Versatile and practical macrocyclic reagent with multiple hydrogen-bonding sites for chiral discrimination in NMR

Article abstract of DOI:10.1021/ja073476s

Bifunctional macrocycles 1-4 and diamide 5 were designed and synthesized. NMR studies demonstrated that, among them, receptor 1 functions as the best chiral solvating agent (shift reagent), which is effective for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, carbonate, lactone, alcohol, sulfoxide, sulfoximine, sulfinamide, isocyanate, or epoxide functionality. The addition of only 5 mol % (69 μg, 0.15 mM) of 1 splits the enantiomeric signals of sulfoxide 13. The excellent performance of 1 as a chiral solvating agent, such as versatility, signal sharpness, high splitting ability, high sensitivity, wide detection window, and synthetic accessibility, is reported. NMR studies revealed that the principal binding site of 1 is the two amide NH groups of the lower segment and that the additional binding site is the pyridyl nitrogen. The V-shaped arrangement of the two 2,6-diacylaminopyridine moieties as constructed in 1 was found to be much more effective for binding a variety of compounds than the parallel alignment of the two binding motifs as constructed in 4. The NO₂ group in 1 enhanced not only the binding ability but also the degree of enantioselectivity. Unexpectedly, the comparisons between 1 and 3 enabled us to find the importance of the relative orientation of the binaphthyl moiety; the orthogonal disposition of the binaphthyl moiety in 1 most effectively brings about the differential ring-current effect on the chiral guest molecule bound, which leads to the high degree of chiral discrimination in NMR.

Full text of DOI:10.1021/ja073476s

Published on Web 08/04/2007
Versatile and Practical Macrocyclic Reagent with Multiple
Hydrogen-Bonding Sites for Chiral Discrimination in NMR
Tadashi Ema,* Daisuke Tanida, and Takashi Sakai*
Contribution from the DiVision of Chemistry and Biochemistry, Graduate School of Natural
Science and Technology, Okayama UniVersity, Tsushima, Okayama 700-8530, Japan
Received May 16, 2007; E-mail: ema@cc.okayama-u.ac.jp
Abstract: Bifunctional macrocycles 1-4 and diamide 5 were designed and synthesized. NMR studies
demonstrated that, among them, receptor 1 functions as the best chiral solvating agent (shift reagent),
which is effective for a wide range of chiral compounds having a carboxylic acid, oxazolidinone, carbonate,
lactone, alcohol, sulfoxide, sulfoximine, sulfinamide, isocyanate, or epoxide functionality. The addition of
only 5 mol % (69 µg, 0.15 mM) of 1 splits the enantiomeric signals of sulfoxide 13. The excellent performance
of 1 as a chiral solvating agent, such as versatility, signal sharpness, high splitting ability, high sensitivity,
wide detection window, and synthetic accessibility, is reported. NMR studies revealed that the principal
binding site of 1 is the two amide NH groups of the lower segment and that the additional binding site is
the pyridyl nitrogen. The V-shaped arrangement of the two 2,6-diacylaminopyridine moieties as constructed
in 1 was found to be much more effective for binding a variety of compounds than the parallel alignment
of the two binding motifs as constructed in 4. The NO2 group in 1 enhanced not only the binding ability but
also the degree of enantioselectivity. Unexpectedly, the comparisons between 1 and 3 enabled us to find
the importance of the relative orientation of the binaphthyl moiety; the orthogonal disposition of the binaphthyl
moiety in 1 most effectively brings about the differential ring-current effect on the chiral guest molecule
bound, which leads to the high degree of chiral discrimination in NMR.
Introduction
complexes often cause signal broadening particularly at a high
magnetic field because of the paramagnetic metal, and some-
times form precipitates via a ligand exchange, while crown
ethers are effective only for amines. In many cases, a large
amount of reagent is needed to give rise to signal splitting.1,2
Because of increasing opportunities for asymmetric synthesis,
a quick and facile way of determining the enantiomeric purity
is required. Chiral solvating agents and shift reagents essentially
have good potential for this purpose because the enantiomeric
purity can be determined just by adding the reagent to a chiral
compound in a small amount of deuterated solvent.1,2 In a rare
but ideal case, a catalytic amount of reagent is enough for chiral
discrimination in NMR. Therefore, chiral solvating agents have
an advantage over chiral derivatizing agents,3 which are used
in excess for derivatization before analysis, and over chiral
HPLC, which consumes much more solvent.
(7) (a) Yanagihara, R.; Tominaga, M.; Aoyama, Y. J. Org. Chem. 1994, 59,
6865-6867. (b) Zheng, Y.-S.; Zhang, C. Org. Lett. 2004, 6, 1189-1192.
(c) Dignam, C. F.; Richards, C. J.; Zopf, J. J.; Wacker, L. S.; Wenzel, T.
J. Org. Lett. 2005, 7, 1773-1776.
(8) (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, D.;
Pe´caut, J.; Bardet, M.; Marchon, J.-C. J. Am. Chem. Soc. 2001, 123, 11067-
11068. (c) Schwenninger, R.; Schlo¨gl, J.; Maynollo, J.; Gruber, K.;
Ochsenbein, P.; Bu¨rgi, H.-B.; Konrat, R.; Kra¨utler, B. Chem.-Eur. J. 2001,
7, 2676-2686. (d) Ema, T.; Ouchi, N.; Doi, T.; Korenaga, T.; Sakai, T.
Org. Lett. 2005, 7, 3985-3988.
(9) Reagents making use of hydrogen bonding: (a) Deshmukh, M.; Dun˜ach,
E.; Juge, S.; Kagan, H. B. Tetrahedron Lett. 1984, 25, 3467-3470. (b)
Bilz, A.; Stork, T.; Helmchen, G. Tetrahedron: Asymmetry 1997, 8, 3999-
4002. (c) Pakulski, Z.; Demchuk, O. M.; Kwiatosz, R.; Osinski, P. W.;
Swierczynska, W.; Pietrusiewicz, K. M. Tetrahedron: Asymmetry 2003,
14, 1459-1462. (d) Sada, K.; Tateishi, Y.; Shinkai, S. Chem. Lett. 2004,
33, 582-583. (e) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am. Chem.
Soc. 2005, 127, 7996-7997. (f) Cuevas, F.; Ballester, P.; Perica`s, M. A.
Org. Lett. 2005, 7, 5485-5487. (g) Koscho, M. E.; Pirkle, W. H.
Tetrahedron: Asymmetry 2005, 16, 3345-3351. (h) Ema, T.; Tanida, D.;
Sakai, T. Org. Lett. 2006, 8, 3773-3775. (i) Gonza´lez-AÄ lvarez, A.; Alfonso,
I.; Gotor, V. Tetrahedron Lett. 2006, 47, 6397-6400. (j) Ma, F.; Ai, L.;
Shen, X.; Zhang, C. Org. Lett. 2007, 9, 125-127.
(10) Reagents making use of π-π stacking: (a) Uccello-Barretta, G.; Balzano,
F.; Martinelli, J.; Berni, M.-G.; Villani, C.; Gasparrini, F. Tetrahedron:
Asymmetry 2005, 16, 3746-3751. (b) Palomino-Scha¨tzlein, M.; Virgili,
A.; Gil, S.; Jaime, C. J. Org. Chem. 2006, 71, 8114-8120. (c) Pe´rez-
Trujillo, M.; Virgili, A. Tetrahedron: Asymmetry 2006, 17, 2842-2846.
(11) Reagents making use of ion pairing: (a) Lacour, J.; Ginglinger, C.; Favarger,
F.; Torche-Haldimann, S. Chem. Commun. 1997, 2285-2286. (b) Lacour,
J.; Vial, L.; Herse, C. Org. Lett. 2002, 4, 1351-1354. (c) Hebbe, V.;
Londez, A.; Goujon-Ginglinger, C.; Meyer, F.; Uziel, J.; Juge´, S.; Lacour,
J. Tetrahedron Lett. 2003, 44, 2467-2471.
Various types of chiral solvating agents or shift reagents have
been reported, such as lanthanide complexes,2,4 cyclodextrins,5
crown ethers,6 calixarenes,7 porphyrins,8 and others.1,9-11 Al-
though a few of them are commercially available, the lanthanide
(1) Weisman, G. R. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1983; Vol. 1.
(2) Fraser, R. R. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1983; Vol. 1.
(3) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519. (b)
Yamaguchi, S. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1983; Vol. 1. (c) Seco, J. M.; Quin˜oa´, E.; Riguera, R.
Chem. ReV. 2004, 104, 17-117.
(4) Inamoto, A.; Ogasawara, K.; Omata, K.; Kabuto, K.; Sasaki, Y. Org. Lett.
2000, 2, 3543-3545.
(5) Wenzel, T. J.; Amonoo, E. P.; Shariff, S. S.; Aniagyei, S. E. Tetrahedron:
Asymmetry 2003, 14, 3099-3104.
(6) (a) Wenzel, T. J.; Thurston, J. E. J. Org. Chem. 2000, 65, 1243-1248. (b)
Wenzel, T. J.; Freeman, B. E.; Sek, D. C.; Zopf, J. J.; Nakamura, T.;
Yongzhu, J.; Hirose, K.; Tobe, Y. Anal. Bioanal. Chem. 2004, 378, 1536-
1547. (c) Lovely, A. E.; Wenzel, T. J. Tetrahedron: Asymmetry 2006, 17,
2642-2648.
9
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J. AM. CHEM. SOC. 2007, 129, 10591-10596
10591

A R T I C L E S
Ema et al.
Chart 1. Chemical Structures of Reagents 1-5
To find practical utility, the ideal performance needs to be
pursued, such as versatility, signal sharpness, high splitting
ability, high sensitivity, wide detection window, and synthetic
accessibility.
Two BINOL derivatives, having an anisotropic ring-current
effect, were selected as chiral units and connected with the
binding units as closely as possible to construct compact
macrocyclic cavities.16 The compounds 1-5, showing reso-
nances only at localized chemical shifts, have wide detection
windows, which is suitable for the analysis of various com-
pounds. The synthesis of 1-5 was quite easy and practical
(Supporting Information).
In this context, we decided to search for a highly versatile
and powerful reagent that is suitable for modern high-field NMR
spectrometers and that can be synthesized easily and inexpen-
sively.9h We employed hydrogen bonding as a driving force of
binding and designed the hydrogen-bond-based reagents 1-5
(Chart 1). We envisioned that bifunctional hosts bearing both
hydrogen-bond donor and acceptor sites could bind a wide range
of compounds. Here, we report how we found the best reagent
1, characterizing the properties of 1-5 in detail. Chiral macro-
cycle 1 is an extremely versatile reagent that is effective for a
wide range of chiral compounds such as carboxylic acid, oxazol-
idinone, carbonate, lactone, alcohol, sulfoxide, sulfoximine,
sulfinamide, isocyanate, and epoxide compounds. Furthermore,
1 showed high sensitivity; in a case, the addition of only 5 mol
% (69 µg, 0.15 mM) of 1 resolved the enantiomeric signals.
NMR Study. To evaluate the chiral discrimination abilities
of chiral hosts 1-5, we measured NMR spectra for 1:1 or 2:1
mixtures of (R)-1-5 and chiral compounds 6-17 in CDCl3.
The results are summarized in Tables 1 and S2-S5 (Supporting
1
Information), where the resonances for the H or 19F nuclei
indicated by the arrows in 6-17 are shown in the right column.
Figure 1 compares the absolute values of the chemical shift
nonequivalences (∆∆δ) induced by complexation with 1-5.
Chemical shift nonequivalences were observed in many cases.
Although macrocycles 1 and 2 with C2 symmetry exerted a high
degree of chiral discrimination, 1 bearing the NO2 group
exhibited a higher resolving power than 2 lacking the NO2
group. It should also be noted that 1 and 2 were superior to
3-5 in the number of successful results (Figure 1). In particular,
it was surprising to find that 3, having the same binding domain
(lower segment) as 1, showed a diminished ability to separate
the enantiomeric signals except for 7, 12, and 15. Interestingly,
the signal splitting pattern caused by complexation with 3 is
opposite to that caused by comlexation with 1 in all cases; for
example, upon complexation with (R)-1 and (R)-3, the resonance
for (R)-7 appeared at the higher and lower field, respectively,
in comparison with that for (S)-7 (Tables 1 and S3). D2-
symmetric macrocycle 4, bearing the two 2,6-diacylaminopy-
ridine moieties in parallel, showed unsatisfactory results, and
diamide 5 was much more ineffective. It is clear from Figure 1
and Tables 1 and S2-S5 that 1 can show the best performance.
Molecular recognition modes leading to these differences will
be addressed later.
Results and Discussion
Molecular Design. We selected 2,6-diacylaminopyridine as
a binding unit, which has both hydrogen-bond donor and
acceptor sites. Hamilton and co-workers have used this multiple
binding motif for the recognition of thymine, barbiturate, and
phosphoric acid.12 The utility of this binding motif has also been
demonstrated by other researchers.13 Using the binding unit, we
designed chiral macrocyclic structures 1-4. We expected that
the functional groups would be preorganized well and that the
amide bonds in such environments would be solvated weakly,
providing effective binding sites. Two 2,6-diacylaminopyridine
moieties in 1-3 are arranged in a V-shape, while those in 4
are aligned in parallel. Diamide 5 was designed as a control to
investigate the importance of the macrocyclic structures. The
orientation of the two amide NH groups in 5 should be restricted
by the intramolecular hydrogen bonds with the pyridyl nitrogen
atom.14 We introduced the NO2 group into 1 and 3 to strengthen
the hydrogen-bond donor ability of the nearest amide groups.15
The spectra in Table 1 are characterized by the remarkable
signal separations achieved by 1. Good enantiomeric discrimina-
tion is seen in many cases (∆∆δ > 0.15 ppm for 7, 8, 10, 11,
13, and 14), where the degrees of the chemical shift differences
(12) (a) Muehldorf, A. V.; Engen, D. V.; Warner, J. C.; Hamilton, A. D. J. Am.
Chem. Soc. 1988, 110, 6561-6562. (b) Chang, S.-K.; Engen, D. V.; Fan,
E.; Hamilton, A. D. J. Am. Chem. Soc. 1991, 113, 7640-7645. (c) Hirst,
S. C.; Tecilla, P.; Geib, S. J.; Fan, E.; Hamilton, A. D. Isr. J. Chem. 1992,
32, 105-111.
(13) For example, see: (a) Feibush, B.; Figueroa, A.; Charles, R.; Onan, K. D.;
Feibush, P.; Karger, B. L. J. Am. Chem. Soc. 1986, 108, 3310-3318. (b)
Aoki, I.; Harada, T.; Sakaki, T.; Kawahara, Y.; Shinkai, S. J. Chem. Soc.,
Chem. Commun. 1992, 1341-1345. (c) Berl, V.; Huc, I.; Khoury, R. G.;
Krische, M. J.; Lehn, J.-M. Nature 2000, 407, 720-723.
(14) (a) Marlin, D. S.; Olmstead, M. M.; Mascharak, P. K. J. Mol. Struct. 2000,
554, 211-223. (b) Affeld, A.; Hu¨bner, G. M.; Seel, C.; Schalley, C. A.
Eur. J. Org. Chem. 2001, 2877-2890.
(15) Chang, S.-Y.; Kim, H. S.; Chang, K.-J.; Jeong, K.-S. Org. Lett. 2004, 6,
181-184.
(16) (a) Diederich, F. Cyclophanes; RSC: Manchester, 1991. (b) Gibson, S.
E.; Lecci, C. Angew. Chem., Int. Ed. 2006, 45, 1364-1377.
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Macrocyclic Reagent with Multiple H-Bonding Sites
A R T I C L E S
Table 1. Selected Regions of NMR Spectra of Racemic Guests 6-17 in the Presence of (R)-1a
a 600 MHz 1H NMR of 6-10 and 12-16; 300 MHz 1H NMR of 17; and 565 MHz 19F NMR of 11 in the presence of (R)-1 (15 mM, 1 equiv except for
12 and 17 (2 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, which are shown only when the signals for the enantiomers are separated well. b At -50 °C.
isocyanate 16, could be analyzed without reaction or decom-
position. Although epoxide 17 could not be differentiated by 1
at 22 °C, the signal for the proton attached to the asymmetric
carbon was split well by decreasing the temperature to -50 °C
(Table 1). Thus, 1 is an extremely versatile reagent that is
effective for carboxylic acid, oxazolidinone, carbonate, lactone,
alcohol, sulfoxide, sulfoximine, sulfinamide, isocyanate, and
epoxide compounds.
When enantiomeric purities of 13 were determined by 600
MHz 1H NMR, a linear correlation (r2 ) 0.99996) was
confirmed between the theoretical and observed % ee values
(Figure 2). A similar result was obtained when the same
1
experiment was done by 300 MHz H NMR. Therefore, 1 can
be used as a reliable reagent for the determination of the
enantiomeric purity. To examine a detection limit, a mixture of
Figure 1. Comparison of the chiral discrimination abilities of 1-5. The
absolute values of the chemical shift nonequivalences (∆∆δ) observed for
6-17 are indicated by the height of the vertical bars. The conditions for
the measurements are shown in the footnote of Table 1. The signals used
for comparison were selected arbitrarily.
(R)-13 (3.5 µg) and (S)-13 (1.385 mg) was analyzed by 1 equiv
1
of (R)-1 (15 mM) on a 600 MHz H NMR spectrometer. As a
result, a singlet signal for the minor enantiomer could be fairly
detected, and the enantiomeric purity was determined to be
99.7% ee, which is close to the theoretical value of 99.5% ee
(Figure 2).
are even comparable to those reported for diastereomers
covalently linked by chiral derivatizing agents.3 In the case of
sulfoxide 13, all four resonances were resolved completely, one
of which exhibited a paramount separation (∆∆δ ) 0.55 ppm).
Enantiomers of fluorine-containing alcohol 11 were discrimi-
nated by 19F NMR. Although the addition of 1 equiv of (R)-1
to diol 12 gave a partial separation, the addition of 2 equiv of
(R)-1 split the signals completely. The highly reactive reagent,
We next investigated the effect of the amount of (R)-1 on
the signal separation because, in principle, less than 1 equiv of
reagent can be enough for the analysis. Figure 3 clearly shows
that decreasing the amount of (R)-1 decreased the degree of
the signal separation. Nevertheless, the addition of only 5 mol
9
J. AM. CHEM. SOC. VOL. 129, NO. 34, 2007 10593

A R T I C L E S
Ema et al.
1
Figure 2. (a) A selected region of 600 MHz H NMR of (S)-13 (1.4 mg,
15 mM) with various enantiomeric purities in the presence of (R)-1 (6.7
mg, 15 mM) in CDCl3 (0.6 mL) at 22 °C. Observed % ee values calculated
from the integrals are indicated in the parentheses. (b) Correlation between
the theoretical and observed % ee values.
Figure 4. (a) Complexation-induced shifts (∆δ) for the Ha-Hd protons of
(R)-1 (12 mM) as a function of [(S)-13] in CDCl3 at 22 °C. (b) Plots of the
complexation-induced shifts (∆δ) for the Ha-Hd protons of (R)-1 as a
function of [(S)-13].
1
Figure 3. 600 MHz H NMR of rac-13 (277 µg, 3 mM) in the presence
of (R)-1 (0-15 mM) in CDCl3 (0.6 mL) at 22 °C. (R)-1: (a) no addition;
(b) 5 mol % (69 µg); (c) 10 mol %; (d) 30 mol %; (e) 100 mol %; (f) 500
mol %. Filled and open circles represent (R)- and (S)-enantiomers,
respectively.
Chart 2. Reagents Developed by Kagan and Helmchen
Figure 5. Double and triple hydrogen bonds between 1 and a guest
molecule.
agent, we first investigated the molecular recognition behavior
of 1. 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 4. Among the Ha-Hd atoms designated in
Figure 5, the Ha protons showed the largest downfield shift (∆δ
) 1.59 ppm at 48 mM (S)-13), which strongly suggests that
the two Ha atoms are hydrogen-bonded with the SdO group of
(S)-13. 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)-6 and the NH signal of (R)-8
also shifted downfield by 1.9 and 1.4 ppm, respectively, when
1 equiv of (R)-1 was added. Therefore, it is likely that lactone
10 and sulfoxide 13 are fixed by the double hydrogen bonds
and that carboxylic acid 6 and oxazolidinone 8 are fixed by the
triple hydrogen bonds as represented by Figure 5, which were
supported by the following thermodynamic analysis.17
% (69 µg, 0.15 mM) of (R)-1 resulted in the baseline separation
of the signals for the S-linked methyl protons of 13. The
advantage of 1 is obvious when 1 is compared with chiral
derivatizing agents, which are used in excess for derivatization
prior to analysis. The progress also becomes clear when the
concentration (0.15 mM) of 1 is compared with that of
traditional reagents; for example, Kagan and Helmchen used
reagents 18 and 19 (Chart 2) at a concentration of 0.1-0.3 M
to analyze sulfoxide 13 and carboxylic acid 6, respectively.9a,b
Most reagents recently reported are used at 1-30 mM.4-11 Thus,
1 is a highly sensitive reagent. On the other hand, the addition
of 5 equiv of 1 brought about a wider separation (Figure 3f).
Clearly, Figure 3 demonstrates that an arbitrary amount of 1
can be added to determine the % ee value, which is practical
and convenient.
Molecular Recognition Modes and Important Factors for
Chiral Discrimination in NMR. 1. NMR Spectroscopic
Study. In view of the best performance of 1 as a chiral solvating
2. Thermodynamic Study. The binding constants (Ka) of
(R)-hosts for several guests were determined by NMR titra-
tions.18 Assuming 1:1 complexation, which was supported by
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Macrocyclic Reagent with Multiple H-Bonding Sites
A R T I C L E S
Table 2. Binding Constants and Chiral Recognition Energies
between Hosts and Guests
ring-current effect resulting from the binaphthyl moiety are
important for chiral discrimination in NMR.
1
a
1 b
host
guest
K
a (M-
)
∆∆G° )
(kcal mol-
The binding constants of 1-5 toward achiral guest, dimeth-
ylsulfoxide (DMSO), were determined to compare the binding
capacities of 1-5 (Table 2). The Ka values decrease in the order
of 1 > 2 > 3, and those of 4 and 5 were too small to determine.
These results clearly demonstrate the importance of the double
hydrogen bonds at the Ha atoms as shown in Figure 5. The larger
binding constants of 1 as compared with 2 are reasonable
because the Ha atoms of 1 are the better hydrogen-bond donor
due to the presence of the NO2 group. A similar effect of the
NO2 group on binding affinity has previously been reported.15
Interestingly, the NO2 group also contributes to the enhancement
of the enantioselectivity toward 6 and 13 (Table 2), although
the chiral cavities of 1 and 2 should be almost the same in size
and shape. Tight binding of the guest molecule is therefore
important for enantioselective binding (chiral recognition). The
binding capacity of 5 was very low probably because the acidity
of the amide NH protons is decreased by the intramolecular
hydrogen bond with the pyridyl nitrogen.
3. Computational Calculations. To investigate the origin
of the functional advantage of 1 over 3 and 4, we performed
the ab initio calculations.20 The optimized structures are shown
in Figure 6. It was first found that the size of the cavity increases
in the following order: 23-membered macrocycle 3 < 25-
membered macrocycle 1 < 26-membered macrocycle 4. In
addition, the V-shaped arrangement of the two 2,6-diacylami-
nopyridine moieties is seen in 1 and 3, while the parallel
alignment of the multiple binding motifs is seen in 4. The
distances between the hydrogen atoms of the lower amides in
1 (the Ha-Ha distance in Figure 5), 3, and 4 are 3.65, 3.52, and
5.31 Å, respectively. Obviously, 1 and 3 have the binding site
suitable for the double hydrogen bonding as illustrated in Figure
5. Thus, the V-shaped arrangement of the two 2,6-diacylami-
nopyridine moieties is important for interacting with a variety
of functional groups.
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-2
(R)-2
(R)-2
(R)-2
(R)-3
(R)-3
(R)-4
(R)-4
(R)-1
(R)-2
(R)-3
(R)-4
(R)-5
(R)-6
(S)-6
(R)-8
(S)-8
(1R,5S)-10
(1S,5R)-10
(R)-13
(S)-13
(R)-14
(S)-14
(R)-6
1670
3050
510
280
51
-0.35
+0.35
+0.26
-0.85
-0.93
-0.14
-0.72
+0.67
33
610
2600
170
830
760
960
140
480
140
45
-
-
860
220
96
(S)-6
(R)-13
(S)-13
(R)-13
(S)-13
(R)-13
(S)-13
DMSO
DMSO
DMSO
DMSO
DMSO
c
c
c
c
-
-
a In CDCl3 at 22 °C. The Ka values were calculated by the nonlinear
least-squares method. The standard deviations were within 8%. b Chiral
recognition energy calculated from -RT ln{Ka(S)/Ka(R)}. c The Ka value
was too small to determine.
Job plots (Supporting Information), we calculated the Ka values
by means of the nonlinear least-squares method applied to the
host’s NH signal downfield shifted upon addition of the guest.
Table 2 summarizes the data.
The relatively large Ka values for 1 suggest that the functional
groups directed inside the cavity of 1 are preorganized well and
solvated weakly, providing effective binding sites as expected.
The Ka values decrease roughly in the following order: car-
boxylic acid ∼ sulfoxide > sulfoximine ∼ oxazolidinone >
lactone, which reflects the number of the hydrogen bonds
between the host and guest (Figure 5) with two exceptions,
carboxylic acid and sulfoxide. When the two-point interaction
systems are compared, the more polar compound, sulfoxide 13,
is bound much more strongly than lactone 10. In the three-
point interaction systems, the more acidic compound, carboxylic
acid 6, is fixed more tightly than oxazolidinone 8 and sulfox-
imine 14. Table 2 also indicates that receptor 1 has a good ability
to recognize the chirality of the guests.19 For example, the Ka
values for (S)-13 and (S)-14 are 4.3- and 4.9-fold higher,
respectively, than those for (R)-13 and (R)-14, the latter of which
amounts to the energetic difference of -0.93 kcal mol-1. The
thermodynamic data for 6, 8, 10, 13, and 14 (Table 2) revealed
that the signal for the enantiomer having a higher affinity for
(R)-1 was shifted to a greater extent than that for the antipodal
enantiomer in most cases (compare Table 1 with Table S1).
Exceptionally, two of the three signals for lactone 10 and the
signal for the S-linked methyl protons of 13 did not obey this
rule. Therefore, both enantioselective binding and the differential
The structures in Figure 6 also indicate that, although 1 and
3 have the same binding domain (lower segment), the latter
has a smaller cavity with the two methoxy groups directed
inside. This is responsible for the smaller Ka values of 3 for 13
and DMSO as compared with those of 1 for 13 and DMSO
(Table 2). Furthermore, we noticed that the binaphthyl moiety
in 1 is just orthogonal to the plane of the lower segment and
that the relative orientation of the binaphthyl moiety in 1 differs
by ca. 90° from that in 3 (Figure 6a and b). This difference can
account for the results that the chiral compounds complexed
(19) Selected examples of enantioselective binding: (a) Cram, D. J. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1009-1112. (b) Famulok, M.; Jeong, K.-
S.; Deslongchamps, G.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1991,
30, 858-860. (c) Hong, J.-I.; Namgoong, S. K.; Bernardi, A.; Still, W. C.
J. Am. Chem. Soc. 1991, 113, 5111-5112. (d) Webb, T. H.; Wilcox, C. S.
Chem. Soc. ReV. 1993, 383-395. (e) Mizutani, T.; Ema, T.; Tomita, T.;
Kuroda, Y.; Ogoshi, H. J. Am. Chem. Soc. 1994, 116, 4240-4250. (f)
Cristofaro, M. F.; Chamberlin, A. R. J. Am. Chem. Soc. 1994, 116, 5089-
5098. (g) Hirose, K.; Ogasahara, K.; Nishioka, K.; Tobe, Y.; Naemura, K.
J. Chem. Soc., Perkin Trans. 2 2000, 1984-1993. (h) Hayashi, T.; Aya,
T.; Nonoguchi, M.; Mizutani, T.; Hisaeda, Y.; Kitagawa, S.; Ogoshi, H.
Tetrahedron 2002, 58, 2803-2811. (i) 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. (j) Tsubaki, K.; Tanima, D.; Nuruzzaman, M.; Kusumoto, T.; Fuji,
K.; Kawabata, T. J. Org. Chem. 2005, 70, 4609-4616. (k) Folmer-
Andersen, J. F.; Lynch, V. M.; Anslyn, E. V. J. Am. Chem. Soc. 2005,
127, 7986-7987. (l) Rekharsky, M. V.; Yamamura, H.; Inoue, C.; Kawai,
M.; Osaka, I.; Arakawa, R.; Shiba, K.; Sato, A.; Ko, Y. H.; Selvapalam,
N.; Kim, K.; Inoue, Y. J. Am. Chem. Soc. 2006, 128, 14871-14880.
(20) Frisch, M. J.; et al. Gaussian 98, revision A.11.4; Gaussian, Inc.: Pittsburgh,
PA, 2002.
(17) The addition of 100 µL of d4-methanol to a 1:1 mixture of (R)-1 and racemic
sulfoxide 13 in CDCl3 (15 mM each, 600 µL) resulted in a significant
decrease in ∆∆δ value; the ∆∆δ values for the 4-methyl and S-linked
methyl protons of 13 were 0.039 and 0.016 ppm, respectively. The
measurement of the spectrum of a 1:1 mixture of (R)-1 and 13 in d6-acetone
also gave a similar result: 0.035 and 0.027 ppm. These results also support
the occurrence of the hydrogen bonding between 1 and 13.
(18) (a) Connors, K. A. Binding Constants; Wiley: New York, 1987. (b)
Fielding, L. Tetrahedron 2000, 56, 6151-6170.
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A R T I C L E S
Ema et al.
differential ring-current effect on the chiral guest molecule
bound, which leads to the high degree of chiral discrimination
in NMR.
Conclusion
In summary, we have developed a readily accessible,
bifunctional macrocycle 1 that can function as a versatile chiral
solvating agent for a wide range of chiral compounds having a
carboxylic acid, oxazolidinone, lactone, alcohol, sulfoxide,
sulfoximine, isocyanate, or epoxide functionality. In a case, 1
showed high sensitivity; only 5 mol % (69 µg, 0.15 mM) of 1
was enough for the complete splitting of the enantiomeric signals
of sulfoxide 13. The resolved signals for these chiral compounds
remained sharp upon complexation with 1, which demonstrates
that hydrogen-bond-based reagent 1 is suitable for high-field
NMR spectrometers. Reagent 1 has excellent characteristics such
as versatility, signal sharpness, high splitting ability, high
sensitivity, wide detection window, and synthetic accessibility,
and such a reagent is unprecedented. NMR studies revealed that
the principal binding site of 1 is the hydrogen-bond donor site
designated as Ha (Figure 5), where lactone 10 and sulfoxide 13
are fixed by the double hydrogen bonds. The third interaction
takes place at the pyridyl nitrogen when carboxylic acid 6 and
oxazolidinone 8 are bound. The V-shaped arrangement of the
two 2,6-diacylaminopyridine moieties as constructed in 1 was
found to be much more effective for binding a variety of
compounds than the parallel alignment of the two binding motifs
as constructed in 4. The NO2 group in 1 enhanced not only the
binding capacity but also the degree of enantioselectivity.
Unexpectedly, the comparisons between 1 and 3 enabled us to
find the importance of the relative orientation of the binaphthyl
moiety; the orthogonal disposition of the binaphthyl moiety with
respect to the lower segment in 1 most effectively brings about
the differential ring-current effect on the chiral guest molecule
bound, which leads to the high degree of chiral discrimination
in NMR. This useful compound 1 is now commercially available
and will contribute widely to high-throughput research in
asymmetric synthesis.
Figure 6. Optimized structures for (a) (R)-1, (b) (R)-3, (c) (R)-4, (d) (R)-
1-(S)-13 complex, and (e) (R)-1-(R)-13 complex. In (d) and (e), (R)-1 is
shown in green, and (S)-13 and (R)-13 are shown in red and magenta,
respectively. The geometries were optimized at the HF/6-31G* level using
Gaussian 98W (Gaussian Inc.) and were drawn with Sybyl 6.4 (Tripos Inc.).
Acknowledgment. We thank Dr. T. Nitoda and Dr. T.
Korenaga (Okayama University) for the measurement of mass
spectra and the assistance of computational calculations, re-
spectively. We are grateful to the SC-NMR Laboratory of
Okayama University for the measurement of NMR spectra.
with (R)-1 and (R)-3 showed the opposite splitting patterns in
all cases as described above (Tables 1 and S3) and that (R)-1
and (R)-3 showed the opposite enantiopreferences for 13 (Table
2). Furthermore, the functional advantage of 1 over 3 (Figure
1) can also be ascribed to this specific orientation of the
binaphthyl moiety. For example, Figure 6d and e clearly
represents how (R)-1 discriminates the enantiomers of sulfoxide
13; the SdO group of 13 is hydrogen bonded with the two
amide NH groups of (R)-1 at the distance of ca. 2.1 Å, and the
tolyl group of (S)-13 is located in the shielding region of the
naphthyl moiety of (R)-1, while that of (R)-13 is directed outside.
These structures are consistent with the fact that the resonances
for the tolyl group of (S)-13 underwent a larger upfield shift in
the presence of (R)-1 (Table 1). Thus, the orthogonal disposition
of the binaphthyl moiety in 1 is effective for having the
Supporting Information Available: Synthetic procedures for
1-5, copies of 1H and 13C NMR spectra of 1-5, NMR spectra
of 6-17 in the presence and absence of 2-5, Job plots,
determination of binding constants by 1H NMR titrations, PFG-
HMBC and NOESY spectra to assign the Ha and Hb signals of
1, and MO calculations of the hosts and the complexes together
with the full list of authors of ref 20. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA073476S
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