Four-Component Reactions towards Fused Heterocyclic Rings

Transcription

1 Four-Component Reactions towards Fused Heterocyclic Rings Etienne Airiau, a icolas Girard a, André Mann* a, Jessica Salvadori b, and Maurizio Taddei b [a] Faculté de Pharmacie, Université de Strasbourg Laboratoire d Innovation Thérapeutique UMR 7200 Université de strasbourg CRS 74, route du Rhin, BP 60024, F Illkirch, France. andre.mann@pharma.u-strasbg.fr [b] Dipartimento Farmaco Chimico Tecnologico Università degli Studi di Siena Via A. Moro 2, Siena, Italy Supporting Information Table of contents General Information Synthesis and characterization of -succinimidylesters 1 and 16 General procedures for hydroformylation Synthesis and characterization of oxazolopiperidones 5 and Synthesis and characterization of oxazoloazepinones Synthesis and characterization of oxazolopyridinediones Synthesis and characterization of 30 and 33 Synthesis and characterization of quinolizinones X-ray crystal structure of compound 27 MR spectra of previous compounds Pages S2 S2-S3 S3 S3-S5 S6 S7-S8 S8 S9-S10 S11 S12-S33 Corresponding Author: Dr André Mann* Faculté de Pharmacie Laboratoire d Innovation Thérapeutique UMR7200 Université de Strasbourg 74, route du Rhin, BP 60024, F Illkirch, France Tel: +33 (0) Fax: +33 (0) andre.mann@pharma.u-strasbg.fr -S1-

2 General Information: All reagents were used as purchased from commercial suppliers without further purification. The reactions were carried out in oven dried or flamed vessels and performed under argon. Solvents were dried and purified by conventional methods prior use. Et 2 and THF were freshly distilled from sodium/benzophenone and dichloromethane was distilled from CaH 2. Toluene was distilled from sodium. Flash column chromatography was performed with Merck silica gel 60, mm ( mesh). Merck aluminium backed plates pre-coated with silica gel 60 (UV 254 ) were used for thin layer chromatography and were visualized by staining with KMn 4. 1 H, 13 C spectra were recorded on Brüker (400 MHz / 100 MHz), (300 MHz / 75 MHz) or (200 MHz / 50 MHz) spectrometers. Conditions are specified for each spectrum (temperature 25 C unless specified). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sex, sextuplet; br, broad. Chemical shifts (δ) are given in ppm relative to the resonance of their respective residual solvent peak, CHCl 3 (7.27 ppm, 1 H; ppm, the middle peak, 13 C). Infrared spectra were taken with a icolet 380 FT-IR. High and low resolution mass spectroscopy analyses were conducted by the Institut Fédératif de Recherche 85 at the University of Strasbourg. Melting points were determined on a Büchi Melting Point B-540 apparatus in open capillary tubes and are uncorrected. Specific rotations were measured with a Perkin-Elmer apparatus using a 10 cm cell with a a 589 nm filter: values are given in 10-1 deg.cm 3.g -1. All the reactions under microwave dielectric heating were carried out in a sealed tube (10 or 80 ml) inside the cavity of a Discover synthesizer (CEM corp.) equipped with the gas addition kit, (max internal pressure 10 bar, max power 150 W). The internal temperature was measured by the vertically-focused IR temperature sensor. Ligand used for hydroformylation: Xantphos Me Biphephos [i] Me PPh 2 PPh 2 t Bu P P t Bu 2,5-Dioxopyrrolidin-1-yl-but-3-enoate 1 (general procedure). Chemical Formula: C 8 H 9 4 Exact Mass: 183,0532 Molecular Weight: 183,1614 In an ice bath, -hydroxysuccinimide (4412 mg, mmol) and, - dicyclohexylcarbodiimide (7550 mg, mmol) were added to a solution of but-3-enoic acid (3000 mg, 2.96 ml, mmol) in anhydrous CH 2 Cl 2 (60 ml). The suspension was stirred at room temperature for 24 h. The suspension was filtered off and the solvent was evaporated to give an oil. The residue was purified by flash chromatography (7:3 pentane-etac) to give 1 as a white solid (5619 mg, 88%). mp C; IR (neat) 1783, 1729, 1198, 1063, 1046 cm -1 ; 1 H MR (CDCl 3, 200 MHz) δ 5.91 (ddt, J = 17.1, 10.1, 6.7 Hz, 1H), (m, 2H), 3.38 (dt, J = 6.7, 1.5 Hz, 2H), 2.82 (s, 4H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (CH), (CH 2 ), 35.5 (CH 2 ), 25.6 (CH 2 ); LRMS-ESI (m/z) (2M+a) +. -S2-

3 Benzyl (1S)-1-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}but-3-enylcarbamate 16 CbzH Su Chemical Formula: C 17 H Exact Mass: 346,1165 Molecular Weight: 346,3346 calcd ; found ( = 2.0 ppm). The product was prepared as described for 1 and isolated by flash chromatography (75:25 hexane-etac) to give a waxy material (80%); IR (neat) 1780, 1725, 1710, 1200, 1063, 1046 cm -1 ; 1 H MR (CDCl 3, 200 MHz) δ 7.32 (m, 5H), 5.98 (s, 1H), 5.82 (m 1H), (m, 2H), 5.08 (s, 2H), (m, 6H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (CH), (2CH), (2CH), 120.7, (CH 2 ), 67.2 (CH 2 ), 51.5 (CH), 36.5 (CH 2 ), 26.5 (CH 2 ); HRMS-ESI (m/z): [M+H] + General procedure A for hydroformylation: A solution of dicarbonylacetylacetonato rhodium(i) (1 mol%) and Biphephos (2 mol%) in anhydrous degassed solvent (3 ml), prepared in a Schlenk glassware under inert atmosphere, was introduced under inert atmosphere into a stainless steel autoclave containing a solution of the desired olefin (1 eq.), compound 1 or 2 (1.2 eq.) and acid (if necesssary) in anhydrous degassed solvent to reach a final concentration of 0.04 M. The autoclave was flushed with H 2 /C (1:1) three times. Then, the autoclave was filled with 5 atm. of H 2 /C (1:1) and heated at the desired temperature with stirring for 12 h. Then, the autoclave was cooled to room temperature and gases were slowly and carefully released. Aqueous saturated a 2 C 3 solution was added and the aqueous layer was extracted three times with EtAc. The organic layer was dried over a 2 S 4, filtered and concentrated to give an oil which was purified by flash chromatography. General procedure B for hydroformylation: A solution of dicarbonylacetylacetonato rhodium(i) (1 mol%) and Biphephos (2 mol%) in anhydrous degassed THF (2 ml), was introduced into a microwave vessel containing a THF solution (2 ml) of the desired olefin (1 eq.), compound 1, 2, 3 or 16 (1.2 eq.) and ptsa (10 mol%) under inert atmosphere. The solution was submitted to pressurized syngas (H 2 /C: 1/1) at 7 atm. and heated at 70 C by microwave irradiation at 150 W (value previously settled on the microwave oven) for 1 h. The flask was cooled and the internal gas released. Aqueous saturated a 2 C 3 solution was added and the aqueous layer was extracted three times with EtAc. The organic layer was dried over a 2 S 4. After filtration and concentration in vacuo the crude mixture was purified by flash chromatography. (3R,8aS)-3-Phenyltetrahydro-2H-oxazolo[3,2-a]pyridin-5(3H)-one 5a. Chemical Formula: C 13 H 15 2 Exact Mass: 217,1103 Molecular Weight: 217,2637 Compound 5a was prepared following the general procedure A starting from (R)-(-)-2-amino-2-phenylethanol (100 mg, 0.73 mmol), 1 (160 mg, 0.87 mmol) and PPTS (9.2 mg, mmol) in THF. The residue was purified by flash chromatography (98:2 EtAc-MeH) to give 5a as a pale yellow solid (128 mg, 81%). mp C {lit.: [ii] C}; IR (neat) 2930, 2871, 1650, 1443, 1307, 996, 698 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ (m, 2H), (m, 3 H), 5.27 (t, J = 7.8 Hz, 1H), 5.02 (dd, J = 9.0, 4.6 Hz, 1H), 4.48 (dd, J = 8.9, 8.0 Hz, 1H), 3.76 (dd, J = 9.0, 7.8 Hz, 1H), 2.52 (ddt, J = 18.0, 5.7, 1.7 Hz, 1H), (m, 1H), 2.34 (ddd, J = 18.0, 11.4, 6.4 Hz, 1H), (m, 1H), 1.77 (tddd, J = 13.8, 11.4, 5.9, 2.8 Hz, 1H), 1.54 (dddd, J = 13.6, 12.7, 9.1, 3.3 Hz, 1H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (CH), (CH), (CH), 88.7 (CH), 72.4 (CH 2 ), 58.1 (CH), 31.3 (CH 2 ), 28.4 (CH 2 ),17.1 (CH 2 ); -S3-

4 [α] 20 D (c 0.6, CH 2 Cl 2 ) {lit.: [iii] [α] 22 D (c 0.6, CH 2 Cl 2 )}; LRMS-ESI (m/z): 218 (M+H) +, 240 (M+a) + ; HRMS-ESI (m/z): [M+H] + calcd ; found ( = 3.0 ppm). (3R,8aR)-3-Phenyltetrahydro-2H-oxazolo[3,2-a]pyridin-5(3H)-one 5b. Chemical Formula: C 13 H 15 2 Exact Mass: 217,1103 Molecular Weight: 217, ( = 2.5 ppm). Purification conditions: 96:4 EtAc-MeH. waxy solid (12 mg, 8%). IR (neat) 2956, 2872, 1651, 1467 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ (m, 4H), (m, 1H), 4.92 (dd, J = 6.7, 0.9 Hz, 1H), 4.86 (dd, J = 9.4, 3.4 Hz, 1H), 4.16 (dd, J = 9.0, 6.8 Hz, 1H), 4.03 (dd, J = 9.0, 1.2 Hz, 1H), (m, 2H), (m, 1H), 2.03 (m, 1H), (m, 2H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (CH), (CH), (CH), 89.0 (CH), 73.9 (CH 2 ), 58.9 (CH), 31.2 (CH 2 ), 28.4 (CH 2 ),17.9 (CH 2 ); [α] 20 D (c 0.6, CH 2 Cl 2 ) {lit.: [iii] [α] 22 D (c 2.2, CH 2 Cl 2 )}; HRMS-ESI (m/z): [M+H] + calcd ; found (3R,8aS)-3-Benzylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-one 11. Ph Chemical Formula: C 14 H 17 2 Exact Mass: 231,1259 Molecular Weight: 231,2903 Compound 11 was prepared following the general procedure A starting from (R)-2-amino-3-phenyl-1-propanol 6 (100 mg, 0.66 mmol), 1 (145 mg, 0.79 mmol) and PPTS (8.3 mg, 0,03 mmol) in THF. The residue was purified by flash chromatography (98:2 EtAc-MeH) to give 11 as a white solid (103 mg, 67%). mp C; IR (neat) 1637, 1450, 1412, 999, 702 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ (m, 2H), (m, 3 H), (m, 2H), 4.03 (dd, J = 9.0, 7.6 Hz, 1H), 3.62 (dd, J = 9.0, 7.6 Hz, 1H), 3.28 (dd, J = 13.4, 3.7 Hz, 1H), 2.80 (dd, J = 13.4, 9.2 Hz, 1H), 2.50 (ddt, J = 18.1, 6.0, 1.8 Hz, 1H), 2.31 (ddd, J = 18.1, 11.8, 6.7 Hz, 1H), (m, 1H), (m, 1H), 1.64 (tddd, J = 13.8, 11.6, 6.0, 2.8 Hz, 1H), 1.40 (dddd, J = 13.8, 12.6, 9.2, 3.3 Hz, 1H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (CH), (CH), (CH), 87.3 (CH), 69.3 (CH 2 ), 55.1 (CH), 37.8 (CH 2 ), 31.4 (CH 2 ), 28.2 (CH 2 ), 17.2 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 0.8 ppm). (3S,8aR)-3-Isopropylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-one 12. Chemical Formula: C 10 H 17 2 Exact Mass: 183,1259 Molecular Weight: 183,2475 Compound 12 was prepared following the general procedure A starting from (S)-(+)-2-amino-3-methyl-1-butanol 7 (100 mg, 0.97 mmol), 1 (213 mg, 1.16 mmol) and PPTS (12.2 mg, 0.05 mmol) in THF. The residue was purified by flash chromatography (97:3 EtAc-MeH) to give 12 as a yellow oil (83 mg, 47%). IR (neat) 2957, 2873, 1648, 1464 cm -1 ; 1 H MR (CDCl 3, 300 MHz) δ 4.73 (dd, J = 8.6, 4.7 Hz, 1H), 4.18 (td, J = 7.5, 6.4 Hz, 1H), 4.03 (dd, J = 8.3, 8.0 Hz, 1H), 3.66 (dd, J = 8.6, 6.9 Hz, 1H), 2.49 (br ddt, J = 17.9, 5.8, 1.9 Hz, 1H), (m, 3H), (m, 1H), 1.66 (tddd, J = 13.7, 11.0, 6.1, 2.6 Hz, 1H), 1.42 (tdd, J = 13.0, 8.6, 3.3 Hz, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H); 13 C MR (CDCl 3, 50 MHz) δ (C), 87.7 (CH), 66.6 (CH 2 ), 59.2 (CH), 31.7 (CH 2 ), 30.1 (CH), 28.5 (CH 2 ), 19.1 (CH 2 ), 17.0 (CH 3 ); [α] 20 D +3.2 (c 1.0, CHCl 3 ) {lit. [iv] [α] 20 D +13 (c 1.1, EtH)}; HRMS-ESI (m/z): [M+H] + calcd ; found ( = 2.4 ppm). -S4-

5 (2S,3R,8aS)-3-Methyl-2-phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-one 13. Ph Chemical Formula: C 14 H 17 2 Exact Mass: 231,1259 Molecular Weight: 231,2903 Compound 13 was prepared following the general procedure A starting from D-(+)-norephedrine 8 (100 mg, 0.66 mmol), 1 (145 mg, 0.79 mmol) and PPTS (8.3 mg, 0.03 mmol) in THF. The residue was purified by flash chromatography (98:2 EtAc-MeH) to give 13 as a colorless oil (83 mg, 67%). IR (neat) 2958, 1628, 1448, 1329 cm -1 ; 1 H MR (CDCl 3, 300 MHz) δ (m, 5H), 5.28 (dd, J = 9.3, 4.2 Hz, 1H), 5.14 (d, J = 6.1 Hz, 1H), 4.87 (dq, J = 6.6, 6.6 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), 0.81 (d, J = 6.6 Hz, 3H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (CH), (CH), (CH), 86.0 (CH), 80.0 (CH), 53.4 (CH), 30.9 (CH 2 ), 29.3 (CH 2 ), 16.7 (CH 2 ), 14.1 (CH 3 ); [α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.0 ppm). Methyl (3R,8aR)- 5-oxohexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-3-carboxylate 14. Me 2 C Chemical Formula: C 9 H 13 4 Exact Mass: 199,0845 Molecular Weight: 199,2038 Compound 14 was prepared following the general procedure B starting from L-Serine methylester 9 (131 mg, 1.10 mmol), 1 (242 mg, 1.32 mmol) and ptsa (20.9 mg, 0.11 mmol) in THF. The residue was purified by flash chromatography (95:5 CH 2 Cl 2 -MeH) to give 14 as a colorless oil (99 mg 45%). IR (neat) 2953, 1720, 1645, 1450 cm -1 ; 1 H MR (CDCl 3, 200 MHz) δ (m, 1H), 4.39 (t, J = 6.3 Hz, 1H), 4.09 (q, J = 6.8 Hz, 1H), (m, 4H), (m, 2H), (m, 4H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), 87.1 (CH), 66.9 (CH), 53.2 (CH 3 ), 52.6 (CH 2 ), 33.2 (CH 2 ), 32.7 (CH 2 ), 19.6 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); LRMS-ESI (m/z): [M+H] + ; HRMS-ESI (m/z): [M+H] + calcd ; found ( = 5.0 ppm) (4aS,5aS,10bR)-2,3,4,4a,6,10b-Hexahydro-1H,5aH-indeno[1',2':4,5][1,3]oxazolo[3,2-a]pyridin-1-one 15 Chemical Formula: C 14 H 15 2 Exact Mass: 229,1103 Molecular Weight: 229,2744 Compound 15 was prepared following the general procedure B starting from (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol 10 (123 mg, 0.82 mmol), 1 (179 mg, 0.98 mmol) and ptsa (15.2 mg, 0.08 mmol) in THF. The residue was purified by flash chromatography (98:2 CH 2 Cl 2 -MeH) to give 15 as a white solid (153 mg, 81%). mp C; IR (neat) 3010, 2950, 1655, 1450, 1390 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 7.57 (d, J = 8.0 Hz, 1H), (m, 3H), 5.89 (d, J = 6.4 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H); 13 C MR (CDCl 3, 100 MHz) δ (C), (C), (C), (CH), (CH), (CH), (CH), 84.8 (CH), 79.1 (CH), 62.4 (CH), 38.7 (CH 2 ), 31.2 (CH 2 ), 28.2 (CH 2 ), 17.2 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); LRMS-ESI (m/z) + : [M+a] + ; HRMS- ESI (m/z): [M+H] + calcd ; found S5-

6 Benzyl (3S,6S,9aR)-5-oxo-3-phenyloctahydro[1,3]oxazolo[3,2-a]azepin-6-ylcarbamate 18 CbzH Ph Chemical Formula: C 22 H Exact Mass: 380,1736 Molecular Weight: 380,4370 Compound 18 was prepared following the general procedure B starting from (S)-(-)-2-amino-2-phenylethanol 17 (50 mg, 0.36 mmol), 16 (151 mg, 0.43 mmol) and ptsa (7 mg, mmol) in THF. The residue was purified by flash chromatography (98:2 CH 2 Cl 2 -MeH) to give 18 as a colorless oil (89 mg, 65%). IR (neat) 3250, 2955, 1690, 1645, 1450, 1390 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ (m, 10H), 6.54 (bs, 1H), 5.21 (m, 1H), (m, 3H), 4.49 and 4.24 (2H, AB part of an ABX system), 3.30 (t, J = 8.0 Hz, 1H), (m, 4H), 1.93 and 1.39 (m, 2H); 13 C MR (CDCl 3, 100 MHz) (C), (C), (C), (6 C and CH), 83.3 (CH), 74.7 (CH), 66.9 (CH), 59.2 (CH 2 ), 57.5 (CH 2 ), 32.2 (CH 2 ), 32.0 (CH 2 ), 21.0 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found Benzyl (3S,6S,9aS)-3-isopropyl-5-oxooctahydro[1,3]oxazolo[3,2-a]azepin-6-ylcarbamate 19 CbzH Chemical Formula: C 19 H Exact Mass: 346,1893 Molecular Weight: 346,4207 Compound 19 was prepared following the general procedure B starting from (R)-(-)-2-amino-3-methyl butanol 7 (50 mg, 0.48 mmol), 16 (201 mg, 0.58 mmol) and ptsa (9 mg, mmol) in THF. The residue was purified by flash chromatography (98:2 CH 2 Cl 2 -MeH) to give 19 as a colorless oil (118 mg, 70%). IR (neat) 3250, 2955, 1695, 1646, 1450, 1390, cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 7.37 (m, 5H), 6.54 (bs, 1H), (m, 3H), 4.49 (m, 1H), 4.14 (m, 1H), 3.60 (m, 2H), (m, 7H), 0.93 (d, J = 7 Hz, 3H), 0.77 (d, J = 7 Hz, 3H); 13 C MR (CDCl 3, 100 MHz) (C), (C), (C), (CH), (2CH), (2 CH), 81.2 (CH), 68.1 (CH), 66.9 (CH), 59.5 (CH 2 ), 58.1 (CH 2 ), 32.1 (CH 2 ), 32.0 (CH 2 ), 28.8 (CH 2 ), 21.0 (CH), 19.9 (CH 3 ), 17.6 (CH 3 ); [α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.0 ppm). Benzyl (5aS,6aS,10S,12aR)-11-oxo-5a,6a,7,8,9,10,11,12a-octahydro-5H-indeno[1',2':4,5][1,3]- oxazolo[3,2-a]-azepin-10-ylcarbamate 20 CbzH Chemical Formula: C 23 H Exact Mass: 392,1736 Molecular Weight: 392,4477 Compound 20 was prepared following the general procedure B starting from (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol 10 (123 mg, 0.82 mmol), 16 (339 mg, 0.98 mmol) and ptsa (16 mg, mmol) in THF. The residue was purified by flash chromatography (98:2 CH 2 Cl 2 -MeH) to give 20 as a white solid (225 mg, 70%). mp: C; IR (KBr) 3010, 2950, 1698, 1655, 1450, 1390 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 7.37 (m, 7H), 7.17 (d, J = 3.0 Hz, 1H), 6.82 (t, J = 3.0 Hz, 1H), 6.54 (bs, 1H), 5.28 (m, 1H), (m, 3H), 3.95 (dd, J = 4.0, 1.0 Hz, 1H), 3.30 (dd, J = 5.0, 2.0 Hz, 1H), 2.91 (dd, J = 5.0, 2.0 Hz, 1H), 2.58 (d, J = 5.0 Hz, 1H), (m, 4H), 1.60 (m, 1H), 1.41 (m, 1H); 13 C MR (CDCl 3, 100 MHz) (C), (C), (C), (C), (C), (CH), (6 CH), 68.2 (CH), 65.4 (CH), 64.5 (CH), 53.4 (CH), 47,6 (CH), 34.4 (CH 2 ), 28.9 (CH 2 ), 21.4 (CH 2 ), 21.2 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.5 ppm). -S6-

7 (3R,8aS)-3-Benzyltetrahydro-2H-oxazolo[3,2-a]pyridine-2,5(3H)-dione 26. Chemical Formula: C 14 H 15 3 Exact Mass: 245,1052 Molecular Weight: 245,2738 Compound 26 was prepared following the general procedure A starting from D-phenylalanine 21 (200 mg, 1.21 mmol), 1 (266 mg, 1.45 mmol) and PPTS (15.2 mg, 0.06 mmol) in THF. The residue was purified by flash chromatography (20:80 pentane-etac) to give 26 as a white solid (204 mg, 69%). mp C; IR (neat) 2939, 1793, 1654, 1439, 1355, 1235, 1176, 1064, 942, 704 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ ,25 (m, 3H), (m, 2H), 4.81 (dd, J = 5.1, 3.6 Hz, 1H), 4.20 (dd, J = 9.2, 4.6 Hz, 1H), 3,25-3,23 (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H); 13 C MR (CDCl 3, 100 MHz) δ (C), (C), (C), (CH), (CH), (CH), 88.6 (CH), 56.4 (CH), 35.8 (CH 2 ), 30.5 (CH 2 ), 28.0 (CH 2 ), 15.8 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); LRMS-ESI (m/z) (M+H) + ; HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.0 ppm). (3R,8aS)-3-Phenyltetrahydro-2H-oxazolo[3,2-a]pyridine-2,5(3H)-dione 27. Compound 27 was prepared following the general procedure A starting from (R)-phenylglycine 22 (200 mg, 1.32 mmol), 1 (291 mg, 1.59 mmol) and PPTS (33.2 mg, 0.13 mmol) in toluene. The residue was purified by flash chromatography (20:80 pentane-etac) to give 27 as a white solid (165 mg, 54%). mp C; IR (neat) 2935, 1778, 1665, 1439, 1356, 1182, 1036, 956 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ (m, 5H), 5.77 (s, 1H), 5.68 (dd, J = 8.8, 4.4 Hz, 1H), (m, 1H), Chemical Formula: C 13 H 13 3 (m, 2H), (m, 1H), (m, 2H); 13 C MR (CDCl 3, 100 Exact Mass: 231,0895 Molecular Weight: 231,2472 MHz) δ (C), (C), (C), (CH), 128.9(CH), (CH), 88.1 (CH), 57.4 (CH), 30.9 (CH 2 ), 28.1 (CH 2 ), 15.9 (CH 2 );[α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+Li] + calcd ; found ( = 1.2 ppm). (3S,8aR)-3-Isopropyltetrahydro-2H-oxazolo[3,2-a]pyridine-2,5(3H)-dione 28. Chemical Formula: C 10 H 15 3 Exact Mass: 197,1052 Molecular Weight: 197,2310 Compound 28 was prepared following the general procedure A starting from L-valine 23 (100 mg, 0.85 mmol), 1 (188 mg, 1.02 mmol) and ptsa (16.2 mg, mmol) in THF. The residue was purified by flash chromatography (20:80 pentane-etac) to give 28 as a white solid (118 mg, 70%). mp C; IR (neat) 2964, 1795, 1658, 1428, 1356, 1232, 1177, 1032, 953 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 5.53 (dd, J = 9.5, 4.5 Hz, 1H), 4.49 (d, J = 5.3 Hz, 1H), 2.59 (ddt, J = 18.6, 6.4, 1.7 Hz, 1H), (m, 1H), 2.39 (ddd, J = 17.5, 10.9, 6.8 Hz, 1H), (m, 1H), (m, 1H), 1.75 (tddd, J = 14.0, 11.5, 6.3, 2.7 Hz, 1H), (m, 1H), 1.08 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); 13 C MR (CDCl 3, 100 MHz) δ (C), (C), 88.8 (CH), 59.9 (CH), 31.3 (CH), 30.9 (CH 2 ), 28.5 (CH 2 ), 18.9 (CH 3 ), 18.7 (CH 3 ), 15.7 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); LRMS-ESI (m/z) (M+H) + ; HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.6 ppm). -S7-

8 (3S,8aR)-3-(2-(Methylthio)ethyl)tetrahydro-2H-oxazolo[3,2-a]pyridine-2,5(3H)-dione 29. S Chemical Formula: C 10 H 15 3 S Exact Mass: 229,0773 Molecular Weight: 229,2960 Compound 29 was prepared following the general procedure A starting from L-methionine 24 (100 mg, 0.67 mmol), 1 (147 mg, 0.80 mmol) and PPTS (8.4 mg, mmol) in THF. The residue was purified by flash chromatography (20:80 pentane-etac) to give 29 as a yellow oil (109 mg, 71%). IR (neat) 2918, 1789, 1736, 1657, 1466, 1409, 1237, 1174, 1064, 950 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 5.60 (dd, J = 9.4, 4.3 Hz, 1H), 4.70 (dd, J = 6.4, 6.2 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 2.24 (ddt, J = 14.3, 8.2, 5.8 Hz, 1H), (m, 1H), 2.09 (s, 3H), (m, 1H), (m, 1H), (m, 1H); 13 C MR (CDCl 3, 100 MHz) δ (C), (C), 88.1 (CH), 53.8 (CH), 30.7 (CH 2 ), 29.8 (CH 2 ), 29.4 (CH 2 ), 28.2 (CH 2 ), 15.9 (CH 3 ), 15.1 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); LRMS-ESI (m/z) (M+H) +, (M-47) + ; HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.0 ppm). Benzyl (3S,6S,9aR)-3-benzyl-2,5-dioxooctahydro[1,3]oxazolo[3,2-a]azepin-6-ylcarbamate 30 CbzH Ph Compound 30 was prepared following the general procedure A starting D-phenylalanine 25 (200 mg, 1.21 mmol), 16 (502 mg, 1.45 mmol) and ptsa (25 mg, mmol) in THF. The residue was purified by flash chromatography (20:80 pentane-etac) to give 30 as a yellow oil (321 mg, 65%). IR (neat) 3300, 2918, 1726, 1700, 1657 cm -1 ; 1 H MR (CDCl 3, 400 MHz) δ 7.30 (m, 6H), 7.25 (m, 4H), 6.54 (bs, 1H), 5.77 (dd, J = 4.0, 2.0 Hz, 1H), 5.13 (dd, J = 4.0, 1.0 Hz, 1H), 5.04 (s, 2H), 3.72 (dd, J = 6.0, 3.0 Hz, 1H) 3.30 (d, J = 8.0 Hz, 1H), 3.16 (dd, J = 8.0, 4.0 Hz, 1H), (m, 6H); 13 C MR (CDCl 3, 100 MHz) δ (C), (C), (C), (C), (C), (6 CH), 88.1 (CH), 66.9 (CH), 58.6 (CH), 58.3 (CH 2 ), 34.2 (CH 2 ), 32.0 (CH 2 ), 30.7 (CH 2 ), 21.1 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found (S)-Methyl 2-amino-3-(1H-indol-3-yl)propanoate 33. H C 2 Me H 2 Chemical Formula: C 23 H Exact Mass: 408,1685 Molecular Weight: 408,4471 Chemical Formula: C 12 H Exact Mass: 218,1055 Molecular Weight: 218,2518 Acetyl chloride (2.09 ml, 29.4 mmol) was added dropwise to MeH (13 ml) at 0 C under argon atmosphere. After five minutes, L-tryptophane (2.00 g, 9.8 mmol) was added and the solution was stirred at reflux for two hours. After cooling, solvent was evaporated and the residue was dissolved in water and saturated aqueous ahc 3 solution was added (50 ml) and the aqueous layer was extracted with CH 2 Cl 2 (3*30 ml). The organic layer was dried over a 2 S 4, filtered and concentrated to give 33 as a pale yellow solid (1.68 g, 79%) which was used without further purification. mp C; IR (neat) 3259, 3295, 1727, 1567, 1450, 1224 cm -1 ; 1 H MR (CDCl 3, 300 MHz) δ 8.23 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), (m, 2H), 7.06 (d, J = 1.5 Hz, 1H), 3.85 (m, 1H), 3.73 (s, 3H), 3.30 (dd, J = 14.2, 4.7 Hz, 1H), 3.07 (dd, J = 14.2, 7.9 Hz, 1H), 1.63 (br s, 2H); 13 C MR (CDCl 3, 75 MHz) δ (C), (C), (C), (CH), (CH), (CH), (CH), (CH), (C), 55.1 (CH), 52.1 (CH 3 ), 30.8 (CH 2 ); [α] 20 D (c 1.0, CHCl 3 ); LRMS-ESI (m/z): (M+H) +, (M-H 2 ) +. -S8-

9 1,2,3,6,7-Hexahydro-9-methoxy-4H-benzo[a]quinolizin-4-one 34. Me Chemical Formula: C 14 H 17 2 Exact Mass: 231,1259 Molecular Weight: 231,2903 Compound 36 was prepared following the general procedure A starting from 2-(3-methoxyphenyl)-ethylamine (100 mg, 0.66 mmol), 1 (145 mg, 0.79 mmol) and BF 3.Et 2 (33 µl, 0.26 mmol) in THF. The residue was purified by flash chromatography (10:90 to 0:100 pentane-etac) to give 36 as a yellow oil (126 mg, 82%). IR (neat) 2929, 2837, 1606, 1503, 1464, 1237 cm -1 ; 1 H MR (CDCl 3, 300 MHz) δ 7.11 (d, J = 8.5 Hz, 1H), 6.78 (dd, J = 8.7, 2.6 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), (m, 1H), 4.61 (dd, J = 10.6, 4.4 Hz, 1H), 3.79 (s, 3H), (m, 2H), (m, 1H), (m, 2H), 2.36 (ddd, J = 17.7, 11.3, 6.4 Hz, 1H), (m, 1H), (m, 1H), (m, 1H); 13 C MR (CDCl 3, 75 MHz) δ (C), (C), (C), (C), (CH), (CH), (CH), 56.6 (CH), 55.4 (CH 3 ), 39.8 (CH 2 ), 32.3 (CH 2 ), 30.7 (CH 2 ), 29.3 (CH 2 ), 19.7 (CH 2 ); HRMS-ESI (m/z): [M+H] + calcd 232,1332; found ( = 1.7 ppm). 1,2,3,6,7,12b-Hexahydroindolo[2,3-a]quinolizin-4(12H)-one 35. H Chemical Formula: C 15 H 16 2 Exact Mass: 240,1263 Molecular Weight: 240,3003 Compound 37 was prepared following the general procedure A as described above from tryptamine (100 mg, 0.62 mmol), 1 (137 mg, 0,75 mmol) and BF 3.Et 2 (15 µl, 0,12 mmol) in THF. The residue was purified by flash chromatography (98:2 EtAc-MeH) to give 37 (119 mg, 79%) as a white solid. mp C; IR (neat) 3200, 2921, 2851, 1607, 1437 cm -1 ; 1 H MR (CDCl 3 + CD 3 D, 300 MHz) δ 7.49 (br d, J = 7.5 Hz, 1H), 7.33 (br d, J = 7.9 Hz, 1H), 7.16 (td, J = 7.5, 1.4 Hz, 1H), 7.10 (td, J = 7.5, 1.5 Hz, 1H), (m, 1H), 4.78 (br dd, J = 9.8, 4.8 Hz, 1H), (m, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 2H); 13 C MR (CDCl 3 + CD 3 D, 50 MHz) δ (C), (C), (C), (C), (CH), (CH), (CH), (CH), (C), 54.7 (CH), 40.5 (CH 2 ), 32.2 (CH 2 ), 28.7 (CH 2 ), 21.0 (CH 2 ), 19.2 (CH 2 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 2.6 ppm). (6S,12bR)-Methyl 1,2,3,4,6,7,12,12b-octahydro-4-oxoindolo[2,3-a]-quinolizine-6-carboxylate 36a. H H C 2 Me Chemical Formula: C 17 H Exact Mass: 298,1317 Molecular Weight: 298,3364 Compound 38a was prepared following the general procedure A as described above from 35 (109 mg, 0.50 mmol) in THF. The residue was purified by flash chromatography (25:75 pentane-etac) to give 38a (79 mg, 53%) as a pale yellow solid. mp C; IR (neat) 3273, 2952, 2850, 1737, 1610, 1429 cm -1 ; 1 H MR (CDCl 3, 300 MHz) δ 8.07 (br s, 1H), 7.53 (dd, J = 6.6, 2.0 Hz, 1H), (m, 1H), (m, 2H), 6.12 (dd, J = 6.4, 1.4 Hz, 1H), (m, 1H), 3.63 (s, 3H), 3.46 (dt, J = 15.7, 1.6 Hz, 1H), 3.07 (ddd, J = 15.7, 6.4, 2.4 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 1H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (C), (C), (C), (CH), (CH), (CH), (CH), (C), 52.6 (CH 3 ), 52.2 (CH), 50.1 (CH), 32.2 (CH 2 ), 29.8 (CH 2 ), 22.9 (CH 2 ), 19.7 (CH 2 ); [α] 20 D (c 1, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 1.9 ppm). -S9-

10 (6S,12bS)-Methyl 1,2,3,4,6,7,12,12b-octahydro-4-oxoindolo[2,3-a]-quinolizine-6-carboxylate 36b. H H C 2 Me Chemical Formula: C 17 H Exact Mass: 298,1317 Molecular Weight: 298,3364 The residue was purified by flash chromatography (25:75 to 0:100 pentane-etac) to give 38b as a yellow solid (19 mg, 13%). mp 197 C; IR (neat) 3269, 2919, 2852, 1742, 1615, 1467 cm -1 ; 1 H MR (CDCl 3, 200 MHz) δ 8.51 (br s, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 4.43 (dd, J = 8.4, 4.9 Hz, 1H), 3.72 (s, 3H), 3.45 (ddd, J = 15.7, 8.4, 1.9 Hz, 1H), 3.05 (ddd, J = 15.7, 4.9, 1.9 Hz, 1H), (m, 3H), (m, 1H), (m, 2H); 13 C MR (CDCl 3, 50 MHz) δ (C), (C), (C), (C), (C), (CH), (CH), (CH), (CH), (C), 56.8 (CH), 54.9 (CH), 52.4 (CH 3 ), 32.5 (CH 2 ), 27.2 (CH 2 ), 22.7 (CH 2 ), 18.4 (CH 2 ); [α] 20 D (c 1, CHCl 3 ); HRMS-ESI (m/z): [M+H] + calcd ; found ( = 0.5 ppm). [i] (a) Cuny, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, (b) Billing, E.; Abatjoglou, A. G.; Bryant, D. R., US 4,668,651, [ii] Amat, M.; Bosch, J.; Hidalgo, J.; Canto, M.; Pérez, M.; Llor,.; Molins, E.; Miravitlles, C.; rozco, M.; Luque, J. J. rg. Chem. 2000, 65, [iii] Royer, J.; Husson, H.-P. Heterocycles 1993, 36, [iv] Micouin, L.; Quirion, J.-C.; Husson, H.-P. Synth Commun. 1996, 26, S10-

11 X-ray crystal structure of compound 27: CCDC RTEP view of compound 27 -S11-

12 1 1 -S12-

13 5a 5a -S13-

14 5b 5b -S14-

15 S15-

16 S16-

17 S17-

18 MeC 14 MeC 14 -S18-

19 -S19-

20 Su CbzH 16 -S20-

21 -S21-

22 -S22-

23 -S23-

24 S24-

25 S25-

26 S26-

27 S27-

28 -S28-

29 S29-

30 S30-

31 S31-

32 36a 36a -S32-

33 36b 36b -S33-