| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1346535 | Tetrahedron: Asymmetry | 2016 | 11 Pages |
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-(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).
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(−)-(2S,3E)-4-(4′-Isopropylphenyl)but-3-en-2-olC13H18OEe = 99%[α]D20 = −24.0 (c 5.4, CH2Cl2)Source of chirality: enzyme-mediated kinetic resolutionAbsolute configuration: (S)
(+)-(2R,3E)-4-(4′-Isopropylphenyl)but-3-en-2-yl propionateC16H22O2Ee >99%[α]D20 = +109.8 (c 1.6, CH2Cl2)Source of chirality: enzyme-mediated kinetic resolutionAbsolute configuration: (R)
(+)-(3S,4E)-3-(4′-Isopropylphenyl)hex-4-enoic acid ethyl esterC17H24O2Ee = 99%[α]D20 = +8.3 (c 4.0, CH2Cl2)Source of chirality: (−)-(2S,3E)-4-(4′-Isopropylphenyl)but-3-en-2-olAbsolute configuration: (S)
(+)-(3S,4E)-3-(2′,5′-Dimethylphenyl)hex-4-enoic acid ethyl esterC16H22O2Ee = 99%[α]D20 = +22.1 (c 1.2, CH2Cl2)Source of chirality: (−)-(2S,3E)-4-(2′,5′-Dimethylphenyl)but-3-en-2-olAbsolute configuration: (S)
(−)-(3S,4E)-3-(Benzo[d][1′,3′]-dioxol-5′-yl)hex-4-enoic acid ethyl esterC15H18O4Ee = 99%[α]D20 = −2.5 (c 0.7, CH2Cl2)Source of chirality: (−)-(2S,3E)-4-(Benzo[d][1′,3′]dioxol-5′-yl)but-3-en-2-olAbsolute configuration: (S)
(+)-(3S,4E)-3-(4′-Isopropylphenyl)hex-4-enoic acidC15H20O2Ee = 99%[α]D20 = +7.8 (c 1.7, CH2Cl2)Source of chirality: (+)-(3S,4E)-3-(4′-Isopropylphenyl)hex-4-enoic acid ethyl esterAbsolute configuration: (S)
(+)-(3S,4E)-3-(2′,5′-Dimethylphenyl)hex-4-enoic acidC14H18O2Ee = 99%[α]D20 = +23.0 (c 1.5, CH2Cl2)Source of chirality: (+)-(3S,4E)-3-(2′,5′-Dimethylphenyl)hex-4-enoic acid ethyl esterAbsolute configuration: (S)
(−)-(3S,4E)-3-(Benzo[d][1′,3′]-dioxol-5′-yl)hex-4-enoic acidC13H14O4Ee = 99%[α]D20 = −7.4 (c 0.1, CH2Cl2)Source of chirality: (−)-(3S,4E)-3-(Benzo[d][1′,3′]-dioxol-5′-yl)hex-4-enoic acid ethyl esterAbsolute configuration: (S)
(+)-cis-(4R,5R,6S)-5-(1-Iodoethyl)-4-(4′-isopropylphenyl)dihydrofuran-2-oneC15H19IO2Ee = 99%[α]D20 = +1.9 (c 0.8, CH2Cl2)Source of chirality: (+)-(3S,4E)-3-(4′-Isopropylphenyl)hex-4-enoic acidAbsolute configuration: (4R,5R,6S)
(−)-trans-(4R,5S,6R)-5-(1-Iodoethyl)-4-(4′-isopropylphenyl)dihydrofuran-2-oneC15H19IO2Ee = 99%[α]D20 = −8.5 (c 1.7, CH2Cl2)Source of chirality: (+)-(3S,4E)-3-(4′-Isopropylphenyl)hex-4-enoic acidAbsolute configuration: (4R,5S,6R)
(−)-cis-(4R,5R,6S)-5-(1-Iodoethyl)-4-(2′,5′-dimethylphenyl)dihydrofuran-2-oneC14H17IO2Ee >99%[α]D20 = −31.1 (c 0.8, CH2Cl2)Source of chirality: (+)-(3S,4E)-3-(2′,5′-Dimethylphenyl)hex-4-enoic acidAbsolute configuration: (4R,5R,6S)
(+)-trans-(4R,5S,6R)-5-(1-Iodoethyl)-4-(2′,5′-dimethylphenyl)dihydrofuran-2-oneC14H17IO2Ee = 99%[α]D20 = +14.6 (c 0.3, CH2Cl2)Source of chirality: (+)-(3S,4E)-3-(2′,5′-Dimethylphenyl)hex-4-enoic acidAbsolute configuration: (4R,5S,6R)
(−)-cis-(4R,5R,6S)-5-(1-Iodoethyl)-4-(benzo[d][1′,3′]-dioxol-5′-yl)dihydrofuran-2-oneC13H13IO4Ee >99%[α]D20 = −4.8 (c 0.10, CH2Cl2)Source of chirality: (−)-(3S,4E)-3-(Benzo[d][1′,3′]-dioxol-5′-yl)hex-4-enoic acidAbsolute configuration: (4R,5R,6S)
(+)-trans-(4R,5S,6R)-5-(1-Iodoethyl)-4-(benzo[d][1′,3′]-dioxol-5′-yl)dihydrofuran-2-oneC13H13IO4Ee >99%[α]D20 = +7.4 (c 0.2, CH2Cl2)Source of chirality: (−)-(3S,4E)-3-(Benzo[d][1′,3′]-dioxol-5′-yl)hex-4-enoic acidAbsolute configuration: (4R,5S,6R)
