Organocatalytic Asymmetric Transferhydrogenation of β- Nitroacrylates: Accessing β²-amino Acids

rganocatalytic Asymmetric Transferhydrogenation of β- Nitroacrylates: Accessing β²-amino Acids Nolwenn J. A. Martin, Xu Cheng and Benjamin List* Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim an der Ruhr, Germany list@mpi-muelheim.mpg.de Supporting Information General Information: All reactions were carried out under argon atmosphere in oven dried glassware with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. All solvents employed in the reactions were distilled from appropriate drying agent prior to use. rganic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Reactions were monitored by thin-layer chromatography (TLC) on silica gel precoated glass plates (0.25 mm thickness, 60F-254, E. Merck). Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using potassium permanganate stains. Flash column chromatography was performed using silica gel 60 (particle size 0.040 0.063 mm) from Merck. 1 H and 13 C NMR spectra were recorded in CDCl 3 (unless otherwise noted) on Bruker DPX- 300, AV-400 and AV-500 spectrometers. Chemical shifts (δ ppm) are relative to tetramethylsilane (TMS) with the resonance of the deuterated solvent as the internal standard (CDCl 3, δ 7.26 ppm for proton NMR and CDCl 3, δ 77.0 ppm for carbon NMR). 1 H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, q = quartet, m = multiplet), coupling constants (J) and assignment. Mass spectra were measured on a Finnigan MAT 8200 (70 ev) by electron ionization, chemical ionization, of fast atom/ion bombardment techniques. Accurate mass determinations were obtained on a Bruker APEX III FT-MS (7 T magnet). Gas chromatography (GC) was performed on Hewlett-Packard 6890 and 5890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using chiral stationary S1

columns 1 specified in the individual experiments. High performance liquid chromatography (HPLC) was performed on a Shimadzu LC-20AD HPLC-system equipped with a spectrophotometric detector (monitoring at 220 nm or 254 nm) using a Chiralpak AS-H column. 2 ptical rotations were measured on a PerkinElmer 343 polarimeter, and [α] D values are reported in 10-1 dg cm 2 g -1 ; concentration (c) is in g/100 ml. Racemic nitroalkane esters (5a-m) described in this paper were prepared by reduction of the nitroacrylates (2a-m) with NaBH 4 or with the thiourea catalyst 7 (Schreiner catalyst). 3 NaBH 4 (3.0 equiv) R 1 C 2 R 2 Ethanol, 0 C R 1 C 2 R 2 2 5 (a) CF 3 CF 3 Et 2 C C 2 Et S N F N N H 3 C CF 3 H H 8 (1.2 equiv) 7 (20 mol%) R 1 C 2 R 2 toluene, 40 C R 1 C 2 R 2 2 5 (b) (a) Rac-5 via reduction with NaBH 4 : To a solution of β-nitroacrylic ester 2 (0.26 mmol) in ethanol (0.6 ml) at 0 C, NaBH 4 (29.5 mg, 0.78 mmol, 3.0 equiv) was added in portions. The reaction mixture was stirred at 0 C for 1h and then treated at 0 C with a saturated aqueous NH 4 Cl solution. The two phases were separated and the aqueous phase extracted with Et 2. The combined organic phases were dried over MgS 4. The volatile compounds were removed in vacuo and the crude product was purified by flash chromatography (1-5 % Et 2 in pentane) to afford the pure β-nitroacrylic esters 5. (b) Rac-5 via reduction using catalyst 7: To a solution of β-nitroacrylic ester 2 (0.26 mmol) in toluene (0.2 ml), catalyst 7 (26.0 mg, 0.05 mmol, 0.2 equiv) and Hantzsch ester 8 (79.0 mg, 0.31 mmol, 1.2 equiv) were added. The reaction mixture was stirred at 40 C for 24-48 h under argon atmosphere until completion of the reaction (TLC control). The solvent was removed in 1 Ivadex-1/PS086 (25 m x 0.25 mm) stationary phase: dimethylpentyl-β-cyclodextrin; G-TA (30 m x 0.25 mm) stationary phase: γ-cyclodextrin trifluoracetyl; BGB 176/SE 52 (29.5 m x 0.25 mm) and BGB-176/BGB-15 (30 m x 0.25 mm) stationary phase: 6-tert-butyldimethylsilyl-β-cyclodextrin. 2 Chiralpak AS-H (25 cm x 0.46 cm) stationary phase: 1-phenylethylcarbamate of amylase. Chiralpak D -H (25 cm x 0.46 cm) stationary phase: 3,5-dimethylphenylcarbamate of cellulose, Chirobiotic T2 (25 cm x 0.21 cm) stationary phase: teicoplanin. 3 (a) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434-439. (b) Zhang, Z.; Schreiner, P. R. Synthesis 2007, 2559-2564. S2

vacuo and the resulting mixture purified by flash column chromatography (1-5 % Et 2 in pentane). The enantiomeric ratios (er) were determined by GC or HPLC analysis specified in the individual experiments, by comparing the samples with the appropriate racemic mixtures. The absolute configuration of nitroalkane ester 5b, amino ester 9c and amino acids 6a and 6k were determined by measuring their optical rotation and comparison with the literature. 4 All other absolute configurations were assigned by analogy. Because aliphatic nitroalkane esters 5k-m are volatile, their yields were determined by GC. Preparation of the Catalyst Catalyst 4 was prepared in analogy to the reported procedure. 5 General Procedure for the Preparation of the Jacobsen-type Catalyst 4: 5 (S)-2-(3-((1R,2R)-2-(2,5-dimethyl-pyrrol-1-yl)cyclohexyl)thioureido)-N,N,3,3-tetramethylbutanamide (4): 5 4 a) Liu, H.; Xu, J.; Du, D.-M. rg. Lett. 2007, 9, 4725-4728.b) Davies, H. M. L.; Ni, A. Chem. Commun. 2006, 3110-3112. c) Davies, H. M. L.; Venkataramani, C. Angew. Chem. Int. Ed. 2002, 41, 2197-2199. d) Swideska, M. A. ; Stewart, J. D. rg. Lett. 2006, 8, 6131-6133. 5 Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558-10559. S3

Coupling of Boc-L-tert-leucine with diethylamine, followed by deproctection: To a solution of N-Boc-L-tert-leucine (4.00 g, 17.29 mmol) in CH 2 Cl 2 (150 ml) was added -benztriazole-1- N,N,N,N -tetraethyluronium hexafluorophosphate (HTBU, 7.20 g, 19.03 mmol, 1.1 equiv). The white suspension was stirred for 5 minutes, followed by the addition of diisopropylethylamine (3.5 ml, 20.75 mmol, 1.2 equiv) and diethylamine (2.0 ml, 19.03 mmol). The reaction mixture was then stirred for 48 h at room temperature. The mixture was combined with CH 2 Cl 2 and water and the organic layer was separated, washed with 1N hydrochloric acid (3x), and dried over MgS 4. The solvent was removed in vacuo to afford the crude Boc-protected amide as colourless oil. The oil was dissolved in trifluoroacetic acid (TFA, 20 ml) at 0 C. The reaction mixture was then stirred for 1 h at room temperature. All volatile compounds were removed in vacuo and the residue was dissolved in water and treated with KH (10% aqueous solution) at 0 C. The resulting mixture was extracted with CH 2 Cl 2 and the combined organic layer was dried over MgS 4. After filtration and then evaporation of the solvent, the crude product was purified by flash chromatography (5-10% EtAc in hexanes) yielding L-tert-leucine diethylamide as colourless oil (2.90 g, 15.57 mmol, 90%). 1 H NMR: (400 MHz, CDCl 3 ) δ 3.73-3.67 (m, 1H, CH 2 CH 3 ), 3.60-3.54 (m, 1H, CH 2 CH 3 ), 3.38 (s, 1H, CHNH 2 ), 3.21-3.15 (m, 1H, CH 2 CH 3 ), 3.09-3.03 (m, 1H, CH 2 CH 3 ), 1.64 (br s, 2H, NH 2 ), 1.74 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ), 1.10 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ), 0.97 (s, 9H, C(CH 3 ) 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 173.8, 57.7, 42.4, 40.3, 35.10, 26.4, 14.7, 13.0; MS (EI): m/z (%) = 186 (3), 129 (20), 100 (4), 86 (100), 72 (11), 58 (4), 44 (6), 29 (7); HRMS: calcd for [C 10 H 22 N 2 ]: 186.1732, found 186.1732. Preparation of (1R,2R)-2-(2,5-dimethyl-pyrrol-1-yl)cyclohexylamine: To a solution of (R,R)- 1,2-diaminocyclohexane (1.50 g, 13.14 mmol) in MeH (75 ml) were added sequentially acetic acid (750 μl, 13.14 mmol, 1.0 equiv) and 2,5-hexanedione (1.55 ml, 13.14 mmol, 1.0 equiv). The mixture was heated at 50 C and stirred for 12 h, then cooled to 23 C and S4

concentrated in vacuo. The residue was partitioned between CH 2 Cl 2 (250 ml) and 4M aqueous NaH (250 ml). The organic phase was separated, and the aqueous phase extracted with CH 2 Cl 2 (3x). The combined organic extracts were dried over MgS 4 and concentrated in vacuo. The residue was purified by flash chromatography (5% MeH in CH 2 Cl 2 ), yielding the product as a yellow oil (2.20 g, 11.44 mmol, 87%). 1 H NMR: (400 MHz, CDCl 3 ) δ 5.77 (br s, 1H, ArCH), 5.75 (br s, 1H, ArCH), 3.61-3.57 (m, 1H, NH 2 CH), 3.29-3.22 (m, 1H, NCH), 2.36 (br s, 3H, CH 3 ), 2.23 (br s, 3H, CH 3 ), 2.03-2.07 (m, 1H, CH cycl.), 1.91-1.78 (m, 4H, CH 2 CH 2 ), 1.40-1.34 (m, 2H, CH cycl.), 1.27-1.23 (m, 1H, CH cycl.), 1.21 (br s, 2H, NH 2 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 129.8, 126.8, 107.9, 105.3, 63.6, 52.9, 35.4, 31.3, 36.2, 25.1, 12.2, 13.7; MS (EI): m/z (%) = 192 (100), 174 (5), 162 (4), 148 (6), 134 (11), 122 (24), 110 (26), 96 (83), 81 (16), 69 (16), 56 (19), 42 (14), 30 (23), 27 (7); HRMS: calcd for [C 12 H 20 N 2 ]: 192.1626, found 192.1629. The physical data were identical in all respects to those previously reported. 10c Formation of catalyst 4: Saturated aqueous NaHC 3 (6 ml) was added to a solution of L-tertleucine diethylamide (300 mg, 1.61 mmol) in CH 2 Cl 2 (12 ml) at 0 C. The mixture was stirred for 30 minutes, then stirring was stopped and thiophosgene (130 μl, 1.77 mmol, 1.1 equiv) was added to the organic phase by syringe. The resulting orange mixture was stirred at 0 C for 2 h. CH 2 Cl 2 (20 ml) was added, and the organic phase separated. The aqueous phase was extracted with CH 2 Cl 2 (3x). The combined organic extracts were dried over MgS 4 and concentrated, yielding (S)-N,N-diethyl-2-isothiocyanato-3,3-dimethylbutanamide (contaminated with tetramethylurea) as a solid, which was used without further purification. The crude product was dissolved in CH 2 Cl 2 (12 ml) and (1R,2R)-2-(2,5-dimethyl-pyrrol-1- yl)cyclohexylamine (370 mg, 1.93 mmol, 1.2 equiv) was added in different portions. The reaction mixture was allowed to stir for 11 h at room temperature. All volatile compounds were removed in vacuo and the residue was purified via flash chromatography (10-15% EtAc in hexanes) yielding the catalyst 4 as light salmon solid (600 mg, 1.43 mmol, 89%). 1 H NMR: (400 MHz, CDCl 3 ) δ 6.28 (br d, J = 9.2 Hz, 1H, NH), 5.71-5.68 (s and d, 3H, ArH, NH), 5.40 (br, 1H, CH(CH 3 ) 3 ), 4.42-4.34 (m, 1H, CH cycl.), 3.86-3.79 (m, 1H, CH cycl.), 3.71-3.60 (m, 2H, CH 2 CH 3 ), 3.33 (q, J = 7.3 Hz, 1H, CH 2 CH 3 ), 3.07 (q, J = 6.8 Hz, 1H, CH 2 CH 3 ), 2.50 (br d, J = 13.2 Hz, 1H, CH 2 cycl.), 2.43-2.16 (br m, 6H, ArCH 3 ), 1.96-1.79 (m, 4H, CH 2 cycl.), 1.50-1.18 (m, 3H, CH 2 cycl.), 1.25 (t, J = 7.1 Hz, 3H, NCH 3 ), 1.10 (t, J = 7.1 Hz, 3H, NCH 3 ), 0.96 (s, 9H, C(CH 3 ) 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 182.1, 170.7, 128.0, 127.7, 108.7, 106.3, 60.0, 59.4, 55.8, 42.9, 40.1, 36.2, 34.0, 32.4, 26.8, 25.8, 24.7, 14.6, S5

12.8; MS (EI): m/z (%) = 420 (100), 387 (4), 324 (10), 286 (10), 234 (69), 203 (8), 175 (89), 155 (60), 129 (5), 96 (38), 45 (33), 74 (17), 41 (13); HRMS: calcd for [C 23 H 40 N 4 S+Na + ]: 443.2815, found 443.2815. General Procedures for the Synthesis of the Nitroacrylic Esters Some α-keto esters were purchased from commercial suppliers and used without further purification (procedure A). The other α-keto esters were prepared according to procedures B, C, D and E. Procedure A: Preparation of the β-nitro-α-hydroxyester: 6 In a dried two-necked round-bottomed flask, the α-keto ester (20.0 mmol) is added to nitromethan (80 ml) followed by the addition of dried triethylamine (0.55 ml, 4.0 mmol). The mixture was then stirred at room temperature until complete conversion (TLC monitoring). Solvent was removed in vacuo, and the residue was purified by flash chromatography to give the β-nitro-α-hydroxyesters. Preparation of the β-nitroacrylic ester: 7 To a stirred solution of β-nitro-α-hydroxyesters (20.0 mmol) in dry CH 2 Cl 2 (100 ml) was added MeS 2 Cl (4.6 ml, 60.0 mmol) and triethylamine (8.3 ml, 60.0 mmol) in succession. After the reaction was over (TLC monitoring), the mixture was poured into ice-cold water. The two phases were separated and the aqueous phase extracted with CH 2 Cl 2 (3x). The combined organic phase was washed with a 15% NaH solution, water and brine and dried over MgS 4. The volatile compounds were removed in vacuo and the crude product was purified by flash chromatography (1-5 % Et 2 in hexanes) to afford the pure β-nitroacrylic esters. Under the conditions of the Procedure A, the dehydration often leads to a mixture of the desired product and the initial α-keto ester (via retro-henry reaction). Consequently, the yield of the desired nitroacrylic esters was often low (20-50%). The procedure has 6 Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. rg. Chem. 2002, 67, 4875-4881. 7 Jayakanthan, K.; Madhusudanan, K. P.; Vankar, Y. D. Tetrahedron 2004, 60, 397-403. S6

been improved by treating the β-nitro-α-hydroxyesters with Ac 2 (in DMS) instead of CH 3 S 2 Cl (see Procedure B). Procedure B: Preparation of the β-nitro-α-hydroxyester: See Procedure A. Preparation of the β-nitroacrylic ester: To a stirred solution of β-nitro-α-hydroxyesters (2.0 mmol) in dry DMS (7 ml) was added Ac 2 (0.57 ml, 6.0 mmol). The reaction was then stirred at room temperature. After the reaction was over (TLC monitoring), the mixture was poured into water. The two phases were separated and the aqueous phase extracted with CH 2 Cl 2 (3x). The combined organic phase was washed with a saturated solution of NaHC 3 and dried over MgS 4. The volatile compounds were removed in vacuo and the crude product was purified by flash chromatography (1-5 % Et 2 in pentane) to afford the pure β- nitroacrylic esters. Procedure C: Preparation of the α-keto ester: 8 The Grignard reagent (2M in Et 2, 18.4 ml, 36.8 mmol) was added over 1h using a syringe automate to a solution of diethyloxalate (5.1 g, 35 mmol) in Et 2 (50 ml) at -78 C. After 1h at -78 C, the mixture was warmed to 10 C and quenched with 3N HCl solution (20 ml) and H 2 (20 ml). The two phase was separated and the aqueous phase extracted with Et 2 (3x). The combined organic phases were washed with a saturated NaCl solution and dried over MgS 4. The volatile compounds were removed in vacuo and the crude product was purified by flash chromatography (5-10 % Et 2 in pentane) to afford the pure α-keto ester. The corresponding β-nitroacrylic ester was obtained as pure product following procedure A or B. 8 Creary, X. J. rg. Chem. 1987, 52, 5026-5030. S7

Procedure D: According to the reported method, 9 to a solution of 2-oxo-2-phenylacetic acid (3.84 g, 25.6 mmol) in benzene (60 ml) at 0 o C and under argon was added DMAP (327 mg, 2.68 mmol), DCC (5.27 g, 25.6 mmol) and RH (50 mmol) in turn. After 12 h at room temperature, the mixture was filtered through celite. The mother liquid was concentrated in vacuo and purified by flash chromatography (10% EtAc in hexanes) to afford the corresponding α-keto ester. The target β-nitroacrylic esters was prepared according to the procedure A or B. Procedure E: According to reported method, 10 a solution of 2-oxo-2-phenylacetic acid (2.5g, 17.3 mmol) and benzyl alcohol (2.24 g, 20.8 mmol) in benzene (15 ml) was refluxed overnight. The reaction was then concentrated in vacuo and purified by flash chromatography (10% EtAc in Hexane) to give corresponding α-keto ester, which was then converted to the target β- nitroacrylic ester according to procedure B. Procedure F: According to the literature, 11 to a solution of tert-butyl 2-(1H-imidazol-1-yl)-2-oxoacetate (4.76 g, 24.0 mmol) in THF (70 ml) was added aryl Grignard reagent (24 mmol) at 0 o C under argon. The mixture was then allowed to warm up to room temperature within 3 hours. The obtained yellow suspension was poured into ice and extracted with ether (2x). The 9 Hu, S.; Neckers, D. C. J. rg. Chem. 1996, 61, 6407-6415. 10 Di Mauro, E. F.; Kozlowshi, M. C. J. Am. Chem. Soc. 2002, 124, 12668-12669. 11 Jonathan S. N.; Harry S. M. J. rg. Chem. 1981, 46. 211-213 S8

organic phase was dried over Na 2 S 4, followed by flash chromatography (10% EtAc in hexanes) to give t-butyl α-keto ester. The corresponding β-nitroacrylic ester was obtained following procedure B. (Z)-Benzyl 3-nitro-2-phenylacrylate (2a): According to the general procedure E, the α-keto ester was synthesized starting from 2-oxo-2- phenylacetic acid (2.50 g, 17.3 mmol) to give benzyl 2-oxo-2-phenylacetate (2.00 g, 46%) as crude product which (2.00 g, 8.29 mmol) was used directly according to the general procedure A. The Henry reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (20% EtAc in hexanes) to yield benzyl 2-hydroxy-3-nitro-2-phenylpropanoate (2.1 g, 84%) as colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.57-7.55 (m, 2H, ArH), 7.37-7.26 (m, 8H, ArH), 5.28 (s, 2H, CH 2 Ph), 5.24 (d, J = 14.1 Hz, 1H, CH 2, H 1 ), 4.66 (d, J = 14.1 Hz, 1H, CH 2, H 2 ), 4.26 (s, 1H, H); 13 C NMR: (CDCl 3, 75 MHz) δ 171.6, 136.2, 134.2, 129.1, 129.0, 128.8, 128.8, 128.7, 128.5, 125.2, 80.6, 69.2,; MS (EI): m/z (%) = 302 (0.03), 166 (29), 123 (16), 105 (80), 91 (100), 77 (20), 65 (15), 51 (9), 39 (7); HRMS: calcd for [C 16 H 15 N 5 ]: 324.0842, found 324.0841. Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (2.00 g, 6.6 mmol) was then converted to the corresponding nitroacrylic benzyl ester. After purification by silica gel chromatography (15% acetone in hexanes) pure benzyl 3-nitro-2-phenylacrylate (400 mg, 21%) was obtained as a yellow oil. Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (0.40 g, 1.33 mmol) was then converted to the corresponding nitroacrylic benzyl ester. After purification by silica gel chromatography (2-5% Et 2 in pentane) pure benzyl 3-nitro-2-phenylacrylate (320 mg, 84%) was obtained as a yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.42-7.33 (m, 11H, ArH and CH ), 5.41 (s, 2H, CH 2 Ph); 13 C NMR: (CDCl 3, 75 MHz) δ 164.6, 142.9, 134.5, 134.4, 132.1, 129.5, 129.3, 128.9, 128.8, 128.6, 127.5, 68.5,; MS (EI): m/z (%) = 283 (0.08), 177 (10), 159 (3), 133 (11), 102 (16), 91 (100), 77 (11), 65 (14), 51 (7), 39 (6); HRMS(ESI): calcd for [C 16 H 13 N 4 +Na]: 306.0737, found 306.0736. (Z)-Methyl 3-nitro-2-phenylacrylate (2b): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from methylbenzoylfomate (3.0 g, 18.3 mmol). The reaction proceeded for 48 h at room temperature, and the crude reaction mixture was then purified by flash chromatography S9

(10-15% EtAc in hexanes) to yield methyl 2-hydroxy-3-nitro-2-phenylpropanoate (3.5 g, 85%) as a colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.61-7.68 (m, 2H, ArH), 7.44-7.37 (m, 3H, ArH), 5.26 (d, J = 14.2 Hz, 1H, CH 2, H 1 ), 4.68 (d, J = 14.2 Hz, 1H, CH 2, H 2 ), 4.23 (s, 1H, H), 3.91 (s, 3H, CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 172.2, 136.3, 135.0, 130.1, 129.2, 129.0, 125.2, 80.0, 76.1, 54.1, 14.2; MS (EI): m/z (%) = 225 (6), 166 (37), 123 (24), 105 (100), 91 (21), 77 (21), 65 (4), 51 (6), 39 (2), 30 (1); HRMS: calcd for [C 10 H 11 N 5 ]: 225.0637, found 225.0640. The β-nitro-α-hydroxyester (3.0 g, 13.3 mmol) was then converted to the corresponding nitroacrylic ester according to the procedure B. After purification by flash chromatography (5% EtAc in hexanes) pure methyl 3-nitro-2-phenylacrylate (1.6 g, 59%) was obtained as a yellow oil. 1 H NMR: (300 MHz, CDCl 3 ) δ 7.54-7.44 (m, 5H, ArH), 7.36 (s, 1H, CH ), 4.00 (s, 3H, CCH 3 ); 13 C NMR: (75 MHz, CDCl 3 ) δ 165.3, 143.1, 134.6, 132.2, 129.7, 129.5, 127.5, 53.4; MS (EI): m/z (%) = 207 (41), 190 (7), 175 (45), 158 (22), 145 (24), 131 (6), 120 (27), 102 (100), 91 (28), 76 (32), 63 (16), 59 (52), 51 (18), 39 (11), 30 (6); HRMS: calcd for [C 10 H 9 N 4 ]: 207.0531, found 207.0530. (Z)-Ethyl 3-nitro-2-phenylacrylate (2c): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from ethylbenzoylfomate (5.0 g, 27.5 mmol). The reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (5-20% EtAc in hexanes) to yield ethyl 2-hydroxy-3-nitro-2-phenylpropanoate (6.2 g, 92%) as a light yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.62-7.58 (m, 2H, ArH), 7.44-7.37 (m, 3H, ArH), 5.26 (d, J = 14.2 Hz, 1H, CH 2, H 1 ), 4.68 (d, J = 14.2 Hz, 1H, CH 2, H 2 ), 4.44-4.31 (m, 2H, CH 2 CH 3 ), 4.24 (d, J = 0.8 Hz, 1H, H), 1.34 (dt, 3H, J = 7.2 Hz, 1.2 Hz, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 171.6, 136.4, 129.1, 128.9, 125.2, 80.8, 76.0, 63.6, 13.9; MS (EI): m/z (%) = 239 (3), 166 (29), 123 (20), 105 (100), 91 (16), 77 (17), 65 (3), 51 (5), 43 (3), 29 (15); HRMS: calcd for [C 11 H 13 N 5 +Na]: 262.0686, found 262.0688; these data are in agreement with those reported in the literature. 12 Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (6.0 g, 25.1 mmol) was then converted to the corresponding nitroacrylic ester (procedure A). After purification by flash chromatography (5% EtAc in hexanes) pure ethyl 3-nitro-2-phenylacrylate (3.5 g, 63%) was obtained as a yellow oil. 12 Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. rg. Chem. 2002, 67, 4875-4881 S10

Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (0.96 g, 4.0 mmol) was then converted to the corresponding nitroacrylic ester (procedure B). After purification by flash chromatography (2-5% Et 2 in pentane) pure ethyl 3-nitro-2-phenylacrylate (0.74 g, 83%) was isolated as a yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.56-7.44 (m, 5H, ArH), 7.35 (s, 1H, CH ), 4.48 (q, J = 7.2 Hz, 2H, CH 2 CH 3 ), 1.40 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 164.7, 143.3, 134.5, 132.1, 129.5, 127.5, 62.5, 13.8; MS (EI): m/z (%) = 221 (19), 204 (2), 193 (2), 175 (40), 158 (11), 145 (11), 132 (6), 120 (17), 102 (89), 91 (24), 77 (26), 63 (11), 51 (12), 39 (6), 29 (100); HRMS: calcd for [C 11 H 11 N 4 ]: 221.0688, found 221.0686. The physical data were identical in all respects to those previously reported. 13 (Z)-Isopropyl 3-nitro-2-phenylacrylate (2d): According to the general procedure D, the α-keto ester was synthesized starting from 2-oxo-2- phenylacetic acid (3.84 g, 25.6 mmol) to give isopropyl 2-oxo-2- phenylacetate (5 g, 88%) as crude product which (3 g, 15.6 mmol) was used directly according to the general procedure A. The Henry reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (15% EtAc in hexanes) to yield i-propyl 2-hydroxy-3-nitro-2-phenylpropanoate (3.5 g, 92%) as colourless solid. Mp 97 100 o C; 1 H NMR: (CDCl 3, 300 MHz) δ 7.65-7.57 (m, 2H, ArH), 7.44-7.34 (m, 3H, ArH), 5.24 (d, J = 14.1 Hz, 1H, CH 2, H 1 ), 5.15-5.23 (m, 1H, CHMe 2 ), 4.66 (d, J = 14.1 Hz, 1H, CH 2, H 2 ), 4.22 (s, 1H, H), 1.35 (d, J = 6.3 Hz, 3H, CHCH 3 ), 1.29 (d, J = 6.3 Hz, 3H, CHCH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 171.1, 136.6, 129.1, 128.8, 125.2, 80.8, 75.9, 71.9, 21.5, 21.4; MS (EI): m/z (%) = 253(0.34), 166 (15), 123 (15), 120 (15), 105 (100), 91 (10), 77 (18), 65 (2), 51 (6), 43 (25); HRMS: calcd for [C 12 H 15 N 5 ]: 253.0950, found 253.0950. The β-nitro-α-hydroxyester (3.00 g, 11.9 mmol) was then converted to the corresponding nitroacrylic isopropyl ester. After purification by silica gel chromatography (10% EtAc in hexanes) pure isopropyl 3-nitro-2-phenylacrylate (2.0 g, 72%) was obtained as a yellow solid. Mp: 49-51 o C; 1 H NMR: (CDCl 3, 400 MHz) δ 7.55-7.44 (m, 5H, ArH), 7.34 (br s, 1H, CH ), 5.41-5.35 (m, 1H, CH(CH 3 ) 2 ), 1.39 (d, J = 6.3 Hz, 6H, CH(CH 3 ) 2 ); 13 C NMR: (CDCl 3, 100 MHz) δ 164.2, 143.4, 134.3, 132.0, 129.7, 129.5, 127.4, 70.9, 21.5; MS (EI): m/z (%) = 235 (9), 193 (15), 175 (76), 165 (12), 147 (11), 132 (8), 120 (14), 102 (100), 91 (12), 76 (17), 63 (7), 51 (6), 43 (99); HRMS: calcd for [C 12 H 13 N 4 ]: 235.0845, found 235.0842. 13 Swiderska, M. A.; Stewart, J. D. rg. Lett. 2006, 8, 6131-6133. S11

(Z)-Tert-butyl 3-nitro-2-phenylacrylate (2e): According to the general procedure D, the α-keto ester was synthesized starting from 2-oxo-2- phenylacetic acid (3.84 g, 25.6 mmol) to give tert-butyl 2-oxo-2-phenylacetate (1.30 g, 25%) as crude product which was used directly according to the general procedure A. The Henry reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (10% EtAc in hexanes) to yield tert-butyl 2-hydroxy- 3-nitro-2-phenylpropanoate (1.3 g, 77%) as colourless oil. 1 H NMR: (CDCl 3, 400 MHz) δ 7.62-7.59 (m, 2H, ArH), 7.42-7.34 (m, 3H, ArH), 5.19 (d, J = 14.0 Hz, 1H, CH 2, H 1 ), 4.65 (d, J = 14.0 Hz, 1H, CH 2, H 2 ), 4.23 (s, 1H, H), 1.52 (s, 9H, (CH 3 ) 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ170.5, 137.0, 128.9, 128.8, 125.2, 85.0, 80.8, 75.9, 27.7; MS (EI): m/z (%) = 268 (0.03), 166 (7), 120 (14), 105 (37), 77 (8), 57 (100), 41 (18), 29 (11); HRMS: calcd for [C 13 H 17 N 5 +H]: 268.1185, found 268.1185. Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (1.25 g, 4.68 mmol) was then converted to the corresponding nitroacrylic tert-butyl ester. After purification by silica gel chromatography (10% EtAc in hexanes) pure tert-butyl 3-nitro-2-phenylacrylate (200 mg, 17%) was obtained as a yellow solid. Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (0.80 g, 2.99 mmol) was then converted to the corresponding nitroacrylic tert-butyl ester. After purification by silica gel chromatography (2-5% Et 2 in pentane) pure tert-butyl 3-nitro-2-phenylacrylate (310 mg, 83%) was isolated as a yellow solid. Mp: 82-83 o C; 1 H NMR: (CDCl 3, 400 MHz) δ 7.54-7.45 (m, 5H, ArH), 7.30 (br s, 1H, CH ), 1.62 (s, 9H, (CH 3 ) 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 163.5, 143.7, 133.7, 131.9, 130.0, 129.5, 127.4, 84.8, 27.9; MS (EI): m/z (%) = 249 (1.89), 193 (15), 176 (22), 158 (6), 102 (30), 57 (100), 41 (17), 29 (11); HRMS: calcd for [C 13 H 15 N 4 ]: 249.1001, found 249.0999. (Z)-Ethyl 3-nitro-2-p-tolylacrylate (2f): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from ethyl 4-methylbenzoylfomate (4.00 g, 20.8 mmol). The reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (10% EtAc in hexanes) to yield ethyl 2-hydroxy-3-nitro-2-p-tolylpropanoate (4.3 g, 82%) as a colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.50-7.45 (m, 2H, ArH), 7.22-7.19 (d, J = 8.0 Hz, 2H, ArH), 5.24 (dd, J = 14.2 Hz, 0.7 Hz, 1H, CH 2, H 1 ), 4.66 (d, J = 14.1 Hz, 1H, CH 2, H 2 ), 4.41-4.30 (m, 2H, CH 2 CH 3 ), 4.19 (s, 1H, H), 2.35 (s, 3H, p-ch 3 Ar), 1.33 (t, S12

J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 171.8, 139.1, 133.5, 129.6, 125.1, 80.8, 75.9, 63.5, 21.0, 13.9; MS (EI): m/z (%) = 253 (5), 180 (17), 137 (8), 119 (100), 105 (3), 91 (21), 65 (6), 29 (3); HRMS: calcd for [C 12 H 15 N 5 ]: 253.0950, found 253.0949. The β-nitro-α-hydroxyester (4.00 g, 15.9 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (3% EtAc in hexanes) pure ethyl 3-nitro-2-p-tolylacrylate (1.9 g, 52%) was obtained as a yellow oil. 1 H NMR: (300 MHz, CDCl 3 ) δ 736-7.33 (m, 2H, ArH), 7.34 (s, 1H, CH ), 7.23-7.20 (m, 2H, ArH), 4.42 (q, J = 7.2 Hz, 2H, CH 2 CH 3 ), 2.34 (s, 3H, p-ch 3 ), 1.34 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (75 MHz, CDCl 3 ) δ 165.0, 143.4, 143.1, 133.6, 130.3, 127.5, 126.6, 62.7, 21.5, 11.9; MS (EI): m/z (%) = 235 (57), 218 (8), 204 (4), 189 (52), 172 (22), 161 (19), 146 (13), 134 (21), 115 (100), 105 (20), 91 (24), 77 (10), 65 (10), 51 (6), 39 (6), 29 (47); HRMS: calcd for [C 12 H 13 N 4 ]: 235.0845, found 235.0842. (Z)-Ethyl 2-(4-methoxyphenyl)-3-nitroacrylate (2g): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from ethyl p-methoxybenzoylfomate (4.0 g, 19.2 mmol). The reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (25% EtAc in hexanes) to yield ethyl 2-hydroxy-3-nitro-2-(4-methoxyphenyl)propanoate (4.2 g, 81%) as a light yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.51 (d, J = 9.0Hz, 2H, ArH), 6.91 (d, J = 9.0 Hz, 2H, ArH), 5.22 (d, J = 14.1 Hz, 1H, CH 2, H 1 ), 4.65 (d, J = 14.1 Hz, 1H, CH 2, H 2 ), 4.42-4.30 (m, 2H, CH 2 Me), 4.18 (s, 1H, H), 3.81 (s, 3H, CH 3 ), 1.33 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 171.8, 160.1, 128.3, 126.6, 114.2, 80.8, 75.7, 63.5, 55.3, 13.9; MS (EI): m/z (%) = 269 (6), 196 (25), 150 (29), 135 (100), 121 (7), 107 (4), 92 (4), 77 (10); HRMS: calcd for [C 12 H 15 N 6 ]: 269.0899, found 269.0897; these data are in agreement with those reported in the literature. 12 Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (3.2g, 13.4 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (20% Acetone in hexanes) pure ethyl 3-nitro-2-(4-methoxyphenyl)acrylate (1.0 g, 34%) was obtained as a yellow oil. Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (0.40 g, 1.49 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (5-15% Et 2 in pentane) pure ethyl 3-nitro-2-(4-methoxyphenyl)acrylate (300 mg, 80%) was obtained as a yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.44 (d, J = 9.0 Hz, 2H, ArH), 7.35 (s, 1H, CH ), 6.96 (d, J = 9.0 Hz, 2H, ArH), 4.48 (q, J = 7.2 Hz, 2H, S13

CH 2 CH 3 ), 3.85 (s, 3H, CH 3 ), 1.40 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 165.2, 163.0, 143.2, 132.3, 129.5, 121.5, 115.5, 62.7, 55.6, 13.9; MS (EI): m/z (%) = 251 (99), 206 (32), 168 (20), 150 (27), 132 (100), 117 (40), 95 (10), 89 (55), 77 (15), 63 (21), 51 (7), 39 (9), 29 (77); HRMS: calcd for [C 12 H 13 N 5 ]: 251.0794, found 251.0796. (Z)-Tert-butyl 2-(4-methoxyphenyl)-3-nitroacrylate (2h): According to the general procedure F, the α-keto ester was synthesized starting from tertbutyl 2-(1H-imidazol-1-yl)-2-oxoacetate (4.76 g, 24.0 mmol) to give tertbutyl 2-oxo-2-(4-methoxyphenyl)acetate (1.50 g, 26%) as crude product which (1.50 g, 6.3 mmol) was used directly according to the general procedure A. The Henry reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (20% EtAc in hexanes) to yield tert-butyl 2-hydroxy-3-nitro-2-(4- methoxyphenyl)propanoate (1.30 g, 69%) as a colourless solid. Mp: 80-82 o C; 1 H NMR: (CDCl 3, 300 MHz) δ 7.51 (d, J = 9.0 Hz, 2H, ArH), 6.91 (d, J = 9.0 Hz, 2H, ArH), 5.15 (d, J = 14.0 Hz, 1H, CH 2, H 1 ), 4.62 (d, J = 14.0 Hz, 1H, CH 2, H 2 ), 4.18 (s, 1H, H), 3.81 (s, 3H, CH 3 ), 1.52 (s, 9H, (CH 3 ) 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 170.7, 160.0, 128.9, 126.5, 114.1, 84.9, 80.9, 75.6, 55.3, 27.7; MS (EI): m/z (%) = 297 (7), 196 (43), 150 (39), 135 (100), 121 (4), 92 (4), 77 (8), 57 (65), 41 (11); HRMS(ESI): calcd for [C 14 H 19 N 6 +Na]: 320.1105, found 320.1104. Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (1.30 g, 4.38 mmol) was then converted to the corresponding nitroacrylic tert-butyl ester. After purification by silica gel chromatography (15% acetone in hexanes) pure tert-butyl 3-nitro-2-(4- methoxyphenyl)acrylate (0.30 g, 25%) was obtained as a yellow solid. Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (0.40 g, 1.35 mmol) was then converted to the corresponding nitroacrylic tert-butyl ester. After purification by silica gel chromatography (5-15% Et 2 in pentane) pure tert-butyl 3-nitro-2-(4- methoxyphenyl)acrylate (263 mg, 70%) was obtained as a yellow solid. Mp 95-96 o C; 1 H NMR: (CDCl 3, 300 MHz) δ 7.47 (d, J = 9.0 Hz, 2H, ArH), 7.29 (s, 1H, CH ), 6.96 (d, J = 9.0 Hz, 2H, ArH), 3.86 (s, 3H, CH 3 ), 1.63 (s, 9H, (CH 3 ) 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 163.9, 162.8, 143.5, 131.7, 129.4, 122.1, 115.0, 84.6, 55.6, 27.9; MS (EI): m/z (%) = 279 (57), 223 (57), 206 (34), 132 (72), 117 (15), 89 (19), 57 (100), 41 (19); HRMS(ESI): calcd for [C 14 H 17 N 5 +Na]: 302.0999, found 302.0998. S14

F (Z)-Tert-butyl 2-(4-fluorophenyl)-3-nitroacrylate (2i): According to the general procedure F, the α-keto ester was synthesized starting from tertbutyl 2-(1H-imidazol-1-yl)-2-oxoacetate (3.80 g, 17 mmol) to give tertbutyl 2-oxo-2-(4-fluorophenyl)acetate (1.40 g, 37%) as crude product which (1.40 g, 6.25 mmol) was used directly according to the general procedure A. The Henry reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (20% acetone in hexanes) to yield tert-butyl 2-hydroxy-3-nitro-2-(4- fluorophenyl)propanoate (1.20 g, 68%) as colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 7.61-7.58 (m, 2H, ArH), 7.11-7.06 (m, 2H, ArH), 5.16 (d, J = 14.0 Hz, 1H, CH 2, H 1 ), 4.62 (d, J = 14.0 Hz, 1H, CH 2, H 2 ), 4.24 (s, 1H, H), 1.52 (s, 9H, (CH 3 ) 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 170.3, 164.2, 161.7, 132.7, 127.3, 127.2, 115.8, 115.6, 85.3, 80.8, 75.6, 27.7; MS (EI): m/z (%) = 286 (0.04), 184 (7), 138 (11), 123 (29), 109 (4), 95 (5), 57 (100), 41 (22); HRMS(ESI): calcd for [C 13 H 16 N 5 F+Na]: 308.0905, found 308.0902. Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (1.20 g, 4.22 mmol) was then converted to the corresponding nitroacrylic tert-butyl ester. After purification by silica gel chromatography (15% acetone in hexanes) pure tert-butyl 3-nitro-2-(4- fluorophenyl)acrylate (0.3 g, 27%) was obtained as a yellow oil. Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (1.20 g, 4.22 mmol) was then converted to the corresponding nitroacrylic tert-butyl ester. After purification by silica gel chromatography (5-15% Et 2 in pentane) pure tert-butyl 3-nitro-2-(4- fluorophenyl)acrylate (315 mg, 85%) was isolated as a yellow oil. 1 H NMR: (CDCl 3, 400 MHz) δ 7.55-7.51 (m, 2H, ArH), 7.25 (s, 1H, CH ), 7.16 (t, J = 9.0 Hz, 2H, ArH), 1.62 (s, 9H, (CH 3 ) 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 166.1, 163.4, 142.6, 133.5, 129.7, 129.6, 126.2, 126.2, 116.9, 116.7, 85.1, 27.9; MS (EI): m/z (%) = 267 (8), 211 (8), 194 (17), 120 (34), 94 (3), 57 (100), 41 (21); HRMS(ESI): calcd for [C 13 H 14 N 4 F+Na]: 290.0799, found 290.0798. S (E)-Ethyl 3-nitro-2-(thiophen-2-yl)acrylate (2j): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from ethyl(thiophen-2-yl)formate (7.00 g, 38.0 mmol). The reaction proceeded for 48 h at room temperature, and the crude reaction mixture was purified by flash chromatography (15% EtAc in hexanes) to yield ethyl 2-hydroxy-3-nitro-2-(thiophen-2- yl)propanoate (6.30 g, 65%) as a green yellow solid. Mp: 59-62 o C; 1 H NMR: (CDCl 3, 400 MHz) δ 7.34 (dd, J = 5.1 Hz, 1.2 Hz, 1H, ArH), 7.15 (dd, J = 3.6 Hz, 1.2 Hz, 1H, ArH), 7.02 (dd, J = 5.1 Hz, 3.6 Hz, 1H, ArH), 5.18 (d, J = 14 Hz, CH 2, H 1 ), 4.76 (d, J =14 Hz, 1H, S15

CH 2, H 2 ), 4.46-4.35 (m, 3H, H and CH 2 CH 3 ), 1.37 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 170.6, 140.4, 127.5, 126.8, 125.1, 80.6, 74.8, 63.9, 13.9; MS (EI): m/z (%) = 245 (10), 199 (12), 172 (58), 126 (44), 111 (100), 97 (17), 84 (8), 65 (2), 39 (8), 29 (15); HRMS: calcd for [C 9 H 11 N 5 S]: 245.0358, found 245.0358. Dehydration (according to Procedure A): The β-nitro-α-hydroxyester (6.18 g, 24.3 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (5% EtAc in hexanes) pure ethyl 3-nitro-2-(thiophen-2-yl)acrylate (2.1 g, 46%) was obtained as a yellow solid. Dehydration (according to Procedure B): The β-nitro-α-hydroxyester (0.40 g, 1.63 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (3-15% Et 2 in pentane) pure ethyl 3-nitro-2-(thiophen-2-yl)acrylate (290 mg, 78%) was isolated as a yellow solid. Mp: 55-57 o C.; 1 H NMR: (CDCl 3, 400 MHz) δ 7.58 (dd, J = 5.2, 1.3 Hz, 1H, ArH), 7.38-7.36 (m, 2H, ArH and CH ), 7.15 (dd, J = 5.1, 3.8 Hz, 1H, ArH), 4.50 (q, J = 7.2 Hz, 2H, CH 2 CH 3 ), 1.42 (t, J = 7.2 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 163.9, 137.7, 133.1, 132.6, 131.6, 131.6, 129.0, 63.1, 13.9; MS (EI): m/z (%) = 227 (28), 182 (28), 154 (25), 138 (31), 112 (73), 108 (100), 97 (15), 83 (43), 69 (30), 58 (20), 45 (39), 39 (10), 29 (82); HRMS: calcd for [C 9 H 9 N 4 S]: 227.0252, found 227.0254. 2 N (E)-Ethyl 2-methyl-3-nitroacrylate (2k): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from ethyl 2- oxopropanoate (5.00 g, 42.2 mmol). The reaction proceeded for 22 h at room temperature, and the crude reaction mixture was purified by flash chromatography (5-20% Et 2 in pentane) to yield ethyl 2-hydroxy-2-methyl-3-nitropropanoate (7.30 g, 96%) as a colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 4.84 (d, J = 13.7 Hz, 1H, CH 2, H 1 ), 4.55 (d, J = 13.8 Hz, 1H, CH 2, H 2 ), 4.39-4.28 (m, 2H, CH 2 CH 3 ), 3.75 (s, 1H, H), 1.45 (s, 3H, CCH 3 ), 1.32 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 173.4, 81.0, 72.4, 63.0, 23.8, 14.0; MS (EI): m/z (%) = 178 (0.03), 134 (1), 117 (1), 104 (61), 85 (2), 73 (1), 58 (32), 43 (100), 29 (63); HRMS: calcd for [C 6 H 11 N 5 +H]: 178.0716, found 178.0718; these data are in agreement with those reported in the literature. 12 The β-nitro-α-hydroxyester (7.20 g, 40.6 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (10% EtAc in hexanes) (E)- ethyl 2-methyl-3-nitroacrylate (0.40 g, 6%) and (Z)-ethyl 2-methyl-3-nitroacrylate (4.40 g, 68%) were obtained as light yellow oils. (E)-Ethyl 2-methyl-3-nitroacrylate: 1 H NMR: S16

(CDCl 3, 400 MHz) δ 7.72 (m, 1H, CH ), 4.31 (q, J = 7.1 Hz, 2H, CH 2 CH 3 ), 2.32 (d, J = 1.7 Hz, 3H, CCCH 3 ), 1.35 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 165.2, 143.9, 136.8, 62.6, 14.0, 13.7; MS (EI): m/z (%) = 159 (0.2), 114 (100), 99 (13), 85 (4), 71 (18), 68 (2), 56 (5), 39 (26), 29 (78), 27 (19); HRMS: calcd for [C 6 H 9 N 4 ]: 159.0532, found 159.0532. (Z)-Ethyl 2-methyl-3-nitroacrylate: 1 H NMR: (CDCl 3, 400 MHz) δ 6.87 (m, 1H, CH ), 4.35 (q, J = 7.1 Hz, 2H, CH 2 CH 3 ), 2.10 (d, J = 1.7 Hz, 3H, CCCH 3 ), 1.34 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 166.1, 140.9, 135.7, 62.4, 17.6, 13.8. The physical data were identical in all respects to those previously reported. 9 2 N (E)-Ethyl 2-(nitromethylene)heptanoate (2l): This nitroacrylic ester was prepared according to the general procedure C. The α-keto ester was synthesized starting from diethyloxalate (9.10 g, 62.1 mmol). After purification by flash chromatography (10 % Et 2 in pentane) ethyl 2-oxoheptanoate (7.70 g, 72%) was obtained as a yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 4.31 (q, J = 7.1 Hz, 2H, CH 2 CH 3 ), 2.81 (t, J = 7.3 Hz, 2H, CH 2 C), 1.65-1.61 (m, 2H, CH 2 CH 2 CH 2 ), 1.38-1.28 (m, 7H: 3H, t, J = 7.1 Hz, CH 2 CH 3 ; 2H, CH 2 CH 2 CH 2 ; 2H, CH 2 CH 2 CH 3 ), 0.91-0.87 (m, 3H, CH 2 CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 194.8, 161.3, 62.3, 39.2, 31.1, 22.6, 22.3, 14.0, 13.8; MS (EI): m/z (%) = 172 (5), 99 (100), 71 (50), 55 (11), 43 (87), 29 (27); HRMS: calcd for [C 9 H 16 3 ]: 172.1099, found 172.1098. The physical data were identical in all respects to those previously reported. 14 The β-nitro-α-hydroxyester was synthesized starting from ethyl 2-oxoheptanoate (7.60 g, 44.3 mmol). The reaction proceeded for 25 h at room temperature, and the crude reaction mixture was purified by flash chromatography (10 % Et 2 in pentane) to yield ethyl 2-hydroxy-2- (nitromethyl)heptanoate (9.70 g, 94%) as a colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 4.81 (d, J = 13.6 Hz, 1H, CH 2, H 1 ), 4.55 (d, J = 13.6 Hz, 1H, CH 2, H 2 ), 4.40-4.29 (m, 2H, CH 2 CH 3 ), 3.69 (s, 1H, H), 1.69-1.61 (m, 2H, CH 2 C), 1.55-1.20 (m, 9H: 3H, t, J = 7.1 Hz, CH 2 CH 3 ; 4H, CH 2 CH 2 CH 2 ; 2H, CH 2 CH 2 CH 3 ), 0.87 (t, J = 6.8 Hz, 3H, CH 2 CH 2 CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 172.9, 80.9, 75.3, 63.0, 36.5, 31.5, 22.3, 22.9, 14.1, 13.8; MS (EI): m/z (%) = 234 (0.4), 160 (22), 134 (3), 117 (100), 99 (95), 95 (7), 71 (47), 58 (17), 43 (81), 29 (41); HRMS: calcd for [C 10 H 19 N 5 +Na]: 256.1155, found 256.1153. This β-nitro-α-hydroxyester (9.60 g, 41.3 mmol) was then converted to the corresponding nitroacrylic ester. After purification by flash chromatography (1% Et 2 in pentane) (E)-ethyl 2-(nitromethylene)heptanoate (0.40 g, 5%) and (Z)-ethyl 2-(nitromethylene)heptanoate (5.40 14 Wong, M.-K.; Chung, N.-W.; He, L.; Wang, X.-C.; Yan, Z.; Tang, Y.-C.; Yang, D. J. rg. Chem. 2003, 68, 6321-6328. S17

g, 61%) were obtained as yellow oils. (E)-Ethyl 2-(nitromethylene)heptanoate: 1 H NMR: (CDCl 3, 400 MHz) δ 7.65 (s, 1H, CH ), 4.31 (q, J = 7.1 Hz, 2H, CCH 2 CH 3 ), 2.75-2.71 (m, 2H, CCH 2 CH 2 ), 1.56-1.51 (m, 2H, CH 2 CH 2 CH 2 ), 1.38-1.31 (m, 7H: 2H, CH 2 CH 2 CH 2 ; 2H, CH 2 CH 2 CH 3 and 3H, CCH 2 CH 3 ), 0.90 (m, 3H, CH 2 CH 3 ); 13 C NMR: (CDCl 3, 100 MHz) δ 165.1, 143.3, 141.2, 62.4, 31.7, 28.2, 27.2, 22.2, 14.0, 13.8; MS (EI): m/z (%) = 216 (0.2), 198 (2), 170 (20), 159 (18), 141 (10), 123 (9), 113 (18), 95 (47), 85 (16), 67 (17), 55 (44), 41 (57), 29 (100); HRMS: calcd for [C 10 H 18 N 4 +H + ]: 216.1236, found 216.1238. (Z)-Ethyl 3-methyl-2-(nitromethylene)butanoate (2m): According to the general procedure A, the β-nitro-α-hydroxyester was synthesized starting from ethyl 3-methyl-2-oxobutanoate (4.70 g, 32.6 mmol). The reaction proceeded for 22 h at room temperature, and the crude reaction mixture was purified by flash chromatography (15% Et 2 in pentane) to yield ethyl 2-hydroxy-3-methyl-2- (nitromethyl)butanoate (6.50 g, 97%) as a colourless oil. 1 H NMR: (CDCl 3, 300 MHz) δ 4.82 (d, J = 6.7 Hz, 1H, CH 2, H 1 ), 4.66 (d, J = 6.7 Hz, 1H, CH 2, H 2 ), 4.40-4.31 (m, 2H, CH 2 CH 3 ), 3.61 (s, 1H, H), 1.98 (quintet, J = 6.8 Hz, 1H, CH(CH 3 ) 2 ), 1.34 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ), 0.99 (d, J = 6.8 Hz, 3H, CH(CH 3 ) 2 ), 0.90 (d, J = 6.8 Hz, 3H, CH(CH 3 ) 2 ); 13 C NMR: (CDCl 3, 75 MHz) δ 173.0, 80.2, 77.5, 62.9, 34.1, 16.8, 16.2, 14.0; MS (EI): m/z (%) = 206 (0.4), 162 (8), 132 (21), 117 (16), 89 (57), 85 (18), 71 (87), 57 (11), 43 (100), 29 (36); HRMS: calcd for [C 8 H 16 N 5 +H]: 206.1028, found 206.1027. The β-nitro-α-hydroxyester (6.50 g, 31.7 mmol) was then converted to the corresponding nitroacrylic ester according to Procedure A. After purification by flash chromatography (1-3% Et 2 in pentane) pure ethyl 3-methyl-2-(nitromethylene)butanoate (1.80 g, 30%) was obtained as a yellow oil. 1 H NMR: (CDCl 3, 300 MHz) δ 6.83 (d, J = 1.3 Hz, 1H, CH ), 4.36 (q, J = 7.2 Hz, 2H, CH 2 CH 3 ), 2.74 (m, 1H, CH(CH 3 ) 2 ), 1.34 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ), 1.20 (d, J = 6.9 Hz, 6H, CH(CH 3 ) 2 ); 13 C NMR: (CDCl 3, 75 MHz) δ 165.6, 150.7, 134.7, 62.2, 31.4, 20.3, 13.8; MS (EI): m/z (%) = 188 (0.1), 172 (3), 142 (38), 127 (9), 114 (36), 95 (7), 84 (6), 67 (25), 53 (23), 43 (100), 29 (90); HRMS: calcd for [C 8 H 14 N 4 +H + ]: 188.0923, found 188.0921. The physical data were identical in all respects to those previously reported. 9 S18

General Procedure for the Asymmetric Transfer Hydrogenation of β-nitroacrylic Esters To a solution of β-nitroacrylic ester 2 (0.30 mmol) in toluene (0.3 ml, 1.0 M), catalyst 4 (12.6 mg, 0.03 mmol, 0.1 equiv) and Hantzsch ester 3 (92.8 mg, 0.30 mmol, 1.0 equiv) were added. The reaction mixture was stirred for 24-48 h at 0 C under argon atmosphere. The solvent was then removed in vacuo 15 and the resulting mixture purified by flash column chromatography. (S)-Benzyl 3-nitro-2-phenylpropanoate (5a): yellow solid; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.35-7.20 (m, 10H, ArH), 5.23-5.08 (m, 3H: 1H, CH 2, H 1 ; 2H, CH 2 Ar), 4.56 (dd, J = 14.6 Hz, 5.2 Hz, 1H, CH 2, H 2 ), 4.48 (dd, J = 9.8 Hz, 5.2 Hz, 1H, ArCHC); 13 C NMR: (100 MHz, CDCl 3 ) δ 170.4, 135.1, 133.1, 129.3, 128.7, 128.5, 128.4, 128.0, 127.9, 75.7, 67.5, 48.8; MS (EI): m/z (%) = 193 (1), 149 (17), 131 (4), 104 (21), 91 (100), 77 (7), 65 (10), 51 (5), 39 (4); HRMS: calcd for [C 16 H 15 N 4 +Na]: 308.0893, found 308.0890. The enantiomers were analyzed by HPLC using a chiral Chiralcel AS-H column (iprh/heptane = 80:20, flow rate = 0.5 ml/min, wavelength = 254 nm). Major enantiomer: t R = 20.68 min, minor enantiomer: t R = 25.37 min. (S)-Methyl 3-nitro-2-phenylpropanoate (5b): light yellow oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (300 MHz, CDCl 3 ) δ 7.40-7.34 (m, 3H, ArH), 7.28-7.25 (m, 2H, ArH), 5.11 (dd, J = 14.4 Hz, 9.9 Hz, 1H, CH 2, H 1 ), 4.55 (dd, J = 14.7 Hz, 5.4 Hz, 1H, CH 2, H 2 ), 4.45 (dd, J = 9.9 Hz, 5.4 Hz, 1H, ArCHC), 3.73 (s, 3H, CH 3 ); 13 C NMR: (75 MHz, CDCl 3 ) δ 171.0, 133.2, 129.4, 128.7, 127.9, 75.7, 52.9, 48.6; MS (EI): m/z (%) = 209 (5), 178 (3), 162 (100), 150 (6), 131 (20), 121 (25), 104 (79), 91 (14), 77 (25), 63 (5), 59 (22), 51 (13), 39 (6); HRMS: calcd for [C 10 H 11 N 4 ]: 209.0688, found 209.0690. The physical data were identical 15 When the conversion was not complete after 48h the remaining Hanztsch ester was destroyed at 0 C with diterbutyl-azodicarboxylate (DBAD) to avoid a non-enantioselective background reaction to occur during solvent evaporation (rt-40 C). S19

in all respects to those previously reported. 16 [α] 26 D = -126.2 (c = 2.8, CHCl 3 ) for 94:6 er of product with (S) stereochemistry. Literature value: [α] 26 D = -150.6 (c = 2.8, CHCl 3, 95:5 er) or [α] 26 D = -134.9 (c = 2.8, CHCl 3, 91:9 er) for product of with (S) stereochemistry. 4a The enantiomers were analyzed by GC using a chiral G-TA column (100 C, 1.0 C/min until 180 C, 15 min at 180 C). Major enantiomer: t R = 38.94 min, minor enantiomer: t R = 41.43 min. (S)-Ethyl 3-nitro-2-phenylpropanoate (5c): light yellow oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.40-7.34 (m, 3H, ArH), 7.28-7.26 (m, 2H, ArH), 5.10 (dd, J = 14.6 Hz, 10.0 Hz, 1H, CH 2, H 1 ), 4.55 (dd, J = 14.6 Hz, 5.2 Hz, 1H, CH 2, H 2 ), 4.42 (dd, J = 10.0 Hz, 5.2 Hz, 1H, ArCHC), 4.27-4.13 (m, 2H, CH 2 CH 3 ), 1.22 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 170.5, 133.4, 129.3, 128.6, 127.9, 75.8, 61.9, 48.8, 13.9; MS (EI): m/z (%) = 223 (3), 176 (47), 150 (6), 132 (11), 104 (100), 91 (5), 77 (11), 63 (2), 51 (5), 39 (2), 29 (31); HRMS: calcd for [C 11 H 13 N 4 ]: 223.0845, found 223.0847. The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (80 C, 1.2 C/min until 180 C, 18 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 56.41 min, minor enantiomer: t R = 55.79 min. (S)-Isopropyl 3-nitro-2-phenylpropanoate (5d): light yellow oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.38-7.32 (m, 3H, ArH), 7.27-7.24 (m, 2H, ArH), 5.07 (m, 2H: 1H, CH(CH 3 ) 2 ; 1 H, CH 2, H 1 ), 4.53 (dd, J = 14.6 Hz, 5.1 Hz, 1H, CH 2, H 2 ), 4.37 (dd, J = 10.1 Hz, 5.1 Hz, 1H, ArCHC), 1.26 (d, J = 6.3 Hz, 3H, CH(CH 3 ) 2 ), 1.12 (d, J = 6.3 Hz, 3H, CH(CH 3 ) 2 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 169.9, 133.5, 129.2, 128.5, 127.8, 69.5, 49.0, 21.6, 21.2; MS (EI): m/z (%) = 237 (2), 190 (18), 178 (6), 150 (12), 131 (5), 104 (100), 91 (3), 78 (9), 63 (1), 51 (3), 43 (60); HRMS: calcd for [C 12 H 15 N 4 ]: 237,1001, found 237.0999. The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (100 C, 1.2 C/min until 170 C, 20 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 36.11 min, minor enantiomer: t R = 35.24 min. (S)-Tert-butyl 3-nitro-2-phenylpropanoate (5e): colorless yellow oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.36-7.33 (m, 3H, ArH), 7.27-7.25 (m, 2H, ArH), 5.04 16 Liu, H.; Xu, J.; Du, D.-M. rg. Lett. 2007, 9, 4725-4728. S20

(dd, J = 14.6 Hz, 10.1 Hz, 1 H, CH 2, H 1 ), 4.49 (dd, J = 14.6 Hz, 5.1 Hz, 1H, CH 2, H 2 ), 4.32 (dd, J = 10.2 Hz, 5.1 Hz, 1H, ArCHC), 1.41 (s, 9H, C(CH 3 ) 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 169.5, 133.9, 129.2, 128.4, 127.8, 82.5, 76.0, 49.7, 27.8; MS (EI): m/z (%) = 251 (0.3), 178 (7), 150 (8), 131 (3), 104 (49), 91 (1), 78 (5), 57 (100), 51 (2), 41 (15), 29 (9). HRMS: calcd for [C 13 H 17 N 4 +Na]: 274.1050, found 274.1049. The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (80 C, 1.2 C/min until 155 C, 18 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 54.84 min, minor enantiomer: t R = 54.36 min. (S)-Ethyl 3-nitro-2-p-tolylpropanoate (5f): colorless oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.19-7.14 (m, 4H, ArH), 5.08 (dd, J = 14.6 Hz, 10.0 Hz, 1H, CH 2, H 1 ), 4.52 (dd, J = 14.6 Hz, 5.2 Hz, 1H, CH 2, H 2 ), 4.38 (dd, J = 10.0 Hz, 5.1 Hz, 1H, ArCHC), 4.26-4.11 (m, 2H, CH 2 CH 3 ), 2.34 (s, 3H, ArCH 3 ), 1.22 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ) ; 13 C NMR: (100 MHz, CDCl 3 ) δ 170.7, 138.5, 130.3, 130.0, 127.7, 75.9, 61.8, 48.4, 21.1. 14.0; MS (EI): m/z (%) = 237 (7), 190 (76), 164 (7), 146 (21), 135 (1), 118 (100), 103 (4), 91 (14), 77 (4), 65 (4), 51 (2), 39 (3), 29 (25); HRMS: calcd for [C 12 H 15 N 4 ]: 237.1001, found 237.0999.The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (80 C, 1.2 C/min until 180 C, 20 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 63.10 min, minor enantiomer: t R = 62.36 min. (S)-Ethyl 2-(4-methoxyphenyl)-3-nitropropanoate (5g): light yellow oil; purification by flash column chromatography (1-5% Et 2 in pentane). 1 H NMR: (300 MHz, CDCl 3 ) δ 7.20-7.16 (m, 2H, ArH), 6.91-6.87 (m, 2H, ArH), 5.06 (dd, J = 14.6 Hz, 10.0 Hz, 1H, CH 2, H 1 ), 4.51 (dd, J = 14.6 Hz, 5.3 Hz, 1H, CH 2, H 2 ), 4.36 (dd, J = 9.9 Hz, 5.3 Hz, 1H, ArCHC), 4.26-4.11 (m, 2H, CH 2 CH 3 ), 3.79 (s, 3H, ArCH 3 ), 1.22 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ); 13 C NMR: (75 MHz, CDCl 3 ) δ 170.8, 159.7, 129.0, 125.2, 114.7, 75.9, 61.8, 55.3, 48.0, 13.9; MS (EI): m/z (%) = 253 (15), 206 (79), 180 (5), 162 (10), 134 (100), 119 (16), 105 (3), 91 (15), 77 (6), 65 (8), 51 (2), 39 (2), 29 (20); HRMS: calcd for [C 12 H 15 N 5 ]: 253.0950, found 253.0948. The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (80 C, 1.2 C/min until 180 C, 18 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 76.43 min, minor enantiomer: t R = 75.88 min. S21

(S)-Tert-butyl 2-(4-methoxyphenyl)-3-nitropropanoate (5h): light yellow oil; purification by flash column chromatography (1-5% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.18 (dd, J = 6.6 Hz, 2.1 Hz, 2H, ArH), 6.88 (dd, J = 6.7 Hz, 2.2 Hz, 2H, ArH), 4.99 (dd, J = 14.5 Hz, 10.1 Hz, 1H, CH 2, H 1 ), 4.46 (dd, J = 14.5 Hz, 5.3 Hz, 1H, CH 2, H 2 ), 4.26 (dd, J = 10.1 Hz, 5.2 Hz, 1H, ArCHC), 3.80 (s, 3H, ArCH 3 ), 1.41 (s, 9H, C(CH 3 ) 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 169.8, 159.6, 128.9, 125.8, 114.6, 82.4, 76.1, 55.3, 48.9, 27.8; MS (EI): m/z (%) = 281 (8), 234 (5), 208 (2), 180 (12), 134 (77), 119 (10), 103 (2), 91 (12), 77 (3), 65 (6), 57 (100), 51 (2), 41 (18); HRMS: calcd for [C 14 H 19 N 5 + Na]: 304.1155, found 304.1155.The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (80 C, 1.2 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 77.46 min, minor enantiomer: t R = 76.74 min. F (S)-Tert-butyl 2-(4-fluorophenyl)-3-nitropropanoate (5i): colorless oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.25-7.23 (m, 2H, ArH), 7.08-7.03 (m, 2H, ArH), 5.03-4.97 (dd, J 1 = 14.5 Hz, J 2 = 9.8 Hz, 1H, CH 2, H 1 ), 4.49 (dd, J = 14.5 Hz, 5.4 Hz, 1H, CH 2, H 2 ), 4.31 (dd, J = 9.8 Hz, 5.5 Hz, 1H, ArCHC), 1.41 (s, 9H, C(CH 3 ) 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 169.4, 163.9, 161.4, 129.7, 129.6, 129.5, 129.5, 116.4, 116.1, 82.7, 75.9, 48.9, 27.9, 27.8; MS (EI): m/z (%) = 269 (1), 196 (6), 168 (10), 122 (40), 101 (4), 75 (2), 57 (100), 41 (21); HRMS: calcd for [C 13 H 16 FN 4 +Na]: 292.0956, found 292.0956. The enantiomers were analyzed by GC using a chiral BGB-176 / BGB-15 column (80 C, 1.2 C/min until 170 C, 18 C/min until 220 C, 5 min at 220 C). Major enantiomer: t R = 54.21 min, minor enantiomer: t R = 53.83 min. S (S)-Ethyl 3-nitro-2-(thiophen-2-yl)propanoate (5j): yellow oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 7.30-7.28 (t, J = 3.2 Hz, 1H, ArH), 7.01-6.98 (m, 2H, ArH), 5.10 (dd, J = 14.3 Hz, 9.5 Hz, 1H, CH 2, H 1 ), 4.70 (dd, J = 9.6 Hz, 5.1 Hz, 1H, ArCHC), 4.63 (dd, J = 14.3 Hz, 5.1 Hz, 1H, CH 2, H 2 ), 4.31-4.16 (m, 2H, CH 2 CH 3 ), 1.31-1.22 (m, 3H, CH 2 CH 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 169.6, 134.4, 127.3, 126.8, 126.1, 75.7, 62.3, 43.8, 13.9; MS (EI): m/z (%) = 229 (1), 182 (72), 156 (7), 138 (25), 110 (100), 97 (5), 84 (6), 77 (5), 66 (10), 58 (4), 45 (9), 29 (29); HRMS: calcd for [C 9 H 11 N 4 S]: 229.0409, found 229.0411. The enantiomers were analyzed by GC using a chiral IVADEX 1 / S22

PS086 column (80 C, 1.2 C/min until 800 C, 18 C/min until 220 C, 10 min at 220 C). Major enantiomer: t R = 63.12 min, minor enantiomer: t R = 63.83 min. (R)-Ethyl 2-methyl-3-nitropropanoate (5k): 17 colorless oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (300 MHz, CDCl 3 ) δ 4.72 (dd, J= 14.0 Hz, 8.0 Hz, 1H, CH 2, H 1 ), 4.40 (dd, J = 14.0 Hz, 5.6 Hz, 1H, CH 2, H 2 ), 4.20 (q, J = 7.1 Hz, 2H, CH 2 CH 3 ), 3.28-3.21 (m, 1H, CHC), 1.30-1.25 (m, 3H, CH 2 CH 3 ); 13 C NMR: (75 MHz, CDCl 3 ) δ 172.4, 76.4, 61.5, 37.6, 14.3, 14.0; MS (EI): m/z (%) = 162 (0.2), 116 (23), 88 (24), 73 (16), 69 (46), 59 (14), 41 (52), 29 (100), 27 (18); HRMS: calcd for [C 6 H 12 N 4 +H]: 162.0766, found 162.0765. The enantiomers were analyzed by GC using a chiral LIPDEX G column (60 C, 1.2 C/min until 120 C, 18 C/min until 220 C, 6 min at 220 C). Major enantiomer: t R = 28.75 min, minor enantiomer: t R = 29.15 min. (R)-Ethyl 2-(nitromethyl)heptanoate (5l): colorless oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (400 MHz, CDCl 3 ) δ 4.73 (dd, J = 14.2 Hz, 9.2 Hz, 1H, CH 2, H 1 ), 4.41 (dd, J = 14.2 Hz, 4.8 Hz, 1H, CH 2, H 2 ), 4.20 (q, J = 7.1 Hz, 2H, CH 2 CH 3 ), 3.20-3.16 (m, 1H, CHC), 1.70-1.65 (m, 1H, CHCH 2 CH 2 ), 1.58-1.55 (m, 1H, CHCH 2 CH 2 ), 1.35-1.26 (m, 9H: 4H, CH 2 CH 2 CH 2 ; 2H, CH 2 CH 2 CH 3 ; 3H (J = 7.1 Hz), CH 2 CH 3 ), 0.90-0.87 (m, 3H, CH 2 CH 2 CH 3 ); 13 C NMR: (100 MHz, CDCl 3 ) δ 172.3, 75.2, 61.3, 43.0, 31.4, 29.2, 26.2, 22.3, 14.1, 13.9; MS (EI): m/z (%) = 216 (0.1), 198 (2), 189 (1), 170 (19), 159 (16), 141 (11), 123 (9), 113 (18), 95 (45), 85 (16), 67 (17), 55 (44), 41 (57), 29 (100); HRMS: calcd for [C 10 H 20 N 4 +H]: 218.1392, found 218.1394. The enantiomers were analyzed by GC using a chiral G-TA column (100 C, 1.2 C/min until 180 C, 10 min at 180 C). Major enantiomer: t R = 27.30 min, minor enantiomer: t R = 26.58 min. (S)-Ethyl 3-methyl-2-(nitromethyl)butanoate (5m): colorless oil; purification by flash column chromatography (2% Et 2 in pentane). 1 H NMR: (300 MHz, CDCl 3 ) δ 4.79 (dd, J = 14.5 Hz, 10.4 Hz, 1H, CH 2, H 1 ), 4.40 (dd, J = 15.1 Hz, 4.0 Hz, 1H, CH 2, H 2 ), 4.21 (q, J = 7.1 Hz, 2H, CH 2 CH 3 ), 3.12-3.05 (m, 1H, 17 The absolute configuration of the nitroester obtained from (Z)-2k has been determined by measuring the optical rotation of its corresponding known β 2 -amino acids: [α] d 20 = + 3.3 (c 0.79, H 2 ). According to the literature (Beddow, J. E.; Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. rg. Biomol. Chem. 2007, 5, 2812-2825), the nitroester obtained from (Z)-2k is therefore (S)-2k. The nitroester obtained from (E)-2k is the opposite enantiomer; thus, it is (R)-2k. S23

CHC), 2.10-2.04 (m, 1H, CH(CH 3 ) 2 ), 1.28 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ), 1.00 (d, J = 4.1 Hz, 3H, CH(CH 3 ) 2 ), 0.98 (d, J = 4.1 Hz, 3H, CH(CH 3 ) 2 ); 13 C NMR: (75 MHz, CDCl 3 ) δ 171.7, 73.7, 61.2, 49.0, 28.8, 19.8, 19.7, 14.1; MS (EI): m/z (%) = 189 (3), 144 (34), 113 (14), 101 (100), 97 (87), 88 (10), 73 (83), 69 (69), 59 (18), 55 (81), 41 (65), 29 (69); HRMS: calcd for [C 8 H 15 N 4 ]: 189.1001, found 189.1003. The enantiomers were analyzed by GC using a chiral G-TA column (80 C, 1.0 C/min until 180 C, 10 min at 180 C). Major enantiomer: t R = 32.46 min, minor enantiomer: t R = 33.57 min. General Procedure for the Synthesis of β²-amino Acids 6 A schlenck tube was charged with Pd/C (7.5 mg, 50% wet, 10%, 0.0035 mmol) under vacuum for 10 min and Benzyl 3-amino-2-phenylpropanoate (10 mg, 0.035 mmol, 97:3 er) in MeH (1 ml) was added, followed by vigorous stirring for 6 h. The reaction mixture was pushed through a celite pad to remove Pd/C. MeH was removed under reduced pressure to afford white solid that was redissolved in 2 ml distilled water. The aqueous phase was extracted 20 with ether (1x) and concentrated in vacuo to give white solid (4.6 mg, 81%, 94% ee). [α] d = -81, (c 0.20, H 2 ). 1 H NMR: (CDCl 3, 500 MHz) δ 7.33-7.21 (m, 5H, ArH), 3.67 (t, J = 7.3 Hz, 1H, CHPh), 3.35 (dd, J = 7.3 and 4.6 Hz, 1H, CH 2 NH 2 ), 3.17 (dd, J = 7.3 and 5.3 Hz, 1H, CH 2 NH 2 ); 13 C NMR: (CDCl 3, 75 MHz) δ 178.2, 137.2, 129.2, 128.1, 127.9, 51.3, 42.3; MS (EI): m/z (%) = 165 (1), 136 (5), 118 (11), 104 (4), 91 (10), 77 (5), 63 (3), 51 (3), 30 (100); HRMS: calcd for [C 9 H 11 ]: 165.078980, found 165.079079. HPLC condition: chirobiotic T2 column, MeH/iPrH = 50:50 (v/v), 0.1 ml/min, t minor = 15.9 min, t major = 23.3 min. Alternative procedures for the Synthesis of β²-amino Acid 6a S24

NH 2 C 2 H (S)-3-Amino-2-phenylpropanoic acid (6a): NiCl. 2 6H 2 (121 mg, 0.512 mmol) was added at -15 o C under argon to a solution of 5c (90 mg, 0.466 mmol) in EtH (3 ml). By adding NaBH 4 (86 mg, 2.33 mmol) in one portion, a clear green solution was achieved. The reaction was allowed to run at 0 o C in a icewater bath for 15 min, followed by the addition of 2 N HCl until the ph of the reaction mixture reach a value of 3. Then saturated NaHC 3 solution was added until a ph of 9 was reached. The mixture was concentrated to remove EtH and then water (10 ml) and ethyl acetate (5 ml) were added. The biphasic mixture was filtered to remove the dark precipitate and the aqueous phase extracted with ethyl acetate (2x 5 ml). The combined organic phase was dried over Na 2 S 4 and concentrated. The residue was purified by silica gel chromatography (75% ethyl acetate in EtH) to give colorless oil (69 mg, 90%). 1 H NMR: (CDCl 3, 500 MHz) δ 7.34-7.26 (m, 5H, ArH), 4.19-4.10 (m, 2H, CH 2 Me), 3.75 (t, J = 7.2 Hz, 1H, CHPh), 3.34 (dd, J = 4.4 and 8.4 Hz, CH 2 NH 2 ), 3.10 (s, 2H, NH 2 ), 3.05 (dd, J = 4.4 and 8.4 Hz, 1H, CH 2 NH 2 ), 1.20 (t, J =7.2 Hz, 3H, CH 3 ); 13 C NMR: (CDCl 3, 75 MHz) δ 172.8, 136.7, 128.8, 128.0, 127.6, 61.0, 54.2, 44.8, 14.0; MS (EI): m/z (%) = 91 (31), 103 (11), 118 (55), 136 (39), 148 (3), 164 (100), 176 (2), 193 (1). HRMS: calcd for [C 11 H 15 ]: 193.110279, found 193.110439. Ethyl 3-amino-2-phenylpropanoate (40 mg, 0.207 mmol) was dissolved in THF/H 2 (4:1, v/v, 2 ml) and LiH (15 mg, 0.622 mmol) added to this solution, which was then stirred at room temperature for 6 h. Then the mixture was concentrated to remove THF. The residue was dilute with distilled water and extracted with ether (2x 2 ml). The aqueous phase was concentrated to1 ml and added to the Dowex 50W 8X (H + form) with 1% ammonia as eluent 20 to give the free amino acid (25 mg, 73%). [α] d = -76, (c 0.62, H 2 ). 1 H NMR: (CDCl 3, 500 MHz) δ 7.33-7.21 (m, 5H, ArH), 3.67 (t, J = 7.3 Hz, 1H, CHPh), 3.35 (dd, J = 7.3 and 4.6 Hz, 1H, CH 2 NH 2 ), 3.17 (dd, J = 7.3 and 5.3 Hz, 1H, CH 2 NH 2 ); 13 C NMR: (CDCl 3, 75 MHz) δ 178.2, 137.2, 129.2, 128.1, 127.9, 51.3, 42.3; MS (EI): m/z (%) = 165 (1), 136 (5), 118 (11), 104 (4), 91 (10), 77 (5), 63 (3), 51 (3), 30 (100); HRMS: calcd for [C 9 H 11 ]: 165.078980, found 165.079079. S25

Procedure for Synthesis of β²-amino Acid 6k To a schlenk tube charged with palladium on charcoal (74 mg, 10 %, 50% wet, 0.0359 mmol, vaccum dried for 1 h before being used) and under hydrogen gas was added the solution of nitroester (80 mg, 0.359 mmol) in methanol (2 ml) at room temperature. The reaction mixture was vigorously stirred at room temperature for 12 h. Then the suspension was pushed through a Celite pad and concentrated to give a colorless oil that was dissolved in HCl (2 ml, 3N, 6 mmol). The achieved solution was stirred for 12 h and concentrated to dryness. The residue was pushed through a DWEX 1X40-50 pad (basic form, 3 cm) with 1% ammonia (60 ml) as eluent. The collected aqueous phase was concentrated to give a colorless oil that solidified slowly (19 mg, 42%). 1 H NMR : (D 2, 500 MHz) δ 3.02-2.90 (m, 2H, CH 2 N), 2.53-2.46 (m, 1H, CHCH 3 ), 1.09 (d, J = 7.3 Hz, 3H, CH 3 ); 13 C NMR: (D 2, 125 MHz) δ 181.7, 42.3, 39.2, 15.1; MS (EI): m/z (%) = 103 (2), 84 (1), 56 (3), 30 (100). HPLC, Chirobiotic T2, acetonitrile/h 2 = 80:20, 0.3 ml/min, ELSD detector. Major enantiomer: t R = 16.4 min, minor enantiomer: t R = 27.8 min. Selected Catalyst Screening Results Results obtained with other types of (bis)thiourea-catalysts: (conversions and enantiomeric rations were determined with GC) S26

CF 3 S F 3 C CF 3 N H S N H N F 3 C F 3 C S S CF 3 NH HN NH HN CF 3 N H H N S N H CF 3 H N CF 3 77% conv., 76:24 er 99% conv., 29:71 er CF 3 39% conv., 63:37 er Results obtained with Jacobsen(-type) thiourea-catalysts: (conversions and enantiomeric rations were determined with GC) S27

GC and HPLC Traces of the Saturated Nitroesters 5a S28

5b S29

5c S30

5d S31

5e S32

5f S33

5g S34

5h S35

F F 5i S36

5j S37

5k S38

5l S39

5m S40

HPLC Traces of the Amino Acids 6a S41

NH 2 C 2 H NH 2 C 2 H 6k S42

NMR Spectra of the Substrates (Nitroacrylic Esters): 2a 2a S43

2b 2b S44

2c 2c S45

2d 2d S46

2e 2e S47

2f 2f S48

2g 2g S49

2h 2h S50

F 2i F 2i S51

2j 2j S52

2 N (E)-2k 2 N (E)-2k S53

(Z)-2k (Z)-2k S54

2 N 2l 2 N 2l S55

2m 2m S56

NMR Spectra of the Products (Saturated Nitroesters): 5a 5a S57

5b 5b S58

5c 5c S59

5d 5d S60

5e 5e S61

5f 5f S62

5g 5g S63

5h 5h S64

F 5i F 5i S65

5j 5j S66