Stereoselective synthesis of (3S,4R)- and (3R,4S)-4-(N-substituted-amino)-2,2-dimethyl-6-nitrochroman-3-ols via the microwave assisted regioselective ring opening of epoxides in the presence of neutral alumina

With the aim of discovering new molecules with potassium channel activating properties, we have designed and synthesized derivatives with structural similarity to cromakalim, an important molecule which shows specific affinity toward potassium channels, based on previous structure–activity investigations by applying different C-4 substitutions. This has been accomplished by using a stereoselective Jacobsen epoxidation and microwave assisted regioselective epoxide opening with neutral alumina as the key reactions.

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(3S,4R)-4-(Benzylamino)-2,2-dimethyl-6-nitrochroman-3-olC18H20N2O4[α]D25=+67.7 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-4-(Cyclohexylmethylamino)-2,2-dimethyl-6-nitrochroman-3-olC18H26N2O4[α]D25=+134.5 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-4-(Cyclohexylamino)-2,2-dimethyl-6-nitrochroman-3-olC17H24N2O4[α]D25=+32.3 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-2,2-Dimethyl-6-nitro-4-((tetrahydrofuran-2-yl)methylamino)chroman-3-olC16H22N2O5[α]D25=+121.6 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-4-(Hexylamino)-2,2-dimethyl-6-nitrochroman-3-olC17H26N2O4[α]D25=+101.5 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-2,2-Dimethyl-6-nitro-4-(4-nitrophenylamino) chroman-3-olC17H17N3O6[α]D25=+102.8 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-4-(Dimethylamino)-2,2-dimethyl-6-nitrochroman-3-olC13H18N2O4[α]D25=+55.9 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-2,2-dimethyl-6-nitro-4-(piperidin-1-yl)chroman-3-olC16H22N2O4[α]D25=+145.6 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-4-(4-(4-Methoxyphenyl)piperazin-1-yl)-2,2-dimethyl-6-nitrochroman-3-olC23H27N3O5[α]D25=+167.8(c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidationAbsolute configuration: (3S,4R)

(3S,4R)-2,2-Dimethyl-6-nitro-4-((S)-1a-phenylethyl amino)chroman-3-olC19H22N2O4[α]D25=+51.5 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidation, (S)-PhenylethylamineAbsolute configuration: (3S,4R,1aS)

(3S,4R)-2,2-Dimethyl-6-nitro-4-((R)-1-phenylethyl amino)chroman-3-olC19H22N2O4[α]D25=+91.2 (c 1.0, CH2Cl2)Source of chirality: Jacobsen’s epoxidation, (R)-PhenylethylamineAbsolute configuration: (3S,4R,1aR)