A New Acyl Radical-Based Route to the 1,5- Methanoazocino[4,3-b]indole Framework of Uleine and Strychnos Alkaloids

Transcription

1 A ew Acyl Radical-Based Route to the 1,5- Methanoazocino[4,3-b]indole Framework of Uleine and Strychnos Alkaloids M.-Lluïsa Bennasar,* Tomàs Roca, and Davinia García-Díaz Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona 08028, Spain R 1 H O R 2 = Et R 3 = H 6-exo cyclization R 1 H R 3 H O H R 2 R 2 = H R 3 = Et 6-endo cyclization R 1 H O Contents Experimental procedures (S2-S16) Copies of 1 H and 13 C MR spectra (S17-S78) S1

2 General Reaction courses and product mixtures were routinely monitored by TLC on silica gel (precoated F254 Merck plates). Drying of organic extracts during the workup of reactions was performed over anhydrous a 2 SO 4. The solvents were evaporated under reduced pressure with a rotary evaporator. Flash chromatography was carried out on SiO 2 (silica gel 60, SDS, mm). Melting points are uncorrected. Unless otherwise indicated, 1 H and 13 C MR spectra were recorded in CDCl 3 solution, using TMS as an internal reference. tert-butyl 3-[1-(-Allylmethoxycarbonylamino)-3-butenyl]indole-1-carboxylate (2). CHO 1. H 2 Boc 2. BrMg 1 3. ClCO 2 Me 68% MeO 2 C A solution of indole-3-carbaldehyde 1 1 (1.20 g, 4.89 mmol), allylamine (3.65 ml, 48.9 mmol) and AcOH (0.28 ml, 4.89 mmol) in anhydrous CH 2 Cl 2 (50 ml) was stirred at rt for 12 h. The reaction mixture was washed with a saturated aqueous a 2 CO 3 solution (3 x 35 ml), dried and concentrated and the resulting residue (crude imine) was dissolved in anhydrous THF (80 ml). Allylmagnesium bromide (1 M in Et 2 O, 5.30 ml, 5.30 mmol) was added dropwise to the above cooled ( 78 ºC) solution and the resulting mixture was stirred at rt for 4 h. The reaction mixture was poured into a saturated aqueous H 4 Cl solution (60 ml) and extracted with AcOEt (3 x 50 ml). The organic extracts were dried and concentrated. Methyl chloroformate (0.53 ml, 6.90 mmol) in anhydrous CH 2 Cl 2 (6 ml) and K 2 CO 3 (1.58 g, mmol) were added to the resulting residue in anhydrous CH 2 Cl 2 (60 ml) and the mixture was stirred at rt for 48 h. The reaction mixture was poured into H 2 O (15 ml), stirred at rt for 20 min and extracted with CH 2 Cl 2 (3 x 40 ml). The organic extracts were dried and concentrated and the residue was chromatographed (3:7 hexanes-ch 2 Cl 2 ) to give 2 as an oil: 1.27 g (68%); 1 H MR (300 MHz) δ 1.69 (s, 9H), 2.74 (m, 2H), 3.55 (m, 2H), 3.78 (br s, 3H), 4.86 (d, J = 10.8 Hz, 1H), 4.93 (d, J = 15.9 Hz, 1H), 5.10 (d, J = 10.8 Hz, 1H), 5.17 (dq, J = 1.2, 1.2, 1.2, 16.8 Hz, 1H), 5.53 (br m, 1H), 5.74 (br m, 1H), 5.85 (br m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.55 (br s, 1H), 8.07 (d, J = 7.8 Hz, 1H); 13 C MR (75.4 MHz) δ 28.2 (CH 3 ), 36.2 (CH 2 ), 45.0 (CH 2 ), 51.4 (CH), 52.7 (CH 3 ), Boc 2 S2

3 83.9 (C), (CH), (CH 2 ), (CH 2 ), (C), (CH), (CH), (CH), (CH), (C), (CH), (CH), (C), (C), (C). Anal. Calcd for C 22 H 28 2 O 4 : C, 68.73; H, 7.34;, Found: C, 68.48; H, 7.41;, Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 75, (tert-Butoxycarbonyl)-3-[(1-methoxycarbonyl)-1,2,3,6-tetrahydro-2- pyridyl]indole-2-carboxylic Acid (3). MeO 2 C MeO 2 C Boc 2 1. LDA, CO 2 2. Grubbs Gen-II CH 2 Cl 2, rt 85% 3 n-buli (1.6 M in hexane, 1.90 ml, 3.0 mmol) was added under Ar to a cooled ( 78 ºC) solution of diisopropylamine (0.40 ml, 3.0 mmol) in anhydrous THF (30 ml) and the resulting solution was stirred at 78 ºC for 30 min. Indole 2 (0.77 g, 2.0 mmol) in anhydrous THF (15 ml) was then added and the resulting red mixture was stirred at 78 ºC for 30 min. CO 2 (gas) was bubbled through the reaction mixture, which immediately turned yellow. After 30 min at 78 ºC, the reaction mixture was quenched with H 2 O, acidified with 2 M aqueous HCl (20 ml) and extracted with Et 2 O (3 x 40 ml). Concentration of the organic extracts gave the carboxylic acid (0.75 g), which was directly used in the next step since chromatographic purification resulted in intensive decomposition. A mixture of this acid and the second generation Grubbs catalyst (0.10 g, 0.12 mmol) in anhydrous CH 2 Cl 2 (25 ml) was stirred at rt for 6 h. The reaction mixture was concentrated and the resulting residue was triturated with Et 2 O to give tetrahydropyridine 3: 0.68 g (85%); 1 H MR (300 MHz) δ 1.63 (s, 9H), 2.53 (m, 1H), 2.87 (m, 1H), 3.70 (s, 3H), 3.80 (d, J = 16.8 Hz, 1H), 4.37 (d, J = 16.8 Hz, 1H), 5.52 (dd, J = 8.7, 3 Hz, 1H), 6.01 (m, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H); 13 C MR (100.6 MHz) δ 27.6 (CH 3 ), 28.2 (CH 2 ), 41.5 (CH 2 ), 45.2 (CH), 53.2 (CH 3 ), 85.1 (C), (CH), (CH), (CH), (C), (CH), (CH), (C and CH), (C), (C), (C), (C), (C); ESI-HRMS [M+H] + calcd for C 21 H 25 2 O , found Boc OH O S3

4 3-[(1-Methoxycarbonyl)-1,2,3,6-tetrahydro-2-pyridyl]indole-2-carboxylic Acid (4). MeO 2 C 3 Boc OH O MeOa 92% MeO 2 C Tetrahydropyridine 3 (0.68 g, 1.70 mmol) in MeOH (5 ml) was added to a solution of MeOa, previously prepared from a (0.12 g, 5.10 mmol) and MeOH (10 ml), and the resulting solution was heated at reflux overnight. The reaction mixture was concentrated and the residue was partitioned between 2 M aqueous HCl (15 ml) and CH 2 Cl 2 (15 ml) and extracted with CH 2 Cl 2 (2 x 10 ml). Concentration of the organic extracts followed by flash chromatography (97:3 CH 2 Cl 2 -MeOH) gave 4 : 0.47 g (92%); 1 H MR (300 MHz) δ 2.53 (dd, J = 18.0, 2.7 Hz, 1H), 2.90 (dd, J = 18.6, 8.1 Hz, 1H), 3.67 (s, 3H), 3.97 (d, J = 17.1 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 6.05 (s, 2H), 6.10 (dd, J = 8.1, 2.7 Hz, 1H), 7.05 (t, J = 8.4 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 9.35 (s, 1H); 13 C MR (75.4 MHz) δ 30.0 (CH 2 ), 41.8 (CH 2 ), 46.1 (CH), 53.2 (CH 3 ), (CH), (CH), (CH), (C), (CH), (C), (CH), (C), (CH), (C), (C), (C); ESI-HRMS [M+H] + calcd for C 16 H 17 2 O , found H OH O 2-Ethylallylamine Methanesulfonate. H 2 CH 3 SO 3 H 2-Methylene-1-butanol methanesulfonate 2 (1.79 g, mmol) was added dropwise to a solution of hexamethylenetetramine (1.68 g, 12.0 mmol) in CH 2 Cl 2 (15 ml) and the mixture was heated at reflux for 4 h. The mixture was cooled (ice-bath) and the crude product was collected by filtration. The quaternary ammonium methanesulfonate salt (2.32 g) was dissolved in H 2 O (5 ml), EtOH (25 ml) and concentrated aqueous HCl (6 ml) and the resulting solution was stirred at 75 ºC for 2 h. The reaction mixture was concentrated and the resulting residue was digested with anhydrous MeOH (20 ml). After filtration, the filtrate was concentrated, digested again with anhydrous MeOH (15 ml) and filtered. The filtrate was concentrated to give 2-ethylallylamine methanesulfonate: 1.30 g (66%); 1 H MR (300 MHz, CD 3 OD) δ 1.14 (t, J = 7.5 Hz, 3H), 2.18 (q, J = 7.5 Hz, 2H), 2.74 (s, 3H), 3.57 (s, 2H), 5.09 (m, 1H), 5.16 (m, 1H). S4

5 2 Plamondon, L.; Wuest, J. D. J. Org. Chem. 1991, 56, tert-butyl 3-[1-(-(2-Ethylallyl)methoxycarbonylamino)-3-butenyl]indole-1- carboxylate (8). CHO 1. H 2 MeO 2 C 1 Boc 2. BrMg 3. ClCO 2 Me 65% Boc 8 Aldehyde 1 (0.58 g, 2.38 mmol) in anhydrous CH 2 Cl 2 (14 ml) and AcOH (0.14 ml, 2.38 mmol) were successively added to a solution of 2-ethylallylamine methanesulfonate (0.86 g, 4.77 mmol) and Et 3 (0.66 ml, 4.77 mmol) in anhydrous CH 2 Cl 2 (10 ml) and the mixture was stirred at rt for 12 h. The reaction mixture was washed with a saturated aqueous a 2 CO 3 solution (3 x 35 ml), dried and concentrated. The resulting crude imine was dissolved in anhydrous THF (40 ml) and successively treated with allylmagnesium bromide (1 M in Et 2 O, 2.80 ml, 2.80 mmol) and methyl chloroformate (0.25 ml, 3.26 mmol) as described for the preparation of 2. The crude product was chromatographed (95:5 hexanes-acoet) to give 8 as an oil: 0.64 g (65%); 1 H MR (300 MHz) δ 0.88 (t, J = 7.2 Hz, 3H), 1.68 (s, 9H), 1.82 (m, 2H), 2.76 (t, J = 6.9 Hz, 2H), (br m, 2H), 3.75 (br s, 3H), 4.58 (s, 1H), 4.60 (s, 1H), 5.07 (dq, J = 10.2, 1.5 Hz, 1H), 5.16 (dq, J = 17.4, 1.5 Hz, 1H), 5.57 and 5.75 (2 br m, 1H), 5.85 (m, 1H), 7.22 (td, J = 8.1, 1.2 Hz, 1H), 7.31 (ddd, J = 8.1, 6.9, 0.9 Hz, 1H), 7.52 (s, 1H), 7.60 (br s, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13 C MR (75.4 MHz) δ 11.9 (CH 3 ), 26.4 (CH 2 ), 28.2 (CH 3 ), 36.3 (CH 2 ), 47.2 (CH 2 ), 51.8 (CH), 52.7 (CH 3 ), 83.9 (C), (CH 2 ), (CH), (CH 2 ), (C), (CH), (CH), (CH), (CH), (C), (CH), (C), (C), (C), (C). Anal. Calcd for C 24 H 32 2 O 4 : C, 69.88; H, 7.82;, Found: C, 69.90; H, 7.77;, S5

6 1-(tert-Butoxycarbonyl)-3-[5-ethyl-(1-methoxycarbonyl)-1,2,3,6-tetrahydro-2- pyridyl]indole-2-carboxylic Acid (9). MeO 2 C Boc 8 MeO 2 C Grubbs Gen-II benzoquinone CH 2 Cl 2, reflux COOH LDA, CO 2 Boc 45% + MeO 2 C Boc O OH 9 (45% overall yield) H A O 25% n-buli (1.6 M in hexane, 0.93 ml, 1.48 mmol) was added under Ar to a cooled ( 78 ºC) solution of diisopropylamine (0.21 ml, 1.48 mmol) in anhydrous THF (15 ml) and the resulting solution was stirred at 78 ºC for 30 min. Indole 8 (0.48 g, 1.17 mmol) in anhydrous THF (10 ml) was then added and the resulting red mixture was stirred at 78 ºC for 30 min. CO 2 (gas) was bubbled through the reaction mixture, which immediately turned pale yellow. After 10 min at 78 ºC, the reaction mixture was quenched with H 2 O, acidified with 2 M aqueous HCl (10 ml) and extracted with CH 2 Cl 2 (3 x 20 ml). The organic extracts were concentrated and the residue was dissolved in a mixture of THF (3 ml) and 2 M aqueous a 2 CO 3 (10 ml) and extracted with Et 2 O (3 x 10 ml). Concentration of the ethereal extracts afforded 3-allyl-(2-ethylallyl)-2,3- dihydroazolo[3,4-b]indol-1-one A: g (25%); 1 H MR (300 MHz) δ 1.14 (t, J = 7.2 Hz, 3H), 2.09 (q, J = 7.5 Hz, 2H), 2.59 (ddd, J = 14.1, 7.5, 7.2 Hz, 1H), 2.93 (m, 1H), 3.80 (d, J = 15.6 Hz, 1H), 4.67 (dd, J = 7.2, 4.2 Hz, 1H), 4.85 (d, J = 15.3 Hz, 1H), 4.99 (s, 2H), 5.09 (dm, J = 17.1 Hz, 1H), 5.09 (d, J = 10.2 Hz, 1H), 5.66 (m, 1H), 7.18 (ddd, J = 8.1, 7.2, 0.9 Hz, 1H), 7.33 (ddd, J = 8.1, 6.9, 0.9 Hz, 1H), 7.66 (m, 2H), 11.7 (s, 1H); 13 C MR (75.4 MHz) δ 12.0 (CH 3 ), 26.3 (CH 2 ), 35.7 (CH 2 ), 45.6 (CH 2 ), 56.4 (CH), (CH 2 ), (CH), (CH 2 ), (2 CH), (C), (CH), (C), (CH), (C), (C), (C), (C); ESI-HRMS [M+H] + calcd for C 18 H 21 2 O , found The above aqueous phase was acidified with 2 M aqueous HCl and extracted with CH 2 Cl 2 (3 x 15 ml). The organic extracts were dried and concentrated to give the carboxylic acid (0.27 g), which was used directly in the next step. A mixture of this acid, 1,4-benzoquinone (14 mg, 0.13 mmol) and the second generation Grubbs catalyst (37 mg, mmol) in anhydrous CH 2 Cl 2 (7 ml) was heated at reflux for 2 h. The S6

7 reaction mixture was extracted with 2 M aqueous a 2 CO 3 (3 x 10 ml). The aqueous phase was washed with Et 2 O (3 x 10 ml), acidified with concentrated aqueous HCl and successively extracted with CH 2 Cl 2 (3 x 10 ml) and AcOEt (3 x 10 ml). The organic extracts were dried and concentrated to give tetrahydropyridine 9: 0.23 g (45%); 1 H MR (400 MHz) δ 1.14 (t, J = 7.6 Hz, 3H), 1.62 (s, 9H), 2.17 (q, J = 7.6 Hz, 2H), 2.55 (d, J = 17.6 Hz, 1H), 2.83 (m, 1H), 3.69 (s, 3H), 3.70 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 17.2 Hz, 1H), 5.41 (d, J = 4.4 Hz, 1H), 5.74 (s, 1H), 7.20 (t, J = 8 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H); 13 C MR (100.6 MHz) δ 11.8 (CH 3 ), 27.7 (CH 3 ), 27.8 (CH 2 ), 28.4 (CH 2 ), 44.5 (CH 2 ), 45.3 (CH), 53.5 (CH 3 ), 85.3 (C), (CH), (CH), (CH), (CH), (C masked), (C), (CH), (C), (C), (C), (C), (C), (C); ESI- HRMS [M+H] + calcd for C 23 H 29 2 O , found Carboxylation at the Tetrahydropyridine Stage. Formation of Lactam C. MeO 2 C Boc 8 RCM MeO 2 C Boc LDA, CO 2 MeO 2 C Boc B 9 (10%) C (30%) O OH + H O A solution of indole 8 (0.10 g, 0.24 mmol), 1,4-benzoquinone (8 mg, mmol) and the second generation Grubbs catalyst (20 mg, mmol) in anhydrous CH 2 Cl 2 (5 ml) was heated at reflux for 1 h. The reaction mixture was concentrated and the resulting residue was chromatographed (4:6 hexanes-ch 2 Cl 2 ) to give tetrahydropyridine B : 86 mg (91%); 1 H MR (300 MHz) δ 1.04 (t, J = 7.5 Hz, 3H), 1.66 (s, 9H), 1.99 (q, J = 7.2 Hz, 2H), 2.47 (dd, J = 6, 17.4 Hz, 1H), 2.75 (d, J = 16.8 Hz, 1H), 3.24 (d, J = 17.4 Hz, 1H), 3.78 (br s, 3H), 4.15 (br m, 1H), 5.64 (s, 1H), (br m, 1H), 7.23 (td, J = 7.8, 1.2 Hz, 1H), 7.31 (td, J = 8.4, 1.5 Hz, 1H), 7.48 (s, 1H), (2 br m, 1H), 8.07 (d, J = 7.5 Hz, 1H). n-buli (1.6 M in hexane, 0.21 ml, 0.33 mmol) was added under Ar to a cooled ( 78 ºC) solution of diisopropylamine (0.05 ml, 0.33 mmol) in anhydrous THF (4 ml) and the resulting solution was stirred at 78 ºC for 30 min. Tetrahydropyridine B (86 mg, 0.22 mmol) in anhydrous THF (2 ml) was added and the resulting red mixture was stirred at 78 ºC for 30 min. CO 2 (gas) was bubbled through the reaction mixture. After 15 min at 78 ºC, the reaction mixture was quenched with H 2 O, acidified with 2 M S7

8 aqueous HCl (5 ml) and extracted with CH 2 Cl 2 (3 x 10 ml). The organic extracts were concentrated and the residue was dissolved in a mixture of THF (1 ml) and 2 M aqueous a 2 CO 3 (5 ml) and washed with Et 2 O (2 x 10 ml). The aqueous phase was acidified with 2 M aqueous HCl and extracted with CH 2 Cl 2 (3 x 10 ml). The organic extracts were concentrated to give 9: 10 mg (10%). Concentration of the ethereal extracts followed by flash chromatography (7:3 hexanes- AcOEt) gave 9-ethyl-2,6c,7,10-tetrahydro-1H-indolizino[2,1-b]indol-1-one C: 18 mg (30%); 1 H MR (300 MHz) δ 1.14 (t, J = 7.6 Hz, 3H), 2.08 (m, 1H), 2.16 (q, J = 7.2 Hz, 2H), 2.87 (td, J = 16, 5.2, 5.2 Hz, 1H), 3.82 (d, J = 18 Hz, 1H), 4.49 (dd, J = 11.6, 5.2 Hz, 1H), 4.55 (d, J = 18 Hz, 1H), 5.64 (d, J = 4.4 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 9.92 (s, 1H); 13 C MR (most significant signals from HSQC) δ 12.3 (CH 3 ), 27.3 (CH 2 ), 30.2 (CH 2 ), 42.5 (CH 2 ), 52.1 (CH), (CH), (CH), (CH), (CH), (CH). ESI-HRMS [M+H] + calcd for C 16 H 17 2 O , found (5-Ethyl-1-methyl-1,2,3,6-tetrahydro-2-pyridyl)indole (13). Me indole Me C 12 AcOH-H 2 O 60% 13 H A solution of indole (7.03 g, 60 mmol) and 2-cyanotetrahydropyridine 12 3 (4.50 g, 30 mmol) in 1:1 AcOH-H 2 O (150 ml) was stirred at rt for 24 h. After addition of concentrated aqueous HCl (1.5 ml), the solution was washed with Et 2 O, basified with 6 M aoh and extracted with CH 2 Cl 2. The solvent was removed and the crude product was chromatographed (98:2 CH 2 Cl 2 -diethylamine) to give 13: 4.32 g (60%); 1 H MR (300 MHz) δ 1.08 (t, J = 7.5 Hz, 3H), 2.05 (q, J = 7.5 Hz, 2H), 2.19 (s, 3H), 2.39 (m, 1H), 2.62 (m, 1H), 2.96 (d, J = 15.9 Hz, 1H), 3.23 (d, J = 15.9 Hz, 1H), 3.74 (dd, J = 8.7, 4.5 Hz, 1H), 5.58 (br s, 1H), 7.15 (m, 2H), 7.19 (td, J = 7.5, 1.2 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 8.69 (br s, 1H); 13 C MR (75.4 MHz) δ 12.1 (CH 3 ), 27.6 (CH 2 ), 34.0 (CH 2 ), 42.9 (CH 3 ), 56.5 (CH), 58.0 (CH 2 ), (CH), (C), (CH), (CH), (CH), (CH), (CH), (C), (C), (C). Anal. Calcd for C 16 H /2H 2 O: C, 77.07; H, 8.49;, Found: C, 77.45; H, 8.46;, S8

9 3 Chapman, R.F.; Phillips,. I. J.; Ward, R. S. Tetrahedron 1985, 41, tert-butyl (14). 3-(5-Ethyl-1-methyl-1,2,3,6-tetrahydro-2-pyridyl)indole-1-carboxylate Me Me 13 H (Boc) 2 O 90% A solution of indole 13 (0.75 g, 3.12 mmol), (Boc) 2 O (0.82 g, 3.75 mmol), Et 3 (0.44 ml, 3.12 mmol) and DMAP (77 mg, 0.63 mmol) in anhydrous CH 2 Cl 2 (30 ml) was stirred at rt overnight. The reaction mixture was poured into a saturated aqueous ahco 3 solution (40 ml) and extracted with CH 2 Cl 2 (3 x 40 ml). The solvent was removed and the crude product was chromatographed (90:10:2 hexanes-acoetdiethylamine) to give 14 as an oil: 0.95 g (90%); 1 H MR (300 MHz) δ 1.08 (t, J = 7.5 Hz, 3H), 1.66 (s, 9H), 2.04 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 2.31 (m, 1H), 2.59 (m, 1H), 2.91 (d, J = 16.5 Hz, 1H), 3.22 (d, J = 16.2 Hz, 1H), 3.59 (dd, J = 9.3, 4.8 Hz, 1H), 5.53 (s, 1H), 7.22 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 7.31 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H); 13 C MR (75.4 MHz) δ 12.2 (CH 3 ), 27.6 (CH 2 ), 28.2 (CH 2 ), 33.4 (CH 2 ), 43.1 (CH 3 ), 56.8 (CH), 57.9 (CH 2 ), 83.4 (C), (CH), (CH), (CH), (C), (CH), (CH), (CH), (C), (C), (C), (C). Anal. Calcd for C 21 H 28 2 O 2 : C, 74.08; H, 8.29;, Found: C, 73.98; H, 8.41;, Boc 1-(tert-Butoxycarbonyl)-3-(5-ethyl-1-methyl-1,2,3,6-tetrahydro-2-pyridyl)indole-2- carboxylic Acid Hydrochloride (15). Me Me H Cl 14 Boc 1. LDA, CO 2 2. HCl 86% 15 Boc O OH n-buli (1.6 M in hexane, 0.46 ml, 0.74 mmol) was added under Ar to a cooled ( 78 ºC) solution of diisopropylamine (0.10 ml, 0.74 mmol) in anhydrous THF (7 ml) and the resulting solution was stirred at 78 ºC for 30 min. Indole 14 (0.17 g, 0.50 mmol) in anhydrous THF (5 ml) was then added and the resulting red mixture was stirred at 78 ºC for 30 min. CO 2 (gas) was bubbled through the reaction mixture, which immediately S9

10 turned yellow. After 30 min at 78 ºC, the reaction mixture was quenched with H 2 O, acidified with 1 M aqueous HCl until ph 4-5 and extracted with CH 2 Cl 2 (3 x 10 ml). Concentration of the organic extracts gave amino acid hydrochloride 15: 0.18 g (86%); 1 H MR (300 MHz) δ 1.03 (t, J = 7 Hz, 3H), 1.58 (s, 9H), 2.04 (m, 2H), 2.44 (br d, J = 17.7 Hz, 1H), 2.68 (s, 3H), 3.02 (m, 1H), 3.58 (br d, J = 15.6 Hz, 1H), 3.93 (br d, J = 15.9 Hz, 1H), 4.53 (br d, J = 8.1 Hz, 1H), 5.60 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.92 (br m, 1H), 8.02 (d, J = 8.4 Hz, 1H); 13 C MR (75.4 MHz) δ 11.4 (CH 3 ), 26.7 (CH 2 ), 27.6 (CH 3 ), 30.0 (CH 2 ), 41.1 (CH 3 ), 56.2 (CH 2 ), 57.4 (CH), 84.9 (C), (CH), (CH), (CH), (CH), (CH), (C), (C), (C), (C), (C), (C), indole C-3 not observed. 3-(5-Ethyl-1-methyl-1,2,3,6-tetrahydro-2-pyridyl)indole-2-carboxylic Hydrochloride (16). Acid Me H Cl 15 Boc O OH 1. MeOa 2. HCl 80% Me H Cl H 16 O OH Amino acid hydrochloride 15 (0.23 g, 0.55 mmol) in MeOH (5 ml) was treated with MeOa, previously prepared from a (63 mg, 2.75 mmol) in MeOH (14 ml), as described for the preparation of 4. After adding H 2 O (10 ml) to the reaction mixture, the MeOH was removed and THF was added to the suspension. The resulting solution was acidified with 1 M aqueous HCl until ph 4-5 and extracted with CH 2 Cl 2 (3 x 10 ml). The organic extracts were concentrated to give hydrochloride 16: 0.14 g (80%); 1 H MR (300 MHz) δ 0.93 (t, J = 7.2 Hz, 3H), 1.92 (m, 2H), 2.40 (m, 1H), 2.54 (s, 3H), 2.99 (m, 1H), 3.56 (d, J = 14.7 Hz, 1H), 4.03 (d, J = 17.1 Hz, 1H), 4.73 (br s, 1H), 5.54 (br s, 1H), 7.03 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 9.03 (br s, 1H), (s, 1H), (br s, 1H); 13 C MR (75.4 MHz) δ 11.4 (CH 3 ), 26.6 (CH 2 ), 31.4 (CH 2 ), 40.9 (CH 3 ), 56.0 (CH 2 ), 57.6 (CH), (C), (CH), (CH), (CH), (CH), (CH), (C), (C), (C), (C), (C). S10

11 tert-butyl carboxylate (19a). 3-[1-(-But-3-enylmethoxycarbonylamino)-2-ethylallyl]indole-1- CHO 1. H 2 MeO 2 C 1 Boc 2. BrMg 3. ClCO 2 Me 56% 19a A solution of indole 1 (0.75 g, 3.06 mmol), 3-butenylamine (0.56 ml, 6.12 mmol) and AcOH (0.18 ml, 3.06 mmol) in anhydrous CH 2 Cl 2 (30 ml) was stirred at rt for 12 h. The reaction mixture was washed with a saturated aqueous a 2 CO 3 solution (3 x 35 ml), dried and concentrated and the resulting residue (crude imine) was dissolved in anhydrous toluene (8 ml). BF 3 -EtO 2 (1.16 ml, 9.20 mmol) was added under Ar to the above cooled ( 78 ºC) solution. After 15 min at 78 ºC, 1-buten-2-ylmagnesium bromide 4 (1 M in THF, 9.20 ml, 9.20 mmol), previously prepared from 2-bromo-1- butene (1.35 g, 10 mmol), Mg (0.48 g, 20 mmol) and 1,2-dibromoethane (0.04 ml, 0.20 mmol) in anhydrous THF (10 ml), was added dropwise to the above cooled solution and the resulting mixture was stirred at 78 ºC for 6 h. The reaction mixture was quenched with 20% aqueous aoh (10 ml) and extracted with Et 2 O (3 x 20 ml). The organic extracts were concentrated and the resulting residue was dissolved in Et 2 O and treated with a saturated Et 2 O solution of HCl (1 ml). The solvent was removed and the resulting oil was triturated with hexanes (4 x 10 ml) and then partitioned between CH 2 Cl 2 (20 ml) and a saturated aqueous a 2 CO 3 solution (20 ml) and extracted with CH 2 Cl 2 (3 x 20 ml). The organic extracts were dried and concentrated. K 2 CO 3 (0.64 g, 4.65 mmol) and methyl chloroformate (0.21 ml, 2.79 mmol) in anhydrous CH 2 Cl 2 (3 ml) were successively added to the resulting residue in anhydrous CH 2 Cl 2 (30 ml) and the mixture was stirred at rt for 30 h. The reaction mixture was poured into H 2 O (15 ml), stirred at rt for 20 min and extracted with CH 2 Cl 2 (3 x 25 ml). The organic extracts were dried and concentrated and the residue was chromatographed (95:5 hexanes-acoet) to give carbamate 19a as an oil: 0.71 g (56%); 1 H MR (400 MHz, mixture of rotamers) δ 1.13 (t, J = 7.2 Hz, 3H), 1.68 (s, 9H), 1.68 (br m, masked, 1H), 2.02 (m, 1H), 2.15 (m, 2H), 3.22 (m, 1H), 3.37 (m, 1H), 3.76 (s, 3H), 4.73 (d, J = 16.8 Hz, 1H), 4.83 (d, J = 10 Hz, 1H), 4.91 (s, 1H), 5.10 (s, 1H), 5.50 (br m, 1H), 5.88 and 6.08 (2 br m, 1H), 7.22 (t, J = 8 Hz, 1H), 7.31 (t, J = 8 Hz, 1H), 7.43 (s, 1H), 7.48 (br m, 1H), 8.09 (d, J = 7.6 Hz, 1H); 13 C MR (100.6 MHz) δ 12.5 (CH 3 ), 27.4 (CH 2 ), 28.2 Boc S11

12 (CH 3 ), 33.9 (CH 2 ), 44.4 (CH 2 ), 52.8 (CH 3 ), 56.4 (CH), 84.0 (C), (CH 2 ), (CH), (CH 2 ), (C), (CH), (CH), (CH), (CH), (C), (C and CH), (C), (C), (C). Anal. Calcd for C 24 H 32 2 O 4 : C, 69.88; H, 7.82;, Found: C, 70.02; H, 7.67;, Sinha, S. C.; Li, L.-S.; Watanabe, S.; Kaltgrad, E.; Tanaka, F.; Rader, C.; Lerner, R. A.; Barbas, C. F. Chem. Eur. J. 2004, 10, tert-butyl carboxylate (19b). CHO 1. H 2 BnO 2 C 1 Boc 2. BrMg 3. ClCO 2 Bn 54% 19b Operating as above, from indole 1 (1.23 g, 5.0 mmol), 3-butenylamine (0.92 ml, 10.0 mmol), 1-buten-2-ylmagnesium bromide (1 M in THF, 15 mmol) and benzyl chloroformate (0.60 ml, 4.21 mmol) carbamate 19b was obtained after flash chromatography (95:5 hexanes-acoet) as an oil: 1.32 g (54%); 1 H MR (300 MHz, mixture of rotamers) δ 1.11 (br m, 3H), 1.68 (s, 9H), 1.68 (br m, masked, 1H), 2.06 (br m, 1H), 2.13 (m, 2H), 3.22 (m, 1H), 3.40 (m, 1H), 4.68 (br d, 1H), 4.80 (d, J = 10.2 Hz, 1H), 4.93 (s, 1H), 5.10 (s, 1H), 5.22 (s, 2H), 5.45 (br m, 1H), 5.94 and 6.10 (2 br s, 1H), 7.20 (t, J = 7.2 Hz, 1H), (m, 8H), 8.09 (d, J = 7.5 Hz, 1H); 13 C MR (75.4 MHz) δ 12.5 (CH 3 ), 27.4 (CH 2 ), 28.2 (CH 3 ), 34.1 (CH 2 ), 44.5 (CH 2 ), 56.5 (CH), 67.2 (CH 2 ), 84.0 (C), (CH 2 ), (CH), (CH 2 ), (C), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (C), (C and CH), (C), (C), (C), (C). Anal. Calcd for C 30 H 36 2 O 4 : C, Boc 73.74; H, 7.43;, Found: C, 73.36; H, 7.31;, tert-butyl carboxylate (20a). 3-[1-(-But-3-enylbenzyloxycarbonylamino)-2-ethylallyl]indole-1-3-[(3-Ethyl-1-(methoxycarbonyl)-1,2,5,6-tetrahydro-2-pyridyl]indole-1- MeO 2 C 19a Boc Grubbs Gen-II benzoquinone CH 2 Cl 2, reflux 72% MeO 2 C Boc 20a S12

13 A solution of 19a (0.55 g, 1.33 mmol), 1,4-benzoquinone (45 mg, 0.41 mmol)) and the second generation Grubbs catalyst (0.13 g, 0.15 mmol) in anhydrous CH 2 Cl 2 (20 ml) was heated at reflux for 1 h. The reaction mixture was concentrated and the resulting residue was chromatographed (1:1 hexanes-ch 2 Cl 2 ) to give tetrahydropyridine 20a: 0.37 g (72%); 1 H MR (400 MHz, mixture of rotamers) δ 1.04 (t, J = 7.2 Hz, 3H), 1.68 (s, 9H), 2.05 (m, 3H), 2.35 (m, 1H), 3.01 (td, J = 12.8, 12.8, 4 Hz, 1H), 3.72 and 3.84 (2 br s, 3H), 3.91 and 4.08 (2 br m, 1H), 5.68 and 5.87 (2 br s, 1H), 5.75 (s, 1H), 7.25 (t, J = 8 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.46 (s, 1H), 7.75 and 7.97 (2 br s, 1H) 8.08 (d, J = 7.2 Hz, 1H); 13 C MR (100.6 MHz) δ 12.2 (CH 3 ), 24.6 and 25.0 (CH 2 ), 27.2 (CH 2 ), 28.2 (CH 3 ), 36.6 (CH 2 ), 50.0 (CH), 52.7 (CH 3 ), 83.9 (C), (CH), (C), (CH), (CH), (CH), (CH), (CH), (C), (C), (C), (C), (C). Anal. Calcd for C 22 H 28 2 O 4.1H 2 O: C, 65.65; H, 7.51;, Found: C, 65.82; H, 7.15;, tert-butyl 3-[1-(Benzyloxycarbonyl)-3-ethyl-1,2,5,6-tetrahydro-2-pyridyl]indole-1- carboxylate (20b). BnO 2 C Boc 19b Grubbs Gen-II benzoquinone CH 2 Cl 2, reflux 71% BnO 2 C Indole 19b (0.55 g, 1.13 mmol), 1,4-benzoquinone (37 mg, 0.34 mmol) and the second generation Grubbs catalyst (0.10 g, 0.11 mmol) were allowed to react as above. After flash chromatography (1:1 hexanes-et 2 O), tetrahydropyridine 20b was obtained: 0.37 g (71%); 1 H MR (300 MHz, mixture of rotamers) δ 1.03 (m, 3H), 1.67 (s, 9H), 2.05 (m, 3H), 2.35 (m, 1H), 3.02 (td, J = 12.3, 4.5 Hz, 1H), 3.97 and 4.10 (2 br m, 1H), 5.28 (br s, 2H), 5.70 and 5.89 (2 br s, 1H), 5.74 (s, 1H), (m, 8H), 7.57 and 7.97 (2 br s, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13 C MR (75.4 MHz) δ 12.1 (CH 3 ), 25.1 (CH 2 ), 27.1 (CH 2 ), 28.2 (CH 3 ), 36.7 (CH 2 ), 50.1 (CH), 67.0 (CH 2 ), 83.9 (C), (CH), (C), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (C), (C), (C), (C), (C), (C). Anal. Calcd for C 28 H 32 2 O 4.1H 2 O: C, 70.27; H, 7.16;, Found: C, 70.55; H, 6.86;, b Boc S13

14 tert-butyl (24). 3-[1-(-But-3-enyl--methylamino)-2-ethylallyl]indole-1-carboxylate CHO 1. H 2 Me 1 Boc 2. BrMg Boc 3. 37% HCHO 24 50% acbh 3 Indole 1 (1.54 g, 6.28 mmol) was allowed to react with 3-butenylamine (1.15 ml, mmol) and 1-buten-2-ylmagnesium bromide (1 M in THF, 19.0 mmol) as described for the preparation of 19a. acbh 3 (0.39 g, 6.16 mmol) was slowly added to a solution of the resulting material and aqueous formaldehyde (37%, 1.56 ml, mmol) in MeC (12 ml) and the mixture was stirred at rt for 15 min. AcOH was then added until ph = 6-7 and the mixture was stirred at rt for 1.5 h. The solvent was removed and the residue was partitioned between 2 M aqueous aoh (15 ml) and Et 2 O (10 ml) and extracted with Et 2 O (3 x 15 ml). The organic extracts were dried and concentrated and the resulting crude product was chromatographed (97:2:1 hexanes-acoetdiethylamine) to give 24 as an oil: 1.15 g (50%); 1 H MR (300 MHz) δ 0.99 (t, J = 7.5 Hz, 3H), 1.68 (s, 9H), 1.99 (m, 1H), 2.14 (m, 1H), 2.23 (s, 3H), 2.29 (m, 2H), 2.49 (t, J = 7.5 Hz, 2H), 4.12 (s, 1H), (m, 3H), 5.27 (s, 1H), 5.80 (m, 1H), 7.21 (td, J = 8.1, 1.5 Hz, 1H), 7.29 (td, J = 8.1, 1.2, 1.2 Hz, 1H), 7.50 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H); 13 C MR (75.4 MHz) δ 11.9 (CH 3 ), 24.6 (CH 2 ), 28.2 (CH 3 ), 31.9 (CH 2 ), 39.9 (CH 3 ), 54.8 (CH 2 ), 69.2 (CH), 83.5 (C), (CH 2 ), (CH), (CH 2 ), (C), (CH), (CH), (CH), (CH), (C), (C), (CH), (C), (C). Anal. Calcd for C 23 H 32 2 O 2.1/4H 2 O: C, 74.06; H, 8.78;, Found: C, 74.06; H, 8.60;, tert-butyl (25). 3-(3-Ethyl-1-methyl-1,2,5,6-tetrahydro-2-pyridyl)indole-1-carboxylate Me 1. HCl Me Boc 2. Grubbs Gen-II benzoquinone CH 2 Cl 2, reflux 24 71% 25 Boc A solution of 24 (0.42 g, 1.15 mmol) in CH 2 Cl 2 (5 ml) was treated with a saturated Et 2 O solution of dry HCl (0.5 ml). The solvent was removed to give the hydrochloride S14

15 salt. A mixture of this material, 1,4-benzoquinone (26 mg, 0.24 mmol) and the second generation Grubbs catalyst (69 mg, mmol) in anhydrous CH 2 Cl 2 (16 ml) was heated at reflux for 24 h. The reaction mixture was washed with 2 M aqueous a 2 CO 3 (3 x 10 ml) and the organic layer was dried and concentrated. The crude product was chromatographed (80:19:1 hexanes-acoet-diethylamine) to give tetrahydropyridine 25 as a brown oil: 0.28 g (71%); 1 H MR (400 MHz) δ 0.91 (t, J = 7.6 Hz, 3H), 1.69 (s, 9H), 1.73 (q, J = 7.6 Hz, 2H), 2.20 (m, 1H), 2.24 (s, 3H), 2.46 (m, 2H), 2.90 (m, 1H), 3.95 (s, 1H), 5.68 (s, 1H), 7.19 (t, J = 8 Hz, 1H), 7.28 (t, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 8.10 (br d, J = 7.2 Hz, 1H); 13 C MR (100.6 MHz) δ 12.3 (CH 3 ), 25.5 (CH 2 ), 27.0 (CH 2 ), 28.2 (CH 3 ), 44.0 (CH 3 ), 50.1 (CH 2 ), 61.8 (CH), 83.6 (C), (CH), (CH), (C), (CH), (CH), (CH), (CH), (C), (C), (C), (C); ESI-HRMS [M+H] + calcd for C 21 H 29 2 O , found (tert-Butoxycarbonyl)-3-(3-ethyl-1-methyl-1,2,5,6-tetrahydro-2-pyridyl)indole-2- carboxylic Acid Hydrochloride (26). Me 1. LDA, CO 2 H Me Cl 25 Boc 2. HCl 71% OH Boc O n-buli (1.6 M in hexane, 1.16 ml, 1.86 mmol) was added under Ar to a cooled ( 78 ºC) solution of diisopropylamine (0.26 ml, 1.86 mmol) in anhydrous THF (10 ml) and the resulting solution was stirred at 78 ºC for 30 min. Indole 25 (0.32 g, 0.93 mmol) in anhydrous THF (5 ml) was then added and the resulting red mixture was stirred at 78 ºC for 30 min. CO 2 (gas) was bubbled through the reaction mixture. After 30 min at 78 ºC, the reaction mixture was quenched with H 2 O (10 ml), washed with Et 2 O (2 x 15 ml), acidified with 1 M aqueous HCl until ph 4-5 and extracted with CH 2 Cl 2 (3 x 15 ml). Concentration of the organic extracts gave amino acid hydrochloride 26: 0.27 g (71%); 1 H MR (300 MHz) δ 0.83 (br m, 3H), 1.61 (s, 9H), 1.64 (m masked, 2H), 2.22 (br m, 1H), 2.66 (br s, 3H), (br m, 2H), 4.61 (br s, 1H), 5.70 (br s, 1H), 7.24 (br m, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H); 13 C MR (100.6 MHz) δ 11.7 (CH 3 ), 23.1 (CH 2 ), 25.6 (CH 2 ), 27.6 (CH 3 ), 42.1 (CH 3 ), 51.5 (CH 2 ), 61.5 (CH), 84.9 (C), (CH), (CH), (CH), (C), (CH), (C), (CH), (C), (C), (C), (C), (C). 26 S15

16 3-(3-Ethyl-1-methyl-1,2,5,6-tetrahydro-2-pyridyl)indole-2-carboxylic Hydrochloride (27). Acid H Me Cl 26 OH Boc O 1. MeOa 2. HCl 80% H Me Cl Amino acid hydrochloride 26 (0.26 g, 0.62 mmol) in MeOH (5 ml) was treated with MeOa, previously prepared from a (0.10 g, 4.33 mmol) in MeOH (20 ml), at reflux temperature overnight. After adding H 2 O (10 ml) to the reaction mixture, the MeOH was evaporated and THF was added to the suspension. The resulting solution was acidified with 1 M aqueous HCl until ph 5-6 and extracted with CH 2 Cl 2 (3 x 15 ml). The organic extracts were concentrated and the resulting brown solid was triturated with Et 2 O (2 x 10 ml) to give hydrochloride 27: 0.16 g (80%); 1 H MR (300 MHz, CD 3 OD) δ 0.88 (br m, 3H), 1.70 (br m, 2H), 2.40 (br m, 1H), 2.75 (masked, 1H), 2.79 (s, 3H), 3.30 (masked, 1H), 3.60 (br m, 1H), 5.35 (br s, 1H), 5.77 (br s, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H). 27 H O OH Conversion of Tetracycle 22b into (±)-20-Epidasycarpidone (29). BnO 2 C H H 22b O H 35% HCHO H 2, Pd-C Me H 68% O H 29 Aqueous formaldehyde (37%, ml, 0.60 mmol) was added to a mixture of benzyl carbamate 22b (24 mg, 0.06 mmol) and 10% Pd/C (8 mg) in MeOH (5 ml) and the suspension was stirred under H 2 for 5 days. Additional Pd/C (8 mg) was added during the process. The catalyst was filtered off and the solvent was evaporated. The crude product was chromatographed (80:19:1 hexanes-acoet-diethylamine) to give 29: 11 mg (68%). H S16

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