ORGANIC
LETTERS
2007
Vol. 9, No. 17
3291-3293
Peptide Nucleic Acid Synthesis by
Novel Amide Formation
Hyunil Lee,* Jae Hoon Jeon, Jong Chan Lim, Hoon Choi, Yeohong Yoon, and
Sung Kee Kim*
PANAGENE INC., 100, Sinsung-dong, Yuseong-gu, Daejeon 305-345, Korea
Received May 29, 2007
ABSTRACT
Synthesis of self-activated peptide nucleic acid (PNA) monomers and an efficient method for PNA synthesis using a benzothiazole-2-sulfonyl
(Bts) group as an amine-protecting group as well as an acid-activating group are reported. Couplings were complete within 120 min, and the
deprotection was performed in 10 min. This Bts strategy provides a high purity PNA oligomer and is appropriate for large-scale synthesis. The
results of the 15-mer PNA oligomer are described.
Peptide nucleic acid (PNA) is a nucleic acid analogue which
was first reported by Nielsen et al. in 19911 and has received
great attention due to many favorable properties including
chemical and thermal stability, resistance to nucleases and
proteases, stronger and faster binding affinity to the comple-
mentary nucleic acid,2 hybridization under low salt concen-
tration,3 and higher specificity and sensitivity to a single
mismatch. Specially, PNA has attracted major attention at
the interface of chemistry and biology because of its
interesting chemical, physical, and biological properties and
its potential to act as an active component for diagnostic,
molecular biological, and pharmaceutical applications.
Generally, PNA oligomers are synthesized using the well-
established solid-phase peptide synthesis protocol.4 There
have been significant improvements in the amide formation
techniques as well as in protecting group strategies in the
last several years in the field of peptide chemistry. Many
kinds of coupling reagents and new protecting groups have
been developed to minimize racemization and/or to improve
the reactivity.5
As is the case in the peptide synthesis, two protection
group strategies have been used for the preparation of PNA
oligomers: Boc/Cbz and Fmoc/Bhoc.6,7 However, these
methods have serious drawbacks due to harsh reaction
conditions and side reactions during either monomer syn-
thesis and/or PNA oligomer synthesis.
(1) Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Science 1991,
254, 1497.
Herein we report a new type of cyclic PNA monomer
and a new efficient method of PNA oligomer synthesis
(2) (a) Kim, S. K.; Nielsen, P. E.; Egholm, M.; Buchardt, O.; Berg, R.
H.; Norden, B. J. Am. Chem. Soc. 1993, 115, 6477. (b) Hyrup, B.; Egholm,
M.; Nielsen, P. E.; Wittung, P.; Norden, B.; Buchardt, O. J. Am. Chem.
Soc. 1994, 116, 7964. (c) Egholm, M.; Buchardt, O.; Christensen, L.;
Behrens, C.; Freier, S. M.; Driver, D. A.; Berg, R. H.; Kim, S. K.; Norden,
B.; Nielsen, P. E. Nature 1993, 365, 566. (d) Egholm, M.; Christensen, L.;
Dueholm, K. L.; Buchardt, O.; Coull, J.; Nielsen, P. E. Nucleic Acids Res.
1995, 23, 217. (e) Wittung, P.; Nielsen, P. E.; Norden, B. J. Am. Chem.
Soc. 1996, 118, 7049. (f) Leijon, M.; Graeslund, A.; Nielsen, P. E.; Buchardt,
O.; Norden, B.; Kristensen, S. M.; Eriksson, M. Biochemistry 1994, 33,
9820.
(4) Christensen, L.; Fitzpatrick, R.; Gildea, B.; Petersen, K. H.; Hansen,
H. F.; Koch, T.; Egholm, M.; Buchardt, O.; Nielsen, P. E.; Coull, J.; Berg,
R. H. J. Peptide Sci. 1995, 3, 175.
(5) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
(6) (a) Buchardt, O.; Egholm, M.; Nielsen, P. E.; Berg, R. H. PCT Int.
Appl. WO 92/20702, 1992. (b) Uhlmann, E.; Peyman, A.; Breipohl, G.;
Will, D. Angew. Chem., Int. Ed. 1998, 37, 2796. (c) Thomson, S. A.; Josey,
J. A.; Cadilla, R.; Gaul, M. D.; Hassaman, C. F.; Luzzio, M. J.; Pipe, A. J.;
Reed, K. L.; Ricca, D. J.; Wiethe, R. W.; Noble, S. A. Tetrahedron 1995,
51, 6179.
(3) (a) Orum, H.; Nielsen, P. E.; Jorgensen, M.; Larsson, C.; Stanley,
C.; Koch, T. H. BioTechniques 1995, 19, 472. (b) Tomac, S.; Sarkar, M.;
Ratilainen, T.; Wittung, P.; Nielsen, P. E.; Norden, B.; Gralund, A. J. Am.
Chem. Soc. 1996, 118, 5544.
(7) Coull, J. M.; Egholm, M.; Hodge, R. P.; Ismail, M.; Rajur, S. B.
PCT Int. Appl. WO 96/40685, 1996.
10.1021/ol071215h CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/28/2007