From vetiver to patchouli: Discovery of a new high-impact spirocyclic patchouli odorant

Article abstract of DOI:10.1002/ejoc.200500085

In the course of synthetic work on new vetiver odorants, a new, potent patchouli odorant was discovered. Its structure was elucidated as 1-hydroxy-1,4,7,7,9-pentamethylspiro-[4.5]decan-2-one (15/16), and both diastereoisomers were synthesized from the previously reported 4,7,7,9-tetramethyl-1-methylenespiro[4.5]decan-2-one by epoxidation with m-chloroperoxybenzoic acid, reduction with lithium aluminum hydride, and subsequent oxidation with pyridinium chlorochromate or Dess-Martin periodinane. The 1,4-unlike-isomer 15 was found to be the diastereoisomer with the most powerful odor, and its excellent odor threshold of 0.067 ng/L air triggered the synthesis of the derivatives 19, 22, 23, and 26 possessing a different methyl substitution pattern or ring size. Glycol cleavage in the oxidation step was circumvented by Swern oxidation. Three further 4-demethylated derivatives, 32, 33, and 34, were prepared by a short sequence consisting of Diels-Alder reaction with 4-methylene-5-oxohexanenitrile (28), reductive radical cyclization mediated by the titanocene(III) complex Cp₂Ti(Ph)(iPr), and standard hydrogenation. Finally, the enantiomers of 15 were separated by forming their SAMP hydrazones, which were subsequently cleaved by ozonolysis. The odor of the racemate 15 was shown to be exclusively due to the (+)-(1S,4R,5R,9S)-configured enantiomer 38, the stereocenters of which superimpose well with those of (-)-patchoulol (3), the odorous principle of patchouli oil. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500085

FULL PAPER
From Vetiver to Patchouli: Discovery of a New
High-Impact Spirocyclic Patchouli Odorant
Philip Kraft,*[a] Walter Eichenberger,[a] and David Frech[a]
Dedicated with respect and admiration to Dr. Roman Kaiser on the occasion of his 60th birthday
Keywords: Fragrances / Olfactory properties / Patchouli / Spiro compounds / Structure–activity relationships
In the course of synthetic work on new vetiver odorants, a
new, potent patchouli odorant was discovered. Its structure
was elucidated as 1-hydroxy-1,4,7,7,9-pentamethylspiro-
[4.5]decan-2-one (15/16), and both diastereoisomers were
synthesized from the previously reported 4,7,7,9-tetramethyl-
1-methylenespiro[4.5]decan-2-one by epoxidation with m-
by Swern oxidation. Three further 4-demethylated deriva-
tives, 32, 33, and 34, were prepared by a short sequence con-
sisting of Diels–Alder reaction with 4-methylene-5-oxohex-
anenitrile (28), reductive radical cyclization mediated by the
titanocene(III) complex Cp2Ti(Ph)(iPr), and standard hydro-
genation. Finally, the enantiomers of 15 were separated by
chloroperoxybenzoic acid, reduction with lithium aluminum forming their SAMP hydrazones, which were subsequently
hydride, and subsequent oxidation with pyridinium chloro- cleaved by ozonolysis. The odor of the racemate 15 was
chromate or Dess–Martin periodinane. The 1,4-unlike-isomer
15 was found to be the diastereoisomer with the most power-
ful odor, and its excellent odor threshold of 0.067 ng/L air
triggered the synthesis of the derivatives 19, 22, 23, and 26
possessing a different methyl substitution pattern or ring
size. Glycol cleavage in the oxidation step was circumvented
shown to be exclusively due to the (+)-(1S,4R,5R,9S)-config-
ured enantiomer 38, the stereocenters of which superimpose
well with those of (–)-patchoulol (3), the odorous principle of
patchouli oil.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
often crystallizes out. This was long known by perfumers,
who hence termed it patchouli camphor. Gal first investi-
gated patchouli camphor in 1869,[2] but only 80 years later
did Treibs propose[3] patchoulol to be the guaiane sesquiter-
pene alcohol 1 (Figure 1). Already a few years later, how-
ever, Büchi et al.[4] proved Treibs’s structure 1 wrong, and
proposed structure 2. This was even proven by a total syn-
thesis[5] starting from homocamphor. Thus, there was con-
siderable astonishment when the X-ray crystal structure[6]
of the chromate of (–)-patchoulol (3) was not in agreement
with structure 2: A Wagner–Meerwein rearrangement in the
course of the peracid oxidation had led to the correct struc-
ture of (–)-patchoulol (3) without having been noticed in
the synthetic work. Thus, (–)-patchoulol (3) was first syn-
thesized unintentionally and unnoticed in an attempt to
confirm the proposed structure 2, which turned out to be
wrong.
In addition, there was also confusion concerning the ol-
factory properties of (–)-patchoulol (3), which Gadamer[7]
had reported in 1903 to be odorless, whereas Treibs and
chemists at Schimmel & Co. saw in it the odorous principle
of patchouli oil.[3] The controversy continued in 1974, when
Teisseire et al.[8] claimed that perfectly pure (–)-patchoulol
(3) was “totally odorless”. According to them, the typical
odor of patchouli oil was predominantly due to (+)-nor-
Introduction
“Interminably, Jamila twirled, lifting and lowering the aquamarine
veil with which she covered her breast and abdomen. Suddenly the
drum beat picked up [...], Jamila dropped her veil, revealing full
breasts [...], and her odor of sweat and patchouli came to us.”
[1]
Harold Nebenzal, ‘Cafe Berlin’
Patchouli, which is said to be the most powerful and fixa-
tive of all scents of the flora, is the sensual fragrant allegory
for India and the Middle East. With its woody–balsamic
odor and well-balanced herbaceous, earthy, camphoraceous
and floral facets, it is indispensable for the creation of sen-
suous oriental fragrances. Together with bergamot oil and
oakmoss, and a floral heart of jasmine and rose, it also
constitutes a key element of chypre perfumes, and in the
prototype of the gourmand family “Angel” (T. Mugler,
1992) by Olivier Cresp and Yves de Chiris, patchouli oil
is essential to balance and contrast the sugary accord of
chocolate and toffee apple. The main constituent of pa-
tchouli oil is (–)-patchoulol, which makes up 35–40% of the
oil, and upon standing, especially under arid conditions,
[a] Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax: +41-44-824-29-26
E-mail: philip.kraft@givaudan.com
Eur. J. Org. Chem. 2005, 3233–3245
DOI: 10.1002/ejoc.200500085
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P. Kraft, W. Eichenberger, D. Frech
FULL PAPER
old of 0.067 ng/L air without much individual variation
among panelists − all the more as, despite many attempts,
no synthetic patchouli odorant is yet commercially avail-
able.[14]
Results and Discussion
In the course of synthetic work on dienones, an intense
vetiver odorant of structure 7 was discovered.[15] A direct
route was developed by Nazarov cyclization of
6
(Scheme 1), and several new analogs were synthesized to
study the structure–odor relationship of these spirocyclic
vetiver odorants by superposition with khusimone.[15] In ac-
cordance with this superposition analysis, an additional 9-
methyl substituent was found to extinguish the vetiver char-
acter, and 12 was only ambery–woody, but not vetiver-like
in smell. This methylene spiroketone had been synthesized
from 3,3,5-trimethylcyclohexanone (8) by Wadsworth–
Horner–Emmons reaction with triethyl 2-phosphonopropi-
onate (9), subsequent Grignard reaction of 10 with allyl-
magnesium chloride under in situ conversion to the lithium
trienolate, and quenching with aqueous hydrochloric acid
under isomerization of the terminal double bond. Nazarov
cyclization of the resulting dienone 11 with formic and
phosphoric acid in refluxing toluene afforded the ambery–
woody odorant 12. However, when we prepared additional
material of 12, some batches possessed a patchouli-like
twist in the odor character, and by GC–olfactometry this
patchouli odor could be attributed to a tiny peak that eluted
some few minutes after 12 on a polar column (Stabilwax,
30 m×0.32 mm ID, ft = 0.25 μm @ 1.4 mL He/min; 12:
Figure 1. The naturally occurring patchouli odorants (–)-patchou-
lol (3), (+)-nor-patchoulenol (4), and nor-tetrapatchoulol (5).
patchoulenol (4), with around 0.5% rather a minor con-
stituent that previously had not been reported to occur in
nature. This immediately met the opposition of Kastner
from Firmenich,[9] who stated that (–)-patchoulol (3) was
recognized by all their perfumers unanimously as the prime
odorant of patchouli oil, exhibiting a “strong, typical pa-
tchouli scent with an earthy, slightly camphoraceous, powdery
cellar note”.[10] (+)-nor-Patchoulenol (4), on the contrary,
was seen by them only as a nuanceur, possessing an “intense
rooty, cellar note reminiscent of potatoes”.[9] Though (+)-
nor-patchoulenol (4) was for Mookherjee et al.[11] a typical
patchouli odorant, they agreed it to be clearly overshad-
owed by (–)-patchoulol (3) in natural patchouli oil. Even in
pure form, (–)-patchoulol (3) was found to be stronger than
(+)-nor-patchoulenol (4) in the dry-down.[11] In addition,
they reported a new constituent with a warm, woody, ear-
thy–camphoraceous smell: nor-Tetrapatchoulol (5, Figure 1).
With a concentration of only 0.001%, however, it did not
contribute much to the overall odor impression of the es-
sential oil, as in the dry-down, 5 was comparable in strength
to 3.[11] The dispute was finally resolved by a stereoselective
synthesis of 3, which proved it to possess a typical patchouli
note.[10,12] Nevertheless, we still find assessments like “the
odor of patchouli oil owes little to its major components” in
the recent literature,[13] perhaps because a great number of
people possess partial anosmias, or at least very different
sensitivities towards patchouli odorants. This complicates
the determination of odor thresholds, but tentatively we de-
termined threshold concentrations of about 0.93 ng/L air
for 3 and about 2.8 ng/L air for 4. Overall, compounds 3–
5 are all patchouli odorants with threshold values in the
range of a few nanograms per liter air. Therefore, we were
very excited when we discovered a new odorant which pos-
Scheme 1. Our synthetic route to novel spirocyclic vetiver odorants
by Nazarov cyclization on the example of 4,7,7,9-tetramethyl-1-
methylenespiro[4.5]decan-2-one (12) and 4,7,7-trimethyl-1-methyl-
enespiro[4.5]decan-2-one (7), the most typical vetiver odorant syn-
sessed a typical patchouli odor profile and an odor thresh- thesized.
3234 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
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From Vetiver to Patchouli: A New High-Impact Spirocyclic Patchouli Odorant
FULL PAPER
29.50 min; patchouli-type impurity: 32.20 min). The con- fication, 14 was then oxidized to the target structure 15/16
tent of the powerful patchouli-like smelling impurity varied employing pyridinium chlorochromate (PCC) on Celite®.
with the conditions of the Nazarov reaction and also the Since the oxidative glycol cleavage of 14 was the main reac-
work-up, and in some cases it was not detectable at all. tion, the yield in the ketols 15/16 was poor. Nevertheless, it
Since it was usually formed in around 0.15–0.9% yield only, proved possible to isolate the diastereoisomer 15 with the
some batches were pooled and the powerful compound en- most powerful odor by simple FC, and thereby to obtain
riched up to a few percent by classical chromatography. Pre- 30 mg of 15 (5%) in the form of colorless crystals that even
parative GC with this enriched material finally afforded a allowed its structure and relative stereochemistry to be con-
sample of about 100 μg, for which the structure of 1-hy- firmed by X-ray crystallography.
droxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (15/16)
was proposed on the basis of NMR spectra.
The X-ray crystal structure of the (1R*,4S*,5S*,9R*)-
configured spiroketol 15 is depicted in Figure 2 with ther-
Bifunctional odorants with a proton-donor–proton-ac- mal ellipsoids drawn at the 50% probability level. Remark-
ceptor unit are rather uncommon, especially if nonaro- able are the short interatomic distances of 3.4 Å between 1-
matic. The few prominent examples comprise lily-of-the- OH and 7-Meax, and of 3.6 Å between 1-Me and 7-Meax,
valley odorants such as hydroxycitronellal and Lyral® [4-(4- which imply considerable steric crowding. Inversion of the
hydroxy-4-methylpentyl)cyclohex-3-enecarbaldehyde], the cyclohexyl chair, however, would bring both the 9-Meax and
strawberry-like-smelling Furaneol® (2,5-dimethyl-4-hy- the 7-Meax substituent into the close proximity of 4-Me,
droxy-2H-furan-3-one), and caramel-type flavor materials which is energetically even more unfavorable, though only
such as maltol and sotolone (4,5-dimethyl-2(5H)-furanone). by 0.1 kcal/mol (PM3). In diastereoisomer 16, the corre-
In the musky, ambery and woody families, no intense bi- sponding conformation becomes more distinctly favored,
functional odorants are known, and that holds all the more that is, by around 5.4 kcal/mol (PM3). It was isolated in an
true for vetiver and patchouli notes, which are far less com- attempt to optimize the oxidation of 14 by employing Dess–
mon anyway. Therefore, the proposed structure for the new Martin periodinane instead of PCC on Celite® (Scheme 2),
high-impact patchouli odorant was rather unusual, and re- but the glycol cleavage of 14 still prevailed vastly. Neverthe-
quired proof by a directed synthesis – and it was also desir- less, it was possible to obtain 60 mg (15%) diastereoisomer-
able to evaluate its olfactory properties.
ically pure 16, the (1R*,4R*,5S*,9R*)-configuration of
The synthesis of 1-hydroxy-1,4,7,7,9-pentamethylspiro- which was unambiguously proven by a NOESY experi-
[4.5]decan-2-one (15/16) started from the methylene spiro- ment. Cross peaks between 1-Me and 4-H established the
ketone 12 as outlined in Scheme 2. Epoxidation of the α,β- like-relationship of the stereocenters C-1 and C-4, while the
unsaturated double bond of 12 with m-chloroperoxybenzoic cyclohexyl chair conformation was determined to corre-
acid (MCPBA) in CH2Cl2 furnished the epoxy ketone 13 in spond to that delineated in Figure 2 by cross peaks between
61% yield after purification by flash chromatography (FC). 1-OH and 7-Meax, 1-Me and 7-Meax, as well as 9-Hax and
This epoxy ketone 13 was reduced to the corresponding diol 1-OH. Diastereoisomer 16 also possessed a characteristic
14 by means of lithium aluminum hydride (LAH) in almost patchouli note, but was far weaker than the 1,4-unlike-iso-
quantitative yield as indicated by GC. Without further puri- mer 15, for which we determined an odor threshold of
0.067 ng/L air, in comparison with 18 ng/L air for 16.
Moreover, the odor character of the 1,4-unlike-isomer 15
was preferred over that of the 1,4-like-isomer 16. On a blot-
Scheme 2. Synthesis of the new high-impact patchouli odorant
(1R*,4S*,5S*,9R*)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-
2-one (15) by epoxidation/LAH reduction and subsequent oxi-
dation of 4,7,7,9-tetramethyl-1-methylenespiro[4.5]decan-2-one
(12).
Figure 2. X-ray crystal structure of (1R*,4S*,5S*,9R*)-1-hydroxy-
1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (15) with thermal ellip-
soids at the 50% probability level.
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ter, 15 was described by perfumers as strong, powerful, and
characteristic of natural patchouli oil, with rich woody–am-
bery and tobacco-like facets.
This interesting odor description prompted the synthesis
of further derivatives of 15, which are compiled in Figure 3.
To further increase the steric bulk, we first desired to intro-
duce an additional methyl substituent at C-9. A synthesis
of 4,7,7,9,9-pentamethyl-1-methylenespiro[4.5]decan-2-one
was already at hand,[15] and we thus decided to follow es-
sentially the same route as we had for the synthesis of 15/
16, except for making use of a Swern oxidation in the last
step to avoid glycol cleavage. Probably because of steric ef-
fects, the epoxidation of 4,7,7,9,9-pentamethyl-1-methyl-
enespiro[4.5]decan-2-one was sluggish but diastereoselec-
tive, and 17 (Figure 3) was obtained in a moderate 29%
yield. Standard LAH reduction of 17 furnished the diol 18
in 84% yield, and again only one diastereoisomer was iso-
lated, the relative stereochemistry of which was unambigu-
ously established by a NOESY experiment. Swern oxidation
of 18 went as expected without glycol cleavage and provided
the (1R*,9R*)-configured target molecule 19 in 65% yield.
Although this was an acceptable chemical yield, the product
19 was difficult to purify for olfactory evaluation. Sulfurous
off-notes were formed from trace impurities upon standing,
and this observation called for additional chromatographic
purification. The odor of 19 was also found to be patchouli-
like, with some pronounced woody inflection; yet, with an
odor threshold of 51 ng/L air, it turned out to be signifi-
cantly weaker than even the corresponding 1,4-like-isomer
16 of the lead structure.
Figure 3. Overview of the structures of the synthesized analogous
ketols 19, 22, 23, 26, 33, and 34 with the respective intermediates
17, 18, 20, 21, 24, and 25.
Apparently, 19 was already sterically too crowded. So, and the like-epoxide 24 which led to the preferred unlike-
instead of increasing the steric bulk, we planned to remove configured spiroketol 26 was isolated by chromatography.
the axial 7-methyl group of the lead compound. The con- Reduction with LAH provided in 76% yield the corre-
former with the diequatorially substituted cyclohexyl chair sponding diol 25, which was oxidized to the target com-
should now energetically be strongly favored over the diaxi- pound 26 by employing PCC on Celite® to avoid the sulfu-
ally configured one (by about 7.2 kcal/mol), thus stabilizing rous-smelling impurities of Swern oxidation. However,
the conformation depicted in Figure 2 for 15. Again, the glycol cleavage competed severely, and only 21 mg (4%) of
starting material (5r*,7R*,9R*)-4,7,9-trimethyl-1-methyl- the unlike-spiroketol 26 was isolated, nevertheless a suf-
enespiro[4.5]decan-2-one was prepared as described in ear- ficient quantity to establish the relative stereochemistry by
lier synthetic work on vetiver odorants.[15] Epoxidation with a NOESY experiment and to characterize 26 as smelling
MCPBA in CH2Cl2 afforded the isomeric mixture 20, which woody, herbaceous, and reminiscent of camphor with a
was reduced with LAH to the corresponding diol mixture weak odor threshold of 184 ng/L air. Since only pro-
21 in 88% yield. Standard Swern oxidation of 21 then pro- nounced earthy aspects were missing, 26 could still be con-
vided the isomeric spiroketols 22 and 23 (in 84% yield), sidered a patchouli odorant, but apparently the lower mol-
which were separated by chromatography. Both emanated ecular boundaries for a patchouli scent in terms of volume
typical patchouli notes, the 1,4-like-isomer 23 possessing and molecular weight had been reached, a fact that was
again a more woody inflection. As for the lead compounds supported by the subsequent findings.
15/16, the 1,4-unlike-isomer 22 was preferred for its more
Nevertheless, there was also interest in the parent core
pronounced patchouli character and its better odor thresh- structure 32 (Scheme 3) of the high-impact patchouli odor-
old of 32 ng/L air relative to 335 ng/L air for the 1,4-like- ant 15. As the 2-hydroxy-2-methylcyclopentanone ring of
isomer 23. Still the lead structure 15 was by far preferred 32 could be formed by a reductive radical cyclization of a
over 22 in terms of both odor and intensity.
cyanoketone, mediated by either Zn–TMSCl–lutidine[16] or
As it had been found in earlier work on vetiver odor- Cp2Ti(Ph)(iPr),[17] a Diels–Alder transformation retrosyn-
ants[15] that a cycloheptyl or cyclooctyl ring could replace thetically revealed 4-methylene-5-oxohexanenitrile (28) as a
a methylated cyclohexyl ring without much shift in the odor suitable starting material. This was synthesized following
character, we wanted to see if this was also true for our new the procedure of Szabó et al.[18] by methylenation of 5-
patchouli odorants. Consequently, 4-methyl-1-methyl- oxohexanenitrile (27) with formaldehyde in the presence of
enespiro[4,6]undecan-2-one[15] was treated with MCPBA, dimethylamine hydrochloride. Diels–Alder reaction of 28
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From Vetiver to Patchouli: A New High-Impact Spirocyclic Patchouli Odorant
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with butadiene (29) in the presence of AlCl3 and 2-nitropro-
pane furnished the corresponding adduct 30 in 81% yield
after chromatographic purification. Reductive radical cycli-
zation of 30 was carried out according to Itoh and cowork-
ers[17] in the presence of Cp2Ti(Ph)(iPr), for which better
yields were reported than for the Zn–TMSCl–lutidine rea-
gent system of Corey and Pyne.[16] For the cyclization of 3-
(1Ј-acetylcyclohex-3Ј-enyl)propionitrile (30) to 1-hydroxy-1-
methylspiro[4.5]dec-7-en-2-one (31), a disappointingly low
7% yield was obtained. The odor of 31 was described by
perfumers as weak, citrusy and fruity, devoid of any pa-
tchouli-type descriptor. Hydrogenation of 31 in the pres-
ence of palladium on charcoal concluded the short se-
quence and provided the target molecule 32 in 70% yield.
Compound 32 was likewise by no means reminiscent of pa-
tchouli oil and emanated only a weak, fruity–floral odor
with a relatively bad odor threshold of 63.5 ng/L air.
Figure 4. X-ray crystal structure of 1-hydroxy-1-methylspiro[4.5]-
decan-2-one (32) with thermal ellipsoids at the 50% probability
level.
On the basis of these conformational considerations, the
original lead compound 15 seemed to possess an ideal sub-
stitution pattern, and the excellent odor threshold of
0.067 ng/L air seemed difficult to improve on. By GC–ol-
factometry of 15 on a chiral phase (Supelco B-DEX110), it
however surprisingly looked as if the odor were due to only
one enantiomer. To find out which one, we decided to make
use of Enders’s SAMP-/RAMP-hydrazone methodology,[19]
which has also been used occasionally for the separation of
racemic ketones or aldehydes by chromatography.[20] The
(–)-(S)-1-amino-2-methoxymethylpyrrolidine auxiliary was
introduced simply by refluxing 15 with SAMP in EtOH.
The resulting hydrazones were separable by silica-gel FC,
and 35 and 36 (Scheme 4) were isolated in 34% and 39%
Scheme 3. Synthesis of the parent ketol 1-hydroxy-1-meth- yield, respectively. An X-ray structure analysis of the
ylspiro[4.5]decan-2-one (32) by reductive intramolecular cyclization
with the titanocene(III) complex Cp2Ti(Ph)(iPr).
Figure 4 delineates the X-ray crystal structure of 1-hy-
droxy-1-methylspiro[4.5]decan-2-one (32), the parent core
structure of the high-impact patchouli odorant 15. In com-
parison with the crystal structure of the latter, the cyclo-
hexyl chair of 32 is inverted and folded away from the sub-
stituents on C-1 in order to minimize steric interactions. So
the importance of the 4-Me group in ‘pushing’ the cyclo-
hexyl ring up to the C-1 substituents can be seen clearly.
This might explain the importance of the 4-Me group for
the patchouli character of 15 and its derivatives. The signifi-
cance of the 4-methyl substitution was also confirmed by
the synthesis of the 1-hydroxy-1,8-dimethylspiro[4.5]decan-
2-ones 33 and 34 (Figure 3), both of which possessed weak,
floral odors, either with leathery or cinnamon nuances, but
clearly no patchouli-like facets. The Diels–Alder reaction
of 4-methylene-5-oxohexanenitrile (28) with isoprene went
smoothly (84% yield), but again the Cp2Ti(Ph)(iPr)-medi-
ated radical cyclization gave only 7% of the desired pro-
duct. After hydrogenation, the stereoisomers 33 and 34
Scheme 4. Separation of the enantiomers of (1R*,4S*,5S*,9R*)-1-
hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (15) via their
SAMP hydrazones 35 and 36.
were separated by flash chromatography, and discriminated
by their deviating 13C-shifts caused by different γ-effects.
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crystalline hydrazone 36 (Figure 5) established its
Having the pure enantiomers 37 and 38 at hand, it was
(1S,4R,5R,9S,2ЈS)-configuration, so all that remained to do indeed proven that only one enantiomer of 15 had an odor.
was cleave the two hydrazones 35 and 36 to the correspond- Only the (+)-(1S,4R,5R,9S)-configured 38 emanated a
ing ketol enantiomers 37 and 38. This, however, turned out strong, powerful, and characteristic patchouli note with
to be more difficult than anticipated, as all the acidic or rich woody–ambery and tobacco-like facets. And its odor
reductive methods attempted for the cleavage of hydra- threshold of 0.027 ng/L air was half that of 15, within ex-
zones[21] led to decomposition. Fortunately, ozonolysis with perimental error. By GC–olfactometry on the chiral phase,
reductive work-up employing thiourea went smoothly, and it was proven that the faint odor that 37 had on the blotter
the (–)-(1R,4S,5S,9R)-configured 37 as well as the (+)- was indeed due only to traces of its enantiomer. As it is also
(1S,4R,5R,9S)-configured enantiomer 38 were isolated in known that only the naturally occurring (–)-enantiomer 3
40% and 34% yield, respectively.
of patchoulol[12] is responsible for the odor of the race-
mate,[10] it was questioned whether the stereochemistry of
3 and 38 would match. Figure 6 details the overlay of the
structures 3 and 38, and indeed their stereocenters superim-
pose well. Interestingly however, the 7-Me2 and 9-Me
groups, which were found crucial for the patchouli odor of
38, lie outside the overlapping areas.
Unfortunately, patchouli oil is a rather inexpensive per-
fumery raw material, making it difficult to introduce a syn-
thetic patchouli odorant, even if it is very powerful, as are
15 or 38. The syntheses presented herein are obviously not
suited for industrial production, and even on the smaller
scale are not yet satisfactory in terms of the number of steps
and yields. Nevertheless, the new high-impact spirocyclic
patchouli odorant 38 and its racemate 15 are structurally
interesting, and together with the presented derivatives pro-
Figure 5. X-ray crystal structure of (+)-(1S,4R,5R,9S,2ЈS)-1-hy- vide new insight into the structure–odor correlation of pa-
droxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one
methoxymethylpyrrolidine hydrazone (36) with thermal ellipsoids
at the 50% probability level.
1Ј-amino-2Ј-
tchouli odorants that indeed seems linked to some extent
with that of vetiver materials like 7.[15]
Figure 6. Superposition analysis of (+)-(1S,4R,5R,9S)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (38, silver) and (–)-patchou-
lol (3, gold).
3238
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3233–3245

From Vetiver to Patchouli: A New High-Impact Spirocyclic Patchouli Odorant
FULL PAPER
42.5/44.6 (4t, C-5, –9), 48.2/48.7 (2t, C-2), 50.1/50.2 (2t, C-7), 67.1/
70.0 (2s, C-3), 213.7/214.9 (2s, C-12) ppm. MS (70 eV): m/z (%) =
236 (2) [M+], 220 (28) [M+ – CH3], 205 (73) [C14H21O+], 178 (36)
Experimental Section
IR: Bruker VECTOR 22/Harrick SplitPea micro ATR, Si. NMR:
Bruker AVANCE DPX-400, Bruker AVANCE 500 (TCI), Bruker
AVANCE 600, TMS int. (δ = 0 ppm). MS: Finnigan MAT 95 (EI:
70 eV), HP Chemstation 6890 GC/5973 Mass Sensitive Detector.
FC: Merck 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); visualization reagent: phosphomolybdic acid spray
and plunge solution (Fluka 02553). Melting points: Büchi Melting
Point B545 (uncorrected). Elemental analyses: Mikroanalytisches
Laboratorium Ilse Beetz, D-96301 Kronach, Germany. X-ray:
Hoffmann-La Roche, CH-4070 Basel, Switzerland; Stoe IPDS I
diffractometer (Image Plate Diffraction System); SHELX-97. Un-
less otherwise stated, all reactions were performed under N2 with
reagents and solvents (puriss. or purum) from Fluka, used without
further purification.
[M+
–
CH3
–
C2H2O], 163 (24) [M+
–
C2H2O
–
2CH3],
+
+
150 [C11H18+], 135 (68) [C11H18 – CH3], 121 (59) [C11H18
–
C2H5], 107 (89) [C11H18 – C3H7], 83 (80) [C6H11+], 55 (88)
[C4H7+], 41 (100) [C3H5+].
+
(1R*,4S*,5S*,9R*)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]de-
can-2-one (15): A solution of 6,6,8,10-tetramethyl-1-oxadis-
piro[2.0.5.3]dodecan-12-one (13, 580 mg, 2.45 mmol) in Et2O
(1.5 mL) was added dropwise with stirring at room temp. to a sus-
pension of lithium aluminum hydride (280 mg, 7.36 mmol) in Et2O
(3.0 mL). After stirring at this temp. for 30 min, the reaction was
quenched by the careful addition of water (5.0 mL) followed by aq.
HCl (5 n, 5.0 mL) at 0 °C. The organic layer was separated, and
the aqueous one extracted with Et2O (2×25 mL). The combined
organic extracts were washed with water (25 mL) and brine
(25 mL), dried (Na2SO4), and concentrated in a rotary evaporator
under reduced pressure to provide the corresponding crude diol
(630 mg). A solution of pyridinium chlorochromate (1.06 g,
4.90 mmol) in CH2Cl2 (4.0 mL) was added at room temp. in one
dash to a vigorously stirred suspension of Celite® (1.00 g) in
CH2Cl2 (8.0 mL). Stirring was continued at this temp. for 10 min,
prior to the addition of the crude diol (630 mg) dissolved in CH2Cl2
(4.0 mL). After stirring for an additional 30 min, the insoluble ma-
terial was removed by vacuum filtration through a pad of Celite®
with thorough washing with CH2Cl2. The organic extracts were
concentrated under reduced pressure, and the resulting residue was
purified by silica-gel FC (pentane/Et2O, 9:1, Rf = 0.46) to afford,
as the most intensely smelling fraction, the title compound 15
(30 mg, 5%) in the form of colorless crystals, mp. 73–74 °C. IR
The odor thresholds were determined by GC–olfactometry: Dif-
ferent dilutions of the sample substance are injected into a gas
chromatograph in descending order of concentration until the pan-
elist 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 fur-
ther diluted. The last concentration detected at the correct reten-
tion time is the individual odor threshold. The reported threshold
values are the geometrical means of the individual odor thresholds
of the different panelists. The chemical purity of the compounds
prepared for olfactory evaluation exceeds 99.9% (GC), and the ol-
factory purity has in addition been validated by the GC-sniffing
technique prior to threshold determination.
CCDC-256512 (15), CCDC-256513 (32) and CCDC-256514 (36)
contain 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_requ-
est/cif.
(ATR): ν = 1738 (s, νC=O), 1098 (s, νC–O), 3456 (s, νO–H), 1382
˜
(m, δCH3) cm–1. 1H NMR (C6D6): δ = 0.31 (dd, J = 12.0, 12.0 Hz,
1 H, 10-Hax), 0.62 (dd, J = 12.0, 12.0 Hz, 1 H, 8-Hax), 0.66 (d, J =
7.5 Hz, 3 H, 4-Me), 0.79 (dt, J = 14.5, 2.5 Hz, 1 H, 6-Hax), 0.81
(d, J = 6.5 Hz, 3 H, 9-Meeq), 0.95 (s, 3 H, 7-Meeq), 1.00 (s, 3 H, 1-
Me), 1.22 (s, 3 H, 7-Meax), 1.35 (mc, 1 H, 4-Hax), 1.36 (ddt, J =
12.0, 6.0, 2.5 Hz, 1 H, 8-Heq), 1.50 (dt, J = 14.5, 2.5 Hz, 1 H, 6-
Heq), 1.57 (ddt, J = 12.0, 6.0, 2.5 Hz, 1 H, 10-Heq), 1.62 (dd, J =
20.0, 3.0 Hz, 1 H, 3-Heq), 2.27 (dd, J = 20.0, 9.5 Hz, 1 H, 3-Hax),
2.34 (mc, 1 H, 9-H), 2.90 (s, 1 H, O-H) ppm. 1H,1H NOESY: 1-
Me×4-Me, 1-Me×6-Heq, 4-Me×6-Hax, 4-Me×6-Heq, 7-Meax ×9-
Hax. 13C NMR (C6D6): δ = 18.4 (q, 4-Me), 23.6 (q, 9-Me), 24.1 (q,
1-Me), 26.4 (d, C-9), 26.5 (q, 7-Meax), 31.6 (s, C-7), 35.2 (q, 7-
Meeq), 39.6 (t, C-3), 40.6 (d, C-4), 42.0 (t, C-6), 46.0 (s, C-5), 47.8
(t, C-10), 49.2 (t, C-8), 81.3 (s, C-1), 221.2 (s, C-2) ppm. MS
6,6,8,10-Tetramethyl-1-oxadispiro[2.0.5.3]dodecan-12-one (13): At
0 °C, a solution of 4,7,7,9-tetramethyl-1-methylenespiro[4.5]decan-
2-one (1.43 g, 6.49 mmol), prepared according to ref.[15] in CH2Cl2
(10 mL), was added dropwise within 45 min to a stirred solution of
3-chloroperbenzoic acid (70%, 1.76 g, 7.14 mmol) in CH2Cl2
(20 mL). After further stirring at 0 °C for 1 h, the cooling bath was
removed, and the reaction mixture was stirred for 3 d, two ad-
ditional portions of 3-chloroperbenzoic acid (70%, 1.76 g,
7.14 mmol) being added after the first and the second day. The
insoluble material was removed by vacuum filtration and washed
with CH2Cl2. The combined organic solutions were washed with
aq. NaHSO3 (20%), half-saturated NaHCO3, and water (50 mL);
the aqueous washings were again extracted with CH2Cl2 (50 mL).
The combined organic extracts were dried (Na2SO4) and concen-
trated in a rotary evaporator. The residue was purified by silica-gel
FC (pentane/Et2O, 19:1, Rf = 0.11) to provide the title compound
(70 eV): m/z (%) = 238 (4) [M+], 220 (1) [M+ – H2O], 205 (1) [M+
–
H2O – CH3], 168 (4) [C11H20O+], 152 (39) [C11H20+], 137 (11)
+
[C11H20 – CH3], 123 (25) / 109 (22) / 95 (15) [CnH(2n–3)+], 83 (100)
[M+ – C9H15O2], 69 (13) [C5H9+], 55 (22) [C4H7+], 43 (36) [C3H7+].
Crystal data and structure refinement: Empirical formula
(930 mg, 61%). IR (ATR): ν = 1753 (s, νC=O), 1457 (m, δH–C– C1 5 H2 6 O2 , molecular mass 238.36, crystal dimensions
˜
1
H), 854 (m, δC–O–C, epoxide), 1196 (νC–O–C, epoxide) cm–1. H 0.5×0.4×0.01 mm, temperature 150 K, wavelength 0.71073 Å, tri-
¯
clinic crystal system, space group P1, unit cell dimensions a =
NMR (CDCl3): δ = 0.68/0.72 (2t, J = 12.5 Hz, 1 H, 7-Hax), 0.83/
0.84 (2d, J = 6.5 Hz, 3 H, 8-Me), 0.94–1.04 (m, 1 H, 9-Hax), 0.91/ 9.6129(19) Å, b = 13.368(3) Å, c = 13.402(3) Å, α = 112.17(3)°, β
0.93 (2s, 3 H, 6-Meeq), 0.95/0.96 (2s, 3 H, 6-Meax), 1.02/1.10 (2d, J
= 6.5 Hz, 3 H, 10-Me), 1.16–1.23 (m, 1 H, 5-Hax), 1.31–1.98 (m, 5
H, 5-, 7-, 9-Heq, 8-, 10-H), 1.99/2.07 (dd, J = 18.5, 12.5 Hz, 1 H,
11-Hb), 2.46/2.76 (dd, J = 18.5, 7.0 Hz, 1 H, 11-Ha), 2.63/2.74/2.93/
2.96 (4d, J = 6.5 Hz, 2 H, 2-H2) ppm. 13C NMR (CDCl3): δ = 13.7/
17.2 (2q, 10-Me), 22.9/23.0 (2q, 8-Meax), 24.4/25.2 (2d, C-8), 26.0/
= 104.57(3)°, γ = 103.52(3)°, V = 1436.1(5) Å3, Z = 4, ρ =
1.102 Mg·m–3, μ(Mo-Kα) = 0.071 mm–1, F(000) 528, θ range 2.35–
26.00°, limiting indices –11 Յ h Յ 11, –16 Յ k Յ 16, –15 Յ l Յ 16,
total reflections collected 10964, symmetry-independent reflections
5162, Rint = 0.0283, refinement full-matrix least-squares on F2, data
5162, parameters 319, goodness-of-fit on F2 0.877, final R indices
26.1 (2q, 6-Meeq), 31.1/34.9 (2s, C-6), 35.0/35.0 (2q, 6-Meax), 35.4/ [I Ͼ 2σ(I)], R1 = 0.0392, wR2 = 0.0861, R indices (all data) R1 =
40.7 (2t, C-11), 36.7/40.9 (2d, C-10), 41.2/41.6 (2s, C-4), 41.8/42.3/ 0.0711, wR2 = 0.0945, Δρ (max, min) = 0.265, –0.124 e Å–3. CCDC
Eur. J. Org. Chem. 2005, 3233–3245
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3239

P. Kraft, W. Eichenberger, D. Frech
FULL PAPER
256512. C15H26O2 (238.4): calcd. C 75.58, H 10.99; found C 75.56,
H 10.99. Odor: Strong, powerful and characteristic of natural pa-
tchouli oil, with rich woody–ambery and tobacco-like facets. Odor
threshold: 0.067 ng/L air.
H) cm–1. 1H NMR (CDCl3): δ = 0.60 (d, J = 15.0 Hz, 1 H, 11-
Hax), 0.92/0.96 (2s, 6 H, 6-,8-Meax), 1.00 (d, J = 14.0 Hz, 1 H, 5-
Hax), 1.08 (d, J = 7.0 Hz, 3 H, 10-Me), 1.10 (d, J = 14.0 Hz, 1 H,
7-Hax), 1.14/1.17 (2s, 6 H, 6-,8-Meeq), 1.34 (dt, J = 14.0, 1.5 Hz, 1
H, 7-Heq), 1.59 (dt, J = 15.0, 1.5 Hz, 1 H, 11-Heq), 1.69 (dt, J =
14.0, 1.5 Hz, 1 H, 5-Heq), 2.11 (dd, J = 18.5, 2.0, 1 H, 9-Hax), 2.70
(d, J = 5.5 Hz, 1 H, 2-Hb), 2.77 (dd, J = 18.5, 7.0, 1 H, 9-Heq),
2.84 (quint. d, J = 7.0, 2.0 Hz, 1 H, 10-H), 3.00 (d, J = 5.5 Hz, 1
H, 2-Ha) ppm. 13C NMR (CDCl3): δ = 17.8 (q, 10-Me), 29.7 (2q,
6-,8-Meeq), 30.7/31.5 (2s, C-6,-8), 35.3 (d, C-10), 35.7 (2q, 6-,8-
Meax), 36.5 (t, C-11), 42.6 (s, C-4), 43.4/45.1 (2t, C-5,-9), 47.1 (t,
C-2), 51.7 (t, C-7), 66.7 (s, C-3), 215.1 (s, C-12) ppm. MS (70 eV):
m/z (%) = 250 (2) [M+], 234 (11) [M+ – O], 219 (100) [M+ – O –
CH3], 208 (6) [M+ – C3H6], 205 (7) [M+ – O – C2H5], 193 (29)
[M+ – O – C3H5], 164 (22) [C11H16O+], 149 (52) [C11H16O+ – CH3],
121 (50) [C11H16O+ – C3H7], 91 (54) [C7H7+], 79 (50) [C6H7+], 55
(48) [C4H7+], 41 (60) [C3H5+].
(1R*,4R*,5S*,9R*)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]de-
can-2-one (16): A solution of Dess–Martin periodinane (780 mg,
1.84 mmol) in CH2Cl2 (20 mL) was added in one dash to a stirred
solution of 1,4,7,7,9-pentamethylspiro[4.5]decan-1,2-diol (14,
400 mg, 1.66 mmol) in CH2Cl2 (15 mL). Stirring was continued at
room temp. for 6 h prior to quenching by dropwise addition of a
solution of Na2S2O3 (950 mg, 6.00 mmol) in satd. aq. NaHCO3
(40 mL). After stirring for 30 min, water (50 mL) was added, the
organic layer was separated, and the aqueous one extracted with
CH2Cl2 (50 mL). The combined organic extracts were washed with
water (50 mL), dried (Na2SO4), vacuum-filtered over a pad of Ce-
lite®, and concentrated in a rotary evaporator. The resulting residue
(430 mg) was separated by repeated silica-gel FC (pentane/Et2O,
9:1, Rf = 0.48) to finally provide the weaker, less polar (1R*,2S*,4R*)-1,4,7,7,9,9-Hexamethylspiro[4.5]decane-1,2-diol
(1R*,4R*,5S*,9R*)-configured diastereoisomer of 1-hydroxy-
1,4,7,7,9-pentamethylspiro[4.5]decan-2-one 16 (60 mg, 15 %) in
(18): A solution of (3R*,10S*)-6,6,8,8,10-pentamethyl-1-oxadi-
spiro[2.0.5.3]dodecan-12-one (17, 5.65 g, 22.6 mmol) in Et2O
(10 mL) was added dropwise within 20 min to a stirred suspension
of lithium aluminum hydride (1.29 g, 33.8 mmol) in Et2O (25 mL).
The reaction mixture was refluxed for 3 h, and then stirred at room
temp. overnight, prior to being quenched at 0 °C by addition of
water (20 mL), followed by aq. HCl (5 n, 20 mL). The organic layer
was separated, and the aqueous one extracted with Et2O
(2 × 50 mL). The combined organic extracts were washed with
pure form as colorless crystals, mp. 72–73 °C. IR (ATR): ν = 1743
˜
(s, νC=O), 1106/1081 (s, νC–O), 3470 (s, νO–H), 1385 (m,
1
δCH3) cm–1. H NMR (CDCl3): δ = 0.64 (t, J = 12.0 Hz, 1 H, 8-
Hax), 0.72 (t, J = 12.5 Hz, 1 H, 10-Hax), 0.78 (d, J = 7.0 Hz, 3 H,
9-Me), 0.94 (s, 3 H, 7-Meeq), 1.00 (d, J = 6.5 Hz, 3 H, 4-Me), 1.02
(d, J = 12.5 Hz, 1 H, 10-Heq), 1.14 (s, 3 H, 3 H, 7-Meax), 1.17 (s,
3 H, 1-Me), 1.20 (d, J = 14.5 Hz, 1 H, 6-Hax), 1.35 (d, J = 12.0 Hz,
1 H, 8-Heq), 1.45 (d, J = 14.5 Hz, 1 H, 6-Heq), 1.82 (dd, J = 16.5, water (50 mL) and brine (25 mL), dried (Na2SO4), and concen-
11.0 Hz, 1 H, 3-Hb), 1.87 (mc, 1 H, 4 H), 2.16 (mc, 1 H, 9-H), 2.54 trated in a rotary evaporator. The resulting residue was purified by
(dd, J = 16.5, 6.5 Hz, 1 H, 3-Ha), 2.84 (s, 1 H, OH) ppm. 1H,1H
NOESY: 1-Me×4-H, 1-Me×7-Meax, 1-OH×7-Meax, 1-OH×9-
Hax, 7-Meax ×9-Hax. 13C NMR (CDCl3): δ = 14.5 (q, 4-Me), 21.4
(q, 1-Me), 23.3 (q, 9-Me), 25.3 (d, C-9), 26.3 (q, 7-Meax), 31.2 (s,
silica-gel FC (pentane/Et2O, 4:1, Rf = 0.10) to provide 18 (4.82 g,
84%). IR (ATR): ν = 1098/1075 (s, νC–O), 1366 (m, δCH ), 3411
˜
3
(m, νO–H) cm–1
.
1H NMR (C6D6): δ = 0.91/0.97 (s, 6 H, 7-,9-
Meax), 0.93 (mc, 2 H, 6-H2), 0.94 (s, 3 H, 1-Me), 1.02 (d, 13.0 Hz,
C-7), 34.8 (q, 7-Meeq), 34.8 (t, C-10), 35.8 (d, C-4), 38.5 (t, C-3), 1 H, 8-Hax), 1.03/1.07 (s, 6 H, 7-,9-Meax), 1.09 (d, J = 15.0 Hz, 1
40.9 (t, C-6), 47.0 (s, C-5), 49.0 (t, C-8), 83.9 (s, C-1), 221.6 (s, C-
H, 10-Hax), 1.17 (d, J = 13.0 Hz, 1 H, 8-Heq), 1.19 (ddd, J = 14.0,
6.0, 4.5 Hz, 1 H, 3-Hb), 1.24 (d, J = 7.5 Hz, 3 H, 4-Me), 1.44 (d, J
2) ppm. MS (70 eV): m/z (%) = 238 (7) [M+], 220 (1) [M+ – H2O],
205 (1) [M+ – H2O – CH3], 168 (2) [C11H20O+], 152 (40) [C11H20+], = 6.5 Hz, 1 H, 2-OH), 1.78 (d, J = 15.0 Hz, 1 H, 10-Heq), 1.81 (s,
137 (12) [C11H20+ – CH3], 123 (26) / 109 (22) / 95 (15) [CnH(2n–3)+], 1 H, 1-OH), 2.11 (mc, 1 H, 4-H), 2.31 (dt, J = 14.0, 9.0 Hz, 1 H,
83 (100) [M+ – C9H15O2], 67 (12) [C5H7+], 55 (24) [C4H7+], 43 (37) 3-Ha), 3.59 (dt, J = 9.0, 6.5 Hz, 1 H, 2-H) ppm. 1H,1H NOESY:
[C3H7+]. Odor: Nice, pleasant and characteristic of natural pa-
tchouli oil, but weaker than the (1R*,4S*,5S*,9R*)-isomer. Odor
threshold: 18 ng/L air.
1-OH×10-Hax, 1-OH×4-Me, 4-Me×10-Heq, 1-Me×2-H, 2-H×6-
Heq, 1-OH×3-Hb, 3-Ha ×6-Heq, 6-Heq ×4-H. 13C NMR (C6D6): δ
= 21.4 (q, 4-Me), 21.7 (q, 1-Me), 30.2/30.6 (2q, 7-,9-Meax), 36.3/
43.5 (2t, C-6,-10), 36.6/37.0 (2q, 7-,9-Meeq), 38.3 (d, C-4), 40.7 (t,
C-3), 49.7 (s, C-5), 51.8 (t, C-8), 77.0 (d, C-2), 84.0 (s, C-1) ppm.
MS (70 eV): m/z (%) = 254 (32) [M+], 236 (2) [M+ – H2O], 221 (8)
[M+ – H2O – CH3], 203 (11) [M+ – 2H2O – CH3], 191 (22)
(3R*,10S*)-6,6,8,8,10-Pentamethyl-1-oxadispiro[2.0.5.3]dodecan-
12-one (17): A solution of 4,7,7,9,9-pentamethyl-1-methylene-
spiro[4.5]decan-2-one[15] (19.0 g, 81.1 mmol) in CH2Cl2 (250 mL)
was added dropwise at 0 °C during 2 h to a stirred solution of 3-
chloroperbenzoic acid (70 %, 40.0 g, 162 mmol) in CH2Cl2
(500 mL). The cooling bath was removed after stirring for 2 h at
0 °C, and the stirring was continued for 5 d at room temp., two
additional portions of 3-chloroperbenzoic acid (70 %, 40.0 g,
162 mmol) being added after the second and fourth day. The reac-
tion mixture was then vacuum filtered through a pad of Celite®,
and poured into ice-cold aq. NaHSO3 (20%, 1 L). The precipitate
formed was removed by vacuum filtration through Celite® and
washed thoroughly with CH2Cl2. Water (200 mL) was added to the
filtrate and the pH was adjusted to 8 by addition of satd. aq.
Na2CO3 (ca. 200 mL). The organic layer was separated and washed
+
[C14H23+], 166 (46) [C12H22+], 151 (28) [C12H22 – CH3], 137 (54) /
123 (39) / 109 (61) [CnH(2n–3)+], 97 (90) [C7H13+], 87 (31) [C4H7O2+],
69 (63) [C5H9+], 55 (68) [C4H7+], 43 (100) [C3H7+].
(1R*,4R*)-1-Hydroxy-1,4,7,7,9,9-hexamethylspiro[4.5]decan-2-one
(19): With rigorous exclusion of moisture, a solution of dimethyl
sulfoxide (340 mg, 4.40 mmol) in CH2Cl2 (1 mL) was injected with
a syringe at –70 °C within 5 min into a stirred oxalyl chloride solu-
tion in CH2Cl2 (2 m, 1.10 mL, 2.20 mmol) diluted with CH2Cl2
(5 mL). After stirring at this temp. for 5 min, (1R*,2S*,4R*)-
1,4,7,7,9,9-hexamethylspiro[4.5]decan-1,2-diol (510 mg,
2.00 mmol) dissolved in CH2Cl2 (1 mL) was injected during 5 min
with water (500 mL), the aqueous layer was extracted with CH2Cl2 dropwise with a syringe. Stirring was continued at –70 °C for
(500 mL). The combined organic extracts were dried (Na2SO4), and
the solvent was removed in a rotary evaporator. The resulting resi-
due (18.8 g) was purified by silica-gel FC (pentane/Et2O, 19:1, Rf
30 min, prior to injection of Et3N (1.01 g, 10.0 mmol). The cooling
bath was removed, and the reaction mixture was allowed to warm
to room temp., prior to being poured into water (50 mL). The or-
= 0.11) to provide 17 (5.89 g, 29%). IR (ATR): ν = 1751 (s, νC=O), ganic layer was separated, and the aqueous one extracted with
˜
1367 (s, δCH3), 852 (m, δC–O–C, epoxide), 1458 (m, δH–C–
CH2Cl2 (2×50 mL). The combined organic extracts were washed
3240
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3233–3245

From Vetiver to Patchouli: A New High-Impact Spirocyclic Patchouli Odorant
FULL PAPER
with water (50 mL), dried (Na2SO4), and concentrated in a rotary
evaporator. Purification of the resulting residue by two silica-gel
(70 eV): m/z (%) = 226 (13) [M+], 208 (5) [M+ – H2O], 193 (2) [M+ –
H2O – CH3], 175 (3) [M+ – 2H2O – CH3], 150 (10) [M+ – 2H2O –
FC (pentane/Et2O, 19:1, Rf = 0.17) furnished 19 (330 mg, 65%). 2CH3], 138 (47) [C10H18+], 109 (100) [C8H13+], 95 (37) [C7H11+], 81
IR (ATR): ν = 1741 (s, νC=O), 1362/1381 (m, δCH ), 1066/1164/ (37) [C6H9+], 55 (48) [C4H7+], 43 (61) [C3H7+].
˜
3
1128 (s, νC–O), 3468 (s, νO–H) cm–1. 1H NMR (CDCl3): δ = 0.96–
(1R*,4S*,5r*,7R*,9S*)-1-Hydroxy-1,4,7,9-tetramethylspiro[4.5]de-
1.18 (m, 3 H, 8-Hax,10-H2), 0.91/0.99 (2s, 6 H, 7-,9-Meeq), 1.02/
1.11 (2s, 6 H, 7-,9-Meax), 1.07 (d, J = 6.5 Hz, 3 H, 4-Me), 1.21 (s,
3 H, 1-Me), 1.33 (d, J = 13.0 Hz, 1 H, 8-Heq), 1.35 (d, J = 14.5 Hz,
1 H, 6-Hax), 1.55 (d, J = 14.5 Hz, 1 H, 6-Heq), 1.82 (dd, J = 19.5,
10.0 Hz, 1 H, 3-Hb), 2.04 (mc, 1 H, 4-H), 2.48 (dd, J = 19.5, 9.0 Hz,
1 H, 3-Ha), 2.86 (s, 1 H, OH) ppm. 13C NMR (CDCl3): δ = 14.7
(q, 4-Me), 20.3 (q, 1-Me), 29.6/31.1 (2s, C-7,-9), 31.6/32.7/34.1/34.4
(4q, 7-,9-Me2), 33.6/37.5/38.8 (3t, C-3,-6,-10), 35.8 (d, C-4), 47.6 (s,
C-5), 49.2 (t, C-8), 83.9 (s, C-1), 220.6 (s, C-2) ppm. MS (70 eV):
m/z (%) = 252 (7) [M+], 237 (1) [M+ – CH3], 219 (1) [M+ – CH3 –
H2O], 191 (3) [C14H23+], 182 (4) [C12H22O+], 166 (66) [C12H22+],
151 (39) [C12H22+ – CH3], 137 (40) / 123 (23) / 109 (37) [CnH(2n–3)+],
97 (100) [C7H13+], 55 (41) [C4H7+], 43 (72) [C3H7+]. C16H28O2
(252.4): calcd. C 76.14, H 11.18; found C 76.18, H 11.13. Odor:
Woody, patchouli. Odor threshold: 51 ng/L air.
can-2-one (22): With rigorous exclusion of moisture, a solution of
dimethyl sulfoxide (680 mg, 8.80 mmol) in CH2Cl2 (2 mL) was in-
jected at –75 °C within 5 min into a stirred oxalyl chloride solution
in CH2Cl2 (2 m, 2.20 mL, 4.40 mmol) diluted with CH2Cl2 (10 mL).
After being stirred at this temperature for 5 min, (4R*,5r*,
7R*,9S*)-1,4,7,9-tetramethylspiro[4.5]decan-1,2-diol (21, 910 mg,
4.00 mmol) dissolved in CH2Cl2 (2 mL) was injected dropwise dur-
ing 5 min with a syringe. Stirring was continued at –70 °C for
15 min, prior to quenching with Et3N (2.02 g, 20.0 mmol). The re-
action mixture was allowed to warm to room temp. and poured
into water (50 mL). The organic layer was separated, and the aque-
ous one extracted with CH2Cl2 (2×50 mL). The combined organic
extracts were washed with water (50 mL) and dried (Na2SO4). After
removal of the solvent in a rotary evaporator, the resulting residue
was purified by silica-gel FC (pentane/Et2O, 9:1, Rf = 0.12) to pro-
6,8,10-Trimethyl-1-oxadispiro[2.0.5.3]dodecan-12-one (20): As de-
vide 22 (530 mg, 59%). IR (ATR): ν = 1732 (s, νC=O), 3428 (s,
˜
scribed above for the preparation of (3R*,10S*)-6,6,8,8,10-penta- νO–H), 1063/1089 (s, νC–O), 1359 (m, δCH3) cm–1
.
1H NMR
methyl-1-oxadispiro[2.0.5.3]dodecan-12-one (17), (5r*,7R*,9S*)-
4,7,9-trimethyl-1-methylenespiro[4.5]decan-2-one[15] (5.21 g,
25.3 mmol) was treated with 70 % 3-chloroperbenzoic acid
(2×8.72 g, 2×50.5 mmol) in CH2Cl2 (75 mL + 150 mL) at room
temp. for 4 d. Work-up with aq. NaHSO3 (20%, 200 mL) and puri-
fication by silica-gel FC (pentane/Et2O, 9:1, Rf = 0.22) provided 20
(CDCl3): δ = 0.46 (pseudo q, J = 12.0 Hz, 1 H, 8-Hax), 0.74 (dq, J
= 13.5, 12.5 Hz, 1 H, 6-Hax), 0.83/0.88 (2d, J = 6.5 Hz, 6 H, 7-,9-
Me), 0.91 (dd, J = 13.5, 13.5 Hz, 1 H, 10-Hax), 1.05 (d, J = 7.5 Hz,
3 H, 4-Me), 1.29 (s, 3 H, 1-Me), 1.41 (dq, 13.5, 2.0 Hz, 1 H, 10-
Heq), 1.67 (mc, 1 H, 9-Hax), 1.69 (dq, 12.0, 2.0 Hz, 1 H, 8-Heq),
1.82 (dq, J = 11.5, 2.0 Hz, 1 H, 6-Heq), 1.91 (mc, 1 H, 7-Hax), 1.96
(2.12 g, 38%). IR (ATR): ν = 1751 (s, νC=O), 1456 (s, δH–C–H), (dd, J = 19.0, 8.0 Hz, 1 H, 3-Hb), 2.09 (ddq, J = 7.5, 7.5, 7.5 Hz,
˜
865 (m, δC–O–C, epoxide), 1367 (m, δCH3) cm–1
.
1H NMR 1 H, 4-H), 2.26 (s, 1 H, O-H), 2.57 (dd, J = 19.0, 9.0 Hz, 1 H, 3-
1
(CDCl3): δ = 0.41/0.44 (2 pseudo q, J = 12.5 Hz, 1 H, 11-Hax),
Ha) ppm. H,1H NOESY: 1-Me×4-Me, 1-Me×10-Hax, 1-Me×10-
0.83/0.85/0.86/0.87 (4d, J = 9.0, 6 H, 6-,8-Me), 0.90–2.13 (m, 8 H, Heq, 1-Me×9-Hax, 4-H×6-Hax. 13C NMR (CDCl3): δ = 15.8 (q, 4-
6-,8-,9-Hax, 5-,7-H2, 11-Heq), 1.04/1.09 (2d, J = 7.0 Hz, 3 H, 10- Me), 22.7 (q, 1-Me), 23.2/23.3 (2q, 7-,9-Me), 28.4 (d, C-9), 29.0 (d,
Me), 2.70/2.74 (2dd, J = 18.5, 9.0 Hz, 1 H, 9-Heq), 2.77–2.95 (m, 1 C-7), 35.8 (t, C-10), 37.4 (d, C-4), 40.5 (t, C-3), 41.1 (t, C-6), 43.8
H, 10-H), 2.82/2.82 (2d, J = 6.5 Hz, 1 H, 2-Hb), 2.96/2.97 (2d, J =
6.5 Hz, 1 H, 2-Ha) ppm. 13C NMR (CDCl3): δ = 13.8/16.9 (q, 10-
Me), 22.8/22.9/22.9/23.0 (4q, 6-,8-Me), 27.4/27.5/27.6/28.3 (4d, C-
(t, C-8), 46.7 (s, C-5), 81.2 (s, C-1), 219.6 (s, C-2) ppm. MS (70 eV):
m/z (%) = 224 (14) [M+], 206 (3) [M+ – H2O], 191 (2) [M+ – H2O –
CH3], 154 (12) [C10H18O+], 138 (60) [C10H18+], 123 (19) / 109 (100) /
6,-8), 35.5/38.6/40.7/41.0/42.2/43.2 (6t, C-5,-9,-11), 43.5/43.7 (2t, C- 95 (27) [CnH(2n–3)+], 81 (29) [C6H9+], 69 (21) [C5H9+], 55 (29)
7), 36.7/38.6 (d, C-10), 40.6/40.8 (2s, C-4), 48.6/49.1 (t, C-2), 66.9/
[C4H7+], 43 (51) [C3H7+]. Odor: Typical patchouli odor. Odor
69.7 (2s, C-3), 213.8/214.9 (2s, C-12) ppm. MS (70 eV): m/z (%) = threshold: 32 ng/L air.
222 (4) [M+], 207 (7) [M+ – CH3], 189 (33) [M+ – CH3 – H2O], 165
(1R*,4R*,5r*,7R*,9S*)-1-Hydroxy-1,4,7,9-tetramethylspiro[4.5]de-
(38) [C11H17O+], 149 (23) [C11H17+], 136 (39) [C10H16+], 121 (38)
[C9H13+], 107 (71) [C8H11+], 95 (71) [C7H11+], 79 (70) [C6H7+], 55
(80) [C4H7+], 41 (100) [C3H5+].
can-2-one (23): In addition to (1R*,4S*,5r*,7R*,9S*)-1-hydroxy-
1,4,7,9-tetramethylspiro[4.5]decan-2-one (22), the silica-gel FC
(pentane/Et2O, 9:1, Rf = 0.27) also furnished 23 (220 mg, 25%). IR
1,4,7,9-Tetramethylspiro[4.5]decan-1,2-diol (21): As described above
for the preparation of (1R*,2S*,4R*)-1,4,7,7,9,9-hexamethylspiro-
[4.5]decane-1,2-diol (18), 6,8,10-trimethyl-1-oxadispiro[2.0.5.3]-
dodecan-12-one (20, 2.11 g, 9.49 mmol) was reduced with lithium
aluminum hydride (530 mg, 14.2 mmol) in refluxing Et2O (5 mL +
10 mL) for 90 min. Quenching with water (10 mL) and aq. HCl
(5 n, 10 mL), usual extraction and purification by silica-gel FC
(pentane/Et2O, 2:1, Rf = 0.20) furnished 21 (1.88 g, 88 %). IR
(ATR): ν = 1744 (s, νC=O), 1095/1119 (m, νC–O), 1371 (m, δCH ),
˜
3
3487 (m, νO–H) cm–1. H NMR (CDCl3): δ = 0.41 (pseudo q, J =
1
12.0 Hz, 1 H, 8-Hax), 0.79/0.88 (2d, J = 6.5 Hz, 6 H, 7-,9-Me), 0.81
(dd, J = 13.5, 13.5 Hz, 1 H, 6-Hax), 0.98 (dd, J = 13.5, 13.5 Hz, 1
H, 10-Hax), 1.01 (d, J = 7.0 Hz, 3 H, 4-Me), 1.08 (dq, J = 15.5,
2.0 Hz, 1 H, 6-Heq), 1.17 (s, 3 H, 1-Me), 1.55 (dq, J = 13.5, 2.0 Hz,
1 H, 10-Heq), 1.68 (dq, J = 12.0, 2.0 Hz, 1 H, 8-Heq), 1.77 (mc, 1
H, 9-Hax), 1.85 (dd, J = 19.0, 11.0 Hz, 1 H, 3-Hb), 1.93 (mc, 1 H,
(ATR): ν = 1455 (s, δH–C–H), 1074/1049 (s, νC–O), 1374 (m, 4-H), 2.23 (mc, 1 H, 7-Hax), 2.53 (dd, J = 19.0, 8.5 Hz, 1 H, 3-Ha),
˜
δCH3), 3397 (m, νO–H) cm–1. 1H NMR (C6D6): δ = 0.40/0.40/0.43
2.76 (s, 1 H, 1 O-H) ppm. 1H,1H NOESY: 4-Me×3-H, 1-Me×4-
(3dd, J = 12.0, 12.0 Hz, 1 H, 10-Hb), 0.62–1.43 (m, 14 H, 3-Hb, Me, 1-Me×6-Heq, 4-Me×10-Hax. 13C NMR (CDCl3): δ = 14.3 (q,
6-,8-H2, 4-,7-,9-Me), 1.13/1.23/1.33 (3s, 3 H, 1-Me), 1.62–2.23 (m, 4-Me), 21.3 (q, 1-Me), 22.9/23.4 (2q, 7-,9-Me), 28.0 (d, C-9), 28.5
6 H, 2-OH, 4-,7-,9-H, 3-,10-Ha), 2.74 (br. s, 1 H, 1-OH), 3.95/3.97/ (d, C-7), 34.8 (t, C-6), 35.3 (d, C-4), 38.7 (t, C-10), 38.9 (t, C-3),
3.60 (3dd, J = 8.0, 6.0 Hz, 1 H, 2-H) ppm. 13C NMR (C6D6): δ =
44.1 (t, C-8), 47.1 (s, C-5), 84.5 (s, C-1), 221.1 (s, C-2) ppm. MS
14.5/15.2/15.8 (3q, 4-Me), 21.4/23.1/23.3 (3q, 1-Me), 23.4/23.4/23.5/
(70 eV): m/z (%) = 224 (15) [M+], 206 (2) [M+ – H2O], 191 (1) [M+ –
23.6/25.3/25.4 (6q, 7-,9-Me), 28.2/28.7/28.8/28.9/29.0/29.1 (6d, C- H2O – CH3], 154 (10) [C10H18O+], 138 (60) [C10H18+], 123 (19) /
7,-9), 34.9/35.1/38.4/38.6/38.8/39.1 (6t, C-6,-10), 39.2/39.9/40.3 (3d,
C-4), 41.3/43.5/43.9/44.1/44.4/65.8 (6t, C-3,-8), 46.7/47.5/49.0 (3s,
109 (100) / 95 (26) [CnH(2n–3)+], 81 (29) [C6H9+], 67 (22) [C5H7+],
55 (28) [C4H7+], 43 (53) [C3H7+]. Odor: Patchouli-like, woody odor.
C-5), 77.4/77.5/79.1 (3d, C-2), 81.3/81.8/84.0 (3s, C-1) ppm. MS Odor threshold: 335 ng/L air.
Eur. J. Org. Chem. 2005, 3233–3245
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3241

P. Kraft, W. Eichenberger, D. Frech
FULL PAPER
(3R*,11R*)-11-Methyl-1-oxadispiro[2.0.6.3]tridecan-13-one (24): As
described above for the preparation of (3R*,10S*)-6,6,8,8,10-
pentamethyl-1-oxadispiro[2.0.5.3]dodecan-12-one (17), 4-methyl-1-
methylenespiro[4.6]undecan-2-one[15] (5.29 g, 27.5 mmol) was
treated with 3-chloroperbenzoic acid (70%, 13.6 g, 55.0 mmol) in
CH2Cl2 (75 mL + 150 mL) at room temp. for 4 d, three additional
portions of 3-chloroperbenzoic acid (70%, 7.00 g, 28.4 mmol) be-
ing added after every day. Work-up with aq. NaHSO3 (20 %,
250 mL) and purification by silica-gel FC (pentane/Et2O, 9:1, Rf
= 0.19) provided 24 (1.01 g, 18%), in addition to the (3R*,11S*)-
Me×3-Hb. 13C NMR (CDCl3): δ = 16.9 (q, 4-Me), 20.5 (q, 1-Me),
23.9/24.3 (2t, C-7,-10), 29.0/31.8/31.9/35.2 (4t, C-6,-8,-9,-11), 37.0
(d, C-4), 40.7 (t, C-3), 48.6 (s, C-5), 82.3 (s, C-1), 219.1 (s, C-
2) ppm. MS (70 eV): m/z (%) = 210 (16) [M+], 192 (3) [M+ – H2O],
177 (3) [M+ – H2O – CH3], 124 (99) [C9H16+], 109 (13) [C8H13+],
95 (100) [C7H11+], 81 (66) [C6H9+], 67 (55) [C5H7+], 55 (45) [C4H7+],
43 (77) [C3H7+]. Odor: Woody, herbaceous, camphoraceous. Odor
threshold: 184 ng/L air.
3-(1Ј-Acetylcyclohex-3Ј-enyl)propionitrile (30): At 0 °C, 2-nitropro-
pane (920 mg, 10.3 mmol) was added to a stirred suspension of
AlCl3 (1.38 g, 10.3 mmol) in CH2Cl2 (10 mL). Next, a solution of
4-methylene-5-oxohexanenitrile[18] (28, 12.8 g, 104 mmol) in
CH2Cl2 (10 mL) was added dropwise at this temp., and after stir-
ring for 5 min butadiene (29, 11.3 g, 209 mmol) was introduced.
The cooling bath was removed, and stirring was continued at room
temp. for 16 h prior to pouring the reaction mixture into water
(500 mL). The organic layer was separated, and the aqueous one
extracted with Et2O (2×500 mL). The combined organic extracts
were dried (Na2SO4) and concentrated in a rotary evaporator. Kug-
elrohr distillation at 150 °C/0.1 mbar provided 30 (14.9 g, 81%) as
diastereomer (R = 0.14, 820 mg, 14%). IR (ATR): ν = 1749 (s,
˜
f
νC=O), 1460 (s, δH–C–H), 830 (m, δC–O–C, epoxide), 1381 (m,
1
δCH3) cm–1. H NMR (CDCl3): δ = 1.05 (d, J = 7.0 Hz, 3 H, 11-
Me), 1.35–1.66 (m, 12 H, 5-H2–10-H2), 1.99 (dd, J = 19.0, 3.0 Hz,
1 H, 12-Hb), 2.37 (dqd, J = 7.5, 7.0, 3.0 Hz, 1 H, 11-H), 2.63 (dd,
J = 19.0, 7.5 Hz, 1 H, 12-Ha), 2.93 (d, J = 6.5 Hz, 1 H, 2-Hb), 2.98
(d, J = 6.5 Hz, 1 H, 2-Ha) ppm. 13C NMR (CDCl3): δ = 17.5 (q,
11-Me), 22.7/23.0 (2t, C-6,-9), 30.1/30.6/31.2/35.8 (4t, C-5,-7,-8,
-10), 35.5 (d, C-11), 43.1 (s, C-4), 51.6 (t, C-2), 67.5 (s, C-3), 215.3
(s, C-13) ppm. MS (70 eV): m/z (%) = 208 (2) [M+], 192 (10)
[C13H20O+], 177 (9) [C13H20O+ – CH3], 164 (17) [C13H20O+ – CO],
a colorless oil. IR (ATR): ν = 1698 (s, νC=O), 653 (s, νH–C=C–H
˜
+
+
150 (24) [C11H18+], 135 (17) [C11H18 – CH3], 122 (51) [C11H18
–
oop), 1362 (m, δCH3), 1439 (m, δH–C–H), 2247 (m, νCN) cm–1.
1H NMR (CDCl3): δ = 1.65 (dt, J = 13.0, 6.5 Hz, 1 H, 6Ј-Hax),
1.89–2.07 (m, 6 H, 3-H2, 2Ј-Hax, 5Ј-H2, 6Ј-Heq), 2.18 (s, 3 H, 2ЈЈ-
H3), 2.20–2.24 (m, 2 H, 2-H2), 2.46 (d, J = 17.0 Hz, 1 H, 2Ј-Heq),
5.67 (pseudo t, J = 12.5 Hz, 2 H, 3Ј-,4Ј-H) ppm. 13C NMR
(CDCl3): δ = 12.4 (t, C-2), 22.2 (t, C-5Ј), 25.2 (q, C-2ЈЈ), 28.3 (t,
C-3), 31.6/31.7 (2t, C-2Ј,-6Ј), 49.3 (s, C-1Ј), 119.5 (s, C-1), 124.0/
126.6 (2d, C-3Ј,-4Ј), 211.5 (s, C-1ЈЈ) ppm. MS (70 eV): m/z (%) =
C2H4], 107 (46) [C8H11+], 93 (65) [C7H9+], 79 (100) [C6H7+], 67 (41)
[C5H7+], 41 (50) [C3H5+].
(1R*,2R*,4S*)-/(1R*,2S*,4S*)-1,4-Dimethylspiro[4.6]undecane-1,2-
diol (25): As described above for the preparation of (1R*,2S*,4R*)-
1,4,7,7,9,9-hexamethylspiro[4.5]decane-1,2-diol (18), (3R*,11S*)-
11-methyl-1-oxadispiro[2.0.6.3]tridecan-13-one (24, 800 mg,
3.84 mmol) was reduced with lithium aluminum hydride (440 mg,
11.5 mmol) in Et2O (2 mL + 4 mL) at ambient temp. for 16 h.
Quenching with water (5 mL) and aq. HCl (5 n, 5 mL), usual ex-
traction and purification by silica-gel FC (pentane/Et2O, 2:1, Rf =
177 (1) [M+], 176 (2) [M+ – H], 162 (2) [M+ – CH3], 148 (2) [M+
–
C2H5], 134 (57) [M+ – C3H7], 123 (15) [C7H9ON+], 93 (35) [C7H9+],
77 (15) [C6H5+], 54 (10) [C4H6+], 43 (100) [C3H7+].
0.16) furnished 25 (620 mg, 76%). IR (ATR): ν = 1076/1049 (s, νC–
˜
1-Hydroxy-1-methylspiro[4.5]dec-7-en-2-one (31): At ambient temp.,
a solution of iPrMgCl (17.0 g, 165 mmol) in Et2O (330 mL) was
added dropwise to a stirred solution of Cp2TiCl2 (37.3 g, 150
mmol) in MePh (300 mL). The reaction mixture was stirred for
30 min at this temp., and a solution of PhMgBr (30.0 g, 165 mmol)
in Et2O (300 mL) was then added within 5 min to the resulting
green solution. After the mixture was stirred at room temp. for
further 30 min, 30 (8.85 g, 49.9 mmol) was added with stirring to
the dark-green Cp2TiPh solution obtained. Stirring was continued
at room temp. for 16 h prior to quenching by addition of aq. HCl
(2 n, 500 mL). The resulting precipitate was filtered off, and the
organic layer of the filtrate separated. The aqueous layer of the
filtrate was extracted with Et2O (1 L), and the combined organic
extracts were washed with brine (500 mL), dried (Na2SO4), and
concentrated in vacuo. Silica-gel FC (pentane/Et2O, 5:1, Rf = 0.33)
O), 1455/1474/1444 (s, δH–C–H), 1377 (m, δCH3), 3388 (m, νO–
1
H) cm–1. H NMR (C6D6): δ = 0.84/0.91 (2d, J = 7.0 Hz, 3 H, 4-
Me), 1.06/1.09 (2s, 3 H, 1-Me), 1.07–2.15 (m, 16 H, 1-,2-OH, 3-H2,
6-H2–11-H2), 1.94/2.29 (2mc, 1 H, 4-H), 3.58 (dt, J = 10.0, 5.0 Hz)/
3.60 (t, J = 7.0 Hz, 1 H, 2-H) ppm. 13C NMR (C6D6): δ = 15.7/
16.3 (2q, 4-Me), 20.1/21.2 (2q, 1-Me), 24.8/25.0/25.1/25.2 (4t, C-7,-
10), 29.1/30.0/32.5/32.8/32.9/33.0/33.2/35.7 (8t, C-6,-8,-9,-11), 39.5/
40.5 (2t, C-3), 41.0/41.3 (2d, C-4), 50.0/51.4 (2s, C-5), 75.9/79.8 (2d,
C-2), 82.9/84.9 (2s, C-1) ppm. MS (70 eV): m/z (%) = 212 (12) [M+],
194 (4) [M+ – H2O], 192 (2) [M+ – H2O – H2], 179 (4) [M+ – H2O –
CH3], 167 (5) [M+ – C2H5O], 149 (22) [C11H17+], 136 (17)
+
[C10H16+], 124 (92) [C9H16+], 109 (20) [C9H16 – CH3], 107 (28)
+
[C10H16 – C2H5], 95 (100) [C7H11+], 87 (36) [C4H7O2+], 81 (96)
[C6H9+], 74 (49) [C3H6O2+], 67 (79) [C5H7+], 55 (92) [C4H7+], 43
(100) [C3H7+].
of the resulting residue provided 31 (600 mg, 7%). IR (ATR): ν =
˜
(1R*,4S*)-1-Hydroxy-1,4-dimethylspiro[4.6]undecan-2-one (26): As
described above for the preparation of (1R*,4S*,5S*,9R*)-1-hy-
droxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (15),
(1R*,2R*,4S*)-/(1R*,2S*,4S*)-1,4-dimethylspiro[4.6]undecane-
1,2-diol (25, 570 mg, 2.69 mmol) was oxidized with pyridinium
chlorochromate (630 mg, 2.95 mmol) on Celite® (630 mg) in
CH2Cl2 (10 + 12 mL) at room temp. for 12 h. Standard work-up
by vacuum filtration through a pad of Celite® furnished after puri-
fication by silica-gel FC (pentane/Et2O, 9:1, Rf = 0.10) 26 (21 mg,
1739 (s, νC=O), 1154/1031 (s, νC–O), 3441 (s, νO–H), 1369 (m,
δCH3) cm–1 1H NMR (CDCl3): δ = 1.15–2.43 (m, 11 H, 3-,4-,
.
6-,9-,10-H2, OH), 1.18 (s, 3 H, 1-Me), 5.61–5.68 (m, 2 H, 7-,8-
H) ppm. 13C NMR (CDCl3): δ = 19.1/19.2 (2q, 1-Me), 22.3/22.4
(2t, C-4), 24.1/25.7/26.5/26.6 (4t, C-9,-10), 29.1/30.6/30.9/31.5 (4t,
C-3,-6), 42.2/42.6 (2s, C-5), 81.6/81.7 (2s, C-1), 124.8/125.0/126.2/
126.3 (4d, C-7,-8), 220.5/220.7 (2s, C-2) ppm. MS (70 eV): m/z (%)
= 180 (7) [M+], 162 (6) [M+ – H2O], 152 (3) [M+ – CO], 147 (4)
[M+ – H2O – CH3], 144 (6) [M+ – 2H2O], 134 (9) [C10H14+], 124
(52) [C9H16+], 94 (52) [C7H10+], 79 (100) [C6H7+], 43 (76) [C3H7+].
C11H16O2 (180.3): calcd. C 73.30, H 8.95; found C 73.30, H 8.94.
Odor: Weak, citrusy, fruity.
4%). IR (ATR): ν = 1733 (s, νC=O), 1100/1059 (s, νC–O), 3429 (s,
˜
1
νO–H), 1382 (m, δCH3) cm–1. H NMR (CDCl3): δ = 1.14 (d, J =
7.0 Hz, 3 H, 4-Me), 1.24 (s, 3 H, 1-Me), 1.26–1.65 (m, 12 H, 6-H2–
11-H2), 1.93 (dd, J = 19.5, 8.0 Hz, 1 H, 3-Hb), 2.08 (s, 1 H, O-H),
2.32 (ddq, J = 9.5, 8.0, 7.0 Hz, 1 H, 4-H), 2.54 (dd, J = 19.5, 9.5 Hz,
1-Hydroxy-1-methylspiro[4.5]decan-2-one (32): A suspension of 31
1 H, 3-Ha) ppm. 1H,1H NOESY: 1-Me ×4-Me, 3-Hb ×4-Me, 1- (85 mg, 0.47 mmol) and Pd/C (10%, 25 mg, 0.024 mmol) in EtOAc
3242
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3233–3245

From Vetiver to Patchouli: A New High-Impact Spirocyclic Patchouli Odorant
FULL PAPER
(1 mL) was evacuated and flushed with N2 three times. After evacu-
ating and flushing with H2 three times, the reaction mixture was
stirred under H2 for 3 d. The catalyst was removed by vacuum fil-
tration through a small pad of silica gel, washed with EtOAc
(3×5 mL), and the combined organic filtrates were concentrated
under reduced pressure. The resulting amorphous residue was crys-
tallized from pentane to afford 32 (60 mg, 70%) as colorless crys-
with N2 three times, and then evacuated and flushed with H2 three
times. After being stirred for 1 d at ambient temp. under a positive
pressure of H2, the catalyst was removed by vacuum filtration
through a small pad of Celite®, and rinsed with EtOAc (3×5 mL).
The organic filtrates were combined, the solvent was evaporated in
a rotary evaporator, and the resulting residue purified by silica-
gel FC (pentane/Et2O, 100:1) to provide the two stereoisomers 33
(100 mg, 33%) and 34 (100 mg, 33%) in pure form.
tals with only very faint odor. IR (ATR): ν = 1739 (s, νC=O), 3455
˜
(s, νO–H), 1127/1140 (s, νC–O), 1369 (m, δCH3) cm–1. 1H NMR
(CDCl3): δ = 1.14 (s, 3 H, 1-Me), 1.15–1.68 (m, 11 H, 6-H2–10-H2,
OH), 2.13–2.36 (m, 4 H, 3-,4-H2) ppm. 13C NMR (CDCl3): δ =
19.4 (q, 1-Me), 21.9/22.1 (2t, C-4,-9), 25.5/26.0 (2t, C-7,-10), 28.0
(t, C-8), 30.6/31.2 (2t, C-3,-6), 44.0 (s, C-5), 81.7 (s, C-1), 220.8 (s,
pseudo-(5s,8s)-1-Hydroxy-1,8-dimethylspiro[4.5]decan-2-one (33):
IR (ATR): ν = 1742 (s, νC=O), 1093/1122/1055 (s, νC–O), 3476 (m,
˜
1
νO–H), 1366 (m, δCH3) cm–1. H NMR (CDCl3): δ = 0.93 (d, J =
7.0 Hz, 3 H, 8-Me), 1.15 (s, 3 H, 1-Me), 1.26–1.83 (m, 10 H,
6-,7-,9-,10-H2, 4-Hb, 8-H), 2.23–2.34 (m, 4 H, 3-H2, 4-Ha,
OH) ppm. 13C NMR (CDCl3): δ = 20.0/20.5 (2q, 1-Me, 8-Meax),
29.4/29.7/30.1/30.2/30.2/30.6 (6t, C-3,-4,-6,-7,-9,-10), 29.9 (d, C-8),
43.3 (s, C-5), 82.7 (s, C-1), 221.6 (s, C-2) ppm. MS (70 eV): m/z (%)
= 196 (37) [M+], 178 (2) [M+ – H2O], 168 (6) [M+ – CO], 150 (6)
[M+ – CO – H2O], 140 (46) [C8H12O2+], 135 (14) [M+ – CO – CH3 –
H2O], 110 (48) [C8H14+], 95 (85) [C7H11+], 87 (37) [C4H7O2+], 81
(55) [C6H9+], 74 (3) [C3H6O2+], 55 (54) [C4H7+], 43 (100) [C3H7+].
Odor: Weak, floral, leathery.
C-2) ppm. MS (70 eV): m/z (%) = 182 (37) [M+], 164 (3) [M+
–
–
H2O], 154 (11) [M+ – CO], 139 (5) [M+ – CO – CH3], 136 (7) [M+
CO – H2O], 126 (46) [C7H10O2+], 121 (19) [M+ – CO – CH3 – H2O],
111 (26) [C7H10O2+ – CH3], 96 (89) [C7H12+], 87 (41) [C4H7O2+], 81
(100) [C6H9+], 43 (92) [C3H7+]. Crystal data and structure refine-
ment: Empirical formula C11H18O2, molecular mass 182.25, crystal
dimensions 0.8×0.2×0.03 mm, temperature 150 K, wavelength
¯
0.71073 Å, triclinic crystal system, space group P1, unit cell dimen-
sions a = 6.3264(13) Å, b = 10.814(2) Å, c = 15.773(3) Å, α =
3
107.04(3)°, β = 91.40(3)°, γ = 90.78(3)°, V = 1031.2(4) Å , Z = 4,
pseudo-(5r,8r)-1-Hydroxy-1,8-dimethylspiro[4.5]decan-2-one (34):
ρ = 1.174 Mg·m–3, μ(Mo-Kα) = 0.079 mm–1, F(000) 400, θ range
1.97–24.12°, limiting indices –7 Յ h Յ 7, –12 Յ k Յ 12, –18 Յ l
Յ 18, total reflections collected 11034, symmetry-independent re-
flections 3086, refinement full-matrix least-squares on F2, data
3086, parameters 235, goodness-of-fit on F2 1.048, final R indices
[I Ͼ 2σ(I)], R1 = 0.0796, wR2 = 0.2319, R indices (all data) R1 =
0.1122, wR2 = 0.2522, Δρ(max, min) = 0.538, –0.264 e·Å–3. CCDC
256513. C11H18O2 (182.3): calcd. C 72.49, H 9.95; found C 72.44,
H 9.96. Odor: Weak, fruity, floral. Odor threshold: 63.5 ng/L air.
IR (ATR): ν = 1741 (s, νC=O), 971/1077/1123 (s, νC–O), 3469 (s,
˜
1
νO–H), 1367 (m, δCH3) cm–1. H NMR (CDCl3): δ = 0.90 (d, J =
6.5 Hz, 3 H, 8-Me), 1.00–1.07 (m, 3 H, 6-,9-,10-Hax), 1.15 (s, 3 H,
1-Me), 1.32 (mc, 1 H, 8-Hax), 1.48–1.61 (m, 6 H, 4-Hb, 7-H2,
6-,9-,10-Heq), 2.12–2.38 (m, 4 H, 3-H2, 4-Ha, OH) ppm. 13C NMR
(CDCl3): δ = 19.3 (q, 1-Me), 22.5 (q, 8-Meeq), 25.1 (t, C-4), 27.6
(t, C-9), 30.5/30.7 (2t, C-6,-10), 30.6 (t, C-3), 31.0 (t, C-7), 32.4 (d,
C-8), 43.6 (s, C-5), 81.6 (s, C-1), 220.9 (s, C-2) ppm. MS (70 eV):
m/z (%) = 196 (36) [M+], 178 (2) [M+ – H2O], 168 (6) [M+ – CO],
150 (5) [M+ – CO – H2O], 140 (35) [C8H12O2+], 135 (14) [M+
–
1-Hydroxy-1,8-dimethylspiro[4.5]decan-2-one (33/34): To a stirred
suspension of AlCl3 (700 mg, 5.25 mmol) in 2-nitropropane
(450 mg, 5.05 mmol) and CH2Cl2 (10 mL) was added at 0 °C a
solution of 4-methylene-5-oxohexanenitrile[18] (28, 6.16 g,
50.0 mmol) in CH2Cl2 (10 mL). Isoprene (6.80 g, 99.8 mmol) was
then added dropwise at this temp. within 20 min, and stirring was
continued at 0 °C for 1 h prior to removal of the cooling bath.
After being stirred further at room temp. for 1 h, the reaction mix-
ture was poured into water (300 mL). The organic layer was sepa-
rated, and the aqueous one extracted with Et2O (2×250 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in a rotary evaporator. The resulting residue was purified by silica-
gel FC (pentane/Et2O, 1:1) to furnish 3-(1Ј-acetyl-4Ј-methylcy-
clohex-3Ј-enyl)propionitrile (8.00 g, 84%). At room temp., a solu-
tion of iPrMgCl (14.3 g, 139 mmol) in Et2O (250 mL) was added
dropwise with stirring to a solution of Cp2TiCl2 (31.3 g, 126 mmol)
in MePh (400 mL). After stirring for 30 min, a solution of PhMgBr
(25.2, 139 mmol) in Et2O (220 mL) was added within 5 min, and
stirring was continued for 1 h. Next, a solution of the prepared 3-
(1Ј-acetyl-4Ј-methylcyclohex-3Ј-enyl)propionitrile (8.00 g,
42.0 mmol) in MePh (400 mL) was added during a period of 1 h
dropwise with stirring, which was continued at room temp. for a
further 16 h. After quenching by addition of aq. HCl (2 n,
500 mL), the organic layer was separated, and the aqueous one
extracted with Et2O (2×500 mL). The combined organic extracts
were washed with brine (500 mL), dried (Na2SO4), and concen-
trated in a rotary evaporator. Silica-gel FC (pentane/Et2O, 5:1) of
the resulting residue provided 1-hydroxy-1,8-dimethylspiro[4.5]dec-
7-en-2-one (600 mg, 7 %). A suspension of Pd/C (10 %, 30 mg,
0.029 mmol) and 1-hydroxy-1,8-dimethylspiro[4.5]dec-7-en-2-one
(300 mg, 1.54 mmol) in EtOAc (3 mL) was evacuated and flushed
CO – CH3 – H2O], 110 (48) [C8H14+], 95 (84) [C7H11+], 87 (40)
[C4H7O2+], 81 (56) [C6H9+], 74 (4) [C3H6O2+], 55 (53) [C4H7+], 43
(100) [C3H7+]. C12H20O2 (196.3): calcd. C 73.43, H 10.27; found C
73.62, H 10.11. Odor: Weak, fruity, cinnamon.
(+)-(1R,4S,5S,9R,2ЈS)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]-
decan-2-one 1Ј-Amino-2Ј-methoxymethylpyrrolidine Hydrazone (35):
(1R*,4S*,5S*,9R*)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]-
decan-2-one (15, 500 mg, 2.10 mmol) and (–)-(S)-1-amino-2-meth-
oxymethylpyrrolidine (SAMP, 340 mg, 2.62 mmol) were refluxed in
EtOH (10 mL) under N2 for 44 h. The solvent was then evaporated,
and the resulting residue taken up in Et2O/water (1:1, 40 mL). The
organic layer was separated, the aqueous one extracted with Et2O
(20 mL), and the combined organic extracts were washed with
water (20 mL) and brine (20 mL), dried (Na2SO4), and concen-
trated to dryness in a rotary evaporator. The resulting residue
(780 mg) was separated into both diastereoisomers by silica-gel FC
(pentane/Et2O, 9:1, Rf = 0.07 for 35, and Rf = 0.17 for 36) to afford
35 (250 mg, 34%) and 36 (290 mg, 39%) in isomerically pure form.
Spectroscopic data for 35: IR (ATR): ν = 1104/1128/1067 (s, νC–
˜
O), 1454 (s, δCH2), 3427 (m, νO–H), 1633 (w, νC=N–NϽ) cm–1.
1H NMR (CDCl3): δ = 0.46 (dd, J = 11.5, 11.5 Hz, 1 H, 10-Hax),
0.67 (dd, J = 12.0, 12.0 Hz, 1 H, 8-Hax), 0.77 (d, J = 6.5 Hz, 3 H,
4-Me), 0.95 (s, 3 H, 7-Meeq), 0.96 (d, J = 7.5 Hz, 3 H, 9-Me), 1.03
(d, J = 12.0 Hz, 1 H, 6-Hax), 1.13 (s, 3 H, 1-Me), 1.18–2.18 (m, 11
H, 3-,3Ј-,4Ј-H2, 4-,9-H, 6-,8-,10-Heq,), 1.33 (s, 3 H, 7-Meax), 2.70
(dd, J = 7.5, 7.0 Hz, 1 H, 5Ј-Hb), 2.81 (dd, J = 7.5, 7.5 Hz, 1 H,
5Ј-Ha), 2.94 (s, 1 H, O-H), 3.27–3.56 (m, 3 H, CH2O, 2Ј-H), 3.36
(s, 3 H, O-Me) ppm. 13C NMR (CDCl3): δ = 18.4 (q, 4-Me), 22.3
(t, C-4Ј), 23.4 (q, 9-Me), 26.2 (q, 1-Me), 26.3 (t, C-3Ј), 26.5 (d, C-
9), 27.4 (q, 7-Meax), 31.4 (s, C-7), 34.1 (t, C-3), 35.1 (q, 7-Meeq),
Eur. J. Org. Chem. 2005, 3233–3245
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3243

P. Kraft, W. Eichenberger, D. Frech
FULL PAPER
41.7 (t, C-6), 44.6 (d, C-4), 47.2 (t, C-10), 47.5 (s, C-5), 49.2 (t, C-
8), 53.6 (t, C-5Ј), 59.2 (q, O-Me), 66.4 (d, C-2Ј), 74.8 (t, CH2O),
80.0 (s, C-1) ppm, C-2: N.R. MS (70 eV): m/z (%) = 350 (1) [M+],
(5 mL) was ozonized at –78 °C for 10 min prior to the addition of
thiourea (200 mg, 1.11 mmol) at 0 °C. The solvent was evaporated
in vacuo, and the resulting residue purified by silica-gel FC (pen-
tane/Et2O, 9:1, Rf = 0.46) to afford the (+)-(1S,4R,5R,9S)-config-
ured 38 (22.8 mg, 34%), the spectroscopic data of which were iden-
tical to those of the racemate 15 (vide supra). Chiral GC (Supelco
B-DEX110, 60 m×0.25 mm ID, ft = 0.25 μm): 98.18%ee. Polarim-
332 (7) [M+ – H2O], 317 (2) [M+ – H2O – CH3], 305 (2) [M+
–
C2H5O], 287 (100) [M+ – C2H5O – H2O], 189 (2) [M+ – C2H5O –
H2O – C7H14], 45 (11) [C2H5O+]. Polarimetry (c 0.99 in EtOH):
22
22
22
[α]2D2 = +133.3, [α] = +121.6, [α] = +151.0, [α] = +417.3.
578
546
436
22
22
etry (c 0.72 in EtOH): [α]2D2 = +35.2, [α] = +37.6, [α] = +45.9,
578
546
(–)-(1R,4S,5S,9R)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-
2-one (37): A stirred solution of (+)-(1R,4S,5S,9R,2ЈS)-1-hydroxy-
1,4,7,7,9-pentamethylspiro[4.5]decan-2-one 1Ј-amino-2Ј-methoxy-
methylpyrrolidine hydrazone (80 mg, 0.23 mmol) in MeOH (5 mL)
was ozonized at –78 °C for 10 min, prior to the addition of thiourea
(200 mg, 1.11 mmol) at 0 °C. The solvent was evaporated in vacuo,
and the resulting residue purified by silica-gel FC (pentane/Et2O,
9:1, Rf = 0.46) to afford the (–)-(1R,4S,5S,9R)-configured 37
(22.0 mg, 40%), the spectroscopic data of which were identical to
those of the racemate 15 (vide supra). Chiral GC (Supelco B-
DEX110, 60 m×0.25 mm ID, ft = 0.25 μm): 94.53%ee. Polarimetry
22
22
[α] = +121.8, [α] = +399.2. Odor: Strong, powerful, and char-
436
365
acteristic of natural patchouli oil, with rich woody–ambery and
tobacco-like facets. Odor threshold: 0.027 ng/L air.
Acknowledgments
For the X-ray structure determinations we are indebted to André
Alker, Dr. Armin Ruf and Dr. Michael Hennig of F. Hoffmann-La
Roche AG, Basel. Thanks are also due to Dr. Roman Kaiser, Erwin
Senn, Irene Hickel and Michael Rothaupt for preparative GC, to
Marcel Redard and Samuel Jordi for additional experimental work,
to Melanie Stang and Thomas Reinmann for the preparation of
larger quantities for further olfactory evaluations, to Dr. Gerhard
Brunner for multidimensional NMR experiments, to Katarina
Grman and Adriana Flückiger for GC-threshold determinations,
to Caroline Gaillardot for GC–olfactometry, and to Jean-Jacques
Rouge for the odor descriptions. Careful proofreading of the manu-
script by Dr. Samuel Derrer, Dr. Markus Gautschi and John An-
thony McStea is also acknowledged with gratitude.
22
22
(c 0.46 in EtOH): [α]2D2 = –38.7, [α]
= –41.5, [α]
= –50.5,
578
546
22
22
[α]
= –132.5, [α]
= –421.8. Odor: Odorless on GC–olfacto-
436
365
metry on the chiral phase; the odor on the smelling strip is there-
fore due to traces of the enantiomer 38.
(+)-(1S,4R,5R,9S,2ЈS)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]-
decan-2-one 1Ј-Amino-2Ј-methoxymethylpyrrolidine Hydrazone (36):
For the preparation see 35 above; yield 290 mg (39%), Rf = 0.17
(pentane/Et2O, 9:1), colorless crystals, mp. 71–75 °C (pentane/
Et O). IR (ATR): ν = 1103/1128/1070 (s, νC–O), 1457 (s, δCH ),
˜
2
2
3427 (m, νO–H), 1633 (w, νC=N–NϽ) cm–1. H NMR (CDCl3): δ
= 0.35 (dd, J = 11.5, 11.5 Hz, 1 H, 10-Hax), 0.64 (dd, J = 12.0,
12.0 Hz, 1 H, 8-Hax), 0.73 (d, J = 6.5 Hz, 3 H, 4-Me), 0.95 (s, 3 H,
7-Meeq), 1.03 (d, J = 12.0 Hz, 1 H, 6-Hax), 1.05 (d, J = 7.5 Hz, 3
1
H, 9-Me), 1.16 (s, 3 H, 1-Me), 1.28 (s, 3 H, 7-Meax), 1.33–2.22 (m, [1] H. Nebenzal, Cafe Berlin, Overlook Press, Woodstock, 1992,
p. 9; German ed.: H. Nebenzal, Café Berlin, Haffmanns Verlag,
Zürich, 1994, pp. 16–17.
[2] H. Gal, Justus Liebigs Ann. Chem. 1869, 150, 374–376.
[3] W. Treibs, Justus Liebigs Ann. Chem. 1949, 564, 141–151.
[4] a) G. Büchi, E. R. Erickson, J. Am. Chem. Soc. 1956, 78, 1262–
1263; b) G. Büchi, E. R. Erickson, N. Wakabayashi, J. Am.
Chem. Soc. 1961, 83, 927–938.
11 H, 3-,3Ј-,4Ј-H2, 4-,9-H, 6-,8-,10-Heq), 2.47 (dd, J = 7.5, 7.0 Hz,
1 H, 5Ј-Hb), 2.76 (dd, J = 7.5, 7.5 Hz, 1 H, 5Ј-Ha), 3.33–3.54 (m,
3 H, CH2O, 2Ј-H), 3.37 (s, 3 H, O-Me), 3.83 (s, 1 H, O-H) ppm.
13C NMR (CDCl3): δ = 19.4 (q, 4-Me), 22.4 (t, C-4Ј), 23.4 (q, 9-
Me), 26.2 (d, C-9), 26.3 (t, C-3Ј), 26.4 (q, 1-Me), 27.1 (q, 7-Meax),
31.4 (s, C-7), 33.4 (t, C-3), 35.2 (q, 7-Meeq), 41.6 (t, C-6), 43.6 (d,
C-4), 46.5 (t, C-5), 47.6 (t, C-10), 49.2 (t, C-8), 54.1 (t, C-5Ј), 59.2
(q, O-Me), 66.2 (d, C-2Ј), 75.3 (t, CH2O), 79.9 (s, C-1) ppm, C-2:
[5] G. Büchi, W. D. MacLeod, J. Am. Chem. Soc. 1962, 84, 3205–
3206.
N.R. MS (70 eV): m/z (%) = 350 (1) [M+], 332 (7) [M+ – H2O], 317 [6] M. Dobler, J. D. Dunitz, B. Gubler, H. P. Weber, G. Büchi, O. J.
(2) [M+ – H2O – CH3], 305 (2) [M+ – C2H5O], 287 (100) [M+
–
Padilla, Proc. Chem. Soc. London 1963, 383.
C2H5O – H2O], 189 (2) [M+ – C2H5O – H2O – C7H14], 45 (9)
[C2H5O+]. Crystal data and structure refinement: Empirical for-
mula C21H38N2O2, molecular mass 350.53, crystal dimensions
0.4×0.3×0.1 mm, temperature 293 K, wavelength 0.71073 Å, or-
thorhombic crystal system, space group P212121, unit cell dimen-
sions a = 9.3720(19) Å, b = 13.955(3) Å, c = 16.782(3) Å, α = 90°,
β = 90°, γ = 90°, V = 2194.8(8) Å3, Z = 4, ρ = 1.061 Mg·m–3,
μ(Mo-Kα) = 0.067 mm–1, F(000) 776, θ range 1.90–24.18°, limiting
indices –10 Յ h Յ 10, –16 Յ k Յ 16, –19 Յ l Յ 19, total reflections
[7] J. Gadamer, T. Amenomiya, Arch. Pharm. 1903, 241, 22–47.
[8] a) P. Teisseire, P. Maupetit, B. Corbier, P. Rouillier, Recherches
(Paris) 1974, 19, 36–61; b) W. E. Oberhänsli, P. Schönholzer,
Recherches (Paris) 1974, 19, 62–68.
[9] D. Kastner, Riechst. Aromen Kosmet. 1977, 27, 79–80.
[10] F. Näf, R. Decorzant, W. Giersch, G. Ohloff, Helv. Chim. Acta
1981, 64, 1387–1397.
[11] B. D. Mookherjee, K. K. Light, I. D. Hill, in: 178th ACS
National Meeting, Washington D.C., Sept. 9–14, 1979, Ab-
stracts of papers, I, AGFD 55; and in: Essential Oils (Eds.:
B. D. Mookherjee, C. J. Mussinan), Allured Publishing Co-
orp.,Wheaton, IL, 1981, pp. 246–272.
[12] G. Ohloff, Düfte – Signale der Gefühlswelt, Verlag Helvetica
Chimica Acta Zürich 2004, pp. 52–53.
collected 20042, symmetry-independent reflections 3471, Rint
=
0.0534, refinement full-matrix least-squares on F2, data 3471,
parameters 233, goodness-of-fit on F2 0.799, final R indices [I Ͼ
2σ(I)], R1 = 0.0352, wR2 = 0.0752, R indices (all data) R1 = 0.0669,
[13] C. Sell, A Fragrant Introduction to Terpenoid Chemistry, Royal
Society of Chemistry, Cambridge, 2003, p. 200.
wR2 = 0.0811, Δρ(max, min) = 0.116, –0.081 e·Å–3. CCDC 256514.
22
Polarimetry (c 1.00 in EtOH): [α]2D2 = +181.6, [α]
= +194.1,
578
[14] G. Fráter, J. A. Bajgrowicz, P. Kraft, Tetrahedron 1998, 54,
22
22
[α] = +237.9, [α] = +610.0.
7633–7703.
546
436
[15] P. Kraft, R. Cadalbert, Synthesis 2002, 2243–2253.
[16] E. J. Corey, S. G. Pyne, Tetrahedron Lett. 1983, 24, 2821–2824.
[17] a) Y. Yamamoto, D. Matsumi, K. Itoh, Chem. Commun. 1998,
875–876; b) Y. Yamamoto, D. Matsumi, R. Hattori, K. Itoh,
J. Org. Chem. 1999, 64, 3224–3229.
(+)-(1S,4R,5R,9S)-1-Hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-
2-one (38): A stirred solution of (+)-(1S,4R,5R,9S,2ЈS)-1-hydroxy-
1,4,7,7,9-pentamethylspiro[4.5]decan-2-one 1Ј-amino-2Ј-methoxy-
methylpyrrolidine hydrazone (100 mg, 0.29 mmol) in MeOH
3244
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3233–3245

From Vetiver to Patchouli: A New High-Impact Spirocyclic Patchouli Odorant
FULL PAPER
[18] L. Szabó, K. Honty, L. Töke, I. Tóth, C. Szántay, Chem. Ber.
1972, 105, 3215–3230.
[19] A. Job, C. F. Janeck, W. Bettray, R. Peters, D. Enders, Tetrahe-
dron 2002, 58, 2253–2329.
[21] D. Enders, L. Wortmann, R. Peters, Acc. Chem. Res. 2000, 33,
157–169.
Received: February 1, 2005
[20] P. Herold, J. W. Herzig, P. Wenk, T. Leutert, P. Zbinden, W.
Fuhrer, S. Stutz, K. Schenker, M. Meier, G. Rihs, J. Med.
Chem. 1995, 38, 2946–2954.
Eur. J. Org. Chem. 2005, 3233–3245
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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