Supporting Information

Supporting Information Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2012 Highly Enantioselective Proline-Catalysed Direct Aldol Reaction of ChloACHTUNGTRENUNGroacetone and Aromatic Aldehydes ngel Martínez-CastaÇeda, BelØn Poladura, Humberto Rodríguez-Solla, Carmen Concellón,* and Vicente del Amo* [a] chem_201103667_sm_miscellaneous_information.pdf

Chemistry- A European Journal SUPPORTING INFORMATION Highly Enantioselective Proline-Catalyzed Direct Aldol Reaction of Chloroacetone and Aromatic Aldehydes Ángel Martínez-Castañeda, Belén Poladura, Humberto Rodríguez-Solla, Carmen Concellón* and Vicente del Amo* Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Claveria 8, 33006, Oviedo, Spain ccf@uniovi.es; vdelamo@uniovi.es General... 1 Preparation of tetrafluoroborate guanidinium salt 8... 3 Standard procedure for the synthesis of α-chloro-β-hidroxyketones 7a-k... 5 (3S,4S)-3-Chloro-4-hydroxy-4-(4-nitrophenyl)butan-2-one (7a)... 6 (3S,4S)-3-Chloro-4-hydroxy-4-(3-nitrophenyl)butan-2-one (7b)... 8 (3S,4S)-3-Chloro-4-hydroxy-4-(2-nitrophenyl)butan-2-one (7c)... 10 (3S,4S)-3-Chloro-4-hydroxy-4-(4-(methoxycarbonyl)phenyl)butan-2-one (7d)... 12 (3S,4S)-3-Chloro-4-(4-cyanophenyl)-4-hydroxybutan-2-one (7e)... 14 (3S,4S)-3-Chloro-4-(3-fluorophenyl)-4-hydroxybutan-2-one (7f)... 16 (3S,4S)-3-Chloro-4-(4-chlorophenyl)-4-hydroxybutan-2-one (7g)... 18 (3S,4S)-3-Chloro-4-(3-chlorophenyl)-4-hydroxybutan-2-one (7h)... 20 (3S,4S)-4-(4-Bromophenyl)-3-chloro-4-hydroxybutan-2-one (7i)... 22 (3S,4S)-4-(2-Bromophenyl)-3-chloro-4-hydroxybutan-2-one (7j)... 24 (3S,4S)-3-Chloro-4-hydroxy-4-phenylbutan-2-one (7k)... 26 Standard procedure for the synthesis of epoxides 10a,c,d,f,k... 28 (3R,4S)-Epoxy-4-(4-nitrophenyl)butan-2-one (10a)... 29 (3R,4S)-Epoxy-4-(2-nitrophenyl)butan-2-one (10c)... 31 (3R,4S)-Epoxy-4-[4-(methoxycarbonyl)-phenyl]-butan-2-one (10d)... 33 (3R,4S)-Epoxy-4-(3-fluorophenyl)butan-2-one (10f)... 35 (3R,4S)-Epoxy-4-phenylbutan-2-one (10k)... 37 Proline-catalyzed aldol reaction, without the addition of guanidinium salt 8... 39 S1

General All commercially available reagents and solvents were used without further purification unless otherwise stated. Liquid aldehydes were in all cases distilled under reduced pressure before use. Flash chromatography of reaction products was carried out using Silica 60A, particle size 230-400 micron (Merk). Analytical thin layer chromatography (TLC) was performed on DC-Alufolien Kieselgel 60F 254 0.2 mm plates (Merk) and compounds were visualised by UV fluorescence or 5% phosphomolybdic acid in methanol. 1 H NMR and 13 C NMR spectra were recorded on a Bruker AC-300 or a Bruker DPX-300 spectrometer, using deuterated solvents and were referenced internally to the residual solvent peak (δ H = 7.26 ppm, δ C = 77.36 ppm) signal. 1 Coupling constants (J-values) are given in hertzs (Hz). The DEPT 135 technique was used to assign methylene (CH 2 ) signals. Chemical shifts are reported as follows: value (number of protons, description of absortion, coupling constant(s) where applicable, assignment). NMR spectra assignation was aided by comparison with literature values for similar compounds. In this experimental section only clear identifiable peaks are assigned. Chiral HPLC analyses were performed on an Agilent 1100 Series apparatus. Optical rotation was measured on a Perkin Elmer 241 digital polarimeter operating at the sodium D line with a 100 mm path cell, and is reported as follows: [α] T D deg. cm 3 g - 1 dm -1 (concentration g/100cm 3 ). 1 H.E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997, 62, 7512. S2

Preparation of tetrafluoroborate guanidinium salt 8 2 N H N N H Triazabicyclo[4.4.0]dec-5-ene (300 mg, 2.16 mmol) was dissolved in methanol (5 ml) and the solution was cooled to 0 ºC before HBF 4 (48% wt. in water, 0.28 ml, 2.16 mmol) was added dropwise. The reaction mixture was vigorously stirred 30 min before the solvent and volatiles were evacuated under reduced pressure (high vacuum pump) to render salt 8 (490 mg, quantitative yield) as an ionic liquid (colourless oil). BF 4 1 H NMR (DMSO-d 6, 300 MHz) δ H = 7.23 (2H, s, 2 x NH), 3.12 (4H, t, J = 6.0 Hz, 2 x CH 2 ), 3.05-3.00 (4H, m, 2 x CH 2 ), 1.72 (4H, quint., J = 6.0 Hz, 2 x CH 2 ); 13 C NMR (DMSO-d 6, 75 MHz) δ C = 151.6 (CN 3 ), 47.3 (CH 2 ), 38.7 (CH 2 ), 21.3 (CH 2 ); 19 F NMR (DMSO-d 6, 282 MHz) δ F = -148.31 (BF 4 ). 13 C 200 175 150 125 100 75 50 25 2 A. Martínez-Castañeda, B. Poladura, H. Rodríguez-Solla, C. Concellón, V. del Amo, Org. Lett, 2011, 13, 3032. S3

1 H 10 9 8 7 6 5 4 3 2 1 19 F 0-25 -50-75 -100-125 -150-175 S4

Standard procedure for the synthesis of α-chloro-β-hydroxyketones 7a-k (SP1). Tetrafluoroborate guanidinium salt 8 (9.1 mg, 0.04 mmol), (S)-proline (6.9 mg, 0.06 mmol) and aldehyde 9a-k (0.4 mmol) were weighed together inside a screw-capped test tube. Chloroacetone (0.32 ml, 4.0 mmol) was added to the mixture and the resulting suspension, placed on a test tube grid, was allowed to stay 20 days inside a standard laboratory fridge (temperature fixed at 0-3 ºC) without agitation or mechanical stirring. The mixture was then quenched with NH 4 Cl (aq. sat.), extracted with DCM (2 x 15 ml) and the organic liquors dried (MgSO 4 ). Solvents and excess of chloroacetone were eliminated under reduced pressure. S5

(3S,4S)-3-Chloro-4-hydroxy-4-(4-nitrophenyl)butan-2-one (7a) 3 O OH Cl NO 2 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 8.26 (2H, d, J = 8.7 Hz, ArH), 7.62 (2H, d, J = 8.7 Hz, ArH), 5.17 (1H, d, J = 8.1 Hz, CHOH), 4.30-4.27 (1H, m, CHCl), 2.42 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 202.9 (C=O), 148.0 (ArC), 145.7 (ArC), 128.2 (2 x ArCH), 123.6 (2 x ArCH), 73.9 (CHOH), 63.5 (CHCl), 28.1 (CH 3 ). 1 H 13 C 3 L. He, Z. Tang, L-F.Cun, A-Q. Mi, Y-Z. Jiang, L-Z. Gong, Tetrahedron, 2006, 62, 346. S6

It was obtained in a maximum of 98% ee. The optical purity was determined by HPLC on chiralpak AS-H column (hexane/2-propanol 85:15); flow rate 0.6 ml/min, λ = 254 nm. S7

(3S,4S)-3-Chloro-4-hydroxy-4-(3-nitrophenyl)butan-2-one (7b) 3 O OH NO 2 Cl 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 8.34-8.33 (1H, m, ArH), 8.27-8.18 (1H, m, ArH), 7.78-7.75 (1H, m, ArH), 7.75-7.56 (1H, m, ArH), 5.17 (1H, d, J = 8.2 Hz, CHOH), 4.31 (1H, d, J = 8.3 Hz, CHCl), 2.44 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 203.0 (C=O), 140.9 (ArC), 133.4 (ArCH), 129.4 (ArCH), 123.6 (ArCH), 122.2 (ArCH), 110.0 (ArC), 73.8 (CHOH), 63.5 (CHCl), 28.1 (CH 3 ). 1 H 13 C S8

It was obtained in a maximum of 97% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 254 nm. S9

(3S,4S)-3-Chloro-4-hydroxy-4-(2-nitrophenyl)butan-2-one (7c) 3 O OH NO 2 Cl 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 7.94 (1H, dd, J = 8.1,1.3 Hz, ArH), 7.77-7.61 (2H, m, ArH), 7.50 (1H, ddd, J = 8.8, 7.2, 1.7 Hz, ArH), 5.73 (1H, d, J = 6.9 Hz, CHOH), 4.52 (1H, J = 7.0 Hz, CHCl), 2.38 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 202.8 (C=O), 148.5 (ArC), 134.0 (ArC), 133.4 (ArCH), 129.3 (ArCH),129.2 (ArCH), 124.7 (ArCH), 70.8 (CHOH), 63.6 (CHCl), 28.1 (CH 3 ). 1 H 13 C S10

It was obtained in a maximum of 97% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 95:5); flow rate 1.0 ml/min, λ = 254 nm. S11

(3S,4S)-3-Chloro-4-hydroxy-4-(4-(methoxycarbonyl)phenyl)butan-2-one (7d) 4 O OH Cl CO 2 Me 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 8.09-8.06 (2H, m, ArH), 7.52-7.49 (2H, m, ArH), 5.11 (1H, d, J = 7.9 Hz, CHOH), 4.33 (1H, d, J = 7.8 Hz, CHCl), 3.94 (3H, s, CO 2 CH 3 ), 2.38 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 202.9 (C=O), 166.7 (CO 2 Me), 143.6 (ArC), 130.4 (ArC), 129.8 (2 x ArCH), 127.1 (2 x ArCH), 74.5 (CHOH), 63.9 (CHCl), 52.2 (CO 2 CH 3 ), 28.0 (CH 3 ). 1 H 13 C 4 G. Guillena, M. C. Hita, C. Nájera, Tetrahedron: Asymmetry, 2007, 18, 1272. S12

It was obtained in a maximum of 97% ee. The optical purity was determined by HPLC on chiralpak AD-H column (hexane/2-propanol 95:5); flow rate 1.0 ml/min, λ = 240 nm. S13

(3S,4S)-3-Chloro-4-(4-cyanophenyl)-4-hydroxybutan-2-one (7e) 3 O OH Cl CN 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 7.70 (2H, d, J = 8.0 Hz, ArH), 7.55 (2H, d, J = 8.1 Hz, ArH), 5.11 (1H, d, J = 8.1 Hz, CHOH), 4.27 (1H, d, J = 8.1 Hz, CHCl), 2.33 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 202.9 (C=O), 143.9 (ArC), 132.2 (2 x ArCH), 127.9 (2 x ArCH), 118.5 (CN), 112.5 (ArC), 74.1 (CHOH), 63.6 (CHCl), 27.1 (CH 3 ). 1 H 13 C S14

It was obtained in a maximum of 98% ee. The optical purity was determined by HPLC on chiralcel OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 240 nm. S15

(3S,4S)-3-Chloro-4-(3-fluorophenyl)-4-hydroxybutan-2-one (7f) O OH F Cl 1 H NMR (CDCl 3, 300 MHz) δ =(anti diastereoisomer) 7.49-7.24 (1H, m, ArCH), 7.21-7.01 (3H, m, ArCH), 5.03 (1H, d, J = 8.0 Hz, CHOH), 4.30 (1H, d, J = 8.0 Hz, CHCl), 2.36 (3H, s, CH 3 ); 13 C NMR (CDCl 3, 75 MHz) δ = (anti diastereoisomer) 203.1 (C=O), 162.5 (d, J = 246.6 Hz, ArC), 141.5 (d, J = 6.9 Hz, ArC), 130.0 (d, J = 8.4 Hz, ArCH), 122.8 (d, J = 3.0 Hz, ArCH), 115.6 (d, J = 21.1 Hz, ArCH), 114.1 (d, J = 22.4 Hz, ArCH), 74.3 (d, J = 2.0 Hz, CHOH), 64.1 (CHCl), 27.8 (CH 3 ). 1 H 13 C S16

It was obtained in a maximum of 94% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 220 nm. S17

(3S,4S)-3-Chloro-4-(4-chlorophenyl)-4-hydroxybutan-2-one (7g) O OH Cl Cl 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 7.39-7.33 (4H, m, ArH), 5.02 (1H, d, J = 8.1 Hz, CHOH), 4.28 (1H, d, J = 8.0 Hz, CHCl), 2.37 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 203.1 (C=O), 137.4 (ArC),134.5 (ArC), 128.7 (2 x ArCH), 128.4 (2 x ArCH), 74.3 (CHOH), 64.2 (CHCl), 27.9 (CH 3 ). 1 H 13 C S18

It was obtained in a maximum of 95% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 220 nm. S19

(3S,4S)-3-Chloro-4-(3-chlorophenyl)-4-hydroxybutan-2-one (7h) O OH Cl Cl 1 H NMR (CDCl 3, 300 MHz) δ = (anti diastereoisomer) 7.43-7.42 (1H, m, ArCH), 7.35-7.24 (3H, m, ArCH), 4.99 (1H, d, J = 8.1 Hz, CHOH), 4.29 (1H, d, J = 8.1 Hz, CHCl), 2.37 (3H, s, CH 3 ); 13 C NMR (CDCl 3, 75 MHz) δ = (anti diastereoisomer) 203.1 (C=O), 141.0 (ArC), 134.4 (ArC), 129.7 (ArCH), 128.8 (ArCH), 127.2 (ArCH), 125.4 (ArCH), 74.3 (CHOH), 64.0 (CHCl), 27.8 (CH 3 ). 1 H 13 C S20

It was obtained in a maximum of 96% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 220 nm. S21

(3S,4S)-4-(4-Bromophenyl)-3-chloro-4-hydroxybutan-2-one (7i) O OH Cl Br 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 7.56-7.48 (2H, m, ArH), 7.33-7.25 (2H, m, ArH), 5.02 (1H, d, J = 8.1 Hz, CHOH), 4.28 (1H, d, J = 8.0 Hz, CHCl), 2.38 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 202.9 (C=O), 166.8 (ArC),144.2 (ArC), 129.6 (2 x ArCH), 127.2 (2 x ArCH), 74.4 (CHOH), 63.4 (CHCl), 27.6 (CH 3 ). 1 H 13 C S22

It was obtained in a maximum of 93% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 220 nm. S23

(3S,4S)-4-(2-Bromophenyl)-3-chloro-4-hydroxybutan-2-one (7j) 3 O OH Br Cl 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 7.60-7.15 (4H, m, ArH), 5.48 (1H, d, J = 6.5 Hz, CHOH), 4.57 (1H, J = 6.4 Hz, CHCl), 2.33 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 202.8 (C=O), 138.0 (ArC), 133.0 (ArCH), 130.0 (ArCH), 128.4 (ArCH), 127.8 (ArCH), 123.1 (ArC), 74.1 (CHOH), 63.4 (CHCl), 28.2 (CH 3 ). 1 H 13 C S24

It was obtained in a maximum of 92% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 97:3); flow rate 1.0 ml/min, λ = 220 nm. S25

(3S,4S)-3-Chloro-4-hydroxy-4-phenylbutan-2-one (7k) 4 O OH Cl 1 H NMR (300 MHz, CDCl 3 ): δ = (anti diastereoisomer) 7.44-7.37 (5H, m, ArH), 5.05 (1H, d, J = 7.9 Hz, CHOH), 4.36 (1H, d, J = 8.0 Hz, CHCl), 2.37 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = (anti diastereoisomer) 203.2 (C=O), 138.8 (ArC), 128.8 (ArCH), 128.5 (2 x ArCH), 127.0 (2 x ArCH), 75.0 (CHOH), 64.4 (CHCl), 27.8 (CH 3 ). 1 H 13 C S26

It was obtained in a maximum of 94% ee. The optical purity was determined by HPLC on chiralcel AD-H column (hexane/2-propanol 98:2); flow rate 0.5 ml/min, λ = 210 nm. S27

Standard procedure for the synthesis of epoxides 10a,c,d,f,k 4 (SP2) 3-Chloro-4-hydroxyketones, dissolved in dry dichloromethane (0.5 ml), were treated with dry triethylamine, or DIPEA (1.32 equiv.) and stirred for 2 days. The reaction was quenched with diethyl ether and HCl (aq. 1N) and the mixture was stirred vigorously for 10 min. The emulsion was extracted with Et 2 O, washed with brine (3 x 5mL) and the organic liquors dried over MgSO 4. Solvents and volatiles were evaporated under vacuum. Purification by flash chromatography (silica gel, EtOAc/hexane) yielded pure epoxides 10a,c,d,f,k. Standard procedure for the synthesis of epoxides 10 in situ (SP3) Reaction mixtures of α-hydroxy-β-ketones, prepared as indicated in SP1, were allowed to get r.t., were diluted with dry dichloromethane (0.5 ml), and were treated with dry triethylamine (1.32 equiv.) and stirred for 2 days. The reaction was quenched with diethyl ether and HCl (aq. 1N) and the mixture was stirred vigorously for 10 min. The emulsion was extracted with Et 2 O, washed with brine (3 x 5mL) and the organic liquors dried over MgSO 4. Solvents and volatiles were evaporated under vacuum. Purification by flash chromatography (silica gel, EtOAc/hexane) yielded pure epoxides 10. S28

(3R,4S)-Epoxy-4-(4-nitrophenyl)butan-2-one (10a) O O NO 2 Yellow oil. Purified by flash chromatography (hexane/etoac, 3:1). 1 H NMR (300 MHz, CDCl 3 ): δ = 8.27-8.25 (2H, m, ArH), 7.50-7.47 (2H, m, ArH), 4.14 (1H, d, J = 1.8 Hz, CH), 3.49 (1H, d, J = 1.7 Hz, CH), 2.24 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = 203.0 (C=O), 148.3 (ArC), 142.3(ArC), 126.5 (2 x ArCH), 124.0 (2 x ArCH), 63.4 (CH), 56.5 (CH), 24.9 (CH 3 ). 1 H 13 C S29

It was obtained in a maximum of 73% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 254 nm. S30

(3R,4S)-Epoxy-4-(2-nitrophenyl)butan-2-one (10c) 4 O O NO 2 Yellow solid, purified by flash chromatography (hexane/etoac, 3:1). 1 H NMR (300 MHz, CDCl 3 ): δ = 8.24-8.21 (1H, m, ArH), 7.75-7.70 (1H, m, ArH), 7.67-7.50 (2H, m, ArH), 4.61 (1H, d, J = 2.0 Hz, CH), 3.42 (1H, dd, J = 2.0, 0.8 Hz, CH), 2.30 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = 203.0 (C=O), 147.3 (ArC), 134.6 (ArCH), 132.3 (ArC), 129.4 (ArCH), 127.1 (ArCH), 125.0 (ArCH), 62.0 (CH), 56.3 (CH), 25.2 (CH 3 ). 1 H 13C S31

It was obtained in a maximum of 90% ee. The optical purity was determined by HPLC on chiralpak AS-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 254 nm. S32

(3R,4S)-Epoxy-4-[4-(methoxycarbonyl)-phenyl]-butan-2-one (10d) 4 O O CO 2 Me Off-white solid, purified by flash chromatography (hexaneetoac, 3:1). 1 H NMR (CDCl 3, 300 MHz) δ = 8.11-7.97 (2H, m, ArCH), 7.43-7.31 (2H, m, ArCH), 4.07 (1H, d, J = 1.8 Hz, CH), 3.93 (3H, s, COCH 3 ), 3.49 (1H, d, J = 1.8 Hz, CH), 2.22 (3H, s, CH 3 ); 13 C NMR (CDCl 3, 75 MHz) δ = 203.6 (C=O), 166.5 (CO 2 Me), 140.0 (ArC), 131.1 (ArC), 130.3 (2 x ArCH), 126.0 (2 x ArCH), 63.4 (CH), 57.1 (CH 3 ), 52.2 (CH), 24.8 (CH 3 ). 1 H 13 C S33

It was obtained in a maximum of 81% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 254 nm. S34

(3R,4S)-Epoxy-4-(3-fluorophenyl)butan-2-one (10f) O O F White solid, purified by flash chromatography (hexane/etoac, 3:1). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.40-7.32 (1H, m, ArH), 7.16-6.92 (3H, m, ArH), 4.02 (1H, d, J = 1.8 Hz, CH), 3.47 (1H, d, J = 1.8 Hz, CH), 2.21 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = 203.6 (C=O), 163.4 (d, J = 247.2 Hz, ArC), 137.7 (d, J = 7.5 Hz, ArC), 130.1 (d, J = 8.3 Hz, ArCH), 121.5 (d, J = 3.2 Hz, ArCH), 116.0 (d, J = 21.1 Hz, ArCH), 112.4 (d, J = 22.9 Hz, ArCH), 63.7 (CH), 57.0 (d, J = 2.4 Hz, CH), 24.8 (CH 3 ). 1 H 13C S35

It was obtained in a maximum of 86% ee. The optical purity was determined by HPLC on chiralpak AS-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 254 nm. S36

(3R,4S)-Epoxy-4-phenylbutan-2-one (10k) 4 O O Colourless oil, purified by flash chromatography (hexane/etoac, 3:1). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.40-7.37 (3H, m, ArH), 7.32-7.28 (2H, m, ArH), 4.03 (1H, d, J = 1.8 Hz, CH), 3.52 (1H, d, J = 1.0 Hz, CH), 2.22 (3H, s, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ = 204.2 (C=O), 135.0 (ArC), 129.0 (ArCH), 128.7 (2 x ArCH), 125.7 (2 x ArCH), 63.5 (CH), 57.8 (CH), 24.8 (CH 3 ). 1 H 13 C S37

It was obtained in a maximum of 87% ee. The optical purity was determined by HPLC on chiralpak OJ-H column (hexane/2-propanol 90:10); flow rate 1.0 ml/min, λ = 220 nm. S38

Overview of the results obtained in the proline-catalyzed aldol reaction, without the addition of guanidinium salt 8: O Cl ArCHO (S)-Proline (15 mol%) NEAT, 0-3 ºC, 20 d No stirring!! O OH Ar Cl anti/syn-7 Cl O 6 OH Ar Ar % Conv. a Regioselectivity a Diastereoselectivity b % ee c 4-NO 2 C 6 H 4 99 88:12 84:16 97 4-CO 2 Me- C 6 H 4 98 93:7 85:15 95 4-CN- C 6 H 4 99 85:15 83:17 96 C 6 H 5 99 94:6 84:16 92 3-NO 2 - C 6 H 4 99 80:20 78:22 97 General conditions: chloroacetone (4.0 mmol), ArCHO (0.4 mmol), (S)-proline (0.06 mmol, 15 mol %), no solvent, reaction mixture was left to stand 20 days inside a standard laboratory fridge (0-3 C) with no stirring. a Determined by 1 H NMR spectroscopy from crude reaction mixtures. b Diastereoisomeric ratio of chlorohydrins anti and syn-7 determined by 1 H NMR spectroscopy from crude reaction mixtures and identified by comparison with similar compounds previously described in the literature. c Enantiomeric excess of chlorohydrins anti-7 as determined by chiral HPLC on crude reaction mixtures. S39