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Miniature high-throughput chemosensing of yield, ee, and absolute configuration from crude reaction mixtures

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Science Advances  12 Feb 2016:
Vol. 2, no. 2, e1501162
DOI: 10.1126/sciadv.1501162
  • Scheme 1

    Concept of chirality sensing and asymmetric reaction analysis with a stereodynamic CD/fluorescence chemosensor and synthesis of bis(2-hydroxy-1-naphthyl)ketone, 1.

  • Fig. 1 Chiroptical sensing of amines, amino alcohols, and amino acids.

    Top: General CD sensing scheme and substrate scope (only one enantiomer of each substrate is shown) of the zinc complex of 1. Middle: (A) CD spectra of the Zn complex derived from 1 and (1R,2R)-4 (blue) and (1S,2S)-4 (red). (B) CD response to (R)-6 (blue) and (S)-6 (red). (C) CD response to (R)-9 (blue) and (S)-9 (red). Bottom: (D) CD spectra of the Zn complex derived from 1 and nonracemic samples of 14. (E) Plots of the CD amplitudes at 338 nm (blue), 385 nm (red), and 445 nm (green) versus ee. (F) Plot of the fluorescence intensity of the Zn complex derived from 1 and varying equivalents of 14. All CD spectra were collected at 1 mM in diethyl ether.

  • Fig. 2 Chiroptical sensing of carboxylic acids, hydroxy acids, and diols.

    Top: Substrate scope using 1 with Me3Al (19 to 24) or Ti(Oi-Pr)4 (25 to 29). Only one enantiomer is shown. Middle: (A) CD spectra of the Al complex derived from 1 and (R)-22 (blue) and (S)-22 (red). (B) Sensor response to (R)-23 (blue) and (S)-23 (red). (C) CD spectra of the Ti complex derived from 1 and (1R,2R)-25 (blue) and (1S,2S)-25 (red). An equivalent of Et3N was added to α-hydroxy acids before analysis. (D) Fluorescence intensity of the Ti complex derived from 1 and varying molar equivalents of 25. (E) Plot of the fluorescence intensity at 600 nm of the Ti complex derived from 1 and varying amounts of 25. (F) Plots of the ICD amplitudes at 375 nm (red) and 470 nm (blue) for the Ti complex derived from 1 and nonracemic samples of 25. (G) ICD intensity at 375 nm (triangles) and 470 nm (diamonds) for the complex obtained from Ti(Oi-Pr)4, 1, and various amounts of (1R,2R)-25 (blue) and (1S,2S)-25 (red). All spectra were collected at 1 mM in diethyl ether. Bottom: Thermodynamically controlled Ti complex formation and equilibrium between homochiral species observed by ESI-MS using (1S,2S)-25 and (2R,3R)-26.

  • Table 1

    CCS of N-methyl ephedrine 14.

    Sample compositionChemosensing results
    EntryEe (%)Conc. (mM)Abs. config.Ee (%), 338 nmEe (%), 385 nmEe (%), 445 nmEe (%), avg.Conc. (mM)Abs. config.
    187.00.56R85.489.582.685.80.60R
    276.01.01R78.579.376.778.21.09R
    326.02.36S27.222.524.324.72.29S
    468.02.93S70.265.364.866.82.96S
    589.03.34S90.686.984.287.23.38S
  • Table 2

    CCS of hydrobenzoin 25, using 1 and Ti(Oi-Pr)4.

    Sample compositionChemosensing results
    EntryEe (%)Conc. (mM)Abs. config.Ee (%), 375 nmEe (%), 470 nmEe (%), avg.Conc. (mM)Abs. config.
    176.00.56R,R79.779.379.50.53R,R
    268.01.01R,R70.566.968.71.01R,R
    312.01.76R,R13.612.613.11.88R,R
    426.02.36S,S24.222.323.32.47S,S
    589.02.93S,S91.386.889.12.72S,S

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/2/2/e1501162/DC1

    General information

    Synthetic procedures

    Enantioselective sensing experiments

    Quantitative ee and concentration analysis

    Ee and concentration analysis of hydrobenzoin 25 obtained by asymmetric Sharpless dihydroxylation

    MS analysis of the in situ complex formation

    Analysis of the sensing mechanism with the stereodynamic Ti complex

    Crystallography

    Scheme S1. General synthesis of 1.

    Fig. S1. 1H and 13C NMR spectra of 2 in CDCl3.

    Fig. S2. 1H and 13C NMR spectra of 3 in CDCl3.

    Fig. S3. 1H and 13C NMR spectra of 1 in CDCl3.

    Fig. S4. Structures of substrates 4 to 29.

    Fig. S5. CD response of the zinc complex of 1 to chiral diamines, amines, and amino alcohols.

    Fig. S6. CD response of the zinc complex of 1 to chiral amino acids.

    Fig. S7. CD response of the aluminum complex of 1 to carboxylic acids.

    Fig. S8. CD response of the titanium complex of 1 to chiral diols.

    Fig. S9. CD spectra obtained from 1, (S)-19, and Me3Al (solid red) and from 1, (S)-19, and B(OMe)3 (dashed red).

    Fig. S10. CD spectra of the Zn complex obtained with 1 and scalemic samples of 14.

    Fig. S11. Exponential relationship between the CD amplitudes at 338 nm (blue), 385 nm (red), and 445 nm (green) and the ee of 14.

    Fig. S12. Fluorescence spectra of the complexes formed from 1, Et2Zn, and varying concentrations of 14 from 0 to 100 mol% (blue) and 120 to 200 mol% (red).

    Fig. S13. Fluorescence intensity (I) measured at 600 nm plotted against the ratio of [14]/[1].

    Fig. S14. Curve fitting of the fluorescence emission at 600 nm.

    Fig. S15. CD spectra of the Ti complex obtained with 1 and scalemic samples of 25.

    Fig. S16. Linear relationship between the CD amplitudes at 375 nm (red) and 470 nm (blue) and the ee of 25.

    Fig. S17. Fluorescence spectra of the complexes formed from 1, Ti(Oi-Pr)4, and varying concentrations of 25 from 0 to 100 mol% (blue) and 120 to 160 mol% (red).

    Fig. S18. Fluorescence intensity (I) measured at 585 nm plotted against the ratio of [25]/[1].

    Fig. S19. Curve fitting of the fluorescence emission at 585 nm.

    Fig. S20. Asymmetric Sharpless dihydroxylation of trans-stilbene.

    Fig. S21. HPLC separation of the product obtained with AD-mix-β at 0°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.

    Fig. S22. HPLC separation of the product obtained with AD-mix-β at 25°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.

    Fig. S23. HPLC separation of the product obtained with AD-mix-β at 50°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.

    Fig. S24. HPLC separation of the product obtained with cinchonine at 25°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.

    Fig. S25. MS spectrum of the complex obtained from 1, Et2Zn, and (1R,2R)-4.

    Fig. S26. MS spectrum of the complex obtained from 1, Et2Zn, and (1R,2S)-10.

    Fig. S27. MS spectrum of the complex obtained from 1, Et2Zn, and (1R,2S)-14.

    Fig. S28. MS spectrum of the complex obtained from 1, Me3Al, and (R)-23.

    Fig. S29. MS spectrum of the complex obtained from 1, Ti(Oi-Pr)4, and (1R,2R)-25.

    Fig. S30. MS spectrum of the complexes obtained from 1, Ti(Oi-Pr)4, and a mixture of (1S,2S)-25 and (2R,3R)-26.

    Fig. S31. MS spectrum of the complexes obtained from 1, Ti(Oi-Pr)4, (1S,2S)-25, and (2S,3S)-26.

    Fig. S32. Excerpt of the NMR spectrum showing the methine proton septet in [Ti(Oi-Pr)4] (red) after addition of one equivalent of 1 (green) and upon addition of one equivalent of 25 (blue).

    Fig. S33. Excerpt of the NMR spectrum showing the methyl doublet of [Ti(Oi-Pr)4] (red) after addition of one equivalent of 1 (green) and upon addition of one equivalent of 25 (blue).

    Fig. S34. CD intensity at 375 nm (triangle) and 470 nm (diamond) for the complex obtained from Ti(Oi-Pr)4, 1, and (1R,2R)-25 (blue) and for (1S,2S)-25 (red).

    Fig. S35. X-ray structure of bis(2-methoxy-1-naphthyl)ketone, 3.

    Fig. S36. X-ray structure of bis(2-hydroxy-1-naphthyl)ketone, 1.

    Table S1. Ee determination of N-methylephedrine.

    Table S2. Experimentally determined concentrations of five samples of varying concentrations.

    Table S3. Ee determination of hydrobenzoin.

    Table S4. Experimentally determined concentrations of five samples of varying concentrations of 25 using the fluorescence response at 600 nm.

    Table S5. Comparison of calculated and actual ee and concentration values of hydrobenzoin obtained by asymmetric Sharpless dihydroxylation.

  • Supplementary Materials

    This PDF file includes:

    • General information
    • Synthetic procedures
    • Enantioselective sensing experiments
    • Quantitative ee and concentration analysis
    • Ee and concentration analysis of hydrobenzoin 25 obtained by asymmetric Sharpless dihydroxylation
    • MS analysis of the in situ complex formation
    • Analysis of the sensing mechanism with the stereodynamic Ti complex
    • Crystallography
    • Scheme S1. General synthesis of 1.
    • Fig. S1. 1H and 13C NMR spectra of 2 in CDCl3.
    • Fig. S2. 1H and 13C NMR spectra of 3 in CDCl3.
    • Fig. S3. 1H and 13C NMR spectra of 1 in CDCl3.
    • Fig. S4. Structures of substrates 4 to 29.
    • Fig. S5. CD response of the zinc complex of 1 to chiral diamines, amines, and amino alcohols.
    • Fig. S6. CD response of the zinc complex of 1 to chiral amino acids.
    • Fig. S7. CD response of the aluminum complex of 1 to carboxylic acids.
    • Fig. S8. CD response of the titanium complex of 1 to chiral diols.
    • Fig. S9. CD spectra obtained from 1, (S)-19, and Me3Al (solid red) and from 1, (S)-19, and B(OMe)3 (dashed red).
    • Fig. S10. CD spectra of the Zn complex obtained with 1 and scalemic samples of 14.
    • Fig. S11. Exponential relationship between the CD amplitudes at 338 nm (blue), 385 nm (red), and 445 nm (green) and the ee of 14.
    • Fig. S12. Fluorescence spectra of the complexes formed from 1, Et2Zn, and varying concentrations of 14 from 0 to 100 mol% (blue) and 120 to 200 mol% (red).
    • Fig. S13. Fluorescence intensity (I) measured at 600 nm plotted against the ratio of 14/1.
    • Fig. S14. Curve fitting of the fluorescence emission at 600 nm.
    • Fig. S15. CD spectra of the Ti complex obtained with 1 and scalemic samples of 25.
    • Fig. S16. Linear relationship between the CD amplitudes at 375 nm (red) and 470 nm (blue) and the ee of 25.
    • Fig. S17. Fluorescence spectra of the complexes formed from 1, Ti(Oi-Pr)4, and varying concentrations of 25 from 0 to 100 mol% (blue) and 120 to 160 mol% (red).
    • Fig. S18. Fluorescence intensity (I) measured at 585 nm plotted against the ratio of 25/1.
    • Fig. S19. Curve fitting of the fluorescence emission at 585 nm.
    • Fig. S20. Asymmetric Sharpless dihydroxylation of trans-stilbene.
    • Fig. S21. HPLC separation of the product obtained with AD-mix-β at 0°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.
    • Fig. S22. HPLC separation of the product obtained with AD-mix-β at 25°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.
    • Fig. S23. HPLC separation of the product obtained with AD-mix-β at 50°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.
    • Fig. S24. HPLC separation of the product obtained with cinchonine at 25°C on a Chiralcel OJ column using hexanes/i-PrOH (92:8, v/v) as mobile phase.
    • Fig. S25. MS spectrum of the complex obtained from 1, Et2Zn, and (1R,2R)-4.
    • Fig. S26. MS spectrum of the complex obtained from 1, Et2Zn, and (1R,2S)-10.
    • Fig. S27. MS spectrum of the complex obtained from 1, Et2Zn, and (1R,2S)-14.
    • Fig. S28. MS spectrum of the complex obtained from 1, Me3Al, and (R)-23.
    • Fig. S29. MS spectrum of the complex obtained from 1, Ti(Oi-Pr)4, and (1R,2R)-25.
    • Fig. S30. MS spectrum of the complexes obtained from 1, Ti(Oi-Pr)4, and a mixture of (1S,2S)-25 and (2R,3R)-26.
    • Fig. S31. MS spectrum of the complexes obtained from 1, Ti(Oi-Pr)4, (1S,2S)-25, and (2S,3S)-26.
    • Fig. S32. Excerpt of the NMR spectrum showing the methine proton septet in Ti(Oi-Pr)4 (red) after addition of one equivalent of 1 (green) and upon addition of one equivalent of 25 (blue).
    • Fig. S33. Excerpt of the NMR spectrum showing the methyl doublet of Ti(Oi-Pr)4 (red) after addition of one equivalent of 1 (green) and upon addition of one equivalent of 25 (blue).
    • Fig. S34. CD intensity at 375 nm (triangle) and 470 nm (diamond) for the complex obtained from Ti(Oi-Pr)4, 1, and (1R,2R)-25 (blue) and for (1S,2S)-25 (red).
    • Fig. S35. X-ray structure of bis(2-methoxy-1-naphthyl)ketone, 3.
    • Fig. S36. X-ray structure of bis(2-hydroxy-1-naphthyl)ketone, 1.
    • Table S1. Ee determination of N-methylephedrine.
    • Table S2. Experimentally determined concentrations of five samples of varying concentrations of 14 using the fluorescence response at 600 nm.
    • Table S3. Ee determination of hydrobenzoin.
    • Table S4. Experimentally determined concentrations of five samples of varying concentrations of 25 using the fluorescence response at 600 nm.
    • Table S5. Comparison of calculated and actual ee and concentration values of hydrobenzoin obtained by asymmetric Sharpless dihydroxylation.

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