Conjugated polyamines such as acylpolyamine toxins5
isolated from natural sources have attracted much interest
in neurobiology and stimulated elaborated approaches.6
Even more intriguing is the structural diversity of cyclic
spermine and spermidine alkaloids, exemplified by the
monocyclic macrolactams celacinnine7 and budmunchia-
mines,8 the bicyclic macrolactams verbamethine9 and
oncinotine,10 the diazocinones and diazepinones dovy-
alicins,11 and the azamacrocyclic motuporamines.12
forward.16 For this reason, new and versatile approaches
to the synthesis of nonsymmetrical PAs are needed. We
present here a novel application of multicomponent
reactions (MCRs) that can provide a direct access to
nonsymmetrical alkyl PAs in only two synthetic steps
(Scheme 1).
Scheme 1. Two-Step Synthesis of Nonsymmetrical PAs by an
N-Split Ugi Multicomponent Reaction/Amide Reduction and
Hydrogenolysis
Over the past decades, it has also been demonstrated
that synthetic PAs could have important functions in
several fields of research. In oncology, it has been shown
that the cellular requirement for natural PAs increases in
cancer cells, thus providing a novel target for therapeutic
intervention.2,13 For this reason, synthetic PA analogues,
able to target the specific polyamine carrier but that do not
display the typical biological activities of natural PAs, have
been used as antitumoral agents, and some have reached
phase II clinical trials (e.g., DENSpm, Figure 1).13,14
In 1993, the first synthesis of nonsymmetrical N-alkyl
derivatives of norspermine appeared and led to the
discovery of cytotoxic agents in several tumoral cell lines.
Indeed, these analogues have demonstrated lower toxicity
and greater therapeutic efficacy than the symmetrically
substituted PAs.15 Despite these promising activities, a
limited number of nonsymmetrical PAs have been syn-
thesized to date. The reason lies in the more challenging
synthesis required. The synthesis of symmetrically sub-
stituted PAs is relatiVely simple and depends on the
availability of the appropriate diamine. The preparation
of their nonsymmetrically substituted counterparts is more
demanding since orthogonal protection of internal and
lateral nitrogen atoms is required, while the purification
of these highly polar compounds is not always straight-
To accomplish this, we leveraged on a recently de-
scribed multicomponent protocol17 where symmetrical
secondary diamines are fed into the four-component Ugi
reaction. This variation “splits” the typical Ugi backbone
within the two diamine nitrogen atoms, with one nitrogen
atom undergoing acylation and the other alkylation.
To combine proof-of-principle and relevance, we in-
vestigated the combination of butylisocyanide (2), N1,N3-
dibenzyl-1,3-propanediamine (13), paraformaldehyde, and
N-acetyl ꢀ-alanine (10). This choice was inspired by the
relevance of the 1,3-propanediamine leitmotif in antitu-
moral PAs3,14 and by the inhability of the classic Ugi
reaction to provide this type of compounds.18 The N-split
Ugi reaction (MeOH, reflux, 16 h) directly provided the
required polyamide scaffold; next, the hurdle of the reduction
of the amides was studied, as the presence of sterically
hindered tertiary amides occasionally leads to low yields and
unwanted byproduct formation.19 After several attempts with
different reducing agents, we finally identified BH3·THF20
(3 equiv for amide group; 60 °C, 120 h) as the most efficient
(4) Oshima, T. Amino Acids 2007, 33, 367–372.
(5) Schulz, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 314–326.
(6) Nihei, K.; Kato, M. J.; Yamane, T.; Konno, K. Tetrahedron 2006,
62, 8335–8550.
(7) Kupchan, S. M.; Hintz, H. P. J.; Smith, R. M.; Karim, A.; Cass,
M. W.; Court, W. A.; Yatagai, M. J. Chem. Soc., Chem. Commun. 1974,
329–330.
(8) Pezzuto, J. M.; Mar, W.; Lin, L.-Z.; Cordell, G. A.; Neszme´lyi, A.;
Wagner, H. Heterocycles 1991, 32, 1961–1967.
(9) Guggisberg, A.; Drandarov, K.; Hesse, M. HelV. Chim. Acta 2000,
83, 3035–3042.
(10) (a) Badawi, M. M.; Guggisberg, A.; van der Broek, P.; Hesse, M.;
Schmid, H. HelV. Chim. Acta 1968, 51, 1813–1817. (b) Guggisberg, A.;
Badawi, M. M.; Hesse, M.; Schmid, H. HelV. Chim. Acta 1974, 57, 414–
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(13) Casero, R. A., Jr.; Marton, L. J. Nat. ReV. Drug DiscoVery 2007,
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(14) (a) Casero, R. A., Jr.; Woster, P. M. J. Med. Chem. 2001, 44, 1–
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Pledgie, A.; Casero, R. A., Jr.; Davidso, N. Anti-Cancer Drugs 2005, 16,
(17) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I. G.;
Pirali, T. Angew. Chem., Int. Ed. 2006, 45, 1099–1102.
(18) It should be noted that although PAs contaning the 1,2-
ethylenediamine skeleton may be obtained using the classical Ugi
reaction, this strategy has never been reported in the literature.
(19) Challis, B. C.; Challis, J. A. The Chemistry of Amides; Wiley: New
York, 1970; pp 795-801.
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A. R.; Casero, R. A., Jr.; Woster, P. M. J. Med. Chem. 1993, 36, 2998–
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