Enantioselective nitroaldol reaction of α-keto esters catalyzed by a copper(II)-bisoxazolidine complex

Article abstract of DOI:10.1055/s-0030-1259000

A wide range of aliphatic and aromatic -keto esters has been transformed to α-hydroxy-β-nitro esters via the Cu(II)-bisoxa-zolidine-catalyzed Henry reaction. In the presence of 10 mol% of the chiral catalyst, nitroaldol products were obtained in up to 95% yield and 76% ee.

Full text of DOI:10.1055/s-0030-1259000

LETTER
2765
Enantioselective Nitroaldol Reaction of a-Keto Esters Catalyzed by a
Copper(II)–Bisoxazolidine Complex
Enantioselective
N
a
itroaldol
R
n
eactionof
a
-
h
K
eto
E
sters ui Xu, Christian Wolf*
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
Fax +1(202)6876209; E-mail: cw27@georgetown.edu
Received 23 August 2010
Initial experiments showed that our methods using bisoxa-
zolidine (+)-1 and either CuOAc or Me2Zn for the enanti-
oselective nitroaldol reaction with aldehydes were not
successful when a-keto esters were employed, and only
racemic product was obtained. We therefore decided to
carefully re-evaluate the catalyst loading and composition
by screening various Lewis acids and counteranion effects
as well as solvents, additives, the reaction temperature,
and the order of premixing catalyst, reagents, and sub-
strate. We first found that the nitroaldol reaction with eth-
yl phenyloxoacetate in the presence of 10 mol% of (+)-1,
10 mol% of Cu(II) triflate, and 20 mol% of triethylamine
in THF provides (R)-ethyl 2-hydroxy-3-nitro-2-phenyl-
propanoate (2) in 81% yield and 50% ee at room temper-
ature (Scheme 2).
Abstract: A wide range of aliphatic and aromatic a-keto esters has
been transformed to a-hydroxy-b-nitro esters via the Cu(II)-bisoxa-
zolidine-catalyzed Henry reaction. In the presence of 10 mol% of
the chiral catalyst, nitroaldol products were obtained in up to 95%
yield and 76% ee.
Key words: asymmetric catalysis, nitroaldol reaction, chiral alco-
hols, copper, oxazolidine
The nitroaldol reaction produces chiral b-hydroxy nitroal-
kanes which are versatile synthetic precursors of a wide
range of compounds, including b-amino alcohols, aziri-
dines, and a-hydroxy carboxylic acids.1 In recent years,
considerable effort has been directed to the development
of asymmetric methods using aldehydes as substrate and
many chiral Co(II),2 Mg(II),3 Zn(II),4 Cr(III),5 Cu(I),6
Cu(II),7 and rare earth metal complexes8 have been intro-
duced to this important transformation.9 Because ketones
are generally less reactive than aldehydes and enantio-
facial differentiation of the carbonyl group is more diffi-
cult, few examples of the asymmetric nitroaldol reaction
with keto esters10 and trifluoromethyl ketones11 have been
reported to date. We recently introduced bisoxazolidine
(+)-112 to the asymmetric nitroaldol reaction with aldehydes
which produces both aliphatic and aromatic b-hydroxy
nitroalkanes in high yields and ee (Scheme 1).13 We now
O
O
HO
NO2
O
1 (10 mol%)
Cu(OTf)2 (10 mol%)
O
+
Et3N (20 mol%)
THF, 25 °C, 20 h
O
MeNO2
81%, 50% ee
Scheme 2 Asymmetric nitroaldol reaction with ethyl phenyloxo-
acetate
wish to report the usefulness of this chiral ligand in the Reducing the amount of the amine additive to 10 mol%
copper(II)-catalyzed enantioselective nitroaldol reaction gave racemic 2 in 20% yield and no product was obtained
of a-keto esters.
when the reaction was conducted in the absence of the
bisoxazolidine ligand. Since changing the solvent to
dichloromethane, acetonitrile, toluene, dioxane, diisopro-
pyl ether, and tert-butyl methyl ether did not improve re-
sults, we decided to screen various secondary and tertiary
amines and optimized the reaction temperature (Table 1).
First, we realized that the yield and ee of 2 slightly in-
crease at –10 °C (entry 1). Replacement of triethylamine
by other amines further improved yields in most cases and
proved to have a dramatic effect on the enantioselectivity.
For example, 2 was produced in only 6–7% ee when pyr-
rolidine and N,N,N¢,N¢-tetramethylethylenediamine were
employed (entries 12 and 15). By contrast, the introduc-
tion of N-methylmorpholine (NMM) to this reaction in-
creased the ee to 70% (entry 7).
OH
OH
O
(+)-1, Me2Zn
(+)-1, CuOAc
S
R
MeNO2
R
+
R
R
H
NO2
NO2
R = aryl: up to 97%, 95% ee
R = alkyl: up to 99%, 86% ee
R = aryl: up to 95%, 89% ee
R = alkyl: up to 97%, 97% ee
R
HN
O
S
S
S
R
S
O
NH
(+)-1
Scheme 1 Asymmetric nitroaldol reactions with aldehydes cataly-
zed by Cu(I) and Zn(II) complexes of bisoxazolidine (+)-1
Counteranion effects were also investigated. Yields and
ee dropped significantly when copper(II) triflate was re-
placed with CuCl2 or Cu(SbF6)2 which was formed by ad-
SYNLETT 2010, No. 18, pp 2765–2770
Advanced online publication: 12.10.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1259000; Art ID: S05410ST
© Georg Thieme Verlag Stuttgart · New York

2766
H. Xu, C. Wolf
LETTER
(Table 2, entries 2 and 3). Other functionalities, such as
methoxy, cyano, and ester groups, do not have a signifi-
cant effect on yields but ee decreased slightly when 6 and
7 were prepared (entries 4–8). As expected, methyl ester
10 is formed with literally the same yield and enantiose-
lectivity as ethyl ester 2 (compare entries 1 and 9). The re-
sults achieved with aliphatic substrates, including diethyl
2-oxohexandioate, range between 83–94% yield and 69–
76% ee and underscore the general scope of this reaction
(entries 10–13).
Table 1 Screening of Amine Additives
O
O
R
1 (10 mol%)
Cu(OTf)2 (10 mol%)
HO
R
NO2
O
O
+
amines (20 mol%)
THF, –10 °C, 24 h
MeNO2
O
Entry
Amine
Yield (%)
86
ee (%)
55
1
2
N
In conclusion, the introduction of the aminoindanol-
derived bisoxazolidine 1 to the copper-catalyzed nitroal-
dol reaction with a-keto esters provides access to a wide
range of a-hydroxy-b-nitro esters carrying a quaternary
chiral center. Both aliphatic and aromatic substrates af-
ford nitroaldol products in high yields and good ee. The
use of bisoxazolidine 1 in other asymmetric reactions is
currently investigated in our laboratories.
92
90
35
55
NH
H
N
3
4
5
92
90
23
42
N
All commercially available reagents and solvents were used without
further purification, and all reactions were carried out under nitro-
gen. Anhydrous THF was used as purchased and not dried any
further. a-Keto esters were purified by silica gel column chromatog-
raphy prior to use. Flash chromatography was performed on Kiesel-
gel 60, particle size 0.032–0.063 mm. NMR spectra were obtained
at 400 MHz (1H NMR) and 100 MHz (13C NMR) using CDCl3 as
solvent. Chemical shifts are reported in ppm relative to TMS.
N
6
7
90
95
92
93
90
93
95
92
90
41
70
55
34
14
30
7
O
NH
O
N
Me
N
General Procedure for the Henry Reaction of a-Keto Esters
A solution of the bisoxazolidine ligand (37.0 mg, 0.10 mmol) and
CuCl2 (13.6mg, 0.10 mmol) in anhyd THF (0.35 mL) was stirred
under nitrogen atmosphere at r.t. for 10 min. Then, AgClO4 (42.0
mg, 0.20 mmol) was added, and the mixture was stirred for another
20 min, transferred to a double-jacketed flask and cooled to –10 °C.
Addition of MeNO2 (610.0 mg, 10 mmol) was followed by stirring
for another 30 min at –10 °C. NMM (20.0 mg, 0.20 mmol) was add-
ed followed by the addition of freshly purified a-keto ester (1.0
mmol). Upon completion, the reaction mixture was directly loaded
on a silica gel column and purified by flash chromatography as de-
scribed below.
8
Me
HN
HN
Me
N
Me
9
N
Me
10
11
12
13
14
N
(R)-Ethyl 2-Hydroxy-3-nitro-2-phenylpropanoate (2)7a,10c
NH
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
1
225.1 mg of a colorless oil (0.94 mmol, 94%, 74% ee). H NMR
42
21
Me
(400 MHz, CDCl3): d = 1.32 (t, J = 7.2 Hz, 3 H), 4.26 (s, 1 H), 4.28–
4.42 (m, 2 H), 4.67 (d, J = 14.0 Hz, 1 H), 5.26 (d, J = 14.0 Hz, 1 H),
7.32–7.44 (m, 3 H), 7.55–7.63 (m, 2 H). 13C NMR (100 MHz,
CDCl3): d = 13.9, 63.5, 76.0, 80.8, 125.2, 128.9, 129.1, 136.5,
171.6. The ee was determined by HPLC on a Chiralcel OD column
using hexanes–IPA (85:15) as the mobile phase: tR1 (minor) = 9.4
min; tR2 (major) = 11.9 min; a = 1.45.
N
N
N
Me
Me
15
N
87
6
N
Me
Me
(R)-Ethyl 2-(4-Bromophenyl)-2-hydroxy-3-nitropropanoate
(3)10f
dition of AgSbF6 to CuCl2. However, in situ formation of
Cu(ClO4)2 from AgClO4 and CuCl2 and the use of 20
mol% of NMM as additive gave (R)-2 in 94% yield and
74% ee at –10 °C (Table 2, entry 1).14
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
1
299.2 mg of a colorless oil (0.94 mmol, 94%, 70% ee). H NMR
(400 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 4.32 (s, 1 H), 4.29–
4.43 (m, 2 H), 4.65 (d, J = 14.0 Hz, 1 H), 5.22 (d, J = 14.0 Hz, 1 H),
7.49 (dd, J = 8.8, 2.4 Hz, 2H), 7.53 (dd, J = 8.8, 2.4 Hz, 2 H). 13
C
Under these conditions, very similar results with a range
of other aromatic a-keto esters were obtained. For exam-
ple, ethyl 4-chlorophenyloxoacetate and ethyl 4-bro-
mophenyloxoacetate gave the corresponding nitroaldol
products 3 and 4 in 94–95% yield and 70–76% ee
NMR (100 MHz, CDCl3): d = 13.9, 63.8, 75.7, 80.5, 123.5, 127.1,
132.0, 135.5, 171.2. The ee was determined by HPLC on a Chiralcel
OD column using hexanes–IPA (85:15) as the mobile phase: tR1
(minor) = 9.6 min; tR2 (major) = 12.5 min; a = 1.51.
Synlett 2010, No. 18, 2765–2770 © Thieme Stuttgart · New York

LETTER
Enantioselective Nitroaldol Reaction of a-Keto Esters
2767
Table 2 Enantioselective Nitroaldol Reaction with a-Keto Esters
HO
R
NO2
O
O
1 (10 mol%)
CuCl2 (10 mol%)
O
+
MeNO2
R
AgClO4 (20 mol%)
NMM (20 mol%)
THF, –10 °C, 24 h
O
O
Entry
1
Substrate
Product
Time (h)
24
Yield (%)b
94
ee (%)c
NO2
HO
O
O
O
74 (R)
O
O
2
NO2
O
HO
O
O
O
2
3
4
5
6
24
24
24
24
24
94
95
95
94
92
70 (R)
76 (R)
70 (R)
64 (R)
66 (R)
O
O
Br
Br
3
NO2
O
HO
O
O
O
Cl
Cl
4
NO2
HO
O
O
O
O
O
t-Bu
t-Bu
MeO
NC
5
NO2
O
HO
O
O
O
O
MeO
6
NO2
O
HO
O
O
O
O
NC
7
NO2
O
HO
O
O
7
8
9
24
24
24
90
92
94
70 (R)
76 (R)
76 (R)
O
O
EtOOC
EtOOC
8
NO2
O
HO
O
O
O
O
O
9
NO2
O
HO
O
O
O
10
NO2
HO
O
O
10
24
83
72 (R)
O
O
O
11
Synlett 2010, No. 18, 2765–2770 © Thieme Stuttgart · New York

2768
H. Xu, C. Wolf
LETTER
Table 2 Enantioselective Nitroaldol Reaction with a-Keto Esters (continued)
HO
R
NO2
O
O
1 (10 mol%)
CuCl2 (10 mol%)
O
+
MeNO2
R
AgClO4 (20 mol%)
NMM (20 mol%)
THF, –10 °C, 24 h
O
O
Entry
11
Substrate
Product
Time (h)
24
Yield (%)b
94
ee (%)c
NO2
O
HO
O
76 (R)
O
O
O
12
O
NO2
O
HO
O
O
12
13
24
24
87
86
71 (R)
O
EtO
EtO
O
O
O
13
NO2
O
HO
O
69 (R)
O
O
14
a All reactions were performed on a 1 mmol scale using 10 mol% of 1, 10 mol% of CuCl2, 20 mol% of AgClO4, 20 mol% of NMM, and 10
equiv of MeNO2 in 0.35 mL of THF.
b Isolated yields.
c The ee and absolute configurations were determined by chiral HPLC analysis using Chiralcel OD, Chiralcel OJ, Chiralpak AD, and Chiralpak
AS as described in the literature.7a,10c,f
(R)-Ethyl 2-(4-Chlorophenyl)-2-hydroxy-3-nitropropanoate
(4)7a,10c,f
126.6, 128.4, 160.1, 171.8. The ee was determined by HPLC on a
Chiralpak AD column using hexanes–IPA (90:10) as the mobile
phase: tR1 (minor) = 23.3 min; tR2 (major) = 25.5 min; a = 1.11.
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
1
260.0 mg of a colorless oil (0.95 mmol, 95%, 76% ee). H NMR
(400 MHz, CDCl3): d = 1.30 (t, J = 7.2 Hz, 3 H), 4.31 (s, 1 H), 4.27–
4.40 (m, 2 H), 4.62 (d, J = 14.0 Hz, 1 H), 5.20 (d, J = 14.0 Hz, 1 H),
7.34 (d, J = 8.8 Hz, 2 H), 7.53 (d, J = 8.8 Hz, 2 H). 13C NMR (100
MHz, CDCl3): d = 13.9, 63.8, 75.7, 80.6, 126.8, 129.0, 135.0, 135.3,
171.3. The ee was determined by HPLC on a Chiralcel OD column
using hexanes–IPA (85:15) as the mobile phase: tR1 (minor) = 8.9
min; tR2 (major) = 10.4 min; a = 1.30.
(R)-Ethyl 2-(4-Cyanophenyl)-2-hydroxy-3-nitropropanoate
(7)10c,f
Purification by flash chromatography (hexanes–EtOAc = 8:2) gave
243.1 mg of a white solid (0.92 mmol, 92%, 66% ee). 1H NMR (400
MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H), 4.26–4.40 (m, 2 H), 4.43
(s, 1 H), 4.63 (d, J = 14.0 Hz, 1 H), 5.23 (d, J = 14.0 Hz, 1 H), 7.66
(d, J = 8.4 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): d = 13.8, 64.1, 75.9, 80.4, 113.1, 118.0, 126.4, 132.6,
141.4, 170.6. The ee was determined by HPLC on a Chiralpak AD
column using hexanes–IPA (90:10) as the mobile phase: tR1
(major) = 20.0 min; tR2 (minor) = 22.1 min; a = 1.13.
(R)-Ethyl 2-(4-tert-Butylphenyl)-2-hydroxy-3-nitropropanoate
(5)
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
280.7 mg of a colorless oil (0.95 mmol, 95%, 70% ee). H NMR
1
(400 MHz, CDCl3): d = 1.31 (s, 9 H), 1.34 (t, J = 7.2 Hz, 3 H), 4.23
(s, 1 H), 4.28–4.38 (m, 2 H), 4.66 (d, J = 14.4 Hz, 1 H), 5.24 (d,
J = 14.4 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4 Hz, 2
H). 13C NMR (100 MHz, CDCl3): d = 13.9, 31.2, 34.6, 63.4, 75.9,
80.8, 125.0, 125.8, 133.5, 152.2, 171.8. Anal. Calcd for C15H21NO5:
C, 61.00; H, 7.17; N, 4.74. Found: C, 60.72; H, 7.26; N, 4.65. The
ee was determined by HPLC on a Chiralcel OD column using hex-
anes–IPA (85:15) as the mobile phase: tR1 (minor) = 6.6 min; tR2
(major) = 8.7 min; a = 1.77.
(R)-Ethyl 2-(4-Ethoxycarbonylphenyl)-2-hydroxy-3-nitropro-
panoate (8)
Purification by flash chromatography (hexanes–EtOAc = 8:2) gave
280.3 mg of a yellow oil (0.90 mmol, 90%, 70% ee). 1H NMR (400
MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 1.40 (t, J = 7.2 Hz, 3 H),
4.31–4.40 (m, 4 H), 4.47 (s, 1 H), 4.70 (d, J = 14.0 Hz, 1 H), 5.30
(d, J = 14.0 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2 H), 8.07 (d, J = 8.4 Hz,
2 H). 13C NMR (100 MHz, CDCl3): d = 13.8, 14.2, 61.2, 63.8, 76.0,
80.5, 125.4, 130.0, 131.2, 141.1, 165.8, 171.1. Anal. Calcd for
C14H17NO7: C, 54.02; H, 5.50; N, 4.50. Found: C, 54.14; H, 5.17; N,
4.39. The ee was determined by HPLC on a Chiralcel OD column
using hexanes–IPA (92:8) as the mobile phase: tR1 (minor) = 29.2
min; tR2 (major) = 33.0 min; a = 1.15.
(R)-Ethyl 2-Hydroxy-2-(4-methoxyphenyl)-3-nitropropanoate
(6)7a,10c,f
Purification by flash chromatography (hexanes–EtOAc = 8:2) gave
253.3 mg of a white solid (0.94 mmol, 94%, 64% ee). 1H NMR (400
MHz, CDCl3): d = 1.30 (t, J = 7.2 Hz, 3 H), 3.77 (s, 3 H), 4.25 (s, 1
H), 4.27–4.36 (m, 2 H), 4.62 (d, J = 14.0 Hz, 1 H), 5.20 (d, J = 14.0
(R)-Ethyl 2-Hydroxy-3-nitro-2-(3-tolyl)propanoate (9)
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
Hz, 1 H), 6.88 (d, J = 8.8 Hz, 2 H), 7.48 (d, J = 8.8 Hz, 2 H). 13
C
233.0 mg of a colorless oil (0.92 mmol, 92%, 76% ee). H NMR
1
NMR (100 MHz, CDCl3): d = 13.9, 55.3, 63.4, 75.7, 80.8, 114.2,
(400 MHz, CDCl3): d = 1.31 (t, J = 7.2 Hz, 3 H), 2.35 (s, 3 H), 4.28
Synlett 2010, No. 18, 2765–2770 © Thieme Stuttgart · New York

LETTER
Enantioselective Nitroaldol Reaction of a-Keto Esters
2769
(s, 1 H), 4.28–4.41 (m, 2 H), 4.65 (d, J = 14.4 Hz, 1 H), 5.25 (d,
J = 14.4 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1
H), 7.36 (d, J = 8.0 Hz, 1 H), 7.42 (s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 13.9, 21.5, 63.5, 76.0, 80.8, 122.2, 125.8, 128.7, 129.8,
136.4, 138.7, 171.7. Anal. Calcd for C12H15NO5: C, 56.91; H, 5.97;
N, 5.53. Found: C, 56.63; H, 5.91; N, 5.68. The ee was determined
by HPLC on a Chiralcel OD column using hexanes–IPA (85:15) as
the mobile phase: tR1 (minor) = 8.5 min; tR2 (major) = 10.6 min;
a = 1.45.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Funding from the National Science Foundation (CHE-0848301) is
gratefully acknowledged.
References and Notes
(R)-Methyl 2-Hydroxy-3-nitro-2-phenylpropanoate (10)10f
(1) For reviews on the asymmetric Henry reaction, see:
(a) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315. (b) Palomo, C.;
Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561.
(2) (a) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.;
Ikeno, T.; Yamada, T. Chem. Lett. 2004, 614. (b) Kogami,
Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis 2004,
1947.
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
211.8 mg of a colorless oil (0.94 mmol, 94%, 76% ee). H NMR
1
(400 MHz, CDCl3): d = 3.89 (s, 3 H), 4.29 (s, 1 H), 4.67 (d, J = 14.0
Hz, 1 H), 5.26 (d, J = 14.0 Hz, 1 H), 7.34–7.42 (m, 3 H), 7.57–7.60
(m, 2 H). 13C NMR (100 MHz, CDCl3): d = 54.0, 76.1, 80.8, 125.2,
128.9, 129.2, 136.3, 172.2. The ee was determined by HPLC on a
Chiralcel OD column using hexanes–IPA (85:15) as the mobile
phase: tR1 (minor) = 12.0 min; tR2 (major) = 15.5 min; a = 1.43.
(3) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam,
M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167.
(4) (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem. Int. Ed. 2002,
41, 861. (b) Palomo, C.; Oiarbide, M.; Laso, A. Angew.
Chem. Int. Ed. 2005, 44, 3881. (c) Colak, M.; Aral, T.;
Hogoren, H.; Demirel, N. Tetrahedron: Asymmetry 2007,
18, 1129. (d) Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682.
(5) Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak, J.
J. Org. Chem. 2009, 74, 753.
(6) (a) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.;
Yanagisawa, A. Angew. Chem. Int. Ed. 2006, 45, 5978.
(b) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X.
Chem. Eur. J. 2007, 13, 829. (c) Jiang, J.-J.; Shi, M.
Tetrahedron: Asymmetry 2007, 18, 1376. (d) Arai, T.;
Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A.
J. Org. Chem. 2008, 73, 4903.
(7) (a) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A.
J. Org. Chem. 2002, 67, 4875. (b) Evans, D. A.; Seidel, D.;
Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692. (c) Foltz, C.; Stecker, B.;
Marconi, G.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade,
L. H. Chem. Commun. 2005, 5115. (d) Maheswaran, H.;
Prasant, K. L.; Krishna, G. G.; Ravikumar, B.; Sridhar, B.;
Kantam, M. L. Chem. Commun. 2006, 4066. (e) Bandini,
M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici,
C. Chem. Commun. 2007, 616. (f) Blay, G.; Climent, E.;
Fernandez, I.; Hernandez-Olmos, V.; Pedro, J. R.
(R)-Ethyl 2-Hydroxy-2-methyl-3-nitropropanoate (11)7a,10c,f
Purification by flash chromatography (hexanes–EtOAc = 8:2) gave
1
147.0 mg of a colorless oil (0.83 mmol, 83%, 72% ee). H NMR
(400 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3 H), 1.39 (s, 3 H), 3.78
(s, 1 H), 4.16–4.31 (m, 2 H), 4.51 (d, J = 13.6 Hz, 1 H), 4.79 (d,
J = 13.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 13.9, 23.8,
62.9, 72.4, 80.9, 173.4. The ee was determined by HPLC on a
Chiralpak AS column using hexanes–IPA (95:5) as the mobile
phase: tR1 (minor) = 13.8 min; tR2 (major) = 15.7 min; a = 1.19.
(R)-Ethyl 2-Hydroxy-3-methyl-2-(nitromethyl)butanoate (12)10f
Purification by flash chromatography (hexanes–EtOAc = 9:1) gave
1
193.0 mg of a colorless oil (0.94 mmol, 94%, 76% ee). H NMR
(400 MHz, CDCl3): d = 0.84 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8
Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.93 (sept, J = 6.8 Hz, 1 H), 3.60
(s, 1 H), 4.25–4.35 (m, 2 H), 4.62 (d, J = 13.6 Hz, 1 H), 4.78 (d,
J = 13.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 13.9, 16.1,
16.7, 34.0, 62.8, 77.5, 80.1, 172.9. The ee was determined by HPLC
on a Chiralpak AS column using hexanes–IPA (95:5) as the mobile
phase: tR1 (minor) = 10.1 min; tR2 (major) = 12.3 min; a = 1.35.
(R)-Diethyl 2-Hydroxy-2-(nitromethyl)hexandioate (13)10c
Purification by flash chromatography (hexanes–EtOAc = 8:2) gave
1
241.3 mg of a colorless oil (0.87 mmol, 87%, 71% ee). H NMR
(400 MHz, CDCl3): d = 1.15 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2 Hz,
3 H), 1.38–1.72 (m, 4 H), 2.15–2.30 (m, 2 H), 3.82 (s, 1 H), 4.03 (q,
J = 7.2 Hz, 2 H), 4.18–4.32 (m, 2 H), 4.50 (d, J = 13.6 Hz, 1 H),
4.75 (d, J = 13.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 13.9,
14.1, 18.2, 33.5, 35.6, 60.3, 63.0, 75.0, 80.7, 172.6, 172.7. The ee
was determined by HPLC on a Chiralcel OJ column using hexanes–
IPA (80:20) as the mobile phase: tR1 (major) = 17.2 min; tR2
(minor) = 23.9 min; a = 1.50.
Tetrahedron: Asymmetry 2006, 17, 2046. (g) Ma, K.; You,
J. Chem. Eur. J. 2007, 13, 1863. (h) Bandini, M.; Benaglia,
M.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. Org. Lett.
2007, 9, 2151. (i) Ginotra, S. K.; Singh, V. K. Org. Biomol.
Chem. 2007, 5, 3932. (j) Arai, T.; Watanabe, M.;
Yanagisawa, A. Org. Lett. 2007, 9, 3595. (k) Gan, C. Can.
J. Chem. 2008, 86, 261. (l) Blay, G.; Domingo, L. R.;
Hernandez-Olmos, V.; Pedro, J. R. Chem. Eur. J. 2008,
4725. (m) Tanaka, K.; Hachiken, S. Tetrahedron Lett. 2008,
49, 2533. (n) Selvakumar, S.; Sivasankaran, D.; Singh, V. K.
Org. Biomol. Chem. 2009, 7, 3156. (o) Zielinska-Blajet,
M.; Skarzewski, J. Tetrahedron: Asymmetry 2009, 20, 1992.
(8) (a) Sasai, J.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M.
J. Am. Chem. Soc. 1992, 114, 4418. (b) Sasai, J.; Suzuki, T.;
Itoh, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 851.
(c) Sasai, H.; Zuzuki, N.; Itoh, K.; Tanaka, T.; Date, K.;
Okamura, K.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115,
10372. (d) Sohtome, Y.; Kato, Y.; Handa, S.; Aoyama, N.;
Nagawa, K.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008,
10, 2231. (e) Nitabaru, T.; Kumagai, N.; Shibasaki, M.
Tetrahedron Lett. 2008, 49, 272.
(R)-Ethyl 2-Hydroxy-2-nitromethyl-4-phenylbutanoate
(14)7a,10c,f
Purification by flash chromatography (hexanes–EtOAc = 10:1)
1
gave 230.1 mg of a colorless oil (0.86 mmol, 86%, 69% ee). H
NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 1.91–2.06
(m, 2 H), 2.49 (m, 1 H), 2.81 (m, 1 H), 3.86 (s, 1 H), 4.24–4.38 (m,
2 H), 4.57 (d, J = 13.6 Hz, 1 H), 4.82 (d, J = 13.6 Hz, 1 H), 7.13–
7.30 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 14.1, 29.0, 38.2,
63.1, 75.0, 80.8, 126.3, 128.3, 128.6, 140.2, 172.6. The ee was de-
termined by HPLC on a Chiralpak AS column using hexanes–IPA
(90:10) as the mobile phase: tR1 (minor) = 13.6 min; tR2
(major) = 18.4 min; a = 1.49.
Synlett 2010, No. 18, 2765–2770 © Thieme Stuttgart · New York

2770
H. Xu, C. Wolf
LETTER
2008, 6, 468. (g) Takada, K.; Takemura, N.; Cho, K.;
Sohtome, Y.; Nagasawa, K. Tetrahedron Lett. 2008, 49,
1623. (h) Bulut, A.; Aslant, A.; Dogan, O. J. Org. Chem.
2008, 73, 7373.
(9) (a) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org.
Lett. 2002, 4, 2621. (b) Palomo, C.; Oiarbide, M.; Mielgo,
A. Angew. Chem. Int. Ed. 2004, 43, 5442. (c) Gan, C.; Lai,
G.; Zhang, Z.; Wang, Z.; Zhou, M.-M. Tetrahedron:
Asymmetry 2006, 17, 725. (d) Sedlak, M.; Drabina, P.;
Keder, R.; Hanusek, J.; Cisarova, I.; Ruzicka, A.
(11) (a) Tur, F.; Saa, J. M. Org. Lett. 2007, 9, 5079. (b) Saa,
J. M.; Tur, F.; Gonzalez, J. Chirality 2009, 21, 836.
(c) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem.
Commun. 2008, 4360.
J. Organomet. Chem. 2006, 691, 2623. (e) Bandini, M.;
Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C.
Chem. Commun. 2007, 616. (f) Mansawat, W.;
Saengswang, I.; U-prasitwong, P.; Bhanthumnavin, W.;
Vilaivan, T. Tetrahedron Lett. 2007, 48, 4235. (g) Colak,
M.; Demirel, N. Tetrahedron: Asymmetry 2008, 19, 635.
(h) Arai, T.; Yokoyama, N.; Yanagisawa, A. Chem. Eur. J.
2008, 2052.
(12) This ligand is commercially available at Strem (catalogue
no. 07-0488) US 20070265255A1 patent pending, .
(13) (a) Liu, S.; Wolf, C. Org. Lett. 2008, 10, 1831.
(b) Yearick Spangler, K.; Wolf, C. Org. Lett. 2009, 11,
4724. For other bisoxazolidine-catalyzed enantioselective
reactions, see: (c) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006,
128, 10996. (d) Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2965.
(14) A control experiment showed that the nitroaldol reaction
proceeds very slowly in the presence of AgClO4 and only
12% of racemic 2 were obtained after 24 h. We therefore
believe that the in situ formation of Cu(ClO4)2 from AgClO4
and CuCl2, which is visible by the precipitation of AgCl, is
quantitative.
(10) (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem.
Commun. 2001, 2222. (b) Du, D.-M.; Lu, S.-F.; Fang, T.;
Xu, J. J. Org. Chem. 2005, 70, 3712. (c) Li, H.; Wang, B.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (d) Pandya,
S. U.; Dickins, R. S.; Parker, D. Org. Biomol. Chem. 2007,
5, 3842. (e) Qin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.;
Feng, X. J. Org. Chem. 2007, 72, 9323. (f) Blay, G.;
Hernandez-Olmos, V.; Pedro, J. R. Org. Biomol. Chem.
Synlett 2010, No. 18, 2765–2770 © Thieme Stuttgart · New York

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