Diastereo- and enantioselective synthesis of orthogonally protected 2,4-diaminocyclopentanecarboxylates: A flip from β-amino- to β,γ-diaminocarboxylates

Article abstract of DOI:10.1021/jo701332v

(Chemical Equation Presented) Conformationally restricted, orthogonally protected 2,4-diaminocarboxylates with a cyclopentane skeleton were efficiently synthesized from β-lactam 6, the syntheses involving strategies of diastereoselective epoxidation of th

Full text of DOI:10.1021/jo701332v

Diastereo- and Enantioselective Synthesis of Orthogonally Protected
2,4-Diaminocyclopentanecarboxylates: A Flip from â-Amino- to
â,γ-Diaminocarboxylates
Lora´nd Kiss,† Eniko´ Forro´,† Reijo Sillanpa¨a¨,§ and Ferenc Fu¨lo¨p*,†,‡
Institute of Pharmaceutical Chemistry and Research Group of Stereochemistry of the Hungarian Academy
of Sciences, UniVersity of Szeged, H-6720 Szeged, Eo¨tVo¨s utca 6, Hungary, and Department of Chemistry,
UniVersity of JyVa¨skyla¨, FIN-40351, JyVa¨skyla¨, Finland
fulop@pharm.u-szeged.hu
ReceiVed July 11, 2007
Conformationally restricted, orthogonally protected 2,4-diaminocarboxylates with a cyclopentane skeleton
were efficiently synthesized from â-lactam 6, the syntheses involving strategies of diastereoselective
epoxidation of the â-lactam and the corresponding monoprotected amino esters with opposite selectivities
followed by regioselective opening of the oxirane ring with sodium azide. The enantiomers were also
prepared. This new class of compounds can be regarded not only as conformationally constrained â,γ-
diamino acid derivatives but also as potential functionalized carbocyclic nucleoside precursors.
3Introduction
Further, the 3-azido-4-hydroxycyclopentanoic acid moiety has
been reported as a synthetic scaffold for â-turn mimetics.4 These
compounds may also be applied as precursors for the synthesis
of carbasugars and carbocyclic nucleosides.
Carbocyclic nucleosides are a family of synthetic and
naturally occurring compounds which have attracted great
interest among chemists and biochemists during recent years.
Many of them exert important biological activities5,6 and are
Among the large family of γ-amino acids, 4-aminocyclopent-
2-ene carboxylic acid 1 and derivatives can serve as confor-
mationally constrained, potentially valuable scaffolds for phar-
maceutical assays as anticancer and antiviral agents and as
important building blocks in the synthesis of peptides.1 They
may also be regarded as conformationally restricted GABA
mimetics.2 Various mono- and dihydroxylated γ-aminocyclo-
pentanecarboxylic acid diastereomers have been incorporated
into tripeptide sequences.3
(2) (a) Pan, Y.; Calvert, K.; Silverman, R. B. Bioorg. Med. Chem. 2004,
12, 5719. (b) Chebib, M.; Duke, R. K.; Allan, R. D.; Johnston, G. A. R.
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Lloyd, R. C.; Taylor, S. J. C.; Chaplin, D. A.; Casy, G.; McCague, R.
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Smith, M. E. B.; Holt, K. E.; Swift, J. P.; Keene, P. A.; Taylor, S. J. C.;
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† Institute of Pharmaceutical Chemistry.
‡ Research Group of Stereochemistry of the Hungarian Academy of Sciences,
University of Szeged.
§ University of Jyva¨kyla¨.
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and references cited therein. (b) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano,
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J. R. Org. Lett. 2005, 7, 4681. (d) Brea, R. J.; Amorin, M.; Castedo, L.;
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10.1021/jo701332v CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/13/2007
8786
J. Org. Chem. 2007, 72, 8786-8790

Synthesis of Protected 2,4-Diaminocyclopentanecarboxylates
potentially effective therapeutic agents for the treatment of viral
infections.7 A number of synthetic carbocyclic nucleosides
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effects. Several naturally occurring carbocyclic nucleosides, such
as aristeromycin,9 neplanocin A,10 and some of their derivatives,
display antitumor and antibiotic activity.11 Synthetic carbocyclic
nucleosides with significant therapeutic properties have also
been discovered. For example, carbovir (2) and abacavir (3)
with antiviral properties have been reported to inhibit the
replication of HIV.1g,12
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The alicyclic â-amino acids have gained great interest in
recent years in view of their pharmacological potential.13 The
natural cispentacin (4), an antifungal antibiotic with a cyclo-
pentane skeleton, is one of the most important derivatives. It is
additionally a component of the antibiotic amipurimycin.13a
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fungipen) 5 is known as an antifungal agent. Cyclic, confor-
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tanecarboxylic acid or 2-amino-3-methoxycyclopentanecarboxylic
acid have been used as building blocks in the synthesis of
peptides.14
The aim of the present work was the synthesis of orthogonally
protected 2,4-diaminocyclopentanecarboxylate diastereomers
containing both the â- and the γ-amino ester unit on a
cyclopentane moiety.
Results and Discussion
Our synthetic strategy was based on the functionalization of
the olefinic bond of the readily available azetidinone 615 via its
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J. Org. Chem, Vol. 72, No. 23, 2007 8787

Kiss et al.
SCHEME 1. Synthesis of Amino Esters 8a-e and Epoxy Lactam 11
SCHEME 2. Synthesis of Epoxy Amino Esters 9a-e
SCHEME 3. Synthesis of 2-Amino-4-azidocarboxylates
14a-e and 14h
epoxidation by two different routes with opposite diastereose-
lectivities. In the first approach, monoprotected â-amino ethyl
esters 8a-c were prepared in good yields from â-lactam 6
through amino ester 7 (Scheme 1, path A). In the next step, the
â-amino esters 8a-c were submitted to epoxidation of the
olefinic bond (Scheme 2). Epoxidation of a mono N-protected
alkene (carbamate or amide) with peracids is known to give a
high degree of cis selectivity, presumably via a hydrogen-
bonding interaction of the amide and the peracidic reagent in
the transition state of the reaction.16 We studied the epoxidations
of amino ethyl esters 8a-c with Boc, Fmoc, or Z protecting
groups in the presence of m-chloroperbenzoic acid in dichlo-
romethane. As expected in all cases, the reaction proceeded
diastereoselectively, furnishing the cis-epoxides 9a-c as single
diastereoisomers in yields of 43-64% yield (Scheme 2).
In a similar way, cis-epoxy derivatives of benzyl aminocar-
boxylates 9d and 9e were synthesized in yields of 51% and
55% by the epoxidation of esters 8d and 8e (Scheme 2). Benzyl
aminocarboxylates 8d and 8e were prepared from lactam 6 via
the protected amino acids 13a and 13b, whose carboxylic group
was benzylated with benzyl chloride in refluxing THF in the
presence of DBU (Scheme 1).
With the above epoxidation procedure, the presence of a
monoprotected amino group (carbamate) on the cyclopentene
skeleton always led to cis selectivity, resulting in the cis-epoxy
amino esters 9a-e.
It was expected that introduction of the oxirane skeleton trans
to the 5-amino group on the cyclopentanecarboxylic amino ester
moiety of 10 would be possible without changing the reaction
conditions or the oxidizing agent, but starting from the Boc-
protected lactam 10 (Scheme 1, path B). In lactam 10, the
tertiary amine would not exert the cis-stereodirecting effect
observed earlier in the transition state of the epoxidation of esters
8a-e. For this reason, the Boc-protected lactam 10 was treated
with m-chloroperbenzoic acid at 0 °C for 5 h (Scheme 1, path
B). In this case, in consequence of the presence of the bulky
Boc group, the “trans”-epoxide 11 was formed exclusively. The
main reason for the opposite, trans selectivity of the lactam
epoxidation may be the fact that in lactam 10 the lone pair of
electrons of the nitrogen is distributed between the carbamate
and the carbonyl of the lactam, lowering the negative charge
on the carbamate oxygen and decreasing the possibility of
hydrogen bonding with the peracid. In lactam 10, therefore, not
only steric but also electronic effects account for the trans
diastereoselectivity.
An extra amino group was introduced in position 4 on the
cyclopentane skeleton of amino esters 8a-e by opening of the
oxirane ring in epoxy aminocarboxylates 9a-e. For this, the
azido group was used as nitrogen source. The reactions with
NaN3 in refluxing EtOH-H2O in the presence of a catalytic
amount of NH4Cl for 4 h in all cases proceeded regio- and
diastereoselectively, giving 4-azido-2-amino esters 14a-e in
yields of 44-73% yield (Scheme 3).
The attack of the azido group took place at position 4 of the
cyclopentane ring of 9, through regioselective opening of the
oxirane ring in esters 9a-e resulting in 4-azido derivatives 14a-
e. The stereochemistry of these azido ester derivatives was
proved unambiguously by NMR and X-ray diffraction analyses.
These expected results are eloquent proof of the trans relative
(16) (a) Smith, M. E. B.; Derrien, N.; Lloyd, M. C.; Taylor, S. J. C.;
Chaplin, D. A.; McCague, R. Tetrahedron Lett. 2001, 42, 1347. (b) Wipf,
P.; Wang, X. Tetrahedron Lett. 2000, 41, 8747. (c) O’Brien, P.; Childs, A.
C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.; Dearden, M. J.; Oxenford, S. J.;
Rosser, C. M. Org. Lett. 2003, 5, 4955. (d) Masesane, I. B.; Steel, P. G.
Tetrahedron Lett. 2004, 45, 5007. (e) Kiss, L.; Forro´, E.; Fu¨lo¨p, F.
Tetrahedron Lett. 2006, 47, 2855.
8788 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of Protected 2,4-Diaminocyclopentanecarboxylates
SCHEME 4. Synthesis of 2-Amino-4-azidocarboxylates 14f and 14g
SCHEME 5. Synthesis of the Orthogonally Protected 2,4-Diaminocarboxylates 16a,f-h
stereochemistry of the 2-amino group and the 4-azido group in
the presence of PPh3/H2O in THF, followed by the reaction with
14a-e (see Supporting Information).
FmocOSu in the presence of triethylamine giving the orthogo-
nally protected diaminocarboxylates 16a,f-h, unfortunately in
low yields (25-32% in the two steps, Scheme 5). It is
noteworthy that when the azido group was reduced by catalytic
hydrogenation in the presence of Pd/C, a complex mixture was
obtained.
When the azide-mediated opening of the oxirane ring in 9a
was effected under similar conditions as previously reported,
but for a longer time (26 h) in refluxing EtOH-H2O, isomer-
ization occurred at position 1 of 9a, giving the γ-azido
diastereomer 14h in only a modest yield (28%). 14h was
obtained in good yield when 14a was stirred in EtOH in the
presence of 1.2 equiv of NaOEt at room temperature for 28 h,
with isomerization occurring at C-1 in 14a (Scheme 3).
Interestingly, after 4 h of heating in EtOH-H2O, the epoxy
amino ester 9c (Fmoc protecting group) gave not only azido
ester 14c but also oxazolone derivative 15 (Scheme 3), probably
via the opening of the oxirane ring with NaN3 in the first step,
followed by the attack of the 3-hydroxy group of 14c on the
carbonyl carbon of the 2-carbamate group. The structure of
oxazolone 15 was proved by means of X-ray diffraction analysis
(see the Supporting Information).
The preparation of a “trans”-epoxy amino ester 9f was
achieved from “trans”-epoxy azetidinone 11 by opening of the
lactam ring on treatment with 1.2 equiv of NaOEt in EtOH at
0 °C. When the ring opening was performed at room temperature
for a longer time (24 h), isomerization occurred at C-1 of 11,
furnishing the epoxy derivative 9g, which could also be obtained
from 9f by epimerization (Scheme 4).
The epoxidation of the amino esters and the ring opening of
the resulting epoxides by using NaN3 were also performed for
the enantiomeric substances (Scheme 6). The starting com-
pounds (1S,5R)-6 and (1R,2S)-12 were prepared through the
Lipolase (lipase B from Candida antarctica)-catalyzed enanti-
oselective ring opening of 7-azabicyclo[4.2.0]oct-3-en-8-one,
using a slightly modified literature procedure.17 The enantiose-
lective ring cleavage of (()-6 was performed successfully (E
> 200) on the 10 g scale by adding the enzyme in portions to
the reaction mixture (see the Supporting Information).
In conclusion, a simple route has been developed for the
synthesis of orthogonally protected â,γ-diaminocyclopentan-
ecarboxylate stereoisomers, based on the diastereoselective
epoxidation reactions and regioselective opening of the oxirane
ring. These new types of compounds are conformationally
constrained diamino carboxylates and can be considered as
functionalized carbocyclic nucleoside precursors.
Experimental Section
The stereochemistry of 9f was determined by means of NMR
and X-ray diffraction analysis, and as expected, the trans position
of the oxirane ring relative to the 2-amino group was observed
(see the Supporting Information).
For epoxides 9f and 9g, the attack of the azido group on the
oxirane ring occurred from the less hindered face (C-4 of 9),
furnishing γ-azido ester diasteromers 14f and 14g, respectively,
in good yields (63% and 66%). Azido amino ester 14f could
also be converted to diastereomer 14g on treatment with 1.2
equiv of NaOEt in EtOH (Scheme 4). The azido function was
converted to the Fmoc-protected amino group by reduction in
General Procedure for the Epoxidation of Compounds 8a-e
and 10. To a solution of amino ester 8a-e or â-lactam 10 (18
mmol) in CH2Cl2 (150 mL) was added m-CPBA (21 mmol) at 0
°C. After the mixture was stirred for 5 h, CH2Cl2 (120 mL) was
added and the resulting mixture was washed with saturated
(17) Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 2004, 15, 2875.
(18) Kanizsai, I.; Szakonyi, Z.; Sillanpa¨a¨, R.; D’Hooghe, M.; De Kimpe,
N.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 2006, 17, 2857.
(19) Sheldrick, G. M. SHELX-97, University of Go¨ttingen, Germany,
1997.
J. Org. Chem, Vol. 72, No. 23, 2007 8789

Kiss et al.
SCHEME 6. Synthesis of the Enantiomers of Aminocarboxylates 14a,f-h and 16a,f-h
NaHCO3/H2O (3 × 150 mL). The organic layer was then dried
(Na2SO4) and concentrated under reduced pressure. The crude
product was chromatographed on silica gel (n-hexane/EtOAc 3:1).
Ethyl (1R*,2R*,3R*,5S*)-2-(tert-butoxycarbonylamino)-6-
oxabicyclo[3.1.0]hexane-3-carboxylate (9a): white solid; yield
Esters 16a,f-h. To a solution of azido ester 14a, 14f, 14g, or 14h
(450 mg, 1.43 mmol) in THF (18 mL) were added PPh3 (375 mg,
1.43 mmol) and H2O (70 mg, 3.9 mmol) , and the mixture was
stirred for 5 h. Et3N (433 mg, 4.29 mmol) and FmocOSu (482 mg,
1.43 mmol) were then added to the solution, and stirring was
continued for another 12 h. The mixture was then taken up in EtOAc
(50 mL), washed with H2O (3 × 50 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (n-hexane/EtOAc
2:1).
Ethyl (1R*,2R*,3S*,4R*)-4-(((9H-fluoren-9-yl)methoxy)car-
bonylamino)-2-(tert-butoxycarbonylamino)-3-hydroxycyclopen-
tanecarboxylate (16a): white solid; yield 27% from 22a; Rf ) 0.40
(n-hexane/EtOAc 1:1); mp 186-190 °C; 1H NMR (400 MHz,
CDCl3, TMS) δ 1.27 (t, J ) 7.15 Hz, 3H), 1.44 (s, 9H), 1.66-
1.70 (m, 1H), 2.51-2.54 (m, 1H), 3.27-3.30 (m, 1H), 3.60 (brs,
1H), 3.97-4.03 (m, 2H), 4.14-4.30 (m, 4H), 4.43-4.45 (m, 2H),
4.85 (brs, 1H), 5.31 (brs, 1H), 7.27-7.43 (m, 4H), 7.56-7.59 (m,
2H), 7.74-7.78 (m, 2H); 13C NMR (400 MHz, CDCl3, TMS) δ
14.8, 29.0, 30.4, 45.9, 47.9, 56.0, 58.9, 62.1, 67.5, 78.3, 80.8, 120.7,
125.6, 127.8, 128.4, 129.1, 129.9, 132.8, 165.2, 170.5, 174.4. Anal.
Calcd for C28H34N2O7: C, 65.87; H, 6.71; N, 5.49. Found: C, 65.61;
H, 6.83; N, 5.10.
1
64%; Rf ) 0.35 (n-hexane/EtOAc 3:1); mp 50-55 °C; H NMR
(400 MHz, CDCl3, TMS) δ 1.27 (t, J ) 7.15 Hz), 1.46 (s, 9H),
1.92-1.99 (m, 1H), 2.65-2.70 (m, 1H), 2.74-2.81 (m, 1H), 3.44-
3.45 (m, 1H), 3.53-3.54 (m, 1H), 4.10-4.20 (m, 2H), 4.38-4.45
(m, 1H), 6.40 (brs, 1H). Anal. Calcd for C13H21NO5: C, 57.55; H,
7.80; N, 5.16. Found: C, 57.81; H, 7.56; N, 5.39.
General Procedure for Opening of the Oxirane Ring in
Amino Esters 9a-g. To a solution of amino ester 9a-g (8.9 mmol)
in EtOH (30 mL) and water (2 mL) were added NaN3 (1.2 g, 17.8
mmol, 2 equiv) and NH4Cl (93 mg, 1.75 mmol, 20 mol %), and
the mixture was stirred under reflux for the time indicated in
Schemes 3 and 4. The mixture was then concentrated under reduced
pressure, and the residue was taken up in EtOAc (150 mL), washed
with water (3 × 100 mL), dried (Na2SO4), and concentrated in
vacuum. The residue was purified by crystallization (n-hexane/
EtOAc) or chromatography on silica gel (n-hexane/EtOAc).
Ethyl (1R*,2R*,3R*,4R*)-4-azido-2-(tert-butoxycarbonylamino)-
3-hydroxycyclopentanecarboxylate (14a): white crystals; yield
73%; Rf ) 0.45 (n-hexane/EtOAc 3:1); mp 100-102 °C; 1H NMR
(400 MHz, CDCl3, TMS) δ 1.28 (t, J ) 7.15 Hz, 3H), 1.44 (s,
9H), 1.91-1.99 (m, 1H), 2.43-2.50 (m, 1H), 3.33-3.38 (m, 1H),
3.74 (brs, 1H), 3.94-4.00 (m, 1H), 4.01-4.04 (m, 1H), 4.11-
4.24 (m, 2H), 4.32-4.42 (m, 1H), 5.25 (brs, 1H); 13C NMR (400
MHz, CDCl3, TMS) δ 14.8, 29.0, 32.7, 45.2, 54.8, 62.5, 66.9, 78.0,
80.6, 156.1, 177.1; MS (ES, pos) m/z 337 (M + Na). Anal. Calcd
for C13H22N4O5: C, 49.67; H, 7.05; N, 17.82. Found: C, 49.33;
H, 7.13; N, 17.52.
Acknowledgment. We are grateful to the Hungarian Re-
search Foundation (OTKA No. F67970 and T049407) and the
National Research and Development Office, Hungary (GVOP-
311-2004-05-0255/3.0) for financial support.
Supporting Information Available: General information,
spectroscopic data for compounds 7, 8a-e, 9b-g, 10-12, 13a,b,
14b-h, 15, and 16f-h, and experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
General Procedure for Azido Group Reduction and Protec-
tion of the Amino Group: Synthesis of Orthogonally Protected
JO701332V
8790 J. Org. Chem., Vol. 72, No. 23, 2007