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 2h (−)-(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-(4S,5R,6S)-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 (4S,5R,6S)-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 (IC50=5.29 and 5.08 vs 36.47 and 33.77 for Jurkat and GL-1 cancer lines respectively).