Total Synthesis of the Hallucinogenic Neoclerodane Diterpenoid

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Supporting Information (55 Pages)

Total Synthesis of Hallucinogenic Neoclerodane Diterpenoid, Salvinorin A Masato Nozawa,†§ Yuhki Suka,† Takashi Hoshi,‡ Toshio Suzuki‡ and Hisahiro Hagiwara*† †



Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan

Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan §

JSPS Research Fellow

[email protected] Tel/Fax: +81-25-262-7368

S2 – S13 S14 – S55

Experimental part for compounds 1, 5 ~ 20. 1

HNMR and 13C spectra of the products 1, 5 ~ 20.

S-1

General Methods All reactions were performed under nitrogen atmosphere unless otherwise noted. All commercially available reagents were used without further purification unless otherwise noted. Dichloromethane was distilled from CaH2 under nitrogen. Diethyl ether and tetrahydrofuran were freshly distilled from benzophenone ketyl radical under nitrogen prior to use. M.p. was determined with a Yanaco MP hot-stage apparatus and was uncorrected. IR spectra were recorded on a Shimadzu FT / IR-4200 spectrophotometer in chloroform unless otherwise indicated. 1H-NMR spectra were obtained for solutions in deuteriochloroform with JEOL DATUM 270 (270 MHz) and Varian Unity 500 plus (500 MHz) instruments with tetramethylsilane as internal standard. J-values are in Hz. 13C-NMR spectra were obtained for solutions in deuteriochloroform with JEOL DATUM 270 (67.5 MHz) Varian Unity 500 plus (125 MHz) instruments. Mass spectral data were obtained with a JEOL GC-Mate spectrometer. Specific rotations were measured with a Horiba SEPA-200 spectrophotometer for solutions in chloroform unless otherwise indicated. Medium pressure LC (MPLC) were carried out on Hitachi LC system.

Experimental OH O

1

O O

5

(13S,4aR)-13-Hydroxy-6,4a-dimethylspiro[1,3-dioxolane-2,5'-3',4',5,6',7',8',4a'-heptahydronaphthal ene]-7-one (5). A solution of enone 4 (11.0 g, 47 mmol) in 10 % methanolic solution of KOH (155 mL) was vigorously stirred in an open air at room temperature for 2.7 days. After addition of solid ammonium chloride (13 g), methanol was evaporated under reduced pressure. From the residue, product was extracted with ethyl acetate twice and the combined organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (eluent: ethyl acetate−n-hexane = 2 : 1) to afford alcohol 5 (8.6 g, 73%) as a colorless viscous oil: [α]D 9.5 (c = 1.01, CHCl3); IR (CHCl3)νmax / cm-1 3031, 2255, 1667, 1468, 1381, 1094; 1H NMR (270 MHz, TMS, CDCl3) δ (ppm) 1.53 (s, 3H), 1.35-1.76 (m, 3H), 1.88 (s, 3H), 1.92-2.05 (m, 2H), 2.14-2.35 (m, 2H), 2.44-2.63 (m, 2H), 3.90-4.05 (m, 4H), 4.94 (t, J = 3.0 Hz, 1H); 13C NMR (67.5 MHz, TMS, CDCl3) δ (ppm) 11.1, 22.6, 24.7, 27.4, 29.0, 33.7, 44.3, 65.0, 65.4, 66.0, 112.3, 132.8, 158.0, 199.4; m/z 252 (M+, 23%), 234(81), 217(82), 105(100) (Found: M+, 252.1362. C14H20O4 requires M, 252.1361).

O OH H

O

O OEt

OEt

O

O O

O

O

6

S-2

7

Ethyl 2-((15S,7R,11R)-15-Hydroxy-7,11-dimethyl-8-oxospiro[1,3-dioxolane-2,7'-bicyclo[4.4.0]decane] -7-yl)acetate (6). To a solution of lithium (106 mg 21 mmol, 2.5 eq) in liquid anhydrous ammonia (60 mL) and THF (10 mL) was added drop wise at –78 oC under a nitrogen atmosphere a solution of enone 5 (1.55 g 6.13 mmol) in anhydrous THF. The blue color persisted for 10 minute. To the enolate solution was added a solution of ethyl iodoacetate (2.2 mL, 18 mmol, 3 eq) in 16 mL of anhydrous THF. After being stirred at –78 oC for 10 minute, the reaction was quenched by addition of solid ammonium chloride. The resulting mixture was extracted with ethyl acetate twice and the combined organic layer was washed successively with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by MPLC (eluent: ethyl acetate−n-hexane = 2 : 3) to afford unsaturated ester 7 (415 mg, 21%) and ester 6 (1.05 g, 51%) as a colorless needle: mp 99 °C; [α]D 87.5 (c = 0.50, CHCl3): IR (CHCl3) νmax/cm-1 3517, 1726 and 1710 ; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.23 (t, J = 7.3 Hz, 1H), 1.41 (s, 3H), 1.56 (s, 3H), 1.40-1.95 (m, 5H), 2.09 (td, J = 14, 5 Hz, 1H), 2.19 (td, J = 14, 5 Hz, 1H), 2.36 (d, J = 1.6 Hz, 1H), 2.43 (ddd, J = 16, 12, 3.0 Hz, 1H), 2.54 (A of AB-type, 17 Hz, 1H), 2.61 (td, J = 16. 5.7 Hz, 1H), 2.98 (B of AB-type, 17 Hz, 1H), 3.81-4.00 (m, 4H), 4.00-4.20 (m, 2H), 4.18 (brs, 1H); 13C-NMR (67.5 MHz, TMS, CDCl3) (ppm) 14.16, 19.37, 24.78, 25.67, 29.07, 33.16, 34.88, 42.80(x2), 46.68, 50.24, 60.35, 65.01, 65.17, 67.40, 112.57, 171.55, 214.43; m/z 340 (M+, 13%), 322(23), 294(26), 99(100) (Found: M+, 340.1884. C18H28O6 requires, 340.1886).





δ

Ethyl 2-((1R,4aR)-1,4a-Dimethyl-2-oxospiro[1,3,4,5,6,7,4a-heptahydronaphthalene-5,2'-1,3dioxolane]yl)acetate (7). colorless oil; IR (CHCl3) νmax/cm-1 1726, 1711, 1600 and 1156 ; 1H-NMR (500 MHz, TMS, CDCl3) δ 1.19 (t, J = 7.0 Hz, 3H), 1.27 (s, 3H), 1.29 (s, 3H), 1.60-1.70 (m, 2H), 1.93 (tdlike, J = 11.5, 7.5 Hz, 1H), 2.14-2.28 (m, 2H), 2.31 (td, J = 11.5, 6.0Hz, 1H), 2.50-2.62 (m, 1H), 2.67 (ddd, J = 18, 6.5, 3.0 Hz, 1H), 2.73 (A of AB-type, 16 Hz, 1H), 3.08 (B of AB-type, 16 Hz, 1H), 3.90-4.10 (m, 4H), 4.06 (q, J = 7.5 Hz, 2H), 5.51 (t, J = 4 Hz, 1H); 13C-NMR (67.5MHz, TMS, CDCl3) (ppm) 14.09, 24.00, 24.40, 24.58, 26.13, 29.85, 35.12, 42.14, 45.73, 50.69, 60.52, 64.91, 65.11, 111.91, 120.29, 144.81, 170.72, 213.70; m/z 322 (M+, 10%), 278(15), 148(100) (Found: M+, 322.1778. C18H26O5 requires, 322.1780).

δ

O OH H

O

OEt O

8

Ethyl 2-((10S,2R,6R)-10-Hydroxy-2,6-dimethyl-3,7-dioxobicyclo[4.4.0]dec-2-yl)acetate (8).



To a solution of the dioxolane 6 (316 mg 0.93 mmol) in ethanol (20 mL, 0.05M) was added HCl (6.8 mL, 3.0 M in H2O) and the resulting solution was stirred at room temperature for 3 h. The reaction was quenched by addition of sodium bicarbonate powder (1.7 g, 20 mmol, 22 eq). The resulting mixture was extracted with diethyl ether twice and the combined organic layer was washed successively with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (eluent: ethyl acetate−n-hexane = 1 : 1) to afford diketone 8 (276 mg, quant.) as a pale yellow solid: mp 92 °C; [α]D 104.2 (c = 0.36, CHCl3): IR (CHCl3) νmax/cm-1 3610, 3507, 1728 and 1707 ; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.22 (t, J = 7.6 Hz, 1H), 1.47 (s, 3H), 1.65 (s, 3H), 1.4-2.3 (m, 7H), 2.40-2.74 (m, 2H), 2.57 (A of AB-type, 17 Hz, 1H), 3.03 (B of AB-type, 17 Hz, 1H), 3.18 (td, J = 14, 6.2 Hz, 1H), 3.98-4.20 (m, 2H), 4.37 (brs, W1/2 9 Hz, 1H); 13C-NMR (67.5MHz, TMS, CDCl3) S-3

δ

(ppm) 14.07, 20.90, 24.46, 31.69, 32.79, 34.58, 35.57, 42.42, 48.15, 49.09, 50.43, 60.41, 66.16, 171.31, 213.54, 214.01; m/z 296 (M+, 11%), 278(50), 232(66), 79(100) (Found: M+, 296.1623. C16H24O5 requires, 296.1624). OH

O O

OH H

H

9

10

(2S,6R,10R)-10-(2-Hydroxyethyl)-6,10-dimethyl-5,9-dimethylenebicyclo[4.4.0]decan-2-ol (10). To a stirred suspension of methyltriphenylphosphonium bromide (723 mg, 2.0 mmol, 6.0 eq) in THF (1.7 mL) was added sodium bis(trimethylsilyl)amide (1.7 mL, 1.0 M solution in THF, 1.7 mmol, 5.0 eq) dropwise



at 0 oC under nitrogen atmosphere. After being stirred for 1 h, a solution of ketone 8 (100 mg 0.34 mmol) in THF (2 mL) was added. The resulting solution was stirred at room temperature for 4 h. The reaction was quenched by addition of aq. ammonium chloride. The product was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silicagel chromatography (eluent: ethyl acetate-n-hexane = 1 : 1) to provide crude bis-olefin 9 (0.1 g) as a colorless oil. Part of the product was purified by MPLC (eluent: ethyl acetate-n-hexane = 1 : 3); [α]D –46.6 (c = 0.18, CHCl3): IR (CHCl3) νmax/cm-1 2938, 1740 and 1642 ; 1

H-NMR (270 MHz,TMS,CDCl3) δ 1.31 (d, J = 1 Hz, 3H), 1.42 (d, J = 0.5 Hz, 3H), 1.43-1.60 (m, 1H), 1.70

(d, J = 11 Hz, 1H), 1.62-1.76 (m, 1H), 2.0-2.5 (m, 5H), 2.62-2.82 (m, 2H), 2.71 (d, J = 15 Hz, 1H), 4.49 (ddd, J = 11, 11, 6 Hz, 1H), 4.51 (brs, 1H), 4.68 (brs, 2H), 4.72 (brs, 1H); 13C-NMR (67.5MHz, TMS, CDCl3)

δ

(ppm) 23.36, 23.43, 26.55(x2), 29.43, 39.60, 39.97, 40.27, 45.31, 49.83, 76.00, 104.83, 105.12, 153.31, 153.82, 172.50; m/z 246 (M+, 20%), 231(27), 147(49), 105(100) (Found: M+, 246.1626. C16H22O2 requires, 246.1620). To a solution of the crude bis-olefin 9 (0.1 g) in anhydrous diethyl ether (7 mL) was added lithium aluminumhydride (38 mg, 1.0 mmol, 3 eq) at 0 oC under nitrogen atmosphere. After being stirred for 0.5 h, the reaction was quenched by cautious addition of aq. ammonium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and evaporated to dryness. MPLC purification of the residue (eluent: ethyl acetate-n-hexane = 1 : 1) provided diol 10 (48 mg, 57% in 2steps) as a white solid: mp 74 °C; [α]D 60.4 (c = 0.80, CHCl3): IR (CHCl3) νmax/cm-1 3617, 3465, 1636, 1084, 1037 and 903 ; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.41 (s, 3H), 1.50 (s, 3H), 1.09-1.60 (m, 4H), 1.67 (dt, J = 13, 4 Hz, 1H), 1.80-1.93 (m, 1H), 1.93-2.12 (m, 3H), 2.23 (dt, J = 14, 4 Hz, 1H), 2.61 (tdlike, J = 14, 5 Hz, 1H), 2.80 (tdlike, J = 14, 5 Hz, 1H), 3.48 (m, 1H), 3.72 (tdlike, J = 10, 5 Hz, 1H), 4.47 (brs, W1/2 9 Hz, 1H), 4.53 (brs, 1H), 4.59 (brs, 1H),

δ

4.67 (brs, 1H), 4.73 (brs, 1H); 13C-NMR (67.5 MHz, TMS, CDCl3) (ppm) 23.52, 27.26, 27.73, 29.94, 37.62, 39.68, 40.29, 41.36, 43.33, 50.64, 58.77, 67.77, 103.62, 105.37, 154.76, 159.17; m/z 250 (M+, 19%), 235 (24), 187 (49), 105 (100) (Found: M+, 250.1938. C16H26O2 requires, 250.1933).

S-4

OTBS OH H

10-2

(1S,8R,4aR)-8,4a-Dimethyl-4,7-dimethylene-8-[2-(tert-butyldimethylsilanyloxy)ethyl]-1,2,3,5,6,8,4a,8 a-octahydronaphthol (10-2). To a solution of diol 10 (48 mg, 0.19 mmol) in anhydrous CH2Cl2 (5 mL) was added triethylamine (32 µl, 0.23 mmol, 1.2 eq), DMAP (12 mg, 0.096 mmol, 0.5 eq) and TBSCl (43 mg, 0.29 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. After being stirred for 1.5 h, the reaction mixture was passed through silicagel column. Evaporation of the solvent followed by MPLC purification (eluent: ethyl acetate-n-hexane = 1 : 1) provided 10-2 (69 mg, 99%) as a colorless oil; [α]D 42.7 (c = 0.63, CHCl3): IR (CHCl3) νmax/cm-1 3632, 1634, 1080 and 899; 1H-NMR (270 MHz, TMS, CDCl3) δ 0.02 (s, 6H), 0.88 (s, 9H), 1.11 (brs, 1H), 1.25 (d, J = 3.5 Hz, 1H), 1.38 (s, 3H), 1.50 (s, 3H), 1.43-1.72 (m, 3H), 1.80-2.11 (m, 4H), 2.20 (dt, J = 14, 4 Hz, 1H), 2.60 (A1 of AB-type, td like, J = 14, 4 Hz, 1H), 2.80 (B1 of AB-type, td like, J = 14, 4 Hz, 1H), 3.40 (A2 of AB-type, td like, J = 9, 5-6 Hz, 1H), 3.67 (B2 of AB-type, td like, J = 9, 5-6 Hz, 1H), 4.49 (brs, W1/2 8 Hz, 1H), 4.53 (s, 1H), 4.59 (s, 1H), 4.63 (s, 1H), 4.70 (s, 1H); 13C-NMR (67.5 MHz,

δ

TMS, CDCl3) (ppm) –5.06 (x2), 18.43, 23.71, 26.10 (x3), 27.60, 27.90, 30.09, 37.71, 39.81, 40.41, 41.80, 43.58, 50.57, 59.25, 67.99, 103.52, 105.40, 154.57, 159.20; m/z 307 (M+−t-Bu, 8%), 289(26), 188(64), 173(100) (Found: M+−t-Bu, 307.2097. C18H31O2Si requires, 307.2093). OTBS MPMO

H

11

(1S,8R,4aR)-1-[(4-Methoxyphenyl)methoxy]-8,4a-dimethyl-4,7-dimethylene-8-[2-(tert-butyldimethyl silanyloxy)ethyl]-1,2,3,5,6,8,4a,8a-octahydronaphthalene (11). To a solution of alcohol 10-2 (1.13 g, 3.09 mmol) in anhydrous DMF (3 mL) was added sodium hydride (60%, 370 mg, 9.26 mmol, 3 eq) at room temperature under nitrogen atmosphere. After being stirred for 25 minute, MPMCl (1.25 mL, 9.26 mmol, 3 eq) was added to the reaction mixture. After being stirred for 3 h, the reaction mixture was quenched by addition of aq. ammonium chloride. The resulting mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. MPLC purification of the residue (eluent: ethyl acetate-n-hexane = 1 : 15) afforded 11 (1.40 g, 94%) as a colorless oil; [α]D 80.0 (c = 0.84, CHCl3): IR (CHCl3) νmax/cm-1 1634, 1613, 1514 and 1464; 1H-NMR (270 MHz, TMS, CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.12 (s, 1H), 1.15-1.30 (m, 1H), 1.32 (s, 3H), 1.48 (s, 3H), 1.50-1.74 (m, 2H), 1.91 (tlike, J = 8 Hz, 2H), 2.02 (brd, J = 14 Hz, 1H), 2.10-2.28 (m, 2H), 2.50-2.83 (m, 2H), 3.30-3.46 (A1 of AB-type, 1H), 3.58-3.74 (B1 of AB-type, 1H), 3.80 (s, 3H), 4.07 (brs, 1H), 4.37 (A2 of AB-type, 11 Hz, 1H), 4.52 (s, 1H), 4.56 (B2 of AB-type, 11 Hz, 1H), 4.57 (s, 1H), 4.61 (s, 1H), 4.69 (s, 1H), 6.88 (d, 8.6 Hz, 2H), 7.29 (d, 8.6 Hz, 2H); 13C-NMR (67.5 MHz,

δ

TMS, CDCl3) (ppm) –4.99 (x2), 18.44, 23.77, 26.13 (x3), 27.46, 28.46, 30.11, 31.35, 39.75 (x2), 40.53, 42.06, 43.64, 51.10, 55.27, 59.26, 70.38, 75.14, 103.08, 105.11, 113.55 (x2), 128.39 (x2), 131.29, 154.87, 159.70; m/z 427 (M+−t-Bu, 0.5%), 309 (1), 121 (100) (Found: M+−t-Bu, 427.2664. C26H39O3Si requires, S-5

427.2668). OTBS MPMO

MPMO

H

MPMO

H

OH

HO

11-2

OTBS

OTBS H

O

O

O

11-3

O

12

{(1S,8S,4aS)-5-(Hydroxymethyl)-8-[(4-methoxyphenyl)methoxy]-1,4a-dimethyl-1-[2-(tert-butyldimet hylsilanyloxy)ethyl]-2-perhydronaphthyl}methan-1-ol (11-2). To a stirred solution of exo-methylene 11 (75 mg, 0.16 mmol) in THF (0.8 mL) was added borane-THF complex (649 µL, 1.20 M solution in THF, 0.78 mmol, 5 eq) at –78 °C under nitrogen atmosphere. After being stirred for 3 hr at room temperature, aq. sodium hydroxide (2.1 mL, 3N, 6.2 mmol, 40 eq) and hydrogen peroxide (0.71 mL, 30%, 6.2 mmol, 40 eq) were added and stirring was continued for 6 hr. The reaction was quenched by addition of 1 N hydrochloric acid. Organic layer was extracted with ethyl acetate twice. Combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was passed through silicagel short column with the aid of ethyl acetate to give crude alcohol 11-2 (78 mg) as a colorless oil: 1H-NMR (270 MHz, TMS, CDCl3) δ 0.09 (m, 6H), 0.92 (m, 9H), 1.00-2.10 (m, 22H), 2.20 (d like, J = 14 Hz, 1H), 3.35 (t like, J = 8.6 Hz, 1H), 3.82 (s, 3H), 3.50-4.00 (m, 4H), 4.26 (m, 1H), 4.51 (B2 of AB-type, 11Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 7 Hz, 2H) (4S,5R,8aR)-4-[(4-Methoxyphenyl)methoxy]-5,8a-dimethyl-5-[2-(tert-butyldimethylsilanyloxy)ethyl] perhydronaphthalene-1,6-dicarbaldehyde (11-3). To a stirred suspension of molecular sieves 4A powder (160 mg), sodium acetate (79 mg, 0.94 mmol, 6 eq) and pyridinium dichromate (352 mg, 0.94 mmol, 6 eq) in dichloromethane (1 mL) was added crude alcohol 11-2 (78 mg) in dichloromethane (2 mL) at room temperature under nitrogen atmosphere. After being stirred for 2 hr, organic layer was passed through silicagel short column with the aid of ethyl acetate–n-hexane as eluent. Evaporation of the solvent gave crude bis-aldehyde 11-3 (68 mg) as a colorless oil: 1H-NMR (270 MHz, TMS, CDCl3) δ 0.02 (m, 6H), 0.85 (m, 9H), 1.00-2.60 (m, 19H), 3.50-3.90 (m, 2H), 3.77 (s, 3H), 3.98 (brs, 1H), 4.12-4.32 (m, 1H), 4.49 (B2 of AB-type, J = 11 Hz, 1H), 6.84 (d, 9.6 Hz, 2H), 7.21 (d, 9.8 Hz, 2H), 9.8 (m, 2H) (4S,1R,5R,6R,8aR)-4-[(4-Methoxyphenyl)methoxy]-5,8a-dimethyl-5-[2-(tert-butyldimethylsilanyloxy) ethyl]perhydronaphthalene-1,6-dicarbaldehyde (12). To a solution of crude bis-aldehyde 11-3 (68 mg) in anhydrous methanol (2.2 mL) was added sodium methoxide (25 mg, 0.47 mmol, 3 eq) at 0 °C under nitrogen atmosphere. After being stirred at room temperature for 2 hr, the reaction was quenched by addition of aq. ammonium chloride and the product was extracted with ethyl acetate twice. Combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (eluent: ethyl acetate−n-hexane = 1 : 2) to afford bis-aldehyde 12 (68 mg, 73% from 11) as a colorless oil: IR (CHCl3) νmax/cm-1 1712, 1466, 1094 and 911; 1H-NMR (500 MHz, TMS, CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H), 1.28 (s, 3H), 1.36 (s, 3H), 1.20-2.08 (m, 11H), 2.23 (dt like, J = 13, 3.0 Hz, 1H), 2.51 (dt, J = 13, 3.0 Hz, 1H), 3.62-3.71 (A1 of AB-type, 1H), 3.71-3.79 (B1 of AB-type, 1H), 3.81 (s, 3H), 4.01 (brs, W1/2, 7 Hz, 1H), 4.29 S-6

(A2 of AB-type, 11 Hz, 1H), 4.52 (B2 of AB-type, 11 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 8.0 Hz,

δ

2H), 9.84 (dd, J = 4.5, 2.3 Hz, 2H); 13C-NMR (125 MHz, TMS, CDCl3) (ppm) –5.34, −5.30, 17.39, 18.45, 18.96, 21.31, 22.41, 26.0 (x3), 28.42, 38.12, 39.76, 40.41, 42.02, 51.59, 55.21, 56.35, 58.90, 63.71, 70.27, 72.96, 113.67 (x2), 128.76 (x2), 130.71, 158.92, 205.49, 205.82; m/z (EI) 459 (1%, M+ − t-Bu-), 309 (10) and 121 (100)

OTBS MPMO

H

O O

O O

13

(8S,1R,2R,5R,4aR)-2,5-Di(1,3-dioxolan-2-yl)-8-[(4-methoxyphenyl)methoxy]-1,4a-dimethyl-1-[2-(tert -butyldimethylsilanyloxy)ethyl]perhydronaphthalene (13). A solution of aldehyde 12 (68 mg, 0.13 mmol), ethylene glycol (0.3 mL), and PTSA (1 mg, 0.007 mmol, 0.05 eq) in 2-ethyl-2-methyl-1,3-dioxolane (0.7 mL) was stirred for 1.5 h at 40 °C under nitrogen atmosphere. Then PTSA (1 mg, 0.007 mmol, 0.05 eq) was added and stirring was continued for 6 hr. The reaction was quenched by addition of aq. sodium hydrogencarbonate at room temperature.The product was extracted with ethyl acetate twice and combined organic layer was washed with brine. Evaporation of the solvent followed by column chromatography of the residue (eluent: ethyl acetate) gave ketal 13 (79 mg, 99%) as a colorless oil ; [α]D 21.2 (c = 0.69, CHCl3): IR (CHCl3) νmax/cm-1 1468, 1086 and 1071; 1H-NMR (270 MHz, TMS, CDCl3) δ 0.05 (s, 6H), 0.90 (s, 9H), 1.00-1.94 (m, 12H), 1.22 (s, 3H), 1.29 (s, 3H), 2.17 (dd, J = 14, 3.0 Hz, 1H), 3.50 (A1 of AB-type, q like, 6.8 Hz, 1H), 3.68 (B1 of AB-type, q like, 6.8 Hz, 1H), 3.79 (s, 3H), 3.70-3.97 (m, 8H), 4.02 (brs, W1/2 8 Hz, 1H), 4.30 (A2 of AB-type, d, J = 11 Hz, 1H), 4.52 (B2 of AB-type, d, J = 11 Hz, 1H), 4.89 (d, J = 1.5 Hz, 1H), 4.94 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H); 13C-NMR (67.5 MHz, TMS, CDCl3)

δ(ppm) –5.08, −5.05, 16.17, 17.61, 18.35, 18.52, 21.34, 26.15

(x3), 29.49, 37.41, 39.06, 40.98, 41.70, 47.00, 52.75, 55.10, 55.24, 58.87, 64.09, 64.29, 64.98, 65.33, 70.00, 74.01, 103.36, 104.05, 113.43 (x2), 128.38 (x2), 131.39, 158.46; m/z 483 (M+−MPM, 0.6%), 351(5), 121(84), 73 (100) (Found: M+−MPM, 483.3143. C26H47O6Si requires, 483.3142).

OH MPMO

H

O MPMO

O

O

H

O O

O O

O

13-2

O

14

2-{(10S,2R,3R,6R,7R)-3,7-Di(1,3-dioxolan-2-yl)-10-[(4-methoxyphenyl)methoxy]-2,6-dimethylbicyclo [4.4.0]dec-2-yl}ethan-1-ol (13-2). To a stirred solution of silyl ether 13 (50 mg, 0.083 mmol) in THF (0.8 mL) was added TBAF (108 µL, 1.0 M in THF, 0.11 mmol, 1.3 eq) at 0 °C under nitrogen atmosphere. After being stirred for 3 h, the reaction was quenched by addition of aq. ammonium chloride. The product was extracted with ethyl acetate twice. S-7

The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by MPLC (eluent: ethyl acetate) to provide alcohol 13-2 (49 mg, quant.) as an amorphous solid; [α]D 17.2 (c = 0.64, CHCl3): IR (CHCl3) νmax/cm-1 3476, 1466, 1381, 1142, 1111 and 1057; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.03-1.35 (m, 4H), 1.23 (s, 3H), 1.29 (s, 3H), 1.45 (tlike, 2H), 1.55-1.97 (m, 7H), 2.18 (dd, J = 14, 3 Hz, 1H), 3.40-4.00 (m, 11H), 3.79 (s, 3H), 4.27 (d, J = 11 Hz, 1H), 4.52 (d, J = 11 Hz, 1H), 4.81 (d, J = 4.6 Hz, 1H), 4.94 (brs, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H); 13C-NMR (67.5 MHz, TMS, CDCl3)

δ(ppm) 16.12, 18.29, 18.75, 21.16, 29.44, 37.34, 39.08, 40.92,

41.83, 47.54, 52.56, 55.07, 55.26, 58.64, 64.10, 64.45, 64.54, 65.33, 69.98, 73.87, 103.33, 104.42, 113.45, 128.51, 131.21, 158.53; m/z 428 (M+−C2Η6Ο2, 4%), 307 (6), 163 (35), 121 (100) (Found: M+− C2Η6Ο2, 428.2561. C26H36O5 requires, 428.2563). 2-{(10S,2R,3R,6R,7R)-3,7-Di(1,3-dioxolan-2-yl)-10-[(4-methoxyphenyl)methoxy]-2,6-dimethylbicyclo [4.4.0]dec-2-yl}ethanal (14). To a stirred suspension of molecular sieves 4A powder (31 mg), sodium acetate (20 mg, 0.24 mmol, 3 eq) and pyridinium dichromate (92 mg, 0.24 mmol, 3 eq) in dichloromethane (1 mL) was added alcohol 13-2 (40 mg) in dichloromethane (1 mL) at room temperature under nitrogen atmosphere. After being stirred for 2 hr, the organic layer was passed through silica-gel short column with the aid of ethyl acetate–n-hexane as eluent. Evaporation of the solvent and MPLC purification of the residue (eluent: ethyl acetate-n-hexane = 1 : 2) gave aldehyde 14 (31 mg, 78%) as a colorless oil: IR (CHCl3) νmax/cm-1 1711, 1381, 1111 and 1100; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.07-1.82 (m, 8), 1.288 (s, 3H), 1.293 (s, 3H), 1.82-1.98 (m, 2H), 2.19 (dd, J = 14,3.2 Hz, 1H), 2.51 (A1 of AB-type, 16, 4.2 Hz, 1H), 2.93 (B1 of AB-type, 16, 1.1 Hz, 1H), 3.70-4.00 (m, 8H), 3.80 (s, 3H), 3.98 (brs, W1/2 7 Hz, 1H), 4.24 (A2 of AB-type, 11 Hz, 1H), 4.53 (B2 of AB-type, 11 Hz, 1H), 4.84 (d, J = 5.7 Hz, 1H), 4.94 (d, J = 1.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 9.82 (dd, J = 4.2, 1.1 Hz, 1H);

13

C-NMR (67.5 MHz, TMS, CDCl3)

δ(ppm) 16.03, 18.07, 19.37, 20.25,

29.05, 37.49, 40.61, 40.96, 48.37, 52.84, 54.30, 54.83, 55.27, 64.13, 64.22, 64.84, 65.32, 69.74, 73.76, 103.30, 104.84, 113.50(x2), 128.61(x2), 131.06, 158.59, 204.01; m/z 488 (M+, 1%), 367 (1), 121 (52), 74 (100) (Found: M+, 488.2783. C28H40O7 requires, 488.2774). O 12 MPMO

H

O 12

OH O

MPMO O

H

OH O O

+

O

O O

15 (12S)

O

16 (12R)

(1S)-2-{(10S,2R,3R,6R,7R)-3,7-Di(1,3-dioxolan-2-yl)-10-[(4-methoxyphenyl)methoxy]-2,6-dimethylbi cyclo[4.4.0]dec-2-yl}-1-(3-furyl)ethan-1-ol (15) and (1R)-2-{(10S,2R,3R,6R,7R)-3,7-di(1,3-dioxolan-2-yl)-10-[(4-methoxyphenyl)methoxy]-2,6-dimethylbi cyclo[4.4.0]dec-2-yl}-1-(3-furyl)ethan-1-ol (16). To a stirred solution of 3-bromofuran (23 µL, 0.25 mmol, 4 eq) in THF (0.1 mL) was added t-BuLi (223 µL, 1.59 M solution in n-pentane, 0.35 mmol, 5.6 eq) at -78 °C under nitrogen atmosphere. After being stirred at -78 °C for 0.5 h, a solution of aldehyde 14 (31 mg, 0.06 mmol) in THF (0.5 mL) was added, and the resulting solution was stirred at -78 °C for 25 minute. The reaction was quenched by addition of aq. ammonium S-8

chloride. After extraction with ethyl acetate twice, combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. MPLC purification of the residue (eluent: ethyl aceate-dichloromethane = 1:1) afforded 12S-furyl alcohol 15 (10 mg, 27%) and 12R-furyl alcohol 16 (14 mg, 39%). 12S-Furyl alcohol (15): colorless oil; [α]D 26.3 (c = 0.19, CHCl3): IR (CHCl3) νmax/cm-1 3550, 2257, 1817, 1794, 1644, 1613, 1466, 1381 and 1098; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.23 (s, 3H), 1.32 (s, 3H), 1.08-2.00 (m, 14H), 2.00-2.23 (m, 2H), 3.79 (s, 3H), 3.68-4.00 (m, 8H), 4.26 (brs, 1H), 4.31 (A of AB-type, 11.3 Hz, 1H), 4.55 (B of AB-type, 11.3 Hz, 1H), 4.74 (d, J = 3.5 Hz, 1H), 4.96 (brs, 2H), 6.38 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.37 (s, 1H); 13C-NMR (67.5 MHz, TMS, CDCl3)

δ(ppm) 16.30, 18.45 (x2), 20.91, 28.65, 37.46, 40.07, 41.01, 46.63, 46.99, 52.58, 55.10, 55.26, 63.86, 64.12, 64.45, 64.66, 65.32, 69.74, 74.33, 103.51, 104.52, 108.49, 113.42 (x2), 128.49 (x2), 131.33, 131.59, 138.15, 143.09, 158.44; m/z 556 (M+, 0.7%), 417(33), 121(100), 73(100) (Found: M+, 556.3041. C32H44O8 requires, 556.3036). 12R-Furyl alcohol (16): colorless oil: IR (CHCl3) νmax/cm-1 3450, 1817, 1796, 1613, 1468 and 1383; 1

H-NMR (270 MHz, TMS, CDCl3) δ 1.26 (s, 3H), 1.31 (s, 3H), 1.08-2.26 (m, 16H), 3.64 (d, J = 6.2 Hz, 1H),

3.79 (s, 3H), 3.70-4.05 (m, 8H), 4.17 (A of AB-type, 11.6 Hz, 1H), 4.50 (B of AB-type, 11.6 Hz, 1H), 4.59 (t, J = 7.0 Hz, 1H), 4.76 (d, J = 6.5 Hz, 1H), 4.96 (d, J = 1.6 Hz, 1H), 6.27 (m, 1H), 6.81 (d, J = 8.6 Hz, 1H),

δ

7.21 (d, J = 8.6 Hz, 1H), 7.24 (m, 1H), 7.36 (t like, J = 2 Hz, 1H); 13C-NMR (67.5 MHz, TMS, CDCl3)

(ppm) 16.01, 18.32, 19.94, 21.18, 28.96, 37.45, 39.57, 40.89, 47.06, 47.64, 51.91, 55.04, 55.23, 63.46, 63.93, 64.12, 64.76, 65.36, 69.46, 73.22, 103.33, 105.02, 108.46, 113.49 (x2), 128.84 (x2), 130.76, 131.20, 137.98, 143.02, 158.64

O

MPMO

H

H

O OH

CHO 17

(3S,13S,1R,6R,7R)-13-(3-Furyl)-11-hydroxy-3-[(4-methoxyphenyl)methoxy]-1,7-dimethyl-12-oxatric yclo[8.4.0.02,7]tetradecane-6-carbaldehyde (17). A solution of (12S)-furyl alcohol 15 (12 mg, 0.022 mmol), PTSA (1 mg) in 5% aq. acetone was heated at 57 °C for 4 h. The reaction mixture was passed through silicagel short column with the aid of ethyl acetate–n-hexane as eluent. Evaporation of the solvent gave crude lactol 17 (10 mg) as a colorless oil: 1

H-NMR (270 MHz, TMS, CDCl3) δ 1.34 (s), 1.37 (s), 1.00-5.30 (m, 17H), 3.77 (s, 3H), 3.90 (brs, W1/2 8 Hz,

1H), 4.23 (A of AB-type, J = 11 Hz, 1H), 4.53 (B of AB-type, J = 11 Hz, 1H), 4.79 (m, 1H), 6.37 (m, 1H), 6.85 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.37 (m, 2H), 9.86 (s, 1H); 13C-NMR (125 MHz, TMS, CDCl3)

δ(ppm) 15.99, 17.34, 17.98, 19.60, 22.64, 28.29, 29.69, 31.58, 35.97, 38.35, 41.48, 45.68, 52.12,

53.96, 55.19, 58.59, 62.43, 64.04, 66.28, 69.86, 72.00, 94.53, 96.17, 108.70, 113.62 (x2), 126.79, 129.29 (x2), 130.47, 138.94, 139.10, 143.03, 143.11, 159.02, 205.66 S-9

O

OH H

H

O OH

CHO 17-2

(3S,13S,1R,6R,7R)-13-(3-Furyl)-3,11-dihydroxy-1,7-dimethyl-12-oxatricyclo[8.4.0.02,7]tetradecane-6carbaldehyde (17-2). To a stirred solution of crude lactol 17 (10 mg) in CH2Cl2 (0.4 mL) was added a solution of DDQ (12 mg, 0.05 mmol, 2 eq) in CH2Cl2 (0.6 mL) and water (71 µL) at 0 oC under nitrogen atmosphere. After being stirred for 1 h, aq. sodium hydrogencarbonate was added. The product was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by flash column chromatography (eluent: ethyl acetate−n-hexane 1 : 1) to provide crude alcohol 17-2 (8 mg) as a pale yellow oil: 1H-NMR (270 MHz, TMS, CDCl3) δ 1.26 (s, 3H), 1.41&1.43 (s, 3H), 1.00-2.90 (m, 11H), 3.60-3.84 (m, 1H), 3.90 (s, 3H), 4.35 (brs, 1H), 4.4-5.4 (m, 2H), 6.42 (m, 1H), 7.33-7.48 (m, 2H), 9.88 (brs, 1H) O

O

H

H

O O

CO2H 17-3

(13S,1R,6R,7R)-13-(3-Furyl)-1,7-dimethyl-12-oxa-3,11-dioxotricyclo[8.4.0.02,7]tetradecane-6-carboxy lic acid (17-3). To a stirred solution of crude alcohol 17-2 (8 mg) and 2-methyl-2-butene (24 µL, 0.22 mmol) in DMF (166 µL) was added pyridinium dichromate (70 mg, 0.19 mmol, 8.6 eq) at room temperature under nitrogen atmosphere. After being stirred for 22 hr, organic layer was passed through silicagel short column with the aid of ethyl acetate as eluent. Evaporation of the solvent gave carboxylic acid 17-3 (3 mg, 40% from 15) as an amorphous solid: [α]D −15 (c = 0.12, CHCl3): IR (CHCl3) νmax/cm-1 2259, 1817, 1794, 1713, 1644, 1466, 1381, 1098 and 911; 1H-NMR (270 MHz, TMS, CDCl3) δ 1.16 (s, 3H), 1.43 (s, 3H), 1.17-2.80 (m, 14H),

δ

5.55 (dd, J = 11, 5 Hz, 1H), 6.38 (m, 1H), 7.40 (m, 2H); 13C-NMR (125 MHz, TMS, CDCl3) (ppm) 15.00 (q), 16.40 (q), 18.10 (t), 25.07 (t), 35.35 (s), 38.12 (t), 41.32 (s), 41.50 (t), 43.78 (t), 51.49 (d), 55.24 (d), 66.03 (d), 72.05 (d), 108.34 (d), 125.53 (s), 139.27 (d), 143.68 (d), 171.47 (s), 188 (s), 208.15 (s); m/z 360 (M+, 11%), 252 (34), 108 (100) (Found: M+, 360.1569. C20H24O6 requires, 360.1573).

S-10

O

O

H

H

O O

CO2Me 18

11.5-12.0 Hz

1.53

2.67

NOE 6% 5.55

NOE 10%

1.42

5.0-5.5 Hz

Methyl (13S,1R,6R,7R)-13-(3-Furyl)-1,7-dimethyl-12-oxa-3,11-dioxotricyclo[8.4.0.02,7]tetradecane -6-carboxylate (2-deacetoxysalvinorin A) (18). To a stirred solution of carboxylic acid 17-3 (3 mg, 0.01 mmol) in CH2Cl2 (172 µL) was added MeOH (35 µL, 0.86 mmol, 100 eq), DMAP (1 mg, 0.004 mmol, 0.5 eq) and DCC (6 mg, 0.03 mmol, 3.5 eq) at room temperature under nitrogen atmosphere. After being stirred for 2 hr, the organic layer was passed through silicagel short column with the aid of ethyl acetate as eluent. Evaporation of the solvent and flash column chromatography of the residue (eluent: ethyl acetate-n-hexane = 1 : 1) gave 2-deacetoxysalvinorin A 18 (3 mg, 90%) as a white solid: IR (CHCl3) νmax/cm-1 2960, 1739, 1725, 1715 and 1161; mp 150 °C; [α]D −22 (c = 0.39, CHCl3): 1H-NMR (500 MHz, TMS, CDCl3) δ 1.13 (s, 3H), 1.42 (s, 3H), 1.20-2.28 (m, 9H), 2.33 (td like, J = 13.5, 7.5 Hz, 1H), 2.45 (dd like, J = 13, 4 Hz, 1H), 2.67 (m, 2H), 3.71 (s, 3H), 5.55 (dd, J = 11.5-12.0, 5.0-5.5 Hz, 1H), 6.38 (dd like, J = 2.0, 1.0 Hz, 1H), 7.39 (t like, J = 1.5-2.0 Hz, 1H), 7.41 (dd like, J = 1.5, 1.0 Hz, 1H); 13C-NMR (125 MHz, TMS, CDCl3)

δ(ppm) 15.00, 16.41, 18.10, 25.12, 35.3, 38.15,

41.40, 41.59, 43.78, 51.54, 51.68, 55.71, 66.09, 72.05, 108.36, 125.56, 139.26, 143.66, 171.47, 172.98, 208.35; m/z 374 (M+, 9%), 293 (5), 108 (100), 94 (85) (Found: M+, 374.1737. C21H26O6 requires, 374.1729).

O

Et3SiO

H

H

O O

CO2Me 19

Methyl (2S,7R,10bR,4aR,6aR)-2-(3-Furyl)-10b,6a-dimethyl-4-oxo-10-(triethylsilanyloxy)5,6,7,8,10a,10b,4a,6a-octahydrobenzo[3,2-f]isochromane-7-carboxylate (19). To a solution of 2-deacetoxysalvinorin A 18 (2 mg, 0.007 mmol) in 0.1 mL of anhydrous THF was added, S-11

dropwise at –78 oC under a nitrogen atmosphere NaHMDS (1.0M in THF, 7 µL, 0.007 mmol, 1 eq). After being stirred for 10 min, TESCl (3 µL, 0.02 mmol, 3 eq) was added and stirring was continued at –78 oC for 20 min. Extra NaHMDS (1.0M in THF, 13 µL, 0.01 mmol, 2 eq) and TESCl (3 µL, 0.02 mmol, 3 eq) was added and stirring was continued for 1 min. The reaction mixture was diluted with THF and the organic layer was passed through silicagel column (eluent: ethyl acetate−n-hexane = 1 : 1) to afford TES enol ether 19 (3 mg, quant.) as a colorless viscous oil; [α]D 13 (c = 0.1, CHCl3): IR (CHCl3) νmax/cm-1 1726, 1466, 1381 and 1098; 1H NMR (500 MHz, TMS, CDCl3) δ (ppm) 0.72 (q, J = 8.0 Hz, 6H), 0.98 (t, J = 8.0 Hz, 9H), 1.20 (s, 3H), 1.22 (s, 3H), 1.23-2.70 (m, 10H), 3.27 (dd, J = 14.5, 6.0 Hz, 1H), 3.66 (s, 3H), 4.73 (m, 1H), 5.46 (dd, J

δ

= 10.5, 6.0 Hz, 1H), 6.39 (m, 1H), 7.40 (m, 1H), 7.41 (m, 1H); 13C-NMR (125MHz, TMS, CDCl3) (ppm) 4.98(x3), 6.76(x3), 14.35, 15.42, 18.34, 24.91, 36.59, 36.79, 37.01, 46.17, 51.30, 52.39, 52.77, 57.02, 71.70, 100.62, 108.43, 126.31, 138.95, 143.68, 150.62, 172.47, 174.22; m/z (EI) 488 (33%, M+), 459 (12), 270 (76) and 87 (100). (Found: M+, 488.2596. C27H40O6Si requires, 488.2594). O

O HO

H

H

O O

CO2Me 20

Methyl (13S,1R,4R,6R,7R)-13-(3-Furyl)-4-hydroxy-1,7-dimethyl-12-oxa-3,11-dioxotricyclo [8.4.0.02,7]tetradecane-6-carboxylate (2-epi-Salvinorin B) (20). A toluene solution of m-CPBA was treated with sodium hydrogencarbonate prior to use. To a stirred mixture of aq. sodium hydrogencarbonate (1 mg) in water (18 µL), extra m-CPBA (2 mg, 0.01 mmol) in toluene (90 µL) was added TES enol ether 19 (3 mg, 0.07 mmol) in toluene (18 µL) at 0 oC under nitrogen atmosphere. After being stirred for 40 min at 0 oC, m-CPBA (1 mg, 0.007 mmol) in toluene (45 µL) was added and stirring was continued for 50 min at 0 oC. The reaction was quenched by addition of aq. sodium hydrogensulfite. Product was extracted with ethyl acetate twice and combined organic layer was washed with aq. sodium hydrogencarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give crude silylether of 2-epi-salvinorin B (3 mg). To a crude silyl ether (3 mg) was added acetic acid (23 µL) and water (23 µL) in THF (45 µL) at room temperature. After being stirred for 1 day, the reaction mixture was passed through anhydrous sodium sulfate and silicagel column (ethyl acetate−n-hexane 1 : 1) and MPLC purification (eluent: ethyl acetate−n-hexane =





3 : 2) afforded 2-epi-salvinorin B 20 2 mg, 70% as a white powder: mp 241 °C; [α]D −44 (c = 0.02, CHCl3): 1

IR (CHCl3) νmax/cm- 1726, 1603, 1291 and 1165; 1H NMR (500 MHz, TMS, CDCl3) δ (ppm) 1.09 (s, 3H), 1.44 (s, 3H), 1.55-1.78 (m, 4H), 2.03-2.20 (m, 3H), 2.27-2.37 (m, 1H), 2.51 (ddlike, J = 5, 12 Hz, 1H), 2.84 (s, 1H), 3.05 (dd, J = 4, 13 Hz, 1H), 3.71 (s, 3H), 4.02-4.06 (m, 1H), 5.55 (dd, J = 5, 12 Hz, 1H), 6.38-6.39 (m, 1H), 7.40-7.42 (m, 2H); 13C-NMR (125 MHz, TMS, CDCl3)

δ(ppm) 15.01, 16.19, 18.12, 32.88, 34.95,

38.42, 42.49, 43.38, 50.07, 51.42, 51.69, 60.19, 72.01, 74.04, 108.38, 125.5, 139.35, 143.69, 171.41, 172.87, 208.61; m/z (EI) 390 (6%, M+), 273 (12) and 94 (100). (Found: M+, 390.1674. C21H26O7 requires, 390.1678).

S-12

O 12 O AcO

H

H

O O

CO2Me Salvinorin A 1

(4S,13S,1R,6R,7R)-13-(3-Furyl)-6-(methoxycarbonyl)-1,7-dimethyl-12-oxa-3,11-dioxotricyclo[8.4.0.02 ,7

]tetradec-4-yl acetate (Salvinorin A) (1).

To a stirred solution of 2-epi-salvinorin B 20 (1 mg, 0.003 mmol) in CH2Cl2 (0.6 mL) was added triphenylphosphine (14 mg, 0.053 mmol, 21 eq), acetic acid (5 µL, 0.08 mmol, 31 eq) and diisopropyl azodicarboxylate (5 µL, 0.02 mmol, 10 eq) at room temperature under nitrogen atmosphere. After being stirred for 12.5 h, extra triphenylphosphine (20 mg, 0.076 mmol, 30 eq), acetic acid (11 µL, 0.17 mmol, 68 eq) and diisopropyl azodicarboxylate (10 µL, 0.048 mmol, 19 eq) was added and stirring was continued at room temperature for 3 hr. The reaction mixture was purified by silicagel column chromatography twice





(eluent: CH2Cl2 : ethyl acetate = 4 : 1, benzene : ethyl acetate = 5 : 1) to provide salvinorin A 1 1 mg, 86% . Salvinorin A (1): white powder; [α]D −41 (c = 0.004, CHCl3): 1H NMR (500 MHz, TMS, CDCl3) δ (ppm)

1.02 (s, 3H), 1.40-1.83 (m, 4H), 1.46 (s, 3H), 2.07 (dd, J = 11.5, 3.5 Hz, 1H), 2.12-2.38 (m, 4H), 2.17 (s, 3H), 2.51 (dd, J = 13.5, 5.0 Hz, 1H), 2.75 (dd, J = 10.5, 6.5 Hz, 1H), 3.73 (s, 3H), 5.15 (t like, J = 9.5 Hz, 1H), 5.53 (dd, J = 11.5, 5.0 Hz, 1H), 6.38 (m, 1H), 7.39 (t like, J = 1.5 Hz, 1H), 7.41 (m, 1H); 13C-NMR (125

δ

MHz, TMS, CDCl3) (ppm) 15.26, 16.42, 18.22, 20.54, 30.87, 35.55, 38.27, 42.16, 43.56, 51.49, 51.92, 53.73, 64.26, 72.05, 75.08, 108.39, 139.41, 143.71, 169.96, 171.00, 171.50, 201.92

S-13

270 MHz NMR CDCl3

OH O O O 5

S-14 S-14

270 MHz NMR CDCl3

OH O O O 5

S-15 S-15

O OH H

OEt O

O O 6

S-16 S-16

O OH H

OEt O

O O 6

S-17 S-17

500MHz NMR CDCl3

O OEt O O O 7

S-18 S-18

O OEt O O O 7

S-19 S-19

O OH H

OEt O

O 8

S-20 S-20

O OEt

OH H

O

O 8

S-21 S-21

O O

H

9

S-22 S-22

O O

H

9

S-23 S-23

OH OH H

10

S-24 S-24

500MHz NMR CDCl3

OH OH H

10

S-25 S-25

OTBS OH H

10-2

S-26 S-26

OTBS OH H

10-2

S-27 S-27

OTBS MPMO

H

11

S-28 S-28

OTBS MPMO

H

11

S-29 S-29

500MHz NMR CDCl3

OTBS MPMO

H

O

O 12

S-30 S-30

500MHz NMR CDCl3

OTBS MPMO

H

O

O 12

S-31 S-31

OTBS MPMO

O

H

O

O O

13

S-32 S-32

OTBS MPMO

O

H

O

O O

13

S-33 S-33

OH MPMO

H

O O

O O 13-2

S-34 S-34

OH MPMO

H

O O

O O 13-2

S-35 S-35

O MPMO

O

H

O

O O 14

S-36 S-36

O MPMO

O

H

O

O O 14

S-37 S-37

500MHz NMR CDCl3 O

MPMO

OH O

H

O O O 16

S-38 S-38

O

MPMO

OH O

H

O O O 16

S-39 S-39

O

MPMO

OH O

H

O O O 15

S-40 S-40

O

MPMO

OH O

H

O O O 15

S-41 S-41

O

MPMO

H

H

O OH

CHO 17

S-42 S-42

O 500MHz NMR CDCl3 MPMO

H

H

O OH

CHO 17

S-43 S-43

270MHz NMR CDCl3 O

HO

H

H

O OH

CHO 17-2

S-44 S-44

500MHz NMR CDCl3

O

O

H

H

O O

CO2H 17-3

S-45 S-45

500MHz NMR CDCl3

O

O

H

H

O O

CO2H 17-3

S-46 S-46

500MHz NMR CDCl3

O

O

H

H

O O

CO2Me 18

S-47 S-47

500MHz NMR CDCl3

O

O

H

H

O O

CO2Me 18

S-48 S-48

500MHz NMR CDCl3

O

O

H

H

O O

CO2Me 18

S-49 S-49

500MHz NMR CDCl3

O

TESO

H

H

O O

CO2Me 19

S-50 S-50

500MHz NMR CDCl3

O

TESO

H

H

O O

CO2Me 19

S-51 S-51

500MHz NMR CDCl3

O

O HO

H

H

O O

CO2Me 20

S-52 S-52

500MHz NMR CDCl3

O

O HO

H

20

S-53 S-53

O O

CO2Me

125.5

H

500MHz NMR CDCl3

O

O AcO

H

H

O O

CO2Me 1

S-54 S-54

500MHz NMR CDCl3

O

O AcO

H

H

O

171.00

O

169.96

CO2Me 1

S-55 S-55