(R)-(4-(Benzyloxycarbonylphenyl)-3-hydroxy-4,4-dimethyl-2-pyrrolidinone) acrylate derivative as a chiral dienophile for the synthesis of enantiopure 2-aminocyclohexane carboxylic acids

Article abstract of DOI:10.1016/j.tetasy.2005.05.024

An asymmetric Diels-Alder reaction between the enantiopure (R)-benzyl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)-benzoate (R)-2 and the N-Z-aminodiene 3 proceeded with total endo diastereoselectivity and was facially controlled in favour of the (

Full text of DOI:10.1016/j.tetasy.2005.05.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2173–2178
(R)-(4-(Benzyloxycarbonylphenyl)-3-hydroxy-4,4-dimethyl-2-
pyrrolidinone) acrylate derivative as a chiral dienophile for the
synthesis of enantiopure 2-aminocyclohexane carboxylic acids
a,
Monique Calmes, Claude Didierjean, Jean Martinez and Olivier Songis
b
a
a
*
`
a
´
´
Laboratoire des Aminoacides, Peptides et Proteines, UMR CNRS 5810 Universites Montpellier I et II,
`
Place Eugene Bataillon, 34095 Montpellier cedex 5, France
´
`
BP 239, 54506 Vandoeuvre les Nancy, France
b
´
´
Laboratoire de Cristallographie et de Modelisation des Materiaux Mineraux et Biologiques, UMR UHP-CNRS 8036,
Received 21 April 2005; accepted 17 May 2005
Abstract—An asymmetric Diels–Alder reaction between the enantiopure (R)-benzyl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-
1-yl)-benzoate (R)-2 and the N-Z-aminodiene 3 proceeded with total endo diastereoselectivity and was facially controlled in favour
of the (30R,1R,2S)-adduct. The two adducts obtained, 4 (the main compound) and 5, were isolated pure after column chromato-
graphy on silica gel. Their LiOH hydrolysis followed by palladium-catalyzed hydrogenation of the double bond concomitant with
hydrogenolysis of the carbamate moiety yielded the enantiopure cis-2-aminocyclohexane carboxylic acids (1R,2S)-8 and (1S,2R)-8.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
This last reaction can be considered as one of the most
powerful transformations in synthetic organic chemis-
try.10 The stereoselective creation of several stereogenic
centres in a single step makes the Diels–Alder reaction
suitable for the preparation of complex molecules.11
Cyclic b-amino acids are an important class of com-
pounds, since they are constituents of natural products,
such as alkaloids, peptides and b-lactam antibiotics.1
These amino acids are often introduced into peptides
to increase or modify their biological activities.2 Fur-
thermore, they have been used for structural and mech-
anistic investigations, since their incorporation into
peptides or peptidomimetics induced conformational
restrictions and provided important structural effects.3
Cyclic b-amino acids also play an important role in
the synthesis of various heterocyclic structures.4
2. Results and discussion
We have recently described the preparation of a new chi-
ral auxiliary, the (R)- or (S)-4-(3-hydroxy-4,4-dimethyl-
2-oxopyrrolidin-1-yl) benzoic acid (R)- or (S)-1 and
found that acrylate derivative 2 was an efficient chiral
dienophile.12 To extend our investigations concerning
the efficiency of compound 1, we examined an alterna-
tive route for the preparation of enantiopure 2-amino-
cyclohexane carboxylic acids using compound (R)-2 as
a chiral dienophile and the readily available N-Z-pro-
tected aminodiene 3.13 The stability of the benzyl carba-
mate function during basic final hydrolysis of the ester
bond of adduct 4 or 5 and the ability to remove this
group by catalytic hydrogenolysis increased interest for
this protecting group. However, the main possible limi-
tation concerning the carbamate moiety could be that it
is reactive under some Lewis acid-catalyzed Diels–Alder
conditions.9c
A number of methods have been reported for the prep-
aration of enantiopure 2-aminocyclohexane carboxylic
acids,4 many of which use an enzymatic or chemoselec-
tive resolution as a key step.3b,4,5 Concerning asymmet-
ric syntheses,1c,6–9 the methods mainly involve a Michael
addition of a chiral amine to a,b-unsaturated esters,1c,4,7
diastereoselective reduction of chiral b-enamino
esters1c,8 or asymmetric Diels–Alder cycloadditions.9
*
Corresponding author. Fax: +33 (0)4 67 14 48 66; e-mail: monique@
univ-montp2.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.024

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M. Calmes et al. / Tetrahedron: Asymmetry 16 (2005) 2173–2178
2174
O
O
O
OH
O
N
N
NH
O
O
O
O
3
(R)-2
(R)-1
OBn
OH
The enantiopure (R)-4-(3-hydroxy-4,4-dimethyl-2-oxo-
pyrrolidin-1-yl) benzoic acid (R)-1 and the correspond-
ing acrylate benzyl ester (R)-2 were prepared as
previously described.12b The 1-(benzyloxycarbonyl-
amino)butadiene 3 was obtained from the Curtius
rearrangement of the 2,4-pentadienyl azide in benzyl
alcohol according to the protocol described by Jessup
et al.13
Concerning the determination of the endo/exo or facial
selectivity of the reaction, we could not directly conclude
by NMR and HPLC analyses. Indeed, no significant
1
differences of the resonance signals on the H and 13C
NMR spectra of compounds 4 and 5, as well as of the
JH1–H2 coupling constant value15 were observed. Fur-
thermore, whatever the conditions and the chiral col-
umns that were used, we only obtained one peak on
their corresponding HPLC chromatograms. Compound
5 (minor adduct) was recrystallized from ethyl acetate/
hexane, while the absolute configuration of the newly
generated stereocentres was determined by X-ray dif-
fraction analysis (Fig. 1).16 From the known (R)-config-
uration of the chiral auxiliary, it was determined that the
minor adduct 5 had a (30R,1S,2R)-configuration, which
resulted from an endo selectivity on the a face. Unfortu-
nately, compound 4, could not be crystallized and was
obtained as an amorphous white solid.
The asymmetric Diels–Alder cycloaddition between
compound (R)-2 and the N-Z-aminodiene 3 was carried
out first without the catalyst in dry toluene at either
room temperature (96 h) or at 60 ꢁC (24 h), to produce
in good yield a separable HPLC mixture of two diaste-
reoisomeric Diels–Alder adducts14 in a 85/15 ratio
(Scheme 1). The reaction was completely regioselective,
giving only the b-amino acid derivatives, since no trace
1
of the c-regioisomer was detected by H NMR of the
crude mixture. The two formed Diels–Alder adducts, 4
(main compound) and 5, were isolated in pure form
after column chromatography on silica gel.
LiOH hydrolysis of compounds (30R,1S,2R)-5 at room
temperature yielded the cis-(1S,2R)-aminocyclohexene
ZHN
ZHN
O
O
O
O
O
O
N
60°C
N
O
+
N
+
O
Toluene
O
NHZ
O
O
O
(R)-2
3
(3'R,1R,2S)-4
OBn
(3'R,1S,2R)-5
OBn
OBn
Scheme 1. Diels–Alder reaction between the acrylate (R)-2 and the N-Z-aminodiene 3.
Figure 1. ORTEP drawing of the adduct 5.

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M. Calmes et al. / Tetrahedron: Asymmetry 16 (2005) 2173–2178
2175
NHBn
O
(1R,2S)-7
(1R,2S)-8
b
OH
NHZ
NH2
a
(3'R,1R,2S)-4
OH
O
O
c
NHZ
(1R,2S)-6
NHBn
O
(1S,2R)-7
(1S,2R)-8
b
OH
a
NHZ
(3'R,1S,2R)-5
OH
O
O
c
NHZ
NH2
(1S,2R)-6
Scheme 2. Reagents: (a) LiOH, H2O, THF; (b) BnNH2, 2-chloro-1-methyl pyridinium iodide, NEt3, CH2Cl2; (c) H2, 10% Pd/C, CH3OH.
carboxylic acid 6 (Scheme 2). It has been previously
described that the cis- and trans-aminocyclohexene
carboxylic acid derivatives, such as phenyl cis- and
trans-6-carbomethoxy-2-cyclohexene-1-yl carbamates17
or cis- and trans-3-(N-p-hydroxycarbonylbenzyloxy-
carbonyl amino)-1-cyclohexene-4-N,N-dimethylcarbox-
of Sc(Otf)3 as Lewis acid rapidly led to a complete deg-
radation of the starting material even at 0 ꢁC.
To complete our investigation and to obtain a racemic
mixture for comparison of its HPLC profile with those
obtained in the asymmetric synthesis experiment, we
performed the Diels–Alder reaction using racemic acry-
late (RS)-2. The HPLC trace of the obtained adducts
showed that all four stereoisomers of the endo cyloaddi-
tion were separable on the Chiralcel OD column. Fur-
thermore, the same HPLC chromatogram was
obtained for the benzyl amide derivative obtained both
from the major mixture assumed to be (30R,1R,2S)/
(30S,1S,2R)-4 or from the minor mixture (30R,1S,2R)/
(30S,1R,2S)-5. This corresponded to the two HPLC
traces of compounds (1R,2S)-7 and (1S,2R)-7 obtained
in the chiral experiment confirming that only endo cyclo-
addition occurred.
1
amides,9c have different H and 13C NMR spectra, as
well as different JH1–H2 coupling constant values. Conse-
quently, we then tried to assign the stereostructure of
adduct 4 using comparisons between the NMR data of
the two acids 6 obtained, respectively, from 4 and from
(30R,1S,2R)-5.
LiOH hydrolysis of compound 4 yielded acid 6 possess-
ing both identical NMR spectra (1H/13C) and JH1–H2
coupling constant values (J = 5.0 Hz)15 and an almost
opposite specific rotation value to that of the acid cis-
(1S,2R)-6 obtained from compound 5. Furthermore,
the same 1H NMR spectrum was obtained from the
two corresponding benzyl amide derivatives 7 (Scheme
2).18
Following the conditions described by Houk et al.,9c
palladium-catalyzed hydrogenation of the double bond
concomitant with the hydrogenolysis of the carbamate
moiety of acids (1R,2S)-6 and (1S,2R)-6, respectively,
yielded b-amino acids (1R,2S)-8 and (1S,2R)-8.
Although the sign and the very small value of the spe-
cific rotation of compounds (1R,2S)-8 and (1S,2R)-8
were not really significant, a comparison with that previ-
ously reported,7b,9c supported our assignment of the
absolute configuration of the new isolated compounds
4–6.
1
Considering the strong analogies between the H NMR
data of compounds 4 and 5, of the two compounds 6
and of the two compounds 7, it can be assumed that
under the conditions used, both the two diastereoiso-
meric Diels–Alder adducts 4 and 5 resulted from an
endo-selective cycloaddition process, that was facially
controlled in favour of the (30R,1R,2S)-4 adduct when
starting from the (R)-dienophile 2. LiOH hydrolysis of
compound (30R,1R,2S)-4 at room temperature yielded
the cis-(1R,2S)-aminocyclohexene carboxylic acid 6
(Scheme 2).
3. Conclusion
The same reaction was performed at room temperature
under the Lewis acid-catalyzed reaction conditions with
Eu(fod)3 (5 mol % or 1 equiv) and also yielded after 72 h
the selective formation of the endo diastereoisomer with-
out significant modification of the facial selectivity.
When the temperature was lowered to 0 ꢁC, no reaction
was observed and the acrylate compound was totally
recovered. Alternatively, the use of a catalytic amount
In conclusion, we have demonstrated that the (R)-benz-
yl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)-
benzoate (R)-2 can be used as a chiral dienophile for the
preparation of the cis-enantiopure 2-aminocyclohexane
carboxylic acid. The two stereogenic created centres on
the cyclohexene ring resulted from an endo-selective
cycloaddition process that was facially controlled in
favour of the (1R,2S)-compound when starting from

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M. Calmes et al. / Tetrahedron: Asymmetry 16 (2005) 2173–2178
2176
the (R)-dienophile 2. Studies are currently in progress to
examine the solid supported version of this reaction and
to evaluate its advantages and drawbacks compared to
the solution approach.
(1.80 g, 3.0 mmol, 38.7% yield) and the pure major dia-
stereoisomers (30R,1R,2S)-4 (0.74 g, 1.2 mmol, 15.9%
yield, Rf = 0.25, 99% de). From the (88/12) mixture of
the esters (30R,1R,2S)-4/(30R,1S,2R)-5, the minor diaste-
reoisomer (30R,1S,2R)-5 was eliminated by filtration
after treatment with hot ethyl acetate (minimum)/hexane
to afford the pure major diastereoisomer (30R,1R,2S)-4
(1.4 g, 2.3 mmol, 30.1% yield, Rf = 0.25, 99% de).
4. Experimental
4.1. General
Crystallization of an aliquot of compound (30R,1S,2R)-
5 from ethyl acetate/hexane yielded colourless crystals
suitable for X-ray analysis.
All reagents were used as purchased from commercial
suppliers without further purification. Solvents were
dried and purified by conventional methods prior to
use. Melting points were determined with a Kofler Heiz-
bank apparatus and are uncorrected. Optical rotations
were measured with a Perkin–Elmer 341 polarimeter.
1H or 13C NMR spectra (1H/13C 2D-correlations)
were recorded with a Bruker A DRX 400 spectro-
meter using the solvent as internal reference. Data
are reported 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 per-
formed with a Waters model 510 instrument with vari-
able detector at 214 nm using: column A: Nucleosil
C18, 3.5 lm, (50 · 4.6 mm), flow: 1 mL/min, H2O
(0.1% TFA)/CH3CN (0.1% TFA) gradient 0 ! 100%
(15 min) and 100% (4 min); column B: Chiralcel OD-R,
5 lm, (250 · 10 mm), flow: 1 mL/min, eluent: H2O
(0.1% TFA)/CH3CN (0.1% TFA) 40/60; column C:
(S,S)-Whelk 01, 5 lm, (250 · 10 mm), flow: 1 mL/min,
eluent: hexane–2-propanol 90/10; column D: Symmetry
ShieldTMC RP 18, 5 lm, (19 · 100 mm), flow: 20 mL/
min, H2O (0.1% TFA)/CH3CN (0.1% TFA) gradient
95:5–85:15 for 5 min, 85:15–35:65 for 55 min and 35:65
for 5 min. The racemic and enantiopure chiral auxilia-
ries (RS)- and (R)-4-(3-hydroxy-4,4-dimethyl-2-oxo-
pyrrolidin-1-yl) benzoic acids (RS)-1 and (R)-1, the
corresponding acrylate benzyl esters (RS)- and (R)-benz-
yl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)-
benzoates (RS)-2 and (R)-2 were prepared as previously
20
D
4.2.1. Compound (30R,1R,2S)-4. Mp 55 ꢁC; ½aꢀ ¼ þ65
(c 0.5, CH2Cl2); tR (HPLC, column A) 15.02 min, tR
(HPLC, column B) 31.46 min; MS (ESI) m/z: 597.2
[(M+H)+]; 1H NMR (CDCl3): d 1.05 (s, 3H, CH3),
1.15 (s, 3H, CH3), 2.02 (m, 4H, 2CH2), 3.02 (br m,
1H, CHCO), 3.44 (d, J = 9.6, 1H, HCH-5), 3.52 (d,
J = 9.6, 1H, HCH-5), 4.61 (br m, 1H, CHNH), 4.96
(d, J = 12.5, 1H, OHCHC6H5), 5.02 (d, J = 12.5, 1H,
OHCHC6H5), 5.27 (s, 2H, OCH2C6H5), 5.34 (s, 1H,
CH-3), 5.62 (d br, J = 10.0, 1H, CH@), 5.65 (d, 1H,
NH), 5.76 (br d, J = 10.0, 1H, CH@), 7.29 (m, 10H,
H-arom), 7.64 (d, J = 9.5, 2H, H-arom), 8.00 (d,
J = 9.5, 2H, H-arom); 13C NMR (CDCl3): d 21.07
(CH3), 22.10 (CH2), 24.27 (CH3), 37.20 (C-4), 43.54
(CHCO), 46.83 (CHNH), 57.41 (C-5), 66.66
(OCH2C6H5), 66.71 (OCH2C6H5), 78.10 (C-3), 118.34
(CH-arom), 126.01 (C-arom), 126.97 (CH@), 128.01,
128.05, 128.20, 128.29, 128.50, 128.63 (CH-arom),
129.54 (CHC@), 130.78 (CH-arom), 136.05, 136.54,
143.04 (C-arom), 155.91, 165.83, 169.62, 172.39 (CO);
HRMS (FAB) Calcd for C35H37N2O7 (MH+)
597.2601. Found 597.2587.
20
D
4.2.2. Compound (30R,1S,2R)-5. Mp 160 ꢁC; ½aꢀ
¼
ꢁ35 (c 0.35, CH2Cl2); tR (HPLC, column A)
14.34 min, tR (HPLC, column B) 37.74 min; MS (ESI)
m/z: 597.2 [(M+H)+]; 1H NMR (CDCl3): d 1.05 (s,
3H, CH3), 1.15 (s, 3H, CH3), 2.02 (m, 4H, 2CH2), 3.02
(br m, 1H, CHCO), 3.44 (d, J = 9.6, 1H, HCH-5), 3.52
(d, J = 9.6, 1H, HCH-5), 4.61 (br m, 1H, CHNH),
5.02 (s, 2H, OCH2C6H5), 5.27 (s, 2H, OCH2C6H5),
5.34 (s, 1H, CH-3), 5.42 (d, 1H, NH), 5.62 (br d,
J = 10.0, 1H, CH@), 5.76 (br d, J = 10.0, 1H, CH@),
7.29 (m, 10H, H-arom), 7.64 (d, J = 9.5, 2H, H-arom),
8.00 (d, J = 9.5, 2H, H-arom); 13C NMR (CDCl3): d
21.07 (CH3), 22.10 (CH2), 24.27 (CH3), 37.20 (C-4),
43.54 (CHCO), 46.83 (CHNH), 57.41 (C-5), 66.71
(OCH2C6H5), 78.10 (C-3), 118.34 (CH-arom), 126.01
(C-arom), 126.97 (CH@), 128.01, 128.05, 128.20,
128.29, 128.50, 128.63 (CH-arom), 129.54 (CH3C@),
130.78 (CH-arom), 136.05, 136.54, 143.04 (C-arom),
155.91, 165.83, 169.62, 172.39 (CO); HRMS (FAB)
Calcd for C35H37N2O7 (MH+) 597.2601. Found
597.2601.
described.12 1-(Benzyloxycarbonylamino)butadiene
3
was obtained from the Curtius rearrangement of penta-
dienolate in benzyl alcohol according to the protocol
described by Jessup et al.13
4.2. [N-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-2-oxo-
pyrrolidin-3-yl]-2-(benzyloxycarbonylamino)cyclohex-3-
ene-1-carboxylate (30R,1R,2S)-4 and (30R,1S,2R)-5
A mixture of 1-(benzyloxycarbonylamino)butadiene 3
(1.58 g, 7.8 mmol, 1.2 equiv) and of (R)-benzyl-4-(3-
acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)-benzo-
ate (R)-2 (1 equiv) (2.55 mg, 6.5 mmol) in dry toluene
(8 mL) was stirred at 60 ꢁC for 24 h. After concentration
in vacuo, a crude product, which contained an 85/15
mixture of two cycloadducts, was obtained. This was
submitted to column chromatography on silica gel,
using hexane–ethyl acetate (7/3) as eluent to yield the
pure minor diastereoisomer (30R,1S,2R)-5 (0.20 g,
0.33 mmol, 4.3% yield, Rf = 0.35, 99% de), a (88/12)
mixture of the esters (30R,1R,2S)-4/(30R,1S,2R)-5
4.3. (1R,2S)/(1S,2R)-2-(Benzyloxycarbonylamino)cyclo-
hex-3-ene-1-carboxylic acid 6
To a solution of compound 4 or 5 in THF was added
dropwise a solution of LiOH, H2O (1.2 equiv) in water

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M. Calmes et al. / Tetrahedron: Asymmetry 16 (2005) 2173–2178
2177
and the mixture stirred at room temperature until com-
pletion of the hydrolysis (ꢂ5 h) (monitored by HPLC
column A). The organic solvent was removed in vacuo,
after which saturated aqueous NaHCO3 was added and
the mixture extracted with CH2Cl2. The aqueous phase
was acidified (pH 1) and then extracted with CH2Cl2.
The combined organic phases were dried over anhy-
drous Na2SO4 and concentrated in vacuo to afford the
expected acid containing about 5% of the compound
(R)-1 as the saponification was not totally regioselective.
A reverse-phase high performance liquid chromatogra-
phy (column D) yielded the expected pure acid 6.
(CH@), 127.38, 127.85, 127.99, 128.09, 128.51, 128.63
(CH-arom), 130.10 (CH@), 136.52, 138.56 (C-arom),
156.27, 172.52 (CO); HRMS (FAB) Calcd for
C22H25N2O3 (MH+) 365.1865. Found 365.1835.
4.4.2. Compound (1S,2R)-7. Synthesized from com-
pound (1S,2R)-6 (9.2 mg, 0.033 mmol). The benzyl
amide derivative (1S,2R)-7 was obtained as a colourless
oil (11.7 mg, 0.32 mmol, 96% yield, 99% ee); tR (HPLC
column A) 11.7 min; tR (HPLC column C) 21.4 min;
1
MS, H and 13C NMR data are identical to those of
compound (1R,2S)-7:
4.3.1. Compound (1R,2S)-6. Synthesized from com-
pound 4 (250 mg, 0.42 mmol) in THF (4 mL), the acid
(1R,2S)-6 was obtained as a colourless oil (49.6 mg,
4.5. (1R,2S)/(1S,2R)-2-Aminocyclohexane-1-
carboxylic acid 8
20
0.18 mmol, 43% yield, >99% ee); ½aꢀ ¼ þ112 (c 2.3,
The
cis-2-aminocyclohex-3-ene-1-carboxylic
acids
D
CH2Cl2); MS (ESI) m/z: 276.1 [(M+H)+]; tR (HPLC
column A) 10.1 min; 1H NMR (CDCl3): d 2.02 (m,
4H, 2CH2), 2.73 and 2.82 (2br s (80/20), 1H, CHCO),
4.46 and 4.55 (2br s (80/20), 1H, CHNH), 4.96 (d,
J = 12.1, 1H, OHCHC6H5), 5.03 (d, J = 12.1, 1H,
OHCHC6H5), 5.36 (br d, J = 9.3, 1H, NH), 5.56 (br d,
J = 10.0, 1H, CH@); 5.71 (br d, J = 10.0, 1H, CH@),
7.22 (m, 5H, H-arom); 13C NMR (CDCl3): d 22.16,
23.02 (CH2), 43.26 (CHCO), 46.98 (CHNH), 66.97
(OCH2C6H5), 127.17 (CH@), 128.14, 128.36, 128.52
(CH-arom), 129.54 (CHC@), 136.33 (C-arom), 156.11,
178.14 (CO); HRMS (FAB) Calcd for C15H18NO4
(MH+) 276.1236. Found 276.1219.
(1R,2S)-8 and (1S,2R)-8 were obtained by catalytic
hydrogenation of the double bond and hydrogenolysis
of the carbamate group, starting from, respectively
(1R,2S)-6 and (1S,2R)-6, using the synthetic route de-
scribed by Houk et al.9c
The physical properties and chemical characteristics of
2-aminocyclohex-3-ene-1-carboxylic acids (1R,2S)-8
and (1S,2R)-8 are identical to those previously
described.7b,9c
References
4.3.2. Compound (1S,2R)-6. Synthesized from com-
pound 5 (113 mg, 0.19 mmol) in THF (2 mL), the acid
(1S,2R)-6 was obtained as a colourless oil (28 mg,
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20
0.102 mmol, 52% yield, 99% ee); ½aꢀ ¼ ꢁ129 (c 1.0,
D
1
CH2Cl2); tR (HPLC column A) 10.1 min; MS, H and
13C NMR data are identical to those of compound
(1R,2S)-6.
4.4. (1R,2S)/(1S,2R)-2-(Benzyloxycarbonylamino)cyclo-
hex-3-ene-1-benzylcarbamoyle 7
The benzyl amide derivatives (1R,2S)-7 and (1S,2R)-7
were obtained using the synthetic route described by
Corey et al.19 starting, respectively, from (1R,2S)-6
and (1S,2R)-6.
4.4.1. Compound (1R,2S)-7. Synthesized from com-
pound (1R,2S)-6 (10 mg, 0.036 mmol). The benzyl
amide derivative (1R,2S)-7 was obtained as a colourless
oil (12.3 mg, 0.034 mmol, 94% yield, 99% ee); tR (HPLC
column A) 11.7 min; tR (HPLC column C) 17.2 min; SM
3. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180; (b)
Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58, 8629–
8659.
4. Fulo¨p, F. Chem. Rev. 2001, 101, 2181–2204.
¨
5. Appella, D. H.; Christianson, L. A.; Karke, I. L.; Powel,
1
(ESI) m/z: 365.3 [(M+H)+]; H NMR (CDCl3): d 1.59
(m, 1H, HCH), 1.89 (m, 2H, CH2), 2.01 (m, 1H,
HCH), 2.56 (br m, 1H, CHCO), 4.14 (dd, J = 5.7 and
14.8, 1H, HNHCHC6H5), 4.29 (dd, J = 5.7 and 14.8,
1H, HNHCHC6H5), 4.40 (br m, 1H, CHNH), 4.87 (d,
J = 12.3, 1H, OHCHC6H5), 4.93 (d, J = 12.3, 1H,
OHCHC6H5), 5.39 (d, J = 9.3, 1H, NH), 5.57 (m, 1H,
HC@), 5.72 (br d, J = 9.8, 1H, HC@), 6.51 (br s, 1H,
NH), 7.26 (m, 10H, H-arom); 13C NMR (CDCl3): d
21.58, 23.87 (CH2), 43.41 (HNCH2C6H5), 44.24
(CHCO), 46.79 (CHNH), 66.74 (OCH2C6H5), 126.73
D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206–
6212; Kaman, J.; Forro, E.; Fulo¨p, F. Tetrahedron:
¨
Asymmetry 2000, 11, 1593–1600; Appella, D. H.; Leplae,
P. R.; Raguse, T. L.; Gellman, S. H. J. Org. Chem. 2000,
65, 4766–4769; Berkessel, A.; Glaubitz, K.; Lex, J. Eur. J.
Org. Chem. 2002, 2948–2952.
6. Perlmetter, P.; Rose, M.; Vounatsos, F. Eur. J. Org.
Chem. 2003, 756–760; Gardiner, J.; Anderson, K. H.;
Downard, A.; Abell, A. D. J. Org. Chem. 2004, 69, 3375–
3382.

`
M. Calmes et al. / Tetrahedron: Asymmetry 16 (2005) 2173–2178
2178
7. (a) Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters, A. S.
15. The JH1–H2 coupling constant value was determined using
decoupling experiments of the protons H5.
J. Chem. Soc., Perkin Trans. 1 1994, 1411–1415; (b) Enders,
D.; Wiedemann, J.; Bettray, W. Synlett 1995, 369–371.
8. Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahe-
dron: Asymmetry 1997, 8, 1445–1451.
9. (a) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
T.; Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc.
1999, 121, 7582–7594; (b) Wipf, P.; Wang, X. Tetrahedron
Lett. 2000, 41, 8747–8751; (c) Cannizzaro, C. E.; Ashley, J.
A.; Janda, K. D.; Houk, K. N. J. Am. Chem. Soc. 2003,
125, 2489–2506; (d) Robiette, R.; Cheboub-Benchaba, K.;
Peeters, D.; Marchand-Brynaert, J. J. Org. Chem. 2003,
68, 9809–9812.
16. Crystal data for ester (30R,1S,2R)-5: Molecular formula
C35H37N2O7, M = 596.2, monoclinic, space group P21, a =
˚
˚
˚
15.5190(5) A, b = 5.9620(2) A, c = 17.0943(7) A, b =
3
ꢁ3
˚
100.827(2)ꢁ, V = 1553.5(1) A , Z = 2, Dc = 1.276 Mg m
.
X-ray diffraction data were collected at room temperature
with Mo Ka radiation using the Bruker AXS Kappa CCD
system. The structure was solved using direct methods and
the model was refined by full-matrix least-squares
procedures on F2 to values of R1 = 0.0591 and of
Rw2 = 0.1168 for 2378 reflections with I > 2r(I). Details
of the crystal structure (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
268576. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: +44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
10. Fringuelli, F.; Tatichi, A. The Diels–Alder Reaction:
Selected Practical Methods; John Wiley and Sons, 2002;
Carruthers, W. In Tetrahedron Organic Chemistry Series.
Cycloaddition Reaction in Organic Synthesis; Pergamon
Press, 1990; Vol. 8.
11. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassili-
kogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1669–
1698.
17. Overman, L. E.; Taylor, G. F.; Houk, K. N.; Domelsmith,
L. N. J. Am. Chem. Soc. 1978, 100, 3182–3189.
18. Preparation of benzyl amide derivatives 7 allowed the
correct separation of the two enantiomers (1R,2S)-7 and
(1S,2R)-7, on the chiral HPLC columns, whereas whatever
the conditions and the chiral columns that were used,
we only obtained one peak on the HPLC chromatogram
of a mixture of the two enantiomers (1R,2S)-6 and
(1S,2R)-6.
`
12. (a) Akkari, R.; Calmes, M.; Martinez Eur. J. Org. Chem.
2004, 2441–2450; (b) Akkari, R.; Calmes, M.; Escale, F.;
`
Iapichella, J.; Rolland, M.; Martinez, J. Tetrahedron:
Asymmetry 2004, 15, 2515–2525.
13. Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org.
Synth. 1980, 59, 1–9.
14. All new adducts were characterized by NMR and by LC/
MS analysis.
19. Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741–
1744.