Total Synthesis of Antheliolide A

Transcription

1 Total Synthesis of Antheliolide A Chandra Sekhar Mushti, Jae-Hun Kim and E. J. Corey* Department of Chemistry and Chemical Biology Harvard University 12 Oxford Street, Cambridge, Massachusetts Supplementary Materials General Procedures: All reactions were performed under an atmosphere of N 2 in flame dried glassware using freshly distilled anhydrous solvents, unless otherwise stated. Dry tetrahydrofuran (THF), toluene (C 7 H 8 ), benzene (C 6 H 6 ), diethyl ether (Et 2 O), methylene chloride (CH 2 Cl 2 ) and triethylamine (Et 3 N) were freshly distilled just before use over Na/benzophenone (THF, Et 2 O, C 6 H 6, C 7 H 8 ) or CaH 2 (CH 2 Cl 2, Et 3 N). Reagent such as Bu 3 SnCH 2 I and PhS(O)Cl were made using literature known procedures just before use. Yields refer to chromatographically and spectroscopically ( 1 H NMR and 13 C NMR) homogenous material, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as a visualizing agent and aqueous solution of either ceric ammoniummolybdate (CAM) or basic potassium permanganate and heat as developing agents. E.Merck silica gel (60 particle size mm) was used for flash column chromatography. Preparative thing layer chromatography S 1

2 separations were carried out on 0.50 mm E. Merck silica gel plates (60F- 254). NMR spectra were recorded on Bruker DRX 500, Varian Unity/INOVA 500, INOVA 600 or Varian Mercury 400 instruments and calibrated using residual undeuterated solvent as an internal standard. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad. IR spectra were recorded either on Thermo-Nicolet Avatar 360 FT-IR on a diamond crystal or Applied Systems (ASI) ReactIR 1000 spectrometers. Optical rotations were measured on Perkin- Elmer 241 polarimeter using Na lamp in a 1 ml cell having 1 decimeter length. Electrospray ionization (ESI) mass spectrometry (MS) experiments were performed on a Platform II mass spectrometer (Micromass, Inc., Beverly, MA). High-resolution mass spectra (HRMS) were recorded on an LCT mass spectrometer (Micromass, Inc., Beverly, MA) using a mass resolution of Abbreviations: TBDPS = tert-butyldiphenylsilyl, DMAP = 4- dimethylaminopyridine, PPTS = pyridinium 4-methylbenzenesulfonate, TsCl = 4- methylbenzenesulfonyl chloride, dba = trans, trans-dibenzylideneacetone, dppb = 1,4- diphenylphosphino butane, KHMDS = potassium bis(trimethylsilyl)amide. Preparation of Vinyl Bromide 2. To a suspension of CuCN (484 mg, 5.4 mmol, 0.1 equiv.) in 10 ml of anhydrous THF at 78 C was added a solution of prenylmagnesium bromide (54 mmol, 0.3 M in THF) over a period of 30 min. The resulting pale yellow suspension was stirred at the same temperature for 30 min, then a solution of 2,3-dibromopropene (5.6 ml, 54 mmol, 1.0 equiv.) in 10 ml of anhydrous THF was added over a period of 15 min. The resulting white suspension was stirred at the same temperature for 2 h and quenched with saturated aqueous NH 4 Cl solution. The resulting biphasic reaction mixture was concentrated and filtered through Celite and washed thoroughly with pentane. The organic layer was separated and the aqueous layer was extracted with pentane (2 X 100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated. The resultant residue was purified by flash chromatography (silica gel, hexanes) to give desired vinyl bromide 2 (9.3 g, yield 91 %) as a colorless liquid. 2: R f = 0.9 (silica gel, hexanes); IR (thin film) ν max 2970, 2927, 1629, 1445, , 884 cm - S 2

3 1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 5.55 (bs, 1 H), 5.39 (bs, 1 H), 5.08 (m, 1 H), 2.44 (m, 2 H), 2.25 (m, 2 H), 1.69 (s, 3 H), 1.63 (s, 3 H). 13 C NMR (125 MHz, CDCl 3 ) δ 134.4, 132.9, 122.2, 116.4, 41.5, 26.6, 25.6, Preparation of Trienol 4. To a solution of vinyl bromide 2 (5.12 g, 27.2 mmol, 1.2 equiv) in 30 ml of anhydrous Et 2 O at 78 C and a solution of t-buli (1.7 M in pentane, 29.4 ml, 50 mmol, 1.8 equiv) was added over a period of 30 min at 78 C. The resulting solution was warmed to 20 C over a period of 4 h, during this period the color of the changed from pale to bright yellow. After this time the reaction was cooled to 78 C and a solution of TBDPS-protected ε-hydroxy aldehyde 3 (8.3 g, 22.7 mmol) in 30 ml of anhydrous Et 2 O was added over a period of 15 min, after 2 h at 78 C saturated aqueous NH 4 Cl solution was added. The organic layer was separated and the aqueous layer was extracted with Et 2 O (2 X 50 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated. The resultant pale yellow oil was purified by flash column chromatography (silica gel, hexane EtOAc, 19:1 9:1) to give trienol 4 (9.5 g, yield 90%) as a colorless viscous oil.(9.5 g, yield 90%). 4: R f = 0.42 (silica gel, PhCH 3 - Et 2 O, 9: 1); IR (thin film) ν max 3371, 2931, 1111, 1050 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (m, 4 H), 7.39 (m, 6 H), 5.4 (m, 1 H), 5.13 (m, 1 H), 5.05 (bs, 1 H), 4.89 (d, J = 1.5 Hz, 1 H), 4.21 (d, J = 3.5 Hz, 2H), 4.05 (dd, J = 7, 5 Hz, 1H), 2.17 (m, 2 H), (m, 6 H), 1.70 (s, 3 H), 1.63 (s, 3 H), 1.45 (s, 3 H), 1.05 (s, 9 H); 13 C NMR (100 MHz, CDCl 3 ) δ 151.9, 137.1, 135.9, 134.3, 132.2, 129.8, 127.9, 124.7, 124.3, 110.0, 75.4, 61.4, 35.8, 33.6, 31.6, 27.1, 26.9, 25.9, 19.4, 18.0, 16.6; HRMS (ESI) calcd for C 31 H 44 O 2 Si + [M + NH 4 ] , found: Preparation of the Z-Homoallyl Alcohol 5. A suspension of KH (washed with hexane and dried in vacuum prior to use) (1.17 g, 29.3 mmol, 2 equiv) in 20 ml of anhydrous THF was cooled to 40 C and added a solution of trienol 4 (7 g, mmol) in 30 ml of anhydrous THF over a period of 15 min. The resulting suspension was warmed to 20 C over 30 min. Freshly prepared Bu 3 SnCH 2 I (8.2 g, mmol, 1.3 equiv) was then added at 20 C and the reaction was allowed to proceed for 16 h with S 3

4 gradual warming 0 C. The reaction was quenched by slow addition of crushed ice at 0 C. The organic layer was separated and the aqueous layer was extracted with hexane (2 X 50 ml), the combined organic layers were washed with saturated brine (2 X 100 ml) dried over anhydrous MgSO 4 and concentrated. The crude yellow oil was subjected to rearrangement without purification. This crude yellow product was dissolved in 60 ml of anhydrous THF and cooled 78 C and to it n-buli (1.58 M in hexanes, 13.5 ml, 21.3 mmol, 1.5 equiv) was added slowly along the walls of the flask over period of 15 min. The resultant dark brown reaction mixture was stirred for 3 h at 78 C. After this period the reaction was quenched by addition saturated aqueous NH 4 Cl solution. The organic layer was separated and the aqueous layer was extracted with Et 2 O (2 X 50 ml). The combined organic layers were washed with saturated brine (2 X 100 ml), dried over anhydrous MgSO 4 and concentrated. The residue was purified by flash column chromatography (silica gel, hexanes EtOAc, 1: 0 4: 1) to give pure the Z-homoallyl alcohol 5 (4.54 g, yield 61% for two steps) as a colorless viscous oil. 5: R f = 0.28 (silica gel, hexanes EtOAc, 5: 1); IR (thin film) ν max 3317, 2958, 2929, 2855, 1425, 1111, 1045, 698 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 7.75 (m, 4 H), 7.43 (m, 6 H), 5.45 (m, 1 H), 5.35 (m, 1 H), 5.14 (m, 1 H), 4.28 (d, J = 6.1 Hz, 2 H), 3.68 (t, J = 7 Hz, 2 H), 2.37 (t, J = 7 Hz, 2 H), 2.18 (m, 2 H), 2.12 (m, 2 H), 2.05 (m, 4 H), 1.73 (s, 3 H), 1.64 (s, 3 H), 1.49 (s, 3 H), 1.10 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 136.9, 135.7, 135.2, 134.2, 131.7, 129.7, 127.7, 127.7, 124.5, 124.2, 61.3, 61.1, 39.9, 37.0, 33.7, 27.1, 27.0, 26.3, 25.9, 19.3, 17.9, 16.5; HRMS (ESI) calcd For C 32 H 46 O 2 Si + [M+NH 4 ] + calcd for , found Preparation of the Racemic Dimethyl Acetal 6. To a solution of the Z- homoallyl alcohol 5 (4.5 g, 9.27 mmol) in 40 ml of dry CH 2 Cl 2 at 22 o C was added Dess-Martin periodinane reagent (4.7 g, mmol, 1.2 equiv) and reaction was allowed to proceed for 30 min at 22 C. After the reaction was complete, all the CH 2 Cl 2 was removed in vacuum and the residue was triturated with hexane. All the solids were removed by filtration through a Celite pad and the hexane solution was concentrated in vacuum to give analytically pure aldehyde which was used in the next step without any purification. The aldehyde was dissolved in trimethyl orthoformate 10 ml (~10 equiv) S 4

5 and to it was added pyridinium tosylate (140 mg, 0.56 mmol, 5 mol %) was added. The reaction was allowed to proceed at 22 C over night. After the reaction was complete, the excess methyl orthoformate was removed in vacuum and the residue was dissolved in Et 2 O and washed with water (2 X 50 ml) and brine (2 X 50 ml), and then dried over anhydrous Na 2 SO 4. The organic layer was concentrated and the residue was purified by flash column chromatography (silica gel, hexanes EtOAc, 1: 0 49: 1) to give pure racemic dimethyl acetal 6 (4.15 g, yield 85%) as a colorless oil. rac-6: R f = 0.43 (silica gel, hexanes EtOAc, 9: 1); IR (thin film): ν max 2967, 2926, 2850, 1106, 1035, 697 cm -1 ; 1 H NMR (600 MHz, CDCl 3 ): δ 7.76 (m, 4 H), 7.44 (m, 6 H), 5.48 (m, 1 H), 5.32 (m, 1 H), 5.17 (m, 1 H), 4.48 (t, J = 5.4 Hz, 1 H), 4.29 (d, J = 6 Hz, 2 H), 3.38 (s, 6 H), 2.43 (d, J = 5.4 Hz, 1 H), 2.22 (m, 2 H), 2.14 (m, 4 H), 2.07 (m, 2 H), 1.74 (s, 3 H), 1.66 (s, 3 H), 1.51 (s, 3 H), 1.12 (s, 9 H); 13 C NMR (100 MHz, CDCl 3 ) δ 137.1, 135.9, 134.7, 134.3, 131.7, 129.8, 127.9, 127.3, 124.5, , 104.6, 61.4, 53.6, 39.9, 37.7, 34.2, 27.1, 26.6, 26.0, 19.4, 18.0, 16.6; HRMS(ESI) calcd for C 34 H 50 O 3 Si + [M+NH 4 ] found Preparation of the Racemic Mixed Acetal Methyl Ester 7. To a mixture of dimethyl acetal 6 (4.15 g, 7.77 mmol) and methyl glycolate (9 ml, mmol, 15 equiv), pyridinium tosylate (58 mg, mmol, 3 mol %) was added and the reaction was heated in a preheated oil bath whose temperature was maintained between 60 to 65 o C. The biphasic reaction mixture was vigorously stirred and continuously purged with a slow stream of dry N 2 gas to remove the MeOH generated during the reaction. The reaction was continued at the same temperature until the reaction mixture became homogenous (usually within 1.5 to 2 h). The reaction mixture was then cooled and transferred to a separatory funnel using Et 2 O, and then washed with water (3 X 25 ml) and brine (2 X 25 ml). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (silica gel, hexanes EtOAc, 1:0 9:1 to give racemic mixed acetal methyl ester 7 (3.34 g, yield 73 %) and 664 mg of starting dimethyl acetal 6 along with aldehyde, which can be recycled to the dimethyl acetal by treating methyl orthoformate and PPTS as before. rac-7: R f = 0.23 (silica gel, hexanes EtOAc, 9:1); IR (thin film) ν max 3072, 2931, 2858, 1760, 1428, S 5

6 1382, 1206, 1111 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 7.69 (m, 4 H), 7.39 (m, 6 H), 5.40 (m, 1 H), 5.25 (m, 1 H), 5.10 (m, 1 H), 5.09 (m, 1 H), 4.64 (t, J = 4.5 Hz, 1 H), 4.22 (bd, J = 6 Hz, 2 H), 4.17 (ABd, J = 16 Hz, 1 H), 4.15 (ABd, J = 16 Hz, 1 H), 3.75 (s, 3 H), 3.35 (s, 3 H), 2.41 (d, J = 4.5 Hz, 2 H), 2.12 (m, 2 H), 2.06 (bs, 4 H), 2.00 (m, 2 H), 1.68 (s, 3 H), 1.59 (s, 3 H), 1.45 (s, 3 H), 1.05 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 170.9, 137.0, 135.8, 134.3, 134.2, 131.7, 129.7, 127.8, 127.5, 124.5, 124.3, 103.5, 62.5, 61.3, 53.9, 52.1, 39.8, 37.5, 34.1, 27.1, 27.0, 26.5, 25.9, 19.4, 17.9, 16.5; HRMS (ESI) calcd for C 36 H 52 O 5 Si + [M+NH 4 ] found Preparation of the rac-bicyclic Ketone 8. A mixture of the mixed acetal 7 (1.03 g, 1.74 mmol) in 8 ml of methanol and 3 N LiOH in water (1.16 ml, 3.48 mmol, 2 equiv) was allowed to react at 23 o C until all the starting material was consumed (usually in 2 h). Then all the MeOH was removed in vacuum and the residue was dissolved in water and cooled to 0 C. To this cooled solution 1.5 N oxalic acid solution in water was added slowly at 0 C until the ph of the aqueous solution was approximately The aqueous layer was immediately extracted with Et 2 O (3 X 25 ml). The combined organic layers were washed with saturated brine solution, then treated with excess anhydrous Et 3 N (approximately 5 equiv) and dried over anhydrous MgSO 4. The organic layer was concentrated in vacuum to give the triethylammonium salt of the carboxylic acid (1 g, 85% yield). The triethylammonium salt (1.0 g, 1.48 mmol) was dissolved in 15 ml of anhydrous toluene and the solution was added slowly over a period of 7 h to a refluxing solution of TsCl (850 mg, 4.46 mmol, 3 equiv) and Et 3 N (3.4 ml, mmol, 6 equiv) in 50 ml of anhydrous toluene. After the addition was complete, the reaction was allowed to proceed for an additional 2 h. Then all toluene was removed in vacuum and the residue was taken up in pyridine (~ 15 to 20 equiv), to the pyridine solution 10 equiv of water was added in portions. After stirring at 23 C for 2 h, the pyridine solution was transferred to a separatory funnel with Et 2 O and washed with water (3 X 25 ml), 1 N HCl (2 X 25 ml), saturated aqueous NaHCO 3 solution (1 X 25 ml) and finally with saturated brine (2 X 25 ml). The Et 2 O layer was finally dried over anhydrous Na 2 SO 4, concentrated in vacuum and the residue was purified by flash column chromatography (silica gel, hexanes EtOAc 1:0 19: 1) to give racemic bicyclic ketone 8 (546 mg, 66%). S 6

7 Found for rac-8: R f = 0.55 (major) and 0.47 (minor) (silica gel, Et 2 O C 7 H 8 1: 19); IR (thin film) ν max 2953, 1781, , 1074 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (m, 4 H), 7.40 (m, 6 H), 5.45 (m, 1 H), 5.24 (d, J = 4.8 Hz, 1 H), 5.13 (m, 1 H), 4.56 (d, J = 3.6Hz, 1 H), 4.25 (s, 1 H), 4.24 (s, 1 H), 3.22 (s, 3 H), 2.85 (dt, J = 7.2, 3.2 Hz, 1 H), (m, 7 H), 1.87 (m, 3 H), 1.71 (s, 3 H), 1.63 (s, 3 H), 1.45 (s, 3 H), 1.07 (s, 9 H); 13 C NMR (100 MHz, CDCl 3 ) δ 211.7, 136.5, 135.8, 134.2, 132.5, 129.8, 129.7, 127.8, 125.0, 123.7, 108.0, 93.5, 62.7, 61.2, 53.9, 46.5, 40.5, 37.8, 37.6, 27.1, 25.9, 25.5, 25.1, 19.4, 17.9, 16.4.; HRMS (ESI) calcd. for C 35 H 48 O 4 Si + [M+NH 4 ] found Preparation of the Optically Pure Propargyl Alcohols 9 and ent-9. To trimethylsilylacetylene (346 µl, 2.45 mmol, 2.5 equiv) in 3 ml of anhydrous THF was added n-buli (1.6 M in hexanes) (1.4 ml, 2.25 mmol, 2.3 equiv) at 78 C and the reaction was allowed to proceed for 30 min. In a separate flame-dried flask anhydrous cerium(iii) chloride (555 mg, 2.25 mmol, 2.3 equiv) was suspended in 5 ml of anhydrous THF and cooled to 78 C. To this cooled suspension of CeCl 3 was added the lithium- (trimethylsilyl)acetylide solution in THF and the mixture was stirred for 1 h at 78 C. To this yellow suspension a solution of the cyclobutanone (±)-8 (546 mg, 0.98 mmol) in 5 ml of anhydrous THF was added slowly over a period of 10 min. The reaction was allowed to proceed for 2 h at 78 C and quenched by addition of solid sodium sulfate decahydrate. The reaction mixture was filtered through a Celite pad, and then the Celite pad was thoroughly washed with Et 2 O. The organic layers were dried over anhydrous Na 2 SO 4 and were concentrated in vacuum to give the expected acetylenic carbinol, which was carried on to the next step without purification. The crude product was dissolved in 5 ml of MeOH and to it 3N LiOH (650 µl, 1.95 mmol, 2 equiv) was added at 23 C, and stirring was continued until all starting material was consumed (within 2 h). Then MeOH was removed in vacuo and the residue was taken up in Et 2 O and washed with water (2 X 25 ml) and saturated brine (1 X 25 ml). The organic layer was dried over anhydrous Na 2 SO 4, concentrated and purified by flash column chromatography (silica gel, hexanes EtOAc 19:1 9:1) to give pure racemic propargyl alcohol 9 (551 mg, 96%) as a colorless viscous oil whose two enatiomers was separated S 7

8 on a Chiral Technologies OD-H HPLC column with 97:3 hexane iproh as eluent to give enantiomerically pure 9 (retention time: 4.75 min) and ent-9 (retention time : 6.14 min). 9 : R f = 0.47 (silica gel, hexanes-etoac 4:1); [α] 23 D = (c = 1.3, CHCl 3 ); IR (thin film) ν max 3439, 3299, 2926, 1106, 1041 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 7.72 (m, 4 H), 7.41 (m, 6 H), 5.47 (m, 1 H), 5.23 (dd, J = 6, 2 Hz, 1 H), 5.09 (m, 1 H), 4.40 (m, 1 H), 4.25 (s, 1 H), 4.24 (s, 1 H), 4.12 (bs, 1 H), 3.52 (s, 3 H), 2.56 (s, 1 H), 2.37 (dd, J = 10, 6 Hz, 1 H), 2.11 (m, 1 H), 2.04 (dd, J = 14.5, 2 Hz, 1 H), 1.94 (m, 5 H), 1.69 (s, 3 H), 1.61 (s, 3 H), 1.47 (s, 3 H), 1.06 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 136.8, 135.7, 134.3, 134.2, 129.7, 127.8, 125.7, 124.7, 123.8, 110.7, 90.4, 87.4, 72.7, 66.0, 61.3, 56.7, 50.9, 49.8, 41.3, 38.0, 37.4, 27.0, 25.9, 24.2, 24.1, 19.3, 17.8, 16.4; HRMS (ESI) calcd. for C 37 H 50 O 4 Si + [M+NH 4 ] , found ent-9: [α] 23 D = (c = 0.61, CHCl 3 ); other spectroscopic data were identical to 9. Preparation of the Sulfinate Ester 10. To a solution of the propargylic alcohol 9 (527 mg, 0.90 mmol) in 5 ml of anhydrous CH 2 Cl 2, DMAP (28 mg, 0.23 mmol, 0.25 equiv) and Et 3 N (210 µl, 1.44 mmol, 1.5 equiv) were added and cooled to 0 o C. Then to this solution freshly prepared PhS(O)Cl (130 µl, 1.08 mmol, 1.2 equiv) was added and reaction was allowed to proceed for 2 h at the same temperature. After reaction was complete CH 2 Cl 2 was removed in vacuum, the residue was taken in Et 2 O and washed successively with water (2 X 25 ml) and brine (1 X 25 ml). Finally the organic layer was dried over anhydrous MgSO 4, concentrated and purified by flash column chromatography (silica gel, hexanes EtOAc, 4: 1) to give sulfinate ester 10 (568 mg, 94%, as a 1.6: 1 mixture of diastereomers). 10: minor diastereomer: R f = 0.21 (minor) (silica gel, C 7 H 8 - Et 2 O 19: 1); [α] 23 D = (c = 1.0, CHCl 3 ); IR (thin film) ν max 3284, 3064, 2929, 1446, 1425, 1111, 1086, 1045 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 7.84 (m, 2 H), 7.70 (m, 4 H), 7.48 (m, 3 H), 7.40 (m, 6 H), 5.38 (m, 1 H), 5.21 (dd, J = 6,3 Hz, 1 H), 5.09 (m, 1 H), 4.36 (m, 1 H), 4.22 (s, 1 H), 4.20 (s, 1 H), 3.26 (s, 3 H), 3.02 (s, 1 H), 2.53 (m, 1 H), 2.02 (dd, J = 14.5, 3 Hz, 1 H), 1.90 (m, 9 H), 1.69 (s, 3 H), 1.60 (s, 3 H), 1.35 (s, 3 H), 1.06 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 146.9, 136.5, 135.7, 134.1, 132.2, 132.0, 129.7, 128.9, 127.8, 125.2, 124.9, 123.7, 110.1, 88.9, 84.0, 80.1, 73.6, 61.2, S 8

9 55.9, 52.1, 49.7, 41.0, 38.3, 37.7, 27.0, 25.8, 24.3, 24.2, 19.3, 17.8, 16.3; HRMS (ESI) calcd. for C 43 H 54 O 5 SSi + [M+NH 4 ] found Major diastereomer: R f = 0.34 (silica gel, C 7 H 8 - Et 2 O 19: 1); [α] 23 D = -1.4 (c = 1.0, CHCl 3 ); 1 H NMR (600 MHz, CDCl 3 ) 7.96 (m, 2 H), 7.71 (m, 4 H), 7.49 (m, 3 H), 7.39 (m, 6 H), 5.46 (m, 1 H), 5.12 (m, 2 H), 4.33 (bs, 1 H), 4.24 (s, 1 H), 4.23 (s, 1 H), 3.11 (s, 3 H), 3.04 (s, 1 H), 2.49 (m, 1 H), 2.09 (m, 2 H), 1.96 (m, 7 H), 1.70 (s, 3 H), 1.62 (s, 3 H), 1.42 (s, 3 H), 1.07 (s, 9 H). Preparation of the TBDPS-protected β-keto Sulfone. The diastereomeric mixture of sulfinate esters 10 (598 mg, 0.84 mmol) was dissolved in 28 ml of anhydrous Ph-CH 3 and to it Pd 2 (dba) 3 (24 mg, mmol, 5 mol %) was added. The dark red reaction mixture was kept in an oil bath at 60 o C and stirred at the same temperature for 2 h. Within 10 min, the color of the reaction mixture changed to yellow brown and stayed the same during entire course of reaction. After this time the reaction mixture was concentrated and filtered through Florisil to give almost pure allene sulfone as a yellow oil. The allene sulfone (568 mg, 0.80 mmol) was taken up in 5 ml of anhydrous CH 2 Cl 2 and to it diethylamine (166 µl, 1.60 mmol, 2 equiv) was added with stirring at 23 C. After 1 h the reaction was complete and reaction mixture was transferred to separatory funnel and washed with 1 N HCl (3 X 25 ml), followed by washing with water (3 X 25 ml) and brine (1 X 25 ml). The organic layer was finally dried over anhydrous Na 2 SO 4, concentrated and purified by flash column chromatography (silica gel, hexanes EtOAc, 9: 1 7: 3) to give pure β-keto sulfone (552 mg, 90%) as viscous oil. TBDPS-protected β- keto sulfone: R f = 0.45 (silica gel, hexanes EtOAc, 4: 1); [α] 23 D = +8.9 (c = 1.23, CHCl 3 ); IR (thin film) ν max 2925, 2851, 1703, 1446, 1323 cm -1 ; 1 H NMR (600 MHz, CDCl 3 ) δ 7.91 (m, 2 H), 7.69 (m, 4 H), 7.66 (m, 1 H), 7.56 (m, 2 H), 7.40 (m, 6 H), 5.34 (m, 1 H), 5.25 (d, J = 6 Hz, 1 H), 5.02 (m, 1 H), 4.26 (ABd, J = 13.2 Hz, 1 H), 4.20 (d, J = 6 Hz, 1 H), 4.17 (ABd, J = 13.2 Hz, 1 H), 4.04 (d, J = 4.2 Hz, 1 H), 3.46 (s, 3 H), 3.36 (dd, J = 8.4, 4.8 Hz, 1 H), 2.12 (m, 2 H), 1.89 (m, 4 H), 1.78 (m, 4 H), 1.66 (s, 3 H), 1.57 (s, 3 H), 1.42 (s, 3 H), 1.04 (s, 9 H); 13 C NMR (100MHz, CDCl 3 ) δ 197.7, 139.9, 136.8, 135.8, 134.4, 132.1, 129.7, 129.5, 128.6, 127.8, 124.4, 123.9, 110.2, 82.8, 66.1, 61.3, S 9

10 58.5, 55.5, 50.3, 40.6, 37.9, 37.6, 37.3, 29.6, 27.1, 25.9, 23.7, 19.4, 17.9, 16.6; HRMS (ESI) calcd for C 43 H 56 O 6 SSi + [M+NH 4 ] found Preparation of the β-keto Sulfone 11. The TBDPS-protected β-keto sulfone 11 (850 mg, 1.17 mmol) was dissolved in 2 ml of anhydrous pyridine and cooled to 0 C. To this cooled solution Py(HF) x (1 ml, 3.72 mmol based on pyridine, 3 equiv) was added and the reaction was allowed to proceed for 3 h with gradual warming to 23 C. After this time the reaction mixture was diluted with Et 2 O and washed successively with cold 1N HCl (2 X 25 ml), water (3 X 25 ml) and saturated brine (1 X 25 ml). The organic layer was dried over anhydrous Na 2 SO 4, concentrated and purified by flash column chromatography (silica gel, hexanes EtOAc, 9: 1 3: 2) to give of β-keto sulfone 11 (477 mg, 89%) as colorless viscous oil. 11: R f = 0.83 (silica gel, hexanes EtOAc 3: 2); [α] 23 D = 10.7 (c = 0.75, CHCl 3 ); IR (thin film) ν max 3411, 2913, 1707, 1446, 1319, 1147, 1029 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 7.90 (d, J = 7.5 Hz, 2 H), 7.67 (t, J = 7 Hz, 1 H), 7.57 (t, J = 7 Hz, 2 H), 5.36 (t, J = 6 Hz, 1 H), 5.24 (d, J = 4.5 Hz, 1 H), 5.02 (t, J = 7.5 Hz, 1 H), 4.27 (ABd, J = 14 Hz, 1 H), 4.15 (m, 3 H), 4.01 (d, J = 4.5 Hz, 1 H), 3.45 (s, 3 H), 3.36 (dd, J = 8.5, 4.5 Hz, 1 H), 2.15 (m, 3 H), 1.87 (m, 6 H), 1.65 (s, 6 H), 1.57 (s, 3 H), 1.38 (m, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 197.6, 141.1, 139.1, 134.5, 132.2, 129.5, 128.6, , , 110.2, 82.9, 66.0, 59.5, 58.5, 55.5, 50.3, 40.6, 37.9, 37.2, 37.1, 29.3, 25.9, 23.7, 17.9, 16.5; HRMS (ESI) calcd for C 27 H 38 O 6 S + [M+NH 4 ] found Preparation of the Methoxy Carbonate Ester of 11. To β-keto sulfone 11 (477 mg, mmol) in 5 ml of anhydrous CH 2 Cl 2 was added DMAP (238 mg, 1.95) at 23 C. To this solution was added methyl chloroformate (113 µl, 1.46 mmol, 1.5 equiv) and the mixture was stirred at the same temperature until the completion of the reaction (usually 3 h). After the completion of reaction CH 2 Cl 2 was removed and the residue was taken up in Et 2 O and washed with water (2 X 25 ml) and brine (1 X 25 ml). Finally the Et 2 O layer dried over anhydrous Na 2 SO 4, concentrated and purified by flash column chromatography (silica gel, 9: 1 7: 3) to give the pure methoxy carbonate ester of 11 (469 mg, yield 88%) as viscous oil. methoxy carbonate ester: R f = 0.42 (silica gel, hexanes S 10

11 EtOAc 3: 2); [α] 23 D = 8.9 (c = 1.58, CHCl 3 ); IR (thin film) ν max 2917, 1740, 1706, 1437, 1323, 1254, 1147, 1029 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (m, 2 H), 7.67 (m, 1 H), 7.57 (m, 2 H), 5.33 (m, 1 H), 5.23 (d, J = 6 Hz, 1 H), 5.01 (m, 1 H), 4.63 (bd, J = 6.8 Hz, 2 H), 4.26 (ABd, J = 13.6, 1 H), 4.16 (ABd, J = 13.6 Hz, 1 H), 4.02 (d, J = 4.4 Hz, 1 H), 3.77 (s, 3 H), 3.45 (s, 3 H), 3.34 (dd, J = 8, 4.4 Hz, 1 H), 2.14 (m, 2 H), 1.86 (m, 8 H), 1.70 (s, 3 H), 1.65 (s, 3 H), 1.56 (s, 3 H); 13 C NMR (400 MHz, CDCl 3 ) δ 197.6, 156.1, 143.0, 139.2, 134.5, 132.2, 129.6, 128.7, 123.9, 118.1, 110.3, 83.0, 66.0, 64.9, 58.7, 55.5, 54.9, 50.4, 40.7, 37.9, 37.4, 37.3, 29.4, 25.9, 23.8, 17.9, 16.9; HRMS (ESI) calcd for C 29 H 40 O 8 S + [M+NH 4 ] found Cyclic β-keto Sulfone 12. A stirred solution of the methyl carbonate of 11 (161 mg, mmol) in anhydrous THF (62 ml) was degassed and charged with Ar gas before successive addition of bis-1,4-diphenylphosphinobutane (112 mg, mmol) and Pd 2 (dba) 3 CHCl 3 (46 mg, mmol). The resulting mixture was degassed and charged with an Ar gas three times respectively before being stirred for 10 min under Ar atmosphere. The resulting yellow mixture was treated with DBU (88 µl, mmol) and heated at C for 2 h. After this period, THF was removed under reduced pressure and the residue was purified by silica gel chromatography (hexane EtOAc, 5:2) to provide a diastereomeric mixture of cyclic β-keto sulfones 12 (104 mg, 76%) as a pale yellow oil. 12: Major diastereomer. R f = 0.67 (silica gel, hexane EtOAc, 5:2); [α] 23 D = 1.6 (c = 1.25, CHCl 3 ); IR (thin film) ν max 2917, 2847, 1703, 1446, 1311 cm -1 ; 1 H NMR (400 MHz) δ 7.93 (m, 2 H), 7.64 (m, 1 H), 7.54 (m, 2 H), 5.22 (d, J = 6.0 Hz, 1 H), 5.03 (m, 1 H), 4.78 (m, 1 H), 4.10 (dd, J = 10.4, 7.2 Hz, 1 H), 3.68 (d, J = 3.2 Hz, 1 H), 3.57 (m, 3 H), 3.40 (dd, J = 6.8, 3.2 Hz, 1 H), 3.33 (ddd, J = 14.4, 12.8, 6.8, 1 H), 2.64 (m, 1H), 2.28 (d, J = 10.8 Hz, 1 H), 2.17 (d, J = 14.4 Hz, 1 H), (m, 2 H), 1.87 (s, 3 H), (m, 3 H), 1.71 (dd, J = 14.4, 6.0, 1 H), 1.64 (s, 3 H), 1.56 (s, 3 H), (m, 3 H); 13 C NMR (125 MHz) δ 206.6, 140.8, 138.4, 134.4, 131.8, (2 C), (2 C), 124.3, 116.9, 109.1, 86.1, 75.7, 55.3, 55.2, 50.2, 45.3, 40.4, 40.1, 38.4, 27.3, 25.9, 23.4, 22.0, 17.9, 16.7; HRMS (ESI) calcd for C 27 H 36 O 5 S + [M + NH 4 ] , found minor diastereomer: R f = 0.33 (Silica gel, hexane EtOAc, 5:2); 1 H NMR (400 MHz) δ 7.89 (m, 2 H), 7.67 (m, 1 H), 7.57 (m, 2 H), 5.07 (d, J = 5.6 Hz, 1 H), (m, 2 H), 4.45 (dd, J = 10.4, 7.6 Hz, 1 H), 3.90 (d, J = 4.4 Hz, 1 H), 3.29 (m, 3 S 11

12 H), 2.86 (m, 1 H), 2.70 (dd, J = 7.2, 4.0, 1 H), 2.55 (m, 1 H), 2.08 (m, 1 H), 2.04 (d, J = 14.4 Hz, 1 H), (m, 3 H), 1.76 (s, 3 H), 1.72 (d, J = 14.4, 6.0, 1 H), 1.56 (s, 3 H), 1.64 (s, 3 H), 1.56 (s, 3 H), 1.23 (m, 1 H), 1.17 (m, 2 H); 13 C NMR (125 MHz) δ 206.4, 142.0, 138.3, 134.2, 132.0, (2 C), (2 C), 124.2, 117.8, 109.4, 83.2, 72.9, 61.4, 54.8, 50.3, 45.2, 40.1, 39.9, 38.1, 30.1, 25.9, 23.6, 23.5, 17. Ketone 13. To a stirred solution of the mixture of diastereomers 12 (27.3 mg, mmol) in THF (3 ml) was added H 2 O (123 µl) and foil Al Hg (73 mg Al, 2.9 mmol), which was freshly prepared from aluminum foil and an aqueous solution of HgCl 2 (3 M). The resulting mixture was stirred at 23 C for 3 h before addition of another portion of Al Hg (73 mg Al, 2.9 mmol) and H 2 O (123 µl). After being stirred at the same temperature for 13 h, the reaction mixture was filtered through a Celite pad which was rinsed thoroughly with Et 2 O. The combined organic filtrate was concentrated under reduced pressure. Short path-silica gel chromatography (20% hexene EtOAc) of the residue furnished cyclic ketone 13 (17 mg, 89%) as a colorless oil. R f = 0.5 (silica gel, hexane EtOAc, 5:2); [α] 23 D = (c = 2.5, CHCl 3 ); IR (thin film) ν max 2914, 2854, cm -1 ; 1 H NMR (500 MHz) δ 5.19 (m, 1 H), 5.14 (d, J = 5.0 Hz, 1 H), 5.01 (m, 1 H), 4.18 (d, J = 3.5 Hz, 1H), 3.38 (s, 3 H), 2.87 (dd, J = 4.0, 7.0 Hz 1 H), 2.81 (m, 1 H), 2.44 (m, 1 H), (m, 5 H), 1.96 (d, J = 9.6 Hz, 1 H), (m, with s at 1.76, 7 H), 1.65 (s, 3 H), 1.58 (s, 3 H), 1.47 (m, 1 H), 1.39 (m, 1 H); 13 C NMR (125 MHz) δ 216.5, 138.4, 131.7, 124.4, 122.5, 109.5, 84.0, 60.1, 54.9, 49.8, 44.7, 41.5, 40.2, 39.9, 38.4, 30.3, 25.9, 23.6, 21.3, 17.9, 16.2; HRMS (CI) calcd for C 21 H 32 O 3 [M + NH 4 ] , found Triene 14. To a stirred solution of ketone 13 (14.8 mg, mmol) in THF (1 ml of) at 0 C added dropwise Tebbe reagent in toluene (140 µl, 0.5 M in toluene, 0.7 mmol). The resulting mixture was stirred at 23 C for 2 h, diluted with Et 2 O and treated with 1 drop of aqueous NaOH (1 M) solution. The heterogeneous solution was dried over Na 2 SO 4, filtered through a Celite pad which was rinsed thoroughly with Et 2 O. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column (hexane EtOAc, 90:10 85:15) to provide triene 14 (12.5 mg, 85%) as a colorless oil. 14: R f = 0.67 (silica gel, hexane EtOAc, 85:15); [α] 23 D = (c = 0.23, CHCl 3 ); IR S 12

13 (thin film) ν max 2925, 2856, cm -1 ; 1 H NMR (400 MHz) δ 5.26 (m, 1 H), 5.15 (d, J = 5.6 Hz, 1 H), (m, 1 H), 4.84 (s, 2H), 4.01 (d, J = 4.4 Hz, 1 H), 3.36 (s, 3 H), (m, 2 H), (m, 7 H), (m, 2 H), 1.70 (s, 3 H), 1.63 (s, 3 H), 1.60 (s, 3 H), (m, 5 H); 13 C NMR (100 MHz) δ 155.9, 136.0, 131.9, 124.6, 124.1, 110.4, 109.3, 90.0, 55.8, 54.6, 48.9, 48.8, 41.1, 40.3, 38.7, 36.9, 31.4, 26.1, 25.9, 23.8, 17.9, 16.1; HRMS (TOF) calcd for C 22 H 34 O 2 [M + H] , found Lactone 15. A stirred solution of trimethylaluminum (1 ml, 2.0 M in toluene, 2 mmol) in toluene (1 ml) was treated at 10 C with phenylselenol (230 µl, 2.1 mmol). The resulting mixture was stirred further at 0 C for 0.5 h. A solution of triene 14 (223 mg, mmol) in CH 2 Cl 2 (3 ml) was added, and the reaction mixture was stirred at 23 C for 2 h. After this period, the reaction mixture was quenched by addition of aq. NaHCO 3 solution, and extracted with CH 2 Cl 2. The organic layer was washed with brine, dried over Na 2 SO 4, and concentrated under reduced pressure. To a stirred solution of crude product in 1:1 acetone-water mixture (11 ml) was added AgNO 3 (458 mg, 2.7 mmol) and the resulting reaction mixture was stirred at 23 C for 2 h. After this period the reaction mixture was filtered through a Celite pad which was rinsed with acetone. After removal of solvents under reduced pressure, the reaction mixture was extracted with CH 2 Cl 2, dried over Na 2 SO 4, and concentrated to afford crude product, which was used in the following step without further purification. Silica gel chromatography (hexane EtOAc, 85:15) of small portion afforded the corresponding inseparable 6:4 diastereomeric mixture of lactols. R f = 0.5 (silica gel, hexane EtOAc, 5:2); IR (thin film) ν max 3386, 2971, 2927, 1437 cm -1 ; 1 H NMR (500 MHz) δ 5.68 (m, 1H, Major), 5.58 (dd, J = 8.0, 4.5 Hz, 1 H, minor), 5.28 (m, 1 H), 5.10 (m, 1 H), 4.88 (s, 1 H, minor), 4.87 (s, 1 H, minor), 4.84 (s, 1 H, Major), 4.83(s, 1 H, Major), 4.13 (d, J = 4.0 Hz, 1 H, minor), 4.0 (d, J = 5.0 Hz, 1 H, minor), 3.68 (d, J = 1.5 Hz, 1 H), (m, 14 H), 1.68 (s, 3 H), 1.63 (s, 3 H, Major), 1.62 (s, 3 H, minor), 1.60 (s, 3 H), 1.4 (m, 1 H); 13 C NMR (125 MHz) δ (Major), (minor), (Major), (minor), (Major), (minor), (minor), 124.5, (Major), (minor), (Major), (Major), (minor), 89.6 (Major), 87.2 (minor), 56.9 (minor), 56.5 (Major), 49.4 (minor), 48.4 (Major), 48.2 (Major), 47.5 (minor), 41.1 (Major), 40.3 (minor), 39.3 S 13

14 (Major), 39.2 (minor), 36.8 (Major), 36.8 (minor), 32.1 (minor), 31.7 (Major), 26.7, 26.4, 23.9, 23.7, 17.9, Next, to a stirred solution of crude lactol in CH 2 Cl 2 (12 ml) at 23 C was added MS-4A (370 mg), NMO (117 mg, 1 mmol) and TPAP (12 mg, 0.34 mmol) successively. The resulting mixture was stirred further at the same temperature for 2.0 h. After this period, the reaction mixture was filtered through a Celite pad which was rinsed with EtOAc. Concentration under reduced pressure followed by silica gel chromatography (hexane EtOAc, 90:10 85:15) provided a 4:1 lactone 15 as a colorless oil (116.7 mg, 55% over 3 steps). Found for 15 (a mixture of two conformational forms of the 9- membered ring): R f = 0.5 (silica gel, hexane EtOAc, 15:85); [α] 23 D = (c = 0.83, CHCl 3 ); IR (thin film) ν max 2970, 2925, 2856, 1775, 1158 cm -1 ; 1 H NMR (500 MHz) δ 5.26 (t, J = 7.5 Hz, 1 H, Major), 5.18 (d, J = 10.5 Hz, 1 H, minor), 5.05 (m, 1 H,), 4.92 (s, 1 H, minor), 4.91 (s, 1 H, Major), 4.88 (s, 1 H, Major ), 4.79 (s, 1 H, minor), 4.38 (d, J = 5.0 Hz, 1 H, Major), 4.30 (d, J = 5.0 Hz, 1 H, minor), 2.76 (d, J = 18.5 Hz, 1 H, Major), 2.74 (d, J = 18.5 Hz, 1 H, minor), (m, 4 H), 2.15 (dt, J = 12.0, 3.5 Hz, 1 H), (m, 5 H), (m, 4 H), 1.66 (s, 3 H), 1.59 (s, 3 H, Major), 1.57 (s, 3 H), 1.56 (s, 3 H, minor), 1.54 (m, 1 H). [α] 23 D = (c 2.05, CHCl 3 ); 13 C NMR (125 MHz) δ 178.6, 152.7, 135.2, 132.7, (minor), (Major), 123.5, (Major), (minor), 87.2 (minor), 86.3 (Major), 60.0 (minor), 57.6 (Major), 49.1 (Major), 48.1 (minor), 44.3, 40.6 (minor), 39.8 (Major), 39.5 (Major), 39.2 (minor), 36.4 (Major), 34.5 (Major), 34.4 (minor), 34.1 (minor), 33.8 (minor), 32.0 (Major), 29.7 (minor), 26.8 (Major), 25.9, 23.2 (Major), 23.0 (minor), 17.9, 16.3; HRMS (TOF) calcd for C 21 H 30 O 2 [M+H] , found Preparation of α-hydroxy Derivative of Lactone 15. To the lactone 15 (57 mg, mmol) in anhydrous THF (2 ml) at 78 C was added a solution of KHMDS (0.5 M in PhCH 3, mmol, 450 µl, 1.3 equiv) stirred for 45 min at 78 C. To this pale yellow solution, a solution of Davis oxaziridine (68 mg, mmol) in 1 ml of anhydrous THF was added at 78 C. The resulting mixture was stirred at the same temperature for 2 h. After this time, the reaction mixture was first quenched with dimethyl sulfide (0.518 mmol, 39 µl) followed by saturated aqueous NH 4 Cl solution. The reaction mixture was warmed to room temperature, the organic layer was separated and S 14

15 aqueous layers were extracted with Et 2 O. The combined organic extract was dried over anhydrous Na 2 SO 4, concentrated and purified by column chromatography (silica gel, hexanes EtOAc 9: 1) to give pure α-hydroxy derivative of lactone 15 as a colorless oil (54 mg, 90%) as a 1: 5 mixture of diastereomers and also as mixture of 9-membered ring conformers. α-hydroxy lactone: R f = 0.55 (major) 0.58 (minor) (silica gel, hexanes EtOAc 7: 3); [α] 26 D 78.8 (c = 0.17, CHCl 3 ); IR (thin film) ν max 3448, 2925, 1767, 1447 cm -1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 5.31 (dd, J= 9, 7 Hz, 0.7 H), 5.20 (bd, J= 11.5 Hz, 0.3 H) (m, 1 H), 4.96 (s, 1 H), 4.95 (s, 1 H), 4.60 (s, 1 H), 4.44 (d, J= 6.5 Hz, 0.7 H), 4.39 (d, J = 6.5 Hz, 0.3 H), 2.5 (bs, 1 H), 2.37 (m, 1 H), 2.24 (dd, J= 12, 6 Hz, 1 H), 2.18 (dt, J= 12, 3 Hz, 1 H), 2.04 (m, 7 H), 1.89 (m, 3 H), 1.68 (bs, 3 H), 1.60 (bs, 6 H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.6, 151.0, 135.1, 132.6, 125.1, 124.1, 113.7, 83.2, 70.6, 57.8, 48.2, 46.6, 39.6, 35.7, 32.4, 30.5, 27.8, 25.9, 23.2, 17.9, 16.3; HRMS (ESI) calcd for C 21 H 30 O + 3 [M+Na] found Preparation of the Antheliolide A. To a solution of the commercial Z/E mixture of 1-bromo-1-propene 56µL, mmol, 4.65 equiv) in 2 ml of anhydrous THF at 78 C was added n-buli (2.5 M in hexanes, 432 µl, 1.08 mmol, 6.6 equiv) over a period of 45 min at 78 C. The reaction mixture was stirred the same temperature for 2 h. Then to this a reaction mixture a solution of α-hydroxy derivative of lactone 15 (54 mg, mmol) in 2 ml anhydrous THF was added and reaction was allowed to proceed for 16 h at the same temperature. After this time, the reaction was quenched by addition of saturated aqueous NH 4 Cl, the organic layer was separated and aqueous layer was extracted with Et 2 O. The combined organic layers was washed with brine (2 X 10 ml), dried over anhydrous Na 2 SO 4 and concentrated to give desired diol 16. This crude product was used in the next step without further purification. To a solution of 16 in 2 ml of CH 2 Cl 2 was added NaIO 4 supported on silica gel (0.66 g/mmol, 547 mg, mmol, 2 equiv) at 23 C. The heterogeneous reaction mixture was vigorously stirred at 23 C for 3 h. Then the reaction mixture was filtered through sintered glass funnel and silica gel was washed thoroughly with CH 2 Cl 2. The dichloromethane layer was concentrated to give pure aldehyde ester 17, which was used in the next step without further purification. The aldehyde ester 17 was dissolved in 1 ml of anhydrous THF and S 15

16 was treated with piperidine (82 µl, mmol, 5 equiv) 23 C. The reaction mixture was stirred at the same temperature for 4 h. After this time, all the THF was removed and the residue was stirred under high vacuum to remove excess piperidine to give vinylogous enamide aldehyde 18. The crude enamide aldehyde 18 (75 mg, mmol) was dissolved in 2 ml of anhydrous C 6 H 6 and to it silica gel (750 mg, 10 times weight of substrate) was added at 23 C. The heterogeneous reaction mixture was vigorously stirred at the same temperature for 6 h. After this time the reaction mixture was filtered through a sintered glass funnel and silica gel was thoroughly washed with C 6 H 6. The organic layer was concentrated in vacuum and the residue was purified by column chromatography (silica gel, hexanes EtOAc 19: 1 4:1) to give pure antheliolide A 1 (40 mg, 60% for 4 steps) as white solid. R f = 0.47 (silica gel, hexane EtOAc 4:1); [α] 23 D = (c = 0.19, CH 2 Cl 2 ) 1 H NMR (500 MHz, C 6 D 6 ) 5.16 (dd, J= 10.5, 5.5 Hz, 1 H), 4.88 (s, 1 H), 4.81 (s, 1 H), 4.17 (d, J= 6.5 Hz, 1 H), 2.58 (d, J= 2 Hz, 3 H), 2.44 (d, J= 10 Hz, 1 H), 2.22 (dd, J= 10, 8 Hz, 1 H), 2.00 (m, 2 h), 1.96 (m, 1 H), 1.94 (m, 1 H), 1.89 (dd, J= 12, 5.5 Hz, 1 H), 1.76 (m, 4 H), 1.61 (m, 2 H), 1.49 (m, 3 H), 1.38 (s, 3 H), 1.08 (s, 3 H), 1.06 (s, 3 H); 13C NMR (125 MHz, C 6 D 6 ) 167.5, 162.7, 149.2, 134.3, 125.4, 115.8, 105.2, 83.8, 80.6, 60.6, 57.8, 46.7, 42.1, 40.1, 39.8, 37.7, 33.6, 30.6, 30.1, 29.6, 27.7, 22.9, 21.0, 16.7; HRMS (ESI) calcd for C 24 H 32 O + 4 [M+H] found S 16