Facile synthesis of @-tide β-strand peptidomimetics: Improved assembly in solution and on solid phase

Article abstract of DOI:10.1021/ol048262j

(Chemical equation presented) The synthesis of @-tide β-strand peptidomimetics has been improved such that oligomers now can be obtained from solution- and solid-phase synthesis protocols approaching the efficiency and flexibility of peptide chemistry. These methods enable the synthesis of @-tide oligomers with a variety of amino acids and with lengths up to 13 units.

Full text of DOI:10.1021/ol048262j

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4483-4485
Facile Synthesis of @-Tide
Peptidomimetics: Improved Assembly in
Solution and on Solid Phase
â-Strand
Scott T. Phillips, Giovanni Piersanti, Matthias Ru
Bettina van Lengerich, and Paul A. Bartlett*
1th, Niko Gubernator,
Center for New Directions in Organic Synthesis,† Department of Chemistry,
UniVersity of California, Berkeley, California 94720-1460
paul@fire.cchem.berkeley.edu
Received August 30, 2004
ABSTRACT
The synthesis of @-tide
â-strand peptidomimetics has been improved such that oligomers now can be obtained from solution- and solid-
phase synthesis protocols approaching the efficiency and flexibility of peptide chemistry. These methods enable the synthesis of @-tide
oligomers with a variety of amino acids and with lengths up to 13 units.
The discovery of molecules that disrupt protein-protein
interactions is a significant challenge and the subject of
intense interest.1 One strategy involves the design of
analogues that mimic the peptide segments involved in the
recognition interface.1d,e While a sequence excised from one
protein partner may in principle be effective for this purpose,
in practice short peptides adopt poorly defined structures and
make undesirable candidates for drug discovery. As a
consequence, a number of strategies have been pursued to
develop nonpeptidic mimics of protein secondary structure,
including the extended â-strand conformation appropriate for
competing with protein-protein interactions that involve
â-sheet-like interfaces.2
We recently reported the synthesis and association behav-
ior of â-strand peptidomimetics called “@-tides”.3 @-Tides
are composed of alternating amino acids and dihydropyri-
dinones (“@-units”), which together predispose the oligomers
to adopt the extended, â-strand conformation. As a conse-
quence of this conformational control, @-tides readily
associate in organic solvent as two-stranded antiparallel
â-sheet-like homodimers. The @-unit is also effective at
templating peptide â-sheet formation in water in the in-
tramolecular context of a â-hairpin.4 However, to explore
the potential for @-tides to disrupt protein-protein interac-
(2) (a) Nowick, J. S.; Lam, K. S.; Khasanova, T. V.; Kemnitzer, W. E.;
Maitra, S.; Mee, H. T.; Liu, R. J. Am. Chem. Soc. 2002, 124, 4972. (b)
Gong, B. Synlett 2001, 582. (c) Smith, A. B., III; Benowitz, A. B.; Guzman,
M. C.; Sprengeler, P. A.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.;
Nagy, Z.; Campbell, R. M.; Cox, D. C.; Olson, G. L. J. Am. Chem. Soc.
1998, 120, 12704. (d) Michne, W. F.; Schroeder, J. D. Int. J. Pept. Protein
Res. 1996, 47, 2. (e) Kirsten, C. N.; Schrader, T. H. J. Am. Chem. Soc.
1997, 119, 12061. (f) Boumendjel, A.; Roberts, J. C.; Hu, E.; Pallai, P. V.;
Rebek, J., Jr. J. Org. Chem. 1996, 61, 4434.
(3) Phillips, S. T.; Rezac, M.; Abel, U.; Kossenjans, M.; Bartlett, P. A.
J. Am. Chem. Soc. 2002, 124, 58.
(4) Phillips, S. T.; Blasdel, L. K.; Bartlett, P. A. J. Am. Chem. Soc.
Submitted for publication.
† The Center for New Directions in Organic Synthesis is supported by
Bristol-Myers Squibb as a Sponsoring Member and Novartis Pharma as a
Supporting Member.
(1) (a) Archakov, A. I.; Govorun, V. M.; Dubanov, A. V.; Ivanov, Y.
D.; Veselovsky, A. V.; Lewi, P.; Janssen, P. Proteomics 2003, 3, 380. (b)
Toogood, P. L. J. Med. Chem. 2002, 45, 1543. (c) Cochran, A. G. Curr.
Opin. Chem. Biol. 2001, 5, 654. (d) Berg, T. Angew. Chem., Int. Ed. 2003,
42, 2462. (e) Zutshi, R.; Brickner, M.; Chmielewski, J. Curr. Opin. Chem.
Biol. 1998, 2, 62. (f) Peczuh, M. W.; Hamilton, A. D. Chem. ReV. 2000,
100, 2479.
10.1021/ol048262j CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/26/2004

tions required significant improvement over the methods
originally developed for their assembly (Scheme 1).3 We now
Scheme 2. Synthesis of Di-@-tide “Amino Acids”
Scheme 1. Original @-Tide Synthesisa
in peptide synthesis, the efficiency of @-tide elongation
depends on the ease with which both the deprotection and
coupling reactions can be accomplished. Scheme 3 illustrates
conditions and typical yields for removal of the N- and
C-terminal protecting groups from representative di-@-tides.
Standard conditions (1:1 TFA-CH2Cl2 for 2 h) were used
for removal of Boc and t-Bu side chain protecting groups.
@-Tide elongation is accomplished by coupling two di-
@-tides or a di-@-tide and an amino acid using HATU5 as
the activation reagent (Schemes 4 and 5). HATU is advanta-
a Side chains [R] are indicated by the three-letter code of the
amino acid itself, along with any side chain protecting group present.
describe @-tide chemistry that is nearly as flexible and
efficient as peptide synthetic methods. Moreover, a variety
of protection strategies are now available for formation of
@-tide oligomers, facilitating the assembly of libraries
incorporating both polar and nonpolar amino acids.
The di-@-tide building blocks were initially obtained from
an ytterbium-catalyzed Michael addition-elimination reac-
tion between an N-protected, C-activated dihydropyridinone
unit and an amino acid protected as the tert-butyl ester.3
While this combination generally affords good yields, amino
acid methyl esters are noticeably less effective in this reaction
(e.g., ca. 40-70% yields), often dimerizing to give the
diketopiperazines. An alternative approach that provides
access to orthogonally protected di-@-tides in fewer steps
involves direct condensation of amino acids with the N-
protected 3,5-piperazinedione (Scheme 2). This method is
compatible with Fmoc, Alloc, and Cbz nitrogen protecting
groups on the @-unit-, Boc-, and t-butyl-protected amino
acid side chains and unprotected amino acids or their methyl
esters. Moreover, the condensation products are often suf-
ficiently pure after extraction that they can be used directly
in subsequent steps. This route also eliminates the two
chromatographic purifications that were necessary in prepa-
ration of the N-protected, C-activated @-unit and the di-@-
tide products as shown in Scheme 1.3
Scheme 3. Deprotection Protocols
With the ready availability of an assortment of differen-
tially protected di-@-tides as building blocks, oligomers can
be assembled in the same fashion as peptides. However, as
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Org. Lett., Vol. 6, No. 24, 2004

geous compared to the previously used PyBroP5 because it
is compatible with DMF, which is important for synthesis
of the longer oligomers that associate more readily in solvents
such as methylene chloride. Moreover, by deprotecting the
Cbz group by hydrogenolysis or the Alloc group with a resin-
bound Pd0 species,6 the triphenylphosphine oxide byproduct
arising from Pd(PPh3)4 is avoided. Removal of this contami-
nant, as well as the phosphine oxide byproduct from PyBroP,
had plagued the previous protocols and necessitated careful
chromatographic purifications. With the protocols illustrated
in Schemes 4 and 5, filtration through a short silica gel plug
is all that is typically required after an extractive workup.
Scheme 6. Improved Solid-Phase Methods
Scheme 4. @-Tide Elongation Using the Alloc Protecting
Group
synthesis and applied to the preparation of oligomers up to
13 units in length (Scheme 6). Isolated yields ranged from
ca. 20-80%, depending on the hydrophobicity and length
of the sequence: high yields were obtained for shorter
nonpolar @-tides (penta- or hepta-@-tides), while lower
yields were observed for polar and longer derivatives.
In summary, improved syntheses of @-tide peptidomi-
metics have been developed in solution and on solid phase.
Ready access to the di-@-tide building blocks with different
protecting groups brings @-tide and peptide chemistry into
alignment and provides an opportunity to explore these
â-strand mimics in a variety of applications.
With the Fmoc protecting group, @-tide assembly on solid
phase now mirrors the protocol used for solid-phase peptide
synthesis. This strategy has been adapted to semiautomated
Acknowledgment. This work was supported by a grant
from the National Institutes of Health and by graduate
fellowships from Eli Lilly (S.T.P.), Boehringer-Ingelheim
(S.T.P.), and MIUR (XVI ciclo-dottorato di ricerca) and the
Universita` degli Studi di Urbino “Carlo Bo” (G.P.).
Scheme 5. @-Tide Elongation Using the Cbz Protecting Group
Supporting Information Available: Experimental pro-
cedures, characterization, and reference spectra for all
compounds depicted (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL048262J
(5) HATU ) N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-
methylene]-N-methylmethanaminium hexafluorophosphate N-oxide; PyBroP
) bromo-tris(pyrrolidino)phosphonium hexafluorophosphate
(6) Bergbreiter, D. E.; Weatherford, D. A. J. Org. Chem. 1989, 54, 2726.
Org. Lett., Vol. 6, No. 24, 2004
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