Author Topic: Salvinorin A  (Read 1085 times)

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Salvinorin A
« on: May 26, 2003, 08:21:00 PM »
Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint, Salvia divinorum
Leander J. Valdes, , III William M. Butler, George M. Hatfield, Ara G. Paul, Masato Koreeda;
J. Org. Chem.; 1984; 49(24); 4716-4720.


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Salvia Divinorum JOC vol49 no24 (1984)
« Reply #1 on: May 26, 2003, 11:06:00 PM »
Divinorin A, a Psychotropic Terpenoid, and Divinorin B from the Mexican Mint Salvia Divinorum

Leander J. Valdes (III), William M. Butler, George M. Hatfield, Ara G. Paul, and Massato Koreeda.

JOC (1984), 49, 4716-4720

School of Pharmacy and Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109

While nonalkaloidal constituents have been implicated as being at least partially responsible for the biological activity of several hallucinogenic plants,2 little has been reported on the structures of such possible hallucinogens.  The Mexican labiate, Salvia Divinorum (Epling and Jativa-M.) is used in divinatory rites by the Mazatec Indians of Oaxaca, Mexico.  An infusion prepared from the crushed fresh leaves of this plant (known locally as ska Maria Pastora) is used to induce “visions” and its psychotropic effects have been verified by a number of researchers.3

Furthermore, upon administration of large doses of the plant extract in animals, one observes behavioral patterns that resemble the “intoxication” the infusion produces in human beings.  Despite previous investigations, the principle(s) responsible for his biological activity has never been identified.4  We now report the isolation and the structures of the new neoclerodane diterpenes, divinorins A and B from S. Divinorum  Divinorin A, the first clearly documented psychotropic terpenoid, 5 exerts a sedative effect on mice when tested in a bioassay based on a modification of Hall’s open field.6 

Extraction method 1:

Lyophilized, pulverized leaves (5.35kg) of S. Divinorum were extracted with ether.  The nonpolar components were removed from the concentrated extract through partition between hexanes and 90% aqueous methanol.  The dried methanolic fraction was crudely purified by silica gel flash column chromatography7 (hexanes-ethyl acetate, 2/1).  Further purification of the combined biologically active fractions by additional silica gel flash chromatography (DCM-methanol, 20/1) followed by repeated recrystallization yielded pure divinorins A (1) [1.2g] and B (3) [50mg].8

Divinorin A (1) had; MP: 242-244*C, [alpha]22D –45.3* (c8.530, CHCl3), had the molecular formula C23H28O8.  The UV spectrum [211nm (e5260)] was indicative of the presence of the furan moiety.  This was further corroborated by the products from the hydrogenation reaction of Divinorin A which was accompanied by hydrogenolysis at C-12.  Thus, catalytic hydrogenation of Divinorin A in methanol over 5% Pd/C provided quantitatively a stereoisomeric mixture (at C-13) of hexahydro derivatives 4.  Although it was difficult to determine the presence of a ketone group from the IR spectrum of Divinorum A alone, as its carbonyl region is strongly absorbed due to three other carbonyl functionalities, the presence of a highly hindered ketone group in Divinorin A became evident from the results of its sodium borohydride reduction.  The sodium borohydride reduction of Divinorin A was found to be extremely sluggish at RT, presumably owing to the severe steric crowding near the ketone located at C-1.  However, reduction at higher temperatures produced the mixture of 2 (40%) and its stereoisomeric diol (40%).  The latter appears to be stereoisomeric at C-8 and/or C-9, which evidently had resulted from its “base-promoted” C-8/C-9 cleavage followed by reclosure prior to the reduction.  The stereochemistry of the diol 2 was secured as identical that of Divinorin A by its conversion to the latter via acetylation with acetic anhydride/pyridine at RT, followed by oxidation with pyridinium chlorochromate.  In contrast, the same sequence of the other diol gave a thus far undetermined stereoisomer of Divinorin A.

Both 1H and13C NMR spectra were particularly informative since all 1H and13C signals could be observed and assigned through extensive proton decoupling, off-resonance decoupling, and selective decoupling experiments.  These provided partial structures which are indicated in connecting thick lines and by solid blocks denoting the quaternary carbons in Fig. 1A.  The linkage between C-1 and C-10 was ascertained from the 1H NMR spectrum in acetone-d6 of the diol 2 the had; MP:  218-220*C, obtained in 40% yield from Divinorin A with sodium borohydride in isopropyl alcohol at 35*C for 2.5hours.  Thus, inspection of the coupling constants involving protons at C-10, C-1 and C-4 (J10beta, 1beta = 2.0Hz, J1beta,2beta = 2.1Hz, J2beta,3beta = 4.9Hz, J2beta,3alpha = 11.4Hz, j3beta,4beta = 2.1Hz, J3alpha,4beta = 13.2Hz) led to the proposed structure 1 for Divinorin A.

This structure was finally confirmed by a single-crystal X-ray diffraction experiment.  A perspective of the final X-ray model, less hydrogen atoms, is shown in Figure 2.  Details of the X-ray analysis are given in the Experimental Section and bond lengths, angles, other crystallographic parameters are provided as supplementary information.

Divinorin B (3) that had; MP: 213-216*C, [alpha]22D –3.39* (c0.441, EtOH), was found to be deactyldivinorin A, which was verified by its conversion into divinorin A via acetylation with acetic acid in pyridine.  The absolute configurations are proposed based upon the CD spectra (MeOH) of Divinorins A (1) [delta e294 –2.63] and B (3) [delta e290 –1.41] and hexahydrodivinorin A (4) [delta e295 –1.67].  While the absolute configurations shown appear to be corroborated by the negative nàpi* Cotton effect of isofructicolone,9 the unambiguous assignment of the absolute configurations of the Divinorins is yet to be made.

Experimental Section:

Microanalysis was performed by Spang Microanalytical Laboratory, Eagle Harbor, MI.  Melting points was taken on a Fischer Johns MP apparatus and are uncorrected.  The ultraviolet spectrum was determined on a Hewlett-Packard 8450A UV/vis spectrophotometer.  Infrared spectra were recorded on a Perkin-Elmer Model 281 spectrometer as KBr disks.  Mass spectra were taken on a Finnigan Model 4023 GC/MS spectrometer.  NMR spectra were obtained on a Bruker WM360 spectrometer (360MHz for 1H and 90.56MHz for 13C) in CDCl3 unless otherwise stated and all chemical shifts are reported in ppm relative to internal TMS.  Optical rotations were determined on a Perkin-Elmer 241 polarimeter using a quartz cell of 10-cm length and 1-mL volume.  Circular dichroism spectra were recorded on a JASCO J-40A automatic recording spectrophotometer using a quartz cell of 20-mm length and 3.5-mL volume.

Collection, Extraction, and Isolation

Live specimens of S. Divinorum were collected at Cerro Quermado (Sept 3, 1979) and Cerro Ranch (March 7, 1980) in Oaxaco, Mexico.  The plants were cultivated at the Matthaei Botanical Gardens, The University of Michigan, in order to provide material for research.

Fresh Salvia leaves (5.350kg) were lyophilized and forced through 7- and 16-mesh screens yielding 674.1g of powdered dry material.  The powder was extracted in 30-40g lots for 24 hours with ethyl ether (1L/lot) using a Soxhlet apparatus and dried in vacuo, giving a total of 27.51g of ether extract.  The extract was partitioned between hexanes (600ml) and 90% aqueous methanol (600ml) for 48 hours using a liquid/liquid extractor and yielded, after removal of the solvent in vacuo, a 7.41g methanol fraction.  The hexane fraction was repartitioned as above and the combined concentrated methanol fractions (9.36g) were subjected to further purification by flash column chromatography.

In a typical experiment, a Fischer Porter 2.5x25cm column containing 55g of silica gel (70-230mesh), which had been treated with 2.75mL of water, was equilibrated with the eluting solvent, hexanes/ethyl acetate (2/1).  500mgs of the methanolic fraction was adsorbed on 5g of silica gel and carefully poured on the pre-equilibrated column.  The eluting solvent was then forced (using N2 pressure) through the column at the flow rate of 25-35mL/min and 100-mL fractions were collected.  Each fraction was followed with bioassay, and fractions 4-9 were determined to be active.  The 9.36g of methanolic fraction yielded 2.349g of desired crude material.  The material recovered was further purified by using another flash column chromatography.  500mg of the crudely purified methanol fraction was chromatographed as above using the eluting solvent, DCM/Methanol (20/1).  The same pressure and flow rate was applied.  The biologically active fractions (3-5) were combined.  The 2.349g of starting material gave 1.515g of impure diterpenes mixture from which pure divinorin A (893mg) was obtained after two recrystallizations from absolute ethanol.  The combined mother liquors were subjected to preparative TLC purification (Merck GF-254, 15x1 mm plate, 20x20cm, developed with CHCl3/MeOH/H2O, 100/10/1), which gave more Divinorin A (305mg; Rf = 0.63) and crude Divinorin B. The crude Divinorin B was further purified by two recrystallizations from methanol, yielding 50mg of Divinorin B (Rf = 0.48). 

Hey Rhodium, (or anyone else for that matter) really wants the information for spectra or the other related compounds analyzed, I'll get around to typing it up.  I just thought this was good information for Salvia because it included a thorough extraction procedure.


  • Guest
« Reply #2 on: May 27, 2003, 11:20:00 AM »
This reminds me of something that happened a while ago... I found the fucking article (full-text), that obviously dosen't count at all!!!


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Excellent ratings aren't a batch of honor to...
« Reply #3 on: May 27, 2003, 01:40:00 PM »
Excellent ratings aren't a batch of honor to be displayed proudly, their main purpose is finding good stuff with TFSE.
I can award you 50 additional excellent ratings if that would make you happy.


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« Reply #4 on: May 27, 2003, 03:32:00 PM »
You'r such a lucky guy, because I agreed your reasoning, I gave you in return at first an exellent, then a good idea, but that left you visually only with a good idea, so you lucky bastard, I had to give you an extra excellent to quench the good idea. Ipso facto: point proven, we can't show 2 karma clarification texts and have some indept fun with the karma rating.
( btw, I like this article, Ann Arbor uni is a very productive one)

On a more practical level:
""Sodium Borohydride Reduction of Divinorin A. (ketone to the diol!)
Divinorin A (1; 260 mg) was dissolved in 120 mL of isopropyl alcohol in a 200-mL round bottomed flask and was treated with 14 mg of sodium borohydride. The mixture was warmed up to 33-35 °C and was kept at that temperature for 2.5 h. The reaction was terminated by addition of 3 mL of methanol.""
On page 4717 of your saved article link, in the top right column they explain that they reduced the, or one of the ketone groups at the 2 and/or 4 position of the Divinorin-A molecule.

So why is this borohydride ketone to diol reduction different from the lowered temperature ketone+amine to imine to amine ones, we use.
They needed elevated temps at 33-35 °C,

( ""The sodium borohydride reduction of divinorin A was found to be extremely sluggish at room temperature, presumably owing to the severe steric crowding near the ketone located at C-1. However, reduction at higher temperatures produced the mixture of product2 (40%) and its stereoisomeric diol (40%)."")
and they got an interesting 20 % other product, with stronger bioassay effects, which they were still working at as a followup project after this publication.

And why do they use isopropyl alcohol as solvent, and terminate the diol reaction with methanol?
This methanol is also used there to quickly react with the still present NaBH4 and render it useless further?


Another interesting technique, found at the top of page 4716, (last part of another publication!) both in left and right column, (C) and (D):

""(D)The quaternary salt was dissolved in water to a concentration
of 3 M and then shaken over ca. 10 g of 5% Pd/C (containing
50% weight water
) under 60 psi of H2 at 50 °C in a Parr shaker.
After hydrogen uptake was complete in 2-3 h, the mixture was
filtered and the two-phase filtrate separated by using ca. 200 mL
of methylene chloride. The lower, organic layer was dried over
MgSO,, filtered, and solvent distilled through a 10-in. Vigreux
column. The residue was 2-methyl-6-(trifluoromethyl)aniline
obtained in 99% assay and 97% yield from quaternary salt.""

It seems to me that they take dry Pd/C, and under vacuum let the charcoal suck up water, 50% by weight, checked with a scale. Meaning 5 gram water in 10 gram of 5% Pd/C.
This will prolly mean the combined weight of the Pd(heavy) plus the charcoal(light), thus ending up with nearly all internal cores of the charcoal filled with water.
I suppose in hydrogenations in aqueous conditions, this will give the catalyst the buoyancy needed to let the surface Pd on the charcoal come in closer contact with the solution and do a better job as when it would be added dry and thus mostly floated on the surface.
Or is there a deeper reason?
Would this technique be usefull in other solvent systems? Let the Pd/C suck up solvent first before adding it to the reaction mix??? LT/

PS: pHarmacist, what a coincidence perhaps, that the english word Agreed comes so close to Greed?
Does this english mean that people agreeing are greedy by nature? That would surprise me.


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Dear pHarmacist.....
« Reply #5 on: May 27, 2003, 08:35:00 PM »
Is there anyway that pHarmacist can get the credit I would have recieved for the ASCII?   All props can go to pHarmacist, I don't care.  I only do the typing thing because I like having ASCII to copy/paste for use in other works.  Not to mention, the more actual words, the more likely the search engine will find this particular (excellent) article.


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New extraction technique.
« Reply #6 on: May 29, 2003, 07:15:00 PM »
Do read

Post 433158 (missing)

(ChemisTris: "Salvinorin A (journal article)", General Discourse)
when you are interested in Salvia divinorum, the member with this name has posted a quite interesting self developed extraction technique. LT/