to study their structure-activity relationship in a systematic
1
manner. Generally, â-peptides are synthesized using N-
6
Fmoc-protected â-amino acid monomers. These â-amino
acids are usually made from corresponding R-amino acids.
The synthesis of Fmoc-â-amino acids from Fmoc-R-amino
acids is nontrivial, and this synthetic procedure allows access
to only a limited number of Fmoc-â-amino acids. This also
renders â-amino acids extremely expensive starting materials.
7
Adopting an approach similar to that of Farrera-Sinfreu,
which they applied for the synthesis of γ-peptides, we have
developed a synthetic strategy to obtain two new families
of â-peptides formed by L-aspartic acid and â-amino-L-
alanine monomers (Figure 1). These monomers allow
3
2
Figure 2. Structure of â - (1) and â -hexapeptides (2, 3).
build the backbone of the peptide and allyl protection was
used to introduce the side chain functionalities. The same
strategy allows the synthesis of either heterooligomeric
â-peptides, such as 1 and 2, or homooligomeric â-peptides
(e.g., 3). In heterooligomeric â-peptides 1 and 2, the different
side chains were introduced after coupling of each monomer
and deallylation of the side chain carboxy or amino group.
Two of the side chains were chosen with a free amino group
(lysine side chain mimic) to keep a balance between both
the hydrophobic and the charged groups and to enhance
solubility in an aqueous medium. In the case of â-peptide
homooligomer 3, the backbone was synthesized first, and
all the side chain allyl protections were removed in the end.
Figure 1. L-Aspartic acid (left) and â-amino-L-alanine (right)
3
2
monomers used in this study for the synthesis of â - and â -peptides,
respectively.
3
2
synthesis of â - and â -peptides with a wide variety of side
chains. The R-carboxy group of L-aspartic acid and the
R-amino group of â-amino-L-alanine (L-diaminopropionic
acid, Dap) are left free for the introduction of different
substituents (to obtain a heterooligomer) during the synthesis
or of the same substituent as a final functionalization step
3
The backbone of â -peptide 1 was prepared from orthogo-
(to obtain a homooligomer). The independent buildup of the
R
nally protected L-aspartic acid, N -Fmoc-L-aspartic acid
backbone and side chain sequences leads to a very high level
of synthetic versatility. Using this strategy, we report here
the synthesis of representative â-peptides from both classes,
R-allyl ester, using BOP with HOBt on rink amide MBHA
resin (Scheme 1). The reaction was monitored by the
ninhydrin test. The side chain was deallylated followed by
the introduction of the corresponding amine using the same
coupling reagents as mentioned above. To achieve complete
deallylation of the side chain carboxyl, the reaction was
optimized by varying (i) the amount of palladium catalyst
used, (ii) the length of the reaction time, and (iii) the
number of times the reaction was repeated (Table S1).8
3
namely, a â -hexapeptide (1, Figure 2) with different side
2
chain substitutions and two â -hexapeptides, one with
different side chain substitutions (2) and the other with no
side chain substitution (3). Finally, CD spectroscopy is used
to elucidate key structural features of the two new families
of compounds in different solvent systems.
3
2
â -Hexapeptide (1) and â -hexapeptides (2 and 3) were
synthesized utilizing a Fmoc/allyl combined solid-phase
strategy (Scheme 1), where Fmoc protection was used to
3 4
Treatment with 0.08 equiv of Pd(PPh ) and 8 equiv of
PhSiH for 35 min and repeating the reaction twice led to
3
complete deallylation. During optimization, the reaction was
monitored by test cleavage followed by analytical reversed-
phase HPLC and mass spectrometric analysis.
(5) (a) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.;
Huang, X.; Barchi, J. J., Jr.; Gellman, S. H. Nature 1997, 387, 381-384.
(
6
b) Arvidsson, P. I.; Rueping, M.; Seebach, D. Chem. Commun. 2001, 649-
2
â -Peptides 2 and 3 were prepared from orthogonally
50. (c) Rueping, M.; Mahajan, Y. R.; Jaun, B.; Seebach, D. Chemistry
R
â
protected â-amino-L-alanine, N -Alloc-N -Fmoc-L-diamino-
propionic acid (4), essentially following the same procedure
2
004, 10, 1607-1615. (d) Hart, S. A.; Bahadoor, A. B.; Matthews, E. E.;
Qiu, X. J.; Schepartz, A. J. Am. Chem. Soc. 2003, 125, 4022-4023.
(
6) Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni, B.; Oberer,
L.; Hommel, U.; Amstutz, R.; Widmer, H. HelV. Chim. Acta 1996, 79, 913-
41.
7) Farrera-Sinfreu, J.; Zaccaro, L.; Vidal, D.; Salvatella, X.; Giralt, E.;
Pons, M.; Albericio, F.; Royo, M. J. Am. Chem. Soc. 2004, 126, 6048-
057.
3
R
as that described for â -peptide 1 (Scheme 1). However, N -
â
9
Alloc-N -Fmoc-L-Dap is not commercially available. It was
(
6
(8) See Supporting Information.
26
Org. Lett., Vol. 9, No. 1, 2007