Efficient synthesis of orthogonally protected spermidine and norspermidine derivatives

Article abstract of DOI:10.1081/SCC-200054211

Several orthogonally protected spermidine and norspermidine derivatives have been synthesized via cyanoethylation of monoprotected 1,4-butanediamine (putrescine) or 1,3-propanediamine followed by protection of their secondary amino groups and final reduct

Full text of DOI:10.1081/SCC-200054211

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Efficient Synthesis of Orthogonally Protected
Spermidine and Norspermidine Derivatives
Ryszard Andruszkiewicz a , Michał Radowski a & Zbigniew Czajgucki a
a Department of Pharmaceutical Technology and Biochemistry , Gdańsk
University of Technology , Gdańsk, Poland
Published online: 16 Aug 2006.
To cite this article: Ryszard Andruszkiewicz , Michał Radowski & Zbigniew Czajgucki (2005) Efficient
Synthesis of Orthogonally Protected Spermidine and Norspermidine Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:8, 1085-1094, DOI:
10.1081/SCC-200054211
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Synthetic Communicationsw, 35: 1085–1094, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054211
Efficient Synthesis of Orthogonally
Protected Spermidine and
Norspermidine Derivatives
Ryszard Andruszkiewicz, Michał Radowski, and Zbigniew Czajgucki
Department of Pharmaceutical Technology and Biochemistry,
´ ´
Gdansk University of Technology, Gdansk, Poland
Abstract: Several orthogonally protected spermidine and norspermidine derivatives
have been synthesized via cyanoethylation of monoprotected 1,4-butanediamine
(putrescine) or 1,3-propanediamine followed by protection of their secondary amino
groups and final reduction of the nitriles with lithium aluminum hydride in etheral
solution at 08C, thus affording protected norspermidine or spermidine that may be
used in the synthesis of polyamine amides or may be further functionalized.
Keywords: Michael addition, polyamines, protecting groups, reduction
The presence of naturally occuring polyamines in a wide variety of
biologically active compounds has led to a great deal of attention being
focused on the synthetic methodologies leading to the preparation of differen-
tially protected target molecules.[1–3] Although direct and selective
N-protection of spermidine or other polyamines may be achieved after
tedious separation of the desired product,[4] many efforts have been made in
the total synthesis and design of the orthogonally protected polyamines.[5–8]
A major problem in the use of polyamines such as spermidine or
Received in Poland November 12, 2004
Address correspondence to Ryszard Andruszkiewicz, Department of Pharma-
´
ceutical Technology and Biochemistry, Gdansk University of Technology, 80-952
´
Gdansk, Poland. Fax: þ48 (58) 3471144; E-mail: ryszarda@chem.pg.gda.pl

1086
R. Andruszkiewicz, M. Radowski, and Z. Czajgucki
norspermidine in the synthesis of amide conjugates is that the synthesis
typically requires the use of a different amino protecting group, so that func-
tional group manipulation can be carried out at other sites on molecule. In
continuation of our previous work on edeine antibiotics and their analogues,
we needed a selectively protected polyamines to be built into edeine
analogs.[9–11] Moreover, the spermidine and norspermidine used in these
syntheses should have free primary or secondary amino groups or should
be easily converted into such derivatives. Therefore, only two protecting
groups may be used for the selective protection of two primary amino
groups located at N1 and N8 and one secondary amino at N4 in spermidine,
and at N1 and N7 primary amino groups and at N4 secondary amino group
in norspermidine. Usually, the most popular amino protecting groups, that
is, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Z), meet the criteria
to be used in the orthogonal protection of spermidine and norspermidine.
Several methods leading to the synthesis of differentially protected spermidine
(e.g., using Michael addition products,[12] reductive alkylaton,[13] or selective
alkylation of primary amines with corresponding bromoalkanes[14] or
mesylates or tosylates[15]) have been described. In this report, we present a
convenient synthetic approach to differentially protected spermidine and nor-
spermidine based on the cyanoethylation reaction of primary amines followed
by protection of the secondary amino group and final reduction of the formed
nitriles to an amino group with LiAlH4 (LAH). The newly formed amino
group may be protected or acylated with properly protected glycine to form
differentially protected glycylspermidine or glycylnorspermidine derivatives.
The first step of the synthesis to obtain orthogonally protected title polyamines
is well known (Scheme 1).[16]
Cyanoethylation reaction of the mono Boc- or Z- protected 1,3-propane-
diamine or 1,4-butanediamine proceeded smoothly in methanolic solution to
furnish the corresponding 1,4-addition products in high yields. Secondary
amino function in nitriles 5, 6, 7, and 8 was protected with the use of benzy-
loxycarbonyl protecting groups in a classical manner. Then, the protected
nitriles were reduced with lithium aluminum hydride (LAH) in dry ethyl
ether solution at low temperature (08C) for 1 h. Thus, the obtained partially
protected spermidine or norspermidine derivatives were subjected to
acylation reaction with benzyloxycarbonyl chloride/di-tert-butyl dicarbonate
to obtain fully protected spermidine or norspermidine with differentially
protected primary and secondary amino groups. Moreover, these partially
protected polyamines were acylated with Boc-Gly to yield spermidine or
norspermidine glycine conjugates 13, 14 in good yield. Removal of glycine-
protecting group allowed us to obtain the compounds that may be directly
used in the synthesis of edeine antibiotics analogues. Additionally, the orthog-
onally and fully protected spermidine or norspermidine 15, 16, 17, and 18 may
be further functionalized after deprotection of their primary or secondary
amino groups, thus forming the suitable protected synthetic synthons.

Scheme 1. (a) ZCl/THF, (b) ZCl/THF, (c) LiAlH4/Et2O, (d) BocGlyOSu/MeOH, (e) Boc2O/THF or ZCl/THF, (f) HCl/1,4-dioxane.

1088
R. Andruszkiewicz, M. Radowski, and Z. Czajgucki
EXPERIMENTAL
All reagents and solvents were of reagent grade. TLC was performed on 60
silica-gel precoated plates. Spots were visualized with ninhydrin or cerium
reagents. Melting points were determined on a Boetius heating block and
are uncorrected. Elemental analyses were performed on a Carlo Erba
1
CHNS-O-EA1108 instrument. H NMR spectra were recorded at 200 MHz
with a Gemini Varian spectrometer.
Protected polyamines (i.e., Boc-1,4-butanediamine,[17] Boc-1,3-propane-
diamine,[17] Cbz-1,4-butanediamine,[18] and Cbz-1,3-propanediamine[18]
)
were prepared according to the literature procedures. N1-(2-cyanoethyl)1,4-
diaminobutane[19] and N1-(2-cyanoethyl)-1,3-diaminopropane[19] were
obtained following the literature procedures.
N1, N4-Dibenzyloxycarbonyl-N1-(2-cyanoethyl)-1,4-butanediamine (7)
A mixture of benzyloxycarbonyl chloride (16.7 g, 100 mmol) in THF (60 mL)
was added dropwise to a stirred solution of N1-(cyanoethyl)-1,4-butanediamine
2, (7.05 g, 50 mmol) and Et3N (10.3 g, 101 mmol) in dry THF (80 mL) at 08C.
After 2 h, the mixture was allowed to warm to room temperature. Stirring was
continued overnight and the solvent was evaporated. The residual oil was
taken up in EtOAc (100 mL) and washed with 3% HCl. The organic layer
was dried over MgSO4 and evaporated to dryness to give a pure product,
which was crystallized from EtOAc-hexane mixture to afford pure 7
(17.38 g, 85%), mp 618C. 1H NMR (CDCl3): d ¼ 1.40–1.70 (m, 4H,
CCH2C), 2.50–2.75 (m, 2H, CH2CN), 3.10–3.30 (m, 2H, CH2NHZ), 3.38
(t, 2H, CH2NZ), 3.52 (t, 2H, NZCH2), 4.80 (br. signal, 1H, NH), 5.11
(s, 2H, CH2Ph), 5.15 (s, 2H, CH2Ph), 7.30–7.45 (m, 10H, arom. H). Anal.
calcd. for C23H27N3O4 (409.47): C, 67.46; H, 6.65; N, 10.26; Found: C,
67.26; H, 6.63; N, 10.18.
N4,N8-Dibenzyloxycarbonylspermidine (11)
To a chilled, 08C suspension of LAH (0.36 g, 9.5 mmol) in dry ethyl ether
(30 mL), a solution of 7 (1.01 g, 2.7 mmol) in dry ethyl ether (20 mL)
was added in several portions with vigorous stirring. After 1 h, the reaction
was quenched by the sequential addition of water (0.7 mL) and EtOAc
(10 mL). The resulting suspension was filtered through a celite pad
washed with EtOAc (2 ꢀ 30 mL), and solvents were evaporated to leave an
yellow oil that was treated with 1 N HCl in dioxane (3.45 mL). After evapor-
ation of a solvent, the residue was dissolved in cold water (50 mL) and
extracted with EtOAc (3 ꢀ 10 mL). The organic layer was discarded and

Synthesis of Spermidine
1089
the aqueous layer was alkalized to pH 8–9 (saturated NaHCO3 solution) and
extracted with chloroform (3 ꢀ 20 mL). The organic layer was dried over
MgSO4, filtered, and evaporated to afford 11 (0.6 g, 53%) as a pale yellow
1
oil. H NMR (CDCl3): d ¼ 1.35–1.75 (m, 6H, CCH2C), 1.75–1.90 (m, 2H,
NH2), 2.60–2.75 (m, 2H, CH2NH2), 3.05–3.45 (m, 6H, CH2NZCH2,
CH2NHZ), 4.80 (br. signal, 1H, amide NH), 5.11 (s, 2H, CH2Ph), 5.15
(s, 2H, CH2Ph), 7.28–7.40 (m, 10H, arom. H). Anal. calcd. for C23H31N3O4
(413.51): C, 66.81; H, 7.56; N, 10.16; Found: C, 66.44; H, 7.44; N, 10.22.
N4, N8-Dibenzyloxycarbonyl-N1-(N-tert-butoxycarbonylglycyl)-
spermidine (14)
To a stirred solution of N4,N8-dibenzyloxycarbonylspermidine 11 (0.57 g,
1.3 mmol) in methanol (30 mL), N-hydroxysuccinimide ester of N-tert-
butoxycarbonylglycine (0.38 g, 1.3 mmol) in methanol (5 mL) was added at
room temperature and left overnight. The solvent was evaporated, the
residue was dissolved in EtOAc (40 mL), and the organic layer was washed
with water, dried over MgSO4, and evaporated to give 14 (0.74 g, 96%) as
1
an oil. H NMR (CDCl3): d ¼ 1.45 [s, 9H, C(CH3)3, 1.45–1.60 (m, 4H,
CCH2C), 1.60–1.75 (m, 2H, CCH2C), 3.05–3.35 (m, 8H, CONHCH2,
CH2NZCH2, CH2NHZ), 3.72–3.82 (m, 2H, NHCH2CO), 4.75 (brs, 1H,
NH), 5.02 (brs, 1H, NH), 5.09 (s, 2H, CH2Ph), 5.12 (s, 2H, CH2Ph), 6.95
(brs, 1H, NH), 7.30–7.40 (m, 10H, arom. H). Anal. calcd. for C30H42N4O7
(570.67): C, 63.14; H, 7.42; N, 9.82; Found: C, 62.40; H, 7.41; N, 9.40.
N4,N8-Dibenzyloxycarbonyl-N1-glycylspermidine hydrochloride (20)
A solution of 14 (0.58g, 1 mmol) in 5 mL of dioxane was treated with 1.5 mL of
2.3 M HCl in dioxane for 1 h at room temperature. The dioxane was removed in
vacuo and the residue was treated with dry ethyl ether to precipitate 20 (0.43 g,
85%) in the form of hygroscopic solid. Mp 110–1138C1H NMR
(CDCl3 þ TFA): d ¼ 1.45–1.75 (m, 4H, CCH2C), 1.80–1.95 (m, 2H,
CCH2C), 3.20–3.50 (m, 8H, CONHCH2, CH2NZCH2, CH2NHZ), 4.10–4.25
(m, 2H, COCH2NHþ3 ), 5.21 (s, 2H, CH2Ph), 5.25 (s, 2H, CH2Ph), 7.30–7.45
(m, 10H, arom. H), 10.85–11.20 (m, ca. 5H, amide NH, NHþ3 ). Anal. calcd.
for C25H35N4O5Cl (507.02): C, 59.22; H, 6.96; N, 11.05; Found: C, 58.76; H,
6.91; N, 10.99.
N1,N3-Dibenzyloxycarbonyl-N1-(2-cyanoethyl)-1,3-propanediamine (5)
A solution of N1-(cyanoethyl)-1,3-propanediamine 1, (5.88 g, 40 mmol) was
treated and the product purified in a similar manner to that described for 7

1090
R. Andruszkiewicz, M. Radowski, and Z. Czajgucki
1
to yield 5 (13.9 g, 88%) as a white solid. Mp 46–498C. H NMR (CDCl3):
d ¼ 1.75 (quintet, 2H, CCH2C), 2.50–2.75 (m, 2H, CH2CN), 3.10–3.25
(m, 2H, CH2NHZ), 3.35–3.60 (m, 4H, CH2NZCH2), 5.10 (s, 2H, CH2Ph),
5.14 (s, 2H, CH2Ph), 5.45 (brs, ca. 1H, NH), 7.30–7.40 (m, 10H, arom. H).
Anal. calcd. for C22H25N3O4 (395.45): C, 66.82; H, 6.37; N, 10.63; Found:
C, 66.30; H, 6.32; N. 10.48.
N4,N7-Dibenzyloxycarbonylnorspermidine (9)
N1,N3-Dibenzyloxycarbonyl-N1-(2-cyanoethyl)-1,3-propanediamine 5 was
reduced with LAH essentially as for the preparation of 11, then worked up
1
as described for 11. Yield: 0.17 g (43%) as a syrup. H NMR (CDCl3):
d ¼ 1.55–1.95 (m, 6H, CCH2C, NH2), 2.65–2.90 (m, 2H, CH2NH2),
3.00–3.60 (m, 6H, CH2NZCH2, CH2NHZ), 4.90 (brs, 1H, amide NH), 5.07
(s, 2H, CH2Ph), 5.11 (s, 2H, CH2Ph), 7.25–7.40 (m, 10H, arom. H). Anal.
calcd. for C22H29N3O4 (399.48): C, 66.14; H, 7.32; N, 10.52; Found:
C, 65.85; H, 7.25; N, 10.44.
N4,N7-Dibenzyloxycarbonyl-N1-(N-tert-butoxycarbonylglycyl)-
norspermidine (13)
Compound 13 was prepared from 9 and N-hydroxysuccinimide ester of N-tert-
butoxycarbonylglycine as described for preparation of 14 (0.16 g, 90%) as a
1
syrup. H NMR (CDCl3): d ¼ 1.45 (s, 9H, C(CH3)3), 1.60–1.80 (m, 4H,
CCH2C), 3.10–3.40 (m, 8H, CONHCH2, CH2NZCH2, CH2NHZ), 3.75–
3.85 (m, 2H, NHCH2CO), 4.85 (brs, 1H, NH), 5.09 (s, 2H, CH2Ph), 5.12
(s, 2H, CH2Ph), 5.20 (brs, 1H, NH), 7.00 (brs, 1H, NH), 7.30–7.45
(m, 10H, arom. H). Anal. calcd. for C29H40N4O7 (556.65): C, 62.57;
H, 7.24; N, 10.07; Found: C, 62.40; H, 7.41; N, 9.95.
N4,N7-Dibenzyloxycarbonyl-N1-glycylnorspermidine hydrochloride (19)
This compound was prepared from 13 according to the procedure used for
preparation of 20. Yield: 0.09 g (94%) as a glassy, hygroscopic solid.
1H NMR (D2O): d ¼ 1.50–1.75 (m, 4H, CCH2C), 2.85–3.30 (m, 8H,
CONHCH2, CH2NZCH2, CH2NHZ), 3.65–3.85 (m, 2H, COCH2NHþ3 ),
4.90–5.10 (m, 4H, 2CH2Ph), 7.20–7.45 (m, 10H, arom. H). Anal. calcd. for
C24H33N4O5Cl (492.99): C, 58.47; H, 6.75; N, 11.36; Found: C, 58.08;
H, 6.55; N, 11.26.

Synthesis of Spermidine
1091
N1-Benzyloxycarbonyl-N4-tert-butoxycarbonyl-N1-(2-cyanoethyl)-
1,4-butanediamine (8)
To a solution of N1-tert-butoxycarbonyl-N4-(2-cyanoethyl)-1,4-butanedi-
amine 4 (1.67 g, 7 mmol) and Et3N (1 mL, 7.5 mmol) in THF (25 mL), benzyl-
oxycarbonyl chloride (1.15 g, 6.5 mmol) in THF (10 mL) was added at 08C
with stirring and left overnight. A precipitate was removed by filtration, the
solvent was evaporated to dryness, and the residue was crystallized from
EtOAc-hexane mixture to obtain 8 (2.14 g, 77%) with mp 61–638C.
1H NMR (CDCl3): d ¼ [1.35–1.70 m, 1.45 s, together 13H, CCH2C,
C(CH3)3)], 2.50–2.75 (m, 2H, CH2CN), 3.00–3.20 (m, 2H, CH2NHBoc),
3.37 (t, 2H, CH2NZ), 3.53 (t, 2H, NZCH2), 4.55 (br. signal, 1H, NH), 5.15
(s, 2H, CH2Ph), 7.30–7.45 (m, 5H, arom. H). Anal. Calcd. for C20H29N3O4
(375.46): C, 63.98; H, 7.79; N, 11.19; Found: C, 63.80; H, 7.77; N, 11.09.
N4-Benzyloxycarbonyl-N8-tert-butoxycarbonylspermidine (12)
This compound was obtained from N1-benzyloxycarbonyl-N4-tert-butoxycar-
bonyl-N1-(2-cyanoethyl)-1,4-butanediamine 8, (0.8 g, 2 mmol) according to
1
the procedure described for compound 11. Yield 0.49 g (61%). H NMR
(CDCl3): d ¼ 1.35–1.95 m, 1.45 s, together 17H, CCH2C, C(CH3)3),
2.65–2.80 (m, 2H, CH2NH2), 3.05–3.50 (m, 6H, CH2NZCH2, CH2NHBoc),
4.65 (br. signal, 1H, NH), 5.11 (s, 2H, CH2Ph), 7.30–7.40 (m, 5H, arom.
H). Anal. Calcd. for C20H33N3O4 (379.49): C, 63.30; H, 8.76; N, 11.07;
Found: C, 63.11; H, 8.65, N, 11.02.
N4-Benzyloxycarbonyl-N1,N8-di-tert-butoxycarbonylspermidine (16)
N4-Benzyloxycarbonyl-N1-tert-butoxycarbonylspermidine (12, 0.39g, 1 mmol)
was dissolved in THF (15 mL) and treated with di-tert-butyldicarbonate (0.28 g,
1 mmol) for 24h at room temperature with occasional stirring. Evaporation of a
1
solvent yielded the title compound (0.48 g, 98%) as an viscous oil. H NMR
(CDCl3): d ¼ 1.20–1.55 (m, 4H, CCH2C), 1.45 (s, 18H, 2C(CH3)3), 1.66
(quintet, 2H, NHCH2CH2CH2NH), 2.95–3.35 (m, 8H, CH2NZCH2,
2CH2NHBoc), 4.45–4.75 (m, 2H, NH), 5.11 (s, 2H, CH2Ph), 7.30–7.45
(m, 5H, arom. H). Anal. Calcd. for C25H41N3O6 (479.41): C, 62.61; H, 8.62;
N, 8.76; Found: C, 62,28; H, 8.55; N, 8.66.
N1,N4-Dibenzyloxycarbonyl-N8-tert-butoxycarbonylspermidine (18)
To a cooled solution of 12 (1.93 g, 5 mmol) in THF (30 mL) and Et3N (0.7 mL,
5 mmol), a solution of benzyloxycarbonyl chloride (0.88 g, 5 mmol) in THF

1092
R. Andruszkiewicz, M. Radowski, and Z. Czajgucki
(5 mL) was slowly added. The reaction mixture was warmed to room tempera-
ture and stirred overnight. The solvent was evaporated, water was added and
the aqueous phase was extracted with EtOAc (3 ꢀ 30 mL). The organic phase
was dried over MgSO4 and the solvent was evaporated to yield a crude yellow
oil. Column chromatography on silica gel and elution with EtOAc-light
petroleum (1:2) afforded 18 (2.25 g, 88%) as an oil. 1H NMR (CDCl3):
d ¼ 1.35–1.60 m, 1.44 s, together 13H, CCH2C, C(CH3)3, 1.70 (quintet, 2H,
NHCH2CH2CH2NH), 3.00–3.40 (m, 8H, CH2NZCH2, CH2NHZ,
CH2NHBoc), 4.50 (br. signal, 1H, NH), 5.09 (s, 2H, CH2Ph), 5.11 (s, 2H,
CH2Ph), 5.65 (brs, 1H, NH), 7.28–7.40 (m, 10H, arom. H). Anal. calcd. for
C28H39N3O6 (513.62): C, 65.48; H, 7.65; N, 8.18; Found: C, 65.18; H, 7.55;
N, 8.08.
N1,N8-Dibenzyloxycarbonyl-N4-tert-butoxycarbonylspermidine (17)
A solution of benzyloxycarbonyl chloride (1.1 g, 6.3 mmol) was added to a
cooled solution of N8-benzyloxycarbonyl-N4-tert-butoxycarbonylspermi-
dine[20] (92.4 g, 6.4 mmol) and Et3N (1.4 mL, 10 mmol) in THF (40 mL) and
stirred overnight. The solvent was evaporated, water was added, and the
residue was extracted with EtOAc (3 ꢀ 40 mL).The organic phase was
dried over MgSO4 and evaporated to yield a crude product that was chromato-
graphed on silica gel and eluted with AcOEt–light petroleum (1:2) to yield 17
1
(2.3 g, 91%) as an oil. H NMR (CDCl3): d ¼ [1.40–1.60 (m), 1.45 (s),
together 13H, CCH2C, C(CH3)3], 1.60–1.75 (m, 2H, NHCH2CH2CH2NH),
3.05–3.35 (m, 8H, CH2NBocCH2, 2CH2NHZ), 4.80–5.05 (br. signal, 2H,
NH), 5.10 (s, 4H, 2CH2Ph), 7.30–7.40 (m, 10H, arom. H). Anal. calcd. for
C28H39N3O6 (513.62): C, 65.48; H, 7.65; N, 8.18; Found: C, 65.20; H,
7.60; N, 8.14.
N1-Benzyloxycarbonyl-N3-tert-butoxycarbonyl-N1-(2-cyanoethyl)-
1,3-propanediamine (6)
A
solution of N1-tert-butoxycarbonyl-N3-(2-cyanoethyl)-1,3-propanedia-
mine[12] 3, (7.74 g, 34.1 mmol) was treated with benzyloxycarbonyl chloride
(5.7 g, 33 mmol) and worked out as decribed for preparation of 8. Yield:
1
11.36 g (94%). H NMR (CDCl3): d ¼ 1.43 (s, 9H, C(CH3)3), 1.66 (quintet,
2H, CCH2C), 2.45–2.70 (m, 2H, CH2CN), 3.05–3.20 (m, 2H, CH2NHBoc),
3.30–3.60 (m, 4H, CH2NZCH2), 5.10 (s, 2H, CH2Ph), 5.15 (br. signal, ca.
1H, NH), 7.30–7.40 (m, 5H, arom. H). Anal. calcd. for C19H27N3O4
(361.43): C, 63.14; H, 7.53; N, 11.63; Found: C, 62.85; H, 7.44; N, 11.44.

Synthesis of Spermidine
1093
N4-Benzyloxycarbonyl-N7-tert-butoxycarbonylnorspermidine (10)
Compound 6 (1.62 g, 4.5 mmol) was converted to N4-benzyloxycarbonyl-N7-
tert-butoxycarbonylnorspermidine analogously as described earlier for prep-
aration of 12. Yield: 0.97 g (61%). 1H NMR (CDCl3): d ¼ 1.44 (s, 9H,
C(CH3)3), 1.50–1.95 (m, 6H, CCH2C, NH2), 2.65–2.85 (m, 2H, CH2NH2),
3.00–3.55 (m, 6H, CH2NZCH2, CH2NHBoc), 4.60 (br. signal, 1H, NH),
5.09 (s, 2H, CH2Ph), 7.25–7.40 (m, 5H, arom. H). Anal. calcd. for
C19H31N3O4 (365.46): C, 62.44; H, 8.55; N, 11.50; Found: C, 62.08;
H, 8.35; N, 11.44.
N4-Benzyloxycarbonyl-N1,N7-di-tert-butoxycarbonylnorspermidine (15)
A solution of N4-benzyloxycarbonyl-N7-tert-butoxycarbonylnorspermidine
10 (0.37 g, 1 mmol) was treated with di-tert-butyldicarbonate and worked
1
out as described for preparation of 16 to obtain 15 (0.38 g, 81%) as an oil. H
NMR (CDCl3): d ¼ 1.43 (s, 18H, 2C(CH3)3), 1.50–1.80 (m, 4H, CCH2C),
[3.00–3.17 (m), 3.20–3.40 (m), together 8H, CH2NZCH2, 2CH2NHBoc],
4.50 (br. signal, 1H, NH), 5.13 (s, 2H, CH2Ph), 5.20 (br. signal, 1H, NH),
7.28–7.40 (m, 5H, arom. H). Anal. calcd. for C24H39N3O6 (465.48):
C, 61.91; H, 8.44; N, 9.03; Found: C, 61.48; H, 8.34; N, 9.10.
ACKNOWLEDGMENT
´
The authors are indebted to the Faculty of Chemistry, Gdansk University of
Technology, for financial support.
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