An efficient protocol for solution- and solid-phase end-group differentiation of spermidine

Article abstract of DOI:10.1016/S0960-894X(02)00519-X

The end-group differentiation of a selectively protected spermidine was achieved through a short sequence of steps. The functionalization of spermidine in solid-phase was monitored by FT-IR.

Full text of DOI:10.1016/S0960-894X(02)00519-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3207–3208
An Efficient Protocol for Solution- and Solid-Phase End-Group
Differentiation of Spermidine
Emerson T. Silva, Andrea S. Cunha and Edson L. S. Lima*
´
Universidade Federal do Rio de Janeiro, Instituto de Quımica, Departamento de Quımica Orgaˆnica,
´
´
Cidade Universitaria, 21945-970, Rio de Janeiro, RJ, Brazil
Received 16 May 2002;accepted 28 June 2002
Abstract—The end-group differentiation of a selectively protected spermidine was achieved through a short sequence of steps. The
functionalization of spermidine in solid-phase was monitored by FT-IR.
# 2002 Elsevier Science Ltd. All rights reserved.
The range of biological activities displayed by con-
jugated polyamines has brought considerable attention
to this class of compounds, making them attractive tar-
gets for synthesis.1 The strategy commonly adopted to
access these substrates lies on the synthesis of the poly-
amine backbone, and subsequent attachment of the
desired chain to one of its terminal amino groups. In the
case of unsymmetrical polyamines, such as spermidine,
the differentiation of the primary amino groups is
required. However, despite its seemingly simple struc-
ture, the selective functionalization of spermidine ter-
minus frequently involves a series of protection and
deprotection steps or the reduction of amino group
equivalents.2 As a result, these synthetic approaches
usually suffer from low yields and long reaction
sequences. Alternative syntheses of orthogonally pro-
tected spermidines is highly desirable.3 As an outgrowth
of our involvement with the solution- and solid-phase
synthesis of spermidine conjugates we have developed a
short, multigram synthesis of a selectively protected
spermidine. Herein we describe a protocol for terminal
amino group differentiation of spermidine, that has
been successfully applied in our laboratories.
Alkylation of 1 with 4-bromobutylphtalimide using
K2CO3 in refluxing acetonitrile over 24 h,6 afforded the
protected spermidine 2 as a colorless oil, in 73% yield.7
To the best of our knowledge, this three-step sequence is
one of the shortest syntheses described for a functiona-
lized spermidine, and we have been performing it in
batches of up to 7 g each.
Subsequent end-differentiation of spermidine 2 was
accomplished either by the treatment with TFA in
CH2Cl2 at room temperature for 19 h to afford amine
3a in 99% yield, or by the hydrazinolysis of the phtal-
imide group in refluxing ethanol for 3 h to give amine 3b
in 82% yield, after purification by flash-chromato-
graphy. Alternatively, the hydrochloride salt of amine 3a
could be obtained in quantitative yield by the reaction
with concentrated HCl in ethanol at room temperature
The route outlined in Scheme 1 begins with the mono-
protection of 1,3-propanediamine with (Boc)2O,4 fol-
lowed by the benzylation of the crude product,5 to
provide the protected diamine 1 in 59% yield (two
steps) after purification by flash-chromathography.
*Corresponding author. Fax: +55-21-2562-7256;e-mail: edson@iq.
ufrj.br.
Scheme 1. Synthesis of a selectively functionalized spermidines.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00519-X

3208
E. T. Silva et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3207–3208
FAPERJ for a fellowship. We also thank the Labora-
tory of Mass Spectrometry of the Instituto de Quımica
of Universidade Estadual de Campinas.
References and Notes
1. (a) For leading references see: Antitumor: Casero, R. A.;
Woster, P. M. J. Med. Chem. 2001, 44, 1. (b) Neurotoxin: Hone,
N. D.;Payne, L. J. Tetrahedron Lett. 2000, 41, 6149. (c)
Immunossupressant: Lebreton, L.;Annat, J.;Derrepas, P.;
Dutartre, P.;Renaut, P. J. Med. Chem. 1999, 42, 27. (d)
Antiparasitic: Chen, S.;Coward, J. K. J. Org. Chem. 1998, 63,
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Shao, B.;Feibush, P.;McGuigan, M.;Tzodikov, N.;Feibush,
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2. (a) Reviews: Kuksa, V.;Buchan, R.;Lin, P. K. T. Synthesis
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M. Tetrahedron 1992, 48, 4475. (c) Bergeron, R. J. Acc. Chem.
Res. 1986, 19, 105.
Scheme 2. Immobilization of spermidine 3a.
3. (a) Araujo, M. J. S. M. P.;Ragnarsson, U.;Almeida, M. L.
S.;Trigo, M. J.. S. A. J. Chem. Res.(S) 1992, 120. (b) Lev-
chine, I.;Rajan, P.;Borloo, M.;Bollaert, W.;Haemers, A.
Synthesis 1994, 37. (c) Lemaire-Audoire, S.;Savignac, M.;
Genet, J. P. Synlett 1996, 75. (d) Araujo, M. J. S. M. P.;
overnight.8 However, the ammonium salt proved
hygroscopic and difficult to handle.
After securing comfortable amounts of spermidine 3a,
we turned our attention to its immobilization on solid
support. The solid-phase reactions were monitored by
FT-IR, and the diagnostic region is presented in Scheme
2. Initially, the Wang resinTM was activated with car-
bonyl-diimidazole in THF for 4 h (Scheme 2).9 Attach-
ment of 3a to resin 4 was carried out in refluxing
CH2Cl2 for 10 h. The disappearance of the acyl-imida-
zole absorption at 1757 cmÀ1 and the appearance of two
absorptions assigned to phtalimide (1766 cmÀ1) and
carbamate (1708 cmÀ1) confirmed this step. Finally,
removal of phtalimide from resin 5 was performed with
aqueous hydrazine in EtOH:THF (1:1), under reflux for
6 h. Resin 6 was assigned based on the disappearance of
the absorption at 1766 cmÀ1 and the positive ninhydrin
test. The use of resin 6 in the synthesis of potential
inhibitors of trypanosomatides’ enzymes is currently
under investigation and will be reported in due course.
Ragnarsson, U.;Trigo, M. J. S. A.;Almeida, M. L. S.
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Chem. Res.(S) 1996, 366. (e) Li, Z.;Fennie, M. W.;Ganem,
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J.;O’Sullivan, M. C. Bioorg. Med. Chem. Lett. 2001, 11, 251.
(f) Zou, Y.;Wu, Z.;Sirisoma, N.;Woster, P. M.;Casero, R.
A., Jr.;Weiss, L. M.;Rattendi, D.;Lane, S.;Bacchi, C. J.
Bioorg. Med. Chem. Lett. 2001, 11, 1613. (g) Amssoms, K.;
Augustyns, K.;Yamani, A.;Zhang, M.;Haemers, A.
Commun. 2002, 32, 319.
Synth.
4. Boturyn, D.;Boudali, A.;Constant, J.-F.;Defrancq, E.;
Lhomme, J. Tetrahedron 1997, 53, 5485.
5. Almeida, M. V.;Ce sar, E. T.;Felı cio, E. C. A.;Fontes,
A. P. S.;Robert-Gero, M. J. Braz. Chem. Soc. 2000, 11, 154.
6. Saab, N. H.;West, E. E.;Bieszk, N. C.;Preuss, C. V.;
Mank, A. R.;Casero, R. A., Jr.;Woster, P. M. J. Med. Chem.
1993, 36, 2998.
7. Data for spermidine 2: colorless oil;IR (thin film) 3393,
3026, 2973, 1771, 1713, 1511, 1396, 1366, 1250, 1172, 721, 530
1
cmÀ1; H NMR (CDCl3, 200 MHz) d 7.61–7.80 (4H, m, Pht-
H), 7.13–7.20 (5H, m, Ph–H), 3.56 (2H, t, J=6.67 Hz,
ÀCH2NPht), 3.41 (2H, s, ÀCH2Ph), 3.35 (2H, q, J=5,53 Hz,
ÀCH2NH), 2.36 (4H, m, ÀCH2NCH2À), 1.40–1.60 (6H, m,
three overlapping CH2), 1.39 (9H, s, three CH3); 13C NMR
(CDCl3, 50 MHz) d 24.20, 26.37, 26.65, 28.47, 37.77, 39.60,
52.14, 53.19, 58.80, 78.61, 123.16, 126.94, 128.25, 128.90,
132.11, 133.88, 139.38, 156.01, 168.36;TLC Rf=0.65 (EtOAc/
hexanes, 1:1);Exact mass calcd for C 27H36N3O4: 465.2627,
found: 465.2624.
In conclusion, we described a short synthesis of a selec-
tively functionalized spermidine and its end-group dif-
ferentiation in solution- and in solid-phase.
Acknowledgements
This work was supported by grants from European
Community
8. Martin, B.;Posse me, F.;Barbier, C. L.;Carreaux, F.;Car-
(ERBIC18-CT98-0372),
International
boni, B.;Seiler, N.;Moulinoux, J.-P.;Delcros, J.-G.
Chem. 2001, 44, 3653.
9. Hauske, R. J.;Dorff, P. Tetrahedron Lett. 1995, 36, 1589.
J. Med.
Foundation for Science (F/3267-1) and FAPERJ (E-26/
170.560/2001). E.T.S. would like to thank CAPES and