Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. Jeremiah P. Malerich, Koji Hagihara, and Viresh H.

Transcription

1 Chiral Squaramide Derivatives are Excellent ydrogen Bond Donor Catalysts Jeremiah P. Malerich, Koji agihara, and Viresh. Rawal* Department of Chemistry, University of Chicago, Chicago, Illinois Supporting Information Table of Contents S2 Control experiments to study bifunctional catalysis S3 General methods S3 Preparation of squaramide 5 S4 General procedure for conjugate addition reactions S4 Product characterization data S10 References S11 NMR spectra S37 PLC traces S1

2 Control experiments to study bifunctional catalysis Entry Additive Time Conversion (measured by 1 NMR) 1 A (10 mol%) 17 h NR 2 Et 3 N (10 mol%) 6 h 30% 3 Et 3 N (10 mol%) + A (10 mol%) 6 h 95% 4 B (10 mol%) 2 h 100% To study the bifunctional nature of bissquaramides bearing basic amines, a series of experiments that attempt to isolate the individual catalytic units of these compounds was performed. Simple squaramide A was not an effective catalyst for the reaction of 6 and 7 (Entry 1). In the presence of Et 3 N, partial conversion was observed after 6 h (Entry 2). The addition of both A and Et 3 N (Entry 3) greatly increased the rate of production of 8 compared to either of the isolated components. Utilizing catalyst B, which incorporates a basic tertiary amine into the squaramide, gives further rate acceleration. These results suggest that while basic activation of the nucleophile is required for the reaction to take place, further rate increase can be attributed to activation of the electrophile by hydrogen bonding. S2

3 Experimental Section. General. Reactions were run in oven dried glassware under N 2 atmosphere. Methylene chloride was purified by passage over activated alumina. Reactions were monitored by TLC on Whatman silica gel 60 Å F254 plates visualized by anisaldehyde and ceric ammonium molybdate staining solutions. Flash column chromatography was performed on Dynamic Adsorbents µ Flash silica gel. NMR spectra were measured on Bruker DRX and DMX spectrometers at 500 Mz for 1 spectra and 125 Mz for 13 C spectra and calibrated from residual solvent signal. Infrared spectra were measured on a Nicolet 6700 FT-IR spectrometer on NaCl plates. Mass spectral analysis was performed by the College of Sciences Major Instrumentation Cluster at ld Dominion University (Norfolk, VA) directed by Susan atcher. Enantiomeric excesses (ee) were determined by PLC analysis using an Agilent 1100 Series instrument with Daicel Chiralpak AD- or Chiralcel D- columns, as indicated. ptical rotation data were measured on a Jasco DIP-1000 Digital Polarimeter at the indicated concentration with units g/100 ml. Preparation of squaramide 5. To a solution of dimethylsquarate (2; 142 mg, 1.00 mmol) in C 2 Cl 2 (4 ml) was added 3,5-bis(trifluoromethyl)-benzylamine (1; 255 mg, 1.05 mmol) C 2 Cl 2 (1 ml). After 18 h, the reaction mixture was filtered, and the filtrate was washed with 1 M Cl(aq) (1 10 ml). The organic layer was dried with Na 2 S 4, filtered, and concentrated to afford 3 (299 mg, 85%) as a white solid: 1 NMR (500 Mz, DMS-d 6, 315K): δ 8.96 (br s, 1), 8.01 (s, 2), 7.95 (s, 1), 4.78 (br s, 2), 4.27 (s, 3). To a solution of 3 (127 mg, mmol) in Me (4 ml) was added a solution of amine 4 1 (88 mg, mmol) in Me (1 ml). After 24 h, the reaction mixture was filtered, and the precipitate was washed with cold Me (2 0.5 ml) to afford squaramide 5 (132 mg, 72 %) as a white solid: 1 NMR (500 Mz, DMS-d 6 ): δ 8.91 (d, J = 4.5 z, 1), 8.40 (d, J = 8.3 z, 1), (m, 5), 7.77 (t, J = 7.5 z, 1), 7.75 (br s, 1), 7.67 (t, J = 7.7 z, 1), 7.62 (d, J = 4.4 z, 1), 6.06 (br s, 1), 5.80 (ddd, J = 17.1, 10.5, 6.5 z, 1), 5.13 (d, J = 17.2 z, 1), 5.04 (d, J = 10.5 z, 1), 4.83 (m, 2), 3.28 (q, J = 9.4 z, 1), 3.08 (dd, J = 13.9, 7.1 z, 1), 2.89 (t, J = 12.2 z, 1), 2.82 (m, 1), 2.75 (dd, J = 14.4, 10.5 z, 1), 2.18 (q, J = 8.0 z, 1), (m, 3), (m, 2); 13 C NMR (125 Mz): δ 183.1, 182.5, 167.7, 167.4, 150.7, 148.5, 145.7, 142.6, 141.0, 130.8, , 129.8, 129.1, 127.4, 126.7, 124.7, 123.6, 122.5, 121.6, 120.3, 114.9, 59.7, 49.3, 46.2, 46.2, 27.7, 26.4, 25.4; RMS (ESI+) Calcd for C F 6 N 4 2 Na + (M+Na) + : , Found: Crystallization from C 2 Cl 2 with minimal Me afforded platelets suitable for x-ray diffraction. See the accompanying.cif file for data. S3

4 General procedure for conjugate addition reactions. To a solution of nitroolefin (0.500 mmol) in C 2 Cl 2 (1.5 ml) was added squaramide 5 (1.5 mg, mmol) and 1,3-dicarbonyl compound (1.000 mmol). Upon consumption of nitroolefin substrate (monitored by TLC), the reaction mixture was concentrated and purified by column chromatography to afford the conjugate addition product. 3-(2-Nitro-1-phenylethyl)-pentane-2,4-dione (8). 2 Flash column chromatography (3:1 hexanes : EtAc) afforded 8 (117 mg, 94%) as a white solid. Analytical data matched previously reported values. 2 PLC (D-, 5% Et in hexanes, 1 ml/min, 210 nm): t major = 24.3 min, t minor = 22.4 min, 99% ee; [α] 26 D = (c = 1.0 in CCl 3 ); Lit. 3 [α] 25 D = (c = 3.0 in CCl 3 ). 3-(2-Nitro-1-p-tolylethyl)-pentane-2,4-dione (10a). 3 Flash column chromatography (3:1 hexanes : EtAc) afforded 10a (129 mg, 98%) as a white solid. Analytical data matched previously reported values. 3 PLC (AD-, 10% ipr in hexanes, 1 ml/min, 230 nm): t major = 15.1 min, t minor = 9.5 min, 97% ee; [α] 27 D = (c = 1.0 in CCl 3 ). 3-[1-(4-Methoxyphenyl)-2-nitroethyl]-pentane-2,4-dione (10b). 3 Flash column chromatography (3:1 hexanes : EtAc) afforded 10b (138 mg, 98%) as a white solid. Analytical data matched previously reported values. 3 PLC (AD-, 10% ipr in hexanes, 1 ml/min, 230 nm): t major = 21.8 min, t minor = 14.4 min, 98% ee; [α] 25 D = (c = 1.0 in CCl 3 ). S4

5 3-[1-(2-Bromophenyl)-2-nitroethyl]-pentane-2,4-dione (10c). Purification by column chromatography (3:1 hexanes : EtAc) afforded 10c (147 mg, 89%) as a pale orange solid: mp C; R f 0.13 (3:1 hexanes : EtAc); IR: 1731, 1704, 1553, 1495, 1427, 1378, 1362 cm -1 ; 1 NMR (500 Mz): δ 7.63 (dd, J = 7.9, 1.2 z, 1), 7.28 (td, J = 7.6, 1.2 z, 1), 7.18 (td, J = 7.8, 1.6 z, 1), 7.13 (dd, J = 7.8, 1.6 z, 1), 4.83 (dd, J = 12.4, 6.4 z, 1), 4.74 (ddd, J = 9.8, 6.4, 4.1 z, 1), 4.67 (dd, J = 12.4, 4.1 z, 1), 4.60 (d, J = 9.7 z, 1), 2.31 (s, 3), 2.04 (s, 3); 13 C NMR (125 Mz): δ 202.0, 200.9, 134.0, 130.0, 128.7, 128.3, 124.6, 76.2, 69.1, 41.0, 31.0, 28.3; [α] 27 D = (c = 1.0 in CCl 3 ); PLC (D-, 10% ipr in hexanes, 1 ml/min, 230 nm): t major = 17.6 min, t minor = 15.9 min, 98% ee; RMS (ESI+) Calcd for C BrN 4 Na + (M+Na) + : , Found: [1-(3-Bromophenyl)-2-nitroethyl]-pentane-2,4-dione (10d). Purification by column chromatography (3:1 hexanes : EtAc) afforded 10d (161 mg, 98%) as a white solid: mp C; R f 0.13 (3:1 hexanes : EtAc); IR: 1730, 1703, 1551, 1495, 1364 cm -1 ; 1 NMR (500 Mz): δ 7.43 (ddd, J = 8.0, 1.8, 1.2 z, 1), 7.35 (t, J = 1.8 z, 1), 7.21 (t, J = 8.0 z, 1), 7.12 (dt, J = 7.1, 1.1 z, 1), 4.64 (dd, J = 12.8, 7.8 z, 1), 4.60 (dd, J = 12.8, 4.8 z, 1), 4.34 (d, J = 10.5 z, 1), 4.20 (ddd, J = 10.5, 7.8, 4.8 z, 1), 2.29 (s, 3), 2.00 (s, 3); 13 C NMR (125 Mz): δ 201.2, 200.4, 138.4, 131.7, 131.0, 130.8, 126.5, 123.3, 77.7, 70.3, 42.2, 30.5, 29.8; [α] 27 D = (c = 1.0 in CCl 3 ); PLC (AD-, 5% ipr in hexanes, 1 ml/min, 230 nm): t minor = 15.9 min, t major = 17.8 min, 97% ee; RMS (ESI+) Calcd for C BrN 4 Na + (M+Na) + : , Found: Br 10e 3-[1-(4-Bromophenyl)-2-nitroethyl]-pentane-2,4-dione (10e). 3 Purification by column chromatography (3:1 hexanes : EtAc) afforded 10e (161 mg, 98%) as a white solid. Analytical data matched previously reported values. 3 PLC (D-, 10% ipr in hexanes, 0.8 ml/min, 230 nm): t major = 35.8 min, t minor = 32.9 min, 98% ee; [α] 27 D = (c = 1.0 in CCl 3 ); Lit. 3 [α] 25 D = 37.2 (c = 1.2 in CCl 3 ). F 10f 3-[1-(2-Fluorophenyl)-2-nitroethyl]-pentane-2,4-dione (10f). Purification by column chromatography (3:1 hexanes : EtAc) afforded 10f (128 mg, 96%) as a white solid: R f 0.16 (3:1 hexanes : EtAc); IR: 1728, 1703, 1550, 1473, 1432, 1379, 1360 cm -1 ; 1 NMR (500 Mz): δ 7.29 (m, 1), 7.17 (td, J = 7.5, 1.8 z, 1), 7.11 (dd, J = 7.6, 1.1 z, 1), 7.07 (m, 1), 4.73 (ddd, J = 12.5, 5.7, 2.7 z, 1), 4.62 (dd, J = 12.6, 3.2, 1), (m, 2), 2.29 (s, 3), 2.02 (s, 3); 13 C NMR (125 Mz): δ 201.4, 200.7, 160.7, 130.5, 130.4, 124.9, 122.8, 116.3, 76.6, 69.0, 37.8, 30.4, 29.2; [α] 27 D = (c = 1.0 in CCl 3 ); PLC S5

6 (AD-, 5% ipr in hexanes, 1 ml/min, 220 nm): t major = 16.5 min, t minor = 13.9 min, 97% ee; RMS (ESI+) Calcd for C FN 4 Na + (M+Na) + : , Found: [1-(2,4-Dichlorophenyl)-2-nitroethyl]-pentane-2,4-dione (10g). Purification by column chromatography (3:1 hexanes : EtAc) afforded 10g as a clear oil (156 mg, 98%): R f 0.13 (3:1 hexanes : EtAc); IR: 1730, 1704, 1550, 1475, 1378, 1360 cm -1 ; 1 NMR (500 Mz): δ 7.44 (d, J = 2.1 z, 1), 7.22 (dd, J = 8.5, 2.1 z, 1), 7.10 (d, J = 8.5 z, 1), 4.81 (dd, J = 12.6, 6.9 z, 1), 4.68 (ddd, J = 10.2, 6.9, 3.9 z, 1), 4.62 (dd, J = 12.5, 3.9 z, 1), 4.54 (d, J = 9.9 z, 1), 2.28 (s, 3), 2.05 (s, 3); 13 C NMR (125 Mz): δ 201.5, 200.5, 135.0, 134.5, 132.1, 130.4, 128.7, 127.9, 75.9, 68.7, 38.4, 30.8, 28.6; PLC (AD-, 10% ipr in hexanes, 1 ml/min, 230 nm): t major = 11.6 min, t minor = 8.9 min, 97% ee; RMS (ESI+) Calcd for C Cl 2 N 4 Na + (M+Na) + : , Found: [2-Nitro-1-(2-nitro-phenyl)-ethyl]-pentane-2,4-dione (10h). Purification by column chromatography (3:1 hexanes : EtAc, then 1:1 hexanes : EtAc) afforded 10h as a pale orange solid (141 mg, 96%): mp C; R f 0.08 (3:1 hexanes : EtAc); IR: 1730, 1703, 1555, 1528, 1359 cm -1 ; 1 NMR (500 Mz): δ 7.93 (dd, J = 8.0, 1.4 z, 1), 7.58 (td, J = 7.8, 1.4 z, 1), 7.48 (td, J = 7.8, 1.4 z, 1), 7.36 (dd, J = 7.8, 1.4 z, 1), 4.97 (dd, J = 13.3, 7.1 z, 1), 4.84 (dd, J = 13.3, 3.7 z, 1), 4.73 (ddd, J = 8.7, 7.2, 3.7 z, 1), 4.67 (d, J = 8.7 z, 1), 2.31 (s, 3), 2.13 (s, 3); 13 C NMR (125 Mz): δ 201.5, 200.5, 149.8, 133.5, 131.2, 129.3, 129.2, 125.6, 76.5, 69.1, 37.1, 31.3, 29.2; [α] 27 D = (c = 1.0 in CCl 3 ); PLC (D-, 10% ipr in hexanes, 1 ml/min, 230 nm): t major = 35.6 min, t minor = 30.5 min, 97% ee; RMS (ESI+) Calcd for C N 2 6 Na + (M+Na) + : , Found: i 3-(1-Furan-2-yl-2-nitroethyl)-pentane-2,4-dione (10i). Purification by column chromatography (3:1 hexanes : EtAc) afforded 10i as a yellow solid (117 mg, 98%): mp C; R f 0.13 (3:1 hexanes : EtAc); IR: 1734, 1698, 1549, 1502, 1384, 1361, 1262 cm -1 ; 1 NMR (500 Mz): δ 7.36 (dd, J = 1.8, 0.7 z, 1), 6.30 (dd, J = 3.2, 1.8 z, 1), 6.18 (d, J = 3.3 z, 1), (m, 2), (m, 2), 2.28 (s, 3), 2.08 (s, 3); 13 C NMR (125 Mz): δ 201.4, 200.8, 149.4, 142.9, 110.8, 108.8, 75.8, 67.9, 36.5, 30.6, 29.3; [α] 27 D = (c = 1.0 in CCl 3 ); PLC (AD-, 10% ipr in hexanes, 1 ml/min, 220 nm): t major = 12.5 min, t minor = 10.7, 97%; RMS (ESI+) Calcd for C N 5 Na + (M+Na) + : , Found: (2-Nitro-1-phenyl-ethyl)-1-phenyl-butane-1,3-dione (12a). 4 Purification by column chromatography (4:1 hexanes : EtAc) afforded compounds 12a (143 mg, 91%) as a 2:1 mixture of diastereomers. Analytical data matched previously reported values. 4 PLC (AD-, 2% ipr in hexanes, 1 ml/min, 230 S6

7 nm): major diastereomer: t major = 44.9 min, t minor = 24.4 min, 95% ee, minor diastereomer: t major = 28.4 min, t minor = 21.6 min, 94% ee. 2-(2-Nitro-1-phenyl-ethyl)-1,3-diphenyl-propane-1,3-dione (12b). 4 Purification by column chromatography afforded 12b (173 mg, 93%) as a white solid. Analytical data matched previously reported values. 4 PLC (D-, 10% ipr in hexanes, 1 ml/min, 230 nm): t major = 33.8 min, t minor = 19.6 min, 96% ee. 1-Furan-2-yl-2-(2-nitro-1-phenylethyl)-butane-1,3-dione (12c). Purification by column chromatography (3:1 hexanes : EtAc) afforded 12c as 1.4:1 mixture of diastereomers (147 mg, 98%): mp C; R f 0.10 (3:1 hexanes : EtAc); IR: 1720, 1657, 1547, 1462 cm -1 ; major diastereomer: 1 NMR (500 Mz): δ 7.65 (s, 1), 7.35 (d, J = 3.4 z, 1), (m, 5), 6.60 (dd, J = 3.4, 1.4 z, 1), 4.94 (d, J = 10.1 z, 1), (m, 2), 4.45 (ddd, J = 10.0, 8.9, 5.0 z, 1), 1.99 (s, 3); 13 C NMR (125 Mz): δ 200.4, 181.8, 152.0, 147.9, 136.0, 129.2, 128.4, 128.0, 119.2, 113.3, 77.7, 64.9, 42.7, 30.3; minor diastereomer: 1 NMR (500 Mz): δ 7.60 (s, 1), (m, 6), 6.53 (dd, J = 3.7, 1.6 z, 1), 5.06 (d, J = 10.1 z, 1), (m, 2), 4.40 (ddd, J = 10.1, 8.3, 4.6 z, 1), 2.25 (s, 3); 13 C NMR (125 Mz): δ 201.1, 181.7, 151.9, 147.4, 136.2, 128.9, 128.1, 127.9, 119.9, 113.2, 78.0, 64.3, 42.8, 29.5; PLC (AD-, 10% ipr in hexanes, 1 ml/min, 220 nm): major diastereomer: t major = 26.9 min, t minor = 18.1 min, 92% ee, minor diastereomer: t major = 20.5 min, t minor = 15.0 min, 81% ee; RMS (ESI+) Calcd for C N 5 Na + (M+Na) + : , Found: Acetyl-4-nitro-3-phenylbutyric acid methyl ester (12d). 5 To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added methyl acetoacetate (11d; 43 µl, 0.40 mmol). After 18 h, the reaction mixture was concentrated, and purification by column chromatography (4:1 hexanes : EtAc) afforded 12d as 1:1 mixture of diastereomers (40 mg, 75%). Analytical data matched previously reported values. 5 PLC (D-, 2% Et in hexanes, 1 ml/min, 230 nm): major diastereomer: t major = 25.7 min, t minor = 28.8 min, 96% ee, minor diastereomer: t major = 43.8 min, t minor = 35.0 min, 98% ee. 2-Acetyl-4-nitro-3-phenylbutyric acid ethyl ester (12e). 5 To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added ethyl acetoacetate (11e; 51 µl, 0.40 mmol). After 8 h, the reaction mixture was concentrated, and purification by column chromatography (8:1 then 4:1 hexanes : EtAc) afforded 12f as 1.6:1 mixture of diastereomers (50 mg, 89%). Analytical data matched previously reported values. 5 PLC (D-, 1% Et in hexanes, 1 S7

8 ml/min, 230 nm): major diastereomer: t major = 28.2 min, t minor = 30.7 min, 97% ee, minor diastereomer: t major = 38.5 min, t minor = 33.8 min, 96% ee. 2-Acetyl-4-nitro-3-phenylbutyric acid tert-butyl ester (12f). 5 To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added tert-butyl acetoacetate (11f; 66 µl, 0.40 mmol). After 12 h, the reaction mixture was concentrated, and purification by column chromatography (16:1 then 8:1 hexanes : EtAc) afforded 12f as 1.6:1 mixture of diastereomers (59 mg, 95%). Analytical data matched previously reported values. 5 PLC (AD-, 5% ipr in hexanes, 1 ml/min, 220 nm): major diastereomer: t major = 11.5 min, t minor = 8.3 min, 96% ee, minor diastereomer: t major = 13.8 min, t minor = 18.0 min, 96% ee. 2-(2-Nitro-1-phenylethyl)-3-oxopentanoic acid methyl ester (12g). To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added methyl propionylacetate (11g; 66 µl, 0.40 mmol). After 9 h, the reaction mixture was concentrated, and purification by column chromatography (8:1 then 4:1 hexanes : EtAc) (4:1 hexanes : EtAc) gave 12g (50 mg, 90%) as a 5:1 mixture of diastereomers: mp C; R f 0.18 (3:1 hexanes : EtAc); IR: 1743, 1711, 1554, 1455, 1433, 1380 cm -1 ; major diastereomer: 1 NMR (500 Mz): δ (m, 3), 7.17 (m, 2), 4.87 (dd, J = 13.8, 5.0 z, 1), 4.82 (dd, J = 13.8, 5.0 z, 1), 4.25 (dt, J = 9.4, 5.0 z, 1), 4.03 (d, J = 9.8 z, 1), 3.76 (s, 3), 2.48 (dq, J = 18.3, 7.1 z, 1), 2.13 (dq, J = 18.3, 7.1 z, 1), 0.84 (t, J = 7.1 z, 3); 13 C NMR (125 Mz): δ 203.1, 168.0, 136.3, 129.1, 128.3, 127.9, 77.7, 60.6, 52.9, 42.7, 37.1, 7.2; minor diastereomer: 1 NMR (500 Mz): δ (m, 3), 7.17 (m, 2), (m, 2), (m, 1), 4.13 (d, J = 9.2 z, 1), 3.53 (s, 3), 2.67 (dq, J = 18.3, 7.3 z, 1), 2.47 (dq, J = 18.3, 7.3 z, 1), 1.06 (t, J = 7.3 z, 3); 13 C NMR (125 Mz): δ 204.1, 167.5, 136.5, 129.0, 128.2, 127.7, 77.5, 60.9, 52.7, 42.4, 36.8, 7.4; PLC (AD-, 2% ipr in hexanes, 1 ml/min): major diastereomer: t major = 32.9 min, t minor = 29.7 min, 96% ee, minor diastereomer: t major = 37.8 min, t minor = 20.9 min, 90% ee; RMS (ESI+) Calcd for C N 5 Na + (M+Na) + : , Found: (2-Methoxyacetyl)-4-nitro-3-phenylbutyric acid methyl ester (12h). To a solution of trans-βnitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added methyl 4-methoxyacetoacetate (11h; 52 µl, 0.40 mmol). After 9 h, the reaction mixture was concentrated, and purification by column chromatography (3:1 hexanes : EtAc) gave 12h (49 mg, 83%) as a 1.3:1 mixture of diastereomers: R f 0.13 (3:1 hexanes : EtAc); IR: 1749, 1728, 1555 cm -1 ; major diastereomer: 1 NMR (500 Mz): δ (m, 3), (m, 2), 4.92 (dd, J = 13.1, 4.6 z, 1), 4.82 (dd, J = 13.1, 8.9 z, 1), (m, 1), 4.24 (d, J = 3.2 z, 1), 3.82 (d, J = 17.4 z, 1), 3.75 (s, 3), 3.67 (d, J = 17.4 z, 1), 3.21 (s, 3); 13 C NMR (125 Mz): δ 201.5, 167.6, 136.1, 129.1, 128.4, 128.0, 77.5, 59.2, 56.2, 52.9, 42.3; minor diastereomer: 1 NMR (500 Mz): δ (m, 3), (m, 2), 4.89 (dd, J = 13.1, 8.5 z, 1), 4.83 (dd, J = 13.1, 4.8 z, 1), (m, 1), 4.21 (d, J = 5.0 z, 1), 4.10 (d, J = 17.6 z, 1), 4.00 (d, J = 17.6 z, 1), 3.54 (s, 3), 3.36 (s, 3); 13 C NMR (125 Mz): δ 202.1, 167.2, 136.2, 129.0, 128.3, 127.9, 77.7, 59.4, 57.1, 52.7, 42.0; PLC (AD-, 2% ipr in hexanes, 1 ml/min): major diastereomer: t major = 44.1 min, t minor = 49.1 min, 94% ee, S8

9 minor diastereomer: t minor = 36.9 min, t major = 62.8 min, 86% ee; RMS (ESI+) Calcd for C N 6 Na + (M+Na) + : , Found: Benzoyl-4-nitro-3-phenylbutyric acid ethyl ester (12i). To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added ethyl benzoylacetate (11i; 52 µl, 0.40 mmol). After 9 h, the reaction mixture was concentrated, and purification by column chromatography (8:1 hexanes : EtAc, then 4:1 hexanes : EtAc) gave 12i (65 mg, 90%) as a 2.6:1 mixture of diastereomers: mp C; R f 0.26 (3:1 hexanes : EtAc); IR: 1735, 1685, 1554 cm -1 ; major diastereomer: 1 NMR (500 Mz): δ 7.86 (d, J = 7.3 z, 2), 7.56 (t, J = 7.3 z, 1), 7.42 (t, J = 7.7 z, 2), (m, 2), (m, 3), 4.97 (dd, J = 12.8, 5.0 z, 1), (m, 2), 4.44 (td, J = 8.7, 5.0 z, 1), 4.18 (q, J = 7.1 z, 2), 1.18 (t, J = 7.1 z, 3); 13 C NMR (125 Mz): δ 192.6, 167.7, 136.7, 136.0, 133.8, 128.9, 128.8, 128.2, 127.9, 77.9, 62.2, 56.3, 43.0, 13.9; minor diastereomer: 1 NMR (500 Mz): δ 8.06 (d, J = 7.3 z, 2), 7.62 (t, J = 7.3 z, 1), 7.49 (t, J = 7.7 z, 2), (m, 2), (m, 3), (m, 1), 4.81 (dd, J = 12.6, 4.6 z, 1), 4.77 (dd, J = 12.6, 8.5 z, 1), 4.49 (ddd, J = 9.6, 8.5, 4.8 z, 1), 3.87 (m, 2), 0.90 (t, J = 7.1 z, 3); 13 C NMR (125 Mz): δ 192.7, 166.9, 136.2, 135.8, 134.2, 128.7, 128.5, 128.3, 128.1, 77.9, 61.9, 57.0, 43.1, 13.6; PLC (D-, 10% ipr in hexanes, 1 ml/min, 230 nm): major diastereomer: t major = 13.3 min, t minor = 15.7 min, 92% ee, minor diastereomer: t major = 31.0 min, t minor = 17.6 min, 83% ee; RMS (ESI+) Calcd for C N 5 Na + (M+Na) + : , Found: Acetyl-2-(2-nitro-1-phenylethyl)-cyclopentanone (12j). 6 To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added 2- acetylcyclopentanone (11j; 48 µl, 0.40 mmol). After 24 h, the reaction mixture was concentrated, and purification by column chromatography (4:1 hexanes : EtAc) gave 12j (37 mg, 90%) as an 18:1 mixture of diastereomers. Analytical data matched previously reported values. 6 PLC (AD-, 5% Et in hexanes, 1 ml/min, 220 nm): major diastereomer: t major = 36.4 min, t minor = 53.8 min, 98% ee, minor diastereomer: t major = 31.2 min, t minor = 20.6 min, 96% ee. 1-(2-Nitro-1-phenylethyl)-2-oxo-cyclopentanecarboxylic acid methyl ester (12k). 6 To a solution of trans-β-nitrostyrene (7; 30 mg, mmol) and squaramide 5 (2.5 mg, mmol) in C 2 Cl 2 (0.6 ml) was added methyl 2-oxocyclopentanecarboxylate (11k; 51 µl, 0.40 mmol). After 24 h, the reaction mixture was concentrated, and purification by column chromatography (8:1 hexanes : EtAc) gave 12j (44 mg, 90%) as a 50:1 mixture of diastereomers. Analytical data matched previously reported values. 6 PLC (D-, 5% Et in hexanes, 1 ml/min, 230 nm): major diastereomer: t major = 22.9 min, t minor = 13.6 min, 93% ee, minor diastereomer: t major = 17.5 min, t minor = 11.6 min, 77% ee. S9

10 3-Acetyl-3-(2-nitro-1-phenylethyl)-dihydrofuran-2-one (12l). To a solution of trans-β-nitrostyrene (7; 75 mg, mmol) and squaramide 5 (1.5 mg, mmol) in C 2 Cl 2 (3.0 ml) was added α- acetylbutyrolactone (11l; 51 µl, 0.40 mmol). After 8 h, the reaction mixture was concentrated, and purification by column chromatography (4:1 hexanes : EtAc then 3:1 hexanes : EtAc) gave 12l (90 mg, 65%) as a 4:1 mixture of diastereomers: mp C; R f 0.16 (3:1 hexanes : EtAc); IR: 1761, 1717, 1555, 1379, 1170 cm -1 ; major diastereomer: 1 NMR (500 Mz): δ (m, 3), (m, 2), 5.07 (dd, J = 13.3, 11.2 z, 1), 4.74 (dd, J = 13.5, 3.7 z, 1), 4.35 (dd, J = 11.2, 3.7 z, 1), 4.10 (td, J = 8.7, 5.7 z, 1), 3.36 (td, J = 8.5, 6.6 z, 1), 2.57 (ddd, J = 13.9, 8.7, 6.5 z, 1), 2.35 (s, 3), (m, 1); 13 C NMR (125 Mz): δ 201.2, 175.3, 134.2, 129.4, 128.6, 76.3, 66.2, 62.9, 46.2, 30.0, 26.5; minor diastereomer: 1 NMR (500 Mz): δ (m, 3), (m, 2), 4.85 (td, J = 13.3, 3.7 z, 1), 4.53 (m, 2), 4.04 (q, J = 8.0 z, 1), 3.86 (td, J = 8.9, 4.4 z, 1), 2.85 (ddd, J = 13.3, 7.9, 4.4 z, 1), 2.50 (s, 3), (m, 1); 13 C NMR (125 Mz): δ 201.2, 175.3, 133.0, 129.2, 129.1, 129.0, 75.0, 66.0, 64.8, 45.6, 26.2, 25.6; PLC (D-, 20% Et in hexanes, 1 ml/min, 210 nm): major diastereomer: t major = 17.4 min, t minor = 10.9 min, 94% ee, minor diastereomer: t major = 39.0 min, t minor = 14.7 min, 91% ee; RMS (ESI+) Calcd for C N 5 Na + (M+Na) + : , Found: References 1) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. rg. Lett. 2005, 7, ) kino, T.; oashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, ) Wang, J.; Li,.; Duan, W..; Zu, L. S.; Wang, W. rg. Lett. 2005, 7, ) Kotrusz, P.; Toma, S.; Schmalz,. G.; Adler, A. Eur. J. rg. Chem. 2004, ) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, ) Deutsch, J.; Niclas,. J.; Ramm, M. J. Prakt. Chem.-Chem. Ztg. 1995, 337, S10

11 F 3 C N Me CF 3 3 (DMS-d 6, 315 K) S11

12 F 3 C N Me CF 3 3 (DMS-d6, rt) S12

13 F 3 C N N N CF 3 5 (DMS-d 6 ) N S13

14 F 3 C N N N CF 3 5 (DMS-d 6 ) N S14

15 Br 10c S15

16 Br 10c S16

17 Br 10d S17

18 Br 10d S18

19 F 10f S19

20 F 10f S20

21 Cl Cl 10g S21

22 Cl Cl 10g S22

23 10h S23

24 10h S24

25 10i S25

26 10i S26

27 Ph 12c S27

28 Ph 12c S28

29 Me Ph 12g S29

30 Me Ph 12g S30

31 Me Me Ph 12h S31

32 Me Me Ph 12h S32

33 Et Ph Ph 12i S33

34 Et Ph Ph 12i S34

35 CMe Ph 12l S35

36 CMe Ph 12l S36

37 8 (D-, 1 ml/min, 5% Et in hexanes, 210 nm) 10a (AD-, 1 ml/min, 10% ipr in hexanes, 230 nm) S37

38 10b (AD-, 10% ipr in hexanes, 1 ml/min, 230 nm) 10c (D-, 10% ipr in hexanes, 1 ml/min, 230 nm) S38

39 10d (AD-, 5% ipr in hexanes, 1 ml/min, 230 nm) 10e (D-, 10% ipr in hexanes, 0.85 ml/min, 230 nm) S39

40 10f (AD-, 5% ipr in hexanes, 1 ml/min, 220 nm) 10g (AD-, 10% ipr in hexanes, 1 ml/min, 230 nm) S40

41 10h (D-, 10% ipr in hexanes, 1 ml/min, 230 nm) 10i (AD-, 10% ipr in hexanes, 1 ml/min, 220 nm) S41

42 12a (D-, 10% ipr in hexanes, 1 ml/min, 230 nm) 12b (D-, 10% ipr in hexanes, 1 ml/min, 230 nm) S42

43 12c (D-, 10% ipr in hexanes, 1 ml/min, 220 nm) 12e (D-, 1 ml/min, 1% Et in hexanes, 230 nm) S43

44 12f (AD-, 5% ipr in hexanes, 1 ml/min, 220 nm) 12g (AD-, 5% ipr in hexanes, 1 ml/min, 230 nm) S44

45 12i (D-, 10% ipr in hexanes, 1 ml/min, 230 nm) 12j (AD-, 5% Et in hexanes, 1 ml/min, 220 nm) S45

46 12k (D-, 10% Et in hexanes, 1 ml/min, 230 nm) 12l (D-, 1 ml/min, 20% Et in hexanes, 210 nm) S46