Enantioselective turnover in glyoxylate-ene reactions catalyzed by chiral copper complexes

Article abstract of DOI:10.1016/j.tetlet.2005.11.159

The catalytic, enantioselective carbonyl-ene reaction of ethyl glyoxylate with α-methylstyrene and 4-halo-α-methylstyrene has been investigated in the presence of copper triflate-bisoxazoline complexes. The reaction proceeded smoothly to give γ,δ-unsatura

Full text of DOI:10.1016/j.tetlet.2005.11.159

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 897–900
Enantioselective turnover in glyoxylate-ene reactions catalyzed
by chiral copper complexes
Manoj K. Pandey, Alakesh Bisai and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 3 November 2005; revised 22 November 2005; accepted 30 November 2005
Available online 19 December 2005
Abstract—The catalytic, enantioselective carbonyl-ene reaction of ethyl glyoxylate with a-methylstyrene and 4-halo-a-methylstyrene
has been investigated in the presence of copper triflate–bisoxazoline complexes. The reaction proceeded smoothly to give c,d-unsatu-
rated-a-hydroxy esters in moderate to good yields and with excellent enantioselectivity (up to 100% ee). A hypothesis has been
provided to explain the reversal of enantioselectivity in the reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
The enantioselective carbonyl-ene reaction promoted by
a catalytic amount of chiral Lewis acid is an excellent
route to optically active homoallylic alcohols. Among
the reversal to a change in the metal centre geometry
from square planar (for 1a) to tetrahedral (for 1b).
6
a,e
1
However, this proposal has not been accepted in the ab-
sence of any credible evidence. It has been argued that
due to the high barrier for square planar to tetrahedral
distortion for four coordinate Cu(2+) complexes, inter-
vention of the latter geometry is less unlikely.5 How-
ever, it is believed that geometrical change does occur,
many variants of this reaction, the glyoxylate-ene reac-
tion is of particular significance as it provides chiral a-
hydroxy esters, which have great synthetic importance.
While Whitesell described the first asymmetric car-
a
2
bonyl-ene reaction using auxiliary based glyoxylate,
6
e
the first example of a catalytic enantioselective ene reac-
but it is quite flexible in nature. In this letter, we
describe our efforts in this area and report a high level
of enantioselectivity in the glyoxylate-ene reaction using
other chiral ligands. We also provide our analysis on the
proposed model to explain the reversal in the
enantioselectivity.
3
tion was reported by Yamamoto and co-workers. This
led to a flurry of activity in this area where major
advances have been made by Mikami, Evans5 and
4
6
–8
others. Excellent enantioselectivity has been achieved
mainly with two types of ligands, the Ti complex of BI-
NOL and C -symmetric Cu(II) complex of bis(oxazolin-
2
yl) (box) ligands 1 (Fig. 1). The sense of asymmetric
induction for the glyoxylate-ene reaction catalyzed by
Earlier we reported the synthesis and application of chi-
ral pyridine bis(diphenyloxazoline)–copper complexes in
9
the Cu(II) complex of 1a (SbF as the counter anion)
the enantioselective allylic oxidation of olefins and
6
1
0
was opposite to that of the Cu(II) complex of 1b (OTf
cyclopropanation reactions. Since these pybox ligands
have not been used for glyoxylate-ene reactions, it was
worthwhile to try them in the first instance. The Cu(II)
5
as the counter anion). This mode of enantioselective
turnover was first observed by Jørgensen who ascribed
Me
O
Me
O
O
H
OH
*
S
S
EtO
+
EtO
N
N
H
Ph
Ph
R
R
O
O
1
1
a R = t-Bu
b R = Ph
2a: 97% ee (S)
b: 87% ee (R)
2
Figure 1. Glyoxylate-ene reaction.
*
0
Corresponding author. Tel.: +91 512 2597291; fax: +91 512 2597436; e-mail: vinodks@iitk.ac.in
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.159

898
M. K. Pandey et al. / Tetrahedron Letters 47 (2006) 897–900
O
SO
R
N
O S
R
N
R
R
O
X
R
O
O
3
a X = N, R = Ph
3b X = N, R = H
c X = CH, R = H
Ph
Ph
S
S
N
N
R
R
N R
N
3
Ph
Ph
5
4
Figure 2.
complex of the ligands 3 (Fig. 2) catalyzed the reaction
of ethyl glyoxylate and a-methylstyrene to give 2a, but
there was virtually no asymmetric induction in the reac-
tion (up to 2% ee). Next, we investigated ligands pos-
sessing structures similar to that of the box ligands 1a
and 1b but with conformational rigidity in the substitu-
ents at the chiral centres. Bisoxazolines 4 and 5 are
such chiral ligands where there is bisoxazoline rigidity
due to the inherent structure (Fig. 2).
Cu(I) complex as catalysts (entries 5 and 6). In all the
above cases using 4 as the chiral ligand, the absolute ste-
reochemistry of the product was S. The glyoxylate-ene
reaction was also carried out using the chiral ligand 5
and the results are summarized in Table 1. A maximum
ee of 70.5% for 2a was obtained using the Cu(II) com-
plex of ligand 5 (entry 7). In virtually all the cases, the
trend in the enantioselectivity with Cu(II) and Cu(I)
complexes was similar but the sense of asymmetric
induction was opposite (entries 7–12).
1
1
12
At the outset, the glyoxylate-ene reaction was carried
out at 0 °C in different solvents using 5 mol % of chiral
The observed enantioselectivity in the above ene reac-
tion catalyzed by copper complexes of ligands 4 and 5
can be rationalized via the transition state models pro-
posed in Figure 3. It is proposed that the ligand 4 and
ethyl glyoxylate forms a tetrahedral complex with
˚
ligand 4 and Cu(OTf) in the presence of 4 A molecular
2
sieves. The chemical yield of 2a remained almost the
same (38–50%), however, the enantioselectivity varied
greatly for each solvent; toluene (72% ee), DCM
(
79.2% ee), CHCl (93.5% ee), hexane (43.2% ee), ether
Cu(OTf) . Although four-cordinate Cu(II) complexes
3
2
(
87% ee), DCE (12% ee), CCl (63% ee). In view of the
prefer square planar geometry, the driving force for
the tetrahedral geometry in this case is the p–p stacking
of one of the phenyl groups on the left hand side and the
carbonyl moiety of the glyoxylate. Since the distance be-
tween the phenyl and carbonyl groups is between 3 and
4
high optical yield in chloroform, it was chosen as the
preferred solvent. Since 4 A molecular sieves enhanced
˚
the enantioselectivity in the above reaction by 4–5%, it
was used in all subsequent reactions. The ene reaction
of ethyl glyoxylate with a-methylstyrene and 4-halo-a-
methylstyrenes was studied with 5 mol % of Cu(II) and
Cu(I) complexes (triflate as the counter anion) of the
chiral ligands 4 and 5 under the above conditions and
the results are reported in Table 1. In the case of a-meth-
ylstyrene, a maximum of 93.5% ee for the product 2a
˚
3.5 A, there might be some attractive interaction, which
would stabilize this tetrahedral geometry. Thus, the Re
face of the aldehyde is blocked by the phenyl ring and
the reaction is promoted from the Si face of the coordi-
nated aldehyde. The results from entries 2, 4 and 6 of
Table 1 indicate that the reaction was equally feasible
with the Cu(I) complex of ligand 4. Since tetrahedral
geometry is more favorable in the case of Cu(I) com-
plexes, it is obvious that the same transition state model
operates to provide the same sense of asymmetric induc-
tion in the reaction. The reversal in the enantioselectivity
with the chiral ligand 5 is typical and can be explained
using a square planar geometry model, which is usually
was obtained using the complex of Cu(OTf) and the
chiral ligand 4 as catalyst (entry 1). The enantioselectiv-
ity dropped to 88.6% on the use of (CuOTf) ÆTol (entry
2
2
2
). A similar trend in the enantioselectivity was obtained
in the case of 4-fluoro-a-methylstyrene (entries 3 and 4).
-Chloro-a-methylstyrene gave the ene product in 100%
ee using the Cu(II) complex and 90.8% ee using the
4
Table 1. Glyoxylate-ene reaction catalyzed by Cu complexes of chiral ligands 4 and 5
OH
H
5
mol% L-Cu triflate,
O
o
EtO
+
CHCl , 4Å MS, 0 C
EtO
3
H
O
Y
Y
O
Entry
Y
L-Cu triflate
Time (h)
Yield (%)
% ee
1
2
3
4
5
6
7
8
9
H
H
F
4–Cu(II)
4–Cu(I)
4–Cu(II)
4–Cu(I)
4–Cu(II)
4–Cu(I)
5–Cu(II)
5–Cu(I)
5–Cu(II)
5–Cu(I)
5–Cu(II)
5–Cu(I)
4
4
3
4
4
5
5
4
3
8
4
5
46
38
31
32
32
34
64
51
40
42
42
30
93.5 (S)
88.6 (S)
91.2 (S)
87.7 (S)
100 (S)
90.8 (S)
70.5 (R)
42.0 (R)
51.8 (R)
56.6 (R)
68.3 (R)
65.4 (R)
F
Cl
Cl
H
H
F
F
Cl
Cl
1
1
1
0
1
2

M. K. Pandey et al. / Tetrahedron Letters 47 (2006) 897–900
899
References and notes
O
N
Ph
O
N
1. For a review on enantioselective carbonyl-ene reactions,
see: (a) Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T.
Synlett 1992, 255–265; (b) Berrisford, D. J.; Bolm, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1717–1719; (c)
Dias, L. C. Curr. Org. Chem. 2000, 4, 305–342.
Ph
O
O
N
Cu
O
O
N
Cu
OEt
O
OEt
O
Ph
2
. Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.;
Chen, H. H.; Deyo, D.; James, D.; Liu, C.-L.; Minto, M.
A. Tetrahedron 1986, 42, 2993–3001.
Re face attack
Complex of 5; Square Planar)
Si face attack
Complex of 4; Tetrahedral)
(
3. Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H.
Tetrahedron Lett. 1988, 29, 3967–3970.
(
Figure 3. Stereochemical model for the glyoxylate-ene reaction.
4. (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc.
1
1
1
990, 112, 3949–3954; (b) Mikami, K. Pure Appl. Chem.
996, 68, 639–644; (c) Mikami, K.; Matsukawa, S. Nature
997, 385, 613–615.
more favorable in the case of Cu(II) complexes.13 There
is no extra stabilization, as proposed in the case of 4, for
change over in the metal geometry from square planar
to tetrahedral. Thus, the glyoxylate-ene reaction with
the Cu(II) complex of chiral ligand 5 proceeds via nor-
mal square planar geometry where the reaction occurs
from the Re face of the coordinated aldehyde. The lower
enantioselectivity in the case of ligand 5 is manifest from
the transition state model. As a result of the ring fusion
at the chiral centres, the fused aryl ring moves away
from the aldehyde, thus making the Si face of the coor-
dinated aldehyde vulnerable to attack to some extent.
The Cu(I) complex of the ligand 5 gave the same sense
of induction (entries 8, 10 and 12) as that of the Cu(II)
complex. This can be explained by invoking octahedral
geometry where two solvent ligands could be assumed
to chelate the copper.
5
6
. (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky,
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(
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888–1898.
7
. For some recent papers in the area, see: (a) Pandiaraju, S.;
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2
001, 123, 3850–3851; (b) Kaden, S.; Hiersemann, M.
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Kogami, Y.; Ikeno, T.; Yamada, T. Bull. Chem. Soc. Jpn.
In conclusion, we have shown that ligands 4 and 5 gave
high enantioselectivity in the glyoxylate-ene reaction. A
1
4
2
003, 76, 49–58; (f) Simonelli, B.; Orlandi, S.; Benglia, M.;
maximum of 100% ee was obtained in this reaction.
Pozzi, G. Eur. J. Org. Chem. 2004, 2669–2673; (g)
Takizawa, S.; Somei, H.; Jayaprakash, D.; Sasai, H.
Angew. Chem., Int. Ed. 2003, 42, 5711–5714; (h) Yuan, Y.;
Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2003, 42,
We have also provided a hypothesis to explain the rever-
sal in enantioselectivity in the reaction. The results
reported here also support the proposition of Jørgensen
for change over in metal geometry to account for the
reversal in enantioselectivity.
5
478–5480; (i) Guo, H.; Wang, X.; Ding, K. Tetrahedron
Lett. 2004, 45, 2009–2012; (j) Mandoli, A.; Orlandi, S.;
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General procedure for the enantioselective glyoxylate-
ene reaction. A mixture of chiral ligand 4 or 5
(
(
0.015 mmol, 6 mol %), (CuOTf)Ætoluene or Cu(OTf)2
0.0125 mmol, 5 mol %) and 4 A powdered molecular
˚
8
9
. For mechanistic aspects of the reaction, see: Morao, I.;
McNamara, J. P.; Hiller, I. H. J. Am. Chem. Soc. 2003,
sieves (50 mg) in chloroform (2.0 mL) was stirred at
room temperature for 1.5 h. Then, the reaction mixture
was cooled to 0 °C and treated with ethyl glyoxylate
1
25, 628–629.
. (a) DattaGupta, A.; Singh, V. K. Tetrahedron Lett. 1996,
7, 2633–2636; (b) Sekar, G.; DattaGupta, A.; Singh, V.
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(
0.25 mmol) followed by a-methylstyrene (0.375 mmol).
3
The resulting mixture was stirred for 3–8 h at the same
temperature. After the reaction was complete (monitor-
ing with TLC), most of the solvent was removed under
reduced pressure and the crude mixture was purified
by column chromatography to give the pure ene product
1
0. DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron
1994, 50, 13725–13730.
11. For the application of chiral ligand 4 in other enantio-
selective reactions, see: (a) Bernardi, L.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5772–5773;
(
Table 1).
(
b) Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am.
Chem. Soc. 2003, 125, 14768–14783; (c) Christensen, C.;
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Acknowledgements
2
223; (d) Lowenthal, R. E.; Masamune, S. Tetrahedron
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We thank the Department of Science and Technology,
India, for a research grant. A.B. thanks the Council of
Scientific and Industrial Research, New Delhi, for a
senior research fellowship.
1
2. For applications of chiral ligand 5 in other enantioselec-
tive reactions, see: (a) Saito, T.; Yamada, T.; Miyazaki, S.;
Otani, T. Tetrahedron Lett. 2004, 45, 9581–9584; (b)
Bandini, M.; Bernardi, F.; Bottoni, A.; Cozzi, P. G.;

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14. The enantiomeric excess in all the cases was determined by
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(
e) Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42,
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6