Photooxidations of 2-(γ,ε-dihydroxyalkyl) furans in Water: Synthesis of DE-Bicycles of the Pectenotoxins

Transcription

1 S1 Photooxidations of 2-(γ,ε-dihydroxyalkyl) furans in Water: Synthesis of DE-Bicycles of the Pectenotoxins Antonia Kouridaki, Tamsyn Montagnon, Maria Tofi and Georgios Vassilikogiannakis* Department of Chemistry, University of Crete, Vasilika Vouton, Iraklion, Crete, Greece Table of contents Part A: Experimental procedures..s2 S10 Part B: Copies of 1 H- and 13 C-NMR spectra..s11 S31

2 S2 Part A: Experimental Procedures R 1 2 R 2 a: R 1 =, R 2 =H b: R 1 =, R 2 = c: R 1 =H, R 2 = A solution of methyl furan (42 mmol), acrolein or methyl vinyl ketone (21 mmol) and hydroquinone (0.42 mmol) in H 2 :CH 3 CH (15 ml:1.5 ml) was heated in a sealed tube at 130 o C for 40 minutes. In the case of substrate 2c, 20 equiv. of furan compared to methyl vinyl ketone were used in order to minimise contamination by the product of disubstitution of the furan. The reaction mixture was left to cool to room temperature, aq. NaHC 3 (5 ml) and Et 2 (25 ml) were then added and the resultant mixture stirred for 15 minutes. The phases were separated and the organic layer was washed with aq. NaHC 3 (3 5 ml), dried with Na 2 S 4 and concentrated in vacuo. In all cases, the products were pure enough to be used in the following step without chromatographic purification (2.6 g, 90% for 2a, 3.0 g, 95% for 2b, 2.2 g, 75% for 2c). 2a: 1 H NMR (300 MHz, CDCl 3 ): δ = 9.77 (t, J = 1.2 Hz, 1H), 5.86 (d, J = 3.0 Hz, 1H), 5.83 (brs, 1H), 2.90 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.22 (s, 3H) ppm; 13 C NMR (75 MHz, CDCl 3 ): δ = 201.2, 151.8, 150.6, 105.9, 105.8, 41.8, 20.6, 13.2 ppm. 2b: 1 H NMR (300 MHz, CDCl 3 ): δ = 5.84 (d, J = 3.0 Hz, 1H), 5.82 (brs, 1H), 2.84 (m, 2H), 2.75 (m, 2H), 2.22 (s, 3H), 2.15 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ = 207.5, 152.6, 150.5, 105.8, 105.7, 41.8, 29.8, 22.2, 13.4 ppm. 2c: 1 H NMR (300 MHz, CDCl 3 ): δ = 7.28 (d, J = 1.0 Hz, 1H), 6.26 (dd, J 1 = 3.1 Hz, J 2 = 1.0 Hz, 1H), 5.99 (d, J = 3.1 Hz, 1H), 2.90 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H), 2.16 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ = 207.3, 154.4, 141.0, 110.1, 105.1, 41.5, 29.7, 22.0 ppm.

3 S3 To a solution of furan 2a or 2b (10 mmol) in anhydrous THF (30 ml) at 0 o C, a solution of CH 2 =CHMgBr (13 ml of 1M in THF, 13 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and after 1 hour stirring the reaction solution was diluted with Et 2 (30 ml) and washed with aq. NH 4 Cl (10 ml). The phases were separated and the organic phase was dried with Na 2 S 4 and concentrated in vacuo. Flash column chromatography (silica gel, petroleum ether:etac = 20:1 10:1) afforded the desired olefins 3a (1.4 g, 85%) and 3b (1.3 g, 72%). 3a: 1 H NMR (300 MHz, CDCl 3 ): δ = 5.89 (m, 3H), 5.24 (td, J 1 = 17.2 Hz, J 2 = 1.2 Hz, 1H), 5.13 (dd, J 1 = 10.4 Hz, J 2 = 1.2 Hz, 1H), 4.15 (q, J = 6.3 Hz, 1H), 2.68 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.86 (brs, -H), 1.85 (q, J = 6.9 Hz, 2H) ppm; 13 C NMR (75 MHz, CDCl 3 ): δ = 153.6, 150.3, 140.7, 114.9, 105.8, 105.5, 72.3, 35.2, 23.9, 13.4 ppm. 3b: 1 H NMR (300 MHz, CDCl 3 ): δ = 5.92 (dd, J 1 = 17.3 Hz, J 2 = 10.7 Hz, 1H), 5.84 (d, J = 3.4 Hz, 2H), 5.24 (dd, J 1 = 17.3 Hz, J 2 = 1.0 Hz, 1H), 5.09 (dd, J 1 = 10.7 Hz, J 2 = 1.0 Hz, 1H), 2.63 (m, 2H), 2.24 (s, 3H), 1.86 (m, 2H), 1.72 (brs, -H), 1.32 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ = 154.1, 150.2, 144.5, 112.0, 105.7, 105.1, 72.9, 40.2, 27.8, 22.7, 13.4 ppm. BH 3 THF (21 ml of 1.0 M solution in THF, 21 mmol) was added to a solution of the olefins 3a and 3b prepared above (7 mmol) in dry THF (20 ml) at room temperature and the mixture was stirred for 2 h. Thereafter, a solution of NaH (3M aq., 16.3 ml) was slowly introduced into the flask and the mixture was stirred for 30 min, before 30% aq. H 2 2 (16.3 ml) was added dropwise. The reaction mixture was stirred for a

4 S4 further 30 minutes, after which time it was partitioned between Et 2 (20 ml) and H 2 (10 ml). The layers were separated and the organic layer was washed with brine (10 ml) and dried with Na 2 S 4. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica gel, petroleum ether:etac = 10:1 1:3) to afford the desired diols 4a (1.05 g, 82%) and 4b (970 mg, 70%). 4a: 1 H NMR (300 MHz, CDCl 3 ): δ = 5.83 (d, J = 2.7 Hz, 1H), 5.81 (brs, 1H), 3.96 (brs, -H plus 1H), 3.77 (m, -H plus 2H), 2.65 (m, 2H), 2.21 (s, 3H), 1.76 (q, J = 7.2 Hz, 2H), 1.67 (m, 2H) ppm; 13 C NMR (75 MHz, CDCl 3 ): δ = 153.6, 150.1, 105.7, 105.3, 70.2, 60.6, 38.2, 35.7, 24.0, 13.3 ppm; HRMS (TF ESI): calcd for C 10 H 16 3 Na: [M + Na] + ; found: b: 1 H NMR (300 MHz, CDCl 3 ): δ = 5.84 (d, J = 2.9 Hz, 1H), 5.82 (brs, 1H), 3.87 (brd, J = 4.3 Hz, 2H), 3.48 (brs, -H), 3.32 (brs, -H), 2.64 (m, 2H), 2.22 (s, 3H), 1.82 (m, 3H), 1.69 (m, 1H), 1.25 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ = 154.0, 150.2, 105.8, 105.1, 73.2, 59.5, 41.4, 40.4, 26.3, 22.6, 13.4 ppm; HRMS (TF ESI): calcd for C 11 H 19 3 : [M + H] + ; found: To a solution of ketone 2b or 2c (10 mmol) in anhydrous THF (30 ml) at 0 o C, a solution of CH 2 =CHCH 2 MgCl (6.5 ml of 2 M in THF, 13 mmol) was added dropwise. The reaction mixture was stirred for 1 hour at room temperature and then Et 2 (30 ml) and aq. NH 4 Cl (10 ml) were added. The organic layer was dried with Na 2 S 4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, petroleum ether:etac = 20:1 10:1) to afford pure alcohols (1.7 g, 87% for R = -, 1.4 g, 78% for R = -H). For R = - : 1 H NMR (300 MHz, CDCl 3 ): δ = 5.87 (m, 1H), 5.85 (d, J = 3.4 Hz, 1H), 5.83 (d, J = 3.4 Hz, 1H), 5.14 (m, 2H), 2.68 (dd, J 1 = 10.1 Hz, J 2 = 6.6 Hz, 2H), 2.26 (d, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.80 (dd, J 1 = 10.1 Hz, J 2 = 6.6 Hz, 2H), 1.21

5 S5 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ = 154.2, 150.2, 133.7, 118.8, 105.8, 105.1, 71.7, 46.4, 39.8, 26.5, 22.6, 13.4 ppm. For R = - H: 1 H NMR (300 MHz, CDCl 3 ): δ = 7.30 (d, J = 1.1 Hz, 1H), 6.27 (t, J = 2.4 Hz, 1H), 5.99 (d, J = 2.9 Hz, 1H), 5.87 (m, 1H), 5.16 (d, J = 10.2 Hz, 1H), 5.14 (d, J = 16.9 Hz, 1H), 2.74 (dd, J 1 = 9.9 Hz, J 2 = 6.7 Hz, 2H), 2.27 (d, J = 7.2 Hz, 2H), 1.82 (dd, J 1 = 9.9 Hz, J 2 = 6.7 Hz, 2H), 1.22 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ = 156.1, 140.8, 133.6, 119.0, 110.1, 104.5, 71.7, 46.4, 39.6, 26.5, 22.5 ppm. To a solution of the olefins prepared above (1.8 mmol) in t-buh:h 2 (8 ml:8 ml) AD-mix-β was added (in four portions each of 750 mg, one every 8 hours) at room temperature and the reaction mixture was stirred for a total of 48 hours. EtAc (8 ml) was then added, followed by Na 2 S 3 (9.0 g) and the stirring was continued for 1 hour, until complete separation of the two phases was seen. The phases were separated and the aqueous phase was re-extracted with EtAc (10 ml). The combined organic phases were dried with Na 2 S 4 and concentrated in vacuo. Column chromatography purification afforded the desired triols (213 mg, 52% for 6b, 250 mg, 65% for 6c). 6b: Mixture of 2 diastereoisomers in 1:1 ratio. 1 H NMR (300 MHz, D 2 ) for both diastereoisomers: δ = 5.98 (d, J = 2.8 Hz, 2H), 5.96 (brs, 2H), 3.96 (m, 2H), 3.54 (m, 2H), 3.46 (m, 2H), 3.16 (s, 4 H), 2.63 (m, 4H), 2.22 (s, 6H), 1.85 (m, 4H), 1.64 (m, 4H), 1.28 (s, 3H for one diastereoisomer), 1.26 (s, 3H for one diastereoisomer); 13 C NMR (75 MHz, D) for both diastereoisomers: δ = 155.5, 155.4, (2C), (2C), 106.1, 106.0, 73.4, 73.2, 70.7, 70.5, 67.8, 67.7, 44.1, 43.4, 42.5, 41.0, 27.3, 26.5, 23.9, 23.4, 13.3 (2C) ppm; HRMS (TF ESI): calcd for C 12 H 21 4 : [M + H] + ; found:

6 S6 6c: Mixture of 2 diastereoisomers in 1:1 ratio. 1 H NMR (300 MHz, D 2 ) for both diastereoisomers: δ = 7.41 (s, 2H), 6.38 (s, 2H), 6.12 (d, J = 2.7 Hz, 2H), 3.95 (m, 2H), 3.54 (td, J 1 = 11.3 Hz, J 2 = 3.4 Hz, 2H), 3.45 (m, 2H), 2.71 (m, 4H), 1.89 (m, 4H), 1.65 (m, 4H), 1.29 (s, 3H for one diastereoisomer), 1.27 (s, 3H for one diastereoisomer) ppm; 13 C NMR (75 MHz, D 2 ) for both diastereoisomers: δ = (2C), (2C), (2C), (2C), 72.7, 72.5, 68.8, 68.7, 66.3, 66.2, 42.8, 42.6, 39.4, 39.3, 25.4 (2C), 22.1, 21.9 ppm; HRMS (TF ESI): calcd for C 11 H 18 4 Na: [M + Na] + ; found: To a solution of the alcohol 4a (900 mg, 4.9 mmol) in dry DMF (15 ml) at room temperature, imidazole (400 mg, 5.9 mmol), TBSCl (735 mg, 4.9 mmol) and 4- DMAP (30 mg, 0.2 mmol) were added. After the mixture had been stirred for 12 hours at this temperature, the reaction was quenched with H (0.5 ml). The stirring continued for a further 1 hour, after which time the mixture was partitioned between Et 2 (30 ml) and H 2 (4x10 ml). The organic phase was dried over Na 2 S 4 and the solvent was removed in vacuo. The desired mono-protected alcohol was isolated (1.17 g, 80%) by flash column chromatography (silica gel, petroleum ether:etac = 50:1 40:1). 1 H NMR (300 MHz, CDCl 3 ): δ = 5.86 (d, J = 2.7 Hz, 1H), 5.83 (brs, 1H), 3.85 (m, 3H), 3.45 (d, J = 2.5 Hz, -H), 2.70 (m, 2H), 2.24 (s, 3H), 1.76 (m, 2H), 1.66 (m, 2H), 0.9 (s, 9H), 0.07 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ): δ = 154.2, 150.2, 105.8, 105.3, 71.3, 62.7, 38.2, 35.8, 25.8 (3C), 24.2, 18.1, 13.5, -5.6 (2C) ppm. To a solution of the mono-protected alcohol prepared above (1.17 g, 3.9 mmol) in dry DMS (23 ml) at room temperature, IBX (1.24 g, 4.4 mmol) was added. After 12

7 S7 hours of stirring at the same temperature, the mixture was filtrated in order to remove the precipitate. The precipitate was washed with Et 2 (10 ml) and this solution, combined with the filtrate, was partitioned between Et 2 (30 ml) and aq. NaHC 3 (15 ml). The phases were separated and the organic layer was re-extracted with H 2 (5 10 ml), to ensure complete removal of DMS. The organic phase was dried with Na 2 S 4 and concentrated in vacuo, to afford the ketone (877 mg, 75%). The crude product was used in the next step without chromatographic purification. To a solution of CH 3 PPh 3 I (1.58 g, 3.9 mmol) in dry THF (13 ml), at 0 o C, a solution of n-buli (2.4 ml of 1.6 M in hexane, 3.9 mmol) was added dropwise. The solution was warmed to room temperature and stirred for 1 h. Thereafter, the red reaction solution was re-cooled to 0 o C and a solution of the ketone prepared above (877 mg, 3.0 mmol) in dry THF (8 ml) was added. The reaction was warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated to half its previous volume and then diluted with petroleum ether (40 ml). The Ph 3 P= that had precipitated, was removed by filtration and the remaining solution was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether:etac = 1:0 50:1) to afford the olefin 8 (662 mg, 75%). 1 H NMR (300 MHz, CDCl 3 ): δ = 5.84 (d, J = 2.6 Hz, 2H), 4.80 (s, 1H), 4.78 (s, 1H), 3.71 (t, J = 7.1 Hz, 2H), 2.71 (t, J = 8.0 Hz, 2H), 2.34 (t, J = 8.0 Hz, 2H), 2.27 (t, J = 7.1, 2H), 2.25 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H) ppm; 13 C NMR (75 MHz, CDCl 3 ): δ = 153.9, 150.2, 146.0, 110.9, 105.8, 105.3, 62.4, 39.5, 34.8, 26.6, 25.9 (3C), 18.3, 13.5, -5.3 (2C) ppm. TBAF (2.7 ml of 1.0 M in THF, 2.7 mmol) was added dropwise to a solution of the olefin 8 (662 mg, 2.2 mmol) in dry THF (13 ml) at 0 o C. The solution was warmed to room temperature and stirred for 1 hour after which time it was diluted with EtAc (10 ml) and washed with H 2 (8 ml). The organic layer was dried with Na 2 S 4 and concentrated in vacuo. The primary alcohol was isolated (350 mg, 88%) by flash column chromatography (silica gel, petroleum ether:etac = 10:1 6:1).

8 S8 1 H NMR (300 MHz, CDCl 3 ): δ = 5.86 (d, J = 2.6 Hz, 1H), 5.84 (brs, 1H), 4.91 (s, 1H), 4.87 (s, 1H), 3.72 (t, J = 6.3 Hz, 2H), 2.73 (t, J = 7.9 Hz, 2H), 2.34 (m, 4H), 2.25 (s, 3H) ppm; 13 C NMR (75 MHz, CDCl 3 ): δ = 153.6, 150.3, 145.0, 112.1, 105.8, 105.5, 60.3, 39.3, 34.1, 26.5, 13.5 ppm. To a solution of the alcohol prepared above (200 mg, 1.1 mmol) in t-buh:h 2 (8 ml:8 ml) at room temperature, AD-mix-β was added (in four portions of 550 mg, one every 8 hours) and the reaction mixture was stirred for a total of 48 hours. Afterwards, EtAc (8 ml) and Na 2 S 3 (9.0 g) were added and the stirring was continued for a further 1 h. The phases were separated and the aqueous phase was reextracted with EtAc (10 ml). The combined organic phases were dried with Na 2 S 4 and concentrated in vacuo. Column chromatography purification (silica gel, petroleum ether:etac = 1:1 1:3) afforded the desired triol 9 (144 mg, 61%). 1 H NMR (300 MHz, D): δ = 5.86 (d, J = 3.0 Hz, 1H), 5.83 (brs, 1H), 3.74 (t, J = 6.7 Hz, 2H), 3.48 (d, J 1 = 11.6 Hz, 1H), 3.44 (d, J 1 = 11.6 Hz, 1H), 2.63 (brt, J = 8.5 Hz, 2H), 2.20 (s, 3H), 1.81 (m, 4H) ppm; 13 C NMR (75 MHz, D): δ = 155.5, 151.2, 106.8, 106.1, 74.9, 68.1, 59.0, 39.5, 36.4, 23.0, 13.4 ppm; HRMS (TF ESI): calcd for C 11 H 18 4 Na: [M + Na] + ; found: General procedure for photooxidation-reduction-cyclization of 2-(γ,εdihydroxyalkyl) furans to DE-type bicyclic ketals. Furanols 4a,b, 6b,c and 9 (0.25 mmol) were dissolved in CH 2 Cl 2, or H 2, (5 ml), containing catalytic amounts of methylene blue, or rose Bengal, as photosensitizer (10-4 M), respectively. The solutions were cooled with an ice bath. xygen was gently bubbled through the solution while it was irradiated with a xenon Variac Eimac Cermax 300 W lamp for 2 15 minutes. The reaction was monitored by TLC. In the case where the reaction solvent was CH 2 Cl 2, an excess of 2 S (50 µl) was added to

9 S9 the crude mixture and the solution was stirred for 12 hours at room temperature. In the case where H 2 was the photooxidation solvent, extractions of the photooxygenation mixture with EtAc (3 5 ml) were undertaken. The combined organic phases were dried with MgS 4 and then treated (as previously) with an excess of 2 S (50 µl) for 12 hours. Afterwards, a catalytic amount of p-tsh (5 mg) was added and the solution was stirred for 3 more hours at the same temperature. The reaction solution was concentrated in vacuo and purified by flash column chromatography (silica gel, petroleum ether:etac = 5:1 3:1 for 5a,b, 5:1 1:1 for 7b,c and 3:1 1:2 for 10) to afford the pure bicyclic ketals 5a (60% in CH 2 Cl 2 and 64% in H 2 ) 5b (58% in CH 2 Cl 2 and 55% in H 2 ), 7b (74% in CH 2 Cl 2 and 77% in H 2 based on dr = 1:1 for the starting material), 7c (68% in CH 2 Cl 2 and 73% in H 2 based on dr = 1:1 for the starting material), and 10 (58% in CH 2 Cl 2 and 60% in H 2 ). 5a 5a: 1 H NMR (300 MHz, CDCl 3 ): δ = 6.68 (d, J = 16.1 Hz, 1H), 6.41 (d, J = 16.1 Hz, 1H), 4.66 (m, 1H), 4.02 (m, 2H), 2.27 (s, 3H), 2.21 (m, 2H), 1.97 (m, 2H), 1.27 (m, 2H) ppm; 13 C NMR (75 MHz, CDCl 3 ): δ = 198.5, 143.3, 130.4, 103.6, 76.0, 59.7, 34.6, 30.7, 28.1, 27.5 ppm; HRMS (TF ESI): calcd for C 10 H 14 3 Na: [M + Na] + ; found: b 5b: 1 H NMR (300 MHz, CDCl 3 ): δ = 6.69 (d, J = 16.1 Hz, 1H), 6.42 (d, J = 16.1 Hz, 1H), 4.00 (m, 2H), 2.27 (s, 3H), (m, 4H), 1.40 (s, 3H), 1.35 (m, 2H); 13 C NMR (75 MHz, CDCl 3 ): δ = 198.5, 143.5, 130.4, 104.1, 81.8, 60.4, 36.3, 35.9, 34.4, 27.3, 26.0 ppm; HRMS (TF ESI): calcd for C 11 H 16 3 Na: [M + Na] + ; found:

10 S10 H 7b 7b: 1 H NMR (300 MHz, CDCl 3 ): δ = 6.71 (d, J = 16.2 Hz, 1H), 6.43 (d, J = 16.2 Hz, 1H), 4.06 (m, 1H), 3.67 (m, 1H), 3.57 (m, 1H), 2.28 (s, 3H), 2.23 (m, 1H), 2.10 (dt, J 1 = 12.8 Hz, J 2 = 4.4 Hz, 1H), (m, 3H), 1.68 (brt, J = 12.1 Hz, 1H), 1.41 (s, 3H), 1.38 (dd, J 1 = 13.6 Hz, J 2 = 4.4 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ = 198.6, 143.2, 130.5, 104.2, 81.5, 70.5, 65.6, 37.7, 36.3, 34.7, 27.2, 25.9 ppm; HRMS (TF ESI): calcd for C 12 H 19 4 : [M + H] + ; found: H 7c 7c: 1 H NMR (300 MHz, CDCl 3 ): δ = 9.61 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 15.8 Hz, 1H), 6.44 (dd, J 1 = 15.8 Hz, J 2 = 7.8 Hz, 1H), 4.09 (m, 1H), 3.69 (m, 1H), 3.58 (m, 1H), 2.27 (m, 1H), 2.12 (dt, J 1 = 13.1 Hz, J 2 = 4.4 Hz, 1H), (m, 3H), 1.72 (brt, J = 12.5 Hz, 1H), 1.43 (s, 3H), 1.39 (dd, J 1 = 9.8 Hz, J 2 = 6.4 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ): δ = 193.4, 152.5, 131.9, 104.1, 81.7, 70.6, 65.6, 37.7, 36.3, 34.6, 25.9 ppm; HRMS (TF ESI): calcd for C 11 H 16 4 Na: [M + Na] + ; found: H 10: 1 H NMR (300 MHz, CDCl 3 ): δ = 6.66 (d, J = 16.0 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.06 (m, 2H), 3.72 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 12.0 Hz, 1H), 2.26 (s, 3H), 2.24 (m, 1H), 2.08 (m, 3H), 1.81 (m, 1H), 1.26 (td, J 1 = 12.6 Hz, J 2 = 2.3 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ = 198.4, 142.9, 130.5, 104.3, 84.4, 66.7, 59.9, 35.4, 31.4, 28.9, 27.4 ppm; HRMS (TF ESI): calcd for C 11 H 16 4 Na: [M + Na] + ; found:

11 S11 Part B: Copies of 1 H- and 13 C-NMR spectra H (2a, 300 MHz, CDCl 3 ) without chromatographic purification (2a, 75 MHz, CDCl 3 ) without chromatographic purification

12 S12 (2b, 300 MHz, CDCl 3 ) without chromatographic purification (2b, 75 MHz, CDCl 3 ) without chromatographic purification

13 S13 H (3a, 300 MHz, CDCl 3 ) (3a, 75 MHz, CDCl 3 )

14 S14 H (3b, 300 MHz, CDCl 3 ) (3b, 75 MHz, CDCl 3 )

15 S15 H H (4a, 300 MHz, CDCl 3 ) (4a, 75 MHz, CDCl 3 )

16 S16 H H (4b, 300 MHz, CDCl 3 ) (4b, 75 MHz, CDCl 3 )

17 S17 (5a, 300 MHz, CDCl 3 ) (5a, 75 MHz, CDCl 3 )

18 S18 (5b, 300 MHz, CDCl 3 ) (5b, 75 MHz, CDCl 3 )

19 S19 (2c, 300 MHz, CDCl 3 ) without chromatographic purification (2c, 75 MHz, CDCl 3 ) without chromatographic purification

20 S20 H (300 MHz, CDCl 3 ) H (75 MHz, CDCl 3 )

21 S21 H (300 MHz, CDCl 3 ) H (75 MHz, CDCl 3 )

22 S22 H H H (6b, 300 MHz, D 2, 1:1 mixture of diastereoisomers) (6b, 75 MHz, D, 1:1 mixture of diastereoisomers)

23 S23 H H H (6c, 300 MHz, D 2, 1:1 mixture of diastereoisomers) (6c, 75 MHz, D 2, 1:1 mixture of diastereoisomers)

24 S24 H (7b, 300 MHz, CDCl 3 ) (7b, 75 MHz, CDCl 3 )

25 S25 H H (7c, 300 MHz, CDCl 3 ) (7c, 125 MHz, CDCl 3 )

26 S c H H H 4 6 H H H 8,H 9 H 6 H 10 H c H H H 4 6 H H H 8,H 9 H 6 H 10 H 5

27 S27 H TBS (300 MHz, CDCl 3 ) H TBS (75 MHz, CDCl 3 )

28 S28 (8, 300 MHz, CDCl 3 ) TBS (8, 75 MHz, CDCl 3 )

29 S29 (300 MHz, CDCl 3 ) H (75 MHz, CDCl 3 ) H

30 S30 H H H (9, 300 MHz, D) H 2 (9, 75 MHz, D)

31 S31 H (10, 300 MHz, CDCl 3 ) (10, 75 MHz, CDCl 3 )