Copyright WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000. Supporting Information for Angew. Chem. Int. Ed. Engineering the Catalysts for Enantioselective Addition of Diethylzinc to Aldehydes with Racemic Amino Alcohols: Nonlinear Effect in Asymmetric Deactivation of Racemic Catalysts Jiang Long and Kuiling Ding* General Considerations. 1H NMR spectra were measured on a Bruker AM300 NMR spectrometer (300 MHz) with CDCl3 as solvent and recorded in ppm relative to internal tetramethylsilane standard. Coupling constants, J, are listed in hertz. Mass spectra (EI, 70 ev) were taken on a HP5989A spectrometer. Elemental analysis was preformed with an Elemental VARIO EL apparatus. Melting points are uncorrected. Optical rotations were measured on a Perkin- Elmer 341 automatic polarimeter. HPLC analyses were carried out on a JASCO 1580 liquid chromatograph with a JASCO CD- 1595 detector and AS-1555 autosampler. GC analyses were performed on a Perkin-Elmer AutoSystem XL gas chromatograph with FID detection. Hexane, tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl under argon and degassed before use. Dichloromethane was distilled from CaH2 before use. All reactions were performed under argon. Preparation and Characterization of Chiral Additives (AA1-AA13) and Racemic Amino Alcohols (DB1-DB5). Scheme 1 NH2 NH LiAlH4 2 OH R * COOH THF R * Reflux AA1-AA7 (S)-2-Amino-1-propanol (L-alaninol) (AA1) 1 A 50-mL round-bottomed flask was charged with a suspension of lithium aluminum hydride (0.34 g, 9 mmol) in 10 mL of dry tetrahydrofuran. The mixture was cooled to 0 oC in an ice bath and L-alanine (4.5 mmol) was added in portions during 1 h. After the addition was complete, the ice bath was removed, the reaction mixture was warmed to room temperature and stirred under reflux for 17 h. The reaction mixture was then cooled to 0oC in an ice bath again and diluted with diethyl ether (10 mL). The reaction was quenched with water (0.3 mL), aqueous 15 % sodium hydroxide (0.3 mL) and water (1.0 mL) respectively. The solution was stirred for 30 min and the white precipitate was filtered through celite. The filter cake was washed with diethyl ether (3×10 mL) and the filtrates are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford AA1 (300 mg, 88%) as a colorless liquid. 1 H NMR (300 MHz, CDCl3) d = 1.04 (d, 3H, J = 6.5 Hz), 2.65 (bs, 1H), 2.95-3.05 (m, 1H), 3.21-3.27 (m, 1H), 3.50-3.55 (m, 1H). Chiral additives AA2-AA7 were prepared from the corresponding amino acids by a similar procedure to that described above. (S)-2-Amino-3-methyl-1-butanol (L-valinol) (AA2) 25 [1] Yield: 100%; [a]D + 14.4 (c = 0.51, EtOH; literature: 21 1 [a]D + 17 (c = 10, ethanol)); H NMR (300 MHz, CDCl3) d = 0.91 (d, 3H, J = 6.8 Hz), 0.93 (d, 3H, J = 6.8 Hz), 1.53- 1.65 (m, 1H) 2.27 (bs, 3H), 2.54-2.60 (m, 1H), 3.28-3.34 (m, 1H),3.62-3.67 (m, 1H). (S)-2-Amino-4-methyl-1-pentanol (L-leucinol) (AA3) 1 Yield: 100%; H NMR (300 MHz, CDCl3) d = 0.88-0.94 (m, 6H), 1.16-1.22 (m, 2H), 1.63-1.75 (m, 1H) 2.36 (bs, 3H), 2.88- 2.93 (m, 1H), 3.21-3.28 (m, 1H), 3.54-3.59 (m, 1H). (S)-2-Amino-3,3-dimethyl-1-butanol (L-tert-leucinol) (AA4) Yield: 98%; m.p. 34-36oC (literature:[1] 33-35 oC); 1H NMR (300 MHz, CDCl3) d = 0.90 (s, 9H), 2.72 (bs, 3H), 3.10-3.22 (m, 1H), 3.53-3.80 (m, 2H). (R)-2-Amino-2-phenylethanol (D-phenylglycinol) (AA5) o [1] o 25 Yield: 90%; m.p. 74-75 C (literature: 75-77 C); [a]D – [1] 20 35.0 (c = 1.0, 1 N HCl; literature: [a]D –31.70 (c = 1 0.76, 1 N HCl)); H NMR (300 MHz, CDCl3) d = 2.29 (bs, 3H), 2 3.52-3.58 (m, 1H), 3.70-3.75 (m, 1H), 4.01-4.06 (m, 1H), 7.26-7.36 (m, 5H). (S)-2-Amino-3-phenyl-1-propanol (L-phenylalaninol) (AA6) o [1] o 25 Yield: 92%; m.p. 88-90 C (literature: 92-94 C); [a]D – [2] 20 24.6 (c = 0.334, EtOH; literature: [a]D – 25.6 (c = 1 1.037, EtOH)); H NMR (300 MHz, CDCl3) d = 2.19 (bs, 3H), 2.48-2.56 (m, 1H), 2.76-2.82 (m, 1H), 3.07-3.15 (m, 1H), 3.36-3.42 (m, 1H), 3.61-3.65 (m, 1H) 7.17-7.36 (m, 5H). (S)-2-Pyrrolidinemethanol (L-prolinol) (AA7) 25 [3] Yield: 94%; [a]D + 22.5 (c = 0.325, C6H5CH3; literature: 20 1 [a]D + 30 (c = 1.6, C6H5CH3)); H NMR (300 MHz, CDCl3) d = 1.30-1.45 (m, 1H), 1.70-1.88 (m, 3H), 2.90 (t, 3H, J = 6.7 Hz), 3.20-3.29 (m, 1H), 3.36-3.39 (m, 1H), 3.53-3.62 (m, 1H). Scheme 2 NH2 NH SOCl . (1) PhMgBr 2 2 NH2 HCl OH (2) + R * R COOH MeOH H3O Ph * R * COOMe Ph AA8-AA13 (S)-2-Amino-1,1-diphenyl-1-propanol (AA8) (a) L-Alanine methyl ester hydrochloride To a 50-mL dry 2-necked round-bottomed flask equipped with a dropping funnel and a condenser were added L-alanine (1.0 g, 11.2 mmol) and 25 mL of absolute methanol, and then the flask was immersed in an ice-bath. Thionyl chloride (0.9 mL, 12 mmol) was added dropwise under stirring during half an hour. The mixture was warmed to room temperature gradually and heated to 40-50oC for 3 h. After standing overnight at room temperature, the mixture was concentrated to give L-alanine methyl ester hydrochloride (1.6 g, 100 %) as a white crystalline solid, m.p. 108-109oC (literature:[1] 109-111oC). (b) (S)-2-Amino-1, 1-diphenyl-1-propanol (AA8) A 500-mL dry 3-necked round-bottomed flask was equipped with a dropping funnel, a condenser and an argon-inlet tube from which the flask was flushed with argon. Magnesium (2.1g, 89 mmol) and a catalytic amount of iodine were added and then about 1/5 of a solution of bromobenzene (14.7 g, 94 mmol) in 90 mL dry THF was charged to initiate the reaction followed by dropwise adding the rest solution over 1h. After the reaction mixture was stirred under reflux for 30 min, the flask was cooled to 0oC in an ice bath. L- 3 Alanine methyl ester hydrochloride (0.84 g, 6 mmol) was added portionwise during 1h. The mixture was stirred overnight at room temperature before it was carefully quenched with saturated ammonium chloride solution (70 mL) and extracted with ethyl acetate (4×40 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel (EtOAc/hexane, 1:1) to yield AA8 (1.2g, 88%) as a white o [4] o 25 solid, m.p. 99-101 C (literature: 101.5-102.5 C); [a]D – [4] 25 95.2 (c = 1.0, CHCl3; literature: [a]D – 82.3 (c = 1.6776, 1 CHCl3)); H NMR (300 MHz, CDCl3) d = 0.95 (d, 3H, J = 6.3 Hz), 1.20-1.70 (bs, 2H), 2.16 (s, 1H), 4.14 (q, 1H, J = 6.3 Hz), 7.15-7.62 (m, 10H). Chiral additives AA9-AA13 were prepared by using an analogous procedure as for the preparation of AA8. (S)-2-Amino-1, 1-diphenyl-3-methyl-1-butanol (AA9) o [5] o 25 M.p. 94-96 C (literature: 94-95 C); [a]D – 117.1 (c = [5] 25 1.0, CHCl3; literature: [a]D – 127.7 (c = 0.639, CHCl3)); 1 H NMR (300 MHz, CDCl3) d = 0.92-0.95 (m, 6H), 1.05-1.72 (bs, 2H), 1.75-1.88 (m, 1H), 3.91 (d, 1H, J = 1.6 Hz), 7.14-7.61 (m, 10H). (S)-2-Amino-1, 1-diphenyl-4-methyl-1-pentanol (AA10) o [6] o 25 M.p. 137-139 C (literature: 132-134 C); [a]D – 81.3 (c = [6] 25 1.0, CHCl3; literature: [a]D – 95.12 (c = 1.006, CHCl3)); 1 H NMR (300 MHz, CDCl3) d = 0.85-0.90 (m, 6H), 1.03-1.12 (m, 1H), 1.22-1.31 (m, 1H), 1.25-1.70 (bs, 2H), 1.54-1.61 (m, 1H), 3.99 (dd, 1H, J = 2.0, 10.2 Hz), 7.18-7.62 (m, 10H). (R)-2-Amino-1,1,2-triphenylethanol (AA11) Yield: 46%; m.p. 129-131 oC (literature:[7] 131-133 oC); 25 [7] 22 []D + 219.1 (c = 1.0, CHCl3; literature: []D + 235.0 1 (c = 1.0, CHCl3)); H NMR (300 MHz, CDCl3) = 4.75 (bs, 1H), 5.01 (s, 1H), 7.01-7.77 (m, 15H). (S)-2-Amino-1,1,3-triphenyl-1-propanol (AA12) o [6] o 25 Yield: 76%; m.p. 148-150 C (literature: 144-145 C); [a]D [6] 25 – 87.4 (1.0, CHCl3; literature: [a]D – 88.50 (c = 0.604, 1 CHCl3)); H NMR (300 MHz, CDCl3) d = 1.33 (m, 2H), 2.40-2.49 (m, 1H), 2.62-2.68 (m, 1H), 4.17 (dd, 1H, J = 2.6, 10.8 Hz), 7.17-7.67 (m, 15H).