Chiral Brønsted acid-catalyzed alkylation of C3-substituted indoles with o-hydroxybenzyl alcohols: highly enantioselective synthesis of diarylindol-2-ylmethanes and evaluation on their cytotoxicity

A chiral phosphoric acid-catalyzed Friedel–Crafts alkylation of o-hydroxybenzyl alcohols with 3-alkylindoles has been established, which was used to construct a biologically important diarylindol-2-ylmethane scaffold in high yields and with good enantioselectivities (up to 99% yield, 90:10 er). Moreover, these novel compounds were subjected to tests to determine the in vitro cytotoxicity against carcinoma Hela cells. Nearly all of the tested compounds exhibited strong or moderate cytotoxicity to Hela cells with IC50 values ranging from 6.821 to 28.042 μg/mL.

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(−)-2-((3,6-Dimethyl-1H-indol-2-yl)(phenyl)methyl)phenolC23H21NO[α]D20 = −8.6 (c 0.73, acetone)Source of chirality: the catalyst

(−)-2-((3,4-Dimethyl-1H-indol-2-yl)(phenyl)methyl)phenolC23H21NO[α]D20 = −16.1 (c 0.7, acetone)Source of chirality: the catalyst

(+)-2-((5-Fluoro-3-methyl-1H-indol-2-yl)(phenyl)methyl)phenolC22H18FNO[α]D20 = +20.5 (c 0.728, acetone)Source of chirality: the catalyst

(+)-2-((5-Bromo-3-methyl-1H-indol-2-yl)(phenyl)methyl)phenolC22H18BrNO[α]D20 = +13.6 (c 0.836, acetone)Source of chirality: the catalyst

(−)-2-((6-Fluoro-3-methyl-1H-indol-2-yl)(phenyl)methyl)phenolC22H18FNO[α]D20 = −3.2 (c 0.788, acetone)Source of chirality: the catalyst

(+)-2-((6-Chloro-3-methyl-1H-indol-2-yl)(phenyl)methyl)phenolC22H18ClNO[α]D20 = +27.2 (c 0.754, acetone)Source of chirality: the catalyst

(−)-2-((3,7-Dimethyl-1H-indol-2-yl)(phenyl)methyl)phenolC23H21NO[α]D20 = −2.5 (c 0.798, acetone)Source of chirality: the catalyst

(−)-4-Bromo-2-((3,6-dimethyl-1H-indol-2-yl)(phenyl)methyl)phenolC23H20BrNO[α]D20 = −1.9 (c 0.428, acetone)Source of chirality: the catalyst

(−)-2-((3,6-Dimethyl-1H-indol-2-yl)(phenyl)methyl)-4-methylphenolC24H23NO[α]D20 = −45.0 (c 0.82, acetone)Source of chirality: the catalyst

(−)-4-(tert-Butyl)-2-((3,6-dimethyl-1H-indol-2-yl)(phenyl)methyl)phenolC27H29NO[α]D20 = −64.4 (c 0.832, acetone)Source of chirality: the catalyst

(−)-2-((4-Chlorophenyl)(3,6-dimethyl-1H-indol-2-yl)methyl)phenolC23H20ClNO[α]D20 = −96.6 (c 0.534, acetone)Source of chirality: the catalyst

(+)-2-((3,6-Dimethyl-1H-indol-2-yl)(4-methoxyphenyl)methyl)phenolC24H23NO2[α]D20 = +13.0 (c 0.8, acetone)Source of chirality: the catalyst

(−)-2-((3,6-Dimethyl-1H-indol-2-yl)(m-tolyl)methyl)phenolC24H23NO[α]D20 = −19.8 (c 0.53, acetone)Source of chirality: the catalyst

(+)-2-(Benzo[d][1,3]dioxol-5-yl(3,6-dimethyl-1H-indol-2-yl)methyl)phenolC24H21NO3[α]D20 = +2.4 (c 0.708, acetone)Source of chirality: the catalyst