Syntheses and?odor of?"bulky group"-modified sandalwood odorants: isophorono-β-santalol analogues

Article abstract of DOI:10.1016/j.ejmech.2006.03.016

Three osmophoric points have been found to be necessary for the scent of sandalwood odorants. One of these points is the bulky group in a certain distance from the osmophoric hydroxyl group. Such a hydrophobic moiety is part of the trimethylcyclopentenyl

Full text of DOI:10.1016/j.ejmech.2006.03.016

European Journal of Medicinal Chemistry 41 (2006) 905–913
http://france.elsevier.com/direct/ejmech
Original article
Syntheses and odor of “bulky group”-modified sandalwood odorants:
isophorono-β-santalol analogues
J. Höfinghoff a, G. Buchbauer a,*, W. Holzer b, P. Wolschann c
a Department of clinical pharmacy and diagnostics, center of pharmacy, university of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
b Department of drug synthesis, center of pharmacy, university of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
c Institute of theoretical chemistry, university of Vienna, Währinger Strasse 17, A-1090 Vienna, Austria
Received in revised form 7 March 2006; accepted 10 March 2006
Available online 27 April 2006
Abstract
Three osmophoric points have been found to be necessary for the scent of sandalwood odorants. One of these points is the bulky group in a
certain distance from the osmophoric hydroxyl group. Such a hydrophobic moiety is part of the trimethylcyclopentenyl derivatives, the so called
campholenals, among them many are known to exert a strong and long lasting sandalwood odor. In continuation of our SAR-studies of sandal-
wood odorants four isophorone analogues of β-santalol have been synthesized. The hydrophobic region of these new isophorone derivatives is
now a trimethylcyclohexene nucleus, so to speak an extension of the cyclopentene part of the campholenals by one methylene group. This
modification changes the sandalwood odor drastically to woody odor notes, reminiscent only to sandalwood odor. The environs of the crowded
trimethylcyclohexene nucleus demonstrate the sensitivity of sandalwood odor on the shape of the hydrophobic, bulky part of β-santalol analo-
gues.
© 2006 Elsevier SAS. All rights reserved.
Keywords: Campholene homologues; Hydrophobic moiety; Isophorone; β-Santalol; Structure–odor-relationship
1. Introduction
noid like ketone with a rather flat structure, however rendered
bulky by the geminal dimethyl group and possessing the same
characteristic structural features as the known campholenic de-
rivatives Brahmanol® (7), or Sandacore®, resp. Madrol® (8)
which belong to the most powerful synthetic sandalwood odor-
ants [12,13,18,20]. The isophorone moiety is similar in its
shape to these molecules also showing a geminal, bulky di-
methyl group and an endocyclic double bond carrying a methyl
group: thus, the isophorone nucleus is a homologue of the
campholenic one extended by a methylene group (Fig. 1a–c).
In continuation of our studies on structure–odor-relationship
of fragrance compounds emitting the sandalwood odor [1–7] it
seemed worthwhile to study the influence of another modified
“bulky group” on the sandalwood character. The “bulky
group” [3] has been the focus of recent efforts to find out
how far a structure modification can be done without loss of
the precious sandalwood scent of the standard molecule β-san-
talol (1) [1,4–6,8–11].
In this paper we report on the synthesis of (Z)-2-isophorono-
β-santalol (2), (Z)-2-dihydroisophorono-β-santalol (3), (Z)-6-
isophorono-β-santalol (4) and (Z)-2-methyl-6-isophorono-β-
santalol (5). All these new analogues show the typical, Z-con-
figurated 2-methyl-2-penten-1-ol side chain, but possess the
isophorone nucleus as the necessary hydrophobic part of such
an odorous molecule [12–19]. Isophorone (6) is a cheap, terpe-
2. Results
2.1. Syntheses
In the following chart (Fig. 2)—showing the general syn-
thetic procedure for the synthesis of 2–5 starting from the un-
saturated, cyclic ketone 6—the letters x and y mean the resi-
dues at the isophorone nucleus. In each case the first step was
an alkylation into the α-position of the keto group using 2-(2-
* Corresponding author.
E-mail address: gerhard.buchbauer@univie.ac.at (G. Buchbauer).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.03.016

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J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
Fig. 1a. Target molecules, part 1.
bromoethyl)-1,3-dioxolane, NaNH2 and hexamethyl disilazane
according to Krotz and Helmchen [21], followed by an acidic
acetal-cleavage using diluted sulfuric acid. This more or less
drastic condition furnished better yields and cleaner products,
leading to the corresponding aldehydes as suitable synthons for
the following carbonyl olefination. On account of the instabil-
ity of these aldehydes (autoxidation) they were used without
further purification in the sequent Horner-Emmons variant of
the Wittig-reaction with triethyl-2-phosphonopropionate/18-
crown-6/K-bis(trimethylsilyl)amide (KN(TMS)2) furnishing
the corresponding Z/E-ester mixtures out of which the pure Z-
isomers could be obtained by column chromatography (CC).
By using such a strongly dissociated base system the Z-isomer
could be achieved in a synthetic useful level [22]. Transforma-
tion of the ketone function of the isophorone nucleus into the
exocyclic methylene group was accomplished using the Tebbe-
reagent which proved itself successful especially in the case of
sterically more voluminous and hindered ketones [23,24]. Fi-
nally, the target allyl alcohols 2–5 were obtained by reduction
of the Z-esters with diisobutylaluminium hydride (DIBAH) in
CH2Cl2 at –78 °C [25,26]. As already described in [1,2] the
proof of the existence of the Z-alcohols could be given by the
1H-NMR spectrum: the allylic proton of the side chain forms a
triplet and could be found characteristically upfield shifted in
the region of about 5.24 ppm in comparison to the same signal
of the E-isomer [27].
The fact that the first alkylation leads to a substitution in
position 2 of the isophorone nucleus instead of position 6—
where moreover the shield effect by the geminal dimethyl
group at C5 renders the bonding with the ethyldioxolane side
chain more difficult—, forced us to use another strategy to ob-
tain the corresponding ethyldioxolane at C6. By introduction of
an formic ester moiety into position 6 [28,29] the geminal pro-
ton has become more acidic and thus enabled also this α-alky-
lation to 9. The resulting reaction mixture consisted of the C2
and the desired C6 derivatives (nearly 1:1) which could be se-
parated by CC. Decarboxylation of the β-ketoester yielded fi-
nally the pure dioxolanylethylisophorone 10. Alkylation of 10
with CH3I/Li-cyclohexylisopropylamide (CIPA) resulted in a
product mixture of five alkylation products, out of which 11
could be isolated in moderate yield. 10 and 11 served as start-
ing products for the synthesis of the target alcohols 4 and 5
according to the reaction scheme depicted in Fig. 2. The gem-
inal methyl ethyldioxolanyl isophorone 12, also an alkylation
product, could not be transformed into the corresponding β-
santalol analogue, probably due to steric reasons.
The stereochemical position of the ethyldioxolanyl side
chain of the starting product for the alcohols 4 and 5 was as-

J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
907
Fig. 3. NOE measurement on compounds 10 and 18.
dioxolanyl side chain is in axial position and the geminal C6-
proton equatorial (see Fig. 3). Also by NOE measurement the
cis equatorial substitution pattern at C2 and C3 of the hydro-
genated isophorone nucleus of 18 was ascertained (Fig. 3).
2.2. Olfactory evaluation
Fig. 1b. Target molecules, part 2.
The odor analysis of the target compounds 2–5 is given in
Table 1. The alcohols 3–5 show a woody odor with various
tonalities, only 2 is devoid of any note in this direction. Inter-
estingly, the methyl-isophorono analogue 5 possesses a long
lasting woody scent which later on develops also a weak note
which reminds faintly of sandalwood. Probably the more
crowded and bulky hydrophobic part by the additional olefinic
methyl group at C2 of 5 causes the weak sandalwood note.
Also the distance of about 6 Å of the side chain hydroxyl
group from the quaternary C-atom is more similar to the stan-
dard [3]. Concerning the chirality of odor molecules, it is
known that if one enantiomer shows sandalwood odor, the ra-
cemate possesses in most cases this fragrance too [2,18,21].
Fig. 1c. Target molecules, part 3.
certained by measuring a NOE: irradiation upon C6-H resulted
in a positive influence on the equatorial CH3-group as well as
irradiation upon the adjacent CH2-group of the side chain
showed an influence on the axial CH3-group. Thus the ethyl-
Fig. 2. General synthetic pathway for the synthesis of the target compounds.

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J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
Table 1
Odor characterization of the newly synthesized target compounds
Compounds
Odor impression
(Z)-2-Methyl-5-(6-methylen-2,4,4-trimethyl-1-cyclohex-1-enyl)-2-penten-1-ol (2)
(Z)-2-Methyl-5-(6-methylen-2,4,4-trimethyl-1-cyclohexyl)-2-penten-1-ol (3)
(Z)-2-Methyl-5-(2-methylen-4,6,6-trimethyl-1-cyclohex-3-enyl)-2-penten-1-ol (4)
(Z)-2-Methyl-5-(2-methylen-3,4,6,6-tetra-methyl-1-cyclohex-3-enyl)-2-penten-1-ol
(5)
Weak coconut like (“aldehyde C18”), lactonic, creamy
At the beginning cinnamon like, later cedar wood like-woody-amber note
Long lasting woody, cedarwood like
Weak woody, later on strong woody with a weak sandalwood note
Table 2
dimethyl group and not meta, whereas this does not matter in
trimethylcyclopentenyl derivatives as in the fencholene deriva-
tive 14 [37]. The overcrowded region in the “upper part” of the
β-ionone-derivative 13 is obvious. The molecular shape of all
newly synthesized compounds does not allow a sufficient as-
sociation of the molecules to related receptor sites.
It has to be assumed that for sandalwood odor recognition a
specific combination of the association at different odorant re-
ceptors leads to the typical scent. If the association at some of
these receptors is changed by geometry modifications of the
ligand under investigation, other tonalities of the same family
will become more dominant. In the present case the modifica-
tions of the molecular shape leads to fragrances, where the
woody tonalities can be recognized mainly. In only one mole-
cule (5) some sandalwood odor note remains.
Spearman- and SOMFA-coefficients of the newly synthesized target
compounds
Compounds
Spearman-coefficient
0.3912
0.5377
0.4459
0.6503
SOMFA-coefficient
0.0123
0.0070
0.1392
0.3194
2
3
4
5
Therefore, olfactory evaluation has been performed on the ra-
cemates only.
2.3. Molecular modeling calculations (Spearman-
and SOMFA-coefficients)
Molecular similarity calculations which hitherto have been
performed on β-santalol analogues [30] showing sandalwood
odor yielded a Spearman-coefficient of > 0.6 and a SOMFA-
coefficient [31] of > 0.5. As can be seen in Table 2 no one of
the four target compounds meets both conditions, therefore the
shift from pure and distinct sandalwood odor to more woody
tonalities can be easily explained. Only the isophorono analo-
gue 5 showing a trace of a sandalwood note is at least in line
with the condition of a Spearman coefficient above 0.6, how-
ever, the SOMFA-coefficient is below the necessary level of
0.5.
4. Experimental protocols
Melting points were investigated on a Kofler apparatus and
1
are uncorrected. The H- and 13C-NMR spectra were recorded
on a Bruker Avance DPX-200 NMR-spectrometer (200 MHz,
CDCl3, 28 °C) (Karlsruhe, Germany) or on a Varian Unityplus
300 NMR-spectrometer (300 MHz, CDCl3, 28 °C) (Palo Alto,
CA). Chemical shifts are given in ppm relative to tetramethyl-
silane (TMS) as internal standard (= 0 ppm). Infrared (IR)
spectra were performed on a Perkin–Elmer FT-IR-spectrophot-
ometer Spectrum 2000 (Oak Brook, IL) (cm−1). Mass spectra
were recorded on a Hewlett–Packard MSD (GC: 5890, MS:
5970, column: HP-5MS 30m × 0.25 mm × 0.25 μm, HP-Part
No. 19091S-433) (Corvallis, OR) or on a Shimadzu DI-
QP5000 instrument (Kyoto, Japan). Purifications were per-
formed either on preparative thin layer chromatography
(PTLC) plates (silica gel 60 F254, 2 mm layer thickness, No.
5717), on thin layer chromatography (TLC) plates (silica gel
60 F254, 0.25 mm layer thickness, No. 5554), or with CC
(KG 60 F 354, 70–230 mesh ASTM, No. 7734) from Merck
(Darmstadt, Germany).
3. Discussion
The bulky and hydrophobic part of the newly synthesized
molecules is not large enough to meet the steric conditions to
emanate a sandalwood odor, even if the condition of the dis-
tance parameter of nearly 6 Å from the side chain hydroxyl
group to the quaternary carbon atom with the geminal dimethyl
group is met. Other factors are not in favor of the desired scent.
SOMFA-shape graphics show that none of the necessary three
centers of a sandalwood odorant (osmophoric oxygen function,
adjacent to it a tiny methyl group and in the distance to it by a
“flexible spacer” a large hydrophobic group) [2,3,8,32–35] cre-
ate in these four isophorono analogues the suitable molecular
shape for an easy docking onto the receptor site. The extension
of the trimethylcyclopentenyl (= campholene) nucleus by a
methylene-group to the isophorone nucleus as in our case
(ortho to the geminal dimethyl group), does not lead to new
sandalwood odorants, whereas another trimethylcyclohexene
nucleus (a β-ionone nucleus with the side chain at C5 and thus
ortho to the geminal dimethyl group) of the sandalwood analo-
gue 13 exerts a strong sandalwood odor indeed [36]. Thus we
can conclude that in trimethylcyclohexene derivatives the ole-
finic methyl group has to be positioned ortho to the geminal
4.1. 2-[2-(1,3-Dioxolan-2-yl)-ethyl]-3,5,5-trimethylcyclohex-2-
en-1-one (15)
A mixture consisting of 1.70 g (43.6 mmol) NaNH2, 6.35 g
(39.3 mmol) hexamethyl disilazane and 50 ml absolute THF
was refluxed in argon atmosphere. After 5 h isophorone (6)
(5.00 g, 36.2 mmol) was added and the refluxing continued
for another 2 h. Finally, an amount of 13.10 g (72.4 mmol)
2-(2-bromoethyl)-1,3-dioxolane was added and the mixture
stirred at 100 °C for 10 h. The reaction was stopped by cooling

J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
909
and mixing with water. This mixture was extracted with ether,
the combined organic layers were dried (MgSO4) and concen-
trated in vacuo. Upon bulb-to-bulb distillation the crude pro-
duct was submitted to CC (pentane/ethyl acetate 80:20) yield-
ing 1.84 g (21.4%) of a light yellow oil. IR (NaCl, liquid film):
n = 1739, 1664, 1633, 1140 cm−1. MS: (m/z; r.I.) = 238 (M+,
5), 223 (1), 193 (7), 178 (4), 166 (7), 135 (3), 123 (3), 110
(12), 86 (20), 73 (100), 67 (12), 53 (11), 45 (28), 43 (12), 41
δ = 0.93 (s, 6H, CH3 9 and 10), 1.22 (t, 3H, CH3 17), 1.74
(s, 3H, CH3 14), 1.85 (s, 3H, CH3 8), 2.17 (m, 6H, CH2 3, 5
and 7), 2.36 (t, 2H, CH2 11), 4.10 (q, 2H, CH2 16), 6.68 (t, 1H,
CH 12). 13C-NMR (CDCl3) [(E)-isomer]: δ = 12.24 (C17),
14.27 (C14), 21.387 (C8), 24.04 (C7), 27.94 (C9 and 10),
32.65 (C4), 47.02 (C3), 51.28 (C5), 60.33 (C16), 128.09
(C13), 133.30 (C1), 141.44 (C12), 153.38 (C2), 168.22
(C15), 198.76 (C6). C17H26O3 (278.39).
1
(21). H-NMR (CDCl3): δ = 0.93 (s, 6H, 9 und 10), 1.62 (m,
4.4. (Z)-2-Methyl-5-(2,4,4-trimethyl-6-methylen-1-cyclohex-1-
enyl)-2-penten-1-ol (2)
2H, 11), 1.86 (s, 3H, 8), 2.14 (m, 4H, 4 und 6), 2.35 (t, 2H, 7),
3.75–3.92 (m, 4H, 13 und 14), 4.77 (t, 1H, 12). 13C-NMR
(CDCl3): δ = 19.67 (7), 21.19 (8), 28.17 (9, 10), 32.65 (5),
32.96 (11), 46.99 (4), 51.26 (6), 64.79 (13, 14), 104.28 (12),
133.72 (2), 152.87 (3), 198.56 (1). C14H22O3 (238.33).
A solution of 17 (0.55 g, 2.0 mmol) in 20 ml absolute THF
was cooled down with ice to 0 °C in argon atmosphere, mixed
drop-wise with Tebbe-reagent (0.5 M in toluene, 7 ml,
3.5 mmol) and afterwards stirred at this temperature for 6 h.
Quenching was accomplished by slowly injecting a 1:1-mix-
ture of ether/CH3OH by a syringe till the end of gas-evolution.
The reaction mixture was filtered through a layer of
Celite/Al2O3 (1:1) and washed with 1 l of ether. The resulting
dark-red oil (0.44 g crude product) was directly used for the
next reaction in order to avoid decomposition on the stationary
phase of a CC.
4.2. 3-(2,4,4-Trimethyl-6-oxo-1-cyclohex-1-enyl)-propanal (16)
A solution of 1.30 g (5.5 mmol) 15 in 25 ml diethyl ether
was stirred with 15 ml 2 N H2SO4 at RT for 25 h and after-
wards extracted three times with ether. The organic layers were
washed with water, dried (MgSO4) and freed from the solvent
in vacuo. The crude 16 (0.92 g), a yellowish oil, was directly
used for the next step, the carbonyl olefination. MS: (m/z; r.I.)
= 194 (M+, 17), 179(4), 166(71, 151(11), 135(12), 123(15),
110(100), 95(22), 82(38), 67(42), 55(18), 53(27). C12H28O2
(204.34).
A solution of the just obtained crude methylene pentenoate
(0.44 g, ≈ 1.6 mmol) in 10 ml anhydrous CH2Cl2 was cooled
down to –78 °C in argon atmosphere and slowly mixed with
7 ml (7 mmol) DIBAH (1 M solution in n-hexane). The result-
ing mixture was stirred overnight slowly getting warm to RT,
then again cooled down to –20 °C and hydrolyzed with 2 ml of
a mixture of CH3OH/H2O (1:1) and stirred for another 3 h at
RT. Afterwards, the solution was mixed with Celite, filtered
through Celite, washed with ethyl acetate and evaporated.
The crude yellowish-brown oil was purified by prep. TLC
(Al2O3, petroleum ether/ethyl acetate 90:10) furnishing 50 mg
(13.5%) of an almost colorless oil of (Z)-2. IR (NaCl, liquid
film): n = 3335, 3087, 2951, 1632, 1605, 1453, 1365,
1006 cm−1. MS: (m/z; r.I.) = 234 (M+, 5), 216 (5), 201 (9),
175 (100), 162 (17), 145 (13), 133 (21), 119 (28), 107 (53),
4.3. (Z)-Ethyl-2-methyl-5-(2,4,4-trimethyl-6-oxo-1-cyclohex-1-
enyl)-2-pentenoate (17)
A solution of triethyl-2-phosphonopropionate (1.52 ml,
7.0 mmol) and freshly re-crystallized 18-crown-6 (8.5 g,
32.2 mmol) in 120 ml distilled THF was cooled down to
–78 °C in argon atmosphere and mixed with KN(TMS)2
(0.5 M in THF, 13.5 ml, 6.8 mmol). Afterwards a solution of
16 (1.25 g, 6.4 mmol) in 20 ml dry THF was added drop-wise
and the mixture stirred for 4 h at –78 °C and finally for 12 h at
RT. Upon quenching with saturated NH4Cl-solution extraction
with ether followed. The combined ethereal layers were dried
(MgSO4) and freed from the solvent by evaporation. The resi-
due, a yellowish-brown oil was purified by CC (ligroin/ethyl
acetate 80:20) yielding in total: 1.14 g (63.7%); pure (Z)-pro-
duct 17: 0.62 g (34.6%), pure (E)-product: 0.09 g (6.7%). IR
(NaCl, liquid film): n = 2957, 1714, 1665, 1632 cm−1. MS: (m/
z; r.I.) [(Z)-isomer] = 278 (M+, 1), 232 (21), 217 (7), 189 (15),
148 (18), 133 (23), 105 (18), 95 (51), 79 (25), 67 (100), 55
(37). [(E)-isomer] = 278 (M+, 1), 232 (20), 217 (7), 189 (13),
148 (17), 133 (20), 105 (15), 95 (44), 83 (23), 67 (100), 53
1
91 (56), 77 (32), 69 (18), 55 (28). H-NMR (CDCl3): δ = 0.80
(s, 6H, CH3 9 and 10), 1.65 (s, 3H, CH3 16), 1.72–1.72 (m,
3H, CH3 8), 1.84 (s, 2H, CH2 3), 1.99 (s, 2H, CH2 5), 2.13 (t,
2H, CH2 11), 2.23–2.28 (m, 2H, CH2 12),4.02 (s, 2H, CH2 15),
4.63 and 4.82 (m, 2H, =CH2), 5.28 (t, 1H, CH 13). 13C-NMR
(CDCl3): δ = 20.36 and 21.30 (C8 and 16), 27.06 and 27.88
(C11 and 12), 28.04 (C10 and 9), 30.02 (C4), 46.727 and
47.49 (C3 and C5), 61.52 (C15), 107.10 (C7), 128.52 (C13),
129.49 (C2), 132.59 (C6), 143.47 (C1). C16H26O (234.38).
1
(33). H-NMR (CDCl3) [(Z)-isomer]: δ = 0.92 (s, 6H, CH3 9
4.5. 2-[2-(1,3-Dioxolan-2-yl)-ethyl]-3,5,5-trimethyl-
and 10), 1.21 (t, 3H, CH3 17), 1.79 (s, 3H, CH3 14), 1.86 (s,
3H, CH3 8), 2.15 (m, 4H, CH2 3 and 5), 2.31-2.45 (m, 4H,
CH2 7 and 11), 4.09 (q, 2H, CH2 16), 5.88 (t, 1H, CH 12).
13C-NMR (CDCl3) [(Z)-isomer]: δ = 14.20 (C17), 20.57
(C14), 21.26 (C8), 24.35 (C7), 28.10 (C9 and 10), 28.75
(C11), 32.59 (C4), 46.95 (C3), 51.20 (C5), 59.91 (C16),
127.28 (C13), 133.50 (C1), 142.06 (C12), 153.30 (C2),
167.98 (C15), 198.67 (C6). 1H-NMR (CDCl3) [(E)-isomer]:
cyclohexan-1-one (18)
A mixture consisting of 0.8 g (3.4 mmol) 15, 0.52 g
(5.2 mmol) triethylamine, 380 mg Pt on activated carbon
(10%) and 80 ml absolute ethanol was hydrogenated at RT
for 20 h. Afterwards the solution was filtered and the solvent
evaporated. Purification of the residue was accomplished by
CC (ligroin/ethyl acetate 80:20) yielding 0.59 g (72.6%) 18

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J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
as a nearly colorless oil. IR (NaCl, liquid film): n = 2957,
1709, 1463, 1138, 942 cm−1. MS: (m/z; r.I.) = 240 (M+, 2),
225 (1), 195 (1), 178 (4), 163 (1), 136 (1), 125 (2), 99 (11),
(s, 3H, CH3 10), 0.97 (s, 3H, CH3 9), 0.98 (m, 3H, CH3 8),
1.22 (t, 3H, CH3 16), 1.37 (t, 1H, H3ax, J = 12.2 Hz), 1.49
2
(m, 1H, H3eq.), 1.53–1.73 (m, 4H, H1, H2 and CH2 7), 1.76
1
83 (6), 73 (100), 55 (16). H-NMR (CDCl3): δ = 0.82 (s, 3H,
(s, 3H, CH3 17), 2.04 (dd, 2H, CH2 5, 2J = 12.4 Hz, 4J
CH3 10), 1.01 (s, 3H, CH3 9), 1.03 (d, 3H, CH3 8) [3J (H-3,3-
Me) = 6.2 Hz], 1.41 (m, 1H, H4ax) [3J (H3ax, H4ax)
= 12.1 Hz], 1.53 and 1.70 (m, 2H, CH2 11), 1.55 (m, 1H,
4aq.) [2J (H4eq, H4ax) = 13.2 Hz], 1.64 (m, 2H, CH2 7),
1.71 (m, 1H, 3ax), 1.91 (m, 1H, 2ax), 2.05 (dd, 1H, 6eq.) [2J
(H6eq., H6ax) = 12.6 Hz, 4J (H6eq., H4eq.) = 2.6 Hz], 2.20 (d,
1H, 6ax) [2J (H6eq., H6ax) = 12.6 Hz, 4J (H6ax, H4eq.)
= 0.9 Hz], 3.82 and 3.93 (m, 4H, CH2 13 and 14), 4.83 (t,
1H, H 12). 13C-NMR (CDCl3): δ = 20.00 (C7), 20.72 (C8),
25.51 (C10), 31.20 (C11), 32.06 (C9), 34.12 (C3), 35.44
(C5), 48.21 (C4), 54.84 (C6), 55.75 (C2), 64.70 (C14). 64.80
(C13), 104.79 (C12), 211.68 (C1). C14H24O3 (240.34).
= 2.3 Hz), 2.15 (d, 2H, CH2 11, J = 12.4 Hz), 4.10 (q, 2H,
3
3
3
CH2 15, J = 12.4 Hz), 6.68 (t, 1H, H12, J = 7.3 Hz). 13C-
NMR (CDCl3) [E-isomer]: δ = 12.28 (C16), 14.25 and 20.77
(C8 and C17), 24.53 (C11), 25.52 (C10), 26.37 (C7), 32.05
(C9), 34.20 (C2), 35.55 (C4), 48.16 (C3), 54.92 (C5), 55.64
(C1), 60.32 (C15), 127.02 (C13), 142.04 (C12), 168.28
(C14), 211.91 (C6). C17H28O3 (280.41).
4.8. (Z)-2-Methyl-5-(2,4,4-trimethyl-6-methylen-1-cyclohexyl)-
2-penten-1-ol (3)
A mixture of 0.3 g (1.1 mmol) 20 in 13 ml absolute THF
and 2.64 ml (1.3 mmol) Tebbe-reagent (0.5 M in toluene) was
treated as already described for the preparation of 2 (first step).
Yield: 0.36 g (crude product) of a dark-red oily liquid.
4.6. 3-(2,4,4-Trimethyl-6-oxo-1-cyclohexyl)-propanal (19)
A solution of 0.80 g (3.3 mmol) 18, 8 ml 2 N H2SO4 and
50 ml ether was stirred at RT for 48 h and hereupon extracted
with ether three times. The combined ethereal layers were
washed with water, dried (MgSO4) and finally freed from the
solvent in vacuo. The crude product 19, a yellowish oil (yield
0.63 g, 70%) was directly used for the next reaction. MS: (m/z;
r.I.) = 196 (M+, 10), 181(15), 168(6), 163(5), 153(9), 140(26),
125(90), 112(12), 97(15), 83(100), 69(47), 55(70), 41(94).
C12H22O2 (196.29).
A solution of the just obtained crude methylene pentenoate
(0.36 g, ≈ 1.3 mmol) was treated according to the instructions
for the preparation of 2 (second step). Yield: 25 mg (7%) 3 as a
nearly colorless oil. IR (NaCl, liquid film): n = 3348, 3082,
2951, 1643, 1455, 1382, 1239, 1009, 891 cm−1. MS: (m/z;
r.I.) = 218 (M+ – 18, 5), 203 (10), 189 (2), 175 (17), 162 (5),
149 (7), 137 (21), 123 (42), 107 (29), 95 (44), 82 (84), 67 (58),
55 (80), 41 (100). 1H-NMR (CDCl3): δ = 0.73 (s, 3H, CH3 11),
0.83 (s, 3H, CH3 10), 0.85 (s, 3H, CH3 9), 0.99–1.62 (m, 6H,
H1, H2, CH2 3, CH2 8), 1.73 (s, 3H, CH3 16), 1.81 (m, 2H,
CH2 5), 1.93–2.11 (m, 2H, CH2 12), 4.03 (s, 2H, CH2 15),
4.58 (d, 2H, olefin. CH2 7, J = 17.5 Hz), 5.24 (t, 1H, H13, J
= 7.7 Hz). 13C-NMR (CDCl3): δ = 20.80 (C9), 21.29 (C16),
24.96 (C12), 25.54 (C11), 28.40 (C8), 31.96 (C10), 32.74
(C4), 33.82 (C2), 48.79 (C1), 49.03 (C3), 50.22 (C5), 61.64
(C15), 107.09 (C7), 128.97 (C13), 134.16 (C14), 148.91 (C6).
C16H28O (236.40).
4.7. (Z)-Ethyl-2-methyl-5-(2,4,4-trimethyl-6-oxo-1-cyclohexyl)-
2-pentenoate (20)
2
3
A solution of triethyl-2-phosphono-propionate (0.84 g,
3.5 mmol) and freshly re-crystallized 18-crown-6 (4.25 g,
16.0 mmol) in 50 ml absolute THF was treated in the same
manner as already described for the preparation of 17 and then
mixed with KN(TMS)2 (0.5 M in THF, 6.4 ml, 3.2 mmol).
Afterwards a solution of 19 (0.63 g, 3.2 mmol) in 20 ml dry
THF was added drop-wise and stirred at –78 °C for 4 h.
Quenching and work up followed the instructions for the pre-
paration of 17. Yield in total: 0.56 g (62.5%); pure (Z)-20:
0.45 g (50.0%), pure (E)-20: 0.05 g (5.6%). IR (NaCl, liquid
film): n = 2958, 1710, 1650, 1462, 1265, 1122 cm−1. MS: (m/
z; r.I.) = 280 (M+, 1), 265 (1), 234 (20), 219 (4), 207 (7), 191
(6), 177 (2), 164 (4), 150 (3), 140 (23), 125 (100), 113 (12), 95
4.9. Ethyl-1-[2-(1,3-dioxolan-2-yl)-ethyl]4,6,6-trimethyl-2-oxo-
1-cyclohex-3-enyl-carboxylate (9)
11.67 ml n-BuLi (1.6 M in n-hexane) were added slowly to
a cooled solution (–20 °C) of 2.31 ml (18.6 mmol) diisopropyl
amide in 45 ml absolute THF and stirred for 20 min whereupon
this mixture was further cooled down to –78 °C and mixed
with 2.0 g (14.5 mmol) 6. After stirring for 1 h at 0 °C and
cooling down again at –78 °C at first 2.1 g (16.5 mmol) di-
methyl-propylene-urea (DMPU) and then 1.72 g (17.4 mmol)
ethyl cyanoformiate were added and stirred using a mechanical
stirring device (a stir bar is not suited enough to mix the at this
temperature resinous mixture). To complete the reaction the
mixture was allowed to get warm at RT overnight. Quenching
with water, extraction with ether and drying the combined
ethereal phases (MgSO4) followed. The residue after evapora-
tion of the solvent was purified by CC (ligroin/ethyl acetate
80:20) to yield 2.20 g (72%) of this intermediate isophorono
ethyl-formiate. C12H18O3 (210.27). IR (NaCl, liquid film):
n = 2975, 1723, 1674, 1441, 1378, 1274, 1209, 1190, 1067,
1
(18), 84 (17), 69 (15), 55 (27), 41 (17). H-NMR (CDCl3) [Z-
isomer]: δ = 0.78 (s, 3H, CH3 10), 0.96 (s, 3H, CH3 9), 0.98
3
(m, 3H, CH3 8), 1.21 (t, 3H, CH3 16, J = 7.0 Hz), 1.41 (t,
3ax), 1.52–1.77 (m, 6H, H1, H2, CH2 7, H3eq.), 1.82 (s, 3H,
CH3 17), 2.04 (dd, 1H, H5eq., 3J = 2.5 Hz, 2J = 12.8 Hz), 2.12
3
(d, 1H, H5ax, J = 12.5 Hz), 2.36 (m, 2H, CH2 11), 4.09 (q,
2H, CH2 15), 5.85 (t, 1H, H12, 3J = 7.52 Hz). 13C-NMR
(CDCl3) [Z-isomer]: δ = 14.23 (C16), 20.60 and 20.78 (C8
and C17), 25.06 (C11), 25.505 (C10), 27.37 (C7), 32.06
(C9), 34.17 (C2), 35.47 (C4), 48.20 (C3), 54.84 (C5), 55.66
(C1), 59.98 (C15), 127.21 (C13), 142.47 (C12), 168.15
(C14), 211.83 (C6). 1H-NMR (CDCl3) [E-isomer]: δ = 0.79

J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
911
1026, 904, 862 cm−1. MS: (m/z; r.I.) =: 210 (M+, 18), 195 (6),
181 (4), 149 (38), 123 (25), 83 (25), 82 (100), 55 (16), 54 (17).
1H-NMR (CDCl3): δ = 1.01–1.06 (2s, 6H, CH3 9 and 10), 1.19
(C13 and 14), 104.20 (C12), 124.43 (C2), 157.93 (C3),
202.28 (C1). C14H22O3 (238.33).
3
4.11. 3-(4,6,6-Trimethyl-2-oxo-1-cyclohex-3-enyl)-propanal
(21)
(t, J = 7.02 Hz, 3H, CH3 12), 1.90 (s, 3H, CH3 8), 1.97–2.50
(dd, 2H, CH2 5), 3.057 (s, 1H, H1), 4.079 (q, 3J = 7.02 Hz, 2H,
CH2 11), 5.855 (s, 1H, H3). 13C-NMR (CDCl3): δ = 14.10
(C12), 24.50–25.15 (C9 and C10), 28.22 (C8), 35.92 (C6),
44.03 (C5), 60.75 (C11), 63.41 (C1), 124.29 (C3), 161.29
(C4), 168.87 (C7), 194.29 (C2).
10 (1.30 g, 5.5 mmol) was dissolved in 25 ml ether, mixed
with 19 ml 2 N H2SO4 and stirred for 48 h. Work up as de-
scribed before (see preparation of 16) furnished 1 g (72%) of
crude 21 which was used directly for the Wittig reaction at the
free aldehyde group. MS: (m/z; r.I.) = 194 (M+, 2), 179(6), 166
(4), 151(7), 138(23), 135(21), 123(100), 110(8), 91(8), 82(82),
67(10), 55(18), 54(17), 51(33). C12H18O2 (194.27).
NaH (0.25 g, 6.3 mmol, 60% dispersion) was washed with
absolute benzene three times and after each washing procedure
the solvent evaporated. To this purified NaH was added care-
fully freshly distilled DMF (20 ml) and a solution of the just
obtained isophorono ethyl-formiate (1.00 g, 4.8 mmol) in
10 ml of dry DMF, followed by stirring at about 40 °C for
1 h. Then freshly purified (filtration over Al2O3 Wölm®) 2-
(2-bromoethyl)-1,3-dioxolane (1.72 g, 9.5 mmol) was added
and stirred at RT for 48 h. Quenching with water, extraction
with ether and drying the combined organic phases (MgSO4)
followed. The residue consisted roughly of two main com-
pounds (~1:1), each showing a molecular ion peak at m/z 310
in the GC/MS. Subsequent CC (ligroin ethyl acetate 80:20)
furnished finally pure 9 (0.52 g, 19%). IR (NaCl, liquid film):
n = 2978, 2886, 2750 1723, 1668, 1443, 1379, 1274, 1191,
1145, 1094, 1034, 946, 863 cm−1. MS: (m/z; r.I.) = 310 (M+,
2), 295 (1), 265 (4), 249 (2), 237 (8), 221 (7), 210 (9), 195
(14), 149 (9), 126 (9), 99 (28), 82 (24), 73 (100), 55 (9), 45
4.12. (Z)-Ethyl-2-methyl-5-(4,6,6-trimethyl-2-oxo-1-cyclohex-
3-enyl)-2-pentenoate (22)
1.20 ml (5.5 mmol) triethyl-2-phosphono-propionate, 6.86 g
(26.0 mmol, freshly re-crystallized) 18-crown-6, 100 ml abso-
lute THF, then 10.85 ml (5.4 mmol) KN(TMS)2 (0.5 M in
THF) and 1 g (≈ 5.2 mmol) 21 in 20 ml absolute THF were
treated as described for the preparation of 17. Also the quench-
ing of the reaction mixture with NH4Cl and the work up fol-
lowed the procedure as already quoted before. Yield: 0.58 g
(40%) 22. IR (NaCl, liquid film): n = 2962, 1713, 1669,
1438, 1378, 1236, 1183, 1131, 1027, 886 cm−1. MS: (m/z; r.
I.) = 278 (M+, 0), 263 (4), 232 (2), 217 (3), 205 (3), 189 (2),
175 (0), 161 (5), 151 (4), 138 (17), 124 (9), 123 (100), 82 (9),
1
(18). H-NMR (CDCl3): δ = 0.93 and 1.13 (2s, 6H, CH3 10
1
and 11), 1.17 (t, 3H, 3J = 7.02 Hz, CH3 13), 1.48–2.02 (m, 4H,
CH2 9 and 14), 1.83 (s, 3H, CH3 8), 2.15 (s, 2H, CH2 5), 3.72–
69 (9), 67 (8), 41 (19), 39 (8). H-NMR (CDCl3): δ = 0.86–
3
0.96 (2s, 6H, CH3 9 and 10), 1.22 (t, 3H, J = 7.2 Hz, CH3
3
17), 1.45–1.59 (m, 2H, CH2 7), 1.81–1.82 (m, 6H, CH3
8
3.92 (m, 4H, CH2 16 and 17), 4.04–4.16 (dq, 2H, J = 4.5 Hz,
and 14), 1.87–1.93 (m, 1H, H1), 2.06–2.08 (d, 2H, 4J = 3.9 Hz,
CH2 5), 2.31–2.43 (q, 2H, 3J = 7.6 Hz, CH2 11), 4.06–4.16 (q,
2H, 3J = 7.1 Hz, CH2 16), 5.72 (m, 1H, H3), 5.81–5.90 (t, 1H,
3J = 7.4 Hz, H12). 13C-NMR (CDCl3): δ = 14.15 (C17), 20.54
(C14), 23.93-24.10 (C9 and 10), 25.02 (C7), 28.45 (C8), 28.61
(C11), 36.11 (C6), 44.42 (C5), 56.35 (C1), 59.95 (C16),
124.64 (C3), 127.56 (C13), 141.56 (C12), 157.79 (C4),
167.98 (C15), 202.11 (C2). C17H26O3 (278.39).
2J = 2.76 Hz, CH2 12), 4.79 (t, 3J = 4,5 Hz, 1H, H15), 5.80 (m,
1H, H3). 13C-NMR (CDCl3): δ = 14.06 (C13), 23.34 (C9),
23.82 (C10 and 11), 24.40 (C10 and 11), 24.40 (C8), 30.08
(C14), 38.91 (C6), 45.05 (C5), 60.53 (C12), 63.10 (C1),
64.66 (C16 and 17), 104.59 (C15), 125.57 (C3), 156.56 (C4),
170.53 (C7), 196.87 (C2). C17H26O5 (310.42).
4.10. 6-[2-(1,3-Dioxolan-2-yl)-ethyl]-3,5,5-trimethylcyclohex-
2-en-1-one (10)
4.13. (Z)-2-Methyl-5-(4,6,6-trimethyl-2-methylen-1-cyclohex-3-
A mixture of 9 (0.10 g, 0.3 mmol) and 1.20 ml of a 5%
KOH-solution (EtOH/H2O 1:1) was heated at 100–105 °C for
48–60 h and after cooling down to RT several extractions with
ether followed. The combined ethereal phases were dried
(MgSO4) and then freed from the solvent by evaporation. Pur-
ification by CC (ligroin/ethyl acetate 70:30) furnished 0.020 g
(20%) 10. IR (NaCl, liquid film): n = 2962, 2890, 1667, 1436,
1379, 1140, 1034, 1730, 1247, 733, 944, 846 cm−1. MS: (m/z;
r.I.) = 238 (M+, 7), 223 (11), 195 (6), 178 (2), 161 (28), 151
(3), 138 (14), 123 (33), 107 (4), 99 (17), 82 (20), 73 (100), 55
(12), 45 (21), 41 (16).1H-NMR (CDCl3): δ = 0.88–0.96 (2s,
6H, CH3 9 and 10), 1.48–1.76 (m, 4H, CH2 8 and 11), 1.83
(s, 3H, CH3 7), 1.87–2.21 (m, 3H, CH2 4 and H6), 3.72–3.92
(m, 4H, CH2 13 and 14), 4.76 (m, 1H, H12), 5.71 (m, 1H, H2).
13C-NMR (CDCl3): δ = 19.75 (C8), 23.93–28.32 (C7, 9 and
10), 32.43 (C11), 35.98 (C5), 44.01 (C4), 56.60 (C6), 64.61
enyl)-2-penten1-ol (4)
A solution of 22 (0.30 g, 1.1 mmol) in 10 ml absolute THF
was cooled down with ice to 0 °C in argon atmosphere, mixed
drop-wise with 2.7 ml (1.4 mmol) Tebbe-reagent (0.5 M in
toluene) and stirred at this temperature for 15 h. Quenching
was accomplished by carefully injecting a 1:1 mixture of
ether/MeOH by a syringe until the gas-evolution has stopped.
The reaction mixture was filtered through a layer of
Celite/Al2O3 (1:1) and washed with 1 l of ether. The resulting
dark-red oil (0.4 g crude product) was directly used for the
ester reduction in order to avoid decomposition on the station-
ary phase of the CC.
A solution of the just obtained crude methylene pentenoate
(0.4 g, ≈ 1.4 mmol) in 7 ml absolute CH2Cl2 was cooled down
to –78 °C in argon atmosphere and slowly mixed with 6.4 ml

912
J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
(6.4 mmol) DIBAH (1 M solution in n-hexane). Further work
up followed the procedure already described for the preparation
of 2. Yield of pure (Z)-4: 0.034 g (13.2%). IR (NaCl, liquid
film): n = 3340, 2929, 2868, 1650, 1610, 1436, 1379, 1008,
879 cm−1. MS: (m/z; r.I.) = 234 (M+, 3), 216 (1), 201 (8),
175 (7), 159 (5), 145 (20), 136 (17), 121 (100), 105 (16), 91
(4), 180(5), 164(1), 152(20), 149(23), 137(100), 124(14), 109
(6), 96(61), 68(28), 67(32), 41(37). C13H20O2 (208.30).
4.16. (Z)-Ethyl-2-methyl-5-(3,4,6,6-tetramethyl-2-oxo-1-
cyclohex-3-enyl)-2-pentenoate (24)
1
(14), 79 (11), 43 (12), 41 (18). H-NMR (CDCl3): δ = 0.76–
0.30 ml (1.4 mmol) Triethyl-2-phosphono propionate,
1.65 g (6.3 mmol) freshly re-crystallized 18-crown-6, 25 ml
absolute THF, then 2.6 ml (1.3 mmol) KN(TMS)2 (0.5 M in
THF) and 0.26 g (1.3 mmol) 23 in 10 ml absolute THF were
treated as described for the preparation of 17. Also the quench-
ing of the reaction mixture with NH4Cl and the work up fol-
lowed the procedure as already described before. This time the
purification was accomplished by TLC (Al2O3, toluene/ethyl
acetate 90:10). Yield: 0.20 g (54.4%) (Z)-24. IR (NaCl, liquid
film): n = 2959, 2930, 1714, 1665, 1454, 1377, 1309, 1235,
1186, 1129, 1097, 1026 cm−1. MS: (m/z; r.I.) = 292 (M+, 1),
247 (1), 246 (1), 219 (3), 203 (2), 175 (6), 152 (17), 138 (11),
137 (100), 122 (4), 109 (3), 96 (6), 91 (5), 67 (15), 55 (7), 53
(7), 43 (10), 41 (20). 1H-NMR (CDCl3): δ = 0.81–0.93 (2s, 6H,
CH3 10 and 11), 1.21 (t, 3J = 7.18 Hz, 3H, CH3 17), 1.44–1.60
0.88 (2s, CH3 9 and 10), 1.33–2.04 (m, 13 H, H1, CH2 5,
11and 12, CH3 8 and 16), 4.05 (m, 2H, CH2 15), 4.55–4.70
(d, 2H, 2J = 30.5 Hz, =CH2 7), 5.21 (t, 1H, 3J = 7.3 Hz,
H13), 5.72 (s, 1H, H3) .13C-NMR (CDCl3): δ = 21.21 (C16),
23.49 (C8), 25.94 (C11), 27.43–28.32 (C9 and 10), 28.58
(C12), 32.87 (C6), 41.44 (C5), 50.82 (C1), 61.71 (C15),
110.29 (C7), 122.62 (C13), 128.97 (C3), 134.00 (C14),
136.05 (C4), 146.25 (C2). C16H26O (234.38).
4.14. 6-[2-(1,3-Dioxolan-2-yl)-ethyl]-2,3,5,5-tetramethyl-
cyclohex-2-en-1-one (11)
To a solution of 3.64 ml (3.1 mmol) cyclohexyl isopropyl
amide (CIPA) in 30 ml absolute THF at 0 °C under inert gas
atmosphere 13.3 ml (21.3 mmol) n-BuLi (1.6 M in n-hexane)
were added carefully whereupon the mixture was allowed to
get warm to RT. By controlling the ambient temperature
(19–23 °C) 10 (1.72 g, 7.2 mmol) in 10 ml absolute THF
and 10 ml (175 mmol) of CH3I were slowly added in the
course of which the color of the mixture turned from amber-
like to dark brown after 20 min. After stirring for 20 h at RT
the mixture was quenched by adding a saturated NH4Cl solu-
tion. Extraction with ether, drying the combined ethereal
phases (MgSO4) and evaporation of the solvent followed. The
crude residue consisted of five methylated products. Yields
upon CC (ligroin/ethyl acetate 80:20): first: 100 mg (5.3%),
second: 80 mg (4.15%), third: 250 mg (13.7%), fourth:
130 mg (7.2%) and finally the fifth as the main product 11:
270 mg (14.9%). IR (NaCl, liquid film): n = 2961, 2886,
1663, 1447, 1378, 1311, 1141, 1038, 944, 899 cm−1. MS:
(m/z; r.I.) = 252 (M+, 8), 237 (4), 207 (2), 175 (22), 151 (14),
137 (28), 121 (4), 99 (24), 96 (17), 73 (100), 67 (17), 45 (26),
41 (23). 1H-NMR (CDCl3): δ = 0.84–0.93 (2s, 6H, CH3 10 and
11), 1.45–1.63 (m, 4H, CH2 9 and 12), 1.67 (s, 3H, CH3 7),
1.78 (s, 3H, CH3 8), 1.91–2.24 (2m, 3H, H6 and CH2 4), 3.72–
3.92 (m, 4H, CH2 14 and 15), 4.78 (m, 1H, H13). 13C-NMR
(CDCl3): δ = 10.84 (C7), 20.01 (C9), 21.01 (C8), 24.32–28.55
(C10 and 11), 32.66 (C12), 35.32 (C5), 45.78 (C4), 56.78
(C6), 64.69–64.73 (C14 and 15), 104.40 (C13), 128.71 (C2),
150.03 (C3), 201.98 (C1). C15H24O3 (252.36).
4
(m, 2H, CH2 9), 1.68 (m, J = 0.62 Hz, 3H, CH3 18), 1.78 (s,
3H, CH3 7), 1.80 (m, 4J = 1.26 Hz, 3H, CH3 8), 1.91–1.97 (m,
3
1H, H1), 2.12 (s, 2H, CH2 5), 2.97 (q, J = 18.1 Hz, 2H, CH2
3
3
12), 4.09 (q, J = 7.08 Hz, 2H, CH2 16), 5.85 (t, J = 7.44 Hz,
1H, H13). 13C-NMR (CDCl3): δ = 10.86–28.61 (C7, 8, 10, 11,
17 and 18), 25.31 (C9), 28.72 (C12), 35.36 (C6), 46.02 (C5),
56.48 (C1), 59.94 (C16), 127.43–128.83 (C3 and 14), 141.86
(C13), 149.86 (C4), 168.03 (C15), 201.81 (C2). C18H28O3
(292.42).
4.17. (Z)-2-Methyl-5-(3,4,6,6-tetramethyl-2-methylen-1-
cyclohex-3-enyl)-2-penten-1-ol (5)
0.20 g (0.70 mmol) 24, 10 ml absolute THF and 1.70 ml
(0.85 mmol) Tebbe-reagent (0.5 M in toluene) were treated as
described for the preparation of 2. The dark-red oily reaction
product (270 mg, ≈ 0.9 mmol) was dissolved in 8 ml absolute
CH2Cl2 and the solution cooled down to –78 °C and finally
mixed drop-wise with 5.30 ml (5.3 mmol) DIBAH (1 M in
CH2Cl2). This mixture was stirred overnight whereupon it
was allowed to warm to RT. The further work up followed
the already described procedure for the preparation of 2. The
crude residue was purified by preparative TLC (Al2O3, to-
luene/ethyl acetate 95:5) and furnished 17 mg (7.4%) 5. IR
(NaCl, liquid film): n = 3352, 2930, 1640, 1607, 1447, 1383,
1008, 878, 735 cm−1. MS: (m/z; r.I.) = 248 (M+, 7), 234 (0),
233 (1), 215 (8), 189 (3), 173 (6), 159 (25), 150 (14), 136 (12),
135 (100), 119 (14), 105 (11), 91 (14), 77 (8), 67 (5), 55 (8),
4.15. 3-(3,4,6,6-Tetramethyl-2-oxo-1-cyclohex-3-enyl)-
propanal (23)
1
43 (13), 41 (18). H-NMR (CDCl3): δ = 0.75–0.85 (2s, 6H,
CH3 11 and 12), 0.87–1.13 (m, 2H, CH2 10), 1.30–2.05 (m,
5H, H1, CH2 5 and 13), 1.52–1.71 (3s, 9H, CH3 8, 9 and 17),
4.02 (m, 2H, CH2 16), 4.55–4.85 (2s, 2H, =CH2 7), 5.21 (m,
1H, H14). 13C-NMR (CDCl3): δ = 14.23–28.58 (C8, 9, 11, 12,
17), 26.08 (C10), 28.58 (C13), 32.38 (C6), 43.96 (C5), 52.93
0.30 g (1.2 mmol) 11, 20 ml ether and 4.2 ml 2 N H2SO4
were stirred for 48 h followed by extraction with ether, collect-
ing the ethereal phases, drying them with MgSO4 and evapor-
ating the solvent. The brown, oily residue (0.26 g) was directly
used for the next reaction. MS: (m/z; r.I.) = 208 (6. M+), 193

J. Höfinghoff et al. / European Journal of Medicinal Chemistry 41 (2006) 905–913
913
[14] E.J. Brunke, E. Klein, in: E. Theimer (Ed.), Fragrance Chemistry. The
Science of the Sense of Smell, Academic Press, New York, 1982, pp.
397–431.
(C1), 61.74 (C16), 108.26 (C7), 123.702 (C4), 129.19 (C14),
130.48–133.87 (C3 and 15), 148.29 (C2). C17H28O (248.41).
[15] E.J. Brunke, E. Klein, in: B.D. Mookherjee, C.J. Mussinan (Eds.), Essen-
tial Oils, Allured Publishing, Wheaton, IL, 1981, pp. 83–103.
[16] G. Ohloff, B. Winter, C. Fehr, in: P.M. Müller, D. Lamparsky (Eds.),
Perfumes, Art, Science and Technology, Elsevier Applied Science, Lon-
don, 1991, pp. 287–330.
[17] P. Weyerstahl, J. Prakt. Chem. 336 (1994) 95–109.
[18] K.J. Rossiter, Chem. Rev. 96 (1996) 3201–3240.
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Acknowledgements
The authors want to thank the former chief perfumers of
Dragoco-Vienna (now Symrise, Vienna) V. Hausmann and W.
Höppner for the olfactory evaluation, and Symrise, Vienna for
its continuing interest in our research. For cooperation with
synthetic work we are grateful to Mag.pharm. G. Schöberl.
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