LETTER
Direct Guanylation of Amino Groups
1305
yields (Table 2, entries 8–12). The present aqueous proto- In conclusion, we developed a direct method for guanyl-
col enabled the direct conversion of ornithine into a pep- ating amino groups via a reaction with cyanamide in wa-
tide structure 1n to the corresponding arginine peptide 2n. ter. The reaction was efficiently catalyzed by Sc(OTf)3
The peptide 1n was smoothly transformed to the peptide under mild conditions. The activated carbodiimides,
2n by a reaction with cyanamide over two days, providing which were, in most cases, prepared independently from
a 56% yield without epimerization under mild conditions substituted cyanamide derivatives, were in fact generated
(Table 2, entry 13).
by the treatment of cyanamide with catalytic amounts of
Sc(OTf)3. Metal–carbodiimide complex readily reacted
with a variety of amines in water to provide various gua-
nidine derivatives in good yields. The lanthanide triflate-
catalyzed conditions developed here enabled the reactions
of previously intransigent substrates that could not be dis-
solved in organic solvents. These approaches enabled ef-
ficient guanylation reactions in water. An ornithine group
in an unprotected peptide could be efficiently transformed
into an arginine congener. The simple procedure, which
involved mixing substrates with Sc(OTf)3 in water, easily
yielded the isolated products after removing the catalyst
by silica gel pad. The application of this method to the
synthesis of guanidine-containing natural products and
pharmacologically important compounds is currently in
progress in our laboratories.
Insights into the reaction mechanism of our Sc(OTf)3-cat-
alyzed reaction were obtained by heating the cyanamide
with stoichiometric amounts of Sc(OTf)3 at 100 °C in
deuterated water under the conditions reported in Tables
1 and 2. The product development was directly monitored
by 13C NMR (Figure 1). After 12 hours, the 13C signal at
δ = 162 ppm, which appeared to be derived from a car-
bodiimide derivative, possibly in complex with a scandi-
um triflate, was clearly observed with disappearance of
the cyanamide carbon signal at δ = 118 ppm. Treatment of
the mixture with aniline 1a quantitatively provided the
guanylated product 2a. Hence, the present Sc(OTf)3-cata-
lyzed reaction involved the in situ generation of a reactive
metalated carbodiimide species that reacted smoothly
with various amino derivatives. Lanthanide metal com-
plexes, such as ytterbium amides or ytterbium triflate, can
accelerate the addition reactions of carbodiimides and
amines.10–12 Sc(OTf)3 was found to activate the process
examined here, suggesting a mechanism underlying the
high reactivity of our catalyzed reaction. We found that
cyanamide could be activated in situ to form reactive car-
bodiimides in the presence of catalytic amounts of
Sc(OTf)3, which reacted directly with various amino de-
rivatives. The procedure developed here removed the
need to preactivate the guanylation reagents, as required
in other guanylation methods.
Acknowledgment
Tsubokura K. and Iwata T. contributed equally to this research. This
work was supported in part by Grants-in-Aid for Scientific Re-
search from the Japan Society for the Promotion of Science,
22651081, 23681047, and 25560410, by a Research Grant from the
Mizutani Foundation for Glycoscience, by a MEXT Grant-in-Aid
for Scientific Research on Innovative Areas ‘Chemical Biology of
Natural Products: Target ID and Regulation of Bioactivity’, and by
a subsidy of the Russian Government ‘Program of Competitive
Growth of Kazan Federal University among World’s Leading Aca-
demic Centers’.
Supporting Information for this article is available online at
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Reference and Notes
(1) (a) Saczewski, F.; Balewski, Ł. Expert Opin. Ther. Pat.
2009, 19, 1417. (b) Saczewski, F.; Balewski, Ł. Expert Opin.
Ther. Pat. 2013, 23, 965. (c) Berlinck, R. G. S. Nat. Prod.
Rep. 2002, 19, 617. (d) Berlinck, R. G. S.; Burtoloso, A. C.
B.; Trindade-Silva, A. E.; Romminger, S.; Morais, R. P.;
Bandeira, K.; Mizuno, C. M. Nat. Prod. Rep. 2010, 27, 1871.
(2) (a) Baker, T. J.; Luedke, N. W.; Tor, Y.; Goodman, M.
J. Org. Chem. 2000, 65, 9054. (b) Hui, Y.; Ptak, R.;
Pallansch, M.; Chang, C.-W. W. Tetrahedron Lett. 2002, 43,
9255. (c) Izdebski, J.; Witkowska, E.; Kunce, D.; Orłowska,
A.; Baranowska, B.; Radzikowska, M.; Smoluch, M. J.
Peptide Sci. 2002, 8, 289.
(3) Representative reviews for recent guanlyation, see:
(a) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, (iv),
49. (b) Bajusz, S.; Ronai, A. Z.; Szekely, J. J.; Miglecz, E.;
Berzetei, J. FEBS Lett. 1980, 110, 85.
(4) For a representative example, see: Bredereck, H.; Bredereck,
K. Chem. Ber. 1961, 94, 2278.
(5) (a) Boukouvalas, J.; Golding, B. T. Angew. Chem. Suppl.
1983, 22, 860. (b) Bernatowicz, M. S.; Wu, Y. L.; Matsueda,
G. R. J. Org. Chem. 1992, 57, 2497. (c) Bernatowicz, M. S.;
Wu, Y. L.; Matsueda, G. R. Tetrahedron Lett. 1993, 34,
3389. (d) Robinson, S.; Roskamp, E. J. Tetrahedron 1997,
Figure 1 13C NMR spectrum of the cyanamide after treatment with
Sc(OTf)3 at 100 °C in deuterated water (MeOH was used as the inter-
nal standard).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1302–1306