KINETIC ANALYSIS OF THE HBTM-CATALYZED ESTERIFICATION OF AN ENANTIOPURE SECONDARY ALCOHOL

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1 Page S1 KIETIC AALYSIS OF THE HBTM-CATALYZED ESTERIFICATIO OF A EATIOPURE SECODARY ALCOHOL Alexander J. Wagner and Scott D. Rychnovsky* Department of Chemistry, 1102 atural Sciences II, University of California, Irvine, Irvine, California srychnov@uci.edu SUPPORTIG IFORMATIO TABLE OF COTETS Experimental procedures for Figures 1, SI-1, and S2 Kinetic analysis based on experiments from Figure S6 Kinetic analysis based on experiments from Figure SI S15 Kinetic analysis based on experiments from Figure S25 Equilibrium Experiments.....S27 MR Spectra from Equilibrium Experiments.S29

2 Page S2 Experimental procedures for Figures 1, SI-1, and 6 General Experimental Details. All reactions were carried out under air. CDCl3 was dried using a 2 SO 4 before use. All volumetric glassware and MR tubes were oven-dried prior to use. 1 H MR spectra were recorded at K on the Bruker DRX CRYO500 at 500 MHz. Chemicals. All purchased chemicals were used without further purification unless otherwise noted. CDCl 3 was purchased from Cambridge Isotope Laboratories. Propionic anhydride was purchased from Sigma-Aldrich and a 1 H MR spectrum was taken before each use to confirm the purity of the anhydride.,-diisopropylethylamine was distilled over CaH 2 prior to use. Secondary alcohol 1 was purchased from TCI America (>98% ee). R-HBTM and S-HBTM were synthesized according to the literature. 1 Figure 1. Stock Solution of S-HBTM S-HBTM (39.8 mg, mmol) was added to a 2 ml volumetric flask. Then, CDCl 3 was added to give exactly 2.0 ml of solution, providing a stock solution of S-HBTM ( M) mm 3 To a 1 ml volumetric flask was added 1 (18.0 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (27.5 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (25.6 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time mm 3 To a 1 ml volumetric flask was added 1 (18.1 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (55.0 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (25.6 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time mm 3 To a 1 ml volumetric flask was added 1 (18.2 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (68.9 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (25.6 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time.

3 Page S mm 3 To a 1 ml volumetric flask was added 1 (17.6 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (110.1 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (25.6 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time. Figure SI-1. Stock Solution of S-HBTM S-HBTM (39.8 mg, mmol) was added to a 2 ml volumetric flask. Then, CDCl 3 was added to give exactly 2.0 ml of solution, providing a stock solution of S-HBTM ( M) mm 2 To a 1 ml volumetric flask was added 1 (18.0 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (68.5 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (12.8 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time mm 2 To a 1 ml volumetric flask was added 1 (18.1 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (69.1 µl, mmol) was added. Then,,diisopropylethylamine (36.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (16.6 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time mm 2 To a 1 ml volumetric flask was added 1 (18.3 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (69.8 µl, mmol) was added. Then,,diisopropylethylamine (36.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (25.6 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time mm 2 To a 1 ml volumetric flask was added 1 (19.0 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (72.5 µl, mmol) was added. Then,,diisopropylethylamine (38.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (64.0 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time.

4 Page S4 Figure 6. Stock Solution of S-HBTM S-HBTM (14.0 mg, mmol) was added to a 2 ml volumetric flask. Then, CDCl 3 was added to give exactly 2.0 ml of solution, providing a stock solution of S-HBTM ( M). Trial 1 To a 1 ml volumetric flask was added 1 (17.7 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (195.1 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (26.0 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time. Trial 2 To a 1 ml volumetric flask was added 1 (8.8 mg, mmol). CDCl 3 (200.0 µl) was added. The stock solution of S-HBTM (193.9 µl, mmol) was added. Then,,diisopropylethylamine (35.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. Then, propionic anhydride (19.5 µl, mmol) was added (t = 0) to initiate the kinetic experiment. The solution was immediately mixed 3 times by glass pipet and then transferred into an MR tube, which was then placed in the spectrometer to collect conversion data over time Birman, V. B.; Li, X. Org. Lett. 2008, 10, Joannesse, C.; Johnston, C. P.; Concellon, C.; Simal, C.; Philp, D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48,

5 Page S5 Tracking Reaction Progress. Reaction progress was monitored by tracking 1 H MR spectral integrations of substrate 1 and the ester product over time. The geminal protons of the hydroxyl group of 1 and the ester group on the product were used during this analysis given their chemical shifts in the spectrum. An example of a spectrum used in the analysis is shown below. The concentration at time t was calculated according to the equation in Formula 1. Formula 1. [ROH] t = [ROH] o x 1 H MR integral ALCOHOL 1 H MR integral ESTER + 1 H MR integral ALCOHOL Two-point rates used in Figures 3 and 5 were calculated according to Formula 2. Formula 2. - ([ROH] 1 [ROH] 2 ) Rate 2-POIT = (t 1 t 2 ) Three-point rates were calculated by running a linear regression in Microsoft Excel. The slope of the linear regression was extrapolated as the rate corresponding to the middle time point of the three points selected.

6 Page S6 Kinetic analysis based on experiments from Figure 1 Figure mm mm mm mm Time (min) mm 3 Time (min) Time (min) Time (min)

7 Page S mm 3 Time (min) Time (min) Time (min) mm 3 Time (min) Time (min) Time (min) mm 3 Time (min) Time (min) Time (min)

8 Page S8 Initial Rates from Figure y = -5.86E-03x E-02 R 2 = 9.98E-01 y = -1.62E-03x E-01 R 2 = 9.93E-01 y = -2.95E-03x E-01 R 2 = 9.96E-01 y = -3.85E-03x E-01 R 2 = 9.97E Time (min) Figure Initial Rate (mm/min) [3] (µm)

9 Page S9 First-Order Integrated Rate Law (IRL) Plot ln[1] y = -1.59E-02x E+00 R 2 = 9.96E y = -7.07E-02x E+00 R 2 = 9.97E-01 y = -3.43E-02x E+00 R 2 = 9.97E-01 y = -4.42E-02x E+00 R 2 = 9.98E-01 Time (min) First-Order IRL Rate Constant Plot First Order IRL Rate Constant (min -1 ) [3] (µm)

10 Page S10 Figure 3 (3 point rate analysis) TOF (Reaction Rate/[3]) mm mm mm mm Figure 3 (2 point rate analysis). TOF (Reaction Rate/[3])

11 Page S11 Figure 3 (3 point rate analysis) Data mm 3 3-point Reaction Rate (mm) TOF (Rate/[3]) 3-point Reaction Rate (mm) TOF (Rate/[3]) E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mm 3 3-point Reaction TOF 3-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E E E E E E E E E E

12 Page S mm 3 3-point Reaction TOF 3-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mm 3 3-point Reaction TOF 3-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E

13 Page S13 Figure 3 (2 point rate analysis) Data mm 3 2-point Reaction TOF 2-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mm 3 2-point Reaction TOF 2-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E E E E E E E E E E E

14 Page S mm 3 2-point Reaction TOF 2-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mm 3 2-point Reaction TOF 2-point Reaction TOF Rate (mm) (Rate/[3]) Rate (mm) (Rate/[3]) E E E E E E E E E E E E E E E E E E E

15 Page S15 Kinetic analysis based on experiments from Figure SI-1 Figure SI mm mm mm mm 2 [1] (M) Time (min) mm 2 Time (min) Time (min) Time (min)

16 Page S mm 2 Time (min) Time (min) Time (min) mm 2 Time (min) Time (min) Time (min) mm 2 Time (min) Time (min) Time (min)

17 Page S17 Initial Rates from Figure SI y = -2.04E-03x E-01 R 2 = 9.92E-01 y = -2.51E-03x E-01 R 2 = 9.95E-01 y = -3.85E-03x E-01 R 2 = 9.97E Time (min) Figure Initial Rate (mm/min) [2] (mm)

18 Page S18 First-Order Integrated Rate Law (IRL) Plot ln[1] y = -1.76E-02x E+00 R 2 = 9.86E-01 y = -2.40E-02x E+00 R 2 = 9.92E-01 y = -4.42E-02x E+00 y = -1.06E-01x E+00 R 2 = 9.98E-01 R 2 = 9.98E-01 Time (min) First-Order IRL Rate Constant Plot First Order IRL Rate Constant (min -1 ) [2] (M)

19 Page S19 Figure 5 (3 point rate analysis). Figure 5 (2 point rate analysis) Rate/[2]

20 Page S20 Figure 5 (3 point rate analysis) Data mm 2 [2] (mm) 3-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E E E E E E E E E E E E E E E E E E E E E E E E E mm 2 [2] (mm) 3-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E E E E E E E E E E

21 Page S E E E E E E E E E E E E E E E E E E mm 2 [2] (mm) 3-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E E E E E E E E E E E E E E E E E E E E E E E E

22 Page S E E E mm 2 [2] (mm) 3-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E E E E E E E E E E Figure 5 (2 point rate analysis) Data mm 2 [1] 1/2 (mm) [2] 1/2 (mm) 2-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E E E E E E E E E E E E E E E E E E E E

23 Page S E E E E E E mm 2 [1] 1/2 (mm) [2] 1/2 (mm) 2-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mm 2 [1] 1/2 (mm) [2] 1/2 (mm) 2-point Reaction Rate (mm/min) Rate/[2] (min -1 ) E E E

24 Page S E E E E E E E E E E E E E E E E E E E E E E E E E E mm 2 [1] 1/2 (mm) [2] 1/2 (mm) 2-point Reaction Rate (mm/min) Rate/[2] E E E E E E E E E E E E

25 Page S25 Kinetic analysis based on experiments from Figure 6 Figure Trial 1 Trial 2 Time-Adjusted Trial Time (min) Trial 1 Time (min) Time (min) Time (min)

26 Page S26 Trial 2 Time (min) Time (min) Time (min) Time-Adjusted Trial 2 Time (min) Time (min) Time (min)

27 Page S27 Equilibrium Experiments S O O Ph O CDCl 3 EtCO 2 S O Ph Trial [3] (mm) [2] (mm) [3] eq (mm) [2] eq (mm) [4] eq (mm) K eq K eq (avg) = ± Trial 1 To a 1 ml volumetric flask was added S-HBTM (26.9 mg, mmol). CDCl 3 (400.0 µl) was added. Then, propionic anhydride (25.6 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. The solution was mixed 3 times by glass pipet and then transferred into an MR tube. The MR tube was placed in the spectrometer at K for 10 minutes before spectral data was collected. Trial 2 To a 1 ml volumetric flask was added S-HBTM (26.8 mg, mmol). CDCl 3 (400.0 µl) was added. Then, propionic anhydride (64.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. The solution was mixed 3 times by glass pipet and then transferred into an MR tube. The MR tube was placed in the spectrometer at K for 10 minutes before spectral data was collected. Trial 3 To a 2 ml volumetric flask was added S-HBTM (53.4 mg, mmol). CDCl 3 (800.0 µl) was added. Then, propionic anhydride (512.9 µl, mmol) was added. CDCl 3 was added up to 2.0 ml. The solution was mixed 3 times by glass pipet and then transferred into an MR tube. The MR tube was placed in the spectrometer at K for 10 minutes before spectral data was collected. Trial 4 To a 2 ml volumetric flask was added S-HBTM (53.3 mg, mmol). CDCl 3 (800.0 µl) was added. Then, propionic anhydride (307.2 µl, mmol) was added. CDCl 3 was added up to

28 Page S ml. The solution was mixed 3 times by glass pipet and then transferred into an MR tube. The MR tube was placed in the spectrometer at K for 10 minutes before spectral data was collected. Trial 5 To a 1 ml volumetric flask was added S-HBTM (13.4 mg, mmol). CDCl 3 (400.0 µl) was added. Then, propionic anhydride (64.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. The solution was mixed 3 times by glass pipet and then transferred into an MR tube. The MR tube was placed in the spectrometer at K for 10 minutes before spectral data was collected. Trial 6 To a 1 ml volumetric flask was added S-HBTM (40.3 mg, mmol). CDCl 3 (400.0 µl) was added. Then, propionic anhydride (64.0 µl, mmol) was added. CDCl 3 was added up to 1.0 ml. The solution was mixed 3 times by glass pipet and then transferred into an MR tube. The MR tube was placed in the spectrometer at K for 10 minutes before spectral data was collected. Figure SI [4] (mm) y = x R 2 = Molar equivalents of 2 The graph shows a linear relationship between the concentration of 4 and the molar equivalents of 2 for trials 1-4, where the concentration of 3 is held constant.

29 Page S29 1 H MR in CDCl 3 at 500 MHz Trial 1 EtCO 2 S O Ph S H Ph H H ppm ppm

30 Page S30 1 H MR in CDCl 3 at 500 MHz Trial 2 EtCO 2 S O Ph S H Ph H H ppm ppm

31 Page S31 1 H MR in CDCl 3 at 500 MHz Trial 3 EtCO 2 S O Ph S H Ph H H ppm ppm

32 Page S32 1 H MR in CDCl 3 at 500 MHz Trial 4 EtCO 2 S O Ph S H Ph H H ppm ppm

33 Page S33 1 H MR in CDCl 3 at 500 MHz Trial 5 EtCO 2 S O Ph S H Ph H H ppm ppm

34 Page S34 1 H MR in CDCl 3 at 500 MHz Trial 6 EtCO 2 S O Ph S H Ph H H ppm ppm

35 Page S35 Trial 6 EtCO 2 S H H O Ph S H Ph Trial 5 Trial 4 Trial 3 Trial 2 Trial 1 6.0ppm

A contribution from the Department of Chemistry, Washington University, Campus Box 1134, One Brookings Drive, Saint Louis, Missouri 63130

BENZOTETRAMISOLE (BTM): A REMARKABLY ENANTIOSELECTIVE ACYL TRANSFER CATALYST Vladimir B. Birman* and Ximin Li A contribution from the Department of Chemistry, Washington University, Campus Box 1134, One