(R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in Diels-Alder reactions

Article abstract of DOI:10.1016/S0957-4166(99)00267-0

A study of the Diels-Alder reactions of the esters derived from acrylic, methacrylic, trans-crotonic and trans-cinnamic acid and the chiral auxiliaries (R)- and/or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (4, 17, 25 and 26, respectively) with different dienes [cyclopentadiene 5, isoprene 8, 11,12-dimethylene-9,10-dihydro-9,10-ethanoanthracene 9 and anthracene 10], catalyzed by titanium tetrachloride, is described. Cyclopentadiene gave adducts with esters (R)- or (S)-4 and (R)-25 with high endo- and facial-diastereoselectivities. Diene 5 reacted with (±)-17 without endo-diastereoselectivity and failed to give a cycloadduct with (±)-26. Isoprene reacted only with ester (S)-4 with high facial-diastereoselectivity. The reaction of 9 with (R)-4 failed, because the diene was not stable under the acid reaction conditions. Adducts derived from 10 and esters (S)-4 and (R)-17 could be obtained with high facial-diastereoselectivity. LiOH-hydrolysis of the adducts derived from esters (R)- or (S)-4 and (R)-25 gave the corresponding enantiopure acids, the chiral auxiliaries being completely recovered unchanged. However, hydrolysis of the adduct derived from 10 and (R)-17, required more drastic basic conditions which partially epimerized the chiral auxiliary. X-Ray diffraction analysis of the adducts derived from 10 and esters (S)-4 and (R)-17, let us establish their relative configurations and, taking into account the absolute configuration of the starting chiral auxiliary, their absolute configurations.

Full text of DOI:10.1016/S0957-4166(99)00267-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3123–3138
(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone
as chiral auxiliaries in Diels–Alder reactions
Pelayo Camps,a,∗ Mercè Font-Bardia,b Sílvia Giménez,a Francesc Pérez,a Xavier Solans b and
Núria Soldevillaa
aLaboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028,
Barcelona, Spain
bDepartament de Cristal.lografia, Mineralogia i Dipòsits Minerals, Facultat de Geologia, Universitat de Barcelona,
Av. Martí Franqués s/n, E-08028, Barcelona, Spain
Received 8 June 1999; accepted 28 June 1999
Abstract
A study of the Diels–Alder reactions of the esters derived from acrylic, methacrylic, trans-crotonic and trans-
cinnamic acid and the chiral auxiliaries (R)- and/or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (4, 17,
25 and 26, respectively) with different dienes [cyclopentadiene 5, isoprene 8, 11,12-dimethylene-9,10-dihydro-
9,10-ethanoanthracene 9 and anthracene 10], catalyzed by titanium tetrachloride, is described. Cyclopentadiene
gave adducts with esters (R)- or (S)-4 and (R)-25 with high endo- and facial-diastereoselectivities. Diene 5 reacted
with (ꢀ)-17 without endo-diastereoselectivity and failed to give a cycloadduct with (ꢀ)-26. Isoprene reacted only
with ester (S)-4 with high facial-diastereoselectivity. The reaction of 9 with (R)-4 failed, because the diene was
not stable under the acid reaction conditions. Adducts derived from 10 and esters (S)-4 and (R)-17 could be
obtained with high facial-diastereoselectivity. LiOH-hydrolysis of the adducts derived from esters (R)- or (S)-4
and (R)-25 gave the corresponding enantiopure acids, the chiral auxiliaries being completely recovered unchanged.
However, hydrolysis of the adduct derived from 10 and (R)-17, required more drastic basic conditions which
partially epimerized the chiral auxiliary. X-Ray diffraction analysis of the adducts derived from 10 and esters (S)-4
and (R)-17, let us establish their relative configurations and, taking into account the absolute configuration of the
starting chiral auxiliary, their absolute configurations. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Some time ago, we described1 a multigram scale synthesis of both enantiomers of 3-hydroxy-4,4-
dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-1, and their use for the formal deracemization of α-
arylpropanoic acids,2 α-substituted α-arylacetic acids,3 α-chloro acids,4 and α-amino acids.5 Also,
∗
Corresponding author. Tel: 34-93 402 45 36; fax: 34-93 403 59 41; e-mail: camps@farmacia.far.ub.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00267-0

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we described their use in an enantioselective synthesis of α-hydroxy acids,6 α-aryloxypropanoic acid
herbicides,4 such as dichlorprop-P and mecoprop-P, and α-amino acids,5 based on the dynamic kinetic
resolution of α-bromo esters derived from these chiral auxiliaries on reaction with different nucleophiles.
A key-point of these transformations is the efficient recovery of the chiral auxiliaries, which are easily
crystallizable non-hygroscopic solids.
Much work has been done in the last two decades to develop asymmetric Diels–Alder reactions,
based on both enantiopure dienes7–9 and enantiopure dienophiles.10–23 In the present decade, interest
had progressively shifted towards catalyzed enantioselective Diels–Alder reactions.24–35
The acrylate of D-pantolactone has been reacted with high facial-diastereoselectivity with dienes 5,11
8,11 10,13 and a 5-substituted cyclopentadiene,19 under TiCl4 catalysis. Also, an (E)-2-cyanocinnamate
derived from D-pantolactone has been reacted with high endo- and facial-diastereoselectivities with
cyclopentadiene20 and butadiene.23
Since (R)-pantolactone is a hygroscopic compound and its (S)-enantiomer is quite expensive, while
both (R)- and (S)-1 are readily available1,36 and easily recoverable, we decided to study the Diels–Alder
reactions of esters derived from these chiral auxiliaries, not only with acrylic acid 3, but also with
other acids such as methacrylic, trans-crotonic and trans-cinnamic acids (16, 23, and 24, respecti-
vely) and different dienes such as cyclopentadiene 5, isoprene 8, 11,12-dimethylene-9,10-dihydro-9,10-
ethanoanthracene 9 and anthracene 10.
2. Results and discussion
Esters derived from (R)-, (S)- or (ꢀ)-1 and the acids 3, 16, 23 and 24 were easily obtained in moderate
yields (60, 60, 71 and 92%, respectively) by reaction of the corresponding alcohol and the acid with
dicyclohexylcarbodiimide (DCC) in CH2Cl2 in the presence of a catalytic amount (5% molar) of 4-
(dimethylamino)pyridine (DMAP). The acrylic ester (S)-4 was prepared in an improved way (97% yield)
by reaction of (S)-1 with acryloyl chloride 2 and Et3N in CH2Cl2 (Scheme 1).
Dienes were all commercially available except 9 which was prepared as described.37 According
to previous work with D-pantolactone acrylates,11 the Diels–Alder reactions were carried out under
TiCl4 catalysis. The formation of double-coordinated complexes between TiCl4 and the dienophiles
derived from D-pantolactone seems to play an important role in connection with the high facial-
diastereoselectivity of these Diels–Alder reactions, cycloaddition taking place preferentially by the Re-
face of the acrylate Cα carbon atom. Under similar reaction conditions, other Lewis acid catalysts, such
as Et2AlCl, unable to form double-coordinated complexes with the dienophile, give cycloadducts with
very poor facial-diastereoselectivities.11
Many reactions were first studied by using the racemic dienophiles, and then carried out with one
or the other enantiopure reagent. The crude products were usually purified by column chromatography,
which may cause some diastereomer enrichment, and the analytical samples of the solid compounds
were obtained by recrystallization from the appropriate solvent, thus obtaining the main diastereomer in
pure form. The pure or enriched samples of the cycloadducts were hydrolyzed under non-epimerizing
conditions,11 by reaction with LiOH·H2O in a mixture of THF and water to give the corresponding
enantiopure or enantioenriched acids. The absolute configuration of the known acids allowed us to
establish the absolute configuration of the corresponding intermediate esters. In two cases, where the
acid had not been previously described or its absolute configuration had not been fully established, the
relative configuration of the Diels–Alder adducts was established by X-ray diffraction analysis, and their

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
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Scheme 1. Endo- and/or facial-diastereoselective Diels–Alder reactions of acrylates (R)- or (S)-4 with dienes 5, 8 and 10
absolute configuration deduced from the knowledge of the absolute configuration of the starting chiral
auxiliary.
Acrylate ester (R)-4 reacted with cyclopentadiene in the presence of 0.68 equiv. of TiCl4 at low
temperature (−55 to −20°C) to give the endo-diastereomer (1R,2R,30R,4R)-6 in 96% yield of recrys-
1
tallized product, as the only detectable diastereomer by H and 13C NMR spectroscopy (Scheme 1).
LiOH-hydrolysis of this product at room temperature for 26 h gave acid (1R,2R,4R)-7 (96% yield)
whose specific rotation, determined under the described conditions (see the Experimental section),
allowed us to establish an o.p. of 97%, in good agreement with the results described for the acrylate
of D-pantolactone,11 taking into account the errors associated with the determination of diastereomeric
excesses by NMR spectroscopy and o.p.’s from specific rotations. Similarly, from (S)-4, (1S,2S,30S,4S)-6
was obtained in 92% yield, from which acid (1S,2S,4S)-7 (95% o.p.) was obtained.
Reaction of (S)-4 with isoprene 8 in the presence of 0.50 equiv. of TiCl4 at a temperature from −20 to
10°C for 15 h gave, in 90% yield, an oily product which consisted mainly of the para-adduct (1R,30S)-
11. Minor signals in the 1H and 13C NMR spectra could be attributable to the other para-adduct. LiOH-
hydrolysis of this product, under similar conditions to that used before, gave acid (R)-14 in 95% yield,
whose specific rotation determined under similar conditions to that described (see the Experimental
section) allowed us to establish an o.p. of 88%. This result is in reasonable agreement with that described
for the related reaction of isoprene and the acrylate of D-pantolactone,11 where the para-adduct was
obtained with 94% d.e.
From a reaction of (S)-4 and diene 9 under similar conditions, no cycloadduct was isolated. The

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dienophile was mainly recovered while 9 was not, probably because of its instability towards TiCl4.
For this reason, the reaction of this diene with the rest of the dienophiles was not attempted.
Reaction of (S)-4 with anthracene 10 required more forcing conditions (18 h at room temperature
and 2 equiv. of TiCl4), giving the cycloadduct (11R,30S)-13 in 87% yield of chromatographed product
and 93% d.e. by 1H NMR spectroscopy. From this reaction, only two diastereomers are possible due to
facial-diastereoselectivity since no endo-/exo-diastereoselectivity is possible for this diene. A reaction
of (ꢀ)-4 and 10 carried out in toluene under AlCl3 catalysis required prolonged reflux and gave a
mixture of two racemic pairs in an approximate ratio of 3:4, the minor pair corresponding to the main
diastereomer in the TiCl4-catalyzed reaction. The signals of the methyl groups in both diastereomers
appeared perfectly separated [1.14 and 1.17 ppm for (11R,30S)-13 and 0.90 and 1.10 ppm for (11S,30S)-
13], which allowed us to easily establish the d.e. of the obtained cycloadduct. Recrystallization of the
chromatographed product derived from (S)-4 and 10 gave crystalline pure (11R,30S)-13. LiOH-hydrolysis
of this compound gave the corresponding acid, (R)-15, as a solid in 99% yield. This is a new compound,
although its enantiomer had been previously prepared by a similar procedure using the acrylate of D-
pantolactone.13 The specific rotation of (R)-15 was slightly greater in absolute value and of opposite
sign to that previously described for its enantiomer. Since the proposed configuration for (S)-15 seems
to come from the facial-diastereoselectivity observed in the Diels–Alder reactions of D-pantolactone
acrylate catalyzed by TiCl4, and to secure this assignment, we carried out an X-ray diffraction analysis
of the cycloadduct obtained from (S)-4 and anthracene (Fig. 1) which allowed us to establish its absolute
configuration as (11R,30S)-13, taking into account the (S)-configuration of the starting chiral auxiliary,
in accord with the expected facial-diastereoselectivity, i.e. addition of the diene to the Re face of the Cα
carbon atom of the acrylate derived from D-pantolactone13 or (R)-1 and vice versa.
Figure 1. Perspective drawing (ORTEP) of (11R,30S)-13
Methacrylate (ꢀ)-17 reacted with cyclopentadiene under somewhat more drastic conditions than those
used with acrylate 4 to give an essentially 1:1 mixture of endo- and exo-diastereomers [(ꢀ)-endo-18 and
(ꢀ)-exo-19] (Scheme 2). Characteristic of (ꢀ)-exo-19 are exo-3-H (δ=2.55 ppm, dd, Jexo-3H/endo-3H =12.0
Hz, Jexo-3H/4H =4.0 Hz) and endo-3-H (δ=0.92 ppm, d, Jexo-3H/endo-3H =12.0 Hz) which compare very well
with the published data for the corresponding acid38 [exo-3-H (δ=2.46 ppm, dd, Jexo-3H/endo-3H =12.1 Hz,

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
3127
Jexo-3H/4H =3.9 Hz) and endo-3-H (δ=0.88 ppm, d, Jexo-3H/endo-3H =12.1 Hz)]. Similarly, in the case of (ꢀ)-
endo-18, exo-3-H (δ=2.00 ppm, dd, Jexo-3H/endo-3H =12.0 Hz, Jexo-3H/4H=3.0 Hz) and endo-3-H (δ=1.50
ppm, d, Jexo-3H/endo-3H =12.0 Hz) compare well with the published data for the corresponding acid38
[exo-3-H (δ=1.88 ppm, dd, Jexo-3H/endo-3H =12.0 Hz, Jexo-3H/4H =2.6 Hz) and endo-3-H (δ=1.15–1.46
ppm, d, Jexo-3H/endo-3H =12.0 Hz)]. The lack of endo-/exo-diastereoselectivity of the above reaction led
us to discard any attempt on the corresponding reaction with (R)- or (S)-17 to establish the facial-
diastereoselectivity.
Scheme 2. Facial-diastereoselective Diels–Alder reaction of methacrylate (R)-4 with anthracene
Under similar reaction conditions to that used above, methacrylate (ꢀ)-17 failed to react with isoprene.
However, (R)-17 was able to react with anthracene to give the corresponding adduct with high facial-
diastereoselectivity. Under the optimum conditions assayed (CH2Cl2, 2 equiv. TiCl4, room temperature,
18 h), (11S,30R)-21 was obtained in 97% yield as the only diastereomer detectable by 1H and 13C NMR
(d.e. >98%). Compound (ꢀ)-17 was not able to react with anthracene under AlCl3 catalysis, and thus, we
1
do not know the characteristic signals in H and 13C NMR of (11R,30R)-21. The relative configuration
of the new compound (11S,30R)-21 was obtained by X-ray diffraction analysis (Fig. 2) of a monocrystal
obtained by careful crystallization of the product from methanol. From this relative configuration and
knowing the absolute configuration of the starting chiral auxiliary, the absolute configuration of this
cycloadduct was deduced.
The facial-diastereoselectivity observed in the reaction of methacrylate (R)-17 and anthracene is
the same observed in the reactions with acrylate (S)-4: from (R)-17, (11S,30R)-21 was obtained while
from (S)-4, (11R,30S)-13 had been obtained. However, the facial-diastereoselectivity in the Diels–Alder
addition to methacrylate esters implies preferential addition by the Si face of the Cα carbon atom of
(R)-17, what is apparently contrary to the situation found in the case of the corresponding acrylates. This
is due to the presence of the methyl group at position α in methacrylate 17, which provokes a change in
the notation of the enantiotopic faces of this Cα carbon atom: the Re face of acrylate esters become the
Si face in methacrylate esters and vice versa.
As expected, hydrolysis of the more hindered ester (11S,30R)-21 required more drastic conditions
(LiOH, THF/H2O, 18 h under reflux) than those generally used to hydrolyze the acrylate cycloadducts.
Under these conditions, epimerization of the chiral auxiliary was important, (R)-1 being recovered in

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
Figure 2. Perspective drawing (ORTEP) of (11S,30R)-21
96% yield but only 50% e.e. (chiral HPLC).1 Since the obtained acid (S)-22 cannot epimerize under the
basic hydrolysis conditions (except via a retro-Diels–Alder/Diels–Alder reaction), the e.e. of the new
acid (S)-22 must be the same as the d.e. of ester (11S,30R)-21, i.e.: >98%.
The trans-cinnamate (ꢀ)-26 failed to react with isoprene, anthracene and cyclopentadiene, and the
trans-crotonate (ꢀ)-25 failed to react with isoprene and anthracene, although (R)-25 was reacted smo-
othly with cyclopentadiene to give, after column chromatography, the endo-adduct (1R,2R,3S,30R,4S)-27
(71% yield) and an exo-adduct, (30R)-exo-2-endo-3-28 (2% yield). Both products showed to be only one
1
diastereomer by H and 13C NMR spectroscopy, whose d.e.s must be >98% (Scheme 3). The absolute
configuration of (1R,2R,3S,30R,4S)-27 was deduced after LiOH-hydrolysis under the standard conditions
(LiOH, THF/H2O, room temperature) to the known acid (1R,2R,3S,4S)-33.39 The o.p. of the oily acid was
shown to be 97%, in good agreement with the d.e. of the corresponding ester. The absolute configuration
of (30R)-exo-2-endo-3-28 could not be deduced due to the small amount of product available, which
precluded its hydrolysis, but the exo-2-endo-3 nature of the adduct could be established by comparison
of its 13C NMR spectrum with the data reported for the corresponding exo-2-endo-3-acid.40
In conclusion, acrylic esters derived from the chiral auxiliaries (R)- or (S)-1, react, as expected, with
different dienes (cyclopentadiene, isoprene and anthracene) under TiCl4 catalysis, with high facial- and
endo-selectivity. However, methacrylic esters derived from these chiral auxiliaries fail to react under
these conditions with poor reactive dienes, such as isoprene, react with cyclopentadiene without endo-
selectivity, but react with anthracene with high facial-selectivity. The less reactive trans-crotonic esters
react only with the more reactive cyclopentadiene with high facial- and endo-selectivity, while the still
less reactive trans-cinnamic esters fail to react with any of the studied dienes. Except for the cycloadduct
(11S,30R)-21, derived from methacrylate (R)-17, the chiral auxiliary was always recovered in high yield
without loss of enantiomeric purity, after controlled LiOH-hydrolysis of the Diels–Alder adducts. The
present work expands the usefulness of the chiral auxiliaries (R)- and (S)-1, for which a simpler synthesis
will soon be submitted for publication.

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
3129
Scheme 3. Endo- and facial-diastereoselective Diels–Alder reaction of trans-crotonate (R)-25 with cyclopentadiene
3. Experimental
Melting points were determined on a MFB 595010 M Gallenkamp melting point apparatus. 1H NMR
1
spectra (500 MHz) were performed on a Varian VXR 500 spectrometer and 300 MHz H and 75.4
1
MHz 13C NMR spectra on a Varian Gemini 300. Except where otherwise stated, H NMR spectra were
recorded at 500 MHz and 13C NMR spectra at 75.4 MHz, always in CDCl3. COSY 1H/1H experiments
1
were carried out by using standard procedures while for the COSY H/13C experiments, the HMQC
sequence with an indirect detection probe was used. Chemical shifts (δ) are reported in ppm related
to internal tetramethylsilane. IR spectra were recorded on an FT/IR Perkin–Elmer spectrometer, model
1600. Optical rotations were measured on a Perkin–Elmer model 241 polarimeter. Solvents were of
analytical grade. Elemental analyses were carried out at the Microanalysis Service of the Centro de
Investigación y Desarrollo (C.I.D.), Barcelona, Spain.
3.1. General procedure for the preparation of esters 4, 17, 25 and 26
A mixture of the acids 3, 16, 23 or 24 (1.00 mmol), (R)- or (S)-1 (1.00 mmol), DCC (1.00 mmol)
and DMAP (0.05 mmol) in anhydrous CH2Cl2 (10 ml) was stirred at room temperature under an argon
atmosphere for 4 days. The mixture was filtered, the filtrate was washed with saturated aqueous solution
of citric acid (3×10 ml) and saturated aqueous NaHCO3 (3×10 ml), dried with anh. Na2SO4 and
concentrated in vacuo. The residue was submitted to column chromatography [silica gel (20 g), CH2Cl2]
to give pure esters 4, 17, 25 or 26.
3.1.1. (R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl acrylate (R)-4
Following the above general procedure, from 3 (1.00 g, 14.0 mmol), (R)-1 (2.87 g, 14.0 mmol), (R)-4
(1.60 g, 44% yield) was obtained as a solid, m.p. 98–100°C (ethanol), [α]D20=+23.9 (c 1.00, CHCl3),
IR (KBr) ν: 1733 and 1703 (C_O st), 1627 (C_C st) cm−1. C15H17NO3 (259.32): calcd: C, 69.48%;
H, 6.61%; N, 5.40%. Found: C, 69.50%; H, 6.63%; N, 5.49%. 1H NMR (300 MHz) δ: 1.15 (s, 3H, 4α-

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
CH3), 1.31 (s, 3H, 4β-CH3), 3.53 (d, J=9.6 Hz, 1H, 5α-H), 3.63 (d, J=9.6 Hz, 1H, 5β-H), 5.48 (s, 1H,
3-H), 5.94 (dd, J=10.4 Hz, J0=1.2 Hz, 1H, β-Htrans), 6.26 (dd, J=17.3 Hz, J0=10.4 Hz, 1H, α-H), 6.54
(dd, J=17.3 Hz, J0=1.2 Hz, 1H, β-Hcis), 7.17 (broad t, J=7.4 Hz, 1H, Hpara), 7.38 (m, 2H, Hmeta), 7.63
(broad d, J=7.8 Hz, 2H, Hortho); 13C NMR δ: 21.1 (CH3, 4α-CH3), 24.8 (CH3, 4β-CH3), 37.5 (C, C4),
57.7 (CH2, C5), 78.3 (CH, C3), 119.4 (CH, Cortho), 124.9 (CH, Cpara), 127.5 (CH, Cα), 128.9 (CH,
Cmeta), 132.1 (CH2, Cβ), 139.0 (C, Cipso), 165.3 (C, COO), 168.8 (C, C2).
3.1.2. (S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl acrylate (S)-4
Following the above general procedure, from 3 (1.00 g, 14.0 mmol), (S)-1 (2.87 g, 14.0 mmol), (S)-4
(1.54 g, 43% yield) was obtained as a solid, m.p. 97–99°C (ethanol), [α]D20=−24.3 (c 1.00, CHCl3), IR
(KBr) ν: 1727 and 1708 (C_O st), 1626 (C_C st) cm−1. C15H17NO3 (259.32): calcd: C, 69.48%; H,
6.61%; N, 5.40%. Found: C, 69.48%; H, 6.60%; N, 5.53%. The NMR data are coincidental with those
of its enantiomer.
3.1.3. (R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl methacrylate (R)-17
Following the above general procedure, from 16 (0.43 g, 5.00 mmol), (R)-1 (1.03 g, 5.00 mmol), (R)-
17 (0.77 g, 60% yield) was obtained as a solid, m.p. 58–60°C (ethanol), [α]D20=+29.6 (c 1.04, CHCl3),
IR (KBr) ν: 1760 and 1712 (C_O st), 1597 (C_C st) cm−1. C16H19NO3 (273.35): calcd: C, 70.31%; H,
7.01%; N, 5.12%. Found: C, 70.24%; H, 7.04%; N, 5.19%. 1H NMR δ: 1.18 (s, 3H, 4α-CH3), 1.32 (s,
3H, 4β-CH3), 2.04 (s, 3H, α-CH3), 3.54 (d, J=9.6 Hz, 1H, 5α-H), 3.64 (d, J=9.6 Hz, 1H, 5β-H), 5.49 (s,
1H, 3-H), 5.69 (broad s, 1H, β-Htrans), 6.28 (broad s, 1H, β-Hcis), 7.18 (broad t, J=7.4 Hz, 1H, Hpara),
7.39 (m, 2H, Hmeta), 7.66 (broad d, J=8.5 Hz, 2H, Hortho). 13C NMR δ: 18.3 (CH3, α-CH3), 21.1 (CH3,
4-αCH3), 24.7 (CH3, 4-βCH3), 37.4 (C, C4), 57.5 (CH2, C5), 78.2 (CH, C3), 119.3 (CH, Cortho), 124.7
(CH, Cpara), 126.8 (CH2, Cβ), 128.8 (CH, Cmeta), 135.2 (C, Cα), 139.0 (C, Cipso), 166.4 (C, COO),
168.8 (C, C2).
3.1.4. (R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl crotonate (R)-25
Following the above general procedure, from 23 (1.00 g, 12.0 mmol), (R)-1 (2.46 g, 12.0 mmol), (R)-
25 (1.50 g, 46% yield) was obtained as a solid, m.p. 97–99°C (ethanol), [α]D20=+31.1 (c 1.84, CHCl3),
IR (KBr) ν: 1719 (C_O st), 1634 (C_C st) cm−1. C16H19NO3 (273.35): calcd: C, 70.31%; H, 7.01%;
N, 5.12%. Found: C, 70.22%; H, 7.13%; N, 5.23%. 1H NMR (300 MHz) δ: 1.14 (s, 3H, 4α-CH3), 1.30
(s, 3H, 4β-CH3), 1.92 (dd, J=6.9 Hz, J0=1.7 Hz, 3H, β-CH3), 3.52 (d, J=9.5 Hz, 1H, 5α-H), 3.63 (d,
J=9.5 Hz, 1H, 5β-H), 5.46 (s, 1H, 3-H), 5.99 (dq, J=15.6 Hz, J0=1.7 Hz, 1H, α-H), 7.12 (dq, J=15.6
Hz, J0=6.9 Hz, 1H, β-H), 7.16 (broad t, J=7.5 Hz, 1H, Hpara), 7.38 (m, 2H, Hmeta), 7.64 (dm, J=7.8
Hz, 2H, Hortho). 13C NMR δ: 18.1 (CH3, β-CH3), 21.1 (CH3, 4α-CH3), 24.9 (CH3, 4β-CH3), 37.5 (C,
C4), 57.7 (CH2, C5), 77.9 (CH, C3), 119.4 (CH, Cortho), 121.8 (C, Cα), 124.8 (CH, Cpara), 128.9 (CH,
Cmeta), 139.1 (C, Cipso), 146.4 (CH, Cβ), 165.5 (C, COO), 169.1 (C, C2).
3.1.5. rac-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl cinnamate rac-26
Following the above general procedure, from 24 (3.70 g, 25.0 mmol), rac-1 (5.12 g, 25.0 mmol),
rac-26 (7.68 g, 92% yield) was obtained as a solid, m.p. 105–106°C (ethanol).6
3.2. (S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl acrylate (S)-4
To a cold (−20°C) solution of (S)-1 (1.02 g, 4.98 mmol) and triethylamine (14 ml, 9.95 mmol) in
anhydrous CH2Cl2 (25 ml), acryloyl chloride (2, 0.50 ml, 5.98 mmol) was added. After 10 min, the

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
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mixture was washed with 1 N HCl (3×25 ml) and saturated aqueous NaHCO3 (3×25 ml). The organic
layer was dried with anh. Na2SO4 and concentrated in vacuo to give solid (S)-4 (1.25 g, 97% yield).
3.3. General procedure for the Diels–Alder reactions of esters 4, 17, 25 or 26 and cyclopentadiene,
isoprene or anthracene
A solution of TiCl4 (0.50, 0.75 or 1.00 mmol) in anhydrous CH2Cl2 (2 ml) was added to a solution
of ester 4, 17, 25 or 26 (1.00 mmol) in anhydrous CH2Cl2 (3 ml). The mixture was stirred at −55, −20,
−15°C or at room temperature for 15 min. Then, a solution of the diene (1.00 or 2.40 mmol) in anhydrous
CH2Cl2 (3 ml) was added and it was stirred for the specified time at the indicated temperature. Powdered
Na2CO3 or a small amount of water was added to destroy the TiCl4 complexes, the mixture was filtered
and the filtrate was dried with anh. Na2SO4. The filtrate was concentrated in vacuo and the residue
was submitted to column chromatography [silica gel (20 g), CH2Cl2 or ethyl acetate/hexane] and/or to
crystallization to give esters 6, 11, 13, 21 or 27.
3.3.1. (1R,2R,30R,4R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl bicyclo[2.2.1]hept-5-ene-
2-carboxylate (1R,2R,30R,4R)-6
Following the above general procedure, from (R)-4 (0.69 g, 2.66 mmol), TiCl4 (0.2 ml, 1.8 mmol) and
cyclopentadiene (0.35 g, 5.32 mmol), after 4 h at −55°C and then 16 h more at a temperature from −55
to −20°C, (1R,2R,30R,4R)-6 (0.83 g, 96% yield) was obtained as a solid, after crystallization from ethyl
acetate:hexane (1:1, 1 ml), m.p. 139–141°C (ethyl acetate–hexane), [α]D20=−41.2 (c 1.00, CHCl3), IR
(KBr) ν: 1744 and 1710 (C_O st) cm−1. C20H23NO3 (325.42): calcd: C, 73.82%; H, 7.13%; N, 4.30%.
Found: C, 73.90%; H, 7.12%; N, 4.27%. 1H NMR δ: 1.15 (s, 3H, 40α-CH3), 1.25 (s, 3H, 40β-CH3), 1.31
(broad d, J=8.0 Hz, 1H, 7-Hsyn), 1.46 (pseudo dq, J=8.0 Hz, J0=2.0 Hz, 1H, 7-Hanti), 1.50 (ddd, J=12.0
Hz, J0=4.0 Hz, J00=3.0 Hz, 1H, 3-Hendo), 1.94 (ddd, J=12.0 Hz, J0=9.5 Hz, J00=4.0 Hz, 1H, 3-Hexo),
2.93 (broad s, 1H, 4-H), 3.18 (dt, J=9.5 Hz, J0=4.0 Hz, 1H, 2-Hexo), 3.28 (broad s, 1H, 1-H), 3.49 (d,
J=9.5 Hz, 1H, 50α-H), 3.59 (d, J=9.5 Hz, 1H, 50β-H), 5.35 (s, 1H, 30-H), 5.93 (dd, J=6.0 Hz, J0=3.0 Hz,
1H, 6-H), 6.25 (dd, J=6.0 Hz, J0=3.0 Hz, 1H, 5-H), 7.15 (broad t, J=7.5 Hz, 1H, Hpara), 7.36 (m, 2H,
Hmeta), 7.60 (dm, J=8.0 Hz, 2H, Hortho). 13C NMR δ: 21.3 (CH3, 40α-CH3), 24.8 (CH3, 40β-CH3),
29.0 (CH2, C3), 37.4 (C, C40), 42.5 (CH, C4), 43.1 (CH, C2), 46.1 (CH, C1), 49.9 (CH2, C7), 57.6 (CH2,
C50), 77.8 (CH, C30), 119.4 (CH, Cortho), 124.8 (CH, Cpara), 128.9 (CH, Cmeta), 131.6 (CH, C6),
138.4 (CH, C5), 139.1 (C, Cipso), 169.1 (C, C20), 173.9 (C, COO).
3.3.2. (1S,2S,30S,4S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl bicyclo[2.2.1]hept-5-ene-
2-carboxylate (1S,2S,30S,4S)-6
Following the above general procedure, from (S)-4 (0.54 g, 2.08 mmol), TiCl4 (0.12 ml, 1.09 mmol)
and cyclopentadiene (0.38 g, 4.16 mmol), after 4 h at −55°C and then 16 h more at a temperature from
−55 to −20°C, (1S,2S,30S,4S)-6 (0.67 g, 92% yield) was obtained as a solid, after crystallization from
ethyl acetate:hexane (1:1, 1 ml), m.p. 140–141°C (ethyl acetate–hexane), [α]D20=+39.3 (c 1.00, CHCl3),
IR (KBr) ν: 1744 and 1716 (C_O st) cm−1. C20H23NO3 (325.42): calcd: C, 73.82%; H, 7.13%; N, 4.30%.
Found: C, 73.74%; H, 7.07%; N, 4.47%. The NMR data are coincidental with those of its enantiomer.
3.3.3. (1R,30S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 4-methylcyclohex-3-enecarboxylate
(1R,30S)-11
Following the above general procedure, from (S)-4 (105 mg, 0.41 mmol), TiCl4 (0.02 ml, 0.2 mmol)
and isoprene (0.08 ml, 0.82 mmol), after 15 min at −20°C and then 15 h more at a temperature from

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−20 to 10°C, (1R,30S)-11 (119 mg, 90% yield) was obtained as an oil, after column chromatography
[silica gel (5 g), CH2Cl2], [α]D20=+6.7 (c 0.85, CHCl3), IR (NaCl) ν: 1740 and 1716 (C_O st) cm−1.
C20H25NO3 (327.44): calcd: C, 73.36%; H, 7.70%; N, 4.28%. Found: C, 73.18%; H, 7.80%; N, 4.23%.
1H NMR δ: 1.11 (s, 3H, 40α-CH3), 1.27 (s, 3H, 40β-CH3), 1.65 (d, J=1.5 Hz, 3H, 4-CH3), 1.81 (m, 1H,
6α-H), 2.02 (complex signal, 2H, 5α-H and 5β-H), 2.09 (m, 1H, 6β-H), 2.30 (complex signal, 2H, 2α-H
and 2β-H), 2.69 (dtd, J=11.0 Hz, J0=7.5 Hz, J00=3.0 Hz, 1H, 1-H), 3.50 (d, J=9.5 Hz, 50α-H), 3.60 (d,
J=9.5 Hz, 1H, 50β-H), 5.37 (m, 1H, 3-H), 5.40 (s, 1H, 30-H), 7.15 (tm, J=7.5 Hz, 1H, Hpara), 7.35 (dd,
J=8.5 Hz, J0=7.5 Hz, 2H, Hmeta), 7.61 (dm, J=8.5 Hz, 2H, Hortho). 13C NMR δ: 21.1 (CH3, 40α-CH3),
23.5 (CH3, 4-CH3), 24.8 (CH3, 40β-CH3), 25.4 (CH2, C6), 27.8 (CH2, C2), 29.0 (CH2, C5), 37.4 (C,
C40), 39.1 (CH, C1), 57.7 (CH2, C50), 77.8 (CH, C30), 118.9 (CH, C3), 119.4 (CH, Cortho), 124.8 (CH,
Cpara), 128.9 (CH, Cmeta), 134.0 (C, C4), 139.1 (C, Cipso), 169.1 (C, C20), 175.2 (C, COO).
3.3.4. (11R,30S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 9,10-dihydro-9,10-ethanoanthracene-11-
carboxylate (11R,30S)-13
Following the above general procedure, from (S)-4 (0.80 g, 3.09 mmol), TiCl4 (0.68 ml, 6.18 mmol)
and anthracene (0.55 g, 3.09 mmol) at room temperature for 18 h, (11R,30S)-13 (1.17 g, 87% yield)
was obtained as a solid, after column chromatography [silica gel (60 g), CH2Cl2], m.p. 175–177°C
(methanol), [α]D20=+5.8 (c 1.06, CHCl3), IR (KBr) ν: 1749 and 1707 (C_O st) cm−1. C29H27NO3
1
(437.56): calcd: C, 79.61%; H, 6.22%; N, 3.20%. Found: C, 79.45%; H, 6.22%; N, 3.21%. H NMR δ:
1.14 (s, 3H, 40α-CH3), 1.17 (s, 3H, 40β-CH3), 2.02 (ddd, J=12.5 Hz, J0=10.5 Hz, J00=2.5 Hz, 1H, 12-
Hanti), 2.18 (ddd, J=12.5 Hz, J0=4.5 Hz, J00=2.5 Hz, 1H, 12-Hsyn), 3.05 (ddd, J=10.5 Hz, J0=5.0 Hz,
J00=2.5 Hz, 1H, 11-H), 3.43 (d, J=9.5 Hz, 1H, 50α-H), 3.51 (d, J=9.5 Hz, 1H, 50β-H), 4.30 (t, J=2.5 Hz,
1H, 9-H), 4.65 (d, J=3.0 Hz, 1H, 10-H), 5.23 (s, 1H, 30-H), 6.99 (td, J=7.0 Hz, J0=1.0 Hz, 1H), 7.01-7.07
(complex signal, 4H) (2-H, 3-H, 6-H and 7-H), 7.10 (tm, J=7.0 Hz, 1H, Hpara N-phenyl), 7.17–7.26
(complex signal, 4H) (1-H, 4-H, 5-H and 8-H), 7.31 (dd, J=8.5 Hz, J0=7.0 Hz, 2H, Hmeta N-phenyl),
7.55 (dm, J=8.5 Hz, 2H, Hortho N-phenyl). 13C NMR δ: 21.3 (CH3, 40α-CH3), 24.7 (CH3, 40β-CH3),
31.0 (CH2, C12), 37.4 (C, C40), 43.7 (CH, C9), 44.1 (CH, C11), 46.8 (CH, C10), 57.6 (CH2, C50), 78.3
(CH, C30), 119.4 (CH, Cortho N-phenyl), 123.4 (CH), 123.5 (CH), 123.6 (CH), 124.7 (CH), 125.5 (CH),
125.7 (CH), 126.2 (CH) and 126.4 (CH) (Ar-CH anthracene), 124.9 (CH, Cpara N-phenyl), 128.9 (CH,
Cmeta N-phenyl), 139.0 (C, Cipso N-phenyl), 139.6 (C), 142.3 (C) and 143.8 (2 C) (Ar-C anthracene),
168.8 (C, C20), 172.8 (C, COO).
3.3.5. Mixture of (ꢀ)-endo- and (ꢀ)-exo-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-methyl-
bicyclo[2.2.1]hept-5-ene-2-carboxylate (ꢀ)-endo-18 and (ꢀ)-exo-19
Following the above general procedure, from rac-17 (0.41 g, 1.50 mmol), TiCl4 (0.08 ml, 0.75 mmol)
and cyclopentadiene (0.20 g, 3.5 mmol), after 4 h at −15°C and then 16 h more at a temperature from
−15°C to room temperature, a solid mixture of (ꢀ)-endo-18 and (ꢀ)-exo-19 in the approximate ratio
of 1:1 (0.37 g, 73% yield) was obtained, after column chromatography [silica gel (40 g), hexane:ethyl
acetate], m.p. 107–109°C (ethyl acetate–hexane).
3.3.6. (11S,30R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 9,10-dihydro-11-methyl-9,10-ethano-
anthracene-11-carboxylate (11S,30R)-21
Following the above general procedure, from (R)-17 (0.68 g, 2.49 mmol), TiCl4 (0.60 ml, 4.98 mmol)
and anthracene (0.45 g, 2.49 mmol) at room temperature for 18 h, (11S,30R)-21 (1.09 g, 96% yield)
was obtained as a solid, after column chromatography [silica gel (50 g), CH2Cl2], m.p. 214–216°C
(methanol), [α]D20=−10.5 (c 1.06, CHCl3), IR (KBr) ν: 1740 and 1710 (C_O st) cm−1. C30H29NO3

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
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1
(451.59): calcd: C, 79.79%; H, 6.48%; N, 3.10%. Found: C, 79.78%; H, 6.52%; N, 3.05%. H NMR δ:
1.21 (s, 3H, 11-CH3), 1.24 (s, 3H, 40β-CH3), 1.26 (s, 3H, 40α-CH3), 1.50 (dd, J=12.5 Hz, J0=2.5 Hz,
1H, 12-Hanti), 2.78 (dd, J=12.5 Hz, J0=3.0 Hz, 1H, 12-Hsyn), 3.50 (d, J=9.5 Hz, 1H, 50α-H), 3.55 (d,
J=9.5 Hz, 1H, 50β-H), 4.27 (t, J=3.0 Hz, 1H, 9-H), 4.43 (s, 1H, 10-H), 5.23 (s, 1H, 30-H), 7.02 (td, J=7.5
Hz, J0=1.5 Hz, 1H), 7.06 (td, J=7.0 Hz, J0=1.5 Hz, 1H), 7.08–7.12 (complex signal, 4 H) (2-H, 3-H,
6-H and 7-H), 7.14 (tm, J=7.5 Hz, 1H, Hpara N-phenyl), 7.23–7.32 (complex signal, 4 H) (1-H, 4-H,
5-H and 8-H), 7.35 (dd, J=8.5 Hz, J0=7.5 Hz, 2H, Hmeta N-phenyl), 7.60 (dm, J=8.5 Hz, 2H, Hortho
N-phenyl). 13C NMR δ: 21.4 (CH3, 40α-CH3), 24.5 (CH3, 40β-CH3), 27.3 (CH3, 11-CH3), 37.3 (C, C40),
39.1 (CH2, C12), 44.3 (CH, C9), 48.9 (C, C11), 52.3 (CH, C10), 57.5 (CH2, C50), 78.3 (CH, C30), 119.2
(CH, Cortho N-phenyl), 123.1 (CH), 123.6 (CH), 124.7 (2 CH), 125.3 (CH), 125.5 (CH), 125.9 (CH)
and 126.3 (2 CH) [Ar-CH anthracene and Cpara N-phenyl (124.7)], 128.9 (CH, Cmeta N-phenyl), 139.1
(C, Cipso N-phenyl), 140.5 (C), 141.2 (C), 143.4 (C) and 143.6 (C) (Ar-C anthracene), 168.8 (C, C20),
175.8 (C, COO).
3.3.7. (1R,2R,3S,30R,4S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 3-methylbicyclo[2.2.1]hept-
5-ene-2-carboxylate (1R,2R,3S,30R,4S)-27 and (30R)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl endo-
3-methylbicyclo[2.2.1]hept-5-ene-exo-2-carboxylate (30R)-exo-2-endo-3-28
Following the above general procedure, from (R)-25 (1.41 g, 5.15 mmol), TiCl4 (0.30 ml, 2.70 mmol)
and cyclopentadiene (0.68 g, 10.3 mmol), after 4 h at −15°C and then 16 h more at a temperature from
−15°C to room temperature, (1R,2R,3S,30R,4S)-27 (1.25 g, 71% yield) was obtained as a solid, after
column chromatography [silica gel (60 g), hexane/diethylether], m.p. 93–95°C (diethyl ether–hexane). A
small amount of a less polar oily adduct, characterized as (30R)-exo-2-endo-3-28 (40 mg, 2% yield), was
also isolated.
3.3.7.1. Analytical and spectroscopic data of (1R,2R,3S,30R,4S)-27. [α]D20=−43.0 (c 2.00, CHCl3),
IR (KBr) ν: 1743 and 1718 (C_O st) cm−1. C21H25NO3·1/4H2O (343.96): calcd: C, 73.33%; H, 7.48%;
N, 4.07%. Found: C, 73.50%; H, 7.47%; N, 4.16%. 1H NMR δ: 1.13 (s, 3H, 40α-CH3), 1.19 (d, J=6.5
Hz, 3H, 3exo-CH3), 1.24 (s, 3H, 40β-CH3), 1.45 (pseudo dq, J=8.5 Hz, J0=1.5 Hz, 1H, 7-Hanti), 1.57
(broad d, J=8.5 Hz, 1H, 7-Hsyn), 1.95 (ddq, J=4.5 Hz, J0=1.5 Hz, J00=7.0 Hz, 1H, 3-Hendo), 2.48 (broad
s, 1H, 4-H), 2.59 (dd, J=4.5 Hz, J0=4.0 Hz, 1H, 2-Hexo), 3.19 (broad s, 1H, 1-H), 3.48 (d, J=9.5 Hz, 1H,
50α-H), 3.57 (d, J=9.5 Hz, 1H, 50β-H), 5.33 (s, 1H, 30-H), 5.98 (dd, J=6.0 Hz, J0=3.0 Hz, 1H, 6-H), 6.31
(dd, J=6.0 Hz, J0=3.0 Hz, 1H, 5-H), 7.14 (broad t, J=7.0 Hz, 1H, Hpara), 7.35 (m, 2H, Hmeta), 7.60
(broad d, J=8.0 Hz, 2H, Hortho). 13C NMR δ: 20.7 (CH3, 3exo-CH3), 21.2 (CH3, 40α-CH3), 24.7 (CH3,
40β-CH3), 37.3 (C, C40), 37.4 (CH, C3), 46.1 (CH and CH2, C1 and C7), 48.7 (CH, C4), 52.0 (CH, C2),
57.4 (CH2, C50), 77.6 (CH, C30), 119.3 (CH, Cortho), 124.7 (CH, Cpara), 128.8 (CH, Cmeta), 132.5
(CH, C6), 139.0 (C, Cipso), 139.2 (C, C5), 169.0 (C, C20), 173.6 (C, COO).
3.3.7.2. Analytical and spectroscopic data of (30R)-exo-2-endo-3-28. [α]D20=+6.68 (c 2.00, CHCl3),
IR (NaCl) ν: 1742 and 1718 (C_O st) cm−1. C21H25NO3.1/4H2O (343.96): calcd: C, 73.33%; H, 7.48%;
1
N, 4.07%. Found: C, 73.58%; H, 7.41%; N, 4.09%. H NMR (300 MHz) δ: 0.96 (d, J=6.9 Hz, 3H, 3-
endo-CH3), 1.16 (s, 3H, 40-αCH3), 1.31 (s, 3H, 40-βCH3), 1.49 (pseudo dq, J=8.6 Hz, J0=1.7 Hz, 1H,
7-Hanti), 1.70 (broad d, J=8.6 Hz, 1H, 7-Hsyn), 1.85 (dd, J=5.0 Hz, J0=1.7 Hz, 1H, 2-Hendo), 2.55 (ddq,
J=3.4 Hz, J0=5.0 Hz, J00=6.9 Hz, 1H, 3-Hexo), 2.75 (broad s, 1H, 4-H), 3.05 (broad s, 1H, 1-H), 3.53 (d,
J=9.5 Hz, 1H, 50α-H), 3.63 (d, J=9.5 Hz, 1H, 50β-H), 5.42 (s, 1H, 30-H), 6.14 (dd, J=5.6 Hz, J0=3.0 Hz,
1H) and 6.23 (dd, J=5.6 Hz, J0=3.1 Hz, 1H) (5-H and 6-H), 7.17 (tt, J=7.4 Hz, J0=1.2 Hz, 1H, Hpara),

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7.38 (m, 2H, Hmeta), 7.63 (dm, J=7.6 Hz, 2H, Hortho). 13C NMR δ: 19.1 (CH3, 3-endo-CH3), 21.2
(CH3, 40α-CH3), 24.8 (CH3, 40β-CH3), 37.3 (C, C40), 39.3 (CH, C3), 47.2 (2 CH, C1 and C4), 48.2
(CH2, C7), 51.2 (CH, C2), 57.7 (CH2, C50), 77.9 (CH, C30), 119.4 (CH, Cortho), 124.8 (CH, Cpara),
128.9 (CH, Cmeta), 135.5 (CH) and 136.3 (CH) (C5 and C6), 139.1 (C, Cipso), 169.1 (C, C20), 175.4
(C, COO).
3.4. General procedure for the hydrolysis of esters 6, 11, 13, 21 and 27
To a solution of the ester 6, 11, 13, 21 or 27 (1.0 mmol) in a mixture of THF (3.0 ml) and water (2.5
ml), solid LiOH·H2O (1.5 or 4.5 mmol) was added and the mixture was stirred at room or at the reflux
temperature till completion of the hydrolysis, following the reaction by TLC. When no more starting
ester remained, the organic solvent was removed in vacuo.
Work-up A: the aqueous residue was extracted with diethyl ether (3×10 ml). The combined organic
phases were dried with anh. Na2SO4 and concentrated in vacuo, to give (R)- or (S)-1. The aqueous phase
was acidified (pH=1) and was extracted with a mixture of n-pentane/CH2Cl2 in the ratio of 98:2 (3×20
ml). The combined organic phases were dried with anh. Na2SO4 and concentrated in vacuo, to give acids
(1R,2R,4R)- or (1S,2S,4S)-7, (R)-14 or (1R,2R,3S,4S)-33.
Work-up B: water (4 ml) was added and the mixture was extracted with CH2Cl2 (3×10 ml). The
combined organic phases were dried with anh. Na2SO4 and concentrated in vacuo, to give (R)- or (S)-
1. The aqueous phase was acidified (pH=1) and was extracted with CH2Cl2 (5×10 ml). The combined
organic phases were dried with anh. Na2SO4 and concentrated in vacuo, to give acids (R)-15 or (S)-22.
3.4.1. (1R,2R,4R)-Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1R,2R,4R)-7
Following the above general procedure at room temperature, from (1R,2R,30R,4R)-6 (148 mg, 0.45
mmol) and LiOH·H2O (81 mg, 1.93 mmol) and after work-up A, (1R,2R,4R)-7 (60 mg, 96% yield) was
obtained as an oil, [α]D20=−142 (c 3.00, 95% ethanol), described: [α]D20=−147 (c 3.00, 95% ethanol),11
o.p. 97%.
3.4.2. (1S,2S,4S)-Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1S,2S,4S)-7
Following the above general procedure at room temperature, from (1S,2S,30S,4S)-6 (140 mg, 0.43
mmol) and LiOH·H2O (80 mg, 1.91 mmol) and after work-up A, (1S,2S,4S)-7 (60 mg, quantitative yield)
was obtained as an oil, [α]D20=+140 (c 3.00, 95% ethanol), described for (1R,2R,4R)-7: [α]D20=−147 (c
3.00, 95% ethanol),11 o.p. 95%.
3.4.3. (R)-4-Methylcyclohex-3-enecarboxylic acid (R)-14
Following the above general procedure at room temperature, from (1R,30S)-11 (242 mg, 0.74 mmol)
and LiOH·H2O (47 mg, 1.11 mmol) and after work-up A, (R)-14 (99 mg, 95% yield) was obtained as
a solid, m.p. 98–99°C (ethyl acetate–hexane), [α]D20=+94.5 (c 4.8, abs. ethanol), described for (S)-11:
[α]D20=−107 (c 4.00, abs. ethanol),11 o.p. 88%.
3.4.4. (R)-9,10-Dihydro-9,10-ethanoanthracene-11-carboxylic acid (R)-15
Following the above general procedure at room temperature, from (11R,30S)-13 (219 mg, 0.50 mmol)
and LiOH·H2O (95 mg, 2.26 mmol) and after work-up B, (R)-15 (124 mg, 99% yield) was obtained
as a solid, m.p. 197.5–199.5°C (ethyl acetate), [α]D20=−7.4 (c 1.8, CHCl3), IR (KBr) ν: 3500–2600,
max. at 3285 (O–H st), 1726 and 1688 (C_O st) cm−1. C17H14O2 (250.31): calcd: C, 81.57%; H, 5.64%.
Found: C, 81.68%; H, 5.75%. 1H NMR δ: 1.93 (ddd, J=12.5 Hz, J0=10.5 Hz, J00=3.0 Hz, 1H, 12-Hanti),

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2.03 (ddd, J=12.5 Hz, J0=4.5 Hz, J00=2.5 Hz, 1H, 12-Hsyn), 2.82 (ddd, J=10.5 Hz, J0=4.5 Hz, J00=2.5
Hz, 1H, 11-H), 4.26 (t, J=2.5 Hz, 1H, 9-H), 4.60 (d, J=2.5 Hz, 1H, 10-H), 7.00-7.07 (complex signal,
4H, 2-H, 3-H, 6-H and 7-H), 7.17–7.24 (complex signal, 4H, 1-H, 4-H, 5-H and 8-H). 13C NMR δ: 30.5
(CH2, C12), 43.7 (CH, C9), 44.0 (CH, C11), 46.5 (CH, C10), 123.1 (CH), 123.5 (CH), 123.6 (CH), 125.0
(CH), 125.8 (2 CH), 126.2 (CH) and 126.3 (CH) (Ar-CH), 139.6 (C), 142.3 (C), 143.6 (C) and 143.7 (C)
(Ar-C), 179.6 (C, COO).
3.4.5. (S)-9,10-Dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (S)-22
Following the above general procedure at the reflux temperature, from (11S,30R)-21 (127 mg, 0.28
mmol) and LiOH·H2O (53 mg, 1.26 mmol) and after work-up B, (S)-22 (72 mg, 96% yield) was
obtained as a solid, m.p. 140–142°C (diethylether–hexane), [α]D20=−26.7 (c 1.08, CHCl3), IR (KBr)
ν: 3300–2400 (O–H st), 1699 (C_O st) cm−1. C18H16O2 (264.34): calcd: C, 81.79%; H, 6.11%. Found:
C, 81.84%; H, 6.28%. 1H NMR δ: 1.06 (s, 3H, 11-CH3), 1.39 (dd, J=12.5 Hz, J0=2.5 Hz, 1H, 12-Hanti),
2.61 (dd, J=12.5 Hz, J0=3.0 Hz, 1H, 12-Hsyn), 4.25 (t, J=2.5 Hz, 1H, 9-H), 4.36 (s, 1H, 10-H), 7.02–7.14
(complex signal, 4H, 2-H, 3-H, 6-H and 7-H), 7.20–7.30 (complex signal, 4H, 1-H, 4-H, 5-H and 8-H),
9–10 (broad s, 1H, COOH). 13C NMR δ: 26.8 (CH3, 11-CH3), 38.6 (CH2, C12), 44.4 (CH, C9), 48.4 (C,
C11), 52.5 (CH, C10), 123.1 (CH), 123.3 (CH), 125.0 (CH), 125.5 (CH), 125.6 (CH), 126.0 (CH), 126.1
(CH) and 126.3 (CH) (Ar-CH), 140.4 (C), 141.1 (C), 143.1 (C) and 143.5 (C) (Ar-C), 182.0 (C, COO).
3.4.6. (1R,2R,3S,4S)-3-Methylbicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1R,2R,3S,4S)-33
Following the above general procedure at room temperature, from (1R,2R,3S,30R,4S)-27 (250 mg,
0.74 mmol) and LiOH·H2O (130 mg, 3.10 mmol) and after work-up A, (1R,2R,3S,4S)-33 (100 mg, 89%
yield) was obtained as an oil, [α]D20=−152 (c 1.00, ethanol 95%), described: [α]D20=−157 (c 1.00, 95%
ethanol),39 o.p. 97%.
3.5. X-Ray crystal-structure determinations of (11R,30S)-13
A prismatic crystal was selected and mounted on a Enraf–Nonius CAD4 four-circle diffractometer.
Unit cell parameters were determined by automatic centering of 25 reflections (12<θ<21°) and refined
by the least-squares method. Intensities were collected with graphite-monochromatized Mo-Kα radia-
tion, using ω/2θ scan technique. Two thousand, six hundred and three reflections were measured in
the range 2.13≤θ≤29.93, of which 2577 were non-equivalent by symmetry [Rint (on I)=0.010]; 2064
reflections were assumed as observed by applying the condition I>2σ(I). Three reflections were measured
every 2 h as orientation and intensity control; significant intensity decay was not observed. Lorentz
polarization but no absorption corrections were made. The structure was solved by direct methods, using
the SHELXS computer program41 and refined by the full-matrix least-squares method with the SHELX-
93 computer program42 using 2527 reflections (very negative intensities were not assumed). The function
P
minimized was w(|Fo|2−|Fc|2)2, where w=[σ2(I)+(0.0762P)2+0.0362P]−1, and P=(|Fo|2+2|Fc|2)/3. f, f0
and f00 were taken from the International Tables of X-Ray Crystallography.43 The extinction coefficient
was 0.013(2). The chirality of the structure was defined by the Flack coefficient, which is equal to
1.66(238) for the given results.44 All H atoms were located from a difference synthesis and refined
with an overall isotropic temperature factor. Goodness of fit=1.122 for all observed reflections. Mean
shift/e.s.d.=0.00. The results are shown in Table 1.45

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
Table 1
Experimental data of the X-ray crystal-structure determination of (11R,30S)-13
3.6. X-Ray crystal-structure determinations of (11S,30R)-21
A prismatic crystal was selected and mounted on a Enraf–Nonius CAD4 four-circle diffractometer.
Unit cell parameters were determined by automatic centering of 25 reflections (12<θ<21°) and refined
by the least-squares method. Intensities were collected with graphite-monochromatized Mo-Kα radia-
tion, using ω/2θ scan technique. Two thousand, six hundred and sixty-nine reflections were measured
in the range 2.34≤θ≤29.97, of which 2516 were non-equivalent by symmetry [Rint (on I)=0.020]; 2024
reflections were assumed as observed by applying the condition I>2σ(I). Three reflections were measured
every 2 h as orientation and intensity control; significant intensity decay was not observed. Lorentz
polarization but no absorption corrections were made. The structure was solved by direct methods, using
the SHELXS computer program41 and refined by the full-matrix least-squares method with the SHELX-
93 computer program42 using 2466 reflections (very negative intensities were not assumed). The function
P
minimized was w(|Fo|2−|Fc|2)2, where w=[σ2(I)+(0.0460P)2+0.1157P]−1, and P=(|Fo|2+2|Fc|2)/3. f, f0
and f00 were taken from the International Tables of X-Ray Crystallography.43 The extinction coefficient
was 0.017(2). The chirality of the structure was defined by the Flack coefficient, which is equal to
0.96(197) for the given results.44 Twenty-six H atoms were located from a difference synthesis and
refined with an overall isotropic temperature factor and 3 H atoms were computed and refined with an
overall isotropic temperature factor by using a ‘riding’ model. Goodness of fit=1.127 for all observed
reflections. Mean shift/e.s.d.=0.00. The results are shown in Table 2.45
Acknowledgements
Fellowships from the Comissionat per a Universitats i Recerca (CUR) of the Generalitat de Catalunya
(GC) to S. Giménez and N. Soldevilla and financial support from the Comisión Interministerial de
Ciencia y Tecnología (CICYT) (Programa Nacional de Tecnología de los Procesos Químicos, Project

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 3123–3138
3137
Table 2
Experimental data of the X-ray crystal-structure determination of (11S,30R)-21
QUI96-0828) and the CUR (Project 1997SGR 00140) are gratefully acknowledged. We thank the Serveis
Científico-Tècnics of the Universitat de Barcelona for recording the NMR spectra, and P. Domènech from
the Centro de Investigación y Desarrollo (C.I.D.) of Barcelona, for carrying out the elemental analyses.
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