(R)- or (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic acid as a new chiral auxiliary for solid phase asymmetric Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetasy.2004.06.012

The synthesis of enantiopure (R)- and (S)-4-(3-hydroxy-4,4-dimethyl-2- oxopyrrolidin-1-yl)benzoic acid is described and the corresponding supported chiral acrylate derivative has been used as a dienophile in solid phase asymmetric Diels-Alder reactions wi

Full text of DOI:10.1016/j.tetasy.2004.06.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2515–2525
(R)- or (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic
acid as a new chiral auxiliary for solid phase asymmetric
Diels–Alder reactions
*
ꢀ
Rhalid Akkari, Monique Calmes, Franßcoise Escale, Julien Iapichella, Marc Rolland and
Jean Martinez
Laboratoire des Aminoacides, Peptides et Protꢁeines, UMR CNRS 5810 Universitꢁes Montpellier I et II, Place Eugꢀene Bataillon, 34095
Montpellier cedex 5, France
Received 2 June 2004; accepted 10 June 2004
Available online 23 July 2004
Abstract—The synthesis of enantiopure (R)- and (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic acid is described and
the corresponding supported chiral acrylate derivative has been used as a dienophile in solid phase asymmetric Diels–Alder reactions
with different dienes. In all cases, the reaction gave the expected compound in good yield and with high regio or endo selectivity.
Moreover, a high facial diastereoselectivity (86–99% de) was obtained using 2,3-dimethylbutadiene, cyclopentadiene or 1,3-cyclo-
hexadiene. In contrast, low to moderate facial diastereoselectivity (40–76% de) was observed with isoprene depending on the
polymer used.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
have been reported so far.11;12 Nevertheless, the usual
advantages of the solid phase strategy, easy work-up,
simple isolation of the desired compounds and facile
separation and recovery of the chiral material, are now
reliable.
The Diels–Alder cycloaddition is a well known organic
reaction, which is widely used to prepared a six-mem-
bered ring with several stereogenic centres in a regio and
stereocontrolled way.1–3 The development of asymmetric
Diels–Alder reactions involves the use of either a chiral
auxiliary1;4;5 or a chiral catalyst.6 Actually, among sev-
eral possible combinations of chiral reactants, reactions
between achiral dienes and chiral dienophiles such as
acrylates or methacrylates of enantiomerically pure
alcohols or amines have been extensively studied.4;5;7
We recently prepared and tested several N-substituted
3-hydroxy-4,4-dimethyl-2-pyrrolidinone acrylate deri-
vatives as dienophiles in Diels–Alder reactions using
isoprene and cyclopentadiene as dienes.13 These exper-
iments pointed out the difficulties associated with some
of these compounds that failed to yield the corre-
sponding cycloadduct. We found that the outcome of
the reaction was dependent on the acrylate structure
and that the 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrol-
idin-1-yl)benzoic acid acrylate derivative was highly
efficient to give the cycloadduct in good yield and with
high regio or endo selectivity in both solution and solid
phase reaction conditions. As part of our programme
directed towards the development of asymmetric reac-
tions on solid support,14 we decided to convert the
racemic 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-
yl)benzoic acid acrylate derivative into the correspond-
ing enantiopure compound and to evaluate its possible
use as a supported chiral auxiliary in asymmetric Diels–
Alder reactions.
In recent years a number of asymmetric organic reac-
tions have been carried out with polymer-supported
chiral reagents or catalysts.8 On the other hand, stereo-
selective syntheses of complex molecules using a poly-
mer-supported chiral auxiliary9 are not always well
developed. This is the case of solid phase Diels–Alder
reactions whose syntheses mainly concern racemic
preparations.10;11 Only very few asymmetric examples
* Corresponding author. Fax: +04-67-144866; e-mail: monique@univ-
montp2.fr
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.012

2516
R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
2. Results and discussion
Racemic 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-
yl)benzoic acid ( )-1 was prepared as previously
described15 in moderate yield under severe conditions by
fusion of an excess of pantolactone 2 and the sodium
salt of the 4-aminobenzoic acid at 190 ꢁC (Scheme 1).
The corresponding racemic benzyl ester 3 was obtained
in high yield using benzyl alcohol, benzotriazolyloxy-
tris-(dimethylamino)phosphonium hexafluorophosphate
(BOP) and N,N-diisopropylethylamine (DIEA). Com-
pound 3 was then transformed into a diastereoisomeric
mixture of (1S,30S)-4 and (1S,30R)-4 using NEt3/DMAP
and (1S)-camphanic acid chloride. Enantiomerically
pure compounds 4 were isolated by chromatographic
separation of the mixture of the two diastereoisomers.
(S)-1 or (R)-1 were finally obtained by saponification of
the camphanyl ester followed by hydrogenolysis of the
benzyl ester.
Figure 1. ORTEP drawing of ester (1S,30S)-4.
The structure of (1S,30R)-4 and (1S,30S)-4 were ascer-
tained from the spectral data and the configuration of
(1S,30S)-4 was assigned on the basis of an X-ray crystal
structure determination (Fig. 1).16 The stereochemistry
of (1S,30S)-4 allowed us to establish that of compound
(S)-1.
polymer remained stable under the reaction conditions
and during the basic final hydrolysis of the ester bond
(Scheme 2, step e). Furthermore, removal of compound
8 from the resin could be performed in acidic medium
(5% TFA in CH2Cl2) (Scheme 2, step d). This strategy
was of great help for the control of the different steps
of the synthesis.
The polymer-supported (R)-4-(3-hydroxy-4,4-dimethyl-
2-oxopyrrolidin-1-yl)benzoic acid (R)-5 was obtained as
previously described,13;14 starting from a Fmoc Rink
amide resin and the (R)-4-(3-hydroxy-4,4-dimethyl-2-
oxopyrrolidin-1-yl)benzoic acid (R)-1. The correspond-
ing supported acrylic ester 6 was prepared via reaction
of the supported alcohol (R)-5 with an excess of both
acryloyl chloride and triethylamine in anhydrous
CH2Cl2 at room temperature.
According to previous studies performed using the
supported racemic acrylic ester ( )-6,13 the supported
Diels–Alder reaction was carried out under optimized
reaction conditions that is, 6 equiv of diene in the pres-
ence of 1.1 equiv of TiCl4 in anhydrous CH2Cl2 at 0 ꢁC
for 16 h.
The reaction of the supported acrylate ester (R)-6 with
isoprene, 2,3-dimethylbutadiene, cyclopentadiene and
1,3-cyclohexadiene,17 gave in good yield (80–98%) the
expected compound 8a, 8b, 8c or 8d after cleavage from
We used a Rink amide resin14 because the benzhyd-
rylamide bond created between the alcohol and the
OH
N
OH
N
a
OH
b
O
O
O
O
O
O
HO
( )-3
2
( )-1
BnO
c
O
(1S,3'S)-4
O
O
(S)-1
O
d
N
(1S,3'RS)-4
O
(1S,3'R)-4
e
O
OBn
f
O
O
N
O
N
OH
OH
(R)-1
BnO
HO
O
(R)-3
Scheme 1. Synthesis of (R)-1 and (S)-1. Reagents and conditions: (a) 4-aminobenzoic acid sodium salt, 190 ꢁC; (b) BnOH, BOP, DIEA, DMF;
(c) (1S)-camphanic acid chloride, NEt3, DMAP, CH2Cl2; (d) chromatographic separation; (e) LiOH, THF, H2O; (f) H2, Pd(OH)2, AcOEt.

R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
2517
OH
N
O
O
N
O
H
H
5
N
O
H
H
O
N
O
a, b
c
O
NHFmoc
O
6
H3CO
H3CO
OCH3
OCH3
R
O
R
O
H2N
O
N
N
O
e
f
O
d
O
O
H
H
8
N
O
e
O
H3CO
R
9
HO2C
OCH3
Scheme 2. Diels–Alder reaction with the supported-acrylate 6. Reagents and conditions: (a) piperidine, DMF; (b) (R)-1, BOP, DIEA, DMF;
(c) acryloyl chloride, NEt3, CH2Cl2; (d) diene, TiCl4, CH2Cl2; (e) TFA, CH2Cl2; (f) LiOH, THF, H2O.
the resin under acidic conditions (Table 1). Concerning
the determination of the regio, endo or facial selectivity
of the reaction, we could not directly conclude even
after several NMR and HPLC analyses. Indeed, no
significant splitting of the resonance signals was
observed on the 1H and 13C NMR spectra of com-
pounds 8a, 8b, 8c and 8d. Whatever the conditions
and chiral columns that were used, we only obtained
one peak on the corresponding HPLC chromatograms.
On the other hand, LiOH hydrolysis of compounds 8a,
8c and 8d at room temperature yielded acids 9a, 9c
and 9d whose specific rotations allowed us to establish
the (S)-configuration for the main newly generated
stereogenic centre.18 LiOH hydrolysis of 8b at room
temperature gave the acids (ꢀ)-9b, assumed to have an
(S)-configuration. 13C NMR spectrum showed that 9a
was mainly the para-compound (>99%)19 and that 9c
and 9d were mainly endo compounds (95% and 98%).20
The accurate stereochemistry of (S)-9a (40% ee), (ꢀ)-9b
(99% ee), (S)-9c (86% ee) and (S)-9d (85% ee), was
determined by chiral HPLC analysis of the corre-
sponding benzyl amide derivatives 10a, 10b, 10c and
10d21 (Table 1).
auxiliary away from the polymer matrix or an amino-
methylated resin to evaluate effects of the Rink linker.
The reaction of acrylate (R)-11 with isoprene (2.0 equiv)
in solution in the presence of 1 equiv of TiCl4 at a
temperature from ꢀ20 ꢁC to 0 ꢁC gave in 85% yield and
with high diastereoisomeric excess (92%)22 the desired
cycloadduct (30R,1S)-12, which consisted of only the
corresponding para-adduct. The absence of the meta
regioisomer was confirmed by 13C NMR analysis of
(S)-methyl cyclohex-3-ene carboxylic acid 9a,19 obtained
after treatment of compound 12 with 2 equiv of lithium
hydroxide monohydrate in THF/water for 4 h. The
enantiomeric excess of (S)-9a (86%), determined by
chiral HPLC analysis of the corresponding benzyl amide
derivatives (S)-10a,21 showed that slight racemization
occurred during the saponification.
The spacer introduced on the Rink amide resin was 6-
aminohexanoic acid as it allowed us to follow the same
strategy while outlying the chiral auxiliary. Reaction of
the corresponding supported acrylate (R)-13 with iso-
prene carried out under previous optimized reaction
conditions (6 equiv diene, 1.1 equiv TiCl4, 0 ꢁC 16 h),
gave the expected compound 14 in good yield (77%)
after acidic removal from the resin. The value of enan-
tiomeric excess (70%) of the corresponding compound
(S)-9a isolated after LiOH treatment, showed that the
introduction of a spacer led to an increase of stereo-
selectivity.
Due to the low enantiomeric excess obtained with iso-
prene, new experiments were investigated. Acrylate
derivative (R)-11, prepared from compound (R)-3, was
first used in solution to examine the effect of the polymer
matrix. In the solid phase, we either used a spacer
introduced on the Rink amide resin to move the chiral
O
O
O
N
N
O
BnO
O
BnO
O
(R)-11
12
O
O

2518
R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
Table 1. TiCl4-catalyzed Diels–Alder reactions of (R)-6 with various dienes
Dienes
Major products 8
Major products 9 and 10
9a: R ¼ OH
10a: R ¼ NHBn
para >99%
H2N
O
8a
80% yield
R
O
N
N
O
O
Ee ¼ 40%
O
O
O
H2N
O
9b: R ¼ OH
10b: R ¼ NHBn
Ee ¼ 99%
8b
95% yield
R
O
O
H2N
O
9c: R ¼ OH
10c: R ¼ NHBn
endo/exo 95/5
Ee ¼ 86%
8c
95% yield
N
N
R
O
O
O
O
O
O
H2N
O
9d: R ¼ OH
10d: R ¼ NHBn
endo/exo 98/2
Ee ¼ 85%
8d
98% yield
R
O
O
O
N
N
O
O
O
NH
H
N
O
O
O
( )5
N
H
H
O
O
(R)-15
O
(R)-13
H3CO
O
N
R
O
OCH3
NH
O
R'
O
O
N
O
HN
( )5
16a R = CH3, R' = H
16b R = CH3, R' = CH3
H2N
O
14
O
O
Finally, we used an aminomethylated resin to obtain the
supported acrylate (R)-15 by treatment of the corre-
sponding supported alcohol with acryloyl chloride. The
Diels–Alder reactions when carried out with (R)-15
under various conditions always gave compound (S)-9a
in moderate yield (10–50%) after direct saponification
on polymer 16. The best result was obtained using
1.1 equiv TiCl4 and 6 equiv of isoprene at 0 ꢁC for 16 h as
in the case of the Rink amide resin. Moderate yields (40–
50%) were also observed when a spacer was introduced
on the aminomethylated resin to move away the chiral
yields (45% and 40%) and with good stereoselectivity
(86% and 94%), respectively.
O
N
O
NH
O
O
16c
1
auxiliary. H and 13C NMR of compound (S)-9a and
chiral HPLC of the corresponding benzyl amide deriv-
atives 10a showed the absence of the meta regioisomer
and an increase of the stereoselectivity (76% ee) when
compared to the Rink amide resin.
3. Conclusion
In conclusion, the supported chiral acrylate derivative of
enantiopure (R)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrr-
olidin-1-yl)benzoic acid reacted with different dienes
under TiCl4 catalysis with high regio or endo selectivity.
A high facial diastereoselectivity was also observed
using 2,3-dimethylbutadiene, cyclopentadiene or 1,3-
cyclohexadiene as dienes. With the poor reactive iso-
To complete our investigations, reactions of (R)-15 with
cyclopentadiene and 2,3-dimethylbutadiene were real-
ized under the best conditions leading to resins 16b and
16c. After direct saponification on the polymer, com-
pounds (ꢀ)-9b and (S)-9c were obtained in moderate

R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
2519
prene, moderate results were obtained. It appeared that
facial diastereoselectivity was dependent on the polymer
used in this case.
afforded a pure mixture of (1S,30S)/(1S,30R) esters 4 in
95% yield (4.46 g, 8.64 mmol). Diastereoisomers
(1S,30R)-4 (1.18 g, 25% yield, Rf ¼ 0:47, 99% de) and
(1S,30S)-4 (0.85 g, 18% yield, Rf ¼ 0:37, 95% de) were
isolated after flash column chromatography on silica gel,
eluting with ether/hexane (7/3). Crystallization of an
aliquot of compound (1S,30S)-4 from diethyl ether/hex-
ane yielded colourless crystals suitable for X-ray anal-
ysis.
4. Experimental section
4.1. General methods
All reagents were used as purchased from commercial
suppliers without further purification, except for trieth-
ylamine (NEt3), which was distilled from KOH and
ninhydrin. Solvents were dried and purified by conven-
tional methods prior to use; THF was freshly distilled
under argon from sodium and benzophenone. Melting
20
D
Compound (1S,30R)-4: mp 105 ꢁC; ½aꢁ ¼ ꢀ6 (c 2, acet-
one); tR (HPLC, column A) 15.1 min; (HPLC, column
B: eluent I) 10.8 min; MS (ESI) m=z: 520.1 [(M+H)þ]; 1H
NMR (CDCl3) 1.02 (s, 3H, CH3), 1.03 (s, 3H, CH3),
1.05 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.25 (s, 3H, CH3),
1.62 (ddd, J ¼ 13:2, 9.2, 4.1, 1H, HCH-50), 1.87 (ddd,
J ¼ 13:2, 10.7, 4.5, 1H, HCH-50), 2.02 (ddd, J ¼ 13:6,
9.2, 4.5, 1H, HCH-60), 2.48 (ddd, J ¼ 13:6, 10.7, 4.1, 1H,
HCH-60), 3.51 (d, J ¼ 9:6, 1H, HCH-5), 3.57 (d,
J ¼ 9:6, 1H, HCH-5), 5.27 (s, 2H, CH2C6H5), 5.43 (s,
1H, CH-3), 7.23–7.37 (m, 5H, H-arom), 7.63 (d, J ¼ 8:9,
2H, H-arom), 7.99 (d, J ¼ 8:9, 2H, H-arom); 13C NMR
(CDCl3) 10.19, 17.05, 17.20, 21.67, 24.92 (CH3), 29.17
(CH2-50), 31.09 (CH2-60), 37.40 (C-4), 54.99 (C-70), 55.41
(C-40), 57.77 (CH2-5), 67.06 (CH2C6H5), 79.47 (CH-3),
91.58 (C-10), 118.79 (CH-arom), 126.54 (C-arom),
128.54, 128.65, 128.99, 131.16 (CH-arom), 136.43,
143.27 (C-arom), 166.14, 167.31, 168.81, 178.69 (CO).
HRMS (FAB) calcd for C30H34NO7 (MHþ) 520.2335,
found 520.2318.
€
points were determined with a Buchi apparatus and are
uncorrected. IR spectra were recorded with a FT-IR
Perkin–Elmer 1000 spectrometer. 1H or 13C NMR
spectra were recorded with a Bruker Advance 300
spectrometer or a Brucker A DRX 400 spectrometer
using the solvent as the internal reference. Data are re-
ported as follows: chemical shifts (d) in parts per million,
coupling constants (J) in hertz. The ESI mass spectra
were recorded with a platform II quadrupole mass
spectrometer (Micromass, Manchester, UK) fitted with
an electrospray source. HPLC analyses were performed
with a Waters model 510 instrument with a variable
detector at 214 nm using: column A: a reverse phase
Nucleosil C18, 3.5l, (50 · 4.6 mm), flow: 1 mL/min, H2O
(0.1% TFA)/CH3CN (0.1% TFA) gradient 0 fi 100%
(15 min) and 100% (4 min); column B: Chiracel OD, 5l,
(250 · 10 mm), flow: 1 mL/min, eluent I: hexane/2-pro-
panol 50/50; eluent II: hexane/2-propanol 98/2; column
C: Chiracel OD-R, 5l, (250 · 10 mm), flow: 1 mL/min,
eluent: H2O (0.1% TFA)/CH3CN (0.1% TFA) 60/40;
column D: (S,S)-Whelk 01, 5l, (250 · 10 mm), flow:
1 mL/min, eluent I: hexane/2-propanol 90/10; eluent II:
hexane/2-propanol 98/2.
20
D
Compound (1S,30S)-4: mp 40 ꢁC; ½aꢁ ¼ ꢀ15 (c 2,
CH2Cl2); tR (HPLC, column A) 15.1 min; (HPLC, col-
umn B: eluent I) 15.6 min; MS (ESI) m=z: 520.1
[(M+H)þ]; 1H NMR (CDCl3) 1.02 (s, 3H, CH3), 1.03 (s,
3H, CH3), 1.05 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.24 (s,
3H, CH3), 1.60 (ddd, J ¼ 13:2, 9.2, 4.1, 1H, HCH-50),
1.86 (ddd, J ¼ 13:2, 10.7, 4.5, 1H, HCH-50), 1.99 (ddd,
J ¼ 13:6, 9.2, 4.5, 1H, HCH-60), 2.41 (ddd, J ¼ 13:6,
10.7, 4.1, 1H, HCH-60), 3.51 (d, J ¼ 9:6, 1H, HCH-5),
3.57 (d, J ¼ 9:6, 1H, HCH-5), 5.27 (s, 2H, CH2C6H5),
5.46 (s, 1H, CH-3), 7.28–7.41 (m, 5H, H-arom), 7.64 (d,
J ¼ 8:9, 2H, H-arom), 8.00 (d, J ¼ 8:9, 2H, H-arom);
13C NMR (CDCl3): d 10.12, 16.84, 17.10, 21.68, 24.79
(CH3), 29.44 (CH2-50), 31.12 (CH2-60), 37.41 (C-4), 55.06
(C-70), 55.21 (C-40), 57.51 (CH2-5), 66.99 (CH2C6H5),
79.15 (CH-3), 91.41 (C-10), 118.78 (CH-arom), 126.42
(C-arom), 128.51, 128.64, 128.99, 131.10 (CH-arom),
136.46, 143.32 (C-arom), 166.08, 166.87, 168.86, 178.32
(CO). HRMS (FAB) calcd for C30H34NO7 (MHþ)
520.2335, found 520.2341.
( )-4-(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)ben-
zoic acid ( )-1 and ( )-benzyl 4-(3-hydroxy-4,4-di-
methyl-2-oxopyrrolidin-1-yl)benzoate ( )-3 were prepared
as previously described.13
4.2. [1-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-2-oxo-
pyrrolidin-3-yl]4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]-
heptane-1-carboxylate 4
To a mixture of ( )-benzyl-4-(3-hydroxy-4,4-dimethyl-
2-oxopyrrolidin-1-yl)benzoate ( )-3 (3.10 g, 9.10 mmol)
and (1S)-camphanic acid chloride (2.18 g, 10.0 mmol,
1.1 equiv) in 100 mL of dry CH2Cl2 were added 4-di-
methylaminopyridine (1.70 g, 13.7 mmol, 1.5 equiv) and
triethylamine (1.90 mL, 13.7 mmol, 1.5 equiv) at 0 ꢁC.
The mixture was then stirred at room temperature for
6 h (TLC: diethyl ether/hexane 7/3, indicated complete
consumption of the starting material). The resulting
mixture was filtered and washed successively with a 1 M
HCl solution (80 mL), a saturated NaHCO3 solution
(80 mL) and water (80 mL), dried over Na2SO4 and
concentrated in vacuo. Rapid column chromatography
on silica gel, eluting with diethyl ether/hexane (7/3),
4.3. (R)-Benzyl 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrol-
idin-1-yl)benzoate (R)-3
To a solution of the diastereoisomer (1S,30R)-4 (731 mg,
1.4 mmol) in THF (20 mL) was added dropwise a solu-
tion of LiOH, H2O (60 mg, 1.4 mmol, 1.0 equiv) in water
(15 mL) and the mixture was stirred at room tempera-
ture until completion of the hydrolysis (1.5 h) [the
reaction was monitored by TLC (hexane/AcOEt/CH2Cl2
(5/4/1))]. The organic solvent was removed in vacuo,

2520
R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
saturated aqueous NaHCO3 (10 mL) added and the
mixture extracted with ethyl acetate (2 · 30 mL). The
combined organic phases were dried over anhydrous
Na2SO4 and concentrated in vacuo to yield compound
(R)-3 as a white solid (467 mg, 1.38 mmol, 99%); mp
(monitored by the ninhydrin test) and the solution re-
moved from the resin by filtration. The resin was washed
with DMF (3 · 15 mL), CH2Cl2 (3 · 15 mL), CH2Cl2/
CH3OH (8/2) (3 · 20 mL), CH2Cl2 (3 · 20 mL) and di-
ethyl ether (3 · 20 mL) and the resin dried under reduced
pressure. From this stirred and swollen resin (1.0 mmol)
in DMF (15 mL), the polymer-bound acrylate (R)-13
was then obtained following the procedure described
for the preparation of polymer (R)-6.
20
1
128 ꢁC; ½aꢁ ¼ þ16 (c 3, CH2Cl2); HPLC, MS, H and
D
13C NMR data are identical to those of the ( )-enan-
tiomer.13
4.4. (R)-4-(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-
yl)benzoic acid (R)-1
4.7. Polymer-bound acrylate (R)-15
A solution of (R)-benzyl-4-(3-hydroxy-4,4-dimethyl-2-
oxopyrrolidin-1-yl)benzoate (R)-3 (440 mg, 1.3 mmol)
was added to a cooled solution (ꢀ20 ꢁC) of 20% palla-
dium hydroxide on charcoal in ethyl acetate (7 mL)
under an argon atmosphere. The mixture was then
stirred for 5 h at room temperature under H2 (the
reaction was monitored by TLC). After filtration
through celite, concentration of the filtrate yielded
Polymer-bound acrylate (R)-15 was obtained following
the procedure described for the preparation of polymer
(R)-6, starting from an aminomethyl resin (2.0 g,
1.8 mmol) and avoiding the Fmoc deprotection step.
4.8. (R)-Benzyl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrr-
olidin-1-yl)-benzoate (R)-11
compound (R)-1 as a white solid (316 mg; 1.27 mmol,
20
D
98%): mp 223 ꢁC; ½aꢁ ¼ þ13 (c 1.5, acetone); HPLC,
Compound (R)-11 was prepared as previously
described13 for the racemic mixture, starting from the
(R)-benzyl-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-
1-yl)benzoate (R)-3 (1.39 g, 4.1 mmol) by treatment with
MS, 1H and 13C NMR data are identical to those of the
( )-enantiomer.13
acryloyl chloride. Compound (R)-11 was obtained as a
20
D
4.5. Preparation of the supported alcohol (R)-5 and the
acrylate derivative (R)-6
colourless oil (1.32 g, 3.36 mmol, 82%); ½aꢁ ¼ þ20 (c
1.4, EtOH); tR (HPLC, column B: eluent I) (R)-11: 9.5
min and (S)-11: 11.6 min; IR, MS, H and 13C NMR
1
After deprotection of the Fmoc group of the Rink amide
resin (2.0 g, 1.0 mmol) by the standard procedure (20%
piperidine in DMF, 40 min), a solution of alcohol (R)-1
(0.37 g, 1.5 mmol, 1.5 equiv), BOP (0.73 g, 1.65 mmol,
1.65 equiv) and DIEA (0.32 mL, 1.80 mmol, 1.8 equiv) in
DMF (15 mL) was added to the resin. The suspension
was stirred for 12 h at room temperature and the solu-
tion removed by filtration from the resin. The resin was
washed with DMF (3 · 15 mL), CH2Cl2 (3 · 15 mL),
CH2Cl2/CH3OH (8/2) (3 · 15 mL), CH2Cl2 (3 · 15 mL)
and diethyl ether (3 · 15 mL) and dried under reduced
pressure. The reaction was monitored by the ninhydrin
test. To this stirred and swollen resin (R)-5 (1.0 mmol) in
anhydrous CH2Cl2 (15 mL) was added 1.2 mL of tri-
ethylamine (8.5 mmol, 8.5 equiv) and then dropwise
0.4 mL of acryloyl chloride (5.0 mmol, 5 equiv) at room
temperature. The suspension was stirred for 4–5 h at the
same temperature and the solution removed from the
resin by filtration. After washing with CH2Cl2
(3 · 20 mL), CH2Cl2/CH3OH (8/2) (3 · 20 mL), CH2Cl2
(3 · 20 mL) and diethyl ether (3 · 20 mL), resin (R)-6 was
dried under reduced pressure.
data are identical to those of the ( )-enantiomer.13
4.9. General procedure for Diels–Alder reaction of the
supported acrylate esters with dienes and for benzydryl-
amine hydrolysis
A solution of 1 M TiCl4 in dry CH2Cl2 was added to the
resin (0.6 mmol) swollen in dry CH2Cl2 (15 mL) at 0 ꢁC
and under argon atmosphere. The reaction mixture was
stirred at the same temperature for 30 min. A solution of
a diene was then added and the suspension stirred for
16 h at the same temperature. The solution was removed
from the resin by filtration, the resin washed with
CH2Cl2 (3 · 15 mL), CH3OH (2 · 15 mL), CH2Cl2/CH3
OH (8/2) (3 · 15 mL), CH2Cl2 (3 · 15 mL) and ethyl
ether (3 · 15 mL) and the resin dried under reduced
pressure. To this resin swollen in dry CH2Cl2 was added
40 mL of a solution of 5% TFA in dry CH2Cl2 and the
reaction mixture stirred for 40 min at room temperature.
The solution was removed from the resin by filtration
and the resin was washed with CH2Cl2 (3 · 15 mL),
CH2Cl2/CH3OH (8/2) (3 · 15 mL), CH2Cl2 (3 · 15 mL).
Evaporation of the combined solvents in vacuo afforded
the expected compound.
4.6. Polymer-bound acrylate (R)-13
After deprotection of the Fmoc group of the Rink amide
resin (2.0 g, 1.0 mmol) by the standard procedure (20%
piperidine in DMF, 40 min), a solution of N-Fmoc-6-
aminohexanoic acid (1.77 g, 5.0 mmol, 5 equiv), BOP
(2.43 g, 5.5 mmol, 5.5 equiv) and DIEA (1.24 mL,
7.0 mmol, 7.0 equiv) in DMF (15 mL) was added. The
suspension was stirred for 12 h at room temperature
4.10. (30R,1S)-[1-(4-Carbamoylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl]-4-methylcyclohex-3-ene-1-carboxyl-
ate (30R,1S)-8a
Synthesized following the general procedure from resin
(R)-6 (0.6 mmol), TiCl4 (1.1 equiv) and isoprene

R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
2521
(6 equiv). Compound 8a was obtained as a colourless
solid (177 mg, 0.48 mmol, 80% yield, 40% de);24 tR
(HPLC column A) 11.43 min; IR, MS, 1H and 13C NMR
data are identical to those of the previously obtained
diastereoisomeric mixture.13
CH2), 1.8 (m, 2H, CH2), 2.62 (m, 1H, CH), 2.86 (td,
J ¼ 7:2 and J ¼ 2:2, 1H, CH-10), 3.04 (m, 1H, CH), 3.68
(d, J ¼ 9:7, 1H, HCH-5), 3.8 (d, J ¼ 9:7, 1H, HCH-5),
5.48 (s, 1H, CH-3), 6.02 (t, J ¼ 7:3, 1H, HC@), 6.19 (t,
J ¼ 7:8, 1H, HC@), 7.23 (s br, 1H, NH), 7.93 (s br, 1H,
NH), 7.84 (d, J ¼ 8:8, 2H, H-arom), 8.01 (d, J ¼ 8:8,
2H, H-arom); 13C NMR (acetone-d6) (endo) 19.28
(CH3), 22.98 (CH3), 23.53 (CH2), 24.14 (CH2), 27.52
(CH2), 29.05 (CH), 31.90 (CH), 36.35 (C-4), 41.66 (CH-
10), 57.99 (C-5), 76.97 (C-3), 117.65 (C-arom), 127.85 (C-
arom), 128.01 (C-arom), 130.27 (HC@), 134.66 (HC@),
142.07 (C-arom), 168.45, 168.84, 173.14 (CO); HRMS
(FAB) Calcd for C22H27N2O4 (MHþ) 383.1971, found
383.1976.
4.11. ())-[1-(4-Carbamoylphenyl)-4,4-dimethyl-2-oxo-
pyrrolidin-3-yl]-3,4-dimethylcyclohex-3-ene-1-carboxyl-
ate ())-8b
Synthesized following the general procedure from resin
(R)-6 (0.6 mmol), TiCl4 (1.1 equiv) and 2,3-dimethyl-
butadiene (6 equiv). Compound 8b was obtained as
a colourless solid (218 mg, 0.57 mmol, 95% yield,
99% de);24 mp 75 ꢁC; tR (HPLC column A) 11.91 min;
20
½aꢁ ¼ ꢀ4 (c 1.7, EtOH); IR (KBr) 3415 (m), 3182 (m),
4.14. (30R,1S)-[1-(4-(5-Carbamoylpentyl)carbamoylphen-
yl)-4,4-dimethyl-2- oxopyrrolidin-3-yl]-4-methylcyclohex-
3-ene-1-carboxylate (30R,1S)-14
D
2939 (m), 1741 (s), 1706 (s), 1672 (s) 1607 (m) cmꢀ1; MS
(ESI) m=z: 385.3 [(M+H)þ], 769.5; 1H NMR (CDCl3): d
1.13 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.60 (s, 3H, CH3),
1.63 (s, 3H, CH3), 1.76 (m, 1H, HCH), 2.03 (m, 3H,
HCH and CH2), 2.17 (m, 2H, CH2), 2.74 (m, 1H,
CHCO), 3.54 (d, J ¼ 9:6, 1H, HCH-5), 3.66 (d, J ¼ 9:6,
1H, HCH-5), 5.44 (s, 1H, CH-3); 7.69 (d, J ¼ 8:8, 2H,
H-arom); 7.89 (d, J ¼ 8:8, 2H, H-arom); 13C NMR
(CDCl3) 18.80, 18.98, 21.04 and 21.41 (CH3), 25.68,
30.51 and 33.68 (CH2), 37.32 (C-4), 40.03 (CHCO),
57.42 (C-5), 78.18 (C-3), 118.81 (CH-arom), 123.50 and
125.56 (CH3C@), 127.62 (C-arom), 128.91 (CH-arom),
142.56 (C-arom), 170.21, 170.83, 175.27 (CO); HRMS
(FAB) Calcd for C22H29N2O4 (MHþ) 385.2127, found
385.2137.
Synthesized following the general procedure from resin
(R)-13 (0.6 mmol), TiCl4 (1.1 equiv) and isoprene
(6 equiv). Compound 14 was obtained as a colourless oil
(223 mg, 0.46 mmol, 77% yield, 70 de);24 tR (HPLC col-
1
umn A) 11.06 min; MS (ESI) m=z: 484.2 [(M+H)þ]; H
NMR (CDCl3): d 1.13 and 1.28 (s, 3H, CH3), 1.41 (m,
2H, CH2), 1.55–1.63 (m, 4H, 2CH2), 1.66 (s, 3H, CH3),
1.80 (m, 2H, CH2), 2.05 (m, 2H, CH2), 2.20 (m, 2H,
CH2), 2.30 (m, 2H, CH2), 2.70 (m, 1H, CHCO), 3.40
(dd, J ¼ 12:8 and J ¼ 6:5, 2H, CH2), 3.53 (d, J ¼ 9:5,
1H, HCH-5), 3.63 (d, J ¼ 9:5, 1H, HCH-5), 5.38 (br,
1H, CH@), 5.41 (s, 1H, CH-3), 5.71 (br, 1H, NH), 6.00
(br, 1H, NH), 6.93 (br, 1H, NH), 7.66 (d, J ¼ 8:38, 2H,
H-arom), 7.82 (d, J ¼ 8:38, 2H, H-arom); 13C NMR
(CDCl3) 21.11, 22.51 and 23.44 (CH3), 24.70, 24.80,
25.38, 26.69, 29.00, 29.09 and 35.45 (CH2), 37.27 (C-4),
39.13 (CH-10), 39.69 (CH2), 57.50 (C-5), 77.70 (C-3),
118.97 (C-arom), 118.86 (CH@), 127.95 (C-arom),
130.66 (C-arom), 134.00 (CH3C@), 141.52 (C-arom),
166.78, 169.46, 175.15 and 175.72 (CO).
4.12. (30R,2S)-[1-(4-Carbamoylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl]bicyclo[2.2.1]hept-5-ene-2-carboxylate
(30R,2S)-8c
Synthesized following the general procedure from resin
(R)-6 (0.6 mmol), TiCl4 (1.1 equiv) and cyclopentadiene
(6 equiv). Compound 8c was obtained as a colourless
solid (210 mg, 0.57 mmol, 95% yield, 86% de);24 mp 123–
20
D
125 ꢁC; ½aꢁ ¼ ꢀ29 (c 1.6, EtOH); tR (HPLC column A)
4.15. (30R,1S)-[1-(4-Benzyloxycarbonylphenyl)-4,4-
dimethyl-2-oxopyrrolidin-3-yl]-4-methylcyclohex-3-
ene-1-carboxylate (30R,1S)-12
10.48 min (95% endo), 10.78 min (5% exo); tR (HPLC
1
column A) 11.43 min; IR, MS, H and 13C NMR data
are identical to those of the previously obtained diaste-
reoisomeric mixture.13
A solution of 1 M TiCl4 (1 equiv) in dry CH2Cl2 was
added to dienophile (R)-11 (236 mg, 0.6 mmol) in dry
CH2Cl2 (10 mL) at ꢀ20 ꢁC and under an argon atmo-
sphere. The mixture was stirred at the same temperature
for 20 min and a solution of isoprene (123 lL, 1.2 mmol,
2 equiv) then added. The mixture was slowly warm up to
0 ꢁC (5 h) and then stirred for 12 h at this temperature.
Powdered Na2CO3Æ10H2O was added to hydrolyze the
TiCl4 complexes, the mixture filtered and the filtrate
concentrated in vacuo. The residue was submitted to
column chromatography on silica gel, eluting with ace-
tone/hexane (2/8) with compound 12 obtained as a col-
ourless oil (235 mg, 0.51 mmol, 85% yield, 92% de);22 tR
(HPLC column A) 14.90 min, (HPLC column B: eluent
II) (30R,1S)-12: 115.47 min and (30R,1R)-12: 144.88 min;
IR, MS, 1H and 13C NMR data are identical to those of
the previously obtained diastereoisomeric mixtures.13
4.13. (30R,2S)-[1-(4-Carbamoylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl]bicyclo[2.2.2]hept-5-ene-2-carboxylate
(30R,2S)-8d
Synthesized following the general procedure from resin
(R)-6 (0.6 mmol), TiCl4 (1.2 equiv) and cyclohexadiene
(10 equiv). Compound 8d was obtained as a colourless
solid (223 mg, 0.59 mmol, 98% yield, 85% de);24 mp 125–
20
D
128 ꢁC; ½aꢁ ¼ ꢀ24 (c 1.5, EtOH); tR (HPLC, column
A): 11.12 min (98% endo), 11.78 (2% exo); IR (KBr)
3440–3210 (m), 2940 (m), 1724 (s), 1702 (s), 1670 (s),
1607 (m) cmꢀ1; SM (ESI) m=z: 383.1 [(M+H)þ], 765.3;
1H NMR (acetone-d6) (endo) d 1.17 (s, 3H, CH3), 1.29 (s,
3H, CH3), 1.51-1.59 (m, 2H, CH2), 1.65–1.73 (m, 1H,

2522
R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
4.16. General procedure for the saponification of
compounds 8a–d, 12 or 14
4.20. (2S)-endo-Bicyclo[2.2.1]hept-5-ene-2-carboxylic
acid (2S)-9c
To a solution of compound 8a–d, 12 or 14 (0.4 mmol) in
THF or in DMF (6 mL) was added dropwise a solution
of LiOH, H2O (0.8 mmol, 2 equiv) in water (1 mL) and
the mixture stirred at room temperature till completion
of the hydrolysis (ꢂ5 h) (monitored by HPLC). The
organic solvent was removed in vacuo, water (10 mL)
and saturated aqueous NaHCO3 (10 mL) then added
and the mixture extracted with CH2Cl2 (2 · 20 mL). The
aqueous phase was acidified (pH ¼ 1) and extracted with
a 98/2 mixture of n-pentane/CH2Cl2 (2 · 30 mL). The
combined organic phases were dried over anhydrous
Na2SO4 and concentrated in vacuo to yield the expected
acid 9a–d.
Synthesized following the general procedure from
compound 8c (147 mg, 0.4 mmol) in DMF. The expected
acid (2S)-9c was obtained (32 mg, 0.23 mmol, 55%
yield, 86% ee);24 tR20(HPLC) 7.9 min (95% endo) and
8.5 min (5% exo); ½aꢁ ¼ ꢀ139 (c 0.8, EtOH); 13C NMR
D
(CDCl3) (endo) 29.50 (CH2), 42.94 (CH), 43.62 (CH2),
46.07 (CH), 50.11 (CH-1), 132.82 (HC@CH), 138.29
(HC@CH), 181.42 (CO).
4.21. (2S)-endo-Bicyclo[2.2.2]hept-5-ene-2-carboxylic
acid (2S)-9d
Synthesized following the general procedure from the
compound 8d (157 mg, 0.4 mmol) in DMF. The expected
acid (2S)-9d was obtained (35 mg, 0.23 mmol, 57% yield,
85% ee);24 tR (HPLC) 8.9 min (98% endo) and 9.4 min
(2% exo); 1H NMR (CDCl3) (endo): d 1.18–1.38 (m, 2H,
CH2), 1.44–1.60 (m, 2H, CH2), 1.62–1.82 (m, 2H, CH2),
2.62 (m, 1H, CHCH2), 2.68 (ddd, J ¼ 2:3, J ¼ 5:5,
J ¼ 9:7, 1H, CH-1), 2.98 (m, 1H, CHCH@), 6.19 (t,
J ¼ J0 ¼ 7:4, 1H, HC@), 6.33 (t, J ¼ J0 ¼ 7:4, 1H,
HC@); 13C NMR (CDCl3) (endo) 23.6 (CH2), 24.63
(CH2), 28.61 (CHCH@), 28.86 (CH2), 31.64 (CHCH@)
41.98 (CHCO2H), 130.67 (HC@), 134.62 (HC@), 181.34
(CO).
4.17. General procedure for the saponification of the
aminomethylated resin 16
To the aminomethylated resin 16 (0.6 mmol) swollen in
dry DMF (10 mL) was added a solution of LiOH, H2O
(1.2 mmol, 2 equiv) in water (2 mL) and the reaction
mixture stirred for 5 h at room temperature. The solu-
tion was removed from the resin by filtration and the
resin washed with THF/H2O (3 · 15 mL), THF/H2O/
NaHCO3 saturated 8/1/1 (3 · 15 mL), THF (3 · 15 mL),
CH2Cl2/CH3OH (8/2) (3 · 15 mL) and CH2Cl2
(3 · 15 mL). After evaporation of the organic solvents in
vacuo, the aqueous phase was acidified (pH ¼ 1) and
extracted with a 98/2 mixture of n-pentane/CH2Cl2 in
the ratio of (3 · 20 mL). The combined organic phases
were dried with anhydrous Na2SO4 and concentrated in
vacuo to give the expected acids 9a, 9b and 9c (40–50%
yield).
4.22. ( )-3-Methyl and ( )-4-methyl cyclohex-3-ene
carboxylic acid mixture
The mixture of ( )-3-methyl and ( )-4-methyl cyclohex-
3-ene carboxylic acids was obtained in 46% yield by the
reaction at 120 ꢁC of isoprene and acrylic acid following
the method described by Kuehne et al.23 tR (HPLC)
9.2 min; 13C NMR (CDCl3): rac-4-Methyl cyclohex-3-
ene carboxylic acid (main product) 23.73 (CH3), 25.56,
27.76, 29.51 (CH2), 39.46 (CHCO2H), 119.46 (CH@),
134.02 (CH3C@), 183.26 (CO); rac-3-Methyl cyclohex-3-
ene carboxylic acid 23.81 (CH3), 24.79, 25.03, 32.18
(CH2), 40.07 (CHCO2H), 121.04 (CH@), 132.39
(CH3C@), 183.12 (CO).
4.18. (S)-4-Methylcyclohex-3-ene carboxylic acid (S)-
9a18
Synthesized following the general procedure from
compounds 8a, 12 or 14 (0.4 mmol) in THF or in DMF,
the expected acid (S)-9a was obtained (34–39 mg, 0.24–
0.28 mmol, 60–70% yield, 40–86% ee);24 tR (HPLC col-
umn A) 9.23 min; 13C NMR (CDCl3): d 23.73 (CH3),
25.56, 27.76, 29.51 (CH2), 39.46 (CHCO2H), 119.46
(CH@), 134.02 (CH3C@), 183.26 (CO).
4.23. ( )-3,4-Dimethyl cyclohex-3-ene carboxylic acid
( )-9b
4.19. ())-3,4-Dimethyl cyclohex-3-ene carboxylic acid
())-9b
Racemic sample of 3,4-dimethyl cyclohex-3-ene car-
boxylic acid ( )-9b was obtained by Diels–Alder reac-
tion between the racemic supported acrylate ester ( )-6
and 3,4-dimethylbutadiene, followed by saponification
on polymer (40% yield). HPLC and NMR data are
identical to those of the (ꢀ)-enantiomer.
Synthesized following the general procedure from
compound 8b (154 mg, 0.4 mmol) in DMF. The expected
acid (ꢀ)-9b was obtained (37 mg, 0.24 mmol, 59% yield,
20
99% ee);24 tR (HPLC column A) 9.9 min; ½aꢁ ¼ ꢀ85 (c
D
1.8, EtOH); 1H NMR (CDCl3) 1.55 (s, 6H, 2CH3),
1.62 (m, 1H, HCH), 1.88–1.95 (m, 3H, HCH and CH2),
2.11 (m, 2H, CH2), 2.50 (m, 1H, CH); 13C NMR
(CDCl3) 18.83 and 18.95 (CH3), 25.56, 30.83 and 33.4
(CH2), 39.99 (CH-1), 123.71 and 125.36 (C@C), 182.51
(CO).
4.24. ( )-Bicyclo[2.2.2]hept-5-ene-2-carboxylic acid ( )-
9d
A racemic mixture of bicyclo[2.2.2]hept-5-ene-2-car-
boxylic acid benzyl ester was obtained as a colourless oil

R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
2523
20
D
in 44% yield (0.66 g, 2.7 mmol, 86/14 endo/exo) by
reaction at 100 ꢁC of cyclohexa-1,3-diene (1.8 mL,
18.7 mmol, 3 equiv) and benzyl acrylate (1.0 g,
6.2 mmol), followed by a column chromatography on
silica gel, eluting with diethyl ether/hexane (1/9)
(Rf ¼ 0:6); tR (HPLC, column A) 13.2 min; MS (ESI)
[(M+H)þ]; ½aꢁ ¼ ꢀ54 (c 1.3, CH2Cl2); 1H NMR
(CDCl3) 1.30 (m, 1H, HCH), 1.57 (s, 6H, 2CH3), 1.67
(m, 1H, HCH), 1.91 (m, 3H, HCH and CH2), 2.20 (m,
2H, HCH and CH), 4.41 (d, J ¼ 5:7, 2H, CH2C6H5),
5.40 (br, 1H, HC@), 5.90 (br, 1H, NH), 7.26–7.36 (m,
5H, H-arom).
1
m=z: 243.0 [(M+H)þ]; H NMR (CDCl3) (endo): d 1.33
(m, 2H, CH2), 1.58 (m, 2H, CH2), 1.80 (m, 2H, CH2),
2.65 (m, 1H, CH), 2.73 (td, J ¼ 7:5 and J ¼ 2:3, 1H,
CH-1), 3.03 (m, 1H, CH), 5.10 (d, J ¼ 12:4, 1H, HCH–
C6H5), 5.17 (d, J ¼ 12:4, 1H, HCH–C6H5), 6.20 (t,
J ¼ J0 ¼ 7:8, 1H, HC@), 6.37 (t, J ¼ J0 ¼ 7:8, 1H,
HC@), 7.38 (m, 5H, C6H5); 13C NMR (CDCl3) (endo)
23.84 and 24.68 (CH2), 28.8 (CH), 29.1 (CH2), 31.88
(CH), 42.16 (CH), 65.38 (OCH2Ph), 127.35 (C-arom),
127.85 (C-arom), 130.69 (HC@), 134.58 (HC@), 135.81
(C-arom), 174.27 (CO).
4.28. ( )-3,4-Dimethylcyclohex-3-ene carboxylic acid
benzyl amide ( )-10b
Synthesized following the general procedure from
compound ( )-9b (15.4 mg, 0.1 mmol). The benzyl
amide derivative ( )-10b was obtained (24 mg, quanti-
tative yield); tR (HPLC column A) 11.3 min; tR (HPLC
column C)25 (ꢀ)-10b: 19.9 min, (þ)-10b: 22.5 min; HPLC
and NMR data are identical to those of the (ꢀ)-enan-
tiomer.
To this benzyl ester in dioxane/water (4/1) was added
NaOH (1.5 equiv) and the mixture stirred for 12 h at
room temperature. After evaporation of the dioxane in
vacuo, the aqueous solution was diluted with a 1 M
solution of NaHCO3 (20 mL) and washed with CH2Cl2
(2 · 20 mL). The aqueous phase was acidified (pH ¼ 1)
and extracted with CH2Cl2 (3 · 20 mL). The combined
organic phases were dried over anhydrous Na2SO4 and
concentrated in vacuo to give the expected acid
( )-endo-9d (0.39 g, 2.6 mmol, 95% yield, 95% endo).
HPLC and NMR data are identical to those of the (2S)-
enantiomer.
4.29. (2S)-Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid
benzyl amide (2S)-10c
Synthesized following the general procedure from
compound (2S)-9c (13.8 mg, 0.1 mmol). The benzyl
amide derivative (2S)-10c was obtained (22 mg, quanti-
tative yield, 86% ee); tR (HPLC column A) (endo):
10.1 min and (exo): 10.7 min; tR (HPLC column D eluent
I) (exo)-(SR)-10c: 21.8 min, (endo)-(S)-10b: 25.4 min and
(endo)-(R)-10b: 27.4 min;26 SM (ESI) m=z: 228.1
1
[(M+H)þ], 455.3; H NMR (CDCl3) (endo) 1.29–1.47
(m, 3H, HCH and CH2), 1.38–2.00 (m, 1H, HCH), 2.92
(m, 2H, CH2), 3.17 (br, 1H, CH-1), 4.38 (d, J ¼ 1:96,
1H, HCH–C6H5), 4.41 (d, J ¼ 1:96, 1H, HCH–C6H5),
5.98 (dd, J ¼ 3:0 and J ¼ 5:7, 1H, HC@), 6.24 (dd,
J ¼ 3:0 and J ¼ 5:7, 1H, HC@), 7.23–7.37 (m, 5H, H-
arom).
4.25. General procedure for the preparation of benzyl
amide derivatives 10a–d
The benzyl amide derivatives 10a–d were obtained using
the synthetic route describe by Sarakinos and Corey25
starting from 9a–d.
4.30. (2S)-Bicyclo[2.2.2]oct-5-ene-2-carboxylic acid
benzyl amide (2S)-10d
4.26. (S)-4-Methylcyclohex-3-ene carboxylic acid benzyl
amide (S)-10a
Synthesized following the general procedure from
compound (2S)-9d (15.2 mg, 0.1 mmol). The benzyl
amide derivative (2S)-10d was obtained (24 mg, quanti-
tative yield, 98% endo, 85% ee); tR (HPLC column A)
10.8 min; tR (HPLC column D eluent II) (2S)-10b:
117.5 min and (2R)-10b: 121.1 min;26 SM (ESI) m=z:
Synthesized following the general procedure from
compound (S)-9a (14 mg, 0.1 mmol). The benzyl amide
derivative (S)-10a was obtained (23 mg, quantitative
yield, 40–86% ee); tR (HPLC column A) 12.1 min; tR
(HPLC column C) (S)-10a: 13.9 min, (R)-10a:
1
1
15.3 min;26 SM (ESI) m=z: 230.2 [(M+H)þ]; H NMR
242.0 [(M+H)þ], 483.3; H NMR (CDCl3) 1.27 (m, 2H,
(CDCl3) 1.65 (s, 3H, CH3), 1.78 (m, 1H, HCH), 1.94–
2.02 (m, 3H, HCH and CH2), 2.18–2.38 (m, 3H, CH and
CH2), 4.46 (d, J ¼ 5:7, 2H, CH2H6C5), 5.40 (br, 1H,
HC@), 5.78 (br, 1H, NH), 7.26–7.36 (m, 5H, H-arom).
CH2), 1.46–1.64 (m, 3H, HCH and CH2), 1.88 (ddd,
J ¼ 2:8, J ¼ 10:1, J ¼ 12:8, 1H, HCH), 2.57–2.65 (m,
2H, 2CH), 2.83 (br, 1H, CH-1), 4.41 (2d, J ¼ 9:7, 2H,
CH2–C6H5), 5.77 (br, 1H, NH), 6.25 (t, J ¼ J0 ¼ 7:2,
1H, HC@), 6.4 (t, J ¼ J0 ¼ 7:2, 1H, HC@), 7.24–7.37
(m, 5H, C6H5).
4.27. ())-3,4-Dimethylcyclohex-3-ene carboxylic acid
benzyl amide ())-10b
4.31. ( )-Bicyclo[2.2.2]oct-5-ene-2-carboxylic acid benzyl
amide ( )-10d
Synthesized following the general procedure from
compound (ꢀ)-9b (15.4 mg, 0.1 mmol). The benzyl
amide derivative (ꢀ)-10b was obtained (24 mg, quanti-
tative yield, 99% ee); tR (HPLC column A) 11.3 min; tR
(HPLC column C)26 19.9 min; SM (ESI) m=z: 244.2
Synthesized following the general procedure from com-
pounds ( )-9d (15.2 mg, 0.1 mmol). The benzyl amide
derivative ( )-10d was obtained (24 mg, quantitative

2524
R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
38, 8777–8780; Phoon, C. W.; Abell, C. Tetrahedron Lett.
1998, 39, 2655–2658; Winkler, J. D.; McCoull, W.
Tetrahedron Lett. 1998, 39, 4935–4936; Faita, G.; Paio,
A.; Quadrelli, P.; Rancati, F.; Seneci, P. Tetrahedron Lett.
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2(10), 1443–1445; Faita, G.; Paio, A.; Quadrelli, P.;
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yield, 86/14 endo/exo); tR (HPLC column A) 10.8 min
(endo) and 11.4 min (exo); tR (HPLC column D eluent
II) (exo)-10c: 67.6 and 73.7 min, (endo)-(2S)-10b:
117.5 min and (endo)-(2R)-10b: 121.1 min;26 NMR data
are identical to those of the (2S)-enantiomer.
References and notes
1. Fringuelli, F.; Tatichi, A. The Diels–Alder Reaction:
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Tetrahedron Lett. 1997, 40, 7115–7118; Winkler, J. D.;
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ding, D. A.; Takata, D. T.; Kwon, C.; Huffman, W. F.;
Samanen, J. Tetrahedron Lett. 1997, 39, 6815–6818;
Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851–1854;
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Poll, T.; Abdel, A. F.; Karge, R.; Linz, G.; Weetman, J.;
Helmchen, G. Tetrahedron Lett. 1989, 30, 5595–5598; (c)
Miyaji, K.; Ohara, Y.; Takahashi, Y.; Tsuruda, T.; Arai,
K. Tetrahedron Lett. 1991, 32, 4557–4560; (d) Fraile, J.
M.; Garcia, J. I.; Garcia, D.; Mayoral, J. A.; Pires, E. J.
Org. Chem. 1996, 61, 9479–9482; (e) Burke, M. J.; Allan,
M. M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry
2000, 11, 2733–2739; (f) Palomo, C.; Oiarbide, M.; Garcia,
J. M.; Gonzalez, A.; Lecumberri, A.; Linden, A. J. Am.
Chem. Soc. 2002, 124, 10288–10289; (g) Kawamura, M.;
Kudo, K. Chirality 2002, 14, 727–730; (h) Lait, S. M.;
Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 2003,
14, 749–756.
8. For recent examples of synthetic solid-supported chiral
reagent or catalyst see: Altava, B.; Burguete, M. I.;
Garcia-Verdugo, E.; Luis, S. V.; Pozo, O.; Salvator, R. V.
Eur. J. Org. Chem. 1999, 2263–2267; Zhengpu, Z.;
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hedron: Asymmetry 2000, 11, 4039–4042; Chinchilla, R.;
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3277–3281; Altava, B.; Burguete, M. I.; Collado, M.;
Garcia-Verdugo, E.; Luis, S. V.; Salvador, R. V.; Vincent,
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ꢀ
13. Akkari, R.; Calmes, M.; Martinez, J. Eur. J. Org. Chem.
2004, 2441–2450.
14. (a) Akkari, R.; Calmes, M.; Mai, N.; Rolland, M.;
ꢀ
Martinez, J. J. Org. Chem. 2001, 66, 5859–5965; (b)
ꢀ
Akkari, R.; Calmes, M.; Di Malta, D.; Escale, F.;
Martinez, J. Tetrahedron: Asymmetry 2003, 14, 1223–
1228.
15. Marieva, T. D.; Kopelevich, V. M.; Torosyan, Zh. K.;
Gunar, V. J. Gen. Chem. URSS (Engl. Transl.) 1979, 49,
191–194.
16. The diffraction data were collected on a Enraf–Nonius
using graphite-monochromate Mo-Ka radiation and the
/-scan technique up to h ¼ 24:94. Crystal data for ester
(1S,30S)-4: Molecular formula C30H33NO7, molecular
weight ¼ 519, orthorhombic, space group P21212, cell
ꢂ
ꢂ
constants: a ¼ 39:2790ð1Þ A, b ¼ 6:8420ð1Þ A, c ¼
3
ꢂ
ꢂ
11:2790ð1Þ A, V ¼ 3031:20ð5Þ A , Z ¼ 4, Dc ¼ 1:14 mg/
m3, T ¼ 298 K, final R ¼ 0:061, final Rw ¼ 0:188. Details
of the crystal structure determination have been deposited
at the Cambridge Crystallographic Data Centre (deposi-
tion number CCDC 234392). The configuration of the
newly generated stereogenic centre of (1S,30S)-4 was
established from the (1S)-absolute configuration of the
camphanic acid part.
17. With cyclohexadiene it was necessary to use 10 equiv of
diene and 1.2 equiv of TiCl4 to obtain a quantitative
reaction after 16 h at 0 ꢁC.
18. Absolute stereochemistry of 9a, 9c and 9d was assigned by
comparing the sign of the specific rotation to that reported
in the literature: Poll, T.; Sobczak, A. F. A.; Karge, R.;
Linz, G.; Weetman, J.; Helmchen, G. Tetrahedron Lett.
1985, 26, 3095–3098.
19. The regioselectivity was assigned by comparison of the 13
C
NMR spectrum to that of the para and meta mixtures
obtained according to the procedure described by:
Kuehne, M. E.; Horne, D. A. J. Org. Chem. 1975, 40,
1287–1292.
9. For recent applications of synthetic solid-supported aux-
iliary see: Moon, H.-S.; Schore, N. E.; Kurth, M. J. J. Org.
Chem. 1992, 57, 6088–6089; Moon, H.-S.; Schore, N. E.;
Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915–8918;
20. The endo selectivity was assigned by comparison of the 13
C
ꢀ
Calmes, M.; Daunis, J.; Hanouneh, A.; Jacquier, R.
NMR spectra to that of the commercially available 70/30
endo/exo mixture for 9c and to that of the endo/exo
mixture prepared as described in the experimental part for
9d.
Tetrahedron: Asymmetry 1994, 5, 817–820; Shuttleworth,
S. J.; Allin, S. M. Tetrahedron Lett. 1996, 37, 8023–8026;
Purandare, A. V.; Natarajan, S. Tetrahedron Lett. 1997,

R. Akkari et al. / Tetrahedron: Asymmetry 15 (2004) 2515–2525
2525
21. Stereochemistry of compounds 10a–d was deduced from
the comparison of HPLC analysis of the corresponding
racemic mixture prepared as described in the experimental
part.
22. The diasteroisomeric excess of compound 12 was deter-
mined from crude product by comparison of chiral HPLC
profile to that of the racemic mixture prepared as
described in the experimental part. Its stereochemistry
was assigned by comparing the sign of the specific
rotation of the corresponding acid 9a isolated after
hydrolysis.
23. Kuehne, M. E.; Horne, D. A. J. Org. Chem. 1975, 40,
1287–1292.
24. Stereochemistry of compounds 8 and 9 was deduced from
the stereochemistry of the corresponding benzylamide
derivatives 10.
25. Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741–1744.
26. HPLC peaks of compounds 10 were assigned from
comparison of the HPLC analysis of the corresponding
diastereoisomeric and enantiomerically enriched mixtures
and by using the absolute configuration of the corre-
sponding enantiomerically enriched compounds 9.