Synthesis of novel functionalized cispentacins through C-C oxidative cleavage of diendo-norbornene β-amino acid

Article abstract of DOI:10.1039/c3ra41963k

Difunctionalized cispentacin derivatives with two new stereogenic centres have been synthesized from a diendo-norbornene β-amino acid in a stereocontrolled route, involving C-C double bond functionalization by dihydroxylation, followed by oxidative ring cleavage and transformation of the dialdehyde intermediates through a Wittig reaction.

Full text of DOI:10.1039/c3ra41963k

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Synthesis of novel functionalized cispentacins through
C–C oxidative cleavage of diendo-norbornene b-amino
acid3
Cite this: RSC Advances, 2013, 3,
9757
a
a
c
ab
´
Maria Cherepanova, Lorand Kiss, Reijo Sillanpaa and Ferenc Fulop*
¨¨
¨ ¨
Received 30th January 2013,
Accepted 23rd April 2013
Difunctionalized cispentacin derivatives with two new stereogenic centres have been synthesized from a
diendo-norbornene b-amino acid in a stereocontrolled route, involving C–C double bond functionalization
by dihydroxylation, followed by oxidative ring cleavage and transformation of the dialdehyde
intermediates through a Wittig reaction.
DOI: 10.1039/c3ra41963k
www.rsc.org/advances
carbocycle C–C double bond, followed by transformation of
the diformyl intermediates. Our present aim was to extend this
Introduction
The five-membered carbocyclic natural b-amino acid cispenta-
cin [(1R,2S)-2-aminocyclopentane-1-carboxylic acid] is known
to possess strong antifungal and antibacterial properties.
methodology so as to obtain novel disubstituted cispentacin
derivatives. The strategy is outlined in Scheme 1. The target
all-cis-disubstituted cispentacin derivatives were planned to be
prepared by oxidative cleavage of the olefinic bond in diendo-
norbornene b-amino acid, followed by Wittig transformation
of the dialdehyde intermediate (Scheme 1).
Preliminary experiments were carried out on the racemic
substances. Racemic diendo-norbornene b-amino acid ( )-1
was readily converted by esterification, N-benzoylation and
olefinic bond dihydroxylation to amino ester ( )-4 (see also ref.
9a). Oxidative cleavage of the C–C bond of the vicinal diol ( )-4
with NaIO4 in THF–H2O furnished all-cis diformyl amino ester
( )-5 (Scheme 2).
Dialdehyde ( )-5 was next used to prepare novel disubsti-
tuted cyclopentane b-amino esters, via the Wittig reaction. The
Wittig reagent was generated from benzyltriphenylphospho-
nium bromide and t-BuOK in THF at 0 uC for 15 min. Addition
of ( )-5 to this mixture resulted after 1 h in all-cis distyryl
cyclopentane amino ester ( )-6 (37%) (Scheme 3). Surprisingly,
the reaction with the Wittig reagent generated from methyl-
triphenylphosphonium bromide and t-BuOK in THF at 0 uC for
15 min yielded not the expected all-cis vinyl-substituted
b-amino ester after 1 h, but ( )-7, which was earlier synthesized
from diformyl amino ester ( )-89d (Scheme 3). In order to avoid
the isomerisation during the reaction of diformyl derivative
( )-5 with methyltriphenylphosphonium bromide–t-BuOK to
Icofungipen
[(1R,2S)-2-amino-4-methylidenecyclopentane-1-
carboxylic acid], another cyclopentane b-amino acid derivative
with an extracyclic methylene function, has been described as
a
strong antifungal agent.1 The five- or six-membered
carbocyclic and heterocyclic b-amino acids are key elements
of a series of bioactive products with antitumoural, antibacter-
ial or antiviral activities.2,3 As conformationally rigid deriva-
tives, alicyclic and N-heterocyclic b-amino acids have been
used as building elements in the construction of novel
bioactive peptides.4,5 In consequence of the enormous
importance of highly functionalized cyclic amino acids,
various methodologies have been applied to synthesize a
number of multisubstituted carbocyclic b-amino acid deriva-
tives with multiple stereogenic centres.6,7 However, few routes
are available for the preparation of alicyclic b-amino acid
regio- and stereoisomers bearing alkyl substituents.8,9d
Results and discussion
We recently reported an efficient and convenient procedure for
the preparation of N-heterocyclic9a–c and substituted alicyclic
b-amino acid derivatives9d from cycloalkene b-amino acids.
The syntheses were based on oxidative cleavage of the
a
¨
¨
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eotvos
u. 6, Hungary
bStereochemistry Research Group of the Hungarian Academy of Sciences, University
¨
¨
of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
c
¨
¨
¨
¨
Department of Chemistry, University of Jyvaskyla, FIN-40014, Jyvaskyla, Finland.
E-mail: fulop@pharm.u-szeged.hu
CCDC reference number 919638. For crystallographic data in CIF or other
3
Scheme 1 Retrosynthetic route to disubstituted cispentacin derivatives.
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Scheme 4 Interconversion of ( )-5 and ( )-8.
Scheme 2 Synthesis of all-cis 3,5-diformyl cispentacin derivative ( )-5.
( )-7 the experimental procedure has been modified by inverse
addition: the in situ generated phosphorane was added to
dialdehyde ( )-5 to reduce the strongly basic medium.
However, carrying out the reaction according to this proce-
dure, after 1 h at room temperature the isomerized product
( )-7 was detected.
The experimental observation of the formation of ( )-7 from
( )-5 may be explained by the isomerization of ( )-5 in the first
step in a keto-enol equilibrium to give the thermodynamically
more stable ( )-8, catalysed by t-BuOK, followed by the Wittig
reaction to yield ( )-7 (Scheme 4). This suggested us to suppose
that the formation of the phosphorane from methyltriphenyl-
phosphonium bromide with t-BuOK required a longer time.
In order to avoid the above isomerisation, the phosphorane
was generated by stirring the phosphonium salt with t-BuOK
not for 15 min, but for 2 h. However, when the resulting
phosphorane was reacted with ( )-5 for either 30 min or 1 h,
( )-7 was again formed.
Scheme 5 Syntheses of disubstituted cispentacin derivatives ( )-10, ( )-11, ( )-
12 and ( )-13.
When ( )-5 was submitted to the Wittig reaction with
methyl-(triphenylphosphoranylidene)acetate in THF at room
temperature for 1 h, the corresponding all-cis 3,5-difunctiona-
lized cispentacin derivative ( )-10 was formed in good yield
(74%) (Scheme 5, Fig. 1).
On treatment with triphenylphosphoranylidene-2-propa-
none, ( )-5 gave in moderate yield the all-cis disubstituted
cyclopentane b-amino acid derivative ( )-11 (Scheme 5). When
subjected to olefinic bond saturation under catalytic hydro-
genation, ( )-10 and ( )-11 yielded the corresponding functio-
nalized cispentacin derivatives ( )-12 and ( )-13 (Scheme 5).
The synthetic method described above was extended to the
preparation of the enantiomerically pure substances, via the
protocol described for the racemic substances. Treatment of
the racemic diendo-norbornene b-amino ester ( )-29a with 1
equivalent of D-(2)-mandelic acid in EtOAc for 10 min gave the
corresponding diastereomeric salt mixture. After repeated
Catalytic hydrogenation of the C–C double bonds in ( )-6
gave the 3,5-disubstituted cispentacin derivative ( )-9
(Scheme 3).
Scheme 3 Syntheses of disubstituted cispentacin derivatives ( )-6, ( )-7 and
( )-9.
Fig. 1 Ortep diagram of compound 10.
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Scheme 6 Syntheses of optically pure disubstituted cispentacin derivatives (+)-
6, (+)-7, (+)-9 and (2)-14.
Scheme 7 Syntheses of enantiomerically pure disubstituted cispentacin deriva-
tives (2)-10, (+)-11, (2)-12 and (+)-13.
crystallization (twice) from EtOAc–EtOH 10 : 1, the pure
diastereomer (monitored by 1H NMR) was filtered off and
treated with a solution of NaHCO3, which resulted in the
enantiomerically pure (2)-2 (25%, ee = 99.9%).
Analogously to the racemic counterpart, (2)-2 was con-
verted by N-benzoylation, dihydroxylation and oxidative ring
opening to the all-cis 3,5-diformyl enantiomer (2)-5
(Scheme 6).
the starting compound determines the configurations of the
newly formed stereogenic centres on the cyclopentane
skeleton. The synthetic procedure was extended to the
preparation of enantiomerically pure products.
Experimental
The absolute configurations of the stereocentres in (2)-5
were determined by chemical correlation. When (2)-5 was
reacted with the Wittig reagent generated from methyltriphe-
nylphosphonium bromide and t-BuOK, it furnished divinyl-
substituted (+)-7 (Scheme 6). Hydrogenolysis of (+)-7 led to (2)-
14; the NMR spectra, HPLC analysis (HPLC ChiralPak IA,
n-hexane–IPA, 0.5 ml min21, 210 nm, the same retention time:
10.05 min, opposite enantiomer 9.09) and comparison of
optical rotations revealed that this compound was identical to
earlier prepared9d by our group from optically pure (+)-8: ethyl
(1S,2R,3S,4R)-2-benzoylamino-3,5-diformylcyclopentanecar-
boxylate, with known absolute configurations (see also
Scheme 3). Since the stereocentres were not affected in the
C–C double bond hydrogenolysis step, it can be assumed from
these results that (2)-5 is ethyl (1S,2R,3R,4S)-2-benzoylamino-
3,5-diformylcyclopentanecarboxylate, and hence (2)-2 has the
1R,2S,3R,4S absolute configuration.
Enantiomer (2)-5 readily reacted with the Wittig reagent
generated from benzyltriphenylphosphonium bromide and
t-BuOK to afford (+)-6, C–C bond saturation of which provided
(+)-9 (Scheme 6).
When reacted with the commercially available phosphor-
anes methyl-(triphenylphosphoranylidene)acetate and triphe-
nylphosphoranylidene-2-propanone, (2)-5 resulted in optically
pure (2)-10 and (+)-11, and saturation of the olefinic bonds
yielded (2)-12 and (+)-13 (Scheme 7).
The chemicals were purchased from Sigma-Aldrich. The NMR
spectra were recorded at 400 MHz with CDCl3 or DMSO as
solvent and tetramethylsilane as internal standard. The
solvents were used as received from the suppliers. Melting
points were determined with a Kofler apparatus. Elemental
analyses were recorded on a Perkin-Elmer CHNS-2400 Ser II
Elemental Analyzer. Silica gel 60 F254 was purchased from
Merck. Mass spectra were recorded on a Finnigan MAT 95S
spectrometer. X-ray crystallography: an Agilent Supernova
diffractometer equipped with an Atlas area-detector, using
Cu-Ka radiation (l = 1.54184 Å).
General procedure for dihydroxylation of N-benzoyl-protected
amino esters
To a solution of N-benzoyl-protected b-amino ester 3 (2 g, 7.7
mmol) and NMO (3 ml, 29 mmol) in acetone (40 ml), a
solution of OsO4 (0.5 ml, 0.03 mmol) in t-BuOH (0.06 M) was
added. The resulting mixture was stirred for 12 h at room
temperature. After completion of the reaction monitored by
TLC, saturated aqueous Na2SO3 solution (120 mL) was added
and the reaction mixture was extracted with CH2Cl2 (3 6 100
ml). The combined organic phases were dried over Na2SO4,
filtered and evaporated in vacuo yielding compound 4.
General procedure for the oxidative cleavage of 4
To a solution of 4 (200 mg, 0.63 mmol) in THF–H2O (11 ml, v/v
10 : 1), NaIO4 (269 mg, 1.26 mmol) was added and the reaction
mixture was stirred for 15 min at room temperature under an
Ar atmosphere, which resulted in diformyl derivative 5. The
mixture was then quenched by the addition of water (20 ml)
and extracted with CH2Cl2 (2 6 15 ml). The combined organic
In conclusion, we have described a convenient way to
access difunctionalized cispentacin derivatives from diendo-
norbornene b-amino acid, involving C–C double bond dihy-
droxylation, vicinal diol oxidation through ring cleavage and
conversion of the dialdehyde derivative formed to functiona-
lized cispentacins through a Wittig reaction. The structure of
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phases were dried over Na2SO4, filtered and evaporated in
vacuo.
Ethyl (1S*,2R*,3R*,5S*)-2-benzamido-3,5-
diphenethylcyclopentanecarboxylate [( )-9]
White solid. Yield: 73%. M.p. 89–92 uC, (Rf 0.2, n-hexane–
EtOAc 3 : 1). 1H NMR (CDCl3, 400 MHz) d: 1.18 (t, 3H, CH3, J =
6.80 Hz), 2.03–2.36 (m, 6H, CH2), 2.85–2.92 (m, 1H, H-1), 2.96–
3.03 (m, 1H, H-3), 3.22–3.33 (m, 1H, H-5), 3.44–3.65 (m, 4H,
ArCH2), 4.14–4.18 (m, 2H, OCH2), 4.46–4.50 (m, 1H, H-2), 7.15–
7.80 (m, 15H, Ar–H). 13C NMR (DMSO, 400 MHz) d: 14.9, 36.3,
43.9, 47.9, 56.5, 60.2, 60.8, 126.8, 126.9, 128.0, 128.1, 129.1,
129.4, 129.5, 130.0, 130.5, 132.0, 132.7, 133.4, 135.3, 137.6,
137.8, 167.0, 173.7. MS: (ESI) m/z = 470.51 (M + 1). Anal. Calcd.
for C31H35NO3: C, 79.28; H, 7.51; N, 2.98. Found: C, 78.97; H,
7.20; N, 2.66.
General procedure for the Wittig reaction
Diformyl derivative 5 (200 mg, 0.63 mmol) was dissolved in dry
THF (5 ml) and the appropriate phosphorane (Wittig reagent)
(1.26 mmol) was added to the solution. After stirring for 1 h at
room temperature the reaction mixture was concentrated in
vacuo and purified by column chromatography on silica gel
(n-hexane–EtOAc).
General procedure for the in situ Wittig reaction
The Wittig reagent was prepared by adding t-BuOK (1.26
mmol) to a solution of the phosphonium salt (1.26 mmol) in
dry THF (5 ml), with stirring for 10 min. Diformyl derivative 5
(200 mg, 0.63 mmol) was dissolved in dry THF (5 ml) and
added dropwise to the solution of the in situ generated Wittig
reagent. After stirring for 1 h at room temperature, the
reaction mixture was concentrated in vacuo and purified by
column chromatography on silica gel (n-hexane–EtOAc).
Dimethyl (2E,2’E)-3,3’-((1R*,3S*,4R*,5S*)-4-benzamido-5-
(ethoxycarbonyl) cyclopentane-1,3-diyl)diacrylate [( )-10]
White solid. 74% yield. M.p. 70–74 uC. (Rf 0.3, n-hexane–EtOAc
1
1 : 1). H NMR (CDCl3, 400 MHz) d: 1.16 (t, 3H, CH3, J = 7.16
Hz), 1.53–1.63 (m, 2H, H-1), 2.89–3.00 (m, 1H, H-3), 3.10–3.25
(m, 2H, H-3, H-5), 3.70 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 4.02–
4.18 (m, 2H, OCH2), 4.70–4.74 (m, 1H, H-4), 5.90 (t, 2H, LC–H),
6,75 (d, 1H, NH, J = 8.77 Hz), 6.87–6.97 (m, 2H, LC–H), 7.37–
7.79 (m, 5H, Ar–H). 13C NMR (DMSO, 400 MHz) d: 14.8, 36.1,
44.2, 47.2, 52.2, 53.1, 56.2, 60.9, 121.6, 121.9, 128.1, 129.0,
132.1, 135.0, 150.1, 150.8, 166.8, 167.0, 172.2. Anal. Calcd. for
C23H27NO7: C, 64.32; H, 6.34; N, 3.26. Found: C, 64.01; H, 6.02;
N, 2.92.
General procedure for C–C double bond saturation
A solution of 7, 10 or 11 (100 mg, 0.32 mmol), containing in
EtOAc (20 mL) 10% mol Pd/C (20 mg) was stirred under a H2
atmosphere for 1 h. The reaction mixture was then filtered
through silica gel and celite. The filtrate was concentrated
under reduced pressure and purified by column chromato-
graphy on silica gel (n-hexane–EtOAc).
Dimethyl 3,3’-((1S*,3R*,4R*,5S*)-4-benzamido-5-
(ethoxycarbonyl)cyclopentane-1,3-diyl)dipropanoate [( )-12]
Ethyl (1S*,2R*,3R*,5S*)-2-benzamido-3,5-
diformylcyclopentanecarboxylate [( )-5)]
Yellow oil, Yield: 72%. (Rf 0.2, n-hexane–EtOAc 1 : 1). 1H NMR
(CDCl3, 400 MHz) d: 1.24–1.29 (m, 3H, CH3), 1.64–2.53 (m,
12H, H-1, H-3, 2 x H-4, 4 x CH2), 3.27–3.34 (m, 1H, H-5), 3.65 (s,
3H, OCH3), 3.71 (s, 3H, OCH3), 4.08–4.31 (m, 2H, OCH2), 4.93–
5.10 (m, 1H, H-4), 6,98 (br s, 1H, NH), 7.42–7.84 (m, 5H, Ar–H).
13C NMR (DMSO, 400 MHz) d: 14.9, 25.7, 27.5, 29.5, 32.9, 33.2,
36.9, 41.4, 51.2, 52.1, 53.1, 53.7, 60.6, 128.1, 129.1, 132.0,
135.6, 167.3, 172.6, 174.1. MS: (ESI) m/z = 434.43 (M + 1). Anal.
Calcd. for C23H31NO7: C, 64.73; H, 7.21; N, 3.23. Found: C,
64.43; H, 6.90; N, 2.91.
Yellow oil. Yield: 85%. (Rf 0.2, n-hexane–EtOAc 1 : 4). 1H NMR
(CDCl3, 400 MHz) d: 1.11 (t, 3H, CH3, J = 7.07 Hz), 2.14–2.34
(m, 1H, H-4), 2.57–2.66 (m, 1H, H-4), 3.16–3.24 (m, 1H, H-5),
3.38–3.46 (m, 1H, H-3), 3.56–3.61 (m, 1H, H-1), 4.00–4.18 (m,
2H, OCH2), 5.21-5.24 (m, 1H, H-2), 7.38–7.91 (m, 5H, Ar-H),
9.74 (s, 1H, COH), 9.95 (s, 1H, COH). 13C NMR (DMSO, 400
MHz) d: 14.7, 24.8, 49.8, 50.8, 53.5, 54.0, 61.4, 127.8, 129.3,
132.4, 134.8, 167.6, 171.9, 203.1, 205.1. Anal. Calcd. for
C17H19NO5: C, 64.34; H, 6.03; N, 4.41. Found: C, 64.02; H,
5.70; N, 4.07.
Ethyl (1S*,2R*,3S*,5R*)-2-benzamido-3,5-bis((E)-3-oxobut-1-
enyl)cyclopentanecarboxylate [( )-11]
Ethyl (1S*,2R*,3S*,5R*)-2-benzamido-3,5-(E,E)-
distyrylcyclopentanecarboxylate [( )-6]
Yellow oil, Yield: 47%. (Rf 0.4, n-hexane–EtOAc 1 : 4). 1H NMR
(DMSO, 400 MHz) d: 0.97–1.10 (m, 3H, CH3), 2.08–2.16 (m, 2H,
CH2), 2.19–2.22 (m, 6H, 2CH3), 2.98–3.20 (m, 1H, H-3), 3.31–
3.45 (m, 1H, H-5), 3.73–3.78 (m, 1H, H-1), 3.93–4.05 (m, 2H,
OCH2), 5.03–5.23 (m, 1H, H-2), 5.81–5.88 (m, 2H, LC–H), 6.69–
6.80 (m, 2H, LC–H), 7.40–7.90 (m, 5H, Ar–H). 13C NMR (DMSO,
400 MHz) d: 14.7, 35.6, 43.2, 45.3, 52.1, 52.5, 55.2, 60.9, 121.2,
122.9, 128.2, 129.0, 132.0, 135.7, 149.1, 150.7, 166.7, 167.8,
171.2. Anal. Calcd. for C23H27NO5: C, 69.50; H, 6.85; N, 3.52.
Found: C, 69.18; H, 6.52; N, 3.20.
White solid. Yield: 37%. M.p. 162–165 uC; (Rf 0.3, n-hexane–
EtOAc 3 : 1). 1H NMR (CDCl3, 400 MHz) d: 1.18 (t, 3H, CH3, J =
6.80 Hz), 2.03–2.16 (m, 2H, CH2), 2.85–2.92 (m, 1H, H-3), 2.96–
3.03 (m, 1H, H-5), 3.22–3.33 (m, 1H, H-1), 4.14–4.18 (m, 2H,
OCH2), 4.47–4.50 (m, 1H, H-2), 6.12–6.28 (m, 2H, LC–H), 6.41–
6.49 (m, 2H, LC–H), 7.15–7.80 (m, 15H, Ar–H). 13C NMR
(DMSO, 400 MHz) d: 14.9, 36.3, 43.9, 47.9, 56.5, 60.2, 60.8,
126.8, 126.9, 128.0, 128.1, 129.1, 129.4, 129.5, 130.0, 130.5,
132.0, 132.7, 133.4, 135.3, 137.6, 137.8, 167.0, 173.7. Anal.
Calcd. for C31H31NO3: C, 79.97; H, 6.71; N, 3.01. Found: C,
79.64; H, 6.40; N, 2.68.
Ethyl (1S*,2R*,3R*,5S*)-2-benzamido-3,5-bis(3-
oxobutyl)cyclopentanecarboxylate [( )-13]
Yellow oil. Yield: 78%. (Rf 0.4, n-hexane–EtOAc 1 : 4). 1H NMR
(CDCl3, 400 MHz) d: 1.20 (t, 3H, CH3, J = 7.16 Hz), 2.48–2.70
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(m, 12H, 5 x CH2, H-3 and H-5) 2.66 (s, 3H, CH3), 2.68 (s, 3H,
CH3), 3.00–3.08 (m, 1H, H-1), 4.05–4.09 (m, 2H, OCH2), 4.62–
4.70 (m, 1H, H-2), 7.44–7.82 (m, 5H, Ar–H), 8.16 (br s, 1H, N–
H). MS: (ESI) m/z = 400.78 (M + 1). Anal. Calcd. for C23H31NO5:
C, 68.80; H, 7.78; N, 3.49. Found: C, 68.45; H, 7.46; N, 3.18.
Ethyl (1S,2R,3R,4S)-2-benzoylamino-3,5-
diformylcyclopentanecarboxylate [(2)-5]
Yellow oil, yield: 78%. [a]2D5 220 (c 0.24, EtOH).
Ethyl (1S,2R,3R,4S)-2-benzoylamino-3,5-
divinylcyclopentanecarboxylate [(+)-7]
Separation of racemic amino ester 2
White solid, yield: 61%. M.p. 93–95 uC. [a]2D5 = +27.3 (c 0.35,
EtOH).9d
A solution of D-(2)-mandelic acid (1 equiv., 1.9 g) in EtOAc (15
mL) was slowly added to a solution of racemic bicyclic diendo-
aminoester 2 (2.3 g) in EtOAc (20 mL). The resulting mixture
was stirred at RT for 10 min. The salt formed was filtered off
and recrystallized twice from EtOAc–EtOH 10 : 1. The ratio of
Ethyl (1S,2R,3S,4R)-2-benzoylamino-3,5-
diethylcyclopentanecarboxylate [(2)-14]
White solid, yield: 90%. M.p. 76–78 uC. [a]2D5 230 (c 0.26,
EtOH). ee = 81%.9d
1
the diastereomeric salts was monitored by H NMR. The pure
diastereomeric salt was then treated with a saturated solution
of NaHCO3, resulting in enantiomerically pure bicyclic diendo-
aminoester (2)-2 (25%, ee = 99.9%; HPLC, Chiralpack IA
column, eluent: n-hexane–IPA (80 : 20), flow rate: 0.5 mL
min21, detection at 210 nm).
Ethyl (1S,2R,3S,4R)-2-benzoylamino-3,5-(E,E)-
distyrylcyclopentanecarboxylate [(+)-6]
White solid, yield: 43%. M.p. 160–162 uC. [a]2D5 = +68 (c 0.31,
EtOH).
Ethyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-
carboxylate[(2)-2]
Ethyl (1S,2R,3R,4S)-2-benzoylamino-3,5-
diphenethylcyclopentanecarboxylate [(+)-9]
Colourless oil. [a]2D5 25 (c 0.45, EtOH).
White solid, yield: 85%. M.p. 87–89 uC. [a]2D5 = +38 (c 0.27,
EtOH). ee = 99%.
Characterization of the enantiomers
Ethyl (1S,2R,3S,4R)-2-benzoylamino-3,5-(E,E)-bis-(2-
methoxycarbonylvinyl)-cyclopentanecarboxylate [(2)-10]
White solid, yield: 72%. M.p. 68–71 uC. [a]2D5 26.5 (c 0.33,
All the 1H NMR spectra recorded on the enantiomeric
substances were the same as those of the corresponding
racemic counterparts.
EtOH).
The ee values were determined by HPLC [Chiralpack IA
column, eluent: n-hexane–IPA 80 : 20, flow rate: 0.5 mL min21
,
Ethyl (1S,2R,3R,4S)-2-benzoylamino-3,5-bis-(2-
methoxycarbonylethyl)cyclopentanecarboxylate [(2)-12]
detection at 260 nm].
Yellow oil, yield: 70%. [a]2D5 27.8 (c 0.36, EtOH); ee = 98%.
Ethyl (1R,2S,3R,4S)-3-benzoylaminobicyclo[2.2.1]hept-5-ene-2-
carboxylate [(2)-3]
Ethyl (1S,2R,3S,4R)-2-benzoylamino-3,5-(E,E)-bis-(3-oxobut-1-
enyl)cyclopentanecarboxylate [(+)-11]
Yellow oil, yield: 47%. [a]2D5 = +43 (c 0.175, EtOH).
White solid, yield: 80%. M.p. 88–90 uC. [a]2D5 262 (c 0.32,
EtOH). 1H NMR (DMSO, 400 MHz) d: 1.04 (t, 3H, CH3, J = 7.20
Hz), 1.39–1.42 (m, 1H, CH2), 1.47–1.52 (m, 1H, CH2), 3.02–3.08
(m, 1H, H-2), 3.26–3.38 (m, 2H, H-1 and H-4), 3.82–4.03 (m,
2H, OCH2), 4.79–4.86 (m, 1H, H-2), 6.33–6.42 (m, 2H, H-5 and
H-6), 7.38–7.51 (m, 3H, Ar–H), 7.53 (br s, 1H, N–H), 7.60–7.64
(m, 2H, Ar–H). 13C NMR (DMSO, 400 MHz) d: 17.8, 46.8, 47.3,
47.6, 47.9, 53.3, 60.8, 127.5, 129.3, 132.1, 134.9, 135.3, 138.2.
166.8, 173.5. Anal. Calcd. for C17H19NO3: C, 71.56; H, 6.71; N,
4.91. Found: C, 71.19; H, 6.99; N, 4.67.
Ethyl (1S,2R,3R,4S)-2-benzoylamino-3,5-bis-(3-
oxobutyl)cyclopentanecarboxylate [(+)-13]
Yellow oil, yield: 83%. [a]2D5 = +28 (c 0.27, EtOH); ee = 96%.
Crystal data for 10:
¯
C
23H27NO7, Mr = 552.64, triclinic, space group P1; a =
10.5092(14) Å, b = 11.2202(16) Å, c = 11.4916(16) Å, a =
115.706(14), b = 94.335(11), c = 113.346(13)u, V = 1069.6(3) Å3, Z
= 2, Dc = 1.333 g cm23, l = 1.54184 Å, m(Cu-Ka) = 0.080 mm21
,
Ethyl (1S,2S,3R,4R,5R,6S)-3-benzoylamino-5,6-
F(000) = 456, and T = 123(2)K. A crystal with the dimensions
0.20 6 0.20 6 0.25 mm was selected for X-ray analysis. An
empirical absorption correction using spherical harmonics
implemented in the SCALE3 ABSPACK scaling algorithm, was
applied with the CrysAlisPro program package.10 A total of
18 491 reflections yielded 4065 unique reflections in the range
4.48u ¡ h ¡ 69.96u (Rint = 0.0217). The structure was solved by
using direct methods with SHELXS11 and was refined by full-
matrix least-squares on F2 with SHELXL.11 Non-hydrogen
atoms were refined anisotropically. CH hydrogen atoms were
fixed at calculated positions and refined by using a riding
model, and NH hydrogen was refined isotropically. The final
indices were R1 = 0.0348 (F2 . 2s(F2), R1 = 0.384 (all data), with
dihydroxybicyclo[2.2.1]heptane-2-carboxylate [(2)-4]
White solid, yield: 85%. M.p. 170–172 uC. [a]2D5 214 (c 0.26,
EtOH). 1H NMR (DMSO, 400 MHz) d: 1.14 (t, 3H, CH3, J = 7.20
Hz), 1.28–1.32 (m, 1H, CH2), 1.76–1.80 (m, 1H, CH2), 2.33–2.40
(m, 2H, H-1 and H-4), 3.05–3.11 (m, 1H, H-2), 3.78–3.84 (m,
1H, H-3), 4.01–4.12 (m, 3H, OCH2 and H-6), 4.40–4.44 (m, 1H,
H-5), 4.55 (br s, 1H, O–H), 4.72 (br s, 1H, O–H), 7.46–7.52 (m,
3H, Ar–H), 7.76–7.82 (m, 2H, Ar–H), 8.47 (br s, 1H, N–H). 13C
NMR (DMSO, 400 MHz) d: 14.8, 31.1, 41.1, 48.2, 48.9, 49.7,
61.1, 67.4, 69.9, 127.8, 129.3, 132.1, 135.3, 167.0, 173.5. Anal.
Calcd. for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C,
63.72; H, 6.32; N, 4.63.
a
goodness-of-fit
=
1.045. Crystallographic data for the
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C. Roemmele, Jr. J. J. Haley, D. R. Mowrey, D. E. Petrillo, J.
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structure of 10 have been deposited in the Cambridge
Crystallographic Data Centre (deposition number: CCDC
919638).
Acknowledgements
We are grateful to the Hungarian Research Foundation (grants
´
OTKA No. NK81371 and K100530) and TAMOP-4.2.2/B-10/1/
2010-0012 for financial support.
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