Versatile and practical chiral shift reagent with hydrogen-bond donor/acceptor sites in a macrocyclic cavity

Article abstract of DOI:10.1021/ol0613665

Bifunctional macrocycle 1 with C₂ symmetry was newly synthesized. NMR studies demonstrated that receptor 1 functions as a chiral shift reagent (solvating agent) that is highly effective for a wide range of chiral compounds having a carboxylic a

Full text of DOI:10.1021/ol0613665

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3773-3775
Versatile and Practical Chiral Shift
Reagent with Hydrogen-Bond Donor/
Acceptor Sites in a Macrocyclic Cavity
Tadashi Ema,* Daisuke Tanida, and Takashi Sakai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and
Technology, Okayama UniVersity, Tsushima, Okayama 700-8530, Japan
ema@cc.okayama-u.ac.jp
Received June 5, 2006
ABSTRACT
Bifunctional macrocycle 1 with C2 symmetry was newly synthesized. NMR studies demonstrated that receptor 1 functions as a chiral shift
reagent (solvating agent) that is highly effective for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, lactone,
alcohol, sulfoxide, sulfoximine, isocyanate, or epoxide functionality. Binding constants were determined to investigate the binding behavior
of 1.
Because of increasing opportunities to synthesize chiral
compounds, a facile and environmentally benign tool to
determine their enantiomeric purities is required. Chiral shift
reagents (solvating agents), using a small amount of deu-
terated solvent without derivatization, have great potential
to achieve quick and green determination as compared with
chiral HPLC or chiral derivatizing agents. Various types of
chiral shift reagents such as lanthanide complexes,1 cyclo-
dextrins,2 crown ethers,3 calixarenes,4 porphyrins,5 and others6
have been developed. However, few of them have been
commercialized except for lanthanide complexes, which often
cause signal broadening particularly at a high magnetic field
because of the paramagnetic metal.
To find practical utility, a highly versatile reagent suitable
for modern high-field NMR spectrometers needs to be
designed carefully, which must be synthesized easily and
inexpensively. In this context, we envisioned that a bifunc-
(5) (a) Simonato, J.-P.; Chappellet, S.; Pe´caut, J.; Baret, P.; Marchon,
J.-C. New J. Chem. 2001, 25, 714-720. (b) Claeys-Bruno, M.; Toronto,
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Org. Lett. 2005, 7, 3985-3988.
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10.1021/ol0613665 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/27/2006

tional host bearing both hydrogen-bond donor and acceptor
sites could bind a wide range of compounds, giving sharp
NMR signals. Here, we report that bifunctional macrocycle
1 functions as a chiral shift reagent that is effective for a
variety of chiral compounds, such as carboxylic acid,
oxazolidinone, lactone, alcohol, sulfoxide, sulfoximine, iso-
cyanate, and epoxide compounds.
Table 1. Selected Regions of NMR Spectra of Racemic Guests
2-10 in the Presence of (R)-1a
We selected N,N′-bis(6-acylamino-2-pyridinyl)isophthala-
mide as a binding unit, which has both hydrogen-bond donor
and acceptor sites. Because Hamilton and co-workers had
demonstrated that macrocycles having this binding unit are
effective hosts for barbiturates and phosphoric acids,7 we
expected that this binding unit would also be useful for other
compounds. We introduced a nitro group to strengthen the
hydrogen-bond donor ability of the nearest amide groups.
BINOL was selected as an inexpensive chiral unit having
an anisotropic ring-current effect and connected with the
binding unit as closely as possible to construct a compact
macrocyclic cavity.8 Synthesis of 1 was quite easy and
practical (Supporting Information).
To investigate the chiral discrimination ability of 1, we
measured NMR spectra for 1:1 mixtures of (R)-1 and chiral
compounds 2-10 in CDCl3. The results are summarized in
1
Table 1. The resonances for the H or 19F nuclei, indicated
by the arrows in 2-10, showed chemical shift nonequiva-
lences upon complexation with (R)-1. The spectra in Table
1 are characterized by the remarkable signal separations
without line broadening. Good enantiomeric discrimination
was achieved in many cases (∆∆δ > 0.15 ppm for 3-8). In
the case of sulfoxide 7, all four resonances were resolved
completely, one of which exhibited a paramount separation
(∆∆δ ) 0.55 ppm). Enantiomers of fluorine-containing
alcohol 6 were discriminated by 19F NMR. The highly
reactive reagent, isocyanate 9, could be analyzed without
reaction or decomposition. Although epoxide 10 could not
be differentiated by 1 at 22 °C, the signal for the proton
attached to the asymmetric carbon was separated by decreas-
ing the temperature to -50 °C (Table 1). We also found
that in some cases even 0.05 equiv of (R)-1 was enough to
1
1
a 600 MHz H NMR of 2-5 and 7-9; 300 MHz H NMR of 10; and
565 MHz 19F NMR of 6 in the presence of (R)-1 (15 mM, 1 equiv) in
CDCl3 at 22 °C. The resonances for the protons or fluorines indicated by
the arrows are shown in the right column. The signals for the enantiomers
were assigned by adding some amount of one enantiomer to the above
solution. Filled and open circles represent (R)/(1R,5S)- and (S)/(1S,5R)-
enantiomers, respectively. b At -50 °C.
afford a baseline separation; e.g., ∆∆δ ) 0.03 ppm for the
4-methyl protons of 7.
To specify the binding sites in 1, the complexation-induced
shifts of the resonances for 1 were measured. A typical
example is shown in Figure 1. Among the Ha-Hd protons
designated in Figure 2, the Ha protons showed the largest
downfield shift (∆δ ) 1.59 ppm at 48 mM (S)-7), which
strongly suggests that the two Ha atoms are hydrogen-bonded
with the SdO group of (S)-7. The Hc signal also underwent
a downfield shift (∆δ ) 0.47 ppm). These trends were
observed in all cases examined. In addition, the CO2H signal
of (S)-2 and the NH signal of (R)-4 also shifted downfield
(7) (a) Chang, S.-K.; Engen, D. V.; Fan, E.; Hamilton, A. D. J. Am.
Chem. Soc. 1991, 113, 7640-7645. (b) Hirst, S. C.; Tecilla, P.; Geib, S. J.;
Fan, E.; Hamilton, A. D. Isr. J. Chem. 1992, 32, 105-111.
(8) For a recent review on macrocycles, see: Gibson, S. E.; Lecci, C.
Angew. Chem., Int. Ed. 2006, 45, 1364-1377.
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Org. Lett., Vol. 8, No. 17, 2006

Table 2. Binding Constants and Chiral Recognition Energies
of (R)-1 for Chiral Guests
a
b
guest
Ka (M-1
)
∆∆G° (kcal mol-1
)
(R)-2
(S)-2
(R)-4
(S)-4
(1R,5S)-5
(1S,5R)-5
(R)-7
(S)-7
(R)-8
1670
3050
510
280
51
-0.35
+0.35
+0.26
-0.85
-0.93
33
610
2600
170
830
(S)-8
a In CDCl3 at 22 °C. The Ka values were calculated by the nonlinear
least-squares method. The standard deviations were within 7%. b Chiral
recognition energy calculated from -RT ln{Ka(S)/Ka(R)}.
Figure 1. Plots of the complexation-induced shifts (∆δ) for the
Ha-Hd protons of (R)-1 (12 mM) as a function of [(S)-7] in CDCl3
at 22 °C.
8. Table 2 also indicates that receptor 1 has a good ability to
recognize the chirality of the guests.9 For example, the Ka
values for (S)-7 and (S)-8 are 4.3- and 4.9-fold higher, respec-
tively, than those for (R)-7 and (R)-8, the latter of which
amounts to the energetic difference of -0.93 kcal mol-1. It
was found that in most cases the signals for the enantiomer
having a higher affinity for (R)-1 were shifted to a greater
extent as compared with those for the antipodal enantiomer.
Enantioselective binding as well as the differential ring-cur-
rent effect of the binaphthyl moiety are important for the high
degree of enantiomeric discrimination in NMR (Table 1).
In summary, readily accessible, bifunctional macrocycle
1 functions as a versatile chiral shift reagent that is highly
effective for a wide range of chiral compounds having a
carboxylic acid, oxazolidinone, lactone, alcohol, sulfoxide,
sulfoximine, isocyanate, or epoxide functionality. Such a
versatile organoreagent is unprecedented. The resolved
signals for these chiral compounds remain sharp upon
complexation with 1, which demonstrates that hydrogen-
bond-based reagent 1 is suitable for high-field NMR
spectrometers. Further work is in progress to commercialize
this useful compound.
by 1.9 and 1.4 ppm, respectively, when 1 equiv of (R)-1
was added (Supporting Information). Therefore, it is likely
that lactone 5 and sulfoxide 7 are fixed by the double
hydrogen bonds and that carboxylic acids 2 and 3 and
oxazolidinone 4 are fixed by the triple hydrogen bonds as
represented by Figure 2, which were supported by MO
calculations and the following thermodynamic analysis.
The binding constants (Ka) of (R)-1 for several guests were
determined by NMR titrations. Assuming 1:1 complexation,
which was supported by Job plots (Supporting Information),
we calculated the Ka values by means of the nonlinear least-
squares method applied to the Ha signal downfield shifted
upon addition of the guest. Table 2 summarizes the data. The
relatively large Ka values suggest that the functional groups
directed inside the cavity of 1 are preorganized well and
solvated weakly, providing effective binding sites. The Ka
values decrease roughly in the following order: carboxylic
acid ∼ sulfoxide > sulfoximine ∼ oxazolidinone > lactone,
which reflects the number of the hydrogen bonds between the
host and guest (Figure 2) with two exceptions, carboxylic acid
and sulfoxide. When the two-point interaction systems are
compared, the more polar compound, sulfoxide 7, is bound
much more strongly than lactone 5. In the three-point inter-
action systems, the more acidic compound, carboxylic acid
2, is fixed more tightly than oxazolidinone 4 and sulfoximine
Acknowledgment. We thank Prof. M. Kojima and Dr.
T. Nitoda (Okayama University) for the measurement of CD
and mass spectra, respectively. We are grateful to the SC-
NMR Laboratory of Okayama University for the measure-
ment of NMR spectra.
Supporting Information Available: Synthetic procedures
1
for 1, Job plots, determination of binding constants by H
NMR titration, PFG-HMBC and NOESY spectra to assign
1
the Ha and Hb signals of 1, copies of H NMR, 13C NMR,
and CD spectra, and MO calculations of the complexes. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0613665
(9) For enantioselective binding, see: (a) Famulok, M.; Jeong, K.-S.;
Deslongchamps, G.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1991, 30,
858-860. (b) Hayashi, T.; Aya, T.; Nonoguchi, M.; Mizutani, T.; Hisaeda,
Y.; Kitagawa, S.; Ogoshi, H. Tetrahedron 2002, 58, 2803-2811. (c) Oliva,
A. I.; Simo´n, L.; Mun˜iz, F. M.; Sanz, F.; Ruiz-Valero, C.; Mora´n, J. R. J.
Org. Chem. 2004, 69, 6883-6885.
Figure 2. Double and triple hydrogen bonds between the host and
guest.
Org. Lett., Vol. 8, No. 17, 2006
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