Supporting Information for. A General Catalyst for the Asymmetric Strecker Reaction. Matthew S. Sigman, Petr Vachal and Eric N.

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1 Copyright WILEY-VC Verlag Gmb, Weinheim, 2000 Angew. Chem Supporting Information for A General Catalyst for the Asymmetric Strecker Reaction Matthew S. Sigman, Petr Vachal and Eric. Jacobsen* arvard University, Department of Chemistry and Chemical Biology, Cambridge, MA General: Fmoc-amino acids were purchased from Advanced Chemtech and used as received. TMSC was purchased from Aldrich and distilled before use. TBSC was purchased from Aldrich and used as received. (R,R)-1,2-Diaminocyclohexane [1] was resolved by literature methods. Salicylaldehydes were synthesized according to published procedures. [1] All solid supported coupling reactions were carried out in fritted 1.5 ml or 10 ml disposable chromatography columns. Reactions were filtered upon completion and rinsed with DMF, TF, C 2 Cl 2 and toluene unless otherwise indicated. The progress of all amino acid coupling reactions was monitored by UV by quantification of dibenzofulvene released from 2 mg resin samples upon Fmoc cleavage. Thiourea formation was monitored by IR for disappearance of isothiocyanate. All imines were prepared as desribed below except for 1v which was prepared using a literature procedure. [2] Imines 1a, [3] 1b, [4] 1c, [3] 1f, [5] 1i, [6] 1m, [7] 1n, [8] 1r, [8] and 1s, [8] have been reported previously. Solid Phase Thiourea Library Synthesis: 2 a,b,c R 1 2 d,e R 1 S R 2 R 3 2 f R 1 S R 2 R 3 R 4 R 5 Synthesis utline: (a) Aminomethylpolystyrene beads split into appropriate number of vials. (b) 2.5 eq Fmoc-amino acid, 2.5 eq BTU, 5 eq DIPEA, 2.5 eq BT, DMF, 2h. (c) 30% piperdine in DMF, 30 min. (d) 0.5 M thiocarbonyl diimidazole, TF, 30 min (rinsed with TF and C 2 Cl 2 only). (e) 0.5 M Diamine, TEA, DMF, 3h. (f) aldehyde, DMF, 1h. S-1

2 Library: R 1 S R 2 R 3 R 5 R 4 Leu Ile Tyr Val Chg t-leu ap L-Amino Acids Leucine Isoleucine Tyrosine( t Bu) Valine Cyclohexylglycine tert-leucine apthylglycine (R, R)-Diamine Turn Element 2 C 2 Aldehydes C C C C C t Bu t Bu t Bu t Bu TIPS t Bu t Bu C C C C C t Bu C 3 t Bu Br t Bu C Library Size : 70 Compounds Library Screening: In 500 µl test tubes, 1mg of resin (one library member per vial, 4.4 mol%), 50 µl of a 200 mm solution of imine (1b) in toluene, and 50 µl of a 250 mm solution of TBSC in toluene were combined. Each vial was sealed with a rubber septum and agitated for 15 h. After this time, a 20 µl aliquot was quenched in a 400 µl solution of trifluoroacetic anhydride (100 mm) in dichloroethane. Conversions and enantioselectivities were determined by autosampling GC equipped with a 20 m x 0.25mm γ-ta chiral column (γ-ta, 112 C isothermal, t r (major) = 4.4 min, t r (minor) = 6.4 min). 80% 70% 60% 50% 40% 30% 20% 10% 0% Aldehyde ap Tyr Leu Ille Val Chg t-leu Amino Acid S-2

3 Imine Formation: General procedure for allyl substituted imines: To a flame-dried 50 ml round bottom flask, were added activated 3 molecular sieves (2g) and 20 ml C 2 Cl 2 (freshly distilled from Ca 2 ). To this solution, substrate (20 mmol)was added followed by syringe addition of allylamine (1.3 equiv., 26 mmol). After 4 hr, the sieves were removed by filtration and washed with C 2 Cl 2 (2 X 10ml). The filtrate was collected and solvent was removed in vacuo. Further purification was accomplished by vacuum distillation. General procedure for benzyl substituted imines: To a flame dried 50 ml round bottom flask, were added activated 3 molecular sieves (2g) and 20 ml C 2 Cl 2 (freshly distilled from Ca 2 ). To this solution, benzyl amine (20 mmol)was added followed by slow syringe addition of aldehyde (1 equiv., 20 mmol). After 4 hr, the sieves were removed by filtration and washed with C 2 Cl 2 (2 X 10ml). The filtrate was collected and solvent was removed in vacuo. Further purification was accomplished by vacuum distillation. C (1d): IR (thin film) 2836, 1646, 1467, 1266 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.22 (s, 1), 7.37 (s, 1) 7.26 (m, 2), 6.96 (ddd, J=1.4, 2.7, 7.9 z, 1), 6.06 (ddd, J=5.7, 10.4, 17.2 z, 1), 5. (ddd, J-1.6, 3.4, 17.2 z, 1), 5.15 (ddd, J=1.4, 3.1, 10.3 z, 1), 4.24 (dd, J=1.5, 5.7 z, 2), 3.80 (s, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 161.6, 159.7, 137.4, 135.7, 129.3, 121.3, 117.3, 115.8, 111.3, 63.2, 55.1; RMS m/z (M + ) calcd , obsd (1e): IR (thin film) 2843, 1648, 1586, 1436 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.73 (s, 1), 8.00 (dd, J=1.7, 7.7 z, 1), 7.34 (ddd, J=1.8, 7.0, 8.3 z, 1), 6.96 (t, J=7.5 z, 1), 6.85 (d, J=8.4 z, 1), 6.07 (ddt, J=5.7, 10.3, 17.2 z, 1), 5. (dd, J=1.7, 17.2 z, 1), 5.13 (dd, J=1.6, 10.3 z, 1), 4.24 (dd, C J=1.6, 5.7 z, 2), 3.79 (s, 3); 13 C MR { 1 3 } (100 Mz, CDCl 3 ) δ 158.5, 157.6, 136.0, 131.6, 127.0, 124.4, 120.5, 115.5, 110.7, 63.5, 55.1; RMS m/z (M + ) calcd , obsd C (1g): IR (thin film) 3061, 2844, 1648, 1586, 1436 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.20 (s, 1), 7.61 (s, 1), 7.51 (d, J=7.5 z, 1), 7.27 (m, 1), 7.19 (d, J=7.6 z, 1), 6.07 (ddt, J= 5.7, 10.3, 17.1, 1), 5.25 (dd, J=1.7, 17.2 z, 1), 5.17 (dd, J=1.6, 10.3 z, 1), 4.22 (dd, J=1.4, 5.7 z, 2), 2.35 (s, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 161.6, 137.8, 135.8, 135.6, 131.1, 128.1, 128.0, 125.3, 115.5, 63.1, 20.8; RMS m/z (M+) + calcd , obsd (1h): IR (thin film) 3072, 2880, 1542, 1435 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.61 (s, 1), 7.93 (dd, J=1.2, 7.6 z, 10, 7.29 (m, 2), 7.19 (d, J=7.4 z, 1), 6.12 (ddt, J=5.6, 10.3, 17.2 z, 1), 5.27 (ddd, J-1.7, 3.5, 17.2 z, 1), 5.18 (ddd, J-1.6, 3.2, 10.3 z, 1), 4.29 (dd, J-1.4, 5.6 z, 2), 2.52 (s, 3); C 13 C MR { 1 3 } (100 Mz, CDCl 3 ) δ 160.4, 137.4, 136.0, 134.0, 130.7, 130.1, 127.4, 126.1, 115.7, 63.9, 19.2; RMS m/z (M + ) calcd , obsd S-3

4 Br (1j): IR (thin film) 2849, 1648, 1566 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.05 (s, 1), 7.83 (s, 1), 7.50 (d, J=7.7 z, 1), 7.40 (d, J=8.1 z, 1), 7.19 (m, 1), 5.97 (ddt, J=5.7, 10.3, 17.2 z, 1), 5.16 (dd, J=1.7, 17.2 z, 1), 5.08 (dd, J=1.5, 10.3 z, 1), 4.15 (dd, J=1.3, 5.7 z, 2); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 159.6, 137.7, 135.1, 133.0, 130.2, 129.6, 126.5, 122.4, 115.8, 62.9; RMS m/z (M + ) calcd , obsd (1k): IR (thin film) 2899, 1636, 1438 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.64 (s, 1), 8.04 (dd, J=1.6, 7.7 z, 1), 7.52 (d, J=8.0 z, 1), 7.22 (m, 2), 6.06 (m, 1), 5.24 (dd, J=1.7, 17.1 z, 1), 5.16 (dd, J=1.4, 10.3 z, 1), 4.28 (dd, J=1.4, 5.7 z, 2); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 160.6, Br 135.4, 134.3, 132.8, 131.6, 128.6, 127.4, 124.9, 116.1, 63.3; RMS m/z (M + ) calcd , obsd (1l): IR (thin film) 2955, 1650, 1462, 1372 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.28 (s, 1), 7.71 (d, J = 10.4 z, 2), 7.45 (d, J = 10.4 z, 2), (s, 1), 6.06 (ddd, J = 5.6, 10.3, 17.1 z, 1), 5.24 (dappq, J = 1.5, 17.1 z, 1), 5.16 (dappq, J = 1.5, 10.3 z, 1), 4.26 (dappq, J = 1.5, 5.6 z, 2), 1.35 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 161.7, 153.9, 135.9, 133.4, 127.9, 125.4, 115.6, 63.4, 34.7, 31.1 ; RMS m/z (M + ) calcd , obsd (1o): IR (thin film) 2925, 1667, 1443 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.41 (d, J = 4.8 z, 1) (s, 1), 5.83 (ddd, J = 5.6, 10.3, 17.2 z, 1), 5.01 (dappq, J = 1.7, 17.2 z, 1), 4.95 (dappq, J = 1.5, 10.3 z, 1), 4.27 (dappq, J = 1.5, 5.6 z, 2), 2.08 (m, 1), (m;10 ); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 169.6, 135.9, 115.1, 63.0, 43.2, 29.4, 25.7, 25.2 ; RMS m/z (M + ) calcd , obsd (1p) IR (thin film) 2919, 1646, 1628, 1495, 1451, 1434 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ; 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 7.94 (s, 1), 7.33 (m, 5), 6.21 (m, 1), 4.71 (s, 2), 2.43 (m, 2), 2.25 (m 2), 1.70 (m, 4); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 164.8, 139.2, 128.3, 127.8, 126.7, 65.2, 49.3, 30.9, 29.6; RMS m/z (M + ) calcd , obsd (1q): IR (thin film) 2959, 1665, 1366 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.28 (t, J = 5.7 z, 1), 7.31 (m, 5), 4.59 (s, 2), 2. (d, J = 5.7 z), 1.01 (s, 9z); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ , 139.2, 128.3, 127.8, 126.7, 65.2, 49.3, 30.9, 29.6; RMS m/z (M+ ) + calcd , obsd (1t): IR (thin film) 3029, 2827, 1664, 1494, cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ (m, 5), 7.10 (d, J = 7.7 z, 1), 4.53 (s, 2), 1.74 (m, 1), 0.89 (m, 2), 0.71 (m, 2); 13 C MR { 1 } (100 Mz, S-4

5 CDCl 3 ) δ 167.7, 139.2, 128.0, 127.4, 126.4, 64.3, 15.9, 5.7; RMS m/z (M + ) calcd , obsd (1u): IR (thin film) 2925, 1667, 1471cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.49 (d, J = 5.1 z, 1) (s, 1), 5.88 (ddd, J = 5.6, 10.3, 17.1 z, 1), 5.04 (dappq, J = 1.2, 17.2 z, 1), 4.99 (dappq, J = 1.4, 10.3 z, 1), 4.27 (dappq, J = 1.4, 5.6 z, 2), 2.33 (m, 1), (m;14 ); 13 C MR {} 100 Mz, CDCl 3 ) δ 170.6, 136.0, 115.2, 62.9, 43.2, 29.0, 26.7, 25.9, 24.9; RMS m/z (M + ) calcd , obsd Asymmetric Strecker general procedure (C): In a flamed dried 5 ml round bottom flask equipped with a stir bar, 5 mg of catalyst (2 mol%, mmol) and 1.6 ml of toluene were combined. Substrate (0.4 mmol, 200mM final concentration) was added by syringe addition. The reaction was stirred at ambient temperature until catalyst completely dissolves. The reaction flask was cooled to 70 ºC by means of a constant temperature bath and 1.3 equiv. of C was added by slow syringe addition (0.52 mmol, 340 µl) of a 1.54 M solution in toluene. After 20h, the reaction was allowed to warm to ambient temperature and quenched with 103 µl of trifluoroacetic anhydride (0.73 mmol, 1.5 equiv). The solvents were removed in-vacuo and the resulting residue was purified by flash chromatography (3:2 hexanes:c 2 Cl 2 ) to afford the Strecker Adduct Asymmetric Strecker general procedure (TMSC + Me): To a flame-dried 10 ml roundbottom flask equipped with a stir bar was added 5 mg catalyst (0.008 mmol, 0.02 equiv.), 1.6 ml toluene and substrate (0.4 mmol, 200 mm final concentration) was added by syringe addition. The reaction was stirred at ambient temperature until catalyst completely dissolved and then cooled to 70 ºC by means of a constant temperature bath. In a flame-dried 5 ml recovery flask equipped with stir bar, add 200 µl toluene and 80 µl TMSC (0.6 mmol; freshly distilled under nitrogen). This solution is cooled to ºC using an ice bath and 24 µl C 3 (0.6 mmol; freshly distilled from Ca 2 under nitrogen) was added. The solution was allowed to stir for one hour and then added to reaction flask by slow syringe addition. After 20h, the reaction was allowed to warm to ambient temperature and quenched with 103 µl of trifluoroacetic anhydride (0.73 mmol, 1.5 equiv). The solvents were removed in-vacuo and the resulting residue was purified by flash chromatography to afford the Strecker Adduct. (2a): Product was obtained in 74% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 95% ee by Chiral PLC F 3 C analysis (Chiralcel AS, 5% IPA/exanes, 1 ml./min, t r (minor) = 6.0 min, t r (major) = 9.8 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2936, C 2249, 1701cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.45 (m, 5), 6.65 (s, 1), 5.66 (m, 1), 5.19 (d, J = 10.2 z, 1), 5.13 (d, J = 17.0 z, 1) 4.15 (dd, J = 4.7, 17.0 z, 1), 3.91 (dd, J = 6.0, 17.0 z, 1); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (q, J = 38 z),131.1, 130.1, 130.0, 129.4, 127.8, 120.3, (q, J = 288 z), 115.2, 49.8, 48.6; RMS m/z (M ) calcd , obsd S-5

6 (2b): Product was obtained in 75% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 95% ee by Chiral GC F 3 C analysis (γ-ta, 112 C isothermal, t r (minor) = 3.8 min, t r (major) = 5.5 min); [α] D = 59.8 (c = 1.0, C 2 Cl 2 ); IR(thin film) 2972, 1705 cm 1 ; 1 C MR (400 Mz, CDCl 3 ) δ 5.87 (m, 1), 5.33 (d, J = 10.4 z, 1), 5.25 (d, J = 17.2 z, 1), 4.25 (s(br), 2), 1.16 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 132.0, 119.0, (q, J = 286 z), 115.3, 56.7, 40.5, 38.1, 26.9; RMS m/z (M ) calcd , obsd (2c): Product was obtained in 98% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 96% ee by Chiral F 3 C PLC analysis (Chiralcel AS, 5% IPA/exanes, 1 ml./min, t r (minor) = C 9.4 min, t r (major) = 10.9 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2940, 1701, 1613 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.36 (d, J = 8.6 z, 2), 6.94 (d, J = 8.6 z, 2), 6.57 (s, 1), 5.65 (m, 1), 5.19 (d, J = 10.2 z, 1), 5.14 (d, J = 17.2 z, 1), 4.15 (dd, J = 4.2, 17.0 z, 1), 3.87 (dd, J = 6.2, 17.0 z, 1), 3.83 (s, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 160.9, (q, J = 38 z), 131.4, 129.5, 121.9, 120.1, (q, J = 288 z), 115.6, 114.8, 55.5, 49.4, 48.3; RMS m/z (M + ) calcd , obsd C (2d): Product was obtained in 99% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 93 % ee by Chiral PLC analysis (Chiralcel AS, 10% IPA/exanes, 1 ml./min, t r (minor) = 5.7 min, C t r (major) = 10.9 min; [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2945, 1703, 1611, 1493, 1437, 1213, 1188, 1146, 1119 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.35(m, 1, 6.99 (m, 3) 6.59 (s, 1), 5.68 (m, 1), 5.19 (d, J = 10.3 C 3 z, 1), 5.15 (d, J = 16.1 z, 1), 4.15 (dd, J = 4.9, 17.0 z, 1), 3.90 (dd, J = 6.4, 17.0 z, 1), 3.81 (s, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 160.3, (q, J = 37 z), 131.4, 131.1, 130.5, 120.2, 119.8, (q, J = 288 z), 115.3, 115.1, 111.7, 55.3, 49.6, 48.5; RMS m/z (M + ) calcd , obsd F 3 C (2e): Product was obtained in 93% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 76% ee by Chiral PLC F 3 C analysis (Chiralcel AS, 10 % IPA/exanes, 1 ml./min, t r (minor) = 5.1 min, C C 3 t r (major) = 10.7 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2946, 1702, 1485, 1256, 1209 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.69 (d, J=7.6 z, 1), 7.45 (m, 1), 7.04 (t, J=7.6 z, 1), 6.92 (d, J=5.2 z, 1), 6.57 (s, 1), 5.68 (m, 1), 5.18 (d, J=10.2 z, 1), 5.18 (d, J=17.1 z, 1), 4.08 (dd, J=5.4, 17.0 z, 1h), 3.85 (m, 4); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (q, J=38 z), 132.3, 131.9, 131.4, 130.6, 130.3, 29.7, 120.7, 119.7, 117.7, 117.4, (q, J=288 z), 115.7, 110.8, 55.5, 48.4, 46.5; RMS m/z (M + ) calcd , obsd F 3 C (2f): Product was obtained in 99% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 95% ee by Chiral PLC analysis (Chiralcel AS, 5% IPA/exanes, 1 ml./min, t r (minor) = C S-6

7 5.5 min, t r (major) = 7.3 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2930, 2249, 1703 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.32 (d, J = 7.9 z, 2), 7.24 (d, J = 7.9 z, 2), 6.60 (s, 1), 5.68 (m, 1), 5.20 (d, J = 10.2 z, 1), 5.14 (d, J = 17.2 z, 1), 4.14 (dd, J = 4.8, 17.0 z, 1), 3.86 (dd, J = 6.5, 17.0 z, 1), 2.39 (s, 3); ); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 140.3, 131.2, 130.0, 127.8, 127.0, 120.2, (q, J =286 z), 115.4, 49.5, 48.4, 21.1; RMS m/z (M + ) calcd , obsd (2g): Product was obtained in 97% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 96% ee by Chiral PLC F 3 C analysis (Chiralcel AS, 5% IPA/exanes, 1 ml./min, t r (minor) = 5.0 min, t r (major) = 9.0 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2930, C 1701, 1289, 1212, 1189, 1153, 1127 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.34 (m, 1), 7.24 (m, 3), 6.60 (s, 1), 5.68 (m, 1), 5.20 (d, J = 10.2 z, 1), 5.14 (d, J = 17.1 z, 1), 4.15 (dd, J = 5.0, 17.0 z, 1), 3.88 (dd, J = 6.4, 17.0 z, 1), 2.39 (s, 3); ); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 139.4, 131.2, 130.7, 129.9, 129.2, 128.4,124.9, (q, J =287 z), 115.3, 49.7, 48.4, 21.3; RMS m/z (M + ) calcd , obsd (2h): Product was obtained in 96% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 95% ee by Chiral GC F 3 C analysis (γ-ta, 100 C, isothermal, t r (minor) = 43 min, t r (major) = 45.6 min);; [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) cm -1 ; 1 MR (400 Mz, C CDCl 3 ) 1 MR (400 Mz, CDCl 3 ) δ 7.71 (d, J=7.6 z, 1), 7.39 (m, 1), 7.32 (m, 1), 7.25 (d, J=7.4 z, 1), 5.59 (m, 1), 5.14 (d, J=10.2 hz, 1), 4.93 (d, J=17.1 z, 1), 4.09 (dd, J=3.1, 16.9 hz, 1), 3.59 (dd, J= 7.2, 16.9 z, 1), 2.14 (s, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (q, J=37 z), 137.0, 131.4, 130.9, 130.5, 129.6, 127.0, 126.7, 120.2, (q, J=288 z), 115.9, 48.1, 47.3, 18.4; RMS m/z (M + ) calcd , obsd (2i): Product was obtained in 89% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 89 % ee by Chiral F 3 C PLC analysis (Chiralcel AS, 5% IPA/exanes, 1 ml./min, t r (minor) = 6.0 min, t r (major) = 7.8 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) C 2936, 1701 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.56 (d, J = 8.4 z, 2), Br 7.31 (d, J = 8.4 z, 2), 6.52 (s, 1), 5.65 (m, 1), 5.21 (d, J = 10.2 z, 1), 5.15 (d, J = 17.1 z, 1), 4.15 (dd, J = 5.5, 17.0 z, 1), 3.92 (dd, J = 6.3, 17.0 z, 1); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 157.7, 132.7, 131.0, 129.5, 124.5, 120.8, 117.4, 114.8, 114.5, 49.6, 49.0; RMS m/z (M + ) calcd , obsd F 3 C Br C (2j): Product was obtained in 87% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 90% ee by Chiral PLC analysis (Chiralcel AS, 7% IPA/exanes, 1 ml./min, t r (minor) = 5.3 min, t r (major) = 7.9min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2933, 1703, 1476, 1420, 1153 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.57 (m, 2), 7.39 (m, 1), 7.31 (m, 1), 6.54 (s, 1), 5.67 (m, 1), 5.22 (d, J = 10.2 z, S-7

8 1), 5.17 (d, J = 17.1 z, 1), 4.16 (dd, J = 5.4, 16.9 z, 1), 3.92 (dd, J = 6.0, 16.9 z, 1); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 133.3, 132.5, 130.9, 130.8, 126.5, 1.4, 120.8, (q, J = 288 z),114.7, 49.5, 49.1 RMS m/z (M + ) calcd , obsd (2k): Product was obtained in 88% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 94 % ee by Chiral PLC F 3 C analysis (Chiralcel AS, 0.5% IPA/exanes, 1 ml./min, t r (major) = 12.9 min, t r (minor) = 13.0 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 1703, C 1438, 1287, 1153 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.82 (dd, J=1.3, 7.7 z, Br 1), 7.63 (d, J=7.9 z, 1), 7.45 (t, J=7.4 z), 7.36 (m, 1), 6.59 (s, 1), 5.64 (m, 1), 5.13 (d, J=10.2 z, 1), 4.97 (d, J=17.1 z, 1), 4.11 (dd, J=4.8, 17.1 z, 1), 3.60 (dd, J=6.6, 17.1 z, 1); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (q, J=38 z), 133.8, 132.0, 131.7, 130.9, 128.5, 128.0, 1.9, 120.1, (q, J=287 z), 65.7, 50.6, 48.0; RMS m/z (M + ) calcd , obsd (2l): Product was obtained in 89% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 97 % ee by Chiral F 3 C PLC analysis (Chiralcel AD, 0.6% IPA/exanes, 1 ml./min, t r (major) = 9.0 min, t r (minor) = 11.4 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin C film) 2966, 1704, 1213, 1154 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.47 (d, J = 8.2 z, 2), 7.37 (d, J = 8.2 z, 2), 6.60 (s, 1), 5.69 (m, 1), 5.21 (d, J = 10.4 z, 1), 5.15 (d, J = 17.2 z, 1), 4.16 (dd, J = 4.7, 17.0 z, 1), 3.92 (dd, J = 6.2, 17.0 z, 1), 1.33 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 38 z), 153.5, 131.2, 127.7, 127.0, 126.3, 120.1, (q, J = 288 z),115.4, 49.5, 48.4, 34.7, 31.1; RMS m/z (M + ) calcd , obsd (2m): Product was obtained in 88% yield as a white solid after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 95% ee by Chiral GC F 3 C Ph C analysis (γ-ta, 120 C isothermal, t r (minor) = 20.2 min, t r (major) = 22.6 min). [α] D = 67.1 (c = 1.0, C 2 Cl 2 ); mp C; IR (thin film) 2975, 294, 1691 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.39 (m, 3), 7.19 (m, 2), 4.97 (d, J = 16.7 z, 1), 4.72 (d, J = 16.7 z, 1), 1.14 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 134.7, 129.1, 128.5, 126.3, (q, J = 287 z), 115.0, 57.6, 52.4, 38.6, 27.3; RMS m/z (M + ) calcd , obsd (2n): Product was obtained in 85% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 86% ee by Chiral PLC F 3 C Ph C analysis (Chiralcel AS, 2% IPA/exanes, 1 ml./min, t r (major) = 6.4 min, t r (minor) = 8.5 min); [α] D = 17.2 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2936, 2857, 1703, 1451, 1153 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.40 (m, 3), 7.32 (m, 2), 4.94 (d, J = 16.3 z, 1), 4.53 (d, J = 16.3 z, 1), 4.37 (d, J = 10.6 z, 1), (m, 6), (m, 5); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 36 z), 133.4, 129.2, 129.1, 127.9, (q, J = 288 z), 115.4, 54.1, 52.1, 38.3, 30.1, 29.1, 25.6, 25.2, 25.1, ; RMS m/z (M + ) calcd , obsd S-8

9 (2o): Product was obtained in 88% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 86% ee by Chiral GC F 3 C analysis (γ-ta, 120 C isothermal, t r (minor) = 11.8 min, t r (major) = 13.9 min); [α] D = 19.9 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2936, 2859, 1704 cm -1 ; C 1 MR (400 Mz, CDCl 3 ) δ 5.85 (m, 1), 5.38 (d, J = 15.7 z, 1), 5.35 (d, J = 9.8 z, 1), 4.65 (d, J = 10.6 z, 1), 4.26 (dd, J = 4.9, 16.9 z, 1) 4.26 (dd, J = 6.9, 16.9 z, 1), 2.09 (m, 2), (m, 4), (m, 5); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 131.6, 120.6, (q, J = 286 z), 115.9, 53.6, 50.4, 38.3, 30.0, 28.9, 25.7, 25.3, 25.1; RMS m/z (M ) calcd , obsd (2p): Product was obtained in 90% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 90% ee by Chiral PLC F 3 C Ph C analysis(chiralcel AS, 3% IPA/exanes, 1 ml./min, t r (minor) = 5.8 min, t r (major) = 8.0 min); [α] D = -4.8 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2937, 1702, 1434, 1209, 1180, 1145 cm -1 ; 1 MR (400 Mz, CDCl 3, 318 K) δ 7.35 (m, 3), 7.26 (m, 2), 6.14 (bs, 1), 5.63 (bs, 1), 4.77 (d, J = 15.9 z, 1), 4.62 (d, J = 15.9 z, 1), 2.06 (m, 2), 1.60 (m, 2), (m, 4); 13 C MR { 1 } (100 Mz, CDCl 3, 318K) δ (J = 36 z), (broad), 128.6, 128.3, 128.1, 127.7, (q, J = 288 z), 114.4, 53.7 (broad), 49.2 (broad), 25.7, 25.1, 21.7, 21.2; RMS m/z (M ) calcd , obsd. (2q): Product was obtained in 85% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 90% ee by Chiral GC F 3 C Ph C analysis (γ-ta, 120 C isothermal, t r (minor) = 24.4 min, t r (major) = 27.3 min); [α] D = 13.1 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2962, 1702, 1449, 1207, 1147 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.41 (m, 3), 7.33 (m, 2), 4.78 (d, J = 16.1 z, 1), 4.68 (d, J = 16.1, 1), 4.51 (dd, J= 10.2, 11.3 z, 1), 2.04 (dd, J = 10.2, 14.3 z, 1), 1.34 (dd, J = 11.3, 14.3, 1), 0.84 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 133.1, 129.2, 129.0, 128.1, (q, J = 288 z), 117.0, 51.4, 45.5, 45.1, 30.1, 28.8; RMS m/z (M + a) + calcd , obsd (2r): Product was obtained in 69% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 78% ee by Chiral GC F 3 C Ph C analysis (γ-ta, 135 C isothermal, t r (minor) = 17.1 min, t r (major) = 21.0 min); [α] D = 18.8 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2962, 2936, 1702, 1427, 1207, 1182, 1144 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ (m, 5), 4.89 (d, J = 16.4 z, 1), 4.71 (appt, J = 9.0 z, 1), 4.67 (d, J = 16.4 z, 1), 1.79 (m, 2), 1.76 (m, 1), (m, 5), 0.82 (t, J = 6.6 z, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 133.5, 129.1, 128.9, 127.7, (q, J = 288 z), 115.8, 51.1, 48.7, 30.5, 27.7, 21.6, 13.4; RMS m/z (M ) calcd , obsd F 3 C Ph (2s): Product was obtained in 74% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 79% ee by Chiral GC analysis (γ- TA, 125 C isothermal, t r (minor) = 12.3 min, t r (major) = 15.1 min); [α] D = C S-9

10 24.7 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2975, 1703, 1448, 1153 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.42 (m, 3), 7.32 (m, 2), 4.92 (d, J = 16.4 z, 1), 4.58 (d, J = 16.4 z, 1), 4.30 (d, J = 10.5 z, 1), 2.26 (dd, J = 6.6, 10.5, 1) 1.07 (d, J = 6.6 z, 3), 0.87 (d, J = 6.6 z, 3); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 133.3, 129.3, 129.1, 127.9, (q, J = 288 z), 115.6, 55.1, 52.1, 29.8, 19.6, 18.5; RMS m/z (M + ) calcd , obsd (2t): Product was obtained in 89% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 91% ee by Chiral GC analysis (γ- F 3 C Ph C TA, 135 C isothermal, t r (minor) = 11.8 min, t r (major) = 15.5 min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 3035, 1702, 1444, 1209, 1187, 1149 cm -1 ; MR (400 Mz, CDCl 3 ) δ 7.41 (m, 3), 7.28 (m, 2), 4.93 (d, J = 16.8 z, 1), 4.77 (d, J = 16.8 z, 1), 4.39 (d, J = 9.0, 1), 1.14 (m, 1), 0.62 (m, 1), 0.48 (m, 1), 0.40 (m, 1), 0.31 (m, 1); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 134.0, 129.1, 128.8, 127.6, 120.5, (q, J = 288 z),; 115.3, 52.4, 50.5, 12.5, 5.0; RMS m/z (M + a) + calcd , obsd (2u): Product was obtained in 65% yield as a clear oil after purification by flash chromatography (3:2 hexanes:c 2 Cl 2 ) and in 90% ee by Chiral GC F 3 C analysis (γ-ta, 130 C isothermal, t r (minor) = 20.7 min, t r (major) = 22.2 min); [α] D = 30.3 (c = 1.0, C 2 Cl 2 ); IR (thin film) 2927, 2858, 1702, C 1448, 1288, 1211, 1184, 1153 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 5.87 (m, 1), 5.38 (d, J = 17.1 z, 1), 5.35 (d, J = 10.2 z, 1), 4.69 (d, J = 11.0 z, 1), 4.26 (dd, J = 4.8, 16.9 z, 1) 4.26 (dd, J = 6.7, 16.9 z, 1), (m, 2), 2.35 (m, 1), 1.87 (m, 1), (m, 11), 1.22 (m, 2); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z), 131.6, 120.5, (q, J = 288 z), 116.4, 53.4, 50.2, 37.8, 28.9, 27.4, 26.7, 26.3, 26.0, 24.9, 24.3; RMS m/z (M+ + 4 ) calcd , obsd (2v) [9] : Product was obtained in 88% yield as a white solid after purification by precipatation from hexanes and in 91% ee by Chiral GC analysis (γ-ta, 125 C isothermal, t r (minor) =.7 min, t r (major) = 33.9 CF 3 C min); [α] D = (c = 1.0, C 2 Cl 2 ); IR (thin film) 2945, 1758, 1453, 1204, 1152 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.35 (m, 3), 7.24 (m, 1), 6.33 (s, 1), 4.20 (m, 1), 3.78 (m, 1), (m, 2); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ (J = 37 z),133.0, 129.5, 129.4, 127.9, 127.3, 126.8, (q, J = 288 z), 116.4, 44.9, 41.8, 41.7, 28.2; RMS m/z (M + ) calcd , obsd CD spectra supporting the stereochemical assignment are provided on p S-39. Preparation of Catalyst 3c: 2 + Fmoc (1) BTU, DIPEA C 3 C (2) Piperidine/Me 2 S-10

11 To a solution of 500 mg of Fmoc-D-tert-Leucine (1.41 mmol) and 0.54 ml of DIPEA (3.11 mmol, 2.2 equiv) in acetonitrile, 590 mg of BTU (1.55 mmol, 1.1 equiv) was added. After 1 min, 309 µl of benzyl amine (2.82 mmol, 2.0 equiv) was added and the reaction stirred for 30 min. The mixture was partitioned between CCl 3 (50 ml) and 2 (50 ml). The organic phase was washed with 2 (2 X 50 ml), dried over a 2 S 4, and concentrated in vacuo. The resulting residue was filtered through a short plug of silica eluting with 4% Me/C 2 Cl 2. The solvent was removed in vacuo and the residue was dissolved in 10 ml 1:1 piperdine/me, stirred for 30 min and partitioned between 50 ml of CCl 3 and 25 ml 2. The organic phase was washed with 2 (25 ml), dried over a 2 S 4 and concentrated in vacuo. Purification by silica gel chromatography (5% Me/C 2 Cl 2 ) afforded 242 mg of a white solid (78% yield, 2 steps): mp C; IR (KBr) 3303, 1650 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 7.33 (m, 5), 7.05 (s, 1), 4.45 (d, J = 0.9 z, 1), 4.43 (d, J = 0.9 z, 1), 3.14 (s, 1), 1.41 (s, 2), 1.01 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 173.4, 138.5, 128.5, 127.8, 127.3, 64.3, 43.0, 34.1, 26.7; RMS (M + ) calcd , obsd Cl pyridine, C 2 Cl 2, 30 min 2 PP-Ester: To a solution of the amine (162 mg, mmol), pyridine (119 ul, 1.47 mmol), and C 2 Cl 2 (12 ml) was added p-nitrophenyl chloroformate (150 mg, mmol). This mixture was allowed to stir for 30 min then the solvent was removed in-vacuo. The resulting residue was purified by silica gel chromatography (5%EtAc/C 2 Cl 2 ) to yield a 262 mg of a white solid (92% yield): IR (KBr) 3324, 2965, 1731, 1654, 1524, 1489, 1347, 1212 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ 8.13 (m, 2), 7.27 (m, 3), 7.17 (m, 4), 6.59 (s, 1), 6.24 (d, J = 9.4 z, 1), 4.41 (dd, J = 6.0, 14.9 z, 1), 4. (J = 6.0, 14.9 z, 1), 4.08 (d, J = 9.4 z, 1), 1.05 (s, 9); (; 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 170.0, 155.6, 153.4, 144.7, 137.4, 128.7, 127.6, 127.5, 125.0, 121.8, 63.2, 43.5, 34.9, 26.5; RMS (M +a) + calcd , obsd (2) 2 (3) C 2 Cl 2, DIPEA, 2 hr Me, 1 hr 3c t Bu t Bu Solution Phase Catalyst: (1) To a solution of the PP ester (254 mg, mmol) and 6.5 ml of C 2 Cl 2 was added diisopropyl ethylamine (115 ul, mmol, 1 equiv.) followed immediately by (S,S)-1,2-diaminocyclohexane (0 mg, 2 mmol, 3 equiv). The reaction immediately turned yellow and was allowed to stir for 2 hr. The resulting mixture was partitioned between C 2 Cl 2 (75 ml) and 20% aq. a(c 3 ) 2 (50 ml). The organic layer was S-11

12 washed with three times with 20% aq. a(c 3 ) 2 (50 ml ea.) until yellow color was removed. After washing with 2 (2 X 50 ml), the organic layer was dried over a 2 S 4, filtered and the solvent removed by reduced pressure. (2) The resulting residue was weighed (191 mg, 80% yield) and disolved in Me (3 ml). This solution was treated with equimolar aldehyde (147 mg, mmol) and allowed to stir for 1 hr. The solvent was removed by reduced pressure and the resulting residue was purified by silica gel chromatography (25% EtAc/exane) to yield 3c as a yellow solid (283 mg, 69% over two steps). IR (KBr) 3309, 2960, 1752, 1684, 1550, 1437, 1270, 1150, 1116 cm -1 ; 1 MR (400 Mz, C 6 D 6 ) δ (s, 1), 8.08 (s, 1), 7. (d, J = 2.6 z, 1), 7.12 (m, 2), 7.08 (m, 2), 7.02 (d, J = 2.6 z, 1), 7.00 (t, J = 7.1 z, 1), 6.67 (m, 1), 5.63 (m, 1), 4.59 (m, 1), 4.37 (dd, J = 14.8, 6.6 z, 1), 4.29 (d, J = 9.1 z, 1), 3.86 (dd, J = 14.8, 4.6 z, 1), 3.43 (m, 1), 3.15 (m, 1), 1.95 (m, 1), (m, 7), 1.51 (s, 9), 1.30 (s, 9), 1.05 (s, 9); 13 C MR { 1 } (100 Mz, CDCl 3 ) δ 177.4, 172.0, 164.3, 158.1, 157.7, 141.7, 138.5, 130.1, 128.4, 127.4, 127.1, 122.6, 121.2, 118.1, 70.3, 61.5, 54.0, 43.1, 38.9, 34.8, 34.7, 31.5, 29.1, 27.1, 26.7, 24.2,.6, 22.6; RMS (Electrospray) (M) + calcd , obsd Synthesis of tert-leucine: Ph C or TMSC/Me 4 mol% Resin Catalyst C Ph 93% ee Procedure A (TMSC). To a flamed dried 50ml round bottom flask, 0.400g (0.60 mmol/g, mmol, 0.04 equiv.) of 3b and 1.07 g (6.10 mmol) of 1n were combined with 17 ml of freshly distilled toluene. The mixture was cooled to -78 C and a solution of C, which was generated from ml (0.245 g, 7.65 mmol, 1.25 equiv.) of anhydrous methanol and ml (0.759 g, 7.65 mmol, 1.25 equiv.) of freshly distilled trimethylsilyl cyanide in 8 ml of freshly distilled toluene at 0 C for 1.5 h and than cooled to 78 C, was added. The reaction mixture was allowed to stir (stirring speed approximately 2 s -1 ) at 75 C for 15h, after which it was warmed to ambient temperature and stirred in vacuo for 2h to remove excess C. Catalyst was filtered off and washed with toluene (2 X 10 ml). The solvent was removed in vacuo at 25 C to yield 1.24 g of a clear oil, 93% ee by chiral GC analysis of the formamide derivative. Procedure B (C): To a flamed dried 100ml round bottom flask, 1.32 g of 1n (7.53 mmol) was dissolved in 24 ml of freshly distilled toluene and 0.540g (0.56 mmol/g, mmol, 0.04 equiv.) of 3b added. The reaction was cooled to 78 C and 17.0 ml of a solution of C in toluene (0.576 M, 9.79 mmol, 1.3 equiv.) was added by syringe addition. The rest of the procedure is identical to Procedure A. C Ph Formic Acid acetic anhydride RT, 5 min C Ph 4 S-12

13 (4): Acetic formic anhydride, which was prepared from 12.5 ml (13.5 g, mol) of acetic anhydride and 5.0 ml (6.10 g, mol) formic acid by heating at 60 C and cooled to 0 C, was added to 1.24 g of the crude Strecker adduct. The reaction mixture was allowed to stir for 5 min and poured into the mixture of ice and water (150 ml) and extracted with dichlormethane (2 X 50 ml). Combined organic layers were washed with 10% aqueous solution of sodium bicarbonate (3 X 300 ml) and brine (100 ml). The organic extracts were dried over a 2 S 4 and the solvent was removed in-vacuo yielding 1.38 g (5.99, 98%) of a white crystalline compound. Recrystallization of 3.73 g (16.2 mmol) of 4 from hexanes (0 ml) yielded 3. g (14.0 mmol, 87%) of white crystals, >99% ee by chiral GC analysis (γ-ta column, isothermal 130 C, t r (D-enantiomer) = 51 min, t r (L-enantiomer) = 56 min). IR (KBr) 29, 1680 cm -1 ; 1 MR (500 Mz, CDCl 3 ) δ 8.51 (s, 0.4), 8. (s, 0.6), 7.35 (m, 5), 5.30 (d, J = 15.4 z, 0.5), 4.73 (d, J = 15.7 z, 0.5), 4.56 (d, J = 15.7 z, 0.5), 4.07 (d, J = 15.4 z, 0.5), 3.95 (s, 1), 1.11 (d, J = 3.7 z, 9); 13 C MR { 1 } (400 Mz, CDCl 3 ) δ 163.9, 162.8, 135.8, 135.2, 129.2, 129.0, 128.5, 128.2, 127.9, 127.6, 116.3, 58.5, 53.8, 51.3, 48. 8, 37.4, 27.0, 26.6; RMS m/z (M + ) calcd , obsd C Ph 6 Ph (6): To a 500ml round bottom flask, 3.00 g (13.0 mmol) of 5 was suspended in 380 ml of sulfuric acid (65% w/w). The Reaction mixture was allowed to stir at 45 C for 16 h followed by pouring into a mixture of ice and water (1.5 l) and extracted with ethylacetate (3 X 500 ml). The organic extracts were dried over a 2 S 4 and the solvent was removed in-vacuo yielding 3.22 g (12.9, 99%) of a white crystalline compound. IR (KBr) 17, 1709 cm -1 ; 1 MR (500 Mz, d 6 -DMS) δ 8.48 (s, 0.85), 8.22 (s, 0.15), 7.25 (m, 5), 4.91 (d, J = 15.3 z, 0.85), 4.79 (d, J = 16.0 z, 0.15), 4.58 (d, J = 16 z, 0.15), 4.53 (s, 0.15), 4.20 (d, J = 15.3 z, 0.85), 3.91 (s, 0.85), 1.01 (s, 1.35), 1.00 (s, 7.65); 13 C MR { 1 } (500 Mz, d 6 -DMS) δ 171.3, 170.4, 164.7, 164.2, 163.9, 163.4, 138.3, 137.5, 128.4, 128.1, 127.4, 126.8, 68.3, 61.7, 5 0.1, 48.4, 35.4, 35.3, 27.5, 27.3; RMS m/z (M + ) calcd , obsd Ph Ph Cl 6 7 (7): To a 1l round bottom flask, 3.2 g (12.8 mmol) of 6 was suspended in 300 ml of concentrated hydrochloric acid. Reaction mixture was allowed to stir at 70 C for 13 h, solvent was removed in vacuo to yield 3.31 g (12.8 mmol, 100%) of white crystalline compound. 1 MR (500 Mz, d 6 -DMS) δ 7.56 (m, 2), 7.40 (m, 3), 4.25 (d, J = 13.5 z, 1), 3.99 (d, J = 13.5 z, 1), 3.22 (s, 1), 1.01 (s, 9); 13 C MR { 1 } (500 Mz, d 6 -DMS) δ 169.1, 130.9, 130.5, 129.2, 128.6, 66.9, 50.3, 33.1, 26.6; RMS m/z (M + ) calcd , obsd S-13

14 Ph Cl 2 Cl 7 tert-leucine Cl Salt: To a 500ml round bottom flask 3.20 g (12.4 mmol) of 7 was dissolved in methanol (200 ml), and under inert atmosphere of nitrogen 1.32 g (1.24 mmol, 0.1 equiv.) of 10% (w/w) palladium on carbon was added. The reaction mixture was allowed to react under atmospheric pressure of 2 for 8 h, and the catalyst was removed by filtration through Celite. The solvents were removed in vacuo to yield 2.08 g (12.4 mmol, 100%) of tert-leucine, >99% ee by chiral PLC analysis (Chiralcel D, 4% Ethanol/exanes, 1 ml./min, t r (D-enantiomer) = 13 min, t r (L-enantiomer) = 20 min) (as -Fmoc methyl ester derivative). otes and References: [1] J. F. Larrow, E.. Jacobsen, Y. Gao, Y. ong, X. ie, C. M. Zepp, J. rg. Chem. 1994, 59, [2] J. C. Pelletier, M. P. Cava, J. rg. Chem. 1987, 52, 616. [3] K. Afrarinkia, C. W. Rees, J. I. G. Cadogan, Tetrahedron 1990, 46, [4] S. D. Worley, Tetrahedron, 1978, 34, 833. [5]. D. Kimpe, R. Jolie, D. D. Smale, J. Chem. Soc. Chem. Commun. 1994, [6] B. K. Banik, G. V. Subbaraju, M. S. Manhas, A. K. Bose, Tetrahedron Lett. 1996, 37, [7] T. W. Bell, Y-L. u, Tetrahedron Lett. 1988, 38, [8] P. G. M. Wuts, Y-W. Jung, J. rg. Chem. 1991, 56, [9] Significant racemization occurs upon prolonged standing or upon attempted purification by flash chromatography. S-14

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39 CD of 2v CD of 2p CD of 2i CD of 2f CD of 2g S-39