Facile synthetic route to selectively protected spermidine homologues

Article abstract of DOI:10.1080/00397910701845431

Several selectively protected spermidine homologues were synthesized via cyanoethylation reaction of monoprotected diamines, subsequent protection of their secondary amino group, hydrolysis of nitrile to primary amide function, and final Hofmann degradati

Full text of DOI:10.1080/00397910701845431

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Facile Synthetic Route to Selectively
Protected Spermidine Homologues
Ryszard Andruszkiewicz a , Ewa Gronek a & Jolanta Hałuszczak a
a Department of Pharmaceutical Technology and Biochemistry, Gdańsk
University of Technology, Gdańsk, Poland
Version of record first published: 22 Feb 2008.
To cite this article: Ryszard Andruszkiewicz, Ewa Gronek & Jolanta Hałuszczak (2008): Facile Synthetic Route
to Selectively Protected Spermidine Homologues, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:6, 905-913
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Synthetic Communicationsw, 38: 905–913, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845431
Facile Synthetic Route to Selectively
Protected Spermidine Homologues
Ryszard Andruszkiewicz, Ewa Gronek,
and Jolanta Hałuszczak
Department of Pharmaceutical Technology and Biochemistry,
´ ´
Gdansk University of Technology, Gdansk, Poland
Abstract: Several selectively protected spermidine homologues were synthesized via
cyanoethylation reaction of monoprotected diamines, subsequent protection of their
secondary amino group, hydrolysis of nitrile to primary amide function, and final
Hofmann degradation of amides to amines with the aid of iodosobenzene diacetate
(PIDA). The protected spermidine homologues may be directly used in the synthesis
of polyamine amides or may be further functionalized.
Keywords: Hofmann degradation, Michael addition, polyamines, protecting groups
Biogenic polyamines are widely distributed in a variety of biologically active
compounds and play key roles in a number of biological processes. A few
reviews on the chemistry and biological properties of polyamines and their
conjugates, including synthetic approaches to polyamine chemistry, have
been published over the past decade.[1,2] Although many efforts have also
been made in the design of new methods for the synthesis of polyamines
and their conjugates on the solid phase,[3–6] there is still need for the
synthesis of orthogonally protected polyamines that may be subsequently
used in the synthesis of polyamine amides. In continuation of our studies on
Received in Poland August 3, 2007
Address correspondence to Ryszard Andruszkiewicz, Department of Pharma-
´ ´
ceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk,
Poland. E-mail: ryszarda@chem.pg.gda.pl
905

906
R. Andruszkiewicz, E. Gronek, and J. Hałuszczak
edeine antibiotic and their analogues with interesting immunomodulatory
properties,[7,8] for further synthesis we needed not only a selectively
protected novel amino acid[9] to be built into edeine analogues but also
modified polyamine homologues. Therefore, we present here a convenient
method for the preparation of a series of spermidine homologues, selectively
protected at different amino groups, so that functional group manipulation
may be performed at the other sites on polyamine molecule (Fig. 1).
Therefore, application of the most popular amino protecting groups [i.e.,
tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Z)] allowed us to obtain
selectively protected spermidine homologues in such a way that any of the
amino group present in the spermidine homologue molecule may be used
for amide linkage formation.
The Michael addition reaction of the mono Boc-protected 1,2-ethane-
diamine, 1,3-propanediamine, or 1,4-butanediamine to acrylonitrile in metha-
nolic solution afforded cyanoetylamines 4, 5, and 6 in high yields (Scheme 1).
Secondary amino function in these nitriles was protected with the use of ben-
zyloxycarbonyl or tert-butoxycarbonyl protecting groups in a classical
manner. Then, the protected nitriles 7, 8, and 9 were subjected to a hydrolysis
reaction in a methanolic ammonia solution and hydrogen peroxide at room
temperature for a prolonged time. Raising the temperature gave rise to
undesired reaction products containing unmasked amino function. Thus, the
obtained partially protected primary amides, 10–15, underwent the
Hofmann rearrangement with the use of iodosobenzene diacetate in a N,N-
dimethylformamide (DMF)/water (1:1, v/v) solution in the presence of a
catalytic amount of pyridine at 208C. The rearrangement reaction proceeded
in good yield, affording protected spermidine homologues 16–21 in good
yield. Then the partially protected triamine derivatives were further reacted
with benzyloxycarbonyl chloride/di-tert-butyl dicarbonate to obtain fully
protected spermidine homologues 22–27 with differentially protected
primary and secondary amino groups. Additionally, the orthogonally and
fully protected spermidine homologues may be further functionalized after
deprotection of their primary or secondary amino groups, thus forming the
suitable protected synthetic synthons.
Figure 1. Chemical structures of protected spermidine homologues.

Spermidine Homologues
907
Scheme 1.
EXPERIMENTAL
Melting points were measured on a Boetius heating block and are uncorrected.
1H NMR spectra were recorded at 200 MHz with a Gemini Varian spec-
trometer. Elemental analyses were performed on a Carlo Erba CHNS-O-EA
1108 analyzer. All reagents and solvents were of reagent grade. Thin-layer
chromatography (TLC) was performed on silica-gel 60 precoated plates.
Spots were visualized with ninhydrin or cerium reagents.
Mono-protected polyamines (i.e., Boc-1,2-ethanediamine, Boc-1,3-
propanediamine, and Boc-1,4-butanediamine) were synthesized following
the reported procedures.[10] Aminonitriles 4–6 and protected aminonitriles
9 and 11 were prepared as previously described.[11]

908
R. Andruszkiewicz, E. Gronek, and J. Hałuszczak
General Procedure for the Preparation of Fully Protected
Aminonitriles
Partially protected aminonitile with a free secondary amino group (50 mmol)
and triethylamine (50 mmol, 7 mL) were dissolved in THF (100 mL) and
cooled to 58C. Then, benzyl chloroformate (50 mmol) was added over
30 min with vigorous stirring. The reaction was kept overnight at room
temperature. The solvent was evaporated; the residue was dissolved in
water and extracted with ethyl acetate (3 ꢀ 50 mL). The organic layer was
washed with 1 M KHSO4 and water, dried over MgSO4, and evaporated to
give the protected aminonitrile. In the case of Boc protection, aminonitrile
(50 mmol) was dissolved in THF (100 mL), and di-tert-butyl dicarbonate
(50 mmol) was adedd with stirring over 15 min at room temperature.
The reaction was kept at room temperature overnight and evaporated; the
residue extracted with ethyl acetate and evaporated to dryness to yield
the final, fully protected compound.
Data
Benzyl 2-cyanoethyl-f2-[(tert-butoxycarbonyl)amino]ethylgcarbamate (7).
Yield: 88%. 1H NMR (CDCl3): d ¼ 1.45 [s, 9H, C(CH3)3], 2.6 (m, 2H,
CH2-CN), 3.25 (m, 2H, NH-CH2), 3.45 (t, 2H, CH2-N, J ¼ 6.8 Hz), 3.55 (t,
2H, N-CH2, J ¼ 6.8 Hz), 5.5 (s, 2H, Ph-CH2-O), 5.6 (br. signal, 1H,
CO-NH), 7.35 (m, 5H, Ph, CH2-O). Anal. calcd. for C18H25N3O4 (347.41):
C, 62.23; H, 7.25; N, 12.10. Found: C, 62.15; H, 7.12; N, 12.33.
tert-Butyl 2-cyanoethyl-f2-[(tert-butoxycarbonyl)amino]ethylgcarbamate
1
(8). Yield: 56%. Mp 70–718C. H NMR (CDCl3): d ¼ 1.45–1.50 [s, 18H,
2C(CH3)3], 2.65 (m, 2H, CH2-CN), 3.25 (m, 2H, NH-CH2), 3.4 (t, 2H,
CH2-N, J ¼ 7.5 Hz), 3.5 (t, 2H, N-CH2, J ¼ 7.5 Hz), 5.6 (br. signal, 1H,
CO-NH). Anal. calcd. for C15H27N3O4 (313.39): C, 57.49; H, 8.68;
N, 13.41. Found: C, 57.22; H, 8.45; N, 13.22.
tert-Butyl 2-cyanoethyl-f3-[(tert-butoxycarbonyl)amino]propylgcarbamate
1
(10). Yield: 64%. H NMR (CDCl3): d ¼ 1.45-1.50 [s, 18H, 2C(CH3)3], 1.7
(m, 2H, CH2-CH2-CH2), 2.6 (m, 2H, CH2-CN), 3.15 (m, 2H, NH-CH2), 3.35
(t, 2H, CH2-N, J ¼ 7.5 Hz)), 3.5 (t, 2H, N-CH2, J ¼ 7.5 Hz), 5.5 (br. signal,
1H, CO-NH). Anal. calcd. for C16H29N3O4 (327.42): C, 58.69; H, 8.93;
N, 12.83. Found: C, 58.42; H, 8.67; N, 12.78.
tert-Butyl 2-cyanoethyl-f4-[(tert-butoxycarbonyl)amino]butylgcarbamate
1
(12). Yield: 75%. H NMR (CDCl3): d ¼ 1.45–1.50 [s, 18H, 2C(CH3)3],
1.7 (m, 2H, CH2-CH2-CH2-CH2), 2.6 (m, 2H, CH2-CN), 3.15 (m, 2H, NH-
CH2), 3.3 (t, 2H, CH2-N, J ¼ 7.1 Hz), 3.45 (t, 2H, N-CH2, J ¼ 7.1 Hz), 5.5

Spermidine Homologues
909
(br. signal, 1H, CO-NH). Anal. calcd. for C17H31N3O4 (341.44): C, 59.80; H,
9.15; N, 12.31. Found: C, 59.68; H, 9.05; N,12.21.
General Procedure for the Preparation of Primary Amides from
Aminonitriles
To a stirred solution of protected aminonitrile (10 mmmol) in 25% methanolic
ammonia (40 mL) and 25% aqueous ammonia (40 mL), 50% hydrogen
peroxide (2 mL) was added and the reaction mixture was left at room tempera-
ture for 48 h. The solvents were evaporated to yield crude yellow oil. Column
chromatography on silica gel and elution with CHCl3–acetone (2/1, v/v)
afforded amide as an oil.
Data
3-fBenzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]aminog pro-
1
pionamide (13). Yield: 76%. H NMR (CDCl3): d ¼ 1.4 [s, 9H, 2C(CH3)3],
2.5 (m, 2H, CH2-CH2-CO), 3.25 (m, 2H, CH2-CH2-N), 3.4 (m, 2H, N-CH2-
CH2), 3.6 (m, 2H, N-CH2-CH2), 4.8 (br. signal, 1H, CO-NH-CH2), 5.1
(s, 2H, Ph-CH2-O), 5.6 and 6.1 (br. signals, 2H, CO-NH2), 7.35 (m, 5H,
Ph,CH2-O). Anal. calcd. for C18H27N3O5 (365.42): C, 59.16; H, 7.45; N,
11.50. Found: C, 58.85; H, 7.41; N, 11.42.
3-ftert-Butoxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]aminogpropionamide
(14). Yield: 88%.%. 1H NMR (CDCl3): d ¼ 1.4 [s, 18H, 2C(CH3)3], 2.5 (m, 2H, CH2-
CH2-CO), 3.20 (m, 2H, CH2-CH2-N), 3.35 (m, 2H, NH-CH2-CH2), 3.55 (m, 2H,
N-CH2-CH2), 4.6 (br. signal, 1H, CO-NH-CH2), 5.6 and 6.25 (br. signals, 2H, CO-
NH2). Anal. calcd. for C15H29N3O5 (331.41): C, 54.36; H, 8.82; N, 12.68. Found:
C, 54.23; H, 8.76; N, 12.55.
3-fBenzyloxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]aminogpropionamide
(15). Yield: 54%. 1H NMR (CDCl3): d ¼ 1.4 [s, 18H, 2C(CH3)3], 1.7 (m, 2H, CH2-
CH2-CH2), 2.5 (m, 2H, CH2-CH2-CO), 3.0 (m, 2H, NH-CH2-CH2), 3.3 (m, 2H,
CH2-CH2-N), 3.55 (m, 2H, N-CH2-CH2), 4.6 (br. signal, 1H, CO-NH-CH2), 5.1
(s, 2H, Ph-CH2-O), 5.6 and 6.25 (br. signals, 2H, CO-NH2), 7.35 (m, 5H, Ph, CH2-
O). Anal. calcd. for C19H29N3O5 (379.45): C, 60.14; H, 7.70; N, 11.07. Found: C,
60.02; H, 7.65; N, 10.95.
3-ftert-Butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]aminogpropionamide
(16). Yield: 53%. 1H NMR (CDCl3): d ¼ 1.4 [s, 18H, 2C(CH3)3], 1.7 (m, 2H, CH2-
CH2-CH2), 2.5 (m, 2H, CH2-CH2-CO), 3.0 (m, 2H, NH-CH2-CH2), 3.3 (m, 2H,
CH2-CH2-N), 3.55 (m, 2H, N-CH2-CH2), 4.6 (br. signal, 1H, CO-NH-CH2), 5.6 and
6.25 (br. signals, 2H, CO-NH2). Anal. calcd. for C16H31N3O5 (345.43): C, 55.63; H,
9.05; N, 12.16. Found: C, 55.51; H, 8.97; N, 12.04.

910
R. Andruszkiewicz, E. Gronek, and J. Hałuszczak
3-fBenzyloxycarbonyl-[4-(tert-butoxycarbonylamino)butyl]aminogpropionamide
(17). Yield: 93%.1H NMR (CDCl3): d ¼ 1.4 [s, 9H, C(CH3)3], 1.5–1.7 (m, 4H, CH2-
CH2-CH2-CH2), 2.5 (m, 2H, CH2-CH2-CO), 3.0 (m, 2H, NH-CH2-CH2), 3.3 (m, 2H,
CH2-CH2-N), 3.55 (m,2H, N-CH2-CH2), 4.7 (br. signal, 1H, CO-NH-CH2), 5.1 (s, 2H,
Ph-CH2-O), 5.8 and 6.6 (br. signals, 2H, CO-NH2), 7.35 (m, 5H, Ph,CH2-O). Anal.
calcd. for C20H31N3O5 (393.47): C, 61.05; H, 7.94; N, 10.68. Found: C, 61.06; H,
7.85; N, 10.47.
3-ftert-Butoxycarbonyl-[4-(tert-butoxycarbonylamino)butyl]aminogpropionamide
(18). Yield: 95%. 1H NMR (CDCl3): d ¼ 1.4 [s, 18H, 2C(CH3)3], 1.5–1.8 (m, 4H,
CH2-CH2-CH2-CH2), 2.5 (m, 2H, CH2-CH2-CO), 3.05 (m,2H, NH-CH2-CH2), 3.3
(m, 2H, CH2-CH2-N), 3.55 (m, 2H, N-CH2-CH2), 4.7 (br. signal, 1H, CO-NH-
CH2), 5.9 and 6.65 (br. signals, 2H, CO-NH2). Anal. calcd. for C17H33N3O5
(359.46): C, 56.80; H, 9.25; N, 11.68. Found: C, 56.68; H, 9.12; N, 11.55.
General Procedure for the Preparation of Amines from Primary
Amides
A solution of primary amide (5 mmol), DMF (10 mL), water (10 mL), and
iodosobenzene diacetate (7.5 mmol) was stirred at temperature colder
than 208C. After 15 min, pyridine (0.2 mL) was added and stirring
was continued overnight. Then, the solvents were evaporated, the residue
was dissolved in a cold solution of 1 M KHSO4. The aqueous solution was
extracted with ethyl acetate, the organic extracts were discarded, and the
aqueous layer was alkalized with 4 M NaOH solution. The alkaline solution
was extracted with ethyl ether; the organic layer was washed with brine,
dried over MgSO4, and evaporated to yield the protected spermidine
homologues.
Data
N-Benzyloxycarbonyl-N-[2-(tert-butoxycarbonylaminoethyl)-ethane-1,2-
1
diamine (19). Yield: 64%. Colorless oil. H NMR (CDCl3): d ¼ 1.4 [s, 9H,
C(CH3)3], 1.6–1.7 (m, 2H, CH2-CH2-CH2), 1.9–2.0 (br. signal, 2H, NH2),
2.85 (m,2H, CH2-CH2-NH2), 3.35 (m, 6H, HN-CH2-CH2-N-CH2-CH2), 5.1
(s, 2H, Ph-CH2), 5.2 (br. signal, 1H, CO-NH-CH2), 7.35 (m, 5H, Ph-CH2).
Anal. calcd. for C17H27N3O4 (337.41): C, 60.52; H, 8.07; N, 12.45. Found:
C, 60.33; H, 7.82; N, 12.21.
N-tert-Butoxycarbonyl-N-[2-(tert-butoxycarbonylaminoethyl)-ethane-
1
1,2-diamine (20). Yield: 67%. Colorless oil. H NMR (CDCl3): d ¼ 1.4 [s,
18H, 2C(CH3)3], 2.0 (m, 2H, NH2), 2.85 (m, 2H, CH2-CH2-NH2), 3.3
(m, 6H, HN-CH2-CH2-N-CH2-CH2), 5.4 (br. signal, 1H, CO-NH-CH2).

Spermidine Homologues
911
Anal. calcd. for C14H29N3O4 (303.40): C, 55.42; H, 9.63; N, 13.85. Found: C,
55.14; H, 9.47; N, 13.70.
N-(2-Aminoethyl)-N-benzyloxycarbonyl-N0-tert-butoxycarbonyl-propane-
1
1,3-diamine (21). Yield: 64%. Yellowish oil. H NMR (CDCl3): d ¼ 1.45 [s,
9H, C(CH3)3], 1.6–1.7 (m, 2H, CH2-CH2-CH2), 1.9–2.0 (m, 2H, NH2), 2.8–
3.1 (br. signal, 4H, CH2-CH2-NH2 and HN-CH2-CH2), 3.2–3.5 (m, 4H, CH2-
CH2-N-CH2-CH2),5.1(s,2H, Ph-CH2), 5.2 (br. signal, 1H, CO-NH-CH2),
7.359 m, 5H, Ph-CH2). Anal. calcd. for C18H29N3O4 (351.44): C, 61.52; H,
8.32; N, 11.96. Found: C, 61.46; H, 8.06; N, 11.55.
N-(2-Aminoethyl)-N,N0-bis-tert-butoxycarbonyl-propane-1,3-diamine (22).
1
Yield: 70%. Colorless oil. H NMR (CDCl3): d ¼ 1.45 [s, 18H, 2C(CH3)3],
1.6–1.7 (q, 2H, CH2-CH2-CH2), 1.9 (m, 2H, NH2), 2.8 (m, 2H, CH2-CH2-
NH2), 3.1 (q, 2H, HN-CH2-CH2),3.25 (m, 4H, CH2-CH2-N-CH2), 4.95 (br.
signal, 1H, CO-NH-CH2). Anal. calcd. for C15H31N3O4 (317.42): C, 56.76;
H, 9.84; N, 13.24; Found: C, 56.47; H, 9.72; N, 13.34.
N-(2-Aminoethyl)-N-benzyloxycarbonyl-N0-tert-butoxycarbonyl-butane-
1
1,4-diamine (23). Yield: 57%. Light yellow oil. H NMR (CDCl3): d ¼ 1.4
[s, 9H, C(CH3)3], 1.55–1.7 (br. signal, 6H, CH2-CH2-CH2-CH2 and CH2-
NH2), 2.9–3.0 (m, 2H, CH2-CH2-NH2)3.1 (m, 2H, HN-CH2-CH2), 3.3
(m, 4H, CH2-CH2-N-CH2), 4.6 (br. signal, 1H, CO-NH-CH2), 5.1 (s, 2H,
Ph-CH2), 7.35 (m, 5H, Ph-CH2). Anal. calcd. for C19H31N3O4 (365.46): C,
62.44; H, 8.55; N, 11.50. Found: C, 62.05; H, 8.20; N, 11.29.
N-(2-Aminoethyl)-N,N0-bis-tert-butoxycarbonyl-butane-1,4-diamine (24).
1
Yield: 73%. Colorless oil. H NMR (CDCl3): d ¼ 1.4 [s, 18H, 2C(CH3)3],
1.5–1.7 (m, 4H, CH2-CH2-CH2-CH2), 1.9 (br. signal, 2H, NH2), 2.9
(m, 2H, CH2-CH2-NH2), 3.1 (m, 2H, HN-CH2-CH2),3.25 (m, 2H, CH2-
CH2-N-CH2), 3.35 (m, 2H, CH2-CH2-N-CH2), 4.85 (br. signal, 1H, CO-NH-
CH2). Anal. calcd. for C16H33N3O4 (331.4): C, 56.98; H, 10.04; N, 12.68.
Found: C, 56.69; H, 10.12; N, 12.39.
General Procedure for the Protection of Spermidine Homologues
A solution of benzyloxycarbonyl chloride (0.34 g, 2 mmol) was added to a
cooled solution of protected spermidine homologues 19, 21, and 23 (2 mmol)
with a free primary amino group and Et3N (0.35 mL, 2.5 mmol) in THF
(20 mL) and stirred overnight. The solvent was evaporated, water was added,
and the residue was extracted with EtOAc (3 ꢀ 20 mL). The organic phase
was dried over MgSO4 and evporated to give the crude product which was chro-
matographed on silica gel and eluted with CHCl3–acetone (10:1, v/v) to yield
the desired product. In the case of Boc protection, spermidine homologues 20

912
R. Andruszkiewicz, E. Gronek, and J. Hałuszczak
and 24 were dissolved in THF (20 mL), and di-tert-butyl dicarbonate (2 mmol)
was added with stirring over 15 min at room temperature. The reaction was kept
at room temperature overnight and evaporated. The residue was extracted with
ethyl acetate and evaporated to dryness to yield the crude product, which was
chromatographed on silica gel and eluted with CHCl3–acetone (10:1, v/v) to
yield the desired fully protected compound.
Data
tert-Butyl f2-[benzyloxycarbonyl-(2-tert-butoxycarbonylaminoethyl)-amino]-
ethylg-carbamate (25). Yield: 79%. Mp 111–1128C. 1H NMR (CDCl3):
d ¼ 1.4 [s, 18H, 2C(CH3)3], 3.25 (m, 4H, CH2-CH2-N-CH2), 3.45 (m, 4H, NH-
CH2-CH2 and CH2-CH2-NH), 4.8 (br. signal, 1H, CO-NH-CH2), 5.0 (br. signal,
CH2-NH-CO), 5.1 (s, 2H, Ph-CH2), 7.35 (m, 5H, Ph-CH2). Anal. calcd. for
C22H35N3O6 (437.53): C, 60.39; H, 8.06; N, 9.60. Found: C, 60.36; H, 7.98; N,
9.51.
tert-Butyl f3-[benzyloxycarbonyl-(2-benzyloxycarbonylaminoethyl)-amino]-
1
propylg-car-bamate (26). Yield: 80%. Oil. H NMR (CDCl3): d ¼ 1.4 [s, 9H,
C(CH3)3], 1.7 (m, 2H, CH2-CH2-CH2), 3.1 (m, 2H, CH2-CH2-NH), 3.35
(m, 6H, HN-CH2-CH2-N-CH2-CH2), 4.6 (br. signal, 1H, -CH2-CH2-NH-CO),
5.1 (s, 2H, Ph-CH2), 5.2(s, 2H, Ph-CH2), 7.3–7.5 (br. signal, 10H, 2 ꢀ Ph-
CH2). Anal. calcd. for C26H35N3O6 (485.57): C, 64.31; H, 7.27; N, 8.65.
Found: C, 64.22; H, 7.09; N, 8.82.
tert-Butyl f3-[benzyloxycarbonyl-(2-tert-butoxycarbonylaminoethyl)-amino]-
1
propylg-carbamate (27). Yield: 78%. Colorless oil. H NMR (CDCl3): d ¼ 1.4
[s, 18H, 2C(CH3)3], 1.7 (m,2H, CH2-CH2-CH2), 3.1 (m, 2H, CH2-CH2-N), 3.3
(m, 6H, CH2-CH2-NH-CH2), 4.6 (br. signal, 1H, CH2-CH2-NH-CO), 5.0 (br.
signal, 1H, CO-NH-CH2), 5.1 (m, 2H, O-CH2-Ph),7.35(m, 5H, Ph-CH2). Anal.
calcd. for C23H37N3O6 (451.56): C, 61.18; H, 8.26; N, 9.31. Found: C, 60.89;
H, 8.12; N, 9.22.
tert-Butyl f4-[benzyloxycarbonyl-(2-tert-butoxycarbonylaminoethyl)-amino]-
1
butylg-car-bamate (28). Yield: 62%. Oil. H NMR (CDCl3): d ¼ 1.4 [s, 18H,
2C(CH3)3], 1.55 (m, 4H, CH2-CH2-CH2-CH2), 3.1(m, 2H, NH-CH2-
CH2),3.35(m, 6H, CH2-CH2-N-CH2-CH2-NH), 4.6 (br. signal, 1H, CH2-NH-
CO), 4.95 (br. signal, 1H, CO-NH-CH2), 5.1 (s, 2H, O-CH2-Ph), 7.35 (m, 5H,
Ph-CH2). Anal. calcd. for C24H39N3O6 (465.58): C, 61.91; H, 8.44; N, 9.03.
Found: C, 61.75; H, 8.22; N, 8.82.
Benzyl f4-[benzyloxycarbonyl-(2-benzyloxycarbonylaminoethy)-amino]-
butylg-carbamate (29). Yield: 65%. Mp 85–868C. 1H NMR (CDCl3):
d ¼ 1.45 [s, 9H, C(CH3)3], 1.6 (m, 4H, CH2-CH2-CH2-CH2), 3.1 (m, 2H,

Spermidine Homologues
913
CH2-CH2-NH), 3.25 (m, 2H, HN-CH2-CH2), 3.4 (m, 4H, CH2-CH2-N-CH2),
4.5 (br. signal, 1H, CO-NH-CH2), 4.9 (br. signal, 1H, CH2-NH-CO), 5.1
(m, 2H, Ph-CH2), 7.3–7.5 (br. signal, 10H, 2 ꢀ Ph-CH2). Anal. calcd. for
C27H37N3O6 (499.6): C, 64.91; H, 7.46; N, 8.41. Found: C, 64.67; H, 7.47;
N, 8.36.
ACKNOWLEDGMENT
´
The authors are indebted to the Faculty of Chemistry, Gdansk University of
Technology, Poland, for financial support.
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