Asymmetric Diels-Alder reaction using a new chiral β-nitroacrylate for enantiopure trans-β-norbornane amino acid preparation

Article abstract of DOI:10.1016/j.tetasy.2007.10.001

The main nitronorbornene adduct derived from the asymmetric Diels-Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)b enzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic

Full text of DOI:10.1016/j.tetasy.2007.10.001

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2491–2496
Asymmetric Diels–Alder reaction using a new chiral b-nitroacrylate
for enantiopure trans-b-norbornane amino acid preparation
a,
a
b
*
`
Monique Calmes, Franc¸oise Escale, Claude Didierjean,
Guillaume Cazalsa and Jean Martineza
a
ˆ
Institut des Biomole´cules Max Mousseron (IBMM) UMR 5247 CNRS-Universite´ Montpellier 1 et 2, Batiment Chimie (17),
Universite´ Montpellier 2, place E. Bataillon, 34095 Montpellier Cedex 5, France
bLaboratoire de Cristallographie et de Mode´lisation des Mate´riaux Mine´raux et Biologiques, UMR UHP-CNRS 8036,
`
BP 239, 54506 Vandoeuvre les Nancy, France
Received 6 September 2007; accepted 1 October 2007
Available online 23 October 2007
Abstract—The main nitronorbornene adduct derived from the asymmetric Diels–Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-
4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic b-
amino acid (1S,2R,3R,4R)-trans-b-norbornane amino acid 9. The enantiomer (1R,2S,3S,4S)-9 could be obtained by the same synthetic
route by using the chiral auxiliary (R)-1.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Compounds containing the bicyclo[2.2.1]heptane structure
are versatile building blocks often used in the synthesis of
agonists or antagonists of biologically active substances,
such as nucleosides4 and prostanoids.5 However, some
b-amino acids possessing a bicyclo[2.2.1]heptane structure
have been used as starting materials for the synthesis of
compounds with medical applications. For example,
among the number of thromboxane A2 (TXA2) receptor
antagonists compound S-1452, a bicyclic sulfonylamide
derivative salt prepared from one of the enantiomers of
trans-endo/exo-3-aminobicyclo[2.2.1]heptane-2-carboxylic
acid, has been found useful for the treatment of thrombotic
disease.6 Furthermore, the racemic form of this non-natu-
ral cyclic b-amino acid has recently been described as a pre-
cursor of a potent and bioavailable integrin VLA-4
antagonist.7 Further applications of these constrained
b-amino acids have been described, particularly in hetero-
cyclic chemistry8 and recently for the synthesis of folda-
mers.9 In the latter case, it has been demonstrated that
the oligomers of constrained cis-diexo-b-norbornene amino
acid residues formed both right and left consecutive six-
membered hydrogen-bonded b-strands for (2S,3R)- and
(2R,3S)-enantiomers, respectively.
In recent years, both the chemistry and the medicinal
chemistry of b-amino acids have become the areas of
intense research activity.1,2 In particular, there has been a
surge of interest with regards to the structure and the func-
tion of conformationally constrained b-amino acids and
their oligomers. Indeed, the incorporation of constrained
cyclic amino acids into peptides or peptidomimetics
induces conformational restriction and provides significant
structural effects that can be used for structural and bio-
mechanistic investigations.3
Although a number of methods have been developed for
the stereoselective preparation of cyclic b-amino acids,
most of them focused on simple cyclic compounds and
access to bicyclic structures has been less developed but
remained attractive.2 In connection with
a project
exploiting the use of a new chiral b-nitroacrylate in
synthesis, we have focused our attention on b-amino acids
possessing a bicyclo[2.2.1]heptane structure obtained by
the Diels–Alder reaction of this acrylate with cyclopenta-
diene (Scheme 2).
The current route to obtain enantiopure cis-3-aminobicy-
clo[2.2.1]heptane-2-carboxylic acids uses the enzyme-cata-
lyzed enantioselective ring opening of the corresponding
*
Corresponding author. E-mail: Monique.Calmes@univ-montp2.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.001

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M. Calmes et al. / Tetrahedron: Asymmetry 18 (2007) 2491–2496
2492
b-lactams.10 The preparation of enantiopure trans deriva-
tives is not so well described. To date and to the best of
our knowledge only an elaborate synthesis, which was used
in the synthesis of compound S-1452, has been reported.6
This synthesis involved the enantioselective fission of the
commercially available bicyclo[2.2.1]hept-5-ene-2,3-endo-
dicarboxylic anhydride with lithium (R)-benzyl mandelate,
followed by hydrogenation of the double bond, epimerisa-
tion of the ester and finally a Curtius rearrangement to
introduce nitrogen.
glyoxylate (S)- or (R)-3 and the corresponding hydrate
(S)- or (R)-4; (b) transformation via a Henry reaction in
the presence of neutral alumina of the glyoxylate function
into the corresponding 50/50 diastereoisomeric mixture of
the alcohol 5; (c) formation of the mesylate derivative
which was spontaneously transformed into the required
nitroacrylate (S)- or (R)-6 (Scheme 1).12
The results of the following Diels–Alder reaction (Scheme
2) are summarized in Table 1 (entries 1–6).
The reaction between nitroacrylate (S)-6 and cyclopentadi-
ene (6 equiv) was first carried out without a catalyst in dry
CH2Cl2 at room temperature to give after 8 h in 96% yield
the corresponding Diels–Alder adducts (Table 1, entry 1).
Analysis of the crude reaction by HPLC (achiral and chi-
2. Results and discussion
We have previously reported the preparation of each enan-
tiomer of a new chiral alcohol, the (S)- or (R)-4-(3-hydr-
oxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) benzoic acid (S)-
or (R)-1, as well as the synthesis of its acrylate derivative
(S)- or (R)-2 and their use in asymmetric synthesis.11
1
ral),13 LC/MS and H NMR,14 showed the formation of
a mixture of the four expected cycloadducts 7, with one
major diastereoisomer (Table 1, entry 1). An enhanced
selectivity could be obtained by running the reaction at
lower temperature, particularly at ꢀ78 ꢁC to give in good
yield a 81/13/5/1 mixture of adducts 7 (Table 1, entries 2
and 3). Under these conditions, the main Diels–Alder
adduct 7 could be isolated in enantiopure form after flash
The nitroacrylate (S)- or (R)-6 was prepared from the acryl-
ate derivative (S)- or (R)-2. The synthesis consisted of (i)
cleavage of the double bond under the classical Lemieux–
Johnson conditions to afford a mixture (10/90) of the
O
O
O
O
O
OH
H
O
H
O
S
a
N
O
S
N
(
)-1 [or (
R
)-1]
(
)-2 [or (R)-2]
O
OH
H
O
O
O
O
O
O
OH
O
H
O
b
O
O
+
H
N
N
H
(S)-4 [or (R)-4]
(
S)-3 [or (R)-3]
OH
H
O
O
O
O
O
NO2
O
O
d
O
c
O
H
O
H
NO2
N
N
(3S,2'SR)-5 [or (3R,2SR)-5]
(S)-6 [or (R)-6]
Scheme 1. Reagents and conditions: (a) acryloyl chloride, NEt3, CH2Cl2, rt; (b) NaIO4, OsO4, H2O–dioxane, rt; (c) CH3NO2, neutral alumine; (d) MsCl,
NEt3, CH2Cl2, 0 ꢁC.
O
O
O
O
O
O
O
O
O
S
a
O
N
N
other adducts
+
O2N
NO2
(1 ,2
(S)-6 [or (R)-6]
R
R
,3
R
,4
S,3'
S
)-7 [or (1
S,2
S
,3
,4
R,3'
R
)-7 ]
O
O
O
O
OH
OH
b
O
c
N
NH Boc
)-9 [or (1R,2S,3S,4S)-9]
NH Boc
,4 ,3' )-8 [or (1
(1
S,2
R,3
R
R
S
R,2
S,3
S,4
S,3'R
)-8]
(1
S,2
R,3
R,4
R
Scheme 2. Reagents and conditions: (a) cyclopentadiene, 6 equiv, CH2Cl2, ꢀ78 ꢁC, 20 h; (b) H2, 10% Pd–C, AcOH, rt, 15 h; (c) LiOH, H2O, THF, rt, 5 h.

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M. Calmes et al. / Tetrahedron: Asymmetry 18 (2007) 2491–2496
2493
Table 1. Diels–Alder reaction of the cyclopentadiene with the nitroacry-
late (S)-6a
group was responsible for the reaction rate acceleration,
without favouring the stereoselectivity.
Entry T (ꢁC) Additive
Time Conversionb Cycloadduct
(equiv)
(h)
(%)
ratioc
Hydrogenation of the nitro group concomitant with the
hydrogenation of the double bond and hydrogenolysis of
the benzyl ester, using palladium on carbon as a catalyst
in acetic acid,17 at room temperature and atmospheric
pressure of the isolated enantiopure cycloadduct
(1R,2R,3R,4S,30S)-7, followed by Boc protection of the
resulting free amine yielded compound (1S,2R,3R,4R,
30S)-8. Finally, LiOH hydrolysis of this compound at room
temperature afforded the expected enantiopure trans-b-nor-
bornane amino acid (1S,2R,3R,4R)-9.
1
2
3
4
5
6
rt
—
—
—
8
15
20
15
5
96
95
95
65/20/11/4
70/17/10/3
81/13/5/1
—
64/25/8/3
64/29/5/2
ꢀ20
ꢀ78
rt
rt
rt
TiCl4 (1)
ZnCl2 (1)
Et2AlCl (1)
0
96d
95d
5
a In CH2Cl2 using 6 equiv of cyclopentadiene, 0.15 M acrylate
concentration.
b Determined by HPLC analysis and based on acrylate disappearance.
c Determined by HPLC (achiral and chiral), LC/MS and 1H NMR
analysis.13,14
The trans-b-norbornane amino acid (1R,2S,3S,4S)-9 could
be obtained by the same synthetic route by using the chiral
auxiliary (R)-1.
d Some non-identified side products were formed.
column chromatography on silica gel using ethyl acetate/
cyclohexane (2/8) as an eluent. This compound was then
recrystallized from acetonitrile, while the absolute configu-
ration of the newly generated stereocenters was determined
by X-ray diffraction analysis (Fig. 1).15 From the known
(S)-configuration of the chiral auxiliary, it was determined
that the main cycloadduct 7 had a (1R,2R,3R,4S,30S)-con-
figuration which resulted from an endo nitro selectivity on
the Ca/Cb re´ face. Attempts to isolate the three minor ad-
ducts 7 in their pure form by column chromatography
failed, so their configuration could not be unambiguously
assigned. However, it can be assumed by using HPLC
3. Conclusion
In conclusion, we found that the chiral nitroacrylate (S)- or
(S)-6 was an efficient dienophile to prepare enantiopure
trans-b-norbornane amino acids by reaction with cyclo-
pentadiene. The Diels–Alder reaction proceeded in dry
CH2Cl2 at ꢀ78 ꢁC in good yield and good endo-nitro selec-
tivity on the Ca/Cb re´ face. This study provides a rare
example of an asymmetric trans-b-norbornane amino acid
preparation.
1
(achiral and chiral), LC/MS and H NMR analysis13,14
as well as the determined configuration of the main diaste-
reoisomer, that under the best conditions the reaction pro-
ceeded with moderate endo-nitro selectivity (84%) and
good facial selectivity (94%).
4. Experimental
4.1. General
In an attempt to increase the stereoselectivity of the reac-
tion, we investigated the use of Lewis acid catalysts that
generally allow the Diels–Alder reaction to proceed with
satisfactory yields and a high level of stereoselectivity.16
From the reaction of the nitroacrylate with cyclopentadi-
ene in the presence of TiCl4 at room temperature, no cyc-
loadduct 7 was isolated (Table 1, entry 4). The addition
of ZnCl2 or Et2AlCl enhanced the reaction rate of the
cycloaddition but had no positive effect on the stereoselec-
tivity. We also observed the formation of some side prod-
ucts particularly when using Et2AlCl as a catalyst (Table
1, entries 5 and 6). It could be assumed that chelation by
the Lewis acid involving the two oxygen atoms of the nitro
All reagents were used as purchased from commercial sup-
pliers without further purification. Solvents were dried and
purified by conventional methods prior to use. Melting
points were determined with a Kofler Heizbank apparatus
and are uncorrected. Optical rotations were measured with
1
a Perkin Elmer 341 polarimeter. H or 13C NMR spectra
(DEPT, 1H/13C 2D-correlations) were recorded with a Bru-
ker A DRX 400 spectrometer using the solvent as an inter-
nal reference. Data are reported as follows: chemical shifts
(d) in parts per million, coupling constants (J) in hertz
(Hz). The ESI mass spectra were recorded with a platform
II quadrupole mass spectrometer (Micromass, Manchester,
UK) fitted with an electrospray source. HPLC analyses
Figure 1. ORTEP drawing of the adduct (1R,2R,3R,4S,30S)-7.

`
M. Calmes et al. / Tetrahedron: Asymmetry 18 (2007) 2491–2496
2494
were performed with a Waters model 510 instrument or a
Beckman System Gold 126 instrument with a variable
detector using: column A: SymmetryShieldTM 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: Whelk-01 (Pirkle), flow: 1 ml/min, elu-
ent I: hexane/2-propanol: 60/40; eluent II: hexane (0.1%
TFA)/2-propanol (0.1% TFA) 60/40. Microwave activa-
tion was performed with a Biotage initiator 2.0 instrument.
yield)19 as a white solid; mp 48–50 ꢁC; tR (HPLC, column
1
A) 10.4 and 10.5 min; MS (ESI) m/z: 457.2 [(M+H)+]; H
NMR (CDCl3) d 1.05 and 1.11 (s, 3H, CH3), 1.29 and
1.30 (s, 3H, CH3), 3.49 and 3.51 (2d, J = 9.7, 1H, 5-H),
3.60 and 3.62 (2d, J = 9.7, 1H, 5-H), 4.79 (m, 2.5H, CHOH
and CH2NO2), 4.89 (t, J1 = J2 = 4.5, 0.5H, CHOH), 5.29
(s, 2H, CH2–C6H5); 5.44 and 5.51 (s, 1H, 3-H), 7.32 (m,
5H, H-arom); 7.63 (d, J = 9.4, 2H, H-arom); 8.02 (d,
J = 9.4, 2H, H-arom); 13C NMR (CDCl3) d 21.0 and
21.1 (CH3), 24.3 and 24.5 (CH3), 37.6 (C-4), 57.4 and
57.5 (C-5), 66.7 and 66.8 (OCH2C6H5), 79.9 and 80.0 (C-
3), 118.6 (CH-arom), 126.5 (C-arom), 128.2, 128.3, 128.6
and 130.8 (CH-arom), 136.0 and 142.6 (C-arom), 165.7
and 165.8 (COCH@CH2), 168.4, 168.5, 170.2 and 170.5
(CO); HRMS (FAB) Calcd for C23H25N2O8 (MH+)
457.1611, found 457.1609.
The enantiopure chiral auxiliary (S)-benzyl 4-(3-hydroxy-
4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1, and the
corresponding acrylate (S)-benzyl-4-(3-acryloyloxy-4,4-di-
methyl-2-oxopyrrolidin-1-yl)benzoate (S)-2 were prepared
as previously described.11b
4.1.1. (S)-Benzyl-4-[4,4-dimethyl-3-(2-oxoacetoxy)-2-oxo-
pyrrolidin-1-yl]benzoate (S)-3 and (S)-benzyl-4-[3-(2.2-di-
hydroacetoxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl]benzoate
(S)-4. OsO4 (20 mg, 0.07 mmol) was added at room tem-
perature to a stirred solution of the (S)-benzyl-4-(3-acryl-
oyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-2
(2.10 g, 6.2 mmol) in 26 ml of a H2O/THF mixture (1/4).
After 5 min, the reaction mixture turned brown, NaIO4
(2.55 g, 11.9 mmol, 1.9 equiv) was slowly added portion-
wise over 10 min and stirring was continued for 2 h. The
reaction mixture was diluted with brine (50 ml), organic
solvent was removed in vacuo and the aqueous phase
was extracted with diethyl ether (3 · 30 ml). The combined
organic extracts were washed with water, 10% aqueous
NaHSO3 solution, dried over anhydrous sodium sulfate
and concentrated in vacuo to yield a mixture of the glyoxyl-
ate (S)-3 and its hydrate (S)-4 (2.35 g, 5.7 mmol, 92% yield)
in a 10/90 ratio as a colourless oil; tR (HPLC, column A)
9.4 min; MS (ESI) m/z: 396.3 and 414.1 [(M+H)+]; 1H
NMR (CD3CN) d 1.14 and 1.19 (s, 3H, CH3), 1.28 and
1.30 (s, 3H, CH3), 3.67 (m, 2H, 5-H), 5.29 (s, 0.9H,
CH(OH)2), 5.35 (s, 2H, CH2–C6H5); 5.48 and 5.59 (s,
1H, 3-H), 7.44 (m, 5H, H-arom), 7.79 (d, J = 10.6, 2H,
H-arom), 8.06 (d, J = 10.6, 2H, H-arom), 9.4 (s, 0.1H,
CO–H) 13C NMR (CD3CN) d 20.1 and 20.2 (CH3), 23.3
and 23.5 (CH3), 37.0 and 37.3 (C-4), 56.8 and 56.9 (C-5),
66.3 (OCH2C6H5), 78.5 and 79.7 (C-3), 87.0 (CH(OH)2),
177.3 (C-arom), 118.7 and 118.8 (CH-arom), 125.8 and
126.1 (C-arom), 128.0, 128.1, 128.6 and 130.3 (CH-arom),
136.6, 142.2 and 143.4 (C-arom), 158.6, 165.5, 168.4, 169.0,
169.8 and 183.7 (CO).
4.1.3. (S)-Benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-
oxopyrrolidin-1-yl)benzoate (S)-6. Mesylchloride (237 ll,
3.0 mmol, 1.05 equiv) was added dropwise at 0 ꢁC and un-
der argon to a stirred solution of compound 5 (1.33 g,
2.9 mmol) in dry CH2Cl2 (16 ml). Then, NEt3 (1.62 ml,
11.6 mmol, 4 equiv) was added dropwise over 5 min with
stirring at the same temperature. Stirring was continued
for an additional 2 min at 0 ꢁC. The reaction mixture di-
luted with diethyl ether (80 ml), was successively washed
with a 0.1 M HCl solution (40 ml) and brine (40 ml), dried
over anhydrous Na2SO4 and concentrated in vacuo. The
crude nitro acrylate (S)-6 (1.14 g, 2.6 mmol, 85% yield)19
was used without further purification in the following step
or could be purified by flash column chromatography using
cyclohexane/ethyl acetate as eluent (7.5/2) to yield pure
compound (S)-6 as a colourless oil (1.00 g, 2.3 mmol,
20
75% yield); ½aꢁD ¼ ꢀ17 (c 1.7, CH2Cl2); tR (HPLC, column
1
A) 11.8 min; MS (ESI) m/z: 439.0 [(M+H)+]; H NMR
(CDCl3) d 1.15 (s, 3H, CH3), 1.28 (s, 3H, CH3), 3.54 (d,
J = 9.7, 1H, 5-H), 3.62 (d, J = 9.7, 1H, 5-H), 5.30 (s, 2H,
CH2–C6H5); 5.46 (s, 1H, 3-H), 7.15 (d, J = 13.5, 1H,
CO–CH@), 7.32 (m, 5H, H-arom); 7.64 (d, J = 9.4, 2H,
H-arom); 7.71 (d, J = 13.5, 1H, NO2CH@), 8.03 (d,
J = 9.4, 2H, H-arom); 13C NMR (CDCl3) d 21.2 (CH3),
24.7 (CH3), 37.4 (C-4), 57.4 (C-5), 66.8 (OCH2C6H5),
77.7 (C-3), 118.5 (CH-arom), 126.4 (C-arom), 126.5
(CH@), 128.2, 128.6 and 130.8 (CH-arom), 132.9 and
143.7 (C-arom), 149.8 (NO2CH@), 162.8 (COCH@CH2),
165.7 and 168.1 (CO); HRMS (FAB) Calcd for
C23H23N2O7 (MH+) 439.1505, found 439.1512.
4.1.2. (3S,20RS)-Benzyl-4-(3-(2-hydroxy-3-nitropropionyl-
oxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (3S,20RS)-
5. Neutral alumina18 (2.4 g, 0.5 g/mmol) was added over
a period of 10 min at 0 ꢁC to a stirred solution of a mixture
of the glyoxylate (S)-3 and its hydrate (S)-4 (2.00 g,
4.8 mmol, assuming all the material is the hydrate) in nitro-
methane (10 ml, 186 mmol). Stirring was continued for an
additional 30 min at 0 ꢁC and then 3 h at room tempera-
ture. To the resulting suspension was added CH2Cl2
(50 ml) and after filtration through Celite the filtrate was
concentrated in vacuo. The crude was submitted to column
chromatography on silica gel using cyclohexane/ethyl ace-
tate as eluent (7/3) to yield a 50/50 diastereoisomeric mix-
ture of the expected compound 5 (1.62 g, 3.55 mmol, 74%
4.1.4. (1R,2R,3R,4S,30S)-[N-(4-Benzyloxycarbonylphenyl)-
4,4-dimethyl-2-oxopyrrolidin-3-yl] 3-nitrobicyclo[2.2.1]hept-
5-ene-2-carboxylate
(1R,2R,3R,4S,30S)-7. Freshly-dis-
tilled cyclopentadiene (980 ll, 6 equiv, 13.8 mmol) was
added to a solution of the nitroacrylate (S)-6 (1.00 g,
2.3 mmol) in dry CH2Cl2 (100 ml) at ꢀ78 ꢁC. The reaction
mixture was stirred for 20 h at the same temperature. Re-
moval of the solvent and of the cyclopentadiene excess in
vacuo afforded in good yield (1.30 g, 2.2 mmol, 95% yield)
a mixture of the four expected cycloadducts (two endo-nitro
isomers and two exo-nitro isomers) in a 81/13/5/1 ratio.
The crude adducts were submitted to flash column chroma-
tography using cyclohexane/ethyl acetate as eluent (8/2) to
yield the enantiopure endo-nitro major adduct

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M. Calmes et al. / Tetrahedron: Asymmetry 18 (2007) 2491–2496
2495
(1R,2R,3R,4S,30S)-7 (0.38 g, 0.76 mmol, 53.1% yield, 99
1) (4 ml) and the mixture was stirred at room temperature
until completion of the hydrolysis (ꢂ5 h) (monitored by
HPLC, column A). The organic solvent was removed in va-
cuo and the aqueous phase was acidified (pH 3). The resi-
due obtained after evaporation of the water was submitted
to column chromatography on silica gel, using CH2Cl2/
ethyl acetate/AcOH (9/1/0.01) as eluent to yield the
expected pure b-amino acid (1S,2R,3R,4R)-9 (35 mg,
20
de) as a white solid; mp 119 ꢁC; ½aꢁD ¼ ꢀ102 (c 0.9,
CH2Cl2); tR (HPLC, column A) 12.3 min; tR (HPLC, col-
umn B, eluent I) 15.7 min; MS (ESI) m/z: 505.1
1
[(M+H)+]; H NMR (CDCl3) d 1.12 (s, 3H, CH3), 1.26
(s, 3H, CH3), 3.10 (dd, J = 2.6 and 3.1, 1H, 4-H), 3.38
(br s, 1H, 2-H), 3.51 (d, J = 9.6, 1H, 50-H), 3.58 (br d,
J = 9.6, 2H, 50-H and 1-H), 5.28 (s, 2H, CH2–C6H5); 5.39
(s, 1H, 30-H), 5.41 (t, J1 = J2 = 3.8, 1H, 3-H), 6.05 (dd,
J = 2.7 and 5.6, 1H, 6-H), 6.45 (dd, J = 3.1 and 5.6, 1H,
5-H), 7.32 (m, 5H, H-arom), 7.64 (d, J = 7.0, 2H, H-arom),
8.01 (d, J = 7.0, 2H, H-arom); 13C NMR (CDCl3) d 21.2
(CH3), 24.6 (CH3), 37.1 (C-40), 46.2 (C-7), 47.4 (C-1),
48.4 (C-2), 48.9 (C-4), 57.4 (C-50), 66.7 (OCH2C6H5),
78.9 (C-3), 87.8 (C-30), 118.4 (CH-arom), 126.2 (C-arom),
128.2, 128.3, 128.4, 128.6 and 130.8 (CH-arom), 133.8
(CH@), 136.0 (C-arom), 139.4 (CH@), 142.9 (C-arom),
165.8, 169.2 and 171.8 (CO); HRMS (FAB) Calcd for
C28H29N2O7 (MH+) 505.1975, found 505.1981.
0.14 mmol, 68% yield) as a white solid; mp 114–115 ꢁC;
20
½aꢁD ¼ ꢀ22 (c 0.9, CH2Cl2); 1H NMR (CDCl3) d 1.12–
1.26 (m, 3H, CH2 and HCH), 1.36–1.54 (m, 4H, CH2),
1.40 (s, 9H, C(CH3)3), 1.62 (m, 1H, HCH), 2.07 (br s,
1H, 4-H), 2.33 (br s, 1H, 2-H), 2.77 (br d, J = 3.8, 1H,
1-H), 3.68 (br d, J = 3.7, 1H, 3-H), 5.06 (br s, 1H, NH);
13C NMR (CDCl3) d 21.86 (CH2), 28.3 (C(CH3)3), 29.7
(CH2), 37.0 (CH2), 39.7 (C-1), 40.2 (C-2), 56.1 (C-3), 56.5
(C-3), 82.1 (C(CH3)3), 158.6 and 174.1 (CO); HRMS
(FAB) Calcd for C13H22NO4 (MH+) 256.1549, found
256.1554.
4.1.5.
(1S,2R,3R,4S,30S)-[N-(4-Carboxyphenyl)-4,4-di-
methyl-2-oxopyrrolidin-3-yl] 3-tert-butoxycarbonylamino-
bicyclo[2.2.1]heptane-2-carboxylate (1S,2R,3R,4S,30S)-8.
Compound (1R,2R,3R,4S,30S)-7 (0.38 g, 0.76 mmol) in
acetic acid (8 ml) was added to a suspension of 10% Pd/
C (ꢂ20 mg) in acetic acid (2 ml). This mixture was stirred
vigorously under 1 atm. of H2 for 15 h at room tempera-
ture. The suspension was filtered through Celite and the fil-
trate was concentrated in vacuo. To the residue dissolved in
ethyl alcohol (15 ml) was added DIEA (0.65 ml, 3.8 mmol,
5.0 equiv) and (Boc)2O (0.30 g, 1.37 mmol, 1.8 equiv). The
resulting mixture was stirred for 15 h at room temperature
(controlled by HPLC, column A). After the removal of the
solvent, the residue was dissolved in aqueous 0.1 M NaOH
(15 ml) and the aqueous phase was washed with ethyl ether
(20 ml), acidified to pH 3 and extracted with diethyl acetate
(3 · 20 ml). The organic layer was dried over Na2SO4, and
concentrated in vacuo to yield the expected compound
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20
white solid; mp 100 ꢁC; ½aꢁD ¼ ꢀ14 (c 1.5, CH2Cl2); tR
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(HPLC, column A) 10.5 min; tR (HPLC, column B, eluent
II) 6.2 min; MS (ESI) m/z: 487.0 [(M+H)+], 430.9, 387.0;
1H NMR (CDCl3) d 1.08 (s, 3H, CH3), 1.25 (br m, 1H,
HCH), 1.28 (s, 3H, CH3), 1.36 (s, 9H, C(CH3)3), 1.40 (br
m, 1H, HCH), 1.58 (br m, 1H, HCH), 1.75 (br d,
J = 10.0, 1H, HCH), 2.00 (br s, 1H, 4-H), 2.37 (br s, 1H,
2-H), 2.56 (br s, 1H, 1-H), 3.49 (br d, J = 9.6, 1H, 50-H),
3.57 (br d, J = 9.6, 1H, 50-H), 4.07 (br s, 1H, 3-H), 5.39
(s, 1H, 30-H), 7.68 (d, J = 8.9, 2H, H-arom), 8.03 (d,
J = 8.9, 2H, H-arom); 13C NMR (CDCl3) d 20.9 (CH2),
21.0 (CH3), 24.6 (CH3), 28.4 (C(CH3)3), 29.7 (CH2), 36.3
(CH2), 37.4 (C-40), 40.3 (C-2), 41.3 (C-1), 54.0 (C-4), 56.1
(C-3), 57.5 (C-50), 77.8 (C-30), 85.2 (C(CH3)3), 118.4 (CH-
arom), 125.3 (C-arom), 131.3 (CH-arom), 143.6 (C-arom),
169.9, 170.6, 172.3 and 173.8 (CO); HRMS (FAB) Calcd
for C26H35N2O7 (MH+) 487.2444, found 487.2429.
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4.1.6. (1S,2R,3R,4R)-3-tert-Butoxycarbonylaminobi-
cyclo[2.2.1]heptane-2-carboxylic acid (1S,2R,3R,4R)-9. A
´
Heller, M.; Varkondi, E.; Pap, A.; Novellino, E.; Keri, G.;
solution of LiOH, H2O (17.6 mg, 0.42 mmol, 2.1 equiv) in
water was added dropwise to a solution of compound
(1S,2R,3R,4R,30S)-8 (100 mg, 0.2 mmol) in THF/H2O (2/
Kessler, H. J. Med. Chem. 2005, 48, 2916–2926; Fulo¨p, F.;
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¨

`
M. Calmes et al. / Tetrahedron: Asymmetry 18 (2007) 2491–2496
2496
4. See, for examples: Katagiri, N.; Ikatsuka, H.; Kaneko, C.;
stationary phase, correspond to the endo/exo mixture. By the
same way, as the four cycloadducts 7 could be totally
separated by using a chiral stationary phase (tR (HPLC,
column B, eluent I) 15.7 min (81%), 17.6 min (5%), 19.8 min
(13%) and 24.6 min (1%)), the facial selectivity (94%) could be
presumed.
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M. J. Med. Chem. 2003, 46, 2436–2445.
6. (a) Ohtani, M.; Matsuura, T.; Watanabe, F.; Narisada, M. J.
Org. Chem. 1991, 56, 2122–2127; (b) Narisada, M.; Ohtani,
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14. Some significant differences of the resonance signals on the
1H and 13C spectra were observed for the different cycload-
ducts 7. For example 6-H and 5-H chemical shifts were
respectively: (6.05 and 6.20 ppm (dd)) (81%), (6.03 and
6.24 ppm (dd)) (13%), (6.46 and 6.48 ppm (dd)) (5%) and
(6.46 and 6.48 ppm (dd)) (ꢂ1%).
15. Crystal data for ester: (1R,2R,3R,4S,30S)-7, Molecular for-
mula C28H28N2O7 M = 504.5, orthorhombic, space group
˚
˚
˚
P212121, a = 6.1315(5) A, b = 9.3117(7) A, c = 43.314(3) A,
V = 2473.0(3) A , Z = 4, Dc = 1.355 Mg mꢀ3. X-ray diffrac-
3
˚
tion data were collected at low temperature with MoKa
radiation using the Bruker AXS Kappa CCD system. The
structure was solved using direct methods and the model was
refined by full-matrix least-square procedures on F2 to values
of R1 = 0.0593 and of Rw2 = 0.1147 for 2627 reflections with
I > 2r(I). Details of the crystal structure (excluding structure
factors) have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number
CCDC 659166. 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].
9. Chandrasekhar, S.; Babu, B. N.; Prabhakar, A.; Sudhakar,
A.; Reddy, M. S.; Kiran, M. U.; Jagadeesh, B. Chem.
Commun. 2006, 1548–1550.
10. See, for examples: Kanerva, L. T.; Csomos, P.; Sundholm,
O.; Bernath, G.; Fulo¨p, F. Tetrahedron: Asymmetry 1996, 7,
¨
1705–1716; Forro, E.; Fulo¨p, F. Org. Lett. 2003, 5, 1209–
¨
1212; Forro, E.; Fulo¨p, F. Tetrahedron: Asymmetry 2004, 15,
573–575.
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1990; Vol. 8, Kobayashi, S.; Jorgensen, K. A. Cycloaddition
Reactions in Organic Synthesis; Wiley-VCH, 2002; Fringuelli,
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Methods; John Wiley & Sons, 2002, and references cited
therein.
¨
`
11. (a) Akkari, R.; Calmes, M.; Martinez, J. Eur. J. Org. Chem.
`
2004, 2441–2450; (b) Akkari, R.; Calmes, M.; Escale, F.;
Iapichella, J.; Rolland, M.; Martinez, J. Tetrahedron: Asym-
`
metry 2004, 15, 2515–2525; (c) Calmes, M.; Didierjean, C.;
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2173–2178; (d) Songis, O.; Didierjean, C.; Martinez, J.;
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955.
`
Calmes, M. Eur. J. Org. Chem. 2007, 3166–3172.
12. The nitro acrylate 6 was synthesized following the conditions
described by Clive et al. for the preparation of the nitro
acrylate ester of the (ꢀ)-8-phenylmenthol: Clive, D. L. J.; Bo,
Y.; Selvakumar, N. Tetrahedron 1999, 55, 3277–3290.
13. It could be assumed that the two separated peaks (tR (HPLC,
column A) 12.2 min (14%) and 12.3 min (86%)) obtained by
HPLC analysis of the crude mixture 7 by using an achiral
18. Neutral alumina was kept in an oven at 120 ꢁC and cooled in
a dessicator with silica gel before usage.
19. Compound 5 contains about 5–7% of the compound (S)-1
(HPLC analysis) as inevitable hydrolysis of the ester bond
during the Henry reaction, that was transformed in an
OMesyl derivative in the following step providing the
nitroacrylate (S)-6.