ORGANIC
LETTERS
2002
Vol. 4, No. 6
869-872
Solution-Phase Synthesis of Aminooxy
Peptoids in the C to N and N to C
Directions†
,‡
Injae Shin* and Kisoo Park
Department of Chemistry, Yonsei UniVersity, Seoul 120-749, Korea
Received October 29, 2001
ABSTRACT
Aminooxy peptoids, which are potential peptidomimetics, were synthesized by a stepwise monomer assembly. Ns-protected N-substituted
aminooxyacetate tert-butyl esters were used as a monomer in both the C to N and the N to C directions. Submonomer synthesis of aminooxy
peptoids is also described.
Peptides are known to have severe limitations for use as
therapeutic agents due to degradation by proteases and low
membrane permeability.1 To overcome these limitations and
to improve bioavailability for therapeutic applications, a
number of backbone-modified peptides (pseudopeptides)
have been designed, synthesized, and characterized for over
a decade.1,2 Peptoids, which are one of the earliest pseudopep-
tides,3 have been extensively studied for their biological
functions4 and structural features.5 Recently, it was found
that peptoids with aminoethyl side chains could transfer DNA
into cells and thus potentially be employed as a novel type
of a gene delivery vehicle.6 Other peptoid analogues such
as ureapeptoids,7 retropeptoids,8 oligomannopeptoids,9 â-pep-
toids,10 and hydrazinoazapeptoids11 have been synthesized
in order to provide more structural diversity and useful
biological properties.
† Abbreviations: DIC, diisopropylcarbodiimide; EDC, 1-ethyl-3-(3′-
dimethylaminopropyl)carbodiimide‚HCl; HOAt, 1-hydroxy-7-azabenzot-
riazole; HBTU, O-benzotriazole-N,N,N′,N′-tetamethyluronium hexafluoro-
phosphate; HOBt, N-hydroxybenzotriazole; PyBop, benzotriazole-1-yl-oxy-
tris-pyrrolidinophosphonium hexafluorophosphate; TFFH, tetramethylfluoro-
formamidinium hexafluorophosphate.
(4) Zuckermann, R. N.; Martin, E. J.; Spellmeyer, D. C.; Stauber, G.
B.; Shoemaker, K. R.; Kerr, J. M.; Figliozzi, G. M.; Goff, D. A.; Siani, M.
A.; Simon, R. J.; Banville, S. C.; Brown, E. G.; Wang, L.; Richter, L. S.;
Moos, W. H. J. Med. Chem. 1994, 37, 2678.
(5) (a) Wu, C. W.; Sanborn, T. J.; Huang, K.; Zuckermann, R. N.; Barron,
A. E. J. Am. Chem. Soc. 2001, 123, 6778. (b) Wu, C. W.; Sanborn, T. J.;
Zuckermann, R. N.; Barron, A. E. J. Am. Chem. Soc. 2001, 123, 2958. (c)
Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.; Barron,
A. E.; Truong, K. T.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.; Zuckermann,
R. N.; Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4309. (d)
Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.; Armand, P.; Bradley,
E. K.; Truong, K. T.; Dill, K. A.; Cohen, F. E.; Zuckermann, R. N. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 4303.
(6) Murphy, J. E.; Uno, T.; Hamer, J. D.; Cohen, F. E.; Dwarki, V.;
Zuckermann, R. N. Proc. Natl. Acad. Sci. U. S.A. 1998, 95, 1517.
(7) (a) Wilson, M. E.; Nowick, J. S. Tetrahedron Lett. 1998, 39, 6613.
(b) Kruijtzer, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J. Tetrahedron Lett.
1997, 38, 5335.
(8) Kruijtzer, J. A. W.; Hofmeyer, L. J. F.; Heerma, W.; Versluis, C.;
Liskamp, R. M. J. Chem. Eur. J. 1998, 4, 1570.
‡ Author to whom correspondence should be addressed. Fax: 82-2-364-
7050. Tel: 82-2-2123-2631.
(1) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(2) (a) Stigers, K. D.; Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol.
1999, 3, 714. (b) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A. Curr.
Opin. Struct. Biol. 1999, 9, 530. (c) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173. (d) Moran, E. J.; Wilson, T. E.; Cho, C. Y.; Cherry, S. R.; Schultz,
P. G. Biopolymers (Peptide Science) 1995, 37, 213.
(3) (a) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J.
Am. Chem. Soc. 1992, 114, 10646-10647. (b) Simon, R. J.; Kania, R. S.;
Zuckermann, R. N.; Huebner, V. D.; Jewell, D. A.; Banville, S.; Ng, S.;
Wang, L.; Rosenberg, S.; Marlowe, C. K.; Spellmeyer, D. C.; Tan, R.;
Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlett, P. A. Proc. Natl. Acad.
Sci. U.S.A. 1992, 89, 9367.
10.1021/ol010251s CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/22/2002