Total Synthesis of Candicanoside A, a Potent Antitumor Saponin Bearing a Rearranged Steroidal Side Chain

Transcription

1 Total Synthesis of Lobatoside E, a Potent Antitumor Cyclic Triterpene Saponin Chunsheng Zhu, Pingping Tang, and Biao Yu* State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of rganic Chemistry, Chinese Academy of Sciences, Shanghai , China byu@mail.sioc.ac.cn Supporting Information Experimental details, characterization data, and NMR spectra for new compounds.

2 BnBr, K 2 C 3,Bu 4 NBr C 2 Cl 2 / 2, 50 o C,94% Bn 8 S1 To a suspension of oleanolic acid 8 (4.56 g, 10 mmol) in C 2 Cl 2 (150 ml) were added a solution of K 2 C 3 (2.76 g, 20 mmol) in water (50 ml), Bu 4 NBr (2.58g, 8 mmol) and BnBr (1.8 ml, 15 mmol). The mixture was stirred at 50 o C for 6 h and was quenched by addition of aqueous Cl (1 N), and followed by dilution with C 2 Cl 2. The organic layerl was separated, washed ( 2 and then brine) and dried over Na 2 S 4. Concentration in vacuo and purification by silica gel flash column chromatography (petroleum ether/etac: 8/1) furnished S1 (5.11 g, 94%) as a white solid: 1 NMR (300 Mz, CDCl 3 ) δ 7.34 (m, 5), 5.30 (s-like, 1), 5.07 (AB, 2), 3.21 (dd, J = 4.8, 9.9 z, 1), 2.91 (dd, J = 3.9, 13.2 z, 1), 1.13, 0.98, 0.92, 0.90, 0.88, 0.78, 0.61 (s, each 3). Bn Jones reagent, acetone 0 o Ctort,92% Bn S1 S2 Benzyl oleanolate S1 (14.40 g, mmol) was dissolved in acetone (250 ml), and Jones reagent (14 ml) was added dropwise at 0 o C. After stirring at 0 o C for 30 min, the reaction mixture was quenched by addition of i-pr, followed by concentration in vacuo to remove acetone. The residue was dissolved in C 2 Cl 2, washed ( 2 and then brine), and dried over Na 2 S 4. Concentration in vacuo and purification by silica gel flash column chromatography (petroleum ether/c 2 Cl 2 : 1/1 to 1/2) furnished S2 (13.28 g, 92%) as a white solid: [α] 25 D = 76.2 (c 1.12, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.34 (m, 5), 5.29 (s-like, 1), 5.08 (AB, 2), 2.91 (dd, J = 4.5, 14.1 z, 1), 2.54 (ddd, J = 6.9, 10.5, 15.6 z, 1), 2.35 (ddd, J = 3.3, 6.6, 15.6 z, 1), 1.13, 1.08, 1.04, 1.01, 0.92, 0.90, 0.65 (s, each 3); ESI-MS m/z 545 [M+] +, 583 [M+K] +. Anal. Calcd for C : C, 81.57;, Found: C, 81.44;, S1

3 Bn 2 N Cl, NaAc, Me/C 2 Cl 2, reflux, 95% Bn N S2 9 Compound S2 (92 mg, 0.17 mmol) was dissolved in Me/C 2 Cl 2 (6 ml/3 ml), and N 2 Cl (18 mg, 0.25 mmol) and NaAc (42 mg, 0.51 mmol) was added at rt. After stirring overnight at reflux, the reaction mixture was diluted by addition of brine, then extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, followed by filtration, concentration in vacuo, and purification by silica gel flash column chromatography (petroleum ether/c 2 Cl 2 : 1/1 to 1/2) to give 9 (96 mg, 95%) as a white foam: [α] 25 D = 17.7 (c 1.12, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.33 (m, 5), 5.29 (s, 1), 5.07 (AB, 2), 3.07 (ddd, J = 3.0, 5.1, 15.3 z, 1), 2.90 (dd, J = 3.6, 13.8 z, 1), 2.14 (m, 1), 1.14, 1.10, 1.04, 0.99, 0.91, 0.89, 0.63 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 177.5, 166.9, 143.7, 136.5, 128.4, 128.3, 128.2, 128.0, 127.9, 122.4, 66.0, 55.9, 47.2, 46.8, 45.8, 41.8, 41.7, 41.5, 40.4, 39.4, 38.5, 37.1, 33.9, 33.1, 32.5, 32.4, 30.7, 27.6, 27.2, 25.8, 23.7, 23.5, 23.3, 23.1, 19.1, 17.1, 16.9, 14.9; RMS (ESI) m/z calcd for C N [M+] +, found N 9 Bn 1) Na 2 PdCl 4,NaAc,Ac,rt 2) Ac 2, Et 3 N, DMAP,C 2 Cl 2,rt 3) Py, TF; Pb(Ac) 4,Ac, -78 o Ac Ctort;NaB 4, aq.na, rt, 72% N To a solution of benzyl 3-hydroxyiminoolean-12-en-28-oate 9 (1.00 g, 1.67 mmol) in Ac (90 ml) were added NaAc (150 mg, 1.83 mmol) and Na 2 PdCl 4 (562 mg, 1.87 mmol). The solution was stirred for 72 h at rt, and ice water (150 ml) was added to give a yellow precipitate. The palladium complex was filtered and dried in vacuo for 24 h. To a solution of this yellow solid in dry C 2 Cl 2 (15 ml) were added DMAP (19 mg, 0.15 mmol), Et 3 N (0.33 ml, 2.36 mmol), and Ac 2 (0.21 ml, 2.21 mmol). The reaction mixture was stirred at rt for 45 min, washed with water and brine, dried over anhydrous Na 2 S 4, filtered, and evaporated at reduced pressure. The crude product was dissolved in dry TF (60 ml), and pyridine (0.12 ml, 1.41 mmol) was added. The reaction mixture Ac 10 Bn S2

4 was stirred for 15 min at rt and cooled at -78 o C, and a solution of Pb(Ac) 4 (708 mg, 1.60 mmol) in Ac (24 ml) was added. and the stirring continued at rt for 30 h. To remove the remaining Pd salts, a solution of NaB 4 (58 mg, 1.52 mmol) in 1 N Na solution (22 ml) was added to the reaction mixture. The mixture was stirred for 15 min and filtered. The filtrate was diluted with C 2 Cl 2, which was washed with saturated aqueous NaC 3 solution, dried over Na 2 S 4, filtered, and evaporated in vacuo to give a white solid. The solid was purified by silica gel flash column chromatography (petroleum ether/etac: 6/1 to petroleum ether/c 2 Cl 2 : 1/2) to give 10 (791 mg, 72%) as a white foam: [α] 25 D = 75.4 (c 1.00, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.33 (m, 5), 5.30 (s-like, 1), 5.07 (AB, 2), 4.16 (AB, 2), 2.91 (dd, J = 3.3, 13.5 z, 1), 2.76 (ddd, J = 3.3, 6.6, 16.2 z, 1), 2.50 (m, 1), 2.17, 2.05, 1.16, 1.11, 0.95, 0.92, 0.89, 0.63 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 177.4, 170.9, 170.6, 169.7, 143.8, 136.4, 128.4, 128.0, 127.9, 122.2, 68.1, 68.0, 66.0, 48.5, 46.8, 46.7, 45.8, 43.9, 41.8, 41.5, 39.2, 37.0, 36.5, 33.9, 33.1, 32.3, 32.0, 30.7, 27.6, 25.7, 25.6, 23.6, 23.5, 23.1, 21.0, 20.3, 20.0, 19.4, 19.3, 16.8, 15.3; RMS (MALDI) m/z calcd for C N 6 Na [M+Na] +, found Bn Na 2 C 3,Me,99% Bn Ac N N Ac 10 S3 A solution of 10 (595 mg, 0.90 mmol) and Na 2 C 3 (478 mg, 4.51 mmol) in Me (90 ml) was stirred at rt for 22 h. After removing Me in vacuo, the resulting colorless solid was dissolved in Et 2. The organic layer was washed with 1 N aqueous Cl solution, saturated aqueous NaC 3 solution and brine, dried over Na 2 S 4, filtered, and evaporated in vacuo to give a solid. The solid was purified by silica gel flash column chromatography (petroleum ether/etac: 4/1) to give S3 (512 mg, 99%) as a white foam: [α] 26 D = 25.1 (c 1.20, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.34 (m, 5), 5.29 (s-like, 1), 5.07 (AB, 2), 3.55 (AB, 2), 3.32 (br, 1), 3.11 (ddd, J = 2.4, 4.8, 18.3 z, 1), 2.90 (dd, J = 4.2, 10.8 z, 1), 1.11 (s, 3), 1.02 (s, 6), 0.91, 0.89, 0.64 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 177.4, 166.1, 143.7, 136.3, 128.3, 127.9, 127.8, 122.2, 67.7, S3

5 65.9, 49.8, 46.9, 46.7, 45.7, 44.6, 41.7, 41.4, 39.2, 37.8, 36.7, 33.8, 33.0, 32.3, 32.2, 30.6, 27.5, 25.8, 23.6, 23.4, 23.0, 18.8, 18.4, 17.3, 16.9, 15.0; RMS (MALDI) m/z calcd for C N [M+] +, found Bn TiCl 3,N 4 Ac, TF/ 2, 95% Bn N S3 S4 To a solution of S3 (113 mg, 0.20 mmol) in TF/ 2 (7 ml/7 ml) were added N 4 Ac (189 mg, 2.45 mmol) and a buffered solution of TiCl 3 (0.42 ml of aqueous Cl solution containing 15% TiCl 3, 0.49 mmol). The mixture was stirred at rt for 10 h, and was then extracted with Et 2. The extract was washed with saturated aqueous NaC 3 solution and brine, dried over Na 2 S 4, filtered, and evaporated in vacuo to give a solid. The solid was purified by silica gel flash column chromatography (petroleum ether/etac: 4/1) to give S4 (104 mg, 95%) as a white foam: [α] 26 D = 61.8 (c 1.00, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.33 (m, 5), 5.30 (s-like, 1), 5.07 (AB, 2), 3.64 (d, J = 12.0 z, 1), 3.41 (d, J = 11.7 z, 1), 2.91 (dd, J = 3.6, 13.2 z, 1), 2.62 (m, 1), 2.42 (br, 1), 2.26 (m, 1), 1.94 (m, 4), 1.13, 1.11, 1.02, 0.92, 0.90, 0.67 (s, each 3); ESI-MS m/z 561 [M+] +. Anal. Calcd for C : C, 77.99;, Found: C, 78.11;, Bn BnC(N)CCl 3,Tf, dioxane, 0 o C,91% Bn S4 11 Bn To the solution of S4 (2.00 g, 3.57 mmol) and BnC(N)CCl 3 (2.00 g, 7.97 mmol) in dioxane (30 ml, dried over 4Å MS) at 0 o C, was added Tf (0.16 ml, 1.80 mmol) dropwise. After stirring for at 0 o C for 1 h, the reaction mixture was quenched by addition of saturated aqueous NaC 3 solution, diluted with brine, and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, followed by filtration, concentration in vacuo, and S4

6 purification by silica gel flash column chromatography (petroleum ether/etac: 20/1) to give 11 (2.10 g, 91%) as a colorless oil: [α] 24 D = 74.3 (c 1.05, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.32 (m, 10), 5.33 (s-like, 1), 5.08 (AB, 2), 4.55 (d, J = 12.3 z, 1), 4.37 (d, J = 12.3 z, 1), 3.52 (d, J = 8.7 z, 1), 3.21 (d, J = 8.7 z, 1), 2.92 (dd, J = 4.2, 13.8 z, 1), 2.44 (m, 1), 1.17, 0.95, 0.93 (s, each 3), 0.91 (s, 6), 0.66 (s, 3); 13 C NMR (125 Mz, CDCl 3 ) δ 216.3, 177.3, 143.6, 138.5, 136.4, 128.3, 128.2, 127.9, 127.8, 127.3, 127.2, 122.4, 75.1, 73.0, 65.9, 51.1, 47.1, 46.7, 46.1, 45.8, 41.8, 41.5, 39.2, 37.2, 36.2, 35.5, 33.8, 33.0, 32.3, 31.9, 30.6, 27.6, 25.7, 23.6, 23.4, 23.0, 19.5, 17.8, 16.8, 15.0; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn 11 Bn 1) LDA, TF, -78 o C,TMSCl, 89% 2) mcpba, C 2 Cl 2,-5to-10 o C 3) TBAF, TF, -5 to -10 o C,94% To TF (10 ml) under stirring at -78 o C, were added i Pr 2 N (3.70 ml, 38 mmol) and n BuLi (20 ml, 1.6 M in hexanes). The stirring continued for 30 min, a solution of 11 (2.10 g, 3.2 mmol) in TF (30 ml) was then added dropwise. After another 1 h, TMSCl (8.20 ml, 64 mmol) was added. After stirring at -78 o C for 1.5 h, the reaction mixture was quenched by addition of saturated aqueous NaC 3 solution, diluted with brine, and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, followed by filtration, concentration in vacuo, and purification by silica gel flash column chromatography (petroleum ether/c 2 Cl 2 : 3.5/1) to give the silyl enol ether M1 (2.02 g, 89%) as a white foam: 1 NMR (300 Mz, CDCl 3 ) δ 7.26 (m, 7), 7.10 (m, 3), 5.52 (s-like, 1), 5.28 (brs, 1), 4.72 (d-like, J = 4.8 z, 1), 4.61 (d, J = 12.6 z, 1), 4.39 (d, J = 13.2 z, 1), 3.29 (d, J = 8.4 z, 1), 3.05 (d, J = 9.0 z, 1), 2.92 (dd, J = 3.0, 14.4 z, 1), 1.13 (s, 2), 0.95 (s, 1), 0.90 (s, 6), 0.85 (s, 3), 0.71 (s, 3), 0.42 (s, 2), 0.35 (s, 1), 0.16 (s, 9), 0.01 (s, 9); 13 C NMR (75 Mz, CDCl 3 ) δ 177.1, 152.4, 143.5, 143.2, 140.1, 140.0, 139.2, 128.1, 128.0, 127.9, 127.4, 127.1, 126.0, 125.9, 125.8, 123.0, 101.6, 73.0, 72.6, 71.0, 70.9, 46.8, 46.0, 45.9, 44.9, 42.3, 41.8, 41.7, 41.6, 39.4, 39.1, 39.0, 35.8, 34.0, 33.1, 32.6, 31.9, 30.7, 29.7, 27.6, 25.7, 23.5, 23.3, 23.2, 19.2, 16.8, 16.4, 15.8, 15.7, Bn 12 Bn S5

7 0.5, -3.7, To a solution of the silyl enol ether M1 (2.40 g, 3.02 mmol) in C 2 Cl 2 (31 ml) under stirring at -7 o C, was added mcpba (1.11 g containing of 70% of mcpba, 4.53 mmol), followed by quenching with 10% aqueous Na 2 S 2 3 solution after 15 min. The resulting mixture was diluted with brine and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4 and followed concentrated in vacuo. The crude product was dissolved in TF (31 ml) at -7 o C, then TBAF (7.60 ml, 1 M) was added. After stirring at -7 o C for 45 min, the reaction mixture was quenched by addition of saturated aqueous NaC 3 solution, and was then diluted with brine, and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (petroleum ether/c 2 Cl 2 : 10/1 to 8/1) gave 12 (1.85 g, 94%) as a white foam: [α] 25 D = 48.6 (c 1.12, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.32 (m, 10), 5.31 (s, 1), 5.08 (AB, 2), 4.65 (d, J = 12.3 z, 1), 4.46 (br, 1), 4.44 (d, J = 12.0 z, 1), 3.81 (d, J = 9.3 z, 1), 3.59 (d, J = 2.1 z, 1), 3.17 (d, J = 9.0 z, 1), 2.92 (dd, J = 3.9, 13.8 z, 1), 2.37 (dd, J = 6.3, 12.0 z, 1), 1.22, 1.14, 0.95, 0.93, 0.91, 0.65 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 213.9, 177.1, 143.6, 138.3, 136.2, 128.2, 128.0, 127.8, 127.7, 127.3, 127.2, 121.9, 72.8, 71.1, 69.2, 65.7, 51.2, 48.6, 47.5, 46.9, 46.4, 45.5, 41.6, 41.1, 39.1, 36.8, 33.6, 32.9, 32.1, 31.7, 30.5, 29.5, 27.3, 25.6, 23.4, 23.3, 22.8, 18.4, 17.5, 16.9, 16.2; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn 4N Cl in Me, reflux, 87% Bn Bn Bn To a solution of 12 (1.85 g, 2.84 mmol) in Me (30 ml), was added Cl (1 ml, 12 M). The mixture was stirred at reflux for 20 min, followed by quenching with saturated aqueous NaC 3 solution. The mixture was diluted with brine and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (petroleum ether/etac: 13/1) to give 13 (1.60 g, 87%) as a white foam: [α] 25 D = 76.3 (c 1.24, S6

8 CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.32 (m, 10), 5.30 (s, 1), 5.07 (AB, 2), 4.65 (d, J = 11.7 z, 1), 4.46 (m, 2), 3.42 (d, J = 4.2 z, 1), 3.33 (d, J = 9.3 z, 1), 3.26 (d, J = 9.3 z, 1), 2.92 (dd, J = 2.7, 12.9 z, 1), 2.44 (d, J = 12.0 z, 1), 1.19, 0.93, 0.91, 0.84, 0.57, 0.55 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 212.0, 177.3, 143.8, 138.5, 136.3, 128.3, 128.2, 127.9, 127.8, 127.5, 127.4, 121.7, 72.8, 72.3, 65.9, 52.8, 48.7, 47.3, 46.6, 46.1, 45.7, 43.2, 41.7, 41.3, 39.6, 33.7, 33.0, 32.2, 31.8, 30.6, 27.5, 25.7, 23.5, 23.2, 22.9, 18.0, 16.7, 16.4, 13.2; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn Ac 2, DMAP, pyridine, 95% Bn Ac 13 S5 Bn Bn To a solution of 13 (115 mg, 0.18 mmol) in pyridine (2 ml) under stirring at rt, were added DMAP (4 mg, 0.04 mmol) and Ac 2 (33 μl, 0.35 mmol). After stirring for 19 h, the solution was diluted with EtAc and washed with 1 N aqueous Cl solution and brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give a solid, which was purified by silica gel column chromatography (petroleum ether/etac: 12/1) to give S5 (119 mg, 95%) as a white foam: [α] 26 D = (c 1.24, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.33 (m, 10), 5.43 (s, 1), 5.30 (s, 1), 5.07 (AB, 2), 5.50 (AB, 2), 3.21 (d, J = 9.9 z, 1), 3.01 (d, J = 9.6 z, 1), 2.92 (dd, J = 4.2, 14.1 z, 1), 2.38 (d, J = 12.0 z, 1), 2.05, 1.19, 0.93, 0.92, 0.87, 0.69, 0.57 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 204.9, 177.1, 169.8, 143.6, 138.0, 136.2, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 121.7, 78.6, 72.6, 71.0, 65.7, 53.5, 47.1, 46.7, 46.5, 45.6, 42.5, 41.6, 41.2, 39.5, 33.7, 32.9, 32.1, 31.7, 30.5, 27.4, 25.7, 23.5, 23.2, 22.8, 20.4, 17.9, 16.4, 16.3, 13.9; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn NaB 4,Me/C 2 Cl 2, -10 o C, 95% Bn Ac Ac Bn S5 Bn 14 S7

9 To a solution of S5 (1.51 g, 2.13 mmol) in C 2 Cl 2 /Me (20 ml/20 ml) under stirring at -10 o C, was added NaB 4 (807 mg, mmol). The stirring continued for 30 min, the solution was quenched by addition of saturated aqueous N 4 Cl solution, and then diluted with brine and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 5.2/1) to give 14 (1.44 g, 95%) as a white foam: [α] 24 D = 79.3 (c 1.30, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.33 (m, 10), 5.30 (s-like, 1), 5.10 (d, J = 3.6 z, 1), 5.07 (AB, 2), 4.44 (AB, 2), 4.22 (d, J = 3.6 z, 1), 3.06 (d, J = 9.6 z, 1), 2.91 (br, 1), 2.89 (d, J = 9.6 z, 1), 2.04, 1.25, 1.13, 0.96, 0.92, 0.91, 0.61 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 177.1, 170.0, 143.3, 138.3, 136.0, 128.1, 127.9, 127.7, 127.6, 127.3, 127.1, 122.3, 75.1, 72.5, 72.3, 68.7, 65.6, 47.6, 46.8, 46.4, 45.4, 43.0, 41.5, 41.1, 40.5, 39.0, 36.2, 33.5, 32.9, 32.1, 32.0, 27.2, 25.6, 23.4, 23.2, 22.7, 20.7, 17.2, 16.6, 14.3; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn BnC(N)CCl 3,Tf, dioxane, 0 o C to rt, 100% Bn Bn Ac Ac 14 S6 Bn Bn To a mixture of 14 (142 mg, 0.20 mmol), BnC(N)CCl 3 (150 mg, 0.60 mmol), and 4 Å MS, was added dioxane (2 ml). The mixture was stirred for 1 h at 0 o C, then Tf (6 μl, 0.06mmol) was added dropwise. After stirring for 2 h, the solution was quenched by addition of saturated aqueous NaC 3 solution, and was then diluted with brine and extracted with C 2 Cl 2. The extract was dried over Na 2 S 4, followed by filtration, and concentration in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 19/1) to give S6 (159 mg, 100%) as a white foam: [α] 26 D = 95.8 (c 1.19, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.26 (m, 15), 5.27 (s, 1), 5.03 (AB, 2), 4.99 (d, J = 3.6 z, 1), 4.53 (d, J = 12.3 z, 1), 4.40, (s, 2), 4.34 (d, J = 11.7 z, 1), 3.97 (d, J = 3.6 z, 1), 3.04 (d, J = 9.3 z, 1), 2.94 (d, J = 9.9 z, 1), 2.87 (dd, J = 3.9, 14.1 z, 1), 2.07 (dd, J = 3.0, 14.4 z, 1), 1.92, 1.18, 1.10, 0.94, 0.89, 0.87, 0.58 (s, each 3); 13 C NMR (125 Mz, CDCl 3 ) δ 177.4, 170.6, 143.7, 139.1, 138.6, S8

10 136.3, 128.3, 128.2, 128.1, 127.9, 127.8, 127.5, 127.3, 127.1, 126.9, 122.4, 76.4, 74.9, 72.7, 72.4, 71.7, 65.9, 47.8, 47.1, 46.7, 45.7, 41.8, 41.3, 40.9, 40.0, 39.3, 36.7, 33.8, 33.0, 32.3, 32.2, 30.6, 27.4, 25.9, 23.6, 23.5, 23.0, 21.0, 17.5, 16.9, 16.2, 14.3; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn Bn NaMe, Me/C 2 Cl 2, reflux, 93% Bn Bn Ac Bn S6 Bn S7 NaMe (cat.) was added to a solution of S6 (903 mg, 1.13 mmol) in Me/C 2 Cl 2 (10 ml / 10 ml), and was stirred for 49 h at reflux. The mixture was diluted with C 2 Cl 2, washed by 1 N aqueous Cl solution and brine, and dried over Na 2 S 4. Filtration, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/etac: 13/1) provided S7 (796 mg, 93%) as a white foam: [α] 26 D = 65.3 (c 1.07, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.25 (m, 15), 5.23 (s, 1), 4.99 (AB, 2), 4.68 (d, J = 11.1 z, 1), 4.52 (d, J = 11.7 z, 1), 4.35 (d, J = 12.3 z, 1), 4.22 (d, J = 11.4 z, 1), 4.82 (d, J = 4.2 z, 1), 3.69 (dd, J = 5.1, 10.2 z, 1), 3.34 (d, J = 9.0 z, 1), 3.02 (d, J = 9.6 z, 1), 2.84 (dd, J = 4.2, 12.9 z, 1), 2.60 (d, J = 9.6 z, 1), 2.19 (dd, J = 2.1, 15.0 z, 1), 1.90 (m, 3), 1.11, 1.08, 0.86, 0.84, 0.77, 0.55 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 177.3, 143.7, 138.9, 138.3, 136.3, 128.8, 128.4, 128.3, 128.1, 127.9, 127.8, 127.4, 127.3, 127.2, 127.1, 122.3, 79.2, 73.5, 72.8, 71.6, 71.2, 65.8, 47.8, 46.8, 46.6, 45.7, 41.9, 41.8, 41.3, 39.3, 39.0, 36.5, 33.8, 33.0, 32.3, 32.2, 30.6, 29.6, 27.4, 25.8, 23.6, 23.5, 22.9, 17.5, 16.8, 16.0, 13.6; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn Bn LiI, collidine, reflux, 98% Bn S7 2 Bn Bn LiI (2.24 g, mmol) was added to a solution of S7 (1.26 g, 1.66 mmol) in collidine (17 ml). The mixture was stirred for 11 h at reflux, and was then diluted with S9

11 C 2 Cl 2, washed by 1 N aqueous Cl solution and brine, and dried over Na 2 S 4. Filtration, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/etac: 6/1) gave 2 (1.09 g, 98%) as a white foam: [α] 25 D = 83.1 (c 1.01, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.28 (m, 10 ), 5.29 (s, 1), 4.73 (d, J = 11.4 z, 1), 4.59 (d, J = 12.3 z, 1), 4.41 (d, J = 12.3 z, 1), 4.28 (d, J = 11.4 z, 1), 3.88 (s, 1), 3.76 (d, J = 3.9 z, 1), 3.38 (d, J = 9.3 z, 1), 3.05 (d, J = 9.0 z, 1), 2.83 (dd, J = 2.4, 12.6 z, 1), 2.25 (d, J = 13.8 z, 1), 1.99 (m, 3), 1.19, 1.14, 0.93, 0.91, 0.76, 0.74 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 184.4, 143.7, 138.9, 138.3, 128.3, 128.1, 127.4, 127.3, 127.2, 122.4, 79.2, 73.5, 72.8, 71.7, 71.3, 47.8, 46.8, 46.4, 45.7, 41.8, 41.6, 40.8, 39.2, 38.9, 36.6, 33.7, 33.0, 32.4, 32.0, 30.6, 27.5, 26.0, 23.5, 23.5, 22.7, 17.4, 17.2, 16.0, 13.5; RMS (MALDI) m/z calcd for C Na [M+Na] +, found L-Arabinose Bn Bn 7 steps, 46%, ref 1 TMSBr, C 2 Cl 2,rt Bn Ac Bn Ac Ac Br S8 3 TMSBr (0.38 ml, 2.80 mmol) was added to a stirred solution of S8 1 (465 mg, 1.12 mmol) in C 2 Cl 2 (12 ml) at 0 o C. After stirring for 10 h at rt, the solution was evaporated in vacuo to give a light-yellow syrup, which was diluted with EtAc and evaporated (for 3 times to remove the remaining TMSBr). The crude product 3 was used for the next step without further purification. D-Galactose 6 steps, 45% Bn Bn TBDPS PhI(Bz) 2,BF 3 Et 2, Bn TBDPS -45to-25 o C,79% Bn Bz Bz S9 S10 BF 3 Et 2 (0.12 ml, 0.92 mmol) was added to a solution of S9 2 (2.59 g, 4.58 mmol) and PhI(Bz) 2 (2.45 g, 5.49 mmol) in C 2 Cl 2 at -45 o C. After stirring for 30 min, the mixture was warmed up to -25 o C and stirred for 30 min. The solution was cooled to -45 o C and Et 3 N (3.2 ml, mmol) was added. The solution was diluted with C 2 Cl 2, washed by brine, and dried over Na 2 S 4. Filtration, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/etac: 11/1) gave S10 (2.92 g, 79%) as a white foam: [α] 24 D = (c 1.28, CCl 3 ); 1 NMR (300 Mz, S10

12 CDCl 3 ) δ 7.96 (m, 4), 7.44 (m, 26), 5.93 (m, 2), 5.06 (d, J = 11.4 z, 1), 4.65 (m, 3), 4.15 (d, J = 1.8 z, 1), 3.82 (m, 4), 1.07 (s, 9); 13 C NMR (75 Mz, CDCl 3 ) δ 165.2, 165.0, 138.3, 137.5, 135.5, 133.4, 133.1, 133.0, 130.1, 129.8, 129.7, 129.6, 128.7, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.5, 93.2, 79.7, 75.9, 74.8, 72.7, 72.2, 70.9, 61.7, 26.9, 19.2; RMS (MALDI) m/z calcd for C SiNa [M+Na] +, found Bn Bn TBDPS Bz S10 Bz 1) N 2 4 2,Ac,DMF,rt; 2) CCl 3 CN, DBU, C 2 Cl 2,rt,50% Bn Bn TBDPS Bz N To a solution of S10 (6.42 g, 7.96 mmol) in DMF (75 ml) under stirring at 0 o C, were added N (2.80 ml, mmol) and Ac (2.80 ml, mmol). After stirring for 10 h at rt, the solution was diluted with EtAc and washed with water and brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give a residue, which was purified by silica gel column chromatography (petroleum ether/etac: 9/1 to 6/1) to give a white foam. The foam was dissolved in C 2 Cl 2 (60 ml), Cl 3 CCN (2.80 ml, mmol) and DBU (0.1 ml, 0.56 mmol) were added. After stirring for 2 h at rt, the solution was evaporated in vacuo to give a residue, which was purified by silica gel column chromatography (petroleum ether/etac: 9/1) to give 5 (3.18 g, 50%) as a white foam: [α] 23 D = 68.4 (c 0.96, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 8.39 (s, 1), 7.98 (d, J = 7.8 z, 2), 7.59 (m, 5), 7.30 (m, 18), 6.60 (d, J = 3.6 z, 1), 5.80 (dd, J = 3.6, 11.1 z, 1), 5.04 (d, J = 11.4 z, 1), 4.72 (m, 3), 4.19 (m, 2), 4.07 (t, J = 6.6 z, 1), 3.87 (t, J = 7.2 z, 1), 3.78 (m, 1), 1.05 (s, 9); 13 C NMR (100 Mz, CDCl 3 ) δ 165.5, 160.4, 138.3, 137.8, 135.5, 133.2, 133.1, 129.7, 129.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 94.5, 76.0, 75.0, 73.9, 73.8, 72.5, 70.2, 62.1, 26.9, 19.2; RMS (MALDI) m/z calcd for C N 7 SiCl 3 Na [M+Na] +, found CCl 3 S11

13 Bz SPh S11 1) i) Bu 2 Sn, toluene, reflux, ii) PMBCl, TBAI, 80 o C; 2)BnBr,Na,TF,0 o Ctort PMB SPh Bn 1) BzCl, Et 3 N, DMAP, C 2 Cl 2, 0 o Ctort; 2) DDQ, C 2 Cl 2 / 2, rt 63% from S11 Bz SPh Bn S12 A mixture of S11 3 (293 mg, 0.81 mmol), Bu 2 Sn (325 mg, 1.30 mmol) in toluene (8 ml) was stirred under reflux, using a Deaan-Stark trap, for 9.5 h. The solution was cooled to ca. 80 o C, and then treated with PMBCl (0.56 ml, 4.14 mmol) and n Bu 4 NI (481 mg, 1.30 mmol). After stirring for 12 h at 80 o C, the mixture was concentrated. The residue was stirred with EtAc (100 ml) at 0 o C for 2 h. The solids were removed by filtration and the filtrate was concentrated. Purification of the residue by silica gel column chromatography (petroleum ether/etac: 4/1) gave a colorless syrup. The syrup was dissolved in TF (10 ml) at 0 o C, followed by addition of Na (82 mg, 60%). After the solution was stirred for 30 min at 0 o C, BnBr (0.24 ml, 2.03 mmol) was added. The stirring continued for 17 h at rt, the solution was then diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give a syrup, which was purified by silica gel column chromatography (petroleum ether/etac: 9/2) to give a colorless syrup. The product above was dissolved in C 2 Cl 2 (5 ml) at 0 o C, followed by addition of DMAP (12 mg, 0.10 mmol), Et 3 N (0.41 ml, 2.87 mmol), and BzCl (0.17 ml, 1.43 mmol). After stirring for 9 h at rt, the solution was diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give a syrupy, which was purified by silica gel column chromatography (petroleum ether/etac: 19/2) to give a colorless syrup. This syrup was dissolved in C 2 Cl 2 / 2 (6.0 ml/0.36 ml) at rt, and DDQ (358 mg, 1.58 mmol) was added. After stirring for 2 h, the reaction was quenched by addition of saturated aqueous NaC 3 solution. The resulting mixture was diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 19/2) to give S12 (230 mg, 63%) as a colorless syrupy: [α] 25 D = (c 0.78, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 8.08 (d, J = 7.2 z, 2), 7.58 (t, J = 7.2 z, 1), 7.47 (m, 4), 7.31 (m, 8), 5.61 (s, 1), 5.22 (t, J = 9.9 z, 1), 4.78 (d, J = 11.1 z, 1), 4.58 (d, J = 12.0 z, 1), 4.40 (m, S12

14 1), 4.07 (d, J = 2.4 z, 1), 4.02 (br, 1), 2.50 (d, J = 8.7 z, 1), 1.28 (d, J = 6.6 z, 3); 13 C NMR (75 Mz, CDCl 3 ) δ 166.6, 137.2, 134.1, 133.2, 131.5, 129.8, 129.1, 128.6, 128.4, 128.1, 128.0, 127.5, 85.1, 79.9, 75.6, 72.6, 70.4, 67.5, 17.4; RMS (MALDI) m/z calcd for C SNa [M+Na] +, found Bz SPh Bn 91% S12 4, TMSTf,4AMS, C 2 Cl 2,-60to-20 o C Bn Bn Bn Bz CA S13 Bn To a mixture of S12 (208 mg, 0.46 mmol), 4 (403 mg, 0.60 mmol), and 4 Å MS, was added dry C 2 Cl 2 (6 ml). The mixture was stirred for 30 min at -60 o C to -20 o C, then TMSTf (0.47 ml, 0.1 M) was added dropwise. After 2.5 h, the reaction was quenched by addition of Et 3 N, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (toluene/c 2 Cl 2 : 1/2) to provide S13 (405 mg, 91%) as a colorless syrup: [α] 24 D = (c 0.99, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 8.05 (d, J = 7.2 z, 2), 7.64 (t, J = 7.2 z, 1), 7.54 (t, J = 7.5 z, 2), 7.25 (m, 25), 5.50 (s, 1), 5.49 (t, J = 9.6 z, 1), 4.99 (t, J = 8.7 z, 1), 4.62 (m, 9), 4.31 (m, 1), 4.18 (m, 2), 3.86 (d, J = 14.7 z, 1), 3.75 (d, J = 11.1 z, 1), 3.62 (m, 2), 3.41 (m, 3), 1.22 (d, J = 6.3 z, 3); 13 C NMR (75 Mz, CDCl 3 ) δ 166.0, 165.3, 138.0, 127.9, 137.7, 137.6, 134.1, 133.4, 130.9, 129.5, 129.0, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.4, 127.2, 101.1, 86.5, 82.3, 79.2, 77.9, 77.4, 75.3, 75.0, 74.2, 74.0, 73.5, 73.4, 68.7, 67.8, 40.2, 17.2; RMS (MALDI) m/z calcd for C SClNa [M+Na] +, found SPh Bn Bn Bn Bz CA S13 SPh Bn DABC, Et, 55 o C 86% Bn Bn Bn To a solution of S13 (52 mg, 0.05 mmol) in Et (2.7 ml), was added DABC (93 mg, 0.81 mmol). The solution was stirred at 55 o C for 9 h, and was then diluted with C 2 Cl 2, and washed with 1 N aqueous Cl solution and brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give a syrup, which was purified by silica gel column chromatography (petroleum ether/etac: 8/1) to give S14 (41 mg, Bz S14 SPh Bn S13

15 86%) as a colorless syrup: [α] 24 D = (c 1.22, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 8.06 (d, J = 7.2 z, 2), 7.60 (t, J = 7.2 z, 1), 7.47 (t, J = 7.5 z, 2), 7.32 (m, 23), 7.17 (m, 2), 5.50 (t, J = 7.5 z, 1), 5.47 (s, 1), 4.83 (t, J = 10.5 z, 3), 4.71 (d, J = 11.7 z, 1), 4.65 (d, J = 11.1 z, 1), 4.53 (s, 2), 4.51 (d, J = 8.4 z, 1), 4.42 (m, 1), 4.32 (d, J = 7.8 z, 1), 4.25 (d, J = 1.5 z, 1), 4.15 (dd, J = 3.6, 9.9 z, 1), 3.73 (d, J = 7.5 z, 1), 3.62 (dd, J = 4.2, 11.1 z, 1), 3.46 (m, 4), 1.28 (d, J = 6.6 z, 3); 13 C NMR (75 Mz, CDCl 3 ) δ 166.3, 138.6, 138.1, 134.1, 133.1, 130.9, 129.6, 128.9, 128.4, 128.2, 127.8, 127.6, 127.4, 127.2, 104.3, 86.3, 83.7, 79.4, 78.6, 77.1, 75.0, 74.9, 74.8, 74.7, 73.8, 73.4, 73.3, 69.2, 67.7, 17.4; RMS (MALDI) m/z calcd for C S [M+] +, found Bn Bn Bn Bz SPh SPh (1) BnBr, Na, TF, 0 o Ctort; (2)PMBCl,Na,TBAI,DMF,rt PMB Bn Bn 78% Bn Bn Bn S14 Bn 6 Compound S14 (30 mg, 0.03 mmol) was dissolved in TF (2 ml) at 0 o C, followed by addition of Na (3 mg, 60%). After stirring at 0 o C for 30 min, BnBr (0.01 ml, 0.07 mmol) was added. After stirred for 24 h at rt, the mixture was diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 7/1) to give a colorless syrup (23 mg). The syrup was dissolved in DMF (2 ml) at 0 o C, followed by addition of Na (2 mg, 60%). After stirring for 30 min at 0 o C, PMBCl (8 μl, 0.05 mmol) and Bu 4 NI (19 mg, 0.05 mmol) were added. After stirring for 7 h at rt, the solution was diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 15/1) to give 6 (26 mg, 78%) as a colorless syrup: [α] 27 D = (c 1.22, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.41 (d, J = 7.5 z, 2), 7.30 (m, 30), 6.79 (d, J = 8.4 z, 2), 5.45 (s, 1), 5.08 (d, J = 11.4 z, 1), 4.98 (d, J = 11.1 z, 1), 4.80 (m, 7), 4.59 (m, 3), 4.38 (d, J = 9.9 z, 1), 4.17 (m, 3), 3.78 (s, 3), 3.69 (m, 5), 3.47 (m, 2), 1.33 (d, J = 6.0 z, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 158.9, 138.3, 138.2, 138.1, 138.0, 137.9, 135.3, 134.5, 130.8, S14

16 130.1, 129.4, 128.7, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 127.3, 127.2, 126.8, 113.5, 103.4, 86.1, 84.4, 82.4, 80.7, 80.3, 77.8, 75.4, 74.8, 74.7, 74.3, 73.3, 72.9, 69.1, 68.6, 54.9, 17.6; RMS (ESI) m/z calcd for C SNa [M+Na] +, found BnBr,Na,DMF,rt,80% Bn S15 S16 Compound S15 4 (230 mg, 1.82 mmol) was dissolved in DMF (2 ml) at 0 o C, followed by addition of Na (365 mg, 60%). After the solution was stirred for 30 min at 0 o C, BnBr (1.08 ml, 9.10 mmol) was added. After stirring for 3 h at rt, the solution was diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give an oil, which was purified by silica gel column chromatography (petroleum ether/etac: 50/1) to give a colorless oil S16 (315 mg, 80%). 1 NMR (300 Mz, CDCl 3 ) δ (m, 5), (m, 2), (m, 4), 4.47 (s, 2), (m, 4), 1.22 (s, 3); 13 C NMR (75 Mz, CDCl 3 ) δ 139.5, 134.3, 128.2, 127.3, 127.1, 117.5, 76.6, 63.4, 42.7, S16 Bn 1) i) 3,Me,-78 o C, ii) 2 2 (30%), C 3 C, reflux 2) Ac 2, rt; 3) PMB, Py, 30% (three steps) C Bn CPMB Diene S16 (200 mg, 0.93 mmol) was dissolved in Me (5 ml) and cooled to -78 o C. zone was passed through the solution until a permanent blue color persisted. The solution was then allowed to warm up to room temperature and the solvent was removed under reduced pressure to yield a colorless oil. This oil was dissolved in acetic acid/hydrogen peroxide (30%) (14 ml, v/v 3:4) and heated under reflux for 6 h. Removal of the solvent under reduced pressure gave an oil. Acetic anhydride (5 ml) was added to the oil and the mixture was stirred at rt for 24 h. The solvent was removed under reduced pressure. This crude product was dissolved in pyridine (3 ml), and PMB (200 mg, 1.45 mmol) was added. The mixture was stirred at rt for 24 h. Evaporation of the solvent in vacuo and purification of the residue by silica gel column chromatography (C 2 Cl 2 /Me: 20/1) gave a colorless oil 7 (104 mg, 30% for three steps). 1 NMR 7 S15

17 (300 Mz, CDCl 3 ) δ (m, 7), 6.85 (d, J = 11.7 z, 2), 5.07 (s, 2), (AB, 2), 3.80 (s, 3), (m, 4), 1.52 (s, 3). Bn Bn Bn + Bn Ac Br 2 3 TBAB, K 2 C 3, EtAc/ 2, 50 o C 80% Bn Bn 15 Bn Bn Ac To a solution of the bromide 3 and triterpene 2 (150 mg, 0.22 mmol) in EtAc/ 2 (4 ml/4 ml), were added K 2 C 3 (93 mg, 0.67 mmol) and Bu 4 NBr (146 mg, 0.45 mmol). The mixture was stirred at 40 o C for 12 h, and was then diluted with EtAc, and washed with 1 N aqueous Cl solution and brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo to give a yellow solid, which was purified by silica gel column chromatography (toluene/etac: 45/1) to give 15 (184 mg, 80% based on 2) as a white foam: [α] 27 D = 38.1 (c 1.11, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.32 (m, 20), 5.64 (d, J = 4.5 z, 1), 5.33 (brs, 1), 5.26 (t, J = 4.8 z, 1), 4.74 (d, J = 11.4 z, 1), 4.66 (s, 2), 4.59 (m, 3), 4.42 (d, J = 12.3 z, 1), 4.29 (d, J = 11.4 z, 1), 4.10 (dd, J = 6.6, 12.0 z, 1), 3.89 (br, 1), 3.72 (m, 3), 3.52 (dd, J = 3.0, 11.7 z, 1), 3.42 (d, J = 9.3 z, 1), 3.10 (d, J = 8.7 z, 1), 2.87 (d, J = 10.5 z, 1), 2.67 (br, 1), 2.27 (d, J = 14.1 z, 1), 2.03, 1.20, 1.14, 0.89, 0.88, 0.85, 0.76 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 175.8, 169.2, 143.3, 138.9, 138.3, 137.8, 137.7, 128.3, 128.1, 127.7, 127.6, 127.4, 127.3, 127.2, 122.5, 91.1, 79.2, 74.9, 73.5, 72.7, 71.8, 71.6, 71.3, 71.2, 69.0, 61.3, 47.8, 46.8, 46.7, 45.6, 41.9, 41.8, 41.0, 39.2, 39.0, 36.5, 33.7, 33.0, 32.4, 31.9, 30.5, 27.6, 25.6, 23.5, 23.4, 22.5, 20.9, 17.5, 16.9, 16.0, 13.6; RMS (ESI) m/z calcd for C Na [M+Na] +, found S16

18 in dry C 2 Cl 2 (10 ml) at -40 o C to -20 o C, 40 min later, TMSTf (0.49 ml, 0.1 M) was added dropwise. After stirring for 2 h, the reaction was quenched by addition of Et 3 N. The mixture was filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (toluene/etac: 60/1) to give 16 (1.43 g, 96%) as a white foam: [α] 22 D = 23.1 (c 0.99, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.31 (m, 35), 5.62 (d, J = 4.5 z, 1), 5.32 (brs, 1), 5.26 (t, J = 5.4 z, 1), 5.05 (t, J = 8.1 z, 1), 4.70 (m, 14 ), 4.34 (d, J = 7.8 z, 1), 4.09 (m, 2), 3.68 (m, 9), 3.51 (dd, J = 2.4, 11.4 z, 1), 3.41 (m, 1), 3.14 (d, J = 9.3 z, 1), 3.01 (d, J = 9.0 z, 1), 2.86 (d, J = 10.8 z, 1), 2.03, 1.21, 1.11, 0.89, 0.87, 0.84, 0.74 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 175.8, 169.2, 165.5, 143.2, 140.1, 138.5, 138.1, 138.0, 137.8, 137.7, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 127.4, 127.3, 127.1, 126.6, 122.7, 101.9, 91.2, 82.6, 81.7, 79.5, 78.1, 75.3, 75.1, 74.9, 74.6, 73.2, 73.1, 72.8, 71.8, 71.3, 71.2, 69.0, 68.7, 61.4, 47.9, 47.4, 46.7, 45.6, 42.2, 42.0, 41.7, 40.9, 40.5, 39.2, 36.5, 33.6, 33.0, 32.5, 31.9, 30.5, 27.6, 25.7, 23.4, 22.5, 20.8, 17.4, 16.9, 16.2, 13.6; RMS (ESI) m/z calcd for C Cl [M+] +, found Bn DABC, Et, 50 o C, 100% Bn Bn Bn Bn CA Bn 16 Bn Bn Ac Bn Bn Bn Bn Bn Bn 17 Ac To a solution of 16 (135 mg, 0.09 mmol) in Et (4.4 ml), was added DABC (148 mg, 1.32 mmol). The solution was stirred at 50 o C for 32 h, then evaporated in vacuo to give a residue, which was purified by silica gel column chromatography (toluene/etac: 25/1) to give 17 (128 mg, 100%) as a white foam: [α] 22 D = 26.6 (c 0.98, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.30 (m, 35), 5.63 (d, J = 4.2 z, 1), 5.33 (brs, 1), 5.26 (t, J = 5.4 z, 1), 5.00 (d, J = 11.4 z, 1), 4.85 (m, 2), 5.54 (m, 11), 4.29 (d, J = 6.6 z, 1), 4.10 (m, 2), 3.66 (m, 9), 3.41 (m, 2), 3.15 (d, J = 9.3 z, 1), 2.86 (d, J = 9.9 z, 1), 2.71 (m, 1), 2.04 (s, 3), 1.25, 1.12, 0.98, 0.89, 0.88, 0.75 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 175.8, 169.2, 143.2, 139.6, 138.7, 138.4, 138.1, 138.0, 137.7, 137.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, S17

19 CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.30 (m, 35), 5.63 (d, J = 4.2 z, 1), 5.33 (brs, 1), 5.26 (t, J = 5.4 z, 1), 5.00 (d, J = 11.4 z, 1), 4.85 (m, 2), 5.54 (m, 11), 4.29 (d, J = 6.6 z, 1), 4.10 (m, 2), 3.66 (m, 9), 3.41 (m, 2), 3.15 (d, J = 9.3 z, 1), 2.86 (d, J = 9.9 z, 1), 2.71 (m, 1), 2.04 (s, 3), 1.25, 1.12, 0.98, 0.89, 0.88, 0.75 (s, each 3); 13 C NMR (75 Mz, CDCl 3 ) δ 175.8, 169.2, 143.2, 139.6, 138.7, 138.4, 138.1, 138.0, 137.7, 137.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, 127.3, 127.1, 126.8, 122.6, 104.4, 91.1, 84.5, 81.9, 79.1, 75.4, 75.0, 74.9, 74.8, 73.2, 72.6, 72.5, 71.7, 71.3, 71.1, 69.0, 61.4, 47.8, 47.6, 46.7, 45.6, 42.0, 41.7, 40.9, 39.2, 36.5, 33.6, 32.9, 32.4, 31.8, 30.5, 27.5, 25.6, 23.4, 22.5, 20.8, 17.4, 17.0, 16.2, 13.9; RMS (MALDI) m/z calcd for C Na [M+Na] +, found Bn Bn Bn Bn Bn 17 Bn Bn Ac TMSTf, C 2 Cl 2, -40to-20 o C, 65% TBDPS Bn Bn N CCl 3 Bn Bn Bn TBDPS Bn To a mixture of 17 (316 mg, 0.22 mmol), 5 (368 mg, 0.43 mmol), and 4 Å MS, was added dry C 2 Cl 2 (6 ml). The mixture was stirred for 30 min at -40 o C to -20 o C, then TMSTf (0.22 ml, 0.1 M) was added dropwise, followed by addition of 5 (368 mg, 0.43 mmol) in C 2 Cl 2 (2 ml) 30 min later, and another potion of 5 (184 mg, 0.22 mmol) in C 2 Cl 2 (1 ml) after 1 h. The stirring continued for 2.5 h, the reaction was then quenched by addition of Et 3 N. The mixture was filtrated. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/etac: 9/1) to give 18 (300 mg, 65%) as a white foam: [α] 23 D = 24.1 (c 1.04, CCl 3 ); 1 NMR (500 Mz, CDCl 3 ) δ 7.88 (d, J = 7.4 z, 2), 7.32 (m, 53), 7.05 (m, 2), 6.94 (m, 3), 5.79 (t, J = 9.0 z, 1), 5.67 (d, J = 4.4 z, 1), 5.31 (brs, 1), 5.27 (t, J = 5.2 z, 1), 5.04 (m, 2), 4.60 (m, 13), 4.39 (m, 5), 4.22 (d, J = 7.6 z, 1), 4.18 (d, J = 2.0 z, 1), 4.12 (m, 1), 4.02 (d, J = 4.2 z, 1), 3.93 (t, J = 9.0 z, 1), 3.74 (m, 4), 3.64 (m, 2), 3.59 (d, J = 3.5 z, 1), 3.54 (m, 3), 3.49 (m, 1), 3.41 (m, 2), 3.21 (m, 1), 2.86 (dd, J = 3.6, 13.4 z, 1), 2.76 (d, J = 9.5 z, 1), 2.08, 1.15, 1.12 (s, each 3), 1.05 (s, 5 Bz Bn Bn Bz Bn 18 Bn Bn Ac S18

20 9), 0.88, 0.87, 0.77, 0.60 (s, each 3); 13 C NMR (125 Mz, CDCl 3 ) δ 175.9, 169.2, 164.9, 143.3, 140.7, 140.4, 138.8, 138.7, 138.3, 138.0, 137.9, 137.8, 135.5, 135.4, 133.3, 132.8, 132.7, 130.1, 129.7, 128.3, 128.2, 128.1, 129.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1, 127.0, 126.7, 126.3, 122.9, 103.8, 100.6, 91.2, 85.6, 83.5, 80.0, 79.9, 78.4, 77.7, 75.0, 74.5, 74.1, 74.0, 73.2, 73.0, 72.7, 72.5, 72.0, 71.7, 71.6, 71.5, 71.3, 69.2, 69.1, 61.2, 61.1, 48.0, 47.6, 46.9, 45.7, 42.5, 42.2, 41.8, 41.1, 39.4, 36.5, 33.8, 33.0, 32.6, 32.0, 30.6, 29.6, 27.7, 26.9, 25.7, 23.6, 23.5, 22.6, 20.9, 19.1, 17.4, 17.1, 16.2, 13.0; RMS (MALDI) m/z calcd for C SiNa [M+Na] +, found Bn Bn Bn TBDPS Bn Bn Bn Bz 18 Bn Bn Ac DBU, Me, C 2 Cl 2,97% Bn Bn Bn TBDPS Bn Bn Bn Bz 19 Bn Bn Bn Bn DBU (0.08 ml, 0.50 mmol) was added to a solution of 18 (154 mg, 0.07 mmol) in Me/C 2 Cl 2 (0.5 ml/1.5 ml) at rt. After stirring for 1 h, the solution was diluted with C 2 Cl 2 and washed with 1 N aqueous Cl solution and brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 5/1 to 4/1) to give 19 (147 mg, 97%) as a white foam: [α] 23 D = 44.0 (c 1.05, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.88 (d, J = 7.2 z, 2), 7.33 (m, 55), 6.91 (m, 3), 5.80 (dd, J = 7.8, 9.9 z, 1), 5.51 (d, J = 6.9 z, 1), 5.32 (brs, 1), 5.05 (m, 2), 4.56 (m, 18), 4.25 (d, J = 8.1 z, 1), 4.19 (s, 1), 4.06 (m, 1), 4.01 (d, J = 2.7 z, 1), 3.92 (t, J = 9.6 z, 1), 3.62 (m, 14), 3.20 (m, 1), 2.88 (d, J = 9.0 z, 1), 2.75 (d, J = 9.0 z, 1), 2.50 (brs, 1), 1.14 (s, 6), 1.05 (s, 9), 0.90 (s, 6), 0.78, 0.57 (s, each 3); 13 C NMR (100 Mz, CDCl 3 ) δ 176.3, 164.9, 143.4, 140.7, 140.4, 138.8, 138.7, 138.3, 138.1, 138.0, 137.9, 137.8, 135.5, 135.4, 133.3, 132.8, 132.7, 130.2, 129.7, 129.6, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 127.1, 126.7, 126.3, 122.9, 103.8, 100.6, 94.2, 85.6, 83.5, 80.1, 79.9, 79.8, 78.4, 77.8, 75.0, 74.6, 74.1, 74.0, 73.3, 73.0, 72.9, 72.7, 72.5, 72.0, S19

21 71.7, 71.6, 71.4, 69.6, 69.1, 63.3, 61.2, 48.0, 47.6, 46.9, 45.8, 42.6, 42.3, 41.9, 41.2, 39.4, 36.5, 33.9, 33.0, 32.5, 32.1, 30.6, 29.6, 27.6, 27.0, 25.7, 23.7, 23.5, 22.8, 19.1, 17.4, 17.2, 16.2, 13.0; RMS (MALDI) m/z calcd for C Si 20 Na [M+Na] +, found Bn Bn Bn TBDPS Bn Bn Bn Bz Bn 19 Bn Bn 6, NIS, TMSTf,C 2 Cl 2, -40 to -20 o C, 81% Bn Bn Bn TBDPS Bn Bn Bn Bz Bn 20 PMB Bn Bn Bn Bn To a mixture of 19 (90 mg, 0.04 mmol), 6 (127 mg, 0.13 mmol), and 4 Å MS in dry C 2 Cl 2 (2 ml) at -40 o C to -20 o C, was added NIS (29 mg, 0.13 mmol). After stirring for 30 min, TMSTf (0.04 ml, 0.05 M) was added, and the stirring continued at this temperature for 6.5 h. The reaction was quenched by addition of Et 3 N. The mixture was filtered. The filtrate was diluted with C 2 Cl 2 and washed with 10% aqueous Na 2 S 2 3 solution and brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac: 6.5/1) to give 20 (103 mg, 81%) as a white foam: [α] 23 D = 8.3 (c 1.10, CCl 3 ); 1 NMR (500 Mz, CDCl 3 ) δ 7.88 (d, J = 4.2 z, 2), 7.55 (d, J = 6.7 z, 2), 7.46 (m, 5), 7.24 (m, 73), 7.05 (m, 2), 6.94 (m, 3), 6.76 (d, J = 8.6 z, 2), 5.91 (s, 1), 5.79 (dd, J = 7.9, 10.0 z, 1), 5.28 (s, 1), 5.05 (m, 3), 4.96 (d, J = 11.0 z, 1), 4.84 (m, 5), 4.62 (m, 15), 4.39 (m, 9), 4.22 (d, J = 7.6 z, 1), 4.18 (m, 2), 4.03 (m, 2), 3.93 (t, J = 9.0 z, 1), 3.82 (dd, J = 1.8, 14.4 z, 2), 3.75 (t, J = 8.6 z, 2), 3.68 (s, 3), 3.67 (m, 12), 3.44 (m, 8), 3.21 (m, 1), 2.86 (dd, J = 3.3, 13.8 z, 1), 2.75 (d, J = 9.5 z, 1), 1.36 (d, J = 6.3 z, 3), 1.16, 1.10 (s, each 3), 1.05 (s, 9), 0.86, 0.84, 0.77, 0.60 (s, each 3); 13 C NMR (100 Mz, CDCl 3 ) δ 175.7, 164.9, 159.1, 143.5, 140.7, 140.5, 138.7, 138.6, 138.5, 138.4, 138.3, 138.2, 138.1, 138.0, 137.8, 135.5, 135.4, 133.3, 132.8, 132.7, 130.4, 130.2, 129.7, 129.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 127.1, 126.8, 126.3, 122.8, 113.7, 103.9, 103.3, Bn Bn Bn S20

22 100.6, 98.5, 91.3, 85.7, 84.7, 83.6, 82.9, 80.9, 80.1, 80.0, 78.5, 78.1, 77.9, 77.8, 76.8, 75.6, 75.0, 74.9, 74.8, 74.6, 74.3, 74.1, 74.0, 73.7, 73.3, 73.2, 73.1, 72.7, 72.6, 72.5, 71.7, 71.6, 71.4, 69.2, 68.8, 61.2, 58.7, 55.1, 48.0, 47.6, 46.9, 45.7, 42.6, 42.3, 41.8, 41.2, 39.5, 36.5, 33.8, 33.1, 32.6, 32.2, 31.9, 31.4, 30.6, 30.2, 29.7, 29.3, 29.1, 27.7, 27.0, 25.9, 23.6, 23.5, 22.7, 22.6, 19.1, 17.9, 17.5, 17.3, 16.3, 14.1, 13.1; RMS (MALDI) m/z calcd for C Si 30 Na [M+Na] +, found Bn Bn Bn TBDPS Bn Bn Bn Bn Bn Bn Bz PMB Bn 20 Bn Bn Bn Bn 1) NaMe, Me/C 2 Cl 2,reflux 2)BnBr,Na,TF,0 o Ctort,51% Bn Bn Bn TBDPS Bn Bn Bn Bn 21 Bn PMB Bn Bn Bn Bn To a solution of 20 (80 mg, 0.03 mmol) in C 2 Cl 2 /Me (2 ml/2 ml) was added a solution of NaMe in Me (0.2 M, 0.54 ml). The mixture was stirred for 3 d at reflux. After cooling to rt, the mixture was neutralized with Dowex-50 ( + ). Filtration, concentration in vacuo, and purification by silica gel column chromatography (toluene/etac: 40/1 to 30/1) provided a white foam (47 mg, 61%) and 20 (15 mg, 19%). The white foam was dissolved in TF (1.5 ml) at 0 o C, followed by addition of Na (8 mg, 60%) and BnBr (0.05 ml, 0.42 mmol). After stirring for 24 h at rt, the solution was diluted with C 2 Cl 2 and washed with brine. The organic layer was dried over Na 2 S 4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (toluene/etac: 40/1) to give 21 (39 mg, 51% based on 20) as a white foam: [α] 25 D = 6.9 (c 0.94 CCl 3 ); 1 NMR (300 Mz, CDCl 3 ) δ 7.25 (m, 84), 6.95 (m, 3), 6.76 (d, J = 11.7 z, 2), 5.91 (s, 1), 5.29 (brs, 1), 4.65 (m, 35), 4.17 (m, 2), 4.04 (m, 3), 3.66 (s, 3), 3.62 (m, 26), 2.84 (d, J = 13.5 z, 1), 2.73 (d, J = 8.4 z, 1), 1.37 (d, J = 5.7 z, 3), 1.17, 1.07 (s, each 3), 1.01 (s, 9), 0.86, 0.84, 0.77, 0.64 (s, each 3); 13 C NMR (100 Mz, CDCl 3 ) δ 175.8, 159.2, 143.6, 140.7, 139.7, 139.3, 139.1, 138.8, 138.7, 138.5, 138.4, 138.3, 138.2, 138.1, 135.6, 135.5, 133.3, 132.9, 130.5, 129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, Bn Bn Bn S21

23 127.5, 127.4, 127.3, 127.2, 127.0, 126.5, 123.0, 113.8, 104.3, 103.5, 102.6, 98.6, 91.4, 86.3, 84.8, 83.5, 83.0, 82.6, 81.1, 81.0, 79.9, 78.6, 78.5, 78.1, 75.8, 75.6, 75.5, 75.1, 74.9, 74.8, 74.4, 74.3, 73.9, 73.8, 73.6, 73.4, 73.1, 72.7, 72.6, 72.3, 71.5, 69.4, 68.9, 68.8, 61.4, 58.9, 55.3, 48.2, 47.7, 47.0, 45.8, 42.5, 41.9, 41.3, 39.6, 36.7, 33.9, 33.2, 32.7, 32.3, 30.8, 29.8, 27.8, 27.1, 26.0, 23.8, 23.7, 22.7, 19.2, 18.0, 17.7, 17.4, 16.4, 13.3; RMS (MALDI) m/z calcd for C SiNa [M+Na] +, found Bn Bn Bn TBDPS Bn Bn Bn Bn Bn Bn Bn Bn Bn TBAF, TF, rt, 98% Bn Bn Bn Bn Bn PMB Bn Bn PMB Bn Bn Bn Bn Bn Bn Bn 21 Bn Bn Bn S17 Bn To a solution of 21 (150 mg, 0.05 mmol) in TF (3 ml) at rt was added Bu 4 NF (1.0 M in TF, 0.3 ml, 0.3 mmol). The solution was stirred at this temperature for 2 h, and was then diluted with C 2 Cl 2, and washed with water. The organic layer was separated and the aqueous layer was extracted with C 2 Cl 2. The combined organic layer was washed with brine, dried over Na 2 S 4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/etac, 3:1) to afford S17 (133 mg, 98%) as a white foam. [α] 27 D = 15.1 (c 1.00, CCl 3 ); 1 NMR (300 Mz, CDCl 3 ): δ (m, 77 ), 6.76 (d, J = 8.7 z, 2 ), 5.88 (br s, 1 ), 5.30 ( br s, 1), (m, 38), (m, 2), 4.03 (t, J = 10.4 z, 1), (m, 34), (m, 2), 1.32 (d, J = 6.6 z, 3), 1.24 (s, 3), 1.09 (s, 3), 0.93 (s, 3), 0.87 (s, 3), 0.85 (s, 3), 0.77 (s, 3); 13 C NMR (75 Mz, CDCl 3 ): δ 175.6, 159.0, 143.4, 139.9, 139.3, 138.7, 138.6, 138.5, 138.3, 138.2, 138.1, 138.0, 137.9, 130.4, 129.3, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6, 127.5, 127.5, 127.4, 127.3, 127.2, 127.2, 126.8, 122.7, 113.6, 104.1, 103.3, 102.7, 98.4, 91.4, 86.2, 84.6, 83.3, 82.8, 82.2, 80.8, 80.7, 79.6, 78.4, 78.3, 78.0, 75.6, 75.5, 75.1, 75.0, 74.9, 74.8, 74.3, 73.6, 73.3, 73.3, 72.8, 72.5, 72.3, 71.3, 69.3, 68.7, 62.1, 58.8, 55.1, 47.9, 47.5, 46.8, 45.7, 42.4, S22

24 41.8, 41.1, 39.4, 36.5, 33.7, 33.0, 32.5, 32.1, 30.6, 29.6, 27.6, 25.8, 23.5, 22.5, 17.9, 17.5, 17.2, 16.2, 13.5; RMS (MALDI) calcd for C Na [M+Na] + : , found Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn PMB Bn Bn Bn S17 Bn Bn 7, C 6 2 Cl 3 CCl, Et 3 N, toluene, 2 h; then DMAP, 2 h, 96% PMB Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn PMB Bn Bn Bn 22 Bn Bn To a solution of 7 (36 mg, 0.10 mmol) and triethylamine (17 μl, 0.12 mmol) in toluene (0.5 ml) at room temperature was added 2,4,6-trichlorobenzoyl chloride (17 μl, 0.11 mmol). After stirring for 2 h, a solution of S17 (133 mg, mmol) and DMAP (17 mg, 0.14 mmol) in toluene (3 ml) was injected to the reaction vessel, and the stirring continued for 1 h. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether/etac, 4:1) to afford 22 (144 mg, 96%) as a white foam. 1 NMR (300 Mz, CDCl 3 ) δ (m, 84), 6.78 (d, J = 7.5 z, 2), 6.76 (d, J = 8.7 z, 2), 5.89 (br s, 1), (m, 1), (m, 50), 4.03 (t, J = 10.4 z, 1), (m, 40), (m, 6), 1.34 (d, J = 5.7 z, 3), 1.22 (s, 3), 1.09 (s, 3), 0.90 (s, 3), 0.86 (s, 3), 0.84 (s, 3), 0.76 (s, 3); RMS (MALDI) calcd for C Na [M+Na] + : , found PMB Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn PMB Bn Bn Bn Bn 22 Bn Bn TFA,C 2 Cl 2 /C 6 5 Me, -20 o C, 95% Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn 23 Bn Bn S23

25 To a solution of 22 (80 mg, mmol) in C 2 Cl 2 /C 6 5 Me (2 ml, v/v 1:1) at -20 o C was added trifluoroacetic acid (0.2 ml). The mixture was stirred at this temperature for 3 h, and was then quenched by the addition of NaC 3. The resulting solution was extracted with C 2 Cl 2, and the combined extracts were washed with brine. The organic layer was dried with Na 2 S 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (C 2 Cl 2 /Me, 20:1) to afford 23 (70 mg, 95%) as a white foam: 1 NMR (300 Mz, CDCl 3 ): δ (m, 80), 5.85 (brs, 1), 5.29 (brs, 1), (m, 68), (m, 2), (m, 3), 1.35 (s, 3), 1.31 (s, 3), 1.23 (s, 3), 1.09 (s, 3), (s, 3), 0.86 (s, 3), 0.87 (s, 3), 0.75 (s, 3). 23 Bn Bn 2,4,6-(C 6 2 Cl 3 )CCl Et Bn Bn 3 N, DMAP. 50% Bn Bn Bn Bn Bn + Bn Bn Bn Bn Bn Bn (S) (R) Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn 24a Bn Bn Bn 24b Bn Bn Bn To a solution of 23 (40 mg, mmol) and triethylamine (11 μl, 0.08 mmol) in toluene (1 ml) at room temperature was added 2,4,6-trichlorobenzoyl chloride (11 μl, 0.07 mmol). After stirring for 12 h, the mixture was diluted with toluene (14 ml), and then DMAP (11 mg, 0.09 mmol) was added to the reaction vessel, and the stirring continued for 12 h. The resulting mixture was concentrated and purified by silica gel column chromatography (petroleum ether/etac, 5:1) to afford 24 (20 mg, 50%, 24a:24b = 1 : 1) as a white foam. 24a: 1 NMR (300 Mz, CDCl 3 ): δ (m, 80), 5.73 (brs, 1), 5.48 (t, J = 9.6 z, 1 ), 5.33 (brs, 1), (m, 1 ), (m, 1 ), (m, 68 ), (m, 2 ), (m, 1 ), (m, 1 ), 1.34 (s, 3), 1.23 (s, 3), 1.09 (s, 3), 0.91 (s, 3), 0.90 (s, 3 ), 0.73 (s, 3); RMS (MALDI) calcd for C Na [M+Na] + : , found b: 1 NMR (300 Mz, CDCl 3 ): δ (m, 80), 5.65 (brs, 1), (m, 3 ), S24

26 (m, 3 ), (m, 70 ), (m, 2 ), (m, 2 ), (m, 1 ), 1.38 (s, 3), 1.23 (s, 3), 1.10 (s, 3), 0.81 (s, 3), 0.73 (s, 3 ); 24a Pd() 2, EA/ethanol, 80% (S) Lobatoside E (1) To a solution of 24a (10 mg, mmol) in EtAc/ethanol (1 ml, v/v 1:1) at room temperature was added Pd() 2 (3 mg). The suspension was stirred under hydrogen pressure for 14 h and then filtered. The filtrate was concentrated, the residue was purified by flash chromatography on DS-silica gel (Me/ 2, 3:1) to afford Lobataside E (1) (4 mg, 80%). Lobataside E (1): [α] 22 D = 6.1 (c 0.20, pyridine) ([α] 22 D = 7.01 (c 0.27, pyridine)) 6 ; 1 NMR (500 Mz, Pyridiene-D 5 / D 2 ): δ 6.09 (s, 1 ), 6.01 (d, J = 6.4 z, 1 ), 6.00 (t, J = 9.7 z, 1 ), 5.48 ( br s, 1 ), 5.17 (br s, 1 ), 5.14 (d, J = 7.4 z, 1 ), 5.09 (d, J = 7.5 z, 1 ), 5.01 (d, J = 7.8 z, 1 ), 4.88 (brs, 1 ), 4.82 (dd, J = 6.8, J = 12.1 z, 1 ), 4.73 (m, 1 ), (m, 2 ), 4.53 (dd, J = 9.8, J = 7.8 z, 1 ), (m, 3 ), (m, 8 ), (m, 6 ), (m, 4 ), 3.75 (m, 1 ), 3.36 (d, J = 15.0 z, 1 ), 3.33 (d, J = 14.7 z, 1 ), 3.23 (d, J = 15.5 z, 1 ), (m, 1 ), 3.04 (d, J = 15.5 z, 1 ), 2.03 (s, 3 ), 1.66 (s, 3 ), 1.54 (s, 3 ), 1.53 (d, J = 6.4 z, 3 ), 1.36 (s, 3 ), 1.24 (s, 3 ), 0.93 (s, 3 ), 0.88 (s, 3 ); 13 C NMR (125 Mz, Pyridiene-D 5 ): δ 176.2, 171.3, 170.8, 144.1, 123.2, 106.1, 105.7, 105.1, 102.0, 94.5, 83.0, 82.2, 79.0, 77.9, 77.6, 77.6, 77.2, 76.7, 75.1, 75.0, 74.9, 73.5, 73.3, 73.1, 72.0, 71.7, 71.5, 70.9, 70.7, 70.3, 68.8, 67.9, 66.7, 66.4, 64.6, 62.6, 62.4, 48.4, 47.6, 47.5, 47.1, 46.9, 46.1, 44.1, 42.7, 42.2, 41.5, 39.9, 36.9, 34.1, 33.3, 33.0, 32.2, 30.7, 28.9, 26.0, 25.5, 23.9, 23.4, 22.8, 18.8, 18.4, 17.7, 17.4, 15.4; RMS (MALDI) calcd for C Na [M+Na] + : , found S25

27 24b Pd() 2, EA/ethanol, 80% (R) 25 To a solution of 24b (10 mg, mmol) in EtAc/ethanol (1 ml, v/v 1:1) at room temperature was added Pd() 2 (3 mg). The suspension was stirred under hydrogen pressure for 14 h and then filtered. The filtrate was concentrated, the residue was purified by flash chromatography on DS-silica gel (Me/ 2, 3:1) to afford 25 (4 mg, 80%). 25: [α] 22 D = 1.3 (c 0.20, pyridine); 1 NMR (500 Mz, pyridiene-d 5 /D 2 ): δ 6.16 (s, 1 ), 6.00 (d, J = 5.5 z, 1 ), 5.97 (t, J = 10.0 z, 1 ), 5.47 ( br s, 1 ), 5.17 (br s, 1 ), 5.13 (d, J = 6.5 z, 1 ), 5.08 (d, J = 7.3 z, 1 ), 5.05 (d, J = 7.8 z, 1 ), 4.88 (brs, 1 ), 4.77 (m, 2 ), 4.63 (m, 2 ), 4.56 (m, 1 ), (m, 20 ), (m, 7 ), 3.40 (d, J = 16.7 z, 1 ), 3.35 (d, J = 14.3 z, 1 ), 3.23 (d, J = 18.0 z, 1 ), (m, 3 ), 1.98 (s, 3 ), 1.68 (s, 3 ), 1.53 (s, 3 ), 1.48 (d, J = 5.2 z, 3 ), 1.28 (s, 3 ), 1.25 (s, 3 ), 0.91 (s, 3 ), 0.87 (s, 3 ); 13 C NMR (125 Mz, pyridine-d 5 ): δ 176.1, 171.2, 170.9, 144.0, 123.1, 106.2, 106.0, 105.0, 101.7, 94.3, 82.8, 81.6, 79.3, 78.0, 77.7, 77.5, 76.9, 76.3, 75.1, 75.0, 74.6, 73.5, 73.3, 73.0, 72.0, 71.4, 70.9, 70.5, 70.4, 69.7, 68.7, 67.7, 66.5, 66.5, 64.2, 62.5, 62.2, 48.4, 47.4, 47.0, 47.0, 46.5, 46.0, 44.1, 42.6, 42.1, 41.1, 39.7, 37.1, 33.9, 33.3, 32.8, 31.9, 30.5, 28.5, 25.9, 25.2, 23.8, 23.3, 22.7, 18.7, 18.3, 17.5, 17.2, Table S1. Comparison of the diagnostic 1 NMR signals of the synthetic 1, 25, and the natural Lobatoside E. Position Natural product 6 Synthetic 1 Synthetic 25 28Rha brs 6.09 brs 6.16 brs 28Ara d (6) 6.01 d (6.4) 6.00 d (5.5) S26

28 28Rha t (10) 6.00 t (9.7) 5.97 t (10) -12 ca Rha dd (1.5, 3) 5.17 brs 5.17 brs 3Glc d (8) 5.14 d (7.4) 5.13 d (6.5) 3Gal d (7.5) 5.09 d (7.5) 5.08 d (7.3) 28Glc d (8) 5.01 d (7.8) 5.05 d (7.8) brs 4.88 brs 4.88 brs 3Gla dd (2, 12) 4.73 m 4.77 m 4.82 dd (7, 12) 4.82 dd (6.8, 12.1) 4.77 m Dicrotalic acid moiety 2 (4 ) 3.01 d (16) 3.04 d (15.5) 3.12 d (17) 3.30 d (16) 3.33 d (14.7) 3.35 d (14.3) 4 (2 ) 3.19 d (17) 3.23 d (15.5) 3.23 d (18) 3.32 d (17) 3.36 d (15) 3.40 d (16.7) s 2.03 s 1.98 s s 1.54 s 1.53 s s 1.66 s 1.68 s s 1.24 s 1.25 s s 1.36 s 1.31 s s 0.93 s 0.91 s s 0.88 s 0.87 s Table S2. Comparison of the 13 C NMR data of the synthetic 1, 25, and the natural Lobatoside E. Position Natural product 6 Synthetic 1 Synthetic 25 C C a C S27

29 C C C C C C C C C C C C C C C C C C C C C C C C C C C Dicrotalic acid moiety S28

30 a Glc Glc Glc Glc a 3Glc Glc Gal Gal Gal Gal a 3Gal Gal Ara Ara Ara Ara Ara Rha Rha Rha Rha Rha S29

31 28Rha Glc Glc Glc Glc a 28Glc Glc a) These values may be interchanged. References (1) Yang, G. B.; Kong, F. Z. Bioorg. Med. Chem. Lett. 2006, 13, 909. (2) Timmers, C. M.; Wigchert, S. C. M.; Leeuwenburgh, M. A.; Van der Marel, G.; Van Boom, J.. Eur.J. rg. Chem. 1998, 58, 91. (3) Yang, Z. Y.; Yu, B. Carbohydr. Res. 2001, 333, 105. (4) Lewer, P.; MacMillan, J. J. Chem. Soc., Perkin Trans , (5) Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; ughes, R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem. Eur. J. 1999, 5, (6) Fujioka, T.; Iwamoto, M.; Iwase, Y.; achiyama, S.; kabe,.; Yamauchi. T.; Mihashi, K. Chem. Pharm. Bull. 1989, 37, S30

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