Supporting information

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1 Supporting information Taking control of P1, P1 and double bond stereochemistry in the synthesis of Phe-Phe (E)-alkene amide isostere dipeptidomimetics Daniel Wiktelius and Kristina Luthman* Department of Chemistry, Medicinal Chemistry, Göteborg University, SE Göteborg, Sweden Experimental procedures and spectral data for all new compounds, including copies of 1 H and 13 C NMR spectra for 3, 4, 5, 8a-b, 9a-b, 10a-b. Contents General: 2 Experimental procedures: 3 11 NMR spectra: Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S1 (20)

2 General. Melting points were recorded with a Büchi B-545 apparatus and are uncorrected. ptical rotations were measured on a Perkin Elmer 341 LC digital polarimeter with a sodium lamp (D-line, wavelength 589 nm). 1 H, 13 C, 19 F and 31 P NMR spectra were recorded on a JEL Eclipse 400 FT NMR spectrometer at 400, 100, 376 and 162 MHz, respectively, in CDCl 3, CD 3 D or DMS-d 6. Chemical shifts are reported in ppm with the following references: 1 H residual CHCl 3 (δ H 7.26), CD 2 HD (δ H 3.31), or DMS-d 5 (δ H 2.50); 13 C CDCl 3 (δ C 77.0), CD 3 D (δ C 49.15), or DMS-d 6 (δ C 39.51); 19 F PhF (δ F 113.1, approx 5µL was added to the sample); 31 P 85% H 3 P 4 (external reference, δ P 0). Coupling constants (J) are given in Hz. 2D CSY, HMQC, HSQC and HMBC NMR spectroscopy was used to validate structural assignments of the signals, if resolution did not permit, no assignment is stated. Analytical thin layer chromatography was performed on aluminium sheets precoated with MERCK silica gel; grade 60 F 254 and the spots were visualized by UV light (254 nm) and treatment with 5% phosphomolybdic acid in ethanol and heating. Flash chromatography was performed on Geduran silica SI-60 ( mm). Reversed phase analytical high performance liquid chromatography (HPLC) was performed on a Waters system (600E system controller, 717 autosampler, 996 photodiode array detector) fitted with a mm Genesis C8 4 µm column, flow was 2 ml/min. Preparative HPLC was performed on a Waters system (600E system controller, 441 detector at 254 nm) fitted with a mm Kromasil 100 C8 10 µm column, flow was 25 ml/min. In both cases a 0.1 M NH 4 Ac or 0.1% TFA buffer / acetonitrile gradient was used for elution. IR spectra were recorded on a Perkin-Elmer 16PC FT-IR and only the major peaks are listed. Elemental analyses were conducted by H. Kolbe Mikroanalytisches Laboratorium, Mülheim an der Ruhr, Germany or MikroKemi AB, Uppsala, Sweden. HRMS was performed by Einar Nilsson, Dept of Chemistry, Lund University, Lund, Sweden. THF and Et 2 were dried and stored over 3Å molecular sieves that had been thoroughly washed with H 2 and acetone and activated at 300 C in high vacuum for 8 h. Butyllithium was titrated with diphenyl acetic acid as indicator. Compounds (S)- and (R)-6 were synthesized as described previously. 1 All other solvents and reagents were used as received. 1 D. Wiktelius, E. K. Larsson and K. Luthman, Tetrahedron: Asymmetry 2006, 17, Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S2 (20)

3 2' 3' F 3 C Bn N H 1 2 H 3 N-Trifluoroacetyl-(S)-phenylalaninol (3). Trifluoroacetic anhydride (1.3 ml, 9.3 mmol) was added dropwise to a solution of (S)- phenylalaninol (1.00 g, 6.61 mmol) and Et 3 N (3.0 ml, 23 mmol) in DCM (40 ml) under a N 2 atmosphere and the mixture was stirred at rt for 7 h. The solvent volume was reduced to ~10 ml by rotary evaporation and EtAc (50 ml) was added. The mixture was washed with sat aq NaHC 3 (50 ml), aq 1 M HCl (50 ml) and brine (50 ml) in sequence. Drying (MgS 4 ), filtration and concentration in vacuo afforded the title compound (1.52 g, 93%) in high purity as white crystals. Mp: C; [α] 20 D 0.5 (c = 0.92, MeH); (Found: C, 53.4; H, 4.9; N C 11 H 12 F 3 N 2 requires C, 53.4; H, 4.5; N 5.7%); ν max (KBr)/cm , 1698, 1558, 1495, 1455, 1226, and 1178; δ Η (CD 3 D) 2.74 (1H, ddd, J 13.8, 9.1 and 1.6, Bn a ), 2.95 (1H, ddd, J 13.8, 5.9 and 1.6, Bn b ), 3.56 (1H, ddd, J 11.2, 6.5 and 2.0, H-2 a ), 3.62 (1H, ddd, J 11.2, 5.1 and 2.0, H-2 b ), (1H, m, H-1) and (5H, m, Ph); δ C (CD 3 D) 37.5 (Bn), 55.3 (C-1), 63.8 (C-2), (q, J CF 287, ), (C-4 ), (2C, Ph), (2C, Ph), (C-1 ) and (q, J 6.9, C=); δ F (CD 3 D) ' 3' F 3 C Bn N H 1 2 Br 4 N-((S)-1-Benzyl-2-bromoethyl))-trifluoroacetamide (4). Triphenylphosphine (0.56 g, 2.12 mmol) and alcohol 3 (0.50 g, 2.02 mmol) were dissolved in MeCN (5 ml) under a N 2 atmosphere and cooled in an ice bath. CBr 4 (0.70 g, 2.12 mmol) was dissolved in MeCN (2 ml) and the solution was added dropwise. The reaction was allowed to warm to rt as the ice melted and was stirred for 48 h. The mixture was then diluted with DCM (50 ml), H 2 (25 ml) was added, and the phases were separated. The aqueous layer was extracted with DCM (50 ml) and the combined organic phases were washed with brine (25 ml), followed by drying (MgS 4 ), filtration and concentration. Purification by gradient flash chromatography (EtAc:hexanes 1:30-1:15) gave the title compound as a white solid (0.53 g, 85%). Mp: C; [α] 20 D +8.8 (c = 1.0, CHCl 3 ); (Found: C, 42.6; H, 3.9; N 4.5. C 11 H 11 BrF 3 N requires C, 42.6; H, 3.6; N, 4.5%); ν max (KBr)/cm , 1702, 1562, Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S3 (20)

4 1376, 1228 and 1165; δ Η (CDCl 3 ) (2H, m, Bn), 3.41 (1H, dd, J 11.0 and 3.7, H-2 a ), 3.56 (1H, dd, J 11.0 and 4.0, H-2 b ), (1H, m, H-1), 6.48 (1H, d, J 5.7, NH) and (5H, m, Ph); δ C (CDCl 3 ) 35.0 (C-2), 38.1 (Bn), 51.0 (C-1), (q, J CF 288, ), (C-4 ), (2C, Ph), (2C, Ph), (C-1 ) and (q, J 6.9, C=); δ F (CDCl 3 ) '' 3'' ' F 3 C 3 N H 2 + Br PPh ' 3' ((S)-3-Phenyl-2-trifluoroacetamido-propyl)-triphenyl phosphonium bromide (5). Bromide 4 (3.87 g, 12.5 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) were dissolved in toluene (40 ml) and the mixture was heated to reflux and stirred for 18 h. The reaction was allowed to cool with the formation of a white precipitate. The solvent volume was reduced by rotary evaporation to approx 10 ml, and Et 2 (50 ml) was added. The excess triphenylphosphine was removed by sonicating the suspension, allowing the particles to settle, and siphoning off the solvent supernatant (the procedure was repeated with 4 50 ml Et 2 ). The white powder was then dried in vacuo over night to give pure 5 (7.26 g, >99%). Mp: C; [α] 20 D +4.3 (c = 1.3, MeH); (Found: C, 60.7; H, 4.5: N, 2.4. C 29 H 26 F 3 NP Br requires C, 60.85; H, 4.6; N, 2.45%; ν max (KBr)/cm , 3042, 1716, 1556, 1440, 1200 and 1157; δ H (DMS-d 6 ) (2H, m, H-3), (1H, m, H-1 a ), (1H, m, H- 1 b ), (1H, m, H-2), (5H, m), (15H, m) and 9.44 (1H, d, J 8.8, NH); δ C (DMS-d 6 ) 25.5 (d, J CP 50.7, C-1), 41.5 (d, J CP 13.8, C-3), 46.4 (d, J CP 4.6, C-2), (q, J CF 289, ), (3C, d, J CP 86.1, C-1 ), (C-4 ), (2C, Ph ), (2C, Ph ), (6C, d, J CP 12.3, Ph ), (6C, d, J CP 10.4, Ph ), (3C, d, J CP 2.7, C- 4 ), (d, J CP 1.9, C-1 ) and (q, J 6.6, C=); δ F (DMS-d 6 ) 74.7; δ P (DMSd 6 ) Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S4 (20)

5 1-Bn CNH Bn H 8a N-((E)-(1S,4R)-1,4-Dibenzyl-5-hydroxy-pent-2-enyl)trifluoroacetamide (8a). Phosphonium salt 5 (1.54 g, 2.69 mmol) was suspended in THF under a N 2 atmosphere and sonicated for 30 min; however, a fully clear solution could not be obtained. The milky suspension was stirred and cooled to 78 C in a C 2(S) / acetone bath. n-butyllithium (1.85 M in hexane, 2.9 ml, 5.4 mmol) was added dropwise to give an orange solution, which upon warming briefly by removing the cooling bath for 10 min turned deep violet. The reaction was again cooled to 78 C and stirred for 30 min. Aldehyde (S)-6 (0.75 g, 2.69 mmol, 84% ee) was dissolved in THF (9 ml) and added dropwise, yielding an orange solution. The excess C 2(S) was removed from the cooling bath and replaced with a magnetic stirrer bar, and the temperature was allowed to increase to 0 C over 1.5 h. Et 2 (20 ml) was added, followed by a 10:1 mixture of sat aq NH 4 Cl and aq 1 M HCl (20 ml) and the layers were separated. The aqueous phase was extracted with Et 2 (2 20 ml) and the combined organic phases were washed with brine (20 ml), dried (MgS 4 ), filtered and concentrated to give a crude oil. Purification by gradient flash chromatography (EtAc:hexanes 1:75-1:20) gave N-((E)- (1S,4R)-1,4-dibenzyl-5-((tert-butyl(dimethyl)silyl)oxy)-pent-2-enyl)-trifluoroacetamide (7a) with some minor impurities (including the diastereomer 7b) as a viscous transparent oil (0.73 g, 55% combined yield) and the product was used as such in the next step. No epimerization or Z-isomer could be detected by NMR (see also 10a below). ν max (neat)/cm , 3087, 3063, 3028, 2359, 1698, 1556, 1496, 1360, 1257, 1185 and 1102; δ H (CDCl 3 ) 0.02 (3H, s, Si-CH a 3 ), 0.03 (3H, s, Si-CH b 3 ), 0.89 (9H, s, t Bu), (2H, m, H-4 and 4-Bn- H a ), (3H, m, 1-Bn and 4-Bn-H b ), (2H, m, H-5), (1H, m, H-1), 5.21 (1H, dd, J 15.5 and 7.0, H-2), 5.48 (1H, dd, J 15.5 and 7.7, H-3), 5.94 (1H, d, J 8.1, NH) and (10H, m, Ph); δ C (CDCl 3 ) 5.44 (Si-CH a 3 ), 5.39 (Si-CH b 3 ), 18.3 (Si-C), 25.9 (3C, t Bu), 37.4 (4-Bn), 40.8 (1-Bn), 50.0 (C-4), 52.7 (C-1), 65.3 (C-5), (q, J CF 288, ), (Ph), (Ph), (2C, Ph), (C-2), (2C, Ph), (2C, Ph), (2C, Ph), (C-3), (Ph), (Ph) and (q, J 6.9, C=); δ F (CDCl 3 ) Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S5 (20)

6 Silyl ether 7a (0.69 g, 1.4 mmol) was dissolved in THF (4 ml) and TBAF (1 M in THF, 5.6 ml, 5.6 mmol) was added and the mixture was stirred for 48 h. The mixture was diluted with EtAc (40 ml) and H 2 (30 ml) and the phases were separated. The aqueous layer was extracted with EtAc (30 ml) and the combined organic phases were washed with brine (20 ml). Drying (MgS 4 ), filtration and concentration afforded a crude oil. Purification by gradient flash chromatography (EtAc:hexanes 4:25-8:25 with 3% MeH throughout) afforded the title compound (0.44 g, 83%) along with the contaminating diastereomer 8b as a white solid. Mp: C; [α] 20 D 71 (c = 0.82, CHCl 3 ); (Found: C, 66.4; H, 6.0; N, 3.6. C 21 H 22 F 3 N 2 requires C, 66.8; H, 5.9; N, 3.7%); ν max (KBr)/cm , 3064, 3028, 2926, 1700, 1558, 1496, 1454, 1185 and 1162; δ H (CDCl 3 ) 1.52 (1H, br s, H), (2H, m, H-4 and 4-Bn-H a ), 2.70 (1H, dd, J 12.8 and 5.5, 4-Bn-H b ), 2.76 (1H, dd, J 13.6 and 8.1, 1-Bn- H a ), 2.93 (1H, dd, J 13.6 and 6.2, 1-Bn-H b ), 3.36 (1H, dd, J 10.7 and 7.3, H-5 a ), 3.52 (1H, dd, J = 10.7 and 4.6, H-5 b ), (1H, m, H-1), 5.29 (1H, dd, J 15.6 and 7.0, H-2), 5.38 (1H, dd, J 15.6 and 7.7, H-3), 6.33 (1H, d, J 7.7, NH) and (10H, m, Ph); δ C (CDCl 3 ) 37.3 (4-Bn), 40.6 (1-Bn), 47.2 (C-4), 53.2 (C-1), 65.0 (C-5), (q, J CF 288, ), (Ph), (Ph), (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-3), (C-2), (Ph), (Ph) and (q, J 6.6, C=); δ F (CDCl 3 ) Bn CNH Bn H 8b N-((E)-(1S,4S)-1,4-Dibenzyl-5-hydroxy-pent-2-enyl)trifluoroacetamide (8b). The procedure described above for 8a was used also to prepare 8b. Reacting phosphonium salt 5 (0.33 g, 0.57 mmol) with aldehyde (R)-6 (0.16 g, 0.57 mmol, 82% ee) furnished N-((E)- (1S,4S)-1,4-dibenzyl-5-((tert-butyl(dimethyl)silyl)oxy)-pent-2-enyl)-trifluoroacetamide (7b) with some minor impurities (including the diastereomer 7a) as a viscous transparent oil (0.16 g, 57% combined yield) and the product was used as such in the next step. No epimerization or Z-isomer could be detected by NMR (see also 10b below). ν max (neat)/cm , 3027, 2953, 2928, 2856, 1698, 1552, 1252, 1205, 1183, 1165 and 1102; δ H (CDCl 3 ) 0.02 (6H, s, Si-CH 3 ), 0.89 (9H, s, t Bu), (2H, m, H-4 and 4-Bn-H a ), 2.74 (1H, dd, J 13.6 and 5.8, 1-BnH a ), (2H, m, 1-Bn b and 4-Bn-H b ), 3.49 (2H, d, J 5.5, H-5), (1H, m, H-1), 5.27 (1H, dd, J 15.6 and 7.0, 1H, H-2), 5.49 (1H, dd, J 15.6 and 8.1, H-3), 5.94 Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S6 (20)

7 (1H, d, J 7.7, NH) and (10H, m, Ph); δ C (CDCl 3 ) 5.44 (Si-CH a 3 ), 5.40 (Si-CH b 3 ), 18.2 (Si-C), 25.9 (3C, t Bu), 37.4 (4-Bn), 40.6 (1-Bn), 46.9 (C-4), 52.4 (C-1), 65.2 (C-5), (q, J CF = 288, ), (Ph), (Ph), (2C, Ph), (3C, C-2 and Ph), (2C, Ph), (2C, Ph), (C-3), (Ph), (Ph) and (q, J 6.9, C=); δ F (CDCl 3 ) The silyl ether 7b was treated with TBAF and the reaction was worked up and the product purified as described for 8a to give alcohol the title compound in >99% yield with some minor impurities including the contaminating diastereomer 8a as a white solid. A small analytical sample was prepared by preparative HPLC (diastereomers 8b and 8a were not separated). Mp: C; [α] 20 D 16 (c = 0.90, CHCl 3 ); (Found: C, 67.05; H, 5.8; N, 3.6. C 21 H 22 F 3 N 2 requires C, 66.8; H, 5.9; N 3.7%); ν max (KBr)/cm , 3028, 2360, 2343, 1704, 1559, 1496, 1454, 1209, 1185, 1162 and 1030; δ H (CDCl 3 ) 1.91 (1H, br s, H), (2H, m, H-4 and 4-Bn-H a ), 2.70 (1H, dd, J 13.2 and 6.2, 4-Bn-H b ), 2.79 (1H, dd, J 13.5 and 6.2, 1-Bn-H a ), 2.85 (1H, dd, J 13.5 and 6.6, 1-Bn-H b ), 3.41 (1H, dd, J 10.6 and 7.3, H-5 a ), 3.54 (1H, dd, J 10.6 and 4.4, H-5 b ), (1H, m, H-1), 5.33 (1H, dd, J 15.5 and 7.0, H- 2), 5.44 (1H, dd, J 15.5 and 7.7, H-3), 6.48 (1H, d, J 7.7, NH) and (10H, m, Ph); δ C (CDCl 3 ) 37.3 (4-Bn), 40.5 (1-Bn), 46.9 (C-4), 52.7 (C-1), 64.8 (C-5), (q, J CF 286, ), (Ph), (Ph), (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-3), (C-2), (Ph), (Ph) and (q, J 6.7, C=); δ F (CDCl 3 ) '' 3'' ' 6 CNH 5 2 9a 1 H Bn 3' 2' (E)-(2R,5S)-2-Benzyl-6-phenyl-5-(trifluoroacetamido)-hex-3-enoic acid (9a). To a stirred solution of Dess-Martin periodinane in DCM (0.15 % wt, 0.75 g solution, 2.7 mmol) at 0 C was added alcohol 8a (67 mg, 0.18 mmol) in MeCN (1 ml). The reaction was allowed to reach rt, and was stirred for 4 h. The solvent volume was reduced to ~1 ml by rotary evaporation, and Et 2 (10 ml), and sat aq Na 2 S 2 3 (3 ml) were added. The resulting emulsion was stirred vigorously for 15 min, after which the mixture was diluted with H 2 (3 ml) and the phases were separated. The aqueous layer was extracted with Et 2 (2 10 ml) Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S7 (20)

8 and the combined organic phases were washed with sat aq NaHC 3 (10 ml) and brine (10 ml), dried (MgS 4 ), filtered and concentrated in vacuo to give N-((E)-(1S,4R)-1,4-dibenzyl- 5-oxo-pent-2-enyl)-trifluoroacetamide as a crude brown oil (68 mg) which was used as such in the next step. ν max (neat)/cm , 3029, 2926, 1704, 1558, 1496, 1455 and 1183; δ H (CDCl 3 ) 2.70 (1H, dd, J 13.9 and 8.4, 4-Bn-H a ), 2.83 (1H, dd, J 13.8 and 7.3, 1-Bn-H a ), 2.89 (1H, dd, J 13.8 and 6.6, 1-Bn-H b ), 3.10 (1H, dd, J 13.9 and 6.2, 4-Bn-H b ), (1H, m, H-4), (1H, m, H-1), 5.40 (1H, dd, J 15.4 and 6.6, H-2), 5.52 (1H, dd, J 15.4 and 8.1, H-3), 6.23 (1H, d, J 8.1, N-H), (10H, m, Ph) and 9.54 (1H, d, J 1.5, H-5); δ C (CDCl 3 ) 35.0 (1-Bn), 40.5 (4-Bn), 52.7 (C-1), 57.0 (C-4), (q, J CF 288, ), (Ph), (Ph), (C-3), (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-2), (Ph), (Ph), (q, J 7.2, C=) and (C-5). The crude aldehyde was dissolved in THF (4.5 ml) and cooled to 0 C and amylene (0.19 ml, 1.8 mmol) was added. NaH 2 P 4 2H 2 (55 mg, 0.36 mmol) and NaCl 2 (80% pure, 60 mg, 0.53 mmol) were dissolved in H 2 (2.3 ml) and the aqueous solution was added dropwise to the reaction mixture, which subsequently was allowed to reach rt and stirring was continued for 2 h. The reaction was quenched by addition of a 1:1 mixture of brine and 1 M HCl (10 ml), followed by EtAc (10 ml) and after stirring for 5 min, the phases were separated. The aqueous layer was extracted with EtAc (2 10 ml) and the combined organic phases were washed with a 1:1 mixture of brine and 1 M HCl (10 ml), dried (MgS 4 ), filtered and concentrated in vacuo to give a crude oil. Purification by gradient flash chromatography (EtAc:hexanes 1:5-1:4 with 1% AcH throughout) gave the title compound along with the contaminating diastereomer 9b as a white solid (31 mg, 44% over two steps). Mp: C; [α] 20 D 61 (c = 0.84, MeH); (Found: C, 64.3; H, 5.1; N, 3.5. C 21 H 20 F 3 N 3 requires C, 64.45; H, 5.15; N, 3.6%); ν max (KBr)/cm , 3088, 3031, 1694, 1555, 1243 and 1179; δ H (CD 3 D) (3H, m, 2-Bn-H a and H-6), 3.03 (1H, dd, J 13.6 and 7.0, 2-Bn-H b ), (1H, m, H-2), (1H, m, H-5), 5.46 (1H, dd, J 15.7 and 7.0, H-4), 5.62 (1H, dd, J 15.7 and 8.3, H-3), (10H, m, Ph) and 9.23 (1H, d, J 8.4, NH); δ C (CD 3 D) 39.7 (2-Bn), 41.5 (C-6), 52.4 (C-2), 55.0 (C-5), (q, J CF 285, ), (Ph), (Ph), (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-3), (C- 4), (C-1 ), (C-1 ), (q, J 6.7, C ) and (CH) peak broadening in the spectra was interpreted as conformer interconversion; δ F (CD 3 D) Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S8 (20)

9 2'' 3'' ' CNH b 1 H Bn 3' 2' (E)-(2S,5S)-2-Benzyl-6-phenyl-5-((trifluoroacetyl)amino)hex-3-enoic acid (9b). Alcohol 8b (100 mg, 0.26 mmol) was oxidized by treatment with Dess-Martin periodinane and the reaction was worked up as described above for 8a to furnish N-((E)-(1S,4S)-1,4- dibenzyl-5-oxo-pent-2-enyl)-trifluoroacetamide as a crude brown oil (110 mg) which was used as such in the next step. ν max (neat)/cm , 3028, 1715, 1662, 1552, 1496, 1454, 1208, 1182 and 1163; δ H (CDCl 3 ) 2.76 (1H, dd, J 13.9, 8.1, 4-Bn-H a ), (2H, m, 1- Bn), 3.10 (1H, dd, J 13.9 and 6.2, 4-Bn-H b ), (1H, m, H-4), (1H, m, H-1), (2H, m, H-2 and H-3), 6.55 (1H, d, J 8.0, N-H), (10H, m, Ph) and 9.57 (1H, d, J 1.8, H-5); δ C (CDCl 3 ) 35.3 (1-Bn), 40.6 (4-Bn), 52.6 (C-1), 56.9 (C-4), (q, J CF 286, ), (Ph), 127.1, 127.2, 127.4, (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), 132.9, (Ph), (Ph), (q, J 6.7, C=), (C-5). The crude aldehyde was oxidized and the product purified as described above for 9a to afford acid 9b along with some minor impurities, including the contaminating diastereomer 9a as a white solid (45 mg, 48% over two steps). A small analytical sample was prepared by preparative HPLC (diastereomers 9b and 9a were not separated). Mp: ; [α] 20 D +4.2 (c = 0.70, MeH); (Found: C, 64.3; H, 5.1; N, 3.4. C 21 H 20 F 3 N 3 requires C, 64.45; H, 5.15; N, 3.6%); ν max (KBr)/cm , 2423, 2360, 1704, 1698, 1454, 1235 and 1164; δ H (CD 3 D) (3H, m, 2-Bn-H a, H-6), 3.00 (1H, dd, J 13.6 and 7.7, 2-Bn-H b ), (1H, m, H-2), (1H, m, H-5), 5.54 (1H, dd, J 15.4 and 6.6, H-4), 5.64 (1H, dd, J 15.4 and 8.4, H-3), (10H, m, Ph) and 9.27 (1H, d, J 8.4, NH); δ C (CD 3 D) 39.8 (2-Bn), 41.6 (C-6), 52.2 (C-2), 54.8 (C-5), (q, J CF 285, ), (Ph), (Ph), (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-3), (C-4), (C-1 ), (C- 1 ), (q, J 6.7, C ) and (CH) peak broadening or splitting in the spectra was interpreted as conformer interconversion; δ F (CD 3 D) 74.9 peak splitting in the spectra was interpreted as conformer interconversion. Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S9 (20)

10 3' 2' _ C a H 3 N 2 4 H 6 3'' 2'' (E)-(2S,5R)-5-Carboxy-1,6-diphenylhex-3-en-2-ammonium trifluoroacetate (10a). Acid 9a (32 mg, mmol) was dissolved in MeH (15 ml) and NH 3 was bubbled gently into the stirred solution for 72 h. The solvent and excess NH 3 were removed by rotary evaporation to give a white semi-solid residue. The ratio of the diastereomers 10a and 10b was found to be 92:8 by HPLC (10-50% MeCN in 0.1% TFA/H 2 gradient), to be compared with the ee of 84% for the starting aldehyde (S)-6. The product was purified by preparative HPLC to yield pure 10a as a glassy highly viscous semi-solid after lyophilization (25 mg, 75% (some losses can be attributed to the separation of the diastereomers and reaction monitoring)). [α] D (c = 0.83, MeH); δ H (CD 3 D) 2.74 (1H, dd, J 13.9 and 7.7, H-6 a ), 2.83 (1H, dd, J 13.2 and 8.8, H-1 a ), (2H, m, H-1 b and H-6 b ), (1H, m, H- 5), (1H, m, H-2), 5.54 (1H, dd, J 15.8 and 7.0, H-4), 5.71 (1H, dd, J 15.8 and 7.7, H-3) and (10H, m, Ph); δ C (CD 3 D) 39.3 (C-6), 40.8 (C-1), 52.0 (C-5), 55.7 (C-2), (Ph), 128.5, 128.9, (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-4), (Ph), (Ph) and (CH); HRMS (ES+) Found: , C 19 H 22 N 2 (MH+) requires ' 2' _ C b H 3 N 2 4 H 6 3'' 2'' (E)-(2S,5S)-5-Carboxy-1,6-diphenylhex-3-en-2-ammonium trifluoroacetate (10b). Acid 9b (40 mg, 0.10 mmol) was treated with NH 3 in MeH as described for 10a to give a crude white semi-solid residue after evaporation. The ratio of the diastereomers 10b and 10a was determined by HPLC as described for 10a to be 90:10, to be compared with the ee of 82% for the starting aldehyde (R)-6. Preparative HPLC afforded pure 10b as a glassy highly viscous semi-solid after lyophilization (36 mg, 86% (some losses can be attributed to the Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S10 (20)

11 separation of the diastereomers and reaction monitoring)). [α] 20 D +38 (c = 1.2, MeH); δ H (CD 3 D) 2.73 (1H, dd, J 13.9 and 7.0, H-6 a ), 2.83 (1H, dd, J 13.6 and 8.4, H-1 a ), (2H, m, H-1 b and H-6 b ), (1H, m, H-5), (1H, m, H-2), 5.51 (1H, dd, J 15.4 and 8.4, H-4), 5.74 (1H, dd, J 15.4 and 8.8, H-3) and (10H, m, Ph); δ C (CD 3 D) 39.6 (C-6), 40.8 (C-1), 52.0 (C-5), 55.9 (C-2), (Ph), 128.5, 129.1, (2C, Ph), (2C, Ph), (2C, Ph), (2C, Ph), (C-4), (C-1 ), (C-1 ) and (CH); HRMS (ES+) Found: , C 19 H 22 N 2 (MH+) requires Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S11 (20)

12 2' 3' 3 1 H NMR (top) 13 C NMR (bottom) F 3 C Bn N H 1 2 H 3 Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S12 (20)

13 2' 3' 4 1 H NMR (top) 13 C NMR (bottom) F 3 C Bn N H 1 2 Br 4 Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S13 (20)

14 2'' 3'' ' 5 1 H NMR (top) 13 C NMR (bottom) F 3 C 3 N H 2 + Br PPh ' 3' Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S14 (20)

15 1-Bn CNH H 4-Bn 8a 8a 1 H NMR (top) 13 C NMR (bottom) Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S15 (20)

16 1-Bn CNH H 4-Bn 8b 8b 1 H NMR (top) 13 C NMR (bottom) Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S16 (20)

17 2'' 3'' ' 6 CNH 5 2 9a 1 H Bn 9a 1 H NMR (top) 13 C NMR (bottom) 3' 2' Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S17 (20)

18 2'' 3'' ' CNH b 1 H Bn 9b 1 H NMR (top) 13 C NMR (bottom) 3' 2' Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S18 (20)

19 3' 2' 1 _ a C H 3 N 2 4 H 6 10a 1 H NMR (top) 13 C NMR (bottom) 3'' 2'' Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S19 (20)

20 3' 2' 1 _ b C H 3 N 2 4 H 6 10b 1 H NMR (top) 13 C NMR (bottom) 3'' 2'' Supporting information: D. Wiktelius and K. Luthman Taking control of P1, P1 and double bond stereochemistry. S20 (20)