SUPPORTING INFORMATION A NOVEL SYNTHESIS OF (-)-HUPERZINE A VIA TANDEM INTRAMOLECULAR AZA-PRINS CYCLIZATION-CYCLOBUTANE FRAGMENTATION

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1 SUPPRTING INFRMATIN A NVEL SYNTESIS F (-)-UPERZINE A VIA TANDEM INTRAMLECULAR AZA-PRINS CYCLIZATIN-CYCLBUTANE FRAGMENTATIN James D. White, Yang Li, Jungchul Kim and Miroslav Terinek Department of Chemistry, regon State University, Corvallis, regon james.white@oregonstate.edu 1. X-ray crystallographic data for 14 and Experimental procedures and characterization data for all new compounds 3. Copies of 1 and 13 C NMR spectra for new compounds

2 General techniques. All reactions requiring anhydrous conditions were conducted in flame dried glass apparatus under an atmosphere of argon. TF, Et 2, C 2 Cl 2, DMF, benzene and acetonitrile were dried by passage through an activated alumina column under argon. DMS was distilled from Ca 2 at 15 mm g and stored over activated 4Å molecular sieves. Anhydrous Me was freshly distilled from Ca 2. Preparative chromatographic separations were performed on silica gel (35-75 µm); reactions were followed by TLC analysis using silica plates with fluorescent indicator (254 nm) and visualized with a UV lamp or phosphomolybdic acid. Reactions were performed at various scale depending upon availability of the starting material and reflect the practical limitation that reactions in a lengthy synthetic sequence must be carried out many times, often by different individuals. Melting points were measured on a capillary melting point apparatus. ptical rotations were measured with a polarimeter at ambient temperature using a 1 ml capacity cell with 1 dm path length. Infrared (IR) spectra were recorded using a thin film supported on KBr discs or dispersed in a KBr pellet. 1 and 13 C NMR spectra were recorded in Fourier transform mode at the field strength specified on a 300, 400 or 700 Mz spectrometer. Spectra were obtained on CDCl 3 solutions on 5 mm diameter tubes, and chemical shifts in ppm (part per million) are quoted relative to the residual signals of chloroform (δ 7.26 ppm, or δc 77.0 ppm). Multiplicities in the 1 NMR spectra are described as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants (J) are reported in z. Low (MS) and high (RMS) resolution mass spectra are reported with ion mass/charge (m/z) ratios as values in atomic mass units. 1

3 1. X-ray crystallographic data for 14 and Supplementary crystallographic information on Cyclobutane 14 2

4 Crystal date and structure refinement for Cyclobutane 14 Empirical formula C BrN 3 Si Formula weight Ternperature Wavelength Crystal system Space group 298(2)K Å Monoclinic P21/c(#14) Unit cell dimensions a = (1) Å α = 90 b = (1) Å β = c = (1) Å γ = 90 Volume (3) Å3 Z 4 Density (calculated) 1.368Mg/m 3 Absorption coefficient 3.126mm -1 F(000) 992 Crystal size 0.30 x 0.17 x 0.10mm 3 Theta range for data collection 4.10 to Index ranges -9<=h<=9, -11<=k<=11, -21<=l<=21 Reflections collected 6087 Independent reflections 2885 [R(int)=0.0558] Completeness to theta = % Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 3

5 Data/restraints/parameters 2885 / 0 / 276 Goodness-of-fit on F Final R indices [I>2sigma(l)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient (14) Largest diff. peak and hole and e. Å -3 4

6 Atomic coordinates ( X 10 4 ) and equivalent isotropic displacement parameters (Å 2 x10 3 ) for Cyclobutane 14. 5

7 Bond lengths [Å] and angles [ ] for Cyclobutane 14. 6

8 7

9 8

10 Anisotropic displacement parameters (Å 2 x10 3 ) for Cyclobutane 14.

11 10

12 ydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x10 3 ) for Cyclobutane

13 12

14 1.2. Supplementary crystallographic information on Pyridone 28 13

15 Crystal date and structure refinement for Pyridone 28 Empirical formula C BrN 2 Formula weight Temperature Wavelength Crystal system Space group 288(2)K Å Monoclinic P21/n(#14) Unit cell dimensions a = (4) Å α = 90 b = 8.024(3) Å β = (2) c = (7) Å γ = 90 Volume (9) Å3 Z 4 Density (calculated) 1.221Mg/m 3 Absorption coefficient 0.638mm -1 F(000) 552 Crystal size 0.30 x 0.30 x 0.05mm 3 Theta range for data collection 4.39 to Index ranges -12<=h<=12, -8<=k<=9, -20<=l<=20 Reflections collected 4696 Independent reflections 2437 [R(int)=0.0347] Completeness to theta = % Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 14

16 Data / restraints / parameters 2437 / 0 / 174 Goodness-of-fit on F Final R indices [I>2sigma(l)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e. Å -3 15

17 Atomic coordinates ( X 10 4 ) and equivalent isotropic displacement parameters (Å 2 x10 3 ) for Pyridone

18 Bond lengths [Å] and angles [ ] for Pyridone

19 18

20 Anisotropic displacement parameters (Å 2 x10 3 ) for Pyridone

21 ydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x10 3 ) for Pyridone

22 2. Experimental procedures and characterization data for all new compounds (S,E)-4-(But-2-en-1-yloxy)cyclohex-2-enone (5). To a solution of 4-hydroxy-2- cyclohexan-1-one (0.33 g, 2.94 mmol) in crotyl bromide (2.5 ml) at 0 C was added silver(i) oxide (1.7 g, 7.36 mmol) in several portions. The mixture was stirred for 6 h at room temperature, after which the excess silver(i) oxide was filtered off and excess crotyl bromide was removed under reduced pressure. The residue was chromatographed on silica, using 15% EtAc in hexane as eluent, to give 0.81 g (59%) of 5 as a colorless oil: [α] D (c 1.51, CCl 3 ); IR (neat) 2946, 2851, 1686, 1251, 1094, 968 cm -1 ; 1 NMR (300 Mz, CDCl 3 ) δ 1.74 (dd, J = 1.2, 6.8 z, 3), (m, 1), (m, 2), (m, 1), 3.98 (m, 2), 4.20 (m, 1), (dtq, J = 1.2, 6.7, 15.4 z, 1), (dtq, J = 1.3, 6.8, 15.3 z, 1), 5.98 (m, 1), 6.97 (ddd, J = 2.2, 3.2, 10.8 z, 1), 5.21 (s, 2), 5.27 (d, J = 13.6 z, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 17.7, 29.1, 35.2, 72.0, 127.0, 129.5, 130.2, 150.7, 198.7; MS (CI) m/z 167 (M+), 149, 141, 123, 113; RMS (CI) m/z (calcd for C : ). (2aR,2a 1 R,3R,3aS,6aS)-3-Methylhexahydro-2-cyclobuta[cd]benzofuran-4(2a)- one (6). A Pyrex photolysis apparatus was charged with a solution of 5 (0.91 g, 5.48 mmol) in C 2 Cl 2 (300 ml) and argon was passed through the solution for 2 h. The solution was cooled to 0 C and irradiated with a 450W medium-pressure mercury lamp for 2 h, after which the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, using 15% EtAc in hexane as eluent, to give 0.52 g 21

23 23 (58%) of 6: [α] D +238 (c 2.3, CCl 3 ); IR (neat) 2954, 2925, 2861, 1697, 1175, 1057, 1013 cm -1 ; 1 NMR (300 Mz, CDCl 3 ) δ 1.19 (d, J = 7.1 z, 3), 1.91 (ddd, J = 2.3, 4.6, 14.2, 14.3 z, 1), (m, 2), (m, 2), 2.58 (m, 1), (ddd, J = 8.6, 14.2, 15.8 z, 1), 3.02 (q, J = 8.8 z, 1), 3.57 (dd, J = 4.5, 9.0 z, 1), 3.85 (d, J = 9.1 z, 1), 3.98 (m, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 21.5, 27.4, 32.7, 37.8, 39.2, 45.4, 47.8, 72.5, 74.0, 211.7; MS (CI) m/z 167 (M+), 157, 149, 141, 137, 123, 113, 95; RMS (CI) m/z (calcd for C : ). (2aR,2a 1 R,3R,3aS,6aS)-3-Methyl-2a 1,3,3a,6a-tetrahydro-2-cyclobuta[cd] benzofuran-4(2a)-one (7). To a solution of 6 (0.020 g, 0.12 mmol) in EtAc (4 ml) was added phenylselenyl chloride (0.035 g, 0.18 mmol) and the mixture was stirred for 1 h at room temperature. The mixture was washed with saturated aqueous NaC 3 (1 ml) and saturated aqueous NaCl (1 ml), then was concentrated under reduced pressure. The residue was dissolved in TF (4 ml) and water (2 ml) and the solution was treated with NaI 4 (77 mg, 0.36 mmol). The mixture was stirred for 3 h at room temperature then was poured into a mixture of Et 2 (10 ml) and water (5 ml). The organic phase was separated, the aqueous phase was extracted with EtAc (3 x 10 ml), and the combined organic extract was washed with brine and dried over anhydrous MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 15% EtAc in hexane as eluent, to give g (81%) of 7 as a colorless oil: [α] D (c 1.0, CCI 3 ); IR (neat) 2955, 2924, 2862, 1668, 1044 cm -1 ; 1 NMR (400 Mz, CDCl 3 ) δ 1.27 (d, J = 7.0 z, 3), 2.31 (m, 1), 22

24 2.58 (dd, J = 8.4, 8.5 z, 1), 2.70 (m, 1), 3.17 (ddd, J = 8.2, 8.2, 8.4 z, 1), 3.59 (dd, J = 4.7, 9.8 z, 1), 3.80 (d, J = 9.7 z, 1), 4.38 (dd, J = 5.1, 8.3 z, 1), 6.15 (d, J = 10.0 z, 1) 7.08 (dd, J = 5.2, 10.1 z, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 21.0, 37.4, 39.4, 44.2, 46.0, 70.4, 71.1, 131.6, 144.7, 198.0; MS (CI) m/z 165 (M+), 147, 139, 135, 111, 95; RMS (CI) m/z (calcd for C : ). (((2aR,2a 1 R,3R,3aS,6R,6aR)-6-Azido-3-methyl-2a,2a 1,3,3a,6,6a-hexahydro-2cyclobuta[cd]benzofuran-4-yl)oxy)triisopropylsilane (11). To a solution of 6 (0.20 g, 1.20 mmol) and TIPSCI (0.31 ml, 1.44 mmol) in TF (5 ml) at 0 C was added slowly KMDS (2.9 ml, 0.5M solution in toluene, 1.44 mmol) and the solution was stirred for 30 min at room temperature. The solution was diluted with Et 2 (20 ml), washed with water and brine, and dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 20% EtAc in hexane as eluent, to give crude silyl enol ether 10. This material was dissolved in C 2 Cl 2 (10 ml) and iodosobenzene (0.32 g, 1.44 mmol) was added to the solution. The resulting suspension was cooled to -19 C, trimethylsilyl azide (0.38 ml, 2.89 mmol) was added and the mixture was stirred at -19 C for 45 min, at which point the suspension had become a white solution. The mixture was allowed to warm to room temperature, the solvent was removed in vacuo, and the residue was filtered and washed with a 1:1 mixture of Et 2 (30 ml) and hexane (30 ml). The filtrate was concentrated under vacuum and the residue was chromatographed on silica, using 4% EtAc in hexane as eluent, to give 0.32 g (73%) of 11 as a colorless oil: [α] D (c 1.2, CCI 3 ); IR 23

25 (neat) 2946, 2866, 2099, 1649, 1377, 1228, 1199 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.05 (dd, J = 2.2, 7.1 z, 18), (m, 3), 1,22 (d, J = 7.0 z, 3), 1.90 (m, 1), 2.29 (dd, J = 6.6, 8.3 z, 1), 2.49 (ddd, J = 5.1, 5.2, 8.3 z, 1), 3.08 (ddd, J = 6.7, 8.4, 8.7 z, 1), 3.51 (dd, J = 5.0, 9.2 z, 1), 3.75 (d, J = 9.5 z, 1), 3,79 (dd, J = 3.1, 6.6 z, 1), 4.20 (dd, J = 2.2, 6.7 z, 1), 4.83 (d, J = 6.7 z, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 12.5 (3C), 17.9 (7C), 21.8, 34.5, 38.6, 40.0, 44,4, 58.7, 72.6, 93.9, 157.8; MS (CI) m/z 364 (M+), 321, 266, 165, 157, 131; RMS (CI) m/z (calcd for C N 3 2 Si: ). 2-Bromo-N-((2aR,2a 1 R,3R,3aS,6R,6aR)-3-methyl-4-((triisopropylsilyl)oxy)- 2a,2a 1,3,3a,6,6a-hexahydro-2-cyclobuta[cd]benzofuran-6-yl)acrylamide (13). To a solution of 11 (0.263 g, mmol) in Et 2 (7 ml) at 0 C was added LiAl 4 (0.041 g, 1.09 mmol) and the suspension was stirred for 1 h. The mixture was diluted with Et 2 and the reaction was quenched with 15% aqueous Na (0.078 ml). The mixture was stirred with MgS 4 (2.63 g) for 2 h, then was filtered and the solids were washed with EtAc. Removal of the solvent under vacuum left virtually pure 12 (0.24 g). In a separate flask, a solution of 2-bromoacrylic acid (0.44 g, 2.90 mmol), oxalyl chloride (0.76 ml, 8.69 mmol) and a catalytic amount of DMF in C 2 Cl 2 (5 ml) was stirred at room temperature for 12 h. The solvent was removed under vacuum and the resulting α-bromoacroyl chloride was added to a solution of 12, prepared above, and triethylamine (0.30 ml, 2.17 mmol) in Et 2 (8 ml) at 0 C. The solution was stirred for 1 h at 0 C, then was diluted with Et 2 (30 ml), washed with aqueous 0.1N CI and 24

26 brine, and dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 13% EtAc in hexane as eluent, to give 0.22 g (59%) of 13 as a colorless oil: IR (neat) 3325 (br), 2943, 2864, 1657, 1495, 1223, 1196 cm -1 ; 1 NMR (400 Mz, CDCI 3 ) δ 1.08 (dd, J = 3.4, 7.0 z, 18), (m, 3), 1.20 (d, J = 7.0 z, 3), 1.92 (m, 1), 2.23 (dd, J = 6.9, 9.2 z, 1), 2.47 (ddd, J = 5.3, 5.8, 8.4 z, 1), 2.99 (m, 1), 3.49 (dd, J = 5.2, 9.1 z, 1), 3.78 (d, J = 9.1 z, 1), 3.82 (dd, J = 2.2, 6.9 z, 1), 4.81 (m, 2), 6,00 (d, J = 1.2 z, 1), 6,22 (br d, J = 6.8 z, 1), 7.00 (d, J = 1.1 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 12.5 (3C), 17.9 (6C), 21.9, 33.9, 38.2, 40.0, 44,4, 48.3, 72.7, 75.9, 97.0, 122.7, 127.5, 156.3, 159.8; MS (CI) m/z 470 (M+), 428, 400, 392, 321, 193, 165, 157; RMS (CI) m/z (calcd for C BrN 3 Si: ). (1R,1aR,1a 1 R,3aR,4aR,6R,6bS)-6-Bromo-1-methyl-6a-((triisopropylsilyl)oxy) decahydro-1-4,6-(epiminomethano)dicyclobuta[cd,f]benzofuran-7-one (14). To a solution of 13 (0.011 g, mmol) in C 2 Cl 2 (2 ml) was added Me 3 Al (0.027 ml, 2M in hexane, mmol) and the solution was stirred at 70 C for 24 h. The solution was diluted with EtAc (10 ml), washed with aqueous NaC 3 (0.5 ml) and brine, and dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 50% EtAc in hexane as eluent, to give g (76%) of 14 as a pale yellow solid: IR (neat) 3296 (br), 2944, 2925, 2866, 1689, 1459, 1195, 1127 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ (m, 21), 1.12 (d, J = 7.1 z, 3), 1.79 (dd, J = 6.6, 9.0 z, 1), 2.19 (m, 1), 2.20 (ddd, J = 5.4, 5.6, 8.7 z, 1), 25

27 2.29 (d, J = 9.0 z, 1), 2.85 (m, 1), 3.00 (dd, J = 7.1, 9.0 z, 1), 3.10 (ddd, J = 1.2, 5.5, 7.0 z, 1), 3.69 (dd, J = 5.4, 9.1 z, 1), 3.90 (dd, J = 6.8, 6.9 z, 1), 3.92 (d, J = 9.2 z, 1), 4.09 (m, 1), 6.11 (br, s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 12.5 (3C), 18.5 (Si- i Pr), 18.6 (Si- i Pr), 22.4, 33.9, 36 2, 36.9, 37.9, 38.4, 41.2, 50.9, 69.0, 75.9, 77.9, 81.4, 172.6; MS (CI) m/z 470 (M+), 428, 406, 390, 362, 321, 250, 232; RMS (CI) m/z (calcd for C BrN 3 Si: ). (2aR,2a 1 R,3R,3aS,4aS,8aR,8bR)-6-Bromo-3-methyloctahydro-2-cyclobuta- [3,4]benzofuro[7,6-b]pyridine-4,7(2a,2a 1 )-dione (15). To a solution of 14 (0.195 g, mmol) in MeN 2 (20 ml) was added aqueous F (48%, 1 ml) and the solution was stirred for 2 h. The mixture was diluted with EtAc (50 ml), washed with aqueous NaC 3 (10 ml) and brine, and dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 90% EtAc in hexane and 1% Me in EtAc as eluent, to give g (64 %) of 15α as a colorless oil and g (22%) of 15β as a colorless oil. 15α: IR (neat) 3193 (br), 3062 (br), 2950, 2916, 2862, 1676, 942 cm-1; 1 NMR (300 Mz, CDCI 3 ) δ 1.27 (d, J = 7.1 z, 3), 2.20 (m, I), ,60 (m, 2), 2.71 (dd, J = 6.8, 9.4 z, 1), 2.95 (m, 1), 3.09 (ddd, J = 4.0, 4.1, 15.3 z, 1), 3.38 (m, 1), 3.66 (dd, J = 5.2, 9.3 z, 1), 3.87 (dd, J = 4.0, 6.7 z, 1), 3.95 (d, J = 9.4 z, 1), 4.38 (dd, J = 4.1, 5.1 z, 1), 4.48 (dd, J = 4.0, 6.9 z, 1), 6.43 (br s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 21.7, 31.2, 36.9, 38.6, 39.6, 41.1, 44.2, 45.4, 54.2, 73.8, 76.1, 169.3, 210.6; MS (CI) m/z 314 (M+), 276, 264, 236, 166; RMS (CI) m/z (calcd for C BrN 3 : ). 15β: IR (neat) 3210 (br), 26

28 3085 (br), 2953, 2923, 2863, 1681, 1270, 1179, 1109 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.21 (d, J = 7.1 z, 3), (m, 2), 2.55 (dd, J = 8.8, 8.9 z, 1), 2.68 (m, 1), 3.18 (m, 3), 3.62 (dd, J = 4.2, 10.6 z, 1), 3.90 (d, J = 10.6 z, 1), 3.91 (m, 1), 4.47 (dd, J = 3.3, 3.4 z, 1), 4.53 (dd, J = 7.0, 10.7 z, 1), 6.53 (br, s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 21.0, 32.6, 37.1, 37.7, 40.8, 41.1, 44.6, 46.7, , 75.8, 168.9, 208.5; MS (CI) m/z 314 (M+), 276, 264, 250, 236, 166; RMS (CI) m/z (calcd C BrN 3 : ). (2aR,2a 1 R,3R,3aS,4aS,5aS,7aR,7bR)-3-Methyloctahydrocyclobuta[3,4]- benzofuro[7,6-b]cyclopropa[c]pyrrole-4,6(2a 1,7b)-dione (16). To a solution of 15 (0.003 g, mmol) in toluene (4 ml) was added DBU ( ml, mmol) and the solution was refluxed for 4 h. The cooled solution was diluted with Et 2 (10 ml), washed with brine, and dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 80% EtAc in hexane and 1% Me in EtAc as eluent, to give g (43%) of 16 as a colorless oil: IR (neat) 2920, 2847, 1699, 1459, 1406, 1064 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.13 (dd, J = 5.2, 5.2 z, 1), 1,25 (d, J = 7.0 z, 3), 1.91 (dd, J = 4.3, 9.3 z, 1), 2.19 (dd, J = 5.1, 9.4 z, 1), 2.30 (m, 1), 2.51 (dd, J = 6.9, 9.2 z, 1), 3.59 (ddd, J = 5.1, 5.3, 7.1 z, 1), 3.48 (m, 1), 3.57 (dd, J = 5.0, 9.2 z, 1), 3.78 (d, J = 5.2 z, 1), 3.90 (d, J = 9.3 z, 1), 4.29, (s, 1), 5.65 (br, s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 17.2, 21.8, 30.0, 35.5, 36.7, 38.4, 44.9, 45.4, 58.9, 73.3, 77.6, 174.5, 206.1; MS (CI) m/z 234 (M+), 180, 164; RMS (CI) m/z (calcd for C N 3 : ). 27

29 N-((2aR,2a 1 R,3R,3aS,6R,6aR)-3-Methyl-4-((triisopropylsilyl)oxy)-2a,2a 1,3,3a,6,6ahexahydro-2-cyclobuta[cd]benzofuran-6-yl)-2-(phenylselanyl)acrylamide (18). To a solution of 11 (0.029 g, mmol) in Et 2 (1 ml) at 0 C was added LiAl 4 (0.005 g, mmol) and the suspension was stirred for 1 h. The mixture was diluted with Et 2 and the reaction was quenched with 15% aqueous Na (0.017 ml). The mixture was stirred with MgS 4 (0.5 g) for 2 h then was filtered and the collected solid was washed with EtAc. The solvent was removed under vacuum to leave crude 12 which was not purified further. In a separate flask, a solution of the 3,5-dinitrobenzoyl chloride (0.037 g, mmol) and Et 3 N (0.045 ml, mmol) in C 2 Cl 2 (1 ml) was prepared and a solution of α-phenylselenoacrylic acid (0.037 g, mmol) in C 2 Cl 2 (1 ml) was added. The solution was stirred for 1 h at room temperature, a solution of crude 12 and DMAP (0.001 g, mmol) in C 2 Cl 2 (0.5 ml) was added, and the mixture was stirred for 1 h. The solvent was removed under vacuum and the residue was chromatographed on silica, using 15% EtAc in hexane as eluent, to give 0.03 g (69%) of 18 as a colorless oil: [α] D (c 1.51, CCl 3 ); IR (neat) 3395 (br), 2944, 2864, 1655, 1649, 1491, 1477, 1223, 1196; 1 NMR (300 Mz, CDCI 3 ) δ ,15 (m, 21), 1.17 (d, J = 7.0 z, 3), 1.85 (m, 1), 2,02 (dd, J = 6.9, 8.1 z, 1), (m, 2), 3.40 (dd, J = 4.2, 9.1 z, 1), 3.58 (dd, J = 2.2, 6.8 z, 1), 3.70 (d, J = 9.2 z, 1), 4.67 (d, J = 7.0 z, 1), 4.73 (ddd, J = 3.3, 7.1, 7.2 z, 1), 6.10 (s, 1), 6.40 (br, d, J = 7.1 z, 1), 6,91 (s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 12.6 (3C), 18.0 (6C), 22,0, 33.6, 38.2, 39.9, 44.3, 48.0, 72.6, 75.9, 97.3, 127.5, 129.5, 131.1, 131.3, 133.1, 28

30 133.2, 156.0, 162.8; MS (CI) m/z 547 (M+), 478, 432, 392, 350, 321, 236, 159; RMS (CI) m/z (calcd for C N 3 SiSe: ). (1R,1aR,1a 1 R,3aR,4aR,6R,6bS)-1-Methyl-6-(phenylselanyl)-6a- ((triisopropylsilyl)oxy)decahydro-1-4,6- (epiminomethano)dicyclobuta[cd,f]benzofuran-7-one (19). To a solution of 18 (0.150 g, mmol) in C 2 Cl 2 (10 ml) was added Me 3 Al (0.42 ml, 2M in hexane, mmol) and the solution was stirred at 80 C for 38 h. The solution was diluted with C 2 Cl 2 (30 ml), saturated aqueous potassium tartrate (30 ml) was added, and the mixture was stirred vigorously for 15 min. The separated aqueous phase was extracted with C 2 Cl 2 (3 x 20 ml) and the combined organic solution was dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 90% EtAc in hexane as eluent, to give g (69 %) of 19 as a white solid: [α] D (c 1.8, CCl 3 ); IR (neat) 3237 (br), 3067 (br), 2955, 2862, 1677, 1470, 1201, 1147, 1123 cm -1 ; 1 NMR (300 Mz, CDC 13 ) δ 1.05 (d, J = 7.0 z, 3), (m, 21), 1.79 (dd, J = 7.0, 9.3 z, 1), (m, 3), 2.84 (m, 1), 3.02 (m, 1), 3.69 (dd, J = 5.2, 9.2 z, 1), 3.84 (dd, J = 5.2, 5.3 z, 1), 3.94 (d, J = 9.1 z, 1), 4.02 (dd, J = 4.7, 4.8 z, 1), 5.80 (br, s, 1), 7.18 (m, 3), 7.60 (m, 2); 13 C NMR (75 Mz, CDCI 3 ) δ 14.6 (3C), 18.7 (Si- i Pr), 18.8 (Si- i Pr), 22.5, 34.1, 35.2, 36.7, 38,1, 39.6, 41.2, 51.4, 64.9, 76.0, 78.1, 82.5, 127.3, 127.9, 128.4, 135.4, 175.4; MS (CI) m/z 547 (M+), 478, 432, 390, 322, 276, 251; RMS (CI) m/z (calcd for C N 3 SiSe: ). 29

31 (2aR,2a 1 R,3R,3aS,4aS,8aR,8bR)-3-Methyl-6-(phenylselanyl)octahydro-2cyclobuta[3,4]benzofuro[7,6-b]pyridine-4,7(2a,2a 1 )-dione (20). To a solution of 19 (0.014 g, mmol) in MeN 2 (1.9 ml) was added aqueous F (48%, 0.1 ml) and the solution was stirred at room temperature for 2 h. The mixture was diluted with EtAc (20 ml), washed with aqueous NaC 3 (5 ml) and brine, and dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 90% EtAc in hexanes as eluent, to give g (40%) of 20a as a colorless oil and g (50%) of 20b as a colorless oil. 20a: IR (neat) 3184 (br), 3070 (br), 2951, 2934, 2859, 1693, 1660, 1475, 1395 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.18 (d, J = 7.1 z, 3), 1.80 (ddd, J = 5.1, 11.7, 14.2 z, 1), 2.19 (m, 1), 2.50 (dd, J = 8.2, 8.4 z, 1), 2.62 (ddd, J = 4.0, 6.9, 7.0 z, 1), 2.83 (ddd, J = 3.5, 8.2, 14.1 z, 1), 3.01 (dd, J = 4.1, 7.1 z, 1), 3.10 (ddd, J = 7.2, 7.3, 8.2 z, 1), 3.58 (dd, J = 4.0, 10.8 z, 1), 3.82 (dd, J = 3.4, 7.1 z, 1), 3.84 (d, J = 10.8 z, 1), 4.01 (dd, J = 8.2, 11.0 z, 1), 4,08 (dd, J = 3.3, 3.4 z, 1), 7.02 (s, 1), 7.32 (m, 3), 7.63 (m, 2); 13 C NMR (75 Mz, CDCI 3 ) δ 21.0, 28.8, 37.1, 37.7, 37.8, 40.3, 44.6, 46.9, 56.6, 72.8, 76.0, 127.6, 128.4, 129.1, 135.4, 172.1, 209.0; MS (CI) m/z 390 (M+), 310, 264, 236, 217, 159; RMS (CI) m/z (calcd for C N 3 Se: ). 20b: 1 NMR (300 Mz, CDCI 3 ) δ 1.24 (d, J = 7.1 z, 3), (m, 2), 2.57 (m, 1), 2.68 (dd, J = 8.2, 8.2 z, 1), 2.79 (ddd, J = 5.1, 5.1, 15.6 z, 1), 2.94 (ddd, J = 5.0, 5.1, 5.1 z, 1), 3.30 (ddd, J = 7.1, 7.1, 7.2 z, 1), 3.60 (dd, J = 5.2, 9.8 z, 1), 3.84 (dd, J = 4.1, 6.9 z, 1), 3.89 (d, J = 9.8 z, 1), 30

32 3.99 (dd, J = 5.1, 7.1 z, 1), 4.30 (dd, J = 4.1, 4.2 z, 1), 6.78 (br, s, 1), 7.29 (m, 3), 7,70 (m, 2); 13 C NMR (75 Mz, CDCI 3 ) δ 21.5, 28.2, 37.2, 39.0, 39.6, 40.1, 44.5, 45.6, 55.0, 73.5, 76.4, 128.1, 129.0, 129.9, 134.9, 172.9, (2aR,2a 1 R,3R,3aS,8bR)-3-Methyl-3,3a,8,8b-tetrahydro-2-cyclobuta[3,4] benzofuro[7,6-b]pyridine-4,7(2a,2a 1 )-dione (21) from 19. To a solution of 19 (0.021 g, mmol) in MeN 2 (10 ml) was added aqueous F (48%, 0.06 ml, 0.15 mmol) dropwise and the mixture was stirred for 1.5 h at room temperature. The solvent was removed under reduced pressure and the residue was taken up into Me (5 ml) and 2 (13 ml). To this solution was added a solution of Nal 4 (0.024 g, 0.11 mmol) in 2 (0.2 ml) and the mixture was stirred for 15 h at room temperature. The solvent was removed under reduced pressure, the residue was taken up into CCI 3 (20 ml), and the solution was washed with saturated NaC 3 (2 ml) and brine (5 ml). The combined aqueous washings were extracted with CCI 3 (4 x 20 ml) and the combined organic extract was dried over MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 2% Me in EtAc as eluent, to give g (83%) of 21 as a colorless solid: mp C; [α] D (c 1.51, CCl 3 ); IR (neat) 2958, 1655, 1638, 1408, 1285, 1248; 1 NMR (300 Mz, CDCI 3 ) δ 1.30 (d, J = 7.0 z, 3), 1.35 (m, 1), 2.75 (dd, J = 8.8, 8.9 z, 1), 2.80 (m, 1), 3.37 (ddd, J = 8.8, 8.8, 8.9 z, 1), 3.57 (dd, J = 4.2, 9.0 z, 1), 3.89 (d, J = 9.0 z, 1), 4.77 (d, J = 8.9 z, 1), 6.60 (d, J = 10.7 z, 1), 8.05 (d, J = 10.8 z, 1), (br, s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 21.2, 37.5, 39.3, 43.3, 46.0, 72.1, 72.2, 114.2, 31

33 120.9, 138.6, 151.2, 165.2, 193.1; MS (CI) m/z 232 (M+), 223, 203, 189, 174, 149, 131, 121; RMS (CI) m/z (calcd for C N 3 : ). (2aR,2a 1 R,3R,3aS,8bR)-7-Methoxy-3-methyl-2a 1,3,3a,8b-tetrahydro-2cyclobuta[3,4]benzofuro[7,6-b]pyridin-4(2a)-one (22). To a solution of 21 (0.029 g, mmol) in CCI 3 (2 ml) was added Ag 2 C 3 (0.173 g, mmol) and MeI (0.47 ml, 7.53 mmol). The mixture was stirred for 40 h at room temperature, then was filtered through a pad of Celite which was washed with Et 2 (10 ml). The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica, using 30% EtAc in hexanes as eluent, to give g (91%) of 22 as a colorless solid: mp C; [α] D (c 2.0, CCl 3 ); IR (neat) 2949, 2920, 2857, 1671, 1594, 1484, 1324, 1269 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.35 (d, J = 7.0 z, 3), 2.34 (m, 1), 2.73 (dd, J = 8.7, 8.8 z, 1), 2.78 (ddd, J = 4.1, 6.8, 7.1 z, 1), 3,32 (dd, J = 8.8, 8.8, 8.9 z, 1), 3.68 (dd, J = 4.2, 9.2 z, 1), 3.85 (d, J = 9.2 z, 1), 4.05 (s, 3), 4.79 (d, J = 7.1 z, 1), 6,80 (d, J = 9.1 z, 1), 8.20 (d, J = 9.1 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 21.5, 37.2, 39.0, 43.9, 46.1, 54.2, 71.9, 77.1, 112.4, 122.8, 137.9, 159.0, 166.6, 196.7; MS (CI) m/z 246 (M+), 216, 192, 175; RMS (CI) m/z (calcd for C N 3 : ). (5aS,6R,7R,7aR)-7-(ydroxymethyl)-2-methoxy-6-methyl-6,7,7a,8- tetrahydrocyclobuta[g]quinolin-5(5a)-one (23). To a solution of 22 (0.020 g, mmol) in 0.2M Na in Me (20 ml) was added activated Zn (0.54 g, 8.2 mmol) and 32

34 the suspension was stirred for 2 h at 90 C. An additional quantity (0.54 g) of activated Zn was then added to the mixture which was stirred for a further 4 h at 90 C. The cooled mixture was neutralized with 1N CI in Me (4 ml) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica, using 40% EtAc in hexanes as eluent, to give g (94%) of 23 as a colorless solid: mp C; IR (neat) 3394 (br), 2916, 2853, 1668, 1625, 1589, 1328 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.11 (d, J = 6.9 z, 3), 2.35 (m, 2), 2.75 (dd, J = 8.2, 8.2 z, 1), 3.10 (m, 3), 3.67 (dd, J = 6.9, 11.1 z, 1), 3.73 (dd, J = 8.1, 11.2 z, 1), 4.00 (s, 3), 6.74 (d, J = 9.3 z, 1), 8.07 (d, J = 9.3 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 20.8, 29.1, 37.9 (2C), 45.4, 46.7, 53.9, 62.0, 109.8, 123.0, 137.6, 162.8, 166.3, 198.0; MS (CI) m/z 248 (M+), 230, 204, 190; RMS (CI) m/z (calcd for C N 3 : ). (5aS,6R,7R,7aR)-2-Methoxy-6-methyl-5-oxo-5,5a,6,7,7a,8- hexahydrocyclobuta[g]quinoline-7-carbaldehyde (24). To a solution of 23 (0.013 g, mmol) in C 2 CI 2 (3 ml) was added Dess-Martin periodinane (0.038 g, 0.11 mmol). The solution was stirred for 1 h at room temperature, then was diluted with Et 2 (5 ml) and 10% aqueous Na 2 S 2 3 (2 ml) was added. The mixture was stirred for 20 min and the aqueous phase was separated and extracted with Et 2 (10 ml). To the combined organic extract was added saturated aqueous NaC 3 (5 ml) and the mixture was stirred for 20 min. The separated organic layer was washed with water (3 ml) and brine (3 ml), and was dried over anhydrous MgS 4. The solvent was removed 33

35 under vacuum and the residue was chromatographed on silica, using 30% EtAc in hexanes as eluent, to give g (93%) of 24 as a colorless oil: IR (neat) 2955, 2925, 1710, 1666, 1590, 1572, 1409, 1321, 1262 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.39 (d, J = 6.9 z, 3), 2.80 (dd, J = 8.1, 8.1 z, 1), 3.02 (m, 4), 3.45 (m, 1), 3.98 (s, 3), 6.67 (d, J = 9.9 z, 1), 8,09 (d, J = 9.9 z, 1), 9.80 (s, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 20.6, 29.7, 31.2, 34.5, 46.0, 54.0 (2C), 110.3, 123.0, 137.5, 161.4, 166.5, 196.8, 201.7; MS (CI) m/z 246 (M+), 217, 202, 160; RMS (CI) m/z (calcd for C N 3 : ) (5aS,6R,7R,7aR)-7-(1-ydroxyethyl)-2-methoxy-6-methyl-6,7,7a,8- tetrahydrocyclobuta[g]quinolin-5(5a)-one (25). To a solution of 24 (0.025 g, 0.10 mmol) in C 2 CI 2 (4 ml) at -78 C was added dropwise MeMgl (1.5M in Et 2, 0.1 ml, 0.15 mmol) and the solution was stirred for 1 h at -78 C. The reaction was quenched with water and the mixture was allowed to warm to room temperature. Et 2 (20 ml) was added and the separated ethereal layer was washed with saturated aqueous NaC 3 (5 ml) and brine (3 ml), and was dried over anhydrous MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 30% EtAc in hexanes as eluent, to give g (40%) of 25a and g (36%) of 25b as colorless oils. 25a: IR (neat) 3408, 2959, 2891, 1650, 1586, 1322, 1269, 1020 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.16 (d, J = 6.9 z, 3), 1.10 (d, J = 7.0 z, 3), 1,60 (s, 1), 2.05 (dd, J = 9.1, 18.0 z, 1), 2.25 (m, 1), 2,70 (dd, J = 9.2, 9.3 z, 1), 3.10 (m, 2), 3.25 (dd, J = 11.9, 20.2 z, 2), 3.87 (m, 1), 3.99 (s, 3), 6.68 (d, 34

36 J = 9.1 z, 1), 8.07 (d, J = 9.1 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 20.9, 21.8, 29.5 (2C), 37.6, 46.2, 51.1, 53.9, 67.6, 109.7, 123.0, 130.9, 137.5, 163.0, 166.3, 198.0; MS (CI) m/z 262 (M+), 244, 228, 175, 146; RMS(CI) m/z (calcd for C N 3 : ). 25b: IR (neat) 3457 (br), 2954, 2920,1669, 1591, 1484, 1415, 1318, 1269 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.22 (d, J = 6.9 z, 3), 1.39 (d, J = 7.0 z, 3), 1.59 (s, 3), 2.03 (m, 1), 2.65 (m, 2), 2.95 (m, 2), 3,13 (dd, J = 11.8, 20.1 z, 2), 4.00 (m, 1), 4,01 (s, 3), 6.64 (d, J = 8.8 z, 1), 8.06 (d, J = 8.8 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 21.6, 22.8, 29.6, 30.1, 38.9, 46.4, 51.0, 53.9, 68.6, 109.8, 124.3, 137.5, 164.7, 166.7, 197.7; MS (CI) m/z 262 (M+), 244, 228, 204, 175, 146; RMS (CI) m/z (calcd for C N 3 : ). (5aS,6R,7R,7aR)-7-Acetyl-2-methoxy-6-methyl-6,7,7a,8-tetrahydrocyclobuta [g]quinolin-5(5a)-one (26). To a solution of 25 (0.024 g, mmol) in C 2 CI 2 (3 ml) was added Dess-Martin periodinane (0.067 g, mmol). The solution was stirred for 2 h at room temperature, after which it was diluted with Et 2 (30 ml) and 10% aqueous Na 2 S 2 3 (5 ml) was added. The mixture was stirred for 10 min and the aqueous phase was separated and extracted with Et 2 (10 ml). To the combined organic solution was added saturated aqueous NaC 3 (5 ml) and the mixture was stirred for 10 min. The separated organic layer was washed with water (5 ml) and brine (5 ml), and was filtered through anhydrous MgS 4. The filtrate was concentrated under vacuum and the residue was chromatographed on silica, using 30% EtAc in hexanes as eluent, to give g (92%) of 26 as a colorless oil: IR (neat) 2944, 2925, 35

37 1704, 1674, 1630, 1591, 1567, 1415, 1327, 1264 cm -1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.31 (d, J = 6.9 z, 3), 2.15 (s, 3), 2.70 (dd, J = 8.5, 8.6 z, 1), 2.90 (dd, J = 10.8, 17.3 z, 1), 3.01 (m, 3), 3.31 (m, 1), 3.97 (s, 3), 6.65 (d, J = 9.0 z, 1), 8.07 (d, J = 8.9 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 20.3, 29.1, 30.1, 32.0, 35.0, 45.1, 53.9, 54.8, 110.1, 122.8, 137.4, 161.8, 166.3, 196.7, 207.1; MS (CI) m/z 260 (M+), 216, 204, 175, 146; RMS (CI) m/z (calcd for C N 3 : ). 1-((5aS,6R,7R,7aR)-2-Methoxy-6-methyl-5-oxo-5,5a,6,7,7a,8- hexahydrocyclobuta[g]quinolin-7-yl)vinyl trifluoromethanesulfonate (27). To a solution of 26 (0.003 g, mmol) in TF (4 ml) at -78 C was added dropwise KMDS (0.058 ml, 0.5M in toluene, mmol) and the solution was stirred for 30 min at -78 C. The solution was warmed to 0 C, a solution of N-(5-chloro-2- pyridyl)triflimide (0.006 g, mmol) in TF (0.5 ml) was added, and the mixture was stirred for 12 h at room temperature. The mixture was diluted with Et 2 (20 ml), water (5 ml) was added, and the phases were separated. The aqueous portion was extracted with Et 2 (2 x 10 ml) and the combined organic extract was washed with brine and was filtered through anhydrous MgS 4. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica, using 25% EtAc in hexanes as eluent, to give g (74%) of 27 as a colorless oil: IR (neat) 2962, 2924, 1669, 1592, 1556, 1418, 1266, 1212, 1142, 913 cm -11 NMR (300 Mz, CDCI 3 ) δ 1.40 (d, J = 6.9 z, 3), 2.69 (m, 1), 2.78 (dd, J = 8.8, 10.3 z, 1), 3.10 (m, 4), 4,00 (s, 3), 4.99 (dd, J = 1.2, 4.8 z, 1), 5.35 (d, J = 4.8 z, 1), 6 68 (d, J 36

38 = 9.9 z, 1), 8.10 (d, J = 9.9 z, 1); 13 C NMR (75 Mz, CDCI 3 ) δ 19.8, 29.6, 32.2, 38.6, 45.8, 46 8, 54.5, 106.0, 110.7, 123.0, 137.9, 155.2, 162.6, 166.9, 196.6; MS (CI) m/z 392 (M+), 258, 242, 214, 190, 175, 146, ; RMS (Cl) m/z (calcd for C F 3 N 5 S: ). (5aS,6R,7R,7aR)-2-Methoxy-6-methyl-7-(prop-1-en-2-yl)-6,7,7a,8- tetrahydrocyclobuta[g]quinolin-5(5a)-one (28). A. From 26. To a suspension of dried methyltriphenylphosphonium bromide (0.521 g, 1.46 mmol) in TF (10 ml) under argon at 0 C was added dropwise n-buli (0.567 ml, 1.55M in hexane, mmol). The solution was stirred for 1 h then was left to stand for 2 h at 0 C. To a solution of 26 (0.025 g, mmol) in TF (7 ml) at -78 C was added dropwise the supernatant solution of Wittig reagent prepared above (1.77 ml, mmol) and the solution was stirred for 1 h at -78 C. The reaction was quenched with water and the mixture was allowed to warm to room temperature. Et 2 (20 ml) was added and the separated ethereal layer was washed with saturated aqueous NaC 3 (5 ml) and brine (3 ml), and was dried over anhydrous MgS 4. The solvent was removed under vacuum and the residue was chromatographed on silica, using 5% EtAc in hexanes and then 15% EtAc in hexanes as eluent, to give g (27%, 54% based on recovered 26) of 28 as a colorless oil: IR (neat) 2948, 2869, 1669, 1591, 1570, 1481, 1410, 1321, 1261 cm - 1 ; 1 NMR (300 Mz, CDCI 3 ) δ 1.31 (d, J = 6.9 z, 3), 1.71 (s, 3), 2.74 (m, 3), 2 88 (dd, J = 8.9, 17.2 z, 1), 3.02 (m, 2), 4.00 (s, 3), 4.70 (s, 1), 4.96 (d, J = 1.2 z, 1), 6.64 (dd, J = 8.1, 9.0 z, 1), 8.10 (d, J = 9.2 z, 1); 13 C NMR (75 Mz, CDCI 3 ) 37

39 δ 20.1, 22.2, 29.3, 32 5, 37.7, 46.1, 50.6, 54.3, 110.2, 111.3, 123.0, 137.9, 143 2, 163.8, 166.6, 197.8; MS (CI) m/z 257 (M+), 242, 228, 190, 175, 163, 149, 135; RMS (CI) m/z (calcd for C N 2 : ). B. From 27. To a solution of 27 (0.020 g, mmol) in dioxane (2 ml) were added hexamethyldistannane (0.018 g, mmol), LiCl (0.007 g, 0.17 mmol), tetrakis(triphenylphosphine)palladium (0.003 g, mmol) and a crystal of BT. The mixture was heated at 90 C for 4 h, then was cooled to room temperature and treated with pyridine (0.2 ml) followed by a solution of pyridinium fluoride (1.5M in TF, 0.4 ml). The mixture was stirred for 20 h at room temperature and filtered through Celite. The filtrate was washed with Cl (10%) and brine, dried over anhydrous MgS 4, and was concentrated under reduced pressure. The residue was purified by chromatography on silica as described above to give g (76%) of 28. Methyl ((5S,E)-11-Ethylidene-2-methoxy-7-methyl-5,6,9,10-tetrahydro- 5,9methanocycloocta[b]pyridin-5-yl)carbamate (30). A. From 28. To a solution of 28 (12.0 mg, mmol) in benzene (1.5 ml) was added methyl carbamate (4.0 mg, mmol) and anhydrous p-toluenesulfonic acid (2.0 mg, mmol). The solution was heated at 60 C for 2.5 h then was cooled to room temperature, washed with Cl (10%), and dried over anhydrous MgS 4. The solution was filtered through a pad of Celite which was washed with Et 2 (3 ml), and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica, using 30% EtAc in hexane as eluent, to give 4.4 mg (37%) of 30 as a colorless oil: IR (neat) 3325, 38

40 1714, 1597, 1529, 1475, 1422, 1322, 1304, 1257, 1034 cm-1; 1 NMR (300 Mz, CDCl 3 ) δ 1.53 (s, 3), 1.73 (d, J = 1.5 z, 3), 2.25 (d, J = 6.8 z, 1), 2.60 (d, J = 6.4 z, 1), 2.83 (d, J = 6.8 z, 1), 3.07 (d, J = 6.4 z, 1), 3.64 (s, 1), 3.90 (s, 3), 5.00 (s, 1), 5.38 (q, J = 2.2 z, 1), 5.47 (d, J = 1.8 z, 1), 6.57 (J = 6.6 z, 1), 7.58 (d, J = 6.6 z, 1); 13 C NMR δ 12.5, 22.6, 33.9, 39.4, 49.1, 51.9, 53.3, 58.7, 108.5, 111.8, 125.6, 130.1, 131.8, 135.4, 136.8, 153.2, 154.8, 162.5; RMS (CI) m/z (calcd for C N 2 3 : ). B. From (-)-uperzine A (1). To a solution of 1 (10 mg, 0.04 mmol) in Me (1 ml) at 0 C was added K 2 C 3 (5.5 mg, 0.06 mmol) and methyl chloroformate (3.3 μl, 4.0 mg, 0.04 mmol). The suspension was stirred for 2 h at room temperature, during which reaction progress was monitored by TLC (10% Me in C 2 Cl 2 ) until consumption of 1 was complete. The mixture was poured into water and extracted with C 2 Cl 2 (3 X 10 ml). The combined extract was washed with brine and dried over MgS 4, and the solvent was removed under reduced pressure to provide crude huperzine A methyl carbamate. To a solution of the crude carbamate obtained above in CCl 3 (1 ml) were added Ag 2 C 3 (11 mg, 0.04 mmol) and MeI (5 μl, 12 mg, 0.08 mmol). The mixture was stirred at reflux until TLC (40% EtAc in hexane, 5% Me in C 2 Cl 2 ) indicated complete consumption of the starting material. The mixture was cooled to room temperature and was filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica, using 5-10% EtAc in hexanes as eluent, to give 4.4 mg of 30 (35%), identical with material prepared by 39

41 method A. (-)-uperzine A (1). To a solution of 30 (3.0 mg, 10 μmol) in CCl 3 (0.3 ml) was added slowly TMSI (14 μl, 0.1 mmol) and the mixture was refluxed for 6 h. The solvent was removed under reduced pressure and the residue was taken up into C 2 Cl 2 (3 ml). The solution was poured into a mixture of saturated aqueous NaC 3 and saturated aqueous Na 2 S 2 3 which was extracted with C 2 Cl 2 (3 X 5 ml). The combined extract was washed with brine, dried over MgS 4, and concentrated under reduced pressure. The residue was purified by chromatography on silica, using 10% Me in EtAc as eluent, to give 1 (2.0 mg, 80%) as a colorless solid: 1 NMR (CDCl 3 ) δ 1.28 (br s, 2), 1,55 (s, 3), 1.68 (d, J = 6.7 z, 3), 2.11 (d, J = 17.0 z, 1), 2.16 (d, J = 17.0 z, 1), 2.74 (dd, J = 1.5, 16.8 z, 1), 2.90 (dd, J = 5.0, 16.8 z, 1), (m, 1), 5.41 (d, J = 4.8 z, 1), 5.49 (q, J = 6.7 z, 1), 6.42 (d, J = 9.4 z, 1), 7.91 (d, J = 9.4 z, 1). 40

42 3. Copies of 1 and 13 C NMR spectra for new compounds 5 41

43 5 42

44 6 43

45 6 44

46 7 45

47 7 46

48 N 3 TIPS 11 47

49 N 3 TIPS 11 48

50 N 2 TIPS 12 49

51 N 2 TIPS 12 50

52 N TIPS Br 13 51

53 N TIPS Br 13 52

54 TIPS N Br 14 53

55 TIPS N Br 14 54

56 N Br 15 55

57 N Br 15 56

58 N 16 57

59 N 16 58

60 N TIPS SePh 18 59

61 N TIPS SePh 18 60

62 TIPS 19 N SePh 61

63 TIPS 19 N SePh 62

64 N SePh 20 63

65 N SePh 20 64

66 N 21 65

67 N 21 66

68 22 N Me 67

69 22 N Me 68

70 N Me 23 69

71 N Me 23 70

72 N Me 24 71

73 N Me 24 72

74 25 N Me 73

75 25 N Me 74

76 26 N Me 75

77 26 N Me 76

78 Tf N Me 27 77

79 Tf N Me 27 78

80 28 N Me 79

81 28 N Me 80

82 N Me N C 2 Me 30 81

83 N Me N C 2 Me 30 82

84 N 2 1 N 83