Supporting Information

Transcription

1 Supporting Information Total Synthesis of (±)-Grandilodine B Chunyu Wang, Zhonglei Wang, Xiaoni Xie, Xiaotong Yao, Guang Li, and Liansuo Zu* School of Pharmaceutical Sciences, Tsinghua University, Beijing, China

2 Supporting Information Table of Contents Materials and Methods...S3 Experimental Procedures...S4 Comparison of NMR Spectrum of Grandilodine B: Isolated vs Synthesized...S NMR Spectrum..S4 2

3 Materials and methods. Unless stated otherwise, reactions were conducted in dry glassware using anhydrous solvents (passed through activated alumina columns). All commercially available reagents were used as received unless otherwise specified. Reaction temperatures were controlled using an IKA magnetic temperature modulator, and unless stated otherwise, reactions were performed at room temperature (RT, approximately 23 C). All reactions under microwave irradiation were performed in a CEM Discover -300W system. Thin-layer chromatography (TLC) was conducted on plates (GF254) supplied by Yantai Chemicals (China) and visualized using a combination of UV, anisaldehyde, iodine, and potassium permanganate staining. Silica gel ( mesh) supplied by Tsingtao Haiyang Chemicals (China) was used for flash column chromatography. H NMR spectra were recorded on Bruker spectrometers (at 400 MHz) and are reported relative to deuterated solvent signals. Data for H NMR spectra are reported as follows: chemical shift ( ppm), multiplicity, coupling constant (Hz) and integration. C NMR spectra are reported in terms of chemical shift. High resolution mass spectra were obtained from the Tsinghua University Mass Spectrometry Facility. 3

4 Experimental Procedures Compound 9 To a suspension of (.6 g, 60.7 mmol), ethyl glyoxylate (6.47 g, 63.4 mmol) and 4A MS (2.0 g) in toluene (240 ml) were sequentially added piperidine (0.3 g, 20.8 mmol) and AcOH (4.6 g, 24.6 mmol) dropwisely at room temperature under nitrogen. Then the mixture was heated to 60 ºC and stirred for another 4 hours. The reaction mixture was concentrated under reduced pressure to afford the crude residue, which was purified directly by silica gel column chromatography (petroleum ether / ethyl acetate = :) to give 9 (.5 g, 80.5%, 9a / 9b = 4:5). Compound 9a, yellow solid R f 0.65 (petroleum ether / ethyl acetate = 3:) H NMR (400 MHz, CDCl 3) δ8.04 (d, J = 8.8 Hz, H), 7.77 (d, J = 7.2 Hz, H), (m, H), 7.24 (d, J = 7.2 Hz, H), 7. (s, H), 4.39 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H),.38 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ 82.7, 66.4, 5.9, 48.6, 7., 6.0, 24.7, 22.9, 7.3, 4.2, 6.9, 53.9, 4.. HRMS: (ESI) m/z calcd for C 4H NO 5Na ([M + Na] + ): ; found: Compound 9b, yellow oil R f 0.60 (petroleum ether / ethyl acetate = 3:) H NMR (400 MHz, CDCl 3) δ8.8 (d, J = 8.8 Hz, H), 7.78 (d, J = 7.6 Hz, H), 7.65 (t, J = 8.4 Hz, H), 7.23 (d, J = 7.6 Hz, H), 6.48 (s, H), 4.28 (q, J = 7.2 Hz, 2H), 3.9 (s, 3H),.34 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ 84.9, 65.6, 5.7, 49.9, 7.3, 6.9, 24.9, 24.8, 22.7, 6.8, 09.2, 6.4, 53.9, 4.3. HRMS: (ESI) m/z calcd for C 4H NO 5Na ([M + Na] + ): ; found: Compound 8 A mixture of 9 (8.2 g, 29.8 mmol) and 0 (6.8 g, 74. mmol) was added to a sealed tube at room temperature under nitrogen. Then the solution was stirred at 20 ºC for 3.0 hours. The mixture was purified directly by silica gel column chromatography (petroleum ether / ethyl acetate = : 4:) to give 8 (0.7 g, 7.6%) as a yellow oil. R f 0.63 (petroleum ether / ethyl acetate = 4:) H NMR (400 MHz, CDCl 3) δ7.97 (d, J = 8.4 Hz, H), (m, H), (m, H), (m, H), (m, H), 3.83 (s, 3H), (m, 2H), (m, H), 2.92 (t, J =.6 Hz, H), (m, H), (m, H), 2.30 (dd, J = 0.0 Hz, 6.4 Hz, H), (m, 2H), 0.62 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ 20.3, 70.4, 52.8, 52.6, 50.2, 7.0, 24.3, 23.5, 22.6, 7.2, 98.0, 68.8, 60.8, 52.8, 48., 33.4, 30.0, 8., 8., 7.8,.3, 2.7, 2.4. HRMS:(ESI) m/z calcd for C 27H 39NO 6NaSi([M+Na] + ): ; found:

5 Compound 30 To a stirred solution of 8 (0.7 g, 2.3 mmol) in THF (600 ml) was added dropwise a solution of TBAF (22.4 ml,.0 M in THF) at -60 o C under nitrogen. The mixture was stirred for 20 min, and then quenched with a saturated aqueous NH 4Cl solution. The resulting cold mixture was extracted with DCM. The combined extracts were washed with brine, dried over Na 2SO 4 and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:) to give 30 (6.0 g, 8.6%) as a white solid. R f 0.48 (petroleum ether / ethyl acetate = 2:) H NMR (400 MHz, CDCl 3) δ8.2 (s, H), 7.82 (d, J = 7.6 Hz, H), 7.68 (t, J = 7.6 Hz, H), 7.22 (t, J = 7.2 Hz, H), (m, 4H), 4.28 (dd, J = 9.6 Hz, 4.4 Hz, 2H), 3.40 (s, H), (m, 2H), 2.58 (t, J = 4.0 Hz, H), 2.4 (d, J = 7.2 Hz, H),.99 (dd, J = 0.0 Hz, 4.4 Hz, H), 0.66 (t, J = 6.8 Hz, 3H). C NMR (00 MHz, CDCl 3) δ 209.4, 200.2, 69., 52.3, 52.2, 7.6, 24.8, 2.6, 7.2, 68., 6., 53.3, 44.5, 39., 34.7, 27.4,.4. HRMS: (ESI) m/z calcd for C 8H 9NO 6Na ([M + Na] + ): 368.; found: Compound 2 A solution of ketone 30 (2.2g, 6.4 mmol), ethylene glycol (0.54 ml) and p-tsoh. H 2O (36.3 mg, 0.9 mmol) in toluene (60 ml) was heated at reflux with azeotropic removal of water by a Dean-Stark apparatus for.5 h. The reaction mixture was cooled to room temperature and treated with saturated NaHCO 3 solution. After extracting with ethyl acetate, the combined organic phases were washed with brine, dried over anhydrous Na 2SO 4, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4:) to give 2 (2.44 g, 97.8%) as a white solid. R f 0.47 (petroleum ether / ethyl acetate = 2:) H NMR (400 MHz, CDCl 3) δ 8. (d, J = 8.8 Hz, H), 7.77 (d, J = 7.6 Hz, H), 7.68 (t, J = 7.6 Hz, H), 7.6 (t, J = 7.2 Hz, H), 7.6 (t, J = 7.2 Hz, H), (m, 4H), 3.87 (s, 3H), (m, 3H), 2.68 (t, J =.6 Hz, H), (m, 5H), 0.60 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ 200.4, 70.5, 52.8, 52.3, 6.9, 24.4, 23.5, 22.5, 7.6, 08.4, 69.7, 64.5, 64.5, 60.7, 52.9, 45.9, 33., 32.5, 30.0,.3. HRMS: (ESI) m/z calcd for C 20H 23NO 7Na ([M + Na] + ): 42.72; found: Compound 7 5

6 To a stirred solution of 2 (2.4 g, 6.2 mmol) in THF (30 ml) was added dropwise a solution of allylmagnesium bromide (7.5 ml,.0 M in THF) at -78 o C under nitrogen. The mixture was stirred for 45 min, and then quenched with a saturated aqueous NH 4Cl solution. The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na 2SO 4 and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:) to give 7 (2.6 g, 96.7%) as a white solid. R f 0.55 (petroleum ether / ethyl acetate = 2:) H NMR (400 MHz, CDCl 3) δ 7.44 (d, J = 8.0 Hz, H), 7.6 (t, J = 8.0 Hz, 2H), 7.00 (t, J = 7.2 Hz, H), (m, H), (m, 2H), 4.04 (s, H), (m, 4H), 3.8 (s, 3H), (m, 3H), (m, H), (m, H), (m, 4H), (m, H),.65 (d, J =.2 Hz, H),.0 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ74., 54.4, 4.0, 5.5, 3.0, 28.5, 23.7, 23.7, 8.7, 8.6, 08.4, 83.6, 75.9, 64.5, 64.4, 6.2, 52.7, 45.7, 4.4, 33.3, 32.2, 27.5,.6. HRMS: (ESI) m/z calcd for C 23H 29NO 7Na ([M + Na] + ): ; found: Compound To a stirred solution of B(C 6F 5) 3 (23.5 mg, 0.24 mmol) in DCM (00 ml) was added dropwise TMSCN (2.4 g, 24. mmol) at -25 o C under nitrogen. Then a solution of 7 (2. g, 4.8 mmol) in DCM (60 ml) was added dropwise to the above solution at -25 o C over 50 min. The mixture was stirred for 2 hours, and then quenched with Et 3N and saturated aqueous NaHCO 3 solution. The organic phase was washed with brine, dried over Na 2SO 4 and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:) to give (.3 g 6.5%) as a white solid. R f 0.46 (petroleum ether / ethyl acetate = 3:) H NMR (400 MHz, CDCl 3) δ 7.56 (d, J = 8.4 Hz, H), 7.34 (d, J = 7.6 Hz, H), 7.23 (d, J = 8.0 Hz, H), 7.0 (t, J = 7.6 Hz, H), (m, H), (m, 2H), (m, 4H), 3.88 (s, 3H), (m, H), (m, H), (m, H), (m, H), (m, H), (m, H), 2.48 (t, J =.6 Hz, H), (m, H),.78 (dd, J = 6.8 Hz, 6.4 Hz, H), (m, H),.00 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ7.6, 54., 42.3, 2.0, 3.0, 29.0, 23.9, 23., 2.2, 9.3, 8.5, 08.0, 73.0, 64.7, 64.5, 6.0, 54.7, 52.9, 44.6, 36.7, 34.6, 32.2, 3.7,.7. HRMS: (ESI) m/z calcd for C 24H 28N 2O 6Na ([M + Na] + ): ; found: Compound 3 2,6-Lutidine (988.7 mg, 9.2 mmol), NaIO 4 (2.0 g, 9.2 mmol), and OsO 4 (.76 ml, 0.4 mmol) were added sequentially to a solution of olefin (.0 g, 2.3 mmol) in a 4: mixture of dioxane / H 2O (40 ml) at room temperature. The reaction was stirred at room temperature for 7 hours and then quenched with aq. Na 2S 2O 3. The mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na 2SO 4 and concentrated. The 6

7 crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 2.5:) to give 3 (889. mg, 87.4 %) as a white solid. R f 0.46 (petroleum ether / ethyl acetate = :) H NMR (400 MHz, CDCl 3) δ 0.2 (s, H), 7.56 (d, J = 8.4 Hz, H), 7.27 (d, J = 8.0 Hz, H), 7.4 (d, J = 7.6 Hz, H), 7.03 (t, J = 7.6 Hz, H), (m, 7H), 3.52 (d, J = 6.8 Hz, H), (m, H), (m, 2H), (m, 3H), 2.45 (t, J =.6 Hz, H),.79 (d, J = 6.8 Hz,, H),.62 (d, J =.2 Hz,, H), 0.98 (t, J = 7.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ97.4, 7.2, 53.9, 42.3, 0.2, 27.7, 24.4, 23.3, 8.8, 8.2, 07.7, 73.3, 64.7, 64.5, 6., 53., 5.3, 45.2, 44.9, 34.4, 3.7, 3.7,.6. HRMS: (ESI) m/z calcd for C 23H 26N 2O 7Na ([M + Na] + ): ; found: Compound 4 To a solution of 3 (802.2 mg,.8 mmol) in MeOH/THF (:2, 2 ml) was added NaBH 4 (7.2 mg,.9 mmol) at 0 ºC. After being stirred for 0 min, the reaction was quenched by the addition of saturated aqueous NH 4Cl solution. The solution was concentrated in vacuo to remove MeOH. Then the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na 2SO 4 and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = :) to give 4 (793.8 mg, 98.5%) as a white solid. R f 0.27 (petroleum ether / ethyl acetate = :) C NMR (00 MHz, CDCl 3) δ7.5, 54., 42.3, 29.8, 29.0, 24., 23., 9.5, 8.5, 07.9, 73., 64.6, 64.6, 60.9, 59.5, 53.8, 52.9, 44.3, 34.5, 34.4, 3.9, 3.7,.6. H NMR (400 MHz, CDCl 3) δ 7.54 (d, J = 8.4 Hz, H), 7.35 (d, J = 7.6 Hz, H), 7.24 (t, J = 7.6 Hz, H), 7.03 (t, J = 7.6 Hz, H), (m, 2H), (m, 4H), 3.87 (s, 3H), (m, H), (m, 2H), (m, 3H), (m, 3H), (m, H), (m, H),.60 (d, J = 2.8 Hz, H), 0.95 (t, J = 7.2 Hz, 3H). HRMS: (ESI) m/z calcd for C 23H 28N 2O 7Na ([M + Na] + ): ; found: Compound 32 To a solution of 4 (775.0 mg,.7 mmol) in THF (5.0 ml) was added 2N HCl (0 ml) at room temperature. After being stirred for 4.5 h at 45 ºC, the reaction was quenched by the addition of saturated aqueous NaHCO 3 solution at 0 ºC. The solution was concentrated in vacuo and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na 2SO 4 and concentrated. The crude product was directly used for next step. R f 0.25 (petroleum ether / ethyl acetate = :.5) H NMR (400 MHz, CDCl 3) δ 7.62 (d, J = 8.4 Hz, H), 7.3 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 7.6 Hz, H), 4.09 (d, J = 5.2 Hz, 2H), 3.84 (s, 3H), (m, 3H), 3.08 (dd, J = 2.0 Hz, 6.4 Hz, H), (m, 7H), 2.33 (s, 3H), 7

8 .04 (t, J = 6.8 Hz, 3H). C NMR (00 MHz, CDCl 3) δ208.6, 70.5, 53.9, 4.7, 0.4, 27.5, 24.0, 23.5, 9.5, 7.6, 73.0, 6.5, 59.5, 54.7, 53., 43.6, 39.6, 37., 34., 30.5,.8. HRMS: (ESI) m/z calcd for C 2H 24N 2O 6Na ([M + Na] + ): ; found: Compound 6 To a solution of the crude 32 (.7 mmol) and imidazole (92.0 mg,.4 mmol) in N,N-dimethylformamide ( ml) was added triisopropylsilyl chloride (. ml, 5.4 mmol) at room temperature. After being stirred for 4.5 hours, the reaction was quenched with saturated aqueous NaHCO 3 solution and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na 2SO 4 and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4.5:) to give 6 (920.0 mg, 95.0% for 2 steps) as a white solid. R f 0.45 (petroleum ether / ethyl acetate = 3:) H NMR (400 MHz, CDCl 3) δ 7.60 (d, J = 8.4 Hz, H), (m, 2H), 7.06 (t, J = 7.2 Hz, H), (m, 2H), 3.85 (s, 3H), (m, 2H), 3.45 (dd, J = 6.4 Hz, 5.2 Hz, H), 3.6 (dd, J =.6 Hz, 5.2 Hz, H), (m, 7H),.-.00 (m, 24H). C NMR (00 MHz, CDCl 3) δ208.0, 70.3, 54.0, 4.6, 0.3, 27.5, 23.8, 9.3, 7.5, 73.0, 6.4, 60.4, 54.3, 53., 43.3, 39.6, 36.8, 34.9, 30.2, 8.,.8, 2.0. HRMS: (ESI) m/z calcd for C 30H 44N 2O 6NaSi ([M + Na] + ): ; found: Compound 5 To a solution of 6 (60.7 mg,. mmol) and N-Benzylhydroxylamine hydrochloride (8. mg,. mmol) in EtOH (0 ml) was added NaHCO 3 (453.7 mg, 5.4 mmol) in one portion, and the resulting suspension was allowed to stir at reflux for 2.5 hours. The suspension was filtered through a pad of Celite. The filter cake was further washed with DCM. The combined filtrates were concentrated to afford the crude nitrone. The above crude residue and methyl acrylate (0.5 ml) were added to a sealed tube with p-xylene (2.0 ml) at room temperature under nitrogen. Then the solution was stirred at reflux for 2.5 hours. The mixture was purified directly by silica gel column chromatography (petroleum ether / ethyl acetate = 4.5:) to give 5 (54.6 mg, 67.0%) as a colorless oil. R f 0.52 (petroleum ether / ethyl acetate = 2:) H NMR (400 MHz, CDCl 3) δ (m, 8H), 7.0 (t, J = 7.6 Hz, H), (m, H), (m, H), (m, 24H). C NMR (00 MHz, CDCl 3) δ72.4, 72.2, 54.4, 42.3, 29.8, 29.7, 29.5, 29., 29.0, 28.7, 28.6, 27.5, 8

9 27.3, 24.2, 24., 24.0, 9., 8.7, 8.6, 74.5, 74.2, 67.2, 66.9, 6.5, 60.8, 60.7, 54.5, 54.5, 53.0, 53.0, 52.5, 43.4, 43., 4.9, 4.7, 34.0, 29.8, 29.6, 29.4, 8.2,.6,.5, 2.. HRMS: (ESI) m/z calcd for C 4H 58N 3O 8Si ([M + H] + ): ; found: Compound 5 To a stirred solution of 5 (450.0 mg, 0.6 mmol) in MeOH (5 ml) was added 0%Pd(OH) 2 on carbon (45.0 mg). The reaction mixture was stirred for day at 37 o C under H 2. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The resulted residue was purified by column chromatography (DCM / MeOH = 40:) to afford 5 (248.6 mg, 66.0%) as a white solid. R f 0.53 (DCM / MeOH = 0:) H NMR (400 MHz, CDCl 3) δ 7.55 (dd, J =.9, 7.6 Hz, H), (m, 3H), 7.36 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.4 Hz, H), 7.22 (t, J = 7.8 Hz, H), 7.0 (t, J = 7.5 Hz, H), 4.72 (s, 0.5H), 4.49 (s, 0.5H), 4.4 (td, J =., 0.0, 4.9 Hz, 2H), 4.02 (d, J =.5 Hz, H), (m, 4H), 3.74 (s,.5h), 3.70 (s,.5h), 3.47 (dq, J = 0.7, 7.2 Hz, H), 3.30 (s, H), 2.99 (s, H), 2.58 (d, J = 4.5 Hz, 3H), 2.44 (d, J = 6.2 Hz, 2H), 2.5 (dp, J =.7, 7.5, 6.8 Hz, 2H),.97 (s, 2H),.79 (dt, J =.8, 3.2 Hz, H), (m, 2H), 0.95 (td, J = 7.2, 2.2 Hz, 3H). C NMR (00 MHz, CDCl 3) δ78.4, 77.9, 7.9, 7.7, 54.6, 54.4, 42.5, 42.0, 29.8, 29.6, 29.6, 29.2, 24.2, 24.0, 23.9, 9.5, 9.2, 8.7, 8.6, 74.9, 74.5, 69.3, 68.9, 6.9, 6.4, 6., 6.0, 56.0, 55.4, 54.4, 54.3, 53., 44., 44.0, 42.5, 42.5, 38.7, 37.7, 34.7, 34.4, 34.2, 33., 29.9, 29.5, 29.0, 8.2, 8.,.8,.6, 2., 2.. HRMS: (ESI) m/z calcd for C 33H 50N 3O 7Si ([M + H] + ): ; found: Compound 4 To a stirred solution of 5 (486.0 mg, 0.77 mmol) in THF (0 ml) was added dropwise a solution of TBAF in THF (0.93 ml, 0.93 mmol) at 0 under N 2 atmosphere. The reaction was stirred for h, and then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (20 ml*2). The combined organic phase was washed with brine, dried over Na 2SO 4, and concentrated. To a solution of the above crude residue in 0 ml DCM at 0 were added 0.87 ml TEA (6.2 mmol) and 0.24 ml MsCl (3. mmol). The reaction was stirred for 5 min, and then quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 ml*2). The combined organics were washed with brine, dried over Na 2SO 4. The solvents were removed under reduced pressure to afford the crude residue, which was purified by silica gel column (DCM/MeOH = 20:) to give the desired product 4 (460.0 mg, 94.7% yield) as a white solid. R f = 0.50 (DCM / MeOH = 20:) H NMR (400 MHz, CDCl3) δ 9.22 (s, 0.5H), δ 9.5 (s, 0.5H), (m, 2H), 7.29 (t, J = 7.8 Hz, H), 7.0 (t, J = 7.6 Hz, H), (m, H), 4.69 (dt, J =.3, 6.4 Hz, 2H), 3.88 (s, 3H), (m, H), (m, 4H), (m, 4H), (m, 4H), (m, H), (m, H), (m, 2H),.93.6 (m, 2H),.02 (dt, J = 2.5, 7.2 Hz, 3H). 9

10 C NMR (00 MHz, CDCl 3) δ 72.2, 72., 7.2, 7., 54.4, 54.3, 42.2, 42., 0.0, 0.0, 28.6, 28.4, 24.9, 24.7, 23.5, 23.5, 9.4, 9.3, 8.3, 8.2, 75.9, 74.4, 74.2, 67.7, 67.4, 6.4, 6.4, 57.2, 56., 54.2, 53.3, 42.6, 42.6, 42.5, 42.5, 39.5, 39.4, 38.0, 37.6, 37.6, 37.3, 34.6, 34.3, 30.7, 30.4, 29.3, 29.0,.7. HRMS: (ESI) m/z calcd for C 26H 34N 3O S 2 ([M + H] + ): ; found: Compound 6 To a stirred solution of 4 (280.0 mg, mmol) in toluene (35 ml) was added Cs 2CO 3 (44.5 mg, mmol). The reaction was heated to 0 o C for 0 h under N 2 atmosphere. After completion, the mixture was cooled to rt, washed with brine, dried over Na 2SO 4. The solvent was removed under reduced pressure to afford the crude residue, which was purified by silica gel column chromatography (DCM/MeOH = 30:) to give the desired product 6 (7.3mg, 49.5% yield) as a white solid. R f 0.53 (DCM / MeOH = 30 : ) H NMR (400 MHz, CDCl 3) δ 7.67 (d, J = 8.3 Hz, H), 7.37 (t, J = 7.9 Hz, H), 7.27 (d, J = 6.9 Hz, H), 7.4 (t, J = 7.6 Hz, H), 5.37 (dd, J = 0.7, 7.4 Hz, H), 4.63 (dd, J = 6.0, 5.6 Hz, H), (m, 2H), 3.83 (s, 3H), 3.7 (q, J = 2.0 Hz, H), (m, H), 3.30 (s, 3H), 2.86 (td, J = 2.8, 0.8, 6.0 Hz, 2H), 2.73 (dd, J = 2.2, 7.3 Hz, H), 2.56 (dd, J = 4.6,.7 Hz, H), (m, H), (m, H), 2. (td, J = 6.4, 5.6, 9.4 Hz, 3H),.78 (dd, J = 4.6, 6.7 Hz, H),.08 (t, J = 7. Hz, 3H). C NMR (00 MHz, CDCl 3) δ 70.4, 69.7, 53.6, 42.8,., 26.3, 24.4, 23.0, 9.2, 7.0, 77.4, 76.6, 72.3, 6.9, 57., 53.8, 53.0, 45.7, 40., 39.9, 35.9, 35., 33.4, 26.9, 26.6, 4.0. HRMS: (ESI) m/z calcd for C 25H 30N 3O 8S ([M + H] + ): ; found: Compound 7 Synthesis of the solution of PhSeNa in EtOH: to a solution of diphenyl diselenide (540.0 mg,.73 mmol) in 30 ml EtOH was added NaBH 4 (.0 mg, 3.46 mmol) at rt. The mixture was stirred for 0 min until becoming colorless. To a solution of 6 (74.0 mg, 0.4 mmol) in ml THF was added PhSeNa/ EtOH (2eq*8) at rt until the substitution was complete. The reaction was quenched by 0 ml saturated sodium bicarbonate solution. The mixture was extracted with Et 2O (0mL*3). The organic phases were combined, washed with brine, dried over Na 2SO 4, and concentrated to afford the crude residue. To a solution of the above residue in 3 ml DCM at 0 0 C was added 30% H 2O 2 (40 mg, mmol). The reaction was stirred for 5 min, and then quenched with saturated sodium thiosulfate solution. The mixture was extracted with ethyl acetate (0 ml*2). The combined organics were washed with brine, dried over Na 2SO 4. The solvent was removed under reduced pressure to afford the crude residue, which was purified by silica gel column chromatography (DCM/ MeOH = 30:) to give the desired product 7 (54.6 mg, 89.6% yield) as a white solid. R f 0.45 (DCM/ MeOH = 30 :). H NMR (400 MHz, CDCl 3) δ7.66 (d, J = 8.0 Hz, H), 7.37 (t, J = 8.4 Hz, H), 7.3 (d, J = 7.6 Hz, H), 7.5 (t, J = 7.2 Hz, H), 7.04 (d, J = 5.2 Hz, H), 6.06 (d, J = 5.6 Hz, H), (m, H), (m, 2H), 3.82 (s, 3H), 0

11 3.69 (q, J = 4.8 Hz, H), 3.32 (t, J = 4.0 Hz, H), (m, 3H), (m, 2H), 2.9 (t, J =.6 Hz, H), (m, H), (m, H),.2 (t, J = 6.8 Hz, H). C NMR (00 MHz, CDCl 3) δ72.7, 7.3, 56.5, 53.4, 42.5, 0.8, 27., 24.3, 24.2, 23., 9., 7.5, 73.0, 62.8, 6.9, 54., 52.9, 40., 35.9, 33.4, 32.0, 25.4, 22.9,.9. HRMS: (ESI) m/z calcd for C 24H 26N 3O 5 ([M + H] + ): ; found: Compound 34 To a stirred solution of 7 (26.5 mg, 0.06 mmol) in DMSO (0.6 ml) were added K 2CO 3 (6.8 mg, 0.2 mmol) and 6.9 ul H 2O 2 (0.6 mmol) at 0 o C. The reaction was then stirred at rt for 2 h under N 2 atmosphere. After completion, the reaction was quenched with sodium thiosulfate solution, and extracted with ethyl acetate (5 ml*2). The combined organic phase was washed with brine, dried over Na 2SO 4. The solvent was removed under reduced pressure to afford the crude residue, which was purified by silica gel column chromatography (DCM/ MeOH = 30:) to give the desired product 34 (24.6mg, 88.9% yield) as white solid. R f 0.35 (DCM/ MeOH = 5: ) H NMR (400 MHz, CDCl 3) δ 7.68 (d, J = 8.2 Hz, H), 7.33 (t, J = 7.4 Hz, H), 7.23 (d, J = 7.5 Hz, H), 7.5 (t, J = 7.5 Hz, H), 6.98 (d, J = 5.7 Hz, H), 6.02 (d, J = 5.7 Hz, H), 5.46 (s, H), 5.30 (s, H), 4.36 (dd, J = 5.8 Hz, H), (m, 3H), 3.80 (s, 3H), (m, H), 3.07 (dd, J = 0.5, 7.9 Hz, H), 2.97 (dd, J = 6.0, 6.5 Hz, H), 2.68 (dd, J = 4.4, 0.5 Hz, H), 2.29 (d, J = 8.3 Hz, 3H), (m, H),.43 (dd, J = 4.4, 7.8 Hz, H),.08 (t, J = 7. Hz, 3H). C NMR (00 MHz, CDCl 3) δ 73.8, 73.3, 72.4, 56.4, 53.6, 42.6, 3.5, 29.6, 24.8, 24.3, 23.6, 8.2, 75., 63.4, 6.4, 6.0, 52.8, 43.0, 37.0, 34.4, 3.8, 24.6, 23.5, 4.0. HRMS: (ESI) m/z calcd for C 24H 28N 3O 6 ([M + H] + ): ; found: Compound 8 To a stirred solution of 34 (0.0 mg, mmol) in DCM (2 ml) was added Me 3O + - BF 4 (0.8 mg, mmol) at 0 o C. The mixture was then stirred at rt for 20 h under N 2 atmosphere. After completion, the reaction was quenched with sodium bicarbonate solution, and extracted with ethyl acetate (5 ml*2). The organics were washed with brine, dried over Na 2SO 4, and concentrated to afford a residue, which was dissolved in 3 ml 0% HCl and ml THF. The mixture was stirred at rt for 4 h. The mixture was extracted with Et 2O (5 ml*3). The organics were washed with brine, dried over Na 2SO 4 and concentrated to afford the crude residue, which was purified by silica gel column chromatography (DCM/ MeOH = 30:) to give 8 (8.5 mg, 82.5% yield) R f 0.50 (DCM/ MeOH = 20: ) H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, H), 7.29 (d, J = 7.8 Hz, H), 7.20 (d, J = 7.6 Hz, H), 7.07 (t, J = 7.5 Hz, H), 7.00 (d, J = 5.6 Hz, H), 6.03 (d, J = 5.6 Hz, H), (m, H), 4.00 (qd, J = 7.2, 2.2 Hz, 2H), 3.79 (s,

12 3H), 3.60 (s, 3H), 3.49 (td, J =.2, 8.5 Hz, H), 3.32 (dd, J = 5.8,.8 Hz, H), 3.8 (dd, J = 6., 6.8 Hz, H), 3.04 (t, J = 8.8 Hz, H), 2.78 (dd, J = 4.8, 9.2 Hz, H), 2.49 (dd, J = 6.7, 5.4 Hz, H), 2.35 (ddd, J = 5.9, 8.7, 2.4 Hz, H), (m, H), (m, H), (m, H),.4 (t, J = 7. Hz, 3H). C NMR (00 MHz, CDCl3) δ 72.6, 72.6, 7.8, 56.3, 53.4, 43.0, 2.0, 29.4, 24.2, 23.9, 23.4, 8.3, 74.2, 62.8, 6.7, 6.5, 52.7, 52.6, 43., 36.7, 33.8, 30.8, 23.7, 4.0. HRMS: (ESI) m/z calcd for C 25H 29N 2O 7 ([M + H] + ): ; found: A solution of 8 (4.0 mg, mmol) in MeOH/H 2SO 4 (.5 ml, 0:, V/V) in a 0 ml sealed tube was microwave irradiated (ν = 2.45 GHz) at 90 C for 2.5 h. The reaction mixture was cooled to 25 C with an air flow, basified with sodium carbonate solution, and extracted with ethyl acetate (5 ml*3). The organics were washed with brine, dried over Na 2SO 4, and concentrated to afford the crude residue, which was purified by silica gel column chromatography (DCM/MeOH = 30:) to give natural product 3b (2.9 mg, 74.7%) as a white solid R f 0.47 (DCM/ MeOH = 20: ) H NMR (400 MHz, CDCl 3) δ 7.55 (d, J = 8.2 Hz, H), 7.29 (t, J = 7.7 Hz, H), 7.20 (d, J = 7.6 Hz, H), 7.08 (t, J = 7.5 Hz, H), 7.00 (d, J = 5.6 Hz, H), 6.03 (d, J = 5.6 Hz, H), 4.50 (dd, J = 5.6, 6.6 Hz, H), 3.80 (s, 3H), 3.60 (s, 3H), 3.56 (s, 3H), (m, H), 3.33 (dd, J = 5.8,.8 Hz, H), 3.8 (dd, J = 6., 6.8 Hz, H), 3.06 (t, J = 8.8 Hz, H), 2.78 (dd, J = 4.8, 9.3 Hz, H), 2.50 (dd, J = 5., 6.6 Hz, H), 2.34 (ddd, J = 6.0, 8.6, 2.5 Hz, H), (m, H), (m, H),.46 (dd, J = 4.9, 8.4 Hz, H). C NMR (00 MHz, CDCl 3) δ 72.9, 72.7, 7.8, 56.3, 53.4, 43.,.9, 29.6, 24.2, 24.0, 23.4, 8.0, 74.2, 62.8, 6.7, 52.8, 52.6, 52., 43.0, 36.7, 33.7, 30.9, 23.7, HRMS: (ESI) m/z calcd for C24H27N2O7 ([M + H] + ): ; found:

13 Comparison of H NMR and C NMR Spectra H NMR spectrum of Grandilodine B (400 MHz, CDCl3): Isolated H NMR spectrum of Grandilodine B (400 MHz, CDCl3): Synthesized C NMR spectrum of Grandilodine B (00 MHz, CDCl3): Isolated C NMR spectrum of Grandilodine B (00 MHz, CDCl3): Synthesized

14 NMR Spectrum H NMR of Compound 9a (400 MHz, CDCl 3) C NMR of Compound 9a (00 MHz, CDCl 3) 4

15 H NMR of Compound 9b (400 MHz, CDCl 3) C NMR of Compound 9b (00 MHz, CDCl 3) 5

16 H NMR of Compound 8 (400 MHz, CDCl 3) C NMR of Compound 8 (00 MHz, CDCl 3) 6

17 H NMR of Compound 30 (400 MHz, CDCl 3) C NMR of Compound 30 (00 MHz, CDCl 3) 7

18 H NMR of Compound 2 (400 MHz, CDCl 3) C NMR of Compound 2 (00 MHz, CDCl 3) 8

19 H NMR of Compound 7 (400 MHz, CDCl 3) C NMR of Compound 7 (00 MHz, CDCl 3) 9

20 H NMR of Compound (400 MHz, CDCl 3) C NMR of Compound (00 MHz, CDCl 3) 20

21 H NMR of Compound 3 (400 MHz, CDCl 3) C NMR of Compound 3 (00 MHz, CDCl 3) 2

22 H NMR of Compound 4 (400 MHz, CDCl 3) C NMR of Compound 4 (00 MHz, CDCl 3) 22

23 H NMR of Compound 32 (400 MHz, CDCl 3) C NMR of Compound 32 (00 MHz, CDCl 3) 23

24 H NMR of Compound 6 (400 MHz, CDCl 3) C NMR of Compound 6 (00 MHz, CDCl 3) 24

25 H NMR of Compound 5 (400 MHz, CDCl 3) C NMR of Compound 5 (00 MHz, CDCl 3) 25

26 H NMR of Compound 5 (400 MHz, CDCl 3) C NMR of Compound 5 (00 MHz, CDCl 3) 26

27 N MeOOC CN HN COOEt OMsO OMs H NMR of Compound 4 (400 MHz, CDCl 3) N MeOOC CN HN COOEt OMsO OMs C NMR of Compound 4 (00 MHz, CDCl 3) 27

28 N MeOOC CN C COOEt N O OMs H NMR of Compound 6 (400 MHz, CDCl 3) N MeOOC CN C COOEt N O OMs C NMR of Compound 6 (00 MHz, CDCl 3) 28

29 H NMR of Compound 7 (400 MHz, CDCl 3) C NMR of Compound 7 (00 MHz, CDCl 3) 29

30 CONH 2 N O MeOOC N COOEt H NMR of Compound 34 (400 MHz, CDCl 3) C NMR of Compound 34 (00 MHz, CDCl 3) 30

31 H NMR of Compound 8 (400 MHz, CDCl 3) C NMR of Compound 8 (00 MHz, CDCl 3) 3

32 H NMR of Compound 9 (400 MHz, CDCl 3) H NMR of Compound 20 (400 MHz, CDCl 3) 32

33 H NMR of Compound 3b (400 MHz, CDCl 3) C NMR of Compound 3b (00 MHz, CDCl 3) 33