A novel solid-phase reductive alkylation route to acridine and dansyl polyamine conjugates

Article abstract of DOI:10.1039/a904023d

Solid-phase organic synthesis (SPOS) routes to target unsymmetrical polyamines and their acridinyl and dansyl conjugates have been developed based upon borane-pyridine complex (BAP) mediated reductive alkylation, azide reduction with triphenylphosphine, and the use of pent-4-enoyl (Pnt) as an orthogonal amine protecting group.

Full text of DOI:10.1039/a904023d

A novel solid-phase reductive alkylation route to acridine and dansyl
polyamine conjugates
a
b
b
b
b
Simon Carrington, Jacques Renault, Sophie Tomasi, Jean-Charles Corbel, Philippe Uriac and
Ian S. Blagbrough*a
a
Department of Pharmacy and Pharmacology, University of Bath, Bath, UK BA2 7AY. E-mail: prsisb@bath.ac.uk
Pharmacochimie des Molécules de Synthèse et des Produits Naturels, Faculté de Pharmacie, Université de Rennes
b
1, 2 Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France
Received (in Cambridge, UK) 19th May 1999, Accepted 11th June 1999
H
N
Solid-phase organic synthesis (SPOS) routes to target
unsymmetrical polyamines and their acridinyl and dansyl
Acr
H2N
N
H
N
conjugates have been developed based upon borane–pyr-
n
idine complex (BAP) mediated reductive alkylation, azide
reduction with triphenylphosphine, and the use of pent-
H
O
1
n = 0
2 n = 1
4-enoyl (Pnt) as an orthogonal amine protecting group.
Polyamines and especially their unsymmetrical conjugates
display a wide range of important biological activities making
them useful as lead compounds for a wide range of potential
therapies.1 These medicinal chemical applications include
potential anti-parasitic drugs as potent inhibitors of the enzyme
trypanothione reductase2 and cytotoxic compounds such as
acridine–spermine conjugates that display significant sequence
H
R1
H2N
N
H
N
R2
1
= NHCO-9-Acr, R2 = H
= N3, R2 = Dan
= NHDan, R2 = Dan
3
4
5
R
R
R
1
1
3
selectivity on binding to an oligonucleotide. It has recently
been shown that dansylated polyamines are novel glutamate
(
NMDA) receptor antagonists.4 (2)-15-Deoxyspergualin, a
O
O
potent immunosupressor, is a spermidine–guanidine conjugate
for the treatment of corticoresistant acute renal graft rejection.5
The regiocontrolled synthesis of unsymmetrical polyamine
S
9-Acr =
Dan =
conjugates continues to attract the attention of bioorganic and
synthetic chemists,5–8 but these approaches often, of necessity,
N
include a number of steps for orthogonal protecting group
introduction and removal that makes the overall multistep
syntheses certainly time consuming and sometimes low yield-
ing. Furthermore, such solution-phase syntheses are simply not
amenable to the rapid preparation of a wide range of conjugates
for biological evaluation, and therefore attention has been
turned recently to the use of solid-phase organic synthesis
NMe2
3
(NaN , DMSO, 25 ºC, 16 h, 95%), ester saponification to azide
primary alcohol 8 (2 M aq. NaOH, MeOH, 25 ºC, 3 h, 85%), and
then Swern oxidation of this alcohol to the desired aldehyde 9
(50%) (Scheme 1). Azide ketone 10 was prepared from the
3
readily available 5-chloropentan-2-one (NaN , cat. NaI,
(
SPOS) for the preparation of polyamine conjugates with the
DMSO, 50 ºC, 18 h, 90%).14 3-Pent-4-enoylaminopropanal 12
9–13
potential for compound-library design.
At the forefront of
was prepared from the corresponding 3-aminopropan-1-ol by
15
these studies are Bradley and co-workers who have addressed
the synthesis of trypanothione (spermidine containing) libraries
in their elegant studies of SPOS for polyamine amides and
N-acylation with the symmetrical anhydride Pnt
2
O
affording
amide primary alcohol 11 (CH Cl , 0 ºC, 1 h, 72%) which was
2
2
oxidised to the desired amide aldehyde 12 (PDC, CH
2
Cl , 25
2
9
lactams. Independently, Houghten and co-workers have re-
ºC, 3 h, 76%).
cently used SPOS reductive alkylation to prepare diazepine
derivatives and parallel SPOS borane reduction of triamides
afforded large numbers of unsymmetrically substituted di-
ethylenetriamines.10
Wang resin was activated under rigorously anhydrous
conditions with 4-nitrophenyl chloroformate (N-methylmor-
1
pholine, CH
2
Cl
2
, 25 ºC, 19 h) and then reacted with N -tert-
1
2,6
butoxycarbonyl-N -(3-aminopropyl)-1,3-diaminopropane
We have designed a series of unsymmetrical polyamine
conjugates 1–5 as targets to illustrate our proof of concept that
reductive alkylation is a practical approach to such substituted
compounds using SPOS methodologies. The potential of this
reductive alkylation route is in the ability to prepare a range of
linear unsymmetrical polyamines. By design, the amine dis-
tribution along the polymethylene chain can be varied, in a
controlled manner, using the sequence elaborated below.
Acridin-9-ylcarbonyl thermine 1 and thermospermine 2 require
reductive alkylation of an aldehyde with an amine bound to the
resin. The corresponding conjugate 3, with a regiospecific
methyl substituent, requires alkylation of this resin using a
methyl ketone. Azide dansyl conjugate 4 and didansylated 5
will be prepared from the same resin-bound intermediate.13
Azide aldehyde 9 was prepared from 4-bromobutyl acetate 6, by
azide nucleophilic displacement of the halide affording 7
(CH Cl
2
2
, 16 h)16 affording resin 13. That this reaction went to
13
completion was verified by the use of gel-phase C NMR
spectroscopy.17 Reductive alkylation of portions of resin 13
with aldehyde 9, ketone 10 and aldehyde 12 afforded resins
1
8
14–16 respectively (BAP, 3:1 DMF–EtOH, 48 h) (Scheme 2).
Washed and dried samples of resins 14 and 15 displayed
characteristically strong IR bands (by diffuse reflectance) for
–1
the resin-bound azide functional group at 2090 cm . Portions
of these resins 14–16 were Boc protected (excess of Boc O,
CH Cl , 2 3 12 h) on the newly formed secondary amines
2
2
2
affording resins 17–19 respectively. A further portion of resin
15 was N-dansylated (2 equiv. dansyl chloride, 2 equiv. N-
methylmorpholine, CH
was cleaved from the resin (1+1 TFA–CH
afford azide dansyl polyamine 4 as a white solid. The remaining
half was reacted with PPh and water (1 equiv. H O, THF, 2 3
2
Cl
2
, 2 3 18 h) and half of this product
2
Cl , 25 ºC, 2 h) to
2
3
2
Chem. Commun., 1999, 1341–1342
1341

O
i
R1
R2
chromatography over silica gel (eluant 8+5+1 CH Cl –MeOH-
2
2
+
O
conc. aq. NH )† in order to remove traces of triamine starting
3
Br
O
material which had been crosslinked.
1
1
1
2
6
7
8
R
R
R
= Ac, R = Br
= Ac, R = N3
= H, R2 = N3
Here we report a novel reductive alkylation SPOS route to
unsymmetrical polyamines and their conjugates. The feasibility
of preparing unsymmetrical polyamines anchored on Wang
resin as a solid support, and then selective unmasking of amines
to reveal sites for conjugation, will find ready applications.
Furthermore, our SPOS uses of Pnt as an amine protecting
group orthogonal to Boc, and of azide reduction with PPh3
should have wide applicability in combinatorial chemistry
where libraries of amines are constructed.
We thank the Atlantic Arc for Medicinal Chemistry (GP2A),
the ARC (Association pour la Recherche sur le Cancer) and the
Ligue Nationale contre le Cancer for financial support of this
project. We acknowledge S. Sinbandhit and M. Le Roch
(Université de Rennes 1) and A. J. Geall (University of Bath) for
useful discussions and their input into these studies.
ii
2
iii
iv
H
N3
N3
O
9
O
O
v
Cl
10
O
vi
HO
NH2
HO
N
H
11
Notes and references
vii
†
Each acridine conjugate 1–3 was homogeneous by TLC (silica gel, eluant
CH Cl –MeOH–conc. aq. NH
mm Supelcosil ABZ + plus column eluting with 70+30 0.1% aq. TFA–
MeCN, UV detection at 256 nm. Unoptimised yields were typically 5% over
2
2
3
(8+5+1) and reverse-phase HPLC using a 5
H
O
O
N
H
6
steps.
12
1
I. S. Blagbrough, S. Carrington and A. J. Geall, Pharm. Sci., 1997, 3,
Scheme 1 Reagents and conditions: i, ZnBr, reflux; ii, NaN
M aq. NaOH, MeOH; iv, (COCl) , DMSO, Et N, CH Cl
cat. NaI, DMSO, 50 °C; vi, Pnt
3
, DMSO; iii, 2
2
23 and references cited therein.
S. Carrington, A. H. Fairlamb and I. S. Blagbrough, Chem. Commun.,
998, 2335 and references cited therein.
2
3
2
2 3
(Swern); v, NaN ,
2
3
2
O, CH
2
Cl
2
; vii, PDC, CH
2
Cl
2
.
1
I. S. Blagbrough, S. Taylor, M. L. Carpenter, V. Novoselskiy, T.
Shamma and I. S. Haworth, Chem. Commun., 1998, 929 and references
cited therein.
O
O
N
H
N
NH2
4
J. Chao, N. Seiler, J. Renault, K. Kashiwagi, T. Masuko, K. Igarashi and
K. Williams, Mol. Pharmacol., 1997, 51, 861.
Boc
reductive
alkylation
13
5 P. Durand, P. Richard and P. Renaut, J. Org. Chem., 1998, 63, 9723 and
references cited therein.
i
6
M. C. O’Sullivan, Q. Zhou, Z. Li, T. B. Durham, D. Rattendi, S. Lane
and C. J. Bacchi, Bioorg. Med. Chem., 1997, 5, 2145.
O
X
R1
7 S. K. Choi, K. Nakanishi and P. N. R. Usherwood, Tetrahedron, 1993,
9, 5777; D. W. Huang, H. Jiang, K. Nakanishi and P. N. R. Usherwood,
O
N
H
N
N
H
4
Boc
Tetrahedron, 1997, 53, 12391.
8
B. T. Golding, A. Mitchinson, W. Clegg, M. R. J. Elsegood and R. J.
Griffin, J. Chem. Soc., Perkin Trans. 1, 1999, 349.
1
1
1
4 X = CH2CH2, R1 = N3
5 X = CHMeCH2, R1 = N3
6 X = CH2, R1 = NHPnt
ii
9 I. R. Marsh, H. Smith and M. Bradley, Chem. Commun., 1996, 941;
I. R. Marsh, H. K. Smith, C. LeBlanc and M. Bradley, Mol. Diversity,
O
1
997, 2, 165; I. R. Marsh and M. Bradley, Tetrahedron, 1997, 53,
X
17317; P. Page, S. Burrage, L. Baldock and M. Bradley, Bioorg. Med.
Chem. Lett., 1998, 8, 1751.
10 A. Nefzi, C. Dooley, J. M. Ostresh and R. A. Houghten, Bioorg. Med.
Chem. Lett., 1998, 8, 2273; A. Nefzi, J. M. Ostresh and R. A. Houghten,
Tetrahedron, 1999, 55, 335.
O
N
H
N
N
R1
Boc
Boc
1
1 B. W. Bycroft, W. C. Chan, N. D. Hone, S. Millington and I. A. Nash,
J. Am. Chem. Soc., 1994, 116, 7415; I. A. Nash, B. W. Bycroft and W. C.
Chan, Tetrahedron Lett., 1996, 37, 2625.
ii
1
7 X = CH2CH2, R1 = N3
20 X = CH2CH2, R1 = NH2
iii
iv
1
1
1
8 X = CHMeCH2, R = N3
1
21 X = CHMeCH2, R = NH2
9 X = CH2, R1 = NHPnt
1
22 X = CH2, R = NH2
1
2 G. Byk, M. Frederic and D. Scherman, Tetrahedron Lett., 1997, 38,
3
219; G. Byk, C. Dubertret, V. Escriou, M. Frederic, G. Jaslin, R.
Scheme 2 Reagents and conditions: i, aldehyde or ketone, BAP, 3+1 DMF-
EtOH; ii, Boc O, CH Cl ; iii, PPh , H O, THF; iv, I , 1+1 H O–THF.
Rangara, B. Pitard, J. Crouzet, P. Wils, B. Schwartz and D. Scherman,
J. Med. Chem., 1998, 41, 224.
2
2
2
3
2
2
2
1
3 S. Tomasi, M. Le Roch, J. Renault, J.-C. Corbel, P. Uriac, B. Carboni,
D. Moncoq, B. Martin and J.-G. Delcros, Bioorg. Med. Chem. Lett.,
1998, 8, 635.
1
8 h) to convert the azide into a primary amine, which has
5,19
previously been reported only for solution-phase synthesis,
and this newly formed amine was then N-dansylated. Cleavage
from the resin yielded didansylated polyamine 5 as a white solid
in 35% yield over the six steps (resin loading, reductive
alkylation, dansylation, azide reduction, dansylation and resin
14 B. Carboni, M. Vaultier and R. Carrie, Tetrahedron, 1987, 43, 1799.
15 R. Madsen, C. Roberts and B. Fraser-Reid, J. Org. Chem., 1995, 60,
7
920.
6 D. M. Dixit and C. C. Leznoff, J. Chem. Soc., Chem. Commun., 1977,
98.
7 G. C. Look, C. P. Holmes, J. P. Chinn and M. A. Gallop, J. Org. Chem.,
994, 59, 7588.
8 N. M. Kahn, V. Arumugam and S. Balasubramanian, Tetrahedron Lett.,
996, 37, 4819; E. E. Swayze, Tetrahedron Lett., 1997, 38, 8465 and
8643.
1
1
1
7
cleavage). Resins 17 and 18 were similarly reacted with PPh
to afford resin-bound primary amines 20 and 21 respectively.
3
1
The Pnt group has been used to protect a variety of substituted
15
amines including amino sugars in solution phase, and
1
nucleotides in SPOS.20 The primary amine protected by a Pnt
group in resin 19 was unmasked by treatment with I
2
and water
19 B. Carboni, A. Benalil and M. Vaultier, J. Org. Chem., 1993, 58,
O–THF, 25 ºC, 18 h) affording resin 22.1
5,20
Resin-
(
1+1 H
2
3736.
2
0 R. P. Iyer, D. Yu, N. H. Ho, T. Devlin and S. Agrawal, J. Org. Chem.,
1995, 60, 8132; I. Habus, J. Xie, R. P. Iyer, W.-Q. Zhou, L. X. Shen and
S. Agrawal, Bioconjugate Chem., 1998, 9, 283.
bound amines 20–22 were acylated using acridine-9-carboxylic
1
acid activated with N -hydroxybenzotriazole (DMF, 2 3 15 h).
The resulting acylated resins were cleaved affording targets 1–3
as their free bases after final purification by flash column
Communication 9/04023D
1342
Chem. Commun., 1999, 1341–1342