Preparation of novel phenylfuran-based cyanohydrin esters: Lipase-catalysed kinetic and dynamic resolution

Article abstract of DOI:10.1016/S0957-4166(03)00286-6

A series of novel (R)-5-phenylfuran-2-yl cyanomethyl butanoates were prepared by Pseudomonas cepacia lipase-catalysed dynamic kinetic resolution in toluene. The method exploits a basic resin both for the racemization and formation of phenylfuran-based cyanohydrins and for the decomposition of acetone cyanohydrin in one-pot with enzymatic enantioselective acylation using vinyl butanoate. The lipase-catalysed methanolysis of racemic 5-phenylfuran-2-yl cyanomethyl butanoates in toluene with E ?100 was shown to be usable when the corresponding (S)-butanoates are needed. Candida antarctica lipase A provided racemic cyanohydrin butanoates with quantitative chemical yields under mild conditions.

Full text of DOI:10.1016/S0957-4166(03)00286-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1895–1904
Preparation of novel phenylfuran-based cyanohydrin esters:
lipase-catalysed kinetic and dynamic resolution
Csaba Paizs,a,b Petri Ta¨htinen,a Katri Lundell,a La´szlo´ Poppe,c Florin-Dan Irimieb and
Liisa T. Kanervaa,*
aLaboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku, Lemminka¨isenkatu 2,
FIN-20520 Turku, Finland
bDepartment of Biochemistry and Biochemical Engineering, Babes¸-Bolyai University, Arany Ja´nos 11,
RO-3400 Cluj-Napoca, Romania
cInstitute for Organic Chemistry and Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences,
Budapest University of Technology and Economics, H-1111 Budapest, Gelle´rt te´r 4, Hungary
Received 24 March 2003; accepted 1 April 2003
Abstract—A series of novel (R)-5-phenylfuran-2-yl cyanomethyl butanoates were prepared by Pseudomonas cepacia lipase-
catalysed dynamic kinetic resolution in toluene. The method exploits a basic resin both for the racemization and formation of
phenylfuran-based cyanohydrins and for the decomposition of acetone cyanohydrin in one-pot with enzymatic enantioselective
acylation using vinyl butanoate. The lipase-catalysed methanolysis of racemic 5-phenylfuran-2-yl cyanomethyl butanoates in
toluene with E ꢀ100 was shown to be usable when the corresponding (S)-butanoates are needed. Candida antarctica lipase A
provided racemic cyanohydrin butanoates with quantitative chemical yields under mild conditions. © 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
tive chemical yields. In these reactions, both isolated
highly optimised enzymes4–6 and unisolated enzymes
such as economical defatted meals7,8 and dechloro-
phylled shoots7 have served as asymmetric catalysts.2
Enzymatic kinetic resolution is another effective biocat-
alytic approach to optically active cyanohydrins. This
has been previously accomplished by the acylation of
racemic cyanohydrins and by the lysis of the acylated
counterparts in the presence of a suitable lipase9,10 or
by the oxynitrilase-catalysed enantioselective decompo-
sition of racemic cyanohydrins.11–13 The main disadvan-
tage of the traditional resolution method is, however,
the maximum 50% theoretical yield of one enantiomer
and the dependence of enantiomeric excess (ee) on the
conversion of a reaction. These disadvantages are over-
come in dynamic kinetic resolution, where a racemic
mixture is transformed to one of the enantiomers by
racemizing the less reactive enantiomer in situ in the
course of the process. This principle was previously
exploited for lipase-catalysed enantioselective acylations
with isopropenyl acetate using an efficient one-pot syn-
thesis of cyanohydrin esters in the presence of a basic
resin.10,14,15 A modification of this method previously
allowed the preparation of (R)-furylbenzotiazol-based
cyanohydrin acetates.16
Phenylfuran-based structures are important units for
the synthesis of various kinds of biologically active
molecules. When a phenylfuran-based structure is
attached to a stereogenic centre in a molecule the
preparation of enantiomers will be required. For that
purpose biocatalysts where enantioselectivity is intro-
duced by the homochirality of an enzyme, are becom-
ing increasingly attractive tools for synthetic
chemistry.1 The value of biocatalysis is now more rele-
vant than ever for environmental reasons in addition to
the demand for high enantioselectivities.
Optically active cyanohydrins are versatile intermedi-
ates for organic synthesis, since cyanohydrin enan-
tiomers can be easily converted to other optically active
compounds. Two main biocatalytic methods are known
for the preparation of optically active cyanohydrins.2,3
The (R)- and (S)-oxynitrilase-catalysed enantioface
addition of hydrogen cyanide to an aldehyde or ketone
offers highly enantiopure products in almost quantita-
* Corresponding author. E-mail: lkanerva@utu.fi
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00286-6

1896
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
2a–e (Scheme 2). In order to supply the need for
(S)-cyanohydrin esters, the lipase-mediated alcoholysis
of racemic butanoates 3a–e was studied (Scheme 3).
Moreover, chemical and lipase-catalysed methods for
the preparation of racemic esters 3a–e for analytical
and substrate purposes are described.
In this work, enzymatic possibilities for the preparation
of highly enantiopure hydroxy-(5-phenylfuran-2-yl)-
acetonitriles were investigated. At the early stage of the
studies it was shown that our model aldehyde 1c was
not a substrate for (R)-oxynitrilase in almond meal and
attention was focused on lipase-catalysed reactions. We
now report the preparation of novel (R)-cyanohydrin
butanoates 3a–e from the corresponding aldehydes 1a–e
and acetone cyanohydrin (source of HCN) by the
lipase-catalysed dynamic kinetic resolution of cyanohy-
drins 2a–e with vinyl butanoate in the presence of
Amberlite IRA-904 basic resin in non-aqueous media
(Scheme 1). Vinyl butanoate was used as an acyl donor
because the resulting butanoates 3a–e were easily sepa-
rated by the chiral HPLC method, whereas the enan-
tiomers of the corresponding acetates were unseparable.
Traditional kinetic resolution provides the enantioselec-
tivity basis for successful dynamic kinetic resolution.
Accordingly, reaction conditions were first optimized
for the lipase-catalysed acylation of novel cyanohydrins
2. Results and discussion
2.1. Kinetic enzymatic resolution by acylation
A large number of commercially available lipases
exhibit a high degree of substrate tolerance, leading to
products with various degrees of enantioselectivity.
Potential lipases were screened for the enantioselective
acylation of cyanohydrin rac-2c as a model substrate
with vinyl butanoate as an irreversible acyl donor using
diisopropyl ether as solvent (Scheme 2). The behaviour
of lipases greatly differs. While lipases AK and F are
Scheme 1. One pot synthesis of (R)-(+)-3a–e by dynamic kinetic resolution.
Scheme 2. Kinetic resolution of racemic cyanohydrins 2a–e.
Scheme 3. Kinetic resolution of racemic cyanohydrin esters 3a–e.

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
Table 2. Acylation of cyanohydrins 2a–e with vinyl
1897
catalytically inactive, lipase PS (E=15 2) and CAL-B
(E=10 0.3) enantioselectively catalyse the reaction. In
the case of CAL-A, a fast reaction leads to the forma-
tion of racemic butanoate 3c with almost quantitative
chemical yields. Since the best selectivity was observed
with lipase PS, this enzyme was used for further studies.
It is worth emphasizing that for catalytic activity of
lipase PS it is essential that immobilized enzyme is
involved. Thus, no reaction between 2c and vinyl
butanoate was observed in the presence of a native
enzyme in toluene within 2 weeks, whereas the initial
rate wo=0.19 mmol mg−1 h−1 was observed when the
present enzyme preparation (the enzyme adsorbed on
Celite in the presence of sucrose)17 was used. Effects of
other immobilization methods on reactivity were not
investigated in this work.
butanoate in toluene by lipase PS preparation (10 mg
ml−1
)
Entry
Resolution
products
E
Time (h)
Conv. (%)
1
2
3
4
5
(S)-2a, (R)-3a
(S)-2b, (R)-3b
(S)-2c, (R)-3c
(S)-2d, (R)-3d
(S)-2e, (R)-3e
1390.2 168
26
47
46
43
39
84915
96
96
96
96
82912
2591
144923
2.2. Dynamic kinetic resolution and the preparation of
(R)-cyanohydrin esters
As a general requirement for enzymatic dynamic kinetic
resolution, the enzyme must stay active throughout the
reaction and the less reactive enantiomer must be
rapidly racemized under the conditions where the
product of an enzyme-catalysed reaction is stable.
Under such conditions, the starting material is always
racemic, allowing the maxim enantiopurity (determined
by the E value for the corresponding kinetic resolution)
at the theoretical zero conversion to the more reactive
enantiomer to be maintained throughout the reaction.
This is extremely important for an enzymatic reaction
proceeding enantioselectively since ee of the product
enantiomer tends to decrease with increasing conver-
sion of kinetic resolution especially at E values less than
100.
In order to enhance enantioselectivity (E values), the
lipase PS-catalysed acylation of cyanohydrin rac-2c
with vinyl butanoate was carried out in different sol-
vents (Table 1). The cost of the high enantioselectivity
in acetonitrile and dichloromethane is a significant drop
in reactivity (conversion reached after the certain time,
entries 1 and 2). Vinyl butanoate and toluene proved to
be the best solvents for the present acylation (entries 7
and 8). Due to the low solubility of cyanohydrin esters
3a, 3d and 3e in vinyl butanoate and for economic
reasons, toluene was chosen for further investigations.
For the production of (R)-cyanohydrin butanoates 3a–
e (Scheme 1), a fast equilibrium between a cyanohydrin
and the corresponding aldehyde (and acetone) and
hydrogen cyanide in the presence of a base is essential
for the present method. In order to show that cyanohy-
drins are smoothly produced at high enough amounts,
the mixture of aldehyde 1c (0.15 mmol) and acetone
cyanohydrin (0.325 mmol) in the presence of the
Amberlite IRA-904 basic resin (5 mg ml−1; 0.65 mmol
ml−1) were studied in toluene at room temperature. The
equilibrium value [2c]/[1c]=6 was reached in less than 3
h clearly satisfying the requirement. In order to verify
the enantiomeric stability of the products, the effect of
the basic resin (5 mg ml−1; 0.65 mmol ml−1) was investi-
gated on the product mixture [(S)-2a–e and (R)-3a–e]
of the above-described kinetic resolution (Scheme 2).
Free (S)-cyanohydrins 2a–e were racemized within less
than 2 h while the enantiopurity of (R)-cyanohydrin
esters 3a–e was still unchanged after 7 days.
Table 1. Solvent effects on the acylation of cyanohydrin
rac-2c with vinyl butanoate by lipase PS preparation (10
mg ml−1
)
Entry Solvent
E
Time (h) Conv. (%)
1
2
3
4
5
6
7
8
Acetonitrile
ꢀ100
ꢀ100
1592
–
168
168
96
168
168
144
96
7
16
45
0
Dichloromethane
Diisopropyl ether
t-Butanol
Tetrahydrofuran
t-Butyl methyl ether 990.2
–
0
35
46
47
Toluene
Vinyl butanoate
82912
70910
96
Lipase PS shows different reactivity and selectivity in
the acylation of racemic cyanohydrins 2a–e with vinyl
butanoate in toluene (Table 2). While conversion in 4
days is only slightly influenced by the position and
properties of the substituents R1 and R2 in 2b–e (entries
2–5), a considerably lower reactivity is evident for
substrate 2a (entry 1). Strongly electron withdrawing
substituents R2 (CO2Et and NO2) seem to result in low
enzymatic enantioselectivities for 2a and 2d (entries 1
and 4), whereas the presence of electron donating
methyl substituent R1 in 2e leads to improved enan-
tioselectivity when compared to that observed for 2d
(entries 5 and 4, respectively).
The amount of the basic resin is critical for the dynamic
kinetic resolution as previously pointed out in the case
of mandelonitrile as a substrate.15 When the amount is
too low it can be neutralized by the formation of
butanoic acid that is liberated from the achiral acyl
donor by the lipase-catalysed action of the water in the
formally dry enzyme preparation and by the presence
of hydrogen cyanide. That the basic resin still is active
at the end of the dynamic kinetic resolution of 2c was
shown by adding a new proportion of acetone cyanohy-
drin. The dark brown color appeared immediately,
indicating that the base-catalysed decomposition of ace-

1898
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
tone cyanohydrin had produced hydrogen cyanide the
formation of which was followed by its base-catalysed
polymerization.18 The dark brown color was also intro-
duced when 10 mg ml−1 (1.3 mmol ml−1) of the resin in
the dynamic kinetic resolution mixture was used instead
of 5 mg ml−1, the high base content totally preventing
the enzymatic acylation.
2.3. Kinetic enzymatic resolution by alcoholysis
For the preparation of cyanohydrin enantiomers by
kinetic resolution, it is advantageous to select a reaction
which gives the desired enantiomer as a less reactive
acylated counterpart because the separation of the reso-
lution products (one enantiomer as a free cyanohydrin
and the other as an acylated counterpart) often leads to
considerable decomposition and racemization of the
free cyanohydrin. Accordingly, racemic cyanohydrin
esters 3a–e were subjected to the lipase PS-catalysed
alcoholysis with methanol and propanol in toluene in
order to prepare (S)-cyanohydrin esters (Scheme 3;
Table 4). Highly enantioselective reactions tended to
stop at 50% conversion, affording the two enantiomers
simultaneously in the resolution mixture.
In the present one-pot synthesis of (R)-cyanohydrin
butanoates 3a–e by lipase PS (Table 3), the observed ee
values are in accordance with the theoretical values that
can be calculated by the equation of Chen et al.19 using
the E values in Table 2 and extrapolating ee to zero
conversion. Finally, gram-scale reactions stopped at
high conversions, indicating that the aldehydes can be
almost totally converted to the corresponding (R)-
cyanohydrin butanoates. The products were also iso-
lated in high chemical yields. As is shown in Table 3,
reaction times are strongly affected by the enzyme
content and temperature, these variables not having an
effect on the high enantiopurities. This allows the
choice between using low amounts of the expensive
enzyme or to save time under otherwise less economical
conditions.
2.4. Preparation of racemic cyanohydrin esters
The above enzyme screening proved CAL-A to be an
excellent, fast and environmentally benign catalyst for
the preparation of racemic ester 3c. Encouraged by this,
cyanohydrins 2a–e were subjected to acylation with
vinyl butanoate in toluene in the presence of CAL-A.
Table 3. Dynamic kinetic resolution of cyanohydrins 2a–e with vinyl butanoate in toluene by lipase PS preparation
a
Entry
Product
Conv. (%)
Yield (%)
Time (h)
Ee (%)
Theoretical ee (%)
[h]D
1
2
3
4
5
6
7
8
(R)-3ab
(R)-3ac
(R)-3ad
(R)-3bb
(R)-3bc
(R)-3bd
(R)-3cb
(R)-3cc
(R)-3cd
(R)-3db
(R)-3dc
(R)-3dd
(R)-3eb
(R)-3ec
(R)-3ed
75
81
86
69
72
73
79
93
94
93
92
92
82
91
92
88
91
93
168
120
72
168
96
36
168
96
36
168
96
36
168
96
80
80
79
97
96
96
95
95
95
91
91
91
98
96
96
85
85
–
98
98
–
97
97
–
92
92
–
+4.4
+4.4
+4.4
+9.0
+8.8
+8.8
+3.2
+3.2
+3.1
+11.1
+11.1
+11.0
+4.8
+4.7
+4.7
86
\99
\99
91
\99
\99
87
\99
\99
95
\99
\99
9
10
11
12
13
14
15
98
98
–
36
a t=25°C, (c 1, CHCl3).
b 10 mg ml−1 of the enzyme preparation, 22–23°C.
c 50 mg ml−1 of the enzyme preparation, 22–23°C.
d 50 mg ml−1 of the enzyme preparation, 45°C.
Table 4. Alcoholysis of cyanohydrin esters 3a–e with an alcohol in toluene by lipase PS preparation (10 mg ml−1
)
Entry
Substrate
ROH (M)
Time (h)
Conv. (%)
Ee(S)-3 (%)
Ee(R)-2 (%)
E
1
2
3
4
5
6
7
8
rac-3a
rac-3b
rac-3c
rac-3c
rac-3c
rac-3c
rac-3d
rac-3e
Methanol (0.8 M)
Methanol (0.8 M)
Methanol (0.8 M)
Methanol (0.4 M)
Propanol (0.8 M)
Propanol (0.4 M)
Methanol (0.8 M)
Methanol (0.8 M)
144
48
48
48
48
48
48
48
47
50
50
49
49
51
50
50
82
\99
\99
91
90
98
93
\99
\99
95
94
92
7092
ꢀ100a
ꢀ100a
13195
9392
12098
ꢀ100a
ꢀ100a
\99
\99
\99
\99
a Only one enantiomer was detected by the HPLC method.

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
1899
In 2 h the substrates were totally transformed to the
butanoate esters 3a–e (method A; Table 5). For the
chemical acylation of the cyanohydrins 2a–e with
butanoic anhydride (method B), the presence of 4-N,N-
dimethylaminopyridine in pyridine and triethylamine is
necessary. The chemical reactions are accompanied by the
formation of several unidentified by-products in addition
to the related aldehydes 1a–e and lead to moderate
chemical yields for 3a–e. Accordingly, the enzymatic
method A is clearly better than the chemical method B
which suffers from the lability of cyanohydrins.
Jeol Lambda 400 spectrometer operating at 399.78 and
1
100.54 MHz, respectively. H spectra were referenced
internally to the solvent signal (CH
spectra to the solvent signal (CDCl3, 77.00 ppm). The
6
Cl3, 7.24 ppm); 13C
6
correct assignment of the chemical shifts was confirmed
by use of standard 13C, H correlation measurements.
1
Either f1-decoupled heteronuclear correlation spec-
troscopy method (CHSHF) or heteronuclear multiple-
quantum correlation spectroscopy method preceding a
bilinear rotation decoupling pulse sequence (HMQC-
BIRD) was used for tracking the direct connectivity
between the 13C and 1H nuclei (methods optimized to 145
1
Hz JCH coupling). For tracking the connectivity over
Table 5. Enzymatic (method A) and chemical (method B)
synthesis of racemic 3a–e
multiple-bonds, either correlation via long-range cou-
pling spectroscopy method (COLOC) or heteronuclear
multiple-bond correlation spectroscopy method preced-
ing a bilinear rotation decoupling pulse sequence
Product
Method A
Yield (%)a
Method B
Yield (%)a
n
Conv. (%)
Time (h)
(HMBC-BIRD) was used (methods optimized to JCH
couplings of 4 or 8 Hz). Mass spectra (MS) were taken
on a VG 7070E mass spectrometer.
rac-3a
rac-3b
rac-3c
rac-3d
rac-3e
\99
\99
\99
\99
\99
95
96
95
94
94
2
2
2
2
2
66
71
68
70
67
Highperformanceliquidchromatography(HPLC)analy-
ses were conducted with a HP 1090 instrument using a
CHIRACEL OD column (0.46×25 cm) and elution with
the mixture of hexane and isopropyl alcohol (9:1).
Baseline enantiomeric separation of all chiral substances
2a–e, 3a–e was performed. For quantitative chromato-
graphic determination, molar abortion constants (m) were
used. UV spectra were taken with a Helios Lambda
spectrofotometer. Thin layer chromatography (TLC) was
carried out using Merck Kieselgel 60F254 sheets. Spots
were visualized by treatment with 5% ethanolic phospho-
molybdic acid solution and heating. Preparative chro-
matographic separations were performed using column
chromatography on Merck Kieselgel 60 (0.063–0.200
mm). Melting points were determined by a hot plate
method and are uncorrected. Optical rotations (c 1,
CHCl3) were determined on a Perkin Elmer 241 polarime-
ter. Elemental analyses of 2a–c (lability of 2d and 2e
prevented the determination) and 3a–e were performed
with a Perkin–Elmer CHNS-2400 Ser II Elemental Analy-
ser. The determination of E was based on equation
E=ln[(1−c)(1−eeS)]/ln[(1−c)(1+eeS)].19 Using linear
regression E is achieved as the slope of a line. All
enzymatic reactions were performed at room temperature
(23–24°C).
a Isolated yield.
3. Conclusion
The present work describes the predictability of dynamic
kinetic resolution for the preparation of novel cyanohy-
drinbutanoates(R)-3a–e(Table3). Themethodcombines
the base-catalysed in situ formation of racemic cyanohy-
drins 2a–e from the corresponding aldehydes 1a–e and
hydrogen cyanide to the in situ lipase-catalysed kinetic
resolution and to the base-catalysed in situ racemization
of the less reactive (S)-2a–e (Scheme 1). In most cases,
more than 99% of an aldehyde was easily transformed
to the corresponding (R)-3 with high enantiopurity, the
efficiency of the method depending on the amount of the
enzyme and temperature. As an advantage of the present
method the separate preparation and purification of
relatively labile cyanohydrins is not necessary. As another
benefit, the handling of hydrogen cyanide is avoided by
making use of the base-lability of acetone cyanohydrin.
In addition, an effective and fast enzymatic method for
the preparation of racemic 3a–e from the corresponding
cyanohydrin with vinyl butanoate in the presence of
CAL-A in toluene is described.
4.1.2. Reagents and solvents. Anilines, furfural, vinyl
butanoate, trimethylsilyl cyanide, CuCl2 and ZnI2 were
products of Aldrich or Fluka. All solvents were purified
and dried by standard methods as required.20 Amberlite
IRA 904 was purchase from Acros and it was conditioned
as previously described.14
The lipase PS-catalysed alcoholysis of racemic 3a–e with
methanol in toluene proved to be a convenient method
for the preparation of (S)-cyanohydrin butanoates 3a–e
through traditional kinetic resolution proceeding at high
enantioselectivity (E ꢀ100).
4.1.3. Biocatalyst. Lipases from Pseudomonas fluorescence
(lipase AK), Pseudomonas cepacia (lipase PS) and Rhizo-
pus oryzae (lipase F) were from Amano Europe, England.
Lipase A (CAL-A) and lipase B (CAL-B, Chirazyme L2)
from Candida antarctica were purchased from
Boehringer-Mannheim. Before use CAL-A and lipases
AK and PS were adsorbed on Celite (4.0 g) by dissolving
the enzyme and sucrose (0.24 g) in Tris–HCl buffer (pH
7.9) and thereafter left to dry at room temperature.17 The
4. Experimental
4.1. Materials and methods
4.1.1. Analytical methods. The 1H and 13C nuclear
magnetic resonance (NMR) spectra were recorded on a

1900
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
final lipase content in the enzyme preparation was 20%
(w/w).
(95), 251 (29), 250 (100) [M]+, 249 (18), 222 (6), 196 (4),
195 (37), 194 (4), 193 (38), 157 (2), 155 (2), 116 (3), 115
(29), 114 (37), 113 (15); 1H NMR (CDCl3, 25°C):
l=6.80 (d, J=3.64 Hz, 1H, C(4)-H), 7.28 (d, J=3.64
Hz, 1H, C(3)-H), 7.53 (d, J=8.56 Hz, 2H, C(3%)-H,
C(5%)-H), 7.64 (d, J=8.56 Hz, 2H, C(2%)-H, C(6%)-H),
4.2. Synthesis of aldehydes 1a–e
5-Phenylfuran-2-carbaldehydes were prepared using the
Meerwein method.21 To a solution of one of the diazo-
9.62 (s, 1H, C(2)-CH6
O); 13C NMR (CDCl3, 25°C):
nium salts R1R2PhN2 Cl− (ca. 0.1 mol) in water (100
+
l=108.04 (C(4)), 123.40 (C(3)), 123.87 (C(4%)), 126.63
(C(2%), C(6%)), 127.81 C(1%), 132.14 ((C(3%), C(5%)), 152.09
ml) furan-2-carbaldehyde (9.6 g, 8.28 ml, 0.1 mol) and
cuprous chloride (9.9 g, 0.1 mol) were added at 0–5°C
and the reaction mass was stirred at room temperature
for 48 h. The product 1a–e was filtered, washed with
water (4×50 ml), dried, purified by column chromatog-
raphy on silica gel with dichloromethane and recrystal-
lized from hexane 1a,b or ethanol 1c–e.
(C(2)), 158.14 (C(5)), 177.2 C(2)-C6 HO; anal. calcd for
C11H7BrO2: C, 52.62; H, 2.81; Br, 31.82. Found: C,
52.66; H, 2.84; Br, 31.85%.
4.2.4. 5-(4-Nitrophenyl)furan-2-carbaldehyde 1d. Yield:
62%; mp: 203°C (lit. 203–204°C)25; m ([mol−1 dm3 cm−1],
u [nm]): 5.08×104 (271), 7.36×104 (330); HRMS M+
found (M+ calculated for C11H7NO4): 217.03725
(217.03751); MS: m/z (relative intensity)=218 (12), 217
(100) [M]+, 216 (6), 188 (3), 187 (19), 172 (1), 171 (6),
170 (2), 160 (2), 159 (6), 143 (2), 142 (4), 131 (4), 117
(2), 116 (3), 115 (32), 114 (22), 113 (8); 1H NMR
(CDCl3, 25°C): l=7.02 (d, J=3.7 Hz, 1H, C (4)-H),
7.35 (d, J=3.7 Hz, 1H, C(3)-H), 7.96 (dd, J=8.97 Hz,
J=2.2 Hz, 2H, C(2%)-H, C(6%)-H), 8.29 (dd, J=8.97 Hz,
J=2.2 Hz, 2H, C(3%)-H, C(5%)-H), 9.71 (s, 1H, C(2)-
4.2.1. 5-(4-Carboxyethylphenyl)furan-2-carbaldehyde 1a.
Yield: 73%; mp: 125°C (lit. 124.5–126°C)22; m ([mol−1
dm3 cm−1], u [nm]): 7.83×104 (270), 11.24×104 (330);
HRMS M+ found (M+ calculated for C14H12O4):
244.07408 (244.07356); MS: m/z (relative intensity)=
246 (2), 245 (12), 244 (81) [M]+, 243 (2), 217 (3), 215
(24), 214 (6), 201 (2), 200 (16), 199 (100), 172 (3), 171
(6), 160 (1), 159 (9), 116 (3), 115 (29), 114 (14), 113 (6);
1H NMR (CDCl3, 25°C): l=1.37 (t, J=7.2 Hz, 3H,
CH6
O); 13C NMR (CDCl3, 25°C): l=110.6 (C(4)),
C(4%)-COOCH2CH3
6 ), 4.36 (q, J=7.2 Hz, 2H, C(4%)-
122.8 (C(3)), 124.4 (C(3%), C(5%)), 125.8 (C(2%), C(6%)),
134.6 (C(1%)), 147.9 (C(4%)), 153.0 (C(2)), 156.3 (C(5)),
COOCH2CH3), 6.92 (d, J=4 Hz, 1H, C(4)-H), 7.30 (d,
6
J=4 Hz, 1H, C (3)-H), 7.83 (d, J=8.52 Hz, 2H,
C(2%)-H, C(6%)-H), 8.06 (d, J=8.52 Hz, 2H, C(3%)-H,
177.6, (C(2)-C
6 HO); anal. calcd for C11H7NO4: C, 60.83;
H, 3.25; N, 6.45. Found: C, 60.86; H, 3.34; N, 6.52%.
C(5%)-H), 9.64 (s, 1H, C(2)-CH
25°C): l=14.24 (C(4%)-COOCH2C
COOCH2CH3), 109.27 (C(4)), 123.09 (C(3)), 124.92
6
O); 13C NMR (CDCl3,
6
H3), 61.17 (C(4%)-
4.2.5.
5-(2-Methyl-4-nitrophenyl)furan-2-carbaldehyde
6
1e. Yield: 65%; mp: 143°C; m ([mol−1 dm3 cm−1], u [nm]):
2.53×104 (272), 3.54×104 (318); HRMS M+ found (M+
calculated for C12H9NO4): 231.05333 (231.05316); MS:
m/z (relative intensity)=232 (2), 231 (14) [M]+, 203 (1),
202 (12), 201 (100), 158 (4), 146 (7), 145 (4), 144 (6), 132
(2), 131 (7), 130 (50), 129 (9), 128 (31), 127 (19), 126 (7),
(C(2%), C(6%)), 130.09 (C(3%), C(5%)), 131.02 (C(4%)),
132.62 (C(1%)), 152.44 (C(2)), 157.88 (C(5)), 165.81
(C(4%)-C6 OOCH2CH3), 177.37 (C(2)-C6 HO); anal. calcd
for C14H12O4: C, 68.85; H, 4.95. Found: C, 68.86; H,
4.89%.
1
119 (4), 118 (12), 117 (2), 116 (9), 115 (20); H NMR
4.2.2. 5-(2-Chlorophenyl)furan-2-carbaldehyde 1b. Yield:
67%; mp: 77°C (lit. 76.5–77°C)23; m ([mol−1 dm3 cm−1], u
[nm]): 1.82×104 (265), 7.29×104 (323); HRMS M+ found
(CDCl3, 25°C): l=2.44 (s, 3H, C(2%)-CH6 3), 6.71 (d,
J=3.84 Hz, 1H, C(4)-H), 7.27 (d, J=3.84 Hz, 1H,
C(3)-H), 7.43 (d, J=8.12 Hz, 1H, C(6%)-H), 7.59 (s, 1H,
C(3%)-H), 7.68 (d, J=8.12 Hz, 1H, C(5%)-H), 9.63 (s, 1H,
(M+
calculated
for
C11H7ClO2):
206.013140
C(2)-CH
H3, 111.51 (C(4)), 120.1 (C(1%)), 122.1 (C(3)), 124.62
6
O); 13C NMR (CDCl3, 25°C): l=21.08 C(2%)-
(206.013457); MS: m/z (relative intensity)=209 (4), 208
(32), 207 (20), 206 (100) [M]+, 205 (27), 204 (3), 180 (2),
179 (1), 178 (6), 152 (2), 151 (18), 150 (6), 149 (56), 116
(2), 115 (17), 114 (17), 113 (10); 1H NMR (CDCl3,
25°C): l=7.24 (m, J=4.1 Hz, 2H, C(4)-H, C(4%)-H),
7.27 (d, J=3.8 Hz, 1H, C(3)-H), 7.30 (ddd, J=7.4 Hz,
J=1.4 Hz, 1H, C(5%)-H), 7.40 (dd, J=7.9 Hz, J=1.5
Hz, 1H, C(3%)-H), 7.93 (dd, J=7.68 Hz, J=1.92 Hz,
C
6
(C(3%)), 129.82 (C(5%)), 133.05 (C(6%)), 141.42 (C(2%)),
147.78 (C(4%)), 152.65 (C(2)), 153.68 (C(5)), 177.56,
C(2)-C6 HO; anal. calcd for C12H9NO4: C, 62.34; H,
3.92; N, 6.06. Found: C, 62.36; H, 3.88; N, 6.12%.
4.3. Synthesis of racemic cyanohydrins 2a–e
1H, C (11)-H), 9.62 (s, 1H, C(2)-CH6
O); 13C NMR
Using a known method,26 a catalytic amount of ZnI2
(3.2 mg, 10 mmol) and trimethylsilyl cyanide (119 mg,
150 ml, 1.2 mmol) were added to a stirred solution of
one of the aldehydes 1a–e (1 mmol) in dry
dichloromethane (10 ml) and the resulting mixture was
stirred at room temperature until the entire quantity of
an aldehyde was transformed. The solvent was evapo-
rated and the crude product redissolved in 10 ml aceto-
nitrile. The formed trimethylsilyl cyanohydrin
decomposed when HCl (3 M, 2 ml) was added. The
reaction mass was evaporated to the final volume of 2
ml and water (3 ml) and dichloromethane (6 ml) were
(CDCl3, 25°C): l=113.14 (C(4)), 122.84 (C(3)), 127.12
(C(5%)), 127.54 (C(1%)), 129.07 (C(3%)), 130.11 (C(4%)),
130.89 (C(6%)), 131.47 (C(2%)), 151.49 (C(2)), 155.35
(C(5)), 177.43 (C(2)-C6 HO); anal. calcd for C11H7ClO2:
C, 63.94; H, 3.41; Cl, 17.16. Found: C, 63.86; H, 3.43;
Cl, 17.25%.
4.2.3. 5-(4-Bromophenyl)furan-2-carbaldehyde 1c. Yield:
75%; mp: 153°C (lit. 153.5–154°C)24; m ([mol−1 dm3
cm−1], u [nm]): 9.83×104 (270), 11.98×104 (329); HRMS
M+ found (M+ calculated for C11H7BrO2): 249.96283
(249.96294); MS: m/z (relative intensity)=253 (11), 252

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
1901
1
added. The aqueous layer was extracted with
dichloromethane (6 ml). The combined organic layers
were dried over anhydrous MgSO4 and the solvent was
removed. The resulted crude cyanohydrins were purified
by recrystallization from hexane rac-2a–c or hexane–
ethyl acetate rac-2d,e.
116 (2), 115 (20), 114 (25), 113 (10); H NMR (CDCl3,
25°C): l=5.57 (s, 1H, C(2)-CH(OH)CN), 6.62 (d, J=3.4
6
Hz, 1H, C(4)-H)), 6.65 (1H, d, J=3.4 Hz, 1H, C(3)-H)),
7.47–7.52 (m, 4H, C(2%)-H), C(3%)-H, C(5%)-H, C(6%)-H));
13C NMR (CDCl3, 25°C): l=57.10 (C(2)-C
6
H(OH)CN),
106.35 (C(4)), 112.38 (C(3)), 116.68 (C(2)-CH(OH)CN),
6
122.26 (C(4%)), 125.59 (C(2%), C(6%)), 128.5 (C(1%)), 131.9
(C(3%), C(5%)), 147.04 (C(2)), 154.84 (C(5)); HPLC
(CHIRACEL OD, 1 ml/min): tR(S) 31.1 min, tR(R) 38.9
min; anal. calcd for C12H8BrNO2: C, 51.83; H, 2.90; Br,
28.73; N, 5.04. Found: C, 51.83; H, 2.93; Br, 28.83 N,
5.13%.
4.3.1.
Hydroxy-[5-(4-carboxyethylphenyl)-furan-2-yl]-
acetonitrile rac-2a. Yield: 92%; mp: 78–80°C; m ([mol−1
dm3 cm−1], u [nm]): 6.59×103 (276), 4.16×104 (321);
HRMS M+ found (M+ calculated for C15H13NO4):
271.08466 (271.08446); MS: m/z (relative intensity)=271
(2) [M]+, 255 (1), 254 (1), 246 (3), 245 (28), 244 (88), 217
(6), 216 (44), 215 (12), 201 (4), 200 (34), 199 (100), 188
(2), 172 (5), 171 (10), 160 (2), 159 (14), 143 (4), 142 (6),
4.3.4. Hydroxy-[5-(4-nitrophenyl)-furan-2-yl]acetonitrile
rac-2d. Yield: 93%; mp: 115–118°C; m ([mol−1 dm3 cm−1],
u [nm]): 3.95×104 (270), 5.25×104 (347); HRMS M+ found
(M+ calculated for C12H8N2O4): 244.04854 (244.04841);
MS: m/z (relative intensity)=244 (1) [M]+, 227 (1), 219
(2), 218 (18), 217 (100), 216 (9), 188 (3), 187 (26), 171 (7),
170 (5), 160 (3), 159 (9), 131 (5), 130 (2), 117 (2), 116 (3),
1
131 (4), 117 (3), 116 (4), 115 (39), 114 (21), 113 (9); H
NMR (CDCl3, 25°C): l=1.38 (t, J=6.8 Hz, 3H, C(4%)-
COOCH2CH3
6
), 4.35 (q, J=6.8 Hz, 2H, C(4%)-
(OH)CN), 6.65 (d,
COOCH2CH3), 5.60 (s 1H, C(2)-CH
6
6
J=3.4 Hz, 1H, C(4)-H), 6.67 (1H, d, J=3.4 Hz, 1H,
C(3)-H), 7.60 (d, J=8.4 Hz, 2H, C(2%)-H, C(6%)-H), 7.95
(d, J=8.4 Hz, 2H, C(3%)-H, C(5%)-H); 13C NMR (CDCl3,
1
115 (37), 114 (23), 113 (9); H NMR (CDCl3, 25°C):
l=5.63 (s 1H, C (2)-CH6 (OH) CN), 6.74 (dd, J=3.4 Hz,
J=0.7 Hz, 1H, C (3)-H)), 6.86 (1H, d, J=3.7 Hz, 1H,
C(4)-H)), 7.80 (ddd, J=9.0 Hz, J=2.2 Hz, 2H, C(2%)-H,
C(6%)-H), 8.25 (d, J=9.0 Hz, J=2.2 Hz, 2H, C(3%)-H,
C(5%)-H); 13C NMR (CDCl3, 25°C): l=57.1 (C(2)-
25°C): l=14.21 (C(4%)-COOCH2C
H(OH)CN), 61.39 (C(4%)-COOCH2CH3), 107.88 (C(4)),
112.15 (C(3)), 116.82 (C(2)-CH(OH)CN), 123.66 (C(2%),
6 H3), 57.11 (C(2)-
C6
6
6
C(6%)), 129.28 (C(4%)), 130.01 (C(3%), C(5%)), 133.58 (C(1%)),
148.15 (C(2)), 154.42 (C(5)), 166.70 (C(4%)-
C6
H(OH)CN), 109.5 (C(4)), 112.6 (C(3)), 116.42 (C(2)-
CH(OH)CN), 124.4 (C(3%), C(5%)), 124.5 (C(2%), C(6%)),
135.2 (C(1%)), 147.1 (C(4%)), 148.9 (C2)), 153.43 (C(5));
HPLC (CHIRACEL OD, 1.5 ml/min): tR(S) 42.4 min,
tR(R) 51.6 min.
6
C6 OOCH2CH3); HPLC (CHIRACEL OD, 1 ml/min):
tR(S) 27.3 min, tR(R): 34.3 min; anal. calcd for
C15H13NO4: C, 66.41; H, 4.83; N, 5.16. Found: C, 66.36;
H, 4.74; N, 5.22%.
4.3.5.
Hydroxy-[5-(2-methyl-4-nitrophenyl)-furan-2-
4.3.2.
Hydroxy-[5-(2-chlorophenyl)-furan-2-yl]aceto-
yl]acetonitrile rac-2e. Semisolid; yield: 81%; m ([mol−1 dm3
cm−1], u [nm]): 6.47×103 (281), 7.41×103 (296); HRMS M+
found (M+ calculated for C13H10N2O4): 258.06433
(258.06406); MS: m/z (relative intensity)=258 (2) [M]+,
232 (2), 231 (10), 203 (12), 202 (100), 186 (2), 146 (6), 145
(3), 144 (5), 130 (5), 129 (40), 128 (21), 127 (13), 126 (4),
nitrile rac-2b. Yield: 90%; mp: 88–89°C; m ([mol−1 dm3
cm−1], u [nm]): 1.53×104 (299); HRMS M+ found (M+
calculated for C12H8ClNO2): 233.02361 (233.02436); MS:
m/z (relative intensity)=236 (1), 235 (8), 234 (4), 233 (26)
[M]+, 231 (1), 219 (2), 218 (13), 217 (5), 216 (39), 209 (4),
208 (32), 207 (23), 206 (100), 205 (27), 204 (3), 180 (3),
179 (1), 178 (7), 153 (5), 152 (5), 151 (21), 150 (7), 149
(67), 140 (2), 139 (1), 138 (5), 123 (2), 116 (3), 115 (24),
1
118 (8), 117 (2), 116 (6), 115 (13); H NMR (CDCl3,
25°C): l=2.41 (s, 3H, C(2%)-CH3
6 ), 5.56 (s, C(2)-
CH
6
(OH)CN), 6.56 (d, J=3.4 Hz, 1H, C(4)-H)), 6.65 (d,
1
114 (24), 113 (15); H NMR (CDCl3, 25°C): l=5.61 (s
J=3.6 Hz, 1H, C(3)-H)), 7.37 (d, J=7.8 Hz, 1H,
C(6%)-H)), 7.53 (s, 1H, C(3%)-H)), 7.55 (d, J=7.8 Hz, 1H,
1H, C(2)-CH6 (OH)CN), 6.71 (d, J=3.4 Hz, 1H, C(3)-H)),
C(5%)-H)); 13C NMR (CDCl3, 25°C): l=20.94 (C7-C
6
H3),
H(OH)CN), 109.98 (C(4)), 111.91 (C(3)),
116.65 (C(2)-CH(OH)CN), 120.64 (C(1%)), 124.41 (C(3%)),
7.10 (d, J=3.4 Hz, 1H, C(4)-H)), 7.24 (ddd, J=7.7 Hz,
J=1.4 Hz, 1H, C(4%)-H), 7.32 (dd, J=7.4 Hz, 1H,
C(5%)-H), 7.44 (d, J=7.92 Hz, 1H, C(3%)-H), 7.84 (dd,
J=7.8 Hz, J=1.4 Hz, 1H, C(6%)-H); 13C NMR (CDCl3,
56.87 (C(2)-C
6
6
129.2 (C(5%)), 133.0 (C(6%)), 140.2 (C(2%)), 147.30 (C(4%)),
148.41 (C(2)), 150.27 (C(5)); HPLC (CHIRACEL OD,
1 ml/min): tR(S) 32.3 min, tR(R) 35.7 min.
25°C): l=57.09 (C(2)-C
112.10 (C(3)), 116.73 (C(2)-CH(OH)C
6
H(OH)CN), 111.67 (C(4)),
N), 126.97 (C(5%)),
6
128.17 (C(1%)), 128.96 (C(3%)), 130.5 (C(2%)), 130.7 (C(6%)),
130.74 (C(4%)), 146.70 (C(2)), 152.04 (C(5)); HPLC
(CHIRACEL OD, 1 ml/min): tR(S) 12.5 min, tR(R) 16.4
min; anal. calcd for C12H8ClNO2: C, 61.69; H, 3.45; Cl;
15.17; N, 5.99. Found: C, 61.65; H, 3.47; Cl, 15.23; N,
6.03%.
4.4. Chemical acylation of racemic cyanohydrins 2a–e
with butanoic anhydride (Method A)
To a solution of one of the cyanohydrins rac-2a–e (0.5
mmol) in dichloromethane (5 ml) butanoic anhydride (79
mg, 81.8 ml, 0.5 mmol), a catalytic amount of 4-N,N-
dimethylaminopyridine in pyridine (5 ml; 1% solution)
and triethylamine (50.5 mg, 69.2 ml, 0.5 mmol) were
added. After stirring 15 min at room temperature the
solvent was evaporated in vacuum and the crude product
was purified by column chromatography using
dichloromethane as eluent. Yields for rac-3a–e are shown
in Table 5.
4.3.3.
Hydroxy-[5-(4-bromophenyl)-furan-2-yl]aceto-
nitrile rac-2c. Yield: 88%; mp: 94–95°C; m ([mol−1 dm3
cm−1], u [nm]): 3.65×104 (299), 3.70×104 (308); HRMS M+
found (M+ calculated for C12H8BrNO2): 276.97409
(276.97384); MS: m/z (relative intensity)=279 (2), 277 (2)
[M]+, 254 (1), 253 (12), 252 (99), 251 (32), 250 (100), 249
(20), 223 (1), 222 (7), 195 (33), 194 (4), 193 (33), 155 (2),

1902
C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
4.4.1. [5-(4-Carboxyethylphenyl)-furan-2-yl]-cyanomethyl
butanoate rac-3a. Semisolid; m ([mol−1 dm3 cm−1 dm3
cm−1], u [nm]): 1.32×103 (274), 5.48×103 (318); HRMS
M+ found (M+ calculated for C19H19NO5): 341.12637
(341.12632); MS: m/z (relative intensity)=343 (1), 342
(9), 341 (42) [M]+, 297 (2), 296 (12), 272 (3), 271 (19),
270 (1), 261 (1), 260 (4), 256 (2), 255 (17), 254 (100), 253
(40), 228 (1), 227 (5), 226 (28), 225 (11), 210 (4), 209
(11), 208 (25), 207 (2), 199 (2), 198 (2), 197 (2), 182 (4),
181 (22), 180 (5), 159 (2), 154 (2), 153 (5), 152 (2), 148
HPLC (CHIRACEL OD, 1 ml/min): tR(R) 9.0 min,
tR(S) 11.8 min; anal. calcd for C16H14ClNO3: C, 63.27;
H, 4.65; Cl, 11.67; N, 4.61. Found: C, 63.33; H, 4.67;
N, 4.62%.
4.4.3.
[5-(4-Bromophenyl)furan-2-yl]-cyanomethyl
butanoate rac-3c. Semisolid; m ([mol−1 dm3 cm−1], u
[nm]): 2.81×104 (273), 1.99×104 (318); HRMS M+ found
(M+ calculated for C16H14BrNO3): 347.01550
(347.01571); MS: m/z (relative intensity)=350 (5), 349
(31), 348 (5), 347 (31) [M]+, 280 (2), 279 (11), 278 (2),
277 (11), 267 (10), 266 (10), 263 (14), 262 (98), 261 (49),
260 (100), 259 (36), 233 (6), 231 (6), 195 (6), 193 (6), 185
(8), 183 (9), 182 (4), 181 (11), 180 (34), 157 (7), 155 (8),
154 (5), 153 (35), 152 (12), 131 (4), 130 (2), 127 (4), 126
(10), 125 (3), 115 (5), 114 (10), 113 (6); 1H NMR
(CDCl3, 25°C): l=0.95 (t, J=7.4 Hz, 3H, C(2)-
1
(2), 127 (6), 126 (4), 115 (3), 114 (4); H NMR (CDCl3,
25°C): l=0.95 (t, J=7.6 Hz, 3H, C(2)-CH(CN)OC-
OCH2CH2CH3
H2CH3), 1.69 (qt, J=7.6 Hz, 2H, C(2)-CH(CN)OC-
OCH2CH2CH3), 2.40 (td, J=7.4 Hz, J=2.2 Hz, 2H,
C(2)-CH(CN)OCOCH2CH2CH3), 4.37 (q, J=7.2 Hz,
2H, C(4%)-COOCH2CH3), 6.53 (s, 1H, C(2)-CH(CN)-
6 ), 1.38 (t, J=7.2 Hz, 3H, C(4%)-COOC-
6
6
6
6
6
OCOCH2CH2CH3), 6.76 (d, J=3.2 Hz, 1H, C(4)-H)),
6.77 (d, J=3.2 Hz, 1H, C(3)-H)), 7.71 (d, J=8 Hz, 2H,
C(2%)-H), C(6%)-H)), 8.05 (d, J=8 Hz, 2H, C(3%)-H),
C(5%)-H)); 13C NMR (CDCl3, 25°C): l=13.39 (C(2)-
CH(CN)OCOCH2CH2CH3
6
), 1.69 (qt, J=7.4 Hz, 2H,
CH3), 2.39 (td, J=7.3 Hz,
C(2)-CH(CN)OCOCH2CH2
6
J=3.5 Hz, 2H, C(2)-CH(CN)OCOCH
6 2CH2CH3), 6.52
(s, 1H, C(2)-CH(CN)OCOCH2CH2CH3), 6.65 (d, J=
6
CH(CN)OCOCH2CH2C
H3), 18.10 (C(2)-CH(CN)OCOCH2C
(C(2)-CH(CN)OCOCH2CH2CH3), 55.60 (C(2)-C
(CN)OCO-CH2CH2CH3), 61.07 (C(4%)-COOCH2CH3),
107.87 (C(4)), 114.05 (C(2)-CH(CN)OCOCH2-
6
H3), 14.27 (C(4%)-COOCH2-
H2CH3), 35.36
H-
3.4 Hz, 1H, C(4)-H), 6.73 (dd, J=3.4 Hz, J=0.5 Hz,
1H, C(3)-H), 7.51 (m, 2H, C(2%)-H, C(6%)-H), 7.53 (m,
2H, C(3%)-H, C(5%)-H); 13C NMR (CDCl3, 25°C): l=
C6
6
6
6
6
13.44 (C(2)-CH(CN)OCO-CH2CH2C
CH(CN)OCOCH2CH2CH3), 35.42 (C(2)-CH(CN)OCO
H2CH2CH3), 55.62 (C(2)-CH(CN)OCOCH2CH2CH3),
106.45 (C(4)), 114.12 (C(2)-CH(CN)OCOCH2CH2-
6 H3), 18.15 (C(2)-
6
6
CH2CH3), 114.57 (C(3)), 123.86 (C(2%), C(6%)), 130.01
(C(4%)), 130.06 (C(3%), C(5%)), 133.26 (C(1%)), 144.36
C6
6
6
(C(2)), 155.26 (C(5)), 166.01 (C(4%)-C
6
OOCH2CH3),
HPLC
CH3), 114.57 (C(3)), 122.47 (C(4%)), 125.73 (C(2%),
C(6%)), 128.5 (C(1%)), 131.99 (C(3%), C(5%)), 143.74 (C(2)),
171.41 (C(2)-CH(CN)OCOCH2CH2CH3);
6
(CHIRACEL OD, 1 ml/min): tR(R) 15.0 min, tR(S)
16.4 min; anal. calcd for C19H19NO5: C, 66.85; H, 5.61;
N, 4.10. Found: C, 66.83; H, 5.62; N, 4.13%.
155.37
(C(5)),
171.48
(C(2)-CH(CN)OC6 OCH2-
CH2CH3); HPLC (CHIRACEL OD, 1 ml/min): tR(R)
17.2 min, tR(S) 18.5 min; anal. calcd for C16H14BrNO3:
C, 55.19; H, 4.05; Br, 22.95; N, 4.02. Found: C, 55.23;
H, 4.07; Br, 22.99, N, 4.10%.
4.4.2.
[5-(2-Chlorophenyl)furan-2-yl]-cyanomethyl
butanoate rac-3b. Semisolid; m ([mol−1 dm3 cm−1], u
[nm]): 1.35×104 (282), 2.47×104 (298); HRMS M+ found
(M+ calculated for C16H14ClNO3): 303.06619
(303.06622); MS: m/z (relative intensity)=306 (2), 305
(11), 304 (6), 303 (31) [M]+, 292 (2), 235 (7), 234 (3), 233
(20), 224 (10), 223 (4), 222 (30), 219 (5), 218 (32), 217
(28), 216 (100), 215 (45), 194 (4), 193 (2), 189 (7), 188
(2), 187 (14), 181 (5), 180 (34), 159 (5), 154 (3), 153 (18),
152 (13), 151 (6), 150 (2), 149 (13), 141 (6), 140 (2), 139
(16), 136 (3), 127 (2), 126 (5), 125 (4), 114 (4), 113 (7),
4.4.4.
[5-(4-Nitrophenyl)-furan-2-yl]-cyanomethyl
butanoate rac-3d. Semisolid; m ([mol−1 dm3 cm−1], u
[nm]): 1.83×104 (270), 3.41×104 (338); HRMS M+ found
(M+
calculated
for
C16H14N2O5):
314.09061
(314.09027); MS: m/z (relative intensity)=315 (6), 314
(33) [M]+, 245 (6), 244 (45), 229 (2), 228 (16), 227 (100),
226 (91), 215 (4), 211 (1), 210 (2), 209 (3), 198 (6), 197
(5), 196 (4), 182 (5), 181 (33), 180 (19), 179 (2), 171 (1),
170 (3), 169 (12), 168 (4), 154 (2), 153 (15), 152 (11), 151
(2), 150 (4), 141 (2), 140 (10), 130 (2), 128 (1), 127 (6),
126 (12), 125 (3), 117 (1), 116 (1), 115 (5), 114 (10), 113
1
112 (7); H NMR (CDCl3, 25°C): l=0.95 (t, J=7.24
Hz, 3H, C(2)-CH(CN)OCOCH2CH2CH3
7.24 Hz, 2H, C(2)-CH(CN)OCOCH2CH2
(td, J=7.4 Hz, J=2.4 Hz, 2H, C(2)-CH(CN)OCO-
CH2CH2CH3), 6.55 (s, 1H, C(2)-CH(CN)OCOCH2-
6
), 1.69 (qt, J=
6
CH3), 2.40
1
(4); H NMR (CDCl3, 25°C): l=0.95 (t, J=7.5 Hz 3H,
6
6
C(2)-CH(CN)OCO CH2CH2CH3
6
), 1.69 (qt, J=7.5 Hz,
6 CH3), 2.41 (td, J=7.4
CH2CH3), 6.77 (d, J=3.6 Hz, 1H, C(3)-H)), 7.12 (d,
J=3.6 Hz, 1H, C(4)-H)), 7.24 (ddd, J=7.7 Hz, J=1.7
Hz, 1H, C(4%)-H)), 7.32 (dd, J=7.6 Hz, 1H, C(5%)-H)),
7.43 (dd, J=8.0 Hz, J=1.2 Hz, 1H, C(3%)-H)), 7.83 (dd,
J=7.9 Hz, J=1.7 Hz, 1H, C(6%)-H)); 13C NMR
2H, C(2)-CH(CN) OCOCH2CH2
Hz, J=2.6 Hz, 2H, C(2)-CH(CN)OCOCH
6.55 (s, 1H, C(2)-CH(CN)OCOCH2CH2CH3), 6.80 (d,
J=3.64 Hz, 1H, C(3)-H), 6.87 (d, J=3.64 Hz, 1H,
C(4)-H), 7.81 (d, J=8.8 Hz, 2H, C(2%)-H, C(6%)-H), 8.24
(d, J=8.8 Hz, 2H, C(3%)-H, C(5%)-H); 13C NMR
(CDCl3, 25°C): l=13.39 (C(2)-CH(CN)OCOCH2CH2-
6 2CH2CH3),
6
(CDCl3,
CH2CH2C
35.38 (C(2)-CH(CN)OCOC
H(CN)OCOCH2CH2CH3), 111.74 (C(4)), 114.13
(C(2)-CH(CN)OCOCH2CH2CH3), 114.2 (C(3), 126.99
25°C):
H3), 18.12 (C(2)-CH(CN)OCOCH2C
H2CH2CH3), 55.59 (C(2)-
l=13.42
(C(2)-CH(CN)OCO-
6
6
H2CH3),
6
C
6
H3),
35.33 (C(2)-CH(CN)OCOC
H(CN)OCOCH2CH2CH3), 109.56 (C(4)), 113.87
(C(2)-CH(CN)OCOCH2CH2CH3), 114.76 (C(3)),
18.09
(C(2)-CH(CN)OCO-CH2C
6 H2CH3),
C6
6
H2CH2CH3), 55.50 (C(2)-
6
C6
(C(5%)), 128.00 (C(1%)), 128.26 (C(3%)), 129.10 (C(4%)),
130.60 (C(2%)), 130.76 (C(6%)), 143.42 (C(2)), 152.57
6
124.30 (C(3%), C(5%)), 124.58 (C(2%), C(6%)), 135.03
(C(1%)), 145.42 (C(2)), 147.15 (C(4%)), 153.84 (C(5)),
(C(5)),
171.42
(C(2)-CH(CN)OC6 OCH2CH2CH3);

C. Paizs et al. / Tetrahedron: Asymmetry 14 (2003) 1895–1904
1903
171.34
(C(2)-CH(CN)OC
6
OCH2CH2CH3);
HPLC
4.7. One-pot synthesis of cyanohydrin esters (R)-(+)-
3a–e
(CHIRACEL OD, 1.5 ml/min): tR(R) 25.3 min, tR(S)
30.2 min; anal. calcd for C16H14N2O5: C, 61.14; H, 4.49;
N, 8.91. Found: C, 61.13; H, 4.52; N, 8.92%.
One of the aldehydes 1a–e (0.15 mmol), acetone
cyanohydrin (28 mg, 30 ml, 0.325 mmol) and vinyl
butanoate (51.3 mg, 57 ml, 0.45 mmol) were added in
dry toluene (3 ml). To this solution Amberlite IRA 904
(−OH form, 5 mg/0.008 equiv.) and lipase PS prepara-
tion (10 or 50 mg ml−1) were added. The reaction
mixture was stirred at room temperature for 168 h. The
enzyme and the resin were filtered off and washed with
toluene (2×0.5 ml). Solvents were distilled off from the
filtrate and the residue was purified by column chro-
matography on silica gel with dichloromethane yielding
(R)-(+)-3a–e (Table 3).
4.4.5.
[5-(2-Methyl-4-nitrophenyl)-furan-2-yl]-cyano-
methyl butanoate rac-3e. Semisolid; m ([mol−1 dm3
cm−1], u [nm]): 2.45×104 (271), 1.12×104 (330); HRMS
M+ found (M+ calculated for C17H16N2O5): 328.10608
(328.10592); MS: m/z (relative intensity)=328 (6) [M]+,
242 (4), 241 (30), 240 (9), 204 (1), 203 (8), 202 (70),
196 (1), 195 (3), 194 (2), 187 (12), 186 (100), 184 (2),
183 (2), 182 (2), 175 (2), 174 (1), 169 (1), 168 (3), 167
(6), 166 (13), 159 (2), 158 (6), 155 (2), 154 (2), 148 (4),
147 (4), 146 (4), 141 (8), 140 (3), 139 (10), 138 (6), 132
(2), 131 (5), 130 (35), 129 (3), 128 (9), 126 (6), 118 (2),
4.8. Kinetic resolution of racemic cyanohydrin esters
3a–e
1
117 (10), 116 (5), 115 (2), 114 (8); H NMR (CDCl3,
25°C): l=0.94 (t, J=7.48 Hz, 3H, C(2)-CH(CN)-
OCOCH2CH2CH3
CH(CN)OCO-CH2CH2
C(2)-CH(CN)OCOCH2
CH
6.58 (d, J=3.4 Hz, 1H, C(4)-H), 6.74 (dd, J=3.5 Hz,
J=0.5 Hz, 1H, C(3)-H), 7.40 (m, J=8.1 Hz, 1H,
C(6%)-H), 7.55 (s, 1H, C(3%)-H), 7.57 (d, J=7.88 Hz, 1H,
C(5%)-H); 13C NMR (CDCl3, 25°C): l=13.40
6 ), 1.68 (qt, J=7.48 Hz, 2H, C(2)-
In a typical small scale experiment, one of the cyanohy-
drin esters rac-3a–e (0.05 mmol) and methanol (12.8
mg, 16.4 ml, 0.4 mmol) were dissolved in dry toluene (1
ml). Lipase PS preparation (10 mg, corresponding to 2
mg of the enzyme) was added. Samples (5 ml) were
taken after 4, 8, 12, 24, 36, 48, 72, 96, 120, 144 h and
diluted with the same solvent (80 ml) as the mobile
phase for HPLC (Table 4).
6
CH3), 2.39 (t, J=7.48 Hz, 2H,
CH2CH3), 2.43 (s, 3H, C(2%)-
6
6
3), 6.48 (s, 1H, C(2)-CH6 (CN)OCOCH2CH2CH3),
(C(2)CH(CN)OCO CH2CH2C
(CN)OCOCH2CH2CH3), 20.97 (C(2%)-C
(C(2)CH(CN)OCO H2CH2CH3), 55.44 (C(2)-C
(CN)OCOCH2CH2CH3), 110.05 (C(4)), 113.96 (C(2)-
CH(CN)OCOCH2CH2CH3), 114.09 (C(3)), 120.42
6
H3), 18.05 (C(2)-CH-
H3), 35.31
H-
6
6
4.9. Absolute configurations
C6
6
In order to determine which enantiomer reacts faster in
the present lipase PS-catalysed reactions, the lipase
PS-mediated kinetic resolution of furan-2-yl-hydroxy-
acetonitrile with vinyl butanoate and vinyl acetate in
toluene were studied. The corresponding (R)-(+)-
butanoic and (R)-(+)-acetic acid esters with [h]2D5=+9.9
(c 1, CHCl3) (ee >98%) and [h]2D5=+22.9 (c 1.5, CHCl3)
(ee 95%) were obtained, respectively. The latter value of
[h]2D5 is in full accordance with the value of [h]2D0=+24.3
(c 1.6, CHCl3) (ee=98%) reported for the (R)-(+)-acetic
ester.27
6
(C(1%)), 124.45 (C(3%)), 129.24 (C(5%)), 132.87 (C(6%)),
140.36 (C(2%)), 144.77 (C(2)), 147.55 (C(4%)), 150.91
(C(5)),
171.36
(C(2)-CH(CN)OC6 OCH2CH2CH3);
HPLC (CHIRACEL OD, 1 ml/min): tR(R) 22.1 min,
tR(S) 25.9 min; anal. calcd for C17H16N2O5: C, 62.19;
H, 4.91; N, 8.53. Found: C, 62.21; H, 4.89; N, 8.57%.
4.5. Enzymatic acylation of racemic cyanohydrins 2a–e
with vinyl butanoate (Method B)
To a solution of one of the cyanohydrins rac-2a–e (0.5
mmol) in anhydrous toluene (1 ml) vinyl butanoate
(171 mg, 190 ml, 1.5 mmol) and CAL-A preparation
(20 mg, corresponding to 2 mg of the enzyme) were
added and the mixture was stirred at room tempera-
ture for 3 h. The enzyme was filtered off and washed
with toluene (2×0.5 ml). Solvents were distilled off
from the filtrate and the residue was purified as above.
Yields for rac-3a–e are shown in Table 5.
Acknowledgements
C.P. is grateful for a grant from CIMO (The Center of
International Mobility) in Finland.
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