2,2′-Dihydroxy-3,3′-dimethoxy-5,5′-dimethyl-6,6′-dibromo-1,1′-biphenyl: preparation, resolution, structure and biological activity

The preparation and resolution of the titled conformationally stable biphenyl 1 has been performed in high chemical yield starting from creosol 2. Enantiopure biphenyls (aR)-(+)-1 and (aS)-(−)-1 were obtained by the corresponding menthylcarbonate diastereomer and successive reduction. The absolute configuration and specific rotation were correlated by X-ray analysis of the crystal structure of diastereopure menthylcarbonate (aS,1R,1′R,2S,2′S,5R,5′R)-(+)-16. Preliminary biological evaluation of both racemic enantiomers of 1 has been carried out on melanoma cell lines and significant and selective anticancer activity has been observed for the enantiomer (aS)-(−)-1.

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(aR)-(+)-2,2′-Dihydroxy-3,3′-dimethoxy-5,5′-dimethyl-6,6′-dibromo-1,1′-biphenylC16H16Br2O4Ee = 99% [by 1H NMR of the corresponding diastereomer][α]D20=13.1 (c 0.5, CHCl3); [α]36520=+103.0 (c 0.5, CHCl3)Source of chirality: (−)-(1R,2S,5R)-menthyl chloroformate (ee 99%)Absolute configuration: (R)

(aS,1R,1R′,2S,2S′,5R,5R′)-(−)-3,3′-Dimethoxy-5,5′-dimethyl-6,6′-dibromo-[1,1′-biphenyl]-2,2′-diyl-O,O′-bis[5-methyl-2-(1-methylethyl)-cyclohexyl]-carbonic esterC38H52Br2O8De = 99% [by 1H NMR][α]D20=+38.7 (c 1.0,CHCl3)Source of chirality: (−)-(1R,2S,5R)-menthyl chloroformate (ee 99%)Absolute configuration: (aS,1R,1R′,2S,2S′,5R,5R′)

(aR,1R,1R′,2S,2S′,5R,5R′)-(−)-3,3′-Dimethoxy-5,5′-dimethyl-6,6′-dibromo-[1,1′-biphenyl]-2,2′-diyl-O,O′-bis[5-methyl-2-(1-methylethyl)-cyclohexyl]-carbonic esterC38H52Br2O8De = 99% [by 1H NMR][α]D20=-72.9 (c 1.0, CHCl3)Source of chirality: (−)-(1R,2S,5R)-menthyl chloroformate (ee 99%)Absolute configuration: (aR,1R,1R′,2S,2S′,5R,5R′)