Enantio- and chemoselective bioreduction of β-keto nitriles by the fungus Curvularia lunata

Article abstract of DOI:10.1016/S0957-4166(00)00348-7

The use of methanol as cosolvent allows the chemoselective reduction of aromatic β-keto nitriles by the fungus Curvularia lunata CECT 2130, yielding the corresponding (S)-β-hydroxy nitriles in a highly enantioselective way. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00348-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3693–3700
Enantio- and chemoselective bioreduction of b-keto nitriles
by the fungus Curvularia lunata
Juan R. Dehli and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica, Universidad de Oviedo, 33071 Oviedo, Spain
Received 29 June 2000; accepted 1 September 2000
Abstract
The use of methanol as cosolvent allows the chemoselective reduction of aromatic b-keto nitriles by the
fungus Curvularia lunata CECT 2130, yielding the corresponding (S)-b-hydroxy nitriles in a highly
enantioselective way. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The importance of optically active b-hydroxy acid derivatives as versatile building blocks in
asymmetric synthesis is well established.1,2 Among the many existing methods to prepare them,
microbial enantioselective reduction of b-keto esters has proved to be one of the most effective
processes.3 Their nitrogenated analogous, b-keto amides, have also been subjected to bioreduc-
tion, but to a more limited extent.4 From the resultant b-hydroxy amides, optically active b- and
g-amino alcohols have been easily obtained.5 This gives the process a high added value, due to
the importance of amino alcohols in both asymmetric synthesis6 and medicinal chemistry.7
Another suitable way to obtain amino alcohols by this strategy would be from b-hydroxy
nitriles. For instance, the antidepressant fluoxetine8 can be readily prepared from 3-hydroxy-3-
phenylpropanenitrile.9 However, one of the most characteristic features of the bioreduction of
a-non substituted b-keto nitriles by bakers’ yeast is the existence of a competing a-ethylation
reaction,10,11 resulting in low chemical yields of the desired products, the corresponding a-non
substituted b-hydroxy nitriles.
We have recently communicated that when an ethanolic solution of 3-oxo-3-phenylpropane-
nitrile, 1a, was incubated with the fungus Curvularia lunata CECT 2130, an almost equimolar
mixture of (S)-3-hydroxy-3-phenylpropanenitrile, 2a (88% ee), and (2R,1%R)-2-(1-hydroxy-1-
phenylmethyl)butanenitrile, 3a, was obtained (see Scheme 1).12
* Corresponding author. Tel/fax: +34 985 10 34 48; e-mail: vgs@sauron.quimica.uniovi.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00348-7

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Scheme 1.
In the course of our work, an attempt to minimize this ethylation reaction by decreasing the
temperature appeared in the literature.13 However, this methodology led to low conversion
values when applied to substituted aromatic b-keto nitriles.
Therefore, the chemoselective bioreduction of b-keto nitriles has remained until now an
unsolved problem. Here we present an alternative and general methodology to carry out this
biotransformation, in most cases in a highly enantioselective fashion.
2. Results and discussion
Since the origin of the ethyl group incorporated in the a position during the incubation of 1a
with C. lunata seemed to be the ethanol used as cosolvent, we decided to substitute it for
N,N-dimethylformamide (DMF) to prevent the synthesis of product 3a and, therefore, optimize
the yield in 2a. However, a significant amount of 3a (ca. 20%) was still obtained. This result
suggests that the ethyl group does not only come from the cosolvent, but also from the ethanol
produced by the fungal metabolism.
Quite surprisingly, when we used methanol as cosolvent (in our aim to introduce a methyl
group in the a position), we obtained compound 2a as the only product in a moderate yield
(55%). Furthermore, the ee value rose from 88 up to 96%. Methanol has been (although
scarcely) used in biotransformations with whole cells14 but, to the best of our knowledge, such
a positive effect in both chemo- and enantioselectivity had not been previously observed. So far,
we do not have a conclusive explanation for the different results obtained with DMF and
MeOH, but some reasonable hypotheses could be: (a) MeOH is able to substitute the EtOH in
the cofactor regenerating process. Therefore, no acetaldehyde is formed, and the ethylation
mechanism cannot go further. (b) MeOH inhibits the bioreduction of the double bond of the
unsaturated ketone by the enoate reductase. As the chemical aldol condensation is reversible
under these aqueous conditions, 1a would be regenerated and the carbonyl reduction would
yield 2a as the only product.
Encouraged by this result, we introduced some experimental modifications in order to
improve the enantioselectivity of the process: we tested some other cosolvents (dimethylsulfoxide
and acetonitrile); we added deshydrogenase inhibitors, such as methyl vinyl ketone, ethyl
chloroacetate,15 allylic alcohol and
L
-cysteine;16 and we changed the concentration of both
substrate 1a and cosolvent (methanol). However, in no case did we reach a value higher than
96% ee.

J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 11 (2000) 3693–3700
3695
In order to check the general applicability of this methodology, we decided to test a series of
different a-non substituted b-keto nitriles bearing an aromatic, heteroaromatic or aliphatic
moiety attached to the carbonyl group (see Scheme 2). Indeed, the corresponding b-hydroxy
nitriles 2 were obtained as the only products (see Table 1) in moderate to good yields and high
to excellent ee, except for 3-hydroxybutanenitrile, 2e. This result can be explained considering
the small difference in size between the methyl and the cyanomethyl groups in compound 1e
and, thus, the difficulty for the enzyme to distinguish between both enantiotopic faces of the
carbonyl group. As a general trend, it seems that higher ee values are reached with aromatic
compounds (2a and 2b), whereas higher yields are obtained with aliphatic ones (2c–e).
Scheme 2.
Table 1
Products obtained in the bioreduction of b-keto nitriles 1a–e by Cur6ularia lunata
Product
R
Yield (%)a
ee (%)b
Abs. config.
2a
2b
2c
2d
2e
Ph
55
55
71
77
65
96
92
83
88
40
S
S
S
S
S
2-Fur
tBu
Cy
Me
a After column chromatography.
b Determined by chiral GC.
Considering that the best stereochemical result was obtained in the case of compound 2a, we
thought it would be of interest to continue our studies of bioreduction testing a series of
aromatic keto nitriles bearing different substituents on the phenyl moiety, as shown on Scheme
3.
Scheme 3.
Once again, the corresponding b-hydroxy nitriles 2f–m were obtained as the only products in
moderate yield and high to very high enantiomeric excesses in most cases, as shown in Table 2.
Although these results might not be extrapolated, some general tendencies in the enantioselectiv-
ity of the biotransformation were observed: (a) a substituent in the para position (compounds

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2h, 2k and 2m) decreases the ee, whereas a substituent in the ortho (2f) or meta (2g, 2j and 2l)
position does not produce significant changes, and sometimes results in even higher values than
that obtained with 2a; (b) considering the para position, a methyl (2k) or methoxy (2m) group
results in a much higher ee value than a chlorine (2h); (c) the nature of the substituent when it
is placed on a meta position (2g, 2j and 2l) is not so influential: ee values higher than 90% are
always reached; (d) a double substitution in meta and para (2i) leads again to a high ee value,
much closer to that obtained with 2g than that with 2h.
Table 2
Products obtained in the bioreduction of aromatic b-keto nitriles by Cur6ularia lunata
Product
R1
R2
R3
Yield (%)a
ee (%)b
Abs. config.
2a
2f
2g
2h
2i
2j
2k
2l
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
Me
H
55
42
57
47
43
59
54
41
42
96
98
97
50
92
94
82
98
83
S
S
S
S
S
S
S
S
S
Cl
H
Cl
Me
H
CF3
H
2m
MeO
a After column chromatography.
b Determined by chiral GC.
All the b-hydroxy nitriles obtained in the bioreduction with C. lunata have S absolute
configuration. For compounds 2a and 2e, it has been assigned by comparison of the sign of the
specific rotation with the value published in the literature (see Section 4). Compound 2c was
hydrolyzed to 3-hydroxy-4,4-dimethylpentanoic acid, followed by treatment with diazomethane
to give the corresponding methyl ester.17 Compound 2d was treated with acetic anhydride to give
its O-acetylated derivative.18 For the aromatic b-hydroxy nitriles, 2b,f–m, the absolute configu-
ration has been tentatively assigned on the basis of three convergent features: (a) the Dl values
1
measured in the H NMR spectra of the MeO group of their MTPA esters,19 using the modified
Mosher’s method20 for secondary alcohols; (b) the Prelog’s rule,21 which C. lunata follows for
the bioreduction of ketones,12,22 considering the aromatic ring as the large substituent, and the
cyanomethyl group as the small one; (c) the elution order on our chiral GC column: in all cases,
the major enantiomer exhibits the longest retention time. As expected, all these aromatic
compounds show the same absolute configuration, independently from the substituent on the
phenyl ring.
3. Conclusion
In summary, a general methodology for the chemo- and enantioselective bioreduction of
b-keto nitriles with the fungus C. lunata CECT 2130 has been accomplished using methanol as
cosolvent. Coupled with our previous communication, we have shown that this fungal strain is
a versatile biocatalyst, and depending on the experimental conditions, it is possible to selectively

J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 11 (2000) 3693–3700
3697
obtain the alkylated product 3 or the reduced one 2. Furthermore, the enantiomeric excesses of
the corresponding b-hydroxy nitriles were very high in many cases, which could lead to a series
of new derivatives of antidepressants in an optically active form by conventional methods.
4. Experimental
4.1. General
The fungus C. lunata was obtained from CECT (Coleccio´n Espan˜ola de Cultivos Tipo).
Reagents were purchased from Avocado, Aldrich Chemie or Lancaster. Solvents were distilled
over an adequate desiccant and stored under nitrogen. Precoated TLC plates of silica gel 60
F254 from Merck were used, while for column chromatography, Merck silica gel 60/230–400
mesh was applied. Melting points were taken using a Gallenkamp apparatus and are uncor-
rected. Optical rotations were measured using a Perkin–Elmer 343 polarimeter. IR spectra were
1
recorded on a Mattson Genesis FT Infrared spectrometer. H and 13C NMR spectra were
1
carried out in CDCl3 using a Bruker AC-300 (300 MHz for H and 75.5 for 13C) spectrometer,
using TMS as internal standard. Mass spectra were recorded on a Hewlett–Packard 5987 A
spectrometer, using electronic impact procedures (75 eV). The ee values were determined by GC
on a Hewlett–Packard 5890 Series II chromatograph, using a Rt-bDEXse (30 m×0.25 mm,
Restek) capillary column and nitrogen as carrier gas (15 psia).
4.2. General procedures for cultures and biotransformations
A loop of a solid culture of C. lunata, from an agar plate, was sown in a test tube containing
3 mL of sterilized Sabouraud’s liquid medium (composed of bactopeptone (10 g), -glucose (20
D
g) in distilled water (1.0 L); pH adjusted to 5.8). After growing over 72 h (rotatory shaker, 200
rpm, 28°C), 0.5 mL of this initial medium were used to inoculate another sterilized medium (75
mL, in a 250 mL Erlenmeyer flask), identical to that used for fungi in Ref. 23. After 72 h of
cultivation (same conditions as above), cells were harvested by filtration (3.90 g wet weight),
washed with aqueous 0.8% NaCl, and suspended in 75 mL of 0.2 M phosphate buffer, pH 6.0.
To this cell suspension, a solution of substrate (75 mg) in warm methanol (0.75 mL) was
added. In some cases, a partial precipitation of the substrate was observed. However, as the
reaction proceeded, this precipitate disappeared. Incubation was then carried out until disap-
pearance of the substrate (6–12 h, TLC monitoring). Then, the mycelium was filtered out again,
and the fungal cake was washed several times with aqueous 0.8% NaCl, until no more product
was recovered. The combined aqueous phases were continuously extracted with AcOEt for 12
hours. After drying over anhydrous Na2SO4, the solvent was evaporated and the product
purified by flash chromatography (eluent: hexane–AcOEt, 5:1).
For the spectral data of compounds 2a and 2e, see Ref. 24. For compound 2c, see Ref. 25 and
for compounds 2d, 2f, 2h and 2m, see Ref. 26. For new compounds (2b, 2g, 2i, 2j, 2k and 2l)
full characterization is given.
4.2.1. (S)-3-Hydroxy-3-phenylpropanenitrile, 2a
Yield, 55%; [h]2D0 −57.7 (c 2.6, EtOH; ee 96%), lit. [h]D20 +58.0 (c ca. 1, EtOH; ee 94% R);24 GC
conditions: 170°C, tR(R) 15.5 min and tR(S) 16.6 min.

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4.2.2. (S)-3-(2-Furyl)-3-hydroxypropanenitrile, 2b
Oil; yield, 55%; [h]2D0 −38.6 (c 1.3, CHCl3; ee 92%); H NMR: l (ppm) 2.88 (d, J 6.3 Hz, 2H,
CH2), 3.01 (br s, 1H, OH), 5.02 (t, J 6.1 Hz, 1H, CHꢀO), 6.35–6.40 (m, 2H, Harom), 7.35–7.45
(m, 1H, Harom); 13C NMR: 24.8 (CH2), 63.6 (CHꢀO), 107.3, 110.4 (CHarom), 116.9 (CN), 142.7
(CHarom), 152.7 (Carom); IR (neat) 3410, 2255 cm−1; MS: m/z (relative intensity) 137 (M+, 15), 119
(9), 97 (100); HRMS calc. for C7H7NO2 137.047678, found 137.047651. GC conditions: 135°C,
tR(R) 31.3 min and tR(S) 33.6 min. Dl of the MeO group of its MTPA ester derivatives: −42 Hz.
1
4.2.3. (S)-3-Hydroxy-4,4-dimethylpentanenitrile, 2c
Yield, 71%; [h]2D0 −32.2 (c 0.6, CHCl3; ee 83%); GC conditions: 105°C, tR(S) 25.4 min and
tR(R) 27.0 min.
4.2.4. (S)-3-Cyclohexyl-3-hydroxypropanenitrile, 2d
Yield, 77%; [h]2D0 −9.4 (c 0.9, CHCl3; ee 88%); GC conditions for its O-acetylated derivative:
150°C, tR(S) 17.4 min and tR(R) 18.5 min.
4.2.5. (S)-3-Hydroxybutanenitrile, 2e
Yield, 65%; [h]2D0 −2.9 (c 0.8, EtOH; ee 40%), lit. [h]D20 +4.1 (c 3.0, EtOH; ee 84% R);24 GC
conditions for its O-acetylated derivative: 115°C, tR(R) 7.0 min and tR(S) 8.2 min.
4.2.6. (S)-3-(2-Chlorophenyl)-3-hydroxypropanenitrile, 2f
Yield, 42%; [h]2D0 −95.1 (c 0.7, CHCl3; ee 98%); GC conditions: 185°C, tR(R) 16.7 min and
tR(S) 18.3 min. Dl of the MeO group of its MTPA ester derivatives: −42 Hz.
4.2.7. (S)-3-(3-Chlorophenyl)-3-hydroxypropanenitrile, 2g
1
Oil; yield, 57%; [h]2D0 −56.8 (c 1.3, CHCl3; ee 97%); H NMR: l (ppm) 2.72 (d, J 6.2 Hz, 2H,
CH2), 3.24 (br s, 1H, OH), 4.98 (t, J 6.0 Hz, 1H, CHꢀO), 7.2–7.4 (m, 4H, Harom); 13C NMR: 27.8
(CH2), 69.1 (CHꢀO), 117.1 (CN), 123.6, 125.6, 128.7, 130.1 (CHarom), 134.6, 142.9 (Carom); IR
(neat) 3431, 2257 cm−1; MS: m/z (relative intensity) 181 (M+, 6), 183 [(M+2)+, 2], 163 (5), 141
(75), 77 (100); HRMS calc. for C9H8ClNO 181.029442, found 181.029264; GC conditions:
185°C, tR(R) 23.7 min and tR(S) 25.2 min. Dl of the MeO group of its MTPA ester derivatives:
−42 Hz.
4.2.8. (S)-3-(4-Chlorophenyl)-3-hydroxypropanenitrile, 2h
Yield, 47%; [h]2D0 −52.1 (c 0.7, CHCl3; ee 50%); GC conditions: 185°C, tR(R) 23.3 min and
tR(S) 24.6 min. Dl of the MeO group of its MTPA ester derivatives: −49 Hz.
4.2.9. (S)-3-(3,4-Dichlorophenyl)-3-hydroxypropanenitrile, 2i
White solid; yield, 43%; mp 85–86°C; [h]2D0 −37.2 (c 0.8, CHCl3; ee 92%); H NMR: l (ppm)
1
2.75 (d, J 6.0 Hz, 2H, CH2), 2.0–3.2 (br s, 1H, OH), 5.03 (t, J 6.1 Hz, 1H, CHꢀO), 7.25 (dd, 1H,
J 2.0, 8.3 Hz, Harom), 7.48 (d, J 8.3 Hz, 1H, Harom), 7.52 (d, J 2.0 Hz, 1H, Harom); 13C NMR:
27.9 (CH2), 68.6 (CHꢀO), 116.8 (CN), 124.8, 127.5, 130.8 (CHarom), 132.6, 132.9, 141.0 (Carom);
IR (KBr) 3425, 2255 cm−1; MS m/z (relative intensity) 215 (M+, 1), 217 [(M+2)+, <1], 219
[(M+4)+, <1], 197 (97), 162 (100); HRMS calc. for C9H7Cl2NO 214.990470, found 214.989396;
GC conditions: 200°C, tR(R) 28.9 min and tR(S) 30.3 min. Dl of the MeO group of its MTPA
ester derivatives: −55 Hz.

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3699
4.2.10. (S)-3-Hydroxy-3-(3-methylphenyl)propanenitrile, 2j
Oil; yield, 59%; [h]2D0 −59.3 (c 0.8, CHCl3; ee 94%); H NMR: l (ppm) 2.37 (s, 3H, CH3), 2.69
(br s, 1H, OH), 2.74 (d, J 6.2 Hz, 2H, CH2), 4.98 (t, J 6.1 Hz, 1H, CHꢀO), 7.15–7.35 (m, 4H,
1
H
arom); 13C NMR: 21.3 (CH3), 27.8 (CH2), 70.0 (CHꢀO), 117.3 (CN), 122.5, 126.0, 128.7, 129.4
(CHarom), 138.6, 140.9 (Carom); IR (neat) 3447, 2254 cm−1; MS: m/z (relative intensity) 161 (M+,
12), 143.0 (10), 121 (100), 93 (83); HRMS calc. for C10H11NO 161.084064, found 161.083587;
GC conditions: 172°C, tR(R) 18.6 min and tR(S) 19.9 min. Dl of the MeO group of its MTPA
ester derivatives: −56 Hz.
4.2.11. (S)-3-Hydroxy-3-(4-methylphenyl)propanenitrile, 2k
Oil; yield, 54%; [h]2D0 −53.4 (c 1.5, CHCl3; ee 82%); H NMR: l (ppm) 2.36 (s, 3H, CH3), 2.68
1
(br s, 1H, OH), 2.72 (d, J 6.5 Hz, 2H, CH2), 4.97 (t, J 6.1 Hz, 1H, CHꢀO), 7.20 (d, J 8.3 Hz,
2H, Harom), 7.27 (d, J 8.5 Hz, 2H, Harom); 13C NMR: 21.0 (CH3), 27.7 (CH2), 69.8 (CHꢀO), 117.4
(CN), 125.3, 129.4 (CHarom), 138.0, 138.5 (Carom); IR (neat) 3433, 2257 cm−1; MS: m/z (relative
intensity) 161 (M+, 6), 143.0 (10), 121 (100), 93 (83); HRMS calc. for C10H11NO 161.084064,
found 161.083519; GC conditions: 172°C, tR(R) 19.1 min and tR(S) 20.3 min. Dl of the MeO
group of its MTPA ester derivatives: −45 Hz.
4.2.12. (S)-3-Hydroxy-3-(3-trifluoromethylphenyl)propanenitrile, 2l
Oil; yield, 41%; [h]2D0 −46.1 (c 1.5, CHCl3; ee 98%); 1H NMR: l (ppm) 2.76 (d, J 6.5 Hz, CH2),
3.29 (br s, 1H, OH), 5.10 (t, J 6.1 Hz, 1H, CHꢀO), 7.50–7.65 (m, 4H, Harom); 13C NMR: 27.9
(CH2), 69.1 (CHꢀO), 117.0 (CN), 123.7 (q, J 273 Hz, CF3), 122.3, 125.4, 128.9, 129.3 (CHarom),
131.0 (q, J 32 Hz, CaromꢀCF3), 141.9 (Carom); IR (neat) 3443, 2258 cm−1; MS: m/z (relative
intensity) 215 (M+, <1), 197 (26), 175 (100), 127 (80); HRMS calc. for C10H6F3N (M+−H2O):
197.045233, found 197.045114; GC conditions: 180°C, tR(R) 14.1 min and tR(S) 15.4 min. Dl of
the MeO group of its MTPA ester derivatives: −55 Hz.
4.2.13. (S)-3-Hydroxy-3-(4-methoxyphenyl)propanenitrile, 2m
Yield, 42%; [h]2D0 −59.7 (c 0.6, CHCl3; ee 83%); GC conditions: 182°C, tR(R) 24.4 min and
tR(S) 25.6 min. Dl of the MeO group of its MTPA ester derivatives: −49 Hz.
4.2.14. Methyl (S)-3-hydroxy-4,4-dimethylpentanoate
A solution of 2c (50 mg, 0.4 mmol) in 5 mL of conc. HCl was refluxed for 1 h. After cooling
and diluting with 15 mL of AcOEt, the organic layer was washed with brine, dried and
evaporated to give a white solid. It was solved in 1 mL THF and 0.2 mL MeOH, and treated
with trimethylsilyldiazomethane (0.4 mL of a 2 M solution in hexane). After 5 hours, solvents
were eliminated, the residue diluted in AcOEt, and washed again with brine. The organic phase
was dried and the solvent eliminated. Purification by flash chromatography gave methyl
(S)-3-hydroxy-4,4-dimethylpentanoate as a colourless oil (49 mg, 0.31 mmol, 77%). [h]2D0 −32.2
(c 0.6, EtOH), lit. [h]2D0 +38.4 (c 2.7, EtOH; ee 98% R).17
4.2.15. (S)-2-Cyano-1-cyclohexylethyl acetate
To a solution of 2d (30 mg, 0.2 mmol) in CH2Cl2, 30 mL of Ac2O (0.3 mmol) and 25 mL of
pyridine (0.3 mmol) were added, and it was stirred for 3 hours. Then, water was added to
quench the reaction, and after extraction with CH2Cl2, drying and evaporation of the solvent,
the crude product was purified by flash chromatography (eluent, hexane:AcOEt, 10:1) to provide

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J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 11 (2000) 3693–3700
(S)-2-cyano-1-cyclohexylethyl acetate (28 mg, 0.14 mmol, 72%). [h]2D0 +39.9 (c 1.5, CHCl3), lit.
[h]2D0 +33.3 (c 0.7, CHCl3; ee 82% S).18
Acknowledgements
This work was supported by the CICYT (project BIO 98-0770). J.R.D. thanks the Spanish
Ministerio de Educacio´n y Cultura for a predoctoral scholarship.
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