Copper-catalyzed enantioselective Henry reactions of α-keto esters: An easy entry to optically active β-nitro-α-hydroxy esters and β-amino-α-hydroxy esters

Article abstract of DOI:10.1021/jo025690z

The catalytic enantioselective Henry reaction of α-keto esters with nitromethane has been developed. The reaction conditions have been optimized by the screening of different chiral Lewis acids, solvents, and bases, and it was found that the copper(II)-tert-butyl bisoxazoline complex in combination with triethylamine catalyzed a highly enantioselective reaction giving optically active β-nitro-α-hydroxy esters in high yields and with excellent enantiomeric excesses. The scope of the reaction is demonstrated by the reaction of a variety of different α-keto esters. The catalytic enantioselective Henry reaction of β,γ-unsaturated-α-keto esters proceeds as a 1,2-addition reaction exclusively, in contrast to the uncatalyzed reaction where both the 1,2- and 1,4-addition products are formed. It is demonstrated that the β-nitro-α-hydroxy esters can be converted into, e.g., Boc-protected β-amino-α-hydroxy esters in high yields and without loss of optical purity. The mechanism for the reaction is discussed, and it is postulated that both the α-keto ester and nitromethane/nitronate is coordinated to the metal center during the reaction course.

Full text of DOI:10.1021/jo025690z

Cop p er -Ca ta lyzed En a n tioselective Hen r y Rea ction s of r-Keto
Ester s: An Ea sy En tr y to Op tica lly Active â-Nitr o-r-h yd r oxy
Ester s a n d â-Am in o-r-h yd r oxy Ester s
Christina Christensen, Karsten J uhl, Rita G. Hazell, and Karl Anker J ørgensen*
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark
kaj@chem.au.dk
Received March 7, 2002
The catalytic enantioselective Henry reaction of R-keto esters with nitromethane has been developed.
The reaction conditions have been optimized by the screening of different chiral Lewis acids, solvents,
and bases, and it was found that the copper(II)-tert-butyl bisoxazoline complex in combination
with triethylamine catalyzed a highly enantioselective reaction giving optically active â-nitro-R-
hydroxy esters in high yields and with excellent enantiomeric excesses. The scope of the reaction
is demonstrated by the reaction of a variety of different R-keto esters. The catalytic enantioselective
Henry reaction of â,γ-unsaturated-R-keto esters proceeds as a 1,2-addition reaction exclusively, in
contrast to the uncatalyzed reaction where both the 1,2- and 1,4-addition products are formed. It
is demonstrated that the â-nitro-R-hydroxy esters can be converted into, e.g., Boc-protected â-amino-
R-hydroxy esters in high yields and without loss of optical purity. The mechanism for the reaction
is discussed, and it is postulated that both the R-keto ester and nitromethane/nitronate is coordinated
to the metal center during the reaction course.
In tr od u ction
reaction of nitromethane and R-keto esters6 using readily
available bisoxazolines as the chiral ligand.7,8
The Henry1 or nitroaldol reaction, which essentially is
a coupling reaction between a carbonyl compound and a
nitroalkane having R-hydrogen atoms, constitutes a
fundamental synthetic tool for the construction of C-C
bonds in organic chemistry.2 The importance of the Henry
reaction is typically further transformations involving the
newly formed â-nitroalkanol functionality such as reduc-
tion, oxidation, or dehydration, depending on the require-
ments and overall goal of the multistep synthetic plan.1,2
In a more complex venture, the Henry reaction will
facilitate the joining of two molecular fragments, under
mild conditions, with the possible formation of one or two
chiral centers at the new C-C bond. The catalytic
enantioselective version of the Henry reaction3 has only
been reported for very few systems, and compared to the
closely related catalytic asymmetric aldol reaction, it has
been met with much lower interest. Shibasaki et al. were
the first to report that rare-earth-lithium-BINOL com-
plexes can be applied as catalysts for the enantioselective
Henry reaction of aldehydes.4,5 More recently, we com-
municated a new copper-catalyzed enantioselective Henry
In this paper, we disclose the development of the
enantioselective Henry reaction of R-keto esters 1 with
nitromethane 2 catalyzed by copper(II) salts in combina-
tion with chiral bisoxazoline ligands 4 in detail (eq 1).
The scope and generality of this reaction is demonstrated
by the synthesis of several optically active â-nitro-R-
hydroxy esters 3, which are easily converted to, e.g., the
corresponding â-amino-R-hydroxy esters. Another inter-
(1) Henry, L. Hebd. CR Seances Acad. Sci. 1895, 120, 1265; Bull.
Soc. Chim. Fr. 1895, 13, 999.
(4) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J . Am.
Chem. Soc. 1992, 114, 4418. (b) Sasai, H.; Suzuki, T.; Itoh, N.;
Shibasaki, M. Tetrahedron Lett. 1993, 34, 851. (c) Sasai, H.; Tokunaga,
T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J . Org. Chem.
1995, 60, 7388. (d) Iseki, K.; Oishi, S.; Shibasaki, M. Tetrahedron Lett.
1996, 37, 9081. (e) Arai, T.; Yamada, Y. M. A.; Sasai, H.; Shibasaki,
M. Chem. Eur. J . 1996, 2, 1368.
(2) For recent reviews dealing with the Henry reaction and its use,
see: (a) Luzzio, F. A. Tetrahedron 2001, 57, 915. (b) Rosini, G. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1999; Vol. 1, p 321. (c) Rosini, G.; Ballini, R. Synthesis 1988,
833. (d) Pinnick, H. W. In Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1990; Vol. 38, Chapter 3.
(3) Shibasaki, M.; Gro¨ger, H. In Comprehensive Asymmetric Ca-
talysis I-IIII; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin-Heidelberg, 1999; Chapter 29.3.
(5) See also: (a) Chinchialla, R.; Na´jera, C.; Sa´nches-Agullo´, P.
Tetrahedron: Asymmetry 1994, 5, 1393. (b) Davis, A. P.; Dempsey, K.
J . Tetrahedron: Asymmetry 1995, 6, 2829.
10.1021/jo025690z CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/23/2002
J . Org. Chem. 2002, 67, 4875-4881
4875

Christensen et al.
TABLE 1. Op tim iza tion of th e Ca ta lytic
esting feature of this reaction is the formation of a chiral
quaternary carbon center, a particularly demanding task
in organic chemistry.9 Furthermore, the mechanistic
detail of the reaction will also be presented and discussed.
En a n tioselective Hen r y Rea ction of Eth yl P yr u va te 1a
a n d Nitr om eth a n e 2a
catalyst
(mol %)
Et3N
(mol %)
yieldb
(%)
eec
(%)
entry
1
2
3
4
5
none
20
20
20
20
20
20
20
20
20
20
>95
>95
>95
11
>95
87
>95
>95
93
0
92
14
18
81
-16
<5
92
77
76
Resu lts a n d Discu ssion
Cu(OTf)2-4a (20)
Cu(OTf)2-4b (20)
Cu(OTf)2-4c (20)
Cu(SbF6)2-4a (20)
Zn(OTf)2-4a (20)
Zn(OTf)2-4b (20)
Cu(OTf)2-4a (20)
Cu(OTf)2-4a (20)
Cu(OTf)2-4a (20)
The initial studies of the catalytic asymmetric Henry
reaction were performed on the reaction of ethyl pyruvate
1a (R ) Me) and nitromethane 2 in the presence of
bisoxazoline ligands (4a -c) in combination with copper-
(II) and zinc(II) salts. The results from these studies are
shown in Table 1.
6
7
8d
9e
10f
63
Ethyl pyruvate 1a reacted smoothly with nitromethane
2 in the presence of 20 mol % Et3N at room temperature
with formation of 2-hydroxy-2-methyl-3-nitropropanoic
acid ethyl ester 3a in more than 95% yield (Table 1, entry
1). A highly enantioselective reaction also proceeded at
room temperature in the presence of 20 mol % of Et3N
and 20 mol % of the copper(II)-(S)-tert-butyl bisoxazoline
complex (Cu(OTf)2-4a ) to give 3a in quantitative yield
and 92% ee (entry 2). Other chiral copper(II) and zinc-
(II) complexes were also tested as catalysts for the
reaction; the application of the (R)-phenyl bisoxazoline
ligand 4b in combination with Cu(OTf)2 did not affect
the yield but led to significant loss in enantioselectivity
(entry 3). With (4R,5S)-phenyl bisoxazoline 4c as the
a
Reaction was performed in 2 mL of dry MeNO2 at room
b
temperature (except entries 8-10) on a 0.5 mmol scale. Deter-
mined by 1H NMR spectroscopy with pentachlorobenzene as the
internal standard. c Determined by chiral GC. Reaction was
d
performed at 0 °C. e Reaction was performed at -24 °C. f Reaction
was performed in nondried MeNO2.
TABLE 2. En a n tioselective Hen r y Rea ction of Eth yl
P yr u va te 1a a n d Nitr om eth a n e 2 Ca ta lyzed by 20 m ol %
Cu (OTf)2-4a a n d 20 m ol % Ba sea
entry
base
yieldb 3 (%)
eec (%)
1
2
3
4
5
6
7
Et3N
N-Me-morpholine
PhNMe2
Bn3N
Et(i-Pr)2N
pyridine
>95
65
14
10
31
6
>95
92
83
9
14
69
13
27
(6) Christensen, C.; J uhl, K.; J ørgensen, K. A. Chem. Commun.
2001, 2222.
(7) For reviews of C2-bisoxazoline-Lewis acid complexes as cata-
lysts, see: (a) Ghosh, A. K.; Mathivanen, P.; Cappiello, J . Tetrahe-
dron: Asymmetry 1998, 9, 1. (b) J ørgensen, K. A.; J ohannsen, M.; Yao,
S.; Audrain, H.; Thorhauge, J . Acc. Chem. Res. 1999, 32, 605. (c)
J ohnson, J . S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
K2CO3
a
Reaction performed in 2 mL of dry MeNO2 at room temper-
ature on a 0.5 mmol scale. Determined by 1H NMR spectroscopy
b
with pentachlorobenzene as the internal standard. c Determined
by chiral GC.
(8) For recent examples of C2-bisoxazoline-Lewis acid complexes
as catalysts, see: (a) Evans, D. A.; Kozlowski, M. C.; Murry, J . A.;
Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples R. J . J . Am. Chem.
Soc. 1999, 121, 669 and references therein. (b) Evans, D. A.; Burgey,
C. S.; Kozlowski, M. C.; Tregay, S. W. J . Am. Chem. Soc. 1999, 121,
686 and references therein. (c) Evans, D. A.; Scheidt, K. A.; J ohnston,
J . N.; Willis, M. C. J . Am. Chem. Soc. 2001, 123, 4480. (d) Evans, D.
A.; Barnes, D. M.; J ohnson, J . S.; Lectka, T.; von Matt, P.; Miller, S.
J .; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J . Am. Chem.
Soc. 1999, 121, 7582 and references therein. (e) Evans, D. A.; Miller,
S. J .; Lectka, T.; von Matt, P. J . Am. Chem. Soc. 1999, 121, 7559 and
references therein. (f) Aggarwal, V. K.; J ones, D. E.; Martin-Castro,
A. M. Eur. J . Org. Chem. 2000, 2939. (g) J ensen, K. B.; Hazell, R. G.;
J ørgensen, K. A. J . Org. Chem. 1999, 64, 2353. (h) Evans, D. A.; Rovis,
T.; Kozlowski, M. C.; Tedrow, J . S. J . Am. Chem. Soc. 1999, 121, 1994.
(i) Evans, D. A.; J ohnson, J . S.; Olhava, E. J . J . Am. Chem. Soc. 2000,
122, 1635. (j) Audrain, H.; Thorhauge, J .; Hazell, R. G.; J ørgensen, K.
A. J . Org. Chem. 2000, 65, 4487. (k) Zhuang, W.; Thorhauge, J .;
J ørgensen, K. A. Chem. Commun. 2000, 459. (l) Evans, D. A.; Tregay,
S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J . Am. Chem. Soc.
2000, 122, 7936 and references therein. (m) Reichel, F.; Fang, X.; Yao,
S.; Ricci, M.; J ørgensen, K. A. Chem. Commun. 1999, 1505. (n)
Gathergood, N.; J ørgensen, K. A. Chem. Commun. 1999, 1869. (o)
Gathergood, N.; Zhuang, W.; J ørgensen, K. A. J . Am. Chem. Soc. 2000,
120, 12517. (p) Zhuang, W.; Gathergood, N.; Hazell, R. G.; J ørgensen,
K. A. J . Org. Chem. 2001, 66, 1009. (q) J ensen, K. B.; Thorhauge, J .;
Hazell, R. G.; J ørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160.
(r) Zhuang, W.; Hansen, T.; J ørgensen, K. A. Chem. Commun. 2001,
347. (s) J uhl, K.; Gathergood, N.; J ørgensen, K. A. Chem. Commun.
2000, 2211. (t) Audrain, H.; J ørgensen, K. A. J . Am. Chem. Soc. 2000,
122, 11543. (u) J uhl, K.; Gathergood, N.; J ørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 2995. (v) Knudsen, K. R.; Risgaard, T.;
Nishiwaki, N.; Gothelf, K. V.; J ørgensen, K. A. J . Am. Chem. Soc. 2001,
123, 5843. (x) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K.; J ørgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (y) J uhl, K.; J ørgensen,
K. A. J . Am. Chem. Soc. 2002, 124, 2420. (z) Thorhauge, J .; Roberson,
M.; Hazell, R. G.; J ørgensen, K. A. Chem. Eur. J . 2002, 8, 1888.
(9) For reviews concerning catalytic formation of molecules with
quaternary carbon centers, see: (a) Corey E. J .; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388. (b) Christoffers, J .; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591.
ligand, only 11% yield and 18% ee of 3a were obtained
(entry 4). The enantioselectivity was dependent on the
counterion, as application of the Cu(SbF6)2-4a complex
resulted in 81% ee of 3a (entry 5) compared with 92% ee
using Cu(OTf)2 as the Lewis acid. The zinc bisoxazoline
complexes Zn(OTf)2-4a and Zn(OTf)2-4b could also cata-
lyze the reaction; however, only minute or no enantiose-
lectivity of 3a was detected (entries 6, 7). In an attempt
to suppress the Et3N-initiated background reaction, the
reaction temperature was lowered to 0 and -24 °C,
respectively; however, this had little effect on the yield
of the reaction, whereas the enantioselectivity dropped
at -24 °C (entries 8, 9).
A series of Brønsted bases were also tested for the
catalytic enantioselective Henry reaction of ethyl pyru-
vate 1a with nitromethane 2. The results of the base
survey are shown in Table 2.
Of the different bases tested, Et3N was clearly the base
of choice for this reaction (Table 2, entry 1). The slightly
less basic N-methyl morpholine gave lower yield and
enantioselectivity (entry 2), while N,N-dimethyl aniline
was not sufficiently basic to catalyze the reaction and
only 14% yield of the Henry adduct 3a was obtained
(entry 3). The bases Bn3N and Et(i-Pr)2N (Hu¨nig’s base)
were tested in the reaction, as these bases are much more
bulky than Et3N but have the same basicity. It was
expected that the bulkiness of these bases would obstruct
coordination to the chiral Lewis acid, giving more unco-
ordinated base and chiral catalyst and hopefully leading
4876 J . Org. Chem., Vol. 67, No. 14, 2002

Catalytic Asymmetric Henry Reactions
TABLE 3. En a n tioselective Hen r y Rea ction of r-Keto
Ester s 1a -l w ith Nitr om eth a n e 2 Ca ta lyzed by
Cu (OTf)2-4a (20 m ol %) in th e P r esen ce of Et3N (20 m ol
%) a s th e Ba sea
TABLE 4. Ca ta lytic En a n tioselective Hen r y Rea ction of
â,γ-Un sa tu r a ted r-Keto Ester s 1m -o w ith Nitr om eth a n e
2 Ca ta lyzed by Cu (OTf)2-4a (20 m ol %) in th e P r esen ce of
Et3N (20 m ol %) a s th e Ba sea
entry
R-keto ester R
Me (1a )
Et (1b)
Et (1b)
(CH2)2Ph (1c)
hexyl (1d )
but-3-enyl (1e)
pent-4-enyl (1f)
3-methyl-butyl (1g)
i-Bu (1h )
product
yieldb (%)
eec (%)
R-keto ester
1
2e
3d,e
4d,e
5
6
7
8
9
10
11
12
13
3a
3b
3b
3c
3d
3e
3f
3g
3h
3i
95
46
73
47
91
97
92
90
99
81
91
99
68
92
90
87
77
93
94
94
94
92
86
88
93
57
entry
R′
R′′
product yieldb (%) eec (%)
1
2
3
Me Ph
Me p-ClC6H4 (1n )
Et Me (1o)
(1m )
3m
3n
3o
95
95
>96
35
30
60
a
Reaction was performed in 2 mL of dry MeNO2 at room
temperature on a 0.5 mmol scale for 24 h. Determined by 1H
b
NMR spectroscopy with pentachlorobenzene as the internal
standard. c Determined by chiral GC or HPLC.
Ph (1i)
p-ClC6H4 (1j)
p-NO2C6H4 (1k )
p-MeOC6H4 (1l)
3j
3k
3l
substituted R-keto esters 1i-l also reacted with 2 in the
presence of Cu(OTf)2-4a as the catalyst to give the
optically active Henry adducts 3i-l in excellent yields
and enantioselectivities (entries 10-12). The electron-
donating methoxy group of ethyl (p-methoxy)phenyl
glyoxylate (1l) caused a lower yield of the Henry adduct
3l, as well as a lower enantioselectivity (entry 13).
During the screening of different 2-keto esters as
substrates for the catalytic enantioselective Henry reac-
tion, the â,γ-unsaturated-R-keto esters 1m -o were also
tested (eq 3). The results are presented in Table 4.
a
Reaction was performed in 2 mL of dry MeNO2 at room
temperature (except entries 3 and 4) on a 0.5 mmol scale for 24 h
(except entries 2-4). Yield of isolated product. c Determined by
b
chiral GC or HPLC. Reaction performed at 50 °C. e Reaction time
d
) 48 h.
to lower catalyst loadings (vide infra). Unfortunately, this
effect was not achieved, and instead lower yields and
enantioselectivities were the results of applying these
bases (entry 4, 5). Pyridine was also tested as a base in
the catalytic enantioselective Henry reaction, but only
6% yield of 3a was formed (entry 6); overly strong
coordination of pyridine to the copper complex could be
the explanation of this result. The inorganic base K2CO3
was a good base for the Henry reaction in terms of yield,
but the enantioselectivity was significantly reduced
compared to that achieved with Et3N (entry 7).
The scope of the catalytic enantioselective Henry
reaction is demonstrated by the reactions of the R-keto
esters 1a -l with nitromethane 2 catalyzed by 20 mol %
Cu(OTf)2-4a and 20 mol % Et3N as shown in eq 2 and
Table 3.
Two different reactions can take place by the addition
of nitromethane 2 to the â,γ-unsaturated R-keto esters
1m -o, the 1,2-addition and/or 1,4-addition reaction,
leading to 3m -o (1,2-addition), 3′m -o (1,4-addition), and
3′′m -o (both 1,4- and 1,2-addition) (eq 3). It is important
to note that in the presence of 20 mol % of Et3N and 20
mol % of Cu(OTf)2-4a , the reaction of 1m -o with 2 gave
the 1,2-addition products 3m -o exclusively. In the
absence of the chiral Lewis acid, the Et3N-induced
reaction gives a mixture of 1,2-addition (3m -o) and 1,4-
addition products (3′m -o) and products obtained from
1,4-addition followed by 1,2-addition (3′′m -o, eq 3). The
catalytic enantioselective reaction of 1m -o with 2 pro-
ceeded with excellent yields and chemoselectivities as
exclusively the 1,2-addition products 3m -o were formed;
however, the enantioselectivity was low with the excep-
tion of 3o, which was formed with 60% ee (Table 3, entry
3). The selective 1,2-addition reaction in the presence of
the chiral Lewis acid could indicate that nitromethane
is coordinated to the metal before deprotonation by the
base and that the nitronate is coordinated also to the
metal when reacting with the keto functionality of the
R-keto ester (vide infra).
Ethyl pyruvate 1a reacted with nitromethane 2 to give
2-hydroxy-2-methyl-3-nitropropanoic acid ethyl ester 3a
in 95% yield and with 92% ee (Table 3, entry 1). The
catalytic enantioselective Henry reaction of the corre-
sponding ethyl analogue 1b proceeded in a similar way
to give 3b in 46% yield and 90% ee at room temperature
(entry 2). The yield of the Henry adduct 3b was increased
to 73% without significant loss in enantioselectivity by
heating the reaction mixture to 50 °C (entry 3). The
R-keto ester 1c reacted with 2 giving a moderate yield
and enantioselectivity (entry 4) compared to the other
reactions presented. A variety of other alkyl-substituted
2-keto esters 1d -h smoothly underwent the catalytic
enantioselective Henry reaction with excellent yields and
enantioselectivities of 3d -h (entries 5-9). The aryl-
P r od u ct Mod ifica tion . The catalytic enantioselective
Henry reaction gives an easy access to different â-nitro-
J . Org. Chem, Vol. 67, No. 14, 2002 4877

Christensen et al.
SCHEME 1
F IGURE 1. Reaction sequence leading to the oxazolidinone
7 and X-ray structure of 7.
R-hydroxy esters. These â-nitro-R-hydroxy esters are
readily transformed into Boc-protected â-amino-R-hy-
droxy esters by the procedure shown in Scheme 1 for the
2-hydroxy-2-methyl-3-nitropropanoic acid ethyl ester 3a .
Treatment of 3a with a catalytic amount of Raney nickel
under a hydrogen atmosphere in EtOH at room temper-
ature for 4 h led to reduction of the nitro moiety. After
addition of 3 equiv of di-tert-butyl dicarbonate and a
catalytic amount of DMAP (20 mol %), the Boc-protected
â-amino-R-hydroxy ester 6 was obtained in 76% yield
based on â-nitro-R-hydroxy ester 3a without a detectable
loss of optical purity.
A similar procedure was applied to the chloro-substi-
tuted â-nitro-R-hydroxy ester 3j. The â-amino-R-hydroxy
ester 5j was protected as oxazolidinone 7 by treatment
with phosgene in toluene in 40% overall yield based on
3j (Figure 1). The oxazolidinone 7 gave crystals suitable
for X-ray crystallography, and due to the presence of the
chlorine atom, the absolute configuration of the chiral
center could be determined to have the (R)-configuration.
Figure 1 also shows the X-ray structure of 7.
TABLE 5. Ca ta lytic En a n tioselective Hen r y Rea ction of
Eth yl P yr u va te 1a a n d Nitr om eth a n e 2 Ca ta lyzed by
Cu (OTf)2-4a (20 m ol %) in th e P r esen ce of Va r iou s
Am ou n ts of Et3Na
Et3N (mol %)
conversionb (%)
eec
erc
5
10
15
20
25
30
35
40
<10
11
27
49
56
92
73
26
10
4
1.7:1
2.9:1
3.6:1
24:1
6.4:1
1.7:1
1.2:1
1.1:1
57
>95
>95
>95
>95
>95
a
Reaction was performed in 2 mL of dry MeNO2 at room
b
temperature on
a
0.5 mmol scale. Determined by 1H NMR
spectroscopy. c Determined by chiral GC.
Mech an istic Con sider ation s. The chiral Lewis acid-
Brønsted base ratio was very crucial to the outcome of
the reaction. A lower concentration of Brønsted base
relative to Lewis acid led to a significant drop in enan-
tioselectivity and yield, whereas a higher concentration
of Brønsted base gave a high yield of racemic Henry
adduct.10 The effect of the concentration of Brønsted base
relative to Lewis acid was examined further, and the
results are presented in Table 5. It appears from the
results in Table 5 that both the yield and enantiomeric
excess are dependent on the amount of base relative to
the catalyst. Figure 2 shows the enantiomeric ratio of
the two enantiomers of the Henry adduct (3a ) as a
function of the concentration of Et3N in the presence of
20 mol % Cu(OTf)2-4a . The graph in Figure 2 shows a
clear maximum at 20 mol % Et3N, indicating that
equimolar amounts of chiral Lewis acid and Et3N con-
stitute the best catalytic system in terms of enantiose-
lectivity.
F IGURE 2. Enantiomeric ratio of Henry adduct 3a as a
function of the concentration of Et3N relative to the Cu(OTf)2-
4a catalyst (20 mol %).
deprotonate nitromethane 2 to give the nitronate 9. The
nitronate can then undergo an enantioselective reaction
with ethyl pyruvate 1a activated by the chiral Lewis acid
(vide infra) or a racemic reaction with uncoordinated 1a .
When the chiral Lewis acid is in excess compared to Et3N,
the equilibrium is shifted toward the inactive complex
8. However, the Henry reaction still proceeds via a less
effective reaction path giving lower conversion and poor
enantioselectivity. When Et3N is in excess compared to
the chiral Lewis acid, the equilibrium is also shifted
toward the inactive complex 8, hence trapping the chiral
Lewis acid. The remaining uncoordinated Et3N then
induces the racemic reaction path, affording only racemic
3a . When equimolar amounts of the chiral Lewis acid
and Et3N are present, the Henry reaction proceeds by a
nucleophilic attack of nitronate 9 (vide infra) on the
The results of the catalytic enantioselective Henry
reaction with various amounts of base can be rationalized
as outlined in Scheme 2. The chiral Lewis acid (Cu(OTf)2-
4a ) and Et3N are in equilibrium with the inactive
complex Cu(Et3N)(OTf)2-bisoxazoline, 8. The Henry reac-
tion proceeds when uncoordinated Et3N is available to
(10) Cu(OTf)2-4a (20 mol %) and Et3N (10 mol %) gave 11%
conversion and 49% ee. Cu(OTf)2-4a (20 mol %) and Et3N (40 mol %)
gave full conversion to the racemic Henry adduct.
4878 J . Org. Chem., Vol. 67, No. 14, 2002

Catalytic Asymmetric Henry Reactions
SCHEME 2
SCHEME 3
in the axial position leading to the proposed square
pyramidal intermediate. Coordination of the R-keto func-
tionality in the ligand plane affords maximum activation
of the keto functionality. Deprotonation of nitromethane
by the base gives the nitronate, and with the coordination
pattern outlined, the si-face of the R-keto functionality
of the R-keto ester is shielded by the tert-butyl substitu-
ent of the chiral bisoxazoline ligand. The re-face is thus
available for approach by the nucleophilic carbon atom
of the nitronate with a chairlike six-membered transition-
state structure as outlined in 12 in Scheme 3. The
enantioselective reaction then proceeds, giving the chiral
Lewis acid product complex 13. Protonation of the
product and ligand exchange of the product and the two
new reactants constitute the final step of the catalytic
cycle.
In summary, a catalytic enantioselective Henry reac-
tion of R-keto esters with nitromethane in the presence
of Et3N using copper(II)-(S)-tert-butyl bisoxazoline as the
catalyst has been developed. The reaction gives optically
active â-nitro-R-hydroxy esters in high yields and with
excellent enantioselectivities. It is also demonstrated that
the Henry adducts can be converted into optically active
â-amino-R-hydroxy esters. On the basis of investigations
of the reaction course and the absolute configuration of
the optically active Henry adducts, a square pyramidal
intermediate is postulated in which the R-keto function-
ality and the oxygen atom of nitromethane coordinate to
copper(II) in the equatorial positions, while the ester
carbonyl oxygen atom has an axial coordination.
R-keto ester coordinated to the chiral catalyst, rather
than on the uncoordinated R-keto ester, since the former
is activated by the Lewis acid.
The absolute configuration of the oxazolidinone 7
showed that the chiral carbon atom formed in the
catalytic enantioselective step has the (R)-configuration.
This absolute configuration is in contrast to what has
normally been found for enantioselective reactions cata-
lyzed by Cu(OTf)2-4a complexes.11 Taking into account
also the reactions of â,γ-unsaturated R-keto esters led
us to propose the mechanism shown in Scheme 3 for the
induction of enantioselectivity in the catalytic reaction.
When the chiral Lewis acid, Cu(OTf)2-4a , is not blocked
by the base, both the R-keto ester and nitromethane are
coordinated to the copper-center-forming intermediate
11. The R-keto functionality and the oxygen atom of
nitromethane are in this intermediate coordinated to the
metal center in the equatorial positions, while the ester
carbonyl oxygen atom is coordinated to the metal center
Gen er a l Meth od s
Commercially available compounds were used without
further purification. Solvents were dried according to standard
procedures. Flash chromatography (FC) was carried out using
silica gel 60 (230-400 mesh). The 1H NMR and 13C NMR
spectra were recorded at 400 and 100 MHz, respectively. The
chemical shifts are reported in ppm downfield to TMS (δ ) 0)
for 1H NMR and relative to the central CDCl3 resonance (δ )
(11) See refs 8a and 8z, and references therein, for a discussion of
intermediate structures.
J . Org. Chem, Vol. 67, No. 14, 2002 4879

Christensen et al.
77.0) for 13C NMR. The enantiomeric excess (ee) of the products
was determined by chiral GC or HPLC (i-PrOH/hexane as the
eluent).
38.2, 29.0, 14.1; HRMS (TOF ES+) calcd for C13H17NO5 [M +
Na]+ 290.1004, found 290.0999.
2-Hyd r oxy-2-n itr om eth yl-octa n oic Acid Eth yl Ester
(3d ). Prepared according to the general procedure using 93.1
mg (0.5 mmol) of R-keto ester 1d . Purification was performed
by FC (CH2Cl2) to yield 113 mg (91%) of 3d as a yellow oil.
The ee was determined by chiral GC, τminor ) 15.8 min, τmajor
) 16.0 min: [R]23D +10.8° (c 1.11, CH2Cl2, 93% ee); 1H NMR δ
4.79 (d, J ) 13.6 Hz, 1H), 4.53 (d, J ) 13.6 Hz, 1H), 4.30 (m,
2H), 3.74 (s, 1H), 1.61 (m, 2H), 1.42 (m, 1H), 1.29 (t, J ) 7.2
Hz, 3H), 1.22 (m, 6H), 1.10 (m, 1H), 0.83 (t, J ) 6.8 Hz, 3H);
13C NMR δ 172.9, 80.8, 75.2, 62.9, 36.4, 31.3, 28.9, 22.4, 22.3,
13.9, 13.8; HRMS (TOF ES+) calcd for C11H21NO5 [M + Na]+
270.1317, found 270.1324.
Ma ter ia ls. 2,2′-Isopropylidenebis[(4S)-4-tert-butyl-2-oxazo-
line], 2,2′-isopropylidenebis[(4R)-4-phenyl-2-oxazoline], meth-
ylenebis[(4R,5S)-4,5-diphenyl-2-oxazoline], Cu(OTf)2, and Zn-
(OTf)2 were purchased commercially and used without further
purification. Ethyl pyruvate 1a , 2-keto butyric acid, ethyl
2-oxo-4-phenylbutyrate 1c, ethyl benzoylformate 1i, ethyl
4-nitrophenylglyoxylate 1k , Raney Ni, 4-(dimethylamino)-
pyridine, di-tert-butyl dicarbonate, and the 20% phosgene
solution in toluene were also purchased commercially. R-Keto
ester 1b was prepared by refluxing 2-keto-butyric acid in
ethanol in the presence of a catalytic amount of HCl followed
by distillation. R-Keto esters 1d -h were prepared in a Grig-
nard reaction of diethyl oxalate and the appropriate bromide
following a literature procedure.12 The bromides used are all
commercially available. R-Keto esters 1j,13 1l,14 1m ,8j and
1n ,o8q were all prepared according to literature procedures.
Gen er a l P r oced u r e for Ca ta lytic Asym m etr ic Hen r y
Rea ction s of r-Keto Ester s. To a flame-dried Schlenk tube
equipped with a magnetic stirrer were added Cu(OTf)2 (36.2
mg, 0.100 mmol) and 2,2′-isopropylidenebis[(4S)-4-tert-butyl-
2-oxazoline] (30.9 mg, 0.105 mmol). The mixture was stirred
under vacuum for 2 h and filled with N2. Dry freshly distilled
MeNO2 (2 mL) was added, and the solution was stirred for 1
h. The R-keto ester (0.5 mmol) was added followed by the
addition of triethylamine (14 µL, 0.1 mmol). The reaction
mixture was stirred for 16 h under N2 and then flushed
through a plug of silica. Solvent was removed in vacuo, and
the residue was purified by FC to give the â-nitro-R-hydroxy
esters.
2-Hyd r oxy-2-n itr om eth yl-h ex-5-en oic Acid Eth yl Ester
(3e). Prepared according to the general procedure using 78.1
mg (0.5 mmol) of R-keto ester 1e. Purification was performed
by FC (10% Et2O in CH2Cl2) to yield 105 mg (97%) of 3e as a
pale yellow oil. The ee was determined by chiral GC, τminor
)
14.7 min, τmajor ) 15.3 min: [R]23D +11.7° (c 1.04, CH2Cl2, 94%
1
ee); H NMR δ 5.75 (m, 1H), 5.00 (m, 2H), 4.82 (d, J ) 13.6
Hz, 1H), 4.57 (d, J ) 13.6 Hz, 1H), 4.34 (m, 2H), 3.72 (s, 1H),
2.24 (m, 1H), 1.95 (m, 1H), 1.76 (m, 2H), 1.33 (t, J ) 7.2 Hz,
3H); 13C NMR δ 172.6, 136.5, 115.7, 80.7, 74.9, 63.0, 35.5, 26.8,
13.9; HRMS (TOF ES+) calcd for C9H15NO5 [M + Na]+
240.0848, found 240.0851.
2-Hyd r oxy-2-n itr om eth yl-h ep t-6-en oic Acid Eth yl Es-
ter (3f). Prepared according to the general procedure using
85.1 mg (0.5 mmol) of R-keto ester 1f. Purification was
performed by FC (10% Et2O in CH2Cl2) to yield 106 mg (92%)
of 3f as a pale yellow oil. The ee was determined by chiral
GC, τminor ) 20.2 min, τmajor ) 21.0 min: [R]23 +13.5° (c 1.09,
D
2-Hyd r oxy-2-m eth yl-3-n itr o-p r op ion ic Acid Eth yl Es-
ter (3a ). Prepared according to the general procedure using
56 µL (0.5 mmol) of the commercially available R-keto ester
1a . Purified by FC (10% Et2O in CH2Cl2) to yield 84 mg (95%)
of 3a as a pale yellow oil. The ee of the product was determined
CH2Cl2, 94% ee): 1H NMR δ 5.73 (m, 1H), 4.98 (m, 2H), 4.81
(d, J ) 13.6 Hz, 1H), 4.55 (d, J ) 13.6 Hz, 1H), 4.34 (m, 2H),
3.69 (s, 1H), 2.05 (m, 2H), 1.64 (m, 3H), 1.33 (t, J ) 7.2 Hz,
3H), 1,25 (m, 1H); 13C NMR δ 172.8, 137.5, 115.3, 80.8, 75.1,
63.0, 35.7, 33.1, 21.7, 4.0;_HRMS (TOF ES+) for C10H17NO5
[M + Na]+; calculated: 254.1004; found: 254.1010.
by chiral GC, τ(minor) ) 23.4 min, τ(major) ) 24.1 min: [R]23
D
+10.2° (c 1.19, CH2Cl2, 92% ee); 1H NMR δ 4.83 (d, J ) 14 Hz,
1H), 4.55 (d, J ) 14 Hz, 1H), 4.34 (m, 2H), 3.71 (s, 1H), 1.45
(s, 3H), 1.33 (t, J ) 7.2 Hz, 3H); 13C NMR δ 173.4, 80.9, 72.3,
62.9, 23.7, 13.8; HRMS (TOF ES+) calcd for C6H11NO5 [M +
Na]+ 200.0535, found 200.0282.
2-Hyd r oxy-5-m eth yl-2-n itr om eth yl-h exa n oic Acid Eth -
yl Ester (3g). Prepared according to the general procedure
using 86.1 mg (0.5 mmol) of R-keto ester 1g. Purification was
performed by FC (10% Et2O in CH2Cl2) to yield 105 mg (90%)
of 3g as a pale yellow oil. The ee of the product was determined
2-Hydr oxy-2-n itr om eth yl-bu tyr ic Acid Eth yl Ester (3b).
Prepared according to the general procedure using 65.1 mg
(0.5 mmol) of R-keto ester 1b. The reaction proceeded for 48 h
at room temperature, and the crude reaction mixture was
purified by FC (gradient from CH2Cl2 to 10% Et2O in CH2Cl2)
to yield 44 mg (46%) of 3b as a colorless oil. The ee of the
product was determined by chiral GC, τminor ) 9.1 min, τmajor
by chiral GC, τminor ) 21.1 min, τmajor ) 21.6 min: [R]23 +9.5°
D
(c 1.11, CH2Cl2, 94% ee); 1H NMR δ 4.81 (d, J ) 13.6 Hz, 1H),
4.56 (d, J ) 13.6 Hz, 1H), 4.34 (dk, J ) 1.2, 7.2 Hz, 2H), 3.68
(s, 1H), 1.64 (m, 2H), 1.50 (m, 1H), 1.36 (m, 1H), 1.33 (t, J )
7.2 Hz, 3H), 0.97 (m, 1H), 0.87 (d, J ) 6.8 Hz, 3H), 0.86 (d, J
) 6.4 Hz, 3H); 13C NMR δ 172.9, 80.9, 75.2, 62.9, 34.4, 31.3,
27.8, 22.3, 22.2, 14.0; HRMS (TOF ES+) calcd for C10H19NO5
[M + Na]+ 256.1161, found 256.1161.
) 9.2 min: [R]23 +20.9° (c 1.0, CHCl3, 90% ee); 1H NMR δ
D
4.81 (d, J ) 13.6 Hz, 1H), 4.54 (d, J ) 13.6 Hz, 1H), 4.32 (m,
2H), 3.72 (s, 1H), 1.68 (m, 2H), 1.30 (t, J ) 6.8 Hz, 3H), 0.89
(t, J ) 7.2 Hz, 3H); 13C NMR δ 172.8, 80.7, 75.5, 62.9, 29.7,
14.0, 6.9; HRMS (TOF ES+) calcd for C7H13NO5 [M + Na]+
214.0691, found 214.0536.
2-Hydr oxy-4-m eth yl-2-n itr om eth yl-pen tan oic Acid Eth -
yl Ester (3h ). Prepared according to the general procedure
using 79.1 mg (0.5 mmol) of R-keto ester 1h . Purification was
performed by FC (10% Et2O in CH2Cl2) to yield 109 mg (99%)
of 3h as a pale yellow oil. The ee of the product was determined
by chiral GC, τminor ) 16.1 min, τmajor ) 17.5 min: [R]23D +21.1°
(c 1.02, CH2Cl2, 92% ee); 1H NMR δ 4.78 (d, J ) 13.6 Hz, 1H),
4.53 (d, J ) 13.6 Hz, 1H), 4.34 (m, 2H), 3.69 (s, 1H), 1.78 (m,
1H), 1.59 (m, 2H), 1.33 (t, J ) 7.2 Hz, 3H), 0.97 (d, J ) 6.4
Hz, 3H), 0.87 (d, J ) 6.8 Hz, 3H); 13C NMR δ 173.2, 81.4, 75.3,
62.9, 44.4, 24.0, 23.7, 23.3, 13.9; HRMS (TOF ES+) calcd for
C9H17NO5 [M + Na]+ 242.1004, found 242.0997.
2-Hyd r oxy-3-n itr o-2-p h en yl-p r op ion ic Acid Eth yl Es-
ter (3i). Prepared according to the general procedure using
79 µL (0.5 mmol) of the commercially available R-keto ester
1i. The product was purified by FC (10% Et2O in pentane) to
yield 97 mg (81%) of 3i as a colorless oil. The ee of the product
was determined by HPLC (90/10 hexane/i-PrOH; flow rate )
1.0 mL/min; τminor ) 11.0 min; τmajor ) 14.1 min): [R]23D -16.2°
(c 1.13, CH2Cl2, 86% ee): 1H NMR δ 7.60 (dd, J ) 2, 8.8 Hz,
2H), 7.42-7.36 (m, 3H), 5.25 (d, J ) 14 Hz, 1H), 4.67 (d, J )
2-Hyd r oxy-2-n itr om eth yl-4-p h en yl-bu tyr ic Acid Eth yl
Ester (3c). Prepared according to the general procedure using
95 µL (0.5 mmol) of the commercially available R-keto ester
1c. The reaction proceeded for 48 h at 50 °C. Purification was
performed by FC (10% Et2O in pentane) to yield 63 mg (47%)
of 3c as a colorless oil. The ee of the product was determined
by HPLC (94/6 hexane/i-PrOH; flow rate ) 1.0 mL/min; τminor
) 13.1 min; τmajor ) 15.5 min): [R]23 +16.5° (c 1.27, CH2Cl2,
D
1
77% ee); H NMR δ 7.30-7.13 (m, 5H), 4.83 (d, J ) 13.6 Hz,
1H), 4.58 (d, J ) 13.6 Hz, 1H), 4.31 (m, 2H), 3.82 (s, 1H), 2.82
(m, 1H), 2.48 (m, 1H), 1.98 (m, 2H), 1.33 (t, J ) 7.2 Hz, 3H);
13C NMR δ 172.6, 140.2, 128.6, 128.3, 126.4, 80.8, 75.0, 63.2,
(12) Macritchie, J . A.; Sicock, A.; Willis, C. L. Tetrahedron: Asym-
metry 1997, 8, 3895.
(13) Hu, S.; Neckers, D. C. J . Org. Chem. 1996, 61, 6407.
(14) Creary, X. J . Org. Chem. 1987, 52, 5026.
4880 J . Org. Chem., Vol. 67, No. 14, 2002

Catalytic Asymmetric Henry Reactions
14 Hz, 1H), 4.36 (m, 2H), 4.21 (s, 1H), 1.33 (t, J ) 7.2 Hz, 3H);
13C NMR δ 171.6, 136.4, 129.0, 128.8, 125.2, 80.7, 75.9, 63.5,
13.8; HRMS (TOF ES+) calcd for C11H13NO5 [M + Na]+
262.0691, found 262.0691.
2-Hyd r oxy-2-n itr om eth yl-p en t-3-en oic Acid Eth yl Es-
ter (3o). Prepared according to the general procedure using
71.1 mg (0.5 mmol) of â,γ-unsaturated R-keto ester 1o. The
crude reaction mixture was flushed through a plug of silica
using Et2O as the eluent, and the yield was determined by 1H
NMR with pentachlorobenzene as the internal standard. The
ee of the product was determined by chiral GC, τminor ) 10.7
min, τmajor ) 11.1 min: 1H NMR δ 6.12 (dk, J ) 6.8, 15.2 Hz,
1H), 5.43 (d, J ) 15.2 Hz, 1H), 4.86 (d, J ) 14 Hz, 1H), 4.47
(d, J ) 14 Hz, 1H), 4.34 (m, 2H), 3.76 (s, 1H), 1.74 (d, J ) 6.8
Hz, 3H), 1.33 (t, J ) 7.2 Hz, 3H); 13C NMR δ 171.8, 130.6,
125.6, 79.9, 75.0, 63.1, 17.5, 13.9; HRMS (TOF ES+) calcd for
C8H13NO5 [M + Na]+ 226.0691, found 226.0611.
3-ter t-Bu toxyca r bon yla m in o-2-h yd r oxy-2-m eth yl-p r o-
p ion ic Acid Eth yl Ester (6). Compound 3a (177.2 mg, 1.0
mmol), prepared following the general procedure, was dis-
solved in EtOH (10 mL), and Raney nickel (400 mg in 5 mL
EtOH) was added. The reaction mixture was stirred under H2
at atmospheric pressure for 4 h at room temperature. Di-tert-
butyl dicarbonate (655 mg, 3.0 mmol) was added followed by
4-N,N-(dimethylamino)pyridine (24 mg, 0.2 mmol). The reac-
tion mixture was stirred at room temperature for an additional
16 h and then flushed through a plug of silica. Solvent was
removed in vacuo, and the residue was purified by FC
(gradient from 5% Et2O in CH2Cl2 to 50% Et2O in CH2Cl2) to
yield 189 mg (76%) of 6 as a colorless oil, which became a solid
upon standing (mp: 59-61 °C). The ee of the product was
determined by chiral GC, τmajor ) 11.7 min, τminor ) 12.0 min:
[R]23D -12.1° (c 1.05, CH2Cl2, 92% ee); 1H NMR δ 5.00 (bs, 1H),
4.18 (m, 2H), 3.73 (s, 1H), 3.56 (dd, J ) 8, 14 Hz, 1H), 3.15
(dd, J ) 4.8, 14 Hz, 1H), 1.37 (s, 9H), 1.33 (s, 3H), 1.24 (t, J )
7.2 Hz, 3H); 13C NMR δ 175.5, 155.9, 79.3, 74.6, 62.1, 48.3,
28.1, 23.0, 14.0; HRMS (TOF ES+) calcd for C11H21NO5 [M +
Na]+ 270.1317, found 270.1319.
2-(4-Ch lor o-p h en yl)-2-h yd r oxy-3-n itr o-p r op ion ic Acid
Eth yl Ester (3j). Prepared according to the general procedure
using 106.3 mg (0.5 mmol) of R-keto ester 1j. The product was
purified by FC (10% Et2O in pentane) to yield 125 mg (91%)
of 3j as a pale yellow oil. The ee of the product was determined
by HPLC (90/10 hexane/i-PrOH; flow rate ) 1.0 mL/min; τminor
) 13.9 min; τmajor ) 16.9 min): [R]23 -17.5° (c 1.02, CH2Cl2,
D
1
88% ee); H NMR δ 7.55 (d, J ) 8.8 Hz, 2H), 7.37 (d, J ) 8.8
Hz, 2H), 5.21 (d, J ) 14.0 Hz, 1H), 4.63 (d, J ) 14.0 Hz, 1H),
4.37 (m, 2H), 4.23 (s, 1H), 1.33 (t, J ) 7.2 Hz, 3H); 13C NMR
δ 171.2, 135.2, 134.9, 129.0, 126.7, 80.5, 75.6, 63.8, 13.8; HRMS
(TOF ES+) for C11H12ClNO5 [M + Na]+ 296.0302, found
296.0323.
2-Hyd r oxy-3-n itr o-2-(4-n itr o-p h en yl)-p r op ion ic Acid
Eth yl Ester (3k ). Prepared according to the general procedure
using 111.6 mg (0.5 mmol) of the commercially available R-keto
ester 1k . The product was purified by FC (CH2Cl2) to yield
141 mg (99%) of 3k as an orange oil. The ee of the product
was determined by HPLC (95/5 hexane/i-PrOH; flow rate )
1.0 mL/min; τminor ) 47.9 min; τmajor ) 50.7 min): [R]23D -15.1°
(c 1.0, CH2Cl2, 93% ee); 1H NMR δ 8.26 (d, ) 8.8 Hz, 2H), 7.84
(d, ) 9.2 Hz, 2H), 5.26 (d, ) 14 Hz, 1H), 4.67 (d, ) 14 Hz, 1H),
4.40 (m, 2H), 4.36 (s, 1H), 1.35 (t, J ) 7.2 Hz, 3H); 13C NMR
δ 170.5, 148.2, 143.1, 126.7, 123.8, 80.2, 75.8, 64.2, 13.8; HRMS
(TOF ES+) calcd for C11H12N2O7 [M + Na]+ 307.0542, found
307.0540.
2-Hydr oxy-2-(4-m eth oxy-ph en yl)-3-n itr o-pr opion ic Acid
Eth yl Ester (3l). Prepared according to the general procedure
using 104.1 mg (0.5 mmol) of R-keto ester 1l. The product was
purified by FC (gradient from 5% EtOAc in pentane to 10%
EtOAc in pentane) to yield 91 mg (68%) of 3l as a colorless
oil. The ee of the product was determined by HPLC (90/10
hexane/i-PrOH; flow rate ) 1.0 mL/min; τmajor ) 38.8 min; τminor
5-(4-Ch lor o-ph en yl)-2-oxo-oxazolidin e-5-car boxylic Acid
Eth yl Ester (7). Compound 3j (137 mg, 0.5 mmol), prepared
following the general procedure, was dissolved in EtOH (4 mL),
and Raney nickel (200 mg in 3 mL of EtOH) was added. The
reaction mixture was stirred under H2 at atmospheric pressure
for 4 h at room temperature. The reaction mixture was filtered
through an HPLC filter, and the solvent was removed in vacuo.
The residue was dissolved in a 20% solution of phosgene in
toluene and left stirring for 16 h. The solvent was removed in
vacuo, and the crude reaction mixture was purified by FC
(gradient from CH2Cl2 to 10% Et2O in CH2Cl2) to give 54 mg
(40%) of 7 as a white powder. Recrystallization from CH2Cl2
in a hexane chamber afforded colorless needles for X-ray
analysis (mp: 154-156 °C). The ee of the product was
determined by HPLC (90/10 hexane/i-PrOH; flow rate ) 1.0
) 45.4 min): [R]23 -10.2° (c 1.16 g/100 mL, CH2Cl2, 88% ee);
D
1H NMR δ 7.50 (d, J ) 8.8 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H),
5.21 (d, J ) 14.4 Hz, 1H), 4.64 (d, J ) 14.4 Hz, 1H), 4.35 (m,
2H), 4.18 (s, 1H), 3.80 (s, 3H), 1.33 (t, J ) 7.2 Hz, 3H); 13C
NMR δ 171.8, 160.1, 128.2, 126.6, 114.2, 80.8, 75.7, 63.5, 55.3,
14.0; HRMS (TOF ES+) calcd for C12H15NO6 [M + Na]+
292.0797, found 292.0796.
2-H yd r oxy-2-n it r om et h yl-4-p h en yl-b u t -3-en oic Acid
Meth yl Ester (3m ). Prepared according to the general
procedure using 95.1 mg (0.5 mmol) of â,γ-unsaturated R-keto
ester 1m . The crude reaction mixture was flushed through a
plug of silica using Et2O as the eluent, and the yield was
determined by 1H NMR with pentachlorobenzene as the
internal standard. The ee of the product was determined by
mL/min; τmajor ) 17.6 min; τminor ) 19.4 min): [R]23 -49.6° (c
D
1.08, CH2Cl2, 92% ee); 1H NMR δ 7.41 (d, J ) 8.8 Hz, 2H),
7.35 (d, J ) 8.8 Hz, 2H), 6.50 (bs, 1H), 4.40 (d, J ) 9.6 Hz,
1H), 4.22 (k, J ) 7.2 Hz, 2H), 3.74 (d, J ) 8.8 Hz, 1H), 1.23 (t,
J ) 7.2 Hz, 3H); 13C NMR δ 169.6, 158.0, 135.7, 135.1, 129.0,
HPLC (90/10 hexane/i-PrOH; flow rate ) 1.0 mL/min; τminor
)
20.5 min; τmajor ) 32.4 min): 1H NMR δ 7.39-7.29 (m, 5H),
6.56 (d, J ) 15.6 Hz, 1H), 6.10 (d, J ) 15.6 Hz, 1H), 4.98 (d,
J ) 13.6 Hz, 1H), 4.57 (d, J ) 13.6 Hz, 1H), 4.32 (s, 1H), 3.92
(s, 3H); 13C NMR δ 171.9, 135.0, 133.6, 128.6, 126.9, 123.1,
79.8, 75.6, 54.0; HRMS (TOF ES+) calcd for C12H13NO5 [M +
Na]+ 274.0691, found 274.0692.
126.1, 83.5, 63.0, 50.8, 13.8; HRMS (TOF ES+) calcd for C12H12
-
ClNO4 [M + Na]+ 292.0353, found 292.0352. See Supporting
Information for X-ray data.
Ack n ow led gm en t. This work was made possible by
a grant from The Danish National Research Foundation.
Note Ad d ed in P r oof. Trost et al. have recently
disclosed a catalytic enantioselective Henry reaction
employing a bimetallic zinc complex.15
4-(4-Ch lor o-p h en yl)-2-h yd r oxy-2-n it r om et h yl-b u t -3-
en oic Acid Meth yl Ester (3n ). Prepared according to the
general procedure using 112.3 mg (0.5 mmol) of â,γ-unsatur-
ated R-keto ester 1n . The crude reaction mixture was flushed
through a plug of silica using Et2O as the eluent, and the yield
1
was determined by H NMR with pentachlorobenzene as the
internal standard. The ee of the product was determined by
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
data for compound 7. This material is available free of charge
via the Internet at http://pubs.acs.org.
HPLC (90/10 hexane/i-PrOH; flow rate 1.0 mL/min; τminor
)
41.9 min; τmajor ) 52.8 min): 1H NMR δ 7.30 (s, 4H), 6.98 (d,
J ) 15.6 Hz, 1H), 6.08 (d, J ) 15.6 Hz, 1H), 4.97 (d, J ) 14
Hz, 1H), 4.56 (d, J ) 14 Hz, 1H), 4.33 (s, 1H), 3.93 (s, 3H); 13
C
J O025690Z
NMR δ 171.8, 134.3, 133.5, 132.5, 128.8, 128.1, 123.7, 79.8,
75.5, 54.1; HRMS (TOF ES+) calcd for C12H12ClNO5 [M + Na]+
308.0302, found 308.0295.
(15) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41,
861.
J . Org. Chem, Vol. 67, No. 14, 2002 4881