solvent predict up to 5 kJ mol21 per hydrogen bond.7 The reason
for the relatively weak binding might be due to some geometric
mismatch, but must be seen primarily as a consequence of
unfavourable secondary interactions between donor and ac-
ceptor groups. These have been elucidated by Jorgensen et al.,9
and were found to be as large as e.g. 2.8 kJ mol21 by systematic
analysis of many amide-type associations in CHCl3.7b
The degree of chiral discrimination (DDG ≈ 7 kJ mol21
)
compares favourably with the few enantioselective peptide
receptors hitherto available.8a,10 Molecular mechanics calcula-
tions (gas phase, e = 3) using CHARMm11 shed light on the
origin of the observed stereoselectivity: only with the -isomer
L
does one obtain after energy minimization a structure with the
four hydrogen bonds, as depicted in Fig. 3. Minimizations with
the
D
-isomer invariably lead to structures without hydrogen
bonds: Unfavourable interactions of the guest (
D
-2) and host
benzyl groups lead to deformation of the backbone, preventing
the formation of hydrogen bonds. As is often the case, the
observed stereoselectivity of association is a consequence of
repulsion between groups which are not involved in the
formation of non-covalent bonds, and which are remote from
the actual binding sites.
Fig. 2 Titration curves of host 1 with guests (-)
at 298 K. The line represents the best fit.
L
-2 and (!) D-2 in CDCl3
Notes and references
† E-mail: ch12hs@rz.uni-sb.de
1 V. Brandmeier, W. H. B. Sauer and M. Feigel, Helv. Chim. Acta, 1994,
77, 70; C. Gailer and M. Feigel, J. Comput. Aided Mol. Des., 1997, 11,
273 and references cited therein.
2 D. S. Kemp, B. R. Bowen and C. C. Muendel, J. Org. Chem., 1990, 55,
4650; D. S. Kemp and Z. Q. Li, Tetrahedron Lett., 1995, 36, 4175 and
4179 and references cited therein.
3 J. P. Schneider and J. W. Kelly, Chem. Rev., 1995, 95, 2169; C. L.
Nesloney and J. W. Kelly, J. Am. Chem. Soc., 1996, 118, 5836 and
references cited therein.
4 J. S. Nowick, E. M. Smith and M. Pairish, Chem. Soc. Rev., 1996, 25,
401; D. L. Holmes, E. M. Smith and J. S. Nowick, J. Am. Chem. Soc.,
1997, 119, 7665; J. S. Nowick, M. Pairish, I. Q. Lee, D. L. Holmes and
J. W. Ziller, J. Am. Chem. Soc., 1997, 119, 5413; J. S. Nowick and S.
Insaf, J. Am. Chem. Soc., 1997, 119, 10903 and references cited
therein.
5 R. R. Gardner, L. A. Christianson and S. H. Gellman, J. Am. Chem. Soc.,
1997, 119, 5041; H. E. Stanger and S. H. Gellman, J. Am. Chem. Soc.,
1998, 120, 4236 and references cited therein.
Fig. 3 Quanta/CHARMm minimized structures of the complex of host 1 and
guest -2. Hydrogen bonds are marked as dashed bonds.
L
6 A. B. Gretchikhine and M. Y. Ogawa, J. Am. Chem. Soc., 1996, 118,
1543 and references cited therein.
Table 1 NMR titration results of host 1 and guests
298 K (The data represent the mean values of two observed N–H signals)
D-2 and L-2 in CDCl3 at
7 (a) H.-J. Schneider, R. K. Juneja and S. Simova, Chem. Ber., 1989, 112,
1211; (b) J. Sartorius and H.-J. Schneider, Chem. Eur. J., 1996, 2, 1446;
H.-J. Schneider, Chem. Soc. Rev., 1994, 22, 227.
Complex
K/M21
DG/kJ mol21
CIS (ppm)
8 (a) For a short review see: H.-J. Schneider, Angew. Chem., Int. Ed.
Engl., 1993, 32, 848; Angew. Chem., 1993, 105, 890; (b) M. Famulok,
K. S. Jeong, D. Deslongchamps and J. Jr. Rebek, Angew. Chem., 1991,
103, 880; (c) R. Liu and W. C. Still, Tetrahedron Lett., 1993, 34, 2573;
(d) A. Borchardt and W. C. Still, J. Am. Chem. Soc., 1994, 116, 373; (e)
J. Dowden, P. D. Edwards and J. D. Kilburn, Tetrahedron Lett., 1997,
38, 1095; (f) E. Martinborough, T. M. Denti, P. P. Castro, T. B. Wyman,
C. B. Knobler and F. Diederich, Helv. Chim. Acta, 1995, 78, 1037; (g)
A. Casnati, E. Di Modugno, M. Fabbi, M. Pelizzi, A. Pochini, F.
Sansone, G. Tarzia and R. Ungaro, Bioorg. Med. Chem. Lett., 1996, 6,
2699; (h) M. Crego, A. Partearroyo, C. Raposo, M. L. Mussons, J. L.
Lopez, V. Alcazar and J. R. Moran, Tetrahedron Lett., 1994, 35, 1435
and references cited therein.
9 W. Jorgensen and J. Pranata, J. Am. Chem. Soc., 1990, 112, 2008.
10 S. S. Yoon and C. W. Still, Tetrahedron Lett., 1994, 35, 8557; J. Am.
Chem. Soc., 1993, 115, 823 and references cited therein.
11 B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S.
Swaminathan and M. Karplus, J. Comput. Chem., 1983, 4, 187; C. L.
Brooks and M. Karplus, Methods Enzymol., 1986, 127, 369; A.T.
Brünger and M. Karplus, Acc. Chem. Res., 1991, 24, 54.
1·
1·D
L
-2
-2 D
80 ± 6%
5 ± 10%
210.8
24.1
1.79
(1.79)
observed two N–H shifts of host compound 1 in comparison to
the CIS value of 1.8 ppm which is expected for a 100% complex
formation. The corresponding CIS for the -enantiomer com-
L
plex calculated from the least-squares fit is close to the N–H
shielding effects observed in related amide-type associations,7b
in line with the structure proposed in Fig. 1. The expected
downfield shifts of the CH(a) protons could not be evaluated
due to small shift changes and/or overlapping with other signals
during the titration. Control experiments with related peptide
derivatives, also bearing adamantyl groups for solubility reason,
showed no self-association in CHCl3; this supports the
suggestion that an effective recognition requires hydrogen
bonds from two sides of the guest as depictet in Fig. 1.
The total binding free energy DG (Table 1) for the ‘best’
isomer
-2 (11 kJ mol21) is relatively small in comparison with
values observed with related systems, which for CHCl3 as
L
Communication 8/05720F
2298
Chem Commun., 1998