An improved total synthesis of spermatinamine, an inhibitor of isoprenylcysteine carboxy methyltransferase

Article abstract of DOI:10.1016/j.tetlet.2010.10.164

An improved total synthesis of spermatinamine, an inhibitor of the anticancer target, isoprenylcysteine carboxy methyltransferase (Icmt) was accomplished from the commercially available 3,4-dibromo-4-hydroxybenzaldehyde via a high yielding reaction sequen

Full text of DOI:10.1016/j.tetlet.2010.10.164

Tetrahedron Letters 52 (2011) 212–214
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Tetrahedron Letters
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An improved total synthesis of spermatinamine, an inhibitor of
isoprenylcysteine carboxy methyltransferase
⇑
Nisar Ullah , Shamsuddeen A. Haladu, Basem A. Mosa
Chemistry Department & Center of Research Excellence in Nanotechnology, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved total synthesis of spermatinamine, an inhibitor of the anticancer target, isoprenylcysteine
carboxy methyltransferase (Icmt) was accomplished from the commercially available 3,4-dibromo-4-
hydroxybenzaldehyde via a high yielding reaction sequence in an overall yield of 31%.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 September 2010
Revised 12 October 2010
Accepted 29 October 2010
Available online 4 November 2010
Keywords:
Spermatinamine
Icmt inhibitor
Anticancer drug
Azlactone formation
Protein farnesyltransferase (FTase) or protein geranylgeranyl-
transferase type I (GGTase-I) mediated protein prenylation, a pro-
cess initiated by covalent attachment of a 15-carbon farnesyl or a
20-carbon geranylgeranyl isoprenoid to a conserved cysteine resi-
due, is critical for the correct localization and function of many key
regulatory proteins in eukaryotic cells.1,2 The so-called CaaX
(C = modified cysteine residue, a = aliphatic residue, and X can be
any of a number of amino acids such as cysteine, serine, methio-
nine, and alanine) motif at the C-terminus of these proteins dictate
the modification of the majority of prenylated proteins. After pre-
nylation of cysteine, removal of the aaX residues by the Ras-con-
verting enzyme 1(Rcel)3,4 generates an exposed carboxyl group
on prenylated cysteine, which is then methylated by isoprenylcys-
teine carboxy methyltransferase (Icmt). These final two processing
steps result in a more hydrophobic protein with a distinctive struc-
ture at the C-terminus and provide a unique determinant of the
protein–protein interaction.5,6
The implication of several CaaX proteins, including members of
the Ras family of GTPases, in oncogenesis and tumor progression
has led to the development of a number of FTase inhibitors (FTIs).7
The lower efficacy than was expected in patients of FTIs, currently
in clinical trials, has been attributed to cross-prenylation whereby,
when FTase is inhibited, GGTase-I can modify the proteins at an
appreciable rate.8,9 Consequently, focus has been directed to target
the post-prenylation enzymes such as Rce1 and Icmt, and inhibi-
tion of the latter, in particular, offers a potential alternative to
FTIs.10
Spermatinamine (1), an inhibitor of Icmt (IC50 = 1.9 lM), is a no-
vel alkaloid with a bromotyrosyl-spermine-bromotyrosyl sequence
and was isolated from the Australian marine sponge, Pseudocerati-
na sp.11,12 Garcia et al. reported the first total synthesis of sperm-
atinamine.13 Their synthetic strategy utilized O-methyl-
L-tyrosine
and spermine as starting materials.
The desired key intermediate, N-4,N-9-dimethylspermine (3),
was synthesized from spermine in three steps (67% overall yield)
after column purification in each step. Column purification of the
final product, spermatinamine, from the polar coupling activating
reagents was difficult and required the use of very polar solvent
mixtures and rendered an overall yield of 15% from O-methyl-L-
tyrosine.
In continuation of our ongoing interest in the total synthesis of
bio-active natural products,14 we disclose an improved total syn-
thesis of spermatinamine (1). We envisioned accomplishing the
synthesis of 1 through a straightforward reaction sequence which
would employ cheap chemicals and improve the overall yield of
the final target compound. The preparation of the key intermediate
3 was accomplished in two steps with an overall yield of 83%, by
the conjugate addition of commercially available N,N0-dimethyl-
1,4-diaminobutane (2) to acrylonitrile to afford the corresponding
Michael adduct, which was hydrogenated at 50 psi, using Ra-Ni as
the catalyst.15 (Scheme 1).
The other segment of the spermatinamine, benzyloxime acid 7,
was prepared as described in Scheme 1. Alkylation of aldehyde 4
with iodomethane in DMF, using K2CO3 as a base afforded alde-
hyde 5 in quantitative yield.16 Heating a mixture of aldehyde 5
and N-acetylglycine to 120 °C in acetic anhydride for 4 h gave
azlactone 617 as a light yellow solid (74%). The hydrolysis of 6 with
⇑
Corresponding author. Tel.: +966 3 8607527; fax: +966 3 8604277.
E-mail address: nullah@kfupm.edu.sa (N. Ullah).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.164

N. Ullah et al. / Tetrahedron Letters 52 (2011) 212–214
213
CN, EtOH
CH3
N
1)
CH3
NH
NH2
H2N
N
HN
CH3
CH3
2) H2, Ra-Ni, EtOH
3
2
O
O
O
H3C
N
CO2H
Br
Br
H
CH3I, DMF, K2CO3
14 h, (quant.)
H
H
HO
H3CO
Ac2O, NaOAc, 120 oC, 4 h
(74%)
Br
Br
4
5
O
O
1) Ba(OH)2, 1,4-dioxane/H2O, 60 oC, 1 h
Br
H3CO
Br
O
OH
N
N
2) BnONH2·HCl, 6 h
(70%)
H3CO
BnO
Br
Br
6
7
Scheme 1.
O
O
Br
H3CO
Br
(COCl)2, DMF (cat.)
OH
Cl
N
N
CH2Cl2, 0 oC, 1 h
(quant.)
H3CO
BnO
BnO
Br
Br
8
7
Br
1) 2,6-lutidine,
CH3
N
THF/DMF, 0 oC
OCH3
Br
OBn
NH2
CH3
N
H2N
N
H
N
N
CH3
2) 8, 0 oC to r.t., 2 h
2
O
(82%)
3
9
Br
OCH3
Br
OH
O
CH3
N
N
H
H2, Pd-black,
Br
N
N
N
H
N
O
CH3
AcOH/1,4-dioxane
(1 atm), 20 h
HO
H3CO
Br
1
(72%)
Scheme 2.
Ba(OH)2 in a mixture of 1,4-dioxane and water at 60 °C gave the
corresponding keto acid, which was condensed in situ with O-ben-
zylhydroxylamine hydrochloride to give E-benzyloxime acid 713,18
in 70% yield.
Having the desired benzyloxime acid 7 and N-4,N-9-dimethyl-
spermine (3) in hand, we next condensed them to generate the
advanced intermediate 9. To this end, acid 7 was transformed into
the corresponding acid chloride 8 using oxalyl chloride in CH2Cl2,
and DMF as a catalyst. After evaporation of the solvents, a solution
of the acid chloride in dry THF was added dropwise to a solution of
amine 3 in a mixture of THF and DMF at 0 °C, using 2,6-lutidine as
the base to produce the desired coupled product 919 in 82% yield
after column purification. Exposure of compound 9 to hydrogena-
tion in a mixture of acetic acid and 1,4-dioxane at 1 atm, using

214
N. Ullah et al. / Tetrahedron Letters 52 (2011) 212–214
Pd-black as the catalyst afforded the target compound 120 in 72%
yield, after column purification. All the spectral data of 1 matched
with those of natural spermatinamine11 (Scheme 2).
15. Albarella, J. P.; Minegar, R. L.; Patterson, W. L.; Dattagupta, N.; Carlson, E.
Nucleic Acids Res. 1989, 17, 4293–4308.
16. Johnson, S. M.; Connelly, S.; Wilson, I. A.; Kelly, J. W. J. Med. Chem. 2008, 51,
6348–6358.
17. Synthesis of azlactone 6: A mixture of aldehyde 5 (2.94 g, 10 mmol), NaOAc
(0.82 g, 10 mmol), and N-acetylglycine (1.17 g, 10 mmol) in Ac2O (20 mL) was
stirred at 120 °C for 4 h. The reaction mixture was cooled to room temperature
and the yellow solid which precipitated was filtered and washed with cold 1:1
pentane/Et2O to yield 6 as a yellow solid (2.78 g, 74%); mp: 154–155 °C; IR
In summary, we have accomplished a facile synthesis of
spermatinamine (1) in an overall yield of 31% from commercially
available 3,4-dibromo-4-hydroxybenzaldehdye.
(neat) (m
max/cmꢀ1) 3233, 2927, 1692, 1662, 1633, 1468, 1416, 1365, 1255,
Acknowledgment
1201, 981, 902, 721. 1H NMR (500 MHz, DMSO-d6): d 2.40 (s, 3H), 3.84 (s, 3H),
7.16 (s, 1H), 8.47 (s, 2H). 13C NMR (125.7 MHz, DMSO-d6): d 15.52, 60.73,
117.90, 125.70, 132.28, 133.88, 135.66, 154.95, 166.88, 168.04. Anal. Calcd for
The research facilities and financial support by KFUPM Grant
No: FT090014 are gratefully acknowledged.
C
12H9Br2NO3: C, 38.43; H, 2.42; N, 3.73. Found: C, 38.40; H, 2.46; N, 3.70.
18. Synthesis of benzyloxime acid 7: A suspension of azlactone 6 (1.5 g, 4 mmol)
and Ba(OH)2 (4.8 g, 28 mmol) in a mixture of 1,4-dioxane/H2O (1:1, 56 mL) was
stirred at 60 °C for 1 h, followed by the addition of O-benzylhydroxylamine
hydrochloride (2.05 g, 12.8 mmol) and the mixture stirred vigorously at the
same temperature for 6 h. The mixture was cooled to 0 °C, acidified to pH 4
with 10% HCl and extracted with EtOAc (50 mL ꢁ 2). The combined organic
extracts were washed with H2O (20 mL), dried over MgSO4, and evaporated
under reduced pressure. The yellow oily material was loaded onto a silica
column eluting with EtOAc/MeOH (10:1) to afford 7 (as a pale-yellow solid,
Supplementary data
Supplementary data (1H, 13C NMR and DEPT spectra of com-
pound 9) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.10.164.
1.28 g, 70%); mp: 115–116 °C; IR (neat) (m
max/cmꢀ1) 3060, 2943, 1692, 1589,
1471, 1416, 1259, 1219, 991, 897, 738, 696. 1H NMR (500 MHz, CDCl3): d 3.80
(s, 2H), 3.83 (s, 3H), 5.30 (s, 2H), 7.40–7.26 (m, 7H). 13C NMR (125.7 MHz,
CDCl3): d 29.13, 78.74, 117.99, 128.56, 128.84, 133.38, 133.59, 135.36, 148.89,
153.03, 163.31. Anal. Calcd for C17H15Br2NO4: C, 44.67; H, 3.31; N, 3.06. Found:
C, 44.64; H, 3.33; N, 3.02.
References and notes
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19. Synthesis of compound 9: To a solution of 7 (0.1 g, 0.22 mmol) in dry CH2Cl2
(5 mL) at 0 °C was added oxalyl chloride (22 lL, 0.26 mmol) dropwise,
followed by one drop of DMF and the reaction mixture stirred for 1 h at 0 °C.
The solvent was evaporated and the acid chloride 8 was kept under high
vacuum for 0.5 h. In another flask, a solution of compound 3 (23 mg, 0.1 mmol)
in a mixture of dry THF (3 mL) and DMF (1 mL) was cooled to 0 °C and to the
mixture was added 2,6-lutidine (64 mg, 0.6 mmol). After being stirred for
10 min, a solution of acid chloride 8 in dry THF (3 mL) was added dropwise.
The mixture was stirred for 2 h at room temperature, diluted with CHCl3
(50 mL) and the organic layer washed with H2O (25 mL), dried over Na2SO4 and
evaporated under vacuum. The resulting pale yellow oil was chromatographed
on silica gel eluting with EtOAc/MeOH/NH4OH (6:4:1) to yield 9 as a thick
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yellow liquid (0.2 g, 82%). IR (neat) (m
max/cmꢀ1) 2941, 2858, 2797, 1664, 1527,
1468, 1420, 1366, 1258, 1203, 996, 906, 726. 1H NMR (500 MHz, CDCl3): d 1.43
(br s, 4H), 1.66 (m, 4H), 2.15 (s, 6H), 2.29 (m, 4H), 2.40 (t, 4H, J = 4.88), 3.37 (q,
4H, J = 6.1), 3.83 (s, 10H), 5.20 (s, 4H), 7.36–7.27 (m, 10H), 7.44 (s, 4H), 7.80 (br
s, 2H). 13C NMR (125.7 MHz, CDCl3): d 24.96, 26.00, 28.72, 39.12, 41.78, 56.25,
57.82, 60.47, 77.33, 117.62, 127.92, 128.24, 128.57, 133.43, 134.94, 136.39,
152.48, 151.52, 161.91. Anal. Calcd for C46H56Br4N6O6: C, 49.84; H, 5.09; N,
7.58. Found: C, 49.80; H, 5.13; N, 7.52.
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