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Amidation of Unactivated Ester Derivatives Mediated by Trifluoroethanol

Christopher G. McPherson,a Nicola Caldwell,a Craig Jamieson,*a Iain Simpsonb and Allan J. B. Watsona

a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK. b AstraZeneca, Oncology Innovative Medicines, Darwin Building, Unit 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2017

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Contents1. General ...........................................................................................................................................3

1.1 Purification of Solvents...............................................................................................................3

1.2 Purification of Starting Materials................................................................................................3

1.3 Experimental Details...................................................................................................................3

1.4 Purification of Products ..............................................................................................................4

1.5 Analysis of Products....................................................................................................................4

1.6 HPLC Methods ............................................................................................................................4

2. General Experimental Procedures..................................................................................................7

2.1 General Procedure A for Investigating the Nature of the Base Species ...........................................7

2.2 General Procedure B for Optimisation of the TFE Mediated Tertiary Amide Formation: Additive Screen.....................................................................................................................................................7

2.3 General Procedure C for Optimisation of the TFE Mediated Tertiary Amide Formation: Base and Solvent Screen ........................................................................................................................................8

2.4 General Procedure D for Optimisation of the TFE Mediated Tertiary Amide Formation: Elevated Temperature Screen...............................................................................................................................9

2.5 General Procedure E for Chiral Secondary Amide Base Screen........................................................9

2.6 General Procedure F for Chiral Secondary Amide Additive Screen ................................................10

2.8 General Procedure G for Investigating the Point of Racemisation in the Chiral Secondary Amide Methodology. .......................................................................................................................................11

2.7 General Procedure H for Synthesis of Secondary Amine Starting Materials ..................................11

2.8 General Procedure I for Synthesis of Chiral Ester Starting Materials via Esterification .................12

2.9 General Procedure J for Synthesis of Chiral Ester Starting Materials via Cbz Protection...............12

3. Characterisation Data ...................................................................................................................12

3.1 Characterisation Data for Synthesised Starting Materials..............................................................12

4. 1H and 13C Spectra for Exemplified Compounds ...........................................................................15

5. Chiral HPLC Spectra ......................................................................................................................59

6. References ....................................................................................................................................71

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1. GeneralAll reagents and solvents were obtained from commercial suppliers and were used without further purification unless otherwise stated. Purification was carried out according to standard laboratory methods.1

1.1 Purification of Solventsi) Anhydrous THF and toluene were obtained from a PureSolv SPS-400-5 solvent

purification system.ii) Acetonitrile, 1,2-Dichloroethane, isopropanol and 2-MeTHF were purified by fractional

distillation under vacuum from CaH2; n-butanol was purified by stirring over 4 Å molecular sieves; CPME was purified by vacuum distillation from sodium metal; 1,4-Dioxane was purified by vacuum distillation from LiAlH4; Dimethyl carbonate was purified by fractional distillation under vacuum from 4 Å molecular sieves; DMF was purified by fractional distillation under vacuum from MgSO4.

iii) Purified solvents were transferred to and stored in septum-sealed oven-dried flasks over previously activated 4 Å molecular sieves and purged with and stored under nitrogen.

1.2 Purification of Starting Materialsi) Methyl benzoate, benzylamine and N-methylbenzylamine used for optimisation

reactions, were purified by vacuum distillation from KOH; trifluoroethanol, used as an additive, was purified by fractional distillation from Na2SO4.

ii) BEMP was purified by vacuum distillation from CaH2; Ca3(PO4)2, Cs2CO3, Cs3PO4, K2CO3, KH2PO4, K2HPO4, K3PO4, Li3PO4, Mg3(PO4)2 and Na3PO4 were stored in a vacuum oven at 60 C; DABCO was recrystallised from MeOH/diethyl ether (1:1); DBU was purified by fractional distillation under vacuum; Et3N was purified by fractional distillation under vacuum over CaH2, Potassium acetate was stored in a desiccator over P2O5; KOAc, KOH and KTFA were stored in a desiccator over P2O5; KOtBu was purified by sublimation.

iii) Dichloromethane, ethyl acetate, methanol, and petroleum ether 40–60 °C for purification purposes were used as obtained from suppliers without further purification.

1.3 Experimental Detailsi) All reactions were carried out using oven-dried glassware, which was evacuated and

purged with N2 before use.ii) Amidation reactions were performed using 25 mL Schlenk reaction vessels.iii) Purging refers to a vacuum/nitrogen-refilling procedure.iv) Room temperature was generally ca. 20 C.v) Reactions were carried out at elevated temperatures using a temperature-regulated

hotplate/stirrer.vi) Amidation reactions at elevated temperatures were carried out using a STEM heating

block.vii) Reactions requiring the use of Radleys tubes with elevated temperatures were

performed in a carousel resting on a temperature-regulated hotplate/stirrer.

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1.4 Purification of Productsi) Thin layer chromatography was carried out using Merck silica plates coated with

fluorescent indicator UV254. These were analysed under 254 nm UV light or developed using potassium permanganate solution.

ii) Flash chromatography was carried out using ZEOprep 60 HYD 40-63 µm silica gel.

1.5 Analysis of Productsi) Fourier Transformed Infra-Red (FTIR) spectra were obtained using an A2 Technologies

ATR 32 machine.ii) 1H and 13C NMR spectra were obtained on a Bruker DRX 500 spectrometer at 500 and

126MHz, respectively or on a Bruker AV3 400 at 400 and 101 MHz, respectively, or on a Bruker AVANCE 400 spectrometer at 400 and 101 MHz respectively. Chemical shifts are reported in ppm and coupling constants are reported in Hz with CDCl3 referenced at 7.26 (1H) and 77.16 ppm (13C), and DMSO referenced at 2.50 (1H) and 39.52 ppm (13C).

iii) Variable temperature NMR experiments were obtained using a Bruker AVANCE 400 spectrometer at 400 and 100 MHz respectively, or a Bruker DRX 500 spectrometer at 500 and 126MHz, respectively at 333 K.

iv) High-resolution mass spectra were obtained on a Thermofisher LTQ Orbitrap XL instrument at the EPSRC National Mass Spectrometry Service Centre (NMSSC), Swansea.

v) Reverse phase HPLC data was obtained on an Agilent 1200 series HPLC using a Machery-Nagel Nucleodur C18 column.

vi) Chiral HPLC data was obtained on an Agilent 1260 Infinity HPLC using a Chiralpak IA column.

vii) Optical rotations were measured at 589 nm using a Perkin Elmer 341 Polarimeter

1.6 HPLC Methodsi) For N-Benzylbenzylamide 2: Reversed phase HPLC analysis was performed using a

gradient method, eluting with 5 – 80% MeCN/H2O over 5 minutes at a flow rate of 2 mL/min, with methyl benzoate, 2,2,2-trifluoroethyl benzoate intermediate, N-benzylbenzamide product 2, and iodobenzene internal standard eluting at 2.0, 2.5, 1.9 and 2.9 minutes, respectively

Time (min) Concentration of MeCN (%)0 51 55

3.9 604.1 804.3 55 5

For N-benzyl-N-methylbenzamide 23: Reversed phase HPLC analysis was performed using a gradient method, eluting with 5 – 60% MeCN/H2O over 8 minutes at a flow rate of 2 mL/min, with methyl benzoate, N-methylbenzylamine, N-benzyl-N-methylbenzamide product 23, and caffeine internal standard eluting at 4.7, 1.0, 5.1 and 2.0, respectively.

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Time (min) Concentration of MeCN (%)0 5

5.5 605.8 58 5

ii) For N-Benzylbenzylamide 2: For reactions using an internal standard, prior HPLC calibration was carried out using samples containing varying molarities of product and iodobenzene, allowing calculation of the response factor by substituting values into the following equation:

𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝐹𝑎𝑐𝑡𝑜𝑟 =(

𝐴𝑟𝑒𝑎𝑀𝑜𝑙𝑎𝑟𝑖𝑡𝑦

)𝑃𝑟𝑜𝑑𝑢𝑐𝑡

(𝐴𝑟𝑒𝑎

𝑀𝑜𝑙𝑎𝑟𝑖𝑡𝑦)𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑

Screening reactions were carried out using a known molarity of iodobenzene internal standard as indicated in the relevant general experimental procedures.Unknown molarities of product were calculated by rearranging the above equation, using the average value for the response factor as determined during calibration.Conversion to product was calculated as a percentage of the theoretical molarity for the reaction.

For N-benzyl-N-methylbenzamide 23: Conversion factor established by running 3 samples with a ratio of 0.25:1 caffeine:analyte, with the average conversion factor calculated by substituting values for each sample into the following equation:

𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 𝑓𝑎𝑐𝑡𝑜𝑟 = 𝑃𝑒𝑎𝑘 𝐴𝑟𝑒𝑎 𝐴𝑛𝑎𝑙𝑦𝑡𝑒

𝑃𝑒𝑎𝑘 𝐴𝑟𝑒𝑎 𝐶𝑎𝑓𝑓𝑒𝑖𝑛𝑒

For standard sampling of reaction mixtures, the ratio of Caffeine:Analyte is 0.25:1. Therefore, when calculating the % conversion:

𝑃𝑒𝑎𝑘 𝐴𝑟𝑒𝑎 𝐴𝑛𝑎𝑙𝑦𝑡𝑒𝑃𝑒𝑎𝑘 𝐴𝑟𝑒𝑎 𝐶𝑎𝑓𝑓𝑒𝑖𝑛𝑒 × 4

= 𝑋

𝑋𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟

= % 𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛

iii) For N-Benzylbenzylamide 2: Samples for HPLC analysis were prepared by diluting a 10 μL aliquot from the reaction mixture to 1 mL with MeCN.

For N-benzyl-N-methylbenzamide 23: Samples for HPLC analysis were prepared through the addition of 7 mL of a 0.05 M caffeine standard to the completed reaction mixture. The resulting solution was then stirred before the removal of a 200 µL aliquot. The

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aliquot was diluted to 1 mL with MeOH, a 200 µL aliquot of the diluted solution was then further diluted with 800 µL MeOH and then filtered for HPLC analysis against established conversion factors.

iv) For compounds 11, 63, 64, 65, 66 and 72: Chiral HPLC was performed using an isocratic method, using a Chiralpak IA column, eluting with 10% IPA/hexanes over 20 minutes with a flow rate of 1 mL/min.For compound 59: Chiral HPLC was performed using an isocratic method, using a Chiralpak IA column, eluting with 5% IPA/hexanes over 1 hour with a flow rate of 1 mL/min.For compounds 60 and 61: Chiral HPLC was performed using an isocratic method, using a Chiralpak IA column, eluting with 10% IPA/hexanes over 1 hour with a flow rate of 1 mL/min.For compound 62: Chiral HPLC was performed using an isocratic method, using a Chiralpak IA column, eluting with 10% IPA/hexanes over 40 min with a flow rate of 1 mL/min.For compounds 69, 70 and 71: Chiral HPLC was performed using an isocratic method, using a ChiralpakIA column, eluting with 5% IPA/hexanes over 40 min with a flow rate of 1 mL/min.The major and minor enantiomers were found to elute as follows:

Product Major enantiomer retention time (min)

Minor enantiomer retention time (min)

11 8.44 11.7859 38.34 N/A60 11.16 17.2461 24.78 51.3262 15.34 24.0663 11.91 10.1264 9.38 8.8765 8.79 10.3166 9.13 16.9169 34.01 N/A70 18.17 N/A71 50.66 N/A72 9.37 N/A

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2. General Experimental Procedures

2.1 General Procedure A for Investigating the Nature of the Base SpeciesTo an oven-dried, purged and sealed Schlenk tube containing trifluoroethanol (20 μL, 0.28 mmol, 0.2 equiv.), base (1.42 mmol, 1 equiv.) and THF (700 μL) was added methyl benzoate (178 µL, 1.42 mmol, 1 equiv.) and benzylamine (155 µL, 1.42 mmol, 1 equiv.). The reaction mixture was heated at 90 °C for 22 h. The reaction mixture was sampled at the end of the required reaction time and the conversion was determined by HPLC with reference to iodobenzene (1.4 M), which was used as an internal standard.

Entry Base pKa Conversion (%)1 KTFA 0 12 KH2PO4 2 13 KOAc 6 14 K2HPO4 7 15 K2CO3 10 26 K3PO4 12 787 KOH 16 58 KOtBu 18 479 Ca3PO4 13 1

10 Cs3PO4 13 111 Li3PO4 13 012 Mg3PO4 13 1613 Na3PO4 13 114 Cs2CO3 10 1115 NMO 7 1316 DABCO 9 417 Et3N 11 118 DBU 12 6119 BEMP 19 8

2.2 General Procedure B for Optimisation of the TFE Mediated Tertiary Amide Formation: Additive ScreenTo an oven-dried, purged and sealed Schlenk tube containing additive (0.28 mmol, 0.2 equiv.), K3PO4 (301 mg, 1.42 mmol, 1 equiv.) and THF (700 μL) was added methyl benzoate (178 µL, 1.42 mmol, 1 equiv.) and N-methylbenzylamine (183 µL, 1.42 mmol, 1 equiv.) was added and the reaction mixture was heated at 90 °C for 22 h. The reaction mixture was sampled at the end of the required reaction time and the conversion was determined by HPLC with reference to a 0.05M caffeine solution.

Entry Additive Conversion (%)1 4-CF3C6H4OH 12 HFIP 0

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3 HOAt 04 HOBt 05 HOCt 06 N-hydroxysuccinimide 07 Oxyma 08 2-Picoline N-oxide 09 TFE 1

2.3 General Procedure C for Optimisation of the TFE Mediated Tertiary Amide Formation: Base and Solvent ScreenTo an oven-dried, purged and sealed Schlenk tube containing trifluoroethanol (20 µL, 0.28 mmol, 0.2 equiv.), base (1.42 mmol, 1 equiv.) and solvent (700 μL) was added methyl benzoate (178 µL, 1.42 mmol, 1 equiv.) and N-methylbenzylamine (183 µL, 1.42 mmol, 1 equiv.) was added and the reaction mixture was heated at 90 °C for 22 h. The reaction mixture was sampled at the end of the required reaction time and the conversion was determined by HPLC with reference to a 0.05M caffeine solution.

Entry Base Solvent Conversion (%)1 DABCO n-butanol 02 K3PO4 n-butanol 33 DBU n-butanol 24 KOtBu n-butanol 225 DABCO CPME 06 K3PO4 CPME 377 DBU CPME 48 KOtBu CPME 969 DABCO DCE 0

10 K3PO4 DCE 011 DBU DCE 012 KOtBu DCE 013 DABCO 1,4-Dioxane 014 K3PO4 1,4-Dioxane 1215 DBU 1,4-Dioxane 316 KOtBu 1,4-Dioxane 3717 DABCO DMC 018 K3PO4 DMC 019 DBU DMC 020 KOtBu DMC 021 DABCO DMF 022 K3PO4 DMF 823 DBU DMF 324 KOtBu DMF 2125 DABCO IPA 026 K3PO4 IPA 927 DBU IPA 228 KOtBu IPA 029 DABCO 2-MeTHF 1

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30 K3PO4 2-MeTHF 4331 DBU 2-MeTHF 532 KOtBu 2-MeTHF 233 DABCO MeCN 034 K3PO4 MeCN 035 DBU MeCN 436 KOtBu MeCN 3237 DABCO THF 238 K3PO4 THF 139 DBU THF 840 KOtBu THF 56

2.4 General Procedure D for Optimisation of the TFE Mediated Tertiary Amide Formation: Elevated Temperature ScreenTo an oven-dried, purged and sealed Schlenk tube containing trifluoroethanol (20 µL, 0.28 mmol, 0.2 equiv.), K3PO4 (301 mg, 1.42 mmol, 1 equiv.) and solvent (700 μL) was added methyl 4-(trifluoromethyl)benzoate (229 µL, 1.42 mmol, 1 equiv.) and the reaction heated at the desired temperature for 30 min. N-methylbenzylamine (183 µL, 1.42 mmol, 1 equiv.) was then added and the reaction mixture was heated at the desired temperature for a further 22 h. The reaction mixture was sampled at the end of the required reaction time and the conversion was determined by HPLC with reference to a 0.05M caffeine solution.

Entry Solvent Temperature (C) Conversion (%)1 THF 90 02a THF 90 70

3a,b THF 90 624a CPME 125 77c

5a 1,4-dioxane 125 93c

6a 2-MeTHF 100 72c

7a,d 1,4-dioxane 125 0c

8a,e 1,4-dioxane 125 0c

9a,f 1,4-dioxane 125 0c

aPreformation of the active ester intermediate for 30 min at reaction temperature. bMethyl benzoate used as ester substrate. cIsolated Yield. dPerformed in the absence of K3PO4. ePerformed in the absence of TFE. fPerformed in the absence of both K3PO4 and TFE.

2.5 General Procedure E for Chiral Secondary Amide Base ScreenTo an oven-dried, purged and sealed Schlenk tube containing 4-(trifluoromethyl)phenol (46 mg, 0.28 mmol, 0.2 equiv.), base (1.42 mmol, 1 equiv.), Boc-L-phenylalanine methyl ester (397 mg, 1.42 mmol, 1 equiv.) and THF (700 μL) was added benzylamine (155 µL, 1.42 mmol, 1 equiv.). The reaction mixture was heated at 90 °C for 22 h then diluted with EtOAc (10 mL), washed with brine (3 x 10 mL), dried over Na2SO4, and concentrated to a residue in vacuo which was purified by silica gel chromatography (1% MeOH/CH2Cl2).

Entry Base Base pKa Yield (%) ee (%)

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1 KTFA 0 46 932 KH2PO4 2 62 873 KOAc 6 55 924 NMO 7 36 925 K2HPO4 7 48 926 DABCO 9 40 857 K2CO3 10 46 758 Cs2CO3 10 34 409 DBU 12 69 16

0 2 4 6 8 10 12 140

10

20

30

40

50

60

70

80

90

100

pKa of base

ee (%

)

2.6 General Procedure F for Chiral Secondary Amide Additive ScreenTo an oven-dried, purged and sealed Schlenk tube containing additive (0.28 mmol, 0.2 equiv.), KOAc (139 mg, 1.42 mmol, 1 equiv.), Boc-L-phenylalanine methyl ester (397 mg, 1.42 mmol, 1 equiv.) and THF (700 μL) was added benzylamine (155 µL, 1.42 mmol, 1 equiv.). The reaction mixture was heated at 90 °C for 22 h then diluted with EtOAc (10 mL), washed with brine (3 x 10 mL), dried over Na2SO4, and concentrated to a residue in vacuo which was purified by silica gel chromatography (1% MeOH/CH2Cl2).

Entry Additive Additive pKa Yield (%) ee (%)1 Picoline n-oxide - 28 872 HOCt 2.2 54 913 HOAt 3.3 32 894 HOBt 4.6 47 915 Oxyma 4.6 50 936 NHS 7.8 58 797 4-CF3C6H4OH 8.7 55 928 HFIP 9.3 35 899 TFE 12.5 31 89

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10a 4-CF3C6H4OH 8.7 44 9211 No additive - 17 8912a No additive - 28 88

aPerformed in the absence of KOAc

2.8 General Procedure G for Investigating the Point of Racemisation in the Chiral Secondary Amide Methodology.

To an oven-dried, purged and sealed Schlenk tube containing KOAc (1 equiv.), Boc-L-phenylalanine methyl ester (397 mg, 1.42 mmol, 1 equiv.) or amide 11 (150 mg, 0.43 mmol, 1 equiv.) was added THF (700/210 μL respectively). The reaction mixture was heated at 90 °C for 22 h then diluted with EtOAc (10 mL), washed with brine (3 x 10 mL), dried over Na2SO4, and concentrated to a residue in vacuo. The ee of the resulting products was then determined by HPLC.

Entry Substrate Initial ee (%) ee upon reaction completion (%)

1 Boc-Phe-OMe 100 1002 11 92 92

2.7 General Procedure H for Synthesis of Secondary Amine Starting MaterialsTo a round-bottomed flask containing a solution of amine (1 equiv.) in DCM (10 mL) at 0 C was added Et3N (2 equiv.) and a solution of di-tert-butyl dicarbonate (1.2 equiv.) in DCM (5 mL). Reaction warmed to room temperature and stirred for 16 h, at which point it was washed sequentially with 2M HCl (10 mL), 5% NaHCO3 (aq) (10 mL) and water (10 mL). Organics dried over Na2SO4 and

0 2 4 6 8 10 12 140

10

20

30

40

50

60

70

80

90

100

pKa of additive

ee (%

)

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concentrated to a residue in vacuo, to which was added THF (10 mL) and NaH (1.1 equiv.) reaction stirred until effervescence had ceased, at which point methyl iodide (1.2 equiv.) was added and the reaction heated at 45 C for 72 hours. THF removed in vacuo, the resulting crude product dissolved in EtOAc (10 mL), washed with water (3 x 10 mL), dried over Na2SO4 and concentrated to a residue in vacuo which was purified by silica gel chromatography (5% EtOAc/Pet. ether 40–60 °C).

To a solution of the resulting N-methylated Boc-protected amine in DCM (10 mL) was added TFA (10 mL). Reaction stirred at room temperature for 16 h, at which point the reaction mixture was concentrated to a residue in vacuo. Resulting crude product dissolved in EtOAc (10 mL) and washed with 2M NaOH (aq) until pH ≥ 9. Organics extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and concentrated in vacuo to afford the desired N-methyl amine.

2.8 General Procedure I for Synthesis of Chiral Ester Starting Materials via EsterificationTo an oven-dried, purged Radleys tube containing carboxylic acid (1 equiv.) was added MeOH (20 mL), and the solution cooled to 0 C. SOCl2 (1.2 equiv.) added dropwise and the reaction refluxed for 16 h. Reaction mixture washed with saturated NaHCO3 (aq) until pH ≥ 8, extracted with DCM (3 x 20 mL), dried over Na2SO4 and concentrated to a residue in vacuo. Resulting crude product was purified by silica gel chromatography (EtOAc/Pet. ether 40–60 °C).

2.9 General Procedure J for Synthesis of Chiral Ester Starting Materials via Cbz ProtectionTo a round-bottomed flask was added ester hydrochloride salt (1 equiv.), N-(benzyloxycarbonyloxy)succinimide (1.1 equiv.), NaHCO3 (2.5 equiv.), THF (7 mL) and water (7 mL). Reaction stirred for 16 h at room temperature, at which point the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). Organics dried over Na2SO4 and concentrated to a residue in vacuo which was purified by silica gel chromatography (EtOAc/pet. ether 40–60 °C).

3. Characterisation Data

3.1 Characterisation Data for Synthesised Starting Materials

N-methyl-3-phenylpropan-1-amine (67).2

NH

Synthesised according to General Experimental Procedure H using 3.7 mmol of 3-phenylpropan-1-amine, affording the title compound as a pale yellow liquid (372 mg, 67%).

max (neat): 3027, 2932, 2857, 2794, 1673, 1455, 1033, 748, 700 cm-1

1H NMR (500 MHz, DMSO-d6): 7.27, (t, J = 7.5 Hz, 2H), 7.17 (dd, J = 16.9, 7.5 Hz, 3H), 2.59 (t, J = 7.6 Hz, 2H), 2.45 (t, J = 7.0 Hz), 1.68 (p, J = 7.8 Hz, 5H)

13C NMR (126 MHz, DMSO-d6): 142.2, 128.2, 128.2, 125.6, 50.9, 36.1, 32.9, 31.0

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HRMS m/z: [M+H]+ Calcd for C10H16N 150.1277, Found 150.1275

1-cyclohexyl-N-methylmethanamine (68).3

NH

Synthesised according to General Experimental Procedure H using 8.8 mmol of cyclohexylmethanamine, affording the title compound as a pale yellow liquid (404 mg, 36%).

max (neat): 2919, 2850, 2788, 1448, 1126, 1150, 742 cm-1

1H NMR (500 MHz, CDCl3): 2.41 (d, J = 9.2 Hz, 4H), 1.74 – 1.64 (m, 5H), 1.49 – 1.42 (m, 2H), 1.28 -1.10 (m, 3H), 0.95 – 0.87 (m, 2H)

13C NMR (126 MHz,CDCl3): 54.3, 44.4, 35.5, 34.4, 33.2, 29.7, 29.7, 25.6, 25.6, 25.0, 25.0

HRMS m/z: [M+H]+ Calcd for C8H18N 128.1434, Found 128.1429

Methyl ((benzyloxy)carbonyl)-D-alaninate (69).4

O

OCbzHN

Synthesised according to General Experimental Procedure J, using 3.58 mmol of methyl D-alaninate hydrochloride, and purified by flash column chromatography (20% EtOAc/Pet. ether 40 – 60 C) to afford the title compound as a pale yellow oil (581 mg, 68%).

max (neat): 3336, 3036, 2993, 2958, 1753, 1684, 1526, 1215, 1174, 1076, 754, 702 cm-1

1H NMR (400 MHz, CDCl3): 7.39 – 7.29 (m, 5H), 5.31 (s, 1H), 5.11 (m, 2H), 4.40 (p, J = 7.2 Hz, 1H), 3.75 (s, 3H), 1.42 (d, J = 7.2 Hz, 3H)

13C NMR (101 MHz,CDCl3): 173.6, 155.7, 136.4, 128.6, 128.3, 128.2, 67.0, 52.5, 49.7, 18.8

HRMS m/z: [M+H]+ Calcd for C12H16NO4 238.1074, Found 238.1076

ee = 100%

Methyl ((benzyloxy)carbonyl)-L-leucinate (70).5

O

ONHCbz

Synthesised according to General Experimental Procedure J, using 2.75 mmol of methyl L-leucinate hydrochloride, and purified by flash column chromatography (20% EtOAc/Pet. ether 40 – 60 C) to afford the title compound as a colourless oil (683 mg, 89%).

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max (neat): 3339, 2956, 1699, 1526, 1262, 1208, 1171, 1046, 739, 700 cm-1

1H NMR (500 MHz, CDCl3): 7.36 – 7.30 (m, 5H), 5.12 (m, 3H), 4.4 (dd, J = 13.8, 8.8 Hz, 1H), 3.74 (s, 3H), 1.74 – 1.61 (m, 2H), 1.55 – 1.49 (m, 1H), 0.94 (m, 6H)

13C NMR (126 MHz,CDCl3): 173.8, 156.1, 136.4, 128.7, 128.3, 128.3, 67.1, 52.6, 52.4, 24.9, 23.0, 22.0

HRMS m/z: [M+H]+ Calcd for C15H22NO4 280.1543, Found 280.1541

ee = 100%

ethyl ((benzyloxy)carbonyl)-L-methioninate (71).6

O

OS

NHCbz

Synthesised according to General Experimental Procedure J, using 2.81 mmol of methyl L-methioninate hydrochloride, and purified by flash column chromatography (20% EtOAc/Pet. ether 40 – 60 C) to afford the title compound as a pale yellow oil (629 mg, 72%).

max (neat): 3326, 2980, 2917, 1705, 1521, 1210, 1046, 1029, 700 cm-1

1H NMR (500 MHz, CDCl3): 7.36 – 7.29 (m, 5H), 5.42 (s, 1H), 5.11 (s, 2H), 4.48 (dd, J = 12.7, 7.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.58 - 2.47 (m, 2H), 2.20 – 2.09 (m, 4H), 1.96 (td, J = 14.4, 7.5 Hz, 1H), 1.28 (t, J = 7.1Hz, 3H)

13C NMR (126 MHz,CDCl3): 172.1, 156.0, 136.3, 128.7, 128.3, 128.3, 67.2, 61.8, 53.4, 32.2, 30.0, 15.6, 14.3

HRMS m/z: [M+H]+ Calcd for C15H22NO4S 312.1264, Found 312.1261

ee = 100%

Methyl (R)-2-hydroxy-2-phenylacetate (72).7

O

O

OH

Synthesised according to General Experimental Procedure I, using 4.93 (mmol) of (R)-2-hydroxy-2-phenylacetic acid, and purified by flash column chromatography (20% EtOAc/Pet. ether 40 – 60 C) to afford the title compound as a colourless oil (643 mg, 80%).

max (neat): 3434, 1738, 1206, 1191, 1068, 977, 739, 696 cm-1

1H NMR (400 MHz, CDCl3): 7.43 -7.31 (m, 5H), 5.18 (d, J = 5.3 Hz, 1H), 3.76 (d, J = 1.7 Hz, 3H), 3.49 – 3.43 (m, 1H)

13C NMR (101 MHz,CDCl3): 174.3, 138.4, 128.8, 128.7, 126.7, 73.0, 53.2

S15

HRMS m/z: [M+H]+ Calcd for C9H11O3 167.0703, Found 167.0701

ee = 100%

Methyl (S)-2-(4-isobutylphenyl)propanoate (73).8

O

O

Synthesised according to General Experimental Procedure I, using 3.64 mmol of (S)-2-(4-isobutylphenyl)propanoic acid, and purified by flash column chromatography (10% EtOAc/Pet. ether 40 – 60 C) to afford the title compound as a pale yellow oil (583 mg, 73%).

max (neat): 2954, 2870, 1738, 1206, 1163, 1066 cm-1

1H NMR (400 MHz, CDCl3): 7.21 – 7.18 (m, 2H), 7.11 – 7.09 (m, 2H), 3.70 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 2.45 (d, J = 7.2 Hz, 2H), 1.92 – 1.76 (m, 1H), 1.49 (d, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H)

13C NMR (101 MHz,CDCl3): 175.4, 140.7, 137.9, 129.5, 127.3, 52.1, 45.2, 30.3, 22.5, 18.8

HRMS m/z: [M+H]+ Calcd for C14H21O2 221.1536, Found 221.15

4. 1H and 13C Spectra for Exemplified CompoundsN-benzyl-N-methylbenzamide (23).

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.23

2.00

2.76

2.23

5.17

2.86

4.60

7.27

7.29

7.31

7.36

7.37

7.39

7.39

7.42

7.44

7.45

N

O

23

S16

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.2

6

37.0

9

50.8

9

55.2

7

126.

9212

7.08

127.

6612

8.29

128.

5412

8.87

129.

7113

6.38

136.

7313

7.17

171.

7017

2.43

N-benzyl-N-methyl-4-(trifluoromethyl)benzamide (24)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.99

2.00

4.78

1.96

1.93

2.85

4.44

4.48

4.69

7.23

7.28

7.29

7.31

7.36

7.37

7.39

7.66

7.67

7.78

7.79

N

O

F3C

N

O

23

24

S17

0102030405060708090100110120130140150160170180190200f1 (ppm)

32.4

8

36.3

6

49.7

7

53.7

9

120.

4112

2.57

124.

7412

5.07

125.

1012

5.13

125.

1612

6.90

127.

0312

7.26

128.

3512

9.10

129.

3612

9.61

129.

8713

6.76

140.

28

169.

01

N-benzyl-4-cyano-N-methylbenzamide (25)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.14

2.23

4.86

2.06

2.00

2.85

4.66

7.28

7.30

7.31

7.34

7.36

7.38

7.39

7.61

7.63

7.88

7.90

N

O

F3C

24

N

O

NC

25

S18

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.5

4

36.8

9

51.0

1

55.1

0

113.

61

118.

2112

6.63

127.

6412

7.83

127.

9412

8.08

128.

4012

8.98

129.

2013

2.53

135.

9713

6.55

140.

6614

0.77

169.

6617

0.35

N-benzyl-4-chloro-N-methylbenzamide (26)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.06

2.00

2.71

2.10

3.99

2.86

4.59

7.27

7.28

7.29

7.31

7.35

7.37

7.39

7.39

7.45

7.46

7.47

7.48

7.50

7.50

N

O

NC 25

N

O

Cl26

S19

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.5

3

37.1

1

51.0

5

55.2

9

126.

7212

7.80

128.

3612

8.51

128.

6812

8.85

134.

7113

5.85

136.

4913

6.94

170.

6617

1.33

N-benzyl-4-methoxy-N-methylbenzamide (28)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.94

2.86

2.00

1.94

2.68

3.79

2.88

3.80

4.60

6.96

6.96

6.97

6.98

6.98

6.99

7.26

7.26

7.27

7.28

7.28

7.30

7.30

7.35

7.36

7.37

7.38

7.38

7.39

7.39

7.40

7.40

7.42

7.42

7.43

N

O

Cl26

N

O

MeO28

S20

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.6

1

37.3

0

51.1

6

55.4

2

113.

77

126.

8712

7.59

128.

4212

8.87

129.

08

137.

16

160.

82

171.

80

N-benzyl-3-methoxy-N-methylbenzamide (29)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.94

2.98

2.00

2.92

5.76

2.86

3.76

4.58

6.95

6.95

6.96

6.97

6.97

6.98

6.99

6.99

7.00

7.01

7.01

7.27

7.29

7.31

7.33

7.35

7.36

7.37

7.38

7.39

7.39

N

O

MeO28

N

O

OMe

29

S21

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.3

5

37.0

9

50.8

9

55.3

8

112.

1411

2.58

115.

5311

5.90

119.

0311

9.24

126.

8412

7.68

128.

3212

8.94

129.

72

159.

70

N-benzyl-2-methoxy-N-methylbenzamide (30)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.82

1.18

3.00

0.79

1.19

8.89

2.68

2.88

3.78

3.83

4.30

4.69

5.71

6.95

6.97

6.99

7.01

7.02

7.04

7.06

7.08

7.09

7.11

7.14

7.16

7.21

7.21

7.22

7.23

7.25

7.27

7.29

7.31

7.33

7.34

7.36

7.37

7.38

7.40

7.42

7.42

N

O

OMe29

N

O

OMe

30

S22

0102030405060708090100110120130140150160170180190200f1 (ppm)

31.6

0

35.0

5

49.1

153

.27

55.2

055

.39

111.

41

120.

2812

0.49

126.

6812

7.07

128.

1512

9.93

136.

6513

7.08

154.

70

168.

15

N-benzyl-N-methylnicotinamide (31)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

2.09

5.78

0.95

1.87

2.90

4.62

7.28

7.30

7.31

7.36

7.38

7.40

7.44

7.45

7.46

7.47

7.85

7.87

8.63

8.64

N

O

OMe

30

N

N

O

31

S23

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.6

2

37.0

8

51.0

9

55.2

8

123.

5012

6.67

127.

8712

8.37

128.

9512

9.14

132.

2113

4.77

135.

0613

6.14

136.

67

147.

8714

8.10

150.

86

169.

1216

9.81

N-benzyl-N-methylfuran-2-carboxamide (32)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.79

2.00

0.89

0.88

2.78

1.89

0.84

3.06

4.72

6.60

6.60

6.60

6.61

7.00

7.26

7.28

7.28

7.35

7.36

7.80

N

N

O

31

N

O

O

32

S24

0102030405060708090100110120130140150160170180190200f1 (ppm)

34.3

635

.92

52.0

054

.33

111.

38

116.

63

127.

0612

7.64

128.

2612

8.84

137.

03

144.

08

148.

10

160.

62

N-benzyl-N-methyl-2-phenylacetamide (33)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.10

2.04

2.17

1.33

0.81

10.0

0

2.82

2.94

3.77

4.53

4.62

7.20

7.21

7.22

7.24

7.27

7.29

7.31

N

O

O

32

N

O

33

S25

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

34.8

3

49.8

952

.64

126.

0012

6.67

127.

2212

7.90

128.

0812

8.72

128.

7312

8.74

128.

7712

8.80

135.

5413

7.54

170.

19

N-benzyl-N-methyl-2-(pyridin-2-yl)acetamide (34)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.09

1.82

0.69

1.21

1.33

0.80

3.46

2.99

0.94

0.86

2.82

2.99

3.91

3.94

4.54

4.69

7.23

7.25

7.31

7.33

7.71

7.73

7.75

8.49

N

O

33

N

O

N

34

S26

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.0

634

.95

42.5

7

49.8

652

.65

121.

3612

3.53

126.

4212

6.63

127.

2012

8.06

136.

04

148.

59

155.

98

169.

46

N-(2-methoxybenzyl)-N-methylbenzamide (39)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.05

3.07

2.00

1.96

0.94

1.13

4.87

2.86

3.76

4.54

6.96

6.97

6.99

7.01

7.18

7.26

7.26

7.28

7.29

7.30

7.42

N

O

N

34

N

O

MeO

39

S27

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.4

0

37.4

5

45.5

3

50.7

355

.18

55.4

5

110.

3912

0.68

120.

8012

4.81

127.

0012

7.80

128.

3912

8.75

129.

2712

9.59

136.

5613

6.76

157.

2715

7.84

171.

6817

2.68

N-methyl-N-phenethylbenzamide (40)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

5.00

2.18

6.83

3.31

2.86

3.54

7.19

7.21

7.22

7.26

7.28

7.38

7.39

7.40

7.41

7.42

7.43

N

O

MeO

39

N

O

40

S28

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.1

633

.57

34.9

038

.37

49.4

8

53.0

7

126.

5612

7.01

128.

4312

8.74

128.

8812

9.03

129.

3012

9.51

136.

7013

8.03

139.

17

171.

4217

2.25

N-methyl-N-(3-phenylpropyl)benzamide (41)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.18

3.93

3.16

2.00

9.95

1.85

1.87

1.89

2.50

2.92

3.32

3.35

7.14

7.16

7.18

7.23

7.25

7.33

7.34

7.35

7.37

7.39

7.40

7.40

7.41

7.42

N

O

40

N

O

41

S29

0102030405060708090100110120130140150160170180190200f1 (ppm)

28.7

829

.93

32.7

932

.93

33.3

637

.62

47.4

0

51.0

2

126.

1512

6.70

127.

0012

8.24

128.

5012

8.58

129.

4513

6.83

140.

9014

1.76

171.

5217

2.10

N-methyl-N-(pyridin-2-ylmethyl)benzamide (43)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

2.16

1.76

4.76

0.96

0.87

2.95

4.66

7.28

7.28

7.28

7.29

7.29

7.29

7.30

7.30

7.30

7.31

7.31

7.31

7.44

7.77

7.77

7.79

7.79

8.55

8.55

8.55

8.56

8.56

8.56

8.57

N

O

41

N

ON

43

S30

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.7

5

38.0

2

53.1

0

57.0

6

121.

0012

2.34

122.

5712

6.98

127.

1912

8.52

129.

7913

6.20

137.

02

149.

4014

9.95

156.

9115

7.32

171.

7417

2.66

N-methyl-N-(thiophen-2-ylmethyl)benzamide (44)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

2.05

1.00

0.84

5.91

2.49

2.50

2.50

2.50

2.51

2.90

4.74

6.99

7.00

7.00

7.01

7.04

7.40

7.40

7.41

7.42

7.42

7.43

7.43

7.44

7.44

7.44

7.45

7.45

7.45

7.46

7.46

7.47

N

ON

43

N

OS

44

S31

0102030405060708090100110120130140150160170180190200f1 (ppm)

32.9

2

36.9

6

45.8

8

50.6

2

125.

7312

6.11

127.

1412

8.55

136.

18

139.

76

174.

05

N-(furan-2-ylmethyl)-N-methylbenzamide (45)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

2.08

0.79

0.85

4.79

0.92

2.89

4.54

6.35

6.42

6.43

6.43

6.43

7.40

7.41

7.41

7.42

7.42

7.43

7.43

7.44

7.44

7.44

7.44

7.45

7.45

7.46

7.47

7.60

7.60

7.60

7.61

N

OS

44

N

OO

45

S32

0102030405060708090100110120130140150160170180190200f1 (ppm)

32.9

8

37.3

0

43.7

6

48.5

3

108.

5610

8.75

110.

49

127.

2212

8.53

129.

77

136.

21

142.

5214

2.80

150.

2715

0.90

171.

4617

2.22

N-(cyclohexylmethyl)-N-methylbenzamide (48)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.93

6.98

3.00

1.72

1.82

2.99

1.17

1.20

1.22

1.55

1.63

1.66

1.67

1.70

2.90

3.23

7.32

7.33

7.34

7.35

7.40

7.41

7.42

7.42

7.42

7.43

7.43

7.44

7.44

7.44

N

OO

45

N

O

48

S33

0102030405060708090100110120130140150160170180190200f1 (ppm)

25.9

025

.97

26.0

526

.38

26.5

426

.61

30.5

730

.91

31.0

633

.27

36.0

036

.46

38.1

938

.54

46.3

5

53.7

0

57.7

1

126.

9712

7.19

128.

4512

8.66

129.

2312

9.38

131.

4013

5.11

137.

0813

7.24

167.

6817

1.77

172.

50

N-(2,2-dimethoxyethyl)-N-methylbenzamide (49)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

6.32

1.80

1.01

2.03

2.99

2.96

3.30

3.44

4.56

7.36

7.36

7.37

7.37

7.37

7.38

7.43

7.43

7.44

N

O

48

N

OOMe

OMe

49

S34

0102030405060708090100110120130140150160170180190200f1 (ppm)

34.4

7

39.5

7

49.9

753

.15

54.8

2

103.

1010

3.50

127.

0712

8.48

129.

65

136.

53

171.

8117

2.60

N-benzyl-4-fluoro-N-methylbenzamide (50)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.18

2.12

4.78

2.09

2.00

2.87

4.60

7.22

7.23

7.24

7.24

7.25

7.26

7.27

7.29

7.31

7.35

7.37

7.39

7.39

7.49

7.50

7.51

7.51

7.52

7.53

N

OOMe

OMe

49

F

N

O

50

S35

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.5

9

37.2

0

51.0

9

55.3

7

115.

5311

5.75

126.

7412

7.77

128.

3512

8.97

129.

3713

2.37

136.

7013

7.02

162.

2616

4.74

170.

68

N-benzyl-N,6-dimethylnicotinamide (51)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.43

2.93

2.00

3.58

2.09

0.93

0.86

2.51

2.90

4.62

7.29

7.30

7.30

7.31

7.32

7.37

7.38

7.40

7.75

7.76

8.53

F

N

O

50

N

N

O

51

S36

0102030405060708090100110120130140150160170180190200f1 (ppm)

24.4

9

33.5

8

37.0

8

51.0

7

55.2

8

122.

9812

6.61

127.

8112

8.32

128.

8912

9.01

129.

1613

5.24

135.

4713

6.24

136.

72

147.

2714

7.55

160.

05

169.

3817

0.12

N-benzyl-N-methylpyrazine-2-carboxamide (52)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.58

1.27

0.85

1.05

4.62

0.84

0.86

0.81

2.93

2.96

4.60

4.73

7.26

7.30

7.33

7.34

7.37

8.64

8.67

8.71

8.73

8.85

8.89

N

N

O

51

N

NN

O

52

S37

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.7

636

.64

51.5

9

54.7

5

127.

5012

7.82

127.

9912

8.36

128.

9213

6.44

136.

5114

2.65

142.

6814

5.40

145.

6214

5.66

149.

8614

9.96

166.

7816

7.05

N-benzyl-N-methyl-1H-pyrrole-2-carboxamide (53)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

2.80

2.00

0.95

0.94

0.94

4.88

1.00

3.11

4.75

6.10

6.10

6.10

6.11

6.11

6.12

6.48

6.90

6.90

6.90

7.26

7.26

7.27

7.28

7.29

7.34

7.35

7.35

7.36

7.36

7.36

7.36

7.37

7.38

11.3

1

N

NN

O

52

N

O

NH

53

S38

0102030405060708090100110120130140150160170180190200f1 (ppm)

36.2

0

52.4

7

109.

7811

2.80

121.

4612

4.87

127.

5012

8.88

137.

26

163.

02

N-benzyl-N-methylthiophene-2-carboxamide (54)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.81

2.00

0.94

2.80

1.92

0.90

0.83

3.08

4.73

7.09

7.10

7.11

7.12

7.27

7.29

7.29

7.31

7.31

7.36

7.36

7.38

7.38

7.39

7.40

7.40

7.44

7.44

7.72

7.73

7.74

7.74

N

O

NH

53

N

O

S

54

S39

0102030405060708090100110120130140150160170180190200f1 (ppm)

35.7

1

53.5

4

126.

9212

7.69

128.

9612

9.23

136.

8813

7.94

164.

89

tert-butyl (2-(benzyl(methyl)amino)-2-oxoethyl)carbamate (55)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

10.7

6

3.00

1.10

0.86

1.64

1.89

4.82

1.39

2.78

2.83

2.90

3.67

3.69

3.84

3.85

4.52

7.22

7.24

7.26

7.30

7.31

7.33

N

O

S

54

N

OHN

Boc

55

S40

0102030405060708090100110120130140150160170180190200f1 (ppm)

27.9

4

33.3

9

41.6

3

50.1

851

.19

77.7

178

.00

126.

4212

6.73

126.

9912

7.25

128.

1012

8.40

137.

29

155.

42

168.

6917

0.48

N-benzyl-N-methyl-2-(2-oxopyrrolidin-1-yl)acetamide (56)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.00

1.99

2.96

2.02

2.02

2.02

4.74

1.95

1.97

1.99

2.19

2.23

2.25

2.27

2.82

2.90

2.92

3.39

3.41

3.42

4.12

4.51

4.57

5.71

7.22

7.24

7.27

7.28

7.32

7.34

7.36

N

OHN

Boc

55

N

ON

O

56

S41

0102030405060708090100110120130140150160170180190200f1 (ppm)

17.2

6

29.7

1

33.5

8

43.4

746

.95

50.1

251

.54

54.4

9

126.

3512

6.76

127.

2812

8.13

128.

40

167.

12

174.

01

N-methyl-N-(pyridin-3-ylmethyl)benzamide (57)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

2.04

0.93

4.69

0.87

1.78

2.89

4.64

7.37

7.39

7.39

7.41

7.44

7.70

8.50

8.50

8.51

8.52

N

ON

O

56

N

O

N

57

S42

0102030405060708090100110120130140150160170180190200f1 (ppm)

33.2

4

37.2

2

48.6

1

52.9

3

123.

8612

7.08

128.

6112

9.96

132.

8113

4.56

135.

8913

6.15

148.

7714

9.24

149.

64

171.

90

N-butyl-N-methylbenzamide (58)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.04

2.10

2.14

3.00

1.92

1.86

2.89

0.85

1.23

1.51

1.53

1.54

2.91

3.32

7.33

7.34

7.34

7.35

7.35

7.35

7.35

7.36

7.41

7.41

7.42

7.42

7.42

7.43

7.43

7.43

7.44

N

O

N57

N

O

58

S43

0102030405060708090100110120130140150160170180190200f1 (ppm)

13.7

414

.03

19.7

020

.23

29.2

330

.49

32.8

137

.56

47.3

4

51.1

8

126.

7712

6.97

128.

4612

9.36

137.

01

171.

3917

2.07

benzyl (R)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (59)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.49

1.00

2.24

2.07

0.87

0.89

10.4

3

1.37

1.39

1.40

1.42

4.26

4.28

4.29

4.36

4.38

4.40

4.41

4.43

4.45

4.46

5.01

5.05

5.08

5.42

6.55

7.22

7.24

7.26

7.26

7.27

7.27

7.28

7.29

7.30

7.31

7.31

7.32

7.32

7.33

7.34

7.35

7.35

7.36

7.37

N

O

58

NH

OCbzHN

59

S44

0102030405060708090100110120130140150160170180190200f1 (ppm)

18.8

2

43.6

5

50.7

5

67.1

8

127.

6812

7.77

128.

1912

8.38

128.

6912

8.85

136.

2113

8.00

156.

15

172.

28

benzyl (S)-(1-(benzylamino)-4-methyl-1-oxopentan-2-yl)carbamate (60)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.35

1.03

2.39

0.89

2.00

2.13

0.76

0.78

9.58

0.94

0.95

0.96

0.99

1.54

1.56

1.58

1.65

1.66

1.66

1.67

1.68

1.68

1.69

1.70

1.71

1.72

1.73

1.73

1.75

4.24

4.25

4.38

4.40

4.42

4.43

4.45

4.46

4.48

4.49

5.05

5.09

5.12

5.13

5.29

5.31

6.52

7.25

7.27

7.29

7.29

7.30

7.30

7.31

7.32

7.34

7.35

7.35

7.36

7.36

7.37

7.38

7.38

NH

OCbzHN

59

NH

O

NHCbz

60

S45

0102030405060708090100110120130140150160170180190200f1 (ppm)

22.1

123

.07

24.8

4

41.5

641

.91

43.6

6

53.7

6

67.2

3

127.

6612

7.79

128.

1712

8.37

128.

6812

8.85

136.

2313

8.02

156.

43

172.

22

benzyl (S)-(1-(benzylamino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (61)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

5.69

2.42

3.00

2.25

0.83

0.81

10.3

2

1.95

1.97

1.99

2.01

2.03

2.05

2.07

2.07

2.08

2.09

2.10

2.12

2.14

2.15

2.47

2.48

2.50

2.51

2.52

2.53

2.54

2.56

2.58

4.35

4.36

4.37

4.39

4.41

4.42

4.44

4.46

4.48

4.49

5.08

5.11

5.53

5.55

6.52

7.24

7.24

7.24

7.25

7.26

7.26

7.27

7.29

7.29

7.29

7.31

7.31

7.32

7.33

7.34

7.35

7.35

7.35

7.35

7.36

7.37

NH

O

NHCbz

60

NH

O

NHCbz

S

61

S46

-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

15.3

3

30.2

931

.71

43.7

7

54.0

5

67.3

1

127.

8012

7.86

128.

2512

8.42

128.

7212

8.93

137.

85

171.

02

(R)-N-benzyl-2-hydroxy-2-phenylacetamide (62)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.00

2.13

1.00

0.99

1.89

8.04

3.86

3.89

4.34

4.36

4.38

4.39

4.41

4.43

4.44

5.01

5.02

6.67

7.16

7.18

7.24

7.25

7.25

7.26

7.27

7.27

7.28

7.28

7.30

7.32

7.33

7.34

7.35

7.35

7.37

7.39

7.39

NH

O

NHCbz

S

61

NH

O

OH

62

S47

0102030405060708090100110120130140150160170180190200f1 (ppm)

43.5

3

74.3

0

126.

9312

7.70

128.

7512

8.83

128.

94

137.

8113

9.55

172.

32

(S)-N-benzyl-2-hydroxy-3-phenylpropanamide (63)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

0.74

1.15

1.11

3.15

1.00

1.96

8.10

2.70

2.91

2.93

2.95

2.97

3.23

3.24

3.26

3.27

4.33

4.34

4.35

4.36

4.37

4.40

4.41

4.44

4.45

4.47

4.49

6.82

7.18

7.20

7.23

7.24

7.25

7.25

7.26

7.27

7.27

7.28

7.29

7.30

7.30

7.31

7.31

7.32

7.32

7.33

7.33

7.34

NH

O

OH

62

NH

O

OH

63

S48

0102030405060708090100110120130140150160170180190200f1 (ppm)

41.0

143

.24

73.0

2

127.

1512

7.65

127.

8812

8.80

128.

8812

9.73

136.

8613

7.96

172.

60

(S)-N-benzyl-2-hydroxypropanamide (64)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.13

1.00

1.01

2.11

0.95

5.21

1.41

1.43

3.53

3.54

4.41

4.42

7.04

7.24

7.24

7.25

7.25

7.26

7.26

7.27

7.27

7.28

7.28

7.29

7.29

7.30

7.30

7.30

7.30

7.31

7.32

7.32

7.33

7.33

7.34

NH

O

OH

63

NH

O

OH

64

S49

0102030405060708090100110120130140150160170180190200f1 (ppm)

21.3

6

43.2

2

68.5

2

115.

68

127.

6812

7.78

128.

84

137.

98

174.

86

(R)-N-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxamide (65)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.31

3.33

1.09

1.13

2.10

1.04

1.00

3.16

2.03

1.38

1.44

4.13

4.14

4.15

4.17

4.29

4.31

4.32

4.34

4.47

4.48

4.52

4.53

4.54

4.55

6.89

7.26

7.26

7.27

7.28

7.28

7.30

7.30

7.32

7.32

7.33

7.33

7.34

7.34

7.34

7.35

7.36

7.36

7.36

NH

O

OH

64

NH

O

O O

65

S50

0102030405060708090100110120130140150160170180190200f1 (ppm)

25.1

226

.28

43.0

7

67.9

2

75.2

1

111.

06

127.

6812

7.73

128.

90

137.

91

171.

24

(S)-N-benzyl-2-(4-isobutylphenyl)propanamide (66)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.01

3.00

1.02

2.00

1.00

1.87

0.97

3.78

5.37

0.89

0.90

1.54

1.56

2.44

2.46

3.55

3.57

3.59

3.61

4.39

4.40

5.61

7.10

7.12

7.12

7.13

7.14

7.19

7.20

7.21

7.21

7.22

7.24

7.24

7.25

7.25

7.25

7.26

7.27

NH

O

O O65

HN

O

66

S51

0102030405060708090100110120130140150160170180190200f1 (ppm)

18.5

7

22.5

0

30.3

2

43.6

545

.13

46.9

6

127.

4612

7.52

128.

7412

9.83

138.

5013

8.59

140.

97

174.

48

N-methyl-3-phenylpropan-1-amine (67)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

2.07

3.14

1.97

2.00

2.84

1.91

1.65

1.66

1.68

1.69

1.71

2.44

2.45

2.47

2.57

2.59

2.60

7.14

7.16

7.18

7.19

7.25

7.27

7.28

HN

O

66

NH

67

S52

0102030405060708090100110120130140150160170180190200f1 (ppm)

30.9

932

.89

36.0

5

50.9

0

125.

5512

8.19

128.

22

142.

21

1-cyclohexyl-N-methylmethanamine (68)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.90

2.95

2.00

4.75

4.28

0.89

0.90

0.92

1.16

1.18

1.20

1.22

1.23

1.25

1.44

1.45

1.46

1.64

1.67

1.67

1.69

1.70

1.71

1.72

1.74

2.40

2.42

NH

67

NH

68

S53

0102030405060708090100110120130140150160170180190200f1 (ppm)

24.9

225

.00

25.5

325

.59

29.6

329

.77

33.1

534

.35

35.4

9

44.4

4

54.2

5Methyl ((benzyloxy)carbonyl)-D-alaninate (69)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.01

2.98

0.84

2.00

0.78

4.64

1.41

1.43

3.75

4.36

4.38

4.40

4.42

4.43

5.08

5.11

5.11

5.15

5.31

7.29

7.30

7.31

7.32

7.32

7.32

7.33

7.34

7.35

7.36

7.37

7.38

7.39

NH

68

O

OCbzHN

69

S54

0102030405060708090100110120130140150160170180190200f1 (ppm)

18.7

6

49.7

052

.53

67.0

2

128.

2112

8.27

128.

63

136.

40

155.

71

173.

57

Methyl ((benzyloxy)carbonyl)-L-leucinate (70)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.00

1.04

2.01

2.82

0.88

2.87

4.90

0.93

0.94

0.96

1.49

1.50

1.51

1.52

1.53

1.54

1.55

1.61

1.62

1.63

1.65

1.66

1.67

1.69

1.70

1.71

1.74

3.74

4.38

4.40

4.41

4.42

5.11

5.14

7.30

7.31

7.32

7.33

7.35

7.36

O

OCbzHN

69

O

ONHCbz

70

S55

0102030405060708090100110120130140150160170180190200f1 (ppm)

21.9

822

.95

24.8

7

41.9

7

52.4

352

.60

67.1

4

128.

2512

8.33

128.

67

136.

38

156.

10

173.

76

ethyl ((benzyloxy)carbonyl)-L-methioninate (71)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.00

1.07

3.92

2.04

1.98

0.97

2.06

0.81

4.62

1.26

1.28

1.30

1.96

1.97

1.99

2.09

2.14

2.15

2.17

2.47

2.49

2.51

2.53

2.54

2.55

2.56

2.58

4.18

4.20

4.22

4.23

4.45

4.47

4.48

4.50

5.11

5.42

7.29

7.30

7.31

7.33

7.34

7.35

7.36

O

ONHCbz

70

O

OS

NHCbz

71

S56

-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

14.2

715

.60

29.9

732

.24

53.3

5

61.8

1

67.1

9

128.

2712

8.36

128.

68

136.

31

156.

00

172.

06

Methyl (R)-2-hydroxy-2-phenylacetate (72)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

0.92

3.00

0.95

4.80

3.43

3.44

3.48

3.49

3.76

3.76

5.18

5.19

7.31

7.31

7.32

7.32

7.33

7.34

7.34

7.35

7.35

7.37

7.37

7.38

7.39

7.39

7.40

7.41

7.41

7.41

7.42

7.43

7.43

O

OS

NHCbz

71

O

O

OH

72

S57

0102030405060708090100110120130140150160170180190200f1 (ppm)

53.1

9

73.0

2

126.

7412

8.67

128.

77

138.

37

174.

28

Methyl (S)-2-(4-isobutylphenyl)propanoate (73).

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

6.30

3.15

1.02

2.09

3.00

1.06

2.01

2.00

O

O

OH

72

O

O

73

S58

0102030405060708090100110120130140150160170180190200f1 (ppm)

18.7

6

22.5

3

30.3

1

45.1

7

52.1

2

127.

2712

9.49

137.

8914

0.70

175.

38

O

O

73

S59

5. Chiral HPLC Spectra

benzyl (R)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (59).

NH

OCbzHN

59

NH

OCbzHN

S60

benzyl (S)-(1-(benzylamino)-4-methyl-1-oxopentan-2-yl)carbamate (60).

NH

O

NHCbz

60

NH

O

NHCbz

S61

benzyl (S)-(1-(benzylamino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (61).

NH

O

NHCbz

S

61

NH

O

NHCbz

S

S62

(R)-N-benzyl-2-hydroxy-2-phenylacetamide (62).

NH

O

OH

62

NH

O

OH

S63

(S)-N-benzyl-2-hydroxy-3-phenylpropanamide (63).

NH

O

OH

63

NH

O

OH

S64

(S)-N-benzyl-2-hydroxypropanamide (64).

NH

O

OH

64

NH

O

OH

S65

(R)-N-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxamide (65).

NH

O

O O

65

NH

O

O O

S66

(S)-N-benzyl-2-(4-isobutylphenyl)propanamide (66).

HN

O

66

HN

O

S67

Methyl ((benzyloxy)carbonyl)-D-alaninate (69).

O

OCbzHN

69

O

OCbzHN

S68

Methyl ((benzyloxy)carbonyl)-L-leucinate (70).

O

ONHCbz

70

O

ONHCbz

S69

ethyl ((benzyloxy)carbonyl)-L-methioninate (71).

O

OS

NHCbz

71

O

OS

NHCbz

S70

Methyl (R)-2-hydroxy-2-phenylacetate (72).

O

O

OH

72

O

O

OH

S71

6. References

1. W. L. F. Armarego and C. L. L. Chai, Purification of Laboratory Chemicals, 6th Ed., Elsevier Inc., Oxford, UK, 2009.

2. A. E. Strom, J. F. Hartwig, J. Org. Chem., 2013, 78, 89093. S. Hanada, T. Ishida, Y. Motoyama, H. Nagashima, J. Org. Chem., 2007, 72, 75514. A. Dumoulin, C. Lalli, P. Retailleau, G. Masson, Chem. Commun., 2015, 51, 53835. P. Kokkala, A. Mpakali, F.-X. Mauvais, A. Papakyriakou, I. Daskalaki, I. Petropoulou, S.

Kavvalou, M. Papathanasopoulou, S. Agrotis, T.-M. Fonsou, P. van Endert, E. Stratikos, D. Georgiadis, J. Med. Chem., 2016, 59, 9107

6. D. Riemer, P. Hirapara, S. Das, ChemSusChem, 2016, 9, 19167. E. Richmond, K. B. Ling, N. Duguet, L. B. Manton, N. Celebi-Olcum, Y.-H. Lam, S. Alsancak, A.

M. Z. Slawin, K. N. Houk, A. D. Smith, Org. Biomol. Chem., 2015, 13, 18078. R. Samanta, J. O. Bauer, C. Strohmann, A. P. Antonchick, Org. Lett., 2012, 14, 5518