Total Synthesis (+)-Cyperolone

Transcription

1 S1 Supporting Information Klahn, Duschek, Liébert, Kirsch Total Synthesis (+)-Cyperolone Philipp Klahn,, Alexander Duschek, Cleménce Liébert, Stefan F. Kirsch,,,* Bergische Universität Wuppertal, Fachbereich C Organische Chemie, Gaußstr. 2, D Wuppertal, Germany Department Chemie, Technische Universität München, Lichtenbergstr. 4, D Garching, Germany Supporting Information Experimental procedures and analytical data and copies of 1 H and 13 C NMR. (8 Pages) List of Contents General experimental details... 2 Synthesis of 3-siloxy-1,5-enynes General procedure A for the oxidative rearrangement of tertiary allylic alcohols... 6 General procedure B for the addition of propargylmagensium bromide to aldehydes... 7 Cycloisomerization of 3-siloxy-1,5-enynes containing tetra-substituted double-bonds Synthesis of 2, 2a, 2b, 2c, 2d, 8 and General procedure C for the cycloisomerization of 3-siloxy-1,5-enynes... 9 Final steps of the total synthesis of (+)-cyperolone Syntheses of cycloisomerization precursors 3a, 3b, 3c, 3d, 7a and 7b Bergische Universität Wuppertal Technische Universität München

2 S2 General experimental details All commercially available chemicals were used without further purification. Moisture sensitive reactions were performed under argon. CH 2 Cl 2 was dried according to published procedures. 3 1 H NMR spectra were obtained on Bruker 5 MHz FT-NMR, 36 MHz FT-NMR and 25 MHz FT-NMR spectrometers. 13 C NMR spectra were recorded at 62.9 MHz and 9.6 MHz. Chemical shifts are reported in ppm relative to solvent signal. Multiplicity is indicated as follows: s (singlet); bs (broad singlet); d (doublet); t (triplet); q (quartet); m (multiplet); dd (doublet of doublets), etc.. High resolution mass spectra and EI were determined on a Finnigan MAT 95S and MAT 82. Optical rotation values were determined on a Perkin- Elmer 241 MC. IR spectra were recorded on a JASCO IR-4 spectrometer using ATR technique. Flash chromatography was performed with E. Merck silica gel (43 6 µm). The eluent used is reported in parentheses (P = Pentanes). Thin-layer chromatography (TLC) was performed on precoated glass-backed plates (Merck Kieselgel 6 F 254 ), and components were visualized by observation under UV light or by treating the plates with KMnO 4 /H 2 SO 4 or CAM (cerium ammonium molybdate in diluted sulfuric acid) followed by heating. 3 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518.

3 S3 Synthesis of 3-siloxy-1,5-enyne 3 (5R)-1-(Chlormethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (4) HO Cl C 11 H 17 ClO 2,71 g/mol A solution of (R)-(-)-carvone (1. ml, 6.38 mmol) and chloroiodomethane (6 µl, 8.29 mmol) in THF (17. ml) under argon atmosphere was cooled down to -78 C and MeLi LiBr (4. ml, 88. mmol, 2.2 M in diethylether) was added dropwise over a period of 25 min. Afterwards the reaction mixture was stirred for 2 min and quenched at -78 C with saturated aqueous ammonium chloride solution (15 ml). The mixture was warmed to r.t. under continuous stirring, diluted with water (5 ml), and the layers were separated. The aqueous layer was extracted with diethylether (2 x 15 ml). The combined organic layers were washed with brine (1x 2 ml) and saturated aqueous ammonium chloride solution, dried over sodium sulfate, and the solvent was removed under reduced pressure. Compound 4 was obtained as a yellow oil (12.64 g, 63. mmol, 99%, d. r. = 4:1), and was used for next reaction without further purification. Major diastereoisomer: R f =.37 (Pentanes/Et 2 O = 4:1, [CAM]), [α] 23 D = -54. (c = 5.7 mg/ml). Minor diastereoisomer: R f =.23 (Pentanes/Et 2 O = 4:1, [CAM]) [α] 23 D = (c = 3.9 mg/ml), 1 H-NMR (36 MHz, CDCl 3 ): Major diastereoisomer: δ [ppm] = 1.52 (td, J = 12.6 Hz, J = 1.5 Hz, 1 H), (m, 6 H), (m, 1 H), (m, 4 H), 3.66 (d, J = 11.4 Hz, 1 H), 3.74 (dd, J = 11.4 Hz, J = 1.5 Hz, 1 H), (m, 2 H), (m, 1 H); Minor diastereoisomer: δ [ppm] = (m, 9 H), 1.99 (br s, 1 H), (m, 1 H), (m, 1 H), 3.57 (d, J =.8 Hz, 1 H), 3.64 (d, J =.8 Hz, 1 H), (m, 2 H), (m, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): Major diastereoisomer δ [ppm] = 17.2, 2.9, 31.2, 38.2, 39.3, 51.2, 73.5, 9.7, 127.3, 134.6, 148.4, diastereoisomer: δ [ppm] = 17.5, 21., 31.4, 37.1, 39.6, 51.7, 72.9, 129.4, 133.2, 9.5, 148.8, LRMS (EI), m/z Major isomere: 22 (5%) [ 37 Cl-M + ], 2 (15%) [ 35 Cl-M + ], 184 (5%) [ 37 Cl- M + H 2 O], 182 (15%) [ 35 Cl-M + H 2 O], 164 (3%), 151 (48%), 147 (9%), 133 (15%), 123 (27%), 9 (%). HRMS m/z calcd for 35 ClC 11 H 15 ( 35 Cl-M + H 2 O)] , found ; calcd for 37 ClC 11 H 15 ( 37 Cl-M + H 2 O)] , found

4 S4 (5R)-1-(Hydroxymethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (5) HO OH C 11 H 18 O 2 182,26 g/mol The chlorohydrine 4 (98.5 mg,.491 mmol) was dissolved in 1,4-dioxane (5. ml), and a potassium hydroxide solution (5. ml, 5. mmol, 1. M in H 2 O) was added at r.t.. The mixture was stirred for 14 min at r.t., 16 min at 5 C, and further 6 min at 75 C. The mixture was cooled to r.t. and the reaction was stopped by addition of brine (3 ml) and extracted with diethylether (5 x 25 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. After purification by flashchromatography through silica gel (Pentanes/Et 2 O = 1:1 1:3) the diol 5 was obtained as a pale yellow solid (5.7 mg,.278 mmol, 57%, d.r. :1). The analytical data are in complete agreement with the previously reported ones. 4 Major diastereoisomer: R f =.15, Minor diastereoisomer: R f =.23 (Pentanes/Et 2 O = 5:5, [CAM]) 1 H-NMR (25 MHz, CDCl 3 ): Major diastereoisomer: δ [ppm] = 1.59 (t, J = 13.3 Hz, 1 H), 1.75 (m, 6 H), (m, 5 H), (m, 1 H), 3.54 (d, J =.7 Hz, 1 H), 3.7 (d, J =.7 Hz, 1 H), 4.74 (m, 2 H), (m, 1 H); (36 MHz, CDCl 3 ): Minor diastereoisomer: δ [ppm] = 1.44 (td, J = 12.4 Hz, J = 1.2 Hz, 1 H), (m, 6 H), (m, 4 H), (m, 2 H), 3.55 (d, J =.1 Hz, 1 H), 3.65 (d, J = 11.1 Hz, 1 H), 4.74 (m, 2 H), (m, 1 H). 13 C-NMR (62.9 MHz, CDCl 3 ): δ [ppm] = 18., 21., 31.4, 37.1, 39.3, 67.2, 68.8, 72.8, 9.4, 128.7, 134.3, M. A. Bergström, K. Luthman, J. L. G. Nilsson, A.-T. Karlberg, Chem. Res. Toxicol. 26, 19,

5 S5 (5R)-2-methyl-5-(prop-1-en-2-yl)-1-(((triisopropylsilyl)oxy)methyl)cyclohex-2-enol HO OTIPS C 2 H 38 O 2 Si 338,26 g/mol Diol 5 (29 mg, 1.59 mmol) and imidazole (217 mg, 3.19 mmol) were dissolved in absolute DMF (1.8 ml) under argon atmosphere. TIPSCl (.5 ml, 2.39 mmol) was added dropwise, and the solution was stirred at r.t. for 24 h. The reaction mixture was poured into water (25 ml) and extracted with diethylether (3 x 2 ml). The combined organic layers were washed with brine (5 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 98:2 95:5), (5R)-2-methyl-5-(prop-1-en-2-yl)-1-(((triisopropylsilyl)oxy)methyl)-cyclohex-2-enol was obtained as a colorless oil (5 mg, 1.48 mmol, 93%). Major diastereoisomer: R f =.3, Minor diastereoisomer: R f =.55 (Pentanes/Et 2 O = 9:1, [CAM]). 1 H-NMR (36 MHz, CDCl 3 ): Major diastereoisomer: δ [ppm] = (m, 21 H), 1.54 (t, J = 13.2 Hz, 1 H), (m, 5 H), 1.74 (s, 3 H), (m, 1 H), (m, 1 H), 2.45 (s, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 1 H); Minor diastereoisomer: δ [ppm] = (m, 21 H), (m, 1 H), 1.72 (s, 3 H), 1.74 (m, 3 H), (m, 2 H), (m, 1 H), (m, 1 H), 2.94 (br s, 1 H), (m, 2 H), 4.72 (m, 2 H), 5.56 (m, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): Major diastereoisomer: δ [ppm] = 12.1, 18.2, 18.2, 21., 31.6, 37.1, 4.1, 69.7, 72.6, 8.9, 127.8, 134.5, 149.7, Minor diastereoisomer: δ [ppm] = 12.1, 17.7, 17.8, 18.1, 2.5, 31.1, 38., 39.8, 66.6, 74.2, 9.3, 126.3, 135.4, 148.9, LRMS (EI), m/z Major diastereoisomer: 338 (5%) [M + ], 32 (1%) [M + H 2 O], 295 (48%) [M + C 3 H 7 ], 279 (4%), 261 (4%), 253 (2%), 239 (8%), 227 (2%), 21 (9%), 187 (3%), 174 (2%), 164 (14%), 151 (%), 147 (96%), 131 (54%), 9 (49%), 5 (86%). HRMS m/z calcd for 35 ClC 11 H 15 ( 35 Cl- M + H 2 O)] , found ; calcd for C 2 H 38 O 2 Si (M + ) , found

6 S6 General procedure A for the oxidative rearrangement of tertiary allylic alcohols (S)-2-Methyl-5-(prop-1-en-2-yl)-3-(((triisopropylsilyl)oxy)methyl)cyclohex-2-enone (6) O TIPSO C 2 H 36 O 2 Si 336,24 g/mol (5R)-2-Methyl-5-(prop-1-en-2-yl)-1-(((triisopropylsilyl)oxy)methyl)cyclohex-2-enol (526 mg, 1.55 mmol) was dissolved in CH 2 Cl 2 (15. ml) at 23 C, and PCC (836 mg, 3.88 mmol) was added. After stirring for 54 h at 23 C, the red-brown mixture was diluted with diethylether (4 ml) and filtered through silica gel rinsed with diethylether ( ml). The combined filtrates were concentrated under reduced pressure and after purification by flashchromatography through silica gel (Pentanes/Et 2 O 9:1), compound 6 was obtained as a pale yellow oil (392 mg, 1.16 mmol, 75%). R f =.24 (Pentanes/Et 2 O = 9:1, [CAM], [UV]); 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = (m, 21 H), 1.72 (d, J =.9 Hz, 3 H), 1.76 (s, 3 H), (m, 2 H), (m, 2 H), (m, 1 H), (m, 2 H), 4.76 (m, 1 H), 4.81 (m, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 149.7, 134.5, 127.8, 8.9, 72.6, 69.7, 4.1, 37.1, 31.6, 21., 18.2, 18.2, LRMS (EI), m/z 336 (2%) [M + ], 39 (4%) [M + C 2 H 3 ], 293 (%) [M + C 3 H 7 ], 275 (72%), 261 (8%), 249 (5%), 237 (%), 221 (13%), 25 (14%), 173 (11%), 162 (11%), 145 (29%), 131 (38%), 3 (69%), 75 (%). HRMS: calcd for C 2 H 36 O 2 Si (M + ) , found

7 S7 General procedure B for the addition of propargylmagensium bromide to aldehydes (1R,5S)-2-Methyl-5-(prop-1-en-2-yl)-1-(prop-2-in-1-yl)-3-(((triisopropylsilyl)oxy)- methyl)-cyclohex-2-enol Magnesium turnings (214 mg, 8.8 mmol) were suspended in dry diethylether (3.8 ml) under argon atmosphere at r.t. mercury(ii) chloride (4. mg, 14.7 µmol) and iodine (11.4 mg, 44.9 µmol) were added, and the Grignard formation was started by addition of two drops of propargylbromide. The reaction mixture was cooled down to C and a solution of propargyl bromide (88 µl, 7.92 mmol, 8% in toluene) and ketone 6 (1.48 g, 4.4 mmol) in diethylether (7.4 ml) were added dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 2 h. The reaction mixture was filtred, and saturated aqueous ammonium chloride solution (4 ml) was added. The layers were separated and the aqueous layer was extracted wit diethylether (2 x 3 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 9:1 4:1), (1R,5S)-2-methyl-5-(prop-1-en-2-yl)-1-(prop-2- in-1-yl)-3-(((triisopropylsilyl)oxy)-meth-yl)-cyclohex-2-enol was obtained as a pale yellow oil (1.6 g, 4.25 mmol, 97%, d. r. > 95:5). R f =.17 (Pentanes/Et 2 O = 9:1, [CAM]); [α] 23 D = -7.6 (c = 3.7 mg/ml, CH 2 Cl 2 ) 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = (m, 21 H), (m, 1 H), 1.7 (s, 3 H), 1.78 (s, 3 H), (m, 3 H), (m, 1 H), (m, 3 H), 2.63 (ddd, J = 16.9 Hz, J = 2.5 Hz, J = 1.4 Hz, 1 H), (m, 2 H), (m, 2 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 11.5, 12.2, 18.2, 21.1, 29.5, 32.3, 38.7, 4.3, 63.3, 71.7, 73.7, 8.5, 9.4, 129.8, 134.3, 149., LRMS (EI), m/z 376 (2%) [M + ], 358 (3%) [M + H 2 O], 337 (5%) [M + H 2 CC CH], 315 (12%), 21 (5%), 185 (14%), 163 (%), 143 (19%), 131 (45%), 119 (45%), 3 (57%). HRMS: calcd for C 23 H 4 O 2 Si (M + ) , found

8 S8 Triethyl(((1R,5S)-2-methyl-5-(prop-1-en-2-yl)-1-(prop-2-in-1-yl)-3-(((triisopropylsilyl)- oxy)methyl)cyclohex-2-en-1-yl)oxy)silane (3) Imidazole (451 mg, 6.62 mmol) and triethylsilyl chloride (1.4 ml, 6.2 mmol) were added to a solution of (1R,5S)-2-methyl-5-(prop-1-en-2-yl)-1-(prop-2-in-1-yl)-3-(((triisopropylsilyl)oxy)-methyl)-cyclohex-2-enol (1.56 g, 4.14 mmol) in DMF (3.9 ml). The reaction mixture was stirred at r.t. for 3 d and then quenched with water. The aqueous layer was extracted with Et 2 O (3 x 4 ml), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column ((Pentanes/Et 2 O = 9 :1) to provide compound 3 (1.92 g, 3.91 mmol, 94%) as a yellow oil. R f =.62 (Pentanes/Et 2 O = 98:2, [CAM]); [α] 23 D = +4.6 (c = 3.2 mg/ml) 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] =.5.71 (m, 6 H),.95 (t, J = 7.9 Hz, 9 H), (m, 21 H), (m, 1 H), 1.66 (s, 3 H), 1.78 (s, 3 H), (m, 1 H), 1.97 (t, J = 2.6 Hz, 1 H), (m, 4 H), 2.59 (ddd, J = 16.8 Hz, J = 2.5 Hz, J = 1.4 Hz, 1 H), 4.22 (s, 2 H), 4.76 (m, 2 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 6.9, 7.3, 11.9, 12.3, 17.9, 18.2, 2.9, 31.4, 32.7, 39.3, 41.1, 63.7, 7.7, 81.7, 8.8, 131.9, 132.5, LRMS (EI), m/z 461 (1%) [M + C 2 H 5 ], 451 (%) [M + H 2 CC CH], 299 (3%), 275 (33%), 265 (%), 223 (12%), 193 (7%), 165 (4%), 115 (29%). HRMS: calcd for C 26 H 51 O 2 Si 2 (M + H 2 CC CH) , found

9 S9 Cycloisomerization of 3-siloxy-1,5-enynes containing tetrasubstituted double-bonds Synthesis of 2, 2a, 2b, 2c, 2d, 8 and 9 General procedure C for the cycloisomerization of 3-siloxy-1,5-enynes (3aS,5S,7aS)-7a-Methyl-5-(prop-1-en-2-yl)-3a-(((triisopropylsilyl)oxy)methyl)-3a,4,5,6- tetrahydro-1h-inden-7(7ah)-one (2) O OTIPS C 23 H 4 O 2 Si 376,65 g/mol Platinum(IV) chloride (121 mg,.359 mmol, 2 mol%) was suspended in toluene (3. ml) at r.t. and 1,5-cyclooctadiene (18 µl, 1.44 mmol) as well as isopropanol (83 µl,.8 mmol) were added. A solution of enyne 3 (881 mg, 1.79 mmol) in toluene (6. ml) was added and the reaction mixture was stirred for 2 min at r.t.. The reaction solution was poured into a mixture of water (2 ml) and brine (2 ml), and was extracted with diethylether (3x 4 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 49:1), ketone 2 was obtained as a pale yellow oil (538 mg, 1.43 mmol, 8%). R f =.36, (Pentanes/Et 2 O = 95:5, [CAM]), [α] D 23 = +4.6 (c = 5.2 mg/ml); 1 H-NMR (25 MHz, CDCl 3 ): δ [ppm] = (m, 21 H), 1.2 (s, 3 H), (m, 4 H), (m, 2 H), (m, 4 H), (m, 1 H), 3.61 (s, 2 H), (m, 1 H), 4.76 (virt. t, J = 1.4 Hz, 1 H), (m, 1 H), (m, 1 H). 13 C-NMR (62.9 MHz, CDCl 3 ): δ [ppm] 12.4, 18.5, 18.8, 2.9, 34.5, 39.6, 42.4, 44.2, 57.2, 57.4, 68.4, 9.9, 133.1, 137., 148.4, LRMS (EI): m/z 376 (2%) [M + ], 333 (%) [M + C 3 H 7 ], 291 (4%), 265 (4%), 239 (5%), 22 (14%), 25 (43%), 185 (15%), 157 (14%), 145 (28%), 131 (27%), 5 (2%), 93 (32%). HRMS (EI): calcd for C 2 H 33 O 2 Si (M + C 3 H 7 ) , found

10 S 3a,4,5,6-tetrahydro-1H-inden-7(7aH)-one (2a) O OTIPS C 24 H 42 O 2 Si 39,29 g/mol Applying compound 3a to the general procedure C (r.t., 3 min), compound 2a was obtained as a colorless oil (25 mg,.63 mmol, 65 %) after purification by flash-chromatography through silica gel (Pentanes:Et 2 O/99:1). R f =.37, (Pentanes/Et 2 O = 95:5, [CAM]), 1 H-NMR (5 MHz, CDCl 3 ): δ [ppm] = 5.5 (s, 1H), (m, 2H), (m, 2H), 2.98 (d, 3 J HH = 15.6 Hz, 1H), (m, 2H), (m, 2H), 1.89 (dd, 3 J HH = 13.9, 3 J HH = 2.5 Hz, 1H), 1.73 (s, 3H), (m, 4H), (m, 3H), 1.2 (s, 3H), (m, 21H). 13 C-NMR (63 MHz, CDCl 3 ): δ [ppm] 13 C NMR (63 MHz, CDCl 3 ) δ 216.1, 148.1, 141.6, 128.9, 9.7, 67., 58.5, 57.5, 44., 39.6, 39.2, 31.9, 2.6, 19.1, 18.3, 14., LRMS (EI): m/z [M + -42] (2%), [M + -43] (82%), (34%), (26%), (53%), (6%), 131. (61%), (75%), 7. (99%), 2.97 (48%), 9.92 (3%), (47%), 58.9 (27%), 4.93 (14%). HRMS (EI): calcd for C 24 H 42 O 2 28 Si (M + ) , found (3aS,5S,7aS)-3,7a-Dimethyl-5-(prop-1-en-2-yl)-3a-((triisopropylsilyloxy)-methyl)- (3aS,5S,7aS)-7a-Methyl-3-phenyl-5-(prop-1-en-2-yl)-3a-((triisopropyl-silyloxy)methyl)- 3a,4,5,6-tetrahydro-1H-inden-7(7aH)-one (2b) O H C 19 H 22 O 266,16 g/mol Applying compound 3b to the general procedure C (r.t., 5 h), compound 2b was obtained as a yellow oil (17 mg,.38 mmol, 43%) after purification by flash-chromatography through silica gel (Pentanes:Et 2 O/99:1 95:5).

11 S11 R f =.4, (Pentanes/Et 2 O = 95:5, [CAM]), 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = (m, 5H), (m, 1H), (m, 1H), 4.5 (s, 1H), 3.9 (s, 2H), 3.15 (dd, J = 16.3, 3.3 Hz, 1H), (m, 2H), 2.28 (dd, J = 16.3, 1.9 Hz, 1H), (m, 2H), 1.7 (d, J = 13.2 Hz, 1H), 1.43 (s, 3H), 1.31 (s, 3H), 1.23 (s, 1H) (m, 21H). 13 C- NMR (91 MHz, CDCl 3 ): δ [ppm] 215.8, 147.9, 146.4, 137.6, 133.4, 128.3, 127.8, 127.2, 9.4, 67.4, 59.6, 59., 43.7, 39.5, 39.2, 31.9, 2.4, 19.2, 18.3, LRMS (EI): m/z 452. [M + ] (2%), 4.5 (23%), 49.5 (77%), (15%), (57%), (45%), (34%), 18.9 (62%), (54%), (47%), (9%), 2.97 (9%), 9.99 (4%), (46%), (56%), (99%), (56%), (87%). HRMS (EI): calcd for C 19 H 22 O 28 Si (M + ) , found (3aS,5S,7aS)-3a-(2-(tert-Butyldimethylsilyloxy)ethyl)-7a-methyl-5-(prop-1-en-2-yl)- 3a,4,5,6-tetrahydro-1H-inden-7(7aH)-one (2c) O TIPSO C 24 H 42 O 2 Si 39,67 g/mol Applying compound 3c to the general procedure C (35 C, 35 min), compound 2c was obtained as a pale yellow oil (2 mg,.292 mmol, 9%) after purification by flashchromatography through silica gel (Pentanes:Et 2 O/99:1). 1 H-NMR (5 MHz, CDCl 3 ): δ [ppm] = (m, 1 H), 5.57 (dd, J = 5.8, 2. Hz, 1 H), 4.76 (s, 1 H), 4.71 (s, 1 H), 3.81 (ddd, J = 9.7, 8.7, 6.4 Hz, 1 H), 3.72 (ddd, J = 9.7, 8.9, 5.6 Hz, 1 H), 3.17 (dd, J = 15.9, 2.8 Hz, 1 H), 2.35 (app ddd, J = 14., 3.8, 2.5 Hz, 1 H), 2.29 (app t, J = 14. Hz, 1 H), (m, 2 H), 2.6 (app dt, J = 16., 2. Hz, 1 H), 1.73 (ddd, J = 12.6, 8.7, 5.6 Hz, 1 H), 1.73 (s, 3 H), 1.65 (ddd, J = 13., 8.6, 6.3 Hz, 1 H), 1.52 (app t, J = 13.6 Hz, 1 H), 1.14 (s, 3 H), (m, 21 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] 215.8, 148., 138.2, 132.2, 9.8, 6.7, 59.1, 53.4, 43.9, 4.4, 4.3, 4.2, 36.6, 2.7, 18.3, 18.1, LRMS (EI): m/z 347 (%) [M + -ipr], 253 (13%), 199 (26%), 93 (22%). HRMS (EI): calcd for C 21 H 35 O 28 2 Si (M + -ipr) , found

12 S12 (3aS,5S,7aS)-7a-Methyl-5-(prop-1-en-2-yl)-3a-((trimethylsilyl)ethynyl)-3a,4,5,6- tetrahydro-1h-inden-7(7ah)-one (2d) O TMS C 18 H 26 OSi 286,17 g/mol A solution of platinum(iv) chloride (84. mg,.25 mmol) in dry toluene (3. ml) was purged under an atmosphere of CO and heated at 12 C for 3 minutes. Once the solution cooled to room temperature, a solution of enyne 2d (286 mg,.7 mmol) in dry toluene (. ml) and isopropanol (.5 ml, 6.25 mmol) were successively added. The resulting mixture was vigorously stirred at 5 C for 4 hours. Then the reaction mixture was quenched with water, extracted with diethylether, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes:Et 2 O/99:1) compound 3d was obtained as a pale yellow oil (98.9 mg,.35 mmol, 48%). 1 H-NMR (5 MHz, CDCl 3 ): δ [ppm] (m, 1 H), 5.55 (app dd, J = 5.5, 2.1 Hz, 1 H), 4.79 (s, 1 H), 4.73 (s, 1 H), 3.13 (dd, J = 15.8, 2.8 Hz, 1 H), (m, 2 H), (m, 3 H), 1.9 (app t, J = 13.5 Hz, 1 H),.15 (s, 9 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] 214., 147., 135.5, 133.9, 1.3, 7.8, 88.3, 58.5, 53.1, 43.4, 41.1, 39.4, 37.8, 2.7, 2.3,.3. LRMS (EI): m/z 286 (15%) [M + ], 271 (37%) [M + -Me], 25 (23%), 189 (2%), 73 (%). HRMS (EI): calcd for C 18 H 26 O 28 Si [M + ] , found

13 S13 3,3a-Dimethyl-3a,4,5,6,7,7a-hexahydro-1H-indene-7a-carbaldehyde (9) O C 12 H 18 O 178,13 g/mol Applying compound 7b to the general procedure C (r.t., 3 h), after purification by flashchromatography through silica gel (P:Et 2 O/1: - 99:1 95:5) compound 9 was obtained as a colorless oil (3 mg,.168 mmol, 41%) after purification by flash-chromatography through silica gel (P:Et 2 O/1: - 99:1 95:5). R f =.65, (Pentanes/Et 2 O = 95:5, [CAM]), 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = 9.75 (s, 1H), 5.26 (d, 3 J HH = 1.6 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 1.61 (dd, 3 J HH = 3.8, 3 J HH = 1.9 Hz, 3H), (m, 7H),.93 (s, 3H). 13 C-NMR (63 MHz, CDCl 3 ): δ [ppm] 27.2, 147.5, 121.1, 58.6, 49.5, 36.6, 35.1, 28.4, 22.7, 22.1, 2.8, LRMS (EI): m/z 194 [M + ] (16%), 179 [M + -CH 3 ] (32%), 149 (35%), 133 (34%), 123 (99%), 9 (44%), 5 (2%), 91 (3%), 43 (59%). HRMS (EI): calcd for C 12 H 18 O (M + ) , found (E)-5-(2-Methylcyclohex-2-enylidene)pentanes-2-one (8) Applying compound 7a to the general procedure C (r.t., 6 h), compound 8 was obtained as a colorless oil (5 mg,.28 mmol, 41%) after purification by flash-chromatography through silica gel (P:Et 2 O/99:1). R f =.27, (Pentanes/Et 2 O = 95:5, [CAM], [UV]), 1 H-NMR (25 MHz, CDCl 3 ): δ [ppm] = 5.6 (t, 3 J HH = 4.2 Hz, 1H), 5.29 (t, 3 J HH = 7. Hz, 1H), (m, 2H), (m, 4H), (m, 2H), 2.13 (s, 3H), 2.7 (d, 3 J HH = 4.1 Hz, 2H), 1.74 (d, 3 J HH = 1.4 Hz, 3H), 1.64 (dt, 3 J HH = 12.5, 3 J HH = 6.2 Hz, 2H). 13 C-NMR (63 MHz, CDCl 3 ): δ [ppm] 28.8, 133.2, 127., 121.4, 43.9, 3.2, 26.2, 26., 23.2, 22.3, 2.3. LRMS (EI): m/z [M+]

14 S14 (6%), (6%), (%), (13%), (16%), (39%), 9. (16%), 91. (21%), (25%), 79. (2%), 66.97(14%), (24%), (2%), (%). HRMS (EI): calcd for C 12 H 18 O (M + ) , found Final steps of the total synthesis of (+)-cyperolone (E)-4-Methyl-N -((3aS,5S,7aS)-7a-methyl-5-(prop-1-en-2-yl)-3a-((triisopropylsilyl)oxymethyl-3a,4,5,6-tetrahydro-1H-inden-7(7aH)-yliden)benzolsulfonohydrazide () N Ts NH OTIPS C 3 H 48 N 2 O 3 SSi 544,31 g/mol p-toluenesulfonylhydrazide (991 mg, 5.32 mmol) and p-toluenesulfonic acid monohydrate (25.3 mg,.133 mmol) were added to a solution of ketone 3 (1. g, 2.65 mmol) in THF (5 ml), and the mixture was heated to reflux for 2 h. After the reaction mixture was cooled down to r.t., saturated aqueous sodium bicarbonate solution was added, and the layers were separated. The aqueous layer was extracted with diethylether (2 x 5 ml), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 9:1 7:3), compound was obtained as a colorless solid (1.33 g, 2.44 mmol, 92%). R f =.64, (Pentanes/Et 2 O = 1:1, [CAM], [UV]), [α] D 23 = (c =.843, CH 2 Cl 2 ); m.p. = 126 C, 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = (m, 2H), (m, 2H), 5.79 (dd, J = 7.9, 2.2 Hz, 1H), 5.45 (d, J = 5.8 Hz, 1H), 4.81 (d, J = 2.9 Hz, 2H), (m, 2H), 2.9 (d, J = 16.8 Hz, 1H), (m, 4H), 2.27 (t, J = 12.3 Hz, 1H), (m, 1H), 1.96 (dd, J = 16.4, 12.3 Hz, 1H), 1.79 (s, 3H), 1.72 (d, J = 12.6 Hz, 1H), 1.58 (t, J = 13.1 Hz, 1H), 1.27 (s, 3H), (m, 21H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 164.4, 148.2, 143.8, 135.6, 135.5, 13.1, 129.3, 128.3, 9.8, 67.4, 57.1, 49.8, 47.2, 36.5, 36.3, 31., 21.7, 2.9, 2.6, 18.1, 12...LRMS (EI): m/z 544 (74%) [M + ], 51 (4%) [M + C 3 H 7 ], 389 (66%) [M + C 7 H 7 O 2 S], 357 (25%), 317 (24%), 269 (19%), 215 (41%), 187 (28%), 157 (31%), 145 (%). HRMS (EI): calcd for C 3 H 48 N 2 O 3 32 S 28 Si (M + ) , found

15 S15 Triisopropyl(((3aS,5R,7aS)-7a-methyl-5-(prop-1-en-2-yl)-3a,4,5,6,7,7a-hexahydro-1Hinden-3a-yl)methoxy)silane (11) OTIPS C 23 H 42 OSi 362,66 g/mol Hydrazine (23.3 mg, 42.8 µmol) was dissolved in CH 2 Cl 2 (1. ml) under argon atmosphere at C, and DIBAL-H (15 µl, 15 µmol, 1 M in hexane) was added dropwise. The resulting yellow solution was stirred for 4 min at C, before the reaction was quenched by addition of potassium sodium tatrate solution (4. ml, 2 mass% in H 2 O), diluted with pentanes ( ml) and warmed to r.t.. After addition of glycerine, the mixture was stirred for 2 h until the layer were fully separated. The layers were separated and the aqueous layer was extracted with pentanes (2 x 15 ml). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes), compound 11 was obtained as a colorless oil (11.9 mg, 32.8 µmol, 77%). R f =.64, (Pentanes, [CAM]), [α] D 23 = (c = 5.4, CH 2 Cl 2 ); 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = (m, 21 H), 1.7 (s, 3 H), (m, 3 H), 1.33 (dt, J = 13.2 Hz, J = 3.3 Hz, 1 H), (m, 1 H), (m, 1 H), 1.72 (s, 3 H), (m, 3 H), 2.38 (dt, J = 15.8 Hz, J = 1.8 Hz, 1 H), 3.4 (d, J = 9.1 Hz, 1 H), 3.49 (d, J = 9.5 Hz, 1 H), 4.68 (s, 2 H), (m, 1 H), (m, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 151.6, 139.2, 13.5, 8.2, 7., 55.2, 48.4, 42.3, 42.3, 39.6, 34.6, 28.2, 21.4, 2., 18.5, LRMS (EI): m/z 319 (79%) [M + C 3 H 7 ], 31 (3%), 277 (12%), 175 (16%), 157 (12%), 145 (2%), 131 (%). HRMS (EI): calcd for C 2 H 35 O 28 Si (M + -ipr) , found

16 S16 ((3aS,5R,7aS)-7a-Methyl-5-(prop-1-en-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-inden-3a-yl)- methanol (12) CH 3 CH 3 HO H C 14 H 22 O 26,16 g/mol TBAF (2.15 ml, 2.15 mmol, 1 M in THF) was added to silylether 11 (52 mg, 1.43 mmol) at r.t., and the resulting solution was stirred for 4 h at r.t. Water ( ml) and saturated aqueous ammonium chloride solution (2 ml) were added, and the mixture was extracted with diethylether (3 x 3 ml). The combined organic layers were washed with brine (9 ml), dried over sodium sulfate and concentrated under reduced pressure. Purification by flashchromatography through silica gel (Pentanes/Et 2 O 9:1 3:1) gave the primary alcohol 12 as a colorless solid (295 mg, 1.43 mmol, %). R f =.3, (Pentanes/Et 2 O = 4:1, [CAM]), [α] 23 D = (c = 1.79, CH 2 Cl 2 ); m.p. = C; 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = (m, 3 H), 1.11 (s, 3 H), 1.39 (dt, J = 7.3 Hz, J = 3.3 Hz, 1 H), (m, 3 H), 1.71 (s, 3 H), 1.75 (m, 1 H), (m, 2 H), (m, 1 H), 3.2 (d, J =.9 Hz, 1 H), 3.47 (d, J =.9 Hz, 1 H), 4.68 (m, 2 H), 5.49 (dd, J = 5.8 Hz, J = 2.5 Hz, 1 H), 5.91 (m, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 15.7, 137., 132.8, 8.3, 69.1, 55.1, 48.8, 42.1, 41.8, 39.6, 34.2, 27.7, 21.1, LRMS (EI): m/z 26 (8%) [M + ], 175 (%) [M + CH 2 OH], 147 (8%), 133 (24%), 119 (31%), 5 (35%).HRMS (EI): calcd for C 14 H 22 O (M + ), , found

17 S17 ((1aR,1bS,3R,5aS,6aS)-5a-Methyl-3-(prop-1-en-2-yl)octahydro-1aH-indeno[1,2- b]oxiren-1b-yl)methanol (13) CH 3 CH 3 HO O H H C 14 H 22 O 2 222,32 g/mol VO(acac) 2 (3.7 mg, 14.1 µmol) was added to a solution of homoallylic alcohol 12 (4 mg, mmol) in CH 2 Cl 2 (9.9 ml) at r.t., and the mixture was stirred until the vanadium complex was fully dissolved. t-buooh (132 µl,.729 mmol, 5.5 M in decane) was added dropwise to the green solution, which turned to dark red, and subsequently to orange-yellow after 2 h at r.t.. Afterwards, further t-buooh (132 µl,.729 mmol, 5.5 M in decane) was added, and the solution was stirred for further 2 h at r.t.. A last portion of t-buooh (132 µl,.729 mmol, 5.5 M in decane) was added and was stirred for 21 h at r.t.. The reaction was stopped by addition of saturated aqueous sodium thiosulfate solution (5 ml) and extracted with CH 2 Cl 2 (3 x 3 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography (P:Et 2 O/9:1-1:1) compound 13 was obtained as a pale yellow oil (39 mg, 1.77 mmol, 89%, brsm. 92%, d.r.>99:1). R f =.31, (Pentanes/Et 2 O = 1:1, [CAM]), [α] 23 D = +6.9 (c = 1.18, CH 2 Cl 2 ); 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] =.88 (s, 3 H), (m, 2 H), (m, 2 H), (m, 3 H), 1.73 (s, 3 H), (m, 2 H), (m, 1 H), (m, 2 H), 3.61 (t, J = 3. Hz, 1 H), 3.72 (dd, J =.8 Hz, J = 5.4 Hz, 1 H), 4.7 (s, 2 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 15., 8.8, 67.7, 66.7, 59.3, 47.7, 47.1, 42.1, 4.4, 38.6, 33.5, 27.1, 21., 2.9. LRMS (EI): m/z 222 (%) [M + ], 27 (5%), 24 (7%), 191 (48%) [M + CH 2 OH], 175 (38%), 161 (31%), 149 (61%), 135 (7%), 9 (89%), 5 (%). HRMS (EI): calcd for C 14 H 22 O 2 (M + ), , found

18 S18 (1aR,1bR,3R,5aS,6aS)-5a-Methyl-3-(prop-1-en-2-yl)octahydro-1aH-indeno[1,2-b]oxiren- 1b-carbaldehyd (14) CH 3 CH 3 O O H H C 14 H 2 O 2 22,31 g/mol Alcohol 13 was dissolved (12.7 mg, 57.1 µmol) in CH 2 Cl 2 (48 µl) at r.t., and i-pr 2 NEt (3. µl, 171 µmol) was added. A solution of SO 3 -pyridine (27.2 mg, 171 µmol) in DMSO (2 µl) was added dropwise, and the mixture was stirred at r.t. for 4 h. Again, i-pr 2 NEt (3. µl, 171 µmol) and solid SO 3 -Pyridin (27.2 mg, 171 µmol) were added, and the reaction mixture was stirred for further 23 h at r.t.. The reaction mixture was diluted with diethylether (25 ml) and washed with water (25 ml). The layers were separated and the aqueous layer was extracted with diethylether (1 x 25 ml). The combined organic layers were washed with saturated aqueous ammonium chloride solution (1x 25 ml), saturated aqueous sodium bicarbonate solution (1 x 25 ml) and brine (1 x 25 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 9:1), aldehyde 14 was obtained as a colorless oil (11.6 mg, 52.7 µmol, 94%). R f =.39, (Pentanes/Et 2 O = 4:1, [CAM]), [α] 23 D = (c = 1.18, CH 2 Cl 2 ). ; 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = 1.4 (s, 3 H), (m, 4 H), (m, 4 H), (m, 4 H), 3.44 (d, J = 2.6 Hz, 1 H), 3.7 (t, J = 2.4 Hz, 1 H), 4.71 (m, 2 H), 9.87 (s, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 24.9, 149.3, 9.4, 64.3, 58.9, 57.7, 45.5, 4.6, 37.2, 34.7, 28.6, 26.6, 25.5, 2.6. IR (ATR): ~ ν [cm -1 ] = 2928 (s), 2861 (m), 2739 (w), 1712 (s), 1645 (m), 1455 (m), 1436 (m), 1372 (m), 893 (m), 849 (m), 834 (m), 738 (m). LRMS (EI): m/z 22 (2%) [M + ], 19 (57%) [M + CH 2 O], 177 (35%), 159 (22%), 149 (46%), 135 (47%), 9 (%).HRMS (EI): calcd for C 13 H 18 O (M + CH 2 O) , found

19 S19 (1aR,1bS,3R,5aS,6aS)-1b-Ethinyl-5a-methyl-3-(prop-1-en-2-yl)-octahydro-1aH-indeno- [1,2-b]-oxiren (15) CH 3 CH 3 O H H C 15 H 2 O 216,32 g/mol Potassium tertbutylate (146 mg, 1.33 mmol) were suspended in THF (3.8 ml) at -78 C and a solution of Seyfert-Gilbert reagent 5 (183 mg, mmol) in THF (3.8 ml) were added dropwise. The reaction mixture was stirred for min and a solution of aldehyde 14 (148. mg,.672 mmol) in THF (3.8 ml) was added dropwise. The reaction mixture was stirred for further 2 h at -78 C and, afterwards, was allowed to warm to -2 C over a period of 6 h. The reaction was stopped by addition of water (3 ml) and extracted with diethylether (3 x 3 ml). The combined organic layers were washed with brine (3 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes:Et 2 O/8:2), alkyne 15 was obtained as a colorless oil (138 mg,.6379 mmol, 95 %), R f =.54, (Pentanes/Et 2 O = 4:1, [CAM]), [α] D 23 = (c = 1.13, CH 2 Cl 2 ); 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = 1.12 (s, 3 H), (m, 2 H), (m, 1 H), (m, 4 H), 1.73 (s, 3 H), (m, 2 H), 2.29 (m, 1 H), 3.41 (d, J = 2.6 Hz, 1 H), 3.57 (dd, J = 3.9, J = 1.8 Hz, 1 H), 4.71 (s, 2 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 148.9, 9.3, 86., 72.2, 65.9, 59., 45.7, 45.5, 4.3, 38.6, 36.5, 34.4, 27.3, 25.8, 2.8. IR (ATR): ν ~ [cm -1 ] = 333 (m), 2933 (s), 2856 (m), 1644 (m), 1454 (s), 1373 (m), 136 (w), 1234 (w), 887 (s), 85 (s). LRMS (EI): m/z 216 (1%) [M + ], 215 (4%) [M + H], 21 (25%) [M + CH 3 ], 187 (27%), 183 (6%), 173 (31%), 159 (45%), 145 (79%), 133 (47%), 131 (75%), 117 (74%), 115 (32%), 5 (73%), 91 (%). HRMS (EI): calcd for C 14 H 17 O (M + CH 3 ) , found J. C. Gilbert, U. Weerasooriya, J. Org. Chem., 1982, 47,

20 S2 (1S,3aS,6R,7aS)-7a-Ethinyl-3a-methyl-6-(prop-1-en-2-yl)octahydro-1H-inden-1-ol (16) CH 3 CH 3 HO H H C 15 H 22 O 218,33 g/mol The epoxide 15 (8 mg,.499 mmol) was dissolved in THF (6.5 ml) under argon atmosphere at r.t.. LiAlH 4 (57. mg, 1.5 mmol) was added, and the reaction mixture was heated to 6 C under argon atmosphere for 24 h. The reaction mixture was cooled to r.t., and water (1.5 ml), 1N NaOH-solution (1.5 ml), and water (4.5 ml) were added consecutively. The overlaying liquid was decanted from the formed precipitate, diluted with Et 2 O (4 ml), and washed with saturated aqueous ammonium chloride solution (4 ml). The layers were separated and the aqueous layer was extracted with diethylether (2 x 4 ml). The combined organic layers were washed with brine (8 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 9:1 4:1), secondary alcohol 16 was obtained as a colorless solid (99.1 mg,.454 mmol, 91%). R f =.24, (Pentanes/Et 2 O = 4:1, [CAM]), [α] D 23 = (c = 1.7, CH 2 Cl 2 ); m.p. = C, 1 H-NMR (36 MHz, CDCl 3 ): δ [ppm] = 1.18 (s, 3 H), (m, 4 H), (m, 3 H), 1.72 (s, 3 H), 1.83 (td, J = 12.7, J = 6.3 Hz, 1 H), 1.96 (d, J = 11.9 Hz, 1 H), 2.1 (ddd, J = 14. Hz, J = 3.8 Hz, J = 2.1 Hz, 1 H), (m, 2 H), 2.36 (s, 1 H), 4.39 (dt, J = 11.6 Hz, J = 8.4 Hz, 1 H), 4.72 (s, 2 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 149.2, 9.2, 85.9, 74.9, 74.1, 52.2, 41.6, 39.4, 36.7, 35.3, 33.3, 3.4, 27.1, 23.1, IR (neat): ν ~ [cm -1 ] = 345 (m), 3279 (m), 2931 (s), 2865 (s), 1646 (m), 1461 (s), 1435 (m), 1375 (m), 1132 (w), 65 (w), 81 (s), 33 (w), 8 (m), 884 (s), 689 (s), 668 (s). LRMS (EI): m/z 218 (2%) [M + ], 23 (28%) [M + CH 3 ], 189 (38%), 175 (34%), 161 (43%), 147 (39%), 133 (53%), 119 (77%), 5 (%). HRMS (EI): calcd for C 14 H 19 O (M + CH 3 ) , found

21 S21 (+)-Cyperolone (1) O CH 3 CH 3 H 3 C HO H H C 15 H 24 O 2 236,17 g/mol Alkyne 16 (5.5 mg, 25.2 µmol) was dissolved in acetone (1. ml), and a solution of red mercury(ii) oxide (5.46 mg, 25.2 µmol) in.73 M H 2 SO 4 (.23 ml) was added dropwise. The resulting grey suspension was stirred for 2 h at r.t.. The reaction mixture was diluted with diethylether (2 ml) and washed with water (2 ml). The layers were separated and the aqueous layer was extracted with Et 2 O (2 ml). The combined organic layers were washed with brine (4 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by flash-chromatography through silica gel (Pentanes/Et 2 O 9:1 4:1), (+)- cyperolone 1 was obtained as a colorless solid (1.8 mg, 7.62 µmol, 3%) as the minor product and lactone 17 was obtained as a colorless oil (2.6 mg, 11.1 µmol, 44%) as the major product. Characterization data for (+)-cyperolone 1 ( 1 H NMR, 13 C NMR, LRMS, HRMS) were indistinguishable from that reported for the naturally occuring material. 6 R f =., (Pentanes/Et 2 O = 4:1, [CAM]), [α] 23 D = (c = 3.7, CHCl 3 ) Lit: 5a [α] 23 D = m.p. = 4 C, 1 H-NMR (5 MHz, CDCl 3 ): δ [ppm] =.98 (s, 3 H), (m, 4 H), (m, 1 H), (m, 3 H), 1.78 (s, 3 H), (m, 3 H), 2.16 (s, 3 H), (m, 1 H), 4.48 (d, J = 6.4 Hz, 1 H), 4.77 (s, 2 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 21.4 (q), 22.7 (q), 27.2 (t), 31.3 (t), 31.5 (q), 31.9 (t), 37.5 (t), 37.6 (t), 39.9 (d), 43. (s), 64.7 (s), 77. (d), 9.2 (t), (s), (s). IR (neat): ~ ν [cm -1 ] = 3436 (br), 386 (w), 2936 (s), 1684 (s), 1643 (m), 146 (s), 1439 (m), 1418 (m), 1376 (m), 1351 (s), 1234 (w), 125 (s), 1195 (s), 1129 (w), 97 (m), 79 (s), 15 (s), 978 (w), 95 (w), 886 (s), 748 (w). LRMS (EI): m/z 236 (17%) [M + ], 218 (%) [M + H 2 O], 28 (%) [M + CO], 23 (7%) [M + H 2 O, CH 3 ], 193 (14%) [M + CH 3 CO], 179 (72%), 175 (53%), 161 (6%), 147 (27%), 133 (%), 123 (74%), 119 (45%), 7 (49%). HRMS (EI): calcd for C 15 H 24 O 2 (M + ) , found a) H. Hikino, K. Aota, Y. Maebayashi, T. Takemoto, Chem. Pharm. Bull. 1966, 14, b) Hikino, H.; Suzuki, N.; Takemoto, T. Chem. Pharm. Bull. 1966, 14, c) G. Mehta, G. L. Chetty, U. R. Nayak, S. Dev, Tetrahedron 1968, 24,

22 S22 (3aS,5aS,8R,9aR)-8-(prop-1-en-2-yl)-5a-methyl-octahydro-indeno[1,7a-b]furan-2-on (17) CH 3 CH 3 O O H H C 15 H 22 O 2 234,33 g/mol R f =.21, (Pentanes/Et 2 O = 4:1, [CAM]), 1 H-NMR (5 MHz, CDCl 3 ): δ [ppm] = 1.3 (s, 3 H), (m, 4 H), 1.51 (dd, J = 12.7 Hz, J = 8.9 Hz, 1 H), (m, 1 H), 1.75 (s, 3 H), (m, 3 H), 2.2 (d, J = 17.9 Hz, 1 H), (m, 1 H), 2.31 (dq, J = 15.2 Hz, J = 9.1 Hz, 1 H), 2.7 (d, J = 17.9 Hz, 1 H), 4.74 (s, 1 H), 4.77 (s, 1 H), 4.91 (dd, J = 8.9 Hz, J = 2.1 Hz, 1 H). 13 C-NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 2.8, 21., 26.8, 29.2, 35.1, 35.9, 38.1, 39., 4.9, 41.8, 53.6, 87.8, 9.2, 148.7, IR (neat): ν ~ [cm -1 ] = 2929 (m), 1772 (s), 1644 (m), 1463 (m), 1415 (w), 1362 (m), 124 (w), 124 (m), 1176 (s), 1159 (s), 35 (m), 13 (m), 997 (m), 978 (m), 93 (w), 886 (s), 851 (w). LRMS (EI): m/z 234 (%) [M + ], 219 (2%) [M + CH 3 ], 26 (7%) [M + CO], 198 (13%), 191 (4%), 181 (89%), 176 (12%), 168 (64%), 163 (18%), 15 (11%), 14 (4%), 137 (23%), 124 (83%), 9 (%).

23 S23 Syntheses of cycloisomerization precursors 3a, 3b, 3c, 3d, 7a and 7b ((1R,5S)-1-(But-2-ynyl)-2-methyl-5-(prop-1-en-2-yl)-3-((triisopropyl-silyloxy)methyl)- cyclohex-2-enyloxy)triethylsilane (3a) Alkyne 3 (2 mg,.47 mmol) was dissolved in THF (1.6 ml) under argon atmosphere at - 78 C and n-buli (359 µl,.896 mmol, 2.5 M in hexane) was added dropwise. The reaction mixture was stirred for 3 min at -78 C. Afterwards the mixture was stirred for further 3 min at C and cooled down to -78 C again. Methyliodide (1 µl, 1.63 mmol) was added dropwise, and the reaction mixture was stirred for 1 h at -78 C. The reaction mixture was warmed to r.t., quenched by addition of saturated aqueous ammonium chloride solution (5 ml) and extracted with diethylether (3 x 5 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. After purification by flashchromatography through silica gel (Pentanes:Et 2 O/99:1), 3a was obtained as a colorless oil (16 mg,.317 mmol, 78%). R f =.69, (Pentanes:Et 2 O/ 99:1, [CAM]), 1 H-NMR (25 MHz, CDCl 3 ): δ [ppm] 4.73 (s, 2H), 4.2 (s, 2H), (m, 5H), (m, 2H), 1.75 (d, 3 J HH = 2.4 Hz, 3H), 1.62 (s, 3H), 1.4 (s, 21H),.93 (t, 3 J HH = 7.8 Hz, 9H), (m, 6H). 13 C-NMR (63 MHz, CDCl 3 ): δ [ppm] 149.7, 132.3, 132., 8.7, 77.4, 76.5, 63.7, 41., 39.1, 32.7, 31.5, 21., 18.3, 17.9, 12.3, 12., 7.3, 7., 3.8. LRMS (EI): m/z [M + -29] (5%), (15%), (35%), (95%), (2%), (33%), (5%), (%), (17%), 3.5 (24%), 87.6 (19%), 75.1 (25%), (13%). HRMS (EI): calcd for C 28 H 51 O 28 2 Si 2 [M + -29] , found

24 S24 Triethyl((1R,5S)-2-methyl-1-(3-phenylprop-2-ynyl)-5-(prop-1-en-2-yl)-3-((triisopropylsilyloxy)methyl)cyclohex-2-enyloxy)silane (3b) Alkyne 3 (3 mg,.611 mmol) was dissolved under argon atmosphere in 1. ml triethylamine and added to a degassed suspension of copper iodide (8.7 mg,.37 mmol), Pd(PPh 3 ) 2 Cl 2 (17.2 mg,.24 mmol) and phenyliodide (75.3 µl,.672 mmol) in 1. ml triethylamine. The reaction mixture was heated to 5 C for 24 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (2 ml) and extracted with diethylether (3x 2 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash-chromatography through silica gel (P:Et 2 O/1: - 99:1), gave 3b as a orange oil (284 mg,.51 mmol, 82%). R f =.71, (P:Et 2 O/ 99:1, [CAM] [UV]) 1 H-NMR (25 MHz, CDCl 3 ): δ [ppm] (m, 2H), (m, 3H), 4.74 (s, 2H), 4.22 (s, 2H), 2.79 (d, 3 J HH = 16.9 Hz, 1H), 2.6 (d, 3 J HH = 16.9 Hz, 1H), (m, 3H), 1.96 (dd, 3 J HH = 19., 3 J HH = 12. Hz, 1H), 1.76 (s, 3H), 1.68 (s, 3H), 1.59 (t, 3 J HH = 9.3 Hz, 1H), (m, 21H),.93 (t, 3 J HH = 7.8 Hz, 9H),.59 (ddd, 3 J HH = 11.5, 3 J HH = 7.9, 3 J HH = 2.7 Hz, 6H). 13 C-NMR (63 MHz, CDCl 3 ): δ [ppm] 149.4, 132.4, 132.1, 131.7, 128.4, 127.6, 124.5, 8.9, 87.8, 83.1, 77.5, 63.7, 41.5, 39.4, 32.6, 32.5, 21.1, 18.3, 12.3, 12.1, 7.4, 7.. LMRS and HRMS data could not be obtained from this compound. Ethyl 2-((1S,5R)-1-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enyl)acetate HO CO 2 Et C 14 H 22 O 3 238,15 g/mol n-buli (63.9 ml, 16 mmol, 2.5 M in hexane) was added slowly to a solution of diisopropylamine (22.6 ml, 16 mmol) in dry THF (15.5 ml) over 4 minutes at C and then the mixture was stirred for a further 3 minutes. The prepared LDA solution was cooled

25 S25 to 78 C and ethyl acetate (15.6 ml, 16 mmol) was introduced dropwise over 4 minutes. The reaction mixture was stirred at 78 C for a further 3 minutes before adding dropwise (R)-carvone (2.8 ml, 133 mmol). The solution was stirred at 78 C for 2 hours and then quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with diethylether and the combined organic layers dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column (Pentanes:EtOAc = 95:5 8:2) to provide ethyl 2-((1S,5R)-1-hydroxy-2-methyl-5-(prop-1-en- 2-yl)cyclohex-2-enyl)acetate (31.3 g, 131 mmol, 99%) as a yellow oil. 1 H NMR (3 MHz, CDCl 3 ): δ [ppm] = (m, 1 H), (m, 2 H), (m, 2 H), 3.86 (s, 1 H), 2.72 (d, J = 14.7 Hz, 1 H), 2.58 (d, J = 14.7 Hz, 1 H), (m, 1 H), (m, 3 H), 1.74 (s, 3 H), 1.73 (s, 3 H), 1.65 (dd, J = 12.5, 1.5 Hz, 1 H), 1.28 (t, J = 7. Hz, 3 H). 13 C NMR (75.5 MHz, CDCl 3 ): δ [ppm] = 173., 148.5, 136.9, 124.6, 9.2, 72.7, 6.8, 42., 41.1, 39.7, 3.9, 2.5, 17.1, LRMS (EI): m/z: 22 (24%) [M + -H 2 O], 18 (11%), 151 (37%), 132 (54%), 9 (%), 82 (98%), 43 (64%). HRMS m/z calcd for C 14 H 22 O 3 (M + ) , found (1S,5R)-1-(2-Hydroxyethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol HO HO C 12 H 2 O 2 196,29 g/mol A solution of ethyl 2-((1S,5R)-1-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enyl)acetate (4.99 g, 21. mmol) in Et 2 O (27. ml)was added to a vigorously stirred suspension of lithium aluminium hydride (797 mg, 21. mmol) in dry diethylether (13. ml) at C. The reaction mixture was stirred 2 hours at r.t. and then quenched with water (1. ml), followed by % aqueous NaOH solution (1.3 ml) and again water (2.3 ml). The mixture was filtered and washed with diethylether. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column (Pentanes:EtOAc = 8:2) to provide (1S,5R)-1-(2-hydroxyethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (3.63 g, 18.3 mmol, 88%) as a yellow oil. 1 H NMR (3 MHz, CDCl 3 ): δ [ppm] = 5.5 (m, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), 3.75 (br. s, 1 H), 3.38 (s, 1 H), (m, 4 H), (m, 1 H),

26 S (s, 3 H), 1.85 (s, 3 H), (m, 2 H). 13 C NMR (75.5 MHz, CDCl 3 ): δ [ppm] = 149., 138.6, 123.7, 9.7, 75.7, 59.7, 4.4, 39.7, 38.2, 31.4, 2.9, LRMS (EI): m/z: 196 (.1%) [M + ], 178 (13%) [M + -H 2 O], 151 (74%), 123 (26%), 9 (%), 95 (24%), 69 (25%), 55 (25%). HRMS m/z calcd for C 12 H 2 O 2 (M + ) , found (1S,5R)-1-(2-triisopropylsilyloxyethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol HO TIPSO C 21 H 4 O 2 Si 352,63 g/mol Imidazole (6.22 g, 91.4 mmol) was added to a solution of diol (1S,5R)-1-(2-(tertbutyl)dimethylsilyloxyethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (17.9 g, 91.4 mmol) in DMF (85.8 ml).the reaction mixture was cooled to C and then triisopropylsilyl chloride (12.1 ml, 91.4 mmol) introduced. The solution was stirred at r.t. for 14 hours and then quenched with water. The aqueous layer was extracted with diethylether and the combined organic layers dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column (Pentanes:EtOAc = 95:5-9:1) to provide (1S,5R)-1-(2-triisopropylsilyloxyethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (17.9 g, 5.8 mmol, 56% - 96% brsm) as a pale yellow oil. 1 H NMR 5 MHz, CDCl 3 ): δ [ppm] = (m, 1 H), 4.72 (d, J = 9.5 Hz, 2 H), 4.8 (s, 1 H), 4.6 (td, J =.1, 3.6 Hz, 1 H), 3.92 (dt, J =.2, 4.8 Hz, 1 H), (m, 1 H), (m, 3 H), (m, 1 H), 1.77 (br. s, 3 H), 1.73 (s, 3 H), 1.69 (dt, J = 14.5, 3.8 Hz, 1 H), 1.65 (app t, J = 13.3 Hz, 1 H), (m, 21 H). 13 C NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 149.4, 139.5, 122.9, 9.1, 74.6, 61., 4.4, 4., 38.8, 31.3, 2.7, 18.2, 17.5, 12.. LRMS (EI): m/z: 334 (1%) [M + -H 2 O], 39 (11%) [M + -ipr], 261 (5%), 161 (83%), 131 (37%), 119 (%), 75 (21%).HRMS m/z calcd for C 18 H 33 O 2 Si (M + -ipr) , found

27 S27 (R)-3-(2-(triisopropylsilyloxyethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone Following the general procedure A, (R)-3-(2-triisopropylsilyloxyethyl)-2-methyl-5-(prop-1- en-2-yl)cyclohex-2-enone was obtained as a pale yellow oil (6.25 g, 17.8 mmol, 86%) after purification by flash-chromatography through silica gel (Pentanes:EtOAc = 95:5 8:2). 1 H NMR 5 MHz, CDCl 3 ): δ [ppm] = 4.79 (s, 1 H), 4.74 (s, 1 H), 3.85 (t, J = 6.5 Hz, 2 H), (m, 5 H), (m, 1 H), 2.27 (dd, J = 15.8, 13.4 Hz, 1 H), 1.79 (s, 3 H), 1.74 (s, 3 H), (m, 21 H). 13 C NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 199.5, 155.7, 147.1, 132., 1.5, 61.6, 42.8, 41.7, 38.8, 37.1, 2.6, 18.2, 12.1, 11.. LRMS (EI): m/z: 35 (33%) [M + ], 37 (%) [M + -ipr], 223 (17%), 159 (18%), 3 (21%), 75 (26%). HRMS m/z calcd for C 21 H 38 O 2 Si (M + ) , found (1R,5S)-3-(2-(triisopropyylsilyloxy)ethyl)-2-methyl-5-(prop-1-en-2-yl)-1-(prop-2- ynyl)cyclohex-2-enol OH TIPSO C 24 H 42 O 2 Si 39,6746 g/mol Following the general procedure B, (1R,5S)-3-(2-(triisopropylsilyloxy)ethyl)-2-methyl-5- (prop-1-en-2-yl)-1-(prop-2-ynyl)cyclohex-2-enol was obtained as a pale yellow oil (2.145 g, 5.49 mmol, 88%) after purification by flash-chromatography through silica gel (Pentanes:EtOAc = 95:5 8:2). 1 H NMR (5 MHz, CDCl 3 ): δ [ppm] = 4.74 (br. s, 2 H), 3.72 (td, J = 7., 1.8 Hz, 2 H), 2.65 (d, J = 17. Hz, 1 H), 2.41 (dd, J = 17., 2.5 Hz, 1 H), (m, 2 H), (m, 3 H),

28 S (t, J = 2.5 Hz, 1 H), (m, 2 H), 1.75 (s, 3 H), 1.73 (s, 3 H), 1.54 (app td, J = 12.5,.9 Hz, 1 H), (m, 21 H). 13 C NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 148.9, 131.8, 131.1, 9.4, 8.7, 71.7, 66.1, 61.9, 4.6, 39.2, 37.6, 29.7, 2.9, 18.3, 15.5, 12.2, 12.. LRMS (EI): m/z: 372 (41%) [M + -H 2 O], 351 (%) [M + -C 3 H 3 ], 198 (31%), 177 (32%), 157 (52%), 145 (89%), 131 (65%), 119 (76%), 3 (43%), 75 (45%), 59 (26%), 43 (17%). HRMS m/z calcd for C 21 H 39 O 2 Si(M + -C 3 H 3 ) , found Triisopropyl(2-((3R,5S)-2-methyl-5-(prop-1-en-2-yl)-3-(prop-2-ynyl)-3- (triethylsilyloxy)cyclohex-1-enyl)ethoxy)silane (3c) OSiEt 3 TIPSO C 3 H 56 O 2 Si 2 54,9354 g/mol Imidazole (4.67 g, mmol) and triethylsilyl chloride (11.6 ml, mmol) were added to a solution of (1R,5S)-3-(2-(triisopropyldimethylsilyloxy)ethyl)-2-methyl-5-(prop-1- en-2-yl)-1-(prop-2-ynyl)cyclohex-2-enol ( g, mmol) in DMF (87 ml). The reaction mixture was stirred at r.t. for 3 hours and then quenched with water. The aqueous layer was extracted with diethylether and the combined organic layers dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column (Pentanes/EtOAc = 95/5) to provide compound 3c ( g, mmol, 85%) as a colorless oil 1 H NMR (5 MHz, CDCl 3 ): δ [ppm] = 4.74 (d, J = 9.3 Hz, 2 H), (m, 2 H), 2.59 (d, J = 16.9 Hz, 1 H), 2.42 (d, J = 12.1 Hz, 1 H), 2.37 (dd, J = 16.9, 2.7 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.97 (t, J = 2.5 Hz, 1 H), 1.75 (s, 3 H), 1.68 (s, 3 H), 1.56 (app t, J = 12.4 Hz, 1 H), (m, 21 H),.95 (t, J = 7.9 Hz, 9 H), (m, 6 H). 13 C NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 149.2, 133.2, 129.7, 9., 82., 77., 7.7, 61.9, 41., 39.5, 37.8, 36.7, 31.5, 2.9, 18.3, 12.4, 12.2, 7.4, 7.. LRMS (EI): m/z: 475 (6%) [M + -Et], 465 (%) [M + -C 3 H 3 ], 291 (%), 265 (12%), 157 (%), 145 (15%), 115 (18%), 87 (24%), 75 (18%). HRMS m/z calcd for C 27 H 53 O 2 Si 2 (M + - C 3 H 3 ) , found

29 S29 (1S,5S)-2-Methyl-1-(2-(trimethylsilyl)ethynyl)-5-(prop-1-en-2-yl)cyclohex-2-enol n-buli (22.2 ml, 55.6 mmol, 2.5 M in hexane) was added dropwise to a stirred solution of trimethylsilylacetylene (7. ml, 5.9 mmol) in dry THF ( ml) was added at 78 C. After 1 hour stirring at 78 C, the mixture was warmed up to C, stirred for a further 15 minutes and once again cooled to 78 C. Then a solution of (R)-carvone (7.3 ml, 46.3 mmol) in dry THF (8. ml) was slowly introduced. The mixture was stirred at 78 C for 1 hour, allowed to warm up to C and stirred another hour. Then the reaction mixture was quenched with water and extracted with diethylether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column (Pentanes:EtOAc = 95:5) to provide (1S,5S)-2- methyl-1-(2-(trimethylsilyl)ethynyl)-5-(prop-1-en-2-yl)cyclohex-2-enol (9.38 g, 37.8 mmol, 82%) as a colorless oil. 1 H NMR (36 MHz, CDCl 3 ): δ [ppm] = 5.5 (dd, J = 3.4, 1.7 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), 2.24 (app td, J = 12., 2.1 Hz, 1 H), (m, 1 H), 2.6 (s, 1 H), (m, 1 H), (m, 3 H), (m, 4 H),.17 (s, 9 H). 13 C NMR (9.6 MHz, CDCl 3 ): δ [ppm] = 148.5, 135.7, 124.7, 9.2, 8.6, 88.5, 7.2, 43.7, 39.8, 31., 2.8, 17.2, -.1.