Di-2,2,2-trifluoro-1-(9-anthryl)ethyl fumarate, an easy starting point for the enantioselective preparation of trans-cyclohexene-4,5-dicarboxylate derivatives by Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetasy.2006.11.047

Di-2,2,2-trifluoro-1-(9-anthryl)ethyl fumarate has been synthesized from fumaric acid and enantiopure Pirkle alcohol. The Diels-Alder reaction with different dienes employing different reaction conditions was assayed, with high diastereomeric excesses obtained. The structure and geometry of the cycloadducts was analyzed by NMR, molecular mechanics and X-ray diffraction. Hydrolysis made it possible to obtain the enantioenriched trans-cyclohexene-4,5-dicarboxylate derivatives and allow us to recover chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2006.11.047

Tetrahedron: Asymmetry 17 (2006) 3237–3243
Di-2,2,2-trifluoro-1-(9-anthryl)ethyl fumarate, an easy
starting point for the enantioselective preparation of
trans-cyclohexene-4,5-dicarboxylate
derivatives by Diels–Alder reaction
Martina Palomino-Schatzlein,a Albert Virgili,a,* Carlos Jaimea and Elies Molinsb
¨
a
`
Departament de Quı´mica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
`
Institut de Ciencia dels Materials de Barcelona (CSIC), Campus de la UAB, 08193 Bellaterra, Barcelona, Spain
b
Received 9 October 2006; accepted 27 November 2006
Available online 4 January 2007
Abstract—Di-2,2,2-trifluoro-1-(9-anthryl)ethyl fumarate has been synthesized from fumaric acid and enantiopure Pirkle alcohol. The
Diels–Alder reaction with different dienes employing different reaction conditions was assayed, with high diastereomeric excesses
obtained. The structure and geometry of the cycloadducts was analyzed by NMR, molecular mechanics and X-ray diffraction. Hydro-
lysis made it possible to obtain the enantioenriched trans-cyclohexene-4,5-dicarboxylate derivatives and allow us to recover chiral
auxiliary.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
stereoselectivity, and at the same time could be used for the
determination of the enantiomeric purity of the product.
Chiral solvating agents (CSAs) are widely used in NMR
spectroscopy to determine enantiomeric purity in a fast
and simple way. In recent years, a large number of different
CSAs have been developed, achieving excellent results in
the enantiodiscrimination of a variety of organic com-
pounds.1 CSAs have the ability to undergo specific non-
convalent interactions with each enantiomer, forming
differentiable diastereomeric complexes. This property has
made it possible for them to be applied as chiral selectors
in other analytical techniques, such as HLPC and gas chro-
matography with good levels in enantioseparation.2
As has been shown in previous papers,4 several arylalkyl-
carbinols, effective CSAs (Fig. 1), can be used as chiral tem-
plates in the catalyzed Diels–Alder reaction of acrylate
with cyclopentadiene, obtaining satisfactory enantiomeric
relations.5 Recently, the synthesis of a chiral, macrocyclic
dienophile based on a new, highly active CSA, a,a0-bis(tri-
fluoromethyl)-1,8-anthracenedimethanol 1, and fumaric
acid has been reported.6 Cycloaddition of cyclopentadiene
leads to one predominant diastereosiomer (de = 80%). This
result is especially interesting as there are very few studies
in which an asymmetric Diels–Alder reaction of a chiral
However, little is known about the application of CSAs as
chiral auxiliaries in asymmetric reactions, one of the most
important subjects in modern organic synthesis.3 Since
the different chiral characters governing the enantiorecog-
nition are of a similar nature to the interactions that are
responsible for stereoselective synthesis, we expect good
chiral induction capacity from CSA derivatives. Especially
interesting would be the case where the CSA would induce
OH
CF
OH
CF
OH
H CF
H
H
3
3
3
1
2
Figure 1. a,a0-Bis(trifluoromethyl)-1,8-anthracenedimethanol 1 and 2,2,2-
trifluoro-1-(9-anthryl)ethanol 2.
*
Corresponding author. Tel.: +34 93 581 2924; fax: +34 93 581 1265;
e-mail: albert.virgili@uab.es
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.047

3238
M. Palomino-Scha¨tzlein et al. / Tetrahedron: Asymmetry 17 (2006) 3237–3243
disubstituted fumaric chain occurs.7 Nevertheless, the
synthesis of CSA 1 occurs through a five-step route with
12% total yield, which makes it difficult to further general-
ize its application. In contrast, 2,2,2-trifluoro-1-(9-
anthryl)ethanol 2 (Pirkle’s alcohol), a widely used chiral
solvating agent, is commercially available.
A structural study of 3 was carried out by NMR and
molecular mechanics. Exchange peaks (negative) were
observed between the proton pairs H1/H8, H2/H7, H3/H6
and H4/H5 in the 2D NOESY/EXSY spectrum, which
gives evidence of the existence of slow rotation around
1
the sp2–sp3 bonds. A sharp singlet at 7.12 ppm in the H
NMR spectrum corresponds to the magnetically equivalent
olefinic protons of 3. The 2D IFSERF NMR experiment,9
enabled us to measure the coupling constant between the
equivalent protons H13’s (15.9 Hz), corresponding to a
trans position.
Herein we report the application of 2,2,2-trifluoro-1-(9-
anthryl)ethanol 2 as a chiral auxiliary for the synthesis of
chiral trans-cyclohexene-4,5-dicarboxylate derivatives,
attaching two molecules of 2 to fumaric acid and studying
cycloaddition with different dienes.
Molecular mechanics calculations (MacroModel package10
with a MM3* force field11) using genetic algorithms12 affor-
ded four conformations of minimal energy for (R,R)-3, as
depicted in Figure 3. 3A is the predominant, most stable
structure and it can be seen that the si–si face is clearly
more accessible than the re–re face. The same happens with
structure 3B. In contrast, the minor conformations 3C and
3D allow attack from both faces. NOE experiments
showed a major cross relaxation between the olefinic pro-
tons H13 and protons H11, H1 and H8, which is coherent
with geometries 3A and 3B. This analysis allows us to pre-
dict that R,R-3 is predisposed for attack at the si–si face.
2. Results and discussion
The overall process takes place in three steps, as outlined in
Figure 2 for the case of cyclopentadiene. First, the chiral
dienophile is synthesized by esterification of commercially
available fumaryl chloride and enantiopure 2,2,2-triflu-
oro-1-(9-anthryl)ethanol 2. Next, the Diels–Alder reaction
takes place, generating the cycloadduct with up to four
new stereogenic centres. The final enantioenriched trans-
cyclohexene-4,5-dicarboxylate derivate was obtained by
the hydrolysis of the cycloadduct, at the same time making
it possible to recover the chiral auxiliary.
O
OH
CF3
R
O
H
O
O
OH
OH
HO
HO
Esterification
2
Hydrolysis
O
O
O
O
H
O
CF3
O
H
CF3
O
H
R
CF3
O
H
CF3
R
Figure 3. Lowest energy conformations of di-2,2,2-trifluoro-1-(9-anthryl)-
ethylfumarate 3 with their relative energy values, obtained by molecular
mechanics calculations.
3
Diels-Alder
4
2.2. Asymmetric Diels–Alder reaction
Diels–Alder reaction of R,R-3 was first performed with
cyclopentadiene, to give cycloadduct 4a. Different catalysts
and solvents were assayed (Table 1). Working at ꢀ78 ꢁC,
the best result was obtained using EtAlCl2 as a catalyst
in dry dichloromethane, obtaining a diastereomeric ratio
of 80%. Diastereoselectivity was measured by integration
of the olefinic signals in the 1H NMR spectrum of the crude
diastereomeric mixture, and corresponds to the enantio-
selectivity of the final product.
Figure 2. Asymmetric synthesis of trans-cyclohexene-1,2-carboxylic deriv-
atives with 2,2,2-trifluoro-1-(9-anthryl)ethanol 2 as a chiral auxiliary.
2.1. Synthesis of the chiral dienophile
Di[1-(9-anthryl)-2,2,2-trifluoroethyl] fumarate 3 was easily
prepared in both enantiomeric forms, (RR) and (SS), via
a one step procedure from fumaryl dichloride and enantio-
pure alcohol 28 in an 80% yield. Two approaches to dieno-
phile 3 are possible: from either the re–re face or from the
si–si face, leading to different diastereoisomers. C2 symme-
try makes both sides of the faces equivalent, leading to the
same isomers.
In the absence of a catalyst, the diastereoselectivity
dropped to 23% de and also the use of Lewis acids TiCl4
and BF3 led to a lower facial selectivity. Furthermore,
the use of more polar solvents seems to prevent the forma-

M. Palomino-Scha¨tzlein et al. / Tetrahedron: Asymmetry 17 (2006) 3237–3243
3239
Table 1. Yield and diastereomeric excess obtained from the cycloaddition
of cyclopentadiene to dienophile 3 at ꢀ78 ꢁC employing different reaction
conditions
temperatures the reaction took place directly between the
diene and dienophile, without the implication of the Lewis
acid.
Catalyst
Solvent
Yield (%)
dea (%)
After having optimized the reaction conditions with cyclo-
pentadiene, other dienes were tested, giving highly satisfac-
tory results, as summarized in Table 2. In each case,
diastereomeric excess, obtained by the integration of sig-
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
TiCl4
CH2Cl2
Toluene
THF
100
50
75
70
80
73
77
100
80
25
29
42
44
23
31
23
Ether
1
Acetonitrile
CH2Cl2
CH2Cl2
CH2Cl2
nals in the H NMR spectrum, correspond to the enantio-
meric excess of the final product. If the diastereomeric
cycloadduct is purified by chromatography or crystalliza-
tion, in all cases an ee of 100% can be achieved.
BF3ÆOEt2
—
a In all cases, the same major diastereoisomer is obtained.
A complete NMR study of major cycloadducts 4a–4d was
performed after purification by column chromatography.
1
tion of the complex dienophile–EtAlCl2, also resulting in
lower diastereomeric excesses.
The H NMR spectrum of 4b is shown in Figure 4. The
signals of the anthracene ring at the exo-position can be
differentiated from that at the endo-position. In all cases,
the NOE effect was observed between the protons of the
central cyclohexene ring and some protons of the chiral
auxiliary, showing that they are close in space. This led
us to conclude that the geometry of the cycloadducts is
not linear, but folded enabling p-interaction between the
anthracene rings.
To see the effect of the reaction temperature, the cyclo-
addition was carried out in a range of ꢀ100 to 50 ꢁC. We
observed that if the temperature was increased, the reaction
was faster, but with a lower diastereoselectivity: a low
temperature favoured the formation of the activated com-
plex between dienophile 3 and Lewis acid; at higher
Table 2. Diels–Alder reaction between (R,R)-3 and several dienes
Cycloadduct
Diene
Conditions
Yield (%)
100
de (%)
82
4a
ꢀ78 ꢁC, 1 h, 1 equiv EtAlCl2
4b
4c
4d
ꢀ78 ꢁC, 3 h, 1 equiv EtAlCl2
ꢀ78 ꢁC, 2 h, 1 equiv EtAlCl2
ꢀ78 ꢁC, 1 h, 1 equiv EtAlCl2
80
90
95
95
90
90
Figure 4. 1H NMR spectrum at 500 MHz of cycloadduct 4b.

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M. Palomino-Scha¨tzlein et al. / Tetrahedron: Asymmetry 17 (2006) 3237–3243
The crystal structure of the 1:1 adduct of 4d and chloro-
form was studied by X-ray diffraction. Compound 4d
appears as approximately symmetric around the C2 axis.
Stacks of parallel anthracene molecules can be observed,
providing stabilization by p-interactions. The absolute con-
figuration of the new stereogenic centres was (S,S), if (R)-2
was used as the chiral auxiliary, and this corresponds to
reaction at the si–si face of the diene. These experimental
results validated the previous hypothesis based on theoret-
ical calculations (Fig. 5).
lysis of the ester in basic aqueous solution generated, after
acidification, the dicarboxylic acids; (ii) the methanolysis
generated the methyl esters and (iii) the reductive hydroly-
sis by LiAlH4 generated the corresponding primary diol.
In all cases, it was possible to recover the chiral auxiliary
quantitatively.
4
Especially interesting was the case of reduction with
LiAlH4 (Fig. 6). 2,2,2-Trifluoro-1-(9-anthryl)ethanol 2 is
highly effective as a chiral solvating agent for alcohols
and amines.13 As we have tested with cyclopentadiene
1
A very similar geometry was obtained for 4d by molecular
as the diene, the H NMR spectrum of the crude mixture
mechanics calculations, performing
a
conformational
after the reduction reaction directly enables the determi-
nation of the enantiomeric excess. Enantiopure alcohol
2 forms diastereomeric complexes with the dialcohol
product that can be differentiated with NMR. This means
that in this kind of reaction it is possible to use a single
chiral receptor for the asymmetric induction and for the
measurement of the enantiomerical purity of the final
product.
search with genetic algorithms. The obtained minimal
energy conformation was also symmetric, but the distance
between anthracene rings is smaller. NOE measurements in
solution agree with the structure obtained by calculations
and are different to the X-ray structure.
2.3. Hydrolysis and determination of the absolute
configuration
The absolute configuration of the final products was deter-
mined by comparison of the specific rotation with the liter-
ature value.14–17 In all cases, the configuration obtained
reveals a si–si face approach.
The last step of the asymmetric reaction cycle was hydro-
lysis of the fumaryl adduct. For all cycloadducts 4a–d,
three different processes could be carried out: (i) the hydro-
Figure 5. Geometry of cycloadduct 4d obtained from (a) X-ray diffraction and (b) molecular mechanics calculations.
O
O
OH
CH2OH
H
CF3
O
S
H
CF3
O
LiAlH4
THF
R
H
H
S
+
H
CF3
R
R
CH2OH
Figure 6. Reductive hydrolysis of adduct 4a.

M. Palomino-Scha¨tzlein et al. / Tetrahedron: Asymmetry 17 (2006) 3237–3243
3241
3. Conclusion
(C4), 130.7 (C1a), 131.0 (C4a), 131.5 (C5a), 131.6 (C10),
131.7 (C8a), 133.7 (C13), 162.5 (C12). HRMS (ESIꢀ) m/z
632.1409 (Mꢀ, d ꢀ1.2 ppm).
It has been shown that the easily available Pirkles alcohol
can be used in a Diels–Alder reaction to obtain enantio-
pure trans-cyclohexene-4,5-dicarboxylate derivatives. The
overall yield of the process is 80–90% with high enantio-
meric relations. Moreover, the chiral auxiliary is recovered
quantitatively, making it possible for it to be scaled-up and
applied generally.
4.3. General procedure for asymmetric Diels–Alder reaction
of fumarate 3
The reaction with cyclopentadiene and EtAlCl2 is typical.
A solution of EtAlCl2 (1 M in hexane, 3.16 ml, 3.16 mmol)
was added to a solution of fumarate 3 (1 g, 1.58 mmol) in
dry CH2Cl2 at ꢀ78 ꢁC followed by freshly distilled cyclo-
pentadiene (529 ll, 7.91 mmol). The resulting mixture was
stirred for 60 min and then filtered over SiO2. To obtain
the major diastereoisomer, the crude material was purified
by flash column chromatography on 100 mg of silica gel
(EtOAc/hexane 1:50).
4. Experimental
4.1. Theoretical calculations
The conformational search was carried out with the genetic
algorithm GACK, which can be downloaded from the
Cambridge Chemistry Department www server at URL:
http://www.ch.cam.ac.uk/. This program works in tandem
with MacroModel, which handles the structural minimiza-
tion using, in our case, the MM3* force field. The poolsize
and the number of generations are important parameters.
These were both set to 32, obtaining 1240 final structures,
of which 382 were different. The cross over rate was set to
1.0 and the mutation rate per molecule to 0.4. Selection
and replacement temperature were 10,000 K and 1000 K,
respectively. The conformational search was repeated five
times with different input structures, obtaining equivalent
results in all cases.
4.4. Cycloadduct (11R,13S,14S,15R,18S,110R)-4a
The above procedure provided 993 mg (85%) of 4a as a
20
white solid: mp 152–154 ꢁC; ½aꢁD = ꢀ62 (c 1.0, CHCl3);
IR (ATR) cmꢀ1: 2303 (C@H), 1753 (C@O). 1H NMR
(500 MHz, CDCl3) d 1.24 (d, J = 9.1 Hz, 1H, H19proR),
1.36 (d, J = 9.1 Hz, 1H, H19proS), 2.94 (m, 2H, H14endo
,
H15), 3.30 (s, 1H, H18), 3.67 (dd, J = 4.5 Hz, J = 4.5 Hz,
1H, H13exo), 5.15 (dd, J = 5 Hz, J = 2.8 Hz, 1H, H17),
6.00 (dd, J = 5 Hz, J = 3 Hz, 1H, H16), 7.53 (m, 2H,
H6endo, H6exo), 7.55 (m, 2H, H3endo, H3exo), 7.63 (m, 1H,
H7endo), 7.60 (m, 2H, H7exo), 7.69 (m, 2H, H2exo, H2endo),
7.80 (q, J = 7.8 Hz, 1H, H11endo), 7.87 (q, J = 7.8 Hz, 1H,
H11exo), 8.05 and 8.04 (d, J = 8.5 Hz, 2H, H5endo, H5exo),
8.08 (d, J = 8.4 Hz, 2H, H4endo, H4exo), 8.39 (d, J = 9 Hz,
1H, H1endo), 8.41 (d, J = 9 Hz, 1H, H1exo), 8.60 (s, 2H,
H10endo, H10exo), 8.77 (d, J = 8.9 Hz, 1H, H8exo), 8.79 (d,
J = 8.9 Hz, 1H, H8endo). 13C NMR (125 MHz, CDCl3) d
45.7 (C18), 47.0 (C14endo, C15), 172.2 (C20), 47.3 (C19),
47.9 (C13exo), 69.3 (C11exo), 69.5 (C11endo), 121.0, 120.9
(C9endo, C9exo), 122.4 (C1endo, C1exo), 124.3 (CF3), 125.1
(C3endo, C6endo, C3exo, C6exo), 126.3, 126.2 (C8endo, C8exo),
126.5, 126.4 (C7endo, C7exo), 127.8 (C2endo, C2exo), 129.3
(C5endo, C5exo), 129.6, 129.5 (C4endo, C4exo), 130.6, 130.5
(C1a endo, C1a exo), 131.1, 131.0 (C4a endo, C4a exo), 131.1,
131.4 (C5a endo, C5a exo), 131.4 (C10e ndo, C10exo), 131.7,
131.6 (C8a endo, C8a exo), 134.6 (C17), 137.3 (C16), 171.0
(C12). HRMS (ESIꢀ) m/z 698.1868 (Mꢀ, d ꢀ2.7 ppm).
NMR spectra were recorded at 400 MHz and 500 MHz for
1H. The temperature was controlled to 0.1 ꢁC. The NMR
signals were identified completely with the aid of several
1D (NOE) and 2D (COSY, NOESY, HMQC and HMB)
spectra.
4.2. (R,R)-Di[1-(9-anthryl)-2,2,2-trifluoroethyl] fumarate 3
A
solution of (R)-1-(9-anthryl)-2,2,2-trifluoroethanol
(2.6 g, 9.42 mmol), DMAP (574 mg, 4.71 mmol) and
freshly distilled Et3N (1.31 ml, 9.42 mmol) in dry CH2Cl2
(250 ml) was stirred under argon in a 500 ml round-bot-
tomed flask, and fumaryl chloride (0.51 ml, 4.71 mmol)
was added dropwise. After 1 h, the reaction mixture was
successively washed with 200 ml portions of aqueous HCl
(10%), a saturated bicarbonate solution and a saturated
sodium chloride solution, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude material
was purified by flash column chromatography over
4.5. Cycloadduct (11R,13S,14S,15R,18S,110R)-4b
The above procedure provided 1.34 g (80%) of 4b as white
20
150 mg of silica gel (CH2Cl2:hexane 1:3) to provide 2.42 g
solid: mp 158–156 ꢁC; ½aꢁD = ꢀ95 (c 1.0, CHCl3); IR
20
of 3 (81%) as yellow crystals: mp 125–127 ꢁC; ½aꢁD = ꢀ80
(ATR) cmꢀ1: 3054–2985 (OH), 2359 (C@H), 1747–1712
(c 1.0, CHCl3); IR (ATR) cmꢀ1: 3054–2986 (OH), 2305
(C@O). 1H NMR (400 MHz, CDCl3)
d 0.82 (d,
1
(C@H), 1740 (C@O). H NMR (500 MHz, CDCl3) d 7.12
J5,6 = 8.5 Hz, 2H, H5), 1.36 (d, J = 8.5 Hz, 2H, H5), 1.60
(d, J = 8.5 Hz, 2H, H5), 1.84 (d, J = 8.5 Hz, 2H, H5),
1.93 (t, J = 8.5 Hz, 2H, H5), 2.51 (s broad, 1H, H18), 4.91
(s broad, 1H, H17), 7.45 (m, 2H, H6), 7.52 (m, 2H), 7.55
(m, 2H, H7), 7.65 (m, 2H, H2), 7.78 (2 · q,
J11,F = 7.8 Hz, 2H, H11), 8.02, 7.99 (d, J = 8.5 Hz, 2H,
H5), 8.05 (d, J = 8.4 Hz, 2H, H4), 8.33, 8.18 (2 · d,
J = 9.0 Hz, 2H, H1), 8.54 (s, 2H, H10), 8.69, 8.63 (2 · d,
J = 8.9 Hz, 2H, H8). 13C NMR (100 MHz, CDCl3) d 19.9
(C20), 23.8 (C19), 31.9 (C15), 32.0 (C18), 45.4 (C13exo), 45.9
(s, 1H, H13), 7.51 (dd, J = 7.3 Hz, J = 7.5 Hz, 1H, H6),
7.55 (dd, J = 7.3 Hz, J = 7.5 Hz, 1H, H3), 7.60 (dd, J =
8.9 Hz, J = 7.3 Hz, 1H, H7), 7.69 (dd, J = 9.0 Hz,
J = 7.3 Hz, 1H, H2), 7.92 (q, J = 7.8, 1H, H11), 8.04 (d,
J = 8.5 Hz, 1H, H5), 8.07 (d, J = 8.4 Hz, 1H, H4), 8.39
(d, J = 9.0 Hz, 1H, H1), 8.59 (s, 1H, H10), 8.69 (d,
J = 8.9 Hz, 1H, H8). 13C NMR (125 MHz, CDCl3) d 70.0
(C11), 120.1 (C9), 122.3 (C1), 124.1 (CF3), 125.1 (C3 and
C6), 125.8 (C8), 126.8 (C7), 128.0 (C2), 129.4 (C5), 129.6

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M. Palomino-Scha¨tzlein et al. / Tetrahedron: Asymmetry 17 (2006) 3237–3243
(C14endo), 70.0, 69.4 (C11), 121.0 (C9), 122.5 (C1), 124.3
(CF3), 125.0 (C3, C6), 126.2 (C8), 126.4 (C7), 127.8, 127.7
(C2endo, C2exo), 129.2 (C5), 129.6, 129.5 (C4endo, C4exo),
130.5 (C1a), 131.1 (C4a), 131.4, 131.3 (C10endo, C10exo),
131.4 (C5a), 131.7 (C8a), 132.2 (C17), 134.2 (C16), 171.9
(C21), 171.9 (C12). (MALDI-TOF, m/z, %, THF-cca):
712.0 (M, 100), 713.0 (90), 714.0 (30).
dom search of 25 reflections, the indexation procedure gave
rise to the cell parameters. Data were collected in the x–20
scan mode. Absorption correction was performed follow-
ing the empirical PSI-scan method. The structural resolu-
tion procedure was made using the WinGX package.18
Solving for structure factor phases was performed by
SHELXS86, and the full-matrix refinement by SHELXL97.19
Non-H atoms were refined anisotropically and H-atoms
were introduced in calculated positions and refined riding
on their parent atoms. Crystallographic data have been
deposited with the CCDC as supplementary material with
the deposition number CCDC 623129.
4.6. Cycloadduct (11R,13S,14S,110R )-4c
The above procedure provided 1.1 g (90%) of 4c as yellow
20
needles: mp 147–149 ꢁC; ½aꢁD = ꢀ80 (c 1.0, CHCl3); IR
(ATR) cmꢀ1: 2304 (C@H), 1753 (C@O). 1H NMR
(500 MHz, CDCl3) d 1.93 (d, 1H, J = 17 Hz, H15proR),
1.99 (d broad, 1H, J = 17 Hz, H18proR), 2.27 (dd, 1H,
J = 17 Hz, J = 5 Hz, H15proS), 2.37 (d broad, 1H,
J = 17 Hz, H18proS), 3.19 (dt, J = 10 Hz, J = 5.8 Hz, 1H,
H13exo), 3.19 (dt, J = 10 Hz, J = 5.8 Hz, 1H, H14endo),
Refinement parameters and crystal data for 4d
Empirical formula
Formula weight
Temperature
C43H33Cl3F6O4
834.04
293(2) K
0
7.49 (m, 2H, H6, H6 ), 5.28 (s broad, 1H, H17), 7.54 (m,
˚
Wavelength
0.71073 A
0
0
2H, H3, H3 ), 7.55 (m, 2H, H7, H7 ), 7.65 (m, 2H, H2,
Crystal system
Space group
Unit cell dimensions
Monoclinic
P21
a = 12.841(3) A
b = 9.314(4) A
0
0
H2 ), 7.76, 7.74 (2 · q, J11,F = J = 7.8 Hz, 2H, H11, H11 ),
0
8.00, 7.99 (d, J = 8.5 Hz, 2H, H5, H5 ), 8.05 (d,
˚
0
J = 8.4 Hz, 2H, H4, H4 ), 8.32, 8.20 (2 · d, J = 9.0 Hz,
˚
0
0
2H, H1, H1 ), 8.54 (2 · s, 2H, H10, H10 ), 8.67, 8.65 (2 · d,
˚
J = 8.9 Hz, 2H, H8, H8 ). 13C NMR (125 MHz, CDCl3) d
22.8 (C16 ), 27.4 (C18), 31.7 (C15), 40.6 (C13exo), 41.2
c = 16.811(5) A
0
a = 92.62(2)ꢁ
0
3
˚
Volume
2008.5 A
0
0
(C14endo), 69.175 (C11), 120.9 (C9, C9 ), 122.6 (C1, C1 ),
0
0
Z
2
124.2 (CF3), 124.9 (C6, C6 ), 125.0 (C3, C3 ), 126.2 (C8,
0
0
0
C8 ), 126.3 (C7, C7 ), 127.7, 127.6 (C2, C2 ), 129.2 (C5,
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data
collection
1.379 Mg/m3
0.298 mmꢀ1
856
0
0
0
0
C5 ), 129.5 (C4, C4 ), 130.5 (C1a, C1a ), 131.0 (C4a, C4a ),
0
0
0
131.2 (C10, C10 ), 131.4 (C5a, C5a ), 131.6 (C8a, C8a ),
131.9 (C17), 172.34 (C12), 172.5 (C19). HRMS (ESIꢀ) m/z
700.2028 (Mꢀ, d ꢀ2.1 ppm).
0.43 · 0.24 · 0.15 mm3
2.43–25.64ꢁ
4.7. Cycloadduct (11R,13S,14S,110R)-4d
Index ranges
ꢀ15 6 h 6 15, 0 6 k 6 11,
ꢀ20 6 l 6 0
The above procedure provided 910 mg (95%) of 4d as yel-
20
Reflections collected
Independent reflections
Completeness to theta
Refinement method
4180
low needles: mp 145–148 ꢁC; ½aꢁD = ꢀ86 (c 1.0, CHCl3); IR
(ATR) cmꢀ1: 3055–2994 (OH), 2359 (C@H), 1749–1704
4040 [R(int) = 0.0637]
25.64ꢁ, 99.5%
Full-matrix least-squares
on F2
(C@O). 1H NMR (400 MHz, CDCl3)
d 2.19 (d,
J = 16.3 Hz, 2H, H15proS, H15proR), 2.32 (d, J = 14.4 Hz,
2H, H18proS, H18proR), 3.18 (m, 1H, H14exo), 3.19 (m, 1H,
H13endo), 7.46 (m, 2H, H3, H6), 7.47 (m, 1H, H7), 7.57
(dd, J = 8.0 Hz, J = 7.3 Hz, 1H, H2), 7.73 (q, J = 7.8,
1H, H11), 8.24 (d, 2 · J = 8.4 Hz, 2H, H4, H5), 8.24 (d,
J = 9.0 Hz, 1H, H1), 8.47 (s, 1H, H10), 8.56 (d,
J = 8.9 Hz, 1H, H8). 13C NMR (100 MHz, CDCl3) d
18.6 (C16, C17), 32.8 (C15, C18), 41.5 (C14endo, C13exo), 68.8
Data/restraints/parameters 4040/1/508
Goodness-of-fit on F2 0.899
Final R indices [I > 2r(I)] R1 = 0.0636, wR2 = 0.1592
R indices (all data)
Absolute structure
parameter
R1 = 0.3575, wR2 = 0.2476
0.1(4)
0
0
(C11), 120.7 (C9, C9 ), 122.4 (C1, C1 ), 123.8 (C16a, C17a),
124.1 (CF3), 124.8 (C3 , C6, C6 ), 126.1 (C8, C8 ), 126.3
(C7, C7 ), 127.5 (C2, C2 ), 129.2 (C5, C5 ), 129.4 (C4, C4 ),
ꢀ3
˚
Largest diff. peak and hole 0.343 and ꢀ0.291 e A
0
0
0
0
0
0
0
0
0
0
130.7 (C1a, C1a ), 130.9 (C4a, C4a ), 131.2 (C10, C10 ),
0
0
131.3 (C5a, C5a ), 131.6 (C8a, C8a ), 172.0 (C12, C20). (MAL-
DI-TOF, m/z, %, THF-cca): 714.1 (M, 100), 715.1 (MH+,
43).
4.9. General procedure for hydrolysis in aqueous solution
To a solution of cycloadduct (11R,13S,14S,15R,18S,110R)-
4a (90 mg, 0.13 mmol) in THF (10 ml) an aqueous solution
of KOH (70 mg, 1.28 mmol) was added. After 4 h, the
THF was evaporated under reduced pressure, the crude di-
luted with water and extracted with several portions of
CH2Cl2. The combined organic extracts were dried over
MgSO4, filtered and concentrated to give 67 mg (95%) of
pure (R)-1-(9-anthryl)-2,2,2-trifluoroethanol 4, after crys-
4.8. Crystal data
A suitable crystal of 4d was selected for X-ray single crystal
diffraction experiment and mounted at the tip of a glass
fibre on an Enraf-Nonius CAD4 diffractometer producing
graphite monochromated MoKa radiation. After the ran-

M. Palomino-Scha¨tzlein et al. / Tetrahedron: Asymmetry 17 (2006) 3237–3243
3243
A.; Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 2002, 67,
753–758.
tallization in CHCl3. The remaining basic aqueous solution
was acidified with concentrated HCl until pH = 1 and
extracted with ether. The combined organic phases were
dried over MgSO4, filtered, concentrated and crystallized
in hexane to recover 22 mg (95%) of pure (1S,2S,3S,4R)-
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid.
2. (a) Koscho, M. E.; Pirkle, W. H. Tetrahedron: Asymmetry
2005, 16, 3345–3351; (b) Taji, H.; Watanabe, M.; Nobuyuki,
N.; Naoki, H.; Ueda, Y. Org. Lett. 2002, 4, 2699–2702; (c)
Pirkle, W. H.; Pochapsky, P. C. Chem. Rev. 1989, 89, 347; (d)
Pirkle, W. H.; House, D. H. J. Org. Chem. 1979, 44, 1957; (e)
Dotsevi, G.; Sogah, Y.; Cram, D. J. J. Am. Chem. Soc. 1975,
97, 1259–1261; (f) Spanik, I.; Zebrowski, W.; Majek, P.;
Skacani, I.; Krupcik, J.; Armstrong, D. W. J. Sep. Sci. 2005,
28, 1347–1356; (g) Hara, S.; Dobashi, A. J. Chromatogr.
1986, 186, 543–552; (h) Oi, N.; Nagase, M.; Doi, T. J.
Chromatogr. 1983, 257, 11–117; (i) Tambute, A.; Begos, A.;
Lienne, M.; Caude, M.; Rosset, R. J. Chromatogr. 1987, 396,
65–81.
4.10. General procedure for methanolysis
To a solution of cycloadduct (11R,13S,14S,15R,18S,110R)-
4a (200 mg, 0.29 mmol) in THF (5 ml) K2CO3 (396 mg,
2.8 mmol) was added following by methanol (5 ml). After
stirring for 4 h, the solution was acidified with HCl (10%)
until pH = 7, and extracted with several portions of ether
and CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure.
The crude material was purified by flash column chroma-
tography on 20 mg of silica gel (CH2Cl2:toluene 1:1) to
furnish 150 mg (95%) of pure (R)-1-(9-anthryl)-2,2,2-
trifluoroethanol and 57 mg (95%) of pure dimethyl
(1R,2S,3S,4S)-bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxilate.
3. (a) Bucciarelli, M.; Forni, A.; Moretti, I.; Torre, G. J. Chem.
Soc., Perkin Trans. 1 1980, 2152–2161; (b) Oppolzer, W.
Angew. Chem., Int. Ed. Engl. 1984, 23, 876–889; (c) Morrison,
J. D.; Mosher, H. S. Asymmetric Organic Reaction; Prentice
Hall: New York, 1971; Chapter 10, p 1076.
`
4. (a) Carriere, A.; Virgili, A.; Figueredo, M. Tetrahedron:
`
Asymmetry 1996, 10, 2793–2796; (b) Carriere, A.; Virgili, A.
Tetrahedron: Asymmetry 1996, 7, 227–230.
5. Gawley, R. E. J. Org. Chem. 2006, 71, 2411–2416.
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7. (a) Furuta, K.; Hayashi, S.; Miwa, Y.; Yamamoto, H.
Tetrahedron Lett. 1987, 28, 5841–5844; (b) Charlton, G.;
Plourde, G.; Koh, K.; Secco, A. Can. J. Chem. 1989, 67, 574–
579; (c) Corey, E. J.; Cheng, X.-M.; Cimprich, K. A.
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Husa, R. K.; Moormann, A. E.; Villamil, C. I.; Flynn, D. L.
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614.
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305–309.
4.11. General procedure for reduction
To a solution of cycloadduct (11R,13S,14S,15R,18S,110R)-
4a (185 mg, 0.27 mmol) in dry THF (12 ml) LiAlH4 (45 mg,
1.18 mmol) was added at 0 ꢁC under argon. After stirring
for 2 h, the solution was acidified with HCl (10%) until
pH = 1, and extracted with several portions of ether and
CH2Cl2. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure.
The crude material was purified by flash column chroma-
tography on 20 mg of silica gel (CH2Cl2/toluene 1:1) to
furnish 137 mg (95%) of pure (R)-1-(9-anthryl)-2,2,2-tri-
fluoroethanol and 39 mg (95%) of pure (1R,2S,3S,4S)-bi-
cyclo[2.2.1]hept-5-ene-2,3-dimethanol.
10. (a) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.;
Liskamp, R.; Caufield, C.; Chang, G.; Hendrickson, T.; Still,
W. C. J. Comput. Chem. 1990, 11, 440–467; (b) MacroModel/
BatchMin, v. 5. Department of Chemistry, Columbia Uni-
versity: New York, 1995.
11. The MM3* force field is a well-documented version of MM3
force field, implemented in MacroModel/Batchmin, v. 5.
12. Nair, N.; Goodman, J. M. J. Chem. Inf. Comput. Sci. 1998,
38, 317–320.
13. Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 1, 263–
331.
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Acknowledgements
Financial support from CYCYT (PPQ2000-0369 and
BQU2003-01231) and a predoctoral grant (FPU) from
´
the Ministerio de Educacion y Ciencia, Spain, are grate-
`
`
fully acknowledged. The Servei de Ressonancia Mangneti-
ca Nuclear of the UAB is also acknowledged for allocating
instrument time. We thank K. Burusco for the help with
computational calculations.
16. Devine, P. N.; Taeboem, O. J. Org. Chem. 1992, 57, 396–399.
17. Maruoka, K.; Akakura, M.; Saito, S.; Ooi, T.; Yamamoto,
H. J. Am. Chem. Soc. 1994, 116, 6153–6158.
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