Recent Advances in Multinuclear NMR

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Feb 7, 2017 - for Chiral Recognition of Organic Compounds ... in chemical, physical, pharmaceutical, and biological systems, inspiring new biomimicry-based ... is still the approach most often applied in modern chemical research [7,8]. ...... You, L.; Zha, D.; Anslyn, E.V. Recent Advances in Supramolecular Analytical ...
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Recent Advances in Multinuclear NMR Spectroscopy for Chiral Recognition of Organic Compounds Márcio S. Silva Centro de Ciências Naturais e Humanas—CCNH—Universidade Federal do ABC—UFABC, Av. Dos Estados 5001, 09210-180 Santo André –SP, Brazil; [email protected]; Tel.: +55-11-4996-8358 Academic Editor: Roman Dembinski Received: 4 January 2017; Accepted: 30 January 2017; Published: 7 February 2017

Abstract: Nuclear magnetic resonance (NMR) is a powerful tool for the elucidation of chemical structure and chiral recognition. In the last decade, the number of probes, media, and experiments to analyze chiral environments has rapidly increased. The evaluation of chiral molecules and systems has become a routine task in almost all NMR laboratories, allowing for the determination of molecular connectivities and the construction of spatial relationships. Among the features that improve the chiral recognition abilities by NMR is the application of different nuclei. The simplicity of the multinuclear NMR spectra relative to 1 H, the minimal influence of the experimental conditions, and the larger shift dispersion make these nuclei especially suitable for NMR analysis. Herein, the recent advances in multinuclear (19 F, 31 P, 13 C, and 77 Se) NMR spectroscopy for chiral recognition of organic compounds are presented. The review describes new chiral derivatizing agents and chiral solvating agents used for stereodiscrimination and the assignment of the absolute configuration of small organic compounds. Keywords: chiral recognition; NMR spectroscopy; chirality; multinuclear; enantiopurity; enantiomeric excess; stereochemistry; absolute configuration

1. Introduction Stereoisomers are compounds with the same molecular formula, possessing identical bond connectivity but different orientations of their atoms in space [1]. Enantiomers are stereoisomers that are mirror images of each other, but at the same time are not superimposable. Chirality is important in chemical, physical, pharmaceutical, and biological systems, inspiring new biomimicry-based innovations [2,3]. Moreover, the need to discriminate between enantiomers and quantify enantiomeric excess (ee) is of extreme importance in the pharmaceutical industry and for asymmetric synthesis [4–6]. Nowadays, the use of chromatography separation of enantiomers on chiral stationary phases is still the approach most often applied in modern chemical research [7,8]. However, the search for new chiral discriminating procedures that allow for quick analysis, high resolution, and utility for many non-volatile or thermally unstable compounds is increasing [9–12]. Among the several stereodiscrimination methods, including X-ray, circular dichroism, fluorescence spectroscopy, and electrophoresis, nuclear magnetic resonance (NMR) spectroscopy continues to be a useful tool for determining the enantiomeric purity and assigning the absolute configuration of chiral molecules [13–21]. NMR active nuclei are isochronous in an achiral medium and do not permit their discrimination, but in a chiral environment these nuclei are anisochronous and chiral discrimination is possible. Therefore, to perform the enantiopurity analysis, a chiral derivatization or solvating agent is essential to produce a nonequivalent diastereomeric mixture and relevant differences in the NMR spectra. Chiral derivatizing agents form a covalent bond with a reactive moiety of the substrate and chiral solvating agents associate with the substrate through non-covalent interactions, such as dipole–dipole

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and ion pairing. In this context, strategies based on different intermolecular reactivities, interactions, and packing orders for a pair of enantiomers are in constant development. Among the active NMR nuclei, 1 H is the most important. The characteristics of 1 H, such as its natural abundance (99.98%) and its high sensitivity to environmental modifications, make it immensely Molecules 2017, 22, 247 2 of 22 versatile in NMR chiral analysis [22]. Nevertheless, 1 H-NMR spectroscopy poses some limitations. The 1 H-NMR spectraand for ion chiral analysis due toon thedifferent numerous scalar couplings, dipole–dipole pairing. In are this severely context, hampered strategies based intermolecular interactions, andbroad packing orders for a pair of enantiomers are in constant development. and thereactivities, overlap combined with and featureless spectra leads to enormous difficulties in 1 H-NMR 1H is the most important. The characteristics of 1H, such as its Among active NMR nuclei, analysis, even forthe small molecules. Consequently, the comparison of the enantiomers using NMR natural abundance (99.98%) and its sensitivity can to environmental modifications, make it spectra and the assignment of absolute high configuration be unclear. The application of different immensely versatile in NMR chiral analysis [22]. Nevertheless, 1H-NMR spectroscopy poses some 19 31 NMR nuclei, mainly 1 F and P, overcomes these limitations. The simplicity of the multinuclear limitations. The H-NMR1 spectra for chiral analysis are severely hampered due to the numerous NMR spectra relative to the H and the larger shift dispersion make these nuclei especially suitable scalar couplings, and the overlap combined with broad and featureless spectra leads to enormous for analysis. difficulties in 1H-NMR analysis, even for small molecules. Consequently, the comparison of the Inenantiomers this review, new chiral derivatization agentsof(CDAs), solvating agents (CSAs), using NMR spectra and the assignment absolute chiral configuration can be unclear. The and 19 31 application different NMR nuclei, mainly and P, overcomes limitations. The simplicity modern methodsoffor stereodiscrimination andFassignment of thethese absolute configuration of organic 1H and the larger shift dispersion make these nuclei 13 C-, 77 Se-NMR of the multinuclear NMR spectra to thespectroscopy compounds by 19 F-, 31 P-, and relative are described. The focus is on articles especially analysis. from 2007 to thesuitable presentfor date. Furthermore, the 2 H nucleus is not described because of the necessity of In this review, new chiral derivatization agents (CDAs), chiral solvating agents (CSAs), and discussing the physical bases in order to understand the quadrupolar electric moment and residual modern methods for stereodiscrimination and assignment of the absolute configuration of organic dipolarcompounds coupling contents [23]. 13C-, and 77Se-NMR spectroscopy are described. The focus is on articles from by 19F-, 31P-, 2.

2007 to the present date. Furthermore, the 2H nucleus is not described because of the necessity of Chiral Recognition discussing the physical bases in order to understand the quadrupolar electric moment and residual 19 dipolar coupling contents [23].

19 F-NMR

F is one of the most useful nuclei for NMR studies [24]. The fluorine element has polar and steric properties as a substituent 2. 19F-NMR Chiral Recognitionand the effects that fluorinated groups can have on the physical and chemical properties of molecules have increased the number of new methods for incorporating 19F is one of the most useful nuclei for NMR studies [24]. The fluorine element has polar and fluorine into target compounds. Furthermore, 19 F-NMR spectroscopy has proved to be a valuable tool steric properties as a substituent and the effects that fluorinated groups can have on the physical and to study the structure and nucleic acidsthe bynumber incorporating fluorinefor labels into DNA and chemical properties of function moleculesof have increased of new methods incorporating 19 RNA [25]. fluorine into target compounds. Furthermore, F-NMR spectroscopy has proved to be a valuable 19 F-NMR frequency and sensitivity are similar to the proton (the fluorine spectra is at Since thestudy tool to the structure and function of nucleic acids by incorporating fluorine labels into DNA andand RNA [25]. 282 MHz the proton spectrum is at 300 MHz), it is convenient to transition from proton to fluorine Since the 19F-NMR frequency and sensitivity are similar to the proton (the fluorine spectra is at NMR experiments. 282 MHz and the proton spectrum is at 300 MHz), it is convenient to transition from proton to A wide variety of fluorine-containing reagents have been developed for NMR chiral fluorine NMR experiments. discrimination [26,27]. In 2015, Nemes et al. described the chiral recognition studies of α-(nonafluoroA wide variety of fluorine-containing reagents have been developed for NMR chiral tert-butoxy)carboxylic acid byIn19 F-NMR spectroscopy [28]. Carboxylic acids 1 and 2 were synthesized discrimination [26,27]. 2015, Nemes et al. described the chiral recognition studies of 19F-NMR to be enantiomerically enriched in order a spectroscopy CDA (Scheme The synthesis of racemic α-(nonafluoro-tert-butoxy)carboxylic acid to by obtain [28].1). Carboxylic acids 1 and 2 wereacids synthesized enantiomerically in order to obtain a CDA (Scheme The synthesis of with carboxylic 1 andto2 be was carried out inenriched two steps. Chiral recognition studies1).were performed racemic carboxylicIn acids and 2measurements, was carried outCin two steps. Chiral recognition studies were (S)-phenylethylamine. the 1NMR 6 D6 solvent was more favorable than CDCl3 in performed with (S)-phenylethylamine. In the NMR measurements, C6D 6 solvent was more favorable the differences (∆δ) of diastereomeric signals. The benefits of these CDAs include the presence of an than CDCl3 in the differences (Δδ) of diastereomeric signals. The benefits of these CDAs include the acidic functional group for a strong interaction, a bulky hydrophobic group OC(CF3 )3 and an aromatic presence of an acidic functional group for a strong interaction, a bulky hydrophobic group OC(CF3)3 19 F-NMR spectra have only one strong singlet to nine ring for a π–π interaction. the Additionally, and an aromatic ring forAdditionally, a π–π interaction. the 19F-NMR spectra have only one strong chemically equivalent fluorine atoms. singlet to nine chemically equivalent fluorine atoms. F 3C

CF3 CF3 O CO2H (R)-1

CF3 F3 C CF3 O CO2H (RS)-1

F 3C

CF3 CF3 O CO2H (R)-2

CDCl3 or C6D6 +

NH2

Δδ = 0.008 ppm (CDCl3) Δδ = 0.029 ppm (C6D6)

(S)-MBA

Scheme 1. α-(nonafluoro-tert-butoxy)carboxylic acid as an 19F {1H} NMR CDA.

Scheme 1. α-(nonafluoro-tert-butoxy)carboxylic acid as an 19 F {1 H} NMR CDA.

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Another fluorine-containing CDA that surpasses the capabilities of Mosher’s acid (MTPA) was prepared by Takahashi et al. (Scheme [29]. Tothe obtain the chiral compounds (R)-3 was and (S)-3, Another fluorine-containing CDA that2)surpasses capabilities of Mosher’s acid (MTPA) Molecules 2017, 22, 247 3 of19 22 prepared by Takahashi et al. (Scheme 2) [29]. To obtain the chiral compounds (R)-3 and (S)-3, high-performance liquid chromatography (HPLC) was carried out. The efficiency of the F-NMR high-performance liquid (HPLC)The wasabsolute carried out. The efficiencyofofchiral the 19F-NMR 3 was nucleus was evaluated with chromatography secondary alcohols. configuration Another fluorine-containing CDA that surpasses the capabilities of Mosher’s acid (MTPA)FICA was nucleus was evaluated with secondary alcohols. The absolute configuration of chiral FICA 3 was determined by by reaction withet(R)-phenylethylamine single-crystal crystallographic prepared Takahashi al. (Scheme 2) [29]. To following obtain the by chiral compounds X-ray (R)-3 and (S)-3, determined by reaction with (R)-phenylethylamine following by single-crystal X-ray crystallographic 19F-NMR high-performance liquid (HPLC) wasof carried out. The efficiency of the than analysis. The magnitude of chromatography the chiral discrimination the FICA esters was larger that of the analysis. The magnitude of the chiral discrimination of the FICA esters was larger than that of the was evaluated with secondary alcohols. Theofabsolute configuration of chiralofFICA 3 was MTPAnucleus esters (Scheme 2). Moreover, the assignment the absolute configuration the alcohols MTPA esters (Scheme 2). Moreover, the assignment of the absolute configuration of the alcohols was was determined bybyreaction withspectroscopy. (R)-phenylethylamine following by single-crystal X-ray crystallographic 19 F-NMR easily performed easily performed by 19F-NMR spectroscopy. analysis. The magnitude of the chiral discrimination of the FICA esters was larger than that of the MTPA esters (Scheme 2). Moreover, the assignment of the absolute configuration of the alcohols was F CO2Me easily performed by 19F-NMR spectroscopy. F FICA - 3 F

(R) CO2Me CO2Me (R)

FICA - 3 F

secondary alcohols secondary alcohols

R1

R2 O

R1

R1 or

FICA R2

R2 O

R1

MTPA R2

or O O MTPA ΔδFICA (FICA) > ΔδF (MTPA) F

(S) CO2Me

Chiral Derivatizing Agents (S)

Scheme 2. 1-fluoroindan-1-carboxylic acid 3 (FICA) as a chiral derivatizing agent for 19F {1H} NMR

Scheme 2. 1-fluoroindan-1-carboxylic acid 3 (FICA) as a chiral derivatizing agent for 19 F {1 H} NMR ΔδF (FICA) > ΔδF (MTPA) Chiral Derivatizing Agents spectroscopy. spectroscopy. 19F {1H} NMR Scheme 1-fluoroindan-1-carboxylic acid by 3 (FICA) chiral agent for A chiral2. ionic liquid 4 was employed Reddyaseta al. for derivatizing chiral recognition of racemic Mosher’s spectroscopy. 19

F-NMR spectroscopy [30]. liquids (ILs) have received considerable attentionMosher’s as saltionic usingliquid Aacid chiral 4 was employed byIonic Reddy et al. for chiral recognition of racemic 19for substitutes volatile organic solvents due to their remarkable properties, such as non-flammable, acid salt using F-NMR spectroscopy [30]. Ionic liquids (ILs) have received considerable attention as A chiral ionic liquid 4 was employed by Reddy et al. for chiral recognition of racemic Mosher’s non-volatile and recyclable. Thus, a chiral ionic liquidremarkable containing D-xylose was synthesized in seven 19 substitutes for volatile organic solvents due to their properties, such as non-flammable, acid salt using F-NMR spectroscopy [30]. Ionic liquids (ILs) have received considerable attention as steps with a good overall yield (56%). The D-xylose is a cheap and readily available starting material. non-volatile andfor recyclable. Thus,solvents a chiraldue ionic liquid containing D-xylose was synthesized in seven substitutes volatile organic to their remarkable properties, such as non-flammable, The chiral recognition study was performed with the racemic Mosher’s acid silver salt in CD3CN non-volatile and recyclable. Thus, a chiral ionic liquidiscontaining D-xylose wasavailable synthesized in seven steps with a good overall yield (56%). The D-xylose a cheap and readily starting material. (Scheme 3). The concentration was varied to observe the signals splitting and line shape of 19F-NMR. steps with a good overall yield (56%). The D-xylose is a cheap and readily available starting material. The chiral recognitionofstudy wasionic performed thetested racemic Mosher’s acid silver salt in CD3 CN The effectiveness the chiral liquid 4 with was also by using a non-racemic Mosher’s acid The chiral recognition study was performed with the racemic Mosher’s acid silver salt in CD3CN 19 F-NMR. (Scheme 3).The Theenantiomeric concentration was observe the splitting by and19F-NMR. line shape of salt. excess (ee)varied of thisto non-racemic saltsignals was determined Moreover, (Scheme 3). The concentration was varied to observe the signals splitting and line shape of 19F-NMR. 1H- and 13C-NMR spectroscopy. the splitting pattern of the chiral ionic liquid 4 wasalso evaluated by The effectiveness of the chiral ionic liquid 4 was tested by using a non-racemic Mosher’s acid The effectiveness of the chiral ionic liquid 4 was also tested by using a non-racemic Mosher’s acid 19 F-NMR. Moreover, the salt. The excess (ee)(ee) of this non-racemic by19F-NMR. salt.enantiomeric The enantiomeric excess of this non-racemicsalt salt was was determined determined by Moreover, 1 13 OCH O 4 was 1H- and 3 splitting of the chiral ionic ionic liquid 4 was evaluated byby HC-NMR spectroscopy. the pattern splitting pattern of the chiral liquid evaluated and 13C-NMR spectroscopy. OCH3 OH OCH 3 N 4 OCH3 N OH NCD3CN or CDCl3 4 N

OMe

O

OMe OMe X CO2 CO2 + CO2 CF3 CF3 CF3 OMe OMe OMe X Racemic (R) (S) CO2 CO2 + CO2 19 1 CF Scheme 3.3 Chiral ionic liquid as aorchiral { 3H} NMR spectroscopy. CF3 CD43CN CDCl3solvating agent for FCF Racemic (R) (S)

Huang et al. described a CSA for a variety of acids using chiral thiophosphoramide 5 derived 1H} NMR spectroscopy. Scheme 3. Chiral ionic liquid 4 as a chiral solvating agent for 19F {19 fromScheme (1R,2S)-1,2-diaminocyclohexane 4) [31]. The interaction ion pairing and hydrogen 3. Chiral ionic liquid 4 as(Scheme a chiral solvating agent for F via {1 H} NMR spectroscopy. bonding provides a large split in values between the enantiomers, especially when the 19F-NMR was Huang et al. described a CSA for a variety of acids using chiral thiophosphoramide 5 derived evaluated. The authors completed the chiral recognition study with phosphonic acids by 31P-NMR from (1R,2S)-1,2-diaminocyclohexane 4) of [31]. The using interaction viathiophosphoramide ion pairing and hydrogen Huang et al. described a CSA for (Scheme a variety acids chiral 5 derived spectroscopy (Scheme 4). 19F-NMR was bonding provides a large split in values between the enantiomers, especially when the from (1R,2S)-1,2-diaminocyclohexane (Scheme palladium 4) [31]. The interaction pairing hydrogen Swager and Zhao prepared amide-based pincer complex via 6 asion a scaffold to31and examine evaluated. Theaauthors completed the chiral recognition study with especially phosphonicwhen acids by P-NMR 19 F-NMR was bonding provides large split in values between the enantiomers, the the chiral discrimination ability of amines (Scheme 5) [32]. Based on well-known coordination spectroscopy (Scheme 4). evaluated. The authors completed thesynthesized chiral recognition study acids by 31 P-NMR chemistry, the complex was easily in two steps. Thewith chiralphosphonic sensor site that undergoes Swager and Zhao prepared amide-based palladium pincer complex 6 as a scaffold to examine facile ligand exchange spectroscopy (Scheme 4). is flanked by fluorine pendant groups that are sensitive to enantiomers. The the chiral discrimination ability of amines (Scheme 5) [32]. Based on well-known coordination observation of splitprepared signals atamide-based precise chemical shifts thatpincer are not concentration-dependent indicated Swager and Zhao palladium 6 as asite scaffold to examine the chemistry, the complex was easily synthesized in two steps. Thecomplex chiral sensor that undergoes chiral facile discrimination ability of amines (Scheme 5) [32].groups Basedthat onare well-known chemistry, ligand exchange is flanked by fluorine pendant sensitive tocoordination enantiomers. The observation split signals at precise shifts thatchiral are not concentration-dependent indicated the complex wasofeasily synthesized inchemical two steps. The sensor site that undergoes facile ligand

exchange is flanked by fluorine pendant groups that are sensitive to enantiomers. The observation of split signals at precise chemical shifts that are not concentration-dependent indicated the formation

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of static onstatic the complexes NMR time Moreover, the accuracy the method evaluated by thecomplexes formation of onscale. the NMR time scale. Moreover, theofaccuracy of the was method was the formation of static complexes on the NMR time scale. Moreover, the accuracy of the method was measuring the enantiomeric excess of the amines with different ratios. evaluated by measuring the enantiomeric excess of the amines with different ratios. evaluated by measuring the enantiomeric excess of the amines with different ratios. + + S S P NH N Et Ph P Ph NH EtN Et Ph Ph5 - CSA Et

OH OH CO2H CO2H

F F

HO HO

CDCl3 CDCl 25 oC3

F F

25 oC

O HNR2 O NR132 O HNR H NR13 O H Δδ = 0.23 ppm Δδ = 0.23 ppm

Cl Cl

5 - CSA + +

O O P OH POH OH OH

O O P OH HNR2 POH OH 1 HNR 3 2 OH NR 1 NR Δδ = 0.19 ppm 3

Cl Cl

CDCl3 CDCl 25 oC3 25 oC

Δδ = 0.19 ppm

1H} and 31P Scheme 4. Chiral thiophosphoramide 6 as a CSA for a variety of carboxylic acids by 19F {19 Scheme 4. Chiral thiophosphoramide 6 as a CSA for a variety of carboxylic acids by F {1 H} and 31 P 1H} NMR Scheme 4. spectroscopy. Chiral thiophosphoramide 6 as a CSA for a variety of carboxylic acids by 19F {1H} and 31P { {1 H} NMR spectroscopy. spectroscopy. {1H} NMR

O O

N Cl Cl

N

Cl

O

+

H 2N R

O

+

H 2N R

Cl

O O

N N

F 3C F 3C

N Pd N N Pd C N

Toluene

O O N O O NH N HN R R NH HN R R oC, 12 h 40 CH3CN CH3CN 40 oC, 12 h

Toluene Reflux, 12 h Reflux, 12 h

O N

O O

N

O N R N R

CF3 C F3C

CF3 CF3 F3C CF3 6 - Chiral Pincer Complex

N Pd N N Pd C N

O O N R N R

C

6 - Chiral Pincer Complex

Scheme 5. Chiral amide-based palladium complex 6 as a chiral derivatizing agent for 19F {1H} NMR Scheme 5. Chiral amide-based palladium complex 6 as a chiral derivatizing agent for 19F {1H} NMR spectroscopy. Scheme 5. Chiral amide-based palladium complex 6 as a chiral derivatizing agent for 19 F {1 H} NMR spectroscopy.

spectroscopy. A practical and simple derivatization protocol for determining the enantiopurity of chiral diols A practical and simple derivatization protocol foral.determining the enantiopurity of chiral diols by 19F-NMR spectroscopy was developed by James et [33]. The experimental procedure consisted 19F-NMR spectroscopy was developed by James et al. [33]. The experimental procedure consisted Aby practical and simple derivatization protocol for determining theacid enantiopurity of chiral diols of mixing an equimolecular amount of 4-fluoro-2-formylphenyl boronic 7, phenylethylamine, of an equimolecular 4-fluoro-2-formylphenyl boronic acidwas 7, phenylethylamine, andmixing thespectroscopy chiral diol in CDCl 3amount at 25 °Cof(Scheme 6). The the method toprocedure synthesize consisted the by 19 F-NMR was developed by James et al.focus [33].ofThe experimental and the chiral diol in CDCl 3 at bifunctional 25 °C (Scheme 6). The focus of the method was to synthesize the fluorine compound 7 as a new template for carrying out the enantiopurity analysis of and of mixing an equimolecular amount of 4-fluoro-2-formylphenyl boronic acid 7, phenylethylamine, fluorine compound 7 as a ◦new bifunctional template for carrying out the enantiopurity analysis of chiral diols. the chiral diol in CDCl3 at 25 C (Scheme 6). The focus of the method was to synthesize the fluorine chiralAdiols. closely related approach was used by Chaudhari and Suryaprakash to perform the compound a 22, new bifunctional template for carrying out the enantiopurity analysis of chiral Molecules 2017, 247 5 ofthe 22 diols. A7 as closely related was used by methyl Chaudhari and Suryaprakash to perform discrimination of chiral approach diacids and chiral alpha amines [34]. The three-component chiral 19F-methyl discrimination of chiralhas diacids and chiral for alpha amines These [34]. The three-component chiral derivatization protocol been NH developed and 13C-NMR. methodologies are based on 2 19F- and 13C-NMR. These methodologies are based on derivatization protocol has been developed for a mixture of diastereomeric iminoboronate esters without any racemization or kinetic resolution. aThe mixture of diastereomeric iminoboronate esters without any racemization or kinetic resolution. Racemic Suryaprakash method was the first procedure for determining the enantiopurity of chiral The Suryaprakash method was the first procedure for determining the enantiopurity of chiral diacids. The generalO protocol involves the reaction of an equimolecular amount of diacids with CDCl3 OH + F amount of diacids with diacids. The general protocol the reaction ofF an equimolecular F 3-fluoro-2-formylboronic acid 8 involves and an enantiopure 4 (Scheme 7). 4A MS / 25oC (R)-methylethylamine N N + in methanol-d OH 13C was 1.24 3-fluoro-2-formylboronic an enantiopure (R)-methylethylamine in methanol-d 4 (Scheme 7). F and ppm and 0.46 ppm, respectively, for the The baseline separation of 819and OHacid B O B O B 19 13C was 1.24 ppm and 0.46 ppm, respectively, for the F and The baseline separation of Chiral diol rac-2-methylsuccinic acid (Scheme 7). O OH O rac-2-methylsuccinic acid (Scheme 7). 7 - CDA Template Scheme 6. Three-component coupling reaction for enatiopurity determination of chiral diols by 19F

Scheme 6. Three-component coupling reaction for enatiopurity determination of chiral diols by 19 F {1H} NMR spectroscopy. {1 H} NMR spectroscopy. NH2

A closely related approach was used by Chaudhari and Suryaprakash to perform the Δδ = 1.24 ppm discrimination of chiral diacids and chiral alpha methyl amines [34]. The three-component chiral 19 F13 C-NMR.F These methodologies are based F O F H derivatization protocol has been CO developed for and 2 Δδ = 0.46 ppm MeOD-d4 + N CH3 + N CH3 on a mixture of diastereomeric iminoboronate esters without any racemization or kinetic resolution. CO H 2 OH B OH

2-methyl succinic acid

B O O

O

B O

O

O

8 - CDA Template O

O

Scheme 7. Three-component coupling reaction for enatiopurity determination of diacids by 19F {1H} and 13C {1H} NMR spectroscopy.

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OH

+

F

5 of 21

OH

CDCl3 4A MS / 25oC

F

N

+

F

N

The Suryaprakash method was the first procedure for determining the enantiopurity of chiral diacids. OH B O B O B Chiral diol O OH O The general protocol involves the reaction of an equimolecular amount of diacids with 3-fluoro-27 - CDA Template formylboronic acid 8 and an enantiopure (R)-methylethylamine in methanol-d4 (Scheme 7). The baseline 13 C was 1.24 ppm and 0.46 ppm, respectively, for the rac-2-methylsuccinic acid separationScheme of 19 F and 6. Three-component coupling reaction for enatiopurity determination of chiral diols by 19F (Scheme 7).{1H} NMR spectroscopy. NH2

Δδ = 1.24 ppm F

O

F

CO2H

F

MeOD-d4

+

N

CO2H

OH B OH

B O O

2-methyl succinic acid

CH3

Δδ = 0.46 ppm N

+

O

B O

CH3 O

O

8 - CDA Template O

O

Scheme 7. Three-component coupling reaction for enatiopurity determination of diacids by 19F {1H}

Scheme 7.13Three-component coupling reaction for enatiopurity determination of diacids by 19 F {1 H} and1 C {1H} NMR spectroscopy. 13 and C { H} NMR spectroscopy. There is great potential for the use of the boronic acid derivatives mentioned above and other related [35–37]for in the recognition of organic and water soluble compounds dueand to other There isprocedures great potential thechiral use of the boronic acid derivatives mentioned above their use as new probes, mainly in biologically relevant species [38]. The boronic acids have Lewis related procedures [35–37] in the chiral recognition of organic and water soluble compounds due acid characteristics and react spontaneously and reversibly with diol compounds. Furthermore, to their use as new probes, mainly in biologically relevant species [38]. The boronic acids have boron chemistry is closely related to the living systems. These characteristics, in addition to the Lewis usefulness acid characteristics and react and reversibly diol compounds. Furthermore, of multinuclear NMRspontaneously spectroscopy, represent valuablewith methodologies to discriminate boron chiral chemistry closely related to the living systems. These characteristics, in addition to the organiciscompounds. usefulness Another of multinuclear NMR spectroscopy, represent methodologies to discriminate chiral fluorine-containing carboxylic acid,valuable F-THENA 9, was recently prepared by chiral Dolsophon et al. The rigid anisotropic structure of F-THENA 9 is useful for assigning the absolute organic compounds. 19F-NMR spectroscopy [39]. The CDA was configuration of secondary alcohols and amines by Another chiral fluorine-containing carboxylic acid, F-THENA 9, was recently prepared by synthesized from a commercially available starting material in six steps (Scheme 8). To establish the Dolsophon et al. The rigid anisotropic structure of F-THENA 9 is useful for assigning the absolute absolute configuration, X-ray analysis was performed. Derivatizations of the (S) and (R) F-THENA 9 configuration of secondary alcohols and amines by 19 F-NMR spectroscopy [39]. The CDA was acids with oxalyl chloride in the presence of a catalytic amount of dimethylformamide allowed for synthesized from aofcommercially available In starting material in shielding six stepseffect (Scheme To the establish 19F-NMR, the formation (S) and (R) F-THENA-Cl. a positive occurs8). from the absolute configuration, X-ray analysis was performed. Derivatizations of the (S) and (R) F-THENA alcohol moiety when an aromatic group is located on the lower side of the F-THENA plane while a value is obtained an aromatic is located on the upper side of the F-THENA 9 acidsnegative with oxalyl in when the presence of agroup catalytic amount of dimethylformamide allowed for Molecules 2017, 22,chloride 247 6 of 22 plane (Scheme The(R) fluorine-containing system, which the formation of (S)8).and F-THENA-Cl.CDA In 19provides F-NMR,a aself-validating positive shielding effectreduces occursthe from the of incorrect Thegroup NMR results wereon strongest when both understand the assignment. conformational features of amide scaffolds in side the assignment of assignments, the absolute alcoholrisks moiety when an aromatic is located the lower ofconfiguration the F-THENA plane while a 19F- and 1H-NMR, were identical. from configuration, Ichikawa et al. studied the characteristic conformation of Mosher’s acid amide, which plane negative value is obtained when an aromatic group is located on the upper side of the F-THENA alternative approach to assignStructural the absolute configuration of amino using for the biological Mosher’s was An elucidated using the Cambridge Database [41]. Amides areacids important (Scheme 8).was The fluorine-containing a self-validating system, which reduces the risks of acid developed by Katritzky etCDA al [40].provides N-acylbenzotriazoles areindustry stable andsince crystalline derivatives systems and are especially important in the pharmaceutical a huge number of of incorrect assignment. Thehave NMR results were strongest when both configuration assignments, carboxylic acids candidates and advantages mainly when compared to acid chlorides that are unstable, molecular drug have nitrogen atoms [42,43]. Furthermore, chiral amines are also used as from 19 F- and 1 H-NMR, were identical. moisture sensitive, to prepare, and need be stored in a deep freeze. Thus, the authors the starting materialdifficult in the formation of new aminotoacids and peptide bonds. synthesized the Mosher-Bt 10 reagent (Scheme 9) from chiral and racemic Mosher’s acid to employ as a new and stable CDA for amino acids and peptides.OThe carboxylicOacid derivative 10 was easily NH2 steps prepared with thionyl chloride andsix1H-benzotriazole (BtH) and their reactions were studied with or representative water-soluble chiral amino acids and peptides in acetonitrile-water medium (Scheme 9). CO2H HO2C CO H 9 2 The assignment ofFthe absolute configuration of F(R)-phenylalanine using theF Mosher-Bt 10 reagent 1 19 13 was performed using H-, F-, and C-NMR spectroscopy. To demonstrate that racemization does (R)-F-THENA (98 % ee) (S)-F-THENA (98 % ee) not occur during the reaction, Mosher amides were subjected to HPLC analysis. Recently, to Shielding effect (lower δF)

Less shielding effect F

F O

O

O

L1

O

L1

O

O

Scheme 8. Assignment of absolute configuration of secondary amines and alcohols employing the

Scheme 8. Assignment of 19 absolute configuration of secondary amines and alcohols employing the F-THENA-Cl CDA by F {1H} NMR spectroscopy. F-THENA-Cl CDA by 19 F {1 H} NMR spectroscopy. SOCl2 Reflux, 50 h

O F 3C MeO

Ph

OH

H N N

(S)-(+)-MTPA

N BtH

N N N

MeO O O

Ph CF3

Mosher Bt 10

+ H2N

CO2H

(R)-Phenylalanine

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understand the conformational features of amide scaffolds in the assignment of the absolute configuration, Ichikawa et al. studied the characteristic conformation of Mosher’s acid amide, which was elucidated approach using the Cambridge Structural Database [41]. Amides are important for biological An alternative to assign the absolute configuration of amino acids using the Mosher’s systems and are especially important in the pharmaceutical industry since a huge number of acid was developed by Katritzky et al [40]. N-acylbenzotriazoles are stable and crystalline derivatives molecular drug candidates have nitrogen atoms [42,43]. Furthermore, chiral amines are also used as of carboxylic acids and have advantages mainly when compared to acid chlorides that are unstable, the starting material in the formation of new amino acids and peptide bonds.

moisture sensitive, difficult to prepare, and need to be stored in a deep freeze. Thus, the authors synthesized the Mosher-Bt 10 reagent (Scheme 9) from Mosher’s acid to employ O chiral and racemic O NH2 six steps as a new and stable CDA for amino acids and peptides. The carboxylic acid derivative 10 was easily or CO2H and 1H-benzotriazole (BtH) and their reactions were studied with prepared with thionyl chloride HO2C CO2H 9 F F F representative water-soluble chiral amino acids and peptides in acetonitrile-water medium (Scheme 9). (98 % ee) (S)-F-THENA (98Mosher-Bt % ee) The assignment of the absolute configuration(R)-F-THENA of (R)-phenylalanine using the 10 reagent was 13 C-NMR spectroscopy. To demonstrate that racemization does not performed using 1 H-, 19 F-, and Shielding effect (lower δF) Less shielding effect occur during the reaction, Mosher amides were subjected to HPLC analysis. Recently, to understand the conformational features of amide scaffolds in the assignmentF of the absolute configuration, Ichikawa F L1 which was elucidated using the et al. studied the characteristic conformation of Mosher’s acid amide, O O O O Cambridge Structural Database [41]. Amides are important O for biological systems and are especially L1 O important in the pharmaceutical industry since a huge number of molecular drug candidates have nitrogen atoms [42,43]. Furthermore, chiral amines are also used as the starting material in the Scheme 8. Assignment of absolute configuration of secondary amines and alcohols employing the formation of new amino acids bonds. F-THENA-Cl CDA by 19Fand {1H} peptide NMR spectroscopy. SOCl2 Reflux, 50 h

O F 3C MeO

Ph

OH

H N N

(S)-(+)-MTPA

N

N N N

MeO O O

Ph

+

CF3

H2N

Mosher Bt 10

CO2H

(R)-Phenylalanine

BtH

AcCN : H2O (2 : 1)

H N HO2C

MeO O

Ph CF3

Scheme 9. Assignment of the absolute configuration of amino acids by 19F {1H} and 13C {1H} NMR

Scheme 9. Assignment of the absolute configuration of amino acids by 19 F {1 H} and 13 C {1 H} NMR spectroscopy. spectroscopy. Cyclodextrins (CDs) were employed as a chiral recognition agent for enantiodiscrimination of emtricitabine a novel nucleoside reverse transcriptase for treatment of Cyclodextrinsenantiomers (CDs) were11,employed as a chiral recognition agentinhibitors for enantiodiscrimination of HIV infection in adults and children, by 19F-NMR spectroscopy [44]. In this protocol, developed by emtricitabine enantiomers 11, a novel nucleoside reverse transcriptase inhibitors for treatment of Rao et al., the influence of the CD cavity sizes (α, β, and γ), temperature and concentration were HIV infection in adults and children, by 19 F-NMR spectroscopy [44]. In this protocol, developed by studied. The method is based on intermolecular interaction between emtricitabine enantiomers 11 Rao etwith al., cyclodextrins the influencein of the CD cavity sizes and γ), temperature concentration D2O solution (Scheme 10).(α, Theβ, hydrophobic nature of suchand cavities provides a were studied. Theenvironment method is based on intermolecular interaction between enantiomers 11 with chiral for enantiodiscrimination. The α-CD has shownemtricitabine better enantiodiscrimination results employing low concentrations (0.01 mM) and temperatures K). Moreover, bindinga chiral cyclodextrins in D2 O solution (Scheme 10). The hydrophobic nature(298 of such cavities the provides 19F-NMR method developed and a 2D 1H ROESY NMR constant (K) was determined using the environment for enantiodiscrimination. The α-CD has shown better enantiodiscrimination results analysis was performed to understand geometry of association α-CD. employing low concentrations (0.01 mM)the and temperatures (298 with K). Moreover, the binding constant

(K) was determined using the 19 F-NMR method developed and a 2D 1 H ROESY NMR analysis was performed to understand the geometry of association with α-CD.

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H2 N

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O N

F

N

H2 N

H2N +

O

O

OH

S

(S,R)-EMT N O

F

F H2N

+

F

O OH HO OH

HO OO O HO OH OH HO α-CD O

O

HO O OH OH O OH

HO

O S

7 of 22

OH

Drug EMT 11 Treatment of HIV Infection

(R,S)-EMT N O

S

O

HO

N

Drug EMT 11 Treatment of HIV Infection

O

OH

(R,S)-EMT OH

O

O N

OH

S (S,R)-EMT

HO

N

OH O O HO

D2O / 298 K HOST-GUEST Complex

D2OOH / 298 K

O OH O OH OH HO O OH O α-CD OH OH OH OO OHO OH

O OH O HO OH

OHO OH O

HOST-GUEST Complex

OH

Scheme 10. Chiral discrimination of emtricitabine 11 by cyclodextrin host–guest complexes using 19F O Scheme1 10. Chiral discrimination of emtricitabine 11 by cyclodextrin host–guest complexes using 19 F H} NMR spectroscopy. { 1

{ H} NMR spectroscopy.

HO

3. Scheme P-NMR10. Chiral ChiralRecognition discrimination of emtricitabine 11 by cyclodextrin host–guest complexes using 19F 31

3.

31 P-NMR 1

Recognition NMR spectroscopy. { H} Chiral

Organophosphorus is an old field of organic chemistry. Organophosphorus compounds are

essential in all chemical sciences, especially the life sciences, because their structurescompounds are a key Organophosphorus is an old field of organic chemistry. Organophosphorus are 3. 31P-NMR Chiral Recognition building block [45,46]. Furthermore, the pharmaceutical and agrochemical industries have prompted essential in all chemical sciences, especially the life sciences, because their structures are a key building studies of phosphorus chemistry Organophosphorus is an old[47]. field of organic chemistry. Organophosphorus compounds are block [45,46]. Furthermore, the pharmaceutical and agrochemical industries have prompted studies of 19F-NMR spectroscopy, the main factors that govern the 31P chemical shift values are Unlike essential in all chemical sciences, especially the life sciences, because their structures are a key phosphorus chemistry [47]. different due to other bond contributions. In this way, a good knowledge of industries organometallic building block [45,46]. Furthermore, the pharmaceutical and agrochemical havechemistry prompted 19 Unlike F-NMR spectroscopy, thevariations. main factors that govern the 31 P chemical shift values are could of help with understanding studies phosphorus chemistrythose [47]. 31P-NMR different due to other bond contributions. In since thisfactors way, athat good knowledge of organometallic chemistry 19F-NMR spectroscopy is highly the useful, compounds from natural normally contain Unlike spectroscopy, main govern the 31Presources chemical shift values are 31P is more abundant (100%), making it a valuable probe for NMR investigations [48]. this nucleus and coulddifferent help with those variations. dueunderstanding to other bond contributions. In this way, a good knowledge of organometallic chemistry 31 Recently, Szyszkowiak and Majewska havesince reviewed the application of 31P-NMR for determination could help spectroscopy with understanding those variations. P-NMR is highly useful, compounds from natural resources normally contain of the absolute configuration of organic compounds [49]. In this review, the model created by 31P-NMR 31 is highly useful, since compounds from natural normally contain this nucleus and spectroscopy P is more abundant (100%), making it a valuable proberesources for NMR investigations [48]. Hammersschmidt and Li, in which the shielding of the phosphorus atom by the phenyl group in 31P is more abundant (100%), making it a valuable probe for31 NMR investigations [48]. this nucleus and Recently, Szyszkowiak and Majewska have reviewed the application of P-NMR for determination (S)-MTPA ester causedand theMajewska signal to appear at a higher field (Schemeof11), was explored [50]. This 31P-NMR Recently, Szyszkowiak have reviewed the[49]. application for model determination of the absolute configuration organic compounds In this review, the created by model, based on Mosher’sofesters, is currently an important tool for assigning the absolute of the absolute configuration of organic compounds [49]. In this review, the model created by 1 Hammersschmidt and Li, organic in which the shielding of the phosphorus atom by the[51]. phenyl group in configuration of many functionalities and structures by H-NMR spectroscopy Hammersschmidt and Li, in which the shielding of the phosphorus atom by the phenyl group in (S)-MTPA ester caused the signal to appear at a higher field (Scheme 11), was explored [50]. This model, (S)-MTPA ester caused the signal to appear at a higher field (Scheme 11), explored [50]. This MeOwas Ph R1 basedmodel, on Mosher’s esters, is currently important for assigning absolute configuration of Otheassigning O based on Mosher’s esters, an is currently antool important tool for the absolute CF3 (R3O)2(O)P 1 OH F3C byand manyconfiguration organic functionalities andfunctionalities structures H-NMR spectroscopy [51]. 1 O of many organic [51]. 1 R2 spectroscopy Cl structures by H-NMR (R3O)2(O)P

R R2

+

MeO

Ph

(S)-(+)-MTPA-Cl O F3C Cl MeO Ph

+

MeO MeO Ph Ph OO CF 3 CF 3 RR22 OO

(R3O)2(O)P R1 R1 (R3O)2(O)P

OH R1 + + 2 R Scheme 11. Assigning of the configuration of α-hydroxyphosphonates from derivatization with MeO Ph 3 (R O)2(O)P (S)-(+)-MTPA-Cl (S)-MTPA-Cl by 31P {1H} NMR spectroscopy. O CF3 R1 R2 O (R3O)2(O)P

The commercially available amino acid derivatives were employed as a CSA to differentiate Scheme 11. of Assigning the configuration of α-hydroxyphosphonates derivatization withand enantiomers chiral ofphosphonates, phosphinates, phosphates, from phosphine oxides, Scheme 11. Assigning of the configuration of α-hydroxyphosphonates from derivatization with (S)-MTPA-Cl31by 31by P {131 H} NMR spectroscopy. phosphonamidates P-NMR spectroscopy [52]. The method developed by Li and Raushel uses 1 (S)-MTPA-Cl by P { H} NMR spectroscopy. N-Fmoc-N’-Boc-L-tryptophan 12 in CDCl3 at 25 °C as a CSA for different phosphorus compounds The commercially available amino acid derivatives were employed as a CSA to differentiate enantiomers of chiral phosphonates, phosphates, phosphine and The commercially available amino acidphosphinates, derivatives were employed as a CSAoxides, to differentiate 31P-NMR spectroscopy [52]. The method developed by Li and Raushel uses phosphonamidates by enantiomers of chiral phosphonates, phosphinates, phosphates, phosphine oxides, and phosphonamidates in method CDCl3 at developed 25 °C as a CSA forand different phosphorus compounds by 31N-Fmoc-N’-Boc-L-tryptophan P-NMR spectroscopy [52]. 12 The by Li Raushel uses N-Fmoc-N’-Boc-L-

tryptophan 12 in CDCl3 at 25 ◦ C as a CSA for different phosphorus compounds (Scheme 12). Although

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(Scheme 12). Although there is a lower anisochrony of the phosphorus atoms, the good baseline

2017,anisochrony 22, 247 of 22 there isMolecules a lower of the phosphorus atoms, the good baseline resolution and8absence of resolution and absence of overlapping signals provided an efficient and fast chiral discrimination overlapping signals provided an efficient and fast chiral discrimination procedure. procedure.

(Scheme 12). Although there is a lower anisochrony of the phosphorus atoms, the good baseline resolution and absence of overlapping signals provided an efficient and fast chiral discrimination procedure. O OH N

HN

O

O O

O OH

O

HN

N O O O O N-Fmoc-N'-Boc-L-tryptophan - 12

N-Fmoc-N'-Boc-L-tryptophan - 12

O

P

H3CO O

O

O O

O O

P Δδ = 0.008 O ppm H3CO

NO2

NO2

O

P

O

O

O

O ΔP δ =O0.028 ppm

Scheme 12. N-Fmoc-N’-Boc-L-tryptophan 12 as

P

O

P

H3CO

NH2

O O O

O

O

P O Δδ =O0.054 ppm O Δδ =O0.046 ppm H CO 3 P NH2 O a CSA for chiral of Δδ = 0.054 ppm ppm discrimination Δδ = 0.046

O

phosphonates,

Δδ = 0.008 ppm Scheme 12. N-Fmoc-N’-Boc-L-tryptophan 12 as a CSA for chiral discrimination of phosphonates, Δδ = 0.028 ppm phosphinates, phosphates, phosphine oxides, and phosphonamidates by 31P {1H} NMR spectroscopy. phosphinates, phosphates, phosphine oxides, and phosphonamidates by 31 P {1 H} NMR spectroscopy.

Scheme 12. N-Fmoc-N’-Boc-L-tryptophan 12 as a CSA for chiral discrimination of phosphonates, Mastranzo et al. demonstrated the use of P(III) and P(V) organophosphorus deriving reagents phosphinates, phosphates, phosphine oxides, and phosphonamidates by 31P {1H} NMR spectroscopy.

for chiral discrimination of carboxylic by P(III) P-NMR In organophosphorus this work, the authors described Mastranzo et al. demonstrated theacids use of and[53]. P(V) derivingthe reagents preparation of C2etsymmetric diaminesthe 13,use which contain theP(V) α-phenyl-ethyl group and the cyclohexane 31 Mastranzo al. demonstrated of P(III) and organophosphorus deriving reagents for chiral discrimination of carboxylic acids by P-NMR [53]. In this work, the authors described the skeleton. The discrimination of chiralacids carboxylic acids [53]. was In performed anauthors NMR tube in three for chiral of carboxylic by 31contain P-NMR this work,inthe described the preparation of Cdiscrimination diamines 13, which the α-phenyl-ethyl group and the cyclohexane 2 symmetric reaction steps (Scheme 13). The chemical shift difference between diastereomers varied in the ranges preparation of C2 symmetric diamines 13, which contain the α-phenyl-ethyl group and the cyclohexane skeleton. The discrimination chiral carboxylic acids was performed in an NMR tube in three reaction of 0.02–2.43 fordiscrimination P(III) andof 0.02–2.14 for P(V). skeleton. The of chiral carboxylic acids was performed in an NMR tube in three steps (Scheme 13). The chemical shift difference between diastereomers varied in the ranges of 0.02–2.43 reaction steps (Scheme 13). The chemical shift difference between diastereomers varied in the ranges for P(III) and 0.02–2.14 for P(V). of 0.02–2.43 for P(III) and 0.02–2.14 for P(V). 31

X

X

NH NH NH

NH Diamine - 13

X

DEA

X

N

P

Cl

RCO2H X

N

PCl3 DEA

X

N

PCl3

N

P

Cl

RCO2H

N N

P O N

N

O R

P O S8

O R

S8

Diamine - 13 P(III) Δδ = 0.02 - 2.43 ppm P(V) Δδ = 0.02 - 2.14 ppm P(III) Δδ = 0.02 - 2.43 ppm P(V) Δδ = 0.02 - 2.14 ppm

X

X

N N

P N

N

S O

P

Scheme 13. Preparation of organophosphorus CDA for chiral discrimination of 31P {1H} NMR spectroscopy.

S O

O R O

R carboxylic

acids by

Scheme 13. Preparation of organophosphorus CDA for chiral discrimination of carboxylic acids by

31P-NMR to The1 same approach employed by Reiner al.chiral who used the acids formation Scheme Preparation ofwas organophosphorus CDAetfor discrimination ofmonitor carboxylic by 31 P 31P13. { H} NMR spectroscopy. 1 of diastereoisomers by a PCl3 reagent [54]. In this procedure, the PCl3 reagent reacted with the chiral { H} NMR spectroscopy. BINOL to form phosphite derivative 14 and after the alcohol or amine was added to obtain a mixture 31P-NMR The same approach was employed by Reiner et al. who used to monitor the formation

of diastereoisomers a PCl 3 reagent [54]. In this procedure, the PCl31 with the The same approachby was employed by Reiner et al. who used 3 reagent P-NMRreacted to monitor thechiral formation BINOL to form phosphite derivative 14 and after the alcohol or amine was added to obtain a mixture of diastereoisomers by a PCl3 reagent [54]. In this procedure, the PCl3 reagent reacted with the chiral BINOL to form phosphite derivative 14 and after the alcohol or amine was added to obtain a mixture of diastereomers (Scheme 14). The chiral discrimination was possible by two diastereomeric 31 P-NMR peaks for both enantiomers of the compounds. The measurements were performed in less than 5 min

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of diastereomers (Scheme 14). The chiral discrimination was possible by two diastereomeric 31P-NMR peaks for both enantiomers of the compounds. The measurements were performed in less with only 500 µL of deuterated solvent. Moreover, the authors examined its application to on-line ee than 5 min with only 500 μL of deuterated solvent. Moreover, the authors examined its application determination standardwith catalytic protocols. to on-linein eecombination determination with in combination standard catalytic protocols. PCl3 OH OH

O P Cl O

E +

R1

R2

E = OH or NH2 Phosphite - 14

(+)-BINOL

O P E O

R2

O P E O

+

R1

Scheme 14. Synthesis of CDA for chiral discrimination of alcohols and amines by

R2 R1

P {131 H} NMR P {1 H} NMR

31

Scheme 14. Synthesis of CDA for chiral discrimination of alcohols and amines by spectroscopy. spectroscopy.

For 31P-NMR chiral discrimination of atropoisomeric phosphine oxides, Demchuk et al. evaluated 31 different CSAs [55]. discrimination The commercially carboxylic acids 15 and 16, which have et provided For P-NMR chiral of available atropoisomeric phosphine oxides, Demchuk al. evaluated good results for NMR chiral discrimination [56,57], and dibenzoyltartaric acids 17 and 18 were different CSAs [55]. The commercially available carboxylic acids 15 and 16, which have provided good applied as CSAs (Scheme 15). The 31P-NMR analyses have shown that in most cases those simple results for NMR chiral discrimination [56,57], and dibenzoyltartaric acids 17 and 18 were applied as chiral acids are very efficient CSAs for the determination of the enantiopurity of atropoisomeric 31 P-NMR analyses have shown that in most cases those simple chiral acids are CSAs (Scheme 15). The bis-phosphine dioxides. To prove the accuracy of the NMR methodology an electronic circular very efficient CSAs for the determination ofelectronic the enantiopurity atropoisomeric dioxides. dichroism spectroscopy was applied. The absorptionsofand chiroptical databis-phosphine of the investigated To prove the accuracy of thethe NMR an electronic circular dichroism spectroscopy compounds corroborate NMRmethodology analyses. Furthermore, computer calculations were carried out to was provide details about the stereochemistry of the complexes. applied. The electronic absorptions and chiroptical data of the investigated compounds corroborate Bedekar etFurthermore, al. synthesized computer modified amides as NMR solvating agentsout for to theprovide chiral discrimination the NMR analyses. calculations were carried details about the of 1,1′-binaphthyl and alpha-substituted acid enantiomers [58]. In this procedure, the chiral isobornyl stereochemistry of the complexes. Molecules 2017, 22,employed, 247 10 of 22 amine 19 was which is readily available and can be used as a starting material to prepare steric bulk amide 20 with three-stereogenic centers for chiral molecular recognition by 31P-NMR analysis CO2H CO2H (Scheme 16). Furthermore, the linear relationship between the observed and actual ee values of binaphthyl 21 was evaluated and confirmed the accuracy of theOH31P-NMR analyses. The strategy was H3COby Kagan et al. [59], in which simple chiral amides were studied as based on the method developed (S)-Mandelic Acid types - 16 - 15 between CSAs for efficient determination (S)-Naproxen of enantiomers several of compounds. The chiral recognition of Kagan’s amide is O achieved by hydrogen-bonding using a different procedure than the CO2H O C(O)NMe2 one outlined by Bedekar et al. The effectiveness of the method was expanded to alpha-carboxylic CO2H CO2H O O acids by 19F-NMR spectroscopy using chiral isobornyl amide 20a and a base (DMAP) to improve the O O O O intermolecular interactions (Scheme 17). In another work of Bedekar et al. a modified Kagan’s amide was synthesized and applied as CSA for hydrogen-bonding based chiral discrimination employing (2R, 3R)-DBTA-MDA - 18 (2R, 3R)-DBTA - 17 1H- and 19F-NMR spectroscopy [60]. The same research group has published the chiral discrimination of binaphthyl 21 by employing a chiral aza-macrocycle 22 [61]. The synthesis of 18 member aza-macrocycles (S,S,S)-22 and (R,R,S)-22 Chiral Solvating Agents was carried out in three steps from the cyclohexene oxide (Scheme 18). To confirm the 3D structure, a single crystal X-ray analysis of both diastereomers was performed. The discrimination ability of aza-macrocycle 22 for binaphthyl phosphoric acid 21 ranged from 0.03 to 0.81 ppm. An additional P(O)Ph2 P(O)Tol2 fluorescence spectroscopy study for understanding the chiral recognition of chiral aza-macrocycle P(O)Ph2 P(O)Tol2 showed an enantioselective quenching interaction. This effect was attributed to the deprotonation of phosphoric acid 21, which is indicated by the appearance of new peak in the UV-Vis spectra. BINAPO

Tol - BINAPO

P(O)Ph2 P(O)Ph2

P(O)Ph2 P(O)Ph2 Tetra-PHEMPO

BIPHEMPO

Scheme 15. Chiral carboxylic acids used as CSAs for enantiodiscrimination of bis-phosphine dioxides by

Scheme 15. Chiral carboxylic acids used as CSAs for enantiodiscrimination of bis-phosphine dioxides 31P {1H} NMR spectroscopy. by 31 P {1 H} NMR spectroscopy. O Cl NH2 Chiral Isobornyl Amine - 19

Ar Et3N

R1 H N O

R2 R1

(S)-Mandelic Acid - 16

(S)-Naproxen - 15 O O

CO2H CO2H O

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O O

C(O)NMe2 CO2H

O

O

O

10 of 21

(2R, 3R)-DBTA-MDA - 18

(2R, 3R)-DBTA - 17

Bedekar et al. synthesized modified amides as NMR agents for the chiral discrimination Chiralsolvating Solvating Agents of 1,10 -binaphthyl and alpha-substituted acid enantiomers [58]. In this procedure, the chiral isobornyl amine 19 was employed, which is readily available and can be used as a starting material to prepare steric bulk amide 20 with three-stereogenic centers for chiral molecular recognition by 31 P-NMR P(O)Ph P(O)Tol2 2 P(O)Ph P(O)Tol analysis (Scheme 16). Furthermore, the linear relationship between the2 observed and actual ee values 2 of binaphthyl 21 was evaluated and confirmed the accuracy of the 31 P-NMR analyses. The strategy BINAPO Tol - BINAPO was based on the method developed by Kagan et al. [59], in which simple chiral amides were studied as CSAs for efficient determination of enantiomers between several types of compounds. The chiral recognition of Kagan’s amide is achieved by hydrogen-bonding using a different procedure than the P(O)Ph2 P(O)Ph2 one outlined by Bedekar et al. The effectiveness of the method P(O)Ph2 P(O)Ph2was expanded to alpha-carboxylic 19 acids by F-NMR spectroscopy using chiral isobornyl amide 20a and a base (DMAP) to improve the Tetra-PHEMPO BIPHEMPO 17). In another work of Bedekar intermolecular interactions (Scheme et al. a modified Kagan’s amide was synthesized and applied as CSA for hydrogen-bonding based chiral discrimination employing 1 HScheme 15. Chiral carboxylic acids used as CSAs for enantiodiscrimination of bis-phosphine dioxides by 19 and F-NMR [60]. 31P {1spectroscopy H} NMR spectroscopy. O

NH2

R1

Ar

Cl

H N

Et3N

R2 R1

O

Chiral Isobornyl Amine - 19

Chiral Amide - 20

CSA

O O P O OH

rac -1,1'- binaphthyl-2,2'-diyl hydrogen phosphate - 21

Scheme 16. Synthesis of isobornyl derived amides as CSA for enantiodiscrimination of binaphthyl by Scheme 16. Synthesis of isobornyl derived amides as CSA for enantiodiscrimination of binaphthyl by 31 P {1 H} NMR spectroscopy. 31P 2017, Molecules 22, 247spectroscopy. {1H} NMR

11 of 22

CO2H Ph F

NO2 H N

DMAP CDCl3

NO2

O

Δδ = 0.01 ppm

O

CO2H

Chiral Amide - 20a F Δδ = 0.01 ppm

Scheme 17. Chiral discrimination of carboxylic acids by 19F {1H} NMR spectroscopy.

Scheme 17. Chiral discrimination of carboxylic acids by 19 F {1 H} NMR spectroscopy. O

O

N The same research group has published Othe chiral discrimination of binaphthyl 21 by employing O a chiral aza-macrocycle 22 [61]. The synthesis of 18 member aza-macrocycles (S,S,S)-22 and (R,R,S)-22 N N was carried out in three steps from the cyclohexene oxide (Scheme 18). To confirm the 3D structure, Ph Ph a single crystal X-ray analysis of3 steps both diastereomers was performed. The discrimination ability of Aza-macrocycle (S.S.S) 22 aza-macrocycle 22 for binaphthyl phosphoric acid 21 rangedCSAfrom 0.03 to 210.81 ppm. An additional O Binaphthyl fluorescence spectroscopy study for understanding the chiral recognition of chiral aza-macrocycle O O N This effect was attributed to the deprotonation of showed an enantioselective quenching interaction. O O phosphoric acid 21, which is indicated by the appearance of new peak in the UV-Vis spectra. N

N

Ph

Ph

Aza-macrocycle (R.R.S)

Scheme 18. Chiral discrimination of Binaphtyhl 21 using the aza-macrocycle by 31P {1H} NMR spectroscopy.

Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21 and derivatives, Nagorny and Tay have developed a simple and reliable protocol for determining the enantiopurity by 31P-NMR spectroscopy [62]. The optical rotation measurements were not

H N

DMAP

NONO O 2 2 H Chiral Amide - 20a N

CDCl3

NO2

CDCl3

O

Molecules 2017, 22, 247

DMAP

Δδ = 0.01 ppm Ph F O CO2H Δδ = 0.01 ppm

F ppm CO2H Δδ = 0.01 O

11 of 21

Chiral Amide - 20a

Scheme 17. Chiral discrimination of carboxylic acids F by 19F {1H} NMR spectroscopy. Δδ = 0.01 ppm O

O

O

O

Scheme 17. Chiral discrimination of carboxylic acids by 19F {1H} NMR spectroscopy. N N O Ph

3 steps O

N

O O Aza-macrocycle (S.S.S) N N 22 Ph

3 steps O

N O Ph

CSA

Binaphthyl 21

Ph

O O Aza-macrocycle (S.S.S) N O O 22 N O

CSA

Binaphthyl 21

N O

Ph N Ph O O Aza-macrocycle (R.R.S) N N

Scheme 18. Chiral discrimination of Binaphtyhl 21 using the aza-macrocycle by 31P {1H} NMR spectroscopy.

Ph Ph using the aza-macrocycle by 31 P {1 H} NMR Scheme 18. Chiral discrimination of Binaphtyhl 21 Aza-macrocycle (R.R.S) spectroscopy. Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21

Scheme 18. Chiral discrimination of Binaphtyhl 21 using athe aza-macrocycle by protocol P { H} NMR and derivatives, Nagorny and Tay have developed simple and reliable forspectroscopy. determining 31P-NMR spectroscopy [62]. The optical rotation measurements were not the enantiopurity by Based on the difficulties in performing the chiral discrimination of BINOL phosphoric acids 21 Based on thecompounds. difficulties inThus, performing chiral amines discrimination oftoBINOL phosphoric acids 21 reliable for Nagorny these the usethe of chiral as CSAs carry out the NMR chiral and derivatives, and and Tay Tay have developed a simple and reliable protocol fordetermining determining the and derivatives, Nagorny have developed a simple and reliable protocol for discrimination of BINOL phosphoric acids derivatives was an elegant alternative (Scheme 19). 31 enantiopurity by P-NMR [62]. The optical rotationrotation measurements were were not reliable for the enantiopurity by2431spectroscopy P-NMR spectroscopy [62]. Thebyoptical measurements Chiral amines 23 and are commercially available and the simple mixture of reagents (10 mgnot of these compounds. Thus, the use of chiral amines as CSAs to carry out the NMR chiral discrimination reliable for these compounds. Thus, the use of chiral amines as CSAs to carry out the NMR chiral BINOL and 1.5 equiv. of CSA) in a deuterated solvent, the 31P-NMR signals of the diastereomer salts discrimination ofacids BINOL phosphoric acids derivatives wastoan (Scheme 19).23 and of BINOL phosphoric derivatives was an elegant alternative (Scheme 19).work, Chiral are observed. The sample concentrations ranged from 4.7 25 elegant mM. Inalternative this theamines authors Chiral amines 23 and 24 are commercially available and by the simple mixture of reagents (10 mg of 24 are commercially available and bythermal the simple mixture ofBINOL reagents (10 mg of BINOL and 1.5 equiv. of studied the epimerization under conditions of the phosphoric acid derivatives using 31P-NMR signals of the diastereomer salts BINOL and 1.5 equiv. of CSA) in a deuterated solvent, the 31 31 the P-NMR protocol developed. CSA) in a deuterated solvent, the P-NMR signals of the diastereomer salts are observed. The sample are observed. The sample concentrations ranged from 4.7 to 25 mM. In this work, the authors concentrations ranged from 4.7 to 25 mM. In this work, the authors studied the epimerization under studied the epimerization under thermal conditions of the BINOL phosphoric acid derivatives using 2 thermaltheconditions of the BINOL phosphoricNHacid derivatives using the 31 P-NMR protocol developed. 31P-NMR protocol developed. 31

1

OH

R1 O O P O R1 XH O R O2 P O XH R2

CSA - 23 NH2 OH or CSA - 23 NH2 or CSA NH2- 24

R1 CSA

CSA

O O P 1 O R X O H 3N R O2 P O X Δδ = 0.14 - 2.69 ppm H 3N R2

Scheme 19. Chiral discrimination of 3,3′-substituted BINOL and H8-BINOL phosphoric acids by 31P Δδ = 0.14 - 2.69 ppm CSA - 24 {1H} NMR spectroscopy. Scheme 19. Chiral discrimination of 3,3′-substituted phosphoric acids by P Scheme 19. Chiral discrimination of 3,30 -substituted BINOL BINOLand andH8-BINOL H8-BINOL phosphoric acids by 31 P 1H} NMR spectroscopy. { {1 H} NMR spectroscopy. 31

The use of 31 P-NMR spectroscopy in organometallics chemistry is a well-known tool for structure elucidation and evaluation of mechanisms [63]. Recently, Gorunova et al. have prepared a chiral phosphine ligand as a derivatizing agent for enantiopurity determination of CN-palladacycles using 31 P-NMR [64]. The phosphine ligand was synthesized in one step from the cheap and naturally occurring chiral menthol 25 (Scheme 20). The enantiopurity determination is carried out in situ, without any complications from geometric isomerism or palladacycle dechelation. Continuing this work, the same authors applied this method to determine the absolute configuration of the CN-palladacycles [65]. The results were based on 31 P-NMR chiral discrimination, density function theory (DFT) calculations and X-ray data. The DFT calculations were carried out to study the rotameric mobility of the phosphinite group and dynamiC-NMR spectroscopy and X-ray data were employed to estimate the chirality transfer efficiency in the phosphinite derivatives.

occurring chiral menthol 25 (Scheme 20). The enantiopurity determination is carried out in situ, without any complications from geometric isomerism or palladacycle dechelation. Continuing this work, the same authors applied this method to determine the absolute configuration of the CN-palladacycles [65]. The results were based on 31P-NMR chiral discrimination, density function theory (DFT) calculations and X-ray data. The DFT calculations were carried out to study the Moleculesrotameric 2017, 22, 247 mobility of the phosphinite group and dynamiC-NMR spectroscopy and X-ray data were 12 of 21 employed to estimate the chirality transfer efficiency in the phosphinite derivatives.

Method B

Method A OH

O

PPh2

OH

Ph2PN(CH3)2

Ph2PCl 25

25 CDA H N Pd Cl

H

Pri

N Pd L

2

Pri

2

Scheme 20. Chiral discrimination of CN-palladacycles by 31P {1H} NMR spectroscopy.

Scheme 20. Chiral discrimination of CN-palladacycles by 31 P {1 H} NMR spectroscopy. 4. 13C-NMR Chiral Recognition

4.

13 C-NMR

Chiral Recognition

C-NMR spectroscopy is an indispensable tool for elucidating the structure of organic 1H-NMR analysis, 13C-NMR is a routine task in organic synthesis and the 13 C-NMR compounds. Together with spectroscopy is an indispensable tool for elucidating the structure of organic compounds. 1 13 C-NMRofisthis study of natural products. The nucleus is hampered by itssynthesis low abundance Together with H-NMR analysis,application a routine task in organic and relative the study of to 1H-, 19F-, and 31P-NMR, but currently with modern equipment (hardware, magnetic fields, probes, 1 natural products. The application of this nucleus is hampered by its low abundance relative to H-, etc.) and new experiments the use of the 13C nucleus has become an attractive alternative [66–68]. 19 F-, and 31 P-NMR, but currently with modern equipment (hardware, magnetic fields, probes, etc.) and Moreover, the use of ab initio calculations to support the interpretation and assignment of 13C-NMR 13 new experiments the use oftool thefor C nucleus hasthe become an attractive alternative [66–68]. Moreover, spectra is an important understanding chiral environment of organic compounds [69]. the use of ab initio et calculations to support the of 13 C-NMR spectra Riguera al. have demonstrated the interpretation applications andand theassignment characteristics that influence the is an 1H-NMR spectroscopy [70]. The same research group has assignment of absolute configuration by important tool for understanding the chiral environment of organic compounds [69]. recentlyet reported the use of 13C-NMR spectroscopy for the and assignment of the absolute that configuration Riguera al. have demonstrated the applications the characteristics influence the of alcohols, amines, carboxylic acids, thiols, cyanohydrins, diols, and amino alcohols [71,72]. group The has 1 assignment of absolute configuration by H-NMR spectroscopy [70]. The same research authors have examined 13 the 13C-NMR data of a collection of chiral samples and the experimental data recently reported the use of C-NMR spectroscopy for the assignment of the absolute configuration of indicated a perfect correlation between the distribution of signs for 13C chemical shifts and 1H-NMR alcohols, amines, carboxylic acids, thiols, cyanohydrins, diols, and amino alcohols [71,72]. The authors of their enantiomers. It is possible to observe that the anisochrony spreads for almost all carbons 13 C-NMR data of a collection of chiral samples have examined the and the experimental data indicated 13 (Scheme 21: carbons marked in blue; CDAs 26 and 27). The C-NMR data follows the same pattern 13 1 1 13 a perfect between theto distribution signs C chemical and H-NMR of their H-NMR, providing a way double checkofthe data.for Furthermore, the shifts C-NMR chemical shifts as correlation can be used a tool fortofully deuterated andanisochrony non-proton-containing organic compounds. enantiomers. It isas possible observe that the spreads for almost all carbons (Scheme 21: 1H-, and 13C-NMR methods 13 C-NMR 1 H-NMR, Heo etin al.blue; have CDAs compared precisiondata of HPLC, to Molecules 2017, 22, 247 13 of 22 carbons marked 26 the andaccuracy 27). Theand follows the same pattern as determine the enantiomeric purity of amino acid derivatives [73]. As shown in Scheme 22, three 13 providing a way to double check the data. Furthermore, the C-NMR chemical shifts can be used as a isomers of the of amino acid (S) derivative withinthe CSA 28positions. in different with of a concentration of carbon peaks (R) and appeared different Theamounts integration each peak was tool for20fully deuterated and non-proton-containing organic compounds. mM. automatically performed by NMR software. The total average accuracy calculated from the carbons was 98% and the total average relative standard deviation was 5.23%. The accuracy and the D OR O reproducibility of the 13C-NMR in comparison to HPLC and 1H-NMR were satisfactory for determining D CD3 O the enantiomeric purity of these compounds. The study was carried out by mixing the (R) and (S) 13

D

OR

D

OR

D H

OH NHR

OR H

OR

SR O

O OCH3

R=

H

OCH3

or

H MPA

9-AMA 26

27

Scheme 21. Prediction of ΔδRS for13C nucleus of chiral organic compounds. Scheme 21. Prediction of ∆δRS for C nucleus of chiral organic compounds. 13

13 C-NMR methods to N Heo et al. have compared the accuracy and precision of HPLC,O 1OH-, and determine the enantiomeric purity of amino acid derivatives [73]. As shown in Scheme 22, three carbon O O H N * peaks of (R) and (S) appeared in different positions. The integration ofH each peak was automatically N N H

O

Chiral Solvating Agent 28

O

A.A. Derivative

High accuracy and precision

Scheme 22. Chiral discrimination of amino acid derivative by 13C {1H} NMR spectroscopy.

D

OR

D

OR

D H

OH NHR

OR H

Molecules 2017, 22, 247

OR

13 of 21

SR

O OCH3 OCH 3 performed by NMR software. The total average accuracy or calculated from the carbons was 98% and R= H H the total average relative standard deviation was 9-AMA 5.23%. The accuracyMPA and the reproducibility of the O

13 C-NMR

in comparison to HPLC and 1 H-NMR for determining the enantiomeric 26 were satisfactory27 purity of these compounds. The study was carried out by mixing the (R) and (S) isomers of the amino acid derivative with Scheme the CSA in different withofachiral concentration of 20 mM. 21. 28 Prediction of ΔδRSamounts for 13C nucleus organic compounds.

O O

O H N H

O

Chiral Solvating Agent 28

N

N * H

N O

O

A.A. Derivative

High accuracy and precision

Scheme 22. Chiral discrimination of amino acid derivative by 13C {1H} NMR spectroscopy.

Scheme 22. Chiral discrimination of amino acid derivative by 13 C {1 H} NMR spectroscopy. For 13C {1H} NMR, quantification of the chiral discrimination is necessary to prevent significant 13 errors theNMR, NMR quantification analysis. Firstly,ofthe ratio should is benecessary improved to due to the significant low For C in {1 H} thesignal/noise chiral discrimination prevent 13C nuclei (1.1%). Another important parameter is the nuclear Overhauser effect that abundance of errors in the NMR analysis. Firstly, the signal/noise ratio should be improved due to the low abundance theAnother proton decoupling. reduce this is effect, inverse gated decoupling of 13 C occurs nucleiduring (1.1%). importantToparameter the the nuclear Overhauser effectpulse thatsequence occurs during and the optimized time acquisition must be used. These and other parameters should be evaluated the proton decoupling. To reduce this effect, the inverse gated decoupling13pulse sequence and the before the NMR analysis to obtain precise multinuclear NMR spectra, mainly for C nuclei. optimized The timedevelopment acquisitionofmust used. These to and other parameters should be evaluated the new be chiral auxiliaries determine the enantiomeric excess or to assignbefore the 13 C nuclei. NMR analysis to obtain precise multinuclear NMR spectra, mainly for absolute configuration by NMR spectroscopy is a difficult and time-consuming task. For this reason, The of newaschiral auxiliaries to determine the enantiomeric excess to assign the development use of natural products a scaffold, either directly or as a starting material to prepare newor chiral agents, configuration is an elegant alternative. on this strategy, Szostakand et al.time-consuming have employed naturally the absolute by NMRBased spectroscopy is a difficult task. For this alkaloid and derivatives CSAs for different functionalities [74]. reason,occurring the use Chinchona of natural29products as a their scaffold, either as directly or as a starting material to prepare Selective modifications of the natural products were performed by tuning their enantiodiscrimination. new chiral agents, is an elegant alternative. Based on this strategy, Szostak et al. have employed The structure of quinine enables modulation, mainly for carbons 9, 22, and 23 (Scheme 23). naturally occurring Chinchona 29 alkaloid and their derivatives as CSAs for different functionalities [74]. Moreover, the presence of a phosphate group supplementing the quinine frame core provides Selective modifications of the natural products were performed by atuning theirammonium enantiodiscrimination. zwitterionic character because it possesses two charged functions, quaternary cation The structure of quinine enables modulation, mainly for carbons 9, 22, and 23 (Scheme 23). Moreover, and a phosphate anion. These characteristics were used with success for enantiodiscrimination of the presence of a phosphate group supplementing quinine frame core provides zwitterionic non-derivatized amino acids (Scheme 23). The chargesthe increase the interaction potency between the 13C-NMR molecules, for two efficient chiralfunctions, discrimination in the DMSO-d 6 solvent byand character becauseallowing it possesses charged a quaternary ammonium cation a phosphate 13C-NMR ranged from 0.025 to 0.145 ppm. spectroscopy. The split signals of anion. These characteristics were used with success for enantiodiscrimination of non-derivatized

amino acids (Scheme 23). The charges increase the interaction potency between the molecules, allowing for efficient chiral discrimination in the DMSO-d6 solvent by 13 C-NMR spectroscopy. The split signals of 13 C-NMR from 0.025 to 0.145 ppm. Moleculesranged 2017, 22, 247 14 of 22

Scheme 23. Natural alkaloid 29 employed as a CSA for chiral discrimination of non-derivatized

Scheme 23. Natural 13alkaloid 29 employed as a CSA for chiral discrimination of non-derivatized amino amino acids by C {1H} NMR spectroscopy. acids by 13 C {1 H} NMR spectroscopy. C {1H} NMR spectroscopy is also a useful tool for discrimination and analysis of complex

13

13mixtures because of the valuable information the carbon spectrum. This strategy C {1 H} NMR spectroscopy is also a usefulcontained tool for indiscrimination and analysis of complex

becomes more mainly when the H-NMR spectra demonstrate broad multiplets and small mixtures because of attractive the valuable information contained in the carbon spectrum. This strategy becomes 1

chemical shift differences between the stereoisomers. As a result, Lankhorst et al. presented a simple 13C-NMR methodology for the discrimination of a complex mixture of α-tocopherol stereoisomers [75]. The traditional methods employed to perform this discrimination, such as gas and liquid chromatography, require multiple steps to prepare the sample and obtain the ideal conditions. In contrast to the 13C-NMR method, the tocopherol mixture and the chiral trifluoroethanol (TFAE) 30

Molecules 2017, 22, 24723. Natural alkaloid 29 employed as a CSA for chiral discrimination of non-derivatized Scheme amino acids by 13C {1H} NMR spectroscopy.

14 of 21

13C {1H} NMR spectroscopy is also aspectra useful demonstrate tool for discrimination and analysis ofsmall complex more attractive mainly when the 1 H-NMR broad multiplets and chemical 13 C-NMR mixtures because of the the stereoisomers. valuable information contained in the carbon spectrum. aThis strategy shift differences between As a result, Lankhorst et al. presented simple becomes more attractive mainly when the 1H-NMR spectra demonstrate broad multiplets and small methodology for the discrimination of a complex mixture of α-tocopherol stereoisomers [75]. The chemical shift differences between the stereoisomers. As a result, Lankhorst et al. presented a simple traditional methods employed to perform this discrimination, such as gas and liquid chromatography, 13C-NMR methodology for the discrimination of a complex mixture of α-tocopherol stereoisomers require[75]. multiple steps prepareemployed the sample and obtain the ideal conditions. Inand contrast The traditionaltomethods to perform this discrimination, such as gas liquid to the 13 C-NMR method, the tocopherol mixture and the chiral trifluoroethanol (TFAE) 30 are dissolved in chromatography, require multiple steps to prepare the sample and obtain the ideal conditions. In 13C-NMR to thethe the stereodiscrimination tocopherol mixture and analysis the chiral (Scheme trifluoroethanol (TFAE) 30 CDCl3contrast to prepare samplemethod, for NMR 24). Furthermore, the 3 to prepare the sample for NMR stereodiscrimination analysis (Scheme 24). are dissolved in CDCl assignment of individual stereoisomers was possible by the synthesis of each tocopherol stereoisomer Furthermore, the assignment of individual stereoisomers was possible synthesis of each from stereochemically pure or enriched building blocks. In this work,by thethe temperature-dependent tocopherol stereoisomer from stereochemically pure or enriched building blocks. In this work, the behavior of the racemate in the presence of TFAE 30 was studied. The temperature ranges affected the temperature-dependent behavior of the racemate in the presence of TFAE 30 was studied. The efficiency of the 13 C chemical shift differences. temperature ranges affected the efficiency of the 13C chemical shift differences.

R1 HO R2

O R3

HO

Tocopherol mixture

CF3 Tocopherols ratio by 13C NMR

30 TFAE

Scheme 24. Discrimination of tocopherols stereoisomers using the CSA 30 (TFAE) by C { 13 Scheme 24. Discrimination of tocopherols stereoisomers using the CSA 30 (TFAE) by H}CNMR {1 H} NMR spectroscopy. spectroscopy. 13

1

Another route to improve the chiral recognition methodologies by NMR spectroscopy is the development new pulse sequences. In this sense, a significant increase inby theNMR number of new NMR is the Another routeofto improve the chiral recognition methodologies spectroscopy experiments has pulse occurred in the lastIndecades. Among these newincrease experiments, shift”ofNMR development of new sequences. this sense, a significant in the“pure number new NMR emerged as a useful tool for chiral studies. This pulse sequence and their derivatives have improved experiments has occurred in the last decades. Among these new experiments, “pure shift” NMR the resolution of 1D and 2D NMR experiments to simplify the typical J(H,H) multiplicity pattern of 1H emerged as a useful tool for chiral studies. This pulse sequence and their derivatives have improved signals to singlets. The Se-NMR experiments make the NMR stereodiscrimination methods simpler 1 the resolution 1D andmainly 2D NMR experiments to simplify the typical JRecently, pattern (H,H) multiplicity and moreofefficient, for complex and overcrowded resonances. Parella et al. have of H signalsexploited to singlets. The Se-NMR experiments stereodiscrimination simpler the application of highly resolvedmake pure the shiftNMR heteronuclear single quantummethods coherence and more efficient, for13complex and overcrowded[76]. resonances. Recently, Parella et al. have (HSQC) spectramainly for 1H- and C-NMR enantiodifferentiation In this study, the authors employed a racemic mixture ofoflactams (R)-PA as ashift CSAheteronuclear to show how the highly resolved 2D HSQC(HSQC) exploited the application highlywith resolved pure single quantum coherence 1 13 spectra for H- and C-NMR enantiodifferentiation [76]. In this study, the authors employed a racemic Molecules 2017, 22, with 247 15 of 22 can be mixture of lactams (R)-PA as a CSA to show how the highly resolved 2D HSQC spectra used to detect and accurately quantify very small anisochrony values (Scheme 25). The values obtained spectra can be used to detect and accurately quantify very small anisochrony values (Scheme 25). from the pure shift HSQC were compared to traditional HSQC and 1D NMR experiments, confirming The values obtained from the pure shift HSQC were compared to traditional HSQC and 1D NMR the advantages of confirming this new pulse sequence.of this new pulse sequence. experiments, the advantages Me N

O Highly Resolved NMR Spectra

Digital Resolution: = +/- 0.5 ppb = +/- 2.6 ppb

1H

13C

HO Pure Shift 2D HSQC NMR

Scheme 25. Highly resolved pure shift HSQC-NMR spectra of lactam.

Scheme 25. Highly resolved pure shift HSQC-NMR spectra of lactam. Stereochemical NMR studies have also received attention based on the development and application of chiral oriented media, such as liquid–crystalline systems [77] and polymer and Stereochemical NMR studies have also received attention based on stretched the development 2H-NMR experiments due to the quadrupolar gels [78]. The main use of these oriented media is for application of chiral oriented media, such as liquid–crystalline systems [77] and stretched polymer moment of the use deuterium nucleus. Chiral oriented media is a flexible approach due that can be applied 2 H-NMR gels [78]. The main of these oriented media is for experiments to the quadrupolar to several organic solvents without the use of solid-state NMR [79]. For this approach, a chiral liquid–crystalline is put into an NMR tube and after addition of an organic solvent and the probe the chiral liquid crystal swells and forms a gel. The gel does not swell isotropically but anisotropically along the glass wall of the tube and the resulting align–angular information relative to the static magnetic field can be obtained. This method is already a common procedure used for biomacromolecules in aqueous solution.

Molecules 2017, 22, 247

15 of 21

moment of the deuterium nucleus. Chiral oriented media is a flexible approach that can be applied to several organic solvents without the use of solid-state NMR [79]. For this approach, a chiral liquid–crystalline is put into an NMR tube and after addition of an organic solvent and the probe the chiral liquid crystal swells and forms a gel. The gel does not swell isotropically but anisotropically along the glass wall of the tube and the resulting align–angular information relative to the static magnetic field can be obtained. This method is already a common procedure used for biomacromolecules in aqueous solution. Based on these features, the chiral recognition by liquid–crystalline systems was extended to other nuclei. The use of 13 C-NMR spectroscopy is a valuable alternative to discriminate chiral environments in oriented media due to a much larger dispersion of chemical shifts. Furthermore, the correlation between 2D NMR experiments for 13 C and 2 H isotopes has the benefit of different pulse sequence as the INEPT-DECANCY and DEPT-DECANCY to improve the resolution and sensitivity. These characteristics were well described by Lesot et al. in a recent review [80]. The use of 19 F-NMR spectroscopy for the measurement of enantiomeric excess was successfully extended to oriented media by Phillips and Sharman [81]. 5.

77 Se-NMR

Chiral Recognition

Selenium organic compounds are related in a broader context of applications [82–84] and selenium is a fundamental component of the living cells of a variety of organisms [85]. Based on these features, the use of 77 Se-NMR spectroscopy emerged as an opportunity for structure and reactivity studies [86]. The application of 77 Se-NMR spectroscopy for chiral recognition has great potential for success due to the characteristics of the selenium nucleus, such as a wide spectral window, reasonably high natural abundance, especially compared with the carbon nucleus, and because the 77 Se isotope is 1 2 and shows no significant nuclear Overhauser effect. Thus, the possibility of developing chiral probes containing selenium has several benefits. In this context, Orlov and Ananikov synthesized a chiral selenide probe as a CDA for determination of enantiomeric purity of alcohols and amines by 77 Se-NMR spectroscopy [87]. The synthesis was performed in two steps achieving 80% yields of CDA 31 (Scheme 26). Selenide chiral probe 31 was successfully applied to enantiodiscrimination of a variety Molecules 2017,amines. 22, 247 16 of 22 of alcohols and OH

SePh

i

ii

SePh

CO2Et

CO2Et

CO2H CDA 31

i = PhSeCN, PBu3, Toluene, 5 oC; ii = HCl/AcOH, 100 oC.

DCC, DCU NMR tube NH2

NH2

OH CF3

F Δδ = 6.06 ppm

Δδ = 1.60 ppm

Δδ = 0.46 ppm

NH2

OH OMe O

Δδ = 2.31 ppm

Δδ = 2.65 ppm

Scheme 26. Chiral discrimination of alcohols and amines employing the selenide CDA 32 as a probe

Scheme 7726. Chiral discrimination of alcohols and amines employing the selenide CDA 32 as a probe by Se {1H} NMR spectroscopy. by 77 Se {1 H} NMR spectroscopy. O

O

i

ii

Ferreira and Gonçalves have carried out to prepare a new chiral Ph OH Ph Ph an inverse OH OH planning procedure SePh NH[88]. Br 2 selenide alcohol as a CDA The article describes the synthesis of chiral selenide alcohol 32 in two CDAwas 32 performed in an NMR steps (Scheme 27). To perform the derivatization, a ”mix and shape” method i = KBr, NaNO2(aq), H2SO4(aq), 0 oC; ii = PhSeSePh, 18-crown-6, NaBH4, THF.

O

O OH

Br

DCC, DMAP NMR tube O

OH Me

OH Ph

CF3 F Δδ = 6.06 ppm

Δδ = 1.60 ppm

Δδ = 0.46 ppm

NH2

OH OMe

Molecules 2017, 22, 247

16 of 21

O Δδ = 2.31 ppm

Δδ = 2.65 ppm

tube, similar to Orlov and Ananikov’s work. and Using selenide alcohol 32, chiral discrimination was Scheme 26. Chiral discrimination of alcohols amines employing the selenide CDA 32 as a probe 1 achieved by for77different carboxylic acids. Se { H} NMR spectroscopy. O Ph

O

i

OH

Ph

ii

OH

NH2

Ph

Br

OH SePh CDA 32

i = KBr, NaNO2(aq), H2SO4(aq), 0 oC; ii = PhSeSePh, 18-crown-6, NaBH4, THF.

O

DCC, DMAP NMR tube

O OH

O OH

Br

OH

Me

Ph Δδ = 40 Hz

Δδ = 22 Hz

Δδ = 51 Hz

Scheme 27. Chiral discrimination of carboxylic acids employing the selenide CDA 33 as a probe by

Scheme 27. Chiral discrimination of carboxylic acids employing the selenide CDA 33 as a probe by 77 {1H} NMR spectroscopy. 77 Se {1Se H} NMR spectroscopy.

Recently, Silva et al. have demonstrated the application of a three-component reaction for chiral discrimination containing thethe selenium atom of bya77three-component Se-NMR spectroscopy [89]. for Thischiral Recently, Silvaof et amines al. have33demonstrated application reaction 77 simple andof inexpensive derivatizing method was successfully employed for a variety of organic discrimination amines 33chiral containing the selenium atom by Se-NMR spectroscopy [89]. This simple 77Se-NMR. In this protocol, the selenide amine reacts with 2-formylphenylboronic acid compounds bychiral and inexpensive derivatizing method was successfully employed for a variety of organic and the by active (+)-BINOL theprotocol, presence the of molecular sieves for 10 min 28). The 1H-NMR acid 77 Se-NMR. compounds In in this selenide amine reacts with(Scheme 2-formylphenylboronic analyses were dependent on the concentration. In highly concentrated media the signals were and the active (+)-BINOL in the presence of molecular sieves for 10 min (Scheme 28). 77The 1 H-NMR broader. It is possible that a self-aggregation interaction occurred during the analysis. For Se-NMR analyses were dependent on the concentration. In highly concentrated media the signals were broader. spectra, this concentration effect was not observed. Moreover, an HPLC analysis was performed for 77 It is possible that aevaluation self-aggregation interaction occurred during comparative of the 77Se-NMR results (Scheme 28). the analysis. For Se-NMR spectra, this concentration was not observed. Moreover, an HPLC analysis was comparative Muraieffect has performed the synthesis of the phosphoroselenoic acid 34 performed as a double for check chiral 77 77 31 evaluation of the Se-NMR results (Scheme 28). discrimination protocol for amines and alcohols by Seand P-NMR spectroscopy [90]. The CDA Molecules 2017, 22, 247 17 of 22 34 was synthesized in a one-pot procedure achieving 94% yields (Scheme 29). All CDAs obtained are stable under air and are purified chromatography. The absolute configuration of the NH2 by column O CDA 34 was confirmed bySeX-ray analysis. The CDA 34 showed high reactivity for primary amines + OH + and alcohols. When tertiary alcohols were employed the reaction did not proceed. Moreover, most OH OH B of the diastereoisomers formed by this protocolOH were separated by simple recrystallization. Recently, Racemic - 33 Murai and Itoh have applied these CDAsBoronic derivatives for the 77Se-(+)-BINOL and 31P-NMR discrimination of Acid remote chirality of primary alcohols [91]. CDCl3 4A MS / 25oC

Se N B O

Se N

+

O

B O

O

(50.4 : 49.6) by Chiral GC (55.2 : 44.8) by 77Se NMR

Scheme 28. Three-component reaction for chiral discrimination of selenide amines by 77Se {1H} NMR

Scheme 28. Three-component reaction for chiral discrimination of selenide amines by 77 Se {1 H} NMR spectroscopy. spectroscopy. 1) Et3N, 0 oC

Murai has performed the synthesis 2) (+)-BINOL of the phosphoroselenoic acid 34 as a double check chiral Se O 3) Se, Toluene, Reflux. P discrimination protocol for amines and alcohols by 77 Se- and 31 P-NMR spectroscopy [90]. The CDA 34 PCl3 O Cl was synthesized in a one-pot procedure achieving 94% yields (Scheme 29). All CDAs obtained are CDA - 34 stable under air and are purified by column chromatography. The absolute configuration of the CDA 34 was confirmed by X-ray analysis. The CDA 34 showed high reactivity for primary amines and 1) Toluene, Reflux. 2) Alcohols, 3 h.

Se O P O O

1) Toluene, Reflux. 2) Amines, 2-18 h.

4A MS / 25oC

Se N

Molecules 2017, 22, 247 B O

Se N

+

O

B O

O

(50.4 : 49.6) by Chiral GC (55.2 : 44.8) by 77Se NMR

17 of 21

alcohols. When tertiary alcohols were employed the reaction did not proceed. Moreover, most of the diastereoisomers formed by this protocol were separated by simple recrystallization. Recently, Murai and Itoh have applied these CDAs derivatives for the 77 Se- and 31 P-NMR discrimination of remote Scheme 28. Three-component reaction for chiral discrimination of selenide amines by 77Se {1H} NMR chirality ofspectroscopy. primary alcohols [91].

PCl3

1) Et3N, 0 oC 2) (+)-BINOL 3) Se, Toluene, Reflux.

Se O P O Cl CDA - 34

1) Toluene, Reflux. 2) Alcohols, 3 h.

Se O P O O R3 *

R2

1) Toluene, Reflux. 2) Amines, 2-18 h.

Se O P O NH R1 *

R

Scheme 29. Phosphoroselenoic acid derivatives for chiral discrimination of amines and alcohols by

Scheme 29. Phosphoroselenoic acid derivatives for chiral discrimination of amines and alcohols by 77Se {1H} and 31P {1H} NMR spectroscopy. 77 Se {1 H} and 31 P {1 H} NMR spectroscopy. 6. Conclusions

6. Conclusions

Numerous efficient and versatile chiral derivatizing and solvating agents have emerged in recent years. These compounds present different chiral recognition abilities sincehave the structure and Numerous efficient and versatile chiral derivatizing and solvating agents emerged in recent conditions can be tuned to improve the molecular interactions. With the expectation of expanding years. These compounds present different chiral recognition abilities since the structure and conditions the chiral probes, using multinuclear NMR spectroscopy provides new possibilities for chiral studies can be tuned to improve the molecular interactions. With the19 expectation of expanding the chiral and the elucidation of their chiral recognition mechanisms. F, 31P, 13C, and 77Se nuclei have probes, using multinuclear NMR spectroscopy provides new possibilities for chiral studies demonstrated efficient results based on their nuclear properties and their incorporation into organicand the 19 F, 31 P, 13 C, and 77 Se nuclei have demonstrated elucidation of their chiral recognition mechanisms. compounds through organic synthesis procedures. efficient results based on their nuclear properties and their incorporation intoand organic compounds Although the use of multinuclear NMR spectroscopy for chiral discrimination assignment of the absolute configuration is attractive, we need to be aware that the reliability of the multinuclear through organic synthesis procedures. NMR analysis should be evaluatedNMR for the respective application due to the different nuclear Although the use of multinuclear spectroscopy for chiral discrimination and assignment of properties and general behavior of each element.

the absolute configuration is attractive, we need to be aware that the reliability of the multinuclear NMR analysis should be evaluated for the respective application due to the different nuclear properties and general behavior of each element. In order to spread the use of multinuclear NMR, new pulse sequence and experimental conditions were developed to improve the time-consuming and accuracy of the NMR spectra. Furthermore, the information obtained from these new experimental procedures can be employed to complement the traditional results and/or used for specific purposes. Acknowledgments: The author thanks the FAPESP 2014/23362-8 project for financial support and the CEM-UFABC for NMR equipment. Conflicts of Interest: The author declares no conflict of interest.

References 1. 2. 3.

Sheldon, R.A. Chirotechnology: Industrial Synthesis of Optically Active Compounds; CRC Press: Boca Raton, FL, USA, 1993. Lurie-Luke, E. Product and technology innovation: What can biomimicry inspire? Biotechnol. Adv. 2014, 32, 1494–1505. [CrossRef] [PubMed] You, L.; Zha, D.; Anslyn, E.V. Recent Advances in Supramolecular Analytical Chemistry Using Optical Sensing. Chem. Rev. 2015, 105, 7840–7892. [CrossRef] [PubMed]

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4. 5. 6. 7. 8.

9.

10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

20. 21. 22. 23.

24. 25. 26.

18 of 21

Lin, G.Q.; Li, Y.M.; Chan, A.S.C. Principles and Applications of Asymmetric Synthesis; John Wiley & Sons: Oxford, UK, 2001. Blaser, H.U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions; Wiley-VCG Verlag GmbH & KgaA: Weinheim, Germany, 2004. Izake, E.L. Chiral Discrimination and enantioselective analysis of drugs: An overview. J. Pharm. Sci. 2007, 96, 1659–1676. [CrossRef] [PubMed] Shen, J.; Okamoto, Y. Efficient Separation of Enantiomers Using Stereoregular Chiral Polymers. Chem. Rev. 2016, 116, 1094–1138. [CrossRef] [PubMed] Harada, N. HPLC Separation of Diastereomers: Chiral Molecular Tools Useful for Preparation of Enantiopure Compounds and Simultaneous Determination of Their Absolute Configurations. Molecules 2016, 21, 1328. [CrossRef] [PubMed] Ilisz, I.; Berkecz, R.; Peter, A. Application of chiral derivatizing agents in the high-performance liquid chromatographic separation of amino acid enantiomers. J. Pharm. Biomed. Anal. 2008, 47, 1–15. [CrossRef] [PubMed] Okamoto, Y.; Ikai, T. Chiral HPLC for efficient resolution of enantiomers. Chem. Soc. Rev. 2008, 37, 2593–2608. [CrossRef] [PubMed] West, C. Enantioselective Separations with Supercritical Fluids—Review. Curr. Anal. Chem. 2014, 52, 99–120. [CrossRef] Polavarapu, P.L. Determination of the Absolute Configurations of Chiral Drugs Using Chiroptical Spectroscopy. Molecules 2016, 21, 1056. [CrossRef] [PubMed] Wenzel, T.J. Discrimination of Chiral Compounds Using NMR Spectroscopy; John Wiley & Sons: Weinheim, Germany, 2007. Wenzel, T.J.; Chisholm, C.D. Using NMR spectroscopy methods to determine enantiomeric purity and assign absolute stereochemistry. Prog. NMR Spectrosc. 2011, 59, 1–63. [CrossRef] [PubMed] Bian, G.; Yang, S.; Huang, H.; Zong, L.; Song, H.; Fan, H.; Sun, X. Chirality sensing of tertiary alcohols by a novel strong hydrogen-bonding donor—Selenourea. Chem. Sci. 2016, 7, 932–938. [CrossRef] Seo, M.-S.; Kim, H. 1 H-NMR Chiral Analysis of Charged Molecules via Ion Pairing with Aluminum Complexes. J. Am. Chem. Soc. 2015, 137, 14190–14195. [CrossRef] [PubMed] Bian, G.; Yang, S.; Huang, H.; Zong, H.; Song, L. A bisthiourea-based 1 H-NMR chiral sensor for chiral discrimination of a variety of chiral compounds. Sens. Actuators B 2016, 231, 129–134. [CrossRef] Lakshmipriya, A.; Chaudhari, S.R.; Suryaprakash, N. Enantio-differentiation of molecules with diverse functionalities using a single probe. Chem. Commun. 2015, 51, 13492–13495. [CrossRef] [PubMed] Bian, G.; Fan, H.; Huang, H.; Yang, S.; Zong, H.; Song, L.; Yang, G. Highly Effective Configurational Assignment Using Bisthioureas as Chiral Solvating Agents in the Presence of DABCO. Org. Lett. 2015, 17, 1369–1372. [CrossRef] [PubMed] Wolf, G.; Cook, A.M.; Dannatt, J.E. Enantiodifferentiation of multifunctional tertiary alcohols by NMR spectroscopy with a Whelk-O type chiral solvating agent. Tetrahedron Asymmetry 2014, 25, 163–169. [CrossRef] Bian, G.; Fan, H.; Yang, S.; Yue, H.; Huang, H.; Zong, H.; Song, L. A Chiral Bisthiourea as a Chiral Solvating Agent for Carboxylic Acids in the Presence of DMAP. J. Org. Chem. 2013, 78, 9137–9142. [CrossRef] [PubMed] Wenzel, T.J.; Chisholm, C.D. Assignment of absolute configuration using chiral reagents and NMR spectroscopy. Chirality 2011, 23, 190–214. [CrossRef] [PubMed] Gil, R.R.; Gayathri, C.; Tsarevsky, N.V.; Matyjaszewski, K. Stretched Poly(methyl methaacrylate) Gel Aligns Small Organic Molecules in Chloroform. Stereochemical Analysis and Diastereotopic Proton NMR Assignment in Ludartin Using Residual Couplings and 3 J Coupling Constant Analysis. J. Org. Chem. 2008, 73, 840–848. [CrossRef] [PubMed] Dolbier, W.R., Jr. Guide to Fluorine NMR for Organic Chemists; John Wiley & Sons: Somerset, NJ, USA, 2009. Cobb, S.L.; Murphy, C.D. 19 F-NMR applications in chemical biology. J. Fluorine Chem. 2009, 130, 132–143. [CrossRef] Apparu, M.; Tiba, Y.B.; Léo, P.M.; Hamman, S.; Coulombeau, C. Determination of the enantiomeric purity and the configuration of β-aminoalcohols using (R)-2-fluorophnylacetic acid (AFPA) and fluorine-19 NMR: Application to β-blockers. Tetrahedron Asymmetry 2000, 11, 2885–2898. [CrossRef]

Molecules 2017, 22, 247

27.

28. 29.

30. 31. 32. 33.

34. 35. 36.

37. 38. 39.

40. 41. 42.

43. 44. 45. 46. 47. 48. 49. 50.

19 of 21

Pomares, M.; Sánchez-Ferrando, F.; Alvarez-Larena, A.; Piniella, J.F. Preparation and Structural Study of the Enantiomers of α,α’-Bis(trifluoromethyl)-9-10-anthracenedimethanol and Its Perdeuterated Isotopomer, Highly Effective Chiral Solvating Agents. J. Org. Chem. 2002, 67, 753–758. [CrossRef] [PubMed] Nemes, A.; Csóka, T.; Béni, S.; Farkas, V.; Rábai, J.; Szabó, D. Chiral Recognition Studies of α-(Nonafluoroterc-butoxy)carboxylic Acids by NMR Spectroscopy. J. Org. Chem. 2015, 80, 6267–6274. [CrossRef] [PubMed] Takahashi, T.; Kameda, H.; Kamei, T.; Koyanagi, J.; Pichierri, F.; Omata, K.; Ishizaki, M.; Nakamura, H. FICA, a new derivatizing agent for determining the absolute configuration of secondary alcohols by 19 Fand 1 H-NMR spectroscopies. Tetrahedron Asymmetry 2013, 24, 1001–1009. [CrossRef] Jayachandra, R.; Reddy, S.R. A remarkable chiral recognition of racemic Mosher’s acid salt by naturally derived chiral ionic liquids using 19 F-NMR spectroscopy. RSC Adv. 2016, 6, 39758–39761. [CrossRef] Huang, H.; Bian, G.; Zong, H.; Wang, Y.; Yang, S.; Yue, H.; Song, L.; Fan, H. Chiral Sensor for Enantiodiscrimination of Varied Acids. Org. Lett. 2016, 18, 2524–2527. [CrossRef] [PubMed] Swager, T.M.; Zhao, Y. Simultaneous Chirality Sensing of Multiple Amines by 19 F-NMR. J. Am. Chem. Soc. 2015, 137, 3221–3224. Yeste, S.L.; Powell, M.E.; Bull, S.D.; James, T.D. Simple Chiral Derivatization Protocols for 1 H-NMR and 19 F-NMR Spectroscopic Analysis of the Enantiopurity of Chiral Diols. J. Org. Chem. 2009, 74, 427–430. [CrossRef] [PubMed] Chaudhari, S.R.; Suryaprakash, N. Simple and efficient methods for discrimination of chiral diacids and chiral alpha-methyl amines. Org. Biomol. Chem. 2012, 10, 6410–6419. [CrossRef] [PubMed] Zhao, Y.; Wager, T.M. Detection and Differentiation of Neutral Organic Compounds by 19 F-NMR with a Tungsten Calix[4]arene Imido Complex. J. Am. Chem. Soc. 2013, 135, 18770–18773. [CrossRef] [PubMed] Axthelm, J.; Görls, H.; Schubert, U.S.; Schiller, A. Fluorinated Boronic Acid-Appended Bipyridinium Salts for Diol Recognition and Discrimination via 19 F-NMR Barcodes. J. Am. Chem. Soc. 2015, 137, 15402–15405. [CrossRef] [PubMed] Gan, H.; Oliver, A.G.; Smith, B.D. Fluorine NMR reporter for phosphate anions. Chem. Commun. 2013, 49, 5070–5072. [CrossRef] [PubMed] Wu, X.; Li, Z.; Chen, X.X.; Fossey, J.S.; James, T.D.; Jiang, Y.-B. Selective Sensing of sccharides using simple boronic acids and their aggregates. Chem. Soc. Rev. 2013, 42, 8032–8048. [CrossRef] [PubMed] Dolsophon, K.; Soponpong, J.; Kornsakulkarn, J.; Thongpanchang, C.; Prabpai, S.; Kongsaeree, P.; Thongpanchang, T. F-THENA: A chiral derivatizing agent for the determination of the absolute configuration of secondary aromatic alcohols with a self-validating system. Org. Biomol. Chem. 2016, 14, 11002–11012. [CrossRef] [PubMed] Katritzky, A.R.; Mohapatra, P.P.; Fedoseyenko, D.; Duncton, M.; Steel, P.J. 1-Benzotriazol-1-yl-3,3,3-trifluoro-2methoxy-2-phenylpropan-1-ones: Mosher-Bt Reagents. J. Org. Chem. 2007, 72, 4268–4271. [CrossRef] [PubMed] Ichikawa, A.; Ono, H.; Mikata, Y. Characteristic Conformation of Mosher’s Amide Elucidated Using the Cambridge Structural Database. Molecules 2015, 20, 12880–12900. [CrossRef] [PubMed] Gotor, V.; Cerrada, S.G.; Mendiola, J.; Frutos, O.; Collado, I.; Fernández, V.G.; Lavandera, I.; Busto, E.; Mata, M.R.; Paul, C.E. Transaminases Applied to the Synthesis of High Added-Value Enantiopure Amines. Org. Process. Res. Dev. 2014, 18, 788–792. Nestl, B.M.; Hammer, S.C.; Nebel, B.A.; Hauer, B. New generation of biocatalysts for organic synthesis. Angew. Chem. Int. Ed. 2014, 53, 3070–3095. [CrossRef] [PubMed] Rao, R.N.; Santhakumar, K. Cyclodextrin assisted enantiomeric recognition of emtricitabine by 19 F-NMR spectroscopy. New J. Chem. 2016, 40, 8408–8417. Karl, D.M. Aquatic ecology. Phophorus, the staff of life. Nature 2000, 406, 31–33. Kochian, L.V. Plant nutrition: Rooting for more phosphorus. Nature 2012, 488, 466–467. [CrossRef] [PubMed] Emsley, J. The 13th Element: The Sordid Tale of Murder, Fire and Phosphorus; Wiley-VCH: New York, NY, USA, 2000; pp. 65–101. Kühl, O. Phosphorus-31 NMR Spectroscopy; Springer: Berlin, Germany, 2008. Szyszkowiak, J.; Majewska, P. Determination of absolute configuration by 31 P-NMR. Tetrahedron Asymmetry 2014, 25, 103–112. [CrossRef] Hammerschmidt, F.; Li, Y.F. Determination of absolute configuration of α-hydroxyphosphonates by 31 P-NMR spectroscopy. Tetrahedron 1994, 50, 10253–10264. [CrossRef]

Molecules 2017, 22, 247

51. 52.

53.

54. 55.

56.

57. 58.

59. 60. 61.

62.

63. 64.

65.

66.

67. 68. 69.

70.

20 of 21

Seco, J.M.; Quiñoá, E.; Riguera, R. Assignment of the Absolute Configuration of Polyfunctional Compounds by NMR Using Chiral Derivatizing Agents. Chem. Rev. 2012, 112, 4603–4641. [CrossRef] [PubMed] Li, Y.; Raushel, F.M. Differentiation of chiral phosphorus enantiomers by 31 P- and 1 H-NMR spectroscopy using amino acid derivatives as chemical solvating agents. Tetrahedron Asymmetry 2007, 18, 1391–1397. [CrossRef] [PubMed] Mastranzo, V.M.; Quintero, L.; Parrodi, C.A. Determination of the enantiomeric excess of chiral carboxylic acids by 31 P-NMR with phosphorylated derivatizing agents from C2 -symmetrical diamines containing the (S)-α-phenylethyl group. Chirality 2007, 19, 503–507. [CrossRef] [PubMed] Reiner, T.; Naraschewski, F.N.; Eppinger, J. 31 P-NMR assays for rapid determination of enantiomeric excess in catalytic hydrosilylations and transfer hydrogenations. Tetrahedron Asymmetry 2009, 20, 362–367. [CrossRef] Demchuk, O.M.; Swierczynska, W.; Pietrusiewicz, K.M.; Woznica, M.; Wojcik, D.; Frelek, J. A convenient application of the NMR and CD methodologies for determination of enantiomeric ratio and absolute configuration of chiral atropoisomeric phosphine oxides. Tetrahedron Asymmetry 2008, 19, 2339–2345. [CrossRef] Fauconnot, L.; Nugier-Chauvin, C.; Noiret, N. Enantiomeric excess determination of some chiral sulfoxides by NMR: Use of (S)-Ibuprofen® and (S)-Naproxen® as shift reagents. Tetrahedron Lett. 1997, 38, 7875–7878. [CrossRef] Wang, F.; Wang, Y.; Polavarapu, P.L.; Li, T.; Drabowicz, J.; Pietrosiewicz, K.M.; Zygo, K. Absolute Configuration of tert-Butyl-1-(2-methylnaphthyl)phosphine Oxide. J. Org. Chem. 2002, 67, 6539–6541. [CrossRef] [PubMed] Kannapan, J.; Jain, N.; Bedekar, A.V. Synthesis and applications of exo N-((1R,2R,4R)-1,7,7trimethylbicyclo[2.2.1]heptan-2-yl)benzamides as NMR solvating agents for the chiral discrimination of 1,1’-binaphthyl-2,2’-diylhydrogenphosphates and α-substituted acids. Tetrahedron Asymmetry 2015, 26, 1102–1107. [CrossRef] Pitchen, P.; Duñach, E.; Juge, S.; Kagan, H.B. An efficient asymmetric oxidation of sulfides to sulfoxides. J. Am. Chem. Soc. 1984, 106, 8188–8193. [CrossRef] Jain, N.; Patel, R.B.; Bedekar, A.V. Modified Kagan’s amide: Synthesis and applications as a chiral solvating agent for hydrogen-bonding based chiral discrimination in NMR. RSC Adv. 2015, 5, 45943–45955. [CrossRef] Khanvilkar, A.N.; Bedekar, A.V. Synthesis and characterization of chiral aza-macrocycles and study of their enantiomer recognition ability for organo-phosphoric acid and phosphoric acid derivatives by 31 P-NMR and fluorescence spectroscopy. Org. Biomol. Chem. 2016, 14, 2742–2748. [CrossRef] [PubMed] Nagorny, P.; Tay, J.H. 31 P-NMR Based Method for Determining Enantiopurity of Chiral Phosphoric Acids and Its Application to the BINOL- and H8-BINOL-Based Chiral Phosphoric Acid Thermal Racemization Studies. Synlett 2016, 27, 551–554. [CrossRef] Pregosin, P.S. NMR in Organometallic Chemistry; Wiley-VCH: Weinheim, Germany, 2012. Gorunova, O.N.; Novitskiy, I.M.; Livantsov, M.V.; Grishin, Y.K.; Kochetkov, K.A.; Dunina, V.V. Enantiopurity determination of CN-palladacycles using 31 P-NMR spectroscopy with (1R,2S,5R)-menthyloxydiphenylphosphine as chiral derivatizing agent. J. Organometal. Chem. 2015, 783, 96–104. [CrossRef] Gorunova, O.N.; Novitskiy, I.M.; Gloriozov, I.P.; Grishin, Y.K.; Roznyatovsky, V.A.; Khrustalev, V.N.; Kochetkov, K.A.; Dunina, V.V. Determination of the Absolute Configuration of CN-Pallacycles by 31 P{1 H} NMR Spectroscopy Using (1R,2S,5R)-Menthyloxydiphenylphosphine as the Chiral Derivatizing Agent: Efficient Chirality Transfer in Phosphinite Adducts. Organometallics 2016, 35, 75–90. [CrossRef] Martin, G.E.; Hilton, B.D.; Blinov, K.A. HSQC-1,1-ADEQUATE and HSQC-1,n-ADEQUATE: Enhanced Methods for Establishing Adjacent and Long-Range 13 C-13 C Connectivity Networks. J. Nat. Prod. 2011, 74, 2400–2407. [CrossRef] [PubMed] Balakshin, M.Y.; Capanema, E.A. Comprehensive structural analysis of biorefinery lignins with a quantitative 13 C-NMR approach. RSC Adv. 2015, 5, 87187–87199. [CrossRef] Verma, R.P.; Hansch, C. Use of 13 C-NMR Chemical Shift as QSAR/QSPR Descriptor. Chem. Rev. 2011, 111, 2865–2899. [CrossRef] [PubMed] Wiitala, K.W.; Cramer, C.J.; Hoye, T.R. Comparison of various density functional methods for distinguishing stereoisomers based on computed 1 H- or 13 C-NMR chemical shifts using diastereomeric penam β-lactams as a test set. Magn. Reson. Chem. 2007, 45, 819–829. [CrossRef] [PubMed] Seco, J.M.; Quiñoá, E.; Riguera, R. The Assignment of Absolute Configuration by NMR. Chem. Rev. 2004, 104, 17–117. [CrossRef]

Molecules 2017, 22, 247

71. 72. 73.

74. 75.

76.

77.

78. 79. 80.

81. 82. 83. 84.

85. 86.

87.

88. 89. 90. 91.

21 of 21

Louzao, I.; Seco, J.M.; Riguera, R. 13 C-NMR as a general tool for the assignment of absolute configuration. Chem. Commun. 2010, 46, 7903–7905. [CrossRef] [PubMed] Louzao, I.; Seco, J.M.; Quiñoá, E.; Riguera, R. The assignment of absolute configuration of cyanohydrins by NMR. Chem. Commun. 2006, 1422–1424. [CrossRef] [PubMed] Heo, K.S.; Hyun, M.H.; Cho, Y.J.; Ryoo, J.J. Determination of optical purity of 3,5-dimethoxybenzoyl-leucine diethylamide by chiral chromatography and 1 H- and 13 C-NMR spectroscopy. Chirality 2011, 23, 281–286. [CrossRef] [PubMed] Szostak, R.E.; Górecki, L.; Berlicki, L.; Slepokura, K.; Mucha, A. Zwitterionic Phosphorylated Quinines as Chiral Solvating Agents for NMR Spectroscopy. Chirality 2015, 27, 752–760. [CrossRef] [PubMed] Lankhorst, P.P.; Netscher, T.; Duchateau, A.L.L. A Simple 13 C-NMR Method for the Discrimination of Complex Mixtures of Stereoisomers: All Eight Stereoisomers of α-Tocopherol Resolved. Chirality 2015, 27, 850–855. [CrossRef] [PubMed] Pérez-Trujillo, M.; Castãnar, L.; Monteagudo, E.; Kuhn, L.T.; Nolis, P.; Virgili, A.; Williamson, R.T.; Parella, T. Simultaneous 1 H- and 13 C-NMR enantiodifferentiation from highly-resolved pure shift HSQC spectra. Chem. Commun. 2014, 50, 10214–10217. [CrossRef] [PubMed] Lesot, P.; Lofan, O.; Aroulanda, C.; Dong, R.Y. 2 H-NMR Studies on Two-Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute-Fiber Affinites. Chem. Eur. J. 2008, 14, 4082–4092. [CrossRef] [PubMed] Kobzar, K.; Kessler, H.; Luy, B. Stretched Gelatin Gels as Chiral Alignment Media for the Discrimination of Enantiomers by NMR Spectroscopy. Angew. Chem. Int. Ed. 2005, 44, 3145–3147. [CrossRef] [PubMed] Gil, R.R. Constitutional, Configurational, and Conformational Analysis of Small Organic Molecules on the Basis of NMR Residual Dipolar Couplings. Angew. Chem. Int. Ed. 2011, 50, 7222–7224. [CrossRef] [PubMed] Lesot, P.; Lafon, O.; Berdagué, P. Correlation 2D-NMR experiments involving both 13 C and 2 H isotopes in oriented media: Methodological developments and analytical applications. Magn. Reson. Chem. 2014, 52, 595–613. [CrossRef] [PubMed] Phillips, A.R.; Sharman, G.J. The measurement of high enantiomeric excess in chiral liquid crystals using 19 F-NMR and exchangeable protons in 2 H-NMR. Chem. Commun. 2004, 11, 1330–1331. [CrossRef] [PubMed] Perin, G.; Lenardão, E.J.; Jacob, R.G.; Panatieri, R.B. Synthesis of Vinyl Selenides. Chem. Rev. 2009, 109, 1277–1301. [CrossRef] [PubMed] Back, T.G. Organoselenium Chemistry: A Practical Approach; Oxford University Press: Oxford, UK, 1999. Santi, C.; Jacob, R.G.; Monti, B.; Bagnoli, L.; Sancineto, L.; Lenardão, E.J. Water and Aqueous Mixtures as Convenient Alternative Media for Organoselenium Chemistry. Molecules 2016, 21, 1482. [CrossRef] [PubMed] Araie, H.; Shiraiwa, Y. Selenium Utilization Strategy by Microalgae. Molecules 2009, 14, 4880–4891. [CrossRef] [PubMed] Bayse, C.A.; Brumaghim, J.L. Biochalcogen Chemistry: The Biological Chemistry of Sulfur, Selenium and Tellurium. In Proceedings of the ACS Symposium Series 1152, Biochalcogen Chemistry: The Biological Chemistry of Sulfur, Selenium, and Tellurium, Clemson, SC, USA, 1 January 2013. Orlov, N.V.; Ananikov, V.P. First principles design of derivatizing agent for direct determination of enantiomeric purity of chiral alcohols and amines by NMR spectroscopy. Chem. Commun. 2010, 46, 3212–3214. [CrossRef] [PubMed] Ferreira, J.G.; Gonçalves, S.M.C. Enantiomeric Excess Detection with (S)-3-Phenyl-2-(selenophenyl)propan1-ol Derivatizing Agent via Mix and Shake 77 Se-NMR. J. Braz. Chem. Soc. 2010, 21, 2023–2026. [CrossRef] Oliveira, S.S.; Cunha, R.L.O.R.; Silva, M.S. 77 Se- and 125 Te-NMR spectroscopy for enantiopurity determination of chalcogen amines. Tetrahedron Lett. 2016, 57, 4556–4559. [CrossRef] Murai, T. Phosphoroselenoic Acid Derivatives Bearing a Binaphthyl Group as a Chiral Molecular Tool. Phosphorus Sulfur Silicon 2008, 889–896. [CrossRef] Murai, T.; Itoh, H. Discrimination of remote chirality of primary alcohols using 1,10 -binaphthyl-2,20 -DIYL phosphoroselenoyl chlorides as a chiral molecular tool. Phosphorus Sulfur Silicon 2016, 191, 163–173. [CrossRef] © 2017 by the author; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).