Preparation of new bis(oxazoline) ligand bearing non-covalent interaction sites and an application in the highly asymmetric Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2005.06.108

New asymmetric bis(oxazoline) (Box) ligand bearing amide group at the oxazoline 4-position, (S,S)-2,2′-methylenebis(4-tert-butylcarbamoyl-2- oxazoline) (1S), was designed and synthesized for selective catalytic reaction. The crystal structure of the terna

Full text of DOI:10.1016/j.tetlet.2005.06.108

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5687–5690
Preparation of new bis(oxazoline) ligand bearing
non-covalent interaction sites and an application in the
highly asymmetric Diels–Alder reaction
Kenji Matsumoto, Koichiro Jitsukawa* and Hideki Masuda
Department of Applied Chemistry, Nagoya Institute of Technology, Nagoya 466-8555, Japan
Received 28 April 2005; revised 16 June 2005; accepted 17 June 2005
Available online 11 July 2005
Abstract—New asymmetric bis(oxazoline) (Box) ligand bearing amide group at the oxazoline 4-position, (S,S)-2,20-methylenebis-
(4-tert-butylcarbamoyl-2-oxazoline) (1S), was designed and synthesized for selective catalytic reaction. The crystal structure of
the ternary copper complex, consisting of 1S and N-benzoyl-N-phenyl-hydroxylamine, demonstrated interligand interactions, such
as hydrogen bonding and CH-p interaction. Catalytic performance of the copper complex with 1S was investigated for an asym-
metric Diels–Alder reaction using benzylidene-2-acetylpyridine and 1,3-cyclohexadiene (CHD). The reaction product was
enantio-pure endo-(pyridin-2-yl)(3-phenylbicyclo[2,2,2]oct-5-ene-2-yl)methanone (BPCD), of which crystal structure was analyzed
by the X-ray method. No stereo- and enantio-isomer of BPCD was detected by chiral HPLC analysis. Introduction of hydrogen
bonding site into 1S can promote the Diels–Alder reaction even though using poor reactive CHD. Without 1S, this reaction did
not give any product. Addition of 2-propanol to this reaction system inhibited the formation of BPCD, indicating that the designed
interligand interaction sites, especially hydrogen bonding, play an important role for catalytic performance.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Interligand interactions around metal center are impor-
tant for demonstrating selectivity and specificity in catal-
ysis of transition metal complexes. In order to achieve
high selectivity and efficiency for asymmetric reactions,
ternary complexes consisting of metal–ligand–substrate
have been designed.1 Generally, biologically specific
and efficient reactions are demonstrated at or near the
active site of enzyme–substrate complex through a com-
bination of some weak non-covalent interactions, such as
hydrogen bond, steric repulsion, electrostatic interac-
tion, and hydrophobic one, etc., which are realized upon
simple metal complexes.2 In the viewpoint of the bio-
inspired chemistry, introduction of hydrogen bonding
site into the ternary complexes provides an approach to
high selectivity and efficiency of catalysis.3 Recently,
chiral bis(oxazoline) (Box) compounds, bearing 4-phenyl
or 4-tert-butyl group at oxazoline ring with C2-symmetry,
have been utilized for various asymmetric reactions.4,5
The large phenyl or tert-butyl group substituted at 4-po-
sition of the oxazoline ring is designed to sterically block
approach of the substrate to the active center of the
catalyst from another side.6,7 Although there have been
many reports on the catalysts containing these chiral
Box ligands, few reports have discussed an attractive int-
erligand interaction mediated upon the ternary com-
plexes.6,8,9 To our knowledge, hydroxymethyl or ester
group substituted at the 4-position has been reported
as a recognition site for the substrate.6,8,10 Introduction
of amide group at or near the ternary complex might be-
come an efficient way of regulating the geometry of the
transition state, because hydrogen bonding interactions
between amide groups are known to stabilize the struc-
ture of supramolecules.11 Here, we describe preparation
of novel Box derivatives bearing amide group as hydro-
gen bonding site at the oxazoline 4-position and their
catalytic application to asymmetric Diels–Alder reaction
(Fig. 1).
The novel Box derivative, (S,S)-2,20-methylenebis(4-
tert-butylcarbamoyl-2-oxazoline) ((S,S)-tBuboxamH2,
1S) and its enantio-isomer, (R,R)-tBuboxamH2, (1R),
was synthesized by reaction of the corresponding L-
and D-serine amide hydrochlorides (7.5 mmol) and
diethyl malonoimidate dihydrochloride (3.0 mmol) in
the presence of triethylamine (6.0 mmol) in acetonirile
solution (40 mL) at room temperature for three days
*
Corresponding author. Tel.: +81 52 735 5240; fax: +81 52 735
5228; e-mail: jitsukawa.koichiro@nitech.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.108

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K. Matsumoto et al. / Tetrahedron Letters 46 (2005) 5687–5690
Steric repulsion
Inhibition ofre-face attack
O
N
H
(S)
Hydrogen
O
bond
N
O
Cu
Promotion of si-face attack
N
N
(S)
O
NH
O
Figure 1. Interligand interactions controlling the selectivity for asym-
metric Diels–Alder reaction.
Figure 2. Crystal structure of [Cu(1S)(bpha)] complex (3). Typical
˚
bond lengths (A) and angles (deg) are as follows: Cu(1)–O(1L)
1.936(3), Cu(1)–O(2L) 1.933(3), Cu(1)–N(1A) 1.927(4), Cu(1)–N(1B)
1.917(4). O(1L)–Cu(1)–O(2L) 83.0(1), O(1L)–Cu(1)–N(1A) 93.4(2),
O(1L)–Cu(1)–N(1B) 170.0(2), O(2L)–Cu(1)–N(1A) 173.1(2).
O
O
O
EtO
OEt
X
Et3N
-Cl+H3N
+
N
O
N
O
1S and the hydroxamate oxygens of BPHA in 3 were
NH NH2
•2HCl
CH3CN, rt. 3days
OH
˚
˚
3.369(6) A for N2A–O1L and 3.246(6) A for N2B-O2L,
respectively, which were within hydrogen bonding
distances. This finding indicates that the amide moiety
introduced into the Box derivative acts as the hydrogen
bonding site. In comparison with the generally used
Box ligand, (S,S)-2,20-methylenebis(4-tert-butyl-2-oxaz-
oline) ((S,S)-tBuboxH2, 4), the stereochemistry around
the oxazoline 4-position of 1S was reverse. In addition,
two tert-butyl groups attached to the amide moiety of
1S were very close to the phenyl substituents of BPHA.
X
X
X = NHtBu (1S)
= OiPr (2S)
O
N
O
R = CONHtBu (1R)
= tBu (4)
N
R
R
Scheme 1. Synthesis of novel Box ligands.
˚
The mean distance of C9Aꢀ ꢀ ꢀPhA was 3.59 A and that
˚
of C8Bꢀ ꢀ ꢀPhB was 3.98 A, respectively. Such an attrac-
(Scheme 1). After evaporation of the reaction solution,
30 mL of water was added to the residue. Organic phase
was extracted with ethyl acetate twice and washed with
brine. Formation of amide compounds, 1S (56% iso-
lated yield) was confirmed on the basis of their 1H
NMR and ESI-mass spectra.12 The ester derivative,
(S,S)-2,20-methylenebis(4-isopropoxycarbonyl-2-oxazo-
line) ((S,S)-iPrboxesH2, 2S), was synthesized according
to the same procedure using L-serine ester hydrochloride
(74% isolated yield). The designed interligand inter-
action was demonstrated on the ternary copper(II)
complex consisting of 1S and N-benzoyl-N-phenyl-
hydroxylamine (BPHA), which was synthesized as
follows: a solution of 1S (35.8 mg, 0.10 mmol), Cu-
(OTf)2Æ6H2O (47.2 mg, 0.10 mmol), and BPHA (21.8
mg, 0.10 mmol) in THF (5 mL) was stirred at room
temperature, to which a few drops of triethylamine in
mixture of CH2Cl2 and diethylether were added. Slow
evaporation of the solvent gave an orange platelet of
single crystals of [Cu(1S)(bpha)] (3) suitable for X-ray
diffraction analysis.13
tive approach of methyl group to aromatic ring is inter-
1
preted by the CH-p interaction, although the H NMR
spectroscopic investigation is not carried out because
of the paramagnetic character of copper(II) species.15
In complex 3, the bond lengths and angles between
copper ion and the nitrogen atoms (Cu1–N1A =
˚
1.927(4), Cu1–N1B = 1.917(4) A and N1A–Cu1–
N1B = 93.3(2)ꢁ) were similar to those of the other
Cu(II)–box complexes previously reported.4,16,17 The
coordination mode of hydroxamic acid moiety of BPHA
to copper(II) was also similar to that of Cu(amin-
ophenylhydroxamic acidato)2 complex.18
Since chiral bis(oxazoline) copper(II) complexes are
known to be versatile catalysts for asymmetric Diels–
Alder reactions,4,16 the catalytic performance of the
transition metal complex consisting of 1S was investi-
gated as illustrated in Scheme 2. Asymmetric Diels–Alder
O
Cu(OTf)2 •6H2O (5 mol %)
In the crystal structure of 3 (Fig. 2), two bidentate
ligands, 1S and BPHA, coordinated to copper(II) ion
with square planar geometry, of which torsion angle
between N1A–Cu1–N1B and O1L–Cu–O2L plane was
7.5ꢁ. The absolute configuration of 3 was determined
on the basis of the Flack parameter of X-ray analysis.14
Notably, the distances between the amide nitrogens of
N
Box ligand (12 mol %)
+
THF, rt., 3 days
N
O
BAP
CHD
BPCD(5)
Scheme 2. Asymmetric Diels–Alder reaction catalyzed by copper-Box
complex.

K. Matsumoto et al. / Tetrahedron Letters 46 (2005) 5687–5690
Table 1. Asymmetric Diels–Alder reaction with BAP and CHDa
5689
reaction was carried out using benzylidene-2-acetyl-
Box ligand
Yield (%)b of 5
ee (%)c
pyridine (BAP) as a dienophile and 1,3-cyclohexadiene
(CHD) as a diene.19 Generally, CHD is known to be a less
reactive diene in comparison with cyclopentadiene,20 but
in this system catalyzed by copper(II) complex with 1S,
the Diels–Alder reaction product was obtained.
1S
78
51d
0e
4
>99
>99
—
>99
>99
—
2S
4
4
0
Nonef
To a reaction mixture of Box ligand (1S, 0.12 mmol)
and Cu(OTf)2Æ6H2O (0.05 mmol) in THF (4 mL) was
added benzylidene-2-acetylpyridine (BAP, 1.0 mmol)
and then stirred for 20 min at room temperature. After
complexation of the ternary copper(II) complex, 1,3-
cyclohexadiene (CHD, 5 mmol) in THF (1 mL) was
added. The reaction solution was stirred for three days
at 20 ꢁC and monitored at appropriate time by HPLC
analysis. Evaporation of THF in vacuo gave a crude res-
idue, which was purified through silica gel column eluted
with a mixture of hexane/ethyl acetate (10:1). Recrystal-
lization of the obtained residue from column separation
in acetone/ethanol solution gave single crystals of the
reaction product, endo-(pyridin-2-yl)(3-phenylbicy-
clo[2,2,2]oct-5-ene-2-yl)methanone (BPCD 5, isolated
yield 51% based on BAP used).21 The crystal structure
of 5 is shown in Figure 3.22 To our knowledge, 5 is
the first Diels–Alder reaction product. Introduction of
hydrogen bonding site into the Box ligand can promote
the Diels–Alder reaction even though using CHD as a
poor reactive diene.
a Reaction condition: Box ligand (0.12 mmol), Cu(OTf)2Æ6H2O
(0.05 mmol), BAP (1.0 mmol), and CHD (5.0 mmol) in THF (5 mL),
20 ꢁC, 3 days.
b Yield was based on the starting BAP and analyzed by HPLC.
c Determined by chiral HPLC.
d Isolated yield.
e Addition of 2-propanol (0.5 mL).
f Only copper salt without Box ligand.
5 was formed in this reaction system. In the cases with-
out copper(II) ion or the Box ligand, this reaction did
not give any reaction product at 25 ꢁC. Using 1R instead
of an antipodal form of 1S, the enantio-isomer of BPCD
was obtained selectively. In the case of ester ligand,
(S,S)-iPrboxesH2 (2S), the yield of 5 was very low (4%
yield in HPLC analysis, after 3 days). The copper(II)
complex having chiral ligand 4 also showed poor cata-
lytic activity for Diels-Alder reaction (4% yield of 5 in
HPLC analysis, after 3 days). These results summarized
in Table 1 indicate that the copper complexes with 2S
and 4 show less reactivity than those with 1S and 1R.
Neither electron-withdrawing ester group such as 2S
nor electron-donating tert-butyl one such as 4 attached
to oxazoline ring affects the reactivity. In order to clarify
the effect of amide group, 2-propanol was added to the
above reaction system consisting of 1S. With co-exis-
tence of 2-propanol, as known to inhibit formation of
hydrogen bonding interaction, Diels–Alder reaction
product 5 was not obtained. Accordingly, the interli-
gand hydrogen bonding interaction as designed plays
an important role for the catalytic activity.
In HPLC analysis with chiral column,23 two product
peaks were observed; one was enantio-pure BPCD (5,
78% yield, >99% ee) and another was an unidentified
compound. Regrettably, the unidentified compound
was unable to be characterized, because it was easily
decomposed to BAP after isolation. Any other peak esti-
mated to be exo-isomer was not detected. The enantio-
isomer of 5, which was formed from the reaction cata-
lyzed by the copper complex consisting of 1R, was not
detected. Obviously, no stereo- and enantio-isomer of
In conclusion, novel chiral bis(oxazoline) ligand bearing
amide group attached to oxazoline 4-position were syn-
thesized from chiral amino acid derivatives. The copper
complex with this ligand showed the catalytic perfor-
mance of the asymmetric Diels–Alder reaction with high
enantio- (>99%) and stereo-selectivities (endo-form
only). Such higher selectivity of the copper complex with
newly prepared ligand compared with the previous Box
one is interpreted by the introduction of the non-cova-
lent interaction sites.
Acknowledgements
This work was supported partly by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan.
Supplementary data
˚
Figure 3. Crystal structure of BPCD (5). Typical bond lengths (A) and
angles (deg) are as follows: O(1)–C(6) 1.214(5), C(7)–C(14) 1.535(5),
C(9)–C(10) 1.537(6), C(12)–C(13) 1.330(6). O(1)–C(6)–C(5) 118.1(4),
O(1)–C(6)–C(7) 123.0(4), C(7)–C(8)–C(9) 106.7(3), C(11)–C(12)–C(13)
113.0(4), C(8)–C(13)–C(12) 114.9(4).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.06.108.

5690
K. Matsumoto et al. / Tetrahedron Letters 46 (2005) 5687–5690
3
3041.3(8) A , l(MoKa) = 7.68 cmꢁ1
, F(000) = 1316.00,
˚
References and notes
Dcalcd. = 1.370 g cmꢁ3. All measurements were made on
a Rigaku/MSC Mercury CCD diffractometer with graph-
ite monochromated MoKa radiation (k = 0.71070 A). The
final cycle of full-matrix least-squares refinement was
based on 2632 observed reflections (I > 2.00r(I)) and 386
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J. Tetrahedron: Asymmetry 1998, 9, 1–45.
˚
variable parameters, R = 0.057, Rw = 0.083.
2
14. Flack parameter
x
is defined as follows: jFj =
2
2
(1 ꢁ x)jF(+)j + xjF(ꢁ)j . In the analysis of 3, the value
of x is 0.018808, which is very close to 0 and far from 1,
indicating that the analyzed structure of 3 is established.
15. Mizutani, M.; Tomosue, S.; Kinoshita, H.; Jitsukawa, K.;
Masuda, H.; Einaga, H. Bull. Chem. Soc. Jpn. 1999, 72,
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1
21. Spectral data for 5: H NMR (300 MHz, CDCl3) d 1.10
(m, 1H), 1.43 (m, 1H), 1.80 (m, 1H), 2.02 (m, 1H), 2.68 (m,
1H), 3.04 (m, 1H), 3.55 (d, 1H), 4.57 (d, 1H), 6.04 (t, 1H),
6.60 (t, 1H), 7.18 (m, 1H), 7.30 (m, 2H), 7.36 (m, 2H), 7.42
(m, 1H), 7.78 (m, 1H), 7.99 (m, 1H), 8,88 (m, 1H). ESI-
mass m/z = 290.1 [C20H19NO+H]+. Anal. Calcd for
C20H19NO: C, 83.01; H, 6.62; N, 4.84. Found: C, 82.90;
H, 6.63; N, 4.82.
10. Ait-Haddou, H.; Hoarau, O.; Cramailere, D.; Pezet, F.;
Daran, J.-C.; Balavoine, G. G. A. Chem. Eur. J. 2004, 10,
699–707.
11. Kitamura, H.; Ozawa, T.; Jitsukawa, K.; Masuda, H.;
Aoyama, Y.; Einaga, H. Inorg. Chem. 2000, 39, 3294–
3300.
22. Crystal data for 5: Formula weight = 289.38 (C20H19NO),
orthorhombic, space group P2221 (No. 20), Z = 8,
1
12. Spectral data for 1S: H NMR (300 MHz, CDCl3) d 1.36
˚
a = 11.886(1), b = 14.941(2), c = 17.519(2) A, V =
(s, 18H), 3.42 (br s, 2H), 4.45–4.55 (m, 4H), 4.59–4.62 (m,
2H), 6.41 (br s, 2H). ESI-mass m/z = 353 [C17H28N4O4+
H]+. For 2S: 1H NMR (300 MHz, CDCl3) d 1.25–1.30
(dd, 12H), 3.47 (br s, 2H), 4.42–4.53 (m, 4H), 4.69–
4.76 (m, 2H), 5.07 (br s, 2H). ESI-mass m/z = 327
[C15H22N2O6+H]+.
3
3112.2(6) A , l(MoKa) = 0.75 cmꢁ1
,
F(000) = 1232.00,
. The final cycle of full-matrix
˚
Dcalcd. = 1.235 g cmꢁ3
least-squares refinement was based on 2637 observed
reflections (I > 2.00r(I)) and 240 variable parameters,
R = 0.087, Rw = 0.169.
23. HPLC condition for analysis of the asymmetric Diels–
Alder reaction: Chiral column, Chiralcel OD-H 25 cm ·
4.6 mm/. Eluent: hexane/2-propanol = 97:3; k = 254 nm.
13. Crystal data for 3: Formula weight = 627.20 (C30H37Cu-
N5O6), orthorhombic, space group P212121 (No. 19),
˚
Z = 4, a = 9.818(2), b = 13.469(2) c = 23.000(4) A, V =