Web Release
Date: November 3,
Copyright © 2001
American Chemical Society Salvinorin C, a New Neoclerodane Diterpene from a Bioactive
Fraction of the Hallucinogenic Mexican Mint Salvia
divinorum University of Michigan Hospital, Pharmacy Services, Ann Arbor, Michigan
48109, School of Pharmacy, Northeast Louisiana University, Monroe, Louisiana
71209, and Departments of Chemistry and Medicinal Chemistry, University of
Michigan, Ann Arbor, Michigan 48109
and
Received September 26, 2001
Abstract: |
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As part of our continuing investigations1-6g of salvinorin A induces profound
hallucinations.10
Salvinorin A is the first diterpene to be identified as a hallucinogen in humans
and is one of the most potent naturally occurring compounds thus far isolated.11
We have discussed the effects of S. divinorum and salvinorin A in animals
and humans and warned of their potential to become drugs of abuse.5
During our research on S. divinorum, salvinorin A was first isolated from
a single pharmacologically active TLC band using a solvent system of 100/10/1
CHCl3/MeOH/H2O. Differences in potency between the
purified diterpene and the original TLC fraction led us to surmise that the
latter contained other strongly bioactive compounds that co-chromatographed with
salvinorin A during the chromatographic separation. Upon changing the solvent
system to 1/1 hexanes/EtOAc, the minor component became separated from
salvinorin A. Even though it is estimated that salvinorin C comprises only about
10% of the pharmacologically active TLC fraction, the rest being salvinorin A,
the fraction was significantly more potent than an equivalent amount of
salvinorin A alone. This seems to indicate that the new diterpene may also have
strong psychotropic activity.
Air-dried, pulverized leaves (0.49 kg) of S. divinorum were extracted
as before2 with ether, and salvinorins were isolated by repeated
flash column chromatography. Final purification of salvinorin C was achieved by
HPLC.12
Repeated recrystallization from hexanes/EtOAc provided pure salvinorin C
(1)13
(38.5 mg): mp 196-198 C, [
]22D +49.3
(c 0.61, CHCl3).
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Salvinorin C (1) has the molecular formula
C25H30O9, and its IR spectrum suggests the
presence of an ,
-unsaturated ester
(1715 cm-1), as well as another ester and a
-lactone (1755 and 1735
cm-1, respectively). Its complete structure was elucidated
by the use of 1H and 13C NMR spectroscopy. NMR data were
compared with those of salvinorin A (2) and the acetate derivatives of
the major product obtained by the NaBH4-reduction of salvinorin A.
Partial structures deduced by the analysis of NMR data are indicated in
connecting thick lines (Figure 1). Although no splitting was visible between H-1
and H-10 in the 1H NMR spectrum of salvinorin C
(J1,10 < 0.8 Hz), irradiation of the H-1 peaks sharpened
the H-10 singlet. In addition, at the same time the H-3 peaks collapsed into a
doublet, confirming the presence of the W-shape coupling between H-1 and H-3
(J = 1.4 Hz). The connectivity between the C-12 and the furan group was
established by the detection of the weak coupling between H-12 and H-16
(4J12,16 = 0.8 Hz).
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Figure 1 Partial structures and their connectivity (bold lines) established by 1H and 13C NMR spectroscopy. |
In an effort to further ascertain the structure of salvinorin C, salvinorin A
(2) was reduced with NaBH4 in isopropyl alcohol (35 C, 2.5 h). As we reported earlier,2
the reaction produced a 2.3:1 mixture of cis-diol 4 and its C-8
epimer14
in 87% combined yield. Attempts at directly forming the 1,2-diacetate from diol
4 proved virtually impossible with Ac2O/pyridine, even at
elevated temperatures, presumably as a result of the severe steric hindrance of
the 1
-OH imposed by the two
1,3-diaxially juxtaposed methyl groups. Instead, the formation of 2-monoacetate
62 was observed. Therefore, in analogy to a similar situation
encountered in our study on forskolin,15
diol 4 was first treated with trimethyl orthoacetate at 100
C in the presence of a catalytic amount of
acetic acid. Immediate acid-catalyzed hydrolysis of the resulting 1,2-cyclic
orthoacetate provided 1-monoaceate 516 in 83% yield,
consistent with the general observation on the selective formation of the axial
monoester of diols obtainable upon
acid hydrolysis of their cyclic ortho
ester derivatives.17 Acetylation of 5 under standard
conditions then afforded the desired 1,2-diacetate 718 in 94%
yield.
Comparison of the 13C NMR chemical shifts of salvinorin C (1), monoacetates 5 and 6, and diacetate 7 (Table 1) gave further credence to the proposed structure of salvinorin C. In addition, examination of the 1H NMR spectra of salvinorin C (1) and diacetate 7 was informative in deducing the A-ring stereochemistry of both compounds. A long-range W-type coupling (1.2 Hz) was observed between the two equatorial Hs at C-1 and C-3 in diacetate 7 as in the case of salvinorin C (vide ante).
These salvinorin compounds from S. divinorum closely resemble a large
number of neoclerodane diterpenes isolated from Latin American Salvia
plants.19
This work was supported in part by research grants from the NIH (to M.K.) and the University of Michigan College of Pharmacy (to L.J.V.).
* In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.
University of Michigan
Hospital.
Northeast Louisiana University.
Department of Chemistry, University
of Michigan.
Department of Medicinal Chemistry,
University of Michigan.
1. Valdés, L. J., III; Díaz, J. L.; Paul, A. G. J. Ethnopharmacol. 1983, 27, 287-312.
2. Valdés, L. J., III; Butler, W. M.; Hatfield, G. M.; Paul, A. G.; Koreeda, M. J. Org. Chem. 1984, 49, 4716-4720.
3. Valdés, L. J., III. J. Nat. Prod. 1986, 49, 171.
4. Valdés, L. J., III; Hatfield, G. M.; Koreeda, M.; Paul, A. G. Econ. Bot. 1987, 41, 283-291.
5. Valdés, L. J., III. J. Psychoactive Drugs 1994, 26, 277-283.
6. Koreeda, M.; Brown, L.; Valdes, L. J., III. Chem Lett. 1990, 2015-2018.
7. Ortega, A.; Blount, J. F.; Marchand, P. S. J. Chem. Soc., Perkin Trans. 1 1982, 2505-2508.
8. Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy-Exciton Coupling in Organic Stereochemistry; University Science Books: Mill Valley, CA, 1983.
9. Valdés, L. J., III. Ph.D. Dissertation, University of Michigan, Ann Arbor, Michigan, 1983. See also: Brimblecombe, R. W.; Green, A. L. Nature (London) 1962, 45, 983.
10. Siebert, D. J. J. Ethnopharmacol. 1994, 43, 53-56.
11. Schultes, R. E.; Hofmann, A. The Botany and Chemistry of Hallucinogens; Charles, C., Ed.; Thomas Publisher: Springfield, IL, 1980.
12. A 10-m Radial Pak Microporasil
silica gel column (10 cm × 8 mm id) eluted with an isocratic solvent mixture of
10% acetonitrile, 30% methyl-tert-butyl ether, and 60% hexanes with a
flow rate of 1.5 mL/min.
13. Salvinorin C (1): IR (KBr) 3150, 2950, 2920, 2850, 1755, 1735, 1715, 1635, 1430, 1370, 1310, 1225, 1140, 1070, 1035, 955, 905, 870, 785, 765 cm-1; HRMS (EI) m/z calcd for C25H30O9 474.1890, found 474.1865.
14. Data for the 8-epimer of diol 4: mp 234-235 C (EtOH); [
]22D +8.8
(c 0.24, MeOH); 1H NMR (400 MHz, acetone-d6)
0.97 (d, 1H, J = 1.1
Hz), 1.33 (s, 3H), 1.43 (ddd, 1H, J = 13.7, 4.5, 3.9 Hz), 1.60 (ddd, 1H,
J = 13.7, 13.6, 5.0 Hz), 1.58-1.68 (m, 1H), 1.70 (s, 3H), 1.82 (dd, 1H,
J = 12.1, 11.6 Hz), 1.91 (dddd, 1H, J = 13.6, 13.3, 4.7, 3.9 Hz),
2.03 (dddd, 1H, J = 13.3, 5.0, 4.5, 1.9 Hz), 2.14 (dd, 1H, J =
11.6, 1.9 Hz), 2.16 (dd, 1H, J = 9.7, 1.9 Hz), 2.17 (ddd, 1H, J =
12.0, 11.5, 9.7 Hz), 2.60 (dd, 1H, J = 4.7, 1.9 Hz), 2.86 (s, 1H, 1-OH),
2.89 (s, 1H, 2-OH), 3.60 (ddd, 1H, J = 11.5, 4.5, 2.3 Hz), 3.62 (s, 3H),
4.09 (dd, 1H, J = 2.3, 1.1 Hz), 5.49 (ddd, 1H, J = 12.1, 1.9, 1.2
Hz), 6.58 (dd, 1H, J = 1.8, 0.7 Hz), 7.57 (dd, 1H, J = 1.8, 1.7
Hz), 7.66 (ddd, 1H, J = 1.7, 1.2, 0.7 Hz); 13C NMR (75 MHz,
acetone-d6)
17.36 (q), 18.91 (t), 26.59 (q), 29.77 (t), 37.43 (s), 37.51 (s), 37.85 (t),
46.85 (d), 49.67 (t), 51.15 (q), 55.38 (d), 55.48 (d), 70.08 (d), 70.21 (d),
71.93 (d), 109.66 (d), 125.90 (s), 140.80 (s), 144.38 (d), 173.75 (s), 174.31
(s). Anal. Calcd for C21H28O7: C, 64.60; H,
7.23. Found: C, 64.14; H, 7.18.
15. Valdes, L. J., III.; Koreeda, M. J. Org. Chem. 1991, 56, 844-846.
16. Data for 5: mp 206-209 C
(hexanes/EtOAc); [
]22D +7.1 (c 0.70, CHCl3);
1H NMR (400 MHz, CDCl3)
1.16 (s, 3H), 1.36 (s, 3H), 1.42
(ddd, 1H, J = 13.9, 13.0, 3.6 Hz), 1.47 (d, 1H, J = 1.7 Hz), 1.60
(dddd, 1H, J = 14.1, 13.9, 12.1, 2.9 Hz), 1.62 (d, 1H, J = 1.7
Hz), 1.72 (ddd, 1H, J = 13.0, 3.5, 2.9 Hz), 1.73 (dddd, 1H, J =
13.0, 4.9, 2.8, 1.0 Hz), 1.90 (dd, 1H, J = 13.2, 11.7 Hz), 2.00 (dddd,
1H, J = 14.1, 3.6, 3.5, 3.2 Hz), 2.07 (s, 3H), 2.11 (ddd, 1H, J =
13.2, 13.0, 12.1 Hz), 2.32 (dd, 1H, J = 13.2, 2.8 Hz), 2.35 (dd, 1H,
J = 12.1, 3.2 Hz), 2.48 (dd, 1H, J = 13.2, 5.4 Hz), 3.64 (s, 1H,
OH), 3.65 (s, 3H), 3.68 (ddd, 1H, J = 12.1, 4.9, 1.7 Hz), 5.54 (dd, 1H,
J = 11.7, 5.4 Hz), 5.60 (ddd, 1H, J = 1.7, 1.7, 1.0 Hz), 6.59 (dd,
1H, J = 1.8, 0.8 Hz), 7.57 (dd, 1H, J = 1.8, 1.5 Hz), 7.68 (ddd,
1H, J = 1.5, 0.8, 0.8 Hz). Anal. Calcd for
C23H30O8: C, 63.58; H, 6.96. Found: C, 63.42;
H, 7.00.
17. King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754-1769.
18. Data for 7: mp 211-214 C
(hexanes/EtOAc); [
]22D -7.5 (c 0.81, CHCl3);
1H NMR (400 MHz, acetone-d6)
1.16 (s, 3H), 1.38 (s, 3H), 1.50
(dddd, 1H, J = 14.0, 12.8, 12.2, 2.6 Hz), 1.62 (d, 1H, J = 1.7
Hz), 1.63 (ddd, 1H, J = 13.0, 12.8, 3.2 Hz), 1.76 (dddd, 1H, J =
12.9, 4.8, 2.8, 1.2 Hz), 1.78 (ddd, 1H, J = 13.0, 3.2, 3.0 Hz), 1.90 (s,
3H), 1.94 (dd, 1H, J = 13.2, 11.7 Hz), 2.02 (dddd, 1H, J = 14.0,
3.3, 3.2, 3.0 Hz), 2.14 (s, 3H), 2.23 (ddd, 1H, J = 13.2, 12.9, 12.4 Hz),
2.32 (dd, 1H, J = 13.2, 5.5 Hz), 2.40 (dd, 1H, J = 12.2, 3.3 Hz),
2.45 (dd, 1H, J = 13.2, 2.8 Hz), 3.67 (s, 3H), 4.81 (ddd, 1H, J =
12.4, 4.8, 3.4 Hz), 5.56 (dd, 1H, J = 11.7, 5.5 Hz), 5.68 (ddd, 1H,
J = 3.4, 1.7, 1.2 Hz), 6.58 (dd, 1H, J = 1.8, 0.8 Hz), 7.56 (dd,
1H, J = 1.8, 1.5 Hz), 7.66 (ddd, 1H, J = 1.5, 0.8, 0.8 Hz). Anal.
Calcd for C25H32O9: C, 63.01; H, 6.77. Found:
C, 62.87; H, 6.71.
19. Rodriguez-Hahn, L.; Alvarado, G.; Cárdenas, J.; Esquivel, B.; Gaviño, R. Phytochemistry 1994, 35, 447-450 and references therein.
salvinorin C (1) | |||||
|
|
|
1-OAc 5 |
2-OAc 6 |
diacetate 7 |
1 |
5.76 br d (5.1) |
69.40 |
71.29 |
71.70 |
71.78 |
2 |
5.55 dd (5.1, 2.4) |
64.36 |
70.10 |
67.33 |
67.34 |
3 |
6.50 dd (2.4, 1.4) |
132.62 |
28.77 |
24.90 |
25.79 |
4 |
|
143.02 |
52.98 |
54.99 |
52.82 |
5b |
|
38.25 |
37.22 |
37.86 |
37.54 |
6 |
2.60 ddd (12.9, 3.3, 3.2) |
37.19 |
40.74 |
40.65 |
40.74 |
6 |
1.23 ddd (12.9, 12.8, 3.9) |
|
|
|
|
7 |
1.82 dddd (14.2, 12.8, 12.4, 3.2) |
18.53 |
18.80 |
18.72 |
18.74 |
7 |
2.09-2.18 m |
|
|
|
|
8 |
2.13 dd (12.4, 3.3) |
52.82 |
51.47 |
52.55 |
51.52 |
9b |
|
37.38 |
37.49 |
36.95 |
37.38 |
10 |
1.50 br s |
51.93 |
54.87 |
55.91 |
54.77 |
11 |
2.49 dd (12.9, 5.9) |
44.43 |
44.48 |
44.39 |
44.31 |
11 |
1.69 dd (12.9, 11.4) |
|
|
|
|
12 |
5.54 dd (11.4, 5.9) |
71.92 |
71.84 |
74.61 |
71.78 |
13 |
|
125.81 |
125.85 |
125.99 |
125.68 |
14 |
6.42 dd (1.9, 1.1) |
108.63 |
108.51 |
108.44 |
108.51 |
15 |
7.43 dd (1.5, 1.1) |
144.19 |
143.83 |
143.71 |
143.78 |
16 |
7.45 dd d (1.9, 1.5, 0.8) |
139.75 |
139.55 |
139.35 |
139.55 |
17 |
|
170.12 |
171.62 |
171.55 |
171.19 |
18 |
|
166.14 |
172.55 |
172.35 |
172.17 |
19 |
1.23 s |
21.86 |
17.66 |
16.81 |
17.66 |
20 |
1.73 s |
15.79 |
16.20 |
17.90 |
16.14 |
CO2CH3 |
3.78 s |
51.99 |
55.15 |
51.29 |
54.99 |
OCOCH3 |
2.05 s |
20.07 |
21.45 |
21.11 |
20.69 |
|
2.13 s |
21.10 |
|
|
21.24 |
OCOCH3 |
|
170.79 |
171.35 |
169.51 |
169.89 |
|
|
171.68 |
|
|
170.32 |
a 400 MHz for 1H and 75 MHz for 13C NMR, J values (Hz) are given in parentheses.b The 13C chemical shift assignments for C-5 and C-9 may be interchanged in each column.