Enantioselective preparation and structural and conformational analysis of the chiral solvating agent α,α′-bis(trifluoromethyl)-1,8- anthracenedimethanol

Article abstract of DOI:10.1016/j.tetasy.2005.08.005

The preparation of the enantiomers of α,α′- bis(trifluoromethyl)-1,8-anthracenedimethanol is described, and their conformational behaviour studied. These enantiomers are very active when used as chiral solvating agents in the presence of several compounds.

Full text of DOI:10.1016/j.tetasy.2005.08.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3084–3093
Enantioselective preparation and structural and
conformational analysis of the chiral solvating agent
0
a,a -bis(trifluoromethyl)-1,8-anthracenedimethanol
a
a
a
b
Miriam P e´ rez-Trujillo, Itziar Maestre, Carlos Jaime, Angel Alvarez-Larena,
b
a,
*
Juan Francesc Piniella and Albert Virgili
a
Departament de Qu ı´ mica, Universitat Aut o` noma de Barcelona, E-08193 Bellaterra, Barcelona, Spain
Departament de Geologia, Universitat Aut o` noma de Barcelona, E-08193 Bellaterra, Barcelona, Spain
b
Received 18 July 2005; accepted 1 August 2005
Dedicated to Professor J. Castells in the 80th anniversary
0
Abstract—The preparation of the enantiomers of a,a -bis(trifluoromethyl)-1,8-anthracenedimethanol is described, and their confor-
mational behaviour studied. These enantiomers are very active when used as chiral solvating agents in the presence of several
compounds.
ꢀ
2005 Elsevier Ltd. All rights reserved.
13
Kishi proposed14 the creation of C NMR databases
in chiral solvents.
1. Introduction
The determination of enantiomeric composition by
NMR using the addition of a chiral solvating agent
If a CSA can be used in moderate quantities (1–3 equiv)
and if both the substrate and the CSA can be recovered
after the analysis, the process of enantiodistinction by
NMR is both economical, and practical. We have de-
1
(
CSA) has been shown to be a valid methodology.
2
After the description of the highly useful Pirkle alco-
hol, several molecules have been used as CSAs: deriva-
tives of binaphthol or of natural compounds such as
quinine and others that form hydrogen bonds or dipo-
lar or p-stacking interactions to generate relatively sta-
ble supramolecular entities. Macrocycles, such as
calixarenes or cyclodextrins, have also been used as
CSAs, with particularly successful results in the aqueous
3
4
15
scribed the preparation and use of the enantiomers
5
6
0
of a,a -bis(trifluoromethyl)-9,10-anthracenedimethanol
1, a highly active CSA that separated most of the mix-
1
6
tures of enantiomers assayed (Scheme 1).
7
8
F C
F C
F C
3
3
3
9
10
phase. Chiral liquid crystals and gels also afford valu-
able methods to differentiate enantiomers.
HO
H
11H
HO
H
HO
11
12
8
9
1
4
8
9
1
The determination of the absolute configuration by
NMR using chiral auxiliaries is better achieved using
5
11
12
5
10
4
1
1
chiral derivatizing agents. The dynamic character of
the association complexes formed using a CSA means
that it is difficult to assume only one defined way of
association, as well as the absolute configuration. How-
H
OH
F C
3
1
2
1
2
0
ever, some examples have been described. A recent
Scheme 1. Structures of (R,R)-a,a -bis(trifluoromethyl)-9,10-anthra-
cenedimethanol 1 and (R,R)-a,a -bis(trifluoromethyl)-9,10-anthracene-
1
3
0
case has been published using Boc-phenylglycine and
dimethanol 2.
The main factors conferring this capacity are: (i) the
presence of two chiral groups containing two highly
*
0
Corresponding author. E-mail: albert.virgili@uab.es
957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.005

M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
3085
acidic hydroxyl groups; (ii) the presence of a large aro-
matic group and (iii) the possibility of a cisoid confor-
mation capable of forming two hydrogen bonds with
the substrate at the same time. Due to its wide range
of application and its capacity to distinguish between
enantiomers, compound 1 has been commercialized.
Thanks to the relatively acidic character of this com-
pound, it can be used to discriminate substrates with
basic functions such as amine groups, carbonyl groups,
etc.
The synthesis was started from 1,8-dichloroanthraqui-
1
7
none 3. The substitution of chlorine by bromine with
KBr gave 1,8-dibromoanthraquinone 4 in 62% yield.
Compound 4 was reduced to 1,8-dibromoanthracene 6
by two consecutive reduction–dehydration reactions
using NaBH as a reducing agent in two different sol-
4
vents (methanol and diglyme). This process has only
1
8
been described for chloro- and iodoanthraquinones.
The first reaction gave 4,5-dibromo-9-anthrone 5 (68%
yield), which was isolated and characterized, while the
second reaction gave compound 6, 1,8-dibromoanthra-
1
9
We hypothesized that the range of CSAs could be
extended by inserting active groups at other positions
on anthracene. We thus decided to attempt the synthesis
cene, in 69.5% yield from quinone 4. Alternatively,
the complete reduction of 4 to 6 was also carried out
after nine days of reaction (71% yield) with a great
0
20
of a,a -bis(trifluoromethyl)-1,8-anthracenedimethanol
excess of aluminium sec-butoxide.
2
, study its structure and examine its inductive chiral
properties. This compound conserves the capacity to
interact with substrates, forming two hydrogen bonds
at the same time. In addition, the accessibility of carbon
atom 10 indicates that this compound might have other
future applications.
By extension of the methodology previously applied,21
the generation of the dilithium derivative from butyl
lithium and the subsequent reaction with trifluoroacetic
anhydride yielded 1,8-trifluoroacetylanthracene 7 (52%).
This intermediate product 7, was isolated and character-
ized by NMR. 1-Trifluoroacetylanthracene 8 was
detected and isolated as a sub-product of the reaction.
2
. Results and discussion
Compound 7 was reduced with NaBH , giving a mixture
of diastereoisomers: meso-2 and racemic (R,R)-2 and
4
2
.1. Synthesis and resolution
(
S,S)-2 in moderate yield (52%). The enantioselective
0
a,a -Bis(trifluoromethyl)-1,8-anthracenedimethanol
2
reduction of diketone 7 was carried out by the asymmet-
ric CBS reduction, as recently applied to the reduction
of 1,8-trifluoroacetylanthracene in the direct prepara-
tion of the enantiomers of 1. In this way, the reduction
of 7 using catecholborane and (S)-oxazaborolidine gave
2
2
was prepared in its enantiopure form and as a mixture
of isomers. The two synthetic routes differ only in the
last step, the reduction of the prochiral diketone 7
2
3
(
Scheme 2).
Cl
O
Cl
Br
O
Br
Br
Br
KBr
NaBH4
5
O
O
O
3
4
NaBH4
Br
Br
F3C
O
F3C
O
1) BuLi
6
2
) (CF CO) O
3 2
7
CBS reduction.
Cat. S
OH
OH
H
H
F3C
OH F3C
F3C
H
H
F3C
OH
NaBH4
1
2
11
9
8
1
7
6
2
3
5
10
R,R)-2
4
(RS,RS)-2+(RS,SR)-2
(
Scheme 2. Synthesis of alcohol 2.

3086
M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
0
(
2
R,R)-a,a -bis(trifluoromethyl)-1,8-anthracenedimethanol
O–HÁ Á ÁO participates in a three-centre hydrogen bond
where an intramolecular O–HÁ Á ÁF is present. Geometric
data of hydrogen bonds are:
in 89% yield, with only 1.7% of meso-2 compound,
which could have been separated by flash chromato-
graphy.
˚
˚
O21H21Á Á ÁO22i: O21–H21, 0.82 A; H21Á Á ÁO22i, 2.00 A;
˚
The enantiomeric composition was always established
by preparation of diacetate derivatives 9 that were sepa-
rated by analytical chiral HPLC. The selectivity was
O21Á Á ÁO22i, 2.753(6) A; O21–H21Á Á ÁO22i, 152ꢁ. i: x + 1,
y, z.
˚
9
7%.
F6Á Á ÁO22H22Á Á ÁO21ii: O22–H22, 0.82 A; H22Á Á ÁO21ii,
˚
˚
2
.20 A; O22Á Á ÁO21ii, 2.882(6) A; O22–H22Á Á ÁO21ii,
˚ ˚
The diacetate derivative of racemic 2, compound 9, was
prepared quantitatively by treatment with acetyl chlo-
ride and used to isolate pure enantiomers by HPLC on
a semi-preparative Whelk-O2 chiral column using hex-
ane/isopropyl alcohol (98:2) as the eluting solvent
141ꢁ; H22Á Á ÁF6, 2.37 A; O22Á Á ÁF6, 2.780(6) A; O22–
H22Á Á ÁF6, 112ꢁ; O21Á Á ÁH22Á Á ÁF6, 107ꢁ. ii: x À 1,
Ày + 1, Àz + 1.
Overlapping of the outside aromatic rings of anthracene
provides additional stabilization to infinite chains by p-
interaction. Two stacks of parallel molecules can be ob-
(
(
3 mL/min). The first compound eluted was (À)-9 (the
R,R)-9 as described below); the second compound
˚
was the optically inactive meso-9 and the third was
+)-9 [(S,S)-9]. Their hydrolysis yielded the correspond-
served in every chain (Fig. 1) with a distance of 3.59 A
(
between two adjacent parallel molecules. Polar groups
(and the network hydrogen bonds) lie between the two
stacks, in the middle of the chain.
ing pure enantiomers (À)-(R,R)-2 and (+)-(S,S)-2,
respectively. The direct formation of the diacetates pre-
pared from each pure enantiomer obtained by the enan-
tioselective reduction of diketone 7, (À)-(R,R)-2 and
The asymmetry observed in the solid phase was not seen
1
(
(
+)-(S,S)-2, also gave the diacetates (À)-(R,R)-9 and
+)-(S,S)-9, respectively.
in the liquid phase. The H NMR (CDCl ) spectrum
3
affords only seven signals, indicating the kinetic equiva-
lence of protons H /H , H /H , H /H and H /H .
2
7
3
6
4
5
11
12
2
.2. Structural study
Moreover, no changes were observed in the spectrum
at low temperature (220 K), indicating a rapid rotation
of the C –C and C –C bonds. The NOE experiment
The crystal structure of (À)-(R,R)-2 was studied by X-
1
11
8
12
2
4
ray. Suitable crystals were obtained from an ether
solution (Fig. 1). In the solid state, the molecule adopts
an asymmetrical conformation. On one side the CF3
group defines a torsion angle of nearly 90ꢁ [C2–C1–
C11–C21, 94.9(6)ꢁ], and on the other side the OH substi-
tute is closest to an almost orthogonal plain to the aro-
matic ring [C7–C8–C12–O22, À98.8(6)ꢁ]. In this case,
one of the fluorine atoms of the trifluoromethyl group
forms a hydrogen bond with the hydroxyl group on
the same stereogenic centre.
(Fig. 2) of (R,R)-2 with saturation of H /H revealed a
11 12
high increase of the intensity of H and a very low
9
increase on H /H , indicating the principal proximity
2
7
of H /H with H9.
1
1
12
The theoretical study of its conformational behaviour
started with a Monte-Carlo search (MacroModel pack-
2
5
26
age, using the AMBER*force field ). All conformers
2
3
were obtained by rotation around the two sp –sp bonds
(C –C and C –C ) and the two C–OH bonds, giving a
1
11
8
12
total of 272 structures. Four sets of conformers were
2
3
Molecules are linked by O–HÁ Á ÁO hydrogen bonds
forming infinite chains, in which each oxygen atom acts
as donor and acceptor. Hence, every molecule is linked
to four neighbours (Fig. 1). Moreover, one of the
identified by the rotation around the sp –sp bonds.
These sets will subsequently be referred to as follows:
trans1 (T1), cis (C), crystal (X) and trans2 (T2)
(Fig. 3). Each set contained several rotamers around
Figure 1. X-ray structure of (À)-(R,R)-2.

M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
3087
H9
H2/7
H4/5
H3/6
H9
H10
H2/7
H11/12
9.6 9.4
9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8
ppm)
7.6 7.4 7.2
7.0
6.8 6.6 6.4
(
1
3
Figure 2. H NMR (CDCl ) spectrum of (R,R)-2 and 1D DPFGNOE spectrum after saturation H11/12.
The energy surface corresponding to the rotation of the
2
3
two sp –sp bonds (i.e., the conversion between the tran-
soid and the cisoid conformers) was obtained using the
dihedral angle driver implemented into the Macromodel
(
Fig. 4).
Figure 3. Representative structures for each conformer set: T1 =
trans1; C = cis; X = crystal; T2 = trans2.
the C–OH bonds. Relative energies obtained for the T1,
C, X and T2 conformers (0.0, 2.9, 6.2 and 8.89 kJ/mol,
respectively), suggest that T1 is the most stable, followed
by C (computed populations based on Boltzmannꢀs
distribution were 71.6%, 20.5%, 5.9% and 2.0%,
respectively).
Figure 4. Contour plot for the potential energy (kJ/mol) surface
corresponding to the rotation of the C
bonds.
1 8
–C11 (x1) and C –C12 (x2)
The transition from T1 to T2 must pass through C. Con-
former X is very close in geometry to T1. The transition
state (TS1) between T1 and C is about 5 kJ/mol less
energetic than that (TS2) between C and T2. The overall
T1 and T2 conformers have a C -symmetry axis and the
2
2
3
CF groups are located in a transoid position. In the C
energy barrier for the free rotation around the sp –sp
3
conformer, the cisoid distribution of the substituents sub-
stitutes is asymmetric, while the X conformer is very sim-
ilar to the X-ray structure. Moreover, T1 is the most
stable and the distance between H and H /H (about
bonds is about 54 kJ/mol.
2.2.1. Chiral induction activity. The behaviour of 2 as a
chiral solvating agent was tested with five racemic mix-
tures: 1-(1-naphthyl)ethylamine 10, 1-aminoindane 11,
1-cis-amino-2-indanol 12 and phenylethanediol 13
and 1-phenylethylamine 14 (Scheme 3). Both enantio-
mers of 2 were used, but as the behaviour of the two
9
11
12
˚
A) is consistent with the NOE obtained in CDCl
3
2
shown in Figure 2. The low proportion of the cisoid (C)
conformer may thus be responsible for the other small
NOE observed (Fig. 2) between H /H and H /H .
1
1
12
2
7

3088
M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
HO
H
H
H
H
H
H2N
HO
C
2
H N
CH3
CH3
8
HH
HH
7
7
9
1
3
2
1
1
H
2
1
OH
1
H
H
NH2
NH2
H
H
1
0
12
14
1
1
13
Scheme 3. Compounds evaluated in the enantiodiscrimination tests.
enantiomers in the presence of the same racemic com-
pound is symmetrical the results are always referred to
those obtained with the (R,R)-2 enantiomer.
compound 13 is more selective, while (R,R)-1 differenti-
ated the H of their enantiomers, (R,R)-2 distinguished
1
the H2.
In all cases the experiments were carried out by adding
portions of CSA to a solution (0.05 M) of the racemic
substrate until a maximum increase of non-equivalence
was obtained (2–2.5 equiv). The signals of each enantio-
mer were identified using mixtures enriched in one of the
enantiomers of a known composition. The enantiomeric
identity was based on the integration of the separated
signals.
For each substrate, the maximum enantiodistinction
was obtained with different quantities of CSA. Table 1
shows the greatest difference of chemical shift of H
NMR obtained for several protons of compounds 10–
14 when some quantities of (R,R)-2 were added. In all
cases, the separation was enough to integrate separately
both enantiomers.
1
The study of the association complexes was carried out
The enantiodifferentiation will be shown in three ways:
the variation of the spectra by the addition of variable
quantities of CSA, the graphic illustration of the values
of the difference obtained or giving the maximum sepa-
ration obtained between the enantiomers.
with substrates 10 and 12. The stoichiometry was
checked using the Job plot, indicating a 1:1 composi-
tion of both binding complex.
2
7
Binding constants28 were measured in CDCl by the
3
2
9,30
equimolecular method,
which is based on the results
Figure 5 shows experiments corresponding to com-
pounds 10 and 11 where the enantiodistinction was plot-
ted in front of the molar relation between the
components. The additional curves show the tendency
for a maximum enantiodistinction for each proton mea-
sured. The differences observed between the chemical
shift of the enantiomers using (R,R)-2 were quantita-
obtained with several solutions of identical relative con-
3
1
centrations of the components that form a 1:1 associ-
ation. Under these conditions, the variation of the
chemical shifts (Dd) analyzed as a function of the (Dd/
1
/2
S )
0
(S = concentration) results in a linear relation
0
1
/2
1/2
[Dd = À(d /K) (Dd/S0) ] (d = chemical shift of pure
c
c
3
2
complex). To avoid competitive processes, we used
each pure enantiomer in separate experiments.
1
5
tively similar to those found using (R,R)-1, but
R,R)-2 also enantiodifferentiates nuclei not separated
(
by (R,R)-1, for example, the signals of H of 11, CH3
Tables 2 and 3 show the equilibrium constants obtained
for the association of (R)-10 and (S)-10 with (R,R)-2 and
for the association of (R,S)-12 and (S,R)-12 with (R,R)-
2 at four temperatures. The values of K and Gibbꢀs
energy are slightly lower than those obtained for (R,R)-
1. The difference between the enantiomers increases at
lower temperature.
1
of 10 and H in 12.
2
The obtained spectra for compounds 12 and 13 are rep-
resented in Figures 6 and 7 where one can observe the
variation of the enantiodistinction by the addition of
several quantities of the CSA (R,R)-2. The action on
15
0
.04
0
.030
.025
.020
.015
.010
.005
.000
∆
(∆δ) 0
∆(∆δ) 0.035
A
H1
H8
B
0
.03
0.025
.02
H2
0
0
0
0
0
0
CH3
H3
H2’
0
.015
0.01
.005
0
H9
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0
0.5
1.0
1.5
2.0
2.5
[(R,R)-2] /[10]
[(R,R)-2] /[11]
3
Figure 5. Evolution of the enantiodifferentiation at 300 K of several protons of 10 (A) and 11 (B) (0.05 M in CDCl ) when several portions of CSA
were added at a range of molar ratios.

M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
3089
(
R,S)-12
*
*
*
(
R,S)-12
(S,R)-12
*
*
Equiv. (R,R)-2(
.4
(S,R)-12
*
*
*
*
*
*
* *
R,S)-12
(S,R)-12
*
* *
1
(
S,R)-12
(
R,S)-12
1
0
.8
.5
0
H2
H1
H3
H3’
0.0
4
.44 4.40 4.36 4.32 4.28 4.24 4.20 4.16 4.12 4.08 4.04 4.00 3.96
ppm)
3
.12
3.04
2.96
2.88
ppm)
2.80
2.72
2.64
(
(
Figure 6. Enantiodifferentiation of 1-cis-amino-2-indanol 12 after the addition of several quantities of (R,R)-2.
Table 2. Equilibrium constants (± SD) of the complexes formed
between the enantiomers of 10 with (R,R)-2, measured by the
*
*
(
R)-13
(S)-13
*
*
(
c)
equimolecular method (in CDCl
3
)
*
** *
T/K (R)-10
(S)-10
À1
ꢀ
À1
ꢀ
K
R
/M
DG R=kJ=mol
K
S
/M
DG S=kJ=mol
(
(
b)
a)
2
270
2
3
55
59 ± 9
51 ± 8
18 ± 4
14 ± 2
À8.6 ± 0.3
À8.8 ± 0.3
À6.9 ± 0.5
À6.6 ± 0.4
102 ± 6
58 ± 4
26 ± 1
22 ± 1
À9.8 ± 0.1
À9.1 ± 0.2
À7.7 ± 0.1
À7.7 ± 0.1
H2’
H2
85
00
3.84
3.80
3.76
3.72
3.68
3.64
ppm)
3.60
3.56
3.52
3.48
3.44
3.40
(
Figure 7. Enantiodifferentiation of phenylethanediol 13 using (R,R)-2:
Table 3. Equilibrium constants (± SD) of the complexes formed
between the enantiomers of 12 with (R,R)-2, measured by the
equimolecular method (in CDCl3)
(
(
a) compound 3 pure; (b) addition of 1 equiv of (R,R)-2 to racemic 3;
c) addition of 1 equiv of (R,R)-2 to a mixture 1.5/1 enriched in the
enantiomer (S)-13.
T/K
(R,S)-12
(S,R)-12
À1
RS/M
ꢀ
À1
SR/M
ꢀ
K
DG RS=kJ=mol
K
DG SR=kJ=mol
Table 1. Maximum difference (D(Dd)) between the enantiomers of
2
2
2
2
55
70
85
98
30 ± 2
19 ± 3
19 ± 5
6 ± 1
À8.5 ± 0.3
À7.3 ± 0.8
À7.3 ± 1.2
À4.6 ± 0.1
113 ± 35
69 ± 2
23 ± 1
9 ± 1
À10.0 ± 1.3
À7.8 ± 0.2
À10.6 ± 0.2
À11.8 ± 0.2
10–14 obtained when (R,R)-2 is added
Substrate + (equiv) of (R,R)-2
Proton
D(Dd)/ppm
10 + (2 equiv)
11 + (2.3 equiv)
12 + (1.4 equiv)
H
H
H
3
8
9
0.030
0.024
0.007
0.013
CH
3
Since the differences between the constants of each pair
of enantiomers are small, the greater enantiodifferentia-
tion observed when (R,R)-2 is used may be attributed to
the differences in the geometry of the complexes rather
than the differences of displacement of the equilibrium.
The thermodynamic factor seems to influence the sepa-
ration of the enantiomers only at low temperatures.
H
1
H
2
H
2
H
3
0.034
0.028
0.010
0.021
0
H
1
H
2
H
3
H
3
0.014
0.030
0.013
0.011
1
0
The H NMR spectrum of 10 with (R,R)-2 shows all the
signals shifted upfield. Although H and CH of 10 are
1
1
3 + (1.5 equiv)
4 + (2.4 equiv)
H
2
0.015
9
3
shielded, the H of (S)-10 is more shielded than that of
9
H
7
0.007
0.009
(
R)-10 and, furthermore, the CH3 of (S)-10 is less
CH
3
shielded than that of (R)-10. Therefore, H and CH
9
3

3090
M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
B
Inter.NOE
H (10)
9
Inter.NOE
A
CH (10)
3
H (2)
9
H (2)
1
1
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
Figure 8. 1D NOE spectra of the association (in CDCl
3
) between (R,R)-2 and S-10 after saturation of CH
3
9
(A) and H (B) of compound 10.
The spectra were obtained using the 1D DPFGNOE sequence at 300 K.
of the enantiomers of 10 show an opposite behaviour in
the presence of (R,R)-2. The diastereomeric complexes
of (R,R)-2 with amine 10 were studied by NOE spectra
and obtained (Fig. 8) via gradient selection
allowed and the search was performed by randomly
2
3
3
changing the C(sp )–C(sp ) and C(sp )–O dihedral
angles between 0ꢁ and 360ꢁ. The conformers obtained
(272) were distributed into four groups (see text) on
the basis of the relative positions of the trifluoromethyl
groups. A potential energy surface corresponding to the
3
3
DPFGNOE.
2
3
Figure 8 presents the NOE spectra of complex [(R,R)-
Æ(S)-10] when H and CH of the amine 10 were satu-
simultaneous movement of both C(sp )–C(sp ) bonds
was also computed with the AMBER*force field.
2
9
3
rated, obtaining intermolecular NOE on H and H
9
11
of the alcohol 2. The opposite experiment, that is, the
saturation of H and H of the (R,R)-2, gives the same
5. Experimental
9
11
results.
NMR spectra were recorded at 400.13 and 500.13 MHz
1
The complex [(R,R)-2Æ(R)-10] gave similar NOE results,
so it was impossible to differentiate the complexes on the
basis of NOE information. The presence of NOE indi-
cates a closeness between the atoms of two components
confirming the formation of the complex.
for H. The temperature was controlled to 0.1 ꢁC. The
NMR signals were identified from several 1D (DEPT,
NOE) and 2D (COSY, HMQC and HMBC) spectra.
The experiments of enantiodiscrimination by NMR
were carried out with 0.5 mL of a solution 0.05 M
(
CDCl ) of the tested compounds 10 to 14. After
3
3. Conclusion
addition (at constant volume) of several portions of
1
0
.2–0.5 equiv of CSA (R,R)-2, H NMR spectra were
We can conclude that there are stereochemical differ-
ences dependent on whether the substrate binds to
measured and the variations of the chemical shifts
were calculated for each addition. The measurements
were continued until maximum enantiodiscrimination
(1.5–2.5 equiv) or until precipitation. The NOE experi-
ments on amine 10 complexes were performed on
degassed samples using DPFGNOE sequence with
a 700 ms mixing time.
(
R,R)-1 or (R,R)-2, which indicates that their use in
combination would enable us to differentiate a wide
range of the substrates.
4
. Computational details
The equimolar method was applied (at four tempera-
The Monte-Carlo search was performed with the appro-
tures) to 0.5 mL of a solution (CDCl ) of each enantio-
3
2
5
priate options in the Macromodel v.5 program with an
mer of the substrate 10 or 12 with the CSA (R,R)-2 at
2
6
1
AMBER*force field.
A total of 1000 steps were
identical concentrations (0.05 M each) and the
H

M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
3091
NMR obtained. New values of the chemical shift were
measured after the addition of 0.1 mL of pure solvent,
four times. A straight line (and the corresponding stan-
dard deviation) was obtained after the representation
NMR (125 MHz, CDCl , 298 K): d = 35.3 (C ), 124.7
3 9
(C4a and C ), 127.1 (C and C ), 128.5 (C and C ),
5a
4
5
2
7
132.9 (C and C ), 137.1 (C and C ), 139.0 (C and
1
8
3
6
8a
C ), 182.9 (C@O). EM m/z (%) = 352 (8), 351 (48),
9
a
1
/2
(
Dd in front of (Dd/Sꢁ) ) of Bouquant and Chucheꢀs
272 (63), 244 (10), 193 (2), 163 (100).
equation. The binding constant K was obtained from
1
/2
the slope ((d /K) ) and the chemical shift of the hypo-
5.3. 1,8-Dibromoanthracene 6
c
thetically pure association complex (d ) from the inter-
c
section of the straight line with the Y-axis. The final
value of K was obtained from the averaged value of
those obtained for each proton measured.
A 7:3 mixture of 1,8-dibromoanthrone 5 and 1,8-di-
bromoanthraquinone 4 (9.8 g, 19.1 mmol of 5 and
8.2 mmol of 4) was suspended in diglyme (200 mL).
The mixture was stirred and flushed with nitrogen for
15 min. NaBH4 (4.21 g, 113.3 mmol) was added and
after 2.5 h, methanol (52 mL) was added followed by an-
Chiral semi-preparative HPLC was carried out using an
(
R,R)-Whelk-O1 (250 mm · 10 mm) column and pre-
parative HPLC using an (R,R)-Whelk-O2 (250 mm ·
other portion of NaBH (1.9 g, 50.2 mmol). The orange
4
2
5
1
5 mm) column.
solution was stirred at room temperature overnight and
then glacial acetic acid added to bring the pH to 3–4, fol-
lowed by concentrated HCl to pH < 2. After stirring at
room temperature for 3 h, water was added and the
resulting yellow precipitate collected, washed with water
and dried. The yellow residue obtained was purified by
flash chromatography on silica gel (hexane 100%) to
provide 1,8-dibromoanthracene 6 (6.6 g, 69.5% with re-
.1. 1,8-Dibromoanthraquinone 4
,8-Dichloroanthraquinone 3 (10 g, 36.10 mmol) was
treated with KBr (20 g, 168.05 mmol), CuCl2 (0.5 g,
.72 mmol) and 85% H PO (20 mL) in nitrobenzene
3
3
4
(
75 mL). Water was distilled from the reaction mixture
until the temperature reached 200 ꢁC. Then the mixture
was refluxed for 48 h. The crude was precipitated from
the cooled mixture with methanol, collected, taken up
in CH Cl and isolated by evaporation of the solvent.
spect to 1,8-dibromoanthraquinone 4). Mp: 168–170 ꢁC.
À1
IR m = 2922, 2851, 1665, 1611, 1432, 1338, 1302 cm
.
1
H NMR (500 MHz, CDCl , 298 K): d = 7.32 (dd,
3
J = 8.5 Hz, J = 7.0 Hz, 2H, H and H ), 7.83 (dd, J =
2
2
3
6
Purification of the solid residue by crystallization in
hot nitrobenzene yielded 10.1 g of a 5:4:1 mixture (esti-
mated by GC–MS) of 4, 1-bromo-8-chloroanthraqui-
none and compound 3, as golden needles. The same
procedure was repeated using the last mixture as starting
material and refluxing for 24 h, to give 8.2 g of 4 (62%).
Mp: 152–154 ꢁC. IR m = 3063, 1679, 1659, 1570, 1311,
7.0 Hz, J = 0.9 Hz, 2H, H2 and H ), 7.97 (dd,
7
J = 8.5 Hz, J = 0.6 Hz, 2H, H and H ), 8.42 (s, 1H,
4
5
1
3
H ), 9.19 (s, 1H, H ). C NMR (125 MHz, CDCl3,
1
0
9
298 K): d = 123.8 (C4a and C ), 126.6 (C and C ),
5a
3
6
127.1 (C ), 128.3 (C ), 128.4 (C and C ), 130.4 (C
9
10
4
5
2
and C ), 131.2 (C and C ), 133.1 (C and C ). EM
7
8a
9a
1
8
m/z (%) = 336 (16), 335 (85), 257 (16), 176 (100).
À1
1
1
238 cm
.
H NMR (500 MHz, CDCl , 298 K):
3
d = 7.53 (dd, J = 7.9 Hz, J = 7.9 Hz, 2H, H and H ),
5.4. 1,8-Trifluoroacetylanthracene 7
3
6
8
.01 (dd, J = 8.0 Hz, J = 1.3 Hz, 2H, H and H ), 8.23
2 7
1
3
(
dd, J = 7.8 Hz, J = 1.2 Hz, 2H, H4 and H5).
C
A solution (2.5 M) of butyllithium in hexane (11.9 mL,
29.8 mmol) was slowly added to an anhydrous diethyl
ether (50 mL) solution of 1,8-dibromoanthracene (4 g,
11.9 mmol) kept under N2 with continuous stirring
and at 0 ꢁC. The reaction was completed after 45 min.
Then the mixture was cooled to À78 ꢁC and an excess
of trifluoroacetic anhydride was added dropwise
(20.3 mL, 143 mmol). After 3 h, the trifluoroacetic anhy-
dride was distilled and the solid residue was purified by
flash chromatography on silica gel (hexane/dichloro-
methane 95/5 v/v) to give diketone 7 (2.30 g, 52%).
Mp: 168–170 ꢁC. IR m = 2961, 2931, 2871, 1703, 1554,
NMR (125 MHz, CDCl , 298 K): d = 122.1 (C and
3
1
C ), 126.8 (C and C ), 133.2 (C and C ), 133.4 (C
3
8
4
5
8a
9a
and C ), 135.0 (C and C ), 141.1 (C and C ), 181.4
6
4a
5a
2
7
(
3
C@O), 181.8 (C@O). EM m/z (%) = 365 (33), 337 (7),
09 (10), 230 (13), 150 (85).
5
.2. 1,8-Dibromo-10-anthrone 5
Sodium borohydride (8.26 g, 218.40 mmol) was added,
portionwise, over 15 min to a stirred suspension of 1,8-
dibromoanthraquinone 4 (10 g, 27.32 mmol) in methanol
À1
1
(
300 mL) at À78 ꢁC. After the addition was complete,
1542, 1174 cm . H NMR (500 MHz, CDCl , 298 K):
3
stirring was continued for 3 h and then concentrated
hydrochloric acid (30 mL) was added. The reaction mix-
ture was heated at reflux overnight and then the yellow
precipitate, which formed was collected, washed with
water and dried to give a 7:3 mixture (as estimated by
GC–MS) of anthrone 5 and quinone 4. Compound 5
was purified by flash chromatography on silica gel with
hexane (6.5 g, 68%). Mp: 264–267 ꢁC. IR m = 2961,
d = 7.64 (dd, J = 7.9 Hz, J = 7.9 Hz, 2H, H and H ),
3
6
8.33 (m, 4H, H , H , H and H ), 8.58 (s, 1H, H ),
2
7
4
5
10
1
3
10.6 (s, 1H, H ). C NMR (CDCl , 298 K): d = 116.4
(q, J = 467.7 Hz, 2C, CF ), 123.3 (C ), 124.4 (C
9
3
1
CF
3
9
3
and C ), 126.8 (C and C ), 128.8 (C ), 129.7 (C
6
4a
5a
10
8a
and C ), 131.5 (C and C ), 133.6 (C and C ), 136.1
9
a
1
8
2
7
(C and C ). EM m/z (%) = 369 (58), 300 (100), 273
4
5
(44), 204 (46), 176 (45).
À1
1
2
918, 2850, 1923, 1737, 1454, 1433, 1259 cm
.
H
NMR (500 MHz, CDCl , 298 K): d = 4.19 (s, 2H, H
1-Trifluoroacetylanthracene 8 was also isolated (0.80 g,
24%). Subl. 115–116 ꢁC. IR m = 3056, 2930, 2859,
3
9
and H9
0
), 7.38 (dd, J = 7.9 Hz, J = 7.9 Hz, 2H, H and
3
À1
1
H ), 7.89 (dd, J = 7.6 Hz, J = 1.3 Hz, 2H, H and H ),
1698, 1614, 1535, 1173, 1132 cm
.
H
NMR
6
2
7
1
3
8
.33 (dd, J = 7.6 Hz, J = 1.2 Hz, 2H, H and H ).
C
(500 MHz, CDCl , 298 K): d = 7.51 (dd, J = 8.5 Hz,
4
5
3

3092
M. P e´ rez-Trujillo et al. / Tetrahedron: Asymmetry 16 (2005) 3084–3093
0
J = 7.3 Hz, 1H, H ), 7.55 (m, 2H, H and H ), 8.00 (m,
5.7. a,a -Bis(trifluoromethyl)-1,8-anthracenedimethyl
diacetate 9
3
6
7
1
8
1
H, H ), 8.07 (m, 1H, H ), 8.26 (d, J = 7.2 Hz, 1H, H ),
5
8
4
.29 (d, J = 8.4 Hz, 1H, H ), 8.46 (s, 1H, H ), 9.54 (s,
2
10
1
3
H, H9).
C NMR (125 MHz, CDCl , 298 K):
Dimethylaminopyridine (DMAP) (12.4 mg, 0.102 mmol),
triethylamine (358.5 mg 3.55 mmol) and acetyl chloride
(200.0 mg, 2.55 mmol) were added to a solution of alco-
hol 2 (mixture of isomers) (95 mg, 0.254 mmol in 15 mL
of anhydrous dichloromethane). After 3 h, the reaction
had finished and the mixture was washed in water
(2 · 20 mL), HCl 1 M (2 · 20 mL) and a solution of
3
d = 123.1 (C ), 125.1 (C ), 125.9 (C or C ), 126.7
3
9
1
4a
1
(
C ), 126.7 (q, J = 121.6 Hz, 2C, CF ) 126.8 (C ),
7 CF 3 6
1
27.8 (C ), 127.9 (C ), 127.9 (C ), 129.2 (C ), 131.6
9a 10 5 8
(
(
(
C4a or C ), 131.8 (C ), 133.5 (C ), 133.7 (C ), 137.3
1 5a 4 8a
2
C ), 181.9 (q, JCF = 33.2 Hz, 2C, C@O). EM m/z
2
%) = 274 (24), 205 (28), 179 (100), 177 (36).
1
0% NaHCO (2 · 20 mL). The organic layer was
separated, dried and evaporated and 113 mg (97%) of
3
0
5
.5. a,a -Bis(trifluoromethyl)-1,8-anthracenedimethanol 2
compound 9 obtained. Mp: 160–162 ꢁC. IR m = 3020,
À1
1
Sodium borohydride (25 mg, 0.661 mmol) was added
to solution of 1,8-trifluoroacetylanthracene
128 mg, 0.346 mmol) in diethyl ether (25 mL). After
min of stirring, methanol (14 mL ca.) was added
1768, 1270, 1212–1124 cm
.
H NMR (500 MHz,
a
7
CDCl , 298 K): d (ppm): 2.25 (s, 3H, CH ), 7.05 (q,
3
3
(
5
J = 6.8 Hz, 2H, H ), 7.51 (dd, J = 7.0 Hz, J = 7.0 Hz,
11
2H, H and H ), 7.74 (d, J = 7.0 Hz, 2H, H and H ),
3 6 2 7
dropwise until the bubbling stopped. After 4.5 h the
reduction was completed. The reaction was quenched
and the crude was washed with water (3 · 25 mL),
the organic layer was separated, dried and concen-
trated. The solid residue (mixture of isomers) was
purified by flash chromatography on silica gel (dichlo-
romethane/hexane 95/5 v/v) to provide a pale yellow
solid (119 mg, 92%).
8.07 (d, J = 8.5 Hz, 2H, H and H ), 8.52 (s, 1H, H ),
4 5 10
1
3
9.22 (s, 1H, H9). C NMR (125 MHz, CDCl , 298 K):
3
d = 20.5 (CH ), 70.2 (C ), 119.0 (C ), 124.8 (C and
3
11
9
3
C ), 128.3 (C and C ), 128.5 (C ), 130.8 (C and C ),
6
2
7
10
4
5
168.9 (C@O).
Similar reaction was carried out from pure enantiomers
25
(R,R)-2 and (S,S)-2 obtaining (R,R)-9. ½aŠ ¼ À8.2 (c 2,
25
MeOH) and (S,S)-9. ½aŠ ¼ þ8.2 (c 2, MeOH) in similar
0
5
dimethanol (R,R)-2
.6. (R,R)-a,a -Bis(trifluoromethyl)-1,8-anthracene-
yield.
A 1 M solution of (S)-methyl oxazaborolidine in toluene
Acknowledgements
(
0.65 mL, 0.65 mmol) was added to a solution of 1,8-tri-
fluoroacetylanthracene 7 (288 mg, 0.78 mmol) in anhy-
drous toluene (10 mL) kept under nitrogen with
continuous stirring. The mixture was cooled to À78 ꢁC
and a 1 M solution of catecholborane in toluene
Financial support from CICYT (BQU2003-01231) and
predoctoral UAB grant to M.P-T. is gratefully acknowl-
edged. V. Jimenez from University of Concepci o´ n,
Chile, is also acknowledged.
(
4.0 mL, 4.0 mmol) slowly added (15 min). The reaction
was stirred at À78 ꢁC for 3 h and then left to warm to
room temperature with stirring overnight. The reaction
was quenched and the mixture was washed in water
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6
2
9
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25
½
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