Synthesis of enantiomers of 3-methyl- and 3-phenyl-3,4-dihydro-2H-[1,4]benzothiazines and their 1,1-dioxides via an acylative kinetic resolution protocol

It has been found that acyl chlorides of (S)-naproxen, N-phthaloyl-(S)-leucine, and N-tosyl-(S)-proline are efficient chiral resolving agents for the acylative kinetic resolution of racemic 3-methyl- and 3-phenyl-3,4-dihydro-3-methyl-2H-[1,4]benzothiazines. Based on the experimental results, a preparative protocol comprising the acylative kinetic resolution followed by isolation of a single (major) diastereoisomeric amide and subsequent hydrolysis of amide bond was proposed. Using this approach with various chiral resolving agents, (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine (ee >99%) were obtained. The oxidation of the corresponding diastereoisomers of the amides followed by deacylation led to the (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-dioxide (ee >97%). This method proved to be less suitable for the preparation of the (S)-enantiomer of 3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine (ee up to 93%) and its sulfone (ee 82%) which were both obtained in low yields. The loss of enantioselectivity for (S)-3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine and its sulfone occurred during hydrolysis of the corresponding diastereoisomerically pure amides.

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(3S,2′S)-3,4-Dihydro-3-methyl-4-[2′-(6″-methoxynaphth-2″-yl)propionyl]-2Н-[1,4]benzothiazineC22H23NO2Sde >99.8%[α]D20 = +35.7 (c 1.07, CHCl3)Source of chirality: (S)-NaproxenAbsolute configuration: (3S,2′S)

(3R,2′S)-3,4-Dihydro-3-phenyl-4-[2′-(6″-methoxynaphth-2″-yl)propionyl]-2Н-[1,4]benzothiazineC28H25NO2Sde >99.8%[α]D20 = −298 (c 1.4, CHCl3)Source of chirality: (S)-NaproxenAbsolute configuration: (3R,2′S)

(3S,2′S)-3,4-Dihydro-3-phenyl-4-[2′-(6″-methoxynaphth-2″-yl)propionyl]-2Н-[1,4]benzothiazineC28H25NO2Sde >99.8%[α]D20 = +132 (c 1.0, CHCl3)Source of chirality: (S)-NaproxenAbsolute configuration: (3S,2′S)

(3S,2′S)-3,4-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazineC23H24N2O3Sde >99%[α]D20 = +382 (c 0.94, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (3S,2′S)

(3R,2′S)-3,4-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazineC23H24N2O3Sde 94.6%[α]D20 = −215 (c 0.67, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (3R,2′S)

(3S,2′S)-3,4-Dihydro-3-phenyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazineC28H26N2O3Sde >99%[α]D20 = +476 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (3S,2′S)

(3S)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazineC9H11NSee 99.4%[α]D20 = −79.0 (c 1.2, CHCl3)Source of chirality: (3S,2′S)-2,3-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazineAbsolute configuration: (3S)

(3R)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazineC9H11NSee 99.2%[α]D20 = +78.7 (c 1.2, CHCl3)Source of chirality: 3,4-Dihydro-3-methyl-4-(N′-tosylprolyl)-2H-[1,4]benzothiazineAbsolute configuration: (3R)

(3S)-3,4-Dihydro-3-phenyl-2H-[1,4]benzothiazineC14H13NSee 92.6%[α]D20 = +55.9 (c 1.0, CHCl3)Source of chirality: (3S,2′S)-3,4-Dihydro-3-phenyl-4-[2′-(6″-methoxynaphth-2″-yl)propionyl]-2Н-[1,4]benzothiazineAbsolute configuration: (3S)

(3S,2′S)-3,4-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazine-1,1-dioxideC23H24N2O3S[α]D20 = +415 (c 1.3, CHCl3)Source of chirality: (3S,2′S)-3,4-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazineAbsolute configuration: (3S,2′S)

(3S,2′S)-3,4-Dihydro-3-phenyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazine-1,1-dioxideC28H26N2O5S[α]D20 = +417 (c 0.64, CHCl3)Source of chirality: (3S,2′S)-3,4-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazineAbsolute configuration: (3S,2′S)

(3R,2′S)-3,4-Dihydro-3-methyl-4-(N′-tosylprolyl)-2H-[1,4]benzothiazine-1,1-dioxideC21H24N2O5S2[α]D20 = −294 (c 1.1, CHCl3)Source of chirality: (3R,2′S)-3,4-Dihydro-3-methyl-4-(N′-tosylprolyl)-2H-[1,4]benzothiazineAbsolute configuration: (3R,2′S)

(3S)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-dioxideC9H11NO2See 99%[α]D20 = −177 (c 1.1, CHCl3)Source of chirality: (3S,2′S)-3,4-Dihydro-3-methyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazine-1,1-dioxideAbsolute configuration: (3S)

(3R)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-dioxideC9H11NO2See 97%[α]D20 = +170 (c 1.0, CHCl3)Source of chirality: (3R,2′S)-3,4-Dihydro-3-methyl-4-(N′-tosylprolyl)-2H-[1,4]benzothiazine-1,1-dioxideAbsolute configuration: (3R)

(3S)-3,4-Dihydro-3-phenyl-2H-[1,4]benzothiazine-1,1-dioxideC14H13NO2See 82%[α]D20 = −54.8 (c 0.6, CHCl3)Source of chirality: (3S,2′S)-3,4-Dihydro-3-phenyl-4-(N′-phthaloylleucyl)-2H-[1,4]benzothiazine-1,1-dioxideAbsolute configuration: (3S)