Supporting Information. Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (-)-Quebrachamine, (+)-Aspidospermidine, (-)-Aspidospermine,

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1 Supporting Information Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (-)-Quebrachamine, (+)-Aspidospermidine, (-)-Aspidospermine, (-)-Pyrifolidine, and Related Natural Products Nengzhong Wang, Shuo Du, Dong Li, and Xuefeng Jiang*, Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai , P. R. China. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai , P. R. China. Index I. General Information... 2 II. Experimental Procedures... 3 III. Optical Ratations IV. References V. X-ray Data VI. Copies of 1 H and 13 C NMR Spectra... 25

2 I. General Information All experiments were conducted under a nitrogen atmosphere unless otherwise noted. Flasks were flame dried and cooled under nitrogen before use. Dry tetrahydrofuran (THF) was obtained by passing commercially available pre-dried, dried by distillation over sodium/benzophenone. Benzene and toluene were distilled over sodium/ benzophenone. Triethylamine (TEA), dichloromethane (DCM), and 1,2-dichloroethane (DCE) were distilled over calcium hydride. For column chromatography, mesh silica gel was employed. Sodium methanolate (NaOMe), potassium tert-butoxide (KOt-Bu) were obtained from TCI. platinum dioxide (PtO 2 ) was obtained from MACKLIN, pyridinium dichromate (PDC), trifluoroacetic acid (TFA), benzyl chloroformate (CbzCl), iodobenzene diacetate (PhI(OAc) 2 ), triethylsilylane (Et 3 SiH), diisobutylaluminium hydride (Dibal-H), Lithium aluminium hydride (LiAlH 4 ) were obtained from Energy Chemical, Dess-Martin periodinane (DMP) was obtained from Adamas. n-butyllithium (n-buli), phenyldrazine (C 6 H 5 NHNH 2 ), 2-methoxylphenyldrazine (2-MeOC 6 H 4 NHNH 2 ) were obtained from J&K. 2,3-dimethoxylphenyldrazine (2,3-MeOC 6 H 3 NHNH 2 ) 1 was prepared from known literature procedure. Methyl cyanoformate (NCCO 2 Me) was obtained from Sigma Aldrich. Unless otherwise noted, commercially available reagents were used as received. 1 H NMR spectra were recorded on Bruker spectrometers (400 and 500 MHz) in CDCl 3 solution and 13 C NMR were recorded on Bruker spectrometers (100 MHz and 125 MHz) in CDCl 3 solution. Data for 1 H spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), integration and are referenced to the residual solvent peak 7.26 ppm for CDCl C NMR spectra are referenced to the residual solvent peak ppm for CDCl 3. Electron impact (EI) ionization mass spectra (MS) were recorded on a HP 5989A mass selective detector. Electrospray ionization (ESI) mass spectra (MS) experiments were performed on an Agilent Technologies 6224 TOF LC/MS. IR spectra were recorded on a TENSOR (27) Series FT-IR Spectrometer. Optical rotations were measured on a Rudolph Automatic Polarimeter. Melting points were determined using a INESA Melting point X-4 apparatus and were uncorrected. 2

3 II. Experimental Procedures General procedure for preparation of 12. To a stirred solution of pyrone 10 (1.0 mmol, 1.0 equiv.) and enecarbamate 11 (1.5 mmol, 1.5 equiv.) in toluene (5 ml) was heated at reflux for 60 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified via flash chromatography on silica gel to afford exo-bicyclolactone 12 and endo-bicyclo-lactone 12. (2S,3aR,4R,7S,7aS)-1-tert-butyl-2-ethyl-5,7-dibromo-8-oxo-2,3,3a,4,7,7a-hexahy dro-1h-4,7-(epoxymethano)indole-1,2-dicarboxylate (12a), purified by chromatography (petroleum ether:etoac = 10:1-5:1) as a white solid (213.2 mg, 48%). Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 6.71 (d, J = 2.1 Hz, 1H), 4.87 (t, J = 2.2 Hz, 1H), 4.83 (d, J = 9.5 Hz, 1H), 4.41 (dd, J = 8.8, 3.2 Hz, 1H), 4.15 (tdd, J = 10.7, 7.4, 3.6 Hz, 2H), 3.27 (td, J = 9.8, 1.8 Hz, 1H), 2.42 (dt, J = 14.5, 8.6 Hz, 1H), (m, 1H), 1.41 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 172.4, 165.6, 154.9, 136.1, 121.5, 81.9, 81.3, 66.8, 63.9, 63.3, 61.5, 42.7, 29.1, 27.9, IR (neat, cm -1 ) 2980, 2933, 1781, 1742, 1705, 1368, 1165, HRMS (ESI) [M+ NH 4 ] + 25 Calcd for C 17 H 25 Br 2 N 2 O , Found [α] D (c 1.0, CHCl 3 ). 3

4 (2S,3aR,4R,7S,7aS)-di-tert-butyl-5,7-dibromo-8-oxo-2,3,3a,4,7,7a-hexahydro-1H- 4,7-(epoxymethano)indole-1,2-dicarboxylate (12b), purified by chromatography (petroleum ether:etoac = 20:1-10:1) as a white solid (266.4 mg, 51%). Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 6.71 (d, J = 2.3 Hz, 1H), 4.85 (t, J = 2.3 Hz, 1H), 4.79 (d, J = 9.4 Hz, 1H), 4.35 (dd, J = 9.1, 2.3 Hz, 1H), 3.24 (dd, J = 17.5, 8.6 Hz, 1H), 2.43 (dt, J = 14.0, 9.3 Hz, 1H), 2.02 (dd, J = 12.9, 10.1 Hz, 1H), 1.45 (s, 9H), 1.44 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 171.9, 165.7, 155.4, 136.3, 121.5, 82.1, 81.7, 81.0, 66.9, 65.1, 63.4, 42.7, 28.5, 28.0, IR (neat, cm -1 ) 2980, 2932, 1782, 1739, 1391, 1367, HRMS (ESI) [M+ NH 4 ] + Calcd for C 19 H 29 Br 2 N 2 O , Found [α] 25 D (c 1.0, CHCl 3 ). (2s,3aR,4R,7R,7aS)-di-tert-butyl-5-bromo-8-oxo-7-((trimethylsilyl)ethynyl)-2,3,3 a,4,7,7a-hexahydro-1h-4,7-(epoxymethano)indole-1,2-dicarboxylate (12c), purified by chromatography (petroleum ether:etoac = 10:1-5:1) as a white solid (242.2 mg, 45%). Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 6.54 (d, J = 2.0 Hz, 1H), 4.76 (t, J = 2.0 Hz, 1H), 4.68 (d, J = 7.3 Hz, 1H), 4.32 (d, J = 8.7 Hz, 1H), 3.07 (dd, J = 18.8, 8.7 Hz, 1H), 2.41 (dt, J = 13.3, 9.7 Hz, 1H), 1.94 (dd, J = 13.6, 8.9 Hz, 1H), 1.44 (s, 9H), 1.41 (s, 9H), 0.18 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 172.1, 167.3, 155.2, 134.9, 121.3, 81.8, 80.9, 80.4, 65.6, 65.1, 53.9, 40.9, 28.0, 0.3. IR (neat, cm -1 ) 2979, 2186, 1780, 1727, 1366, 1153, 843, 701. HRMS (ESI) [M+H] + Calcd for C 24 H 35 BrNO 6 Si , Found [α] 25 D (c 1.0, CHCl 3 ). 4

5 To a stirred solution of 3-Ethyl-5-bromo-2-pyrone 10c (8.36 g, mmol, 1.0 equiv.) and enecarbamate (S)-11b (16.64 g, mmol, 1.5 equiv.) in toluene (206 ml) was heated at reflux for 60 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified via flash chromatography on silica gel (petroleum ether:etoac = 20:1) to afford exo-bicyclolactone 12d (10.40 g, 54% yield) as a white solid, endo-bicyclo-lactone 12d (1.42 g, 7% yield) as white foam and recover the starting material 3-Ethyl-5-bromo-2-pyrone 10c (2.56 g). (2s,3aR,4R,7R,7aS)-di-tert-butyl-5-bromo-7-ethyl-8-oxo-2,3,3a,4,7,7a-hexahydro- 1H-4,7-(epoxymethano)indole-1,2-dicarboxylate (12d): Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 6.39 (s, 1H), 4.74 (s, 1H), 4.30 (t, J = 10.8 Hz, 2H), 3.08 (d, J = 7.2 Hz, 1H), 2.40 (dd, J = 22.9, 9.7 Hz, 1H), (m, 3H), 1.44 (s, 9H), 1.39 (s, 9H), 1.02 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 172.3, 171.1, 156.0, 133.0, 122.3, 81.7, 80.9, 80.4, 65.3, 64.8, 58.3, 42.4, 27.9, 23.3, 9.6. IR (neat, cm -1 ) 2925, 1763, 1736, 1460, 1227, 1152, HRMS (ESI) [M+ NH 4 ] + Calcd for C 21 H 34 BrN 2 O , Found [α] 25 D (c 1.0, CHCl 3 ). (2s,3aR,4S,7S,7aS)-di-tert-butyl-5-bromo-7-ethyl-8-oxo-2,3,3a,4,7,7a-hexahydro- 1H-4,7-(epoxymethano)indole-1,2-dicarboxylate (12d ): Mp o C. 1 H NMR (500 MHz, CDCl 3 ) δ 6.36 (s, 1H), 4.94 (s, 1H), 4.27 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), 1.77 (td, J = 13.9, 6.8 Hz, 1H), (m, 18H), 1.04 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 172.0, 171.1, 155.9, 131.6, 119.6, 81.9, 81.1, 80.6, 64.2, 61.0, 57.9, 43.8, 30.4, 28.0, 27.9, 24.1, 9.8. IR (neat, cm -1 ) 2963, 1739, 1262, 1099, 1024, 803,

6 HRMS (ESI) [M+H] + Calcd for C 21 H 31 BrNO , Found [α] D (c 1.0, CHCl 3 ). (2s,3aR,4R,7R,7aS)-1-((benzyloxy)carbonyl)-5-bromo-7-ethyl-8-oxo-2,3,3a,4,7, 7a-hexahydro-1H-4,7-(epoxymethano)indole-2-carboxylic acid (14): To a 50 ml round-bottom flask with magnetic stir bar was added exo-bicyclo-lactone 12d (10.40 g, mmol, 1.00 equiv.) and TFA (20 ml). The resulting solution was stirred for 5 h at room temperature. The resulting residue was concentrated under reduced pressure to afford the corresponding amino acid, which was used subsequently without further purification. To a suspension of the amino acid in THF/H 2 O (2:1, 220 ml) was added NaHCO 3 (37.34 g, mmol, equiv.) and CbzCl (18.77 g, mmol, 5.00 equiv.) at room temperature, The resulting mixture was stirredfor 15 h. The reaction was acidified with 4N HCl until the PH 2-3 and the mixture was extracted with EtOAc five times. The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac = 2:1) to afford acid 14 (6.48 g, 66% yieldfor two steps) as a white solid. Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J = 18.3 Hz, 4H), 6.34 (s, 1H), 5.94 (s, 1H), 4.99 (s, 2H), 4.73 (s, 1H), 4.49 (d, J = 7.4 Hz, 1H), 4.30 (d, J = 9.4 Hz, 1H), 3.07 (dd, J = 17.5, 8.5 Hz, 1H), 2.43 (dt, J = 13.8, 9.1 Hz, 1H), (m, 1H), 1.90 (s, 1H), 0.96 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 177.3, 170.9, 156.4, 135.3, 132.7, 128.5, 128.3, 128.1, 122.6, 80.6, 68.0, 64.7, 63.9, 58.0, 42.8, 28.4, 23.2, 9.5. IR (neat, cm -1 ) 2925, 1753, 1394, 1257, 1185, 1087, HRMS (ESI) [M+ NH 4 ] + Calcd for C 20 H 24 BrN 2 O , Found [α] 25 D (c 0.5, CHCl 3 ). 6

7 (3aR,4R,7R,7aS)-benzyl-5-bromo-7-ethyl-8-oxo-2,3,3a,4,7,7a-hexahydro-1H-4, 7-(epoxymethano)indole-1-carboxylate (15): To a stirred solution of acid 14 (6.48 g, mmol, 1.00 equiv.) in DCM (140 ml) and under argon atmosphere was added PhI(OAc) 2 (9.30 g, mmol, 2.00 equiv.) and I 2 (0.73 g, 2.89 mmol, 0.20 equiv.). The solution was stirred for 2 h under a 200W light at room temperature. Then the solution was added Et 3 SiH (8.37 g, mmol, 5.00 equiv.) and stirred for 30 min. The mixture was concentrated under reduced pressure. The resulting residue was purified via flash chromatography on silica gel (petroleum ether:etoac = 20:1) to afford amine 15 (5.38 g, 92% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 5H), 6.38 (s, 1H), 5.10 (dd, J = 29.0, 12.2 Hz, 2H), 4.94 (t, J = 1.9 Hz, 1H), 4.21 (d, J = Hz, 2H), 3.23 (td, J = 11.6, 7.3 Hz, 1H), 2.93 (t, J = 9.6 Hz, 1H), (m, 3H), 1.81 (s, 1H), 1.02 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 171.8, 155.6, 136.0, 131.6, 128.4, 128.1, 127.8, 122.6, 83.8, 67.5, 61.5, 56.2, 47.0, 43.1, 28.2, 22.2, 8.8. IR (neat, cm -1 ) 2926, 1759, 1702, 1407, 1259, 1196, 1095, HRMS (ESI) [M+ NH 4 ] + Calcd for C 19 H 24 BrN 2 O , Found [α] 25 D (c 1.0, CHCl 3 ). (3aR,4R,7R,7aS)-benzyl-5-bromo-7-ethyl-4-hydroxy-7-((E)-3-methoxy-3-oxoprop -1-en-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-indole-1-carboxylate (16): To a stirred solution of amine 15 (5.38 g, mmol, 1.00 equiv.) in toluene (120 ml) at 78 o C was added Dibal-H (12 ml, mmol, 1.50 equiv., 1.5 M in toluene) through 7

8 syringe over 30 min. Following the addition, the reaction was allowed to warm to 40 o C. After stirring for 3 h, the reaction was quenched with sat. aq. potassium sodium tartrate (20 ml). The mixture was concentrated under reduced pressure and extracted with EtOAc (3 x 50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressureto afford the corresponding hemiacetal, which was used subsequently without further purification. To a stirred solution of hemiacetal and Ph 3 P=CHCO 2 Me (6.01 g, mmol, 1.50 equiv.) in toluene (120 ml) was heated at reflux for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified via flash chromatography on silica gel (petroleum ether:etoac = 3:1) to afford a mixture of α, β-unsaturated esters 16a/16b (4.12 g, 74% yield for two steps) as a colorless oil. rotamer A: 1 H NMR (400 MHz, CDCl 3 ) δ (m, 5H), 6.91 (d, J=16.1 Hz, 1H), 5.94 (s, 1H), 5.78 (dd, J= 32.9, 16.7 Hz, 1H), 5.15 (d, J=4.8 Hz, 2H), 4.54 (d, J= 6.9 Hz, 1H), 4.36 (d, J= 6.7 Hz, 1H), 3.71(s, 3H), 3.41 (dd, J= 18.5, 10.6 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), 0.86 (t, J= 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.5, 155.6, 153.1, 136.7,132.1,128.5, 127.9,127.6, 120.6, 68.0, 67.0, 60.9,48.9, 45.2, 44.0, 33.3, 25.2, 8.5. rotamer B: 1 H NMR (400 MHz, CDCl 3 ) δ (m, 5H), 6.81 (d, J=16.0 Hz, 1H), 5.84 (s, 1H), 5.72 (s, 1H), (m, 2H), 4.50 (d, J= 7.1 Hz, 1H), 4.27 (d, J= 6.6 Hz, 1H), 3.71 (s, 3H), 3.50 (dd, J= 19.0, 10.3 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), 1.41 (td, J=14.4, 7.3 Hz, 1H), 0.67 (t, J= 7.3Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.4, 154.8, 152.6, 136.1, 128.5, 128.3, 127.2, 127.0, 120.8, 67.6,60.1,51.6,48.7, 45.5, 44.6, 32.4, 24.3, 8.3. IR (neat, cm -1 ) 3396, 2925, 1701, 1414, 1257, HRMS (ESI) [M+NH 4 ] + Calcd for C 22 H 30 BrN 2 O , Found [α] 25 D (c 1.0, CHCl 3 ). 8

9 (31S,6aS,9S,9aR)-6a-ethyl-9-hydroxyoctahydro-1H-pyrrolo[3,2,1-ij]quinolin- 4(2H)-one (17): A 2 L round-bottomed flask with magnetic stir bar was charged with the mixture of α, β-unsaturated esters 16a/16b and MeOH (887 ml), then was added Et 3 N (4.48 g, mmol, 5.00 equiv.) and Pd/C (10 wt%, 1.88 g, 1.77 mmol, 0.20 equiv.). The flask was evacuated and back-filled with H 2, After stirring for 8 h under a H 2 atmosphere (balloon), the mixture was filtered through a short pad of Celite that was carefully rinsed with EtOAc (3 x 50 ml). The filtrate was concentrated in vacuo and then the resulting residue was dissolved with H 2 O (10 ml). The aqueous phase was extracted with EtOAc (5 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 50:1) to afford lactam 17 (1.43 g, 72% yield) as a white solid. Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), 3.29 (t, J = 11.1 Hz, 1H), 3.12 (d, J = 4.6 Hz, 1H), (m, 2H), (m, 1H), (m, 6H), (m, 1H), (m, 1H), (m, 1H), 1.11 (d, J = 13.4 Hz, 1H), 0.86 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.9, 66.8, 64.0, 45.6, 40,1, 32.9, 30.7, 29.7, 27.8, 27.6, 25.1, 17.5, 7.1. IR (neat, cm -1 ) 3375, 2923, 2854, 1736, 1615, 1462, 1288, HRMS (EI) [M] + Calcd for C 13 H 21 NO , Found [α] 25 D (c 0.5, CHCl 3 ). (31S,6aR,9aR)-6a-ethyloctahydro-1H-pyrrolo[3,2,1-ij]quinolin-9(2H)-one (13): 9

10 To a stirred solution of lactam 17 (1.43 g, 6.40 mmol, 1.00 equiv.) in THF (64 ml) at 78 o C was added LiAlH 4 (1.22 g, mmol, 5.00 equiv.) in three portions. Following the addition, the reaction was allowed to warm to reflux. After stirring for 10 h, the reaction was quenched subsequently with H 2 O (1.2 ml), 15% NaOH (1.2 ml) and H 2 O (3.6 ml).the mixture was stirred for another 30 min then filtered through a short pad of Celite then concentrated under reduced pressure to afford the corresponding amine, which was used subsequently without further purification. To a solution of the crude amine in DCM (130 ml) at 0 o C was added Dess Martin periodinane (10.86 g, mmol, 4.00 equiv.). The resulting mixture was allowed to warm to room temperature. After stirring for 1h, the reaction was quenched with saturated aq. NaHCO 3 (50 ml) and saturated aq. Na 2 S 2 O 3 (50 ml). The resulting mixture was stirred for another 30 min. The organic layer was separated, and the aqueous layer was extracted with DCM (3 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac = 5:1 to 2:1) to afford tricyclic ketone 13 (1.08 g, 77% yield for two steps) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 2.97 (td, J = 8.7, 3.0 Hz, 2H), 2.63 (dd, J = 7.4, 5.5 Hz, 1H), (m, 2H), (m, 2H), ( m, 3H), 1.76 (td, J = 11.2, 4.0 Hz,1H), (m, 1H), (m, 2H), (m, 2H), (m, 1H), 1.07 (td, J = 13.3, 4.6 Hz, 1H), 0.90 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ211.2, 73.4, 53.1, 52.8, 48.1, 36.7, 34.7, 32.8, 30.0, 26.0, 21.2, 21.2, 7.0. IR (neat, cm -1 ) 2926, 1730,1460, 1261, 1075, HRMS (EI) [M] + Calcd for C 13 H 21 NO , Found [α] 25 D (c 0.5, CHCl 3 ). { lit. 2 [α] 29 D (c 0.88, CHCl 3 ). lit. 3 [α] 24 D (c 0.5, CHCl 3 ). }. 10

11 To a stirred solution of tricyclic ketone 13 (207.3 mg, 1.0 mmol, 1.0 equiv.) and phenyldrazine (162.2 mg, 1.5 mmol, 1.5 equiv.) in benzene (10 ml) was heated at reflux for 3 h.the resulting mixture was cooled to room temperature, the solvent was evaporated, the mixture was redissolved in acetic acid (10 ml) and was heated at reflux for 3 h. After cooling to room temperature, the resulting mixture was basified with 2 M NaOH until the PH 8-9 and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:10:0.5) to afford (+)-dehydroaspidospermidine (18a) (178.6 mg, 64% yield for two steps) as a yellow oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (td, J = 7.4, 0.9 Hz, 1H), (m, 2H), 3.10 (ddd, J = 14.2, 12.0, 5.2 Hz, 1H), 2.75 (ddd, J = 14.1, 10.4, 3.5 Hz, 1H), 2.58 (ddd, J = 11.5, 8.5, 5.7 Hz, 1H), 2.45 (td, J = 12.6, 3.1 Hz, 1H), 2.40 (s, 1H), (m, 2H), (m, 1H), 1.64 (dd, J = 12.4, 5.6 Hz, 1H), (m, 2H), 1.46(d, J = 13.5 Hz, 1H), 1.00 (td, J = 13.6, 4.9 Hz, 1H), (m, 2H), 0.49 (t, J = 7.4 Hz, 3H). 13 C NMR(125 MHz, CDCl 3 ) δ 192.4, 154.4, 147.1, 127.4, 125.1, 121.0, 120.1, 79.0, 61.3, 54.5, 52.0, 36.5, 35.1, 33.2, 29.7, 27.2, 23.7, 22.0, 7.3. IR (neat, cm -1 ) 2931, 1709, 1660, 1459, 1257, HRMS (EI) [M] + Calcd for C 19 H 24 N , Found [α] D (c 0.5, CHCl 3 ). { lit. 4 [α] D (c 1.0, CHCl 3 ). lit. 5 [α] D ±2 (c 0.5, CHCl 3 ). Lit. 6 [α] D 236±7 (EtOH)} To a stirred solution of tricyclic ketone 13 (140.0 mg, mmol, 1.0 equiv.) in EtOH (7 ml) was added sodium carbonate (107.4 mg, mmol, 1.5 equiv.) and 2-methoxylphenyldrazine hydrochloride (176.8 mg, mmol, 1.5 equiv.) at room temperature. The mixture was stirred for another 30 min then filtered through a short pad of Celite then concentrated under reduced pressure. Water was further removed using a benzene water azeotrope. The mixture was redissolved in acetic acid (10 ml) and was heated at 95 o C for 1 h. After cooling to room temperature, the resulting 11

12 mixture was basified with 2 M NaOH until the PH 8-9 and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:10:0.5) to afford (+)-dehydrodeacetylaspidospermine (18b) (138.6 mg, 66% yield for two steps) as a yellow oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.13 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 3.96 (s, 3H), 3.16 (d, J = 7.4 Hz, 2H), (m, 1H), (m, 1H), 2.56 (dd, J = 15.0, 10.0 Hz, 1H), 2.44 (dd, J = 17.9, 7.2 Hz, 1H), 2.37 (s, 1H), 2.15 (dt, J = 12.1, 9.6 Hz, 2H), 1.84 (ddd, J = 17.5, 13.1, 8.8 Hz, 1H), (m, 3H), 1.47 (d, J = 13.1 Hz, 1H), 0.99 (td, J = 13.6, 4.7 Hz, 1H), (m, 2H), 0.50 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 190.9, 151.1, 149.2, 142.3, 126.3, 113.5, 110.1, 79.1, 61.8, 55.7, 54.5, 52.0, 36.5, 35.2, 33.2, 29.7, 27.2, 23.6, 22.0, 7.3. IR (neat, cm -1 ) 2929, 1713, 1460, 1256, HRMS (EI) [M] + Calcd for C 20 H 26 N 2 O , Found [α] 25 D (c 0.5, CHCl 3 ) To a stirred solution of tricyclic ketone 13 (207.3 mg, 1.0 mmol, 1.0 equiv.) and 2,3-dimethoxylphenyldrazine (229.8 mg, 1.5 mmol, 1.5 equiv.) in benzene (10 ml) was heated at reflux for 3 h. The resulting mixture was cooled to room temperature, the solvent was evaporated, the mixture was redissolved in acetic acid (10 ml) and was heated at 95 o C for 3 h. After cooling to room temperature, the resulting mixture was basified with 2 M NaOH until the PH 8-9 and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:10:0.5) to afford (+)-dehydrodeacetylpyrfolidine (18c) (157.5 mg, 46% yield for two steps) as a yellow oil. 1 H NMR (500 MHz, CDCl 3 ) δ 6.91 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.14 (s, 3H), 3.87 (s, 3H), 3.15 (t, J = 7.5 Hz, 2H), 3.07 (td, J = 13.9, 5.1 Hz, 1H), 2.78 (ddd, J = 13.8, 10.5, 3.0 Hz, 1H), (m, 1H), 2.42 (t, J = 11.5 Hz, 1H), 2.32 (s, 1H), (m, 2H), (m, 2H), (m, 2H), 1.45 (d, J = 13.0 Hz, 1H), 0.99 (td, J = 13.5, 4.6 Hz, 1H), (m, 2H), 0.50 (t, J = 12

13 7.4 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.0, 151.8, 146.2, 141.5, 141.1, 114.6, 108.8, 79.4, 61.8, 60.8, 56.4, 54.5, 52.0, 36.4, 35.6, 33.2, 29.8, 27.3, 23.8, 22.0, 7.3. IR (neat, cm -1 ) 2961, 1257, 1010, 788. HRMS (EI) [M] + Calcd for C 21 H 28 N 2 O , Found [α] 25 D (c 0.3, CHCl 3 ) To a stirred solution of (+)-dehydroaspidospermidine (18a) (91.5 mg, 0.33 mmol, 1.0 equiv.) in dry THF (3 ml) at 78 o C was added n-buli (280 µl, 0.66 mmol, 2.0 equiv., 2.4 M in hexanes). The reaction was stirred under argon at 78 ºC for 30 minutes then methyl cyanoformate (55.5 mg, 0.66 mmol, 2.0 equiv.) in THF (0.3 ml) was added via syringe over 5 min. The resulting mixture was stirred at 78 ºC for another 30 min. Progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride(5 ml) and the mixture was extracted with EtOAc (3 x 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:20:0.5) to afford (+)-vincadifformine (1) (57.3 mg, 51%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 7.19 (d, J = 5.7 Hz, 1H), 7.12 (td, J = 7.7, 1.1 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 3.76 (s, 3H), 3.12 (d, J = 9.1 Hz, 1H), (m, 1H), 2.72 (d, J = 15.1 Hz, 1H), (m, 1H), (m, 2H), 2.27 (d, J = 15.1 Hz, 1H), 2.05 (td, J = 11.2, 6.5 Hz, 1H), (m, 2H), 1.70 (d, J = 8.2 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 169.1, 167.6, 143.2, 137.8, 127.4, 121.1, 120.5, 109.3, 92.6, 72.5, 55.5, 51.7, 50.9, 50.9, 50.5, 45.2, 38.1, 32.8, 29.4, 25.7, 7.1. IR (neat, cm -1 ) 3363, 2927, 1730, 1676, 1607, 1464, 1249, HRMS (EI) [M] + Calcd for 13

14 C 21 H 26 N 2 O , Found [α] D (c 0.2, CHCl 3 ). {lit. 4 [α] D (c 1.0, CHCl 3 ). lit. 7 [α] D ( c 0.2, EtOH). lit. 8 [α] D 600 (EtOH)} To a stirred solution of (+)-dehydroaspidospermidine (18a) (84 mg, 0.3 mmol, 1.0 equiv.) and KOH (10 ml, 1% KOH in MeOH) was added potassium borohydride (161.8 mg, 3.0 mmol, 10.0 equiv.). Following the addition, the reaction was allowed to warm to reflux. After stirring for 13 h. The mixture was concentrated under reduced pressure. The resulting residue was purified via flash chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:20:0.5) to afford (-)-quebrachamine (5) (42.5 mg, 50% yield) as a white solid. Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (s, 1H), (m, 1H), (m, 1H), (m, 2H), 3.26 (dt, J = 11.9, 1.6 Hz, 1H), (m, 1H), 2.85 (ddd, J = 14.7, 4.4, 2.9 Hz, 1H), (m, 2H), (m, 2H), 2.35 (td, J = 11.5, 4.5 Hz, 1H), 2.26 (td, J = 11.3, 3.1 Hz, 1H), 1.93 (ddd,j = 13.8, 6.8, 2.0 Hz, 1H), (m, 2H), 1.52 (d, J = 11.9 Hz, 1H), (m, 2H), 1.23 (dd, J = 14.6, 7.0 Hz, 1H), (m, 2H), 0.86 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 139.9, 134.8, 128.9, 120.2, 118.7, 117.4, 110.0, 108.7, 56.7, 55.1, 53.3, 37.1, 34.8, 33.5, 32.1, 22.7, 22.5, 22.0, 7.8. IR (neat, cm -1 ) 2924, 1462, 1258, HRMS (EI) [M] + Calcd for C 19 H 26 N , Found [α] 25 D (c 0.5, CHCl 3 ). {lit [α] D (c 0.6, CHCl 3 ). lit. 5 [α] 26 D 118±5 (c 0.1, CHCl 3 )}. 14

15 To a stirred solution of (-)-quebrachamine (5) (28.0 mg, 0.1 mmol, 1.0 equiv.) in dry THF (2 ml) at 0 o C was added NaH (40.0 mg, 1.0 mmol, 10.0 equiv., 60% dispersion in mineral oil). The reaction was stirred under argon at 0ºC for 30 minutes then methyl iodide (71.0 mg, 0.5 mmol, 5.0 equiv.) was added. The resulting mixture was warm to room temperature for 15 h. The reaction mixture was quenched with saturated ammonium chloride (5 ml) and the mixture was extracted with EtOAc (3 x 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:10:0.5) to afford (-)-N-methylquebrachamine (19) (23.2 mg, 78%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 3.67 (s, 3H), 3.34 (d, J = 12.0 Hz, 1H), 2.92 (dd, J = 12.1, 4.4 Hz, 1H), 2.86 (ddd, J = 14.8, 4.5, 2.1 Hz, 1H), 2.78 (ddd, J = 15.6, 10.5, 1.7 Hz, 1H), 2.63 (ddd, J = 15.6, 6.8, 1.7 Hz, 1H), 2.45 (ddd, J = 11.4, 4.4, 2.2 Hz, 1H), (m, 1H), (m, 2H), 1.79 (dd, J = 13.6, 5.5 Hz, 1H), (m, 1H), (m, 1H), 1.49 (d, J = 12.0 Hz, 1H), (m, 3H), (m, 2H), 0.88 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 141.9, 136.2, 127.7, 119.7, 118.2, 117.3, 108.4, 108.2, 56.6, 55.2, 53.5, 37.6, 34.8, 32.3, 32.0, 29.7, 22.6, 22.5, 19.0, 7.9. IR (neat, cm -1 ) 2961, 1258, 1011, 789, 700. HRMS (EI) [M] + Calcd for C 20 H 28 N , Found [α] 25 D (c 0.2, CHCl 3 ). {lit. 10 [α] D -80 (CHCl 3 ).}. To a stirred solution of (+)-dehydroaspidospermidine (18a) (140.0 mg,

16 mmol, 1.0 equiv.) in THF (5 ml) at 78 o C was added LiAlH 4 (190.0 mg, 5.0 mmol, 10.0 equiv.) in three portions. Following the addition, the reaction was allowed to warm to reflux. After stirring for 12 h, the reaction was quenched subsequently with H 2 O (190µL), 15% NaOH (190 µl) and H 2 O (570 µl). The mixture was stirred for another 30 minthen filtered through a short pad of Celite then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:50:1) to afford (+)-aspidospermidine (2) (117.8 mg, 83% yield) as a white solid. Mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (d, J = 7.4 Hz, 1H), 7.01 (td, J = 7.6, 1.2 Hz, 1H), 6.72 (td, J = 7.4, 0.9 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 3.51 (dd, J = 11.0, 6.2 Hz, 1H), 3.12 (dd, J = 10.1, 7.5 Hz, 1H), 3.05 (d, J = 10.8 Hz, 1H), (m, 3H), (m, 2H), (m, 1H), (m, 2H), (m, 4H), 1.12 (td, J = 27.0, 13.5 Hz, 1H), 1.05 (dt, J = 13.5, 3.0 Hz, 1H), (m, 1H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 149.4, 135.6, 127.0, 122.7, 118.9, 110.2, 71.2, 65.6, 53.8, 53.3, 52.9, 38.8, 35.6, 34.4, 29.9, 28.0, 23.0, 21.7, 6.7. IR (neat, cm -1 ) 2931, 2778, 1606, 1480, 1462, 1256, 1178, HRMS (EI) [M] + Calcd for C 19 H 26 N , Found [α] 25 D 20.8 (c 0.5, EtOH). {lit [α] D (c 0.5, EtOH). lit [α] D 20.8 (c 1.0, CHCl 3 ). lit. 11 [α] D 21 (EtOH).}. To a stirred solution of (+)-dehydrodeacetylaspidospermine (18b) (96.0 mg, 0.31 mmol, 1.0 equiv.) in THF (3 ml) at 78 o C was added LiAlH 4 (58.7 mg, 1.55 mmol, 5.0 equiv.) in three portions. Following the addition, the reaction was allowed to warm to 45 o C. After stirring for 13 h, the reaction was quenched subsequently with H 2 O (59 µl), 15% NaOH (59 µl) and H 2 O (177 µl). The mixture was stirred for another 30 minthen filtered through a short pad of Celite then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 60:30:0.5) to afford (+)-deacetylaspidospermine (20a) (51.1 mg, 53% yield) as a pale yellow solid. Mp o C. 1 H NMR (500 MHz, CDCl 3 ) δ 6.74 (dd, J = 7.4, 1.3 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.64 (dd, J = 7.7, 1.3 Hz, 1H), 3.82 (s, 3H), 3.57 (dd, J = 11.1, 6.2 Hz, 1H), 3.11 (td, J = 8.9, 2.8 Hz, 1H), 16

17 3.05 (d, J = 10.8 Hz,1H), (m, 1H), (m, 1H), 2.19 (s, 1H), (m, 2H), (m, 3H), (m, 2H), 1.46 (d, J = 8.5 Hz, 1H), (m, 1H), 1.09 (td, J = 27.0, 13.5 Hz, 1H), 1.04 (dt, J = 13.5, 3.0 Hz, 1H), (m, 1H), 0.63 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 145.9, 138.2, 136.6, 119.5, 115.3, 108.8, 71.3, 66.0, 55.2, 54.0, 53.9, 53.0, 38.4, 35.6, 34.5, 29.9, 28.2, 23.0, 21.8, 6.8. IR (neat, cm -1 ) 3367, 2930, 2778, 1614, 1591, 1461, 1258, HRMS(EI) [M] + Calcd for C 20 H 28 N 2 O , Found [α] 25 D 4.7 (c 1.0, CHCl 3 ). {lit. 12 [α] D 3 (CHCl 3 ). lit [α] D 2.9 (c 0.9, EtOH).}. To a stirred solution of (+)-dehydrodeacetylpyrfolidine (18c) (101.5 mg, 0.30 mmol, 1.0 equiv.) in THF (3 ml) at 78 o C was added LiAlH 4 (56.6 mg, 1.49 mmol, 5.0 equiv.) in three portions. Following the addition, the reaction was allowed to warm to 45 o C. After stirring for 13 h, the reaction was quenched subsequently with H 2 O (57 µl), 15% NaOH (57 µl) and H 2 O (171 µl). The mixture was stirred for another 30 minthen filtered through a short pad of Celite then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:10:0.1) to afford (+)-deacetylpyrfolidine (20b) (72.8 mg, 71% yield) as a pale yellow solid. Mp o C. 1 H NMR (500 MHz, CDCl 3 ) δ 6.72 (d, J = 8.1 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 3.82 (s, 3H), 3.63 (s, 1H), 3.54 (dd, J = 10.9, 6.2 Hz, 1H), 3.10 (td, J = 8.75, 2.5 Hz, 1H), 3.04 (d, J = 10.5 Hz, 1H), 2.30 (dt, J = 12.6, 8.6 Hz, 1H), 2.22 (dd, J = 18.1, 8.7 Hz, 1H), 2.15 (s, 1H), (m, 2H), (m, 3H), (m, 3H), (m, 1H), (m, 2H), (m, 1H), 0.63 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 151.9, 143.1, 134.2, 130.1, 117.4, 102.6, 71.3, 66.5, 60.0, 55.8, 53.9, 53.3, 53.0, 38.9, 35.6, 34.5, 29.9, 28.2, 23.0, 21.7, 6.8. IR (neat, cm -1 ) 2926, 1619, 1461, 1257, 1089, HRMS (EI) [M] + Calcd for C 21 H 30 N 2 O , Found [α] 25 D 1.0 (c 0.5, CHCl 3 ). {lit. 14 [α] D 7 (CHCl 3 ).}. 17

18 To a stirred solution of (+)-aspidospermidine (2) (36.9 mg, 0.13 mmol, 1.0 equiv.) in pyridine (0.5 ml) was added acetic anhydride (0.5 ml) at room temperature. The resulting mixture was stirred for 3 h. After cooling to 0 o C, the reaction was quenched withaqueous ammonia solution (1 ml) and the mixture was extracted with DCM (3 x 10 ml). The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:50:2) to afford (-)-N-acetylaspidospermidine (21a) (36.9 mg, 88%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ 8.12 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 14.2, 7.4 Hz, 2H), 7.03 (t, J = 7.5 Hz, 1H), 4.06 (dd, J = 11.2, 6.2 Hz, 1H), 3.13 (td, J = 9.1, 2.7 Hz, 1H), 3.06 (d, J = 10.8 Hz, 1H), 2.30 (s, 1H), 2.26 (s, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), 1.65 (d, J = 14.1 Hz, 1H), (m, 4H), (m, 2H), (m, 1H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 168.4, 140.6, 138.5, 127.4, 124.2, 122.3, 118.2, 70.7, 68.2, 53.8, 52.8, 52.6, 39.7, 35.5, 34.0, 30.0, 25.7, 23.2, 23.0, 21.5, 6.8. IR (neat, cm -1 ) 2963, 1659,`1478, 1399, 1258, HRMS (EI) [M] + Calcd for C 21 H 28 N 2 O , Found [α] 25 D (c 0.5, CHCl 3 ). {lit [α] D -15 (c 0.5, CHCl 3 ).}. (-)-aspidospermine (3) (14.6 mg, 83%) as a white solid: prepared in a manner similar to (-)-N-acetylaspidospermidine, but using (+)-deacetylaspidospermine (20a) (15.6 mg). Mp o C. 1 H NMR (500 MHz, CDCl 3 ) δ 7.06 (t, J = 7.9 Hz, 1H), (m, 2H), 3.87 (s, 3H), 3.11 (td, J = 9.0, 2.9 Hz, 1H), 3.02 (d, J = 10.3 Hz, 1H), (m, 5H), (m, 4H), (m, 2H),

19 (m, 3H), (m, 1H), (m, 1H), (mz, 2H), (m, 1H), 0.60 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.6, 149.4, 143.8, 129.3, 126.0, 115.5, 111.0, 71.1, 69.5, 55.4, 53.6, 53.2, 52.5, 38.0, 35.5, 34.2, 30.1, 24.7, 23.1, 23.0, 21.6, 6.8. IR (neat, cm -1 ) 2931, 1462, 1488, 1454, 1379, 1257, 1181, HRMS(EI) [M] + Calcd for C 22 H 30 N 2 O , Found [α] 25 D (c 0.4, CHCl 3 ). {lit [α] D (c 0.48, CHCl 3 ). lit. 14 [α] D -93 (CHCl 3 ).}. (-)-pyrifolidine (4) (32.7 mg, 85%) as a white solid: prepared in a manner similar to (-)-N-acetylaspidospermidine, but using (+)-deacetylpyrifolidine (20b) (34.2 mg). Mp o C. 1 H NMR (500 MHz, CDCl 3 ) δ 6.82 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 2H), 3.07 (d, J = 37.6 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 1H), (m, 5H), (m, 1H), (m, 3H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 0.63 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.6, 152.5, 139.5, 135.4, 133.7, 117.4, 108.8, 71.0, 69.6, 59.8, 56.2, 53.6, 52.7, 52.4, 38.3, 35.5, 34.1, 30.0, 24.9, 23.1, 22.9, 21.5, 6.8. IR (neat, cm -1 ) 2959, 1453, 1257, 1009, 788, 700. HRMS (EI) [M] + Calcd for C 23 H 32 N 2 O , Found [α] 25 D (c 0.75, CHCl 3 ). {lit. 16 [α] D -93 (CHCl 3 ). lit. 12 [α] D -94 (CHCl 3 ).}. To a stirred solution of (+)-aspidospermidine (2) (32.0 mg, 0.11 mmol, 1.0 equiv) in actone (1 ml) was added Me 2 SO 4 (71.5 mg, 0.57 mmol, 5.0 equiv) and potassium tert-butoxide(12.7 mg, 1.13 mmol, 10.0 equiv) at room temperature. The resulting mixture was stirredfor 1 h. The reaction mixture was quenched with saturated ammonium chloride (5 ml) and the mixture was extracted with EtOAc (3 x 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column 19

20 chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:50:2) to afford (+)-N-methylaspidospermidine (21b) (31.6 mg, 94%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.06 (td, J = 7.6, 1.2 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.63 (td, J = 7.4, 0.8 Hz, 1H), 6.37 (d, J = 7.7 Hz, 1H), 3.43 (dd, J = 10.8, 5.7 Hz, 1H), 3.13 (td, J = 9.1, 2.7 Hz, 1H), 3.06 (d, J = 10.1 Hz, 1H), 2.75 (s, 3H), (m, 3H), (m, 2H), (m, 2H), 1.63 (d, J = 13.5 Hz, 1H), (m, 3H), 1.22 (dt, J = 5.9, 2.7 Hz, 1H), (m, 2H), ( m, 1H), 0.63 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 150.5, 136.8, 127.2, 122.1, 117.1, 106.4, 71.7, 71.2, 53.8, 53.0, 52.6, 39.1, 35.5, 34.5, 31.4, 30.1, 22.9, 22.0, 21.7, 6.8. IR (neat, cm -1 ) 2930, 2781, 1605, 1483, 1375, 1257, 1181, HRMS (EI) [M] + Calcd for C 20 H 28 N , Found [α] 25 D 23.1 (c 0.5, CHCl 3 ). {lit [α] D 26 (c 0.76, CHCl 3 ). lit [α] D 24.4±2 (c 1.25, CHCl 3 ). lit. 10 [α] D 21 (CHCl 3 )}. To a stirred solution of (+)-aspidospermidine (2) (36.9 mg, 0.13 mmol, 1.0 equiv.) in pyridine (0.5 ml) was added propionic anhydride (0.5 ml) at room temperature. The resulting mixture was stirred for 3 h. After cooling to 0 o C, the reaction was quenched with aqueous ammonia solution (1 ml) and the mixture was extracted with DCM (3 x 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:etoac:et 3 N = 100:50:2) to afford (-)-demethoxypalosine (21c) (38.1 mg, 87%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ 8.15 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 15.5, 7.5 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 4.11 (dd, J = 11.2, 6.2 Hz, 1H), 3.13 (td, J = 9.0, 2.6 Hz, 1H), 3.06 (d, J = 10.9 Hz, 1H), 2.56 (dq, J = 14.9, 7.4 Hz, 1H), 2.44 (dq, J = 15.1, 7.4 Hz, 1H),

21 (s, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), 1.65 (d, J = 13.6 Hz, 1H), ( m, 4H), 1.24 (t, J = 7.4 Hz, 3H), (m, 2H), (m, 1H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 172.0, 140.8, 138.4, 127.4, 124.1, 122.3, 118.2, 70.7, 67.2, 53.8, 52.8, 52.6, 39.7, 35.5, 34.1, 30.0, 28.2, 25.8, 23.0, 21.6, 9.6, 6.8. IR (neat, cm -1 ) 2932, 1660, 1477, 1399, 1257, HRMS (EI) [M] + Calcd for C 22 H 30 N 2 O , Found [α] 25 D (c 0.5, CHCl 3 ). {lit. 15 [α] 25 D -20 (CHCl 3 )}. 21

22 III. Optical Rotations Entry Natural products Our results Synthesis Isolation 1 (+)-dehydroaspidospermidine (18a) [α] D (c 0.5, CHCl 3 ) [α] D (c 1.0, CHCl 3 ) 4 [α] D ±2 (c 0.5, CHCl 3 ) 5 2 (+)-dehydrodeacetylaspidospermine (18b) [α] D 236±7 (EtOH) 6 [α] D (c 0.5, CHCl 3 ) (+)-dehydrodeacetylpyrifolidine (18c) [α] D (c 0.3, CHCl 3 ) (+)-vincadifformine (1) [α] D (c 0.2, CHCl 3 ) [α] D (c 1.0, CHCl 3 ) 4 [α] D ( c 0.2, EtOH) 7 [α] D 600 (EtOH) 8 5 (-)-quebrachamine (5) [α] D (c 0.5, CHCl 3 ) [α] D (c 0.6, CHCl 3 ) 9 [α] D ±5 (c 0.1, CHCl 3 ) 5 6 (-)-N-methylquebrachamine (19) [α] D (c 0.2, CHCl 3 ) - [α] D -80 (CHCl 3 ) 10 7 (+)-aspidospermidine (2) [α] D (c 0.5, EtOH) [α] D (c 0.5, EtOH) 3 [α] D (c 1.0, CHCl 3 ) 4 [α] D 21 (EtOH) 11 8 (+)-deacetylaspidospermine (20a) [α] D (c 1.0, CHCl 3 ) - [α] D 3 (CHCl 3 ) 12 [α] D (c 0.9, EtOH) 13 9 (+)-deacetylpyrifolidine (20b) [α] D (c 0.5, CHCl 3 ) - [α] D 7 (CHCl 3 ) (-)-N-acetylaspidospermidine (21a) [α] D (c 0.5, CHCl 3 ) - [α] D (c 0.5, CHCl 3 ) (-)-aspidospermine (3) [α] D (c 0.4, CHCl 3 ) [α] D (c 0.48, CHCl 3 ) 2 [α] D -93 (CHCl 3 ) (-)-pyrifolidine (4) [α] D (c 0.75, CHCl 3 ) - [α] D -93 (CHCl 3 ) 16 [α] D -94 (CHCl 3 ) (+)-N-methylaspidospermidine (21b) [α] D (c 0.5, CHCl 3 ) [α] D (c 0.76, CHCl 3 ) 17 [α] D ±2 (c 1.25, CHCl 3 ) 5 [α] D 21 (CHCl 3 ) (-)-demethoxypalosine (21c) [α] D (c 0.5, CHCl 3 ) - [α] D (CHCl 3 ) 15 21

23 IV. References: 1. White, J. D.; Yager, K. M.; Yakura, T. J. Am. Chem. Soc. 1994, 116, Fukuda, Y.; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, Pandey, G.; Burugu, S. K.; Singh, P. Org. Lett. 2016, 18, Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature. 2011, 475, Mokry, J.; Kompis, I.; Spiteller, G. Collect. Czech. Chem. Commun. 1967, 32, Klyne, W.; Swan, R. J.; Bycroft, B. W.; Schumann, D.; Schmid, H. Helv. C him. Acta. 1965, 48, Pandey, G.; Kumara, P. C. Org. Lett. 2011, 13, Zsadon, B.; Kaposi, P. Tetrahedron Lett. 1970, 11, Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, Walser, A.; Djerassi, C. Helv. Chim. Acta. 1965, 48, Camerman, A.; Camerman, N.; Kutney, J. P.; Piers, E.; Trotter, J. Tetrahedron Lett. 1965, 6, Mclean, S. Can. J. Chem. 1964, 42, Erra-Balsells, R. Phytochemistry. 1988, 27, Djerassi, C.; Gilberrt, B.; Shoolery, J. N.; Johnson, L. F.; Biemann, K. Experientia. 1960, 16, Gilbert, B.; Duarte, A. P.; Nakagawa, Y.; Joule, J. A.; Floers, S. E.; Brissolses, J. A.; Campello, J.; Carrazzoni, E. P.; Owellen, R. J.; Blossey, E. C.; Brown, K. S.; Djerassi, C. Tetrahedron. 1965, 21, Biemann, K.; Spiteller, M. F.; Spiteller, G. Tetrahedron Lett. 1961, 2, Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,

24 V. X-ray Data Analysis X-ray crystal structure of 14 (CCDC ) Table 1. Crystal data and structure refinement for 14. Identification code 14 Empirical formula C20 H20 Br N O 6 Formula weight Temperature 296 K Wavelength Å Crystal system space group Monoclinic P2(1) Unit cell dimensions a = (4) Å α= 90 o. Volume (7) Å 3 b = (4) Å β = (1) o c = (4) Å γ = 90 o. Z Calculated density g/cm 3 Absorption coefficient mm -1 F(000) Crystal size 0.11 x 0.13 x 0.11 mm These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via 23

25 X-ray crystal structure of 2 (CCDC ) Table 2. Crystal data and structure refinement for 2. Identification code 2 Empirical formula C19 H26 N2 Formula weight Temperature 296 K Wavelength Å Crystal system space group Monoclinic P2(1) Unit cell dimensions a = (16) Å α= 90 o. b = (19) Å Volume (8) Å 3 β = 90 o c = (3) Å γ = 90 o. Z Calculated density g/cm 3 Absorption coefficient mm -1 F(000) Crystal size 0.13 x 0.14 x 0.27 mm These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via 24

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