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ArticleSeptember 5, 2022

Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid Derivatives
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Alessandra Recchimurzo
Alessandra Recchimurzo
Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy
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Federica Balzano*
Federica Balzano
Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy
*Email: [email protected]
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https://orcid.org/0000-0001-6916-321X
Gloria Uccello Barretta*
Gloria Uccello Barretta
Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy
*Email: [email protected]
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Luca Gherardi
Luca Gherardi
Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy
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The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2022, 87, 18, 11968–11978

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https://doi.org/10.1021/acs.joc.2c00814

Published September 5, 2022

CC-BY 4.0 .

Abstract

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A C2-symmetrical bis-thiourea chiral solvating agent (CSA), TFTDA, for NMR spectroscopy has been obtained by reacting (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3,5-bis(trifluoromethyl)phenyl isothiocyanate. TFTDA shows remarkable propensity to enantiodiscriminate N-trifluoroacetyl (N-TFA) and N-acetyl (N-Ac) derivatives of amino acids with free carboxyl functions, with the co-presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the third achiral additive, which is needed for substrate solubilization. TFTDA shows enhanced enantiodiscriminating efficiency in comparison with the corresponding monomeric counterpart, TFTMA, pointing out cooperativity between its two symmetrical entities. A wide range of amino acid derivatives have been efficiently enantiodiscriminated in CDCl₃, with high enantioresolution quotients, which guarantee high quality in applications devoted to the quantification of enantiomers. High enantiodiscriminating efficiency is maintained also in diluted 5 mM conditions or in the presence of sub-stoichiometric amounts of CSA (0.3 equiv). The role of phenolic hydroxyls in the DABCO-mediated interaction mechanism between TFTDA and the two enantiomeric substrates has been pointed out by means of diffusion-ordered spectroscopy (DOSY) and rotating frame Overhauser effect spectroscopy (ROESY) experiments. A conformational model for both the CSA and its diastereomeric solvates formed with the two enantiomers of N-acetyl leucine has also been conceived on the basis of ROE data in order to give a chiral discrimination rationale.

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Subjects

Introduction

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Crucial role of chirality in life sciences has raised awareness of the scientific community to issues related to the availability of accurate, reproducible, and direct methods for the quantification of enantiomeric excesses (ees), among which chiral chromatography (1−4) and NMR (5−11) spectroscopy have attained huge popularity.

NMR methods of differentiation of enantiomeric mixtures are based on the use of suitable chiral auxiliaries able to induce anisochrony of enantiomer resonances by transferring them into a diastereomeric environment. Three main classes of chiral auxiliaries for NMR spectroscopy have been developed which are named chiral derivatizing agents (CDAs), chiral solvating agents (CSAs), and chiral lanthanide shift reagents (CLSRs). CSAs are particularly attractive from a practical point of view since any chemical derivatization is not required like in the case of CDAs, and they are simply mixed to the enantiomeric mixture under analysis directly into the NMR tube. CSAs are diamagnetic and hence do not produce unwanted line-broadening effects, like in the case of CLSRs, which can be detrimental for the accurate quantification of enantiomer resonances.

Several classes of CSAs have been proposed spanning from low molecular weight organic compounds to natural products or highly preorganized cyclic and acyclic structures. (6−10) In the design of new CSAs for enantiomer differentiation by NMR, some fundamental requirements must be taken into consideration, that is, the presence of aromatic moieties able to exert, on the enantiomeric substrates, anisotropic effects and/or π–π interactions, leading to improved chemical shift differentiation, and the presence of hydrogen-bond donor/acceptor functions in order to stabilize the diastereomeric pairs formed in solution. Chiral thioureas, the potential of which as organocatalysts has been successfully demonstrated, (12−16) have emerged also as CSAs (17−31) for NMR endowed with remarkable enantiodiscriminating efficiency mainly due to their improved hydrogen-bond donating ability in comparison with the corresponding urea systems. Three main synthetic schemes have been followed in the design of bis-thiourea CSAs. The production of C2-symmetrical systems by reacting inexpensive chiral amines with thiophosgene, (26,28,30,31) linking achiral diamines like 1,8-diaminoantracene to α-amino acid esters via thiourea groups, (24,26) or the reaction of chiral diamines, mainly (1S,2S)-/(1R,2R)-1,2-diphenylethane-1,2-diamine (21,23,25,27) or (1S,2S)-1,2-diaminocyclohexane, (17) with 2 equiv of isothiocyanate has led to efficient CSAs. Effectiveness of the 3,5-bis(trifluoromethyl)phenyl moiety in boosting enantiodiscriminating efficiency both of amide and urea CSAs has also been widely proved. (23,25,27,32)

Interestingly, achiral additives like 4-dimethylaminopyridine (DMAP) or 1,4-diazabicyclo[2.2.2]octane (DABCO) play an active role in the chiral discrimination pathways, bridging together the CSA and enantiomers. (18−21,23,25,27)

2-[(1R)-1-Aminoethyl]phenol (MA) and (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine (DA) have been recently proposed (18,19) as new chiral platforms for the production of mono- and bis-thiourea CSAs, with the idea of expanding the network of hydrogen bonds available for the interaction between the CSA and enantiomeric pairs, in virtue of the presence of acid phenolic hydroxyls. The reaction of MA and DA with benzoyl isothiocyanate (18,19) led to the thiourea derivatives BTMA and BTDA (Figure 1), which were remarkably effective in the differentiation of NMR signals of N-3,5-dinitrobenzoyl (N-DNB) derivatives of amino acids both with free or derivatized carboxyl functions. (18,19)

Figure 1. CSAs and amino acid derivative structures (TFA = trifluoroacetyl, Ac = acetyl, and DNB = 3,5-dinitrobenzoyl).

Here, we evaluate the potential, as CSA, of a new C2-symmetric bis-thiourea system (TFTDA, Figure 1) based on DA (Figure 1), containing the 3,5-bis(trifluoromethyl)phenyl moiety, which is expected to affect acidity of thiourea NHs and hence complexing and enantiodiscriminating capabilities of the CSA. TFTDA has been employed in the differentiation of enantiomers of two different kinds of N-amino acid derivatives (Figure 1), that is, N-trifluoroacetyl (N-TFA, compounds 1–10, Figure 1) and N-acetyl derivatives (N-Ac, compounds 11–17, Figure 1), respectively, endowed with a fluorinated probe, suitable for the observation of enantiomers by ¹⁹F NMR, or an acetyl group, the signals of which are sharp singlets in a spectral region cleared of CSA signals. For comparison with previously reported BTDA, (18) also N-DNB derivatives of amino acids (compounds 18–20, Figure 1) and N-DNB derivatives of amino acid methyl esters (compounds 21–23, Figure 1) were taken into consideration.

Relevance of the co-presence of 2-hydroxyphenyl and 3,5-bis(trifluoromethyl)phenyl moieties was pointed out by comparing the TFTDA enantiodiscriminating efficiency to that of previously reported chiral auxiliary TFTPA (Figure 1), (23,25,27) having the same chemical structure, but devoid of phenolic hydroxyls.

Possible cooperativity of the two 3,5-bis(trifluoromethyl)phenylthiourea pendants of TFTDA was investigated by comparing TFTDA to its monomer analogous TFTMA (Figure 1). On considering that only few cases of CSAs able to produce efficient enantiodiscrimination in sub-stoichiometric conditions are reported, (22,32−37) potential of TFTDA in this area was also evaluated.

To gain more information on the nature of the intermolecular interactions responsible for the chiral discrimination, NMR investigations have been carried out based on ROESY and DOSY experiments for the detection of through space dipolar interactions and translational diffusion, respectively.

Results and Discussion

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¹H and ¹⁹F Enantiodiscrimination Experiments

Thiourea derivatives TFTDA and TFTMA were synthetized and obtained in a nearly quantitative yield, by reacting DA and MA with 2 or 1 equiv of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (Scheme 1), respectively. BTDA and TFTPA were prepared in an analogous way. NMR characterization data are collected in the Experimental Section and Supporting Information.

Scheme 1. Synthesis of **TFTMA**, **TFTDA,** and **TFTPA**

Enantiodiscrimination experiments were performed by comparing the NMR spectra of binary equimolar mixtures 1–20/DABCO and ternary mixtures 1–20/DABCO/CSA in the suitable total concentration and molar ratio chiral substrate-to-CSA and solvent. The achiral additive DABCO, which has been demonstrated to be actively engaged in the chiral discrimination pathways, (18−21,23,25,27,32) also acted as a solubility promoter for amino acid derivatives with poor solubility in the organic solvents considered in this investigation (CDCl₃ and C₆D₆). The analysis of N-3,5-dinitrobenzoylamino acid methyl esters (21–23) did not require the presence of DABCO. (18,19) The enantiodiscriminating efficiency was evaluated by measuring the chemical shift nonequivalence (ΔΔδ = |Δδ_R – Δδ_S| = |δ_R – δ_S|, ppm; where Δδ_R = δ_R – δ_F, Δδ_S = δ_S – δ_F, and δ_F is the chemical shift of the free substrate), that is, the difference of the chemical shifts of the corresponding nuclei of the two enantiomers δ_R and δ_S in the presence of the CSA.

First, we looked for enantiodiscriminating peculiarities of bis-thiourea TFTDA as compared to previously reported BTDA. To this aim, we dealt with four different kinds of derivatives of alanine, valine, and phenylglycine, on considering derivatives with free carboxyl functions as N-TFA (1–3), N-Ac (11–13), N-DNB (18–20), and N-DNB-amino acid methyl esters (21–23). Superior capacity of BTDA to enantiodiscriminate amino acid derivatives endowed with N-DNB derivatizing groups was fully demonstrated in 15 mM equimolar mixtures, with even better performances for amino acid derivatives having free carboxyl functions (Figure 2, Table S1 in Supporting Information). As a general trend, ortho- and para-protons of the 3,5-dinitrophenyl moiety of the two enantiomers of phenylglycine, valine, and alanine underwent high differentiation up to 0.208 ppm, as in the case of ortho-protons of 20. Nonequivalences measured in the mixtures containing derivatives 18–23 and TFTDA were instead remarkably lower (<0.026 ppm, Table S1 in Supporting Information).

Figure 2. ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to DNB resonances of **18–23** (15 mM)/DABCO/**BTDA** or **TFTDA** (1:1:1). ○ and ● indicate *ortho*- and *para*-DNB resonances, respectively. * indicates CSA resonances. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.

The reverse is true regarding N-TFA derivatives 1–3 which were remarkably better enantiodiscriminated by TFTDA than they were by BTDA (Figure 3, Table S1 in Supporting Information). As a matter of fact, both NH and CH protons in the ¹H NMR spectra and CF₃ nuclei in the ¹⁹F spectra showed nonequivalences ranging from 0.012 to 0.096 ppm and from 0.050 to 0.099 ppm, respectively. The highest values measured in the presence of BTDA were 0.033 ppm for the NH proton of 3 and 0.021 ppm for the fluorine nuclei of 1, that is, remarkably lower.

Figure 3. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral regions corresponding to CF₃ resonances of **1–3** (15 mM) and ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to acetyl resonances of **11–13** (15 mM) in the presence of 1 equiv of DABCO and **BTDA** or **TFTDA**. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.

Similarly, in the case of NH and acetyl protons of 11–13, higher nonequivalences were measured in the presence of TFTDA than those obtained in the presence of BTDA (Figure 3, Table S1 in Supporting Information). The sole exception was 13, that is, the N-Ac derivative of phenylglycine, which gave very similar nonequivalences for the acetyl protons in the presence of BTDA or TFTDA. Anyway, TFTDA induced remarkably higher nonequivalences on NH (0.130 ppm) and CH (0.106 ppm) than those measured in the presence of BTDA (0.040 and 0.016 ppm for NH and CH, respectively).

To definitely highlight the peculiarities of TFTDA in the panorama of bis-thiourea systems, we compared TFTDA enantiodifferentiation of 6 and 16 with that of a very similar CSA (TFTPA), (27) devoid of phenolic hydroxyls (Table 1). TFTDA allowed to attain better enantiomer differentiation: twofold increase of nonequivalence for CF₃ of N-TFA leucine (6) and about 30-fold for acetyl of N-Ac leucine (16).

Table 1. ¹H (600 MHz) and ¹⁹F (564 MHz) Nonequivalences (ΔΔδ = |δ_R – δ_S|, ppm; CDCl₃, 25 °C) for 6 and 16 (15 mM) in Equimolar Mixtures with TFTDA or TFTPA and in the Presence of 1 equiv of DABCO

	TFTDA	TFTPA
sub	CF₃/Ac	CF₃/Ac
6	0.090	0.047
16	0.190	0.006

The in-depth analysis of the enantiodiscrimination data requires a further comment which deals with the comparison between nonequivalence (ΔΔδ) and enantioresolution quotient (E) data, (38) which also takes into account the average linewidth, making aware of the fact that high nonequivalences do not guarantee the quality of enantiodifferentiation for enantiomer quantification. Three cases can be targeted, with partial (0 < E < 1), moderate (E ca. 1), and high (E ≫ 1) enantioresolution.

Coming back to our data, we can observe that enantioresolution quotient E (Table S1 in Supporting Information) is largely greater than 1 for protons belonging to the derivatizing motif, thus guaranteeing a very high quality of enantiodifferentiation: E ranges from 2 to 13.9 for protons of N-DNB in the mixture with BTDA and becomes very high for N-Ac (13.3 < E < 28.0) and N-TFA (7 < E < 13.6) amino acid derivatives in the mixture with TFTDA due to differentiation of sharp singlets produced by acetyl and CF₃ moieties. As a matter of fact, the very high nonequivalences of 0.208 and 0.185 ppm, respectively, measured for the ortho- (doublet) and para- (triplet) protons of 20 in its mixture with BTDA (Figure 2) corresponded to the remarkable Es of 13.9 and 8.4. On the other hand, for the acetyl protons of 12 in its mixture with TFTDA (Figure 3), an enantioresolution quotient of 18.4 was calculated, even though the nonequivalence was lower, that is, 0.129 ppm. The same is true for the fluorine resonances of N-TFA amino acid derivatives, sharp singlets of which allow, as an example, us to obtain an enantioresolution quotient of 13.6 for a nonequivalence magnitude of 0.099 ppm, as measured in the case of the mixture 2/TFTDA/DABCO.

Ultimately, the possibility to detect nonequivalences on probe moieties of the amino acid derivatives, which produce sharp singlets, guarantees accurate enantiomer quantification even when enantiomer differentiations, that is, nonequivalences, are lower.

Once pointed out the remarkable enantiodiscriminating efficiency of TFTDA toward N-Ac and N-TFA amino acids, dimeric TFTDA and monomeric TFTMA (Figure 4, Tables S2 and S3 in Supporting Information) were compared in the enantiodiscrimination of the three representative N-TFA derivatives 1–3 and N-Ac derivatives 11–13. Not only nonequivalences of 15 mM equimolar mixtures were remarkably lower in the presence of 1 equiv of the monomer CSA, TFTMA, in comparison with dimeric TFTDA, but also adding a further equivalent of TFTMA did not allow us to get the same nonequivalence magnitude found in the 15 mM equimolar mixture containing dimeric TFTDA (Figure 4).

Figure 4. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral regions corresponding to CF₃ resonances of **1–3** (15 mM) and ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to acetyl resonances of **11–13** (15 mM) in the presence of 1 equiv of DABCO and 1 equiv of **TFTDA** or 2 equiv of **TFTMA**. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.

For example, fluorine signals of the two enantiomers of 1 were differentiated to be 0.018 and 0.066 ppm in the mixtures containing equimolar amounts of TFTMA and TFTDA, respectively (Table S2 in Supporting Information). Nonequivalence induced by 2 equiv of TFTMA increased up to 0.023 ppm, which was lower than that measured in the equimolar mixture containing TFTDA (Figure 2). Therefore, cooperativity can be envisaged between the two thiourea arms of TFTDA, acting in concert, rather than independently, in the stabilization of the complexes formed with the enantiomeric pairs. Accordingly, on the basis of Job’s plot (Figure S1 in Supporting Information), the 1-to-1 stoichiometric ratio was found for the two complexes formed by TFTDA and the two enantiomers of the N-acetyl derivative of leucine 16. An eventual independent interaction of the TFTDA arms would have favored a 1-to-2 CSA to the chiral substrate stoichiometric ratio.

To deal with enantiodiscriminating versatility of TFTDA, besides compounds 1–3 and 11–13, already discussed, we extended our analysis to N-TFA derivatives 4–10 and N-Ac ones 14–17 (Figure 1). Equimolar 15 mM mixtures were analyzed in CDCl₃ in the presence of 1 equiv of DABCO (Table 2 and Figure 5 showing CF₃ and acetyl resonances).

Figure 5. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral regions corresponding to CF₃ (△) of **1–10** (15 and 5 mM) and ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to acetyl (△) of **11–17** (15 and 5 mM) in the presence of 1 equiv of DABCO (2 equiv for 10) and **TFTDA**. ▲ indicates the *syn* stereoisomer of 8. □ indicates methylthio resonances of 7 and **17,** and + indicates side chain protons of 7. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.

Table 2. ¹H (600 MHz) and ¹⁹F (564 MHz) Nonequivalences (ΔΔδ = |δ_R – δ_S|, ppm; CDCl₃, 25 °C) and Enantioresolution Quotients (E, in Parentheses) for 1–17 (15 mM or 5 mM) in Equimolar Mixtures with TFTDA and in the Presence of 1 equiv (for 1–9 and 11–17) or 2 equiv (for 10) of DABCO

	15 mM		5 mM
sub	NH	CF₃/Ac	NH	CF₃/Ac
1	0.054 (0.9)	0.066 (8.1)	0.038 (0.7)	0.051 (7.1)
2	0.048 (0.8)	0.099 (13.6)	0.040 (0.7)	0.109 (15.1)
3	0.082 (1.5)	0.050 (7.0)	0.014 (0.3)	0.036 (4.9)
4	0.222 (3.9)	0.093 (13.5)	0.216 (4.1)	0.096 (13.5)
5		0.087 (12.6)	0.064 (1.2)	0.055 (7.6)
6	0.110 (1.9)	0.090 (9.7)	0.105 (1.9)	0.115 (16.1)
7^a		0.078 (11.2)		0.047 (6.8)
8		0.042 (6.1), 0.034 (4.9)		0.011 (1.5), 0.044 (6.1)
9		0.025 (3.6)		0.029 (4.0)
10	1.249 (21.9)	0.219 (31.3)	1.391 (25.7)	0.228 (31.4)
11	0.152 (2.3)	0.196 (28.0)	0.108 (1.7)	0.163 (25.7)
12	0.066 (1.0)	0.129 (18.4)	0.088 (1.4)	0.179 (28.4)
13	0.130 (2.0)	0.092 (13.3)	0.129 (2.1)	0.117 (18.8)
14	0.166 (2.5)	0.171 (24.4)	0.158 (2.5)	0.191 (30.3)
15	0.112 (1.7)	0.144 (20.6)	0.118 (1.8)	0.178 (28.3)
16	0.156 (2.4)	0.191 (27.3)	0.157 (2.5)	0.246 (39.0)
17^b	0.057 (0.9)	0.171 (24.4)	0.024 (0.5)	0.238 (38.2)

^{^a}

Nonequivalences of 0.030 ppm (E = 4.8) and 0.026 ppm (E = 3.5) were measured for the MeS group at 15 and 5 mM, respectively.

^{^b}

Nonequivalences of 0.021 ppm (E = 2.3) and 0.051 ppm (E = 6.3) were measured for the MeS group at 15 and 5 mM, respectively.

¹⁹F nonequivalences ranged from 0.025 ppm for tryptophan derivative 9 to the very high value of 0.219 ppm measured in the case of glutamic acid derivative 10, solubilization of which, however, required the presence of 2 equiv of DABCO. Interestingly, very high nonequivalences were also detected for the ¹H resonances of NH protons, which reached the value of 1.249 ppm for glutamic acid derivative 10 (Table 2). Nonequivalences detected for the acetyl protons of derivatives 11–17 were once again very high, in the range 0.092 ppm for 13 up to 0.196 ppm for 11 (Table 2, Figure 5). In almost all cases, a very high enantiodiscriminating efficiency is guaranteed with no concern about the quality of enantiodiscrimination, always with enantioresolution quotients largely greater than 1 (Table 2). It is noteworthy that in the case of proline derivative 8, nonequivalence was detected for the possible syn- and anti-stereoisomers. The methylthio group of methionine derivatives 7 and 17 were even efficiently enantiodifferentiated (Figure 5, Table 2).

The use of less polar C₆D₆ would be expected to bring about an enhancement of enantiomer differentiation since this solvent, compared to CDCl₃, should interfere to a less extent with the stabilization of diastereomeric pairs. Surprisingly, nonequivalences measured for the CF₃ and acetyl nuclei of amino acid derivatives were lower in C₆D₆ than those detected in CDCl₃ (Table S4, Figures S2–S4 in Supporting Information). Exceptions were 11 and 16 with very similar values in the two solvents and 4 and 8 with higher values in C₆D₆. CH and NH moieties were better differentiated in the most apolar solvent, even though this was not a general trend, as no differentiation at all was found for the NH protons of the two enantiomers of 2–4. Even in cases of very high differentiation of NH protons, however, direct detection of their resonances can be made difficult by unwanted superimpositions with CSA resonances (Figure S5 in Supporting Information), and to extract their signals, 1D TOCSY experiments must be performed by selective perturbation at the frequencies of their J-connected CH protons.

Going on with the use of CDCl₃ as the solvent enabling us to detect enhanced differentiation of the probe signals, acetyl and trifluoroacetyl, we evaluated ability of TFTDA to maintain detectable nonequivalences also in more diluted solution. To this aim, progressively diluted equimolar solutions of TFTDA and N-Ac derivatives 11–17 were analyzed (Figure S6, Table S5 in Supporting Information). Unexpected results were obtained since dilution did not seem to affect significantly the enantiomer differentiation. Nonequivalence of acetyl protons of 11 started from a high value of 0.196 ppm at 15 mM and underwent a small decrease to a value of 0.163 ppm at 5 mM. For derivatives 12–17, dilution even brought a nonequivalence increase up to 39% (Figure S6 in Supporting Information).

Analogously, nonequivalences measured in the fluorine spectra of N-TFA derivatives seemed to be scarcely responsive to dilution with fluctuating results, that is, almost unchanged nonequivalences for 2, 4, 9, and 10, a decrease for 1, 3, 5, and 7, and an increase for 6 and 8 (Figures 5 and S7 in Supporting Information).

Explaining such a kind of behavior is not trivial because dilution should cause a decrease of enantiomer bound fractions and, consequently, a decrease of nonequivalence. Observing even an opposite trend suggests the co-presence of simultaneous complexation equilibria. Therefore, we took into consideration the occurrence of eventual self-aggregation processes involving the CSA, by comparing its NMR spectra at 15 and 5 mM (Figure S8 and Table S6 in Supporting Information). In spite of the very limited concentration range, the chemical shift of the NH(3) proton of TFTDA, adjacent to the 3,5-bis(trifluoromethyl)phenyl moiety, was low-frequency shifted for 0.46 ppm in the 5 mM solution, compared to the 15 mM solution, witnessing its involvement in intermolecular hydrogen bonds reasonably due to self-aggregation, which is less favored in more diluted solution. The same trend was found for NH(2) but with a minor response to the concentration change (0.03 ppm): this last proton lies, in fact, in the inner part of the CSA structure. To confirm such a kind of hypothesis, we performed DOSY (39) experiments in progressively diluted solution (15–3 mM) to measure the diffusion coefficient of the CSA (Table 3).

Table 3. ¹H NMR (600 MHz, CDCl₃, 25 °C) Diffusion Coefficient (D × 10¹⁰ m² s^–1) of TFTDA at Different Concentrations

	15 mM	5 mM	3 mM
D × 10¹⁰ (m²/s)	5.16 ± 0.06	5.72 ± 0.03	6.19 ± 0.06

In the spherical approximation, diffusion coefficient D depends on the hydrodynamic radius (r_H), based on the Stokes–Einstein equation (eq 1)

(1)

where k is the Boltzmann constant, T is the absolute temperature, and η is the dynamic viscosity of the solution.

In the presence of the self-aggregation processes, the diffusion coefficient is the weighted average of its value in the monomer (D_M) and self-aggregated species (D_SA) (eq 2)

(2)

where χ_M and χ_SA are the monomer and self-aggregated species molar fractions, and D_M and D_SA are the diffusion coefficients of the monomer and self-aggregated species, respectively.

A decrease of the diffusion coefficient, proportional to the molar fraction of the self-aggregated species, is expected in more concentrated solutions due to the increased molecular sizes of the self-aggregated species.

The CSA diffusion coefficient in 3 mM solution was equal to 6.19 × 10^–10 m² s^–1 and decreased to a value of 5.16 × 10^–10 m² s^–1 in 15 mM solution, confirming a contribution to the measured diffusion coefficient coming from a self-aggregated form of the CSA. On this basis, we can conclude that in more diluted solution, a greater amount of the non-aggregated form of the CSA is present in solution, available for the interaction with the two enantiomers of the chiral substrates and hence for their enantiodifferentiation.

In light of the above-said peculiar behavior, we also investigated the possibility to operate in CSA sub-stoichiometric conditions, which, in principle, should better discourage self-aggregation phenomena in favor of heteroaggregation of the CSA with enantiomers of amino acid derivatives. Therefore, equimolar 5 mM solutions of the N-TFA derivatives 1–3 and N-Ac derivatives 11–13 were compared to mixtures at the same substrate concentration (5 mM) but in the presence of 0.3 equiv of the CSA (Table 4 and Figure S9 in Supporting Information). In sub-stoichiometric conditions, nonequivalences both of CF₃ nuclei of N-TFA and of COCH₃ protons of N-Ac derivatives underwent a maximum reduction of nonequivalence by one-quarter but still giving very high enantioresolution quotients, ranging from 3.5 to 4.9 for 1–3 and from 4.8 to 15.4 for 11–13. Therefore, sub-stoichiometric conditions, which are quite unusual for CSAs, (22,32−37) can be suitably exploited, also employing the new dimeric thiourea CSA, TFTDA.

Table 4. ¹H (600 MHz) and ¹⁹F (564 MHz) Nonequivalences (ΔΔδ = |δ_R – δ_S|, ppm; CDCl₃, 25 °C) and Enantioresolution Quotients (E, in Parentheses) of CF₃ for 1–3 and of Ac for 11–13 (5 mM) in the Presence of 1 equiv of DABCO and 0.3 or 1 equiv of TFTDA

	ΔΔδ (ppm)
	0.3 equiv TFTDA	1 equiv TFTDA
1	0.025 (3.5)	0.051 (7.1)
2	0.035 (4.9)	0.109 (15.1)
3	0.032 (4.4)	0.036 (4.9)
11	0.097 (15.4)	0.163 (25.7)
12	0.082 (13.1)	0.179 (28.4)
13	0.030 (4.8)	0.117 (18.8)

Suitability of TFTDA as the CSA for real ee determination was evaluated in enantiomerically enriched samples of 3 (+90% e.e.) in equimolar 15 mM solution (Figure 6). The relationship between gravimetric and NMR data was excellent, with the absolute error within ±1%.

Figure 6. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral region corresponding to CF₃ resonances of enantiomerically enriched (ee +90, R/S = 95:5) 3 (15 mM) in the presence of 1 equiv of DABCO and 1 equiv of **TFTDA**.

NMR Investigation of Chiral Recognition Processes

First, we looked for a conformational model for the CSA, TFTDA, even though this task was difficult to achieve in consideration of the symmetry of the system. Despite this, selected ROEs (Figure S10 in Supporting Information) allowed us to impose some spatial proximity constraints, which led to the schematic representation in Figure 7. In detail, the intense dipole–dipole interaction detected between the methine protons CH1 and the adjacent NH(2) protons of the thiourea moiety (Figure S10 in Supporting Information) allowed us to locate these two protons in a cisoid arrangement. NH(2) protons showed the expected reciprocal ROE effect at the frequency of CH1 protons but no effect at all on NH(3) (Figure S10 in Supporting Information). Therefore, the two NHs are in reciprocal transoid positions. Accordingly, a ROE between NH(2) and ortho protons of the 3,5-bis(trifluomethyl)phenyl moiety bound to NH(3) was detected (Figure S10 in Supporting Information). Therefore, ROE data support a syn–anti conformation for TFTDA in CDCl₃ solution. Interestingly relevant ROE effects were detected between the phenolic protons and protons of the 3,5-bis(trifluoromethyl)phenyl groups (Figure S10 in Supporting Information) to witness their spatial proximity, which reasonably is due to attractive π–π interactions between the 2-hydroxyphenyl and 3,5-bis(trifluoromethyl)phenyl groups.

Figure 7. Schematic 3D representation of **TFTDA** according to NMR data and its Newman projection.

Reasonably, electron-withdrawing CF₃ groups not only produce the expected enhancement of acidity of thiourea moieties, but also enhance the π-acidic character of the aromatic moieties they are bound to, thus favoring intramolecular attractive π–π interactions with the phenolic rings (as supported by ROE measurements) at the expense of intermolecular interactions. On this basis, the lower enantiodiscriminating efficiency of TFTDA with respect to BTDA toward substrates bearing N-3,5-DNB derivatizing groups can be rationalized.

As a next step, we went deeply into the role of DABCO in the enantiodifferentiation phenomena caused by TFTDA, beyond its solubilizing effect on the amino acid derivatives having free carboxyl functions. To this aim, first, we compared the diffusion coefficients of DABCO (15 mM) in CDCl₃ as a pure compound and in equimolar binary mixtures DABCO/TFTDA. To better understand the role of DABCO in the presence of phenolic protons, we also analyzed DABCO diffusion behavior in the presence of TFTPA (1 equiv), devoid of phenolic OHs.

The diffusion coefficient of pure DABCO was 14.5 × 10^–10 m² s^–1 and remarkably lowered to the value of 7.1 × 10^–10 m² s^–1 in the presence of TFTDA, by contrast in the presence of TFTPA, its value slightly decreased to 13.9 × 10^–10 m² s^–1 (Table S7 in Supporting Information).

The above results can be rationalized on the hypothesis that phenolic hydroxyls are themselves involved in the DABCO-mediated tight network of hydrogen bond interactions. To support the above conclusion, 1D ROESY experiments were carried out by selective perturbation at the frequency of DABCO protons in the mixture containing equimolar amounts of DABCO (15 mM) and TFTDA (Figure S11a in Supporting Information). Very intense dipolar interactions were detected at the frequency of phenolic protons, together with lower intensity ROEs at the frequency of H4 and H5 protons of the 3,5-bis(trifluoromethyl)phenyl moiety in the DABCO/TFTDA binary mixture (Figure S11 in Supporting Information).

To go deeper into the interaction mechanism responsible for the chiral discrimination, we focused on the equimolar ternary mixtures containing DABCO (15 mM), TFTDA, and the two enantiomers of N-acetyl leucine (16), where N-acetyl groups underwent remarkable enantiomeric differentiation in the presence of the CSA. 1D ROESY experiments were performed to detect intermolecular dipolar interactions and hence define proximity constraints between the two enantiomeric substrates and the CSA. The methoxy group of (S)-16 produced comparable intermolecular ROEs on the protons H9 and H4 belonging to the 2-hydroxyphenyl and 3,5-bis(trifluoromethyl)phenyl moieties, respectively (Figure S12 in Supporting Information). Alkyl protons of its isobutyl group showed selectivity for the protons of the fluorinated aromatic ring (Figure S13 in Supporting Information). The reverse was found for (R)-16, with its acetyl moiety in closer proximity of the 3,5-bis(trifluoromethyl)phenyl group of the CSA (Figure S12 in Supporting Information) and almost equivalent ROEs at the frequency of 2-hydroxyphenyl and 3,5-bis(trifluoromethyl)phenyl groups (Figure S13 in Supporting Information) for alkyl protons of the isobutyl group. Interestingly, the methine protons of the two enantiomers of 16 gave very similar ROEs on the two aromatic rings of the CSA (Figure S14 in Supporting Information). In the ternary mixtures, DABCO protons produce dipolar interactions with amino acid protons and π-acid aromatic moiety of the CSA and its o-hydroxyphenyl moiety, which means that the base lies in between all of these groups (Figure S11b,c in Supporting Information). TFTDA retains its free state syn–anti conformation in the presence of the enantiomers of N-Ac and N-TFA amino acid derivatives, as demonstrated by the detection of NH(2)-H4 ROE in the mixture TFTDA/substrate/DABCO (examples are reported in Figures S15 and S16 in Supporting Information). According to this bound state conformational preference, highly differentiated complexation shifts were detected for the two NH protons, that is, very low (0.05–0.09 ppm) for NH(2) and remarkably high (0.59–0.82 ppm) for NH(3) interacting with the enantiomeric substrates (Table S8 in Supporting Information). Even though unexpected, the interaction of thiourea receptors in their syn–anti conformation is already reported in the literature. (18,40−45)

Therefore, it can be concluded that the main stabilizing interactions are DABCO-mediated hydrogen bond interactions involving the thiourea moiety, NH(3) in particular, phenolic hydroxyls of the CSA, and the carboxyl function of the amino acid derivative. In this way, the two enantiomers always face the CSA from the same side and only an interchange between the two groups (acetyl vs alkyl) bound to the chiral center of the amino acid occurs, which is responsible for the chemical shift differentiation due to the anisotropic effects exerted by the aromatic moieties of the CSA. A schematic representation of the two diastereomeric solvates, which brings together all the information coming from ROEs and complexation shifts, is given in Figure 8.

Figure 8. Schematic model of two diastereomeric complexes (S)-16/**TFTDA**/DABCO and (R)-16/**TFTDA**/DABCO.

Finally, we calculated the association constants for the two diastereomeric complexes. On the basis of the analysis of progressively diluted solution in the range from 15 to 2 mM, comparable values of 29.4 ± 3 and 29.6 ± 3 M^–1 were calculated for (R)-16/TFTDA and (S)-16/TFTDA, respectively (Figure S17 in Supporting Information).

Therefore, it can be assessed that enantiomer differentiation in the NMR spectra is mainly due to anisotropic effects of aromatic moieties of the CSA, rather than thermodynamic differentiation of the two diastereomeric complexes.

Conclusions

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N-Derivatization of amino acids as N-trifluoroacetyl and N-acetyl derivatives makes possible the NMR differentiation of their enantiomers by detection of their fluorine signals and acetyl protons, respectively, both producing sharp signals ideal for accurate integration. Bis-thiourea TFTDA containing both 2-hydroxyphenyl and 3,5-bis(trifluoromethyl)phenyl moieties represents a CSA with high selectivity and enantiodiscriminating efficiency toward these two classes of amino acid derivatives. The synthesis both of the CSA and amino acid derivatives is very practical and does not require purification steps.

Very high nonequivalences are measured in 15 mM equimolar solution CSA/substrate/DABCO, which remain quite unaffected by dilution, at least up to 5 mM, thus allowing us to reduce the consumption of the CSA. Contrary to what was observed for the majority of CSAs reported in the literature, TFTDA has the unusual characteristic of producing efficient enantiodiscrimination also in the CSA sub-stoichiometric conditions. Ability of TFTDA to produce enantioresolution both in diluted and sub-stoichiometric conditions can be ascribed to its tendency to self-aggregate in solution, which is better inhibited both in diluted solutions or in the presence of enantiomeric substrate excesses.

TFTDA reasonably engages both its two lateral arms in the stabilization of the diastereomeric solvates formed with the two enantiomers of each amino acid derivative, as supported by comparison with the corresponding monomeric CSA and by the one-to-one complexation stoichiometric ratio. DABCO mediates the hydrogen bond interactions involving the carboxylate of the amino acid derivative, the thiourea, and phenolic moieties of the CSA.

Finally, TFTDA adopts a syn–anti conformation, even in the bound form, acting via a single NH hydrogen bond with the amino acid derivatives that can cooperatively form the hydrogen bond with the hydroxyls of the phenol moiety of the CSA.

Experimental Section

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Materials

(1R,2R)-1,2-Bis(2-hydroxyphenyl)ethylenediamine (DA), 2-[(1R)-1-aminoethyl]phenol (MA), 3,5-bis(trifluoromethyl)phenyl isothiocyanate, and deuterated chloroform (CDCl₃) were purchased from Aldrich and used without further purification. All N-Ac derivatives 11–17 were purchased from Alfa Aesar. Derivatives 1–10 and 18–23 were prepared, as described in refs (33) and (19), respectively. The NMR characterization is reported in ref (33). BTDA and BTMA were prepared, as described in ref (19).

General Methods

¹H, ¹⁹F, and ¹³C{¹H} NMR measurements were carried out on a spectrometer operating at 600, 564, and 150 MHz for ¹H, ¹⁹F, and ¹³C nuclei, respectively. The samples were analyzed in the C₆D₆ or CDCl₃ solution, ¹H and ¹³C chemical shifts are referred to tetramethylsilane (TMS) as the secondary reference standard, ¹⁹F chemical shifts are referred to trifluorotoluene as the external standard, and the temperature was controlled (±25 °C). For all of the 2D NMR spectra which were employed for the characterization of CSAs, the spectral width used was the minimum required in both dimensions. The gCOSY (gradient correlation spectroscopy) and TOCSY (total correlation spectroscopy) maps were recorded by using a relaxation delay of 1 s and 200 increments of 4 transients, each with 2K points. For TOCSY maps, a mixing time of 80 ms was set. The 1D-TOCSY spectra were recorded using a selective pulse, transients ranging from 128 to 256, a relaxation delay of 3 s, and a mixing time of 80 ms. The 2D-ROESY (rotating-frame Overhauser enhancement spectroscopy) maps were recorded by using a relaxation time of 3 s and a mixing time of 0.4 s; 256 increments of 16 transients of 2K-points each were collected. The 1D-ROESY spectra were recorded using a selective inversion pulse with transients ranging from 256 to 1024, a relaxation delay of 5 s, and a mixing time of 0.4 s. The gHSQC (gradient heteronuclear single quantum coherence) and gHMBC (gradient heteronuclear multiple bond correlation) spectra were recorded with a relaxation time of 1.2 s, 128–200 increments with 16 transients, each of 2K-points. The gHMBC experiments were optimized for a long-range coupling constant of 8 Hz. The assignment of ¹H NMR and ¹³C{¹H} NMR chemical shifts, reported below, is shown in Figures S18–S21 in Supporting Information. DOSY (diffusion-ordered spectroscopy) experiments were carried out using a stimulated echo sequence with self-compensating gradient schemes and 64 K data points. Typically, g was varied in 20 steps (2–32 transients each), and Δ and δ were optimized in order to obtain an approximately 90–95% decrease in the resonance intensity at the largest gradient amplitude. The baselines of all arrayed spectra were corrected prior to processing the data. After data acquisition, each FID was apodized with 1.0 Hz line broadening and Fourier transformed. The data were processed with DOSY macro (involving the determination of the resonance heights of all the signals above a pre-established threshold and the fitting of the decay curve for each resonance to a Gaussian function) to obtain pseudo two-dimensional spectra with NMR chemical shifts along one axis and calculated diffusion coefficients along the other.

Synthesis TFTMA

3,5-Bis(trifluoromethyl)phenyl isothiocyanate (0.470 g, 1.70 mmol, 1 equiv) was added to MA (0.240 g, 1.70 mmol, 1 equiv) in CH₂Cl₂ (20 mL) at room temperature, under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 h and monitored by ¹H NMR. The solvent was removed by evaporation under vacuum to afford chemically pure TFTMA in a nearly quantitative yield.

TFTMA. Straw yellow amorphous solid (0.684 g, 1.67 mmol, 98.5% yield) having mp 129–131 °C. [α]²³_D = 38.4 (c = 0.5, CHCl₃). ¹H NMR (CDCl₃, 600 MHz): δ 7.90 (s, 1H), 7.70 (s, 3H), 7.24 (d, 1H, J = 7.6 Hz), 7.20 (t, 1H, J = 7.6 Hz), 7.00 (d, 1H, J = 7.6 Hz), 6.95 (t, 1H, J = 7.6 Hz), 6.83 (d, 1H, J = 7.6 Hz), 6.12 (br s, 1H), 5.73 (s, 1H), 1.60 (d, 3H, J = 7.1 Hz). ¹³C{¹H} NMR (CDCl₃, 150 MHz): δ 178.9, 153.0, 138.5, 132.9 (q, C_CF = 33.7 Hz), 129.4, 128.0, 127.1, 123.8, 122.7 (q, C_CF = 273.8 Hz), 121.5, 119.4, 116.7, 51.9, 20.3. ¹⁹F NMR (CDCl₃ 564 MHz): δ −63.04. Anal. Calcd for C₁₇H₁₄N₂SOF₆: C, 50.00; H, 3.46; N, 6.86. Found: C, 49.94; H, 3.51; N, 6.89.

Synthesis TFTDA

3,5-Bis(trifluoromethyl)phenyl isothiocyanate (2.10 g, 7.58 mmol, 2 equiv) was added to DA (0.975 g, 3.79 mmol, 1 equiv) in CH₂Cl₂ (20 mL) at room temperature, under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 h and monitored by ¹H NMR. The solvent was removed by evaporation under vacuum to afford chemically pure TFTDA in a nearly quantitative yield.

TFTDA. White amorphous solid (2.94 g, 3.74 mmol, 98.8% yield) having mp 169–172 °C. [α]²³_D = −49.6 (c = 0.5, CHCl₃). ¹H NMR (CDCl₃, 600 MHz): δ 8.37 (s, 2H), 7.93 (br s, 2H), 7.76 (s, 4H), 7.72 (s, 2H), 7.05 (t, 2H, J = 7.7 Hz), 6.95 (br s, 2H), 6.72 (t, 2H, J = 7.7 Hz), 6.68 (d, 2H, J = 7.7 Hz), 6.33 (s, 2H), 6.08 (br s, 2H). ¹³C {¹H} NMR (CDCl₃, 150 MHz): δ 180.4, 153.1, 138.6, 133.3 (q, C_CF = 33.8 Hz), 130.4, 130.4, 130.2, 124.3, 123.2 (q, C_CF = 272.2 Hz), 122.0, 120.0, 117.2, 61.2.¹⁹F NMR (CDCl₃ 564 MHz): δ −63.06. Anal. Calcd for C₃₂H₂₂N₄S₂O₂F₁₂: C, 48.86; H, 2.82; N, 7.12. Found: C, 48.82; H, 2.86; N, 7.03.

Synthesis TFTPA

3,5-Bis(trifluoromethyl)phenyl isothiocyanate (0.290 g, 1.08 mmol, 2 equiv) was added to (1R,2R)-1,2-diphenylethane-1,2-diamine (0.115 g, 0.54 mmol, 1 equiv) in CH₂Cl₂ (20 mL) at room temperature, under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 h and monitored by ¹H NMR. The solvent was removed by evaporation under vacuum to afford chemically pure TFTPA in a nearly quantitative yield.

TFTPA. White amorphous solid (0.390 g, 0.51 mmol, 94% yield), ¹H NMR (CDCl₃, 600 MHz): δ 7.98 (s, 2H), 7.72 (s, 4H), 7.70 (s, 2H), 7.48 (br s, 2H), 7.25–7.22 (m, 6H), 7.16 (br s, 4H), 6.01 (br s, 2H). ¹³C {¹H} NMR (CDCl₃, 150 MHz): δ 180.6, 138.4, 136.7, 133.1 (q, C_CF = 34.5 Hz), 129.1, 128.6, 127.6, 123.9, 122.7 (q, C_CF = 273.1 Hz), 119.7, 64.9.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c00814.

Nonequivalences and enantioresolution quotients for 1–3, 11–13, 18–23 in the presence of 1 equiv of DABCO and BTDA or TFTDA; nonequivalences and enantioresolution quotients for 1–3 DABCO in the presence of TFTDA or TFTMA at different molar ratios; nonequivalences and enantioresolution quotients for 11–13/DABCO in the presence of TFTDA or TFTMA at different molar ratios; stoichiometry determination; nonequivalences and enantioresolution quotients for 1–17 in the presence of TFTDA and DABCO in C₆D₆ and CDCl₃; ¹H and ¹⁹F NMR spectra of 1–10 in the presence of DABCO and TFTDA in CDCl₃ and C₆D₆; ¹H NMR spectra of 11–17 in the presence of DABCO and TFTDA in CDCl₃ and C₆D₆; ¹H NMR and 1D-TOCSY spectra of 2, 4–6, 13, and 17 in the presence of DABCO/TFTDA in C₆D₆; nonequivalences for 11–17 in equimolar mixtures 11–17/DABCO/TFTDA as a function of concentration; nonequivalences for 11, 13–17/DABCO (1:1) in the presence of 1 equiv of TFTDA at different substrate concentration; nonequivalences for 1–10 in equimolar mixtures 1–10/DABCO/TFTDA as a function of the concentration; ¹H NMR spectra of TFTDA at 15 and 5 mM; ¹H NMR chemical shift data for TFTDA in 15 and 5 mM solutions; ¹⁹F NMR spectra of 1–3 and ¹H NMR spectra of 11–13 in the presence of 1 equiv of DABCO and of 1 or 0.3 equiv of TFTDA; 2D ROESY map TFTDA at 30 mM; diffusion coefficients of pure DABCO (15 mM) in an equimolar mixture TFTDA and TFTPA; 1D ROESY of DABCO in the presence of TFTDA; 1D ROESY of 16 protons in equimolar mixtures (R)-16 or (S)-16/DABCO/TFTDA; ¹H chemical shifts and complexation shift for (R)-16 and (S)-16/DABCO/TFTDA equimolar mixtures; ROESY maps of TFTDA/substrate/DABCO; association constant determination; and ¹H and ¹³C{¹H} NMR spectra of TFTMA and TFTDA (PDF)

jo2c00814_si_001.pdf (2.58 MB)

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Author Information

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Corresponding Authors
- Federica Balzano - Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy; https://orcid.org/0000-0001-6916-321X; Email: [email protected]
- Gloria Uccello Barretta - Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy; Email: [email protected]
Authors
- Alessandra Recchimurzo - Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy
- Luca Gherardi - Department of Chemistry and Industrial Chemistry, University of Pisa, via Moruzzi 13, 56124 Pisa, Italy
Notes
The authors declare no competing financial interest.

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Uccello-Barretta, Gloria; Balzano, Federica
Topics in Current Chemistry (2013), 341 (Differentiation of Enantiomers II), 69-131CODEN: TPCCAQ; ISSN:0340-1022. (Springer GmbH)
This chapter will describe the general features and main categories of chiral solvating agents (CSAs) for NMR spectroscopy, spanning from low-medium sized CSAs to macrocyclic ones. CSAs based on chiral ionic liqs. (CILs) will be introduced in view of their increasing popularity, and, finally, a short paragraph will be dedicated to special applications of CSAs in particular exptl. conditions. Several valuable works, which are mainly devoted to investigate enantiodifferentiation mechanisms by NMR, will not be discussed. The main objective is to identify the current trend in the research areas dedicated to the development of new CSAs for NMR spectroscopy.
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Wenzel, T. J. Chiral Derivatizing Agents, Macrocycles, Metal Complexes, and Liquid Crystals for Enantiomer Differentiation in NMR Spectroscopy. Top. Curr. Chem. 2013, 341, 1– 68, DOI: 10.1007/128_2013_433
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Chiral Derivatizing Agents, Macrocycles, Metal Complexes, and Liquid Crystals for Enantiomer Differentiation in NMR Spectroscopy
Wenzel, Thomas J.
Topics in Current Chemistry (2013), 341 (Differentiation of Enantiomers II), 1-68CODEN: TPCCAQ; ISSN:0340-1022. (Springer GmbH)
Enantiomerically pure chiral auxiliary agents are often used in NMR spectroscopy to facilitate the differentiation of enantiomers. Chiral derivatizing agents are covalently bound to the substrate and differences in chem. shifts of the resulting diastereomeric complexes are used in the anal. Macrocycles such as cyclodextrins, crown ethers, and calix[4]resorcinarenes are chiral solvating agents that assoc. with the substrate through non-covalent interactions. Enantiomeric differentiation occurs in the NMR spectrum because of the diastereomeric nature of the assocd. complexes and/or because of the differences in assocn. consts. between the two enantiomers and the chiral reagent. Metal complexes are Lewis acids that bind to suitable Lewis base donor compds. Exchange of substrate can be slow or fast depending on the particular metal ion, mimicking the behavior of a chiral derivatizing or solvating agent, resp. Chiral liq. crystals undergo a partial alignment in an applied magnetic field and enantiomers dissolved in the liq. crystal undergo a partial alignment as well. If the alignment of the two enantiomers is different, enantiomeric differentiation can potentially be obsd. by differences in chem. shifts, differences in dipolar coupling consts., and different magnitudes of splitting of quadrupolar nuclei such as deuterium. The chiral reagents described herein can be used to det. enantiomeric compn. and sometimes to assign abs. configuration. Significant discoveries as well as recent findings with each of these types of systems are described.
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Khun, T. L.; Corral-Motiram, K.; Athersuch, T. J.; Parrella, T.; Pérez-Trujillo, M. Simultaneous Enantiospecific Detection of Multiple Compounds in Mixture using NMR Spectroscopy. Angew. Chem., Ind. Ed. 2020, 59, 23615– 23619, DOI: 10.1002/anie.202011727
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Maria Faisca Phillips, A.; Pombeiro, A. J. L. Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems. Eur. J. Org. Chem. 2021, 2021, 3938– 3969, DOI: 10.1002/ejoc.202100364
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Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems
Maria Faisca Phillips, Ana; Pombeiro, Armando J. L.
European Journal of Organic Chemistry (2021), 2021 (29), 3938-3969CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The presence of a halogen atom in a mol. can have a large effect in its properties; for instance, halogens are used in drugs to improve lipophilicity, membrane permeability and absorption, and even the blood-brain barrier permeability. As highlighted in this review, there are nowadays a range of highly selective, versatile halogenating reagents, electrophilic, nucleophilic or radical in nature, which operate under mild conditions, allowing late-stage functionalization of complex mols. in cascade reactions. Recent developments in organocatalyst design revealed novel Cinchona alkaloids derivs., chiral phosphoric acids, amines, phosphines and several bifunctional catalysts, mostly thiourea- or squaramide-based, which introduced chirality, with high levels of enantio- and diastereoselection, in the formation of one or multiple chiral centers in a single synthetic operation, as shown. The literature published in this field from 2014 to 2020 were surveyed.
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Wang, J.; Tao, Y. Synthesis of Sustainable Polyesters via Organocatalytic Ring-Opening Polymerization of O -carboxyanhydrides: Advances and Perspectives. Macromol. Rapid Commun. 2021, 42, 2000535, DOI: 10.1002/marc.202000535
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Synthesis of Sustainable Polyesters via Organocatalytic Ring-Opening Polymerization of O-carboxyanhydrides: Advances and Perspectives
Wang, Jianqun; Tao, Youhua
Macromolecular Rapid Communications (2021), 42 (3), 2000535CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Sustainable polyesters can be furnished via ring-opening polymn. (ROP) of O-carboxyanhydrides (OCAs). Various catalysts, esp. metal-based catalysts, are devised to achieve controlled ROP of OCAs. In the following mini review, the recent progress on the organocatalytic ROP of OCAs, including the usage of thiourea-based bifunctional single-mol. organocatalysts for eliminating epimerization in OCAs polymn. is summarized. Moreover, the future development of the organocatalytic ROP of OCAs for the synthesis of sustainable polyesters will be discussed.
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Parvin, T.; Yadav, R.; Choudhury, L. H. Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs). Org. Biomol. Chem. 2020, 18, 5513– 5532, DOI: 10.1039/d0ob00595a
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Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs)
Parvin, Tasneem; Yadav, Rahul; Choudhury, Lokman H.
Organic & Biomolecular Chemistry (2020), 18 (29), 5513-5532CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
A review. One-pot multiple bond-forming reactions under metal-free conditions have tremendous potential in org. and medicinal chem. considering their synthetic efficiency and eco-friendliness. In this direction, organocatalysis, i.e. application of org. mols. as catalysts, in multicomponent reactions is one of the best combinations for the prepn. of complex mols. in min. steps under green reaction conditions. Thiourea-based org. mols. show excellent catalytic activity in various transformations by their unique double H-bonding activation process. Chiral org. mols. having a thiourea backbone are well-recognized catalysts for the enantioselective synthesis of diverse products from asym. two- or multicomponent reactions. Simultaneous dual activation of the electrophile and the nucleophile in an MCR by using bifunctional thiourea-based chiral organocatalysts has gained considerable interest in recent times. Although several review articles are available in the literature on organocatalysis, asym. domino reactions, or multicomponent reactions using various organocatalysts, however, to date there has been no dedicated review article on this emerging topic, i.e. asym. multicomponent reactions catalyzed by thiourea-based organocatalysts. Thus, this review aims to highlight the recent applications of thiourea-based organocatalysts in asym. multicomponent reactions.
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Jain, I.; Malik, P. Advances in urea and thiourea catalyzed ring opening polymerization: A brief overview. Eur. Polym. J. 2020, 133, 109791, DOI: 10.1016/j.eurpolymj.2020.109791
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Advances in urea and thiourea catalyzed ring opening polymerization: A brief overview
Jain, Isha; Malik, Payal
European Polymer Journal (2020), 133 (), 109791CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
A review. Hydrogen bond-mediated organocatalysis has emerged as a very powerful strategy for the synthesis of structurally well-defined polymers. Urea and thiourea derivs. are among one of the extensively explored hydrogen-bonding organocatalysts for ring opening polymn. These catalytic systems have potential to exquisitely control the activity and selectivity of the polymn. processes, the field has witnessed astonishing development in recent years. This review documents advances in the field of urea and thiourea catalyzed ring-opening polymn. since their debut in 2005, with an emphasis on seminal work of Hedrick and Waymouth groups. The first part of the review discusses one component bifunctional urea and thiourea catalyzed ring-opening polymn. of cyclic monomers and in the second part newly developed two component bifunctional urea and thiourea catalysts are described. The third part provides an overview of dual urea and thiourea-base catalyzed ringopening polymn. and copolymn. of cyclic monomers such as esters, carbonates, phosphates, anhydrides and epoxides. The final part is concluded by highlighting the challenges and future opportunities for urea and thiourea systems in polymer synthesis.
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Steppeler, F.; Iwan, D.; Wojaczyńska, E.; Wojaczyński, J. Chiral thioureas-preparation and significance in asymmetric synthesis and medicinal chemistry. Molecules 2020, 25, 401, DOI: 10.3390/molecules25020401
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Chiral thioureas-preparation and significance in asymmetric synthesis and medicinal chemistry
Steppeler, Franz; Iwan, Dominika; Wojaczynska, Elzbieta; Wojaczynski, Jacek
Molecules (2020), 25 (2), 401pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
A review. For almost 20 years, thioureas have been experiencing a renaissance of interest with the emerged development of asym. organocatalysts. Due to their relatively high acidity and strong hydrogen bond donor capability, they differ significantly from ureas and offer, appropriately modified, great potential as organocatalysts, chelators, drug candidates, etc. The review focuses on the family of chiral thioureas, presenting an overview of the current state of knowledge on their synthesis and selected applications in stereoselective synthesis and drug development.
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Zhang, H.; Zhao, H.; Wen, J.; Zhang, Z.; Stavropoulos, P.; Li, Y.; Ai, L.; Zhang, J. Discrimination of Enantiomers of amides with two stereogenic centers enabled by chiral bisthiourea derivatives using ¹H NMR spectroscopy. Org. Biomol. Chem. 2021, 19, 6697– 6706, DOI: 10.1039/d1ob00742d
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Discrimination of enantiomers of amides with two stereogenic centers enabled by chiral bisthiourea derivatives using 1H NMR spectroscopy
Zhang, Hanchang; Zhao, Hongmei; Wen, Jie; Zhang, Zhanbin; Stavropoulos, Pericles; Li, Yanlin; Ai, Lin; Zhang, Jiaxin
Organic & Biomolecular Chemistry (2021), 19 (30), 6697-6706CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Enantiomers of a few new amides contg. two stereogenic centers have been derived from D- and L-α-amino acids as guests for chiral recognition by 1H NMR spectroscopy. A variety of chiral amides with two or more stereogenic centers often exist in the products of catalytic asym. synthesis, natural products or their total synthetic products, and chiral drugs. It would be a challenging and meaningful work to explore their chiral recognition. For this purpose, a class of novel chiral bisthiourea derivs. 1-9 has been synthesized from (1S,2S)-(+)-1,2-diaminocyclohexane, D-α-amino acids, and isothiocyanates as chiral solvating agents (CSAs). CSAs 1-9 proved to afford better chiral discriminating results towards most amides with two stereogenic centers, which have been rarely studied as chiral substrates by 1H NMR spectroscopy. In particular, CSAs 7, 8 and 9, featuring 3,5-bis(trifluoromethyl)benzene residues, exhibit outstanding chiral discriminating capabilities towards all amides, providing well-sepd. 1H NMR signals and sufficiently large nonequivalent chem. shifts. To test their practical application in the detn. of enantiomeric excess, 1H NMR spectra of chiral amides (G16) with different optical purities were measured in the presence of CSAs 7 and 8, resp. Their ee values (up to 90%) were accurately calcd. by the integration of the NH proton of the CONHPh group of G16. To better understand the chiral discriminating behavior, Job plots of (±)-G16 with CSA 7 and (±)-G17 with CSA 8 and the assocn. consts. (Ka) of (S,R)-G16 and (R,S)-G16 with CSA 7 were evaluated, resp. In order to further reveal any underlying intermol. hydrogen bonding interactions, theor. calcns. of the enantiomers of (S,R)-G16 and (R,S)-G16 with CSA 7 were performed by means of the hybrid d. functional theory (B3LYP) with the std. basis sets of 3-21G of the Gaussian 03 program, resp.
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Recchimurzo, A.; Micheletti, C.; Uccello-Barretta, G.; Balzano, F. A Dimeric Thiourea CSA for the Enantiodiscrimination of Amino Acid Derivatives by NMR Spectroscopy. J. Org. Chem. 2021, 86, 7381– 7389, DOI: 10.1021/acs.joc.1c00340
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A Dimeric Thiourea CSA for the Enantiodiscrimination of Amino Acid Derivatives by NMR Spectroscopy
Recchimurzo, Alessandra; Micheletti, Cosimo; Uccello-Barretta, Gloria; Balzano, Federica
Journal of Organic Chemistry (2021), 86 (11), 7381-7389CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The reaction of benzoyl isothiocyanate with (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine afforded a new thiourea chiral solvating agent I (CSA) with a very high ability to differentiate 1H and 13C NMR signals of simple amino acid derivs., even at low concns. The enantiodiscrimination efficiency was higher with respect to that of the parent monomer, a thiourea deriv. of 2-((1R)-1-aminoethyl)phenol, thus putting into light the relevance of the cooperativity between the two mol. portions of the dimer in a cleft conformation stabilized by interchain hydrogen bond interactions. An achiral base additive (DABCO or DMAP) played an active role in the chiral discrimination processes, mediating the interaction between the CSA and the enantiomeric mixts. The chiral discrimination mechanism was investigated by NMR spectroscopy through the detn. of complexation stoichiometries, assocn. consts., and the stereochem. of the diastereomeric solvates.
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Recchimurzo, A.; Micheletti, C.; Uccello-Barretta, G.; Balzano, F. Thiourea Derivative of 2-[(1R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy. J. Org. Chem. 2020, 85, 5342– 5350, DOI: 10.1021/acs.joc.0c00027
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Thiourea Derivative of 2-[(1R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy
Recchimurzo, Alessandra; Micheletti, Cosimo; Uccello-Barretta, Gloria; Balzano, Federica
Journal of Organic Chemistry (2020), 85 (8), 5342-5350CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Thiourea derivs. of 2-[(1R)-1-aminoethyl]phenol, (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, (1R,2R)-(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, and (R)-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using NMR (NMR) spectroscopy. Thiourea deriv., prepd. by reacting 2-[(1R)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of N-3,5-dinitrobenzoyl (DNB) derivs. of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.2.2]octane(DABCO)/N,N-dimethylpyridin-4-amine (DMAP)/(NBu4OH) is required both to solubilize amino acid derivs. with free carboxyl groups in CDCl3 and to mediate their interaction with the chiral auxiliary to attain efficient differentiation of the NMR signals of enantiomeric substrates. For ternary systems CSA/substrate/DABCO, the chiral discrimination mechanism has been ascertained through the NMR detn. of complexation stoichiometry, assocn. consts., and stereochem. features of the diastereomeric solvates.
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Gunal, S. E.; Tuncel, S. T.; Dogan, I. Enantiodiscrimination of carboxylic acids using single enantiomer thioureas as chiral solvating agents. Tetrahedron 2020, 76, 131141, DOI: 10.1016/j.tet.2020.131141
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There is no corresponding record for this reference.
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Chen, Z.; Fan, H.; Yang, S.; Bian, G.; Song, L. Chiral sensors for determining the absolute configurations of α-amino acid derivatives. Org. Biomol. Chem. 2018, 16, 8311– 8317, DOI: 10.1039/c8ob01933a
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Chiral sensors for determining the absolute configurations of α-amino acid derivatives
Chen Zhongxiang; Fan Hongjun; Yang Shiwei; Bian Guangling; Song Ling
Organic & biomolecular chemistry (2018), 16 (37), 8311-8317 ISSN:.
A simple strategy for configurational assignments of alpha-amino acids has been developed by comparison of the proton NMR chemical shift values of the alpha hydrogens of N-phthaloyl protected alpha-amino acids in the presence of (R)-CSA 1 and (S)-CSA 1, respectively. Highly resolved NMR spectra can be obtained directly on the mixed solution of the chiral solvating agents with N-phthaloyl protected alpha-amino acids in NMR tubes, giving well distinguishable proton signals without interference which dramatically improve the accuracy of assignment and hasten the assigning procedure. The strategy is widely applicable for varied natural and non-natural amino acids.
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Ito, S.; Okuno, M.; Asami, M. Differentiation of enantiomeric anions by NMR spectroscopy with chiral bisurea receptors. Org. Biomol. Chem. 2018, 16, 213– 222, DOI: 10.1039/c7ob02318a
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Differentiation of enantiomeric anions by NMR spectroscopy with chiral bisurea receptors
Ito, Suguru; Okuno, Manami; Asami, Masatoshi
Organic & Biomolecular Chemistry (2018), 16 (2), 213-222CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
Chiral anionic species are ubiquitous and play important roles in biol. systems. Despite the recent advancements in synthetic anion receptors bearing urea functionalities, urea-based chiral solvating agents (CSAs) that can sep. the NMR signals of racemic anions remain limited. Herein, three dibenzofuran-based C2-sym. chiral bisureas were synthesized from the reaction of (R,R)-4,6-bis(1-aminopropyl)dibenzo[b,d]furan with Ph isocyanate, Ph thioisocyanate, or tosyl isocyanate. The chiral anion recognition properties of these bisureas were examd. by 1H NMR spectroscopy using DL-tetrabutylammonium mandelate (TBAM) as a model substrate. A clear baseline sepn. of the enantiomeric signals of the benzylic proton of TBAM was achieved upon mixing with 0.5 equiv of bis(phenylurea). In contrast to previous urea-based chiral anion receptors that differentiate the enantiomers of chiral anions by forming 1 : 1 host-guest complexes, a high chiral recognition ability of chiral bis(phenylurea) was achieved owing to the generation of an equil. between free guests, 1 : 1 host-guest complexes, and 1 : 2 host-guest complexes. Chiral bis(phenylurea) was also successfully employed in the sepn. of the enantiomeric 1H NMR signals of various racemic anions.
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Bian, G.; Yang, S.; Huang, H.; Zong, H.; Song, L. A bisthiourea-based ¹H NMR chiral sensor for chiral discrimination of a variety of chiral compounds. Sens. Actuators, B 2016, 231, 129– 134, DOI: 10.1016/j.snb.2016.03.002
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A bisthiourea-based 1H NMR chiral sensor for chiral discrimination of a variety of chiral compounds
Bian, Guangling; Yang, Shiwei; Huang, Huayin; Zong, Hua; Song, Ling
Sensors and Actuators, B: Chemical (2016), 231 (), 129-134CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
A simple one-step synthesized bisthiourea has been used as a highly efficient and versatile chiral sensor for rapid chiral discrimination and enantiomeric excess detn. of a wide range of chiral compds. contg. alc., sulfoxide, lactone, epoxide, amino alc., amide, β-chiral carboxylic acid and remote chiral carboxylic acid with the use of 1H NMR signals.
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Cios, P.; Romański, J. Enantioselective recognition of sodium carboxylates by an 1,8-diaminoanthracene based ion pair receptor containing amino acid units. Tetrahedron Lett. 2016, 57, 3866– 3869, DOI: 10.1016/j.tetlet.2016.07.053
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Enantioselective recognition of sodium carboxylates by an 1,8-diaminoanthracene based ion pair receptor containing amino acid units
Cios, Paulina; Romanski, Jan
Tetrahedron Letters (2016), 57 (34), 3866-3869CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
An anthracene based ion pair receptor contg. two amino acid units supported by cation and anion binding domains has been synthesized and shown to exhibit enhanced anion binding affinities in the presence of sodium cations. The receptor's ability to recognize enantiomers was studied using chiral carboxylates derived from 2-phenylbutyric acid, mandelic acid, and three Boc-protected amino acids. Sodium cation coordination does not influence chiral recognition but does affect the strength of anion binding. The greatest enhancement of anion binding in the presence of sodium cations was found for halides, and the highest enantiodiscrimination was found for Boc-N-tryptophan. Comparative anion and salt binding studies revealed that the simultaneous action of multiple binding domains in the structure of receptor 1 is responsible for its stronger salt assocn. and better enantioselectivity than in the case of mono-supported receptor 2.
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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, DOI: 10.1021/acs.orglett.5b00030
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Highly Effective Configurational Assignment Using Bisthioureas as Chiral Solvating Agents in the Presence of DABCO
Bian, Guangling; Fan, Hongjun; Huang, Huayin; Yang, Shiwei; Zong, Hua; Song, Ling; Yang, Genjin
Organic Letters (2015), 17 (6), 1369-1372CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A highly effective 1H NMR method for detg. the abs. configurations of various chiral α-hydroxyl acids and their derivs. has been developed with the use of bisthioureas (R)-CSA 1 and (S)-CSA 1 as chiral solvating agents in the presence of DABCO, giving distinguishable proton signals with up to 0.66 ppm chem. shift nonequivalence. Computational modeling studies were performed with Gaussian09 to reveal the chiral recognition mechanism.
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Ulatowski, F.; Jurczak, J. Chiral Recognition of Carboxylates by a Static Library of Thiourea Receptors with Amino Acid Arms. J. Org. Chem. 2015, 80, 4235– 4243, DOI: 10.1021/acs.joc.5b00403
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Chiral Recognition of Carboxylates by a Static Library of Thiourea Receptors with Amino Acid Arms
Ulatowski, Filip; Jurczak, Janusz
Journal of Organic Chemistry (2015), 80 (9), 4235-4243CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Chiral recognition is based on a large network of very subtle interactions whose outcome is difficult to predict. A combinatorial approach is therefore the most suitable to search for the most efficient receptor and obtain a structure-enantioselectivity correlation. The authors have synthesized a set of 12 receptors constructed with 1,9-diaminoanthracene and α-amino acid esters, linked via thiourea groups. The assocn. consts. and enantioselectivities for the complexes with mandelate and N-acetylphenylalanine were detd. by competitive NMR titrns. Assocn. consts. quite regularly depend on the substituents in the receptor structure, but the distribution of enantioselectivities across the library could not easily be rationalized.
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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, DOI: 10.1021/jo4013546
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A Chiral Bisthiourea as a Chiral Solvating Agent for Carboxylic Acids in the Presence of DMAP
Bian, Guangling; Fan, Hongjun; Yang, Shiwei; Yue, Huifeng; Huang, Huayin; Zong, Hua; Song, Ling
Journal of Organic Chemistry (2013), 78 (18), 9137-9142CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A simple chiral bisthiourea (I) was used as a highly effective and practical chem. solvating agent (CSA) for diverse α-carboxylic acids in the presence of DMAP. Excellent enantiodiscrimination based on well-resolved α-H NMR signals of the enantiomers of carboxylic acids can be obtained without interference from the chiral bisthiourea and DMAP. To check the practicality of the chiral bisthiourea/DMAP for enantiomeric detn., the ee values of mandelic acid (MA) samples over a wide ee range were detd. by integration of the α-H signal of MA in 1H NMR. A discrimination mechanism is proposed, that the formation of two diastereomeric ternary complexes between the chiral bisthiourea and two in situ formed enantiomeric carboxylate-DMAPH+ ion pairs discriminates the enantiomers of carboxylic acids. Computational modeling studies show that the chem. shift value of α-H of (S)-MA is greater than that of (R)-MA in ternary complexes, which is consistent with exptl. observation. 1-dimensional and 2-dimensional NOESY spectra demonstrate the intermol. noncovalent interactions between the protons on the arom. rings of chiral bisthiourea and α-H of the enantiomers of racemic α-methoxy phenylacetic acids in the complexes.
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Trejo-Huizar, K. E.; Ortiz-Rico, R.; Peña-González, M. d. L. A.; Hernández-Rodríguez, M. Recognition of chiral carboxylates by 1,3-disubstituted thioureas with 1-arylethyl scaffolds. New J. Chem. 2013, 37, 2610– 2613, DOI: 10.1039/c3nj00644a
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Recognition of chiral carboxylates by 1,3-disubstituted thioureas with 1-arylethyl scaffolds
Trejo-Huizar, Karla Elisa; Ortiz-Rico, Ricardo; Pena-Gonzalez, Maria de los Angeles; Hernandez-Rodriguez, Marcos
New Journal of Chemistry (2013), 37 (9), 2610-2613CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
Chiral thioureas with 1-arylethyl and 1-arylethyl-2-2-2-trifluoroethyl (Ar = Ph, 1-Napht, 9-Anthr) scaffolds were used as hosts to recognize acetate and chiral mandelates. The higher binding obtained with the trifluoromethyl analog is also reflected in the higher selectivity factor for one enantiomer. The C2 symmetry was also indispensable to obtain selectivity.
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Foreiter, M. B.; Gunaratne, H. Q. N.; Nockemann, P.; Seddon, K. R..; Stevenson, P. J.; Wassell, D. F. Chiral Thiouronium salts: Synthesis, characterization and application in NMR enantio-discrimination of chiral oxoanions. New J. Chem. 2013, 37, 515– 533, DOI: 10.1039/c2nj40632b
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Chiral thiouronium salts: synthesis, characterisation and application in NMR enantio-discrimination of chiral oxoanions
Foreiter, Magdalena B.; Gunaratne, H. Q. Nimal; Nockemann, Peter; Seddon, Kenneth R.; Stevenson, Paul J.; Wassell, David F.
New Journal of Chemistry (2013), 37 (2), 515-533CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
Chiral thioureas and functionalised chiral thiouronium salts were synthesized starting from the relatively cheap and easily available chiral amines: (S)-methylbenzylamine and rosin-derived (+)-dehydroabietylamine. The introduction of a delocalised pos. charge to the thiourea functionality, by an alkylation reaction at the sulfur atom, enables dynamic rotameric processes: hindered rotations about the delocalised CN and CS bonds. Hence, four different rotamers/isomers may be recognized: syn-syn, syn-anti, anti-syn and anti-anti. Extensive 1H and 13C NMR studies have shown that in hydrogen-bond acceptor solvents, such as perdeuteriated DMSO, the syn-syn conformation is preferable. On the other hand, when using non-polar solvents, such as CDCl3, the mixt. of syn-syn and syn-anti isomers is detectable, with an excess of the latter. Apart from this, in the case of S-butyl-N,N'-bis(dehydroabietyl)thiouronium ethanoate in CDCl3, the 1H NMR spectrum revealed that strong bifurcated hydrogen bonding between the anion and the cation causes global rigidity without signs of hindered rotamerism observable on the NMR time scale. This suggested that these new salts might be used as NMR discriminating agents for chiral oxoanions, and are indeed more effective than their archetypal guanidinium analogs or the neutral thioureas. The best results in recognition of a model substrate, mandelate, were obtained with S-butyl-N,N'-bis(dehydroabietyl)thiouronium bistriflamide. It was confirmed that the chiral recognition occurred not only for carboxylates but also for sulfonates and phosphonates. Further 1H NMR studies confirmed a 1 : 1 recognition mode between the chiral agent (host) and the substrate (guest); binding consts. were detd. by 1H NMR titrns. in solns. of DMSO-d6 in CDCl3. It was also found that the anion of the thiouronium salt had a significant influence on the recognition process: anions with poor hydrogen-bond acceptor abilities led to the best discrimination. The presence of host-guest hydrogen bonding was confirmed in the X-ray crystal structure of S-butyl-N,N'-bis(dehydroabietyl)thiouronium bromide and by computational studies (d. functional theory).
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Hernández-Rodríguez, M.; Juaristi, E. Structurally simple chiral thioureas as chiral solvating agents in the enantiodiscrimination of α-hydroxy and α-amino carboxylic acids. Tetrahedron 2007, 63, 7673– 7678, DOI: 10.1016/j.tet.2007.05.021
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Structurally simple chiral thioureas as chiral solvating agents in the enantiodiscrimination of α-hydroxy and α-amino carboxylic acids
Hernandez-Rodriguez, Marcos; Juaristi, Eusebio
Tetrahedron (2007), 63 (32), 7673-7678CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
C2-Sym. chiral thioureas (S,S)-RCHMeNHC(S)NHCHMeR (R = Ph, 1-naphthyl) (I) were prepd. in good yields by the reaction of 2 equiv of (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine with 1 equiv of thiophosgene under basic conditions. The presence of asym. elements in I, and their capacity to act as receptors for anionic species via hydrogen bonding were exploited in the development of 1H NMR spectroscopic enantiodiscrimination of chiral carboxylic acids. In particular, the diastereomeric complexes derived from thioureas I with ammonium salts of the chiral acids gave rise to well sepd. signals of the α-hydrogens and simple integration provides the corresponding enantiomeric ratios. Furthermore, it was obsd. that Cα-H in the (R)-enantiomers of the chiral α-hydroxy- and α-amino acids consistently appears downfield relative to the same signals in the (S)-enantiomers.
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Kyne, G. M.; Light, M. E.; Hursthouse, M. B.; de Mendoza, J.; Kilburn, J. D. Enantioselective amino acid recognition using acyclic thiourea receptors. J. Chem. Soc., Perkin Trans. 1 2001, 1258– 1263, DOI: 10.1039/b102298a
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Enantioselective amino acid recognition using acyclic thiourea receptors
Kyne, Graham M.; Light, Mark E.; Hursthouse, Mike B.; de Mendoza, Javier; Kilburn, Jeremy D.
Journal of the Chemical Society, Perkin Transactions 1 (2001), (11), 1258-1263CODEN: JCSPCE; ISSN:1472-7781. (Royal Society of Chemistry)
A series of acyclic thiourea derivs., I (X = CH, N), II and III, designed to create a cleft with four hydrogen bond donors suitable for carboxylate recognition, have been prepd., and their ability to bind to N-protected amino acid carboxylate salts has been investigated. The crystal structure of I (X = N) has been detd. showing that it forms a hydrogen bonded centrosym. dimer in the solid-state, in a conformation appropriate for the desired binding of carboxylates. The thioureas show good discrimination between different amino acids; the thioureas contg. chiral moieties show moderate enantioselectivity for a range of amino acid derivs.
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Jain, N.; Khanvilkar, A. N.; Sahoo, S.; Bedekar, A. V. Modification of Kagan’s amide for improved activity as Chiral Solvating Agent in enantiodiscrimination during NMR analysis. Tetrahedron 2018, 74, 68– 76, DOI: 10.1016/j.tet.2017.11.036
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Modification of Kagan's amide for improved activity as Chiral Solvating Agent in enantiodiscrimination during NMR analysis
Jain, Nilesh; Khanvilkar, Aditya N.; Sahoo, Sibaprasad; Bedekar, Ashutosh V.
Tetrahedron (2018), 74 (1), 68-76CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
A modification is proposed in Kagan's amide to improve its ability to offer stronger hydrogen bonding and hence better ability to bind with substrates. Introduction of chlorine in the amide arom. ring along with the two nitro groups, increases the acidic character of amide hydrogen and makes the hydrogen bond stronger, the concept is tested by making three derivs. of Kagan's amide and the effect is confirmed by NMR anal. The modified chlorinated Kagan's amides were then tested as chiral solvating agents for detection of optical purity of several types of substrates where the supramol. recognition is measured by in situ NMR anal. Several guest mols. such as amide, sulfoxide, epoxy-keto, hydroxy acid, diacid and phosphoric acid were scanned for this study and its efficiency is further established by comparison with samples of known optical purity.
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Recchimurzo, A.; Maccabruni, F.; Uccello Barretta, G.; Balzano, F. Quinine as highly responsive chiral sensor for the ¹H and ¹⁹F NMR enantiodiscrimination of N-trifluoroacetyl amino acids with free carboxyl functions. Analyst 2022, 147, 1669– 1677, DOI: 10.1039/d2an00166g
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Quinine as a highly responsive chiral sensor for the 1H and 19F NMR enantiodiscrimination of N-trifluoroacetyl amino acids with free carboxyl functions
Recchimurzo, Alessandra; Maccabruni, Fabio; Uccello Barretta, Gloria; Balzano, Federica
Analyst (Cambridge, United Kingdom) (2022), 147 (8), 1669-1677CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
Hydrogen-bond accepting and enantiodiscriminating abilities of quinine (Qui) have been exploited in the enantiodiscrimination of N-trifluoroacetyl (TFA) derivs. of amino acids by NMR (NMR) spectroscopy. NMR 1H and 19F resonances of derivs. of alanine, valine, leucine, norvaline, phenylalanine, phenylglycine, methionine, glutamic acid, proline, and tryptophan were well differentiated employing CDCl3 and/or C6D6 as solvent, with Qui acting in some cases not only as enantiodiscriminating agent, but also as soly. promoter. For derivs. sol. in both solvents, the best results were obtained in benzene-d6, with very high nonequivalence values, which were detectable not only starting from very low equimolar concns. of 0.1 mM, but also in the presence of sub-stoichiometric amts. of Qui. The quality of enantiodifferentiation has been also evaluated by means of the enantioresoln. quotient E. The method has been applied to the detection and quantification of mixts. of amino acid derivs. by single point measurements.
34
Fang, L.; Lv, C.; Wang, G.; Feng, L.; Stavropoulos, P.; Gao, G.; Ai, L.; Zhang, J. Discrimination of Enantiomers of Dipeptide Derivatives with Two Chiral Centers by Tetraaza Macrocyclic Chiral Solvating Agents Using ¹H NMR Spectroscopy. Org. Chem. Front. 2016, 3, 1716– 1724, DOI: 10.1039/c6qo00521g
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Discrimination of enantiomers of dipeptide derivatives with two chiral centers by tetraaza macrocyclic chiral solvating agents using 1H NMR spectroscopy
Fang, Lixia; Lv, Caixia; Wang, Guo; Feng, Lei; Stavropoulos, Pericles; Gao, Guangpeng; Ai, Lin; Zhang, Jiaxin
Organic Chemistry Frontiers (2016), 3 (12), 1716-1724CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
1H NMR spectroscopy is often used to discriminate enantiomers of chiral analytes and det. their enantiomeric excess (ee) by various chiral auxiliaries. In reported research, these studies were mainly focused on chiral discrimination of chiral analytes with only one chiral center. However, many chiral compds. possessing two or more chiral centers are often found in natural products, chiral drugs, products of asym. synthesis and biol. systems. Therefore, it is necessary to investigate their chiral discrimination by effective chiral auxiliaries using 1H NMR spectroscopy. In this paper, a new class of tetraaza macrocyclic chiral solvating agents (TAMCSAs) with two amide (CONH), two amino (NH) and two phenolic hydroxyl (PhOH) groups has been designed and synthesized for chiral discrimination towards dipeptide derivs. with two chiral centers. These dipeptide derivs. are important chiral species because some of them are used as clin. drugs and special dietary supplements for treatment of human diseases, such as L-alanyl-L-glutamine and aspartame. The results show that these TAMCSAs have excellent chiral discriminating properties and offer multiple detection possibilities pertaining to 1H NMR signals of diagnostic split protons. The nonequivalent chem. shifts (up to 0.486 ppm) of various types of protons of these dipeptide derivs. were evaluated with the assistance of well-resolved 1H NMR signals in most cases. In addn., enantiomeric excesses (ee) of the dipeptide derivs. with different optical compns. have been calcd. based on integration of well-sepd. proton signals. At the same time, the possible chiral discriminating behaviors have been discussed by means of Job plots, ESI mass spectra and a proposed theor. model of (±)-G1 with TAMCSA 1c. Addnl., the assocn. consts. of enantiomers of (±)-G5 with TAMCSA 1a were calcd. by employing the nonlinear curve-fitting method.
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Tanaka, K.; Iwashita, T.; Sasaki, C.; Takahashi, H. Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives. Tetrahedron: Asymmetry 2014, 25, 602– 609, DOI: 10.1016/j.tetasy.2014.03.009
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Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives
Tanaka, Koichi; Iwashita, Tomoharu; Sasaki, Chihiro; Takahashi, Hiroki
Tetrahedron: Asymmetry (2014), 25 (8), 602-609CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
Novel 46-membered chiral rhombamine macrocycles I (X = CH2, O) and 8b were synthesized by [2+2] cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and subsequent redn. with NaBH4. The x-ray crystal structure of 1:4 dioxane complex with I (X = CH2) indicated a rhombus conformation of the chiral macrocycle. I (X = CH2, O) were tested as chiral shift reagents for a wide range of α-substituted carboxylic acids and amino acid derivs. Enantiodiscrimination of 1H NMR signals was obsd. with ΔΔδ values of up to 0.214 ppm.
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Quinn, T. P.; Atwood, P. D.; Tanski, J. M.; Moore, T. F.; Folmer-Andersen, J. F. Aza-crown macrocycles as chiral solvating agents for mandelic acid derivatives. J. Org. Chem. 2011, 76, 10020– 10030, DOI: 10.1021/jo2018203
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Aza-Crown Macrocycles as Chiral Solvating Agents for Mandelic Acid Derivatives
Quinn, Thomas P.; Atwood, Philip D.; Tanski, Joseph M.; Moore, Tyler F.; Folmer-Andersen, J. Frantz
Journal of Organic Chemistry (2011), 76 (24), 10020-10030CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
New chiral macrocycles contg. the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and oligoethylene glycol-derived spacers were prepd. in enantiomerically pure form. Four of the macrocycles were characterized by x-ray crystallog., which reveals a consistent mode of intramol. N-H···N hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles differentiate the enantiomers of mandelic acid (MA) by 1H NMR spectroscopy in CDCl3; within macrocycles tested, enantiodiscrimination were promoted by (i) a meta-linkage geometry about the arene spacer, (ii) the presence of naphthalene, rather than phenylene-derived arene spacers, and (iii) increasing length of the oligoethylene glycol bridge. 1H NMR titrns. were performed with optically pure MA samples, and the data were fitted to a simultaneous 1:1 and 2:1 binding model, yielding ests. of 2:1 binding consts. between some of the macrocycles and MA enantiomers. In several cases, NOESY spectra of the MA:macrocycle complexes show differential intramol. correlations between protons adjacent to the amine and carboxylic acid groups of the macrocycles and MA enantiomers, resp., thus demonstrating geometric differences between the diastereomeric intermol. complexes. The three most effective macrocycles were employed as chiral solvating agents (CSAs) to det. the enantiomeric excess (ee) of 18 MA samples over a wide ee range and with very high accuracy (1% abs. error).
37
Klika, K. D. Use of sub-stoichiometric amounts of chiral auxiliaries for enantiodifferentiation by NMR; caveats and potential utility. Tetrahedron: Asymmetry 2009, 20, 1099– 1102, DOI: 10.1016/j.tetasy.2009.03.036
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Use of sub-stoichiometric amounts of chiral auxiliaries for enantiodifferentiation by NMR; caveats and potential utility
Klika, Karel D.
Tetrahedron: Asymmetry (2009), 20 (10), 1099-1102CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
Chem. shift (δ) order reversal of the population-weighted averaged NMR signals for enantiomers when using sub-stoichiometric levels of a chiral auxiliary (CA) can occur when the δ difference between the enantiomer-CA complexes and the signal of the free enantiomers is greater for the less-stable complex. The potential utility of CA titrn. curves with regard to ΔG evaluation, configuration detn., and modeling validation is considered.
38
Pérez-Trujillo, M.; Monteagudo, E.; Kuhn, L. T. NMR-aided differentiation of enantiomers: signal enantioresolution. Anal. Chim. Acta 2015, 876, 63– 70, DOI: 10.1016/j.aca.2015.02.069
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NMR-aided differentiation of enantiomers: Signal enantioresolution
Perez-Trujillo, Miriam; Parella, Teodor; Kuhn, Lars T.
Analytica Chimica Acta (2015), 876 (), 63-70CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
NMR-aided enantiodiscrimination using chiral auxiliaries (CAs) is a recognized method for differentiating enantiomers and for measuring enantiomeric ratios (er). Up to the present, the study, optimization, and comparison of such methods have been performed based on the enantiodifferentiation of NMR signals via analyzing non-equiv. chem.-shift values (ΔΔδ) of the diastereoisomeric species formed. However, a poor and non-reliable comparison of results is often obtained via the anal. of ΔΔδ exclusively. In here, the concept of enantioresoln. of an individual NMR signal and its importance for NMR-aided enantiodifferentiation studies is introduced and discussed. In addn., the enantioresoln. quotient, E, is proposed as the parameter to describe its quantification. Complementary to measuring ΔΔδ, the exptl. detn. of E allows a more reliable interpretation of the results and opens up new possibilities for the study of enantiodifferentiation data derived from novel NMR expts., setup improvements or new CAs. Finally, the different relationships between signal enantiodifferentiation, signal enantioresoln., and other main exptl. issues of enantiodifferentiation expts. are addressed.
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Supady, A.; Hecht, S.; Baldauf, C. About Underappreciated Yet Active Conformations of Thiourea Organocatalysts. Org. Lett. 2017, 19, 4199– 4202, DOI: 10.1021/acs.orglett.7b01782
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About Underappreciated Yet Active Conformations of Thiourea Organocatalysts
Supady, Adriana; Hecht, Stefan; Baldauf, Carsten
Organic Letters (2017), 19 (16), 4199-4202CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Conformational dynamics can define the function of organocatalysts. While the accepted mechanism of Schreiner's catalyst features a double hydrogen bond to the substrate that only forms with the anti-anti conformation of its central thiourea group, our electronic-structure theory study reveals that binding of the model substrate Me vinyl ketone prefers syn-anti conformations. We find a new mechanism featuring π stacking interactions and highlight the need for extensive structure searches for flexible mols., esp. when aiming for structure-based design of catalytic activity.
41
Madarász, A.; Dósa, Z.; Varga, S.; Soós, T.; Csámpai, A.; Pápai, I. Thiourea Derivatives as Brønsted Acid Organocatalysts. ACS Catal. 2016, 6, 4379– 4387, DOI: 10.1021/acscatal.6b00618
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Thiourea Derivatives as Bronsted Acid Organocatalysts
Madarasz, Adam; Dosa, Zsolt; Varga, Szilard; Soos, Tibor; Csampai, Antal; Papai, Imre
ACS Catalysis (2016), 6 (7), 4379-4387CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
Combined computational-exptl. studies were carried out to parallel two mechanistic models for tetrahydropyranylation of alcs. catalyzed by Schreiner's thiourea. The results challenge the common mechanistic view that the catalytic effect is related to stabilizing double hydrogen-bonding interactions between the thiourea and the alc., which promote the attack on 3,4-dihydro-2H-pyran (DHP) (hydrogen bonding (HB) mechanism). In the alternative mechanism that we propose, thiourea acts as a Bronsted acid, protonating DHP to form an oxacarbenium ion, which reacts with the alc. (Bronsted acid (BA) mechanism). Computations point to clear preference of transition states assocd. with the BA mechanism and, accordingly, predict similar catalytic activity for N-methylated thiourea and thiouracil. These predictions are confirmed exptl. Reactions with deuterated alcs. yield both syn and anti products, providing further support for the Bronsted acid mechanism.
42
Nie, S.-X.; Guo, H.; Huang, T.-Y.; Ao, Y.-F.; Wang, D.-X.; Wang, Q.-Q. Xenon binding by a tight yet adaptive chiral soft capsule. Nat. Commun. 2020, 11, 6257, DOI: 10.1038/s41467-020-20081-8
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Xenon binding by a tight yet adaptive chiral soft capsule
Nie, Shi-Xin; Guo, Hao; Huang, Teng-Yu; Ao, Yu-Fei; Wang, De-Xian; Wang, Qi-Qiang
Nature Communications (2020), 11 (1), 6257CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
Xenon binding has attracted interest due to the potential for xenon sepn. and emerging applications in magnetic resonance imaging. Compared to their covalent counterparts, assembled hosts that are able to effectively bind xenon are rare. Here, we report a tight yet soft chiral macrocycle dimeric capsule for efficient and adaptive xenon binding in both crystal form and soln. The chiral bisurea-bisthiourea macrocycle can be easily synthesized in multi-gram scale. Through assembly, the flexible macrocycles are locked in a bowl-shaped conformation and buckled to each other, wrapping up a tight, completely sealed yet adjustable cavity suitable for xenon, with a very high affinity for an assembled host. A slow-exchange process and drastic spectral changes are obsd. in both 1H and 129Xe NMR. With the easy synthesis, modification and reversible characteristics, we believe the robust yet adaptive assembly system may find applications in xenon sequestration and magnetic resonance imaging-based biosensing.
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Phillips, A. M. F.; Prechtl, M. H. G.; Pombeiro, A. J. L. Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts. Catalysts 2021, 11, 569, DOI: 10.3390/catal11050569
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Non-covalent interactions in enantioselective organocatalysis: theoretical and mechanistic studies of reactions mediated by dual H-bond donors, bifunctional squaramides, thioureas and related catalysts
Phillips, Ana Maria Faisca; Prechtl, Martin H. G.; Pombeiro, Armando J. L.
Catalysts (2021), 11 (5), 569CODEN: CATACJ; ISSN:2073-4344. (MDPI AG)
A review. Chiral bifunctional dual H-bond donor catalysts have become one of the pillars of organocatalysis. They include squaramide, thiosquaramide, thiourea, urea, and even selenourea-based catalysts combined with chiral amines, cinchona alkaloids, sulfides, phosphines and more. They can promote several types of reactions affording products in very high yields and excellent stereoselectivities in many cases: conjugate addns., cycloaddns., the aldol and Henry reactions, the Morita-Baylis-Hilman reaction, even cascade reactions, among others. The desire to understand mechanisms and the quest for the origins of stereoselectivity, in attempts to find guidelines for developing more efficient catalysts for new transformations, has promoted many mechanistic and theor. studies. In this review, we survey the literature published in this area since 2015.
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Heshmat, M. Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst. J. Phys. Chem. A 2018, 122, 7974– 7982, DOI: 10.1021/acs.jpca.8b04589
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Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst
Heshmat, Mojgan
Journal of Physical Chemistry A (2018), 122 (40), 7974-7982CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
In this work, we report an energy decompn. and electronic structure anal. using DFT calcns. for the C-C coupling step in the Henry reaction with cinchona thiourea as catalyst and DMF solvent to unravel the origin of enantioselectivity. We found that the conformation of flexible thiourea moiety is affected by the solvent, and in the preferred conformation of thiourea in strong Lewis basic DMF solvent, the N-H sites are in the opposite direction, i.e., in trans conformation. Hence, the thiourea moiety acts via single hydrogen bonding with substrates. The conformation of the substrates with respect to the forming C-C bond plays crit. role to increase orbital interaction between two substrates and enhances hydrogen bond strength between substrates and catalyst, which in turn stabilizes the pos. charge developing on the catalyst at the transition state for one of the enantiomers (S). Thus, the enantioselectivity has electronic structure origin. The stronger H-bond formation in the S enantiomer has been confirmed by the calcd. IR spectra and is in agreement with thus far exptl. and computational results.
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Ren, J.; Diprose, J.; Warren, J.; Esnouf, R. M.; Bird, L. E.; Ikemizu, S.; Slater, M.; Milton, J.; Balzarini, J.; Stuart, D. I.; Stammers, D. K. Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses. J. Biol. Chem. 2000, 275, 5633– 5639, DOI: 10.1074/jbc.275.8.5633
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Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases: Structural and biochemical analyses
Ren, Jingshan; Diprose, Jonathan; Warren, Jonathan; Esnouf, Robert M.; Bird, Louise E.; Ikemizu, Shinji; Slater, Martin; Milton, John; Balzarini, Jan; Stuart, David I.; Stammers, David K.
Journal of Biological Chemistry (2000), 275 (8), 5633-5639CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-2 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolythiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC50 of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC50 of 5 nM) and also inhibits HIV-2 RT (IC50 of 2.2 μM). X-ray crystallog. structure detns. of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compds. bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC)·(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.

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Figure 1
Figure 1. CSAs and amino acid derivative structures (TFA = trifluoroacetyl, Ac = acetyl, and DNB = 3,5-dinitrobenzoyl).
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Scheme 1
Scheme 1. Synthesis of TFTMA, TFTDA, and TFTPA
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Figure 2
Figure 2. ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to DNB resonances of 18–23 (15 mM)/DABCO/BTDA or TFTDA (1:1:1). ○ and ● indicate ortho- and para-DNB resonances, respectively. * indicates CSA resonances. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.
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Figure 3
Figure 3. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral regions corresponding to CF₃ resonances of 1–3 (15 mM) and ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to acetyl resonances of 11–13 (15 mM) in the presence of 1 equiv of DABCO and BTDA or TFTDA. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.
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Figure 4
Figure 4. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral regions corresponding to CF₃ resonances of 1–3 (15 mM) and ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to acetyl resonances of 11–13 (15 mM) in the presence of 1 equiv of DABCO and 1 equiv of TFTDA or 2 equiv of TFTMA. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.
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Figure 5
Figure 5. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral regions corresponding to CF₃ (△) of 1–10 (15 and 5 mM) and ¹H NMR (600 MHz, CDCl₃, 25 °C) spectral regions corresponding to acetyl (△) of 11–17 (15 and 5 mM) in the presence of 1 equiv of DABCO (2 equiv for 10) and TFTDA. ▲ indicates the syn stereoisomer of 8. □ indicates methylthio resonances of 7 and 17, and + indicates side chain protons of 7. Racemic or enantiomerically enriched samples of amino acid derivatives were analyzed. Nonequivalences in ppm are reported on resonances.
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Figure 6
Figure 6. ¹⁹F NMR (564 MHz, CDCl₃, 25 °C) spectral region corresponding to CF₃ resonances of enantiomerically enriched (ee +90, R/S = 95:5) 3 (15 mM) in the presence of 1 equiv of DABCO and 1 equiv of TFTDA.
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Figure 7
Figure 7. Schematic 3D representation of TFTDA according to NMR data and its Newman projection.
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Figure 8
Figure 8. Schematic model of two diastereomeric complexes (S)-16/TFTDA/DABCO and (R)-16/TFTDA/DABCO.
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References
This article references 45 other publications.
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  A review. Detn. of enantiomeric ratios in food and beverages is a research area of great interest because enantiomers can exhibit different biol. activities. Chiral anal. can provide valuable information about food safety, bioactivity, quality and traceability. In this work, the potential of sepn. techniques such as liq. chromatog., gas chromatog., supercrit. fluid chromatog. and capillary electrophoresis for chiral anal. of food is reviewed. The anal. of enantiomers based on other chiral methodologies such as countercurrent chromatog., sensors, biosensors and direct mass spectrometry (MS) anal. is also included. The present review article provides an updated perspective on the importance of chiral anal. in food matrixes and beverages covering the period from Feb. 2017 to July 2019, following the previous work published in this journal on the same topic (G. D'Orazio et al., TrAC-Trends in Anal. Chem. 96 (2017) 151-171).
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  Balzano, F.; Uccello-Barretta, G.; Aiello, F. Chiral Analysis by NMR Spectroscopy: Chiral Solvating Agents. In Chiral Analysis: Advances in Spectroscopy, Chromatography and Emerging Methods, 2nd ed.; Polavarapu, P. L., Ed.; Elsevier Ltd.: Amsterdam, The Netherlands, 2018; pp 367– 427.
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  Recent advances in multinuclear NMR spectroscopy for chiral recognition of organic compounds
  Silva, Marcio S.
  Molecules (2017), 22 (2), 247/1-247/21CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  NMR (NMR) is a powerful tool for the elucidation of chem. structure and chiral recognition. In the last decade, the no. of probes, media, and expts. to analyze chiral environments has rapidly increased. The evaluation of chiral mols. and systems has become a routine task in almost all NMR labs., allowing for the detn. of mol. 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 1H, the minimal influence of the exptl. conditions, and the larger shift dispersion make these nuclei esp. suitable for NMR anal. Herein, the recent advances in multinuclear (19F, 31P, 13C, and 77Se) NMR spectroscopy for chiral recognition of org. compds. are presented. The review describes new chiral derivatizing agents and chiral solvating agents used for stereodiscrimination and the assignment of the abs. configuration of small org. compds.
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  Uccello-Barretta, Gloria; Balzano, Federica
  Topics in Current Chemistry (2013), 341 (Differentiation of Enantiomers II), 69-131CODEN: TPCCAQ; ISSN:0340-1022. (Springer GmbH)
  This chapter will describe the general features and main categories of chiral solvating agents (CSAs) for NMR spectroscopy, spanning from low-medium sized CSAs to macrocyclic ones. CSAs based on chiral ionic liqs. (CILs) will be introduced in view of their increasing popularity, and, finally, a short paragraph will be dedicated to special applications of CSAs in particular exptl. conditions. Several valuable works, which are mainly devoted to investigate enantiodifferentiation mechanisms by NMR, will not be discussed. The main objective is to identify the current trend in the research areas dedicated to the development of new CSAs for NMR spectroscopy.
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  Enantiomerically pure chiral auxiliary agents are often used in NMR spectroscopy to facilitate the differentiation of enantiomers. Chiral derivatizing agents are covalently bound to the substrate and differences in chem. shifts of the resulting diastereomeric complexes are used in the anal. Macrocycles such as cyclodextrins, crown ethers, and calix[4]resorcinarenes are chiral solvating agents that assoc. with the substrate through non-covalent interactions. Enantiomeric differentiation occurs in the NMR spectrum because of the diastereomeric nature of the assocd. complexes and/or because of the differences in assocn. consts. between the two enantiomers and the chiral reagent. Metal complexes are Lewis acids that bind to suitable Lewis base donor compds. Exchange of substrate can be slow or fast depending on the particular metal ion, mimicking the behavior of a chiral derivatizing or solvating agent, resp. Chiral liq. crystals undergo a partial alignment in an applied magnetic field and enantiomers dissolved in the liq. crystal undergo a partial alignment as well. If the alignment of the two enantiomers is different, enantiomeric differentiation can potentially be obsd. by differences in chem. shifts, differences in dipolar coupling consts., and different magnitudes of splitting of quadrupolar nuclei such as deuterium. The chiral reagents described herein can be used to det. enantiomeric compn. and sometimes to assign abs. configuration. Significant discoveries as well as recent findings with each of these types of systems are described.
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  Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems
  Maria Faisca Phillips, Ana; Pombeiro, Armando J. L.
  European Journal of Organic Chemistry (2021), 2021 (29), 3938-3969CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The presence of a halogen atom in a mol. can have a large effect in its properties; for instance, halogens are used in drugs to improve lipophilicity, membrane permeability and absorption, and even the blood-brain barrier permeability. As highlighted in this review, there are nowadays a range of highly selective, versatile halogenating reagents, electrophilic, nucleophilic or radical in nature, which operate under mild conditions, allowing late-stage functionalization of complex mols. in cascade reactions. Recent developments in organocatalyst design revealed novel Cinchona alkaloids derivs., chiral phosphoric acids, amines, phosphines and several bifunctional catalysts, mostly thiourea- or squaramide-based, which introduced chirality, with high levels of enantio- and diastereoselection, in the formation of one or multiple chiral centers in a single synthetic operation, as shown. The literature published in this field from 2014 to 2020 were surveyed.
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  Synthesis of Sustainable Polyesters via Organocatalytic Ring-Opening Polymerization of O-carboxyanhydrides: Advances and Perspectives
  Wang, Jianqun; Tao, Youhua
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  A review. Sustainable polyesters can be furnished via ring-opening polymn. (ROP) of O-carboxyanhydrides (OCAs). Various catalysts, esp. metal-based catalysts, are devised to achieve controlled ROP of OCAs. In the following mini review, the recent progress on the organocatalytic ROP of OCAs, including the usage of thiourea-based bifunctional single-mol. organocatalysts for eliminating epimerization in OCAs polymn. is summarized. Moreover, the future development of the organocatalytic ROP of OCAs for the synthesis of sustainable polyesters will be discussed.
14. 14
  Parvin, T.; Yadav, R.; Choudhury, L. H. Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs). Org. Biomol. Chem. 2020, 18, 5513– 5532, DOI: 10.1039/d0ob00595a
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  Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs)
  Parvin, Tasneem; Yadav, Rahul; Choudhury, Lokman H.
  Organic & Biomolecular Chemistry (2020), 18 (29), 5513-5532CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A review. One-pot multiple bond-forming reactions under metal-free conditions have tremendous potential in org. and medicinal chem. considering their synthetic efficiency and eco-friendliness. In this direction, organocatalysis, i.e. application of org. mols. as catalysts, in multicomponent reactions is one of the best combinations for the prepn. of complex mols. in min. steps under green reaction conditions. Thiourea-based org. mols. show excellent catalytic activity in various transformations by their unique double H-bonding activation process. Chiral org. mols. having a thiourea backbone are well-recognized catalysts for the enantioselective synthesis of diverse products from asym. two- or multicomponent reactions. Simultaneous dual activation of the electrophile and the nucleophile in an MCR by using bifunctional thiourea-based chiral organocatalysts has gained considerable interest in recent times. Although several review articles are available in the literature on organocatalysis, asym. domino reactions, or multicomponent reactions using various organocatalysts, however, to date there has been no dedicated review article on this emerging topic, i.e. asym. multicomponent reactions catalyzed by thiourea-based organocatalysts. Thus, this review aims to highlight the recent applications of thiourea-based organocatalysts in asym. multicomponent reactions.
15. 15
  Jain, I.; Malik, P. Advances in urea and thiourea catalyzed ring opening polymerization: A brief overview. Eur. Polym. J. 2020, 133, 109791, DOI: 10.1016/j.eurpolymj.2020.109791
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  Advances in urea and thiourea catalyzed ring opening polymerization: A brief overview
  Jain, Isha; Malik, Payal
  European Polymer Journal (2020), 133 (), 109791CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)
  A review. Hydrogen bond-mediated organocatalysis has emerged as a very powerful strategy for the synthesis of structurally well-defined polymers. Urea and thiourea derivs. are among one of the extensively explored hydrogen-bonding organocatalysts for ring opening polymn. These catalytic systems have potential to exquisitely control the activity and selectivity of the polymn. processes, the field has witnessed astonishing development in recent years. This review documents advances in the field of urea and thiourea catalyzed ring-opening polymn. since their debut in 2005, with an emphasis on seminal work of Hedrick and Waymouth groups. The first part of the review discusses one component bifunctional urea and thiourea catalyzed ring-opening polymn. of cyclic monomers and in the second part newly developed two component bifunctional urea and thiourea catalysts are described. The third part provides an overview of dual urea and thiourea-base catalyzed ringopening polymn. and copolymn. of cyclic monomers such as esters, carbonates, phosphates, anhydrides and epoxides. The final part is concluded by highlighting the challenges and future opportunities for urea and thiourea systems in polymer synthesis.
16. 16
  Steppeler, F.; Iwan, D.; Wojaczyńska, E.; Wojaczyński, J. Chiral thioureas-preparation and significance in asymmetric synthesis and medicinal chemistry. Molecules 2020, 25, 401, DOI: 10.3390/molecules25020401
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  Chiral thioureas-preparation and significance in asymmetric synthesis and medicinal chemistry
  Steppeler, Franz; Iwan, Dominika; Wojaczynska, Elzbieta; Wojaczynski, Jacek
  Molecules (2020), 25 (2), 401pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
  A review. For almost 20 years, thioureas have been experiencing a renaissance of interest with the emerged development of asym. organocatalysts. Due to their relatively high acidity and strong hydrogen bond donor capability, they differ significantly from ureas and offer, appropriately modified, great potential as organocatalysts, chelators, drug candidates, etc. The review focuses on the family of chiral thioureas, presenting an overview of the current state of knowledge on their synthesis and selected applications in stereoselective synthesis and drug development.
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  Zhang, H.; Zhao, H.; Wen, J.; Zhang, Z.; Stavropoulos, P.; Li, Y.; Ai, L.; Zhang, J. Discrimination of Enantiomers of amides with two stereogenic centers enabled by chiral bisthiourea derivatives using ¹H NMR spectroscopy. Org. Biomol. Chem. 2021, 19, 6697– 6706, DOI: 10.1039/d1ob00742d
  17
  Discrimination of enantiomers of amides with two stereogenic centers enabled by chiral bisthiourea derivatives using 1H NMR spectroscopy
  Zhang, Hanchang; Zhao, Hongmei; Wen, Jie; Zhang, Zhanbin; Stavropoulos, Pericles; Li, Yanlin; Ai, Lin; Zhang, Jiaxin
  Organic & Biomolecular Chemistry (2021), 19 (30), 6697-6706CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Enantiomers of a few new amides contg. two stereogenic centers have been derived from D- and L-α-amino acids as guests for chiral recognition by 1H NMR spectroscopy. A variety of chiral amides with two or more stereogenic centers often exist in the products of catalytic asym. synthesis, natural products or their total synthetic products, and chiral drugs. It would be a challenging and meaningful work to explore their chiral recognition. For this purpose, a class of novel chiral bisthiourea derivs. 1-9 has been synthesized from (1S,2S)-(+)-1,2-diaminocyclohexane, D-α-amino acids, and isothiocyanates as chiral solvating agents (CSAs). CSAs 1-9 proved to afford better chiral discriminating results towards most amides with two stereogenic centers, which have been rarely studied as chiral substrates by 1H NMR spectroscopy. In particular, CSAs 7, 8 and 9, featuring 3,5-bis(trifluoromethyl)benzene residues, exhibit outstanding chiral discriminating capabilities towards all amides, providing well-sepd. 1H NMR signals and sufficiently large nonequivalent chem. shifts. To test their practical application in the detn. of enantiomeric excess, 1H NMR spectra of chiral amides (G16) with different optical purities were measured in the presence of CSAs 7 and 8, resp. Their ee values (up to 90%) were accurately calcd. by the integration of the NH proton of the CONHPh group of G16. To better understand the chiral discriminating behavior, Job plots of (±)-G16 with CSA 7 and (±)-G17 with CSA 8 and the assocn. consts. (Ka) of (S,R)-G16 and (R,S)-G16 with CSA 7 were evaluated, resp. In order to further reveal any underlying intermol. hydrogen bonding interactions, theor. calcns. of the enantiomers of (S,R)-G16 and (R,S)-G16 with CSA 7 were performed by means of the hybrid d. functional theory (B3LYP) with the std. basis sets of 3-21G of the Gaussian 03 program, resp.
18. 18
  Recchimurzo, A.; Micheletti, C.; Uccello-Barretta, G.; Balzano, F. A Dimeric Thiourea CSA for the Enantiodiscrimination of Amino Acid Derivatives by NMR Spectroscopy. J. Org. Chem. 2021, 86, 7381– 7389, DOI: 10.1021/acs.joc.1c00340
  18
  A Dimeric Thiourea CSA for the Enantiodiscrimination of Amino Acid Derivatives by NMR Spectroscopy
  Recchimurzo, Alessandra; Micheletti, Cosimo; Uccello-Barretta, Gloria; Balzano, Federica
  Journal of Organic Chemistry (2021), 86 (11), 7381-7389CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The reaction of benzoyl isothiocyanate with (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine afforded a new thiourea chiral solvating agent I (CSA) with a very high ability to differentiate 1H and 13C NMR signals of simple amino acid derivs., even at low concns. The enantiodiscrimination efficiency was higher with respect to that of the parent monomer, a thiourea deriv. of 2-((1R)-1-aminoethyl)phenol, thus putting into light the relevance of the cooperativity between the two mol. portions of the dimer in a cleft conformation stabilized by interchain hydrogen bond interactions. An achiral base additive (DABCO or DMAP) played an active role in the chiral discrimination processes, mediating the interaction between the CSA and the enantiomeric mixts. The chiral discrimination mechanism was investigated by NMR spectroscopy through the detn. of complexation stoichiometries, assocn. consts., and the stereochem. of the diastereomeric solvates.
19. 19
  Recchimurzo, A.; Micheletti, C.; Uccello-Barretta, G.; Balzano, F. Thiourea Derivative of 2-[(1R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy. J. Org. Chem. 2020, 85, 5342– 5350, DOI: 10.1021/acs.joc.0c00027
  19
  Thiourea Derivative of 2-[(1R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy
  Recchimurzo, Alessandra; Micheletti, Cosimo; Uccello-Barretta, Gloria; Balzano, Federica
  Journal of Organic Chemistry (2020), 85 (8), 5342-5350CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Thiourea derivs. of 2-[(1R)-1-aminoethyl]phenol, (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, (1R,2R)-(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, and (R)-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using NMR (NMR) spectroscopy. Thiourea deriv., prepd. by reacting 2-[(1R)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of N-3,5-dinitrobenzoyl (DNB) derivs. of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.2.2]octane(DABCO)/N,N-dimethylpyridin-4-amine (DMAP)/(NBu4OH) is required both to solubilize amino acid derivs. with free carboxyl groups in CDCl3 and to mediate their interaction with the chiral auxiliary to attain efficient differentiation of the NMR signals of enantiomeric substrates. For ternary systems CSA/substrate/DABCO, the chiral discrimination mechanism has been ascertained through the NMR detn. of complexation stoichiometry, assocn. consts., and stereochem. features of the diastereomeric solvates.
20. 20
  Gunal, S. E.; Tuncel, S. T.; Dogan, I. Enantiodiscrimination of carboxylic acids using single enantiomer thioureas as chiral solvating agents. Tetrahedron 2020, 76, 131141, DOI: 10.1016/j.tet.2020.131141
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  Chen, Z.; Fan, H.; Yang, S.; Bian, G.; Song, L. Chiral sensors for determining the absolute configurations of α-amino acid derivatives. Org. Biomol. Chem. 2018, 16, 8311– 8317, DOI: 10.1039/c8ob01933a
  21
  Chiral sensors for determining the absolute configurations of α-amino acid derivatives
  Chen Zhongxiang; Fan Hongjun; Yang Shiwei; Bian Guangling; Song Ling
  Organic & biomolecular chemistry (2018), 16 (37), 8311-8317 ISSN:.
  A simple strategy for configurational assignments of alpha-amino acids has been developed by comparison of the proton NMR chemical shift values of the alpha hydrogens of N-phthaloyl protected alpha-amino acids in the presence of (R)-CSA 1 and (S)-CSA 1, respectively. Highly resolved NMR spectra can be obtained directly on the mixed solution of the chiral solvating agents with N-phthaloyl protected alpha-amino acids in NMR tubes, giving well distinguishable proton signals without interference which dramatically improve the accuracy of assignment and hasten the assigning procedure. The strategy is widely applicable for varied natural and non-natural amino acids.
22. 22
  Ito, S.; Okuno, M.; Asami, M. Differentiation of enantiomeric anions by NMR spectroscopy with chiral bisurea receptors. Org. Biomol. Chem. 2018, 16, 213– 222, DOI: 10.1039/c7ob02318a
  22
  Differentiation of enantiomeric anions by NMR spectroscopy with chiral bisurea receptors
  Ito, Suguru; Okuno, Manami; Asami, Masatoshi
  Organic & Biomolecular Chemistry (2018), 16 (2), 213-222CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  Chiral anionic species are ubiquitous and play important roles in biol. systems. Despite the recent advancements in synthetic anion receptors bearing urea functionalities, urea-based chiral solvating agents (CSAs) that can sep. the NMR signals of racemic anions remain limited. Herein, three dibenzofuran-based C2-sym. chiral bisureas were synthesized from the reaction of (R,R)-4,6-bis(1-aminopropyl)dibenzo[b,d]furan with Ph isocyanate, Ph thioisocyanate, or tosyl isocyanate. The chiral anion recognition properties of these bisureas were examd. by 1H NMR spectroscopy using DL-tetrabutylammonium mandelate (TBAM) as a model substrate. A clear baseline sepn. of the enantiomeric signals of the benzylic proton of TBAM was achieved upon mixing with 0.5 equiv of bis(phenylurea). In contrast to previous urea-based chiral anion receptors that differentiate the enantiomers of chiral anions by forming 1 : 1 host-guest complexes, a high chiral recognition ability of chiral bis(phenylurea) was achieved owing to the generation of an equil. between free guests, 1 : 1 host-guest complexes, and 1 : 2 host-guest complexes. Chiral bis(phenylurea) was also successfully employed in the sepn. of the enantiomeric 1H NMR signals of various racemic anions.
23. 23
  Bian, G.; Yang, S.; Huang, H.; Zong, H.; Song, L. A bisthiourea-based ¹H NMR chiral sensor for chiral discrimination of a variety of chiral compounds. Sens. Actuators, B 2016, 231, 129– 134, DOI: 10.1016/j.snb.2016.03.002
  23
  A bisthiourea-based 1H NMR chiral sensor for chiral discrimination of a variety of chiral compounds
  Bian, Guangling; Yang, Shiwei; Huang, Huayin; Zong, Hua; Song, Ling
  Sensors and Actuators, B: Chemical (2016), 231 (), 129-134CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
  A simple one-step synthesized bisthiourea has been used as a highly efficient and versatile chiral sensor for rapid chiral discrimination and enantiomeric excess detn. of a wide range of chiral compds. contg. alc., sulfoxide, lactone, epoxide, amino alc., amide, β-chiral carboxylic acid and remote chiral carboxylic acid with the use of 1H NMR signals.
24. 24
  Cios, P.; Romański, J. Enantioselective recognition of sodium carboxylates by an 1,8-diaminoanthracene based ion pair receptor containing amino acid units. Tetrahedron Lett. 2016, 57, 3866– 3869, DOI: 10.1016/j.tetlet.2016.07.053
  24
  Enantioselective recognition of sodium carboxylates by an 1,8-diaminoanthracene based ion pair receptor containing amino acid units
  Cios, Paulina; Romanski, Jan
  Tetrahedron Letters (2016), 57 (34), 3866-3869CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  An anthracene based ion pair receptor contg. two amino acid units supported by cation and anion binding domains has been synthesized and shown to exhibit enhanced anion binding affinities in the presence of sodium cations. The receptor's ability to recognize enantiomers was studied using chiral carboxylates derived from 2-phenylbutyric acid, mandelic acid, and three Boc-protected amino acids. Sodium cation coordination does not influence chiral recognition but does affect the strength of anion binding. The greatest enhancement of anion binding in the presence of sodium cations was found for halides, and the highest enantiodiscrimination was found for Boc-N-tryptophan. Comparative anion and salt binding studies revealed that the simultaneous action of multiple binding domains in the structure of receptor 1 is responsible for its stronger salt assocn. and better enantioselectivity than in the case of mono-supported receptor 2.
25. 25
  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, DOI: 10.1021/acs.orglett.5b00030
  25
  Highly Effective Configurational Assignment Using Bisthioureas as Chiral Solvating Agents in the Presence of DABCO
  Bian, Guangling; Fan, Hongjun; Huang, Huayin; Yang, Shiwei; Zong, Hua; Song, Ling; Yang, Genjin
  Organic Letters (2015), 17 (6), 1369-1372CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A highly effective 1H NMR method for detg. the abs. configurations of various chiral α-hydroxyl acids and their derivs. has been developed with the use of bisthioureas (R)-CSA 1 and (S)-CSA 1 as chiral solvating agents in the presence of DABCO, giving distinguishable proton signals with up to 0.66 ppm chem. shift nonequivalence. Computational modeling studies were performed with Gaussian09 to reveal the chiral recognition mechanism.
26. 26
  Ulatowski, F.; Jurczak, J. Chiral Recognition of Carboxylates by a Static Library of Thiourea Receptors with Amino Acid Arms. J. Org. Chem. 2015, 80, 4235– 4243, DOI: 10.1021/acs.joc.5b00403
  26
  Chiral Recognition of Carboxylates by a Static Library of Thiourea Receptors with Amino Acid Arms
  Ulatowski, Filip; Jurczak, Janusz
  Journal of Organic Chemistry (2015), 80 (9), 4235-4243CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Chiral recognition is based on a large network of very subtle interactions whose outcome is difficult to predict. A combinatorial approach is therefore the most suitable to search for the most efficient receptor and obtain a structure-enantioselectivity correlation. The authors have synthesized a set of 12 receptors constructed with 1,9-diaminoanthracene and α-amino acid esters, linked via thiourea groups. The assocn. consts. and enantioselectivities for the complexes with mandelate and N-acetylphenylalanine were detd. by competitive NMR titrns. Assocn. consts. quite regularly depend on the substituents in the receptor structure, but the distribution of enantioselectivities across the library could not easily be rationalized.
27. 27
  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, DOI: 10.1021/jo4013546
  27
  A Chiral Bisthiourea as a Chiral Solvating Agent for Carboxylic Acids in the Presence of DMAP
  Bian, Guangling; Fan, Hongjun; Yang, Shiwei; Yue, Huifeng; Huang, Huayin; Zong, Hua; Song, Ling
  Journal of Organic Chemistry (2013), 78 (18), 9137-9142CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A simple chiral bisthiourea (I) was used as a highly effective and practical chem. solvating agent (CSA) for diverse α-carboxylic acids in the presence of DMAP. Excellent enantiodiscrimination based on well-resolved α-H NMR signals of the enantiomers of carboxylic acids can be obtained without interference from the chiral bisthiourea and DMAP. To check the practicality of the chiral bisthiourea/DMAP for enantiomeric detn., the ee values of mandelic acid (MA) samples over a wide ee range were detd. by integration of the α-H signal of MA in 1H NMR. A discrimination mechanism is proposed, that the formation of two diastereomeric ternary complexes between the chiral bisthiourea and two in situ formed enantiomeric carboxylate-DMAPH+ ion pairs discriminates the enantiomers of carboxylic acids. Computational modeling studies show that the chem. shift value of α-H of (S)-MA is greater than that of (R)-MA in ternary complexes, which is consistent with exptl. observation. 1-dimensional and 2-dimensional NOESY spectra demonstrate the intermol. noncovalent interactions between the protons on the arom. rings of chiral bisthiourea and α-H of the enantiomers of racemic α-methoxy phenylacetic acids in the complexes.
28. 28
  Trejo-Huizar, K. E.; Ortiz-Rico, R.; Peña-González, M. d. L. A.; Hernández-Rodríguez, M. Recognition of chiral carboxylates by 1,3-disubstituted thioureas with 1-arylethyl scaffolds. New J. Chem. 2013, 37, 2610– 2613, DOI: 10.1039/c3nj00644a
  28
  Recognition of chiral carboxylates by 1,3-disubstituted thioureas with 1-arylethyl scaffolds
  Trejo-Huizar, Karla Elisa; Ortiz-Rico, Ricardo; Pena-Gonzalez, Maria de los Angeles; Hernandez-Rodriguez, Marcos
  New Journal of Chemistry (2013), 37 (9), 2610-2613CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  Chiral thioureas with 1-arylethyl and 1-arylethyl-2-2-2-trifluoroethyl (Ar = Ph, 1-Napht, 9-Anthr) scaffolds were used as hosts to recognize acetate and chiral mandelates. The higher binding obtained with the trifluoromethyl analog is also reflected in the higher selectivity factor for one enantiomer. The C2 symmetry was also indispensable to obtain selectivity.
29. 29
  Foreiter, M. B.; Gunaratne, H. Q. N.; Nockemann, P.; Seddon, K. R..; Stevenson, P. J.; Wassell, D. F. Chiral Thiouronium salts: Synthesis, characterization and application in NMR enantio-discrimination of chiral oxoanions. New J. Chem. 2013, 37, 515– 533, DOI: 10.1039/c2nj40632b
  29
  Chiral thiouronium salts: synthesis, characterisation and application in NMR enantio-discrimination of chiral oxoanions
  Foreiter, Magdalena B.; Gunaratne, H. Q. Nimal; Nockemann, Peter; Seddon, Kenneth R.; Stevenson, Paul J.; Wassell, David F.
  New Journal of Chemistry (2013), 37 (2), 515-533CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  Chiral thioureas and functionalised chiral thiouronium salts were synthesized starting from the relatively cheap and easily available chiral amines: (S)-methylbenzylamine and rosin-derived (+)-dehydroabietylamine. The introduction of a delocalised pos. charge to the thiourea functionality, by an alkylation reaction at the sulfur atom, enables dynamic rotameric processes: hindered rotations about the delocalised CN and CS bonds. Hence, four different rotamers/isomers may be recognized: syn-syn, syn-anti, anti-syn and anti-anti. Extensive 1H and 13C NMR studies have shown that in hydrogen-bond acceptor solvents, such as perdeuteriated DMSO, the syn-syn conformation is preferable. On the other hand, when using non-polar solvents, such as CDCl3, the mixt. of syn-syn and syn-anti isomers is detectable, with an excess of the latter. Apart from this, in the case of S-butyl-N,N'-bis(dehydroabietyl)thiouronium ethanoate in CDCl3, the 1H NMR spectrum revealed that strong bifurcated hydrogen bonding between the anion and the cation causes global rigidity without signs of hindered rotamerism observable on the NMR time scale. This suggested that these new salts might be used as NMR discriminating agents for chiral oxoanions, and are indeed more effective than their archetypal guanidinium analogs or the neutral thioureas. The best results in recognition of a model substrate, mandelate, were obtained with S-butyl-N,N'-bis(dehydroabietyl)thiouronium bistriflamide. It was confirmed that the chiral recognition occurred not only for carboxylates but also for sulfonates and phosphonates. Further 1H NMR studies confirmed a 1 : 1 recognition mode between the chiral agent (host) and the substrate (guest); binding consts. were detd. by 1H NMR titrns. in solns. of DMSO-d6 in CDCl3. It was also found that the anion of the thiouronium salt had a significant influence on the recognition process: anions with poor hydrogen-bond acceptor abilities led to the best discrimination. The presence of host-guest hydrogen bonding was confirmed in the X-ray crystal structure of S-butyl-N,N'-bis(dehydroabietyl)thiouronium bromide and by computational studies (d. functional theory).
30. 30
  Hernández-Rodríguez, M.; Juaristi, E. Structurally simple chiral thioureas as chiral solvating agents in the enantiodiscrimination of α-hydroxy and α-amino carboxylic acids. Tetrahedron 2007, 63, 7673– 7678, DOI: 10.1016/j.tet.2007.05.021
  30
  Structurally simple chiral thioureas as chiral solvating agents in the enantiodiscrimination of α-hydroxy and α-amino carboxylic acids
  Hernandez-Rodriguez, Marcos; Juaristi, Eusebio
  Tetrahedron (2007), 63 (32), 7673-7678CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  C2-Sym. chiral thioureas (S,S)-RCHMeNHC(S)NHCHMeR (R = Ph, 1-naphthyl) (I) were prepd. in good yields by the reaction of 2 equiv of (S)-1-phenylethylamine or (S)-1-(1-naphthyl)ethylamine with 1 equiv of thiophosgene under basic conditions. The presence of asym. elements in I, and their capacity to act as receptors for anionic species via hydrogen bonding were exploited in the development of 1H NMR spectroscopic enantiodiscrimination of chiral carboxylic acids. In particular, the diastereomeric complexes derived from thioureas I with ammonium salts of the chiral acids gave rise to well sepd. signals of the α-hydrogens and simple integration provides the corresponding enantiomeric ratios. Furthermore, it was obsd. that Cα-H in the (R)-enantiomers of the chiral α-hydroxy- and α-amino acids consistently appears downfield relative to the same signals in the (S)-enantiomers.
31. 31
  Kyne, G. M.; Light, M. E.; Hursthouse, M. B.; de Mendoza, J.; Kilburn, J. D. Enantioselective amino acid recognition using acyclic thiourea receptors. J. Chem. Soc., Perkin Trans. 1 2001, 1258– 1263, DOI: 10.1039/b102298a
  31
  Enantioselective amino acid recognition using acyclic thiourea receptors
  Kyne, Graham M.; Light, Mark E.; Hursthouse, Mike B.; de Mendoza, Javier; Kilburn, Jeremy D.
  Journal of the Chemical Society, Perkin Transactions 1 (2001), (11), 1258-1263CODEN: JCSPCE; ISSN:1472-7781. (Royal Society of Chemistry)
  A series of acyclic thiourea derivs., I (X = CH, N), II and III, designed to create a cleft with four hydrogen bond donors suitable for carboxylate recognition, have been prepd., and their ability to bind to N-protected amino acid carboxylate salts has been investigated. The crystal structure of I (X = N) has been detd. showing that it forms a hydrogen bonded centrosym. dimer in the solid-state, in a conformation appropriate for the desired binding of carboxylates. The thioureas show good discrimination between different amino acids; the thioureas contg. chiral moieties show moderate enantioselectivity for a range of amino acid derivs.
32. 32
  Jain, N.; Khanvilkar, A. N.; Sahoo, S.; Bedekar, A. V. Modification of Kagan’s amide for improved activity as Chiral Solvating Agent in enantiodiscrimination during NMR analysis. Tetrahedron 2018, 74, 68– 76, DOI: 10.1016/j.tet.2017.11.036
  32
  Modification of Kagan's amide for improved activity as Chiral Solvating Agent in enantiodiscrimination during NMR analysis
  Jain, Nilesh; Khanvilkar, Aditya N.; Sahoo, Sibaprasad; Bedekar, Ashutosh V.
  Tetrahedron (2018), 74 (1), 68-76CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  A modification is proposed in Kagan's amide to improve its ability to offer stronger hydrogen bonding and hence better ability to bind with substrates. Introduction of chlorine in the amide arom. ring along with the two nitro groups, increases the acidic character of amide hydrogen and makes the hydrogen bond stronger, the concept is tested by making three derivs. of Kagan's amide and the effect is confirmed by NMR anal. The modified chlorinated Kagan's amides were then tested as chiral solvating agents for detection of optical purity of several types of substrates where the supramol. recognition is measured by in situ NMR anal. Several guest mols. such as amide, sulfoxide, epoxy-keto, hydroxy acid, diacid and phosphoric acid were scanned for this study and its efficiency is further established by comparison with samples of known optical purity.
33. 33
  Recchimurzo, A.; Maccabruni, F.; Uccello Barretta, G.; Balzano, F. Quinine as highly responsive chiral sensor for the ¹H and ¹⁹F NMR enantiodiscrimination of N-trifluoroacetyl amino acids with free carboxyl functions. Analyst 2022, 147, 1669– 1677, DOI: 10.1039/d2an00166g
  33
  Quinine as a highly responsive chiral sensor for the 1H and 19F NMR enantiodiscrimination of N-trifluoroacetyl amino acids with free carboxyl functions
  Recchimurzo, Alessandra; Maccabruni, Fabio; Uccello Barretta, Gloria; Balzano, Federica
  Analyst (Cambridge, United Kingdom) (2022), 147 (8), 1669-1677CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
  Hydrogen-bond accepting and enantiodiscriminating abilities of quinine (Qui) have been exploited in the enantiodiscrimination of N-trifluoroacetyl (TFA) derivs. of amino acids by NMR (NMR) spectroscopy. NMR 1H and 19F resonances of derivs. of alanine, valine, leucine, norvaline, phenylalanine, phenylglycine, methionine, glutamic acid, proline, and tryptophan were well differentiated employing CDCl3 and/or C6D6 as solvent, with Qui acting in some cases not only as enantiodiscriminating agent, but also as soly. promoter. For derivs. sol. in both solvents, the best results were obtained in benzene-d6, with very high nonequivalence values, which were detectable not only starting from very low equimolar concns. of 0.1 mM, but also in the presence of sub-stoichiometric amts. of Qui. The quality of enantiodifferentiation has been also evaluated by means of the enantioresoln. quotient E. The method has been applied to the detection and quantification of mixts. of amino acid derivs. by single point measurements.
34. 34
  Fang, L.; Lv, C.; Wang, G.; Feng, L.; Stavropoulos, P.; Gao, G.; Ai, L.; Zhang, J. Discrimination of Enantiomers of Dipeptide Derivatives with Two Chiral Centers by Tetraaza Macrocyclic Chiral Solvating Agents Using ¹H NMR Spectroscopy. Org. Chem. Front. 2016, 3, 1716– 1724, DOI: 10.1039/c6qo00521g
  34
  Discrimination of enantiomers of dipeptide derivatives with two chiral centers by tetraaza macrocyclic chiral solvating agents using 1H NMR spectroscopy
  Fang, Lixia; Lv, Caixia; Wang, Guo; Feng, Lei; Stavropoulos, Pericles; Gao, Guangpeng; Ai, Lin; Zhang, Jiaxin
  Organic Chemistry Frontiers (2016), 3 (12), 1716-1724CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
  1H NMR spectroscopy is often used to discriminate enantiomers of chiral analytes and det. their enantiomeric excess (ee) by various chiral auxiliaries. In reported research, these studies were mainly focused on chiral discrimination of chiral analytes with only one chiral center. However, many chiral compds. possessing two or more chiral centers are often found in natural products, chiral drugs, products of asym. synthesis and biol. systems. Therefore, it is necessary to investigate their chiral discrimination by effective chiral auxiliaries using 1H NMR spectroscopy. In this paper, a new class of tetraaza macrocyclic chiral solvating agents (TAMCSAs) with two amide (CONH), two amino (NH) and two phenolic hydroxyl (PhOH) groups has been designed and synthesized for chiral discrimination towards dipeptide derivs. with two chiral centers. These dipeptide derivs. are important chiral species because some of them are used as clin. drugs and special dietary supplements for treatment of human diseases, such as L-alanyl-L-glutamine and aspartame. The results show that these TAMCSAs have excellent chiral discriminating properties and offer multiple detection possibilities pertaining to 1H NMR signals of diagnostic split protons. The nonequivalent chem. shifts (up to 0.486 ppm) of various types of protons of these dipeptide derivs. were evaluated with the assistance of well-resolved 1H NMR signals in most cases. In addn., enantiomeric excesses (ee) of the dipeptide derivs. with different optical compns. have been calcd. based on integration of well-sepd. proton signals. At the same time, the possible chiral discriminating behaviors have been discussed by means of Job plots, ESI mass spectra and a proposed theor. model of (±)-G1 with TAMCSA 1c. Addnl., the assocn. consts. of enantiomers of (±)-G5 with TAMCSA 1a were calcd. by employing the nonlinear curve-fitting method.
35. 35
  Tanaka, K.; Iwashita, T.; Sasaki, C.; Takahashi, H. Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives. Tetrahedron: Asymmetry 2014, 25, 602– 609, DOI: 10.1016/j.tetasy.2014.03.009
  35
  Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives
  Tanaka, Koichi; Iwashita, Tomoharu; Sasaki, Chihiro; Takahashi, Hiroki
  Tetrahedron: Asymmetry (2014), 25 (8), 602-609CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
  Novel 46-membered chiral rhombamine macrocycles I (X = CH2, O) and 8b were synthesized by [2+2] cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and subsequent redn. with NaBH4. The x-ray crystal structure of 1:4 dioxane complex with I (X = CH2) indicated a rhombus conformation of the chiral macrocycle. I (X = CH2, O) were tested as chiral shift reagents for a wide range of α-substituted carboxylic acids and amino acid derivs. Enantiodiscrimination of 1H NMR signals was obsd. with ΔΔδ values of up to 0.214 ppm.
36. 36
  Quinn, T. P.; Atwood, P. D.; Tanski, J. M.; Moore, T. F.; Folmer-Andersen, J. F. Aza-crown macrocycles as chiral solvating agents for mandelic acid derivatives. J. Org. Chem. 2011, 76, 10020– 10030, DOI: 10.1021/jo2018203
  36
  Aza-Crown Macrocycles as Chiral Solvating Agents for Mandelic Acid Derivatives
  Quinn, Thomas P.; Atwood, Philip D.; Tanski, Joseph M.; Moore, Tyler F.; Folmer-Andersen, J. Frantz
  Journal of Organic Chemistry (2011), 76 (24), 10020-10030CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  New chiral macrocycles contg. the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and oligoethylene glycol-derived spacers were prepd. in enantiomerically pure form. Four of the macrocycles were characterized by x-ray crystallog., which reveals a consistent mode of intramol. N-H···N hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles differentiate the enantiomers of mandelic acid (MA) by 1H NMR spectroscopy in CDCl3; within macrocycles tested, enantiodiscrimination were promoted by (i) a meta-linkage geometry about the arene spacer, (ii) the presence of naphthalene, rather than phenylene-derived arene spacers, and (iii) increasing length of the oligoethylene glycol bridge. 1H NMR titrns. were performed with optically pure MA samples, and the data were fitted to a simultaneous 1:1 and 2:1 binding model, yielding ests. of 2:1 binding consts. between some of the macrocycles and MA enantiomers. In several cases, NOESY spectra of the MA:macrocycle complexes show differential intramol. correlations between protons adjacent to the amine and carboxylic acid groups of the macrocycles and MA enantiomers, resp., thus demonstrating geometric differences between the diastereomeric intermol. complexes. The three most effective macrocycles were employed as chiral solvating agents (CSAs) to det. the enantiomeric excess (ee) of 18 MA samples over a wide ee range and with very high accuracy (1% abs. error).
37. 37
  Klika, K. D. Use of sub-stoichiometric amounts of chiral auxiliaries for enantiodifferentiation by NMR; caveats and potential utility. Tetrahedron: Asymmetry 2009, 20, 1099– 1102, DOI: 10.1016/j.tetasy.2009.03.036
  37
  Use of sub-stoichiometric amounts of chiral auxiliaries for enantiodifferentiation by NMR; caveats and potential utility
  Klika, Karel D.
  Tetrahedron: Asymmetry (2009), 20 (10), 1099-1102CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)
  Chem. shift (δ) order reversal of the population-weighted averaged NMR signals for enantiomers when using sub-stoichiometric levels of a chiral auxiliary (CA) can occur when the δ difference between the enantiomer-CA complexes and the signal of the free enantiomers is greater for the less-stable complex. The potential utility of CA titrn. curves with regard to ΔG evaluation, configuration detn., and modeling validation is considered.
38. 38
  Pérez-Trujillo, M.; Monteagudo, E.; Kuhn, L. T. NMR-aided differentiation of enantiomers: signal enantioresolution. Anal. Chim. Acta 2015, 876, 63– 70, DOI: 10.1016/j.aca.2015.02.069
  38
  NMR-aided differentiation of enantiomers: Signal enantioresolution
  Perez-Trujillo, Miriam; Parella, Teodor; Kuhn, Lars T.
  Analytica Chimica Acta (2015), 876 (), 63-70CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
  NMR-aided enantiodiscrimination using chiral auxiliaries (CAs) is a recognized method for differentiating enantiomers and for measuring enantiomeric ratios (er). Up to the present, the study, optimization, and comparison of such methods have been performed based on the enantiodifferentiation of NMR signals via analyzing non-equiv. chem.-shift values (ΔΔδ) of the diastereoisomeric species formed. However, a poor and non-reliable comparison of results is often obtained via the anal. of ΔΔδ exclusively. In here, the concept of enantioresoln. of an individual NMR signal and its importance for NMR-aided enantiodifferentiation studies is introduced and discussed. In addn., the enantioresoln. quotient, E, is proposed as the parameter to describe its quantification. Complementary to measuring ΔΔδ, the exptl. detn. of E allows a more reliable interpretation of the results and opens up new possibilities for the study of enantiodifferentiation data derived from novel NMR expts., setup improvements or new CAs. Finally, the different relationships between signal enantiodifferentiation, signal enantioresoln., and other main exptl. issues of enantiodifferentiation expts. are addressed.
39. 39
  Morris, G. A., Emsley, J. W. Diffusion-ordered spectroscopy. In Multidimensional NMR Methods for the Solution State; Wiley and Sons: Chichester, U.K., 2010; pp 515– 532.
  There is no corresponding record for this reference.
40. 40
  Supady, A.; Hecht, S.; Baldauf, C. About Underappreciated Yet Active Conformations of Thiourea Organocatalysts. Org. Lett. 2017, 19, 4199– 4202, DOI: 10.1021/acs.orglett.7b01782
  40
  About Underappreciated Yet Active Conformations of Thiourea Organocatalysts
  Supady, Adriana; Hecht, Stefan; Baldauf, Carsten
  Organic Letters (2017), 19 (16), 4199-4202CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Conformational dynamics can define the function of organocatalysts. While the accepted mechanism of Schreiner's catalyst features a double hydrogen bond to the substrate that only forms with the anti-anti conformation of its central thiourea group, our electronic-structure theory study reveals that binding of the model substrate Me vinyl ketone prefers syn-anti conformations. We find a new mechanism featuring π stacking interactions and highlight the need for extensive structure searches for flexible mols., esp. when aiming for structure-based design of catalytic activity.
41. 41
  Madarász, A.; Dósa, Z.; Varga, S.; Soós, T.; Csámpai, A.; Pápai, I. Thiourea Derivatives as Brønsted Acid Organocatalysts. ACS Catal. 2016, 6, 4379– 4387, DOI: 10.1021/acscatal.6b00618
  41
  Thiourea Derivatives as Bronsted Acid Organocatalysts
  Madarasz, Adam; Dosa, Zsolt; Varga, Szilard; Soos, Tibor; Csampai, Antal; Papai, Imre
  ACS Catalysis (2016), 6 (7), 4379-4387CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  Combined computational-exptl. studies were carried out to parallel two mechanistic models for tetrahydropyranylation of alcs. catalyzed by Schreiner's thiourea. The results challenge the common mechanistic view that the catalytic effect is related to stabilizing double hydrogen-bonding interactions between the thiourea and the alc., which promote the attack on 3,4-dihydro-2H-pyran (DHP) (hydrogen bonding (HB) mechanism). In the alternative mechanism that we propose, thiourea acts as a Bronsted acid, protonating DHP to form an oxacarbenium ion, which reacts with the alc. (Bronsted acid (BA) mechanism). Computations point to clear preference of transition states assocd. with the BA mechanism and, accordingly, predict similar catalytic activity for N-methylated thiourea and thiouracil. These predictions are confirmed exptl. Reactions with deuterated alcs. yield both syn and anti products, providing further support for the Bronsted acid mechanism.
42. 42
  Nie, S.-X.; Guo, H.; Huang, T.-Y.; Ao, Y.-F.; Wang, D.-X.; Wang, Q.-Q. Xenon binding by a tight yet adaptive chiral soft capsule. Nat. Commun. 2020, 11, 6257, DOI: 10.1038/s41467-020-20081-8
  42
  Xenon binding by a tight yet adaptive chiral soft capsule
  Nie, Shi-Xin; Guo, Hao; Huang, Teng-Yu; Ao, Yu-Fei; Wang, De-Xian; Wang, Qi-Qiang
  Nature Communications (2020), 11 (1), 6257CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
  Xenon binding has attracted interest due to the potential for xenon sepn. and emerging applications in magnetic resonance imaging. Compared to their covalent counterparts, assembled hosts that are able to effectively bind xenon are rare. Here, we report a tight yet soft chiral macrocycle dimeric capsule for efficient and adaptive xenon binding in both crystal form and soln. The chiral bisurea-bisthiourea macrocycle can be easily synthesized in multi-gram scale. Through assembly, the flexible macrocycles are locked in a bowl-shaped conformation and buckled to each other, wrapping up a tight, completely sealed yet adjustable cavity suitable for xenon, with a very high affinity for an assembled host. A slow-exchange process and drastic spectral changes are obsd. in both 1H and 129Xe NMR. With the easy synthesis, modification and reversible characteristics, we believe the robust yet adaptive assembly system may find applications in xenon sequestration and magnetic resonance imaging-based biosensing.
43. 43
  Phillips, A. M. F.; Prechtl, M. H. G.; Pombeiro, A. J. L. Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts. Catalysts 2021, 11, 569, DOI: 10.3390/catal11050569
  43
  Non-covalent interactions in enantioselective organocatalysis: theoretical and mechanistic studies of reactions mediated by dual H-bond donors, bifunctional squaramides, thioureas and related catalysts
  Phillips, Ana Maria Faisca; Prechtl, Martin H. G.; Pombeiro, Armando J. L.
  Catalysts (2021), 11 (5), 569CODEN: CATACJ; ISSN:2073-4344. (MDPI AG)
  A review. Chiral bifunctional dual H-bond donor catalysts have become one of the pillars of organocatalysis. They include squaramide, thiosquaramide, thiourea, urea, and even selenourea-based catalysts combined with chiral amines, cinchona alkaloids, sulfides, phosphines and more. They can promote several types of reactions affording products in very high yields and excellent stereoselectivities in many cases: conjugate addns., cycloaddns., the aldol and Henry reactions, the Morita-Baylis-Hilman reaction, even cascade reactions, among others. The desire to understand mechanisms and the quest for the origins of stereoselectivity, in attempts to find guidelines for developing more efficient catalysts for new transformations, has promoted many mechanistic and theor. studies. In this review, we survey the literature published in this area since 2015.
44. 44
  Heshmat, M. Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst. J. Phys. Chem. A 2018, 122, 7974– 7982, DOI: 10.1021/acs.jpca.8b04589
  44
  Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst
  Heshmat, Mojgan
  Journal of Physical Chemistry A (2018), 122 (40), 7974-7982CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
  In this work, we report an energy decompn. and electronic structure anal. using DFT calcns. for the C-C coupling step in the Henry reaction with cinchona thiourea as catalyst and DMF solvent to unravel the origin of enantioselectivity. We found that the conformation of flexible thiourea moiety is affected by the solvent, and in the preferred conformation of thiourea in strong Lewis basic DMF solvent, the N-H sites are in the opposite direction, i.e., in trans conformation. Hence, the thiourea moiety acts via single hydrogen bonding with substrates. The conformation of the substrates with respect to the forming C-C bond plays crit. role to increase orbital interaction between two substrates and enhances hydrogen bond strength between substrates and catalyst, which in turn stabilizes the pos. charge developing on the catalyst at the transition state for one of the enantiomers (S). Thus, the enantioselectivity has electronic structure origin. The stronger H-bond formation in the S enantiomer has been confirmed by the calcd. IR spectra and is in agreement with thus far exptl. and computational results.
45. 45
  Ren, J.; Diprose, J.; Warren, J.; Esnouf, R. M.; Bird, L. E.; Ikemizu, S.; Slater, M.; Milton, J.; Balzarini, J.; Stuart, D. I.; Stammers, D. K. Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses. J. Biol. Chem. 2000, 275, 5633– 5639, DOI: 10.1074/jbc.275.8.5633
  45
  Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases: Structural and biochemical analyses
  Ren, Jingshan; Diprose, Jonathan; Warren, Jonathan; Esnouf, Robert M.; Bird, Louise E.; Ikemizu, Shinji; Slater, Martin; Milton, John; Balzarini, Jan; Stuart, David I.; Stammers, David K.
  Journal of Biological Chemistry (2000), 275 (8), 5633-5639CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-2 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolythiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC50 of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC50 of 5 nM) and also inhibits HIV-2 RT (IC50 of 2.2 μM). X-ray crystallog. structure detns. of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compds. bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC)·(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c00814.
- Nonequivalences and enantioresolution quotients for 1–3, 11–13, 18–23 in the presence of 1 equiv of DABCO and BTDA or TFTDA; nonequivalences and enantioresolution quotients for 1–3 DABCO in the presence of TFTDA or TFTMA at different molar ratios; nonequivalences and enantioresolution quotients for 11–13/DABCO in the presence of TFTDA or TFTMA at different molar ratios; stoichiometry determination; nonequivalences and enantioresolution quotients for 1–17 in the presence of TFTDA and DABCO in C₆D₆ and CDCl₃; ¹H and ¹⁹F NMR spectra of 1–10 in the presence of DABCO and TFTDA in CDCl₃ and C₆D₆; ¹H NMR spectra of 11–17 in the presence of DABCO and TFTDA in CDCl₃ and C₆D₆; ¹H NMR and 1D-TOCSY spectra of 2, 4–6, 13, and 17 in the presence of DABCO/TFTDA in C₆D₆; nonequivalences for 11–17 in equimolar mixtures 11–17/DABCO/TFTDA as a function of concentration; nonequivalences for 11, 13–17/DABCO (1:1) in the presence of 1 equiv of TFTDA at different substrate concentration; nonequivalences for 1–10 in equimolar mixtures 1–10/DABCO/TFTDA as a function of the concentration; ¹H NMR spectra of TFTDA at 15 and 5 mM; ¹H NMR chemical shift data for TFTDA in 15 and 5 mM solutions; ¹⁹F NMR spectra of 1–3 and ¹H NMR spectra of 11–13 in the presence of 1 equiv of DABCO and of 1 or 0.3 equiv of TFTDA; 2D ROESY map TFTDA at 30 mM; diffusion coefficients of pure DABCO (15 mM) in an equimolar mixture TFTDA and TFTPA; 1D ROESY of DABCO in the presence of TFTDA; 1D ROESY of 16 protons in equimolar mixtures (R)-16 or (S)-16/DABCO/TFTDA; ¹H chemical shifts and complexation shift for (R)-16 and (S)-16/DABCO/TFTDA equimolar mixtures; ROESY maps of TFTDA/substrate/DABCO; association constant determination; and ¹H and ¹³C{¹H} NMR spectra of TFTMA and TFTDA (PDF)
- jo2c00814_si_001.pdf (2.58 MB)
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Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid DerivativesClick to copy article linkArticle link copied!

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Introduction

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1H and 19F Enantiodiscrimination Experiments

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NMR Investigation of Chiral Recognition Processes

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Synthesis TFTMA

Synthesis TFTDA

Synthesis TFTPA

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Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid Derivatives
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¹H and ¹⁹F Enantiodiscrimination Experiments