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Mechanistic study of the retro-aza-Michael reaction in saccharothriolide L: identification of 2-amino-4-methylphenol as an effective protecting tool for the Michael acceptor


Saccharothriolide L (1), a derivative of saccharothriolides (STLs) produced by the rare actinomycete Saccharotrix sp. A1506, was synthesized through the precursor-directed in situ synthesis (PDSS) method. The structure of 1 was determined by 1D and 2D NMR and HR-ESI-MS data analyses. A comparison of the rate of the retro-aza-Michael reaction between saccharothriolide L (1) and saccharothriolide B (2) indicated that the 2-amino-4-methylphenol group in 1 might be an effective masking tool for highly reactive, bioactive α, β-unsaturated carbonyl compounds.

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We thank MicroBioPharm Japan Co. Ltd. for providing the strain of Saccharothrix sp. A1506. This work was supported in part by the Chugai Foundation for Innovative Drug Discovery Science: C-FINDs (2023-CF-01 to HK), the National Natural Science Foundation of China (82104025 to SL and 22377042 to DM), the Senior Talent Foundation of Jiangsu University (5501290012 to SL and 5501290011 to DM), the Jiangsu Provincial Double-Innovation Doctor Program (JSSCBS20221203 to SL and JSSCBS20221208 to DM), a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (grant numbers, 17H06401, 19H02840, 22H04901, 23H04882, and 24H00493, all awarded to HK), and the Platform Project for Supporting Drug Discovery and Life Science Research from the Japan Agency for Medical Research and Development (AMED), Japan (HK).

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Correspondence to Hideaki Kakeya.

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Lu, S., Ren, L., Mao, D. et al. Mechanistic study of the retro-aza-Michael reaction in saccharothriolide L: identification of 2-amino-4-methylphenol as an effective protecting tool for the Michael acceptor. J Antibiot (2024).

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