A mild biosynthesis of lactones via enantioselective hydrolysis of hydroxynitriles

Article abstract of DOI:10.1016/j.tetasy.2007.07.034

We have developed a biocatalytic method to produce lactones and related compounds via the enzymatic hydrolysis of γ- and β-hydroxynitriles. The synthesis is a mild, general, and environmentally friendly way to enantioselectively hydrolyze nitriles with commercially available nitrilase enzymes. The synthesis of four pheromones is demonstrated via a one-step method.

Full text of DOI:10.1016/j.tetasy.2007.07.034

Tetrahedron: Asymmetry 18 (2007) 1888–1892
A mild biosynthesis of lactones via enantioselective
hydrolysis of hydroxynitriles
Julie A. Pollock, Karen M. Clark, Bethany J. Martynowicz, Matthew G. Pridgeon,
Matthew J. Rycenga, Kristen E. Stolle and Stephen K. Taylor*
Department of Chemistry, Hope College, Holland, MI 49422-9000, United States
Received 3 May 2007; accepted 30 July 2007
Abstract—We have developed a biocatalytic method to produce lactones and related compounds via the enzymatic hydrolysis of c- and
b-hydroxynitriles. The synthesis is a mild, general, and environmentally friendly way to enantioselectively hydrolyze nitriles with com-
mercially available nitrilase enzymes. The synthesis of four pheromones is demonstrated via a one-step method.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Chemical hydrolysis of nitriles to carboxylic acids requires
extremely harsh conditions usually involving reflux in con-
centrated acid or base for extended reaction times at high
temperatures.2 The microbial hydrolysis of hydroxynitriles
that produces lactones in good yield under mild conditions
has been developed. Initial investigations in our lab used
Rhodococcus rhodochrous whole cells,3 which include three
types of hydrolytic enzymes: nitrilase, nitrile hydratase, and
amidase (Scheme 1).
Many components of natural flavors and fragrances, insect
pheromones, and building blocks for the synthesis of natu-
ral products and pharmaceuticals are c-butyrolactones.1
The physiological functionality of these lactones is usually
dependent on the enantiomeric purity of the lactone,1
implying that an enantioselective synthesis is important
when preparing the desired stereoisomers. The hydrolysis
of 4-hydroxynitriles to the corresponding hydroxyacid
and subsequent lactonization is a method of producing
these biologically active compounds (Eq. 1) via a one-step
process.
O
Nitrilase
NH3
R
C
N
R
C
OH
Nitrile
Hydratase
O
Amidase
O
C
OH
OH
O
R
R
R
NH2
COOH
CN
-R
R
2
1
Scheme 1. Enzymes used for hydrolysis of nitriles.
ð1Þ
When nitrilases became commercially available, our
emphasis moved to the direct hydrolysis of c-hydroxynitr-
iles to hydroxyacids, and the subsequent internal esterifica-
1a
1b
1c
1d
1e
1f
Et
Bu
C5H11
C8H17
CH2CH(CH3)2
CH(CH3)2
tion to
a lactone (Eq. 1). The benefits of using
biotransformations in performing this chemistry include
mild, environmentally friendly conditions (pH 6 or 7 and
temperatures ranging from 15 °C to 35 °C), clean reactions
due to the selectivity of the nitrilase enzyme, and a general
synthesis method. This work shows that nitrilases can be
*
Corresponding author. Tel.: +1 616 395 7637; fax: +1 616 395 7118;
e-mail: staylor@hope.edu
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.07.034

J. A. Pollock et al. / Tetrahedron: Asymmetry 18 (2007) 1888–1892
1889
enantioselective in their hydrolysis.4 The enantioselective
hydrolysis of a c-hydroxynitrile with a straight side chain
served as a straightforward model (see Table 1). However,
we also wanted to determine the optimum conditions for
this and other analogs. We also investigated the reactivity
of branched side chains of c-hydroxynitriles with nitrilases.
Two straight side chain b-hydroxynitriles were investigated
to determine if having the stereogenic center closer to the
reacting nitrile group had a significant effect.
to make sure that the enzyme did not convert much of the
second enantiomer to the product. Stopping the reaction at
around 30–40% conversion typically gave adequate
enantioselectivity.
From the early experiments NIT 1002, 1003, and 1004
seemed to be the most promising, hence we focused on
improving the selectivity of these enzymes by decreasing
the temperature from 35 °C to 30 °C and the pH from 7
to 6. We also examined three other substrates with ethyl-
1a, pentyl- 1c, and octyl- 1d R-groups where the (R)-enan-
tiomeric lactone products 2a, 2c, and 2d are pheromones of
the Trogoderma beetle,8 rice weevil,9 and rove beetle,10–12
respectively. The pentyl side chain gave the most selective
results, as seen in Table 2. The selectivity was adequate
to serve as a synthesis for these important pheromones.
Reactions that have an E of approximately 10 or higher
have been highlighted.
2. Results and discussion
The c-hydroxynitrile precursors were synthesized using our
general nitrile enolate-epoxide ring opening reaction;5 these
substrates were used extensively in this study.
2.1. Straight-chain isomers
Since we found that in most cases decreasing the tempera-
ture to 30 °C increased the selectivity slightly, we tried
reducing the temperature further to 15 °C in the hope of
obtaining more selective results. In most cases, the temper-
ature actually decreased the E-value and extended the reac-
tion times.
The initial investigations evaluated six commercially avail-
able nitrilase enzymes and their ability to convert enanti-
oselectively
4-hydroxyoctanenitrile
1b
to
the
corresponding lactone. As seen in Table 1, NIT 1001 gave
a racemic product; NIT 1002 and 1003 favored the (R)-
enantiomer, whereas NIT 1004, 1005, and 1006 were selec-
tive for the (S)-enantiomer. The (R)-enantiomer is the par-
asitic wasp pheromone.6
2.2. Chain branching
Table 1. Initial enzymatic lactonization of 4-hydroxyoctanenitrile 1b–2b
at 35 °C, 200 rpm, and pH 7
Next, increasing the selectivity was attempted by using a
branched substrate, 4-hydroxy-6-methylheptanenitrile
(R = isobutyl, Table 3). The branched precursor appar-
ently did not fit into the active site of NIT 1001 and
1006, so it did not convert to the lactone. NIT 1004 was
the only enzyme that transformed both the branched and
straight-chain substrates.
O
OH
OH
O
Bu
Bu
COOH
CN
Bu
2b
Reaction time (h) % Conversion R:S ratio ee
1b
Another branched side chain analogue, 4-hydroxy-5-meth-
ylhexanenitrile, was investigated. Chiral GC or chiral
HPLC could not be used to determine the enantioselectiv-
ity of the reaction. However, the ability of the enzymes to
hydrolyze the nitrile is noteworthy, as seen in Table 4.
Enzyme
E
NIT 1001
NIT 1002
NIT 1003
NIT 1004
NIT 1005
NIT 1006
11
16
16
1
11
48
41
28
27
18
21
6
50:50
66:34
76:24
29:71
45:55
40:60
0
1.0
32 2.2
52 3.8
42 2.7
10 1.3
20 1.5
2.3. Proximity effect
In kinetic resolutions such as these (involving racemic
starting materials), enantioselectivity is a key factor. The
formal calculation of enantioselectivity E was performed
as described by Faber,7 and he discusses why E should ap-
proach 20 when excellent kinetic resolution is desired.
To enhance our study, reactions on b-hydroxynitriles were
performed, where the stereogenic center is closer to the
reacting nitrile group (Eq. 2). The specific b-hydroxynitrile
used was 3-hydroxyheptanenitrile 3. It should be noted that
a lactone does not spontaneously form because of steric
influences (a four-membered ring lactone is difficult to
form). The results (Table 5) show an improved enantiose-
lectivity using NIT 1002 for hydrolysis.
This work shows that the most important part of this syn-
thesis was to stop the enzymatic reaction before 50% con-
version, as is usually true for kinetic resolutions.7
Generally, enzymes are more selective for one enantiomer
of the racemic reactant. Therefore, the enzyme will first
convert this to the product until the more reactive enantio-
mer is depleted. In order to achieve selective results, we had
OH
OH
Nitrilase
CN
COOH
3
4
ð2Þ
Supplied by BioCataytics, Inc.

1890
J. A. Pollock et al. / Tetrahedron: Asymmetry 18 (2007) 1888–1892
Table 2. Results of nitrilases 1002, 1003, and 1004 with c-hydroxynitrile substrates with side chains of 2, 4, 5, and 8 carbons at optimal pH, temperature,
and 200 rpm
O
OH
OH
O
R
R
COOH
CN
R
1
2
Substrate
Lactone
Enzyme
pH
Time (h)
Temp (°C)
% Conversion to 2
R:S
ee
E
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
NIT 1002
NIT 1002
NIT 1002
NIT 1002
NIT 1003
NIT 1003
NIT 1003
NIT 1003
NIT 1004
NIT 1004
NIT 1004
NIT 1004
6
6
7
7
7
6
7
6
6
6
6
6
21.5
24
11.5
11.25
4.6
24
4.6
24
1.75
1.75
1.75
4
37–38
30
30
30
30
30
30
30
30
15
40
42
16
47
26
30
44
3
75:25
82:18
85:15
79:21
77:23
90:10
94:6
60:40
31:69
27:73
25:75
37:63
50
64
70
58
54
80
88
20
38
46
50
26
3.3
6.9
9.3
4.2
1.3
11.8
22.6
1.7
2.3
2.8
30
30
30
6
8
29
3.1
1.9
Table 3. Results of nitrilases with substrate 1e reacting to product 2e at pH 7 and 200 rpm
O
OH
OH
Nitrilase
O
COOH
CN
1e
Time (h)
2e
Enzyme
Temp (°C)
% Conversion
R:S ratio
ee
E
NIT 1001
NIT 1002
NIT 1003
NIT 1004
NIT 1005
NIT 1006
114.5
0.5
51
2
27
36
30
36
35
36
36
0
33
28
27.5
15
0
—
—
48
0
70
6
—
3.6
1
7.3
1.2
—
74:26
50:50
15:85
47:53
—
114.5
—
Table 4. Hydrolysis of 4-hydroxy-5-methylhexanenitrile with nitrilases
1002, 1003, and 1004 at pH 7
Table 5. Reactions of substrate 3 with nitrilases 1002, 1003, and 1004;
conversion to product 4
Enzyme
Reaction time (h) % Conversion R:S ratio ee
E
O
OH
NIT 1002
NIT 1003
NIT 1004
5
30
18.6
13
30
19
9:91
25:75
70:30
82 11.4
O
50
40
3.7
2.6
CN
and b-hydroxynitriles provide a picture of the potential of
these three classes of compounds in enantioselective syn-
thesis. Although the stereogenic center of c- and b-sub-
strates is distant from the reacting center, significant
chiral enantioselection can still be achieved. This reaction
can be carried out under much milder reaction (e.g., neutral
pH and 30 °C) conditions than typical chemical hydrolysis.
More selective enzymes will be developed, but the synthesis
of the rice weevil pheromone 2c using this chemistry is al-
ready demonstrated to be a viable procedure (E >20). We
hope our publication alerts the chemical community to
the potential of these types of reactions.
Enzyme
% Conversion
Temp (°C)
Time (h)
NIT 1002
NIT 1003
NIT 1004
33
29
32
30
32
32
1.5
19
23
3. Conclusion
The investigation of a-hydroxynitriles (cyanohydrins) was
recently communicated.4b These substrates undergo highly
enantioselective hydrolysis. Their work and our study of c-

J. A. Pollock et al. / Tetrahedron: Asymmetry 18 (2007) 1888–1892
1891
Table 6. GC and HPLC retention times for c-lactones and b-hydroxyacid
synthesized
4. Experimental
The nitrilase enzymes used were from BioCatalytics, Inc.
We made hydroxynitriles 1a–d and characterized and
proved their product purities before (Eq. 2),5 and the opti-
cally active lactones were too (made by conventional tech-
niques using optically active epoxides).11,12 Compound 1e
Substrate used Product made Enantiomer Retention time (min)
1a
1b
1c
1d
1e
3
2a
2b
2c
2d
2e
4
(R)
(S)
41.9
43.8
(R)
(S)
21.2
22.1
1
is the only new compound reported, and the 13C and H
(R)
(S)
36.8
38.0
NMR spectra data (and HRMS, etc.) have been supplied
to prove the identity and purity of it (>95%). All reported
enzymatic reactions were performed in duplicate or
triplicate.
(R)
(S)
49.5
49.9
(R)
(S)
16.5
16.8
4.1. General enzymatic procedure
(R)
(S)
4.6
5.8
The enzymatic reactions were performed by adding
approximately 30 mg of hydroxynitrile to less than 10 mg
of nitrilase enzyme in 5 mL of sodium phosphate buffer
in a 20 mL vial. The vial was loosely capped and placed
in an orbit shaker bath at 200 rpm for various periods of
time at the desired temperature. There was some difficulty
with the hydroxyacid failing to completely lactonize, but
when the reaction mixture was allowed to sit for at least
an hour in slightly acidic conditions (pH 3 or 4), more lact-
onization would occur. The reaction mixture was run
through a plug of Florisil with ethyl acetate to remove
the enzyme. The product was extracted twice using 1:1
ethyl acetate–diethyl ether and dried over anhydrous
MgSO4. The solvents were evaporated. The percent conver-
chiral GC (Betadex)-Rt 16.5 min [17% area, (R)-enantio-
mer], 16.8 [83% area, (S)-enantiomer].
When the reaction time was 127 h with NIT 1004, 91%
pure racemic 4-isobutyl-c-butyrolactone15 2f was obtained,
1H NMR d (CHCl3), approximately 0.9 (6H, 2d, J = 7 Hz),
1.25–1.9 (5H, m), 2.15–2.3–2.4 (1H, m), 2.5–2.6 (2H, m),
4.5–4.7 (1H, m).15
4.2.1. Preparation of 3-hydroxyheptanenitrile 3.16,17
Under a nitrogen atmosphere, 10 mL of LDA (2.0 M)
was cooled to ꢀ78 °C. Anhydrous THF (10.5 mL) was
added, immediately followed by acetonitrile (1.1 mL).
After stirring for 1 h, valeraldehyde (2.1 mL) was added
in 10 mL of anhydrous THF and the reaction continued
to stir for 30 min at ꢀ78 °C. TMSCl (4 mL) was added
dropwise and 10 min later, methanol (5.7 mL) was added.
The yellow/white solution was warmed to room tempera-
ture overnight. The white precipitate was filtered using
ethyl acetate and the THF evaporated. The solid was dis-
solved in ethyl acetate and washed with saturated NH4Cl
and NaCl.14 The solvent was removed in vacuo, and the
product purified through distillation, bp 60–63 °C
1
sion was determined using H 400 MHz NMR and inte-
grating the hydrogens at the stereogenic centers of both
the reactant and the product. The lactone was isolated by
small-scale column chromatography using deactivated sil-
ica and dichloromethane. Chiral gas chromatography (Bet-
acyclodextrin column, oven temperature: 100–160 °C) was
used to determine the ratio of enantiomers for the c-
butyrolactones. The (R)-enantiomer eluted first (this was
assumed for 2e). For the b-hydroxynitriles, the spontane-
ous lactonization of the b-hydroxyacid did not occur due
to ring strain. The enantiomers were separated by high per-
formance liquid chromatography using a chiral column
(Chiralcel OD-H). The acid was first derivatized with a
chromophore (esterification with benzyl bromide using
K2CO3 for deprotonation of the acid13) and the selectivity
was determined by detection of the enantiomers with a UV
detector.14 Table 6 shows the retention times for each prod-
uct investigated.
(0.25 mm), IR (NaCl disks) 3400 (OH) and 2250 cmꢀ1
,
1H NMR (CDCl3) d 0.93 (t, J = 7 Hz, 1H), 1.25–1.5 (m,
4H), 1.55–1.7 (m, 2H), 2.46 (dd, J = 6 and 16.4 Hz, 1H),
2.52 (dd, J = 5 and 16.5 Hz, 1H), 3.96 (m, 1H), 2.1 (br,
OH): 13C NMR (CDCl3) d 13.9, 22.4, 26.1, 27.5, 36.2,
67.7, and 117.7.16,17
4.2. 4-Hydroxy-6-methylheptanenitrile 1f + NIT 1004
4.2.2. 3-Hydroxyheptanoic acid 4.18,19 Compound 4 was
prepared by the general enzymatic procedure. The resulting
oil was dissolved in 15 mL of 1:1 EtOAc–ether, and the or-
ganic layer was extracted with 5% NaHCO3. The aqueous
layer was acidified to pH 3 by the dropwise addition of 1 M
HCl, after which it was extracted with 15 mL of 1:1
EtOAc–ether solvent mixture. After drying over Na2SO4,
the organic layer was evaporated. The resulting organic
product was analyzed. 1H NMR (CDCl3) d 0.91 (t,
J = 7 Hz, 3H), 1.25–1.6 (m, 6H), 2.4–2.6 (m, 2H), 2.7–3.5
(br, 2OH), 4.0 (m, 1H); IR (NaCl disks) 3650–2700
(COOH) 1715 (–C@O), 2250 (w, –CN). This acid was most
often isolated as the ester.19
In a 20 mL vial, 0.0073 g of NIT 1004 0.0341 g of the 4-
hydroxyoctanenitrile, and 5 mL of pH 7 sodium phosphate
buffer were combined. The vial was loosely capped and
placed in the orbit shaker bath (35 °C, 200 rpm) for
1.5 h. The solution was made slightly acidic by adding
1 M HCl. The reaction mixture was filtered through a plug
of Florisil using ethyl acetate and then extracted with 1:1
ethyl acetate–diethyl ether. The organic layers were dried
over anhydrous MgSO4 and the solvents were evaporated
(0.019 g, 55% crude yield). 1H NMR: d 3.81 (1H, hydroxy-
nitrile), 4.57 (0.28H, lactone), 22% conversion. The lactone
was isolated, and the R:S ratio was determined through

1892
J. A. Pollock et al. / Tetrahedron: Asymmetry 18 (2007) 1888–1892
4.2.3. Esterification of 3-hydroxyheptanoic acid 3.13 3-
Hydroxyheptanoic acid (20 mg prepared from the nitrilase
reaction) was dissolved in 1.0 mL of dry DMF. Under
nitrogen, K2CO3 (0.040 g) and benzyl bromide (20 lL)
were added. The white-yellow reaction mixture was stirred
for 3 h. Ether (5 mL) and water (5 mL) were then added.
After extraction with ether, the organic layer was washed
with 15% NaCl and dried over anhydrous MgSO4. The sol-
vent was evaporated giving approximately 10 mg of the es-
ter of 4.
1979, 44, 2169–2175; (e) Gopalan, A.; Lucero, R.; Jacobs, H.;
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4. (a) Robertson, D. E.; Chaplin, J. A.; DeSantis, G.; Podar,
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4.3.1. 4-Hydroxy-6-methylheptanenitrile 1e. The clear,
colorless oil was purified through distillation (102–103 °C
at 1.5 mmHg); 50–65% yield; IR: 3365 (br), 2249 (–CN),
1
1665, 1601 1140, 1084, 1051 cmꢀ1; H NMR: d 3.80 (1H,
6. Paddon-Jones, G. C.; Moore, C. J.; Bracknell, D. J.; Konig,
m), 2.51 (2H, m), 1.91 (1H, s), 1.70 (3H, m), 1.40 (1H,
m), 1.25 (1H, m), 0.94 (3H, d, J = 6.7 Hz), 0.93 (3H, d,
J = 6.7 Hz); 13C NMR: d 13.6, 21.9, 23.2, 24.5, 32.9,
46.4, 67.9, 119.9; TLC: Rf = 0.30 in 1:1 hexanes–ethyl ace-
tate; Cap. GC: tR = 11.73 min (29 m capillary column, HP
6890, 50 °C for 4 min then 10 °C/min up to 300 °C for
20 min); MS (EI) m/z 141 (1), 84 (59), 69 (100); 41 (77):
HRMS (EI) 141.1154 (calcd) 141.1149 (actual).
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7. E ¼
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We would like to acknowledge Pfizer Inc. for donating the
orbit shaker bath and the Michigan State University Mass
Spectrometry Facility. We gratefully acknowledge support
from the National Science Foundation REU program
(#0243828), Research Corporation and GlaxoSmithKline,
Inc.
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