Synthesis of all four enantiomers of 1-aminoindane-2-carboxylic acid, a new cispentacin benzologue

Article abstract of DOI:10.1016/S0957-4166(00)00375-X

Racemic cis- and trans-1-aminoindane-2-carboxylic acids (3 and 5) were prepared from indene by chlorosulphonyl isocyanate addition followed by ring opening and isomerisation. The intermediate racemic hydroxymethylated β-lactam 6 was resolved through the lipase-catalysed asymmetric acylation of the primary hydroxy group at the (R)-stereogenic centre. High enantioselectivities (E>200) were observed when the enzymatic reactions were performed with lipase AK or lipase PS as catalyst and vinyl acetate or vinyl butyrate as acyl donor. The hydrolysis and isomerisation resulted in all four enantiomers (9, 11, 13 and 14) of 1-aminoindane-2-carboxylic acid, a new benzologue of cispentacin.

Full text of DOI:10.1016/S0957-4166(00)00375-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4179–4187
Synthesis of all four enantiomers of
1-aminoindane-2-carboxylic acid, a new cispentacin
benzologue
Ferenc Fu¨lo¨p,a,* Ma´rta Palko´,a Judit Ka´ma´n,a La´szlo´ La´za´ra and Reijo Sillanpa¨a¨b
aInstitute of Pharmaceutical Chemistry, University of Szeged, PO Box 121, H-6701 Szeged, Hungary
bDepartment of Chemistry, University of Turku, FIN-20014 Turku, Finland
Received 5 September 2000; accepted 15 September 2000
Abstract
Racemic cis- and trans-1-aminoindane-2-carboxylic acids (3 and 5) were prepared from indene by
chlorosulphonyl isocyanate addition followed by ring opening and isomerisation. The intermediate
racemic hydroxymethylated b-lactam 6 was resolved through the lipase-catalysed asymmetric acylation of
the primary hydroxy group at the (R)-stereogenic centre. High enantioselectivities (E>200) were observed
when the enzymatic reactions were performed with lipase AK or lipase PS as catalyst and vinyl acetate
or vinyl butyrate as acyl donor. The hydrolysis and isomerisation resulted in all four enantiomers (9, 11,
13 and 14) of 1-aminoindane-2-carboxylic acid, a new benzologue of cispentacin. © 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Although of less importance than their a-analogues, b-amino acids are also present in
peptides and different heterocycles, and their free forms and derivatives exhibit interesting
pharmacological effects.1–6 A decade ago, (1R,2S)-2-aminocyclopentanecarboxylic acid (cis-
pentacin), an antifungal antibiotic, was isolated from Bacillus cereus7 and Streptomyces setonii.8
cis-2-Aminocyclopentanecarboxylic acid is also a component of the antibiotic amipurimycin.9
The research groups of Seebach and Gellman recently reported oligopeptide chains which can
fold into stable helical structures.10,11 Gellman‘s group synthesised and investigated12–14 trans-2-
aminocyclopentane- and trans-2-aminocyclohexanecarboxylic acid oligomers which display a
stable helical conformation.
Besides the fact that they themselves possess pharmacological activity, the alicyclic b-amino
acids can be used as building blocks for the preparation of modified (unnatural) analogues of
* Corresponding author. Tel: 36 62 545564; fax: 36 62 545705; e-mail: fulop@pharma.szote.u-szeged.hu
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00375-X

4180
F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
biologically active peptides. In consequence of the natural occurrence and the novel biological
activity, chemical interest in investigations of the alicyclic b-amino acids has rapidly increased.
Our present aim was the synthesis of the title alicyclic b-amino acids.
2. Results and discussion
2.1. Synthesis of the racemic i-amino acid substrates
The pathways of the syntheses of the racemic amino acids 3 and 5 are shown in Scheme 1.
Chlorosulphonyl isocyanate addition15–17 to indene takes places regio- and stereoselectively, in
accordance with the Markovnikov orientation, resulting in b-lactam 2. Treatment of 2 with
hydrochloric acid resulted in amino acid hydrochloride 3, while treatment with ethanolic hydrogen
chloride led to ethyl ester 4. Sodium ethoxide isomerisation of 4, followed by acidic hydrolysis,
resulted in the trans amino acid hydrochloride 5. The free amino acids of 3 and 5 were liberated
by ion-exchange chromatography.
The N-hydroxymethylated b-lactam 6, the starting substance of the enzymatic reactions, was
prepared from 2 with paraformaldehyde under sonication.
Scheme 1.
2.2. Enzymatic resolutions
N-Hydroxymethylated b-lactams were earlier readily resolved18 by means of lipase AK- or lipase
PS-catalysed asymmetric acylation of the primary hydroxy group at the (S) stereogenic centre.
The investigated related substrates were: N-hydroxymethylated 7-azabicyclo[3.2.0]heptan-7-one,
7-azabicyclo[4.2.0]octan-8-one, 7-azabicyclo[4.2.0]oct-3-en-8-one and 7-azabicyclo[4.2.0]oct-4-en-
8-one.19,20 The enantioselectivities (E) varied in the range 40–200 when vinyl butyrate was used
as acyl donor. Acetone proved to be the best solvent for the transformations.
At the beginning of this work, we had some doubt as to whether similarly high selectivities would
be achieved, since the steric demand of the benzologue of 7-azabicyclo[3.2.0]heptan-7-one is
increased. In the small-scale experiments (Table 1), it was found that lipase AK and lipase PS
are each excellent catalysts, both in vinyl acetate- and in vinyl butyrate-mediated acylation

F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
4181
(E>200). In the present case, replacement of acetone by acetonitrile or tetrahydrofuran did not
lead to lower E values; excellent selectivities were still attained (E>200). Finally, for the
gram-scale resolution of 6, lipase AK and vinyl butyrate in THF were used. With this method,
after a reaction time of 2.5 hours, product 8 was obtained in 44% yield, and substrate 7 in 42%
yield, after chromatographic separation, both with ee=99%.
Table 1
Effects of vinyl esters (0.2 M) and solvent on the acylation of 6 (0.1 M) in the presence of lipase PSa or AKa
(50 mg ml−1) at room temperature
Solvent
Acyl donorb
Enzyme
Time (h)
Conv. (%)
Ees (%)
Eep (%)
E
Acetone
Acetone
Acetone
THF
THF
Acetonitrile
VA
VB
VB
VB
VB
VB
Lipase AKa
Lipase AKa
Lipase PSa
Lipase PSa
Lipase AKa
Lipase AKa
4
7
7
7
2.5
8
49
47
40
46
49
49
94
88
66
85
96
93
98
99
99
98
99
98
\200
\200
\200
\200
\200
\200
a Contains 20% (w/w) of lipase adsorbed on Celite in the presence of sucrose.
b VA=vinyl acetate, VB=vinyl butyrate.
Scheme 2.

4182
F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
Enantiomers 7 and 8 were transformed to the corresponding b-amino acids 9 and 11 and
esters 10 and 12, similarly to the racemic compounds (Scheme 2). Isomerisation of esters 10 and
12, followed by hydrolysis, resulted in the trans enantiomers 13 and 14, respectively, with high
optical purity (ee=99%).
2.3. Absolute configurations
X-ray investigation revealed the absolute configuration of 12. Amino ester 12 was transformed
to thiourea 15 by reacting it with (1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propyl isothio-
cyanate (DANI), a newly developed chiral derivatising agent.21,22 The X-ray structure (Fig. 1)
clearly shows the (R,R) configuration of the starting 12. In the early cases, S selectivity was
observed19,20 in the enzyme-catalysed acylation of hydroxymethylated b-lactams, while in the
present case R selectivity was found. It is necessary to mention that in these reactions the same
stereochemical demands are fulfilled around the asymmetric centres, but only the sequence of
priority of the substituents on the substrates differs.
Figure 1. ORTEP plot of the X-ray structure of thiourea 15. The thermal ellipsoids are drawn at the 25% probability
level. Only the main component of the disordered ester chain is shown
3. Conclusions
Starting from indene, the syntheses of all four enantiomers of 1-aminoindane-2-carboxylic
acid proved possible by a combination of lipase-catalysed O-acylation and some simple
synthetic transformations. The synthesised b-amino acids, all four enantiomers (9, 11, 13 and 14)
of 1-aminoindane-2-carboxylic acid, are promising compounds for the synthesis of partially
saturated heterocycles, peptides and peptidomimetics, as potential pharmacons.

F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
4183
4. Experimental
4.1. Materials and methods
Vinyl acetate was purchased from Aldrich Chemical Co. and vinyl butyrate from Fluka.
Lipase PS and lipase AK were obtained from Amano Pharmaceuticals, and Novozym 435 as an
immobilised preparation from Novo Nordisk. Before use, lipase PS (5 g) was dissolved in
Tris–HCl buffer (0.02 M; pH 7.8) in the presence of sucrose (3 g), followed by adsorption on
Celite (17 g) (Sigma). The lipase preparation thus obtained contained 20% (w/w) of lipase.
The ee values of the unreacted alcohol 7 and the produced ester 8 and amino esters 10 and
12 were determined by gas chromatography on a Chrompack CP-Chirasil-DEX CB column (25
m). Amino esters 10 and 12 were derivatised with acetic anhydride in the presence of
4-dimethylaminopyridine and pyridine before the gas chromatographic analysis. The ee values of
the amino acid enantiomers 9, 11, 13 and 14 were determined by HPLC on an APEX ODS
column (0.46×25 cm, Jones Chromatography Ltd.), with 0.1% aqueous trifluoroacetic
acid:methanol (45:55) as eluent. For chiral derivatisation, (1S,2S)-1,3-diacetoxy-1-(4-nitro-
phenyl)-2-propyl isothiocyanate was used, according to the literature.21,22
1
Optical rotations were measured with a Perkin–Elmer 341 polarimeter. H NMR spectra were
recorded on a Bruker Avance DRX 400 spectrometer. Chemical shifts are given in l (ppm)
relative to TMS (CDCl3) or to TSP (D2O) as internal standards; multiplicities were recorded as
s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), m (multiplet) and om
(overlapping multiplet). Melting points were determined on a Kofler apparatus.
4.2. 3,4-Benzo-6-azabicyclo[3.2.0]heptan-7-one, ( )-2
A solution of 15.57 g (0.11 mol) N-chlorosulphonyl isocyanate in dry diethyl ether (50 ml)
was added rapidly to 11.62 g (0.10 mol) freshly distilled indene dissolved in dry diethyl ether
(200 ml). The resulting colourless solution was stirred for 2 hours at room temperature, after
which n-hexane (100 ml) was added and the crystalline product was filtered off. The crystalline
N-chlorosulphonyl derivative was dissolved in diethyl ether (200 ml) and added, dropwise and
with stirring, to a mixture of Na2SO3 (10 g) in water (50 ml) and diethyl ether (50 ml). During
the addition, the aqueous phase was kept slightly alkaline by addition of 10% KOH solution.
( )-2 crystallised out and was filtered off (7.92 g) from the mixture. A second crop of ( )-2 was
obtained as follows: from the above filtrate, the organic phase was separated, and the aqueous
part was extracted twice with diethyl ether. The combined organic layer was dried (Na2SO4) and
evaporated. The combined crude products were recrystallised from ethyl acetate–methanol,
which afforded 10.03 g (63%) colourless crystals of ( )-2, mp 188–189°C, lit.23 mp 183–184°C.
1H NMR (400 MHz, CDCl3) l (ppm): 3.07 (1H, dd, J=17.5, 10.5, CH2), 3.35 (1H, d, J=17.4,
CH2), 4.02 (1H, m, CHCO), 5.03 (1H, d, J=4.2, CHN), 6.28 (1H, broad s, NH), 7.18–7.36 (4H,
om, C6H4). Analysis: calculated for C10H9NO: C, 75.45; H, 5.70; N, 8.80; found: C, 75.61; H,
5.91; N, 8.65.
4.3. cis-1-Aminoindane-2-carboxylic acid hydrochloride, ( )-3
The b-lactam ( )-2 (1.59 g, 0.01 mol) was refluxed in 36% hydrochloric acid (10 ml) for 12
hours. After standing overnight, the precipitated crystalline product was separated by filtration
and recrystallised from ethanol–diethyl ether (1.68 g, 79%), mp 220–222°C.

4184
F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
1H NMR (400 MHz, D2O) l (ppm): 3.37 (2H, d, J=8.9, CH2), 3.74 (1H, dd, J=15.9, 8.7,
CHCO), 5.01 (1H, d, J=7.0, CHN), 7.42 (3H, m, C6H4), 7.53 (1H, d, J=7.5, C6H4). Analysis:
calculated for C10H12ClNO2: C, 56.21; H, 5.66; N, 6.56; found: C, 56.35; H, 5.56; N, 6.72.
The free amino acid base was liberated by ion-exchange chromatography with DOWEX 50,
mp 265–266°C.
1H NMR (400 MHz, D2O) l (ppm): 3.22 (1H, dd, J=16.3, 9.6, CH2), 3.32 (1H, dd, J=16.3,
8.6, CH2), 3.51 (1H, m, CHCO), 4.85 (1H, d, J=6.8, CHN), 7.37 (1H, m, C6H4), 7.44 (2H, m,
C6H4), 7.51 (1H, d, J=7.5, C6H4). Analysis: calculated for C10H11NO2: C, 67.78; H, 6.26; N,
7.90; found: C, 67.49; H, 6.48; N, 7.97.
4.4. Ethyl cis-1-aminoindane-2-carboxylate hydrochloride, ( )-4
The b-lactam ( )-2 (0.01 mol, 1.59 g) was refluxed in ethanol (50 ml) containing 22% dry
hydrogen chloride for 8 hours. The solvent was evaporated off, and the crystalline product was
recrystallised from ethanol–diethyl ether (1.98 g, 82%), mp 210–211°C.
1H NMR (400 MHz, CDCl3) l (ppm): 1.27 (3H, t, J=7.1, CH3), 3.24 (1H, dd, J=18.0, 10.8,
CHCH2), 3.54 (2H, m, CHCH2, CHCO), 4.20 (2H, q, J=7.1, OCH2), 4.81 (1H, d, J=6.2,
CHN), 7.25 (3H, m, C6H4), 7.80 (1H, d, J=7.6, C6H4). Analysis: calculated for C12H16ClNO2:
C, 59.63; H, 6.67; N, 5.79; found: C, 59.82; H, 6.56; N, 5.43.
4.5. trans-1-Aminoindane-2-carboxylic acid hydrochloride, ( )-5
Sodium (0.60 g) was dissolved in dry ethanol (20 ml), 2.05 g (0.01 mol) base ( )-4 was added
to this solution and the mixture was heated at 70°C for 7 hours. The yellow solution was
evaporated and refluxed with 10% hydrochloric acid (20 ml) for 10 hours. After standing
overnight, the solution was filtered and evaporated to dryness. The residue was dissolved in hot
methanol, and the removal of solvent gave 1.80 g crude product, which was recrystallised from
ethanol–diethyl ether (1.45 g, 60%), mp 220–222°C.
1H NMR (400 MHz, D2O) l (ppm): 3.23 (1H, m, CH2), 3.51 (2H, m, CH2, CHCO), 5.17 (1H,
d, J=5.3, CHN), 7.40 (3H, m, C6H4), 7.51 (1H, d, J=7.0, C6H4). Analysis: calculated for
C10H12ClNO2: C, 56.21; H, 5.66; N, 6.56; found: C, 56.44; H, 5.73; N, 6.40.
The free amino acid base was liberated by ion-exchange chromatography with DOWEX 50,
mp 234–235°C.
1H NMR (400 MHz, D2O) l (ppm): 3.13 (1H, dd, J=16.0, 7.0, CH2), 3.22 (1H, m, CH2), 3.46
(1H, dd, J=16.0, 8.7, CHCO), 5.04 (1H, d, J=6.0, CHN), 7.40 (3H, m, C6H4), 7.48 (1H, d,
J=7.4, C6H4). Analysis: calculated for C10H11NO2: C, 67.78; H, 6.26; N, 7.90; found: C, 67.66;
H, 6.38; N, 7.72.
4.6. Preparation of racemic 3,4-benzo-6-hydroxymethyl-6-azabicyclo[3.2.0]heptan-7-one, ( )-6
Compound 2 (6.00 g, 37.69 mmol) was dissolved in THF (250 ml), and paraformaldehyde
(1.36 g), potassium carbonate (0.52 g, 3.77 mmol) and water (3.8 ml) were added. The solution
was sonicated for 5 hours. The solvent was evaporated off and the residue was dissolved in ethyl
acetate. The solution was dried over Na2SO4, the solvent was evaporated off and the product
was recrystallised from a THF–diisopropyl ether mixture to afford white crystals of 6 (5.06 g,
71%,), mp 112–114°C.

F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
4185
1H NMR (400 MHz, CDCl3) l (ppm): 3.08 (2H, m, CHCH2, OH), 3.33 (1H, d, J=17.4,
CHCH2), 4.01 (1H, m, CHCO), 4.39 (1H, dd, J=11.6, 9.0, CH2OH), 4.87 (1H, dd, J=11.6, 5.8,
CH2OH), 5.17 (1H, d, J=4.3, CHN), 7.28 (3H, m, C6H4), 7.42 (1H, d, J=7.4, C6H4). Analysis:
calculated for C11H11NO2: C, 69.83; H, 5.86; N, 7.40; found: C, 69.39; H, 6.23; N, 7.30.
4.7. General procedure for small-scale experiments
The N-hydroxymethyl-b-lactam ( )-6 (0.1 M solution) in an organic solvent (1 ml) was added
to lipase PS (50 mg ml−1) or lipase AK (50 mg ml−1). Vinyl acetate or butyrate (0.2 M in the
reaction mixture) was added and the mixture was shaken at room temperature. The progress of
the reaction was followed by taking samples from the reaction mixture at intervals and analysing
them by gas chromatography.
4.8. Gram-scale resolution of ( )-6
Racemic 6 (4.00 g, 21.14 mmol) was dissolved in THF (200 ml), lipase AK (10.58 g) and vinyl
butyrate (4.83 g, 42.28 mmol) were added and the mixture was stirred at room temperature.
After 2.5 hours, a few drops of triethylamine were added in order to enhance the stability of the
unreacted acid-labile 7, and the enzyme was filtered off at 50% conversion. The THF was
evaporated off. The residue was chromatographed on silica, with elution with
dichloromethane:ethyl acetate (9:1) for separation of the ester (1R,5R)-8 (2.43 g, 9.37 mmol;
[h]2D5=−91.8 (c=0.51, CHCl3); ee=99%) as a colourless oil. Elution with dichloromethane:ethyl
acetate (1:1) afforded the unreacted (1S,5S)-7 (1.68 g, 8.88 mmol; [h]2D5=+137 (c=0.36, CHCl3);
ee=99%; mp 138–140°C) as white crystals.
1H NMR (400 MHz, CDCl3) l (ppm) for 8: 0.96 (3H, t, J=7.4, CH3), 1.66 (2H, m,
CH2CH2CH3), 2.30 (2H, t, J=7.4, CH2CH2CH3), 3.09 (1H, dd, J=17.4, 10.5, CHCH2), 3.32
(1H, d, J=17.4, CHCH2), 4.00 (1H, m, CHCO), 4.97 (1H, d, J=11.4, OCH2), 5.07 (1H, d,
J=11.4, OCH2), 5.11 (1H, d, J=4.4, CHN), 7.30 (3H, m, C6H4), 7.61 (1H, d, J=7.4, C6H4).
Analysis: calculated for C15H17NO3: C, 69.48; H, 6.61; N, 5.40; found: C, 69.12; H, 6.71; N,
5.48.
1
The H NMR data for 7 are similar to those for ( )-6. Analysis found: C, 69.71; H, 5.91; N,
7.35.
4.9. Acid hydrolysis of 7 and 8
Compound 7 (0.40 g, 2.11 mmol) was dissolved in 18% HCl (14 ml) and refluxed for 2 hours
at 70°C. The solvent was evaporated off, and the residue was recrystallised from ethanol–diethyl
ether, which afforded white crystals of (1S,2S)-9 (0.35 g, 1.64 mmol; [h]2D5=+5.7 (c=0.50,
MeOH); mp 281–282°C; ee=99%).
1
The H NMR data for 9 are similar to those for ( )-3. Analysis found: C, 56.34; H, 5.58; N,
6.53.
Similarly, 8 (1.00 g, 3.86 mmol) afforded white crystals of (1R,2R)-11 (0.50 g, 2.34 mmol;
[h]2D5=−5.3 (c=0.50, MeOH); mp 273–275°C; ee=99%). The H NMR data for 11 are similar
1
to those for 9 and ( )-3. Analysis found: C, 56.29; H, 5.71; N, 6.60.

4186
F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
4.10. Preparation of esters 10 and 12
Similarly as in Section 4.4, (1S,5S)-7 (0.80 g, 4.23 mmol) afforded white crystals of (1S,2S)-10
(0.73 g, 3.02 mmol; [h]2D5=+6.0 (c=0.50, H2O); mp 208–209°C; ee=99%). The H NMR data
1
for 10 are similar to those for ( )-4. Analysis found: C, 59.74; H, 6.61; N, 5.75.
Similarly, (1R,5R)-8 (1.00 g, 3.86 mmol) afforded white crystals of (1R,2R)-12 (0.70 g, 2.90
mmol; [h]2D5=−6.2 (c=0.50, H2O); mp 214–216°C; ee=99%). The H NMR data for 12 are
1
similar to those for 10 and ( )-4. Analysis found: C, 59.69; H, 6.59; Cl, 14.62; N, 5.84.
4.11. Preparation of trans-1-aminoindane-2-carboxylic acid hydrochloride enantiomers 13 and
14
With the procedure described in Section 4.5, (1S,2S)-10 (0.40 g, 1.65 mmol) afforded
(1S,2R)-13 crude material. Since the product contained ꢀ20% cis isomer, the isomerisation was
carried out again, yielding white crystals of (1S,2R)-13 (0.13 g, 0.61 mmol; [h]2D5=−76.8 (c=0.5,
1
H2O); mp 217–220°C; ee=99%). The H NMR data for 13 are similar to those for ( )-5.
Analysis found: C, 56.11; H, 5.69; Cl, 16.47; N, 6.48.
With the above procedure, (1R,2R)-12 (0.40 g, 1.65 mmol) afforded (1R,2S)-14 (0.21 g, 0.98
1
mmol; [h]2D5=+75.8 (c=0.5, H2O); mp 220–222°C; ee=99%). The H NMR data for 14 are
similar to those for 13 and ( )-5. Analysis found: C, 56.28; H, 5.62; Cl, 16.52; N, 6.61.
4.12. Preparation of thiourea derivative 15
The free base of ethyl ester 12 (0.08 g, 0.39 mmol) was dissolved in diethyl ether (10 ml), and
(1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propyl isothiocyanate (0.14 g, 0.41 mmol) was added.
The mixture was allowed to stand at room temperature for a few hours. The white crystals of
15 were separated. The product was recrystallised from diisopropyl ether–diethyl ether, mp
145–148°C.
4.13. X-ray crystallography
All data were collected on a Rigaku AFC5S diffractometer, with graphite-monochromated
,
Mo Ka radiation (=0.71069 A) in the ꢀ–2q scan mode at room temperature. The lattice
parameters were calculated by least-squares refinements of 20 reflections. The weak reflections
[I<10|(I)] were rescanned up to two times. For 15, 2819 reflections were collected (2qmax=50°).
The data were corrected for Lorentz and polarisation effects.
4.13.1. Crystal data for 15
C26H27N3O8S, Mr=541.57, orthorhombic, space group P212121 (no. 19), lattice parameters:
3
−3
,
,
a=11.127(4), b=22.908(3), c=10.665(4) A, Z=4, V=2718.6(14) A , Dc=1.323 g cm , v (Mo
Ka)=0.172 mm−1, F(000)=1136, T=294 K; a colourless plate, crystal dimensions 0.22×0.24×
0.32 mm.
The structure was solved by direct methods (SIR-92)24 and refined by full-matrix least-squares
techniques (SHELXL-97)25 to an R1 value of 0.048 (wR2=0.112). These final R values are based
on the reflections with I>2|(I). The heavy atoms were refined anisotropically. The hydrogen
atoms on the aliphatic carbons (C1, C2, C12 and C13) and on the nitrogen atoms were refined

F. Fu¨lo¨p et al. / Tetrahedron: Asymmetry 11 (2000) 4179–4187
4187
with fixed isotropic temperature factors (1.2Ueq of the carrying atom) and the remaining
hydrogen atoms were included in the calculated positions with fixed isotropic temperature
factors (1.2 or 1.5 times Ueq of the carrying atom). The ester group at C8 has two orientations.
The population of the major component is 56(5)%. Calculations were performed with teXsan for
Windows26 crystallographic software. Fig. 1 was drawn with ORTEP-3 for Windows.27
Acknowledgements
The authors would like to thank the OTKA (grant no. T 030452) and MKM (grant no. FKFP
0535/1999) for financial support.
References
1. Enantioselective Synthesis of i-Amino Acids; Juaristi, E., Ed.; Wiley-VHC: New York, 1997.
2. Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999, 6, 905.
3. Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med. Chem. 1999, 6, 955.
4. Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983.
5. Fu¨lo¨p, F. In Studies in Natural Product Chemistry; Atta-ur-Rahman, Ed. The chemistry of 2-aminocyclopentane-
carboxylic acid. Elsevier Science: New York, 2000; pp. 273–306.
6. Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461; Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters,
I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1411; Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7,
1595.
7. Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.; Kawaguchi, H. J. Antibiot. 1989, 42, 1749.
8. Iwamoto, T.; Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto, S.; Okuhara, M.; Kohsaka, M.; Imanaka, H.;
Kawabata, K.; Inamoto, Y.; Sakane, K. J. Antibiot. 1990, 43, 1.
9. Knapp, S. Chem. Rev. 1995, 95, 1859.
10. Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.; Barchi, J. J.; Gellman, S. H. Nature
1997, 387, 381; Porter, E. A.; Wang, X.; Lee, H. S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565.
11. Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim.
Acta 1996, 79, 913.
12. Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121,
6206.
13. Appella, D. H.; Durell, S. L.; Barchi, J. J.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309.
14. Barchi, J. J.; Huang, X.; Appella, D. H.; Christianson, L. A.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc.
2000, 122, 2711.
15. Rasmussen, J. K.; Hassner, A. Chem. Rev. 1976, 76, 389.
16. Dhar, D. N.; Murthy, K. S. K. Synthesis 1986, 437; Kamal, A.; Sattur, P. B. Heterocycles 1987, 26, 1051.
17. Szakonyi, Z.; Fu¨lo¨p, F.; Berna´th, G.; Evanics, F.; Riddell, F. G. Tetrahedron 1998, 54, 1013.
18. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Chemistry; Wiley-VHC: Weinheim, 1999.
19. Csomo´s, P.; Kanerva, L. T.; Berna´th, G.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 1996, 7, 1789.
20. Ka´ma´n, J.; Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 2000, 11, 1593.
21. Pe´ter, M.; Pe´ter, A.; Fu¨lo¨p, F. Chromatographia 1999, 50, 307.
22. Pe´ter, M.; Pe´ter, A.; Fu¨lo¨p, F. J. Chromatogr. A 2000, 871, 115.
23. Murray, R. J.; Cromwell, N. H. J. Heterocyclic Chem. 1974, 11, 979.
24. Altomare, A.; Cascarano, M.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl.
Crystallogr. 1994, 27, 435.
25. Sheldrick, G. M. SHELX-97; University of Go¨ttingen: Germany, 1997.
26. Molecular Structure Corporation. teXsan for Windows. Single Crystal Structure Analysis Software. Version 1.01.
MSC: 3200 Research Forest Drive, The Woodlands, TX 77381, USA, 1997.
27. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.