Chiral δ-iodo-γ-lactones derived from cuminaldehyde, 2,5-dimethylbenzaldehyde and piperonal: chemoenzymatic synthesis and antiproliferative activity

Abstract Six enantiomeric pairs of β-aryl-δ-iodo-γ-lactones 8a – c , 9a – c derived from cuminaldehyde, 2,5-dimethylbenzaldehyde and piperonal were synthesized with high enantiomeric purities (ee 93–99%) from enantiomerically enriched allyl alcohols 3a – c . The key step in the synthesis of lactones 8a and 9a was the kinetic resolution of racemic ( E )-4-(4′-isopropylphenyl)but-3-en-2-ol 3a by a lipase-catalysed transesterification. Among the five tested enzymes, the most effective and enantioselective was lipase B from Candida antarctica and after 2 h (−)-( S )-alcohol 3a and (+)-( R )-propionate 5 were obtained with ee’s ⩾99%. The transfer of chirality from alcohols ( S )- 3a – c and ( R )- 3a – c to γ,δ-unsaturated esters ( S )- 6a – c and ( R )- 6a – c via a stereoselective Johnson–Claisen rearrangement followed by hydrolysis and iodolactonization afforded the final lactones 8a – c and 9a – c . The configurations of their stereogenic centres were assigned based on crystallographic analysis and/or the iodolactonization mechanism. In 42 of 48 tests, the synthesized lactones showed antiproliferative activity against four selected cancer lines (Jurkat, D17, GL-1, CLBL-1). The trans -stereoisomers were more active than the cis -stereoisomers and the highest activity was found for lactone (−)- trans -(4 S ,5 R ,6 S )- 9c with a 1,3-benzodioxole substituent and both enantiomers of the trans -lactone with a 2,5-dimethylphenyl substituent: (+)- 9b and (−)- 9b . Among the trans -lactones, those with a (4 S ,5 R ,6 S )-configuration exhibited higher activity than their enantiomers and the most significant difference was observed for the enantiomers of the trans -lactone with a 1,3-benzodioxole substituent 9c (IC 50  = 5.29 and 5.08 vs 36.47 and 33.77 for Jurkat and GL-1 cancer lines respectively).