Subtilisin-catalyzed resolution of N-acyl arylsulfinamides.
We report the first biocatalytic route to sulfinamides (R-S(O)-NH2), 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. Gram-scale 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.
Savile
Christopher K
CK
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec, H3A 2K6, Canada.
Magloire
Vladimir P
VP
Kazlauskas
Romas J
RJ
D000577:Amides / Q000737:chemistry* / Q000302:isolation & purification; D000588:Amines / Q000138:chemical synthesis; D002384:Catalysis; D006868:Hydrolysis; D008958:Models, Molecular; D013237:Stereoisomerism; D013379:Substrate Specificity; D020860:Subtilisin / Q000737:chemistry*; D013441:Sulfinic Acids / Q000737:chemistry* / Q000302:isolation & purification
D000577:Amides; D000588:Amines; D013441:Sulfinic Acids; D020860:Subtilisin