Synthetic analogues of naturally occurring spider toxins: Synthesis of 2-(Hydroxyphenyl)propanamides of spermidine and spermine

Article abstract of DOI:10.1002/1522-2675(20010418)84:4<797::AID-HLCA797>3.0.CO;2-2

In a study on structure-activity relationships of spider toxins, six model compounds, namely the spermidine derivatives 6, 8, and 16 as well as the spermine derivatives 24, 27, and 32 were synthesized. The synthesis proceeds through stepwise construction of the polyamine backbone, including protection and deprotection of the amino functions. The differentiation of the derivatives by analytical and spectroscopic methods is discussed.

Full text of DOI:10.1002/1522-2675(20010418)84:4<797::AID-HLCA797>3.0.CO;2-2

Helvetica Chimica Acta ± Vol. 84 (2001)
797
Synthetic Analogues of Naturally Occurring Spider Toxins:
Synthesis of 2-(Hydroxyphenyl)propanamides of Spermidine and Spermine
by Kasim Popaj1), Armin Guggisberg, and Manfred Hesse*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
In a study on structure-activity relationships of spider toxins, six model compounds, namely the spermidine
derivatives 6, 8, and 16 as well as the spermine derivatives 24, 27, and 32 were synthesized. The synthesis
proceeds through stepwise construction of the polyamine backbone, including protection and deprotection of
the amino functions. The differentiation of the derivatives by analytical and spectroscopic methods is discussed.
Introduction. ± Naturally occurring spider toxins are potent inhibitors of glutamate
receptors of the central nervous system. These receptors are believed to be involved in
higher neural functions such as memory and learning, and neurological disorders, e.g.,
hypoxemia, epilepsy, Huntingtonꢀs, Alzheimerꢀs and Parkinsonꢀs diseases [1]. In recent
years, there has been considerable interest in the isolation and identification of the
constituents of spider toxins. These toxins are characterized as consisting of a variety of
related compounds with a novel structure that contains one phenolic group in addition
to a polyamine moiety [2]. The discovery of the bizarrely structured polyamine-
containing toxins, which block glutamate receptors, led to the synthesis of a large
variety of compounds [3 ± 5]. As a continuation of our previously published results [6],
it was of interest to carry out the synthesis of new model compounds of the spider toxins
and to study their biological activity [7].
Synthesis and Discussion. ± In one sequence of amide formation and removal of the
protecting groups, we synthesized three spermidine and three spermine derivatives. For
the synthesis of the target compounds, we chose the 3,4-dihydrocoumarin (1; cf.
Scheme 2) or its protected and ring-opened equivalent 3-[2-(benzyloxy)phenyl]propa-
noic acid (2) as phenolic substrates, which were coupled with suitably protected
spermidine or spermine derivatives 3 and 4, respectively.
Synthesis of the Spermidine Derivatives. For amide formation, we followed the
method of Mukaiyama and co-workers [8]. According to Scheme 1, the propanoic acid
derivative 2 was treated with benzyl N-({8-[(benzyloxy)carbonyl]amino}-4-azaoctyl)-
carbamate (3) [9] in the presence of 1-methyl-2-chloropyridinium iodide to give, in
quantitative yield, the protected amide 5. Removal of the benzyl (Bn) and (benzyloxy)-
carbonyl (Z) protecting groups by hydrogenolysis (H2/Pd) led to the deprotected
amine 6. For analytical purposes, 6 was converted to its N,N''-diacetyl derivative 7.
Transamidation of the tertiary amide 6 was achieved with KH in propane-1,3-diamine
according to [10 ± 12]. The resulting secondary amide 8 and its N,N''-diacetyl derivative
9 show different properties in comparison to the isomers 6 and 7, respectively.
1
)
Part of the Ph.D. thesis of K.P., Universität Zürich, 1999.

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 1
OBn
O
3
NHZ
1
2'
OH
ZHN
N
H
1'
3
2
a)
OR
O
OBn
O
H
N
1'
NHZ
2
3'
b)
N
R
N
1
8'
5
3''
NHR
NHZ
6 R = H
c)
7 R = Ac
d)
OR
O
H
1'
8'
N
N
3'
2
N
H
R
1
12'
R
8 R = H
c)
9 R = Ac
a) 1-Methyl-2-chloropyridinium iodide, Et3N, CH2Cl2, r.t.; 98%. b) H2/10% Pd/C, AcOH, r.t.; 95%. c) AcONa,
Ac2O, r.t., 80%. d) KH, propane-1,3-diamine, r.t.; 90%.
To confirm the isomerization of 6 to its counterpart 8, the amine 8 was prepared by
an independent procedure, which is outlined in Scheme 2. 3-[(2-Benzyloxy)phenyl]-
propanoyl chloride (10) was converted to the N-acylspermidine derivative 12 by
treatment with bis(Boc)-spermidine 11 [13] in AcOEt. Removal of the Bn groups in 12
by hydrogenolysis followed by treatment with CF3COOH gave 8 in 65% yield. The
synthesis of 8 was best accomplished by aminolysis of 3,4-dihydrocoumarin (1). The
direct acylation of the primary amines with 1 proved to be more efficient for the
preparation of amides. Therefore, treatment of the bis(Boc)-protected spermidine 11
with 1 led to the amide 13 in 96% yield, which, after removal of the Boc groups, gave
the amine 8.
The preparation of 16, an isomer of 8, was performed with the starting material N-
(4-aminobutyl)-1,2,3,4,5,6-hexahydropyrimidine (14), obtained by reaction of HCOH
with spermidine [14]. Treating 14 with 1 gave the aminal 15. Deprotection with methanolic

Helvetica Chimica Acta ± Vol. 84 (2001)
799
Scheme 2
O
O
1
or
H
N
+
H2N
N
Boc
OBn
O
11
Boc
Cl
10
a)
OR
O
H
N
N
N
Boc
H
Boc
12 R = Bn
13 R = H
b)
c)
8
a) 1, EtOH, r.t., 96%; 10, EtOAc, Et3N, 08, 99%. b) H2/10% Pd/C, AcOH, r.t. c) CF3COOH, r.t., 95%.
HCl led to the expected product, but in 60% yield only (Scheme 3). For analytical purposes,
compound 16 was transformed to the corresponding N,N'-diacetyl derivative 17.
The isomer 16 was also prepared by an alternative procedure starting from N-(4-
aminobutyl)-3-(2-hydroxyphenyl)propanamide (18), formed in high yield by reaction
of butane-1,4-diamine with 1. The introduction of a third amino group in 18 by
treatment with acrylonitrile gave a mixture of compounds, containing the mononitrile
19 as the main component and the dinitrile 20. The mixture was subjected to catalytic
reduction of the nitriles to give the amines 16 and 21 (ratio 84 :16), which were then
separated (Scheme 4).
Synthesis of the Spermine Derivatives. Spermine derivatives, like those of
spermidine, were similarly synthesized. Following the strategy of aminolysis, we first
prepared compound 24 (60% yield) by treating spermine with 1 equiv. of 1. In this
experiment, compound 23, in which spermine had reacted with two molecules of 1, was
also obtained (Scheme 5). However, with spermine in excess, the reaction can be
directed to form product 24 only. Compound 24 was transformed to its N,N',N''-
triacetyl derivative 25.
In EtOH the aminolysis of 1 and the tris(Z)-protected spermine 4 in a 1:1 molar
ratio gave none of the desired compound 26 even after prolongation of the reaction

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 3
8
1
N
NH
H2N
10
4
14
a)
12'
OR
O
1'
N
NH
2
3'
N
1
8'
14'
H
15 R = H
b)
OR
O
R
N
H
1'
N
3'
2
N
R
1
8'
12'
H
16 R = H
17 R = Ac
c)
a) 1, EtOH, r.t.; 92%. b) HCl, MeOH, r.t.; 60%. c) NaOAc, Ac2O, r.t., 80%.
time to 30 h. Only when both components were allowed to react 7 d in toluene under
reflux, 32% of compound 26 could be isolated. Cleavage of the Z-protecting groups by
hydrogenolysis led to the amine 27 in an overall yield of 27% (Scheme 6). For
analytical purposes 27 was converted into its N,N',N''-triacetyl derivative 28. As
mentioned before, 1 seems to be a selective reagent for primary amines at room
temperature, while secondary amines react only under drastic conditions.
An alternative route with higher yield was once more found in the method of
Mukaiyama and co-workers for amide formation [8], which was used to prepare the
target compound 27. Thus, starting from the acid 2 and the spermine derivative 4, the
amide 29 was obtained in the presence of 1-methyl-2-chloropyridinium iodide. After
removal of the protecting groups by hydrogenolysis (H2/Pd), the desired product 27
was formed in 90% yield (Scheme 7). The overall yields from the two preparations of
compound 27 (27% vs. 85%) were quite different. Finally, 27 was converted to its
unbranched isomer 24 analogously to isomerization of 6 by treatment with KH in
propane-1,3-diamine.
In the preparation of the derivative 32, we followed the strategy of polyamine chain
elongation by the method of aminolysis. Starting from the spermidine derivative 15, by
a Michael reaction, 30 was prepared by treatment with equimolar amounts of

Helvetica Chimica Acta ± Vol. 84 (2001)
801
Scheme 4
OH
O
NH2
N
H
18
a)
OH
O
R
N
1'
11'
3'
2
N
CN
8'
1
H
19 R = H
20 R = (CH2)2CN
b)
NH2
OH
O
3''
1'
N
NH2
3'
2
N
1
8'
12'
16
H
21
a) Acrylonitrile, MeOH, r.t.; 98%. b) H2/Raney-Ni, 25% aq. NH3 soln., EtOH, r.t.; 16: 80%, 21: 15%.
acrylonitrile. Reduction of the nitrile and chromatography of the reaction mixture
afforded three products. The target compound 32 was obtained in 20% yield, while 31
in 36% yield and the monomethylated derivative of 32, namely 34, in 16% yield
(Scheme 8). Compound 32 was acetylated to the N,N',N''-triacetyl derivative 33.
Attempts to prepare 32 by hydrolysis of the aminal 31, analogously to the trans-
formation of 15 to 16 (Scheme 3) gave no positive results. The formation of 34 could be
explained by reduced immonium species formed by opening of the aminal 30.
Differentiation of the Spermidine Derivatives 6, 8, and 16. The triamine spermidines
contain three distinguishable amino groups. The three mono-substituted spermidine
derivatives 6, 8, and 16 are different from each other. It was mentioned before that the
N,N-disubstituted amide 6 can be converted to 8 by base or acid treatment or by
gradual rearrangement without addition of reagents [12] (Zip reaction). Under the
same conditions the isomers 8 and 16 are stable (Scheme 9). Unambiguous differ-
entiation of all the three isomers by spectroscopic means seems to be possible,
although, since the 1H- and 13C-NMR spectra of the isomers 8 and 16 are very similar,
their differentiation by NMR is quite difficult. Also, due to their similar polarities, no
striking differences in their Rf values were observed. Only the melting points of the
hydrochlorides are different. Therefore, we investigated chemical reactions to differ-

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 5
H
O
O
N
NH2
+
H2N
N
H
1
22
a)
OH
O
H
H
1'
8'
N
H
N
N
18'
2
N
1
H
O
OH
23
+
OR
O
R
N
H
1'
8'
N
N
2
N
R
1
16'
H
R
24 R = H
25 R = Ac
b)
a) EtOH, r.t.; 23: 39%, 24: 60%. b) AcONa, Ac2O, r.t.; 90%.
entiate the three isomers. As shown, the treatment of propane-1,3-diamine or some of
its derivatives with HCOH led to the corresponding hexahydropyrimidines, butane-1,4-
diamine does not react under these conditions. When the three isomers 6, 8, and 16
were treated with HCOH, compound 8 formed the hexahydropyrimidine derivative 35,
and 16 gave the isomer 15, while 6 was recovered unchanged. On the other hand, we
have shown that 1 reacts with primary amines only. Therefore, 6 could be converted to
the triamide 36 by treatment with 1, while the isomers 8 and 16 form the same diamide
37 (Scheme 9). The spectroscopic differentiation of the two reaction products is much
1
easier (e.g., in the IR spectrum (CHCl3), amide absorption is at 1630 cm for 35 and at
1
1640 and 1520 cm for 15). It should be mentioned that, during the derivatization
reactions, no spontaneous isomerization occurred.
Mass-Spectral Differentiation of the Acetyl Derivatives of 6, 8, and 16. In the course
of the structural elucidation of polyamine alkaloids such as oncinotine [15] or
verbascenine, the mass-spectral analysis (EI mode) of acylated, and of especially
acetylated, degradation products has been proved to be a very valuable method.
Therefore, the three isomers 6, 8, and 16 were converted to the corresponding N,N',O'-
triacetyl derivatives 7, 9, and 17, respectively, by treatment with Ac2O/NaOAc so that
the same methodology could be applied to differentiate the three isomers. The EI mass
spectra of the three compounds are shown in the Figure. It is known that N,N',N''-

Helvetica Chimica Acta ± Vol. 84 (2001)
803
Scheme 6
Z
O
O
N
NHZ
ZHN
N
+
H
4
1
a)
OH
O
Z
N
NHZ
N
26
NHZ
b)
OR
O
R
N
H
N
R
1'
2
3'
N
1
12'
8'
3''
NHR
27 R = H
c)
28 R = Ac
a) Toluene, reflux, 7 d; 32%. b) H2/10% Pd/C, AcOH, r.t.; 87%. c) NaOAc, Ac2O, r.t.; 77%.
triacetylspermidine derivatives under EI-MS conditions show a characteristic frag-
mentation pattern giving rise to the so-called peak triade [16].
Depending on the substitution of the spermidine unit with the 2-hydroxy-
dihydrocoumaroyl residue at N(1), N(5), or N(10), different fragment ions are
expected. During the formation of the ions of this peak triade the substituents of the
propane-1,3-diamine part of the spermidine moiety at N(1) and N(5) are lost, only that
‡´
‡´
at N(10) remains. Therefore, the triades formed from 7 and 9 are the same, while that
of 17 is different (Scheme 10).
‡´
For differentiation of 7 and 9, further fragmentation pathways had to be devised.
By another reaction, the central N-substituent is omitted. As in compounds 9 and 17,
the same residue was placed at the N(5)-atom. The corresponding fragmentations
appear in the case of 9 and 17 at the same mass, m/z 376; only 7 yielded a different
result at m/z 228. In addition, by a set of other fragment ions, m/z 112 (7 and 9) and 260
(17), the three isomers 7, 9, and 17 can be differentiated (Scheme 11).

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 7
OBn
Z
N
NHZ
COOH
+
ZHN
N
H
4
2
a)
OBn
O
Z
1'
N
NHZ
3'
2
1
N
12'
8'
3''
29
NHZ
b)
OH
O
H
N
NH2
N
NH2
27
c)
24
a) 1-Methyl-2-chloropyridinium iodide, Et3N, CH2Cl2, r.t.; 94%. b) H2/10% Pd/C, AcOH, r.t.; 90%. c) KH, 1-
propane-1,3-diamine, r.t., or gradual rearrangement without reagents [12].
The mass-spectral analysis of the corresponding spermine derivatives will be
published elsewhere.
We thank the analytical departments of our institute for measurements, especially Dr. Laurent Bigler for
mass-spectral analysis, and the Swiss National Science Foundation for the financial support.
Experimental Part
General. All commercially available reagents were used without further purification. All reactions were
followed by TLC (Merck silica gel 60 F254). The detection was either by UV light or with Ce(SO4)2 and Schlittler
reagent. Column chromatography (CC): Merck silica gel 60 (40 ± 60 m). M.p.: Mettler FP5. Hydrogenation: Parr
Instruments Company, Inc. IR [cm 1]: Perkin-Elmer 781; measured as 2 ± 3% soln. in CHCl3 (Fluka, for
1
spectroscopy), unless otherwise stated. H-NMR (CDCl3): Bruker ARX-300 (300 MHz) or Bruker AMX-600
(600 MHz), chemical shifts d in ppm using Me4Si (ˆ0 ppm) as internal standard, coupling constants J in Hz.
13C-NMR (CDCl3): Bruker ARX-300 (75 MHz) or Bruker AMX-600 (150 MHz); MS: Finnigan SSQ-700,

Helvetica Chimica Acta ± Vol. 84 (2001)
805
Scheme 8
OH
O
N
NH
N
H
15
a)
12'
OH
O
16'
1'
N
N
2
N
CN
8'
14'
H
30
b)
OH
O
N
N
NH2
N
H
31
+
OR
O
R
R
N
H
N
N
N
H
R
32 R = H
c)
33 R = Ac
+
OH
O
H(Me)
Me(H)
N
1'
N
NH2
2
N
H
1
16'
8'
34
a) Acrylonitrile, MeOH, r.t.; quant. b) H2/Raney-Ni, 25% aq. NH3 soln. EtOH, r.t., SiO2; 31: 36%, 32: 20%, 34:
16%. c) NaOAc, Ac2O, r.t.; 82%.
chemical ionization (Cl) with NH3, Finnigan MAT 90, electron impact (EI; 70 eV), and Finnigan TSQ-700,
electrospray ionization (ESI). Compounds 25, 28, 33 were measured with a Bruker ESQUIRE-LE quadrupole
ion-trap instrument (Bruker-Franzen GmbH, D-Bremen) connected to an orthogonal electrospray ion source
(Hewlett-Packard, Palo Alto, CA 94304, USA). The MS detector was operated under the following conditions:
N2 nebulizer gas: 15 psi; dry N2: 8 l/min; dry temp.: 2508; cap. voltage: 4200 V; end plate: 3700 V; capillary exit:
100 V; skimmer 1:25 V. The MS acquisitions were performed at normal resolution (0.6 u at the half-peak-
height), under ion-charge-control (ICC) conditions (10000) in the mass range from m/z 100 to 800 and a 36 trap
drive value; average of 8 scans were reported.
1. Synthesis of N-(4-Aminobutyl)-N-(3-aminopropyl)-3-(2-hydroxyphenyl)propanamide (6). From 3-[2-
(Benzyloxy)phenyl]propionic Acid (2) and Benzyl N-(8-{[(Benzyloxy)carbonyl]amino}-4-azaoctyl)carbamate
(3). N-(4-{[(Benzyloxy)carbonyl]amino}butyl)-N-(3-{[(benzyloxy)carbonyl]amino}propyl)-3-[2-(benzyloxy)-
phenyl]propanamide (5). A suspension of 2 (512 mg, 2 mmol), 1-methyl-2-chloropyridinium iodide (613 mg,
2.4 mmol), and Et3N (533 mg, 5.3 mmol) in CH2Cl2 (10 ml) were stirred 20 min at r.t. After addition of a soln. of
3 (826 mg, 2 mmol) in CH2Cl2 (10 ml), the mixture was stirred overnight at r.t. The solvent was evaporated, the

806
Helvetica Chimica Acta ± Vol. 84 (2001)
O
O
O
O
b
b
b
a
a
a

Helvetica Chimica Acta ± Vol. 84 (2001)
807
Figure. Mass spectra (EI mode, direct inlet, 70 eV): a) 3-(2-Acetoxyphenyl)-N-[4-(acetylamino)butyl]-N-[3-
(acetylamino)propyl]propanamide (7); b) 3-(2-acetoxyphenyl)-N-(3-{N-acetyl-N-[4-(acetylamino)butyl]ami-
no}propyl)propanamide (9); and c) 3-(2-acetoxyphenyl)-N-(4-{N-acetyl-N-[3-(acetylamino)propyl]amino}bu-
tyl)propanamide (17)
residue was taken up in CH2Cl2 (100 ml), washed with 0.3n aq. HCl soln. and dried (Na2SO4). Removal of the
solvent and purification of the residue by CC (SiO2; CH2Cl2/MeOH 46 :1) gave 1.25 g (96%) of 5. Colorless oil.
IR: 3445m, 3000m, 2935m, 1715vs, 1625s, 1505s, 1450s, 1375m, 1220s, 1135m, 1110m, 1080m, 1015m, 910w, 855w,
695m, 585w. 1H-NMR: 7.41 ± 7.27 (m, 15 arom. H); 7.19 ± 7.13 (m, H C(4), H C(6)); 6.91 ± 6.87 (m, H C(3),

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 10. Peak Triade of Compounds 7, 9, and 17
N
H
(CH2)4
N
H
O
R3
7
9
+• R3 = Me m/z 169
+• R3 = Me m/z 169
17+• R3 = (CH2)2PhOAc m/z 317
O
R1
–COR
1
NH
N H
(CH2)4
N
H
O
O
–CH2NHCOMe
5
R2
N
R2
(CH2)4
7+• R2 = Me m/z 157
+• R2 = Me m/z 157
17+• R2 = (CH2)2PhOAc m/z 305
9
10
HN
O
R3
–NHCOR
7+• R1 = R3 = Me, R2 = (CH2)2PhOAc
9
+• R1 = (CH2)2PhOAc, R2 = R3 = Me
17+• R1 = R2 = Me, R3 = (CH2)2PhOAc
N
H
(CH2)4
N
H
O
R3
7+• R3 = Me m/z 143
+• R3 = Me m/z 143
17+• R3 = (CH2)2PhOAc m/z 291
9
H
C(5)); 5.82, 4.79 (2 br. s, 2 NHCO); 5.08 (s, PhCH2); 5.05, 5.02 (2s, 2 PhCH2); 3.16 ± 3.11 (m, CH2(1''),
CH2(5')); 3.01 ± 2.95 (m, CH2(3''), CH2(8')); 2.96 (t, J ˆ 7.1, CH2(1')); 2.57 (t, J ˆ 7.2, CH2(2')); 1.60 ± 1.65 (m,
CH2(2'')); 1.49 ± 1.22 (m, CH2(6'), CH2(7')). 13C-NMR: 173.1 (s, C(3')); 156.5, 156.3 (2s, 2 CO); 137.1 (s, C(2));
136.8, 136.4 (2s, 2 arom. C); 130.4 (d, C(4)); 128.1 (d, C(6)); 128.0 (s, C(1)); 120.9 (d, C(5)); 111.6 (d, C(3));
128.3, 127.9, 127.5 (3d, 15 arom. C); 69.7 (t, PhCH2); 66.6, 66.3 (2t, 2 PhCH2); 47.0 (t, C(1'')); 45.2 (t, C(5')); 42.1
(t, C(8')); 40.3 (t, C(3'')); 37.4 (t, C(2')); 33.1 (t, C(2'')); 27.3 (t, C(1')); 27.1 (t, C(7')); 25.8 (t, C(6')). CI-MS: 652
‡
‡
(< 5, [M ‡ 1] ), 544 (63), 436 (100, [M of 3 ‡ Na] ).
Compound 6. To a suspension of 10% Pd/C (600 mg) in conc. AcOH (110 ml) was added a soln. of 5 (1.98 g,
3 mmol), and the mixture was hydrogenated overnight in a Parr apparatus at 3.5 bar H2 pressure. The mixture
was filtered over Celite, the filtrate evaporated, and the residue was purified by CC (SiO2; CHCl3/MeOH/25%
aq. NH3 soln. 10 :4 :1) to give 880 mg (99%) of 6 (colorless oil), which were taken up in EtOH (8 ml) and
treated dropwise with 0.3n aq. HCl soln. (pH 1). Removal of the solvent in vacuo and crystallization of the
residue from EtOH yielded 1.05 g (96%) 6 ´ 2 HCl. Colorless crystals. M.p. 204 ± 2058. IR: 3150m, 2930s, 1620s,

Helvetica Chimica Acta ± Vol. 84 (2001)
809
Scheme 11
MeOC
MeOC
1
COMe
N
H
NH
H
H
N
N
(CH2)3
(CH2)3
O
R
N
H
N
– COR
5
N
O
H
Me
m/z 112
O
Me
N
H
N
10
HN
Me
O
O
Me
7+•
m/z 228
ROC
ROC
COR
N
H
N
H
N
H
H
(CH2)3
N
(CH2)3
O
– MeCO
N
H
N
Me
O
H
Me
O
N
Me
m/z 112
N
HN
Me
H
R
N
O
O
Me
9+•
m/z 376
O
O
R
COMe
NH
N H
N
H
– MeCO
N
O
O
H
N
H
R
R
O
N
H
N
(CH2)3
N
m/z 260
Me
(CH2)3
NH
N
H
17+•
MeOC
MeOC
R = (CH2)2PhOAc
1455m, 1375m, 1305m, 1245m, 1150m, 1095m, 945w, 885w, 840m, 655w. 1H-NMR: 7.07 ± 7.03 (m, H C(4),
m/z 376
H
C(6)); 6.84 ± 6.74 (m, H C(3), H C(5)); 3.59 (br., 2 NH2); 3.38 (t, J ˆ 6.8, CH2(1'')); 3.18 (t, J ˆ 7.2,
CH2(5')); 2.92 (t, J ˆ 6.6, CH2(1')); 2.66 (t, J ˆ 6.8, CH2(3''), CH2(8')); 2.59 (t, J ˆ 7.0, CH2(2')); 1.62 (quint., J ˆ
6.6, CH2(2'')); 1.60 ± 1.35 (m, CH2(6'), CH2(7')). 13C-NMR: 173.6 (s, C(3')); 155.4 (s, C(2)); 130.5 (d, C(4)); 128.0
(s, C(1)); 127.6 (d, C(6)); 119.6 (d, C(5)); 116.5 (d, C(3)); 47.6 (t, C(1'')); 45.9, 45.5 (2t, C(5')); 43.0, 41.2 (2t,
C(8')); 38.9, 38.5 (2t, C(3'')); 34.2 (t, C(2')); 30.7, 30.2 (2t, C(2'')); 26.1 (t, C(1')); 25.9 (t, C(7')); 24.8 (t, C(6')).
‡
‡
ESI-MS: 294 ([M ‡ 1] ). ESI-MS/MS (of m/z 294.2, 15 eV): 294 (100, [M ‡ 1] ), 277 (45), 259 (10), 223 (10),

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Helvetica Chimica Acta ± Vol. 84 (2001)
‡
‡
206 (46, [M 87] ), 146 (28, [M of spermidine ‡ 1] ), 129 (<10), 72 (12). ESI-MS/MS (of m/z 294.2, 20 eV):
‡
‡
‡
294 (10, [M ‡ 1] ), 277 (17), 259 (<10), 206 (100, [M 87u] ), 146 (10, [M of spermidine ‡ H] ), 129 (<10),
112 (11), 72 (26).
3-(2-Acetoxyphenyl)-N-[4-(acetylamino)butyl]-N-[3-(acetylamino)propyl]propanamide (7). A suspension
of 6 (9 mg, 0.03 mmol) and AcONa (50 mg, 0.6 mmol) in Ac2O (5 ml) was stirred overnight at r.t.; then, the
mixture was evaporated. The residue was taken up in sat. aq. K2CO3 soln., extracted with CHCl3, and dried
(Na2SO4). Evaporation of the solvent and chromatography of the residue (SiO2; CHCl3/MeOH 19 :1) gave
10 mg (80%) of 7. Pale-yellow oil. 1H-NMR: 7.23 ± 7.14 (m, H C(4), H C(6)); 7.02 ± 6.99 (m, H C(3),
H
C(5)); 6.78, 6.08 (2 br. s, 2 NHAc); 3.39 (t, J ˆ 8.4, CH2(3''); 3.29 (t, J ˆ 6.1, CH2(8')); 3.19 ± 3.11 (m, CH2(1''),
CH2(5')); 2.90 (t, J ˆ 7.4, CH2(1')); 2.54 (t, J ˆ 7.5, CH2(2')); 2.00, 1.92 (2s, 3 MeCO); 1.65 (quint., J ˆ 6.4,
‡
‡
CH2(2'')); 1.56 ± 1.41 (m, CH2(6'), CH2(7')). ESI-MS: 458 (25, [M ‡ K] ), 442 (80, [M ‡ Na] ), 420 (100, [M ‡
‡
‡
1] ), 378 (18). ESI-MS/MS (of m/z 420.3, 15 eV): 420 (70, [M ‡ 1] ), 378 (100), 360 (10), 319 (12), 230 (40),
‡
212 (16). ESI-MS/MS (of m/z 420.3, 20 eV): 420 (<10, [M ‡ 1] ), 378 (65), 360 (<10), 319 (12), 230 (100),
212 (28), 171 (17), 100 (14). ESI-MS/MS/MS (of m/z 230.3, 40 eV): 230 (48), 213 (<10), 171 (<10), 114
(<10), 100 (100), 72 (<10). ESI-MS/MS/MS (of m/z 230.3, 42 eV): 230 (34), 213 (<10), 171 (<10), 114
(<10), 100 (100), 72 (<10). EI-MS: See Fig. 1,a.
3-(2-Hydroxyphenyl)-N-[3-({4-[3-(2-hydroxyphenyl)propanamido]butyl}[3-(2-hydroxyphenyl)propanoyl]-
amino)propyl]propanamide (36). To a soln. of 6 ´ 2 HCl (60 mg, 0.2 mmol) in EtOH (7 ml) was added MeONa
(33 mg, 0.6 mmol), and the mixture was stirred 30 min at r.t. The solvent was removed in vacuo, the residue was
dissolved in EtOH (10 ml) and treated with a soln. of 3,4-dihydrocoumarin (1, 101 mg, 2.2 mmol). After 1 h
stirring at r.t., the mixture was evaporated and purified by CC (SiO2; CHCl3/MeOH 19 :1) to yield 91 mg (94%)
of 36. Colorless oil. IR: 3000m, 1640m, 1520m, 1485m, 1410w, 1305w, 1220m, 1095w, 1035w, 925w, 840w, 665m,
620w. 1H-NMR: 9.20, 9.06, 8.95 (3s, 3 OH); 7.08 ± 7.00 (m, 3 H C(4), 3 H C(6)); 6.84 ± 6.73 (m, 3 H C(3), 3
H
C(5)); 3.12 ± 3.10 (m, CH2(9'), CH2(12')); 3.05 (t, J ˆ 7.1, CH2(5'), CH2(7')); 2.90 (t, J ˆ 6.6, CH2(1'),
CH2(1''), CH2(16')); 2.55 (t, J ˆ 7.0, CH2(2'), CH2(2''), CH2(15')); 1.50 (quint., CH2(6')); 1.31 ± 1.30 (m, CH2(10'),
CH2(11')). 13C-NMR: 174.4, 174.3, 173.2 (3s, C(3'), C(3''), C(14')); 154.7, 154.5, 154.4 (3s, 3 C(2)); 130.4, 130.3
(2d, 3 C(4)); 127.8, 127.7 (2d, 3 C(6)); 127.4, 127.2 (2s, 3 C(1)); 120.1, 120.0 (2d, 3 C(5)); 116.4, 116.3 (2d, 3 C(3));
47.5 (t, C(7')); 45.6 (t, C(9')); 43.2 (t, C(5')); 38.8 (t, C(12')); 36.9, 36.7, 36.6 (3t, C(2'), C(2''), C(15')); 33.8 (t,
‡
C(6')); 28.4, 26.8, 26.4 (3t, C(1'), C(1''), C(16')); 26.1 (t, C(11')); 25.6 (t, C(10')). EI-MS: 612 (100, [M ‡ Na] ),
‡
590 (15, [M ‡ 1] ).
2. Synthesis of N-{3-[(4-Aminobutyl)amino]propyl}-3-(2-hydroxyphenyl)propanamide (8). 2.1. From 6. A
suspension of KH (500 mg, 12 mmol) in propane-1,3-diamine (5 ml) was stirred at r.t. 30 min under Ar. A soln.
of 6 (110 mg, 0.38 mmol) in propane-1,3-diamine (5 ml) was added dropwise and stirring was continued for
1.5 h. The mixture was treated carefully with 0.3n aq. HCl soln. and the solvents were removed in vacuo. The
residue was taken up in sat. aq. K2CO3 soln. (5 ml), extracted with CHCl3, and the org. layer was dried
(Na2SO4). Evaporation of the solvent and purification of the residue by CC (SiO2; CHCl3/MeOH/25 aq. NH3
soln. 10 :4 :1) yielded 100 mg (90%) of 8 as slightly yellow-colored oil, which was crystallized as hydrochloride
8 ´ 2 HCl. M.p. 116 ± 1188 (EtOH). IR: 3300w (br.), 2930m, 1640s, 1520m, 1455m, 1370w, 1240w, 1175w, 1135m,
1010w, 900w, 835w, 650w. 1H-NMR: 7.58 (br., NHCO); 7.08 ± 7.03 (m, H C(4), H C(6)); 6.84 ± 6.76 (m,
H
C(3), H C(5)); 3.21 (t, J ˆ 6.2, CH2(5')); 2.89 (t, J ˆ 7.0, CH2(1')); 2.76 (t, J ˆ 6.4, CH2(12')); 2.63 (t, J ˆ 6.4,
CH2(7'), CH2(9')); 2.56 (t, J ˆ 7.0, CH2(2')); 1.66 (quint., J ˆ 6.5, CH2(6')); 1.64 ± 1.58 (m, CH2(10'), CH2(11')).
13C-NMR: 174.6 (s, C(3')); 154.6 (s, C(2)); 130.2 (d, C(4)); 127.5 (d, C(6)); 127.2 (s, C(1)); 119.8 (d, C(5)); 116.0
(d, C(3)); 48.9 (t, C(7')); 46.6 (t, C(9')); 41.0 (t, C(5')); 37.3 (t, C(12')); 36.5 (t, C(2')); 30.0 (t, C(1')); 28.2 (t,
‡
C(6')); 26.5 (t, C(11')); 25.8 (t, C(10')). ESI-MS: 294 ([M ‡ 1] ). ESI-MS/MS (of m/z 294.2, 15 eV): 294 (100,
‡
‡
[M ‡ 1] ), 277 (25), 259 (<10), 223 (<10), 206 (26, [M 87u] ), 146 (10), 129 (<10), 75 (<10), 72 (10). ESI-
‡
‡
MS/MS (of m/z 294.2, 20 eV): 294 (16, [M ‡ 1] ), 277 (20), 259 (11), 206 (100, [M 87] ), 146 (<10), 129
(<10), 112 (<10), 75 (10), 72 (27).
3-(2-Acetoxyphenyl)-N-(3-{(acetyl)[4-(acetylamino)butyl]amino}propyl)propanamide (9). Analogously to
the preparation of 7, from 8 (9 mg, 0.03 mmol) and AcONa (50 mg, 0.6 mmol) in Ac2O (5 ml), 10.5 mg (84%) of
9 were obtained after workup. 1H-NMR: 7.23 ± 7.12 (m, H C(4), H C(6)); 7.02 ± 6.98 (m, H C(3), H C(5));
6.71, 5.70 (br., NHAc); 3.30 ± 3.28 (m, CH2(12')); 3.25 ± 3.19 (m, CH2(5')); 3.14 ± 3.10 (m, CH2(7'), CH2 (9'));
2.88 (t, J ˆ 7.2, CH2(1')); 2.43 (t, J ˆ 7.2, CH2(2')); 2.07, 2.01 (2s, 3 MeCO); 1.59 (quint., J ˆ 6.6, CH2(6')); 1.54 ±
1.50 (m, CH2(10'), CH2(11')). 13C-NMR2): 171.8 (s, C(3')); 170.2 (s, 3 CO); 148.8 (s, C(2)); 130.2 (d, C(4)),
The 13C-NMR signal of C(2) in the spectrum of 9 is not observed.
2
)

Helvetica Chimica Acta ± Vol. 84 (2001)
811
C(6)); 126.0 (d, C(5)); 122.2 (d, C(3)); 48.1 (t, C(12')); 42.1 (t, C(7')); 38.7 (t, C(9')); 36.7 (t, C(5')); 35.7 (t,
C(2')); 27.3 (t, C(1')); 27.0 (t, C(6')); 26.1 (t, C(11')); 25.9 (t, C(10')); 23.1, 21.2, 20.9 (3q, 3 MeCO). ESI-MS: 458
‡
‡
‡
(10, [M ‡ K] ), 442 (26, [M ‡ Na] ), 420 (100, [M ‡ 1] ), 378 (34). ESI-MS/MS (of m/z 420.3, 20 eV): 378
(11, [M ‡ 2 Ac]2‡), 318 (26), 230 (100), 213 (50), 206 (20), 112 (<10), 100 (17). ESI-MS/MS (of m/z 420.3,
30 eV): 318 (20), 248 (12), 230 (14), 213 (76), 206 (100), 171 (17), 143 (16), 114 (52), 100 (80), 72 (22). ESI-
MS/MS/MS (of m/z 230.3, 40 eV): 230 (20), 213 (22), 114 (14), 100 (100), 72 (10). ESI-MS/MS/MS (of m/z
230.3, 42 eV): 230 (<10), 213 (15), 114 (15), 100 (100), 72 (16). ESI-MS: See the Figure, b.
1-[3-(4-Aminobutyl)-1,2,3,4,5,6-hexahydropyrimidin-1-yl]-3-(2-hydroxyphenyl)propan-1-one (35). Analo-
gously to the treatment of 6 ´ 2 HCl, from 8 ´ 2 HCl (30 mg, 0.082 mmol) and 37% formaline (3 drops) in MeOH
(5 ml), 15 mg (60%) of 35 were obtained after workup. IR: 2940m, 1630s, 1450m, 1305w, 1230m, 1135w, 1095m,
1005w, 905w, 655w. 1H-NMR: 7.12 ± 7.04 (m, H C(4), H C(6)); 6.93 ± 6.76 (m, H C(3), H C(5)); 4.50 (br. s,
NH2); 4.17, 4.06 (2s, CH2(9')); 3.59 (t, J ˆ 5.7, Ha C(5')); 3.43 (t, J ˆ 5.7, Hb C(5')); 2.91 (t, J ˆ 8.0, CH2(1'));
2.83 (t, J ˆ 6.2, CH2(13')); 2.72 (t, J ˆ 7.0, CH2(7')); 2.69 (t, J ˆ 7.6, CH2(2')); 2.37 (t, J ˆ 6.6, CH2(10')); 1.63 ± 1.51
(m, CH2(6')); 1.59 ± 1.53 (m, CH2(11'), CH2(12')). 13C-NMR: 173.3 (s, C(3')); 154.8 (s, C(2)); 130.2 (d, C(4));
127.8 (d, C(6)); 127.4 (s, C(1)); 120.0 (d, C(5)); 116.9 (d, C(3)); 66.5, 62.5 (2t, C(9')); 53.2 (t, C(5')); 45.5 (t,
C(7')); 40.3 (t, C(10')); 39.9 (t, C(13')); 34.0 (t, C(2')); 27.5 (t, C(1')); 25.1 (t, C(12')); 24.6 (t, C(11')). EI-MS: 306
‡
([M ‡ 1] ).
3,3'-Bis(2-hydroxyphenyl)-N,N'-(4-azaoctane-1,8-diyl)bis[propanamide] (37). Analogously to the prepa-
ration of 36, from 8 ´ 2 HCl (55 mg, 0.15 mmol), MeONa (100 mg) and 1 (66 mg, 0.45 mmol) in MeOH (10 ml),
63 mg (94%) of 37 were obtained after workup. IR: 2960m, 1640m, 1520m, 1485m, 1410m, 1380w, 1220m,
1105m, 1025w, 925w, 840w, 800m, 665m, 620w. 1H-NMR: 7.08 ± 7.03 (m, 2 H C(4), 2 H C(6)); 6.84 ± 6.76 (m, 2
H
C(3), 2 H C(5)); 3.22 (t, J ˆ 6.5, CH2(5')); 3.15 (t, J ˆ 6.5, CH2(12')); 2.88 (t, J ˆ 7.0, CH2(1'), CH2(16'));
2.56 ± 2.53 (m, CH2(7'), CH2(9')); 2.51 (t, J ˆ 7.2, CH2(2'), CH2(15')); 1.59 (quint., J ˆ 6.4, CH2(6')); 1.42 ± 1.38
(m, CH2(10'), CH2(11')). 13C-NMR: 174.3, 174.1 (2s, C(3'), C(14')); 154.6 (s, 2 C(2)); 130.1 (d, 2 C(4)); 127.6 (d, 2
C(6)); 127.4 (s, 2 C(1)); 120.0 (d, 2 C(5)); 116.3 (d, 2 C(3)); 48.5 (t, C(7')); 46.4 (t, C(9')); 38.9 (t, C(5')); 37.2 (t,
C(12')); 36.8 (t, C(2')); 36.7 (t, C(15')); 28.1 (t, C(6')); 26.4 (t, C(1')); 25.9 (t, C(16')); 25.4 (t, C(11')); 25.3 (t,
‡
C(10')). ESI-MS: 442 ([M ‡ 1] ).
2.2. From 2 and Di(tert-butyl) N-(1-Aminopropyl)-N,N'-(butane-5,8-diyl)bis[carbamate] (11). 3-[(2-
Benzyloxy)phenyl]-N-(3-{[(tert-butoxy)carbonyl](4-{[(tert-butoxy)carbonyl]amino}butyl)amino}propyl}pro-
panamide (12). A mixture of 2 (512 mg, 2 mmol), DMF (2 drops) and SOCl2 (713 mg, 6 mmol) in toluene
(20 ml) was heated at 1008. After 2 h, the mixture was cooled to r.t., the solvent was evaporated, and the residue
was dried at 10 3 bar. To the soln. of crude 3-(2-hydroxyphenyl)propanoyl chloride (10; 545 mg, 2 mmol) and
Et3N (606 mg, 6 mmol) in AcOEt (20 ml) was added at 08 the soln. of 11 (690 mg, 2 mmol) in EtOAc (10 ml).
The mixture was stirred for 1 h at r.t., the solvent was evaporated, and the residue purified by CC (SiO2; CHCl3/
MeOH 19 :1) to give 1.16 g (99%) of 12. Colorless oil. IR: 3445m, 2960m, 1645vs, 1600m, 1490s, 1450s, 1415s,
1365s, 1290m, 1220s, 1165vs, 1110m, 1015w, 900w, 860m, 690w, 655w. 1H-NMR: 7.46 ± 7.31 (m, 5 arom. H); 7.19 ±
7.15 (m, H C(4), H C(6)); 6.91 ± 6.87 (m, H C(3), H C(5)); 6.62 (br., NHBoc); 5.09 (s, PhCH2); 4.68 (br.,
NHCO); 3.15 ± 3.13 (m, CH2(5')); 3.11 ± 3.09 (m, CH2(12')); 3.07 ± 3.05 (m, CH2(7'), CH2(9')); 3.01 (t, J ˆ 7.3,
CH2(1')); 2.49 (t, J ˆ 7.2, CH2(2')); 1.53 ± 1.52 (m, CH2(6')); 1.50 ± 1.46 (m, CH2(10'), CH2(11')); 1.43, 1.42 (2s, 2
Me3C). 13C-NMR: 172.6 (s, C(3')); 156.5, 156.0 (2s, 2 CO); 153.1 (s, C(2)); 137.3 (s, arom. C); 130.2 (d, C(4));
129.5 (s, C(1)); 128.5 (d, C(6)); 127.4, 127.2, 127.0 (3d, 5 arom. C); 120.7 (d, C(5)); 111.6 (d, C(3)); 79.6, 79.1 (2s,
2 Me3C); 69.9 (t, PhCH2); 46.4 (t, C(12')); 43.1 (t, C(7')); 40.0 (t, C(9')); 36.6 (t, C(5')); 35.4 (t, C(2')); 28.3 (q, 2
‡
Me3C); 27.3 (t, C(1')); 27.0 (t, C(6')); 26.8 (t, C(11')); 25.6 (t, C(10')). ESI-MS: 606 ([M ‡ Na] ).
N-[3-([(tert-Butoxy)carbonyl](4-{[(tert-butoxy)carbonyl]amino}butyl}amino)propyl]-3-(2-hydroxyphe-
nyl)propanamide (13). To a soln. of 12 (1.05 g, 1.8 mmol) in AcOH (110 ml) was added 10% Pd C (500 mg),
and the mixture was hydrogenated overnight in a Parr apparatus at 3.5 bar H2 pressure. Filtration, evaporation,
and purification of the residue by CC (SiO2; CHCl3/MeOH/25% aq. NH3 soln. 10 :4 :1) gave 805 mg (90%) of
13. Colorless oil. IR: 3445m, 2460m, 1615vs, 1580m, 1490s, 1450s, 1415s, 1365s, 1305m, 1230s, 1160vs, 1100w,
1
1035w, 1005w, 945w, 905s, 855m, 645w. H-NMR: 7.11 ± 7.03 (m, H C(4), H C(6)); 6.90 ± 6.78 (m, H C(3),
H
C(5)); 4.68 (br., NHBoc); 3.18 ± 3.16 (m, CH2(5')); 3.13 ± 3.11 (m, CH2(12')); 3.09 ± 3.07 (m, CH2(7'),
CH2(9')); 2.90 (t, J ˆ 6.5, CH2(1')); 2.61 (t, J ˆ 6.3, CH2(2')); 1.61 ± 1.57 (m, CH2(6')); 1.50 ± 1.47 (m, CH2(10'),
CH2(11')); 1.44, 1.43 (2s, 2 Me3C). 13C-NMR: 174.0 (s, C(3')); 156.0 (s, 2 CO); 154.9 (s, C(2)); 130.4 (d, C(4));
127.9 (s, C(1)); 127.7 (d, C(6)); 120.0 (d, C(5)); 117.3 (d, C(3)); 79.9, 78.5 (2s, 2 Me3C); 46.6 (t, C(12')); 43.5 (t,
C(7')); 39.9 (t, C(9')); 37.0 (t, C(5')); 36.0 (t, C(2')); 28.3 (q, 2 Me3C); 27.3 (t, C(1')); 26.8 (t, C(6')); 25.5 (t,
C(11')); 24.6 (t, C(10')).

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Helvetica Chimica Acta ± Vol. 84 (2001)
Compound 8. A soln. of 13 (805 mg, 1.63 mmol) in CF3COOH (TFA) (10 ml) was stirred overnight at r.t.
The removal of the solvent and chromatography of the residue (SiO2; CHCl3/MeOH/25% aq. NH3 soln. 5 :3 :1)
1
gave 300 mg (65%) of 8, which was crystallized as its hydrochloride, which was identical (TLC, IR, H-NMR,
13C-NMR, and MS analysis) to the compound described under 2.1.
2.3. From 1 and 11. Compound 13. A soln. of 1 (148 mg, 1 mmol) and 11 (545 mg, 1 mmol) in EtOH (5 ml)
was stirred 1 h at r.t. The mixture was evaporated and the residue purified by CC (SiO2; CHCl3/MeOH 19 :1):
473 mg (96%) of 13. Slightly yellow-colored oil. Compound 13 was found to be identical (TLC, IR, 1H-NMR,
13C-NMR, and MS analysis) with the compound described under 2.2.
Compound 8. A soln. of 13 (470 mg, 0.95 mmol) in CF3COOH (7 ml) was stirred overnight at r.t., and the
mixture was evaporated. Chromatography of the residue (SiO2; CHCl3/MeOH/25% aq. NH3 soln. 5 :3:1)
yielded 280 mg (95%) of 8, which was crystallized as its hydrochloride. Compound 8 was found to be identical
(TLC, IR, 1H-NMR, 13C-NMR, and MS analysis) with the compound described under 2.2.
3. Synthesis of N-{4-[N-(3-Aminopropyl)amino]butyl}-3-(2-hydroxyphenyl)propanamide (16). 3.1 From 1-
(4-Aminobutyl)-1,2,3,4,5,6-hexahydropyrimidine (14) and 1. N-[4-(1,2,3,4,5,6-Hexahydropyrimidin-1-yl)butyl]-
3-(2-hydroxyphenyl)propanamide (15). To a soln. of 14 (50 mg, 0.31 mmol) in EtOH (5 ml) was added dropwise
a soln. of 1 (51 mg, 0.51 mmol) in EtOH (5 ml). The mixture was stirred 1 h at r.t. and then evaporated. The
residue was purified by CC (SiO2; CHCl3/MeOH/25% aq. NH3 soln. 85 :14 :1) to give 90 mg (92%) of 15.
Amorphous solid. IR: 3250m (br.), 2940vs, 2710s, 1640vs, 1520s, 1485s, 1450s, 1320m, 1300m, 1220s, 1165m,
1
1100m, 1035w, 1010w, 975w, 885w, 835m, 655m, 620w. H-NMR: 7.09 ± 7.03 (m, H C(4), H C(6)); 6.85 ± 6.75
(m, H C(3), H C(5)); 6.68 (br., NHCO); 5.59 (br., NH); 3.40 (s, CH2(14')); 3.20 ± 3.14 (m, CH2(5')); 2.92 (t,
J ˆ 6.8, CH2(1')); 2.83 (t, J ˆ 5.5, CH2(12')); 2.57 (t, J ˆ 6.5, CH2(8')); 2.55 (t, J ˆ 6.3, CH2(2')); 2.24 (t, J ˆ 6.7,
CH2(10')); 1.64 (quint., J ˆ 5.4, CH2(11')); 1.54 ± 1.45 (m, CH2(6'), CH2(7')). 13C-NMR: 173.7 (s, C(3')); 155.0 (s,
C(2)); 130.3 (d, C(4)); 127.8 (s, C(1)); 127.6 (d, C(6)); 119.9 (d, C(5)); 116.9 (d, C(3)); 69.4 (t, C(14')); 54.3 (t,
C(8')); 52.7 (t, C(10')); 44.7 (t, C(12')); 39.2 (t, C(5')); 37.0 (t, C(2')); 27.0 (t, C(1')); 26.3 (t, C(11')); 25.2 (t, C(6'));
‡
23.7 (t, C(7')). CI-MS: 306 (100, [M ‡ 1] ), 166 (17), 158 (25), 101 (13).
Compound 16. Through a soln. of 15 (250 mg, 0.8 mmol) in MeOH (7 ml) was bubbled a stream of HCl gas
for 3 min. The mixture was evaporated, and the residue was washed with EtOH and purified by CC (SiO2;
CHCl3/EtOH/25% aq. NH3 soln. 5 :3 :1) to give 140 mg (60%) of 16 as colorless oil, which was crystallized as its
hydrochloride 16 ´ 2 HCl. M.p. 133 ± 1358 (EtOH). IR (KBr): 2965vs, 1637vs, 1593s, 1551s, 1503m, 1489m, 1455s,
1383m, 1241m, 1157w, 1102w, 1042w, 757m, 589w. 1H-NMR: 7.39 (br., NHCO); 7.07 ± 7.01 (m, H C(4),
H
C(6)); 6.85 ± 6.74 (m, H C(3), H C(5)); 3.20 ± 3.15 (m, CH2(5')); 2.88 (t, J ˆ 7.1, CH2(1')); 2.83 (t, J ˆ 6.5,
CH2(12')); 2.74 (t, J ˆ 6.8, CH2(10')); 2.61 (t, J ˆ 6.6, CH2(8')); 2.54 (t, J ˆ 7.1, CH2(2')); 1.73 (quint., J ˆ 6.7,
CH2(11')); 1.47 ± 1.41 (m, CH2(6'), CH2(7')). 13C-NMR: 174.1 (s, C(3')); 154.7 (s, C(2)); 130.1 (d, C(4)); 127.5 (s,
C(1)); 127.4 (d, C(6)); 119.7 (d, C(5)); 116.0 (d, C(3)); 48.8 (t, C(7')); 47.2 (t, C(9')); 39.7 (t, C(5')); 39.0 (t,
‡
C(12')); 36.7 (t, C(2')); 32.1 (t, C(11')); 26.6 (t, C(1')); 26.5 (t, C(6')); 25.9 (t, C(7')). ESI-MS: 294 ([M ‡ 1] ).
‡
‡
ESI-MS/MS (of m/z 294.4, 20 eV): 294 (100, [M ‡ 1] ), 277 (24), 220 (52, [M 73] ), 202 (16), 146 (36), 129
‡
(26), 112 (43), 75 (<10), 72 (30). ESI-MS/MS (of m/z 294.4, 22 eV): 294 (42, [M ‡ 1] ), 277 (32), 220 (100,
‡
[M 73u] ), 202 (27), 148 (20), 146 (27), 129 (38), 112 (100), 84 (11), 72 (56).
3-(2-Acetoxyphenyl)-N-(4-{(acetyl)[3-(acetylamino)propyl]amino}butyl)propanamide (17). Analogously
to the preparation of 7, from 16 (40 mg, 0.136 mmol) and AcONa (60 mg, 0.7 mmol) in Ac2O (5 ml), 45 mg
(80%) of 17 was obtained after workup. 1H-NMR: 7.25 ± 7.12 (m, H C(4), H C(6)); 7.01 ± 6.97 (m, H C(3),
H
C(5)); 6.87 (br., NHCO); 6.42, 5.83 (2 br., s, NHAc); 3.35 (t, J ˆ 6.3, CH2(12')); 3.25 (t, J ˆ 6.1, CH2(5'));
3.21 ± 3.11 (m, CH2(8'), CH2(10')); 2.88 (t, J ˆ 7.4, CH2(1')); 2.39 (t, J ˆ 7.4, CH2(2')); 2.07, 1.96 (2s, 3 MeCO); 1.63
(quint., J ˆ 6.0, CH2(11')); 1.48 ± 1.33 (m, CH2(6'), CH2(7')). 13C-NMR: 171.8 (s, C(3')); 171.0, 170.2 (2s, 3 CO);
148.8 (s, C(2)); 132.3 (s, C(1)); 130.4 (d, C(4)); 127.5 (d, C(6)); 126.1 (d, C(5)); 122.4 (d, C(3)); 48.1 (t, C(12'));
42.0 (t, C(8')); 38.5 (t, C(10')); 36.3 (t, C(5')); 35.7 (t, C(2')); 27.2 (t, C(1')); 26.7 (t, C(11')); 26.1 (t, C(7')); 25.7 (t,
‡
‡
‡
C(6')); 23.2, 21.1, 20.8 (3q, 3 MeCO). ESI-MS: 458 (20, [M ‡ K] ), 442 (100, [M ‡ Na] ), 420 (49, [M ‡ 1] ),
‡
378 (16). ESI-MS/MS (of m/z 420.3, 15 eV): 420 (89, [M ‡ 1] ), 378 (100), 360 (36), 319 (11), 230 (40), 171
(<10), 100 (<10). ESI-MS/MS (of m/z 420.3, 20 eV): 378 (100), 360 (48), 318 (27), 230 (92), 213 (16), 171
(18), 100 (10). ESI-MS/MS/MS (of m/z 230.3, 40 eV): 230 (74), 213 (31), 114 (12), 100 (100), 72 (24). ESI-
MS/MS/MS (of m/z 230.3, 42 eV): 230 (12), 213 (17), 114 (11), 100 (100), 72 (33). ESI-MS: See Fig. 1,c.
3.2. From 1 and Butane-1,4-diamine. N-(4-Aminobutyl)-3-(2-hydroxyphenyl)propanamide (18). A mixture
of butane-1,4-diamine (1.79 g, 20 mmol) and 1 (1 g, 6.8 mmol) in EtOH (25 ml) was stirred 1 h at r.t.
Evaporation of the solvent and chromatography of the residue (SiO2; CHCl3/MeOH/25% aq. NH3 soln. 12 :4 :1)
yielded 1.4 g (90%) of 18. Colorless oil. 1H-NMR: 7.08 ± 7.01 (m, H C(4), H C(6)); 6.89 (br., NHCO); 6.84 ±
6.75 (m, H C(3), H C(5)); 3.15 (t, J ˆ 6.4, CH2(5')); 2.88 (t, J ˆ 7.1, CH2(1')); 2.64 (t, J ˆ 6.0, CH2(8')); 2.53 (t,

Helvetica Chimica Acta ± Vol. 84 (2001)
813
J ˆ 6.9, CH2(2')); 1.56 ± 1.39 (m, CH2(6'), CH2(7')). 13C-NMR: 173.9 (s, C(3')); 154.7 (s, C(2)); 130.3 (d, C(4));
127.6 (s, C(1)); 127.5 (d, C(6)); 119.8 (d, C(5)); 116.4 (d, C(3)); 40.7 (t, C(5')); 39.1 (t, C(8')); 36.9 (t, C(2')); 29.1
‡
(t, C(7')); 26.2 (t, C(1')); 25.3 (t, C(6')). ESI-MS: 237 ([M ‡ 1] ).
N-{4-[(2-Cyanoethyl)amino]butyl}-3-(2-hydroxyphenyl)propanamide (19). To a stirred soln. of 18 (1.38 g,
5.58 mmol) in MeOH was added dropwise acrylonitrile (372 mg, 7.02 mmol), and the stirring was continued at
r.t. for 24 h. After evaporation and purification by CC (SiO2; CHCl3/MeOH/25% aq. NH3 soln. 85 :14 :1), 1.68 g
(99%) of 19 and N-{4-[bis(2-cyanoethyl)amino]butyl}-3-(2-hydroxyphenyl)propanamide (20) were obtained.
1H-NMR: 7.13 ± 7.04 (m, H C(4), H C(6)); 6.90 ± 6.80 (m, H C(3), H C(5)); 6.09 (br., NHCO); 3.22 (t, J ˆ
6.6, CH2(5')); 2.94 (t, J ˆ 6.8, CH2(1')); 2.72 (t, J ˆ 6.5, CH2(10')); 2.66 (t, J ˆ 6.6, CH2(8')); 2.60 (t, J ˆ 7.1,
CH2(2')); 2.42 (t, J ˆ 6.6, CH2(11')); 1.58 ± 1.44 (m, CH2(6'), CH2(7')). 13C-NMR: 173.1 (s, C(3')); 153.3 (s, C(2));
130.7 (d, C(4)); 128.0 (d, C(6)); 127.7 (s, C(1)); 120.2 (d, C(5)); 117.4 (d, C(3)); 99.7 (s, CN); 49.8 (t, C(8')); 45.11
(t, C(10')); 37.3 (t, C(5')); 37.0 (t, C(2')); 31.2 (t, C(7')); 26.1 (t, C(1')); 24.6 (t, C(6')). ESI-MS: 312 (5, [M ‡
‡
‡
Na] ), 290 (100, [M ‡ 1] ).
Compound 16 and N-{4-Bis(3-aminopropyl)amino]butyl}-3-(2-hydroxyphenyl)propanamide (21). To a
soln. of 19 (1.65 g, 5.7 mmol) in EtOH (90 ml) and 25% aq. NH3 soln. (25 ml) was added Raney-Ni (700 mg),
and the mixture was hydrogenated over night in a Parr apparatus at 3.5 bar H2 pressure. The mixture was filtered
over Celite, the filtrate was evaporated, and the residue was chromatographed (SiO2; CHCl3/MeOH/25% aq.
NH3 soln. 5 :3 :1): 1.35 g (80%), 1st fraction) of 16 and 260 mg (15%, 2nd fraction) of 21 were obtained. Both
products were converted to their hydrochlorides by treatment with 0.3n aq. HCl soln.
Data of 16: Compound 16 was found to be identical (TLC, IR, 1H-NMR, 13C-NMR, and MS analysis) to the
compound described under 3.1.
Data of 21: 1H-NMR: 7.37 (br., NHCO); 7.07 ± 7.01 (m, H C(4), H C(6)); 6.85 ± 6.74 (m, H C(3),
H
C(5)); 3.17 ± 3.15 (m, CH2(5')); 2.89 (t, J ˆ 7.0, CH2(1')); 2.81 (t, J ˆ 6.5, CH2(12'), CH2(3'')); 2.55 (t, J ˆ 6.9,
CH2(2')); 2.45 (t, J ˆ 6.8, CH2(10'), CH2(1'')); 2.34 (t, J ˆ 6.5, CH2(8')); 1.95 (br., 2 NH2); 1.65 (quint., J ˆ 6.6,
CH2(11'), CH2(2'')); 1.39 ± 1.35 (m, CH2(6'), CH2(7')). 13C-NMR: 174.0 (s, C(3')); 154.9 (s, C(2)); 130.2 (d,
C(4)); 127.5 (s, C(1)); 127.4 (d, C(6)); 119.6 (d, C(5)); 116.1 (d, C(3)); 53.2, 52.3 (2t, C(10'), C(1'')); 49.1 (t,
C(8')); 39.8 (t, C(5')); 38.8, 38.7 (2t, C(12'), C(3'')); 36.7 (t, C(2')); 27.1 (t, C(11'), C(2'')); 26.8 (t, C(1')); 25.7 (t,
‡
C(7')); 24.0 (t, C(6')). ESI-MS: 351 ([M ‡ 1] ).
4. Synthesis of N-[3-({4-[(3-Aminopropyl)amino]butyl}amino)propyl]-3-(2-hydroxyphenyl)propanamide
(24). 4.1. From 1 and Spermine (22). 3,3'-Bis[3-(2-hydroxyphenyl)]-N,N'-(4,9-diazadodecane-1,12-diyl)bis-
[propanamide] (23) and 24. To a stirred soln. of spermine (242 mg, 1.2 mmol) in EtOH (150 ml) was added
dropwise the soln. of 1 (177 mg, 1.2 mmol) in EtOH (60 ml), and the stirring was continued for 1 h at r.t. The
solvent was removed, and the residue was purified by CC (SiO2; CH2Cl2/EtOH/25% aq. NH3 soln. 6 :3 :1):
233 mg (39%) of 23 (1st fraction) and 252 mg (60%) of 24 (2nd fraction) were obtained, which were crystallized
as hydrochlorides.
Data of 23: M.p. 198 ± 2008 (EtOH). IR: 3300s (br.), 2940s, 2825m, 1640vs, 1520s, 1450s, 1370m, 1300m,
1230s, 1150w, 1100m, 1015s, 945w, 835w, 650w. 1H-NMR: 7.32 (br., 2 NHCO); 7.06 ± 7.01 (m, 2 H C(4), 2
H
C(6)); 6.82 ± 6.74 (m, 2 H C(3), 2 H C(5)); 3.20 (t, J ˆ 6.0, CH2(5'), CH2(16')); 2.88 (t, J ˆ 6.6, CH2(1'),
CH2(20')); 2.76 (t, J ˆ 7.0, CH2(7'), CH2(14')); 2.54 (t, J ˆ 6.7, CH2(2'), CH2(19')); 2.52 ± 2.49 (m, CH2(9'),
CH2(12')); 1.57 (quint., J ˆ 6.4, CH2(6'), CH2(15')); 1.52 ± 1.51 (m, CH2(10'), CH2(11')). 13C-NMR: 174.1 (s,
C(3'), C(18')); 154.8, (s, 2 C(2)); 130.3 (d, 2 C(4)); 127.5 (d, 2 C(6)); 127.4 (s, 2 C(1)); 119.7 (d, 2 C(5)); 116.2 (d, 2
C(3)); 48.7 (t, C(9'), C(12')); 46.5 (t, C(7'), C(14')); 37.6 (t, C(5'), C(16')); 36.7 (t, C(2')); 27.9 (t, C(1'), C(20'));
‡
26.9 (t, C(6'), C(15')); 25.7 (t, C(10'), C(11')). ESI-MS: 499 ([M ‡ 1] ).
Data of 24: M.p. 294 ± 2968 (EtOH). IR (CHCl3): 3300w, 2930s, 2840m, 1640s, 1520m, 1455m, 1370w, 1300w,
1235m, 1110m, 1005w, 940w, 885w, 835w, 655w. 1H-NMR: 7.45 (br., NHCO); 7.08 ± 7.02 (m, H C(4), H C(6));
6.81 ± 6.75 (m, H C(3), H C(5)); 3.22 (t, J ˆ 6.5, CH2(5')); 2.89 (t, J ˆ 7.0, CH2(1')); 2.76 (t, J ˆ 7.0, CH2(16'));
2.66 (t, J ˆ 7.1, CH2(7'), CH2(14')); 2.54 (t, J ˆ 6.7, CH2(2')); 2.52 ± 2.50 (m, CH2(9'), CH2(12')); 1.66 (quint., J ˆ
7.2, CH2(6')); 1.59 (quint., J ˆ 6.5, CH2(15')); 1.54 ± 1.50 (m, CH2(10'), CH2(11')). 13C-NMR: 175.5 (s, C(3'));
154.9 (s, C(2)); 130.5 (d, C(4)); 127.6 (d, C(6)); 127.5 (s, C(1)); 119.9 (d, C(5)); 116.1 (d, C(3)); 53.1 (t, C(9'));
53.0 (t, C(12')); 51.0 (t, C(7')); 50.9 (t, C(14')); 43.6 (t, C(5')); 41.6 (t, C(16')); 40.6 (t, C(2')); 36.0 (t, C(6')); 32.1 (t,
‡
C(15')); 31.0 (t, C(1')); 30.9 (t, C(11')); 29.8 (t, C(10')). ESI-MS: 351 ([M ‡ 1] ). ESI-MS/MS (of m/z 351.3,
‡
‡
20 eV): 351 (39, [M ‡ 1] ), 277 (75), 259 (21), 206 (53, [M 144u] ), 203 (10), 129 (100), 72 (30). ESI-MS/
‡
MS (of m/z 351.3, 25 eV): 277 (19), 259 (11), 206 (100, [M 144u] ), 129 (67), 112 (63).
3-(2-Acetoxyphenyl)-N-{3-[(acetyl)(4-{(acetyl)[3-(acetylamino)propyl]amino}butyl)amino]propyl}propan-
amide (25). Analogously to the preparation of 7, from 24 ´ 3 HCl (6 mg), AcONa (50 mg) in Ac2O (5 ml),
‡
‡
5.6 mg (90%) of 25 were obtained after workup. ESI-MS: 499 (15 [M ‡ Na] ), 477 (100, [M ‡ 1] ), 371 (20),

814
Helvetica Chimica Acta ± Vol. 84 (2001)
329 (17), 312 (5). ESI-MS/MS (of 477.3, fragmentation amplification (FA) 1.0 V): 459 (12), 417 (9), 329 (100),
312 (10), 287 (3), 213 (4), 171 (4). ESI-MS/MS/MS (of m/z 477.3/329.3, FA 1.0 V): 329 (30), 312 (45), 287 (27),
269 (17), 230 (62), 213 (60), 171 (100), 114 (14), 100 (70). ESI-MS/MS/MS (of m/z 477.3/417.1, FA 1.0 V): 399
(11), 319 (11), 269 (25), 213 (12), 206 (100), 171 (43).
5. Synthesis of N-{4-[(3-Aminopropyl)amino]butyl}-N-(3-aminopropyl)-3-(2-hydroxyphenyl)propan-
amide (27). 5.1. From 1 and Dibenzyl N,N'-[4-(Benzyloxycarbonyl)-4,9-diazadodecane-1,12-diyl]bis[carbamate]
(4). N-(3-{[(Benzyloxy)carbonyl]amino}propyl)-N-{4-[(3-{[(benzyloxy)carbonyl]amino}propyl)amino]bu-
tyl}- 3-(2-hydroxyphenyl)propanamide (26). A mixture of 4 (605 mg, 1 mmol) and 1 (148 mg, 1 mmol) in
toluene (20 ml) was stirred under reflux for 7 d. After cooling to r.t., the solvent was removed in vacuo, and the
residue was purified by CC (SiO2; CHCl3/MeOH 49 :1) to give 250 mg (33%) of 26. Slightly yellow oil. IR:
1
3440m, 2940m, 1710vs, 1610s, 1505s, 1440s, 1365m, 1235s, 1135m, 1080m, 1010m, 905w, 840w, 690w. H-NMR:
9.05 (br. s, OH); 7.35 ± 7.30 (m, 15 arom. H); 7.10 ± 7.00 (m, H C(4), H C(6)); 6.88 ± 6.80 (m, H C(3),
H
C(5)); 5.58 (br., 2 NHCO); 5.08 (s, 3 PhCH2); 3.36 ± 3.33 (m, CH2(3''), CH2(12')); 3.26 ± 3.13 (m, CH2(1''),
CH2(5')); 3.04 ± 3.02 (m, CH2(8'), CH2(10')); 2.90 (t, J ˆ 6.5, CH2(1')); 2.60 (br., CH2(2')); 1.70 ± 1.68 (m,
CH2(2''), CH2(11')); 1.66 ± 1.42 (m, CH2(6'), CH2(7')). 13C-NMR: 174.0 (s, C(3')); 156.4 (s, 3 CO); 154.9 (s,
C(2)); 136.6 (s, 3 arom. C); 130.4 (d, C(4)); 128.4 (s, C(1)); 128.3 (d, C(6)); 128.1, 127.9, 127.7 (3d, 15 arom. C),
120.0 (d, C(5)); 117.5 (d, C(3)); 67.3, 66.4 (2t, 3 PhCH2)); 47.3 (t, C(8')); 46.3 (t, C(10')); 46.1 (t, C(3'')); 43.9 (t,
C(12')); 42.9 (t, C(1'')); 37.7 (t, C(5')); 34.4 (t, C(2')); 27.6 (t, C(2'')); 25.6 (t, C(1')); 25.2 (t, C(11')); 24.9 (t, C(7'));
‡
24.6 (t, C(6')). ESI-MS: 775 ([M ‡ Na] ).
Compound 27. A suspension of 10% Pd/C (120 mg) and 26 (245 mg, 0.31 mmol) in AcOH (110 ml) was
hydrogenated overnight in a Parr apparatus at 3.5 bar H2 pressure. The catalyst was filtered off, the filtrate was
evaporated, and the residue was purified by CC (SiO2; CH2Cl2/EtOH/25% aq. NH3 soln. 5 :3 :1): 110 mg
(100%) of 27, which was crystallized as hydrochloride 27 ´ 3 HCl (colorless foam). IR: 3380w, 2930s, 1610s,
1455m, 1375m, 1305w, 1235m, 1115w, 1095w, 945w, 885w, 840m, 700w, 655w. 1H-NMR (CD3OD): 8.09 (br.,
‡
‡
NH2, 2 NH3); 7.10 ± 7.01 (m, H C(4), H C(6)); 6.83 ± 6.72 (m, H C(3), H C(5)); 3.47 (t, J ˆ 6.6, CH2(3''));
3.36 (t, J ˆ 6.8, CH2(12')); 3.17 ± 3.11 (m, CH2(1''), CH2(5')); 3.06 (t, J ˆ 7.5, CH2(1')); 2.87 (t, J ˆ 7.3, CH2(10'));
2.82 (t, J ˆ 7.3, CH2(8')); 2.72 (t, J ˆ 7.6, CH2(2')); 2.13 (quint., J ˆ 7.5, CH2(2'')); 1.88 (quint., J ˆ 6.8, CH2(11'));
1.73 ± 1.68 (m, CH2(6'), CH2(7')). 13C-NMR (CD3OD): 176.4 (s, C(3')); 156.4 (s, C(2)); 131.3 (d, C(4)); 128.7 (d,
C(6)); 128.1 (s, C(1)); 120.6 (d, C(5)), 116.1 (d, C(3)); 48.6 (t, (C(8')); 46.1 (t, C(10')); 45.8 (t, C(3'')); 43.5 (t,
C(12')); 38.1 (t, C(1'')); 37.8 (t, C(5')); 33.9 (t, C(2')); 28.1 (t, C(1'')); 27.8 (t, C(1')); 26.8 (t, C(11')); 25.2 (t, C(7'));
‡
24.4 (t, C(6')). ESI-MS: 351 (15, [M ‡ 1] ), 206 (58), 129 (90), 112 (100). ESI-MS/MS (of m/z 351.3, 20 eV):
‡
‡
351 (100, [M ‡ 1] ), 331 (10), 277 (19), 206 (33, [M 144u] ), 203 (44), 129 (100), 72 (40). ESI-MS/MS (of m/z
‡
‡
351.3, 25 eV): 351 (10, [M ‡ 1] ), 277 (<10), 206 (59, [M 144] ), 203 (11), 129 (92), 112 (100).
5.2. From 2 and 4. N-(3-{[Benzyloxy)carbonyl]amino}propyl)-N-{4-[(3-{[(benzyloxy)carbonyl]amino}-
propyl)amino]butyl}-3-[2-(benzyloxy)phenyl]propanamide (29). To a mixture of 1-methyl-2-chloropyridinium
iodide (460 mg, 1.8 mmol), Et3N (363 mg, 3.6 mmol), and 2 (384 mg, 1.5 mmol) in CH2Cl2 (25 ml) was added a
soln. of 4 (907 mg, 1.5 mmol) in CH2Cl2 (10 ml). The mixture was stirred overnight at r.t., and the solvent was
evaporated. The residue was dissolved in CHCl3 (80 ml), washed with 0.3n aq. HCl soln., and dried (Na2SO4).
Evaporation of the solvent and chromatography of the residue (SiO2; CHCl3/MeOH 49 :1) furnished 1.22 g
(94%) 29. Colorless oil. IR: 3440w, 2930w, 1700s, 1630s, 1510s, 1450m, 1370w, 1300m, 1215s, 1130m, 1110m,
1075m, 1020m, 910w, 855w, 620w. 1H-NMR: 7.41 ± 7.27 (m, 20 arom. H); 7.19 ± 7.14 (m, H C(4), H C(6));
6.90 ± 6.85 (m, H C(3), H C(5)); 5.82, 5.58 (2 br. s, 2 NHCO); 5.26 (s, PhCH2); 5.06, 5.04, 5.03 (3s, 3 PhCH2);
3.29 ± 3.21 (m, CH2(1''), CH2(5')); 3.10 ± 3.02 (m, CH2(3''), CH2(12')); 3.01 ± 2.99 (m, CH2(8'), CH2(10')); 2.96 (t,
J ˆ 8.1, CH2(1')); 2.55 ± 2.50 (m, CH2(2')); 1.62 (quint., J ˆ 6.5, CH2(2''), CH2(11')); 1.57 ± 1.44 (m, CH2(6'),
CH2(7')). 13C-NMR: 173.1 (s, C(3')); 156.5, 156.4 (2s, 3 CO); 137.1 (s, C(2)); 136.8 (s, 3 arom. C); 130.4 (d, C(4));
128.5 (d, C(6)); 127.8 (s, C(1)); 128.4, 128.1, 127.5 (3d, 20 arom. C); 120.9 (d, C(5)); 111.6 (d, C(3)); 69.8 (t,
PhCH2)); 67.1, 66.3 (2t, 3 PhCH2)); 47.0 (t, C(8')); 46.2 (t, C(10')); 45.0 (t, C(3'')); 43.9 (t, C(12')); 41.9 (t, C(1''));
37.4 (t, C(5')); 33.2 (t, C(2')); 29.3 (t, C(2'')); 27.6 (t, C(1')); 27.2 (t, C(11')); 25.5 (t, C(7')); 24.9 (t, C(6')). ESI-MS:
‡
865 ([M ‡ Na] ).
Compound 27. Analogously to the preparation of 6, from 29 (930 mg, 1.1 mmol) and 10% Pd/C (500 mg) in
conc. AcOH (110 ml), 340 mg (90%) of 27 were obtained after workup. Compound 27 was found to be identical
1
(TLC, IR, H-NMR, 13C-NMR, and MS analysis) with the compound described under 5.1.
3-(2-Acetoxyphenyl)-N-[3-(acetylamino)propyl]-N-(4-{[3-(acetylamino)propyl]amino}butyl)propanamide
(28). Analogously to the preparation of 7, from 27 ´ HCl (5 mg), AcONa (50 mg) in Ac2O (5 ml), 4 mg (77%) of
‡
‡
28 were obtained after workup. ESI-MS: 499 (3, [M ‡ Na] ), 477 (100, [M ‡ 1] ), 371 (3), 329 (15). ESI-MS/
MS (of 477.3, FA 1.0 V): 459 (7), 417 (17), 329 (100), 312 (6); 311 (9), 213 (5), 171 (9). ESI-MS/MS/MS (of m/z

Helvetica Chimica Acta ± Vol. 84 (2001)
815
477.3/329.3, FA 1.0 V): 329 (25), 312 (48), 287 (33), 269 (13), 230 (58), 213 (85), 171 (100), 114 (14), 100 (78).
ESI-MS/MS/MS (of m/z 477.3/329.3, FA 1.0 V): 329 (25), 312 (48), 311 (15), 287 (33), 269 (13), 230 (58), 213
(85), 171 (100), 114 (14), 100 (78). ESI-MS/MS/MS (of m/z 477.3/417.3, FA 1.0 V): 269 (26), 220 (43), 213 (26),
171 (100).
6. Synthesis of N-(12-Amino-5,9-diazadodecyl)-3-(2-hydroxyphenyl)propanamide (32). N-{4-[2-(Cya-
noethyl)-1,2,3,4,5,6-hexahydropyrimidin-1-yl]butyl}-3-(2-hydroxyphenyl)propanamide (30). To a soln. of 15
(715 mg, 2.34 mmol) in MeOH (30 ml) was added dropwise acrylonitrile (161 mg, 3 mmol) in MeOH (5 ml),
and the mixture was stirred overnight at r.t. Removal of the solvent in vacuo and chromatography of the residue
(SiO2; CHCl3/MeOH/25% aq. NH3 soln. 90 :10 :1) gave 837mg (100%) of 30. Colorless oil. IR: 2940m, 2800w,
1640vs, 1520m, 1485m, 1415m, 1365w, 1220s, 1105m, 1035w, 970w, 925w, 800m, 655m, 620w. 1H-NMR: 7.11 ± 7.03
(m, H C(4), H C(6)); 6.90 ± 6.77 (m, H C(3), H C(5)); 6.73 (br., NHCO); 3.22 (t, J ˆ 6.2, CH2(5')); 3.17 (s,
CH2(14')); 2.90 (t, J ˆ 6.2, CH2(1')); 2.70 (t, J ˆ 7.2, CH2(15')); 2.59 (t, J ˆ 6.2, CH2(8')); 2.57 (t, J ˆ 6.3, CH2(2'));
2.46 (t, J ˆ 6.6, CH2(10'), CH2(12')); 2.32 (t, J ˆ 6.7, CH2(16')); 1.67 (quint., J ˆ 5.5, CH2(11')); 1.51 ± 1.42 (m,
CH2(6'), CH2(7')). 13C-NMR: 174.0 (s, C(3')); 155.0 (s, C(2)); 130.4 (d, C(4)); 128.0 (s, C(1)); 127.7 (d, C(6));
120.0 (d, C(5)); 118.7 (s, CN); 117.4 (d, C(3)); 75.1 (t, C(14')); 54.0 (t, C(8')); 52.0 (t, C(15')); 51.8 (t, C(12')); 50.2
(t, C(10')); 39.4 (t, C(5')); 37.0 (t, C(2')); 27.0 (t, C(1')); 24.7 (t, C(11')); 24.2 (t, C(7')); 22.9 (t, C(6')); 16.5 (t,
‡
C(16')). ESI-MS: 359 (100, [M ‡ 1] ), 263 (18).
1-[2-(4-Aminobutyl)-1,2,3,4,5,6-hexahydropyrimidin-1-yl]-3-(2-hydroxyphenyl)propan-1-one (35), N-(12-
Amino-5-methyl-5,9-diazadodecyl)-3-(2-hydroxyphenyl)propanamide (34), and N-(12-Amino-5,9-diazadodec-
yl)-3-(2-hydroxyphenyl)propanamide (32). A suspension of Raney-Ni (200 mg) and 30 (830 mg, 2.23 mmol) in
EtOH (90 ml) and 25% aq. NH3 soln. (25 ml) was hydrogenated overnight in a Parr apparatus at 3.5 bar H2
pressure. The mixture was filtered, and the filtrate was evaporated. Purification of the residue by CC (SiO2;
CHCl3/EtOH/25% aq. NH3 soln. 6 :3 :1) yielded 310 mg (36%, 1st fraction) of 31, 140 mg (16% 2nd fraction) of
34, and 170 mg (20%, 3rd fraction) of 32, which was crystallized as its hydrochloride 32 ´ 3 HCl.
Data of 31: IR: 2930s, 1640s, 1520m, 1485m, 1450m, 1370m, 1305w, 1220m, 1100m, 1035m, 975w, 925w,
875w, 800w, 655m, 620w. 1H-NMR: 7.22 (br., NHCO); 7.06 ± 7.01 (m, H C(4), H C(6)); 6.88 ± 6.74 (m,
H
C(3), H C(5)); 3.38, 3.04 (2s, CH2(14')); 3.19 ± 3.17 (m, CH2(5')); 2.89 (t, J ˆ 6.7, CH2(1')); 2.77 (t, J ˆ 5.8,
CH2(17')); 2.55 (t, J ˆ 6.8, CH2(2')); 2.38 (t, J ˆ 7.0, CH2(10'), CH2(12')); 2.30 ± 2.26 (m, CH2(8'), CH2(14')); 1.64
(quint., J ˆ 6.4, CH2(11'), CH2(16')); 1.55 ± 1.38 (m, CH2(6'), CH2(7')). 13C-NMR: 173.6 (s, C(3')); 155.1 (s,
C(2)); 130.3 (d, C(4)); 128.0 (s, C(1)); 127.4 (d, C(6)); 119.6 (d, (C(5)); 116.4 (d, C(3)); 75.8 (t, C(14')); 54.3 (t,
C(8')); 53.0 (t, C(15')); 52.4 (t, C(12')); 52.2 (t, C(10')); 40.4 (t, C(5')); 39.2 (t, C(17')); 36.9 (t, C(2')); 29.3 (t,
‡
C(16')); 28.8 (t, C(1')); 25.7 (t, C(11')); 24.2 (t, C(7')); 23.6 (t, C(6')). ESI-MS: 385 (16, [M ‡ Na] ), 363 (100,
‡
[M ‡ 1] ).
Data of 34: 1H-NMR: 7.38 (br., NHCO); 7.06 ± 7.00 (m, H C(4), H C(6)); 6.79 ± 6.72 (m, H C(3),
H
C(5)); 3.20 ± 3.16 (m, CH2(5')); 2.88 (t, J ˆ 7.1, CH2(1')); 2.78 (t, J ˆ 6.7, CH2(16')); 2.73 ± 2.67 (m, CH2(8'),
CH2(10')); 2.53 (t, J ˆ 7.0, CH2(2')); 2.37 (t, J ˆ 5.0, CH2(12'), CH2(14')); 2.19, 2.17 (2s, Me); 1.67 (quint., J ˆ 6.1,
CH2(11'), CH2(15')); 1.59 ± 1.45 (m, CH2(6'), CH2(7')). 13C-NMR: 173.5 (s, C(3')); 155.2 (s, C(2)); 130.2 (d,
C(4)); 127.9 (s, C(1)); 127.3 (d, C(6)); 119.4 (d, (C(5)); 116.2 (d, C(3)); 56.1 (t, C(10') or C(8')); 55.5 (t, C(12') or
C(14')); 48.8 (t, C(8') or C(10')); 48.2 (t, C(14') or C(12')); 41.9 (q, Me); 40.2 (t, C(5')); 39.2 (t, C(16')); 36.9 (t,
‡
C(2')); 31.6 (t, C(11')); 29.5 (t, C(15')); 26.7 (t, C(1')); 26.0 (t, C(7')); 24.5 (t, (6')). ESI-MS: 365 (100, [M ‡ 1] ),
183 (17, [M ‡ 2]2‡).
Data of 32: M.p. 243 ± 2458 (EtOH). IR (KBr): 3290s, 2943vs, 2772vs, 2505m, 1633s, 1548m, 1489m, 1455s,
1406m, 1357w, 1247m, 1169w, 1102w, 1044w, 1006w, 720m. 1H-NMR (D2O): 7.11 ± 7.05 (m, H C(4), H C(6));
6.89 ± 6.80 (m, H C(3), H C(5)); 3.13 ± 3.10 (m, CH2(5')); 3.09 ± 3.06 (m, CH2(8')); 3.03 (t, J ˆ 7.0, CH2(10'),
CH2(12'), CH2(14')); 2.91 (t, J ˆ 7.2, CH2(16')); 2.80 (t, J ˆ 7.1, CH2(1')); 2.44 (t, J ˆ 7.0, CH2(2')); 2.08 (quint., J ˆ
5.6, CH2(11')); 2.03 (quint., J ˆ 5.6, CH2(15')); 1.48 ± 1.30 (m, CH2(6'), CH2(7')). 13C-NMR (D2O): 175.8 (s,
C(3')); 153.5 (s, C(2)); 130.5 (d, C(4)); 127.9 (d, C(6)); 126.8 (s, C(1)); 120.5 (d, (C(5)); 115.4 (d, C(3)); 47.2 (t,
C(10')); 44.6 (t, C(12')); 44.5 (t, C(8')); 44.2 (t, C(14')); 38.3 (t, C(5')); 35.6 (t, C(2')); 26.0 (t, C(1')); 25.3 (t,
‡
C(11')); 23.6 (t, C(15')); 22.6 (t, C(7')); 22.5 (t, C(6')). ESI-MS: 351 (100, [M ‡ 1] ), 176 (65, [M ‡ 2]2‡). ESI-
‡
‡
MS/MS (of m/z 351.4, 24 eV): 351 (100, [M ‡ 1] ), 277 (52), 259 (10), 220 (18, [M 130] ), 203 (46), 129 (10),
‡
115 (64), 112 (34), 98 (28). ESI-MS/MS (of m/z 351.4, 26 eV): 351 (100, [M ‡ 1] ), 277 (58), 259 (20), 220 (39,
‡
[M 130] ), 203 (27), 129 (19), 115 (100), 112 (96), 98 (82), 72 (18).
3-(2-Acetoxyphenyl)-N-(4-{(acetyl)[3-({(acetyl)[3-(acetylamino)propyl]}amino)propyl]amino}butyl)pro-
panamide (33). Analogously to the preparation of 7, from 32 ´ 3 HCl (6 mg), AcONa (50 mg) in Ac2O (5 ml);
‡
‡
5.1 mg (82%) of 33 were obtained after workup. ESI-MS: 515 (3, [M ‡ K] ), 499 (9, [M ‡ Na] ), 477 (100,
‡
[M ‡ 1] ), 371 (10), 329 (10), 287 (4). ESI-MS/MS (of m/z 477.3, FA 1.0 V): 459 (23), 417 (46), 329 (100), 319

816
Helvetica Chimica Acta ± Vol. 84 (2001)
(23), 269 (7), 220 (7), 213 (16), 199 (11), 171 (2). ESI-MS/MS/MS (of m/z 477.3/329.3, FA 1.0 V): 329 (2), 312
(3), 311 (4), 287 (4), 269 (17), 213 (100), 199 (38), 171 (2), 114 (10). ESI-MS/MS/MS (of m/z 477.3/417.3, FA
1.0 V): 399 (5), 376 (2), 319 (85), 318 (100), 270 (5), 269 (5), 220 (44), 202 (14).
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Received November 30, 2000