ORGANIC
LETTERS
2001
Vol. 3, No. 15
2341-2344
Efficient Introduction of Protected
Guanidines in BOC Solid Phase Peptide
Synthesis
Yongda Zhang and Alan J. Kennan*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received May 18, 2001
ABSTRACT
Reaction of primary amines with pyrazole 1 results in rapid and efficient guanidinylation, either in solution or on solid phase. The reaction
affords sulfonamide-protected products required for BOC solid phase peptide synthesis (SPPS) in a single step under mild conditions.
Incorporation of orthogonally protected side chain amines permits the synthesis of peptides containing arginine analogues, one of which
could not be prepared by coupling of preformed amino acids.
The widespread occurrence of guanidine groups in natural
products has inspired considerable development of synthetic
methodology.1 In particular, a number of elegant methods
for on-resin functionalization have been disclosed, though
most involve more than one step.2 Here we report a new
reagent (1), capable of guanidinylating primary amines with
impressive speed and efficiency. Reaction with side chain
amines during peptide synthesis allows one-step introduction
of protected guanidines compatible with BOC methodology.
The synthesis of 1 and its application in both solution and
solid phase contexts is described.
In the course of peptide-based molecular recognition
studies, we sought to prepare sequences containing chain-
shortened or -elongated arginine analogues. Given the
standard use of N-tosyl-protected arginine in BOC synthesis,
initial efforts targeted N-tosyl monomers. Although the
corresponding amino acids proved simple to prepare, their
use in peptide synthesis was impractical.3 Thus, an alternative
strategy of on-resin functionalization was pursued. Incorpo-
ration of amino acids bearing FMOC-protected side chain
amines, followed by sequential treatment with piperidine and
a guanidinylating agent, was expected to afford the desired
peptides.
(1) (a) Moroni, M.; Koksch, B.; Osipov, S. N.; Crucianelli, M.; Frigerio,
M.; Bravo, P.; Burger, K. J. Org. Chem. 2001, 66, 130-133. (b) Brewer,
M.; Rich, D. H. Org. Lett. 2001, 3, 945-948. (c) Katritzky, A. R.; Rogovoy,
B. V.; Chassaing, C.; Vvedensky, V. J. Org. Chem. 2000, 65, 8080-8082.
(d) Barawkar, D. A.; Kwok, Y.; Bruice, T. W.; Bruice, T. C. J. Am. Chem.
Soc. 2000, 122, 5244-5250. (e) Linton, B. R.; Carr, A. J.; Orner, B. P.;
Hamilton, A. D. J. Org. Chem. 2000, 65, 1566-1568. (f) Schneider, S. E.;
O’Neil, S. N.; Anslyn, E. V. J. Am. Chem. Soc. 2000, 122, 542-543. (g)
Baker, T. J.; Luedtke, N. W.; Tor, Y.; Goodman, M. J. Org. Chem. 2000,
65, 9054-9058. (h) Luedtke, N. W.; Baker, T. J.; Goodman, M.; Tor, Y.
J. Am. Chem. Soc. 2000, 122, 12035-12036. (i) Feichtinger, K.; Sings, H.
L.; Baker, T. J.; Matthews, K.; Goodman, M. J. Org. Chem. 1998, 63,
8432-8439. (j) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
Org. Chem. 1998, 63, 3804-3805.
(2) (a) Burgess, K.; Chen, J. In Solid-Phase Organic Synthesis; Burgess,
K., Ed.; John Wiley & Sons: New York, 2000; pp 1-23. (b) Gomez, L.;
Gellibert, F.; Wagner, A.; Mioskowski, C. Chem.sEur. J. 2000, 6, 4016-
4020. (c) Dahmen, S.; Braese, S. Org. Lett. 2000, 2, 3563-3565. (d) Zapf,
C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett. 2001, 3,
1133-1136. (e) Ghosh, A. K.; Hol, W. G. J.; Fan, E. J. Org. Chem. 2001,
66, 2161-2164. (f) Mamai, A.; Madalengoitia, J. S. Org. Lett. 2001, 3,
561-564.
An appropriate reagent was suggested by reports that
pyrazole 2 produces bis-Boc protected guanidines from
(3) For example, use of N-Boc-R-amino-γ-N-tosylguanidinobutyric acid
gave little or no desired product even using extended coupling times and
excess reagents.
10.1021/ol016139b CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/27/2001