X. Gu et al. / Tetrahedron Letters 44 (2003) 5863–5866
5865
torial positions. The bridge-head H configuration can
be explained thermodynamically because the 2,5-trans-
relationship is more stable than the 2,5-cis due to steric
effects in thiazolidine formation.
chain and hemiaminal formation as discussed in our
previous paper.10 Osmylation and diol oxidation can be
completed in 2 h in THF/H2O, and without further
purification, thiazolidine formation was accomplished
in 6 h at room temperature using pyridine (Scheme 4).
The bicyclic lactam formation was accomplished in
tandem at 50°C in 4 days with no epimerization. The
b-methyl-L-cysteine (14b) used was synthesized by
modification of our recently reported method.11,23 For
purification and characterization, the bicyclic moieties
were converted to the methylated products using dia-
zomethane. The bicyclic products 16a and 16b with
different side chain groups can be synthesized in about
50% yield in three steps from the starting material 12.
The bicyclic dipeptide with different chiralities at the 3
and 4 positions (Scheme 4) also was synthesized in
comparable yield by using the (2R,3R)-amino acid as
starting material.
In summary, two enantiomers of b-substituted v-unsat-
urated amino acids have been synthesized on a large
scale. By using these novel amino acids, [4,3,0]-BTD
with two b-side chain groups and five controlled chiral
centers have been synthesized in five steps. This highly
efficient strategy makes it possible to introduce chiral
side chain functionalities in these b-turn mimetics,
which in turn can be inserted into targeted peptides in
a few steps.
Supporting information available
Experimental procedures and spectroscopic characteri-
1
zation ([h]D, H NMR, 13C NMR, HRMS) of all new
compounds.
1
The H NMR spectra of the bicyclic structures were
3
assigned by DQF-COSY. The J coupling constants of
H3 and H4 in 16a and b are 9.2 Hz, which indicates an
anti-relationship of these two hydrogens. This further
confirmed the assigned stereochemistry of the major
product 8 from the Ni(II)-alkylation. The bridge-head
H was assigned as S in all the [4,3,0]-bicyclic dipeptides.
NMR NOE studies also confirmed the bridge-head H
configuration (Fig. 2). The 1,3-diaxial proton’s NOE in
the piperidine ring of 16b indicated a pseudo-chair like
conformation, and the large 1,4-diaxial proton’s NOE
in 16c indicated a boat-like conformation which ensures
both large substitutions Ph- and TFA-HN- are in equa-
Acknowledgements
This work was supported by US Public Health Service
grants DK 17420, DA 06284 and DA 13449. The DRX
500 MHz NMR spectrometer was obtained by a grant
from the NSF (9729350). The views expressed are those
of the authors and are not necessarily those of the
USPHS.
References
1. For recent reviews of b-turn mimetics, see: (a) Souers, A.
J.; Ellman, J. A. Tetrahedron 2001, 57, 7431; (b) Halab,
L.; Gosselin, F.; Lubell, W. D. Biopolymers (Pept. Sci.)
2000, 55, 101.
2. For reviews, see: (a) Rose, R. D.; Gierasch, L. M.; Smith,
J. A. Adv. Protein Chem. 1985, 37, 109; (b) Rizo, J.;
Gierasch, L.-M. Ann. Rev. Biochem. 1992, 61, 387.
3. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789.
4. (a) Nagai, U.; Sata, K.; Nakamura, R.; Kato, R. Tetra-
hedron 1993, 49, 3577; (b) Nagai, U.; Sato, K. Tetra-
hedron Lett. 1985, 26, 647.
5. Estiarte, M. A.; Rubiralta, M.; Diez, A. J. Org. Chem.
2000, 65, 6992 and references cited therein.
6. Preissner, R.; Goede, A.; Rother, K.; Osterkamp, F.;
Koert, U.; Froemmel, C. J. Computer-Aided Molecular
Design 2001, 15, 811.
Scheme 4. Synthesis of bicyclic dipeptides derivatives with
side chain groups.
7. Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998,
120, 5363.
8. (a) Hruby, V. J.; Al-Obeidi, F.; Kazmiershi, W. Biochem.
J. 1990, 268, 249; (b) Hruby, V. J.; Li, G.; Haskell-Lue-
vano, C.; Shenderovich, M. Biopolymers (Pept.) Sci.
1997, 43, 219.
9. The stereochemistry of this designed bicyclic 2 is one of
sixteen possible diastereomers, which provide all the pre-
determined topographies for bicyclic b-turn mimetics.
10. Gu, X.; Tang, X.; Cowell, S.; Ying, J.; Hruby, V. J.
Tetrahedron Lett. 2002, 43, 6669.
Figure 2. Proposed conformations and their transient NMR
NOE of bicyclic dipeptides.