Efficient synthesis of iminoctadine, a potent antifungal agent and polyamine oxidase inhibitor (PAO)

Article abstract of DOI:10.1055/s-2007-983898

Iminoctadine (1,17-diguanidino-9-azaheptadecane), isolated from a mixture of polyamines and guanidines known as guazatine that is used in agriculture as a fungicide, showed interesting activity as human antifungal agent and PAO inhibitor. In this paper, w

Full text of DOI:10.1055/s-2007-983898

PAPER
3013
Efficient Synthesis of Iminoctadine, a Potent Antifungal Agent and Polyamine
Oxidase Inhibitor (PAO)
Efficient
S
ynth
r
esis of
I
a
minoctadin
n
e
cesco Raffi, Federico Corelli, Maurizio Botta*
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy
Fax +39(577)234333; E-mail: botta@unisi.it
Received 29 May 2007; revised 29 June 2007
Table 1 Components of Guazatine Acetate3
Abstract: Iminoctadine (1,17-diguanidino-9-azaheptadecane), iso-
lated from a mixture of polyamines and guanidines known as guaza-
tine that is used in agriculture as a fungicide, showed interesting
activity as human antifungal agent and PAO inhibitor. In this paper,
we propose a straightforward synthetic strategy for obtaining pure
iminoctadine tris(trifluoroacetate) in high overall yield.
Component
Proportion
(%)
A
B
C
D
E
F
H2NC(=NH)NH(CH2)8NH2
9.8
30
H2NC(=NH)NH(CH2)8NHC(=NH)NH2
H2NC(=NH)NH(CH2)8NH(CH2)8NH2
H2NC(=NH)NH(CH2)8NH(CH2)8NHC(=NH)NH2
H2NC(=NH)NH(CH2)8N[C(=NH)NH2](CH2)8NH2
Key words: guazatine, antifungal agent, Candida albicans,
polyamine oxidase inhibitor
1.7
5.1
8.1
The opportunistic human pathogen Candida albicans and
other non-albicans species have acquired considerable
clinical significance as infectious agents in immunocom-
promised patients. The pathogenic species of Candida de-
rive their importance not only from the severity of their
infections, but also from their ability to develop resistance
against a variety of antifungal agents. In fact, widespread
and prolonged use of azoles has led to the rapid develop-
ment of multidrug resistance (MDR), which poses a major
hurdle in antifungal therapy.1
H2NC(=NH)NH(CH2)8N[C(=NH)NH2](CH2)8NHC 30
(=NH)NH2
G
H
NH2(CH2)8NH(CH2)8(CH2)8NH2
3.1
H2NC(=NH)NH(CH2)8N[C(=NH)NH2](CH2)8N
[C(=NH)NH2](CH2)8NH2
1.4
I
H2NC(=NH)NH(CH2)8N[C(=NH)NH2](CH2)8N
[C(=NH)NH2](CH2)8NHC(=NH)NH2
5.1
Polyamine oxidase is a FAD-containing enzyme that cat-
alyzes the catabolic conversion of spermine (4,9-diaza-
dodecane-1,12-diamine) into spermidine (4-azaoctane-
1,8-diamine) and putrescine (butane-1,4-diamine), with
the release of 3-aminopropanal and oxygen peroxide.
tal structure of the complex PAO–iminoctadine was de-
scribed in the literature.4a–c
To extend the knowledge of the biological activity of im-
inoctadine, a major quantity of this compound was re-
quired. Originally iminoctadine was prepared by Evans
Medical Ltd. by reaction of 9-azaheptadecane-1,17-di-
amine with S-methylisothiouronium sulfate and it was pu-
rified by low-pressure fraction distillation; this
purification failed in our hands.5 Nowadays a difficult pu-
rification from guazatine is the only way to obtain pure
iminoctadine; moreover, a few milligrams for analysis are
extremely expensive.6
Spermine, spermidine, and putrescine are present in most
living organisms, where they are involved in the growth,
differentiation, and death of normal and cancerous tissues
cells. Using PAO as a target for modulating cell
polyamine concentration it is possible to increase or de-
crease the progression of a tumor.2
Iminoctadine (1,17-diguanidino-9-azaheptadecane, 1)
(Figure 1) is the common name of a component in a mix-
ture of polyamines and guanidines known as guazatine,
which is used in agriculture as a fungicide (Table 1).3
NH
NH
(CH2)8
(CH2)8
H2N
N
In preliminary tests, iminoctadine (1) showed a micro-
molar minimal inhibiting concentration (MIC50) against
some Candida species with potency comparable to that of
fluconazole, making it a promising antifungal agent that is
different from azole compounds.3 In addition it showed a
nanomolar inhibitor activity against polyamine oxidase
(PAO) extracted from maize (Zea mais). Recently, a crys-
N
H
N
NH2
H
H
1
Figure 1 Iminoctadine
In our first synthetic approach, commercial triamine 9-
azaheptadecane-1,17-diamine was reacted with 1,3-
bis(tert-butoxycarbonyl)-2-methylisothiourea as guanidi-
nylating agent.7 Surprisingly we obtained only traces of
the desired compound and small amount of other products
that were difficult to purify.
SYNTHESIS 2007, No. 19, pp 3013–3016
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-983898; Art ID: Z13307SS
© Georg Thieme Verlag Stuttgart · New York

3014
F. Raffi et al.
PAPER
R
R
N
N
(CH2)8
(CH2)8
H2N
N
H
R
(CH2)8
(CH2)8
NH2
R
N
H
N
N
H
a
N
N
H
H
H
2
R = Boc
Scheme 1 Reaction conditions: (a) BocHNC(=NBoc)SMe, THF–MeOH (5:3), 50 °C.
R
R
R
N
N
N
1
R
(CH2)8
(CH2)8
R
Cbz
R
(CH2)8
(CH2)8
R
N
H
N
N
H
N
N
H
N
N
H
N
N
H
H
H
H
H
3
4
N
R = Boc
H
O
Cbz
(CH2)7
+
(H2C)7
R
N
H2N
H
N
H
N
H
6
5
Scheme 2
O
In order to obtain pure iminoctadine we attempted to syn-
thesize 9-azaheptadecane-1,17-diamine (2), no longer
commercially available, by a transamination reaction
starting from octane-1,8-diamine and using 69% nitric
acid with heating to 200 °C. A mixture of linear
polyamines was obtained that was purified by low-pres-
sure fraction distillation, as reported in literature, but this
was demonstrated by us to be very difficult and low-yield-
ing.8a,b
b
c
H2N
H2N
OH
70%
63%
OR
7
7
7 R = H
9
a
100%
8 R = Me
O
d
CbzHN
CbzHN
H
OH
96%
7
7
10
6
We decided to change our strategy for the synthesis of 1
to the step-by-step synthesis shown in Scheme 2. Our new
approach proposes obtaining the final product iminocta-
dine 1 after simple tert-butoxycarbonyl (Boc) deprotec-
tion of 3, which is in turn obtained by guanidinylation of
4 after selective benzyloxycarbonyl (Cbz) deprotection.
The intermediate 4 could be prepared by a reductive ami-
nation of the aldehyde 6 with protected amine 5
(Scheme 2).
Scheme 3 Reaction conditions: (a) AcCl, anhyd MeOH, reflux, 3 h;
(b) LiAlH4, anhyd THF, reflux, 48 h; (c) CbzCl, NaHCO3, THF, H2O,
r.t., 16 h; (d) Dess–Martin periodinane, anhyd CH2Cl2, r.t., 4 h.
O
CbzHN
H
7
NBoc
6
a
RHN
8 N
8 N
NHBoc
+
H
H
H
65%
8-[2,3-Bis(tert-butoxycarbonyl)guanidino]octan-1-amine
(5) was synthesized by reaction of octane-1,8-diamine
with 1,3-bis(tert-butoxycarbonyl)-2-methylisothiourea in
tetrahydrofuran–methanol solution at 50 °C as previously
described.7 8-[(Benzyloxycarbonyl)amino]octanal (6)
was obtained starting from 8-aminooctanoic acid (7) (ca-
prilic acid), which was converted into its methyl ester 8
with acetyl chloride in anhydrous methanol in quantitative
yield.9 Reduction of the amino ester 8 with lithium alumi-
num hydride in anhydrous tetrahydrofuran gave amino al-
cohol 9 in very good yield. The amino group of 9 was
protected using benzyl chloroformate in tetrahydrofuran–
water solution in the presence of sodium hydrogen car-
bonate to give 10.10 Compound 10 was oxidized using
Dess–Martin periodinane affording aldehyde 6 in excel-
lent yield (Scheme 3).11
N
NHBoc
NBoc
4 R = Cbz
11 R = H
H2N
b
7
100%
5
80%
c
NBoc
NBoc
NHBoc
BocHN
N
H
8 N
H
8 N
H
3
100%
d
NH
NH
H2N
N
8 N
H
8 N
H
NH2
H
3 CF3CO2H
1·3 TFA
The reductive amination between intermediates 5 and 6 in
the presence of sodium triacetoxyborohydride was per-
formed in anhydrous 1,2-dichloroethane at room temper-
ature under an argon atmosphere to afford 4 in 65%
yield.12 Hydrogenolysis of 4 with 10% palladium on car-
bon in methanol yielded the corresponding amine 11,13
Scheme 4 Reaction conditions: (a) NaB(OAc)3H, anhyd DCE, r.t.,
overnight; (b) H2, 10% Pd/C, MeOH, r.t., 5 h; (c) (BocHN)2C=NTf,
Et3N, CH2Cl2, r.t., 6 h; (d) 10% TFA–anhyd CH2Cl2, r.t., 24 h.
which was treated with 1,3-bis(tert-butoxycarbonyl)-2-
triflylguanidine as a guanidinylating agent to give protect-
Synthesis 2007, No. 19, 3013–3016 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Iminoctadine
100%) as a white solid; mp 129 °C.
IR (CHCl3): 3459, 2976, 1731, 1438, 1391, 1236, 1046, 877 cm–1
1H NMR (CDCl3): d = 3.66 (s, 3 H), 2.98 (br s, 2 H), 2.30 (t, J = 7
Hz, 2 H), 1.76 (br s, NH2), 1.63–1.58 (m, 2 H), 1.34 (br s, 8 H).
3015
ed iminoctadine 3.14 In the last step 3 was deprotected
with freshly distilled 10% trifluoroacetic acid in anhy-
drous dichloromethane solution to give the desired imi-
noctadine (1) as its tris(trifluoroacetate) salt (Scheme 4).
13C NMR (CDCl3): d = 174.4, 51.7, 40.1, 34.1, 29.0, 28.8, 27.8,
The proposed synthetic approach offers an easy and
straightforward way to obtain highly pure iminoctadine
tris(trifluoroacetate) in 22% overall yield and on a large
scale; this material is required for possible applications as
an antifungal agent and a PAO inhibitor.
26.4, 24.9.
MS (ESI): m/z = 174.2 [M + H]+.
Anal. Calcd for C9H19NO2: C, 62.39; H, 11.05; N, 8.08. Found: C,
62.21; H, 11.25; N, 8.29.
8-Aminooctan-1-ol (9)
Reactions requiring anhydrous conditions were carried out in oven-
dried or flame-dried glassware. For reactions at low temperatures an
acetone–dry ice bath was used. Reagents used were of commercial
grade and, when necessary, were purified prior to use. Solvents used
were distilled prior to use: THF was distilled from Na/benzophe-
none under N2, CH2Cl2 and DCE were distilled from CaH2, MeOH
was dried on Mg turnings in the presence of a small amount of I2.
LiAlH4 (1 g, 26.6 mmol) was added in 2 portions (100 + 900 mg) to
a stirred suspension of 8 (2.3 g, 13.3 mmol) in anhyd THF (150 mL)
in an ice bath. The mixture was heated at reflux for 48 h, cooled to
r.t. and poured onto ice. The aqueous layer was extracted a few
times with CH2Cl2 and the combined organic phases were washed
with brine and dried (Na2SO4). The solvent was evaporated under
reduced pressure to give 9 (1.35 g, 70%) as a white solid; mp 65 °C.
TLC was carried out on plastic precoated silica gel 60 F254 plates
(Merck, layer thickness 0.20 mm) containing the fluorescent indica-
tor UV254. Flash chromatography was performed with Merck silica
gel 60 (40–63 mm, 230–400 mesh).
IR (CHCl3): 3623, 3358, 2931, 1666, 1586, 1463, 1050, 879 cm–1.
1H NMR (CDCl3): d = 3.60 (t, J = 6 Hz, 2 H), 2.60 (t, J = 6 Hz, 2
H), 1.53 (br s, 3 H), 1.46–1.42 (br s, 4 H), 1.21–1.16 (m, 8 H).
13C NMR (CDCl3): d = 63.0, 42.4, 34.0, 33.0, 30.3, 29.6, 27.0, 29.9.
MS (ESI): m/z = 146.2 [M + H]+.
Melting points (uncorrected) were determined on a Gallenkap appa-
ratus. IR spectra were recorded with a Perkin-Elmer Spectrum BX
as a CHCl3 soln in a KBr cell. 1H NMR spectra were obtained with
Bruker AC 200 (200 MHz) and Varian VXR 300 (300 MHz) spec-
trometers; 13C NMR were recorded with Varian VXR 300 (75
MHz); residual CHCl3 (d = 7.24) was used as an internal reference.
Mass spectra were recorded with the Agilent 1100 series MSD sin-
gle-quadrupole instrument, equipped with the orthogonal spray API
(Agilent Technologies, Palo Alto, CA). N2 was used as nebulizer
and drying gas (350 °C). Mass spectra were acquired over the scan
range m/z 100–1500 using a step size of 0.1 u. The nebulizer gas,
the drying gas, the capillary voltage and the vaporizer temperature
were set at 2.75 bar, 9 L/min, 300 V, and 350 °C, respectively. Ele-
mental analyses (C, H, N) were performed in-house using a Perkin-
Elmer 240C elemental analyzer.
Anal. Calcd for C8H19NO: C, 66.16; H, 13.19; N, 9.64. Found: C,
65.92; H, 13.44; N, 9.41.
8-[(Benzyloxycarbonyl)amino]octan-1-ol (10)
A stirred soln of 9 (256 mg, 1.76 mmol) and NaHCO3 (163 mg, 1.94
mmol) in THF–H2O (1:1, 20 mL) was cooled to –5 °C and Cbz-Cl
(277 mL, 1.94 mmol) was added dropwise. The mixture was allowed
to warm to r.t., and after 16 h the mixture was extracted with EtOAc
(3 × 15 mL). The combined organic phases were washed with brine
and dried (Na2SO4). The solvent was evaporated under reduced
pressure, and the residue was purified by flash chromatography (pe-
troleum ether–EtOAc, 1:1) affording 10 (310 mg, 63%) as a white
solid; mp 60 °C.
IR (CHCl3): 3625, 3452, 3068, 2933, 1715, 1515, 1237, 908 cm–1.
8-[2,3-Bis(tert-butoxycarbonyl)guanidino]octan-1-amine (5)
To a stirred soln of octane-1,8-diamine (1.3 g, 9 mmol) in THF–
H2O (5:3, 22 mL) at 50 °C was added dropwise over 1 h a soln of
1H NMR (CDCl3): d = 7.31 (br s, 5 H), 5.08 (s, 2 H), 4.90 (br s, 1
H), 3.57 (t, J = 6.5 Hz, 2 H), 3.16–3.12 (m, 2 H), 2.39 (br s, 1 H),
1.51–1.45 (m, 4 H), 1.29 (br s, 8 H).
13C NMR (CDCl3): d = 156.8, 136.9, 128.7, 128.2, 128.0, 66.7,
62.9, 41.3, 32.9, 30.1, 29.5, 29.4, 26.9, 25.9.
1,3-bis(tert-butoxycarbonyl)-2-methylisothiourea (870 mg,
3
mmol) in THF (16 mL). After 16 h, the mixture was concentrated
under reduced pressure, and the residue was purified by flash chro-
matography (MeOH–Et3N–EtOAc 3:2:95), affording 5 (1.03 g,
89%) as a pale yellow oil.
MS (ESI): m/z = 302.1 [M + Na]+.
IR (CHCl3): 330, 2932, 1719, 1635, 1416, 1369, 1134, 1054, 908
cm–1.
1H NMR (CDCl3): d = 8.24 (br s, NH), 3.34–3.27 (m, 2 H), 2.70 (t,
J = 7 Hz, 2 H), 1.48 (br s, NH2), 1.42 (s, 9 H), 1.41 (s, 9 H), 1.23
(m, 12 H).
13C NMR (CDCl3): d = 163.7, 156.3, 153.4, 83.2, 79.4, 41.0, 40.8,
30.4, 30.1, 29.2, 28.6, 28.3, 28.0, 27.8, 27.5, 27.3, 26.9, 26.7, 26.6.
Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C,
69.01; H, 9.28; N, 4.83.
8-[(Benzyloxycarbonyl)amino]octanal (6)
A stirred suspension of Dess–Martin periodinane (3.41 g, 8.03
mmol) in anhyd CH2Cl2 (5 mL) was cooled on an ice bath, and a
soln of 10 (1.725 g, 6.18 mmol) in anhyd CH2Cl2 (70 mL) was add-
ed dropwise. The mixture was allowed to warm to r.t. and it was
stirred at r.t. until the reaction had gone to completion. The crude
mixture was diluted with pentane (5 mL), filtered, and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography (petroleum ether–EtOAc, 7:30) to give the aldehyde 6
(1.650 g, 96%) as a yellow oil.
MS (ESI): m/z = 387.1 [M + H]+, 409.1 [M + Na]+, 287.1 [M –
100]+, 187.2 [M – 200]+.
Anal. Calcd for C19H38N4O4: C, 59.04; H, 9.91; N, 14.49. Found: C,
59.28; H, 10.14; N, 14.25.
Methyl 8-Aminooctanoate (8)
IR (CHCl3): 3452, 3069, 2934, 1720, 1515, 1456, 1236, 1046, 870
cm–1.
1H NMR (CDCl3): d = 9.58 (s, 1 H), 7.20 (br s, 5 H), 5.16 (br s, 1
H), 4.95 (s, 2 H), 3.08–3.00 (m, 2 H), 2.29–2.16 (m, 2 H), 1.48–1.43
(m, 2 H), 1.35 (br s, 2 H), 1.17 (br s, 6 H).
Freshly distilled AcCl (17.17 mL, 241.5 mmol) was added dropwise
to a stirred suspension of 8-aminooctanoic acid (7, 15.36 g, 96.6
mmol) in anhyd MeOH (86 mL) under N2 at 0 °C. The mixture was
heated at reflux temperature for 3 h, and the solvent and excess
AcCl were evaporated under reduced pressure affording 8 (16.71 g,
Synthesis 2007, No. 19, 3013–3016 © Thieme Stuttgart · New York

3016
F. Raffi et al.
PAPER
13C NMR (CDCl3): d = 202.7, 156.5, 136.6, 128.3, 127.8, 127.6,
MS (ESI): m/z = 756.8 [M + H]+.
66.30, 43.6, 41.3, 29.7, 28.8, 28.6, 28.5, 26.3.
Anal. Calcd for C38H73N7O8: C, 60.37; H, 9.73; N, 12.97. Found: C,
60.19; H, 9.92; N, 12.77.
MS (ESI): m/z = 300.0 [M + Na]+.
Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C,
69.06; H, 8.61; N, 4.81.
1,17-Diguanidino-9-azaheptadecane Tris(trifluoroacetate)
[Iminoctadine Tris(trifluoroacetate, 1·3TFA]
A 10% soln of freshly distilled TFA in anhyd CH2Cl2 (3 mL) was
added to 3 (77 mg, 0.102 mmol) under argon at r.t. The mixture was
stirred at r.t. for 24 h and concentrated under reduced pressure giv-
ing 1 (71.1 mg, 100%) as a brown oil.
IR (CHCl3): 3467, 3355, 2927, 1662, 1408, 1203, 921 cm–1.
1H NMR (CD3OD): d = 3.17 (t, J = 7 Hz, 4 H), 2.96 (t, J = 8 Hz, 4
H), 1.66–1.61 (m, 4 H), 1.59–1.55 (m, 4 H), 1.36 (br s, 16 H).
13C NMR (CDCl3): d = 157.5, 48.7, 41.2, 29.5, 28.8, 28.6, 26.3,
26.2, 26.0.
MS (ESI): m/z = 356.1 [M + H]+.
1-[(Benzyloxycarbonyl)amino]-17-[2,3-bis(tert-butoxycarbon-
yl)guanidino]-9-azaheptadecane (4)
A soln of 5 (810.6 mg, 2.1 mmol) in anhyd DCE (10 mL) was added
dropwise to a stirred soln of aldehyde 6 (582 mg, 2.1 mmol) in an-
hyd DCE (20 mL) at r.t.. The mixture was stirred at r.t. and, after 10
min, NaB(OAc)3H (623 mg, 2.94 mmol) was added and it was
stirred at this temperature overnight. The mixture was concentrated
under reduced pressure, diluted with aq sat. NaHCO3 soln, and ex-
tracted with EtOAc (3 × 10 mL). The combined organic phases
were washed with brine and dried (Na2SO4). The solvent was evap-
orated under reduced pressure, and the residue was purified by flash
chromatography (MeOH–Et3N–EtOAc, 3:2:95), affording amine 4
(886.4 mg, 65%) as a yellow oil.
Anal. Calcd for C24H44F9N7O6: C, 41.32; H, 6.36; N, 14.05. Found:
C, 41.55; H, 6.6; N, 14.28.
IR (CHCl3): 3452, 3329, 2932, 1718, 1635, 1515, 1416, 1134, 1027,
914, 808 cm–1.
Acknowledgment
1H NMR (CDCl3): d = 8.23 (br s, NH), 7.29 (br s, 5 H), 5.04 (s, 2
H), 4.95 (br s, NH), 3.39–3.29 (m, 2 H), 3.17–3.07 (m, 2 H), 2.83–
2.75 (m, 4 H), 1.81–1.77 (m, 4 H), 1.45 (br s, 18 H), 1.27 (br s, 20
H).
13C NMR (CDCl3): d = 163.3, 156.2, 155.8, 153.0, 136.5, 128.2,
128.1, 127.7, 127.5, 127.4, 82.7, 78.9, 66.5, 47.3, 47.1, 40.7, 35.5,
29.6, 29.5, 28.9, 28.8, 28.7, 28.6, 28.0, 27.8, 26.5, 26.4, 25.5, 25.0.
We are grateful to Italian Ministero dell’Istruzione, dell’Università
e della Ricerca (PRIN Anno 2006-prot.2006030948_002). Techni-
cal assistance from Dr. Antonio Vivi director of NMR centre of
Siena University, Dr. Alessandra Zizzari for HPLC analysis. Dr.
Suvi Rajamäki (Ph.D.) is thanked for comments and suggestions for
the manuscript.
MS (ESI): m/z = 648.6 [M + H]+, 670.6 [M + Na]+.
References
Anal. Calcd for C35H61N5O6: C, 64.88; H, 9.49; N, 10.81. Found: C,
65.14; H, 9.68; N, 11.01.
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17-[2,3-Bis(tert-butoxycarbonyl)guanidino]-9-azaheptadecan-
1-amine (11)
A soln of 4 (335 mg, 0.517 mmol) in MeOH (10 mL) and 10% Pd-
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psi) at r.t. for 5 h. The mixture was filtered through Celite and the
solvent was evaporated under reduced pressure affording 11 (265.2
mg, 100%) as a pale yellow oil.
IR (CHCl3): 3331, 2933, 1715, 1634, 1416, 1369, 1134, 910 cm–1.
1H NMR (CDCl3): d = 8.20 (br s, NH), 3.36–3.30 (m, 2 H), 2.72–
2.66 (m, 6 H), 1.41 (br s, 9 H), 1.38 (br s, 9 H), 1.22–1.17 (m, 24 H).
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(7) Carmignani, M.; Volpe, A. R.; Botta, B.; Espinal, R.; De
Bonnevaux, S. C.; De Luca, C.; Botta, M.; Corelli, F.; Tafi,
A.; Sacco, R.; Delle Monache, G. J. Med. Chem. 2001, 44,
2950.
13C NMR (CDCl3): d = 163.8, 156.3, 153.5, 83.2, 79.4, 50.1, 41.2,
34.1, 29.9, 29.6, 29.4, 29.2, 28.6, 28.4, 28.2, 27.5, 27.0.
MS (ESI): m/z = 514.3 [M + H]+.
Anal. Calcd for C27H55N5O4: C, 63.12; H, 10.79; N, 13.63. Found:
C, 63.34; H, 10.99; N, 13.4.
(8) (a) Asada, T.; Miura, Y.; Yoshino, T. EP 0013554, 1980.
(b) Hudson, H. R.; Pianka, M.; Powroznik, L.; Lynch, V. P.
J. Labelled Compd. Radiopharm. 1980, 17, 1980.
(9) Hover, J. A.; Bock, C. W.; Bhat, K. L. Heterocycles 2003,
60, 791.
(10) Zehavi, U.; Sharon, N. J. Org. Chem. 1964, 29, 3654.
(11) Dess, D. D.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
(12) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(13) Dardonville, C.; Rozas, I.; Goya, P.; Giron, R.; Goicoechea,
C.; Martin, M. M. Bioorg. Med. Chem. 2003, 11, 1283.
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Chem. 1998, 63, 3.
1,17-Bis[2,3-bis(tert-butoxycarbonyl)guanidino]-9-azahepta-
decane (3)
Et3N (67 mL, 0.48 mmol) and 1,3-bis(tert-butoxycarbonyl)-2-tri-
flylguanidine (188 mg, 0.48 mmol) were added to a stirred soln of
11 (226 mg, 0.44 mmol) in CH2Cl2 (8 mL), and the mixture was
stirred at r.t. for 6 h. The mixture was concentrated under reduced
pressure and purified by flash chromatography (MeOH–Et3N–
EtOAc, 3:2:95) affording 3 (265.7 mg, 80%) as a yellow oil.
IR (CHCl3): 3330, 2932, 1720, 1635, 1578, 1416, 1369, 1134, 1026,
908 cm–1.
1H NMR (CDCl3): d = 8.24 (br s, NH), 3.39–3.29 (m, 4 H), 2.55 (t,
J = 7 Hz, 4 H), 1.44 (br s, 36 H), 1.25 (br s, 24 H).
13C NMR (CDCl3): d = 163.8, 156.3, 153.5, 83.1, 79.4, 50.0, 41.1,
29.9, 29.5, 29.4, 29.1, 28.5, 28.3, 27.4, 26.9.
Synthesis 2007, No. 19, 3013–3016 © Thieme Stuttgart · New York