The 3-(3-pyridine)propionyl anchor group for protease-catalyzed resolutions: p-toluenesulfinamide and sterically hindered secondary alcohols

Christopher K. Savile, Romas J. Kazlauskas

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1183-1192
Number of pages10
JournalAdvanced Synthesis and Catalysis
Volume348
Issue number10-11
DOIs
StatePublished - Jul 1 2006

Keywords

  • Biocatalysis
  • Chiral auxiliary
  • Enantioselective
  • Protease
  • Resolution

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