and increase the peptide stability, and this has therefore led
to the formation of a number of such products.12,13
Various enantioselective methods are known for the
Scheme 1. Cyclic â-Lactams Used as â-Amino Acid
Precursors
14-16
synthesis of â-lactams.
Enantioselective methods or
1
7
kinetic resolutions lead to enantiomeric â-lactams. Since
nucleophilic attack opens the ring without difficulty, these
4,18
compounds can be used as â-amino acid precursors. When
an amine is used as nucleophile, the product is the corre-
sponding amide.19 The strategy is generally referred to as
20
the â-lactam synthon method. Palomo and co-workers
utilized this synthetic strategy in the liquid phase for the
synthesis of short peptide segments.21 Our present aim was
to extend the peptide synthetic strategies to cyclic â-peptides
and to use diverse cyclic â-lactams in peptide syntheses, on
a solid support.
A variety of model cyclic â-lactams were selected: a five-
membered ring (()-1 (a racemic cispentacin precursor), an
eight-membered ring with a double bond, (()-3, and a
benzene-fused five-membered system (()-5 (indan system),
Scheme 1. The syntheses of the starting model compounds
were straightforward: 1,2-dipolar cycloaddition of chloro-
sulfonyl isocyanate (CSI) to cyclopentene, 1,5-cyclooctadi-
ene, or indene, respectively, resulting in the corresponding
23
t-Boc chemistry. The peptide chains were elongated on an
MBHA resin, and the syntheses were carried out manually.
Couplings of Gly and Ala were first performed with
dicyclohexylcarbodiimide (DCC) without difficulty. After the
incorporation of Ala, the Boc-protected â-lactams were
introduced into the growing peptide chain, with KCN as
catalyst in DMF. In the last step, Ala was again inserted.
Amino acid incorporation was monitored by the ninhydrin
22
â-lactams, which after tert-butoxypyrocarbonate treatment
afford the corresponding racemic N-Boc â-lactams. The
enantiomeric N-Boc-protected (1S,5R)-6-azabicyclo[3.2.0]-
heptan-7-one was prepared by lipolase-catalyzed kinetic
resolution of (()-6-azabicyclo[3.2.0]heptan-7-one, followed
by N-Boc protection.1
24
test. The completed peptide resins were treated with liquid
HF/dimethyl sulfide/p-cresol/p-thiocresol at 0 °C for 1 h.
HF was removed, and the resulting free peptides were
solubilized in 10% aqueous acetic acid, filtered, and lyo-
philized. The crude peptides were investigated and purified
by reversed-phase HPLC. The model peptides were charac-
terized by mass spectrometry, using a tandem quadrupole
mass spectrometer equipped with an electrospray ion source.
Scheme 2 shows the synthetic pathway when, for example,
7a
The peptide sequences 10-13 (H-Ala-ACXC)-Ala-Gly-
NH ) were synthesized by a solid-phase technique, utilizing
2
(11) (a) Martinek, T. A.; T o´ th, G. K.; Vass, E.; Holl o´ si, M.; F u¨ l o¨ p, F.
Angew. Chem., Int. Ed. 2002, 41, 1718. (b) Martinek, T. A.; F u¨ l o¨ p, F. Eur.
J. Biochem. 2003, 270, 3657.
(12) (a) Boz o´ , B.; F u¨ l o¨ p, F.; T o´ th, G. K.; T o´ th, G.; Szucs, M.
(
1S,5R)-6-azabicyclo[3.2.0]heptan-7-one was used for the
Neuropeptides 1997, 31, 367. (b) T o´ th, G.; Keresztes, A.; T o¨ mb o¨ ly, C.;
P e´ ter, A.; F u¨ l o¨ p, F.; Tourw e´ , D.; Navratilova, E.; Varga, E.; Roeske, W.
E.; Yamamura, H. Y.; Sz u¨ cs, M.; Borsodi, A. Pure Appl. Chem. 2004, 76,
synthesis of tetrapeptide 10. The HPLC analysis indicated
that no epimerization occurred during the synthesis. When
racemic â-lactams 1, 3, and 5 were used, the HPLC profiles
showed two separate tetrapeptide signals with the same
molecular mass. The peaks were easily separated, except in
the case of (()-6-azabicyclo[3.2.0]heptan-7-one, where the
diastereomeric peaks for the tetrapeptide partly overlapped.
The model tetrapeptides (Table 1) synthesized (H-Ala-
9
51.
13) Strijowski, U.; Sewald, N. Org. Biomol. Chem. 2004, 2, 1105. De
(
Pol, S.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew. Chem., Int.
Ed. 2004, 43, 511. (c) Hajen., A.; Schmitt, M. A.; Ngassa, F. N.; Thomasson,
K. A.; Gellman, S. H. Angew. Chem., Int. Ed. 2004, 43, 505. (d) Ezquierdo,
S.; Kogan, M. J.; Parella, T.; Moglioni, A. G.; Branchadell, V.; Giralt, E.;
Ortuno, R. M. J. Org. Chem. 2004, 69, 5093.
(
14) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oirbide, M. Eur. J. Org.
Chem. 1999, 3223.
15) (a) Adam, W.; Groer, P.; Humpf, H.-U.; Saha-M o¨ ller, C. R. J. Org.
(
2
ACXC)-Ala-Gly-NH ) were as follows: 10, H-Ala-(1S,2R-
Chem. 2000, 65, 4919. (b) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young,
B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626. (c) Alonso,
E.; del Pozo, C.; Gonz a´ lez, J. J. Chem. Soc., Perkin Trans. 1 2002, 571.
(16) (a) Adam, W.; Groer, P.; Humpf, H.-U.; Saha-M o¨ ller, C. R. J. Org.
Chem. 2000, 65, 4919. (b) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young,
B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626. (c) Alonso,
E.; del Pozo, C.; Gonz a´ lez, J. J. Chem. Soc., Perkin Trans. 1 2002, 571.
Table 1. HPLC and MS Characterization of the Synthetized
Model Peptidesa
(
17) (a) Forr o´ , E.; F u¨ l o¨ p, F. Org. Lett. 2003, 5, 1209. (b) Park, S.; Forr o´ ,
E.; Grewal, H.; F u¨ l o¨ p, F.; Kazlauskas, R. J. AdV. Synth. Catal. 2003, 345,
86. (c) Forr o´ , E.; F u¨ l o¨ p, F. Tetrahedron: Asymmetry 2004, 15, 573. (d)
code
calcd m
found m
HPLC tR (A)
HPLC tR (B)
9
b
10
11
12
327.39
327.39
367.75
375.43
328
328
368
376
6.14
6.12
12.70
Forr o´ , E.; F u¨ l o¨ p, F. Tetrahedron: Asymmetry 2004, 15, 0000. (e) A recent
review: Forr o´ , E.; F u¨ l o¨ p, F. Mini ReV. Org. Chem. 2004, 1, 93.
b
b
6.44
c
c
17.22
(18) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oirbide, M. Synlett 2001,
d
15.33d
1
2, 1813.
19) (a) Llin a´ s, A.; Page, M. I. Org. Biomol. Chem. 2004, 2, 651. (b)
13
14.33
(
a
Szakonyi, Z.; F u¨ l o¨ p, F. ArkiVoc 2003, xiv, 225.
HPLC column: Vydac HS 201 (4.6 × 250 mm). The solvent system
(
20) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997, 26, 377.
used was 0.1% trifluoroacetic acid (TFA) in water, 0.1% TFA, 80%
b
(21) (a) Palomo, C.; Ganboa, I.; Oirbide, M.; Sciano, G. T.; Miranda, J.
acetonitrile in water, gradients: 5% f 80% in 25 min, flow 1.2 mL/min,
c
I. ArkiVoc 2002, v, 8. (b) Palomo, C.; Oirbide, M.; Bindi, S. J. Org. Chem.
998, 63, 2469. (c) Palomo, C.; Oirbide, M.; Landa, A.; Esnal, A.; Linden,
A. J. Org. Chem. 2001, 66, 4180.
detection at 220 nm. 15% f 30% in 30 min, flow 1 mL/min, detection at
220 nm. d 0% f 60% in 20 min, flow 1 mL/min, detection at 220 nm.
1
4240
Org. Lett., Vol. 6, No. 23, 2004