Three-component chiral derivatizing protocols for NMR spectroscopic enantiodiscrimination of hydroxy acids and primary amines

Article abstract of DOI:10.1021/jo202334d

The novel three-component chiral derivatization protocols have been derived for ¹H and ¹⁹F NMR spectroscopic discrimination of a series of chiral hydroxy acids by their coordination and self-assembly with optically active α-methylbenzylamine and 2-formylphenylboronic acid. In addition, the optically pure (S)-mandelic acid in combination with 2-formylphenylboronic acid permits visualization of enantiomers of primary amines. These protocols have been demonstrated on enantiodiscrimination of chiral amines and hydroxy acids.

Full text of DOI:10.1021/jo202334d

Article
pubs.acs.org/joc
Three-Component Chiral Derivatizing Protocols for NMR
Spectroscopic Enantiodiscrimination of Hydroxy Acids and
Primary Amines
Sachin Rama Chaudhari†,‡ and N. Suryaprakash*,‡
†Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
‡NMR Research Centre, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: The novel three-component chiral derivati-
1
zation protocols have been derived for H and 19F NMR
spectroscopic discrimination of a series of chiral hydroxy
acids by their coordination and self-assembly with optically
active α-methylbenzylamine and 2-formylphenylboronic acid.
In addition, the optically pure (S)-mandelic acid in combina-
tion with 2-formylphenylboronic acid permits visualization of
enantiomers of primary amines. These protocols have been
demonstrated on enantiodiscrimination of chiral amines and
hydroxy acids.
will be disproportional to that of two enantiomers of the
original mixture, preventing the precise measurement of ee in
such situations. To circumvent this problem, we have derived
efficient and cost-effective three-component protocols for
determining the enantiopurity of hydroxy acids and primary
amines. In the present study, we have investigated only racemic
mixtures with the main focus of differentiating enantiomers.
However, the study using scalemic mixtures can be employed
for the measurement of ee. The three-component derivatization
protocols using 2-formylphenylboronic acid and (S)-BINOL for
determining the enantiomeric purity of chiral primary amines,
diamines, and the mixture of 2-formylphenylboronic acid
and enantiopure α-methylbenzylamine to determine the
enantiopurity of diols have been reported.7 In line with the
developments of James et. al,7 we are reporting two different
three-component derivatizing agents for measurement of the
enantiomeric purity of chiral hydroxy acids and chiral primary
amines.
INTRODUCTION
■
Differentiation of enantiomers is important in diverse
disciplines, such as chiral synthesis, mechanistic studies,
catalysis, kinetics geochronology, biochemistry, pharmacol-
ogy, and medicine.1 Several methods have been employed
to achieve enantiodiscrimination from either racemic or
scalemic mixtures.2 The determination of enantiopurity by
nuclear magnetic resonance (NMR) spectroscopy is a largely
explored area. Nevertheless, NMR spectroscopy is intrinsically
blind to discriminate the enantiomers in the commonly utilized
achiral NMR solvents. To utilize NMR as an analytical tool, the
substrates must be converted to a pair of diastereomers, which
is accomplished by the utilization of any of the chiral auxiliaries,
such as chiral derivatizing agents (CDAs), chiral solvating agents
(CSAs), or chiral lanthanide shift reagents.3 Several reagents,
such as amines, amino alcohols, diamines, amides, and macro-
cyclic compounds, have been reported to address the problems
of determining the enantiopurity of chiral acids.4 However, few
such derivatives are utilized to determine the enantiomeric
RESULTS AND DISCUSSION
1
■
purities of carboxylic acids by H NMR, because of negligible
Chiral Discrimination of Hydroxy Acids. The chiral
hydroxyl acids are a class of compounds that have never
been tested to date, to the best of our knowledge, using
three-component derivatizing protocols. For hydroxy acids,
the protocol involves their derivatization with 2-formylphe-
nylboronic acid and an enantiopure (R)-α-methylbenzyl-
amine in CDCl3. The reaction mixture was stirred for 5 min
chemical shift differences between diastereomers. Although the
amine or amide-based CSAs can afford relatively large chemical
shift differences between the substrate enantiomers, the pre-
paration of such reagents usually requires multistep syntheses,
limiting their practical application. In the case of primary
amines MTPA (Mosher) or MPA (Trost) amide,5 crown ethers
and their derivatives6 are employed for their discrimination.
Generally, a higher concentration of the auxiliary is required
when crown ethers are employed since it is difficult to achieve
discrimination because of poor resolution of the spectrum at
lower concentrations. When Mosher or Trost are utilized, due
to the problem of kinetic resolution, the ratio of diastereomers
1
at room temperature. Subsequently, H NMR spectra of an
aliquot were recorded to obtain the quantitative yield of
Received: November 11, 2011
Published: December 6, 2011
© 2011 American Chemical Society
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Article
diastereomers of iminoboronate esters, (R,S) and (R,R), as
shown in Scheme 1.
To investigate the scope and limitations of this chiral deriv-
atization protocol, a range of hydroxy acids were then deriv-
atized. The chemical shift differences observed between the
enantiomers in 1H NMR spectra of 1−6 are reported in Table 1,
along with their chemical structures.
Discrimination of Primary Amines. We have extended
the strategy for discrimination of primary amines utilizing
1 equiv of racemic primary amine, optically pure (S)-mandelic
acid, and 2-formylphenylboronic acid. This is reported in
Scheme 2.
Scheme 1. Three-Component Reaction of
2-Formylphenylboronic Acid, (R)-α-Methylbenzylamine,
and (rac) Hydroxy Acids (1−6) to Yield Diastereomeric
Iminoboronate Esters (R,S)-1−6 and (R,R)-1−6
The reaction mixture was stirred for 5 min at room tem-
1
perature. The H NMR spectra of an aliquot were recorded.
The 1H NMR spectrum revealed a 1:1 mixture of two
diastereoisomeric complexes (S,R) and (S,S). The 400 MHz 1H
NMR spectrum of (R/S)-α-methylbenzylamine given in Figure 3
clearly identifies the two discriminated peaks.
The convincing results were achieved for several other
primary amines using this novel three-component deriv-
atizing protocol. The chemical shift differences between
the enantiomers observed in the 1H NMR spectra of
7−14 are reported in Table 2, along with their chemical
structures.
1
The analysis of H NMR spectrum recorded at 400 MHz
gave different peaks for (R,S):(R,R). As no kinetic resolution
occurs in the present protocol, it is possible to obtain the
accurate enantiomeric excess. The H NMR spectrum of
CONCLUSIONS
1
■
New three-component chiral derivatizing systems for NMR
spectroscopic determination of the enantiopurity of hydroxy
acids and chiral amines have been developed. The easy
preparation of these three-component systems acts as
convenient and fast derivatization protocols that are ideal
for routine analysis of chiral molecules. There are distinct
advantages of these protocols over other methods. First,
the different sets of integral areas of peaks can be employed
for the measurement of ee. Second, the discrimination is
observed at the chemical sites of both protons and fluorine
that are separated by more than five bonds from the stereogenic
center.
(R/S)-mandelic acid is given Figure 1. The discriminated
peaks marked A and C in Scheme 1 and that of the proton
marked D in (R/S)-mandelic acid is shown with expansion.
The chemical shift difference (Δδ)R/S measured are given in
Table 1.
In the subsequent stage, the possibility of utilizing the 19F
NMR in fluorinated molecules was explored. The 19F spectrum
of (R/S)-4-trifluoromethyl mandelic acid results in two 19F
peaks pertaining to two enantiomers whose integral areas are
approximately in the ratio of 1:1. The 376 MHz 19F NMR
spectrum of (R/S)-4-trifluoromethyl mandelic acid is given in
Figure 2.
1
Figure 1. H NMR spectrum (400 MHz) of (R/S)-mandelic acid exhibiting the enantiodiscrimination as given in Scheme 1.
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1
Table 1. H Chemical Shift Differences between
Diastereomers Measured at 400 MHz NMR Spectrometer
a
for Racemic Mixtures of 1−6
Figure 2. 19F NMR spectrum (376 MHz) of (R/S)-p-trifluoromethyl
mandelic acid.
Scheme 2. Three-Component Reaction of
2-Formylphenylboronic Acid, (S)-Mandelic Acid, and (rac)
Primary Amines (7−14) to Yield Diastereomeric
Iminoboronate Esters (S,S)-7−14 and (S,R)-7−14
1
Figure 3. H NMR spectrum (400 MHz) of (R/S)-α-methylbenzyl-
a
Note: the protons A, B, and C are labeled in Scheme 1. Other
amine exhibiting the discriminated peaks as given in Scheme 2.
protons are marked in the respective figures.
stirred using a Teflon-coated magnetic stirrer. To this, 80 mg of (R)-α-
methylbenzylamine and 80 mg of chiral hydroxyl acid was transferred
to the round-bottom flask. The mixture was stirred for 5 min.
An aliquot (0.5 mL) of the reaction mixture was transferred to the
EXPERIMENTAL SECTION
■
2-Formylphenylboronic acid, (S)-mandelic acid, R-α-methylbenzyl-
amine, 1−6 hydroxy acids (see Table 1), 7−14 primary amines (see
Table 2), and chloroform-d all of high purity were purchased. All the
reagents were taken in a round-bottom flask. A 100 mg portion of
2-formylphenylboronic acid was transferred to the round-bottom flask.
To this transfer, 5 mL of CDCl3 was added to the reaction vessel
using a glass syringe fitted with a disposable needle. The mixture was
1
NMR tube. The H NMR spectrum was recorded at 400 MHz and
chemical shifts were referenced with respect to TMS (0.00 ppm).
A similar procedure was repeated for the discrimination of chiral
amines, where enantiopure (S)-mandelic acid was used instead of (R)-
α-methylbenzylamine.
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Table 2. H Chemical Shift Differences between
ACKNOWLEDGMENTS
■
Diastereomers Measured at 400 MHz for Racemic Mixtures
N.S. gratefully acknowledges the financial aid for this work by
the Department of Science and Technology, New Delhi, for
Grant No. SR/S1/PC-32/2008, and S.R.C. thanks UGC, New Delhi,
for SRF. Nilamoni Nath and Sankeerth Hebbar are thanked for
helpful discussions.
a
of 7−14
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a
Note: protons a and b are marked in Scheme 2. Other protons are
marked in the respective figures.
ASSOCIATED CONTENT
■
S
* Supporting Information
The H and 19F spectra of the investigated molecules. This
1
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: ++91 80 22933300. Fax: ++91 80 23601550. E-mail: nsp@
sif.iisc.ernet.in.
■
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