Sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds

Tetrahedron: Asymmetry 28 (2017) 1061–1069

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy

Sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds Brielle E. Dalvano, Thomas J. Wenzel ⇑ Department of Chemistry, Bates College, Lewiston, ME 04240, USA

a r t i c l e

i n f o

Article history: Received 9 May 2017 Revised 3 July 2017 Accepted 14 July 2017 Available online 1 August 2017

a b s t r a c t The utility of a series of sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic substrates is described. Sulfated a-, b- and c-cyclodextrin with degrees of substitution of 12, 13 and 14, respectively, a sulfated b-cyclodextrin with a degree of substitution of 9 and a sulfobutyl ether b-cyclodextrin with a degree of substitution of 6.3 are examined. Results with 33 water-soluble cationic organic salts are reported. Chiral differentiation with the sulfated cyclodextrins is compared to prior results obtained with anionic carboxymethylated and phosphated cyclodextrins. The highly sulfated cyclodextrins are often more effective at causing enantiomeric differentiation in 1H NMR spectra than the sulfobutyl ether, carboxymethylated and phosphated cyclodextrins, and are recommended as the first choice of a chiral solvating agent for the analysis of chiral cationic organic salts in aqueous solution. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction Chiral solvating agents (CSAs) are often used for enantiodifferentiation in NMR spectroscopy.1–7 Cyclodextrins (CDs) are cyclic oligosaccharides containing D-glucose units. a-, b- and c-CD (Fig. 1) contain six, seven and eight glucose rings, respectively. Neutral8–20 and charged cyclodextrin derivatives21–48 have been frequently used as CSAs in NMR spectroscopy and in chromatographic and capillary electrophoretic separations.49 Many compounds form inclusion complexes with CDs by insertion of a portion of the molecule, often an aryl ring, into the cavity. However, there are examples of chiral recognition with CD derivatives where association of the compound did not involve the formation of an inclusion complex.11–13 When inclusion complexes are formed, the different sizes of a-, b- and c-CD allow the chiral recognition of different sized compounds. Native CDs represent one of the few systems useful for chiral NMR recognition in aqueous solutions. Water-soluble CDs with anionic carboxymethyl (CM-CD),21–33 sulfate (S-CD),30,31,34–36 sulfobutylether (SBE-CD),26,37–39 sulfopropylether,40 thiocarboxymethyl41 and phosphate (P-CD)42 groups have also been studied as water-soluble NMR CSAs (Fig. 1). When comparisons are made, these studies find that anionic CDs are more effective chiral NMR solvating agents for water-soluble cationic substrates than neutral native CDs. Similarly cationic CDs containing amine,43,44 ⇑ Corresponding author. E-mail address: [email protected] (T.J. Wenzel). http://dx.doi.org/10.1016/j.tetasy.2017.07.003 0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

xylylenediamine,45 and trialkylammonium groups46–48 are more effective for water-soluble anionic substrates than neutral native CDs. Carboxymethylated and trimethylammonium-derivatized CDs are commercially available but often have a degree of substitution (DS) of about 2. Prior reports have found that randomly substituted CM-CDs and trimethylammonium-CDs with high degree of substitution (11 for b-CD)25,47 are considerably more effective than the commercially available derivatives with low degree of substitution. Unfortunately, CM-CDs with high degree of substitution are not commercially available and investigators wishing to use these in chiral NMR applications would have to synthesize and purify them. Prior reports have described the use of a commercially available S-b-CD with a degree of substitution of 9 as a chiral NMR solvating agent for a limited range of cationic substrates.30,31 Similarly, prior reports describing the use of commercially available SBE-b-CD in chiral NMR applications involve a limited range of substrates.26,37–39 S-CDs with much higher degree of substitution values (S-a-CD, degree of substitution = 12; S-b-CD-HDS, degree of substitution = 13; S-c-CD, degree of substitution = 14) are commercially available, but have not to our knowledge been evaluated as chiral NMR solvating agents. The utility of these S-CDs with high degree of substitution are evaluated herein on a wide range of water-soluble, cationic organic salts. Their effectiveness is compared to a commercially available SBE-b-CD with a degree of substitution of 6.3 and the S-b-CD with a degree of substitution of 9 (S-b-CD-LDS). In addition, the enantiomeric differentiation with the five different sulfated CDs examined herein is compared to

1062

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

RO

OR

RO

OR

OR

RO

O

O O

O RO

O

O RO

O RO

CD: R=H S-CD: R = H or -SO3-Na+ SBE-CD: R = H or -(CH2)4SO3-Na+ CM-CD: R = H or -CH2CO2-Na+ P-CD: R = H or -PO32-(Na+)2

Figure 1. Structure of cyclodextrins (CD) and their sulfated (S-CD), sulfobutyl ether (SBE-CD), carboxymethylated (CM-CD) and phosphated (P-CD) derivatives.

prior published results of many of the same substrates with the CM-CDs25,32,33 and P-CDs with lower and higher degree of substitution.42 As will be shown, the highly sulfated CDs are often the most effective at causing enantiodifferentiation in the 1H NMR spectra of cationic substrates. 2. Results and discussion Five different anionic sulfated CDs (S-a-CD, S-b-CD-LDS, S-b-CDHDS, SBE-b-CD, S-c-CD) are evaluated as chiral NMR solvating agents. 1 H NMR spectra are recorded for 10 mM solutions of the cationic forms of a-methylbenzylamine 1, N,a-dimethylbenzylamine 2, N,N-dimethyl-1-phenethylamine 3, N-allyl-a-methylbenzylamine 4, b-methylphenethylamine 5, 1-methyl-3-phenylpiperazine 6, ephedrine 7, a-(methylaminoethyl)benzyl alcohol 8, 2-tert-butylamino-1-phenylethanol 9, a-(1-aminoethyl)-4-hydroxybenzyl alcohol 10, tyrosinol 11, 3-dimethylamino-2-methylpropiophenone 12, cis-(2-benzylamino)cyclohexanemethanol 13, alanine methyl ester 14, 2-phenylglycine methyl ester 15, phenylalanine methyl ester 16, tyrosine 17, 4-chlorophenylalanine methyl ester 18, 4-chlorophenylalanine ethyl ester 19, carbobenzyloxy serine 20, 2-methylindoline 21, trans-1-amino-2-indanol 22, cis-1-amino-2indanol 23, tryptophan 24, tryptophan methyl ester 25, 1-methyltryptophan methyl ester 26, 1-(1-naphthyl)ethylamine 27, N,N-dimethyl-1-(1-naphthyl)ethylamine 28, propranolol 29, pheniramine 30, brompheniramine 31, doxylamine 32, and carbinoxamine 33 (Fig. 2) with all five of the sulfated cyclodextrins at 5, 10 and 20 mM. The cationic form of the substrate was assured by using commercially available hydrochloride salts or by addition of an excess of deuterium chloride when preparing stock solutions of the substrates. While all but one of the substrates contains an aromatic ring, the substituent groups span a broad range of functional groups. All 33 of the substrates were previously examined with a series of anionic P-CDs42 and 23 of them were examined with a series of CM-CDs.25,32,33 The ensuing discussion compares the effectiveness of the sulfated cyclodextrins to the enantiomeric differentiation reported in these previous reports. The largest magnitude of enantiomeric differentiation observed in the 1H NMR spectra of the substrates with each sulfated cyclodextrin is reported herein. In some cases, the best enantiodifferentiation is not reported with the CD at 20 mM either because of overlapping peaks in the spectrum or because a larger value is obtained at 5 or 10 mM CD. Substrates 1–6 contain amine and aryl moieties. Enantiomeric differentiation is observed in the 1H NMR spectra of 1–5 with one or more of the sulfated CDs (Table 1). While a number of the resonances exhibit small enantiomeric differentiation (<0.010 ppm), substantial enantiomeric differentiation (>0.030 ppm) is observed in one resonance of 2–5 with one or more of the sulfated CDs. Another two resonances have differentiation greater than 0.020 ppm. The S-b-CDs are by far the most effective of the sulfated CDs with 1–5. S-a-CD (CH of 4) and SBE-b (H20 of 4) are most effective for only one resonance each. While S-c-CD is generally far less effective than the S-b-CDs, there are some

exceptions such as the methine resonance of 3, methylene resonances of 4 and methyl group of 5 where S-c-CD causes larger enantiomeric differentiation than the other sulfated CDs. Whereas previous studies with CM-CDs have shown that the more highly substituted derivatives are more effective chiral NMR solvating agents,25,32,33 the comparison of S-b-CD-LDS and S-b-CD-HDS for 1–5 shows no meaningful difference of one over the other. The enantiomeric differentiation with S-b-CD-HDS is better than that with S-b-CD-LDS in many cases, but the values are usually similar in magnitude. With the exception of the H20 proton of 4, 15 of the 16 resonances of 1–5 that exhibit enantiomeric differentiation with the anionic CDs are aliphatic hydrogen atoms. Data for 1–5 show how relatively modest changes in the structure of a substrate can have pronounced effects on the degree of enantiodifferentiation. The differentiation of the C-methyl resonance of 1-phenylethylamine (1, 0.012 ppm) is markedly smaller than the differentiation of the corresponding C-methyl resonance in the N-methyl (2, 0.039 ppm), N,N-dimethyl (3, 0.043 ppm) and allyl-substituted (4, 0.045 ppm) derivatives with S-b-CD-HDS. The nitrogen atom of 1–4 is expected to have an important role in their association with the CDs, so the influence of substitution at the amine group is not surprising. However, methyl substitution at the amine group of 1–4 does not noticeably impact the magnitude of the enantiodifferentiation of the methine resonances. Another group of substrates contains aryl, amine and either hydroxyl (7–11, 13) or carbonyl (12) moieties. Enantiomeric differentiation is observed in three of more resonances of 7–13 with one or more of the sulfated CDs (Table 2). Enantiomeric differentiation of aliphatic and aromatic resonances is observed with 9–13. Four of the substrates, 7, 8, 10 and 12, have resonances with enantiomeric differentiation greater than 0.030 ppm in mixtures with one or more of the sulfated CDs. Another five resonances have differentiation between 0.020 and 0.030 ppm. As with 1–6, the S-b-CDs are effective for more resonances in 7–13 than the other anionic CDs, causing enantiomeric differentiation in two or more resonances of each substrate. S-a-CD (H40 of 9, O-CH of 10 and N-CH20 of 13) and SBE-b-CD (CH2 of 8) are most effective for only a few resonances. S-c-CD causes enantiomeric differentiation for two resonances each in 11 (CH2, CH20 ) and 12 (CH20 , H30 ) that are much better than any other of the anionic CDs. There are seven resonances where S-b-CD-HDS produces enantiomeric differentiation in 9–13 and S-b-CD-LDS does not. There are only two resonances where S-b-CD-LDS causes enantiomeric differentiation in 8 and 13 and S-b-CD-HDS does not. For other resonances of 7–13, when Sb-CD-LDS and S-b-CD-HDS both cause enantiomeric differentiation, the values are close in magnitude. Compounds 7–9 have similar a,b-hydroxy amino motifs that differ in the identity of substituent groups on the aliphatic moiety. They provide another example where relatively modest structural differences have significant impact on the degree of enantiodifferentiation. For example, the differentiation of the methine proton (CH) with S-b-CD-HDS varies considerably for 7 (0.053 ppm), 8 (0.040 ppm) and 9 (0 ppm).

1063

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069 H N

NH 2

H N

N

H

NH2

6 5

H

2' 3'

1 OH

4'

3

2

OH

H N

2'

NH2 1

2 5

4

2

8 7

2

6

3

27 4'

5

28

4

3' N O

N H

7

2 NH 2

OH

5'

N H

6'

4'

3'

2

3'

5 6

3

Cl

2 NH2

N

7

O

26 2

3

4

5' 6'

N

29 4'

O

4

25

O

5

6'

6'

5

24

2

O

O

4 6

N H

8

20

OH NH2

OH

O

O OH

NH2

O

5'

5'

H N

HO

O

19

N

NH2

2

2'

3'

16 O

O

Cl

trans 22 cis 23

21

4

3

O NH2

15

14

NH2

O O

18

N H

3

NH2 O

O

Cl

11

NH2

4'

OH

3' HO

O

3'

O

17 3

OH

O

2'

2'

3'

OH NH2

3'

10

13 O

H 2N 2'

2'

HO

N H

12

HO

H N

3'

OH

4'

3'

6

9

N

3

NH2

4'

O

2' 3'

N

5

OH

2'

H N

8

7

4

H N 2

4'

3'

2

3

Br

N

N

N

30

31

N O

N

32

N

33

Figure 2. Structures of substrates. Each was examined in its protonated form with the P-CDs.

Table 1 Enantiomeric differentiation in ppm in the 1H NMR spectra (400 MHz) of 1–6 (10 mM) with sulfated CDs, CM-CDs32,33 and P-CDs42 in D2O. Concentration of the cyclodextrin is 20 mM unless otherwise indicated. Largest enantiodifferentiation shown in bold. S-a-CD 1 2

3

4

5 6 a b

CH CH3 CH N-CH3 C-CH3 CH N-CH3 C-CH3 CH N-CH CH2 CH20 CH3 H20 CH3 CH3

0.007 0 0 0.007 0.006 0.006b 0 0.009 0.007b 0 0 0.019a 0.005 0 0 0

S-b-CD-LDS b

0.006 0.011 0 0.015 0.035 0.002b 0 0.045 0.006a 0.005b 0 0 0.040 0 0.013 0

S-b-CD-HDS b

0.006 0.012 0 0.019 0.039 0 0.019b 0.043 0.007 0 0 0 0.045 0 0.015a 0

SBE-b-CD

S-c-CD

CM-CDs

CDs

0 0 0 0 0.003b 0 0 0.006a 0.005 0 0 0 0.006a 0.010 0 0

0 0 0 0 0 0.028b 0 0.003b 0.004a 0 0.019a 0.020a 0 0 0.031 0

0.010 – b 0 0 0.013 – b 0.008 – b 0 0 0.010 – b 0 0 0 0 0.010 – a 0 0.007 – b 0.008 – b

0.004 – c-HDS 0.007 – c-HDS 0.008 – b-LDS 0.006 – b-LDS 0 0.048a – a-HDS 0 0.029b – a-LDS 0 0 0 0 0 0 0 0

10 mM. 5 mM.

Figure 3 shows a comparison of the methyl resonance of a racemic mixture of 10 (10 mM) with the five different sulfated CDs at 20 mM. The absence of enantiomeric differentiation with

SBE-b-CD (Fig. 3f) and partial differentiation with S-a-CD (Fig. 3b) is apparent. S-b-CD-LDS, S-b-CD-HDS and S-c-CD cause baseline differentiation that is suitable for determining enantiomeric purity.

1064

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

Table 2 Enantiomeric differentiation in ppm in the 1H NMR spectra (400 MHz) of 7–13 (10 mM) with sulfated CDs, CM-CDs32 and P-CDs42 in D2O. Concentration of the cyclodextrin is 20 mM unless otherwise indicated. Largest enantiodifferentiation shown in bold.

7

8

9

10

11

12

13

a b

CH CH-OH N-CH3 C-CH3 CH CH20 N-CH3 CH-OH CH2 CH20 H40 N-CH O-CH CH3 H20 H30 O-CH2 O-CH20 CH2 CH20 H20 H30 CH2 CH20 N-CH3 N-CH30 CH3 H20 H30 H40 N-CH2 N-CH20 O-CH2 O-CH20 H30

S-a-CD

S-b-CD-LDS

S-b-CD-HDS

SBE-b-CD

S-c-CD

CM-CDs

P-CDs

0 0 0 0.007 0.010a 0 0 0 0 0 0.011 0 0.013a 0.016 0 0 0.009 0.008 0 0 0.007 0.005 0.032 0 0 0.006 0.002 0.018 0.009 0 0.008b 0.023a 0.004b 0.008b 0

0.076 0 0.003a 0.027 0.045 0.015 0.022 0 0 0 0 0 0 0.038 0.012 0.015 0 0 0 0 0.010 0.013 0.033 0 0.022 0.016 0.033 0.020 0 0.041 0.014 0.022 0 0.018 0.009

0.053a 0 0.010 0.033 0.040a 0 0.028 0.017a 0.016a 0 0 0.034a 0 0.040 0.013 0.015 0.009 0.011 0 0 0.008 0.011 0.033b 0 0.028 0.019 0.033 0.021 0.005b 0.038 0.009a 0.021a 0.017a 0 0.010

0 0 0.008 0.004 0.025 0.029 0 0 0 0 0 0 0 0 0.008 0.013 0 0 0 0 0 0.009 0.033 0 0 0 0.005 0.012 0 0 0.012 0.018 0 0.013b 0

0 0 0.006 0.020 0.011b 0 0 0 0 0 0 0 0.011 0.046 0 0.013 0.010a 0 0.006b 0.011b 0 0.009 0.033b 0.033a 0 0 0.019 0.010b 0.026b 0.022b 0 0 0.006 0.012 0

0 0 0.010 – b 0 0 0 0.015 – b

0.034 – b-LDS 0.030 – b-LDS 0.008 – b-LDS 0.005 – b-LDS 0 0 0 0.025 – b-HDS 0.008 – b-LDS 0.009 – a-HDS 0 0 0.006a – a-LDS 0.004 – b-HDS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0.008 – a 0.021 – b 0.014 – b

10 mM. 5 mM.

Figure 3. 1H NMR (400 MHz, D2O) of the methyl resonance of (a) 10 (10 mM, racemic) with 20 mM (b) S-a-CD, (c) S-b-CD-LDS, (d) S-b-CD-HDS, (e) S-c-CD, and (f) SBE-b-CD.

Figure 4. 1H NMR (400 MHz, D2O) of the diastereotopic benzyl CH2 protons of (a) 13 (10 mM, enriched with the 1R,2S-enantiomer) with SBE-b-CD at (b) 10 mM and (c) 20 mM.

Figure 4 shows the benzyl methylene resonances of a solution of 13 (10 mM) enriched in the 1R,2S-enantiomer with SBE-b-CD at 10 and 20 mM. While SBE-b-CD does not cause the largest enantiomeric differentiation of these two resonances among all of the anionic CDs examined, the spectra show an interesting observation in that the order of the two enantiomers is reversed for the two resonances. For the downfield resonance, the 1R,2S enantiomer is

more deshielded whereas for the upfield resonance, the 1S,2R enantiomer is more deshielded. Substrates 14–20 are a series of amino acids in either their ester 14–16, 18, 19 or acid 17, 20 form. None of the sulfated CDs produced enantiomeric differentiation in the spectrum of 14. However, two or more resonances of 15–20 exhibit enantiomeric differentiation with one or more of the sulfated CDs, and in three

1065

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

cases 17–19, one resonance has enantiomeric differentiation greater than 0.040 ppm (Table 3). Enantiomeric differentiation of aromatic and aliphatic resonances is observed with 17–19. There is only one resonance (CH2 of 17) where S-c-CD causes the largest enantiomeric differentiation of 14–20 among the anionic CDs. Whereas SBE-b-CD is relatively ineffective for 1–13, there are several resonances (CH of 17, CH2 of 18, 19 and 20) where SBE-b-CD causes substantial enantiomeric differentiation that is larger than observed with any of the other anionic CDs. S-a-CD causes the largest enantiomeric differentiation for a few resonances (CH2 of 16, H30 of 18, CH of 20) compared to the other anionic CDs. The S-bCD-LDS and S-b-CD-HDS derivatives combined cause the largest enantiomeric differentiation for the most resonances of 14–20. The methyl esters of phenylglycine 15 and phenylalanine 16 provide another example where a relatively small difference such as an additional methylene group can lead to a significant difference in the enantiodifferentiation. In the presence of S-b-CD-LDS, the methoxy resonance in 15 (0.003 ppm) is considerably less differentiated that than in 16 (0.025 ppm). However, changing the methyl ester of 4-chlorophenylalanine 18 to an ethyl ester 19 has little effect on the magnitude of the enantiodifferentiation with the different sulfated CDs. Substrates 21–26 contain bicyclic indoline, indane and indole rings. One or more of the sulfated CDs are effective at causing enantiomeric differentiation in aliphatic and/or aromatic 1H resonances of 21–23, 25 and 26 (Table 4). Differentiation equal to or greater than 0.030 ppm is observed for one or two resonances of 23, 25 and 26 with one of the sulfated CDs. Another eight resonances exhibit enantiomeric differentiation between 0.020 and 0.030 ppm when mixed with one of the sulfated CDs. None of the sulfated CDs are effective in differentiating the enantiomers of 24. Not surprisingly, the S-a-CD, which has the smallest cavity size of the sulfated CDs, causes enantiomeric differentiation in the fewest number of resonances of 21–26. S-b-CD-HDS and S-b-CD-LDS each have particular resonances of 21–26 where they cause slightly larger enantiomeric differentiation, but the difference is

never great enough to recommend one over the other. The H3 and H30 methylene resonances of 23 (10 mM) with S-b-CD-LDS at 5, 10 and 20 mM are shown in Figure 5. The resonance of the 1R,2S-enantiomer exhibits the greater amount of deshielding for both the H3 and H30 resonances. The splitting of the downfield resonance is sufficiently large to allow for a determination of enantiomeric purity. The S-c-CD derivative is especially effective for 25 and 26, one notable example being the large enantiomeric differentiation (0.083 ppm) for the methoxy resonance of 25. A comparison of the enantiodifferentiation for the trans-22 and cis-23 isomers of 1-amino-2-indanol shows that in some cases the geometry has a pronounced effect. For example, H4 shows no differentiation with S-a-CD in 23, but is differentiated is 22 (0.010 ppm). Conversely, S-b-CD-LDS causes large differentiation of H4 in 23 (0.028 ppm) but no differentiation of the same resonance in 22. No enantiodifferentiation if observed for tryptophan 24 with any of the sulfated CDs, whereas tryptophan methyl ester 25 and 1-methyltryptophan methyl ester 26 have many differentiated resonances. Furthermore, the magnitude of the differentiation of comparable resonances in 25 and 26 are similar for any particular sulfated CD. Substrates 27–29 contain naphthyl rings. Not surprisingly, the S-c-CD derivative, which has the largest and most complementarily sized cavity for naphthyl rings, is the most effective at causing enantiomeric differentiation in the 1H NMR spectra of 27–29 (Table 5). However, S-a-CD, S-b-CD and SBE-b-CD do cause enantiomeric differentiation of some resonances. The diastereotopic N-methyl resonances of an (R)-enriched sample of 28 (10 mM) with the five sulfated cyclodextrins (20 mM) are shown in Figure 6. The largest enantiomeric differentiation of the more downfield resonance occurs with S-c-CD whereas S-a-CD causes the best results for the more upfield resonance. Especially interesting is the reversal in the order of the enantiomers between the more downfield and upfield resonance in every combination. However, the order for S-a-CD, S-b-CD-LDS and S-b-CD-HDS (Fig. 6b–d) is the reverse of that seen for SBE-b-CD and S-c-CD (Fig. 6e and f).

Table 3 Enantiomeric differentiation in ppm in the 1H NMR spectra (400 MHz) of 14–20 (10 mM) with sulfated CDs, CM-CDs33 and P-CDs42 in D2O. Concentration of the cyclodextrin is 20 mM unless otherwise indicated. Largest enantiodifferentiation shown in bold.

14 15 16

17

18

19

20 a b

10 mM. 5 mM.

CH CH O-CH3 CH CH2 CH20 O-CH3 CH CH2 CH20 H20 H30 CH CH2 CH20 O-CH3 H20 H30 CH CH2 CH20 CH3 H20 H30 Ar-CH2 CH-OH

S-a-CD

S-b-CD-LDS

S-b-CD-HDS

SBE-b-CD

S-c-CD

0 0.007 0 0.009b 0.011a 0 0 0 0 0 0.005 0.010 0.015b 0 0 0.012 0 0.019 0.015b 0 0 0.012 0 0.019 0 0.008

0 0.003a 0.003a 0 0 0.009b 0.025 0 0.015 0 0 0.009 0.011a 0.019a 0 0.011 0.017 0 0.011a 0.019a 0 0.011 0.017 0 0 0

0 0.005 0 0.016b 0 0 0.029 0 0.009b 0 0 0.009 0.017a 0.018b 0.008a 0.016 0.018 0 0.017a 0.018b 0.008a 0.016 0.018 0 0 0

0 0 0 0 0 0.009 0 0.042 0.010b 0.008b 0 0.010 0.006 0.044 0 0 0 0.008 0.006 0.044 0 0 0 0.008 0.019 0

0 0 0.003b 0 0.008 0 0 0 0 0.017b 0 0.006b 0.016b 0 0 0.010 0 0.007b 0.016b 0 0 0.010 0 0.007b 0 0

CM-CDs 0.019 – a 0 0.016 – a 0.007 – a 0 0.012 – b 0.019 – a 0.009 – a 0 0.006 – b 0.005 – b 0.004 – b 0.008 – b 0 0.012 – b 0.006 – b 0.009 – b

0 0

P-CDs 0.007a – a-LDS 0 0.007b – b-HDS 0.044 – c-LDS 0 0 0.005 – b-HDS 0.004a – c-LDS 0.007 – a-LDS 0 0 0 0.004a – b-HDS 0.009a – b-HDS 0 0.005a – b-HDS 0.010 – a-HDS 0.009 – a-HDS 0.004 – a-LDS 0.035a – c-HDS 0.005 – a-LDS 0.002 – b-HDS 0.021 – b-LDS 0.037a – b-LDS 0.014 – a-HDS 0

1066

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

Table 4 Enantiomeric differentiation in ppm in the 1H NMR spectra (400 MHz) of 21–26 (10 mM) with sulfated CDs, CM-CDs33 and P-CDs42 in D2O. Concentration of the cyclodextrin is 20 mM unless otherwise indicated. Largest enantiodifferentiation shown in bold.

21

22

23

24 25

26

a b

CH2 H2 H3 H30 CH3 H3 H30 H4 H5 H1 H2 H3 H30 H4 H5 CH2 CH CH2 O-CH3 H2 H4 H5 H6 H7 CH N-CH3 O-CH3 H2 H4 H5 H6 H7

S-a-CD

S-b-CD-LDS

S-b-CD-HDS

SBE-b-CD

S-c-CD

CM-CDs

P-CDs

0 0 0 0.009a 0 0.014 0 0.010 0 0 0 0.023 0.015a 0 0 0 0 0 0 0 0.015b 0 0 0.016b 0 0 0 0 0 0 0 0

0 0 0.008 0.011 0.004 0 0 0 0 0.006 0.015 0.022 0.041 0.028 0.017 0 0 0 0.007a 0 0.013 0.008b 0.007a 0.014 0.013b 0.017b 0.019b 0.013a 0 0 0 0.020a

0 0 0.006 0.006a 0.005 0.014b 0.026b 0 0.018 0 0 0.025 0.033a 0.026 0.018 0 0 0 0.006b 0 0.013 0.016b 0 0.013 0 0.013b 0 0.012a 0 0 0 0.024

0 0.007 0.018 0.007a 0.002 0 0 0 0 0 0 0.025 0.016 0 0 0 0.010a 0 0 0.013 0 0 0 0 0.008 0 0 0 0.023 0 0.008 0.010

0 0 0.007 0 0 0 0 0.008 0 0 0 0.011 0.006 0 0 0 0 0.015a 0.083 0.012a 0.024 0.018b 0.017 0.025a 0 0.025a 0 0.011 0.025 0 0.030b 0.022

0.009 – b 0 0 0 0.015 – b

0.007 – a-LDS 0 0 0 0.009a – c-LDS 0 0 0 0 0 0 0 0 0 0 0.007a – a-HDS 0 0 0 0 0 0 0 0 0 0 0.012b – c-HDS 0 0 0 0 0

0 0.036 – c 0.013 – a 0 0.010 – c 0.008 – c 0.019 – b 0.019 – b 0.022 – b 0.016 – b 0 0 0.011 – b 0 0.019 – b 0.019 – b 0.020 – b

10 mM. 5 mM.

Figure 5. 1H NMR (400 MHz, D2O) of the diastereotopic H30 (downfield) and H3 (upfield) protons of (a) 23 (10 mM, enriched with the 1R,2S-enantiomer) with S-b-CD-LDS at (b) 5 mM, (c) 10 mM, and (d) 20 mM.

effective as the other sulfated CDs. S-a-CD is also more limited in its utility with 30–33, although the H40 and H60 resonances of 33 are exceptions. S-b-CD-LDS, S-b-CD-HDS and S-c-CD have broad utility for each of 31–33, with each CD having several resonances where it causes the largest enantiomeric differentiation in the 1H NMR spectrum. Figure 7 shows the H40 and H60 resonances of 30 (10 mM) with the five sulfated CDs (20 mM). S-a-CD, S-c-CD and SBE-b-CD cause partial differentiation of H40 and no or partial differentiation of H60 . S-b-CD-LDS and S-b-CD-HDS cause baseline differentiation of H40 , but S-b-CD-HDS is slightly better. However, S-b-CD-LDS causes slightly better results for H60 than S-b-CD-HDS. As seen throughout the compounds examined herein, relatively small structural changes can have significant impacts on the degree of enantiodifferentiation. An example from this group involves pheniramine 30 and brompheniramine 31. The H50 resonance of 30 is not differentiated in the presence of S-c-CD, whereas the same proton in 31 is differentiated by 0.071 ppm. Also, the H60 resonance of 30 is differentiated by 0.043 ppm with S-b-CD-LDS, but is not differentiated in 31. 3. Comparison of the different anionic cyclodextrins

As seen with 1–4, the presence of N-methyl groups in 28 causes some significant changes in the enantiodifferentiation compared to the analogous protons in 27. For example, S-c-CD does not cause differentiation of the aryl resonances of 27 but does differentiate several aryl resonances of 28. Substrates 30–33 are a series of antihistamines that have both an aryl and pyridyl ring. The relatively large enantiomeric differentiation observed in the 1H NMR spectra of 30–33 with the anionic CDs (Table 6) as compared with 1–29 is noteworthy. With two notable exceptions (N-CH3 of 31, H40 of 32), SBE-b-CD is not as

23 of the 33 substrates have been examined with sulfated, phosphated and carboxymethylated CDs and Tables 1–6 provide the best previous enantiomeric differentiation with the P-CDs42 and CM-CDs.25,32,33 As with previous reports using CDs as chiral NMR solvating agents1–3 and chromatographic phases,49 there is not a single anionic cyclodextrin species that is consistently most effective for all of the cationic substrates. One reason is because of the difference in size of a-, b- and c-CD and the more complementary fit of phenyl-containing compounds with a- and b-CD

1067

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

Table 5 Enantiomeric differentiation in ppm in the 1H NMR spectra (400 MHz) of 27–29 (10 mM) with sulfated CDs, CM-CDs33 and P-CDs42 in D2O. Concentration of the cyclodextrin is 20 mM unless otherwise indicated. Largest enantiodifferentiation shown in bold.

27c

28

29

a b c

CH3 H2 H3 CH N-CH3 N-CH30 C-CH3 H2 H3 H4 H5 H6 H7 H8 N-CH2 O-CH2 C-CH3 H2 H5 H8

S-a-CD

S-b-CD-LDS

S-b-CD-HDS

SBE-b-CD

S-c-CD

0 0 0 0 0.042 0.022 0 0 0 0 0 0 0 0.032 0 0 0 0 0 0

0.015 0 0.018b 0 0.013 0.008 0.015 0.026 0 0 0 0 0 0.030 0 0 0 0 0 0.028

0.017 0 0 0 0.015 0.006 0.017 0.031 0 0 0 0 0 0.032 0 0 0 0.016 0 0.030

0 0.018 0 0 0.014b 0.017 0 0.009 0 0.019 0.016 0 0 0 0.009b 0 0 0 0 0

0.029 0 0 0 0.006 0.027 0.047 0.081 0.049b 0.029b 0.014b 0.006a 0.014b 0 0 0 0.009 0.021 0.006 0.007

CM-CDs

P-CDs

0 0 0 0.017 – c 0 0.022 – c

0.005a – c-HDS 0 0 0.020 – b-HDS 0.016a – c-LDS 0 0.011a – c-LDS 0 0 0.013a – c-LDS 0 0 0 0.011a – c-LDS 0.008a – b-HDS 0.006b – c-HDS 0.027 – b-LDS 0 0 0

10 mM. 5 mM. No differentiation of H2–H8 signals was seen for 27.

Figure 6. 1H NMR (400 MHz, D2O) of diastereotopic N(CH3)2 resonances of (a) 28 (10 mM, enriched with the R-enantiomer) with 20 mM (b) S-a-CD, (c) S-b-CD-LDS, (d) S-b-CD-HDS, (e) S-c-CD, and (f) SBE-b-CD.

and bicyclic aryl compounds with b- and c-CD. Another reason is that the location and number of substituent groups on the cyclodextrin are important in determining enantiomeric differentiation. The high degree of substitution of sulfate groups in the CD-S species examined herein may block access of some substrates to the cavity. However, the results obtained herein strongly support the conclusion that the commercially available S-CDs are highly recommended over CM-CDs, P-CDs and SBE-b-CD as the first CSAs to evaluate for enantiomeric differentiation of water-soluble cationic organic salts. A total of 110 resonances of the 23 common substrates show some degree of enantiomeric differentiation with at least one of the anionic CDs. Including the four cases where two or more different CDs caused the same degree of enantiodifferentiation, a sulfated CD causes the largest enantiomeric differentiation of 81 resonances, a CM-CD is most effective for 22 resonances and a P-CD is best for 11 resonances. Of the 110 resonances that were differentiated with at least one anionic CD, 97 were differentiated with a sulfated CD, 61 with a CM-CD and 48 with a P-CD. For the ten substrates examined only with P-CDs and sulfated CDs, a total of 54 resonances exhibit enantiomeric differentiation. Larger enan-

tiomeric differentiation is observed for 48 resonances with a sulfated CD whereas only six are better with a P-CD. Of the 54 resonances, 51 were differentiated with a sulfated CD and 16 with a P-CD. The 1H NMR spectra of only three substrates, 6, 14 and 24, show no enantiomeric differentiation with any of the sulfated CDs. Among the different sulfated CDs, the S-a-CD and SBE-b-CD are far less effective at causing enantiomeric differentiation both in terms of the number of differentiated resonances and magnitude of differentiation. Of the 164 resonances for the 33 substrates that exhibit enantiomeric differentiation with an anionic CD, 148 exhibited enantiomeric differentiation with one or more of the sulfated CDs; 57 with S-a-CD, 93 with S-b-CD-LDS, 98 with S-b-CDHDS, 59 with SBE-b-CD and 85 with S-c-CD. Of all the anionic CDs, S-b-CD-LDS and S-b-CD-HDS are by far the most effective in terms of the number of resonances for which enantiomeric differentiation is observed and the magnitude of the differentiation. There is no clear advantage in using either S-b-CD-LDS or S-b-CD-HDS as both often cause enantiomeric differentiation of about similar magnitudes for the same resonances. Either S-b-CD-LDS or S-b-CD-HDS is warranted as the first choice for substrates that contain a phenyl ring. The use of S-c-CD is warranted as the first choice for substrates containing naphthyl rings. If all of the preferred choices (S-b-CD-L, S-b-CD-H or S-c-CD) are ineffective with a compound, it is then worth trying commercially available S-a-CD, SBE-b-CD or the P-CDs. If these fail to cause enantiomeric differentiation in the 1H NMR spectrum, utilization of the CM-CDs is a final option. 4. Experimental 4.1. Sulfated cyclodextrins Sodium salts of sulfated a-cyclodextrin (S-a-CD, degree of substitution = 12), sulfated b-cyclodextrin (S-b-CD-HDS, degree of substitution = 13), sulfobutylether-b-cyclodextrin (SBE-b-CD, degree of substitution = 6.3), and sulfated c-cyclodextrin (S-c-CD, degree of substitution = 14) were obtained from CycloLab Ltd., Budapest, Hungary. Sulfated b-cyclodextrin with a lower degree of substitution (S-b-CD-LDS, degree of substitution = 9) was obtained from Sigma Aldrich, Milwaukee, WI.

1068

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

Table 6 Enantiomeric differentiation in ppm in the 1H NMR spectra (400 MHz) of 30–33 (10 mM) with sulfated CDs, CM-CDs25,33 and P-CDs42 in D2O. Concentration of the cyclodextrin is 20 mM unless otherwise indicated. Largest enantiodifferentiation shown in bold.

30

31

32

33

a b c d e

CH N-CH2 N-CH20 H4 H30 H40 H60 CH N-CH2 N-CH3 H2 H3 H30 H40 H50 H60 N-CH2 O-CH2 N-CH3 N-CH30 C-CH3 H4 H30 H40 H50 H60 CH N-CH3 N-CH30 H2 H3 H30 H40 H50 H60

S-a-CD

S-b-CD-LDS

S-b-CD-HDS

SBE-b-CD

S-c-CD

CM-CDs

P-CDs

0 0 0 0 0.018 0.021 0 0 0 0 0 0 0 0 0 0 0 0 0.018 0 0 0 0 0.043 0 0.006 0 0.012 0.015 0 0 0 0.038 0 0.064a

0 0 0.187 0 0.029 0.071 0.043 0 0 0.015a 0.047c 0.025c 0.040c 0.061a 0 0 0 0 0.036 0 0 0 0.034 0.019 0.018 0.014 0.037 0.021a 0 0.022 0.021b 0.005b 0.030 0 0.029

0.018b 0 0.146a 0 0 0.080 0.036 0 0 0.016a 0.080 0.044 0.043c 0.056d 0 0 0 0 0.047 0.009a 0 0 0.044 0.021 0.017 0.009 0.044 0.017a 0.014 0.022 0.021b 0.020b 0.021a 0 0.025a

0 0 0 0 0.032a 0.013 0.014 0 0 0.051 0.018b 0 0 0 0 0 0 0 0 0 0 0 0 0.048 0.018 0.014 0.007 0 0 0 0 0 0.019 0 0

0 0 0 0 0.045 0.020 0.014 0 0.011a 0 0 0.010b 0.020e 0.061e 0.071e 0.043e 0 0 0 0 0 0.036a 0.028 0.031 0.029 0.036a 0.034 0 0.037 0.042 0.041 0 0.020b 0.032 0.036b

0.039 – a 0 0 0.018 – c 0.075 – a 0.080 – a 0.042 – b 0.021 – a 0 0 0.034 – b 0.040 – c 0.069 – a 0.074 – b 0 0.047 – b 0 0 0 0 0.021 – b 0 0.010 – c 0.021 – b 0 0.013 – b 0.013 – b 0 0 0.021 – c 0.004 – b 0 0.020 – a 0 0.027 – c

0 0.011a – b-HDS 0.013a – b-HDS 0 0 0.005a – b-HDS 0 0.015 – c-HDS 0 0.016 – a-HDS 0.005 – b-LDS 0.014 – b-HDS 0.012a – c-LDS 0.015 – b-HDS 0.017 – c-HDS 0 0.011a – b-LDS 0.011a – a-LDS 0 0 0.006 – b-HDS 0 0.009 – b-LDS 0 0.021 – b-HDS 0.018a – b-LDS 0.020 – c-HDS 0 0 0.019 – a-LDS 0 0 0 0 0

10 mM. 5 mM. 6 mM. 7 mM. 3 mM.

4.3. Apparatus Proton (1H) NMR spectra were obtained using a Bruker Avance 400 MHz NMR spectrometer. Samples were run in D2O with 8 scans at ambient probe temperature. 4.4. Procedure

Figure 7. 1H NMR (400 MHz, D2O) of the H40 and H60 pyridyl signals of (a) 30 (10 mM, racemic) with 20 mM (b) S-a-CD, (c) S-b-CD-LDS, (d) S-b-CD-HDS, (e) S-cCD, and (f) SBE-b-CD.

Stock solutions (40 mM) of sulfated CDs and stock solutions (20 mM) of cationic substrates enriched in one enantiomer (when available) were prepared in D2O. CD and substrate solutions were kept at ambient temperature. Appropriate aliquots of CD, substrate, and D2O were combined in NMR tubes to obtain a 600 lL solution of 20, 10, or 5 mM CD and 10 mM substrate. Thirty-three substrates 1–33 in their protonated cationic form were each tested with the five anionic CDs at the three different CD concentrations.

4.2. Substrates

Acknowledgements

Substrates were obtained from commercial sources either as hydrochloride salts or neutral compounds. Neutral substrates were converted to their hydrochloride salts in deuterium oxide (D2O) by adding an excess of deuterium chloride (DCl).

We thank the National Science Foundation, United States, (Research at Undergraduate Institutions Program Grant CHE1145061; Major Research Instrumentation Program, Grant CHE0115579) for supporting this work.

B. E. Dalvano, T. J. Wenzel / Tetrahedron: Asymmetry 28 (2017) 1061–1069

References 1. Uccello-Barretta, G.; Balzano, F. Top. Curr. Chem 2013, 341, 69. 2. Wenzel, T. J.; Chisholm, C. D. Prog. NMR Spec. 2011, 59, 1. 3. Wenzel, T. J. Discrimination of chiral compounds using NMR spectroscopy; Wiley Press: Hoboken, NJ, 2007. 4. Webb, T. H.; Wilcox, C. S. Chem. Soc. Rev. 1993, 22, 383. 5. Parker, D. Chem. Rev. 1991, 91, 1441. 6. Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 1, 263. 7. Uccello-Baretta, G.; Balzano, F.; Salvadori, P. Curr. Pharm. Des. 2006, 12, 4023. 8. Greatbanks, D.; Pickford, R. Magn. Reson. Chem. 1987, 25, 208. 9. Casy, A. F.; Mercer, A. D. Magn. Reson. Chem. 1988, 26, 765. 10. Uccello-Barretta, G.; Balzano, F.; Menicagli, R.; Salvadori, P. J. Org. Chem. 1996, 61, 363. 11. Uccello-Barretta, G.; Cuzzola, A.; Balzano, F.; Menicagli, R.; Salvadori, P. Eur. J. Org. Chem. 2009, 1998, 1998. 12. Uccello-Barretta, G.; Cuzzola, A.; Balzano, F.; Menicagli, R.; Iuliano, A.; Salvadori, P. J. Org. Chem. 1997, 62, 827. 13. Uccello-Barretta, G.; Ferri, L.; Balzano, F.; Salvadori, P. Eur. J. Org. Chem. 2003, 2003, 1741. 14. Jursic, B. S.; Patel, P. K. Carbohyd. Res. 2006, 341, 2858. 15. Uccello-Barretta, G.; Sicoli, G.; Balzano, F.; Schurig, V.; Salvadori, P. Tetrahedron: Asymmetry 2006, 17, 2504. 16. Uccello-Barretta, G.; Nazzi, A.; Balzano, F.; Levkin, P. A.; Schurig, V.; Salvadori, P. Eur. J. Org. Chem. 2007, 2007, 3219. 17. Uccello-Barretta, G.; Balzano, F.; Pertici, F.; Jicsinszky, L.; Sicoli, G.; Schurig, V. Eur. J. Org. Chem. 2008, 2008, 1855. 18. Rudzinska, E.; Dziedziola, G.; Berlicki, L.; Kafarski, P. Chirality 2010, 22, 63. 19. Perez-Trujillo, M.; Lindon, J. C.; Parella, T.; Keun, H. C.; Nicholson, J. K.; Athersuch, T. J. Anal. Chem. 2012, 84, 2868. 20. Uccello-Barretta, G.; Schurig, V.; Balzano, F.; Vanni, L.; Aiello, F.; Mori, M.; Ghirga, F. Chirality 2015, 27, 95. 21. Yashima, E.; Yamada, M.; Yamamoto, C.; Nakashima, M.; Okamoto, Y. Enantiomer 1997, 2, 225. 22. Uccello-Barretta, G.; Balzano, F.; Sicoli, G.; Scarselli, A.; Salvadori, P. Eur. J. Org. Chem. 2005, 2005, 5349. 23. Kuroda, Y.; Suzuki, Y.; He, J.; Kawabata, T.; Shibukawa, A.; Wada, H.; Fujima, H.; Go-oh, Y.; Imai, E.; Nakagawa, T. J. Chem. Soc., Perkin Trans. 1995, 2, 1749. 24. Holzgrabe, U.; Mallwitz, H.; Branch, S. K.; Jefferies, T. M.; Wiese, M. Chirality 1997, 9, 211. 25. Dignam, C. F.; Randall, L. A.; Blacken, R. D.; Cunningham, P. R.; Lester, S. G.; Brown, M. J.; French, S. C.; Aniagyei, S. E.; Wenzel, T. J. Tetrahedron: Asymmetry 2006, 17, 1199.

1069

26. Owens, P. K.; Fell, A. F.; Coleman, M. W.; Berridge, J. C. J. Chromatogr. A 1998, 797, 149. 27. Chankvetadze, B.; Schulte, G.; Bergenthal, D.; Blaschke, G. J. Chromatogr. A 1998, 798, 315. 28. Park, K.; Kim, K. H.; Jung, S.; Lim, H.; Hong, C.; Kang, J. J. Pharm. Biomed. Anal. 2002, 27, 569. 29. Lee, S.; Yi, D.; Jung, S. Bull. Korean Chem. Soc. 2004, 25, 216. 30. Smith, K. J.; Wilcox, J. D.; Mirick, G. E.; Wacker, L. S.; Ryan, N. S.; Vensel, D. A.; Readling, R.; Domush, H. L.; Amonoo, E. P.; Shariff, S. S.; Wenzel, T. J. Chirality 2003, 15, S150. 31. Wenzel, T. J.; Amoono, E. P.; Shariff, S. S.; Aniagyei, S. Tetrahedron: Asymmetry 2003, 14, 3099. 32. Provencher, K. A.; Wenzel, T. J. Tetrahedron: Asymmetry 2008, 19, 1797. 33. Provencher, K. A.; Weber, M. A.; Randall, L. A.; Cunningham, P. R.; Dignam, C. F.; Wenzel, T. J. Chirality 2010, 22, 336. 34. Chankvetadze, B.; Burjanadze, N.; Maynard, D. M.; Bergander, K.; Bergenthal, D.; Blaschke, G. Electrophoresis 2002, 23, 3027. 35. Kahle, C.; Deubner, R.; Schollmayer, C.; Scheiber, J.; Baumann, K.; Holzgrabe, U. Eur. J. Org. Chem. 2005, 2005, 1578. 36. Zhou, Z.; Thompson, R.; Reamer, R. A.; Lin, Z.; French, M.; Ellison, D.; Wyvratt, J. Electrophoresis 2003, 24, 2448. 37. Chankvetadze, B.; Endresz, G.; Bergenthal, D.; Blaschke, G. J. Chromatogr. A 1995, 717, 245. 38. Owens, P. K.; Fell, A. F.; Coleman, M. W.; Berridge, J. C. J. Inclusion Phenom. Macrocyclic Chem. 2000, 38, 133. 39. Sun, P.; MacDonnell, F. M.; Armstrong, D. W. Inorg. Chem. Acta 2009, 362, 3073. 40. Fejos, I.; Kazsoki, A.; Sohajda, T.; Marvanyos, E.; Volk, B.; Szente, L.; Beni, S. J. Chromatogr. A 2014, 1363, 348. 41. Kano, K.; Hasegawa, H. J. Am. Chem. Soc. 2001, 123, 10616. 42. Mollings Puentes, C.; Wenzel, T. J. Beilstein J. Org. Chem. 2017, 13, 43. 43. Kano, K.; Hasegawa, H. J. Inclusion Phenom. Macrocyclic Chem. 2001, 41, 41. 44. Brown, S. E.; Coates, J. H.; Duckworth, P. A.; Lincoln, S. F.; Easton, C. J.; May, B. L. J. Chem. Soc. Faraday Trans. 1993, 89, 1035. 45. Park, K. K.; Lim, H. S.; Park, J. W. Bull. Korean Chem. Soc. 1999, 20, 211. 46. Rekharsky, M.; Yamamura, H.; Kawai, M.; Inoue, Y. J. Am. Chem. Soc. 2001, 123, 5360. 47. Chisholm, C. D.; Wenzel, T. J. Tetrahedron: Asymmetry 2011, 22, 62. 48. Dowey, A. E.; Mollings Puentes, C.; Carey-Hatch, M.; Sandridge, K. L.; Krishna, N. B.; Wenzel, T. J. Chirality 2016, 28, 299. 49. Zhang, X.; Zhang, Y.; Armstrong, D. W. Comprehensive Chirality 2012, 8, 177.