Tandem Thio-Michael Addition/Remote Lactone Activation of 5-Hydroxymethylfurfural-Derived δ-Lactone-Fused Cyclopentenones

Funding Information: We thank the Fundação para a Ciência e a Tecnologia (SFRH/BD/120829/2016, SFRH/BD/148211/2019, UIDB/04138/2020, UIDP/04138/2020, PTDC/QUI‐QOR/32008/2017 and GHTM‐UID/04413/2020). The project leading to this application has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 951996. J. A. S. C. thanks the Fundação para a Ciência e a Tecnologia (FCT) for Scientific Employment Stimulus 2020/02383/CEECIND. Publisher Copyright: © 2022 The Authors. ChemSusChem published by Wiley-VCH GmbH.The creation of structurally diverse chemical entities from fairly simple biorefinery products remains a challenge. In this work 5-hydroxymethylfurfural (HMF) was identified as a key synthon for preparing highly complex cyclopentenones (CP) via tandem 1,4-addition/elimination/remote lactone activation to external O- and N-nucleophiles in δ-lactone-fused-CPs hotspots. This scaffold was also reactive enough to be incorporated into model cysteine-peptides in low concentrations, paving the way to a potential translation generating complexity in the synthesis of small peptides. The new enones also exhibited activity against intraerythrocytic Plasmodium falciparum (IC50=1.32 μm).publishersversionpublishe