Catalytic Enantioselective Mannich Type Reaction with β Phenylsulfonyl Acetonitrile. Supporting Information

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1 Catalytic Enantioselective Mannich Type Reaction with β Phenylsulfonyl Acetonitrile Pedro B. González, Rosa Lopez, Claudio Palomo.* Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, San Sebastián, Spain Contents Supporting Information 1. General..S1 2. Materials S2 3. Experimental Procedures, Analytical and Spectroscopical Data...S Preparation of catalysts G and E.. S General procedure for the synthesis of β sulfonyl acetonitriles..s Screening of reaction conditions for PTC reactions...s General procedure for the addition of α cyano sulfone 1 to α-amido sulfones 2...S General procedure for the addition of α-cyano sulfone 1 to N Boc protected imines 4....S Charazterization of adducts 3... S General procedure for the preparation of racemic adducts and determination of the enantiomeric excess in adducts 3.S Stereochemical assignment.. S H and 13 C data of selected compounds.s8 5. HPLC chromatograms of selected compounds (racemic and non-racemic).s28 1. General. All non aqueous reactions were carried out under a nitrogen atmosphere in oven dried (120 ºC) glassware and with efficient magnetic stirring. Purification of reaction products was carried out by flash column chromatography using silica gel 60 ( mm, mesh). Non acid silica gel was prepared by through stirring of silica gel 60 with a saturated solution of sodium bicarbonate (300 ml of solution for 100 g of silica gel) and evaporation of water in an oven at 80 ºC for 72 h. Analytical thin layer chromatography (TLC) was performed on 0.25 mm silica gel 60 F plates. Visualization was accomplished with UV light and a solution obtained by admixing in 470 ml of water ammonium molibdate (21 g), cerium sulphate (1 g) and concentrated sulphuric acid (31 ml), followed by heating. Melting points were determined with a capillary apparatus and are uncorrected. Infrared spectra were recorded on a FT IR spectrometer. 1 H and 13 C NMR spectra were recorded on 200, 300, and 500 MHz spectrometers and are reported in ppm from internal tetramethylsilane (TMS). Optical rotations were measured at 25 ± 0.2 ºC in a Polarimeter. Analytical high performance liquid S1

2 chromatography (HPLC) was performed on chromatographs, equipped with UV lamp detector, using capillary columns. 2. Materials. All solvents were of p.a. quality and were dried by standard procedures prior to use if necessary. Unless otherwise specified, materials were obtained from commercial sources and used without purification. N Boc protected α amido sulfones 2, N Boc protected imines 4 1 catalysts F, 2 H, 3 and I 4 were prepared according to reported procedures. 3. Experimental Procedures, Analytical and Spectroscopical Data Preparation of catalysts G and E. Catalyst G 5 OMe OH N Cl - N CF 3 Quinidine (1.5 g, 4.6 mmol) was added to a solution of 2 trifluoromethylbenzyl chloride (360 ml, 5.1 mmol) in ethanol (37 ml), DMF (45 ml) and chloroform (1.5 ml) and the reaction mixture was stirred at 100 ºC for 6 h. After cooling at room temperature, the mixture was diluted with methanol (25 ml) and dropwidse added to Et 2 O (1 L) while stirring. The precipited was filtered, washed with additional Et 2 O and purified by column chromatography (CH 2 Cl 2 /MeOH mixtures 95/5) to give G ( 2.1g, 87%) as a yellowish solid; m.p ºC;[α ] D (c=0.5, CHCl 3 ); IR (KBr) 2927, 1617, 1501 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.76 (1 H, d, J 4.5), 8.40 (1 H, d, J 7.5), 8.04 (1 H, d, J 9.2), 7.93 (1 H, s), 7.86 (1 H, d, J 4.5), 7.81 (1 H, d, J 7.6), 7.68 (2 H, dd, J 15.4, 7.5), 7.38 (1 H, dd, J 9.2, 2.6), 7.13 (1 H, d, J 2.4), (2 H, m), 6.16 (1 H, ddd, J 17.5, 10.3, 7.6), 5.30 (1 H, s), 5.26 (1 H, d, J 6.5), (2 H, m), 4.00 (3 H, s), 3.71 (3 H, dt, J 23.0, 10.3), 2.76 (1 H, t, J 10.3), (2 H, m), 1.98 (1 H, s), 1.85 (2 H, t, J 8.9), 1.06 (1 H, t, J 13.3), 0.91 (1 H, dt, J 20.4, 6.5); 13 C (75 MHz, CDCl 3 ) δ 158.3, 147.7, 144.3, 143.0, 138.0, 135.9, 133.0, 132.3, 131.1, 128.1, 128.0, 125.5, 125.1, 121.7, 120.7, 118.6, 100.1, 70.8, 64.5, 60.4, 56.5, 55.6, 54.8, 38.7, 27.0, 24.4, 21.6; Anal. Calcd. for C 28 H 30 ClF 3 N 2 O 2 (519.00): C 64.80; H 5.83; N Found: C 64.95; H 5.80; N (a) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, (b) Rampalakos, C.; Wulff, W. D. Adv. Synth. Catal. 2008, 350, Arai, S.; Tsuge, H.; Oku, M.; Miura, M.; Shiori, T. Tetrahedron 2002, 58, Gioia, C.; Fini, F.; Mazzanti, A.; Bernardi, L.; Ricci, A. J. Am. Chem. Soc. 2009, 131, Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini, F.; Fochi, M.; Pettersen, D.; Sgarnazi, V.; Ricci, A. Chem. Eur. J. 2007, 13, Procedure adapted from: Ku, J. M.; Yoo, M.S.; Park, H.; Jew, S. S.; Jeong, B. S. Tetrahedron 2007, 63, S2

3 Catalyst E OMe OBn N Cl - N To a mixture of the N benzyl quinidinium chloride (1 mmol, 1 equiv., g) and benzyl chloride (1 mmol, 1 equiv., ml) in CH 2 Cl 2 (5 ml) at room temperature, a solution of NaOH (4 mmol, 1.3 equiv., 0.16 g) in H 2 O (0.5 ml) was added. The reaction mixture was stirred overnight and then extracted with CH 2 Cl 2 (3 x 3 ml). The organic layers were washed with water (1 x 4 ml), dried over MgSO 4 and concentrated under reduced pressure. Purification by flash column chromatography (CH 2 Cl 2 /MeOH, 95/5) afforded pure E (0.35 g, 64%) as a white solid; m.p ºC; [α ] D (c=0.3, CHCl 3 ); IR (KBr) 1617, 1497, 1310 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.87 (1 H, d, J 4.3), 8.06 (1 H, d, J 9.2), 7.64 (3 H, s), (10 H, m), 6.14 (1 H, s), (1 H, m), 5.26 (1 H, d, J 10.5), 5.14 (1 H, d, J 17.3), 4.76 (1 H, d, J 11.3), 4.33 (2 H, s), (3 H, m), 3.42 (1 H, s), 2.71 (1 H, dd, J 20.7, 9.9), 2.43 (4 H, m), 1.97 (2 H, s), 1.74 (1 H, s), 1.28 (1 H, d, J 11.1); 13 C (75 MHz, CDCl 3 ) δ 159.3, 146.4, 145.0, 137.7, 135.7, , 131.7, 130.4, 129.2, 129.1, 127.5, 127.3, 123.6, 120.0, 117.6, 101.1, 72.2, 71.3, 65.7, 61.2, 57.2, 55.6, 53.9, 37.7, 27.2, 23.5, 22.3; Anal. Calcd. for C 34 H 37 ClN 2 O 2 (541.12): C 75.47; H 6.89; N 5.18;. Found: C 75.41; H 6.57; N General procedure for the synthesis of β sulfonyl acetonitriles. 6 To a mixture of the corresponding thiol (11 mmol, 1.1 equiv.) and DBU (10 mmol, 1 equiv., 1.6 ml) in dry THF (15 ml), was added dropwise 2 bromoacetonitrile (10 mmol, 1 equiv., 0.7 ml at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature until disappearance of the starting thiol as monitored by TLC (typically 5 h), then quenched with H 2 O (5 ml) and extracted with CH 2 Cl 2 (3 x 30 ml). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The crude was dissolved into glacial acetic acid (10 ml) and hydrogen peroxide 30% (2.5 ml) was added dropwise. The reaction mixture was stirred and heated for 10h at 85 ºC. After solvents elimination, the residue was treated with brine (30 ml), extracted with EtOAc (3 x 30 ml), dried over MgSO 4, and the solvent eliminated under reduced pressure. The product was purified by flash chromatography using a mixture of ethyl acetate/hexane (1/3) as eluent. 2 (o Tolylsulfonyl)acetonitrile (I) Me O 2 S Yield 1.8 g (91%); white solid; m.p ºC; IR (KBr) 2920, 2252, 1325, 1128 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.10 (d, J=7.7 Hz, 1H), 7.65 (m, 1H), (m, 2H), 4.14 (s, 2H), 2.77 (s, 3H); 13 C (75 MHz, CDCl 3 ) δ 138.9, 135.3, 135.1, 133.4, 131.3, 110.3, 45.2, 20.6; HRMS (CI) for C 9 H 10 NO 2 S(M+H) + calcd , found Adapted from: (a) Llamas, T.; Gómez Arrayás, R.; Carretero, J. C.; Angew. Chem. Int. Ed., 2007, 46, (b) Epsztajn, J.; Bieniek, A.; Plotka, M. W.; Suwald, K.; Tetrahedron, 1989, 45, S3

4 2 (2 tert-butylphenylsulfonyl)acetonitrile (II) tbu O 2 S , found Yield 1.9 g (78%); yellowish foam; IR (KBr) 2927, 2245, 1336, 1138 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.1 Hz, 1H) 7.50 (d, J=7.1 Hz, 1H), 4.23 (s, 2H), 1.62 (s, 9H); 13 C (75 MHz, CDCl 3 ) δ , 135.2, 134.7, 129.4, 127.2, 110.5, 47.4, 37.3, 32.0; HRMS (CI) for C 12 H 16 NO 2 S(M+H) + calcd Screening of reaction conditions for PTC reactions. a Ph NHPG + SO 2 Tol-p SO 2 R 1) 2) Cat. (20 mol%) Base(130 mol%) Toluene, Tª (ºC), 60h Mg, TMSCl, 1,2 dibromoethane MeOH, RT, 3h Ph NHPG Entry Cat. R Sulfone PG Base Tª(ºC) Conv.(%) ee(%) 1 D Ph 1 Boc CsOH.H 2 O 30 > D 2-Me-C 4 H 6 I Boc CsOH.H 2 O D 2-t-Bu-C 4 H 6 II Boc CsOH.H 2 O D t-bu III Boc CsOH.H 2 O 30 N.R. 5 D Ph 1 Cbz CsOH.H 2 O H Ph 1 Boc CsOH.H 2 O H Ph 1 Boc K 2 CO a Reactions carried out as described in section 3.4. S4

5 3.4. General procedure for the addition of α cyano sulfone 1 to α amido sulfones 2 (procedure I) R + SO 2 Tol-p 1 SO 2 Ph 2 1) 2) Cat. H (20 mol%) CsOH.H 2 O Tol/CH 2 Cl 2, 70 ºC, 60h Mg, TMSCl, 1,2 dibromoethane MeOH, RT, 3h R 3 To a mixture of the corresponding N Boc protected α amido sulfone 1 (0.5 mmol, 1equiv.), catalyst H (0.06 mmol, 0.12 equiv., g) and the α cyano sulfone 2 (0.65 mmol, 1.3 equiv., g) in toluene/ch 2 Cl 2 (9:1, 2 ml) at 70 ºC, was added CsOH. H 2 O (0.65 mmol, 1.3 equiv., g) under a nitrogen atmosphere. After stirring at the same temperature for 60 h, the reaction mixture was treated with HCl (2 ml, 0.1 N) and extracted with CH 2 Cl 2 (3 x 3 ml). The organic layers were combined, washed with HCl (1 x 2 ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was dissolved in methanol (1.5 ml) and added to a suspension of Mg (powder), 1,2 dibromoethane (1 drop) and TMSCl (1 drop) in methanol (1.5 ml) at 0 ºC. After 3 h at room temperature, the reaction mixture was quenched with a saturated solution of NH 4 Cl (5 ml) and extracted with CH 2 Cl 2 (3 x 6 ml) 7. The organic layers were combined and washed with brine (1 x 4 ml), dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using mixtures of ethyl acetate/hexane as the eluent General procedure for the addition of α cyano sulfone 1 to N Boc protected imines 4 (Procedure II). R NBoc + 4 SO 2 Ph 2 1) (DHQ) 2 PYR (20 mol%) CH 2 Cl 2, 40 ºC, 18h 2) Mg, TMSCl, 1,2 dibromoethane MeOH, RT, 3h R 3 To a mixture of the corresponding imine 4 (0.5 mmol, 1 equiv.), (DHQ) 2 PYR (0.1 mmol, 0.2 equiv., g) in dry CH 2 Cl 2 (2 ml), was added the α cyano sulfone 2 (0.65 mmol, 1.3 equiv., g) at 50 ºC under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 18 h, then quenched with HCl (2 ml, 0.1 N) and extracted with CH 2 Cl 2 (3 x 3 ml). The organic layer was washed with HCl (1 x 2 ml), dried over MgSO 4 and concentrated under reduced pressure. The residue was then exposed to the same reaction conditions described above in procedure II Characterization of adducts 3. Characterisations of adducts 3 was made for those of the highest enantiomeric excess obtained either by procedure I or II. (R) 3 (N tert Butoxycarbonylamino)-3 phenylpropanitrile (3a) The title compound was prepared according to general procedure I starting from 1a. Yield g (72%); white solid; m.p ºC; [α] D (c=0.45, EtOH); IR (KBr) ν 2249, 1701, 1516, cm -1 ; 1 H 7 Sulfone removal adapted from: Alexakis, A.; Mossé, S. Org. Lett. 2005, 7, S5

6 NMR (300 MHz, CDCl 3 ) δ 7.41 (m, 5H), (m, 2H), (m, 2H), 1.50 (s, 9H); 13 C (75 MHz, CDCl 3 ) δ 154.8, 138.5, 129.2, 128.7, 126.2, 116.9, 80.6, 51.3, 28.2, 25.2; Chiral HPLC (Chiralpak IA column; hexane:iproh 95:5; 0.5 ml/min, 210 nm) t R (major) = 30 min, t R (minor)= 34 min; 76% ee; After recrystallization from a mixture of toluene:hexane, 94% ee; [α] D (c=0.45, EtOH) ([α] D Lit (c=0.45, EtOH)); 8 HRMS (EI) for C 14 H 18 N 2 O 2 (M + ) calcd , found (R) 3 (N tert Butoxycarbonylamino)-3 (4 methylphenyl)propanitrile (3b) Me The title compound was prepared according to general procedure II starting from 4b. Yield g (73%); white solid; m.p ºC; [α] D (c=0.5, EtOH); IR (film) 2252, 1680, 1515 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), 2.91 (m, 2H), 2.39 (s, 3H), 1.49 (s, 9H); 13 C (75 MHz, CDCl 3 ) δ 154.8, 138.5, 135.6, 129.8, 126.1, 117.1, 80.5, 51.1, 28.3, 25.2, 21.1; Chiral HPLC (Chiralpak IB column; hexane:iproh 90:10; 0.5 ml/min, 210 nm) t R (major) = 18 min, t R (minor)= 23 min; 84% ee; HRMS (EI) for C 15 H 20 N 2 O 2 (M + ) calcd , found (R) 3 (N tert Butoxycarbonylamino)-3 (2 methylphenyl)propanitrile (3c) The title compound was prepared according to general procedure I starting from 1c. Yield g (71%); white solid; m.p ºC; [α] D +30,6 (c=0.6, EtOH); IR (KBr) 2252, 1700, 1526 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 4H), 5.25 (dd, J=12.4, 6.9 Hz, 1H), 5.00 (br s, Me 1H), (m, 2H), 2.43 (3 H, s), 1.49 (9 H, s); 13 C (75 MHz, CDCl 3 ) δ 154.7, 136.6, 135.7, 131.2, 128.5, 126.8, 124.8, 117.1, 80.5, 47.4, 28.3, 24.2, 19.2; Chiral HPLC (Chiralpak IA column; hexane:iproh 97:3; 0.5 ml/min, 210 nm) t R (major) = 34 min, t R (minor)= 38 min; 76% ee; After recrystallization from a mixture of toluene:hexane, 92% ee; [α] D = (c=0,4, EtOH); HRMS (EI) for C 15 H 20 N 2 O 2 (M + ) calcd , found (R) 3 (N tert Butoxycarbonylamino)-3 (2 naphtyl)propanitrile (3d) The title compound was prepared according to general procedure I starting from 1d. Yield g (75%); white solid; m.p ºC; [α] D (c=0.3, EtOH); IR (KBr) 2252, 1706, 1512 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 3H), 7.59 (m, 4H), 5.87 (dd, J=11.9, 7.0 Hz), 5.24 (d, J=7.4 Hz, 1H), 3.26 (dd, J=16.6, 6.6 Hz, 1H), 3.06 (dd, J=16.6, 4.7 Hz, 1H), 1.45 (s, 9H); 13 C (75 MHz, CDCl 3 ) δ 154.8, 134.1, 130.4, 129.7, 129.4, 129.2, 127.1, 126.2, 125.2, 123.1, 122.3, 117.1, 80.7, 47.0, 28.3, 24.3;Chiral HPLC (Chiralpak IA column; hexane:iproh 90:10; 0.5 ml/min, 210 nm) t R (major) = 19 min, t R (minor)= 35 min; 74% ee; After recrystallization from a mixture of toluene:hexane, 99% ee; [α] D (c=0.3, EtOH); HRMS (EI) for C 18 H 21 N 2 O 2 (M + ) calcd , found (R) 3 (N tert Butoxycarbonylamino)-3 (4 methoxyphenyl)propanitrile (3e) The title compound was prepared according to general procedure II starting from 4e. Yield g (72%); white foam; [α] D (c=0.4, MeO 8 Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G. Tetrahedron, 1995, 51, S6

7 EtOH); IR (KBr) 2251, 1680, 1615, 1514 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.26 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), (m, 2H), 3.85 (s, 3H), 2.96 (m, 2H), 1.49 (s, 9H); 13 C (75 MHz, CDCl 3 ) δ 159.8, 154.8, 130.6, 127.5, 117.1, 114.5, 80.5, 55.3, 50.9, 28.3, 25.2; Chiral HPLC (Chiralpak ADH column; hexane:iproh 90:10; 0.5 ml/min, 210 nm) t R (major) = 34 min, t R (minor)= 38 min; 64% ee; HRMS (EI) for C 15 H 21 N 2 O 3 (M + ) calcd. 276,1474, found (R) 3 (N tert Butoxycarbonylamino)-3 (4 chlorophenyl)propanitrile (3f) Cl The title compound was prepared according to general procedure I starting from 1f. Yield g (85%); white solid; m.p ºC; [α] D (c=0.3, EtOH); IR (KBr) 2250, 1699, 1531 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.36 (m, 4H), 5.12 (d, J=7.2 Hz, 1H), 4.99 (m, 1H), 2.94 (m, 2H), 1.47 (s, 9H); 13 C (75 MHz, CDCl 3 ) δ 154.7, 137.1, 134.6, 129.4, 127.6, 116.7, 80.9, 50.7, 28.3, 25.1; Chiral HPLC (Chiralpak IA column; hexane:iproh 90:10; 0.5 ml/min, 210 nm) t R (major) = 20 min, t R (minor)= 28 min; 55% ee; After recrystallization from a mixture toluene:hexane, 90% ee; [α] D (c=0.3, EtOH); Anal. Calcd. for C 14 H 17 ClN 2 O 2 (280,75): C 59.89; H 6.10; N Found: C 60.07; H 6.26; N General procedure for the preparation of racemic adducts and determination of the enantiomeric excess in adducts 3. The general procedure described in section 3.3 in the absence of the phase transfer catalyst was followed. The determination of enantiomeric excesses was performed by HPLC analyses. Chromatograms of crude and purified compounds were compared with those obtained for the racemic samples Stereochemical assignment. The absolute configuration of adduct 3a (obtained by both procedures I and II) was deduced from comparison of the optical rotation value with published data (see section 3.5). An uniform reaction mechanism was assumed for the rest of substrates. S7

8 4. 1 H and 13 C NMR data of selected compounds 3a f1 (ppm) S8

9 3a f1 (ppm) S9

10 3b f1 (ppm) S10

11 3b f1 (ppm) S11

12 3c f1 (ppm) S12

13 3c f1 (ppm) S13

14 3d f1 (ppm) S14

15 3d f1 (ppm) S15

16 MeO 3e f1 (ppm) S16

17 MeO 3e f1 (ppm) S17

18 Cl 3f f1 (ppm) S18

19 Cl 3f f1 (ppm) S19

20 OMe OBn N Cl - N E f1 (ppm) S20

21 OMe OBn N Cl - N E f1 (ppm) S21

22 OMe OH N Cl - N G CF f1 (ppm) S22

23 OMe OH N Cl - N G CF f1 (ppm) S23

24 Me O 2 S I S24

25 Me O 2 S I S25

26 tbu O 2 S II S26

27 tbu O 2 S II S27

28 5. HPLC chromatograms of selected compounds 3a 0,60 Racemic 0,40 30,665 34,600 0, , , ,00 (DHQ) 2 PYR 0,20 31,076 35, , , ,00 S28

29 1,00 0,50 30,902 PTC 34, , , ,00 After recrystalización: 51% yield; 99% ee 0,05 29,975 33, , , ,00 S29

30 3b Racemic 0,10 0,05 18,028 22,566-0,05 14,00 16,00 18, ,00 24,00 26,00 28,00 3 1,00 (DHQ) 2 PYR 0,80 0,60 0,40 0,20 18,031 22,659 16,00 18, ,00 24,00 26,00 28,00 3 S30

31 PTC 0,20 18,503 23,405 16,00 18, ,00 24,00 26,00 28,00 S31

32 3c Racemic 1,00 0,80 0,60 0,40 34,060 38,629 0, , , ,00 5 (DHQ) 2 PYR 0,20 32,762 0,10 37,331 25, , ,00 S32

33 PTC 1,00 0,80 0,60 0,40 0,20 33,929 38, , , ,00 5 After recrystalización: 47% yield; 94% ee 0,50 34,404 39, , , ,00 5 S33

34 3d Racemic 2,00 1,00 19,176 35,286 16,00 18, ,00 24,00 26,00 28, ,00 34,00 36,00 38,00 4 (DHQ) 2 PYR 0,20 18,235 0,10 34,610 16,00 18, ,00 24,00 26,00 28, ,00 34,00 36,00 38,00 S34

35 PTC 0,60 0,40 18,792 0,20 35,077 16,00 18, ,00 24,00 26,00 28, ,00 34,00 36,00 38,00 4 After recrystalización: 50 % yield; 99% ee 0,50 19,243 36, , ,00 4 S35

36 MeO 3e Racemic 0,20 0,10 34,106 37,936 25, ,00 4 0,20 0,10 (DHQ) 2 PYR 34,129 37,992 26,00 28, ,00 34,00 36,00 38, ,00 S36

37 PTC 0,60 32,447 0,40 0,20 36,494 24,00 26,00 28, ,00 34,00 36,00 38, ,00 S37

38 Cl 3f Racemic 1,50 1,00 21,415 29,073 0,50 16,00 18, ,00 24,00 26,00 28, ,00 34,00 (DHQ) 2 PYR 1,00 0,80 0,60 0,40 20,234 28,119 0,20 16,00 18, ,00 24,00 26,00 28, ,00 34,00 S38

39 PTC 0,20 0,10 20,355 16,00 18, ,00 24,00 26,00 28, ,00 34,00 26,741 After recrystalización: 37% yield; 90% ee 0,50 20,558 26,757 16,00 18, ,00 24,00 26,00 28, ,00 34,00 S39