A new access route to functionalized cispentacins from norbornene β-amino acids

Article abstract of DOI:10.1002/chem.201203183

An efficient and simple new stereocontrolled access route to novel disubstituted cispentacin derivatives with multiple stereogenic centers from norbornene β-lactam has been developed. The synthesis involves olefinic bond functionalization by dihydroxylation followed by oxidative ring cleavage and transformation of the dialdehyde intermediate through a Wittig reaction. Copyright

Full text of DOI:10.1002/chem.201203183

DOI: 10.1002/chem.201203183
A New Access Route to Functionalized Cispentacins from
Norbornene b-Amino Acids
Lorꢀnd Kiss,[a] Maria Cherepanova,[a] Eniko˝ Forrꢁ,[a] and Ferenc Fꢂlçp*[a, b]
Abstract: An efficient and simple new stereocontrolled access route to novel di-
A
Keywords: cyclopentanes
matic resolution oxidation
stereochemistry · Wittig reactions
· enzy-
E
·
·
tionalization by dihydroxylation followed by oxidative ring cleavage and transfor-
mation of the dialdehyde intermediate through a Wittig reaction.
Introduction
methods are regio- and stereoselective iodooxazination and
iodooxazoline formation, iodolactonization,[6] iodolactamiza-
tion,[7] stereoselective epoxidation and regioselective oxirane
opening,[8] stereoselective dihydroxylation[9] and functionali-
zation through 1,3-dipolar cycloaddition.[10] Other strategies
include [2+2] cycloaddition,[11] syntheses from substituted
cyclic b-keto esters,[12] ring-opening metathesis,[13] cross-
metathesis of the imino esters resulting from fluorinated
imidoyl chlorides and ethyl acrylate,[14] and lithium amide
Cyclic b-amino acids with valuable pharmacological poten-
tial have generated increasing interest during the past two
decades. These compounds are precursors of bioactive b-lac-
tams and are important elements of many natural products.
A number of derivatives of this class of compounds, such as
cispentacin [(1R,2S)-2-aminocyclopentanecarboxylic acid],
icofungipen [(1R,2S)-2-amino-4-methylenecyclopentanecar-
boxylic acid], and oryzoxymycin, are strong antifungal
agents or antibiotics.[1] The conformationally rigid alicyclic
and heterocyclic b-amino acids are highly important building
blocks for the synthesis of peptides to be applied in drug re-
search.[2]
Highly functionalized cyclic amino acids have become of
great interest in organic and medicinal chemistry research
during the past ten years. Cyclohexane amino acids, such as
Tamiflu, the O-heterocyclic amino acid Zanamivir and relat-
ed derivatives,[3,4] and the cyclopentane amino acid Perami-
vir and its analogues,[5] exert important antiviral activities.
Consequently, in view of this enormous pharmacological po-
tential, the synthesis of multisubstituted cycloalkane amino
acids has been a focus in synthetic and medicinal chemistry.
The main strategies relating to the synthesis of highly
functionalized cyclic amino acids are based on the function-
promoted conjugate addition to a,b-unsaturated carbox
ACHTUNGTRENNUNGyl-
AHCTUNGTRENNUNG
ed cispentacin derivatives are to be found in the literature.
A general method for the preparation of alkylated cyclic b-
amino acid derivatives is the lithium amide mediated conju-
gate addition to a,b-unsaturated carboxylates.[15] A less gen-
eral approach is the transformation of alkylated bicyclic an-
hydrides by ammonolysis and Hoffman degradation.[1g]
Results and Discussion
The aim of this work is to describe a novel approach to the
preparation of difunctionalized cispentacins from a b-lactam
derived exo-norbornadiene.
The concept of the synthetic route, represented in the ret-
rosynthetic scheme (Scheme 1), was the functionalization of
ꢀ
alization of a ring C C double bond or on the ring closure
ꢀ
of already substituted carboxylate entities, followed by
transformation into amino acids or amino carboxylates. In
the framework of the first approach, the most relevant
the C C ring double bond of the di-exo-norbornene b-
lactam by stereoselective dihydroxylation, conversion of the
ꢀ
vicinal dihydroxylated amino ester by oxidative C C bond
[a] Dr. L. Kiss, M. Cherepanova, Dr. E. Forrꢀ, Prof. F. Fꢁlçp
Institute of Pharmaceutical Chemistry, University of Szeged
6720 Szeged, Eçtvçs u. 6, (Hungary)
E-mail: fulop@pharm.u-szeged.hu
[b] Prof. F. Fꢁlçp
Stereochemistry Research Group of the
Hungarian Academy of Sciences, University of Szeged
6720 Szeged, Eçtvçs u. 6, (Hungary)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203183.
Scheme 1. Retrosynthetic scheme for the preparation of difunctionalized
cispentacins from a b-lactam derived exo-norbornadiene.
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Chem. Eur. J. 2013, 19, 2102 – 2107

FULL PAPER
cleavage with ring opening to generate the corresponding di-
aldehyde derivative, followed by Wittig transformation with
different phosphoranylides and reduction of the olefinic
bond (Scheme 1).
The initial b-lactam, 1, was transformed by known proce-
dures[9c–e] through lactam ring opening with ethanolic HCl
solution, N-benzoylation, and dihydroxylation of amino
ester 2 with N-methylmorpholine N-oxide (NMO) and a cat-
alytic amount of OsO4 into the corresponding vicinal cis-
diol 3 (Scheme 2). Bicyclic dihydroxylated amino ester 3
Scheme 3. Synthesis of difunctionalized cispentacin derivatives 7 and 8
from dialdehyde 4.
Scheme 2. Synthesis of dialdehyde 4 from b-lactam 1. THF: tetrahydro-
furan.
good yields (Scheme 3). It is important to note that the
structure of the initial norbornene b-aminocarboxylate de-
termined the configuration of the newly formed stereogenic
centers at positions C3 and C5 in these products.
By analogous synthetic procedures, novel substituted cis-
pentacin derivatives were prepared by using various com-
mercially available phosphoranes. When dialdehyde 4 was
treated with methyl (triphenylphosphoranylidene)acetate in
THF (Scheme 4), the corresponding Wittig product 9, with
ꢀ
was next subjected to oxidative C C cleavage with sodium
periodate. In contrast with similar transformations of mono-
cyclic dihydroxylated amino esters, in which the correspond-
ing dialdehydes could not be isolated,[9c–e] the dialdehyde
formed in the present case, in which the two formyl moieties
are in a trans relationship relative to the carboxylate and
amide groups, proved to be a stable, isolable compound
(Scheme 2).
ꢀ
two C C double bonds, was formed in relatively good yield
(74%). In a similar transformation, amino ester 4 was treat-
ed with (triphenylphosphoranylidene)-2-propanone in THF
to give the olefinic product 10. Compounds 9 and 10 were
Amino ester 4, bearing two formyl substituents, was an
excellent precursor for further functionalizations,[16] for ex-
ample, the preparation of alkyl-substituted cispentacins. In
ꢀ
order to create a C C double bond, compound 4 was sub-
jected to an in situ Wittig reaction (Scheme 3). Methyltri-
phenylphosphonium bromide was treated with potassium
tert-butoxide in dry THF for 15 min to furnish the corre-
sponding phosphorane, which was treated immediately with
dialdehyde 4. The reaction resulted in the corresponding di-
alkenylated b-aminocyclopentanecarboxylate 5 in moderate
yield (51%). Similarly, compound 4 treated with the phos-
phorane derived from benzyltriphenylphosphonium bromide
gave the corresponding dialkenylated b-amino ester 6 in
34% yield (Scheme 3). Next, amino esters 5 and 6 were hy-
drogenated under catalytic conditions into the correspond-
ing dialkyl-substituted cispentacin derivatives 7 and 8 in
Abstract in Hungarian: Norbornꢀnvꢁzas b-laktꢁmbꢂl kiin-
dulva sztereokontrollꢁlt ꢁtalakꢃtꢁsokkal nꢀgy sztereogꢀn cent-
rumot tartalmazꢂ diszubsztituꢁlt ciszpentacin szꢁrmazꢀkokat
˝
˝ ˝
ꢁllꢃtottunk elo. A szintꢀzisfflt kulcslꢀpꢀsei a gyuru szꢀn-szꢀn
˝
˝ ˝
kettos kçtꢀsꢀnek dihidroxilꢁlꢁsa, majd oxidatꢃv gyurunyitꢁst
˝
˝
kçveto Wittig reakciꢂval tçrtꢀno funkcionalizꢁlꢁsai voltak.
Scheme 4. Synthesis of difunctionalized cispentacin derivatives 11 and 12
from dialdehyde 4.
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F. Fꢁlçp et al.
then subjected to hydrogenolysis in the presence of a cata-
lytic amount of Pd/C to furnish the corresponding difunc-
tionalized cispentacin derivatives 11 and 12 (Scheme 4).
The newly developed protocol described above for the
synthesis of functionalized cispentacins allowed the prepara-
tion of these compounds in enantiomerically pure form.
Hence, racemic b-lactam 1 was subjected to enantioselective
lactam ring opening by a facile, solvent-free enzymatic
method,[17] which was scaled up successfully (Scheme 5).
Scheme 6. Synthesis of optically active difunctionalized cispentacin deriv-
atives (ꢀ)-7 and (+)-8 from dialdehyde (+)-4.
In conclusion, we have developed a novel synthetic access
route to difunctionalized cispentacin derivatives from a di-
exo-norbornene b-amino acid through dihydroxylation, per-
AHCTUNGTREGiNNUN odate oxidation involving ring cleavage, and conversion of
the dialdehyde derivative formed into the functionalized de-
rivatives through a Wittig reaction. The structure of the ini-
tial compound determines the stereochemistry of the newly
formed stereogenic centers on the cyclopentane framework
of the products. The developed method based on oxidative
ring cleavage and dialdehyde-intermediate transformations
under different conditions might be generalized and applied
toward the synthesis of a variety of substituted cispentacin
Scheme 5. Enzymatic resolution of racemic b-lactam 1 and synthesis of
enantiomerically pure dialdehyde 4.
Lactam 1 was mixed well with
Lipolase, water was added, and
the mixture was shaken in an
incubator shaker at 708C. The
resulting enantiomerically pure
amino acid (ꢀ)-13 (ee>98%)
and unreacted b-lactam (+)-1
(ee=99%) were easily separat-
ed (see the Experimental Sec-
tion). Next, treatment of enan-
tiomer (+)-1 with HCl/EtOH,
followed by benzoylation, af-
Scheme 7. Synthesis of optically active difunctionalized cispentacin derivatives (+)-11 and (+)-12 from dialde-
hyde (+)-4.
forded optically pure (+)-2,
which, after dihydroxylation
ꢀ
and C C bond cleavage, led to
dialdehyde (+)-4 (Scheme 5).
The in situ Wittig reaction of (+)-4 furnished olefinic de-
derivatives. The synthetic procedure was extended to the
preparation of these substances in enantiomerically pure
form.
ꢀ
rivatives (+)-5 and (+)-6, after which C C double-bond sat-
uration by catalytic hydrogenation led to substituted cispen-
tacin derivatives (ꢀ)-7 and (+)-8 in optically active forms
(Scheme 6).
The reaction of diformyl amino ester (+)-4 with methyl
(triphenylphosphoranylidene)acetate or (triphenylphosphor-
anylidene)-2-propanone afforded enantiomers (+)-9 and
(+)-10, respectively, the hydrogenation of which furnished
b-amino acid derivatives (+)-11 and (+)-12 in enantiomeri-
cally pure form (Scheme 7).
Experimental Section
General information: The chemicals were purchased from Sigma–Al-
drich. The NMR spectra were recorded at 400 MHz with CDCl3 or [D6]-
dimethylsulfoxide ([D6]DMSO) as the solvent and tetramethylsilane as
an internal standard. The solvents were used as received from the suppli-
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Chem. Eur. J. 2013, 19, 2102 – 2107

Synthesis of Functionalized Cispentacins
FULL PAPER
ers. 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.
466.85 [M+1]; elemental analysis: calcd (%) for C31H31NO3: C 79.97, H
6.71, N 3.01; found: C 79.64, H 6.41, N 3.32.
Dimethyl 3,3’-((1R*,3S*,4S*,5R*)-4-benzamido-5-(ethoxycarbonyl)cyclo-
pentane-1,3-diyl)diacrylate (9): White solid; yield: 74%; m.p. 152–1548C;
Rf =0.45 (n-hexane/EtOAc 1:1); 1H NMR (CDCl3, 400 MHz): d=1.16 (t,
J=7.16 Hz, 3H; CH3), 1.53–1.63 (m, 2H; CH2), 2.89–3.00 (m, 1H; H5),
3.10–3.25 (m, 2H; H1, H3), 3.70 (s, 3H; OCH3), 3.75 (s, 3H; OCH3),
4.02–4.18 (m, 2H; OCH2), 4.72 (q, J=8.99 Hz, 1H; H4), 5.88–5.92 (m,
General procedure for dihydroxylation of N-protected amino esters:[9e]
OsO4 (0.5 mL, 0.03 mmol) in tBuOH (0.06m) was added to a solution of
N-protected b-amino ester (ꢁ)-2 (2 g, 7.72 mmol) and NMO (3 mL,
29.1 mmol) in acetone (40 mL), and the resulting mixture was stirred for
12 h at room temperature. After completion of the reaction, as moni-
tored by TLC, saturated aqueous Na2SO3 solution (120 mL) was added,
and the reaction mixture was extracted with CH2Cl2 (3ꢃ50 mL). The
combined organic phases were dried over Na2SO4, filtered, and evaporat-
ed in vacuo. The crude product was purified by means of column chroma-
tography on silica gel (n-hexane/EtOAc 1:4).
ꢀ
ꢀ
2H; C=C H), 6.75 (brs, 1H; NH), 6.87–6.97 (m, 2H; C=C H), 7.37–
7.79 ppm (m, 5H; ArH); 13C NMR ([D6]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 ppm; MS (ESI): m/z 430.42 [M+1]; ele-
mental analysis: calcd (%) for C23H27NO7: C 64.32, H 6.34, N 3.26;
found: C 64.68, H 6.01, N 3.01.
Ethyl (1R*,2S*,3S*,5R*)-2-benzamido-3,5-di(3’-oxobut-1-enyl)cyclopen-
tanecarboxylate (10): Yellow solid; yield: 43%; m.p. 110–1138C; Rf =0.3
(n-hexane/EtOAc 1:1); 1H NMR (CDCl3, 400 MHz): d=1.18 (t, J=
7.22 Hz, 3H; CH3), 1.55–1.70 (m, 2H; CH2), 2.20–2.31 (m, 6H; 2CH3),
2.91–3.03 (m, 1H; H1), 3.11–3.27 (m, 2H; H3, H5), 4.05–4.20 (m, 2H;
General procedure for oxidative C-C cleavage (dialdehyde formation):
NaIO4 (269 mg, 1.26 mmol) was added to a solution of dihydroxylated
amino ester (ꢁ)-3 (200 mg, 0.63 mmol) in THF/H2O (11 mL, 10:1), and
reaction mixture was stirred for 10 min at room temperature under an Ar
atmosphere. The mixture was then quenched by addition of water
(20 mL) and extracted with CH2Cl2 (2ꢃ15 mL). The combined organic
phases were dried over Na2SO4, filtered, and evaporated in vacuo. The
crude material was purified by column chromatography on silica gel (n-
hexane/EtOAc 1:4).
ꢀ
OCH2), 4.73–4.76 (m, 1H; H2), 6.11–6.15 (m, 2H; C=C H), 6.69–6.80
ꢀ
(m, 2H; C=C H), 6.90 (brs, 1H; NH), 7.40–7.75 ppm (m, 5H; ArH);
13C NMR ([D6]DMSO, 400 MHz): d=14.7, 27.6, 36.5, 44.3, 47.5, 53.4,
56.7, 61.0, 128.1, 129.0, 131.4, 131.8, 132.1, 135.0, 148.9, 149.5, 167.0,
172.1, 198.8 ppm; MS (ESI): m/z 398.67 [M+1]; elemental analysis: calcd
(%) for C23H27NO5: C 69.50, H 6.85, N 3.52; found: C 69.28, H 6.53, N
3.16.
Ethyl (1R*,2S*,3R*,5S*)-2-benzamido-3,5-diformylcyclopentanecarbox-
ACHTUNGTRENNUNGylate (4): White solid; yield: 75%; m.p. 114–1168C; Rf =0.4 (n-hexane/
EtOAc 1:4); 1H NMR (CDCl3, 400 MHz): d=1.26 (t, J=7.11 Hz, 3H;
CH3), 2.22–2.40 (m, 2H; CH2), 3.13–3.21 (m, 1H; H5), 3.33–3.40 (m, 1H;
H3), 3.47–3.51 (m, 1H; H1), 4.17–4.25 (m, 2H; OCH2), 4.78–4.83 (m,
1H; H2), 7.39–7.78 (m, 5H; ArH), 9.72–9.78 ppm (m, 2H; COH);
13C NMR ([D6]DMSO, 400 MHz): d=14.7, 24.6, 48.4, 52.2, 52.5, 55.7,
61.2, 128.2, 129.0, 132.1, 135.2, 167.1, 171.6, 202.5, 202.8 ppm; MS (ESI):
m/z 318.67 [M+1]; elemental analysis: calcd (%) for C17H19NO5: C 64.34,
H 6.03, N 4.41; found: C 64.21, H 6.40, N 4.64.
General procedure for saturation of the olefinic bond: A solution of ole-
finic compound (ꢁ)-5, (ꢁ)-6, (ꢁ)-9, or (ꢁ)-10 (100 mg, 0.32 mmol) and
Pd/C (20 mg, 10mol%) in EtOAc (20 mL) was stirred under a H2 atmos-
phere for 1 h. The reaction mixture was then filtered through silica gel
and celite. The filtrate was concentrated under reduced pressure and pu-
rified by column chromatography on silica gel (n-hexane/EtOAc).
Ethyl
(1R*,2S*,3R*,5S*)-2-benzamido-3,5-diethylcyclopentanecarbox-
AHCTUNGTRENGyNNU late (7): White solid; yield: 89%; m.p. 74–778C; Rf =0.7 (n-hexane/
General procedures for Wittig reaction:
EtOAc 3:1); 1H NMR (CDCl3, 400 MHz): d=0.93 (t, J=7.44 Hz, 6H;
H1, H9), 1.18 (t, J=7.04 Hz, 3H; CH3), 1.24–1.70 (m, 5H; CH2), 1.93–
2.03 (m, 1H; CH2), 2.12–2.24 (m, 2H; H3 and H5), 2.81–2.87 (m, 1H;
H1), 4.00–4.18 (m, 2H; OCH2), 4.40–4.43 (m, 1H; H2), 6.77 (brs, 1H;
NH), 7.38–7.81 ppm (m, 5H; ArH); 13C NMR ([D6]DMSO, 400 MHz):
d=13.1, 14.7, 26.9, 28.5, 36.9, 43.3, 45.9, 54.3, 57.4, 60.4, 128.2, 128.9,
131.9, 135.5, 167.0, 173.8 ppm; MS (ESI): m/z 318.33 [M+1]; elemental
analysis: calcd (%) for C19H27NO3: C 71.89, H 8.57, N 4.41; found: C
71.58, H 8.30, N 4.16.
Procedure A: The dialdehyde derivative (ꢁ)-4 (200 mg, 0.63 mmol) was
dissolved in dry THF (5 mL), and the corresponding Wittig reagent
(1.26 mmol) was added to the solution. After being stirred for 1 h at
room temperature, the reaction mixture was concentrated in vacuo and
purified by column chromatography on silica gel (n-hexane/EtOAc).
Procedure B: The Wittig reagent was prepared first by adding tBuOK
(1.26 mmol) to
a solution of the corresponding phosphonium salt
(1.26 mmol) in dry THF (5 mL), and the mixture was stirred at 08C for
10 min. The dialdehyde derivative (ꢁ)-4 (200 mg, 0.63 mmol) was dis-
solved in dry THF (5 mL) and added dropwise to the solution of the in
situ generated Wittig reagent mixture. After being stirred for 1 h at room
temperature, the reaction mixture was concentrated in vacuo and purified
by column chromatography on silica gel (n-hexane/EtOAc).
Ethyl (1R*,2S*,3R*,5S*)-2-benzamido-3,5-diphenethylcyclopentanecar-
boxylate (8): White solid; yield: 73%; m.p. 63–668C; Rf =0.3 (n-hexane/
EtOAc 3:1); 1H NMR ([D6]DMSO, 400 MHz): d=1.19 (t, J=7.17 Hz,
3H; CH3), 1.55–2.15 (m, 8H; CH2), 2.61–2.81 (m, 4H; CH2, H3, H5),
2.92–2.97 (m, 1H; H1), 4.03–4.19 (m, 2H; OCH2), 4.53–4.56 (m, 1H;
H2), 6.77 (brs, 1H; NH), 7.14–7.80 ppm (m, 15H; ArH); 13C NMR
([D6]DMSO, 400 MHz): d=14.8, 34.5, 34.6, 36.3, 37.4, 37.5, 41.1, 44.3,
54.5, 57.6, 60.6, 126.4, 126.5, 128.1, 128.9, 129.0, 129.1, 131.9, 135.5, 142.8,
143.1, 167.1, 173.8 ppm; MS (ESI): m/z 470.50 [M+1]; elemental analy-
sis: calcd (%) for C31H35NO3: C 79.28, H 7.51, N 2.98; found: C 78.92, H
7.21, N 2.61.
Ethyl
(1R*,2S*,3S*,5R*)-2-benzamido-3,5-divinylcyclopentanecarbox-
ACHTUNGTRENNUNGylate (5): White solid; yield: 51%; m.p. 92–948C; Rf =0.6 (n-hexane/
EtOAc 3:1); 1H NMR (CDCl3, 400 MHz): d=1.16 (t, J=7.08 Hz, 3H;
CH3), 1.41–1.59 (m, 1H; CH2), 2.09–2.17 (m, 1H; CH2), 2.68–2.78 (m,
1H; H1), 2.95–3.08 (m, 2H; H3, H5), 4.02–4.18 (m, 2H; OCH2), 4.57–
ꢀ
ꢀ
4.60 (m, 1H; H2), 4.98–5.16 (m, 4H; C=C H), 5.76–5.88 (m, 2H; C=C
H), 6.71–6.88 (m, 1H; NH), 7.35–7.80 ppm (m, 5H; ArH); 13C NMR
([D6]DMSO, 400 MHz): d=14.7, 37.1, 42.7, 45.7, 53.7, 56.7, 60.6, 115.4,
115.9, 128.3, 128.8, 135.3, 138.5, 140.4, 141.2, 167.0, 172.7 ppm; MS (ESI):
m/z 314.42 [M+1]; elemental analysis: calcd (%) for C19H23NO3: C 72.82,
H 7.40, N 4.47; found: C 72.55, H 7.21, N 4.64.
Dimethyl 3,3’-((1S*,3R*,4S*,5R*)-4-benzamido-5-(ethoxycarbonyl)cyclo-
pentane-1,3-diyl)dipropanoate (11): Yellowish-white solid; yield: 89%;
m.p. 91–928C; Rf =0.3 (n-hexane/EtOAc 1:1); 1H NMR (CDCl3,
400 MHz): d=1.16 (t, J=7.05 Hz, 3H; CH3), 1.55–2.46 (m, 12H; CH2,
H3, H5), 2.84–2.90 (m, 1H; H1), 3.63 (s, 3H; OCH3), 3.67 (s, 3H;
OCH3), 4.00–4.14 (m, 2H; OCH2), 4.41–4.44 (m, 1H; H2), 6.85 (brs, 1H;
NH), 7.39–7.52 ppm (m, 5H; ArH); 13C NMR ([D6]DMSO, 400 MHz):
d=14.7, 29.3, 30.5, 32.7, 32.8, 37.0, 41.0, 44.1, 52.0, 54.1, 57.2, 60.5, 128.1,
128.9, 131.9, 135.4, 166.9, 173.4, 173.9, 174.0 ppm; MS (ESI): m/z 434.42
[M+1]; elemental analysis: calcd (%) for C23H31NO7: C 63.73, H 7.21, N
3.23; found: C 63.41, H 7.50, N 2.98.
Ethyl
(1R*,2S*,3S*,5R*)-2-benzamido-3,5-distyrylcyclopentanecarbox-
ACHTUNGTRENNUNGylate (6): White solid; yield: 34%; m.p. 120–1238C; Rf =0.2 (n-hexane/
EtOAc 3:1); 1H NMR ([D6]DMSO, 400 MHz): d=0.96 (t, J=7.06 Hz,
3H; CH3), 1.58–1.62 (m, 1H; CH2), 2.13–2.21 (m, 1H; CH2), 3.02–3.16
(m, 2H; H3, H5), 3.25–3.29 (m, 1H; H1), 3.89–3.93 (m, 2H; OCH2),
ꢀ
4.63–4.66 (m, 1H; H2), 6.28–6.53 (m, 4H; C=C H), 7.16–7.81 (m, 15H;
ArH), 8.44 ppm (brs, 1H; NH); 13C NMR ([D6]DMSO, 400 MHz): d=
14.8, 38.3, 45.4, 48.2, 54.3, 57.4, 60.8, 126.8, 128.2, 129.0, 129.4, 130.3,
130.7, 132.0, 132.4, 133.1, 135.3, 137.8, 167.1, 172.8 ppm; MS (ESI): m/z
Ethyl (1R*,2S*,3R*,5S*)-2-benzamido-3,5-di(3’-oxobutyl)cyclopentane-
carboxylate (12): Yellow oil; yield: 86%; Rf =0.4 (n-hexane/EtOAc 1:4);
1H NMR (CDCl3, 400 MHz): d=1.20 (t, J=7.05 Hz, 3H; CH3), 1.52–1.96
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F. Fꢁlçp et al.
(m, 6H; CH2), 2.12 (s, 3H; CH3), 2.20 (s, 3H; CH3), 2.45–2.62 (m, 4H;
CH2, H3, H5), 2.87–2.90 (m, 1H; H1), 4.05–4.20 (m, 2H; OCH2), 4.40–
4.44 (m, 1H; H2), 6.90 (brs, 1H; NH), 7.40–7.85 ppm (m, 5H; ArH);
13C NMR ([D6]DMSO, 400 MHz): d=14.8, 28.0, 29.3, 30.5, 37.3, 41.0,
42.0, 42.1, 44.0, 54.2, 57.3, 60.5, 128.1, 128.9, 131.9, 135.4, 166.9, 173.6,
208.9, 209.1 ppm; MS (ESI): m/z 402.42 [M+1]; elemental analysis: calcd
(%) for C23H31NO5: C 68.80, H 7.78, N 3.49; found: C 68.59, H 7.53, N
3.20.
Ethyl (1S,2R,3S,5R)-2-benzamido-3,5-di(3’-methoxy-3’-oxopropyl)cyclo-
pentanecarboxylate ((+)-11): White solid; yield: 79%; [a]2D5 =+44.3 (c=
0.33, EtOH); ee=97%; tR =24.46 min (antipode: 21.34 min).
Ethyl (1S,2R,3S,5R)-2-benzamido-3,5-di(3’-oxobutyl)cyclopentanecarbox-
ylate ((+)-12): White solid; yield: 86%; [a]2D5 =+35 (c=0.375, EtOH);
ee=96%; tR =33.02 min (antipode: 32.62 min).
Preparative-scale resolution of exo-3-azatricyclo[4.2.1.02.5]non-7-en-4-one
((ꢁ)-1): Crystalline racemic 1 (2 g, 14.8 mmol) was mixed well with Lipo-
lase (lipase B from Candida antarctica, produced by submerged fermenta-
tion of a genetically modified Aspergillus oryzae microorganism and im-
mobilized on a macroporous resin, purchased from Sigma–Aldrich; 6 g;
the possibility of reusing the enzyme in several cycles with E>200 and
only a slight decrease in catalytic activity makes the process an economi-
cal one). Water (136 mL, 7.52 mmol) was added as a nucleophile, and the
mixture was shaken in an incubator shaker at 708C for 7 days. The un-
reacted b-lactam (+)-1 was washed off the surface of the enzyme with
EtOAc (4ꢃ25 mL). Then b-amino acid (ꢀ)-13 was washed out with dis-
tilled water (4ꢃ25 mL). The easy separation of the products is due to the
solubility of the lactam in EtOAc and the solubility of the amino acid in
water, whereas the enzyme is not soluble in EtOAc or water.
(1R,2R,5S,6S)-b-lactam ((+)-1): yield: 917 mg, 46%; [a]2D5 = +121.1 (c=
0.5; CHCl3); m.p. 94–958C; ee=99%. (1R,2R,3S,4S)-b-amino acid ((ꢀ)-
13): yield: 1.02 g, 45%; [a]D25 =ꢀ12.6 (c=0.5; H2O); m.p. >2608C; ee>
98%. The 1H NMR spectroscopic data for the products were identical
with those given in the literature.[18] The ee value for (+)-1 was deter-
mined by using a gas chromatograph equipped with a CP-Chirasil-Dex
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA nos.:
NK81371 and K100530) for financial support and acknowledge the re-
ceipt of Bolyai Jꢄnos Fellowships for L.K. and E.F.
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CB column (1208C for 4 min ! 1708C (temperature rise: 108Cminꢀ1
;
140 kPa)): retention time for (+)-1: 10.72 min (antipode: 10.55 min). The
ee value for (ꢀ)-13 was determined by using same GC column, but after
double derivatization[19] (1208C for 7 min ! 1708C (temperature rise:
108Cminꢀ1; 70 kPa)): retention time for (ꢀ)-13: 14.66 min (antipode:
14.86 min).
Characterization of the enantiomeric products: All 1H NMR spectra re-
corded for the enantiomeric substances were the same as for the corre-
sponding racemic counterparts. The ee values were determined by HPLC
(Chiralpack IA column, eluent: n-hexane/IPA (80:20), flow rate:
0.5 mLminꢀ1, detection at 260 nm).
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Ethyl (1S,2S,3R,4R)-3-benzamidobicycloACTHUNTGRNEUNG[2.2.1]hept-5-ene-2-carboxylate
((+)-2): White solid; yield: 75%; [a]2D5 =+35 (c=0.23, EtOH).
Ethyl (1S,2S,3R,4R,5S,6R)-3-benzamido-5,6-dihydroxybicyclo[2.2.1]hep-
tane-2-carboxylate ((+)-3): White solid; yield: 85%; [a]2D5 =+18.5 (c=
ACHTUNGTRENNUNG
0.325, EtOH); ee=97%; tR =15.57 min (antipode: 14.69 min).
Ethyl (1S,2R,3S,5R)-2-benzamido-3,5-diformylcyclopentanecarboxylate
((+)-4): White solid; yield: 72%; [a]2D5 =+29 (c=0.29, EtOH).
Ethyl
(1S,2R,3R,5S)-2-benzamido-3,5-divinylcyclopentanecarboxylate
((+)-5): White solid; yield: 49%; [a]2D5 =+29.5 (c=0.25, EtOH); ee=
96%; tR =12.51 min (antipode: 10.78 min).
Ethyl
(1S,2R,3S,5R)-2-benzamido-3,5-diethylcyclopentanecarboxylate
((ꢀ)-7): White solid; yield: 90%; [a]2D5 =ꢀ2 (c=0.235, EtOH); ee=47%;
tR =10.65 min (antipode: 10.04 min).
Ethyl (1S,2R,3R,5S)-2-benzamido-3,5-di((E)-styryl)cyclopentanecarbox-
ylate ((+)-6): White solid; yield: 39%; [a]2D5 =+38.3 (c=0.31, EtOH);
ACHTUNGTRENNUNG
ee=96%; tR =22.22 min (antipode: 17.28 min).
Ethyl (1S,2R,3S,5R)-2-benzamido-3,5-diphenethylcyclopentanecarboxACTHNUTRGNEyUNG late
((+)-8): White solid; yield: 71%; [a]2D5 =+37 (c=0.27, EtOH); ee=96%;
tR =15.55 min (antipode: 12.69 min).
Ethyl (1S,2R,3R,5S)-2-benzamido-3,5-di(3’-methoxy-3’-oxoprop-1-enyl)cy-
clopentanecarboxylate ((+)-9): White solid; yield: 75%; [a]2D5 =+39.3 (c=
0.385, EtOH); ee=97%; tR =38.59 min (antipode: 26.82 min).
Ethyl (1S,2R,3R,5S)-2-benzamido-3,5-di((E)-3-oxobut-1-enyl)cyclopenta-
necarboxylate ((+)-10): White solid; yield: 45%; [a]2D5 =+33 (c=0.245,
EtOH); ee=96%; tR =53.46 min (antipode: 22.44 min).
2106
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2102 – 2107

Synthesis of Functionalized Cispentacins
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Received: September 7, 2012
Revised: November 13, 2012
Published online: December 19, 2012
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Chem. Eur. J. 2013, 19, 2102 – 2107
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2107