First Enantioselective Synthesis of the Diazatricyclic Core of Madangamine Alkaloids

Transcription

1 First Enantioselective Synthesis of the Diazatricyclic Core of Madangamine Alkaloids Mercedes Amat,* Maria Pérez, Stefano Proto, Teresa Gatti, and Joan Bosch* Laboratory of rganic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona S1

2 Table of Contents General procedures Experimental procedures and spectroscopic data for all new compounds Copies of 1 MR and 13 C MR spectra for selected new compounds S3 S4-S26 S27-S70 S2

3 GEERAL PRCEDURES. All air sensitive manipulations were carried out under a dry argon or nitrogen atmosphere. TF and toluene were carefully dried and distilled from sodium/benzophenone prior to use. C 2 Cl 2 was dried and distilled from Ca 2. Acetone was dried over Drierite and distilled. ther solvents and all standard reagents were purchased from Aldrich, Fluka or Alfa Aesar and were used without further purification. Drying of organic extracts during the work-up of reactions was performed over anhydrous a 2 S 4 or MgS 4. Evaporation of solvents was accomplished with a rotatory evaporator. Thin-layer chromatography was performed on Merck TLC plates (silica gel 60 F 254 ). The spots were visualized by exposure to UV light and revealed with an aqueous solution of 1% KMn 4, iodine or hexachloroplatinate. Chromatography refers to flash column chromatography and was carried out on Si 2 (silica gel 60, mesh). Melting points were determined in a capillary tube and are uncorrected. MR spectra were recorded at 300 or 400 Mz ( 1 ) and 75.4 or Mz ( 13 C), and chemical shifts are reported in δ values downfield from TMS or relative to residual chloroform (7.26 ppm, 77.0 ppm) as an internal standard. Data are reported in the following manner: chemical shift, multiplicity, coupling constant (J) in hertz (z), integrated intensity, and assignment (when possible). Multiplicities are reported using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; ap, apparent. IR spectra were performed in a spectrophotometer icolet Avantar 320 FT-IR and only noteworthy IR absorptions (cm -1 ) are listed. Mass spectra (MS) data are reported as m/z (%). igh resolution mass spectra (RMS) were recorded at Serveis Cientifico-Tècnics, University of Barcelona, (spectrometer of mass LC/MSD TF of Agilent Technologies) using electronic impact or chemical ionization with methane. In this last method the mass of the fragment has been obtained [M+] +. Elemental analysis were obtained with a Microanalyzer (EA 1108 CS- Carlo Erba Instruments) from the service of microanalysis located in Centre d Investigació i Desenvolupament (CID), Barcelona. The values of optical rotation were measured on a polarimeter Perkin-Elmer, model 241, using a 1 dm cell with a total volume of 1 milliliter. S3

4 C 6 5 Se t-bu 2 C C 6 5 (3R,8S,8aR)-8-Allyl-6-(tert-butoxycarbonyl)-5-oxo-3-phenyl-6-(phenylselenyl)-2,3,6,7,8,8ahexahydro-5-oxazolo[3,2-a]pyridine. Lithium bis(trimethylsilyl)amide (3.85 ml of a 1 M solution in TF, 3.85 mmol) was slowly added at 78 C to a solution of lactam 1 (450 mg, 1.75 mmol) in anhydrous TF (30 ml), and the resulting mixture was stirred for 90 min. Then, di-tert-butyl dicarbonate (420 mg, 1.92 mmol) in TF (2 ml) and, after 90 min of continuous stirring at 78 C, phenylselenyl chloride (503 mg, 2.62 mmol) in TF (4 ml) were added to the solution. The resulting mixture was stirred for a further 1 h and poured into saturated aqueous 4 Cl. The aqueous layer was extracted with EtAc, and the combined organic extracts were dried over anhydrous MgS 4 and concentrated under reduced pressure. Flash chromatography (1:9 to 2:8 EtAc hexane) of the resulting oil afforded the C-6 epimers a (520 mg) and b (320 mg) of the seleno derivative as brown oils (93% overall yield). Epimer a (major, higher R f ): 1 MR (400 Mz, CDCl 3, ETCR): δ= 1.29 [s, 9, (C 3 ) 3 C], 1.79 (dd, J = 14.4, 12.3 z, 1, -7), 1.93 (m, 1, C 2 allyl), 1.98 (m, 1, -8), 2.36 (dd, J = 14.4, 3.0 z, 1, -7), 2.43 (m, 1, C 2 allyl), 3.87 (d, J = 9.0 z, 1, -8a), 3.95 (dd, J = 9.0, 6.0 z, 1, -2), 3.99 (dd, J = 9.0, 2.1 z, 1, -2), 4.82 (dd, J = 6.0, 2.1 z, 1, -3), 5.03 (3m, 2, C 2 =), 5.70 (dddd, J = 16.5, 10.8, 8.1, 6.6 z, 1, C=), (m, 10, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 27.5 [(C 3 ) 3 C], 34.5 (C 2 allyl), 36.7 (C-7), 37.9 (C-8), 55.8 (C-6), 59.3 (C-3), 74.0 (C-2), 82.8 [(C 3 ) 3 C], 91.5 (C-8a), (C 2 =), , (C-o, m, p), (C-i), (C=), (C-i), (C=), (C=); IR (acl): v = 1665, 1726 cm -1 (C=); RMS calcld for [C Se + ]: , found: Epimer b (minor, lower R f ): 1 MR (400 Mz, CDCl 3, ETCR): δ= 1.45 [s, 9, (C 3 ) 3 C], 1.95 (m, 1, C 2 allyl), 1.99 (dd, J = 15.0, 10.8 z, 1, -7), 2.10 (dd, J = 15.0, 4.5 z, 1, -7), 2.20 (m, 1, -8), 2.48 (m, 1, C 2 allyl), 4.08 (dd, J = 9.0, 1.2 z, 1, -2), 4.17 (dd, J = 9.0, 6.6 z, 1, -2), 4.61 (d, J = 8.7 z, 1, -8a), 4.95 (dd, J = 6.6, 1.2 z, 1, -3), 4.98 (3m, 2, C 2 =), 5.56 (dddd, J = 16.5, 10.2, 8.4, 6.0 z, 1, C=), (m, 10, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 27.8 [(C 3 ) 3 C], 34.2 (C-7), 35.2 (C 2 allyl), 36.9 (C-8), 56.8 (C-6), 59.4 (C-3), 73.9 (C-2), 82.9 [(C 3 ) 3 C], 91.6 (C-8a), (C 2 =), , (C-o, m, p), (C-i), (C=), (C-i), (C=), (C=); IR (acl): v = 1661, 1732 cm -1 (C=); RMS calcd for [C Se + ]: , found: S4

5 C 6 5 t-bu 2 C (3R,8S,8aR)-8-Allyl-6-(tert-butoxycarbonyl)-5-oxo-3-phenyl-2,3,8,8a-tetrahydro-5oxazolo[3,2-a]pyridine (2). Aqueous 2 2 (30%, 0.37 ml, 12.4 mmol) and pyridine (0.17 ml, 2.01 mmol) were added to a solution of the above selenides (0.92 g, 1.77 mmol) in C 2 Cl 2 (159 ml). The resulting mixture was stirred at room temperature for 2 h and poured into distilled water. The two phases were separated, and the organic layer was washed with water, dried, and concentrated under reduced pressure to give crude unsaturated lactam 2, which was used in the next reaction without further purification. Compound 2 (spectroscopic data from the crude): 1 MR (300 Mz, CDCl 3 ): δ= 1.49 [s, 9, (C 3 ) 3 C], 2.31 (dt, J = 14.4, 9.3, 9.3 z, 1, C 2 allyl), 2.68 (ddm, J = 14.4, 4.8 z, 1, C 2 allyl), 2.89 (dddd, J = 10.5, 9.3, 4.8, 1.8 z, 1, - 8), 4.15 (dd, J = 9.0, 1.2 z, 1, -2), 4.22 (dd, J = 9.0, 6.6 z, 1, -2), 4.87 (d, J = 10.5 z, 1, -8a), 5.05 (dd, J = 6.6, 1.2 z, 1, -3), 5.24 (m, 2, C 2 =), 5.86 (dddd, J = 16.5, 10.2, 8.7, 5.7 z, 1, C=), (m, 6, -7, Ar); 13 C MR (75.4 Mz, CDCl 3 ): δ= 28.0 [(C 3 ) 3 C], 33.7 (C 2 allyl), 41.0 (C-8), 58.2 (C-3), 74.5 (C-2), 82.1 [(C 3 ) 3 C], 90.0 (C-8a), (C 2 =), 126.6, (C-o, m), (C-p), (C-6), (C=), (C-i), (C-7), (C=), (C=); IR (acl): v = 1675, 1731 cm -1 (C=). (3R,7R,8S,8aR)-6-(tert-Butoxycarbonyl)-7,8-diallyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro- 5-oxazolo[3,2-a]pyridine. LiCl (301 mg, 7.11 mmol) was dried at 80 C for 1 h under vacuum (10 15 mmg) in a two-necked, 100 ml round-bottomed flask. Then, CuI (1.35 g, 7.11 mmol) and TF (20 ml) were added under inert atmosphere, and the mixture was stirred at room temperature for 5 min. The suspension was cooled at 78 C, and allylmagnesium bromide (1 M in Et 2, 7.11 ml), TMSCl (0.9 ml, 7.11 mmol), and the crude unsaturated lactam 2 (1.77 mmol) in TF (20 ml) were successively added. The resulting mixture was stirred at 78 C for 18 h. The reaction was quenched with saturated aqueous 4 Cl, and filtered through Celite. The aqueous layer was extracted with EtAc, and the combined S5

6 organic extracts were dried over anhydrous MgS 4 and concentrated under reduced pressure. Flash chromatography (1:9 to 3:7 EtAc-hexane) gave the C-6 epimers a (major, 494 mg, 71% from selenide derivative) and b (minor, 77 mg, 11% from selenide derivative) of the diallyl derivative as colourless oils (82% overall yield). Epimer a (major, lower R f ) (6S): [α] 22 D = 70.7 (c = 0.5 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.35 [s, 9, (C 3 ) 3 C], 1.80 (dt, J = 12.3, 9.0, 9.0 z, 1, C 2 allyl), 2.20 (dt, J = 13.8, 10.2, 10.2 z, 1, C 2 allyl), 2.33 (dm, J = 11.4 z, 1, -7), 2.45 (dm, J = 13.8 z, 1, C 2 allyl), 2.63 (m, 2, -8, C 2 allyl), 3.30 (s, 1, -6), 4.00 (dd, J = 9.0, 1.2 z, 1, -2), 4.14 (dd, J = 9.0, 6.9 z, 1, -2), 4.60 (d, J = 9.6 z, 1, -8a), 4.92 (dd, J = 6.9, 1.2 z, 1, -3), (m, 4, C 2 =), 5.68 (dddd, J = 15.0, 10.5, 8.4, 4.8 z, 1, C=), 5.84 (dddd, J = 15.3, 9.9, 8.4, 4.8 z, 1, C=), (m, 5, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 27.8 [(C 3 ) 3 C], 31.6, 31.7 (C 2 allyl), 36.5 (C-7), 38.7 (C-8), 52.8 (C-6), 59.6 (C-3), 74.1 (C-2), 81.8 [(C 3 ) 3 C], 89.4 (C- 8a), 117.4, (C 2 =), 126.4, (C-o, m), (C-p), 134.7, (C=), (C-i), (C=), (C=); IR (acl): v = 1664, 1729 cm -1 (C=); elemental analysis calcd (%) for C : C 72.52, 7.86, 3.52; found: C 72.49, 7.94, Epimer b (minor, higher R f ) (6R): 1 MR (300 Mz, CDCl 3 ): δ= 1.47 [s, 9, (C 3 ) 3 ], 1.86 (m, 1, C 2 allyl), 2.18 (m, 1, C 2 allyl), 2.33 (m, 2, -7, C 2 allyl), 2.51 (m, 2, -8, C 2 allyl), 3.21 (d, J = 8.1 z, 1, -6), 4.05 (dd, J = 9.0, 1.2 z, 1, -2), 4.18 (dd, J = 9.0, 6.6 z, 1, -2), 4.77 (d, J = 9.0 z, 1, -8a), 4.94 (dd, J = 6.6, 1.2 z, 1, -3), (m, 4, C 2 =), 5.73 (m, 1, C=), 5.89 (m, 1, C=), (m, 5, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 27.8 [(C 3 ) 3 C], 32.7, 35.5 (C 2 allyl), 36.7 (C-7), 41.6 (C-8), 54.4 (C-6), 59.0 (C-3), 73.8 (C- 2), 81.9 [(C 3 ) 3 C], 89.8 (C-8a), 118.2, (C 2 =), 126.4, (C-o, m), (C-p), 132.7, (C=), (C-i), (C=), (C=); IR (acl): v = 1669, 1727 cm -1 (C=); MS m/z (%): 397 (2) [M + ],381 (5), 342 (8), 341 (34), 340 (21), 324 (17), 300 (12), 296 (27), 256 (15), 254 (38), 214 (16), 146 (26), 128 (12), 120 (28), 117 (15), 104 (100); RMS calcld for [C ]: , found: (3R,7S,8S,8aR)-7,8-Diallyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5-oxazolo[3,2- a]pyridine (3). From the above epimer a: TFA (1.5 ml, 0.02 mmol) was added to a solution of the major epimer of the above diallyl derivative (406 mg, 1.02 mmol) in anhydrous C 2 Cl 2 (4 S6

7 ml) at room temperature under inert atmosphere, and the resulting mixture was stirred for 30 minutes. The reaction was quenched with saturated aqueous a 2 C 3. The aqueous phase was washed with C 2 Cl 2 (2 5 ml), and the combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated. The crude was then redissolved in anhydrous toluene (15 ml), and the resulting solution was heated at reflux for 18 h. The resulting solution was cooled and poured into brine, the aqueous phase was extracted with EtAc, and the combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (3:7 to 6:4 Et 2 -hexane) afforded compound 3 (285 mg, 94%) as a colourless oil. From the above epimer b: perating as above, from the minor epimer of the diallyl derivative (150 mg, mmol) in anhydrous C 2 Cl 2 (4 ml), TFA (1.6 ml), and then refluxing toluene (5 ml), compound 3 (82 mg, 73%) was obtained after chromatographic purification: [α] 22 D = 17.0 (c = 0.2 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.81 (ddd, J = 13.6, 10.8, 8.8 z, 1, C 2 allyl), 2.13 (m, 2, -7, -8), 2.23 (m, 1, C 2 allyl), 2.28 (dd, J = 18.0, 6.0 z, 1, -6), 2.38 (m, 1, C 2 allyl), 2.44 (dd, J = 18.0, 1.6 z, 1, -6), 2.64 (dt, J = 14.0, 5.2, 5.2 z, 1, C 2 allyl), 4.00 (dd, J = 8.8, 0.8 z, 1, -2), 4.13 (dd, J = 8.8, 6.8 z, 1, -2), 4.63 (d, J = 9.2 z, 1, -8a), 4.89 (dd, J = 6.8, 0.8 z, 1, -3), (m, 4, C 2 =), 5.69 (m, 1, C=), 5.86 (dddd, J = 16.0, 10.4, 8.8, 6.0 z, 1, C=), (m, 5, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 32.2 (2C 2 allyl), 32.5 (C-7), 36.3 (C-6), 42.2 (C-8), 59.4 (C-3), 73.8 (C-2), 89.6 (C-8a), (C 2 =), (C 2 =), 126.3, (C-o, m), (C-p), (C=), (C=), (C-i), (C=); IR (acl): v = 1661 cm -1 (C=); elemental analysis calcd (%) for C / 4 2 : C 75.59, 7.85, 4.64; found: C 75.49, 7.76, (3R,6aS,10aS,10bR)-5-xo-3-phenyl-2,3,6,6a,7,10,10a,10b-octahydro-5-oxazolo[3,2- a]isoquinoline (4). Second generation Grubbs catalyst (340 mg, 0.4 mmol) was added to a solution of lactam 3 (1.59 g, 5.3 mmol) in C 2 Cl 2 (756 ml). The mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. Flash chromatography (1:9 to 3:7 EtAc-hexane) afforded tricyclic lactam 4 (1.34 g, 93%) as a brown solid: m.p C; S7

8 [α] 22 D = (c = 1.0 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= (m, 1, -7), 2.13 (dd, J = 16.4, 5.6 z, 1, -7), 2.23 (d, J = 18.0 z, 1, -6), 2.30 (m, 2, -10a, -6a), 2.45 (s, 2, -10), 2.54 (dd, J = 18.0, 6.4 z, 1, -6), 3.98 (d, J = 9.2 z, 1, -2), 4.11 (dd, J = 9.2, 6.8 z, 1, -2), 4.86 (d, J = 9.6 z, 1, -10b), 4.91 (d, J = 6.8 z, 1, -3), 5.70 (m, 2, -8, -9), (m, 5, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 25.6 (C-10), 28.5 (C-7), 29.1 (C-6a), 36.0 (C-10a), 38.3 (C-6), 59.4 (C-3), 73.6 (C-2), 87.3 (C-10b), 124.6, (C-8, C-9), 126.3, (C-o, m), (C-p), (C-i), (C=); IR (acl): v = 1658 cm -1 (C=); elemental analysis calcd (%) for C / 4 2 : C 74.56, 7.18, 5.11; found: C 74.67, 7.09, (4aS,8aS)-2-[(1R)-2-ydroxy-1-phenylethyl]-3-oxo-1,4,4a,5,8,8a-hexahydroisoquinoline (5). Et 3 Si (155 µl, 0.97 mmol) and TiCl 4 (171 µl, 1.56 mmol) were added to a solution of lactam 4 (105 mg, 0.39 mmol) in anhydrous C 2 Cl 2 (10 ml), and the resulting dark solution was heated at reflux for 24 h. The mixture was poured into saturated aqueous ac 3 (10 ml), and the resulting solution was extracted with C 2 Cl 2. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:9 EtAc-hexane to only EtAc) gave isoquinoline 5 (98 mg, 92%) as a white solid: m.p C; [α] 22 D = 20.5 (c = 0.4 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.93 (m, 2, -5, -8), 2.15 (m, 4, -5, -8, -4a, -8a), 2.40 (dd, J = 18.0, 6.0 z, 1, -4), 2.54 (dd, J = 18.0, 5.6 z, 1, -4), 2.88 (dd, J = 12.0, 4.0 z, 1, -1), 3.16 (dd, J = 12.0, 7.2 z, 1, -1), 3.64 (br. s, 1, ), 4.08 (m, 1, -2 ), 4.14 (dd, J = 11.2, 5.2 z, 1, -2 ), 5.60 (m, 2, -6, -7), 5.89 (dd, J = 9.2, 5.2 z, 1, -1 ), (m, 5, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 26.2, 27.6 (C-5, C-8), 28.7 (C-4a), 29.7 (C-8a), 36.0 (C-4), 44.7 (C-1), 57.1 (C-1 ), 60.4 (C-2 ), 124.3, (C-6, C-7), (C-p), 127.5, (C-o, m), (C-i), (C=); IR (acl): v = 3375 cm -1 (), 1614 cm -1 (C=), elemental analysis calcd (%) for C : C 75.25, 7.80, 5.16; found: C 74.96, 7.78, S8

9 (4aS,8aS)-3-xo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (6). Into a three-necked, 100 ml round-bottomed flask equipped with a coldfinger condenser charged with dry ice-acetone were condensed 15 ml of 3 at 78 C, and then a solution of lactam 5 (190 mg, 0.70 mmol) in TF (10 ml) was added. The temperature was raised to 33 C and sodium metal was added in small portions until the blue colour persisted. The mixture was stirred at 33 C for 1 min. The reaction was quenched by the addition of solid 4 Cl until the blue colour disappeared, and then the mixture was stirred at room temperature for 4 h. The resulting residue was digested at room temperature with C 2 Cl 2, and the suspension was filtered through Celite. The solution was concentrated under reduced pressure. Flash chromatography of the resulting oil (1:2 EtAc-hexane to 60:1 EtAc-Me) afforded bicyclic lactam 6 (98 mg, 93%) as a white solid: m.p C; [α] 22 D = 30.2 (c = 1.0 in Me); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= (m, 2, -8, -5), (m, 4, -8, -5, -4a, -8a), 2.30 (dd, J = 16.8, 6.4 z, 1, -4), 2.38 (dd, J = 16.8, 4.4 z, 1, -4), 3.23 (ddd, J = 12.0, 6.0, 2.0 z, 1, -1), 3.31 (ddd, J = 12.0, 4.8, 1.6 z, 1, -1), 5.63 (s, 2, -6, -7), 6.73 (br. s, 1, ); 13 C MR (100.6 Mz, CDCl 3 ): δ= 26.0 (C-8), 28.3 (C-5), 29.1, 29.2 (C-4a, C-8a), 34.8 (C-4), 44.6 (C-1), 124.5, (C-6, C-7), (C=); IR (acl): v = 3300 cm -1 (), 1665 cm -1 (C=); elemental analysis calcd (%) for C 9 13 : C 71.49, 8.67, 9.26; found: C 71.42, 8.58, Boc (4aS,8aS)-2-(tert-Butoxycarbonyl)-3-oxo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (7). nbuli (375 µl of a 1.6 M solution in hexane, 0.59 mmol) was added dropwise to a stirred solution of bicyclic lactam 6 (90 mg, 0.59 mmol) in anhydrous TF (7 ml) at 78 C. After 10 min a solution of di-tert-butyl dicarbonate (197 mg, 0.89 mmol) in anhydrous TF (2 ml) was added via cannula, and the stirring was continued for an additional 30 min at 78 C. The reaction was quenched by the addition of saturated aqueous 4 Cl solution, and the resulting solution was extracted with EtAc. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (2:8 EtAc-hexane) afforded lactam 7 (135 mg, 90%) as a white solid: m.p C; [α] 22 D = 20.2 (c = 0.45 in S9

10 CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.49 [s, 9, (C 3 ) 3 C], 1.84 (dd, J = 18.0, 6.8 z, 1, -5), 1.97 (m, 1, -8), 2.20 (m, 4, -5, -8, -8a, -4a), 2.42 (dd, J = 17.6, 6.0 z, 1, -4), 2.50 (dd, J = 17.6, 5.2 z, 1, -4), 3.53 (dd, J = 13.2, 5.6 z, 1, - 1), 3.58 (dd, J = 13.2, 4.4 z, 1, -1), 5.61 (m, 2, -6, -7); 13 C MR (100.6 Mz, CDCl 3 ): δ= 25.9 (C-8), 27.9 (C-5), 27.9 [(C 3 ) 3 C], 29.3 (C-4a), 29.9 (C-8a), 38.4 (C-4), 49.0 (C-1), 82.8 [(C 3 ) 3 C], 124.3, (C-7, C-6), (C), (C=); IR (acl): v = 1715, 1698 cm -1 (C=); RMS (ESI) calcd for [C a]: , found: ; elemental analysis calcd (%) for C : C 66.91, 8.42, 5.57; found: C 66.78, 8.49, (4aS,8aS)-3-xo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (8). nbuli (1.6 M in hexane, 1.24 ml, 1.98 mmol) was added dropwise at 78 C to a stirred solution of bicyclic lactam 6 (250 mg, 1.65 mmol) in anhydrous TF (10 ml). After stirring for 45 min at 78 C, a solution of p-toluenesulfonyl chloride (347 mg, 1.82 mmol) in anhydrous TF (2 ml) was added via transfer, and the stirring was continued for 4 h at 78 C. The reaction was quenched by the addition of saturated aqueous 4 Cl solution, and the resulting solution was extracted with EtAc. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (2:8 EtAc-hexane) afforded lactam 8 (432 mg, 86% yield): m.p C; [α] 22 D = 17.5 (c = 0.14 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.74 (dm, J = 17.2 z, 1, -5), 1.96 (dm, J = 17.2 z, 1, -8), 2.19 (m, 2, -5, -4a), 2.31 (m, 2, -8, -8a), 2.33 (dd, J = 18.0, 7.2 z, 1, -4), 2.42 (s, 3, C 3 ), 2.43 (dd, J = 18.0, 5.1 z, 1, -4), 3.85 (dd, J = 12.0, 5.1 z, 1, -1), 3.89 (dd, J = 12.0, 6.0 z, 1, -1), 5.61 (s, 2, -6, -7), 7.30 (d, J = 8.8 z, 2, -m), 7.89 (d, J = 8.8 z, 2, -o); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.6 (C 3 ), 25.5 (C-8), 27.9 (C-5), 28.9 (C-4a), 30.2 (C-8a), 37.1 (C-4), 49.3 (C-1), 124.1, (C-6, C-7), (Co), (C-m), (C-i), (C-p), (C=); IR (acl): v = 1690 cm -1 (C=), 1165 cm -1 (S 2 ); RMS (ESI) calcd for [C S + ] , found ; elemental analysis calcd (%) for C S: C 62.93, 6.27, 4.59; found: C 62.93, 6.36, S10

11 (4aR,8aS)-2-(tert-Butoxycarbonyl)-4-(methoxycarbonyl)-3-oxo-1,2,3,4,4a,5,8,8aoctahydroisoquinoline. Lithium bis(trimethylsilyl)amide (660 µl of a 1 M solution in hexane, 0.66 mmol) was added at 78 C to a solution of lactam 7 (128 mg, 0.51 mmol) in anhydrous TF (12 ml). After 1h, methyl chloroformate (40 µl, 0.51 mmol) was added, and the stirring was continued at 78 C for 2 h. The reaction was quenched with saturated aqueous 4 Cl, and the resulting solution was extracted with EtAc. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated. Flash chromatography (1:9 EtAc-hexane) afforded the -Boc methoxycarbonyl derivative (152 mg, 97%) as a pale yellow solid: m.p C; [α] 22 D = (c = 0.6 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.52 [s, 9, (C 3 ) 3 C], 1.84 (dm, J = 18.0 z, 1, -5), 2.00 (dm, J = 18.0 z, 1, -8), 2.18 (dm, J = 18.0 z, 1, -8), 2.26 (dm, J = 18.0 z, 1, -5), 2.33 (m, 1, -8a), 2.57 (m, 1, -4a), 3.44 (d, J = 9.2 z, 1, -4), 3.57 (dd, J = 13.2, 5.6 z, 1, -1), 3.64 (dd, J = 13.2, 4.4 z, 1, -1), 3.77 (s, 3, C 3 ), 5.61 (m, 2, -6, -7); 13 C MR (100.6 Mz, CDCl 3 ): δ= 25.3 (C-8), 27.6 (C-5), 27.9 [(C 3 ) 3 C], 28.5 (C-8a), 33.3 (C-4a), 49.5 (C-1), 52.5 (C 3 ), 53.8 (C-4), 83.4 [(C 3 ) 3 C], 123.9, (C-6, C-7), (C), (C=), (C=). IR (acl): v = 1743, 1718 cm -1 (C=); RMS (ESI) calcd for [C a]: , found: ; elemental analysis calcd (%) for C : C 62.12, 7.49, 4.53; found: C 62.13, 7.46, (4R,4aR,8aS)-2-(tert-Butoxycarbonyl)-4-[2-(1,3-dioxolan-2-yl)ethyl]-4-(methoxycarbonyl)- 3-oxo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (9). a (6 mg of a 60% dispersion in mineral oil, 0.17 mmol) was added at 0 C to a stirring solution of the above -Boc methoxycarbonyl derivative (40 mg, 0.13 mmol) in anhydrous DMF (3 ml). After 30 min, 2-(2-iodoethyl)-1,3- dioxolane (265 mg, 1.17 mmol) was added at 0 C, and the solution was stirred at 60 C S11

12 overnight. The reaction was quenched by the addition of water and saturated aqueous 4 Cl, and the resulting solution was extracted with EtAc. The combined organic extracts were dried over a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:9 EtAc-hexane to only EtAc) afforded lactam 9 (27 mg, 50%). Minor amounts of the deprotected derivative 10 (5 mg) and starting material (4 mg) were also obtained. Compound 9: [α] 22 D = 46.0 (c = 0.7 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.51 [s, 9, (C 3 ) 3 C], 1.74 (m, 1, -2 ), (m, 3, -8, -5, -2 ), 2.16 (m, 4, -5, -4a, 2-1 ), 2.37 (dm, J = 18.0 z, 1, -8), 2.54 (m, 1, -8a), 3.53 (t, J = 10.0 z, 1, -1), 3.57 (dd, J = 10.0, 5.6 z, 1, -1), 3.73 (s, 3, C 3 ), 3.83 (m, 2, C 2 ), 3.95 (m, 2, C 2 ), 4.87 (t, J = 4.4 z, 1, C 2 ), 5.60, 5.61 (2s, 2, -6, -7); 13 C MR (100.6 Mz, CDCl 3 ): δ= 24.7 (C-5), 27.1 (C-8a), 27.9 [(C 3 ) 3 C], 28.0 (C-8), 29.5 (C-2 ), 31.2 (C-1 ), 38.8 (C-4a), 46.9 (C-1), 52.0 (C 3 ), 59.9 (C-4), 64.8 (2C 2 ), 83.1 [(C 3 ) 3 C], (C 2 ), 124.1, (C-6, C-7), (C), (C=), (C=); IR (acl): v = 1743, 1726, 1719 cm -1 (C=); RMS (ESI) calcd for [C a]: , found: (4R,4aR,8aS)-4-[2-(1,3-Dioxolan-2-yl)ethyl]-4-(methoxycarbonyl)-3-oxo-1,2,3,4,4a,5,8,8aoctahydroisoquinoline (10). TFA (56 µl, 0.73 mmol) was added at room temperature to a stirred solution of bicyclic lactam 9 (58 mg, 0.14 mmol) in anhydrous C 2 Cl 2 (4 ml), and the resulting mixture was stirred for 40 min. The reaction was quenched with saturated aqueous a 2 C 3, and the aqueous layer was extracted with C 2 Cl 2. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (8:2 EtAc-hexane to EtAc) afforded lactam 10 (36 mg, 84%) as a colourless oil: [α] 22 D = 76.5 (c = 0.96 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.80 (m, 2, -5, -2 ), 1.91 (d, J = 18.0 z, 1, -8), 2.05 (td, J = 12.4, 12.4, 4.4 z, 1, - 2 ), (m, 4, -5, 2-1, -4a), 2.35 (dm, J = 18.0 z, 1, -8), 2.56 (m, 1, -8a), 3.11 (dm, J = 11.6 z, 1, -1), 3.38 (t, J = 11.6 z, 1, -1), 3.73 (s, 3, C 3 ), 3.84 (m, 2, C 2 ), 3.96 (m, 2, C 2 ), 4.87 (t, J = 4.4 z, 1, C 2 ), 5.60 (m, 2, -6, -7), 6.29 (br. s, 1, ); 13 C MR (100.6 Mz, CDCl 3 ): δ= 24.6 (C-5), 26.9 (C-8a), 27.9 (C-8), 29.6 (C-2 ), 31.3 (C-1 ), 39.1 (C-4a), 42.7 (C-1), 51.9 (C 3 ), 56.9 (C-4), 64.8, 64.9 (2C 2 ), (C 2 ), 124.1, (C-6, C-7), (C=), (C=); IR (acl): v = 1727, 1655 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: S12

13 (4R,4aR,8aS)-4-[2-(1,3-Dioxolan-2-yl)ethyl]-4-(hydroxymethyl)-1,2,3,4,4a,5,8,8aoctahydroisoquinoline (11). LiAl 4 (19 mg, 0.48 mmol) was added under argon atmosphere at 0 C to a solution of compound 10 (50 mg, 0.16 mmol) in anhydrous TF (7 ml), and the mixture was heated at reflux for 3 h. The resulting suspension was cooled to 0 C, and the reaction was quenched with distilled water. The aqueous layer was extracted with Et 2, and the combined organic extracts were dried and concentrated to give a colourless oil. Flash chromatography (EtAc, Biotage special ) afforded amino alcohol 11 (32 mg, 74%) as a yellow oil, which was immediately used in the next reaction: [α] 22 D = 27.9 (c = 2.2 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.68 (m, 2, 2-2 ), 1.78 (m, 3, -5, 2-1 ), 1.87 (m, 1, -4a), 1.98 (dm, J = 16.4 z, 1, -8), 2.13 (m, 1, -8a), 2.18 (dd, J = 16.4, 8.4 z, 1, -8), 2.22 (m, 1, -5), (m, 4, -1, -3), 3.33 (d, J = 11.2 z, 1, C 2 ), 3.41 (d, J = 11.2 z, 1, C 2 ), 3.87 (m, 2, C 2 ), 3.99 (m, 2, C 2 ), 4.90 (t, J = 4.4 z, 1, C 2 ), 5.58 (m, 2, -6, -7); 13 C MR (100.6 Mz, CDCl 3 ): δ= 22.0 (C-8), 24.1 (C-1 ), 27.1 (C-2 ), 29.0 (C-5), 29.2 (C-8a), 34.0 (C-4a), 39.5 (C-4), 46.8 (C-1, C-3), 64.3 (C 2 ), 64.9, 64.9 (2C 2 ), (C 2 ), 124.5, (C-6, C-7); IR (acl): v = 3303, 3481 cm -1 (, ); RMS (ESI) calcd for [C ]: , found: (4R,4aR,8aS)-4-[2-(1,3-Dioxolan-2-yl)ethyl]-4-(hydroxymethyl)-2-(p-methoxybenzenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (12). Anhydrous Et 3 (27 µl, mmol) and p-methoxybenzenesulfonyl chloride (31 mg, 0.15 mmol) were added at 0 C under argon atmosphere to a stirred solution of octahydroisoquinoline 11 (40 mg, 0.15 mmol) in anhydrous C 2 Cl 2 (1.5 ml). After 3 h of stirring at 0 C, the reaction was quenched with saturated aqueous 4 Cl solution, and the resulting solution was extracted with C 2 Cl 2. The combined organic S13

14 extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:2 EtAc-hexane to EtAc) afforded compound 12 (49 mg, 75%): 1 MR (300 Mz, CDCl 3, CSY): δ= 1.68 (m, 2, 2-2 ), (m, 6, -5, -4a, 2-8, 2-1 ), 2.24 (d, J = 11.7 z, 1, -3), 2.30 (t, J = 9.9 z, 1, -1), 2.33 (m, 2, -5, -8a), 3.29 (d, J = 9.9 z, 1, -1), 3.33 (d, J = 11.2 z, 1, C 2 ), 3.39 (d, J = 11.2 z, 1, C 2 ), 3.42 (d, J = 11.7 z, 1, -3), 3.87 (m, 2, C 2 ), 3.87 (s, 3, C 3 ), 3.99 (m, 2, C 2 ), 4.87 (t, J = 4.8 z, 1, C 2 ), (m, 2, -6, -7), 6.98 (d, J = 9.0 z, 2, -m), 7.68 (d, J = 9.0 z, 2, -o); 13 C MR (75.4 Mz, CDCl 3 ): δ= 21.2 (C-8), 23.8 (C-1 ), 26.7 (C-2 ), 28.1 (C-8a), 28.5 (C-5), 32.9 (C-4a), 40.7 (C-4), 46.6, 47.1 (C-1, C-3), 55.5 (C 3 ), 63.7 (C 2 ), 64.9, 65.0 (2C 2 ), (C 2 ), (C-m), 124.2, (C-6, C- 7), (C-i), (C-o), (C-p); IR (acl): v = 3623 cm -1 (), 1150 cm -1 (S 2 -); RMS (ESI) calcd for [C S + ]: , found: (4R,4aR,8aS)-4-[2-(1,3-Dioxolan-2-yl)ethyl]-4-(methanesulfonyloxymethyl)-2-(pmethoxybenzenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline. Anhydrous Et 3 (47 µl, 0.33 mmol) and methanesulfonyl chloride (43 µl, 0.56 mmol) were added at 0 C under inert atmosphere to a stirred solution of compound 12 (49 mg, 0.11 mmol) in anhydrous C 2 Cl 2 (1.5 ml). After 2 h of stirring at room temperature, the reaction was quenched with saturated aqueous 4 Cl solution, and the resulting solution was extracted with C 2 Cl 2. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:2 EtAc-hexane to EtAc) afforded the mesylate derivative (46 mg, 80%) as a yellow oil: 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.56 (m, 1, -2 ), 1.68 (m, 1, -2 ), (m, 6, 2-1, -5, 2-8, -4a), (m, 2, -5, -8a), 2.36 (d, J = 11.6 z, 2, -3, -1), 3.04 (s, 3, C 3 S 2 ), 3.24 (d, J = 11.6 z, 1, - 3), 3.34 (m, 1, -1), 3.84 (m, 2, C 2 ), 3.86 (s, 3, C 3 ), 3.94 (m, 2, C 2 ), 3.96 (d, J = 9.6 z, 2, C 2 S), 4.85 (t, J = 4.4 z, 1, C 2 ), (m, 2, -6, -7), 6.98 (d, J = 8.8 z, 2, -m), 7.66 (d, J = 8.8 z, 2, -o); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.3 (C- 8), 25.1 (C-1 ), 27.3 (C-2 ), 27.9 (C-8a), 28.3 (C-5), 32.9 (C-4a), 37.3 (C 3 S 2 ), 39.5 (C-4), 46.5 (C-3), 46.6 (C-1), 55.6 (C 3 ), 64.8, 64.9 (C 2 ), 69.9 (C 2 S), (C 2 ), S14

15 (C-m), 123.7, (C-7, C-6), (C-i), (C-o), (C-p); IR (acl): v = 1158 cm -1 (S 2 -); RMS (ESI) calcd for [C S 2 + ]: , found: (4S,4aR,8aS)-4-(Azidomethyl)-4-[2-(1,3-dioxolan-2-yl)ethyl]-2-(p-methoxybenzenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline. a 3 (53 mg, mmol) was added to a solution of the above mesylate (70 mg, mmol) in anhydrous DMF (2 ml), and the mixture was heated at 90 C. After 48 h, more a 3 (53 mg, mmol) was added, and the reaction was stirred at 90 C for an additional 24 h. The resulting mixture was quenched with distilled water. The aqueous layer was extracted with C 2 Cl 2, and the combined organic extracts were dried and concentrated under reduced pressure to give an oil. Flash chromatography (2:8 to 1:1 EtAc-hexane) afforded the azide (53 mg, 84%): [α] 22 D = (c = 2.15 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= (m, 2, -8, -2 ), (m, 2, -4a, -8), (m, 4, -2, -5, 2-1 ), 2.20 (d, J = 12.0 z, 1, -3), 2.25 (m, 1, -5), 2.31 (d, J = 8.0 z, 1, -1), 2.34 (m, 1, -8a), 3.18 (s, 2, C 2 3 ), 3.24 (d, J = 12.0 z, 1, -3), 3.37 (d, J = 8.0 z, 1, -1), 3.85 (m, 2, C 2 ), 3.86 (s, 3, C 3 ), 4.00 (m, 2, C 2 ), 4.87 (t, J = 4.4 z, 1, C 2 ), (2m, 2, - 6, -7), 6.97 (d, J = 9.2 z, 2, -m), 7.67 (d, J = 9.2 z, 2, -o); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.3 (C-8), 25.9 (C-1 ), 27.5 (C-2 ), 27.9 (C-8a), 28.4 (C-5), 33.6 (C-4a), 39.8 (C- 4), 46.2 (C-3), 47.0 (C-1), 54.2 (C 2 3 ), 55.5 (C 3 ), 64.8, 64.9 (C 2 ), (C 2 ), (C-m), 123.8, (C-7, C-6), (C-i), (C-o), (C-o), (C-p); IR (acl): v = 2102 cm -1 ( 3 ); RMS (ESI) calcd for [C S + ]: , found: S15

16 (4S,4aR,8aS)-4-(Aminomethyl)-4-[2-(1,3-dioxolan-2-yl)ethyl]-2-(p-methoxybenzenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (13). A solution of the above azide (38 mg, 0.08 mmol) in TF (2 ml) was added via cannula at room temperature to a stirred suspension of LiAl 4 (38 mg, 0.13 mmol) in anhydrous TF (1 ml). After 3 h of heating at reflux, the reaction was quenched by slow addition of distilled water, and the resulting solution was extracted with EtAc. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (EtAc to 9:1 EtAc- Me) afforded amine 13 (27 mg, 76%) as a colourless oil: [α] 22 D = 12.5 (c = 1.7 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.57 (m, 1, -2 ), 1.68 (m, 1, -2 ), (m, 6, -4a, -5, 2-8, 2-1 ), 2.16 (d, J = 12.0 z, 1, -3), 2.26 (masked, 2, C 2 ), 2.27 (d, J = 10.8 z, 1, -1), 2.38 (m, 1, -5), 2.52 (m, 1, -8a), 3.31 (d, J = 12.0 z, 1, -3), 3.40 (dd, J = 10.8, 3.2 z, 1, -1), 3.85 (m, 2, C 2 ), 3.86 (s, 3, C 3 ), 3.99 (m, 2, C 2 ), 4.89 (t, J = 4.0 z, 1, C 2 ), 5.48, 5.54 (2m, 2, -6, -7), 6.98 (d, J = 9.2 z, 2, -m), 7.68 (d, J = 9.2 z, 2, -o); 13 C MR (100.6 Mz, CDCl 3, 50 C): δ= 21.2 (C-8), 24.2 (C-1 ), 27.1 (C-2 ), 28.0 (C-8a), 28.6 (C-5), 33.7 (C-4a), 39.7 (C-4), 43.3 (C 2 ), 46.4 (C-1), 47.3 (C-3), 55.5 (C 3 ), 64.8, 64.9 (C 2 ), (C 2 ), (C-m), 124.2, (C-6, C-7), (C-i), (C-o), (C-p); IR (acl): v = 3387 cm -1 ( 2 ); RMS (ESI) calcd for [C S + ]: , found: (4S,4aR,6S,7S,8aS)-4-[2-(1,3-Dioxolan-2-yl)ethyl]-7-hydroxy-6,4-(iminomethano)-2-(pmethoxybenzenesulfonyl)perhydroisoquinoline (14). A solution of amine 13 (89 mg, 0.20 mmol) in anhydrous TF (4 ml) was added via cannula under inert atmosphere to a suspension of g(ccf 3 ) 2 (133 mg, 0.31 mmol) in TF (5 ml), previously cooled at 0 C. After stirring at room temperature for 3 h, the mixture was concentrated, and redissolved in C 2 Cl 2 (5 ml). Saturated acl solution (5 ml) was added and the mixture was stirred for 1 h, and extracted S16

17 with C 2 Cl 2. The combined organic extracts were dried over anhydrous K 2 C 3 and concentrated under reduced pressure to give a solid residue. xygen was bubbled at 10 C into a suspension of ab 4 (12 mg, 0.31 mmol) in (CF 3 ) 2 C (3 ml) for 30 minutes. Then, a solution of the above solid in (CF 3 ) 2 C (6 ml) was added over a 3 h period via a syringe pump with continuous introduction of 2. After the addition, bubbling of 2 into the mixture was continued for 30 minutes, and the mixture was then filtered through a Celite pad, which was washed several times with EtAc. The filtrate was concentrated under reduced pressure. Flash chromatography (5:95 Me-C 2 Cl 2 ) afforded amino alcohol 14 (40 mg, 43%) as a white solid. Minor amounts of the starting amine 13 (8 mg) were also isolated. 14: [α] 22 D = 12.5 (c = 0.35 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.37 (s, 1, - 4a), 1.50 (m, 3, -5, 2-2 ), 1.75 (m, 4, -5, -8, 2-1 ), 1.98 (d, J = 11.6 z, 1, -3), 2.13 (m, 1, -8a), 2.31 (dd, J = 11.4, 2.8 z, 1, -1), 2.43 (ddd, J = 16.4, 11.6, 4.8 z, 1, -8), 2.52 (d, J = 13.2 z, 1, C 2 ), 2.87 (s, 1, -6), 3.26 (d, J = 11.6 z, 1, -3), 3.41 (d, J = 13.2 z, 1, C 2 ), 3.53 (d, J = 11.4 z, 1, -1), 3.85 (m, 2, C 2 ), 3.88 (s, 3, C 3 ), 3.96 (m, 2, C 2 ), 4.03 (s, 1, -7), 4.85 (t, J = 4.4 z, 1, C 2 ), 6.98 (d, J = 9.2 z, 2, -m), 7.66 (d, J = 9.2 z, 2, -o); 13 C MR (100.6 Mz, CDCl 3 ): δ= 23.2 (C-1 ), 27.6 (C-2 ), 29.8 (C-5), 30.7 (C-8a), 33.8 (C-8), 34.3 (C-4), 35.4 (C-4a), 46.4 (C 2 ), 50.5 (C- 6), 51.5 (C-1), 53.2 (C-3), 55.6 (C 3 ), 64.9 (C 2 ), 70.8 (C-7), (C 2 ), (C-m), (C-i), (C-o), (C-p); IR (KBr): v = 3402 cm -1 (), 3279 cm -1 (); MS m/z (%): 452 (1) [M + ], 391 (5), 282 (17), 281 (100), 263 (18), 250 (11), 236 (3), 220 (3), 219 (4), 210 (4), 209 (28), 201 (7), 191 (4), 182 (5), 180 (5), 172 (10), 164 (5), 123 (5), 108 (6), 107 (11); RMS (ESI) calcd for [C S + ]: , found: (4R,4aR,8aS)-4-(11-Benzyloxyundecyl)-2-(tert-butoxycarbonyl)-4-(methoxycarbonyl)-3- oxo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (15). a (25 mg of a 60% dispersion in mineral oil, 0.68 mmol) was washed with anhydrous hexane, and a TF solution (3 ml) of the -Boc methoxycarbonyl derivative (100 mg, 0.32 mmol) prepared from 7 was added dropwise at 0 C under argon atmosphere. The mixture was stirred at 0 C for 45 min, and then 11-(benzyloxy)- 1-iodoundecane (650 mg, 1.68 mmol) was added. The resulting solution was heated at reflux overnight. The reaction was quenched with saturated aqueous 4 Cl solution, and the resulting S17

18 solution was extracted with EtAc. The combined organic extracts were dried over a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:99 Et 2 -hexane and then 7:3 EtAc-hexane) afforded compound 15 (94 mg, 52%) and minor amounts (10 mg, 7 %) of the deprotected derivative 17. Compound 15: [α] 22 D = 27.3 (c = 0.6 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= (m, 16, C 2 ), 1.51 [s, 9, (C 3 ) 3 C], 1.60 (m, 2, -10 ), 1.90 (dd, J = 16.0, 3.2 z, 1, -5), 1.96 (t, J = 18.4 z, 1, -8), 2.01 (m, 2, 2-1 ), 2.11 (dm, J = 16.0 z, 1, -5), 2.16 (m, 1, -4a), 2.35 (dd, J = 18.4, 6.0 z, 1, -8), 2.52 (m, 1, -8a), 3.46 (t, J = 6.8 z, 2, 2-11 ), 3.53 (t, J = 13.2 z, 1, -1), 3.55 (dd, J = 13.2, 10.8 z, 1, -1), 3.72 (s, 3, C 3 ), 4.50 (s, 2, C 2 benzyl), 5.60 (m, 2, -6, -7), 7.26 (m, 1, Ar), 7.33 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 24.7 (C-5), 25.1, 26.1 (C 2 ), 27.3 (C-8a), 27.8 (C-8), 27.9 [(C 3 ) 3 C], (C 2 ), 29.7 (C-10 ), 37.4 (C-1 ), 38.8 (C-4a), 47.0 (C-1), 51.9 (C 3 ), 60.5 (C-4), 70.5 (C-11 ), 72.8 (C 2 benzyl), 82.8 [(C 3 ) 3 C], 124.1, (C-6, C-7), (C-p), 127.5, (C-o, m), (C-i), (C), (C=), (C=); IR (acl): v = 1718, 1666 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: (4aR,8aS)-4-Methoxycarbonyl-3-oxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline. Lithium bis(trimethylsilyl)amide (528 µl of a 1 M solution in hexane, 0.53 mmol) was added at 78 C to a stirred solution of lactam 8 (124 mg, 0.41 mmol) in anhydrous TF (5 ml). After stirring for 1 h at 78 C, methyl chloroformate (31 µl, 0.41 mmol) was added and stirring was continued for 3 h at 78 C. The reaction was quenched by the addition of saturated aqueous 4 Cl, and the resulting solution was extracted with EtAc. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:9 to 3:7 EtAc-hexane) afforded the -tosyl methoxycarbonyl derivative (136 mg, 91% yield): 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.77 (dm, J = 18.0 z, 1, -5), 1.93 (m, 1, -8), 2.25 (m, 2, -5, -8), 2.43 (s, 3, C 3 ), 2.45 (m, 1, -8a), 2.55 (m, 1, -4a), 3.33 (d, J = 8.0 z, 1, -4), 3.68 (s, 3, C 3 ), 3.89 (dd, J = 12.0, 6.0 z, 1, -1), 3.95 (dd, J = 12.0, 4.4 z, 1, -1), 5.63 (m, 2, 6, 7), 7.31 (d, J = 8.4 z, 2, -m), 7.88 (d, J = 8.4 z, 2, -o); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.6 (C 3 ), 25.2 (C-8), 27.3 (C-5), 28.8 (C-8a), 33.2 (C-4a), 49.3 (C-1), 52.7 (C 3 ), 53.2 (C-4), S18

19 123.8, (C-6, C-7), (C-o), (C-m), (C-i), (C-p), (C=), (C=); IR (acl): v = 1740, 1686 cm -1 (C=); RMS (ESI) calcd for [C S + ] , found ; elemental analysis calcd (%) for C S: C 59.49, 5.82, 3.85; found: C 59.45, 5.84, (4R,4aR,8aS)-4-(11-Benzyloxyundecyl)-4-(methoxycarbonyl)-3-oxo-2-(p-toluenesulfonyl)- 1,2,3,4,4a,5,8,8a-octahydroisoquinoline (16). a (13 mg of a 60% dispersion in mineral oil, mmol) was washed with anhydrous hexane, and the above -tosyl methoxycarbonyl derivative (80 mg, 0.21 mmol) in anhydrous DMF (3 ml) was added dropwise at 0 C. The mixture was stirred at 0 C for 1 h, and then 11-(benzyloxy)-1-iodoundecane (678 mg, 1.75 mmol) was added. The resulting solution was heated at 60 C for 20 h. After cooling to room temperature, saturated aqueous 4 Cl was added, and the resulting solution was extracted with ether. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (0.5:9.5 to 1:1 EtAc-hexane) afforded compound 16 (102 mg, 75% yield): [α] 22 D = 21.6 (c = 0.52 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= (m, 16, C 2 ), 1.60 (m, 2, -10 ), 1.85 (m, 3, -5, 2-1 ), (m, 2, -8, -5), 2.15 (ddd, J = 9.6, 5.6, 3.2 z, 1, -4a), 2.38 (m, 1, -8), 2.42 (s, 3, C 3 ), 2.56 (m, 1, -8a), 3.46 (t, J = 6.8 z, 2, -11 ), 3.55 (s, 3, C 3 ), 3.75 (t, J = 12.0 z, 1, -1), 3.98 (dd, J = 12.0, 4.8 z, 1, -1), 4.50 (s, 2, C 2 benzyl), 5.61 (m, 2, -6, -7), 7.29 (m, 7, Ar), 7.88 (d, J = 8.0 z, 2, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.6 (C 3 ), 24.6 (C-5), 24.9, 26.2 (C 2 ), 27.8 (C-8), 28.1 (C- 8a), (C 2 ), 37.4 (C-1 ), 38.6 (C-4a), 46.9 (C-1), 51.9 (C 3 ), 59.8 (C-4), 70.5 (C- 11 ), 72.8 (C 2 benzyl), 124.2, (C-6, C-7), (C-p), 127.6, 128.3, 128.7, (C-o, m), 135.8, (C-i), (C-p), (C=), (C=); IR (acl): v = 1735, 1693 cm -1 (C=); RMS (ESI) calcd for [C S + ] , found S19

20 (4R,4aR,8aS)-4-(11-Benzyloxyundecyl)-4-(methoxycarbonyl)-3-oxo-1,2,3,4,4a,5,8,8aoctahydroisoquinoline (17). From compound 15. perating as described for the preparation of compound 10, from bicyclic lactam 15 (202 mg, 0.35 mmol) in anhydrous C 2 Cl 2 (9 ml) and TFA (134 µl, 1.75 mmol), compound 17 (132 mg, 80%) was obtained after purification by flash chromatography (1:9 to 4:6 EtAc-hexane). From compound 16: Sodium metal (96 mg, 4.01 mmol) was added at room temperature to a solution of naphthalene (267 mg, 4.03 mmol) in TF (6 ml). After stirring for 2 h, part of the mixture (4.18 ml) was added to a solution of sulfonamide 16 (202 mg, 0.32 mmol) in TF (2 ml) at 78 C. After 10 min, saturated aqueous 4 Cl was carefully added, and the resulting solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried (a 2 S 4 ), and concentrated under reduced pressure. Flash chromatography (1:9 to 1:1 EtAc-hexane) afforded secondary amine 17 (138 mg, 90%): [α] 22 D = 51.9 (c = 1.4 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= (m, 16, C 2 ), 1.61 (m, 2, 2-10 ), 1.83 (m, 1, -5), 1.90 (m, 1, -8), 1.97 (m, 2, 2-1 ), 2.19 (m, 2, -4a, -5), 2.36 (dm, J = 18.4 z, 1, -8), 2.54 (m, 1, -8a), 3.12 (ddd, J = 12.0, 5.6, 4.4 z, 1, -1), 3.38 (t, J = 12.0 z, 1, -1), 3.46 (t, J = 8.0 z, 2, 2-11 ), 3.72 (s, 3, C 3 ), 4.50 (s, 2, C 2 benzyl), 5.60 (m, 2, -6, -7), 5.83 (br. s, 1, ), 7.26 (m, 1, Ar), 7.33 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 24.7 (C- 5), 25.4, 26.1 (C 2 ), 27.1 (C-8a), 27.9 (C-8, C 2 ), 29.3 (C-10 ), 29, (C 2 ), 37.7 (C-1 ), 39.0 (C-4a), 42.9 (C-1), 51.8 (C 3 ), 57.5 (C-4), 70.5 (C-11 ), 72.8 (C 2 benzyl), 124.1, (C-6, C-7), (C-p), 127.6, (C-o, m), (C-i), (C=), (C=); IR (acl): v = 1729, 1665 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: (4R,4aR,8aS)-4-(11-Benzyloxyundecyl)-4-(hydroxymethyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline. perating as described for the preparation of compound 11, from compound 17 (167 mg, 0.36 mmol) in anhydrous TF (17 ml) and LiAl 4 (43 mg, 1.07 mmol), the title amino S20

21 alcohol was obtained as a colourless oil, which was used in the next step without further purification: 1 MR (400 Mz, CDCl 3, ETCR): δ= 1.25 (m, 16, C 2 ), 1.61 (m, 4, 2-1, 2-10 ), 1.80 (dm, J = 16.4 z, 1, -5), 1.88 (m, 1, -4a), 1.99 (m, 1, -8), 2.15 (m, 2, -8, -8a), 2.18 (dm, J = 16.4 z, 1, -5), 2.56 (d, J = 12.0 z, 1, -3), 2.64 (d, J = 12.0 z, 1, -3), 2.67 (m, 2, -1), 3.39 (d, J = 11.2 z, 1, C 2 ), 3.42 (d, J = 11.2 z, 1, C 2 ), 3.46 (t, J = 6.6 z, 2, 2-11 ), 4.50 (s, 2, C 2 benzyl), 5.60 (m, 2, -6, - 7), 7.25 (m, 1, Ar), 7.33 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.1 (C-8), 23.2, 26.2 (C 2 ), 29.0 (C-8a, C-5), (C 2 ), 31.3 (C-10 ), 34.1 (C-4a), 39.5 (C-4), 46.8 (C-1), 47.0 (C-3), 64.9 (C 2 ), 70.5 (C-11 ), 72.9 (C 2 benzyl), (C-6, C-7), (C-p), 127.6, (C-o, m), (C-i); RMS (ESI) calcd for [C ]: , found: (4R,4aR,8aS)-4-(11-Benzyloxyundecyl)-2-(tert-butoxycarbonyl)-4-(hydroxymethyl)- 1,2,3,4,4a,5,8,8a-octahydroisoquinoline (18). Di-tert-butyl dicarbonate (87 mg, 0.36 mmol) was added dropwise to a solution of the above amino alcohol (0.36 mmol) in anhydrous C 2 Cl 2 (8 ml) at room temperature under inert atmosphere. The mixture was stirred for 2 h, poured into water, and the resulting solution was extracted with C 2 Cl 2. The combined organic extracts were washed with brine, dried over anhydrous MgS 4, and concentrated under reduced pressure. Flash chromatography (Al 2 3, C 2 C 2 to 1:99 Me-C 2 C 2 ) gave alcohol 18 (140 mg, 75% overall yield from 17) as a colourless oil: [α] 22 D = (c = 1.1 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.26, 1.34 (2m, 18, C 2 ), 1.45 [s, 9, (C 3 ) 3 C], 1.59 (m, 2, 2-10 ), 1.82 (d, J = 18.4 z, 1, -5), 1.88 (m, 1, -4a), 2.02 (tm, J = 18.8 z, 1, -8), 2.11 (dm, J = 18.8 z, 1, -8), 2.19 (m, 1, -8a), 2.21 (dm, J = 18.4 z, 1, - 5), 2.66 (d, J = 12.0 z, 1, -3), 2.72 (masked, 1, -1), 2.86 (dm, J = 12.0 z, 1, -3), 2.96 (m, 1, -1), 3.37 (s, 2, C 2 ), 3.45 (masked, 1, -3), 3.46 (t, J = 6.5 z, 2, 2-11 ), 3.50 (masked, 1, -1), 3.59 (d, J = 14.4 z, 1, -1), 3.80 (d, J = 12.0 z, 1, -3), 4.50 (s, 2, C 2 benzyl), 5.59 (m, 2, -6, -7), 7.27 (m, 1, Ar), 7.32 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.5 (C-8), 23.3, 26.1 (C 2 ), 27.7 (C-8a), 28.4 [(C 3 ) 3 C], 28.5 (C-5), (C 2 ), 34.4 (C-4a), 40.5, 40.9 (C-4), 43.7 (C-3), 44.6 (C-1, C-3), 45.8 (C-1), 63.6, 64.2 (C 2 ), 70.4 (C-11 ), 72.7 (C 2 benzyl), 79.3 [(C 3 ) 3 C], (C-6, C-7), S21

22 (C-p), 127.5, (C-o, m), (C-i), 155.3, (C); IR (acl): v = 1690 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: (4R,4aR,8aS)-4-(11-Benzyloxyundecyl)-2-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline. perating as described for the preparation of the mesylate derived from 12, from alcohol 18 (58 mg, 0.11 mmol) in anhydrous C 2 Cl 2 (1.0 ml), anhydrous Et 3 (77 µl, 0.55 mmol), and methanesulfonyl chloride (26 µl, 0.33 mmol), the title mesylate (78 mg) was obtained as a yellow oil, which was used in the next reaction without purification: 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.26, 1.33 (2m, 18, C 2 ), 1.45 [s, 9, (C 3 ) 3 C], 1.60 (m, 2, 2-10 ), 1.83 (d, J = 18.4 z, 1, -5), (m, 4, -4a, 2-8, -8a), 2.24 (dm, J = 18.4 z, 1, -5), 2.75, 2.78 (2s, 2, -3, -1), 3.01 (s, 3, C 3 S 2 ), 3.46 (t, J = 6.5 z, 2, 2-11 ), (m, 2, -1, -3), 3.99 (s, 2, C 2 S), 4.50 (s, 2, C 2 benzyl), 5.60 (m, 2, -6, -7), 7.25 (m, 1, Ar), 7.34 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.5 (C-8), 23.3, 26.2 (C 2 ), 27.6 (C-8a), 28.4 [(C 3 ) 3 C, C-5], (C 2 ), 34.4 (C-4a), 37.2 (C 3 S 2 ), 39.7 (C-4), 43.4 (C-3), 43.9 (C-1, C-3), 44.6 (C- 1), 70.1 (C 2 S), 70.5 (C-11 ), 72.8 (C 2 benzyl), 79.7 [(C 3 ) 3 C], 123.8, (C-6, C-7), (C-p), 127.6, (C-o, m), (C-i), 155.1, (C); IR (acl): v = 1724 cm -1 (C=), 1273 cm -1 (S 2 -). (4R,4aR,8aS)-4-(Azidomethyl)-4-(11-benzyloxyundecyl)-2-(tert-butoxycarbonyl)- 1,2,3,4,4a,5,8,8a-octahydroisoquinoline (19). perating as in the preparation of the azide derived from 12, from the above crude of the -Boc mesylate (0.11 mmol) in anhydrous DMF (1.0 ml), a 3 (47 mg, 0.66 mmol), and, after 48h, additional a 3 (47 mg, 0.66 mmol), an oil S22

23 was obtained. Flash chromatography (hexane to 2:8 EtAc-hexane) gave azide 19 (53 mg, 87% overall yield from alcohol 18): [α] 22 D = 22.6 (c = 2.7 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.27, 1.34 (2m, 18, C 2 ), 1.46 [s, 9, (C 3 ) 3 C], 1.62 (m, 2, -10 ), 1.72 (dm, J = 17.6 z, 1, -5), 1.88 (m, 1, -4a), 1.95 (dm, J = 17.6 z, 1, -8), 2.04 (m, 1, -8), 2.16 (m, 1, -8a), 2.24 (dm, J = 17.6 z, 1, -5), 2.65 (m, 2, -3, -1), 3.20 (s, 2, C 2 3 ), 3.47 (t, J = 6.4 z, 2, 2-11 ), 3.64, 3.83 (2m, 2, -1, -3), 4.51 (s, 2, C 2 benzyl), 5.60 (m, 2, -6, -7), 7.25 (m, 1, Ar), 7.34 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.5 (C-8), 23.3, 26.1 (C 2 ), 27.7 (C-8a), 28.4 [(C 3 ) 3 C], (C-5, C 2 ), 35.0 (C-4a), 40.2 (C-4), 43.4, 45.0 (C-1, C-3), 54.1 (C 2 3 ), 70.5 (C-11 ), 72.8 (C 2 benzyl), 79.5 [(C 3 ) 3 C], 124.1, (C-6, C-7), (C-p), 127.5, (C-o, m), (C-i), (C); IR (acl): v = 2097 cm -1 ( 3 ), 1691 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: (4S,4aR,8aS)-4-(Aminomethyl)-4-(11-benzyloxyundecyl)-2-(tert-butoxycarbonyl)- 1,2,3,4,4a,5,8,8a-octahydroisoquinoline (20). Ph 3 P (25 mg, 0.09 mmol) was added to a solution of azide 19 (40 mg, 0.07 mmol) in TF- 2 (2.2 ml, 10:1), and the resulting mixture was stirred at room temperature overnight. The solvents were then removed under reduced pressure. Flash chromatography (EtAc to 95:5 EtAc-Me) of the residue gave amine 20 (21 mg, 55%) as a pale yellow oil: [α] 22 D = 7.4 (c = 1.1 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.25, 1.34 (2m, 18, C 2 ), 1.45 [s, 9, (C 3 ) 3 C], 1.59 (m, 2, -10 ), 1.81 (m, 2, -4a, -5), 1.98 (m, 1, -8), 2.06 (m, 1, -8), 2.20 (m, 1, -8a), 2.22 (dm, J = 18.4 z, 1, -5), 2.49 (m, 1, -3), 2.58 (d, J = 13.6 z, 2, C 2 2 ), 2.65 (dm, J = 12.8 z, 1, -1), 3.47 (t, J = 6.4 z, 2, -11 ), 3.62 (dm, J = 13.6 z, 1, -3), 3.83 (dm, J = 12.8 z, 1, -1), 4.50 (s, 2, C 2 benzyl), 5.59 (m, 2, -6, -7), 7.26 (m, 1, Ar), 7.34 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 21.5 (C-8), 23.3, 26.1 (C 2 ), 27.8 (C-8a), 28.4 [(C 3 ) 3 C], 28.6 (C-5), (C 2 ), 35.1 (C-4a), 39.8 (C-4), 43.6 (C-1), 45.0 (C 2 2, C-3), 70.5 (C-11 ), 72.8 (C 2 benzyl), 79.3 [(C 3 ) 3 C], 124.4, (C-6, C-7), (C-p), 127.6, (C-o, m), (C-i), (C); IR (acl): v = 3300 cm -1 ( 2 ), 1690 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: S23

24 (4S,4aR,6S,7S,8aS)-4-(11-Benzyloxyundecyl)-2-(tert-butoxycarbonyl)-7-hydroxy-6,4- (iminomethano)perhydroisoquinoline (21). perating as in the above preparation of amino alcohol 14, from amine 20 (46 mg, 0.09 mmol) in anhydrous TF (2.7 ml), g(ccf 3 ) 2 (57 mg, 0.13 mmol) in TF (2 ml), C 2 Cl 2 (5 ml), saturated acl (5 ml), and then ab 4 (5.2 mg, 0.13 mmol) in (CF 3 ) 2 C (4 ml), an oil was obtained. Flash chromatography (95:5 C 2 Cl 2 -Me) gave pure amino alcohol 21 (19 mg, 40% yield). Minor amounts of the starting amine 20 (6 mg) were recovered. Amino alcohol 21: [α] 22 D = (c = 0.9 in CDCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.26, 1.34 (2m, 18, C 2 ), 1.45 [s, 9, (C 3 ) 3 C], 1.60 (m, 3, -4a, -10 ), 1.74 (m, 1, -8), 1.80 (m, 2, -5), 2.00 (m, 2, -8a, -8), (m, 3, -3, -1, C 2 ), 2.91 (s, 1, -6), 3.04 (m, 1, C 2 ), 3.47 (t, J = 6.4 z, 2, -11 ), (m, 2, -3, -1), 4.02 (s, 1, -7), 4.50 (s, 2, C 2 benzyl), 7.26 (m, 1, Ar), 7.33 (m, 4, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 23.1 (C 2 ), 23.2 (C- 5), 26.1 (C 2 ), 28.4 [(C 3 ) 3 C], (C 2 ), 31.2 (C-8a), 33.5 (C-8), 33.9 (C-4), 35.1 (C- 4a), 36.2 (C 2 ), 46.2, 46.4 (C 2 ), (C-1, C-3), 50.6 (C-6), 70.4 (C-7), 70.5 (C-11 ), 72.8 (C 2 benzyl), 79.5 [(C 3 ) 3 C], (C-p), 127.6, (C-o, m), (C-i), (C); IR (acl): v = 3408, 3368 cm -1 (, ), 1692 cm -1 (C=); RMS (ESI) calcd for [C ]: , found: (4R,4aR,6S,7S,8aS)-4-(11-Benzyloxyundecyl)-2-(tert-butoxycarbonyl)-7-hydroxy-6,4- (iminomethano)-9-(p-methoxybenzenesulfonyl)perhydroisoquinoline (22): Et 3 (6 µl, mmol) was added dropwise at 0 C to a stirring solution of tricyclic compound 21 (18 mg, mmol) in anhydrous C 2 Cl 2 (2 ml). Then a solution of p-methoxybenzenesulfonyl chloride (9 mg, mmol) in anhydrous C 2 Cl 2 (2 ml) was transferred via cannula, and the stirring was continued for 3 h at 0 C. The reaction was quenched with saturated aqueous S24

25 4 Cl, and the resulting solution was extracted with C 2 Cl 2. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:9 to 1:1 EtAc-hexane) afforded protected compound 22 (17 mg, 72%) and starting material 21 (5 mg). 22: [α] 22 D = (c = 0.9 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.05 (m, 2, C 2 ), 1.25, 1.36 (2m, 19, -8, C 2 ), 1.43 [s, 9, (C 3 ) 3 C], 1.50 (m, 1, -4a), (m, 4, -5, -8, 2-10 ), 1.95 (m, 1, -5), 2.42 (m, 1, -8a), 2.55 (m, 1, -3), 2.78 (m, 1, -1), 3.08 (dm, J = 17.6 z, 1, C 2 ), 3.27 (d, J = 17.6 z, 1, C 2 ), 3.47 (t, J = 8.8 z, 2, -11 ), 3.84 (s, 3, C 3 ), 3.84 (masked, 2, -3, -1), 3.92 (s, 1, -7), 4.00 (s, 1, -7), 4.51 (s, 2, C 2 benzyl), 6.92 (d, J = 11.2 z, 2, -m), 7.26 (m, 1, Ar), 7.33 (m, 4, Ar), 7.74 (d, J = 11.2 z, 2, -o); 13 C RM (100.6 Mz, CDCl 3 ): δ 22.5 (C-5), 22.8 (C 2 ), 26.1 (C 2 ), 28.4 [(C 3 ) 3 C], (C-8, C 2 ), 30.2 (C-8a), 32.4 (C-4), 34.9 (C-4a), 36.4 (C 2 ), 46.5 (C 2 ), (C-1, C-3), 50.9 (C-6), 55.5 (C 3 ), 67.8 (C-7), 70.5 (C-11 ), 72.8 (C 2 benzyl), 79.8 [(C 3 ) 3 C], (C-m, Mbs), (C-p, Bn), 127.6, (C-o, m, Bn), (C-i, Mbs), (C-o, Mbs), (C-i, Bn), (C), (C-p, Mbs); IR (acl): v = 3500 cm -1 (), 1690 cm -1 (C=); RMS (ESI) calcd for [C S + a] , found Preparation of 22 via azido epoxide 24. m-chloroperoxybenzoic acid (90 mg, technical grade 85%; 72 mg, pure oxidant, 0.44 mmol) was added to a cold (0 C) solution of azide 19 (122 mg, 0.22 mmol) in C 2 Cl 2 (3.5 ml), and the mixture was allowed to warm slowly to room temperature. After 4 h of stirring, the mixture was washed with saturated aqueous ac 3 and saturated aqueous a 2 S 2 3. The organic solution was dried over anhydrous a 2 S 4 and concentrated under reduced pressure to give (4R,4aR,6R,7S,8aS)-4-(Azidomethyl)-4-(11- benzyloxyundecyl)-2-(tert-butoxycarbonyl)-6,7-epoxyperhydroisoquinoline (24, 149 mg), which was used in the next step without further purification: 1 MR (400 Mz, CDCl 3 ): δ= 1.26, 1.33 (2m, 18, C 2 ), 1.43 [s, 9, (C 3 ) 3 C], 1.45 [s, 9, (C 3 ) 3 C], 1.61 (m, 3, -4a, 2-10 ), 1.68 (m, 1, -8), (m, 3, -8a, 2-5), 2.07 (td, J = 16.0, 16.0, 7.6 z, 1, -8), (m, 2, -1, -3), (m, 4, -6, -7, C 2 3 ), 3.46 (t, J = 6.8 z, 2, -11 ), 3.61 (m, 1, -1), 3.78 (dm, J = 12.4 z, 1, -3), 4.50 (s, 2, C 2 benzyl), 7.28 (m, 3, Ar), 7.33 (m, 2, Ar); 13 C MR (100.6 Mz, CDCl 3 ): δ= 20.1 (C-5), 23.1, 26.1 (C 2 ), 26.8 (C-8), 28.3 [(C 3 ) 3 C], (C 2, C-8), 31.3 (C-8a), 32.0, 32.1 (C 2 ), 34.3 (C-4a), 39.7 (C-4), 43.6, 44.5, 45.1 (C-1, C-3), 49, (C-6, C-7), 54.1 (C 2 3 ), 70.4 (C-11 ), 72.7 (C 2 benzyl), 79.8 [(C 3 ) 3 C], (C-p), (C-o), (C-m), (C-i), (C). Me 3 P (287 µl of a 1 M solution in TF, mmol) was added to a solution of crude epoxide 24 in TF/ 2 (4 ml, 9:1), and the mixture was stirred at room temperature for 7 h. S25

26 The resulting solution was concentrated under reduced pressure to afford crude amino alcohol 21 (210 mg) as a pale yellow oil. perating as in the above preparation of 22, from a solution of crude 21, p-methoxybenzenesulfonyl chloride (50 mg, 0.24 mmol), and Et 3 (36 µl, 0.26 mmol) in anhydrous C 2 Cl 2 (3.2 ml), pure compound 22 (70 mg, 45% overall yield from azide 19) was obtained after flash chromatography (1:9 to 1:1 EtAc-hexane). (4R,4aR,6S,8aS)-4-(11-Benzyloxyundecyl)-2-(tert-butoxycarbonyl)-6,4-(iminomethano)-9- (p-methoxybenzenesulfonyl)-7-oxoperhydroisoquinoline (23): Dess-Martin periodinane (82 mg, 0.19 mmol) was added under inert atmosphere at room temperature to a solution of tricyclic compound 22 (0.08 mmol) in C 2 Cl 2 (3 ml). After 4h of stirring at room temperature, a saturated (1:1) solution of ac 3 -a 2 S 2 3 was slowly added. The resulting mixture was stirred vigorously for 1 h and extracted with C 2 Cl 2. The combined organic extracts were dried over anhydrous a 2 S 4, filtered, and concentrated under reduced pressure. Flash chromatography (1:9 to 6:4 EtAc-hexane) afforded ketone 23 (43 mg, 78%) as a colourless oil. [α] 22 D = (c = 1.7 in CCl 3 ); 1 MR (400 Mz, CDCl 3, CSY, ETCR): δ= 1.27 (m, 18, C 2 ), 1.35 [s, 9, (C 3 ) 3 C], 1.62 (m, 3, C 2, -5), 1.65 (m, 1, -8a), 1.74 (dd, J = 16.8, 11.6 z, 1, -8), 2.10 (m, 1, -4a), 2.32 (m, 1, -8), 2.43 (d, J = 14.0 z, 1, - 5), (m, 3, -3, -1, C 2 ), 3.47 (t, J = 6.4 z, 2, 2-11 ), 3.57, (m, 3, -3, -1, C 2 ), 3.82 (s, 3, C 3 ), 4.38 (s, 1, -6), 4.50 (s, 2, C 2 benzyl), 6.89 (d, J = 10.0 z, 2, -m), 7.29 (m, 3, Ar), 7.34 (m, 2, Ar), 7.65 (d, J = 10.0 z, 2, -o); 13 C-RM (100.6 Mz, CDCl 3 ): δ= 23.0 (C 2 ), 26.2 (C 2 ), 28.3 [(C 3 ) 3 C], 29.3 (C-5), (C 2 ), 33.7 (C-8a), 34.4 (C-4), 35.6, 35.8 (C 2 ), 36.6 (C-4a), 43.2 (C-8), (C-1, C-3, C 2 ), 55.4 (C 3 ), 56.9 (C-6), 70.5 (C-11 ), 72.8 (C 2 benzyl), 80.1 [(C 3 ) 3 C], (C-m Mbs), (C-p benzyl), 127.6, (C-o, m benzyl), (C-i Mbs), (C-o Mbs), (C-i benzyl), (C), (C-p Mbs), (C=). IR (acl): v = 3408, 3279 cm -1 (, ), 1692 cm -1 (C=). RMS (ESI) calcd for [C S + a]: found: S26

27 C 6 5 t-bu 2 C 2 S27

28 C 6 5 t-bu 2 C 2 S28

29 C 6 5 tbu 2 C S29

30 C 6 5 tbu 2 C S30

31 C S31

32 C S32

33 C S33

34 C S34

35 C S35

36 C S36

37 6 S37

38 6 S38

39 Boc 7 S39

40 Boc 7 S40

41 Ts 8 S41

42 Ts 8 S42

43 Me 2 C Boc S43

44 Me 2 C Boc S44

45 Me 2 C Boc 9 S45

46 Me 2 C Boc 9 S46

47 Me 2 C 10 S47

48 Me 2 C 10 S48

49 Mbs 12 S49

50 Mbs 12 S50

51 3 Mbs S51

52 3 Mbs S52

53 Mbs 14 S53

54 Mbs 14 S54

55 Me 2 C Boc Bn 9 15 S55

56 Me 2 C Boc Bn 9 15 S56

57 Me 2 C Ts S57

58 Me 2 C Ts S58