ORGANIC
LETTERS
2006
Vol. 8, No. 25
5817-5820
Carbocations in Action. Design,
Synthesis, and Evaluation of a Highly
Acid-Sensitive Naphthalene-Based
Backbone Amide Linker for Solid-Phase
Synthesis
Michael Pittelkow, Ulrik Boas, and Jørn B. Christensen*
Department of Chemistry, UniVersity of Copenhagen, UniVersitetsparken 5,
DK-2100, Copenhagen Ø, Denmark
Received September 30, 2006
ABSTRACT
The design, synthesis, and properties of an extremely acid-labile backbone amide linker based on a regiospecifically substituted tetraalkoxy
naphthaldehyde core are presented. This handle enables cleavage of peptide backbone amides (secondary amides) off a solid support using
as little as 0.5% TFA in CH2Cl2. This proceeds without cleavage of tert-butyl ethers and tert-butyl esters. The design is based on a DFT study
that predicted the most stabile alkoxy-substituted methyl naphthyl carbocation.
Acid-labile handles remain the most widely used in solid-
phase organic synthesis, and there is an immense interest in
handles with high acid lability enabling release of the
substrate from the solid phase under mild conditions. To this
end, one important issue is the possibility of performing
controlled release of protected peptide segments for further
manipulation by segment coupling strategies.1-3
amide-containing substrate, e.g., peptides to be released in
a “traceless” manner by using a backbone amide functionality
as the anchor point to the solid phase (Scheme 1).4,5 The
acid lability of a BAL-type handle correlates to a large extent
with the ease of formation of the benzyl-like carbocation,
which forms during release of the product from the resin
(for leaving groups with comparable electronic and steric
properties).6 Solid-phase synthesis utilizing a BAL strategy
starts at an aromatic aldehyde situated on an electron-rich
aromatic core. In solid-phase synthesis of peptides by the
BAL strategy, the first step is a reductive amination of the
BAL formyl group with the amino group of a C-terminal
The Barany and Ellman groups introduced the backbone
amide linker (BAL) concept, which enables release of an
(1) (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. (b) Letsinger,
R. L.; Kornet, M. J. J. Am. Chem. Soc. 1963, 85, 3045.
(2) (a) Methods of Organic Chemistry; Goodman, M., Felix, A., Moroder,
L., Toniolo, C., Eds.; Houben-Weyl, Georg Thieme Verlag: Stuttgart, New
York, 2002; Vol. E22a. (b) Thompson, L. A.; Ellman, J. A. Chem. ReV.
1996, 96, 555. (c) Merrifield, R. B. Angew. Chem., Int. Ed. Engl. 1985, 24,
799.
(4) Jensen, K. J.; Songster, M. F.; Va´gner, J.; Alsina, J.; Albericio, F.;
Barany, G. J. Am. Chem. Soc. 1998, 120, 5441.
(3) For general reviews on handles: (a) Songster, M. F.; Barany, G.
Methods Enzymol. 1997, 289, 126. (b) Backes, B. J.; Ellman, J. A. Curr.
Opin. Chem. Biol. 1997, 1, 86. (c) James, I. W. Tetrahedron 1999, 55,
4855. (d) Virta, P.; Katajisto, J.; Niittyma, T.; Lo¨nnberg, H. Tetrahedron
2003, 59, 5137.
(5) (a) Boojamra, C. G.; Burow, K. M.; Ellman, J. A. J. Org. Chem.
1995, 60, 5742. (b) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.;
Ellman, J. A. J. Org. Chem. 1997, 62, 1240.
(6) Other factors may influence the cleavage properties: Norrby, P.-O.;
Jensen, K. J. Int. J. Pept. Res. Ther. 2006, in press.
10.1021/ol062410j CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/10/2006