Synthesis and characterization of Boc-protected 4-amino- and 5-amino-pyrrole-2-carboxylic acid methyl esters

Article abstract of DOI:10.1016/j.tetlet.2006.04.135

Syntheses of Boc-protected 4-amino- and 5-amino-pyrrole-2-carboxylic acid methyl esters have been achieved and the structures of these compounds have been fully characterized by detailed NMR studies.

Full text of DOI:10.1016/j.tetlet.2006.04.135

Tetrahedron Letters 47 (2006) 4631–4634
Synthesis and characterization of Boc-protected 4-amino- and
5-amino-pyrrole-2-carboxylic acid methyl estersq
Tushar Kanti Chakraborty,* Sandip P. Udawant, Saumya Roy, Bajjuri Krishna Mohan,
Kolla Srinivasa Rao, Samit Kumar Dutta and Ajit Chand Kunwar*
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 March 2006; revised 19 April 2006; accepted 26 April 2006
Available online 19 May 2006
Abstract—Syntheses of Boc-protected 4-amino- and 5-amino-pyrrole-2-carboxylic acid methyl esters have been achieved and the
structures of these compounds have been fully characterized by detailed NMR studies.
Ó 2006 Elsevier Ltd. All rights reserved.
A common approach to restrict the conformational de-
grees of freedom in small peptides involves the design
H2N
H2N
and synthesis of structurally rigid non-peptide scaffolds
which, when inserted in the appropriate sites in peptides,
produce the specific secondary structures required for
binding to their receptors. This has led to an exponential
growth in the number of reports on the development of
large varieties of constrained peptidomimetic scaffolds.1
Many of these designer templates are based on de novo
structural entities with several functional groups an-
chored on a single ensemble. 5-(Aminomethyl)-pyrrole-
2-carboxylic acid 1 is one such structure that has been
used as a dipeptide isostere in synthetic peptides2 and
in the development of new DNA-binding agents.3 In
continuation of our work on the development of new
pyrrole-based monomeric building blocks, we were
interested in the synthesis of 4-amino-pyrrole-2-carbox-
ylic acid 2 and its 5-amino congener 3. The synthesis of
compound 2 has been reported4 and it has been used re-
cently to develop novel guanidinium-based carboxylate
receptors.5 We were interested in developing an alterna-
tive route based on our earlier synthesis of 5-(amino-
methyl)-pyrrole-2-carboxylic acid.2a The results of this
study are described here.
OH
OH
OH
H2N
N
H
N
H
N
H
O
O
O
1
2
3
products, 5 and 6, respectively, in 2:3 ratio and in 95%
total yield, which could be separated easily by standard
silica gel column chromatography (Scheme 1).6 Com-
pound 5 was oxidized to an acid 7 in 92% yield. The acid
was treated with diphenyl phosphoryl azide (DPPA) in
the presence of Et3N and the intermediate isocyanate
was reacted with t-butanol to furnish the 4-t-butylcarba-
mate 8 in 50% yield.7,8 Aldehyde 6 was similarly con-
verted to the 5-substituted product 9.8
To our surprise, compound 8, and not 9, was found to
be identical with the product synthesized by us following
the method reported earlier by Dervan et al.4 with a
slight modification that was also followed by Schmuck
et al.,5 that is, using MeONa/MeOH instead of EtO-
Na/EtOH to get the methyl ester. It is to be noted here
that this step in Dervan’s method is inconsequential as
far as the question of whether the 4- or 5-isomer is
formed is concerned, which is settled in the previous
step.
Vilsmeier–Haack reaction of pyrrole-2-carboxylic acid
methyl ester 4 gave a mixture of 4-formyl and 5-formyl
Keywords: 4-Amino-pyrrole-2-carboxylic acid; 5-Amino-pyrrole-2-car-
boxylic acid; Peptidomimetics.
To confirm the structures of the two products, 8 and 9,
detailed NMR experiments were carried out at 30 °C in
DMSO-d6. For the spectral assignments, decoupling
and nuclear Overhauser effect spectroscopy (NOESY)
q IICT Communication No. 060315.
*
Corresponding authors. Tel.: +91 40 27193154; fax: +91 40
27193108/27160757; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.135

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T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 4631–4634
OHC
POCl3, DMF
1,2-dichloroethane
OMe
OMe
OMe
OHC
+
N
H
N
H
N
H
1 h at rt, then reflux for 15 min;
cool and neutralize with 10%
Na2CO3 at 0 oC (ref. 6)
95%
O
O
O
4
5
[2:3]
6
HO2C
BocHN
DPPA, Et3N, CH3CN, 5 h
then tBuOH, reflux, 15 h
NaClO2, NaH2PO4,
30% H2O2, CH3CN
OMe
OMe
5
N
H
N
H
92%
50%
O
O
7
8
same as above
OMe
BocHN
6
N
(37% in two steps)
H
O
9
Scheme 1.
6.5
7.0
4
1
6
5
3
2
5
8.0
9.0
4
1 4
6
H
Boc-HN
1
OMe
10.0
3
H
N
H
O
2
11.0
12.0
2
12.0
10.0
8.0
6.0
4.0
2.0
Figure 1. NOE correlation and NOESY spectrum for 8.
experiments were carried out. NOESY experiments, in
addition, provided crucial information about the proxi-
mity of the protons. The aromatic C–H signals for both
8 and 9 appeared as a dd with J = 2.6, 1.8 Hz for the
former and J = 4.0, 2.3 Hz for the latter. D2O exchange
studies transformed them into doublets with 2.6 Hz cou-
pling in 8 and 4.0 Hz in 9. In view of the range reported
Consolidation of the above spectral data along with the
heteronuclear single quantum correlation spectroscopy
(HSQC) experiments, allows us to assign H(3), H(5/4),
C(3) and C(5/4) at 6.60, 6.96, 105.5 and 112.7 ppm for
8 and at 6.70, 5.78, 115.8 and 95.1 ppm for 9, respec-
tively. To arrive at an unambiguous structure for 8
and 9, NOESY experiments were additionally
performed.
3
for the unsubstituted pyrrole,9 only JH(3)–H(4) has a
value of about 3.5 Hz, whereas all other couplings are
about 2.6 Hz or smaller. This suggests a 2,4-substitution
pattern for 8 and a 2,5-substitution pattern for 9. Fur-
ther support for these observations was obtained from
1JH–C couplings. In pyrrole, one bond proton–carbon
NOE studies on 8 confirmed that our findings on its
structure are at variance to those of Dervan et al. The
low-field pyrrole proton H(5) (d = 6.96 ppm) shows
NOE correlations with both the NH protons as well as
the Boc–CH3 group (Fig. 1), while the other pyrrole pro-
ton H(3) (d = 6.60 ppm) shows NOEs with NH–Boc,
Boc–CH3 and OMe protons. These observations give
conclusive proof for 8 as N-Boc-4-amino-pyrrole-2-car-
boxylic acid methyl ester.
1
couplings are distinctive with JH(3)–C(3) ꢀ 170 Hz and
1JH(2)–C(2) ꢀ 182 Hz.10 Our experiments show that for
1
8 they are 190.3 and 174.7 Hz whereas for 9 the JHÀC
s
have values of 174.0 and 175.4 Hz., further confirming a
2,4-substitution pattern for 8 and 2,5-substitution in 9.

T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 4631–4634
4633
2
1
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
1
1
H
H
2
OMe
Boc-HN
N
H
O
2
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0
Figure 2. NOE correlation and NOESY spectrum for 9.
ton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789–12854; (h) Giannis, A.;
Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244–
1267.
For compound 9, the two aromatic protons in the pyr-
role ring show strong NOE correlations in the NOESY
spectrum (Fig. 2). Further, observation of a NOE
cross peak between H(4)–BocNH, in addition to con-
firming the assignments for H(3) and H(4) at
d = 6.70 ppm and d = 5.78 ppm, respectively, provides
emphatic evidence for their vicinal disposition, and
confirms 9 as N-Boc-5-amino-pyrrole-2-carboxylic acid
methyl ester.
2. (a) Chakraborty, T. K.; Krishna Mohan, B.; Kiran
Kumar, S.; Kunwar, A. C. Tetrahedron Lett. 2002, 43,
2589–2592; (b) Chakraborty, T. K.; Mohan, B. K.;
Kumar, S. K.; Kunwar, A. C. Tetrahedron Lett. 2003,
44, 471–473; (c) Bonauer, C.; Zabel, M.; Ko¨nig, B. Org.
Lett. 2004, 6, 1349–1352; (d) Bonauer, C.; Ko¨nig, B.
Synthesis 2005, 2367–2372; (e) Kruppa, M.; Bonauer, C.;
´
Michlova, V.; Ko¨nig, B. J. Org. Chem. 2005, 70, 5305–
5308.
In addition, compound 8 was transformed into its ethyl
ester 10 by a base-catalyzed trans-esterification process.
The spectral data of 10 matched exactly those of the
compound reported by Dervan et al.11 These findings
imply that the reported structure of the compound pre-
pared by Dervan et al. is likely to be different. Based on
the NMR studies described here, we conclude that the
amino-substituted pyrrole-2-carboxylic acid reported
earlier4 was actually the 4-amino isomer.
3. Chakraborty, T. K.; Mohan, B. K.; Gnanamani, M.;
Maiti, S. Tetrahedron Lett. 2005, 46, 647–651.
4. Marques, M. A.; Doss, R. M.; Urbach, A. R.; Dervan, P.
B. Helv. Chim. Acta 2002, 85, 4485–4517.
5. Schmuck, C.; Dudaczek, J. Tetrahedron Lett. 2005, 46,
7101–7105.
6. Khan, M. K. A.; Morgan, K. J.; Morrey, O. P. Tetrahe-
dron 1966, 22, 2095–2105.
7. Urbach, A. R.; Szewczyk, J. W.; White, S.; Turner, J. M.;
Baird, E. E.; Dervan, P. B. J. Am. Chem. Soc. 1999, 121,
11621–11629.
Acknowledgements
8. Selected physical data of 8: white solid; mp 185–186 °C;
1H NMR (500 MHz, DMSO-d6): d 11.65 (br, 1H, pyrr-
oleNH), 9.09 (br, 1H, BocNH), 6.96 (dd, J = 2.6, 1.8 Hz,
1H, 5-H), 6.60 (dd, J = 2.6, 1.8 Hz, 1H, 3-H), 3.73 (s, 3H,
CO2CH3), 1.44 (s, 9H, Boc); 13C NMR (150 MHz,
DMSO-d6): d 160.8, 152.8, 125.1, 119.0, 112.7, 105.5,
78.5, 51.1, 28.2; MS (FAB): m/z (%) 240 (50) [M]+.
Selected physical data of 9: white solid; mp 118 °C; 1H
NMR (500 MHz, DMSO-d6): d 10.63 (br, 1H, pyrro-
leNH), 9.57 (br, 1H, BocNH), 6.70 (dd, J = 4.0, 2.3 Hz,
1H, 3-H), 5.78 (dd, J = 4.0, 2.3 Hz, 1H, 4-H), 3.71 (s, 3H,
CO2CH3), 1.45 (s, 9H, Boc); 13C NMR (150 MHz,
DMSO-d6): d 160.4, 152.5, 133.7, 115.8, 115.2, 97.0,
80.2, 50.9, 28.0; MS (FAB): m/z (%) 241 (48) [M+H]+.
9. Pretsch, E.; Seibl, J.; Simon, W.; Clerc, T. In Tables of
Spectral Data for Structure Determination of Organic
Compounds; Springer: Berlin, 1981.
The authors wish to thank CSIR, New Delhi, for re-
search fellowships (S.P.U., S.R., B.K.M. and S.K.D.).
References and notes
1. For references see: (a) The Murray Goodman Memorial
Issue. In Peptide Science; Taulane, J. P., Deber, C. M.,
Eds.; Wiley InterScience, 2005; Vol. 80, pp 59–391; (b)
Synthesis of peptides and peptidomimetics. In Houben-
Weyl Methods of Organic Chemistry; Goodman, M., Felix,
A., Moroder, L., Toniolo, C., Eds.; Thieme: Stuttgart,
2004; 22b; (c) Souers, A. J.; Ellman, J. A. Tetrahedron
2001, 57, 7431–7448; (d) Tetrahedron 2000, 56, 9725–
9841; (e) Bioorg. Med. Chem. 1999, 7, 1–192; (f) Hruby, V.
J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Bio-
polymers 1997, 43, 219–248; (g) Hanessian, S.; McNaugh-
10. Weigert, F. J.; Roberts, J. D. J. Am. Chem. Soc. 1968, 90,
3543–3549.

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T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 4631–4634
11. Selected physical data of 10: white solid; mp 195–196 °C;
1H NMR (400 MHz, DMSO-d6): d 11.46 (s, 1H, pyrrole-
NH), 9.04 (s, 1H, BocNH), 6.94 (br, 1H, 5-H), 6.60 (br,
1H, 3-H), 4.20 (q, J = 7.3 Hz, 2H, CO2CH2CH3), 1.44 (s,
9H, Boc), 1.26 (t, J = 7.3 Hz, 3H, CO2CH2CH3); 13C
NMR (100 MHz, DMSO-d6): d 160.2, 152.6, 124.8, 119.2,
112.4, 105.3, 78.3, 59.3, 28.1, 14.3; MS (FAB): m/z (%) 254
(34) [M]+.