Synthesis and olfactory evaluation of (4afl*,8afl*)-1,1,8a- trimethyl- Decahydronaphthalen-4a-ol: A cis -decalol intersection structure of (-)-patchoulol and (5fl*,6S*)-1,1,6-trimethylspiro[4.5]decan-6-ol

Article abstract of DOI:10.1055/s-0028-1083269

Superposition analysis of (-)-patchoulol (1) and the spi- rocyclic patchouli odorant (5R*,6S*)-1,1,6-trmiethylspiro[4.5]de- can-6-ol (3) suggested the intersection structure (4a5*,8a5*)- 1,1,8a-trimethyldecahydronaphthalen-4a-ol (4) as potential patchouli

Full text of DOI:10.1055/s-0028-1083269

6
2
PAPER
Synthesis and Olfactory Evaluation of (4aR*,8aR*)-1,1,8a-Trimethyl-
decahydronaphthalen-4a-ol: A cis-Decalol Intersection Structure of
(
–)-Patchoulol and (5R*,6S*)-1,1,6-Trimethylspiro[4.5]decan-6-ol
a
a
a
b
A
c
i s -Decalol Inte
s
r
sectionS
t
tructur er id Jahnke, Christian Burschka, Reinhold Tacke,* Philip Kraft*
a
Institut für Anorganische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax +49(931)8884609; E-mail: r.tacke@mail.uni-wuerzburg.de
Givaudan Schweiz AG, Fragrance Research, Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax +41(44)8242926; E-mail: philip.kraft@givaudan.com
b
Received 13 August 2008
Dedicated with best wishes to Professor Werner Tochtermann on the occasion of his 75th birthday
dimethyl moiety of (–)-patchoulol (1) was no prerequisite
for its characteristic odor. The bridgehead methyl substit-
uent of 1, however, seems odor determining as its removal
Abstract: Superposition analysis of (–)-patchoulol (1) and the spi-
rocyclic patchouli odorant (5R*,6S*)-1,1,6-trimethylspiro[4.5]de-
can-6-ol (3) suggested the intersection structure (4aS*,8aS*)-
4
decreases the camphoraceous character, while rendering
1
,1,8a-trimethyldecahydronaphthalen-4a-ol (4) as potential
patchouli odorant. The synthesis commenced with the Robinson an- the overall odor impression mainly woody.5
nulation of mesityl oxide with 2-cyanocyclohexanone, accessible
3,8
In attempts to mimic the tricyclo[5.3.1.0 ]undecane ses-
by intramolecular cyclization of pimelonitrile. Weitz–Scheffer ep-
oxidation of the resulting Michael system with hydrogen peroxide
in the presence of sodium hydroxide and subsequent Wharton rear-
quiterpene skeleton of 1, alternative spirocyclic motifs
6
have recently been designed, in the course of which the
rangement employing hydrazine hydrate and acetic acid furnished intermediate 3 with an unusually characteristic patchouli
with complete cis-selectivity (4aR*,8aR*)-8a-hydroxy-5,5-dimeth- note was discovered (odor threshold 5.0 ng/L air). The
yl-1,2,3,4,4a,5,6,8a-octahydronaphthalene-4a-carbonitrile
(14),
typical patchouli, woody odor profile of (5R*,6S*)-1,1,6-
trimethylspiro[4.5]decan-6-ol (3, Figure 1) is all the more
surprising since the geometry of the methyl carbinol func-
tion is inverted to what one would expect when the gem-
possibly due to neighboring group participation of the cyano func-
tion in the epoxidation step. Subsequent hydrogenation of the allylic
double bond with palladium on carbon as catalyst, followed by re-
duction of the nitrile group with DIBAL-H afforded (4aR*,8aR*)-
8
a-(aminomethyl)-1,1-dimethyldecahydronaphthalen-4a-ol (16), dimethyl motifs of compounds 1 and 3 would be superim-
which was deaminated with hydroxylamine-O-sulfonic acid to af- posed. So, the spiro[4.5]decan-6-ol 3 coins a different
ford the target compound 4 that possesses an interesting woody superposition motif.
odor with green-mossy, camphoraceous, and patchouli-type facets.
Key words: annulations, cis-decalins, epoxidations, neighboring
group effects, odorants
With about one third of all fine fragrances containing
patchouli oil [Pogostemon cablin (Blanco) Benth.] as im-
portant base-note ingredient, it is quite remarkable that no
synthetic patchouli odorant has as yet been introduced to
perfumery, especially since the price of this natural mate-
rial fluctuates considerably and has been on an upward
1
2
spiral for the last few years. Despite some controversy,
its main constituent (35–40%), the sesquiterpene alcohol
–)-patchoulol (1), is primarily responsible for the typical
(
well-balanced woody–earthy–camphoraceous odor pro-
file of the essential oil, and 1 is even used in perfumery in
isolated form, for example, under the name Healingwood
(
IFF).
While a sterically congested structure and a secondary or
tertiary alcohol group were considered structurally impor-
3
tant features of patchouli odorants, it was recently dem-
onstrated by the synthesis of the ketol 2 that the gem-
Figure 1 Patchouli odorants, decalin odorants, and the derivation of
the cis-decalol intersection target structure 4
SYNTHESIS 2009, No. 1, pp 0062–0068
0
2
.
0
1
.2
0
0
9
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083269; Art ID: C04208SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
A cis-Decalol Intersection Structure
63
It was thus very tempting to explore this new motif by a leads to the substituted cyclohexanol 6, which Weyerstahl
biflexible superposition analysis, which was performed and co-workers synthesized and reported to smell cam-
7
with the MOE 2007.09 software package, and is delineat- phoraceous and earthy, with woody and patchouli aspects
ed in Figure 2. Interestingly, only one of the methyl being absent.9
groups of the gem-dimethyl moiety of 1 is mapped by the
cyclohexyl ring of 3, but the gem-dimethyl moiety of 3 su-
perimposes on the bridgehead methyl substituent of (–)-
patchoulol (1), stressing its importance as hydrophobic el-
ement. The spiro[4.5]decan-6-ol 3, in fact, intersects the
natural lead 1 in such a way as to complete a cis-decalol
system with the hydroxy function and the bridgehead
methyl group of 1 on the bridgehead positions of the deca-
lin ring, C-4a and C-8a, respectively. In fact, the frame-
work of (–)-patchoulol (1) contains a cis-decalin system,
which becomes most apparent if one dissects the C-1–C-
This makes the synthesis of compound 4 even more excit-
ing. Besides, bridgehead decalols are interesting target
structures in itself since the trans-configured (–)-geosmin
(
7), which emanates the typical earthy odor of freshly
ploughed soil, is one of the most intense odorants known
10
to date, with an odor threshold of 0.002 ng/L air. Its cis-
configured stereoisomers display odors reminiscent of ce-
darwood and camphor set against the earthy background
11
of the trans-isomer. The cis-decalin derivatives 8 and 9,
mentioned in connection with the triaxial rule of amber-
12
gris odorants and devised as cis-decalin superstructures
1
1 bond as indicated in Figure 1. This cis-decalin intersec-
of geosmin and dihydroambrinol (2,5,5-trimethyldecahy-
dronaphthalen-2-ol), were reported to exhibit camphora-
tion structure indeed embraces the perimeter of the (–)-
patchoulol (1) molecule. Dissecting the bond C-1–C-11
would result in a methyl group at position C-1 in the 4a-
decalol. Thus, looking at the superposition analysis in
Figure 2, it seems the cyclopentyl ring of 3 hints at ex-
tending this to a geminal 1,1-dimethyl group, which
would eliminate a stereocenter.
12
ceous odors only.
However, the synthesis of 8 and 9, 4-methyl homologues
of our target structure 4, has never been published. The
steric crowd around the three quaternary carbon atoms C-
1
, C-4a, and C-8a in 4 actually does represent a synthetic
challenge, though the geminal 1,1-dimethyl moiety could
come in handy for the cis-selective introduction of the hy-
droxy function as it should hinder a nucleophilic attack
from the a-face of a 1,1,8a-trimethyldecalin system. The
introduction of the gem-dimethyl moiety was envisaged
in the construction of the core decalin ring system by
Robinson annulation.
However, the reactivity of 4-methylpent-3-en-2-one as
hindered Michael acceptor system was an issue, and it
seemed sensible to enhance the carbanion character of the
Michael partner by an auxiliary a-cyano function. Liu and
co-workers13 have recently employed such a-cyano ke-
tones in an elegant modification of the Robinson annula-
tion to furnish a,a-disubstituted b,g-unsaturated
cyclohexanone systems by reductive removal of the cyano
Figure 2 Biflexible superposition analysis of (–)-patchoulol (1, de- function in a subsequent alkylation step. In the construc-
picted in silver) on the patchouli-smelling (5R*,6S*)-1,1,6-trimethyl- tion of our target compound 4, the auxiliary cyano func-
spiro[4.5]decan-6-ol (3, displayed in gold) with the MOE 2007.09
tion could, however, even be reduced to the required
bridgehead 8a-methyl group in the concluding steps of the
software package7
projected synthesis. Furthermore, it was tempting to study
Not taking the spiro[4.5]decan-6-ol 3 into account, one if this cyano function could be utilized as participating
can derive the resulting target structure 4 imaginarily also neighboring group in the syn-delivery of an oxygen nu-
from (–)-patchoulol (1) alone, by transposing one methyl cleophile on the adjacent bridgehead position.
group from C-6 to C-7, dissecting the C-1–C-11 bond, and
Subjecting acrylonitrile to the conditions of a Weitz–
Scheffer epoxidation does in fact not provide the corre-
abstracting the gem-dimethyl moiety. These severe struc-
tural simplifications, however, can preserve the patchouli
odor characteristics of the natural lead 1 only if the bind-
ing motif on the olfactory receptor corresponds to the su-
perposition analysis in Figure 2, so it puts these structural
features to the test.
14
sponding epoxynitrile, but gylcidamide, via rearrange-
15
ment of the intermediate peroxyacrylimidic acid. Thus,
in favor of the Michael system, the hydroperoxide anion
preferentially attacks the cyano carbon atom, which is
more positively charged than the b-carbon atom of the
So far, seco-structures of (–)-patchoulol (1) did not dis- a,b-unsaturated carbonyl group. A cyano function might
play the typical patchouli odor characteristics. On dissect- therefore very well exert a syn-selective neighboring-
ing the C-6–C-7 bond of 1, Spreitzer observed that the group effect on the nucleophilic attack of the hydroperox-
patchouli odor was lost, and 5 only smelled intensely ide anion on a Michael acceptor via a reversibly formed
8
woody. Dissection of the C-1–C-11 and C-7–C-8 bonds peroxycarboximidic acid species, though, to the best of
Synthesis 2009, No. 1, 62–68 © Thieme Stuttgart · New York

6
4
A. Jahnke et al.
PAPER
our knowledge, this has not yet been described. Neighbor- conditions, illustrating the importance of the nitrile func-
ing group participation in the Weitz–Scheffer epoxidation tion.
by intramolecular syn-delivery of the hydroperoxide an-
The stage was now set for the crucial Weitz–Scheffer
epoxidation of the cyano enone 12 employing the stan-
dard conditions, that is, 30% aqueous hydrogen peroxide
1
6
ion had only been reported for oxo and hydroxy
14
1
7
groups.
In the projected synthesis of the target compound 4, the in methanol with aqueous sodium hydroxide. The yield of
cyano function should be utilized (a) as activating auxilia- the reaction was only moderate (23%), but the reaction
ry to enable a Robinson annulation with 4-methylpent-3- provided exclusively one single diastereomer, and much
en-2-one, (b) as neighboring group for the syn-selective to our satisfaction, the single-crystal X-ray diffraction
introduction of the oxygen functionality, and finally (c) as analysis (Figure 3a) indeed established the configuration
precursor for the 8a-methyl group.
of the 4,4-dimethyl-2-oxooctahydro-4aH-naphtho[1,8a-
b]oxirene-4a-carbonitrile (13) obtained to be
1R*,4aS*,8aR*), that is, cis with respect to the bridge-
The elaborated seven-step synthesis of the target com-
(
pound 4 is delineated in Scheme 1. Thorpe–Ziegler
1
8
head atoms. Though the steric hindrance of the axial 5-
methyl group in 12 might also favor the nucleophilic at-
tack of the hydroperoxide anion on the enone from the op-
posite face, this complete selectivity could additionally
involve the participation of the cyano function. Weitz–
Scheffer epoxidation of differently substituted methyl oc-
talones only furnished mixtures of a- and b-epoxides in
condensation of pimelonitrile (10) employing sodium N-
methylanilide, generated in situ from sodium hydride and
1
3b
N-methylaniline, provided the starting a-cyanocyclo-
hexanone (11) in 92% yield after quenching with water
and concentrated hydrochloric acid, standard workup, and
chromatographic purification.
19
ratios of 46:54 and 22:78, respectively. Thus, neighbor-
ing group participation of the cyano function with in-
tramolecular syn-delivery of the hydroperoxide anion
seems to be a likely reason for the exclusive formation of
the (1R*,4aS*,8aR*)-configured epoxide 13. The nucleo-
philic attack of the hydroperoxide anion might be guided
by the cyano group in a syn-directive manner as visualized
in the proposed transition state TS in Figure 4.
1
2
. NaH
MeNHPh
THF
. H3O+
92%
O
O
CN
11
NC
CN
3
DBU, MePh
16%
10
aq H2O2
MeOH
NaOH
H2NNH2
MeOH
AcOH, H2O
O
O
O
2
3%
40%
NC
12
NC
OH
13
1
. DIBAL-H
OH
H2, Pd/C
MeOH
hexane
cyclohexane
83%
2. H2O
3%
8
NC
NC
15
14
OH
1. NH OSO H
OH
2
3
MeOH
NaOH
2
. H3O+
0%
4
H2N
4
(TGT)
16
woody, green-mossy,
camphoraceous, patchouli
Scheme 1 Synthesis of the cis-configured target compound 4 from
pimelonitrile by Robinson annulation, Weitz–Scheffer epoxidation,
Wharton olefination with subsequent hydrogenation, nitrile reduc-
tion, and concluding deamination
Robinson annulation of 2-oxocyclohexanecarbonitrile
(
11) with 4-methylpent-3-en-2-one and stoichiometric
amounts of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
base in refluxing toluene afforded, after repeated flash
chromatography, the desired annulation product 12, albeit
in a rather disappointing yield (16%), which was account-
ed to the steric demand of the Michael acceptor. Nota
bene, ethyl 2-oxocyclohexanecarboxylate does not react
at all with 4-methylpent-3-en-2-one under these reaction
Figure 3 Molecular structures of 13 (a) and 16 (b) in the crystal
with thermal ellipsoids at the 50% probability level
Synthesis 2009, No. 1, 62–68 © Thieme Stuttgart · New York

PAPER
A cis-Decalol Intersection Structure
65
that is compatible with a wide variety of functional groups
including hydroxy functions, is hydroxylamine-O-sulfon-
ic acid (HOS) as introduced by Doldouras and Kol-
lonitsch.21 This hydrodeamination is thought to proceed
via N-amination of the amine to the corresponding hydra-
zine under alkaline conditions. Nitrene, also formed from
HOS under these conditions, then oxidizes the alkyl hy-
drazine to the corresponding metastable alkyldiazene (di-
imide), which decomposes to the alkane under extrusion
of dinitrogen.21 Accordingly, to control the evolution of
dinitrogen, a solution of the primary amine 16 in methanol
was treated repeatedly with aqueous sodium hydroxide
and HOS, and the mixture was refluxed for 15 minutes af-
ter each complete addition. After neutralization with 2 M
hydrochloric acid, diethyl ether extraction, chromato-
graphic purification, and bulb-to-bulb distillation, the tar-
get compound 4 was obtained in 40% as a colorless,
odoriferous solid. The identities and chemical purities of
Figure 4 Possible transition state TS accounting for the observed
exclusive syn-delivery of the hydroperoxide anion in the reaction
1
2 →13
Preserving the generated stereochemical information at
the bridgehead positions, now the epoxide was to be
opened and the carbonyl group to be removed. For this
2
0
purpose, the Wharton oxygen transposition with subse-
quent hydrogenation of the resulting allylic alcohol
seemed to be the method of choice. Accordingly, the a,b-
epoxy ketone 13 was reductively rearranged with hydra-
zine hydrate in methanol at ambient temperature in the
presence of acetic acid to afford the corresponding
4
and compounds 12–16 were established by C,H,N ele-
mental analyses and NMR experiments, and the olfactory
purity of the target compound 4 was additionally assured
by GC–olfactometry.
The olfactory evaluation of the target compound 4 by ex-
pert perfumers was both, gratifying and disappointing.
Gratifying, since the main odor character of 4 was neither
predominantly earthy, such as that of (–)-geosmin (7), nor
predominantly camphoraceous, such as that of the related
cis-decalols 8 and 9 (Figure 1). Instead, the main odor
character of 4 was woody, green-mossy. However, cam-
phoraceous aspects were also present as a side note, as
was a patchouli tonality. Disappointingly, however, this
patchouli note was not the dominant theme, as had been
hoped for, and the odor threshold of 13.1 ng/L air was in-
ferior to that of the lead structure 3 (5.0 ng/L air), though
GC–olfactometry on a chiral stationary phase revealed
only one enantiomer of 4 to be responsible for the odor
impression of the racemate, while the other enantiomer
was odorless. Thus, the smelling enantiomer should pos-
sess half the odor threshold of the racemate (6.6 ng/L air).
Unfortunately, the steric crowd around the hydroxy func-
tion of 4 prevented the esterification with (–)-camphanoyl
chloride as chiral resolving agent, and the olfactory prop-
erties of the racemate were not interesting enough to ven-
ture into an enantioselective approach, such as a Juliá–
Colonna epoxidation of the enone 12.
(
4aR*,8aR*)-configured allylic alcohol 14 in 40% yield.
7
Subsequent hydrogenation of this D -octalol 14 in metha-
nol in the presence of catalytic amounts of palladium on
carbon
furnished
the
(4aR*,8aR*)-configured
(4aR*,8aR*)-8a-hydroxy-4,4-dimethyldecahydronaphtha-
lene-4a-carbonitrile (15) in 83% yield.
All that was missing now to complete the synthesis of the
target compound 4, was the reduction of the auxiliary cy-
ano function of the nitrile 15 to a methyl group. Though
this could in principle have been accomplished together
with the reduction of the allylic double bond in 14, even
the separate reduction of the nitrile function turned out to
be more difficult than anticipated, probably because of the
severe steric crowd around the three quaternary carbon
centers 4, 4a, and 8a in 15. So a two-step detour, consist-
ing of hydride reduction and subsequent deamination, had
to be taken. In the hydride reduction of the cyano function
of 15, lithium aluminum hydride (LAH) performed sur-
prisingly badly. However, excess diisobutylaluminum hy-
dride (DIBAL-H) in refluxing cyclohexane worked out
fine, and the 8a-aminomethyl-4a-decalol was obtained in
8
3% yield. Since DIBAL-H possesses only one hydride
Nevertheless, in contrast to the patchoulol partial struc-
tures 5 and 6 (Figure 1), the target compound 4 is clearly
reminiscent of patchouli oil, even if that is not its main
character. This demonstrates that decalin systems could
indeed be interesting patchouli odorants and that the su-
perposition analysis in Figure 2 might reveal some insight
into the binding geometry of patchouli odorants on the rel-
evant olfactory receptor(s). Only very recently, 4-ethyl-
per molecule, one can speculate that after reaction with
the hydroxy function of 15, with release of one molar
equivalent of H , an intramolecular chelate ring is formed,
2
incorporating the cyano function and thereby activating it
towards intermolecular reduction by a second equivalent
of DIBAL-H. The retention of the cis-configuration of the
decalin skeleton of 16 and its overall structure could be es-
tablished by NMR experiments in conjunction with a sin-
gle crystal X-ray diffraction analysis (Figure 3b).
8
,8a-dimethyldecahydronaphthalen-1-ol, prepared as iso-
meric mixture by Diels–Alder reaction of 4-ethyl-2-meth-
ylcyclohex-2-en-1-one with penta-1,3-diene, hydrogen-
ation, and subsequent LAH reduction, was disclosed as
woody patchouli odorant with camphoraceous aspects.22
The reductive deamination of the amino alcohol 16 was
all that remained to conclude the synthesis of the target
compound 4. One of the most reliable selective and mild
reagents for the reductive deamination of primary amines
Synthesis 2009, No. 1, 62–68 © Thieme Stuttgart · New York

6
6
A. Jahnke et al.
PAPER
In conclusion, besides the olfactory aspects, this paper en-2-one (10.2 g, 104 mmol) in toluene (60 mL). The reaction mix-
ture was heated under reflux for 20 h, and subsequently allowed to
cool to r.t., followed by the addition of 2 M aq HCl (60 mL). The
organic layer was separated and the aqueous layer extracted with
presents an interesting strategy for the construction of
sterically demanding cis-decalin systems, for making use
of neighboring-group effects in directing selectivity, and
for employing cyano functions as versatile auxiliary
groups. The underlying methodology should thus be of
broader applicability in synthetic chemistry.
Et O (2 × 50 mL). The organic extracts were combined, washed
2
with aq sat. NaHCO (50 mL), and dried (Na SO ). The solvent was
3
2
4
removed under reduced pressure and the resulting residue purified
by column chromatography on silica gel (50 × 3 cm diameter, silica
gel 35–70 mm, 180 g, hexane–EtOAc, 3:2). The relevant fractions
(GC) were combined, and the solvent was removed under reduced
All reactions involving chemicals sensitive to H O and/or O were
2
2
pressure to afford compound 12; yield: 1.32 g (16%); colorless sol-
carried out under a dry argon atmosphere. The organic solvents used
were dried and purified according to standard procedures and stored
id; mp 117 °C, R = 0.6 (hexane–EtOAc, 3:2).
f
1
H NMR (300.1 MHz, CDCl ): d = 1.05 [s, 3 H, 5-(CH ) )], 1.27 [s,
under dry N . Starting materials, reagents, and solvents were pur-
3
3 a
2
3
H, 5-(CH ) ], 1.38 (m , 1 H, H-2 ), 1.62 (m , 1 H, H-4 ), 1.80–1.99
chased from Aldrich or Acros and were used without further purifi-
cation (except for 4-methylpent-3-en-2-one, which was obtained
from Merck). Bulb-to-bulb distillations were performed with a
Büchi B-580 apparatus, analytical TLC on silica gel (TLC aluminum
sheets, silica gel 60F254, Merck, 105554) with 5% phosphomolybdic
acid in EtOH as visualization reagent. Melting points were deter-
mined with a Büchi Melting Point B-540 apparatus and are uncor-
3 b c a c a
(
m, 2 H, H -3), 1.98 (m , 1 H, H-2 ), 2.18 (m , 1 H, H-4 ), 2.24 (d,
2 c b c b
J = 16.0 Hz, 1 H, H-6 ), 2.51 (m , 1 H, H-1 ), 2.59 (m , 1 H, H-1 ),
a
c
a
c
b
2
.53 (d, J = 16.0 Hz, 1 H, H-6 ), 5.91 (d, J = 2.0 Hz, 1 H, H-8).
b
1
3
C NMR (75.5 MHz, CDCl ): d= 22.9 [1-(CH ) )], 23.1 (CH , C-
3
3
a
2
3), 25.8 [5-(CH ) )], 26.8 (CH , C-2), 31.6 (CH , C-4), 33.7 (CH ,
3
b
2
2
2
C-1), 37.9 (C , C-5), 48.4 (C , C-4a), 49.6 (CH , C-6), 119.6 (CN),
q
q
2
1
13
rected. The H and C NMR spectra were recorded at 23 °C on a
125.7 (CH, C-8), 157.1 (C , C-8a), 196.8 (C , C-7).
q
q
1
13
Bruker DRX-300 ( H, 300.1 MHz; C, 75.5 MHz) or Bruker
+
GC/EI-MS: t = 7.15 min; m/z (%) = 203 (15, [M ]), 147 (100).
1
13
R
Avance 500 NMR spectrometer ( H, 500.1 MHz; C, 125.8 MHz)
using CDCl as the solvent. The 2D C, C INADEQUATE exper-
1
3
13
Anal. Calcd for C13H17NO (203.3): C, 76.81; H, 8.43; N, 6.89.
Found: C, 76.53; H, 8.40; N, 6.92.
3
iment of 4 was recorded on a Bruker DMX-600 NMR spectrometer
1
13
using a H, C cryo probe. Chemical shifts (ppm) were determined
1
13
relative to internal CHCl ( H, d = 7.24; CDCl ) or CDCl ( C, d =
(1R*,4aS*,8aR*)-4,4-Dimethyl-2-oxooctahydro-4aH-naph-
tho[1,8a-b]oxirene-4a-carbonitrile (13)
3
3
3
1
7
7.0; CDCl ). Analysis and assignment of the H NMR data were
supported by H, H COSY, C, H HMQC, and C, H HMBC ex-
periments. Assignment of the C NMR data was supported by
C, H HMQC, C, H HMBC, INADEQUATE, and DEPT-135 ex-
3
1
1
13
1
13
1
At 0 °C, 30% aq H O (d = 1.11 g/mL, 12.0 mL, 106 mmol) was
2 2
1
3
added in a single portion to a stirred solution of 12 (7.00 g, 34.4
mmol) in MeOH (120 mL), followed by the addition of 2 M aq
NaOH (14 mL), also in a single portion. The reaction mixture was
1
3
1
13
1
periments. The GC/EI-MS studies were performed on a Thermo
MS-8060 gas chromatograph [Phenomenex Zebron ZB-1 capillary
stirred at 0 °C for 90 min, prior to the addition of aq sat. Na
(100 mL). The aqueous layer was separated and washed with Et
SO )
4
S O
2 2 3
–
1
column; length, 15 m; i.d. 0.32 mm; flow rate, 0.73 mL min , in-
O
2
–
1
jector, split 36.6 mL min , split ratio 1:25, 220 °C; carrier gas, He;
(2 × 100 mL). The combined organic extracts were dried (Na
2
–
1
temperature program, 80 °C (2 min) with 20 °C min ] and a
Thermo TRIO 1000 mass spectrometer (EI-MS, 70 eV). Elemental
analyses were performed on a VarioMicro of Elementar Analysen-
systeme GmbH. For the X-ray diffraction experiments, suitable sin-
gle crystals were mounted in inert oil (perfluoropolyalkyl ether,
and concentrated under reduced pressure to a volume of about 70
mL. The resulting suspension was filtered and the colorless solid
washed with Et O (2 × 15 mL) to furnish compound 13; yield: 1.70
2
g (23%); colorless solid; mp 170 °C.
1
H NMR (500.1 MHz, CDCl ): d = 1.06 [s, 3 H, 4-(CH ) ], 1.37 (m ,
3
3
a
c
ABCR) on a glass fiber and then transferred to the cold N gas
2
1 H, H-8 ), 1.45 (m , 1 H, H-7 ), 1.45 [s, 3 H, 4-(CH ) )], 1.50 (m ,
a c a 3 b c
stream of the diffractometer [BrukerNonius KAPPA-APEX II, with
1
H, H-5 ), 1.79–1.94 (m, 2 H, H -6), 2.00 (m , 1 H, H-7 ), 2.17 (dd,
a 2 c b
Göbel mirror, Mo K radiation (l = 0.71073 Å)]. The structures
a
J = 18.0, 0.5 Hz, 1 H, H-3 ), 2.22 (m , 1 H, H-5 ), 2.30 (m , 1 H, H-
a
c
b
c
2
3
were solved by direct methods. All non-hydrogen atoms were re-
fined anisotropically.2 A riding model was employed in the refine-
ment of the H atoms.
8b), 2.45 (d, J = 18.0 Hz, 1 H, H-3 ), 3.06 (s, 1 H, H-1).
b
4
1
3
C NMR (125.8 MHz, CDCl ): d = 22.2 (CH , C-6), 24.1 (CH , C-
3
2
2
7
), 27.2 [4-(CH ) )], 29.1 [4-(CH ) )], 31.2 (CH , C-5), 32.1 (CH ,
3 a 3 b 2 2
Olfactory evaluations were performed by expert perfumers with a
C-8), 36.4 (C , C-4), 47.42 (CH , C-3), 47.43 (C , C-4a), 59.4 (CH,
q
2
q
1
0% solution of the sample substance in EtOH and 10% solution of
C-1), 66.9 (C , C-8a), 119.5 (CN), 202.7 (C , C-2).
q
q
the sample substance in dipropylene glycol (DPG) on smelling blot-
ters. Odor thresholds were determined by GC olfactometry: Differ-
ent dilutions of the sample substance were injected into a gas
chromatograph in descending order of concentration until the pan-
elist failed to detect the respective substance at the sniffing port. The
panelist smelled in blind and pressed a button on perceiving an
odor. If the recorded time matched the retention time, the concen-
tration was halved. The last concentration detected at the correct re-
tention time is the individual odor threshold. The reported threshold
value represents the geometrical mean of the individual odor thresh-
olds of the different panelists.
+
GC/EI-MS: t = 7.22 min; m/z (%) = 219 (5, [M ]), 83 (100).
R
Anal. Calcd for C H NO (219.3): C, 71.21; H, 7.81; N, 6.39.
1
3
17
2
Found: C, 70.99; H, 8.01; N, 6.16.
Crystal Structure Analysis25
A single crystal of the dimensions 0.3 × 0.05 × 0.05 mm was ob-
tained from a solution of 13 (150 mg) in Et O–EtOAc (2:1, 7.5 mL)
by slow evaporation of the solvent mixture; C H NO ,
Mr = 219.28, analysis at 100 (2) K, trigonal, space group P3 (no.
2
1
3
17
2
2
145), a = 12.6998(5) Å, b = 12.6998(5) Å, c = 6.0414(4) Å,
3
3
–1
V = 843.894(7) Å , Z = 3, r
= 1.294 mg/cm , m = 0.087 mm ,
calcd
5
,5-Dimethyl-7-oxo-1,2,3,4,4a,5,6,7-octahydronaphthalene-4a-
carbonitrile (12)
,8-Diazabicyclo[5.4.0]undec-7-ene (9.00 g, 59.1 mmol) was added
F(000) 354, 2q range 2.70–57.46°, 7813 collected reflections, 2861
unique reflections (R = 0.0510), refinement full-matrix least-
int
2
1
squares methods on F for all unique reflections, 1 restraint, 150
at r.t. to a stirred solution of 2-oxocyclohexanecarbonitrile (11; 5.00
g, 40.6 mmol), prepared according to ref. 14b, and 4-methylpent-3-
parameters, S = 1.034, R1 = 0.0431 [I
data) = 0.1057, max/min electron density +0.306/–0.1086 e Å .
> 2s(I)], wR2 (all
–3
Synthesis 2009, No. 1, 62–68 © Thieme Stuttgart · New York

PAPER
4aR*,8aR*)-8a-Hydroxy-5,5-dimethyl-1,2,3,4,4a,5,6,8a-octa-
A cis-Decalol Intersection Structure
67
(
off and washed successively with H O (4 × 10 mL) and Et O
2
2
hydronaphthalene-4a-carbonitrile (14)
(4 × 10 mL). The filtrate was combined with the washings, the or-
At 0 °C, 80% aq hydrazine hydrate (d = 1.03 g/mL, 1.50 mL, 24.7
mmol) was added dropwise with stirring within 30 min to a solution
of 13 (1.60 g, 7.30 mmol) in MeOH (250 mL). After complete ad-
dition, the reaction mixture was allowed to warm to r. t., and glacial
AcOH (84.0 mg 1.40 mmol) was added in a single portion. The mix-
ture was stirred for 1 h at r.t. and then added in a single portion to a
stirred mixture consisting of CH Cl (500 mL) and H O (100 mL).
ganic layer was separated, and the aqueous layer was extracted with
Et O (2 × 25 mL). The organic extracts were combined, dried
(Na SO ), and concentrated under reduced pressure. The resulting
oily residue was purified by bulb-to-bulb distillation (150 °C/0.50
mbar) to afford compound 16 as a highly viscous liquid, which crys-
tallized within 24 h at 20 °C; yield: 220 mg (83%); colorless solid;
mp 53 °C.
2
2
4
2
2
2
Stirring was continued for 10 min at 20 °C, prior to the separation
of the organic layer, drying (Na SO ), and removal of the solvent
under reduced pressure. The resulting oily residue was purified by
1
H NMR (500.1 MHz, CDCl ): d = 0.74 [s, 3 H, 1-(CH ) )], 1.07
c a c a c a c
3
3 a
2
4
(
m , 1 H, H-8 ), 1.08 (m , 1 H, H-2 ), 1.10 (m , 1 H, H-4 ), 1.30 (m ,
1
3
1
H, H-3 ), 1.34–1.47 (m, 2 H, H -7), 1.38 (m , 1 H, H-5 ), 1.38 [s,
a 2 c a
column chromatography on silica gel (50 × 3 cm diameter, silica gel
H, 1-(CH ) ], 1.43 (m , 1 H, H-6 ), 1.51 (m , 1 H, H-8 ), 1.51 (m ,
3
b
c
a
c
b
c
3
5–70 mm, 180 g, hexane–EtOAc, 2:1). The relevant fractions (GC)
H, H-6 ), 1.54 (m , 1 H, H-2 ), 1.75 (m , 1 H, H-5 ), 1.90 (ddd,
b
c
b
c
b
were combined, and the solvent was removed under reduced pres-
J = 13.5, 13.5, 3.5 Hz, 1 H, H-4 ), 1.97 (m , 1 H, H-3 ), 3.06 and
3
not detected.
13
b
c
b
sure to furnish compound 14; yield: 600 mg (40%); colorless solid;
2
.26 (AB system, J = 15.0 Hz, 2 H, CH H NH ), OH resonance
AB A B 2
mp 131–132 °C; R = 0.7 (hexane–EtOAc, 2:1).
f
1
H NMR (500.1 MHz, CDCl ): d = 1.12 (m , 1 H, H-2 ), 1.13 [s, 3
3
c
a
C NMR (125.8 MHz, CDCl ): d = 18.1 (CH , C-3), 21.5 (CH , C-
3
2
2
H, 5-(CH ) )], 1.30 (ddd, J = 13.5, 13.5, 4.0 Hz, 1 H, H-4 ), 1.36 [s,
3
a
a
7
8
5
), 23.2 (CH , C-6), 27.2 [1-(CH ) ], 28.7 [1-(CH ) ], 28.9 (CH , C-
2 3 a 3 b 2
3
H, 5-(CH ) ], 1.55 (ddddd, J = 13.5, 13.5, 13.5, 3.5, 3.5 Hz, 1 H,
3 b
), 34.3 (CH , C-4), 37.8 (C , C-1), 38.7 (CH , C-2), 39.6 (CH , C-
2
q
2
2
H-3 ), 1.63–1.71 (m, 2 H, H-3 , H-2 ), 1.73 (ddd, J = 13.5, 13.5, 3.5
a
b
b
), 42.2 (CH NH ), 43.1 (C , C-8a), 76.2 (C , C-4a).
2
2
q
q
Hz, 1 H, H-1 ), 1.82 (m , 1 H, H-1 ), 1.98 (dd, J = 3.5, 2.5 Hz, 2 H,
a
c
b
+
GC/EI-MS: t = 8.04 min; m/z (%) = 211 (2, [M ]), 149 (100).
H -6), 2.05 (m , 1 H, H-4 ), 5.47 (dt, J = 10.0, 2.0 Hz, 1 H, H-7),
R
2
c
b
5
.80 (dt, J = 10.0, 4.0 Hz, 1 H, H-8), OH resonance not detected.
Anal. Calcd for C H NO (211.3): C, 73.88; H, 11.92; N, 6.63.
Found: C, 73.68; H, 11.86; N, 6.52.
1
3
25
1
3
C NMR (125.7 MHz, CDCl ): d = 22.9 (CH , C-3), 23.1 (CH , C-
3
2
2
2
5
8
), 27.3 [5-(CH ) )], 28.3 [5-(CH ) )], 29.8 (CH , C-4), 25.5 (C , C-
3 a 3 b 2 q
Crystal Structure Analysis25
), 36.5 (CH , C-6), 40.5 (CH , C-1), 51.6 (C , C-4a), 70.9 (C , C-
2
2
q
q
A single crystal of the dimensions 0.29 × 0.12 × 0.10 mm was ob-
a), 121.3 (CN), 128.8 (CH, C-7), 129.4 (CH, C-8).
tained directly from the reaction mixture; C H NO, Mr = 211.34,
+
13 25
GC/EI-MS: t = 6.75 min; m/z (%) = 205 (30, [M ]), 69 (100).
R
analysis at 99(2) K, monoclinic, space group P2 /n (no. 14),
1
Anal. Calcd for C H NO (205.3): C, 76.06; H, 9.33; N, 6.82.
Found: C, 76.00; H, 9.33; N, 7.00.
a = 7.3270(2) Å, b = 8.2084(3) Å, c = 20.7399(6) Å,
13
19
3
3
b = 98.347(2)°, V = 1234.15(7) Å , Z = 4, r
= 1.137 mg/cm ,
m = 0.070 mm , F(000) 472, 2q range 3.96–66.34°, 34782 collected
calcd
–
1
(
4
4aR*,8aR*)-8a-Hydroxy-4,4-dimethyldecahydronaphthalene-
a-carbonitrile (15)
reflections, 4695 unique reflections (R = 0.0431), refinement full-
int
2
matrix least-squares methods on F for all unique reflections, 158
At r.t., Pd/C (250 mg, 10 wt%, 235 mmol of Pd) was added in a sin-
gle portion to a stirred solution of 14 (900 mg, 4.38 mmol) in MeOH
parameters, S = 1.065, R1 = 0.0459 [I > 2s(I)], wR2 (all
–3
data) = 0.1342, max/min electron density +0.465/–0.197 e Å .
(30 mL). The suspension was then stirred under an atmosphere of
H for 24 h. The precipitate was filtered off and washed with MeOH
(4aR*,8aR*)-1,1,8a-Trimethyldecahydronaphthalen-4a-ol (4)
At 40 °C, 2.5 M aq NaOH (21.0 mL, 52.5 mmol) was added in a sin-
gle portion to a stirred solution of 16 (550 mg, 2.60 mmol) in MeOH
(22 mL), followed by the addition of hydroxylamine-O-sulfonic
acid (550 mg, 4.86 mmol), also in a single portion. The resulting
suspension was heated under reflux for 15 min and then allowed to
cool to 40 °C. The last 3 steps were repeated 7 times, prior to final
2
(
2 × 10 mL). The filtrate was combined with the washings, and the
resulting solution was dried (Na SO ) and concentrated under re-
2
4
duced pressure to afford compound 15; yield: 750 mg (83%); color-
less solid; mp 122 °C.
1
H NMR (500.1 MHz, CDCl ): d = 0.96 [s, 3 H, 4-(CH ) )], 1.30–
3
3 a
1
.41 (m, 2 H, H -3), 1.35 (m , 1 H, H-7 ), 1.35 (m , 1 H, H-1 ), 1.43
2 c a c a
addition of 2 M aq HCl (50 mL). Et O (50 mL) was added, the or-
2
(
m , 1 H, H-2 ), 1.44 [s, 3 H, 4-(CH ) )], 1.58 (m , 1 H, H-5 ), 1.60
c a 3 b c a
ganic layer separated, and the aqueous layer extracted with Et O
2
(
m , 1 H, H-6 ), 1.62 (m , 1 H, H-8 ), 1.64 (m , 1 H, H-7 ), 1.72 (m ,
c a c a c b c
(
2 × 50 mL). The combined organic extracts were dried (Na SO ),
2
4
1
H, H-6 ), 1.73 (m , 1 H, H-8 ), 1.78 (m , 1 H, H-1 ), 1.89 (m , 1
b c b c b c
the solvent was removed under reduced pressure, and the resulting
residue was purified by column chromatography on silica gel
(50 × 1.5 cm diameter, silica gel 15–40 mm, 50 g, hexane–EtOAc,
5:1). The relevant fractions (GC) were combined, the solvent was
removed under reduced pressure, and the resulting residue was then
purified by bulb-to-bulb distillation (60–80 °C/0.3 mbar) to afford
compound 4; yield: 205 mg (40%); colorless, odoriferous solid; mp
H, H-2 ), 1.91 (m , 1 H, H-5 ), OH resonance not detected.
b
c
b
1
3
C NMR (125.5 MHz, CDCl ): d = 17.2 (CH , C-2), 23.0 (CH , C-
3
2
2
7
), 23.2 (CH , C-6), 27.5 [4-(CH ) )], 28.9 [4-(CH ) )], 29.2 (CH ,
2 3 a 3 b 2
C-5), 30.9 (CH , C-1), 34.2 (CH , C-3), 36.5 (C , C-4), 40.8 (CH ,
2
2
q
2
C-8), 52.3 (C , C-4a), 73.0 (C , C-8a), 121.8 (CN).
q
q
+
GC/EI-MS: t = 6.86; m/z (%) = 189 (25, [M – H O]), 41 (100).
R
2
3
4 °C; R = 0.4 (hexane–EtOAc, 4:1).
f
Anal. Calcd for C H NO (207.3): C, 75.32; H, 10.21; N, 6.76.
1
3
21
Odor Description: woody odor with green-mossy, camphoraceous
and patchouli-type facets; odor threshold: 13.1 ng/L air. The odor of
the racemate is due entirely to the first eluting enantiomer on a
chiral Hydrodex-b-6-TDBM (25 m × 0.25 mm) column as revealed
Found: C, 74.92; H, 9.95; N, 6.73.
(
4aR*,8aR*)-8a-(Aminomethyl)-1,1-dimethyldecahydronaph-
thalen-4a-ol (16)
by GC–olfactometry (60 kPa H , split 1:20, 150 °C isothermal),
At r.t., a 1.1 M solution of DIBAL-H (20.0 mL, 22.0 mmol) in cy-
clohexane was added in a single portion to a stirred solution of 15
2
which accordingly possesses a threshold of 6.6 ng/L air.
(260 mg, 1.25 mmol) in hexane (5 mL). The reaction mixture was
1
H NMR (500.1 MHz, CDCl ): d = 0.73 [s, 3 H, 1-(CH ) ], 0.96 [s,
3
3 a
heated under reflux for 16 h and then cooled to 0 °C. Subsequently,
MeOH (5 mL) was added dropwise with stirring within 10 min, fol-
lowed by the addition of brine (5 mL). The precipitate was filtered
3
H, 1-(CH ) ], 1.12 (m , 1 H, H-2 ), 1.16 (s, 3 H, 8a-CH ), 1.17
3 b c eq 3
(
(
m , 1 H, H-4 ), 1.22 (m , 1 H, H-5 ), 1.34 (m , 1 H, H-6 ), 1.37
c eq c eq c eq
m , 1 H, H-3 ), 1.38 (m , 1 H, H-8 ), 1.37–1.50 (m, 2 H, H -7),
c
eq
c
ax
2
Synthesis 2009, No. 1, 62–68 © Thieme Stuttgart · New York

6
8
A. Jahnke et al.
PAPER
1
.54 (m , 1 H, H-6 ) 1.56 (m , 1 H, H-8 ), 1.51–1.61 (ddd,
Helvetica Chimica Acta: Zürich, Wiley-VCH: Weinheim,
2006, 152.
c
ax
c
eq
J = 13.0, 13.0, 4.0 Hz, 1 H, H-2 ), 1.66 (ddd, J = 13.5, 13.5, 4.5 Hz,
ax
1
H, H-5 ), 1.83 (ddddd, J = 14.0, 14.0, 14.0, 3.5, 3.5 Hz, 1 H, H-
(11) Marshall, J. A.; Hochstetler, A. R. J. Org. Chem. 1968, 33,
2593.
ax
3ax), 2.03 (ddd, J = 14.0, 14.0, 4.5 Hz, 1 H, H-4 ), OH resonance
ax
not detected.
(12) Ohloff, G. In Gustation and Olfaction; Ohloff, G.; Thomas,
A. F., Eds.; Academic Press: New York, 1971, 178.
1
3
C NMR (125.8 MHz, CDCl ): d = 13.4 (8a-CH ), 18.1 (CH , C-
3
3
2
(
13) (a) Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S.; Liu, H.-J.
Synlett 2001, 214. (b) Liu, H.-J.; Ly, T. W.; Tai, C.-L.; Wu,
J.-D.; Liang, J.-K.; Guo, J.-C.; Tseng, N.-W.; Shia, K.-S.
Tetrahedron 2003, 59, 1209.
6
), 21.7 (CH , C-3), 23.7 (CH , C-7), 26.4 [1-(CH ) ], 27.3 [1-
2 2 3 a
(
(
CH ) ], 31.0 (CH , C-8), 33.9 (CH , C-4), 36.7 (C , C-1), 37.3
3 b 2 2 q
CH , C-2), 39.2 (CH , C-5), 42.2 (C , C-8a), 74.9 (C , C-4a).
2
2
q
q
+
GC/EI-MS: t = 6.16 min; m/z (%) = 196 (5, [M ]), 82 (100).
R
(14) Weitz, E.; Scheffer, A. Ber. Dtsch. Chem. Ges. 1921, 54,
327.
15) (a) Payne, G. B.; Williams, P. H. J. Org. Chem. 1961, 26,
51. (b) Sugiyama, S.; Ôhigashi, S.; Sawa, R.; Hayashi, H.
Bull. Chem. Soc. Jpn. 1989, 62, 3202.
2
Anal. Calcd for C H O (196.3): C, 79.53; H, 12.32. Found: C,
13
24
(
7
9.62; H, 12.67.
6
Acknowledgment
(16) (a) Trost, B. M.; Salzmann, T. N. J. Chem. Soc., Chem.
Commun. 1975, 571. (b) Trost, B. M.; Bogdanowicz, M. J.;
Frazee, W. J.; Salzmann, T. N. J. Am. Chem. Soc. 1978, 100,
Thanks are due to Dr. Rüdiger Bertermann and Dr. Matthias Grüne
for performing the NMR spectra measurements, to Alain E. Alchen-
berger and Dominique Lelievre for the olfactory evaluation, to
Heinz Koch for the GC–olfactometry studies on chiral stationary
phase, and to Katarina Grman for the odor threshold determinations.
A.J. is grateful to Givaudan Schweiz AG for financial support.
5
512.
17) (a) Adam, W.; Kilic, H.; Saha-Möller, C. R. Synlett 2002,
10. (b) Zilbeyaz, K.; Sahin, E.; Kilic, H. Tetrahedron:
Asymmetry 2007, 18, 791.
18) (a) Ziegler, K.; Eberle, H.; Ohlinger, H. Liebigs Ann. Chem.
(
(
(
5
1933, 504, 94. (b) Schaefer, J. P.; Bloomfield, J. J. Org.
React. 1967, 15, 1.
References
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(
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(25) Crystallographic data (excluding structure factors) for the
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(16). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44(1223)336033; e-mail:
2
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Synthesis 2009, No. 1, 62–68 © Thieme Stuttgart · New York