Synthesis of new chiral bis-oxazoline ligand with zinc triflate-selective chelating ability and its applications

Article abstract of DOI:10.3987/COM-05-S(K)49

New chiral bis-oxazoline ligand (10) with a dihydroanthracene skeleton was synthesized and its application to enantioselective Diels-Alder reaction and Henry reaction has revealed extremely zinc triflate-selective chelating ability of 10.

Full text of DOI:10.3987/COM-05-S(K)49

HETEROCYCLES, Vol. 66, 2005
433
HETEROCYCLES, Vol. 66, 2005, pp. 433 – 440. © The Japan Institute of Heterocyclic Chemistry
Received, 1st September, 2005, Accepted, 18th October, 2005, Published online, 21st October, 2005. COM-05-S(K)49
SYNTHESIS OF NEW CHIRAL BIS-OXAZOLINE LIGAND
WITH ZINC TRIFLATE-SELECTIVE CHELATING ABILITY
AND ITS APPLICATIONS
Kazuishi Makino, Ikuko Ogawa, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan. E-mail: hamada@p.chiba-u.ac.jp
Abstract – New chiral bis-oxazoline ligand (10) with a dihydroanthracene
skeleton was synthesized and its application to enantioselective Diels-Alder
reaction and Henry reaction has revealed extremely zinc triflate-selective
chelating ability of 10.
INTRODUCTION
Enantioselective synthesis using chiral semicorrins as bidentate ligands with nitrogen was first described
by Pfaltz and co-workers in 1986.1 Since then a number of chiral bis-oxazolines equivalent to chiral
semicorrins have been developed and become an important family of chiral auxiliaries and their
combinations with metal salts have been shown to be especially useful and versatile catalysts for a variety
of enantioselective reactions, for example, Diels-Alder cycloaddition, aldol condensation,
cyclopropanation, and ene reaction processes.2 We describe here the synthesis of a new bis-oxazoline
ligand with zinc triflate-selective chelating ability and its application to enantioselective Diels-Alder
cycloaddition reaction and Henry reaction.
RESULTS AND DISCUSSION
In designing the bis-oxazoline ligand we envisaged that flexibility of the space distance between two
oxazolines in the chiral auxiliary might serve to enhance its chelating ability despite various sizes of the
metals. Thus, we chose a dihydroanthracene as flexible tether between two oxazolines and designed
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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R2
R2
ligand (1) with cis-two oxazolines at C9 and C10-quaternary
carbons serving as a hinge between two aromatic rings as shown
in Figure 1.
M
N
N
O
O
3
3
sp
sp
R1
R1
Synthesis of the chiral bis-oxazoline ligand commenced with
preparation of cis-dicarboxylic acid (6) as shown in Scheme 1.
Adduct (2) derived from known Diels-Alder reaction of readily
available 9,10-dimethylanthracene3 was ozonized at –65 to
1
Figure 1
–55 °C for 8 h and quenched with triphenylphosphine at –55 to 5 °C for 13 h to give bis-α-keto ester (3).
Reduction of 3 with lithium aluminum hydride and glycol cleavage of the obtained diol (4) with sodium
periodate produced aldehyde (5), which was oxidized with sodium chlorite to afford the cis-dicarboxylic
acid (6) in 31% yield (four steps). Conversion of 6 to acid chloride (7) and subsequent condensation with
(S)-phenylglycinol in the presence of triethylamine afforded amide (8) in 75% yield (two steps).
Oxazoline-formation from 8 in one step was unexpectedly difficult. Therefore, after conversion of 8 to
chloride (9) the oxazoline ring was formed by treatment of 9 with potassium hexamethyldisilazide in
tetrahydrofuran to furnish bis(oxazolinyl)dihydroanthracene (10) in 88% yield.
R
Ph
Ph
O
Ph
HN
HN
CO2Me
Me
R
R
N
N
Me
Me
Me
Me
Me
Me
MeO2C
Me
O
O
h
a
f
2
O
3: R = C(O)CO2Me
4: R = C(OH)CH2OH
5: R = CHO
b
c
Ph
R
10
d
6: R = COOH
8: R = OH
g
e
7: R = COCl
9: R = Cl
Reagents amd conditions: (a) O3, CH2Cl2, -65 to - 55 °C, 8 h, then Ph3P, -55 to 5 °C, 13 h (b)
LiAlH4, THF, 0 to 23 °C, 15 h (c) NaIO4, MeOH, H2O, 23 °C, 30 h (d) NaClO2, 2-methyl-2-butene,
KH2PO4, t-BuOH, H2O, 0 to 23 °C , 27 h, 31%(4 steps) (e) (COCl)2, DMF (cat.), CH2Cl2, 0 to 23
°C, 22.5 h (f) (S)-phenylglycinol, Et3N, CH2Cl2, 0 to 23 °C, 20 h, 75% (2 steps) (g) SOCl2, THF, 23
°C to reflux, 16 h, 49% (h) KHMDS, THF, 0 to 23 °C, 16 h, 88%
Scheme 1
We chose Diels-Alder cycloaddition reaction4 of cyclopentadiene with N-acryroyloxazolidinone as a
bench-mark reaction for bis-oxazoline ligand (10) and extensively surveyed metal salts for combination
with 10. The results are summarized in Table 1. The chiral catalyst was prepared prior to the reaction by
complexation of metal salts (10 mol%) with 10 (11 mol%) in methylene chloride at 23 °C for 8.5 h. After

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435
the catalyst solution was cooled to –78 °C, the Diels-Alder reaction was carried out by adding
cyclopentadiene and N-acryroyloxazolidinone. Ferric chloride, nickel chloride, silver triflate, scandium
triflate, and ytterbium triflate catalyzed the reaction with excellent endo-selectivity but gave no
enantioselectivity. These results suggest that the reaction might proceed in incomplete or no complexation
of the metal salts with 10. Enantioselectivity of stannic triflate and cupric triflate was low (entries 1 and
3). Zinc triflate afforded the products with moderate endo/exo (75:25) selectivity. However, we were
pleased to find that the analysis of the products showed surprisingly high enantiomeric excesses of both
endo- and exo-products (entry 4). The enantiomeric excesses and absolute configurations of the products
were determined by HPLC analysis and comparison with the literature value.5 From the result of zinc
triflate we carefully examined several zinc salts, zinc chloride, zinc iodide, zinc cyanide, and zinc acetate,
which were found to be fruitless in the Diels-Alder reaction (entries 5-8). The above results reveal that 10
has extremely selective chelating ability to zinc triflate and completely forms the chiral catalyst for the
Diels-Alder reaction.
Table 1 Catalytic Asymmetric Diels-Alder Reactiona
metal (10 mol%)
O
O
ligand (10) (11 mol%)
exo
+
H
+
O
N
O
S
CH2Cl2
O
N
O
3 eq
1 eq
endo
exo
ee (%)
endo
ee (%)
endo : exob
conditions
entry
metal salt
Sn(OTf)2
Yb(OTf)3
Cu(OTf)2
Zn(OTf)2
ZnCl2
-78 to 23 °C, 36 h
-78 to -10 °C, 14 h
-78 to 23 °C, 14 h
-78 to 5 °C, 12 h
-78 to 10 °C, 18 h
-78 to 10 °C, 18 h
-78 to 10 °C, 18 h
-78 to 10 °C, 18 h
1
2
3
4
5
6
7
8
93 : 7
85 : 15
36 : 64
75 : 25
95 : 5
94 : 6
94 : 6
93 : 7
20
3
22
N.D.
0
35
>99
16
12
15
13
>99
0
ZnI2
17
14
19
Zn(CN)2
Zn(OAc)2
a) The yield was quantitative. b) The endo/exo ratio was determined by 1H-NMR spectral analysis.
To explore the potential of the bis-oxazoline (10), we next investigated catalytic asymmetric Henry
reaction.6 We chose ethyl benzoylformate as the substrate and surveyed metal salts for the bis-oxazoline
ligand (10) as shown in Table 2.7 The chiral catalyst was prepared by mixing metal salts (20 mol%) and
10 (21 mol%) in nitromethane at 23 °C for 1 h. The Henry reaction was performed by adding ethyl
benzoylformate and triethylamine (20 mol%) to the chiral catalyst solution and stirring at 23 °C for 45 h

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under argon atmosphere. Again, zinc triflate in combination with 10 was indicated to be the most
effective chiral catalyst for the Henry reaction. In addition, cupric triflate was found to catalyze
enantioselectively the reaction in 85%ee but the yield was moderate with recovery of the starting material.
Other zinc salts were again ineffective.
Table 2 Catalytic Asymmetric Henry Reaction
CH NO (0.25 M)
Et N (20 mol%)
3
3
2
O
OH
*
CO Et
CO Et
2
Ph
Ph
metal (20 mol%)
ligand (21 mol%)
23 °C, 45 h
2
NO
2
a
ee (%)
entry
yield (%)
metal salt
Cu(OTf)
Zn(OTf)
1
2
3
4
5
52 (quant)
92 (quant)
51(79)
85 (-)
71 (+)
11 (+)
4 (+)
2
2
ZnCl
2
ZnI
76 (87)
2
Zn(CN)
89 (quant)
11 (+)
2
a) The value in the parenthesis shows the conversion yield.
In conclusion, we have demonstrated the synthesis of new chiral bis-oxazoline ligand (10) with a
dihydroanthracene tether and its application to the enantioselective Diels-Alder cycloaddition and Henry
reaction. The new bis-oxazoline ligand (10) was found to bear extremely selective chelating ability to
zinc triflate. Further applications of the bis-oxazoline ligand (10) are underway in this laboratory.
EXPERIMENTAL
Melting points were measured with a SIBATA NEL-270 melting point apparatus. Infrared spectra were
recorded on a JASCO FT/IR-230 Fourier Transform infrared spectrophotometer. Optical rotations were
measured on a JASCO DIP-14 polarimeter and a JASCO P-1020 polarimeter with a sodium lamp and
1
were recorded as follows: [α]DT (c g/100 mL, solvent). H NMR spectra were recorded on a JEOL
JNM-GSX 400A spectrometer (400 MHz) and a JNM ECP400 spectrometers (400MHz). Chemical shifts
were recorded in ppm from tetramethylsilane or chloroform as the internal standard. FAB mass spectra
were obtained with a JEOL JMS-HX110A spectrometer. HPLC was carried out with JASCO UV-970
(detector) and PU-980 (pump) high pressure liquid chromatography.
9,10-Dimethyl-9,10-dihydroanthracene-9,10-dicarboxylic acid (6)
To methylene chloride (CH2Cl2, 200 mL) saturated with O3 at –65 ºC was added dropwise a solution of 2
(12.0 g, 34.4 mmol) in CH2Cl2 (125 mL) over 5 h. After the mixture was additionally stirred at –55 ºC for
3 h, argon gas was bubbled into the mixture for 30 min. Triphenylphosphine (36.1 g, 138 mmol) was

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added to the stirred solution at –55 ºC and the resulting mixture was allowed to gradually warm to 5 ºC
over 13 h. After the mixture was concentrated in vacuo, the residue was washed with ethyl acetate-hexane
to afford 3 (5.80 g) as brown solids, which were used for the next step without further purification.
A solution of 3 (5.80 g) in THF (75 mL) was added dropwise to a stirred suspension of LiAlH4 (2.31 g,
60.8 mmol) in THF (35 mL) at 0 ºC under argon atmosphere and the mixture was gradually warmed to 23
ºC over 15 h. After the reaction was quenched with 6M hydrochloric acid, the mixture was extracted with
CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo
to afford 4 (6.16 g), which was used for the next step without purification.
Sodium periodate (12.7 g, 59.3 mmol) was added to a solution of 4 (6.16 g) in MeOH (240 mL) and H2O
(60 mL) at 23 ºC and the mixture was stirred for 30 h. After filtration, saturated aqueous NaHCO3 was
added to the filtrate. The resulting mixture was concentrated in vacuo and extracted with ethyl acetate.
The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford
5 (4.0 g), which was used for the next step without further purification.
A solution of NaClO2 (80%, 10.1 g, 89 mmol) in H2O (17 mL) was added dropwise to a stirred solution
of 5 (4.0 g), 2-methyl-2-butene (15.7 mL, 148 mmol), and KH2PO4 (4.03 g, 29.7 mmol) in t-BuOH (60
mL) at 0 ºC. After stirring the mixture for 27 h at 23 ºC, aqueous NaOH (1M in H2O) was added and the
resulting mixture was washed with CH2Cl2. The aqueous layer was acidified with concd HCl and
extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo to afford 6 (3.14 g, 31% in 4 steps) as yellow solids: mp 292-294 ºC;
IR (KBr): 2975, 1710, 1490, 1447, 1405, 1376, 1283, 1109, 1038, 928, 758, 721, 676 cm-1; 1H-NMR (400
MHz, DMSO): δ 1.60 (s, 6H), 7.22-7.25 (m, 4H), 7.29-7.32 (m, 4H), 12.6 (s, 2H); 13C-NMR (100 MHz,
DMSO): δ 31.7, 49.0, 125.5, 126.2, 135.8, 17.2. Anal. Calcd for C18H16O4: C, 72.96; H, 5.44. Found: C,
72.76; H, 5.40.
9,10-Dimethyl-9,10-dihydroanthracene-9,10-dicarboxylic acid bis[(1S)-2-hydroxy-1-phenylethyl]-
amide (8)
To a solution of the carboxylic acid (6) (4.03 g, 13.6 mmol) in CH2Cl2 (68 mL) at 0 °C was added
dropwise oxalyl chloride (3.5 mL, 40.3 mmol) and DMF (1 drop) and the solution was stirred at 23 °C for
22.5 h. The mixture was concentrated in vacuo to afford 7 (3.91 g) as white solids, which were used for
the next step without further purification.
Triethylamine (17 mL, 123 mmol) and a solution of 7 (3.91 g,) in CH2Cl2 (190 mL) were added dropwise
to a stirred solution of (S)-phenylglycinol (3.92 g, 28.5 mmol) in CH2Cl2 (68 mL) at 0 °C. After stirring
the mixture at 23 °C for 20 h, the reaction mixture was washed with brine. The organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column

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chromatography (CHCl3/MeOH = 20:1) to afford 8 (5.46 g, 75% in 2 steps) as white amorphous solids:
25
1
[α] D +7.9° (c 1.05, CHCl3); IR (KBr): 3384, 3060, 1648, 1523, 1277, 1036 cm-1; H-NMR (400 MHz,
CDCl3): δ 1.95 (s, 6H), 3.57 (dd, J = 11.5, 5.6 Hz, 2H), 3.61 (dd, J = 11.7, 4.1 Hz, 2H), 4.85-4.89 (m, 2H),
6.95 (d, J = 7.6 Hz, 2H), 6.97-7.00 (m, 4H), 7.20-7.36 (m, 12H), 7.47-7.50 (m, 2H); 13C-NMR(100 MHz,
CDCl3): δ 29.4, 50.1, 55.7, 65.6, 126.4, 127.2, 127.5, 127.6, 127.9, 128.1, 128.5, 136.7, 137.2, 139.1,
175.9; HRMS(FAB): Calcd for C34H35N2O4: 535.2597 (M+H)+; Observed: 535.2562.
9,10-Dimethyl-9,10-dihydroanthracene-9,10-dicarboxylic acid bis[(1S)-2-chloro-1-phenylethyl]-
amide (9)
To a stirred solution of 8 (5.20 g, 9.73 mmol) in THF (92 mL) at 23 °C was added dropwise SOCl2 (3.5
mL, 47.9 mmol) and the mixture was refluxed for 16 h. The resulting mixture was diluted with ethyl
acetate, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2:1) to
13
afford 9 (2.71 g, 49%) as white amorphous solids: [α] D -8.9° (c 1.08, CHCl3); IR (KBr): 3341, 3259,
3061, 1651, 1265, 1032 cm-1; 1H-NMR (400 MHz, CDCl3): δ 1.93 (s, 6H), 3.54 (dd, J = 11.5, 7.1 Hz, 2H),
3.65 (dd, J = 11.5, 4.6 Hz, 2H), 5.19 (dt, J = 7.1, 4.9 Hz, 2H), 6.56 (d, J = 7.6 Hz, 2H), 6.96-7.00 (m, 4H),
13
7.17-7.36 (m, 12H), 7.47-7.49 (m, 2H); C-NMR (100 MHz, CDCl3): δ 30.0, 47.2, 50.3, 54.3, 60.4,
126.4, 127.5, 127.8, 127.9, 128.0, 128.5, 136.6, 136.8, 138.4, 175.3; HRMS(FAB): Calcd for C34H33N2O2
Cl2: 571.1919 (M+H)+; Observed: 571.1886.
9,10-Bis[(4’S)-4’-phenyl-2’-oxazolinyl]-9,10-dimethyl-9,10-dihydroanthracene (10)
To a solution of dichloride (9) (905.8 mg, 1.58 mmol) in THF (16 mL) at –20 °C was added dropwise
KHMDS (0.5 M in toluene, 6.4 mL, 3.20 mmol) under argon atmosphere and the resulting mixture was
gradually warmed to 23 °C. After stirring for 16 h, the reaction was quenched with saturated aqueous
NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography
13
(hexane/ethyl acetate = 3:1) to afford 10 (695.9 mg, 88%) as white amorphous solids: [α] D -254.4° (c
1
1.14, CHCl3); IR (KBr): 2979, 1649, 1491, 1446, 1228, 1096, 963 cm-1; H-NMR (400 MHz, CDCl3): δ
1.91 (s, 6H), 4.07 (t, J = 8.8 Hz, 2H), 4.56 (dd, J = 10.0, 8.8 Hz, 2H), 5.34 (dd, J = 10.0, 8.8 Hz, 2H),
13
7.32–7.45 (m, 14H), 7.48–7.54 (m, 4H); C-NMR (100 MHz, CDCl3): δ 34.2, 44.7, 69.7, 75.4, 127.0,
128.8, 136.7, 142.2, 172.3; HRMS (FAB): Calcd for C34H31N2O2: 499.2386 (M+H)+; Observed:
499.2373.

HETEROCYCLES, Vol. 66, 2005
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Diels-Alder Cycloaddition Reaction
A mixture of metal salt (10 mol%) and ligand (10) (11 mol%) in CH2Cl2 (1 mL) at 23 °C was stirred for
8.5 h under argon atmosphere. After the mixture was cooled to –78 °C, a solution of the
N-acryroyloxazolidinone (71.4 mg, 0.506 mmol) in CH2Cl2 (1 mL) followed by cyclopentadiene (125 µL,
1.52 mmol) were added dropwise. The resulting solution was gradually warmed to 5 °C over 12 h. The
reaction mixture was then diluted with ethyl acetate (1 mL) and hexane (1.5 mL) at 5 °C and applied
directly to silica gel column chromatography with ethyl acetate/hexane (1:1). After concentration of the
collected fractions, the Diels-Alder adduct was obtained quantitatively. Enantiomeric excess was
determined by HPLC analysis with Daicel Chiralcel OD-H column (hexane/isopropanol/ethyl acetate =
95:2:3, flow rate: 0.9 mL/min, exo: tminor = 30.7 min, tmajor = 31.9 min; endo: tmajor = 35.1 min, tminor = 42.1
min).
Henry Reaction
The mixture of metal salts (20 mol%) and ligand (21 mol%) was dried in vacuo for 2 h. Then, MeNO2
(960 µL, 0.25 M) was added and the solution was stirred for 1 h. Ethyl benzoylformate (95%, 40 µL,
0.239 mmol) and Et3N (20 mol%) were added dropwise to the mixture. After stirring the mixture at 23 °C
for 45 h under argon atmosphere, the reaction mixture was applied directly to a short column of silica gel
and then eluted with hexane/ethyl acetate (6:1) to remove the metal salts. After concentration of the
fractions, the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8:1) to
afford β-nitro-α-hydroxy ester. Enantiomeric excess was determined by HPLC analysis with Daicel
Chiralcel OJ column (hexane/isopropanol = 9:1, flow rate: 1.0 mL/min, tminor = 25.1, tmajor = 30.8 min).
ACKNOWLEDGEMENTS
The paper is dedicated to the memory of the late Professor Kenji Koga, Emeritus Professor of Tokyo
University. This work was financially supported in part by a Grant-in-Aid for Scientific Research (B)
from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
REFERENCES
1. H. Fritschi, U. Leutenegger, and A. Pfaltz, Angew. Chem., Int. Ed., Engl., 1986, 25, 1005.
2. A. Pfaltz, Acc. Chem. Res., 1993, 26, 339; A. K. Ghosh, P. Mathivanan, and J. Cappiello,
Tetrahedron: Asymmetry, 1998, 9, 1; A. Pfaltz, Synlett, 1999, 835; H. A. McManus and P. J. Guiry,
Chem. Rev., 2004, 104, 4151.
3. J. Sauer, H. Wiest, and A. Mielert, Chem. Ber., 1964, 97, 3183.

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4. For recent reviews on catalytic asymmetric Diels-Alder reactions, see: E. J. Corey, Angew. Chem.,
Int. Ed., Engl., 2002, 41, 1650; D. A. Evans and J. S. Johnson, 'Comprehensive Asymmetric
Catalysis,' Vol. 3, ed. by E. N. Jacobson, A. Pfaltz, and H. Yamamoto, Springer, Berlin, 1999, pp.
1177-1235; E. J. Corey and A. Guzman-Perez, Angew. Chem., Int. Ed. Engl., 1998, 37, 388; K.
Ishihara and H. Yamamoto, Eur. J. Org. Chem., 1999, 527.
5. D. A. Evans, S. Miller, T. Lectka, and P. Matt, J. Am. Chem. Soc., 1999, 121, 7559.
6. For recent reviews on Henry reactions, see: C. Palomo, M. Oiarbide, and A. Mielgo, Angew. Chem.,
Int. Ed. Engl., 2004, 43, 5442; M. Shibasaki and N. Yoshikawa, Chem. Rev., 2002, 102, 2187; F. A.
Luzzio, Tetrahedron, 2001, 57, 915; G. Rosini and R. Ballini, Synthesis, 1988, 833; G. Rosini,
'Comprehensive Organic Synthesis,' Vol. 2, ed. by B. M. Trost, I. Fleming, and C. H. Heathcock,
Pergamon, Oxford, 1991, pp. 321-340; H. W. Pinnick, 'Organic Reactions,' Vol. 38, ed. by L. A.
Paquette, John Wiley & Sons, New York, 1990, Chapter 3.
7. C. Christensen, K. Juhl, and K. A. Jorgensen, Chem. Commun., 2001, 2222; C. Christensen, K. Juhl,
R. G. Hazell, and K. A. Jorgensen, J. Org. Chem, 2002, 67, 4875; D.-M. Du, S.-F. Lu, T. Fang, and
J. Xu,. J. Org. Chem., 2005, 70, 3712.