Aminoindanol-based chiral derivatizing agents for the determination of the absolute configuration of carboxylic acids

Article abstract of DOI:10.1039/c2ob26168e

New chiral derivatizing agents have been prepared through a simple, short-step synthesis. The absolute configuration of α-chiral carboxylic acids can be assigned on the basis of the NMR chemical shift difference between diastereomeric esters. Because of the modular structures of the agents, the anisotropic effect could be easily manipulated to afford large chemical shift differences even in polar solvents.

Full text of DOI:10.1039/c2ob26168e

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ARTICLE TYPE
Aminoindanol-based chiral derivatizing agents for the determination of
the absolute configuration of carboxylic acids
Minjung Park,a Seon-mi Kima and Kihang Choi*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
New chiral derivatizing agents have been prepared through a
simple, short-step synthesis. The absolute configuration of -
chiral carboxylic acids can be assigned on the basis of the
NMR chemical shift difference between diastereomeric esters.
10 Because of the modular structure of the agents, the
anisotropic effect could be easily manipulated to afford large
chemical shift differences even in polar solvents.
Fig. 1 Structures of CDAs for the absolute configuration assignment of -
chiral carboxylic acids.
Introduction
50 can be prepared simply starting from an achiral material with a
strong anisotropic group. Using this approach, we have recently
developed tartaric acid-based CDAs for primary amines3a and
serine-based CDAs for secondary alcohols.3b Herein, we would
like to report aminoindanol-based CDAs for -chiral carboxylic
55 acids.
15 With the progress of asymmetric synthesis and natural product
chemistry, considerable efforts have been devoted to the
development of simple and efficient methods for the absolute
configuration assignment of chiral compounds. One of the
traditional approaches especially useful for non-crystalline
20 compounds is the NMR anisotropy method1 in which the chiral
compound is derivatized with two enantiomers of a chiral
derivatizing agent (CDA) and the NMR spectra are compared to
obtain the chemical shift difference () between the two
resulting diastereomers. Proper analysis of the  values based on
25 the diastereomer conformations and the anisotropic shielding
effect produced by the CDA can lead to the absolute
configuration assignment of the chiral compound. To reduce
possible errors in this analysis, there have been continuous
efforts2 to develop new CDAs with strong anisotropic effects and
30 rigid structures producing large  values.
It is a simple and well accepted concept that the anisotropic
effect of a CDA can be improved by increasing the size of the
CDA’s anisotropic group (an aromatic ring in most cases). In
reality, however, the manipulation of the anisotropic effect is not
35 straightforward because most of the CDAs currently used have its
anisotropic group directly attached to their chiral centers. With
this traditional design, two enantiomers of a new CDA should be
prepared by asymmetric synthesis or chiral resolution, and then
the absolute configuration of each enantiomer should be assigned
40 without ambiguity.
Results and discussion
Among the relatively small number of CDAs developed for the
determination of the absolute configuration of carboxylic acids,4
2-phenyl-1-cyclohexanol (1, Fig. 1) is one of the most widely
60 used and commercially available agents.4a We envisioned that
aminoindanol derivative 2 could serve as a CDA for carboxylic
acids because of its structural similarities with 1: both are rigid,
cyclic secondary alcohols and, once carboxylic acids are
connected to the hydroxyl group through an ester bond, the
65 agent’s aromatic ring is expected to be positioned close to the
attached acid. Unlike compound 1 in which the aromatic group is
directly attached to a chiral center, compound 2 has an aromatic
group linked through a cyclic imide group to cis-1-amino-2-
indanol, which is readily available from the chiral pool. Therefore,
70 we expected that the aromatic group of compound 2 could be
varied in a simple and straightforward manner.
To investigate the utility of compound 2 as a new CDA, we
prepared the corresponding esters of -chiral carboxylic acids of
known absolute configuration. First, both enantiomers of
75 compound 2 were synthesized in high yields by reacting
corresponding enantiomers of cis-1-amino-2-indanol with
phthalic or 1,8-naphthalic anhydride. These indanol derivatives
were then coupled with chiral carboxylic acids using
conventional carboxylic-acid activating reagents.5 The 1H NMR
Exploring alternative approach to develop new CDAs with
relatively small amount of time and cost, we have used a modular
chiral pool method in which the chiral center and the anisotropic
group of a CDA are derived from two separate chiral and achiral
45 starting materials.3 Because the chiral center is derived directly
from chiral pool, a new CDA with improved anisotropic effect
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Fig. 2  values of 2a (in lightface) and 2b (in boldface) esters of chiral
carboxylic acids. The 1H NMR spectra were recorded in CDCl3.
Fig. 4 Stable conformers of (1R,2S)-2a ester of isobutyric acid (R1 = R2 =
40 Me). The energy differences between the most stable conformer sp1 and
the next three stable conformers sp2-4 are less than 5 kJ/mol.
Table 1  values of 2a and 2b esters of (S)-2-methylbutyric acid
obtained in various NMR Solvents
2a
2b
a
Solvent
CDCl3
[D8]toluene
[D6]acetone
[D4]methanol
CH3CH- CH3CH2- CH3CH- CH3CH2-
4.8
2.4
20.7
32.7
+0.11
+0.08
+0.13
+0.13
+0.14
+0.16
–0.13
–0.10
–0.14
–0.14
–0.16
–0.18
+0.15
+0.13
+0.16
+0.18
+0.20
+0.20
–0.20
–0.18
–0.21
–0.23
–0.26
–0.27
5
[D3]acetonitrile 37.5
[D6]DMSO 46.7
Fig. 3 Conformational analysis of (1R,2S)- and (1S,2R)-2a esters and the
expected shielding effect on the carboxylic acid substituents.
a Solvent dielectric constant from ref.9
signals of the prepared esters were assigned using COSY and
NOESY NMR spectroscopic methods and the chemical shifts
45
through simple and straightforward synthesis. The values
obtained with compound 2a in CDCl3 are similar or slightly
greater in magnitude than the corresponding values reported with
compound 1.4a A second version compound 2b with a lager
10 were compared between the two diastereomeric esters to calculate
chemical shift differences ( = (1R,2S) - (1S,2R)).
As summarized in Fig. 2, all the tested compounds showed the
same trend in their  values: if the general structure of
carboxylic acids is represented as in Fig. 3, the chemical shift
15 difference between the diastereomeric esters are always negative
for the R1 substituent and positive for the R2 substituent. This
consistent and uniform distribution of the  values could be
explained on the basis of conformer search calculations.6 In the
lowest energy conformation of the 2a ester of isobutyric acid7
20 (sp1 in Fig. 4), the (C2—O)—(C—C) ester bond adopts an anti
planar conformation, and the (H—C2)—(O—C) and (O—C)—
(C—H) bonds (with dihedral angles 1 and 2, respectively)
adopt syn periplanar conformations. This overall arrangement
around the ester bond is consistent well with the general
25 conformational preference of carboxylic esters.1a,4a The aromatic
ring of the phthalimide group faces toward the ester group and
this orientation is preferred to minimize the steric interaction
between the cyclic imide and indanol ring structures. In this
representative conformation, the phthalimide group is positioned
30 more closely to the methyl group corresponding to the R1
substituent than to the other methyl group corresponding to the R2
substituent. Therefore, it is expected that the value should be
positive for the R1 substituent and negative for the R2 substituent,
and this is in good agreement with the experimental results (Fig.
35 2).
50 anisotropic group afforded significantly enhanced values.8
These values have same signs as those of corresponding 2a esters
suggesting that the anisotropic group change has little effect on
the overall conformational preference and, therefore, the structure
analysis shown in Fig. 3 is also applicable to 2b esters.
55
Next, we tested the solvent dependence of the  value to find
out whether the agents could be used as effective CDAs in
various solvents. The  values of 2a and 2b esters of (S)-2-
methylbutyric acid (R1 = Et, R2 = Me) were measured in
commonly used NMR solvents (Table 1). All these values have
60 same signs as those obtained in CDCl3 indicating that the esters
retain the same conformational preference in the tested solvents.
Interestingly, the  values of this simple carboxylic acid get
increased with the solvent polarity suggesting that compound 2
could be used as a reliable CDA even in polar solvents.
To further understand the solvent effect on the  values, we
examined solvation energies of the stable conformations sp1-4 of
the isobutyric acid 2a ester (Fig. 4). According to Table 2
comparing the energies of solvation in CHCl3 and in DMSO,
conformers sp1 and sp2 show relatively large changes in
70 solvation energy (Esol). This is presumably because these
conformers with positive dihedral angle 1 have larger solvent-
accessible polar surface areas, especially around the indanol
65
As anticipated, the anisotropic effect of CDA 2 could be
manipulated effectively by installing different anisotropic groups
2
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Table 2 Solvation energy (Esol) of the 2a ester of isobutyric acida
25 carboxylic acids. The agents were prepared through efficient one-
step reaction between an achiral cyclic anhydride and readily
available cis-aminoindanol, and the anisotropic effect of the agent
could be changed easily by employing different cyclic anhydrides
in the synthesis. The diastereomeric esters of compound 2
30 showed significantly large chemical shift differences in various
NMR solvents suggesting that this CDA could be used as a
reliable and versatile reagent for the absolute configuration
assignment of -chiral carboxylic acids.
b
Esol (kJ/mol)
1/2
(degree)
Esol
(kJ/mol)
Conformer
CHCl3
DMSO
sp1
sp2
sp3
sp4
+39.6/+53.8
+37.7/–36.1
–45.2/–44.3
–38.9/+39.3
–67.85
–69.47
–68.05
–68.70
–68.55
–70.45
–68.04
–69.13
–0.70
–0.98
+0.01
–0.43
a Calculated using an empirical solvation model, SM8, parameterized for
the 6-31G* basis set.10 b Esol = Esol(DMSO) – Esol(CHCl3).
Experimental
35 2-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)isoindoline-
1,3-dione ((1R,2S)-2a): (1R,2S)-1-Amino-2-indanol (0.50 g, 3.3
mmol) and phthalic anhydride (0.51 g, 1.0 equiv.) were
suspended in toluene (30 mL), and N,N-diisopropylethylamine
(DIEA, 0.59 mL, 1.0 equiv.) was added. The mixture was
40 refluxed overnight while the water formed was removed using a
Dean-Stark apparatus. After cooling down to room temperature,
the resulting mixture was washed with aqueous HCl (1 N),
saturated NaHCO3 solutions and brine. The organic layer was
dried over anhydrous Na2SO4 and concentrated under reduced
45 pressure. The residue was purified by SiO2 chromatography to
give the title compound as a yellowish-white solid (0.81 g, 87 %).
22
1
m.p. 138–141°C. [α]D = –52 (c = 0.5 in CHCl3). H NMR (400
MHz, CDCl3) δ 7.83–7.88 (m, 2 H), 7.72–7.77 (m, 2 H), 7.28–
3
7.35 (m, 2 H), 7.10–7.23 (m, 2 H), 5.82 (d, J = 6.3 Hz, 1 H,
50 C1H), 4.75–4.81 (m, 1 H, C2H), 3.36 (dd, J = 16.6 Hz, J = 6.2
2
3
2
3
Hz, 1 H, C3H), 3.26 (dd, J = 16.6 Hz, J = 3.3 Hz, 1 H, C3H’),
2.70 (d, J = 10.8 Hz, 1 H, OH). 13C NMR (100 MHz, CDCl3) δ
3
169.3, 140.2, 137.2, 134.4, 132.0, 128.7, 127.2, 125.7, 124.3,
123.6, 74.4, 57.9, 41.4. HRMS (FAB) calcd. for [M+H]+
55 C17H14NO3: 280.0974, found: 280.0969.
2-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)isoindoline-
1,3-dione ((1S,2R)-2a): The procedure described for (1R,2S)-2a
was followed except that (1S,2R)-1-amino-2-indanol was used
60 instead of (1R,2S)-1-amino-2-indanol. The spectral data were
virtually identical to those of (1R,2S)-2a except [α]D22 = +53 (c =
0.5 in CHCl3).
5
1
Fig. 5  values of 2b esters of chiral carboxylic acids. H NMR spectra
were recorded in [D6]DMSO.
2-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-1H-benzo-
65 [de]isoquinoline-1,3(2H)-dione ((1R,2S)-2b): The procedure
described for (1R,2S)-2a was followed except that 1,8-naphthalic
anhydride was used instead of phthalic anhydride. Yield: 88%.
m.p. 207–214°C. [α]D22 = –123 (c = 0.5 in CHCl3). 1H NMR (400
MHz, CDCl3) δ 8.45–8.74 (m, 2 H), 8.23–8.28 (m, 2 H), 7.71–
oxygen atom. As a result, conformers sp1 and sp2 are expected to
10 be populated more in DMSO than in CHCl3. The phthalic group
and the attached acid get slightly closer in conformers sp1 and
sp2 than in sp3 and sp4 so that the  values are expected to be
increased in DMSO.
The results obtained in [D6]DMSO with diverse carboxylic
15 acids (Fig. 5) clearly show that compound 2b could be used as a
reliable CDA in this polar NMR solvent also. Although the
solvent effect strongly depends on the acid structure (Fig. 2 vs.
Fig. 5) presumably because of the variation in conformational
flexibility and intramolecular interaction, large  values with
20 consistent signs are observed not only for the protons close to the
chiral center but also for the protons six or seven bonds away.
3
3
70 7.84 (m, 2 H), 7.36 (d, J = 6.4 Hz, 1 H), 7.27 (t, J = 7.4 Hz, 1
H), 7.18 (t, 3J = 7.4 Hz, 1 H), 7.04 (d, 3J = 7.4 Hz, 1 H), 6.67 (d,
2
3J = 7.1 Hz, 1 H, C1H), 4.90–4.97 (m, 1 H, C2H), 3.49 (dd, J =
2
16.8 Hz, 3J = 6.7 Hz, 1 H, C3H), 3.31 (dd, J = 16.8 Hz, 3J = 2.7
Hz, 1 H, C3H’), 3.18 (d, 3J = 11.3 Hz, 1 H, OH). 13C NMR (100
75 MHz, CDCl3) δ 166.5, 165.3, 139.6, 138.9, 134.4 (2 C), 132.1,
131.8, 131.6, 128.4, 127.8, 127.3, 127.2, 126.8, 125.6, 123.2,
123.0, 122.6, 74.2, 59.8, 42.4. HRMS (FAB) calcd. for [M+H]+
C21H16NO3: 330.1130, found: 330.1126.
Conclusions
In summary, we have presented aminoindanol-based CDAs for
the determination of the absolute configuration of -chiral
80 2-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-1H-benzo-
[de]iso-quinoline-1,3(2H)-dione ((1S,2R)-2b): The procedure
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1996, 37, 4737; (e) Y. Nagai and T. Kusumi, Tetrahedron Lett., 1995,
36, 1853.
Partial epimerizaton (< 10%) at the chiral center of carboxylic acids
was observed during the synthesis of 2a or 2b esters of -aryl
carboxylic acids.
Spartan’10 (Wavefunction, Inc.) was used for the calculation. A
Monte Carlo conformation search was performed by using the
MMFF force field to find stable conformations, which were then used
as initial structures for the density functional geometry optimization
(B3LYP/6-31G*).
In the computational studies, isobutyric acid was chosen as the
simplest model of -branched carboxylic acids.
For the case of compound 1, the size of the aromatic group has little
effect on the chemical shift difference: replacing the benzene ring
with naphthyl or anthryl rings did not produce higher shift.4a This
was ascribed due to the direction of maximum shielding focused on
the immediate neighbour of the chiral center.
described for (1R,2S)-2a was followed except that (1S,2R)-1-
amino-2-indanol and 1,8-naphthalic anhydride were used instead
of (1R,2S)-1-amino-2-indanol and phthalic anhydride,
respectively. The spectral data were virtually identical to those of
(1R,2S)-2b except [α]D22 = +121 (c = 0.5 in CHCl3).
65
70
75
80
5
6
5
General Procedure for the Preparation of compound 2 esters:
A carboxylic acid, bis(2-oxo-3-oxazolidinyl)-phosphinic chloride
(BOP-Cl, 1.5 equiv.), and 4-(dimethylamino)pyridine (0.1 equiv.)
10 were dissolved in DMF. To the solution was added DIEA (2.5
equiv.) followed by compound 2a or 2b (1.0 equiv.). After
stirring overnight, the mixture was diluted with EtOAc and
washed with brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue
15 was purified by SiO2 chromatography.
7
8
9
NMR Solvent Data Chart, Cambridge Isotope Laboratories, Inc.,
Andover, MA.
10 A. V. Marenich, R. M. Olson, C. P. Kelly, C. J. Cramer and D. G.
Acknowledgement
Truhlar, J. Chem. Theory Comput., 2007, 3, 2011.
This work was supported by Priority Research Centers Program
(grant no. 2010-0020209) of Ministry of Education, Science and
Technology/National Research Foundation of Korea.
20 Notes and references
a Department of Chemistry and Research Institute for Natural Sciences,
Korea University, Seoul 136-701, Republic of Korea. Fax: 82 2 3290
3121; Tel:82 2 3290 3141; E-mail: kchoi@korea.ac.kr
† Electronic Supplementary Information (ESI) available: Copies of the
25 NMR spectra and characterization data for 2a, 2b, and their esters. See
DOI: 10.1039/b000000x/
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