Synergy of Prediction Rule and Total Synthesis in Solving the Stereochemical Puzzle of Valactamides

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Abstract
Natural products with diverse functional groups and stereogenic centers have inspired therapeutics and underpin the modern drug discovery process. Their three-dimensional molecular structures need to be unambiguously determined in order to be realized as clinical candidates or to achieve further activity-guided structural optimization. Although recent advances in spectroscopic methods have made it possible for researchers to determine the structures of microgram samples of complex natural products, there is no universally accepted method for determining the relative and absolute configuration of a naturally occurring compound. We report the determination of the full stereostructure of valactamide A, an eight-stereogenic-center-containing fungal metabolite by the synergy of prediction rule-guided analysis and chemical synthesis. The expedient total synthesis resulted in unambiguous verification of the predicted stereochemistry for valactamide A.
Funding Information
  • Basic and Applied Basic Research Foundation of Guangdong Province (2022A1515110592, 2023A1515012715)
  • Department of Education of Guangdong Province (2021ZDJS097)
  • Japan Society for the Promotion of Science
  • National Natural Science Foundation of China (21901013, 32370069, 22171014)
  • Natural Science Foundation of Guangdong Province (2021A1515010344)
  • 2022 Shenzhen Sustainable Supporting Funds for Colleges and Universities (20220811103834002)
  • Technology & Innovation Bureau of Longgang District (RCTDPT-2019-008)

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