Enantioselective synthesis of epimeric cis-3-carboxycyclopentylglycines

Article abstract of DOI:10.1016/j.tetasy.2005.11.011

Two epimeric chiral cyclopentylglycines (-)-16 and (+)-17, functionalised with a carboxy group cis to the amino acid group, were prepared starting from chiral 2-amino-3-oxo-norbornanecarboxylic acid derivative exo-9 by combining two classical reactions such as the Diels-Alder and retro-Claisen reactions. Compounds 16 and 17 are non-proteinogenic amino acids of biological interest containing conformational constraints in which the skeletons of both 2-aminoadipic acid and 2-aminopimelic acid are included.

Full text of DOI:10.1016/j.tetasy.2005.11.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 61–67
Enantioselective synthesis of epimeric
cis-3-carboxycyclopentylglycines
Francesco Caputo,a Francesca Clerici,a Maria Luisa Gelmi,a
Sara Pellegrinoa,* and Tullio Pilatib
a
`
`
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, Universita di Milano, Via Venezian 21, I-20133 Milano, Italy
b
`
CNR Centro Studio delle Relazioni tra Struttura e Reattivita Chimica, via Golgi 19, Milano, Italy
Received 11 October 2005; accepted 10 November 2005
Available online 5 December 2005
Abstract—Two epimeric chiral cyclopentylglycines (ꢀ)-16 and (+)-17, functionalised with a carboxy group cis to the amino acid
group, were prepared starting from chiral 2-amino-3-oxo-norbornanecarboxylic acid derivative exo-9 by combining two classical
reactions such as the Diels–Alder and retro-Claisen reactions. Compounds 16 and 17 are non-proteinogenic amino acids of biolo-
gical interest containing conformational constraints in which the skeletons of both 2-aminoadipic acid and 2-aminopimelic acid are
included.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
cyclopentanecarboxylic acids (ꢀ)-16 and (+)-17, respec-
tively. The key reagent for our synthesis is the new chiral
2-amino-3-oxo-norbornanecarboxylic acid derivative
exo-9, which was obtained from the Diels–Alder cyclo-
adduct exo-5 of acrylate 3 and cyclopentadiene 4.
The use of the (ꢀ)-8-phenylmenthyl group in acrylate
3 as chiral auxiliary allowed us to control the exo/endo
selectivity in the Diels–Alder reaction, increasing the
amount of exo adduct, the true starting material for
the preparation of 16 and 17. The facial diasteroselectiv-
ity was also improved and compound exo-5 was
obtained with an excellent diastereomeric excess (99%).
Cyclopentylglycines functionalised with
a carboxy
group at the 3-position of the cyclopentyl ring are
non-proteinogenic amino acids of biological interest
containing conformational constraints in which the skel-
etons of both 2-aminoadipic acid and 2-aminopimelic
acid, two natural amino acids of biological importance,
are included. The former amino acid is a constituent of
penicillin N1 and is an important analogue of glutamic
acid.2 The second amino acid is produced by Asplenium
unilaterale3 and was used for the preparation of
small peptides characterised by antibacterial activity.4
Recently, heterosubstituted 3-carboxycyclopentylglycines
were prepared and their biological activity toward neuro-
aminidase evaluated.5 The preparation of two racemic
and epimeric 3-carboxycyclopentylglycine derivatives
was reported by us.6 In view of the potential biological
interest in these compounds and their possible use for
the preparation of modified bioactive peptidomimetics
and by considering that the chirality of amino acids is
of essential importance in biological interactions, we
herein report on the chiral synthesis of the (1S,3R,
10R)-epimer and (1S,3R,10S)-3-(amino-carboxymethyl)-
The above amino acids were obtained from (+)-exo-9 by
way of a retro-Claisen reaction that allowed us to con-
trol the cis-relationship between the two carbon residues
on the cyclopentyl ring. The absolute configuration of
each stereocentre of (ꢀ)-16 and (+)-17 was unequivo-
cally assigned by X-ray analysis.
2. Results and discussion
The new (ꢀ)-8-phenylmenthyl derivative exo-5 was pre-
pared from cyclopentadiene 4 and the new chiral syn-
thon (ꢀ)-8-phenylmenthyl 2-benzoylaminoacrylate Z-3
by the way of the Diels–Alder reaction. Acrylate 3 was
*
Corresponding author. Tel.: +39 0250314481; fax: +39
0250314476; e-mail: sara.pellegrino@unimi.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.011

62
F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 61–67
synthesised by reacting oxazolone 1 with (ꢀ)-8-phenyl-
menthol using bis-(dibutylchlorotin) oxide7 as the catal-
yst and operating in toluene at reflux. Ester 2 (85%) was
obtained and protected on the oxygen atom as the car-
bonate. Acrylate 3 was obtained in 93% yield (Scheme
1).
had to be faced. It must be also underlined that
improvement of the yields of the exo adduct is of syn-
thetic relevance, because it is the starting material for
the preparation of the keto compound 9. In fact, as
reported for the corresponding methyl ester,6 it is impos-
sible to deprotect the carbonate function of the endo-
norbornane derivative, thus preventing preparation of
the corresponding keto compound. Concerning the ste-
reochemical outcome of the cycloaddition reaction using
the (ꢀ)-8-phenylmenthyl group, as a chiral auxiliary
with respect to the use of (ꢀ)-menthyl group some
advantages have been obtained because the cycloaddi-
tion reaction (i) is more diastereoselective in terms of
exo/endo selectivity (exo/endo = 7:1) and (ii) proceeds
with a better face diasteroselectivity for each exo (de
99%) and endo (de 94%) couple.
The cycloaddition reaction of 3 with cyclopentadiene 4
was performed using Mg(ClO4)2 as the catalyst and
operating in toluene and with ultrasound (Scheme 1).
1
The H NMR analysis of the crude reaction mixture
showed the presence of the diastereomers of the exo
and endo series in a 7:1 ratio. In principle, the cycload-
dition reaction can afford four diastereomers: two exo
adducts and two endo adducts. HPLC analysis showed
the presence of a main compound (85.5%), correspond-
ing to ester exo-5, as well as a trace amount (0.3%) of the
second exo isomer.
The structure of the two major cycloadducts was con-
firmed by NMR (1H, 13C, COSY, Hetcor reverse exper-
iments) and the configuration by a NOESY experiment.
For compound exo-5, spatial proximity was observed
between H-3 (5.67 d) and the bridge proton at 1.70 d
as well as with H-4 (3.20 d). H-3 (5.30 d) of endo-6
showed spatial proximity both with H-4 (2.96 d) and,
importantly, with the olefinic proton H-5 (6.25 d), thus
confirming its trans-position with respect to the bridge.
As further confirmation of the endo configuration, a
positive Overhauser effect was observed between NH
(6.45 d) and the bridge proton at 2.03 d.
Both endo-isomers were also present (12% and 0.9%,
respectively). The reaction mixture was chromato-
graphed allowing us to isolate the main isomer exo-5
(76%) and compound endo-6 (11%) (pure compounds
according to HPLC analyses). The minor diastereomers
of the exo/endo series were not characterised.
The synthesis of the analogous menthyl derivatives,
which has been previously reported,7 suffered from some
limitations: (i) the exo/endo ratio (7:3) and (ii) the de val-
ues for each couple of exo (de 80%) and endo (de 85%)
compounds were not excellent. Accordingly, difficulties
in the separation and purification of the single isomers
Literature data for the cycloaddition of (ꢀ)-phenylmen-
thyl 2-aminoacrylate8 or acrylate esters9 with butadiene
Me
Me
Ph
Me
Ph
Me
Me
O
O
O
Ph
Me
O
O
Me
Me
(Bu2SnCl)2O
toluene
EtOCOCl/-10 °C
O
CH2Cl2/TEA
Ph
+
NHCOPh
NHCOPh
HO
N
Me
70%
OH
OCO2Et
90%
Me
OH
Z-2
(-)-Z-3
Z-1
Me
Me
Me
Me
Me
O
O
O
O
+
NHCOPh
toluene
Mg(ClO4)2
))), 87%
EtO2CO
NHCOPh
EtO2CO
B
A
Me
R
S
NHCOPh
OCO2Et
R
S
Me
Ph
+
R
O2C
Me
S
Me
S
CO2
R
PhCONH
OCO2Et
Me
Ph
(-)-exo-5
(-)-endo-6
Me
Scheme 1.

F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 61–67
63
and cyclopentadiene, respectively, reported that the
phenyl group of the menthyl substituent has a shielding
effect on the CaRe side of the double bond, thus favour-
ing the addition of the diene on the si face. Based on
these considerations and by comparison of the steric
outcome of the cycloaddition reaction of (ꢀ)-menthyl
2-aminoacrylate derivative and cyclopentadiene (X-ray
analyses are given),7 we were able to assign the
(1S,2R,3S,4R)- and (1R,2R,3S,4S)-absolute configura-
tion at the stereocentres of the norbornene skeleton in
the exo-5 and endo-6 compounds, respectively. The high
face diasteroselectivity observed in the present case can
be ascribed to secondary interactions between the diene
and carbonyl functions of both amide and carbonate
groups (intermediate A), which favour the formation
of the exo cycloadduct 5. Through intermediate B, the
endo compound 6 is formed (Scheme 1).
acids into the corresponding methyl esters. By reacting
10 and 11 with trimethylsilyldiazomethane, a mixture
of methyl esters 12 and 13 was isolated in 91%
yield (Scheme 3). Compounds (+)-12 and (+)-13 were
obtained in their pure forms by semi-preparative HPLC
separation.
As confirmed by NMR data, the cis-configuration of the
carbon groups linked to the cyclopentyl ring was
assured by the mechanism of retro-Claisen reaction.
1
The H NMR spectra of compounds 10 and 11 and of
the corresponding esters (+)-12 and (+)-13 are consis-
tent with those reported in the literature for similar
compounds.6
In order to unequivocally assign the stereochemistry of
the amino acid centre, an X-ray analysis was performed
on compound (+)-12 characterised by the R configura-
tion of C-a (Fig. 1).
The key starting material for the preparation of the epi-
meric 3-carboxy-cyclopentylglycines was the chiral (ꢀ)-
phenylmenthyl 2-benzoylamino-3-oxo-bicylo[2.2.1]hep-
tane-2-carboxylate (+)-exo-9. As depicted in Scheme 2,
compound (+)-exo-9 was prepared in 89% overall yield
starting from exo-5. Compound exo-5 was reduced to
the norbornane derivative (ꢀ)-exo-7. The selective
deprotection of the hydroxy group on C-3 with sodium
carbonate in ethanol at room temperature gave the 3-
hydroxy derivative (ꢀ)-exo-8, which was oxidised to
ketone (+)-exo-9 with pyridinium chlorochromate
(PCC) in dichloromethane.
RO2C
R
PhCONH
Me
R
S
R =
Me
O
(+)-exo-9
Me
Ph
Py/H2O
83%
NHCOPh
RO2C
H
S
R
H
CO2R
NHCOPh
H
H
R
S
R
S
+
b-Keto ester 9 was successfully transformed into a mix-
ture of epimeric cyclopentylglycines 10 and 11 (1:1 ratio,
83%) using a retro-Claisen reaction and operating in
pyridine/H2O (2:1) at reflux (Scheme 3). These com-
pounds could not be separated as such, but the target
compound was obtained by transforming the carboxylic
H
CO2H
H
CO2H
11
10
1. LiOH
MeOH
2. H3O+
Me3SiCHN2
MeOH
91%
62%
NHCOPh
RO2C
H
S
R
H
CO2R
NHCOPh
H
H
R
S
R
S
+
H2, Pd/C
EtOH
RO2C
PhCONH
RO2C
H
CO2Me
(+)-12
H
CO2Me
PhCONH
96%
(+)-13
OCO2Et
OCO2Et
(-)-exo-7
1. LiOH, MeOH
2. H3O+
(-)-exo-5
58%
NHCOPh
HO2C
Na2CO3
EtOH
S
98%
R
H
H
CO2H
NHCOPh
H
H
R
R
S
+
S
RO2C
RO2C
H
CO2H
H
CO2H
PCC
(-)-15
PhCONH
(+)-14
CH2Cl2
95%
PhCONH
O
OH
6 M HCl
85%
6 M HCl
85%
(+)-exo-9
(-)-exo-8
NH3+ Cl-
HO2C
H
S
H
CO2H
NH3+ Cl-
Me
R
H
H
R
S
R
S
+
R =
H
CO2H
(-)-16
CO2H
H
Me
Me
Ph
(+)-17
Scheme 2.
Scheme 3.

64
F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 61–67
The absolute configuration of the three stereocentres
was unequivocally determined.
4. Experimental
Melting points were measured with a Buchi B-540 heat-
¨
ing unit and are uncorrected. NMR spectra were
recorded with an AVANCE 500 Bruker at 500 MHz
1
for H NMR and 100 MHz for 13C NMR. Chemical
shifts, relative to TMS as internal standard, are given
in d values. IR spectra were taken with a Perkin–Elmer
1725X FT-IR spectrophotometer. Optical rotations were
measured with a Perkin–Elmer MODEL343 Plus Polari-
meter. Flash chromatography was performed using a
Biotage Flash+ Chromatography System. Ethanol-free
CH2Cl2 was used in all experiments.
Figure 1. ORTEPIII projection of (+)-12 with the crystallographic
numbering scheme. Ellipsoids at 20% probability level. H atoms not to
scale.
4.1. (ꢀ)-Phenylmenthyl (Z)-2-benzoylamino-3-hydroxy-
acrylate Z-2
Operating under a nitrogen atmosphere, anhydrous oxa-
zolone 1 (3.6 g, 19.0 mmol) was suspended in anhydrous
toluene (30 mL). (ꢀ)-Phenylmenthol (2.7 g, 11.5 mmol)
and bis-(dibutylchlorotin)oxide (1 g, 1.86 mmol) were
added and the mixture refluxed for 24 h (TLC: CH2Cl2/
Et2O, 2:1). The solvent was evaporated and the
crude reaction mixture chromatographed on silica
The hydrolysis of the (ꢀ)-8-phenyl-menthyl ester
group of compounds 12 and 13 required basic condi-
tions. Starting from 13 and operating in MeOH in the
presence of LiOH (4 equiv) at room temperature, a mix-
ture of amides was formed. H NMR analysis showed
the presence of the expected epimer 15, as the major
1
gel (CH2Cl2) to give ester Z-2 (3.4 g, 70%). Mp 195 ꢁC
compound, as well as isomer 14 (4:1, 58% yield) (Scheme
3).
25
(i-Pr2O). ½aꢁD ¼ ꢀ41 (c 1, CHCl3). mmax (Nujol)
3360, 1650 cmꢀ1
;
1H NMR (CDCl3): d 12.00 (d,
J = 12.1 Hz, 1H, exch., OH), 8.24 (br s, 1H, exch.,
NH), 7.90–7.10 (m, 10H, ArH), 6.39 (d, J = 12.1 Hz,
1H, H-3), 5.02–4.89 (m, 1H, OCH), 2.22–2.09 (m, 1H,
CHmenth), 1.94–0.90 (m, 7H, CHmenth and CH2menth),
1.33 (s, 3H, Me), 1.12 (s, 3H, Me), 0.91 (d, J = 6.2 Hz,
3H, Me); 13C NMR (CDCl3): d 166.1, 164.7, 151.6,
147.2, 132.6, 132.3, 128.9, 128.2, 127.3, 125.2, 106.9,
75.8, 50.6, 41.8, 39.5, 34.6, 31.4, 29.0, 26.5, 23.8, 21.8.
Anal. Calcd: C, 74.08; H, 7.41; N, 3.32. Found: C,
74.03; H, 7.44; N, 3.28.
Since epimerisation of the amino acid carbon could
not be avoided when starting from pure compounds,
we planned a direct hydrolysis of a mixture of 10
and 11. Operating under the above reaction conditions,
a mixture of dicarboxylic acids 14 and 15 was ob-
tained (62% yield, 1:1 ratio). These compounds were
separated by a flash column chromatography (see
Section 4).
Finally, the hydrolysis of the amide functionality was
performed under acidic conditions (6 M HCl). 1H
NMR analysis of crude reaction mixtures showed that
epimerisation of the amino acid function did not occur
and pure amino acids (ꢀ)-16 and (+)-17 were isolated
starting from the single epimer (+)-14 and (ꢀ)-15,
respectively.
4.2. (ꢀ)-Phenylmenthyl (Z)-2-benzoylamino-3-ethoxy-
carbonyloxy-acrylate Z-3
Operating under a nitrogen atmosphere, ester 2 (3.4 g,
8.1 mmol) was dissolved in anhydrous CH2Cl2
(60 mL). The solution was cooled to ꢀ10 ꢁC and ethyl
chlorocarbonate (0.8 mL, 8.8 mmol) was added. A solu-
tion of TEA (1.1 mL, 8.8 mmol), dissolved in CH2Cl2
(4 mL), was added dropwise. After 3 h (TLC: cyclohex-
ane/AcOEt, 4:1), the organic layer was washed with HCl
(20 mL, 10%) and dried over Na2SO4. The solvent was
evaporated and the crude reaction mixture crystallised
3. Conclusion
In conclusion, two epimeric chiral 3-carboxycyclopen-
tylglycines (ꢀ)-16 and (+)-17 were successfully pre-
pared using a very efficient protocol consisting in the
synthesis of the chiral 2-amino-3-oxo-norbornanecarb-
oxylic acid derivative exo-9, obtained in 99% de,
through a Diels–Alder reaction followed by its trans-
formation into the above amino acids by the way of
a retro-Claisen reaction. The difficulties related to the
separation, epimerisation of the amino acid stereocen-
tre and deprotection of both ester and amide groups
were overcome and the pure enantiomers isolated.
to give pure compound 3 (3.6 g, 90%). Mp 133 ꢁC (i-
25
Pr2O). ½aꢁD ¼ ꢀ11:2 (c 1, CHCl3). mmax (Nujol) 3580,
1
1780, 1650 cmꢀ1; H NMR (CDCl3): d 7.82–7.05 (m,
10H, ArH), 7.42 (s, 1H, H-3), 6.70 (s, 1H, exch., NH),
5.08–4.95 (m, 1H, OCH), 4.34 (q, J = 7.0 Hz, 2H,
OCH2), 2.22–2.09 (m, 1H, CHmenth), 1.91–0.90 (m, 7H,
CHmenth, CH2menth), 1.38 (t, J = 7.0 Hz, 3H, OCH2Me),
1.35 (s, 3H, Me), 1.22 (s, 3H, Me), 0.90 (d, J = 6.2 Hz,
3H, Me); 13C NMR (CDCl3): d 165.1, 163.4, 152.3,

F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 61–67
65
151.4, 140.5, 134.0, 132.2, 128.8, 128.4, 127.9, 125.6,
125.1, 113.0, 75.8, 66.0, 50.7, 41.8, 39.7, 34.7, 31.6,
29.5, 26.6, 23.6, 22.0, 14.3. Anal. Calcd: C, 70.57; H,
7.15; N, 2.84. Found: C, 70.54; H, 7.17; N, 2.82.
C (10%, 570 mg, 0.5 mmol) as the catalyst at 25 ꢁC
and 1 atm. After 2 h (1H NMR monitoring), the catalyst
was filtered and the solvent eliminated. Pure compound
exo-7 (2.9 g, 96%) was obtained after crystallisation.
25
Mp 135 ꢁC (i-Pr2O). ½aꢁD ¼ ꢀ18 (c 1, CHCl3). mmax (Nu-
1
4.3. (ꢀ)-Phenylmenthyl 2-benzoylamino-3-ethoxycarbon-
yloxy-bicyclo[2.2.1]hept-5-ene-2-carboxylate exo-5 and
endo-6
jol) 3450, 3400, 1738, 1673 cmꢀ1; H NMR (CDCl3): d
7.79–7.07 (m, 10H, ArH), 6.62 (s, 1H, exch., NH),
5.13 (d, J = 4.4 Hz, 1H, H-3), 4.91–4.80 (m, 1H,
OCH), 4.24 (q, J = 7.0 Hz, 2H, OCH2), 3.00 (br s,
1H, H-1), 2.55 (br s, 1H, H-4), 2.27–2.09 (m 1H,
CHmenth), 2.00–1.85 (m, 1H, CHmenth), 1.63 (d,
J = 11.0, 1H, H-7), 1.59–0.73 (m, 11H, H-5, H-6, H-7,
CH2menth), 1.31 (t, J = 7.0 Hz, 3H, OCH2Me), 1.18 (s,
3H, Me), 1.16 (s, 3H, Me), 0.86 (d, J = 6.3 Hz, 3H,
Me); 13C NMR (CDCl3): d 171.4, 167.2, 153.9, 151.4,
134.3, 131.8, 128.8, 128.2, 127.4, 125.9, 125.3, 78.0,
77.5, 64.6, 63.2, 50.3, 43.7, 41.2, 40.2, 40.1, 34.8, 33.8,
31.6, 28.6, 27.5, 25.4, 23.7, 21.0, 19.8, 14.5. Anal. Calcd:
C, 72.75; H, 7.78; N, 2.49. Found: C, 72.79; H, 7.81 N;
2.45.
Operating in a sealed tube, acrylate Z-3 (3.6 g,
7.3 mmol), diene 4 (3 mL, 36 mmol) and Mg(ClO4)2
(1.2 g, 9.9 mmol) were suspended in anhydrous toluene
(65 mL) and the solution sonicated for 36 h (TLC: cyclo-
hexane/AcOEt, 10:1). The crude reaction mixture was
chromatographed on silica gel (cyclohexane/AcOEt,
100:1–5:1) to give two fractions containing pure adducts
exo-5 (3 g, 76%) and endo-6 (430 mg, 11%), respectively,
which were analysed by HPLC (Chiral Cel OD column:
250 · 4.6 mm; hexane/i-PrOH, 90:10; T = 30 ꢁC,
flow = 0.8 mL/min, k = 254 nm).
25
4.3.1. (1S,2R,3S,4R)-exo-5. Oil. ½aꢁD ¼ ꢀ29 (c 1,
4.5. (ꢀ)-Phenylmenthyl (1R,2R,3S,4S)-2-benzoylamino-
3-hydroxy-bicyclo[2.2.1]heptane-2-carboxylate exo-8
CHCl3). mmax (Nujol) 3440, 1750, 1670 cmꢀ1; H NMR
1
(CDCl3): d 7.67–7.09 (m, 10H, ArH), 6.35–6.31 (m,
1H, H-5), 6.25–6.19 (m, 1H, H-6), 6.19 (s, 1H, exch.,
NH), 5.67 (d, J = 3.6 Hz, 1H, H-3), 4.97–4.84 (m, 1H,
OCH), 4.21 (q, J = 7.0 Hz, 2H, OCH2), 3.41 (br s, 1H,
H-1), 3.20 (br s, 1H, H-4), 2.23–2.05 (m, 1H, CHmenth),
2.06–1.96 (m, 1H, CHmenth), 1.70, 1.57 (AB system,
J = 9.9 Hz, 2H, H-7), 1.61–0.77 (m, 6H, CH2menth),
1.27 (t, J = 7.0 Hz, 3H, OCH2Me), 1.27 (s, 3H,
Mementh), 1.20 (s, 3H, Mementh), 0.88 (d, J = 6.2 Hz,
3H, Mementh); 13C NMR (CDCl3): d 171.3, 167.1,
154.1, 151.6, 137.3, 135.9, 134.4, 131.7, 128.7, 128.2,
127.3, 125.9, 125.3, 80.1, 77.8, 66.1, 64.5, 50.2, 49.5,
46.5, 43.8, 41.3, 40.3, 34.9, 31.6, 28.3, 27.5, 25.8, 22.0,
14.4. Anal. Calcd: C, 72.96; H, 7.38; N, 2.50. Found:
C, 73.00; H, 7.33; N, 2.53.
Carbonate exo-7 (2.9 g, 5.17 mmol) was dissolved in
anhydrous EtOH (100 mL) and lyophilised Na2CO3
(841 mg, 7.9 mmol) added. The mixture was stirred at
25 ꢁC for 24 h (TLC: CH2Cl2/Et2O, 10:1). Na2CO3
was filtered over a Celite column and the solvent evap-
orated. After crystallisation of the crude reaction mix-
ture, pure compound exo-8 (2.4 g, 95%) was obtained.
25
Mp 202 ꢁC (i-Pr2O). ½aꢁD ¼ ꢀ12 (c 1, CHCl3). mmax (Nu-
1
jol) 3440, 1750, 1670 cmꢀ1; H NMR (CDCl3): d 7.76–
7.10 (m, 10H, ArH), 6.45 (s, 1H, exch., NH), 4.86–
4.77 (m, 1H, OCH), 4.31 (br s 1H, H-3), 2.73–2.69 (m,
2H, 1 exch., OH and H-1), 2.38 (br s, 1H, H-4), 2.20–
0.80 (m, 14H, H-5, H-6, H-7, CHmenth, CH2menth),
1.25 (s, 3H, Me), 1.15 (s, 3H, Me), 0.90 (d,
J = 6.6 Hz, 3H, Me); 13C NMR (CDCl3): d 172.8,
168.8, 152.1, 134.5, 131.9, 128.7, 128.2, 127.4, 125.8,
125.1, 77.1, 74.3, 63.7, 50.0, 44.3, 41.7, 41.5, 40.0,
34.9, 33.7, 31.6, 27.5, 27.2, 26.5, 24.1, 22.0, 18.7. Anal.
Calcd: C, 76.04; H, 8.03; N, 2.86. Found: C, 76.00; H,
8.07; N, 2.80.
25
4.3.2. (1R,2R,3S,4S)-endo-6. Oil. ½aꢁD ¼ ꢀ20 (c 1,
1
CHCl3). mmax (Nujol) 3470, 1740, 1670 cmꢀ1; H NMR
(CDCl3): d 7.85–7.12 (m, 10H, ArH), 6.45 (s, 1H, exch.,
NH), 6.25 (br s, 2H, H-5, H-6), 5.30 (d, J = 1.4 Hz, 1H,
H-3), 4.85–4.72 (m, 1H, OCH), 4.27–4.09 (m, 2H,
OCH2), 3.01 (br s, 1H, H-1), 2.96 (br s, 1H, H-4),
2.15–2.11 (m, 1H, CHmenth), 2.03, 1.78 (AB system,
J = 10.7 Hz, 2H, H-7), 1.95–1.80 (m, 1H, CHmenth),
1.95–0.70 (m, 6H, CH2menth) 1.28 (s, 3H, Mementh),
1.26 (t, J = 7.0 Hz, 3H, OCH2Me), 1.20 (s, 3H,
Mementh), 0.85 (d, J = 4.2 Hz, 3H, Mementh); 13C NMR
(CDCl3): d 170.1, 167.4, 154.2, 151.6, 137.4, 135.1,
134.7, 131.9, 129.4, 129.3, 128.9, 128.5, 128.3, 127.7,
127.5, 126.1, 125.8, 125.5, 78.8, 77.8, 65.9, 64.6, 50.4,
49.6, 48.7, 46.3, 41.4, 40.5, 35.0, 31.8, 29.6, 27.3, 24.8,
22.1, 14.4. Anal. Calcd: C, 72.96; H, 7.38; N, 2.50.
Found: C, 72.92; H, 7.41; N, 2.48.
4.6. (ꢀ)-Phenylmenthyl (1R,2R,4S)-2-benzoylamino-3-
oxo-bicyclo[2.2.1]heptane-2-carboxylate exo-9
Compound exo-8 (2.4 g, 4.9 mmol) was treated, under a
nitrogen atmosphere, with PCC (6.3 g, 29.4 mmol) in
anhydrous CH2Cl2 (150 mL). The solution was stirred
at room temperature for 2 h (TLC: cyclohexane/AcOEt,
1:1). The reaction mixture was filtered through a silica
gel column (cyclohexane/AcOEt, 1:1). Keto compound
exo-9 (1.6 g, 95%) was obtained and crystallised. Mp
25
128 ꢁC (i-Pr2O). ½aꢁD ¼ þ16 (c 1, CHCl3). mmax (Nujol)
1
3440, 1750, 1670 cmꢀ1; H NMR (CDCl3): d 7.81–7.10
4.4. (ꢀ)-Phenylmenthyl (1R,2R,3S,4S)-2-benzoylamino-
3-ethoxycarbonyloxy-bicyclo[2.2.1]heptane-2- carboxyl-
ate exo-7
(m, 10H, ArH), 6.65 (s, 1H, exch., NH), 5.03–4.90 (m,
1H, OCH), 3.73 (br s, 1H, H-4), 2.74 (d, J = 3.7 Hz,
1H, H-1), 2.22 (d, J = 12.5 Hz, 1H, H-7), 2.03–1.80
(m, 2H, CHmenth), 1.80–0.71 (m, 11H, H-5, H-6, H-7,
CH2menth), 1.27 (s, 3H, Me), 1.20 (s, 3H, Me), 0.86 (d,
J = 6.2 Hz, 3H, Me); 13C NMR (CDCl3): d 210.0,
Compound exo-5 (3.0 g, 5.37 mmol) was suspended in
EtOH (100 mL) and reduced with hydrogen using Pd/

66
F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 61–67
167.6, 166.1, 150.7, 133.7, 132.2, 128.8, 128.3, 127.5,
125.9, 125.5, 78.3, 72.3, 50.5, 48.4, 44.2, 41.8, 40.5,
34.7, 34.6, 31.6, 29.9, 29.7, 27.6, 24.3, 22.3, 21.9. Anal.
Calcd: C, 76.36; H, 7.65; N, 2.87. Found: C, 76.34; H,
7.65; N, 2.85.
data for compound (+)-12 are available (CCDC deposi-
tion number 265248).
4.11. Methyl (1S,3R,10S)-3-(benzoylamino-(ꢀ)-phenyl-
menthoxy carbonyl-methyl)cyclopentanecarboxylate 13
25
4.7. Retro-Claisen reaction of ketone exo-9
Oil. ½aꢁD ¼ þ10 (c 1, CHCl3). mmax (Nujol) 3340, 1730,
1700, 1664 cmꢀ1; H NMR (CDCl3): d 7.84–7.10 (m,
1
Pure ketone exo-9 (1 mmol) was dissolved in pyridine
(3 mL) and H2O (1.5 mL). The reaction mixture was
heated at reflux for 3 h (TLC: CH2Cl2/Et2O, 2:1). The
solvent was evaporated and the residue taken up with
a HCl solution (10%, 10 mL). The aqueous layer was
extracted with a mixture of THF/AcOEt (1:1, 3 · 7 mL).
The organic layer was separated and dried over Na2SO4
to give a mixture of the two diastereomeric amino acid
derivatives 10 and 11 (1:1, 420 mg, 83%). Any attempt
to separate epimers 10 and 11 failed.
10H, ArH), 6.59 (d, J = 8.4 Hz, 1H, exch., NH), 4.87–
4.74 (m, 1H, OCH), 4.19 (dd, J = 8.4, 5.1 Hz, 1H,
CHN), 3.60 (s, 3H, OMe), 2.75–2.68 (m, 1H, H-1),
2.17–0.87 (m, 15H, H-2, H-3, H-4, H-5, CHmenth
,
CH2menth), 1.31 (s, 3H, Me), 1.22 (s, 3H, Me), 0.88 (d,
J = 6.5 Hz, 3H, Me); 13C NMR (CDCl3): d 177.3,
171.4, 168.8, 151.0, 134.2, 131.8, 128.8, 127.4, 125.5,
76.4, 54.2, 51.9, 50.7, 43.4, 42.8, 41.6, 39.7, 34.7, 33.2,
31.5, 28.0, 26.9, 26.7, 24.5, 22.0. Anal. Calcd: C, 73.63;
H, 7.77; N, 2.77. Found: C, 73.56; H, 7.73; N, 2.72.
4.8. (1S,3R,10R)- and (1S,3R,10S)-3-(Benzoylamino-phen-
ylmenthoxycarbonyl-methyl)cyclopentanecarboxylic
acids 10 and 11
4.12. Deprotection of the carboxylic group
To a solution of pure (+)-13 (516 mg, 1 mmol) or a mix-
ture of 10 and 11 (1:1, 502 mg, 1 mmol) in MeOH
(10 mL), LiOH (13: 96 mg, 4 mmol, 10; 11: 48 mg,
2 mmol) was added. The reaction mixture was stirred
at room temperature for 24 h. The solvent was evapo-
rated and the crude reaction mixture taken up with
H2O (10 mL) and extracted with AcOEt (3 · 5 mL).
The aqueous layer was acidified with 2 M HCl (3 mL)
and extracted with THF/AcOEt (1:1, 3 · 5 mL). The
organic layer was dried over Na2SO4 and evaporated
under vacuum to obtain a mixture of the free carboxylic
derivatives (+)-14/(ꢀ)-15 (from (+)-13: 168 mg, 58%,
1:4; from 10/11: 180 mg, 62%, 1:1). It was possible to
separate compound 14 from 15 by a flash chromatogra-
phy (Flash+Cartridge column: 25+M, CH2Cl2/MeOH/
AcOH, 10:1:0.1, flow: 20 mL/min; 14: Rf = 0.15; 15:
Rf = 0.08).
Mixture of epimers (1:1). mmax (Nujol) 3300, 1725,
1660 cmꢀ1 1H NMR (CDCl3): d 7.82–7.10 (m, 20H,
;
ArH), 6.95 (10: d, J = 8.4 Hz, 1H, exch., NH), 6.59
(11: d, J = 8.0 Hz, 1H, exch., NH), 4.87–4.79 (m, 2H,
OCH), 4.59 (10: dd, J = 8.4, 4.4 Hz, 1H, CHN), 4.17
(11: dd, J = 8.0, 5.4 Hz, 1H, CHN), 2.84–2.71 (m, 2H,
H-1), 2.17–0.79 (m, 30H, H-2, H-3, H-4, H-5, CHmenth
,
CH2menth), 1.31 (s, 6H, Me), 1.28 (s, 3H, Me), 1.21 (s,
3H, Me), 0.89 (d, J = 6.4 Hz, 3H, Me), 0.87 (d,
J = 6.4 Hz, 3H, Me).
4.9. Esterification reaction of 10 and 11
To a solution of 10 and 11 (1:1, 100 mg, 0.2 mmol) in
MeOH (6 mL), (CH3)3SiCH2N2 (2 M in Et2O, 1 mmol,
0.5 mL) was added. After stirring under N2 for 30 min,
the solvent was removed under vacuum and a mixture
of methyl esters 12 and 13 (1:1, 94 mg, 91%) was
obtained. It was possible to separate 12 (40 mg,
0.07 mmol, 40%) from 13 (30 mg, 0.06 mmol, 30%) by
semi-preparative HPLC (Supelco C18 column;
250 · 10 mm; 10 lm, MeCN/H2O, 70:30; T = 30 ꢁC,
flow = 5 mL/min, k = 254 nm; 12: tR = 14.1 min; 13:
tR = 15.4 min).
4.13. (1S,3R,10R)-3-(Benzoylamino-carboxy-methyl)-
cyclopentanecarboxylic acid 14
25
Mp 210 ꢁC (CH2Cl2). ½aꢁD ¼ þ20 (c 1, MeOH). mmax
1
(KBr) 3450, 1707, 1640 cmꢀ1; H NMR (CD3OD): d
7.95–7.42 (m, 5H, ArH), 4.54 (d, J = 6.9 Hz, 1H,
CHN), 2.95–2.75 (m, 1H, H-1), 2.75–2.45 (m, 1H, H-
3), 2.20–1.50 (m, 6H, H-2, H-4, H-5); 13C NMR
(CD3OD): d 184.3, 177.9, 168.6, 134.7, 131.3, 128.3,
127.3, 58.6, 47.8, 43.0, 32.9, 30.4, 28.8. Anal. Calcd: C,
61.85; H, 5.88; N, 4.81. Found: 61.68; H, 6.05; N, 4.70.
4.10. Methyl (1S,3R,10R)-3-(benzoylamino-(ꢀ)-phenyl-
menthoxy carbonyl-methyl)cyclopentanecarboxylate 12
25
Mp 131 ꢁC (Et2O). ½aꢁD ¼ þ23 (c 1, CHCl3). mmax (Nu-
4.14. (1S,3R,10S)-3-(Benzoylamino-carboxy-methyl)-
cyclopentanecarboxylic acid 15
jol) 3340, 1730, 1700, 1665 cmꢀ1; H NMR (CDCl3): d
1
7.90–7.04 (m, 11H, ArH and NH), 4.93–4.80 (m, 1H,
OCH), 4.60 (dd, J = 8.0, 4.4 Hz, 1H, CHN), 3.66 (s,
3H, OMe), 2.85–2.79 (m, 1H, H-1), 2.32–0.77 (m, 15H,
H-2, H-3, H-4, H-5, CHmenth, CH2menth), 1.28 (s, 3H,
Me), 1.20 (s, 3H, Me), 0.85 (d, J = 6.3, 3H, Me); 13C
NMR (CDCl3): d 177.6, 171.4, 167.8, 151.0, 134.3,
131.8, 128.7, 128.2, 127.5, 125.8, 125.6, 77.0, 55.2,
52.2, 49.8, 43.3, 41.8, 40.6, 40.2, 34.7, 31.6, 30.4, 29.9,
28.7, 28.1, 27.3, 26.4, 22.0. Anal. Calcd: C, 73.63; H,
7.77; N, 2.77; Found: C, 73.59; H, 7.80; N, 2.73. X-ray
25
Mp 193 ꢁC (CH2Cl2). ½aꢁD ¼ ꢀ14:5 (c 1, MeOH). mmax
(KBr) 3450, 1707, 1640 cmꢀ1; H NMR (CD3OD): d
1
7.90–7.35 (m, 5H, ArH), 4.54 (d, J = 7.7 Hz, 1H,
CHN), 2.95–2.75 (m, 1H, H-1), 2.68–2.40 (m, 1H, H-
3), 2.25–2.00 (m, 1H, H-2), 1.98–1.50 (m, 5H, H-2, H-
4, H-5); 13C NMR (CD3OD): d 185.4, 179.0, 169.7,
136.0, 132.6, 129.6, 128.6, 59.6, 48.7, 44.8, 36.0, 30.7,
28.7. Anal. Calcd: C, 61.85; H, 5.88; N, 4.81. Found:
61.71; H, 6.00; N, 4.74.

F. Caputo et al. / Tetrahedron: Asymmetry 17 (2006) 61–67
67
4.15. Deprotection of the amino group
Acknowledgements
In a sealed tube, pure compound (+)-14 or (ꢀ)-15
(291 mg, 1 mmol) was suspended in 6 N HCl (6 mL)
and heated at 100 ꢁC for 12 h. The reaction mixture
was cooled at 0 ꢁC and the precipitated benzoic acid
was filtered. The aqueous layer was washed with Et2O
(3 · 4 mL) and evaporated under vacuum allowing to
obtain the pure amino acid hydrochloride (ꢀ)-16
(159 mg, 85%) or (+)-17 (159 mg, 85%).
We thank MIUR (PRIN 2002) and CRUI (Vigoni Pro-
gram), for financial support.
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4.16. (1S,3R,10R)-3-(Amino-carboxy-methyl)-cyclo-
pentanecarboxylic acid hydrochloride 16
25
Oil. ½aꢁD ¼ ꢀ5 (c 1, H2O). mmax (Nujol) 3340, 1660 cmꢀ1
;
1H NMR (D2O): d 3.84 (d, J = 7.0 Hz, 1H, CHN), 2.91–
2.75 (m, 1H, H-1), 2.43–2.28 (m, 1H, H-3), 2.15–1.98 (m,
1H, H-2), 1.82–1.39 (m, 5H, H-2, H-4, H-5); 13C NMR
(D2O): d 180.8, 172.0, 56.4, 43.1, 40.6, 32.4, 29.1, 28.0.
Anal. Calcd: C, 51.33; H, 7.00; N, 7.48. Found: C,
51.26; H, 7.08; N, 7.41.
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T. J. Org. Chem. 2001, 66, 6299–6304.
4.17. (1S,3R,10S)-3-(Amino-carboxy-methyl)-cyclo-
pentanecarboxylic acid hydrochloride 17
25
Oil. ½aꢁD ¼ þ9 (c 1, H2O); mmax (Nujol) 3340, 1660 cmꢀ1
;
´
8. Avenoza, A.; Cativiela, C.; Fernandez-Recio, M. A.;
1H NMR (D2O): d 3.85 (d, J = 8.3 Hz, 1H, CHN), 2.88–
2.72 (m, 1H, H-1), 2.43–2.28 (m, 1H, H-3), 2.19–1.87 (m,
1H, H-2), 1.80–1.59 (m, 5H, H-2, H-4, H-5); 13C NMR
(D2O): d 180.6, 171.9, 56.4, 43.1, 40.5, 32.5, 28.5, 27.9.
Anal. Calcd: C, 51.33; H, 7.00; N, 7.48. Found: C,
51.21; H, 7.10; N, 7.38.
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