Supporting Information

Transcription

1 Supporting Information Asymmetric Catalysis of the Carbonyl-Amine Condensation: Kinetic Resolution of Primary Amines Sayantani Das, Nilanjana Majumdar, Chandra Kanta De, Dipti Sankar Kundu, Arno Döhring, and Benjamin List* Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 4547 Mülheim an der Ruhr, Germany General Information S2 1a. General Procedure for the kinetic resolution of rac-amines for Table 1 S3 1b. General Procedure for the kinetic resolution of rac-amines for Chart 1 S3 1c. Procedure for the large scale experiment S4 1d. Pyrrole formation from 1,4-diketone S5 2. Determination of s-factor S6 3. Determination of absolute configuration S6 4. Product characterization S H and 13 C NMR spectra S14 6. HPLC traces S32 S1

2 General Information Unless otherwise stated, all reagents were purchased from commercial suppliers and purified prior to use. Racemic amines were purchased from Aldrich, abcr and TCI. Diketones were purchased from Aldrich and abcr. All solvents used in the reactions were distilled from appropriate drying agents prior to use. Reactions were monitored by thin layer chromatography (TLC) on silica gel pre-coated plastic sheets (.2 mm, Macherey-Nagel). Visualization was accomplished by irradiation with UV light at 4 nm and/or KMnO 4 stain. Neutral Al 2 O 3 (Type I) was purchased from Aldrich. Column chromatography was performed on neutral Al 2 O 3 (Type III). Proton and carbon NMR spectra were recorded on a Bruker AV- 5 spectrometer in deuterated solvents. Proton chemical shifts are reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl 3 δ 7.26 and CD 2 Cl 2 δ 5.32 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, s = sextet, h = heptet, m = multiplet, br = broad), coupling constants (Hz) and integration. 13 C chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl 3 δ and CD 2 Cl 2 δ53.84 ppm). High resolution mass spectra were determined on a Bruker APEX III FTMS (7 T magnet). Optical rotations were determined with an Autopol IV polarimeter (Rudolph Research Analytical) at 589 nm and C. Data are reported as follows: [α] temp λ, concentration (c in g/1 ml), and solvent. Enantiomeric ratios (er) were determined by HPLC analysis employing a chiral stationary phase column specified in the individual experiment, by comparing the samples with the appropriate racemic mixtures. S2

3 1a. General Procedure for the Kinetic Resolution of rac-amines for Table 1 An oven-dried 2 ml GC vial was charged with catalyst 3 (5 mol%,.5 equiv.,.1 mmol) and a magnetic stirring bar. To this vial Et 2 O (. ml) was added followed by racamine (1. equiv.,. mmol, 3.2 µl) under argon atmosphere. The mixture was then stirred at rt for 5 min. 5Å Molecular sieve ( mg) was then added and the mixture immediately cooled to 78 C. To the mixture, diketone 2 (.55 equiv.,.14 mmol) was added under argon atmosphere. The reaction vial was warmed to 5 C. After 2 h, the reaction was quenched with triethylamine (.5 equiv.,.1 mmol, 1.7 µl) and benzoic anhydride (.45 equiv.,.112 mmol, 2.5 mg) was added. It was further stirred at rt for 3 min. The crude mixture was directly purified without further work-up on SiO 2 preparative TLC using 5% Et 2 O/DCM (v/v) and 2% EtOAc/i-Hexane as eluents for product 4 and benzoylated derivative 5a respectively. 1b. General Procedure for the Kinetic Resolution of rac-amine for Chart 1 An oven-dried 4 ml vial was charged with catalyst 3c (5 mol%,.5 equiv., 5.36 mg) and a magnetic stirring bar. To this vial Et 2 O (.8 ml) was added followed by rac-amine (1. equiv.,.1 mmol) (Note 1) under argon atmosphere. The mixture was then stirred at rt for 5 min. 5Å Molecular sieve (1 mg) was then added and the mixture immediately cooled to 78 C. To the mixture, diketone 2c (.55 equiv.,.55 mmol, 6.4 µl in.2 ml Et 2 O) (Note 2) was added through the cold side-wall of the vial under argon atmosphere. The reaction vial was warmed to 5 C and was stirred for 24 h (Note 3). After 24 h, the reaction was quenched S3

4 with triethylamine (.6 equiv.,.6 mmol, 8.4 µl) and benzoic anhydride (.5 equiv.,.5 mmol, 11.4 mg) was added. It was further stirred at rt for 3 min. The crude mixture was directly purified without further work up (Note 4). Purification was performed on neutral Al 2 O 3 (Type III) using % Et 2 O/Pentane (v/v) to 5% Et 2 O/Pentane (v/v) as eluent. The products 4 were obtained as light yellow oils and the benzoylated products 5 were obtained as white solids. Note 1: It was found that the rac-amines form white solids upon exposure to air. These were freshly distilled and stored in Schlenk flasks under argon atmosphere prior to use. Note 2: Diketones were freshly distilled and stored in Schlenk flasks under argon atmosphere prior to use. It was found that the diketones turn yellow over time. The unknown yellow impurities can be removed under high vacuum (5x1-2 mbar at rt for 1 min). Note 3: A proper stirring for the reaction mixture is needed due to high loading of Molecular sieve. Typically, the raction mixture was stirred at 4 5 rpm speed. Note 4: Due to the low stability of the products 4 on SiO 2, purification was performed using neutral Al 2 O 3 (Type III). 1c. Procedure for the Large Scale Experiment An oven-dried ml flask was charged with catalyst 3c (1 mol%,.1 equiv., 94. mg) and a magnetic stirring bar. To this vial Et 2 O (7 ml) was added followed by rac-amine (1. equiv., 8.7 mmol, 1. g) under argon atmosphere. The mixture was then stirred at rt for 1 min. 5Å Molecular sieve (9 g) was then added and the mixture immediately cooled to 78 C. To the mixture, diketone 2c (.55 equiv., 4.8 mmol,.56 ml in 17 ml Et 2 O) was added through the cold side-wall of the vial under argon atmosphere over 1 min. The reaction flask was warmed to 5 C and was stirred for 5 d. After 5 d, the reaction was quenched with triethylamine (.6 equiv., 5.2 mmol,.73 ml) and benzoic anhydride (.5 equiv., 4.3 mmol, S4

5 .98 g) was added. It was further stirred for 1 h and then 3 min at rt. The crude mixture was directly purified without further work up as a solid-load over celite. Purification was performed on neutral Al 2 O 3 (Type III) using 2% Et 2 O/Pentane (v/v) to 5% Et 2 O/Pentane (v/v) as eluent. The product 4g was obtained as light yellow oil in 41% isolated yield and the benzoylated product 5g was obtained as white solid in 46% isolated yield. Deprotection step: A 4 ml vial was charged with 4g (42. mg,.2 mmol, er = 6:94) and a magnetic stirring bar. To this vial MeOH (.4 ml) was added followed by NH 2 OH.HCl (1.2 equiv.,.24 mml, 16.7 mg). The reaction mixture was stirried at rt for 1.5 h and MeOH was removed. The crude product was dissolved in.5 ml of CH 2 Cl 2 and Et 3 N (1.3 equiv.,.26 mmol, 36. µl). It was then cooled to C and benzoic anhydride (1.2 equiv.,.24 mmol, 54 mg) was added. The reaction mixture was stirried at rt for 3 min. The benzoylated product was purified on SiO 2 preparative TLC and the ee was determined by HPLC (er = 6:94). 1d. Pyrrole formation from 1,4-diketone An oven-dried GC vial was charged with catalyst 3a (1 mol%) and a magnetic stirring bar. To this vial PhMe (. ml) was added followed by rac-amine (1. equiv.,. mmol). To the mixture, diketone (.5 equiv.,.12 mmol) was added and the vial was cooled to 2 C and was stirred for 13 d. The s factor was determined as above. S5

6 2. Determination of the s-factor: Conversion (C) was determined by measuring the ee of both the product and the benzoylated derivative of the unreacted recovered starting material by HPLC. ee p is the enantiomeric excess of the product and ee SM is the enantiomeric excess of the recovered unreacted starting material. The s-factor can be calculated using the calculated conversion Determination of the Absolute Configuration: The absolute configuration of 4a was determined by HPLC trace comparison with the commercially available enantio-pure (R)-1a. The absolute configuration of 4i was determined by HPLC trace comparison with the commercially available enantio-pure (R)-1i. 1. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. S6

7 4. Product Characterization (R,Z)-3-methyl-4-((1-phenylethyl)amino)but-3-en-2-one (4a): Prepared according to the general procedure as light yellow oil in 37% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ (12.31, br s, 1H), (m, 2H), (m, 3H), 4.7 (p, J = 7., 1H), 2.12 (s, 3H), 1.82 (s, 3H), 1.8 (s, 3H), 1.5 (d, J = 6.9, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 195.5, 161.3, 145.7, 129.1, 127.3, 126., 99.1, 3.5, 28.8,.2, 15.9, HRMS m/z (ESI): calcd. for C 14 H 2 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 34 nm, t R = 3.2 min (minor) and t R = 5.3 min (major). er = 6.5:93.5.[α] D = 629 (c.4, CH 2 Cl 2 ). 4a: er = 7:93, 5a: er = 11.9:88.1. calculated conversion = 47% calculated s-factor = 3 (R,Z)-3-methyl-4-((1-phenylpropyl)amino)pent-3-en-2-one (4b): Prepared according to the general procedure as light yellow oil in 5% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ (12.44, br s, 1H), (m, 2H), (m, 3H), 4.46 (q, J = 6.8 Hz, 1H), 2.12 (s, 3H), (m, 8H),.94 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 195.4, 161.8, 144.3, 129., 127.3, 126.7, 99., 59.9, 32.1, 28.8, 15.9, 14.9, 1.9. HRMS m/z (ESI): calcd. for C 15 H 22 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 359 nm, t R = 2.8 min (minor) and t R = 5.8 min (major). er = 11.5:88.5. [α] D = 486 (c.4, CH 2 Cl 2 ). 4b: er = 11.5:88.5, 5b: er = 12.3:88.7. calculated conversion = 5% calculated s-factor = 17 (R,Z)-4-((1-(2-fluorophenyl)ethyl)amino)-3-methylpent-3-en-2-one (4c): Prepared according to the general procedure as light yellow oil in 5% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ (br s, 1H), (m, 2H), (m, 1H), (m, 1H), 5.3 (p, J = 7. Hz, 1H), 2.12 (s, 3H), 1.82 (s, 3H), 1.81 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 195.8, 16.9, 16. (d, J = 244 Hz), (d, J = 13.9 Hz), 129. (d, J = 7.8 Hz), (d, J = 4.2), 1.1 (d, J = 3.2 Hz), (d, J = 22.2), 99.4, 47.2 (J = 3.1), 28.8, 23.5, 15.6, HRMS m/z S7

8 (ESI): calcd. for C 14 H 19 N 1 O 1 F 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 343 nm, t R = 2.9 min (minor) and t R = 4.7 min (major). er = 7.3:92.7. [α] D = 557 (c.4, CH 2 Cl 2 ). 4c: er = 7.3:92.7, 5c: er = 9.4:9.6 calculated conversion = 49% calculated s-factor = 32 (R,Z)-3-methyl-4-((1-(m-tolyl)ethyl)amino)pent-3-en-2-one (4d): Prepared according to the general procedure as light yellow oil in 5% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12.3 (br s, 1H), (m, 1H), (m, 3H), 4.65 (p, J = 6.9 Hz, 1H), 2.33 (s, 3H), 2.12 (s, 3H), 1.82 (s, 3H), 1.8 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 195.4, 161.3, 145.6, 138.9, 129., 128.1, 126.7, 123.1, 98.9, 53.7, 28.8,.2, 21.6, 15.9, HRMS m/z (ESI): calcd. for C 15 H 22 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 34 nm, t R = 2.8 min (minor) and t R = 4.6 min (major). er = 8.1:91.9. [α] D = 567 (c.4, CH 2 Cl 2 ). 4d: er = 8.1:91.9, 5d: er = 7.4:92.6 calculated conversion = 5% calculated s-factor = 31 (R,Z)-4-((1-(3-fluorophenyl)ethyl)amino)-3-methylpent-3-en-2-one (4e): Prepared according to the general procedure as light yellow oil in 45% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12. (br s, 1H), (m, 1H), 7.4 (d, J = 7.9 Hz, 1H), (m, 2H), 4.7 (p, J = 6.9 Hz, 1H), 2.13 (s, 3H), 1.81 (s, 3H), 1.8 (s, 3H), 1.49 (d, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 195.9, (d, J = 245 Hz), 161., (d, J = 6.3 Hz), 13.8 (d, J = 8.5 Hz), (d, J = 3. Hz), (d, J = 21.2), (d, J = 22.3), 99.4, 53.3, 28.9,., 15.9, HRMS m/z (ESI): calcd. for C 14 H 19 N 1 O 1 F 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 34 nm, t R = 3.3 min (minor) and t R = 7.3 min (major). er = 6.8:93.2. [α] D = 548 (c.4, CH 2 Cl 2 ). S8

9 4e: er = 6.8:93.2, 5e: er = 12.4:87.6 calculated conversion = 47% calculated s-factor = 31 (R,Z)-3-methyl-4-((1-(p-tolyl)ethyl)amino)pent-3-en-2-one (4f): Prepared according to the general procedure as light yellow oil in 45% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ (br s, 1H), (m, 4H), 4.66 (p, J = 6.9 Hz, 1H), 2.31 (s, 3H), 2.11 (s, 3H), 1.82 (s, 3H), 1.8 (s, 3H), 1.74 (d, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 195.3, 161.3, 142.6, 137.1, 129.7, 1.9, 98.9, 53.4, 28.8,.2, 21.1, 15.9, HRMS m/z (ESI): calcd. for C 15 H 22 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 34 nm, t R = 2.7 min (minor) and t R = 4.6 min (major). er =.6.5:93.5. [α] D = 623 (c.4, CH 2 Cl 2 ). 4f: er = 6.5:93.5, 5f: er = 15.7:84.3 calculated conversion = 45% calculated s-factor = 23 (R,Z)-3-methyl-4-((5-methylhexan-2-yl)amino)pent-3-en-2-one (4g): Prepared according to the general procedure as light yellow oil in 38% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12.5 (br s, 1H), (m, 1H), 2.6 (s, 3H), 1.96 (s, 3H), 1.82 (s, 3H), (m, 3H), (m, 2H), 1.16 (d, J = 6.5 Hz, 3H),.88 (d, J = 6.6 Hz, 6H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 194.1, 161.4, 97.8, 49.7, 36.1, 35.6, 27.7 (1), 22.7 (), 22.4, 15.4, HRMS m/z (ESI): calcd. for C 13 H 26 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 96:4, flow rate = 1. ml/min, λ = 339 nm, t R = 4.1 min (minor) and t R = 4.3 min (major). er = 4.9:95.1. [α] D = 94. (c.4, CH 2 Cl 2 ). 4g: er = 4.9:95.1, 5g: er = 12.2:87.8. calculated conversion = 46% calculated s-factor = 44 (R,Z)-3-methyl-4-((4-phenylbutan-2-yl)amino)pent-3-en-2-one (4h): Prepared according to the general procedure as light yellow oil in 47% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ (br s, 1H), (m, 2H), (m, 3H), (m, 1H), (m, 2H), 2.8 (s, 3H), 1.9 (s, 3H), (m, 2H), 1.83 (s, 3H), 1.12 (d, J = 6.5 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 194.5, 161.4, 142.2, 128.8, S9

10 128.7, 126.2, 89.1, 48.6, 39.8, 32.6, 28.6, 22.5, 15.4, HRMS m/z (ESI): calcd. for C 16 H 24 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 96:4, flow rate = 1. ml/min, λ = 335 nm, t R = 5.9 min (minor) and t R = 6.9 min (major). er = 8.1:91.9. [α] D = 19 (c.4, CH 2 Cl 2 ). 4h: er = 8.1:91.9, 5h: er = 1.4:89.6. calculated conversion = 49% calculated s-factor = 27 (R,Z)-4-(heptan-2-ylamino)-3-methylpent-3-en-2-one (4i): Prepared according to the general procedure as light yellow oil in 44% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12.4 (br s, 1H), (m, 1H), 2.6 (s, 3H), 1.97 (s, 3H), 1.82 (s, 3H), (m, 2H), (m, 6H), 1.16 (d, J = 6.4 Hz, 3H),.88 (t, J = 7. Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 194.1, 161.4, 97.7, 49.4, 38.3, 32.2, 28.6, 26.2, 23., 22.4, 15.4, 14.9, HRMS m/z (ESI): calcd. C 13 H 26 N 1 O 1 for [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using the following parameters: ChiralpakOD-3, heptane/ i-proh = 96:4, flow rate = 1. ml/min, λ = 34 nm, t R = 4.5 min (major) and t R = 6.5 min (minor). er = 9.4:9.6. [α] D = 9 (c.4, CH 2 Cl 2 ). 4i: er = 9.4:9.6, 5i: er = 5.5:94.5. calculated conversion = 52% calculated s-factor = 28 (R,Z)-3-methyl-4-(pentan-2-ylamino)pent-3-en-2-one (4j): Prepared according to the general procedure as light yellow oil in 39% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12.5 (br s, 1H), (m, 1H), 2.6 (s, 3H), 1.97 (s, 3H), 1.81 (s, 3H), (m, 4H), 1.16 (d, J = 6.5 Hz, 3H),.91 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 194.1, 161.5, 97.7, 49.1, 4.5, 28.6, 22.4, 19.6, 15.4, 14.9, HRMS m/z (ESI): calcd. for C 11 H 22 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 96:4, flow rate = 1. ml/min, λ = 336 nm, t R = 5.1 min (major) and t R = 5.4 min (minor). er = 12.4:87.6. [α] D = 67 (c.4, CH 2 Cl 2 ). 4j: er = 12.4:87.6, 5j: er = 11:89. S1

11 calculated conversion = 51% calculated s-factor = 17 (R,Z)-3-methyl-4-((4-methylpentan-2-yl)amino)pent-3-en-2-one (4k): Prepared according to the general procedure as light yellow oil in 38% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12.2 (br s, 1H), (m, 1H), 2.6 (s, 3H), 1.98 (s, 3H), 1.82 (s, 3H), (m, 1H), (m, 1H), (m, 1H), 1.15 (d, J = 6.3 Hz, 3H),.91 (d, J = 6.6 Hz, 3H),.88 (d, J = 6.6 Hz, 3H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 194.2, 161.4, 97.8, 47.4 (8), 47.4 (6), 28.6,.4, 23., 22.9, 22.6, 15.3, HRMS m/z (ESI): calcd. for C 12 H 24 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 96:4, flow rate = 1. ml/min, λ = 339 nm, t R = 3.8 min (minor) and t R = 6.5 min (major). er = 6.4:93.6. [α] D = 6 (c.4, CH 2 Cl 2 ). 4k: er = 6.4:93.6, 5k: er = 14.6:85.4. calculated conversion = 45% calculated s-factor = 31 (R,Z)-3-methyl-4-((6-methylheptan-2-yl)amino)pent-3-en-2-one (4l): Prepared according to the general procedure as light yellow oil in 39% yield. 1 H NMR (5 MHz, CD 2 Cl 2 ): δ 12.4 (br s, 1H), (m, 1H), 2.6 (s, 3H), 1.97 (s, 3H), 1.82 (s, 3H), (m, 3H), (m, 2H), (m, 5H),.87 (d, J = 6.6 Hz, 6H). 13 C NMR (126 MHz, CD 2 Cl 2 ): δ 194.1, 161.4, 97.8, 49.4, 39.2, 38.6, 28.6, 28.3, 24.3, 22.7 (4), 22.7 (1), 22.4, 15.4, HRMS m/z (ESI): calcd. for C 14 H 28 N 1 O 1 [M+H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 96:4, flow rate = 1. ml/min, λ = 33 nm, t R = 4.4 min (major) and t R = 6.5 min (minor). er = 6.9:93.1. [α] D = 99 (c.4, CH 2 Cl 2 ). 4l: er = 6.9:93.1, 5l: er = 12.5:87.5 calculated conversion = 47% calculated s-factor = 3 S11

12 (S)-N-(5-methylhexan-2-yl)benzamide (5g): 1 H NMR (5 MHz, CDCl 3 ): δ (m, 2H), 7.48 (tt, J = 1.3, 7.3 Hz, 1H), (m, 2H), 5.95 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 3H), (m, 2H), 1.23 (d, J = 6.6 Hz, 3H),.88 (d, J = 6.7 Hz, 6H). 13 C NMR (126 MHz, CDCl 3 ): δ 166.9, 135.2, 131.3, 128.6, 126.9, 46.1, 35.3, 35., 28.1, 22.7, HRMS m/z (ESI): calcd. for C 14 H 2 N 1 O 1 [M H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 85:15, flow rate = 1. ml/min, λ = 248 nm, t R = 3.2 min (minor) and t R = 3.9 min (major). er = 12.2:87.8. [α] D = 6 (c.4, CH 2 Cl 2 ). (S)-N-(4-phenylbutan-2-yl)benzamide (5h): 1 H NMR (5 MHz, CDCl 3 ): δ (m, 2H), 7.46 (tt, J = 1.3, 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), (m, 2H), (m, 3H), 5.98 (d, J = 7.9 Hz, 1H), (m, 1H), 2.71 (t, J = 7.8 Hz, 2H), (m, 2H), 1.27 (d, J = 6.7 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ 166.9, 141.9, 135., 131.4, (1), (), 128.5, 126.9, 126., 45.8, 38.7, 32.6, HRMS m/z (ESI): calcd. for C 17 H 18 N 1 O 1 [M H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i- PrOH = 85:15, flow rate = 1. ml/min, λ = 238 nm, t R = 5.9 min (minor) and t R = 11. min (major). er = 1.4:89.6. [α] D = 6 (c., CH 2 Cl 2 ). (S)-N-(heptan-2-yl)benzamide (5i): 1 H NMR (5 MHz, CDCl 3 ): δ (m, 2H), 7.47 (tt, J = 1.3, 7.4 Hz, 1H), (m, 2H), 5.98 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 2H), (m, 6H), 1.22 (d, J = 6.6 Hz, 3H),.87 (t, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ 166.9, 135.2, 131.3, 128.6, 126.9, 45.9, 37.1, 31.8,.9, 22.7, 21.1, HRMS m/z (ESI): calcd. for C 14 H 2 N 1 O 1 [M H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 238 nm, t R = 5. min (minor) and t R = 5.7 min (major). er = 5.5:94.5. [α] D = 3 (c.7, CH 2 Cl 2 ). (S)-N-(pentan-2-yl)benzamide (5j): 1 H NMR (5 MHz, CDCl 3 ): δ (m, 2H), 7.47 (tt, J = 1.3, 7.4 Hz, 1H), 7.41 (tt, J = 1.5, 7.6 Hz, 2H), 5.93 (d, J = 5.9 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), 1.23 (d, J = 6.6 Hz, 3H),.93 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ 166.9, 135.2, S12

13 131.4, 128.6, 126.9, 45.6, 39.4, 21.2, 19.5, HRMS m/z (ESI): calcd. for C 12 H 16 N 1 O 1 [M H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 232 nm, t R = 4.9 min (minor) and t R = 6.2 min (major). er = 11:89. [α] D = 2 (c.17, CH 2 Cl 2 ). (S)-N-(4-methylpentan-2-yl)benzamide (5k): 1 H NMR (5 MHz, CDCl 3 ): δ (m, 2H), 7.48 (tt, J = 1.4, 7.5 Hz, 1H), (m, 2H), 5.89 (d, J = 7.1 Hz, 1H), (m, 1H), (m, 1H), 1.48 (ddd, J = 6.3, 8.3, 14.2 Hz, 1H), 1.34 (ddd, J = 6.3, 8.1, 13.9 Hz, 1H),1.22 (d, J = 6.5 Hz, 3H),.95 (d, J = 6.7 Hz, 3H),.94 (d, J = 6.7 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ 166.8, 135.2, 131.4, 128.6, 126.9, 46.7, 44.1,.3, 22.9, 22.7, HRMS m/z (ESI): calcd. for C 13 H 18 N 1 O 1 [M H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 238 nm, t R = 4. min (minor) and t R = 5.9 min (major). er = 14.6:85.4. [α] D = 2 (c.21, CH 2 Cl 2 ). (S)-N-(6-methylheptan-2-yl)benzamide (5l): 1 H NMR (5 MHz, CDCl 3 ): δ (m, 2H), 7.47 (tt, J = 1.3, 7.3 Hz, 1H), (m, 2H), 5.99 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 3H), (m, 2H), 1.22 (d, J = 6.7 Hz, 3H), (m, 2H),.86 (d, J = 6.7 Hz, 6H). 13 C NMR (126 MHz, CDCl 3 ): δ 166.9, 135.2, 131.3, 128.6, 126.9, 45.9, 38.9, 37.4, 28., 24., 22.7, 22.6 (7), HRMS m/z (ESI): calcd. for C 15 H 22 N 1 O 1 [M H]: ; found: The enantiomeric ratio was measured by HPLC analysis using ChiralpakOD-3, heptane/ i-proh = 9:1, flow rate = 1. ml/min, λ = 228 nm, t R = 4.9 min (minor) and t R = 5.4 min (major). er = 12.5:87.5. [α] D = 13 (c.24, CH 2 Cl 2 ). S13

14 1 H and 13 C NMR Spectra of Product 4a ppm ppm S14

15 1 H and 13 C NMR Spectra of Product 4b ppm ppm S15

16 1 H and 13 C NMR Spectra of Product 4c ppm ppm S16

17 1 H and 13 C NMR Spectra of Product 4d ppm ppm S17

18 1 H and 13 C NMR Spectra of Product 4e ppm ppm S18

19 1 H and 13 C NMR Spectra of Product 4f ppm ppm S19

20 1 H and 13 C NMR Spectra of Product 4g ppm ppm S2

21 1 H and 13 C NMR Spectra of Product 4h ppm ppm S21

22 1 H and 13 C NMR Spectra of Product 4i ppm ppm S22

23 1 H and 13 C NMR Spectra of Product 4j ppm ppm S23

24 1 H and 13 C NMR Spectra of Product 4k ppm ppm S24

25 1 H and 13 C NMR Spectra of Product 4l ppm ppm S

26 1 H and 13 C NMR Spectra of Benzoylated Product 5g ppm ppm S26

27 1 H and 13 C NMR Spectra of Benzoylated Product 5h ppm ppm S27

28 1 H and 13 C NMR Spectra of Benzoylated Product 5i ppm ppm S28

29 1 H and 13 C NMR Spectra of Benzoylated Product 5j ppm ppm S29

30 1 H and 13 C NMR Spectra of Benzoylated Product 5k ppm ppm S3

31 1 H and 13 C NMR Spectra of Benzoylated Product 5l ppm ppm S31

32 HPLC Trace of 4a 5 34nm4nm (1,) Dataf ile Name:DAT-SB-99-pdt-RAC-Me-acac-OD ml-18min.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm4nm (1,) Datafile Name:dec-dd-Me-Pdt-dil.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S32

33 HPLC Trace of 5b 7 228nm,4nm (1,) Datafile Name:DAT-SC-9B-der.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Dataf ile Name:dec-dd-Me-der-re.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S33

34 HPLC Trace of 4b 6 359nm,4nm (1,) Dataf ile Name:DOA-AB-77-Pdt-Etamine-OD mL-15min.lcd , 1, 2, 3, 4, 5, 6, 7, min nm,4nm (1,) Dataf ile Name:dec-dd-382-alpha-Et-pdt.lcd , 1, 2, 3, 4, 5, 6, 7, min S34

35 HPLC Trace of 5b 2nm4nm (1,) Dataf ile Name:DOA-AB-72-OD mL-15min.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm4nm (1,) Dataf ile Name:dec-dd-382-alpha-Et-der.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S35

36 HPLC Trace of 4c 343nm4nm (1,) Dataf ile Name:2-F-pdt-rac-OD ml.lcd , 2, 3, 4, 5, 6, 7, min nm,4nm (1,) Dataf ile Name:MBB-MA-21pdt.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, min S36

37 HPLC Trace of 5c 4 238nm,4nm (1,) Dataf ile Name:DAT-SC-63-der-RAC-2-Fluoro-OD ml-15min.lcd , 2, 3, 4, 5, 6, 7, 8, min nm,4nm (1,) Dataf ile Name:MBB-MA-21der.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, 8, min S37

38 HPLC Trace of 4d 4 34nm,4nm (1,) Dataf ile Name:DOA-AB-87-Pdt-3Meamine-OD mL-15min.lcd 3 2 1, 1, 2, 3, 4, 5, 6, min nm,4nm (1,) Dataf ile Name:dec-dd Me-pdt.lcd , 1, 2, 3, 4, 5, 6, min S38

39 HPLC Trace of 5d 4 23nm4nm (1,) Datafile Name:DOA-AB-88-der-3-Meamine-OD mL-15min.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Dataf ile Name:dec-dd Me-der.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S39

40 HPLC Trace of 4e 34nm,4nm (1,) Dataf ile Name:DAT-SC-57-pdt-RAC-3-Fluoro-OD ml-15min.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Datafile Name:MBB-MA-22pdt-re.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S4

41 HPLC Trace of 5e 3 231nm,4nm (1,) Dataf ile Name:DAT-SC-58-der-RAC-3-Fluoro-OD ml-15min.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Datafile Name:MBB-MA-22der.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S41

42 HPLC Trace of 4f 34nm,4nm (1,) Dataf ile Name:DOA-AB-85-pdt-RAC-4-Meaminer-OD ml-15min.lcd 7,5 5, 2,5,,,5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, 5,5 min nm,4nm (1,) Dataf ile Name:dec-dd Me-pdt.lcd ,,5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, 5,5 min S42

43 HPLC Trace of 5f 22nm4nm (1,) Dataf ile Name:DOA-AB-84-der-4-Meamine-OD mL-15min.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Dataf ile Name:dec-dd Me-der.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min S43

44 HPLC Trace of 4g 339nm,4nm (1,) Datafile Name:DOA-AB-91-pdt-OD mL.lcd ,,5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, 5,5 min nm,4nm (1,) Dataf ile Name:dec-dd-386-pdt.lcd ,5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, 5,5 min S44

45 HPLC Trace of 5g nm,4nm (1,) Dataf ile Name:DOA-AB-92-der-OD mL.lcd , 2, 3, 4, 5, 6, 7, min nm,4nm (1,) Dataf ile Name:dec-dd-386-der.lcd , 2, 3, 4, 5, 6, 7, min S45

46 HPLC Trace of 4h 6 335nm,4nm (1,) Datafile Name:DAT-SC-82-RAC-pdt-OD ml.lcd , 2,5 5, 7,5 1, 12,5 min nm,4nm (1,) Datafile Name:dec-dd-387-pdt-new.lcd , 2,5 5, 7,5 1, 12,5 min S46

47 HPLC Trace of 5h 237nm,4nm (1,) Datafile Name:DAT-SC-81-der-OD mL.lcd , 2,5 5, 7,5 1, 12,5 min nm,4nm (1,) Dataf ile Name:dec-dd-387-der.lcd , 2,5 5, 7,5 1, 12,5 min S47

48 HPLC Trace of 4i 34nm,4nm (1,) Dataf ile Name:DAT-SC-85-pdtr-2hepty lamine-od ml-3.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min nm4nm (1,) Dataf ile Name:dec-dd-389-pdt ml.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min S48

49 HPLC Trace of 5i 238nm,4nm (1,) Dataf ile Name:DAT-SC-84-der-2hepty lamine-od ml.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm4nm (1,) Datafile Name:dec-dd-389-der.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S49

50 HPLC Trace of 4j 336nm,4nm (1,) Dataf ile Name:DOA-AB-11-OD ml-pdt.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, min nm4nm (1,) Dataf ile Name:dec-dd-39-pdt-new.lcd , 2, 3, 4, 5, 6, 7, min S5

51 HPLC Trace of 5j 232nm,4nm (1,) Dataf ile Name:DOA-AB-1-der-RAC-2pentamine-OD ml.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm4nm (1,) Dataf ile Name:dec-dd-39-der-new.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min S51

52 HPLC Trace of 4k 3 339nm,4nm (1,) Dataf ile Name:DOA-AB-16-Pdt-b7558-OD mL-15min-re.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Dataf ile Name:dec-dd-391-pdt-new1.lcd , 1, 2, 3, 4, 5, 6, 7, 8, 9, min S52

53 HPLC Trace of 5k 1 236nm4nm (1,) Datafile Name:DAT-SC-11-der-b-7558-OD mL-15min.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) 35 Datafile Name:dec-dd-391-der-new1.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min S53

54 HPLC Trace of 4l 3 33nm,4nm (1,) Dataf ile Name:DOA-AB-pdt-b7945-OD ml.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min nm,4nm (1,) Dataf ile Name:dec-dd-392-pdt-new.lcd , 2, 3, 4, 5, 6, 7, 8, 9, min S54

55 HPLC Trace of 5l 1 226nm4nm (1,) Dataf ile Name:DAT-SC-111-der-b7945-OD mL-15min.lcd 75 5, 1, 2, 3, 4, 5, 6, 7, min nm,4nm (1,) Dataf ile Name:dec-dd-392-der.lcd , 2, 3, 4, 5, 6, 7, min S55