengfu Yu, Hanyu Zhang, Xia Wu, Miao Liu & Xin-Shan Ye

  2. WuXi AppTec (Tianjin) Co., Ltd., Tianjin, China

    Yun Yang, Chunmei Geng & Zisen Cong

Authors
  1. Wenlong Yao
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  2. De-Cai Xiong
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Contributions

X.-S.Y. conceived the research. W.Y., D.-C.X. and X.-S.Y. designed the experiments. W.Y. assembled the synthesizer and performed most of the synthetic experiments. Y.Y., C.G. and Z.C. assembled the synthesizer. F.L., B.-H.L., X.Q., L.-N.W., W.-Y.X., N.Y., H.Z., X.W. and M.L. synthesized monosaccharide and disaccharide building blocks. W.Y., D.-C.X. and X.-S.Y. analysed the data. W.Y. and X.-S.Y. wrote the manuscript. X.-S.Y. supervised the project.

Corresponding author

Correspondence to Xin-Shan Ye.

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Competing interests

X.-S.Y., W.Y. and D.-C.X. are applying for Chinese patents filed by Peking University. The other authors declare no competing interests.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary handling editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Experimental details, supplementary sections 1.1–2.5, Figs. 1–21, Schemes 1–30 and Tables 1–4.

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Yao, W., Xiong, DC., Yang, Y. et al. Automated solution-phase multiplicative synthesis of complex glycans up to a 1,080-mer. Nat. Synth 1, 854–863 (2022). https://doi.org/10.1038/s44160-022-00171-9

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