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Cyclodextrin Derivatives as Chiral SelectorsЧInvestigation of the Interaction with (R S)-Methyl-2-chloropropionate by Enantioselective Gas Chromatography NMR Spectroscopy and Molecular Dynamics Simulation.

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[7] N. Wiberg, J. Organomer. Chem. 1984,273,141; S . Vollbrecht, U. Klingebiel, D. Schmidt-Base, Z. Naturforsch. B 1991, 46, 709.
[8] Crystal structure analysis of 6 : monoclinic. P2,/a, a = 17.919(18). b =
16.238(16), c = 34.53(3) A, j3 = 90.83(6)”, V = 10047 A3, Z = 8; 7501 reflections ( I > 2 4 four-circle diffractometer, Mo,, radiation, w scan),
R = 0.065, R, = 0.059 (As, Si, 0, C anisotropic, H in calculated positions,
isotropic temperature factors, phenyl rings as rigid groups, 921 parameters).‘”’
[9] The arsaalkenes 8 and 9 were characterized by ‘H NMR as well as ” C
NMR spectroscopy and also mass spectrometry. The 1,3,2,4-dioxadisilethane 7 [a(’%) = - 6.38; MS (EI, 70 eV): m/z 900 ( M i , 84(%), 435
(Is,SiH+, IOO)] is identical with the product from the oxidation of
Is,Si=SiIs, with 0,: R. West, A. Millevolte, 24th Organosilicon Symposium, April 12-13 1991, El Paso, USA.
[lo] T. C . Klebach, H. van Dongen, F. Bickelhaupt, Angew. Chem. 1979, 91,
423; Angew. Chem. Int. Ed. Engl. 1979,18, 395; G. Becker, G. Gutekunst,
Z. Anorg. Allg. Chem. 1980, 470, 144.
1111 Further details of the crystal structure investigation may be obtained from
the Fachinformationszentrum Karlsruhe. Gesellschaft fur wissenschaftlich-technische Information mbH, D-W-7514 Eggenstein-Leopoldshafen 2
(FRG) on quoting the depository number CSD-55937, the names of the
authors, and the journal citation.
pentyl)-P-CD (Lipodex D, 2).[41On capillary columns coated
with 2, the enantiomers of 1 are resolved with an unusually
large separation factor (c( = 2.02, on a 25 m “fused-silica
capillary” at 333 K AAG& = 2 kJmol-’).
The ‘HNMR spectrum of a solution of 1 and 2 in a nonpolar solvent ([D,,]cyclohexane, [D ‘Jhexane) shows significantly different signals for (R)-1 and (S)-1. All signals of the
( S ) enantiomer are shifted to lower field by up to A6 = 0.5
in comparison to the ( R ) enantiomer (Fig. 1). Futhermore,
Cyclodextrin Derivatives as Chiral SelectorsInvestigation of the Interaction with (&!?)-Methyl2-chloropropionate by Enantioselective Gas
Chromatography, NMR Spectroscopy, and
Molecular Dynamics Simulation**
By Jutta E. H . Kohler, Manfred ffohla,Martina Richters,
and Wilfried A . Konig*
Dedicated to Professor Ernst Bayer
on the occasion of his 65th birthday
Enantiomeric substrates form energetically and structurally distinguishable host-guest complexes with cyclodextrins and their derivatives. This is shown, for example, in the
investigation of chiral substrates in the presence of cyclodextrins by enantioselective chromatography,“] NMR spectroscopy,[’] and X-ray structure analysis.[31To understand
the host-guest interaction and thereby, the “chiral recognition” it would be very useful to obtain information concerning the spatial relationship between host and guest molecules
in molecular complexes.
The model we investigated involves (R,S)-methyl-2-chloropropionate 1 complexed with heptakis(3-O-acetyl-2,6-di-OOR6
2,R3= R6 = n-pentyl, R3 = acetyl
[*] Dr. J. E. H. Kohler. M. Hohla
Consortium fur Elekrochemische Industrie
Zielstattstrasse 20, D-W-8000 Munchen 70 (FRG)
Prof. Dr. W. A. Konig. M. Richters
Institut fur Organische Chemie der Universitat
Martin-Luther-King-Platz 6, D-W-2000 Hamburg 13 (FRG)
[*‘I This work was supported by the Deutscbe Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. Engl. 31 (1992j No. 3
Fig. 1. 400 MHz ‘H NMR spectra of (R,S)-1 (below) with the signals of the
methyl (a), methine (b), and methoxy groups (c), of (R,S)-1 and 2 in mol ratio
1:2.25 (middle; the resonance signals a, b, and c show different chemical shifts
for the enantiomers) and of 2 ( above). All spectra were recorded in [D,,]cyclohexane.
the methine proton of (S)-1does not show a quartet, but a
signal of higher order (Fig. 2). This could indicate a nonequivalence of the coupling CH, protons as a result of a
specific interaction with the chiral host molecule in the inclusion complex.
The differences in the chemical shift values decrease on
raising the temperature and also on increasing the hostguest ratio. Similar, though less pronounced effects appeared in the ‘H NMR spectra of solutions of 2 and either
(R,S)-methyl-2-bromopropionate, (R,S)-methyllactate, or
(R,S)-methylmandelate. In every case, the protons of the
enantiomer retained more strongly on the GC column also
absorb at lower field. Thus, in principle, cyclodextrin derivatives are suitable as chiral shift reagents. A similar example
of discrimination for the enantioselective inclusion of enantiomers was reported by A. Collet et al.”’ for bromochlorofluoromethane and a synthetic cryptophane.
Verlagsgeselischaf~mbH, W-6940 Weinheim, 1992
0570-0833/92/0303-0319$ 3 X t .2S/O
Fig. 2. Resonance signal of the methine proton of (R)-1 (right) and (S)-1 (le
Recording conditions as for Figure 1 .
To investigate why (S)-1 complexes more effectively wi
2, a total of four models for molecular dynamics (MD) sir
ulations[‘I was applied (Fig. 3).
s- u p
R - down
Fig. 3. Molecular dynamic models of complexes from 1and 2. The numbers 2,
3, and 6 (in the upper left picture) indicate the position of the snbstituents at
C-2, C-3, and C-6, respectively, of the glucose units of 2. This position is the
same in all four models.
Based on the known X-ray structure data of P-CD,”] the
side chains of 2 were fixed in the 2, 3, and 6 positions of the
glucose units, in such a way that they were oriented as evenly
as possible vertically upwards (wider opening of the cavity,
substituents at C-2 and (2-3, see Fig. 3 ) and downwards (substituents at C-6). The substrates (S)-1and (R)-1 were placed
vertically in both orientations (Fig. 3) in the cavity of 2.
Following this, the energy was minimized (under vacuum
at 0 K) and then an M D simulation using the Discover program (version 2.6) over five picoseconds @s) was carried
out.[8]During the first picosecond the simulation proceeded
at a temperature of 3 K, in order to carefully relax the possibly existing large strains of the energy-minimized structures.
In the course of the second to fifth picosecond the temperature was 300 K. Both the “S-down” and the “R-down” complexes proved to be unstable. Already, after the third picosecond, the guest molecule has left the cavity of 2 (Fig. 4a, b).
After 5 ps, the host and guest are completely separated. A
return is not likely as a result of the high speed of the substrate.
The “S-up” complex proved to be the most stable. After
the fifth picosecond, the substrate is still found in the cavity
of 2 (Fig. 4c). For the “R-up” complex, after this time, the
guest molecule is outside the cavity but still in the active
region of the hydrophobic side-chains (Fig. 4 d).
‘cVCH Verlagsgesellschafi mbH, W-6940 Weinheim, 1992
Fig. 4. Molecular dynamic trajectories over 5 ps for the complexes “S-down”
(a), “R-down” (b), “S-up” (c). and “R-up” (d) from 1 (yellow and orange) and
2 (blue). The upper left picture shows the starting structnre of each, next to
which are shown the simulated structures obtained after 1 and 2 ps, and in the
second row, those occurring after 3,4, and 5 ps. Further explanations see text.
These results are in agreement with the GC and NMR
results, which show that (S)-1 forms the more stable complex
with 2. Furthermore, NOE measurements on the (S)-l/2and
(R)-1/2systems showed that the methoxy group is, in agreement with the “up” orientation of the substrate, in the vicinity of the C-3 proton of the glucose units. A detailed spatial
assignment has hitherto not been possible due to the complexity of the NMR spectra.
It should be noted, that a period of 5 ps is not sufficient for
an unequivocal result, in the sense of statistical mechanics
and with regard to the molecular dynamics. We will continue
these studies with the aim to obtain information about the
interactions existing for the complexation between host and
guest molecules, from the trajectories obtained via simulations over considerably longer periods.
Received: September 17, 1991 [Z4918IE]
German version: Angew. Chem. 1992, 104, 362
CAS Registry numbers:
1, 40705-03-1 ; (R)-l/2, 138667-23-9; (S)-1/2, 138667-24-0; 2, 120614-93-9.
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5350-5354; we have used the CVFF force field without cross terms with
harmonic potential.
0570-0833/92/0303-0320 $3.50+.25/0
Angen,. Chem. In(. Ed. Engl. 31 (1992) N o . 3
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chloropropionate, simulation, molecular, enantioselectivity, gas, dynamics, derivatives, selectorsчinvestigation, chiral, methyl, spectroscopy, nmr, interactiv, chromatography, cyclodextrin
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