Synthesis and applications of exo N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)benzamides as NMR solvating agents for the chiral discrimination of 1,1′-binaphthyl-2,2′-diyl hydrogenphosphates and α-substituted acids

Article abstract of DOI:10.1016/j.tetasy.2015.08.008

A series of exo N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)benzamides were prepared from (R)-isobornyl amine and screened as chiral solvating agents to discriminate the isomers of 1,1′-binaphthyl-2,2′-diyl hydrogenphosphates by ³¹P

Full text of DOI:10.1016/j.tetasy.2015.08.008

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Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and applications of exo N-((1R,2R,4R)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-yl)benzamides as NMR solvating
agents for the chiral discrimination of 1,10-binaphthyl-2,20-diyl
hydrogenphosphates and a-substituted acids
Jayaraman Kannappan a,b, Nilesh Jain c, Ashutosh V. Bedekar c,
⇑
a Apicore Pharmaceuticals Pvt. Ltd, Block No. 252-253, Dhobikuva Village, Padra-Jambusar Highway, Padra Taluka, Vadodara 391 440, India
b Department of Chemistry, Amet University, 135, East Coast Road, Kanathur, Chennai 603 112, India
c Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara 390 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of exo N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)benzamides were prepared from
(R)-isobornyl amine and screened as chiral solvating agents to discriminate the isomers of 1,10-binaph-
thyl-2,20-diyl hydrogenphosphates by 31P NMR analysis. A linear relationship between the experimental
and calculated enantiomeric purity was established indicating the potential use of the system to deter-
mine the ee for samples of this acid of unknown enantiomeric purity. The amides were also screened for
Received 30 July 2015
Accepted 14 August 2015
Available online xxxx
chiral discrimination of some
a
-substituted acids by 19F NMR analysis.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
enantiomers.5 The two enantiomers of the chiral sample show
the same signals in the NMR and cannot be recognized in an achiral
environment of the NMR spectroscopy. Hence, some modifications
are required to distinguish between the signals in this technique.
The enantiomers which typically appear as identical signals in
the NMR spectra when converted into diastereomers, show
resolved spectroscopic patterns. Converting the analyte sample to
diastereomers can carried out in two ways, by forming covalent
bonds with chiral derivatizing agents6 or alternatively by forming
temporary supramolecular interactions with chiral solvating (or
complexing) agents.7 One such routinely used technique involves
the in situ preparation of diastereomeric lanthanide chelate com-
plexes.8 However, there are some inherent problems such as the
broadening of signals, low solubility in NMR solvents, and their
high cost. The second option is probably simpler, and more practi-
cal and hence has been investigated considerably in recent years.
In the case of chiral solvating agents, the temporary formation of
diastereomers with enantiomerically pure reagents results in
non-equivalence of the chemical shifts of the protons of the two
enantiomers of the analyte.9 This technique of using chiral solvat-
ing agents has distinct advantages of simplicity, more accurate
analysis against the derivatization process with chiral derivatizing
agents, and it is non-destructive due to weak non-covalent interac-
tions. Such intermolecular supramolecular interactions include
The synthesis and study of chiral molecules is a well-estab-
lished and expanding area of modern chemistry. The importance
of a wide range of chiral molecules is not merely restricted to
bioactive molecules such as pharmaceuticals, chemicals inducing
flavors, and fragrances, but also covers many other areas of molec-
ular recognition and material science. Moreover, the activity is
often linked to the chiral information and absolute conformation
of the optically active compounds. Hence it is important to unam-
biguously establish detailed chiral information, enantiomeric pur-
ity, and absolute configuration. This has necessitated the need for
quick, accurate, and reliable techniques to establish the ratio of
the enantiomers in chiral samples. More commonly used contem-
porary techniques for such measurements are based on chromato-
graphic1 separations such as GC and HPLC, but their success mainly
depends on the competence and selectivity of the chiral stationary
phases of the columns. More spectroscopic techniques, such as
mass spectrometry,2 IR, UV, and fluorescence spectroscopy,3 circu-
lar dichroism, and electrophoresis4 have been developed to deter-
mine the enantiomeric purity of molecules. Among these other
methods, NMR spectroscopy has emerged as an advantageous
technique for the fast and accurate determination of the ratio of
dipole–dipole, charge transfer, van der Waals,
the formation of H-bonding. A variety of compounds such as
p–p stacking, and
⇑
Corresponding author. Tel.: +91 265 2795552.
E-mail address: avbedekar@yahoo.co.in (A.V. Bedekar).
http://dx.doi.org/10.1016/j.tetasy.2015.08.008
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kannappan, J.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.008

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J. Kannappan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
amines, amides, lactams, carboxylic acids, and cyclodextrins with
suitable coordination sites and orientations have been developed
to effectively function as chiral solvating agents. The success of this
technique depends on the adequate combination of these interac-
tions between the two partners of the complex. Hence, even
though a large number of chiral solvating agents are available,
there is a need to design more molecules, which can be readily pre-
pared in enantiomerically pure form, while they may be easily
modified to suit the particular requirement.
The chiral amide of 3,5-dinitro benzoic acid 1a reported by
Kagan et al. is one of the earliest and well-studied chiral solvating
agents for efficiently discriminating between several types of
molecules by NMR analysis.10 This is a simple molecule with basic
down-field shifts of appropriate examples in the 1H NMR experi-
ments. Recently we have presented our results with a modified
Kagan type amide 1e and demonstrated its slightly superior chiral
solvating ability for a variety of substrates.14 We have an ongoing
interest in developing chiral solvating agents suitable for a variety
of analytes15 and herein we report another molecule. The deriva-
tives of Kagan’s amide mentioned in Chart 1 have a similar feature
of having aromatic systems on the both arms of the amide func-
tionality, although not directly attached in case of 1d. Herein we
report an amide of chiral isobornyl amine with various aromatic
acid counterparts and discuss their suitability as chiral solvating
agents in some chiral analytes.
functional units present to enable hydrogen-bonding and
p–p
2. Result and discussions
interactions with substrates for tight complex formations under
NMR conditions. These types of compounds were first developed
by Pirkle et al. for the Whelk-O type materials for separation of chi-
ral compounds on HPLC columns.11 Over the years, a few more
derivatives of Kagan’s amide have been explored with good success
in the molecular recognition of chiral compounds (Chart 1).12 The
range of chiral analytes successfully screened with these chiral sol-
vating agents include amides12c sulfoxides,10b,d multifunctional
tert-alcohols,12d and phosphine oxides.10c
The synthesis of modified amides is based on using chiral iso-
bornyl amine 2, which is a readily available material. The rigid
bicyclic framework of isobornyl amine with three stereogenic cen-
ters will provide the steric bulk for chiral molecular recognition
during the NMR analysis, although it may not offer
p–p interac-
tions from both the sides of the amide unit. A series of such amides
4a–4h were synthesized by simple condensation of isobornyl
amine 2 and suitable acid chlorides 3 in the presence of a triethy-
lamine as base (Scheme 1).
All of the amide derivatives of 4 were purified by column chro-
matography, crystallization, and characterized by the usual spec-
troscopic and analytical tools. The 3,5-dinitro derivative 4f was
also characterized by its single crystal X-ray analysis (Fig. 1).16
The molecule is crystallized in the P212121 space group, and two
molecules are held together by hydrogen bonding between
NH–C@Oꢀ ꢀ ꢀH–N–CO with the bond length of 2.114 Å.
The widely accepted mode of interaction between the chiral
solvating agent and analyte molecule involves hydrogen bonding,
N–Hꢀ ꢀ ꢀO@X (X = C or S of analyte), and the
p
–
p
a
interaction
cleft like
between the aromatic units.12d In one case,
conformation is created by perpendicularly arranged dinitro
benzoyl and the naphthalene rings in case of 1b;12c similar types
of explanations are offered for the other derivatives 1c and 1d.13
The proposed interactions were also corroborated by up-field and
O
O
NO2
NO2
N
H
N
H
NO2
NO2
1a
1b
NO2
O
O
N
NO2
F3C
NO2
NH
N
H
NH
HN
O
O
CF3
NO2
1e
1c
1d
Chart 1. Kagan’s amide 1a and its analogues.
O
R'
R''
R'
Cl
Ar
( )
R
(
)
R
3a-g
H
N
NH2
(R)
(R)
Et3N
( )
R
(
)
R
O
2
4a
: R' = R'' = H (88%)
4b: R' = H, R'' = F (74%)
4c
: R' = H, R' = NO2 (76%)
4d: R' = Cl, R'' = H (67%)
4e
O2N
CF3
(
)
R
H
N
: R' = CF3, R'' = H (73%)
4f: R' = NO2, R'' = H (79%)
4g
(R)
(
)
R
O
: R' = NO2, R'' = Cl (67%)
4h
Scheme 1. Synthesis of isobornyl derived amides.
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3
responsible for the inefficiency of the chiral discrimination. For
similar studies, the use of an external base to assist in the
abstraction of this proton for subsequent ionic interactions with a
molecule of chiral solvating agents is available in the literature.9l
Hence, we investigated a few organic bases with the present chiral
solvating agent 4f and the effect was measured (Table 1). Initially
triethyl amine was scanned where a slightly larger shift was
detected but failed to observe any discrimination. However, when
stronger bases were screened, a significant shift was observed, but
more importantly the chiral discrimination was also seen. Among
the bases, DABCO and pyridine showed good resolution in the 31P
signal of the two isomers of 5, while DMAP showed the best
discrimination. The effectiveness of a base for this behavior is due
to combined effect of the presence of the aromatic ring to offer
p
p–
interaction as well as its basicity (pKa).19
Table 1
Effect of base of the recognition of ( )-5 with chiral solvating agent 4fa
Figure 1. ORTEP diagram of 4f.
No
Base
Induced chemical
Chemical shift
shift (D
d)b
non-equivalence (DDd)b
Catalytic asymmetric synthesis is one of the most efficient tech-
niques employed to generate a large amount of chiral material using
a small quantity of chiral catalysts. Recently chiral Brønsted acids,
such as phosphoric acid derivatives 1,10-binaphthyl-2,20-diyl hydro-
gen phosphate 5 (BINPA) and its derivatives, have found wide use as
chiral catalysts. Many reactions have been developed to generate a
stereogenic center in an enantioselective manner using this class
of catalyst.17 For successful applications in asymmetric reactions,
the acid catalysts need to be of enantiomerically pure form and
hence it was necessary to develop a tool for the quick and accurate
determination of its enantiomeric purity (Chart 2).
The enantiomeric purity of acid 5 and similar compounds can
be determined by various techniques, but a very efficient, non-de-
structive, quick, and reliable one has recently been developed
using nuclear magnetic resonance (NMR) spectroscopy. Usually
1H NMR analysis is used to detect the signals separated by in situ
chiral discrimination caused by supramolecular interactions
between chiral solvating agent and the analyte. In some cases
other nuclei such as 13C, 19F, 31P, 77Se, and even 195Pt have been
used as the probe to detect the ratio of isomers.14 There are a
few reports on the development and use of some chiral solvating
agents to determine the composition of isomers of 5, an important
catalyst by 31P NMR analysis.18 Although Kagan’s amide 1a has
been used as a probe to resolve the signals of compounds contain-
ing phosphorus by 31P NMR,10c,12a there are no reports on its use
for the analysis of 5. The present set of chiral solvating agents,
4a–4h, was systematically screened to determine their efficiency
to discriminate between the isomers of 5 by recording the
separation of signals by the 31P NMR analysis. The initial
experiment of recording 31P NMR of racemic 5 with modified
Kagan’s amide 4f in CDCl3 resulted in small shift of the signal,
but no split was observed (Table 1). The shift of the signal from
c
1
2
3
4
5
6
—
0.05
ꢁ1.45
ꢁ0.45
0.32
0.44
0.66
—
—
c
Triethyl amine
DBU
DABCO
Pyridine
DMAP
0.030
0.166
0.140
0.303
All 31P NMR spectra run at 20 mmol in CDCl3 in a ratio of ( )-5/chiral solvating
a
agents 4f/base (1:2:1).
b
In ppm.
Not observed.
c
The proposed intermediate involves three components, that is,
the chiral solvating agent, the deprotonated ion of 5, and protonated
base.9l,m Hence, we further investigated the ratio of the three species
participating in the possible mode of interactions (Table 2).
Marginally better parameters were observed when higher amounts
of base and chiral solvating agent were used. Similar observations
in the case of thiourea based chiral solvating agents were reported
for enhanced selectivity with higher amounts of reagent.20
Table 2
Composition of DMAP, to chiral solvating agent 4f and analytea
No
Base
Chiral solvating agent
( )-5
D
db
DDdb
1
2
3
4
1
1
2
1
1
2
2
3
1
1
1
1
1.050
0.660
0.563
0.265
0.262
0.303
0.299
0.266
All 31P NMR spectra run at 20 mmol in CDCl3.
In ppm.
a
b
Having established the efficacy of DMAP to be a more suitable
base for the present analysis we further scanned the rest of the
chiral solvating agent molecules (Table 3). In all cases, the shift
the original position was recorded as induced chemical shift (Dd)
while the difference in the two split signals due to recognition of
analyte by chiral solvating agents is referred to as a chemical
Table 3
Screening chiral solvating agents for recognition of ( )-5a
No
Chiral solvating
Induced chemical
Chemical shift
agents 4
shift (D
d)b
non-equivalence (DDd)b
shift non-equivalence
(DDd). The neutral nature of chiral
solvating agent 4f to abstract the acidic hydrogen of 5 is probably
c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
1.77
1.77
1.57
1.70
1.13
0.66
0.82
1.33
—
—
c
0.013
c
—
—
c
O
O
O
O
O
O
0.303
0.251
0.020
P
P
OH
OH
4g
4h
a
All 31P NMR spectra run at 20 mmol in CDCl3 in the ratio of ( )-5/chiral sol-
5
5
(R)-
vating agents 4f/DMAP (1:2:1).
(S)-
b
In ppm.
c
Chart 2. Enantiomers of 1,10-binaphthyl-2,20-diyl hydrogenphosphate 5.
Not observed.
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in the signal (Dd) was considerable but the chiral discrimination
O
COOH
was observed in the case 4c, 4f, and 4g. These three derivatives
have a strong electron withdrawing nitro group attached on the
acid component of the amides. The beneficial effect of the presence
of 3,5-dinitro functionality for effective interactions has also been
observed in earlier studies,10d,12c,14 however, the structurally
similar 4d and 4e were not suitable to resolve the signals of 5.
COOH
Ph
F
6a
F
6b
Δδ = 2.24
Δδ = 1.16
ΔΔδ
ΔΔδ
= 0.01
= 0.01
We also prepared 4g with
a 3,5-dinitro-4-chloro unit and
Chart 3. Structures of fluorine containing analytes with
NMR with 4f (2.0 equiv) and DMAP (1.0 equiv) in CDCl3 (20 mmol).
Dd and D
dd values of 19F
scanned for chiral solvating agent activity. This was found to be
effective with reasonably good results, but with a slightly lower
value of chemical shift non- equivalence compared to 4f. The
presence of the slightly larger chlorine atom might contribute to
the steric crowding and nullifying the electronic effects.
Structurally different 4h, but with two strongly electron
withdrawing groups was also effective but to a lesser degree
when compared to dinitro derivative 4f.
were recorded with 4f (2.0 equiv) and DMAP (1.0 equiv). The
separation of signals for the fluorine atom and its shift area is
presented in Chart 3.
3. Conclusion
The ability of the chiral discrimination of the present chiral sol-
vating agents was further studied in order to establish the linear
relationship between the observed and actual values of ee for
Herein we have synthesized a series of chiral exo-(1R,2R,4R)-N-
(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)benzamides from (R)-
isobornyl amine and screened them as chiral solvating agents to
determine the ratio of isomers of 1,10-binaphthyl-2,20-diyl hydro-
gen phosphates by 31P NMR analysis. The chiral solvating agent
was also screened to discriminate between the signals of a few
establishing its practical utility as
a chiral solvating agent
(Fig. 2). The observed ee values were found to be within the accept-
able limits of the actual values, which confirm the accuracy and
consistency of the analysis.
The use of chiral solvating agents for determining the enan-
tiomeric purity by 1H NMR analysis is emerging as a useful tool
and hence we decided to scan different types of analytes to prove
its wider applicability. Hence we further scanned 4f, the most
a
-functionalized acids in 19F NMR analysis. Conditions were also
standardized for the quantitative determination of the ratio of
enantiomers in the controlled experiment, which opens up possi-
bilities for this technique to be used for the determination of the
ee of unknown samples of these analytes.
promising of the present chiral solvating agents, for a-substituted
acids since they form an important class of chiral compounds. The
importance of chiral drugs in medicinal chemistry is a well estab-
lished phenomenon. Herein we scanned 4f for a few chiral drugs
and drug intermediates. Non steroidal anti-inflammatory agents
such as flurbiprofen 6a, are important chiral drugs.21 We also
extended our study with the analysis of 6b, an intermediate of
Nebivolol, a b-blocker agent.22 Herein we observed the separation
of signals in the 19F NMR in the case of 6a and 6b, when spectra
4. Experimental
4.1. General
Thin layer chromatography was performed on silica gel plates
quoted on aluminim sheets. The spots were visualized under UV
Figure 2. (a) Selected region of 31P NMR spectra of scalemic mixture of 5 in the presence of 4f; values in parenthesis indicate the observed ee; (b) its correlation between
theoretical and observed % ee values.
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