Ring reversal of a spirocyclic patchouli odorant: Molecular modeling, synthesis, and odor of 6-hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one

Article abstract of DOI:10.1002/ejoc.200600815

Molecular modeling calculations on the recently discovered high-impact patchouli odorant (+)-(1S,4R,5R,9S)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5] decan-2-one (1) indicated that ring reversal of the spirocyclic system should lead to molecules in which two of the five methyl substituents could be spared without significantly affecting the overall shape or conformational equilibrium. Intramolecular ene reactions promised simple access to the desired target compound, (5R*,6R*)-6-hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one (2), but all attempts failed utterly. The elaborated alternative six-step synthesis of target structure 2 commenced with the addition of HCl gas to 5-bromo-2-methyl-2-pentene (16), giving 1-bromo-4-chloro-4-methylpentane (15). Spiroannulation of cyclohexanone with this building block by TiCl ₄-mediated alkylation of the TMS enolate 14 and subsequent cyclization by means of tBuOK afforded 1,1-dimethylspiro[4.5]decan-6-one (12). The reaction of this spirocyclic ketone with MeLi furnished the corresponding tertiary alcohol 17, which was dehydrated by Appel-Lee bromination with concomitant dehydrohalogenation. The resulting alkene mixture containing 1,1,6-trimethylspiro[4.5]dec-6-ene (4) as the major component was subjected to the ketohydroxylation method developed by Plietker to provide, after repeated chromatography, target compound 2 in 33 % yield. To study the influence of the gem-dimethyl position on the olfactory properties, the analogous spirocyclic 2,2,6-trimethylketone 22 was also synthesized. Spiroannulation of cyclohexanone with 1,4-dibromo-2,2-dimethylbutane (18), with the use of 2.2 equiv. tBuOK as base, furnished 2,2-dimethylspiro[4.5]decan-6-one (19). The reaction of 19 with MeLi and subsequent Appel-Lee bromination/dehydrohalogenation led to an isomeric mixture containing 2,2,6-trimethylspiro[4.5]dec-6-ene (21) as the main component. The ketohydroxylation method according to the protocol of Plietker concluded the synthesis of the second target structure 22. In contrast to methyl carbinol 17, which has a typical woody-earthy patchouli odor, the odor of target molecule 2 was displaced towards the camphoraceous and minty side. The 2,2,6-trirnethylalcohol 20 emanated a camphoraceous and vetiver-type note, while the second target molecule, 22, was only weakly woody, cedar-like, and powdery in smell. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600815

FULL PAPER
DOI: 10.1002/ejoc.200600815
Ring Reversal of a Spirocyclic Patchouli Odorant: Molecular Modeling,
Synthesis, and Odor of 6-Hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one
Philip Kraft*[a] and Audrey Bruneau[a][‡]
Dedicated with best wishes to Dr. Dieter Merkel[‡‡]
Keywords: Ketohydroxylation / Olfactory properties / Patchouli / Spiro compounds / Structure–activity relationships
Molecular modeling calculations on the recently discovered
high-impact patchouli odorant (+)-(1S,4R,5R,9S)-1-hydroxy-
1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (1) indicated
that ring reversal of the spirocyclic system should lead to
molecules in which two of the five methyl substituents could
be spared without significantly affecting the overall shape
or conformational equilibrium. Intramolecular ene reactions
promised simple access to the desired target compound,
(5R*,6R*)-6-hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one
(2), but all attempts failed utterly. The elaborated alternative
six-step synthesis of target structure 2 commenced with the
oped by Plietker to provide, after repeated chromatography,
target compound 2 in 33% yield. To study the influence of
the gem-dimethyl position on the olfactory properties, the
analogous spirocyclic 2,2,6-trimethylketone 22 was also syn-
thesized. Spiroannulation of cyclohexanone with 1,4-di-
bromo-2,2-dimethylbutane (18), with the use of 2.2 equiv.
tBuOK as base, furnished 2,2-dimethylspiro[4.5]decan-6-one
(19). The reaction of 19 with MeLi and subsequent Appel–
Lee bromination/dehydrohalogenation led to an isomeric
mixture containing 2,2,6-trimethylspiro[4.5]dec-6-ene (21) as
the main component. The ketohydroxylation method accord-
addition of HCl gas to 5-bromo-2-methyl-2-pentene (16), giv- ing to the protocol of Plietker concluded the synthesis of the
ing 1-bromo-4-chloro-4-methylpentane (15). Spiroannulation
of cyclohexanone with this building block by TiCl4-mediated
alkylation of the TMS enolate 14 and subsequent cyclization
by means of tBuOK afforded 1,1-dimethylspiro[4.5]decan-6-
second target structure 22. In contrast to methyl carbinol 17,
which has a typical woody-earthy patchouli odor, the odor of
target molecule 2 was displaced towards the camphoraceous
and minty side. The 2,2,6-trimethylalcohol 20 emanated a
one (12). The reaction of this spirocyclic ketone with MeLi camphoraceous and vetiver-type note, while the second tar-
furnished the corresponding tertiary alcohol 17, which was
dehydrated by Appel–Lee bromination with concomitant de-
hydrohalogenation. The resulting alkene mixture containing
get molecule, 22, was only weakly woody, cedar-like, and
powdery in smell.
1,1,6-trimethylspiro[4.5]dec-6-ene (4) as the major compo- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
nent was subjected to the ketohydroxylation method devel-
Germany, 2007)
“And one of her shopgirls, Martine, was already tickling
the tip of my ear with her finger wet with patchouli (press-
ing the sting of her breast, at the same time, beneath my
armpit), and Charlotte [...] aimed an atomizer at me,
pressing its bulb, as if inviting me to an amorous skirmish.”
Italo Calvino, “The Name, the Nose”[1b]
Introduction
“E una delle commesse, Martine, già mi titillava sotto
lЈorecchio col polpastrello bagnato di patchoulì (e intanto
spingeva sotto la mia ascella il pungolo del suo seno), e
Charlotte [...] mi prendeva di mira stringendo la peretta
del polverizzatore come invitandomi a una schermaglia
amorosa.”
Although patchouli leaves had been used since antiquity
as insect repellants,[2] and although “camphoraceous” is
considered a prime anti-erogenous attribute in perfumery,
the typical camphoraceous, woody, and earthy scent of
patchouli oil has always had a sensual and seductive conno-
tation. Indian girls ritually used to perfume their hands
with jasmine, their feet with saffron, and their backs with
patchouli oil to bewitch a lover, and even in modern per-
fumery, about one third of all fine fragrances launched con-
tain patchouli as a main base-note ingredient. Despite in-
tense work in this domain, no synthetic substitute has so
Italo Calvino, “Il nome, il naso”[1a]
[a] Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax: +41-44-824-29-26
E-mail: philip.kraft@givaudan.com
[‡] Master’s thesis of Audrey Bruneau, Université de Nantes,
France, carried out during her six-month stay at the Givaudan
Fragrance Research Center, Switzerland.
[‡‡] Dr. Dieter Merkel has made many outstanding contributions
to the chemistry of odorants, terpenoids, and essential oils.
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P. Kraft, A. Bruneau
FULL PAPER
far been able to replace this, in the truest sense of the word,
“essential” oil. At $40–50/kg, patchouli oil is on the one
hand rather cheap and difficult to compete with, and on
the other hand, it is very difficult to find odorants in which
the three prime olfactory attributes, “camphoraceous”,
“woody”, and “earthy”, are as perfectly balanced. Recently,
however, we discovered a very powerful spirocyclic odorant
of structure 1 that exhibits a very natural and typical pa-
tchouli odor.[3] With an odor threshold of 0.027 ng/L air,[3]
it is even 30 times more intense than (–)-patchoulol, the
principal odorant of patchouli oil.[2] The importance of the
methyl substituents of compound 1 in pushing the cyclo-
hexyl ring in the direction of the carbinol function was
shown by X-ray crystallography in comparison with a 7,7,9-
demethyl analog, and this steric proximity seemed essential
for the olfactory properties of the spirocyclic patchouli
odorant 1. Unfortunately, its synthesis is rather cumber-
some and costly; and thus, more easily accessible alternative
structures are much in demand. To minimize torsional
(Pitzer) strain, a spiro atom in a cyclopentyl ring should
be situated at the flap of a C2-symmetric, envelope-shaped
conformer, and inversion or puckering of the ring should
energetically be significantly more restricted than that in an
analogously substituted cyclohexyl chair. These conforma-
tional considerations keyed the idea of reversing the spi-
rocyclic rings of lead structure 1. This ring reversal could
simplify the structure in that: (a) a 2-hydroxy-2-methyl-
cyclohexanone substructure could mimic the like-config-
ured 2-hydroxy-2,4-dimethylcyclopentanone ring, thus
omitting one stereogenic methyl group, and (b) only one
gem-dimethyl group in the cyclopentyl ring of the inverted
spirocyclic system should be necessary to mimic the steric
bulk of the trimethylcyclohexyl unit, as it is less prone to
inversion and puckering. To mimic the short interatomic
distance between 7-Meax (Figure 1) and 1-Me in lead struc-
ture 1, the gem-dimethyl moiety should best be situated in
α-position to the spiro atom. As shown in Figure 1, the re-
sulting target structure 2 (black model) can indeed be su-
perimposed very well on lead compound 1 (depicted in
gold) in this biflexible alignment with the MOE software
package. Although the cyclohexyl ring in lead molecule 1
became twisted upon superposition, it did not invert; a bar-
rier of only 0.1 kcalmol–1 had been estimated for this ring
inversion.[3] So the two structures, 1 and 2, are indeed quite
similar with regard to their geometry and steric demand,
and even if a potentially simpler synthetic access to a pa-
tchouli odorant is not possible, the olfactory properties of
the derived target molecule 2 make it interesting in its own
right for structure–odor correlation.
Figure 1. Biflexible alignment of target molecule 2 and the lead
structure,
1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one
(1), with the MOE software package.
one (Figure 2). Ene reactions proceed by the interaction of
the LUMO of the alkene (enophile) with the HOMO of
the allylic partner (ene), and an electron-withdrawing group
such as the conjugated carbonyl function in dienone 3 po-
larizes the LUMO much more than the HOMO, with the
result that the LUMO coefficients of the chain double bond
At first sight, the spirocyclic ring system seems easily ac-
cessible by a thermal Alder ene reaction[4] of 2-methyl-3-
(4Ј-methylpent-4Ј-enyl)cyclohex-2-en-1-one (3, Figure 2).
Yet, both double bonds of dienone 3 bear allylic hydrogen
atoms, and consequently both can act as ene components.
Transition state A, with the ring double bond as the ene
component, would lead to the desired spiro[4.5]decane sys-
tem, while B, with the chain double bond as the ene compo-
Figure 2. HOMO and LUMO frontier orbitals as calculated for 2-
methyl-3-(4Ј-methylpent-4Ј-enyl)cyclohex-2-en-1-one (3) on the
Hartree–Fock 6-31G* level to determine the course of a thermal
nent, provides 1-methyl-8-methylenespiro[5.5]undecan-2- Alder ene reaction.
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Ring Reversal of a Spirocyclic Patchouli Odorant
FULL PAPER
in this case actually vanish, as was confirmed by the frontier et al. had done.[8] Alcohol 10 was first converted into its
orbital calculations on the Hartree–Fock 6-31G* level, toluenesulfonate and then treated with LiBr in 1,2-dime-
which are delineated in Figure 2. Accordingly, only the con- thoxyethane to provide 5-bromo-2-methylpent-1-ene (7) in
jugated double bond of 3 can act as the enophile, forcing 38% yield after chromatography. This was then transformed
the side chain to become the ene component, and B the into the corresponding Grignard reagent, and according to
only transition state electronically possible. The transition the procedure of Pirrung[10] added to 3-methoxy-2-methyl-
state B, however, leads to the wrong spirocyclic ring system, cyclohex-2-enone (6),[11] which had been prepared in 77%
and thus this idea was abandoned.
yield by etherification of methyl dihydroresorcinol with tri-
Nevertheless, an intramolecular ene reaction seemed an methyl orthoformate in the presence of TsOH (Scheme 2).
appealing strategy for the construction of the spirocycle,
and the course of the cycloaddition could be directed by a
metallo ene reaction. This transform-guided strategy keyed
the retrosynthetic analysis presented in Scheme 1. Target
compound 2 could be devised by oxidative cleavage of an
epoxide,[5] itself accessible by oxidation of the ene retron 4.
A palladium ene reaction,[6] for instance, would reveal the
dienol acetate 5 as the precursor of the spiro[4.5]dec-6-ene
4. After reduction of the corresponding ketone, dienol ace-
tate 5 is available by Grignard reaction of 3-methoxy-2-
methylcyclohex-2-enone (6) with 5-bromo-2-methylpent-1-
ene (7), by applying the Stork–Danheiser trick.[7] Bromide 7
leads retrosynthetically to the corresponding γ-unsaturated
ester 8, a product of a Johnson–Claisen rearrangement, af-
ter condensation of an allyl alcohol with an ortho ester.
Scheme 2. Synthetic attempts by metallo ene reactions.
The Grignard reaction of the vinylogous ester 6 with (4-
methylpent-4-enyl)magnesium bromide provided dienone 3,
by means of the Stork–Danheiser trick,[7] in 67% yield after
acidic hydrolysis and chromatography. Having the ene ret-
ron 3 in hand, it was obviously interesting to check if the
thermal ene reaction would indeed proceed, and if it would
lead, as anticipated, to the undesired 1-methyl-8-methyl-
enespiro[5.5]undecan-2-one via transition state B. With a
slow flow of argon, a 0.5- solution of dienone 3 in toluene
Scheme 1. Retrosynthetic analysis of the modeled target molecule was therefore passed at atmospheric pressure through a ver-
2.
tical 35-cm tube packed with glass rings and placed in a
pyrolysis oven. The experiment was conducted at different
temperatures, and GC monitoring indicated no reaction up
to 450 °C, at which point decomposition to a complex prod-
uct mixture without ene reaction products was observed.
Results and Discussion
Following the retrosynthetic analysis sketched out above, Heating dienone 3 in tetraethylene glycol dimethyl ether to
commercially available 2-methylprop-2-en-1-ol (9) was 270 °C for two days also provided only a mixture of iso-
treated with triethyl orthoacetate in the presence of propi- meric dienones and products of solvent degradation. Never-
onic acid with distillative removal of the formed EtOH in theless, our strategy remained the application of a metallo
accordance with the procedure of Avery et al.,[8] and the ene reaction, mediated either by magnesium[12] or by palla-
[3,3]-sigmatropic rearrangement of the intermediate allyl vi- dium/zinc.[13] For this purpose, dienone 3 was reduced to
nyl ether provided the γ-unsaturated ester 8 in 71% yield alcohol 11; however, all attempts to convert this into the
after purification by fractional distillation. LiAlH4 re- corresponding chloride by the Appel reaction[14] with CCl4
duction of the ethyl ester 8 in Et2O furnished 4-methylpent- or N-chlorosuccinimide (NCS), with TMSCl in the presence
4-en-1-ol (10) in 87% yield. However, pentenol 10 could not of BiCl3,[15] with AcCl and EtOH,[16] or by making use of
be converted directly into its bromide, and even the mild the Corey–Kim reagent prepared in situ from NCS and
conditions of the Appel–Lee bromination[9] only led to a Me2S[17] failed utterly because of elimination and successive
complex product mixture with 2,2-dimethyltetrahydrofuran reactions. As a result, the magnesium ene approach was
as the main product and 2,5-dibromo-2-methylpentane as abandoned in favor of a palladium-mediated ene reaction,
the most important side product. Thus, the detour was which allowed for an acetate leaving group in the formation
taken by bromide displacement of the tosylate, just as Avery of the allyl palladium complex. Steglich esterification[18] of
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P. Kraft, A. Bruneau
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the allyl alcohol 11 went smoothly, and acetate 5 was iso- (14) was then selectively α-alkylated with the tert-substi-
lated quantitatively. However, because of the severely steri- tuted chloro side of the bifunctional building block 15 in
cally shielded tetrasubstituted allylic double bond of acetate CH2Cl2 in the presence of titanium tetrachloride as stoi-
5, it turned out to be impossible to substitute the acetate chiometric Lewis acid. The resulting 2-(5Ј-bromo-2Ј-meth-
group by an electron-rich Pd0 nucleophile such as Pd- ylpentan-2Ј-yl)cyclohexanone (13) was isolated by flash
[PPh3]4, Pd[OAc]2/PPh3 or Pd[OAc]2/nBu3P (10 mol-%) in chromatography in 31% yield and cyclized in the next step
acetic acid, THF, or ether. Upon heating, only the elimi- in the presence of potassium tert-butoxide in toluene. The
nation products were obtained, particularly in acetic acid. desired spirocyclic ketone 12 was isolated in 50% yield, to-
Moreover, heating acetate 5 in acetic acid without any cata- gether with the cyclic enol ether, 5,5-dimethyl-2,3,4,5,6,7,8-
lyst resulted in the same product mixture. So finally, the octahydro-1-benzoxepine, as the main byproduct (14%).
metallo ene approach to 1,1,6-trimethylspiro[4.5]dec-6-ene The C-6 methyl group was then introduced by treatment of
(4) failed completely, and a new route to this central inter- ketone 12 with methyllithium at room temp., which, after
mediate had to be sought. In view of the intrinsic problem mild hydrolysis and chromatographic purification, provided
of the tetrasubstituted double bond in π-allyl palladium the tertiary alcohol 17 in 69% yield. The gem-dimethyl
chemistry, it also did not seem very promising to attempt group, which is situated right in the Bürgi–Dunitz trajectory
the synthesis of the key intermediate 4 by palladium-cata- of the carbonyl function of 12, blocks that side of the car-
lyzed spirocyclization[19] of a precursor with a malonate- bonyl plane and forces the incoming nucleophile to ap-
substituted nucleophilic side chain.
proach from the opposite direction. The resulting unlike-
As delineated in the alternative retrosynthesis in configuration of methyl carbinol 17 was proven by 2D
Scheme 3, instead of the ene disconnection to precursor 5 NMR experiments of the corresponding methoxymethyl
or a replacement of the geminal methyl substituents by ester (MOM) ether, prepared by protection of the tertiary hy-
groups, an auxiliary carbonyl function in α-position to the droxy group with chloromethyl methyl ether, in the presence
spiro atom can strategically be easily placed by retrosyn- of excess sodium iodide and diisopropyl ethylamine in
thetic hydration of the double bond, which reveals a simple DME according to the procedure of Narasaka.[22] The ob-
Grignard methyl carbinol retron. The resulting spirocyclic served NOE cross peak between 1-Meax and 10-Hax indi-
ketone 12 can thus easily be constructed by a simple enolate cated a relative (5R*,6S*)-configuration of MOM 17. Dis-
alkylation. For this disconnection, the fully substituted sin- tinct cross peaks of the OCH2O methylene group with both
gle bond is out of question, as the steric constraints would the equatorial and the axial methyl substituents at C-1
only cause elimination of the tert-halide precursor but prob- proved this conformation, in which the axial MOM group
ably no ring closure. This shifts the construction of the qua- is freely rotary, parallel to the plane of the cyclohexyl ring.
ternary dimethyl-substituted carbon atom to the stage of
the halo ketone 13, but for the regio- and position-specific
α-tert-alkylation of ketones, Reetz et al.[20] had worked out
a reliable Lewis acid mediated methodology. Disconnecting
the bond between the two highest substituted carbon atoms
provides the silyl enol ether of cyclohexanone 14 and 1-
bromo-4-chloro-4-methylpentane (15) as building blocks,
the latter of which should be accessible by addition of HCl
gas to 1a-homoisoprenyl bromide (16).
Scheme 3. Alternative retrosynthetic analysis of the central inter-
mediate 4.
Scheme 4. Synthesis of target structure 2 from 5-bromo-2-meth-
ylpent-2-ene (16).
As summarized in Scheme 4, the addition[21] of HCl gas
to 5-bromo-2-methylpent-2-ene (16) in the presence of
ZnCl2 in Et2O went smoothly and provided the 1-bromo-
In the next step of our synthesis of α-hydroxy ketone 2,
ω-chloro building block 15 in 74% yield. Following the pro- methyl carbinol 17 was selectively dehydrated to the pivotal
cedure of Reetz et al.,[20] cyclohexenyloxy trimethylsilane intermediate 4 by Appel–Lee bromination[23] and concomi-
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Ring Reversal of a Spirocyclic Patchouli Odorant
FULL PAPER
tant dehydrohalogenation.[23b] In the presence of Celite®,
Despite some slight resemblance to patchouli, the odor
the reaction of alcohol 17 with triphenylphosphane and tonality of our first target structure 2 was displaced towards
CBr4 in toluene provided alkene 4 as the main component the camphoraceous and minty side of the patchouli odor
(53%, GC) of a mixture of isomers. As it proved impossible attributes. So the question was raised as to whether this was
to isolate the desired isomer 4 by flash chromatography, the due to the position of the gem-dimethyl moiety and what
isomeric mixture containing 4 was employed without fur- the analogous 2,2,6-trimethylketone (22) would smell like.
ther purification. Initially, it was envisaged that target struc- Transposition of this bulky hydrophobic unit from C-1 to
ture 2 would be achieved by oxidative cleavage of the corre- C-2 could even improve the superposition on lead structure
sponding epoxide.[5] This was obtained by epoxidation with 1 as depicted in Figure 1. At least it would not compare
MCPBA in CH2Cl2 in moderate 21% yield as the major much worse than the first target molecule 2. The synthesis
compound (79%, GC) of an inseparable isomeric mixture. of this new target structure, 6-hydroxy-2,2,6-trimeth-
However, subsequent oxidation with DMSO under acidic ylspiro[4.5]decan-7-one (22), commenced with the spiroan-
conditions according to Tsuji and Cohen[24a] or Santosusso nulation of cyclohexanone with 1,4-dibromo-2,2-dimeth-
and Swern[24b] provided almost exclusively dehydration ylbutane (18). This bifunctional building block 18 was pre-
products. Jones oxidation[25] furnished a mixture composed pared from diethyl 2,2-dimethylsuccinate by reduction with
of rearrangement and elimination products, such as 1,1-di- LiAlH4 and bromination of the resulting 2,2-dimethylbu-
methyl-6-methylenespiro[4.5]decan-7-one. Employing PCC tane-1,4-diol with phosphorus tribromide in the presence
under similar reaction conditions[26] provided a complex of pyridine according to the procedure of Brown and van
mixture, which, apart from elimination products, also con- Gulick.[31] The spiroannulation of cyclohexanone with the
tained some minor components with the expected molecu- 1,4-dibromide 18 was effected by 2.2 equiv. potassium tert-
lar ion of m/z = 210. Yet, as it turned out to be impossible butoxide in refluxing toluene, and this furnished 2,2-di-
to separate and isolate these, it was attempted to open the methylspiro[4.5]decan-6-one (19) in a moderate 21% yield,
epoxide to the corresponding vic-diol with perchloric acid after purification by flash chromatography with subsequent
in aqueous THF[27] and to oxidize the latter to α-hydroxy Kugelrohr distillation. Following the route elaborated for
ketone 2. However, this reaction was not clean either, and the synthesis of the first target compound 2, the 2,2-di-
it led to a complex inseparable mixture.
methyl ketone 19 was treated with methyllithium in Et2O
Instead of subjecting the alkene mixture containing 4 at room temp. The corresponding methyl carbinol 20 was
now to an Upjohn dihydroxylation protocol[28] by em- isolated in 95% yield and subsequently dehydrated by Ap-
ploying N-methylmorpholine N-oxide as stoichiometric pel–Lee bromination with in situ dehydrohalogenation to
oxidant in the presence of catalytic amounts of OsO4, the provide 2,2,6-trimethylspiro[4.5]dec-6-ene (21) as the main
direct ketohydroxylation method developed by Plietker[29] component of an inseparable mixture of alkene isomers.
appeared to us to be a very elegant one-step alternative. Subjecting this isomeric mixture containing 21 to the
Just like the Katsuki–Sharpless oxidation,[30] the Plietker Plietker ketohydroxylation reaction afforded the second
ketohydroxylation reaction uses catalytic amounts of target structure 22 in 22% yield as a colorless liquid
RuO4, generated in situ from RuCl3 with Oxone® (Scheme 5).
(2KHSO5·KHSO4·K2SO4) as stoichiometric oxidant, but in
contrast to the Katsuki–Sharpless conditions, the Plietker
protocol does not lead to cleavage of the double bond, al-
though the cyclic ruthenate formed by [3+2] cycloaddition
and subsequent oxidation was proposed to be identical.[29c]
Yet, instead of an electrocyclic fragmentation as in the case
of the Katsuki–Sharpless reaction, in the presence of
Oxone® the nucleophilic addition of the peroxomonosulfate
anion (SO52–) leads to the formation of an α-hydroxy
ketone. In addition, the reaction is diastereoselective and an
attack from the least hindered face should furnish target
compound 2 with the desired like-stereochemistry. Sub-
jecting the alkene mixture containing 1,1,6-trimeth-
ylspiro[4.5]dec-6-ene (4) to the Plietker ketohydroxylation
reaction indeed provided, after purification by repeated
chromatography, the (5R*,6R*)-configured 6-hydroxy-
1,1,6-trimethylspiro[4.5]decan-7-one 2 in 33% yield as a col-
orless, semicrystalline solid. The like-configuration of our
first target compound 2 was unambiguously assigned by the
prominent cross peaks between the hydroxy function and 4-
Ha in the NOESY spectrum, which proved that the hydroxy
function at C-6 and the C-4 methylene unit were in cis-1,2
Scheme 5. Synthesis and olfactory properties of the isomeric 6-hy-
relation to one another.
droxy-2,2,6-trimethylspiro[4.5]decan-7-one (22).
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P. Kraft, A. Bruneau
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acteristics. Methyl carbinol 17 is the only typical patchouli
odorant of this series, and although weaker than our lead
Olfactory Properties and Conclusions
The key odor descriptors for “patchouli” are “camphora- compound 1, it indicates that the study of further substitu-
ceous”, “woody” and “earthy”,[32] and in the odor profile of tion patterns is promising. The synthetic sequence reported
the intense patchouli lead compound 1, these are perfectly in this paper opens up a new, short, and easy-to-perform
balanced, accompanied only by slightly woody-ambery and procedure for access to related target structures.
tobacco-like facets. Our spirocyclic ketol target 2 displayed
a camphoraceous, minty, eucalyptol-like odor with slightly
woody and earthy facets, and only a slight resemblance to
Experimental Section
IR: Bruker VECTOR 22/Harrick SplitPea micro ATR, Si; fre-
quencies in order of decreasing intensity. NMR: Bruker AVANCE
DPX-400, Bruker AVANCE 500 (TCI), Bruker AVANCE 600,
TMS as internal standard taken as δ = 0 ppm. MS: Finnigan MAT
95 (EI: 70 eV), HP Chemstation 6890 GC/5973 Mass Sensitive De-
tector. FC: Merck Kieselgel 60 (40–63 µm). TLC: Merck Kieselgel
60 F254 (particle size 5–20 µm, layer thickness 250 µm on glass,
5 cmϫ10 cm); visualization reagent: phosphomolybdic acid spray
and plunge soln. (Fluka 02553). Melting points: Büchi Melting
Point B545 (uncorrected). Elemental analyses: Mikroanalytisches
patchouli. Thus, the camphoraceous side of the racemic spi-
rocyclic target structure 2 outweighed the woody and earthy
character, and with an odor threshold of 17.2 ng/L air, it
was about 250 times weaker than the racemic lead com-
pound 1, for which an odor threshold of 0.067 ng/L air was
measured.[3] The low odor intensity and the pronounced
camphoraceous character of ketol 2 could be an indication
that the spirocyclic cyclopentyl ring sterically hinders the
interaction of the receptor with the hydroxy function, which
is the osmophore of (–)-patchoulol as indicated by the Laboratorium Ilse Beetz, 96301 Kronach, Germany. Unless other-
wise stated, all reactions were performed under N2 with reagents
and solvents (puriss. or purum) from SAFC that were used without
further purification. 1,4-Dibromo-2,2-dimethylbutane (18) was pre-
pared from diethyl 2,2-dimethylsuccinate by reduction with LiAlH4
and subsequent bromination with phosphorus tribromide accord-
ing to the procedure of Brown and van Gulick.[31]
weaker intensity of a ketol analog prepared in a recent pub-
lication.[2] Indeed, the odor of ketol 2 is not far from that
of 2-(1,1-dimethylethyl)-4-methylcyclohexanol (Rootanol®),
which emanates a camphoraceous, minty odor with earthy
and root-like nuances.[33] So the bulky tert-butyl substituent
could to some extent mimic the fused gem-dimethyl cy-
clopentyl ring. In the alcohol precursor 17 to the first target
compound 2, the configuration of the hydroxy group is in-
verted, and thus sterically even less accessible for a receptor,
as it is situated on the same side of the cyclohexyl plane as
the gem-dimethyl substituent. However, with an odor
threshold of 5 ng/L air, methyl carbinol 17 is stronger in
The odor thresholds were determined by GC olfactometry: Dif-
ferent dilutions of the sample substance were injected into a gas
chromatograph in descending order of concentration until the pan-
elist failed to detect the corresponding substance at the sniffing
port. The panelist smelled in blind and pressed a button upon per-
ceiving an odor. If the recorded time matched the retention time,
the sample was further diluted. The last concentration detected at
odor than target compound 2, and it displays a far more the correct retention time was recorded as the individual odor
threshold. The reported threshold values are the geometrical means
of the individual odor thresholds of the different panelists.
typical patchouli odor with well-balanced woody, earthy,
and camphoraceous elements and only a weakly borneol-
like undercurrent.
Ethyl 4-Methylpent-4-enoate (8): A mixture of 2-methylprop-2-en-
1-ol (9, 50.0 g, 693 mmol) and triethyl orthoacetate (283 g,
1.74 mol) was heated at 125 °C for 4 h in the presence of propionic
acid (3.08 g, 41.6 mmol) with continuous removal of the distilled
EtOH (82 mL). The reaction mixture was cooled to room temp.,
diluted with Et2O (200 mL), washed with aq. HCl solution (1 ,
2ϫ100 mL), saturated aq. NaHCO3 solution (2ϫ200 mL), and
brine (2ϫ200 mL). After being dried (Na2SO4) and filtered, the
organic solution was concentrated in a rotary evaporator under
reduced pressure. The resulting residue was purified by fractional
distillation in a Vigreux assembly to furnish, at 31.5–33.0 °C/
The second target structure 22 was, with an odor thresh-
old of 233 ng/L air, the weakest odorant of the series, and
only characterized by woody, cedar-type facets and a some-
what powdery connotation. As ketol 22 was obtained and
evaluated as the racemic mixture of both diastereoisomeric
forms, apparently no stereoisomer possesses a distinct ol-
factory profile, let alone typical patchouli characteristics.
The intermediate methyl carbinol 20, also a racemic mix-
ture of diastereoisomers, in fact the decarbonyl analog of
22, is, with a threshold of 68 ng/L air, significantly stronger 2 mbar, compound 8 (69.9 g, 71%) as a colorless liquid. IR (ATR):
ν = 1734 (νC=O), 1153 (νC–O–C), 888 (γ=C–H, 1,1-disubst.), 1030
˜
than the second target compound 22, but clearly weaker
than the first target molecule 2. Moreover, like the first tar-
get compound 2, the odor profile of methyl carbinol 20 is
also dominated by camphoraceous aspects. Some earthy
and woody facets are present as well, yet the woody note is
more similar to vetiver than patchouli oil, with some resem-
blance to grapefruit peel.
(νC–O–C), 1371 (δCH3), 1445 (δC–H), 1651 (νC=C), 3079 (ν=C–
H) cm–1. 1H NMR (CDCl3): δ = 1.26 (t, J = 7.0 Hz, 3 H, CH2CH3),
1.75 (br. s, 3 H, 4-Me), 2.33 (mc, 2 H, 3-H2), 2.45 (mc, 2 H, 2-H2),
4.13 (q, J = 7.0 Hz, 2 H, CH2CH3), 4.69 (mc, 1 H, 5-HE), 4.74 (mc,
1 H, 5-HZ) ppm. 13C NMR (CDCl3): δ = 14.2 (q, CH2CH3), 22.4
(q, 4-Me), 32.6 (2t, C-2,-3), 60.2 (t, CH2CH3), 110.3 (t, C-5), 144.1
(s, C-4), 173.2 (s, C-1) ppm. MS (EI): m/z (%) = 142 (10) [M+], 114
(1) [M+ – C2H4], 97 (20) [M+ – C2H5O], 96 (18) [M+ – C2H6O],
69 (100) [C5H9+], 55 (20) [C4H7+], 41 (42) [C3H5+]. Odor: Fruity,
In conclusion, the carbonyl function of ketols 2 and 22
seems to be responsible for the shift of the odor character
towards the camphoraceous side. Odor intensity and pa- reminiscent of strawberries, pineapple, and ethyl 2-methylpentano-
ate (Manzanate®).
tchouli character are, however, influenced more distinctly
by the position of the gem-dimethyl group, and the 1,1-di-
methyl substitution favors the typical patchouli odor char- in portions with vigorous stirring over 120 min to a solution of
4-Methylpent-4-en-1-ol (10): LiAlH4 (13.1 g, 344 mmol) was added
2262
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2257–2267

Ring Reversal of a Spirocyclic Patchouli Odorant
FULL PAPER
ethyl 4-methylpent-4-enoate (8, 69.9 g, 499 mmol) in dry Et2O
(42.7 g, 77%) as a slightly yellowish amorphous solid. IR (ATR):
(500 mL), while the temp. was maintained between –10 and –5 °C ν = 1600 (νC=C), 1629 (νC=O), 1091 (ν C–O–C), 1243 (ν C–O–
˜
as
s
1
(dry ice/EtOH bath). The resulting suspension was heated under
reflux for an additional 2 h, and the reaction was quenched be-
tween 0 and 5 °C by careful addition of water (13 mL), aq. NaOH
solution (15%, 13 mL), and water (39 mL) with vigorous stirring
over a period of 60 min. After the mixture was stirred for further
30 min at room temp., the resulting precipitate was filtered off and
washed with Et2O (300 mL). The filtrate was dried (Na2SO4) and
concentrated in a rotary evaporator under reduced pressure. The
resulting residue (57.5 g) was used for tosylation and bromination
without further purification, a sample purified by fractional distil-
lation in a Vigreux assembly furnished, at 40–45 °C/2 mbar, com-
pound 10 (43.5 g, 87%) in pure form as a colorless liquid. IR
C), 1376 (δCH3), 1351 (νasC–C) cm–1. H NMR (CDCl3): δ = 1.68
(t, J = 1.5 Hz, 3 H, 2-Me), 1.99 (quint, J = 6.5 Hz, 2 H, 5-H2),
2.33 (t, J = 6.5 Hz, 2 H, 4-H2), 2.58 (tq, J = 6.5, 1.5 Hz, 2 H, 6-
H2), 3.83 (s, 3 H, OCH3) ppm. 13C NMR (CDCl3): δ = 7.2 (q, 2-
Me), 20.8 (t, C-5), 24.7 (t, C-4), 36.2 (t, C-6), 55.1 (q, OCH3), 114.6
(s, C-2), 171.9 (s, C-3), 198.7 (C-1) ppm. MS (EI): m/z (%) = 140
(100) [M+], 125 (22) [M+ – CH3], 112 (40) [M+ – CO], 95 (18) [M+ –
C2H5O], 83 (54) [C5H7O+], 69 (18) [C4H5O+], 54 (88) [C4H6+], 43
(73) [C3H7+].
(؎)-2-Methyl-3-(4Ј-methylpent-4Ј-enyl)cyclohex-2-en-1-one (3):
A
suspension of Mg turnings (2.08 g, 86.0 mmol) and 1-bromo-4-
methyl-4-pentene (7, 3 drops) in THF (4 mL) was heated with a
heating gun until an exothermic reaction set in. Thereupon, the
reaction mixture was diluted with THF (40 mL) and heated under
reflux for 5 min. The hot plate was switched off, 1-bromo-4-meth-
ylpent-4-ene (7, 7.35 g, 45.1 mmol) was added dropwise with stir-
ring over 20 min, and the reaction mixture was heated under reflux
for 10 min. The freshly prepared Grignard solution was cooled to
room temp. and added dropwise with stirring to a solution of 3-
methoxy-2-methylcyclohex-2-en-1-one (6, 4.07 g, 29.0 mmol) in
THF (10 mL). The reaction mixture was then heated under reflux
for 20 min, cooled to room temp., and poured into ice (20 g)/aq.
HCl (10%, 25 mL). After being stirred at room temp. for 2 h, the
resulting mixture was saturated with NaCl, and the layers were
separated. The aqueous one was extracted with Et2O (3ϫ50 mL),
and the combined organic layers were washed in turn with satu-
rated aq. NaHCO3 solution (3ϫ50 mL), water (3ϫ50 mL), and
brine (2ϫ50 mL). After being dried (Na2SO4) and filtered, the or-
ganic solution was concentrated in a rotary evaporator under re-
duced pressure. The resulting residue was purified by silica gel FC
(pentane/Et2O, 8:2, Rf = 0.33) to provide compound 3 (3.72 g,
(ATR): ν = 3318 (νO–H), 884 (γ=C–H, 1,1-disubst.), 1444 (δC–H),
˜
1650 (νC=C), 1375 (δCH3), 3075 (ν=C–H) cm–1. 1H NMR
(CDCl3): δ = 1.69 (tt, J = 8.0, 6.5 Hz, 2 H, 2-H2), 1.73 (br. s, 3 H,
4-Me), 2.09 (t, J = 8.0 Hz, 2 H, 3-H2), 2.40 (s, 1 H, OH), 3.63 (t,
J = 6.5 Hz, 2 H, 1-H2), 4.71 (m, 2 H, 5-H2) ppm. 13C NMR
(CDCl3): δ = 22.3 (q, 4-Me), 30.5 (t, C-2), 34.0 (t, C-3), 62.5 (t, C-
1), 110.1 (t, C-5), 145.4 (s, C-4) ppm. MS (EI): m/z (%) = 100 (1)
[M+], 82 (5) [M+ – H2O], 81 (9) [C6H9+], 72 (17) [C4H8O+], 69 (20)
[C5H9+], 67 (84) [C5H7+], 56 (100) [C4H8+], 41 (91) [C3H5+], 31
(13) [CH3O+]. Odor: Fatty, green, ethereal, with a slightly powdery
character.
1-Bromo-4-methylpent-4-ene (7): A mixture of 4-methylpent-4-en-
1-ol (10, 48.0 g, 479 mmol) and TsCl (137 g, 719 mmol) in pyridine
(192 mL) was stirred at 0 °C for 3 h prior to being poured into
toluene (350 mL) and careful addition of aq. HCl (6 , 1 L) with
stirring below 10 °C (ice/water bath). The layers were separated,
and the aqueous layer was extracted with Et2O (3ϫ300 mL). The
combined organic layers were washed with water (2ϫ300 mL), sat-
urated aq. Na2CO3 solution (2ϫ300 mL), and brine (2ϫ300 mL).
After being dried (Na2SO4) and filtered, the organic solution was
concentrated in a rotary evaporator under reduced pressure, and
the resulting crude 4-methyl-4-pentenyl 4Ј-methylbenzenesulfonate
(70.2 g, 276 mmol, 58% yield) was heated with anhydrous LiBr
67%) as a slightly yellowish oil. IR (ATR): ν = 1661 (νC=O), 884
˜
(γ=C–H, 1,1-disubst.), 1356 (νasC–C), 1376 (δsCH3), 1326/1303
(rβ=CH), 1454 (δasCH3), 1430 (δs=CH2 ip) cm–1. 1H NMR
(CDCl3): δ = 1.57–1.65 (m, 2 H, 2Ј-H2), 1.73 (br. s, 3 H, 2-Me),
(50.4 g, 580 mmol) in 1,2-dimethoxyethane (600 mL) under reflux 1.77 (t, J = 1.5 Hz, 3 H, 4Ј-Me), 1.93 (tdd, J = 7.5, 7.0, 6.0 Hz, 2
for 35 min. The reaction mixture was cooled to room temp. and
poured into saturated aq. Na2CO3 solution. The layers were sepa-
rated, and the aqueous one was extracted with Et2O (2ϫ200 mL).
The combined organic extracts were washed with saturated aq.
Na2CO3 solution (3ϫ200 mL) and brine (2ϫ200 mL). After being
dried (Na2SO4) and filtered, the organic solution was concentrated
in a rotary evaporator under reduced pressure, and the resulting
residue was purified by silica gel FC (pentane/Et2O, 9:1, Rf = 0.92)
to provide compound 7 (29.6 g, 38% overall yield) as a slightly
H, 5-H2), 2.06 (t, J = 7.5 Hz, 2 H, 4-H2), 2.24 (t, J = 8.0 Hz, 2 H,
1Ј-H2), 2.34 (td, J = 6.0, 1.5 Hz, 2 H, 3Ј-H2), 2.39 (dd, J = 7.0,
6.0 Hz, 2 H, 6-H2), 4.69 (mc, 1 H, 5Ј-HE), 4.74 (mc, 1 H, 5Ј-HZ)
ppm. 13C NMR (CDCl3): δ = 10.5 (q, 2-Me), 22.3 (q, 4Ј-Me), 22.5
(t, C-5), 25.2 (t, C-2Ј), 30.8 (t, C-4), 34.8 (t, C-6), 37.6/37.7 (2t, C-
1Ј,-3Ј), 110.4 (t, C-5Ј), 130.9 (s, C-2), 145.0 (s, C-4Ј), 158.8 (s, C-
3), 199.4 (s, C-1) ppm. MS (EI): m/z (%) = 192 (18) [M+], 177 (12)
[M+ – CH3], 164 (9) [M+ – CO], 149 (38) [M+ – CO – CH3], 136
(78) [M+ – C4H8], 124 (100) [M+ – C5H8], 108 (93) [C8H12+], 96
yellowish liquid. IR (ATR): ν = 888 (γ=C–H, 1,1-disubst.), 1439 (83) [C7H12+], 79 (75) [C6H7+], 69 (75) [C5H9+], 55 (74) [C4H7+], 41
˜
1
(δC–H), 641 (νC–Br), 1650 (νC=C), 1375 (δCH3) cm–1. H NMR
(CDCl3): δ = 1.72 (br. s, 3 H, 4-Me), 2.00 (quint, J = 7.0 Hz, 2 H,
2-H2), 2.16 (t, J = 7.0 Hz, 2 H, 3-H2), 3.40 (t, J = 7.0 Hz, 2 H, 1-
H2), 4.72 (mc, 1 H, 5-HE), 4.76 (mc, 1 H, 5-HZ) ppm. 13C NMR
(CDCl3): δ = 22.3 (q, 4-Me), 30.6 (t, C-2), 33.2 (t, C-1), 36.0 (t, C-
3), 111.0 (t, C-5), 143.9 (s, C-4) ppm. MS (EI): m/z (%) = 162 (3)
[M+], 134 (1) [M+ – C2H4], 83 (9) [M+ – Br], 67 (12) [C5H7+], 56
(100) [C4H8+], 55 (42) [C4H7+], 41 (26) [C3H5+].
(98) [C3H5+].
(؎)-2-Methyl-3-(4Ј-methylpent-4Ј-enyl)cyclohex-2-en-1-ol (11): At
0 °C, 2-methyl-3-(4Ј-methylpent-4Ј-enyl)cyclohex-2-en-1-one (3,
3.88 g, 20.2 mmol) was added dropwise to a stirred suspension of
LiAlH4 (383 mg, 10.1 mmol) in dry Et2O (50 mL). The cooling
bath was removed, and stirring was continued at room temp. for
15 min, prior to pouring the reaction mixture into ice/water
(100 mL). The product was extracted with Et2O (3ϫ25 mL), and
the combined extracts were washed with brine (2ϫ50 mL), dried
(Na2SO4), filtered, and concentrated in a rotary evaporator under
reduced pressure to furnish compound 11 (3.87 g, 99%) as a color-
3-Methoxy-2-methylcyclohex-2-en-1-one (6): A mixture of 2-methyl-
cyclohexane-1,3-dione (50.0 g, 396 mmol), trimethyl orthoformate
(63.1 g, 595 mmol) and TsOH (754 mg, 4.38 mmol, 1 mol-%) in
methanol (400 mL) was stirred at room temp. for 2 d. The resulting
yellow solution was concentrated in a rotary evaporator under re-
duced pressure, and the residue was purified by silica gel FC (pen-
tane/Et2O, 8:2 Ǟ Et2O pure, Rf = 0.16) to provide compound 6
less oil. IR (ATR): ν = 3319 (νO–H), 885 (γ=C–H), 965 (γ=C–O–
˜
H), 1649 (νC=C), 1439 (δC–H), 1373 (δCH3), 1271 (νC–O), 3073
(ν=C–H) cm–1. 1H NMR (C6D6): δ = 1.42 (mc, 1 H, 5-Hb), 1.48
(ddddd, J = 14.0, 7.0, 7.0, 0.5, 0.5 Hz, 1 H, 2Ј-Hb), 1.58 (mc, 1 H,
Eur. J. Org. Chem. 2007, 2257–2267
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2263

P. Kraft, A. Bruneau
FULL PAPER
6-Hb), 1.63 (mc, 1 H, 5-Ha), 1.66 (s, 3 H, 4Ј-Me), 1.68 (mc, 1 H, 6-
Ha), 1.69 (br. s, 1 H, O–H), 1.76 (br. s, 3 H, 2-Me), 1.77–1.83 (m,
[M+ – C3H6Cl], 107 (4) [M+ – Cl – C4H8], 83 (100) [M+ – Cl –
HBr], 77 (42) [C3H6Cl+], 67 (116) [C5H7+], 56 (52) [C4H8+], 55 (55)
2 H, 4-H2), 1.93 (t, J = 7.0 Hz, 2 H, 1Ј-H2), 1.94 (mc, 1 H, 2Ј-Ha), [C4H7+], 41 (58) [C3H5+].
1.95 (t, J = 7.0 Hz, 2 H, 3Ј-H2), 3.85 (t, J = 4.0 Hz, 1 H, 1-H), 4.79
(s, 1 H, 5Ј-HE), 4.81 (s, 1 H, 5Ј-HZ) ppm. 13C NMR (C6D6): δ =
16.0 (q, 2-Me), 18.8 (t, C-5), 22.2 (q, 4Ј-Me), 26.0 (t, C-2Ј), 29.9 (t,
C-4), 32.6 (t, C-6), 33.3 (t, C-1Ј), 37.9 (t, C-3Ј), 69.2 (d, C-1), 110.1
(t, C-5Ј), 128.7 (s, C-2), 134.0 (s, C-3), 145.4 (s, C-4Ј) ppm. MS
(؎)-2-(4Ј-Bromo-1Ј,1Ј-dimethylbutyl)cyclohexan-1-one (13): A cold
(–40 °C) solution of titanium tetrachloride (49.0 mL, 450 mmol) in
CH2Cl2 (200 mL) was added over 4 min, at –40 °C and with vigor-
ous stirring, to a mixture of 1-trimethylsiloxycyclohexene (14,
76.7 g, 450 mmol) and 1-bromo-4-chloro-4-methylpentane (15,
99.8 g, 500 mmol) in CH2Cl2 (900 mL). Following complete ad-
dition, the dark red mixture was stirred at –40 °C overnight, prior
to pouring the cold mixture into ice/water (1:1, 3 L) with vigorous
stirring. The layers were separated, and the organic layer was
washed with saturated aq. NaHCO3 solution (3ϫ600 mL) and
water (3ϫ600 mL). The combined aqueous layers were extracted
with CH2Cl2 (in portions, 100 mL CH2Cl2 per L). The organic ex-
tracts were combined, dried (Na2SO4), and concentrated in a rotary
evaporator under reduced pressure. The resulting residue was puri-
fied by silica gel FC (pentane/Et2O, 19:1, Rf = 0.30) to afford com-
(EI): m/z (%) = 194 (2) [M+], 179 (1) [M+ – CH3], 176 (20) [M+
–
H2O], 138 (18) [M+ – C4H8], 123 (29) [M+ – C4H8 – CH3], 111
(100) [C8H15+], 105 (49) [C8H9+], 93 (65) [C7H9+], 79 (42) [C6H7+],
67 (23) [C5H7+], 55 (45) [C4H7+], 41 (44) [C3H5+]. C13H22O
(194.31): calcd. C 80.35, H 11.41; found C 80.36, H 11.38. Odor:
green-earthy, linalool-like, with citrusy and slightly pyrazine-like
facets.
(؎)-2-Methyl-3-(4Ј-methylpent-4Ј-enyl)cyclohex-2-en-1-yl Acetate
(5): N,NЈ-Dicyclohexylcarbodiimide (2.27 g, 11.0 mmol) was added
at 0 °C to a stirred solution of 2-methyl-3-(4Ј-methylpent-4Ј-enyl)-
cyclohex-2-en-1-ol (11, 1.94 g, 10.0 mmol), AcOH (600 mg,
9.99 mmol) and 4-(dimethylamino)pyridine (120 mg, 0.982 mmol)
in CH2Cl2 (30 mL). Stirring was continued at room temp. for 16 h
prior to filtration of the insoluble materials. The filter cake was
washed with CH2Cl2 (10 mL), and the combined extracts were con-
centrated in a rotary evaporator under reduced pressure. The re-
sulting residue was purified by silica gel FC (pentane/Et2O, 19:1,
Rf = 0.47) to provide compound 5 (2.33 g, 99%) as a colorless
pound 13 (36.4 g, 31%) as a yellow liquid. IR (ATR): ν = 1705
˜
(νC=O), 1125 (νasC–C), 1448 (δC–H), 1386 (δsCH3), 835/647 (νC–
1
Br) cm–1. H NMR (C6D6): δ = 0.87 (s, 3 H, 1Ј-Me), 0.96 (s, 3 H,
1Ј-Me), 1.14 (mc, 1 H, 4-Hb), 1.15 (mc, 1 H, 3-Hb), 1.24 (mc, 1 H,
2Ј-Hb), 1.29 (mc, 1 H, 5-Hb), 1.46 (mc, 1 H, 4-Ha), 1.43–1.52 (m, 2
H, 3Ј-H2), 1.50 (mc, 1 H, 2Ј-Ha), 1.59 (mc, 1 H, 5-Ha), 1.72 (mc, 1
H, 3-Ha), 1.80 (ddd, J = 12.5, 4.5, 1.0 Hz, 1 H, 2-H), 1.84 (tdd, J
= 12.5, 6.0, 1.0 Hz, 1 H, 6-Hb), 2.13 (dddd, J = 12.5, 4.5, 3.0,
2.0 Hz, 1 H, 6-Ha), 2.97 (mc, 2 H, 4Ј-H2) ppm. 13C NMR (C6D6):
δ = 24.4 (q, 1Ј-Me), 24.7 (q, 1Ј-Me), 25.9 (t, C-4), 27.8 (t, C-3Ј),
28.3 (t, C-5), 29.1 (t, C-3), 33.9 (s, C-1Ј), 34.2 (t, C-4Ј), 38.6 (t, C-
2Ј), 43.9 (t, C-6), 57.9 (d, C-2), 210.1 (s, C-1) ppm. MS (EI): m/z
(%) = 260 (1) [M+], 245 (1) [M+ – CH3], 180 (1) [M+ – HBr], 163
(1) [C6H12Br+], 139 (2) [M+ – C3H6Br], 98 (100) [C6H10O+], 83 (19)
[C6H11+], 70 (9) [C5H10+], 69 (11) [C5H9+], 55 (20) [C4H7+], 41 (15)
[C3H5+].
oil. IR (ATR): ν = 1233 (νC–O), 1731 (νC=O), 885 (γ=C–H, 1,1-
˜
disubst.), 960 (δ=C–H), 1010 (νC–O–C), 1369 (δCH3), 2934 (ν=C–
H), 1164 (νC–O–C), 1441 (δC–H) cm–1. 1H NMR (C6D6): δ = 1.37
(mc, 1 H, 5-Hb), 1.38–1.46 (m, 2 H, 2Ј-H2), 1.59 (mc, 1 H, 6-Hb),
1.60 (mc, 1 H, 5-Ha), 1.62 (s, 3 H, 4Ј-Me), 1.63 (s, 3 H, 2-Me), 1.73
(mc, 1 H, 4-Hb), 1.75 (s, 3 H, OCOCH3), 1.79 (mc, 1 H, 6-Ha), 1.84
(mc, 1 H, 4-Ha), 1.89 (t, J = 8.0 Hz, 2 H, 1Ј-H2), 1.90 (t, J = 7.0 Hz,
2 H, 3Ј-H2), 4.76 (s, 1 H, 5Ј-HE), 4.79 (s, 1 H, 5Ј-HZ), 5.40 (br. s,
1 H, 1-H) ppm. 13C NMR (C6D6): δ = 15.6 (q, 2-Me), 18.8 (t, C-
5), 20.6 (q, OCOCH3), 22.0 (q, 4Ј-Me), 25.7 (t, C-2Ј), 29.2 (t, C-6),
29.4 (t, C-4), 33.1 (t, C-1Ј), 37.6 (t, C-3Ј), 71.6 (d, C-1), 110.0 (t,
C-5Ј), 124.7 (s, C-2), 136.9 (s, C-3), 145.1 (s, C-4Ј), 169.8 (s, OC-
(؎)-1,1-Dimethylspiro[4.5]decan-6-one (12): A solution of 2-(4Ј-
bromo-1Ј,1Ј-dimethylbutyl)cyclohexan-1-one (13, 32.7 g, 125 mmol)
in toluene (150 mL) was added slowly, at room temp. and with
mechanic stirring, to a suspension of potassium tert-butoxide
(15.4 g, 138 mmol) in toluene (250 mL) over a period of 60 min. In
the course of the addition, which was exothermic but was adjusted
to a reaction temperature below 35 °C, the mixture thickened and
liquefied again. The mixture was then heated at 70 °C for 60 min.
After being cooled, the resulting solution was diluted in Et2O
(250 mL) and washed with saturated aq. NH4Cl solution
(3ϫ100 mL) and brine (3ϫ100 mL). After being dried (Na2SO4),
the organic phase was concentrated in a rotary evaporator under
reduced pressure. The resulting residue was purified by silica gel
FC (pentane/Et2O, 39:1, Rf = 0.30) to furnish compound 12
OCH3) ppm. MS (EI): m/z (%) = 236 (1) [M+], 194 (1) [M+
–
C2H2O], 180 (2) [M+ – C4H8], 176 (37) [M+ – C2H4O2], 161 (11)
[M+ – C2H4O2 – CH3], 147 (5) [M+ – C4H9O2], 133 (19) [M+
C5H11O2], 121 (54) [M+ – C6H11O2], 120 (42) [M+ – C2H4O2
–
–
C4H8], 108 (51) [C8H12+], 105 (80) [C8H9+], 93 (100) [C7H9+], 91
(72) [C7H7+], 79 (54) [C6H7+], 60 (12) [C2H4O2+], 55 (27) [C4H7+],
43 (39) [C2H3O+]. C15H24O2 (236.35): calcd. C 76.23, H 10.24;
found C 76.19, H 10.20.
1-Bromo-4-chloro-4-methylpentane (15): Gaseous hydrogen chloride
was slowly bubbled through a solution of 5-bromo-2-methyl-2-pen-
tene (16, 110 g, 675 mmol) and zinc chloride (4.60 g, 33.8 mmol,
5 mol-%) in Et2O (675 mL) at room temp. over a period of 27 h.
The mixture was then stirred at room temp. overnight, washed with
saturated aq. NaHCO3 solution (2ϫ200 mL), and dried (Na2SO4).
After evaporation of the solvent in a rotary evaporator under re-
duced pressure, the residue was purified by fractional distillation
in a Vigreux assembly to furnish, at 45–46 °C/2 mbar, compound
(11.2 g, 50%) as a colorless liquid. IR (ATR): ν = 1697 (νC=O),
˜
1450 (δC–H), 1128 (νasC–C), 1384 (δsCH3) cm–1. 1H NMR (C6D6):
δ = 0.82/1.03 (2s, 6 H, 1-Me2), 1.23 (mc, 1 H, 9-Hb), 1.27 (mc, 1 H,
10-Hb), 1.33 (mc, 1 H, 4-Hb), 1.38 (mc, 1 H, 2-Hb), 1.39 (mc, 1 H,
9-Ha), 1.39–1.46 (m, 2 H, 8-H2), 1.50 (mc, 1 H, 3-Hb), 1.58 (mc, 1
H, 10-Ha), 1.67 (dtdd, J = 13.0, 10.0, 6.0, 4.5 Hz, 1 H, 3-Ha), 1.95
(ddd, J = 12.0, 10.0, 7.0 Hz, 1 H, 2-Ha), 2.10 (mc, 1 H, 7-Hb), 2.11
(mc, 1 H, 4-Ha), 2.22 (mc, 1 H, 7-Ha) ppm. 13C NMR (C6D6): δ =
20.4 (t, C-3), 22.0 (t, C-9), 24.6/25.5 (2q, 1-Me2), 25.7 (t, C-8), 33.8
(t, C-10), 35.5 (t, C-4), 40.4 (t, C-2), 40.8 (t, C-7), 44.1 (s, C-1),
15 (100 g, 74%) as a colorless liquid. IR (ATR): ν = 1260
˜
(ωCH2BrCH2), 1369 (δCH3), 1100 (rβCH2CH2), 1452 (δC–H), 761
(νasC–Cl), 1150 (tCH2BrCH2CH2), 647 (νsC–Br), 1386 (δsCH3),
1
1296 (νCH3ClC–CH3) cm–1. H NMR (CDCl3): δ = 1.59 (s, 6 H,
4-Me2), 1.88 (mc, 2 H, 3-H2), 2.07 (mc, 2 H, 2-H2), 3.44 (t, J = 60.4 (s, C-5), 212.8 (s, C-6) ppm. MS (EI): m/z (%) = 180 (11) [M+],
6.5 Hz, 2 H, 1-H2) ppm. 13C NMR (CDCl3): δ = 28.6 (t, C-2), 32.5 124 (9) [M+ – C4H8], 111 (100) [C7H11O+], 95 (16) [C7H11+], 81
(2q, 4-Me2), 33.6 (t, C-1), 44.5 (t, C-3), 69.9 (s, C-4) ppm. MS (EI): (15) [C6H9+], 70 (11) [C5H10+], 67 (18) [C5H7+], 55 (24) [C4H7+], 41
m/z (%) = 183 (1) [M+ – CH3], 165/163 (24)/(25) [M+ – Cl], 121 (2)
(16) [C3H5+]. C12H20O (180.29): calcd. C 79.94, H 11.18; found C
2264
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2257–2267

Ring Reversal of a Spirocyclic Patchouli Odorant
FULL PAPER
79.80, H 11.26. Odor: camphoraceous, eucalyptol-like, and her-
baceous, reminiscent of rosemary with a slight woody inflection.
240 (1) [M+], 225 (1) [M+ – CH3], 208 (2) [M+ – CH3OH], 193 (3)
[M+ – CH3OH – CH3], 177 (80) [C13H21+], 163 (13) [C12H19+], 136
(29) [C10H16+], 121 (24) [C9H13+], 109 (53) [C8H13+], 95 (72)
[C7H11+], 81 (47) [C6H9+], 69 (32) [C5H9+], 55 (42) [C4H7+], 45 (100)
[C3H9+].
(؎)-(5R*,6S*)-1,1,6-Trimethylspiro[4.5]decan-6-ol (17): At room
temp., 1,1-dimethylspiro[4.5]decan-6-one (12, 3.61 g, 20.0 mmol)
was injected by syringe over 2 min to a stirred solution of meth-
yllithium (1.6  in Et2O, 40.0 mL, 64.0 mmol). Stirring was contin-
ued for 30 min at room temp., prior to quenching with cold satu-
rated aq. NH4Cl solution (50 mL). After separation of the layers,
the aqueous one was extracted with Et2O (2ϫ30 mL). The organic
extracts were combined and washed in turn with saturated aq.
NaHCO3 solution (3ϫ30 mL) and brine (3ϫ30 mL). After being
dried (Na2SO4), the resulting solution was concentrated in a rotary
evaporator under reduced pressure. The resulting residue was puri-
fied by silica gel FC (pentane/Et2O, 37:3, Rf = 0.27) to furnish
(؎)-1,1,6-Trimethylspiro[4.5]dec-6-ene (4): At room temp., tri-
phenylphosphane (2.83 g, 10.8 mmol) was added in portions to a
stirred suspension of 1,1,6-trimethylspiro[4.5]decan-6-ol (17, 1.77 g,
9.00 mmol), tetrabromomethane (3.58 g, 10.8 mmol) and Celite®
(750 mg) in toluene (20 mL). The reaction mixture was stirred at
room temp. for 1 h prior to filtering off the insoluble materials.
This filter cake was macerated with hexane (15 mL), and the wash-
ings were again filtered. The combined filtrates were washed with
saturated aq. NaHCO3 solution (15 mL) and brine (15 mL), and,
after being dried (Na2SO4), they were concentrated in a rotary
compound 17 (2.71 g, 69%) as a colorless liquid. IR (ATR): ν =
˜
1172 (νC–O, tert-OH), 1044/929 (νC–O, trans-gauche), 1375 evaporator under reduced pressure. The resulting residue was puri-
(δsCH3), 1448 (δC–H), 1474 (δC–O–H), 3499 (νO–H) cm–1. 1H fied by filtration (pentane) over a pad of silica gel to furnish a
NMR (CDCl3): δ = 0.99/1.20 (2s, 6 H, 1-Me2), 1.28 (mc, 1 H, 9-
slightly cloudy mixture of isomers containing compound 4 (1.69 g
Hb), 1.29 (mc, 1 H, 10-Hb), 1.30 (mc, 1 H, 7-Hb), 1.30 (s, 3 H, 6- of mixture, GC: 37% in 4, 39% yield). IR (ATR): ν = 2922/2863
˜
Me), 1.39–1.46 (m, 2 H, 3-H2), 1.46–1.64 (m, 2 H, 2-H2), 1.52–1.63 (νC–H), 1442 (δC–H), 1373 (δsCH3), 803 (νC=C–H, out-of-plane,
(m, 2 H, 8-H2), 1.54 (mc, 1 H, 9-Ha), 1.60–1.73 (m, 2 H, 4-H2), trisubst.), 1703 (νC=C) cm–1. 1H NMR (CDCl3): δ = 0.94/0.96 (2s,
1.63 (mc, 1 H, 7-Ha), 1.67 (mc, 1 H, 10-Ha), 1.72 (mc, 1 H, OH).
13C NMR (CDCl3): δ = 20.5 (t, C-8), 21.8 (t, C-3), 22.8 (t, C-9),
28.2/28.3 (2q, 1-Me2), 28.8 (q, 6-Me), 29.9 (t, C-10), 32.5 (t, C-4),
6 H, 1-Me2), 1.40–1.85 (m, 10 H, 2-, 3-, 4-, 9-, 10-H2), 1.74 (td, J
= 2.0, 1.5 Hz, 3 H, 6-Me), 1.92–1.97 (m, 2 H, 8-H2), 5.38 (mc, 1
H, 7-H) ppm. 13C NMR (CDCl3): δ = 19.9 (t, C-9), 21.7 (t, C-3),
41.1 (t, C-7), 42.7 (t, C-2), 46.6 (s, C-1), 52.8 (s, C-5), 76.5 (s, C-6) 23.3 (q, 6-Me), 25.7 (t, C-8), 26.5/27.0 (2q, 1-Me2), 34.5 (t, C-10),
ppm. MS (EI): m/z (%) = 196 (7) [M+], 178 (9) [M+ – H2O], 163
(75) [M+ – CH3 – H2O], 136 (60) [M+ – C3H8O], 122 (50) [M+
38.7 (t, C-4), 43.8 (t, C-2), 44.6 (s, C-1), 49.9 (s, C-5), 124.1 (d, C-
–
7), 139.7 (s, C-6) ppm. MS (EI): m/z (%) = 178 (19) [M+], 163 (2)
C4H10O], 109 (64) [C8H13+], 95 (54) [C7H11+], 82 (91) [C6H10+], 71 [M+ – CH3], 135 (8) [M+ – C3H7], 121 (17) [M+ – C4H9], 108 (100)
(86) [C5H11+], 67 (51) [C5H7+], 55 (63) [C4H7+], 43 (100) [C3H7+]. [M+ – C5H10], 93 (92) [M+ – C5H10 – CH3], 82 (51) [C6H10+], 79
Odor: patchouli, woody, earthy, and camphoraceous with some
borneol-like undercurrent. Odor threshold: 5 ng/L air.
(31) [C6H7+], 67 (15) [C5H7+], 55 (19) [C4H7+], 41 (22) [C3H5+].
(؎)-(5R*,6R*)-6-Hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one (2):
At room temp., Oxone® (29.2 g, 47.5 mmol) was added in one dash
to a stirred suspension of NaHCO3 (2.00 g, 23.8 mmol) and
RuCl3·2H2O (39.4 mg, 0.162 mmol) in EtOAc/CH3CN/H2O (6:6:1,
130 mL). After being stirred for 5 min at room temp., the resulting
suspension was cooled down to 0 °C (ice/water bath), prior to ad-
dition of the crude 1,1,6-trimethylspiro[4.5]dec-6-ene mixture
(1.69 g, 37% in 4, 3.49 mmol). The reaction mixture was stirred at
0 °C for 40 min, diluted with EtOAc (100 mL), and filtered by suc-
tion through a sintered funnel. The filter cake was washed with
saturated aq. Na2SO3 solution (2ϫ25 mL), dried (Na2SO4), and
concentrated in a rotary evaporator under reduced pressure. The
resulting residue was purified by repeated silica gel FC (pentane/
EtOAc, 19:1, Rf = 0.35; pentane/Et2O, 9:1, Rf = 0.45) and subse-
quent recrystallization (MeOtBu) to furnish target compound 2
(244 mg, 33%) in the form of a colorless semicrystalline solid. M.p.
(؎)-(5R*,6S*)-6-(Methoxymethoxy)-1,1,6-trimethylspiro[4.5]-
decane: A mixture of NaI (300 mg, 2.00 mmol) and chloromethyl
methyl ether (224 mg, 2.50 mmol) in DME (1 mL) was stirred at
room temp. for 10 min, prior to addition of a solution of 1,1,6-
trimethylspiro[4.5]decan-6-ol (17, 98.2 mg, 0.500 mmol) and di-
isopropyl ethylamine (355 mg, 2.75 mmol) in DME (3 mL). After
being stirred at room temp. for an additional 1 h and at reflux for
5.5 h, the reaction mixture was cooled to room temp., and the reac-
tion was quenched by addition of saturated aq. Na2CO3 solution
(4 mL) and water (3 mL). The crude product was extracted with
CH2Cl2 (4ϫ5 mL), and the combined organic extracts were
washed with brine (5 mL). After the extracts were dried (Na2SO4)
and filtered, the solvent was removed in a rotary evaporator under
reduced pressure. The resulting residue was purified by silica gel
FC (pentane/Et2O, 9:1, Rf = 0.75) to furnish the title compound
(64.0 mg, 53%) as a colorless liquid. IR (ATR): ν = 1028 (ν CH – 50–51 °C. IR (ATR): ν = 1705 (νC=O), 1149/1123 (νC–O), 1370
˜
˜
s
3
O–CH2), 1003/919 (νsCH2–O–C), 1087/1153 (νasCH3–O–CH2),
(δsCH3), 1466 (δCH2), 3447 (νO–H) cm–1. 1H NMR (C6D6): δ =
1.10 (s, 3 H, 1-Meax), 1.11 (mc, 1 H, 10-Hb), 1.12 (mc, 1 H, 4-Hax),
2874 (νH–CHO2), 1135/1113/1178 (νasCH2–O–C), 1450 (δC–H),
1376 (δsCH3) cm–1. H NMR (CDCl3): δ = 1.06 (s, 3 H, 1-Meax), 1.27 (s, 3 H, 6-Me), 1.33–1.41 (m, 2 H, 9-H2), 1.36 (mc, 1 H, 3-
1
1.15 (s, 3 H, 1-Meeq), 1.22 (dddd, J = 13.0, 3.5, 3.5, 1.5 Hz, 1 H,
10-Heq), 1.31 (s, 3 H, 6-Meeq), 1.33 (mc, 1 H, 9-Hb), 1.35 (mc, 1 H,
Hb), 1.41 (s, 3 H, 1-Meeq), 1.42 (mc, 1 H, 2-Hb), 1.50 (mc, 1 H, 10-
Ha), 1.54 (mc, 1 H, 2-Ha), 1.66 (mc, 1 H, 3-Ha), 2.05 (mc, 1 H, 8-
3-Hb), 1.37 (mc, 1 H, 7-Hb), 1.43 (mc, 1 H, 2-Hb), 1.45 (mc, 1 H, Hb), 2.14 (mc, 1 H, 4-Heq), 2.20 (mc, 1 H, 8-Ha), 4.59 (s, 1 H, O–
3-Ha), 1.52 (mc, 1 H, 9-Ha), 1.53–1.59 (m, 2 H, 8-H2), 1.56 (mc, 1 H) ppm. 1H, 1H NOESY (C6D6): 1-Meax ϫ6-Me, 1-Meeq ϫ6-Meax,
H, 2-Ha), 1.61–1.71 (m, 2 H, 4-H2), 1.63 (mc, 1 H, 7-Ha), 1.91 1-Meeq ϫ6-OH, 4-Heq ϫ6-OH. 13C NMR (C6D6): δ = 19.3 (t, C-
(dddd, J = 13.0, 13.0, 3.5, 1.0 Hz, 1 H, 10-Hax), 3.42 (s, 3 H, 3), 21.5 (t, C-9), 23.0 (q, 6-Me), 25.5 (q, 1-Me), 26.6 (t, C-4), 28.2
OCH3), 4.68/4.70 (2d, J = 17.0 Hz, 2 H, OCH2O) ppm. 1H, 1H (q, 1-Me), 28.5 (t, C-10), 36.0 (t, C-8), 42.5 (t, C-2), 45.8 (s, C-1),
NOESY (CDCl3): 1-Meax ϫ10-Hax, 1-Meax ϫ10-Heq, 1- 56.7 (s, C-5), 80.4 (s, C-6), 213.5 (s, C-7) ppm. MS (EI): m/z (%) =
Meeq ϫOCH2O, 1-Meax ϫOCH2O, 6-Meeq ϫOCH2O. 13C NMR
210 (14) [M+], 195 (3) [M+ – CH3], 192 (1) [M+ – H2O], 182 (8)
(CDCl3): δ = 20.4 (t, C-8), 22.0 (t, C-3), 22.6 (t, C-9), 24.4 (q, 6- [M+ – C2H4], 167 (8) [M+ – C3H7], 149 (49) [M+ – C3H7 – H2O],
Meeq), 27.6 (q, 1-Meax), 29.4 (q, 1-Meeq), 29.7 (t, C-10), 31.4 (t, C-
4), 36.5 (t, C-7), 42.7 (t, C-2), 46.8 (s, C-1), 53.3 (s, C-5), 56.3 (q,
OCH3), 81.9 (s, C-6), 90.7 (t, OCH2O) ppm. MS (EI): m/z (%) =
139 (12) [M+ – C5H11], 122 (21) [C9H14+], 109 (42) [C8H13+], 95
(46) [C7H11+], 82 (41) [C6H10+], 71 (44) [C5H11+], 55 (50) [C4H7+],
43 (100) [C3H7+]. C13H22O2 (210.31): calcd. C 74.24, H 10.54;
Eur. J. Org. Chem. 2007, 2257–2267
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2265

P. Kraft, A. Bruneau
FULL PAPER
found C 74.20, H 10.47. Odor: camphoraceous, agrestic, minty,
reminiscent of eucalyptol, with woody and earthy facets, slightly
reminiscent of patchouli. Odor threshold: 17.2 ng/L air.
ceous, earthy, somewhat reminiscent of vetiver and grapefruit peel.
Odor threshold: 68 ng/L air.
(؎)-2,2,6-Trimethylspiro[4.5]dec-6-ene (21): At room temp., tri-
phenylphosphane (4.71 g, 18.0 mmol) was added in portions to a
stirred suspension of 2,2,6-trimethylspiro[4.5]decan-6-ol (20, 2.94 g,
15.0 mmol), tetrabromomethane (5.96 g, 18.0 mmol) and Celite®
(1.25 g) in toluene (30 mL). The reaction mixture was stirred at
40 °C for 1 d, prior to filtering off the insoluble materials. The filter
cake was extracted with hexane (15 mL), and the combined extracts
were filtered again. The combined filtrates were concentrated in a
rotary evaporator under reduced pressure, and the resulting residue
was purified by filtration (pentane) over a pad of silica gel to fur-
nish a slightly cloudy mixture containing compound 21 as the main
product (2.73 g of mixture, GC: 43% in 21, 44% yield). MS (EI):
(؎)-2,2-Dimethylspiro[4.5]decan-6-one (19): At room temp., a solu-
tion of 1,4-dibromo-2,2-dimethylbutane (18, 20.0 g, 82 mmol) pre-
pared according to ref.[31] and cyclohexanone (8.05 g, 82 mmol) in
toluene (200 mL) was added slowly with mechanical stirring to a
suspension of potassium tert-butoxide (20.2 g, 180 mmol) in tolu-
ene (300 mL) over a period of 80 min. The resulting reaction mix-
ture was heated to 95 °C overnight and then cooled. At room
temp., the resulting solution was diluted with Et2O (300 mL) and
washed in turn with saturated aq. NH4Cl solution (4ϫ100 mL)
and brine (4ϫ100 mL). After being dried (Na2SO4), the combined
organic extracts were concentrated in a rotary evaporator under
reduced pressure, and the resulting residue was purified by silica
gel FC (pentane/Et2O, 29:1, Rf = 0.36) and subsequent Kugelrohr
distillation (82 °C/0.2 mbar) to furnish compound 19 (3.07 g, 21%)
m/z (%) = 178 (45) [M+], 163 (87) [M+ – CH3], 149 (11) [M+
C2H5], 135 (18) [M+ – C3H7], 122 (38) [M+ – C4H8], 107 (67) [M+
–
–
C5H11], 93 (100) [M+ – C6H13], 81 (48) [C6H9+], 67 (26) [C5H7+],
55 (30) [C4H7+], 41 (35) [C3H5+].
as a colorless oil. IR (ATR): ν = 1703 (νC=O), 1127 (ν C–C), 1449
˜
as
(δC–H), 1384 (δsCH3) cm–1. H NMR (CDCl3): δ = 0.95/1.03 (2s,
1
(؎)-6-Hydroxy-2,2,6-trimethylspiro[4.5]decan-7-one (22): At room
temp., Oxone® (46.1 g, 75.0 mmol) was added in one dash to a
stirred suspension of NaHCO3 (3.15 g, 37.5 mmol) and
RuCl3·2H2O (62.2 mg, 0.255 mmol) in EtOAc/CH3CN/H2O (6:6:1,
195 mL). After 5 min of stirring at room temp., the resulting sus-
pension was cooled down to 0 °C (ice/water bath), prior to addition
of the crude 2,2,6-trimethylspiro[4.5]dec-6-ene mixture (43% in 21,
2.68 g, 6.46 mmol). The reaction mixture was stirred at 0 °C for
40 min, diluted with EtOAc (150 mL), and filtered by suction
through a sintered funnel. The filter cake was washed with satu-
rated aq. Na2SO3 solution (2ϫ35 mL), dried (Na2SO4), and con-
centrated in a rotary evaporator under reduced pressure. The re-
sulting residue was purified by repeated silica gel FC (pentane/
Et2O, 19:1, Rf = 0.21; pentane/Et2O, 9:1, Rf = 0.43) to furnish the
second target compound 22 (272 mg, 22%) as a ca. 1:1 mixture of
6 H, 2-Me2), 1.29 (d, J = 13.5 Hz, 1 H, 1-Hb), 1.42 (dd, J = 10.0,
7.0 Hz, 2 H, 3-Hb), 1.44 (dd, J = 10.0, 7.0 Hz, 2 H, 3-Ha), 1.53 (dt,
J = 12.5, 7.0 Hz, 1 H, 4-Hb), 1.66–1.73 (m, 2 H, 9-H2), 1.72–1.78
(m, 2 H, 10-H2), 1.77–1.84 (m, 2 H, 8-H2), 1.99 (d, J = 13.5 Hz, 1
H, 1-Ha), 2.23 (dt, J = 12.5, 7.0 Hz, 1 H, 4-Ha), 2.40 (t, J = 6.5 Hz,
2 H, 7-H2) ppm. 13C NMR (CDCl3): δ = 22.8 (t, C-9), 27.4 (t, C-
8), 28.9/30.0 (2q, 2-Me2), 34.3 (t, C-4), 39.3 (t, C-7), 39.4 (s, C-2),
40.2 (t, C-3), 41.6 (t, C-10), 49.5 (t, C-1), 57.4 (s, C-5), 214.1 (s, C-
6) ppm. MS (EI): m/z (%) = 180 (29) [M+], 165 (39) [M+ – CH3],
147 (18) [M+ – CH3 – H2O], 136 (16) [M+ – C3H8], 121 (18) [M+
–
C3H8 – CH3], 111 (100) [C7H11O+], 95 (45) [C7H11+], 81 (47)
[C6H9+], 67 (30) [C5H7+], 55 (34) [C4H7+], 41 (27) [C3H5+]. C12H20O
(180.29): calcd. C 79.94, H 11.18; found C 79.98, H 11.10. Odor:
very weak with slightly earthy and minty aspects.
diastereoisomers in the form of a colorless oil. IR (ATR): ν = 1706
˜
(؎)-2,2,6-Trimethylspiro[4.5]decan-6-ol (20): At room temp., 2,2-di-
methylspiro[4.5]decan-6-one (19, 3.00 g, 16.6 mmol) was injected
by syringe over 2 min to a stirred solution of methyllithium (1.6 
in Et2O, 33.3 mL, 53.2 mmol). Stirring was continued for 30 min
at room temp., prior to quenching with cold saturated aq. NH4Cl
solution (50 mL). After separation of the layers, the aqueous one
was extracted with Et2O (3ϫ25 mL). The organic extracts were
combined and washed in turn with saturated aq. NaHCO3 solution
(3ϫ25 mL) and brine (3ϫ25 mL). After being dried (Na2SO4), the
resulting solution was concentrated in a rotary evaporator under
reduced pressure. The resulting residue was purified by silica gel
FC (pentane/Et2O, 37:3, Rf = 0.21) to furnish the diastereomeric
mixture of compound 20 (3.11 g, 95%) as a colorless liquid. IR
(νC=O), 1142 (νC–O), 1364 (δsCH3), 1462 (δCH2), 3478 (νO–H)
1
cm–1. H NMR (CDCl3): δ = 0.84/1.02 (2d, J = 13.0 Hz, 1 H, 1-
Hb), 0.93/0.99/1.08/1.09 (4s, 6 H, 2-Me2), 1.08/1.10 (2s, 3 H, 6-Me),
1.12/1.22 (2mc, 1 H, 4-Hb), 1.24/2.07 (2mc, 2 H, 10-H2), 1.27–1.35
(m, 2 H, 9-H2), 1.30/1.33 (2mc, 1 H, 3-Hb), 1.34/1.99 (2mc, 1 H, 8-
Hb), 1.42/1.97 (2d, J = 13.0 Hz, 1 H, 1-Ha), 1.43/1.60 (2mc, 1 H,
3-Ha), 1.60/2.14 (2mc, 1 H, 4-Ha), 2.01/2.09 (2mc, 1 H, 8-Ha), 4.14/
4.19 (2s, 1 H, OH) ppm. 13C NMR (CDCl3): δ = 22.3/22.6 (2q, 6-
Me), 22.5/22.6 (2t, C-9), 28.9/29.4/30.3/31.6 (4q, 2-Me2), 31.2/34.6
(2t, C-4), 35.3/36.2 (2t, C-10), 36.3/36.3 (2t, C-8), 38.7/39.7 (2s, C-
2), 40.3/41.8 (2t, C-3), 44.5/49.1 (2t, C-1), 55.4/56.2 (2s, C-5), 79.4/
80.6 (2s, C-6), 213.7/213.8 (2s, C-7) ppm. MS (EI): m/z (%) = 210
(40) [M+], 195 (3) [M+ – CH3], 192 (2) [M+ – H2O], 182 (4) [M+
–
CO], 177 (11) [M+ – CH3 – H2O], 167 (25) [M+ – CH3 – CO], 149
(97) [M+ – CH3 – H2O – CO], 122 (41) [C9H14+], 109 (49) [C8H13+],
95 (59) [C7H11+], 87 (64) [C5H11O+], 71 (52) [C5H11+], 55 (61)
[C4H7+], 43 (100) [C3H7+]. C13H22O2 (210.31): calcd. C 74.24, H
10.54; found C 74.20, H 10.50. Odor: weak, woody, cedar-like, with
a powdery connotation. Odor threshold: 233 ng/L air.
(ATR): ν = 1464 (δO–H, ip), 1364 (δ CH ), 1115/1174 (νC–O, tert-
˜
s
3
OH), 3473 (νO–H) cm–1. 1H NMR (CDCl3): δ = 1.01/1.01/1.03/
1.05 (4s, 6 H, 2-Me2), 1.16/1.17 (2s, 3 H, 6-Me), 1.15/1.19 (2d, J =
18.0/14.0 Hz, 1 H, 1-Hb), 1.31 (br. s, 1 H, OH), 1.34/1.36 (2mc, 1
H, 10-Hb), 1.36/1.42 (2mc, 1 H, 4-Hb), 1.28–1.45 (m, 4 H, 8-,9-H2),
1.36–1.47 (m, 2 H, 3-H2), 1.40–1.48 (m, 2 H, 7-H2), 1.50/1.69 (2mc,
1 H, 1-Ha), 1.59/1.61 (2mc, 1 H, 10-Ha), 1.76/1.93 (2mc, 1 H, 4-Ha)
ppm. 13C NMR (CDCl3): δ = 22.3/22.4 (2t, C-8), 22.8/22.9 (2t, C-
9), 24.5/24.7 (2q, 6-Me), 30.0/30.5/30.6/31.1 (4q, 2-Me2), 32.5/34.0
(2t, C-4), 36.7/37.1 (2t, C-10), 37.9/38.3 (2t, C-7), 39.0/39.1 (2s, C-
Acknowledgments
2), 40.9/41.2 (2t, C-3), 47.6/48.8 (2t, C-1), 51.4/51.5 (2s, C-5), 74.0/ We are indebted to Professor Dr. Jean-Paul Quintard, Université de
74.3 (2s, C-6) ppm. MS (EI): m/z (%) = 196 (9) [M+], 181 (24)
[M+ – CH3], 178 (12) [M+ – H2O], 163 (100) [M+ – CH3 – H2O],
Nantes, for making this external master’s thesis of Audrey Bruneau
possible. We thank Professor Manfred T. Reetz, Max-Planck-Insti-
tut für Kohlenforschung Mülheim an der Ruhr, for the procedure
for the preparation of 1-bromo-4-chloro-4-methylpentane (15) from
149 (13) [M+ – C2H7O], 136 (64) [M+ – C3H8O], 121 (44) [M+
–
C4H11O], 107 (35) [C8H11+], 95 (41) [C7H11+], 81 (52) [C6H9+], 71
(78) [C4H7O+], 55 (41) [C4H7+], 43 (63) [C3H7+]. Odor: camphora- the diploma thesis of Athanassios Giannis[21]. Thanks are also due
2266
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Eur. J. Org. Chem. 2007, 2257–2267

Ring Reversal of a Spirocyclic Patchouli Odorant
FULL PAPER
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Received: September 18, 2006
Published Online: January 3, 2007
Eur. J. Org. Chem. 2007, 2257–2267
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www.eurjoc.org
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