A. Brennauer et al. / Tetrahedron Letters 48 (2007) 6996–6999
6999
Acknowledgment
Support of this work by the Research Training Program
(Graduiertenkolleg GRK 760) of the Deutsche For-
schungsgemeinschaft is gratefully acknowledged.
Supplementary data
Supplementary data includes synthesis and analytical
data of the discussed compounds as well as details about
the kinetic measurements. Supplementary data associ-
ated with this article can be found, in the online version,
Scheme 4. Hypothetical mechanism for the formation of putative
isomerization product 6 from 1-(3-aminopropyloxycarbonyl)guanidine
3a, supported by HPLC–MS analysis: after an incubation period of
60 min two peaks of identical mass, 161 Da (MH+), with capacity
factors of 0.55 (3a) and 1.88 (6) were detected, whereas at 0 min only
one peak corresponding to 3a was identified.
References and notes
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In conclusion, acylguanidines are promising, less polar
bioisosteres of the strongly basic guanidino group.
However, acylguanidines tend to decompose when sub-
jected to alkaline conditions. The alkaline hydrolysis of
acetylguanidine proceeds with a half-life of 9.6 h.
Decomposition can be extremely accelerated if an
intramolecular nucleophilic attack is possible, as demon-
strated by the cleavage of 1-(5-aminopentanoyl)guani-
dine, which is completely converted to d-lactam within
minutes in alkaline solution. However, there are pro-
nounced differences in the reaction rates of linear 1-(x-
aminoalkanoyl)guanidines depending on the length of
the chain.
Compared to aminoalkanoylguanidines, the analogous
aminoalkoxycarbonyl-substituted guanidines are con-
siderably more stable toward alkaline hydrolysis. In gen-
eral the oxa analogs are inert in aqueous buffer at pH
10.4 and 25 °C. However, the reaction can be facilitated
by intramolecular nucleophilic groups in appropriate
distance to the electrophilic center.
On one hand, the degradation pathways described in
this study should be taken into account in the design
and synthesis of aminoalkanoylguanidines such as
NG-substituted argininamides, which are useful building
blocks for the preparation of fluorescent and radiola-
beled NPY receptor antagonists. On the other hand,
the 5-aminopentanoyl spacer could potentially serve as
an easily cleavable linker for the immobilization of gua-
nidines on solid support or as tunable protecting group
for the guanidino function based on the principle of
‘assisted cleavage’.
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