Solid-Phase Polyamine Synthesis Using Piperazine and Piperidine Building Blocks

Article abstract of DOI:10.1021/ol035610t

(Equation presented) Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using S_N2 alkylation of resin-bound secondary amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this a

Full text of DOI:10.1021/ol035610t

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4183-4185
Solid-Phase Polyamine Synthesis Using
Piperazine and Piperidine Building
Blocks
,†
Christian A. Olsen,† Matthias Witt,‡ Jerzy W. Jaroszewski,† and Henrik Franzyk*
Department of Medicinal Chemistry, The Danish UniVersity of Pharmaceutical
Sciences, UniVersitetsparken 2, DK-2100 Copenhagen, Denmark, and Bruker Daltonik
GmbH, Fahrenheitstrasse 4, D-28359 Bremen, Germany
hf@dfuni.dk
Received August 26, 2003
ABSTRACT
Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using SN2 alkylation of resin-bound secondary
amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this alkylation was investigated. The methodology was employed
for the total synthesis of novel analogues of wasp polyamine toxins (philanthotoxins).
Polyamines constitute an essential part of a large number of
biologically active compounds, e.g., polyamine toxins such
as philanthotoxin-433 [PhTX-433 (1)], an active constituent
of the venom of the Egyptian digger wasp Philanthus
triangulum.1 PhTX-433 is a nonselective inhibitor of iono-
tropic glutamate receptors (iGluRs) and nicotinic acetylcho-
line receptors (nAChRs).2 Because of their therapeutic
potential,3 methods for solid-phase synthesis of philantho-
toxin analogues have attracted considerable interest. Wang
et al. reported total syntheses of polyamine toxins using
borane reduction of a polyamide as the key step.4 A reductive
amination strategy has been reported by Chhabra et al.5 Also,
alkylations under Fukuyama-Mitsunobu conditions6 and
alkylation of resin-bound sulfonamides with alkyl bromides7
have been described. In the present work, simple SN2
alkylation of resin-bound secondary amines with alkyl
sulfonates has been investigated. Previously, N-alkylation
of piperidine and piperazine derivatives with nitrobenzene-
sulfonates was demonstrated to be an efficient solution-phase
method.8 Furthermore, resin-bound sulfonates have been
employed for the synthesis of secondary amines.9
* To whom correspondence should be addressed: Phone: +45-
35306255. Fax: +45-35306040.
† The Danish University of Pharmaceutical Sciences.
‡ Bruker Daltonik GmbH.
(1) (a) Eldefrawi, A. T.; Eldefrawi, M. E.; Konno, K.; Mansour, N. A.;
Nakanishi, K.; Eugene, O.; Usherwood, P. N. R. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 4910-4913. (b) Karigiannis, G.; Papaioannou, D. Eur. J.
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1230.
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10.1021/ol035610t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/10/2003

In previous SAR studies, enhanced biological activity of
philanthotoxin analogues was observed for compounds
having polyamine moieties with added alkyl branching10 or
lacking one of the inner basic sites.11
Bearing these results in mind, we envisaged that com-
pounds 2 and 4 would represent a novel type of philantho-
toxins with conformational rigidity, increased lipophilicity,
and altered proteolytic properties.11,12 Accordingly, we
developed an elongation strategy using SN2 alkylation of
resin-bound secondary amines for the synthesis of 2 and 4.
secondary amine (giving sulfonamides as products). The
solvent mixtures THF/CH2Cl2 and THF/toluene gave com-
parable results, the first affording a slightly higher yield and
the latter less transsulfonation.13 On the basis of these results,
the THF/CH2Cl2 mixture was chosen for the synthesis of 2.
Contrary to model experiments in solution, transsulfonation
appeared to be a much more pronounced side-reaction on
solid phase.14
For the synthesis of the polyamine moiety of 2, building
block 7 and resin 9 were prepared (Scheme 2). The
Scheme 2. Preparation of Building Block 7 and Resin 9
2-(trimethylsilyl)ethoxycarbonyl (Teoc) group was chosen
for N-protection of 2-(4-piperidyl)ethanol due to its con-
venient deprotection with tetrabutylammonium fluoride
(TBAF).15
Treatment of the N-protected amino alcohol with 2-ni-
trobenzenesulfonyl chloride (NsCl) and triethylamine (TEA)
afforded 7 in 74% overall yield. Loading of N-aminoethyl-
N′-Teoc-protected piperazine (8) onto a polystyrene trityl
chloride resin followed by treatment with TBAF afforded
resin 9. Direct loading of an unprotected triamine gave only
75% selectivity in favor of the primary amino group, which
necessitated introduction of the Teoc group prior to resin
derivatization.
Initially, a commercially available trityl resin preloaded
with piperazine was monoalkylated with the O-(2-nitroben-
zenesulfonyl) derivative of 3-phenylpropanol, 5, in selected
solvent mixtures (Scheme 1). The product was cleaved from
Scheme 1. Test Reaction for Assessment of Solvent Effect on
Single Alkylation of Resin-Bound Piperazine
Compound 2 was synthesized by the sequence shown in
Scheme 3. Resin 9 was shaken with 7 (3 equiv) in the
presence of diisopropylethylamine (DIEA) for 16 h at 50
°C, and the Teoc group was removed to afford resin 10. The
amino acid residue (Tyr) was introduced by acylation of 10
with an active pentafluorophenyl (Pfp) ester, Fmoc-Tyr(But)-
OPfp.16 Removal of the Fmoc group with piperidine was
a THF/DMF, THF/CH2Cl2, or THF/PhMe (1:1).
(11) (a) Strømgaard, K.; Brierley, M. J.; Andersen, K.; Sløk, F. A.;
Mellor, I. R.; Usherwood, P. N. R.; Krogsgaard-Larsen, P.; Jaroszewski, J.
W. J. Med. Chem. 1999, 42, 5224-5234. (b) Mellor, I. R.; Brier, T. J.;
Pluteanu, F.; Strømgaard, K.; Saghyan, A.; Eldursi, N.; Brierley, M. J.;
Andersen, K.; Jaroszewski, J. W.; Krogsgaard-Larsen, P.; Usherwood, P.
N. R. Neuropharmacology 2002, 44, 70-80.
the resin with TFA/CH2Cl2 (1:1) and quantitatively analyzed
by 1H NMR (CD3OD) using toluene as an internal standard.
Surprisingly, use of THF/DMF as a solvent gave the lowest
yield and also the highest degree of transsulfonation of the
(12) Jaroszewski, J. W.; Matzen, L.; Frølund, B.; Krogsgaard-Larsen,
P. J. Med. Chem. 1996, 39, 515-521.
1
(9) (a) Virgilio, A. A.; Schu¨rer, S. C.; Ellman, J. A. Tetrahedron Lett.
1996, 37, 6961-6964. (b) Lee, C. E.; Kick, E. K.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 9735-9747. (c) Renault, J.; Lebranchu, M.; Lecat,
A.; Uriac, P. Tetrahedron Lett. 2001, 42, 6655-6658.
(10) (a) Bruce, M.; Bukownik, R.; Eldefrawi, A. T.; Eldefrawi, M. E.;
Goodnow, R.; Kallimopoulos, T.; Konno, K.; Nakanishi, K.; Niwa, M.;
Usherwood, P. N. R. Toxicon 1990, 28, 1333-1346. (b) Olsen, C. A.;
Jørgensen, M. R.; Witt, M.; Mellor, I. R.; Usherwood, P. N. R.; Jaroszewski,
J. W.; Franzyk, H. Eur. J. Org. Chem. 2003, 3288-3299.
(13) From H NMR, the yields of coupling product (6) were estimated
to be: 30% (THF/DMF), 82% (THF/CH2Cl2), and 73% (THF/PhMe).
(14) In a larger scale solid-phase experiment, the preloaded piperazine
resin (300 mg) was alkylated with 5 in THF/CH2Cl2 resulting in isolation
of N1-mononosylpiperazine (18%), while no sulfonamide formation was
observed in solution-phase reactions.
(15) (a) Carpino, L. A.; Tsao, J.-H. J. Chem. Soc., Chem. Commun. 1978,
358-359. (b) Koh, J. S.; Ellman, J. A. J. Org. Chem. 1996, 61, 4494-
4495.
4184
Org. Lett., Vol. 5, No. 22, 2003

Scheme 3. Synthesis of 2
Scheme 4. Synthesis of 4
followed by N-acylation with pentafluorophenyl butanoate
to give 11. Finally, simultaneous cleavage from the resin
and removal of the O-tert-butyl group were achieved by
treatment with TFA/CH2Cl2 (1:1), and the product was
purified by successive reversed-phase VLC and HPLC to
afford 2 as the tris(TFA) salt in 28% overall yield.
Compound 3 was prepared by performing a sequence
similar to that described above for the synthesis of 2, starting
from a commercially available trityl resin preloaded with
piperazine. The product was isolated in 60% yield as the
tris(TFA) salt by reversed-phase VLC and HPLC.
In the synthesis of compound 4, two successive N-
alkylation steps with nosylate 7 were necessary. To improve
the overall yield, each treatment with 7 was repeated twice,
first for 16 h and then for 2 h, before removal of the Teoc
group. Introduction of the amino acid unit (Tyr), N-acylation,
and cleavage from the resin were performed as in the
syntheses of 2 and 3. In initial attempts to obtain 4 using
THF/CH2Cl2 in the N-alkylation step, only compound 3 was
obtained in 80% yield. This result indicated that the required
SN2 reaction apparently was favored by the close proximity
to the trityl linker. Consequently, the more hydrophobic THF/
toluene mixture was applied in the N-alkylations (Scheme
4), and then the product 4 could be isolated in 26% overall
yield as the tris(TFA) salt.
For comparison, the sequence shown in Scheme 4 was
performed with the less reactive methanesulfonyl (mesyl)
derivative of N-Teoc-2-(4-piperidyl)ethanol. In this case, only
19% of 3 was isolated, along with 29% of piperazine
N-acylated with N-butyryltyrosine. Thus, a highly reactive
sulfonate such as nosylate is necessary to achieve moderate
yields in alkylations of secondary amines on solid support.
In the route presented here for the synthesis of these novel
philanthotoxins, an alkylation approach to new tertiary
amines on solid support was applied. Using this solid-phase
strategy allowed a number of tedious purification steps of
the highly polar intermediates to be avoided, and the final
products 2-4 were obtained after single reversed-phase VLC
and HPLC purification steps.
In the case of compound 4, two sequential couplings
proved to be feasible when an appropriate solvent mixture
was selected. The present method is a useful alternative to
a procedure previously reported by Zaragoza et al.,17 which
involves alkylation of secondary amines with alcohols
employing (cyanomethyl)trialkylphosphonium iodide, a re-
agent that is not commercially available. For synthesis of
N-monosubstituted piperazines on solid support, another
somewhat more elaborate method consisting of amide bond
formation followed by borane reduction has been reported
by Salvino et al.18 We have now demonstrated, that alkylation
of resin-bound secondary amines using readily available
nosylates represents an efficient and relatively mild synthetic
protocol.
The novel philanthotoxins are currently undergoing ex-
tensive biological evaluation in electrophysiological iGluR
and nAChR assays, the results of which will be published
elsewhere.
Acknowledgment. We thank the Danish Technical
Research Council (Grant No. 26-00-0312) and the Novo
Nordisk Foundation for financial support. We also thank Ms.
Uraiwan Ngamrabiab Adamsen for technical assistance and
Dr. Jørgen Olsen for performing ESI-MS/MS.
Supporting Information Available: Experimental pro-
cedures for the preparation and characterization of 2-4 and
(16) (a) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37, 3404-
3409. (b) Green, M.; Judd, B. Tetrahedron Lett. 1990, 31, 5851-5852. (c)
Wellendorph, P.; Jaroszewski, J. W.; Hansen, S. H.; Franzyk, H. Eur. J.
Med. Chem. 2003, 38, 117-122.
(17) Zaragoza, F.; Stephensen, H. J. Org. Chem. 2001, 66, 2518-2521.
(18) Salvino, J. M.; Gerard, B.; Ye, H. F.; Sauvagnat, B.; Dolle, R. E.
J. Comb. Chem. 2003, 5, 260-266.
1
7-9, together with selected H NMR, ESI-MS/MS, and
HRMS spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL035610T
Org. Lett., Vol. 5, No. 22, 2003
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