Diastereoselective Access to Trans-2-Substituted Cyclopentylamines

Transcript

1 Supporting Information Diastereoselective Access to Trans-2-Substituted Cyclopentylamines Antoine Joosten, Emilie Lambert, Jean-Luc Vasse, Jan Szymoniak ICMR -UMR 6229, CRS - Université de Reims Champagne-Ardenne, BP1039, Reims Cedex 2, France S2-S25 : Experimental procedures and characterization of compounds. S 1

2 Experimental procedures and characterization of compounds. All reactions were conducted under an atmosphere of argon. Prior to use, THF and Et 2 were distilled under argon from sodium benzophenone ketyl, allylbromide, (i-pr) 2 H, Et 3 and CH 2 Cl 2 were distilled under argon from CaH 2, Cp 2 Zr(H)Cl was prepared according to known procedure, 1 reagents were used as received. 1 H and 13 C MR spectra were recorded in CDCl 3, unless specified, on a Brucker AC-250. Mass spectra were recorded on a Micromass Q-TF micro MS spectrometer. (E)-Ethyl 5-phenylpent-4-enoate 2 C Ph 2 Et A mixture of 1-phenylprop-2-en-1-ol (3.23 g, 24 mmol), ethyl orthoacetate (27.2 g, 168 mmol) and propionic acid (0.1 g, 1.45 mmol) was stirred for 1 h at 140 C to allow the distillative removal of ethanol. The excess of reagents was removed by distillation. Bulb to bulb distillation of the residue gave the title compound in 68% yield. 1 H MR (250 MHz, CDCl 3 ) δ 1.21 (t, J = 7.1 Hz, 3 H), (m, 4 H), 4.11 (q, J = 7.1 Hz, 2 H), 6.17 (dt, J = 15.9, 6.2 Hz), 6.40 (d, J = 15.9 Hz, 1 H), (m, 5 H). 2-(Trityloxymethyl)pent-4-en-1-ol 3 Tr To a solution of 2-(hydroxymethyl)pent-4-en-1-ol (1.7 g, 14 mmol) and pyridine (2 ml) in CH 2 Cl 2 (12 ml), was added TrCl (3.94 g, 14 mmol) and the mixture was stirred at rt for 18 h, then diluted with CH 2 Cl 2 (60 ml). The organic solution was washed with HCl (1 M, 4 x 10 ml), dried over a 2 S 4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EP/AcEt (90:10) to give the title compound (1.65g, 33%). 1 H MR (250 MHz, CDCl 3 ) δ 1.90 (m, 1 H), 2.07 (t, J = 7.0Hz, 1 H), 2.25 (br s, 1 H), 3.11 (dd, 1H, J = 9.1, 6.9 Hz, 1 H) 3.28 (dd, J = 9.2, 4.3 Hz, 1 H), (m, 2 H), (m, 2 H), 5.68 (ddt, J = 17.1, 10.1, 7.0 Hz, 1 H), (m, 9 H), 7.43 (d, J = 6.9 Hz, 6 H). 1 (a) Buchwald, S. L.; La Maire, S. J.; ielsen, R. B.; Watson, B. T.; King, S. M. Tetrahedron Lett. 1987, 28, ; (b) Buchwald, S. L.; La Maire, S. J.; ielsen, R. B.; Watson, B. T.; King, S. M. rg. Synth. 1993, 71, Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brockson, T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, Bartoli, J.; Carceller, E.; Merlos, M.; Garcia-Rafanell, J. ; Forn, J. J. Med. Chem. 1991, 34, S 2

3 Allylation of ester : Procedure A To a solution of (i-pr) 2 H (1.75 ml, 12.5 mmol) in THF (15 ml) was added at 0 C a solution of n- BuLi (2.5 M, 11.5 mmol, 4.6 ml) and the resulting solution was stirred for 15 min at 0 C then cooled to -78 C. A solution of ester (10 mmol) in THF (30 ml) was added dropwise and the resulting mixture was stirred for 40 min at -78 C. Allylbromide (1.3 ml, 15 mmol) was added dropwise, and the stirring was continued at -78 C for 2h and the reaction was quenched by adding a saturated aqueous solution of H 4 Cl (20 ml). The aqueous layer was extracted with Et 2 (2 x 20 ml), the organic phases were combined, washed with HCl (1 M, 20 ml), brine (20 ml), dried over MgS 4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with a PE /AcEt mixture. Methyl 2-phenylpent-4-enoate 4 C 2 Me Ph btained as a colorless oil in 92% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 95/5). 1 H MR (250 MHz, CDCl 3 ) δ (m, 1 H), (m, 1 H), (m, 4 H), (m, 2 H), 5.70 (ddt, J = 17.1, 10.2, 6.8 Hz, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 37.5, 51.3, 51.9, 116.2, 127.3, 127.9, 128.6, 135.2, 138.5, Methyl 2-(2-bromophenyl)pent-4-enoate C 2 Me Br btained as a colorless oil in 91% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 95/5). 1 H MR (250 MHz, CDCl 3 ) δ 2.51 (dt, J = 14.1, 6.8 Hz, 1 H), 2.70 (m, 1 H), 3.65 (s, 3 H), 4.26 (dd, J = 10.3, 8.5 Hz, 1 H), (m, 2 H), 5.71 (ddt, J = 13.7, 10.1, 6.8 Hz, 1 H), 7.09 (td, J = 7.9, 1.8 Hz, 1 H), 7.26 (td, J = 7.2, 1.1 Hz, 1 H), 7.36 (dd, J = 7.8, 1.7 Hz, 1 H), 7.55 (dd, J = 8.0, 1.1 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 37.1, 49.7, 52.1, 117.3, 124.7, 127.8, 128.7, 128.8, 133.0, 134.8, 138.1, Methyl 2-(4-methoxyphenyl)pent-4-enoate C 2 Me Me 4 Sosa, J. R.; Tudjarian, A. A.; Minehan, T. G. rg. Lett., 2008, 10, S 3

4 btained as a yellow oil in 99% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 85/15). 1 H MR (250 MHz, CDCl 3 ) δ 2.49 (m, 1 H), 2.79 (m, 1 H), (m, 4 H), 3.77 (s, 3 H), (m, 2 H), 5.71 (ddt, J = 13.7, 10.1, 6.8 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 2 H), 7.22 (d, J = 8.6 Hz, 2 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 37.7, 50.6, 52.0, 55.2, 114.0, 117.0, 129.0, 130.6, 135.4, 158.9, 174.2; HRMS-ESI : m/z [M + H] + calcd for C 13 H 17 3 : ; found : Tert-butyl 3-[1-(méthoxycarbonyl)but-3-enyl]-1H-indole-1-carboxylate C 2 Me Boc btained as a colorless oil in 83% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 95/5). 1 H MR (250 MHz, CDCl 3 ) δ 1.66 (br s, 9 H), 2.68 (m, 1 H), 2.90 (dt, J = 15.5, 7.9 Hz, 1 H), 3.67 (br s, 3 H), 3.91 (dd, J = 7.9, 7.1 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 2 H), (m, 2 H), 8.14 (d, J = 7.8 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 28.3, 36.3, 42.7, 52.2, 83.8, 115.4, 117.3, 119.4, 122.7, 123.6, 124.6, 129.5, 135.2, 135.5, 149.7, 173.6, 1 C is missing; ν 2980, 1729, 1454, 1371, 1256, Methyl 2-Allyloctanoate C 2 Me btained as a pale yellow oil in 95% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 98/2). 1 H MR (250 MHz, CDCl 3 ) δ 0.88 (t, J = 6.7 Hz, 3 H), 1.26 (m, 8 H), (m, 2 H), (m, 3 H), 3.66 (s, 3 H), (m, 2 H), 5.74 (ddt, J = 16.8, 10.1, 6.7 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 14.1, 22.7 (2C), 29.3, 31.7, 32.0, 36.6, 45.5, 51.4, 116.7, 135.7, Methyl 2-isopropylpent-4-enoate C 2 Me btained as a colorless oil in 96% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 95/5). 1 H MR (250 MHz, CDCl 3 ) δ 0.92 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 7.0 Hz, 3 H), 1.88 (m, 1 H), (m, 3 H), 3.66 (s, 3 H), (m, 2 H), 5.74 (m, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 20.6, 20.7, 30.7, 34.4, 51.5, 52.8, 116.7, 136.3, Ethyl 2-(dibenzylamino)pent-4-enoate S 4

5 C 2 Me Bn 2 btained as a colorless oil in 83% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 90/10). 1 H MR (250 MHz, CDCl 3 ) δ 1.33 (t, J = 7.1 Hz, 3 H), 2.51 (t, J = 7.1 Hz, 2 H), 3.41 (dd, J = 7.8, 7.5 Hz, 1 H), 3.54 (d, J = 13.9 Hz, 2 H), 3.93 (d, J = 13.9 Hz, 2 H), (m, 2 H), 5.03 (d, J = 10.4 Hz, 1 H), 5.04 (d, J = 16.9 Hz, 1 H), 5.72 (ddt, J = 16.9, 10.4, 6.9 Hz, 1 H), (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 14.6, 34.0, 54.4, 60.1, 60.6, 116.8, 126.9, 128.2, 128.8, 135.0, 139.5, Methyl 2-(3-benzyloxypropyl)pent-4-enoate C 2 Me Bn btained as a colorless oil in 83% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 95/5). 1 H MR (250 MHz, CDCl 3 ) δ (m, 4 H), (m, 3 H), 3.45 (app t, J = 5.4 Hz, 2 H), 3.65 (s, 3 H), 4.48 (s, 2 H), (m, 2 H), 5.72 (ddt, J = 17.0, 10.1, 7.0 Hz, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 27.4, 28.4, 36.4, 45.0, 51.3, 69.8, 72.8, 116.7, 127.4, 127.5, 128.3, 135.3, 138.4, Ethyl 2-cinnamylpent-4-enoate C 2 Et Ph btained as a pale yellow oil in 81% yield. 1 H MR (250 MHz, CDCl 3 ) δ 1.22 (t, J = 7.1 Hz, 3 H), (m, 5 H), 4.12 (q, J = 7.1 Hz, 2 H), (m, 2 H), 5.77 (ddt, J = 17.1, 10.1, 6.9 Hz, 1 H), 6.13 (dt, J =15.9, 7.1 Hz, 1 H), 6.41 (d, J = 15.9 Hz, 1 H), (m, 5 H). Methyl 2-(benzyloxy)pent-4-enoate 5 C 2 Me Bn A solution of n-buli (1.6 M in hexane, 15.8 ml, 25.3 mmol) was added to a solution of HMDS (7.04 g, 33.8 mmol) in THF (25 ml) at 0 C. The resulting solution was stirred for 15 min then cooled down to -78 C. A solution of allyl 2-benzyloxyacetate (1.74 g, 8.4 mmol) in THF was added dropwise and the resulting mixture was stirred at -78 C for 45 min. Freshly distilled TMSCl (5.36 ml, 42.2 mmol) was added and the stirred was continued for 10 min, the reaction was slowly warmed to rt. After 2 h of stirring, a saturated aqueous solution of H 4 Cl (10 ml) was added. The layers were separated and the aqueous phase was extracted with Et 2 (3 x 30 ml). The organic phases were combined, dried over MgS 4, filtered, then a steam of CH 2 2 was bubbled through until a deep yellow colour persists. The 5 Boudreau, M. A.; Vederas, J. C. rg. Biomol. Chem. 2007, 5, S 5

6 solution was concentrated under reduced and the residue was purified by flash chromatography on silica gel using a mixture of EP/AcEt (95:5) as eluent to give the title compound (1.70 g, 92%) as a colorless oil. 1 H MR (250 MHz, CDCl 3 ) δ 2.36 (t, J = 6.6 Hz, 2 H), 3.54 (s, 3 H), 3.85 (t, J = 6.6 Hz, 1 H), 4.26 (d, J = 11.8 Hz, 1 H), 4.53 (d, J = 11.8 Hz, 1 H), (m, 2 H), 5.71 (ddt, J = 17.1, 10.1, 6.6 Hz, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 37.1, 51.5, 72.0, 77.5, 117.8, 127.7, 127.8, 128.2, 132.9, 137.3, Methyl 2-(4-methoxybenzyloy)pent-4-enoate 6 C 2 Me PMB btained according to the above method in 94% yield as a pale yellow oil. 1 H MR (250 MHz, CDCl 3 ) δ 2.41 (t, J = 6.6 Hz, 2 H), 3.63 (s, 3 H), 3.69 (s, 3 H), 3.89 (t, J = 6.3 Hz, 1 H), 4.28 (d, J = 11.4 Hz, 1 H), 4.53 (d, J = 11.4 Hz, 1 H), (m, 2 H), 5.71 (ddt, J = 17.1, 10.1, 7.0 Hz, 1 H), 6.77 (d, J = 8.6 Hz, 2 H), 7.17 (d, J = 8.6 Hz, 2 H). Methyl 2-hydroxypent-4-enoate 7 C 2 Me To a solution of the above compound (3.75 g, 15 mmol) in a mixture of CH 3 C / H 2 (9:1, 300 ml), was added CA (26.3 g, 48 mmol) at rt. After 1 h of stirring, the reaction mixture was filtered and concentrated under reduced pressure. H 2 (50 ml) and CH 2 Cl 2 (50 ml) were added, the organic phase was dried over MgS 4 filtered and concentrated under vacuum. The residue was distillated under reduced pressure to give the expected alcohol as a colorless oil (1.35 g, 66%). 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), 2.80 (br s, 1 H), 3.69 (s, 3 H), 4.19 (dd, J = 6.3, 4.7 Hz, 1 H), (m, 2 H), 5.49 (ddd, J = 17.0, 10.4, 7.1 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 38.6, 52.4, 70.0, 18.7, 132.4, Methyl 2-trityloxypent-4-enoate C 2 Me Tr The above compound (1.35 g, 10 mmol) was added to a solution of TrCl (3.34 g, 12 mmol) and DBU (2.1 ml, 14 mmol) in CH 2 Cl 2 (45 ml). The reaction mixture was stirred for 48h at rt and then quenched with H 2 (30 ml). The organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (3 x 20 ml). The combined organic phases were dried over MgS 4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on 6 Probst, ; Haudrechy, A.; Plé, K. J. rg. Chem. 2009,73, Lee, J. G.; Choi, K. I., Pae, A..; Kok, H. Y.; Kang, Y.; Cho, Y. S. J. Chem. Soc., Perkin Trans , S 6

7 silica gel using a mixture of PE / CH 2 Cl 2 (7:3) as eluent to give the title compound in 56% yield as a white solid. 1 H MR (250 MHz, CDCl 3 ) δ 2.44 (m, 2 H), 3.20 (s, 3 H), 4.20 (t, J = 6.0 Hz, 1 H), (m, 2 H), 5.79 (ddt, J = 17.4, 9.2, 7.2 Hz, 1 H), (m, 9 H), 7.47 (d, J = 6.6 Hz, 6 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 38.7, 51.0, 73.1, 87.9, 118.0, 127.1, 127.7, 129.0, 132.5, 143.7, ) Preparation of aldehyde via DIBAL-H reduction of ester Procedure B: Procedure B A DIBAL-H solution (1 M in hexane, 11 mmol) was added dropwise to a solution of ester (10 mmol) in CH 2 Cl 2 (60 ml) at -78 C and the resulting mixture was stirred for 1h at at -78 C. An aqueous Rochelle salt solution (10%, 20 ml) was added and the heterogenous mixture was stirred for 15 min at rt. The aqueous layer was extracted with CH 2 Cl 2 (3 x 20 ml), the organics phases were combined, dried over MgS 4, filtered and concentrated under reduced pressure. The residue was purified by filtration on silica gel to give the corresponding aldehyde. 2-Phenylpent-4-enal 8 CH Ph btained as a colorless oil in 84% yield. 1 H MR (250 MHz, CDCl 3 ) δ (m, 1 H), 2.84 (m, 1 H), (m, 1 H), (m, 2 H), 5.70 (ddt, J = 17.0, 10.1, 6.9 Hz, 1 H), (m, 5 H), 9.65 (d, J = 1.6 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 33.9, 58.7, 117.2, 127.7, 128.9, 129.1, 134.9, 135.7, (2-bromophenyl)pent-4-enal CH Br btained as a colorless oil in 70% yield. 1 H MR (250 MHz, CDCl 3 ) δ 2.50 (dt, J = 14.7, 7.4 Hz, 1 H), 2.86 (dt, J = 14.4, 6.6 Hz, 1 H), 4.23 (t, J = 7.2 Hz, 1 H), (m, 2 H), 5.74 (ddt, J = 17.0, 10.1, 6.9 Hz, 1 H), (m, 2 H), 7.31 (td, J = 7.5, 1.1 Hz, 1 H), 7.62 (dd, J = 7.9, 1.1 Hz, 1 H), 9.71 (s, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 33.5, 57.1, 117.5, 125.7, 128.0, 129.2, 130.0, 133.4, 134.5, 135.8, isopropylpent-4-enal 9 8 Zhang, M.; Hu, Y.; Zhang, S. Chem. Eur. J. 2009, 15, Downing, M. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, S 7

8 CH btained as a colorless oil in 81% yield. 1 H MR (250 MHz, CDCl 3 ) δ 0.98 (d, J = 2.7 Hz, 3 H), 1.00 (d, J = 2.7 Hz, 3 H), (m, 1 H), (m, 2 H), (m, 1 H), (m, 2 H), (m, 1 H), 9.65 (d, J = 2.7 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 20.2, 20.4, 28.4, 30.8, 57.9, 117.1, 136.1, allyloctanal CH btained as a colorless oil in 74%. 1 H MR (250 MHz, CDCl 3 ) δ 0.87 (t, J = 6.8 Hz, 3 H), 1.28 (m, 8 H), (m, 1 H), (m, 1 H), (m, 3 H), (m, 2 H), 5.74 (ddt, J = 16.9, 10.1, 6.8 Hz, 1 H), 9.61 (d, J = 2.3 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 14.2, 22.7, 27.0, 28.5, 29.4, 31.7, 33.2, 51.4, 117.2, 135.1, ) Two steps synthesis of aldehyde via LAH reduction of ester followed by PCC oxidation of the resulting alcohol (Procedure C) Procedure C: A solution of ester (15 mmol) in Et 2 (35 ml) was added dropwise to a suspension of LiAlH 4 (0.63 g, 16.6 mmol) in Et 2 (15 ml) at 0 C and the resulting mixture was stirred for 2h at rt then water (20 ml) was carefully added. The aqueous layer was extracted with Et 2 (3 x 20 ml), the organic phases were combined, washed with brine (20 ml), dried over MgS 4, filtered and concentrated under vacuum to give the corresponding alcohol which was used in the next step without purification. To a mixture of PCC (3 g, 14 mmol) and celite (5 g) in CH 2 Cl 2 (60 ml) was added a solution of the alcohol (12 mmol) in CH 2 Cl 2 (20 ml), and the resulting mixture was stirred for 2h at rt. The crude reaction mixture was filtered through silica gel eluting with CH 2 Cl 2 to give the corresponding aldehyde which was used in the next step without purification. 2-(4-methoxyphenyl)pent-4-enal CH Me btained as a yellow oil in 88% yield. 1 H MR (250 MHz, CDCl 3 ) δ (m, 1 H), 2.80 (m, 1 H), 3.56 (m, 1 H), 3.77 (s, 3 H), (m, 2 H), 5.70 (ddt, J = 17.0, 10.1, 6.9 Hz, 1 H), S 8

9 (m, 2 H), (m, 2 H), 9.63 (d, J = 1.7 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 33.9, 55.2, 57.8, 114.5, 117.0, 127.5, 129.9, 135.1, 159.1, Trityloxymethylpent-4-enal CH Tr btained as a white solid in 68% yield. 1 H MR (250 MHz, CDCl 3 ) δ 2.28 (m, 1 H), (m, 2 H), 3.34 (dd, J = 9.4, 5.8 Hz, 1 H), 3.43 (dd, J = 9.4, 4.4 Hz, 1 H), (m, 2 H), 5.62 (m, 1 H), (m, 9 H), (m, 6 H), 9.66 (d, J = 1.5 Hz, 1H); 13 C MR (62.5 MHz, CDCl 3 ) δ 30.5, 52.4, 61.9, 117.8, 127.6, 128.4, 128.4, 129.1, 135.2, 203.9, 1 C are missing. (E)-2-Allyl-5-phenylpent-4-enal CH Ph btained as a white solid in 61% yield. 1 H MR (250 MHz, CDCl 3 ) δ (m, 5 H), 5.09 (d, J = 10.3 Hz, 1 H), 5.10 (d, J = 16.6 Hz, 1 H), 5.77 (ddt, J = 16.6, 10.3, 7.0 Hz, 1 H), 6.13 (dt, J = 15.4, 7.0 Hz, 1 H), 6.43 (d, J = 15.6 Hz, 1 H), (m, 5 H), 9.70 (d, J = 1.3 Hz, 1H); 13 C MR (62.5 MHz, CDCl 3 ) δ 31.6, 32.5, 50.9, 117.5, 126.0, 126.2, 127.3, 128.4, 132.5, 134.6, 137.0, ) Two steps synthesis of aldehyde via LAH reduction of ester followed by Swern oxidation : Procedure D A solution of ester (15 mmol) in Et 2 (35 ml) was added dropwise to a suspension of LiAlH 4 (0.63 g, 16.6 mmol) in Et 2 (15 ml) at 0 C and the resulting mixture was stirred for 2h at rt then water (20 ml) was carefully added. The aqueous layer was extracted with Et 2 (3 x 20 ml), the organic phases were combined, washed with brine (20 ml), dried over MgS 4, filtered and concentrated under vacuum to give the corresponding alcohol which was used in the next step without purification. DMS (0.76 ml, 10.7 mmol) was added dropwise to a solution of oxalyl chloride (0.46 ml, 5.35 mmol) in CH 2 Cl 2 (25 ml) at -78 C and the resulting mixture was stirred for 15 min at -78 C for 20 min. A solution of 2-(dibenzylamino)pent-4-en-1-ol (1 g, 3.55 mmol) in CH 2 Cl 2 (13 ml) was added dropwise at -78 C. The stirring was continued for 2h, then Et 3 (2.5 ml, 17.8 mmol) was added. After 1h of stirring the reaction was slowly warmed to rt then water (10 ml) and brine (10 ml) were successively added. The aqueous layer was extracted with CH 2 Cl 2 (3 x 20 ml), the organic phases were combined, dried over MgS 4, filtered and concentrated under vacuum. The residue was filtrated over a plug of silica gel eluting with EP/AcEt (90/10) to give the corresponding aldehyde which was used directly in the next step. S 9

10 2-(Dibenzylamino)pent-4-enal CH Bn 2 btained as a colorless oil in 92% yield. 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), 3.31 (t, J = 6.8 Hz, 1 H), 3.72 (d, J = 13.7 Hz, 2 H), 3.81 (d, J = 13.7 Hz, 2 H), (m, 2 H), 5.81 (m, 1 H), 7.31 (m, 10 H), 9.71 (s, 1 H) ; 13 C MR (62.5 MHz, CDCl 3 ) δ 28.9, 55.0, 66.9, 117.2, 127.5, 128.5, 128.9, 135.6, 139.1, Benzyloxypent-4-enal 10 CH Bn btained as a colorless oil in 81% yield. 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), 3.81 (td, J = 6.7, 1.8 Hz, 1 H), 4.56 (d, J = 11.8 Hz, 1 H), 4.66 (d, J = 11.8 Hz, 1 H), (m, 2 H), 5.81 (ddt, J = 17.1, 10.1, 7.0 Hz, 1 H), (m, 5 H), 9.63 (d, J = 1.8 Hz, 1 H); 13 C MR (250 MHz, CDCl 3 ) δ 34.5, 72.3, 82.6, 118.3, 127.8, 127.9, 128.4, 132.3, 137.1, Trityloxypent-4-enal CH Tr btained as a colorless oil in 88% yield. 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), 3.99 (m, 1 H), (m, 2 H), 5.89 (ddt, J = 17.3, 9.5, 7.2 Hz, 1 H), (m, 9 H), 7.50 (d, J = 8.2 Hz 6 H), 8.70 (d, J = 3.2 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 37.0, 78.1, 87.7, 118.7, 127.5, 128.0, 128.7, 132.0, 143.7, Condensation of aldehyde with -benzylethanoamine : Procedure E: A solution of aldehyde (3 mmol) and -benzyaminolethanol (425 µl, 3 mmol) in toluene (10 ml) was heated for 3 h. The solvent was removed under vacuum to give quantitatively the corresponding oxazolidine 1 which was used in the next step without purification. 3-Benzyl-2-(1-phenylbut-3-enyl)oxazolidine 1a Ph Bn btained as a colorless oil as a 57/43 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 4.43 H, major + minor), 2.93 (dt, 1 H, J = 11.2, 5.8 Hz, 0.57 H, major), (m, 4 H, major + minor), 4.34 (d, J = 4.3 Hz, 0.57 H, major), 4.48 (d, J = 4.5 Hz, 0.43 H, minor), (m, 10 Cerè, V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron 1999, 55, S 10

11 2 H, major + minor) (m, 1 H, major + minor), (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 34.2 (major), 36.2 (minor), 49.5 (minor), 50.0 (major), 51.7 (minor), 52.1 (major), (minor), (major), 64.5 (minor), 64.9 (major), 99.1 (minor), 99.6 (major), (major), (minor), (minor), (major), (major), (minor), (minor), (major), (major), (major), (major + minor), (major), (minor), (minor), (major), (major + minor), (minor), (major); HRMS-ESI : m/z [M + H] + calcd for C 20 H 24 : ; found : ; IR (film) ν 3395, 3064, 3029, 2942, 2885, 1641, 1496, 1454, 1075, 755, Benzyl-2-(1-(2-bromophenyl)but-3-enyl)oxazolidine 1b Br Bn btained as a colorless oil as a 62/38 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 2.38 H, major + minor), (m, 1 H, major + minor), (m, 0.62 H, major), 3.41 (dd, J = 13.1, 3.2 Hz, 1 H, major + minor), (m, 2 H, major + minor), 3.86 (dd, J = 6.9, 5.8 Hz, 1 H, major + minor), (m, 1 H, major + minor), 4.30 (d, J = 3.8 Hz, 0.62 H, major), 4.51 (d, J = 4.6, 0.38 H), (m, 2 H, major + minor), (m, 1 H, major + minor), 7.00 (t, J = 7.5 Hz, 1 H, major + minor), (m, 6.62 H, major + minor), 7.41 (d, J = 7.6 Hz, 0.38 H, minor), 7.52 (d, J = 7.9 Hz, 1 H, major + minor); 13 C MR (62.5 MHz, CDCl 3 ) δ 33.1 (major), 36.6 (minor), 46.7 (major), 46.9 (minor), 51.5 (minor), 52.1 (major), 57.8 (major), 58.6 (minor), 64.6 (minor), 65.3 (major), 98.3 (major), 99.2 (minor), (major), (minor), (major), (minor), (minor), (major), (minor), (major), (major + minor), (major), (minor), (minor), (major), (minor), (major), (minor), (major), (major + minor), (minor), (major), 1C (major + minor) is missing; MS-ESI : m/z [M+H] Benzyl-2-[1-(4-methoxyphenyl)but-3-enyl]oxazolidine 1c Bn Me btained as a yellow oil as a 58/42 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 4 H, major + minor), (m, 0.58 H, major), (m, 1.58 H, major + minor), (m, 5.84 H, major + minor), 4.3 (d, J = 4.0 Hz, 0.58 H, major), 4.44 (d, J = 4.3 Hz, 0.42 H, minor), (m, 2 H, major + minor), (m, 1 H, major + minor), (m, 2 H, S 11

12 major + minor), (m, 7 H, major + minor); 13 C MR (62.5 MHz, CDCl 3 ) δ 34.2 (major), 36.3 (minor), 48.7 (minor), 49.1 (major), 51.7 (minor), 52.2 (major), (minor), (major), 58.5 (major + minor), 64.6 (minor), 65.0 (major), 99.2 (minor), 99.8 (major), (minor), (major), (major), (minor), (major), (minor), (major), (minor), (major + minor), (major), 130.1, (minor), (minor), (major), (minor), (major), (major), (minor), (minor), (major); MS-ESI : m/z [M+H] d appears to be unstable and was not isolated. 3-Benzyl-2-(dec-1-en-4-yl)oxazolidine 1e Bn btained as a colorless oil as a 55/45 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 3 H, major + minor), (m, 11 H, major + minor), (m, 1.55 H, major + minor), (m, 1.45 H, major + minor), (m, 1 H, major + minor), (m, 1 H, major + minor), 3.39 (d, J = 1.4 Hz, 0.45 H, minor), 3.44 (d, J = 1.4 Hz, 0.55 H, major), (m, 3 H, major + minor), (m, 2 H, major + minor), (m, 1 H, major + minor), (m, 5 H, major + minor); 13 C MR (62.5 MHz, CDCl 3 ) δ 14.2 (major + minor), 22.8 (major + minor), 27.2 (major), 27.5 (minor), 28.1 (minor), 29.8 (major), 29.9 (minor), 30.3 (major), 32.0 (major + minor), 33.1 (major), 35.3 (minor), 98.4 (major), 98.7 (minor), (major), (minor), (major + minor), (major + minor), (major + minor), (minor), (major), (major), (minor); HRMS-ESI : m/z [M + H] + calcd for C 20 H 32 : ; found : Benzyl-2-(2-methylhex-5-en-3-yl)oxazolidine 1f Bn btained as a colorless oil as a 65/35 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 6 H, major + minor), (m, 1 H, major + minor), 1.88 (m, 0.65 H, major), (m, 1.65 H, major + minor), (m, 1.35 H, major + minor), (m, 0.35 H, minor) (m, 1 H, major + minor), 3.33 (d, J = 13.1 Hz, 0.65 H, major), 3.47 (d, J = 13.2 Hz, 0.35 H, minor), (m, 3 H, major + minor), 4.19 (d, J = 2.8 Hz, 0.65 H, major), 4.25 (d, J = 5.8 Hz, 0.35 H, minor), 4.98 (dd, J = 19.7, 13.7 Hz, 2 H, major + minor), (m, 1 H, major + minor), (m, 5 H, major + minor); 13 C MR (62.5 MHz, CDCl 3 ) δ 18.7 (minor), 20.1 (major), 20.4 (major), 21.6 (minor), 26.7 (minor), 28.7 (major), 30.6 (major), 31.6 (minor), 46.2 (minor), 46.5 (major), 51.6 (minor), 51.9 (major), 57.5 (major), 58.5 (minor), 63.7 (minor), 65.1 (major), 97.1 (major), 98.8 (minor), (major), (minor), (major + minor), (major + minor), S 12

13 128.7 (major), (minor), (minor), (major), (minor), (major); HRMS-ESI : m/z [M + H] + calcd for C 17 H 26 : ; found : ,-dibenzyl-1-(3-benzyloxazolidin-2-yl)but-3-en-1-amine 1g Bn 2 Bn btained as a colorless oil as a 73/27 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 3 H, major + minor), (m, 2 H, major + minor), 3.27 (m, 0.73 H, major), (m, 7.27 H, major + minor), 4.46 (br s, 0.73 H, major), 4.55 (d, J = 13.1 Hz, 0.27 H, minor), 5.03 (dd, J = 19.7, 10.9 Hz, 2 H, major + minor), (m, 1 H, major + minor), (m, 15 H, major + minor); 13 C MR (62.5 MHz, CDCl 3 ) δ 30.2 (major), 33.8 (minor), 51.2 (minor), 51.7 (major), 54.4 (major), 54.5 (minor), 57.2 (major), 58.7 (major), 58.9 (minor), 59.4 (minor), 63.3 (minor), 65.8 (major), 96.0 (major), 99.9 (minor), (major), (minor), (minor), (minor), (major), (minor), (minor), (major), (major + minor), (major + minor), (major + minor), (major + minor), (minor), (major), (major), (minor), (major), (minor); MS-ESI : m/z [M+H] + 414; IR (film) ν 3028, 2954, 2871, 286, 1495, 1453, 1373, 1058, 1028, 749, Benzyl-2-(7-benzyloxyhept-1-en-4-yl)oxazolidine 1h Bn Bn btained as a colorless oil as a 50/50 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 5 H), (m, 1.5 H), (m, 1.5 H), (m, 1 H), (m, 3 H), (m, 3 H), 4.16 (m, 1 H), 4.47 (s, 1 H), 4.48 (s, 1 H), (m, 2 H), (m, 1 H), (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 24.5, 26.6, 27.3, 27.5, 32.9, 35.2, 40.4, 40.6, 51.8, 52.0, 57.7, 57.9, 64.4, 64.5, 70.6, 70.8, 72.70, 72.75, 98.1, 98.4, 115.4, 115.9, 127.0, 127.3, , , , (2 C), (2 C), 137.1, 137.9, 138.6, Benzyl-2-(3-benzyloxybut-3-en-4-yl)oxazolidine 1i Bn Bn btained as a colorless oil as a 3/2 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), (m, 1 H), 3.06 (m, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), 3.92 (d, J = 13.3 Hz, 0.6 H), 4.01 (d, J = 13.2 Hz, 0.4 H), (m, 1 H), (m, 1 H), 4.72 (d, J = 11.2 Hz, 0.6 H), 4.77 (d, J = 11.4 Hz, 0.4 H), (m, 2 H), 5.87 (m, 1 H), S 13

14 (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 34.9 (major), 35.5 (minor), 51.7 (major), 51.9 (minor), 58.7 (minor), 59.0 (major), 64.4 (major), 64.5 (minor), 72.6 (major), 72.9 (minor), 79.8 (minor), 80.2 (major), 97.8 (minor + major), (minor + major), (minor + major), (minor + major), (minor), (major), (minor + major), (minor + major), (minor + major), (major), (minor), (major), (minor), (minor + major); 3-Benzyl-2-(3-trityloxybut-3-en-4-yl)oxazolidine 1j Tr Bn btained as a colorless oil as a 3/2 mixture of diastereomers. 1 H MR δ (m, 3 H), 2.87 (m, 1 H), 3.06 (d, J = 13.2 Hz, 0.6 H), (m, 1 H), 3.50 (m, 0.6 H), (m, 2.4 H), (m, 1 H), 4.24 (d, J = 13.2 Hz, 0.4 H), (m, 2 H), (m, 1 H), (m, 14 H), 7.54 (d, J = 7.3 Hz, 6 H); 13 C MR δ 34.9 (major), 36.4 (minor), 52.7 (major), 53.0 (minor), 58.5 (major), 59.3 (minor), 65.4 (major), 66.3 (minor), 75.3 (major), 75.6 (minor), 97.8 (minor), 98.0 (major), (major), (minor), (major + minor), (major + minor), (major + minor), (major), (minor), (major), (minor), (major + minor), (minor), (major), quaternary C are missing. HRMS-ESI : m/z [M + H] + calcd for C 33 H 34 2 : ; found : Benzyl-2-(1-trityloxypent-3-enyl)oxazoline 1k Tr Bn btained as a colorless oil as a 50/50 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ 1.77 (m, 0.5 H), 1.92 (m, 0.5 H), (m, 3H), (m, 1 H), (m, 3 H), 3.61 (m, 0.5 H), (m, 2.5 H), 4.41 (d, J = 4.7 Hz, 0.5 H), 4.48 (d, J = 4.7 Hz, 0.5 H), (m, 2 H), (m, 1 H), (m, 14 H), (m, 6 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 30.5, 32.8, 42.4, 42.5, 51.6 (2 C), 57.7, 58.1, 62.1, 63.2, 64.2, 64.4, 86.4, 86.5, 96.4, 96.6, 115.3, 115.9, 126.7, 126.9, (2 C), 12.2, 128.5, 128.6, (2 C), 137.1, 137.6, , , 144.3, Benzyl-2-[(E)-1-phenylhepta-1,6-dien-4-yl)oxazoline 1l Ph Bn btained as a colorless oil as a 1/1 mixture of diastereomers. 1 H MR (250 MHz, CDCl 3 ) δ 1.73 (m, 1 H), (m, 3H), (m, 2 H), 3.07 (dt, J = 9.7, 5.7 Hz, 1 H), 3.45 (d, J = 13.8 Hz, 1 H), (m, 3 H), 4.24 (m, 1 H), (m, 2 H), 5.83 (m, 1 H), (m, 1 H), 6.38 (d, J = S 14

15 16.1 Hz, 1 H), (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 31.8, 32.8, 33.7, 34.9, 41.4, 41.5, 52.0 (2 C), 57.7, 57.8, 64.5, 64.7, 97.7, 97.8, 115.8, 116.1, 125.9, 126.0, 126.7, 126.8, (2 C), (2 C), (2 C), , , 129.1, 130.0, 130.8, 131.0, 137.1, 137.7, (2 C), (2 C). General procedure for the preparation of 2, Procedure F: To a solution of oxazolidine 1 (1 mmol) in CH 2 Cl 2 (5 ml) was added in one portion Cp 2 Zr(H)Cl (309 mg, 1.2 mmol). The resulting mixture was stirred until complete dissolution (c.a min) then BF. 3 Et 2 was added (125 µl, 1 mmol) and the resulting solution was stirred for 30 min at rt. CH 2 Cl 2 (5 ml) and HCl (1 M, 2 ml) were added and the heterogeneous mixture was vigorously stirred. The organic layer was washed with HCl (1 M, 2 ml), a saturated aqueous solution of a 2 C 3 (2 x 2 ml), dried over MgS 4, filtered and concentrated under vacuum. 2-[-Benzyl--(2-phenylcyclopentyl)amino]ethanol 2a Ph Bn btained as a yellow oil in 89% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/20). 1 H MR (250 MHz, CDCl 3 ) δ (m, 5 H), 2.03 (m, 1 H), 2.42, (br s, 1 H), 2.57 (dt, J = 13.1, 4.7 Hz, 1 H), 2.80 (ddd, J = 13.1, 8.3, 4.7 Hz, 1 H), 2.97 (dt, J = 10.2, 7.9 Hz, 1 H), 3.30 (dt, J = 10.2, 8.3 Hz, 1 H), 3.47 (dt, J = 11.1, 4.7 Hz, 1 H), 3.53 (m, 2 H), 3.69 (d, J = 13.8 Hz, 1 H), (m, 2 H), (m, 8 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 24.0, 26.6, 34.5, 48.7, 53.0, 57.6, 62.5, 70.5, 126.3, 127.1, 128.3, 128.5, 128.7, 129.0, 129.1, 140.6; HRMS-ESI : m/z [M + a] + calcd for C 20 H 25 a : ; found : ; IR (film) ν 3426, 3028, 2955, 2871, 1494, 1453, 1055, 754, {-Benzyl--[2-(2-bromophenyl)cyclopentyl]amino}ethanol 2b Bn Br btained as a yellow oil in 88% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/10). 1 H MR (250 MHz, CDCl 3 ) δ (m, 1 H), (m, 3 H), (m, 1 H), (m, 1 H), 2.46 (br s, 1 H), (m, 2 H), (m, 6 H), (m, 4 H), (m, 4 H), 7.53 (dd, J = 7.9, 1.1 Hz, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.8, 25.9, 33.8, 46.0, 51.3, 55.5, 58.5, 67.3, 125.2, 127.1, 127.6, 127.8, 128.1, 128.3, 128.8, 132.9, 139.5, 143.7; MS-ESI : m/z [M+H] + 374; HRMS-ESI : m/z [M + H] + calcd for C 20 H 25 Br : ; found : ; IR (film) ν 3378, 3060, 2956, 2870, 1655, 1471, 1386, 1051, 1024, 752. S 15

16 Trans-2-{-benzyl--[2-(4-methoxyphenyl)cyclopentyl]amino}ethanol 2c Me Bn btained as a yellow oil in 78% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 75/25). 1 H MR (250 MHz, CDCl 3 ) δ (m, 1 H), (m, 1 H), (m, 3 H), (m, 1 H), 2.46 (br s, 1 H), 2.58 (dt, J = 13.0, 3.8 Hz, 1 H), 2.82 (ddd, J = 13.0, 8.8, 4.4 Hz, 1 H), 2.93 (dt, J = 10.3, 8.5 Hz, 1 H), 3.27 (dt, J = 10.3, 8.5 Hz, 1 H), 3.40 (dt, J = 10.8, 4.4 Hz, 1 H), (m, 2 H), 3.71 (d, J = 13.8 Hz, 1 H), 3.81 (s, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), (m, 4 H), (m, 3 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.8, 24.3, 33.6, 47.4, 51.1, 55.3, 55.7, 58.4, 68.1, 113.9, 127.0, 128.3, 128.6, 136.3, 139.6, 158.1, 1 C is missing; HRMS-ESI : m/z [M + H] + calcd for C 21 H 28 2 : ; found : ; ; IR (film) ν 3324, 2954, 2870, 2835, 1513, 1246, {-Benzyl--[(1RS, 2SR)-2-(-Boc-indol-3-yl)]cyclopentylamino}ethanol 2d Boc Bn btained as a colorless oil in 79% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/20). 1 H MR (250 MHz, CDCl 3 ) δ (m, 13 H), 1.98 (m, 1 H), 2.16 (m, 1 H), 2.53 (br s, 1 H), (m, 1 H), 2.85 (ddd, J = 12.9, 7.6, 4.6 Hz, 1 H), 3.26 (dd, J = 9.0, 8.4 Hz, 1 H), (m, 2 H), (m, 2 H), 3.75 (d, J = 13.8 Hz, 1 H), (m, 2 H), (m, 4 H), (m, 2 H), 7.50 (d, J = 7.6 Hz, 1 H), 8.17 (m, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 23.3, 25.7, 28.3, 32.8, 38.8, 51.6, 56.2, 58.7, 66.5, 83.4, 115.4, 119.5, 122.0, 122.3, 123.8, 124.3, 127.1, 128.3, 128.7, 130.2, 135.9, 139.5, 149.8; MS-ESI : m/z [M+H] + 435; ; IR (film) ν 3376, 2957, 2871, 1730, 1453, 1373, 1253, 1155, 745. Trans-2-(-Benzyl--(2-hexylcyclopentyl)amino)ethanol 2e Bn btained as a colorless oil in 91% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 85/15). 1 H MR (250 MHz, CDCl 3 ) δ 0.95 (t, J = 7.0 Hz, 3 H), (m, 2 H), (m, 8 H), (m, 4 H), (m, 3 H), 2.63 (dt, J = 13.1, 3.7 Hz, 1 H), 2.76 (br s, 1 H), (m, 2 H), 3.50 (ddd, J = 10.7, 4.8, 3.7 Hz, 1 H), 3.51 (d, J = 13.6 Hz, 1 H), 3.62 (ddd, J = 10.7, 9.2, 3.7 Hz, 1 H), 3.86 (d, J = 13.6 Hz, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 14.2, 22.8, 23.2, 24.4, 28.3, 29.7, 30.9, 32.0, 34.8, 42.0, 52.1, 56.1, 58.7, 67.3, 127.2, 128.5, S 16

17 128.9, 140.2; HRMS-ESI : m/z [M + H] + calcd for C 20 H 34 : ; found : ; IR (film) ν 3383, 2953, 2923, 2855, 1454, 1055, 699. Trans-2-[-Benzyl--(2-isopropylcyclopentyl)amino]ethanol 2f Bn btained as a pale yellow oil in 92% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/20). 1 H MR (250 MHz, CDCl 3 ) δ 0.67 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H), (m, 1 H), (m, 7 H), 2.23 (dt, J = 13.1, 3.3 Hz, 1 H), (br s, 1 H), 2.82 (ddd, J = 13.1, 10.2, 5.0 Hz, 1 H), 2.95 (q, J = 7.7 Hz, 1 H), 3.39 (d, J = 13.4 Hz, 1 H), 3.44 (ddd, J = 10.2, 5.0, 3.3 Hz, 1 H), 3.60 (td, J = 10.2, 3.3 Hz, 1 H), 3.79 (d, J = 13.4 Hz, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 18.1, 22.2, 24.0, 24.3, 26.5, 30.0, 48.2, 51.4, 56.1, 58.5, 64.0, 127.2, 128.5, 129.1, 139.9; HRMS-ESI : m/z [M + a] + calcd for C 17 H 27 : ; found : ; IR (film) ν 3421, 2953, 2870, 1453, 1054, 736, 699. Trans-2-(-Benzyl--(2-(dibenzylamino)cyclopentyl)amino)ethanol 2g Bn 2 Bn btained as a yellow oil in 98% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/20). 1 H MR (250 MHz, CDCl 3 ) δ (m, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), 2.45 (dt, J = 13.2, 3.7 Hz, 1 H), 2.59 (ddd, J = 13.2, 8.6, 4.2 Hz, 1 H), 3.16 (br s, 1 H), 3.21 (q, J = 7.7 Hz, 1 H), (m, 4 H), 3.48 (ddd, J = 10.6, 8.6, 3.7 Hz, 1 H), 3.62 (d, J = 13.4 Hz, 1 H), 3.70 (d, J = 13.6 Hz, 2 H), (m, 2 H), (m, 5 H), (m, 8 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.0, 22.5, 24.6, 51.2, 54.7, 55.7, 58.6, 62.4, 63.1, 126.8, 126.9, 128.1, 128.2, 128.8, 128.9, 139.6, 139.7; HRMS-ESI : m/z [M + H] + calcd for C 28 H 35 2 : ; found : ; IR (film) ν 3405, 3026, 2951, 2870, 1494, 1452, 1058, 745, {-benzyl--[(1SR, 2RS)-2-(3-benzyloxypropyl)cyclopentyl]amino}ethanol 2h Bn Bn btained as a yellow oil in 91% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/20). 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), (m, 9 H), 2.54 (dt, J = 13.0, 3.9 Hz, 1 H), (m, 3 H), (m, 4 H), 3.55 (ddd, J = 13.1, 9.8, 2.8 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 4.48 (s, 2 H), (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.9, S 17

18 24.0, 28.2, 30.5, 30.8, 41.5, 51.7, 55.8, 58.5, 67.2, 70.5, 72.7, 127.0, 127.4, 127.5, 128.2, 128.3, 128.6, 138.6, 139.9; HRMS-ESI : m/z [M + H] + calcd for C 28 H 35 2 : ; found : {-benzyl--[2-(benzyloxy)cyclopentyl]amino}ethanol 2i btained, as a 1/1 mixture of diastereomers in 77% combined yield. Diastereomers were separated by flash chromatography on silica gel (eluent : EP/AcEt : 90/10). Cis-2-(-benzyl--(2-(benzyloxy)cyclopentyl)amino)ethanol Bn Bn Colorless oil; 1 H MR (250 MHz, CDCl 3 ) δ 1.58 (m, 1 H), (m, 3 H), (m, 2 H), (m, 3 H), 3.36 (td, J = 8.6, 5.9 Hz, 1 H), (m, 2 H), 3.68 (d, J = 13.6 Hz, 1 H), 3.80 (d, J = 13.6 Hz, 1 H), 4.00 (m, 1 H), 4.48 (d, J = 13.4 Hz, 1 H), 4.60 (d, J = 13.4 Hz, 1 H), (m, 10 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 21.7, 25.6, 30.6, 52.3, 56.0, 58.6, 68.0, 71.2, 81.8, 127.1, 127.5, 127.7, 128.3, 128.4, 128.8, , ; MS-ESI : m/z [M+H] IR (film) ν 3373, 2933, 2875, 1719, 1652, 1452, 1272, 1068, 701. Trans-2-(-benzyl--(2-(benzyloxy)cyclopentyl)amino)ethanol Bn Bn Colorless oil; 1 H RMR (250 MHz, CDCl 3 ) δ 1.50 (m, 1 H), 1.56 (m, 1 H), (m, 4 H), (m, 2 H), 3.02 (ddd, J = 10.5, 7.4, 5.0 Hz, 1 H), 3.15 (br s, 1 H), 3.47 (app t, J = 5.2 Hz, 2 H), 3.82 (d, J = 14.3 Hz, 1 H), 3.85 (d, J = 14.3 Hz, 1 H), 3.93 (td, J = 4.5, 1.9 Hz, 1 H), 4.39 (d, J = 1.7 Hz, 1 H), 4.57 (d, J = 11.7 Hz, 1 H), (m, 10 H) ; 13 C MR (62.5 MHz, CDCl 3 ) δ 20.4, 26.5, 28.9, 53.7, 57.1, 59.2, 65.5, 70.3, 79.4, 127.0, 127.5, 127.8, 128.3, 128.7, 138.5, 2 C is missing; MS- ESI : m/z [M+H] ; IR (film) ν 3361, 2961, 2875, 1715, 1653, 1452, 1274, 1071, {-Benzyl--[(1RS, 2RS)-2-trityloxycyclopentyl]amino}ethanol 2j Tr Bn btained as a yellow oil in 74% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 90/10). 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), (m, 3 H), 1.84 (m, 1 H), 2.47 (app t, J = 4.6 Hz, 2 H), 2.68 (br s, 1 H), (m, 5 H), 3.85 (app q, J = 4.6 Hz, 1 H), (m, 14 H), 7.43 (d, J = 6.6 Hz, 6 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.8, 24.0, 32.7, 52.7, 56.4, 58.9, 69.8, 78.7, 86.6, 126.8, 127.1, 127.6, 128.3, 128.9, 129.1, 139.6, 145.1; HRMS-ESI : m/z [M + H] + calcd for C 33 H 36 2 : ; found : S 18

19 2-{-benzyl--[(1RS, 2SR)-2-(trityloxymethyl)cyclopentyl]amino}ethanol 2k Tr Bn btained as a yellow oil in 81% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 80/20). 1 H MR (250 MHz, CDCl 3 ) δ (m, 5 H), 1.91 (m, 1 H), 2.17 (m, 1 H), (m, 2 H), 2.68 (ddd, J = 12.8, 8.0, 4.8 Hz, 1 H), 2.88 (t, J = 8.0 Hz, 2 H), 3.13 (dd, J = 8.8, 4.5 Hz, 1 H), (m, 3 H), 3.65 (d, J = 13.7 Hz, 1 H), 7.08 (m, 2 H), (m, 12 H), 7.42 (d, J = 6.8 Hz, 6 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 23.4, 25.0, 29.3, 42.2, 51.8, 55.8, 58.6, 64.0, 66.5, 86.3, , , 127.6, 128.2, 128.4, 128.7, 139.8, 144.2; HRMS-ESI : m/z [M + H] + calcd for C 34 H 38 2 : ; found : {benzyl[(1SR, 2RS)-2-cinnamylpentyl]amino}ethanol 2l Ph Bn btained as a yellow oil in 78% yield after purification by flash chromatography on silica gel (eluent : EP/AcEt : 90/10). 1 H MR (250 MHz, CDCl 3 ) δ 1.21 (m, 1 H), 5.09 (m, 3 H), 1.73 (m, 2 H), (m, 2 H), 2.41 (m, 1 H), 2.54 (dt, J = 13.0, 3.5 Hz, 1 H), (m, 3 H), 3.42 (d, J = 13.6 Hz, 1 H), (m, 1 H), 3.47 (m, 1 H), 3.80 (d, J = 13.6 Hz, 1 H), 6.11 (dt, J =15.9, 7.1 Hz, 1 H), 6.28 (d, J = 15.9 Hz, 1 H), (m, 10 H); 13 C MR (250 MHz, CDCl 3 ) δ 22.8, 23.8, 30.2, 37.4, 41.7, 51.5, 55.9, 58.5, 66.2, 125.9, 126.7, 127.0, (2 C), 128.6, 129.2, 130.7, 137.6, 139.8; HRMS-ESI : m/z [M + H] + calcd for C 23 H 30 : ; found : Preparation of -Boc cyclopentylamines 3 : Procedure G. A mixture of 2 (0.47 mmol) in Me (5 ml) and Pd/C (10%, 50 mg) is stirred for 12 h under an atmosphere of H 2 at rt. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the corresponding debenzylated aminoalcohol. A solution of the above aminoalcohol (97 mg, 0.47 mmol) in CH 2 Cl 2 (2.5 ml) was added to a solution of Pb(Ac) 4 (266 mg, 0.57 mmol) in Me (2.5 ml) at 0 C. The resulting mixture was stirred for 30 min at 0 C. H 2.HCl (329 mg, 4.7 mmol) was added and the stirring was continued for 30 min. The solvent was removed under reduced pressure. The resulting solid was triturated with CH 2 Cl 2 (10 ml), and the solid was filtered off. The organic phase was washed with a saturated aqueous solution of a 2 C 3 (15 ml), dried over MgS 4, filtered and concentrated. CH 2 Cl 2 (10 ml), Et 3 (80 µl, 0.6 mmol) and Boc 2 (124 mg, 0.57 mmol) were added, and the resulting mixture was stirred for 2 h at rt. S 19

20 The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with EP/AcEt (90/10). Tert-butyl 2-phenylcyclopentylcarbamate 3a Ph HBoc btained as white crystals in 87% yield after purification by column chromatography on silica gel using EP/AcEt : (90/10) as eluent. Mp 100 C; 1 H MR (250 MHz, CDCl 3 ) δ 1.35 (s, 9 H), (m, 2 H), (m, 4 H), (m, 1 H), 3.97 (m, 1 H), 4.53 (m, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.3, 28.4, 32.8, 33.0, 52.3, 58.4, 79.2, 126.5, 127.5, 128.5, 142.9, 155.7; HRMS-ESI : m/z [M + a] + calcd for C 16 H 23 2 a : ; found : ; IR (film) ν 3377, 2960, 2935, 2869, 1683, 1522, 1368, 1169, 699. Tert-butyl 2-(4-methoxyphenyl)cyclopentylcarbamate 3c Me HBoc btained as a white solid in 71% yield after purification by column chromatography on silica gel using EP/AcEt : (90/10) as eluent. Mp 102 C; 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H) 1.37 (s, 9 H), (m, 4 H), 2.72 (m, 1 H), 3.77 (s, 3 H), 3.90 (m, 1 H), 4.46 (br s, 1 H), 6.84 (d, J = 8.6 Hz, 2 H), 7.16 (d, J = 8.6 Hz, 2 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.1, 28.4, 32.8 (2 C), 51.5, 55.3, 58.4, 79.2, 114.0, 128.4, 134.8, 155.7, 158.3; HRMS-ESI : m/z [M + a] + calcd for C 17 H 25 3 a : ; found : ; IR (film) ν 3377, 2960, 2936, 2870, 1682, 1511, 1367, 1247, , 823. Tert-butyl (1RS, 2RS)-2-trityloxymethylcyclopentylcarbamate 3k Tr HBoc btained as a white paste in 80% yield after purification by column chromatography on silica gel using EP/AcEt : (90/10) as eluent. 1 H MR (250 MHz, CDCl 3 ) δ (m, 11 H), (m, 2 H), (m, 2 H), 2.09 (m, 1 H), 3.12 (d, J = 4.4 Hz, 2 H), 3.59 (app quint, J = 7.2 Hz, 1 H), 4.79 (br s, 1 H), (m, 9 H), 7.43 (d, J = 7.0 Hz, 6 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.2, 27.6, 28.3, 33.4, 46.4, 55.7, 66.0, 78.8, 86.5, 126.8, 127.7, 128.7, 144.1, 155.6; HRMS-ESI : m/z [M + a] + calcd for C 30 H 35 3 a : ; found : Tert-butyl (Trans)-2-(methoxycarbonyl)cyclopentylcarbamate 4 S 20

21 Me 2 C HBoc A solution of 3k (480 mg, 1.04 mmol) in Ac / H 2 (4:1; 2 ml) was stirred for 2 h at rt. The solvent was removed under reduced pressure. The residue (180 mg, 0.84 mmol) was diluted in a mixture of acetone / H 2 (1 : 1, 5 ml), then Ru 2 (15 mg, 0.11 mmol) and ai 4 (583 mg, 2.72 mmol) were added. The mixture was stirred for 4 h at rt. H 2 (10 ml) and CH 2 Cl 2 (10 ml) were added, the organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (2 x 5 ml). The organic phases were combined, dried over a 2 S 4, filtered and concentrated under vacuum. The residue was diluted in Me (50 ml) and a solution of TMSCH 2 (2 M in Et 2, 0.9 ml) was added dropwise. After 1 h of stirring, the solvent was removed under vacuum. The residue was purified by flash column chromatography on silica gel eluting with CH 2 Cl 2 to give 4 (187 mg, 74%) as a white solid. Mp 58 C; 1 H MR (250 MHz, CDCl 3 ) δ 1.43 (s, 9 H), 1.47 (m, 1 H), 1.72 (m, 2 H), (m, 3 H), 2.59 (app q, J = 8.1 Hz, 1 H), 3.69 (s, 3 H), 4.11 (br m, 1 H), 4.71 (br s, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 22.8, 28.1, 28.2, 32.9, 50.7, 51.8, 56.0, 79.2, 155.2, 175.2; HRMS-ESI : m/z [M + a] + calcd for C 12 H 21 4 a : ; found : ; IR (film) ν 3368, 2977, 2954, 2878, 1731, 1683, 1529, 1370, 1294, 1172, 1048, Tert-butyl (1SR, 2RS)-2-(3-benzyloxypropyl)cyclopentylcarbamate 3h Bn HBoc A mixture of 2h (3.11 g, 8.48 mmol) in Me (65 ml) and Pd/C (10%, 450 mg) is stirred for 12 h under an atmosphere of H 2 at rt. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue (2.23 g) was diluted in Me / CH 2 Cl 2 (1:1, 60 ml), then Pb(Ac) 4 (4.13 g, 8.86 mmol) was added at 0 C. The resulting mixture was stirred for 30 min at 0 C. H 2. HCl (5.65 g, 80 mmol) was added and the stirring was continued for 30 min. The solvent was removed under reduced pressure. The resulting solid was triturated with CH 2 Cl 2 (10 ml), and the solid was filtered off. The organic phase was washed with a saturated aqueous solution of a 2 C 3 (15 ml), dried over MgS 4, filtered and concentrated under vacuum. The residue was diluted with CH 2 Cl 2 (40 ml). Et 3 (1.2 ml, 8.9 mmol) and Boc 2 (1.83 g, 8.4 mmol) were added and the resulting mixture was stirred for 2h at rt. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using EP/AcEt : (90/10) as eluent to give 3h (2.43 g, 86%). 1 H MR MR (250 MHz, CDCl 3 ) δ (m, 3 H), (m, 15 H), 1.83 (app hex, J = 6.5 Hz, 1 H), 2.00 (app hex, J = 6.6 Hz, 1 H), 3.44 (t, J = 5.9 Hz, 1 H), 3.52 (m, 1 H), 4.47 (s, 2 H), 4.61 (br d, J = 7.7 Hz, 1 H), (m, 5 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 21.7, 28.2, 29.9, 30.1, 32.8, 46.1, 57.2, 70.3, 72.6, 78.5, 127.2, 127.3, 128.0, 138.4, 155.4, 1 C is missing; HRMS-ESI : m/z [M + H] + calcd for C 20 H 32 3 : ; found : S 21

22 Tert-butyl octahydrocyclopenta[b]pyridine-1-carboxylate 5 H Boc H A mixture of 3h (2.32 g, 6.96 mmol) in Me (50 ml) and Pd/C (10%, 250 mg) is stirred for 12 h under an atmosphere of H 2 at rt. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to quantitatively give the correspond alcohol (1.57 g, 94%) as a colorless oil. 1 H MR (250 MHz, CDCl 3 ) δ (m, 3 H), 1.44 (s, 9 H), (m, 6 H), 1.86 (app hex, J = 6.5 Hz, 1 H), 2.03 (app hex, J = 6.7 Hz, 1 H), 2.33 (br s, 1 H), (m, 3 H), 4.52 (br s, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 21.9, 28.4, 29.6, 30.0, 31.0, 32.9, 46.4, 57.4, 62.7, 79.1, To a mixture of the above compound (1.51g, 6.2 mmol) and Et 3 (1.15 ml, 8 mmol) in CH 2 Cl 2 (20 ml) was slowly added MsCl (0.78 g, 6.8 mmol) at rt. After 4 h of stirring, the reaction was quenched with H 2 (5 ml). The organic layer was washed with H 2 (2 x 5 ml) dried over a 2 S 4, filtered and concentrated under vacuum to give the corresponding mesylate which was used in the next step without purification. To a solution of the crude mesylate (2.0 g, 6.2 mmol) in THF (15 ml) was added a solution of ahmds (1 M in THF, 8 ml) at 0 C. After 2h of stirring at rt, water (20 ml) was added and the aqueous layer was extracted with Et 2 (3 x 10 ml). The organic phases were combined, washed with aqueous HCl (1 M, 10 ml), aqueous ahc 3 (10%, 10 ml), brine (10 ml), dried over MgS 4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using CH 2 Cl 2 as eluent to give the title compound as a colorless oil (1.13 g, 81%). 1 H MR (250 MHz, CDCl 3 ) δ (m, 2 H), (m, 17 H), 2.33 (m, 1 H), 2.49 (m, 1 H), 2.65 (ddd, J = 13.3, 9.5, 3.3 Hz, 1 H), 3.92 (dt, J = 13.3, 3.7 Hz, 1 H) ; 13 C MR (62.5 MHz, CDCl 3 ) δ 20.0, 21.1, 27.7, 28.4, 29.2, 31.5, 44.7, 45.6, 63.2, 79.1, 156.2; HRMS-ESI : m/z [M + a] + calcd for C 13 H 23 2 a : ; found : Bromo--(2-chloro-6-methylphenyl)propanamide 6 Br H Cl To a vigorously stirred solution of 2-chloro-6-methylaniline (1.18 g, 7.06 mmol) in Ac (7 ml) was added successively a solution of Aca (1.73 g, mmol) in water (12 ml) and 3- bromopropanoyl chloride at 5 C. After 45 min of stirring the precipitate was collected by filtration, washed with H 2, and recrystallized from Me to give 6 as white crystals (1.34 g, 70%). Mp 122 C; 1 H MR (250 MHz, CDCl 3 ) δ 2.15 (s, 3 H), 2.91 (t, J = 6.1 Hz, 2 H), 3.61 (t, J = 6.1 Hz, 2 H), S 22

23 7.30 (m, 3 H), 7.83 (br s, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 18.8, 27.1, 39.1, 126.8, 127.8, 128.8, 131.5, 132.1, 138.0, 168.7; HRMS-ESI : m/z [M + H] + calcd for C 10 H 12 BrCl : ; found : ; IR (film) ν 3243, 3040, 1658, 1532, 1454, 773. (±)Rodocaine 7 H H Cl H To a solution of 5 (270 mg, 1.2 mmol) in CH 2 Cl 2 (10 ml) was added TFA (1 ml) at 0 C, and the resulting mixture was stirred for 30 min at 0 C and the solvent and the excess of reagent were removed under vacuum. CH 2 Cl 2 (20 ml) was added and the organic solution was washed with a saturated aqueous solution of a 2 C 3 (10 ml), dried over MgS 4, filtered and concentrated under reduced pressure. The residue was diluted with DMF (1 ml) then K 2 C 3 (165 mg) and 6 (305 mg, 1.1 mmol) were successively added. The mixture was stirred for 12h at rt. AcEt (20 ml) and H 2 (20 ml) were added. The organic phase was washed with H 2 (2 x 5 ml), dried over MgS 4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography to give the target molecule (229 mg, 65%) as a white solid. Mp 95 C; 1 H MR (250 MHz, CDCl 3 ) δ 1.04 (qd, J = 12.4, 3. 9 Hz, 1 H), 1.18 (m, 1 H), (m, 2 H), (m, 3 H), (m, 5 H), 2.03 (m, 1 H), 2.26 (s, 3 H), 2.40 (dt, J = 12.8, 4.0 Hz, 1 H), 2.49 (ddd, J = 17.2, 4.0, 3.5 Hz, 1 H), 2.80 (ddd, J = 17.2, 12.2, 4.0 Hz, 1 H), 3.26 (ddd, J = 12.8, 12.2, 3.5 Hz, 1 H), 3.32 (dt, J = 11.3, 2.3 Hz, 1 H), 7.10 (t, J = 7.7 Hz, 1 H), 7.14 (d, J = 7.4 Hz, 1 H), 7.26 (d, J = 7.4 Hz, 1 H), (br s, 1 H); 13 C MR (62.5 MHz, CDCl 3 ) δ 19.2, 20.0, 26.0, 29.2, 29.3, 29.8, 32.2, 45.1, 51.5, 52.4, 71.0, 127.1, 127.4, 129.1, 131.4, 133.5, 137.9, 171.1; HRMS-ESI : m/z [M + H] + calcd for C 18 H 26 Cl 2 : ; found : ; IR (film) ν 3240, 2932, 2871, 2801, 1688, 1660, 1525, Tert-butyl (S)-1- (-methoxy--methylcarbamoyl)but-3-enylcarbamate 11 H Boc To a solution of -Boc-2-allylglycine (0.75 g, 3.5 mmol) and Et 3 (0.49 ml, 3.5 mmol) in CH 2 Cl 2 (10 ml) was added PyBP (1.82 g, 3.5 mmol) followed after 5 min by,-dimethylhydroxylamine hydrochloride (373 mg, 3.8 mmol) and the reaction mixture was stirred for 4h. The mixture was diluted with AcEt (50 ml) and washed with HCl (1 M, 3 x 10 ml), ahc 3 (10% 3 x 10 ml) and brine (10 ml). The organic phase wad dried over a 2 S 4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a 11 Rishel, M. J.; Hecht, S. M. rg. Lett. 2001, 3, S 23