Asymmetric copper-catalyzed Diels-Alder reaction revisited: Control of the structure of bis(oxazoline) ligands

Article abstract of DOI:10.1016/j.tet.2013.06.093

Synthesis of 1,4-bis(oxazoline) ligands bearing a bicyclo[2,2,2]backbone derived from 9,10-dihydro-9,10-ethanoanthacene trans-dicarboxylic acid was revisited. Starting from l- or d-amino alcohols and either (S,S) or (R,R)-dihydroethano trans-dicarboxylic acid, a complete series of ligands was evaluated in the copper-catalyzed Diels-Alder reaction. The most efficient ligands with a phenyl substituent on the oxazoline ring afforded enantiomeric excess up to 98%. This is different from previous results indicating that the best enantioselectivity involved a diastereomeric ligand with the meso-backbone.

Full text of DOI:10.1016/j.tet.2013.06.093

Accepted Manuscript
Asymmetric copper-catalyzed Diels-Alder reaction revisited: control of the structure of
bis(oxazoline) ligands
Paul Le Maux, Vincent Dorcet, Gé rard Simonneaux
PII:
S0040-4020(13)01052-1
10.1016/j.tet.2013.06.093
TET 24569
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 April 2013
Revised Date: 20 June 2013
Accepted Date: 25 June 2013
Please cite this article as: Le Maux P, Dorcet V, Simonneaux G, Asymmetric copper-catalyzed Diels-
Alder reaction revisited: control of the structure of bis(oxazoline) ligands, Tetrahedron (2013), doi:
10.1016/j.tet.2013.06.093.
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ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
Asymmetric copper-catalyzed Diels-Alder reaction revisited: control of the
structure of bis(oxazoline) ligands.
a,
a,
b
Paul Le Maux, * Vincent Dorcet and Gérard Simonneaux *
a
Institut des Sciences Chimiques de Rennes, UMR CNRS 6226, Ingénierie Chimique et
b
Molécules pour le Vivant, and Centre de Diffractométrie, UMR CNRS 6226, Université de
Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
Abstract
Synthesis of 1,4-bis(oxazoline) ligands bearing a bicyclo[2,2,2]backbone derived from
9
,10-dihydro-9,10-ethanoanthacene trans-dicarboxylic acid was revisited. Starting from L- or
D-amino alcohols and either (S,S) or (R,R)-dihydroethano trans-dicarboxylic acid, a complete
series of ligands was evaluated in the copper-catalyzed Diels-Alder reaction. The most
efficient ligands with a phenyl substituent on the oxazoline ring afforded enantiomeric excess
up to 98%. This is different from previous results indicating that the best enantioselectivity
involved a diastereomeric ligand with the meso-backbone.
Keywords: Chiral bis(oxazoline) synthesis; Bicyclo[2.2.2] backbone; Diels-Alder catalysis;
Copper; Enantioselectivity.
*
Corresponding author. E-mail address: paul.lemaux@univ-rennes1.fr (P. Le Maux).
2

ACCEPTED MANUSCRIPT
1
. Introduction
Chiral bis(oxazoline) ligands have emerged as one class of important and efficient C2-
1
-9
symmetric ligands in numerous metal-catalyzed asymmetric transformations. Among them,
a novel class of oxazoline ligands with multiple elements of chirality has been synthesized
from readily available chiral diacid and chiral amino alcohol (Fig. 1). Besides the central
chirality element in the oxazoline moiety, these ligands possess an additional chirality element
10-12
13
in the backbone such as 1,3-dioxolane I,
bicyclo [2,2,1] II, [2,2,2] III, cyclohexane
1
4,15
16
IV,
and cyclopentane V.
Fig. 1.
Although the Diels-Alder reaction between acrylimide dienophiles and
cyclopentadiene was the most successful application of the Cu(II)-bis(oxazoline) catalytic
17-31
system with enantiomeric excess up to 99%,
its application with the ligands I, II, III, IV
and V was less effective in enantioselectivity. In particular, the ligand III, previously
13
introduced by Takacs et al., has particularly focused our attention since the best
enantioselectivity (75%) in the Diels-Alder reaction surprisingly involves the meso-backbone
13
and poor results were obtained with the other chiral configurations. Moreover, the authors
indicated that a phenomenon of epimerization was observed during the synthesis of these
ligands. These results inspired us to reinvestigate the synthesis of these ligands with more
convenient routes to better control the stability of their relative configuration.
3

ACCEPTED MANUSCRIPT
In the present work we revisit this class of bis(oxazoline) ligands in which the two
oxazolines are separated by a dihydroethanoanthracene backbone (Figure 1, III). With the
goal to rationalize and optimize the results obtained in catalysis, a more convenient
preparation of the ligand was first described and the four diastereomers were preparated in
pure form. The effect of structure change of the ligands on the stereochemical outcome of the
asymmetric copper-catalyzed Diels-Alder reaction between N-acryloyloxazolidinone or N-
crotonyloxazolidinone and cyclopentadiene was then fully investigated yielding high
enantiomeric excess (up to 98%). As expected, the best ees were obtained with pure R,R and
S,S bis(oxazoline), provided that the chirality of the backbone matched correctly the chirality
of the bis(oxazoline).
2
. Results and Discussion
The bis(oxazoline) ligands were synthesized from the corresponding 9,10-dihydro-
,10-ethanoanthacene trans-(11S,12S) and trans-(11R,12R) dicarboxylic acid (1) as shown in
9
32
Scheme 1. After chiral separation with brucine, conversion of the diacid into the
16
corresponding acid dichloride by reaction with the oxalyl chloride was accomplished within
h. After removing the solvent and excess oxalyl chloride, the product was used in the next
1
step without purification. Overnight reaction with 2.2 equiv of the amino alcohol in the
presence of triethylamine afforded the expected bis-hydroxyamide 3 as a white solid in 60-
1
8
5% yield. The H NMR analysis confirmed the presence of the desired product as a single
diastereomer. It should be noted that some epimerization occurs with the previously requisited
13
procedure in forming the diamide intermediate.
Conversion of bis(hydroxyamide) 3 to the corresponding bis(oxazoline) 4 was carried
2 2
out in one step by reaction with diethylaminosulfur trifluoride in CH Cl at -78°C followed by
4

ACCEPTED MANUSCRIPT
16,9
base induced cyclisation in 50-80% yield. For the ligand 4d, the bis(hydroxyamide) 3d was
first converted into the bis(amide) dichloride with SOCl and then the cyclization was
2
achieved with aqueous NaOH in 73% yield. The dihydroxyamide 6 with the meso-backbone
33
was synthesized from the anhydride 5 (not the acid) and the (R)-phenylglycinol in the
presence of the coupling reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)
3
4,16
in 77% yield.
The corresponding meso-bis(oxazoline) ligand 7 was prepared using a similar route
2 2
with diethylaminosulfur trifluoride in CH Cl at -78°C. After purification on column
1
chromatography, the H NMR spectrum shows peaks corresponding to ligands 4a and
1
4
e'(15%) due to epimerization (Fig. 2(A)).The H NMR analysis confirms the progressive
disappearance of 7 after 24h (50%, Fig. 2(B)) and after 48 hours, there is total conversion into
the ligands 4a and 4e' in a ratio 53/47 (Fig. 2(C)).
5

ACCEPTED MANUSCRIPT
1
2
12
COOH
HOOC
1
1
HOOC
11
COOH
COOH
+ HOOC
+
Dioxane, Xylene
(
-)-(11S,12S)
1
(+)-(11R,12R)
Brucine Ethanol
COOH
COCl
ClOC
HOOC
ClCOCOCl
CH2Cl2, 0°C
(
-)-2
(-)-1
HOOC
ClOC
COCl
COOH
ClCOCOCl
CH2Cl2, 0°C
(
+)-2
(+)-1
R
R
HO
N
*
O
COCl
OH
a) Et2NSF3
b) K2CO3
*
N
O
*
O
ClOC
N
H
H2N
R
H
Et N
R
3
*
N
H
O
OH
R
+
2
CH Cl
2
CH2Cl2, -78°C
(
-)-2 -(11S,12S)
R = Ph, i-Pr, t-Bu, H
3
a
R = Ph, C*(R)
4a R = Ph, C*(R)
4a' R = Ph, C*(S)
4b R = i-Pr, C*(S)
3
a' R = Ph, C*(S)
3
b
R = i-Pr, C*(S)
R = t-Bu, C*(S)
R = H
3
c
d
4c
4d
R = t-Bu, C*(S)
3
R = H
R
OH
R
*
N
O
HO
O
ClOC
N
*
*
a) Et2NSF3
b) K2CO3
N
H
O
COCl
R
H2N
R
H
*
Et3N
N
O
R
OH
H
+
2
CH Cl
2
CH2Cl2, -78°C
R = Ph
(
+)-2 -(11R,12R)
3e
R = Ph, C*(S)
4e
R = Ph, C*(S)
3
e' R = Ph, C*(R)
4e' R = Ph, C*(R)
Ph Ph
*
Ph
Ph
N
*
N
a) Et2NSF3
*
N
N
*
O
O
(
-)-2 -(11S,12S)
2 3
b) K CO
Et3N
CH Cl
Racemic
+
(R)-Phenylglycinol
3f
O
+
O
(
+)-2 -(11R,12R)
2 2,
CH Cl -78°C
2
2
Racemic 4f
Ph
Ph
OH
OH
O
C
N
O
a) Et2NSF3
b) K2CO3
N
O
O
C
H2N
Ph
H
N
O
O
EEDQ
THF
H
Ph
Ph
OH
N
O
+
H
CH2Cl2, -78°C
(R)-Phenylglycinol
5
6
7
Scheme 1.
6

ACCEPTED MANUSCRIPT
(C)
7
4a
4e'
(B)
(A)
5.00
4.50
4.00
3.50
ppm (t1)
Fig. 2
35
An X-ray structure of the bis(oxazoline) ligand 4a has been solved (Fig. 3). X-ray
diffraction analysis shows that the two chiral oxazoline rings are slightly twisted pushing the
two oxazolinyl phenyl towards the metal centre. In contrast, X-ray structure of the other
diastereomer ligand 4e' (using the (R)-phenyl glycinol and trans-(11R,12R)-dicarboxylic acid
13
1
), showed that the two oxazolinyl phenyl are far away from the metal centre in the
complex.
7

ACCEPTED MANUSCRIPT
Fig. 3.
The Diels-Alder reaction of N-acryloyloxazolidinone 8a or N-crotonyloxazolidinone
1
9
8
b and cyclopentadiene in the presence of various chiral catalysts derived from the ligands 4
and Cu(II) triflate was then investigated. The catalytic results are summarized in Table 1.
8

ACCEPTED MANUSCRIPT
Table 1.
Diels-Alder reaction of 8 with cyclopentadiene catalyzed by Cu(II)(OTf) /bis(oxazoline)
2
a
complexes
b
c
d
Entry
Ligand
Time (min)
Temp (°C) Yield (%)
endo/exo (%)
eeendo (%) (config.)
1
2
3
4
5
6
7
8
4a
4a’
4b
4c
5
10
30
240
10
5
20
20
20
20
20
20
20
20
20
20
0
95
80
80
50
80
95
82
80
82
85
95
93
95
92
94/6
75/25
85/15
88/12
88/12
94/6
93 (R)
21 (R)
16 (R)
10 (S)
20 (R)
94 (S)
22 (S)
76 (R)
77 (R)
89 (R)
95 (R)
98 (R)
96 (S)
98 (S)
4d
4e
4e'
15
10
5
76/24
90/10
88/12
93/7
e
4f
9
7
f
f
1
0
4a
240
5
11
12
13
14
4a
4a
4e
4e
96/4
30
5
-40
0
98/2
96/4
45
-40
98/2
a
Molar ratio of metal/ligand/diene/dienophile: 1/1.2/150/50.
b
Isolated yield of cycloadducts after silica gel chromatography.
c
1
Determined by H NMR and HPLC.
d
Determined by chiral HPLC (Chiralcel OD-H column) and comparison of known optical rotation.
e
Ligand prepared from the racemic trans-dicarboxylic acid 1 and (-)-(R)- phenylglycinol.
f
N-crotonyloxazolidinone as dienophile.
From the results of Table 1, it is shown that the ligands 4a and 4e with the phenyl
substituted oxazoline gave the best ee (93-94%) and endo/exo diastereoselectivity (94/6)
(entries 1 and 6). With the ligand 4a' or 4e', in which the chirality of the oxazoline ring has
9

ACCEPTED MANUSCRIPT
been inverted, the ee was decreased (21%), as well as the diastereoselectivity (75/25) (entries
2
and 7). The ligands with i-Pr 4b and t-Bu 4c gave low ee (< 20%) (entries 3 and 4). The
high reactivity of the catalyst leads to short reaction times (5-10mn) with yields in the range
0-95%, excepted for the bulky t-Bu group (50% yield) in which a longer reaction time was
necessary (4 hours). We also decided to test N-crotonyloxazolidinone 8b as a substrate to
8
13
compare our results with those previously reported. In our hands, the endo-cycloadduct 9
was obtained with 89% ee and R configuration, using 4a as ligand (entry 10), whereas it was
1
3
previously reported an enantiomeric excess of 28% with S configuration in a similar
situation.
The effect of temperature was studied with ligands 4a and 4e. The highest ee and
diastereoselectivity was obtained at -40°C (98% and 98/2 respectively) (entries 12 and 14).
The influence of substitution both on the oxazoline ring and on the backbone moiety
has been investigated with the goal of better understanding the stereocontrol of the Cu(II)-
catalyzed reaction. According to the structure (Fig. 3), we have prepared and tested the four
diastereomeric ligands 4 with the phenyl group on the oxazoline ring (as represented in Fig.
4
). By changing combination of the enantiomers derived from (+) or (-)-trans-dicarboxylic
acid and aminoalcohol, the stereochemistry of the four asymmetric centres can be adjustable.
There are two sets of enantiomer pairs corresponding to the ligands 4a, 4e and 4a', 4e'. The
two phenyl groups on the oxazoline ring of ligand 4a and 4e are placed nearer to the reaction
centre than those of 4a' and 4e', and consequently, have a larger effect on the
enantioselectivity (93% versus 21%). These results show that the degree of asymmetric
induction depends of the chirality on the oxazoline ring in 4a and 4a’ or 4e and 4e'.
Furthermore, with the ligands 4a and 4a’ or 4e and 4e', the same endo-9(R) or 9(S) -
cycloadduct was obtained. The sense of asymmetric induction was logically inverted with the
1
0

ACCEPTED MANUSCRIPT
enantiomeric ligands 4a and 4e or 4a’ and 4e' but also with the ligands 4a and 4e' or 4a’ and
4
e. These results demonstrate that the chiral sense of enantioselection was determined by the
chirality of the backbone. To complete the study, it was also noted that ligand 4d with no
substituent on the oxazoline ring gave an enantioselectivity of 20% (entry 5). This value was
similar to the enantioselectivity obtained with ligand 4a' (entry 2).
In our hands, the ligand 7 gave an ee = 77% for endo-9 (R)-cycloadduct (entry 9).
Actually, this value is very close to that obtained with the ligand 4f derived from the racemic
trans-dicarboxylic acid 1 and (-)-(R)-phenylglycinol, ee = 76% endo-9(R)-cycloadduct (entry
8
). Taking into account the epimerization observed in the NMR study, an epimerization of the
ligand 7 may also occur in the catalytic conditions. Since the epimerization is time dependent,
a study of the ee obtained using ligand 7 over the time course of the catalytic reaction might
be necessary. However, the short time of the catalytic reaction (<5 min) makes this study too
13
difficult. It should be noted that previous results gave an ee of 75% for endo-9(R)-
cycloadduct, quite similar to our results (77% ee).
Fig. 4.
1
1

ACCEPTED MANUSCRIPT
3
. Conclusion
In conclusion, the synthesis of bis(oxazoline) ligands with four asymmetric centres by
combination of the two chiral sources derived from the dihydroethanoanthracene diacid and
aminoacids are revisited, and well-structured chiral ligands have been isolated and
characterized. The copper-catalyzed asymmetric Diels-Alder reaction between N-
acryloyloxazolidinone and N-crotonyloxazolidinone with cyclopentadiene was carried out
with these chiral ligands. The best adapted combination for the ligands 4a and 4e gave ees up
to 98% at -40°C. Studies on the potential of these ligands for other metal-catalyzed
asymmetric reactions are now in progress.
4
4
. Experimental
.1. General
All reactions were performed under argon. Solvent was distilled from appropriate drying
agent, CH Cl from CaH . Commercially available reagents were used without further
2
2
2
purification unless otherwise stated. All reactions were monitored by TLC with Merck
precoated aluminium foil sheets (silica gel 60 with fluorescent indicator UV254). Column
chromatographies were carried out using silica gel from Acros (0.063-0.200 mm). Melting
1
13
points were measured on a banc Kofler. H NMR and C NMR in CDCl were recorded
3
using Bruker (Advance 400dpx) spectrometer at 400 and 100 MHz respectively.The
following abbreviations are used in connexion with NMR; s=singlet, d=doublet, t=triplet,
q=quartet and m=multiplet. Chiral HPLC analysis was performed on a Varian Prostar 218
system equipped with a Chiralcel OD-H column. Optical rotations were recorded with a
Perkin-Elmer 341 polarimeter. High resolution mass spectra were performed by the Centre
Regional de Mesures Physiques de l’Ouest (CRMPO) at Rennes, France, on a Q-Tof2
spectrometer in ESI positif mode.
1
2

ACCEPTED MANUSCRIPT
4
3
.2. General procedure of preparation of bis-hydroxyamides 3a, 3a’, 3b, 3c, 3d, 3e, 3e',
f and 6
Oxalyl chloride (3 equiv) was added dropwise to a cooled suspension (0°C) of the trans-
diacide (-)-1 or (+)-1 and dimethylformamide (15 mol %) in CH Cl (5 mL/mmol) under
2
2
argon. The reaction mixture was stirred at room temperature for 2 h to give a yellow solution
of the trans-diacide chloride (-)-2 or (+)-2. The solvent and excess oxalyl chloride were
removed in high vacuum, the residue was taken up in CH Cl (4 mL/mmol) and added slowly
2
2
to a cold solution (0°C) of the corresponding amino alcohol (2.2 equiv) and Et
3
N (5 equiv) in
CH Cl (2 mL/mmol) under argon. Stirring was continued for 16 h at room temperature. After
2
2
evaporation, the crude product was purified by column chromatography (Hexane-EtOAc-
MeOH).
4
.2.1.
(11S,12S)-Bis[(2’-hydroxy-1’-(R)-phenylethyl)]-amido-9,10-dihydro-9,10-
ethanoanthacene 3a
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11S,12S)-dicarboxylic acid 1 (0.5 g,1.7 mmol) and (-)-
(R)- phenylglycinol (0.65 g, 3.74 mmol). Purification by column chromatography (hexane-
20
EtOAc, 1:9) yielded a white solid (840 mg, 93%): m.p.= 147-148 °C; [α]D = -34 (c 1.44,
1
CHCl
3
); H NMR (400 MHz , CDCl3): δ = 2.91 (s, 2H), 3.66 (br s, 4H), 4.59 (s, 2H), 4.90 (br
1
3
s, 2H), 7.06-7.32 (m, 18H); C NMR (100 MHz, CDCl
3
): δ = 46.8, 49.6, 55.8, 66.07, 123.4,
1
25.4, 126.3, 126.7, 127.6, 128.6, 138.8, 140.1, 143.0, 173.5; HRMS [ESI]: m/z calcd for
+
C H N O Na: 555.2259 (M+Na) , found: 555.2255.
34
32
2
4
4
.2.2.
(11S,12S)-Bis[(2’-hydroxy-1’-(S)-phenylethyl)]-amido-9,10-dihydro-9,10-
ethanoanthacene 3a'
1
3

ACCEPTED MANUSCRIPT
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11S,12S)-dicarboxylic acid 1 (0.5 g,1.7 mmol) and (+)-
(S)- phenylglycinol (0.65 g, 3.74 mmol). Purification by column chromatography (EtOAc-
2
D
0
MeOH , 0:1) yielded a white solid (720 mg, 80%): m.p.= 174 °C: [α]
= +32 (c 0.84,
1
CHCl
3
); H NMR (400 MHz , CDCl3): δ = 2.96 (s, 2H), 3.68 (dd, J = 6.4, 11.6 Hz, 2H), 3.73
(dd, J = 3.6, 11.4 Hz, 2H), 4.59 (s, 2H), 4.90 (dd, J = 7.2, 11.2 Hz, 2H), 7.00-7.04 (m, 6H),
1
3
7
4
.16-7.22 (m, 8H), 7.28, 7.58 (2d, J = 8 Hz, 4H); C NMR (100 MHz, CDCl ): δ = 45.9,
3
8.9, 56.2, 65.6, 123.4, 125.3, 125.9, 126.7, 127.3, 128.4, 139.6, 140.4, 143.3, 173.5; HRMS
+
[
ESI]: m/z calcd for C34
H
32
N
2
O
4
Na: 555.2259 (M+Na) , found: 555.2255.
4
.2.3.
(11S,12S)-Bis[(2’-hydroxy-1’-(S)-isopropylethyl)]-amido-9,10-dihydro-9,10-
ethanoanthacene 3b
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11S,12S)-dicarboxylic acid 1 (0.5 g,1.7 mmol) and (+)-
L-Leucinol (0.438 g, 3.74 mmol). Purification by column chromatography (hexane-EtOAc,
2
D
0
9
:1) yielded a white solid (635 mg, 80%): m.p.= 134-135 °C; [α]
3
= -18 (c 0.55 , CHCl );
1
H NMR (400 MHz , CDCl3): δ = 0.78, 0.80 (2d, J = 6.4 Hz, 12H), 1.09-1.16, 1.22-1.29 (2m,
H), 1.39-1.47 (m, 2H), 2.88 (s, 2H), 3.23 (dd, J = 6.8, 11.4 Hz, 2H), 3.46 (dd, J = 3.6, 11.6
4
13
Hz, 2H), 3.85 (br s, 2H), 4.46 (s, 2H), 7.00-7.06 (m, 4H), 7.21, 7.24 (2d, J = 6.8 Hz, 4H); C
NMR (100 MHz, CDCl
3
): δ = 22.0, 23.2, 24.8, 40.2, 46.9, 49.6, 65.4, , 123.2, 125.4, 126.21,
+
1
5
4
40.3, 143.2, 173.8; HRMS [ESI]: m/z calcd for C30
H
40
N
2
O
4
Na: 515.2885 (M+Na) , found:
15.2883.
.2.4.
(11S,12S)-Bis[(2’-hydroxy-1’-(S)-tert-butylethyl)]-amido-9,10-dihydro-9,10-
ethanoanthacene 3c
1
4

ACCEPTED MANUSCRIPT
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11S,12S)-dicarboxylic acid 1 (1.0 g, 3.4 mmol) and (+)-
(
(
,
S)-tert-Leucinol (0.876 g, 7.48 mmol). Purification by column chromatography
2
0
EtOAc:MeOH, 4:1) yielded a white solid (1.27 g, 77%): m.p.= 220 °C; [α]365 = +57 (c 0.95
1
CHCl
3
); H NMR (400 MHz , CDCl
3
): δ = 2.90 (s, 2H), 2.92 (t, J = 6.8 Hz, 2H), 3.36-3.43
(m, 2H), 3.73-3.79 (m, 4H), 4.62 (s, 2H), 7.10-7.17 (m, 4H), 7.28, 7.42 (2d, J = 6.4 Hz, 4H);
1
3
C NMR (100 MHz, CDCl ): δ = 26.8, 33.5, 46.3, 50.5, 59.6, 62.4, , 123.2, 125.7, 126.3,
3
+
1
26.4, 140.2, 143.4, 174.7; HRMS [ESI]: m/z calcd for C30
found: 515.2887.
.2.5. (11S,12S)-Bis[(2’-hydroxy-ethyl)]-amido-9,10-dihydro-9,10-ethanoanthacene 3d
H
40
N
2
O
4
Na: 515.2885 (M+Na) ,
4
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11S,12S)-dicarboxylic acid 1 (1 g, 3.40 mmol), and
ethanolamine (0.457 g, 7.48 mmol) in THF (5 ml/mmol). Recrystallization from methanol
20
D
1
yielded a white solid (578 mg, 45%): m.p.= 262 °C; [α]
= +40 (c 2.25, CH
3
OH); H NMR
(
400 MHz , CD
quintuplet, J = 7.2 Hz, 4H), 7.24 (d, J = 6.8 Hz, 2H), 7.35 (d, J = 6.4 Hz, 2H); C NMR (100
3
OD): δ = 3.28-3.33 (m, 6H), 3.56 (t, J = 6 Hz, 4H), 4.60 (s, 2H), 7.09
1
3
(
MHz, CD OD): δ = 40.9, 46.5, 59.7, 122.0, 123.8, 124.9, 139.1, 141.7, 172.6; HRMS [ESI]:
3
+
m/z calcd for C22
.2.6.
H
24
N
2
O
4
Na: 403.1633 (M+Na) , found: 403.1633.
4
(11R,12R)-Bis[(2’-hydroxy-1’-(S)-phenylethyl)]-amido-9,10-dihydro-9,10-
ethanoanthacene 3e
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11R,12R)-dicarboxylic acid 1 (0.5 g,1.7 mmol) and (+)-
(S)- phenylglycinol (0.65 g, 3.74 mmol). Purification by column chromatography (hexane-
2
0
EtOAc, 1:9) yielded a white solid (820 mg, 91%): m.p.= 137-138 °C; [α]
D
= +30 (c 0.51,
1
5

ACCEPTED MANUSCRIPT
1
CHCl ); H NMR (400 MHz , CDCl3): δ = 2.92 (s, 2H), 3.64 (m, 4H), 4.58 (s, 2H), 4.89 (dd,
3
13
J = 5.0, 11.8 Hz, 2H), 7.04-7.30 (m, 18H); C NMR (100 MHz, CDCl ): δ = 46.1, 50.1, 55.8,
3
6
6.7, 123.5, 125.5, 126.5, 126.6, 127.8, 128.8, 138.5, 140.0, 143.0, 173.6; HRMS [ESI]: m/z
+
calcd for C34
.2.7.
H
32
N
2
O
4
Na: 555.2259 (M+Na) , found: 555.2255.
4
(11R,12R)-Bis[(2’-hydroxy-1’-(R)-phenylethyl)]-amido-9,10-dihydro-9,10-
ethanoanthacene 3e'
The product was synthesized according to the general procedure described above from 9,10-
dihydro-9,10-ethanoanthacene trans-(11R,12R)-dicarboxylic acid 1 (0.5 g,1.7 mmol) and (-)-
(
R)- phenylglycinol (0.65 g, 3.74 mmol). A white precipitate was formed in the solution and
it was filtered, washed with CH CL and dried in vacuum to provide the corresponding
bis(hydroxyamide) (768 mg, 85%): m.p.= 148-150°C; [α]D = -31 (c 0.71, CHCl ); H NMR
2
2
20
1
3
(400 MHz , CDCl3): δ = 3.19 (s, 2H), 3.75 (br s, 4H), 4.69 (s, 2H), 4.95 (br d, 2H), 7.02 (dd, J
1
3
=
4.0, 8.4 Hz, 2H), 7.19-7.31 (m, 14H), 7.90 (d, J = 7.2 Hz, 2H); C NMR (100 MHz,
CDCl
3
): δ = 46.7, 49.3, 56.1, 65.7, 123.4, 125.4, 126.0, 126.0, 126.7, 128.5, 139.4, 140.4,
+
1
5
4
9
43.3, 173.5; HRMS [ESI]: m/z calcd for C34
H
32
N
2
O
4
Na: 555.2259 (M+Na) , found:
55.2255.
.2.8.
(11S,12S+11R,12R)-Bis[(2’-hydroxy-1’-(R)-phenylethyl)]-amido-9,10-dihydro-
,10-ethanoanthacene 3f
The product was synthesized according to the general procedure described above from
racemic- 9,10-dihydro-9,10-ethanoanthacene trans-dicarboxylic acid 1 (0.5 g,1.7 mmol) and
(-)-(R)- phenylglycinol (0.65 g, 3.74 mmol). Purification by column chromatography
2
0
(
EtOAc), yielded a white solid (690 mg, 76%): m.p.= 150 °C; [α]589 = -33 (c 1.94, CHCl3);
1
H NMR (400 MHz , CDCl3): δ = 3.08 (s, 2H), 3.66 (br s, 4H), 4.60 (s, 2H), 4.87 (br s, 2H),
1
3
6
3
.93-7.22 (m, 16H), 7.77 (d, J = 7.2 Hz, 2H); C NMR (100 MHz, CDCl ): δ = 45.9, 49.3,
1
6

ACCEPTED MANUSCRIPT
5
6.1, 65.8, 123.4, 125.4, 126.0, 126.7, 127.4, 128.5, 139.4, 140.4, 143.3, 173.58; HRMS
+
[
ESI]: m/z calcd for C H N O Na: 555.2259 (M+Na) , found: 555.2255
34
32
2
4
4
.2.9. Bis[(2’-hydroxy-1’-(R)-phenylethyl)]-amido-9,10-dihydro-9,10-ethanoanthacene 6
The product was synthesized from the cis-9,10-dihydro-9,10-ethanoanthacene dicarboxylic
anhydride 5 (225mg, 0.9 mmol), (-)-(R)- phenylglycinol (156mg, 0.9 mmol) and N-
Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (247 mg, 1.0 mmol) in 10 ml of THF at
ambiante temperature for 48 h. Purification by column chromatography (EtOAc-MeOH , 9:1)
2
0
1
yielded a white solid (185 mg, 77%): m.p.= 125-127 °C; [α]589 = -73 (c 0.82 , CHCl
NMR (400 MHz , CDCl3): δ = 3.12 (dd, J = 12.0, 22.8 Hz, 2H), 3.23, 3.26 (2d, J = 6.8 Hz,
H), 3.57-3.63 (m 2H), 3.73, 3.75 (2d, J = 3.6 Hz, 1H), 4.040 (dd, J = 7.2,14.4 Hz, 1H), 4.41
3
); H
1
1
3
(
br s, 1H), 4.80 (m, 1H), 4.90 (m, 1H), 7.02-7.36 (m, 18H); C NMR (100 MHz, CDCl ): δ =
3
4
1
1
6.2, 47.0, 49.4, 50.6, 55.5, 56.2, 65.2, 65.6 123.5, 123.6, 124.5, 126.3, 126.4, 126.9, 127.0,
27.1, 127.2, 127.7, 127.8, 128.7, 128.7, 138.8, 139.3, 139.5, 141.9, 142.4, 142.8, 172.4,
+
73.1; HRMS [ESI]: m/z calcd for C34
H
32
N
2
O
4
Na: 555.22598 (M+Na) , found: 555.2257.
4
7
.3. General procedure of preparation of bis(oxazoline) 4a, 4a’, 4b, 4c, 4d, 4e, 4e', 4f, and
Diethylaminosulfur trifluoride (2.2 equiv) was added dropwise to a cooled suspension (-
8°C) of the corresponding bis-hydroxyamide in dry CH Cl (10 mL/mmol) under argon.
After stirring for 3-5 h at the indicated temperature, anhydrous K CO (3 equiv) was added
7
2
2
2
3
and the reaction mixture was allowed to warm to room temperature. A saturated aqueous
NaHCO solution was added and after phase separation the aqueous layer was extracted with
3
2 2 4
CH Cl . After drying over MgSO and evaporation, the crude product was purified by column
chromatography (Hexane-EtOAc).
1
7

ACCEPTED MANUSCRIPT
4
.3.1. (11S,12S)-Bis[(4’R)-phenyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 4a
The product was synthesized from 3a (0.7 g, 1.31 mmol) according to the general procedure
described above Purification by column chromatography (hexane-EtOAc, 3:2) yielded a white
2
D
0
1
solid (513 mg, 78%): m.p.= 85-86 °C; [α]
3
= +83 (c 0.96, CHCl ); H NMR (400 MHz ,
CDCl3): δ = 3.68 (s, 2H), 4.01 (t, J = 8.0 Hz, 2H), 4.57 (t, J = 9.2 Hz, 2H), 4.82 (s, 2H), 5.01
1
3
(
t, J = 8.4 Hz, 2H), 7.08-7.27 (m, 14H), 7.34, 7.38 (2d, J = 6.4 Hz, 4H); C NMR (100 MHz,
CDCl ): δ = 42.9, 47.0, 69.3, 75.3, 123.9, 125.1, 126.1, 126.3, 126.6, 127.4, 128.6, 140.5,
3
+
1
4
4
42.4, 142.5, 168.8; HRMS [ESI]: m/z calcd for C34
H
29
N
2
O
2
: 497.2229 (M+H) , found:
97.2229.
.3.2. (11S,12S)-bis[(4’S)-phenyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 4a'
The product was synthesized from 3a' (0.50 g, 0.94 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 3:2) yielded a
20
D
1
white solid (300 mg, 68%): m.p.= 177 °C; [α]
3
= +31 (c 0.87, CHCl ); H NMR (400 MHz ,
CDCl3): δ = 3.83 (s, 2H), 3.86 (t, J = 8.0 Hz, 2H), 4.50 (dd, J = 8.4, 10.0 Hz, 2H), 4.78 (s,
2
6
1
H), 4.92 (t, J = 8.8 Hz, 2H), 6.40 (d, J = 8.4 Hz, 4H), 7.05-7.18 (m, 12H), 7.23, 7.36 (2d, J =
13
.8 Hz, 4H); C NMR (100 MHz, CDCl ): δ = 43.1, 46.5, 69.1, 75.9, 124.5, 124.9, 126.3,
3
26.3, 126.4, 127.2, 128.4, 140.9, 142.0, 142.1, 169.2; HRMS [ESI]: m/z calcd for
+
C
34
H
29
N
2
O
2
: 497.2229 (M+H) , found: 497.2229
4
.3.3. (11S,12S)-Bis[(4’S)-isopropyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 4b
The product was synthesized from 3b (0.5 g, 1.0 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 2:3) yielded a
2
0
1
white solid (295 mg, 63%): m.p.= 67-69 °C; [α]D = -11 (c 0.52, CHCl ); H NMR (400 MHz
3
,
CDCl3): δ = 0.65, 0.71 (2d, J = 6.8 Hz, 12H), 0.78, 0.92 (2 quintuplets, J = 7.2 Hz, 4H), 1.30
(
septuplet, J = 6.8 Hz, 2H), 3.46 (s, 2H), 3.69 (t, J = 7.2 Hz, 2H), 3.80 (quintuplet, J = 7.6 Hz,
1
8

ACCEPTED MANUSCRIPT
2
H), 4.13 (t, J = 8.0 Hz, 2H), 4.60 (s, 2H), 6.97-7.05 (m, 4H); 7.13, 7.27 (2d, J = 6.8 Hz, 4H);
1
3
C NMR (100 MHz, CDCl ): δ = 22.6, 22.7, 24.9, 42.3, 45.8, 46.9, 64.0, 73.4, 124.0, 124.6,
3
1
37 2 2
25.8, 126.1, 140.6, 141.8, 166.9; HRMS [ESI]: m/z calcd for C30H N O : 457.2855,
+
(
M+H) , found: 457.2857.
4
.3.4. (11S,12S)-Bis[(4’S)-tert-butyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 4c
The product was synthesized from 3c (0.5 g, 1.02 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 3:1) yielded a
2
D
0
1
white solid (404 mg, 86%): m.p.= 84-86 °C; [α]
3
= -19 (c 0.51 , CHCl ); H NMR (400
MHz , CDCl3): δ = 3.56 (s, 2H), 3.59 (t, J = 9.2 Hz, 2H), 3.86 (t, , J = 8.4 Hz, 2H), 4.07 (t, J =
1
3
8
.4 Hz, 2H), 4.60 (s, 2H), 6.92, 6.98 (2t, J = 7.2 Hz,4H), 7.10, 7.23 (2d, J = 7.2 Hz, 4H); C
NMR (100 MHz, CDCl ): δ = 25.6, 32.9, 43.0, 46.5, 69.1, 75.3, 123.7, 124.9, 125.97, 126.0,
3
+
1
40.8, 142.3, 167.2; HRMS [ESI]: m/z calcd for C H N O : 457.2855 (M+H) ,
30
37
2
2
found:457.2855.
4
.3.5. (11S,12S)-Bis(oxazoline)-9,10-dihydro-9,10-ethanoanthacene 4d
The bis(hydroxyamide) 3d (250 mg, 0.66 mmol) in CH Cl (5 ml) was treated with SOCl
1.56 g, 13.1 mmol). After 15 min, the solution was heated at reflux for 3 h, then recooled to
room temperature and washed sequentially with cold water (10 ml), 0.1 M K CO (2 x 10 ml),
2
2
2
(
2
3
and saturated aqueous NaCl (10ml). After drying over MgSO
4
and evaporation, the crude
1
bisamide dichloride was obtained as a white solid (175 mg, 93%): H NMR (400 MHz ,
CDCl3): δ = 2.84 (s, 2H), 3.45 (m, 8H), 4.55 (s, 2H), 7.04-7.11 (m, 4H), 7.24, 7.29 (2d, J =
+
6
4
.4 Hz, 4H). HRMS [ESI]: m/z calcd for C H N O Cl Na: 439.0956 (M+Na) , found:
22
22
2
2
2
39.0957.
A mixture of the crude bisamide dichloride, 170mg (0.41 mmol), and Na0H (500 mg, 30
mmol) in 50% aqueous MeOH (5 ml) was heated under reflux for 4 hours. After cooling, the
1
9

ACCEPTED MANUSCRIPT
mixture was extracted with CH CL and washed with saturated aqueous NaCl. Column
2
2
chromatography on silica (EtOAc/MeOH, 9:1) yielded the ligand 4d as a white solid (102 mg,
2
D
0
1
7
3%): m.p.= 95-98 °C;, 0.102g (73%). [α]
= +34 (c 1.23, CHCl
3
); H NMR (400 MHz ,
CDCl
3
): δ = 3.38 (s, 2H), 3.44-3.64 (m, 4H), 4.06-4.16 (m, 4H), 4.62 (s, 2H), 6.99-7.05 (m,
1
3
4
1
3
4
H), 7.15, 7.25 (2d, J = 6.4 Hz, 4H); C NMR (100 MHz, CDCl
3
): δ = 42,7, 46.9, 54.1, 67.8,
23.8, 124.7, 126.0, 126.2, 140,4, 142.3, 168.4; HRMS [ESI]: m/z calcd for C H N O :
22
21
2
2
+
45.1603 (M+H) , found: 345.1611.
.3.6. (11R,12R)-Bis[(4’S)-phenyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 4e
The product was synthesized from 3e (0.5 g, 0.94 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 3:2) yielded a
2
0
1
white solid (440 mg, 68%): m.p.= 81-82 °C; [α]D = -82 (c 0.65, CHCl ); H NMR (400 MHz
3
,
CDCl3): δ = 3.58 (s, 2H), 3.92 (t, J = 8.0 Hz, 2H), 4.48 (t, J = 8.4 Hz, 2H), 4.72 (s, 2H),
1
3
5
4.90 (t, J = 8.0 Hz, 2H), 6.96-7.18 (m, 14H), 7.24, 7.28 (2d, J = 6.4 Hz, 4H); C NMR (100
MHz, CDCl
3
): δ = 43,1 46.5, 69.1, 75.9, 124.5, 124.9, 126.3, 126.3, 126.4, 127.2, 128.4,
+
1
4
4
40.9, 142.0, 142.1, 169.2; HRMS [ESI]: m/z calcd for C34
97.2229.
.3.7. (11R,12R)-Bis[(4’R)-phenyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 4e'
H
29
N
2
O
2
:497.2229 (M+H) , found:
The product was synthesized from 3e' (0.5 g, 0.94 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 3:2) yielded a
20
D
1
white solid (407 mg, 63%): m.p.= 178 °C; [α]
3
= -33 (c 0.87, CHCl ); H NMR (400 MHz ,
CDCl3): δ = 3.83 (s, 2H), 3.87 (t, J = 8.0 Hz, 2H), 4.50 (dd, J = 8.4, 10.0 Hz, 2H), 4.78 (s,
2
6
H), 4.92 (t, J = 8.8 Hz, 2H), 6.41 (d, J = 7.2 Hz, 4H), 7.05-7.18 (m, 10H), 7.23, 7.36 (2d, J =
13
3
.8 Hz, 4H); C NMR (100 MHz, CDCl ): δ = 43.1, 46.5, 69.1, 75.9, 124.5, 124.9, 126.3,
2
0

ACCEPTED MANUSCRIPT
1
26.3, 126.4, 127.2, 128.4, 140.9, 142.0, 142.1, 169.2; HRMS [ESI]: m/z calcd for
+
C H N O : 497.2229 (M+H) , found: 497.2229.
34
29
2
2
4
4
.3.8.(11S,12S+11R,12R)-Bis[(4’R)-phenyloxazoline]-9,10-dihydro-9,10-ethanoanthacene
f
The product was synthesized from 3f (0.5 g, 0.94 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 3:2) yielded a
2
0
1
white solid (230 mg, 52%): m.p.= 91-95 °C; [α]D = +13 (c 10, CHCl ); H NMR (400 MHz ,
3
CDCl3): δ = 3.58 (s, 2H), 3.83 (s, 2H), 3.87, 3.91 (2t, J = 8.0 Hz, 4H), 4.45-4.53 (m, 4H),
4
.72 (s, 2H), 4.78 (s, 2H), 4.87-4.95 (m, 4H), 6.41 (d, J = 6.0 Hz, 4H), 6.96-7.37 (m, 32H);
1
3
3
C NMR (100 MHz, CDCl ): δ = 42.8, 43.1, 46.5, 47.0, 69.1, 69.2, 75.3, 75.9, 123.8, 124.5,
1
1
24.8, 125.1, 126.1, 126.2, 126.3, 126.3, 126.4, 126.5, 127.2, 127.4, 128.4, 128.5, 140.4,
40.9, 142.1, 142.3, 142.5, 168.8, 169.2; HRMS [ESI]: calcd for C H N O : 497.2229
34
29
2
2
+
(
M+H) , found: 497.2229.
4
.3.9. Bis[(4’R)-phenyloxazoline]-9,10-dihydro-9,10-ethanoanthacene 7
The product was synthesized from 6 (0.3 g, 0.56 mmol) according to the general procedure
described above. Purification by column chromatography (hexane-EtOAc, 3:2) yielded a
20
1
white solid (90 mg, 54%): m.p.= 60-62 °C; [α]D = +43, c 0.58, CHCl ); H NMR (400 MHz
3
,
CDCl3): δ = 3.18 (d, J = 10.8 Hz, 1H), 3.35 (t, J = 8.4 Hz, 1H), 3.43 (d, J = 8.4 Hz, 1H), 3.54
(dd, J = 2.0, 10.8 Hz, 1H), 4.04, 4.07 (2d, J = 8.4 Hz, 1H), 4.29, 4.31 (2d, J = 8.4 Hz, 1H),
4
.56 (d, J = 2Hz, 1H), 4.81 (s, 1H), 4.93 (t, J = 9.2 Hz, 2H), 5.03 (t, J = 9.4 Hz, 1H), 6.84-7.25
13
(
m, 17 H), 7.42-7.44 (m, 1H). C NMR (100 MHz, CDCl ): δ = 41.6, 41.7, 46.5, 48.8, 69.0,
3
6
1
9.1, 74.6, 74.8, 123.5, 124.0, 124.6, 125.7, 126.3, 126.4, 126.5, 126.7, 126.9, 127.1, 127.3,
28.4, 128.6, 140.7, 141.2, 142.3, 142.4, 142.6, 143.7, 168.0, 168.2. HRMS [ESI]: m/z calcd
+
for C34
H
29
N
2
O
2
: 497.2229 (M+H) , found: 497.2229.
2
1

ACCEPTED MANUSCRIPT
4
.4. General procedure for asymmetric Diels-Alder reaction
A mixture of Cu(II)(OTf) (5ꢀmol, 10 mol % ) and the ligand 4 (6 ꢀmol,) in dry CH Cl (0.2
2
2
2
ml) was stirred for 0.5 h at room temperature under argon. The dienophile (50 ꢀmol in 50 ꢀl
CH Cl ) and freshly distilled cyclopentadiene (150 ꢀmol) were then respectively added. The
2
2
reaction was monitored by TLC and stopped after consumption of the starting substrate. The
reaction mixture was purified on silica gel with hexane-ethyl acetate (3:1) to give a mixture of
endo and exo isomers of cycloadducts 9. The yield was calculated on the basis of the isolated
1
products. The endo/exo ratio was determined by H NMR analysis and confirmed by HPLC
analysis. The enantiomeric excess of the cycloadduct was determined by chiral HPLC
analysis: Daicel Chiralcel OD-H column, hexane-i-PrOH, 95:5, flow rate = 1 ml/min,
detection: 220 ηm. The absolute configuration of the cycloadduct endo-9 product was
assigned based upon the comparison of the sign of optical rotation with the literature values:
(+) for (R)-9 and (-) for (S)-9.
Supplementary data
1
13
Copies of H and C NMR spectra of bis(hydroxyamide) 3a, 3a’, 3b, 3c, 3d, 3e, 3e', 3f and
1
13
6
, copies of H and C NMR spectra of bis(oxazoline) 4a, 4a’, 4b, 4c, 4d, 4e, 4e', 4f and 7,
HPLC chromatograms of selected Diels-alder reactions, X-ray crystallographic data of ligand
a.
4
Legends
Fig. 1. Structure of various chiral bis(oxazoline) ligands linked with a rigid backbone.
1
Fig. 2. H NMR study of the epimerization of ligand 7 in CDCl
3
(A) After purification; Time: 1h
2
2

ACCEPTED MANUSCRIPT
(
B) Time: 24h
C) Time: 48h
(
Fig. 3. ORTEP drawing and atom labeling of ligand 4a
Fig. 4. Cu(II)-complexes of the four diastereomeric ligands 4 and the correlation between
structure of the ligand and configuration of the cycloadduct
Scheme 1. Synthesis of different chiral bis(oxazoline) with a dihydroethanoanthracene
backbone.
References and notes
1
2
3
4
5
6
7
8
9
1
.
.
.
.
.
.
.
.
Bolm, C. Angew. Chem. Int. Ed. 1991, 30, 542-543.
Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-345.
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron Asymmetry 1998, 9, 1-45.
Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467-3494.
McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151-4202.
Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561-3651.
Fraile, J. M.; García, J. I.; Mayoral, J. A. Coord. Chem. Rev. 2008, 252, 624-646.
Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359-5406.
.
0.
Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2011, 111, PR284-PR437.
Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron Asymmetry 1996,
7
, 2453-2462.
1
1
1.
2.
Bedekar, A. V.; Andersson, P. G. Tetrahedron Lett. 1996, 37, 4073-4076.
Bedekar, A. V.; Koroleva, E. B.; Andersson, P. G. J. Org. Chem. 1997, 62, 2518-
2
526.
1
1
3.
4.
Takacs, J. M.; Quincy, D. A.; Shay, W.; Jones, B. E.; Ross II, C. R. Tetrahedron
Asymmetry 1997, 8, 3079-3087.
Kato, K.; Tanaka, M.; Yamamura, S.; Yamamoto, Y.; Akita, H. Tetrahedron Lett.
2
003, 44, 3089-3092.
1
1
1
1
1
2
2
5.
6.
7.
8.
9.
0.
1.
Ma, L.; Du, D.-M.; Xu, J. J. Org. Chem. 2005, 70, 10155-10158.
Atodiresei, I.; Schiffers, I.; Bolm, C. Tetrahedron Asymmetry 2006, 17, 620-633.
Corey, E. J.; Imai, N.; Zhang, H. Y. J. Am. Chem. Soc. 1991, 113, 728-729.
Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-6810.
Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238-1256.
Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460-6461.
Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J. Angew. Chem.
Int. Ed. 1995, 34, 798-800.
2
2
2.
3.
Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1996, 37, 7481-7484.
Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121,
7
559-7573.
2
3

ACCEPTED MANUSCRIPT
2
4.
Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.;
Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc.
1
999, 121, 7582-7594.
2
2
2
2
5.
6.
7.
8.
Evans, D. A.; Tomislaw, R.; S., J. J. Pure Appl. Chem. 1999, 71, 1407-1415.
Johannsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757-5762.
Desimoni, G.; Faita, G.; Righetti, P. P. Tetrahedron Lett. 1996, 37, 3027-3030.
Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem. Eur. J. 2009, 15, 9674-
9
677.
2
3
9.
0.
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron Lett. 1996, 37, 3815-3818.
Davies, I. W.; Gerena, L.; Cai, D.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
Tetrahedron Lett. 1997, 38, 1145-1148.
3
1.
Takacs, J. M.; Lawson, E. C.; Michael Reno, J.; Youngman, M. A.; Quincy, D. A.
Tetrahedron Asymmetry 1997, 8, 3073-3078.
3
3
3
3
2.
3.
4.
5.
Brienne, M.-J.; Jacques, J. Bull. Soc. Chim. Fr. 1973, 190-197.
Bachmann, W. E.; Scott, L. B. J. Am. Chem. Soc. 1948, 70, 1458-1461.
Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651-1652.
Crystal structure data deposited at the Cambridge Crystallographic Data Centre with
deposit number CCDC 935282.
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Supporting Information
Control of the Structure of Bis(oxazoline) Ligands in the Asymmetric
Copper-Catalyzed Diels-Alder reaction Revisited
a,*
a,*
b
Paul Le Maux Vincent Dorcet and Gérard Simonneaux
a
Institut des Sciences Chimiques de Rennes, UMR CNRS 6226, Ingénierie Chimique et
b
Molécules pour le Vivant, and Centre de Diffractométrie, UMR CNRS 6226, Université de
Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
paul.lemaux@univ-rennes1.fr
Table of contents
1
1
13
H and C NMR spectra of compounds 3 and 6
S2-S10
S11-S19
S20-S24
S25-S32
13
H and C NMR spectra of ligand 4 and 7
Selected HPLC chromatograms of Diels-Alder reactions
X-ray crystallographic study of 4a
S1

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1
13
H and C NMR spectra of bis(hydroxyamide) 3 and 6
HO
O
OH
O
(S)
(S)
N
(R) Ph
H
N
H
Ph (R)
3a
7
.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
1
5
0
000
HO
O
OH
O
(S)
(S)
N
(R) Ph
H
N
H
Ph (R)
3a
00
150
100
50
ppm (f1)
S2

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HO
O
OH
O
(S)
(S)
N
(S) Ph
H
N
H
Ph (S)
3a'
8
.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
HO
O
OH
O
(S)
(S)
N
(S) Ph
H
N
H
Ph (S)
3a'
150
100
50
ppm (f1)
S3

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3
2
000
500
HO
2000
O
OH
O
(S)
(S)
i-Pr
N
(S)
H
i-Pr
N
H
(S)
1
1
5
0
500
000
00
3b
7
.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
ppm (f1)
HO
O
OH
O
(S)
i-Pr
N
H
(S)
i-Pr
N
H
(S)
(S)
3b
1
50
100
50
ppm (t1)
S4

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HO
O
OH
O
(S)
(S)
N
H
(S) t-Bu
N
H
t-Bu (S)
3c
7
.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (f1)
HO
O
OH
O
(S)
(S)
N
(S) t-Bu
H
N
H
t-Bu (S)
3c
1
50
100
50
ppm (f1)
S5