yeast.nitrostyrene.reduction, biotransformation
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Mechanism of the yeast mediated reduction of nitrostyrenes in light
petroleum
Anita F. McAnda, Kade D. Roberts, Andrew J. Smallridge,* Abilio Ten and
Maurie A. Trewhella
Department of Chemical Sciences, Victoria University of Technology, PO Box 14428, MCMC,
Melbourne, 8001, Australia
The yeast mediated reduction of a range of á- and â-deutero substituted nitrostyrenes has been conducted
in light petroleum in the presence of a small amount of water or D
2
O. NMR analysis of the products from
these reactions has allowed the determination of the mechanism of this yeast reduction reaction.
The results indicate that initially, a reversible non-stereoselective protonation occurs at the â-centre,
followed by stereoselective addition of hydride at the á-position.
Introduction
The yeast mediated reduction of b-nitrostyrenes † has been stud-
ied using yeast in both an aqueous
1,2
and an organic solvent
system.
3
In all cases reported, the reduction of nitrostyrenes
with substituents in the
petroleum)
3
gave 1-deutero-2-nitro-1-phenylethane
2
in 65%
isolated yield and with no loss of deuterium from the
a
-carbon
(Scheme 2).
D
D
-position gave rise to the production
of racemic products, whilst stereoselective reduction was
observed for
b
Yeast
NO
2
NO
2
Ph
Ph
light petroleum, H
2
O
-substituted nitrostyrenes. The lack of stereo-
selectivity in the aqueous systems had been attributed to
racemisation of the product under the mildly basic reaction
conditions,
4
however it was shown that this racemisation was
not occurring in the organic solvent system.
3
In order to explain
this unusual lack of stereoselectivity associated with a yeast
reduction reaction, a clearer understanding of the reaction
mechanism is required.
Even though yeast has been extensively used to effect chiral
reductions in organic synthesis
5
very little work has been
undertaken to elucidate the mode of action of this reduction
reaction. Fuganti and co-workers have studied the mechanism
of the yeast mediated reduction of cinnamyl alcohol and cin-
namaldehyde (Scheme 1)
6
and a number of a,b-unsaturated
a
1
2
Scheme 2 ‡
0.28 10
2
1
deg cm
2
g
2
1
indicating that some stereoselectivity had occurred
at the
1
The product obtained had a specific rotation of
-carbon. To determine the enantiomeric excess of the
product the nitro group was reduced to the amine using LiAlH
4
and the Mosher’s amide formed. NMR analysis of the amide in
the presence of the shift reagent Eu(fod)
3
indicated a 61% ee
based upon integration of the proton at the
a
-centre. The find-
ing that the reduction was partially stereoselective is not sur-
prising since
a
-nitrostyrene is stereoselectively reduced
by yeast in an aqueous reaction system;
2
it is at the b-centre that
the lack of stereoselectivity has been observed.
1,3
a
-methyl-
b
D
D
H
Reduction of â-deutero-â-nitrostyrene 3
b-Deutero-b-nitrostyrene
3
was prepared from
[
2
H
3
]
nitrometh-
ane and benzaldehyde in good yield and with 95% incorpor-
ation of deuterium at the b-carbon when the reaction was
conducted in D
2
O. Reduction of this compound with yeast in
the organic solvent system gave a 59% yield of a mixture of
2-nitro-1-phenylethane
4
and 2-deutero-2-nitro-1-phenylethane
5
in a ratio of 4 : 1 (Scheme 3).
R
R
Yeast
Ph
Ph
H
D
D
R = CH
2
OH, CHO
Scheme 1
lactones
7–9
using an aqueous reaction system. Through the use
of deuterium labelling they have shown that yeast stereo-
selectivity delivers both the hydride and the proton in an
anti
fashion. The yeast reduction of nitrostyrenes must involve a
somewhat different mechanism since a racemic product results.
NO
2
NO
2
NO
2
Yeast
Ph
Ph
Ph
+
D
D
light petroleum, H
2
O
3
4
5
Results and discussion
Reduction of á-deutero-â-nitrostyrene 1
a
Scheme 3
The loss of deuterium is a clear indication that exchange is
occurring at some stage during the reaction. We have previously
shown that deuterium is not incorporated at the
-nitrostyrene
1
was prepared from nitromethane
and a-deuterobenzaldehyde in good yield with 100% deuterium
incorporation at the
-Deutero-
b
-centre when
2-nitro-1-phenylethane
4
is stirred in light petroleum, D
2
O and
yeast, indicating that exchange does not occur between the
water present in the reaction and the reduced product
4
.
3
To
show that exchange does not occur between protons bound to
b
-carbon. Reduction with bakers yeast
using the previously reported reaction conditions (1 mmol
substrate, 11 g yeast, 0.8 ml water per g yeast, 50 ml light
a
† Throughout the text the compounds are referred to as
b
-nitrostyrenes
with the substituents prefixed as
-nitrostyrene)
to assist in the description of where hydride and proton attack is occur-
ring. IUPAC nomenclature, (
E
)-2-nitro-1-phenyl
[
1-2
H
]
propene, is used
in the Experimental section.
a
- or
b
- (
e.g.
:
a
-deutero-
b
‡ It is assumed that the major isomer produced is the (
S
)-enantiomer as
this is the case for reduction of
a
-methyl-
b
-nitrostyrene under similar
conditions.
J. Chem. Soc., Perkin Trans. 1, 1998
501
the yeast and the reduced nitrostyrene, 2-deutero-2-nitro-1-
phenylethane
5
, prepared by sodium borohydride reduction
of
b
-position. It is of course not
possible to directly observe the reversible nature of the proton-
ation in this case due to the presence of the methyl group.
The fact that no deuterium loss occurs in the reduction of
-carbon and hydride attack at the
a
-nitrostyrene
3
, was stirred in light petroleum,
D
2
O and yeast. No loss of deuterium was observed. Taken to-
gether, these two observations confirm that the hydrogen atoms
bound to the b-carbon in 2-nitro-1-phenylethane
4
are non-
exchangeable under the reaction conditions; the exchange at
the b-centre must therefore be occurring prior to product
formation.
Reduction of b-deutero-b-nitrostyrene
3
using a small
amount of yeast (7 g mmol
2
1
) resulted in incomplete reduction
and the recovered starting material
6
did not contain deuterium
(Scheme 4). The formation of reduced material, devoid of deu-
b
-deutero-
b
a
-nitro-
styrene
7
indicates that the reversible protonation occurs
exclusively at the
-deutero-
b
-nitrostyrene
1
and
a
-deutero-
b
-methyl-
b
-carbon and hydride attack therefore occurs
solely at the a-carbon. The electronic preference for hydride
attack at the
b
-carbon was demonstrated by the reduction of
these nitrostyrenes using NaBD
4
, a reaction which delivers
deuteride exclusively to the
a
a
-carbon (Scheme 6).
D
NO
2
NaBD
4
NO
2
Ph
Ph
NO
2
R = Me, H
Ph
R
R
NO
2
Ph
Scheme 6
NO
2
D
Yeast
+
Ph
4
5
light petroleum, H
2
O
D
Reactions using D
2
O
Other workers have concluded that in yeast mediated reduction
reactions conducted in aqueous systems, the yeast delivers the
hydride but the proton comes from the water.
7
If this mechan-
ism is reflected in the present system, replacing the water with
D
2
O should result in little or no loss of deuterium from the
b-centre. Reduction of b-deutero-b-nitrostyrene
3
with yeast
(7 g mmol
2
1
) in light petroleum and using D
2
O, in place of
the small amount of water usually employed, resulted in the
recovery of
NO
2
3
Ph
6
Scheme 4
terium, therefore arises
via
reduction of non-deuterated nitro-
styrene, rather than by loss of deuterium from the reduced
product.
The production of both deuterated and non-deuterated
products and substrates in the reaction can best be explained if
the initial step in the reaction is a reversible protonation of the
nitrostyrene at the
-nitrostyrene
6
and 2-nitro-1-phenylethane
4
as
well as the corresponding b-deuterated analogues,
3
and
5
(Scheme 7). The loss of deuterium in this system indicates that
b
-carbon followed by hydride attack at the
a-carbon. The protonation is yeast catalysed, as loss of deuter-
ium does not occur if
b
NO
2
-nitrostyrene
3
is stirred in
light petroleum and water in the absence of yeast. Previous
reports on the mechanism of yeast reduction of carbon–
carbon double bonds have not determined whether hydride
attack or protonation occurs first, but have assumed that the
mechanism is similar to metal hydride reduction where hydride
attack is the first step. Clearly, in the case of nitrostyrenes, the
first step in the reduction is a yeast catalysed protonation rather
than a hydride attack.
b
-deutero-
b
Ph
NO
2
Ph
NO
2
D
Yeast
+
Ph
4
5
light petroleum, D
2
O
D
NO
2
3
Ph
6
Scheme 7
the protonation at the
-centre is not only yeast catalysed but
also that the proton is delivered by the yeast rather than coming
directly from the water present.
Reduction of b-nitrostyrene
6
using the same D
2
O system
resulted in the production of the same four compounds
3
,
4
,
5
and
6
. The production of the deuterated compounds in this
system indicates that (not surprisingly) ready exchange occurs
between the yeast and the D
2
O, with the result that the yeast
can deliver both protons and deuterons.
In both of the previous reactions a small amount (<5%)
of the dideurated product 1,2-dideutero-1-phenyl-2-
nitroethane
9
was detected (Scheme 8). The identity of this
b
Reduction of á-deutero-â-methyl-â-nitrostyrene 7
Whilst the foregoing reactions have provided considerable evi-
dence regarding the mechanism of the yeast mediated reduction
of b-nitrostyrenes, of more interest was the mechanism of
reduction of
-nitrostyrenes, since this reaction pro-
duces a potentially useful chiral centre, as previously mentioned
however, all attempts to date have produced racemic material.
a-Deutero-b-methyl-b-nitrostyrene
7
was prepared from nitro-
ethane and
b
-methyl-
b
-deuterobenzaldehyde in 50% yield with 100%
incorporation of deuterium at the a-carbon. The yeast medi-
ated reduction of this compound gave 1-deutero-2-nitro-1-
phenylpropane
8
, as an equimolar mixture of diastereomers,
in 66% yield with no loss of deuterium from the
a
D
-position
(Scheme 5). The retention of the deuterium could be clearly
a
NO
2
NO
2
Yeast
light petroleum, D
2
O
Ph
Ph
+
3
–
6
D
D
D
6
9
NO
2
Yeast
NO
2
Ph
Ph
Scheme 8
light petroleum, H
2
O
7
8
Scheme 5
dideuterated product was confirmed by
2
H–
2
H TOCSY NMR
spectroscopy. A crosspeak was observed between the deuterium
signals at the 1- and 2-position indicating that both signals
came from a single molecule. This result strongly suggests that
some exchange is occuring between the D
2
O and the NADPH
in the yeast, so that the yeast can deliver both a deuteride and a
deuteron.
Further evidence for this exchange came from the reduction
of b-methyl-b-nitrostyrene
10
, using the D
2
O reaction system,
seen in a
1
H–
1
H COSY NMR experiment which showed no
crosspeak between the two diastereotopic protons at the
a-position indicating there was no material present containing
two protons at this carbon atom and therefore complete reten-
tion of the deuterium had occurred. This retention of deuter-
ium supports the mechanism proposed for the reduction of
b-nitrostyrenes, with reversible protonation occurring at the
502
J. Chem. Soc., Perkin Trans. 1, 1998
where a significant amount of the dideurated product 1,2-
dideutro-2-nitro-1-phenylpropane
11
was detected using
2
H–
2
H
TOCSY NMR spectroscopy (Scheme 9). Since protonation has
Preparation of nitrostyrenes
(
E
)-2-Nitro-1-phenylethene 6.
A mixture of methanol (2 ml),
benzaldehyde (1.0 ml, 9.8 mmol) and nitromethane (0.63 ml,
11.6 mmol) was cooled to
2
10
8
C. To this mixture, sodium
hydroxide (464 mg, 11.6 mmol) in water (1 ml) was added with
stirring at a rate such that the temperature of the mixture did
not exceed 15
D
NO
2
NO
2
D
NO
2
Yeast
light petroleum, D
2
O
Ph
Ph
8
C and the reaction mixture was allowed to stand
for 15 min. Water (7 ml) was added to dissolve the resultant
precipitate and the solution was added slowly to 4
Ph
+
D
HCl (4.7
ml) with stirring. The yellow precipitate formed was filtered off
and washed with cold water. The precipitate was placed in a
beaker immersed in hot water whereby the yellow precipitate
melted and two layers were formed. On cooling, crude product
solidified and the remaining liquid was removed. The crude
solid was then recrystallised from ethanol to give 2-nitro-1-
phenylethene (0.799 g, 54%) mp 57–58
8
C (lit.,
12
57–58
8
C);
d
H
(300 MHz) 7.53 (5H, m, Ph), 7.61 (1H, d,
J
13.5, 2-H), 8.03
(1H, d,
J
13.5, 1-H).
(
E
)-2-Nitro-1-phenyl
[
1-
2
H
]
ethene 1.
The title compound was
obtained using
[
a-
2
H
]
benzaldehyde in place of benzaldehyde.
Yield: 0.874 g, 60% (100% deuterium incorporation at the
m
10
11
Scheme 9
been shown to occur exclusively at the b-carbon the incorpor-
ation of deuterium at the
-position can only come from
exchange of deuterium between NADPH and the D
2
O.
Guenther
et al
. have demonstrated
in vitro
that the NADH
specific diaphorase, lipoamide dehydrogenase, catalyses the
exchange of hydride between NADH and water.
10
Lipoamide
dehydrogenase is a subunit of the enzyme pyruvate dehydro-
genase, an enzyme that is abundant in yeast. It is proposed that
the exchange between NADPH and D
2
O is catalysed by an
enzyme of this type present in the yeast.
a
-
carbon), mp 57–58
8
C;
d
H
(300 MHz) 7.53 (5H, m, Ph), 7.61
(1H, t,
J
1.8, 2-H);
a
d
D
(46 MHz) 8.02 (1-D).
(
E
)-2-Nitro-1-phenyl
[
2-
2
H
]
ethene 3.
The title compound was
obtained using
[
2
H
3
]
nitromethane in place of nitromethane
and the NaOH solution was made using D
2
O instead of water.
Yield: 0.825 g, 57% (95% deuterium incorporation at the
Conclusion
The reduction of a number of deuterated nitrostyrenes in an
organic solvent system incorporating a small amount of either
water or D
2
O has allowed us to determine that the yeast medi-
ated reduction of these compounds proceeds
via
the following
mechanism: a reversible non-stereoselective protonation at the
b
-
carbon), mp 58
8
C (lit.,
12
54–55
8
C);
d
H
(300 MHz) 7.52 (5H, m,
Ph), 8.02 (1H, t,
J
2.1, 1-H);
b
d
D
(46 MHz) 7.61 (2-D).
(
E
)-2-Nitro-1-phenylprop-1-ene 10.
Nitroethane (1.0 ml, 13.9
mmol) and cyclohexylamine (1.3 ml) were added to benzalde-
hyde (1.0 ml, 9.8 mmol) in glacial acetic acid (5.3 ml). The
mixture was held at 100
-carbon followed by a stereoselective addition of a hydride at
the a-carbon (Scheme 10). It is unclear at this stage whether the
8
R
2
R
2
C for 6 h, cooled and diluted with
water (1 ml). The reaction mixture was cooled overnight in a
water bath. The crystals formed were filtered and air dried. The
crude solid was recrystallised from ethanol to give (
E
)-2-nitro-
1-phenylprop-1-ene (0.99 g, 62%), mp 64–65
R
2
NO
2
NO
2
H
–
NO
2
H
+
Ph
Ph
Ph
R
1
R
1
R
1
8
C (lit.,
13
64–65
8
C)
d
H
(300 MHz) 2.48 (3H, s, CH
3
), 7.47 (5H, m, Ph), 8.11 (1H,
s, 1-H).
(
E
)-2-Nitro-1-phenyl
[
1-
2
H
]
prop-1-ene 7.
The title compound
was obtained using
[
Scheme 10
reversible protonation is catalysed in a non-stereoselective
manner or whether two (or more) enzymes with opposite enan-
tioselectivities are involved. This mechanism accounts for the
finding that stereoselective reduction occurs at the
-
2
H
]
benzaldehyde instead of benzalde-
hyde. Yield: 0.780 g, 50% (100% deuterium incorporation at the
a
a
-centre but
not at the b-centre, in yeast mediated reductions of this type.
This work complements other studies concerned with the mode
of action of yeast mediated reduction reactions, however the
use of an organic solvent system has enabled a more detailed
determination of the mechanism to be achieved.
a
8
d
H
(300 MHz) 2.48 (3H, s, CH
3
), 7.47
(5H, m, Ph);
d
D
(46 MHz) 8.11 (1-D).
-carbon), mp 62–63
C;
Yeast reactions
Reduction of (
E
)-2-nitro-1-phenylethene 6.
(
E
)-2-Nitro-1-
phenylethene
6
(0.3 g, 2.0 mmol), yeast (22.13 g, 11 g mmol
2
1
of
6
), H
2
O (17.7 ml) (0.8 ml per g of yeast) and light petroleum
(200 ml) were stirred at room temperature for 24 h. The solvent
was removed by filtration and the yeast was washed with
dichloromethane (3 × 50 ml). The filtrates were combined and
evaporated
in vacuo
to give a residue which was bulb-to-bulb
distilled to give 2-nitro-1-phenylethane
4
(0.216 g, 72%), bp
150
Experimental
General
NMR spectra were recorded using Bruker DPX300 and
DRX500 spectrometers at 300 and 500 MHz (
1
H) and 46 MHz
(
2
H).
1
H NMR and
1
H–
1
H COSY NMR spectra were recorded
as deuterochloroform solutions using tetramethylsilane (
8
0.0
ppm) as an internal reference.
J
Values are given in Hz.
2
H
NMR and
2
H–
2
H TOCSY NMR spectra were recorded in
chloroform solutions using deuterochloroform (
d
= 7.26 ppm)
as an internal reference.
2
H–
2
H TOCSY NMR spectra were
recorded using a similar method to that described by Chandra-
kumar and Ramamoorthy.
11
Bulb-to-bulb distillations were
carried out using a Buchi-GKR 50 distillation unit.
[
a
]
D
Values
are given in units of 10
2
1
deg cm
2
g
2
1
.
[
a-
2
H
]
Benzaldehyde was purchased from ISOTEC Inc.
[
2
H
3
]
Nitromethane and D
2
O were purchased from Cambridge
Isotopic Laboratories. All other chemicals were purchased from
the Aldrich Chemical Company. AR grade light petroleum (40–
60
8
C) was used without further purification. Mauripan Instant
Dry Yeast was generously supplied by Mauri Foods Ltd,
Australia.
d
=
d
H
(300 MHz) 3.34 (2H, t,
J
7.5, 1-H), 4.63
(2H, t,
J
7.5, 2-H), 7.3 (5H, m, Ph).
Reduction of (
E
)-2-nitro-1-phenyl
[
1-
2
H
]
ethene 1.
(
E
)-2-Nitro-
1-phenyl
[
1-
2
H
]
ethene
1
(0.3 g, 2.0 mmol) was stirred with yeast
(21.98 g, 11 g mmol
2
1
of
1
), H
2
O (17.5 ml) and light petroleum
(150 ml) for 24 h to give 2-nitro-1-phenyl
[
1-
2
H
]
ethane
2
(0.198
g, 65%) bp 150
C/0.5 mmHg;
8
C/0.5 mmHg;
[
]
D
1
d
H
(300
MHz) 3.33 (1H, tt,
J
9.6, 2.1, 1-H), 4.63 (2H, dt,
J
7.5, 0.9, 2-
H), 7.3 (m, 5H, Ph);
a
0.28 (
c
5 in CHCl
3
);
d
D
(46 MHz) 3.33 (1-D). A sample of this
nitroalkane was reduced to the amine using LiAlH
4
in diethyl
ether and then converted into the MTPA amide. An NMR spec-
trum was taken in the presence of 0.2 m Eu(fod)
3
shift reagent.
Integration of the methine proton in the 1-position indicated a
61% ee.
Reduction of (
E
)-2-nitro-1-phenyl
[
2-
2
H
]
ethene 3.
(
E
)-2-Nitro-
1-phenyl
[
2-
2
H
]
ethene
3
(0.4 g, 2.7 mmol) was stirred with yeast
J. Chem. Soc., Perkin Trans. 1, 1998
503
(29.3 g, 11 g mmol
2
1
of
3
), H
2
O (23.4 ml) and light petroleum
(200 ml) for 24 h to give a mixture of 2-nitro-1-phenylethane
and 2-nitro-1-phenyl
[
2-
2
H
]
ethane
5
(0.176 g), bp 150
2-Nitro-1-phenyl
[
1-
2
H
]
propane 8.
Using a similar procedure
(
E
)-2-nitro-1-phenylprop-1-ene
7
gave the title compound
8
as
a mixture of diastereomers (0.096 g, 57%);
8
C/0.5
mmHg;
d
H
(300 MHz)
4
: 3.34 (2H, t,
J
7.5, 1-H), 4.63 (2H, t,
J
7.5, 2-H), 7.3 (5H, m, Ph);
5
: 3.34 (2H, d,
J
7.4, 1-H), 4.62 (1H,
tt,
J
7.4, 2.1, 2-H), 7.3 (5H, m, Ph);
d
D
(46 MHz) 4.60 (2-D).
Reduction of (
E
)-2-nitro-1-phenyl
[
1-
2
H
]
prop-1-ene 7.
(
E
)-2-
Nitro-1-phenyl
[
1-
2
H
]
prop-1-ene
7
(0.3 g, 1.2 mmol) was stirred
with yeast (20.10 g, 11 g mmol
2
1
of
7
), H
2
O (16.1 ml) and light
petroleum (200 ml) for 24 h, to give 2-nitro-1-phenyl
[
1-
2
H
]
propane
8
as a mixture of diastereomers (0.198 g, 66%), bp
150
8
C/0.5 mmHg;
d
H
(300 MHz) 1.57 (3H, dd,
J
6.9, 1.2, CH
3
),
3.02 (1H, dt,
J
6.9, 1.8, 1-H), 3.33 (1H, dt,
J
6.9, 2.1, 1-H), 4.81
(1H, quintet,
J
6.6, 2-H), 7.28 (m, 5H, Ph).
Reduction of (
E
)-2-nitro-1-phenylprop-1-ene 10.
(
E
)-2-Nitro-
1-phenylprop-1-ene
10
(0.3 g, 1.8 mmol) was stirred with yeast
(12.8 g, 7 g mmol
2
1
of
10
), D
2
O (10.2 ml) and light petroleum
(150 ml) for 24 h to give a mixture of starting material
and reduced products (0.201 g, 67%) bp 150
d
H
(300 MHz) 1.57
(3H, dd,
J
6.9, 1.2, CH
3
), 3.02 (1H, dt,
J
6.9, 1.8, 1-H), 3.33 (1H,
dt,
J
6.9, 2.1, 1-H), 4.81 (1H, quintet,
J
6.6, 2-H), 7.28 (m, 5H,
Ph);
d
D
(46 MHz) 3.03 (1-D), 3.36 (1-D).
References
1 M. Takeshita, S. Yoshida and Y. Kohno,
Heterocycles
, 1994,
37
, 553.
2 H. Ohta, N. Kobayashi and K. Ozaki,
J. Org. Chem.
, 1989,
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, 1.
8
C/0.5 mmHg;
d
D
(46 MHz) 2.99 (1-D), 3.31 (1-D, 4.77 (2-D).
Sodium borodeuteride reductions
2-Nitro-1-phenyl
[
1-
2
H
]
ethane.
(
)-2-Nitro-1-phenylnitro-
ethene (0.15 g, 1 mmol) was dissolved in a mixture of 12 ml
chloroform (8 ml per g silica gel) and 2.3 ml isopropanol (1.5 ml
per g silica gel) and stirred with 1 g silica gel. NaBD
4
(0.16 g, 4.1
mmol) was added in small amounts, until the yellow colour due
to the nitrostyrene disappeared. The mixture was then filtered,
washed with brine (15 ml), extracted with dichloromethane (20
ml), dried over NaSO
4
and the dichloromethane evaporated
in
vacuo
to give the title compound (0.11 g, 73%);
d
H
(300 MHz)
3.33 (1H, tt,
J
9.6, 2.1, 1-H), 4.63 (2H, dt,
J
7.5, 0.9, 2-H), 7.3
(m, 5H, Ph);
Paper
7/06353I
Received
1
st September
1997
Accepted
21
st October
1997
d
D
(46 MHz) 3.33 (1-D).
504
J. Chem. Soc., Perkin Trans. 1, 1998
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