Chemo- and Stereoselective Reduction of an α-cyanoketone by Bakers' Yeast at Low Temperature

Article abstract of DOI:10.1021/ol990833y

(Matrix Presented) The bakers' yeast mediated reduction of 3-oxo-3-phenylpropanenitrile (1) proceeds at 4 °C to give exclusively (S)-3-hydroxy-3-phenylpropanenitrile (3) in 59% yield. This is in contrast to the corresponding reaction at room temperature w

Full text of DOI:10.1021/ol990833y

ORGANIC
LETTERS
1
999
Vol. 1, No. 12
879-1880
Chemo- and Stereoselective Reduction
of an r-Cyanoketone by Bakers’ Yeast
at Low Temperature
1
Peter Florey, Andrew J. Smallridge,* Abilio Ten, and Maurie A. Trewhella
School of Life Sciences and Technology, Victoria UniVersity of Technology (F008),
P.O. Box 14428, Melbourne City MC 8001, Australia
andrew.smallridge@Vu.edu.au
Received July 19, 1999
ABSTRACT
The bakers’ yeast mediated reduction of 3-oxo-3-phenylpropanenitrile (1) proceeds at 4 °C to give exclusively (S)-3-hydroxy-3-phenylpropanenitrile
3) in 59% yield. This is in contrast to the corresponding reaction at room temperature which yields a mixture of reduction and alkylation
products. This work demonstrates the use of low temperature to improve yeast selectivity.
(
The use of bakers’ yeast to stereoselectively reduce R-cy-
anoketones has been hampered by a competing alkylation
reaction which results in the nonstereoselective addition of
an ethyl group R to the nitrile.1 For example, treatment of
The alkylated compound is thought to be formed via an
aldol type condensation between acetaldehyde, present in the
yeast, and the R-cyanoketone (1) followed by reduction of
the resultant alkene (4) (Scheme 2). We have previously
-3
1
with bakers’ yeast in an organic solvent at room temper-
ature gives a mixture of racemic 2-ethyl-3-oxo-3-phenyl-
propanenitrile (2) (40% isolated yield) and (S)-3-hydroxy-
3
Scheme 2
3-phenylpropanenitrile (3) (10%) (Scheme 1). The corre-
sponding reduction in water at room temperature still gives
a mixture, but with the hydroxy nitrile (3) as the major
product (2:1).
Scheme 1
shown that it is possible to control this reaction in an organic
solvent to give exclusively the alkylated product, in good
yield, by adding acetaldehyde to the reaction mixture.3
We now wish to report that the use of bakers’ yeast in an
aqueous medium at low temperature (4 °C) results in the
exclusive formation of the reduction product.
1
0.1021/ol990833y CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/23/1999

Thus, the cyanoketone (1: R ) H) (725 mg, 5 mmol) was
added to a precooled (4 °C) suspension of bakers’ yeast (50
g) in water (450 mL) and stirred at 4 °C for 7 days. The
mixture was extracted with ethyl acetate (5 × 150 mL), and
the combined extracts were dried and evaporated. Flash-pad
chromatography of the residue with ether-petroleum ether
afforded the (S)-alcohol (3: R ) H) as a colorless oil (437
slowly than the unsubstituted cyanoketone and longer reac-
tion times would be required to obtain complete conversion.
The alkylation reaction is however still totally suppressed
in these reactions at the low reaction temperature.
Conducting the reactions in petroleum ether at low
temperature did result in more of the reduction product being
formed, but it did not prevent alkylation from also occurring.
The mechanism of the alkylation has been proposed to
involve the oxidation of ethanol to acetaldehyde which
undergoes an aldol reaction with the R-cyanoketone; reduc-
tion of the resultant alkene yields the alkylated product
2
0
-57 (c 1.1, EtOH), lit.4 [R]
20
mg, 59%), [R]
D
D
(R
enantiomer) +58 (c 1.0, EtOH) (Scheme 3). Under these
2
,3
(
Scheme 2). It is highly likely that the alkylation and
Scheme 3
reduction reactions utilize two (or more) different enzymes
and that by lowering the reaction temperature the enzyme(s)
involved in the alkylation reaction have been selectively
deactivated. This is the first instance of the use of low
temperature to alter the selectivity of a yeast reaction
although there has been one previous report of the use of
low temperature to slow a yeast reduction reaction; reduction
of 1-phenyl-1,2-propanedione at reduced temperature results
in the reduction of only one of the two ketone groups.5
The present work demonstrates the utility of the use of
low reaction temperatures to improve the selectivity of a
reaction conditions, no alkylated material (2) could be
detected.
Reaction of the substituted cyano ketones (1: R ) 2-OMe,
3
3
-OMe) with bakers’ yeast at 4 °C for 7 d gave a mixture of
starting material and reduced material (3: R ) 2-OMe,
-OMe); no trace of alkylated material could be detected in
yeast reaction. Coupled with our earlier work it is now
possible to alter the reaction conditions for the yeast-mediated
reaction of an R-cyanoketone to selectively obtain either the
alkylated product (2) or the reduced product (3).
3
the reaction mixture. The presence of unreacted starting
material in the reaction mixture indicates that at the lower
reaction temperature the substituted cyanoketones react more
Acknowledgment. We thank Mauri Integrated Ingredi-
ents (a division of Burns Philp, Australia) for their generous
supply of bakers’ yeast (Tandaco brand) and Circadian
Technologies Ltd. for financial support.
(
(
1) Itoh, T.; Takagi, Y.; Fujisawa, T. Tetrahedron Lett. 1989, 30, 3811.
2) Fuganti, C.; Pedrocchi-Fantoni, G.; Servi, S. Tetrahedron Lett. 1990,
3
3
1, 4195.
(3) Smallridge, A. J.; Ten, A.; Trewhella, M. A. Tetrahedron Lett. 1998,
OL990833Y
9, 5121.
(4) Itoh, T.; Takagi, Y.; Nishiyama, S. J. Org. Chem. 1991, 56, 1521.
(5) Takeshita, M.; Sato, T. Chem. Pharm. Bull. 1989, 37(4), 1085.
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Org. Lett., Vol. 1, No. 12, 1999