Enantioselective catalytic Diels-Alder reaction of ethyl 2-benzoylacrylate with chiral bis(oxazoline)- or mono(oxazoline)-magnesium complex

Article abstract of DOI:10.1039/a702920i

The magnesium catalysed Diels-Alder reaction of 2-benzoylacrylate gave the endo-adduct enantioselectively with bis(oxazoline) 5 as a C₂-symmetric ligand or mono-(oxazoline) 4 as a non-C2-symmetric ligand.

Full text of DOI:10.1039/a702920i

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Enantioselective catalytic Diels–Alder reaction of ethyl 2-benzoylacrylate with
chiral bis(oxazoline)– or mono(oxazoline)–magnesium complex
Yuko Honda,a Tadamasa Date,b Hajime Hiramatsub and Masashige Yamauchi*a
a Faculty of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-02, Japan
b Analytical Research Laboratory, Tanabe Seiyaku C., Ltd, Kashima, Yodogawaku, Osaka 352, Japan
The magnesium catalysed Diels–Alder reaction of
2-benzoylacrylate gave the endo-adduct enantioselectively
with bis(oxazoline) 5 as a C2-symmetric ligand or mono-
(oxazoline) 4 as a non-C2-symmetric ligand.
and I2 (co-catalyst) in CH2Cl2 at room temperature by Corey’s
procedure,2b the enantioselectivity was not particularly high
(Table 1, entry 1), but the selectivity was much improved with
the complex prepared in refluxing MeCN (entry 2). The
diastereoisomers showed one spot by TLC and could not be
resolved by column or medium pressure chromatography, but
the ratio was determined by 1H NMR spectroscopy as
mentioned in our previous report,4 and in most cases only the
endo-isomer was obtained (Table 1).
A great deal of effort has been invested in enantioselective
Diels–Alder reactions catalysed by chiral Lewis acids, and
tremendous advances have been achieved in recent years.1
C2-Symmetric ligand–metal complexes have proven to be
excellent catalysts, and in most cases N-a,b-unsaturated
acyloxazolidinones have been used as two-point dienophile
binding agents in these reactions.2 Recently, non-C2-symmetric
phosphinoaryloxazolines have been shown to be effective
ligands for Pd-catalysed asymmetric allylic substitution.3 We
have reported a highly diastereoselective and endo/exo selective
Diels–Alder reaction of (1AR,2AS,5R)-5-methyl-2-methyl-
2-(1-phenylethyl)cyclohexyl 2-benzoylacrylate with cyclopen-
tadiene catalysed by a Lewis acid.4 This suggests that an
enantioselective Diels–Alder reaction should occur using ethyl
2-benzoylacrylate 1,5 a two-point binding dienophile, in the
presence of a chiral Lewis acid. Herein, we describe the
magnesium-catalysed Diels–Alder reaction of 1, as dienophile,
with cyclopentadiene using N-[(1R)-2-chloro-1-phenylethyl]-
2-ethyl-2-[(4R)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]butyr-
amide 4 as a non-C2-symmetric chiral ligand and bis(oxazoline)
5 as a C2-symmetric chiral ligand.
As 1 proved to be a suitable dienophile, we next examined the
reaction
using
N-[(1R)-2-chloro-1-phenylethyl]-2-ethyl-
2-[(4R)-4-phenyl-4,5-dihydrooxazol-2-yl]butyramide 4 as a
chiral ligand. Compound 4 was synthesized by treatment of
dichloride 3 with an equimolar amount of NaOH in MeOH–
H2O at 60 °C. In contrast to the fact that most of the
bis(oxazoline)s used as chiral ligands are oily materials, the
mono(oxazoline) 4 exists as colourless prisms (mp 127–128 °C
from EtOAc) and is therefore easy to handle. The reaction with
the complex prepared from 4:MgI2 :I2 (1:1:1) in CH2Cl2 at
room temperature also gave poor enantioselectivity (entry 3).
When the reaction was performed with the complex prepared in
refluxing MeCN, the ee increased to 87% (entry 4). Inter-
estingly, the enantioselectivities of the reactions with the
complex prepared from MgI2 :4:I2 (1:2:2) were almost equal
or slightly higher (entries 5,6). It is well known that head or tail
enrichment may occur during chromatography on achiral
columns of samples containing an excess of one enantiomer.2i,6
Our initial efforts were focussed on the possibility that ethyl
2-benzoylacrylate 1 should be a good two-point binding
dienophile in an enantiomeric Diels–Alder reaction with
cyclopentadiene by use of bis(oxazoline) 5–magnesium com-
plex. In the reaction with the complex prepared from 5, MgI2
1
We therefore collected all the Diels–Alder adducts before H
NMR and HPLC analyses. After separation of the endo adduct
by preparative HPLC, if necessary, the enantioselectivities were
determined by analytical HPLC.‡ Furthermore, the ligands
Table 1 Asymmetric catalytic Diels–Alder reaction of ethyl 2-benzoyl-
acrylate
Et
Et
Et
Et
N
O
O
O
O
Cl
Cl
Cl
ii
O
O
i
O
O
Ph
OEt
Ph
NH HN
NH
+
Ph
OEt
OEt
Ph
Ph
Ph
ii
Ph
O
2a
O
–90 °C
3
4
1
2b
Et
N
Et
N
Catalyst
MgI2
Diels–Alder adduct
O
O
Ligand
Yield
(%)
%Ee of
2a
Entry (equiv.) (equiv.) Conditions
2a:2b
97:3
Ph
Ph
5
1
2
3
4
5
6
0.2
0.2
0.2
0.2
0.1
0.2
5 (0.2) CH2Cl2, room 74
69.8
85.3
18.3
87.0
87.3
88.6
temp., 3 h
Scheme 1 Reagents: i, NaOH (1 equiv.), MeOH–H2O; ii, NaOH (excess),
5 (0.2) MeCN, reflux, 81
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
MeOH–H2O
1 h
4 (0.2) CH2Cl2, room 76
temp., 3 h
O
4 (0.2) MeCN, reflux, 88
Ph
1 h
i
2a
Br
4 (0.2) MeCN, reflux, 88
1 h
O
O
4 (0.4) MeCN, reflux, 75
6
1 h
Scheme 2 Reagents: i, Br2, CCl4
Chem. Commun., 1997
1411

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‡ Preparative HPLC was carried out with a JASCO Megapak SIL-10
column (1.0 3 25 cm; eluate 5% AcOEt in hexane) and analytical HPLC
with a Daisel CHIRALCEL OD column (0.46 3 25 cm; eluate 0.1%
propan-2-ol in hexane).
were recovered almost quantitatively from column chromatog-
raphy as the last fraction. The absolute configuration of 2a was
confirmed by treatment of 2a with bromine in CCl4 to give
bromo-lactone 6, whose absolute structure was determined by
X-ray crystallography (Fig. 1).§
§ Crystal data for 6: C15H13O3Br, M = 321.16, orthorhombic, space group
P212121, a = 10.935(1), b = 18.884(1), c = 6.326 (1) Å, U = 1287.7(2)
Å3, Z = 4, Dc = 1.66 g cm23, m(Cu-Ka) = 4.37 mm21. Reflections were
measured on a Rigaku AFC5R diffractometer in the range 4.7 < q < 65.1°
(Cu-Ka radiation) with the w–2q scan technique, 2154 reflections were
used for all calculations. The structure was solved by direct methods
[SHELX-86 (ref. 7)] and refined anisotropically on F2 (SHELXL-93 (ref.
8)]. All hydrogen atoms were refined for all parameters; wR2(F2) = 0.0773
with R(F) = 0.0303 for 225 parameters. The absolute configuration was
determined Flack’s c-parameter (ref. 9) 20.02(2). CCDC 182/514.
O(13)
C(8)
C(15)
C(16)
C(12)
C(17)
C(6)
C(4)
C(3)
C(2)
C(14)
C(5)
C(19)
C(18)
Br(1)
C(7)
C(9)
References
1 R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994; K. Ishihara and H. Yamamoto, in Advances in Catalytic
Processes, ed. M. P. Doyle, JAI Press, London, 1995.
O(10)
O(11)
Fig. 1 ORTEP diagram of 6
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The almost perfect diastereoselectivity of the reaction can be
rationalised to be due to the steric hindrance of the benzene ring
situated nearly perpendicular to the ene in the fixed metal-
chelated enedione as mentioned earlier.4 However, the reaction
mechanism giving high enantioselectivity using mono(oxazo-
line) is unclear. An attempt to capture the complex of the Lewis
acid–chiral ligand or Lewis acid–ligand–dienophile in crystal
form has not been successful. Further investigations to clarify
the precise structures of the catalysts formed from 4:MgI2 :I2
(1:1:1 and 2:1:2) and the reaction mechanism as well as to
develop other asymmetric reactions using this complex are now
in progress.
Footnotes
4 M. Yamauchi, Y. Honda, N. Matsuki, T. Watanabe, T. Date and H.
Hiramatsu, J. Org. Chem., 1996, 61, 2719.
* E-mail: yamauchi@josai.ac.jp
† General experimental procedure: a mixture of the ligand, MgI2 and I2 in
the solvent was treated under the conditions shown in Table 1. The solvent
was removed and the resulting complex was dissolved in CH2Cl2 (1.0 ml)
and cooled at 290 °C. To this solution 1 (1 mmol) in CH2Cl2 (1.5 ml) was
added and stirred for 30 min, then cyclopentadiene (1.5 mmol) in CH2Cl2
(2.5 ml) was added slowly for a period of 3 h. After the reaction was
completed the reaction mixture was quenched with water and washed with
5% aqueous Na2S2O3. The organic layer was dried and evaporated. The
resulting residue was subjected to column chromatography to yield the
adducts.
5 M. Yamauchi, S. Katayama and T. Watanabe, Synthesis, 1982, 935.
6 W.-L. Tsai, K. Hermann, E. Hug, B. Rohde and A. S. Dreiding, Helv.
Chim. Acta, 1985, 68, 2238; P. Diter, S. Tandien, O. Samuel and H. B.
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7 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
8 G. M. Sheldrick, SHELXL-93, University of Go¨ttingen, Germany,
1993.
9 H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 676.
Received in Cambridge, UK, 29th April 1997; 7/02920I
1412
Chem. Commun., 1997