Enantioselective glyoxylate-ene reaction using a novel spiro bis(isoxazoline) ligand in copper catalysis

Article abstract of DOI:10.1016/j.tetasy.2007.02.004

Novel chiral spiro bis(isoxazoline) ligands 3 and 4 are synthesized from an optically active olefin. The Cu(II)-spiro bis(isoxazoline) complex prepared in situ from Cu(OTf)₂ and 3 promoted the glyoxylate-ene reaction in high yield and moderate

Full text of DOI:10.1016/j.tetasy.2007.02.004

Tetrahedron: Asymmetry 18 (2007) 372–376
Enantioselective glyoxylate-ene reaction using a novel
spiro bis(isoxazoline) ligand in copper catalysis
Kazuhiko Wakita, Gan B. Bajracharya, Midori A. Arai, Shinobu Takizawa,
Takeyuki Suzuki and Hiroaki Sasai*
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
Received 21 December 2006; accepted 1 February 2007
Abstract—Novel chiral spiro bis(isoxazoline) ligands 3 and 4 are synthesized from an optically active olefin. The Cu(II)-spiro bis(isox-
azoline) complex prepared in situ from Cu(OTf)2 and 3 promoted the glyoxylate-ene reaction in high yield and moderate enantioselec-
tivity (up to 70%).
Ó 2007 Published by Elsevier Ltd.
5 mol % Cu(OTf)2
O
O
1. Introduction
6 mol % 3
H
+
*
OEt
OEt
MS 4Å
CH2Cl2, 0 oC
O
The search for novel chiral ligands is one of the most chal-
lenging tasks in asymmetric catalysis.1 The development of
chiral spiro ligands for asymmetric induction is particularly
interesting since the spiro skeleton has unique chirality and
displays unusual reactivity.2,3 For example, we reported a
novel chiral spiro bis(isoxazoline) ligand [SPRIX] 1 con-
taining a spiro[4.4]nonane skeleton (Fig. 1). These spiro
ligands promoted the Pd-catalyzed asymmetric Wacker-type
cyclization of alkenyl alcohols,2b intramolecular amino-
carbonylation of alkenyl amines and tosylamides,2c and
intramolecular cyclization of 2-alkynoates.2d Recently, we
reported the synthesis of chiral spiro bis(isoxazole) ligands
2.4a Herein, we report a new design and synthesis of chiral
spiro bis(isoxazoline) ligands 3 and 4 starting from enantio-
merically pure olefin derivative 11. The complex generated
from 3 and Cu(OTf)2 efficiently promoted the asymmetric
OH
5
6
7
up to 70% ee
Scheme 1. Cu(II)-Spiro bis(isoxazoline)-catalyzed glyoxylate-ene reaction.
glyoxylate-ene reaction of various olefins 5 with ethyl
glyoxylate 6 (Scheme 1).
The carbonyl-ene reaction is an important carbon–carbon
bond forming transformation.5 Yamamoto et al. reported
the first example of an asymmetric ene reaction of prochiral
aldehydes and alkenes catalyzed by chiral organoaluminum
reagents.6 Mikami and Nakai have reported a catalytic
enantioselective ene reaction with glyoxylate esters by
using a Ti–BINOL complex.7,8 Jørgensen9 and Evans10
explored the use of Cu(II)–bis(oxazoline) complexes for
enantioselective carbonyl-ene reactions; further, numerous
reports have been made about the use of bis(oxazoline) as a
ligand.11 However, to the best of our knowledge, bis(isox-
azoline) ligands have never been used in the carbonyl-ene
reactions.
H
H
H
H
H
H
H
R
R
R
R
R
R
N
N
O
NN
N
N
O
O
O
O
O
H
SPRIX 1
spiro bis(isoxazole) 2
spiro bis(isoxazoline) 3 and 4
This work
2. Results and discussion
Figure 1. Chiral spiro ligands.
We decided to start our study with the design of new spiro
bis(isoxazoline) ligands 3 and 4. The perceived conforma-
tional rigidity in these ligands is due to the inherent
*
Corresponding author. Tel.: +81 6 6879 8465; fax: +81 6 6879 8469;
e-mail addresses: sasai@sanken.osaka-u.ac.jp; hsasai@mac.com
0957-4166/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.02.004

K. Wakita et al. / Tetrahedron: Asymmetry 18 (2007) 372–376
373
P
M
H
H
H
H
CH2CH2I
R
R
H
H
H
H
EtO
OEt
R
R
R
R
+
+
R
R
R
R
H
H
R
O
R
O
O
R
O
R
NN
NN
intramolecular double
nitrile oxide cycloaddition
O
H
O
H
H
H
N
N
HO
OH
3
4
8
9
10
N
θ
OAc
CH(CO2Me)2
C
C
N
Trost's
asymmetric allylic alkylation
θ = out-of-plane angle
12
11
Scheme 2. Synthetic strategy for novel spiro bis(isoxazoline) ligands.
fused-ring system. It was envisioned that these ligands
could be prepared using the intramolecular double nitrile
oxide cycloaddition of 8.12 The molecular modeling calcu-
lation using MM2 showed that diastereomer 3 has a short
followed by reflux overnight to produce the desired (R)-
3-(2-iodoethyl)cyclohexene 9 in 87% yield from 13 in three
steps.
˚
N–N atomic distance (3.04 A) and a small out-of-plane
The synthesis of the target spiro bis(isoxazoline) ligands 3
and 4 was completed as shown in Scheme 4. Compound
10 was treated with 2.2 equiv of NaH and 2.2 equiv of 9 suc-
cessively to obtain diethyl (R,R)-2,2-bis(2-cyclohex-2-enyl-
ethyl)malonate 15 in quantitative yield. Malonate 15 was
reduced with LiAlH4 to obtain diol 16 in 84% yield. After
Swern oxidation of 16, the resulting dialdehyde was treated
with NH2OH–HCl in pyridine at 0 °C without further puri-
fication. The reaction mixture was then stirred at room tem-
perature for 6 days to produce dioxime 8 in 86% yield over
two steps.14 The treatment of dioxime 8, which had an
(R,R)-configuration, with 5% aq NaOCl produced 70%
yield of the desired spiro bis(isoxazoline) ligands via the
intramolecular double nitrile oxide cycloaddition. The two
diastereomers 3 and 4 were separated by silica gel column
chromatography (hexane/ethyl acetate = 5/1 to 1/1) in a
ratio of 12:88. It is important to note that these chiral spiro
bis(isoxazoline) ligands 3 and 4 could be obtained in enan-
tiomerically pure forms simply by column chromatographic
separation, and the other diastereomers were not detected.
As shown in Scheme 2, the configuration of the spiro
chiral center (P or M) was tentatively assigned by NMR
angle between the two C@N bonds (59.8°) as compared
to diastereomer 4, which showed an N–N atomic distance
and out-of-plane angle between the two C@N bonds of
˚
4.09 A and 89.5°, respectively. As shown in the retrosyn-
thetic analysis (Scheme 2), the key intermediate 8 can be
prepared by the alkylation of diethyl malonate 10 with a
chiral alkylating reagent (R)-3-(2-iodoethyl)cyclohexene 9;
this reagent can be easily synthesized through the asymmet-
ric allylic alkylation of cyclohex-2-enyl acetate 12.13
In order to prepare the cyclization precursor 8, beginning,
iodide 9 was prepared as shown in Scheme 3. The asymmet-
ric allylic alkylation of 12 produced 11 with 95% ee as
reported by Trost.13 Malonate 11 was treated with an
aqueous solution of NaCl (1.1 equiv) and DMSO to obtain
methyl (ꢀ)-(cyclohex-2-enyl)acetate (13) in 82% yield.
Reduction with LiAlH4 produced alcohol 14, which was
used directly in the subsequent steps without purification.
After mesylation, the crude mesylate was added dropwise
to a solution of NaI in acetone at room temperature then
OAc
CH(CO2Me)2
CH2CO2Me
(a)
(b)
(c)
CH CH I
2
2
EtO
OEt
(a)
+
quant.
O
O
EtO
OEt
12
11
13
74%, 95% ee
82%
O
O
9
10
15
O
CH2CH2OH
CH2CH2I
R
R
(d, e)
NH PPh2
NH PPh2
(b)
84%
(c, d)
86% (2 steps)
H
H
N
N
OH OH
16
14
9
HO
OH
O
87% (3 steps)
8
(e)
70%, >99% ee
3
+
4
(1R,2R)-Trost ligand
(12:88)
Scheme 3. Synthesis of (R)-3-(2-iodoethyl)cyclohexene 9. Reagents and
conditions: (a) dimethyl malonate (3.1 equiv), Cs2CO3 (3 equiv), [Pd(g3-
C3H5)Cl]2 (3 mol %), (1R,2R)-Trost ligand (9 mol %), CH2Cl2, 40 °C; (b)
NaCl, H2O, DMSO, 160 °C; (c) LiAlH4, THF, rt; (d) MsCl, NEt3,
CH2Cl2, 0 °C; (e) NaI, acetone, reflux.
Scheme 4. Synthesis of the target spiro bis(isoxazoline) ligands. Reagents
and conditions: (a) NaH, DMSO, rt; (b) LiAlH4, THF, rt; (c) (COCl)2,
CH2Cl2, DMSO, ꢀ78 °C, NEt3; (d) NH2OH–HCl, pyridine, 0 °C then rt;
(e) 5% aq NaOCl, CH2Cl2, rt.

374
K. Wakita et al. / Tetrahedron: Asymmetry 18 (2007) 372–376
analysis.15,16 Ligand 3 is stable in air, and to moisture, and
even under acidic, basic, and oxidative conditions at room
temperature.17
Table 2. Cu(OTf)2-3-catalyzed enantioselective glyoxylate-ene reactions
between ethyl glyoxylate and various olefinsa
Entry Olefin
Product
Yieldb eec
(%)
(%)
After obtaining the new spiro ligands, in order to elucidate
their potential as chiral ligands, we examined the asymmet-
ric glyoxylate-ene reaction of a-methyl styrene 5a with ethyl
glyoxylate 6 and compared the catalyst activity with our
previously synthesized chiral spiro ligands.18 The results
are shown in Table 1. We were pleased to find that the
glyoxylate-ene reaction in the presence of 10 mol % of
Cu(OTf)2 and 12 mol % of ligand 3 in CH2Cl2 at 0 °C
provided the desired product ethyl 2-hydroxy-4-phenyl-4-
pentenoate 7a in 47% yield and 66% ee (entry 2).19 By com-
paring entries 1 and 2, it can be seen that spiro ligand 3
accelerated the glyoxylate-ene reaction significantly. As
revealed from the MM2 calculations (vide supra), it was
not surprising that the use of ligand 4 did not show
any enantioselectivity (entry 3). Interestingly, except for i-
Pr-SPRIX 1b (R = i-Pr), the catalysts formed from ligands
1a (R = H), 2a (R = H), and 2b (R = Me) gave lower ees
(entries 4–7). The loading of the catalyst can be reduced
to 5 mol % without losing enantioselectivity (entry 8). The
counterion effect was examined using the catalyst prepared
by mixing CuBr2 (5 mol %), AgSbF6 (10 mol %), and ligand
3 (6 mol %) in CH2Cl2.10 This catalyst showed a higher
reactivity but decreased the enantioselectivity (entry 9).
Gratifyingly, the use of molecular sieves in the presence of
5 mol % of Cu(OTf)2 and 6 mol % of ligand 3 improved
both the yield and ee up to 70% (entry 10). No remarkable
effect on the enantioselectivity was observed when the reac-
tions were run at ꢀ5 and ꢀ10 °C. The reaction conducted at
0 °C was found to be optimal in terms of both yield and ee.
Cl
Cl
O
1
23
67
*
OEt
OH
7b
5b
MeO
MeO
O
*
2
3
70
48
34
65
OEt
OH
5c
5d
7c
O
*
OEt
OH
7d
O
*
OEt
4
>99
64
OH
5e
7e
a Reaction conditions: olefin (0.20 mmol), ethyl glyoxylate (6 equiv),
Cu(OTf)2 (5 mol %), ligand 3 (6 mol %), MS 4 A (100 mg), CH2Cl2,
˚
0 °C, 30 h.
b Isolated yield.
c Determined by HPLC analysis using a chiral stationary phase column
(Daicel Chiralpak AS, hexane/i-PrOH = 10/1, flow rate = 0.5 mL/min).
in Table 2.20 The ene reaction of 4-chloro-a-methylstyrene
5b with 6 produced the corresponding product 7b with 67%
ee, albeit with a poor yield (entry 1). An electron-donating
substituent at the para-position as in substrate 5c reduced
the enantioselectivity but provided a good chemical yield
(70%) (entry 2). The bulky naphthalene substituent in 5d
was well tolerated (entry 3). The olefin substrate can also
be adopted into cyclic systems; quantitative yield with
moderate ee (64%) was obtained by using 5e (entry 4).
The reaction of 6 with other olefins has been investigated
under optimized conditions and the results are summarized
Table 1. Screening of chiral spiro ligands for asymmetric glyoxylate-ene
reaction
10 mol % Cu(OTf)
12 mol % ligand
O
2
O
3. Conclusion
H
+
*
OEt
OEt
o
CH Cl , 0 C, 30 h
2
2
O
OH
In conclusion, we have designed and synthesized a new
class of chiral spiro bis(isoxazoline) ligands 3 and 4 bearing
seven stereocenters. Optical resolutions were not required
to obtain these chiral spiro ligands, which could simply
be obtained by a normal column chromatography in enan-
tiomerically pure forms; this shows the advantage of the
methodology used to prepare these chiral ligands. We have
demonstrated the first example of a bis(isoxazoline) ligand
accelerated copper-catalyzed enantioselective glyoxylate-
ene reaction providing the chiral alkenoates with up to
70% ee. Further investigations to identify the active cata-
lytic species and applications of the spiro ligands in asym-
metric catalysis are in progress.
5a
6 (6 equiv.)
7a
Entry
Ligand
Yielda (%)
% ee (configuration)b
1
2
3
4
5
6
7
8c
9d
10c,e
None
30
47
35
58
45
60
58
55
70
83
—
66 (S)
1
1
51
1
14
68 (S)
29 (S)
70 (S)
3
4
1a (R = H)
1b (R = i-Pr)
2a (R = H)
2b (R = Me)
3
3
3
a Isolated yield.
b Determined by HPLC analysis using a chiral stationary phase column
(Daicel Chiralpak AS, hexane/i-PrOH = 10/1, flow rate = 0.5 mL/min).
c Catalyst loading: 5 mol % of Cu(OTf)2 and 6 mol % of ligand 3.
d The copper catalyst was prepared by pre-mixing CuBr2 (5 mol %),
AgSbF6 (10 mol %) and 3 (6 mol %).
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
e
˚
In the presence of MS 4 A.

K. Wakita et al. / Tetrahedron: Asymmetry 18 (2007) 372–376
375
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26
ane–Et2O). ½aꢁD ¼ ꢀ90:0 (c 1.07, CHCl3). 1H NMR
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robi[3H-naphtho[1,8-cd]isoxazole] 3: Mp 203 °C (decomp.).
21
1
½aꢁD ¼ þ95:7 (c 0.22, CHCl3). H NMR (270 MHz, CD2Cl2)
d 1.00–1.23 (m, 6H), 1.38–1.60 (m, 8H), 1.72–1.91 (m, 6H),
2.06–2.09 (m, 2H), 3.16 (t, J = 8.8 Hz, 2H), 4.51 (ddd,
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315.2092. Analytical data for (M,5aR,5a0R,8aR,8a0R,
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decahydro-3,30-spirobi[3H-naphtho[1,8-cd]isoxazole]
4:
24
1
mp 123–125 °C (EtOH). ½aꢁD ¼ þ40:4 (c 1.07, CHCl3). H
NMR (270 MHz, CD2Cl2) d 1.17–1.30 (m, 6H), 1.40–1.63
(m, 8H), 1.73–1.80 (m, 2H), 1.96–2.12 (m, 4H), 2.43–2.55
(m, 2H), 3.18 (dd, J = 8.9, 6.7 Hz, 2H), 4.52–4.61 (m, 2H).
13C NMR (68 MHz, CD2Cl2) d 19.4, 25.8, 27.3, 27.5, 32.4,
32.7, 39.9, 48.1, 78.1, 160.6. IR (neat) 2924, 2860, 2341,
1450, 1353, 899, 845, 729 cmꢀ1. FAB-LRMS m/z: [M+H]+
315. Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.33, N,
8.91. Found: C, 72.51; H, 8.44; N, 9.02.
8. We have also reported polymer supported multicomponent
catalysts for carbonyl-ene reactions, see: (a) Takizawa, S.;
Somei, H.; Jayaprakash, D.; Sasai, H. Angew. Chem., Int. Ed.

376
K. Wakita et al. / Tetrahedron: Asymmetry 18 (2007) 372–376
16. The assignment of the absolute configuration of ligands 3 and
4 was based on the different behavior of these ligands to the
Pd salt. Thus, mixing of equimolar (P)-3 and Pd(OCOCF3)2
showed a symmetric 1H NMR spectrum (CD2Cl2) and
significant low field shifts of the methyne protons, which
indicated an efficient complexation due to the structural
geometry, while (M)-4 gave only insoluble material.
17. Acidic conditions: MeOH–aqueous 1 M HCl (1:1) at rt for
24 h. Basic conditions: MeOH–aqueous 1 M NaOH (1:1) at rt
for 24 h. Oxidative conditions: MeOH–35% aqueous H2O2
(1:1) at rt for 24 h.
19. The absolute configuration of the major enantiomer of 7a was
determined to be S by comparing the HPLC profile with the
values reported in Ref. 7d.
20. The general procedure for the glyoxylate-ene reaction: A
mixture of ligand
(0.010 mmol, 5 mol %), and MS 4 A (100 mg) in CH2Cl2
3 (0.012 mmol, 6 mol %), Cu(OTf)2
˚
(0.56 mL) was stirred at 0 °C for 2 h. To this solution, olefin 5
in 1 M CH2Cl2 solution (0.20 mL, 0.20 mmol) and
6
(0.24 mL, 1.2 mmol, 50% toluene solution) were added. After
stirring for 30 h at 0 °C, the reaction was quenched by the
addition of water, and extracted with ether. The organic layer
was dried over Na2SO4 and concentrated. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate = 5/1) to give product 7. The enantiomeric excess of
the products was determined by HPLC analysis using chiral
stationary phase column (Daicel Chiralpak AS, hexane/
i-PrOH = 10/1, flow rate = 0.5 mL/min).
18. The Pd-catalyzed asymmetric tandem cyclization of alkenyl
alcohol 17 using newly synthesized ligand 3 gave unsatisfac-
tory results. See Refs. 2b, 4a and 11h.
Pd(OCOCF3)2 (20 mol %)
H
3 (22 mol %)
OBz
p-benzoquinone (4 equiv.)
CH2Cl2, rt
O
HO
OBz
17
18
48% yield, 20% ee