Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A

Article abstract of DOI:10.1021/ol800101v

(Chemical Equation Presented) Total synthesis of salvinorin A (1), a neoclerodane diterpenoid having the most potent hallucinogenic activity and a selective K-opioid agonist, was completed in 20 steps starting from enantiomerically pure hydroxy-Wieland-Miescher ketone 5.

Full text of DOI:10.1021/ol800101v

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
hagiwara@gs.niigata-u.ac.jp
Tel/Fax: +81-25-262-7368
S2 – S13 Experimental part for compounds 1, 5 ~ 20.
1 13
S14 – S55 HNMR and C 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 CaH under nitrogen. Diethyl ether and tetrahydrofuran were freshly distilled from
2
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
1
chloroform unless otherwise indicated. H-NMR spectra were obtained for solutions in deuteriochloroform
with JEOL DATUM 270 (270 MHz) and Varian Unity 500 plus (500 MHz) instruments with
13
tetramethylsilane as internal standard. J-values are in Hz. C-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] 9.5 (c = 1.01,
D
1
3031, 2255, 1667, 1468, 1381, 1094; H NMR (270 MHz, TMS, CDCl ) δ
CHCl ); IR (CHCl )
3
ꢀ
3
max / cm-1
3
(
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),
1
.90-4.05 (m, 4H), 4.94 (t, J = 3.0 Hz, 1H); C NMR (67.5 MHz, TMS, CDCl ) δ (ppm) 11.1, 22.6, 24.7,
+
7.4, 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),
3
3
2
1
3
+
05(100) (Found: M , 252.1362. C H O requires M, 252.1361).
1
4
20
4
O
O
OH
H
OEt
O
OEt
O
O
O
O
O
6
7
S-2

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
o
mL) was added drop wise at –78 C 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
o
ethyl iodoacetate (2.2 mL, 18 mmol, 3 eq) in 16 mL of anhydrous THF. After being stirred at –78 C 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%)
1
and ester 6 (1.05 g, 51%) as a colorless needle: mp 99 °C; [α] 87.5 (c = 0.50, CHCl ): IR (CHCl ) νmax/cm-
D
3
3
1
3
3
517, 1726 and 1710 ; H-NMR (270 MHz, TMS, CDCl ) δ 1.23 (t, J = 7.3 Hz, 1H), 1.41 (s, 3H), 1.56 (s,
3
H), 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
1
AB-type, 17 Hz, 1H), 3.81-4.00 (m, 4H), 4.00-4.20 (m, 2H), 4.18 (brs, 1H); C-NMR (67.5 MHz, TMS,
3
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,
+
7.40, 112.57, 171.55, 214.43; m/z 340 (M , 13%), 322(23), 294(26), 99(100) (Found: M , 340.1884.
+
6
C H O requires, 340.1886).
6
1
8
28
Ethyl 2-((1R,4aR)-1,4a-Dimethyl-2-oxospiro[1,3,4,5,6,7,4a-heptahydronaphthalene-5,2'-1,3-
dioxolane]yl)acetate (7).
colorless oil; IR (CHCl ) νmax/cm- 1726, 1711, 1600 and 1156 ; H-NMR (500 MHz, TMS, CDCl ) δ 1.19
1
1
3
3
(
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
2
5
3
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),
.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),
1
.51 (t, J = 4 Hz, 1H); C-NMR (67.5MHz, TMS, CDCl ) (ppm) 14.09, 24.00, 24.40, 24.58, 26.13, 29.85,
3
3
+
5.12, 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%),
+
78(15), 148(100) (Found: M , 322.1778. C H O requires, 322.1780).
1
8
26
5
O
OH
H
OEt
O
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 H O) and the resulting solution was stirred at room temperature for 3 h. The reaction was quenched
2
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,
1
quant.) as a pale yellow solid: mp 92 °C; [α] 104.2 (c = 0.36, CHCl ): IR (CHCl ) ν /cm- 3610, 3507,
D
3
3
max
1
1
728 and 1707 ; H-NMR (270 MHz, TMS, CDCl ) δ 1.22 (t, J = 7.6 Hz, 1H), 1.47 (s, 3H), 1.65 (s, 3H),
3
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
1
td, J = 14, 6.2 Hz, 1H), 3.98-4.20 (m, 2H), 4.37 (brs, W1/2 9 Hz, 1H); C-NMR (67.5MHz, TMS, CDCl )
3
(
3
S-3

(
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,
+
+
2
13.54, 214.01; m/z 296 (M , 11%), 278(50), 232(66), 79(100) (Found: M , 296.1623. C H O requires,
16 24 5
2
96.1624).
OH
O
H
OH
H
O
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
o
at 0 C 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
1
acetate-n-hexane = 1 : 3); [α] –46.6 (c = 0.18, CHCl ): IR (CHCl ) ν /cm- 2938, 1740 and 1642 ;
D
3
3
max
1
H-NMR (270 MHz,TMS,CDCl ) δ 1.31 (d, J = 1 Hz, 3H), 1.42 (d, J = 0.5 Hz, 3H), 1.43-1.60 (m, 1H), 1.70
3
(
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,
1
J = 11, 11, 6 Hz, 1H), 4.51 (brs, 1H), 4.68 (brs, 2H), 4.72 (brs, 1H); C-NMR (67.5MHz, TMS, CDCl )
3
3
(
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,
+
+
1
53.82, 172.50; m/z 246 (M , 20%), 231(27), 147(49), 105(100) (Found: M , 246.1626. C H O requires,
16 22 2
2
46.1620).
To a solution of the crude bis-olefin 9 (0.1 g) in anhydrous diethyl ether (7 mL) was added lithium
o
aluminumhydride (38 mg, 1.0 mmol, 3 eq) at 0 C 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;
1
α] 60.4 (c = 0.80, CHCl ): IR (CHCl ) ν /cm- 3617, 3465, 1636, 1084, 1037 and 903 ; H-NMR (270
1
D
3
3
max
MHz, TMS, CDCl ) 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,
3
1
1
4
3
H), 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,
H), 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),
1
.67 (brs, 1H), 4.73 (brs, 1H); C-NMR (67.5 MHz, TMS, CDCl ) (ppm) 23.52, 27.26, 27.73, 29.94, 37.62,
3
3
+
9.68, 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. C H O requires, 250.1933).
(
1
6
26
2
S-4

OTBS
OH
H
1
0-2
(
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 CH Cl (5 mL) was added triethylamine (32 µl,
2
2
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] 42.7 (c = 0.63, CHCl ): IR
D
3
1
1
(
CHCl ) ν /cm- 3632, 1634, 1080 and 899; H-NMR (270 MHz, TMS, CDCl ) δ 0.02 (s, 6H), 0.88 (s, 9H),
3
max
3
1
2
1
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),
.20 (dt, J = 14, 4 Hz, 1H), 2.60 (A of AB-type, td like, J = 14, 4 Hz, 1H), 2.80 (B of AB-type, td like, J =
1
1
4, 4 Hz, 1H), 3.40 (A of AB-type, td like, J = 9, 5-6 Hz, 1H), 3.67 (B of AB-type, td like, J = 9, 5-6 Hz,
2
2
1
3
H), 4.49 (brs, W1/2 8 Hz, 1H), 4.53 (s, 1H), 4.59 (s, 1H), 4.63 (s, 1H), 4.70 (s, 1H); C-NMR (67.5 MHz,
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,
+
3.58, 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),
4
+
73(100) (Found: M −t-Bu, 307.2097. C H O Si requires, 307.2093).
1
1
8
31
2
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
=
1 : 15) afforded 11 (1.40 g, 94%) as a colorless oil; [α] 80.0 (c = 0.84, CHCl ): IR (CHCl ) νmax/cm-
D 3 3
1
1
1
634, 1613, 1514 and 1464; H-NMR (270 MHz, TMS, CDCl ) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.12 (s, 1H),
3
.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 (A of AB-type, 1H), 3.58-3.74 (B of AB-type,
1
1
1
1
H), 3.80 (s, 3H), 4.07 (brs, 1H), 4.37 (A of AB-type, 11 Hz, 1H), 4.52 (s, 1H), 4.56 (B of AB-type, 11 Hz,
2 2
1
H), 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); C-NMR (67.5 MHz,
3
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,
4
1
2.06, 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,
+
59.70; m/z 427 (M −t-Bu, 0.5%), 309 (1), 121 (100) (Found: M −t-Bu, 427.2664. C H O Si requires,
+
2
6
39
3
S-5

4
27.2668).
OTBS
OTBS
OTBS
MPMO
MPMO
MPMO
H
H
H
OH
O
O
1
1-2
O
11-3
O
12
HO
{(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
1
alcohol 11-2 (78 mg) as a colorless oil: H-NMR (270 MHz, TMS, CDCl ) δ 0.09 (m, 6H), 0.92 (m, 9H),
3
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,
4
H), 4.26 (m, 1H), 4.51 (B of AB-type, 11Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 7 Hz, 2H)
2
(
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
1
eluent. Evaporation of the solvent gave crude bis-aldehyde 11-3 (68 mg) as a colorless oil: H-NMR (270
MHz, TMS, CDCl ) 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
3
(
brs, 1H), 4.12-4.32 (m, 1H), 4.49 (B of AB-type, J = 11 Hz, 1H), 6.84 (d, 9.6 Hz, 2H), 7.21 (d, 9.8 Hz, 2H),
2
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
1
1
(
CHCl ) ν /cm- 1712, 1466, 1094 and 911; H-NMR (500 MHz, TMS, CDCl ) δ 0.06 (s, 6H), 0.89 (s, 9H),
3
max
3
1
3
.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),
.62-3.71 (A of AB-type, 1H), 3.71-3.79 (B of AB-type, 1H), 3.81 (s, 3H), 4.01 (brs, W , 7 Hz, 1H), 4.29
1
1
1/2
S-6

(
A of AB-type, 11 Hz, 1H), 4.52 (B of AB-type, 11 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 8.0 Hz,
2 2
1
H), 9.84 (dd, J = 4.5, 2.3 Hz, 2H); C-NMR (125 MHz, TMS, CDCl ) (ppm) –5.34, −5.30, 17.39, 18.45,
3
2
1
7
1
3
8.96, 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,
+
2.96, 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
21 (100)
OTBS
MPMO
O
H
O
O
13
O
(
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
1
oil ; [α] 21.2 (c = 0.69, CHCl ): IR (CHCl ) ν /cm- 1468, 1086 and 1071; H-NMR (270 MHz, TMS,
1
D
3
3
max
CDCl ) 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,
3
1
3
H), 3.50 (A of AB-type, q like, 6.8 Hz, 1H), 3.68 (B of AB-type, q like, 6.8 Hz, 1H), 3.79 (s, 3H),
1 1
.70-3.97 (m, 8H), 4.02 (brs, W1/2 8 Hz, 1H), 4.30 (A of AB-type, d, J = 11 Hz, 1H), 4.52 (B of AB-type, d,
2
2
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
1
Hz, 2H); C-NMR (67.5 MHz, TMS, CDCl ) (ppm) –5.08, −5.05, 16.17, 17.61, 18.35, 18.52, 21.34, 26.15
3
3
(
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,
+
4.01, 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),
7
7
+
3 (100) (Found: M −MPM, 483.3143. C H O Si requires, 483.3142).
26
47
6
OH
O
MPMO
MPMO
O
O
H
H
O
O
O
O
O
O
1
3-2
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
1
an amorphous solid; [α] 17.2 (c = 0.64, CHCl ): IR (CHCl ) ν /cm- 3476, 1466, 1381, 1142, 1111 and
D
3
3
max
1
1
1
4
2
4
1
4
057; H-NMR (270 MHz, TMS, CDCl ) δ 1.03-1.35 (m, 4H), 1.23 (s, 3H), 1.29 (s, 3H), 1.45 (tlike, 2H),
3
.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),
.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,
1
H); C-NMR (67.5 MHz, TMS, CDCl ) (ppm) 16.12, 18.29, 18.75, 21.16, 29.44, 37.34, 39.08, 40.92,
3
3
1.83, 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,
+
28.51, 131.21, 158.53; m/z 428 (M −C Η Ο , 4%), 307 (6), 163 (35), 121 (100) (Found: M − C Η Ο ,
+
2
6
2
2
6
2
28.2561. C H O requires, 428.2563).
36
26
5
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
1
aldehyde 14 (31 mg, 78%) as a colorless oil: IR (CHCl ) ν /cm- 1711, 1381, 1111 and 1100; H-NMR
1
3
max
(
270 MHz, TMS, CDCl ) 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 =
3
1
8
1
9
2
1
4,3.2 Hz, 1H), 2.51 (A of AB-type, 16, 4.2 Hz, 1H), 2.93 (B of AB-type, 16, 1.1 Hz, 1H), 3.70-4.00 (m,
1 1
H), 3.80 (s, 3H), 3.98 (brs, W1/2 7 Hz, 1H), 4.24 (A of AB-type, 11 Hz, 1H), 4.53 (B of AB-type, 11 Hz,
2
2
H), 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),
1
.82 (dd, J = 4.2, 1.1 Hz, 1H); C-NMR (67.5 MHz, TMS, CDCl3) (ppm) 16.03, 18.07, 19.37, 20.25,
3
9.05, 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,
+
03.30, 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. C H O requires, 488.2774).
(
2
8
40
7
O
O
12
12
OH
O
OH
O
MPMO
MPMO
H
H
O
O
+
O
O
O
O
15 (12S)
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 L, 0.25 mmol, 4 eq) in THF (0.1 mL) was added t-BuLi (223
.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
(
µ
µL,
1
-
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,
3
9%).
1
2S-Furyl alcohol (15): colorless oil; [α] 26.3 (c = 0.19, CHCl ): IR (CHCl ) ν /cm- 3550, 2257, 1817,
1
1
1
D 3 3 max
1
794, 1644, 1613, 1466, 1381 and 1098; H-NMR (270 MHz, TMS, CDCl ) δ 1.23 (s, 3H), 1.32 (s, 3H),
3
.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
1
3
(
d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.37 (s, 1H); C-NMR (67.5 MHz, TMS, CDCl )
3
(
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,
6
1
5
4.45, 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,
+
43.09, 158.44; m/z 556 (M , 0.7%), 417(33), 121(100), 73(100) (Found: M , 556.3041. C H O requires,
+
3
2
44
8
56.3036).
1
1
2R-Furyl alcohol (16): colorless oil: IR (CHCl ) ν /cm- 3450, 1817, 1796, 1613, 1468 and 1383;
3 max
1
H-NMR (270 MHz, TMS, CDCl ) δ 1.26 (s, 3H), 1.31 (s, 3H), 1.08-2.26 (m, 16H), 3.64 (d, J = 6.2 Hz, 1H),
3
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),
1
3
7
.21 (d, J = 8.6 Hz, 1H), 7.24 (m, 1H), 7.36 (t like, J = 2 Hz, 1H); C-NMR (67.5 MHz, TMS, CDCl )
3
(
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,
6
1
4.12, 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,
43.02, 158.64
O
MPMO
O
H
H
OH
CHO
1
7
(
3S,13S,1R,6R,7R)-13-(3-Furyl)-11-hydroxy-3-[(4-methoxyphenyl)methoxy]-1,7-dimethyl-12-oxatric
2
,7
yclo[8.4.0.0 ]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
5
7 °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, CDCl ) δ 1.34 (s), 1.37 (s), 1.00-5.30 (m, 17H), 3.77 (s, 3H), 3.90 (brs, W1/2 8 Hz,
3
1
6
H), 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),
13
.85 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.37 (m, 2H), 9.86 (s, 1H); C-NMR (125 MHz, TMS,
CDCl3) (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,
5
1
3.96, 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),
30.47, 138.94, 139.10, 143.03, 143.11, 159.02, 205.66
S-9

O
OH
H
O
H
OH
CHO
1
7-2
2
3S,13S,1R,6R,7R)-13-(3-Furyl)-3,11-dihydroxy-1,7-dimethyl-12-oxatricyclo[8.4.0.0 ]tetradecane-6-
,7
(
carbaldehyde (17-2).
To a stirred solution of crude lactol 17 (10 mg) in CH Cl (0.4 mL) was added a solution of DDQ (12 mg,
2
2
o
0
.05 mmol, 2 eq) in CH Cl (0.6 mL) and water (71 µL) at 0 C under nitrogen atmosphere. After being
2 2
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
1
provide crude alcohol 17-2 (8 mg) as a pale yellow oil: H-NMR (270 MHz, TMS, CDCl ) δ 1.26 (s, 3H),
3
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
O
H
H
O
CO H
2
1
7-3
2
13S,1R,6R,7R)-13-(3-Furyl)-1,7-dimethyl-12-oxa-3,11-dioxotricyclo[8.4.0.0 ]tetradecane-6-carboxy
,7
(
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
1
an amorphous solid: [α] −15 (c = 0.12, CHCl ): IR (CHCl ) ν /cm- 2259, 1817, 1794, 1713, 1644, 1466,
D
3
3
max
1
1
5
381, 1098 and 911; H-NMR (270 MHz, TMS, CDCl ) δ 1.16 (s, 3H), 1.43 (s, 3H), 1.17-2.80 (m, 14H),
3
13
.55 (dd, J = 11, 5 Hz, 1H), 6.38 (m, 1H), 7.40 (m, 2H); C-NMR (125 MHz, TMS, CDCl ) (ppm) 15.00
3
(
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),
6
6.03 (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. C H O requires, 360.1573).
20 24 6
S-10

O
O
O
H
H
O
CO Me
2
1
8
11.5-12.0 Hz
1.53
2.67
NOE 6%
5.55
NOE 10%
5.0-5.5 Hz
1.42
2
Methyl (13S,1R,6R,7R)-13-(3-Furyl)-1,7-dimethyl-12-oxa-3,11-dioxotricyclo[8.4.0.0 ]tetradecane
,7
-
6-carboxylate (2-deacetoxysalvinorin A) (18).
To a stirred solution of carboxylic acid 17-3 (3 mg, 0.01 mmol) in CH Cl (172 µL) was added MeOH (35
2
2
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
1
mg, 90%) as a white solid: IR (CHCl ) ν /cm- 2960, 1739, 1725, 1715 and 1161; mp 150 °C; [α] −22 (c
3
max
D
1
=
0.39, CHCl ): H-NMR (500 MHz, TMS, CDCl ) δ 1.13 (s, 3H), 1.42 (s, 3H), 1.20-2.28 (m, 9H), 2.33 (td
3
3
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,
1
3
J = 1.5, 1.0 Hz, 1H); C-NMR (125 MHz, TMS, CDCl3) (ppm) 15.00, 16.41, 18.10, 25.12, 35.3, 38.15,
4
2
1.40, 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,
+
08.35; m/z 374 (M , 9%), 293 (5), 108 (100), 94 (85) (Found: M , 374.1737. C H O requires, 374.1729).
+
2
1
26
6
O
Et SiO
3
O
H
H
O
CO Me
2
1
9
Methyl (2S,7R,10bR,4aR,6aR)-2-(3-Furyl)-10b,6a-dimethyl-4-oxo-10-(triethylsilanyloxy)-
,6,7,8,10a,10b,4a,6a-octahydrobenzo[3,2-f]isochromane-7-carboxylate (19).
5
To a solution of 2-deacetoxysalvinorin A 18 (2 mg, 0.007 mmol) in 0.1 mL of anhydrous THF was added,
S-11

o
dropwise at –78 C under a nitrogen atmosphere NaHMDS (1.0M in THF, 7 µL, 0.007 mmol, 1 eq). After
o
being stirred for 10 min, TESCl (3 µL, 0.02 mmol, 3 eq) was added and stirring was continued at –78 C for
2
0 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
1
mg, quant.) as a colorless viscous oil; [α] 13 (c = 0.1, CHCl ): IR (CHCl ) ν /cm- 1726, 1466, 1381 and
D
3
3
max
1
1
3
=
098; H NMR (500 MHz, TMS, CDCl ) δ (ppm) 0.72 (q, J = 8.0 Hz, 6H), 0.98 (t, J = 8.0 Hz, 9H), 1.20 (s,
3
H), 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
1
3
10.5, 6.0 Hz, 1H), 6.39 (m, 1H), 7.40 (m, 1H), 7.41 (m, 1H); C-NMR (125MHz, TMS, CDCl ) (ppm)
3
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,
+
00.62, 108.43, 126.31, 138.95, 143.68, 150.62, 172.47, 174.22; m/z (EI) 488 (33%, M ), 459 (12), 270 (76)
1
+
and 87 (100). (Found: M , 488.2596. C H O Si requires, 488.2594).
2
7
40
6
O
O
O
H
H
HO
O
CO Me
2
2
0
Methyl (13S,1R,4R,6R,7R)-13-(3-Furyl)-4-hydroxy-1,7-dimethyl-12-oxa-3,11-dioxotricyclo
2
8.4.0.0 ]tetradecane-6-carboxylate (2-epi-Salvinorin B) (20).
,7
[
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
o
toluene (90 µL) was added TES enol ether 19 (3 mg, 0.07 mmol) in toluene (18 µL) at 0 C under nitrogen
o
atmosphere. After being stirred for 40 min at 0 C, m-CPBA (1 mg, 0.007 mmol) in toluene (45 µL) was
o
added and stirring was continued for 50 min at 0 C. 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] −44 (c = 0.02, CHCl ):
D 3
1
IR (CHCl ) ν /cm- 1726, 1603, 1291 and 1165; H NMR (500 MHz, TMS, CDCl ) δ (ppm) 1.09 (s, 3H),
1
3
max
3
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
13
m, 1H), 7.40-7.42 (m, 2H); C-NMR (125 MHz, TMS, CDCl ) (ppm) 15.01, 16.19, 18.12, 32.88, 34.95,
3
3
2
8.42, 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,
+
08.61; m/z (EI) 390 (6%, M ), 273 (12) and 94 (100). (Found: M , 390.1674. C H O requires, 390.1678).
+
2
1
26
7
S-12

O
12
O
O
H
H
AcO
O
CO Me
2
Salvinorin A 1
2
(
4S,13S,1R,6R,7R)-13-(3-Furyl)-6-(methoxycarbonyl)-1,7-dimethyl-12-oxa-3,11-dioxotricyclo[8.4.0.0
tetradec-4-yl acetate (Salvinorin A) (1).
To a stirred solution of 2-epi-salvinorin B 20 (1 mg, 0.003 mmol) in CH Cl (0.6 mL) was added
,
7
]
2
2
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: CH Cl : ethyl acetate = 4 : 1, benzene : ethyl acetate = 5 : 1) to provide salvinorin A 1 1 mg, 86% .
2 2
1
Salvinorin A (1): white powder; [α] −41 (c = 0.004, CHCl ): H NMR (500 MHz, TMS, CDCl ) δ (ppm)
D
3
3
1
2
5
.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),
.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),
1
.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); C-NMR (125
3
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,
5
3.73, 64.26, 72.05, 75.08, 108.39, 139.41, 143.71, 169.96, 171.00, 171.50, 201.92
S-13

2
70 MHz NMR CDCl3
OH
O
O
O
5
S-14
S-14

2
70 MHz NMR CDCl3
OH
O
O
O
5
S-15
S-15

O
OH
OEt
O
H
O
O
6
S-16
S-16

O
OH
OEt
O
H
O
O
6
S-17
S-17

5
00MHz NMR CDCl3
O
OEt
O
O
O
7
S-18
S-18

O
OEt
O
O
O
7
S-19
S-19

O
OH
OEt
O
H
O
8
S-20
S-20

O
OH
OEt
O
H
O
8
S-21
S-21

O
H
O
9
S-22
S-22

O
H
O
9
S-23
S-23

OH
OH
H
1
0
S-24
S-24

5
00MHz NMR CDCl3
OH
OH
H
1
0
S-25
S-25

OTBS
OH
H
1
0-2
S-26
S-26

OTBS
OH
H
1
0-2
S-27
S-27

OTBS
MPMO
H
1
1
S-28
S-28

OTBS
MPMO
H
1
1
S-29
S-29

5
00MHz NMR CDCl3
OTBS
O
MPMO
H
O
1
2
S-30
S-30