Modelos scoring

General procedure for the kinetic resolution

Approximately 20-25 mg of activated 4 Å molecular sieves was added to an oven dried 1 dram vial containing a Teflon coated stir bar. (+)-Benzotetramisole (0.1mmol or 0.125 mmol) was weighed out under N2 and added to the vial. Most of the substrates were

directly weighed and added to the 1 dram vial then 900 µL of THF was added. If the substrate is D,L-pantolactone, weigh 260 mg (2 mmol) D, L-pantolactone and add to an oven dried 2 mL volumetric flask as quickly as possible and then fill with solvent to make a solution under argon. Employ an air tight syringe to add 500 µL solutions to the 1 dram vial followed by another 400 µL pure solvent to the vial. In the next step, 0.3 mmol of the amine base was added to the vial. If the amine base is a solid, the base is

added before the addition of any other liquid. After all reagents excluding triphenylsilyl chloride were added, electrical tape was used to seal the cap of the 1 dram vial and it was cooled to -78 °C. Recrystallized triphenylsilyl chloride (Ph3SiCl) (296 mg) was weighed

into an oven dried 1 mL volumetric flask and dissolve in THF to make a 1M Ph3SiCl

solution. 300 µL of this 1 M Ph3SiCl solution was added to the reaction vial(s) that have

already been cooled to -78 °C. After react 24-48 hours, the reaction was quenched by 0.5 ml of methanol. The NMR of the crude mixture was taken.

Column chromatography was performed to separate the product and unreacted starting material employing the solvent system ethyl acetate/hexane 50:50. For the amide substrate, the starting material and the catalyst is still the co-elute. This mixture was washed with 1.5 mL 5% HCl and extracted by diethyl ether three times. The organic layers were combined then dried over anhydride Na2SO4. The product was then reacted

with 2 mL of a 1M TBAF solution in THF to remove the silyl group.

When the substrate is DL-pantolactone, both recovered starting material and desilylated product need to be benzoylated for the HPLC analysis. The recovered DL-pantolactone from the kinetic resolution reactions is reacted with excess 80 µL benzoyl chloride (80 µL) and triethylamine (110 µL) catalyzed by 4-dimethylaminopyridine (DMAP) (12mg, 0.1 mmol) in 2 mL dichloromethane. The reaction was quenched by saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (2*2 mL). Then column

chromatography was run in 1:9 ethyl acetate/hexane to afford benzoylated starting material.

General procedure to make α-hydroxy carboxylic acid (GP1).

To a 10 mL microwave reaction vessel with a Teflon coated-stir bar was added the α- hydroxy carboxylic acid, aniline and p-toluenesulfonic acid. The vessel was put into the microwave reactor (CEM DiscoverSP with SynergyD software). The microwave reactor was set as follows: Maximum pressure, 75 MPa; Maximum power, 75W. After the reaction, the vessel was cooled down by flowing nitrogen. The NMR conversion was checked right after the cooling process. The sample was transfered to a separatory funnel by dichloromethane. The sample was washed with 6N HCl, sat. NaHCO3 and sat. NaCl.

Then the organic phase was dried over NaSO4, filtered and evaporated at reduced

pressure.

2-Hydroxy-3-methyl-N-phenylbutanamide

According to the GP1, 2-hydroxy-3-methylbutanoic acid (3 mmol, 354.39 mg) was react with aniline (6 mmol, 559.8 mg) with catalytic amount of p-toluenesulfonic acid monohydrate (0.6 mmol, 114.12mg). The yield of 2-hydroxy-3-methyl-N- phenylbutanamide is 475 mg, 2.49 mmol, 83% yield. It’s pale yellow solid 1H NMR: (400 MHz, CDCl3) δ ppm 7.62 – 7.53 (m, 2H), 7.39 – 7.29 (m, 2H), 7.17 – 7.08 (m, 1H),

4.13 (d, J = 3.1 Hz, 1H), 2.56 (s, 1H), 2.32 (pd, J = 6.9, 3.1 Hz, 1H), 1.08 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H) 13C NMR (100 MHz, CDCl3) δ ppm 171.10, 137.16,

2-Hydroxy-N-phenylbutanamide

According to the GP1, D,L-2-hydroxybutyric acid (5 mmol, 520.5 mg) was reacted with aniline (10 mmol, 933 mg) under a catalytic amount of p-toluenesulfonic acid monohydrate (0.1 mmol, 19.02 mg). The yield of 2-hydroxy-N-phenylbutanamide is 792 mg, 4.4 mmol, 88% yield. 1H NMR:(400 MHz, CDCl3) δ ppm 8.37 (s, 1H), 7.62 – 7.54 (m, 2H), 7.39 – 7.29 (m, 2H), 7.18 – 7.08 (m, 1H), 4.24 (dt, J = 8.1, 4.3 Hz, 1H), 2.49 (d, J = 5.3 Hz, 1H), 1.99 (dtd, J = 15.0, 7.5, 4.0 Hz, 1H), 1.81 (dp, J = 14.6, 7.3 Hz, 1H), 1.05 (t, J = 7.4 Hz, 3H). ). 13C NMR (100 MHz, CDCl3) δ ppm δ 171.33, 132.43, 129.05, 124.47, 119.68, 104.99, 77.32, 77.01, 76.69, 73.63, 27.88, 9.17 2-Hydroxy-N-phenylpropanamide

According to the GP1, D,L-lactic acid (5 mmol, 450.4 mg) was reacted with aniline (15 mmol, 1.40 g) under a catalytic amount of p-toluenesulfonic acid monohydrate (1 mmol, 190.2 mg). The yield of 2-hydroxy-N-phenylpropanamide is 308 mg, 1.87 mmol, 37% yield. 1H NMR:(400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 7.59 – 7.51 (m, 2H), 7.37 – 7.24

(m, 2H), 7.17 – 7.08 (m, 1H), 4.35 (q, J = 6.8 Hz, 1H), 3.21 (s, 1H), 1.52 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 172.57, 137.12, 129.04, 124.58, 119.80, 77.34,

Benzyl-2-hydroxypropanoate

To a round bottom flask with Teflon-coated stir bar and DL lactic acid (3.45 mmol, 313.26 mg) was added 7 mL MeOH-water (1:9) solution and then a 20% CsCO3 solution

was added dropwisely to make pH=7. The solvent was removed under reduced pressure. DMF was added to the flask and removed under reduced pressure again. The flask was put in an ice bath and benzyl bromide (3.11 mmol, 560.4 mg) was added dropwise. The reaction was run at room temperature for 18 h then partitioned between water and ether. The aqueous layer was extracted by ether three times then the ether extracts were combined and dried over NaSO4. The solution was decanted and the solvent was removed

under reduced pressure. The yield is 523 mg, 3.21 mmol, 93% yield. 1H NMR:(400 MHz, CDCl3) δ ppm 7.37 (tt, J = 7.1, 4.0 Hz, 5H), 5.26 – 5.14 (m, 2H), 4.40 – 4.27 (m,

1H), 2.79 (s, 1H), 1.44 (dd, J = 6.9, 3.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ppm

175.54, 135.18, 128.65, 128.63, 128.54, 128.52, 128.24, 128.23, 128.17, 77.35, 77.23, 77.03, 76.71, 69.49, 69.37, 67.30, 67.25, 66.83, 66.73, 66.70, 20.42, 20.37, 20.07, 16.85.

mp range = 36-37oC. 1H NMR:(400 MHz, CDCl3) δ ppm 8.39 (s, 1H), 7.69 – 7.60 (m, 6H), 7.51 – 7.35 (m, 9H), 7.32 – 7.17 (m, 4H), 7.07 (ddt, J = 7.1, 6.4, 1.8 Hz, 1H), 4.32 (d, J = 3.0 Hz, 1H), 2.19 (hd, J = 6.9, 3.0 Hz, 1H), 0.97 (dd, J = 24.2, 6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 170.70, 137.06, 135.58, 132.95, 130.64, 128.90, 128.29, 128.26, 128.23, 124.33, 119.64, 79.52, 77.40, 77.08, 76.76, 33.32, 18.91, 16.79. . IR (neat, cm-) 3393, 3070, 3051, 2963, 2930, 1671, 1601, 1521, 1441, 1428, 1315, 1178, 1116, 1050, 872, 822, 740, 692. HRMS (ESI) calculated for (C29H29NO2Si) : 451.1969,

Observed: 451.1968. Optical Rotation [α]25

D: = +43.9 (c = 8.3) CHCl3 N-Phenyl-2-((triphenylsilyl)oxy)butanamide mp range = 56-59 oC. 1H NMR:(300 MHz, CDCl3) 8.57 (s, 1H), 7.69 – 7.20 (m, 19H), 7.09 (tt, J = 7.3, 1.3 Hz, 1H), 5.27 (d, J = 1.4 Hz, 1H), 4.49 (td, J = 4.7, 1.4 Hz, 1H), 2.02 – 1.83 (m, 1H), 1.83 – 1.55 (m, 1H), 0.94 (td, J = 7.4, 1.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ ppm 171.01, 158.70, 137.18, 135.39, 132.97, 130.67, 130.61, 128.96, 128.29, 128.25, 128.21, 124.37, 119.59, 77.47, 77.04, 76.62, 75.58, 75.46, 27.92, 8.33. IR (neat, cm-) 3389, 3069, 2969, 2933, 1689, 1600, 1521, 1442, 1428, 1312, 1237, 1187, 1115, 1012, 885, 833, 743, 692. HRMS (ESI) calculated for (C28H27NO2Si): 437.1811,

Observed: 437.1811. Optical Rotation [α]25

N-Phenyl-2-((triphenylsilyl)oxy)propanamide . mp range = 94-97 oC 1H NMR:(400 MHz, CDCl3) δ ppm 8.68 (s, 1H), 7.68-7.06 (m, 20H), 4.51 (q, J = 6.7 Hz, 1H), 1.46 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 171.78, 137.28, 135.33, 132.94, 130.66, 129.00, 128.26, 127.89, 124.37, 119.54, 77.35, 77.03, 76.72, 71.37, 21.71. IR (neat, cm-) 3390, 3069, 3024, 2929, 2686, 1600, 1522, 1441, 1428, 1368, 1313, 1240, 1187, 1115, 1079, 1048, 1028, 970, 910, 787, 739, 710. HRMS (ESI) calculated for (C27H25NO2Si): 423.1651, Observed: 423.1655.

Optical Rotation [α]25 D: = +30.8 (c = 8.3) CHCl3 Benzyl 2-((triphenylsilyl)oxy)propanoate//YZ-2-87. Oil liquid, 1 H NMR:(300 MHz, CDCl3) δ ppm 7.67 – 7.52 (m, 6H), 7.48 – 7.27 (m, 12H), 7.21 (dd, J = 6.9, 3.3 Hz, 2H), 4.98 (d, J = 3.4 Hz, 2H), 4.49 (q, J = 6.8 Hz, 1H), 1.47 (d, J = 6.7 Hz, 3H).13C NMR (75 MHz, CDCl3) δ ppm 173.28, 135.58, 135.51, 135.39, 133.71, 130.14, 130.07, 128.50, 128.25, 128.24, 128.22, 127.89, 127.86, 77.46, 77.34, 77.03, 76.61, 69.03, 66.49, 21.23. IR (neat, cm-) 3430, 2957, 1722, 1178, 1118, 1033, 989, 919, 854, 743, 711. HRMS (ESI) calculated for (C28H27O3Si-C6H5) : 361.1254, Observed:

361.1260. Optical Rotation [α]25