Practical method for crystalline-liquid resolution of chrysanthemic acids utilizing chiral 1,1′-binaphthol monoethyl ethers directed for process chemistry

We have developed an efficient practical resolution method for (1R,3R)-trans-chrysanthemic acid 1 and (1R,3S)-trans-2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2, based on the preliminary results of the simpler analogues, (1R)-2,2-dichlorocyclopropanecarboxylic acid 3 and (1R)-2,2-dimethylcyclopropanecarboxylic acid 4, using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers (R)-5b as the key auxiliary. Direct esterifications of 1, 2, 3, and 4 with (R)-5b gave four sets of (1R)- and (1S)-diastereomeric esters 8, 9, 6, and 7, respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of (R)-5b (>90%).

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(1R)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC26H20Cl2O3[α]D23=+34.1 (c 1.80, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R)-[(R)]

(1S)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC26H20Cl2O3[α]D23=-38.6 (c 0.90, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1S)-[(R)]

(1R)-[(R)-2′-Methoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC25H18Cl2O3[α]D23=+36.9 (c 1.35, CHCl3)Source of chirality: (R)-1,1′-binaphthol monomethyl etherAbsolute configuration: (1R)-[(R)]

(1S)-[(R)-2′-Methoxy-1,1′-binaphth-2-yl] 2,2-dichlorocyclopropanecarboxylateC25H18Cl2O3[α]D24=-39.7 (c 4.2, CHCl3)Source of chirality: (R)-1,1′-binaphthol monomethyl etherAbsolute configuration: (1S)-[(R)]

(1R)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl] 2,2-dimethylcyclopropanecarboxylateC28H26O3[α]D25=+7.4 (c 1.00, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R)-[(R)]

(1R,3R)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl]3-(2′,2′-dimethylethenyl)-2,2-dimethylcyclopropanecarboxylateC32H32O3[α]D24=+88.5 (c 1.00, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R,3R)-[(R)]

(1S,3S)-[(R)-2′-Ethoxy-1,1′-binaphth-2-yl]3-(2′,2′-dimethylethenyl)-2,2-dimethylcyclopropanecarboxylateC32H32O3[α]D23=-53.5 (c 1.35, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1S,3S)-[(R)]

(1R,3S)-[(R)-2′-Ethoxy-1,1′binaphth-2-yl] 3-(2′,2′-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylateC30H26Cl2O3[α]D29=+77.4 (c 1.00, CHCl3)Source of chirality: (R)-1,1′-binaphthol monoethyl etherAbsolute configuration: (1R,3S)-[(R)]

(1S,3R)-[(R)-2′-Ethoxy-1,1′binaphth-2-yl] 3-(2′,2′-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylateC30H26Cl2O3[α]D25=-40.2 (c 4.45, CHCl3)Source of chirality: (R)-1,1′-binaphtholAbsolute configuration: (1S,3R)-[(R)]

(1R,3S)-2,2-Dimethyl-3-(2′,2′-dichloroethenyl)cyclopropanecarboxylic acidC8H10Cl2O2Ee = 99%[α]D23=+25.1 (c 1.10, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)

(1R,3S)-2,2-Dimethyl-3-(2′,2′-dimethylethenyl)cyclopropanecarboxylic acidC10H16O2Ee = 98%[α]D23=-38.6 (c 0.90, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,3S)