Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2014.03.009

Novel 46-membered chiral rhombamine macrocycles (R,R,R,R)-8a and 8b were synthesized by [2+2] cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and subsequent reduction with NaBH ₄. The X-ray crystal structure of 1:4 dioxane complex with (R,R,R,R)-8a indicated a rhombus conformation of the chiral macrocycle. Compounds (R,R,R,R)-8a and 8b were tested as chiral shift reagents for a wide range of α-substituted carboxylic acids and amino acid derivatives. Enantiodiscrimination of ¹H NMR signals was observed with ΔΔδ values of up to 0.214 ppm.

Full text of DOI:10.1016/j.tetasy.2014.03.009

Tetrahedron: Asymmetry 25 (2014) 602–609
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Ring-expanded chiral rhombamine macrocycles for efficient NMR
enantiodiscrimination of carboxylic acid derivatives
a
a
b
Koichi Tanaka a, , Tomoharu Iwashita , Chihiro Sasaki , Hiroki Takahashi
⇑
a Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering and High Technology Research Center, Kansai University, Suita,
Osaka 564-8680, Japan
b Graduate School of Human and Environmental Studies, Kyoto Univesity, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 46-membered chiral rhombamine macrocycles (R,R,R,R)-8a and 8b were synthesized by [2+2]
cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and
subsequent reduction with NaBH4. The X-ray crystal structure of 1:4 dioxane complex with (R,R,R,R)-
8a indicated a rhombus conformation of the chiral macrocycle. Compounds (R,R,R,R)-8a and 8b were
Received 21 December 2013
Accepted 7 March 2014
Available online 7 April 2014
tested as chiral shift reagents for a wide range of a-substituted carboxylic acids and amino acid deriva-
tives. Enantiodiscrimination of 1H NMR signals was observed with DDd values of up to 0.214 ppm.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
enantiodiscrimination for only a limited number of carboxylic
acids. We and Gawronski have reported on chiral triangleamines
The use of chiral shift reagents for NMR spectroscopy is one of
the most convenient methods for achieving the rapid determina-
tion of the enantiomeric excess (ee) of a chiral compound.1 This
method has the advantage of simple implementation without the
need for chiral derivatization of the analyte. A wide variety of chi-
ral shift reagents, such as lanthanide complexes, crown ethers,
cyclodextrins, and porphyrins, have been developed.2 However, re-
ports on chiral macrocyclic compounds as efficient chiral shift re-
agents remain scarce.3 For example, teraazapyridinophanes 1–34
and the aza-crown macrocycle 45 have been reported as chiral shift
reagents for carboxylic acids; however, these compounds show
5a6a and 5b6b,c as chiral shift reagents for secondary alcohols, cya-
nohydrins, propargylic alcohols, and some carboxylic acids. Better
results for the enantiodiscrimination of carboxylic acid derivatives
have been obtained by using phenolic hexaazamacrocycle 67 and
30-membered chiral rhombamine macrocyle 7.8 In the latter case,
four benzene moieties are involved in the CH–p interactions be-
tween the host and guest molecules. Herein we report the synthe-
sis of ring-expanded 46-membered chiral rhombamine macrocyles
8a and 8b with eight benzene moieties and their successful appli-
cation as chiral NMR shift reagents for a wide range of carboxylic
acids and amino acid derivatives.
R
N
N
NH
NH
HN
HN
NH
NH
HN
HN
N
N
2
R
1a
: R = H
1b: R = OCH2Ph
⇑
Corresponding author. Tel.: +81 06 6368 0861; fax: +81 06 6339 4026.
E-mail address: ktanaka@kansai-u.ac.jp (K. Tanaka).
http://dx.doi.org/10.1016/j.tetasy.2014.03.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
603
O
O
N
NH
O
O
NH
NH
HN
NH
HN
N
4
3
Me
R
R
HN
NH
HN
NH
OH
HN
NH
R
R
HN
HO
OH
NH
H
N
HN
R
H
N
NH
Me
Me
R
5a: R = H
5b: R = Ph
6
X
X
NH
HN
NH
HN
NH
HN
NH
HN
X
X
7a
: X = CH2
7b
: X = O
8a: X = CH2
8b: X = O
R
H
9
a: R = OH
b: R = Me
c: R = OMe
d: R = Br
R
a
b
c
: R = OH
: R = Cl
: R = Br
CO2H
Me
CO2H
H
10
a: R = Me
b: R = i-Pr
a: R = Me
b: R = i-Pr
O
R
H
O
R
H
c
c
: R = i-Bu
: R = i-Bu
Me
N
CO2H
PhCH2O
N
H
CO2H
d
d
: R = CH2Ph
: R = CH2Ph
H
11
12
O
O
CH2Ph
CO2H
O
CH2Ph
Me
N
H
CO2H
N
H
t-BuO
N
H
CO2H
H
H
O
13
14
15
to a similar procedure to that employed for the preparation of com-
pounds 7a and 7b. The identities of 8a and 8b were confirmed by
electrospray ionization-mass spectrometry and NMR analysis.
The structure of (R,R,R,R)-8a was determined by X-ray crystal
structure analysis. Compound (R,R,R,R)-8a crystallized in the tri-
clinic space group P1 and Z = 1. The asymmetric unit contained
2. Results and discussion
The novel chiral rhombamine macrocyles 8a and 8b were syn-
thesized by treating enantiomerically pure (R,R)-1,2-cyclohexane-
diamine with the corresponding dialdehydes followed by NaBH4
reduction of the intermediate [2+2] macrocyclic imines, according

604
K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
an (R,R,R,R)-8a molecule and four 1,4-dioxane molecules, which
were located in the cavity of (R,R,R,R)-8a (Fig. 1). Two carbon atoms
of one of the dioxane molecules were disordered with occupancy
factors of 0.57:0.43 [(C80a, C82a) and (C80b, C82b)]. The shape
of the host molecule is close to a rhombus with the side lengths
of CgAꢀ ꢀ ꢀC20, C20ꢀ ꢀ ꢀCgB, CgBꢀ ꢀ ꢀC53, and C53ꢀ ꢀ ꢀCgA are 13.633,
13.656, 13.609, and 13.617 Å, respectively (CgA and CgB represent
the centers of gravity of the cyclohexane rings). The lengths of the
diagonal lines are 15.358 Å (C20ꢀ ꢀ ꢀC53) and 22.514 Å (CgAꢀ ꢀ ꢀCgB)
and the cavity volume is 549 Å3. The biphenyl moieties in each side
are twisted out of coplanarity. Dihedral angles of biphenyl groups
A1, A2, B1, and B2 are 34.71°, 45.33°, 45.30°, and 39.60°,
respectively.
0.60 eq
0.50 eq
0.40 eq
0.30 eq
0.25 eq
(R)
(S)
0.20 eq
0.15 eq
Chiral shift experiments were carried out by obtaining 1H NMR
spectra (400 MHz) of mixtures of (R,R,R,R)-macrocycles 7a,b or
8a,b and racemic carboxylic acids 9a–d in CDCl3 at room tempera-
ture. For example, upon the addition of 0.25 equiv of (R,R,R,R)-8a,
0.125 eq
0.10 eq
none
the chemical shift values of the methyne protons (CaH) attached
to the asymmetric carbons of (S)- and (R)-mandelic acids 9a exhib-
ited 0.437 and 0.346 ppm upfield shifts, respectively. Furthermore,
upon the gradual addition of (R,R,R,R)-8a, the 1H NMR signals (see
Fig. 2) for the CH protons of 9a moved upfield, and the difference in
the chemical shifts of the two enantiomers increased gradually.
The difference of 0.091 ppm for the two enantiomers at 0.25 equiv
was found to be the best result for chiral recognition (Fig. 2). It is
also noteworthy that the further addition of (R,R,R,R)-8a led to a
decrease in the chemical shift difference; thus, no signal splitting
was observed in the presence of 0.6 equiv of (R,R,R,R)-8a. Job plots
for (R,R,R,R)-8a with (R)- and (S)-9a at a total concentration of
40 mM are shown in Figure 3. A maximum was observed when
the ratio of (R,R,R,R)-8a versus (R)- or (S)-9a was 1:4 (X = 0.2),
which suggests that the host (R,R,R,R)-8a, such as a dioxane, forms
a 1:4 complex with (R)- or (S)-9a.
5.3
5.2
5.1
5.0
4.9
4.8 ppm
Figure 2. Change in the chemical shifts of the benzyl protons of (R)- and (S)-
mandelic acids 9a upon increasing the concentration of (R,R,R,R)-8a (conditions:
rac-9a, 20.0 mM in CDCl3, 400 MHz). A separate experiment revealed that (S)-9a
underwent a larger upfield shift than its counterpart.
(R,R,R,R)-8a + (S)-9a
(R,R,R,R)-8a + (R)-9a
Figure 3. Job plot of (R,R,R,R)-8a with (R)- and (S)-9a. The
Dd stands for chemical
shifts change of the CH proton of 9a in the presence of (R,R,R,R)-8a. X stands for the
mole fraction of host, [(R,R,R,R)-8a]/{[(R,R,R,R)-8a]+[9a]}. Total concentration is
40 mM.
observed for the methyne proton (C
phenylacetic acid derivative 9b in the presence of 8a and 8b
(Table 1, entry 2), while -bromo- and -methylphenyl propionic
aH) signals of a-methoxy
a
a
acids 9c and 9d gave poor results (Table 1, entries 3 and 4). It is also
interesting to note that chiral discrimination was observed for the
OMe signals of 9b, and that the non-equivalence (DDd) was much
larger in the presence of 8a and 8b than in the presence of 7a and
7b (Table 1, entry 2). For the propionic acid derivatives 10a–c, chi-
ral discrimination was observed for the Me and methyne proton
Figure 1. ORTEP drawing of 1:4 complex of (R,R,R,R)-8a with 1,4-dioxane and
selected atoms labeled. A and B represent cyclohexane rings. A1, A2, B1, and B2
represent the biphenyl moieties.
The chemical shift differences (DDd) for the methyne protons
(CaH) signals, as can be seen in Table 2. For example, the Me pro-
(CaH) attached to the asymmetric carbons of the enantiomers of
ton signal of 10b was split into two doublets with chemical shift
rac-phenylacetic acid derivatives 9a–d in the presence of
0.25 equiv of (R,R,R,R)-7a, 7b, 8a, and 8b in CDCl3 are listed in
Table 1. For all of the carboxylic acids 9a–d tested, the signals for
non-equivalence (DDd = 0.023 ppm) in the presence of 0.25 equiv
of 8b (Table 2, entry 6). Generally, better separation (higher DD
values) was observed in the presence of 8a and 8b.
d
the protons (C
a
H) attached to the stereogenic centers of the enan-
Macrocycles 8a and 8b also show excellent enantiodiscriminat-
ing ability for several amino acid derivatives including N-benzyl-
oxycarbonyl amino acids 12a–d, N-Boc amino acid 13, N-benzoyl
amino acid 14, and N-phthaloyl alanine 15, while macrocycles 7a
and 7b showed good enantiodiscriminating ability for sterically
less bulky N-acetyl amino acids (Table 3, entries 8–11). In general,
tiomers were split, and the baseline separation was sufficient for
accurate integration. For mandelic acid 9a, the DDd values (0.091
and 0.097) in the presence of 8a and 8b were much larger than
those (0.058 and 0.052) in the presence of 7a and 7b, respectively
(Table 1, entry 1). Similarly, efficient chiral discrimination was

K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
605
Table 1
Partial 1H NMR spectra of rac-phenylacetic acid derivatives 9a–9d in the presence of 0.25 equiv of 7a, 7b, 8a, and 8b
a400 MHz in CDCl3.
bData reported in Ref. 8.
Table 2
Partial 1H NMR spectra of rac-propionic acid derivatives 10a–10c in the presence of 0.25 equiv of 7a, 7b, 8a, and 8b
a400 MHz in CDCl3.
bData reported in Ref. 8.
macrocycle 8 provided larger DDd values for the
a-Me and NH pro-
a-Me proton signals for N-benzyloxycarbonyl amino acids 12a–c,
tons of these guest molecules than macrocycle 7 (Table 3, entries
12–15). In particular, upon addition of 0.25 equiv of (R,R,R,R)-8a,
the chemical shift values of the NH proton signals for N-benzyloxy-
carbonyl-phenylalanine 12d provided the largest chemical shift
non-equivalence (DDd = 0.214 ppm; Table 3, entry 15). Similarly,
(R,R,R,R)-8 provided clear baseline separation of the NH and
N-Boc amino acid 13, N-benzoyl amino acid 14, and N-phthaloyl
alanine 15 (Table 3, entries 12–18). These results imply that the
molecular structure of macrocycle 8 fits the guest molecules
12–15 better than that of macrocycle 7.
The side lengths for (R,R,R,R)-7a were 9.440, 9.156, 8.394, and
9.109 Å.8 The molecular shape of 7a was a square rather than a

606
K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
Table 3
Partial 1H NMR spectra of rac-
a-amino acid derivatives in the presence of 0.25 equiv of 7a, 7b, 8a, and 8b
a400 MHz in CDCl3.
bData reported in Ref. 8.
rhombus. Intramolecular hydrogen bonds were observed between
both neighboring amines in 7a, while 8a does not have such intra-
molecular hydrogen bonds between the neighboring amines,
meaning that all of the lone pairs of amines for 8a are oriented out-
ward for the macrocyclic ring in the crystal as shown in Figure 4.
Accordingly the guest carboxylic acids easily react with 8a com-
pared to 7a. The conformation of the macrocycles 7a and 8a was
determined by the four torsion angles of C(cy)—N—C(sp3)—C(Ar).
In the case of 8a, all of the torsion angles are an anti conformation,
while 7a one is gauche and the others lie in an anti conformation.
All of the phenyl rings in 8a lie almost perpendicular to the
plane of the paper, while all of the phenyl groups in 7a are
placed in an inconsistent manner to the plane of the paper. There-
fore, the shielding and/or deshielding efficiently affect(s) the guest

K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
607
40 %ee
%ee (prepared)
Figure 6. Correlation between theoretical and observed % ee values.
Finally, we attempted to determine the ee of amino acid 12d via
integration of the corresponding NMR signals in the presence of
0.25 equiv of (R,R,R,R)-8a. Samples containing different ee values
for 12d were prepared, and their NMR spectra in the presence of
(R,R,R,R)-8a were obtained (Fig. 5). An excellent linear correlation
(R2 = 0.996) between the theoretical and experimental ee values
was observed (Fig. 6).
Additional information on the solution structure of the com-
plexes was then obtained by nuclear Overhauser effect spectros-
copy (NOESY). The 2D NOESY spectrum of (S)-Boc-phenylalanine
13 in the presence of 0.25 equiv of (R,R,R,R)-8a showed cross peaks
between the CH3(a) and Hb protons of (S)-13 and the aromatic
Figure 4. Space filling diagrams of (R,R,R,R)-8a (top) four dioxane molecules are
omitted for clarity and (R,R,R,R)-7a (bottom) in the crystals. The detailed crystal
data of (R,R,R,R)-7a are from Ref. 8.
protons of (R,R,R,R)-8a, most likely due to the presence of CH–
p
molecules. The reactivity for the guest carboxylic acids and
conformation of 8a are responsible for the efficient chiral
discrimination.
interactions between the host and guest in addition to the major
acid–base attractive interaction (Fig. 7). In contrast, the NOESY
spectrum of (R)-Boc-phenylalanine 13 in the presence of
(S)
100 %ee
(R)
80 %ee
60 %ee
40 %ee
20 %ee
0 %ee
δ ppm
Figure 5. Selected region of the 400 MHz NMR spectra of 12d of various
enantiomeric purities in the presence of 0.25 equiv of (R,R,R,R)-8a.
Figure 7. A portion of the 400 MHz NOESY spectrum of a solution of (S)-Boc-
phenylalanine 13 (16 mM) and (R,R,R,R)-8a (4.0 mM) in CDCl3 at 25 °C.

608
K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
Ar atmosphere. The reaction mixture was cooled, then the precip-
itates were filtered off through Celite and water (50 mL) was added
to the filtrate. After the two layers were separated, the water layer
was extracted with CH2Cl2 and the organic layer was dried over
potassium carbonate and concentrated. The residue was purified
via silica gel chromatography (CHCl3) to give 4,40-methylene-
bis(biphenyl-4-carbaldehyde)10 as a white solid (908 mg, 53%
yield). Mp 182–183 °C; 1H NMR (CDCl3) d 4.10 (s, 2H), 7.35 (d,
J = 8.0 Hz, 4H), 7.60 (d, J = 8.4 Hz, 4H), 7.74 (d, J = 8.4 Hz, 4H),
7.94 (d, J = 8.4 Hz, 4H), 10.05 (s, 2H); 13C NMR (CDCl3) d 41.30,
127.5, 127.6, 129.6, 130.3, 135.1, 137.7, 141.2, 146.9, 191.9;
IR(cmꢁ1): 3362, 3029, 2921, 2841, 2733, 1916, 1700, 1602, 1577,
1558, 1525, 1493, 1432, 1389, 1310, 1281, 1225, 1190, 1171,
1125, 1003, 919.
4.2.2. Chiral rhombamine macrocycle 8a
A
mixture of (R,R)-trans-cyclohexane-1,2-diamine (120 mg,
1.06 mmol) and
4,40-methylenebis(biphenyl-4-carbaldehyde)
(400 mg, 1.06 mmol) in CHCl3 was stirred at room temperature
for 24 h. A large excess of NaBH4 (400 mg, 10.6 mmol) in MeOH
was then added carefully and the mixture was stirred for 72 h.
The reaction mixture was quenched with water. After the two lay-
ers were separated, the water layer was extracted with CH2Cl2. The
combined organic layers were dried (K2CO3) and the solvents were
evaporated in vacuo. The residue was purified via basic silica gel
chromatography (CHCl3) to give (R,R,R,R)-8a as a white solid
(454 mg, 49% yield). Mp >300 °C; ½a D25
ꢂ
= ꢁ18 (c 0.10, CHCl3); 1H
NMR (CDCl3) d 1.10 (m, 4H), 1.27 (m, 4H), 1.76 (m, 4H), 1.93 (m,
4H), 2.22–2.34 (m, 8H), 3.64 (d, J = 13 Hz, 2H), 3.96 (d, J = 13 Hz,
2H), 4.06 (s, 4H), 7.27 (d, J = 8 Hz, 8H), 7.36 (d, J = 8 Hz, 8H), 7.50
(d, J = 7.2 Hz, 16H); 13C NMR (CDCl3) d 25.0, 31.5, 41.1, 50.4, 61.0,
126.9, 127.1, 128.4, 129.3, 138.8, 139.5, 139.7, 139.9; IR(cmꢁ1):
3293, 3022, 2922, 2851, 2360, 1498, 1448, 1397, 1115, 1005,
901; [M+H]+ = 917.8; Anal. Calcd for C66H68N4: C, 86.42; H, 7.47;
N, 6.11. Found: C, 86.31; H, 7.52; N, 6.05.
Figure 8. A portion of the 400 MHz NOESY spectrum of a solution of (R)-Boc-
phenylalanine 13 (16 mM) and (R,R,R,R)-8a (4.0 mM) in CDCl3 at 25 °C.
0.25 equiv of (R,R,R,R)-8a showed less prominent cross peaks
(Fig. 8). This difference may be due to the fact that (R,R,R,R)-8a
forms a tighter complex with (S)-Boc-phenylalanine 13 than with
(R)-Boc-phenylalanine 13.
4.2.3. 4,40-Oxybis(biphenyl-4-carbaldehyde)
3. Conclusion
4-Formylphenylboronic acid (2.73 g, 18.3 mmol), bis-(4-bromo-
phenyl)ether (3.01 g, 9.15 mmol), Pd(PPh3)4 (170 mg, 0.15 mmol)
and a potassium carbonate solution (8.01 g, 58.0 mmol) in water
(20 mL) were dissolved in 1,2-dimethoxyethane (200 mL). The
mixture was heated at 110 °C for 24 h under an Ar atmosphere.
The reaction mixture was cooled, then the precipitates were
filtered off through Celite and water (50 mL) was added to the
filtrate. After the two layers were separated, the water layer was
extracted with CH2Cl2 and the organic layer was dried over potas-
sium carbonate and concentrated. The residue was purified via
recrystallization from toluene to give 4,40-oxybis(biphenyl-4-carb-
aldehyde) as a white solid (548 mg, 16% yield). Mp >300 °C; 1H
NMR (CDCl3) d 7.17 (d, J = 8.8 Hz, 4H), 7.65 (d, J = 8.8 Hz, 4H),
7.75 (d, J = 8.4 Hz, 4H), 7.96 (d, J = 8.4 Hz, 4H), 10.06 (s, 2H); 13C
NMR (CDCl3) d 119.4, 127.4, 128.9, 129.8, 130.3, 135.1, 146.3,
157.4, 191.8; IR(cmꢁ1): 2924, 2854, 1901, 1692, 1601, 1524,
1491, 1460, 1377, 1276, 1177, 1118, 817; Anal. Calcd for
Two new size-expanded chiral rhombamine macrocycles,
(R,R,R,R)-8a and 8b have been synthesized. Their enantiodiscrimi-
nating ability was investigated by 1H NMR spectroscopy. Com-
pared to (R,R,R,R)-7a and 7b, both compounds exhibited better
enantiodiscriminating ability toward a wide range of carboxylic
acids and amino acid derivatives. Further studies on the mecha-
nism of the chiral recognition and the design of new macrocyclic
amines are currently in progress.
4. Experimental
4.1. General method
1H and 13C NMR spectra were recorded in CDCl3 on a JEOL JNM-
GSX400 or JEOL JNM-AL400 FT-NMR spectrometer. IR spectra were
recorded with a JASCO FT-IR 4100 spectrometer. Column chroma-
tography was carried out using silica gel 60 (0.063–0.200 mm,
Merck). The optical rotations were measured with a ATAGAO AP-
100 polarimeter.
C26H18O3: C, 82.52; H, 4.79. Found: C, 82.58; H, 4.52.
4.2.4. Chiral rhombamine macrocycle 8b
mixture of (R,R)-trans-cyclohexane-1,2-diamine (150 mg,
A
1.32 mmol) and 4,40-oxybis(biphenyl-4-carbaldehyde) (500 mg,
1.32 mmol) in CHCl3 was stirred at room temperature for 24 h. A
large excess of NaBH4 (400 mg, 10.6 mmol) in MeOH was then
added carefully and the mixture was stirred for 72 h. The reaction
mixture was quenched with water. After the two layers were sep-
arated, the water layer was extracted with CH2Cl2. The combined
organic layers were dried (K2CO3) and the solvents were
evaporated in vacuo. The residue was recrystallized from toluene
4.2. Synthesis of size-expanded chiral rhombamine macrocycles
4.2.1. 4,40-Methylenebis(biphenyl-4-carbaldehyde)
4-Formylphenylboronic acid (1.36 g, 9.08 mmol), bis-(4-bromo-
phenyl)methane9 (1.48 g, 4.54 mmol), Pd(PPh3)4 (300 mg,
0.209 mmol) and
a
potassium carbonate solution (4.01 g,
29.0 mmol) in water (10 mL) were dissolved in 1,2-dimethoxyeth-
ane (100 mL). The mixture was heated at 110 °C for 30 h under an

K. Tanaka et al. / Tetrahedron: Asymmetry 25 (2014) 602–609
609
to give (R,R,R,R)-8b as a white solid (396 mg, 33% yield). Mp
These solutions were distributed among 13 NMR tubes, with the
molar fractions X of 9a in the resulting solutions increasing from
0.05 to 1.0, and the total concentration of (R,R,R,R)-1a and (R)- or
(S)-9a was 40 mM. The complexation induced shifts (Dd) were
multiplied by X and plotted against X itself to afford a 1:4 (host–
guest) binding model.
>300 °C; ½a 2D5
ꢂ
= ꢁ40 (c 0.10, CHCl3); 1H NMR (CDCl3) d 1.12 (m,
4H), 1.30 (m, 4H), 1.79 (m, 4H), 1.88 (m, 4H), 2.24–2.34 (m, 8H),
3.64 (d, J = 13 Hz, 2H), 3.98 (d, J = 13 Hz, 2H), 7.09 (d, J = 8 Hz,
8H), 7.38 (d, J = 8 Hz, 8H), 7.50 (d, J = 8 Hz, 8H), 7.54 (d, J = 8 Hz,
8H); 13C NMR (CDCl3) d 25.1, 31.7, 50.7, 61.3, 119.1, 126.8, 128.3,
128.5, 136.1, 139.0, 139.9, 156.6; IR(cmꢁ1): 3391, 3035, 2931,
2856, 1647, 1598, 1522, 1494, 1396, 1245, 1172,1110, 1005, 878,
813; [M+H]+ = 921.5; Anal. Calcd for C64H64N4O2: C, 83.44; H,
7.00; N, 6.08. Found: C, 83.25; H, 6.90; N, 6.17.
4.6. Determination of the enantiomeric purity of mandelic acid
In order to evaluate the accuracy of the determination of ee, we
prepared six samples containing N-carbobenzoxy-phenylalanine
12d with 0%, 20%, 40%, 60%, 80%, and 100% ee, respectively (all
samples were prepared by adding 0.25 equiv of (R,R,R,R)-8a in
the solution of 12d (40 mM in 0.6 mL of CDCl3), and determined
their enantiopurities based on the integrations of the 1H NMR sig-
nals of NH proton of 12d.
4.3. X-ray crystal structure analysis of (R,R,R,R)-8a
A suitable crystal for X-ray analysis was obtained by recrystalli-
zation from 1,4-dioxane and mounted in a loop. Data collection was
performed on a Rigaku Saturn724+ CCD area detector diffractometer
[graphite monochromated MoKa radiation (k = 0.71073 Å); x
scans] with a Rigaku low temperature equipment. The crystal struc-
tures were solved by the direct method (SIR9710) and refined by the
full-matrix least-squares method (SHELXL9711). All non-hydrogen
atoms were refined anisotropically. C—H atoms were placed in geo-
metrically calculated positions using the riding model. N—H hydro-
gen atoms have been located from difference Fourier maps and
refined. All calculations were performed using crystallographic soft-
ware Yadokai-XG 2009.12 Crystallographic data (excluding struc-
ture factors) for the structures described in this paper have been
deposited with the Cambridge Crystallographic Data Centre (Sup-
plementary publication no. CCDC 978036). Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 (0) 1223336033 or e-mail:
deposit@ccdc.cam.ac.uk). Crystal data for 1:4 complex of (R,R,R,R)-
8a with 1,4-dioxane: C66H68N4ꢀ4C4H8O2, M = 1269.66, triclinic,
References
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a = 6.2084(19) Å, b = 17.048(6) Å, c = 17.455(6) Å,
a = 109.344(4)°,
b = 97.037(4)°,
group P1, Z = 1,
c
l
= 92.022(3)°, V = 1724.3(10) Å3, T = 100(2) K, space
= 0.078 mmꢁ1, 19386 reflections measured, 13657
independent reflections (Rint = 0.0229). The final R1 and wR(F2)
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4.4. NMR chiral shift experiments
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(R,R,R,R)-8a or (R,R,R,R)-8b (0.0048 mmol) with several carboxylic
acids or amino acid derivatives (0.019 mmol) in CDCl3 (0.6 mL)
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4.5. Determination of the stoichiometry of the host–guest
complex (Job plots)
Compound (R,R,R,R)-8a, and (R)- and (S)-mandelic acid 9a were
separately dissolved in CDCl3 with a concentration of 40 mM.
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