Mining Chromatographic Enantioseparation Data Using Matched Molecular Pair Analysis

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molecules

Article

Mining Chromatographic Enantioseparation Data Using Matched Molecular Pair Analysis

Robert P. Sheridan^1,*, Patrick Piras^2,*, Edward C. Sherer¹, Christian Roussel², William H. Pirkle³and Christopher J. Welch^4,*

1 Department of Structural Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA;

[email protected]

2 Aix Marseille Université, Centrale Marseille, CNRS, iSm2, 13397 Marseille CEDEX 20, France;

[email protected]

3 Department of Chemistry, University of Illinois, Urbana, IL 61801, USA; [email protected]

4 Department of Process Research & Development, Merck Research Laboratories, Rahway, NJ 07055, USA

* Correspondence: [email protected] (R.P.S.); [email protected] (P.P.);

[email protected] (C.J.W.); Tel.: +1-732-594-0032 (C.J.W.) Academic Editor: Yoshio Okamoto

Received: 13 July 2016; Accepted: 16 September 2016; Published: 29 September 2016

Abstract:We apply matched molecular pair (MMP) analysis to data from ChirBase, which contains literature reports of chromatographic enantioseparations. For the 19 chiral stationary phases we examined, we were able to identify 289 sets of pairs where there is a statistically significant and consistent difference in enantioseparation due to a small chemical change. In many cases these changes highlight enantioselectivity differences between pairs or small families of closely related molecules that have for many years been used to probe the mechanisms of chromatographic chiral recognition; for example, the comparison of N-H vs. N-Me analytes to determine the criticality of an N-H hydrogen bond in chiral molecular recognition. In other cases, statistically significant MMPs surfaced by the analysis are less familiar or somewhat puzzling, sparking a need to generate and test hypotheses to more fully understand. Consequently, mining of appropriate datasets using MMP analysis provides an important new approach for studying and understanding the process of chromatographic enantioseparation.

Keywords:matched molecular pairs; chiral chromatography; chiral recognition

1. Introduction

Finding which type of chiral stationary phase (CSP) will provide the best chromatographic separation for the enantiomers of a given molecule is mostly a trial-and-error process, and since the number of commercial CSPs is now very large, testing a representative sample of columns becomes difficult and time-consuming, even with automated screening of columns. It would be useful to predict in advance which CSP to choose for a particular molecule. There are longstanding rules of thumb to aid in the prediction of enantioseparability for specific CSPs [1–7], and several attempts have been made over the years to create more broadly applicable statistical models of enantioseparation based on literature data [8–11]. Recently, we attempted to generate descriptor-based QSAR (quantitative structure-activity relationship) enantioselectivity models [12] for a subset of 19 CSPs based on literature data compiled in ChirBase, a database containing more than 200,000 entries of literature-reported chromatographic enantioseparations [13]. This attempt was a partial success, leading to the generation of self-consistent QSAR models for four of the 19 CSPs, and allowing for reasonably accurate predictions of enantioseparability for in-house racemic compounds from the Merck sample repository that were not included in the training sets of the models.

Molecules2016,21, 1297; doi:10.3390/molecules21101297 www.mdpi.com/journal/molecules

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Molecules2016,21, 1297 2 of 28

The limited ability to find trends in more CSPs using descriptor-based QSAR methods was somewhat disappointing, but conventional QSAR is not the only way to find activity trends.

In this paper we discuss the use of matched molecular pair (MMP) methods [14] for investigating enantioseparation data. MMP techniques find local chemical changes in similar compounds and look for trends where the same type of chemical change is associated with a consistent change in activity. Trends identified by MMP are complementary to those found by conventional QSAR, mostly because conventional QSAR is looking for features that correlate with absolute low or high activity, whereas MMP is looking for activity differences between molecules that can be anywhere in the activity range. There are two major types of algorithms for identifying matched pairs: ones based on maximum common substructure and ones based on the change of predefined fragments. These types of algorithms can identify different pairs.

In this paper we apply MMP analysis to the enantioseparation data from our previous study, and find that, using this approach, many more statistically significant trends are found among the 19 CSPs than were obtained using conventional QSAR. We can see many small changes in structure that lead to very large differences in enantioseparation on specific CSPs. While the causes of these effects are not completely understood, we hope that providing this data may induce others to study this problem and experimental approach in further detail. To our knowledge, this is the first attempt to apply MMP methods to chromatographic enantioseparation data.

2. Results and Discussion

Definitions of alpha, Zmax, etc. are given in the Experimental Section. The number of clusters, the expected Zmax, and the number of statistically significant clusters is shown in Table1. Interestingly, all four CSP_NOs that were statistically significant in cross-validation in our previous QSAR study have at least one statistically significant cluster, but 10 CSP_NOs for which we could not find any trend in our previous study have at least one statistically significant cluster. Especially interesting is CSP_NO 23735 (Chiralpak-AD), which afforded no statistically significant QSAR model in our previous study, but which has 65 statistically significant MMP clusters. The full list of Z, meanDiff, StdDiff, plus citations and SMILES for individual compounds in significant clusters, regardless of restrictions about citations, are provided in Supporting Information.

An example cluster is shown in Figure1(Cluster 1 from CSP_NO 23735). In this example, activity data for all 12 pairs was taken from a single publication by Yuan and coworkers [15]. Interestingly, this publication was focused on the synthesis of these compounds, and did not comment on the somewhat remarkable differences in chromatographic enantioselectivity.

Figure2shows Cluster 2 from CSP_NO 23735, a highly significant cluster with 10 pairs coming from seven different citations. Increased enantioselectivity for nitro vs. methyl ketone is observed across the entire series.

Table2lists a summary of statistically significant clusters where within each A-B pair the value of αcomes from the same citation or the same set of authors, and the cluster contains at least two pairs.

The citations are also listed in the table. The chemical change is summarized by the first pair in the cluster. Since the order of pairs in the cluster is arbitrary, the first pair may not have the largest change in enantioseparation. The other pairs have the same change in very similar molecules, as is seen in Figures1and2.

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Molecules2016,21, 1297 3 of 28

Table 1.Stationary Phase in Chirbase Studied in this Work.

CSP_NO Description Unique

Molecules Meanα Stdevα Total Clusters

Expected maxZ (95th Percentile)

Number of Significant Clusters

394 Chiral-AGP 574 1.65 0.90 519 3.9 0

2966 Crownpak-CR(+)¹ 346 2.03 1.52 416 3.8 4

3575 Ultron-ES-OVM 190 1.55 0.59 90 3.4 0

15723 Chirobiotic-R 462 1.93 1.51 636 3.9 0

23735 Chiralpak-AD 11167 1.45 0.64 8348 4.6 65

45167 Chiralpak-AS 3665 1.48 0.68 4296 4.4 30

45172 Chiralpak-IA 1373 1.53 0.81 2099 4.2 11

45173 Chiralcel-OD 14350 1.47 0.64 22112 4.8 48

90201 Chiralcel-CA-1 470 1.82 1.51 561 3.9 2

90220 Chiralcel-OF 291 1.40 0.63 257 3.7 4

90246 Chiralcel-OJ 4256 1.44 0.63 5108 4.4 20

90292 (DNB)-Leu¹ 610 1.71 1.17 1296 4.1 5

90589 Whelk-O¹ 1754 1.59 1.01 2246 4.2 14

90613 Chiralcel-OZ 314 1.53 0.76 204 3.6 0

90704 Chirobiotic-V 351 1.37 0.73 411 3.8 16

90752 Chiralpak-AY 216 1.67 0.99 108 3.5 0

90879 Chirobiotic-T¹ 1154 2.20 1.96 1920 4.2 20

91119 Chirobiotic-TAG 308 1.87 1.59 329 3.8 7

91423 Chiralpak-IB 680 1.39 0.62 876 4.0 11

1Statistically significant by descriptor-based QSAR.

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Molecules2016,21, 1297 4 of 28

Molecules 2016, 21, 1297 4 of 27

Figure 1. Expanded view of Cluster 1 for CSP_NO 23735 (Chiralpak-AD). There are 12 pairs (a–l) in this cluster. Differences in the structure are highlighted in red. Next to each compound is shown the Chirbase compound number and log(α). The meanDiff within each pair is written between the molecules.

This is an example of a cluster where all the values of α come from the same reference.

a)

b)

c)

d)

e)

f)

g)

h)

i)

j)

k)

l)

Figure 1.Expanded view of Cluster 1 for CSP_NO 23735 (Chiralpak-AD). There are 12 pairs (a–l) in this cluster. Differences in the structure are highlighted in red. Next to each compound is shown the Chirbase compound number and log(α). The meanDiff within each pair is written between the molecules. This is an example of a cluster where all the values ofαcome from the same reference.

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Molecules2016,21, 1297 5 of 28

Molecules 2016, 21, 1297 5 of 27

Figure 2. Expanded view of Cluster 2 for CSP_NO 23735 (Chiralpak-AD). There are 10 pairs in this cluster. Differences in structure are highlighted in red. Next to each compound is shown the Chirbase compound number and log(α). The meanDiff within each pair is written between the molecules. This is an example of a cluster were the values of α can come from different references. See supporting information for conformational modeling showing differences in preferred conformations of nitro and methyl ketone analogs.

104139 0.72 0.32 128031 0.22

126057 0.46 0.25 158127 0.21

166222 0.48 0.26 158126 0.22

126055 0.49 0.31 158131 0.18

126062 0.09 0.03 128044 0.06

166233 0.86 0.44 128043 0.43 126056 0.81 0.57 158134 0.24

121326 0.58 0.34 128038 0.24 O

O O

ONO O

O O

O

O O O

O O

ONO O

O O

O

Br Br

O O O

O O

ONO O

O O

O

Cl Cl

O O O

O O

ONO O

O O

O

O O O

O O

ONO O

O O

O

S S

104143 0.36 0.25 158137 0.11

O O O

O O

ONO O

O O

O

O O O

O O

ON O O

O O

O

O O

O O O

O O

ON O O

O O

F₃C O F₃C

O O O

O O

ONO O

O O

O

O O O

O O

ONO O

O O

O

114061 0.40 0.32 128036 0.08 Figure 2.Expanded view of Cluster 2 for CSP_NO 23735 (Chiralpak-AD). There are 10 pairs in this cluster. Differences in structure are highlighted in red. Next to each compound is shown the Chirbase compound number and log(α). The meanDiff within each pair is written between the molecules.

This is an example of a cluster were the values ofαcan come from different references. See supporting information for conformational modeling showing differences in preferred conformations of nitro and methyl ketone analogs.

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Molecules2016,21, 1297 6 of 28

Table 2.Clusters where M > 1 and the activities for A and B come from the same reference.

CSP_NO Cluster Z No. Pairs Mean (Diff) Std (Diff) Example Reference

23735 Chiralpak-AD 1 11.52 12 0.43 0.23

Molecules 2016, 21, 1297 6 of 27

Table 2. Clusters where M > 1 and the activities for A and B come from the same reference.

CSP_NO Cluster Z No. Pairs Mean (Diff) Std (Diff) Example Reference

23735 Chiralpak-AD 1 11.52 12 0.43 0.23 [15]

5 6.93 6 0.35 0.03 [16]

27 5.62 2 0.49 0.24 [17]

28 5.61 2 0.49 0.27 [17]

35 5.47 2 0.48 0.08 [18,19]

44 5.14 2 0.46 0.07 [18,19]

[15]

5 6.93 6 0.35 0.03

Molecules 2016, 21, 1297 6 of 27

23735 Chiralpak-AD 1 11.52 12 0.43 0.23 [15]

5 6.93 6 0.35 0.03 [16]

27 5.62 2 0.49 0.24 [17]

28 5.61 2 0.49 0.27 [17]

35 5.47 2 0.48 0.08 [18,19]

44 5.14 2 0.46 0.07 [18,19]

[16]

27 5.62 2 0.49 0.24

Molecules 2016, 21, 1297 6 of 27

23735 Chiralpak-AD 1 11.52 12 0.43 0.23 [15]

5 6.93 6 0.35 0.03 [16]

27 5.62 2 0.49 0.24 [17]

28 5.61 2 0.49 0.27 [17]

35 5.47 2 0.48 0.08 [18,19]

44 5.14 2 0.46 0.07 [18,19]

[17]

28 5.61 2 0.49 0.27

Molecules 2016, 21, 1297 6 of 27

23735 Chiralpak-AD 1 11.52 12 0.43 0.23 [15]

5 6.93 6 0.35 0.03 [16]

27 5.62 2 0.49 0.24 [17]

28 5.61 2 0.49 0.27 [17]

35 5.47 2 0.48 0.08 [18,19]

44 5.14 2 0.46 0.07 [18,19]

[17]

35 5.47 2 0.48 0.08

Molecules 2016, 21, 1297 6 of 27

23735 Chiralpak-AD 1 11.52 12 0.43 0.23 [15]

5 6.93 6 0.35 0.03 [16]

27 5.62 2 0.49 0.24 [17]

28 5.61 2 0.49 0.27 [17]

35 5.47 2 0.48 0.08 [18,19]

44 5.14 2 0.46 0.07 [18,19]

[18,19]

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Molecules2016,21, 1297 7 of 28

Table 2.Cont.

44 5.14 2 0.46 0.07

Molecules 2016, 21, 1297 6 of 27

23735 Chiralpak-AD 1 11.52 12 0.43 0.23 [15]

5 6.93 6 0.35 0.03 [16]

27 5.62 2 0.49 0.24 [17]

28 5.61 2 0.49 0.27 [17]

35 5.47 2 0.48 0.08 [18,19]

44 5.14 2 0.46 0.07 [18,19] [18,19]

45 5.10 5 0.29 0.24

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29]

[20]

46 5.08 2 0.45 0.24

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29]

[19,21]

47 5.05 2 0.45 0.19

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29]

[22]

61 4.80 4 0.31 0.01

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29]

[23]

65 4.78 4 0.31 0.16

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29]

[24,25]

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Molecules2016,21, 1297 8 of 28

Table 2.Cont.

45167 Chiralpak-AS 1 7.84 2 0.76 0.07

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29]

[26–28]

28 4.57 2 0.44 0.29

Molecules 2016, 21, 1297 7 of 27

45 5.10 5 0.29 0.24 [20]

46 5.08 2 0.45 0.24 [19,21]

47 5.05 2 0.45 0.19 [22]

61 4.80 4 0.31 0.01 [23]

65 4.78 4 0.31 0.16 [24,25]

45167 Chiralpak-AS 1 7.84 2 0.76 0.07 [26–28]

28 4.57 2 0.44 0.29 [29] [29]

45173 Chiralcel-OD 1 8.36 2 0.90 0.01

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32]

[30]

2 8.29 12 0.35 0.20

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32]

[31]

3 8.05 2 0.86 0.08

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32]

[30]

5 7.27 4 0.54 0.08

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32]

[30]

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Molecules2016,21, 1297 9 of 28

Table 2.Cont.

6 7.00 4 0.52 0.09

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32]

[30]

7 6.86 4 0.51 0.05

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32]

[30]

9 6.71 3 0.55 0.40

Molecules 2016, 21, 1297 8 of 27

45173 Chiralcel-OD 1 8.36 2 0.90 0.01 [30]

2 8.29 12 0.35 0.20 [31]

3 8.05 2 0.86 0.08 [30]

5 7.27 4 0.54 0.08 [30]

6 7.00 4 0.52 0.09 [30]

7 6.86 4 0.51 0.05 [30]

9 6.71 3 0.55 0.40 [30,32] [30,32]

11 6.65 2 0.71 0.00

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37]

[33]

15 6.17 3 0.51 0.09

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37]

[34,35]

16 5.86 2 0.62 0.06

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37]

[36,37]

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Molecules2016,21, 1297 10 of 28

Table 2.Cont.

17 5.85 2 0.62 0.06

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37]

[30]

18 5.82 2 0.62 0.06

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37]

[30]

19 5.76 3 0.48 0.13

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37]

[30,34,35]

20 5.72 2 0.61 0.29

Molecules 2016, 21, 1297 9 of 27

11 6.65 2 0.71 0.00 [33]

15 6.17 3 0.51 0.09 [34,35]

16 5.86 2 0.62 0.06 [36,37]

17 5.85 2 0.62 0.06 [30]

18 5.82 2 0.62 0.06 [30]

19 5.76 3 0.48 0.13 [30,34,35]

20 5.72 2 0.61 0.29 [37] [37]

23 5.61 2 0.60 0.26

Molecules 2016, 21, 1297 10 of 27

23 5.61 2 0.60 0.26 [37]

25 5.49 2 0.58 0.46 [30,32]

27 5.43 2 0.57 0.01 [30,32]

28 5.43 2 0.58 0.06 [30]

33 5.11 2 0.55 0.01 [30]

35 5.10 2 0.54 0.03 [30,32]

[37]

25 5.49 2 0.58 0.46

Molecules 2016, 21, 1297 10 of 27

23 5.61 2 0.60 0.26 [37]

25 5.49 2 0.58 0.46 [30,32]

27 5.43 2 0.57 0.01 [30,32]

28 5.43 2 0.58 0.06 [30]

33 5.11 2 0.55 0.01 [30]

35 5.10 2 0.54 0.03 [30,32]

[30,32]

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Molecules2016,21, 1297 11 of 28

Table 2.Cont.

27 5.43 2 0.57 0.01

Molecules 2016, 21, 1297 10 of 27

23 5.61 2 0.60 0.26 [37]

25 5.49 2 0.58 0.46 [30,32]

27 5.43 2 0.57 0.01 [30,32]

28 5.43 2 0.58 0.06 [30]

33 5.11 2 0.55 0.01 [30]

35 5.10 2 0.54 0.03 [30,32]

[30,32]

28 5.43 2 0.58 0.06

Molecules 2016, 21, 1297 10 of 27

23 5.61 2 0.60 0.26 [37]

25 5.49 2 0.58 0.46 [30,32]

27 5.43 2 0.57 0.01 [30,32]

28 5.43 2 0.58 0.06 [30]

33 5.11 2 0.55 0.01 [30]

35 5.10 2 0.54 0.03 [30,32]

[30]

33 5.11 2 0.55 0.01

Molecules 2016, 21, 1297 10 of 27

23 5.61 2 0.60 0.26 [37]

25 5.49 2 0.58 0.46 [30,32]

27 5.43 2 0.57 0.01 [30,32]

28 5.43 2 0.58 0.06 [30]

33 5.11 2 0.55 0.01 [30]

35 5.10 2 0.54 0.03 [30,32]

[30]

35 5.10 2 0.54 0.03

Molecules 2016, 21, 1297 10 of 27

23 5.61 2 0.60 0.26 [37]

25 5.49 2 0.58 0.46 [30,32]

27 5.43 2 0.57 0.01 [30,32]

28 5.43 2 0.58 0.06 [30]

33 5.11 2 0.55 0.01 [30]

35 5.10 2 0.54 0.03 [30,32] [30,32]

37 5.07 2 0.54 0.31

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48]

[37]

(12)

Molecules2016,21, 1297 12 of 28

Table 2.Cont.

44 4.95 3 0.41 0.08

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48]

[38–40]

47 4.82 2 0.52 0.01

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48]

[30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48]

[41,42]

2 4.25 8 0.42 0.29

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48]

[43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48]

[44–46]

16 4.59 2 0.45 0.00

Molecules 2016, 21, 1297 11 of 27

37 5.07 2 0.54 0.31 [37]

44 4.95 3 0.41 0.08 [38–40]

47 4.82 2 0.52 0.01 [30]

90201 Chiralcel-CA-1 1 5.31 3 0.82 0.07 [41,42]

2 4.25 8 0.42 0.29 [43]

90246 Chiralcel-OJ 1 7.91 5 0.47 0.10 [44–46]

16 4.59 2 0.45 0.00 [47,48] [47,48]

(13)

Molecules2016,21, 1297 13 of 28

Table 2.Cont.

19 4.45 2 0.43 0.07

Molecules 2016, 21, 1297 12 of 27

19 4.45 2 0.43 0.07 [37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21 [49–52]

4 4.41 3 0.38 0.01 [53]

90589 Whelk-O 10 4.58 2 0.51 0.17 [54]

12 4.43 4 0.33 0.03 [55]

13 4.31 2 0.47 0.02 [54]

[37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21

Molecules 2016, 21, 1297 12 of 27

19 4.45 2 0.43 0.07 [37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21 [49–52]

4 4.41 3 0.38 0.01 [53]

90589 Whelk-O 10 4.58 2 0.51 0.17 [54]

12 4.43 4 0.33 0.03 [55]

13 4.31 2 0.47 0.02 [54]

[49–52]

4 4.41 3 0.38 0.01

Molecules 2016, 21, 1297 12 of 27

19 4.45 2 0.43 0.07 [37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21 [49–52]

4 4.41 3 0.38 0.01 [53]

90589 Whelk-O 10 4.58 2 0.51 0.17 [54]

12 4.43 4 0.33 0.03 [55]

13 4.31 2 0.47 0.02 [54]

[53]

90589 Whelk-O 10 4.58 2 0.51 0.17

Molecules 2016, 21, 1297 12 of 27

19 4.45 2 0.43 0.07 [37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21 [49–52]

4 4.41 3 0.38 0.01 [53]

90589 Whelk-O 10 4.58 2 0.51 0.17 [54]

12 4.43 4 0.33 0.03 [55]

13 4.31 2 0.47 0.02 [54]

[54]

12 4.43 4 0.33 0.03

Molecules 2016, 21, 1297 12 of 27

19 4.45 2 0.43 0.07 [37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21 [49–52]

4 4.41 3 0.38 0.01 [53]

90589 Whelk-O 10 4.58 2 0.51 0.17 [54]

12 4.43 4 0.33 0.03 [55]

13 4.31 2 0.47 0.02 [54]

[55]

13 4.31 2 0.47 0.02

Molecules 2016, 21, 1297 12 of 27

19 4.45 2 0.43 0.07 [37]

90292 Pirkle DNB-Leu 1 5.47 9 0.27 0.21 [49–52]

4 4.41 3 0.38 0.01 [53]

90589 Whelk-O 10 4.58 2 0.51 0.17 [54]

12 4.43 4 0.33 0.03 [55]

13 4.31 2 0.47 0.02 [54] [54]

(14)

Molecules2016,21, 1297 14 of 28

Table 2.Cont.

14 4.26 2 0.47 0.05

Molecules 2016, 21, 1297 13 of 27

14 4.26 2 0.47 0.05 [56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34 [58]

13 4.30 2 0.33 0.36 [58]

15 4.13 4 0.20 0.25 [58]

16 4.10 2 0.31 0.26 [58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06 [59]

90879 3 5.29 2 0.85 0.02 [59]

[56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34

Molecules 2016, 21, 1297 13 of 27

14 4.26 2 0.47 0.05 [56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34 [58]

13 4.30 2 0.33 0.36 [58]

15 4.13 4 0.20 0.25 [58]

16 4.10 2 0.31 0.26 [58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06 [59]

90879 3 5.29 2 0.85 0.02 [59]

[58]

13 4.30 2 0.33 0.36

Molecules 2016, 21, 1297 13 of 27

14 4.26 2 0.47 0.05 [56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34 [58]

13 4.30 2 0.33 0.36 [58]

15 4.13 4 0.20 0.25 [58]

16 4.10 2 0.31 0.26 [58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06 [59]

90879 3 5.29 2 0.85 0.02 [59]

[58]

15 4.13 4 0.20 0.25

Molecules 2016, 21, 1297 13 of 27

14 4.26 2 0.47 0.05 [56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34 [58]

13 4.30 2 0.33 0.36 [58]

15 4.13 4 0.20 0.25 [58]

16 4.10 2 0.31 0.26 [58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06 [59]

90879 3 5.29 2 0.85 0.02 [59]

[58]

16 4.10 2 0.31 0.26

Molecules 2016, 21, 1297 13 of 27

14 4.26 2 0.47 0.05 [56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34 [58]

13 4.30 2 0.33 0.36 [58]

15 4.13 4 0.20 0.25 [58]

16 4.10 2 0.31 0.26 [58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06 [59]

90879 3 5.29 2 0.85 0.02 [59]

[58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06

Molecules 2016, 21, 1297 13 of 27

14 4.26 2 0.47 0.05 [56,57]

90704 Chirobiotic-V 12 4.52 2 0.34 0.34 [58]

13 4.30 2 0.33 0.36 [58]

15 4.13 4 0.20 0.25 [58]

16 4.10 2 0.31 0.26 [58]

90879 Chirobiotic-T 1 6.57 4 0.70 0.06 [59]

90879 3 5.29 2 0.85 0.02 [59]

[59]