Efficient synthesis of hydroxy-substituted cispentacin derivatives

Article abstract of DOI:10.1002/ejoc.200800345

Starting from N-protected cis- and trans-2-aminocyclopent-3-enecarboxylic acid derivatives, isomers of 2-amino-3-hydroxycyclopentanecarboxylic acid (8 and 12) were prepared via oxazoline intermediates, whereas the stereoisomeric 2-amino-3,4-dihydroxycyclo

Full text of DOI:10.1002/ejoc.200800345

FULL PAPER
DOI: 10.1002/ejoc.200800345
Efficient Synthesis of Hydroxy-Substituted Cispentacin Derivatives
Gabriella Benedek,[a] Márta Palkó,[a] Edit Wéber,[a] Tamás A. Martinek,[a] Eniko˝ Forró,[a]
and Ferenc Fülöp*[a,b]
Keywords: Amino acids / Hydroxycispentacin / Hydroxylation / Diastereoselectivity / Regioselectivity
Starting from N-protected cis- and trans-2-aminocyclopent-
3-enecarboxylic acid derivatives, isomers of 2-amino-3-hy-
droxycyclopentanecarboxylic acid (8 and 12) were prepared
via oxazoline intermediates, whereas the stereoisomeric 2-
amino-3,4-dihydroxycyclopentanecarboxylic acids 14 and 17
were synthesized by OsO4-catalyzed oxidation. The enantio-
mers of 8 and 14 were also prepared by the same pathway.
The structures, stereochemistry and relative configurations
of the synthesized compounds were proved by NMR spec-
troscopy.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
lactonization or via the corresponding oxazine deriva-
tives.[24,25] Another method involves the hydroxylation of
the 2-aminocyclohexenecarboxylic acid by functionalization
of the olefinic bond by epoxidation.[26–28]
Introduction
The importance of alicyclic β-amino acids,[1,2] derived
from β-lactams,[3,4] has recently increased because of their
occurrence in many pharmacologically important com-
pounds.[5] They can also be introduced into peptides to in-
crease and modify their biological activity.[6] These com-
pounds are found in a large number of natural products,
some of which, for example, cispentacin [(1R,2S)-2-amino-
cyclopentanecarboxylic acid], exhibit antifungal activity.[7–9]
The 4-methylene analogue of cispentacin[10–12] (Icofung-
ipen, PLD-118) is a representative of a novel class of anti-
fungals that are active in vitro against Candida species.[13]
This β-amino acid actively accumulates in yeast, competi-
tively inhibiting isoleucyl-tRNA synthetase and conse-
quently disrupting protein biosynthesis.[14,15]
Hydroxy-functionalized β-amino acids play an important
role in medicinal chemistry because they also occur in many
important and essential products such as Paclitaxel (Taxol)
and Docetaxel (Taxotere), which have chemotherapeutic ef-
fects.[16–18] Although of less biological importance than
their open-chain analogues, some cyclic hydroxylated β-
amino acid derivatives have antibiotic (oryzoxymycin)[19–22]
or antifungal activities and are building blocks for pharma-
ceutically important natural substances.[23]
Only a few syntheses of hydroxylated 2-aminocyclopen-
tanecarboxylic acid derivatives have been reported.[29–32]
For example, 2-amino-4-hydroxycyclopentanecarboxylic
acid was synthesized from the 4-methylene analogue of cis-
pentacin. After esterification and protection, ozonolysis of
the olefinic bond, reduction of the carbonyl group, hydroly-
sis and deprotection resulted in a diastereomeric (3:1) mix-
ture of the 4-hydroxylated amino acid.[10,31] The all-cis-2-
amino-4-hydroxycyclopentanecarboxylic acid was access-
ible by a Curtius reaction of the half acid derived from the
meso-diester of the appropriate 4-oxocyclopentane and sub-
sequent removal of the oxo group by Clemensen re-
duction.[30] (1R,2S,5S)-5-Amino-2-hydroxycyclopentane-
carboxylic acid can be obtained by lithium amide conjugate
addition to ε-oxo α,β-unsaturated esters and subsequent in-
tramolecular cyclization.[29] The polyhydroxylated trans-2-
aminocyclopentanecarboxylic acid was formed from a -
glucose derivative via a bicyclic sugar nitrolactone.[32]
The aim of this work was to functionalize the olefinic
bond of cis-2-amino-3-cyclopentenecarboxylic acid and to
synthesize and structurally analyze new mono- or dihy-
droxy-substituted derivatives.
In our earlier work we described several methods for the
synthesis of hydroxy-substituted cyclohexane β-amino ac-
ids. The introduction of a hydroxy group into the cyclohex-
ane ring was accomplished stereoselectively starting from
cis- and trans-2-aminocyclohexenecarboxylic acids by iodo-
Results and Discussion
Diastereomerically pure β-lactam 2 was prepared by 1,2-
cycloaddition of chlorosulfonyl isocyanate (CSI) in Et2O at
–10 °C by a modification of a literature procedure.[33] Ring-
opening of the β-lactam with ethanolic HCl resulted in the
amino ester hydrochloride 3, which was protected with
AcCl, di-tert-butyl dicarbonate or benzyl chloroformate to
give N-acylated esters 4a–c (Scheme 1). An alternative syn-
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
6720 Szeged, Eötvös utca 6, Hungary
Fax: +36-62-545705
E-mail: fulop@pharm.u-szeged.hu
[b] Stereochemistry Research Group of the Hungarian Academy of
Sciences, University of Szeged,
6720 Szeged, Eötvös utca 6, Hungary
3724
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Hydroxy-Substituted Cispentacin Derivatives
thesis of 3 comprised hydrolysis of β-lactam 2 with concen- served in the crude product, according to Markovnikov’s
trated aqueous HCl at room temperature to amino acid hy- rule.[34] Bromooxazoline 6 was then converted into oxazol-
drochloride 5, which was esterified in the presence of EtOH ine 7 by reduction of the bromo group with Bu3SnH under
and SOCl2 to give amino ester hydrochloride 3, which was argon. When 7 was heated to reflux in a 20% aqueous solu-
then acylated by the above methods.
tion of HCl, partial cis Ǟ trans isomerization took place,
and ion-exchange chromatography followed by fractional
crystallization resulted in (1S*,2R*,3S*)-2-amino-3-hy-
droxycyclopentanecarboxylic acid (12). From the mother
liquor the all-cis-2-amino-3-hydroxycyclopentanecarboxylic
acid (8) was also isolated by crystallization (Scheme 2).
The isomerization of 4a with NaOEt gave the trans-N-
acetyl amino ester 9. It is known from the literature that
such reactions are generally not quantitative and the yields
are therefore low.[28] Hydrolysis of 7 followed by isomeri-
zation resulted in the corresponding (1S*,2R*,3S*)-2-
amino-3-hydroxycyclopentanecarboxylic acid (12).
Compounds 6, 7, 10 and 11 were characterized by NMR
Scheme 1. Reagents and conditions: (i) CSI, Et2O, 3 h, –10 °C,
Na2SO3, 61%; (ii) HCl/EtOH, room temp., 1 h, 64%; (iii) R = Ac: measurements. The values of 3J(3a-H,6a-H) were in the
Et3N, AcCl, CHCl3, 2 h, room temp., 73%; R = Boc: Et3N, Boc2O,
range of 7.2–7.8 Hz, and large NOE signals were observed
toluene, 2 h, room temp., 69%; R = Z: Et3N, ZCl, THF, 16 h, room
between 3a-H and 6a-H, which supports the expected cis
temp., 65%; (iv) concd. HCl, 74%; (v) SOCl2, EtOH, 30 min, 0 °C;
ring anellation. The fact that no coupling was observed be-
3 h room temp.; 1 h, ∆T, 86%.
tween 6-H and 6a-H for 6 and 10 suggests a trans-diequato-
The selective iodolactonization of cis- and trans-2- rial orientation. Consequently, the 6-bromo group should
3
amino-4-cyclohexenecarboxylic acids and cis-2-amino-3-cy- be trans relative to the oxazoline ring. In 6 and 7, J(3a-
clohexenecarboxylic acid has previously been reported.[24,25] H,4-H) = 7.2 Hz, and the large NOE signal between 3a-H
The iodolactonization of cis-2-tert-butoxycarbonylamino- and 4-H indicates a cis (synperiplanar) orientation for 3a-
cyclopent-3-enecarboxylic acid with I2/KI/NaHCO3 was at- H and 4-H, and consequently a cis orientation for the C-4
tempted, but not even traces of the iodolactone product substituent relative to the oxazoline ring. For 10 and 11,
were observed. The starting compound remained un- no coupling was observed between 4-H and 3a-H, which
changed, most probably because of the unstable lactone indicates that 4-H and 3a-H are perpendicular to each
ring.
other. This, together with the small NOE signal between 4-
Another possible way to introduce a hydroxy group is H and 3a-H, suggests a trans-diequatorial orientation for
the epoxidation of the double bond and then opening of the hydrogen atoms and a trans-diaxial orientation for the
the oxirane ring.[28] Epoxidation of ethyl cis-2-acetylamino- C-3a and C-4 substituents.
(4a) and ethyl cis-2-benzyloxycarbonylaminocyclopent-3-
For 12, the small NOE signal between 1-H and 2-H and
3
enecarboxylate (4c) in the presence of m-chloroperbenzoic the value of J(1-H,2-H) = 9.5 Hz suggest a trans-diaxial
acid in CH2Cl2 gave the corresponding cis-epoxides.[28] In orientation. Thus, the C-1 and C-2 substituents are trans.
the presence of NaBH4 in EtOH, the oxirane ring remained 3J(2-H,3-H) = 5.0 Hz indicates an equatorial position for
unchanged.
3-H, which, together with the large NOE between 2-H and
When N-acetyl derivative 4a was treated with N-bromo- 3-H, points to cis-oriented C-2 and C-3 substituents. The
succinimide (NBS), bicyclic bromooxazoline derivative 6 large NOE signal between 1-H and 2-H and the value
was obtained regio- and diastereoselectively (Scheme 2). 3J(1-H,2-H) = 6.5 Hz for 8 suggest a cis-oriented C-1 car-
Not even traces of other regio- or diastereomers were ob- boxy group relative to the C-2 amino group. This is sup-
Scheme 2. Reagents and conditions: (i) NBS, CH2Cl2, 3 h, room temp., 71–86%; (ii) Bu3SnH, CH2Cl2, Ar, 20 h, ∆T, 63–65%; (iii) 20%
HCl/H2O, 24 h, ∆T, 22–67%; (iv) NaOEt, EtOH, 24 h, room temp., 37%.
Eur. J. Org. Chem. 2008, 3724–3730
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F. Fülöp et al.
FULL PAPER
ported by the fact that an NOE signal was observed be- protected amino group are in equatorial positions. In this
tween 1-H and 3-H in 8, whereas no signal was observed case, the hydroxy groups have the same steric orientation as
between these hydrogen atoms in 12.
the protected amino group in the final product. This can be
The osmium-catalyzed dihydroxylation of olefins is one rationalized by the probability of an electrostatically advan-
of the most efficient methods for the preparation of vicinal tageous interaction in the intermediate complex of OsO4
diols.[35,36] Ethyl 2-benzoylaminocyclopent-3-enecarboxyl- and 15 between the partially positive amide hydrogen atom
ate has been successfully dihydroxylated with OsO4 and 4- and the partially negative oxygen atom attacking the sp2
methylmorpholine N-oxide (NMO).[36] The facile dihydrox- carbon atom vicinal to the protected amine substituent.
ylation of olefins 4a–c by oxidation with catalytic OsO4 and This interaction is possible only if OsO4 is in juxtaposition
NMO as the stoichiometric co-oxidant afforded the desired with the NHBoc moiety.
products 13a–c as single diastereomers in good yields
In the ring closures of the 1,2-disubstituted 1,2- and 1,3-
(Scheme 3). Not even traces of other diastereomers were difunctionalized cycloalkanes, striking differences were ob-
1
observed in the crude product, as determined by H NMR served in the cyclization reaction: although the cis isomers
spectroscopy. The ester functions of 13a–c were then hy- reacted readily, their trans counterparts did not undergo
drolyzed and the amino group then deprotected to furnish ring closure in most cases.[37,38]
the desired (1R*,2R*,3S*,4R*)-2-amino-3,4-dihydroxycy-
clopentanecarboxylic acid (14).
On this basis, we also attempted to prove the relative
configurations of 14 and 17 chemically. Compound 14 was
esterified with CH2N2 and then allowed to react in MeOH
with 1 equiv. of p-nitrobenzaldehyde. A well-defined prod-
1
uct was obtained. H NMR spectroscopy indicated that in
CDCl3 this compound exists solely as the open Schiff base
form.[38] A well-defined signal was observed at δ = 8.4 ppm
(s, 1 H, N=CH). No peaks were detected in the interval δ
= 5–6 ppm (ring closure product: s, 1 H, NCHO), which
underlines the trans orientation of the 2-NH2 and 3-OH
substituents. In contrast, for the similar transformation of
17, both the open Schiff base form and the ring-closure
product were observed in the 1H NMR spectra, which
points to a cis orientation of the 2-NH2 and 3-OH substitu-
ents.
Scheme 3. Reagents and conditions: (i) 2.0 wt.-% solution of OsO4
in tBuOH, NMO, acetone, 4 h, room temp.; R = Ac: 47%; R =
Boc: 56%; R = Z: 58%; (ii) R = Ac: 20% HCl/H2O, ∆T, 48 h; R
= Boc: 10% HCl/H2O, 24 h, room temp.; R = Z: 5% Pd/C, H2,
EtOH, 12 h, room temp.; 20% HCl/H2O, ∆T, 24 h, 35–37%; (iii)
NaOEt, EtOH, 24 h, room temp., 51%.
3
For 15, the value J(1-H,2-H) = 8.6 Hz and the small
NOE signal between 1-H and 2-H suggest a trans orienta-
tion for 1-H and 2-H. Consequently, the C-1 and C-2 sub-
stituents are trans. Compound 9 exhibits the same coupling
pattern and stereochemistry. For 16 and 17, the values
The isomerization of 4b with NaOEt resulted in trans-N- 3J(1-H,2-H) = 6–7 Hz and the small NOE signals between
Boc amino ester 15. By a transformation similar to that of 1-H and 2-H point to a trans orientation for 1-H and 2-H.
the cis isomer 4a, trans-N-Boc amino ester 15 reacted via Consequently, the carboxy and amino groups should again
the dihydroxy ester intermediate 16 to yield the correspond- be trans. The relative orientation of the hydroxy groups is
ing
(1S*,2R*,3R*,4R*)-2-amino-3,4-dihydroxycyclopen- cis because of the large NOE and the small coupling con-
stant between 3-H and 4-H, and they are located on the
tanecarboxylic acid (17) (Scheme 3).
For 13c the value 3J(1-H,2-H) = 8.1 Hz and the very same side of the cyclopentane ring as the C-2 substituent.
large NOE signal between 1-H and 2-H indicate a cis (syn- This is proved by the large NOE between 2-H and 3-H.
periplanar) orientation of the C-1 and C-2 substituents. The Moreover, in 16, which was dissolved in [D6]DMSO for the
3-H and 4-H atoms and consequently the C-3 and C-4 hy- NMR experiments, NOE signals were observed between the
droxy groups should also be cis relative to each other be- NH and OH groups. The positions of the hydroxy groups
cause of the large NOE signal between 3-H and 4-H and are supported by the fact that no NOE signal was detected
the value 3J(3-H,4-H) = 3.5 Hz. Moreover, the hydroxy between 1-H and 3-H or between 1-H and 4-H, whereas a
groups are located on opposite sides of the cyclopentane small NOE was found between 2-H and 4-H.
ring to the C-1 and C-2 substituents; this can be concluded
All the above reactions were also performed starting
from the small NOE signal between 2-H and 3-H, the large from the enantiomeric (1R,2S)-2-aminocyclopent-3-enecar-
signal between 3-H and the NH group, and the absence of boxylic acid hydrochloride [(+)-5]. Compound (+)-5 was
an NOE signal between 3-H and 1-H or between 4-H and prepared by Lipolase (lipase B from Candida antarctica)
1-H. The same pattern was detected for 13a,b.
catalyzed enantioselective ring cleavage of rac-6-azabicy-
The double bonds in 4a–c undergo oxidation on the steri- clo[3.2.0]hept-3-en-7-one (2) in iPr2O at 70 °C.[39] This
cally less hindered side of the ring. The diastereoselectivity enantiopure amino acid was transformed with SOCl2 into
of the dihydroxylation of 15 is not likely to be determined ethyl (1R,2S)-2-aminocyclopent-3-enecarboxylate hydro-
by simple steric repulsion because both the ester and the chloride [(+)-3]. The 3-hydroxy- and 3,4-dihydroxyamino
3726
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3724–3730

Synthesis of Hydroxy-Substituted Cispentacin Derivatives
HCl (50 mL) was stirred at room temperature for 1 h. After re-
moval of the solvent, amino ester hydrochloride 3 was obtained,
which was recrystallized from EtOH/Et2O. Colourless crystals
(5.62 g, 64%), m.p. 190–193 °C (ref.[28] 198–200 °C). 1H NMR
(400 MHz, [D6]DMSO, 30 °C): δ = 1.24 (t, J = 7.1 Hz, 3 H,
CH3CH2), 2.60 (dd, J = 8.8, 16.8 Hz, 1 H, 5-Heq), 2.76 (dddd, J =
2.0, 4.5, 8.1, 16.8 Hz, 1 H, 5-Hax), 3.42 (ddd, J = 7.7, 8.1, 8.8 Hz,
1 H, 1-H), 4.09–4.18 (m, 2 H, CH3CH2), 4.28 (d, J = 7.7 Hz, 1 H,
2-H), 5.78–5.82 (m, 1 H, 3-H), 6.12–6.17 (m, 1 H, 4-H), 8.19 (s, 3
H, NH2) ppm. 13C NMR (100 MHz, [D6]DMSO, 30 °C): δ = 14.8,
34.9, 44.6, 56.1, 61.7, 128.2, 137.7, 171.8 ppm. C8H14ClNO2
(191.70): calcd. C 50.08, H 7.30, Cl 18.52, N 7.30; found C 50.12,
H 7.45, N 7.19.
acid derivatives (+)-8 and (–)-14, respectively, were synthe-
sized similarly to the corresponding rac compounds
(Schemes 2 and 3).
Conclusion
Effective and stereoselective routes to mono- and dihy-
droxylated cis- and trans-2-aminocaclopentanecarboxylic
acid has been developed via oxazoline intermediates and
OsO4-catalyzed oxidation, respectively. Ongoing work uses
these amino acids to create foldameric structures.
Ethyl cis-2-Aminocyclopent-3-enecarboxylate Hydrochloride (3):
Thionyl chloride (4.42 g, 37.15 mmol) was added dropwise with
stirring to dry EtOH (31 mL) at –15 °C. Compound 5 (5.55 g,
30.92 mmol) was added in one portion to this mixture, which was
then stirred at 0 °C for 30 min. After stirring at room temperature
for 3 h, the mixture was refluxed for a further 1 h and then concen-
trated. The residue was recrystallized from EtOH/Et2O to give
colourless crystals. Yield (5.59 g, 86%); m.p. 190–193 °C (ref.[28]
Experimental Section
General Procedures: 1H NMR spectra were recorded at
400.13 MHz and 13C NMR spectra at 100.62 MHz in D2O or in
[D6]DMSO at ambient temperature with a Bruker AM 400 spec-
trometer. Some spectra were recorded with a Bruker AV 600 spec-
trometer at 600.20 and 150.94 MHz for the 1H and 13C NMR spec-
tra, respectively. Chemical shifts are given in δ (ppm) relative to
TMS as the internal standard. Elemental analyses were performed
with a Perkin-Elmer CHNS-2400 Ser II Elemental Analyzer. Melt-
ing points were measured with a Kofler melting point apparatus
and are uncorrected. The ee for (1R,2S)-2-aminocyclopent-3-en-
ecarboxylic acid hydrochloride [(+)-5] (Ͼ99%) was determined by
gas chromatography on a Chromopak Chiralsil-Dex CB column
(25 m) after double derivatization with (i) CH2N2 and (ii) Ac2O in
the presence of 4-dimethylaminopyridine and pyridine [120 °C for
5 min Ǟ 190 °C (rate of temperature rise 10 °C/min, 140 kPa), re-
tention time: 11.51 min], whereas the ee for the corresponding ethyl
(1R,2S)-2-aminocyclopent-3-enecarboxylate hydrochloride [(+)-3]
(Ͼ99%) was determined under the same conditions, but the sample
was derivatized only with Ac2O (retention time: 12.28 min). As the
ee of ethyl (1R,2S)-2-aminocyclopent-3-enecarboxylate hydrochlo-
ride [(+)-3] is Ͼ99% and not even traces of other diastereomers
were detected in the prepared compounds by 1H NMR spec-
troscopy, the ee values for the products are undoubtedly Ͼ99%.
1
198–200 °C). H NMR (400 MHz, [D6]DMSO, 30 °C): δ = 1.24 (t,
J = 7.1 Hz, 3 H, CH3CH2), 2.60 (dd, J = 8.8, 16.8 Hz, 1 H, 5-Heq),
2.76 (dddd, J = 2.0, 4.5, 8.1, 16.8 Hz, 1 H, 5-Hax), 3.42 (ddd, J =
7.7, 8.1, 8.8 Hz, 1 H, 1-H), 4.09–4.18 (m, 2 H, CH3CH2), 4.28 (d,
J = 7.7 Hz, 1 H, 2-H), 5.78–5.82 (m, 1 H, 3-H), 6.12–6.17 (m, 1 H,
4-H), 8.19 (s, 3 H, NH2) ppm. 13C NMR (100 MHz, [D6]DMSO,
30 °C): δ = 14.8, 34.9, 44.6, 56.1, 61.7, 128.2, 137.7, 171.8 ppm.
C8H14ClNO2 (191.70): calcd. C 50.08, H 7.30, Cl 18.52, N 7.30;
found C 50.12, H 7.45, N 7.19.
Ethyl cis-2-Acetylaminocyclopent-3-enecarboxylate (4a): Et3N
(4.05 g, 40 mmol) and AcCl (1.88 g, 24 mmol) were added to a sus-
pension of 3·HCl (3.83 g, 20 mmol) in CHCl3 (50 mL), and the
mixture was stirred at room temperature for 2 h and then washed
with water (2ϫ20 mL). The aqueous layer was extracted with
CHCl3 (2ϫ30 mL). The combined organic phases were dried
(Na2SO4) and the solvents evaporated. The residue was purified
by column chromatography (n-hexane/EtOAc, 1:3) to afford white
crystals (2.88 g, 73%), m.p. 84–86 °C. 1H NMR (400 MHz, [D6]-
DMSO, 30 °C): δ = 1.14 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.74 (s, 3
H, COCH3), 2.41 (dd, J = 8.7, 16.7 Hz, 1 H, 5-Heq), 2.73 (dddd, J
= 2.3, 4.9, 7.2, 16.7 Hz, 1 H, 5-Hax), 3.27 (ddd, J = 7.2, 8.6, 8.7 Hz,
1 H, 1-H), 3.93–4.05 (m, 2 H, CH3CH2), 5.17 (dd, J = 8.6, 9.2 Hz,
1 H, 2-H), 5.51–5.54 (m, 1 H, 3-H), 5.90–5.94 (m, 1 H, 4-H), 7.75
(d, J = 9.2 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO,
30 °C): δ = 14.0, 22.2, 33.3, 45.8, 55.0, 59.7, 129.5, 132.8, 168.7,
172.3 ppm. C10H15NO3 (197.24): calcd. C 60.90, H 7.67, N 7.10;
found C 60.67, H 8.05, N 7.47.
cis-6-Azabicyclo[3.2.0]hept-3-en-7-one (2):
(10.5 g, 74.19 mmol) in dry Et2O (50 mL) was added dropwise to
solution of freshly distilled 1,3-cyclopentadiene (7.00 g,
A solution of CSI
a
105.90 mmol) dissolved in dry Et2O (100 mL) at –10 °C. After the
addition was completed, the resulting colourless solution was
stirred for 40 min. The reaction mixture was then poured into a
stirred solution of Na2SO3 (7.6 g, 60.8 mmol) in water (100 mL)
and the pH was adjusted to 8–9 with 15% KOH. After stirring at
0 °C for 3 h, the organic layer was separated and the aqueous layer
washed with Et2O (2ϫ250 mL) and then with EtOAc
(2ϫ250 mL). The combined organic layers were dried with
Na2SO4, and the solution was concentrated to dryness under re-
duced pressure. The residue was purified by column chromatog-
raphy (n-hexane/EtOAc, 1:3) to afford white crystals (7.04 g, 61%),
m.p. 30–32 °C (ref.[33] oil). 1H NMR (400 MHz, CDCl3, 30 °C): δ
= 2.42–2.49 (m, 1 H, 2-H), 2.69–2.76 (m, 1 H, 2-H), 3.82–3.84 (m,
1 H, 1-H), 4.50–4.51 (m, 1 H, 5-H), 5.93–5.95 (m, 1 H, 4-H), 6.01–
6.03 (m, 1 H, 4-H), 6.01–6.03 (m, 1 H, 3-H), 6.48 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, CDCl3, 30 °C): δ = 31.5, 54.0, 59.9,
131.3 137.7, 173.0 ppm. C6H7NO (109.13): calcd. C 66.04, H 6.47,
N 12.84; found C 66.22, H 6.55, N 12.61.
Ethyl
cis-2-tert-Butoxycarbonylaminocyclopent-3-enecarboxylate
(4b): Et3N (4.05 g, 40 mmol) and di-tert-butyl dicarbonate (5.24 g,
24 mmol) were added to a suspension of 3·HCl (3.83 g, 20 mmol)
in toluene (50 mL) at 0 °C. Stirring was continued at room tem-
perature for 2 h, after which the organic layer was washed with
H2O (2ϫ20 mL) and the aqueous layer extracted with EtOAc. The
combined organic phases were dried (Na2SO4) and the solvents
evaporated. The residue was recrystallized from n-hexane to give a
white solid (3.52 g, 69%), m.p. 97–99 °C (ref.[28] 89–91 °C). 1H
NMR (600 MHz, [D6]DMSO, 25 °C): δ = 1.17 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.35 (s, 9 H, tBu), 2.32 (dd, J = 8.5, 16.5 Hz, 1 H, 5-
Heq), 2.72 (dddd, J = 2.5, 4.5, 7.4, 16.5 Hz, 1 H, 5-Hax), 3.21 (ddd,
J = 7.4, 8.5, 8.6 Hz, 1 H, 1-H), 3.97–4.04 (m, 2 H, CH3CH2), 4.85
(dd, J = 8.6, 9.4 Hz, 1 H, 2-H), 5.51–5.54 (m, 1 H, 3-H), 5.86 (dd,
Ethyl cis-2-Aminocyclopent-3-enecarboxylate Hydrochloride (3): A
solution of β-lactam 2 (5 g, 45.82 mmol) in EtOH containing 22%
Eur. J. Org. Chem. 2008, 3724–3730
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3727

F. Fülöp et al.
FULL PAPER
J = 2.1, 5.1 Hz, 1 H, 4-H), 6.70 (d, J = 9.4 Hz, 1 H, NH) ppm.
13C NMR (150 MHz, [D6]DMSO, 25 °C): δ = 14.0, 28.2, 33.0, 46.2,
56.9, 59.7, 77.6, 129.3, 132.7, 154.6, 171.8 ppm. C13H21NO4
(255.32): calcd. C 61.16, H 8.29, N 5.49; found C 61.18, H 8.63, N
5.83.
Ethyl (3aR*,4R*,6R*,6aR*)-6-Bromo-2-methyl-4,5,6,6a-tetrahydro-
3aH-cyclopentaoxazole-4-carboxylate (6): Yield: 2.41 g, 86%. 1H
NMR (400 MHz, [D6]DMSO, 30 °C): δ = 1.21 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.87 (s, 3 H, CH3), 2.07 (dd, J = 5.8, 14.9 Hz, 1 H, 5-
H
eq), 2.17 (ddd, J = 4.8, 12.5, 14.9 Hz, 1 H, 5-Hax), 3.40 (ddd, J =
6.2, 7.2, 12.5 Hz, 1 H, 4-H), 4.04–4.15 (m, 2 H, CH3CH2), 4.55 (d,
J = 4.8 Hz, 1 H, 6-H), 4.88 (dd, J = 7.2, 7.3 Hz, 1 H, 3-H), 5.05
(d, J = 7.3 Hz, 1 H, 7-H) ppm. 13C NMR (100 MHz, [D6]DMSO,
30 °C): δ = 13.9, 15.0, 34.7, 48.2, 53.5, 60.9, 72.4, 89.4, 164.6,
170.9 ppm. C10H14BrNO3 (276.13): calcd. C 43.50, H 5.11, N 5.07;
found C 43.39, H 5.13, N 5.20.
Ethyl
cis-2-Benzyloxycarbonylaminocyclopent-3-enecarboxylate
(4c): Benzyl chloroformate (5.12 g, 30 mmol) was added to a solu-
tion of 3·HCl (3.83 g, 20 mmol) and Et3N (4.05 g, 40 mmol) in
THF (160 mL) at 0 °C. After stirring at room temperature for 16 h,
the mixture was taken up in EtOAc (300 mL), washed with H2O,
dried with Na2SO4, and concentrated under reduced pressure. The
residue was recrystallized from n-hexane to give a white solid (4.2 g,
Ethyl (3aR*,4S*,6R*,6aR*)-6-Bromo-2-methyl-4,5,6,6a-tetrahydro-
3aH-cyclopentaoxazole-4-carboxylate (10): Yield: 1.99 g, 71%. 1H
NMR (600 MHz, [D6]DMSO, 25 °C): δ = 1.21 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.89 (s, 3 H, CH3), 2.19–2.27 (m, 1 H, 5-Heq), 2.40 (ddd,
J = 4.6, 5.0, 14.5 Hz, 1 H, 5-Hax), 2.78 (ddd, J = 2.8, 5.1, 7.8 Hz,
1 H, 4-H), 4.12–4.22 (m, 2 H, CH3CH2), 4.35 (d, J = 4.8 Hz, 1 H,
6-H), 4.81 (d, J = 7.8 Hz, 1 H, 3a-H), 5.01 (d, J = 7.8 Hz, 1 H, 6a-
H) ppm. 13C NMR (150 MHz, [D6]DMSO, 25 °C): δ = 13.3, 13.9,
35.8, 49.7, 52.1, 60.5, 72.4, 88.9, 162.8, 171.9 ppm. C10H14BrNO3
(276.13): calcd. C 43.50, H 5.11, N 5.07; found C 43.42, H 5.17, N
4.95.
65%), m.p. 55–57 °C (ref.[28] 60–65 °C). H NMR (400 MHz, [D6]-
1
DMSO, 30 °C): δ = 1.08 (t, J = 7.1 Hz, 3 H, CH3CH2), 2.36 (dd,
J = 8.6, 16.7 Hz, 1 H, 5-Heq), 2.74 (dddd, J = 2.3, 4.8, 8.2, 16.7 Hz,
1 H, 5-Hax), 3.28 (ddd, J = 8.2, 8.6, 9.0 Hz, 1 H, 1-H), 3.95 (q, J
= 7.1 Hz, 2 H, CH3CH2), 4.89–5.00 (m, 3 H, 2-H, OCH2Ph), 5.53–
5.57 (m, 1 H, 3-H), 5.89 (d, J = 4 Hz, 1 H, 4-H), 7.26 (d, J = 9.5 Hz,
1 H, NH), 7.28–7.39 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, [D6]-
DMSO, 30 °C): δ = 14.8, 33.9, 47.1, 58.4, 60.6, 66.0, 128.6, 129.1,
130.1, 133.9, 138.0, 156.2, 172.5 ppm. C16H19NO4 (289.33): calcd.
C 66.42, H 6.62, N 4.84; found C 66.54, H 6.92, N 5.11.
General Procedure for the Dehalogenation of Bromooxazolines 6 and
10 to 7 and 11: Bu3SnH (4.07 g, 14 mmol) was added to a solution
of the bromooxazoline (1.93 g, 7 mmol) in CH2Cl2 (120 mL) under
Ar, and the reaction mixture was stirred at 40 °C for 20 h. The
solvent was then evaporated and the residue purified by column
chromatography on silica gel (n-hexane/EtOAc, 9:1) to afford the
oxazoline as an oil.
cis-2-Aminocyclopent-3-enecarboxylic Acid Hydrochloride (5): A
solution of β-lactam 2 (5 g, 45.82 mmol) in concentrated HCl
(50 mL) was stirred at room temperature for 1 h. After removal of
the solvent, the resulting amino acid hydrochloride 5 was recrys-
tallized from EtOH/Et2O to give a white crystalline solid (5.55 g,
74%), m.p. 185–188 °C (ref.[28] 178–180 °C). 1H NMR (400 MHz,
D2O, 30 °C): δ = 2.58–2.64 (m, 2 H, 5-H), 3.26 (q, J = 8.2 Hz, 1
H, 1-H), 4.24 (d, J = 7.6 Hz, 1 H, 2-H), 5.79–5.83 (m, 1 H, 3-H),
6.18 (d, J = 4.4 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, D2O,
30 °C): δ = 34.9, 47.8, 57.0, 128.5, 137.7, 180.1 ppm. C6H10ClNO2
(163.6): calcd. C 44.05, H 6.16, Cl 21.67, N 8.56; found C 43.85,
H 6.32, N 8.45.
Ethyl
(3aR*,4R*,6aS*)-2-Methyl-4,5,6,6a-tetrahydro-3aH-cyclo-
pentaoxazole-4-carboxylate (7): Yield: 0.89 g, 65%. 1H NMR
(400 MHz, [D6]DMSO, 30 °C): δ = 1.19 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.54–1.69 (m, 3 H, 5-Hax, 5-Heq, 6-H), 1.81–1.86 (m, 4
H, 6-H, CH3), 2.88 (ddd, J = 6.2, 7.2, 12.5 Hz, 1 H, 4-H), 3.99–
4.12 (m, 2 H, CH3CH2), 4.60 (dd, J = 7.2, 7.3 Hz, 1 H, 3a-H), 4.89
(dd, J = 4.8, 7.3 Hz, 1 H, 6a-H) ppm. 13C NMR (100 MHz, [D6]
DMSO, 30 °C): δ = 14.1, 15.0, 24.4, 33.4, 50.1, 60.4, 73.4, 84.2,
165.6, 171.8 ppm. C10H15NO3 (197.24): calcd. C 60.90, H 7.67, N
7.10; found C 60.97, H 7.38, N 7.35.
Ethyl trans-2-Acetylaminocyclopent-3-enecarboxylate (9): Freshly
prepared NaOEt (1.46 g, 21.54 mmol) was added to a solution
of ethyl cis-2-acetylaminocyclopent-3-enecarboxylate (4a; 5.5 g,
21.54 mmol) in anhydrous EtOH (40 mL), and the mixture was
stirred at room temperature for 24 h. It was then concentrated un-
der reduced pressure and taken up in EtOAc, washed with H2O
(2ϫ20 mL), dried with Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatography (n-
hexane/EtOAc, 1:3) to afford white crystals (2.05 g, 37%), m.p. 56–
58 °C. 1H NMR (400 MHz, [D6]DMSO, 30 °C): δ = 1.18 (t, J =
7.1 Hz, 3 H, CH3CH2), 1.79 (s, 3 H, COCH3), 2.43 (dddd, J = 2.0,
4.2, 5.8, 15.8 Hz, 1 H, 5-Heq), 2.66–2.79 (m, 2 H, 1-H, 5-Hax), 4.07
(q, J = 7.1 Hz, 2 H, CH3CH2), 4.97–5.03 (m, 1 H, 2-H), 5.54–5.58
(m, 1 H, 3-H), 5.80–5.84 (m, 1 H, 4-H), 8.06 (d, J = 7.4 Hz, 1 H,
NH) ppm. 13C NMR (100 MHz, [D6]DMSO, 30 °C): δ = 14.9, 23.4,
36.3, 50.0, 59.5, 61.0, 131.9, 131.9, 169.5, 175.0 ppm. C10H15NO3
(197.24): calcd. C 60.90, H 7.67, N 7.10; found C 60.78, H 7.56, N
7.02.
Ethyl
(3aR*,4S*,6aS*)-2-Methyl-4,5,6,6a-tetrahydro-3aH-cyclo-
pentaoxazole-4-carboxylate (11): Yield: 0.87 g, 63%. 1H NMR
(400 MHz, [D6]DMSO, 30 °C): δ = 1.19 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.65–1.87 (m, 4 H, 5-H, 6-H), 1.86 (s, 1 H, CH3), 2.73
(d, J = 7.1 Hz, 1 H, 4-H), 4.07 (q, J = 7.1 Hz, 2 H, CH3CH2), 4.56
(d, J = 7.7 Hz, 1 H, 3a-H), 4.92 (dd, J = 5.8, 7.7 Hz, 1 H, 6a-H)
ppm. 13C NMR (100 MHz, [D6]DMSO, 30 °C): δ = 14.2, 14.9,
26.5, 33.4, 51.5, 61.1, 74.9, 84.4, 164.6, 173.6 ppm. C10H15NO3
(197.24): calcd. C 60.90, H 7.67, N 7.10; found C 60.51, H 7.49, N
7.42.
Synthesis of Stereoisomeric 2-Amino-3-hydroxycyclopentanecarbox-
ylic Acids 8 and 12: A solution of oxazoline derivative 7 (0.6 g,
3.04 mmol) was dissolved in aqueous HCl (20%, 20 mL) and
heated at reflux for 24 h. The solvent was then evaporated to afford
the crude amino acid hydrochloride. The free amino acid base was
liberated by ion-exchange chromatography with Dowex 50. After
concentration, the residue was dissolved in water (5 mL) and di-
General Procedure for the Synthesis of Bromooxazolines 6 and 10:
A solution of N-acetylamino ester 4a or 9 (2 g, 10.14 mmol) in
CH2Cl2 (80 mL) was treated with 1.1 equiv. of NBS, and the reac-
tion mixture was stirred at room temperature for 3 h. When the
reaction was complete (monitored by TLC), the mixture was luted with acetone (25 mL). After filtration, the solution was left
treated with aqueous NaOH solution (10%, 3ϫ20 mL). The aque-
ous solution was next extracted with CH2Cl2 (3ϫ40 mL), the com-
bined organic layers were dried (Na2SO4) and the solvents evapo-
rated. The residue was purified by column chromatography
(CH2Cl2/EtOAc, 10:1) to give a yellow oil.
to stand in a refrigerator for 1 h, which resulted in crystalline
(1S*,2R*,3S*)-2-amino-3-hydroxycyclopentanecarboxylic acid (12)
as the main product. From the mother liquor, all-cis-2-amino-3-
hydroxycyclopentanecarboxylic acid (8) was isolated as a dia-
stereomerically enriched (9:1) mixture, which was separated from
3728
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3724–3730

Synthesis of Hydroxy-Substituted Cispentacin Derivatives
12 by crystallization (water/acetone). Compound 12 was synthe-
sized in the same way starting from 11 (0.6 g, 3.04 mmol).
170.1, 174.2 ppm. C10H17NO5 (231.25): calcd. C 51.94, H 7.41, N
6.06; found C 52.15, H 7.71, N 6.42.
(1R*,2R*,3S*)-2-Amino-3-hydroxycyclopentanecarboxylic Acid (8): Ethyl
(1R*,2R*,3S*,4R*)-2-tert-Butoxycarbonylamino-3,4-dihy-
droxycyclopentanecarboxylate (13b): Compound 13b was prepared
Compound 8 was prepared as a white crystalline solid (0.11 g,
25%), m.p. 250–255 °C (dec.). 1H NMR (600 MHz, D2O, 25 °C): as a white crystalline solid (0.81 g, 56%), m.p. 122–124 °C. 1H
δ = 1.63–1.70 (m, 1 H, 4-H), 1.89–2.07 (m, 3 H, 4-H, 5-Hax, 5- NMR (400 MHz, [D6]DMSO, 30 °C): δ = 1.16 (t, J = 7.1 Hz, 3 H,
Heq), 2.92 (ddd, J = 6.5, 7.0, 8.7 Hz, 1 H, 1-H), 3.60 (dd, J = 5.4,
6.5 Hz, 1 H, 2-H), 4.31 (ddd, J = 5.4, 5.9, 6.7 Hz, 1 H, 3-H) ppm.
13C NMR (150 MHz, D2O, 25 °C): δ = 25.3, 30.0, 44.9, 55.0, 71.1,
CH3CH2), 1.37 (s, 9 H, tBu), 1.64 (ddd, J = 2.3, 8.7, 14.0 Hz, 1 H,
5-Hax), 2.07 (ddd, J = 6.1, 7.0, 14.0 Hz, 1 H, 5-Heq), 3.11 (ddd, J
= 7.0, 8.7, 9.0 Hz, 1 H, 1-H), 3.72–3.77 (m, 1 H, 3-H), 3.89–4.06
180.4 ppm. C6H11NO3 (145.16): calcd. C 49.65, H 7.64, N 9.65; (m, 4 H, 2-H, 4-H, CH3CH2), 4.51 (d, J = 3.5 Hz, 1 H, OH), 4.60
found C 49.41, H 7.43, N 9.58.
(d, J = 6.2 Hz, 1 H, OH), 6.72 (d, J = 8.4 Hz, 1 H, NH) ppm. 13C
NMR (100 MHz, [D6]DMSO, 30 °C): δ = 14.9, 29.1, 33.3, 43.9,
57.8, 60.6, 70.5, 76.7, 78.4, 156.2, 174.0 ppm. C13H28NO6 (289.33):
calcd. C 53.97, H 8.01, N 4.84; found C 54.21, H 8.35, N 5.20.
(1S*,2R*,3S*)-2-Amino-3-hydroxycyclopentanecarboxylic
Acid
(12): Compound 12 was prepared as a white crystalline solid
(0.097 g, 22% from 7; 0.20 g, 45% from 11), m.p. 262–266 °C
(dec.). 1H NMR (400 MHz, D2O, 30 °C): δ = 1.65–1.78 (m, 2 H,
Ethyl (1R*,2R*,3S*,4R*)-2-Benzyloxycarbonylamino-3,4-dihydrox-
4-H, 5-H), 2.01–2.10 (m, 1 H, 4-H), 2.15–2.25 (m, 1 H, 5-H), 2.80 ycyclopentanecarboxylate (13c): Compound 13c was prepared as a
(q, J = 9.2 Hz, 1 H, 1-H), 3.61 (dd, J = 5.1, 9.3 Hz, 1 H, 2-H), 4.33
(ddd, J = 2.6, 4.9, 5.1 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz,
D2O, 30 °C): δ = 25.9, 31.5, 48.3, 57.6, 71.3, 181.4 ppm. C6H11NO3
(145.16): calcd. C 49.65, H 7.64, N 9.65; found C 49.41, H 7.43, N
9.58.
white crystalline solid (0.93 g, 58%), m.p. 118–121 °C. 1H NMR
(400 MHz, [D6]DMSO, 30 °C): δ = 1.08 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.66 (ddd, J = 2.3, 9.2, 13.6 Hz, 1 H, 5-Hax), 2.10 (ddd,
J = 6.0, 7.3, 13.6 Hz, 1 H, 5-Heq), 3.14 (ddd, J = 7.3, 8.9, 9.2 Hz,
1 H, 1-H), 3.72–3.78 (m, 1 H, 3-H), 3.90–3.99 (m, 3 H, 4-H,
CH3CH2), 4.06 (ddd, J = 7.7, 8.8, 8.9 Hz, 1 H, 2-H), 4.56 (d, J =
3.9 Hz, 1 H, OH), 4.67 (d, J = 6.1 Hz, 1 H, OH), 5.01 (d, J =
2.2 Hz, 2 H, OCH2Ph), 7.27 (d, J = 8.8 Hz, 1 H, NH), 7.30–7.39
(m, 5 H, Ph) ppm. 13C NMR (100 MHz, [D6]DMSO, 30 °C): δ =
14.8, 33.2, 43.8, 58.1, 60.6, 66.1, 70.4, 76.6, 128.6, 129.2, 138.0,
156.9, 173.8 ppm. C16H21NO6 (323.35): calcd. C 59.23, H 6.55, N
4.33; found C 59.01, H 6.39, N 4.52.
Ethyl trans-2-tert-Butoxycarbonylaminocyclopent-3-enecarboxylate
(15): Freshly prepared NaOEt (0.79 g, 11.75 mmol) was added to
a
solution of ethyl cis-2-tert-butoxycarbonylaminocyclopent-3-
enecarboxylate (4b) (3 g, 11.75 mmol) in anhydrous EtOH (35 mL),
and the mixture was stirred at room temperature for 24 h. It was
then concentrated under reduced pressure, taken up in EtOAc and
washed with H2O (2ϫ20 mL). The combined organic phases were
dried (Na2SO4) and the solvents evaporated. The residue was
Ethyl
(1S*,2R*,3R*,4R*)-2-tert-Butoxycarbonylamino-3,4-dihy-
recrystallized from n-hexane to give a white solid (1.53 g, 51%),
m.p. 65–67 °C. H NMR (400 MHz, [D6]DMSO, 30 °C): δ = 1.18 a white crystalline solid (0.78 g, 54%), m.p. 150–153 °C. H NMR
droxycyclopentanecarboxylate (16): Compound 16 was prepared as
1
1
(t, J = 7.1 Hz, 3 H, CH3CH2), 1.38 (s, 9 H, tBu), 2.40 (dd, J = 6.9,
16.0 Hz, 1 H, 5-Heq), 2.65 (dd, J = 9.6, 16.0 Hz, 1 H, 5-Hax), 2.81 CH3CH2), 1.37 (s, 9 H, tBu), 1.77–1.88 (m, 2 H, 5-H), 2.74–2.79
(ddd, J = 6.9, 8.6, 9.6 Hz, 1 H, 1-H), 4.08 (q, J = 7.1 Hz, 2 H, (m, 1 H, 1-H), 3.72–3.76 (m, 1 H, 3-H), 3.89 (ddd, J = 4.7, 8.4,
CH3CH2), 4.72–4.76 (m, 1 H, 2-H), 5.52–5.55 (m, 1 H, 3-H), 5.75– 8.7 Hz, 1 H, 2-H), 3.93–3.97 (m, 1 H, 4-H), 4.03 (q, J = 7.1 Hz, 2
(600 MHz, [D6]DMSO, 25 °C): δ = 1.16 (t, J = 7.1 Hz, 3 H,
5.77 (m, 1 H, 4-H), 7.08 (d, J = 8.0 Hz, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO, 30 °C): δ = 14.9, 29.1, 36.0, 50.1, 60.9, 61.2,
78.1, 131.4, 132.1, 156.2, 174.7 ppm. C13H21NO4 (255.32): calcd. C
61.16, H 8.29, N 5.49; found C 60.99, H 8.21, N 5.37.
H, CH3CH2), 4.68 (d, J = 6.0 Hz, 1 H, OH), 4.83 (d, J = 4.2 Hz,
1 H, OH), 6.28 (d, J = 8.7 Hz, 1 H, NH) ppm. 13C NMR
(150 MHz, [D6]DMSO, 25 °C): δ = 14.0, 28.1, 33.4, 46.0, 55.5, 59.9,
71.0, 72.7, 77.8, 154.9, 174.7 ppm. C13H28NO6 (289.33): calcd. C
53.97, H 8.01, N 4.84; found C 54.08, H 7.79, N 5.03.
General Procedure for the Dihydroxylation of N-Acylamino Esters
4a–c and 15: OsO4 (3.2 mL, 0.25 mmol; a 2.0 wt.-% solution in
tBuOH) was added to a stirred solution of N-methylmorpholine
N-oxide (1.73 g, 14.81 mmol) and 4a–c or 15 (5 mmol) in acetone
(35 mL), and the mixture was stirred for 4 h. When the reaction
was complete (monitored by TLC), the mixture was treated with
aqueous Na2SO3 (20 mL). The aqueous layer was extracted with
EtOAc (3ϫ20 mL), the combined organic layers were dried
(Na2SO4), and the solvent was removed by evaporation under re-
duced pressure to afford 13a–c and 16, which were recrystallized
from EtOAc.
General Synthesis of the Stereoisomeric 2-Amino-3,4-dihydroxycy-
clopentanecarboxylic Acids 14 and 17: A solution of dihydroxy ester
13b or 16 (2.3 mmol) was dissolved in aqueous HCl (20%, 20 mL),
and the mixture was stirred at room temperature for 24 h. In the
case of 13a, the mixture was refluxed for 48 h. The solvent was
then evaporated to afford the crude amino ester hydrochloride. The
free amino acid base was liberated by ion-exchange chromatog-
raphy with Dowex 50. An exception was for 13c: the protected dihy-
droxy amino acid was first stirred with 10% Pd/C (80 mg) in EtOH
(30 mL) under H2 for 2 h. The catalyst was then filtered off, and the
filtrate was concentrated under reduced pressure and subsequently
treated with aqueous HCl by the above method.
Ethyl
(1R*,2R*,3S*,4R*)-2-Acetylamino-3,4-dihydroxycyclopen-
tanecarboxylate (13a): Compound 13a was prepared as a white
crystalline solid (0.54 g, 47%), m.p. 160–162 °C. 1H NMR
(400 MHz, [D6]DMSO, 30 °C): δ = 1.14 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.69 (ddd, J = 2.3, 9.2, 13.7 Hz, 1 H, 5-Hax), 1.77 (s, 3
H, COCH3), 2.09 (ddd, J = 6.1, 7.0, 13.7 Hz, 1 H, 5-Heq), 3.11
(ddd, J = 7.0, 8.9, 9.2 Hz, 1 H, 1-H), 3.73–3.78 (m, 1 H, 3-H),
3.91–4.07 (m, 3 H, 4-H, CH3CH2), 4.24 (ddd, J = 7.8, 8.4, 8.9 Hz,
(1R*,2R*,3S*,4R*)-2-Amino-3,4-dihydroxycyclopentanecarboxylic
Acid (14): Compound 14 was prepared as a white crystalline solid
(0.13 g, 35%), m.p. 230–232 °C. H NMR (400 MHz, D2O, 30 °C):
1
δ = 2.14 (ddd, J = 2.3, 9.3, 14.8 Hz, 1 H, 5-Hax), 2.23 (ddd, J =
5.9, 6.8, 14.8 Hz, 1 H, 5-Heq), 3.11 (ddd, J = 6.8, 8.9, 9.3 Hz, 1 H,
1-H), 3.60 (dd, J = 8.4, 8.9 Hz, 1 H, 2-H), 4.15–4.23 (m, 2 H, 3-H,
1 H, 2-H), 4.57 (d, J = 3.9 Hz, 1 H, OH), 4.63 (d, J = 6.4 Hz, 1 4-H) ppm. 13C NMR (100 MHz, D2O, 30 °C): δ = 35.2, 41.0, 55.5,
H, OH), 7.80 (d, J = 8.4 Hz, 1 H, NH) ppm. 13C NMR (100 MHz,
[D6]DMSO, 30 °C): δ = 14.9, 23.3, 33.4, 43.5, 56.0, 60.6, 70.4, 76.6,
69.9, 75.5, 180.6 ppm. C6H11NO4 (161.16): calcd. C 44.72, H 6.88,
N 8.69; found C 44.89, H 8.25, N 9.01.
Eur. J. Org. Chem. 2008, 3724–3730
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3729

F. Fülöp et al.
FULL PAPER
[10]
J. Mittendorf, F. Kunisch, M. Matzke, H. C. Militzer, A.
Schmidt, W. Schönfeld, Bioorg. Med. Chem. Lett. 2003, 13,
433–436.
J. Mittendorf, J. Benet-Buchholz, P. Fey, K. H. Mohrs, Synthe-
sis 2003, 136–140.
(1S*,2R*,3R*,4S*)-2-Amino-3,4-dihydroxycyclopentanecarboxylic
Acid (17): Compound 17 was prepared as a white crystalline solid
(0.12 g, 37%), m.p. 175–179 °C. H NMR (400 MHz, D2O, 30 °C):
δ = 2.06–2.23 (m, 2 H, 5-H), 3.26 (ddd, J = 7.5, 9.2, 9.6 Hz, 1 H,
1-H), 3.92 (dd, J = 6.1, 6.3 Hz, 1 H, 3-H), 4.21–4.29 (m, 2 H, 3-H,
4-H) ppm. 13C NMR (100 MHz, D2O, 30 °C): δ = 32.9, 44.9, 54.1,
71.9, 72.0, 177.2 ppm. C6H11NO4 (161.16): calcd. C 44.72, H 6.88,
N 8.69; found C 44.95, H 6.71, N 8.89.
1
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(1R,2R,3S)-2-Amino-3-hydroxycyclopentanecarboxylic Acid (+)-(8)
and (1R,2R,3S,4R)-2-Amino-3,4-dihydroxycyclopentanecarboxylic
Acid (–)-(14): The same synthetic route as used for the racemic
compounds 8 and 14 was applied, starting from cis-2-aminocyclo-
pentenecarboxylic acid hydrochloride [(+)-(5)],[39] via intermediate
(+)-6 or (–)-13b. The 1H NMR spectroscopic data for the inter-
mediates and products are similar to those for the racemates.
[14]
[15]
[16]
[17]
Ethyl (1R,2S)-2-Aminocyclopent-3-enecarboxylate Hydrochloride
(+)-(3): White crystals, m.p. 89–91 °C, [α]2D0 = +85.4 (c = 0.5,
EtOH).
[18]
[19]
Ethyl (1R,2S)-2-Acetylaminocyclopent-3-enecarboxylate (+)-(4a):
White crystals, m.p. 109–111 °C, [α]2D0 = +33.5 (c = 0.5, EtOH).
[20]
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Ethyl
(3aR,4R,6R,6aR)-6-Bromo-2-methyl-4,5,6,6a-tetrahydro-
3aH-cyclopentaoxazole-4-carboxylate (+)-(6): Yellow oil, [α]2D0
+71.1 (c = 0.5, CH2Cl2).
=
Ethyl (3aR,4R,6aS)-2-Methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta-
oxazole-4-carboxylate (+)-(7): Yellow oil, [α]2D0 = +96.8 (c = 0.5,
EtOH).
(1R,2R,3S)-2-Amino-3-hydroxycyclopentanecarboxylic Acid (+)-(8):
White crystals, m.p. 228 °C (dec.), [α]2D0 = +28.4 (c = 0.584, H2O).
Ethyl (1R,2S)-2-tert-Butoxycarbonylaminocyclopent-3-enecarboxyl-
ate (+)-(4b): Colourless crystals, m.p. 89–90 °C, [α]2D0 = +45.1 (c =
0.5, EtOH).
Ethyl (1R,2R,3S,4R)-2-tert-Butoxycarbonylamino-3,4-dihydroxycy-
clopentanecarboxylate (–)-(13b): White crystals, m.p. 118–120 °C,
[α]2D0 = –117.2 (c = 0.5, EtOH).
(1R,2R,3S,4R)-2-Amino-3,4-dihydroxycyclopentanecarboxylic Acid
(–)-(14): White crystals, m.p. 223 °C (dec.), [α]2D0 = –112.6 (c = 0.5,
H2O).
Acknowledgments
The authors acknowledge the receipt of OTKA grant T 049407 and
a Bolyai fellowship for E. F. and T. A. M.
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Received: April 3, 2008
Published Online: June 4, 2008
3730
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3724–3730