Bis(oxazoline) derived cationic aqua complexes: Highly effective catalysts for enantioselective Diels-Alder reactions

Article abstract of DOI:10.1016/S0957-4166(98)00362-0

Cationic aqua complex derived from bidentate inda-box ligand and Cu(ClO₄)₂·6H₂O is an excellent catalyst (5-10 mol%) for enantioselective (92-99% ee) Diels-Alder reactions of cyclopentadiene and various bidentate dienophil

Full text of DOI:10.1016/S0957-4166(98)00362-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3687–3691
Bis(oxazoline) derived cationic aqua complexes: highly effective
catalysts for enantioselective Diels–Alder reactions
∗
Arun K. Ghosh, Hanna Cho and John Cappiello
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA
Received 7 August 1998; accepted 3 September 1998
Abstract
Cationic aqua complex derived from bidentate inda-box ligand and Cu(ClO4)2·6H2O is an excellent catalyst
(
5–10 mol%) for enantioselective (92–99% ee) Diels–Alder reactions of cyclopentadiene and various bidentate
dienophiles. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The versatility of chiral bis(oxazoline)–metal complexes has been documented in numerous asymmet-
1
ric syntheses. Particularly notable is the utility of bis(oxazoline)–metal complexes in enantioselective
2
Diels–Alder reactions. Recently, metal complexes of cis-1-aminoindan-2-ol derived conformationally
constrained bis(oxazoline) ligand (inda-box) have been shown to undergo enantioselective Diels–Alder
reactions of cyclopentadiene with various bidentate dienophiles.3 Of various metal–ligand complexes
,4
we have examined, inda-box–Cu(OTf) complex consistently exhibited excellent enantioselectivities
2
3
compared to phenylglycinol derived Ph-box–Cu(OTf) complex. While the cis-1-aminoindan-2-ol is
2
structurally related to phenylglycinol, the corresponding inda-box is conformationally more constrained
since the aromatic ring and the alcohol moiety are linked by a methylene group, thereby restricting the
rotational freedom of the aromatic ring completely. As a consequence, inda-box–metal complexes are
expected to limit transition state geometries far more effectively than the corresponding phenylglyci-
nol derived Ph-box–metal complexes. This may explain the difference in observed enantioselectivity.
While the inda-box–Cu(OTf) complex provided quite impressive enantioselectivity and isolated yields,
2
this catalytic system is far from satisfactory because of a number of limitations which include low
reaction temperature, longer reaction time and air sensitivity of the catalyst complexes. In view of
these limitations, the recent report by Kanemasa and Curran on the development of various air stable
0
cationic aqua complexes of tridentate ligand (R,R)-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (1)
∗
Corresponding author. E-mail: arunghos@uic.edu
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00362-0

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A. K. Ghosh et al. / Tetrahedron: Asymmetry 9 (1998) 3687–3691
Fig. 1.
5
(
Fig. 1) and various metal perchlorates is very intriguing to us. In an effort to examine the effectiveness
of cationic aqua complexes derived from constrained bidentate ligands to carry out enantioselective
Diels–Alder reactions, we have prepared various aqua complexes of inda-box ligand and investigated
Diels–Alder reactions. Among various metal perchlorates examined, inexpensive commercially available
Cu(ClO ) ·6H O turned out to be the most effective. Herein, we report that the reaction of cyclopenta-
4
2
2
diene with various bidentate dienophiles in the presence of 5–10 mol% of aqua complexes derived from
3
(
1S,2R)-inda-box ligand 2 and Cu(ClO ) ·6H O afforded excellent endo/exo selectivity as well as endo
4
2
2
enantioselectivity. Of particular note, other bidentate bis(oxazoline) ligands such as t-Bu-box (3) and
Ph-box (4) ligands are considerably less efficient (6–41% ee) under similar reaction conditions.
Scheme 1.
Various aqua complexes (6) were prepared by reaction of an equimolar mixture of metal perchlorate
and (1S,2R)-inda-box in CH Cl at 23°C for 8–10 h (Scheme 1). While the metal perchlorates are
2
2
insoluble in CH Cl , in the presence of bis(oxazoline) ligand the resulting metal–ligand complexes fully
2
2
dissolve in CH Cl at 23°C. For example, suspension of Cu(ClO )·6H O and (1S,2R)-inda-box 2 in
2
2
4
2
CH Cl resulted in a clear lime green solution after stirring at 23°C for 8 h. The ligand–metal complexes
2
2
so prepared (5–10 mol%), were cooled to the specified temperature and 1 equiv. of dienophile (5a–c)
followed by 4–6 equiv. of freshly cracked cyclopentadiene were added. The progress of the reaction
was monitored by TLC. The reaction was quenched with saturated aqueous NaHCO solution. After
3
workup and chromatography over silica gel, the resulting Diels–Alder cycloadducts were analyzed by
1
6
H NMR (400 MHz) and chiral HPLC analysis (Daicel Chiralcel OD column, 10% isopropanol:hexane
as the eluent). The Diels–Alder reactions of acryloyl-N-oxazolidinone (5a) and cyclopentadiene in
the presence of cationic complexes derived from various metal perchlorates [M(ClO ) ·6H O; M=Cu,
4
2
2
Co, Zn, Ni, Mg] and (1S,2R)-inda-box (2) ligand were first examined. Among various metal perchlo-
rates, Cu(ClO ) ·6H O exhibited the best enantioselectivities (98% ee, entry 2) while Zn(ClO ) and
4
2
2
4 2
Mg(ClO ) have shown almost no enantioselectivity (<10% ee) at 0°C. However, cationic complexes
4
2
derived from Cu(ClO ) ·6H O and other bidentate bis(oxazoline) ligands (3 and 4; Fig. 1) were in-
4
2
2
effective, providing considerably lower endo enantioselectivities (6% ee and 41% ee, respectively) of
5
the cycloadduct 7a. As tridentate ligand DBFOX 1 has been shown to provide excellent endo enantio-

A. K. Ghosh et al. / Tetrahedron: Asymmetry 9 (1998) 3687–3691
3689
Table 1
Enantioselective Diels–Alder reaction of Dienophile 5 with cyclopentadiene
selectivity with a range of metal perchlorates, cationic aqua complex derived from Cu(ClO ) ·6H O and
4
2
2
bidentate inda-box ligand has exhibited comparable enantioselectivities.
The results of various Diels–Alder reactions are summarized in Table 1. As shown, reaction
of cyclopentadiene and variously substituted acryloyl-N-oxazolidinone (5a–c) in the presence of
Cu(ClO ) ·6H O derived aqua complex proceeded with excellent endo selectivity as well as endo
4
2
2
enantioselectivity over a range of temperatures. Acryloyl-N-oxazolidinone (5a) exhibited excellent
endo/exo selectivity (>99:1), endo enantioselectivity (98% ee, entry 4) at −30°C and excellent isolated
7
yield (87%). The reaction time was considerably shorter (3 h at −30°C) than the reaction at −78°C
(10 h). The reaction was virtually complete within 1 h at 0°C providing very high endo enantio-
selectivity (95% ee, entry 5). The Diels–Alder reaction of crotonyl oxazolidinone (5b) and fumaroyl-
N-oxazolidinone (5c) with 10 mol% catalyst complex (entries 9 and 11) also provided excellent enantio-
selectivity (99% ee at −30°C for 7b and 92% ee at −78°C for 7c). The enantiomeric excess of endo
adduct 7c could not be determined by direct HPLC analysis using Daicel Chiralcel OD column since
products peaks are inseparable under a variety of solvent systems and assay conditions. However, the
enantioselectivity of 7c was determined after its conversion to the corresponding iodolactone 8 and
comparison of optical rotation. As shown in Scheme 2, treatment of cycloadduct 7c with iodine, KI
2
3
3
23
and NaHCO in aqueous CH Cl at 23°C for 16 h afforded 8 ([α]
+38.1 (c 0.84; CHCl ); lit. ; [α]
3
2
2
D
3
D
−
39.2 (c 4.65; CHCl ); 94% ee) in 62% yield after silica gel chromatography. The reaction of isoprene
3
8
and fumaroyl-N-oxazolidinone (5d) was also investigated with 10 mol% aqua complex derived from
Cu(ClO ) ·6H O and inda-box. The reaction proceeded at 23°C for 24 h to provide the cycloadduct 9
4
2
2
23
9
23
in 75% yield and 72% enantiomeric excess ([α]
CH Cl ); 93% ee).
−125 (c 1.0; CH Cl ); lit. ; [α]
−161 (c 1.1;
D
2
2
D
10
2
2
In summary, cationic aqua complex of inexpensive Cu(ClO ) ·6H O and readily prepared constrained
4
2
2
bidentate bis(oxazoline) (2) provided a highly effective catalytic system for enantioselective Diels–Alder
reactions over a range of temperatures. The observed enantioselectivities with aqua Cu(II)-complex are
comparable to the tridentate DBFOX 1 ligand designed by Kanemasa and Curran, and co-workers.5

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A. K. Ghosh et al. / Tetrahedron: Asymmetry 9 (1998) 3687–3691
Scheme 2.
The present protocol further broadens the scope and synthetic utility of readily prepared inda-box
ligands. Synthetic application of the current catalytic system is in progress. The following example is
representative of this procedure.
2. Preparation of cycloadduct 7c
To a stirred suspension of Cu(ClO ) ·6H O (91 mg, 0.25 mmol) in CH Cl (2 ml) at 23°C, (1S,2R)-
4
2
2
2
2
inda-box 2 (98 mg, 0.3 mmol) was added. The resulting mixture was stirred for 10 h until the
Cu(ClO ) ·6H O completely dissolved providing a lime green solution. The resulting cationic aqua
4
2
2
complex was cooled to −78°C, and fumaroyl-N-oxazolidinone 5c (526 mg, 2.47 mmol) in CH Cl (0.5
2
2
ml) was added. Freshly cracked cyclopentadiene (1 ml, 15 mmol) was added dropwise at −78°C and the
resulting mixture was stirred for 7 h. After this period, the reaction was quenched with aqueous NaHCO3
solution. The mixture was extracted with chloroform (2×10 ml) and the combined organic layer was
washed successively with water and brine, and dried over anhydrous Na SO . Evaporation of the solvents
2
4
under reduced pressure afforded a crude residue which was purified by column chromatography over silca
gel (25% ethyl acetate:hexane as eluent) to provide the cycloadduct 7c (635 mg, 95% yield) and its exo
1
isomer as a mixture (92:8) by HPLC. H NMR (400 MHz, CDCl ) δ 6.31 (dd, 1H, J=3.2, 5.6 Hz), 5.87
3
(
dd, 1H, J=2.8, 5.6 Hz), 4.39 (t, 2H, J=8.1 Hz), 4.30 (t, 1H, J=4.1 Hz), 4.13–3.89 (m, 4H), 3.39 (br s,
1
H), 3.15 (br s, 1H), 2.84 (dd, 1H, J=1.6, 4.7 Hz), 1.71 (br d, 1H, J=8.8 Hz), 1.45 (dd, 1H, J=1.6, 8.8
13
Hz), 1.22 (t, 3H, J=7.2 Hz); C NMR (100 MHz, CDCl ) δ 174.08, 172.70, 153.14, 138.09, 133.19,
3
−1
62.00, 60.63, 48.26, 47.56, 47.38, 46.57, 46.32, 42.82, 14.10; IR (neat) 2983, 1779, 1741, 1694 cm
;
+
mass (CI): m/z 280 (M +H).
3. Determination of optical purity of the endo-isomer 7c
Enantiomeric excess of endo adduct was calculated from the known optical rotation of the iodolactone
derived from 7c. The above mixture of cycloadducts (mixture of endo and exo) was converted to
8
iodolactone 8 as follows: to a stirred solution of the mixture of cycloadducts (58 mg, 0.208 mmol) in
CH Cl (4 ml) were added water (1 ml), solid NaHCO (125 mg, 1.49 mmol), KI (66 mg, 0.4 mmol) and
2
2
3

A. K. Ghosh et al. / Tetrahedron: Asymmetry 9 (1998) 3687–3691
3691
solid iodine (777 mg, 3.06 mmol). The resulting mixture was stirred at 23°C for 16 h. After this period,
the reaction was quenched with saturated sodium thiosulfate solution and the mixture was extracted
with chloroform (2×10 ml). The combined organic layer was washed with brine, dried over anhydrous
Na SO and concentrated. The crude iodolactone was purified by silica gel chromatography (25% ethyl
2
4
23
3
23
acetate:hexane as the eluent) to afford 8 (44 mg, 62% yield). [α]
+38.1 (c 0.84; CHCl ); lit. , [α]
D
3
D
1
−
39.2 (c 4.65; CHCl ); 94% ee (2S-isomer). H NMR (400 MHz, CDCl ) δ 5.13 (d, 1H, J=5.0 Hz),
3
3
4
.20–4.15 (m, 2H), 3.88 (d, 1H, J=2.7 Hz), 3.22–3.20 (m, 1H), 3.10 (d, 1H, J=4.5 Hz), 3.01 (br s, 1H),
2
.82 (br s, 1H), 2.32 (dd, 1H, J=1.3, 12.0 Hz), 1.96 (dd, 1H, J=2.2, 11.9 Hz), 1.29–1.24 (m, 3H); 13
C
NMR (100 MHz, CDCl ) δ 177.16, 170.01, 88.37, 61.87, 50.46, 50.28, 46.08, 40.80, 34.94, 27.88, 14.06;
3
−1
+
IR (neat) 2979, 2928, 2848, 1783, 1729, 1555, 1236, 1194, 1007 cm ; mass (CI): m/z 337 (M +H).
Acknowledgements
Financial support of this work by the National Institute of Health (GM 55600) is gratefully acknow-
ledged. We also thank Merck Research Laboratories and Sepracor for optically active cis-aminoindanol
for our studies.
References
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120, 3074.
6
7
. Daicel OD column is available from Chiral Technologies, 730 Springdale Drive, Exton, PA.
. Chiral catalyst (8 mol%) derived from inda-box ligand and Cu(OTf)
enantioselectivity (94–98% ee) at −78°C.
2
provided similar endo/exo selectivity (>99:1), endo
8. Kool, J.; Feringa, B. L. Synlett 1995, 1025.
9. Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340.
10. All new compounds gave satisfactory spectroscopic and analytical results.