An efficient synthesis of orthogonally protected spermidine

Article abstract of DOI:10.1081/SCC-120002114

A major problem in the use of spermidine for the synthesis of biologically interesting compounds is the selective orthogonal protection of the three different amino groups. Our approach is based on the Fukuyama reaction, starting from putrescine and 3-amino-l-propanol and affording N⁸-benzyloxycarbonyl- N¹-tert-butyloxycarbonyl- N⁴-(2-nitrobenzenesulfonyl)spermidine (5) in 5 steps in high yield.

Full text of DOI:10.1081/SCC-120002114

SYNTHETIC COMMUNICATIONS, 32(3), 319–328 (2002)
AN EFFICIENT SYNTHESIS
OF ORTHOGONALLY PROTECTED
SPERMIDINE
K. Amssoms, K. Augustyns,* A. Yamani,
M. Zhang, and A. Haemers
Medicinal Chemistry, University of Antwerp (UIA),
Universiteitsplein 1, B-2610 Antwerp, Belgium
ABSTRACT
A major problem in the use of spermidine for the synthesis
of biologically interesting compounds is the selective ortho-
gonal protection of the three different amino groups. Our
approach is based on the Fukuyama reaction, starting
from putrescine and 3-amino-1-propanol and affording
N8-benzyloxycarbonyl-N1-tert-butyloxycarbonyl-N4-(2-nitro-
benzenesulfonyl)spermidine (5) in 5 steps in high yield.
Spermidine and its analogues are useful compounds for the synthesis
of several biologically interesting molecules. Glutathionylspermidine and
trypanothione have been found in the parasites of the genera Trypanosoma
and Leishmania and function in a similar way as does glutathione in
mammalian cells.1 Polyamines are implicated in cell proliferation and are
*Corresponding author. Fax: 32-(0)3-820 27 39; E-mail: koen.Augustyns@
uia.ua.ac.be
319
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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AMSSOMS ET AL.
therefore being investigated as chemotherapeutic agents and immuno-
suppressives. They are also frequently found in toxins or siderophores.
A major problem in the use of polyamines, such as spermidine, is the
selective protection of the three amino functions with different orthogonal
protecting groups. Several approaches have been published and were
reviewed2 for the synthesis of spermidine analogues, but only a few
methods are reported for the synthesis of orthogonally protected spermidine
molecules: N8-benzyloxycarbonyl-N1-tert-butyloxycarbonyl-N4-fluorenyl-
methyloxycarbonylspermidine,3
N8-benzyloxycarbonyl-N1-phthaloyl-N4-
tosylspermidine,4
N4-benzyl-N1-tert-butyloxycarbonyl-N8-trifluoroacetyl
spermidine5 and N4-benzyl-N1-phthaloyl-N8-tert-butyloxycarbonylspermi-
dine.6 Two protected spermidine molecules attached to a resin are published:
a
N1-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)-N8-(4-monomethyl-
trityl)spermidine attached with N4 to a carbonate. Wang resin7 and a
N4-tert-butyloxycarbonyl-N1-fluorenylmethyloxycarbonylspermidine atta-
ched with N8 to a Dde linker.8 These molecules indifferently suffer from a
lengthy and difficult synthesis with low yield. Another disadvantage of some
of these molecules is the need for rather harsh conditions for removal of the
protecting groups such as phthaloyl, tosyl and trifluoroacetyl. Therefore we
planned a synthesis of an orthogonally protected spermidine which would
counteract the above mentioned disadvantages.
The key step in our synthesis is a Fukuyama reaction9 using a
2-nitrobenzenesulfonyl protection. Monosulfonylated putrescine hydro-
chloride (1) was obtained using putrescine in a 3-fold excess following a
modification of a procedure10 described by Fukuyama et al. The remaining
free amino group was then protected with benzyl chloroformate yielding 2.
Compound 2 is a key building block in our synthesis and could be obtained
pure in 43% yield on multigram scale from putrescine without chromato-
graphic purifications. Alkylation of 2 in a Fukuyama reaction with N-Boc-
3-amino-1-propanol-mesylate (4) gave the fully orthogonally protected
spermidine 5. Intermediate 2 was also successfully used for the mono-
alkylation of a 20-fold excess of 1,3-dibromopropane affording 7. Com-
pound 7 was used in the synthesis of a protected hydroxylamine analogue
of spermidine (8) and 7 is also a useful intermediate for the synthesis of
phosphinate analogues of glutathionylspermidine.11,12
Selective removal of the 2-nitrobenzenesulfonyl protection from
N4 of 5 was accomplished with sodium thiophenolate, followed by intro-
duction of an extra benzyloxycarbonyl protecting group giving the pro-
tected spermidine 6. The tert-butyloxycarbonyl from N1 of 5 could also
be selectively removed using trifluoroacetic acid. This proves the
orthogonallity of the protecting groups of the spermidine 5, which is a

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321
Scheme 1. Synthesis of orthogonally protected spermidines.
highly attractive feature for the usually difficult synthesis of spermidine
analogues.
In conclusion, the orthogonally protected spermidine analogue
N 8-benzyloxycarbonyl-N1-tert-butyloxycarbonyl-N4-(2-nitrobenzenesul-
fonyl)spermidine (5) was obtained in 5 steps from putrescine and 3-amino-1-
propanol with a minimum of chromatographic separations and in good
yield. This compound could be highly valuable in the research of spermidine
analogues as biologically active compounds.

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AMSSOMS ET AL.
EXPERIMENTAL PART
Starting materials and reagents were purchased from Acros Chimica,
Aldrich, Sigma or Bachem. Thin Layer Chromatography (TLC) was per-
formed on POLYGRAM SIL G/UV254 plates precoated with silica gel
(Macherey-Nagel GmbH & Co., Germany). Column chromatography was
performed with Silica gel 60, 230–400 mesh (Merk) or Silica gel H, 5–40 ꢀM
(Fluka, Switzerland). 1H-NMR spectra were recorded on a Varian EM 360-L
(60 MHz) or Brucker Avance DRX 400 spectrometer (400 MHz). 13C-NMR
spectra were recorded on a Brucker Avance DRX 400 spectrometer
(100 MHz). The chemical shifts are given in ppm (ꢁ) and are relative to tetra-
methylsilane (TMS), coupling constants (J) are in Hertz. Fast Atom
Bombardment (FABþ) mass spectra were obtained on a VG 70-SEQ
hybrid mass spectrometer (VG Analytical Ltd., Manchester, U.K.), equipped
with an Ion Tech saddle field atom gun (FAB) and using glycerol as matrix.
Analytical HPLC was run on a Gilson instrument (Viliers-le-Bel, France)
equipped with an Ultrasphere ODS column (4.6 Â 250 mm, 5 ꢀM, Beckman,
Fullerton, CA, USA). The mobile phase was A: TFA/water (0.1%) and B:
TFA/acetonitrile (0.1%). A 35 min linear gradient from 10–90% B was
carried out. The flow rate was 1 mL/min the injection volume was 20 ꢀL
and detection was at 214 nm. Tetrahydrofuran (THF) was dried with CaCl2
and then distilled from sodium and benzophenone. Dichloromethane
(CH2Cl2) was distilled from calcium hydride. Anhydrous dimethylformamide
was obtained from Aldrich.
N-(2-Nitrobenzenesulfonyl)-1,4-diaminobutane Hydrochloride (1)
A solution of 2-nitrobenzenesulfonyl chloride (5.15 g, 22.6mmol) in
dry THF (10 mL) was added dropwise to a stirred solution of putrescine
(6.80 mL, 67.7 mmol) and N-methylmorpholine (2.48 mL, 2.26mmol) in dry
THF (25 mL) over a period of 2 h. The volatile components were removed
under reduced pressure and the residue was partitioned between 5%
NaHCO3 (100 mL) and CH2Cl2 (100 mL). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2 Â 60 mL). The combined
organic layers were dried over Na2SO4 and concentrated to afford an oil. The
residue was diluted with 1 N HCl (60 mL) and the precipitated material was
filtered off. The filtrate was extracted with Et2O (2 Â 60 mL) and was then
basified (pH 11) by addition of ammonium hydroxide (29%). The aqueous
layer was extracted with CH2Cl2 (4 Â 80 mL). The organic extracts were
combined, dried over MgSO4 and evaporated. The oil was treated with 1 N

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323
HCl and extracted with EtOAc (2 Â 60 mL). The water layer was evaporated
to afford 1 (3.83 g, 12.4 mmol, 55%) as a yellow powder.
1H-NMR (DMSO þ D2O) (400 MHz): ꢁ 1.45–1.53 (m, 2H, CH2),
1.53–1.62 (m, 2H, CH2), 2.76(t, 2H, J ¼ 7.27, CH2), 2.91 (t, 2H, J ¼ 6.55,
CH2), 7.85–7.90 (m, 2H, CH (2Â) of C6H4SO2NO2), 7.94–7.97 (m, 1H, CH
of C6H4SO2NO2), 8.00–8.03 (m, 1H, CH of C6H4SO2NO2); MS (FABþ)
m/z 274 [M þ H]þ; HPLC Rt ¼ 10.03 min (100%, Only one peak was
observed).
N-Benzyloxycarbonyl-N-(2-nitrobenzenesulfonyl)-
1,4-diaminobutane (2)
To a cooled (0ꢀC) and stirred solution of 1 (3.09 g, 10.0 mmol) in
dioxane (100 mL), 1 N NaOH (10 mL) was added. Benzyl chloroformate
(1.57 mL, 11.0 mmol) and 1 N NaOH (11 mL, 11.0 mmol) were added in
ten portions, alternatingly, while the mixture was vigorously stirred. The
temperature was raised to room temperature. The reaction was completed in
about 12 h. The solution was concentrated and extracted with Et2O
(2 Â 40 mL). The aqueous layer was acidified with 2 N HCl to pH 2 and
extracted with EtOAc (4 Â 40 mL). The combined organic solutions were
washed with water (40 mL) and brine (40 mL). The organic layer was
dried over MgSO4 and the solvent was removed under reduced pressure
to afford 2 (3.17 g, 7.80 mmol, 78%) as a yellow powder.
1H-NMR (CDCl3) (400 MHz) ꢁ 1.42–1.58 (m, 4H, CH2 (2Â)),
3.00–3.15 (m, 4H, CH2 (2Â)), 5.05 (s, 2H, C6H5CH2), 5.13 (t, 1H, J ¼ 5.98,
NH), 5.58–5.68 (m, 1H, NH), 7.32 (s, 5H, C6H5), 7.62–7.70 (m, 2H, CH
(2Â) of C6H4SO2NO2), 7.72–7.80 (m, 1H, CH of C6H4SO2NO2), 8.02–8.10
(m, 1H, CH of C6H4SO2NO2); MS (FABþ) m/z 408 [M þ H]þ; HPLC
Rt ¼ 22.50 min (99%, Only one major peak was observed).
N-tert-Butyloxycarbonyl-3-amino-1-propanol (3)
To a cooled (0ꢀC) and stirred solution of 3-amino-1-propanol (1.00 g,
13.3 mmol) in dioxane (27 mL) and water (14 mL), 1 N NaOH (14 mL) was
added. Di-tert-butyl pyrocarbonate (3.30 g, 14.6mmol) was added and the
solution was stirred overnight. The solution was concentrated under
reduced pressure and acidified with 1 N HCl to pH 2. The water layer was
extracted with EtOAc (3 Â 40 mL) and the combined organic layers were
washed with water (40 mL) and brine (40 mL). The organic layer was dried
and evaporated to afford 3 (2.30 g, 13.2 mmol, 99%) as a colourless oil.

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AMSSOMS ET AL.
1H-NMR (CDCl3) (60 MHz) d 1.37 (s, 9H, C(CH3)3), 1.20–1.90 (m,
2H, CH2), 2.95–3.42 (m, 2H, CH2), 3.63 (t, 2H, J ¼ 6.00, CH2), 4.15 (s, 1H,
OH), 5.40–5.90 (brs, 1H, NH); MS (FABþ) m/z 176[M þ H]þ.
N-tert-Butyloxycarbonyl-3-amino-1-propanol-mesylate (4)
A solution of 3 (1.88 g, 9.90 mmol) and Et3N (1.66 mL, 11.9 mmol) in
dry CH2Cl2 (20 mL) was cooled to 0ꢀC. A solution of mesyl chloride
(0.93 mL, 11.9 mmol) in dry CH2Cl2 (5 mL) was added dropwise. The sol-
ution was stirred for 12 h at room temperature. The solution was concen-
trated and the residue was dissolved in EtOAc (50 mL). The EtOAc solution
was washed with 5% NaHCO3 (50 mL), 1N HCl (50 mL) and brine (50 mL),
dried over MgSO4 and concentrated. Purification by column chromatogra-
phy (gradient elution from 20% Et2O in hexane to 80% Et2O in hexane)
yielded 4 (1.63 g, 6.43 mmol, 65%) as a white crystalline product.
1H-NMR (CDCl3) (60 MHz) ꢁ 1.40 (s, 9H, C(CH3)3), 1.70–2.19 (m,
2H, CH2), 3.02 (s, 3H, CH3), 2.90–3.48 (m, 2H, CH2), 4.25 (t, 2H, J ¼ 8.00,
CH2), 4.90–5.40 (brs, 1H, NH); MS (FABþ) m/z 254 [M þ H]þ.
N8-Benzyloxycarbonyl-N1-tert-butyloxycarbonyl-N4-
(2-nitrobenzenesulfonyl)-spermidine (5)
A suspension of 2 (1.00 g, 2.46mmol), 4 (0.68 g, 2.70 mmol) and
Cs2CO3 (0.80 g, 2.46mmol) in dry DMF (10 mL) was stirred for 12 h at
60ꢀC. After addition of water (100 mL), the solution was extracted with
EtOAc (3 Â 30 mL). The organic layer was washed with brine (4 Â 50 mL),
dried over MgSO4 and evaporated under reduced pressure. Purification by
column chromatography (gradient elution from 100% CH2Cl2 to 1%
MeOH in CH2Cl2) afforded 5 (0.97 g, 1.72 mmol, 70%).
1H-NMR (CDCl3) (400 MHz) ꢁ 1.42 (s, 9H, C(CH3)3), 1.42–1.51
(m, 2H, CH2), 1.51–1.60 (m, 2H, CH2), 1.68–1.75 (m, 2H, CH2),
3.07–3.17 (m, 4H, CH2 (2Â)), 3.22–3.35 (m, 4H, CH2 (2Â)), 5.10–5.20
(brs, 1H, NH), 5.45–5.55 (brs, 1H, NH), 7.32 (s, 5H, C6H5), 7.55–7.59 (m,
1H, CH of C6H4SO2NO2), 7.62–7.68 (m, 2H, CH (2Â) of C6H4SO2NO2),
7.90–7.95 (m, 1H, CH of C6H4SO2NO2); 13C-NMR (CDCl3) d 25.2 (CH2),
26.8 (CH2), 28.2 (C(CH3)3), 28.5 (CH2), 37.3 (CH2), 40.1 (CH2), 45.2 (CH2),
47.2 (CH2), 66.3 (C6H5CH2), 78.9 (C(CH3)3), 124.0, 127.8, 127.8, 128.3,
130.1, 131.6, 132.9, 133.4, 136.5, 147.8 (Carom), 155.9 (CO), 156.3 (CO);
MS (FABþ) m/z 565 [M þ H]þ; HPLC Rt ¼ 26.26 min (100%, Only one
peak was observed).

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325
N1-tert-Butyloxycarbonyl-N4,N8-
dibenzyloxycarbonylspermidine (6)
To a solution of 5 (0.69 g, 1.23 mmol) in dry DMF (5 mL), sodium
thiophenolate (0.28 g, 2.09 mmol) was added under dry atmosphere of
N2. The solution was stirred overnight at room temperature. After dilution
with water (100 mL), the solution was extracted with EtOAc (4 Â 30 mL).
The combined organic layers were washed with brine (4 Â 30 mL), dried
over MgSO4 and evaporated to dryness. The yellow oil was used without
further purification and was dissolved in dioxane (15 mL). After cooling
in 0ꢀC, benzyl chloroformate (0.35 mL, 2.46mmol) and 1 N NaOH
(2.46mL, 2.46mmol) were added in ten portions, alternatingly, while the
mixture was vigorously stirred. The temperature was risen to room tempera-
ture. The reaction was completed in about 12 h. The solution was concen-
trated and acidified with 2 N HCl to pH 2. The solution was extracted with
EtOAc (3 Â 30 mL). The combined organic layers were washed with 5%
NaHCO3 (30 mL), water (30 mL) and brine (30 mL). The organic layer
was dried over MgSO4 and evaporated. Purification by column chromato-
graphy, on elution with CH2Cl2 yielded 6 (0.47 g, 0.92 mmol, 75%) as a
colourless oil.
1H-NMR (CDCl3) (400 MHz) d 1.42 (s, 9H, C(CH3)3), 1.38–1.46
(m, 2H, CH2), 1.48–1.57 (m, 2H, CH2), 1.64 (t, 2H, J ¼ 6.52, CH2),
3.00–3.10 (m, 2H, CH2), 3.10–3.30 (m, 6H, CH2 (3Â)), 4.65–4.80 (brs, 1H,
NH), 5.07 (s, 2H, C6H5CH2), 5.10 (s, 2H, C6H5CH2), 5.22–5.38 (brs, 1H,
NH), 7.31 (s, 5H, C6H5), 7.32 (s, 5H, C6H5); MS (FABþ) m/z 514 [M þ H]þ;
HPLC Rt ¼ 28.07 min (100%, Only one peak was observed).
N-Benzyloxycarbonyl-N0-3-bromopropyl-N0-
(2-nitrobenzenesulfonyl)-1,4-diaminobutane (7)
To a suspension of Cs2CO3 (0.40 g, 1.23 mmol) in dry DMF (10 mL), 2
(0.50 g, 1.23 mmol) and 1,3-dibromopropane (2.49 mL, 24.6mmol) were
added. The mixture was stirred for 24 h at 60ꢀC. A solution of 0.1 N HCl
(75 mL) was added and the resulting solution was extracted with EtOAc
(3 Â 30 mL). The organic layer was washed with water (30 mL) and brine
(30 mL). The organic solution was dried over MgSO4, evaporated and pur-
ified by column chromatography (CH2Cl2) affording 7 (0.42 g, 0.80 mmol,
65%) as a colourless oil.
1H-NMR (CDCl3) (400 MHz) d 1.41–1.52 (m, 2H, CH2), 1.52–1.63
(m, 2H, CH2), 2.03–2.13 (m, 2H, CH2), 3.10–3.21 (m, 2H, CH2),
3.25–3.37 (m, 4H, CH2 (2Â)), 3.37–3.43 (m, 2H, CH2), 4.90–5.02 (brs, 1H,

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AMSSOMS ET AL.
NH), 5.13 (s, 2H, C6H5CH2), 7.33 (s, 5H, C6H5), 7.56–7.61 (m, 1H, CH of
C6H4SO2NO2), 7.62–7.69 (m, 2H, CH (2Â) of C6H4SO2NO2), 7.95–8.01
(m, 1H, CH of C6H4SO2NO2); MS (FABþ) m/z 528 and 530 [M þ H]þ;
HPLC Rt ¼ 26.79 min (95%, Only one major peak was observed).
N1-Benzyloxy-N1-tert-butyloxycarbonyl-N8-benzyloxycarbonyl-
N4-(2-nitrobenzenesulfonyl)spermidine (8)
A solution of sodium hydride (60% in mineral oil, 0.03 g, 0.80 mmol)
and tert-butyl N-(benzyloxy)carbamate (0.18 g, 0.80 mmol) in dry DMF
(5 mL) was stirred for 50 min at room temperature. After cooling the sol-
ution to 0ꢀC 7 (0.42 g, 0.80 mmol) in dry DMF (5 mL) was added dropwise.
The mixture was stirred for 24 h at 60ꢀC. Water (100 mL) was added and the
resulting solution was extracted with EtOAc (3 Â 30 mL). The organic layer
was washed with brine (30 mL), dried over MgSO4 and concentrated.
Purification by column chromatography, on elution with CH2Cl2 yielded
8 (0.35 g, 0.53 mmol, 66%) as a colourless oil.
1H-NMR (CDCl3) (400 MHz) d 1.38–1.58 (m, 4H, CH2 (2Â)), 1.48
(s, 9H, C(CH3)3), 1.75–1.85 (m, 2H, CH2), 3.05–3.15 (m, 2H, CH2),
3.20–3.32 (m, 4H, CH2 (2Â)), 3.40 (t, 2H, J ¼ 6.78, CH2), 4.78 (s, 2H,
C6H5CH2), 5.00–5.10 (brs, 3H, C6H5CH2 and NH), 7.32 (s, 5H, C6H5), 7.33
(s, 5H, C6H5), 7.47–7.52 (m, 1H, CH of C6H4SO2NO2), 7.52–7.58 (m, 2H,
CH (2Â) of C6H4SO2NO2), 7.88–7.93 (m, 1H, CH of C6H4SO2NO2);
13C-NMR (CDCl3) d 25.1 (CH2), 25.6(CH ), 26.5 (CH2), 27.9 (C(CH3)3),
2
40.0 (CH2), 45.0 (CH2), 46.6 (CH2), 46.9 (CH2), 66.0 (C6H5CH2), 76.5
(C6H5CH2), 81.2 (C(CH3)3), 123.7, 127.6, 127.6, 128.1, 128.1, 128.2, 130.1,
131.4, 132.7, 133.2, 135.1, 136.4, 147.6 (Carom), 156.0 (CO), 156.1 (CO); MS
(FABþ) m/z 671 [M þ H]þ; HPLC Rt ¼ 31.09 min (100%, Only one peak
was observed).
ACKNOWLEDGMENTS
The authors are grateful to the Fund of Scientific Research – Flanders
(Belgium), the INCO program of the European Community and
the Flemisch Community for support. K. Amssoms is a fellow of the
Institute for the Promotion of Innovation by Science and Technology in
Flanders (IWT).

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REFERENCES
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Received in the USA March 19, 2001

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