Goldilocks Effect of Water in Lewis-Brønsted Acid and Base Catalysis

Transcription

1 Supporting Information Goldilocks Effect of Water in Lewis-Brønsted Acid and Base Catalysis Benedict J. Barron, a,b Wing-Tak Wong, b Pauline Chiu b and King Kuok (Mimi) ii a * [a] Department of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, United Kingdom. mimi.hii@imperial.ac.uk [b] Department of Chemistry, and The State Key Laboratory of Synthetic Chemistry, The University of ong Kong, Pokfulam Road, ong Kong. Table of contents: 1. General remarks S1 - S2 2. Supporting graphs and tables S2 - S8 3. Experimental and Characterisation Data S8 - S and 13 C aza-michael adduct spectroscopic data S35 - S50 5. PLC chromatographs of aza-michael adducts and TQ derivatives S51 - S58 6. References S59 - S60 1 General Remarks All manipulations involving air-sensitive reagents were performed using standard Schlenk techniques. Column chromatography was performed on silica gel (60 Å, mesh). All anhydrous solvents used were collected from a solvent purification system (Innovative Technology) or were distilled from Ca2 under argon. All commercially available reagents were used as received. Palladium salts were provided by Johnson Matthey plc, through an academic loan agreement. 1 and 13 C MR spectra were obtained on a Bruker DX 300 spectrometer, Bruker Avance 400 spectrometer, Bruker DX 500 spectrometer or Bruker Avance 600 spectrometer operating at 300 Mz, 400 Mz, 500 Mz or 600 Mz respectively for 1, and at 75 Mz, 101 Mz, 126 Mz or 151 Mz for 13 C. 19 and 31 P MR spectra were recorded on a Bruker Avance 400 spectrometer operating at 376 Mz and 162 Mz respectively. The chemical shifts are reported in (ppm) and were referenced to residual 1 and 13 C signals of deuterated solvent. 31 P spectra were referenced to 3P4. 19 spectra were referenced to CCl3.The coupling constants (J) are reported in ertz (z). Splitting patterns were designated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. ull assignment of resonance signals was aided by 2D MR experiments: CSY, SQC, MBC and ESY.

2 Infrared spectra were recorded on Perkin Elmer Spectrum 100 T-IR spectrometer fitted with an ATR accessory. ptical rotation values were measured on a Perkin Elmer 343 Polarimeter using a 10 cm solution cell and an ADP440+ Polarimeter using a 5cm solution cell. Concentration is given in g/100 ml. Melting points (uncorrected) were determined on a Gallenhamp apparatus or a Ziess Axiolab microscope with LIKAM TC92 temperature control module. PLC analyses was performed on a Agilent 1100 Series or a Waters Analytical/Preparative PLC system equipped with a 1525 Binary Pump, a 2707 Autosampler, and a variable wavelength Waters 2498 UV detector operating with Breeze 2 software. Chiral columns used were Chiralpak AD- or AD-3, and Chiralcel D-, D-3 and J- columns. Detection was effected by UV absorption at 254 nm. Elemental analyses were carried out by the Science Technical Support Unit at London Metropolitan University. Electrospray ionisation mass spectroscopy (ESI MS) was recorded on a Waters LCT premier spectrometer. Electron impact mass spectrometry (EI MS) was recorded on a innigan MAT 95 mass spectrometer. Both spectrometers recorded low and high resolution. 2 Supporting data 2.1 General ptimisation of reaction conditions Table S1. ptimisation of reaction conditions with p-3a. Boc Boc 2 cat. (R)- 1 (5 mol%) p - 3a 4 p - 5a Entry a Solvent Molarity (M) Temp. (ºC) Time (h) Yield b (%) ee c (%) 1 T 0.2 r.t n.d. 2 T 0.1 r.t n.d. 3 T 0.05 r.t T 0.29 r.t n.d. 5 T 0.2 r.t Me- T 0.2 r.t Me- T 0.1 r.t n.d.

3 8 toluene 0.2 r.t n.d. 9 toluene 0.1 r.t n.d. 10 toluene 0.05 r.t toluene T d toluene toluene e toluene a General reaction conditions: catalyst 1/p-3a/4 (0.05/1/1) where 1 eq. is 0.2 mmol, b Yields were calculated from 1 MR integrations. c Enantioselectivity determined by chiral PLC using Daicel AD- column. d 1.5 equivalents of p-3a used. e 1.5 equivalents of 4 used. Table S2. Protected PDA substrate screening study with complex 1 in toluene. Toluene Entry a Amine Yield b (%) Ee c (%) 1 p-3a 74 (70) 87 2 m-3a 30 (31) 80 3 p-3b 5 (n.d.) n.d. 4 m-3b 7 (n.d.) 76 5 p-3c 36 (32) 80 6 m-3c 29 (21) 63 7 p-3d 10 (n.d.) 43 8 m-3d 22 (19) 66 9 p-3e 16 (14) m-3e 18 (15) 66 a General reaction conditions: catalyst 1/3a-e/4 (0.05/1/1.5) where 1 eq. is 0.2 mmol, [3a-e] = 0.05 M in toluene, 48 h, 45 ºC. b Yields were calculated from 1 MR integrations. Yields in parenthesis are isolated yields. c Enantioselectivity determined by chiral PLC.

4 a) b) 8 7 Conversion (%) Ratio (p-5a-e : 6) Time (h) Time (h) igure S1. Amine: 3a (Boc), 3b (Ac), 3c (TA), 3d (Piv), 3e (Ts). Reaction conditions: 1/3/4 (0.05 : 1 : 1), T-d8, [3] = 0.16 M, 45 C. Conversion calculated from 1 MR integrations. a) 1 MR reaction profile study of the rate of reaction with various PDA derivatives utilizing protocol A, through consumption of 4. b) Product ratio between aza- Michael adduct 5 and hydrogenated Michael acceptor 6. Table S3. Temperature effect study on side product formation. 2 m - 3c 4 1 eq. 1eq. Complex 1 (5 mol %) T (0. 29 M), 48 h r.t.- 65 C TA 6 m - 5c m - 7c Entry a,b Temperature ( C) Unreacted 4 (%) Yield (%) m-5c a Reaction conditions: catalyst 1/m-3c/4 (0.05:1:1), [PDA] = 0.29 M in T, 48 h. b Calculated from 1 MR integrations. c Calculation of m-7c signal integration not possible. Table S4. urther variations in reaction conditions to establish side product formation.

5 2 p-3a 4 p-5a 6 p-7a Rac-Catalyst 1 p-3a p-5a (0-5 mol%) p-3a p-5a T (0.2 M) (0-1 eq.) h, C 6 + p-7a Entry a Starting material ratios Time Temp. Product ratios b p-3a 4 p-5a 1 (h) ( C) p-3a 4 p-5a 6 p-7a n.d n.d a Reaction conditions: catalyst 1/p-5a/4 (0.05:1:1), [4] = 0.2 M in T, h, ºC. b Calculated from 1 MR integrations. Complex 2 igure S2. 31 P MR spectra of mixtures of complex 1, p-3a (2 eq.) and water in T. a) Complex 1 + p-3a (2 eq.). b) 2 (5 eq.). c) 2 (15 eq.). d) 2 (50 eq.). e) 2 (200 eq.).

6 igures S3. Supporting ESI mass spectrometry data for the double charged Pd-µ-hydroxy µ- amido complexes: a) [{(R-BIAP)Pd}2(MeC64)()] 2+ (m/z = ). b) [{(R-BIAP)Pd}2(Me2C64)()] 2+ (m/z = ). c) [{(R-BIAP)Pd}2(BCC64)()] 2+ (m/z = ).

7 Table S5. Slow addition experiment study using substrates p-3a, 4 and complex 1. a 4, 1 eq. Complex 1 (0.05 eq., 5 mol%) BC 2 p-3a, 1eq ml/h via syringe pump Tol/T (19/1), 48 h, 45 C BC p - 5a Yield b (ee c )/% ormal Addition Slow Addition 71 (85) 70 (81) a General reaction conditions: catalyst 1/p-3a/4 (0.05/1/1) where 1 eq. is 0.2 mmol, [3a] = 0.05 M in toluene/t (19:1), 45 ºC, 48 h. In slow addition: Amine p-3a (416 mg, 2 mmol) was dissolved in toluene/t (4:1) (5 ml) and introduced to the mixture of 4 (287 mg, 2 mmol) and catalyst 1 (106 mg, 5 mol%) in toluene at 45 ºC at 0.11 ml/h over 48 h. b Yields were calculated from 1 MR integrations. Values in parenthesis denotes isolated yields. c Enantioselectivity determined by chiral PLC using Daicel AD- column. Table S6. Anhydrous substrate screening of PDA triflate salts 3a-e.Tf with 4 and complex 2. PG 2 Tf 1.5 eq. 1 eq. Complex 2 (2.5 mol%) 30 C, 48 h T PG Tf 3b-e Tf 4 5b-e. Tf Entry a Amine Yield (%) b ee (%) c 1 p-3b 9 n.d. 2 m-3b 11 n.d. 3 p-3c m-3c p-3d m-3d n.d. n.d. 7 p-3e m-3e 27 80

8 a Reaction conditions: catalyst 2/3b-e.Tf/4 (0.025:1.5:1),[4] = 0.5 M in T, 30 C, 48 h. b Calculated from 1 MR integrations. c Determined by chiral PLC. Table S7. Water effect on Pd-μ-hydroxo μ-amido complex m-9e. Ts Ts 2 Tf m-3e. Tf 4 m-5e Entry a Catalyst Water added (6 eq.) Yield b (%) ee c (%) 1 2 no yes m-9e no m-9e yes a Reaction conditions: 2/m-3e.Tf/4 (0.025:1.5:1), [4] = 0.5 M in T, 30 C, 20 h, ac3 base work up, EtAc extraction. Catalyst m-2e was prepared in situ and left for 1 h before use. b Calculated from 1 MR integrations using 1,3,5-trimethoxybenzene as an internal standard. c Determined by chiral PLC. 3 Experimental and Characterisation data 3.1 Catalysts and intermediates characterisation data. 3.2 Synthesis of Synthesis of -(but-2-enoyl) carbamic acid methyl ester (4). 3.3 Phenylenediamine (PDA) synthesis and characterisation data. 3.4 PDA triflate salt synthesis and characterisation data. 3.5 aza-michael adduct characterisation data. 3.6 Redox side product characterisation data. 3.7 Tetrahydroquinoline derivatives characterisation data. 3.1 Catalyst and intermediates Complexes 1 and 2 were synthesised as previously reported and all characterisation data matched that of previous literature. 1 Racemic reactions were performed using rac-1 to provide racemates for the development of PLC analytical methods.

9 Complexes of type 9 could not be successfully isolated and fully characterised. A representative in situ characterisation of Pd-µ-hydroxy µ-amido dimers p-9a and m-9e were performed. In CDCl3, complex 2 was treated with a stock solution of p-3a or m-3e in CDCl3 (1.1 eq.). The solution was stirred for 1h and analysed by MR spectroscopy and mass spectrometry. Complex p-9a. 2+ PPh 2 Pd P Ph 2 Ph 2 P Pd Ph 2 P Tf Tf - - A dark red solution. 1 MR (400 Mz, Chloroform-d) δ (s, 1, µ-). 31 P MR (162 Mz, Chloroform-d) δ (dd, J = 28.7 & 4.9), (d, J = 23.2), (dd, J = 23.4 & 4.7), (d, J = 28.7). MS (ESI): m/z [M 2+ -2(Tf - )] calcd for C998023P4Pd2: ; found: (doubly charged ion). 1, 31 P MR and ESI MS spectra: igures S4. In situ 1 MR spectra (CDCl3) for Pd-µ-hydroxy µ-amido dimer p-9a.

10 igures S5. In situ 31 P MR spectra (CDCl3) for Pd-µ-hydroxy µ-amido dimer p-9a. MS29345 (0.312) Is (1.00,1.00) C997823P4Pd : T MS ES+ 1.39e12 % MS (0.312) : T MS ES+ 1.51e3 % m/z igure S6. Isotopic distribution analysis for complex p-9a. Top: calculated. Bottom: bserved.

11 Complex m-9e. 2+ PPh 2 Pd P Ph 2 Ph 2 P Pd Ph 2 P Tf Tf - - Ts A light red solution. 1 MR (400 Mz, Chloroform-d) δ (br s, 1, µ-). 31 P MR (162 Mz, Chloroform-d) δ (d, J = 23.5 & 4.2), (d, J = 20.8), (dd, J = 20.8 & 4.1), (d, J = 23.8).MS (ESI): m/z [M 2+ -2(Tf - )] calcd for C P4Pd2S: ; found: (doubly charged ion). 1, 31 P MR and ESI MS spectra: igures S7. In situ 1 MR spectra (CDCl3) for Pd-µ-hydroxy µ-amido dimer m-9e.

12 igures S8. In situ 31 P MR spectra (CDCl3) for Pd-µ-hydroxy µ-amido dimer m-9e. MS29524 (0.340) Is (1.00,1.00) C P4Pd2S : T MS ES+ 1.37e12 % MS (0.340) 100 % : T MS ES+ 1.53e m/z

13 igure S9. Isotopic distribution analysis for complex m-9e. Top: calculated. Bottom: bserved. Catalytic procedures are described in the Experimental Section of the manuscript. 3.2 Synthesis of -(but-2-enoyl) carbamic acid methyl ester (4). 2 Synthesis of methyl--(chloroacetyl) carbamate. A 100 ml round-bottomed flask fitted with a stir bar was charged with methyl carbamate (7.50 g, 100 mmol) and chloroacetyl chloride (8.20 ml, 103 mmol). A condenser was fitted and the apparatus was purged under nitrogen. The reaction mixture was then heated to 110 C with stirring for 40 minutes. The reaction mixture was allowed to cool to room temperature and volatile by-products were removed under vacuum. The residue was triturated in 30 ml of Et2. The product was collected via filtration and dried under vacuum. Cl A grey solid. Yield g (86%). Mp C (lit ºC). υmax/cm -1 (neat): 3400, 2948, 1792, 1710, MR (400 Mz, CDCl3) δ 8.05 (br s, 1, ), 4.49 (s, 2, C2), 3.82 (s, 3, Me). 13 C MR (101 Mz, CDCl3) δ (C), (C), 53.7 (Me), 43.7 (C2). Synthesis of methyl carbamate phosphonate ester. A 100 ml round-bottomed flask fitted with a stir bar was charged with methyl--(chloroacetyl) carbamate (12.80 g, 85 mmol) and P(Et)3 (37 ml, 216 mmol). An air condenser was fitted and the flask was purged with nitrogen. The reaction was heated to 80 C with stirring until the starting material was fully consumed (ca. 45 h, as determined by TLC analysis). The reaction was allowed to cool down to room temperature. Petroleum ether (40-60 C) was added (50 ml) to the stirred mixture. This was then decanted and the step repeated 5 times with 10 ml, of petroleum ether, to remove excess P(Et)3. The crude product was used directly in the next step without further purification. P A yellow solid. Mp C (lit C). υmax/cm -1 (neat): 3167, 2989, 1779, 1704, 1536, 1204, MR (400 Mz, CDCl3) δ 9.23 (s, 1, ), (m, 4, C2C3), 3.73 (s, 3, Me), 3.29 (d, J = 22.1, 2, PC2), 1.31 (t, J = 7.1, 6, C2C3). 13 C MR

14 (101 Mz, CDCl3) δ (C), (C), 63.1 (d, J = 6.2, C2), 53.1 (Me), 35.9 (d, J = 130, C2P), 16.4 (d, J = 6.7, C2C3). Synthesis of -(But-2-enoyl) carbamic acid methyl ester (4). A 100 ml round-bottomed flask was fitted with a stir bar and charged with a solution of methyl carbamate phosphonate ester (15.00 g, 59 mmol) in T (60 ml). The reaction was cooled with an external ice bath. DBU (8.85 ml, 59 mmol) and acetaldehyde (3.66 ml, 215 mmol) were added sequentially with stirring. The reaction was allowed to warm up to room temperature. Upon completion of the reaction (as determined by TLC analysis), EtAc (600 ml) and water (150 ml) were added to the reaction mixture. The aqueous phase was further extracted with 3 x 100 ml EtAc. The combined organic phase was washed with brine (200 ml), dried over MgS4 and under vacuum. The crude product was recrystallised from EtAc. A white crystalline solid. Yield 6.83 g (81%). Mp C (lit ). υmax/cm -1 (neat): 3258, 1771, 1680, 1644, 1505, MR (400 Mz, CDCl3) δ 7.59 (br s, 1, ), (m, 1, C3C), 6.84 (dd, 1, J= 1.6, 15.2, CC), 3.78 (s, 3, Me) 1.94 (dd, 3, J = 1.6, 6.8, C3). 13 C MR (101 Mz, CDCl3) δ (), (C), (CC), (CC3), 53.2 (Me), 18.6 (CC3). 3.3 Synthesis of phenylenediamine (PDA) substrates. General procedure for synthesis of mono-boc protected phenylenediamines (o,m,p-3a). 4 A 250 ml round-bottomed flask fitted with a stir bar was charged with p-phenylenediamine (5.75 g, 55 mmol) in C2Cl2 (250 ml). The flask was purged with nitrogen and an external ice bath was fitted. A solution of Boc2 (2.29 g, 11 mmol) in C2Cl2 (50 ml) was added by syringe over 90 minutes with vigorous stirring. The ice bath was removed and the reaction mixture left for 4 h. The solvent was removed under vacuum and the product purified by column chromatography. (4-Aminophenyl)carbamic acid tert-butyl ester (p-3a). 2 White solid. Yield 2.01 g (92% wrt Boc2). Rf = 0.4 (pet. ether/etac, 6:4); Mp C (lit C). υmax/cm -1 (neat): 3366, 2985, 1690, 1521, 1427, 1233, 1157, 1055, 822.

15 MR (400 Mz, CDCl3) δ 7.12 (br d, 2, aryl), 6.62 (d, J = 8.4, 2, aryl), 6.35 (br s,, ), 3.50 (br s, 2, 2), 1.49 (s, 9, t Bu). 13 C MR (101 Mz, CDCl3) δ 153.5, 142.5, 129.8, 121.0, 115.7, 80.1, (3-Aminophenyl)carbamic acid tert-butyl ester (m-3a). 2 ff-white solid. Yield 1.97 g (90%). Rf = 0.4 (pet. ether/etac, 1:1). Mp C (lit C). υmax/cm -1 (neat): 3438, 3359, 2977, 1707, 1550, 1449, 1243, 1159, 1052, MR (400 Mz, CDCl3) δ 7.03 (t, J = 7.6, 1, aryl), 6.96 (br s, 1, aryl), 6.55 (dd, J = 8.4, 1.6, 1, aryl), 6.46 (br s, 1, ), 6.36 (dd, J = 1.6, 8.4, 1, aryl), 3.56 (br s, 1, 2), 1.51 (s, 9, t Bu). 13 C MR (101 Mz, CDCl3) δ 152.8, 147.3, 139.5, 129.8, 110.0, 108.7, 105.2, 80.5, (2-Aminophenyl)carbamic acid tert-butyl ester (o-3a). 22 Using the same procedure as above, with 3 equivalences of o-phenylenediamine. A Brown solid. Yield 2.03 g (93%). Rf = 0.4 (pet. ether/etac, 3:1); Mp C (lit C). 1 MR (400 Mz, CDCl3) δ 7.26 (d, J = 7.6, 1, aryl), 6.99 (td, J = 8.0, 1.2, 1, aryl), 6.77 (t, J = 7.6, 1, aryl), 6.74 (d, J = 8, 1, aryl), 6.42 (br s, 1, ), 3.70 (br s, 2, 2), 1.51 (s, 9, t Bu). 13 C MR (400 Mz, CDCl3) δ 153.9, 140.0, 126.1, 124.8, 119.5, 117.6, 80.5, Synthesis of protected nitroanilines. Synthesis of trifluoroacetamide protected nitroanilines. 7 Under inert conditions, a 100 ml round-bottomed flask equipped with a stir bar was charged with 4-nitroaniline (3.00 g, 21.7 mmol) in anhydrous acetonitrile (30 ml). The reaction mixture was stirred at room temperature and trifluoroacetic anhydride (3.13 ml, 22 mmol) was added drop wise via syringe. The reaction was left stirring overnight. Cold water was added to the reaction mixture whereupon a brown solid precipitated out. The solution was filtered and the

16 solid washed with sat. aq. ac3 (3 x 20 ml) and Et2 (30 ml). The solid was dried under reduced pressure. -(4-itro-phenyl)-2,2,2-trifluoro-acetamide. 2 A yellow solid. Yield = 4.65 g (92%). Mp C (lit C). υmax/cm -1 (neat): 3324, 3115, 1742, 1568, 1502,1137, 1109, 856, MR (400Mz, DMS-d6) δ (s, 1, ), 8.30 (d, J = 8.8, 2, aryl), 7.95 (d, J = 8.8, 2, aryl). 13 C MR (101 Mz, DMS-d6) δ (q, J = 37.6), 144.1, 142.4, 124.9, 121.1, (q, J = 288 z). -(3-itro-phenyl)-2,2,2-trifluoro-acetamide. 2 Using the same procedure as above for 3-nitroaniline (3.00 g, 21.7 mmol). An orange solid. Yield 4.44 g (87%). Mp C (lit C). υmax/cm -1 (neat): 3399, 3426, 3292, 2885, 1708, 1692, 1617, 1189, 1155, MR (400 Mz, DMS-d6) δ (s, 1, ), 8.61 (t, J = 2.1, 2, aryl), (m, 2, aryl), 7.69 (t, J = 8.2, 1, aryl). 13 C MR (101 Mz, DMS-d6) δ (q, J = 37.5), 147.9, 137.6, 130.5, 126.9, 120.1, (q, J = 289), (3-itro-phenyl)-acetamide. 2 Using the same procedure as above, with 3-nitroaniline (2.00 g, 14.4 mmol) and acetic anhydride (1.44 ml, 15.2 mmol). A yellow solid. Yield 2.12 g (81%). Mp C (lit 10

17 C). υmax/cm -1 (neat): 3261, 3193, 3129, 3096, 1672, 1599, 1526, 1349, 1324, 1294, MR (400 Mz, DMS-d6) δ (s, 1, ), 8.61 (br s, 1, aryl), (m, 2, aryl), 7.58 (t, J = 8.2, 1, aryl), 2.09 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 169.1, 147.9, 140.4, 130.1, 124.8, 117.5, 113.0, Synthesis of -(4-itro-phenyl)-acetamide 11 A 50 ml round-bottomed flask equipped with a stir bar was charged with 4-nitroaniline (1.38 g, 10 mmol) partially dissolved in EtAc (20 ml). The flask was purged with nitrogen. Compound Ac2 (1 ml, 10.5 mmol) was added dropwise via syringe. The reaction was left stirring overnight. The solvent was removed under reduced pressure and the product triturated in Et2 (30 ml). The product was dried under reduced pressure. 2 An off-white solid. Yield 1.66 g (92%). Mp C (lit C). υmax/cm -1 (neat): 3274, 3219, 3159, 3095, 1679, 1565, 1501, 1345, 1301, 1267, 1113, 848, MR (400 Mz, DMS-d6) δ (s, 1, ), 8.20 (d, J = 9.2, 2, aryl), 7.82 (d, J = 9.2, 2, aryl), 2.11 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 169.6, 145.6, 142.2, 125.2, 118.7, Synthesis of tosyl-protected nitroanilines. A 100 ml double-necked round-bottomed flask equipped with a stir bar was charged with 4- nitroaniline (2.00 g, 14.5 mmol) and purged with nitrogen. Dry C2Cl2 (75 ml) and pyridine (14.5 ml, 174 mmol) were added to the flask via syringe. Under a positive pressure of nitrogen, solid tosyl chloride (3.32 g, 17.4 mmol) was added to the reaction mixture slowly with stirring. The progress of the reaction was determined by TLC analysis. Upon completion, the organic phase was washed with Cl (1 M, 3 x 75 ml), sat. ac3 (3 x 75 ml), and brine (3 x 30 ml). The organic phase was dried over MgS4 and the solvent removed under reduced pressure. -(4-nitrophenyl)-4-methylbenzene-1-sulfonamide 12 S 2 A yellow solid. Yield 3.03 g (71%). Mp C (lit C). υmax/cm -1 (neat): 3334, 3084, 2924, 1593, 1520, 1494, 1463, 1337, 1290, 1152, 1089, (400 Mz, CDCl3) δ

18 8.12 (d, J = 9.2, 2, aryl), 7.77 (d, J = 8.0, 2, aryl), 7.40 (s, 1, ), 7.29 (d, J = 8.0, 2, aryl), 7.21 (d, J = 9.2, 2, aryl), 2.40 (s, 3, Me). 13 C MR (101 Mz, CDCl3) δ 144.8, 144.6, 143.0, 136.1, 130.4, 127.2, 125.6, 118.2, (3-nitrophenyl)-4-methylbenzene-1-sulfonamide. S 2 ollowed an identical procedure as above using 3-nitroaniline (2.00 g, 14.5 mmol). A yellow solid. Yield 3.29 g (78%). Mp C (lit C). υmax/cm -1 (neat): 3269, 3092, 1523, 1344, 1156, 1090, MR (400 Mz, CDCl3) δ (m, 2, aryl), 7.77 (d, J = 8.4, 2, aryl), (m, 3, aryl and ), 7.30 (d, J = 8.4, 2, aryl), 2.42 (s, 3, Me). 13 C MR (101 Mz, CDCl3) δ 148.9, 145.0, 138.2, 135.5, 130.4, 130.2, 127.5, 126.3, 119.7, 115.2, Synthesis of pivalamide-protected nitroanilines. 14 A 100 ml round-bottomed flask equipped with a stir bar was charged with 4-nitroaniline (2.76 g, 20 mmol) in EtAc (50 ml). Triethylamine (2.92 ml, 21 mmol) was added to the reaction mixture with stirring and an external ice bath was fitted. The flask was purged with nitrogen and pivaloyl chloride (2.71 ml, 22 mmol) was added dropwise to the solution via syringe with vigorous stirring. After addition, the ice bath was removed and the reaction left stirring overnight. The solution was washed with hydrochloric acid (0.5 M, 3 x 50 ml) and brine (3 x 15 ml). The organic layer was dried over MgS4 and the solvent removed under reduced pressure. 2,2-Dimethyl--(4-nitrophenyl)propionamide. 2 A fine yellow powder. Yield 3.32 g (75%). Mp C (lit C). υmax/cm -1 (neat): 3309, 3115, 1663, 1542, 1496, 1340, 1301, 1247, 1161, MR (400 Mz, CDCl3) δ 8.20 (d, J = 9.2, 2, aryl), 7.73 (d, J = 9.2, 2, aryl), 7.61 (s, 1, ), 1.34 (s, 9, t Bu). 13 C MR (101 Mz, CDCl3) δ 177.1, 144.0, 143.6, 125.2, 119.4, 40.2, ,2-Dimethyl--(3-nitrophenyl)propionamide.

19 2 ollowed the same procedure as above using 3-nitroaniline (2.76 g, 20 mmol). An orange solid. Yield 2.67 g (60%). Mp ºC (lit ºC). υmax/cm -1 (neat): 3308, 2982, 1663, 1525, 1475, 1424, 1401, 1343, 1245, 1177, MR (400 Mz, CDCl3) δ (s, 1, ), 8.61 (t, J = 2.1, 1, aryl), (m, 2, aryl), 7.69 (t, J = 8.2, 1, aryl), 1.32 (s, 9, t Bu). 13 C MR (101 Mz, CDCl3) δ 177.5, 148.5, 139.4, 129.7, 126.1, 118.8, 115.1, 39.9, ydrogenation reactions ydrogenation procedure A. 16 A two-necked 100 ml round-bottomed flask fitted with a stir bar was charged with the appropriate protected nitroaniline. The solid was dissolved in Me/Et/T solvent system, depending on solubility. Pd/C (10%) was added to the solution. The flask was purged with nitrogen and put under a reduced pressure. ydrogen was added to the vessel via syringe and the mixture was vigorously stirred. The progress of the reaction was determined by TLC analysis. n completion, the reaction mixture was filtered through celite. The solvent was removed under reduced pressure and the product dried under vacuum. ydrogenation procedure B. An Endeavor parallel reactor was employed in this procedure: A 4 ml glass liner was charged with the appropriate protected nitroaniline (0.5 mmol). The solid was dissolved in a suitable solvent. Pd/C (10%) was added to the solution (0.05 eq.). The reaction tube was fitted in one of the 8 high pressure vessels, fitted with built-in stir paddles. The chambers were sealed. The reaction conditions were programmed to: initially purge the reaction vessel with nitrogen, commence stirring at 250 rpm, pressurize and heat the reaction vessel under hydrogen to the desired pressure and temperature, maintain the reaction conditions for an allotted time with monitoring of hydrogen consumption, and finally purge the reaction vessel on completion. The reaction mixture was filtered through celite. The solvent was removed under reduced pressure and the product dried under vacuum. The progress of the reaction was monitored by consumption of hydrogen gas using the Biotage Endeavor software. -(4-Amino-phenyl)-acetamide (p-3b). 2

20 Using hydrogenation procedure B with -(4-nitro-phenyl)-acetamide (0.10 g, 0.55 mmol) in Me/T (1:1, 4 ml). Reaction conditions: 2.5 bar and 45 C, 2h. An off white solid. Yield g (83%). Mp C (lit C). υmax/cm -1 (neat): 3369, 3242, 1658, 1551, 1511, 1370, 1321, 1265, MR (400 Mz, DMS-d6) δ 9.47 (s, 1, ), 7.18 (d, J = 8.7, 2, aryl), 6.48 (d, J = 8.7, 2, aryl), 4.81 (s, 2, 2), 1.95 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 167.2, 144.6, 128.6, 120.8, 113.8, (3-Amino-phenyl)-acetamide (m-3b). 2 Using hydrogenation procedure A with -(3-nitro-phenyl)-acetamide (0.95 g, 5.3 mmol) in Et (30 ml). A light brown solid. Yield 0.74 g (93%). Mp C (lit C). υmax/cm - 1 (neat): 3412, 3377, 3299, 1678, 1607, 1548, 1491, 1436, 1323, 1259, 848, MR (400 Mz, DMS-d6) δ 9.60 (s, 1, ), 6.93 (t, J = 2.0 z, 1, aryl), 6.89 (t, J = 8 z, 1, aryl), 6.66 (d, J = 8.8, 1, aryl), 6.24 (dd, J = 8, 2, 1, aryl), 5.02 (s, 2, 2), 2.00 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 168.0, 149.0, 140.0, 128.9, 109.2, 107.1, 104.8, (4-Amino-phenyl)-2,2,2-trifluoro-acetamide (p-3c). 2 Using hydrogenation procedure A with -(4-nitro-phenyl)-2,2,2-trifluoro-acetamide (1.00 g, 4.3 mmol) in Et (40 ml). The crude product was recrystallised using Et2 and pet. ether, affording light pink crystals. Yield 0.79 g (90%). Mp C (lit C). υmax/cm -1 (neat): 3406, 3334, 3185, 3016, 2880, 1710, 1512, 1249, 1144, 1126, 824, MR (400 Mz, DMS-d6) δ (s, 1, ), 7.29 (d, J = 8.8, 2, aryl), 6.57 (d, J = 8.8, 2, aryl), 5.14 (br s, 2, 2). 13 C MR (101 Mz, DMS-d6) δ (q, J = 37.1), 146.8, 124.7, 122.6, (q, J = 288), (3-Amino-phenyl)-2,2,2-trifluoro-acetamide (m-3c).

21 2 Using hydrogenation procedure A with -(3-nitro-phenyl)-2,2,2-trifluoro-acetamide (2.00 g, 8.6 mmol) in Et (40 ml). A light brown solid. Yield 1.65 g (94%). Mp C. υmax/cm - 1 (neat): 3399, 3426, 3292, 2885, 1708, 1692, 1617, 1189, 1155, MR (400 Mz, DMS-d6) δ (s, 1, ), 7.00 (t, J = 8.0, 1, aryl), 6.95 (t, J = 2.0, 1, aryl), (m, 1, aryl), (m, 1, aryl), 5.24 (s, 2, 2). 13 C MR (101 Mz, DMSd6) δ (q, J = 36.5), 149.3, 136.9, 129.2, (q, J = 290), 111.4, 108.6, MS (ESI): m/z [M + MeC + + ] calcd for C101133: ; found: ,2-Dimethyl--(4-aminophenyl)propionamide (p-3d). 2 Using hydrogenation procedure B with 2,2-dimethyl--(4-nitrophenyl)propionamide (0.15 g, 0.67 mmol) in Me/T (2:1, 4 ml). Reaction conditions: 2.5 bar at 45 C, 2h. Yield g (60%). Mp C (lit C). υmax/cm -1 (neat): 3420, 3344, 3318, 2964, 1659, 1644, 1541, 1425, 1280, 1240, MR (400 Mz, DMS-d6) δ 8.81 (s, 1, ), 7.19 (d, J = 8.6, 2, aryl), 6.49 (d, J = 8.6 z, 2, aryl), 4.84 (s, 2, 2), 1.19 (s, 9, t Bu). 13 C MR (75 Mz, DMS-d6) δ 175.7, 144.7, 128.4, 122.4, 113.6, ,2-Dimethyl--(3-aminophenyl)propionamide (m-3d). 2 Using hydrogenation procedure B with 2,2-dimethyl--(3-nitrophenyl)propionamide (0.15 g, 0.67 mmol) in Et (4 ml). Reaction conditions: 1 bar and 60 C, 1h. Yield g (84%). Mp C (lit C). υmax/cm -1 (neat): 3450, 3358, 2298, 1696, 1609, 1588, 1535, 1497, 1432, 1401, 1313, 1208, MR (400 Mz, DMS-d6) δ 8.85 (s, 1, ), 6.93 (t, J = 2.0, 1, aryl), 6.89 (t, J = 8.0, 1, aryl), (m, 1, aryl), (m, 1, aryl), 4.98 (s, 2, 2), 1.19 (s, 9, t Bu). 13 C MR (101 Mz, DMS-d6) δ 176.5, 149.2, 140.3, 129.0, 109.8, 108.9, 106.8, 27.7, 21.9.

22 -(4-aminophenyl)-4-methylbenzene-1-sulfonamide (p-3e). S 2 Using hydrogenation procedure A with -(4-nitrophenyl)-4-methylbenzene-1-sulfonamide (0.82 g, 2.82 mmol) in Me (30 ml). An off-white solid. Yield g (70%). Mp C (lit C). υmax/cm -1 (neat): 3428, 3332, 3257, 2974, 1628, 1599, 1507, 1451, 1393, 1320, 1283, 1158, MR (400 Mz, DMS-d6) δ 9.37 (s, 1, ), 7.51 (d, J = 8.0, 2, aryl), 7.30 (d, J = 8.0, 2, aryl), 6.66 (d, J = 8.7, 2, aryl), 6.37 (d, J = 8.7, 2, aryl), 4.94 (s, 2, 2), 2.33 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 146.4, 142.6, 136.9, 129.3, 126.8, 125.4, 124.5, 113.9, (3-aminophenyl)-4-methylbenzene-1-sulfonamide (m-3e). S 2 Using hydrogenation procedure A with -(3-nitrophenyl)-4-methylbenzene-1-sulfonamide (0.92 g, 3.15 mmol) in Et (30 ml) with heating at 45 C. A brown solid, Yield 0.62 g (75%). Mp C (lit C). υmax/cm -1 (neat): 3489, 3394, 3265, 1615, 1596, 1503, 1413, 1305, 1152, MR (400 Mz, DMS-d6) δ 9.87 (s, 1, ), 7.64 (d, J = 8.2, 2, aryl), 7.33 (d, J = 8.2, 2, aryl), 6.80 (t, J = 7.9, 1), 6.36 (t, J = 2.1, 1, aryl), (m, 2, aryl), 5.19 (br s, 2, 2), 2.33 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 149.1, 142.9, 138.4, 137.0, 129.5, 129.3, 126.7, 109.9, 107.5, 105.3, PDA triflate salt characterisation data. General Procedure for formation of mono-protected PDA triflate salts 15 A dry 100 ml Schlenk tube equipped with a stir bar was charged with amine (1 eq.) and purged with dry nitrogen. Dry C2Cl2 (5 ml/mmol) was added via syringe through a rubber septum with stirring. With the solid fully dissolved, an external ice bath was applied. Triflic acid (1 eq.) was added dropwise under a positive flow of nitrogen using a graduated pipette, whereupon a white solid precipitated out of solution. The ice bath was removed and reaction was left stirring for 1 hour. The solid was collected under an inert atmosphere using a Schlenk sinter filter stick. The solid is then washed with dry hexanes (3 x 15 ml/mmol) to remove any impurities or excess triflic acid. The product was then dried under vacuum. -(4-Amino-phenyl)-acetamide triflate salt (p-3b Tf).

23 Tf. 2 A pink solid. Mp C. υmax/cm -1 (neat): 3353, 2981, 2649, 1645, 1517, 1296, 1237, 1222, 1182, 1162, 1023, MR (400 Mz, DMS-d6) δ (s, 1, ), 9.79 (br s, 3, 2) 7.68 (d, J = 8.8, 2, aryl), 7.29 (d, J = 8.8, 2, aryl), 2.05 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 168.8, 137.7, 129.9, 122.2, 120.5, ound: C, 36.09;, 3.57;, Calc. for C911324S: C, 36.00;, 3.69;, 9.33%. -(3-Amino-phenyl)-acetamide triflate salt (m-3b Tf). Tf. 2 A white solid. Mp C. υmax/cm -1 (neat): 3321, 2989, 2631, 1652, 1590, 1559, 1453, 1244, 1227, 1169, 1027, 1027, 784, MR (400 Mz, DMS-d6) δ (s, 1, ), 9.78 (br s, 3, 2), 7.92 (d, J = 1.7, 1, aryl), (m, 2, aryl), 7.02 (td, J = 4, 2, 1, aryl), 2.07 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 169.4, 140.9, 132.2, 130.6, 118.9, 117.9, 114.8, ound: C, 36.05;, 3.78;, Calc. for C911324S: C, 36.00;, 3.69;, 9.33%. -(4-Amino-phenyl)-2,2,2-trifluoro-acetamide triflate salt (p-3c Tf). Tf. 2 A white solid. Mp C. υmax/cm -1 (neat): 3324, 2978, 1705, 1544, 1517, 1279, 1236, 1223, 1180, 1156, 1033, 913, 825, MR (400 Mz, DMS-d6) δ (s, 1, ), 7.79 (d, J = 8.7, 2, aryl), 7.40 (d, J = 8.7, 2, aryl). 19 MR (377 Mz, DMS-d6) δ -73.9, C MR (101 Mz, DMS-d6) δ (q, J = 37.3), 136.2, 129.8, 124.0, 122.8, (q, J = 288.6). ound: C, 30.57;, 2.15;, Calc. for C98624S: C, 30.52;, 2.28;, 7.91%. -(3-Amino-phenyl)-2,2,2-trifluoro-acetamide triflate salt (m-3c Tf). Tf. 2

24 A white solid. Mp C. υmax/cm -1 (neat): 3286, 3054, 1702, 1598, 1289, 1245, 1210, 1186, 1151, 1140, 1026, 894, 788, MR (400 Mz, DMS-d6) δ (s, 1, ), 9.17 (br s, 3, 2) 7.80 (br s, 1, aryl), (m, 1, aryl), 7.51 (td, J = 1.2, 8.0, 1, aryl), 7.17 (d, J = 8, 1, aryl). 19 MR (377 Mz, DMS-d6) δ -73.9, C MR (101 Mz, DMS-d6) δ (q, J = 37.0), 137.9, 130.9, 122.2, 120.1, 119.5, 115.8, (q, J = 288.6). ound: C, 30.70;, 2.18;, Calc. for C98624S: C, 30.52;, 2.28;, 7.91%. 2,2-Dimethyl--(4-nitrophenyl)propionamide triflate salt (p-3d Tf). Tf. 2 A white solid. Mp C. υmax/cm -1 (neat): 3352, 2981, 2650, 1645, 1512, 1294, 1239, 1220, 1180, 1162, MR (400 Mz, DMS-d6) δ 9.80 (s, 3, 2), 9.39 (br s, 1, ), 7.83 (d, J = 9.0, 2, aryl), 7.29 (d, J = 9.0, 2, aryl), 1.23 (s, 9, t Bu). 13 C MR (101 Mz, DMS-d6) δ 177.2, 139.9, 126.3, 123.8, 121.7, ound: C, 42.27;, 4.97;, Calc. for C S: C, 42.10;, 5.01;, 8.18%. 2,2-Dimethyl--(3-aminophenyl)propionamide triflate salt (m-3d Tf). Tf. 2 A white solid. Mp C. υmax/cm -1 (neat): 3329, 2987, 2632, 1645, 1585, , 1256, 1228, 1165, 1032, 783, MR (400 Mz, DMS-d6) δ 9.43 (s, 1, ), 7.89 (t, J = 2.1, 1, aryl), 7.51 (dd, J = 8.0, 2.2, 1, aryl), 7.38 (t, J = 8.0, 1, aryl), 6.97 (dd, J = 7.9, 2.2, 1, aryl), 1.23 (s, 9, t Bu). 13 C MR (101 Mz, DMS-d6) δ 177.4, 141.1, 133.2, 130.2, 119.3, 117.5, 114.4, ound: C, 41.99;, 4.97;, Calc. for C S: C, 42.10;, 5.01;, 8.18%. -(4-aminophenyl)-4-methylbenzene-1-sulfonamide triflate salt (p-3e Tf). Tf. 2 Ts A white solid. Mp C. υmax/cm -1 (neat): 3440, 2971, 2649, 1621, 1512, 1272, 1224, 1179, 1026, MR (400 Mz, DMS-d6) δ (s, 1, ), 8.43 (s, 3, 2), 7.60 (d, J = 8.0, 2, aryl), 7.33 (d, J = 8.0, 2, aryl), 7.01 (d, J = 8.4, 2, aryl), 6.92 (d, J = 8.4,

25 2, aryl), 2.33 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 143.6, 137.0, 134.3, 134.0, 130.1, 127.2, 122.5, 121.1, ound: C, 40.88;, 3.54;, 6.75 Calc. for C S2: C, 40.77;, 3.67;, 6.79%. -(3-aminophenyl)-4-methylbenzene-1-sulfonamide triflate salt (m-3e Tf). Tf. 2 Ts A white solid. Mp C. υmax/cm -1 (neat): 3450, 3170, 3067, 2994, 2662, 1502, 1243, 1146, 1025, 968, 900, 793, MR (400 Mz, DMS-d6) δ (s, 1, ), 9.71 (br s, 3, 2), 7.69 (d, J = 8, 2, aryl), 7.37 (d, J = 8, 2, aryl), 7.19 (s, 1, aryl), 7.13 (m, 1, aryl), (m, 2, aryl), 2.34 (s, 3, Me). 13 C MR (101 Mz, DMS-d6) δ 144.1, 139.6, 136.8, 131.2, 130.4, 130.3, 127.2, 118.8, 118.7, 114.1, ound: C, 40.68;, 3.71;, 6.75.Calc. for C S2: C, 40.77;, 3.67;, 6.79%. 3.5 aza-michael adduct characterisation data. [3-(4-carbamic acid tert-butyl ester -phenylamino)-butyryl]carbamic acid methyl ester (p-5a). A white solid. Yield 62 mg (92%). PLC: Diacel Chiralpak AD-, 15% IPA in n-hexane, 1.4 ml/min, tr (major) = 23.8 min, tr (minor) = 30.9 min, 95% ee. [α]d 24 = (c = 1, CCl3, 95% ee). Mp C. Rf = 0.25 (Pet. ether/etac, 6:4). υmax/cm -1 (neat): 3383, 3366, 2923, 2853, 1757, 1690, 1524, 1496, 1456, 1237, 1156, 1134, 1046, MR (400 Mz, CDCl3) δ 8.32 (br s, 1, ), 7.17 (br d, 2, aryl), 6.32 (d, J = 8.8, 2, aryl), 6.43 (br s, 1, ), (m, 1, MeC), 3.77 (s, 3, Me), (m, 1, C2), (m, 1, C2), 1.52 (s, 9, t Bu), 1.28 (d, J = 6.4, 3, R2CMe). 13 C MR (101 Mz, CDCl3) δ (C2C), (C2 t Bu), (C2Me), (Caryl), (Caryl), (Caryl), (Caryl), 80.5 (C(C3)3), 53.5 (Me), 47.3 (-CMe), 42.6 (-C2C), 28.8 (C(C3)3), 21.2 (- CMe). MS (ESI): m/z [M + a + ] calcd for C172535a: ; found: [3-(3-carbamic acid tert-butyl ester -phenylamino)-butyryl]carbamic acid methyl ester (m-5a).

26 An off-white solid. Yield 56 mg (79%). PLC: Diacel Chiralpak J-, 20% IPA in n-hexane, 1.0 ml/min, tr (major) = 28.7 min, tr (minor) = 39.7 min, 96% ee. [α]d 24 = (c = 1.1, CCl3, 96% ee). Mp C. Rf = 0.3 (Pet. ether/etac, 3:2). υmax/cm -1 (neat): 3318, 2960, 2925, 1766, 1693, 1608, 1517, 1482, 1229, 1154, 1046, 769, MR (400 Mz, CDCl3) δ 8.24 (s, 1, ), 7.07 (t, J = 8.0, 1, aryl), 6.85 (s, 1, ), (m, 2, aryl, ), 6.33 (dd, J = 8.0, 2.2, 1, aryl), (m, 1, MeC), 3.74 (s, 3, Me), 3.01 (dd, J = 15.6, 6.2, 1, C2), 2.80 (dd, J = 15.6, 6.2, 1, C2), 1.51 (s, 9, t Bu) 1.28 (d, J = 6.4, 3, R2CMe). 13 C MR (101 Mz, CDCl3) δ (C2C), (C2 t Bu), (C2Me), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), 80.5 (C(C3)3), 53.1 (Me), 46.2 (-CMe), 42.4(-C2C), 28.4 (C(C3)3), 20.9 (-CMe). MS (ESI): m/z [M + a + ] calcd for C172535a: ; found: [3-(-(4-Amino-phenyl)-acetamide)-butyryl]carbamic acid methyl ester (p-5b). A light red solid. PLC: Yield 52 mg (82%). PLC Diacel Chiralpak AD-, 15% IPA in n- hexane, 1.4 ml/min, tr (major) = 27.4 min, tr (minor) = 39.6 min, 90% ee. [α]d 22 = (c = 0.5, Me, 90% ee). Mp C. Rf = 0.1 (C2Cl2/Me, 100:2.5). υmax/cm -1 (neat): 3282, 2970, 1768, 1665, 1609, 1481, 1220, 1197, 1168, MR (400 Mz, CDCl3) δ 8.37 (br s, 1, ), 7.46 (br s, 1, ), 7.22 (d, J = 8.8, 2, aryl), 6.54 (d, J = 8.8, 2, aryl), (m, 1, C), 3.74 (s, 3, Me), 2.94 (dd, J = 15.8, 6.0, 1, C2), 2.77 (dd, J = 15.8, 6.0, 1, C2), 2.10 (s, 3, MeC), 1.25 (d, J = 6.4, 3, R2CMe). 13 C MR (101 Mz, CDCl3) δ (C2C), (C()Me), 152.1(C2Me), (Caryl), (Caryl), (Caryl), (Caryl), 53.1 (Me), 46.5 (-CMe), 42.1(C2), 24.3 (RC()Me), 20.8 (- CMe). MS (ESI): m/z [M + a + ] calcd for C141934a: ; found: [3-(-(3-Amino-phenyl)-acetamide)-butyryl]carbamic acid methyl ester (m-5b).

27 A light brown solid. Yield 47 mg (75 %). PLC: Diacel Chiralpak AD-, 15% IPA in n- hexane, 1.4 ml/min, tr (major) = 21.8 min, tr (minor) = 30.3 min, 94% ee. [α]d 21 = + 15 (c = 1, Me, 94% ee). Rf = 0.2 (C2Cl2/Me, 100:2.5). Mp C. υmax/cm -1 (neat): 3314, 2959, 2920, 2851, 1770, 1666, 1610, 1512, 1480, 1371, 1221, 1196, 1166, 1044, MR (400 Mz, CDCl3) δ 7.94 (br s, 1, ), 7.27 (br s, 1, ), 7.10 (t, J = 8.0, 1, aryl), 7.01 (t, J = 2.0,1, aryl), 6.72 (dd, J = 8.0, 2.0, 1, aryl), 6.40 (dd, J = 8.0, 2.0, 1, aryl), (m, 1, C), 3.78 (s, 3, Me), 3.03 (dd, J = 16.0, 6.2, 1, C2), 2.84 (dd, J = 16.0, 6.2, 1, C2), 2.16 (s, 3, MeC), 1.30 (d, J = 6.4, 3, R2CMe). 13 C MR (101 Mz, Chloroform-d) δ (C2C), (C()Me), (C2Me), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), 53.1 (Me), 46.1 (-CMe), 42.2 (C2), 24.7 (RC()Me), 20.7 (-CMe). MS (ESI): m/z [M + + ] calcd for C141934: ; found: [3-(-(4-Amino-phenyl)-2,2,2-trifluoro-acetamide)-butyryl]carbamic acid methyl ester (p-5c). An off-white solid. Yield 58 mg (83%). PLC: Daicel Chiralpak AD-, 15% IPA in n-hexane, 1.4 ml/min, tr (major) = 13.3 min, tr (minor) = 17.6 min, 96% ee. [α]d 22 = - 4 (c = 1.8, Me, 96% ee). Rf = 0.15 (Pet. ether/etac, 3:2). Mp C. υmax/cm -1 (neat): 3256, 1787, 1686, 1511, 1235, 1158, 1048, 906, MR (400 Mz, CD3D) δ 7.37 (d, J = 8.9, 2, aryl), 6.68 (d, J = 8.9, 2, aryl), (m, 1, C), 3.74 (s, 3, Me) 2.80 (dd, J = 15.3, 6.0, 1, C2), 2.56 (dd, J = 15.3, 6.0, 1, C2), 1.25 (d, J = 6.4, 3, R2CMe). 13 C MR (101 Mz, CD3D) δ (C2C), (q, J = 37.2, C()C3), (C2Me), (Caryl), (Caryl), (Caryl), (q, J = 289, C3), (Caryl), 53.0 (Me), 47.0 (-CMe), 44.1 (C2), 20.7 (-CMe). MS (ESI): m/z [M + + ] calcd for C : ; found: [3-(-(3-Amino-phenyl)-2,2,2-trifluoro-acetamide)-butyryl]carbamic acid methyl ester. (m-5c).

28 A white solid. Yield 57 mg (82%). PLC: Diacel Chiralpak AD-, 10% IPA in n-hexane, 1.4 ml/min, tr (major) = 16.9 min, tr (minor) = 19.0 min, 96% ee. [α]d 22 = (c = 1.7, Me, 96% ee). Rf = 0.2 (Pet. ether/etac, 6:4). Mp C. υmax/cm -1 (neat): 3291, 2962, 1768, 1709, 1615, 1488, 1215, 1191, 1145, 1045, 772, MR (400 Mz, CDCl3) δ 8.15 (br s, 1, ), 8.08 (br s, 1, ), 7.12 (t, J = 8.1, 1, aryl), 6.97 (t, J = 2.2, 1, aryl), 6.81 (dd, J = 8.1, 2.2, 1, aryl), 6.47 (dd, J = 8.1, 2.2, 1, aryl), (m, 1, C), 3.75 (s, 3, Me), 3.03 (dd, J = 16.0, 6.2, 1, C2), 2.82 (dd, J = 16.0, 6.2, 1, C2), 1.27 (d, J = 6.5, 3, R2CMe). 13 C MR (101 Mz, CDCl3) δ (C2C), (q, J = 37.0, C()C3), (C2Me), 148.1(Caryl), (Caryl), (Caryl), (q, J = 290 z, C3), (Caryl), (Caryl), (Caryl), 53.5 (Me), 46.4 (-CMe), 42.6 (C2), 21.1 (-CMe). MS (ESI): m/z [M + + ] calcd for C : ; found: [3-(2,2-Dimethyl--(4-aminophenyl)propionamide)-butyryl]carbamic acid methyl ester (p-5d). An orange solid. Yield 49 mg (73%). PLC: Diacel Chiralpak D-, 20% IPA in n-hexane, 1.4 ml/min, tr (major) = 15.5 min, tr (minor) = 30.6 min, 99% ee. [α]d 23 = -7.8 (c = 1.2, CCl3, 99% ee). Rf = 0.1 (C2Cl2/EtAc, 4:1). Mp C. υmax/cm -1 (neat): 3348, 2962, 1770, 1708, 1645, 1513, 1310, 1220, 1165, MR (400 Mz, CDCl3) δ 8.11 (s, 1, ), 7.30 (d, J = 8.8, 2, aryl), 7.22 (s, 1, ), 6.61 (d, J = 8.8, 2, aryl), (m, 1, C), 3.77 (s, 3, Me), 2.99 (dd, J = 16.0, 6.2, 1, C2), 2.83 (dd, J = 16.0, 6.2, 1, C2), 1.31 (s, 9, t Bu), 1.28 (d, J = 6.5, 3, R2CMe). 13 C MR (101 Mz, CDCl3) δ (C() t Bu), (C2C), (C2Me), (Caryl), (Caryl), (Caryl), (Caryl), 53.0 (Me), 46.6 (-CMe), 42.2 (C2), 39.3 (C(C3)3), 27.7 (C(C3)3), 20.7 (- CMe). MS (ESI): m/z [M + + ] calcd for C172534: ; found: [3-(2,2-Dimethyl--(3-aminophenyl)propionamide)-butyryl]carbamic acid methyl ester (m-5d).

29 A light green solid. Yield 54 mg (82%). PLC: Diacel Chiralpak D-, Gradient 10% (5% increase every 10 minutes) IPA in n-hexane, 1.0 ml/min, tr (major) = 23.1 min, tr (minor) = 25.8 min, 96% ee. [α]d 23 = (c = 1.5, CCl3, 96% ee). Rf = 0.1 (C2Cl2/EtAc, 4:1). Mp C. υmax/cm -1 (neat): 3356, 2964, 1770, 1656, 1609, 1512, 1479, 1206, 1168, 1045, MR (400 Mz, CDCl3) δ 8.06 (s, 1, ), 7.29 (s, 1, ), 7.10 (t, 1, J = 2.0, aryl), 7.08 (t, 1, J = 8.0, aryl), 6.69 (dd, J = 8.0, 2.0, 1, aryl), 6.38 (dd, J = 8.0, 2.0, 1, aryl), (m, 1, C), 3.76 (s, 3, Me), 3.01 (dd, J = 15.6, 6.0, 1, C2), 2.78 (dd, J = 15.6, 6.0, 1, C2), 1.29 (s, 9, t Bu), 1.28 (d, J = 6.6, 3, R2CMe). 13 C MR (101 Mz, CDCl3) δ (C() t Bu), (C2C), (C2Me), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), 53.1 (Me), 46.3 (-CMe), 42.4 (C2), 39.8 (C(C3)3), 27.7 (C(C3)3), 20.8 (-CMe). MS (ESI): m/z [M + + ] calcd for C172534: ; found: [3-( -(4-aminophenyl)-4-methylbenzene-1-sulfonamide)-butyryl]carbamic acid methyl ester (p-5e). S A white solid. Yield 70 mg (86%). PLC: Diacel Chiralpak AD-, 25% IPA in n-hexane, 1.4 ml/min, tr (major) = 30.9 min, tr (minor) = 37.6 min, 94% ee. [α]d 22 = (c = 1.1, CCl3, 94% ee). Rf = 0.35 (C2Cl2/EtAc, 4/1). Mp C. υmax/cm -1 (neat): 3328, 3260, 1783, 1710, 1614, 1506, 1315, 1154, MR (400 Mz, CDCl3) δ 7.82 (s, 1, ), 7.57 (d, J = 8.0, 2, aryl), 7.20 (d, J = 8.0, 2, aryl), 6.82 (d, J = 8.4, 2, aryl), (m, 3, aryl and ), (m, 1, C), 3.76 (s, 3, Me), 3.05 (dd, J = 16.0, 6.0, 1, C2), 2.87 (dd, J = 16.0, 6.0, 1, C2), 2.38 (s, 3, Ph-Me), 1.26 (d, J = 6.4, 3, CMe). 13 C MR (101 Mz, CDCl3) δ (C2C), (C2Me), (Caryl), (Caryl), (Caryl), (2C, Caryl), (2C, Caryl), (2C, Caryl), (2C, Caryl), 53.6 (Me), 46.7 (-CMe) (C2), 22.0 (Ph-Me), 21.1 (-CMe). MS (ESI): m/z [M + + ] calcd for C192435S: ; found: [3-( -(3-aminophenyl)-4-methylbenzene-1-sulfonamide)-butyryl]carbamic acid methyl ester (m-5e).

30 S A white solid. Yield 64 mg (78%). PLC: Diacel Chiralpak AD-, 25% IPA in n-hexane, 1.4 ml/min, tr (major) = 47.6 min, tr (minor) = 64.4 min, 94% ee. [α]d 22 = (c = 1.3, CCl3, 94% ee). Rf = 0.35 (C2Cl2/EtAc, 4:1). Mp C. υmax/cm -1 (neat): 3257, 2965, 1767, 1700, 1606, 1496, 1327, 1152, 1090, MR (400 Mz, CDCl3) δ 8.24 (s, 1, ), 7.67 (d, J = 8.2, 2, aryl), 7.37 (br s, 1, ), 7.17 (d, J = 8.2, 2, aryl), 6.98 (t, J = 8.0, 1, aryl), (m, 2, aryl), 6.34 (dd, J = 8.0, 2.0, 1, aryl), (m, 1, C), 3.77 (s, 3, Me), 3.02 (dd, J = 16.0, 6.2, 1, C2), 2.84 (dd, J = 16.0, 6.2, 1, C2), 2.34 (s, 3, Ph-Me), 1.23 (d, J = 6.3, 3, CMe). 13 C MR (101 Mz, CDCl3) δ (C2C), (C2Me), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl), (2C, Caryl), (2C, Caryl), (Caryl), (Caryl), (Caryl), 53.1 (Me), 45.9 (-CMe), 42.1 (C2), 21.5 (Ph-Me), 20.6 (CMe). MS (ESI): m/z [M + + ] C192435S: ; found: Synthesis of (S)-(+) (4-nitrophenylamino)butyric acid. A 10 ml round bottom flask fitted with a stir bar was charged with 1-iodo-4-nitrobenzene (0.249 g, 1 mmol), (S)-3-amino-butyric acid (0.103 g, 1 mmol), CuI (0.022 g, 0.2 mmol) and K2C3 (0.345 g, 2.5 mmol). The flask was fitted with a condenser, rubber septum and was purged with argon. DM (5 ml) and water (0.1 ml) was added via syringe and the reaction was heated to 100 ºC with stirring. After 42 hours, the reaction mixture was allowed to cool and concentrated under vacuum. The reaction mixture was then diluted with water (5 ml) and acidified to p 5 using aq. Cl (0.5 M). The reaction mixture was extracted using EtAc (3 x 25 ml washes). The organic layers were combined and concentrated under vacuum. The product was purified using column chromatography. 2

31 A bright yellow solid. Yield g (44%). Rf = 0.2 (Me/C2Cl2, 3:100). Mp C (lit C). [α]d 22 = (c = 0.5, CCl3, 99% ee). υmax/cm -1 (neat): 3354, 2925, 1709, 1599, 1300, 1279, 1185, 1110, MR (500 Mz, CDCl3) δ 8.09 (d, J = 9.1, 2, aryl), 6.56 (d, J = 9.1, 2. aryl), (m, 1, C), 2.68 (dd, J = 15.7, 6.0, 1, C2), 2.60 (dd, J = 15.7, 6.0, 1, C2), 1.37 (d, J = 6.4, 3, CMe). 13 C MR (126 Mz, CDCl3) δ (C2), (Caryl), (Caryl),, (Caryl), (Caryl), 45.5(CMe), 40.1 (C2), 20.4 (CMe). MS (EI): m/z [M + + ] calcd for C101224: ; found: (4-aminophenylamino)butyric acid. A 10 ml round bottom flask was fitted with a stir bar and charged with 3-(4- nitrophenylamino)butyric acid (0.050g, mmol). The solid was dissolved in Me (5 ml) and palladium on charcoal (5%, 10 mg) was added to the solution. ydrogen was added to the vessel via syringe and the mixture was vigorously stirred. The progress of the reaction was determined by TLC analysis. n completion, the reaction mixture was filtered through celite. The solvent was removed under reduced pressure and the product dried under vacuum. The crude product was used without purification. 2 A dark blue solid. Mp C. υmax/cm -1 (neat): 3252, 2971, 1707, 1609, 1567, 1515, 1505, 1455, 1393, 1267, 1146, 1085, MR (500 Mz, D2) δ 7.16 (d, J = 8.8, 2, aryl), 6.96 (d, J = 8.8, 2, aryl), (m, 1, C), 2.52 (dd, J = 16.1, 6.2, 1, C2), 2.45 (dd, J = 16.1, 6.2, 1, C2), 1.30 (d, J = 6.6, 3, CMe), ote: - peak not visible. 13 C MR (126 Mz, D2) δ (C2), (Caryl), (Caryl), (Caryl), (Caryl), 55.4 (CMe), 39.9 (C2), 16.8 (CMe). MS (EI): m/z [M + + ] calcd for C101422: ; found: (4-(carbamic acid tert-butyl ester )phenylamino)butyric acid (10). A 5 ml round bottomed flask fitted with a stir bar was charged with the above β-amino acid (0.015 g, mmol), fitted with a rubber septum and purged with argon. The solid was dissolved in T/Me (3:1, 4 ml) and the reaction mixture was cooled to 0 ºC. Boc2 ( g, mmol) in T (2 ml) was added dropwise to the reaction. The reaction mixture was allowed to warm to room temperature and left overnight (18 h). The reaction mixture was concentrated under vacuum and purified using column chromatography.

32 An off white solid, Diacel Chiralpak AD-, 10% IPA in n-hexane, 1.0 ml/min, tr (major) = 35.2 min, tr (minor) = 42.3 min. [α]d 25 = (c = 1.2, CCl3, 99% ee). Rf 0.4 (Me/C2Cl2 5:100). Melting point C. υmax/cm -1 (neat): 3323, 2970, 2924, 2853, 1694, 1614, 1516, 1391, 1236, 1154, MR (500 Mz, CDCl3) δ 7.18 (br d, J = 8.2, 2, aryl), 6.69 (d, J = 8.2, 2, aryl), 6.49 (br s, 1, ), (m, 1, C), 2.58 (dd, J = 15.6, 6.5, 1, C2), 2.49 (dd, J = 15.6, 6.5, 1, C2), 1.50 (s, 9, t Bu), 1.26 (d, J = 6.2, 3, CMe). 13 C MR (126 Mz, CDCl3) δ (C2), (C t Bu) (Caryl), (Caryl), (Caryl), (Caryl), 48.2 (CMe), 40.4 (C2), 28.4 ( t Bu), (CMe). MS (EI): m/z [M + + ] calcd for C152224: ; found: Redox side product characterisation data. Butyryl-carbamic acid methyl ester (6). A white solid. Mp C (lit C). Rf = 0.7 (pet. ether/etac, 6/4). υmax/cm -1 (neat): 3254, 3183, 2961, 2928, 1754, 1688, 1504, 1244, 1179, 1031, MR (400 Mz, CDCl3) δ 7.34 (br s, 1, ), 3.77 (s, 3, Me), 2.74 (t, J = 7.4, 2, MeC2C2C), (m, 2, MeC2C2C), 0.98 (t, J = 7.4, 3, MeC2-). 13 C MR (101 Mz, CDCl3) δ (C2C()), 152.1(C2Me), 53.0 (Me), 37.9 (C2C()), 17.7(C2), 13.7 (Me). MS (ESI): m/z [M +MeC + a + ] calcd for C81423a: 209.1; found: (Z)-methyl (3-((3-(2,2,2-trifluoroacetamido)phenyl)amino)but-2-enoyl)carbamate (m- 7c). C 3 A white solid. M.p ºC. υmax/cm -1 (neat): 2958, 1709, 1609, 1582, 1325, 1220, 1142, 1097, MR (400 Mz, CDCl3) δ (s, 1, ), 8.27 (s, 1, ), (m, 1, aryl), (m, 2, aryl), 7.10 (s, 1, ), (m, 1, aryl), 5.85 (s, 1, C), 3.75 (s, 3, Me), 2.09 (s, 3, Me). 19 MR (376 Mz, CDCl3) δ (C3). 13 C MR (151 Mz, Chloroform-d) δ (C2Me), (C), (q, J = 37.3 z, C()C3), (RC()), (Caryl), (Caryl), (Caryl), (Caryl), (Caryl),