TY - JOUR
T1 - Subtilisin-catalyzed resolution of N-acyl arylsulfinamides
AU - Savile, Christopher K.
AU - Magloire, Vladimir P.
AU - Kazlauskas, Romas J.
PY - 2005/2/23
Y1 - 2005/2/23
N2 - We report the first biocatalytic route to sulfinamides (R-S(O)-NH 2), whose sulfur stereocenter makes them important chiral auxiliaries for the asymmetric synthesis of amines. Subtilisin E did not catalyze hydrolysis of N-acetyl or N-butanoyl arylsulfinamides, but did catalyze a highly enantioselective (E > 150 favoring the (R)-enantiomer) hydrolysis of N-chloroacetyl and N-dihydrocinnamoyl arylsulfinamides. Gramscale resolutions using subtilisin E overexpressed in Bacillus subtilis yielded, after recrystallization, three synthetically useful auxiliaries: (R)-p- toluenesulfinamide (42% yield, 95% ee), (R)-p-chlorobenzenesulfinamide (30% yield, 97% ee), and (R)-2,4,6-trimethylbenzenesulfinamide (30% yield, 99% ee). Molecular modeling suggests that the N-chloroacetyl and N-dihydrocinnamoyl groups mimic a phenylalanine moiety and thus bind the sulfinamide to the active site. Molecular modeling further suggests that enantioselectivity stems from a favorable hydrophobic interaction between the aryl group of the fast-reacting (R)-arylsulfinamide and the S1′ leaving group pocket in subtilisin E.
AB - We report the first biocatalytic route to sulfinamides (R-S(O)-NH 2), whose sulfur stereocenter makes them important chiral auxiliaries for the asymmetric synthesis of amines. Subtilisin E did not catalyze hydrolysis of N-acetyl or N-butanoyl arylsulfinamides, but did catalyze a highly enantioselective (E > 150 favoring the (R)-enantiomer) hydrolysis of N-chloroacetyl and N-dihydrocinnamoyl arylsulfinamides. Gramscale resolutions using subtilisin E overexpressed in Bacillus subtilis yielded, after recrystallization, three synthetically useful auxiliaries: (R)-p- toluenesulfinamide (42% yield, 95% ee), (R)-p-chlorobenzenesulfinamide (30% yield, 97% ee), and (R)-2,4,6-trimethylbenzenesulfinamide (30% yield, 99% ee). Molecular modeling suggests that the N-chloroacetyl and N-dihydrocinnamoyl groups mimic a phenylalanine moiety and thus bind the sulfinamide to the active site. Molecular modeling further suggests that enantioselectivity stems from a favorable hydrophobic interaction between the aryl group of the fast-reacting (R)-arylsulfinamide and the S1′ leaving group pocket in subtilisin E.
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U2 - 10.1021/ja045397b
DO - 10.1021/ja045397b
M3 - Article
C2 - 15713087
AN - SCOPUS:13944260776
SN - 0002-7863
VL - 127
SP - 2104
EP - 2113
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 7
ER -