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Anthony R. Lingham et al- Studies Towards the Synthesis of Salvinorin A

Anthony R. Lingham et al- Studies Towards the Synthesis of Salvinorin A

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CSIRO
PUBLISHING
Full Paper 
 Aust. J. Chem.
2006
,
59
, 340348 www.publish.csiro.au/journals/ajc
StudiesTowards the Synthesis of SalvinorinA
 Anthony R. Lingham
,
A
 Helmut M. Hügel 
,
A
andTrevor J. Rook 
A,B
A
RMIT University, School ofApplied Sciences, MelbourneVIC 3001,Australia.
B
Corresponding author. Email: trevor.rook@rmit.edu.auSalvinorin A
1
, a psychoactive neoclerodane diterpenoid from the Mexican sage
S. divinorum
, has gained inter-est as a selective
κ
-opioid receptor agonist. Non-racemic 3-furylamines
9a
and
9b
have been prepared from(
+
)-pseudoephedrine and (
)-ephedrine for application in the stereoselective synthesis of the ketone ring of 
1
.Diels–Alder reaction of 
9b
with methyl acrylate in aqueous media, followed by selective ether bridge cleavage, hasallowed access to the cyclohexenone
17
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
20
to the furyl alcohol
19
followed by Reformatski-mediated ring closure.Manuscript received: 20 December 2005.Final version: 25 May 2006.
Introduction
Infusions prepared from the leaves of the Lamiaceae
Salviadivinorum
(Epling and Jativa-M.) are traditionally used indivinatory rites by the Mazatec Indians of Oaxaca, Mex-ico. The
trans
-neoclerodane diterpene salvinorin A
1
has been isolated
[1,2]
from bioactive fractions of the plant extractand identified to be the principal pharmacologically activecomponent.
[3]
The absolute stereochemistry of salvinorin Ahas been determined by several methods.
[2,4]
Extensive receptor assays have indicated that salvinorinA acts selectively as a potent
κ
-opioid receptor (KOR)agonist
[5,6]
exhibiting similar efficacy to known KOR ago-nists U69,593 and TRK-820.
[7]
The biological properties of salvinorin A are unique, considering it is a non-nitrogenousopioid agonist and displays hallucinogenic effects similar to LSD
3
, mescaline
4
, and DMT
5
(Fig. 1) while lackingstructural similarity to these classical alkaloids.It has been reported that the diterpene
1
is localizedwithin glandular trichomes
[8]
as a secondary metabolite inconcentrations up to 0.37% (dry leaf). Salvinorins B
2
,
[2]
C,
[9]
D–F,
[10]
and G
[11]
have also been isolated from leaf extracts, along with salvinicins A and B
[12]
and divinatorinsA, B, and C
[13]
and D and E
[11]
in low concentrations. So far there have been no reports of isolated metabolites possessingKOR activity higher than that of 
1
. Recent efforts to eluci-date structure–activity relationships of 
1
have involved themodification of the C2-acetoxy and C4-ester substituents.The semisynthetic methoxymethyl C2 analogue has shownincreased potency as a KOR agonist,
[14]
and affinity for the
µ
-opioid receptor has been reported in analogues containingaromatic C2-ester substituents.
[15]
C4-modified analogueshave been reported to possess reduced binding affinity
[16]
ROOOOOOO
Salvinorin A
1
: R
AcSalvinorin B
2
: R
H
NNH
34 5
OOONH
2
NHNHNHHO
Fig. 1.
andby-productsfromesterhydrolysisunderbasicconditionshave been shown to involve the oxidation of ringA.
[17]
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).
[18]
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.
[19]
However such medication may be problematic because
1
produces dysphoric effects, whichare considered undesirable in medicinal use.
© CSIRO 2006 10.1071/CH05338 0004-9425/06/050340
 
Synthesis of SalvinorinA 341
Many labdane and clerodane diterpenes possess similar structures to salvinorin A but differ vastly in bioactivity.The furyl lactone moiety in salvinorin A is identical to thatobserved in the molluscicide ricciocarpinA
[20]
and has beenfound necessary for the insect antifeedant properties of bac-chotricuneatin A.
[21]
Syntheses of neoclerodane diterpenesare not common in the literature and novel synthetic path-ways are necessary to prepare these biologically importantditerpenes. In this paper we wish to report on our progresstowardsanenantioselectiveroutetoketoneringAof 
1
,alongwithpreliminarystudiestowardsamodelroutetothelactonering C.
RetrosyntheticAnalysis
DissectionofthetricyclicringstructureatC9/C10andC6/C7 presents a functionalized cyclohexanone, ring A
18
, and an
α
,
β
-unsaturated lactone, ring C
22
, as precursors in a conver-gent synthesis (Scheme 1). Stereocentres adjacent to ketoneandesterfunctionalitiescontainacidicprotonsandwereiden-tified as potential sites for racemization during preparationand purification.CyclohexanoneringAwasretrosyntheticallyderivedfromtheDiels–Alderadductbetweena3-furylamine
9
andmethyl
OOOOOOOOOOOOOOOClOOBrOHOOOONR
1
R
2
122199
13 5681019182321221711121314161520
20
HHO
AC18MAC
Scheme 1.
Retrosynthesis of salvinorinA.
acrylate (MAC). Hydrolysis of the amine substituent pro-vides a direct route to the 7-oxabicyclo[2.2.1]heptane (or 7-oxanorbornane) species
12
(Scheme 3). The chemistry of 7-oxabicyclo[2.2.1]heptanecompoundshasbeenextensivelyexploredandreviewedbyVogelandLeDrian.
[22]
Ringopen-ing of 
12
to the cyclohexenone
16
provides the core of theketone ring present in both
1
and
2
(Scheme 5). Acetyla-tion followed by 1,4-addition allows access to the convergent precursor 
18
.Ring C was derived from rudimentary precursors, as
α
-halovinyl esters may be achieved through a deconjuga-tion/esterification procedure using
α
-bromocrotonyl chlo-ride.Reformatski-mediatedringclosureofthe
α
-bromoestefollowedbydehydrationleadstothelactoneringC.Couplingof 
18
and
22
should be possible through a Michael-typeaddition using methodology developed by Stork et al.,
[23]
followed by olefin metathesis and hydrogenation.
Results and Discussion
7-Oxa[2.2.1]bicycloheptane structures serve as useful inter-mediates in the preparation of specifically functionalizedmolecules for natural product synthesis. Hetero-substitutedfurans have found use as reactive dienes in the prepara-tion of 7-oxa[2.2.1]bicycloheptane structures using Diels– Alder methodology.A general method for the preparation of 3-furylamineshasbeendevelopedbyourgroup
[24]
andprod-ucts have shown high reactivity in cycloaddition reactionswith methyl acrylate.
[25]
This has allowed the preparation of racemic 7-oxabicyclo[2.2.1]heptanone structures and inves-tigation into their chemical transformations has been part of ongoing studies.Face selectivity in the cycloaddition reactions of chiral3-furylamines has been reported by Schlessinger et al.
[26]
and is mediated by steric interactions of a proline-derivedauxiliary. This methodology has been applied successfullyto the total synthesis of (
+
)-cyclophellitol.
[27]
Our currentinvestigation has led us to examine the utility of the nat-urally occurring ephedrine isomers as asymmetric aminesubstituents on the furan moiety.Furans prepared from (1
,2
)-(
+
)-pseudoephedrine
9a
and (1
 R
,2
)-(
)-ephedrine
9b
were obtained in high yieldsfrom the starting amines by optimized procedures. Under conditions required for cyclization, tetrahydropyran-2-yloxy(THP) group migration to the benzylic oxygen was observedin NMR and GC-MS analysis, indicating the formation of furan
8
(Scheme 2). THP deprotection was subsequently performed by gentle heating with
p
-toluenesulfonic acid inethanol. Furan products were stable for long periods uponstorage at
18
C.Studies of Diels–Alder reactions involving achiral5-methyl-3-furylamines with MAC demonstrated bothdichloromethane (DCM) and water to be suitable reactionmedia.
[25]
Cycloadditions of 
9a
and
9b
carried out in DCMwere quantitative as were heterogeneous reactions in water withtheaidofultrasonicirradiation.Furylaminescontainingaromaticsubstituentshavebeenshowntoreacttocompletionwithout sonication,
[25]
suggesting that the sonication in this
 
342 A. R. Lingham, H. M. Hügel, and T. J. Roo
OOTHPNOH
(b, c)(d)
ONOHONOTHPOOTHP
(a)
6 786
(e)(b, c, d)
ONOH
9b9a
Scheme 2.
(a) (
+
)-Pseudoephedrine, THF; (b) TFA, DCE; (c) aq. NaOH; (d)
p
-TsOH, EtOH, 60
C; (e) (
)-Ephedrine.
OOON
(a)(b)
9a
or
9b
O
OOOOOOO
exo endo 
1012a 12b
123456
MAC
OOONO
H
11
OH
Scheme 3.
(a) DCM or water; (b)AcOH, NaOAc, H
2
O.
Table 1. Enantioselective Diels–Alder reactions using ephedrine auxiliaries
Results produced on
1.0mmol scalesRun MAC [equiv.] Solvent
[
C] Time [h]
endo
/
exo
A
e.e.
(
12a
)
e.e.
(
12b
) Yield [%]
B
1
9a
3.0 DCM
50 to rt 8.0 99:1 85 n.d. 902
9a
1.5 Water 1020 1.5 9:1 75 75 833
9b
3.0 DCM
50 to rt 8.0 3:1 56 46 874
9b
1.5 Water 1020 1.5 1:1 18 60 81
A
Ratio of diastereoisomers (
12a
/
12b
).
B
Combined yield of 
endo
and
exo
products.
case is simply a means of suspending the furan in solution,rather than a rate-enhancing phenomenon. NMR studies on the cycloadduct of 
9a
prepared in DCMshowed the product to exist preferentially as the oxazoli-dine
11
. The disappearance of both the spiro and methylenecarbon signals at
δ
C
108.5 and 41.5ppm in acidic D
2
Osuggests facile reversion to the enamine
10
, although fullcharacterization of 
10
could not be obtained. Upon heat-ing in strong acidic solutions (pH 1),
10
underwent a retroDiels–Alder reaction rather than hydrolysis. This led to aloss in enantio- and diastereomeric excesses along with slowdecomposition.Aftermanyattempts,effectivehydrolysiswasachieved by gentle heating in a buffer solution of sodiumacetate/acetic acid (pH 5.5) to give the ketones
12a
and
12b
in good combined yields (81–90%; Scheme 3). Diastere-omeric ratio (
endo
/
exo
) and enantiomeric excesses (
e.e.
) of 
12a
and
12b
were measured by chiral gas chromatographyon a diethyl-
tert 
-butyl-
β
-cyclodextrin column (MeGA, Italy;Table 1). Chiral GC analysis revealed both ephedrine iso-mers to direct face-selectivity in the same manner, whereasthe diastereomeric outcome was quite different.Small-scale reactions carried out using
9a
in aqueousmedia achieved good enantioselectivity for both diastere-omers of 
12
. Reasonable enantiomeric excess was observedfor the
exo
-cycloadduct using
9b
, achieving 60%
e.e.
and providing a 1:1 ratio of diastereoisomers when bath tempera-ture was maintained between 10 and 20
C (Table 1, entry 4).Aqueous reactions on multigram scales required three equiv-alents of acrylate to ensure the consumption of all startingmaterials,butdidnotperformas wellandaloss of12to15%
e.e.
was commonly encountered. The addition of miscibleco-solvents (DMF, dioxane, alcohols) or surfactants (TBAI),toaidintheaqueoussolubilityofreagents,ledtoanoticeabledecrease in enantioselectivity.High selectivity was observed for the
endo
-adduct pre- paredfrom
9a
inDCMandthemultigramreactionperformedcomparably well (80%
e.e.
). Clean reduction of the enamine
10a
was achieved using sodium triacetoxyborohydride,
[28]
 performed from NaBH
4
in acetic acid (Scheme 4). The dis-tilled amine
13
underwent crystallization as the perchloratesalt to provide a diastereomerically pure product as shown by
1
H and
13
C NMR data. X-Ray crystal structure data onthe major isomer revealed facial selectivity in the [4
π
+
2
π
]cycloaddition for the (1
,4
) isomer (Fig. 2). The enaminereduction was observed to be selective for the less-hindered
exo
-face.

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