The syntheses of cyclic spermine alkaloids: Analogues of buchnerine and budmunchiamine C

Article abstract of DOI:10.1002/hlca.200390033

The syntheses of two macrocyclic spermine alkaloids, analogues 1 and 2 of budmunchiamine C and buchnerine, in which N,N′-bis(2-aminoethyl)hexane-1,6-diamine (PA 262; 4) replaces spermine as polyamine backbone, were accomplished by two different methods. The first synthetic approach was based on a metal-template intramolecular amidation of tetraamino esters prepared from a Michael addition of protected PA 262 10 to ethyl hexadec-2-ynoate (12) and ethyl prop-2-ynoate 17. respectively (see Schemes 4 and 5. resp.). The consecutive Michael addition of ethane-1,2-diamine to unsaturated esters and aminolysis was employed in the second synthetic approach to prepare the precursors 23 and 24 (Scheme 6). The macrocyclic lactams were then constructed by macrocyclization of sulfonamido derivatives 25 and 26 in DMF with Cs₂CO₃ as catalyst.

Full text of DOI:10.1002/hlca.200390033

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The Syntheses of Cyclic Spermine Alkaloids: Analogues of Buchnerine
and Budmunchiamine C
by Yi Li1) and Manfred Hesse*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
The syntheses of two macrocyclic spermine alkaloids, analogues 1 and 2 of budmunchiamine C and
buchnerine, in which N,N'-bis(2-aminoethyl)hexane-1,6-diamine (PA 262; 4) replaces spermine as polyamine
backbone, were accomplished by two different methods. The first synthetic approach was based on a metal-
template intramolecular amidation of tetraamino esters prepared from a Michael addition of protected PA 262
10 to ethyl hexadec-2-ynoate (12) and ethyl prop-2-ynoate 17, respectively (see Schemes 4 and 5, resp.). The
consecutive Michael addition of ethane-1,2-diamine to unsaturated esters and aminolysis was employed in the
second synthetic approach to prepare the precursors 23 and 24 (Scheme 6). The macrocyclic lactams were then
constructed by macrocyclization of sulfonamido derivatives 25 and 26 in DMF with Cs2CO3 as catalyst.
1. Introduction. From the leaves of Clerodendrum buchneri GÏrke (Verbena-
ceae), the macrocyclic spermine alkaloid buchnerine was isolated [1], which is
characterized by the presence of a 17-membered macrocyclic lactam ring reflecting
spermine (ˆ N,N'-bis(3-aminopropyl)butane-1,4-diamine) and 4-methoxycinnamoyl
precursor units (Fig. 1). Another class of spermine alkaloids, the budmunchiamine A
C, was isolated as a mixture from the seeds of Albizia amara Bolv. (Leguminosae) [2].
These compounds belong to the class of pithecolobine alkaloids reported by Wiesner
and co-workers [3] and feature the same 17-membered lactam ring as the basic skeleton
and an aliphatic chain at C(4). The budmunchiamines differ from each other only in the
length of their aliphatic chains.
Fig. 1. Structures of budmunchiamine C and buchnerine
The total synthesis of (Æ)-buchnerine was first accomplished by Yamamoto and co-
workers in 1996 [4]. Their synthetic design was based on a strategy in which the linear
tetraamino ester was envisaged as an ideal precursor of the macrocyclic spermine
skeleton. The construction of macrocyclic lactams was efficiently carried out by the
metal-templated cyclization of tetraamino esters. Among several organometallic
1
)
Part of the Ph. D. thesis of Y. L. , Universit‰t Z¸rich, 2002.

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reagents used, antimony(III) ethoxide was found to be the most effective intra-
molecular cyclization catalyst. By the same synthetic procedure, the syntheses of
budmunchiamine A C have recently been completed in our research group [5].
The macrocyclic lactams containing the biogenic base spermine are of particular
interest in view of their broad activity in biological systems. The research on the
budmunchiamine alkaloids established that this class of alkaloids inhibits the catalytic
activity of DNA polymerase, RNA polymerase, and HIV-1 reverse transcriptase [6].
These interesting results prompted us to make further studies in this field. We expected
that the comparison of synthetic analogues with their natural counterparts will be able
to reveal some more insights to the DNA/alkaloid interactions and help to conduct the
study of polyamine alkaloids for pharmacological application in the future.
It was well known that the polyamine backbones of alkaloids play a key role in their
binding to DNA. The binding of polycationic amines to DNA by purely electrostatic
interactions and H-bonding leads to the stabilization of the double and triple helices of
DNA [7], and this stability depends, to a large extent, on the number of N-atoms, the
distance between the N-atoms, and the charges that these molecules can bear at
physiological pH values [8][9].
Based on these findings, model compounds 1 and 2 were chosen as the analogues of
budmunchiamine C and buchnerine, respectively (Fig. 2). Change of the basic skeleton
of natural alkaloids involves the substitution of spermine with N,N'-bis(2-amino-
ethyl)hexane-1,6-diamine (PA 262), which has the same chain length as spermine, but
the amino groups are separated by two and six instead of three and four CH2 groups.
Fig. 2. Structures of isobudmunchiamine C and isobuchnerine
We describe in this paper the syntheses of these two spermine-alkaloid analogues by
two different macrocyclization methods. The synthetic potential of the Yamamoto
procedure in macrolactamization was studied with different tetraamino esters, and its
synthetic advantage was compared with the alkylation of sulfonamide derivatives under
high-dilution conditions.
2. Results and Discussion. The first attempt to synthesize isobudmunchiamine C
(1) is outlined in Scheme 1. The key synthetic step was to construct the tetraamino ester
precursor, i.e., 6, for the employment of the Yamamoto protocol.
When hexane-1,6-diamine was treated with bromoacetonitrile in MeCN in the
presence of KF/Celite, the dinitrile 3 was selectively obtained in good yield. KF/Celite
acted as a weak-base catalyst for the nucleophilic alkylation in aprotic solvent [10]. The
subsequent hydrogenation, which was carried out in the presence of Raney-Ni catalyst

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Scheme 1
a) BrCH2CN, KF/Celite, MeCN, r.t., 2 d; 71%. b) H2, Raney-Ni, 25% NH4OH soln., EtOH, r.t., 20 h; 98%. c) 5,
EtOH, 408, 2 d; 12%. d) Sb(OEt)3, benzene, reflux, 20 h; 60%.
in EtOH at 50 psi, provided N,N'-bis(2-aminoethyl)hexane-1,6-diamine (4; PA 262).
However, Michael addition of this polyamine to ethyl hexadec-2-enoate (5) in EtOH at
408 furnished the tetraamino ester 6 in a disappointing yield of only 12%. The yield
could not be improved even after prolonged reaction time or at elevated temperature.
Although catalysis was suggested to be desirable and necessary for an efficient reaction
[11], neither base nor acid catalysts were found suitable in our case. The subsequent
antimony-templated cyclization was carried out by means of the procedure developed
by Yamamoto and co-workers [4]. Thus, amino ester 6 was refluxed for 22 h in dry
benzene in the presence of antimony(III) ethoxide. The main product was isolated by
chromatography in a yield of 60%. However, the absence of the amide NH signal in the
1H-NMR spectrum (ca. 8.0 ppm) and the typical double carbonyl absorption (1650 and
1515 cmÀ1 in CHCl3) in the IR spectrum of this product suggested the presence of an N-
substituted lactam 7 or 8 rather than a 17-membered macrocyclic lactam. This was
further confirmed by the molecular mass and the positive result of the test with the
¾
Fluram reagent, which clearly showed the presence of a primary amino group in the
cyclization product. Although the 7-membered-ring lactam 7 has strong preference, the
possibility of forming 14-membered-ring lactam 8 could not be precluded since these
two structures have quite similar 1H- and 13C-NMR spectra. The assignment of
structure 7 to the cyclization product was based on a base-catalyzed ring-enlargement
reaction, taking advantage of the different N-substituents of lactams 7 and 8. When the

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Yamamoto-cyclization product was treated with potassium tert-butoxide in boiling
toluene, no reaction occurred. Since it is well established that the −Zip× reaction
proceeds reasonably well when a linear unit with two to four atoms has to be
incorporated into the ring [12], the lactam 8 with a 2-aminoethyl substituent at the
amide N-atom should undergo a ring enlargement smoothly to be transformed into
lactam 16 (precursor of 1) in the presence of strong base (Scheme 2), while this is
impossible in the case of lactam 7.
Scheme 2
A similar procedure had been successfully employed by us [5] in the syntheses of
budmunchiamine A C; the antimony-templated cyclization proceeded smoothly to
give the macrocyclic lactam rings. In those cases, the formation of the 17-membered
ring is favored over the formation of the 8-membered ring. This is reasonable since the
enthalpy effects, especially Pitzer strain and transannular interactions, come into play in
the ring-closure reactions to form medium-sized rings, particularly those with eight to
eleven members.
It became evident that the internal amino groups of the tetraamino ester should be
protected to prevent this macrocyclization from happening. Thus, the protected
polyamine 10 was prepared by catalytic hydrogenation of compound 9, which was
obtained from the reaction of dinitrile 3 with TsCl (Scheme 3). However the
subsequent Michael addition of protected polyamine 10 to ethyl hexadec-2-enoate
(5) proceeded even more sluggishly than that of its unprotected counterpart PA 262
(4). Thus, ethyl hexadec-2-ynoate (12), the more-active unsaturated ester, was
prepared and used to improve the reactivity of the Michael addition of the protected
polyamine. Coupling of the commercially available 1-bromotridecane with lithium
acetylenide/ethane-1,2-diamine complex gave alkyne 11 [13] in high yield. Treatment of
11 with butyllithium and ethyl chloroformate (ˆethyl carbonochloridate) furnished
ethyl hexadec-2-ynoate (12) in 90% yield [14].
The unsaturated amino ester 13, obtained from the Michael addition of 10 to 12 in
56% yield (Scheme 4), was subjected to catalytic hydrogenation over PtO2 in MeOH/

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Scheme 3
a) TsCl, Et3N, CH2Cl2, r.t., 12 h; 90%. b) H2, Raney-Ni, 25% NH4OH soln., EtOH, r.t., 20 h; 95%. c) DMSO,
r.t., 1 h; 91%. d) BuLi, ethyl carbonochloridate THF, 08, 1 h; 85%.
CHCl3 at a pressure of 55 psi to give the tetraamino ester 14 in an excellent yield of
90%.
The mechanism proposed for the antimony-templated cyclization is based on a
rather suitable size of the antimony(III) ion and on the formation of a metal-amino
complex as the intermediate [8]. Since all the tetraamino esters used successfully in the
construction of macrocyclic lactams contain three internal secondary amino groups, the
two tosyl protecting groups at the chain N-atoms of tetraamino ester 14 might decrease
the effectiveness of the antimony coordination and prevent the cyclization sterically.
However, it was gratifying to find that refluxing of 14 in benzene in the presence of
antimony(III) ethoxide resulted in the formation of 17-membered macrolactam 15 in a
moderate yield of 60%. The mild electrolytic detosylation [15] of lactam 15 was carried
out with 0.1m NH4Cl in 95% EtOH as catholyte and anolyte to afford lactam 16 in 80%
yield. Lactam 16 was then treated with 37% aqueous H2CO solution in AcOH at 08, and
the imino derivative obtained was reduced directly by NaCNBH3. Thus, isobudmunchi-
amine C (1) was finally obtained by this modified Eschweiler Clark methylation
reaction [5] in a yield of 88%.
Starting from the prop-2-ynoate 17, the synthesis of buchnerine analogue 2 was
carried out in an analogous approach (Scheme 5). Compound 17 was prepared from 4-
iodoanisole by a Pd-catalyzed cross-coupling reaction according to [4b]. In contrast to
ethyl hexadec-2-ynoate (12), the subsequent Michael addition of 17 with polyamine 10

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315
Scheme 4
a) 10, EtOH, reflux, 2 h; 56%. b) H2, PtO2, EtOH/CHCl3, r.t., 4 h; 90%. c) Sb(OEt)3, benzene, reflux, 22 h;
60%. d) Electrolysis; 80%. e) 1. Formaline (37%), AcOH, 08; 2. NaCNBH3, r.t.; 88%.
proceeded smoothly with an improved yield. The equilibrium of this reaction was
driven in the direction of the product because of the increased stability of compound 18
due to the resonance of the enamino moiety with the phenyl group. Hydrogenation of
the unsaturated amino ester 18, followed by antimony-templated cyclization of
tetraamino ester 19 furnished the macrocyclic lactam 20. Finally, isobuchnerine (2) was
obtained after removal of the tosyl protecting group by the electrolysis procedure.
Although the preparation of analogues of buchnerine and budmunchiamine C by
this route was practical and convenient, the yield was limited by the multiple steps.
Therefore, we decided to explore shorter synthetic routes to these two model
compounds.
Ring closure by N-alkylation of the corresponding N-tosyl derivatives with alkali-
metal carbonates under high-dilution conditions is a general method to construct the
macrocyclic-lactam rings in the synthesis of polyamine alkaloids [16][17] (see Fig. 3).
This procedure was normally carried out in aprotic polar solvent such as DMF with
Cs2CO3 as base to deprotonate the N-tosyl derivatives.
The key step in applying this method to the synthesis of macrocyclic spermine
alkaloids is the formation of the precursor for this cyclization. The problem has been

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Scheme 5
a) 10, EtOH, reflux, 2 h; 65%. b) H2, PtO2, EtOH/CHCl3, r.t., 4 h; 90%. c) Sb(OEt)3, benzene, reflux, 22 h;
67%. d) Electrolysis; 98%.
Fig. 3. Construction of macrocyclic lactam rings by N-alkylation of N-tosyl derivatives under high-dilution
conditions

Helvetica Chimica Acta Vol. 86 (2003)
317
approached by the reaction of 3-phenylprop-2-enoic acid derivatives with primary
amines. The amine would be added at the 3-position, and then a 3-(alkylamino)-3-
phenylpropenamide would be formed by aminolysis. However, it was found that this
potential derivatization could not be carried out experimentally [18]. Recently, a
modified protocol to construct macrocyclic spermine alkaloids was reported by
Guggisberg et al. [19] in their synthesis of protoverbine. The 3-phenylprop-2-enamide
was obtained when a 3-phenylprop-2-enoate was heated with propane-1,3-diamine in
refluxing xylene.
Thus, the application of this method to the syntheses of the analogues of buchnerine
and budmunchiamine C was examined. The methyl esters of the unsaturated acid,
prepared according to the reported procedure for their ethyl counterparts [5], were
used in these studies due to their high reactivity towards amines. When the unsaturated
esters 21 and 22 were heated with neat ethane-1,2-diamine at 708 for 1 d (Scheme 6),
the polyaminoamides 23 and 24 were obtained almost quantitatively by consecutive
Michael addition and aminolysis. After evaporation of the excess amount of ethane-1,2-
diamine, these products of high purity were used directly in the next step without
further purification, because of their strong polarities. The missing hydrocarbon
skeleton fragments between the amino groups of 23 and 24, which contain already all
four N-atoms of the polyamine skeleton, were introduced by a modified Richman
Atkins procedure [20]. The protection/activation by tosylation gave the disubstituted
derivatives 25 and 26, respectively, which were cyclizated with hexane-1,6-diyl
bis[mesylate] in DMF in the presence of Cs2CO3 to give the macrolactams 15 and 20,
respectively.
Scheme 6
a) Ethane-1,2-diamine, 708, 1 d; quant. b) TsCl, Et3N, CH2Cl2, 12 h; 25 (65%); 26 (67%). c) MsO(CH2)6OMs,
Cs2CO3, DMF, 508, 2 d; 15 (40%); 20 (55%).

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Compared with the metal-templated macrolactamization (Schemes 4 and 5), the
procedure of Scheme 6 is much more versatile. The high yield and short route allow to
synthesize similar spermine alkaloids on a large scale.
We thank the analytical units of our institute for spectra and analyses. Financial support of this work by the
Swiss National Science Foundation is gratefully acknowledged.
Experimental Part
General. All reactions involving air-sensitive reagents were performed under Ar. Solvents and reagents
were purchased from Fluka. For hydrogenations, an apparatus of Parr Instruments Company Inc. was used.
TLC: Merck precoated silicon-gel 60F-254 plates. Column chromatography (CC): silica gel 60 (Merck; 230
400 mesh). FC ˆ flash chromatography. M.p.: Mettler FP-5/FP-52; uncorrected. IR Spectra: Perkin-Elmer 297
spectrometer; as film, unless otherwise stated. 1H- and 13C-NMR Spectra: Bruker ARX-300 at 300 and 75 MHz,
resp.; d in ppm. rel. to internal SiMe4, coupling constants J in Hz. MS: chemical ionization (CI) with NH3 as
reactant gas on a Finnigan MAT-90 and electrospray ionization (ESI) on a Finnigan TSQ-700 mass
spectrometer; in m/z (rel. %).
N,N'-(Hexane-1,6-diyl)bis[aminoacetonitrile] (3). To a mixture of hexane-1,6-diamine (1.25 g, 10.7 mmol)
and KF/Celite (13.5 g) in MeCN (250 ml) was added a soln. of bromoacetonitrile (2.70 g, 22.6 mmol) in MeCN
(50 ml) within 1 h. The mixture was stirred at r.t. for 2 d and then filtered. The residue was washed with MeCN.
The combined org. phase was evaporated and the residue was purified by FC (CH2Cl2/MeOH 10 :1): 3 (1.52 g,
71%). Light yellow oil. IR: 3332m, 2930s, 2857s, 2233w, 1473m, 1421w, 1381w, 1330w, 1175w, 1129s, 8 70m, 748w.
1H-NMR: 3.60 (s, 4 H); 2.73 (t, J ˆ 6.8, 4 H); 1.59 1.45 (m, 4 H); 1.43 1.32 (m, 4 H); 1.24 (br. s, 2 H).
‡
13C-NMR: 117.7 (s); 48.6, 37.2, 29.2, 26.7 (4 t). CI-MS: 165 ([M ‡ H] ).
N,N'-Bis(2-aminoethyl)hexane-1,6-diamine (4). To a soln. of 3 (1.0 g, 5.15 mmol) in EtOH (100 ml) and
25% aq. NH3 soln. (28ml) was added Raney-Ni (2.8g). The hydrogenation was carried out at r.t. under 50 psi
for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate evaporated: 4 (1.02 g, 98%).
Colorless oil. IR: 3300s, 2920s, 2860s, 1560m, 1450s, 1400w, 1375w, 1260m, 1120s, 1090m, 1050w, 1010w, 8 70m.
1H-NMR: 2.82 (t, J ˆ 6.0, 4 H); 2.72 2.57 (m, 8H); 1.84 (br. s, 6 H); 1.58 1.43 ( m, 4 H); 1.40 1.28( m, 4 H).
‡
13C-NMR: 52.2, 49.5, 41.4, 29.8, 27.1 (5 t). CI-MS: 203 (100, [M ‡ H] ), 160 (30).
Ethyl 16-Amino-3-tridecyl-4,7,14-triazahexadecanoate (ˆ Ethyl 3-{{2-{{6-[(2-Aminoethyl)amino]hexyl}-
amino}ethyl}amino}hexadecanoate; 6). To a soln. of 4 (2.02 g, 10.0 mmol) in EtOH (100 ml) was added a
soln. of ethyl hexadec-2-enoate (5; 2.82 g, 10.0 mmol) in EtOH (30 ml). The mixture was stirred for 2 d at 408.
Evaporation and purification of the residue by FC (CH2Cl2/MeOH/25% aq. NH4OH soln. 8:2 :1) gave 6 (0.58g,
12%). Colorless oil. IR: 3300s, 2925s, 2854s, 1733s, 1658m, 1559w, 1464s, 1371w, 1303w, 1179w, 1126w, 1036w,
721w. 1H-NMR: 4.13 (q, J ˆ 7.1, 2 H); 2.92 (quint., J ˆ 6.2, 1 H); 2.79 (q, J ˆ 5.7, 2 H); 2.74 2.62 (m, 6 H); 2.61
2.55 (m, 4 H); 2.38( d, J ˆ 6.3, 2 H); 1.55 1.43 (m, 4 H); 1.42 1.29 (m, 10 H); 1.28 1.20 ( m, 26 H); 0.88 (t, J ˆ
6.7, 3 H). 13C-NMR: 172.6 (s); 60.2 (t); 54.7 (d); 52.7, 49.9, 49.8, 46.2, 41.9, 39.6, 34.6, 31.9, 30.2, 29.7, 29.6, 29.6,
‡
29.3, 29.3, 27.4, 25.8, 22.2 (17 t); 14.3, 14.1 (2 q). CI-MS: 485 (100, [M ‡ H] ), 439 (12), 300 (8), 227 (18), 203
(62).
4-{6-[(2-Aminoethyl)amino]hexyl}hexahydro-7-tridecyl-5H-1,4-diazepin-5-one (7). A soln. of 6 (0.100 g,
0.207 mmol) in dry benzene (20 ml) was treated with molecular sieves for 2 h under reflux. After cooling to r.t.,
antimony(III) ethoxide (69 mg, 0.268mmol) was added. The mixture was stirred for 20 h under reflux. The
mixture was cooled to 108, quenched with EtOH, and evaporated. Purification of the residue by FC (CH2Cl2/
MeOH/25% aq. NH4OH soln. 100 :15 :3) afforded 7 (54 mg, 60%). Colorless oil. IR: 3300m, 2920s, 2850s, 1680s,
1475m, 1460s, 1430m, 1120w, 750s, 660m. 1H-NMR: 3.54 (q, 1 H); 3.49 3.40 (m, 2 H); 3.28 3.08 ( m, 2 H);
2.84 2.70 (m, 4 H); 2.38 2.50 ( m, 6 H); 1.58 1.20 ( m, 36 H); 0.88 (t, J ˆ 6.5, 3 H). 13C-NMR: 173.6 (s); 53.7
(d); 52.5, 51.4, 49.6, 48.5, 48.2, 46.2, 41.7, 37.0, 31.7, 29.9, 29.5, 29.5, 29.3, 29.1, 27.8, 26.9, 26.6, 25.7, 22.5 (19 t); 13.9
‡
(q). CI-MS: 439 (100, [M ‡ H] ), 396 (5).
N,N'-(Hexane-1,6-diyl)bis[N-(2-cyanomethyl)-4-methylbenzenesulfonamide] (9). To a soln. of 3 (0.87 g,
4.48mmol) and Et 3N (1.4 ml, 10.1 mmol) in CH2Cl2 (25 ml) was added dropwise a soln. of TsCl (1.75 g,
9.18mmol) in CH 2Cl2 (10 ml). After stirring at r.t. for 12 h, the mixture was diluted with CH2Cl2 (50 ml),
washed with sat. aq. NaHCO3 soln., H2O, and brine, and dried (MgSO4). The residue obtained after evaporation
was purified by recrystallization (MeOH): 9 (2.26 g, 90%). Colorless crystals. M.p. 131 1328. IR (KBr): 2924m,
2875m, 1629m, 1579m, 1495w, 1452m, 1425m, 1347s, 1324m, 1310w, 1277w, 1226w, 1197w, 1160s, 1136m, 1090m,

Helvetica Chimica Acta Vol. 86 (2003)
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1
1067m, 1049w, 98 7w, 936m, 8 78s, 8 50m, 8 17m, 754m, 727s, 664s, 597w, 572m, 542m. H-NMR: 7.72 (d, J ˆ 8.2,
4 H); 7.36 (d, J ˆ 8.2, 4 H); 4.24 (s, 4 H); 3.18( t, J ˆ 7.1, 4 H); 2.44 (s, 6 H); 1.66 1.52 (m, 4 H); 1.42 1.34
(m, 4 H). 13C-NMR: 144.6, 134.3 (2 s); 130.1, 127.5 (2 d); 113.6 (s); 47.2, 35.1, 26.9 (3 t); 21.6 (q). CI-MS: 520 (80,
‡
‡
‡
[M ‡ NH4] ), 364 (56, [M ‡ NH4 À Ts] ), 347 (100, [M À Ts] ).
N,N'-(Hexane-1,6-diyl)bis[N-(2-aminoethyl)-4-methylbenzenesulfonamide] (10). To a soln. of 9 (2.0 g,
3.98mmol) in EtOH (100 ml) was added 25% aq. NH 4OH soln. (28ml). The mixture was hydrogenated at r.t.
under 55 psi for 20 h in the presence of Raney-Ni (1.2 g). The mixture was filtered through a pad of Celite and
evaporated. The residue was purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 100 :6 :1): 10 (1.93 g, 95%).
Glasslike solid. IR (CHCl3): 3300s, 2940s, 2860m, 1670w, 1600m, 1510w, 1490w, 1460m, 1335s, 1305w, 1160s,
1090m, 1020w, 8 15m, 650m. 1H-NMR: 7.67 (d, J ˆ 8.2, 4 H); 7.29 (d, J ˆ 8.2, 4 H); 3.19 3.02 (m, 8H); 2.83
(t, J ˆ 6.4, 4 H); 2.41 (s, 6 H); 1.58 1.45 ( m, 4 H); 1.41 (br. s, 4 H); 1.32 1.29 (m, 4 H). 13C-NMR: 143.2, 136.5
‡
(2 s); 129.7, 127.1 (2 d); 51.8, 49.2, 41.1, 28.7, 26.1 (5 t); 21.4 (q). ESI-MS: 511 ([M ‡ 1] ).
Pentadec-1-yne (11). A mixture of lithium acetylenide/ethane-1,2-diamine (1.75 g, 19.0 mmol) in dried
DMSO (7.5 ml) was cooled to 88. Within 10 min, 1-bromotridecane (3.95 g, 14.96 mmol) was added dropwise
while the temp. was maintained at 88. Then, the mixture was allowed to warm to r.t. and held at r.t. for 1 h.
Subsequently, H2O (3.5 ml) was added carefully to the vigorously stirred soln., maintaining the temp. below 358.
The hydrolyzed mixture was poured into H2O (50 ml), and the resulting mixture was extracted with hexane
(3 Â 100 ml). The combined extract was dried (MgSO4) and evaporated and the residue distilled (808/0.09 Torr):
11 (2.80 g, 91%). IR: 3315m, 2925s, 2854s, 2115w, 1466m, 1377w, 1273w, 1064w, 721w, 626m. 1H-NMR: 2.17
(dt, J ˆ 6.9, 2.6, 2 H); 1.91 (t, J ˆ 2.6, 1 H); 1.59 1.45 (m, 2 H); 1.44 1.32 (m, 2 H); 1.31 1.20 (m, 18H); 0.88
(t, J ˆ 6.7, 3 H). 13C-NMR: 84.5 (s); 67.8( d); 31.8, 29.5, 29.3, 29.2, 28.9, 28.6, 28.3, 22.5, 18.2 (9 t); 13.9 (q).
Ethyl Hexadec-2-ynoate (12). To a soln. of 11 (4.16 g, 20.0 mmol) in THF (40 ml) was added a soln. of 1.6m
BuLi in hexane (16.7 ml, 26.7 mmol) at À 108. After stirring for 30 min, a soln. of ethyl carbonochloridate
(2.39 g, 22.0 mmol) in THF (10 ml) was added at À 108. Then, the mixture was stirred for 1 h at 08, quenched
with sat. aq. NH4Cl soln., and extracted with AcOEt. The combined org. phase was washed with H2O and brine,
dried (MgSO4), and evaporated. The residue was purified by CC (hexane/AcOEt 100 :1): 12 (4.76 g, 85%).
Colorless oil. IR: 2926s, 2855s, 2236m, 1714s, 1466m, 1366w, 1250s, 1074m, 8 64w, 752m. 1H-NMR: 4.20 (q, J ˆ 7.2,
2 H); 2.31 (t, J ˆ 7.1, 2 H); 1.64 1.52 (m, 2 H); 1.46 1.35 (m, 2 H); 1.34 1.18( m, 21 H); 0.88 (t, J ˆ 6.9, 3 H).
13C-NMR: 153.9, 89.4, 73.2 (3 s); 61.7, 31.9, 29.7, 29.6, 29.4, 29.3, 29.0, 28.9, 27.6, 22.7, 18.7 (11 t); 14.1 (q). CI-MS:
‡
235 (100, [M À EtO] ), 168(90), 154 (48), 139 (25).
Ethyl 16-Amino-7,14-bis[(4-methylphenyl)sulfonyl]-3-tridecyl-4,7,14-triazahexadec-2-enoate (ˆ Ethyl 3-{{2-
{{6-{(2-Aminoethyl)[(4-methylphenyl)sulfonyl]amino}hexyl}[(4-methylphenyl)sulfonyl]amino}ethyl}amino}-
hexadec-2-enoate; 13). A soln. of 10 (0.545 g, 1.07 mmol) and 12 (0.390 g, 1.07 mmol) in dry EtOH (30 ml) was
heated under reflux for 2 h. After cooling, the mixture was evaporated, and the residue purified by CC (CH2Cl2/
MeOH/25% aq. NH4OH soln. 97:3.5 :0.3): 13 (0.47 g, 63%). Colorless oil. IR: 3382w, 3285w, 2926s, 2855s, 1651s,
1605s, 1495m, 1464m, 1338s, 1239m, 1159m, 1049m, 954w, 8 15w, 78 6w, 724w. 1H-NMR: 8.58 (br. s, 1 H); 7.70, 7.68
(2 d, J ˆ 8.3, 4 H); 7.31 (d, J ˆ 8.0, 4 H); 4.48 (s, 1 H); 4.06 (q, J ˆ 7.1, 2 H); 3.49 3.39 (m, 2 H); 3.17 3.04
(m, 8H); 2.84 ( t, J ˆ 6.3, 2 H); 2.41 (s, 6 H); 2.18( t, J ˆ 7.3, 2 H); 1.58 1.42 ( m, 6 H); 1.40 1.17 (m, 29 H); 0.89
(t, J ˆ 7.3, 3 H). 13C-NMR: 170.6, 165.4, 143.3, 143.0, 136.4, 135.9 (6 s); 129.6, 129.5, 127.0, 82.2 (4 d); 58.2, 51.7,
49.8, 49.1, 49.0, 42.5, 41.0, 32.0, 31.7, 29.4, 29.3, 29.2, 29.1, 28.7, 28.5, 28.0, 26.0, 25.9 (18 t); 21.3, 14.4, 13.9 (3 q).
‡
ESI-MS: 563 (47, [M ‡ 1] ), 511 (100).
Ethyl 16-Amino-7,14-bis[(4-methylphenyl)sulfonyl]-3-tridecyl-4,7,14-triazahexadecanoate (ˆ Ethyl 3-{{2-
{{6-{(2-Aminoethyl)[(4-methylphenyl)sulfonyl]amino}hexyl}[(4-methylsulfonyl]amino}ethyl}amino}hexadeca-
noate; 14). A mixture of 13 (0.32 g, 0.40 mmol) and PtO2 (50 mg) in CHCl3 (0.8ml) and EtOH (40 ml) was
stirred at r.t. under H2. After 4 h, the mixture was filtered through a pad of Celite, the filtrate evaporated, and the
residual oil purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 95 :5 :0.5): 14 (0.28g, 90%). Colorless oil.
IR: 2926s, 2855s, 1732s, 1653w, 1599m, 1494w, 1465m, 1339s, 1240w, 1159s, 1119w, 1091m, 1036w, 949w, 8 15m,
723m, 654m. 1H-NMR: 7.68( d, J ˆ 8.2, 4 H); 7.34 7.26 (m, 4 H); 4.13 (q, J ˆ 7.1, 2 H); 3.20 3.04 (m, 8H); 2.91
(quint., J ˆ 6.1, 1 H); 2.84 (t, J ˆ 6.4, 2 H); 2.75 (t, J ˆ 6.8, 2 H); 2.41 (s, 6 H); 2.37 2.34 (m, 2 H); 1.58 1.44
(m, 4 H); 1.40 1.28( m, 34 H); 0.88 (t, J ˆ 6.7, 3 H). 13C-NMR: 172.3, 143.1, 142.9, 136.6, 136.4 (5 s); 129.6,
129.5, 127.0 (3 d); 60.1, 54.7, 51.7, 49.1, 48.9, 48.7, 45.5, 41.0, 39.2, 34.4, 31.7, 29.6, 29.5, 29.2, 28.7, 28.5, 26.1, 26.0,
‡
25.6, 22.5 (20 t); 21.3, 14.1, 13.9 (3 q). ESI-MS: 793 ([M ‡ 1] ).
1,11-Bis[(4-methylphenyl)sulfonyl]-7-tridecyl-1,4,8,11-tetraazacycloheptadecan-5-one (15). a) From 14: To
a soln. of 14 (104 mg, 0.131 mmol) in dry benzene (10 ml) was added antimony(III) ethoxide (41 mg,
0.157 mmol). The mixture was heated under reflux for 1 d under Ar. After cooling to 108, the reaction was

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Helvetica Chimica Acta Vol. 86 (2003)
quenched with EtOH. The residue obtained after evaporation was purified by CC (CH2Cl2/MeOH 100 :4): 15
(59 mg, 60%). Colorless oil.
b) From 25: A mixture of 25 (0.5 g, 0.753 mmol) and Cs2CO3 (0.49 g, 1.51 mmol) in dry DMF (100 ml) was
stirred at 608 for 15 min. After cooling to r.t., a soln. of hexane-1,6-diyl bis[methanesulfonate] (0.206 g,
0.753 mmol) in dry DMF (50 ml) was added dropwise. After stirring for 1 d at 408, the mixture was evaporated.
The residue was purified by CC (CH2Cl2/MeOH 40 :1): 15 (0.31 g, 55%). IR: 3384w, 3302w, 2923s, 2854s, 1728w,
1667s, 1598w, 1535m, 1463m, 1338s, 1300w, 1159s, 1090m, 1037w, 98 2w, 913w, 8 75m, 727m, 653m. 1H-NMR: 7.72,
7.65 (2 d, J ˆ 8.5, 4 H); 7.30 (d, J ˆ 8.4, 4 H); 3.52 3.34 (m, 2 H); 3.28 3.17 ( m, 2 H); 3.16 3.07 (m, 4 H);
3.06 2.88 (m, 4 H); 2.84 2.74 (m, 1 H); 2.48 2.14 ( m, 2 H); 2.41 (s, 6 H); 1.59 1.50 (m, 4 H); 1.49 1.34
(m, 4 H); 1.33 1.18( m, 26 H); 0.88 (t, J ˆ 6.5, 3 H). 13C-NMR: 172.4, 143.4, 143.0, 136.1, 135.1 (5 s); 129.6,
129.5, 127.1, 54.9 (4 d); 50.7, 49.5, 45.8, 39.6, 38.8, 34.1, 31.7, 29.5, 29.2, 28.5, 27.8, 25.8, 25.0, 24.8, 22.5 (15 t); 21.3,
‡
13.9 (2 q). ESI-MS: 747 ([M ‡ 1] ).
7-Tridecyl-1,4,8,11-tetraazacycloheptadecan-5-one (16). According to [15]: The electrolysis was carried out
at 58 under Ar with 0.1m NH4Cl in 94% EtOH as catholyte and anolyte. When the reaction was finished, the
cathodic soln. was evaporated. The residue was dissolved in H2O, saturated with K2CO3, and extracted with
CH2Cl2. The combined org. phase was dried (Na2CO3) and evaporated, and the residue purified by CC (CH2Cl2/
MeOH/25% aq. NH4OH soln. 7:3 :1). From 300 mg of 15, 144 mg (80%) of 16 was obtained. Slightly yellow oil.
IR: 3285m, 2924s, 2853s, 1650s, 1551m, 1465m, 1369w, 1133w, 1028w, 965w, 8 09w, 724w. 1H-NMR: 8.32 (m, 1 H);
3.40 (m, 2 H); 3.00 (br. s, 3H); 2.90 2.66 (m, 11 H); 2.45 (dd, J ˆ 2.9, 15.5, 1 H); 2.23 (dd, J ˆ 7.4, 15.5, 1 H);
1.65 1.53 (m, 2 H); 1.53 1.38( m, 6 H); 1.37 1.15 (m, 24 H); 0.88 (t, J ˆ 6.9, 3 H). 13C-NMR: 172.4 (s); 55.2
(d); 49.2, 48.9, 47.8, 45.6, 39.4, 38.4, 33.5, 31.7, 29.5, 29.4, 29.1, 27.9, 27.4, 25.9, 25.1, 24.8, 22.5 (17 t); 13.9 (q). ESI-
‡
MS: 497 (45), 439 (100, [M ‡ 1] ).
Ethyl 3-(4-Methoxyphenyl)prop-2-ynoate (17). To a soln. of ethyl prop-2-ynoate (1.96 g, 20 mmol) in THF
(50 ml) was added 1.6m BuLi in hexane (12.5 ml, 20 mmol) at À 788. After stirring for 30 min at À 788, a soln. of
anh. zinc chloride (8.2 g, 60 mmol) in THF (60 ml) was added. The mixture was allowed to warm to r.t. and
stirred for 1 h. To the ice-cooled soln. were added 4-iodoanisole (2.34 g, 10 mmol) and dichlorobis(triphenyl-
phosphine)palladium(II) (0.35 g, 0.5 mmol). After stirring at 508 for 3 h, the mixture was filtered through a
Celite pad. The filtrate was extracted with Et2O, the combined extract dried (MgSO4) and evaporated, and the
residue purified by CC (hexane/AcOEt 6 :1): 17 (1.40 g, 68%). Colorless oil. IR: 2983w, 2841w, 2206s, 1705s,
1605s, 1567w, 1511s, 1463w, 1390w, 1367m, 1288s, 1253s, 1195s, 1165s, 1110w, 1025m, 947w, 8 3m4 , 748m.
1H-NMR: 7.54 (dd, J ˆ 2.2, 6.7, 2 H); 6.87 (dd, J ˆ 2.1, 6.8, 2 H); 4.29 (q, J ˆ 7.1, 2 H); 3.82 (s, 3 H); 1.35 (t, J ˆ 7.1,
3 H). 13C-NMR (CDCl3): 161.4, 154.2 (2 s); 134.8, 114.2 (2 d); 111.3, 86.7, 80.0 (3 s); 61.7 (t); 55.1, 14.0 (2 q). CI-
‡
‡
MS: 222 (100, [M ‡ NH4] ), 205 (56, [M ‡ 1] ), 176 (20), 150 (17).
Ethyl 16-Amino-7,14-bis[(4-methylphenyl)sulfonyl]-3-(4-methoxyphenyl)-4,7,14-triazahexadec-2-enoate
(ˆ Ethyl 3-{{2-{{6-{(2-Aminoethyl)[(4-methylphenyl)sulfonyl]amino}hexyl}[(4-methylphenyl)sulfonyl]ami-
no}ethyl}amino}-3-(4-methoxyphenyl)prop-2-enoate; 18). A soln. of 17 (1.70 g, 8.33 mmol) and 10 (4.25 g,
8.33 mmol) in EtOH (50 ml) was heated under reflux for 2 h. After cooling, the soln. was evaporated, and the
residue purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 100 :3 :0.3): 18 (3.87 g, 65%). IR (CHCl3):
3300w, 2940s, 2860m, 1645m, 1610s, 1570w, 1510w, 1490w, 1465w, 1340m, 1305w, 1290w, 1250m, 1160s, 1090m,
1030m, 910w, 8 60w, 8 40w, 8 15w. 1H-NMR: 8.47 (br. s, 1 H); 7.68( d, J ˆ 8.2, 2 H); 7.57 (d, J ˆ 8.3, 2 H); 7.33 7.23
(m, 6 H); 6.92 (d, J ˆ 8.8, 2 H); 4.60 (s, 1 H); 4.13 (q, J ˆ 7.1, 2 H); 3.83 (s, 3 H); 3.31 3.20 (m, 2 H); 3.17 2.97
(m, 6 H); 2.96 2.88 (m, 2 H); 2.85 (t, J ˆ 6.4, 2 H); 2.42, 2.40 (2 s, 6 H); 1.90 (br. s, 2 H); 1.58 1.10 ( m, 8 H);
1.26 (t, J ˆ 7.1, 3 H ) . 13C-NMR: 170.3, 164.2, 160.5, 143.3, 136.3 (5 s); 129.7, 129.2 (2 d); 127.9 (s); 127.2, 127.1,
113.9, 86.6 (4 d); 58.8 (t); 55.4 (q); 51.8, 49.4, 49.2, 48.9, 43.6, 41.1, 28.9, 28.4, 26.2, 26.0 (10 t); 21.5, 14.6 (2 q).
‡
ESI-MS: 715 ([M ‡ H] ).
Ethyl 16-Amino-7,14-bis[(4-methylphenyl)sulfonyl]-3-(4-methoxyphenyl)-4,7,14-triazahexadecanoate
(ˆ Ethyl 3-{{2-{{6-{(2-Aminoethyl)[(4-methylphenyl)sulfonyl]amino}hexyl}[(4-methylphenyl)sulfonyl]ami-
no}ethyl}amino}-3-(4-methoxyphenyl)propanoate; 19). A mixture of 18 (2.25 g, 3.15 mmol), PtO2 (90 mg) in
CHCl3 (0.8ml), and EtOH (40 ml) was stirred at r.t. under H 2. After 12 h, the mixture was filtered through a
pad of Celite, the filtrate evaporated, and the residual oil purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln.
100 :6 :0.6): 19 (2.02 g, 90%). Slightly yellow oil. IR: 3379w, 2936s, 2864m, 1730s, 1599w, 1611w, 1513m, 1494w,
1463m, 1337s, 1305w, 1248m, 1158s, 1110w, 1091m, 1034m, 952w, 8 16w, 753m. 1H-NMR: 7.69, 7.63 (2 d, J ˆ 8.3,
4 H); 7.33 7.16 (m, 6 H); 6.83 (d, J ˆ 8.2, 2 H); 4.10 (t, J ˆ 7.1, 2 H); 3.98( m, 1 H); 3.17 2.95 (m, 8H); 2.85
(t, J ˆ 6.4, 2 H); 2.67 2.47 (m, 4 H); 2.41, 2.40 (2 s, 6 H); 1.55 (br. s, 3 H); 1.54 1.33 (m, 4 H); 1.23 1.12
(m, 4 H); 1.20 (t, J ˆ 7.2, 3 H). 13C-NMR: 171.5, 158.8, 143.1, 142.9, 136.6, 136.4 (6 s); 129.6, 129.4, 128.0, 127.0,

Helvetica Chimica Acta Vol. 86 (2003)
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113.8(5 d); 60.3 (t); 58.7 (d); 55.1 (q); 51.6, 49.1, 48.6, 48.2, 45.7, 42.9, 41.0, 28.7, 28.4, 26.1, 26.0 (11 t); 21.3, 14.0
‡
(2 q). ESI-MS: 717 (100, [M ‡ 1] ), 515 (25).
7-(4-Methoxyphenyl)-1,11-bis[(4-methylphenyl)sulfonyl]-1,4,8,11-tetraazacycloheptadecan-5-one (20).
a) From 19: A mixture of 19 (0.200 g, 0.279 mmol) and antimony(III) ethoxide (80 mg, 0.307 mmol) in dry
benzene (20 ml) was refluxed under Ar for 22 h. After cooling to 108, the reaction was quenched with EtOH.
The residue obtained after evaporation was purified by CC (CH2Cl2/MeOH 100 :3): 20 (125 mg, 67%).
Colorless oil.
b) From 26: A mixture of 26 (1.0 g, 1.70 mmol) and Cs2CO3 (1.16 g, 3.57 mmol) in dry DMF (150 ml) was
stirred at 608 for 15 min. After cooling to r.t., a soln. of hexane-1,6-diyl bis[methanesulfonate] (0.466 g,
1.70 mmol) in dry DMF (50 ml) was added dropwise. The mixture was stirred for 1 d at 408 and then evaporated.
The residue was purified by CC (CH2Cl2/MeOH 50 :1): 20 (0.69 g, 61%). IR: 3308w, 2933m, 2862m, 1674s,
1512m, 1461m, 1387m, 1336s, 1249m, 1160s, 1091s, 1033w, 98 4w, 919w, 8 17w, 727w. 1H-NMR: 7.67, 7.63 (2 d, J ˆ
8.5, 4 H); 7.37 7.15 (m, 8H); 6.85 ( d, J ˆ 8.6, 2 H); 4.10 4.02 (m, 1 H); 3.80 (s, 3 H); 3.63 3.48( m, 2 H);
3.44 3.30 (m, 2 H); 3.27 2.92 (m, 6 H); 2.68 2.59 ( m, 2 H); 2.57 2.48( m, 2 H); 2.42, 2.40 (2 s, 6 H); 1.90 (br.
s, 1 H); 1.75 1.55 (m, 4 H); 1.53 1.34 (m, 4 H). 13C-NMR: 171.7, 158.7, 143.5, 142.9, 136.0, 135.1 (6 s); 129.7,
129.5, 127.7, 127.2, 127.1, 58.9 (6 d); 55.1 (q); 50.9 (t); 49.8( t); 49.7, 49.2, 46.5, 44.2, 39.0, 28.8, 28.2, 25.3 (10 t); 21.3
‡
(q). ESI-MS: 671 ([M ‡ 1] ).
(2-Methoxy-2-oxoethyl)triphenylphosphonium Bromide. A suspension of Ph3P (22 g, 84 mmol) and methyl
bromoacetate (12.8 g, 84 mmol) in toluene (200 ml) was heated for 2 h at 808 and stirred overnight at r.t. The
white precipitate was filtered, washed with toluene, and dried under h.v. to give (2-methoxy-2-oxoethyl)-
triphenylphosphonium bromide (33.0 g, 95%). M.p. 160 1618. IR (KBr): 3007w, 2802m, 1723s, 1587w, 1485w,
1
1440m, 1423m, 1385w, 1320s, 1201s, 1161w, 1110s, 996w, 8 90w, 8 77m, 8 00w, 748w, 727w, 68 8m. H-NMR: 7.95
7.63 (m, 15 H); 5.58( d, J ˆ 13.6, 2 H); 3.59 (s, 3 H). 13C-NMR: 165.0 (s); 135.0, 133.9, 133.8, 130.3, 130.1 (5 d);
118.3, 117.2 (2 s); 53.3 (q); 33.3, 32.5 (2 t).
Methyl Hexadec-2-enoate (21). To a soln. of MeONa (prepared from Na (0.725 g, 31.5 mmol)) in MeOH
(150 ml), (2-methoxy-2-oxoethyl)triphenylphosphonium bromide (13.07 g, 31.5 mmol) was added in small
portions at 108. After stirring for 1 h at r.t., a soln. of myristaldehyde (ˆtetradecanal; 6.36 g, 30.0 mmol) in
CH2Cl2 (30 ml) was added dropwise. The resulting soln. was stirred overnight at r.t. and then evaporated. The
residue was filtered through a short column of silica gel with Et2O to give 21 (6.5 g, 80%) as a (E)/(Z)-mixture
(1.6 :1). A sample of this mixture was separated by CC (hexane/Et2O 50 :1) for analyses. IR: 2925s, 2854s, 1729s,
1
1659m, 1466m, 1436m, 1311w, 1269m, 1196m, 1174m, 1127w, 1043w, 98 1w, 8 19w, 720w. H-NMR: (Z)-isomer:
6.21 (dt, J ˆ 11.5, 7.5, 1 H); 5.75 (dt, J ˆ 11.5, 1.7, 1 H); 3.70 (s, 3 H); 2.64 (qt, J ˆ 1.7, 7.3, 2 H); 1.50 1.37
(m, 2 H); 1.36 1.22 (m, 20 H); 0.88 (t, J ˆ 6.5, 3 H). 13C-NMR: 166.7 (s); 150.8, 119.0 (2 d); 50.8( q); 31.8, 29.5,
29.3, 29.2, 28.8, 22.5 (6 t); 13.9 (q). (E)-isomer: 6.99 (dt, J ˆ 15.6, 7.0, 1 H); 6.82 (dt, J ˆ 15.6, 1.6, 1 H); 3.72
(s, 3 H); 2.19 (qt, J ˆ 1.6, 7.0, 2 H); 1.50 1.40 (m, 2 H); 1.38 1.22 ( m, 20 H); 0.88 (t, J ˆ 6.5, 3 H). 13C-NMR:
167.0 (s); 149.7, 120.7 (2 d); 51.2 (q); 32.1, 31.8, 29.5, 29.2, 29.0, 27.9, 22.5 (7 t); 13.9 (q). CI-MS: 286 (100, [M ‡
‡
‡
NH4] ), 269 (40, [M ‡ 1] ).
Methyl 3-(4-Methoxyphenyl)prop-2-enoate (22). Through a suspension of 4-methoxycinnamic acid (5.0 g,
28.1 mmol) in MeOH (150 ml) was passed gaseous HCl until it became clear. The soln. obtained was refluxed
for 4 h. After removal of the solvent, the residue was recrystallized from MeOH to give 22 (4.8g, 90%). White
crystals. M.p. 86 878. IR (KBr): 2948m, 2843m, 1716s, 1637s, 1603s, 1574m, 1513s, 1433m, 1331m, 1303m, 1288s,
1256s, 1206s, 1175s, 1111m, 1026m, 1012m, 98 4m, 962w, 933w, 8 39s, 8 23s, 768m, 633w. 1H-NMR: 7.65 (d, J ˆ 16,
1 H); 7.48( d, J ˆ 8.6, 2 H); 6.90 (d, J ˆ 8.8, 2 H); 6.29 (d, J ˆ 16, 1 H); 3.83, 3.78 (2 s, 6 H). 13C-NMR: 167.7, 161.4
(2 s); 144.5, 129.7 (2 d); 127.2 (s); 115.3, 114.3 (2 d); 55.4, 51.5 (2 q).
N-(2-Aminoethyl)-3-[(2-aminoethyl)amino]hexadecanamide (23). A soln. of 21 (2.0 g, 7.46 mmol) in
ethane-1,2-diamine (20 ml) was stirred for 1 d at 708. After cooling, the excess amount of ethane-1,2-diamine
was evaporated: 23 (2.70 g, quant.). Light yellow oil. IR: 3291m, 2923s, 2853s, 1652s, 1552m, 1467m, 1344w,
1108w, 952w. 1H-NMR: 8.21 (br. s, H); 3.33 3.25 (m, 2 H); 2.93 2.85 (m, 1 H); 2.84 2.79 (m, 4 H); 2.72 2.59
(m, 2 H); 2.40, 2.20 (2 q, 2 H); 1.40 (br. s, 5 H); 1.34 1.18( m, 24 H); 0.88 (t, J ˆ 6.5, 3 H). 13C-NMR: 172.3 (s);
‡
54.8( d); 48.7, 41.9, 41.8, 41.5, 39.5, 34.0, 31.7, 29.5, 29.2, 25.7, 22.5 (11 t); 13.9 (q). CI-MS: 357 ([M ‡ 1] ).
N-(2-Aminoethyl)-3-[(2-aminoethyl)amino]-3-(4-methoxyphenyl)propanamide (24). A soln. of 22 (2.0 g,
10.4 mmol) in ethane-1,2-diamine (30 ml) was stirred for 1 d at 708. After cooling, the excess amount of ethane-
1,2-diamine was evaporated: 24 (3.0 g, quant.). Light yellow oil. IR: 3268s, 2934s, 2846s, 1649s, 1610m, 1552m,
1512s, 1461m, 1356w, 1303w, 1248s, 1178m, 1112w, 1032m, 952w, 8 33m, 732w. 1H-NMR: 7.60 (m, 1 H); 7.21, 6.86
(2 d, J ˆ 8.7, 4 H); 3.97 (m, 1 H); 3.77 (s, 3 H); 3.38 3.17 ( m, 2 H); 2.87 2.71 (m, 4 H); 2.55 2.40 (m, 4 H);

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2.47 (s, 5 H). 13C-NMR: 172.1, 158.9, 134.9 (3 s); 127.8, 114.0, 58.9 (3 d); 55.1 (q); 48.3, 44.5, 41.4, 40.9 (4 t). ESI-
‡
MS: 281 ([M ‡ 1] ).
N-{2-{[(4-Methylphenyl)sulfonyl]amino}ethyl}-3-{{2-{[(4-methylphenyl)sulfonyl]amino}ethyl}amino}hexa-
decanamide (25). To a soln. of 23 (1.91 g, 5.36 mmol) in CH2Cl2 (30 ml) containing Et3N (5.41 g, 53.6 mmol)
was added slowly a soln. of TsCl (2.04 g, 10.7 mmol) in CH2Cl2 (20 ml) at 08. After stirring at r.t. for 12 h, the
mixture was diluted with CH2Cl2 (50 ml), washed with H2O and brine, and dried (Na2SO4). The residue
obtained after removal of the solvent was purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 96 :3.5 :0.3): 25
(2.31 g, 65%). Light yellow oil. IR: 3284m, 2925s, 2854s, 1651s, 1596w, 1549m, 1495w, 1455m, 1327s, 1160s, 1093s,
949w, 8 74m, 661m. 1H-NMR: 8.23 (br. s, 1 H); 7.70, 7.66 (2 d, J ˆ 8.3, 4 H); 7.21 (d, J ˆ 8.7, 4 H); 3.40 3.21
(m, 2 H); 3.15 2.89 (m, 4 H); 2.82 2.68 (m, 2 H); 2.67 2.50 (m, 1 H); 1.28 1.05 ( m, 24 H); 0.80 (t, J ˆ 6.4,
3 H). 13C-NMR: 172.9, 143.3, 143.2, 136.9 (4 s); 129.6, 126.9, 126.8, 54.5 (4 d); 45.0, 43.0, 39.6, 38.4, 33.9, 31.8,
‡
29.5, 29.2, 25.6, 22.5 (10 t); 21.3, 13.9 (2 q). CI-MS: 665 (100, [M ‡ 1] ), 571 (20), 493 (10), 429 (30).
3-(4-Methoxyphenyl)-N-{2-{[(4-methylphenyl)sulfonyl]amino}ethyl}-3-{{2-{[(4-methylphenyl)sulfonyl]-
amino}ethyl}amino}propanamide (26). To a soln. of 24 (3.10 g, 11.06 mmol) in CH2Cl2 (50 ml) containing Et3N
(11.18g, 0.111 mol), a soln. of TsCl (4.22 g, 22.14 mmol) in CH 2Cl2 (20 ml) was slowly added at 08. After stirring
at r.t. for 12 h, the mixture was diluted with CH2Cl2 (100 ml), washed with H2O and brine, dried (Na2SO4), and
evaporated. The residue was purified by CC (CH2Cl2/MeOH 95 :4): 26 (4.4 g, 67.5%). Light yellow oil. IR:
3280s, 3010s, 1650s, 1610w, 1510s, 1460w, 1440w, 1420w, 1325m, 1305w, 1250w, 1225m, 1210m, 1150s, 1090s,
1035w, 930w, 790s, 730s, 670s. 1H-NMR: 7.98( m, 1 H); 7.80 7.70 (m, 4 H); 7.30 7.20 (m, 4 H); 7.08( d, J ˆ 8.6,
2 H); 6.78( d, J ˆ 8.7, 2 H); 6.10 (br. s, 2 H); 3.94 3.83 (m, 1 H); 3.74 (s, 3 H); 3.47 3.28( m, 2 H); 3.16 3.03
(m, 2 H); 3.02 2.80 (m, 2 H); 2.60 2.44 (m, 3 H); 2.43 2.30 (m, 2 H); 3.38( s, 6 H). 13C-NMR: 172.5, 158.8,
143.4, 143.3, 136.9, 134.4 (6 s); 129.8, 129.7, 127.7, 127.0, 126.9, 114.0, 58.3 (7 d); 55.2 (q); 45.5, 44.0, 42.9, 42.6, 38.9
‡
‡
(5 t); 21.5 (q). CI-MS: 611 (100, [M ‡ Na] ), 589 (100, [M ‡ 1] ), 375 (35).
Hexane-1,6-diyl Bis[methanesulfonate]. To a suspension of hexane-1,6-diol (2.0 g, 16.9 mmol) in THF
(30 ml), Et3N (5.9 ml, 42.4 mmol) and MsCl (2.9 ml, 37.2 mmol) were added at 08. After stirring at r.t. for 2 h,
the mixture was evaporated. The residue was extracted with CH2Cl2, the combined extract washed with H2O,
5% aq. HCl soln., and brine, dried (MgSO4), and evaporated. The crude product was purified by
recrystallization (AcOEt/hexane): 4.3 g (92%). Colorless needle-like crystals. M.p. 58 59 8. IR (KBr): 3033w,
3019w, 2953w, 2923w, 1480w, 1351s, 1228w, 1173s, 1068w, 1024w, 98 7s, 954s, 8 51s, 750m. 1H-NMR: 4.23 (t, J ˆ 6.4,
4 H); 3.00 (s, 6 H); 1.83 1.70 (m, 4 H); 1.52 1.42 (m, 4 H). 13C-NMR: 69.6 (t); 37.2 (q); 28.8, 24.8 (2 t). CI-MS:
‡
292 ([M ‡ NH4] ).
1,8,11-Trimethyl-7-tridecyl-1,4,8,11-tetraazacycloheptadecan-5-one (Isobudmunchiamine C; 1). To a soln. of
16 (84 mg, 0.192 mmol) in AcOH (10 ml) was added 37% formaldehyde soln. (3 ml) at 08. After stirring at 08 for
7 min, a soln. of NaCNBH3 (250 mg, 4 mmol) in MeOH (1 ml) was added. The mixture was stirred overnight at
r.t. The reaction was quenched with 2n aq. HCl soln. at 58. The residue obtained after evaporation was dissolved
in sat. aq. K2CO3 soln. and extracted with CH2Cl2, the combined org. phase dried (Na2SO4) and evaporated, and
the residue purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 90 :10 :1): 1 (82 mg, 88%). Slightly yellow oil.
IR: 3306m, 2925s, 2853s, 2789m, 1711w, 1648s, 1538m, 1463m, 1367w, 1279w, 1127w, 1038w. 1H-NMR: 8.28 (br.
s, 1 H); 3.44 3.18( m, 2 H); 2.88 2.76 (m, 1 H); 2.75 2.62 (m, 1 H); 2.59 2.39 (m, 7 H); 2.38 2.32 ( m, 2 H);
2.30 2.18( m, 2 H); 2.29 (s, 6 H); 2.20 (s, 3 H); 1.63 1.37 (m, 8H); 1.36 1.14 ( m, 24 H); 0.88 (t, J ˆ 6.5, 3 H).
13C-NMR: 172.7 (s); 61.3 (d); 56.7, 55.8, 55.4, 49.7 (4 t); 42.7, 41.9 (2 q); 37.2, 36.9 (2 t); 36.5 (q); 31.7, 29.6, 29.5,
‡
29.4, 29.3, 29.1, 28.1, 27.1, 25.9, 25.5, 25.1, 25.0, 22.5 (13 t); 13.9 (q). CI-MS: 481 ([M ‡ 1] ).
7-(4-Methoxyphenyl)-1,4,8,11-tetraazacycloheptadecan-5-one (ˆ Isobuchnerine; 2). As described for 16,
from 20 (320 mg): 170 mg (98%) of 2. Slightly yellow oil. IR: 3290s, 2930s, 2854m, 1650s, 1611w, 1552m, 1512s,
1462s, 1364w, 1303w, 1249s, 1178m, 1130m, 1035m, 923w, 8 32m, 732m. 1H-NMR: 8.02 (m, 1 H); 7.18( d, J ˆ 8.6,
2 H); 6.84 (d, J ˆ 8.6, 2 H); 3.96 (m, 1 H); 3.77 (s, 3 H); 3.45 3.25 (m, 2 H); 2.83 2.74 (m, 2 H); 2.73 2.43
(m, 10 H); 2.35 (br. s, 3 H); 1.66 1.27 (m, 8 H). 13C-NMR (CDCl3): 171.8, 158.6, 134.7 (3 s); 127.5, 117.8, 58.7
‡
(3 d); 55.1 (q); 49.2, 48.8, 48.1, 47.9, 46.3, 44.1, 38.8, 28.8, 28.0, 25.4, 25.2 (11 t). CI-MS: 363 ([M ‡ 1] ).

Helvetica Chimica Acta Vol. 86 (2003)
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Received June 27, 2002