Aust. J. Chem.
, 340–348 www.publish.csiro.au/journals/ajc
StudiesTowards the Synthesis of SalvinorinA
Anthony R. Lingham
Helmut M. Hügel
andTrevor J. Rook
RMIT University, School ofApplied Sciences, MelbourneVIC 3001,Australia.
Corresponding author. Email: email@example.comSalvinorin A
, a psychoactive neoclerodane diterpenoid from the Mexican sage
, has gained inter-est as a selective
-opioid receptor agonist. Non-racemic 3-furylamines
have been prepared from(
)-pseudoephedrine and (
)-ephedrine for application in the stereoselective synthesis of the ketone ring of
.Diels–Alder reaction of
with methyl acrylate in aqueous media, followed by selective ether bridge cleavage, hasallowed access to the cyclohexenone
with preservation of stereochemistry at C2. A model route to the lactonering has also been achieved through a one-pot deconjugation/esterification procedure of 2-bromocrotonyl chloride
to the furyl alcohol
followed by Reformatski-mediated ring closure.Manuscript received: 20 December 2005.Final version: 25 May 2006.
Infusions prepared from the leaves of the Lamiaceae
(Epling and Jativa-M.) are traditionally used indivinatory rites by the Mazatec Indians of Oaxaca, Mex-ico. The
-neoclerodane diterpene salvinorin A
has been isolated
from bioactive fractions of the plant extractand identified to be the principal pharmacologically activecomponent.
The absolute stereochemistry of salvinorin Ahas been determined by several methods.
Extensive receptor assays have indicated that salvinorinA acts selectively as a potent
-opioid receptor (KOR)agonist
exhibiting similar efficacy to known KOR ago-nists U69,593 and TRK-820.
The biological properties of salvinorin A are unique, considering it is a non-nitrogenousopioid agonist and displays hallucinogenic effects similar to LSD
, and DMT
(Fig. 1) while lackingstructural similarity to these classical alkaloids.It has been reported that the diterpene
is localizedwithin glandular trichomes
as a secondary metabolite inconcentrations up to 0.37% (dry leaf). Salvinorins B
have also been isolated from leaf extracts, along with salvinicins A and B
and divinatorinsA, B, and C
and D and E
in low concentrations. So far there have been no reports of isolated metabolites possessingKOR activity higher than that of
. Recent efforts to eluci-date structure–activity relationships of
have involved themodification of the C2-acetoxy and C4-ester substituents.The semisynthetic methoxymethyl C2 analogue has shownincreased potency as a KOR agonist,
and affinity for the
-opioid receptor has been reported in analogues containingaromatic C2-ester substituents.
C4-modified analogueshave been reported to possess reduced binding affinity
andby-productsfromesterhydrolysisunderbasicconditionshave been shown to involve the oxidation of ringA.
Growing concern in regards to its potential as a drugof abuse has led to prohibition of both plant material andactive component in some countries (Australia, Denmark,Italy).
However, interest by the medicinal and pharma-cological community has grown, as novel psychotomimeticstructures offer opportunities to explore the role of thereceptor systems in humans. The use of KOR agonists hasgained interest as a novel approach to relief from CNS-acting drug dependence.
However such medication may be problematic because
produces dysphoric effects, whichare considered undesirable in medicinal use.
© CSIRO 2006 10.1071/CH05338 0004-9425/06/050340