Chiral Lewis base catalyzed enantioselective acetylcyanation of α-oxo esters

Article abstract of DOI:10.1002/ejoc.200900055

Acetyl cyanide adds to alkyl benzoylformates and to 2-oxoalkanoates to yield enantioenriched acylated cyanohydrins in one step in the presence of a catalytic amount of a chiral base. The reaction is accelerated by Lewis acids and by the addition of a cata

Full text of DOI:10.1002/ejoc.200900055

FULL PAPER
DOI: 10.1002/ejoc.200900055
Chiral Lewis Base Catalyzed Enantioselective Acetylcyanation of α-Oxo Esters
Fei Li,[a][‡] Khalid Widyan,[a][‡‡] Erica Wingstrand,[a] and Christina Moberg*[a]
Dedicated to Professor Karl Hult on the occasion of his 65th birthday
Keywords: Acylation / Addition reactions / Asymmetric catalysis / Cyanides / Kinetic resolution / Lewis bases
Acetyl cyanide adds to alkyl benzoylformates and to 2-oxoal-
yield. Ethyl pyruvate and tert-butyl 2-oxobutanoate were
kanoates to yield enantioenriched acylated cyanohydrins in more reactive, and essentially full conversion to the products
one step in the presence of a catalytic amount of a chiral
base. The reaction is accelerated by Lewis acids and by the
addition of a catalytic amount of methanol. Under optimized
conditions, 94% of a 94:6 mixture of the O-acetylated and
with 69 and 82% ee, respectively, was achieved. The reac-
tion proceeds by a non-selective addition of cyanide ion to
give the non-protected cyanohydrin followed by a dynamic
kinetic resolution to provide the enantioenriched acetylated
non-protected cyanohydrins was formed from methyl benzo- product.
ylformate in the presence of cinchonidine; from this mixture
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
the acylated compound with 66% ee was isolated in 77%
Germany, 2009)
a catalyst consisting of a chiral Lewis acid and an achiral
Lewis base, acylcyanation of aldehydes proceeds in one
step, yielding O-acylated cyanohydrins from a variety of
acyl cyanides with excellent yields and enantioselectivities
and perfect atom economy.[7] Cyano esters obtained by this
procedure have useful applications[8] at the same time as
they serve as versatile synthetic intermediates.[9]
So far, no examples of direct cyano ester formation from
ketones have been reported. We decided to attempt the
same conditions as those used for aldehydes for the addition
of acetyl cyanide to prochiral ketones. We have now found
that activated α-oxo esters serve as substrates for the ad-
dition, although under slightly different conditions, proba-
bly as a result of a different reaction mechanism.
Introduction
The addition of cyanide to the carbonyl function of alde-
hydes and ketones is currently receiving considerable atten-
tion due to the usefulness of the products obtained as inter-
mediates in organic synthesis.[1] A variety of enantioselec-
tive catalytic systems based on Lewis acids and/or Lewis
bases have been employed for the additions, in many cases
providing highly enantioenriched products.[2]
Reactions with ketones as substrates are particularly
challenging as they require control of the stereochemistry
of a quaternary center. However, several successful exam-
ples of such additions have been reported. Trimethylsilyl cy-
anide has most commonly been employed as cyanide source
in additions to ketones, thus providing direct access to O-
protected cyanohydrins. Lewis base[3] or bifunctional acti-
vation incorporating a metal-centered Lewis acid[4] or a hy-
drogen-bond donor[5] has been employed for this purpose.
Cyanoformates have also been added to ketones, affording
enantioenriched carbonates by using chiral Lewis bases as
catalysts.[6] We have recently found that, in the presence of
Results and Discussion
First the same conditions as those used for additions to
aldehydes were attempted for the reaction of methyl benzo-
ylformate (1a) with acetyl cyanide (Scheme 1). Thus, sub-
jecting 1a to 2 equiv. of acetyl cyanide in the presence of a
catalyst composed of 5% Ti(salen) dimer 2, introduced and
used by Belokon, North and co-workers for silylcyanation
of both aldehydes[10] and ketones[11] and 10% triethylamine
in dichloromethane, resulted after 5 h at room temperature
in 50% conversion to a 84:16 mixture of O-acetylated cya-
nohydrin 3a and nonprotected cyanohydrin 4a (Table 1, En-
try 1). The ratio of the two compounds increased slightly
over time (88:12 after 30 h) although the total yield of the
two products remained essentially constant. To our disap-
[a] KTH School of Chemical Science and Engineering, Organic
Chemistry,
10044 Stockholm, Sweden
[‡] Present address: State Key Laboratory of Fine Chemicals, Dal-
ian University of Technology,
Zhongshan Road 158-46, Dalian 116012, P. R. China
[‡‡]Permanent address: Department of Chemistry, Tafila Technical
University,
Tafila, Jordan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900055.
Eur. J. Org. Chem. 2009, 3917–3922
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Li, K. Widyan, E. Wingstrand, C. Moberg
FULL PAPER
pointment, the desired cyano ester was obtained as a race- conditions of slow addition, some alcohol 4a was observed
mate. The reaction also occurred in the absence of the Ti in the initial part of the reaction, but after 16 h 97% conver-
catalyst, but at a lower rate (30% conversion after 16 h, sion to 3a, still as a racemate, was observed (Entry 6). A
Entry 2). Even a reaction performed at –40 °C, in the pres- more active catalytic system also resulted when triethyl-
ence of 2, did not lead to any selectivity (Entry 3). The ad- amine was replaced by DMAP, with 96% conversion to a
dition of 1.2 equiv. of methanol resulted in a more rapid 98:2 ratio of 4a and 3a observed in the presence of Ti com-
reaction, providing 72% conversion to a 74:26 3a/4a mix- plex 2 after 6 h at room temperature (Entries 7 and 8, to be
ture after 16 h at room temperature (Entry 4). Similar cata- compared to Entries 1 and 2).
lytic activity was observed in the absence of triethylamine,
We were pleased to find that the use of the chiral base
although a product mixture consisting mainly of the cinchonidine (5) in place of triethylamine resulted in the
alcohol 4a was obtained (13:87, Entry 5). The formation formation of enantioenriched cyano ester. Thus, a catalyst
of nonprotected cyanohydrin was suppressed when acetyl composed of cinchonidine and (R,R)-salen dimer gave 48%
cyanide was added slowly over 30 min. Thus, in a reaction of a 52:48 mixture of 3a and 4a, the former with 29% ee,
performed without methanol at room temperature under after 4 h at 0 °C followed by 13 h at room temperature (En-
try 9). The same enantiomer of 3a, with the same selectivity
(30 vs. 29% ee) was obtained when the (R,R)-salen dimer
was replaced by its enantiomer (Entry 10), demonstrating
again that chirality transfer from the titanium complex is
inefficient.
Higher conversions and higher enantioselectivities were
achieved at lower temperature by omitting the Lewis acid.
After 6 h at –40 °C, 99:1 mixtures of 3a and 4a were ob-
tained, the former with 66% ee (Entries 11 and 12), with
slightly higher conversions observed in the presence of
Scheme 1. Acetylcyanation of alkyl benzoylformates.
MeOH (77 compared to 69%). Slow addition of acetyl cya-
Table 1. Lewis acid/Lewis base catalyzed additions of acetyl cyanide to keto esters 1a–c.
Entry[a]
Oxo ester
Lewis acid
Lewis base
MeOH
[mol-%]
Time
[h]
Temperature
Conversion
ee
[°C]
(%)[b] 3/4
(%)[c]
3
1
1a
2
Et3N
–
5
30
16
16
16
16
16[d]
3
room temp.
room temp.
room temp.
–40
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
0 to room temp.
0 to room temp.
50, 84:16
51, 88:12
30, 67:33
30, 57:43
72, 74:26
70, 13:87
97, 100:0
76, 86:14
96, 98:2
48, 76:24
65, 88:12
48, 52:48
53, 66:34
69, 99:1
77, 99:1
91, 93:7
20, 51:49
n.d.
7, 71:29
21, 63:37
41, 96:4
53, 99:1
67, 99:1
40
96, 100:0
40, 68:32
82, 99:1
30, 50:50
30, 50:50
34, 67:33
0
0
–
0
0
0
0
0
0
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
–
2
2
2
2
2
Et3N
Et3N
Et3N
–
Et3N
DMAP
–
–
120
120
–
–
6
3
6
8
1a
–
DMAP
–
–
–
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
1c
1c
2
ent-2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5
–
–
–
4+13
4+14
6
29
30
66
66
66
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
5
5
–40
–40
–40
–40
–40
–40
–40
–40
5
10
10
10
10
–
10
–
10
10
10
–
10
10
10
10
10
6
5
6[e]
6
6
7
6
16[f]
42
34
44
34
64
8
8
48
21
6
8
9
9
6
–40
5
6+12
6
3
6
16
6
–40 to room temp.
6
–40
room temp.
DMAP
–
5
5
6
7
9
0
0
0
0
0
49
53
0
–
–
6
6
6[f]
45
[a] Reaction conditions: 10 mol-% Lewis acid (when relevant), 10 mol-% Lewis base (5 mol-% 9), the indicated mol-% MeOH, 0.12 mmol
1
of oxo ester and 0.24 mmol of acetyl cyanide in 0.5 mL of CH2Cl2. [b] Determined by H NMR spectroscopy. [c] Determined by chiral
HPLC. [d] Acetyl cyanide was added over 30 min. [e] Acetyl cyanide was added over 3 h. [f] Opposite enantiomer.
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Enantioselective Acetylcyanation of α-Oxo Esters
nide, over 3 h, improved the conversion to 91% (Entry 13). ence of 5, without Lewis acid (Table 2, Entry 1). Under
From a reaction run under these conditions 3a, with 66% these conditions, the enantioselectivity was low, however
ee, was isolated in 77% yield. Replacement of cinchonidine (41% ee). Somewhat higher selectivity was observed at
by O-methylated (6) or O-silylated (7) cinchonidine or by –78 °C (47–53% ee), but conversions were lower, in particu-
quinine (8) or (DHQD)2AQN [hydroquinidine (anthra- lar in reactions without MeOH (Entries 2 and 3). In con-
quinone-1,4-diyl) diether, 9] resulted in inferior enantio- trast to the situation with 1a, highest enantioselectivities
selectivities and lower conversions, both in the presence and were achieved by using (DHQD)2AQN (9) as a Lewis base
absence of methanol (Entries 14–19). The reaction using O- (Entries 4–6); at –78 °C essentially full conversion to 3d
silylated cinchonidine 7 gave the opposite enantiomer as the with 68% ee was observed in the presence of MeOH (En-
major product (Entry 15); similar inversion of stereochem- try 6). Sterically hindered tert-butyl ester 1e also reacted
istry was previously observed in hydrogenations using cin- smoothly with acetyl cyanide in the presence of triethyl-
chonidine derivatives.[12]
amine (98% conversion after 3 h at room temperature, En-
Ethyl benzoylformate (1b) reacted with acetyl cyanide in try 7), and this substrate resulted in higher enantio-
the presence of 5 in the same way as 1a to provide, under selectivity than 1d when chinchonidine was used as base
the optimized conditions, acylated cyanohydrin 3b in 67% (82% ee, Entry 8). Use of other chiral bases (6, 7, 9) pro-
isolated yield and 64% ee (Table 1, Entry 20), whereas the vided the product with lower selectivity (Entries 9–11).
same reaction run in the presence of O-methylated cin-
chonidine 6 resulted in poor selectivity (Entry 21). Sterically
crowded tert-butyl ester 1c reacted smoothly with acetyl cy-
anide in the presence of DMAP at room temperature (En-
try 22). However, use of chiral bases 5, 6, 7, and 9 resulted
in lower or no selectivity (Entries 23–27) than observed
with 1a and b.
Mechanistic Aspects
Ethyl pyruvate (1d) proved to be considerably more reac-
tive than the aromatic oxo esters. Essentially full conversion
Our results demonstrate that the Lewis base is responsi-
to product 3d was achieved within 4 h at –40 °C in the pres- ble for the chirality transfer to the product because racemic
Table 2. Lewis acid/Lewis base catalyzed additions of acetyl cyanide to oxo ester 1d,e.
Entry[a]
Oxo ester
Lewis base
MeOH
[mol-%]
Time
[h]
Temperature
Conversion
ee
[°C]
(%)[b] 3c
(%)[c]
3
1
2
1d
1d
5
5
10
10
4
1
3
3
1
3
1
3
1
3
6
3
3
3
3
3
–40
–78
–78
–78
–40
–40
–40
–40
–78
98
63
60
53
89
99
54
58
71
96
99
98
98
98
98
98
41
47
47
53
64
64
69
69
68
69
68
–
3
4
1d
1d
5
9
–
10
5
6
1d
1d
9
9
–
10
–78
–78
7
8
9
10
11
1e
1e
1e
1e
1e
Et3N
–
room temp.
–78
5
6
7
9
10
10
10
10
82
16
0
–78
–78
–78
65
[a] Reaction conditions: 10 mol-% Lewis base (5 mol-% 7), the indicated amount of MeOH, 0.36 mmol of oxo ester and 0.72 mmol of
1
acetyl cyanide (added over 30 min) in 1.5 mL of CH2Cl2. [b] Determined by H NMR spectroscopy. [c] Determined by chiral GC.
Eur. J. Org. Chem. 2009, 3917–3922
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F. Li, K. Widyan, E. Wingstrand, C. Moberg
FULL PAPER
Scheme 2. Acylation of 4a in the presence of 3a.
product is obtained in the presence of 2 and an achiral
Lewis base, and because the same enantiomer, with the
same selectivity, is obtained when 2 is replaced with ent-2
in the presence of cinchonidine (5). A further observation
comes from Entries 1, 7 and 8 of Table 1, which show that
the ratio 3a/4a increases during the catalytic reaction, sug-
gesting that the cyanohydrin 4a may be an intermediate in
the formation of product 3a. This was indeed verified by
monitoring a reaction performed in the presence of in situ
prepared Ti(salen) complex 5 and MeOH in toluene at
room temperature over time. Under these conditions 91%
conversion to a 3.1:1 mixture of 3a and 4a was achieved
after 5 h. The total amount of the two products remained
constant, but the 3a/4a ratio changed to 7.3:1 and 14.1:1
after 20 and 48 h, respectively.
In principle, the enantioselection can take place either in
the addition of cyanide to the prochiral oxo ester or in the
acylation of the initially formed cyanohydrin. In order to
elucidate which step is responsible for the selectivity, the ee
of the cyanohydrin 4a was determined. Under the condi-
tions used for the analysis of the cyano ester (chiral HPLC),
the enantiomers of 4a did not separate. Therefore, a reac-
tion mixture containing 3a and 4a was treated with propi-
onic anhydride in the presence of Sc(OTf)3,[13] thus afford-
ing a mixture of the original acetates 3a (Scheme 2) and
propionates 10a, formed from 4a. This allowed the ee values
of both cyano ester 3a and the ester derived from 4a to be
determined by HPLC from a single experiment. It was
found that whereas the ee of 3a obtained from a reaction
run with 0.5 equiv. of MeOH at –40 °C for 4 h was 53%,
the ethyl ester 10a, and thus 4a, were found to be essentially
racemic (2% ee). The catalytic reaction therefore most
probably proceeds by a non-selective cyanation followed by
a dynamic kinetic resolution to form the enantioenriched
O-acetylated product. This is similar to what was found by
Tian and Deng[6] in the cyanocarbonation of ketones and
is consistent with the observation that in a few cases the
enantioselectivity decreased slightly as the reaction pro-
ceeded.
nide present as an impurity in the acylating agent. Racemic
4, resulting from reaction of 1 with cyanide, is acylated by
13, obtained from the chiral base and acetyl cyanide, which
is known to be in equilibrium with dimer 14.[17] This pro-
cess is a dynamic kinetic resolution, which requires a rapid
equilibrium between 1 and 4. The acylated amine 13 is ex-
pected to be a more efficient acyl transfer reagent than ace-
tyl cyanide, in accordance with the high ratio of 4a to 3a
observed in the absence of tertiary amine (compare, e.g.,
Table 1, Entries 4 and 5). Acylation liberates cyanide, which
enables catalytic turnover.
Scheme 3. Plausible mechanism for enantioselective acetylcyan-
ation of α-oxo esters.
Compounds of the type prepared through the catalytic
method presented here have found some applications. The
ethyl ester 3b has previously been prepared in racemic form
and used for the preparation of β-lactons acting on the cen-
tral nervous system,[18] and racemic naphthyl analogues
have been prepared by radical reaction.[19] Our new pro-
cedure thus offers a convenient route to enantioenriched 3b.
Recognizing that acylation of 4a is the enantioselective
step, use of known chiral acyl transfer reagents was con-
siderred to be of interest. We are not aware of any examples
of enantioselective acylations of tertiary cyanohydrins.
Therefore chiral DMAP analogue 11[14] and reagent 12,[15]
exhibiting high selectivity in acylations of secondary
alcohols, were tested in the acetylcyanation of 1a. However,
with both reagents, poor conversions, even at room tem-
perature, and poor enantioselectivities were observed.
Conclusions
Acetylcyanation of alkyl benzoylformates and 2-oxoalk-
anoates is catalyzed by Lewis bases and proceeds by initial
Our results are consistent with the mechanism shown in addition of cyanide to the oxo group of the substrate fol-
Scheme 3. The reaction is supposed to be initiated by HCN, lowed by acyl transfer from the reagent obtained from ace-
produced from acetyl cyanide and methanol,[16] or by cya- tyl cyanide and chiral amine. The chiral induction origi-
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Enantioselective Acetylcyanation of α-Oxo Esters
at –40 °C for 6 h, then moved to a freezer and stirred for another
12 h. Workup as described above gave 3b (99 mg) as a colorless oil,
which slowly solidified in 67% isolated yield and 64% ee. HPLC
(Daicel Chiralcel OD-H, 250ϫ4.6 mm, 2-propanol/hexane, 1:99,
flow 0.5 mL/min, detection at 220 nm): tR (minor) = 20.0 min, tR
(major) = 29.2 min. M.p. 58–60 °C. [α]2D0 = –68.4 (c = 1.6, in
CHCl3, sample with 64% ee). 1H NMR (CDCl3, 500 MHz): δ =
7.72–7.74 (m, 2 H), 7.46–7.48 (m, 3 H), 4.22–4.34 (m, 2 H), 2.30
(s, 3 H), 1.26–1.29 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 169.0, 163.8, 131.0, 130.6, 129.1, 126.1, 114.9, 74.5,
64.0, 20.3, 13.7 ppm. C13H13NO4 (247.25): calcd. C 63.15, H 5.30,
N 5.67; found C 63.18, H 5.35, N 5.38.
nates from a dynamic kinetic resolution during acylation of
the initially formed racemic cyanohydrin. This mechanism
is different from that of acylcyanations of prochiral alde-
hydes.[7] The latter type of reactions requires dual Lewis
acid/Lewis base activation and proceeds by Lewis acid pro-
moted enantioselective addition of cyanide to the carbonyl
function. Chiral Lewis bases have minor influence on the
enantioselectivity, and no intermediate non-protected cy-
anohydrin is observed in the latter type of reactions.
Experimental Section
tert-Butyl 2-Acetoxy-2-cyano-2-phenylacetate (3c): α-Oxo ester 1c
(0.6 mmol, 124 mg, 1 equiv.) and methanol (60 m in CH2Cl2,
1 mL, 10 mol-%) were added to a solution of cinchonidine
(17.7 mg, 10 mol-%) in CH2Cl2 (1.5 mL). After the solution was
cooled to 0 °C, acetyl cyanide (86 µL, 1.2 mmol, 2 equiv.) was
added slowly over 30 min. The reaction mixture was stirred at 0 °C
for 16 h. The reaction solution was concentrated in vacuo, and the
residue was purified by silica gel chromatography using diethyl
ether/hexane (1:8) as eluent to give the product (130 mg), as color-
less oil in 79% isolated yield and 53% ee. HPLC (Daicel Chiralcel
QD-H, 250ϫ4.6 mm, 2-propanol/hexane, 0.1:99.9, flow 0.5 mL/
min, detection at 220 nm): tR (major) = 24.9 min]: tR (minor) =
26.9 min. [α]2D0 = –49.0 (c = 1.0, in CHCl3, sample with 53% ee).
1H NMR (CDCl3, 400 MHz): δ = 7.68–7.74 (m, 2 H), 7.43–7.48
(m, 3 H), 2.29 (s, 3 H), 1.46 (s, 9 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 169.4, 162.8, 131.9, 130.8, 129.4, 126.4, 115.7, 86.3,
75.4, 29.9, 20.8 ppm. C15H17NO4 (275.3): calcd. C 65.44, H 6.22,
N 5.09; found C 65.37, H 6.33, N 5.02.
General: CH2Cl2 was distilled from CaH2. oxo esters 1a, 1b and
1d were commercial and used without further purification. Acetyl
cyanide[7c,20] was prepared from acetyl bromide and CuCN, and
1c[21] and 1e were prepared by reaction of benzoylformic acid and
propionylformic acid, respectively, with methansulfonyl chloride
and tert-butyl alcohol.[22] O-Methylcinchonidine (6) and O-(tri-
methylsilyl)cinchonidine (7) were prepared by O-functionalization
of cinchonidine.[12] Conversions were determined by 1H NMR
spectroscopy, and enantiomeric excesses were determined by chiral
HPLC (Daicel Chiralcel OD-H, 250ϫ4.6 mm) or by GC/MS using
a chiral column [Chiraldex, G-TA (gamma cyclodextrin trifluo-
roacetyl), 30 mϫ0.25 mm]. 1H NMR spectra were recorded at 500
or 400 MHz, 13C NMR spectra at 125 or 100 MHz. The 1H and
13C chemical shifts are reported in ppm relative to the solvent as
internal standard.
Procedure for Optimization of Reaction Conditions: The Lewis acid
(0.012 mmol, 10 mol-% based on Ti), Lewis base (0.012 mmol,
10 mol-%) and the indicated amount of methanol in CH2Cl2
(0.2 mL) were added to a CH2Cl2 solution (0.3 mL) of methyl ben-
zoylformate (1a, 17 µL, 0.12 mmol, 1 equiv.). The reaction started
by addition of acetyl cyanide (17 µL, 0.24 mmol, 2 equiv.) by a sy-
ringe (in the cases of slow addition, the acetyl cyanide was dis-
solved in 30 µL of CH2Cl2) at the indicated temperature. The reac-
tion was monitored by 1H NMR spectra of samples taken from the
reaction mixture, and the products were analyzed by chiral HPLC.
Ethyl 2-Acetoxy-2-cyanopropanoate (3d): Ethyl pyruvate (1d,
174 µL, 1.5 mmol) and methanol (6.1 µL, 0.15 mmol) were added
to a solution of (DHQD)2AQN (64.3 mg, 0.075 mmol) in dry
CH2Cl2 (6.25 mL). After the solution was cooled to –78 °C, acetyl
cyanide (213 µL, 3 mmol) was added slowly over 30 min. The reac-
tion mixture was stirred at –78 °C for 4 h, diluted with Et2O and
filtered through silica, and the solvent was evaporated under vac-
uum. The residue was purified by bulb-to-bulb distillation followed
by silica gel chromatography using diethyl ether/hexane (1:1) as elu-
ent to give a sample of the pure product (30%) as a colorless oil.
GC [Chiraldex, G-TA (gamma cyclodextrin trifluoroacetyl),
30 mϫ0.25 mm, GC parameters: 70 °C (hold 1 min), 4 °C/min up
to 95 °C and then 15 °C/min up to 120 °C (hold 43 min)]: tR
(minor) = 15.9 min, tR (major) = 17.7 min. [α]2D0 = –48.0 (c = 1.7,
in CDCl3, sample with 57% ee). 1H NMR (CDCl3, 500 MHz): δ =
4.29–4.35 (m, 2 H), 2.18 (s, 3 H), 1.87 (s, 3 H), 1.33 (t, 3 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 168.8, 165.3, 115.7, 69.3, 63.7,
23.6, 20.1, 13.8 ppm.
Methyl 2-Acetoxy-2-cyano-2-phenylacetate (3a): α-Oxo ester 1a
(85 µL, 0.6 mmol, 1 equiv.) and methanol (60 m in CH2Cl2, 1 mL,
10 mol-%) were added to a solution of cinchonidine (17.7 mg,
10 mol-%) in CH2Cl2 (1.5 mL). After the solution was cooled to
–40 °C, acetyl cyanide (86 µL, 1.2 mmol, 2 equiv.) was added in
portions of about 2 µL during 3 h. The reaction mixture was stirred
at –40 °C for 6 h, then moved to a freezer and stirred for another
12 h. The final reaction solution was concentrated in vacuo, and
the residue was purified by silica gel chromatography using diethyl
ether/hexane (1:8) as eluent to give 3a (107 mg) as a white powder
in 77% isolated yield and 66% ee. HPLC (Daicel Chiralcel OD-H,
250ϫ4.6 mm, 2-propanol/hexane, 1:99, flow 0.5 mL/min, detection
at 220 nm): tR (minor) = 26.4 min, tR (major) = 34.6 min. M.p. 47–
tert-Butyl 2-Acetoxy-2-cyanobutanoate (3e): tert-Butyl 2-oxobut-
anoate (1e, 9.5 µL, mmol) and methanol (60 m in CH2Cl2,
0.1 mL, 10 mol-%) were added to a solution of cinchonidine
(1.75 mg, 10 mol-%) in dry CH2Cl2 (0.25 mL). After the solution
was cooled to –78 °C, acetyl cyanide (8.6 µL, 0.12 mmol) was
added slowly over 30 min. The reaction mixture was stirred at
–78 °C for 3 h, diluted with Et2O and filtered through silica, and
the solvent was evaporated under vacuum. GC [Chiraldex, G-TA
49 °C. [α]2D0 = –56.8 (c = 1.0, in CHCl3, sample with 66% ee). H
1
NMR (CDCl3, 500 MHz): δ = 7.72–7.73 (m, 2 H), 7.45–7.49 (m, 3
H), 3.84 (s, 3 H), 2.30 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 169.1, 164.4, 130.9, 130.7, 129.2, 126.1, 114.8, 74.4, 54.5,
20.3 ppm.
Ethyl 2-Acetoxy-2-cyano-2-phenylacetate (3b): α-Oxo ester 1b (gamma cyclodextrin trifluoroacetyl), 30 mϫ0.25 mm, GC param-
(95 µL, 0.6 mmol, 1 equiv.) and methanol (60 m in CH2Cl2, 1 mL,
10 mol-%) were added to a solution of cinchonidine (17.7 mg,
10 mol-%) in CH2Cl2 (0.5 mL). After the solution was cooled to
–40 °C, acetyl cyanide (86 µL, 1.2 mmol, 2 equiv.) was added in
portions of about 2 µL during 3 h. The reaction mixture was stirred
eters: 95 °C (hold 4 min), 15 °C/min up to 120 °C (hold 25 min)]:
tR (minor) = 16.1 min, tR (major) = 16.4 min. [α]2D0 = –60.0 (c =
1.0, in CDCl3, sample with 82% ee). 1H NMR (CDCl3, 400 MHz):
δ = 2.18 (s, 3 H), 2.08–2.12 (m, 2 H), 1.52 (s, 3 H), 1.16 (t, J =
7.2 Hz, 3 H) ppm.
Eur. J. Org. Chem. 2009, 3917–3922
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3921

F. Li, K. Widyan, E. Wingstrand, C. Moberg
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Acknowledgments
This work was supported by a scholarship from the China Scholar-
ship Council to F. L. and by a scholarship from Erasmus Mundus
External Cooperation Window Lot 3 (EMECW3) to K. W.
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Received: January 19, 2009
Published Online: June 30, 2009
3922
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3917–3922