Stereoselective synthesis of 1-methoxyspiroindoline phytoalexins and their amino analogues

The stereoselective synthesis of the spiroindoline phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer were achieved by the bromine-induced spirocyclization of 1-methoxybrassinin using chiral auxiliaries (+)- and (−)-menthol, followed by oxidation of the obtained menthyl ethers. The TFA-catalyzed methanolysis of chiral 1-methoxyspirobrassinol menthyl ethers provided (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and its other three unnatural stereoisomers. The enantiomers of the 2-amino analogues of the indole phytoalexin (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether were prepared by the TFA-catalyzed replacement of the chiral alkoxy group with an amine. The synthesized compounds were tested in vitro on cancer cell lines and examined with enantiopure 2-amino analogues of the indole phytoalexin (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether, which showed in most cases, lower activity than the corresponding racemates.

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(2R,3R)-1-Methoxyspirobrassinol-(1S,2R,5S)-menthyl etherC22H32N2O2S2[α]D25 = −8.9 (c 0.74, CHCl3)>99% eeAbsolute configuration: (2R,3R) (1S,2R,5S)Source of chirality: (1S, 2R, 5S)-(+)-menthol

(2R,3R)-1-Methoxyspirobrassinol methyl etherC13H16N2O2S2[α]D25 = −10.8 (c 0.1, CHCl3)97% eeAbsolute configuration: (2R,3R)Source of chirality: (1S, 2R, 5S)-(+)-menthol

(2R,3R)-1-Methoxy-2-(3,4-dichlorophenylamino)-2′-(methylsulfanyl)spiro{indoline-3,5′-[4′,5′]dihydrothiazole}C18H17Cl2N3OS2[α]D25 = +116.2 (c 0.4, CHCl3);96% eeAbsolute configuration: (2R,3R)Source of chirality: (1S, 2R, 5S)-(+)-menthol

(2R,3R)-1-Methoxy-2-(4-trifluoromethylphenylamino)-2′-(methylsulfanyl)spiro{indoline-3,5′-[4′,5′]dihydrothiazole}C19H18F3N3OS2[α]D25 = +20.2 (c 0.15, CHCl3)99% eeAbsolute configuration: (2R,3R)Source of chirality: (1S, 2R, 5S)-(+)-menthol

(2R,3R)-1-Methoxy-2-(4-methylphenylamino)-2′-(methylsulfanyl)spiro{indoline-3,5′-[4′,5′]dihydrothiazole}C19H21N3OS2[α]D25 = +211.7 (c 0.15, CHCl3)95% eeAbsolute configuration: (2R,3R)Source of chirality: (1S, 2R, 5S)-(+)-menthol

(2R,3R)-1-Methoxy-2-(4-methoxyphenylamino)-2′-(methylsulfanyl)spiro{indoline-3,5′-[4′,5′]dihydrothiazole}C19H21N3O2S2[α]D25 = +226.2 (c 0.1, CHCl3)96% eeAbsolute configuration: (2R,3R)Source of chirality: (1S, 2R, 5S)-(+)-menthol