An efficient synthesis of new diastereomeric enantiopure 1-aminocyclopentane-1,2,4-tricarboxylic acids

Article abstract of DOI:10.1016/j.tetasy.2006.05.001

Novel 1-aminocyclopentane-1,2,4-tricarboxylic acids 11 and 14 containing the glutamic acid skeleton were prepared as two diastereomers characterized by having the carbonyl groups in positions two and four cis to each other and trans with respect to the 1-carboxylic group and as all cis relationship, respectively. The reaction sequences, that is, Diels-Alder reaction to give norbornene cycloadducts, oxidative cleavage of the double bond of the cycloadducts, ensured the proper stereochemistry of both diastereomers. Each diastereomer was prepared in enantiopure form starting from exo- and endo-2-amino-norbornene-2-carboxylic acid derivatives 5 and 6 obtained through a very efficient asymmetric synthesis.

Full text of DOI:10.1016/j.tetasy.2006.05.001

Tetrahedron: Asymmetry 17 (2006) 1430–1436
An efficient synthesis of new diastereomeric enantiopure
1-aminocyclopentane-1,2,4-tricarboxylic acids
Francesco Caputo, Francesca Clerici, Maria Luisa Gelmi,* Sara Pellegrino and Donato Pocar
` `
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, Universita di Milano, Via Venezian 21, I-20133 Milano, Italy
Received 13 April 2006; accepted 1 May 2006
Available online 30 May 2006
Abstract—Novel 1-aminocyclopentane-1,2,4-tricarboxylic acids 11 and 14 containing the glutamic acid skeleton were prepared as two
diastereomers characterized by having the carbonyl groups in positions two and four cis to each other and trans with respect to the
1-carboxylic group and as all cis relationship, respectively. The reaction sequences, that is, Diels–Alder reaction to give norbornene cyc-
loadducts, oxidative cleavage of the double bond of the cycloadducts, ensured the proper stereochemistry of both diastereomers. Each
diastereomer was prepared in enantiopure form starting from exo- and endo-2-amino-norbornene-2-carboxylic acid derivatives 5 and 6
obtained through a very efficient asymmetric synthesis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
also considered (i.e., 1-aminocyclopentane-1,3,4-tricarbox-
ylic acids).1d In this case, the activity and selectivity of each
isomer toward metabotropic receptor subtypes is strictly
dependent on the stereochemistry. Accordingly, research
in this field is considered to be of great interest.
The preparation of constrained carbocyclic amino acids,1
functionalized with a second carboxylic group in a suitable
position, is an important synthetic target, because these
compounds contain the skeleton of glutamic acid. This
amino acid is one of the most important transmitters in
the CNS and is also involved in several brain disorders.2
The above amino acids are generally characterized by
a,a-disubstitution, and for this reason, they have great met-
abolic stability. Furthermore, the rigidity of the backbone
allows us to design different stereoisomers. Depending on
the rigidity of the ring, its size and the stereochemistry of
the substituents, selectivity toward the different Glu recep-
tors can be gained.3 These are classified as ionotropic
(iGluRs) and metabotropic (mGluRs).4 As cited above,
the different stereoisomers can have different activities
toward the different subtypes. For example, the diastereo-
meric 1-aminocyclopentane-1,3-dicarboxylic acids (ACDP)
are characterized by the activity and selectivity on metabo-
tropic mGluRs.5 The (ꢀ)-(1S,3R)-isomer is a potent ago-
nist on I, II mGluRs, the (+)-(1S,3S)-isomer is selective
on II mGluRs. 2-Aminobicyclo[3.1.0]-hexane-2,6-dicar-
boxylic acid is a selective agonist for group II mGluRs.6
The introduction of a third carboxylic group, as a potential
group capable of forming ionic or hydrogen bonds, was
As part of our research program7 on a,a-disubstituted car-
bocyclic amino acid syntheses, we herein report on the
preparation of two new diastereomeric 1-aminocyclopen-
tane-1,2,4-tricarboxylic acids 11 and 14 (Scheme 1). The
CO2H
HO2C
CO2H
NH2
CO2H
NH2
HO2C
CO2H
11
14
NHCOMe
CO2R
CO2R
NHCOMe
endo-6
exo-5
R = 8-(-)-Phenylmenthyl
*
Corresponding author. Tel.: +39 0250314481; fax: +39 0250314476;
e-mail: marialuisa.gelmi@unimi.it
Scheme 1.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.001

F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 1430–1436
CO2R
NHCOMe
1431
synthetic strategy for their preparation took advantage of
using a sequence of simple and efficient reactions, that is,
Diels–Alder reaction, which allows us to obtain both
exo/endo norbornene amino acids 5 and 6; the oxidative
cleavage of the C5–C6 bond of the cycloadducts giving
the cyclopentyl ring functionalized with two new carbox-
ylic groups.
+
3
4
R = 8-(-)-Phenylmenthyl
Mg(ClO4)2 ,
CH2Cl2,
ultrasound, 84%
Me
Me
Me
O
2. Results and discussion
Me
Me
O
Me
The synthesis of 1-aminocyclopentane-1,2,4-tricarboxylic
acids was performed starting from norbornene derivatives
exo-5 and endo-6 obtained by reacting aminoacrylates 3
and cyclopentadiene 4 (Scheme 3). (ꢀ)-8-Phenylmenthyl
acrylate 3 is a known compound, which can be obtained
in 47% yield, according to the literature.8 To improve its
yield, a new efficient protocol was adopted, that is, by
reacting 2-acetamidoacrylic acid 1 with dicyclohexylcarbo-
diimide (DCC) in dichloromethane under an inert atmo-
sphere. The corresponding 4-methyleneoxazolone 2 was
obtained. It is an unstable compound, very sensitive to
moisture. For this reason, after filtration of the
dicyclohexylurea under a nitrogen atmosphere and solvent
elimination, oxazolone 2 was immediately reacted, in
refluxing benzene, with (ꢀ)-8-phenylmenthol in the pres-
ence of bis-(dibutylchlorotin)oxide as catalyst. Chiral acry-
late 3 was obtained in an excellent yield (98%) (Scheme 2).
O
O
+
NHCOMe
NHCOMe
B
A
RO2C
NHCOMe
CO2R
+
MeCONH
(+)-(1R,2S,4R)-endo-6
(-)-(1S,2S,4S)-exo-5
KOH, EtOH
Δ, then H3O+
79%
The asymmetric synthesis of the new cycloadducts exo-5
and endo-6 was carried out by starting from enantiopure
acrylate 3 performing the Diels–Alder reaction in dichloro-
methane as the solvent, Mg(ClO4)2 (0.3 equiv) as the cata-
lyst and with ultrasound (14 h) (Scheme 3). A mixture of
exo-5 and endo-6 (84%) was obtained in 83:17 ratio and
with high diastereoselectivity for each exo (de 97%) and
endo (de 96%) couple of diastereomers (HPLC analysis).
Pure compounds exo-5 (de 99%) and endo-6 (de 99%) were
isolated by chromatographic separation and crystallization.
HO2C
MeCONH
(-)-(1S,2S,4S)-exo-7
Scheme 3.
As a confirmation of the stereochemistry assigned to the
cycloadducts, a significative positive Overhauser effect
(Noesy experiments) was observed between the NH and
both H-3endo and H-6 in the exo-adduct, and between the
NH and H-7s in the endo-compound.
The structure of cycloadducts exo-5 and endo-6 was deter-
mined by NMR experiments (1H, 13C, COSY, NOESY
NMRs). 1H NMR spectra revealed differences between
the two diastereomers: typical signals at 5.94–5.89 (m,
H-6), 6.37–6.33 (m, H-5), 2.84 (m, H-4, H-1), 2.60 (dd,
H-3exo), 1.15 (dd, H-3endo), 1.78 (m, H-7s), 1.38 (m, H-7x),
4.88 (NH), and 1.76 (MeCO) are present for the exo-ad-
duct. Signals at 5.78–5.74 (m, H-6), 6.36–6.32 (m, H-5),
2.90 (br s, H-4), 1.76 (dd, H-3exo), 2.22 (dd, H-3endo), 2.56
(m, H-1), 1.67 (m, H-7s), 1.50 (m, H-7x), 5.42 (NH), and
1.93 (MeCO) characterize the spectrum of the endo adduct.
The absolute configuration of all the stereocenters in com-
pound exo-5 was assigned indirectly by the hydrolysis of
the (ꢀ)-8-phenylmenthyl ester function to the correspond-
ing acid (Scheme 3). The known9 (ꢀ)-2-acetylamino-bicy-
clo[2.2.1]hept-5-ene-2-carboxylic acid exo-7 was obtained,
Me
Ph
Me
O
O
Me
O
O
N
2
CO2H
NHCOMe
R*OH, cat.
DCC
Me
CH2Cl2
r.t.
benzene
Δ, 98%
NHCOMe
1
3
Scheme 2.

1432
F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 1430–1436
which is characterized by the (1S,2S,4S)-configuration
(Scheme 3).
An analogous protocol was followed for the deprotection
of 9 (Scheme 5). When 9 was hydrolyzed under basic con-
ditions, amino acid C was first formed which was then
transformed into anhydride (+)-(3aS,5R,6aS)-12 (88%)
when warming during the work-up. The deprotection of
the nitrogen atom under acid conditions gave compound
(+)-(3aS,5R,6aS)-13 (95%). The formation of the anhy-
dride can be ascribed to the cis relationship between the
two carboxylic groups at C-1 and C-2 (intermediate C).
The stereochemical outcome of this reaction showed that the
diene attacked the dienophile on the less hindered Si-face
(intermediates A and B), which is in agreement with the
results observed for the synthesis of the analogous (ꢀ)-men-
thyl10 or (ꢀ)-8-phenylmenthyl derivatives.11 Accordingly,
the stereochemistry assigned to the endo adduct (+)-6 is
1R,2S,4R.
The structure of 12 was confirmed by NMR. The H-6a pro-
ton resonates at d 3.20 (dd, J 7.6, 9.8). Signals at 3.07–2.90
(H-5), 2.57 (dd, J 9.2, 13.6, H-4), 2.39–2.11 (H-4 and H-6),
and 1.88 (Me) d are present. The 13C NMR spectrum re-
vealed the presence of signals at a lower field with respect
to the ester 9 (d 180.0, 178.1, 176.5, 175.5, 67.6, 55.0,
43.2, 40.5, 33.9, 24.2).
Compounds exo-5 and endo-6 were the key reagents for the
preparation of enantiopure diastereomeric 1-aminocyclo-
pentane-1,2,4-tricarboxylic acids 8 and 9, respectively. This
synthetic target was achieved by oxidative cleavage of the
double bond of the norbornene ring assuring stereochemi-
cal control of the three carboxylic functions.
Compound 5 was treated with an aqueous solution of
potassium permanganate (3.3 equiv) at 0 ꢁC in acetone.
The exothermic reaction gave the tricarboxylic acid deriva-
tive (ꢀ)-(1S,2R,4S)-8, which was isolated in good yield
(81%) (Scheme 4).
The formation of the anhydride was confirmed by IR spec-
troscopy of compounds 13ÆHCl in which an absorption at
1713 cmꢀ1 was present, corresponding to the carbonyl of
an anhydride function. As expected, compound 13 was
very hygroscopic. When a sample of 13 was not stored in
a dry atmosphere and the IR spectrum then recovered, a
new absorption at 1594 cmꢀ1 was present instead of that
at 1713 cmꢀ1, the same absorbtion observed in the IR spec-
trum of diastereomer 11. We can conclude that the forma-
tion of anhydride 13 or of tricarboxylic acid 14 (Scheme 5)
is strictly dependent on the presence or absence of
moisture.
The same protocol was adopted starting from norbornene
endo-6. Enantiopure compound (ꢀ)-(1S,2S,4R)-9 (78%)
was isolated (Scheme 5).
In both cases, a single diastereomer was obtained contain-
ing three stereocenters. Starting from exo-5, compound 8,
having the 2,4-cis-carboxylic groups trans to the 1-carbox-
ylic group, was obtained. Starting from endo-6, the cis rela-
tionship of the three carboxylic groups in 9 was assured.
As further confirmation of the presence of the anhydride
function, compound 13 was treated with methanol in the
presence of silica gel to give monomethoxy ester 15 (78%)
(Scheme 5). The reaction is regioselective with only the car-
boxylic group at C-2 esterified (see below spectroscopic
data).
The hydrolysis of the ester function was achieved under
basic conditions. Acid (ꢀ)-(1S,2R,4S)-10 (80%) was obtained
by hydrolyzing (ꢀ)-8-phenylmenthyl ester 8 using KOH in
ethanol at reflux (2 h). Subsequent hydrolysis of the amido
function under acidic conditions (6 M HCl, reflux, 14 h)
gave diastereomer (+)-(1S,2R,4S)-11 in 83% yield (Scheme
4).
The structure of all compounds was confirmed by analyti-
cal and spectroscopic data (1H, 13C NMR, COSY, C/H
1
Hetcor). Some examples are detailed. The H NMR spec-
trum of amino acid 11ÆHCl showed signals at 3.22 (dd, J
12.8, 8.9, H-2), 3.03–2.95 (m, H-4), 2.65–2.55 (m, H-3),
2.29 (dd, J 14.8, 10.4, H-5), 2.08 (dd, J 14.8, 3.3, H-50),
and 1.89–1.78 (m, H-30) d. The assigned stereochemistry
was further confirmed by a NOESY experiment which re-
vealed a positive Overhauser effect between H-3 at low field
and H-2 and H-4 and H-3/H-5 (2.29 d). In particular, the
NOE effect between H-2 and H-4 confirms the cis relation-
ship between carboxylic groups at C-2 and C-4.
CO2H
RO2C
RO2C
KMnO4, acetone
MeCONH
0˚C, 81%
MeCONH
CO2H
(-)-(1S,2S,4S)-exo-5
(-)-(1S,2R,4S)-8
R = 8-(-)-Phenylmenthyl
The 1H NMR of 15 showed signals associated with a
methyl group (d 3.69), H-2 (d 3.26; dd, J 11.3, 8.0), H-4
(d 3.23–3.13; m), H-5 (d 2.58; dd, J 14.7, 9.1), H-50 (d
2.33; dd, J 14.4, 9.2), and H-3 (d 2.50–2.38; m). As shown
by a Noesy experiment, a cis relationship was found
between protons at 3.26, 3.18, 2.33 d, thus confirming the
assigned stereochemistry. Carbon atoms resonate at 177.8
(CO2H-4), 174.5 (CO2H-1), 173.2 (CO2Me-2), 66.4 (C-1),
52.7 (OMe), 52.2 (C-2), 41.2 (C-4), 39.1 (C-5), 31.6 (C-3).
An HMBC experiment assured the regiochemistry of the
esterification reaction. In fact, correlations were observed
1. KOH, EtOH, Δ
2. H3O+, 80%
CO2H
CO2H
HO2C
HO2C
6M HCl, Δ
MeCONH
83%
CO2H
NH2
CO2H
(-)-(1S,2R,4S)-10
(+)-(1S,2R,4S)-11
Scheme 4.

F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 1430–1436
1433
CO2H
NHCOMe
CO2R
CO2R
KMnO4, acetone
0˚C, 78%
NHCOMe
HO2C
HO2C
HO2C
(+)-(1R,2S,4R)-endo-6
R = 8-(-)-Phenylmenthyl
(-)-(1S,2S,4R)-9
1. KOH, EtOH, Δ
2. H3O+, 88%
O
6a
CO2H
O
CO2H
3a
5
O
NHCOMe
NHCOMe
HO2C
C
(+)-(3aS,5R,6aS)-12
6M HCl, Δ
95%
O
CO2H
O
H2O
CO2H
NH2
O
NH2
HO2C
(+)-(3aS,5R,6aS)-13
(+)-(1S,2S,4R)-14
SiO2, MeOH
78%
CO2Me
CO2H
NH2
HO2C
(+)-(1S,2S,4R) -15
Scheme 5.
between the carbonyl function of the ester group and the
H-2 and H-3 protons but not with H-5 protons.
4. Experimental
4.1. General
3. Conclusion
Mps were determined using a Buchi 510 (capillary) appara-
¨
tus. 1H NMR spectra were recorded with an AVANCE 500
1
In conclusion, two new diastereomeric 1-aminocyclopen-
tane-1,2,4-tricarboxylic acids of biological interest were
prepared through an efficient synthetic procedure, consist-
ing of three steps, that is, the Diels–Alder cycloaddition
reaction, the oxidation of a double bond, and the deprotec-
tion of the amino acid function. The regiochemical and ste-
reochemical control of three carboxylic groups, that is, two
2,4-cis carboxylic groups trans to 1-carboxylic group and
all cis tricarboxylic groups, was carried out easily and
safely, starting from exo- and endo-norbornene derivatives.
Each diastereomeric 1-aminocyclopentane-1,2,4-tricarbox-
ylic acid was prepared in an enantiopure form starting
from norbornene derivatives obtained by the way of a very
efficient asymmetric synthesis.
Bruker at 500 MHz for H NMR and 100 MHz for 13C
NMR. Chemical shifts, relative to TMS as internal stan-
dard, are given in d values. J values are given in Hertz.
TLC: ready-to-use silica gel plates. Column chromatogra-
phy: silica gel [Kieselgel 60–70 230 ASTM (Merck)] with
the eluant indicated. IR spectra were taken with a Per-
kin–Elmer 1725X FT-IR spectrophotometer. [a]D were
measured with a Perkin–Elmer MODEL343 Plus Polari-
meter. DOWEX 50WX 4-50 and Dowex 1 · 4–400 column
ion-exchange resins were used.
4.1.1. 8-(ꢀ)-Phenylmenthyl 2-acetylaminoacrylate, (ꢀ)-
3. Operating under a nitrogen atmosphere, to a stirred
suspension of acrylate 1 (2.22 g, 17.2 mmol) in anhydrous

1434
F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 1430–1436
CH2Cl2 (80 mL), DCC (3.55 g, 17.2 mmol) was added and
the reaction mixture stirred at room temperature. After 2 h,
the reaction mixture was cooled at 0 ꢁC and quickly filtered
under a nitrogen atmosphere. The resulting solution was
evaporated to give oxazolone 2 as a yellow oil. Operating
in a screw-cap tube, to a solution of (ꢀ)-8-phenylmenthol
(2.40 g, 10.3 mmol) and bis(dibutylchlorotin)oxide (1.3 g,
2.35 mmol) in dry benzene (30 mL), compound 2, dissolved
in dry benzene (20 mL), was added in two portions within
24 h. The reaction mixture was stirred and then heated for
36 h at reflux. After solvent evaporation, the crude reaction
mixture was purified by flash chromatography on silica gel
(cyclohexane/EtOAc, 3:1) to afford pure 3 (3.50 g, 98%) as
a yellow oil.
(CDCl3): d 172.2, 170.2, 152.4, 141.0, 130.3, 128.2, 125.9,
125.2, 77.0, 64.7, 52.2, 50.0, 48.7, 43.0, 41.3, 40.1, 39.3,
35.0, 31.6, 27.4, 27.3, 26.7, 23.4, 22.0. Anal. Calcd for
C26H35NO3: C, 76.25; H, 8.61; N, 3.42. Found: C, 76.23;
H, 8.63; N, 3.40.
4.2.3. (ꢀ)-(1S,2S,4S)-2-Acetylamino-bicyclo[2.2.1]hept-5-
ene-2-carboxylic acid, (ꢀ)-7. Operating in a screw-cap
tube, to a stirred solution of (ꢀ)-exo-5 (1.06 g, 2.6 mmol)
in EtOH (5 mL, 95%), KOH (292 mg, 5.2 mmol) was
added. The reaction mixture was stirred and heated at
110 ꢁC for 2 h. After solvent evaporation the crude mate-
rial was dissolved in water and extracted with Et2O
(3 · 10 mL). The aqueous layer was separated and then
acidified to pH 5 with 2 N HCl. A solid was separated, fil-
tered, washed with cold water, and dried. Acid (ꢀ)-exo-7
4.1.2. 2-Methyl-4-methylene-5(4H)-oxazolone, 2. Crude
compound. IR (Nujol) 1820, 1640 cmꢀ1; 1H NMR (CDCl3)
(400 mg, 79%) was isolated as colorless crystals. Mp
25
d 6.04 (s, 1H), 5.94 (s, 1H), 2.17 (s, 3H). Compound 3:
225 ꢁC (EtOH); ½aꢁD ¼ ꢀ118 (c 0.3, CHCl3). Lit.:
25
25
½aꢁD ¼ ꢀ64:5 (c 0.5, CHCl3); IR (Nujol) 3400, 3360,
½aꢁD ¼ ꢀ106 (c 1.2, MeOH).9 Spetroscopic data are in
1
1693 cmꢀ1; H NMR (CDCl3) d 7.38–7.02 (m, 5H), 6.27
agreement with the reported data.10
(s, 1H), 5.29 (s, 1H), 5.00–4.87 (m, 1H), 2.17–2.10 (m,
1H), 2.05 (s, 3H), 1.95–0.81 (m, 8H), 1.30 (s, 3H), 1.21 (s,
3H), 0.88 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3) d
168.5, 162.9, 151.3, 130.8, 128.3, 125.4, 125.2, 109.1, 76.6,
50.4, 41.5, 39.6, 34.5, 31.4, 28.1, 26.6, 25.0, 24.7, 21.7.
4.3. General procedure for the oxidation reaction
A solution of pure cycloadduct (ꢀ)-exo-5 or (+)-endo-6
(290 mg, 0.71 mmol) in acetone (10 mL) was added at
0 ꢁC under stirring to a mixture of potassium permanga-
nate (370 mg, 2.34 mmol) in water (2 mL). The tempera-
ture was kept below 5 ꢁC during the addition and then
allowed to rise at 25 ꢁC. After 3 h, Na2S2O5 (444 mg,
2.34 mmol) was added and the mixture stirred for an addi-
tional 20 min. The solution was carefully acidified to pH 2
with HCl (37%). The reaction mixture was extracted with
AcOEt (3 · 10 mL). The combined organic layers were
dried over Na2SO4 and evaporated to give a crude solid,
which was purified by crystallization giving (ꢀ)-8
(270 mg, 81%) and (ꢀ)-9 (260 mg, 78%), respectively, as
white solids.
4.2. Cycloaddition reaction
Operating under a nitrogen atmosphere, to a stirred solu-
tion of acrylate 3 (3.65 g, 10.3 mmol) in anhydrous CH2Cl2
(100 mL), freshly distilled cyclopentadiene 4 (3.5 mL,
42 mmol) and MgClO4 (0.7 g, 3.14 mmol) were added.
The reaction was sonicated for 14 h. After solvent evapora-
tion, the reaction mixture was chromatographed on flash
silica gel (cyclohexane/AcOEt, 1:1). Pure exo-5 (2.77 g,
65%), a mixture of exo-5/endo-6 (0.25 g, 6%) and pure
endo-6 (0.56 g, 13%) were isolated and analyzed by HPLC
(Phenomenex LUNA C18 column: 250 · 4.6 mm; MeCN/
H2O, 7:3; T = 30 ꢁC, flow = 0.8 mL/min, k = 254).
4.3.1. (1S,2R,4S)-(ꢀ)-8-Phenylmenthyl 1-acetylaminocyclo-
pentane-1,2,4-tricarboxylate,
(ꢀ)-8. Mp
188–189 ꢁC
25
4.2.1. (1S,2S,4S)-(ꢀ)-8-Phenylmenthyl 2-acetylamino-bicy-
(CHCl3). ½aꢁD ¼ ꢀ41:4 (c 0.9, MeOH); IR (Nujol) 3344,
clo[2.2.1]hept-5-ene-2-carboxylate, (ꢀ)-exo-5. Mp 188–
3192, 1721, 1620 cmꢀ1 1H NMR (acetone-d6) d 11.50–
;
25
189 ꢁC (acetone). ½aꢁD ¼ ꢀ49:7 (c 0.8, CHCl3); IR (Nujol)
9.80 (br s, 2H, exch.), 7.42–7.10 (m, 5H), 4.87–4.74 (m,
1H), 3.22 (dd, J 8.8, 8.4, 1H), 3.01–2.89 (m, 2H), 2.69
(dd, J 13.6, 6.6, 1H), 2.51–2.36 (m, 2H), 2.09–1.94 (m,
4H), 1.84 (s, 3H), 1.55–1.50 (m, 2H), 1.41 (s, 3H), 1.28 (s,
3H), 1.10–0.75 (m, 2H), 0.84 (d, J 6.3, 3H); 13C NMR (ace-
tone-d6) d 175.2, 173.7, 170.6, 169.6, 150.9, 128.2, 126.0,
125.4, 76.7, 67.1, 49.6, 49.5, 41.0, 40.3, 39.9, 38.1, 34.5,
31.7, 31.5, 30.4, 27.5, 23.5, 22.3, 21.4. Anal. Calcd for
C26H35NO7: C, 65.94; H, 7.45; N, 2.96. Found: C, 65.82;
H, 7.40; N, 2.73.
cmꢀ1 3390, 1702, 1677; 1H NMR (CDCl3) d 7.42–7.15
(m, 5H), 6.37–6.33 (m, 1H), 5.94–5.89 (m, 1H), 4.88 (s,
1H, exch.), 4.76–4.64 (m, 1H), 2.84 (br s, 2H), 2.60 (dd, J
12.8, 3.8, 1H), 2.20–2.00 (m, 2H), 1.78–0.81 (m, 11H),
1.76 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H), 0.86 (d,
J = 6.6 Hz, 3H); 13C NMR (CDCl3) d 173.6, 169.9,
152.9, 142.1, 132.0, 128.3, 126.0, 124.9, 77.0, 65.6, 50.4,
50.0, 47.2, 42.9, 41.0, 40.2, 39.9, 35.0, 31.6, 28.6, 27.1,
25.3, 23.2, 22.0. Anal. Calcd for C26H35NO3: C, 76.25; H,
8.61; N, 3.42. Found: C, 76.20; H, 8.64; N, 3.39.
4.3.2. (1S,2S,4R)-(ꢀ)-8-Phenylmenthyl 1-acetylaminocyc-
4.2.2. (1R,2S,4R)-(ꢀ)-8-Phenylmenthyl 2-acetylamino-bicy-
lopentan-1,2,4-tricarboxylate, (ꢀ)-9. Mp 185–187 ꢁC
25
clo[2.2.1]hept-5-ene-2-carboxylate, (+)-endo-6. Mp 230 ꢁC
(Et2O); ½aꢁD ¼ ꢀ3:7 (c 0.8, CH3OH); IR (Nujol) 3343,
25
1
(acetone). ½aꢁD ¼ þ79:6 (c 0.6, CHCl3); IR (Nujol) cmꢀ1
1722, 1625 cmꢀ1; H NMR (CDCl3) d 7.40–7.03 (m, 5H),
1
3239, 1731, 1636; H NMR (CDCl3) d 7.39–7.15 (m, 5H),
6.72 (s, 1H, exch.), 5.08–4.95 (m, 1H), 3.76–3.55 (m, 1H),
2.83 (br s, 1H), 2.79 (br s, 1H), 2.35–1.85 (m, 6H), 1.99
(s, 3H), 1.75–0.80 (m, 4H), 1.32 (s, 3H), 1.20 (s, 3H), 0.83
(d, J 6.6, 3H); 13C NMR (acetone-d6) d 173.9, 172.1,
170.7, 170.4, 150.6, 128.2, 125.9, 125.6, 78.1, 67.0, 54.3,
6.36–6.32 (m, 1H), 5.78–5.74 (m, 1H), 5.40 (s, 1H, exch.),
4.71–4.59 (m, 1H), 2.90 (br s, 1H), 2.56 (br s, 1H), 2.24–
1.96 (m, 3H), 1.91 (s, 3H), 1.77–0.70 (m, 11H), 1.37 (s,
3H), 1.19 (s, 3H), 0.84 (d, J = 6.6 Hz, 3H); 13C NMR

F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 1430–1436
1435
50.4, 41.5, 41.0, 40.8, 40.4, 34.4, 33.0, 31.5, 31.0, 27.7, 22.8,
22.4, 21.4; Anal. Calcd for C26H35NO7: C, 65.94; H, 7.45;
N, 2.96. Found: C, 65.90; H, 7.41; N, 2.76. m/z 496.4
[M+23].
1H NMR (D2O) d 3.20 (dd, J 7.6, 9.8, 1H), 3.07–2.90 (m,
1H), 2.57 (dd, J 9.2, 13.6, 1H), 2.39–2.11 (m, 3H), 1.88
(s, 3H); 13C NMR d (D2O) 180.0, 178.1, 176.5, 175.5,
67.6, 55.0, 43.2, 40.5, 33.9, 24.2. Anal. Calcd for
C10H11NO6: C, 49.80; H, 4.60; N, 5.81. Found: C, 49.48;
H, 4.75; N, 5.67.
4.3.3. (1S,2R,4S)-1-Acetylaminocyclopentane-1,2,4-tricar-
boxylic acid, (ꢀ)-10. Operating in a screw-cap tube,
KOH (107 mg, 1.9 mmol) was added to a solution of (ꢀ)-
8 (150 mg, 0.32 mmol) in EtOH (95%, 3 mL) and the reac-
tion mixture was heated at 120 ꢁC under stirring for 24 h.
After removal of the solvent, the residue was dissolved in
degassed water (15 mL) and extracted with Et2O
(3 · 10 mL). The aqueous layer was adjusted to pH 9,
and the solution deposited on a Dowex 1 · 4–400 column
(AcOꢀ, 200–400 mesh, 1 · 10 cm). The resin was rinsed
with boiled water, and the tricarboxylic acid was eluted
with 2 M AcOH. Evaporation of AcOH solution gave
4.3.6. (3aS,5R,6aS)-3a-Amino-1,3-dioxo-hexahydro-cyclo-
penta[c]furan-5-carboxylic acid, (+)-13. Operating in a
screw-cap tube, a solution of (+)-12 (120 mg, 0.46 mmol)
in 6 M HCl (3 mL) was stirred and heated at 120 ꢁC for
14 h. HCl was removed by evaporation and the crude
material dissolved in water (10 mL). The resulting solution
was adjusted to pH 4 with 1 M NaOH and deposited on a
Dowex 50 · 4 column (H+, 20–50 mesh, 1 · 10 cm). The re-
sin was rinsed with water and the amino acid was eluted
with aqueous NH4OH (0.5 M). Ninhydrin positive frac-
tions were pooled and evaporated to give (+)-13 (95 mg,
(ꢀ)-10 (67 mg, 80%) as a white solid. Mp 207–208 ꢁC
25
(THF/AcOEt). ½aꢁD ¼ ꢀ63:3 (c 0.5, MeOH); IR (Nujol)
95%) as a solid. TLC CH2Cl2/MeOH/NH4OH (15%) =
25
3320, 1743, 1720, 1692, 1600 cmꢀ1
;
1H NMR (D2O) d
5:3:0.9. ½aꢁD ¼ þ6:7 (c 0.25, H2O). 1H NMR d (D2O)
3.53–3.46 (m, 1H), 3.06–2.88 (m, 1H), 2.48–2.16 (m, 4H),
1.83 (s, 3H); 13C NMR d (D2O) 178.8, 176.5, 175.3,
174.3, 67.2, 49.4, 39.7, 38.1, 31.3, 21.7. Anal. Calcd for
C10H13NO7: C, 46.34; H, 5.06; N, 5.40. Found: C, 46.25;
H, 5.15; N, 5.33.
3.00–2.70 (m, 2H), 2.40–1.90 (m, 4H); 13C NMR d (D2O)
181.3, 178.0 (br s), 175.4 (br s), 66.1, 54.6, 43.3, 38.4,
32.8. EI: m/z 217 (43%), 199 (30%); LCQ: m/z 216 [Mꢀ]
(100%), 198 (15%). Compound 13ÆHCl: IR (Nujol) 3600–
1
3150, 1713, 1594 cmꢀ1; H NMR d (D2O) 3.30–3.00 (m,
2H), 2.65–2.21 (m, 4H). Compound 14: IR (KBr) 3418,
4.3.4. (1S,2R,4S)-1-Aminocyclopentane-1,2,4-tricarboxylic
acid, (+)-11. Operating in a screw-cap tube, a solution
of (ꢀ)-10 (94 mg, 0.36 mmol) in 6 M HCl (1 mL) was stir-
red and heated at 120 ꢁC for 14 h. HCl was removed by
evaporation and the crude material dissolved in water
(10 mL). The resulting solution was adjusted to pH 4 with
1 M NaOH and deposited on a Dowex 50 · 4 column (H+,
20–50 mesh, 1 · 10 cm). The resin was rinsed with water
and the amino acid eluted with aqueous NH4OH (0.5 M).
Ninhydrin positive fractions were pooled and evaporated
3195, 1594 cmꢀ1
.
4.3.7. (1S,2S,4R)-1-Aminocyclopentan-1,2,4-tricarboxylic
acid 2-methyl ester, (+)-15. Silica gel (50 mg) was added
to a stirred solution of (+)-13 (200 mg, 1 mmol) in MeOH
(5 mL) and the mixture was stirred overnight at room
temperature. (TLC: CH2Cl2/MeOH/NH4OH(33%)/H2O,
5:3:0.3:0.6.) After filtration of the silica gel, the solution
was evaporated under reduced pressure. Crystallization of
the crude material (MeOH/H2O) afforded pure compound
to give (+)-11 (65 mg, 83%) as a solid. TLC CH2Cl2/
(+)-15 (180 mg, 78%) as a solid. Mp 265 ꢁC (MeOH/H2O).
25
25
MeOH/NH4OH (15%) = 5:3:0.9. ½aꢁD ¼ þ3:1 (c 0.26,
½aꢁD ¼ þ14 (c 0.20, H2O); IR (Nujol) 3343, 1790,
1
1
H2O). IR (Nujol) 3600–2500, 1598 cmꢀ1; H NMR (D2O)
1425 cmꢀ1; H NMR (D2O) d 3.69 (s, 3H), 3.26 (dd, J
d 3.22 (dd, J 12.8, 8.9, 1H), 3.03–2.95 (m, 1H), 2.65–2.55
(m, 1H), 2.29 (dd, J 14.8, 10.4, 1H), 2.08 (dd, J 14.8, 3.3,
1H), 1.89–1.78 (m, 1H). 13C NMR d (D2O) 185.0, 178.9,
175.7, 68.1, 52.5, 43.8, 39.9, 33.8. Anal. Calcd for
C8H11NO6: C, 44.24; H, 5.11; N, 6.45. Found: C, 43.85;
11.3, 8.0, 1H), 3.23–3.13 (m, 1H), 2.58 (dd, J 14.7, 9.1, 1H),
2.50–2.38 (m, 2H), 2.33 (dd, J 14.4, 9.2, 1H); 13C NMR
(D2O) d 177.8, 174.5, 173.2, 66.4, 52.7, 52.2, 41.2, 39.1,
31.6. Anal. Calcd for C9H13NO6: C, 46.75; H, 5.67; N,
6.06. Found: C, 46.51; H, 5.71; N, 5.88. m/z [M+] = 232.1.
1
H, 5.54; N, 6.13; m/z 218.1 [M+]. Compound 11ÆHCl: H
NMR (D2O/DCl) d 3.62 (dd, J 12.4, 8.0, 1H), 3.20–3.00
(m, 1H), 2.62–2.40 (m, 2H), 2.26–1.98 (m, 2H).
Acknowledgements
4.3.5. (3aS,5R,6aS)-3a-N-Acetylamino-1,3-dioxo-hexahy-
dro-cyclopenta[c]furan-5-carboxylic acid, (+)-12. Operat-
ing in a screw-cap tube, KOH (185 mg, 3.3 mmol) was
added to a solution of (ꢀ)-9 (263 mg, 0.55 mmol) in EtOH
(4 mL, 95%) and the reaction heated at 120 ꢁC for 48 h un-
der stirring. After removal of the solvent, the residue was
dissolved in degassed water (15 mL) and extracted with
Et2O (3 · 10 mL). The aqueous layer was adjusted to
pH 9 and the solution deposited on a Dowex 1 · 4–400 col-
umn (AcOꢀ, 200–400 mesh, 1 · 10 cm). The resin was
rinsed with degassed water, and the tricarboxylic acid
We thank CARIPLO FOUNDATION for financial
support.
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