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Optical Chirality Sensing with a Stereodynamic Aluminum Biphenolate Probe Zeus A. De los Santos, Leo A. Joyce, Edward C. Sherer, Christopher J. Welch, and Christian Wolf J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01301 • Publication Date (Web): 18 Jul 2018 Downloaded from http://pubs.acs.org on July 19, 2018

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The Journal of Organic Chemistry

Optical Chirality Sensing with a Stereodynamic Aluminum Biphenolate Probe Zeus A. De los Santos,a Leo A. Joyce,b* Edward C. Sherer,b Christopher J. Welch,c* and Christian Wolfa* a

Department of Chemistry, Georgetown University, Washington DC.

Email [email protected] b

Department of Process and Analytical Chemistry, Merck Research Laboratories, Rahway, NJ.

Email: [email protected] c

Welch Innovation, LLC., Cranbury, NJ.

Email: [email protected]

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract The determination of the enantiopurity and the concentration of chiral compounds by chiroptical sensing with molecular probes is increasingly attractive for high-throughput screening applications including streamlined asymmetric reaction development. In this study, we use stereodynamic aluminum biphenolate complexes for quantitative ee and concentration analysis of amino alcohols and α-hydroxy acids. An important feature of the tropos biphenolate ligand used is the presence of phenylacetylene antennae for optimal chirality recognition and CD/UV responses at high wavelengths. The complexation-driven chirality amplification yields strong CD signals which allows quantitative chiroptical sensing with good accuracy. We show that aluminate biphenolate sensors can exhibit linear and nonlinear correlations between the induced CD signals and the enantiomeric composition or concentration of the chiral substrate.


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Introduction Chiroptical high-throughput screening methods that allow fast determination of the concentration and enantiomeric excess of chiral compounds have received considerable attention in recent years.1 Although chiral chromatography2and NMR spectroscopy3 remain a well-established and widely used technique in the pharmaceutical sciences, chiroptical sensing is emerging as a powerful alternative with a variety of benefits, in particular with regard to accelerated asymmetric reaction analysis4 and diagnostics.5 To this end, several metal-based sensors for ee analysis have been introduced.6 Numerous enantioselective reactions catalyzed by chiral metal complexes carrying a atropos ligand that is stable to racemization such as BINOL have been reported. In these cases, chirality information is transferred in the transition state from the metal complex onto the prochiral substrate. If the asymmetric induction process is successful a chiral reaction product is formed in nonracemic form and in high enantiopurity. The direction of the asymmetric induction achieved in asymmetric catalysis can be reversed in the ground state when a chiral substrate coordinates to a metal complex carrying a tropos ligand. In such a case, the stereodynamic chromophoric ligand can act as a chiroptical reporter unit that yields information of the absolute configuration and ee of the substrate which is the basic concept of this study.

Chart 1. Structure of the antenna biphenol 1.



We recently introduced a stereodynamic biphenol scaffold 1 equipped with phenylacetylene appendages that extend the π-system of the stereodynamic biphenol core and assist in the complexation-driven chirality amplification upon coordination of a chiral substrate.7 We demonstrated that the enantiomeric zinc complexes of 1 undergo rapid interconversion at room temperature and therefore exist as a CD-silent racemic mixture in the absence of a chiral bias. Coordination of a chiral substrate, however, disturbs the equilibrium between the enantiomeric biphenolate zinc species which gives rise to characteristic CD signals that can be used for ee analysis of amino alcohols and amines. Unfortunately, concentration analysis was not possible with the zinc biphenolate sensor. We now report the use of aluminum complexes formed in situ from 1 and either trimethylaluminum or aluminum triisopropoxide for chiroptical sensing of a variety of amino alcohols and α-hydroxy acids. In contrast to our previous work, both ee and concentration analysis are accomplished with sufficient accuracy for highthroughput screening purposes. Depending on the mixing protocol employed in the sensing experiment, either linear or nonlinear relationships between the induced CD (ICD) signals and the enantiomeric composition of mandelic acid samples can be observed which, to the best of our knowledge, is unprecedented. Results and Discussion The axially chiral ligand 3,3',5,5'-tetrakis(phenylethynyl)-1,1'-biphenyl-2,2'-diol, 1, was prepared on a gram scale following our previously described procedure.7a To evaluate the possibility of chirality sensing with stereodynamic metal complexes carrying biphenolate 1 as the reporter unit we chose a small library containing the representative α-hydroxy acids 2-7 and amino alcohols 8-14 (Figure 1). Initially, we examined in situ formation of Al, Ti and Zr complexes using ligand 1, one equivalent of mandelic acid, 2, or 1-amino-1,2-diphenylethanol, 9,


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and stoichiometric amounts of triethylamine and either Me3Al, Al(Oi-Pr)3, Ti(Oi-Pr)4 or Zr(OiPr)4. We observed weak chiroptical signals with the titanium and zirconium complexes and noticed that the CD signals were changing over several hours which may be attributed to slow aggregation processes.

Figure 1. Structures of the α-hydroxy acids and amino alcohols tested. Only one enantiomer is shown.

Scheme 1. General concept of the chiroptical sensing of nonracemic 2 using Me3Al, ligand 1 and Et3N. The direction of the asymmetric induction and the CD reporter unit are illustrated in blue and red, respectively.



Fortunately, we obtained stable CD signals for all α-hydroxy acids and amino alcohols tested including the beta blocker atenolol, 12, using Me3Al or Al(Oi-Pr)3 (Scheme 1 and SI). The reaction of mandelic acid, 1, and Me3Al in the presence of triethylamine is quantitative due to the irreversible formation of methane and we expected formation of the mononuclear complex 15 possibly among other aluminate species. The close proximity of the chiral substrate and the biphenolate ligand in 15 generates an effective chiral bias in the stereodynamic reporter unit. As a result, we observed a positive Cotton effect at approximately 370 nm when (R)-mandelic acid was employed and a negative Cotton effect when the (S)-enantiomer was used (Figure 2). The generation of strong CD responses at high wavelengths is important and generally desired to avoid interference with chiral impurities that might be present in an unknown sample. Further CD analysis revealed that the complex formation is complete within 50 minutes (see SI). The time required for equilibration might be reduced at higher temperatures but we point out that hundreds of sensing assays can be conducted in parallel using multi-well plate technology which would greatly reduce the analysis time per sample. A similar chiroptical response was obtained with other analytes including hexahydromandelic acid, 4, 3-hydroxybutanoic acid, 6, and aminobutan-1,3-diol, 13, which highlights that the aluminum biphenolate sensor can be successfully applied to nonaromatic analytes as well (see Figure 2 and SI).


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Figure 2. Top: CD Spectra obtained from 1, Et3N, Me3Al and the enantiomers of 2 and 4. Middle: CD Spectra obtained from 1, Et3N, Me3Al and the enantiomers of 6 and 13. Bottom: CD Spectra obtained from 1, Et3N, Al(Oi-Pr)3, and the enantiomers of 2 and 3. The measurements with Me3Al and Al(Oi-Pr)3 were recorded at 0.1 and 0.2 mM, respectively, in acetonitrile. The chiroptical responses of the aluminum biphenolate probes to the R- and S-enantiomers of the analytes are shown in blue and red, respectively.

We computationally explored the aluminum biphenolate complexes with mandelic acid in order to rationalize the experimentally observed CD spectra. Initially, we were interested in determining which axially chiral conformation of the biphenolate sensor would be lowest in energy upon binding (R)-2. Conformers with each enantiomer of the complex were determined beginning with a similar aluminum biphenolate compound whose crystal structure was reported in the literature.8 The P-enantiomer of the biphenol sensor was minimized using the B3LYP/631G** level of theory, and the lowest energy conformer was appended to the aluminum center. Next the lowest energy conformer of (R)-2 was added at the two empty coordinate sites on the aluminum to form the full complex. The geometry of the full complex was then optimized using M062X/6-311+G**, and the same process was repeated beginning with the M-enantiomer of the 7 ACS Paragon Plus Environment


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sensor. The complex formed between the aluminum P-biphenolate sensor and (R)-2 was more stable than the M-biphenolate analogue sensor by 2.8 kcal/mol (Figure 3A).

With this

information in hand, we next turned our efforts to the calculation of the ECD spectrum for the Pbiphenolate aluminum complex with the (R)-2 analyte.

Time-dependent density functional

theory (TD-DFT) was carried out using CAM-B3LYP/6-311++G** on the previously optimized coordinates. The calculated spectra were then compared to the observed spectra as shown in Figure 3B.

The longest wavelength Cotton effect is positive in the experimental and the

calculated CD spectra. A similarity factor calculated according to a literature procedure9 gave a match of 0.78 for the R,P-complex compared to only 0.07 for the S,M-enantiomer, demonstrating a good fit between the calculated and experimentally obtained spectra. This sense of asymmetric induction is in agreement with the conceptual schematic shown in Scheme 1.

Figure 3. Computational analysis of the asymmetric amplification and ICD effect with (R)mandelic acid as substrate. A) Optimized geometries for the M- and P-aluminum biphenolate sensor conformations with (R)-2. B) Comparison of the calculated and the experimental CD spectra of the thermodynamically favored R,P-complex.


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The distinct CD responses observed with a simple mix-and-measure protocol encouraged us to examine if quantitative ee sensing is possible. We therefore subjected mixtures of mandelic acid with varying enantiomeric excess to our sensing protocol with Me3Al. The analysis revealed a complex relationship between the induced CD signals at approximately 340 and 370 nm and the sample ee (Figure 4 and SI). We obtained the strongest chiroptical responses when the sensor and 2 were first mixed in THF and then diluted after 30-60 minutes with acetonitrile for CD analysis. Replacement of ACN by other solvents (dichloromethane, ethyl acetate, diethyl ether, THF) showed a profound but generally detrimental effect on the CD effects (SI). Additional studies revealed that a change in the mixing protocol significantly alters the CD responses. When the sensor and nonracemic 2 were mixed at 2.0 mM (10 mM) in THF and diluted with ACN to 0.01 (0.1 mM) for CD analysis we observed a positive nonlinear effect (NLE). By contrast, CD sensing of a 2.0 mM reaction mixture diluted to 0.1 mM gave a negative NLE and CD sensing at 0.2 mM of a 20 mM reaction mixture showed a linear relationship between the ICD signals and the sample ee. Few chirality probes that exhibit nonlinear effects (NLEs) have been described in the literature and it has been demonstrated that NLEs can be advantageous to enhance ee sensing accuracy.10 However, a chiroptical sensor system that can display linear CD/ee correlations or both positive and negative NLEs has to the best of our knowledge not been reported to date.



Figure 4. CD Sensing of varying enantiomeric compositions of 2 with the aluminum biphenolate sensor prepared in situ from Me3Al, Et3N and 1. Left: The sensor and 2 were with mixed at 10 mM in THF and CD spectra were collected after dilution to 0.1 mM with ACN. Right: Plots of induced CD amplitudes at 368 nm versus %ee of 2. Blue line: The initial mixing concentration of the sensor and 2 was 2 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.01 mM. Green line: The initial mixing concentration of the sensor and 2 was 10 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.1 mM. Red line: The initial mixing concentration of the sensor and 2 was 2.0 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.1 mM. Purple line: The initial mixing concentration of the sensor and 2 was 20.0 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.2 mM.

With a calibration curve that captures the nonlinear chiroptical response of the stereodynamic aluminum complex in hand, we applied the sensing protocol with our biphenolate reporter ligand and Me3Al do determine the enantiomeric composition of five mandelic acid samples. The samples covered a wide ee range with either (R)- or (S)-2 as the major enantiomer


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(Table 1). The samples were simply mixed with Et3N, Me3Al and biphenol 1 in THF and stirred 30-60 minutes prior to dilution with ACN for CD analysis. The absolute configuration of the major enantiomer was determined from the sign of the observed Cotton effect and the amplitude at 370 nm was then used for ee determination. The sensing results compare well with the actual values and typically deviate by just a few percent. For example, sensing of the sample containing the (S)-enantiomer of 2 in 89.0% ee gave the correct absolute configuration and 86.2% ee (entry 5).

Table 1. Experimentally determined ee’s and absolute configuration of five samples of 2 using Me3Al and 1. Entry

Sample Composition abs. config. %ee

Chiroptical Sensing abs. config.a %eeb

1

R

76.0

R

80.3

2

R

12.0

R

15.7

3

S

26.0

S

22.5

4

S

68.0

S

62.7

5 S 89.0 S 86.2 b Based on the sign of the CD response. Based on the CD amplitude at 368 nm. The initial mixing concentration of the samples was 10 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.1 mM. a

We then examined the sensing system prepared from Al(Oi-Pr)3 and the reporter ligand 1. To our surprise we found perfectly linear relationships between the induced chiroptical signal at 370 nm and the enantiopurity of mandelic acid, 2, even at different mixing and CD sensing concentrations (Figure 5). Further studies revealed a quantifiable UV change at 370 nm that can be used for concentration analysis (SI). However, this remains an unusual chirality sensing



system. When we varied the amount of (R)-2 from 0 to 100 mol% of the aluminum biphenolate sensor, we obtained a sigmoidal curve showing that the CD response of the probe does not increase linearly with the relative amount of the enantiopure substrate which is typically observed for these type of sensing assays (Figure 5).

Figure 5. CD curves obtained with the aluminum biphenolate prepared from Al(Oi-Pr)3, Et3N and 1 in the presence of 2 with varying ee. Top left: The sensor and 2 were mixed at 20 mM in THF and CD spectra were collected after dilution to 0.2 mM with ACN. Top right: Linear relationships between the induced CD amplitudes at 370 nm and the enantiomeric excess of 2. Orange line: The initial mixing concentration of the sensor and 2 was 10 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.1 mM, Blue line: The initial mixing concentration was 20 mM in THF, final concentration for CD analysis was 0.2 mM after addition of ACN. Bottom: Nonlinearity between the CD amplitudes at 370 nm using Al(Oi-Pr)3, Et3N, 1 and varying amounts of (R)-2 (0 to 100 mol%) at 0.2 mM in THF/ACN. 12 ACS Paragon Plus Environment

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Another set of mandelic acid samples was then prepared and subjected to stereochemical (absolute configuration and ee) and concentration analysis. The results are shown in Table 2. Again, the aluminum biphenolate sensor correctly reports the absolute configuration of the major enantiomer present and yields ee values with sufficient accuracy for high-throughput screening purposes. It is noteworthy that the method gives reliable data with samples of low and high enantiopurity. Sensing of the sample containing the (R)-enantiomer of 2 in 87.0% ee gave the correct absolute configuration and 84.3% ee and the analysis of a sample with just 12% ee gave 12.1% ee (see entries 1 and 3). Furthermore, UV sensing allowed determination of the total concentration independent of the enantiomeric sample composition (entries 6-10).

Table 2. Experimentally determined ee’s, absolute configuration and concentrations of five samples of 2 using Al(Oi-Pr)3 and 1. Entry

a

Composition abs. config. %ee

CD Sensing abs. config.a %eeb

Entry

Concentration (mM)

UV Sensing (mM)c

1

R

87.0

R

84.3

6

2.4

2.6

2

R

76.0

R

72.5

7

6.6

7.0

3

R

12.0

R

12.1

8

10.6

11.0

4

S

26.0

S

30.9

9

14.4

16.2

5

S

68.0

S

67.5

10

17.6

b

18.0 c

Based on the sign of the CD response. Based on the CD amplitude at 370 nm. Based on the change in the UV absorbance at 370 nm. The initial mixing concentration of the samples was 20 mM in THF, the final concentration after dilution with ACN for CD analysis was 0.2 mM.



The finding that the aluminum biphenolate complexes prepared from ligand 1 and either Me3Al or Al(Oi-Pr)3 exhibit various nonlinear and linear relationships between the induced signals and the enantiomeric excess of mandelic acid is unprecedented and deserves additional discussion. The reaction of equimolar amounts of Me3Al, triethylamine, 1 and 2 was initially expected to generate a mixture of aluminate complexes and triethylammonium in quantitative yields as shown in Scheme 1. Importantly, the sensing systems are stable give reproducible results, MS and CD studies showed the aluminum sensor to still be intact and not to have undergone degradation after several hours. An increase in the mixing time from 1 to 4 hours prior to CD analysis did also not change the observed ICD effects. All attempts to grow single crystals of mandelic acid derived aluminum biphenolates for crystallographic analysis were unsuccessful and NMR spectra of the different sensing systems were inconclusive. We therefore resorted to mass spectrometric measurements. ESI-MS analysis of a sample prepared from Me3Al, ligand 1, analyte 2 and Et3N revealed that an equilibrium of several aluminate complexes including the mononuclear complexes 15, 16 and 17 is formed (Scheme 2 and SI). The same MS results were obtained with chloromandelic acid, 3. We suspected that the dinuclear complex 18 might also be present. Because the m/z signals of 15 and 18 are indistinguishable by our MS method we prepared a solution containing both (R)-2 and (R)-3 for MS analysis and successfully identified the mixed dinuclear aluminum complex containing 2 biphenolate ligands and both 2 and 3. We then used (S)-2 and (R)-3 in the same experiment and found that the heterochiral complex is also formed. In contrast to 16 and 17, the mononuclear species 15 and the homo- and heterochiral dinuclear aluminum complexes 18 are likely to contribute individually to the macroscopically observed CD signal. The coexistence of these species which are likely to have different thermodynamic stabilities and


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concentrations can explain the nonlinear effects between the CD amplitude and the sample ee.10a It also complicates the determination of the absolute configuration of new compounds unless reference samples or calculated spectra for comparison are available. Interestingly, replacement of Me3Al with Al(Oi-Pr)3 in the exact same set of MS experiments did show formation of 15-17, while dinuclear complexes such as 18 were not detected. The absence of homo- and heterochiral dinuclear aluminum complexes is in agreement with the observed linear CD response. However, the variety of linear and nonlinear ICD/ee relationships observed with the aluminum biphenolate sensor and mandelic acid indicate that this sensing system is very likely much more complicate than the equilibrium shown in Scheme 2.

Scheme 2. Aluminate complexes detected by ESI-MS (negative mode) analysis. The dinuclear complex 18 may either be bridged by 2 substrate molecules as shown or by the biphenolate ligands.

In conclusion, we have demonstrated that stereodynamic aluminum biphenolate complexes can be used for chiroptical determination of the absolute configuration, enantiomeric 15 ACS Paragon Plus Environment


excess and concentration of amino alcohols and α-hydroxy acids. Chiroptical measurements and computational analysis show that the coordination of the substrate to the aluminum biphenolate moiety generates a chiral bias in the tropos ligand. This chiral amplification process coincides with a strong CD output which allows quantitative sensing with good accuracy. Linear and nonlinear effects between the induced CD signals and the enantiomeric composition and concentration of mandelic acid were observed using the chirality probe assembled in situ from the biphenol ligand and either Me3Al or Al(Oi-Pr)3. This unprecedented behavior may be attributed in part to complex equilibria and the formation of mono- and dinuclear aluminum species that were identified by ESI-MS experiments. Experimental Section General Information. All commercially available reagents and solvents were used without further purification. Reactions were carried out in a glove box (reactions with Me3Al) or under air (reactions with Al(Oi-Pr)3). General CD Analysis Procedure. A stock solution of 1 (2, 10 or 20 mM) in THF was prepared and portions of 0.5 mL were transferred into 4 mL vials. Solutions of the substrates (0.025, 0.125 or 0.25 M) were prepared with 0.5 mL of THF (2-7) or 0.5 mL of ACN (8-14). To each vial containing 0.5 mL stock solution was added one equivalent (0.04 mL) of the substrate, one equivalent of either Me3Al (2.0 M in hexanes) or Al(Oi-Pr)3 (0.25 M in THF), and one equivalent of Et3N. The mixture was stirred for 1 hour at 25 oC and CD analysis was conducted with final sample concentrations of 0.01 to 0.2 mM using ACN as the diluting solvent. CD spectra were collected with a standard sensitivity of 100 mdeg, a data pitch of 2.0 nm, a bandwidth of 1 nm, a scanning speed of 500 nm s-1, and a response of 0.5 s using a quartz cuvette (1 cm path length). The data were baseline corrected and smoothed using a binomial


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equation. Control experiments with the substrates showed that 2-14 are CD silent in the region of interest. Ee determination of hydroxy acid 2 with Me3Al and 1. A calibration curve was constructed using nonracemic samples of 2. A stock solution of 1 (0.01 M in THF) was prepared and 0.5 mL portions were placed into 4 mL vials. Solutions of 2 (0.125 M in THF) in varying ee compositions (+100.0, +80.0, +60.0, +40.0, +20.0, 0.0, -20.0, -40.0, -60.0, -80.0, -100.0) were prepared. To each vial containing 0.5 mL of the stock solution of 1 was added one equivalent (0.04 mL, 0.125 M) of the substrate and one equivalent of Me3Al (2.5 µL, 2.0 M in hexanes) and Et3N. CD analysis was carried out as described above at 1.0 x 10-4 M in ACN. Ee determination of hydroxy acid 2 with Al(Oi-Pr)3 and 1. A calibration curve was constructed using nonracemic samples of 2. A stock solution of 1 (0.02 M in THF) was prepared and 0.5 mL portions were placed into 4 mL vials. Solutions of 2 (0.25 M in THF) in varying ee compositions (+100.0, +80.0, +60.0, +40.0, +20.0, 0.0, -20.0, -40.0, -60.0, -80.0, -100.0) were prepared. To each vial containing 0.5 mL of the stock solution of 1 was added one equivalent (0.04 mL) of the substrate and one equivalent of Al(Oi-Pr)3 (0.04 mL, 0.25 M in THF) and Et3N. CD analysis was carried out as described above. Determination of the concentration of 2. The change in the UV signature upon addition of various amounts of 2 was investigated. A stock solution of 1 (0.02 M in THF) was prepared and 0.5 mL portions were placed into 4 mL vials. Stock solutions of 2 (0.25 M in THF) were prepared. To the solutions of 1 were added one equivalent of Al(Oi-Pr)3 (40 µL, 0.25 M in THF), Et3N and 2 in varying amounts (0, 20, 40, 60, 80, and 100 mol% of 1). After stirring the mixtures for 1 hour at 20 mM in THF, the samples were diluted with CHCl3 to 0.06 mM for UV analysis using an average scanning time of 0.1 s, a data interval of 1 nm and a scan rate of 600 nm/min.



Supporting Information Available. Copies of CD, UV, MS spectra and computational details. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgements The authors are grateful to the Merck Research Laboratories New Technologies Review & Licensing Committee (MRL NT-RLC) for providing funding for this project. This work was supported in part by the U.S. National Science Foundation (CHE-1464547 and CHE-1764135).

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Cent. Sci. 2016, 2, 332. (b) Storch, G. Haas, M. Trapp. O. Attracting Enantiomers: Chiral Analytes That Are Simultaneously Shift Reagents Allow Rapid Screening of Enantiomeric Ratios by NMR Spectroscopy. Chem. Eur. J. 2017, 23, 5414. 4 (a) Shabbir, S. H.; Clinton, J. R.; Anslyn, E. V. A General Protocol for Creating HighThroughput Screening Assays for Reaction Yield and Enantiomeric Excess Applied to Hydrobenzoin. Proc. Natl. Acad. Sci. USA 2009, 106, 10487. (b) Nieto, S.; Dragna, J. M.; Anslyn, E. V. A Facile Circular Dichroism Protocol for Rapid Determination of Enantiomeric Excess and Concentration of Chiral Primary Amines. Chem. Eur. J. 2010, 16, 227. (c) Bentley, K. W.; Zhang, P.; Wolf, C. Miniature High-Throughput Chemosensing of Yield, Ee, and Absolute Configuration from Crude Reaction Mixtures. Science Adv. 2016, 2, e1501162. (d) Bentley, K. W.; Proano, D.; Wolf, C. Chirality Imprinting and Direct Asymmetric Reaction Screening Using a Stereodynamic Bronsted/Lewis Acid Receptor. Nat. Commun. 2016, 7, 12539. (e) De los Santos, Z. A.; Wolf, C. Chiroptical Asymmetric Reaction Screening via Multicomponent Self-assembly. J. Am. Chem. Soc. 2016, 138, 13517. (f) Biedermann, F.; Nau, W. M. Noncovalent Chirality Sensing Ensembles for the Detection and Reaction Monitoring of Amino Acids, Peptides, Proteins and Aromatic Drugs. Angew. Chem. Int. Ed. 2014, 53, 5694. (g) Feagin, T. A.; Olsen, D. P.; Headman, Z. C.; Heemstra, J. M. High-Throughput Enantiopurity Analysis using Enantiomeric DNA-based Sensors. J. Am. Chem. Soc. 2015, 137, 4198. (h) Giuliano, M. W.; Lin, C. Y.; Romney, D. K.; Miller, S. J.; Anslyn, E. V. A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts for Asymmetric Baeyer-Villiger Oxidation. Adv. Synth. Catal. 2015, 357, 2301.



5 Thanzeel, F. Y.; Wolf, C. Substrate-specific Amino Acid Sensing Using a Molecular d/lCysteine Probe for Comprehensive Stereochemical Analysis in Aqueous Solution. Angew. Chem. Int. Ed. 2017, 56, 7276. 6 (a) Matile, S.; Berova, N.; Nakanishi, K.; Novkova, S.; Philpova, L.; Blagoev, B. Porphyrins: Powerful Chromophores for Structural Studies by Exciton-coupled Circular Dichroism. J. Am. Chem. Soc. 1995, 117, 7021. (b) Huang, X.; Fujioka, N.; Pescitelli, G.; Koehn, F. E.; Williamson, R. T.; Nakanishi, K.; Berova, N. Absolute Configurational Assignments of Secondary Amines by CD-Sensitive Dimeric Zinc Porphyrin Host. J. Am. Chem. Soc. 2002, 124, 10320. (c) Nieto, S.; Lynch, V.; Anslyn, E. V.; Kim, H.; Chin, J. High-Throughput Screening of Identity, Enantiomeric Excess, and Concentration Using MLCT Transitions in CD Spectroscopy. J. Am. Chem. Soc. 2008, 130, 9232. (d) Holmes, A. E.; Das, D.; Canary, J. W. ChelationEnhanced Circular Dichroism of Tripodal Bisporphyrin Ligands. J. Am. Chem. Soc. 2007, 129, 1506. (e) Li, X.; Burrell, C. E.; Staples, R. J.; Borhan, B. Absolute Configuration for 1,nGlycols: A Nonempirical Approach to Long-Range Stereochemical Determination. J. Am. Chem. Soc. 2012, 134, 9026. (f) Dragna, J. M.; Pescitelli, G.; Tran, L.; Lynch, V. M.; Anslyn, E. V.; di Bari, L. An Exciton-Coupled Circular Dichroism Protocol for the Determination of Identity, Chirality, and Enantiomeric Excess of Chiral Secondary Alcohols. J. Am. Chem. Soc. 2012, 134, 4398. (g) Joyce, L. A.; Maynor, M. S.; Dragna, J. M.; da Cruz, G. M.; Lynch, V. M.; Canary, J. W.; Anslyn, E. V. A Simple Method for the Determination of Enantiomeric Excess and Identity of Chiral Carboxylic Acids. J. Am. Chem. Soc. 2011, 133, 13746. (h) Zhang, P.; Wolf, C. Sensing of the Concentration and Enantiomeric Excess of Chiral Compounds with Tropos Ligand Derived Metal Complexes. Chem. Commun. 2013, 49, 7010. (i) Bentley, K. W.; Wolf, C. Stereodynamic Chemosensor with Selective Circular Dichroism and Fluorescence Readout for in 20 ACS Paragon Plus Environment

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Situ Determination of Absolute Configuration, Enantiomeric Excess, and Concentration of Chiral Compounds. J. Am. Chem. Soc. 2013, 135, 18052. (j) De los Santos, Z. A.; Legaux, N. M.; Wolf, C. Chirality Sensing with Stereodynamic Copper(I) Complexes Chirality 2017, 29, 663. (k) Zardi, P.; Wurst, K.; Licini, G.; Zonta, C. Concentration-Independent Stereodynamic gProbe for Chiroptical Enantiomeric Excess Determination. J. Am. Chem. Soc. 2017, 139, 15616. 7 (a) Bentley, K. W.; Joyce, L. A.; Sherer, E. C.; Sheng, H.; Wolf, C.; Welch, C. J. Antenna Biphenols: Development of Extended Wavelength Chiroptical Reporters. J. Org. Chem. 2016, 81, 1185. Other selected 2,2’-biphenol CD sensors: (b) Wezenberg, S. J.; Salassa, G.; EscuderoAdan, E. C.; Benet-Buchholz, J.; Kleij, A. W. Effective Chirogenesis in a Bis(metallosalphen) Complex Through Host-Guest Binding with Carboxylic Acids. Angew. Chem. 2011, 50, 713. (c) Anyika, M.; Gholami, H.; Ashtekar, K. D.; Acho, R.; Borhan, B. Point-to-Axial Chirality Transfer – A New Probe for “Sensing” the Absolute Configuration of Monoamines. J. Am. Chem. Soc. 2014, 136, 550. 8 Yang, X.; Wang, L.; Yao, L.; Zhang, J.; Tang, N.; Wang, C.; Wu, J. Synthesis, Characterization of Bulky Aluminium Alkoxide and Application in the Ring-opening Polymerization of ε-Caprolactone. Inorg. Chem. Comm. 2011, 14, 1711. 9 Bruhn, T.; Schaumloffel, A.; Hemberger, Y.; Bringmann, G. SpecDis: Quantifying the Comparison of Calculated and Experimental Electronic Circular Dichroism Spectra. Chirality 2013, 25, 243. 10 Selected examples: (a) Bentley, K. W., Nam, Y. G.; Murphy, J. M.; Wolf, C. Chirality Sensing of Amines, Diamines, Amino Acids, Amino Alcohols, and α-Hydroxy Acids with a Single Probe. J. Am. Chem. Soc. 2013, 135, 18052. (b) Seifert, H. M.; Jiang, Y.-B.; Anslyn, E. V. Exploitation of the Majority Rules Effect for the Accurate Measurement of High Enantiomeric 21 ACS Paragon Plus Environment


Excess Value Using CD Spectroscopy. Chem. Commun. 2014, 50, 15330. (c) Chen, X.-X.; Jiang, Y.-B.; Anslyn, E. V. A Racemate-Rules Effect Supramolecular Polymer for Ee Determination of Malic Acid in the High Ee Region. Chem. Commun. 2016, 52, 12669.


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