Supporting Information. First Total Synthesis of Achilleol B: Reassignment of its Relative Stereochemistry

Transcription

1 Supporting Information First Total Synthesis of Achilleol B: Reassignment of its Relative Stereochemistry Jesús, F. Arteaga, Victoriano Domingo, José F. Quílez del Moral, Alejandro F. Barrero* Department of rganic Chemistry, Institute of Biotechnology, University of Granada, Avda. Fuentenueva, Granada, Spain S1

2 General Experimental Section: All air- and water-sensitive reactions were performed in flasks flame-dried under a positive flow of argon and conducted under an atmosphere of argon. Tetrahydrofuran (THF) was freshly distilled immediately prior to use from sodium/benzophenone and strictly deoxygenated for 30 min under argon for the Cp 2 TiCl 2 /Mn reaction. Reagents were purchased at the higher commercial quality and used without further purification, unless otherwise stated. Silica gel SDS 60 (35-70 µm) was used for flash column chromatography. ptical rotations were measured on a Perkin-Elmer 141 polarimeter, using CHCl 3 as the solvent. IR spectra were recorded with a Mattson model Satellite FTIR instrument as NaCl plates (films). NMR studies were performed with Varian Direct Drive 400 MHz, 500 MHz and Bruker ARX 400 spectrometers. The accurate mass determination was carried out with a AutoSpec-Q mass spectrometer arranged in a EBE geometry (Micromass Instrument, Manchester, UK) and equipped with a FAB (LSIMS) source. The instrument was operated at 8 KV of accelerating voltage and Cs+ were used as primary ions. 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 the visualizing agent and a solution of phosphomolybdic acid in ethanol and heat as developing agent. Geranylacetone: Commercially available. (R,E)-9,10-dihydroxy-6,10-dimethylundec-5-en-2-one (13). To a mixture of tert-butanol (15 ml) and water (15 ml) was added 2.67 g of AD-mix-β (5.712 mmol K 3 Fe(CN) 6, mmol of K 2 C 3, mmol [K 2 s 2 (H) 4 ] and 0.02 mmol (DHQD) 2 -PHAL ligand (hydroquinidine 1,4-phtalazinediyl diether)). The resulting mixture was stirred mechanically at 25 C, until two clear phases were obtained. Then, CH 3 S 2 NH 2 (0.181 g, mmol) was added and the mixture was cooled to 0 C. The resulting heterogeneous slurry was stirred vigorously at 0 C, as geranyl acetone (0.370 g, 1.90 mmol) was added at once. Stirring was continued at 0 C for 24 h. At this time the oxidation was completed and solid sodium sulphite (2.48 g) was added. The mixture was S2

3 allowed to warm to room temperature and stirred until two clear phases were obtained. Ethyl acetate (50 ml) and water (15 ml) were added, and after separation of the layers, the aqueous phase was further extracted with ethyl acetate (3 20 ml). The combined organic extract was washed with a 2 N aqueous NaH solution (25 ml), dried (Na 2 S 4 ), and concentrated under reduced pressure. This crude product was purified by flash chromatography (hexane/et 2, 1:3) to afford 151 mg of starting material and 173 mg (0.76 mmol) of 13 as a clear colourless viscous oil. [α] 20 D = º (c 1.30, CHCl 3 ); IR (film): ν máx 3424, 2970, 1709, 1376, 1163, 1078, 760 cm -1 ; 1 H RMN (CDCl 3, 300 MHz): δ 5.00 (1H, t, J = 7.0 Hz), 3.19 (1H, d, J = 8.3 Hz), 2.39 (2H, m), 2.17 (2H, m), 2.03 (3H, s), (2H, m), 1.55 (3H, s), (2H, m), 1.07 (3H, s), 1.01 (3H, s); 13 C RMN (CDCl 3, 75 MHz): δ 208.6, 135.6, 123.6, 79.9, 68.4, 43.9, 34.0, 31.0, 27.5, 23.9, 22.5, 23.8, 18.4 ppm; HRFABMS: calcd. for C 13 H 25 3 [M+H] , found: H H 13 (R,E)-2,6-dimethyl-9-(2-methyl-1,3-dioxolan-2-yl)non-6-ene-2,3-diol (14). To a solution of 13 (173 mg, 0.76 mmol) in ethylene glycol (4.5 ml), 4Å molecular sieves and ptsh (145 mg, 0.76 mmol) were added. The mixture was stirred at room temperature for 1h. Aqueous sodium carbonate was then added, and the resulting mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure.the residue was flash-chromatrographed to afford 137 mg (0.51 mmol) of diol 14 1 together with 32 mg of starting ketone. Compound 14 was isolated as a colourless oil. [α] 20 D = º (c 1.0, CHCl 3 ); IR (film): ν máx 3415, 2976, 2928, 1712, 1384, 1251, 1136, 1056, 947, 860 cm -1 ; 1 H RMN (300 MHz, CDCl 3 ): δ 5.13 (1H, t, J = 6.9 Hz), 3.92 (4H, m), 3.28 (1H, d, J = 8.3 Hz), (4H, m), (4H, m), 1.58 (3H, s), 1.32 (3H, s), 1.17 (3H, s), 1.14 (3H, s); 13 C RMN (75 MHz, 1 Rapoport, H.; Snyder, C.; Bondinell, W. J. rg. Chem. 1971, 36, S3

4 CDCl 3 ): δ 135.4, 125.2, 110.4, 78.5, 73.3, 65.0 (2C), 39.4, 37.1, 30.0, 26.8, 24.1, 23.7, 23.1, 16.2; HRFABMS: calcd. for C 15 H 28 4 Na [M+Na] , found: H H 14 2-methyl-2-((E)-4-methyl-6-((R)-3,3-dimethyloxiran-2-yl)hex-3-enyl)-1,3-dioxolane (15). To a solution of 14 (111mg, 0.41 mmol) and catalytic DMAP in anhydrous pyridine (5mL) cooled at - 12º C under Argon atmosphere, was added dropwise MsCl (0.24 ml, 2.45 mmol). After 40 minutes (TLC monitoring), the mixture was diluted with t-bume and treated with sat NaHC 3 solution. After additional 15 minutes stirring at room temperature, the mixture was extracted with Et 2 (3 x 10 ml), the organic layer washed with HCl 1N (1x 10mL), brine and dried over anhydrous Na 2 S 4 and finally concentrated under reduced pressure. The mesylated crude was dissolved 15 ml of methanol and 225 mg of K 2 C 3 were added. After stirring for 10 minutes, the formation of epoxide was complete (TLC monitoring). Then, the reaction was quenched by diluting with H 2 and t-bume. The organic layer washed with 1N HCl (2 x 10 ml), sat.nahc 3 (2 x 10 ml) and brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel (hexane/t-bume, 3:1) to afford 78 mg (74% yield in two steps) of the monoepoxide [α] 20 D = -11.8º (c 1.2, CHCl 3 ); IR (film): ν máx 3726, 3627, 2959, 2928, 2877, 1450, 1376, 1249, 1220, 1124, 1056, 947, 863 cm -1 ; 1 H RMN (400 MHz, CDCl 3 ): δ 5.17 (1H, t, J = 7.0 Hz), 3.95 (4H, m), 2.69 (1H, t, J = 6.9 Hz), (4H, m), (4H, m), 1.62 (3H, s), 1.32 (3H, s), 1.29 (3H, s), 1.25 (3H, s); 13 C RMN (100 MHz, CDCl 3 ): δ 134.3, 124.6, 109.9, 64.6, 64.2, 58.3, 55.9, 39.0, 36.3, 27.4, 24.9, 23.8, 22.6, 18.7, 15.9; HRFABMS: calcd. for C 15 H 26 3 Na [M+Na] , found: Barrero, A. F.; Cuerva, J. M.; Alvarez-Manzaneda, E. J.; ltra, J. E.; Chahboun, R. Tetrahedron Lett. 2002, 43, S4

5 15 (1S,3R)-2,2-dimethyl-3-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-4-methylenecyclohexanol (16). A mixture of Cp 2 TiCl 2 (62 mg, 0.24 mmol) and Mn dust (532 mg, 9.68 mmol) in strictly deoxygenated THF (7 ml) was stirred at room temperature until the red solution turned green. Then, a solution of the oxirane 15 (305mg, 1.20 mmol), 2,4,6-collidine (1.1 ml, 8.33 mmol), and TMSCl (0.6 ml, 4.76 mmol) in strictly deoxygenated THF (3 ml) was added to the solution of Cp 2 TiCl. The reaction mixture was stirred for 2 h, and then quenched with 2 N aq HCl. The aqueous layer was then extracted with t- BuMe. The combined organic layers were washed with brine dried over anhydrous Na 2 S 4, and concentrated under reduced pressure. The mixture was purified by column chromatography (hexane/t- BuMe, 3:1) on silica gel to afford 196 mg (77%) of the corresponding monocyclic alcohol. A suspension of this alcohol (100 mg, 0.39 mmol) and NaI 2H 2 (372 mg, 2.0 mmol) in acetonitrile (30 ml) was added CeCl 3 7H 2 (560 mg, 1.5 mmol), and the resulting mixture was stirred for 15 h at room temperature. The reaction mixture was diluted with ether and washed with H 2 (2 x 40ml). The organic layer was separated, and the aqueous layer was extracted with ether (1x 40 ml). The combined organic layers were washed once with saturated brine solution and dried over anhydrous sodium sulfate. The extracts were then concentrated under reduced pressure and the the residue was purified through flash chromatography to give 78 mg (95%) of the corresponding hydroxy ketone 16 3 as a colourless oil. [α] D = -13.9º (c 1.0, CH 2 Cl 2 ); 1 H RMN (400 MHz, CDCl 3 ) δ: 4.84 (1H, s), 4.5 (1H, s), 3.38 (1H,dd, J = 4.1, 8.9 Hz), 2.51 (1H, ddd, J = 5.0, 9.1, 14.3 Hz), (2H, m), 2.08 (3H, s), (6H, m), 1.01 (3H, s), 0.74 (3H, s). 13 C RMN (100 MHz, CDCl 3 ) δ: 209.3, 147.2, 108.8, 76.9, 52.0, 43.0, 40.6, 32.2, 32.0, 26.1, 19.7, Tsangarakis, C.; Arkoudis, E.; Raptis, C.; Stratakis, M. rg. Lett. 2007, 9, S5

6 H 16 4-((1R,3S)-3-tert-butildimetilsililoxy-2,2-dimethyl-6-methylenecyclohexyl)butan-2-one (17). To a stirred solution of 16 (230 mg, 1.13 mmol) in DMF (13 ml), imidazole (335 mg, 4.9 mmol) and TBSCl (742 mg, 4.9 mmol) were added at room temperature. After stirring for 16 h (TLC monitoring), the mixture was diluted with tbume and water and extracted with tbume. The combined organic layer was washed with 2N HCl, brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (hexane/t-bume, 95:5) on silica gel to afford 336 mg (91%) of the corresponding silylated derivative 17. [α] D = +11.3º (c 1.0, CH 2 Cl 2 ); 1 H RMN (400 MHz, CDCl 3 ), δ: 4.80 (1H), 4.48 (1H), 3.38 (1H, dd, J = 3.6, 7.1 Hz), 2.44 (1H, ddd, J = 17.1, 7.4, 7.1 Hz), 2.3 (1H, m), 2.21 (1H, ddd, J = 17.1, 8.1, 4.6 Hz), 2.08 (3H, s), 1.96 (1H, m), 1.84 (1H, m), 1.65 (1H, m), 1.6 (1H, m), 1.51 (2H, m), 0.91 (3H, s), 0.88 (9H, s), 0.81 (3H, s), 0.02 (6H, s); 13 C RMN (100 MHz, CDCl 3 ) δ: 209.7, 148.1, 109.1, 76.9, 52.4, 43.2, 40.4, 32.0, 29.8, 29.9, 27.1, 25.9, 25.8, 21.0, 18.0, TBS 17 (1S,3R)-1-tert-butildimetilsililoxy -3-((E)-5-hydroxy-3-methylpent-3-enyl)-2,2-dimethyl-4- methylenecyclohexanol (18). To a suspension of NaH (7 mg, mmol) in THF (1 ml) cooled at 0ºC, triethylphosphonoacetate (0.05 ml, mmol) was added dropwise under inert atmosphere. After stirring for 5 min, ketone 17 (43 mg, mmol) in anhydrous THF (0.5 ml) was added. The solution was stirred for 24h and then diluted with ether, washed with H 2 and brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. To an ice cooled solution of the Horner-Wadsworth-Emmons adduct 18 in toluene (15 ml) DIBALH (1M solution in hexanes, 1 ml, 1 mmol) was added. The mixture was stirred for 10 min. S6

7 After usual work-up, the residue was purified by column chromatography to give 35 mg (74% two steps) of 18. [α] D = -5.5º (c 1, CHCl 3 ); IR (film): ν máx 3560, 2960, 2925, 2856, 1645, 1097, 1022, 804 cm -1 ; 1 H NMR (CDCl 3, 400 MHz): δ 5.38 (1H, t, J = 6.9 Hz), 4.80 (1H, s), 4.54 (1H, s), 4.12 (2H, d, J = 6.9 Hz), 3.37 (1H, dd, J = 7.2, 3.6 Hz), 2.34 (1H, ddd, J = 12.3, 7.5, 4.7 Hz), 1.90 (1H, ddd, J = 12.9, 8.3, 4.3 Hz), (7H, m), 1.65 (3H, s),0.91 (3H, s), 0.87 (9H, s), 0.78 (3H, s), 0.03 (3H, s), 0.02 (3H, s); 13 C NMR (CDCl 3, 100 MHz): δ 148.3, 141.8, 123.0, 108.7, 77.1, 59.4, 52.4, 40.5, 38.9, 32.2, 29.5, 27.1, 26.0, 25.9, 24.9, 24.8, 24.1, 18.2, 16.4; -4.1, -4.9; HRFABMS: calcd. for C 21 H 40 2 SiNa [M+Na] , found TBS CH 2 H 18 (-)-Elegansidiol (11): To a magnetically stirred solution 18 (40 mg, 0.11 mmol) was added tetrabutylammonium fluoride (1 M solution in THF, 0.32 ml, 0.32 mmol) at room temperature. The reaction was stirred at 60 C for 1h. After dilution with EtAc, the mixture was washed with brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. The resulting was flash-chromatographed to afford 24 mg (89%)of (-)-elegansidiol. 4 [α] D = -3.2º (c 0.9, CHCl 3 ); IR (film): ν máx 3384, 2930, 2852, 1717, 1645, 1449, 1379, 1261, 1183, 1082, 1023, 890 cm -1 ; EIMS m/z 238 [M + ],(1), 220 (8), 205 (35), 187 (27), 175 (24), 159 (18), 134 (27),119 (45), 107 (62), 96 (100), 81 (64), 67 (44), 55 (54), 43(85), 41 (83); 1 H NMR (500 MHz, CDCl 3 ): δ 5.40 (1H, tq, J = 6.9 Hz), 4.88 (1H, bs, 1H), 4.60 (1H, bs), 4.15 (2H, d, J = 6.9 Hz), 3.42 (1H, dd, J = 9.6, 4.2 Hz), 2.33 (1H, dt, J = 13.1, 4.4 Hz), 2.13 (1H, m), 1.99 (1H, dt, J = 12.1, 4.8 Hz), (2H, m), (5H, m), 1.68 (3H, s), 1.03 (3H, s), 0.73 (3H, s); 13 C NMR (125 MHz, CDCl 3 ): δ 147.1, 140.1, 123.1, 108.3, 77.2, 59.3, 51.2, 40.4, 38.7, 32.7, 32.0, 26.0, 23.8, 16.2, 15.7; HRFABMS: calcd. for C 15 H 27 2 [M+H] , found Barrero, A.; Alvarez-Manzaneda, E.; MarHerrador, M.; Alvarez-Manzaneda, R.; Quilez, J.; Chahboun, R.; Linares, P.; Rivas, A. Tetrahedron Lett. 1999, 40, S7

8 H CH 2 H 11 ((1S,3R)-3-((E)-5-bromo-3-methylpent-3-enyl)-2,2-dimethyl-4-methylenecyclohexyloxy)(tertbutyl)dimethylsilane (19). To a solution of 15 (35 mg, 0.1 mmol) in dry Et 2 (1.5 ml) cooled at 0ºC was added of PBr 3 (4 µl, 0.04 mmol). The resulting solution was stirred at 0ºC for 10 min, and then diluted with Et 2 and washed with brine. The organic layer was dried over Na 2 S 4 and concentrated under reduced pressure. The resulting bromide 20 (39 mg) was used in the next reaction without purification. Br TBS 19 (+)-Farnesirerol B (12): Bromide 19 (72 mg, mmoles) alkylated the potassium salt of 7-hydroxycoumarin, which was prepared in situ from 7-hydroxycoumarin (57 mg, 0.35 mmoles) and K 2 C 3 (73 mg, mmoles) in dry acetone (2 ml). The reaction was complete after 12 h at room temperature. The mixture was then concentrated under reduced pressure, extracted with t-bume and washed with brine. Purification of the resulting crude by flash chromatography (hexane/ t-bume, 3:1) afforded 73 mg of the silyl derivative of farnesiferol B 12a. To a solution of the resulting crude in 4 ml of THF was added tetrabutylammonium fluoride (0.60 ml) at room temperature. The reaction was stirred at 60 C for 1h. After dilution with EtAc, the mixture was washed with brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (hexane/ t-bume, 1:1) to afford 43 mg (78%) of (+)-farnesiferol B. [α] D = +8.5 (c 1, CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 ): δ 7.63 (1H, d, J = 9.5 Hz), 7.35 (1H, d, J = 8.5 Hz), 6.85 (1H, dd, J = 8.5, 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 6.25 (1H, d, J = 9.5 Hz), 5.45 (1H, t, J = 7.0 Hz), 4.88 (1H, s), (2H, S8

9 d, J = 7.0 Hz), 4.59 (1H, s), 3.39 (1H, dd, J = 9.5 Hz, 4.0 Hz), 2.33 (1H, td, J = 13.0, 5.0 Hz), 2.19 (1H, m), (3H, m), 1.76 (3H, s), (4H, m), 1.02 (3H, s), 0.74 (3H, s); 13 C NMR (125 MHz, CDCl 3 ): δ 162.1, 161.3, 155.9, 147.1, 143.5, 142.8, 128.7, 118.4, 113.4, 113.0, 112.4, 108.6, 101.6, 77.1, 65.5, 51.0, 40.5, 38.4, 32.7, 32.1, 26.0, 23.4, 16.8, HRFABMS: calcd. for C 24 H 31 4 [M+H] ; found H 12 (-)-Achilleol A (2): To a solution of farnesylphenylsulphone 20 (180 mg, 0.52 mmol) in THF (7 ml) was added n- butyllithium (2.5 M solution in hexane, 0.2 ml, 0.5 mmol) at -78ºC. The resulting yellow mixture was stirred for 10 min and a solution of bromide 19 (53 mg, 0.13 mmol) in THF (7 ml) was added dropwise. The mixture was allowed to warm for 4 h, and then diluted with t-bume and quenched with water. The organic layer was washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. Purification by flash chromatography (hexane: t-bume, 10:1) afforded the epimeric mixture of sulphones 21 (64 mg, 78%). To a solution of Li (19 mg) in EtNH 2 (0.6 ml) was added at 78 ºC a solution of 21 (13 mg, 0.02 mmol) in THF (1 ml). The mixture was stirred for 30 min. MeH and saturated NH 4 Cl was then added, and the mixture was further stirred for 10 min. The aqueous layer was extracted with t-bume (2 x 5 ml), and the combined organic extracts were washed with brine, dried over Na 2 S 4, filtered, and concentrated in a vacuum. Purification by flash chromatography (hexane: t- BuMe, 6:1) afforded 9 mg (83%) of the silylated derivative of achilleol A 2a. To a solution of the silyl derivative 2a (16 mg, 0.03 mmol) in THF (1 ml) was added tetrabutylammonium fluoride (1M solution in THF, 0.18 ml, 0.18 mmol) at room temperature. The reaction was stirred at 60 C for 24 h. After S9

10 dilution with EtAc, the mixture was washed with brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (hexane/t-bume, 3:1) to afford 12 mg (94%) of (-)-achilleol A (2). [α] D = -6.9º (c 0.9, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 )= δ (4H, m), 4.86 (1H, bs), 4.59 (1H, bs), 3.39 (1H, dd, J = 9.9, 4.3 Hz), 2.31 (1H, dt, J = 13.1, 4.7 Hz), (14H, m), (2H, m), (4H, m), 1.66 (3H, s), 1.59 (12H, s), 1.01 (3H, s), 0.70 (3H, s); 13 C NMR (125 MHz, CDCl 3 ; DEPT) δ 147.3, 135.5, 135.2, 135.0, 131.3, 124.5,124.5, 124.4, 124.4, 108.5, 77.4, 51.0, 40.6, 39.9, 39.8, 38.7, 33.3, 32.3, 28.4, 28.3, 26.9, 26.8, 26.0, 25.8, 23.8, 17.8, 16.2, 16.1, 16.1, H 2 ((1S)-2,2-dimethyl-3-((E)-3-methyl-5-(phenylsulfonyl)pent-3-enyl)-4-methylenecyclohexyloxy) (tert-butyl) dimethylsilane (22): To a stirred solution of 19 (210 mg, 0.5 mmol) in dry DMF (5 ml) was added at 0ºC phenylsulfinate sodium (123 mg, 0.75 mmol). After stirring for 3h the reaction was diluted with t-bume, washed with HCl 2 N (2 x 5 ml), brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel 3:1 (hexane/t-bume) to afford 171 mg (72 %) of the corresponding sulfone 22. IR (film): ν máx 2951, 2935, 2856, 1646, 1472, 1447, 1387, 1317, 1253, 1151, 1086, 888, 835, 773 cm -1 ; 1 H NMR (CDCl 3, 500 MHz): δ 7.86 (2H, bd, J = 7.4 Hz), 7.62 (1H, bt, J = 7.4 Hz), 7.52 (2H, bt, J = 7.4 Hz), 5.15 (1H, dt, J = 6.9, 1.0 Hz), 4.80 (1H, s), 4.50 (1H, s), 3.80 (2H, d, J = 7.9 Hz), 3.37 (1H, dd, J = 7.3, 3.6 Hz), 2.30 (1H, ddd, J = 12.9, 8.0, 4.6 Hz), (1H, m), 1.91 (1H, ddd, J = 12.9, 8.3, 4.7 Hz), (6H, m), 1.31 (3H, s), 0.91 (3H, s), 0.88 (9H, s), 0.77 (3H, s), 0.04 (3H, s), 0.03 (3H, s); 13 C NMR (CDCl 3, 125 MHz): δ 148.3, 141.8, S10

11 123.0, 108.7, 77.1, 59.4, 52.4, 40.5, 38.9, 32.2, 29.5, 27.1, 26.0, 25.9, 24.9, 24.8, 24.1, 18.2, 16.4; HRFABMS: calcd. for C 27 H 44 3 SSiNa [M+Na] , found S 2 Ph TBS 22 (-)-Achilleol B To a solution of 23 (162 mg, 0.33 mmol), in THF (2 ml) was added n-butyllithium (2 M solution in hexane, 0.16 ml, 0.32 mmol) at -78ºC. The resulting yellow mixture was stirred for 10 min and a solution of 21 (31 mg, 0.11 mmol) of bromide 23 5 in THF (5 ml) was added dropwise. The mixture was allowed to warm for 2 h. The mixture was then diluted with t-bume and quenched with water. The organic layer was washed with brine, dried over Na 2 S 4 and concentrated under reduced pressure. Purification by flash chromatography (hexane: t-bume, 10:1) afforded the epimeric mixture of sulphones 24 (53 mg, 71 %). To a solution of Li (32 mg) in EtNH 2 (4 ml) was added at 78 ºC a solution of 24 (22 mg, mmol) in THF (2 ml). The mixture was stirred for 30 min. MeH and saturated NH 4 Cl was then added, and the mixture was further stirred for 10 min. The aqueous layer was extracted with t-bume (2 x 10 ml), and the combined organic extracts were washed with brine, dried over Na 2 S 4, filtered, and concentrated in a vacuum. Purification by flash chromatography (hexane: t- BuMe, 10:1) afforded 15 mg (87%) of the silylated derivative of (-)-achilleol B. To a solution of the silyl derivative of achilleol B (26 mg, 0.05 mmol) in THF (1 ml) was added tetrabutylammonium fluoride (1M solution in THF, 0.15 ml, 0.15 mmol) at room temperature. The reaction was stirred at 60 C for 12 h. After dilution with EtAc, the mixture was washed with brine, dried over anhydrous Na 2 S 4 and concentrated under reduced pressure to afford 8 mg of starting material and 16 mg (98 %) of (-)-achilleol B. [α] D = -10.9º (c 0.9, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 )= δ 5.12 (1H, t, J = 7.0 Hz), 4.88 (1H, bs), 4.62 (1H, bs), 3.40 (1H, dd, J = 10.0, 4.5 Hz), 2.32 (1H, dt, J = 13.2, 4.5 Hz), 2.21 (1H, 5 Barrero, A. F.; Arseniyadis, S.; Quilez del Moral, J. F.; Herrador, M. M.; Rosellón, A. Synlett 2005, S11

12 ddd, J = 13.1, 10.0, 6.6 Hz), 2.08 (1H, ddd, J = 13.2, 10.3, 3.8 Hz), (7H, m), (8H, m), 1.61 (3H, s), 1.58 (3H, s), 1.39 (1H, ddd, J = 13.0, 3.7, 2.6 Hz), 1.35 (1H, dd, J = 13.8, 3.9 Hz), 1.23 (1H, dt, J = 13.3, 3.5 Hz), 1.12 (1H, m), 1.04 (3H, s), 0.97 (1H, t, J = 13.0 Hz), 0.90 (3H, s), 0.88 (3H, s), 0.82 (3H, s), 0.82 (1H, m), 0.72 (3H, s); 13 C NMR (125 MHz, CDCl 3 ) δ 147.5, 135.2, 133.8, 124.8, 124.1, 108.6, 77.5, 51.3, 43.2, 42.5, 40.8, 38.9, 36.8, 34.8, 33.4, 33.3, 32.4, 31.9, 31.6, 31.2, 29.7, 27.4, 27.2, 26.7, 26.1, 24.4, 24.0, 18.9, 16.2, H H reassigned achilleol B S12

13 H H 13 1 H NMR: 300 MHz 13 C NMR: 75 MHz S13

14 H H 14 1 H NMR: 300 MHz 13 C NMR: 75 MHz S14

15 15 1 H NMR: 400 MHz 13 C NMR: 100 MHz S15

16 H 16 1 H NMR: 400 MHz 13 C NMR: 100 MHz S16

17 TBS 17 1 H NMR: 400 MHz 13 C NMR: 100 MHz S17

18 TBS CH 2 H 18 1 H NMR: 400 MHz 13 C NMR: 100 MHz S18

19 Natural elegansidiol H CH 2 H 11 1 H NMR: 300 MHz 13 C NMR: 75 MHz S19

20 Synthetic elegansidiol H CH 2 H 11 1 H NMR: 500 MHz 13 C NMR: 125 MHz S20

21 H 12 1 H NMR: 500 MHz 13 C NMR: 125 MHz S21

22 Synthetic achilleol A H 2 1 H NMR: 500 MHz 13 C NMR: 125 MHz S22

23 Natural achilleol A H 2 1 H NMR: 500 MHz 13 C NMR: 125 MHz S23

24 S 2 Ph 1 H NMR: 500 MHz 13 C NMR: 125 MHz TBS 22 S24

25 Synthetic achilleol B H 1 H NMR: 500 MHz 13 C NMR: 125 MHz H reassigned achilleol B S25

26 Natural achilleol B H 1 H NMR: 300 MHz 13 C NMR: 75 MHz H reassigned achilleol B S26