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

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 (IC(50)=1.32 μm).