Total synthesis and olfactory evaluation of (1R*,3S*,6S*, 7S*,8S*)-3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8] undecan-2-one: A new synthetic route to the patchoulol skeleton

Article abstract of DOI:10.1002/ejoc.200500975

The superposition analysis of (-)-patchoulol (1), the odorous principle of patchouli oil, with the recently discovered high-impact spirocyclic patchouli odorant (+)-(1S,4R,5R,9S)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (2) resulted in the que

Full text of DOI:10.1002/ejoc.200500975

FULL PAPER
DOI: 10.1002/ejoc.200500975
Total Synthesis and Olfactory Evaluation of (1R*,3S*,6S*,7S*,8S*)-
3-Hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]undecan-2-one:
A New Synthetic Route to the Patchoulol Skeleton
Philip Kraft,*[a] Christophe Weymuth,[a][‡] and Cornelius Nussbaumer[b][‡‡]
Dedicated with best wishes to Dr. Charles Fehr on the occasion of his 60th birthday
Keywords: Fused-ring systems / Olfactory properties / Patchouli / Prins reaction / Structure–activity relationships
The superposition analysis of (–)-patchoulol (1), the odorous
principle of patchouli oil, with the recently discovered
high-impact spirocyclic patchouli odorant (+)-(1S,4R,5R,9S)-
tramolecular Prins reaction with an equimolar amount of p-
toluenesulfonic acid monohydrate, the ideally preformed
precursor 4 cyclized to (1R*,2R*,3S*,7R*,8S*)-2-hydroxy-
4,8-dimethyltricyclo[5.3.1.03,8]undec-4-en-11-one (13), com-
prising the complete carbon framework of the target com-
pound 3. A Barton–McCombie deoxygenation of the corre-
sponding O-phenoxythiocarbonyl derivative, followed by
oxidation of the lithium enolate of the resulting ketone 14
with the molybdenum peroxide reagent MoO5–pyridine–
DMPU, and the face-selective hydrogenation of the obtained
(1R*,3S*,7S*,8S*)-3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]-
undec-5-en-2-one (15) concluded the synthesis of the target
molecule 3, which was accompanied by its odorless C-6 epi-
mer epi-3 in the ratio 84:16. Both the target structure 3 and
its unsaturated precursor 15 possessed pronounced patchouli
odors, albeit slightly weaker in threshold than (–)-patchoulol
(1). This proved the superposition analysis of the templates 1
1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one
(2)
resulted in the question as to whether patchoulol
a
derivative in which the gem-dimethyl group is replaced
by a carbonyl function would be a powerful patchouli
odorant. The total synthesis of the racemic super-
structure (1R*,3S*,6S*,7S*,8S*)-3-hydroxy-6,8-dimethyltri-
cyclo[5.3.1.03,8]undecan-2-one (3) was accomplished in 13
steps from the inexpensive commercial odorant Cyclal C (7)
with a total yield of 7%. Conversion of 7 to the corresponding
enamine 8 and subsequent copper-catalyzed oxidative de-
gradation afforded 2,4-dimethylcyclohex-3-enone (6), which
was subjected to a Robinson annulation with 1,4-dimeth-
oxybutan-2-one (9). The carbonyl function of the resulting
annulation product 10 was removed by LAH reduction, acyl-
ation with Ac2O, and dissolving metal reduction. The deoxy- and 2 to be correct and provided novel insight into the struc-
genated methyl enol ether 12 thus obtained was then cleaved
by mild hydrolysis with oxalic acid, and the resulting 2,9-
dimethyl-∆1-octalin-5-one (5) was hydroxymethylenated by
Claisen ester condensation with ethyl formate to provide the
tural requirements of patchouli odorants. As 3 was an inter-
mediate in a total synthesis of rac-1, the synthesis also consti-
tutes a new formal total synthesis of racemic patchoulol (rac-
1).
cis-configured (2Z)-2,3,4,4a,8,8a-hexahydro-2-(hydroxymeth- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ylene)-4a,6-dimethylnaphthalen-1(7H)-one (4). In a novel in-
Germany, 2006)
“Kudra doused him with enough patchouli to stampede a
herd of elephants. His eyes flew open like the hatch covers
of an exploding ship, and he commenced to sniff at his
extremities, as if he were wildly in love with himself.”
Introduction
Patchouli, the name of which was borrowed from the Ta-
mil ‘patch ilai’ for ‘green leaf’, became popular in Europe
in the early 19th century with the fashion of cashmere
shawls that accompanied the tiny bodices that revealed the
necklines of elegant ladies. To protect the fine cashmere
wool on its long voyage to Europe, the precious folds of
cloth were layered with leaves of patchouli, which was the
most effective moth repellant then known. Its woody-bal-
samic scent with its well-balanced herbaceous, earthy, cam-
phoraceous, and floral facets soon turned out to be as much
a draw for buyers as the colorful cashmere itself, and thus
patchouli rose from a bug repellant to a popular perfumery
raw material. The recently released perfume “Bornéo 1834”
Tom Robbins, ‘Jitterbug Perfume’[1]
[a] Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax: +41-44-824 29 26
E-mail: philip.kraft@givaudan.com
[b] Luzi Fragrance Compounds AG,
Industriestrasse 9, 8305 Dietlikon, Switzerland
[‡] This work was carried out during a six-month research stay at
Givaudan Schweiz AG.
[‡‡] Formerly of Givaudan Schweiz AG
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(Les Salons du Palais Royal Shiseido, 2005) by Christopher floral family, no intense bifunctional odorants with a pro-
Sheldrake and Serge Lutens tells this story with the extreme ton-donor–proton-acceptor unit within a 3-Å distance[12]
content of 57% (!) decolorized patchouli oil juxtaposed to were known, and thus the ketol motive of 2 was a striking
about 8% of Iso E Super® and Vertofix® each and 1% of exception for a patchouli odorant. It was therefore tempting
Cyperus scariosus oil, and then skillfully contrasted with a to superimpose the spirocyclic hydroxyketone 2 on the tri-
bitter-sweet, nutty chocolate accord around the 2,3,5-tri- cyclic alcohol 1, the odorous principle of patchouli oil.[11]
methylpyrazine-containing base Chocovan as well as with As shown in Figure 1, the two structures match best when
the incense-like smelling opoponax resinoid and myrrh ex- the gem-dimethyl-substituted carbon atom of (–)-patchou-
tract: Early in 1834, Paris went literally crazy for the pa- lol (1) lies over the carbonyl carbon atom of 2. This raises
tchouli-scented fabrics imported via Borneo, Java, and Su- the question as to whether a patchoulol derivative in which
matra, while the resulting crisis of the local textile industry the gem-dimethyl group is replaced by a carbonyl function
in Lyon culminated in April in an uprising of the weavers would smell patchouli-like, and how intensely it would do
with some three hundred victims.
so. If the superstructure 3 reflects the true geometry in
Nowadays, well over 1200 tons of patchouli oil is pro- which the patchouli odorants 1 and 2 are bound to the re-
duced per annum by steam distillation of the dried and fer- ceptor(s), it actually could even be more potent than (–)-
mented leaves of Pogostemon cablin (Blanco) Benth. (syn. patchoulol (1).
Pogostemon patchouli Pellet). The 40–90-cm tall scrub is
Surprisingly, this target structure 3 had already been pre-
cultivated not only in Indonesia, Malaysia, and the Philip- pared by Yamada et al.[6] as an intermediate in the total
pines, but also in India, China, Madagascar, the Seychelles, synthesis of ( )-patchoulol and ( )-seychellene via the
the West Indies, Brazil, and Uruguay. With a content of 35– base-catalyzed cyclization of a cyclohexenone derivative.
40%, the sesquiterpene alcohol (–)-patchoulol (1, Figure 1) However, no odor description had been reported for 3, so
is the main component of the essential oil and contributes it was very exciting to examine if simply no attention had
markedly to its characteristic odor. Several total syntheses been paid to the olfactory properties or if the compound
of racemic and enantiopure 1 have been reported,[2–10] but was odorless after all. Since Yamada et al.[6] had introduced
not surprisingly, no route to this complex tricyclic structure the ketol function of 3 by selective α-hydroxylation of the
proved commercially feasible. Due to its low price of corresponding lithium enolate with the molybdenum perox-
around $40–50/kg, no other synthetic odorant has thus far ide reagent (MoO5–pyridine–HMPA, MoOPH),[13] it
been able to compete with patchouli oil.
seemed reasonable to introduce the hydroxy function at the
end of the synthetic sequence in the same way. For the con-
struction of the tricyclic homoisotwistane skeleton, we
wanted, however, to explore a new route via an intramol-
ecular Prins reaction. This approach should afford the cor-
rect stereochemistry at C-4 by a simple hydrogenation. As
delineated in Scheme 1, the Prins retron reveals the hy-
droxymethylene ketone 4 as the synthetic precursor, which
was expected to epimerize readily at the bridgehead carbon
atoms under acidic reaction conditions and react out of this
cis/trans-equilibrium. The hydroxymethylene moiety can be
introduced by a classical Claisen ester condensation with
ethyl formate, which gives 3,4,4a,7,8,8a-hexahydro-4a,6-di-
methylnaphthalen-1(2H)-one (5). This octalinone 5 could
be synthesized from 2,4-dimethylcyclohex-3-enone (6) by a
Robinson annulation with a methoxymethyl vinyl ketone
Figure 1. (–)-Patchoulol (1), the high-impact spirocyclic α-ketol 2,
and the target compound 3 that was derived by superposition
analysis of the former two.
Recently, however, we discovered a very powerful pa-
tchouli odorant of structure 2[11] which possesses an odor
threshold of 0.027 ng/L air, over 30 times lower than that
of 1 (0.93 ng/L air). Except for the fruity, the sweet and the Scheme 1. Retrosynthetic analysis of the target superstructure 3.
1404 Eur. J. Org. Chem. 2006, 1403–1412
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A New Synthetic Route to the Patchoulol Skeleton
FULL PAPER
synthon according to the methodology of Wenkert et al.,[14] (9), which was introduced by Wenkert et al.[14] as a synthetic
followed by reductive removal of the carbonyl function equivalent of 1-methoxybut-3-en-2-one. The convenient an-
formed, for instance by Wolff–Kishner reduction. The re- nulation reagent 9 was prepared according to the protocol
quired deconjugated cyclohexenone 6 is not yet known in of Hennion and Kupiecki[16] from but-2-yne-1,4-diol in
the literature, but should be easy to obtain on a multigram 79% total yield by alkylation of the alcoholate with di-
scale without isomerization from the inexpensive commer- methyl sulfate and hydration of the resulting butynediol di-
cial odorant Cyclal C (7, ca. $30/kg) by copper-catalyzed methyl ether with catalytic amounts of red mercury() oxide
oxygenation of its enamine according to the protocol of van and sulfuric acid in aqueous methanol. Condensation of
Rheenen.[15]
this reagent 9 with 2,4-dimethylcyclohex-3-enone (6) was
conducted between –10 °C and –5 °C by employing cata-
lytic amounts of potassium tert-butoxide as base in tert-
butanol/diethyl ether. The annulation product 10 was ob-
tained after purification by chromatography in 60% yield
as crystalline material. Besides the main product 10, the
conjugated 2,4-dimethylcyclohex-2-enone was obtained in
28% yield, formed by isomerization of the starting material
6.
Results and Discussion
Following the synthetic plan sketched out above, Cyclal
C (7) was first converted into its enamine 8 by standard
reaction with morpholine in refluxing cyclohexane in the
presence of catalytic amounts of p-toluenesulfonic acid
monohydrate with azeotropic removal of the formed water
in a Dean–Stark trap (Scheme 2). The morpholine enamine
8 was thus obtained in 96% yield by distillation in vacuo.
While aldehyde enamines such as 8 are stable towards mol-
ecular oxygen at ambient temperature, they readily react
with oxygen in the presence of catalytic amounts of cop-
per() chloride under oxidative cleavage of the enamine
double bond.[15] The process hence results in an amine N-
carbaldehyde and the corresponding carbonyl compound
without the formyl group. The copper-catalyzed oxidative
degradation of the morpholine enamine 8 in acetonitrile at
30 2 °C went smoothly and furnished the required build-
ing block 2,4-dimethylcyclohex-3-enone (6) after distillation
in an excellent 92% yield. The deconjugated cyclohexenone
6 proved astonishingly stable towards isomerization, even
upon prolonged storage.
Next, the carbonyl function of 10 had to be removed,
but since all attempts to attain this by a Wolff–Kishner re-
duction failed utterly, a stepwise pathway was taken. First,
the keto enol ether 10 was transformed to the correspond-
ing hydroxy enol ether 11 by standard lithium aluminum
hydride reduction in an almost quantitative yield. The un-
like-configuration of the hydroxy enol ether 11 (11:like-11,
96:4, GC) is the consequence of the 4a-methyl group on the
α-face of 10, which is situated right in the Bürgi–Dunitz
trajectory of the carbonyl function, thus forcing the hydride
nucleophile to approach from the opposite side. This rela-
tive stereochemistry was deduced from the strong nuclear
Overhauser effect between 2-Hax and 4-Hax, the latter hy-
drogen atom of which is in trans-diaxial relation to 4a-Me,
as a distinct crosspeak in the COSY-DQF spectrum shows.
The hydroxy group of 11 was then transformed into the
corresponding acetate by reaction with acetic anhydride
and triethylamine in the presence of 4-dimethylaminopyri-
dine as acylation catalyst. The acetate intermediate was
subsequently subjected to the dissolving metal reduction of
Barton et al.,[17] employing tert-butanol and lithium metal
in liquid ammonia.[18] After these two steps and purifica-
tion by silica-gel filtration and Kugelrohr distillation, the
deoxygenated methyl enol ether 12 was obtained in 77%
yield, while 18% of the hydroxy enol ether substrate 11 was
recovered, which corresponds to a 94% yield based on reco-
vered starting material. Evidenced by pronounced cros-
speaks between 4a-Me and 8a-H as well as between 4a-Me
and 6-Hb in the NOESY spectrum, the cis/trans ratio of 12
was determined as 73:27. The deoxygenated enol ether 12
was then cleaved by mild hydrolysis in aqueous methanol
in the presence of catalytic amounts of oxalic acid to pro-
vide the central octalinone intermediate 5 in 99% yield with
the cis/trans ratio 89:11, again confirmed by the crosspeaks
8-Hb ×4a-Me and 8a-H×4a-Me, respectively, in the
NOESY experiment. The 2,9-dimethyl-∆1-octalin-5-one (5),
which possessed a pleasant woody, green-earthy, sweet,
fruity-grapefruit odor with slightly minty aspects, had been
prepared by W. S. Johnson et al.[19] by a different route on
Scheme 2. Synthesis of the central intermediate 3,4,4a,7,8,8a-hexa-
hydro-4a,6-dimethylnaphthalen-1(2H)-one (5).
In the next step, this cyclohex-3-enone 6 was subjected a milligram scale, but our new route opened up an easy-to-
to a Robinson annulation with 1,4-dimethoxybutan-2-one perform multigram access to isomerically pure 5. As far as
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P. Kraft, C. Weymuth, C. Nussbaumer
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reported, the spectroscopic data were identical to those in configuration was confirmed by an X-ray crystal structure
the literature.[19]
(Figure 2), which indeed revealed a dihedral angle φ =
The hydroxymethylene moiety was constructed in the –104.3° between the hydrogen bonds of C-2 and C-3. As
next step by a standard Claisen ester condensation[20] of was expected for ketols with an AH/B distance above
the octalinone 5 with ethyl formate between 0 °C and room 3 Å,[12] both isomers 13 and 2-epi-13 were devoid of any
temperature in THF, employing sodium hydride as base and odor (distance OH/O = 4.84 Å in the X-ray crystal structure
a catalytic amount of methanol. The crystalline product 4 of 13). After removal of the C-2 hydroxy function, however,
was obtained by chromatography and crystallization, and an odor should be detectable.
it was found to now exist exclusively in cis-configuration
(Scheme 3). This is due to the strong intramolecular hydro-
gen bridge, which causes 1,3-diaxial interactions between
4a-Meax and 3-Hax and 8-Hax in the more strained trans-
isomer. Density-functional calculations on the B3LYP level
with the 6-31G* basis set indicated the cis-isomer 4 to be
favored by 8.12 kJ/mol (1.94 kcal/mol) over the trans-iso-
mer, which explains why the trans-isomer was no longer de-
tectable in the NMR spectrum. Thus, the intramolecular
hydrogen bridge between the hydroxymethylene moiety and
the carbonyl group ideally preformed the cis-geometry re-
quired for the central Prins reaction to take place.
Figure 2. X-ray crystal structure of ( )-(1R*,2R*,3S*,7R*,8S*)-2-
hydroxy-4,8-dimethyltricyclo[5.3.1.03,8]undec-4-en-11-one (13) with
thermal ellipsoids at the 50% probability level.
To study the odor of the ∆5-unsaturated ketol 15 as well,
and to make use of the haptophilicity of the hydroxy group
of 15 to direct the hydrogen from the same face upon hydro-
genation, it was decided first to deoxygenate the secondary
alcohol of 13. A reliable method that works under neutral
conditions and is well compatible with a variety of func-
tional groups including carbonyl functions and double
bonds is the Barton–McCombie reaction.[21] It takes advan-
Scheme 3. Hydroxymethylenation, Prins-type cyclization, and con-
tage of the radicophilic nature of the thiocarbonyl group,
cluding functional group transformations that lead to the tricyclic
especially in O-phenoxythiocarbonyl derivatives of alcohols
target structure 3.
as introduced by Robins et al.,[22] but suffers the drawback
of relying on tributylstannane as reducing agent, which
Immersing a stirred mixture of 4 with an equimolar leads to the formation of toxic and smelly tin-containing
amount of p-toluenesulfonic acid monohydrate in benzene byproducts. Roberts et al.,[23] and Schummer and Höfle,[24]
for a quarter of an hour in a hot oil bath at 85 °C, effected however, demonstrated that this disadvantage can be avo-
the crucial Prins reaction, and after chromatographic purifi- ided by employing organosilanes as radical-based reducing
cation, the epimeric homoisotwistaneketol mixture 13/2-epi- agents[25] in the Barton–McCombie reaction. For the deoxy-
13 (ratio ca. 4:1) was isolated in 74% yield as a colorless genation of compound 13, the procedure of Schummer and
solid. Crystallization from Et2O/hexane furnished the main Höfle[24] was followed, which uses tris(trimethylsilyl)-
stereoisomer 13 in pure form in 59% yield. The relative con- silane (TTMSS) as reagent. The β-ketol 13 was first acyl-
figuration of C-2 was proposed on the basis of a prominent ated at room temp. with phenoxythiocarbonyl chloride in
crosspeak between 2-H and 4-Me in the NOESY spectrum, dichloromethane to furnish, through catalysis by DMAP,
the high-field shift of 2-H at δ = 3.69 ppm shielded by the the corresponding crystalline O-phenylcarbonothioate in
double bonds, and the diminishingly small coupling con- 96% yield after work-up and chromatographic purification.
stant between 2-H and 3-H, which indicated a dihedral an- This was then reduced with TTMSS in refluxing benzene in
gle of φ = 85°–105° in a vicinal Karplus correlation. This the presence of AIBN [2,2Ј-azobis(2-methylpropionitrile)]
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A New Synthetic Route to the Patchoulol Skeleton
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as radical initiator. To facilitate the separation, the tris(tri- to block the face of the carbonyl group, while the hapto-
methylsilyl)silanol formed and the other silanol byproducts philicity[30] of the 3-hydroxy function should make it bind
were converted into the corresponding fluorosilanes by ti- to the catalyst surface and thus direct the delivery of the
tration with a tetrabutylammonium fluoride (TBAF) solu- hydrogen from this side of the molecule. The reduction of
tion in THF after the usual work-up procedure. By subse- the unsaturated ketol 15 under these conditions in a hydro-
quent flash chromatography, the unsaturated tricyclic gen atmosphere at ambient pressure was indeed diastereo-
ketone 14 was isolated in 88% yield, which results in a total selective in this way, but unfortunately not completely. It
yield of 84% for the deoxygenation of the secondary provided the odoriferous target molecule 3 together with its
alcohol 13. Indeed, ketone 14 proved not to be odorless, odorless C-6 epimer epi-3 with unaltered OH/H unit in 84%
but instead emanated a fresh, minty-camphoraceous and yield after chromatographic purification in the ratio 84:16,
eucalyptol-like smell with a slight woody inflexion which which corresponds to a 71% yield of the target compound
was, however, devoid of any earthy tonality or any resem- 3 and 13% of its C-6 epimer epi-3. Changing the solvent to
blance to (–)-patchoulol (1).
2-propanol to increase the shielding of the carbonyl side
As the molybdenum peroxide reagent (MoO5–pyridine– upon hemiketalization brought no improvement in yield or
HMPA, MoOPH),[13] should only attack the lithium eno- selectivity. However, for olfactory characterization, it was
late but not other double bonds,[26] the introduction of the interesting to have obtained the odorless epimer epi-3 as
C-3 hydroxy group was next on the agenda. In accordance well. The correct relative stereochemistry of the target
with the results of Yamada et al.,[6] the enolization of structure 3 was unambiguously established by prominent
ketone 14 was expected to be completely C-3 regioselective. crosspeaks between 6-H and 8-Me as well as between 11-
Applying the guidelines that Köbrich[27] established for the Ha and 6-Me in the NOESY experiment. From our target
application of Bredt’s rule, the ∆1,2-system should corre- molecule 3, the synthesis of which was accomplished in a
spond to an S = 6 [2,2,2] Bredt-forbidden olefin, while the total of 13 steps from Cyclal C (7) with 7% yield and 9%
∆
2,3-enol should not be a Bredt alkene, as its ring strain yield based on recovered starting material, it is 5 additional
would be in the order of an S = 7 [3,3,1] bicycle. In agree- steps in the synthesis of Yamada et al.[6] to rac-patchoulol
ment with this were density-functional calculations on the (rac-1). These 5 steps transformed the ketol 3 in a total of
B3LYP level with the 6-31G* basis set, which favored the 12% based on reacted material to rac-1, the racemate of the
∆
2,3-enol system by as much as 159 kJ/mol (38.0 kcal/mol). odorous principle of patchouli oil. So, our new route to the
For the oxidation of the lithium enolate of 14, however, we ketol 3 constitutes as well a new formal total synthesis of
wanted to avoid the toxicity of the complexed hexameth- racemic patchoulol rac-1; yet, above all we were of course
ylphosphoramide (HMPA) and thus switched to oxodi- interested in the olfactory properties of our target molecule
peroxymolybdenum(pyridine)-1,3-dimethyl-3,4,5,6-tetrahydro- 3, and Yamada et al.[6] indeed had completely missed its
2(1H)-pyrimidinone (MoO5–pyridine–DMPU, MoOPD),[28] pronounced patchouli character.
which in some cases was reported to give even superior
yields. It was prepared by the procedure of Vedejs and
Larsen,[26] but by replacing the carcinogenic HMPA with
Olfactory Properties and Conclusion
DMPU. Work-up and purification followed the paper of
Anderson and Smith,[28] where also the analytical data re-
(–)-Patchoulol (1) possesses a typical woody–balsamic
ported for MoOPD were in agreement with our own. The odor with herbaceous, earthy, camphoraceous, and floral
lithium enolate of 14 was prepared at –78 °C with lithium facets that make a dominant contribution to the overall
diisopropylamide (LDA) in THF, and the MoO5–pyridine– odor of the essential oil,[31] which of course is more com-
DMPU was added at –30 °C to it in one dash. Usual work- plex, narcotic and medicinal, because of the presence of nu-
up and purification by silica-gel FC furnished the unsatu- merous other odoriferous constituents, amongst them pa-
rated odoriferous ketol 15 in 51% yield, while 9% of the tchouli pyridine[32] and epiguaipyridine,[32] which make pa-
starting material 14 was recovered. Much to our delight, tchouli oil blend so well with roast, nut, and chocolate
the unsaturated 15 with the double bond in the same posi- notes. For (–)-patchoulol (1) an odor threshold of 0.93 ng/
tion as in (+)-nor-patchoulenol,[11] already possessed a re- L air was determined,[11] while the characteristic patchouli-
fined, typical, and powerful patchouli scent.
like smelling spirocyclic ketol 2 with woody-ambery, to-
To complete the synthesis of our target superstructure 3, bacco-like facets was much stronger with a threshold of
all that was missing was the diastereoselective hydrogena- 0.027 ng/L air. While epi-3 is odorless, both the target com-
tion of the C-5(6) double bond of ketol 15. In analogy to pound 3 as well as its unsaturated precursor 15 share the
the total syntheses of rac-patchoulol (rac-1) by Magee, typical patchouli note of the templates 1 and 2, which dem-
Stork, and Fludzinski[9] and especially of the enantioselec- onstrates that the superposition analysis in Figure 1 is cor-
tive syntheses of the Valeriananoids A–C by Srikrishna and rect and relevant, as ketols are generally odorless, especially
Satyanarayana,[29] which feature analogous diastereoselec- those with a molecular weight in the sesquiterpenoid range.
tive hydrogenations of 3-hydroxytricyclo[5.3.1.03,8]undec-5- (1R*,3S*,7S*,8S*)-3-Hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]-
ene systems, it was expected that Pd on charcoal in meth- undec-5-en-2-one (15) was described by our perfumers to
anol would give optimal selectivity. Hemiketal formation by be more natural and distinct in its patchouli character and
reaction of the carbonyl group with methanol was expected to emanate a powerful and pronounced patchouli odor with
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P. Kraft, C. Weymuth, C. Nussbaumer
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(puriss. or purum) from Fluka, used without further purification.
Cyclal C (7) is a product of Givaudan, and the commercial grade
was used. The annulation reagent 1,4-dimethoxybutan-2-one (9)
was synthesized from but-2-yne-1,4-diol according to the procedure
of Hennion and Kupiecki.[16] The molybdenum peroxide reagent
(MoO5–pyridine–DMPU, MoOPD) was freshly prepared by fol-
lowing the literature procedure of Vedejs and Larsen,[26] but replac-
ing HMPA with DMPU according to Anderson and Smith.[28] In
this latter paper, the work-up, purification, and analytical data for
MoOPD are detailed.[28]
a fresh, camphoraceous tonality, and warm, woody, slightly
earthy facets, while the saturated, (1R*,3S*,6S*,7S*,8S*)-
configured
3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]un-
decan-2-one (3) possesses a woody–patchouli-like note with
an agrestic tonality and slightly fruity-lactonic aspects; an
animalic side became more apparent in the dry-down.
Whereas 15 became more agrestic after 4 h, both were lin-
ear in smell overall. On blotter, 15 was more powerful than
3, and this was also reflected in the lower odor threshold
of 1.4 ng/L air for the unsaturated ketol 15 as compared to
2.1 ng/L air for the saturated ketol 3. Both 3 and 15 are
actually weaker than the natural lead structure (–)-patchou-
lol (1; 0.93 ng/L air), so the additional carbonyl group did
not improve the binding to the receptor (distance OH/O
around 2.6 Å). Yet, as all are more or less in the same range,
the polar carbonyl function of compounds 3 and 15 could
indeed replace the hydrophobic gem-dimethyl group of 1
without much effect on the odor character and intensity –
a very surprising finding which indicates that the superposi-
tion 1 + 2 in Figure 1 most probably reflects the real bind-
ing situation of the ligand on the patchouli receptor(s).
So, even though we did not discover a superior patchouli
odorant in the superstructures 3 and 15, we gained ad-
ditional insight in the structure–odor requirements of the
patchouli receptor(s). The total synthesis of the target mole-
cules 3 and 15 commenced with the copper-catalyzed oxi-
dative degradation of the formyl group of the inexpensive
commercial product Cyclal C (7) to afford, via its enamine
8, the building block 6 for the construction of octalinone 5
by Robinson annulation with subsequent simple functional
group manipulations. A classical Claisen ester condensation
on octalinone 5 then provided the nicely preformed cis-con-
figured substrate 4 for the central Prins cyclization. The tri-
cyclic Prins product 13 comprised the complete carbon
framework of the target compound 3, to which it was trans-
formed by Barton–McCombie deoxygenation, MoOPD
oxidation of the lithium enolate, and face-selective hydro-
genation. As the target molecule 3 constitutes an intermedi-
ate in the rac-patchoulol synthesis of Yamada et al.,[6] the
presented sequence is also a new formal total synthesis of
rac-patchoulol (rac-1).
The odor thresholds are determined by GC-olfactometry: Different
dilutions of the sample substance are injected into a gas chromato-
graph in descending order of concentration until the panelist fails
to detect the respective substance at the sniffing port. The panelist
smells in blind and presses a button on perceiving an odor. If the
recorded time matches the retention time, the sample is further di-
luted. The last concentration detected at the correct retention time
is the individual odor threshold. The reported threshold values are
the geometrical means of the individual odor thresholds of the dif-
ferent panelists.
CCDC 287802 (13) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(
)-(E/Z)-4-[(2ЈЈ,4ЈЈ-Dimethylcyclohex-3ЈЈ-enylidene)methyl]-
morpholine (8): Morpholine (209 g, 2.40 mol) was carefully added
to a stirred solution of Cyclal C (7, Givaudan, 276 g, 2.00 mol) in
cyclohexane (500 mL). Then, p-toluenesulfonic acid monohydrate
(250 mg, 1.32 mmol) was added, and the resulting reaction mixture
was refluxed in a Dean–Stark apparatus. After 20 h, when water
(55 mL, theor. 36 mL) had been collected in the trap, the reaction
was stopped, and the solvent with the excess morpholine was re-
moved under reduced pressure. The resulting residue was purified
by fractional distillation in a Vigreux assembly to furnish, at 80 °C/
0.05 mbar, the enamine 8 (398 g, 96%) as a colorless oil with the
(E)/(Z)-ratio 53:47. IR (ATR): ν = 1115 (s, ν C–N), 863/837 (s,
˜
as
νsC–N), 1449 (m, δCH2), 1359 (m, δCH3), 1667 (w, νC=C) cm–1.
1H NMR (CDCl3): δ = 1.06/1.07 (2d, J = 7.0 Hz, 3 H, 2ЈЈ-Me),
1.63/1.64 (2 br. s, 3 H, 4ЈЈ-Me), 1.96–2.02 (m, 2 H, 5ЈЈ-,6ЈЈ-Hax),
2.23–2.29 (m, 1 H, 5ЈЈ-Heq), 2.53–2.68 (m, 5 H, 3-,5-H2, 6ЈЈ-Heq),
3.71/3.37 (2t, J = 4.0 Hz, 4 H, 2-,6-H2), 5.27 (d, J = 1.5 Hz, 1 H,
3ЈЈ-H), 5.30 (qd, J = 7.0, 1.5 Hz, 1 H, 2ЈЈ-H), 5.44 (s, 1 H, 1Ј-H)
ppm. 13C NMR (CDCl3): δ = 21.6/22.3 (2q, 2ЈЈ-Me), 22.0/26.4 (2t,
C-6ЈЈ), 23.4/23.5 (2q, 4ЈЈ-Me), 31.2/35.6 (2d, C-2ЈЈ), 31.5/32.5 (2t,
C-5ЈЈ), 53.5/53.7 (2t, C-3,-5), 66.8/66.8 (2t, C-2,-6), 126.6/127.1 (2d,
C-3ЈЈ), 132.6/132.8 (2d, C-1Ј), 132.7/132.9/133.2/133.5 (4s, C-1ЈЈ,
-4ЈЈ) ppm. MS (EI): m/z (%) = 207 (14) [M+], 192 (100) [M+ – CH3],
134 (9) [C9H12N+], 121 (11) [C9H13+], 105 (35) [C8H9+], 91 (23)
[C7H7+], 86 (17) [C4H8ON+], 79 (15) [C6H7+].
Experimental Section
IR: Bruker VECTOR 22/Harrick SplitPea micro ATR, Si; fre-
quencies in order of decreasing intensity. NMR: Bruker AVANCE
( )-2,4-Dimethylcyclohex-3-enone (6): CuCl (4.95 g, 50.0 mmol)
DPX-400, Bruker AVANCE 500 (TCI), Bruker AVANCE 600, was added to a solution of the enamine 8 (207 g, 1.00 mol) in
TMS int. (δ = 0 ppm). MS: Finnigan MAT 95 (EI: 70 eV), HP MeCN (800 mL). Using a gas stirrer, i.e. a mechanical stirrer that
Chemstation 6890 GC/5973 Mass Sensitive Detector. FC: Merck allows a reactant gas to be dispersed via the propelled stirrer
Kieselgel 60 (40–63 µm). TLC: Merck Kieselgel 60 F254 (particle
size 5–20 µm, layer thickness 250 µm on glass, 5 cm×10 cm); visu-
alization reagent: phosphomolybdic acid spray and plunge solution
(Fluka 02553). Melting points: Büchi Melting Point B545 (uncor-
rected). Elemental analyses: Mikroanalytisches Laboratorium Ilse
blades, O2 was then bubbled through the reaction mixture, with
occasional cooling of the flask in an ice/water bath to adjust the
temp. at 28–32 °C. Reaction control by GC indicated the complete
consumption of the starting material after 1 h. The gas flow was
thus stopped, and the reaction mixture was poured into half-satu-
Beetz, 96301 Kronach, Germany. X-ray: Hoffmann-La Roche, CH- rated aq. NaHCO3 solution. The product was extracted with pen-
4070 Basel, Switzerland; Stoe IPDS I diffractometer (Image Plate
Diffraction System); SHELX-97. Unless otherwise stated, all reac-
tions were performed under nitrogen with reagents and solvents
tane (3×), and the combined organic extracts dried (Na2SO4) and
concentrated in a rotary evaporator under reduced pressure. The
resulting yellowish residue was distilled in a Vigreux assembly em-
1408
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1403–1412

A New Synthetic Route to the Patchoulol Skeleton
FULL PAPER
ploying a water aspirator as vacuum source to provide, at 60–62 °C/
25 mbar, the β,γ-unsaturated ketone 6 (114 g, 92%) as a colorless
Ha), 3.58 (s, 3 H, OMe), 4.38 (dd, J = 9.0, 7.0 Hz, 1 H, 2-Hax),
1
1
5.09 (br. s, 1 H, 5-H) ppm. H, H NOESY (C6D6): 2-Hax ×4-Hax.
liquid. IR (ATR): ν = 1714 (s, νC=O), 1443 (m, δCH ), 1191 (m, 1H, 1H COSY-DQF (C6D6): 4-Hax ×4a-Me (4J trans-diaxial). 13C
˜
2
1
νasC–C–C), 1343 (m, δCH3) cm–1. H NMR (CDCl3): δ = 1.13 (d,
NMR (CDCl3): δ = 20.3 (t, C-8), 23.2 (q, 6-Me), 26.5 (q, 4a-Me),
J = 7.0 Hz, 3 H, 2-Me), 1.76 (ddd, J = 2.5, 1.0, 1.0 Hz, 3 H, 4- 27.6 (t, C-3), 32.2 (t, C-7), 34.3 (t, C-4), 36.1 (s, C-4a), 59.0 (d, C-
Me), 2.38–2.57 (m, 4 H, 5-,6-H2), 2.88 (mc, 1 H, 2-H), 5.33 (dq, J
2), 65.3 (q, O-Me), 127.9 (s, C-8a), 131.1 (s, C-6), 132.0 (d, C-5),
= 6.0, 1.0 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3): δ = 16.7 (q, 2-
147.5 (s, C-1) ppm. MS (EI): m/z (%) = 208 (7) [M+], 193 (100)
Me), 22.7 (q, 4-Me), 31.0 (t, C-5), 37.1 (t, C-6), 42.7 (d, C-2), 125.3 [M+ – CH3], 190 (12) [M+ – H2O], 175 (52) [M+ – CH3 – H2O],
(d, C-3), 133.7 (s, C-4), 212.8 (s, C-1) ppm. MS (EI): m/z (%) = 124
(49) [M+], 109 (1) [M+ – CH3], 82 (72) [M+ – C2H2O], 67 (100)
[M+ – C2H2O – CH3], 53 (14) [C4H5+], 39 (17) [C3H3+].
161 (76) [M+ – CH3 – CH3OH], 143 (36) [M+ – CH3 – H2O –
CH3OH], 133 (29) [C10H13+], 128 (23) [C8H16O+], 119 (33)
[C9H11+], 105 (42) [C8H9+], 91 (52) [C7H7+], 45 (4) [C2H5O+], 31
(2) [CH3O+]. C13H20O2 (208.30): calcd. C 74.96, H 9.68; found C
74.99, H 9.62.
( )-4,4a,7,8-Tetrahydro-1-methoxy-4a,6-dimethylnaphthalen-2(3H)-
one (10): A solution of 9 (13.2 g, 100 mmol) in Et2O (140 mL) was
added between –10 °C and –5 °C dropwise over a period of 3.5 h
to a stirred solution of 6 (12.4 g, 100 mmol) and tBuOK (2.80 g,
25.0 mmol) in Et2O/tBuOH (10:1, 110 mL) immersed in an ice/
EtOH cooling bath. Upon completed addition, the cooling bath
was removed, and the reaction mixture was warmed to room temp.
Stirring was continued for further 2 d at ambient temp., before the
brownish reaction mixture was transferred into a separating funnel
by rinsing the reaction flask with Et2O followed by saturated aq.
NH4Cl. The organic layer was separated and washed with brine
prior to drying (Na2SO4) and evaporation of the solvent in a rotary
evaporator. The resulting yellow residue was purified by silica-gel
FC (pentane/Et2O, 5:1, Rf = 0.25) followed by distillation in a Kug-
elrohr apparatus at 130–140 °C/0.1 mbar to afford the annulation
product 10 (12.4 g, 60%) as a colorless semi-crystalline solid, m.p.
( )-cis/trans –1,2,4a,5,6,8a-Hexahydro-8-methoxy-3,4a-dimethyl-
naphthalene (12): At room temp., Ac2O (12.3 g, 120 mmol) was
added dropwise with stirring to a solution of the methoxy alcohol
11 (23.1 g, 111 mmol), Et3N (12.1 g, 120 mmol), and 4-dimeth-
ylaminopyridine (0.61 g, 4.99 mmol) in Et2O (200 mL), upon which
the reaction mixture warmed to 30 °C. Stirring was continued at
ambient temp. for 2 h, prior to pouring the reaction mixture onto
crushed ice. The product was extracted with pentane (3×), and the
combined organic extracts were washed with half-saturated brine,
dried (MgSO4), and concentrated under reduced pressure. Fil-
tration of the resulting residue over silica gel (100 g, pentane/Et2O,
4:1) gave, after evaporation of the solvent in a rotary evaporator
and Kugelrohr distillation at 140 °C/0.05 mbar, the acetate of 11
(27.7 g, 99%) as a colorless oil. A solution of this acetate (27.5 g,
110 mmol) and tBuOH (8.15 g, 110 mmol) in Et2O (100 mL) was
then added at –78 °C dropwise over a period of 30 min to a stirred
dark-blue solution of Li (2.30 mg, 331 mmol) in liq. NH3 (800 mL),
prepared in advance by condensing NH3 in the reaction flask at
–78 °C (dry ice/Me2CO cooling bath), adding Li wire in pieces of
ca. 0.3 cm, and stirring the resulting mixture for 1 h at this temp.
After stirring for 2 h at –78 °C, the cooling bath was removed, and
the reaction mixture was allowed, with further stirring, to warm
to –40 °C within about 1 h. At this temp., solid NH4Cl was care-
fully added in small portions until the solution became colorless.
The NH3 was allowed to evaporate overnight, the resulting residue
was transferred into a separating funnel with Et2O and water, and
the organic layer was separated. The aqueous layer was extracted
with Et2O/pentane (1:1, 3×), and the combined organic extracts
were washed with brine to neutrality. Drying of the organic solu-
tion (Na2SO4), and evaporation of the solvent in a rotary evapora-
tor afforded a residue (22.0 g) that was separated by filtration
through silica gel (120 g, pentane/Et2O, 4:1) with subsequent Kug-
elrohr distillation to provide, at 80–90 °C/0.04 mbar, the methyl
enol ether 12 (16.4 g, 78%, cis/trans ratio 73:27) as a colorless li-
quid, and at 120 °C/0.04 mbar, the starting material 11 (4.17 g,
18%; total yield of 12 from 11 based on recovered starting material:
ca. 30 °C. IR (ATR): ν = 1674 (s, νC=O), 1095/1073 (s, νC–O),
˜
1620 (m, νC=C), 1446 (m, δCH2), 1346 (m, δCH3) cm–1. 1H NMR
(CDCl3): δ = 1.26 (s, 3 H, 4a-Me), 1.69 (d, J = 1.5 Hz, 3 H, 6-Me),
1.72 (ddd, J = 13.5, 5.0, 3.0 Hz, 1 H, 4-Heq), 1.86 (ddd, J = 13.5,
13.5, 5.0 Hz, 1 H, 4-Hax), 2.07–2.17 (m, 3 H, 7-H2, 8-Hb), 2.46
(ddd, J = 18.0, 5.0, 3.0 Hz, 1 H, 3-Heq), 2.61 (ddd, J = 18.0, 13.5,
5.0 Hz, 1 H, 3-Hax), 3.06 (ddd, J = 14.0, 10.5, 8.0 Hz, 1 H, 8-Ha),
3.62 (s, 3 H, OMe), 5.12 (q, J = 1.5 Hz, 1 H, 5-H) ppm. 13C NMR
(CDCl3): δ = 21.6 (t, C-8), 22.9 (q, 6-Me), 24.8 (q, 4a-Me), 31.1 (t,
C-3), 34.4 (t, C-7), 35.2 (t, C-4), 37.0 (s, C-4a), 60.4 (q, OMe), 130.3
(d, C-5), 132.0 (s, C-6), 146.5 (s, C-8a), 153.0 (s, C-1), 194.2 (s, C-
2) ppm. MS (EI): m/z (%) = 206 (153) [M+], 191 (100) [M+ – CH3],
175 (2) [M+ – CH3O], 163 (67) [M+ – C2H3O], 147 (17) [M+
–
CH3O – CO], 131 (13) [C10H11+], 105 (26) [C8H9+], 91 (35) [C7H7+],
31 (1) [CH3O+]. C13H18O2 (206.28): calcd. C 75.69, H 8.80; found
C 75.67, H 8.87.
( )-(2R*,4aS*)-2,3,4,4a,7,8-Hexahydro-1-methoxy-4a,6-dimethyl-
naphthalen-2-ol (11): At –15 °C (ice/EtOH bath), a solution of 10
(20.6 g, 100 mmol) in Et2O (180 mL) was added dropwise over a
period of 2.5 h to a stirred suspension of LiAlH4 (1.90 g, 50 mmol)
in Et2O (200 mL). At this temp., the reaction was quenched with
water (2.0 mL), aq. NaOH (15 %, 2.0 mL), and again water
(6.0 mL) in turn, and after 30 min of stirring at room temp., the
insoluble material was filtered off by suction and carefully washed
with Et2O. The combined filtrates were concentrated in a rotary
evaporator to furnish a colorless viscous oil (21.1 g), which was
further purified by Kugelrohr distillation to provide, at 160 °C/
0.025 mbar, the methoxy alcohol 11 (20.4 g, 98%) in almost isomer-
ically pure form (11/like-11, 96:4, GC). Upon standing, colorless
94%). Analytical data of the main cis-isomer: IR (ATR): ν = 1138/
˜
1075/1212/1032 (s, νC–O–C), 841 (s, δC=C–H oop), 1448 (m,
δCH2), 1353 (m, δCH3), 1682/1666 (m, νC=C) cm–1 1H NMR
.
(CDCl3): δ = 0.96 (s, 3 H, 4a-Me), 1.24 (ddd, J = 13.0, 5.0, 5.0 Hz,
1 H, 5-Hb), 1.43 (ddd, J = 13.0, 7.5, 7.5 Hz, 1 H, 5-Ha), 1.54 (mc,
1 H, 1-Hb), 1.64 (d, J = 1.5 Hz, 3 H, 3-Me), 1.78–1.90 (m, 2 H, 2-
H2), 1.83 (mc, 1 H, 8a-H), 1.91 (mc, 1 H, 1-Ha), 1.96–2.02 (m, 2 H,
6-H2), 3.50 (s, 3 H, O–Me), 4.56 (t, J = 4.0 Hz, 1 H, 7-H), 5.03 (tq,
J = 1.5, 1.5 Hz, 1 H, 4-H) ppm. 1H, 1H NOESY (CDCl3): 4a-
Me×8a-H, 4a-Me×6-Hb. 13C NMR (CDCl3): δ = 20.8 (t, C-6),
23.7 (q, 3-Me), 24.9 (t, C-1), 26.3 (q, 4a-Me), 29.2 (t, C-2), 32.2 (t,
C-5), 34.4 (s, C-4a), 43.3 (d, C-8a), 54.0 (q, O–Me), 92.2 (d, C-7),
crystals formed, m.p. 51 °C. IR (ATR): ν = 1062/1016 (s, νC–O),
˜
1113/1144/1238 (s, νC–O–C), 3300 (br. m, νO–H), 1667 (m, νC=C),
1440 (m, δCH2). 1H NMR (CDCl3): δ = 1.14 (s, 3 H, 4a-Me), 1.40
(ddd, J = 13.5, 13.5, 3.0 Hz, 1 H, 4-Hax), 1.47 (ddd, J = 13.5, 4.0,
4.0 Hz, 1 H, 4-Heq), 1.63 (d, J = 1.0 Hz, 3 H, 6-Me), 1.74 (dddd,
J = 16.5, 13.5, 9.0, 4.0 Hz, 1 H, 3-Hax), 1.92–2.12 (m, 4 H, 3-Heq, 131.0 (d, C-4), 132.5 (s, C-3), 157.1 (s, C-8) ppm. MS (EI): m/z (%)
7-H2, 8-Hb), 2.43 (s, 1 H, O–H), 2.79 (dd, J = 8.0, 2.0 Hz, 1 H, 8-
= 192 (4) [M+], 177 (100) [M+ – CH3], 145 (10) [M+ – CH3
–
Eur. J. Org. Chem. 2006, 1403–1412
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1409

P. Kraft, C. Weymuth, C. Nussbaumer
FULL PAPER
CH3OH], 119 (5) [C9H11+], 105 (11) [C8H9+], 91 (15) [C7H7+], 79 (CDCl3): 5-H×4a-Me, 5-H×6-Me, 8a-H×4a-Me, 1Ј-H×3-H. 13C
(5) [C6H7+]. C13H20O (192.30): calcd. C 81.20, H 10.48; found C
81.22, H 10.50.
NMR (CDCl3): δ = 20.1 (t, C-3), 23.0 (t, C-8), 23.6 (q, 6-Me), 27.6
(q, 4a-Me), 27.9 (t, C-7), 33.6 (t, C-4), 33.7 (s, C-4a), 45.5 (d, C-
8a), 107.9 (s, C-2), 129.1 (d, C-5), 133.8 (s, C-6), 184.7 (s, C-1),
189.7 (d, C-1Ј) ppm. MS (EI): m/z (%) = 206 (98) [M+], 191 (100)
[M+ – CH3], 188 (4) [M+ – H2O], 177 (11) [M+ – CHO], 173 (27)
( )-cis/trans-3,4,4a,7,8,8a-Hexahydro-4a,6-dimethylnaphthalen-
1(2H)-one (5): Anhydrous oxalic acid (480 mg, 5.33 mmol) was
added in one dash at room temp. to a vigorously stirred solution
of the methyl enol ether 12 (4.81 g, 25.0 mmol) in a solvent mixture
of MeOH (40 mL) and water (14 mL). Within 10 min of stirring,
the milky-white emulsion became a clear colorless solution. Vigor-
ous stirring was continued for a further 60 min, prior to pouring
the reaction mixture into pentane/water (1:1, 100 mL). The organic
layer was separated, the aqueous one extracted with pentane (4×),
and the combined organic extracts were washed with brine to which
saturated aq. NaHCO3 (1 mL) was added for neutralization. After
drying (MgSO4) and evaporation of the solvent under reduced
pressure in a rotary evaporator, the crude product (4.50 g) was ob-
tained, which was purified by distillation in a Kugelrohr apparatus
to furnish, at 110 °C/0.25 mbar, the octalinone 5 (4.44 g, 99%, cis/
trans ratio 89:11) as a colorless odoriferous liquid. Analytical data
[M+ – CH3 – H2O], 163 (75) [M+ – C2H3O], 145 (70) [M+
–
C2H3O – H2O], 107 (72) [C8H11+], 91 (77) [C7H7+], 77 (50) [C6H5+],
55 (52) [C4H7+], 41 (41) [C3H5+], 29 (13) [CHO+]. C13H18O2
(206.28): calcd. C 75.69, H 8.80; found C 75.71, H 8.75.
(
)-(1R*,2R*,3S*,7R*,8S*)-2-Hydroxy-4,8-dimethyltricyclo-
[5.3.1.03,8]undec-4-en-11-one (13): A stirred mixture of 4 (4.12 g,
20.0 mmol) and p-toluenesulfonic acid monohydrate (3.80 g,
20.0 mmol) in benzene (40.0 mL) was immersed in an oil bath pre-
heated at 85 °C. After a reaction time of 15 min, the flask was
removed from the heating bath, and the product mixture was co-
oled down to room temp., upon which a reddish semi-crystalline
material was formed. Without further work-up, this material was
loaded on top of an FC column and the product eluted (pentane/
Et2O, 2:1, Rf = 0.13) to provide 13/2-epi-13 (ca. 4:1, 3.07 g, 74%)
as a colorless and odorless solid. Crystallization (Et2O/hexane) at
low temp. afforded the isomerically pure title compound 13 (2.45 g,
59%) as colorless and odorless crystals, m.p. 80–81 °C. IR (ATR):
of the main cis-isomer: IR (ATR): ν = 1702 (s, νC=O), 1446/1427
˜
1
(m, δCH2), 831/813 (m, δC=C–H oop), 1345 (w, δCH3) cm–1. H
NMR (C6D6): δ = 0.91 (s, 3 H, 4a-Me), 1.23 (mc, 1 H, 4-Hb), 1.36–
1.42 (m, 3 H, 3-H2, 4-Ha), 1.47 (s, 3 H, 6-Me), 1.53 (mc, 1 H, 8-
Hb), 1.62 (mc, 1 H, 7-Hb), 1.84 (t, J = 5.0 Hz, 1 H, 8a-H), 1.87
(mc, 1 H, 2-Hb), 2.10–2.21 (m, 3 H, 2-,7-,8-Ha), 4.90 (q, J = 1.5 Hz,
ν = 1696 (s, νC=O), 3421 (s, νO–H), 1296/1337 (m, δC–O–H), 1059
˜
(m, νC–O), 1373 (m, δCH3), 1434 (m, δH–C–H) cm–1. 1H NMR
(CDCl3): δ = 0.93 (s, 3 H, 8-Me), 1.51 (mc, 1 H, 9-Hb), 1.53 (mc, 1
H, 10-Hb), 1.69 (br. s, 1 H, 3-H), 1.71 (dd, J = 2.0, 2.0 Hz, 3 H, 4-
Me), 1.76 (mc, 1 H, 9-Ha), 1.91 (dt, J = 6.5, 2.0 Hz, 1 H, 7-H), 2.20
(mc, 1 H, 6-Hb), 2.25 (mc, 1 H, 10-Ha), 2.43 (mc, 1 H, 6-Ha), 2.48
(td, J = 5.5, 4.0 Hz, 1 H, 1-H), 3.69 (d, J = 4.0 Hz, 1 H, 2-H), 5.21
(br. t, J = 2.5 Hz, 1 H, 5-H) ppm. 1H, 1H NOESY (CDCl3): 2-
H×4-Me, 3-H×4-Me, 3-H×8-Me, 6-H×8-Me, 7-H×8-Me. 13C
NMR (CDCl3): δ = 16.7 (t, C-10), 22.4 (q, 4-Me), 23.0 (q, 8-Me),
26.5 (t, C-6), 30.5 (t, C-9), 33.5 (s, C-8), 47.9 (d, C-7), 49.2 (d, C-
1), 53.4 (d, C-3), 71.8 (d, C-2), 119.5 (d, C-5), 134.8 (s, C-4), 219.3
1
1
1 H, 5-H) ppm. H, H NOESY (C6D6): 3-Ha ×4a-Me, 3-Hb ×4a-
Me, 8-Hb ×4a-Me, 8a-H×4a-Me. 13C NMR (CDCl3): δ = 20.6 (t,
C-8), 21.9 (t, C-3), 23.5 (q, 6-Me), 27.5 (t, C-7), 29.0 (q, 4a-Me),
37.0 (t, C-4), 38.5 (s, C-4a), 40.3 (t, C-2), 54.2 (d, C-8a), 129.5 (d,
C-5), 133.8 (s, C-6), 213.2 (s, C-1) ppm. MS (EI): m/z (%) = 178
(57) [M+], 163 (43) [M+ – CH3], 145 (100) [M+ – CH3 – H2O], 135
(29) [M+ – CH3CO], 119 (14) [C9H11+], 107 (40) [C8H11+], 91 (44)
[C7H7+], 77 (25) [C6H5+], 55 (24) [C4H7+], 41 (18) [C3H5+]. C12H18O
(178.27): calcd. C 80.85, H 10.18; found C 80.74, H 10.13. Odor:
woody, green-earthy, sweet, fruity-grapefruit with slightly minty as-
pects.
(s, C-11) ppm. MS (EI): m/z (%) = 206 (58) [M+], 191 (28) [M+
CH3], 188 (5) [M+ – H2O], 178 (11) [M+ – CO], 173 (19) [M+
–
–
( )-cis-(2Z)-2,3,4,4a,8,8a-Hexahydro-2-(hydroxymethylene)-4a,6-di-
methylnaphthalen-1(7H)-one (4): At 0 °C, a solution of the octalin-
one 5 (8.91 g, 50.0 mmol) and HCO2Et (4.44 g, 59.9 mmol) in an-
hydrous THF (50 mL) was added dropwise with stirring to a sus-
pension of NaH (1.56 g, 65.0 mmol) in dry THF (150 mL). MeOH
(1.0 mL) was added, and stirring was continued at 0 °C for 1 h
and then overnight at room temp., prior to transferring the pink
heterogeneous reaction mixture into a separating funnel with Et2O
followed by rinsing with saturated aq. NH4Cl. By addition of aq.
HCl (2 ) with vigorous shaking of the separating funnel, the mix-
ture was acidified (pH 4). The aqueous layer was separated and
extracted with Et2O (2×), and the combined organic extracts were
washed with brine, dried (MgSO4), and concentrated in a rotary
evaporator. Purification of the resulting yellowish-brown residue
(10.7 g) by silica-gel FC (pentane/Et2O, 20:1, Rf = 0.40) and subse-
quent Kugelrohr distillation of the combined product fractions
(10.0 g) furnished, at 100–110 °C/0.04 mbar, the cis-configured hy-
droxymethylene ketone 4 (9.96 g, 97%) as colorless crystals, m.p.
CH3 – H2O], 160 (76) [M+ – CO – H2O], 145 (85) [C10H25+], 107
(100) [C8H11+], 91 (92) [C7H7+]. Crystal structure data and refine-
ment: empirical formula C13H18O2, molecular mass 206.27, crystal
dimensions 0.5×0.4×0.07 mm, temperature 110 K, wavelength
0.71073 Å, orthorhombic crystal system, space group Pbca, unit
cell dimensions a = 7.5226(15) Å, b = 13.876(3) Å, c = 21.808(4) Å,
α = 90°, β = 90°, γ = 90°, V = 2276.3(8) Å3, Z = 8, ρ = 1.204
Mg/m3, µ(Mo-Kα) = 0.079 mm–1, F(000) 896, θ range 3.08–25.98°,
limiting indices –8 Յ h Յ 9, –17 Յ k Յ 14, –26 Յ l Յ 26, total
reflections collected 12049, symmetry-independent reflections
2236, Rint = 0.0468, refinement full-matrix least-squares on F2, data
2236, parameters 139, goodness-of-fit on F2 1.071, final R indices
[I Ͼ 2σ(I)], R1 = 0.0436, wR2 = 0.1131, R indices (all data) R1 =
0.0494, wR2 = 0.1171, ∆ρ(max, min) = 0.412, –0.164 e·Å–3. CCDC
287802. C13H18O2 (206.28): calcd. C 75.69, H 8.80; found C 75.67,
H 8.79.
66–67 °C. IR (ATR): ν = 1584 (s, νC=C–OH enol), 1159 (s, νHC– ( )-(1R*,3R*,7S*,8S*)-6,8-Dimethyltricyclo[5.3.1.03,8]undec-5-en-
˜
OH), 894/873/849/828 (s, δC=C–H oop), 1316 (s, δC–O–H), 1372
2-one (14): At room temp., a solution of phenoxythiocarbonyl chlo-
(s, δCH3), 993 (s, δC=C–H oop conj. C=O), 1615 (s, νC=O intra-
ride (2.07 g, 12.0 mmol) in CH2Cl2 (10 mL) was added dropwise
1
mol. H bond), 1444 (m, δCH2) cm–1. H NMR (CDCl3): δ = 1.02 with stirring to a solution of β-ketol 13 (2.06 g, 10.0 mmol) and
(s, 3 H, 4a-Me), 1.41 (dt, J = 13.5, 6.0 Hz, 1 H, 4-Hb), 1.58 (dt, J 4-dimethylaminopyridine (2.44 g, 20.0 mmol) in CH2Cl2 (50 mL),
= 13.5, 6.0 Hz, 1 H, 4-Ha), 1.64 (s, 3 H, 6-Me), 1.87 (mc, 2 H, 7-
upon which the temp. of the resulting yellow reaction mixture rose
H2), 1.96 (mc, 2 H, 8-H2), 2.17 (dd, J = 7.0, 4.5 Hz, 1 H, 8a-H),
to 28 °C. Stirring was continued for 2 d at ambient temp., prior to
2.25 (t, J = 6.0 Hz, 2 H 3-H2), 5.03 (tq, J = 1.5, 1.5 Hz, 1 H, 5-H), pouring the reaction mixture in ice/water (1:1). The organic layer
8.77 (s, 1 H, 1Ј-H), 14.6 (s, 1 H, O–H) ppm. 1H, 1H NOESY
was separated, the aqueous one was extracted with CH2Cl2 (3×),
1410
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1403–1412

A New Synthetic Route to the Patchoulol Skeleton
FULL PAPER
and the combined organic extracts were washed with ice/aq. HCl
(1 , 1:1) and brine. After filtration through a wad of cotton wool,
the organic solution was concentrated in a rotary evaporator under
reduced pressure. The resulting yellowish-brown residue (4.04 g)
was purified by silica-gel FC (pentane/Et2O, 10:1, Rf = 0.33) to
furnish ( )-O-(1R*,2R*,3S*,7R*,8S*)-4,8-dimethyl-11-oxotricy-
clo[5.3.1.03,8]undec-4-en-2-yl O-phenylcarbonothioate (3.29 g,
96%) as colorless crystals, m.p. 103.5–104.5 °C (Et2O/hexane). This
O-phenylcarbonothioate (2.40 g, 7.01 mmol) was then added to a
vered starting material: 56%) as colorless crystals, m.p. 112–113 °C
(Et O/hexane). IR (ATR): ν = 1087 (s, νC–O), 1716 (s, νC=O),
˜
2
3417 (s, νO–H), 839 (s, δC=C–H oop), 1444 (m, δCH2), 1390 (m,
1
δCH3) cm–1. H NMR (CDCl3): δ = 0.94 (s, 3 H, 8-Me), 1.40 (mc,
1 H, 9-Hb), 1.60 (ddd, J = 12.5, 5.0, 1.5 Hz, 1 H, 9-Ha), 1.64 (dt,
J = 3.0, 1.5 Hz, 3 H, 6-Me), 1.85–1.99 (m, 5 H, 7-H, 10-,11-H2),
2.01 (s, 1 H, O–H), 2.41 (dddd, J = 15.5, 6.0, 1.5, 1.0 Hz, 1 H, 4-
Hb), 2.32 (ddd, J = 5.0, 3.0, 1.5 Hz, 1 H, 1-H), 2.41 (ddq, J = 15.5,
5.0, 1.5 Hz, 1 H, 4-Ha), 5.10 (tq, J = 4.0, 1.5 Hz, 1 H, 5-H) ppm.
solution of tris(trimethylsilyl)silane (2.09 g, 8.40 mmol) and 2,2Ј- 13C NMR (CDCl3): δ = 18.6 (q, 8-Me), 21.8 (q, 6-Me), 24.6 (t, C-
azobis(2-methylpropionitrile) (230 mg, 1.40 mmol) in benzene
(50 mL), and the resulting reaction mixture was refluxed with stir-
ring for 90 min. After the reaction mixture had cooled down to
room temp., it was diluted with Et2O (50 mL) and washed in turn
with aq. NaHCO3 (5%, 2×), aq. HCl (0.5 , 1×) and brine (2×).
After drying (MgSO4) and evaporation of the solvent in a rotary
evaporator, the residue was dissolved in Et2O/pentane (1:1, 50 mL),
and a solution of tetrabutylammonium fluoride in THF (1 ) was
added dropwise with stirring until TLC control (SiO2, hexane/
EtOAc, 10:1; phenol: Rf = 0.20, silanol: Rf = 0.35, 14: Rf = 0.40)
indicated complete conversion of the tris(trimethylsilyl)silanol
formed. The solvent mixture was removed under reduced pressure,
and the resulting residue purified by silica-gel FC (hexane/EtOAc,
20:1) to provide the unsaturated tricyclic ketone 14 (1.17 g, 88%)
11), 26.5 (t, C-10), 31.0 (t, C-9), 33.4 (t, C-4), 36.6 (s, C-8), 41.1 (d,
C-1), 44.5 (d, C-7), 75.4 (s, C-3), 117.1 (d, C-5), 137.8 (s, C-6),
220.6 (s, C-2) ppm. MS (EI): m/z (%) = 206 (5) [M+], 191 (1) [M+
CH3], 188 (64) [M+ – H2O], 178 (24) [M+ – CO], 173 (4) [M+
–
–
H2O – CH3], 160 (63) [C12H16+], 145 (52) [C11H13+], 135 (33)
[C10H15+], 121 (67) [C9H13+], 97 (100) [C7H13+], 91 (41) [C7H7+],
77 (40) [C6H5+], 55 (31) [C4H7+], 41 (27) [C3H5+]. C13H18O2
(206.28): calcd. C 75.69, H 8.80; found C 75.72, H 8.71. Odor (10%
DPG, blotter): Powerful and pronounced patchouli note, more nat-
ural and distinct than 3, with a fresh, camphoraceous tonality and
warm, woody, slightly earthy facets; +4 h, woody–patchouli-like,
with a more evolved agrestic side; +24 h, woody–patchouli-like,
with a natural earthiness, and now more agrestic than 3. More
powerful than 3 on blotter. Odor threshold: 1.4 ng/L air.
as a colorless liquid. IR (ATR): ν = 1715 (s, νC=O), 1435 (m,
˜
(
)-(1R*,3S*,6S*,7S*,8S*)-3-Hydroxy-6,8-dimethyltricyclo-
δC=C–CH2), 866/774/837/819 (m, δC=C–H oop), 1375 (m, δCH3)
[5.3.1.03,8]undecan-2-one (3): Under nitrogen, Pd/C (10%, 50 mg,
0.048 mmol) was added to a stirred solution of the unsaturated
ketol 15 (206 mg, 1.00 mmol) in dry MeOH (6 mL). The reaction
flask was evacuated and flushed with H2 three times, and the reac-
tion mixture was then vigorously stirred at ambient temperature
and pressure in hydrogen for 23 h. The catalyst was removed by
filtration through a glass-fiber micro filter, rinsed with MeOH
(2×6 mL), and the combined organic filtrates were concentrated
under reduced pressure. The residue was taken up in Et2O, and the
resulting solution was filtered once again through a glass-fiber
micro filter and evaporated in a rotary evaporator. A slightly
brownish oil (215 mg), was thus obtained. It was further purified
by silica-gel FC (pentane/Et2O, 5:1, Rf = 0.14) to furnish the odor-
iferous target compound 3 together with its odorless C-6 epimer
epi-3 (3/epi-3, 84:16, 175 mg, 84%) as colorless crystals, m.p. 48–
1
cm–1. H NMR (CDCl3): δ = 0.90 (s, 3 H, 8-Me), 1.54 (ddd, J =
13.5, 11.0, 3.0 Hz, 1 H, 9-Hb), 1.63 (d, J = 1.5 Hz, 3 H, 6-Me),
1.64–1.85 (m, 5 H, 9-Ha, 10-,11-H2), 1.97 (dt, J = 6.5, 2.0 Hz, 1 H,
H-3), 2.02 (ddd, J = 12.5, 10.5, 1.5 Hz, 1 H, H-7), 2.15 (dddq, J =
18.5, 4.5, 4.5, 1.5 Hz, 1 H, 4-Hb), 2.22 (ddd, J = 5.5, 3.5, 1.5 Hz, 1
H, 1-H), 2.61 (ddt, J = 18.5, 4.5, 2.0 Hz, 1 H, 4-Ha), 5.17 (tq, J =
3.5, 2.0 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3): δ = 22.3 (q, 6-
Me), 22.7 (q, 8-Me), 23.5 (t, C-11), 25.6 (t, C-10), 31.2/32.5 (2t, C-
4,-9), 33.2 (s, C-8), 41.3/42.1 (2d, C-1,-3), 49.3 (d, C-7), 117.6 (d,
C-5), 137.6 (s, C-6), 221.3 (s, C-2) ppm. MS (EI): m/z (%) = 190
(100) [M+], 175 (24) [M+ – CH3], 172 (13) [M+ – H2O], 162 (7)
[M+ – CO], 157 (22) [M+ – CH3 – H2O], 147 (20) [C11H15+], 135
(66) [C10H15+], 119 (27) [C9H11+], 107 (72) [C8H11+], 91 (80)
[C7H7+], 77 (37) [C6H5+], 55 (24) [C4H7+], 41 (23) [C3H5+]. C13H18O
(190.28): calcd. C 82.06, H 9.53; found C 82.02, H 9.57. Odor:
fresh, minty, camphoraceous, eucalyptol-like with a slight woody
inflexion.
51 °C. Spectroscopic data for the main isomer 3: IR (ATR): ν =
˜
1711 (s, νC=O), 1101 (s, νC–O), 1460 (m, δCH2), 3443 (br. m, νO–
H), 1380 (w, δCH3) cm–1. 1H NMR (C6D6): δ = 0.58 (d, J = 7.0 Hz,
3 H, 6-Me), 0.76 (ddd, J = 26.0, 14.0, 5.0 Hz, 1 H, 5-Hb), 0.97 (s,
3 H, 8-Me), 1.00 (ddd, J = 13.0, 13.0, 5.0 Hz, 1 H, 9-Hb), 1.07 (mc,
1 H, 5-Ha), 1.17 (ddd, J = 14.5, 12.0, 2.5 Hz, 1 H, 11-Hb), 1.27
(mc, 1 H, 11-Ha), 1.29 (mc, 1 H, 7-H), 1.43 (ddt, J = 16.0, 11.5,
5.0 Hz, 1 H, 10-Hb), 1.57 (ddd, J = 17.5, 12.5, 5.0 Hz, 1 H, 4-Hb),
( )-(1R*,3S*,7S*,8S*)-3-Hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]-
undec-5-en-2-one (15): At –78 °C, a solution of the unsaturated tri-
cyclic ketone 14 (950 mg, 4.99 mmol) in anhydrous THF (30 mL)
was added dropwise with stirring within 30 min to a freshly pre-
pared solution of lithium diisopropylamide in THF (0.95 ,
9.5 mL, 9.03 mmol). Stirring was continued at –78 °C for a further 1.68–1.76 (m, 3 H, 4-Ha, 6-H, 10-Ha), 2.01 (ddd, J = 13.0, 11.5,
30 min, prior to removal of the cooling bath. When the reaction
mixture had reached –30 °C, the MoO5–pyridine–DMPU complex
(3.45 g, 9.00 mmol) was added in one dash with vigorous stirring.
After further stirring of the resulting light-yellow solution for
90 min, between –30 °C and –20 °C, saturated aq. Na2SO3 (15 mL)
was added, and the reaction mixture was warmed to room temp.
prior to being transferred into a separating funnel with brine. This
mixture was extracted with Et2O (3×50 mL), and the combined
3.5 Hz, 1 H, 9-Ha), 2.19 (ddd, J = 6.0, 5.0, 2.5 Hz, 1 H, 1-H), 2.84
(s, 1 H, O–H) ppm. 1H, 1H NOESY (C6D6): 6-H×8-Me, 11-Ha ×6-
Me. 13C NMR (C6D6): δ = 18.4 (q, 6-Me), 19.4 (q, 8-Me), 22.6 (t,
C-11), 26.3 (t, C-10), 27.4 (t, C-5), 29.0 (t, C-9), 30.2 (d, C-6), 33.2
(t, C-4), 39.4 (s, C-8), 43.1 (d, C-1), 43.7 (d, C-7), 77.3 (s, C-3),
222.1 (s, C-2) ppm. MS (EI): m/z (%) = 208 (23) [M+], 180 (22)
[M+ – CO], 165 (23) [M+ – CO – CH3], 147 (13) [M+ – CO – CH3 –
H2O], 138 (33) [C10H18+], 125 (65) [C9H17+], 109 (20) [C8H13+], 98
organic extracts were washed with brine to neutrality, dried (100) [C7H14+], 83 (74) [C6H11+], 67 (22) [C5H7+], 55 (34) [C4H7+],
(MgSO4), and concentrated in a rotary evaporator under reduced
pressure. The resulting brownish viscous oil (1.53 g) was purified
by silica-gel FC (pentane/Et2O, 5:1) to furnish, besides recovered
starting material 14 (88.0 mg, 9 %, Rf = 0.50), the unsaturated
odoriferous ketol 15 (526 mg, 51%, Rf = 0.20; yield based on reco-
41 (24) [C3H5+]. C13H20O2 (208.30): calcd. C 74.96, H 9.68; found
C 75.00, H 9.70. Odor of 3 (10% DPG, blotter): Woody–patchouli-
like, with an agrestic tonality and slightly metallic-fruity facets;
+4 h, woody–patchouli-like, earthy, with slightly fruity-lactonic as-
pects, and an animalic side more pronounced as in 15; +24 h,
Eur. J. Org. Chem. 2006, 1403–1412
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1411

P. Kraft, C. Weymuth, C. Nussbaumer
FULL PAPER
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Acknowledgments
For the X-ray structure determinations we thank André Alker, Dr.
Armin Ruf, and Dr. Michael Hennig of F. Hoffmann-La Roche
AG, Basel. Thanks are also due to Walter Eichenberger for experi-
mental assistance, to Dr. Gerhard Brunner for many multidimen-
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Received: December 13, 2005
Published Online: February 17, 2006
1412
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Eur. J. Org. Chem. 2006, 1403–1412