A new strategy for the preparation of heterocyclic β-amino esters: orthogonally protected β-amino esters with a piperidine skeleton

Article abstract of DOI:10.1016/j.tetlet.2007.11.043

A simple strategy is presented for the introduction of a nitrogen atom into the carbocycle of an aminocyclopentenecarboxylic ester via dihydroxylation of the olefinic bond, followed by NaIO₄-mediated cleavage of the diol intermediate and ring e

Full text of DOI:10.1016/j.tetlet.2007.11.043

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 339–342
A new strategy for the preparation of heterocyclic
b-amino esters: orthogonally protected b-amino esters
with a piperidine skeleton
a
a
a
a,b,
*
}
´
´
Lorand Kiss, Brigitta Kazi, Eniko Forro and Ferenc Fulop
¨ ¨
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eo¨tvo¨s u. 6, Hungary
bResearch Group of Heterocyclic Chemistry, University of Szeged, H-6720 Szeged, Eo¨tvo¨s u. 6, Hungary
Received 5 September 2007; revised 31 October 2007; accepted 7 November 2007
Available online 13 November 2007
Abstract—A simple strategy is presented for the introduction of a nitrogen atom into the carbocycle of an aminocyclopentene-
carboxylic ester via dihydroxylation of the olefinic bond, followed by NaIO4-mediated cleavage of the diol intermediate and ring
expansion, resulting in new regioisomeric 3-amino-4-piperidinecarboxylic acid derivatives. This method permits the preparation
of amino esters with a piperidine skeleton in enantiomerically pure form.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
interesting biological (e.g., antimicrobial) activities.2
b-Amino acids with a pyrrolidine skeleton have been
used for the synthesis of glycosylated hexapeptides,3
and have been described as potent influenza neuramini-
dase inhibitors.4 Both five-membered nitrogen-contain-
ing heterocyclic b-amino acids and six-membered
4-aminopiperidine-3-carboxylic acids can be incorpo-
rated into peptides with a 14-helical structure.5 Iduronic
acid-type 1-N-iminosugars, six-membered derivatives
with a nitrogen atom in the ring, exhibit antimetastatic
and enzyme inhibitory activities.6 Enamino 1-carboxyl-
ates with a piperidine skeleton are important elements
in the synthesis of selective small opioid receptor antago-
nists.7 Furthermore, 4-amino-1-oxyl-2,2,6,6-tetramethyl-
piperidine-3-carboxylic acid, a b-amino acid with a
piperidine skeleton has been synthesized in enantiomeri-
cally pure form from 2,2,6,6-tetramethyl-4-piperidone.8
Enamino carboxylate enantiomers with a piperidine
skeleton have been used for the preparation of cinchona
alkaloids.9 In addition, b-amino piperidine carboxylates
have been synthesized in optically pure form via lithium
amide-promoted asymmetric conjugate addition-
cyclization.10
As a consequence of their biological effects, conforma-
tionally constrained alicyclic b-amino acids have gener-
ated great interest among chemists and biochemists.
Such structures are found in many natural products,
b-lactams and antibiotics. The incorporation of con-
formationally restricted b-amino acids into biologically
active peptides is of considerable interest as concerns
the preparation of peptide-based drug molecules.1
In recent years, conformationally rigid heterocyclic
b-amino acids have received appreciable attention in
view of their biological potential. As a result of their
natural occurrence, biological activities and chemical
interest, the number of investigations of these medici-
nally valuable molecules has increased rapidly. One of
the largest groups of such heterocyclic b-amino acid
derivatives is that with one nitrogen atom in the ring.
b-Peptides containing 3-aminopyrrolidine-4-carboxylic
acid and 3-aminopyrrolidine-2-carboxylic acid struc-
tural moieties have been shown to adopt helical second-
ary structures, and they have been reported to display
Our aim was to develop a route for the synthesis of the
diastereomers of six-membered b-amino carboxylates
with one nitrogen atom in the ring. The b-amino esters
2a–c11a with a cyclopent-3-ene skeleton, prepared from
b-lactam 1, were considered to be suitable starting
Keywords: Cyclic b-amino acids; Piperidine; Dihydroxylation; Ring
closure; Enzymatic resolution.
*
Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705;
e-mail: fulop@pharm.u-szeged.hu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.043

340
L. Kiss et al. / Tetrahedron Letters 49 (2008) 339–342
HO
COOEt
NHR
COOEt
i
ii
COOEt
Ph
N
HO
NHR
lit. 11
NHR
4a: R = Boc
4b: R = Z
2a: R = Boc
2b: R = Z
3a: R = Boc
3b: R = Z
O
NH
lit. 11
1
HO
HO
COOEt
COOEt
NHBoc
i
COOEt
NHBoc
ii
Ph
N
NHBoc
2c
3c
4c
Scheme 1. Synthesis of racemic piperidine-4-carboxylates 4a–c. Reagents and conditions: (i) KMnO4, CH2Cl2, BnEt3NCl, 0 °C, 2 h, 3a: 47%, 3b:
44%, 3c: 48%; (ii) (a) NaIO4, THF/H2O, rt, 1 h; (b) NaCNBH3, 1 equiv AcOH, CH2Cl2/THF, BnNH2, rt, 4 h, 4a: 16% (two steps), 4b: 22% (two
steps), 4c: 17% (two steps).
materials for this purpose. The synthetic approach was
based on the ring cleavage of cis-2-aminocylopentene-
carboxylates 2a,b and trans-2-aminocylopentenecar-
boxylate 2c, followed by ring expansion (Scheme 1). In
the first step, amino esters 2a–c were subjected to
KMnO4-mediated dihydroxylation in the presence of
various phase transfer catalysts (e.g., tetrabutylammo-
nium chloride, 18-crown-6 ether or benzyltriethylammo-
nium chloride). It was found that the dihydroxy
derivatives 3a–c were formed in the highest yields in
the presence of benzyltriethylammonium chloride. Dur-
ing the KMnO4 oxidation process, only one cis-func-
tionalized dihydroxy b-amino carboxylate 3a–c was
obtained, diastereoselectively, from the cis amino esters
2a,b and the trans derivative 2c. No other diastereomer
was detected in the crude reaction mixture. The relative
stereochemistry was assigned on the basis of NOESY
experiments. The two hydroxy groups are presumably
formed on the opposite side to the carboxylate at C-1
in the cyclopentane skeleton.
The next step in the synthetic route was the oxidation of
the diol with NaIO4. The C–C bond cleavage of com-
pounds 3a–c was accomplished in THF/H2O at room
temperature for 1 h under an argon atmosphere. After
extraction with CH2Cl2 the resulting dialdehyde was
subjected to reductive ring closure in the presence of
NaCNBH3, 1 equiv of AcOH and benzylamine at room
temperature for 4 h. Through reductive amination in the
final step, the ring closure furnished the desired hetero-
cyclic b-amino esters with a piperidine skeleton. It is
noteworthy that the reduction could not be performed
in the presence of NaBH4; only NaCNBH3 proved to
be a suitable reductant agent in this reaction.
1R
COOH
1S
NH
O
O
i
+
2S
NH
( )-1
5R
NH2HCl
(+)-5
(-)-1 ee > 99%
ii
HO
1S
4S
(-)-4a
4R
COOEt
1S
COOEt
iii
v
COOEt
2R
NHBoc
3S
NHBoc
2S
Ph
N
HO
NHBoc
(+)-3a
(-)-2a
iv
HO
HO
COOEt
1R
1R
2S
NHBoc
(-)-3c
COOEt
iii
COOEt
v
3S
NHBoc
2R
NHBoc
Ph
N
(-)-4c
(-)-2c
Scheme 2. Synthesis of ethyl 1-benzyl-3-(tert-butoxycarbonylamino)piperidine-4-carboxylate enantiomers (ꢀ)-4a, (ꢀ)-4c. Reagents and conditions:
(i) Lipolase, iPr2O, 70 °C, 4 h; (ii) (a) EtOH/HCl, 0 °C, 1 h, 83%; (b) Boc2O, TEA, THF, rt, 12 h, 77%; (iii) KMnO4, CH2Cl2, BnEt3NCl, 0 °C, 2 h,
(+)-3a: 46%, (ꢀ)-3c: 50%; (iv) NaOEt, EtOH, rt, 18 h, 68%; (v) (a) NaIO4, THF/H2O, rt, 1 h; (b) NaCNBH3, 1 equiv AcOH, CH2Cl2/THF, BnNH2,
rt, 4 h, (ꢀ)-4a: 28% (two steps), (ꢀ)-4c: 30% (two steps).

L. Kiss et al. / Tetrahedron Letters 49 (2008) 339–342
341
Amino esters 4a and 4c were also synthesized for the
enantiomeric substances (Scheme 2).
2.3. Ethyl (3S,4S)-1-benzyl-3-(tert-butoxycarbonyl-
amino)piperidine-4-carboxylate [(ꢀ)-4a]
25
The starting compound (1S,5R)-1 was prepared
through the Lipolase (lipase B from Candida Antarc-
tica)-catalyzed enantioselective ring opening of 7-azabi-
cyclo[4.2.0]oct-3-en-8-one, using a slightly modified
literature procedure.11b The enantioselective ring cleav-
age of ( )-1 was performed successfully (E > 200) on a
10 g scale by adding the enzyme in portions to the
reaction mixture. Following the route presented above
the preparation of (ꢀ)-4a and (ꢀ)-4c was accomplished
in enantiomerically pure form (Scheme 2). An advan-
tage of the procedure is that the known stereocentres
of the starting materials are unaffected during the syn-
thetic steps, which allows the determination of the
absolute configurations of the chiral centres in the final
products.
Colourless oil, yield: 28% (two steps), ½aꢁD ꢀ17 (c 0.24,
EtOH). 1H NMR (CDCl3, 400 MHz): d = 1.25 (t,
J = 7.09 Hz, 3H, CH3), 1.41 (s, 9H, CH3), 1.66–1.74
(m, 1H, CH2), 1.89–2.08 (m, 2H, H-4 and CH2), 2.22–
2.30 (m, 1H, NCH2), 2.45–2.53 (m, 1H, NCH2), 2.71–
2.82 (m, 2H, NCH2), 3.48 (s, 2H, NCH2Ar), 4.07–4.15
(m, 2H, OCH2), 4.17–4.25 (m, 1H, H-3), 5.33–5.40 (m,
1H, NH), 7.25–7.33 (m, 5H, ArH); 13C NMR (CDCl3,
400 MHz): d = 14.8, 29.1, 45.1, 48.0, 52.4, 58.7, 61.3,
63.3, 78.3, 79.8, 127.8, 128.9, 129.5, 138.7, 154.6,
173.6; Anal. Calcd. for C20H30N2O4: C, 66.27; H, 8.34;
N, 7.73. Found: C, 65.91; H, 8.03; N, 7.30.
2.4. Ethyl (3S,4R)-1-benzyl-3-(tert-butoxycarbonyl-
amino)piperidine-4-carboxylate [(ꢀ)-4c]
25
In conclusion, a simple strategy has been developed
for the preparation of cyclic b-amino ester diastereo-
mers containing a piperidine skeleton, based on dihydr-
Colourless oil, yield: 30% (two steps), ½aꢁD ꢀ13 (c 0.13,
EtOH). 1H NMR (CDCl3, 400 MHz): d = 1.25 (t,
J = 7.09 Hz, 3H, CH3), 1.42 (s, 9H, CH3), 1.82–2.00
(m, 2H, CH2), 2.10–2.31 (m, 2H, H-4, NCH2), 2.32–
2.65 (m, 2H, NCH2), 2.71–2.83 (m, 1H, NCH2),
3.41–3.50 (m, 1H, NCH2Ar), 4.00–4.1 (m, 1H, H-3),
4.11–4.19 (m, 2H, OCH2), 4.83–4.97 (m, 1H, NH),
7.25–7.33 (m, 5H, ArH); 13C NMR (CDCl3,
400 MHz): d = 14.2, 28.4, 48.3, 51.1, 57.1, 59.3, 60.6,
62.7, 70.2, 77.6, 127.1, 128.3, 128.9, 138.1, 154.9,
173.1; Anal. Calcd. for C20H30N2O4: C, 66.27; H, 8.34;
N, 7.73. Found: C, 65.95; H, 8.01; N, 7.36.
oxylation of
a
b-aminocyclopentene carboxylate,
cleavage of the resulting dihydroxy compound,
followed by reduction and amine-mediated ring expan-
sion. We are currently studying the application of such
transformations for the synthesis of other heterocyclic
b-amino acids in both racemic and enantiomerically
pure forms.
2. Experimental
Compound characterizations are given only for enantio-
meric substances.
Acknowledgements
We are grateful to the Hungarian Research Foundation
(OTKA Nos. F67970 and T049407) and the National
Research and Development Office, Hungary (GVOP-
311-2004-05-0255/3.0) for financial support.
2.1. Ethyl (1S,2S,3R,4S)-2-(tert-butoxycarbonylamino)-
3,4-dihydroxycyclopentanecarboxylate [(+)-3a]
25
White solid, mp 117–120 °C, yield 46%, ½aꢁD +110 (c
1
0.17, EtOH). H NMR (CDCl3, 400 MHz): d = 1.27 (t,
J = 7.14 Hz, 3H, CH3), 1.48 (s, 9H, CH3), 2.08–2.14
(m, 1H, CH2), 2.16–2.24 (m, 1H, CH2), 3.24–3.34 (m,
1H, H-1), 3.98–4.04 (m, 1H, H-3), 4.08–4.22 (m, 4H,
OCH2, H-2, H-4), 5.55 (s, 1H, NH); 13C NMR (CDCl3,
400 MHz): d = 14.8, 29.0, 34.4, 42.6, 57.5, 61.8, 70.9,
79.6, 81.1, 157.2, 175.1; Anal. Calcd. for C13H23NO6:
C, 53.97; H, 8.01; N, 4.84. Found: C, 53.64; H, 7.90;
N, 4.59.
References and notes
1. (a) Fulo¨p, F. Chem. Rev. 2001, 101, 2181; (b) Martinek, T.
¨
¨
´
A.; Fulo¨p, F. Eur. J. Biochem. 2003, 270, 3657; (c) Palko,
M.; Kiss, L.; Fulo¨p, F. Curr. Med. Chem. 2005, 12, 3063;
¨
´
(d) Fulo¨p, F.; Martinek, T. A.; Toth, G. K. Chem. Soc.
¨
Rev. 2006, 35, 323; (e) Enantioselective Synthesis of b-
Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V., Eds.;
John Wiley & Sons: Hoboken, 2005.
2.2. Ethyl (1R,2S,3R,4S)-2-(tert-butoxycarbonylamino)-
3,4-dihydroxycyclopentanecarboxylate [(ꢀ)-3c]
2. (a) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.;
Gellman, S. H. Nature 2000, 404, 565; (b) Porter, E. A.;
Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2002,
124, 7324; (c) Porter, E. A.; Weisblum, B.; Gellman, S. H.
J. Am. Chem. Soc. 2005, 127, 11516.
3. Simpson, G. L.; Gordon, A. H.; Lindsay, D. M.;
Promsawan, N.; Crump, M. P.; Mulholland, K.; Hayter,
B. R.; Gallagher, T. J. Am. Chem. Soc. 2006, 128, 10638.
4. Wang, G. T.; Chen, Y.; Wang, S.; Gentles, R.; Sowin, T.;
Kati, W.; Muchmore, S.; Giranda, V.; Stewart, K.; Sham,
H.; Kempf, D.; Laver, W. G. J. Med. Chem. 2001, 44,
1192.
25
1
Colourless oil, yield: 50%, ½aꢁD ꢀ20 (c 0.15, EtOH). H
NMR (CDCl3, 400 MHz): d = 1.25 (t, J = 7.25 Hz, 3H,
CH3), 1.44 (s, 9H, CH3), 1.97 (m, 1H, CH2), 2.07–2.18
(m, 1H, CH2), 2.89–2.99 (m, 1H, H-1), 4.06–4.12 (m,
1H, H-2), 4.12–4.18 (m, 3H, OCH2, H-3), 4.25–4.32
(m, 1H, H-4), 5.14 (d, J = 8.05 Hz, 1H, NH); 13C
NMR (CDCl3, 400 MHz): d = 14.5, 28.7, 34.1, 47.5,
56.4, 31.4, 72.3, 77.4, 80.3, 156.2, 175.1; Anal. Calcd.
for C13H23NO6: C, 53.97; H, 8.01; N, 4.84. Found: C,
53.62; H, 7.88; N, 4.54.
5. Schinnerl, M.; Murray, J. K.; Langenhan, J. M.; Gellman,
S. H. Eur. J. Org. Chem. 2003, 721.

342
L. Kiss et al. / Tetrahedron Letters 49 (2008) 339–342
6. (a) Nishimura, Y.; Satoh, T.; Adachi, H.; Kondo, S.;
hedron Lett. 2003, 44, 3381; (b) Wright, K.; Sarciaux,
M.; Castries, A.; Wakselman, M.; Mazaleyrat, J.-P.;
Toffoletti, A.; Corvaja, C.; Crisma, M.; Peggion, C.;
Formaggio, F.; Toniolo, C. Eur. J. Org. Chem. 2007,
3133.
Takeuchi, T.; Azetaka, M.; Fukuyashu, H.; Iizuka, Y. J.
Am. Chem. Soc. 1996, 118, 3051; (b) Nishimura, Y.; Satoh,
T.; Adachi, H.; Kondo, S.; Takeuchi, T.; Azetaka, M.;
Fukuyasu, H.; Iizuka, Y. J. Med. Chem. 1997, 40, 2626; (c)
Brown, J. R.; Nishimura, Y.; Esko, J. D. Bioorg. Med.
Chem. Lett. 2006, 16, 532.
´
9. Jankowski, R.; Joseph, D.; Cave, C.; Dumas, F.; Ourev-
itch, M.; Mahuteau, J.; Morgant, G.; Pavlovic, N. B.;
d’Angelo, J. Tetrahedron Lett. 2003, 44, 4187.
10. Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N.
M.; Kruchinin, D.; Price, P. D.; Smith, A. D. Org. Biomol.
Chem. 2005, 1284.
7. (a) Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai,
S.; Nakashima, H.; Kato, T.; Ohta, H.; Iwasawa, Y. J.
Med. Chem. 1999, 42, 5261; (b) De Risi, C.; Pollini, G. P.;
Trapella, C.; Peretto, I.; Ronzoni, S.; Giardina, G. A. M.
Bioorg. Med. Chem. 2001, 9, 1871.
´
11. (a) Kiss, L.; Forro, E.; Sillanpa¨a¨, R.; Fulo¨p, F. J. Org.
¨
´
8. (a) Wright, K.; Crisma, M.; Toniolo, C.; To¨ro¨k, R.;
Chem. 2007, 72, 8786; (b) Forro, E.; Fulo¨p, F. Tetra-
¨
´
Peter, A.; Wakselman, M.; Mazaleyrat, J.-P. Tetra-
hedron: Asymmetry 2004, 15, 2875.