Unexpected tethering in the synthesis of methyl-substituted acetyl-1-oxaspiro[4.5]decanes: Novel woody-ambery odorants with improved bioavailability

Article abstract of DOI:10.1002/ejoc.200700833

To study the olfactory properties of spirocyclic analogs of Iso Gamma (3) with improved water solubility and bioavailability, it was envisaged to spiroannulate 1-acetyl-1,2-dimethylcyclohexanone at the 4-position with a 3,3-dimethyl-tetrahydrofuran-2-yl moiety that would mimic the polarity of the double bond by its ether function. 3,3-Dimethyl-4-methylenehex-5-en-1-ol (9) was prepared by copper(I)-mediated 1,4-conjugate addition of the Grignard reagent of chloroprene (7) to 3-methylbut-2-enal with subsequent LAH reduction. However, the Diels-Alder reaction of diene 9 with (E)-3-methylpent-3-en-2-one in the presence of Me₂AlCl unexpectedly provided exclusively the undesired meta adduct 10, as was discovered after cyclization to 11 with MeSO ₃H. The wrong selectivity was due to a tethering effect of the Lewis acid, and this could be evaded by changing the carbonyl function of the dienophile to a hydroxy group. Thereby the (5′R*,7′S*, 8′S*)-configured 1-(4′,4′,7′,8′-tetramethyl- 1′-oxaspiro[4.5]decan-7′/8′-yl)ethan-1-ones 11 and 14, as well as the like-configured 1-(4′,4′,7′-trimethyl-1′- oxaspiro[4.5]-decan-7′/8′-yl)ethan-1-ones 16 and 19, were prepared selectively and studied for their odor characters, threshold values, and octanol/water partition coefficients. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700833

FULL PAPER
DOI: 10.1002/ejoc.200700833
Unexpected Tethering in the Synthesis of Methyl-Substituted
Acetyl-1-oxaspiro[4.5]decanes: Novel Woody–Ambery Odorants
with Improved Bioavailability
Philip Kraft*[a] and Kasim Popaj[a]
Dedicated to Professor Elias J. Corey on the occasion of his 80th birthday
Keywords: Biodegradation / Diels–Alder reactions / Fragrances / Structure–activity relationships / Tethering effects
To study the olfactory properties of spirocyclic analogs of Iso
Gamma (3) with improved water solubility and bioavail-
ability, it was envisaged to spiroannulate 1-acetyl-1,2-di-
methylcyclohexanone at the 4-position with a 3,3-dimethyl-
tetrahydrofuran-2-yl moiety that would mimic the polarity of
the double bond by its ether function. 3,3-Dimethyl-4-meth-
10, as was discovered after cyclization to 11 with MeSO3H.
The wrong selectivity was due to a tethering effect of the
Lewis acid, and this could be evaded by changing the car-
bonyl function of the dienophile to a hydroxy group. Thereby
the (5ЈR*,7ЈS*,8ЈS*)-configured 1-(4Ј,4Ј,7Ј,8Ј-tetramethyl-1Ј-
oxaspiro[4.5]decan-7Ј/8Ј-yl)ethan-1-ones 11 and 14, as well
ylenehex-5-en-1-ol (9) was prepared by copper(I)-mediated as the like-configured 1-(4Ј,4Ј,7Ј-trimethyl-1Ј-oxaspiro[4.5]-
1,4-conjugate addition of the Grignard reagent of chloro-
prene (7) to 3-methylbut-2-enal with subsequent LAH re-
duction. However, the Diels–Alder reaction of diene 9 with
(E)-3-methylpent-3-en-2-one in the presence of Me2AlCl un-
expectedly provided exclusively the undesired meta adduct
decan-7Ј/8Ј-yl)ethan-1-ones 16 and 19, were prepared selec-
tively and studied for their odor characters, threshold values,
and octanol/water partition coefficients.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Due to its transparent woody–ambery character, Iso E
Super remains one of the most important odorants both in
terms of production volume and number of perfumes in
which it is used. While its main component, the α-isomer 1,
bearing the double bond between the bridgehead carbon
atoms, is very weak in smell, with an odor threshold of
500 ng/L,[1,2] the β-isomer 2, which has been termed Iso E
Super Plus[3] or Arborone,[4] determines the odor of this
perfumery raw material with an odor threshold that is
100,000 times lower. The β-isomer 2 constitutes only 3–4%
of commercial grade Iso E Super, but recently a higher-
quality material, in which the β-isomer is enriched by a fac-
tor of two, has been manufactured by a different process.
This quality is known as Iso Gamma Super,[2] since it con-
tains in addition 18% of the γ-isomer 3, which also pos-
sesses a very pleasant woody–ambery odor note (Figure 1).
Recently, we reported on the synthesis of potent spirocy-
clic ketones,[3] including the spirocyclic Georgywood analog
4, which emanated the soft, woody–ambery odor of the β-
isomer 2 accompanied by additional aspects of orris. These
Figure 1. The woody–ambery benchmark odorants 1–3, the power-
ful soft, woody–ambery spirocyclic ketone 4, and two intense pa-
tchouli-like, woody spirocycles 5 and 6.
rigidified spirocyclic analogs had been designed to probe
the α-helical leu-gly-gly-leu motif that Hong and Corey[4]
had proposed for the binding of 2, and to elucidate the
active conformation(s) of these woody–ambery odorants on
the olfactory receptor(s). Despite its limited conformational
flexibility, the spirocyclic analog 4 proved to be a very
powerful odorant with an odor threshold of 0.094 ng/L
air.[3] Moreover, the spirocyclic ketol 5 was discovered to be
one of the most powerful patchouli odorants,[5] possessing
an odor threshold of 0.027 ng/L, in addition to woody–am-
[a] Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax: +41-44-824-29-26
E-mail: philip.kraft@givaudan.com
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bery, tobacco-like facets, and the dimethylcyclopentyl-spi-
roannulated cyclohexanol 6 also displayed very interesting
olfactory properties,[6] again in the patchouli direction, but
with additional woody, earthy, and camphoraceous under-
tones.
It thus seemed interesting to study spirocyclic analogs of
Iso Gamma (3), but these should exhibit an improved water
solubility and bioavailability, since all Iso E Super isomers
1–3 have a calculated octanol/water partition coefficient of
log(Pow calcd. = 5.01 and are prone to bioaccumulation. The
)
log(Pow) value corresponds to the bioavailability of the sub-
stances in aquatic systems, and a high log(Pow) value indi-
cates bad biodegradability or even persistency in the envi-
ronment. According to the European REACH regulations
now in place, all substances with log(Pow)Ͼ4.5 are sus-
pected of being persistent in the environment. To mimic and
even augment the polarity of the γ-double bond of 3, it was
therefore planned to spiroannulate 1-acetyl-1,2-dimethylcy-
clohexanone at the 4-position with a 3,3-dimethyltetra-
hydrofuran-2-yl moiety. Thereby, the calculated octanol/
Scheme 1. Synthesis of undesired meta-configured 7-acetyl-4,4-di-
methyl-1-oxaspiro[4.5]decanes 11 and 16 by an aluminum-tethered
Diels–Alder reaction.
water partition coefficient log(Pow calcd.
)
improves from
= 3.48 for the
log(Pow calcd. = 5.01 for 1–3 to log(Pow calcd.
)
)
first target structure 14 (Scheme 2), which makes 14 an at-
tractive target compound also from an environmental point bearing an alkyl substituent at the 2-position react with ac-
of view.
ceptor-substituted olefins to give predominantly the para-
configured Diels–Alder adduct, especially in the presence
of Lewis acids that by complexation with the acceptor
group extend the allylic cation character of the dienophile
and polarize the LUMO even more. By lowering the
Results and Discussions
At first glance, synthetic access to target structure 14 by LUMO energy of the olefin, Lewis acids also increase the
the Diels–Alder reaction and a subsequent acid-catalyzed reactivity of Diels–Alder reactions. Without the addition of
cyclization seemed rather straightforward. The appropriate an aluminum Lewis acid, no reaction was observed between
starting material, chloroprene (7), is an inexpensive bulk diene 9 and (E)-3-methylpent-3-en-2-one. However, in the
chemical prepared by gas-phase chlorination of butadiene presence of 10 mol-% of dimethylaluminum chloride, the re-
with subsequent dehydrohalogenation. The preparation of action went smoothly, and only one regioisomer was
the corresponding Grignard reagent of chloroprene (7) is formed with complete selectivity. Yet, as was discovered by
not possible by direct reaction with magnesium in ether, 2D NMR spectroscopy of the subsequent cyclization prod-
THF, or xylene, as reported by Aufdermarsh,[7] but it can uct 11, the formed Diels–Alder adduct 10 did not have the
be achieved in the presence of anhydrous zinc(II) chloride, desired and expected para-orientation, but was indeed
as Nunomoto and Yamashita found 15 years later.[8] We, meta-configured.
however, decided to employ the entrainment method of
As detailed HOMO/LUMO investigations offered no ex-
Pearson et al.,[9] which uses, in addition to zinc(II) chloride, planation, it was concluded that the aluminum Lewis acid
1,2-dibromoethane as entrainer to activate the magnesium must have tethered the Diels–Alder reaction to complete
surface. The 1,2-dibromoethane reacts with magnesium, meta-selectivity. Such a tethering of [4+2] cycloadditions by
and the intermediate magnesium species immediately de- magnesium and aluminum salts was first described by Stork
composes to MgBr2 and ethene, thereby generating a highly and Chan in connection with allylic dienols,[11] and Batey
activated, nascent metal surface.[10] In this manner, the et al.[12] also reported a case of a homoallylic dienol in a
Grignard reagent of the 2-chlorobuta-1,3-diene (7) was con- boron-tethered Diels–Alder reaction with (E)-dicyclohex-
veniently prepared, and its copper(I)-mediated 1,4-conju- ylbuta-1,3-dienyl boronate. Bertozzi et al.[13] enabled other-
gate addition to 3-methylbut-2-enal furnished dienal 8 in wise “noncompatible” combinations of dienes and dieno-
54% yield after chromatographic purification (Scheme 1). philes by temporary tethering allylic dienols with allylic alk-
The corresponding dihomoallylic dienol 9 was isolated in enols by using AlMe3 or ZnMe2, and more recently Bar-
90% yield by standard lithium aluminum hydride (LAH) riault et al.[14] examined Diels–Alder reactions of dienes
reduction in THF.
with an allylic alcohol function at the α- or β-position in
As the hydroxy function of 9 was too far away from the the presence of PhMgBr or MgBr2·OEt2 and triethylamine.
diene double bonds to have any decisive influence on the Covalent tethering of Diels–Alder reactions is also possible,
frontier orbitals, it was expected that 9 would behave like a and type 2 intramolecular Diels–Alder reactions have been
normal 2-alkyl-substituted buta-1,3-diene. Buta-1,3-dienes extensively reviewed.[15,16] Already in the 1980s, Tamao, Ko-
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Novel Woody–Ambery Odorants with Improved Bioavailability
bayashi, and Ito demonstrated covalent tethering on the ex- ances, its main note was green-metallic, and with an odor
ample of silicon,[17] while Shea and co-workers reported on threshold of 149 ng/L air it was rather weak.
uncatalyzed[18a] and Et2AlCl-catalyzed[18b] intramolecular
cycloadditions with high meta-selectivity.
The problem was therefore to avoid the undesired tether-
ing effect, so that the Diels–Alder reaction would take the
To the best of our knowledge, a tethering with a dihomo- desired course. Though this could have been done by pro-
allylic dienol such as 9 has never been observed. The pro- tection of the hydroxy function of 9, we wanted to employ
posed transition state A (Figure 2) involves an unusual 4- the same diene 9 without protecting groups and wondered
alumina-3,5-dioxabicyclo[7.3.1]tridec-1(12),2,9(13),10(11)- if the increased acidity of the corresponding allyl alcohol
tetraene ring system, in which transannular strain in the 10- dienophile would not prevent the reaction of the catalytic
membered ring favors an endo-orientation of the dienophile. amounts of Me2AlCl with the dihomoallylic dienol, so that
Even if (8Z)-4,4,7,8,10,10-hexamethyl-5-methylene-3,4,5,10- complexes with multiple allyl alcohol ligands would rather
tetrahydro-2H-oxecine is taken as a completely flexible result. First, an intermediate allyloxy(methyl)aluminum
model of this partial ring, the global minimum (PM3) of chloride species should be formed, and frontier-orbital cal-
the (6Z)-isomer representing the endo-conformation is fa- culations indicated this also to exhibit a lower LUMO en-
vored by 20 kJ/mol (4.8 kcal/mol) over the (6E)-isomer rep- ergy and therefore an enhanced reactivity. Most import-
resenting an exo-orientation. A better model to account for antly, however, the tethering effect should thereby be
the complete regio- and stereoselectivity of the reaction, “switched off” and could thus indirectly be proven. Indeed,
which furnished 10 in a good yield of 55%, could not be as the 2D NMR experiments of the final product revealed,
devised, and further studies concerning the endo-/exo-selec- the Diels–Alder reaction of 9 with (3E)-3-methylpent-3-en-
tivity of the reaction were beyond the scope of this work.
2-ol in refluxing toluene in the presence of 20 mol-% of Me2-
AlCl provided exclusively the desired para product 12, al-
beit in a mere 17% yield, which is due to the thermal insta-
bility of diene 9 (Scheme 2). Matsubara et al.[19] had also
reported a 17.2% yield for the thermal Diels–Alder reaction
of alloocimene with allyl alcohol to afford the slightly
woody-smelling diastereomeric mixture of the correspond-
ing Diels–Alder adducts, again due to thermal instability.
Thus, one could have also suspected a purely thermal
course of the Diels–Alder reaction in our case, but we can
exclude a purely thermal course, since only decomposition
products, but no adduct 12, were formed in the absence of
Me2AlCl. An alternative explanation for the non-tethering
in the case of the allyl alcohol could be an excessively high
activation energy of the formed complex, as the dienophile
Figure 2. Proposed 10-membered transition state A for the Diels–
Alder reaction of the dihomoallylic dienol 9 and (E)-3-methylpent-
3-en-2-one, tethered by dimethylaluminum chloride.
The undesired course of the Diels–Alder reaction was is less reactive, and type 2 cycloadditions typically show
discovered in the cyclization product 11. Treatment of high activation energies.[16]
the hydroxy cyclohexenone 10 with methanesulfonic
Diol 12 was then treated, in analogy to the synthesis of
acid in CH2Cl2 at –20 °C furnished exclusively the 11, with methanesulfonic acid at –40 °C, and the resulting
(5ЈR*,7ЈS*,8ЈS*)-configured 1-(4Ј,4Ј,7Ј,8Ј-tetramethyl-1Ј- cyclization product 13 was isolated in 71% by flash
oxaspiro[4.5]decan-7Ј-yl)ethan-1-one (11). This high dia- chromatography (FC). After oxidation of the remaining hy-
stereoselectivity, for which low temperatures were indis- droxy function of 13 with pyridinium chlorochromate
pensable, is explicable by the bis(equatorial) orientation of (PCC) on Celite in CH2Cl2, the target compound 14 was
the 1Ј-acetyl and 6Ј-methyl substituent with the axial 1Ј- obtained in 88% yield as a single diastereomer. The relative
methyl group, forcing the hydroxy function to attack the (5RЈ,7ЈS,8ЈS)-stereochemistry was unambiguously derived
cationic center from the same side in order to avoid 1,3- from distinct crosspeaks of 7Ј-Hax with 2-Meeq, 6Ј- and 10Ј-
diaxial interaction of 1Ј-Meax with Me2C-2ЈЈ. The side Hax with 4Ј-Me2 as well as 8Ј-Meax with 4Ј-Me2 in the
chain can thus swing in the direction of the carbenium ion NOESY spectrum after assignment of all atoms by HSQC
only from the side of the axial methyl group on the carbon and INADEQUATE experiments. As the equatorially situ-
atom that also bears the acetyl moiety. This stereochemistry ated side chain of 12 is now displaced by one position, the
of 11 was proven by distinct NOE effects between 7Ј-Meax steric interaction of the hydroxy group with the axial methyl
and 9Ј-Hax, 4Ј-Meax and 10Ј-Hax, as well as 4Ј-Meeq and 6Ј- group on the acetyl carbon atom predominates, and the side
Hax, with assignments of the atoms by INADEQUATE and chain swings in the opposite direction as in the cyclization
HSQC experiments. The meta-configured 7-acetyl-1-oxa- of 10; yet, consequently lower temperatures are necessary
spiro[4.5]decane 11 was thus isolated in 90% yield as a sin- to ensure a clean course of the cyclization. So, by changing
gle diastereoisomer. Yet, not only was it spiroannulated at the dienophile, we could avoid tethering and arrive at our
the wrong position, but also the odor character was not target molecule 14. However, in terms of olfactory proper-
that which was desired. Though 11 smelled sweet, with a ties, the 8-acetyl-substituted 4,4,7,8-tetramethyl-1-oxa-
distinct woody–earthy character as well as root-like nu- spiro[4.5]decane was also disappointing: with an odor
Eur. J. Org. Chem. 2008, 261–268
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P. Kraft, K. Popaj
FULL PAPER
was assigned first by 2D NMR spectroscopy. As the target
structure 19 was crystalline, the trans-orientation of the
tetrahydrofuran oxygen atom with respect to the methyl
substituent could be confirmed independently by a single-
crystal X-ray structure analysis (Figure 3).
Figure 3. Molecular structure of (Ϯ)-(5ЈR*,8ЈR*)-1-(4Ј,4Ј,8Ј-tri-
methyl-1Ј-oxaspiro[4.5]decan-8Ј-yl)ethan-1-one (19) in the crystal,
with thermal ellipsoids at the 50% probability level.
Olfactory Properties and Water Solubility
Scheme 2. Synthesis of the para-configured 8-acetyl-substituted
target compounds 14 and 19 by Diels–Alder reaction with (3E)-3-
methylpent-3-en-2-ol and 3-methylbut-3-en-2-ol.
Of all acetyl-1-oxaspiro[4.5]decanes investigated, the like-
8-acetyl trimethyloxaspiro[4.5]decane 19 possesses the low-
est odor threshold (92.1 ng/L air), and it is also the one that
threshold of 346 ng/L air, it was even weaker than 11, and resembles the lead structure Iso E Super (1) most closely in
despite earthy-woody accents, its main odor character was character. Its odor was described as woody–ambery, remi-
green-metallic just as was 11 – so the position of the spiro- niscent of 1, with some agrestic, conifer-type facets, and a
annulated dimethyltetrahydrofuran ring was not of the ex- slightly medicinal touch. The meta-configured analog, the
pected importance.
like-7-acetyl trimethyloxaspiro[4.5]decane 16 was quite sim-
To study the structure–odor relationship and the selectiv- ilar in odor intensity (99.4 ng/L air). Its woody character
ity of the Diels–Alder reaction in more detail, it was was, however, purely cedarwood-like, without ambery fac-
planned to investigate the reactions of diene 9 with 3-meth- ets, but instead with a strong fruity inclination, and ad-
ylbut-3-en-2-one and its corresponding alcohol. As was the ditional agrestic as well as spicy facets. The introduction of
case for (E)-3-methylpent-3-ene-2-one, the Me2AlCl-cata- an 8-methyl group into 16 diminished the odor intensity
lyzed Diels–Alder reaction of 3-methylbut-3-en-2-one with significantly, and a threshold value of 149 ng/L air was
9 provided also the meta-configured adduct 15, in a slightly measured for the respective 7-acetyl tetramethyloxa-
increased yield of 61%. Cyclization of 15 at –20 °C in the spiro[4.5]decane 11. The odor also shifted towards sweet,
presence of methanesulfonic acid afforded the correspond- green, and metallic attributes, while a woody tonality ac-
ing like-configured 7-acetyl-1-oxaspiro[4.5]decane 16 in companied by earthy and root-like nuances was perceptible
91% yield as a single diastereoisomer, the stereochemistry only in the background. The first target structure 14 was the
of which was again assigned by NOESY and HSQC experi- weakest of the series investigated, and, with an odor threshold
ments. The woody aspects now came to the fore, and 16 of 346 ng/L air, not far from the very weak α-isomer 1 of Iso E
emanated a fruity, cedarwood note with slightly agrestic Super with an odor threshold of 500 ng/L air. Its weak green-
and spicy facets. The odor threshold also improved to metallic odor with earthy-woody accents was indeed quite
99.4 ng/L air, though this is still not very potent.
close in character to its 7-acetyl analog 11.
Again the presumed tethering of the aluminum Lewis
While for Iso E Super (1) the octanol/water partition co-
acid could be evaded by changing over to the corresponding efficient according to the OECD guideline No. 117[20] is
allylic alcohol. Diels–Alder reaction of 3-methylbut-3-en-2- log(Pow) = 5.7, log(Pow)Ͻ4.5 was measured for all target
ol with dienol 9 in the presence of 20 mol-% Me2AlCl in compounds. The most water-soluble odorants investigated
refluxing toluene furnished the para-configured adduct 17 were the crystalline 8-acetyl trimethyloxaspiro[4.5]decane
in a slightly improved yield of 22%. Subsequent acid-cata- 19 and its meta-configured 7-acetyl analog 16, for which a
lyzed cyclization employing methanesulfonic acid in log(Pow) = 3.2 was measured in both cases. As expected, the
CH2Cl2 at –40 °C provided the spirocyclic alcohol 18 in tetramethyloxaspiro[4.5]decanes 11 and 14 were less water-
73% yield. This was oxidized by PCC on Celite in CH2Cl2 soluble, the meta-configured 7-acetyl analog 11 being the least
to afford the final target compound 19 in 90% yield after water-soluble with log(Pow) = 4.0. For the para-configured
purification by flash chromatography (FC). The like-stereo- 8-acetyl 14, an intermediate value of log(Pow) = 3.7 was deter-
chemistry of the 8-acetyl trimethyloxaspiro[4.5]decane 19 mined according to the OECD guideline No. 117.[20]
264
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Novel Woody–Ambery Odorants with Improved Bioavailability
lene, 100g, 565 mmol) and 1,2-dibromoethane (22.2 g, 119 mmol)
in THF (800 mL) was then added within 1 h. After being kept at
reflux for an additional 2 h, the reaction mixture was cooled to
–60 °C, and CuBr·Me2S (18.6 g, 90.5 mmol) was added portionwise
within 45 min. After further stirring for 20 min at this temp., a
solution of 3-methylbut-2-enal (76.1 g, 905 mmol) in THF
(200 mL) was added over a period of 30 min. The reaction mixture
was then quenched at –10 °C by addition of satd. aq. NH4Cl solu-
tion (700 mL), and the product was extracted with Et2O
(3ϫ500 mL). The combined organic extracts were washed with
brine (2ϫ200 mL), dried (Na2SO4), and concentrated under re-
duced pressure. The resulting residue was purified by silica gel FC
(pentane/Et2O, 98:2, Rf = 0.20) to furnish 8 (42.2 g, 54%). IR
Conclusions
All target compounds display an improved bioavail-
ability, but only (5ЈR*,8ЈR*)-1-(4Ј,4Ј,8Ј-trimethyl-1Ј-oxa-
spiro[4.5]decan-8Ј-yl)ethan-1-one (19) resembles the com-
mercial Iso E Super closely in olfactory character. With an
odor threshold of 92.1 ng/L, this is, however, much weaker
than the commercial Iso E Super quality with 3–4% of the
high-impact β-isomer 2. Even though the woody–ambery
odorant 19 is thus economically not competitive; it repre-
sents a forward-looking idea for the design of novel odor-
ants with improved bioavailability. The Me2AlCl-mediated
tethering concept of dihomoallylic dienols such as 9, which
can simply be controlled by the functional group of the di-
enophile, leading to complete meta-selectivity of the Diels–
Alder reaction in case of an α,β-unsaturated carbonyl com-
pound, and complete para-selectivity in case of an allylic
hydroxy dienophile, will certainly be useful for directing the
selectivity of related Diels–Alder reactions. As Diels–Alder
reactions constitute one of the most important C–C-bond-
forming reactions, the extension of the tethering concept to
dihomoallylic dienol systems should have a broader appli-
cability to organic synthesis, and possibly could even be ex-
tended much further still.
(neat): ν = 1719 (s, νC=O), 1466 [w, δas(CH3)], 1366 [w, δs(CH3)],
˜
902 (m, δC=C–H) cm–1. 1H NMR (CDCl3): δ = 1.26 (s, 6 H, 3-Me2),
2.40 (d, J = 3.0 Hz, 2 H, 2-H2), 4.88 (dd, J = 1.0, 1.0 Hz, 1 H, 6-
HE), 5.11 (dd, J = 11.0, 2.0 Hz, 1 H, 6-HZ), 5.21 (dd, J = 1.0,
1.0 Hz, 1 H, 1Ј-HZ), 5.44 (dd, J = 17.0, 2.0 Hz, 1 H, 1Ј-HE), 6.42
(dddd, J = 17.0, 11.0, 1.0, 1.0 Hz, 1 H, 5-H), 9.62 (d, J = 3.0 Hz,
1 H, 1-H) ppm. 13C NMR (CDCl3): δ = 27.6 (q, 3-Me2), 37.1 (s,
C-3), 53.4 (t, C-2), 109.9 (t, C-1Ј), 116.4 (t, C-6), 135.9 (d, C-5),
153.4 (s, C-4), 203.0 (d, C-1) ppm. MS (EI): m/z (%) = 138 (2)
[M]+, 120 (3) [M – CH3]+, 96 (100) [M – C2H2O]+, 95 (26) [M –
C2H3O]+, 81 (95) [C6H9]+.
3,3-Dimethyl-4-methylenehex-5-en-1-ol (9): At 0–2 °C, a solution of
8 (40.3 g, 292 mmol) in THF (500 mL) was added dropwise with
stirring over a period of 1.5 h to a suspension of LiAlH4 (11.1 g,
292 mmol) in THF (300 mL), and the reaction mixture was stirred
for additional 4 h at room temp., prior to cautious quenching at
0 °C with water (11.1 mL), followed by aq. NaOH solution (15%,
11.1 mL), and again water (33.3 mL). The resulting precipitate was
stirred for 30 min at room temp., filtered off with suction, and
washed with Et2O (200 mL). The filtrate was concentrated, and the
resulting residue was purified by silica gel FC (pentane/Et2O, 8:2,
Rf = 0.18) to afford 9 (36.8 g, 90%) as a colorless liquid. IR (neat):
Experimental Section
IR: Bruker VECTOR 22/Harrick SplitPea micro ATR, Si. NMR:
Bruker AVANCE DPX-400, Bruker AVANCE 500 (TCI), TMS int.
(= 0 ppm). MS: Finnigan MAT 95 (EI: 70 eV), HP Chemstation
6890 GC / 5973 Mass-Sensitive Detector. FC (flash chromatog-
raphy): Brunschwig Silica 100726 (32–63 μm, 60 Å). TLC: Merck
Kieselgel 60 F254 (particle size 5–20 μm, layer thickness 250 μm on
glass, 10 cmϫ10 cm); visualization reagent: phosphomolybdic acid
spray (Merck 1.00480.0100). Melting points: Büchi Melting Point
B545 (uncorr.). Elemental analyses: Mikroanalytisches Laborator-
ium Ilse Beetz, 96301 Kronach, Germany. X-ray: Hoffmann-La
Roche, CH-4070 Basel, Switzerland; Stoe IPDS I diffractometer
(Image Plate Diffraction Systems); SHELX-97.[21] Unless otherwise
stated, all reactions were performed under a N2 atmosphere. Start-
ing materials, reagents, and solvents were used without further pu-
rification: SAFC or Acros, except 2-chlorobuta-1,3-diene (7, 50%
in xylene) from ABCR, 76151 Karlsruhe, Germany.
ν = 3320 (m, νO–H), 1461 [w, δas(CH3)], 1363 [w, δs(CH3)], 1021 (m,
˜
1
νC–O), 897 (s, δC=C–H) cm–1. H NMR (CDCl3): δ = 1.11 (s, 6 H,
3-Me2), 1.62 (br. s, 1 H, OH), 1.70 (dt, J = 7.5, 7.5 Hz, 2 H, 1-H2),
3.56 (t, J = 7.5 Hz, 2 H, 2-H2), 4.80 (dd, J = 1.0, 1.0 Hz, 1 H, 6-
HE), 5.05 (dd, J = 11.0, 2.0 Hz, 1 H, 6-HZ), 5.15 (dd, J = 1.0,
1.0 Hz, 1 H, 1Ј-HZ), 5.42 (dd, J = 17.0, 2.0 Hz, 1 H, 1Ј-HE), 6.41
(dddd, J = 17.0, 11.0, 1.0, 1.0 Hz, 1 H, 5-H) ppm. 13C NMR
(CDCl3): δ = 27.6 (q, 3-Me2), 37.0 (s, C-3), 43.5 (t, C-2), 59.9 (t,
C-1), 109.1 (t, C-1Ј), 115.3 (t, C-6), 136.5 (d, C-5), 154.7 (s, C-4)
ppm. MS (EI): m/z (%) = 125 (3) [M – CH3]+, 96 (100) [M –
C2H4O]+, 81 (71) [M – C2H4O]+.
Odor thresholds were determined by GC–olfactometry: Different
dilutions of the sample substance were injected into a gas chroma-
tograph in descending order of concentration until the panelist
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
retention time is the individual odor threshold. The reported
threshold values are the geometrical means of the individual odor
thresholds of different panelists.
(؎)-(1ЈR*,6ЈR*)-1-[3Ј-(4ЈЈ-Hydroxy-2ЈЈ-methylbutan-2ЈЈ-yl)-1Ј,6Ј-di-
methylcyclohex-3Ј-enyl]ethan-1-one (10): At 0 °C, a Me2AlCl solu-
tion (1 m in hexanes, 3.30 mL, 3.30 mmol) was added within 5 min
to a solution of 9 (4.63 g, 33.0 mmol) and (E)-3-methylpent-3-en-
2-one (3.88 g, 39.6 mmol) in CH2Cl2 (10 mL). The reaction mixture
was stirred overnight at room temp., poured into water (100 mL),
and extracted with Et2O (3ϫ200 mL). The combined organic ex-
tracts were dried (Na2SO4), and the solvents were evaporated. The
resulting residue was purified by silica gel FC (pentane/Et2O, 1:1,
R = 0.18) to furnish 10 (4.32 g, 55%). IR (neat): ν = 3377 (m,
˜
f
3,3-Dimethyl-4-methylenehex-5-enal (8): At room temp., a solution
of 1,2-dibromoethane (9.58 g, 51.0 mmol) in THF (50 mL) was
added to a stirred suspension of Mg turnings (22.0 g, 905 mmol)
in THF (50 mL), the reaction being initiated by occasional heating
with a heat gun. A solution of ZnCl2 in Et2O (1 m, 5.60 mL,
5.60 mmol) was added by syringe, which caused vigorous reflux.
Under reflux, a solution of 2-chlorobuta-1,3-diene (7, 50% in xy-
νO–H), 1698 (s, νC=O), 1454 [m, δas(CH3)], 1353 [m, δs(CH3)], 1020
1
(m, νC–O) cm–1. H NMR (CDCl3): δ = 0.80 (d, J = 7.0 Hz, 3 H,
6Ј-Me), 1.00 (s, 6 H, 2ЈЈ-Me2), 1.04 (d, J = 7.0 Hz, 3 H, 1-Me),
1.65 (t, J = 8.0 Hz, 2 H, 3ЈЈ-H2), 1.69–1.80 (m, 1 H, 5Ј-Hb), 1.90
(br. s, 1 H, OH), 2.05–2.08 (m, 1 H, 5Ј-Ha), 2.06 (qd, J = 7.0,
1.0 Hz, 1 H, 2Ј-Hax), 2.11–2.12 (m, 1 H, 6Ј-H), 2.16 (s, 3 H, 2-H3),
2.34 (qd, J = 7.0, 1.0 Hz, 1 H, 2Ј-Heq), 3.55 (td, J = 8.0, 5.5 Hz, 2
Eur. J. Org. Chem. 2008, 261–268
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
265

P. Kraft, K. Popaj
FULL PAPER
H, 4ЈЈ-H2), 3.57–3.59 (m, 1 H, 4Ј-H) ppm. 13C NMR (CDCl3): δ = (؎)-(1RS,5ЈR*,7ЈS*,8ЈS*)-1-(4Ј,4Ј,7Ј,8Ј-Tetramethyl-1Ј-oxaspiro-
15.9 (q, 6Ј-Me), 16.2 (q, 1Ј-Me), 25.2 (q, C-2), 27.4/27.5 (2q, 2ЈЈ- [4.5]decan-8Ј-yl)ethan-1-ol (13): At –40 °C, MeSO3H (740 mg,
Me2), 31.4 (t, C-5Ј), 32.2 (d, C-6Ј), 33.2 (t, C-2Ј), 37.2 (s, C-2ЈЈ), 7.70 mmol) was added within 10 min to a stirred solution of 12
42.9 (t, C-3ЈЈ), 50.7 (s, C-1Ј), 60.0 (t, C-4ЈЈ), 117.8 (d, C-4Ј), 140.8 (1.54 g, 6.41 mmol) in CH2Cl2 (50 mL). The resulting dark-brown
(s, C-3Ј), 214.3 (s, C-1) ppm. MS (EI): m/z (%) = 238 (2) [M]+, 223
(3) [M – CH3]+, 195 (74) [M – C2H3O]+, 151 (58) [C11H19]+, 43
(100) [C2H3O]+.
solution was allowed to slowly warm to 0 °C, and it was stirred for
3 h at this temp., then 3 h at room temp. The reaction mixture was
poured into water (100 mL) and extracted with Et2O (3ϫ300 mL).
The combined organic layers were washed with brine (2ϫ100 mL),
dried (Na2SO4), and the solvents were evaporated. The resulting
residue was purified by silica gel FC (pentane/Et2O, 6:4, Rf = 0.15)
(؎)-(5ЈR*,7ЈS*,8ЈS*)-1-(4Ј,4Ј,7Ј,8Ј-Tetramethyl-1Ј-oxaspiro[4.5]de-
can-7Ј-yl)ethan-1-one (11): At –20 °C, MeSO3H (1.87 g, 19.5 mmol)
was added within 15 min to a stirred solution of 10 (3.82 g,
16.2 mmol) in CH2Cl2 (80 mL). The resulting dark brown solution
was warmed slowly to 0 °C, stirred for 1 h at this temp. and then
for 4 h at room temp., prior to being poured into water (200 mL)
and extracted with Et2O (3ϫ300 mL). The combined organic ex-
tracts were washed with brine (2ϫ100 mL), dried (Na2SO4), and
the solvents were evaporated. The resulting residue was purified by
silica gel FC (pentane/Et2O, 95:5, Rf = 0.17) to provide the odorif-
to furnish 13 (1.10 g, 71%). IR (neat): ν = 3430 (m, νO–H), 1457
˜
[m, δas(CH3)], 1366 [m, δs(CH3)], 1033 (s, νC–O) cm–1. 1H NMR
(CDCl3): δ = 0.69 (s, 3 H, 8Ј-Me), 0.75/0.80 (2d, J = 7.0 Hz, 3 H,
7Ј-Me), 0.95/0.96 (2s, 6 H, 4-Me2), 1.12/1.15 (2d, J = 6.5 Hz, 3 H,
2-H3), 1.19–1.26 (m, 2 H, 6Ј-, 9Ј-Hax), 1.32–1.38 (m, 2 H, 9Ј-Heq,
10Ј-Hax), 1.46/1.50 (2q, J = 7.0 Hz, 1 H, 7Ј-H), 1.69–1.73 (m, 2 H,
6Ј-Heq, 3Ј-Hax), 1.78–1.83 (m, 2 H, 3Ј-, 10Ј-Heq), 3.72–3.78 (m, 2
H, 2Ј-H2), 3.79–3.80 (m, 1 H, 1-H), 5.08 (br. s, 1 H, OH) ppm. 13
C
erous title compound 11 (3.44 g, 90%). IR (neat): ν = 1698 (s,
˜
NMR (CDCl3): δ = 14.5/14.8 (2q, 7Ј-Me), 15.6/15.7 (2q, 8Ј-Me),
17.0/17.2 (2q, C-2), 23.6/23.9 (2q, 4Ј-Me2), 25.6/26.0 (2t, C-9Ј),
25.8/26.2 (2t, C-10Ј), 29.8/32.0 (2d, C-7Ј), 35.4/35.6 (2t, C-6Ј), 39.0/
39.4 (2s, C-4Ј), 39.9/40.1 (2t, C-3Ј), 42.5/42.6 (2s, C-8Ј), 67.9 (t, C-
2Ј), 71.9/74.4 (2d, C-1), 84.0/84.2 (2s, C-5Ј) ppm. MS (EI): m/z (%)
= 240 (15) [M]+, 222 (2) [M – H2O]+, 195 (5) [M – C2H5O]+, 125
(100) [C8H13O]+, 45 (26) [C2H5O]+.
νC=O), 1469 [m, δas(CH3)], 1365 [m, δs(CH3)], 1026 (m, νC–O) cm–1.
1H NMR (CDCl3): δ = 0.71/0.73 (2s, 4Ј-Me2), 0.76 (d, J = 7.0 Hz,
3 H, 8Ј-Me), 1.02 (td, J = 17.0, 4.0 Hz, 1 H, 10Ј-Hax), 1.25 (mc, 1
H, 6Ј-Hax), 1.28 (mc, 1 H, 9Ј-Hax), 1.33 (s, 3 H, 7Ј-Me), 1.34 (mc,
1 H, 6Ј-Heq) 1.35 (mc, 1 H, 3Ј-Hax), 1.36 (mc, 1 H, 10Ј-Heq), 1.39
(td, J = 6.5, 3.0 Hz, 1 H, 3Ј-Heq), 1.62 (qd, J = 17.0, 3.5 Hz, 1 H,
10Ј-Heq), 1.86 (s, 3 H, 2-H3), 1.93 (tq, J = 17.0, 7.0 Hz, 1 H, 8Ј-H),
3.59 (td, J = 6.5, 3.0 Hz, 2 H, 2Ј-H2) ppm. 1H,1H NOESY (CDCl3):
(؎)-(5RЈ*,7ЈS*,8ЈS*)-1-(4Ј,4Ј,7Ј,8Ј-Tetramethyl-1Ј-oxaspiro[4.5]de-
can-8Ј-yl)ethan-1-one (14): At room temp., PCC (1.17 g,
5.43 mmol) was added portionwise to a suspension of 13 (870 mg,
3.62 mmol) and Celite (3.00 g) in CH2Cl2 (15 mL). The reaction
mixture was stirred for 5 h at room temp., filtered through a pad
of Celite, and washed with Et2O (10 mL). The filtrate was concen-
trated, and the resulting residue was purified by silica gel FC (pen-
tane/Et2O, 95:5, Rf = 0.14) to furnish the odoriferous title com-
7Ј-Meax ϫ9Ј-Hax,
H
4Ј-Meax ϫ10Ј-Hax,
4Ј-Meeq ϫ6Ј-Hax,
8Ј-
ax ϫ10Ј-Hax, 8Ј-Hax ϫ6Ј-Hax. 13C NMR (CDCl3): δ = 16.0 (q, 7Ј-
Me), 17.5 (q, 8Ј-Me), 23.7/23.9 (2q, 4Ј-Me2), 25.4, (q, C-2), 27.1 (t,
C-9Ј), 31.0 (t, C-10Ј), 35.6 (d, C-8Ј), 38.9 (t, C-6Ј), 39.7 (t, C-3Ј),
43.6 (s, C-4Ј), 52.3 (s, C-7Ј), 63.1 (t, C-2Ј), 84.0 (t, C-5Ј), 213.3 (s,
C-1) ppm. MS (EI): m/z (%) = 238 (5) [M]+, 223 (2) [M – CH3]+,
195 (22) [M – C2H3O]+, 169 (58) [C10H17O2]+, 125 (100) [C8H13O]+,
43 (36) [C2H3O]+. C15H26O2 (238.4): calcd. C 75.58, H 10.99; found
C 75.62, H 10.97. Odor (10% DPG, blotter): Sweet, green-metallic
odor with a woody tonality and earthy, root-like nuances. Odor
threshold: 149 ng/L air. Partition coefficient (HPLC): log(Pow) =
4.0.
pound 14 (760 mg, 88%) as a colorless liquid. IR (neat): ν = 1700
˜
(s, νC=O), 1457 [m, δas(CH3)], 1364 [m, δs(CH3)], 1029 (m, νC–O
)
cm–1. 1H NMR (C6D6): δ = 0.64 (d, J = 7.0 Hz, 3 H, 7Ј-Me), 0.77/
0.79 (2s, 6 H, 4Ј-Me2), 0.93 (mc, 1 H, 6Ј-Hax), 0.95 (s, 3 H, 8Ј-Me),
1.07 (mc, 1 H, 10Ј-Hax), 1.12 (mc, 1 H, 9Ј-Hax), 1.24 (mc, 1 H, 10Ј-
Heq), 1.28 (mc, 1 H, 6Ј-Heq), 1.50 (t, J = 7.5 Hz, 2 H, 2Ј-H2), 1.93
(s, 3 H, 2-H3), 2.08 (td, J = 12.5, 4.0 Hz, 1 H, 9Ј-Heq), 2.49 (mc, 1
(؎)-(4ЈR*,5ЈR*,1ЈЈR*)-3-[4Ј-(1ЈЈ-Hydroxyethyl)-4Ј,5Ј-dimethylcyclo-
1
H, 7Ј-Hax), 3.61 (t, J = 7.5 Hz, 2 H, 3Ј-H2) ppm. H,1H NOESY
hex-1Ј-enyl]-3-methylbutan-1-ol (12):
A mixture of 9 (6.32 g,
(C6D6): 8Ј-Meax ϫ10Ј-Hax, 7Ј-Hax ϫ2-Meeq, 6Ј-Hax ϫ4Ј-Me2, 8Ј-
Meax ϫ4Ј-Me2, 10Ј-Hax ϫ4Ј-Me2. 13C NMR (C6D6): δ = 12.5 (q,
8Ј-Me), 17.6 (q, 7Ј-Me), 23.6/23.7 (2q, 4Ј-Me2), 24.3 (q, C-2), 26.0
(t, C-10Ј), 31.5 (d, C-7Ј), 32.0 (t, C-9Ј), 35.1 (t, C-6Ј), 40.3 (t, C-
3Ј), 42.4 (s, C-4Ј), 51.5 (s, C-8Ј), 63.1 (t, C-2Ј), 83.8 (s, C-5Ј), 214.6
(s, C-1) ppm. MS (EI): m/z (%) = 238 (22) [M]+, 223 (5) [M –
CH3]+, 195 (10) [M – C2H3O]+, 169 (68) [C10H17O2]+, 125 (100)
[C8H13O]+, 43 (100) [C2H3O]+. C15H26O2 (238.4): calcd. C 75.58,
H 10.99; found C 75.51, H 10.95. Odor (10% DPG, blotter): Weak,
green-metallic odor, with slightly earthy-woody accents. Odor
threshold: 346 ng/L air. Partition coefficient (HPLC): log(Pow) =
3.7.
45.1 mmol), (3E)-3-methylpent-3-en-2-ol (9.02 g, 90.0 mmol), and
Me2AlCl (1 m in hexanes, 9.0 mL, 9.0 mmol) in toluene (100 mL)
was heated at reflux for 3 d. After the heating source was removed,
the reaction mixture was poured into water (100 mL) and extracted
with Et2O (3ϫ400 mL). The combined organic extracts were dried
(Na2SO4), and the solvents were evaporated. The resulting residue
was purified by silica gel FC (pentane/Et2O, 3:7, Rf = 0.17) to pro-
vide 12 (1.84 g, 17%). IR (neat): ν = 3358 (m, νO–H), 1454 [m,
˜
δas(CH3)], 1376 [m, δs(CH3)], 1052 (s, νC–O), 905 (m, δC=C–H) cm–1.
1H NMR (CDCl3): δ = 0.68/0.69 (2s, 3 H, 4Ј-Me), 0.81/0.84 (2d, J
= 6.5 Hz, 3 H, 5Ј-Me), 1.02/1.03 (2s, 6 H, 3-Me2), 1.14/1.16 (2d, J
= 6.5 Hz, 3 H, 2ЈЈ-H3), 1.62–1.66 (m, 2 H, 2-H2), 1.70–1.73 (m, 1
H, 3Ј-Hax), 1.75–1.77 (m, 1 H, 6Ј-Hax), 1.84–1.87 (m, 1 H, 5Ј-H),
1-[3Ј-(4ЈЈ-Hydroxy-2ЈЈ-methylbutan-2ЈЈ-yl)-1Ј-methylcyclohex-3Ј-en-
2.08–2.10 (m, 1 H, 3Ј-Heq), 2.11–2.15 (m, 1 H, 6Ј-Heq), 3.53/3.54 yl]ethan-1-one (15): In analogy to the preparation of 10, compound
(2t, J = 7.5 Hz, 2 H, 1-H2), 3.73–3.76 (m, 1 H, 1ЈЈ-H), 5.33–5.36
15 was obtained from 9 (4.21 g, 30.0 mmol), 3-methyl-3-buten-2-
one (3.03 g, 36.0 mmol), and a solution of Me2AlCl (1 m in hex-
(m, 1 H, 2Ј-H) ppm. 13C NMR (CDCl3): δ = 15.1/15.2 (2q, 5Ј-Me),
15.3/15.6 (2q, 4Ј-Me), 17.0/17.2 (2q, C-2ЈЈ), 25.6 (t, C-6Ј), 27.2/27.5/ anes, 3.0 mL, 3. 0 mmol) in CH2Cl2 (10 mL) after standard workup
27.7/28.0 (4q, 3-Me2), 31.1/31.9 (2d, C-5Ј), 37.3/37.4 (2s, C-3), 38.6/
38.8 (2s, C-4Ј), 42.9/43.2 (2t, C-3Ј), 60.1/60.2 (2t, C-2), 67.9 (t, C-
1), 70.5/72.7 (2d, C-1ЈЈ), 117.7/118.0 (2d, C-2Ј), 141.7/141.8 (2s, C-
1Ј) ppm. MS (EI): m/z (%) = 240 (2) [M]+, 222 (3) [M – H2O]+,
195 (12) [M – C2H5O]+, 109 (80) [C8H13]+, 45 (35) [C2H5O]+.
and silica gel FC (pentane/Et2O, 1:1; Rf = 0.17). Yield 61%
(4.11 g); colorless oil. IR (neat): ν = 3391 (m, νO–H), 1700 (s, νC=O),
˜
1458 [m, δas(CH3)], 1355 [m, δs(CH3)], 1024 (m, νC–O) cm–1. 1H
NMR (CDCl3): δ = 1.02/1.03 (2s, 6 H, 2ЈЈ-Me2), 1.11 (s, 3 H, 1Ј-
Me), 1.54–1.60 (m, 2 H, 5Ј-, 6Ј-Hax), 1.63 (td, J = 7.5, 3.0 Hz, 2 H,
266
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Eur. J. Org. Chem. 2008, 261–268

Novel Woody–Ambery Odorants with Improved Bioavailability
3ЈЈ-H2), 1.85–1.90 (m, 2 H, 2Ј-Hax, 6Ј-Heq), 2.01–2.07 (m, 2 H, 1 H, 1-H), 3.77 (t, J = 7.5 Hz, 2 H, 2Ј-H2) ppm. 13C NMR (CDCl3):
2Ј-, 5Ј-Heq), 2.14 (s, 3 H, 2-H3), 3.48 (t, J = 7.5 Hz, 2 H, 4ЈЈ-H2), δ = 15.6 (q, 8Ј-Me), 17.1 (q, C-2), 23.8 (q, 4Ј-Me2), 26.0 (t, C-7Ј,
5.43–5.45 (m, 1 H, 4Ј-H) ppm. 13C NMR (CDCl3): δ = 21.7 (t, C-5Ј),
23.1 (q, 1Ј-Me), 24.6 (q, C-2), 27.5/27.7 (2q, 2ЈЈ-Me2), 31.3 (t, C-
-9Ј), 29.7 (t, C-6Ј, -10Ј), 36.5 (s, C-4Ј), 40.1 (t, C-3Ј), 42.5 (s, C-8Ј),
62.9 (t, C-2Ј), 77.1 (d, C-1), 83.6 (s, C-5Ј) ppm. MS (EI): m/z (%)
2Ј), 33.9 (t, C-6Ј), 37.2 (s, C-2ЈЈ), 43.2 (t, C-3ЈЈ), 46.0 (s, C-1Ј), 59.9 = 226 (5) [M]+, 208 (2) [M – H2O]+, 125 (100) [C8H13O]+, 45 (9)
(t, C-4ЈЈ), 117.7 (d, C-4Ј), 142.6 (s, C-3Ј), 213.8 (s, C-1) ppm. MS
(EI): m/z (%) = 224 (2) [M]+, 211 (2) [M – CH3]+, 206 (5) [M –
H2O]+, 180 (36) [C12H20O]+, 43 (100) [C2H3O]+.
[C2H5O]+.
(؎)-(5ЈR*,8ЈR*)-1-(4Ј,4Ј,8Ј-Trimethyl-1Ј-oxaspiro[4.5]decan-8Ј-yl)-
ethan-1-one (19): In analogy to preparation of 14, the odoriferous
title compound 19 was obtained from 18 (1.24 g, 5.48 mmol) and
PCC (1.77 g, 8.22 mmol) in CH2Cl2 (20 mL) after standard workup
and silica gel FC (pentane/Et2O, 95:5, Rf = 0.13). Yield 90%
(؎)-(5ЈR*,7ЈR*)-1-(4Ј,4Ј,7Ј-Trimethyl-1Ј-oxaspiro[4.5]decan-7Ј-yl)-
ethan-1-one (16): In analogy to the preparation of 11, the odorifer-
ous title compound 16 was obtained from 15 (3.37 g, 15.0 mmol)
and MeSO3H (1.73 g, 18.0 mmol) in CH2Cl2 (80 mL) after stan-
dard workup and silica gel FC (pentane/Et2O, 95:5; Rf = 0.16).
(1.10 g); colorless crystals, m.p. 49.3–50.5 °C. IR (neat): ν = 1697
˜
(s, νC=O), 1467 [m, δas(CH3)], 1367 [m, δs(CH3)], 1030 (s, νC–O
)
cm–1. H NMR (C6D6): δ = 0.76 (s, 6 H, 4Ј-Me2), 0.93 (s, 3 H, 8Ј-
Me), 1.10 (td, J = 13.0, 4.0 Hz, 2 H, 6Ј-, 10Ј-Hax), 1.28 (mc, 2 H,
7Ј-, 9Ј-Hax), 1.31 (mc, 2 H, 6Ј-, 10Ј-Heq), 1.47 (t, J = 7.5 Hz, 2 H,
3Ј-H2), 1.84 (s, 3 H, 2-H3), 2.11 (td, J = 13.0, 4.0, Hz, 2 H, 7Ј-, 9Ј-
1
Yield 91% (3.07 g); colorless liquid. IR (neat): ν = 1701 (s, νC=O),
˜
1470 [m, δas(CH3)], 1365 [m, δs(CH3)], 1028 (m, νC–O) cm–1. 1H
NMR (C6D6): δ = 0.74/0.78 (2s, 6 H, 4Ј-Me2), 0.86 (td, J = 7.5,
3.0 Hz, 1 H, 10Ј-Hax), 1.16 (td, J = 7.0, 3.5 Hz, 1 H, 8Ј-Hax), 1.37
(s, 3 H, 7Ј-Me), 1.41 (mc, 1 H, 10Ј-Heq), 1.43 (mc, 1 H, 9Ј-Heq),
1.45 (mc, 1 H, 3Ј-Hax), 1.47 (mc, 1 H, 6Ј-Hax), 1.49 (mc, 1 H, 3Ј-
Heq), 1.50 (mc, 1 H, 8Ј-Heq), 1.56 (mc, 1 H, 6Ј-Heq), 1.82 (s, 3 H,
2-H3), 1.86 (2t, J = 7.5 Hz, 9Ј-Hax), 3.57 (mc, 2 H, 2Ј-H2) ppm.
1H,1H NOESY (C6D6): 7Ј-Meax ϫ2Ј-Hax, 1-Meeq ϫ4Ј-Meeq, 4Ј-
Meax ϫ8Ј-Hax. 13C NMR (C6D6): δ = 18.4 (t, C-9Ј), 21.8 (q, 7Ј-
Me), 23.6/23.8 (2q, 4Ј-Me2), 23.9 (q, C-2), 30.5 (t, C-10Ј), 33.5 (t,
C-8Ј), 35.7 (t, C-6Ј), 39.7 (t, C-3Ј), 43.8 (s, C-4Ј), 48.1 (s, C-7Ј), 63.1
(t, C-2Ј), 84.3 (s, C-5Ј), 212.1 (s, C-1) ppm. MS (EI): m/z (%) = 224
(2) [M]+, 209 (2) [M – CH3]+, 181 (30) [M – C2H3O]+, 155 (100)
[C9H15O2]+, 43 (100) [C2H3O]+. C14H24O2 (224.3): calcd. C 74.95,
H 10.78; found C 74.98, H 10.70. Odor (10% DPG, blotter): Fruity,
cedarwood note with slightly agrestic and spicy facets. Odor thresh-
old: 99.4 ng/L air. Partition coefficient (HPLC): log(Pow) = 3.2.
1
Heq), 3.58 (t, J = 7.5 Hz, 2 H, 2Ј-H2) ppm. H,1H NOESY (C6D6):
4Ј-Meax ϫ6Ј-Hax, 6Ј-Hax ϫ8Ј-Meax, 9Ј-Hax ϫ1-Meeq. 13C NMR
(C6D6): δ = 18.5 (q, 8Ј-Me), 23.7 (2q, 4Ј-Me2), 24.3 (q, C-2), 26.2
(2t, C-6Ј, -10Ј), 29.5 (2t, C-7Ј, -9Ј), 40.2 (t, C-3Ј), 42.4 (s, C-4Ј),
46.6 (s, C-8Ј), 69.9 (t, C-2Ј), 82.8 (s, C-5Ј), 212.0 (s, C-1) ppm. MS
(EI): m/z (%) = 224 (6) [M]+, 209 (2) [M – CH3]+, 155 (27)
[C9H15O2]+, 125 (100) [C8H13O]+, 43 (45) [C2H3O]+. Crystal struc-
ture data and refinement: empirical formula C14H24O2, molecular
mass 224.33, crystal dimensions 0.38ϫ0.2ϫ0.02 mm, temperature
110 K, wavelength 0.71073 Å, monoclinic crystal system, space
group P21/c, unit cell dimensions a = 10.714(2) Å, b = 10.263(2) Å,
c = 11.781(2) Å, α = 90°, β = 101.60(3)°, γ = 90°, V = 1268.9(4) Å3,
Z = 4, ρ = 1.174 Mg/m3, μ(Mo-Kα) = 0.076 mm–1, F(000) 496, θ
range 1.94–23.26°, limiting indices –11ՅhՅ11, –11ՅkՅ11,
–13ՅlՅ13, total reflections collected 10287, symmetry-indepen-
dent reflections 1770, Rint = 0.1127, refinement full-matrix least-
squares on F2, data 1770, parameters 149, goodness-of-fit on F2
0.747, final R indices [IϾ2σ(I)], R1 = 0.0372, wR2 = 0.0644, R
indices (all data) R1 = 0.0928, wR2 = 0.0737, Δρ(max, min) = 0.220,
–0.153 e/Å3. CCDC-646998 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. C14H24O2 (224.3): calcd. C
74.95, H 10.78; found C 74.97, H 10.72. Odor (10% DPG, blotter):
Woody–ambery odor, reminiscent of Iso E Super (1), with some
agrestic, conifer-type facets also present in Cashmeran (1,1,2,3,3-
(؎)-3-[4Ј-(1ЈЈ-Hydroxyethyl)-4Ј-methylcyclohex-1Ј-enyl]-3-methyl-
butan-1-ol (17): In analogy to the preparation of 12, compound
17 was obtained from 9 (7.01 g, 50.0 mmol), 3-methylbut-3-en-2-ol
(8.61 g, 100 mmol), and Me2AlCl (1 m in hexanes, 10.0 mL,
10.0 mmol) in toluene (100 mL) after standard workup and silica
gel FC (pentane/Et2O, 3:7, Rf = 0.16). Yield 22% (2.49 g); colorless
oil. IR (neat): ν = 3332 (m, νO–H), 1458 [m, δas(CH3)], 1374 [m,
˜
δs(CH3)], 1058 (s, νC–O), 912 (m, δC=C–H) cm–1. 1H NMR (CDCl3):
δ = 0.81/0.82 (2s, 3 H, 4Ј-Me), 1.04/1.05 (2s, 6 H, 3-Me2), 1.12/1.14
(2d, J = 6.5 Hz, 3 H, 2ЈЈ-H3), 1.35–1.42 (m, 2 H, 2-H2), 1.54–1.60
(m, 1 H, 5Ј-Hax), 1.61–1.69 (m, 2 H, 5Ј-Heq, 3Ј-Hax), 1.84–1.87 (m,
1 H, 6Ј-Hax), 1.97–2.09 (m, 2 H, 3Ј-Heq, 6Ј-Heq), 3.51 (td, J = 7.0,
4.0 Hz, 2 H, 1-H2), 3.73–3.76 (m, 1 H, 1ЈЈ-H), 5.38–5.42 (m, 1 H,
2Ј-H) ppm. 13C NMR (CDCl3): δ = 17.3/17.4 (2q, 4Ј-Me), 18.0/
18.2 (2q, C-2ЈЈ), 21.2/25.5 (2t, C-6Ј), 27.4/27.5/27.6/27.7 (4q, 3-
Me2), 30.4/31.1 (2t, C-5Ј), 34.0/34.6 (2t, C-3Ј), 35.3/35.4 (2s, C-3),
37.1/37.2 (2s, C-4Ј), 42.8/43.2 (2t, C-2), 60.1/67.8 (2t, C-1), 72.7/
74.3 (2d, C-1ЈЈ) 118.0/118.2 (2d, C-2Ј), 142.1/142.5 (2s, C-1Ј) ppm.
MS (EI): m/z (%) = 226 (2) [M]+, 208 (13) [M – H2O]+, 163 (52)
[C12H19]+, 121 (100) [C9H13]+, 45 (39) [C2H5O]+.
pentamethyl-6,7-dihydro-5H-indan-4-one) accompanied by
a
slightly medicinal touch. Odor threshold: 92.1 ng/L air. Partition
coefficient (HPLC): log(Pow) = 3.2.
Acknowledgments
For the X-ray crystal structure analysis we are indebted to André
Alker of F. Hoffmann-La Roche AG, Basel. Furthermore, we are
grateful to Dr. Gerhard Brunner for numerous complex and multi-
dimensional NMR experiments, to Dr. Fabian Kuhn for the mass-
spectrometric data, and to Katarina Grman for odor threshold de-
terminations. In addition, we sincerely thank Isabelle Querbach of
Givaudan SA, Vernier, for the measurement of log(Pow) values,
Alain E. Alchenberger for the olfactory evaluations, and Dr. Peter
Gygax for useful comments and fruitful discussions. Proofreading
of the manuscript by Dr. Samuel Derrer, Tony McStea, and Dr.
Markus Gautschi is also acknowledged with gratitude.
(؎)-(1R*,5ЈS*,8ЈS*)-1-(4Ј,4Ј,8Ј-Trimethyl-1Ј-oxaspiro[4.5]decan-8Ј-
yl)ethan-1-ol (18): In analogy to the preparation of 13, compound
18 was obtained from 17 (2.15 g, 9.50 mmol) and MeSO3H (1.10 g,
11.5 mmol) in CH2Cl2 (70 mL) after standard workup and silica
gel FC (pentane/Et2O, 6:4, Rf = 0.13). Yield 73% (1.57 g); colorless
oil. IR (neat): ν = 3449 (s, νO–H), 1456 [m, δas(CH3)], 1365 [m,
˜
1
δs(CH3)], 1019 (s, νC–O) cm–1. H NMR (CDCl3): δ = 0.85 (s, 3 H,
8Ј-Me), 0.96 (s, 6 H, 4Ј-Me2), 1.11 (d, J = 6.5 Hz, 3 H, 2-H3), 1.35–
1.39 (m, 2 H, 7Ј-, 9Ј-Hax), 1.41–1.46 (m, 2 H, 6Ј-, 10Ј-Hax), 1.49–
1.50 (m, 2 H, 7Ј-, 9Ј-Heq), 1.52–1.55 (m, 2 H, 6Ј-, 10Ј-Heq), 1.81 (t,
J = 7.5 Hz, 2 H, 3Ј-H2), 2.18 (br. s, 1 H, OH), 3.42 (q, J = 6.5 Hz,
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