Asymmetric Henry reaction catalyzed by C2-symmetric tridentate bis(oxazoline) and bis(thiazoline) complexes: Metal-controlled reversal of enantioselectivity

Article abstract of DOI:10.1021/jo050097d

(Chemical Equation Presented) C₂-symmetric tridentate bis(oxazoline) and bis(thiazoline) ligands with a diphenylamine backbone have been investigated in the catalytic asymmetric Henry reaction of α-keto esters with different Lewis acids. Their

Full text of DOI:10.1021/jo050097d

Henry reaction of R-keto esters with nitromethane in the
presence of readily available chiral bis(oxazoline) cata-
lysts. Trost et al. have recently disclosed a catalytic
enantioselective Henry reaction employing a bimetallic
zinc complex.4 Recently, Reiser et al.5a and Lin5b have
demonstrated that the Henry reaction could be promoted
by diethylzinc in the presence of either diamines or amino
alcohols. Evans’ group has successfully developed the
asymmetric Henry reaction of aldehydes using bis-
(oxazoline)-copper acetate complexes.6
Although some privileged chiral catalysts have been
synthesized, the structural features accounting for their
superior performance have not been elucidated.9 Because
of their ready accessibility, modular nature and proven
success in various catalytic asymmetric reactions, C2-
symmetric chiral bis(oxazoline) ligands have gained much
attention of chemists to their designing and applications
in recent years.10 Our group has paid continuing atten-
tion to the synthesis and application of the bis(oxazoline)
and bis(thiazoline) ligands.11 During the development of
asymmetric synthetic methodology, the challenge of
preparing both enantiomers must be met. Reversal of
Asymmetric Henry Reaction Catalyzed by
C2-Symmetric Tridentate Bis(oxazoline)
and Bis(thiazoline) Complexes:
Metal-Controlled Reversal of
Enantioselectivity
Da-Ming Du,* Shao-Feng Lu, Tao Fang, and Jiaxi Xu*
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry
and Molecular Engineering, Peking University,
Beijing 100871, P. R. China
dudm@pku.edu.cn
Received January 17, 2005
(2) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418-4420. (b) Sasai, H.; Suzuki, T.; Itoh, N.;
Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. J. Am. Chem. Soc.
1993, 115, 10372-10373. (c) Sasai, H.; Yamada, Y. M. A.; Suzuki, T.;
Shibasaki, M. Tetrahedron 1994, 50, 12313-12318. (d) Sasai, H.;
Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388-7389. (e) Iseki, K.; Oishi, S.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1996, 37, 9081-9084.
C2-symmetric tridentate bis(oxazoline) and bis(thiazoline)
ligands with a diphenylamine backbone have been investi-
gated in the catalytic asymmetric Henry reaction of R-keto
esters with different Lewis acids. Their Cu(OTf)2 complexes
furnished S enantiomers, while Et2Zn complexes afforded
R enantiomers, both of them with higher enantioselectivities
(up to 85% ee). Reversal of enantioselectivity in asymmetric
Henry reactions was achieved with the same chiral ligand
by changing the Lewis acid center from Cu(II) to Zn(II). The
results show that the NH group in C2-symmetric tridentate
chiral ligands plays a very important role in controlling both
the yields and enantiofacial selectivity of the Henry products.
(3) (a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun.
2001, 2222-2223. (b) Christensen, C.; Juhl, K.; Hazell, R. G.; Jør-
gensen, K. A. J. Org. Chem. 2002, 67, 4875-4881.
(4) (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41,
861-863. (b) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org.
Lett. 2002, 4, 2621-2623.
(5) (a) Klein, G.; Pandiaraju, S.; Reiser, O. Tetrahedron Lett. 2002,
43, 7503-7506. (b) Zhong, Y.-W.; Tian, P.; Lin, G.-Q. Tetrahedron:
Asymmetry 2004, 15, 771-776.
(6) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692-12693.
(7) For recent other examples of Henry reaction, see: (a) Chinchilla,
R.; Najera, C.; Sanchez-Agullo, P. Tetrahedron: Asymmetry 1994, 5,
1393-1402. (b) Davis, A. P.; Dempsey, K. J. Tetrahedron: Asymmetry
1995, 6, 2829-2840. (c) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int.
Ed. 1999, 38, 1931-1934. (d) Ma, D. W.; Pan, Q. B.; Han, F. S.
Tetrahedron Lett. 2002, 43, 9401-9403. (e) Ooi, T.; Doda, K.; Maruoka,
K. J. Am. Chem. Soc. 2003, 125, 2054-2055. (f) Kogami, Y.; Nakajima,
T.; Ashizawa, T.; Kezuka, S.; Ikeno, T.; Yamada, T. Chem. Lett. 2004,
614-615. (g) Kudyba, I.; Raczko, J.; Urban´czyk-Lipkowskaa, Z.;
Jurczaka, J. Tetrahedron 2004, 60, 4807-4820.
(8) For recent examples of aza-Henry reaction, see: (a) Yamada, K.;
Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 3504-3506. (b) Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001,
980-982. (c) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K.
V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843-5844. (d)
Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew.
Chem. 2001, 113, 3080-3083; Angew. Chem., Int. Ed. 2001, 40, 2992-
2925. (e) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem.
Soc. 2004, 126, 3418-3419. (f) Okino, T.; Nakamura, S.; Furukawa,
T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627.
(9) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
(10) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45. (b) Jørgensen, K. A.; Johannsen, M.; Yao,
S.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605-613. (c)
Pfaltz, A. Synlett 1999, 835-842. (d) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325-335. (e) Helmchen, G.; Pfaltz, A. Acc. Chem.
Res. 2000, 33, 336-345. (f) Fache, F.; Schulz, E.; Tommasino, M. L.;
Lemaire, M. Chem. Rev. 2000, 100, 2159-2231. (g) Braunstein, P.;
Naud, F. Angew. Chem., Int. Ed. 2001, 40, 680-699. (h) Rechavi, D.;
Lemaire, M. Chem. Rev. 2002, 102, 3467-3493. (i) Sutcliffe, O. B.;
Bryce, M. R. Tetrahedron: Asymmetry 2003, 14, 2297-2325. (j) Guiry,
P. J.; McManus, H. A. Chem. Rev. 2004, 104, 4151-4202.
The Henry or nitroaldol reaction, a coupling reaction
between a nitroalkane and a carbonyl compound, forms
a new carbon-carbon bond and generates a â-nitro
alcohol, which can further be converted to various valu-
able structural motifs.1 Catalytic asymmetric Henry
reactions have gained particular attention and made
much progress in recent years.2-8 Shibasaki and co-
workers have reported2 that rare-earth-lithium-BINOL
complexes could be applied as catalysts for the enantio-
selective reaction of aldehydes with nitroalkanes. Jør-
gensen and co-workers reported3 the catalytic asymmetric
* To whom correspondence should be addressed. Phone: +86-10-
6275-1497. Fax: +86-10-6275-1708.
(1) For reviews on nitroaldol (Henry) reactions, see: (a) Rosini, G.
In Comprehensive Organic Synthesis; Trost, B. M., Heathcock, C. H.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 321-340. (b) Ono, N. The
Nitro group in Organic Synthesis; Wiley-VCH: New York, 2001;
Chapter 3, pp 30-69. (c) Shibasaki, M.; Gro¨ger, H. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, Heidelberg, 1999; Chapter 29.3. (d) Shibasaki,
M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-
1256. (e) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. (f) Shibasaki,
M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2209. (g) Westermann,
B. Angew. Chem., Int. Ed. 2003, 42, 151-153.
10.1021/jo050097d CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/26/2005
3712
J. Org. Chem. 2005, 70, 3712-3715

TABLE 1. Asymmetric Henry Reaction Catalyzed by
Complexes of Et2Zn-1 and Et2Zn-2a
entry
ligand
yieldb (%)
eec (%)
configd
FIGURE 1.
SCHEME 1
1
2
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
80
49
73
76
62
56
38
25
44
68
77
73
47
79
57
38
56
6
R
R
R
R
R
R
R
R
R
R
3
4
5
6
7
8
9
68
2
enantioselectivity is most obviously achieved through
the use of enantiomeric ligands. However, the chiral
ligand is not always readily or economically available in
both antipodes. For example, sparteine is a ligand
available in only one enantiomer. In such cases there is
motivation to devise means of reversing stereochemical
outcomes with the single enantiomeric ligand available.12
One appealing way to reverse enantioselectivity would
involve use of different Lewis acids.13,14 Herein, we
further investigate C2-symmetric tridentate chiral bis-
(oxazoline) ligands 1 and corresponding bis(thiazoline)
ligands 2 (Figure 1) in the enantioselective catalytic
Henry reaction.11a,15 Reversal of enantioselectivity with
the same chiral ligand was achieved by changing the
Lewis acid center from Cu(II) to Zn(II) (Scheme 1).
In our previous paper,11a we reported that Cu(OTf)2-1
and Cu(OTf)2-2 complexes can catalyze the Henry reac-
tion of R-keto esters with nitromethane. We found that
the configuration of the major enantiomer of the Henry
product is S when Cu(OTf)2-1 was used as a catalyst
(up to 82%ee), while it changed to R configuration
with Zn(OTf)2-1.11a However, the enantioselectivity of
Zn(OTf)2-bis(oxazoline)-catalyzed Henry product is only
16% ee, which is not enough for us to draw a decisive
conclusion that different Lewis acids cause reversal of
enantioselectivity with the same chiral ligand.
10
a Reaction conditions: ethyl pyruvate 3a (0.25 mmol) with
nitromethane (10 mmol) in 2 mL of THF. b Isolated yield by
column chromatography. c Determined by HPLC on an OB column
(hexane/2-propanol 90:10, 1.0 mL/min). d The absolute configura-
tion of the products was assigned by comparison with the literature
values.3b
TABLE 2. Effect of Ligand 1d and Et2Zn Loading on the
Asymmetric Henry Reactiona
entry
1d (%)
Et2Zn (%)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
20
20
20
20
20
10
5
20
30
40
50
60
25
13
81
78
76
79
76
64
27
73
72
79
83
82
74
56
a The reaction was performed with ethyl pyruvate (0.25 mmol)
3a and nitromethane (10 mmol) in 2 mL of THF. b Isolated yield
by column chromatography. c Determined by HPLC on an OB
column (hexane/2-propane 90:10, 1.0 mL/min.).
To further explore this phenomenon, we used Et2Zn-1
and Et2Zn-2 complexes to catalyze the Henry reaction
(Table 1). To our delight, enhancements of both the yields
and enantioselectivities were observed (Table 1, entries
1 and 4). At the same time, the absolute configuration of
the major enantiomer is R (Table 1, entries 1-10). This
result demonstrates that reversal of enantioselectivity
can be achieved with the same chiral ligand by changing
the metal from Cu(II) to Zn(II). C2-symmetric bis-
(thiazoline) ligands 2 combined with Et2Zn also give the
same sense and degree of enantioselectivitiy.11a
Since Et2Zn-1d gave the highest enantioselectivity,
we chose it as the catalyst to further optimize the reaction
conditions. First, the effect of ratio of Et2Zn to ligand 1d
was investigated. The reaction of 3a with nitromethane
in the presence of 20 mol % of 1d and 20 mol % of Et2Zn
as the catalyst in THF gave 81% yield with 73% ee. With
the increase of the ratio of Et2Zn to ligand 1d, the yield
of Henry product is relatively constant (Table 2, entries
1-5), while the enantioselectivity reaches the highest at
a ratio of 2.5 (Table 2, entry 4) and the enantioselectivity
is maintained at higher ratios (Table 2, entry 5). We
supposed that some Et2Zn was consumed in the opera-
tion conditions and the ratio of Et2Zn to ligand 1d should
be kept at 2.5 to guarantee the best enantioselectivity.
We also tried to reduce the catalyst loading. However,
(11) (a) Lu, S. F.; Du, D. M.; Zhang, S. W.; Xu, J. X. Tetrahedron:
Asymmetry 2004, 15, 3433-3441. (b) Fu, B.; Du, D. M.; Wang, J. B.
Tetrahedron: Asymmetry 2004, 15, 119-126. (c) Fu, B.; Du, D. M.;
Xia, Q. Synthesis 2004, 221-226. (d) Wang, Z. Y.; Du, D. M.; Xu, J. X.
Synth. Commun. 2004, 35, 307-321. (e) Du, D. M.; Fu, B.; Hua, W. T.
Tetrahedron 2003, 59, 1933-1938. (f) Xu, D. C.; Du, D. M.; Ji, N.;
Wang, Z. Y.; Hua, W. T. Synth. Commun. 2003, 33, 2563-2574. (g)
Wang, Z. Y.; Du, D. M.; Wu, D.; Hua, W. T. Synth. Commun. 2003, 33,
1275-1283. (h) Fu, B.; Du, D. M. Chin. J. Chem. 2003, 21, 597-599.
(i) Du, D. M.; Wang, Z. Y.; Xu, D. C.; Hua, W. T. Synthesis 2002, 2347-
2352.
(12) (a) Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001, 5, 719-755. (b)
Kim, Y. H. Acc. Chem. Res. 2001, 34, 955-962. (c) Beak, P.; Basu, A.;
Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 552-560. (d) Wilkinson, J. A.; Rossington, S. B.; Leonard, J.;
Hussein, N. Tetrahedron Lett. 2004, 45, 1191-1193. (e) Tan, Y.-L.;
Widdowson, D. A.; Wilhelm, R. Synlett 2001, 1632-1634.
(13) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron Lett.
1996, 37, 3815-3818. (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C.
P. J. Am. Chem. Soc. 1998, 120, 6615-6616. (c) Sibi, M. P.; Chen, J.
J. Am. Chem. Soc. 2001, 123, 9472-9473. (d) Yabu, K.; Masumoto, S.;
Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908-9909.
(14) (a) Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T.
Synlett 2004, 1703-1706. (b) Mao, J. C.; Wan, B. S.; Zhang, Z. J.;
Wang, R. L.; Wu, F.; Lu, S. W. J. Mol. Catal. A: Chem. 2004, 225,
33-37.
(15) McManus, H. A.; Guiry, P. J. J. Org. Chem. 2002, 67, 8566-
8573 and references therein.
J. Org. Chem, Vol. 70, No. 9, 2005 3713

TABLE 3. Effects of Solvents on the Asymmetric Henry
Reactiona
TABLE 4. Enantioselective Henry Reaction of r-Keto
Esters 3a-h with Nitromethane Catalyzed by Et2Zn-1da
entry
solvent
T (°C) time (h) yieldb (%) eec (%)
1
2
CH3CN
0
0
7
7
21
52
64
60
63
65
26
83
81
59
97
33
61
74
67
67
66
41
77
61
65
84
Et2O
3
THF
0
7
4
CH3NO2
CH2Cl2
ClCH2Cl2Cl
toluene
hexane
hexane
hexane
hexaned
0
7
5
0
7
6
0
7
7
0
7
8
0
7
9
30
-20
0
7
entry
R (R-keto ester)
product
yieldb (%)
eec (%)
10
11
7
24
1
2
3
4
5
6
7
8
Me (3a)
CF3 (3b)
Ph (3c)
Ph(CH2)2 (3d)
Et (3e)
Bu (3f)
4a
4b
4c
4d
4e
4f
97
36
96
95
70
92
88
85
84
13
16
71
85
82
65
80
a The reaction was performed with ethyl pyruvate 3a (0.25
mmol), nitromethane (10 mmol), 10 mol % of 1d, and 25 mol % of
Et2Zn in 2 mL of solvent. b Isolated yield by column chromatog-
raphy. c Determined by HPLC on an OB column (hexane/2-pro-
pane 90:10, 1.0 mL/min.). d Using 20 mol % of 1d and 50 mol % of
Et2Zn.
i-Bu (3g)
Octyl (3h)
4g
4h
a Reaction was performed with R-keto esters 3 (0.25 mmol) and
nitromethane (10 mmol) in 2 mL of hexane. b Isolated yield by
column chromatography. c Determined by HPLC.16
poorer yield and enantioselectivity were obtained, espe-
cially when the loading was below 10 mol % (entries 6
and 7).
Subsequently, we found that solvent played a signifi-
cant effect on both the yields and enantioselectivity of
the Henry products (Table 3). Under 10 mol % catalyst
loading, various solvents were examined. The results
clearly demonstrate the superiority of hexane as a solvent
in terms of yield and enantioselectivity (Table 3, entry
8). The enantioselectivity decreased above or below the
optimized temperature (0 °C) (Table 3, entries 9 and 10).
An increase of the catalyst loading from 10 to 20 mol %
in hexane gave a significant increase in conversion and
enantioselectivity (Table 3, entry 11). We have also tried
different sequences of the addition of reactants and
additives (such as â-amino alcohols and naphthols), but
no better result was obtained.
With the optimized reaction conditions in hand (20 mol
% ligand 1d; 50 mol % Et2Zn; in hexane, 0 °C, 24 h), we
then examined the Henry reaction of other R-keto esters
(Table 4). It was found that the strong electron-with-
drawing group CF3 reduces the yield and enantioselec-
tivity significantly (Table 4, entry 2). When the phenyl
group is adjacent to the carbonyl group of the R-keto
ester, high yield but low ee were observed (Table 4, entry
3). The results showed that unbranched alkyl groups
afforded high yields and good enantioselectivities (Table
4, entries 1 and 4-8) at the same time. Both the
electronic and steric effects play important roles in the
yield and enantioselectivity in the reaction.
To determine if the ligand had any role in improving
the efficiency of catalysis, we performed the reaction in
the absence of 1d. The yield of the reaction of 3a with
nitromethane declined to 58% in the absence of ligand
1d. This result suggests that the ligand may improve
catalyst stability or turnover frequency. The coordination
of N atoms in the oxazoline rings to zinc(II) may increase
the polarity of the alkyl-Zn bond to great extent, and
the result is the enhancement of the donor property of
the alkyl group and the acceptor character of the Zinc
atom.17
SCHEME 2 a
a Reagents and conditions: (i) SOCl2, DMF, reflux 4 h; (ii)
L-phenylalaninol, DCM, Et3N, rt, 12 h; (iii) TsCl, Et3N, DMAP,
DCM, reflux 12 h.
To determine the function of the NH group in the
ligands 1 and 2, a new C2-symmetric bis(oxazoline) ligand
7, in which the NH group was replaced by methylene
group, was designed and synthesized from the corre-
sponding dicarboxylic acid 5 via intermediate 6 (Scheme
2).16 When ligand 7 was used instead of ligand 1d to carry
out the asymmetric Henry reaction of 3a under the
optimized conditions in Table 4, 4a was obtained in 83%
yield with only 4% ee. However, when ligand 7 was used
to perform Cu(OTf)2-catalyzed asymmetric Henry reac-
tion of 3a as in Scheme 1, the corresponding reaction gave
the product in 39% yield with 35% ee, while the config-
uration of the major enantiomer is R consistent with
the known facts of bidentate C2-symmetic bi(oxazo-
line)-Cu(OTf)2-catalyzed Henry reaction reported by
Jørgensen.3b
Jørgensen et al. have proposed a mechanism to eluci-
date the enantioselectivity in which both the R-keto ester
and nitronate coordinate to the copper to form an
intermediate A (Figure 2). For our case, in this paper,
we assumed an intermediate B for the Cu(II)-ligand
complex catalyzed Henry reaction. The NH group be-
tween two phenyl groups cannot be deprotonated by
Et3N. Thus, the NH is available to act as a hydrogen bond
donor to orient the nitronate. The other two nitrogen
atoms from oxazoline rings can coordinate to Cu(II), and
the R-keto ester also chelates Cu(II) as suggested by
Jørgensen et al. in their intermediate A.3b In this case,
the R-keto ester is activated by Lewis acid and nitronate
(16) See the Supporting Information for details.
(17) Boersma, J. In Comprehensive Organometallic Chemistry;
Wilkinson, G., Ed.; Pergamon Press: New York, 1982; Chapter 16.
3714 J. Org. Chem., Vol. 70, No. 9, 2005

tridendate coordination and hydrogen donation of NH
group in ligands 1 and 2 plays a crucial role in the
enantioselective catalytic Henry reaction. The similar “
NH effect” has been observed in the catalytic asymmetric
transfer hydrogenation.18
In summary, we have expanded the application of
C2-symmetric tridentate bis(oxazoline) and bis(thiazo-
line) ligands containing a diphenylamine unit in the
Lewis acid catalyzed asymmetric Henry reaction of R-keto
esters with nitromethane. The Et2Zn complex catalyzed
Henry reaction proceeds in high yields and can give the
optically active products in higher enantioselectivity (up
to 85% ee) when unbranched alkyl groups are adjacent
to the carbonyl group. The most important result is that
with the same (S,S)-bis(oxazoline) or (S,S)-bis(thiazoline)
ligands Cu(OTf)2 complexes preferentially furnish the S
enantiomer, while Et2Zn complexes produce the R enan-
tiomer. The reversal of enantioselectivity in the asym-
metric Henry reaction can be achieved with the same
chiral ligand by changing the Lewis acid center from Cu-
(II) to Zn(II), thus killing two (enantiomeric) birds with
one stone. Furthermore, we have demonstrated that the
NH group in C2-symmetric tridentate chiral ligands 1 and
2 is crucial for the reversal enantioselectivity with
different Lewis acids.
FIGURE 2.
is oriented by hydrogen bond. The S enantiomer is
preferred by a nucleophilic attack of nitronate on the
R-keto ester from the si-face under the chiral environ-
ment formed by C2-symmetric tridentate chiral ligand
and the copper atom.
In our previous work, the Zn(OTf)2-ligand complex
had been observed to give the major enantiomer opposite
to that obtained by the Cu(II)-ligand complex.11a How-
ever, in that case the ee value was too poor to merit
explanation. However in this work, for Et2Zn-ligand
complex catalyzed asymmetric Henry reaction, good ee
values were achieved. With the same (S,S)-bis(oxazoline)
or (S,S)-bis(thiazoline) ligands, the absolute configuration
of the Henry adduct is R which means that the chiral
carbon atom forms in the way that nitromethane attacks
from the re-face of the R-keto functionality of the R-keto
ester. We presumed an intermediate C in our Et2Zn
catalytic system. Diethylzinc causes the deprotonation
of NH between two phenyl groups and leaves two electron
Experimental Section
General Procedure for the Catalytic Enantioselective
Henry Reaction. To a mixture of ligand 1d (24.4 mg, 0.05
mmol) and hexane (2 mL) at 0 °C was added Et2Zn (125 µL,
0.125 mmol, 1.0 M in hexane) under nitrogen. The mixture was
allowed to stir for 0.5 h, and R-keto ester 3 (0.25 mmol) was
added followed by nitromethane (0.54 mL, 10 mmol). After being
stirred for 24 h at 0 °C, the mixture was quenched by diluted
HCl (2 mL, 1 mol/L) and then extracted with ether (5 mL × 2).
Purification by column chromatography afforded the desired
Henry product 4. The ee was determined by HPLC on OB, OJ,
or AS column.
2-Hydroxy-2-methyl-3-nitropropionic Acid Ethyl Ester
(4a). Compound 4a was prepared according to the general
procedure using 29.1 mg (0.25 mmol) of R-keto ester 3a and
purified by column chromatography (25% AcOEt in petroleum
ether) to yield 43.0 mg (97%) of 4a as a pale yellow oil. The ee
was determined by chiral HPLC on an OB column (hexane/
2-propanol 90:10, 1.0 mL/min, tminor ) 12.0 min, tmajor ) 13.6
1
pairs on the nitrogen atom. H NMR of ligand 1d with
Et2Zn (1:2) in CDCl3 shows the disappearance of the
signal of NH proton. The two imine nitrogen atoms of
the oxazoline rings coordinate the same zinc atom with
the diphenylamine anion nitrogen coordinating both zinc
atoms simultaneously, utilizing both available electron
pairs. Thus, a dinuclear Zn catalyst forms. One zinc atom
is fixed by three nitrogen atoms and chelated by R-keto
ester. Another zinc atom, which is coordinated by the
nitrogen atom between phenyl groups and nitronate, has
to be located above the re-face of the R-keto functionality.
Then, R-keto ester is activated and nitronate is oriented
by two zinc atoms, respectively. The Henry reaction
proceeds by the nucleophilic attack of nitronate on the
R-keto ester from the re-face under the chiral environ-
ment formed by C2-symmetric tridentate chiral ligand
and two zinc atoms.
min). [R]20 ) +15.5 (c ) 0.26, CH2Cl2, 84% ee) [lit.3b [R]23
)
D
D
+10.2 (c 1.19, CH2Cl2, 92% ee)]. 1H NMR (CDCl3): δ ) 4.86 (d,
J ) 13.8 Hz, 1H), 4.58 (d, J ) 13.8 Hz, 1H), 4.34 (m, 2H), 3.85
(s, 1H), 1.46 (s, 3H), 1.33 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3):
δ )173.4, 80.9, 72.4, 63.0, 23.8, 13.9.
Acknowledgment. This project was supported by
the National Natural Science Foundation of China
(Grant Nos. 20372001 and 20172001) and Peking Uni-
versity.
Supporting Information Available: Experimental pro-
cedures, copies of 1H NMR and 13C NMR spectra of 7, and the
HPLC spectra data for determining the enantiomeric purity
of the Henry products. This material is available free of charge
via the Internet at http://pubs.acs.org.
In addition, the result of the asymmetric Henry reac-
tion with ligand 7 also provides evidence for our hypoth-
esis. Replacement of the NH group by a CH2 group
results in observation of the same phenomenon as that
observed by Jørgensen. Ligand 7 with Cu(OTf)2 prefer-
entially affords the R enantiomer while ligand 7 with
Et2Zn affords poor enantioselectivity. The reversal of
enantioselectivity proves that the potential ability of
JO050097D
(18) (a) Gao, J. X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15,
1087-1089. (b) Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron:
Asymmetry 1995, 6, 705-718. (c) Jiang, Y.; Jiang, Q.; Zhang, X. J.
Am. Chem. Soc. 1998, 120, 3817-3818.
J. Org. Chem, Vol. 70, No. 9, 2005 3715