Mild and efficient synthesis of N1,N5,N 10-tri-tert-butoxycarbonyl spermine

Article abstract of DOI:10.1080/00397911.2010.523856

This article describes a mild and efficient synthesis of N ¹,N⁵,N¹⁰-tri-tert-butoxycarbonyl spermine from putrescine, with a 41% overall yield. The key steps include a Michael addition and Raney nickel (W-2) reduction. The advantages of this synthesis include a simple procedure, mild conditions, and good yields. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.523856

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Mild and Efficient Synthesis of N 1,N 5,N
10-Tri-tert-butoxycarbonyl Spermine
Xiangjun Feng a , Wenpin Xia a , Yu Luo a & Wei Lu a
a Department of Chemistry , Institute of Medicinal Chemistry, East
China Normal University , Shanghai , China
Accepted author version posted online: 18 Jul 2011.Published
online: 14 Sep 2011.
To cite this article: Xiangjun Feng , Wenpin Xia , Yu Luo & Wei Lu (2012) Mild and Efficient
Synthesis of N 1,N 5,N 10-Tri-tert-butoxycarbonyl Spermine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:2, 274-278, DOI:
10.1080/00397911.2010.523856
To link to this article: http://dx.doi.org/10.1080/00397911.2010.523856
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Synthetic Communications1, 42: 274–278, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523856
MILD AND EFFICIENT SYNTHESIS OF N1,N5,N10-TRI-
TERT-BUTOXYCARBONYL SPERMINE
Xiangjun Feng, Wenpin Xia, Yu Luo, and Wei Lu
Department of Chemistry, Institute of Medicinal Chemistry, East China
Normal University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract This article describes a mild and efficient synthesis of N1,N5,N10-tri-tert-butoxy-
carbonyl spermine from putrescine, with a 41% overall yield. The key steps include a
Michael addition and Raney nickel (W-2) reduction. The advantages of this synthesis
include a simple procedure, mild conditions, and good yields.
Keywords Michael addition; Raney nickel (W-2) reduction; synthesis; N1,N5,N10-tri-Boc
spermine
INTRODUCTION
Natural polyamines, such as putrescine, spermine, and spermidine (Fig. 1), are
widely distributed in the plant and animal kingdoms. They play crucial roles in a
number of cell processes and possess a variety of pharmacological properties.[1,2]
Because of nitrogen protonation at physiological pH, polyamines exist essentially
as polycations in vivo.[3,4] These polycationic polyamine molecules have high affinities
for DNA through electrostatic attraction. Thus, they can bind preferentially to
negatively charged phosphate groups, resulting in stabilization of DNA and RNA
duplexes.[5–8]
The critical role of polyamines in vivo has stimulated considerable interest in the
synthesis of polyamines and their analog. A variety of symmetrical and unsymmetri-
cal polyamine analogues have been synthesized and tested. Among these polyamines
and their analog, spermine and its analog constitute one of the most important
research areas. Spermine can be attached to some drugs to develop prodrugs, which
have improved cellular import, increased affinity for DNA, and selective uptake.[2,9]
It is generally difficult to synthesize selectively protected polyamines because
of the frequent requirement for selective protection and deprotection. N1,N5,
Received November 5, 2009.
Address correspondence to Wei Lu, Institute of Medicinal Chemistry, Department of Chemistry,
East China Normal University, North Zhongshan Road, Shanghai 200062, China. E-mail: wlu@chem.
ecnu.edu.cn
274

SYNTHESIS OF N1,N5,N10-TRI-BOC SPERMINE
275
Figure 1. Structures of the spermidine, putrescine, and spermine.
N10-Tri-tert-butoxycarbonyl spermine 1 (Fig. 2) is a useful intermediate in the
synthesis of polyamine conjugates, polyamine amides, and analog.
However, only three synthetic routes for this compound have been reported,
and all suffer from several drawbacks. In the methods of Geall and Blagbrough[10,11]
and Wellendorph et al.,[12] expensive starting materials (spermine) and low tempera-
ture (ꢀ70 ꢁC) were needed. In Jasys et al.’s synthesis,[13] two selective protection
reactions resulted in troublesome purification and poor yields. In Bueno et al.’s
Figure 2. Structures of the N1,N5,N10-tri-Boc spermine and N5, N10-di-Boc spermine.
Scheme 1. Synthesis of N1,N5,N10-tri-Boc spermine. Reagents and conditions: (a) (i) acrylonitrile, EtOH,
rt, 8 h; (ii) (Boc)2O, EtOH, rt, 12 h; (b) Raney Ni, H2, EtOH (sat. NH3), 10 h; and (c) (i) (Boc)2O, EtOH, rt,
12 h; (ii) Raney Ni, H2, EtOH (sat. NH3), 12 h.

276
X. FENG ET AL.
synthesis,[6] the selective protection of N5,N10-di-tert-butoxycarbonyl spermine 5
(Fig. 2) with Boc-ON resulted in poor yields and the purification was troublesome.
In our study of polyamine conjugates, compound 1 is required as a precursor. We
used this to subsequently develop an efficient preparation of N1,N5,N10-tri-Boc
spermine 1 as shown in Scheme 1.
RESULTS AND DISCUSSION
Michael addition of 1,4-diaminobutane with acrylonitrile in ethanol afforded
the aminonitrile product (Scheme 1). The solvent was then removed under reduced
pressure, the residue was dissolved in dichloromethane, and di-tert-butyl dicarbonate
was added to afford the Boc-protected dinitrile. The crude product was crystallized
to afford compound 2 as a light pink solid in 86% yield from putrescine.[6,14]
Actually, without workup, the aminonitrile product can be directly treated with
di-tert-butyl dicarbonate in ethanol to afford the Boc-protected dinitrile in a simpler
operation and with only as slightly lower overall yield.
Raney nickel (W-2) reduction of compound 2 (in ethanol saturated with NH3)
afforded a mixture of compounds 4 and 3, which could be separated by chromato-
graphic purification over silica gel to afford pure 4 in 50% yield and pure 3 in 15%
yield. The reduction is a key reaction for the successful synthesis of N1,N5,N10-tri-
Boc spermine 1. In this step, time control is the key to the success of the reaction,
so the reduction must be closely monitored by thin-layer chromatography (TLC).
Compound 4 can be fully converted to 3, as indicated by thin-layer chromatography
(TLC), if the reaction time is extended to 20 h.
Compound 4 was protected with di-tert-butyl dicarbonate in ethanol, and then
the solvent was removed under reduced pressure. The residue was dissolved in
ethanol saturated with NH3, followed by a catalytic hydrogenation with Raney
nickel (W-2), to afford N1,N5,N10-tri-Boc spermine 1 in 96% yield.
In summary, an efficient protocol for the synthesis of N1,N5,N10-tri-Boc spermine
1 was developed. The current route, which has the advantages of inexpensive reagents,
simple procedures, mild conditions, and good yields, could be more cost efficient than
previously reported synthetic routes for this compound.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker DRX-500 (500 MHz). 13C NMR
spectra were obtained on a JNM-EX400 (100 MHz). Mass spectra (MS) were deter-
mined on a Finnigan MAT-95 mass spectrometer. All reagents were used directly as
obtained commercially, unless otherwise noted.
N4,N9-Di(tert-butyloxycarbonyl)-3-(4-[(2-cyanoethyl)-amino]
butylamino)propanenitrile 2
A solution 1,4-diaminobutane (8.8 g, 0.1 mol) in 100 mL EtOH was cooled to
0 ꢁC, and acrylonitrile (10.6 g, 0.2 mol) (1 M solution in EtOH) was added. The
solution was allowed to warm to room temperature and stirred at room temperature
for an additional 8 h. Then, di-tert-butyl dicarbonate (48 g, 0.22 mol, 1 M in EtOH)

SYNTHESIS OF N1,N5,N10-TRI-BOC SPERMINE
277
was added, the mixture was stirred at room temperature for another 12 h, the solvent
was removed under reduced pressure, and the residue was crystallized from pertro-
leum ether/ethyl acetate (3:1) to give pure 2 as a light pink solid (32.0 g, 82%).
1H NMR (CDCl3): d 1.47 (s, 18 H), 1.52–1.56 (m, 4 H), 1.56–1.63 (m, 4 H),
3.29 (m, 4 H), 3.45 (t, J ¼ 7 Hz, 4 H). 13C NMR (CDCl3, 100 MHz): d 17.28,
25.50, 28.36, 47.11, 48.48, 80.56, 118.18, 155.03. HRMS-FAB m=z 417.2471
([M]þ þ Naþ) (calcd. for C20H34N4O4 394.2580).
N1,N4-Di(tert-butyloxycarbonyl)-N1-2-cyanoethyl-N4-3-
aminopropyl-1,4-butanediamine 4
Raney nickel (2.5 g, 0.022 mol) was added to a solution of 2 (5 g, 0.012 mol) in
150 mL NH3 saturated ethanol, then the reaction was stirred under a H2 atmosphere
at room temperature for 10 h. The catalyst was removed by filtration, the filtrate was
concentrated under reduced pressure, and then the residue was purified by column
chromatography on silica gel with CH2Cl2=MeOH (15:1) to give the product 4 as
a viscous oil (2.5 g, 50%) and then CH2Cl2=MeOH=NH3 ꢂ H2O (40:1:1) to give pure
3 as a viscous oil (0.8 g, 15%).
Compound 4. 1H NMR (CDCl3): d 1.43–1.48 (m, 18 H), 1.52–1.56 (m, 4 H),
1.61–1.65 (m, 2 H), 2.64–2.67 (m, 4 H), 3.18–3.26 (m, 6 H), 3.44 (t, J ¼ 6 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): d 17.3, 25.4, 28.2, 31.2, 40.1, 43.5, 46.7, 48.2, 53.3,
79.9, 118.8, 156.2. HRMS-FAB m=z 399.296
C20H38N4O4 398.2893).
6
([M]þ þ Hþ) (calcd. for
Compound 3. 1H NMR (CDCl3): d 1.32 (s, 4 H), 1.45 (s, 18 H), 1.50 (s, 4 H),
1.63–1.67 (m, 4 H), 2.69 (s, 4 H), 3.16–3.28 (m, 8 H). 13C NMR (CDCl3, 100 MHz): d
25.41, 28.31, 31.64, 39.13, 44.07, 46.48, 79.15, 155.63. HRMS-FAB m=z 425.3098
([M]þ þ Naþ) (calcd. for C20H42N4O4 402.3206).
N1,N5,N10-Tri(tert-butyloxycarbonyl)-spermine 1
Di-tert-butyl dicarbonate (3.7 g, 0.017 mol, 1 M in EtOH) was added to a sol-
ution 4 (5.6 g, 0.014 mol) in 180 mL EtOH, the reaction stirred at room temperature
for 12 h, and the solvent then was removed under reduced pressure. The residue
was dissolved in 100 mL NH3 saturated ethanol, then Raney nickel (3.5 g, 0.03 mol)
was added. The reaction stirred under a H2 atmosphere at room temperature for
12 h. The catalyst was removed by filtration, and the filtrate was concentrated under
reduced pressure to give the product 1 as viscous oil (7.0 g, 96%). 1H NMR (CDCl3):
d 1.43 (s, 27 H), 1.63 (s, 4 H), 2.12–2.15 (m, 4 H), 2.66 (s, 2 H), 3.07–3.21 (m, 10 H).
13C NMR (CDCl3, 100 MHz): d 25.7, 26.8, 28.4, 32.2, 37.5, 39.1, 44.0, 46.5, 79.4, 156.0,
166.9. HRMS-FAB m=z 503.3801 ([M]þ þ Hþ) (calcd. for C25H50N4O6 502.3730).
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support for New Century Excellent
Talents in University (NCET). We also thank the Laboratory of Organic Functional
Molecules and the Sino-French Institute of ECNU for support.

278
X. FENG ET AL.
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