Macrocyclization of di-Boc-guanidino-alkylamines related to guazatine components: Discovery and synthesis of innovative macrocyclic amidinoureas

Article abstract of DOI:10.1002/ejoc.200801109

The synthesis of new and innovative macrocyclic amidinoureas from linear di-Boc-guanidino-alkylamines related to guazatine was accomplished. The macrocyclization reaction proceeds under mild conditions affording 11- to 16-membered rings with a new and pre

Full text of DOI:10.1002/ejoc.200801109

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801109
Macrocyclization of Di-Boc-guanidino-alkylamines Related to Guazatine
Components: Discovery and Synthesis of Innovative Macrocyclic Amidinoureas
Daniele Castagnolo,[a] Francesco Raffi,[a] Gianluca Giorgi,[b] and Maurizio Botta*[a]
Keywords: Macrocyclization / Amidinourea / Aminoguanidine
The synthesis of new and innovative macrocyclic amidino-
ureas from linear di-Boc-guanidino-alkylamines related to
guazatine was accomplished. The macrocyclization reaction
inoureas were also synthesised. The strict correlation be-
tween macrocyclic amidinoureas and the natural product
guazatine makes them very actractive also from a biological
proceeds under mild conditions affording 11- to 16-mem- point of view.
bered rings with a new and previously undescribed structure
in good yields. Enantiomerically pure macrocyclic amid-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
containing the biogenetic base spermine are of great interest
in view of the broad activity, which was established for the
spermine-containing compounds in biological systems.[8]
More recently, novel macrocylcic urea compounds were pre-
pared showing potent Chk1 (serine/threonine protein kin-
ase) inhibitory activity.[9] Herein we report the first design
and synthesis of a novel class of macrocyclic amidinoureas
with general structure B starting from linear precursors di-
Boc-guanidino-alkylamines A related to guazatine compo-
nents.[10] (Figure 1).
Introduction
The guanidine and urea functional groups are crucial
components in many medicinally interesting molecules,[1]
and therefore practical methods for straightforward synthe-
ses of guanidine- or urea-containing molecules are of great
interest in drug discovery and lead optimization.[2] Simi-
larly, amidinoureas, molecules containing both guanidine
and urea moieties, are of great interest in medicinal chemis-
try in treating gastrointestinal, spasmolytic, cardiovascular
disorders and parasitic infestations. Furthermore, amid-
inourea has also been shown to be the essential structural
feature for antimalarial compounds[3] and for the potent
antibacterial TAN-1057A-D,[4] a naturally occurring dipep-
tide–amidinourea antibiotic isolated from the bacteria Flex-
ibacter sp. PK-74 and PK-176. Few methods have been re-
ported so far for the synthesis of linear amidinoureas, and
most of them are inefficient or require numerous steps.[2a,5,6]
However, no examples of cyclic or macrocyclic amid-
inoureas are known so far. The design and synthesis of
macrocyclic structures with an appropriate ring size and
predictable function is an important research topic and still
remains an attractive challenge in organic synthesis. For in-
stance, macrocyclic peptides play a significant role in bio-
logy since they can interact with a large protein surface dis-
rupting protein–protein interaction,[7] which is a new im-
portant target in medicinal chemistry. Less common natural
macrocyclic polyamine lactams and macrocyclic lactams
Figure 1. General structures of linear di-Boc-guanidino-alkyl-
amines and macrocyclic amidinoureas.
The strict correlation between these macrocyclic amid-
inoureas and guazatine components, which in our recent
studies were found to have a potent antifungal activity on
all the Candida strains with MIC50 values ranging between
10 and 80 µ,[10b] makes these compounds very attractive
both from a synthetic as well as a biological point of view.
Results and Discussion
[a] Dipartimento Farmaco Chimico Tecnologico, Università degli
Studi di Siena,
During our recent studies on guazatine-analogous com-
pounds,[10c,11] we observed that aminoguanidines such as A,
bearing both a di-Boc-guanidine and an amine moiety, were
converted by simply heating in THF into unexpected deriv-
atives with unrecognized structure.[10c] Hence, a series of
aminoguanidine precursors 2 were synthesised starting
Via A. de Gasperi 2, 53100 Siena, Italy
Fax: +39-0577-234333
E-mail: botta@unisi.it
[b] Dipartimento di Chimica, Università degli Studi di Siena,
Via A. Moro, 53100 Siena, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Innovative Macrocyclic Amidinoureas
from guanidine 1 (Scheme 1) with the aim to investigate and
Hence, as 2b was forming, its free amino group immedi-
generalize their behaviour under the same conditions and ately collapsed on the quaternary electrophilic carbon atom
to understand the structure of the newly formed reaction to afford in this way the stable six-membered cyclic guan-
products. Reaction of 1 with different diamines led to ami- idine 5 as illustrated in Scheme 1. Amine 2i was obtained
noguanidine precursors 2a–h in high yield. Surprisingly, by reaction of 1 with -lysine methyl ester in 72% yield.[12]
when 1 was treated with 1,3-diaminopropane compound 5 Secondary amines 2j–l were synthesised through reductive
was isolated in 94% yield as the only product. HPLC-MS amination reaction of 2g with different aldehydes (namely
analysis revealed that in the early stages of the reaction the benzaldehyde for 2j, valeraldehyde for 2k and cinnamal-
linear product 2b was present in the reaction mixture to- dehyde for 2l).[13] Finally, coupling of 2g with N-Cbz-ala-
gether with a larger amount of 5.
nine and N-Cbz-phenylalanine in the presence of DCC led
to 2mЈ,nЈ which were converted into precursors 2m,n,
respectively, after removal of the Cbz protecting group by
hydrogenolysis. The di-Boc-aminoguanidine 2g, which is the
protected component GN of guazatine,[10] was then chosen
to investigate the new reaction. Heating of 2g in THF at
70 °C for 8 h afforded the macrocyclic amidinourea 3g
(48%) as the major product together with the dimer 4g
(8%) (Scheme 3). The innovative structure of macrocycle 3g
was confirmed by X-ray analysis (Figure 2). The proposed
Scheme 1. Synthesis of macrocyclization precursors. Reagents and
conditions: (i) alkyldiamine, Et3N, DCM (90–98%); (ii) lysine
methyl ester, Et3N, DCM (72%); (iii)1,3-diaminopropane, Et3N,
DCM (94%); (iv) aldehyde, NaBH4/pTSA, DCE (40–55%); (v) N-
Cbz-alanine (for 2mЈ) or N-Cbz-phenylalanine (for 2nЈ), EDC,
HOBt, DIPEA, DMF; (vi) H2, Pd/C, EtOH (52% for 2m, 49% for
2n; 2 steps).
Figure 2. X-ray structure of macrocycle 3g.
Scheme 2. Proposed mechanism for the macrocyclization.
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D. Castagnolo, F. Raffi, G. Giorgi, M. Botta
SHORT COMMUNICATION
mechanism for the macrocyclization reaction of 2g is out-
lined in Scheme 2. Linear amidinoureas have been pre-
viously prepared by Rault and Miel through cross reaction
of tri-Boc- or di-Boc-guanidines with different amines un-
der mild conditions and in the presence of a base.[6] The
authors also proposed that their formation could proceed
via an isocyanate intermediate,[6a] formed from the Boc-
protecting group by an E1cB mechanism with a conjugate
base and subsequent addition of external amines as nucleo-
philic agents.[2b] Since in our cases no external conjugate
bases are present in the reaction mixtures, we hypothesised
that the amino group of aminoguanidines 2 could work
both as the conjugate base in the formation of the isocyan-
ate intermediate and as the nucleophilic agent. The forma-
tion of the dimer 3b might be due to the cross attack of two
isocyanate intermediates.
Precursors 2a–n were then refluxed in THF for the re-
quired time to afford cyclic amidinoureas 3 and in some
cases the corresponding dimers 4 (Scheme 3). Finally, 3 and
4 were treated with TFA to afford deprotected amid-
inoureas 6 and dimers 7. The yields are reported in Table 1.
Surprisingly, when 2a was refluxed in THF, cyclic guan-
idine 8 was formed after only 2 h and isolated as the only
product of the reaction in 92% yield (Scheme 3). No traces
of the desired amidinourea 3a were detected (Entry 1). The
Scheme 3. Macrocyclization reactions. Reagents and conditions: (i)
THF, 70 °C (6–51%); (ii) TFA, DCM (quant.); (iii) THF, 70 °C
(92%).
formation of the more stable five-membered ring 8 was fav- cycle 3h (Entry 7), whereas from 2i only the dimer 4i was
oured over the formation of the more constrained seven- formed (Entry 8). Macrocyclization of secondary amines
membered ring 3a. Heating of 2c,d in THF led to the for- 2j–l occurred in refluxing THF to afford 3j–l together with
mation of dimers 4c,d as the only products (Entries 2, 3).[14] traces of the corresponding dimers 4j–l (Entries 9–11). Fi-
When 2e was refluxed in THF, cycle 3e was isolated in 6% nally, compounds 2m,n afforded the macrocylcic amidi-
yield together with 12% of dimer 4e (Entry 4).[15] On the noureas 3m,n as the only products with complete retention
other hand, amines 2f,g led to 3f,g as major products (30– of configuration (Entries 12–13). No traces of dimeric com-
48% yield) together with smaller amounts of their dimers pounds 4m,n were detected. It is clear that a linear corre-
4f,g (Entries 5–6). Heating of 2h led exclusively to macro- lation exists between the length of the chain of 2 and the
Table 1. Results and yields of the macrocyclization reactions.
Entry
Amine 2
n
R1
R2
Time [h]
Cycle 3 (%)[a]
Dimer 4 (%)[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
a
c
d
e
f
g
h
i
j
k
l
m
n
2
4
5
6
7
8
9
5
8
8
8
8
8
H
H
H
H
H
H
H
H
Bn
2
7
7
7
7
7
7
7
7
7
7
7
7
n.d.[b,c]
n.d.[b]
n.d.[b]
6
30
48
n.d.[b]
20
15
12
9
8
51
n.d.[b]
13
n.d.[b]
31
6
4
pentyl
cinnamyl
39
32
44
42
traces[d]
n.d.[b]
n.d.[b]
Bn
CH3
[a] Isolated yield. [b] n.d. = no detected compound; compound was not formed. [c] Cyclic guanidine 8 was formed. [d] Traces of dimer
4l were observed by HPLC-MS analysis.
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Innovative Macrocyclic Amidinoureas
formation of 3 and/or 4. When the length of the chain of 2
is n = 4–6, dimers 4c–e and 4i were isolated as the major
(or only) products (Entries 2–4 and 8). On the contrary,
when the chain length is n = 9, no traces of dimeric com-
pound 4h were detected, and 3h was the only product.
The amidinourea moiety being planar, the macrocycliza-
tion is conformationally hindered when the length of the
chain is n = 4, 5. The amino group is too far away to reach
the isocyanate moiety on the same molecule, and it prefers
to cross-react with the isocyanate moiety of a second mole-
cule to lead to the formation of dimers 4. On the other
hand, when n Ͼ 6, aminoguanidine 2 has a greater confor-
mational flexibility, and the amino group can reach the iso-
cyanate moiety to lead to macrocyles 3 bearing a planar
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Conclusion
A novel class of innovative macrocyclic amidinoureas 3e–
h,j–n was discovered and synthesised from easily accessible
aminoguanidines 2 in good yields and under mild condi-
tions. In particular, enantiomerically pure 3m,n could repre-
sent interesting scaffolds in the synthesis of peptidomimetic
compounds. Macrocyclic amidinoureas also represent an
attractive class of new compounds with strong antifungal
activity,[17] such as guazatine,[10] or potential antibacterial
activity, resembling the structure of natural macrolide anti-
biotics. Preliminary biological results seem to be promising.
The macrocyclization dimers 4c–g,i–k were obtained as si-
deproducts in moderate yields; they also prove to be an
interesting new class of macrocycles containing two amid-
inourea moieties, and are at the moment under biological
study.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental data, 1H and 13C NMR spectra; selected crystal
data and ORTEP view of 3g.
[15] When 2e was heated in THF at 0.3 m instead of 3.0 m con-
centration, compounds 3e and 4e were always isolated in a 1:2
ratio. Thus, formation of dimers 4 results to be independent of
the concentration of the reaction solution and is strictly corre-
lated to the structure of the substarte 2.
Acknowledgments
[16]
a) G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981, 14, 95;
b) L. Mandolini, Adv. Phys. Org. Chem. 1986, 22, 1.
USA patent application has been submitted.
Received: November 10, 2008
We are grateful to the Italian Ministero dell’Istruzione, dell’Univer-
sità e della Ricerca (PRIN Anno 2006 prot.-2006030948_002). Dr.
Antonio Vivi, director of the NMR Centre of the University of
Siena, is acknowledged for technical assistance.
[17]
Published Online: December 8, 2008
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