Stereoselective biocatalytic synthesis of (S)-2-hydroxy-2-methylbutyric acid via substrate engineering by using "thio-disguised" precursors and oxynitrilase catalysis.
3-Tetrahydrothiophenone (4) and 4-phenylthiobutan-2-one (7) were used as masked 2-butanone equivalents to give the corresponding cyanohydrins 5 (79 % yield, 91 % ee) and 8 (95 % yield, 96 % ee) in an enzymatic cyanohydrin reaction applying the hydroxynitrile lyase (HNL) from Hevea brasiliensis. After hydrolysis and desulphurisation the desired intermediate (S)-2-hydroxy-2-methylbutyric acid (10) was obtained with 99 % ee. Interestingly, when applying (R)-selective HNL from Prunus amygdalus again the (S)-cyanohydrin 5 was formed (62 % ee). The absolute configuration of 5 was verified by crystal structure determination of the corresponding hydrolysis derived carboxylate. The fact that both enzymes yield the same enantiomer was analysed and interpreted by molecular modelling calculations.
Fechter
Martin H
MH
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 16, 8010 Graz, Austria.
Gruber
Karl
K
Avi
Manuela
M
Skranc
Wolfgang
W
Schuster
Christian
C
Pöchlauer
Peter
P
Klepp
Kurt O
KO
Griengl
Herfried
H
D000446:Aldehyde-Lyases / Q000737:chemistry / Q000378:metabolism*; D002087:Butyrates / Q000138:chemical synthesis*; D002384:Catalysis; D018360:Crystallography, X-Ray; D028482:Hevea / Q000201:enzymology*; D006868:Hydrolysis; D006880:Hydroxy Acids; D008956:Models, Chemical; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism*; D027861:Prunus / Q000201:enzymology*; D013237:Stereoisomerism
C521666:2-hydroxy-2-methylbutyric acid; D002087:Butyrates; D006880:Hydroxy Acids; D009570:Nitriles; C430593:cyanohydrin; D000446:Aldehyde-Lyases; C021541:mandelonitrile lyase; C079359:hydroxymandelonitrile lyase