Asymmetric synthesis of chiral spiro bis(isoxazoline) and spiro (isoxazole-isoxazoline) ligands

Article abstract of DOI:10.1016/j.tetasy.2010.03.006

Asymmetric synthesis of novel chiral ligands, bis(isoxazoline) on a spiro[4.4]nonane scaffold and isoxazole-isoxazoline on a spiro[4.5]decane scaffold, has been achieved by utilizing an enantiomerically pure alcohol as the starting material.

Full text of DOI:10.1016/j.tetasy.2010.03.006

Tetrahedron: Asymmetry 21 (2010) 379–381
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of chiral spiro bis(isoxazoline) and spiro
(isoxazole–isoxazoline) ligands
*
Kazuhiro Takenaka, Toyohiro Nagano, Shinobu Takizawa, Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric synthesis of novel chiral ligands, bis(isoxazoline) on a spiro[4.4]nonane scaffold and isoxaz-
ole–isoxazoline on a spiro[4.5]decane scaffold, has been achieved by utilizing an enantiomerically pure
alcohol as the starting material.
Received 29 September 2009
Accepted 9 December 2009
Available online 8 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
spiro[5.5]undecane
spiro[4.4]nonane
spiro[4.5]decane
1. Introduction
H
H
H
H
H
A series of chiral ligands based on a spiro framework has been
attracting widespread interest in catalytic asymmetric synthesis.1,2
We have demonstrated the utility of spiro ligands in enantioselec-
tive reactions where the known chiral ligands have not provided
any successful results. For example, spiro bis(isoxazoline) ligands
(SPRIXs) 13 and spiro (isoxazole–isoxazoline) hybrid ligands 24
promoted Pd-catalyzed asymmetric Wacker-type cyclizations.
We have recently realized the first enantioselective reaction via a
PdII/PdIV catalytic cycle using a Pd–SPRIX complex.5
H
H
H
H
H
N
N
N N
O
O
N
N
H
O
H
H
H
H
H
O
O
O
3
4
5
2. Results and discussion
Retrosynthetic analysis (Scheme 1) suggested that the chiral
bis(isoxazoline) ligand 4 could be obtained via an intramolecular
double nitrile oxide cycloaddition of dioxime 6. The precursor 6
was envisioned to arise from the alkylation of malonate with
(S)-cyclohex-2-enylmethanol 7. We intended to make use of the
asymmetric allylic alkylation of methyl cyclohex-2-enyl carbonate
8 developed by Trost for the preparation of 7.8 Scheme 2 depicts
the preparation of the key alkenyl alcohol 7.9 Enantiomerically
pure (S)-3-(nitromethyl)cyclohex-1-ene 9 was obtained from 8
according to the literature.8 The nitromethyl functionality of 9
was then converted into the hydroxymethyl group via the corre-
sponding carboxylic acid 10, leading to the enantiomerically pure
7 in 60% overall yield. The preparation of the target spiro bis(isox-
azoline) ligand 4 was completed as shown in Scheme 3. To install
the chiral olefinic appendage of 7, we utilized the Mitsunobu
H
H
H
R1
R2
R
R
R
R
R3
N N
N
N
O
O
O
O
spiro bis(isoxazoline)
spiro isoxazole–isoxazoline
1
2
(R)-SPRIX
As a result, the development of efficient synthetic methods for
chiral spiro ligands is an important task in asymmetric catalysis.6
The resolution of racemates through fractional crystallization or
chromatography is generally required for obtaining spiro ligands
in enantiomerically pure form. The elimination of such a tedious
operation would provide a simplified and timesaving protocol for
their preparation. Thus, we have succeeded in the asymmetric syn-
thesis of spiro bis(isoxazoline) ligand 3 containing a spiro[5.5]
undecane skeleton.7 As a new entry into the chiral spiro ligand
family, bis(isoxazoline) 4 and isoxazole–isoxazoline 5 having a
spiro[4.4]nonane and a spiro[4.5]decane skeleton, respectively,
were designed. Herein, we report the preparation of new chiral spiro
ligands 4 and 5 by utilizingan enantiomerically pure alkenyl alcohol,
for which no resolution is necessary.
OCO2Me
OH
H
H
4
7
+
8
N
N
RO
OR
HO
OH
6
O
O
* Corresponding author. Tel.: +81 6 6879 8465; fax: +81 6 6879 8469.
E-mail address: sasai@sanken.osaka-u.ac.jp (H. Sasai).
Scheme 1. Retrosynthetic analysis of spiro bis(isoxazoline) ligand 4.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.006

380
K. Takenaka et al. / Tetrahedron: Asymmetry 21 (2010) 379–381
a
O
>99% ee
OCO2Me
8
87%
NH PPh2
NH PPh2
NO2
9
c
b
O
O
7
87%
79%
OH
10
(1R,2R)-Trost ligand
Scheme 2. Synthesis of (S)-cyclohex-2-enylmethanol 7. Reagents and conditions:
(a) Pd2(dba)3ꢀCHCl3 (3 mol %), (1R,2R)-Trost ligand (8 mol %), CH3NO2 (8 equiv),
Bu4NCl (1.1 equiv), N,O-bis(trimethylsilyl)-acetamide (1.1 equiv), CH2Cl2, rt, 12 h;
(b) NaNO2 (4 equiv), AcOH (10 equiv), DMSO, 40 °C, 10 h; (c) LiAlH4 (1.5 equiv),
Et2O, 0 °C, 3 h.
Figure 1. ORTEP drawing of 4. The hydrogen atoms except for those at the
bridgehead positions are omitted for clarity. Selected distance: N. . .N = 3.263 Å.
Mitsunobu conditions, followed by reduction with LiAlH4, furnished
diol 15 in 46% yield over three steps. After Swern oxidation of 15, the
resultingdialdehydewastreatedwithNH2OHꢀHClinpyridinetogive
dioxime 16 (66% over two steps). Vigorous stirring of a CH2Cl2 solu-
tion of 16 with an aqueous NaOCl at room temperature afforded a
77% yield of a mixture of 5 and 50, with a diastereomeric ratio of
61:39.12 The enantiomerically pure hybrid ligand 5 was isolated by
column chromatography on silica gel and its structure was fully
characterized by NMR, MS, and X-ray analysis (Fig. 2).16,17
reaction with bis(2,2,2-trifluoroethyl) malonate 11.10 Thus, the
reaction of 11 with 7 in the presence of PPh3 and 1,10-(azodicar-
bonyl)dipiperidine (ADDP) was conducted to produce the alkylated
malonate 12,11 which was reduced to diol 13 without isolation
(66% over two steps). Swern oxidation of 13 and subsequent treat-
ment with NH2OHꢀHCl in pyridine afforded the chiral dioxime 6 in
71% yield (two steps). The following intramolecular double nitrile
oxide cycloaddition of 6 proceeded smoothly to give a 71:29 dia-
stereomeric mixture of 4 and 40 in 88% combined yield.12 Although
the 1,3-dipolar cycloaddition might theoretically take place on
either face of the double bond, only the cis-fused octahydroinde-
no[1,7-cd]isoxazole rings were constructed in this intramolecular
cyclization.13 Consequently, no other diastereomers including
trans-fused products were detected. It should also be noted that
the diastereomeric ratio was remarkably improved upon; com-
pared to that of ligand 3 [3 (P-form):30 (M-form) = 12:88].7 Both
the products 4 and 40 were readily obtained in enantiomerically
pure forms by simple chromatographic purification.14 The isolated
ligand 4 was identified by 1H and 13C NMR, 1H–1H COSY, and ESI-
MS. The relative and absolute configuration of 4 was unequivocally
established by X-ray analysis (Fig. 1).15
H
b, c
a
11
F3CH2CO
OCH2CF3
46%
(3 steps)
O
O
14
H
H
d, e
H
H
66%
(2 steps)
N
N
HO
OH
HO
OH
15
16
H
H
S
R
R
R
f
H
R
H
+
:
R
R
R
77%
N N
N N
H
H
O
O
H
O
H
O
a
5
5'
39)
F3CH2CO
OCH2CF3
F3CH2CO
OCH2CF3
(61
O
O
O
O
11
12
Scheme 4. Synthesis of the chiral spiro (isoxazole–isoxazoline) hybrid ligand 5.
Reagents and conditions: (a) 4-pentyn-1-ol (1.1 equiv), PPh3 (1.5 equiv), ADDP
(1.5 equiv), toluene, rt, 17 h; (b) 7 (1.2 equiv), PPh3 (2 equiv), ADDP (2 equiv),
toluene, 50 °C, 18 h; (c) LiAlH4 (1.8 equiv), THF, rt, 10 h; (d) (COCl)2 (3.8 equiv),
DMSO (5.2 equiv), CH2Cl2, ꢁ78 °C, 30 min, then Et3N (9 equiv), rt, 1.5 h; (e)
NH2OHꢀHCl (16 equiv), pyridine, 50 °C, 7 d; (f) aq NaOCl, CH2Cl2, rt, 37 h.
b
c, d
6
66%
71%
(2 steps)
(2 steps)
HO
OH
13
H
R
H
H
H
M
P
R
R
R
e
H
H
H
H
+
:
R
R
R
R
R
R
R
R
88%
N
N
N
N
H
H
H
H
O
O
O
O
4
4'
(71
29)
Scheme 3. Synthesis of the chiral bis(isoxazoline) ligand 4. Reagents and condi-
tions: (a) 7 (2.5 equiv), PPh3 (4.3 equiv), ADDP (4.6 equiv), toluene, 50 °C, 15 h; (b)
LiAlH4 (1.8 equiv), THF, rt, 7 h; (c) (COCl)2 (3.8 equiv), DMSO (5.2 equiv), CH2Cl2,
ꢁ78 °C, 1 h, then Et3N (9 equiv), rt, 1.5 h; (d) NH2OHꢀHCl (19 equiv), pyridine, 50 °C,
9 d; (e) aq NaOCl, CH2Cl2, rt, 37 h.
Figure 2. ORTEP drawing of 5. The hydrogen atoms except for those at the
bridgehead positions are omitted for clarity. Selected distance: N. . .N = 3.587 Å.
The enantiomerically pure spiro (isoxazole–isoxazoline) hybrid
ligand 5 was also prepared in a similar manner to that described
for the bis(isoxazoline) 4 (Scheme 4). Thus, the introduction of an al-
kyne and the chiral olefin components into the malonate 11 under
As a preliminary experiment to investigate the utility of the novel
chiral ligands 4 and 5, we performed a Pd-catalyzed enantioselective
oxidative cyclization of an alkenyl alcohol. A mixture of 2-benzyl-

K. Takenaka et al. / Tetrahedron: Asymmetry 21 (2010) 379–381
381
3. (a) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795; (b) Arai, M. A.; Kuraishi,
M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907; (c) Shinohara, T.; Arai, M.
A.; Wakita, K.; Arai, T.; Sasai, H. Tetrahedron Lett. 2003, 44, 711; (d) Muthiah, C.;
Arai, M. A.; Shinohara, T.; Arai, T.; Takizawa, S.; Sasai, H. Tetrahedron Lett. 2003,
44, 5201; (e) Bajracharya, G. B.; Koranne, P. S.; Tsujihara, T.; Takizawa, S.;
Onitsuka, K.; Sasai, H. Synlett 2009, 310; (3f) Tsujihara, T.; Shinohara, T.;
Takenaka, K.; Takizawa, S.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Org. Chem.
2009, 74, 9274.
4. Koranne, P. S.; Tsujihara, T.; Arai, M. A.; Bajracharya, G. B.; Suzuki, T.; Onitsuka,
K.; Sasai, H. Tetrahedron: Asymmetry 2007, 18, 919.
5. Tsujihara, T.; Takenaka, K.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Am. Chem.
Soc. 2009, 131, 3452.
6. (a) Takizawa, S.; Yogo, J.; Tsujihara, T.; Onitsuka, K.; Sasai, H. J. Organomet.
Chem. 2007, 692, 495; (b) Takenaka, K.; Nakatsuka, S.; Tsujihara, T.; Koranne, P.
S.; Sasai, H. Tetrahedron: Asymmetry 2008, 19, 2492.
7. Wakita, K.; Bajracharya, G. B.; Arai, M. A.; Takizawa, S.; Suzuki, T.; Sasai, H.
Tetrahedron: Asymmetry 2007, 18, 372.
8. Trost, B. M.; Surivet, J.-P. Angew. Chem., Int. Ed. 2000, 39, 3122.
9. Asymmetric synthesis of the five-membered alkenyl alcohol was reported. See:
Zanoni, G.; Porta, A.; Brunoldi, E.; Vidari, G. J. Org. Chem. 2006, 71, 8459.
10. Takacs, J. M.; Xu, Z.; Jiang, X.-t.; Leonov, A. P.; Theriot, G. C. Org. Lett. 2002, 4,
3843.
11. We could not obtain the desired alkylated product through the conventional
method using malonate anion and an alkyl halide due to the instability of 3-
(bromomethyl)cyclohex-1-ene. The instability of the analogous alkyl bromide,
see: Bartley, D. M.; Coward, J. K. J. Org. Chem. 2005, 70, 6757.
2-(3-methyl-2-butenyl)-1,3-propanediol17and4 equivof p-benzo-
quinone in CH2Cl2 was stirred at 15 °C for 48 h in the presence of
10 mol % of Pd(OCOCF3)2 and 12 mol % of chiral ligand (Scheme 5).18
A Pd catalyst bearing ligand 4 promoted the reaction to give the de-
sired 6-endo cyclized product 18 in 49% yield with 19% ee. The spiro
(isoxazole–isoxazoline) hybrid ligand 5 gave a better result: 18 was
obtained in 94% yield and 51% ee. It was previously found that under
identical conditions, ligands 1 (R = i-Pr)19 and 2 (R1 = R2 = i-Pr,
R3 = 2-biphenyl)6b gave 18 in 49% yield with 91% ee and 69% yield
with 82% ee, respectively. Presumably, the i-Pr substituents on the
isoxazoline ring of 1 and 2 contribute to the high selectivity.
Although the trimethylene moieties fused to the isoxazoline rings
of 4 and 5 were insufficient to create effective asymmetric environ-
ments in this reaction, the hybrid ligand 5 significantly enhanced the
catalyticactivity. Hence, the introductionof a bulky substituentonto
the bridgehead position adjacent to the oxygen atom would lead to
more useful chiral ligands that are expected to display excellent
catalytic activity and enantioselectivity.
12. The diastereomeric ratio was determined by the 1H NMR of the crude product.
13. (a) Wollenberg, R. H.; Goldstein, J. E. Synthesis 1980, 757; (b) Tsantali, G. G.;
Dimtsas, J.; Tsoleridis, C. A.; Takakis, I. M. Eur. J. Org. Chem. 2007, 258.
14. Synthetic procedure of ligand 4: To a solution of 6 (218 mg, 0.750 mmol) in
CH2Cl2 (14 mL) was added aqueous NaOCl (>5.0% chlorine, 2.4 mL) at 0 °C,
which was stirred for 37 h at room temperature. After dilution with H2O, the
mixture was extracted with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by silica gel
column chromatography (hexane/EtOAc = 2/1) to give 4 (117 mg, 62%) and 40
Pd(OCOCF3)2
ligand
Bn
OH
Bn
OH
p-benzoquinone
HO
O
CH2Cl2, 15 °C, 48 h
17
18
4
ligand : 49% yield, 19% ee
ligand : 94% yield, 51% ee
5
(49 mg, 26%) as a white solid. Analytical data for ligand 4: ½a D20
¼ ꢁ120 (c 0.44,
ꢂ
CHCl3). Mp: 238–240 °C. 1H NMR (CDCl3): d 0.86–0.97 (m, 2H), 1.43–1.60 (m,
4H), 1.64–1.78 (m, 4H), 1.95–2.02 (m, 2H), 2.23–2.31 (m, 2H), 2.45–2.54 (m,
4H), 3.81 (t, J = 8.6 Hz, 2H), 4.74 (virtual q, J = 8.6 Hz, 2H). 13C NMR (CDCl3): d
20.3, 27.1, 28.5, 33.9, 38.3, 53.1, 56.9, 79.5 175.4. ESI-HRMS. Calcd for
C17H22N2O2Na: 309.1579. Found: 309.1589.
Scheme 5. Pd-catalyzed enantioselective oxidative cyclization of 17. The ratio of 17
(mol)/Pd (mol)/ligand (mol)/p-benzoquinone (mol)/CH2Cl2 (L) = 1.0/0.1/0.12/4.0/4.0.
15. Single crystals were obtained from a solution of the enantiopure 4 in CH2Cl2/i-
PrOH by slow evaporation. Crystal data: space group P212121 (#19),
a = 10.9552(19) Å, b = 11.820(2) Å, c = 10.754(2) Å, V = 1392.5(4) Å3, Z = 4,
3. Conclusion
Dcalcd = 1.366 g/cm3, R = 0.0568 (I > 2.00
r(I)), Rw = 0.1157 (I > 2.00r(I)),
In conclusion, we have accomplished the asymmetric synthesis
of novel spiro bis(isoxazoline) and spiro (isoxazole–isoxazoline) li-
gands, in which an enantiomerically pure alkenyl alcohol is utilized
as the key building block. No tedious resolution was required for
the preparation of these chiral spiro ligands, which could be ob-
tained in an enantiomerically pure form simply by column chro-
matography. Further studies on the utility of these new chiral
spiro ligands and their modifications are currently in progress
and will be reported in due course.
GOF = 2.149. Crystallographic data (excluding structure factors) for the
structure of 4 have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 745562 and can be
obtained free of charge via the Internet at http://www.ccdc.cam.ac.uk/
data_request/cif.
16. Synthetic procedure of ligand 5: To a solution of 16 (171 mg, 0.653 mmol) in
CH2Cl2 (13 mL) was added aqueous NaOCl (>5.0% chlorine, 1.3 mL) at 0 °C,
which was stirred for 37 h at room temperature. After dilution with H2O, the
mixture was extracted with CH2Cl2. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by silica gel
column chromatography (hexane/EtOAc = 3/1) to give 5 (78 mg, 60%) and 50
(52 mg, 40%) as a white solid. Analytical data for ligand 5: ½a D24
¼ ꢁ92:5 (c 0.43,
ꢂ
CHCl3). Mp: 165–166 °C. 1H NMR (CDCl3): d 0.94–1.05 (m, 1H), 1.37–1.47 (m,
1H), 1.57–1.64 (m, 1H), 1.75–1.93 (m, 4H), 1.96–2.07 (m, 3H), 2.34–2.42 (m,
1H), 2.45–2.60 (m, 2H), 2.72–2.78 (m, 2H), 3.96 (t, J = 9.1 Hz, 1H), 4.76 (virtual
q, J = 8.6 Hz, 1H), 8.14 (t, J = 1.3 Hz, 1H). 13C NMR (CDCl3): d 18.2, 19.8, 20.0,
28.7, 29.2, 32.9, 36.1, 38.2, 52.4, 55.2, 79.5, 114.3, 153.6, 163.2, 174.4. ESI-
HRMS. Calcd for C15H18N2O2Na: 281.1266. Found: 281.1240.
Acknowledgments
This research was supported in part by a Grant-in-Aid for Scien-
tific Research on Priority Areas ‘Advanced Molecular Transforma-
tion of Carbon Resources’ from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. Thanks are also gi-
ven to the technical staff of the Comprehensive Analysis Center of
ISIR for their assistance.
17. Single crystals were obtained from a solution of the enantiopure 5 in EtOH by
slow evaporation. Crystal data: space group P21 (#4), a = 13.165(8) Å,
b = 7.912(4) Å,
c = 6.204(3) Å,
b = 98.53(4)°,
V = 639.1(6) Å3,
Z = 2,
Dcalcd = 1.342 g/cm3, R = 0.0671 (all reflections), Rw = 0.1184 (all reflections),
GOF = 2.898. Crystallographic data (excluding structure factors) for the structure
of 5 have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 745563 and can be obtained free of
charge via the Internet at http://www.ccdc.cam.ac.uk/data_request/cif.
18. Typical procedure for the Pd-catalyzed oxidative cyclization of 4: A solution of
enantiopure ligand (0.0030 mmol) and Pd(OCOCF3)2 (0.8 mg, 0.0025 mmol) in
CH2Cl2 (0.1 mL) was stirred at 25 °C for 2 h under a nitrogen atmosphere. To
this solution were added p-benzoquinone (10.8 mg, 0.10 mmol) and 17
(5.9 mg, 0.025 mmol). The reaction mixture was stirred at 15 °C for 48 h, and
then filtered through a short pad of silica gel, which was rinsed with ethyl
acetate. The filtrate was concentrated under reduced pressure. Product yield
was determined by GC analysis (hexamethylbenzene was used as an internal
standard, TCOL = 180 °C, TINJ = 250 °C, TDET = 250 °C: hexamethylbenzene,
4.96 min; 18, 10.97 min). The residue was purified by preparative TLC (silica
gel, hexane/ethyl acetate = 3/1) to afford product 18. The enantiomeric excess
of the product was determined by HPLC analysis using a chiral stationary phase
column (Daicel Chiralpak AD, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min,
k = 215 nm: 5.6 min and 6.9 min).
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