TY - JOUR
T1 - The 3-(3-pyridine)propionyl anchor group for protease-catalyzed resolutions
T2 - p-toluenesulfinamide and sterically hindered secondary alcohols
AU - Savile, Christopher K.
AU - Kazlauskas, Romas J.
PY - 2006/7
Y1 - 2006/7
N2 - Compared to an acetyl acyl group, the 3-(3-pyridine)propionyl group increases substrate binding to many proteases and substrate solubility in water, thereby increasing the rates of protease-catalyzed reactions. For example, proteases reacted up to six hundred-fold faster with the 3-(3-pyridine)propionyl ester of 1-phenylethanol than with the corresponding acetate ester. In addition, the 3-(3-pyridine)propionyl group enables a simple, mild acid extraction to separate the remaining starting material and product. To demonstrate the synthetic usefulness of this strategy, we resolved multi-gram quantities of (R)- and (S)-p-toluenesulfinamide with α-chymotrypsin and gram quantities of (R)- and (S)-2,2-dimethylcyclopentanol with subtilisin Carlsberg. The 3-(3-pyridyl)propionyl group was better for these resolutions than the corresponding acetate or dihydrocinnamate because it decreased the reaction time due to increased reactivity, decreased the reaction volume due to increased substrate solubility and enabled purification without chromatography. Molecular modeling suggests the enantioselectivity of α-chymotrypsin toward (R)-p-toluenesulfinamide is high (E = 52) because of a favorable hydrophobic interaction between the p-tolyl group of the fast-reacting (R)-enantiomer and leaving group pocket. The enantioselectivity of subtilisin Carlsberg toward (S)-2,2-dimethylcyclopentanol is high (E = 43) because the large substituent (the 2,2-dimethyl quaternary carbon) of the slow-reacting (R)-enantiomer cannot fit in the S1′ leaving group pocket.
AB - Compared to an acetyl acyl group, the 3-(3-pyridine)propionyl group increases substrate binding to many proteases and substrate solubility in water, thereby increasing the rates of protease-catalyzed reactions. For example, proteases reacted up to six hundred-fold faster with the 3-(3-pyridine)propionyl ester of 1-phenylethanol than with the corresponding acetate ester. In addition, the 3-(3-pyridine)propionyl group enables a simple, mild acid extraction to separate the remaining starting material and product. To demonstrate the synthetic usefulness of this strategy, we resolved multi-gram quantities of (R)- and (S)-p-toluenesulfinamide with α-chymotrypsin and gram quantities of (R)- and (S)-2,2-dimethylcyclopentanol with subtilisin Carlsberg. The 3-(3-pyridyl)propionyl group was better for these resolutions than the corresponding acetate or dihydrocinnamate because it decreased the reaction time due to increased reactivity, decreased the reaction volume due to increased substrate solubility and enabled purification without chromatography. Molecular modeling suggests the enantioselectivity of α-chymotrypsin toward (R)-p-toluenesulfinamide is high (E = 52) because of a favorable hydrophobic interaction between the p-tolyl group of the fast-reacting (R)-enantiomer and leaving group pocket. The enantioselectivity of subtilisin Carlsberg toward (S)-2,2-dimethylcyclopentanol is high (E = 43) because the large substituent (the 2,2-dimethyl quaternary carbon) of the slow-reacting (R)-enantiomer cannot fit in the S1′ leaving group pocket.
KW - Biocatalysis
KW - Chiral auxiliary
KW - Enantioselective
KW - Protease
KW - Resolution
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U2 - 10.1002/adsc.200606040
DO - 10.1002/adsc.200606040
M3 - Article
AN - SCOPUS:33746685089
SN - 1615-4150
VL - 348
SP - 1183
EP - 1192
JO - Advanced Synthesis and Catalysis
JF - Advanced Synthesis and Catalysis
IS - 10-11
ER -