Simple syntheses of cyclic polyamines using selectively N-tritylated polyamines and succinic anhydride

Article abstract of DOI:10.1016/S0040-4039(02)00335-0

Treatment of selectively N-tritylated spermidine and spermine derivatives with succinic anhydride, followed by PyBrOP-mediated intramolecular amide bond formation and LiAlH₄ reduction, allows for an easy and general entry to cyclic polyamine derivatives.

Full text of DOI:10.1016/S0040-4039(02)00335-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2593–2596
Simple syntheses of cyclic polyamines using selectively
N-tritylated polyamines and succinic anhydride
Maria Militsopoulou, Nikolaos Tsiakopoulos, Christos Chochos, George Magoulas and
Dionissios Papaioannou*
Department of Chemistry, University of Patras, GR-265 00 Patras, Greece
Received 6 November 2001; revised 7 February 2002; accepted 12 February 2002
Abstract—Treatment of selectively N-tritylated spermidine and spermine derivatives with succinic anhydride, followed by
PyBrOP-mediated intramolecular amide bond formation and LiAlH4 reduction, allows for an easy and general entry to cyclic
polyamine derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
Linear polyamines (PAs), like spermidine (SPD, 1) and
spermine (SPM, 2) and conjugates (PACs) are widely
distributed in living organisms and are associated with
interesting biological functions. A variety of open-
chain, branched and cyclic PA analogues and PACs
have been synthesized in order to determine structure–
activity relationships and identify lead compounds for
the development of PA-based pharmaceuticals.1 We
have shown that the PA skeleton of N-alkylated PAs
and PACs of the alkaloid kukoamine A (KukA, 3) type
can be assembled simply using the N-hydroxysuccin-
imide (HOSu) or 1-hydroxybenzotriazole (HOBt) active
esters (4 and 5, Fig. 1) of the N-triphenylmethyl (trityl,
Trt)-protected amino acids b-alanine (Ala) and g-
aminobutyric acid (gAba) to acylate suitable amino
components, followed by LiAlH4 reduction of the
amides.2–4 We now wish to report on a simple synthetic
protocol which allows the preparation of cyclic PAs
(CPAs) of variable ring-sizes using selectively N-trityl-
ated SPM and SPD derivatives, such as N1,N12-Trt2-
SPM (6),2a N4-Trt-SPD (7) and N1-Trt-SPD (8)2c and
cyclic anhydrides, such as succinic anhydride, to bridge
intramolecularly the polyamine moieties.
Thus, reaction of the SPM derivative 6 with an equimo-
lar amount of succinic anhydride produced a 55% yield
of the anticipated acid 9 (Scheme 1), which precipitated
out from the solution of the reactants in CH2Cl2. Small
amounts of unreacted 6 and some diacylated derivative
10 remained in the reaction solution. The condensing
agent, bromotripyrrolidinophosphonium hexafluoro-
phosphate (PyBrOP), was then chosen to bring about
the required intramolecular amide bond formation.
Indeed, dropwise addition, over 5 h, of a solution of 9
i
and Pr2NEt in CHCl3 to a solution of PyBrOP, also in
CHCl3, and then stirring at ambient temperature for an
Figure 1. Structures of compounds encountered in this work.
Keywords: spermine; spermidine; cyclic anhydride; cyclic polyamine; trityl group.
* Corresponding author. E-mail: d.a.papaioannou@chemistry.upatras.gr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00335-0

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M. Militsopoulou et al. / Tetrahedron Letters 43 (2002) 2593–2596
Scheme 1. Synthesis of cyclic SPM and KukA analogues. Reagents and conditions: (i) succinic anhydride, CH2Cl2, 0°C, 1 h then
25°C, 1 day, 55%; (ii) PyBrOP/iPr2NEt, CHCl3, 25°C, 2 days, FCC (CHCl3/MeOH=8:2), 57%; (iii) LiAlH4, THF, reflux 5 h, 78%;
(iv) CF3CO2H/CH2Cl2 (1:4), 25°C, 30 min; (v) 15/Et3N, DMF, 0°C, 30 min then 25°C, 24 h, FCC (CHCl3/MeOH/conc. NH3
(9:1:0.1), 47%; (vi) H2 (1 atm)/10% Pd–C, AcOH/MeOH/H2O (5:4:0.2), 25°C, 4 h, then 2N HCl in MeOH, 89%; (vii)
HOSu/N,N%-dicyclohexylcarbodiimide, THF/DMF (3:1), 0°C, 1 h then 25°C, 2 days, 72%.
suitable tosylamides7,8 or amine nucleophiles9 as the
ring-forming reaction.
additional 2 days produced bislactam 11 in 57% yield
following routine purification by flash column chro-
matography.5 Subsequently, the amide functions were
readily reduced with LiAlH4 in refluxing THF to give
the cyclic SPM derivative 12 in 78% yield. The Trt-
groups were then cleaved off with a 20% trifluoroacetic
acid solution in CH2Cl2. The SPM analogue 13 thus
obtained could be readily converted to the novel con-
formationally restricted KukA analogue 16 in 42%
overall yield through double acylation with the isolable
active ester 15 followed by catalytic hydrogenolysis.2b
Ester 15 was readily obtained in 72% yield upon con-
densing acid 142b with HOSu in the presence of N,N%-
dicyclohexylcarbodiimide.6 It should be noted that
syntheses of several cyclic SPD and SPM analogues or
other PAs have been reported using the alkylation of
The suitability of this protocol for the preparation of
other CPAs was tested with the preparation of the SPD
derived heterocycles 21 and 26 (Scheme 2). The prepa-
ration of these CPAs required the availability of the
selectively monotritylated SPD derivatives 7 and 8,
respectively. For the needs of this project, derivative 82c
was obtained in a 40% overall yield by selective
monoacylation of a ten-fold excess of 1,4-diamino-
butane with the active ester 4, followed by LiAlH4
reduction. On the other hand, derivative 7 was readily
obtained in 64% yield through selective bistri-
fluoroacetylation of SPD at the primary amino
functions10 followed by N4-tritylation and alkaline
Scheme 2. Synthesis of cyclic SPDs. Reagents and conditions: (i) CF3CO2Et/H2O, MeCN, reflux, 12 h, 92%; (ii) TrtCl/iPr2NEt,
DMF, 0°C, 30 min then 25°C, 1 h, FCC (PhMe/EtOAc=8:2), 91%; (iii) K2CO3, H2O/MeOH, reflux, 90 min, FCC (CHCl3/
MeOH/conc. NH3=8:2:0.2), 77%; (iv) succinic anhydride, CH2Cl2, 0°C, 1 h then 25°C, 1 day, FCC (CHCl3/MeOH/conc.
NH3=7:3:0.3), 38% (17+18) and 50% (22+23); (v) PyBrOP/iPr2NEt, CHCl3, 25°C, 2 days, 56% (20) and FCC (CHCl3/MeOH=
95:5), 50% (25); (vi) LiAlH4, THF, reflux, 2 days, FCC (CHCl3/MeOH/conc. NH3=8:2:0.2), 44% (21) and 35% (26).

M. Militsopoulou et al. / Tetrahedron Letters 43 (2002) 2593–2596
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Scheme 3. Synthesis of the cyclic octa-amine 31 and hexa-amine 33. Reagents and conditions: (i) Trt-Ala-g-Aba-OSu/iPr2NEt,
DMF, 25°C, 1 day, FCC (EtOAc), 70%; (ii) LiAlH4, THF, reflux, 2–3 days, FCC: (a) (CHCl3/MeOH/conc. NH3=9:1:0.1), 56%
(28) and 23% (29), (b) (CHCl3/MeOH/conc. NH3=9:1:0.1), 70% (31) and (c) (CHCl3/MeOH=9:1), 65% (33); (iii) succinic
anhydride, CHCl3, 0°C, 1 h then 25°C, 1 day, FCC (CHCl3/MeOH/conc. NH3=8:2:0.2), 77% [28] and 68% [29]; (iv)
PyBrOP/iPr2NEt, CHCl3, 25°C, 1–2 days, FCC (CHCl3/MeOH/conc. NH3=8:2:0.2), 70% (30) and 72% (32).
In conclusion, the present methodology provides easy
access to cyclic polyamines of variable ring-sizes using
simple and readily available N-tritylated polyamines
and cyclic anhydrides. Further applications of this pro-
tocol in the synthesis of other medicinally interesting
cyclic polyamine analogues and conjugates are cur-
rently under investigation.
hydrolysis. Treatment of intermediates 7 and 8 with
succinic anhydride produced the expected mixtures of
regioisomers 17, 18 and 22, 23 which were readily
separated in 38 and 50% yields by flash column chro-
matography from unreacted starting materials and
diacylated byproducts 19 and 24, respectively.
Although, separation of these regioisomers (e.g. of 17
and 18) was also possible, the mixtures were used as
such in the next cyclization step. Indeed, PyBrOP-medi-
ated cyclization of these intermediates produced unex-
ceptionally, the corresponding cyclic bisamides 20 and
25 in 56 and 50% yields, respectively. From these
amides, the projected cyclic SPD derivatives 21 and 26
were obtained in 44 and 35% yields, respectively, upon
LiAlH4 reduction.
Acknowledgements
The European Commission and the Greek Ministry of
Education are gratefully acknowledged for financial
support in the form of fellowships (M.M. and N.T.)
and consumables.
This methodology was extended to accommodate even
more complex polyamine molecules, as exemplified by
the preparation of the cyclic octa-amine 31 and hexa-
amine 33 (Scheme 3). Thus, bisacylation of 6 by the
isolable active ester Trt-Ala-gAba-OSu2c produced the
tetra-amide 27 in 70% yield. LiAlH4 reduction of 27
gave a mixture of the expected branched octa-amine 28
(56% yield) and the hexa-amine 29 (23%) together with
6 and the alcohol Trt-NH(CH2)3NH(CH2)4OH. The
last three components were obviously produced
through a LiAlH4-mediated mono- and dideacylation
of 27.11 However, the octa-amine 28 and the hexa-
amine 29 could be separated by flash column chro-
matography and when first treated with succinic
anhydride and then subjected to PyBrOP-mediated
cyclization gave the corresponding bislactams 30 and 32
in 54 and 49% yields. Finally, LiAlH4-mediated reduc-
tion of these produced, unexceptionally, the cyclic octa-
amine (31) and hexa-amine (33) derivatives in 70 and
65% yields, respectively.
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