Highly diastereoselective addition of Et2AlCN to β-keto amides derived from (S)-4-isopropyl-2-oxazolidinone

Article abstract of DOI:10.1016/j.tetasy.2003.07.004

The addition of Et₂AlCN in the presence of ZnBr₂ or Et₂AlCl to 1,3-dicarbonyl compounds derived from (S)-4-isopropyl-2- oxazolidinone, proceeds with high diastereoselectivity (94-98% de) and good chemical yields. This type

Full text of DOI:10.1016/j.tetasy.2003.07.004

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2693–2698
Highly diastereoselective addition of Et AlCN to b-keto amides
2
derived from (S)-4-isopropyl-2-oxazolidinone
Virginia Flores-Morales, Mario Fern a´ ndez-Zertuche* and Mario Ord o´ n˜ ez*
Centro de Investigaciones Qu ´ı micas. Universidad Aut o´ noma del Estado de Morelos,
Av. Universidad No. 1001. 62210 Cuernavaca, Mor. Mexico
Received 29 May 2003; accepted 14 July 2003
Abstract—The addition of Et AlCN in the presence of ZnBr or Et AlCl to 1,3-dicarbonyl compounds derived from (S)-4-isopro-
2
2
2
pyl-2-oxazolidinone, proceeds with high diastereoselectivity (94–98% de) and good chemical yields. This type of addition to chiral
b-dicarbonyl substrates represents a new synthetic methodology leading to the formation of enantiomerically pure cyanohydrins.
©
2003 Elsevier Ltd. All rights reserved.
1
. Introduction
As part of our ongoing program directed towards the
design of chiral b-substituted-g-amino acids, we herein
report the highly diastereoselective cyanation of b-keto
amides with the Nagata’s reagent. One of these
cyanohydrins has been converted in a three-step proce-
dure to (2R,3R)-4-acetylamino-2,3-dimethyl-3-hydroxy-
butyric acid 7, as an example of a new g-amino acid
with a quaternary b-hydroxy-a,b-dimethylated substitu-
tion pattern.
The cyanation reaction of carbonyl compounds is one
of the most versatile procedures for the synthesis of
cyanohydrins; a variety of nucleophilic cyanide reagents
1
can already be employed. The production of optically
active cyanohydrins is of continuing interest to organic
chemists due to the central role of these compounds in
the enantioselective synthesis of several classes of valu2-
able intermediates, including b-hydroxy-a-amino acids,
3
4
a-hydroxy-b-amino acids,
a-hydroxyketones,
b-
5
6
7
hydroxy nitrones, b-amino alcohols, a-amino acids
2
. Results and discussion
8
and a-hydroxy acids.
Initially, the reaction of propionimides 1 with lithium
diisopropylamide (LDA) in THF at −78°C and the
Among these methods, trimethylsilyl cyanide (TMSCN)
and HCN are already widely used in innumerable addi-
9
10
corresponding acid 1 chlorides under previously
tions to aldehydes, imines (Strecker’s reaction),
4c
1
1
12
described conditions,
afforded the chiral b-keto
ketones and nitrones. However, in the absence of a
catalyst, no reaction occurs between TMSCN and a
carbonyl or imine compound; therefore, it is necessary
to use several additives along with Lewis acids, both in
catalytic and stoichiometric amounts to promote such
amides 2a–g with good yields and high diastereoselec-
tivity (Table 1).
The addition reaction of Et AlCN to b-keto amides
2
1
3
2
a–g was carried out in dry toluene from −78 to 0°C, in
additions. On the other hand the highly diastereose-
lective reduction of a-methyl-b-keto amides has pro-
vided a useful alternative to asymmetric aldol reactions
either the absence or presence of Lewis acids, the results
are shown in Table 2.
14
in organic synthesis. However, to the best of our
knowledge, the cyanation reaction of b-keto amides has
not yet been described.
From the results summarized in Table 2, it can be seen
that the reaction of 2a and 2b with Et AlCN in the
2
absence of a Lewis acid, resulted only in the recovery of
the starting material in the crude reaction (entries 1 and
2
). The same result was also seen when the reaction of
*
0
Corresponding authors. E-mail: mfz@ciq.uaem.mx; palacios@
buzon.uaem.mx
2a and 2b was carried out in the presence of ZnBr2
957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.004

2
694
V. Flores-Morales et al. / Tetrahedron: Asymmetry 14 (2003) 2693–2698
Table 1. Preparation of chiral b-keto amides 2a–g
9 and 10) proceeded with high diastereoselectivity, with
as the major product. The high diastereoselectivity
observed in 2c and 2d with either ZnBr or Et AlCl can
3
2
2
be attributed to the 1,3-dicarbonyl moiety of these
compounds coordinating to the Lewis acid metals (Zn
or Al) thus yielding a rigid chelate. Low temperature
NMR studies have shown the ability of Et AlCl and
2
ZnBr to form six-membered ring chelates with oxazo-
2
15
lidinone substrates. Therefore, cyanide addition to the
carbonyl group takes place from the side opposite to
the a-methyl group, affording diastereomer 3 predomi-
nantly. The diastereomeric relation of 3 to 4 was deter-
Entry
2
R
R%
Yield (%)
De (%)a
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
H
Me
Ph
Me
Ph
p-Cl-Ph
p-MeO-Ph
p-Me-Ph
22
77
75
79
88
71
89
–
–
1
mined by a 400 MHz H NMR in the crude product by
Me
Me
Me
Me
Me
98
96
98
98
98
integration of some characteristic signals, eg. the a-
methyl signal of 3c and 4c at 1.30 (d, J=7.2 Hz) and
1.42 (d, J=7.2 Hz), respectively. We also used the
signal of the methyl groups bound to the quaternary
centers at 1.58 and 1.70. For 3d and 4d, the diastereo-
selectivity relation was determined by the integration of
the a-methyl signal at 1.06 (d, J=6.8 Hz) and 1.00 (d,
J=7.2 Hz), respectively.
2g
a
Diastereomeric ration was measured by 1H NMR at 400 MHz.
(
entries 3 and 4). The lack of reactivity of these com-
pounds can be attributed to the high stability of the
enolic form generated.
The use of other Lewis acids such as MgI2 in the
addition of Et AlCN was also evaluated (entries 11 and
2
However, the reaction of compound 2c in the absence
of a Lewis acid (entry 5) generated a mixture of 3c and
1
2). However low yields and diastereoselectivities in the
presence of MgI2 were observed suggesting a weak
chelate interaction between the Mg and the carbonyl
oxygens or perhaps even the existence of an open
4
c with a 50:50 ratio, whereas 2d, under the same
conditions (entry 6) provided 3d and 4d now with a
diastereoselectivity of 80:20, in favor of the
diastereomer 3d.
16
transition state. In the case of 2d, (entry 12) although
the chemical yield is lower, the magnitude of the
diastereoselectivity observed is comparable to the case
when the reaction was carried out in the absence of the
Lewis acid (entry 6).
The reaction of compounds 2c–d with Et AlCN in the
2
presence of ZnBr (entries 7 and 8) or Et AlCl (entries
2
2
Table 2. Addition of Et AlCN to b-keto amides 2a–g
2
Lewis acida
Yield (%)c
(3:4)
d
Entry
2
R
R%
Et AlCN (equiv.)
2
b
b
b
b
1
2
3
4
5
6
7
8
9
2a
2b
2a
2b
2c
2d
2c
2d
2c
2d
2c
2d
2e
2f
H
H
H
H
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
p-Cl-C H
p-MeO-C H
2.0
2.0
4.0
4.0
2.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
8.0
8.0
–
–
–
–
–
–
ZnBr2
ZnBr2
–
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
77
63
77
82
77
79
33
23
60
27
65
50:50
80:20
94:6
98:2
94:6
95:5
80:20
78:22
98:2
98:2
98:2
–
ZnBr2
ZnBr2
Et AlCl
Et AlCl
MgI2
2
10
11
12
13
14
15
2
MgI2
ZnBr2
ZnBr2
ZnBr2
6
4
6
4
2g
p-Me-C H
6
4
a
b
c
1
.2 equiv.
The reaction did not proceed.
Yield of major diastereomer.
d
Determined by 1H NMR at 400 MHz.

V. Flores-Morales et al. / Tetrahedron: Asymmetry 14 (2003) 2693–2698
2695
In order to investigate whether a stereoelectronic effect
cyanohydrin. In both cases, only 3f and 3g were
1
is operating in the addition reaction of Et AlCN, the
detected by H NMR.
2
b-keto amides 2e–g substituted in the para position of
the phenyl ring with chloro, methoxy and methyl
The configuration at the carbinol center for the
groups were subjected to the addition of Et AlCN
under the same reaction conditions. When compound
cyanohydrins 3c and 3d was assigned by X-ray diffrac-
2
17
tion studies (Fig. 1). On the basis of these, we
assumed the same stereochemistry for all the cyanohy-
drins derived from the aromatic substrates.
2
e (p-Cl) was treated with 4.0 equiv. of Et AlCN in the
2
presence of ZnBr , a highly diastereoselective addition
2
−
of CN to the carbonyl group was observed (entry 13)
with only 3e being detected by NMR.
In order to illustrate the usefulness of this method,
compound 3c was converted in a three-step procedure
to the g-amino acid 7 (Scheme 1). The reduction of the
cyano group on 3c was carried out by hydrogenolysis
using Raney Ni in acetic anhydride at room tempera-
ture and atmospheric pressure, affording the N-acetyl
derivative 5 in 95% yield.
In all the other cases, the presence of an electron-donat-
ing group (MeO and Me) on the aromatic ring,
decreases the reactivity of the carbonyl group meaning
that an excess of the Et AlCN reagent (8.0 equiv.) must
2
be used in order to achieve some conversion of 2f and
2g (entries 14 and 15) to the corresponding cyanohy-
drins. However, under these conditions, using an excess
of Nagata’s reagent also induces the epimerization of
the remaining starting material or the resulting
Although we attempted to remove the chiral auxiliary
directly from compound 5 to obtain the g-amino acid 7
using the well established lithium peroxide protocol
Figure 1. X-Ray crystal structure of 3c and 3d.

2
696
V. Flores-Morales et al. / Tetrahedron: Asymmetry 14 (2003) 2693–2698
3
.1.1.
propyl]-(S)-4-isopropyl-2-oxazolidinone 2e. To a cooled
−78°C) solution of diisopropylamine (0.54 mL, 3.89
mmol) in dry THF (15 mL) was added n-butyllithium
3.46 mL of a 1.17 M solution in hexane, 4.1 mmol).
(2R)-3-[2-Methyl-1,3-dioxo-3-(p-chlorophenyl)-
(
(
The mixture was stirred at −78°C for 30 min after
which a solution of 1 (0.60 g, 3.28 mmol) in dry THF
(
10 mL) was added. The resulting solution was stirred
for 45 min at −78°C and a solution of 4-chloro−ben-
zoylchloride (0.82 mL, 6.5 mmol) in dry THF (25 mL)
added dropwise via cannula. After being stirred at
−
78°C for 1.5 h, the reaction mixture was allowed to
reach −10°C and quenched by the addition of a satu-
rated aqueous NH Cl solution (10 mL). The organic
4
phase was separated and the aqueous layer extracted
with CH Cl (2×15 mL). The combined organic extracts
2
2
Scheme 1.
were dried over Na SO and evaporated under reduced
2
4
pressure. The crude product was purified by column
chromatography using hexane:ethyl acetate (85:15) as
the eluent to give 2e as a white solid 0.93 g, 88% yield.
1
8
developed by Evans, we observed under these basic
conditions the decomposition of 5 by a retro aldol
pathway, a process favoured by the presence of the
tertiary OH group. In order to circumvent this prob-
lem, we therefore considered protection of the OH
group under acid conditions. We introduced the 1-
ethoxyethyl ether (EE) group in the presence of pyri-
dinium p-toluensulfonate (PPTS), conditions that led to
the formation of 6 in quantitative yield, which without
further purification, was treated with lithium peroxide
in aqueous THF, affording the g-amino acid 7 in 84%
yield, and 77% yield of the recovered chiral auxiliary.
25
1
Mp: 89–90°C. [h] =−84.6 (c 2.89, CHCl ). H NMR
D
3
(
400 MHz, CDCl ): l 7.92 (AA%BB%, J=8.8, 2H), 7.46
3
(AA%BB%, J=8.8, 2H), 5.28 (q, J=7.2, 1H), 4.51 (dt,
J=8.4, 3.5, 1H), 4.30 (dd, J=9.2, 1H), 4.24 (dd, J=
9
0
1
5
1
.2, 3.2, 1H), 2.49–2.57 (m, 1H), 1.43 (d, J=7.2, 3H),
13
.95 (d, J=7.0, 6H). C NMR (100 MHz, CDCl ): l
3
96.7, 170.1, 154.4, 139.8, 134.1, 130.2, 129.2, 63.9,
−1
8.9, 48.7, 28.6, 18.0, 14.8, 13.6. IR cm : 2969.7,
776.8, 1712.8, 1683.1, 1630.6. Anal. calcd for
C H ClNO : C, 59.35; H, 5.60; N, 4.33. Found: C,
16
18
4
6
0.10; H, 5.79; N, 4.39%.
In summary, we have demonstrated that diethylalu-
minum cyanide (Nagata’s reagent) acts as an outstand-
ing cyanating agent able to react with chiral b-keto
amides to afford the corresponding cyanohydrins in
good yield and high diastereoselectivity, which can be
used in the synthesis of several other compounds of
interest.
3
.1.2. (2R)-3-[2-Methyl-1,3-dioxo-3-(p-methoxyphenyl)-
propyl]-(S)-4-isopropyl-2-oxazolidinone 2f. The reaction
was carried out starting from 1 (0.50 g, 2.70 mmol)
following the procedure described for the preparation
of 2e. The crude product was purified by column
chromatography using hexane:ethyl acetate (80:20) as
the eluent to give 2f as a white solid 0.62 g, 71% yield.
2
5
1
Mp: 97.7–99.9°C. [h] =−91.0 (c 5.55, CHCl ).
NMR (400 MHz, CDCl ): l 7.95 (AA%BB%, J=8.8, 2H),
H
D
3
3. Experimental
3
6
.95 (AA%BB%, J=8.8, 2H), 5.33 (q, J=7.2, 1H), 4.50
The reaction flasks and other glass equipment were
heated in an oven at 130°C overnight and assembled in
(dt, J=8.4, 3.5, 1H), 4.29 (dd, J=9.2, 1H), 4.23 (dd,
J=9.2, 3.0, 1H), 3.86 (s, 3H), 2.49–2.57 (m, 1H), 1.44
(d, J=7.2, 3H), 0.95 (d, J=6.8, 6H). C NMR (100
13
a stream of dry N . Solvents were purified and dried
2
according to standard procedures. Flash chromatogra-
phy was performed with silica gel 60 (230–400 mesh).
Silica gel F254 plates were used for TLC monitoring.
Melting points were determined in a B u¨ chi B-540
apparatus in open capillary tubes and are uncorrected.
Optical rotations were measured at room temperature
MHz, CDCl ): l 196.4, 170.7, 163.8, 154.3, 131.1,
3
128.6, 114.1, 63.8, 58.8, 55.6, 48.4, 28.6, 18.0, 14.8, 13.9.
−
1
IR cm : 2967.0, 1777.2, 1709.5, 1671.6, 1601.3. Anal.
calcd for C H NO : C, 63.94; H, 6.63; N, 4.39.
17
21
5
Found: C, 63.96; H, 6.83; N, 4.31%.
(
20–23°C) using a Perkin–Elmer model 241 polarimeter
concentration in g/100 mL). Microanalyses were regis-
3.1.3. (2R)-3-[2-Methyl-1,3-dioxo-3-(p-methylphenyl)-
(
propyl]-(S)-4-isopropyl-2-oxazolidinone 2g. The reac-
tion was carried out starting from 1 (0.35 g, 1.89 mmol)
following the procedure for the preparation of 2e.
The crude product was purified by column chromatog-
raphy using hexane:ethyl acetate (70:30) as the eluent to
give 2g as a white solid 0.51 g, 89% yield. Mp: 114–
tered on a Elemental VARIO EL III. IR spectra were
recorded on a Brucker vector 22 FT-IR. NMR spectra
were recorded on an Inova Varian at 400 and 200 MHz
1
13
for H and 100 and 50 MHz for C. The J values are
given in Hertz.
2
5
1
1
14.5°C. [h] =−89.2 (c 2.51, CHCl ). H NMR (400
D 3
3
.1. Preparation of b-keto amides 2a–g
MHz, CDCl ): l 7.87 (AA%BB%, J=8.4, 2H), 7.27
3
(AA%BB%, J=8.4, 2H), 5.34 (q, J=7.2, 1H), 4.50 (dt,
Compounds 1 and 2a–g were synthesized and purified
J=8.4, 3.5, 1H), 4.29 (dd, J=9.2, 1H), 4.23 (dd, J=
9.2, 3.2, 1H), 2.49–2.57 (m, 1H), 2.41 (s, 3H), 1.44
14c
according to the protocol described by Evans et al.

V. Flores-Morales et al. / Tetrahedron: Asymmetry 14 (2003) 2693–2698
2697
1
3
(
d, J=7.2, 3H), 0.95 (d, J=7.2, 6H). C NMR (100
3.2.4. (2R,3R)-3-[2-Methyl-3-cyano-3-hydroxy-1-oxo-3-
MHz, CDCl ): l 197.5, 170.7, 154.4, 144.1, 133.2,
29.6, 129.0, 63.9, 58.9, 48.7, 28.6, 21.8, 18.1, 14.9, 13.9.
IR cm : 2968.0, 1777.2, 1711.2, 1677.0, 1615.9. Anal.
calcd for C H NO : C, 67.31; H, 6.98; N, 4.62.
phenylpropyl]-(S)-4-isopropyl-2-oxazolidinone
3d.
3
1
Obtained from 2d (0.445 g, 1.54 mmol) following the
−
1
method B with ZnBr as the Lewis acid, and purified by
2
trituration of the crude oil with a 90:10 mixture of
1
7
21
4
Found: C, 67.56; H, 7.26; N, 4.61%.
hexane and isopropyl alcohol to give 3d as a white solid
25
0
.40 g, 82% yield. Mp: 160–163°C. [h] =+35.5 (c 2.45,
D
1
CHCl ). H NMR (400 MHz, CDCl ): l 7.58–7.61 (m,
3
3
3
.2. General procedures for the addition of Et AlCN.
2
2H), 7.36–7.45 (m, 3H), 5.46 (s, 1H), 4.52 (q, J=7.0,
1H), 4.51 (dd, J=8.0, 3.6, 1H), 4.33 (dd, J=9.2, 1H),
2.29 (dd, J=9.2, 3.6, 1H), 2.45–2.52 (m, 1H), 1.06 (d,
Preparation of cyanohydrins 3c–g
3
.2.1. Method A. To a stirred solution of 2.0 equiv. of
J=6.8, 3H), 0.96 (d, J=7.0, 3H), 0.94 (d, J=7.0, 3H).
C NMR (100 MHz, CDCl ): l 176.9, 153.4, 136.6,
3
13
a Et AlCN (1.0 M in toluene) in dry toluene at −78°C,
2
was added dropwise 1.0 equiv. of a 0.1 M solution of
b-keto amides 2a–g in anhydrous toluene. The reaction
was stirred at −78°C for 6 h, allowed to rise to −40°C
and maintained at this temperature for 5 min. After this
period of time, the reaction mixture was quenched by
the addition of a mixture of 6 mL of methanol and 4
mL of concentrated HCl. The organic phase was sepa-
129.3, 128.9, 125.9, 121.3, 73.8, 63.7, 59.0, 47.1, 28.6,
−1
18.1, 14.7, 11.3. IR cm : 3411.3, 2966.7, 1781.6,
1673.2, 1377.6. Anal. calcd for C H N O , 64.54, H,
17
20
2
4
6.37, N, 8.86. Found: C, 64.52, H, 6.43, N, 8.93%.
3
.2.5. (2R,3R)-3-[2-Methyl-3-cyano-3-hydroxy-1-oxo-3-
(
p-chlorophenylpropyl]-(S)-4-isopropyl-2-oxazolidinone
2
rated and the aqueous layer extracted with CH Cl2
3e. The product was not isolated in a sufficiently pure
form for either elemental analysis or for determining
the specific rotation.
(
3×10 mL). The combined organic layers were dried
over anhydrous Na SO and concentrated in vacuo to
2
4
afford 3c–g as oils. The crude cyanohydrins were
analysed by 400 MHz H and C NMR.
1
13
3
.2.6. (2R,3R)-3-[2-Methyl-3-cyano-3-hydroxy-1-oxo-3-
(
p-methoxyphenylpropyl]-(S)-4-isopropyl-2-oxazolidinone
3
.2.2. Method B. A 0.1 M solution of 1.0 equiv. of
3f. The product was not isolated in a sufficiently pure
form for either elemental analysis or for determining
the specific rotation.
b-keto amide 2a–g and 1.2 equiv. of the corresponding
Lewis acid (ZnBr2 Et AlCl or MgI ) in dry toluene
,
2
2
under N2 atmosphere was stirred for 1 h at room
temperature. In a separate flask, a solution containing
3
.2.7. (2R,3R)-3-[2-Methyl-3-cyano-3-hydroxy-1-oxo-3-
4
.0 equiv. of Et AlCN (1.0 M in toluene) was cooled to
78°C. The first solution was transferred to the
2
(p-methylphenylpropyl]-(S)-4-isopropyl-2-oxazolidinone
−
3
g. The product was not isolated in a sufficiently pure
Et AlCN solution. The reaction mixture was stirred at
2
form for either elemental analysis or for determining
−
78°C for 6 h, allowed to rise to −40°C and maintained
the specific rotation.
at this temperature for 5 min. The reaction was then
quenched by the addition of a mixture of 6 mL of
methanol and 4 mL of concentrated HCl. The organic
phase was separated and the aqueous layer extracted
with CH Cl (3×10 mL). The combined organic layers
3
.2.8.
(2R,3S)-3-[4-N-Acetylamino-2,3-dimethyl-3-
hydroxy-1-oxobutyl]-(S)-4-isopropyl-2-oxazolidinone.
The catalyst for this reaction (Raney Ni) was washed
with absolute ethanol (2×1 mL) and acetic anhydride
2
2
were dried over anhydrous Na SO4 and evaporated
2
(
2×1 mL). A solution of 3c (100 mg, 0.39 mmol), Raney
under reduced pressure to afford 3c–g as oils. The
Ni 0.12 mg, Ac O (0.5 mL) and NaOAc (0.59 mmol)
1
2
crude cyanohydrins were analysed by 400 MHz H and
was stirred for 48 h under hydrogen gas at room
temperature. The mixture was filtered through a sin-
tered glass filter and the precipitate successively washed
1
3
C NMR.
3
.2.3.
(2R,3S)-3-[2-Methyl-3-cyano-3-hydroxy-1-
with ethyl acetate (5.0 mL) and H O (5.0 mL). The
2
oxobutyl]-(S)-4-isopropyl-2-oxazolidinone 3c. Obtained
from 2c (0.50 g, 2.20 mmol) following the method B
filtrate was placed in a separatory funnel and the
organic layer separated. The aqueous layer was further
extracted with ethyl acetate (2×5 mL). The combined
organic layers were dried over anhydrous Na SO ,
with ZnBr as the Lewis acid, and purified by tritura-
tion of the crude oil with a 90:10 mixture of hexane and
2
2
4
isopropyl alcohol to give 3c as a white solid 0.433 g
filtered and evaporated under reduced pressure afford-
2
5
25
7
7% yield. Mp: 106–109°C. [h] =+62.5 (c 1.24,
ing 5 as a colorless oil (95%). [h] =+19.7 (c 3.22,
D
D
1
1
CHCl ). H NMR (400 MHz, CDCl ): l 4.96 (s, 1H),
CHCl ). H NMR (400 MHz, CDCl ): l 6.36 (s, 1H),
3
3
3
3
4
.49 (dt, J=8.4, 3.6, 1H), 4.34 (dd, J=9.2, 1H), 4.29
4.44–4.47 (m, 1H), 4.30 (dd, J=9.2, 1H), 4.25 (dd,
J=9.2, 2.8, 1H), 4.00 (q, J=7.0, 1H), 3.40 (dd, J=14.0,
6.4, 1H), 3.30 (dd, J=14.0, 5.4, 1H), 2.35–2.43 (m, 1H),
2.05 (s, 3H), 1.20 (d, J=7.2, 3H), 1.17 (s, 3H), 0.93 (d,
(
(
dd, J=9.2, 3.2, 1H), 4.20 (q, J=7.0, 1H), 2.43–2.50
m, 1H), 1.58 (s, 3H), 1.30 (d, J=7.2, 3H), 0.95 (d,
1
3
J=7.0, 3H), 0.94 (d, J=7.0, 3H). C NMR (100 MHz,
CDCl ): l 176.0, 153.8, 121.9, 69.3, 63.8, 59.1, 45.1,
13
J=7.2, 3H), 0.90 (d, J=7.2, 3H). C NMR (100 MHz,
3
−
1
2
2
8.7, 24.0, 18.1, 14.8, 11.3. IR cm : 3438.8, 2965.6,
359.6, 1778.9, 1698.1, 1387.8. Anal. calcd for
CDCl ): l 175.7, 171.3, 155.2, 75.0, 63.8, 59.5, 48.5,
3
−
1
42.6, 28.9, 23.2, 20.6, 18.1, 14.9, 13.3. IR cm : 3388.3,
2968.8, 1775.8, 1696, 1550.8, 1379.9. MS (EI): m/z 228
(45), 210 (5), 130 (95), 111 (22), 97 (18), 86 (47), 73 (76),
C H N O :C, 56.68; H, 7.13; N, 11.02. Found: C,
12
18
2
4
56.68; H, 7.16; N, 11.23%.

2
698
V. Flores-Morales et al. / Tetrahedron: Asymmetry 14 (2003) 2693–2698
5
7 (100), 43 (65). Anal. calcd for C H N O C, 55.98,
Warmerdam, E. G. J. C.; van Rijn, R. D.; Brussee, J.;
Kruse, C. G.; van der Gen, A. Tetrahedron: Asymmetry
14
24
2
4
H, 8.05, N, 9.32. Found: C, 55.88, H, 7.9, N, 9.15%.
1
996, 7, 1723; (c) Cativiela, C.; Diaz-de-Villegas, M. D.;
3
.2.9. (2R,3S)-4-Acetylamino-2,3-dimethyl-3-hydroxybu-
tyric acid 7. A 0.05 M solution of substrate 5, 0.22 g
0.73 mmol) in dry dichloromethane under nitrogen
atmosphere was treated at 0°C with ethyl vinyl ether
2.0 equiv) followed by a catalytic amount of pyri-
Galvez, J. A. Tetrahedron 1996, 52, 687.
4. Jackson, W. R.; Jacobs, H. A.; Jayatilake, G. S.;
Matthews, B. R.; Watson, K. G. Aust. J. Chem. 1990, 43,
(
2
045.
(
5
6
. Hulsbos, E.; Marcus, J.; Brussee, J.; van der Gen, A.
Tetrahedron: Asymmetry 1997, 8, 1061.
. (a) Roos, J.; Effenberger, F. Tetrahedron: Asymmetry
dinium p-toluenesulfonate (PPTS). The resulting mix-
ture was then stirred for 6 h at 0°C. The solvent was
evaporated and the residue dissolved in ethyl acetate
2002, 13, 1855; (b) Effenberger, F.; Eichhorn, J. Tetra-
(
(
10.0 mL), washed with saturated aqueous NaHCO3
5.0 mL) and brine (5.0 mL). The combined organic
hedron: Asymmetry 1997, 8, 469.
. Decicco, C. P.; Grover, P. Synlett 1997, 529.
. Ziegler, T.; H o¨ rsch, B.; Effenberger, F. Synthesis 1990,
7
8
layers were dried over anhydrous Na SO , filtered and
evaporated under reduced pressure affording 6 as a
yellow oil in a quantitative yield. Without any isolation,
the oil dissolved in a mixture of THF/H O (3:1) to
obtain a 0.05 M solution of substrate 6, which was
treated at 0°C with 4.0 equiv. of 30% H O followed by
2
4
5
75.
9
. (a) Andr e´ s, J. M.; Mart ´ı nez, M. A.; Pedrosa, R.; P e´ rez-
Encabo, A. Tetrahedron: Asymmetry 2001, 12, 347; (b)
Ward, D. E.; Hrapchark, M. J.; Sales, M. Org. Lett.
2
2
2
2
000, 2, 57; (c) Belokon, Y. N.; North, M.; Parsons, T.
2
.0 equiv. of LiOH. The resulting mixture was stirred
for 9 h at 0°C and quenched with 10% aqueous HCl
until reaching pH and then extracted with
Org. Lett. 2000, 2, 1617.
1
1
0. (a) Acherki, H.; Alvarez-Ibarra, C.; Dios, A.; Quiroga,
M. L. Tetrahedron 2002, 58, 3217; (b) Vachal, P.; Jacob-
sen, E. N. Org. Lett. 2000, 2, 867.
1. (a) Masumoto, S.; Yabu, K.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 2919; (b) Hamashima, Y.;
Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42,
691; (c) Garc ´ı a Ruano, J. L.; Mart ´ı n Castro, A. M.;
Rodr ´ı guez, J. H. J. Org. Chem. 1992, 57, 7235.
2
dichloromethane (3×5.0 mL). The aqueous layer was
evaporated under reduced pressure to afford 93 mg,
8
4% yield of the amino acid 7, as a highly hygroscopic
1
white solid. H NMR (400 MHz, D O): l 3.48 (AB,
2
J=11.0, 2H), 3.30 (AB, J=11.0, 2H), 2.51 (q, J=7.2,
13
1
H), 2.03 (s, 3H), 1.4 (s, 3H), 1.05 (d, J=7.2, 3H).
C
NMR (100 MHz, D O): l 183.5, 176.5, 78.8, 66.6, 49.6,
2
−
1
2
6.2, 14.6, 9.0. IR cm : 3444.8, 1737.1. MS (EI): m/z
12. Merino, P.; Trejo, T.; Revueltas, J.; Romero, P.; Cicchi,
S.; Munnucci, V.; Brandi, A.; Goti, A. Tetrahedron:
Asymmetry 2003, 14, 367.
+
(
M −H O)=171 (11), 130 (55), 116 (11), 112 (22), 98
28), 86 (100), 72 (58), 57 (67), 43 (85). The product was
2
(
not isolated in a sufficiently pure form for either ele-
mental analysis or for determining the specific rotation.
13. (a) Gr o¨ ger, H. Chem. Eur. J. 2001, 7, 5246; (b) Bandini,
M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Tetrahedron Lett. 2001, 42, 3041 and references cited
therein.
Acknowledgements
14. (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi,
M.; Rinaldi, S.; Sambri, L. Tetrahedron Lett. 2001, 42,
6
093; (b) Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetra-
We wish to thank CONACYT of Mexico (Grants
hedron Lett. 1985, 26, 4643; (c) Evans, D. A.; Ennis, M.
D.; Le, T.; Mandel, N.; Mandel, G. J. Am. Chem. Soc.
28762-E and 3112P-E9607) for financial support for
this work. One of us, VFM, also wishes to thank
CONACYT for a Graduate Scholarship (112917). We
also thank H. H o¨ pfl and H. Tlahuext for their valuable
technical help for the obtention of the X-ray structures.
1984, 106, 1154; (d) Oishi, T.; Nakata, T. Acc. Chem.
Res. 1984, 17, 338; (e) DiPardo, R. M.; Bock, M. G.
Tetrahedron Lett. 1983, 24, 4805.
1
1
1
5. (a) Castellino, S.; Wesley, J. D. J. Am. Chem. Soc. 1993,
115, 2986; (b) Taniguchi, M.; Fujii, H.; Oshima, K.;
Utimoto, K. Tetrahedron 1993, 49, 11169.
References
6. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprensive
Asymmetric Catalyst; Springer: New York, 1999; Vols.
1. (a) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33,
1–3.
1
555; (b) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649; (c)
7. The crystal structures have been deposited at the Cam-
bridge Crystallographic Data Centre along with the crys-
tal structures of compounds 2c, 2d and 2g. 2c (CCDC
North, M. Tetrahedron: Asymmetry 2003, 14, 147 and
references cited therein.
2
3
. Zandbergen, P.; Brussee, J.; van der Gen, A. Tetrahedron:
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. (a) Tromp, R. A.; van der Hoeven, M.; Amore, A.;
Brussee, J.; Overhand, M.; van der Marel, G. A.; van der
Gen, A. Tetrahedron: Asymmetry 2001, 12, 1109; (b)
207811); 2d (CCDC 207813); 2g (CCDC 207815); 3c
(
CCDC 207812); 3d ( CCDC 207814).
1
8. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
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