Supplementary Materials for

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1 Supplementary Materials for Enantio- and Diastereodivergent Dual Catalysis: α-allylation of Branched Aldehydes Simon Krautwald, David Sarlah, Michael A. Schafroth, Erick M. Carreira* *Corresponding author. Published 31 May 2013, Science 340, 1065 (2013) DOI: /science This PDF file includes: Materials and Methods Supplementary Text Tables S1 to S8 References

2 Materials and Methods General Unless otherwise noted, all reactions were carried out under an atmosphere of nitrogen, and all reagents were purchased from commercial suppliers and used without further purification. Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 TLC glass plates and visualized with 254 nm light and ceric ammonium nitrate staining solutions followed by heating. Purification of reaction products was carried out by flash chromatography using Brunschwig silica 32-63, 60Å and analytical grade hexane, ethyl acetate and dichloromethane as eluents with bar pressure. All allylic alcohols were prepared by the reaction of the corresponding aldehyde with vinylmagnesium bromide. Analytical data were in accordance with previously reported values (23, 24, 34, 35). The ligands L1, (R)-L and (S)-L were prepared following known procedures (34). Aldehydes were purchased from commercial suppliers and distilled prior to use, or prepared following procedures described in the literature (36 39). The cinchona alkaloid derived primary amines were also prepared following procedures described in the literature (40, 41). 1 H-NMR spectra were recorded on Bruker AV 400 MHz or VARIAN Mercury 300 MHz spectrometers and are reported in ppm with the solvent resonance employed as the internal standard (CHCl 3 at 7.26 ppm). Peaks are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br = broad signal, coupling constant(s) in Hz, integration). 13 C-NMR spectra were recorded with 1 H- decoupling on Bruker AV 101 MHz spectrometers and are reported in ppm with the solvent resonance employed as the internal standard (CDCl 3 at ppm). Infrared spectra were measured neat on a Perkin-Elmer spectrum BX FT-IR spectrometer. The peaks are reported as absorption maxima (n, cm -1 ). High resolution mass spectral data were obtained at the mass spectrometry service operated by the Laboratory of Organic Chemistry at ETH Zurich on a VG-TRIBRID for electron impact ionization (EI) and Varian IonSpec spectrometer (ESI) and are reported as (m/z). Enantiomeric excesses were determined on a Jasco2080Plus supercritical fluid chromatography (SFC) system. The descriptors major enantiomer and minor enantiomer in the characterization section refer to the major and minor enantiomers of the major diastereoisomer. Optical rotations were measured with a Jasco DID-1000 Polarimeter, 10 cm, 1 ml cell. X-ray crystallographic data was collected by Dr. W. Bernd Schweizer of the Laboratorium für Organische Chemie at ETH Zurich. Melting points were measured on a Büchi B 540 melting point apparatus and are uncorrected.

3 Synthesis and Characterization of Products General Procedure for Iridium/Primary Amine Catalyzed α-allylation of Branched Aldehydes A) Preparation of Racemic Products (as SFC standards) [{Ir(cod)Cl} 2 ] (3.4 mg, 5.0 μmol, 0.02 equiv) and L1 (8.2 mg, 20.0 μmol, 0.08 equiv) were dissolved in reagent grade 1,2-dichloroethane (0.5 ml) in a screw capped glass vial. The vessel was purged with nitrogen and the mixture was vigorously stirred for 15 min. To the resulting red solution were added sequentially allylic alcohol 2 (0.25 mmol, 1.0 equiv), aldehyde 1 (0.275 mmol, 1.1 equiv), benzhydryl amine (9.2 mg, 50 μmol, 0.2 equiv), and trichloroacetic acid (20 mg, mmol, 0.5 equiv). The resulting solution was stirred at room temperature for 24 h. The mixture was concentrated in vacuo. A 1 H NMR spectrum of the crude mixture was recorded to determine the d.r. The mixture was then purified by flash chromatography to afford the product. B) Preparation of Enantioenriched Products (Figure 2) [{Ir(cod)Cl} 2 ] (5.0 mg, 7.5 μmol, 0.03 equiv) and (R)-L (15 mg, 30.0 μmol, 0.12 equiv) were dissolved in reagent grade 1,2-dichloroethane (0.5 ml) in a screw capped glass vial. The vessel was purged with nitrogen and the mixture was vigorously stirred for 15 min. To the resulting red solution were added sequentially allylic alcohol 2 (0.25 mmol, 1.0 equiv), aldehyde 1 (0.275 mmol, 1.1 equiv), cinchona-alkaloid derived primary amine (A2 or A3) (7.3 mg, 25 μmol, 0.1 equiv), and trichloroacetic acid (20 mg, mmol, 0.5 equiv). The resulting solution was stirred at room temperature for 24 h. The mixture was concentrated in vacuo. A 1 H NMR spectrum of the crude mixture was recorded to determine the d.r. The mixture was then purified by flash chromatography to afford the product.

4 C) Preparation of Enantioenriched Products (Figure 3) [{Ir(cod)Cl} 2 ] (3.4 mg, 5.0 μmol, 0.02 equiv) and (R)-L (10.2 mg, 20.0 μmol, 0.08 equiv) were dissolved in reagent grade 1,2-dichloroethane (0.5 ml) in a screw capped glass vial. The vessel was purged with nitrogen and the mixture was vigorously stirred for 15 min. To the resulting red solution were added sequentially allylic alcohol 2 (0.25 mmol, 1.0 equiv), aldehyde 1 (0.275 mmol, 1.1 equiv), cinchona-alkaloid derived primary amine (A2 or A3) (7.3 mg, 25 μmol, 0.1 equiv), and trichloroacetic acid (20 mg, mmol, 0.5 equiv). The resulting solution was stirred at room temperature for 24 h. The mixture was concentrated in vacuo. A 1 H NMR spectrum of the crude mixture was recorded to determine the d.r. The mixture was then purified by flash chromatography to afford the product.

5 Synthesis of All Stereoisomers of 3a (2R,3R)-2-methyl-2,3-diphenylpent-4-enal ((R,R)-3a) The corresponding compound was prepared following general procedure C using (R)-L, A2, alcohol 2a and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (48 mg, 77% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.74 (s, 1H), (m, 3H), (m, 5H), (m, 2H), 5.95 (ddd, J = 16.8, 10.4, 8.9 Hz, 1H), (m, 2H), 4.16 (d, J = 8.9 Hz, 1H), 1.39 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.5, 139.8, 138.2, 137.2, 129.9, 128.9, 128.4, 128.1, 127.5, 127.0, 117.9, 57.8, 55.6, IR (neat) 3060, 3028, 2982, 2932, 1722, 1599, 1494, 1446, 1359, 1266, 1180, 1157, 1075, 923, 759, 699 cm -1 ; HRMS (EI): m/z calcd for C 18 H 18 O [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 8.17 min, t R (2) = 9.41 min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 58.1 (c = 1.0, CHCl 3 ). (2R,3S)-2-methyl-2,3-diphenylpent-4-enal ((R,S)-3a) The corresponding compound was prepared following general procedure C using (S)-L, A2, alcohol 2a and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 15:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (49 mg, 78% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.83 (s, 1H), (m, 3H), (m, 5H), (m, 2H), 6.17 (ddd, J = 16.9, 10.3, 8.8 Hz, 1H), (m, 2H), 4.21 (d, J = 8.8 Hz, 1H), 1.51 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.6, 139.6, 138.8, 136.8, 129.6, 128.5, 128.1, 127.9, 127.4, 126.7, 118.6, 57.6, 55.7, IR (neat) 3060, 3028, 2982, 2932, 1722, 1599, 1494, 1446, 1359, 1266, 1180, 1157, 1075, 923, 759, 699 cm -1 ; HRMS (EI): m/z calcd for C 18 H 18 O [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C,

6 >99% ee (t R (1, minor enantiomer) = 8.17 min, t R (2, major enantiomer) = 9.41 min, t R (3) = min, t R (4) = min); [α] 19 D = (c = 1.0, CHCl 3 ). (2S,3S)-2-methyl-2,3-diphenylpent-4-enal ((S,S)-3a) The corresponding compound was prepared following general procedure C using (S)-L, A3, alcohol 2a and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (44 mg, 71% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (R,R)-3a (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 8.17 min, t R (2) = 9.41 min, t R (3, minor enantiomer) = min, t R (4, major enantiomer) = min); [α] 19 D = (c = 1.0, CHCl 3 ). (2S,3R)-2-methyl-2,3-diphenylpent-4-enal ((S,R)-3a) The corresponding compound was prepared following general procedure C using (R)-L, A3, alcohol 2a and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (50 mg, 80% yield). 1 H NMR, 13 C NMR and IR data were identical with that of the enantiomer (R,S)-3a (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = 8.17 min, t R (2, minor enantiomer) = 9.41 min, t R (3) = min, t R (4) = min); [α] 19 D = 31.5 (c = 1.0, CHCl 3 ).

7 Derivatization of (R,R)-3a for x-ray analysis: Synthesis of (R,R)-3a-carbamate A solution of (R,R)-3a (150 mg, 0.6 mmol) in 1/1 THF/methanol (8 ml) was cooled to 0 C. NaBH 4 (23 mg, 0.6 mmol, 1.0 equiv) was added in portions. When TLC showed complete consumption of the starting material, dichloromethane and water were added and the phases were separated. The aqueous phase was extracted with dichloromethane (1x), and the combined organic phases were dried over MgSO 4, filtered and concentrated in vacuo. To the crude alcohol (148 mg) in dichloromethane (5.0 ml) was added p- bromophenylisocyanate (356 mg, 1.8 mmol, 3 equiv) followed by triethylamine (0.42 ml, 3.0 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 24 hours. The mixture was directly loaded onto a column and eluted with hexane/ethyl acetate (9/1). This afforded the product as a colorless solid (284 mg, 73% yield). Recrystallization of this material from dichloromethane/methanol (slow diffusion) afforded colorless crystals. 1 H NMR (400 MHz, CDCl 3 ) δ (s, 1H), (m, 6H), (m, 3H), 7.18 (dd, J = 6.7, 3.6 Hz, 3H), (m, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.71 (dt, J = 8.4, 3.6 Hz, 2H), (m, 1H), 5.01 (dd, J = 10.2, 1.6 Hz, 1H), 4.85 (d, J = 16.9 Hz, 1H), 4.49 (d, J = 10.5 Hz, 1H), 4.13 (d, J = 10.5 Hz, 1H), 3.29 (d, J = 9.3 Hz, 1H), 1.03 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 155.4, 151.0, 141.2, 139.8, 137.3, 136.8, 135.9, 132.4, 132.1, 130.4, 129.6, 128.1, 128.1, 127.5, 127.0, 126.9, 122.5, 121.6, 117.5, 116.9, 74.0, 57.4, 44.8, IR (neat) 3282, 3061, 2977, 1728, 1696, 1593, 1537, 1487, 1398, 1372, 1299, 1266, 1236, 1178, 1134, 1114, 1072, 959, 909, 824, 769, 729, 700 cm -1 ; HRMS (ESI): m/z calcd for C 32 H 28 Br 2 N 2 NaO 3 [M+Na] , found [α] 19 D = 16.5 (c = 1.0, CHCl 3 ). Melting point C.

8 (2R,3R)-3-(4-fluorophenyl)-2-methyl-2-phenylpent-4-enal (3b) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2b and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (53 mg, 79% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.70 (s, 1H), (m, 3H), (m, 2H), (m, 4H), 5.91 (ddd, J = 16.9, 10.3, 8.7 Hz, 1H), (m, 2H), 4.12 (d, J = 8.7 Hz, 1H), 1.37 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.4, (d, J = Hz), 137.9, 137.1, (d, J = 3.4 Hz), (d, J = 7.8 Hz), 128.8, 128.5, 127.7, 118.0, (d, J = 21.1 Hz), 57.8, 54.8, F NMR (376 MHz, CDCl 3 ) δ IR (neat) 3058, 2982, 2933, 1722, 1600, 1508, 1445, 1266, 1223, 1160, 835, 700 cm -1 ; HRMS (EI): m/z calcd for C 18 H 17 FO [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 6.28 min, t R (2) = 6.80 min, t R (3, major enantiomer) = 7.83 min, t R (4, minor enantiomer) = 9.03 min); [α] 19 D = 28.6 (c = 1.0, CHCl 3 ). (2R,3R)-3-(4-iodophenyl)-2-methyl-2-phenylpent-4-enal (3c) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2c and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (81 mg, 86% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.68 (s, 1H), (m, 2H), (m, 3H), (m, 2H), (m, 2H), 5.88 (ddd, J = 16.9, 10.3, 8.8 Hz, 1H), (m, 2H), 4.08 (d, J = 8.8 Hz, 1H), 1.37 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.2, 139.6, 137.7, 137.1, 136.7, 132.0, 128.9, 128.5, 127.7, 118.3, 92.5, 57.6, 55.0, IR (neat) 3058, 3023, 2980, 2933, 1722, 1599, 1583, 1484, 1444, 1399, 1265, 1063, 1005, 921, 819, 700 cm -1 ; HRMS (EI): m/z calcd for C 18 H 17 IO [M] , found ; SFC Daicel Chiralpak IA, 2% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = min, t R (2, minor

9 enantiomer) = min, minor diastereomer not separated); [α] 19 D = 50.6 (c = 2.0, CHCl 3 ). (2R,3R)-3-(3-bromophenyl)-2-methyl-2-phenylpent-4-enal (3d) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2d and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (60 mg, 73% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.69 (s, 1H), (m, 4H), (m, 2H), (m, 2H), (m, 1H), 5.88 (ddd, J = 16.9, 10.3, 8.9 Hz, 1H), (m, 2H), 4.09 (d, J = 8.9 Hz, 1H), 1.38 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.0, 142.3, 137.6, 136.6, 133.0, 130.1, 129.6, 128.9, 128.6, 128.5, 127.8, 122.1, 118.4, 57.7, 55.2, IR (neat) 3056, 2980, 1723, 1592, 1565, 1495, 1474, 1445, 1429, 1374, 1073, 1029, 996, 924, 762, 701 cm -1 ; HRMS (EI): m/z calcd for C 18 H 17 BrO [M] , found ; SFC Daicel Chiralcel OJ- H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 9.39 min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 10.8 (c = 2.0, CHCl 3 ). (2R,3R)-2-methyl-3-(4-nitrophenyl)-2-phenylpent-4-enal (3e) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2e and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 15:1. Purification by flash chromatography (hexane/etoac = 10/1) afforded the product as a colorless solid (38 mg, 52% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), (m, 2H), (m, 3H), (m, 4H), 5.95 (ddd, J = 16.9, 10.2, 8.9 Hz, 1H), 5.11 (ddd, J = 10.2, 1.2, 0.7 Hz, 1H), (m, 1H), 4.21 (d, J = 8.9 Hz, 1H), 1.40 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 201.5, 147.9, 146.9, 137.1, 136.1, 130.9, 128.8, 128.7, 128.1, 123.2, 119.1, 57.8, 55.5, IR (neat) 2981, 1721, 1597, 1516, 1494, 1342, 1109, 925, 849, 700 cm -1 ; HRMS (ESI): m/z calcd for

10 C 18 H 17 NNaO 3 [M+Na] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 63.2 (c = 1.0, CHCl 3 ). Synthesis of All Stereoisomers of 3f (2R,3R)-2-methyl-2-phenyl-3-(4-formylphenyl)pent-4-enal ((R,R)-3f) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2f and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (50 mg, 72% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (s, 1H), 9.68 (s, 1H), (m, 2H), (m, 3H), (m, 4H), 5.95 (ddd, J = 16.9, 10.3, 8.9 Hz, 1H), (m, 2H), 4.20 (d, J = 8.9 Hz, 1H), 1.39 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 201.8, 192.0, 147.3, 137.5, 136.4, 135.2, 130.7, 129.4, 128.8, 128.6, 127.9, 118.7, 57.8, 55.8, IR (neat) 3058, 3027, 2982, 2933, 2826, 1720, 1696, 1604, 1574, 1495, 1445, 1212, 1171, 922, 827, 700 cm -1 ; HRMS (EI): m/z calcd for C 19 H 18 O 2 [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = (c = 1.0, CHCl 3 ). (2S,3R)-2-methyl-2-phenyl-3-(4-formylphenyl)pent-4-enal ((S,R)-3f) The corresponding compound was prepared following general procedure B using (R)-L, A3, alcohol 2f and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 20:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (47 mg, 67% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (s, 1H), 9.73 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), (m, 3H), 7.04 (dd, J = 8.1, 1.0 Hz, 2H),

11 6.98 (d, J = 8.0 Hz, 2H), (m, 1H), 5.25 (d, J = 10.2 Hz, 1H), 5.19 (d, J = 16.9 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 1.53 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 201.6, 192.1, 147.1, 137.9, 135.9, 134.9, 130.4, 129.2, 128.7, 128.1, 127.7, 119.4, 57.6, 55.5, IR (neat) 2987, 1722, 1695, 1606, 1576, 1494, 1446, 1420, 1360, 1267, 1212, 1172, 1068, 1018, 830, 760, 701 cm -1 ; HRMS (EI): m/z calcd for C 19 H 18 O 2 [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = min, t R (2, minor enantiomer) = min, t R (3) = min, t R (4) = min); [α] 19 D = 38.5 (c = 1.0, CHCl 3 ). (2R,3S)-2-methyl-2-phenyl-3-(4-formylphenyl)pent-4-enal ((R,S)-3f) The corresponding compound was prepared following general procedure B using (S)-L, A2, alcohol 2f and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 20:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (44 mg, 63% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (S,R)-3f (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, minor enantiomer) = min, t R (2, major enantiomer) = min, t R (3) = min, t R (4) = min); [α] 19 D = (c = 1.0, CHCl 3 ). (2S,3S)-2-methyl-2-phenyl-3-(4-formylphenyl)pent-4-enal ((S,S)-3f) The corresponding compound was prepared following general procedure B using (S)-L, A3, alcohol 2f and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (52 mg, 75% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (R,R)-3f (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = min, t R (2) = min, t R (3, minor enantiomer) = min, t R (4, major enantiomer) = min); [α] 19 D = (c = 1.0, CHCl 3 ).

12 (2R,3R)-2-methyl-2-phenyl-3-(3-(trifluoromethyl)phenyl)pent-4-enal (3g) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2g and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (51 mg, 64% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.70 (s, 1H), (m, 1H), (m, 4H), (m, 4H), 5.94 (ddd, J = 16.9, 10.3, 8.8 Hz, 1H), (m, 2H), 4.17 (d, J = 8.8 Hz, 1H), 1.37 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.0, 140.9, 137.4, 136.6, (q, J = 1.2 Hz), (q, J = 32.2 Hz) 128.8, 128.6, 128.5, 127.9, (q, J = 3.9 Hz), (q, J = Hz), (q, J = 3.8 Hz), 118.6, 57.8, 55.4, F NMR (376 MHz, CDCl 3 ) δ IR (neat) 3063, 2985, 2937, 1724, 1494, 1446, 1326, 1266, 1163, 1119, 1073, 922, 700 cm -1 ; HRMS (EI): m/z calcd for C 19 H 17 F 3 O [M] , found ; SFC Daicel Chiralcel OJ- H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 3.67 min, t R (2) = 3.91 min, t R (3, minor enantiomer) = 4.12 min, t R (4, major enantiomer) = 4.33 min); [α] 19 D = 22.7 (c = 1.0, CHCl 3 ). Methyl 4-((3R,4R)-4-methyl-5-oxo-4-phenylpent-1-en-3-yl)benzoate (3h) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2h and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (55 mg, 71% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.69 (s, 1H), (m, 2H), (m, 3H), (m, 2H), (m, 2H), 5.94 (ddd, J = 16.9, 10.3, 8.9 Hz, 1H), (m, 2H), 4.18 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H), 1.37 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.0, 167.1, 145.3, 137.6, 136.6, 130.0, 129.3, 128.9, 128.8, 128.5, 127.8, 118.5, 57.7, 55.6, 52.2, IR (neat) 3058, 3024, 2984, 2950, 1716, 1609, 1495, 1435, 1277, 1183, 1110, 1019, 921, 701 cm -1 ; HRMS (ESI): m/z calcd for C 20 H 20 NaO 3 [M+Na] , found ; SFC Daicel Chiralpak IC, 5% MeOH, 2.0 ml/min. 25 C, >99% ee (t R (1) = 9.21 min, t R (2,

13 major enantiomer) = 9.64 min, t R (3) = min, t R (4, minor enantiomer) = min); (after NaBH 4 reduction to the corresponding primary alcohol) Daicel Chiralpak IB, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = min, t R (2, major enantiomer) = min, t R (3) = min, t R (4, minor enantiomer) = min) [α] 19 D = (c = 1.0, CHCl 3 ). (2R,3R)-2-methyl-2-phenyl-3-(o-tolyl)pent-4-enal (3i) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2i and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (48 mg, 73%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (s, 1H), (m, 3H), (m, 4H), (m, 1H), 6.57 (dd, J = 7.8, 1.1 Hz, 1H), 5.92 (ddd, J = 16.7, 10.3, 8.6 Hz, 1H), (m, 2H), 4.41 (d, J = 8.6 Hz, 1H), 2.34 (s, 3H), 1.39 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 203.0, 138.7, 138.3, 138.2, 136.7, 130.7, 129.3, 129.1, 128.3, 127.6, 126.6, 125.6, 117.2, 58.3, 50.3, 20.6, IR (neat) 3060, 3023, 2977, 1722, 1634, 1600, 1490, 1461, 1444, 1370, 1159, 1050, 1030, 997, 917, 737 cm -1 ; HRMS (EI): m/z calcd for C 19 H 20 O [M] , found ; SFC (after NaBH 4 reduction to the corresponding primary alcohol) Daicel Chiralcel OJ-H, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, minor enantiomer) = 7.41 min, t R (2) = 7.71 min, t R (3, major enantiomer) = 7.98 min, t R (4) = 9.03 min); [α] 19 D = 63.2 (c = 1.0, CHCl 3 ). (2R,3R)-3-(4-methoxyphenyl)-2-methyl-2-phenylpent-4-enal (3j) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2j and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (30 mg, 43% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.73 (s, 1H), (m, 3H), (m, 2H), (m, 2H), (m, 2H),

14 5.91 (ddd, J = 16.9, 10.3, 8.7 Hz, 1H), 5.01 (m, 2H), 4.11 (d, J = 8.7 Hz, 1H), 3.77 (s, 3H), 1.38 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.7, 158.6, 138.3, 137.4, 131.8, 130.9, 128.8, 128.4, 127.5, 117.6, 113.5, 57.9, 55.3, 54.8, IR (neat) 3058, 2933, 2835, 1721, 1609, 1510, 1463, 1444, 1302, 1265, 1246, 1179, 1032, 832, 700 cm -1 ; HRMS (EI): m/z calcd for C 19 H 20 O 2 [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 42.8 (c = 1.0, CHCl 3 ). Synthesis of All Stereoisomers of 3k (2R,3R)-3-(3-methoxyphenyl)-2-methyl-2-phenylpent-4-enal ((R,R)-3k) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2k and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (47 mg, 67% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.74 (s, 1H), (m, 3H), (m, 2H), (m, 1H), 6.75 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), (m, 1H), 5.92 (ddd, J = 17.5, 9.6, 9.0 Hz, 1H), (m, 2H), 4.11 (d, J = 9.0 Hz, 1H), 3.68 (s, 3H), 1.39 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.5, 159.3, 141.4, 138.2, 137.1, 129.1, 129.0, 128.4, 127.6, 122.4, 117.9, 115.5, 112.5, 57.7, 55.7, 55.2, IR (neat) 3058, 2938, 2834, 1722, 1598, 1582, 1490, 1464, 1453, 1264, 1248, 1156, 1045, 920, 755, 698 cm -1 ; HRMS (EI): m/z calcd for C 19 H 20 O 2 [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 9.65 min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 42.3 (c = 2.0, CHCl 3 ).

15 (2S,3R)-3-(3-methoxyphenyl)-2-methyl-2-phenylpent-4-enal ((S,R)-3k) The corresponding compound was prepared following general procedure B using (R)-L, A3, alcohol 2k and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 15:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (51 mg, 73% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.82 (s, 1H), (m, 3H), 7.12 (dd, J = 5.3, 3.1 Hz, 2H), 7.03 (t, J = 7.9 Hz, 1H), (m, 1H), 6.48 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 4.17 (d, J = 8.9 Hz, 1H), 3.60 (s, 3H), 1.49 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.5, 159.0, 141.2, 138.9, 136.6, 128.7, 128.5, 128.1, 127.4, 122.0, 118.6, 115.3, 112.4, 57.5, 55.8, 55.1, IR (neat) 2979, 2834, 1722, 1599, 1582, 1491, 1445, 1373, 1317, 1264, 1247, 1153, 1044, 997, 921, 887, 779, 698 cm -1 ; HRMS (EI): m/z calcd for C 19 H 20 O 2 [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = 9.65 min, t R (2, minor enantiomer) = min, t R (3) = min, t R (4) = min); [α] 19 D = 28.5 (c = 1.0, CHCl 3 ). (2R,3S)-3-(3-methoxyphenyl)-2-methyl-2-phenylpent-4-enal ((R,S)-3k) The corresponding compound was prepared following general procedure B using (S)-L, A2, alcohol 2k and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (47 mg, 67% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (S,R)-3k (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, minor enantiomer) = 9.65 min, t R (2, major enantiomer) = min, t R (3) = min, t R (4) = min); [α] 19 D = (c = 1.0, CHCl 3 ).

16 (2S,3S)-3-(3-methoxyphenyl)-2-methyl-2-phenylpent-4-enal ((S,S)-3k) The corresponding compound was prepared following general procedure B using (S)-L, A3, alcohol 2k and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 14:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (51 mg, 73% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (R,R)-3k (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 9.65 min, t R (2) = min, t R (3, minor enantiomer) = min, t R (4, major enantiomer) = min); [α] 19 D = (c = 1.0, CHCl 3 ). (2R,3R)-3-(2-methoxyphenyl)-2-methyl-2-phenylpent-4-enal (3l) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2l and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (37 mg, 53% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.78 (s, 1H), (m, 5H), 7.19 (tdd, J = 7.9, 5.7, 2.2 Hz, 1H), (m, 3H), 5.96 (ddd, J = 16.9, 10.3, 8.8 Hz, 1H), (m, 2H), 4.82 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 1.37 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.3, 156.8, 139.3, 136.7, 130.4, 128.6, 128.4, 128.1, 128.0, 127.2, 120.3, 118.0, 110.7, 58.4, 55.4, 46.6, IR (neat) 3059, 2938, 2835, 1720, 1598, 1583, 1491, 1463, 1444, 1264, 1242, 1162, 1049, 1028, 919, 755, 700 cm -1 ; HRMS (EI): m/z calcd for C 19 H 20 O 2 [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 8.48 min, t R (2) = 9.68 min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 9.7 (c = 1.0, CHCl 3 ).

17 (2R,3R)-2-methyl-2-phenyl-3-(p-tolyl)pent-4-enal (3m) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2m and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (44 mg, 67% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.74 (s, 1H), (m, 3H), (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), (m, 2H), 5.92 (ddd, J = 16.8, 10.5, 8.8 Hz, 1H), (m, 2H), 4.13 (d, J = 8.8 Hz, 1H), 2.30 (s, 3H), 1.39 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.7, 138.3, 137.3, 136.7, 136.6, 129.8, 128.9, 128.8, 128.4, 127.5, 117.7, 57.8, 55.2, 21.2, IR (neat) 3056, 3023, 2980, 2921, 1722, 1512, 1494, 1444, 1373, 1188, 1074, 1029, 918, 815, 699 cm -1 ; HRMS (EI): m/z calcd for C 19 H 20 O [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 7.88 min, t R (2) = 9.23 min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 67.1 (c = 1.0, CHCl 3 ). (2R,3R)-2-methyl-3-(naphthalen-2-yl)-2-phenylpent-4-enal (3n) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2n and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 14:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (62 mg, 83% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.79 (s, 1H), (m, 1H), (m, 2H), (m, 6H), (m, 2H), 7.03 (dd, J = 8.5, 1.8 Hz, 1H), 6.06 (ddd, J = 16.7, 10.5, 8.7 Hz, 1H), (m, 2H), 4.34 (d, J = 8.7 Hz, 1H), 1.43 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.5, 138.2, 137.4, 137.2, 133.3, 132.5, 129.0, 128.9, 128.5, 128.1, 127.9, , , 127.5, 126.1, 125.9, 118.1, 57.9, 55.6, IR (neat) 3057, 3022, 2979, 1722, 1633, 1598, 1507, 1494, 1444, 1373, 1272, 1074, 920, 819, 748, 700 cm -1 ; HRMS (EI): m/z calcd for C 22 H 20 O [M] , found ; SFC (after NaBH 4 reduction to the corresponding primary alcohol) Daicel Chiralpak IB, 10% MeOH, 2.0 ml/min., 25 C,

18 >99% ee (t R (1) = min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = (c = 1.0, CHCl 3 ). Synthesis of All Stereoisomers of 3o (2R,3R)-2-methyl-2-phenyl-3-(thiophen-3-yl)pent-4-enal ((R,R)-3o) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2o and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (41 mg, 64% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.71 (s, 1H), (m, 3H), (m, 2H), (m, 1H), 6.89 (ddd, J = 3.0, 1.3, 0.5 Hz, 1H), 6.73 (dd, J = 5.0, 1.3 Hz, 1H), 5.88 (ddd, J = 17.0, 10.3, 8.7 Hz, 1H), (m, 2H), 4.35 (d, J = 8.7 Hz, 1H), 1.45 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.3, 140.2, 138.4, 136.7, 128.7, 128.6, 128.5, 127.6, 124.9, 123.1, 117.8, 57.7, 50.9, IR (neat) 3087, 2980, 2932, 1721, 1598, 1495, 1445, 1358, 1265, 1076, 1028, 920, 843, 788, 760, 699 cm -1 ; HRMS (EI): m/z calcd for C 16 H 16 OS [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 8.64 min, t R (2) = 8.91 min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 77.0 (c = 1.0, CHCl 3 ). (2S,3R)-2-methyl-2-phenyl-3-(thiophen-3-yl)pent-4-enal ((S,R)-3o) The corresponding compound was prepared following general procedure B using (R)-L, A3, alcohol 2o and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 11:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (45 mg, 70% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.76 (s, 1H), (m, 3H), (m, 2H), 7.06 (dd, J = 4.8, 3.0 Hz, 1H), (m, 1H), 6.51 (d, J = 5.0 Hz, 1H), 6.06 (ddd, J = 16.8, 10.3, 8.9 Hz, 1H), (m, 2H), 4.36 (d, J = 8.9 Hz, 1H), 1.49 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 202.3, 139.8,

19 138.8, 136.5, 128.6, 128.4, 128.0, 127.5, 124.4, 122.7, 118.5, 57.6, 51.2, IR (neat) 2980, 1722, 1636, 1598, 1495, 1445, 1373, 1081, 1029, 999, 919, 775, 700 cm -1 ; HRMS (EI): m/z calcd for C 16 H 16 OS [M] , found ; SFC Daicel Chiralcel OJ- H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = 8.64 min, t R (2, minor enantiomer) = 8.91 min, t R (3) = min, t R (4) = min); [α] 19 D = 57.2 (c = 1.0, CHCl 3 ). (2R,3S)-2-methyl-2-phenyl-3-(thiophen-3-yl)pent-4-enal ((R,S)-3o) The corresponding compound was prepared following general procedure B using (S)-L, A2, alcohol 2o and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 10:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (41 mg, 64% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (S,R)-3o (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, minor enantiomer) = 8.64 min, t R (2, major enantiomer) = 8.91 min, t R (3) = min, t R (4) = min); [α] 19 D = (c = 1.0, CHCl 3 ). (2S,3S)-2-methyl-2-phenyl-3-(thiophen-3-yl)pent-4-enal ((S,S)-3o) The corresponding compound was prepared following general procedure B using (S)-L, A3, alcohol 2o and hydratropaldehyde. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 1/1) afforded the product as a colorless oil (45 mg, 70% yield). 1 H NMR, 13 C NMR, and IR data were identical with that of the enantiomer (R,R)-3o (see above). SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 8.64 min, t R (2) = 8.91 min, t R (3, minor enantiomer) = min, t R (4, major enantiomer) = min); [α] 19 D = (c = 1.0, CHCl 3 ).

20 (2S,3R)-2-methyl-3-phenyl-2-propylpent-4-enal (3p) The corresponding compound was prepared following general procedure C using (R)-L, A2, alcohol 2a and 2-methylvaleraldehyde. 1 H NMR analysis of the crude mixture showed a d.r. of 6:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (41 mg, 76% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.57 (s, 1H), (m, 2H), (m, 1H), (m, 2H), 6.19 (dt, J = 16.8, 9.8 Hz, 1H), 5.19 (dd, J = 10.1, 1.5 Hz, 1H), 5.13 (ddd, J = 16.8, 1.5, 0.7 Hz, 1H), 3.50 (d, J = 9.8 Hz, 1H), (m, 1H), 1.45 (ddd, J = 13.9, 12.5, 4.7 Hz, 1H), (m, 1H), (m, 1H), 1.05 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.8, 140.3, 136.3, 129.1, 128.5, 127.0, 118.2, 56.7, 52.4, 37.1, 17.6, 16.0, IR (neat) 3063, 2960, 2933, 2873, 1720, 1493, 1465, 1453, 1379, 1156, 1072, 995, 919, 702 cm -1 ; HRMS (EI): m/z calcd for C 15 H 20 O [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, minor enantiomer) = 6.48 min, t R (2, major enantiomer) = 7.21 min, minor diastereomer not separated); [α] 19 D = 46.7 (c = 1.0, CHCl 3 ). (2S,3R)-2-methyl-2-(2-nitroethyl)-3-phenylpent-4-enal (3q) The corresponding compound was prepared following general procedure C using (R)-L, A2 (0.2 equiv), trichloroacetic acid (1.0 equiv), alcohol 2a and 2-methyl-4-nitrobutanal. 1 H NMR analysis of the crude mixture showed a d.r. of 6.5:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (33 mg, 53% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.50 (s, 1H), (m, 3H), (m, 2H), 6.19 (dt, J = 16.8 Hz, 9.9 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 3.51 (d, J = 9.6 Hz, 1H), (m, 1H), (m, 1H), 1.13 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.4, 138.4, 135.1, 129.2, 128.9, 127.6, 119.5, 71.8, 56.7, 51.2, 30.6, IR (neat) 3062, 2978, 1720, 1549, 1453, 1380, 1073, 996, 927, 704 cm -1 ; HRMS (ESI): m/z calcd for C 14 H 17 NNaO 3 [M+Na] , found

21 ; SFC Daicel Chiralcel OJ-H, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = min, t R (2) = min, t R (3, minor enantiomer) = min, t R (4) = min); [α] 19 D = 59.7 (c = 1.0, CHCl 3 ). (4S,5R)-4-formyl-4-methyl-5-phenylhept-6-en-1-yl benzoate (3r) The corresponding compound was prepared following general procedure C using (R)-L, A2 (0.2 equiv), trichloroacetic acid (1.0 equiv), alcohol 2a and 4-methyl-5-oxopentyl benzoate. 1 H NMR analysis of the crude mixture showed a d.r. of 4:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (52 mg, 62% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.60 (s, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 5H), 6.20 (dt, J = 16.8, 9.8 Hz, 1H), 5.20 (dd, J = 10.0, 1.4 Hz, 1H), 5.15 (ddd, J = 16.8, 1.4, 0.7 Hz, 1H), (m, 2H), 3.53 (d, J = 9.8 Hz, 1H), (m, 4H), 1.11 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.2, 166.7, 139.8, 136.0, 133.1, 130.4, 129.7, 129.1, 128.6, 128.5, 127.1, 118.5, 65.1, 56.6, 52.0, 30.7, 23.7, IR (neat) 3063, 3030, 2975, 1714, 1491, 1451, 1314, 1271, 1175, 1110, 1070, 1026, 921, 700 cm -1 ; HRMS (EI): m/z calcd for C 16 H 18 O [M C 6 H 6 O 2 ] , found ; SFC Daicel Chiralpak IB, 2% MeOH, 2.0 ml/min. 25 C, >99% ee (t R (1) = min, t R (2) = min, t R (3, minor enantiomer) = min, t R (4, major enantiomer) = min; (after NaBH 4 reduction to the corresponding primary alcohol) Daicel Chiralpak IB, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, minor enantiomer) = min, t R (2, major enantiomer) = min, minor diastereomer not separated); [α] 19 D = 34.6 (c = 1.0, CHCl 3 ).

22 (2S,3R)-2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2-methyl-3-phenylpent-4-enal (3s) The corresponding compound was prepared following general procedure C using (R)-L, A2 (0.2 equiv), trichloroacetic acid (1.0 equiv), alcohol 2a and 5-(1,3-dioxoisoindolin-2- yl)-2-methylpentanal. 1 H NMR analysis of the crude mixture showed a d.r. of 4.5:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (67 mg, 74% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (s, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), 6.15 (dt, J = 16.7, 9.9 Hz, 1H), 5.16 (dd, J = 10.1, 1.5 Hz, 1H), 5.12 (ddd, J = 16.7, 1.5, 0.8 Hz, 1H), (m, 2H), 3.48 (d, J = 9.9 Hz, 1H), (m, 2H), (m, 2H), 1.05 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.0, 168.4, 139.8, 136.0, 134.1, 132.2, 129.1, 128.5, 127.1, 123.4, 118.5, 56.4, 51.9, 38.3, 31.5, 23.5, IR (neat) 3062, 2975, 2939, 1771, 1705, 1615, 1466, 1437, 1396, 1360, 1187, 1070, 1021, 751, 719 cm -1 ; HRMS (EI): m/z calcd for C 23 H 23 NO 3 [M] , found ; SFC Daicel Chiralcel OJ-H, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 9.65 min, t R (2) = min, t R (3, major enantiomer) = min, t R (4, minor enantiomer) = min); [α] 19 D = 23.5 (c = 1.0, CHCl 3 ). (R)-tert-butyl 3-formyl-3-((R)-1-phenylallyl)indoline-1-carboxylate (3t) The corresponding compound was prepared following general procedure C using (R)-L, A2, alcohol 2a and tert-butyl 3-formylindoline-1-carboxylate. 1 H NMR analysis of the crude mixture showed a d.r. >20:1. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a yellow oil (70 mg, 77% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.63 (s, 1H), 7.87 (s, broad, 1H), (m, 5H), (m, 3H), 5.97 (ddd, J = 17.1, 10.3, 7.3 Hz, 1H), 5.16 (d, J = 10.3 Hz, 1H), 4.96 (dt, J = 17.1, 1.4 Hz, 1H), 4.45 (d, J = 10.9 Hz, 1H), (m, 2H), 1.55 (s, 9H). 13 C NMR (101 MHz,

23 CDCl 3 ) δ 197.2, 152.1, 143.7, 138.3, 135.5, 129.9, 129.0, 128.9, 127.7, 124.7, , , 119.4, 115.5, 81.2, 62.2, 54.0, 50.1, IR (neat) 2977, 1722, 1703, 1597, 1483, 1454, 1381, 1355, 1336, 1293, 1246, 1147, 1053, 925, 752 cm -1 ; HRMS (ESI): m/z calcd for C 23 H 25 NNaO 3 [M+Na] , found ; SFC Daicel Chiralcel OJ- H, 2% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = 5.96 min, t R (2, minor enantiomer) = 7.69 min, minor diastereomer not separated); [α] 19 D = (c = 1.0, CHCl 3 ). (R)-2,2-dimethyl-3-phenylpent-4-enal (3u) The corresponding compound was prepared following general procedure C using (R)-L, A2 alcohol 2a and isobutyraldehyde. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (40 mg, 85% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.58 (s, 1H), (m, 3H), (m, 2H), 6.18 (ddd, J = 16.9, 10.2, 9.3 Hz, 1H), (m, 2H), 3.50 (d, J = 9.3 Hz, 1H), 1.08 (s, 3H), 1.00 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.1, 139.8, 136.5, 129.3, 128.4, 127.0, 118.1, 56.3, 49.4, 20.6, IR (neat) 3063, 2976, 2932, 1722, 1600, 1583, 1492, 1466, 1453, 1366, 1185, 1139, 1072, 995, 919, 744, 702 cm -1 ; HRMS (EI): m/z calcd for C 13 H 16 O [M] , found ; SFC Daicel Chiralpak IA, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = 4.02 min, t R (2, minor enantiomer) = 4.48 min); [α] 19 D = 74.4 (c = 1.0, CHCl 3 ). (R)-1-(1-phenylallyl)cyclohexanecarbaldehyde (3v) The corresponding compound was prepared following general procedure C using (R)-L, A2, alcohol 2a and cyclohexanecarbaldehyde. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil (41 mg, 72% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.53 (s, 1H), 7.28 (m, 2H), (m, 1H), (m, 2H), 6.18 (dt, J = 16.8, 9.9 Hz, 1H), (m, 2H), 3.28 (d, J = 9.9 Hz, 1H), (m, 1H), (m, 1H), (m, 3H), 1.35 (ddd, J = 9.3, 8.4, 3.4

24 Hz, 1H), (m, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ 208.3, 139.7, 136.3, 129.2, 128.4, 127.0, 117.9, 58.5, 52.6, 30.4, 30.0, 25.6, 23.0, IR (neat) 3063, 2930, 2854, 1717, 1600, 1491, 1451, 1242, 1202, 1128, 1071, 917, 702 cm -1 ; HRMS (EI): m/z calcd for C 16 H 20 O [M] , found ; SFC Daicel Chiralcel OJ-H, 1% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = min, t R (2, minor enantiomer) = min); [α] 19 D = 33.3 (c = 1.0, CHCl 3 ). (R)-tert-butyl 4-formyl-4-(1-phenylallyl)piperidine-1-carboxylate (3w) The corresponding compound was prepared following general procedure C using (R)-L, A2, alcohol 2a and tert-butyl 4-formylpiperidine-1-carboxylate. Purification by flash chromatography (hexane/etoac = 20/1) afforded the product as a colorless oil (65 mg, 79% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.59 (s, 1H), (m, 3H), (m, 2H), 6.14 (dt, J = 16.8, 9.9 Hz, 1H), 5.19 (dd, J = 9.9 Hz, 1.4 Hz, 1H), 5.12 (dd, J = 16.8, 0.5 Hz, 1H), 3.94 (s, 2H), 3.30 (d, J = 9.9 Hz, 1H), 2.65 (s, 2H), 2.08 (dd, J = 13.7, 2.2 Hz, 1H), 1.84 (dd, J = 14.5, 12.9 Hz, 1H), 1.59 (d, J = 12.5 Hz, 1H), (m, 1H), 1.42 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.7, 154.9, 138.8, 135.4, 129.1, 128.6, 127.3, 118.8, 79.7, 58.2, 51.3, 41.1, 29.5, IR (neat) 3063, 2975, 2928, 1722, 1688, 1477, 1453, 1423, 1365, 1279, 1264, 1244, 1173, 1155, 922, 704 cm -1 ; HRMS (ESI): m/z calcd for C 20 H 27 NNaO 3 [M+Na] , found ; SFC Daicel Chiralpak IA, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1, major enantiomer) = 6.00 min, t R (2, minor enantiomer) = 6.90 min); [α] 19 D = 18.3 (c = 1.0, CHCl 3 ). (2R,3S,E)-3-butyl-2-methyl-2-phenylhepta-4,6-dienal (3x) The corresponding compound was prepared following general procedure B using (R)-L, A2, alcohol 2x and hydratropaldehyde (1.5 equiv). 1 H NMR analysis of the crude mixture showed a d.r. of 5:1. Purification by flash chromatography (hexane/ch 2 Cl 2 = 2/1) afforded the product as a colorless oil containing 5% of an inseparable regio-isomeric

25 impurity (according to 1 H NMR) (39 mg, 57% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.67 (s, 1H), (m, 2H), (m, 3H), 6.15 (dt, J = 16.9, 10.2 Hz, 1H), 5.84 (dd, J = 15.1, 10.6 Hz, 1H), 5.25 (dd, J = 15.1, 9.3 Hz, 1H), (m, 1H), 4.91 (dd, J = 10.2, 1.6 Hz, 1H), (m, 1H), 1.44 (s, 3H), (m, 6H), 0.86 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ , , , , , , , , , 57.54, 48.57, 30.51, 30.08, 22.75, 16.27, IR (neat) 2959, 2930, 2859, 1721, 1600, 1495, 1445, 1375, 1266, 1070, 1028, 1004, 971, 898, 760, 699 cm -1 ; HRMS (EI): m/z calcd for C 18 H 24 O [M] , found ; SFC (after NaBH 4 reduction to the corresponding primary alcohol) Daicel Chiralpak IA, 5% MeOH, 2.0 ml/min., 25 C, >99% ee (t R (1) = 4.43 min, t R (2, major enantiomer) = 5.82, t R (3) = 7.23 min, t R (4, minor enantiomer) = 7.60); [α] 19 D = 10.9 (c = 1.0, CHCl 3 ).

26 SFC Traces 1) Synthesis of All Stereoisomers of 3a 2) All other Compounds

27 1) Synthesis of All Stereoisomers of 3a Racemic

28 Enantiomerically Pure

29

30

31

32 2) All Other Compounds Racemic Enantiomerically Pure

33 Racemic one diastereoisomer not separated Enantiomerically Pure

34 Racemic Enantiomerically Pure

35 Racemic Enantiomerically Pure

36 Racemic Enantiomerically Pure

37

38 Racemic

39 Enantiomerically Pure Racemic

40 Enantiomerically Pure Racemic

41 Enantiomerically Pure Racemic

42 Enantiomerically Pure Racemic

43 Enantiomerically Pure Racemic

44 Enantiomerically Pure

45

46 Racemic Enantiomerically Pure

47 Racemic Enantiomerically Pure

48 Racemic Enantiomerically Pure

49 Racemic Enantiomerically Pure

50

51 Racemic one diastereoisomer not separated

52 Enantiomerically Pure Racemic

53 Enantiomerically Pure Racemic

54 Enantiomerically Pure Racemic one diastereoisomer not separated

55 Enantiomerically Pure Racemic

56 Enantiomerically Pure Racemic

57 Enantiomerically Pure Racemic

58 Enantiomerically Pure Racemic

59 Enantiomerically Pure Racemic

60 Enantiomerically Pure Racemic Peaks 2, 3, 5 and 8 due to regio-isomeric impurity.

61 Enantiomerically Pure

62 NMR Spectra

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90 X-ray data for (R,R)-3a-carbamate ORTEP Representation at 30% Probability A clear colourless plate-like specimen of C 32 H 28 Br 2 N 2 O 3, approximate dimensions mm x mm x mm, was used for the X-ray crystallographic analysis. The X- ray intensity data were measured on a Bruker Nonius APEX-II system equipped with a graphite monochromator. A total of 1659 frames were collected. The total exposure time was 9.22 hours. The frames were integrated with the Bruker SAINT software package using a narrow frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of reflections to a maximum θ angle of (0.77 Å resolution), of which 6548 were independent (average redundancy 7.311, completeness = 99.8%, R int = 6.42%, R sig = 5.65%) and 5435 (83.00%) were greater than 2σ(F 2 ). The final cell constants of a = (8) Å, b = (11) Å, c = (19) Å, volume = (4) Å 3, are based upon the refinement of the XYZ-centroids of 8768 reflections above 20 σ(i) with < 2θ < Data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmission was The calculated minimum and maximum transmission coefficients (based on crystal size) are and

91 The structure was solved and refined using the OLEX2 and Bruker SHELXTL Software Package, using the space group P , with Z = 4 for the formula unit, C 32 H 28 Br 2 N 2 O 3. The final anisotropic full-matrix least-squares refinement on F 2 with 365 variables converged at R1 = 3.44%, for the observed data and wr2 = 6.39% for all data. The goodness-of-fit was The largest peak in the final difference electron density synthesis was e - /Å 3 and the largest hole was e - /Å 3 with an RMS deviation of e - /Å 3. On the basis of the final model, the calculated density was g/cm 3 and F(000), 1312 e -. Table S1. Sample and crystal data for ca Identification code ca Chemical formula C 32 H 28 Br 2 N 2 O 3 Formula weight Temperature 100(2) K Wavelength Å Crystal size x x mm Crystal habit clear colourless plate Crystal system orthorhombic Space group P Unit cell dimensions a = (8) Å α = 90 b = (11) Å β = 90 c = (19) Å γ = 90 Volume (4) Å 3 Z 4 Density (calculated) g/cm 3 Absorption coefficient mm -1 F(000) 1312

92 Table S2. Data collection and structure refinement for ca Diffractometer Bruker Nonius APEX-II Theta range for data collection 2.49 to Index ranges Reflections collected <=h<=13, -16<=k<=16, -27<=l<=27 Independent reflections 6548 [R(int) = ] Coverage of independent reflections 99.8% Absorption correction multi-scan Max. and min. transmission and Structure solution technique direct methods Structure solution program SHELXS-97 (Sheldrick, 2008) Refinement method Full-matrix least-squares on F 2 Refinement program SHELXL-97 (Sheldrick, 2008) Function minimized Σ w(f 2 o - F 2 c ) 2 Data / restraints / parameters 6548 / 3 / 365 Goodness-of-fit on F Δ/σ max Final R indices 5435 data; I>2σ(I) R1 = , wr2 = all data R1 = , wr2 = Weighting scheme w=1/[σ 2 (F o 2 )+(0.0250P) P] where P=(F o 2 +2F c 2 )/3 Absolute structure parameter 0.0(0) Largest diff. peak and hole and eå -3 R.M.S. deviation from mean eå -3