SUMMARY
The use of parallel synthesis protocols for asymmetric reaction discovery has increased the need for new methods to rapidly determine enantiomeric excess (ee) values. Most chirality sensing is performed on stereocenters that are α (i.e., proximal) to the target functional group. Finding a general approach to detect more distant point chirality would increase the substrate scope of such assays. Herein, we demonstrate a design principle to “reach out” to more distant stereocenters, in this case β-chirality in primary alcohols. Therefore, we see the design principles established in this work as a step forward in sensing distant point chirality and, eventually, multi-stereocenter relationships.
Graphical Abstract
The use of parallel synthesis protocols for asymmetric reaction discovery has increased the need for new methods to rapidly determine enantiomeric excess (ee) values. Most chirality sensing is performed on stereocenters that are α (i.e., proximal) to the target functional group. Herein, we demonstrate a design principle to “reach out” to more distant stereocenters. Therefore, we see the design principles established in this work as a step forward in sensing distant point chirality and, eventually, multi-stereocenter relationships.
INTRODUCTION
The utilization of designed and synthesized drugs for medicinal applications has played a critical role in increasing the average human lifespan.1–3 Around 50% of all drugs contain at least one stereocenter.4 Thus, the need to create chiral molecules continues to inspire the synthetic community.5–7 As such, the ever-increasing demand for asymmetric synthetic methods, in turn, increases the need for analytical techniques.
Modern methods for catalyst discovery, such as high-throughput experimentation, accelerate the discovery of ideal asymmetric transformations.8,9 These methods call for measuring the enantiomeric excess (ee) in hundreds, if not thousands, of reactions.5 Analyzing the ee of 1,000 samples by high-performance liquid chromatography (HPLC) can take anywhere from 2 to 10 min per optimized run depending on the column and solvent system. Because HPLC analysis by nature is serial and not parallel, it would take 33–167 h (i.e., 1 week) to analyze 1,000 reactions. Thus, many groups are creating rapid optical methods to determine ee, and assays for several classes of functional groups have been created.10,11
Our group has developed a series of ee assays that target chiral amines,12 carboxylic acids,13 ketones,14 and alcohols.15 Zonta has recently developed sensors for chiral sulfonamides and amides,14 and Anzenbacher,16 Pu,17 Wolf,18 and You,19 along with others,20 have also reported several chirality sensors.21 Nearly without exception, the stereocenter in the chiral analyte is a, i.e., as proximal as possible, to the functional group being analyzed. Thus, armed with the ability to determine the ee of stereocenters proximal to many common functional groups, we are working to build assemblies that can sense stereocenters that are more remote from their functional groups. Finding methods to detect elements of chirality distal from functional groups will increase the substrate scope and utility of the optical methods.
In this work, we present a general strategy and then show how we redesigned the chemical components of our previous sensing assay for α-chiral secondary alcohols, directing it to detect the ee of β-chiral primary alcohols. Finally, we present a design strategy that utilizes induced atropisomerism to alter the optical wavelength of these circular dichroism (CD)-based sensors.
RESULTS AND DISCUSSION
Design Criteria
Few groups have ever reported the optical sensing of b-chiral stereocenters.22 We have previously reported a CD-based method to determine the ee of α-, β-, and some γ-chiral carboxylic acids (Figure 1).13,23 Our methods used a single Cu(II)-coordination complex (1). The chiral carboxylate anions coordinate the metal, and the stereocenters place a twist into the associated quinolines that results in exciton coupled circular dichroism (ECCD). As the depiction of 1 with a docked carboxylic acid reveals, there is a cavity created by the ligands that is deep enough that remote stereocenters can still be near the quinolines involved in ECCD. Further, we found that within a series of α-chiral carboxylates, the difference in steric size of the groups on the stereocenter dictate the helical twist of the quinolines and, thus, the magnitude of the CD signals.13,23
Figure 1.
The Copper Complex Coordinates to a Carboxylic Acid and the Quinoline Twists Are Dictated by the Point Chirality of the Stereocenters (α or β)
The lesson is clear: place chromophores proximal to the site of the point stereocenter in a manner such that they are twisted by that stereocenter, and the more that helical twist is affected by steric differences on the stereocenter, the larger the ECCD. We chose to pursue primary alcohols with β-stereocenters to explore this design principle. The secondary alcohol ee assay that we have previously developed (Figure 2A) involves a four-component reversible covalent-bonding assembly involving zinc triflate, dipicolylamine (DPA), the chiral alcohol of interest, and a 3-substituted-2-pyridinecarboxaldehyde (2-X). The assembly creates a new stereogenic hemiaminal ether as part of a trisaminoethylamine (TREN) ligand to the zinc, resulting in diastereomers (3) with chiral alcohols. This new stereocenter induces a twist into the pyridine rings (Figure 2B) that results in ECCD and the magnitude of the CD signal reports the ee of chiral secondary alcohols.
Figure 2. Molecular Assemblies Used in This Study.
(A) Formation of multi-component zinc hemiaminal ether assembly 3.
(B) Differing twists of terpyridine rings between diastereomers results in opposing CD signals (θ) at 270 nm. CEM·HCl (N-chloroethylmorpholine hydrochloride). (Inset) Assemblies (3a–3i) prepared from 2a to 2i to examine the steric effects of 3-substitution on a β stereocenter.
We have found that the magnitude of the CD signal depends upon the diastereomeric ratio (dr) of 3.24,25 For example, the new R- or S-stereocenter at the hemiaminal ether carbon induces a preference of opposing pyridine twists and opposite CD Cotton effects. If the concentration of diastereomers is equal (dr > 1), the enantiopurity of the alcohol is not detectable, even for a completely enantiopure sample. However, if the diastereomers are unequal (dr > 1), the assembly displays a CD signal. Correspondingly, larger dr values for different chiral alcohols result in larger CD signals.
Furthermore, we reported a method to enhance the magnitude of the CD response to the steric differences on the alcohol’s stereocenter by varying C3 position (X-group) on the o-formylpyridine (2a).25 In particular, when X = CH3 (i.e., 2b), the largest dynamic range of CD signals was obtained, thereby lowering the error on measuring ee values. It appears that increasing steric interactions from the X-group enhances the sensitivity of the assay to detect steric differences between the differing groups on the alcohol’s stereocenter.
As discussed above, we wanted to extend the utility of this four-component assembly to primary alcohols with distant stereocenters. To accomplish this, we took our lead from assembly 1, as well as the enhanced sensitivity in the alcohol assay from varying the steric interactions. We thus combined these ideas to create an alcohol-binding site that places chromophores that are large enough to interact with the remote stereocenters and do so via varying steric interactions with the X-groups on compound 2. To test our design strategy, we routinely used Ac-LSer-OMe (ASE, Ser = serine) as a model β-chiral primary alcohol.
We first increased the bulk of the 3-position on 2 by tosylating a hydroxyl group (Figure 3A). Unfortunately, the tosyl substituent in the assembly (i.e., 3c, X = tolsyate [-OTs]) showed no diastereomeric preference with ASE incorporated into the assembly of Figure 2. Although a tosyl group is clearly larger than a methyl group, the ability to rotate this group away from the bound alcohol via the connecting oxygen relieves any steric interactions that the tosyl group could induce, and the oxygen lone pairs are smaller than the C–H bonding pairs of a methyl group.26 In fact, a tosyl group has a smaller cyclohexane A value than a methyl group for this reason.27 Thus, we needed to extend the sterics through a less flexible group, one that would project out straight from the 3-position, and aryl groups seemed an obvious choice (Figure 3B). The trigonal planar geometry at the 3α carbon (Figure 3B) would prevent the steric relief rendered by the bent geometry of an oxygen, and the length could reach the more remote stereocenters (Figure 3B).
Figure 3. Steric Interactions in the Assembly between a Tosyl and a Phenyl on Assembly 3.
Tosyl (A) and phenyl (B).
To probe the intensity of steric interactions created between the 2-X substituents and a b-chiral stereocenter, we examined the diastereomeric ratios of the corresponding assemblies (3-X) with ASE (Figure S2). The dr values were determined by integrating the 1H-NMR singlet resonances of the hemiaminal protons, which appear in the 4.5–6 ppm range (Figure 4).15 These studies showed that 3d (X = Ph) had the largest measurable steric interaction with ASE (dr = 1.8), while 3b (X = CH3) had none; the dr was 1.0 within experimental error (blue value for ASE in Figure 4). With a comparison of α-chiral secondary alcohol, PE, a dr value of 2.0 was obtained for 3b (blue value for PE in Figure 4). Thus, while a methyl group can influence the dr for an α-stereocenter, it is not large enough to interact with a β-stereocenter. We then compared 3b and 3d by screening several different alcohols with both these assemblies (Figure 4). Almost universally there was an increase in dr when using the 3d assembly (derived from 2d) indicating that the steric size of the 3-phenyl substituent was able to increase the thermodynamic difference between diastereomers.
Figure 4. Chiral Alcohols Used in This Study.
dr values of 3-X assemblies for alcohol when incorporated in the assembly using 2b (blue). dr values of alcohol are incorporated in the assembly using 2d (red).
Once we established that the 3-phenyl group increased the energy difference between diastereomers, we wanted to assess the relationship between dr and CD signal for assembly 3d (X = Ph). Based upon previous results,15,25 we expected that larger dr values for this assembly would result in larger CD signals for the ECCD coupling of the pyridine ligands around 270–275 nm. In accordance with these expectations, a linear increase in CD signal was seen between 270 and 275 nm as dr increased (Figure 5A). However, both the dr values and their associated ellipticity values were quite small. Upon examination of a wider wavelength range, we noticed that the θmax was between 220 and 250 nm for these new assemblies, but this larger signal did not depend upon dr. Thus, we suspected that these signals were not a result of the terpyridine twist (Figure 5B). However, these CD signals are more useful in our analytical method because they have larger ellipticities.
Figure 5. The Hemiaminal Assemblies Were Formed by Incubating Aldehyde 2d and Different Chiral Alcohols to Generate 3d.
(A) For each hemiaminal assembly mixture, the CD signal from the terpyridine twist (270–275 nm) is plotted against their corresponding dr values.
(B) The CD at λmax for each hemiaminal assembly is plotted against their respective diastereomeric ratios.
We postulated that these CD signals at the lower wavelengths (220–240 nm) were arising from an aryl-aryl ring twist because the twist of chiral binaphthyls is normally seen around 215–230 nm (Figure 6A).28 We suspected that the 3-phenyl ring was being twisted about its axis with the pyridine, giving rise to an induced CD signal. To verify this hypothesis, we examined the reaction of ASE with bis-ortho-substituted aldehydes 2e and 2f to generate the 3e and 2f assemblies in the anticipation that such substitution would have a rotational barrier about the 3-aryl axis. By increasing this barrier, we expected to increase the prominence of a twisted aryl-aryl conformation (Figure 6B).
Figure 6. NMR Evidence of Atropisomerism in Certain Assemblies.
(A) The free rotation of the phenyl ring increases its steric bulk.
(B) The rotation of a disubstituted ring with R1 and R2. If R1 ≠ R2, atropisomers are formed.
(C–F) 1H-NMR spectra of hemiaminal ether proton (blue) in different assemblies: (C) phenyl (3d), (D) 2,6-dimethylphenyl (3e), (E) o-tolyl (3g), and (F) 1-naphthyl (3h). Hindered rotation results in formation of diastereomeric atropisomers, which results in four proton resonances instead of two.
Investigation into Atropisomerism
If our hypothesis about the rotation of the aryl ring is correct, the assemblies having an o-tolyl (3g) and 1-naphthyl (3h) should exist as atropisomers. If the aryl-aryl axes of assemblies created from 2g and 2h have hindered the rotation about the 3-aryl axis, the slow rotation about the axes should give rise to 1H-NMR spectra that differentiate the position of the methyl in 3g and fused benzo ring in 3h (Figure 6B). In fact, 1H-NMR spectroscopy studies of these assemblies validate this idea. Normally, the formation of the hemiaminal ether functional group in these assemblies (3) with a chiral alcohol results in two resonances associated with the methine hydrogen (Figure 6A), indicative of the two diastereomers implied in Figure 2A. For example, an assembly derived from 2d gives only two hemiaminal-associated resonances (Figure 6C). Therefore, the emergence of an additional set of hemiaminal peaks is conclusive evidence of the formation of an additional set of chemically unique diastereomers (Figure 6B). For example, the o-tolyl assembly 3g displays four hemiaminal resonances when incubated with ASE (Figure 6E), but assemblies 3d and 3e only show two analogous proton peaks when incubated with the same alcohol (Figures 6C and 6D). Similarly, a 1H-NMR spectrum of the assembly 3h and ASE shows four peaks that correspond to the methine proton instead of the two protons that the phenyl shows (Figure 6F). These data suggest that assembly 3h also contains an element of helical stereoisomerism about the aryl-aryl axis.
Given that CD signals arise from twists along a helical stereochemical element between the two aryl rings joined at the C3 position (Figure 7A), we realized that such induced CD could be exploited to shift the wavelength of ellipticity into the visible-light region. Inspired by this observation, we synthesized both an anthracene- and azo-containing aldehyde (2f and 2i, respectively) specifically to test this hypothesis. The azo dye was made according to a previously published preparation.29 It was subsequently borylated and Suzuki coupled to form 2i (50% yield, Scheme S1). The CD spectrum of assemblies derived from 2f and 2i (giving 3f and 3i, respectively) with both 1-phenylethanol (PE) and 2-phenylbutanol (PBA) display peaks from 350 to 400 nm and 400 to 500 nm, respectively, which corresponds to the absorbance of the anthracene and 3-azo chromophores (Figures 7B and 7C). From these data and the lack of correlation between dr and CD signal intensity for several alcohols (Figure 5B), we conclude that the signals outside of 270–275 nm are from atropisomeric diastereomerism rather than ECCD, which are biased to one enantiomer of the diastereomer by the chiral alcohol.
Figure 7. Atropisomerism Allows for Redshifting of CD Signal.
(A) Atropisomers result from chromophore twists about the aryl-aryl bond.
(B) Normalized CD spectra of different molecular assemblies when incubated with (R)-PE.
(C) Normalized CD spectra of different molecular assemblies when incubated with (R)-PBA.
Optical Sensing of ee for Chiral Primary Alcohols
Armed with the discovery of atropisomerism in the prepared assemblies, we turned our attention back to developing an optical assay for the ee of β-chiral primary alcohols. It was clear that atropisomerism has a strong influence on the determination of θ. Thus, we chose to develop the assay around the use of 2g because its corresponding assembly 3g gave the largest CD signal with ASE, and its atropisomers interconverted slowly enough to be seen by 1H NMR spectroscopy. Thus, 2g was incubated with the alcohols in Figure 3. In comparison to the 2d-derived assemblies, the 3g assemblies generally gave higher ellipticities at the same concentrations (Figure 8), even for alcohols that gave almost no signal for the phenyl-based 3d assembly. A further investigation of the outlier alcohol 2,3-dichloro-3-phenylpropanol (PDP) revealed that it has a substantial intrinsic CD signal that overlaps with the observed λmax values in assemblies 3d and 3g. Therefore, the 3g assembly amplifies the CD signal better than 3d in which the alcohol has no meaningful overlapping CD signal.
Figure 8. The θ at λmax Is Shown for Different Hemiaminal Ether Assemblies.
Assemblies derived from 3d (dark blue) as the aldehyde component are compared to assemblies with 3g (light blue) as the aldehyde component. The ee of all alcohols in this assay was 99%, with the exception of PHP (ee = 53%) and PDP (ee = 68%).
In order to determine the practicality of the 2g-derived assemblies for the detection of ee in β-chiral primary alcohols, we examined if there was a signal dependent response between the ee and θ. Chiral alcohols were incubated with 2g in the presence of DPA, zinc triflate, and CEM · HCl. The optical response for each pair was examined at different enantiomeric excesses. For all of the primary alcohols in Figure 9, the optical response correlated linearly with changes in ee. These calibration curves demonstrate that ee could be determined for enantiomeric mixtures of primary β-alcohols. Smaller differences in ee were used to generate the calibration curves of anti-PDP and PHP, as they were not obtained in their enantiopure form. Fortunately, the assembly was sensitive enough to detect these lower enantiopurities.
Figure 9. Solutions of Primary Alcohols (175 mM) with Known Enantiopurities (ee) Were Created and Incubated an Assembly Using 2g.
Calibration curves were extracted from (W) at specified wavelengths: (A) 255 nm, (B) 254 nm, (C) 236 nm, (D) 229 nm, (E) 269 nm, and (F) 240 nm.
Given the successes described above, we wanted to test if assembly 3g could be used to determine the ee values of unknown β-chiral alcohol in a blind study. Solutions of three commercially available alcohols were prepared by the Miller lab at Yale and shipped to the Anslyn lab at UT Austin. To avoid bias, all of the samples were tested by the Anslyn lab without knowledge of the chemical structure of the alcohol or the ee of the sample. Since the assay is concentration dependent, the Miller lab prepared all samples with the same concentration of alcohols. When the assemblies were prepared by the Anslyn lab, the same volume of alcohol solution was added to each sample. Calibration curves were made from solutions of known ee values for each alcohol (labeled A, B, and C). Afterward, the ee values for the four unknown samples of each alcohol, 12 in total, were calculated through their corresponding calibration curves. The calculated ee values were then shared with the Miller lab and compared to the actual ee values and structures of A, B, and C. Fortunately, all of the calculated ee values were close to the actual values, with an absolute experimental error of 5% relative error (Table 1, error not including the first value in the table that we deem as an outlier). We noticed a wide range of response for unknown C3 at the lower ee concentration (±20% ee). We suspect that we were reaching the lower limit of ee detection for unknown C (~15% ee). This low sensitivity is likely alcohol specific because this lack of sensitivity was not seen in other alcohol solutions with similarly low ee values, such as A4 (Table 1). Overall, this blind study proves that the use of assembly 3g is a viable method for determining the ee of β-chiral primary alcohols.
Table 1.
Blind Study Results
| Unknown | ee (%) | |
|---|---|---|
| Actual | Calculated | |
| A1 | −81 | −40 ± 7 |
| A2 | −40 | −44 ± 4 |
| A3 | 37 | 45 ± 4 |
| A4 | 18 | 22 ± 2 |
| B1 | 28 | 26 ± 1 |
| B2 | 75 | 74 ± 3 |
| B3 | −58 | −57 ± 16 |
| B4 | 52 | 46 ± 3 |
| C1 | −94 | −85 ± 7 |
| C2 | −45 | −41 ± 4 |
| C3 | −16 | −20 ± 20 |
| C4 | 82 | 87 ± 6 |
Actual and calculated enantiomeric excesses (ee) values for the unknown b-chiral primary alcohols.
Conclusions
In conclusion, we have successfully reengineered a previously reported four-component assembly to optically sense β-chirality in primary alcohols. We are able to use our assay to determine the ee of various β-chiral primary alcohols. In order to accomplish this, we generated biphenyl, diastereomeric atropisomers that are biased to one enantiomer of the diastereomer by the appended chiral alcohol at a hemiaminal ether center. Further, we show that the strategy of “reaching out” to the remote stereocenter can also be used to tune the wavelength of detection for these sensors. The detection of β-chirality is an integral step toward creating reversible covalent assemblies to analyze alpha-beta diastereomeric relationships. Future efforts will focus on disseminating the use of these optical CD sensors throughout the synthetic community, which will enable the screening of 100 reactions in less than 5 min.
Supplementary Material
HIGHLIGHTS.
Molecular recognition principles for sensing more distant stereogenic centers
Reversible covalent sensors of beta chirality in alcohols were developed
Atropisomeric chromophores are used to redshift CD signal output
The Bigger Picture.
Controlling the synthesis of stereogenic centers is key in the development of therapeutics and biomaterials. High-throughput experimentation (HTE), coupled with modern data analysis methods such as machine learning, can potentially enable the discovery of new asymmetric catalysts. However, these methods demand large sample numbers—upward of 104 reactions for training. While parallel synthesis techniques are capable of producing enough reactions to satisfy these demands, enantiomeric excess (ee) analysis on that scale is a current challenge. Therefore, our group and others are developing optical ee sensors for high-throughput screening. We present herein a general principle for developing chirality sensors for stereocenters that are remote from common organic functional groups. These new analytical methods, and advances presented herein, would bridge that gap between big data analysis and asymmetric catalysis, granting access to the next generation of chiral materials and medicines.
ACKNOWLEDGMENTS
This project was supported by National Institutes of Health (NIH) grant GM077437. This work also was supported by NIH grant R35-GM132092. The IRACDA fellowship program (NIH grant 1K12GM102745) supported M.B.M. The NMR spectrum was taken with the Bruker Avance III 500, which was provided by NIH grant OD021508-01. Further, we acknowledge the Welch Regents Chair to E.V.A. (F-0046).
Footnotes
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.2019.10.003.
DECLARATION OF INTERESTS
E.V.A. is a co-founder of EnantioSense Inc. along with Christian Wolf of Georgetown University. No funding was derived from EnantioSense; the objective of this company is to commercialize optical methods for ee determination.
REFERENCES AND NOTES
- 1.Kinch MS, Haynesworth A, Kinch SL, and Hoyer D (2014). An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039. [DOI] [PubMed] [Google Scholar]
- 2.Murphy SL (2000). Deaths: Final Data for 1998. Natl. Vital Stat 48, 1–106. [PubMed] [Google Scholar]
- 3.Heron M (2018). Deaths: leading causes for 2016. Natl. Vital Stat. Rep 67, 1–77. [PubMed] [Google Scholar]
- 4.Nguyen LA, He H, and Pham-Huy C (2006). Chiral drugs: an overview. Int. J. Biomed. Sci. IJBS 2, 85–100. [PMC free article] [PubMed] [Google Scholar]
- 5.Reid JP, and Sigman MS (2018). Comparing quantitative prediction methods for the discovery of small-molecule chiral catalysts. Nat. Rev. Chem 2, 290–305. [Google Scholar]
- 6.Liao K, Yang YF, Li Y, Sanders JN, Houk KN, Musaev DG, and Davies HML (2018). Design of catalysts for site-selective and enantioselective functionalization of non-activated primary C–H Bonds. Nat. Chem 10, 1048–1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bae HY, Höfler D, Kaib PSJ, Kasaplar P, De CK, Döhring A, Lee S, Kaupmees K, Leito I, and List B (2018). Approaching sub-Ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction. Nat. Chem 10, 888–894. [DOI] [PubMed] [Google Scholar]
- 8.Renom-Carrasco M, and Lefort L (2018). Ligand libraries for high throughput screening of homogeneous catalysts. Chem. Soc. Rev 47, 5038–5060. [DOI] [PubMed] [Google Scholar]
- 9.Trapp O (2008). Gas chromatographic high-throughput screening techniques in catalysis. J. Chromatogr. A 1184, 160–190. [DOI] [PubMed] [Google Scholar]
- 10.Jo HH, Lin CY, and Anslyn EV (2014). Rapid optical methods for enantiomeric excess analysis: From enantioselective indicator displacement assays to exciton-coupled circular dichroism. Acc. Chem. Res 47, 2212–2221. [DOI] [PubMed] [Google Scholar]
- 11.Herrera BT, Pilicer SL, Anslyn EV, Joyce LA, and Wolf C (2018). Optical analysis of reaction yield and enantiomeric excess: a new paradigm ready for prime time. J. Am. Chem. Soc 140, 10385–10401. [DOI] [PubMed] [Google Scholar]
- 12.Dragna JM, Pescitelli G, Tran L, Lynch VM, Anslyn EV, and Di Bari L (2012). In situ assembly of octahedral Fe(II) complexes for the enantiomeric excess determination of chiral amines using circular dichroism spectroscopy. J. Am. Chem. Soc 134, 4398–4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Joyce LA, Maynor MS, Dragna JM, da Cruz GM, Lynch VM, Canary JW, and Anslyn EV (2011). A simple method for the determination of enantiomeric excess and identity of chiral carboxylic acids. J. Am. Chem. Soc 133, 13746–13752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Leung D, and Anslyn EV (2011). Rapid determination of enantiomeric excess of a-chiral cyclohexanones using circular dichroism spectroscopy. Org. Lett 13, 2298–2301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.You L, Berman JS, and Anslyn EV (2011). Dynamic multi-component covalent assembly for the reversible binding of secondary alcohols and chirality sensing. Nat. Chem 3, 943–948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Akdeniz A, Minami T, Watanabe S, Yokoyama M, Ema T, and Anzenbacher P (2016). Determination of enantiomeric excess of carboxylates by fluorescent macrocyclic sensors. Chem. Sci 7, 2016–2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Yu S, and Pu L (2010). Pseudoenantiomeric fluorescent sensors in a chiral assay. J. Am. Chem. Soc 132, 17698–17700. [DOI] [PubMed] [Google Scholar]
- 18.Bentley KW, Proano D, and Wolf C (2016). Chirality imprinting and direct asymmetric reaction screening using a stereodynamic Brønsted/lewis acid receptor. Nat. Commun 7, 12539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ni C, Zha D, Ye H, Hai Y, Zhou Y, Anslyn EV, and You L (2018). Dynamic covalent chemistry within biphenyl scaffolds: reversible covalent bonding, control of selectivity, and chirality sensing with a single system. Angew. Chem. Int. Ed. Engl 57, 1300–1305. [DOI] [PubMed] [Google Scholar]
- 20.Chen Z, Wang Q, Wu X, Li Z, and Jiang YB (2015). Optical chirality sensing using macrocycles, synthetic and supramolecular oligomers/polymers, and nanoparticle based sensors. Chem. Soc. Rev 44, 4249–4263. [DOI] [PubMed] [Google Scholar]
- 21.Hembury GA, Borovkov VV, and Inoue Y (2008). Chirality-sensing supramolecular systems. Chem. Rev 108, 1–73. [DOI] [PubMed] [Google Scholar]
- 22.Tanasova M, Anyika M, and Borhan B (2015). Sensing remote chirality: stereochemical determination of β-, γ-, and δchiral carboxylic acids. Angew. Chem. Int. Ed. Engl 54, 4274–4278. [DOI] [PubMed] [Google Scholar]
- 23.Joyce LA, Canary JW, and Anslyn EV (2012). Enantio- and chemoselective differentiation of protected α-amino acids and b-homoamino acids with a single copper(II) host. Chemistry 18, 8064–8069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.You L, Pescitelli G, Anslyn EV, and Di Bari L (2012). An exciton-coupled circular dichroism protocol for the determination of identity, chirality, and enantiomeric excess of chiral secondary alcohols. J. Am. Chem. Soc 134, 7117–7125. [DOI] [PubMed] [Google Scholar]
- 25.Lin CY, Giuliano MW, Ellis BD, Miller SJ, and Anslyn EV (2016). From substituent effects to applications: enhancing the optical response of a four-component assembly for reporting ee values. Chem. Sci 7, 4085–4090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Robb MA, Haines WJ, and Csizmadia IG (1973). Theoretical definition of the size of electron pairs and its stereochemical implications. J. Am. Chem. Soc 95, 42–48. [Google Scholar]
- 27.Eliel EL (1965). Conformational analysis in mobile cyclohexane systems. Angew. Chem. Int. Ed 4, 761–774. [Google Scholar]
- 28.Fujiwara T, Taniguchi Y, Katsumoto Y, Tanaka T, Node M, Ozeki M, Yamashita M, and Hosoi S (2012). Induced circular dichroism in chiral N-methyl amides possessing an achiral binaphthyl chromophore and its application to absolute configuration determination of aliphatic chiral amines. Tetrahedron Asymmetry 23, 981–991. [Google Scholar]
- 29.Kato TA, Matsuda T, Matsui S, Mizutani T, and Saeki K (2002). Activation of the aryl hydrocarbon receptor by methyl yellow and related congeners: structure-activity relationships in halogenated derivatives. Biol. Pharm. Bull 25, 466–471. [DOI] [PubMed] [Google Scholar]
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