Design of Selenium-Based Chiral Chemical Probes for Simultaneous Enantio- and Chemosensing of Chiral Carboxylic Acids with Remote Stereogenic Centers by NMR Spectroscopy

Article abstract of DOI:10.1002/chem.201602884

Selenium-based enantiopure chiral chemical probes have been designed in a modular way starting from available amino alcohols. The probes developed were found to be efficient in chemoselective interaction with carboxylic functions of chiral substrates leading to diastereomeric amide formation and in sensing α-, β-, and remote (up to seven bonds away from the carboxylic group) chiral centers by using⁷⁷Se NMR spectroscopy. As a result, it was possible to determine the enantiomeric ratio of structurally diverse individual chiral acids including polyfunctional compounds and drugs with high accuracy. An approach to analyzing the crude reaction mixtures has been successfully developed by using bifunctional selenium- and fluorine-containing chiral probes. More importantly, it was revealed that, based on the⁷⁷Se NMR data obtained, it is possible to obtain primary information about the location and nature of the substituents at the chiral center (chemo- and enantiosensing), which can simplify the structural elucidation of complex compounds. The derivatization procedure takes as little as 5 min and can be performed directly in an NMR tube followed by NMR measurements without any isolation and purification steps.

Full text of DOI:10.1002/chem.201602884

DOI: 10.1002/chem.201602884
Full Paper
&
Structure Elucidation
Design of Selenium-Based Chiral Chemical Probes for
Simultaneous Enantio- and Chemosensing of Chiral Carboxylic
Acids with Remote Stereogenic Centers by NMR Spectroscopy
Sergey A. Shyshkanov and Nikolai V. Orlov*[a]
In the memory of our colleague and friend Dr. P. A. Belyakov
Abstract: Selenium-based enantiopure chiral chemical
probes have been designed in a modular way starting from
available amino alcohols. The probes developed were found
to be efficient in chemoselective interaction with carboxylic
functions of chiral substrates leading to diastereomeric
amide formation and in sensing a-, b-, and remote (up to
seven bonds away from the carboxylic group) chiral centers
by using 77Se NMR spectroscopy. As a result, it was possible
to determine the enantiomeric ratio of structurally diverse
individual chiral acids including polyfunctional compounds
and drugs with high accuracy. An approach to analyzing the
crude reaction mixtures has been successfully developed by
using bifunctional selenium- and fluorine-containing chiral
probes. More importantly, it was revealed that, based on the
77Se NMR data obtained, it is possible to obtain primary in-
formation about the location and nature of the substituents
at the chiral center (chemo- and enantiosensing), which can
simplify the structural elucidation of complex compounds.
The derivatization procedure takes as little as 5 min and can
be performed directly in an NMR tube followed by NMR
measurements without any isolation and purification steps.
Introduction
this is less convenient compared with chromatographic meth-
ods, on another hand it opens wide possibilities to variate the
structures of the probes, reaching the highest selectivity and
sensitivity. Numerous fluorescent and colorimetric chiral chemi-
cal probes have been designed for this purpose, which so far
have shown promising results in the determination of enantio-
meric excess (ee) and absolute configuration of different chiral
compounds.[3] The probes are constructed in a modular way so
various reacting units, responsible for selective recognition of
a molecule or molecular fragment, and sensing units are at-
tached to a chiral core (Scheme 1). Different to the numerous
chiral derivatizing agents previously developed in which the
chiral center had to be created upon introduction of the react-
ing and sensing units into a molecule (singular design), modifi-
cation of chiral probes does not require any impact on a chiral
center, which already exists in a suitable chiral core. As a result,
the methods of synthesis of the probes are simplified and do
Development of asymmetric synthesis and catalysis has seen
tremendous progress in recent decades.[1] The new trend in
this field is multi-bond forming one-pot reaction cascades that
open access to nature-mimicking chiral compounds.[2] To ach-
ieve these in a rational way, a demand arises to monitor the
chemo-, regio-, diastereo-, and enantioselectivity at different
steps in the one-pot sequence, thus requiring efficient, reliable,
and quick analytical methods to be used. In addition, it is
highly desirable to gain structural information concerning the
products formed. Although chiral HPLC and GC are widely
used nowadays to determine enantiomeric excess of the chiral
compounds, they have some limitations in the case of analysis
of crude reaction mixtures especially those containing transi-
tion metals. Individually, they can provide no data about the
structure of the products formed and combined use of HPLC
or GC and HRMS is required. Keeping these in mind, rapidly
improving spectral methods (NMR, UV, UV/Vis) can be consid-
ered as an attractive and more powerful alternative. As these
methods are achiral themselves, auxiliary enantiopure chiral
compounds are required to selectively react with an analyzed
sample for enantiodiscrimination to be generated. Although
[a] S. A. Shyshkanov, Dr. N. V. Orlov
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
Leninsky Prospekt, 47, Moscow, 119991 (Russia)
E-mail: onv@ioc.ac.ru
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201602884.
Scheme 1. Modular versus singular design of chiral chemical probes for
analysis of chiral compounds by using NMR spectroscopy.
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not require asymmetric steps. What is more important is that it
becomes extremely easy to perform fine tuning to reach the
best selectivity for definite compounds to be analyzed and
sensitivity of the response. Such an approach can be highly
beneficial if used in NMR spectroscopy. The method has been
shown to provide accurate and reliable data on chirality sens-
ing,[4] but, until recently, it has been lacking easily variable
chiral probes and required time- and reagent-consuming deri-
vatization procedures. However, continuous improvement of
derivatization procedures and introduction of new chiral auxil-
iaries during the last decade has resulted in the development
of fast methods (within minutes) to form diastereomers
directly in an NMR tube, thus avoiding isolation and purifica-
tion steps before NMR analysis (so-called “mix and shake”
protocols).[5]
((R)-SeBA) 3a and (R)-1-((4-fluorophenyl)selanyl)butan-2-amine
((R)-4F-SeBA) 3b. The choice of selenium-containing sensing
unit was determined by the high NMR sensitivity of this nu-
cleus to structural changes in the molecular environment[5g,6o,p]
so it gives the possibility to probe even challenging remote
stereogenic centers, which are often present in natural prod-
ucts and drugs. Thus, the target selenium-based chiral probes
3a and 3b were obtained on a gram scale in four steps start-
ing from readily available and inexpensive enantiopure amino
alcohol 1 (Scheme 2).[10] The key step—introduction of a chirali-
Based on our previous investigations, we envisaged the
development of a modular chiral chemical probe that can be
easily modified for selective recognition of various functional-
ized chiral organic compounds by NMR spectroscopy. In addi-
tion, introduction of NMR-active heteronuclei (such as 19F, 31P,
77Se) can improve the sensitivity of the analysis and simplify as-
signment of the diastereomers formed as only the signals of
analyzed compounds bound to the probe are observed in the
spectra.[6] In this paper, we describe the design of new seleni-
um-based and dual selenium/fluorine chiral probes used for
enantio- and chemosensing of chiral carboxylic acids, which
are of high demand in laboratory organic synthesis and cataly-
sis[7] as well as in the pharmaceutical industry, perfumery, and
agriculture.[8]
Scheme 2. Synthetic approach to chiral NMR probes (R)-SeBA 3a and
(R)-4F-SeBA 3b.[10]
ty sensing SeAr group—was performed by using in situ re-
duced Ar2Se2 (Ar=Ph for 3a and 4-FC6H4 for 3b) followed by
one-pot amino-group deprotection with concentrated HCl so-
lution added to the reaction mixture. The original extraction
method for isolation and purification developed gave 68% iso-
lated yield (starting from 1) of free base 3a of high chemical
purity. In a similar manner, pure 3b was obtained in 34% un-
optimized yield. As the stereogenic center was not involved in
the reaction, the products were obtained in enantiopure form,
which was confirmed by NMR analysis of the corresponding
diastereomeric amides formed upon interaction with enantio-
pure (R)-methoxyphenylacetic acid. Thus, the fact that there
was no decrease in enantiomeric purity after isolation indicat-
ed that the products are stable under acidic and basic condi-
tions. It should be mentioned that the purification procedure
developed is much faster than other methods used, such as
chromatography, and gave better isolated yields (in the case of
other methods, the isolated yield was less than 40%).
Results and Discussion
Design criteria and synthesis of the probes
For an efficient chiral probe for carboxylic functions to be cre-
ated, first the choice of suitable reacting unit should be consid-
ered. Among various types of functional groups able to react
with carboxylic acids, the NH2 group seems to be the most
suitable. Given appropriate promoters, it quickly reacts with
acids to form amides. It is also important that many chiral
amines are commercially available in enantiopure form and
thus can be used as a ready chiral core to develop sensitive
and selective chiral probes. Although formation of salts can
also be used for recognition of enantiomers simply upon
mixing of an acid and amine, we did not consider such a possi-
bility. Indeed, diastereomeric amides usually give much better
discrimination of signals in NMR spectra (i.e., enantiosensitivity
of a sensor) compared with diastereomeric solvation com-
plexes and for the former the value of enantiodiscrimination
does not depend on the concentration of the chiral sensor.[9]
Besides the reacting site, a second functionality should be
present in the molecule to provide the possibility for easy
introduction of various sensing units depending on the
particular analytical needs. a-Amino alcohols fulfill both these
criteria so commercially available (R)-2-amino-1-butanol 1 was
chosen as a chiral core for the synthesis of selenium-based
chiral chemical probes—(R)-1-(phenylselanyl)butan-2-amine
Investigation of the probe’s enantiosensing capacity
First of all, we tested the enantiosensing ability of (R)-SeBA 3a
in CDCl3 as the most common deuterated solvent used in NMR
spectroscopy to analyze the vast majority of organic com-
pounds. Mixing the different chiral carboxylic acids and
promoter N,N’-dicyclohexylcarbodiimide (DCC) in CDCl3 directly
in an NMR tube resulted in immediate formation of a white
suspension upon shaking (Scheme 3, left). After that, chiral
probe 3a (as little as 10 mg) was added and insoluble particles
of dicyclohexylurea (DCU) were formed in 1–2 min, which were
removed to the top of the solution by centrifugation directly
in the NMR tube (Scheme 3, right).[11] The 1H NMR spectrum
was measured after centrifugation and formation of diastereo-
mers was confirmed.[12] It should be emphasized that insoluble
particles did not affect quality of the NMR spectra so no addi-
tional purification or isolation of diastereomers formed was
necessary prior to NMR analysis. Thus, DCC-promoted derivati-
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such remote centers are challenging for recognition, chiral
probe 3a showed remarkable enantiosensitivity and two base-
line resolved signals of the diastereomers with the difference
in chemical shift being 0.39 and 0.21 ppm, respectively, were
observed in the 77Se NMR spectra (representative example of
77Se NMR spectrum of 26 is shown in the insert of Scheme 4,
part C). Again, the resolution of signals observed in [D8]toluene
was better than in CDCl3 (Scheme 4). It should be mentioned
that despite free OH groups being present in the analyzed
prostaglandines 25 and 26 no side reaction of ester formation
occurred, thus the developed chiral probe 3a is highly chemo-
selective for carboxylic groups.
Scheme 3. DCC-promoted “in tube” derivatization of chiral carboxylic acids
with chiral probe (R)-SeBA 3a.
As expected, removing the chiral center one or more bond
away from the carboxylic group resulted in a decrease in the
enantiodiscrimination capacity of the probe (compare homolo-
gous acids 5 and 17, Scheme 4). However, in the case of acids
18–24 the difference in chemical shifts of the signals in the
77Se NMR spectra was compatible to a-chiral carboxylic acids
(Scheme 4). This fact indicates that the difference in 77Se chem-
ical shifts of diastereomers depends not only on the structural
but also on the conformational composition of the considered
diastereomers in solution and can be caused by intra- or inter-
molecular weak interactions stabilizing a particular conforma-
tion of a diastereomer. Consideration and prediction of such
weak interactions is still a challenging task and is a matter of
numerous studies.[14]
zation using the chiral probe (R)-SeBA 3a can be performed di-
rectly in an NMR tube and it takes less than 5 min to prepare
samples suitable for NMR analysis.
As expected, two baseline resolved signals of diastereomers
were observed in the 77Se NMR spectrum, thus proving the
utility of the method. Different model chiral carboxylic acids
were successfully analyzed by using (R)-SeBA 3a and the high
enantiosensitivity of the chiral probe developed, expressed in
baseline resolved signals of diastereomers 4–32 (Scheme 4). In
addition, the protocol developed well tolerated different func-
tional groups on the acids analyzed (hydroxyl, keto, ether,
ester, sulfide, halogen, nitro, and secondary amino groups),
thus excluding side reactions leading to acid degradation or
formation of complex mixtures of diastereomers. This allowed
correct assignment and accurate quantitative measurements of
enantiomeric purity to be made (see below). It should be men-
tioned that less than 5 min is required to register 77Se NMR
spectra suitable for correct recognition and assignment of
diastereomers although longer time is needed to perform
accurate quantitative measurements.
Finally, analysis of a-amino acids 27–31 and polyfunctional
compounds such as bile acid 32 has been successfully per-
formed by using probe 3a (Scheme 4, part D).[15] Although free
amino acids could not be analyzed by using the derivatization
protocol developed, use of Boc- and Fmoc-protected deriva-
tives allowed us to overcome solubility limitations. Both pro-
tecting groups were tolerant to the derivatization conditions.
The differences in chemical shifts obtained for 27–31 were
comparable to a-chiral carboxylic acids and the value obtained
for 32 was in the range of chiral acids with remote stereogenic
centers (compare part D with parts A and C in Scheme 4). The
only modification in experimental derivatization procedure was
the necessity to add a polar co-solvent to the CDCl3 solution
to obtain a narrow peaks for the diastereomers in the
77Se NMR spectra.[10]
Excellent results were obtained for a-chiral carboxylic acids
4–16 (Scheme 4, part A): the average difference in chemical
shifts was 0.5–1.5 ppm, with the maximum difference being
2.28 ppm for diastereomeric amides 12 (Scheme 4, part A). The
only exceptions were the diastereomeric amides of Mosher’s
acid 13 with quaternary stereogenic center, which gave no
split of signals in CDCl3. However, when derivatization was per-
formed in [D8]toluene, two separate signals of diastereomers
13 with a difference of 0.33 ppm were observed.[13] In the case
of other analyzed acids possessing quaternary stereocenters,
no such problems were encountered and signals of corre-
sponding diastereomers 15, 16, 21–24 were baseline resolved
even in CDCl3. We have found that chiral probe (R)-SeBA 3a is
efficient for sensing not only stereogenic centers in the a-posi-
tion of the carboxylic acids analyzed but also for acids with
more remote chiral centers. Diastereomers of b-carboxylic
acids 17–21 were easily recognized and the difference in the
chemical shifts was still enough for baseline resolution of sig-
nals in the 77Se NMR spectra (Scheme 4, part B). To determine
the enantiosensitivity threshold of the probe developed, we
have analyzed two racemic prostaglandines 25 and 26 with
the closest chiral center seven bonds away from the carboxylic
group (the stereocenter under consideration is marked with an
asterisk in Scheme 4, part C). Although chiral molecules with
A representative range of chiral carboxylic acids has been
used to test the enantiosensing capacity of probe 3b. Derivati-
zation was performed in an NMR tube in a similar manner as
for 3a (see Scheme 3) and the diastereomers obtained were
analyzed by 77Se and 19F NMR spectroscopy (Scheme 5).
As can be seen, introduction of fluorine into the probe did
not significantly influence the difference in chemical shifts of
diastereomers in the 77Se NMR spectra (compare the data in
Schemes 4 and 5). Again, chiral carboxylic acids containing ste-
reogenic centers in the a-, b-, and more remote positions were
successfully analyzed. The only difference from 3a was in the
case of diastereomers 34 and 37, which contained fluorine
substituents in the chiral acid analyzed. In this case, broaden-
ing of the signals of the diastereomers in the 77Se NMR spectra
was observed when CDCl3 was used as a solvent. The picture
observed was quite similar to that obtained for the diastereo-
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Scheme 4. The difference in the 77Se NMR chemical shifts (in ppm) of the signals of diastereomers 4–32 obtained from the corresponding chiral carboxylic
acids and (R)-SeBA 3a in CDCl3 (data in [D8]toluene are given in parenthesis) and representative fragments of 77Se NMR spectra of selected diastereomers. A:
a-carboxylic acids; B: b-carboxylic acids; C: carboxylic acids with remote stereogenic centers; D: polyfunctional carboxylic acids (mixture of CDCl3/CD3OD is
used as a solvent, see text for details). Detailed data for the experimental NMR parameters of the spectra presented are given in the Supporting Information.
mers 27–32 of polyfunctional chiral acids with the probe 3a
and may result from weak interactions in solution (see above).
Again, addition of a polar co-solvent, [D4]MeOH, to the CDCl3
solution allowed us to obtain narrow peaks for the diastereo-
mers in the 77Se NMR spectra. In addition, excellent results
were obtained in the 19F NMR spectra. Despite the fact that the
fluorine atom is located in an even more remote position of
the probe compared to selenium, baseline resolved signals
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the derivatization even at incomplete conversion of the ana-
lyzed acid.[10] As the difference in the chemical shifts of the dia-
stereomers does not depend on their concentration, we were
sure of the accuracy of assignment and determination of the
d.r. of the diastereomers regardless of the completeness of the
transformation of the analyzed chiral acids into the corre-
sponding amides.
Thus, the chiral probe 3a was used to analyze the enantio-
meric purity of several chiral drugs containing carboxylic func-
tions (such as profens 6, 7, 9 isolated directly from pills and
bile acid 32 in Scheme 4).[15] Given the chemical shifts of both
diastereomers, the acids to be analyzed were derivatized with
enantiopure (R)-SeBA 3a and 77Se NMR spectra were recorded.
When the conversion of the analyzed acid was full, approxi-
mately 6000–8000 scans were enough to obtain a good signal-
to-noise ratio and precisely determine the intensity of the
signal of a minor diastereomer. However, up to 40000 scans
(overnight acquisition) were required to perform accurate d.r.
determinations in the case of low conversions. The spectra ob-
tained revealed the presence of only one diastereomer of the
bile acid with the second being out of the detection limit of
the NMR method (that is, less than 1%). In the case of profens,
racemates were detected for diastereomers of ketoprofen 6
and ibuprofen 7 and 98% ee was detected in the case of (S)-
naproxen 9, which is in full agreement with that reported. A
representative example of the 77Se NMR spectra with enantio-
pure diastereomer of cholic acid 32 (black spectrum) and a mix-
ture of both diastereomers (R/S=3:1, green spectrum) is
shown in the insert of Scheme 4, part D (for other examples,
see the Supporting Information).
Scheme 5. The difference in 77Se and 19F (bold) NMR chemical shifts (in ppm)
of the signals of diastereomers 33–38 obtained from the corresponding
chiral carboxylic acids and (R)-4F-SeBA 3b in CDCl3. [a] Mixture of
CDCl3/CD3OD used as a solvent, see text for details.
were observed even for diastereomers 38. More importantly,
the 19F NMR spectra could be obtained using one scan only so
NMR analysis took less than 1 min. Thus, the whole procedure
from sample preparation to spectrum obtained took less than
10 min for the 19F NMR spectra. This is of high importance for
high-throughput screening of numerous samples and can be
useful in asymmetric synthesis and catalysis.
In addition to the analysis of pure samples, we have extend-
ed the derivatization procedure of chiral carboxylic acids in
crude reaction mixtures. The possibility to perform NMR moni-
toring of enantiomeric excess of chiral products in crude reac-
tion mixtures is of high practical importance nowadays. As we
have shown that diastereomers can be formed directly in an
NMR tube followed by NMR analysis without isolation and pu-
rification steps, we considered that the derivatization protocol
developed can be implemented with a crude reaction mixture
as well. To test this, we chose the formation of chiral carboxylic
acids by lanthanide-catalyzed oxidative CÀO coupling of 1,3-di-
carbonyl compounds with diacyl peroxide recently developed
by Terent’ev et al. (Scheme 6).[16] After the completion of the
reaction, an aliquot of the crude reaction mixture was taken,
the solvent was evaporated under reduced pressure, and the
residue was derivatized by using the typical protocol discussed
above.[10]
Determination of enantiomeric purity of chiral carboxylic
acids by using the probes developed
In addition to excellent enantiodiscrimination in 77Se NMR
spectra, the diastereomeric ratio (d.r.) of amides 4–32 formed
was measured with high accuracy (usually within 1%).[10] Pro-
vided no racemization, kinetic resolution, or side reactions take
place during the derivatization process, the diastereomeric
ratio measured will be equal to the enantiomeric ratio (e.r.) of
the initial chiral acids.
As the chiral probes developed have been found to be
stable to racemization in basic and acidic conditions as well as
during the storage in air in the cold, we studied possible side
reactions during the derivatization process. In the studied deri-
vatization system, chiral acids can form stable salts with 3 or
unreactive adducts with DCC. All these side reactions can con-
sume enantiomers of acids in different amounts, thus leading
to kinetic resolution and special precautions should be made
to exclude them. To prevent salt formation, the chiral acid to
be analyzed was mixed with DCC first to form the activated
adduct so no free acid was present in the system (confirmed
by 1H NMR spectroscopy). After that, chiral probe 3a or 3b
was added to the mixture, resulting in the formation of the
diastereomers. To study side reactions in the presence of DCC,
special NMR monitoring was performed by using probe 3a,
which revealed that no kinetic resolution took place during
Unfortunately, it was difficult to completely remove moisture
from the analyzed sample. This resulted in very low conversion
of the acid to amide with both chiral probes 3a and 3b, thus
no signals were detected in the 77Se NMR spectra even after
overnight acquisition. However, this problem was overcome
when the 19F NMR spectrum was registered by using the probe
3b for derivatization. Despite low conversion of the acid into
amide, signals of the diastereomers were definitely observed in
the 19F NMR spectrum even after one scan acquisition and
these could be easily assigned.[10] The presence of other com-
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to structural changes in a molecule. Such data are of primary
importance for structural elucidation in modern organic and
bioorganic chemistry.[17] Usually, a wide range of 2D NMR ex-
periments is used for this purpose, so it would be highly desir-
able to develop simple, quick, and reliable methods to gain
primary information about a studied structure. For this pur-
pose, we have analyzed two parameters from the 77Se NMR
spectra of diastereomers obtained with the chiral probe 3a:
chemical shifts of the signals of diastereomers of different car-
boxylic acids (dSe) and the difference between the signals of
diastereomers of these acids (DdSe). As solvents can cause
large shifts in signals in 77Se NMR spectra, data for structures
27–32 obtained in CDCl3/CD3OD were excluded from consider-
ation. The combined data for diastereomers 4–26 are repre-
sented in a plot in Figure 1 (see Scheme 4, parts A–C for the
structures of the diastereomers). As can be seen from the plot,
the signals of the diastereomers of structurally different chiral
acids are located across a wide range of the 77Se NMR scale,
thus confirming the high chemosensitivity of the selenium nu-
cleus (Figure 1, horizontal axis). A correlation is observed be-
tween chemical shifts of signals in the 77Se NMR spectrum and
electronic effects of substituents at chiral centers of the model
chiral acids analyzed. In general, the greater the electronegativi-
ty of the substituents at the chiral center, the more the signals of
the diastereomers are shifted downfield on the 77Se NMR scale.
Thus, the most upfield signals resulted from the acids contain-
ing aliphatic or aromatic substituents at the a-chiral center (4–
10) and are located in the region 235–239 ppm. It should be
noted that electron-withdrawing groups or atoms located far
from the chiral center have almost no influence on the chemi-
cal shift (compare 5, 6, and 7, Figure 1). When heteroatoms (Br,
O, N, with Se being an exception) or electron-withdrawing
groups (NO2, CF3) are introduced at the chiral center of the
acids, the signals of the diastereomers are shifted downfield
and are found in the region 239–245 ppm (11–14, Figure 1). Al-
though a similar trend is observed for b-chiral centers (17–21),
the substituent effect is less pronounced in this case and all
Scheme 6. 19F NMR monitoring of the enantiomeric ratio of the chiral acid in
crude reaction mixtures by using (R)-4F-SeBA 3b. Fragment of 19F NMR
spectrum with signals of diastereomers 38.
ponents in the reaction mixture (including metal salt) did not
influence the derivatization procedure or quality of the NMR
spectrum so the product in the crude reaction mixture was
successfully analyzed within several minutes and a 1:1 ratio of
signals for the diastereomers was observed in the 19F NMR
spectrum (see insert in Scheme 6).
Chemosensing of chiral centers by using chiral probe 3a
Usually, the only difference in the chemical shifts or the relative
position of signals of diastereomers in NMR spectra are taken
into consideration to determine enantiomeric excess or the ab-
solute configuration of the analyzed compounds.[4a,h,j] However,
the values of chemical shifts of the diastereomers’ signals can
also give important information about the structure of the ana-
lyzed compound owing to the high sensitivity of heteronuclei
Figure 1. Chemosensitivity and enantiosensitivity of the chiral probe 3a on the 77Se NMR scale in CDCl3 (a-chiral centers for diastereomers 4–16 are marked
with diamonds, b-chiral centers for diastereomers 17–21 are marked with circles, and more remote chiral centers for diastereomers 22–26 are marked with
triangles).
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the signals are located in a narrow range, 238–241 ppm, of the
77Se NMR scale. Finally, the diastereomers of acids with carbox-
ylic substituents at the chiral center (15, 16, 22–24, Figure 1)
are the most downfield ones (246–254 ppm).[18] In this case, re-
moteness of the chiral center from the carboxylic group did
not influence the value of the chemical shift, dSe, with amides
22–24 being more downfield compared with 15 and 16.
Hence, based on these results obtained from routine 1D NMR
experiments, it is possible to suggest what type of substituents
is located at the chiral center of the studied molecule.
nium-based chiral probes with improved chemo- and enantio-
sensing capacities will allow better differentiation of signals of
structurally diverse chiral acids and will be of high importance
for quick and reliable structure elucidation.
Conclusion
Novel selenium-based chiral chemical probes (R)-SeBA and (R)-
4F-SeBA have been synthesized and were found to be efficient
for selective and quick interaction with carboxylic functions,
giving diastereomers directly in an NMR tube without the
need to isolate and purify the amides formed prior to NMR
analysis. The derivatization method developed is general and
can be implemented for structurally diverse chiral carboxylic
acids as well as amino acids and polyfunctional compounds
containing carboxylic functions (including drugs); different
functional groups are tolerated. Both 77Se and 19F NMR spec-
troscopy have shown excellent results in the enantiodiscrimi-
nation of chiral carboxylic acids with stereogenic centers situ-
ated in the a-, b-, or even more remote (up to seven bonds
away from the carboxylic group) positions. In addition to easy
assignment of the signals of diastereomers, this method is suit-
able for the accurate determination of enantiomeric ratios
(equal to the observed diastereomeric ratio) of pure samples
as well as of crude reaction mixtures (by 19F NMR spectrosco-
py), which is very useful for monitoring reactions for asymmet-
ric synthesis and catalysis. Finally, by using the probe (R)-SeBA,
we have revealed that it is possible to gain primary informa-
tion about the nature of the chiral center of the analyzed acids
based on the chemical shifts of the diastereomers dSe and the
difference in the chemical shifts of diastereomers DdSe in the
77Se NMR spectra. Excellent empirical correlation between the
position of the signals of diastereomers on the 77Se NMR scale
and the acid structure is observed for a-chiral carboxylic acids.
Reliable assumptions about the nature of substituents at the
chiral center of the acid can be made for diastereomers pos-
sessing DdSe values more than 1.0 ppm, whereas for those
with smaller enantiodiscrimination it is still possible to distin-
guish between homologous structures. The development of
a range of chiral chemical probes with improved properties for
the NMR analysis of chiral functionalized compounds is in
progress in our laboratory.
When we consider the correlation between the difference in
the 77Se chemical shifts of the diastereomers DdSe and the
nature of substituents at the chiral center, it is clear that the
closer the analyzed chiral center is to the carboxylic function,
the larger the difference in the chemical shifts of diastereomers
observed in the 77Se NMR spectra (compare 5 and 17 in
Figure 1, vertical axis). Another thing that influences the DdSe
parameter is the nature of the substituents at the chiral center.
When aromatic substituents or electron-withdrawing heteroa-
toms are bound to the a-chiral center of the acid, the differ-
ence in the chemical shifts increases (compare 5, 7, and 12 in
Figure 1, vertical axis). This can be caused by the anisotropic
current of the aromatic ring, the influence of which will be dif-
ferent for a pair of diastereomers.[19] The most pronounced
effect is observed for amides 15 and 16 with rigid locations of
the phenyl ring: when the phenyl substituent is located cis to
the amide group, the difference observed is almost an order of
magnitude larger than for trans-orientation of the substituents
(Figure 1, Scheme 4). It is clear that in the case of flexible con-
formations, this effect on the difference in the chemical shifts
of diastereomers can vary significantly, thus in some cases the
influence of the aromatic ring may be neglected. Most likely,
this is the case for diastereomers 13, which show no enantio-
discrimination in CDCl3 (Figure 1, Scheme 4).
Upon removing the chiral center from the reacting site, the
difference in the chemical shifts of the diastereomers decreases
(Figure 1, Scheme 4). In the case of a-chiral carboxylic acids 4–
16, the minimum difference observed was more than 0.5 ppm
(with the diastereomers 13 and 15 being the only exceptions),
with a maximum difference of DdSe 2.28 ppm being obtained
for amide 12. However, DdSe values were not more than
1.0 ppm for carboxylic acids with b- or remote stereogenic
centers, 17–26 (Figure 1, Scheme 4).
Thus, taking into consideration these two parameters (dSe
and DdSe), it is possible to make primary assumptions about
the structure of the chiral acid analyzed. Although some com-
plications may arise when acids with different locations of
chiral center (a-, b-, or remote) are compared, it is clear from
the plot presented that the region above 1.0 ppm on the verti-
cal axis (DdSe) is specific for a-chiral carboxylic acids. Hence, if
the signals of the diastereomers of an unknown structure are
located in this region, unambiguous assignment to an a-chiral
carboxylic acid can be made and the nature of the substituents
at the chiral center can be proposed. Data from the complicat-
ed region (less than 1 ppm) can be still valuable to distinguish
between structurally similar compounds (such as homologous
acids 5 and 17). We believe that the development of new sele-
Experimental Section
NMR spectroscopy
1H and 77Se NMR measurements were performed by using Bruker
Avance 400 and 600 MHz spectrometers, 19F NMR measurements
were performed by using a Bruker Avance 400 MHz spectrometer.
All spectra were recorded in CDCl3 (unless otherwise noted) at
303 K without spinning of the NMR tube. H and 19F NMR measure-
1
ments were carried out with a single 908 pulse. The spectra were
processed with a Linux workstation using the TopSpin 2.1 software
package. 1H chemical shifts are reported relative to the corre-
sponding solvent signals used as internal reference; CFCl3 (0 ppm)
and Ph2Se2 (463 ppm) were used for 19F and 77Se NMR spectrosco-
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py, respectively, as external references. The detailed description of
the NMR data is given in the Supporting Information.
the color of the suspension changed to light yellow. The reaction
temperature was increased slowly to room temperature and the
reaction mixture was stirred overnight.
Experimental setup and processing of 1D 77Se NMR data
The reaction was quenched with water (10 mL). Then, concentrat-
ed HCl (20 mL) was added to the reaction vessel to remove the
Boc group and stirring was continued for an additional 2 h at
room temperature. The solution was gently concentrated under re-
duced pressure. H2O (20 mL) was added to the residue and the so-
lution was washed with CH2Cl2 (6ꢁ20 mL). Excess KOH was added
to the water layer (a white suspension was formed upon neutrali-
zation of the 3·HCl adduct). The pure product was extracted with
Et2O (2ꢁ25 mL). The combined organic layers were washed with
H2O (4ꢁ20 mL), dried with Na2SO4, and the solvent was removed
under reduced pressure. Isolated yield 68% (1.159 g). Light-yellow
oil.
1H NMR (600 MHz, CDCl3, 258C, TMS): d=0.92 (t, J=7.5 Hz, 3H,
Me), 1.35–1.41 (m, 1H, CH2), 1.45 (br. s, 2H, NH2), 1.50–1.57 (m, 1H,
CH2), 2.78 (dd, J=11.5, 3.4 Hz, 1H, CH2Se), 2.79–2.85 (m, 1H, CHN),
3.10 (dd, J=11.5, 3.4 Hz, 1H, CH2Se), 7.19–7.26 (m, 3H, Ph),
7.51 ppm (dd, J=7.9, 1.8 Hz, 2H, Ph); 13C{1H} NMR (150.9 MHz,
CDCl3, 258C, TMS): d=10.6, 30.7, 37.3 (JSe =63.7 Hz), 52.3, 126.8,
129.0, 130.3, 132.7 ppm; 77Se{1H} NMR (114.5 MHz, CDCl3, 258C,
Ph2Se2): d=247.92; HRMS (ESI): calcd for C10H16NSe [M+H]+:
230.0443; found: 230.0447.
1
The spectrum was collected in the 77Se observation and H decou-
pling mode. A standard waltz16 decoupling was applied in this
77Se{1H} experiment. Spectral parameters: 77Se 308 pulses, a relaxa-
tion delay of 3.0 s, a 1.0 s acquisition time, 2400–40000 scans, and
46000 Hz spectral window. The data was zero filled to 32k matrix
and processed with exponential multiplication (LB=1).
General
Unless otherwise noted, all experiments were performed in air. Re-
agents were obtained from Acros and Aldrich and used as supplied
(checked by NMR spectroscopy and GC before use). The acids to
prepare diastereomers 18–24, 37, and 38 can be synthesized ac-
cording to published procedures.[16,20] The acids to prepare diaste-
reomers 4, 8, and 10 were synthesized according to published pro-
cedures.[5g,7d] Solvents were purified according to published meth-
ods. The samples for analysis with the chiral chemical probes de-
veloped were prepared by using chiral compounds of known
enantiomeric content. For the experiments shown in Tables S1 and
S2 in the Supporting Information deuterated solvents were used as
received.
High-resolution mass spectra were recorded with a Bruker maXis
instrument equipped with an electrospray ionization (ESI) ion
source. All measurements were performed in a positive (+MS) ion
mode (interface capillary voltage: 4500 V) with scan range m/z=
50–3000. External calibration of the mass spectrometer was per-
formed with Electrospray Calibrant Solution (Fluka). Direct syringe
injection was used for the all analyzed solutions in MeCN (flow
rate: 3 mLminÀ1). Nitrogen was used as the nebulizer gas (0.4 bar)
and dry gas (4.0 LminÀ1); the interface temperature was set at
1808C. All the spectra were processed by using the Bruker Data-
Analysis 4.0 software package.
Synthesis of (R)-1-((4-fluorophenyl)selanyl)butan-2-amine
((R)-4F-SeBA, 3b)
The product was synthesized by using the same procedure as for
3a. Isolated yield (unoptimized) 34% (0.204 g). Yellow oil.
1H NMR (600 MHz, CDCl3, 258C, TMS): d=0.92 (t, J=7.5 Hz, 3H,
Me), 1.34–1.43 (m, 1H, CH2), 1.43–1.48 (br. s, 2H, NH2), 1.49–1.57
(m, 1H, CH2), 2.76 (dd, J=11.8, 3.6 Hz, 1H, CH2Se), 2.76–2.81 (m,
1H, CHN), 3.05 (dd, J=11.8, 3.6 Hz, 1H, CH2Se), 6.94–6.99 (m, 2H,
Ph), 7.49–7.54 ppm (m, 2H, Ph); 13C{1H} NMR (150.9 MHz, CDCl3,
258C, TMS): d=10.8, 30.5, 38.4 (JSe =63.3 Hz), 52.5, 116.4 (JF =
21.3 Hz), 124.6, 135.5 (JF =8.1 Hz), 162.5 ppm (JF =246.4 Hz);
77Se{1H} NMR (114.5 MHz, CDCl3, 258C, Ph2Se2): d=246.67 ppm (JF =
4.3 Hz); 19F{1H} NMR (376.5 MHz, CDCl3, 258C, CFCl3): d=
À115.40 ppm; HRMS (ESI): calcd for C10H15FNSe [M+H]+: 248.0348;
found: 248.0352.
Synthesis of (R)-2-((tert-butoxycarbonyl)amino)butyl
methanesulfonate (2)
N-Boc-protected (R)-2-amino-1-butanol was synthesized according
to the modified literature procedure[21] with quantitative yield (stir-
ring at 408C for 2 h was used instead of room temperature).
To obtain rac-3, a similar synthetic procedure was used starting
from commercially available rac-2-amino-1-butanol.
The crude adduct obtained was dissolved in CH2Cl2 (20 mL), which
was followed by addition of Et3N (1.2 equiv) and cooling to 08C. A
solution of MeSO2Cl (1.1 equiv) in CH2Cl2 (20 mL) was added drop-
wise to the reaction mixture under stirring. The reaction tempera-
ture was increased slowly to room temperature and the reaction
mixture was stirred overnight. The product was washed with H2O
(5ꢁ20 mL), dried with Na2SO4, and the solvent was removed under
reduced pressure. Mesylate 2 was obtained in quantitative yield as
a light-yellow solid. The product was identified according to the
literature data.[22]
Typical procedure for the analysis of the samples of chiral
carboxylic acids with chiral probe (R)-SeBA
The acid to be analyzed (4.0ꢁ10À5 mol) and DCC (0.0098 g, 4.7ꢁ
10À5 mol) were dissolved in 0.1 mL of an appropriate deuterated
solvent (CDCl3 or [D8]toluene) in an NMR tube and the mixture was
shaken for 1–2 min.[11] A white suspension was formed. (R)-SeBA 3a
(0.0075 mL, 0.0100 g, 4.4ꢁ10À5 mol) was subsequently added and
the mixture was shaken for 1–2min. After that, the same deuterat-
ed solvent (0.5 mL, CDCl3 or [D8]toluene) was added into the NMR
tube. The insoluble particles were separated to the top of the
CDCl3 solution (to the bottom in the case of [D8]toluene) by centri-
fugation of the NMR tube for 1 min at 1500 rpm.[10] The 1H and
77Se NMR spectra were recorded directly without any further
purification steps.
Synthesis of (R)-1-(phenylselanyl)butan-2-amine ((R)-SeBA,
3a)
A mixture of mesylate 2 (2.0 g, 7.5 mmol) and Ph2Se2 (1.168 g,
3.7 mmol) was placed in a 150 mL round-bottomed flask followed
by addition of argon-flushed ethanol (50 mL); a yellow suspension
was formed. The mixture was cooled to À58C and NaBH4 (0.849 g,
22.0 mmol) was added portion-wise under an argon atmosphere
under stirring. The mixture was stirred for an additional 10 min and
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Typical procedure for the analysis of the samples of poly-
functional chiral carboxylic acids with chiral probe SeBA
The acid to be analyzed (4.0ꢁ10À5 mol) and DCC (0.0098 g, 4.7ꢁ
10À5 mol) were dissolved in 0.2 mL of CDCl3 in an NMR tube and
the mixture was shaken for 1–2 min.[11] A white suspension was
formed. SeBA 3a (0.0075 mL, 0.0100 g, 4.4ꢁ10À5 mol, R- or a mix-
ture of R- and S-enantiomers 3:1 depending on the aim of the
analysis)[15] was subsequently added and the mixture was shaken
for 1–2 min. After that, CD3OD (0.4 mL) was added into the NMR
tube. A clear solution was formed, thus negating the need for the
centrifugation procedure. The 1H and 77Se NMR spectra were
recorded directly without any further purification steps.
Similar derivatization protocols were used to obtain diastereomers
with 3b (0.0075 mL, 0.0100 g, 4.1ꢁ10À5 mol).
Acknowledgments
This research was supported by RSF grant no. 14-50-00126. We
thank Prof. K. K. Pivnitsky, Prof. S. L. Ioffe, Prof. A. D. Dilman,
and V. A. Vil’ from Zelinsky Institute of Organic Chemistry RAS,
Dr. E. V. Budynina from Moscow State University, and N. V. Ter-
ent’eva from Ceilidh Moscow for giving us samples of several
chiral carboxylic acids. We also thank Dr. L. L. Khemchyan for
recording HRMS spectra.
Keywords: chiral acids · chiral selenium-containing probes ·
enantiomeric purity · NMR spectroscopy · structure elucidation
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1
Nevertheless, H NMR spectra are given in the Supporting Information.
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chiral probes 3a or 3b was found to be much less efficient compared
Received: June 16, 2016
Published online on && &&, 0000
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
10
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
a-, b-, and beyond: Selenium-based
chiral chemical probes were designed
and show high efficiency in sensing
chiral centers of structurally diverse and
multifunctional chiral carboxylic acids
by 77Se NMR spectroscopy. Besides accu-
rate quantitative measurements, it was
possible to perform primary analysis of
the nature of the stereogenic centers in
the compounds analyzed.
&
Structure Elucidation
S. A. Shyshkanov, N. V. Orlov*
&& – &&
Design of Selenium-Based Chiral
Chemical Probes for Simultaneous
Enantio- and Chemosensing of Chiral
Carboxylic Acids with Remote
Stereogenic Centers by NMR
Spectroscopy
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
11
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ