Development of a novel chiral spiro ligand bearing oxazoline

Article abstract of DOI:10.1016/j.tetasy.2004.09.037

The synthesis of bis(oxazoline) ligand 1 bearing a spiro skeleton is achieved via double ring-closing metathesis (RCM) of tetraene 2 and subsequent oxazoline ring formation using N-bromosuccinimide (NBS). The Cu-spiro bis(oxazoline) complexes prepared fro

Full text of DOI:10.1016/j.tetasy.2004.09.037

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3693–3697
Development of a novel chiral spiro ligand bearing oxazoline
Takahiro Kato, Kazuyoshi Marubayashi, Shinobu Takizawa and Hiroaki Sasai*
Department of Chemistry, The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki,
Osaka 567-0047, Japan
Received 6 August 2004; accepted 21 September 2004
Abstract—The synthesis of bis(oxazoline) ligand 1 bearing a spiro skeleton is achieved via double ring-closing metathesis (RCM) of
tetraene 2 and subsequent oxazoline ring formation using N-bromosuccinimide (NBS). The Cu-spiro bis(oxazoline) complexes pre-
pared from 1 and Cu(OTf)2 or Cu(OAc)2 act efficiently as chiral catalysts for promoting carbonyl-ene reactions or Henry reactions
with good enantiocontrol.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Over the past decade, a large number of chiral oxazoline
ligands have been prepared and successfully applied in a
variety of asymmetric reactions.3 The incorporation of
oxazoline heterocyclic units into a rigid spiro skeleton
would provide a new class of chiral ligands.4
The design of enantiomerically pure chiral ligands is one
of the most important challenges in the development of
asymmetric catalysts.1 Recently, our group reported the
first design and synthesis of chiral spiro ligands bearing
isoxazolines [spiro bis(isoxazoline) ligands; SPRIXs],2a–e
pyrazoles,2f and isoxazoles,2g as shown in Figure 1. The
rigidity of the spirocyclic framework of these ligands,
and of SPRIXs in particular, appears to reduce the con-
formational obscurity in the transition state and conse-
quently promote Pd(II)-mediated enantioselective
reactions such as the Wacker-type cyclization of alkenyl
alcohols2b and the carbonylation of alkenylamines in the
presence of carbon monoxide.2c
2. Results and discussion
The first step was to design a spiro bis(oxazoline) com-
pound with seven stereogenic centers (Scheme 1).
Among all the possible diastereomers of the spiro com-
pounds, only 1, which can be constructed by the reac-
tion of (M*,S*,S*)-3 with N-bromosuccinimide
(NBS),5 was expected to function as a bidentate ligand.
In fact, the result of molecular modeling for all diaster-
eomers on MOPAC (AM1) suggested that 1 has the
M
M
M
˚
shortest N–N atomic distance (2.74A) and the smallest
out-of-plane angle between the two C–N bonds (51.5ꢁ).
H
H
S
S
i-Pr
i-Pr
i-Pr
i-Pr
N
N
N
N
N
H
N N
O
N
H
O
O
O
(M,S,S)-i-Pr-SPRIX
spiro bis(pyrazole)
ligand
spiro bis(isoxazole)
ligand
Br
∗
Br
∗
∗
∗
O
∗
∗
O
∗
∗
N
&
N
Figure 1. Chiral spiro ligands bearing isoxazolines, pyrazoles, and
isoxazoles.
O
X
X
N
Ph
Ph
Ph
Spiro
Spiro
Skeleton
Bis(oxazoline) 1
Oxazoline
To investigate further the unique chirality of spiro lig-
ands in enantioselective reactions, we herein report the
first design and synthesis of spiro bis(oxazolines) 1 and
compare the ligand-acceleration effect of 1 with SPRIXs.
Scheme 1. Design of spiro bis(oxazoline) 1.
Our retrosynthetic strategy for spiro bis(oxazoline) 1 is
outlined in Scheme 2. In this strategy, the key com-
pound (M*,S*,S*)-3 is synthesized by ring-closing
metathesis (RCM)6 of tetraene (S*,S*)-2 prepared by
*
Corresponding author. Tel.: +81 6 6879 8465; fax: +81 6 6879
8469; e-mail: sasai@sanken.osaka-u.ac.jp
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.037

3694
T. Kato et al. / Tetrahedron: Asymmetry 15 (2004) 3693–3697
Double
RCM
M*
M
NBS
1
S*
S*
HN
S*
S*
∗
S
∗
t-Bu
N
N
t-Bu
Ph
NH HN
Ph
NH
Ph
Ph
S
O
O
O
O
O
O
(M*,S*,S*)-3
(S*,S*)-2
4
Scheme 2. Retro synthetic strategy for spiro bis(oxazoline) 1.
the stereoselective addition of vinyl metal reagents to
chiral t-butanesulfinyl imines 4.7
i) Swern oxidation
ii) (S)-8, Ti(OEt)4, THF
(Rs)-9
In order to construct the cyclization precursor 3 with the
(M*,S*,S*) configuration, (Rs,Rs)-4 was prepared as
follows (Scheme 3): diethyl 2,2-diallyl malonate 5 was
converted to the Weinreb amide 6 in 85% yield by the
reaction of MeONHMe with i-PrMgBr.8 After the
reduction of 6 by LiAlH4, the obtained mono-aldehyde
7 was used directly in the next imine formation. In the
presence of Ti(OEt)4, condensation of 7 with (R)-t-butyl
sulfinamine (R)-8 afforded (Rs)-9 in 55% yield. After the
oxidation of (Rs)-9, the resulting aldehyde was reacted
with (R)-8 to afford (Rs,Rs)-4 in 78% yield.9
2 steps in 79%
t-Bu
N
N
t-Bu
S
O
S
O
S*s
R*s
meso-4
4 eq
Li
+
meso-4
toluene, -78oC
74%
S*
S*
S*
R*
t-Bu
S*s
NH HN
t-Bu t-Bu
R*s
NH HN
t-Bu
S
S
S
S
S*s
R*s
O
O
O
O
(S*,R*,S*s,R*s)-10
(S*,S*,S*s,R*s)-10
(S*,S*,S*s,R*s)-10:(S*,R*,S*s,R*s)-10 = 8:1
Scheme 4. Diastereoselective 1,2-addition of vinyl lithium reagent to
meso-4.
(a)
(b)
EtO
OEt
NH2
H
EtO
N
OMe
(d)
O
O
OH
7
O
O
O
was treated with HCl (4.0M in dioxane) to cleave the
t-butyl sulfinimine moiety, with the resulting product re-
acted with benzoic acid chloride to afford the cyclization
precursor (S*,S*)-2 in 88% yield (Scheme 5).
5
6
O
S
(c)
t-Bu
OH
N
t-Bu
t-Bu
N
N
t-Bu
(R)-8
S
Rs
O
S
S
O
Rs
Rs
O
(Rs)-9
(Rs,Rs)-4
i) HCl (4.0 M in dioxane), MeOH
S*
NH HN
S*
ii) PhCOCl, CH2Cl2, Et3N
2 steps in 88%
Ph
Ph
Scheme 3. Synthesis of t-butanesulfinyl imine (Rs,Rs)-4. Reagents and
conditions: (a) MeONHMe–HCl, i-PrMgBr, THF, ꢁ20ꢁC, 85%; (b)
LiAlH4, THF; (c) 7, Ti(OEt)4, THF, 55% (two steps from 6); (d) (i)
Swern oxidation, (ii) (R)-8, Ti(OEt)4, THF, 78% (two steps from (Rs)-
9).
(S*,S*,S*s,R*s)-10
O
O
(S*,S*)-2
Scheme 5. Synthesis of cyclization precursor (R*,R*)-2.
Diastereoselective 1,2-addition of vinyl metal reagents
to (Rs,Rs)-4 was then examined. However, the diastereo-
selective 1,2-addition of vinyl metal reagents, such as
vinyl magnesium bromide or vinyl lithium, with or with-
out a Lewis acid to (Rs,Rs)-4 predominantly afforded
undesired adduct (S,R,Rs,Rs)-10 in low yields (ꢀ20%).
RCM of (S*,S*)-2 with Grubbsꢀs catalyst 116b pro-
ceeded to afford the desired spiro amide (M*,S*,S*)-3
(36%) and (M*,R*,R*)-3 (30%), together with a trace
amount of 12 (Scheme 6). Finally, the desired spiro
bis(oxazoline) ligand 1 was synthesized in 82% yield
via oxazoline ring formation promoted by NBS, as
shown in Scheme 6. This reaction proceeded with high
diastereoselectivity, with no other diastereomer being
observed.
Thus, meso-4 with an (S*s,R*s)-configuration was also
prepared using (Rs)-9 with (S)-8 in 79% yield according
to the method described for (Rs,Rs)-4. The obtained
meso-4 was then reacted with vinyl metal reagents.
Among the various conditions attempted, the use of
vinyl lithium (toluene solution) for meso-4 gave the
desired product (S*,S*,S*s,R*s)-10 together with
(S*,R*,S*s,R*s)-10 as an undesirable diastereomer in a
ratio of 8:1, as shown in Scheme 4. Diastereomer
(S*,S*,S*s,R*s)-10 and (S*,R*,S*s,R*s)-10 were separa-
ble by silica gel column chromatography (acetone/hex-
ane = 1:6). A solution of (S*,S*,S*s,R*s)-10 in MeOH
The coordinative ability of spiro bis(oxazoline) ligand 1
to transition metals was briefly examined by mixing 1
with metal salts such as CuCl2, Pd(OCOCF3)2, and
Pd(CH3CN)2Cl2 in CH2Cl2. In all cases, the mixture
of 1 and metal salts produced characteristic color
changes. In particular, all peaks in the nuclear magnetic
resonance (NMR) spectrum of the complex (1-
Pd(CH3CN)2Cl2; 1/1) were significantly shifted down-
field compared to the original spectrum. These results

T. Kato et al. / Tetrahedron: Asymmetry 15 (2004) 3693–3697
3695
MesN
NMes
Ru
PCy3
O
Cl
Cl
Ph
NH
Ph
∗
M*
M*
Grubbs's cat. 11
(S*,S*)-2
+
+
∗
HN
R*
NH
R*
∗
NH
∗
HN
∗
S*
NH
S*
toluene, 90 o
C
∗
Ph Ph
Ph
Ph
Ph
O
O
O
O
O
(M*,S*,S*)-3
(M*,R*,R*)-3
12
trace
36%
30%
Br
∗
Br
∗
∗
NBS
CH2Cl2
82%
∗
O
∗
(M*,S*,S*)-3
∗
∗
N
O
N
Ph
Ph
rac-1
Scheme 6. Synthesis of spiro bis(oxazoline) 1.
indicate the spontaneous formation of metal complexes
with ligand 1. X-ray analysis of a single crystal obtained
by recrystallization from a 1:1 mixture of ligand 1 with
PdCl2 in acetone–hexane revealed a PdCl2–1 complex
structure in which 1 acts as a bidentate ligand (Fig. 2).10
Enantiomerically pure 1 was readily obtained by separa-
tion using a chiral stationary phase column.11 Initially,
enantiomerically pure 1 was applied in the Pd(II)-medi-
ated enantioselective Wacker-type cyclization of the
alkenyl alcohol (Table 1).2b
In contrast to using Pd(II)–SPRIX and Pd(II)–17 (en-
tries 2 and 3),2e no cyclization product was detected when
the Pd–bis(oxazoline) complex was utilized (entries 1 and
4). This clearly shows that the isoxazoline moieties in
the ligand play an important role in promoting the
Figure 2. ORTEP drawing of PdCl2–( )-1 complex.
Table 1. Comparison of acceleration effects of isoxazoline and oxazoline ligands on asymmetric tandem cyclization
Pd(OCOCF3)2 (20 mol %)
Ligand (22 mol %)
H
O
O
OB
OB
z
15
16
+
OBz
p-benzoquinone (4 eq)
O
OBz
HO
CH2Cl2, rt
14
13
z
Entry
Ligand
Time (h)
Yield (%)a
Product ratio [ee (%)]
14
15
16
1
2b
(ꢁ)-1
50
8
Trace
73
—
57(93)
—
20(31)
—
23(48)
(M,S,S)-i-Pr–SPRIX
Et
Et
Et
Et
3
4
23
91
41
41
18
—
N
N
O
O
17
O
O
45
67
Trace
3426
—
—
N
N
t-Bu
t-Bu
None
18
5
66
8
a Total yield.
b The reaction at 0ꢁC for 85h gave 14 (65%, 95% ee), 15 (5%, 45% ee), and 16 (26%, 60% ee).

3696
T. Kato et al. / Tetrahedron: Asymmetry 15 (2004) 3693–3697
cyclization. The lack of catalytic activity when 1 and 1812
were applied in the above reaction may be attributable to
the strong Lewis basicity of the metal-coordinating oxazo-
lines in comparison with that for isoxazolines.2e
44, 5201; (e) Shinohara, T.; Wakita, K.; Arai, M. A.;
Arai, T.; Sasai, H. Heterocycles 2003, 59, 587; (f)
Takizawa, S.; Honda, Y.; Arai, M. A.; Kato, T.; Sasai,
H. Heterocycles 2003, 60, 2551; (g) Wakita, K.; Arai, M.
A.; Kato, T.; Shinohara, T.; Sasai, H. Heterocycles 2004,
62, 831.
Although the Pd(II)–1 complex did not promote the tan-
dem reaction from 13 to 14, the Cu(II)–1 complex cata-
lyzed both the carbonyl-ene reaction13 of a-methyl
styrene with ethyl glyoxylate, and the Henry reaction14
of nitromethane with p-nitrobenzaldehyde to afford the
corresponding products with moderate enantioselectiv-
ity (Scheme 7). These results indicate that spiro
bis(oxazoline) functions effectively as an asymmetric lig-
and. This ligand-acceleration ability is a promising fea-
ture that has proven to be useful in studies of other
catalytic asymmetric reactions.
3. Review of bis(oxazoline) ligands for asymmetric catalysis:
(a) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339; (b) Ghosh, A.
K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1; (c) Johnson, J. S.; Evans, D. A. Acc. Chem. Res.
2000, 33, 325; (d) McManus, H. A.; Guiry, P. J. Chem.
Rev. 2004, 104, 4151.
4. Several chiral ligands with spiro skeletons have been
reported (a) Chan, A. S. C.; Hu, W.-H.; Pai, C.-C.; Lau,
C.-P.; Jiang, Y.-Z.; Mi, A.-Q.; Yan, M.; Sun, J.; Lou,
R.-L.; Deng, J.-G. J. Am. Chem. Soc. 1997, 119, 9570; (b)
Tamura, N.; Takahashi, T.; Nakajima, M.; Hashimoto S.
Abstracts, 26th Symposium on Progress in Organic
Reactions and Syntheses, Osaka, Japan, November 20–
21, 2000; p 58; (c) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu,
S.-F.; Fan, B.-M.; Duan, H.-F.; Zhou, Q.-L. J. Am. Chem.
Soc. 2003, 125, 4404; (d) Kandula, S. V.; Puranik, V. G.;
Kumar, P. Tetrahedron Lett. 2003, 44, 5015; (e) Lait, S.
M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry
2004, 15, 155.
(-)-1 (12 mol %)
O
OH
Cu(OTf) (10 mol %)
2
H
OEt
+
OEt
Ph
o
Ph
CH Cl , 0 C, 30h
2
2
O
O
62%, 84% ee
(-)-1 (5.5 mol %)
5. (a) Goodman, L.; Winstein, S. J. Am. Chem. Soc. 1957, 79,
4788; (b) Baldwin, J. E.; Kelly, D. R.; Ziegler, C. B. J.
Chem. Soc., Chem. Commun. 1984, 133.
6. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413;
(b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953; (c) Bassindale, M. J.; Hamley, P.;
Leitner, A.; Harrity, J. P. A. Tetrahedron Lett. 1999, 40,
3247; (d) Martin, R.; Alcon, M.; Pericas, M. A.; Riera, A.
J. Org. Chem. 2002, 67, 6896.
OH
Cu(OAc) (5 mol %)
2
NO
2
p-NO -C H CHO + MeNO
2
2
6
4
p-NO -C H
6 4
2
EtOH, rt, 24h
98%, 65% ee
Scheme 7. Asymmetric reactions promoted by Cu(II)-spiro bis(oxaz-
oline) ligand 1.
3. Conclusion
7. (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman,
J. A. J. Am. Chem. Soc. 1998, 120, 8011; (b) Cogan, D. A.;
Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883; (c) Tang,
T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001,
66, 8772; (d) Plobeck, N.; Powell, D. Tetrahedron:
Asymmetry 2002, 13, 303; (e) Owens, T. D.; Souers, A.
J.; Ellman, J. A. J. Org. Chem. 2003, 68, 3.
In conclusion, novel spiro bis(oxazoline) 1 was synthe-
sized as a new class of bidentate ligand, and the coordi-
native ability of 1 for metal salts was confirmed by
NMR and X-ray crystallographic analysis.
8. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 5461.
Acknowledgements
9. The direct conversion of 5 to 4 via the corresponding
dialdehyde resulted in a low yield of 4.
10. Crystal data for PdCl2–( )-1 complex: monoclinic, space
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan and the Uehara
Memorial Foundation. We thank the technical staff of
the Materials Analysis Center of the Institute of Scien-
tific and Industrial Research (ISIR), Osaka University,
for technical assistance.
˚
˚
˚
group C2/c, a = 12.05(1) A, b = 14.87(1) A, c = 14.54(1) A,
˚
3
b = 112.43(6)ꢁ, V = 2408(3) A , Z = 4 , R = 0.037, Rw =
0.021.
11. HPLC conditions: Daicel Chiralpak AD (/ 2cm · 25cm),
i-PrOH/hexane = 1:29, 5.0mL/min, 31min [(M,R,R,R,
26
R,R,R)-1, ½aꢂD = ꢁ112.7 (c 0.69, CHCl3)], 41min
26
[(P,S,S,S,S,S,S)-1, ½aꢂD = +113.4( c 0.67, CHCl3)]. The
absolute configuration of 1 was determined by exciton CD
Cotton effects in CHCl3.
References
12. (a) Rush, S.; Reinmuth, A.; Risse, W. Macromolecules
1997, 30, 7375; (b) Moye-Sherman, D.; Welch, M. B.;
Reibenspies, J.; Burgess, K. Chem. Commun. 1998, 2377;
(c) Stavenger, R. A.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2001, 40, 3417.
13. Procedure for carbonyl-ene reaction: A mixture of ligand
(ꢁ)-1 (0.012mmol) and Cu(OTf)2 (0.006mmol) in CH2Cl2
(0.8mL) was stirred at 0ꢁC for 2h. To this solution was
added a-methyl styrene (0.20mmol) and ethyl glyoxylate
(1.2mmol). After stirring for a further 30h at 0ꢁC, the
reaction was quenched by the addition of water, and
extracted with CH2Cl2. The organic layer was dried over
MgSO4 and concentrated. The residue was purified by
1. (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Comprehensive Asymmetric Synthesis I–III; Springer:
Berlin, 1999; (b) Ojima, I., Ed. Catalytic Asymmetric
Synthesis, 2nd ed.; Wiley-VCH: New York, 2000; (c)
Kobayashi, Y., Ed. Latest Frontiers of Organic Synthesis;
Research Signpost, 2002.
2. (a) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1,
1795; (b) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J.
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T. Kato et al. / Tetrahedron: Asymmetry 15 (2004) 3693–3697
3697
silica gel column chromatography (ethyl acetate/hex-
ane = 1:8) to afford the product in 62% yield with 84%
ee. The enantiomeric excess of the products was deter-
mined by HPLC analysis using a chiral stationary phase
column (Daicel Chiralpak AS, hexane/i-PrOH = 9:1, flow
rate = 0.5mL/min).
at rt, the volatile components were removed under reduced
pressure and the residue was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:8) to afford the
product in 98% yield with 65% ee. The enantiomeric excess
of the products was determined by HPLC analysis using a
chiral stationary phase column (Daicel Chiralcel OD-H,
hexane/i-PrOH = 9:1, flow rate = 1.0mL/min). The prod-
uct was identical in all respects to the spectra reported by
Evans et al., Evans, D. A.; Seidel, D.; Rueping, M.; Lam,
H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc.
2003, 125, 12692.
14. Procedure for Henry reaction: A mixture of ligand (ꢁ)-1
(0.055mmol) and Cu(OAc)2ÆH2O (0.05mmol) in EtOH
(1.5mL) was stirred at rt for 1h. To the resulting clear blue
solution was added nitromethane (10mmol) and p-nitro-
benzaldehyde (1.0mmol). After stirring for a further 24h