Substituted hepta-1,6-dien-3-ones with green/fruity odours green/galbanum olfactophore model

Article abstract of DOI:10.1016/S0968-0896(03)00189-5

Following an analysis of available SAR data on green/galbanum-smelling molecules, a series of new 2-substituted hepta-1,6-dien-3-ones and their analogues were prepared and their olfactory properties evaluated. The study allowed to select efficient new odourants - potential substitutes for natural galbanum oil - and to generate an olfactophore model for the green/galbanum note.

Full text of DOI:10.1016/S0968-0896(03)00189-5

Bioorganic & Medicinal Chemistry 11 (2003) 2931–2946
Substituted Hepta-1,6-dien-3-ones with Green/Fruity Odours
Green/Galbanum Olfactophore Model
Jerzy A. Bajgrowicz,* Katja Berg-Schultzy and Gerhard Brunner
¨
Givaudan Schweiz AG, Fragrance Research, Uberlandstrasse 138, CH-8600 Dubendorf, Switzerland
¨
Received 31 January 2003; accepted 21 March 2003
Abstract—Following an analysis of available SAR data on green/galbanum-smelling molecules, a series of new 2-substituted hepta-
1,6-dien-3-ones and their analogues were prepared and their olfactory properties evaluated. The study allowed to select efficient new
odourants—potential substitutes for natural galbanum oil—and to generate an olfactophore model for the green/galbanum note.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
ship data not only in terms of the odour quality, but
also of its static and dynamic quantity, that is, the per-
ception threshold and duration.5 Despite recent pro-
gress in the functional expression of odourant receptors6
which belong to the omnipresent family of G protein
coupled receptors (GPCRs), no practical assay to
measure odourant–olfactory receptor affinity is cur-
rently available.7 At present, a rational odourant design
is hardly possible and most often limited to the classical
‘me-too’ or ‘mecano’ approaches.8
QSAR studies in the domain of olfaction are difficult to
carry out because of the elusive definition of ‘activity’,
let alone its measurement.1 Even within a given odour
family, for example, woody, musky or green, the odour
quality changes from one structure to another in an
almost continuous spectrum of shades and nuances. In
addition, it often varies with the concentration, that is,
over time. This phenomenon is mainly due to the com-
plexity of the olfactory mechanism, in the primary event
of which molecules of a defined structure bind simulta-
neously to several of probably up to 1000 different
receptor types. Unequal sensitivities of the activated
receptors towards the same odourant may be respon-
sible for more or less pronounced changes of its odor
profile with the concentration. Moreover, a single
receptor protein may interact with several different
ligands.2 In other words, each odour sensation is trig-
gered by a chord played on a ‘keyboard’ of odourant
receptors—in agreement with the recently proven com-
binatorial coding of odour perception3—and these
chords are often partially superposable.
All these difficulties notwithstanding, fragrance chemists
keep searching for olfactophores, that is, common elec-
tronic shapes of the active conformers of different
chemical structures responsible for the same (or very
similar) odour sensations.1b,c These entities, analogous
to the pharmacophores used in the medicinal chemistry,
would allow applications of the well established meth-
odologies of lead finding and optimisation. Because of
the above-mentioned limitations, a routine QSAR
approach to the olfactophore search is impossible at this
point. However, for preliminary studies training set
structures can be classified into two or three groups:
active, inactive and those with an intermediate activity,
that is, significantly weaker and/or of a less similar
olfactory profile compared to the template molecule(s).
On the other hand, the high variability of the astonish-
ingly big olfactory repertoire of the human genome4
gives rise to frequent hyper- hypo- and an-osmias
(abnormal sensitivities to a given odour). This hampers
the acquisition of significant structure–odour relation-
Galbanum oil and resinoid, produced from Ferula gal-
baniflua Boissier and Buhse and Ferula rubricaulis Bois-
sier growing in Iran,9 are important perfumery raw
materials of a characteristic harsh, green, slightly spicy
and fruity odour. They are complex mixtures of pro-
ducts in which minor constituents, particularly (3E,5Z)-
*Corresponding author. Tel.: +41-1-824-23-70; fax: +41-1-824-29-26;
e-mail: jerzy.bajgrowicz@givaudan.com.
yPresent address: Roche Vitamin Ltd., CH-4070 Basel, Switzerland.
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00189-5

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J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
undeca-1,3,5-triene{ (1; Fig. 1), play important olfactory
roles. Since the serendipitous discovery of Dynascone1
(2; main olfactory constituent), having a green/galba-
num, fruity (pineapple-like) scent,13 the galbanum-type
odourants have been widely applied in fine and func-
tional perfumery, most often to impart fruity-green
notes.1c The odour of Dynascone1 (2) resembles that of
undecatriene 1, but is significantly less fatty and more
fruity. The fruity-pineapple aspect is even more present
in other similar synthetic products such as 3,14 415 and
5.16,17
1,1-dimethylcyclohexyl moiety was replaced by the
eight-membered ring without significant change of the
scent (especially within the amber/woody note) of such
modified odourants were reported.21 Therefore, we also
prepared isomeric tert-butylcyclohexyl and cyclooctenyl
analogues of 2 (28a–d), according to the usual reaction
sequence depicted in Scheme 3.
The already mentioned series of bicyclic structures 7
(X=CH2), mimicking 2 and 6, was obtained19 in the
same way. These complex mixtures of stereoisomers
were of little help for this study. Nevertheless, the main
odour vector of 1-(octahydronaphthalen-2-yl)pent-4-en-
1-one 7a, one of the best compounds of the series, was
isolated by preparative GC, its structure was elucidated
and its odour measured and evaluated. The olfactory
properties of the corresponding intermediate alcohols
and the 1,2- and 6,7-dihydro- (Scheme 2) and 4-oxa20
analogues of the best rated candidates were compared
to those of the parent hepta-1,6-dien-3-ones to confirm
the contribution of the carbonyl group (ketone versus
ester) and both C¼C double bonds to the total odour
sensation and to generate a possibly reliable green/gal-
banum olfactophore model.
Results and Discussion
Chemistry and structure–odour relationships (SORs)
Looking for more efficient—that is, more intense and
substantive (long-lasting) and less costly—substitutes of
galbanum oil, we have recently prepared and claimed
series of bicyclic derivatives 618 and 7.19,20 The con-
jugated C¼C bond appears to enhance significantly the
green/galbanum odour note of these products. Its posi-
tion in the ring is also important; it has already been
found13a that the odour of a-Dynascone1 (2) is much
stronger than that of its b isomer (34 in Table 2), the
latter having no galbanum character. This tendency was
confirmed for the spiro-analogues 6.
The syntheses of compounds 8 are straightforward and
easy to apply on an industrial scale.22 The most general
one (Scheme 1) consists of a Mannich methylenation of
an aldehyde, followed by addition of the Grignard
reagent prepared from 4-bromobut-1-ene (commercially
available and easily accessible from 1,4-dibromobutane)
and a smooth oxidation of the resulting allylic alcohols
15. The a,b-unsaturated aldehydes, necessary to prepare
the ethylidene and propylidene homologues (8b and 8s)
of 8a—one of the most promising candidate for devel-
opment and introduction into the perfumers’ palette—
were obtained by cross-aldol condensation under the
Mukaiyama conditions23 followed by dehydration. The
most strained isopropylidene analogue 8q was synthe-
sised via cyclohexylacetate anion addition to acetone.
An alternative preparation of 8 consists of condensation
of a ketone with ethyl cyanoacetate followed by reduc-
tion of the a,b-unsaturated ester group, TMS protection
In order to further probe the spatial requirements of the
possible lipophilic pocket of a galbanum-type odourant
receptor, and to find the best position of the conjugated
C¼C bond, a series of substituted hepta-1,6-dien-3-ones
8 was prepared according to the reaction in Scheme 1.
Different 2-substituents (alkyls; cycloalk(en)yls, aryls,
with and without a spacer), as well as other structural
modifications, such as simple mono- and di-substitution
of the conjugated methylene group (8b, 8s and 8q; Table
1) and its replacement by an isoelectronic and tenta-
tively bioisosteric cyclopropane ring (24a and 24b;
Scheme 2), were tried. The olfactory importance of the
gem-dimethyl group is well known among fragrance
chemists, and rather astonishing examples where the
Figure 1. Important green/galbanum smelling compounds.
{1, often called ‘galbanolene’ because of its origin and odour,10 is widespread in nature. It has been found in fruits and vegetables11 and constitutes a
powerful pheromone of marine brown algae; as a sperm attractant in Cystophora siliquosa J. Ag., it was given the name of ‘cystophorene’.12

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2933
Scheme 1. Preparation of hepta-1,6-dien-3-ones 8: (a) R, R2, R3=H: CH2O, Et2NH, H2SO4; R, R2=H, R3=Me, Et: (1) TMSCl, Et3N, DMF; (2)
R2CHO, TiCl4, Ti(OiPr)4; (3) I2, Á; R=OEt, R1, R2=Me: (1) LDA, AcMe; (2) LAH; (3) MnO2; (b) CH2¼CH(CH2)2MgBr; (c) DIBAH; (d) MnO2
or PCC/CH2Cl2; (e) (1) H2, Pd/C; (2) KOH; (3) HCl; (4) CH2O, pyridine; (f) NaBH4; or (1) H2, Pd/C; (2) NaBH4; (g) TMSCl, NEt3; (h) (1)
CH2¼CH(CH2)2MgBr, toluene; (2) H+; (i) NCCH2CO2Et, AcNH4, AcOH.
shown in Table 1. The ketones are sorted by increasing
GC OT, their green/galbanum odour note intensityx is
indicated by three descriptors: high, medium, and low.
For the sake of clarity, only two simple (no diastereo-
isomerism) alcohols 15 corresponding to the most active
ketones are included, as their scents were always weaker
and very different from the green/galbanum one.
These structure-odour relationship (SOR) data confirm
the importance of the three electron rich structural fea-
tures: a carbonyl group and both C¼C double bonds.
Astonishingly, and contrary to our previous results in
the domain of sandalwood odourants,28,29 the replace-
ment of the Á1 C¼C double bond by a cyclopropane ring
Scheme 2. Preparation of analogues of 8: (a) n-BuMgBr; (b) MnO2 or
PCC/CH2Cl2; (c) H2, Pd/C; (d); Me2S(O)¼CH2; (e) CH2¼CH(CH2)2-
resulted in a total loss of the green galbanum scent
(8aꢀ24b). It became also clear that slight differences in the
steric hindrance of the bulky group can lead to dramatic
changes in the olfactory properties of apparently very
similar structures: for example, 8dꢀ8l (trans vs cis);
8c>8m (cis vs trans); 8a>8e=8f>8o and 8c>8i (ring size
difference); 8a >8k (cyclohexyl linked directly or via a
CH2 spacer); 8a=8b >8q=8s (small substituents at C1).
MgBr, toluene.
of the obtained cyanoalcohol and a one pot Grignard
addition/dehydration step. A cyclopropane ring was
introduced via the Corey–Chaykovsky reaction (24a
and 24b), while hydrogenation of the intermediate a,b-
unsaturated aldehyde 14 and the use of a saturated
Grignard reagent provided the corresponding hepten-3-
ones 21 and 18 (Scheme 2). The syntheses of 1-(tert-
butylcyclohexyl), 1-cyclooctenyl and 1-octalinylpent-4-
en-1-ones 28a–d and 7a via the Meyer–Schuster rear-
rangement of the corresponding propargylic alcohols 27
were analogous to the published experimental proce-
dures for similar structures13b,18,19 (Scheme 3).
Olfactophore model
In the generation of the green/galbanum olfactophore
model only single stereoisomer and racemic molecules
were selected among active and intermediate com-
pounds. Up to four stereoisomer mixtures were allowed
in the third group of inactive ones (Table 1). The Cata-
lystTM software30 we used for the olfactophore genera-
tion is well suited for such cases of undefined absolute
configuration.31 Also, our GC-sniffing technique of
odour analysis makes low the risk of false negatives due
to a possible antagonistic effect of a constituent.
The results of olfactory evaluations (predominance of
the green/galbanum odour character and intensity of
this odour note) and odour thresholds (the lowest con-
centration at which any odour of the material is per-
ceived) measured by the GC sniffing methods24 are
Scheme 3. Preparation of substituted cycloalkenylpent-4-en-1-ones 7 and 28: (a) C2H2, tBuOK; (b) KOH, H2C¼CHCH2Cl, CuCl; (c) HCO2H, Á.
xIn other words, the strength of the green/galbanum component of the overall odour.

2934
J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
Table 1. Substituted hepta-1,6-dien-3-ones and their analogues, prepared and used in the green/galbanum olfactophore generation; sorted by
increasing odour threshold order
Compd
Structurea
GC
OTb
Green/
galbanum
odour
intensityc
Conf.d Fite Á Ef Compd
Structurea
GC
OTb
Green/
galbanum
odour
intensityc
Conf.d Fite Á Ef
2
8a
8b
1
1
High
High
221 10.8 5.1
190 10.25.4
8o
8p
10
Medium
51 10.3 6.2
2
.
2 10
Medium
metallic, green
28
8.9 3.5
2
2
2
2
2
2
2
2
2
2
2
2
.
2 10
8c
7a
8d
8e
8f
2High
40 10.0 8.6
8q
8r
Medium
fruity, sweet
201 9.0 9.8
.
2 10
2High
44 11.0 0.0
Medium
green, fruity
54 10.5 9.5
.
2 10
4
9
High
High
High
High
38 10.29.4
28d
8s
Medium
fruity, pear
24
34
8.1 8.7
9.7 0.0
.
2 10
19210.0 5.9
Medium
green, fruity
.
3 10
10
237 10.0 3.6
41 10.6 7.6
15a
24a
8t
Low
fruity, green
440 8.8 2.4
.
3 10
28a
8g
28b
8h
8i
10
20
30
40
60
60
90
Low
animal, green
77
49
9.4 0.0
9.5 8.9
.
4 10
Low
rosy, fruity
44
9.5 8.4
Medium
green, fruity
.
4 10
Low
green, fatty
3298.2.8
8u
Low
green, plastic
328.1 4.2
.
4 10
High
High
212 10.6 1.8
8v
Low
metallic, tarragon
86 10.6 6.7
.
5 10
26
9.1 9.4
15e
18
Low
metallic
425 8.5 7.5
.
8 10
8j
Medium
apple, pineapple
6210.7 4.0
Low
acidic, fruity
24
17
9.2 4.6
8.5 5.2
.
9 10
8k
Medium
41
9.9 8.5
8w
Low
anisic
(continued on next page)

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2935
Table 1 (continued)
Compd
Structurea
GC
OTb
Green/
galbanum
odour
intensityc
Conf.d Fite Á Ef Compd
Structurea
GC
OTb
Green/
galbanum
odour
intensityc
Conf.d Fite Á Ef
8l
102
102
102
102
102
Low
dill
57
9.25.6
8x
24b
8y
103
Low
woody, amber
145 9.282
3
.
2 10
8m
28c
8n
21
Medium
green
37 10.4 4.1
Low
green, pineapple
218 8.0 9.3
3
3
.
4 10
Low
fruity, liquor
828.3 6.6
Low
sandalwood
7.7 10.0 9.2
.
5 10
Low
green, fruity
48 10.7 2.7
8z
Low
waxy, fruity
88
9.4 3.5
Low
fruity, pineapple
458
8.4 8.6
aRelative configuration, racemate(s) if not otherwise stated.
bMeasured using the GC/sniff technique24 on a DBTM-1 or DBTM-5 15 m  0.53 mm/1.5 mm column by 3–5 panelists; relative values (per weight)
compared to 8a.
cEvaluated by the GC/sniff technique24 as in b, and on the blotter. In italics the main odour note if not predominantly green/galbanum; only the
main two odour descriptors are reported.
dNumber of conformers (‘best’ mode) for the olfactophore generation.
eQuality of the compound mapping to the hypothesis (‘fast’ mode). The fit value depends on the weights assigned to the hypothesis features and the
displacements of the features from the centres of the location constraints; a perfect mapping would correspond to the fit value equivalent to the sum
of the weights of the features (in our case 16.17; the weights of the features A, B1, B2, C and C0, depicted in Figure 2, being 2.89, 2.02, 2.02, 4.62, and
4.62, respectively).
fStrain energy difference between the best fitting and the most stable conformer (in kcal/mol).
A training set of 37 compounds described in this paper
(10 active, 10 medium and 17 inactive; Table 1) was
completed by 25 similar molecules reported elsewhere
(Table 2). The undecatriene 1, structurally very different
and difficult to classify because of the strong (and in our
view detrimental) fatty note that accompanies its very
intense green odour, was not included.
The methodology applied to the generation of the green/
galbanum olfactophore model was similar to those
reported for other odour notes.1b,1c,28,29 In the first step,
the conformational modelk that covers the whole con-
formational space was built for each of the 74 structures
of the training set; the stereoisomers of inactive com-
pounds were considered as separate structures. Applying
a 10 kcal/mol energy cutoff,32 between 25 and 237 con-
formations were obtained for each structure, depending
on its conformational flexibility (Tables 1 and 2). In
order to derive quantitative olfactophore models
(HypoGen33), the three categories of structures—
endowed with high, medium and low green/galbanum
odour intensity—were arbitrarily assigned a biological
activity of 10À5, 10À3 and 0.1, respectively. The gener-
Figure 2. 8a mapping the green/galbanum olfactophore model.
kFor exact definitions of the CatalystTM terms (in italics when first
cited in the text) and methodology see (ref 31).
A: hydrophobe, Bn: C=C or ether, C!C0: HBA.

2936
J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
Table 2. Other training set structures used in the olfactophore generation
Compd
Structurea
Lit.b
Green/
galbanum
odour
intensityc
Conf.d Fite Á Ef Compd
Structurea
Lit.
Green/
galbanum
odour
intensityc
Conf.d Fite Á Ef
2
13a
18
High
High
26 10.0 0.0
25 11.0 4.7
35
36
13a
13a
Low
25
8.0 0.0
floral, green,
fruity
6a
Low
floral
(ionone-like)
3210.7 7.3
6b
6c
29
30
31
32
8A
5a
18
18
High
High
High
43 10.7 0.0
37
38
39
40
41
42
43
44
13a
25
Low
fruity
(mouldy)
37
44
74
19
44
57
51
84
9.20.0
329.3 6.7
Low
mushroom-earthy,
floral
8.3 0.1
8.7 3.4
7.4 0.2
9.0 2.3
9.1 3.6
9.9 7.7
9.3 1.4
13a
13a
13a
13a
20
31 10.20.0
25
Low
amber-like,
cistus
Medium
floral
(ionone-like)
41
26
9.8 7.5
8.6 2.6
25
Low
floral, green,
aromatic
Medium
25
Low
pineapple
Medium
fruity
57 10.6 3.6
13a
26
Low
fruity
(pineapple)
Medium
fruity,
pineapple
228 10.5 1.2
13a Low
25 floral (ionone),
woody, marine
13a
17
Medium
fruity
(pineapple)
34
9.6 4.5
13a
25
Low
floral, fruity,
woody
5b
4
16
Medium
rose,
green apple
328.7 4.4
45
3
27
14
Low
pineapple,
camomile
198
49
2.9 9.7
8.0 2.3
13a
15
Medium
64
43
9.6 8.1
Low
sweet-fruity
(pineapple)
34
13a
Low
floral,
fruity
8.6 1.8
aRacemates for chiral structures.
bSource of odour descriptions.
cIn italics the main odour note if not predominantly green/galbanum.
dCf. Table 1.
eCf. Table 1.
fCf. Table 1.

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2937
Figure 3. All the 15 best green/galbanum odorants from the training set aligned on the olfactophore model; front (left) and side view.
Independent variation of the interpharmacophore fea-
ture spacing, weight and tolerance factors and of the
minimum and maximum number and type of functions
led to a series of hypotheses with a satisfactory pre-
dictive character. They all consist of a set of one hydro-
phobe and one custom double bond/ether function that
represents the bulky lipophilic part of a green/galbanum
odourant, and of another double bond/ether function
and an HBA, corresponding to the side-chain bearing
the osmophoric1b carbonyl group. This series of similar
hypotheses differs by the positions of the two functions
mapped by the side chain, due to the flexibility of the
pent-4-enoyl and allyloxycarbonyl fragments of the
training set structures.
The best hypothesis (correlation34 0.6), mapped by the
best green/galbanum odourant from this study (8a) and
by all the strong odourants with this odour from the
training set, is depicted in Figures 2and 3 , respectively.
While it was impossible to unequivocally determine the
best relative positions of the HBA and of the side-chain
hydrophobe, the bulky lipophilic part of the olfacto-
phore could be fairly well defined. The Connolly sur-
face35 of these parts of the best 15 molecules aligned on
the best hypothesis (Fig. 4) could represent the lipo-
philic pocket of the green/galbanum receptor(s). For the
inactive molecules, structurally closely related to the
active ones, which map all the functions of our best
hypotheses (cf. fit parameter in Tables 1 and 2) this
surface constitutes a good discrimination tool.36
Figure 4. Connolly surface, generated on the alignment from Figure 3.
8a and two structurally different strong green/galbanum odorants 1
(green) and 5a (white), also aligned on the model but not used in the
surface generation, are highlighted.
ated models (also called hypotheses) are 3D arrange-
ments of selected chemical features, that best correlate
with the input activity data. In our case, they were
composed of an oriented hydrogen-bond acceptor
(HBA), 2–4 hydrophobes and 1–2custom functions, the
latter corresponding either to a C¼C double bond or to
an C–O–C ether group.
The undecatriene 1, of a much more fatty and less fruity
odor than those of the active compounds from this
study, maps very well all the functions of the best
hypothesis except the HBA (Fig. 3).

2938
J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
Conclusions
eous formaldehyde 35% (82g, 1.0 mol) and cyclohex-
ylacetaldehyde (101 g, 0.8 mol) were added slowly to
diethylamine (73 g, 1.0 mol) at 0 ꢁC. After stirring at
80 ꢁC overnight, the reaction mixture was extracted with
MTBE. The combined organic phases were washed with
H2O until neutral pH, dried (MgSO4) and concentrated
in vacuo. The crude product was distilled under reduced
pressure using a Widmer column (80 ꢁC/10 torr) to give
This study allowed to prepare new, excellent green/gal-
banum-type odourants and to increase the pool of ana-
logues indispensable to acquire useful structure–odour
relationship (SOR) data. Their analysis gave rise to an
olfactophore model for this type of odour, which—
whatever its limitations—has already proved useful in
the design of new odourants. Further research is neces-
sary to define the exact geometry of the flexible part of
active structures. However, our preliminary results
indicate that any side-chain substitution decreases the
green/galbanum odour intensity.
1
14a37 (89.5 g, 81%). H NMR: d 9.51 (s, 1H), 6.21 (s,
1H), 5.94 (s, 1H), 2.47 (tt, J=11.9, 2.9, 1H), 1.82–1.67
(m, 5H), 1.43–1.28 (m, 2H), 1.26–1.07 (m, 3H). 13C
NMR: d 194.7 (d), 155.5 (s), 132.7 (t), 35.8 (d), 32.0 (2t),
26.4 (2t), 26.1 (t). MS: 138 (M+, 40), 123(22), 109(73),
95(90), 91(28), 79(61), 67(100), 55(39), 41(53). IR: nmax
2927vs, 2853s, 2701w, 1694vs, 1624w, 1449m, 1265m,
943m, 892m.
It should be kept in mind that, because of the proved
combinatorial coding of odour perception,3 the com-
plete model of an olfactophore consists probably of sev-
eral hypotheses (electronic shapes), corresponding to a
set of different receptors, the activation of which is pre-
requisite to the odour sensation. Consequently, some
flexibility of the butenyl side chain could be indis-
pensable for odourants to adapt to the binding sites of
all the receptors of the green/galbanum accord. In this
respect, the less well-correlated CatalystTM hypotheses
could also be useful.
2-Cyclohexylhepta-1,6-dien-3-ol (15a). A solution of 14a
(69 g, 0.5 mol) in Et2O (100 mL) was slowly added to
but-1-enylmagnesium bromide prepared by addition of
4-bromobut-1-ene (81 g, 0.6 mol) in 100 mL of ether to
magnesium turnings (13.2g, 0.55 mol) in 300 mL of
ether at 0 ꢁC. The reaction mixture was then allowed to
warm to room temperature and was stirred for addi-
tional 3 h and quenched with 2N HCl. The organic
layer was washed with H2O until neutral pH, dried
(MgSO4) and concentrated in vacuo. The crude product
was distilled using a Vigreux column (91 ꢁC/0.15 torr) to
Experimental
General
1
give 15a (85 g, 88%). H NMR: d 5.85 (ddt, J=17.1,
10.2, 6.6, 1H), 5.05 (dq, J=17.1, 1.8, 1H), 5.04 (t, J=1.0,
1H), 4.98 (ddt, J=10.2, 2.0, 1.1, 1H), 4.88 (s, 1H), 4.09 (dd,
J=7.8, 5.3, 1H), 2.25–2.06 (m, 2H), 1.89 (tt, J=11.4, 2.7,
1H), 1.80–1.55 (m, 8H), 1.35–1.05 (m, 5H). 13C NMR: d
158.0 (s), 138.3 (d), 114.6 (t), 107.7 (t), 74.1 (d), 40.4 (d),
35.0 (t), 33.9 (t), 33.3 (t), 30.0 (t), 26.8 (t), 26.7 (t), 26.1
(t). MS: 194 (M+, 1), 176(4), 165(3), 151(9), 139(11),
122(11), 109(15), 95(37), 83(66), 79(43), 71(34), 67(50),
55(100), 41(50). IR: nmax 3361s, 3076w, 2926vs, 2852s,
1641w, 1448m, 1064m, 907s, 889m. Anal. calcd for
C13H22O: C, 80.35; H, 11.41. Found: C, 80.50; H, 11.43%.
All reagents and solvents were commercially available and
were used without any purification. All products reported
were obtained as colourless oils, if not otherwise stated.
GC: DBTM-WAX, DBTM-1, DBTM-5, and DBTM-1701
columns. Flash chromatography: Merck silica gel 60
(230–400 mesh). TLC: Merck silica gel 60 F254 anal.
plates. IR spectra: Bruker Vector 22 with Harrick ATR
SplitPeaTM device; neat (ATR); in cmÀ1. NMR: Bruker
1
DPX-400; H at 400 and 13C at 100 MHz; in CDCl3;
chemical shifts (d) in ppm downfield from TMS; cou-
pling constants J in Hz; NOESY, and GRASP COSY-
DQF, HMBC and HMQC data were used in signal
attributions. MS and GC/MS: Finnigan MAT 212 and
Hewlett Packard MSD 5973 (EI, 70 eV) with HP-5MS
column; intensities (in brackets) in % rel. to the base
peak. HRMS: Finnigan MAT 95 (EI, 70 eV). Elemental
analyses (C, H): Carlo Erba EA 1108; the results are within
0.4% of theoretical values. Molecular modelling: on SGI
Octane R12000 workstation using CatalystTM (generation
of conformational models and olfactophore hypotheses)30
and Moloc35 (surfaces) software. Conformational model
generation (‘best’ mode, ÁE=10 kcal/mol) were repeated
till no new conformers were added. The best hypothesis
was generated with spacing=100 pm, and variable
weight and tolerance.
2-Cyclohexylhepta-1,6-dien-3-one (8a). 15a (85 g, 0.44
mol) was oxidised with MnO2 (804 g, 9.2mol) in hexane
(2L) at room temperature. After stirring for 96 h, the
reaction mixture was filtered over Celite1 and the sol-
vent was evaporated in vacuo. Distillation (70 ꢁC/
0.04 torr) of the crude product (71 g) yielded 8a (43.5 g,
51%). 1H NMR: d 5.95 (s, 1H), 5.83 (ddt, J=17.1, 10.4,
6.5, 1H), 5.65 (d, J=1.1, 1H), 5.04 (dq, J=17.1, 1.7,
1H), 4.97 (ddt, J=10.4, 1.7, 1.3, 1H), 2.77 (m, 2H), 2.57
(ttd, 11.9, 3.1, 1.0, 1H), 2.36 (dtt, 8.0, 6.5, 1.5, 2H),
1.80–1.65 (m, 5H), 1.41–1.28 (m, 2H), 1.24–1.01 (m, 3H).
13C NMR: d 201.3 (s), 154.3 (s), 137.3 (d), 121.2 (t), 115.0
(t), 37.5 (d), 37.2 (t), 32.6 (2t), 28.4 (t), 26.5 (2t), 26.2 (t).
MS: 192(M +, 11), 177(4), 163(50), 149(29), 137(78),
121(9), 109(65), 95(22), 81(34), 77(12), 67(100), 55(61),
41(29). IR: nmax 2926vs, 2852s, 1681vs, 1641w, 1449m,
1414w, 997w, 913m. Anal. calcd for C13H20O: C, 81.20;
H, 10.48. Found: C, 81.15; H, 10.48%.
General procedure for the synthesis of hepta-1,6-dien-3-
ones 8
The following hepta-1,6-dien-3-ones 8 were prepared
according to the general procedure A. Most of the acro-
leins 14 were obtained by the Mannich methylenation
Method A; via acroleins 14. 2-Cyclohexylpropenal (14a).
Successively, sulphuric acid 62% (79 g, 0.5 mol), aqu-

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2939
described for 14a. The acroleins 14c+m, 14i+p, and
14o were prepared via acrylonitriles 13. Their syntheses,
as well as those of 3-monosubstituted acroleins 14b and
14s, intermediates in the preparation of 8b and 8s, are
exemplified below. The unstable 14q, difficult to purify,
was prepared and used as a crude mixture with the
intermediate 2-cyclohexyl-3-hydroxy-3-methylbutanal
(vide infra).
(M+, 4), 191(6), 178(16), 177(44), 151(45), 149(33),
123(23), 110(18), 109(17), 107(14), 105(10), 95(35),
93(21), 81(100), 79(24), 67(42), 55(64), 41(28). 8l (1st
1
eluted): H NMR: d 5.95 (s, 1H), 5.83 (ddt, J=17.1,
10.2, 6.5, 1H), 5.65 (d, J=1.3, 1H), 5.03 (dq, J=17.1,
1.6, 1H), 4.97 (ddt, J=10.2, 1.7, 1.3, 1H), 2.77 (m, 2H),
2.60 (ttd, J=10.4, 3.7, 1.1, 1H), 2.36 (m, 2H), 1.88 (m,
1H), 1.72(m, H2 ), 1.51–1.33 (m, 4H), 1.14–0.99 (m,
2H), 0.96 (d, J=7.2, 3H). 13C NMR: d 201.7 (s), 154.2
(s), 137.4 (d), 121.2 (t), 115.0 (t), 37.2 (t), 37.0 (d), 35.1
(2t), 28.3 (t), 27.5 (d), 26.6 (2t), 18.1 (q). MS: 206 (M+,
7), 192(11), 191(7), 178(19), 177(50), 151(41), 149(35),
133(45), 123(20), 110(27), 109(27), 107(20), 105(24),
95(48), 93(45), 91(25), 81(100), 79(31), 67(46), 55(82),
41(35). IR (8d+8l): nmax 2922vs, 2850s, 1681vs, 1641m,
1448s, 1377m, 997m, 912s. Anal. calcd for C14H22O: C,
81.50; H, 10.75. Found: C, 81.46; H, 10.68%.
(E)-3-Cyclohexylocta-2,7-dien-4-one (8b). Contained
1
10% of the (Z)-isomer. H NMR: d 6.49 (q, J=7.1,
1H), 5.82(ddt, J=17.1, 10.3, 6.5, 1H), 5.02(dq,
J=17.1, 1.7, 1H), 4.96 (ddt, J=10.3, 1.8, 1.2, 1H), 2.68
(m, 2H), 2.54 (tt, J=12.0, 3.4, 1H), 2.32 (dtt, J=7.8,
6.5, 1.3, 2H), 1.87 (d, J=7.1, 3H), 1.84–1.61 (m, 5H),
1.48–1.10 (m, 5H). 13C NMR: d 202.3 (s), 147.3 (s),
137.6 (d), 135.2(d), 114.8 (t), 38.2(d), 38.0 (t), 30.2(2t),
28.7 (t), 27.1 (2t), 26.0 (t), 14.2 (q). MS: 206 (M+, 10),
191(15), 177(16), 164(9), 151(100), 123(19), 109(8),
95(12), 81(80), 79(18), 67(43), 55(49), 41(20). IR: nmax
2926vs, 2853s, 1672s, 1641w, 1450m, 1267w, 993w,
911m. HRMS: calcd for C14H22O: 206.1671. Found:
206.1672.
2-Cyclopentylhepta-1,6-dien-3-one (8e). 1H NMR: d 5.95
(s, 1H), 5.83 (ddt, J=17.1, 10.3, 6.5, 1H), 5.70 (d,
J=1.5, 1H), 5.04 (dq, J=17.1, 1.7, 1H), 4.95 (ddt,
J=10.2, 1.8, 1.3, 1H), 2.93 (m, 1H), 2.79 (m, 2H), 2.37
(m, 2H), 1.91–1.82 (m, 2H), 1.74–1.55 (m, 4H), 1.35–
1.24 (m, 2H). 13C NMR: d 201.6 (s), 152.7 (s), 137.3 (d),
120.7 (t), 115.0 (t), 40.0 (d), 37.3 (t), 31.9 (2t), 28.4 (t),
24.8 (2t). MS: 178 (M+, 1), 163(2), 149(18), 137(5),
123(43), 110(8), 95(100), 83(9), 79(15), 67(73), 55(61),
41(23). IR: nmax 2953vs, 2869s, 1681vs, 1641m, 1414m,
997m, 913s. Anal. calcd for C12H18O: C, 80.85; H,
10.18. Found: C, 81.03; H, 10.21%.
cis- and trans-2-(2-Methylcyclopentyl)hepta-1,6-dien-3-
one (8c+8m). 14:9 mixture, separated on DBTM-5 col-
1
umn. 8c (2nd eluted): H NMR: d 6.07 (s, 1H), 5.84
(ddt, J=17.2, 10.5, 6.4, 1H), 5.66 (d, J=1.5, 1H), 5.05
(dq, J=17.2, 1.8, 1H), 4.98 (ddt, J=10.2, 1.6, 1.3, 1H),
3.05 (m, 1H), 2.78 (m, 2H), 2.37 (m, 2H), 2.30 (m, 1H),
1.92(m, 1H), 1.77–1.51 (m, 4H), 1.29 (m, 1H), 0.54 (d,
J=7.2, 3H). 13C NMR: d 201.6 (s), 150.0 (s), 137.4 (d),
122.8 (t), 115.0 (t), 43.6 (d), 37.1 (t), 34.6 (d), 33.4 (t),
28.5 (t), 27.7 (t), 22.7 (t), 16.8 (q). MS: 192 (M+, 10),
177(14), 164(20), 163(56), 151(20), 149(27), 137(93),
135(15), 121(15), 110(22), 109(100), 107(22), 95(26),
81(52), 79(23), 67(96), 55(96), 53(31), 41(42), 39(27).
HRMS: calcd for C13H20O: 192.1514. Found: 192.1525.
2-Benzylhepta-1,6-dien-3-one (8g). 1H NMR: d 7.28–
7.10 (m, 5H), 6.03 (s, 1H), 5.78 (ddt, J=17.1, 10.2, 6.6,
1H), 5.58 (t, J=1.4, 1H), 4.99 dq (J=17.1, 1.6, 1H),
4.94 (ddt, J=10.2, 1.8, 1.3, 1H), 3.58 (s, 2H), 2.74 (m,
2H), 2.32 (dtt, J=7.8, 6.4, 2.9, 2H). 13C NMR: d 200.3
(s), 148.2 (s), 139.0 (s), 137.2 (d), 129.0 (2d), 128.3 (2d),
126.1 (d), 125.1 (t), 115.1 (t), 37.0 (t), 36.9 (t), 28.2 (t).
MS: 200 (M+, 10), 199(12), 172(58), 171(22), 159(25),
145(39), 129(19), 117(100), 116(27), 115(73), 91(47),
65(12), 55(18), 38(12). IR: nmax 3028m, 2920m, 1679vs,
1641m, 1494m, 1433m, 1076m, 915s, 744m. HRMS:
calcd for C14H16O: 200.1201. Found: 200.1198.
1
8m (1st eluted): H NMR: d 6.00 (s, 1H), 5.84 (ddt,
J=17.2, 10.5, 6.9, 1H), 5.70 (d, J=1.0, 1H), 5.04 (dq,
J=17.2, 1.6, 1H), 4.98 (ddt, J=10.2, 1.6, 1.3, 1H), 2.82
(m, 2H), 2.49 (m, 1H), 2.37 (m, 2H), 2.02–1.84 (m, 3H),
1.63 (m, 2H), 1.36–1.19 (m, 2H), 0.91 (d, J=6.3, 3H).
13C NMR: d 201.8 (s), 151.9 (s), 137.4 (d), 121.6 (t),
115.0 (t), 47.6 (d), 39.8 (d), 37.4 (t), 34.4 (t), 33.5 (t), 28.5
(t), 23.4 (t), 18.6 (q). MS: 192 (M+, 12), 177(19), 164(32),
163(84), 151(23), 150(31), 149(27), 137(87), 135(19),
123(13), 121(17), 119(34), 110(23), 109(80), 107(25),
95(39), 93(27), 81(53), 79(29), 67(100), 55(96), 53(33),
43(31), 41(49). HRMS: calcd for C13H20O: 192.1514.
Found: 192.1515. IR (8c+8m): nmax 2954vs, 2870s,
1681vs, 1641m, 1450m, 1413m, 1376m, 997m, 913s.
(ꢂ)-2-[(10R*,3aR*,6aR*)-Octahydropentalen-1-yl]hepta-
1
1,6-dien-3-one (8h). H NMR: d 5.93 (s, 1H), 5.85 (ddt,
J=17.1, 10.4, 6.4, 1H), 5.67 (dt, J=5.6, 2.0, 1H), 5.62
(s, 1H), 5.43 (dt, J=5.6, 2.2, 1H), 5.05 (dq, J=17.1, 1.6,
1H), 4.98 (d, J=10.2, 1H), 3.51 (m, 1H), 3.16 (m, 1H),
2.80 (m, 2H), 2.39 (m, 2H), 2.19 (m, 1H), 1.76 (m, 1H),
1.68–1.55 (m, 2H), 1.53–1.39 (m, 3H). 13C NMR: d
201.0 (s), 152.9 (s), 137.3 (d), 136.6 (d), 130.9 (d), 121.8
(t), 114.9 (t), 53.3 (d), 49.7 (d), 49.5 (d), 37.1 (t), 35.0 (t),
31.5 (t), 28.3 (t), 24.9 (t). MS: 216 (M+, 3), 201(7),
188(61), 187(100), 175(19), 161(74), 133(24), 131(19),
117(18), 105(53), 91(76), 79(41), 77(30), 65(17), 55(40),
41(17). IR: nmax 3044w, 2946vs, 2863s, 1680vs, 1641m,
1446m, 996m, 912s. Anal. calcd for C15H20O: C, 83.29;
H, 9.32. Found: C, 83.18; H, 9.28%.
trans- and cis-2-(4-Methylcyclohexyl)hepta-1,6-dien-3-
one (8d+8l). 25:22 mixture separated on DBTM-1 col-
1
umn. 8d (2nd eluted): H NMR: d 5.96 (s, 1H), 5.83
(ddt, J=17.1, 10.2, 6.5, 1H), 5.69 (d, J=1.3, 1H), 5.03
(dq, J=17.1, 1.6, 1H), 4.97 (ddt, J=10.2, 1.7, 1.3, 1H),
2.77 (m, 2H), 2.52 (ttd, J=11.6, 3.0, 1.0, 1H), 2.36 (m,
2H), 1.72–1.55 (m, 4H), 1.49–1.27 (m, 3H), 1.17–0.99
(m, 2H), 0.89 (d, J=6.6, 3H). 13C NMR: d 201.4 (s),
154.3 (s), 137.4 (d), 121.3 (t), 115.0 (t), 37.3 (t), 37.1 (d),
32.4 (d), 32.3 (2t), 31.6 (2t), 28.3 (t), 22.4 (q). MS: 206
cis- and trans-2-(2-Methylcyclohexyl)hepta-1,6-dien-3-
one (8i+8p). 62:37 mixture, separated on DBTM-5 col-
umn. 8i (2nd eluted): 1H NMR: d 6.01 (s, 1H), 5.83 (ddt,

2940
J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
J=17.1, 10.2, 6.6, 1H), 5.51 (d, J=1.3, 1H), 5.04 (dq,
J=17.1, 1.7, 1H), 4.97 (ddt, J=10.2, 1.8, 1.4, 1H), 2.86
(dtd, J=12.9, 3.5, 0.9, 1H), 2.86–2.68 (m, 2H), 2.40–
2.33 (m, 2H), 1.94 (m, 1H), 1.81–1.24 (m, 8H), 0.69 (d,
J=7.3, 3H). 13C NMR: d 201.5 (s), 152.6 (s), 137.3 (d),
122.2 (t), 114.9 (t), 40.2 (d), 37.3 (t), 32.7 (t), 29.7 (d),
28.3 (t), 26.6 (t), 24.2 (t), 20.1 (t), 12.2 (q). MS: 206
(M+, 32), 191(15), 178(15), 177(42), 165(27), 164(33),
151(71), 149(41), 133(17), 123(39), 109(29), 95(45),
83(41), 81(100), 79(28), 67(51), 55(86), 53(26), 41(40).
HRMS: calcd for C14H22O: 206.1671. Found: 206.1659.
8p (1st eluted): 1H NMR: d 6.05 (s, 1H), 5.84 (ddt,
J=17.1, 10.2, 6.6, 1H), 5.69 (s, 1H), 5.04 (dq, J=17.1,
1.7, 1H), 4.97 (ddt, J=10.2, 1.8, 1.4, 1H), 2.86–2.68 (m,
2H), 2.40–2.33 (m, 2H), 2.31 (td, J=11.4, 3.2, 1H),
1.81–0.98 (m, 9H), 0.71 (d, J=6.4, 3H). 13C NMR: d
201.2 (s), 153.3 (s), 137.3 (d), 122.6 (t), 114.9 (t), 44.3
(d), 37.0 (t), 36.9 (d), 35.5 (t), 34.3 (t), 28.4 (t), 26.6 (t),
26.4 (t), 20.1 (q). MS: 206 (M+, 44), 191(16), 178(17),
177(45), 165(29), 164(37), 163(21), 151(76), 149(45),
133(40), 123(38), 109(33), 107(26), 105(26), 95(51),
93(36), 81(95), 79(33), 67(54), 55(100), 53(30), 41(50).
HRMS: calcd for C14H22O: 206.1671. Found: 206.1681.
IR (8i+8p): nmax 2925vs, 2853s, 1681vs, 1641m, 1446m,
1414w, 1047m, 913m.
1414m, 998m, 913s. HRMS: calcd for C10H16O:
152.1201. Found: 152.1191.
1
2-Cyclooctylhepta-1,6-dien-3-one (8o). H NMR: d 5.97
(s, 1H), 5.83 (ddt, J=17.1, 10.3, 6.5, 1H), 5.67 (d,
J=1.0, 1H), 5.05 (dq, J=17.1, 1.7, 1H), 4.97 (ddt,
J=10.2, 1.8, 1.2, 1H), 2.86 (m, 1H), 2.77 (m, 2H), 2.36
(m, 2H), 1.73–1.39 (m, 14H). 13C NMR: d 201.2 (s),
155.8 (s), 137.4 (d), 121.5 (t), 114.9 (t), 37.2 (t), 36.9 (d),
32.0 (2t), 28.4 (t), 26.7 (2t), 26.2 (t), 25.6 (2t). MS: 220
(M+, 4), 205(2), 191(30), 179(19), 177(14), 149(28),
137(15), 135(17), 123(21), 121(24), 109(32), 110(22),
95(94), 81(79), 67(54), 55(100), 41(47). IR: nmax 2920vs,
2851s, 1680vs, 1641m, 1446m, 1045w, 996m, 912m.
Anal. calcd for C15H24O: C, 81.76; H, 10.98. Found: C,
81.78; H, 11.05%.
3-Cyclohexyl-2-methylocta-2,7-dien-4-one
(8q).
1H
NMR d 5.86 (ddt, J=17.0, 10.4, 6.6, 1H), 5.07 (dq,
J=17.0, 1.6, 1H), 4.99 (ddt, J=10.4, 1.8, 1.3, 1H), 2.59
(m, 2H), 2.44–2.33 (m, 3H), 1.80–1.72 (m, 2H), 1.71–
1.62(m, 3H), 1.70 (s, 3H), 1.60 (s, 3H), 1.33–1.06 (m,
5H). 13C NMR: d 210.8 (s), 142.8 (s), 137.5 (d), 127.4
(s), 115.1 (t), 44.8 (t), 39.4 (d), 31.6 (2t), 27.3 (t), 26.7
(2t), 25.9 (t), 22.0 (q), 19.2 (q). MS: 220 (M+, 5), 205(7),
191(8), 166(12), 165(100), 137(8), 109(12), 95(25),
81(35), 69(52), 55(32), 41(21). IR: nmax 2925vs, 2853s,
1712s, 1694s, 1642w, 1449s, 1377m, 1202m, 996m, 911s.
C15H24O: 220.1827. Found: 220.1827.
1
6-Methyleneundec-1-en-5-one (8j). H NMR: d 5.98 (s,
1H), 5.83 (ddt, J=17.1, 10.4, 6.6, 1H), 5.71 (s, 1H), 5.03
(dq, J=17.1, 1.7, 1H), 4.97 (ddt, J=10.4, 1.8, 1.3, 1H),
2.78 (m, 2H), 2.36 (dtt, J=7.8, 6.6, 1.4, 2H), 2.26 (m,
2H), 1.45–1.23 (m, 6H), 0.88 (t, 3H). 13C NMR: d 200.8
(s), 148.9 (s), 137.2(d), 123.2(t), 114.8 (t), 36.7 (t), 31.4
(t), 30.7 (t), 28.2 (t), 28.0 (t), 22.3 (t), 13.8 (q). MS: 180
(M+, 1), 165(2), 151(7), 125(26), 123(20), 109(12),
95(20), 81(14), 69(46), 67(11), 55(100), 43(13), 41(25),
39(15). IR: nmax 2957vs, 2928vs, 2859s, 1680vs, 1641m,
1437m, 1368w, 997m, 913s. Anal. calcd for C12H20O: C,
79.94; H, 11.18. Found: C, 79.74; H, 11.20%.
(E)-6-Cyclohexylnona-1,6-dien-5-one (8s). Contained
1
5% of the (Z)-isomer. H NMR d 6.35 (t, J=7.3, 1H),
5.83 (ddt, J=17.1, 10.2, 6.5, 1H), 5.03 (dq, J=17.1, 1.7,
1H), 4.96 (ddt, J=10.2, 1.8, 1.2, 1H), 2.70 (m, 2H), 2.51
(tt, J=12.1, 3.4, 1H), 2.32 (m, 2H), 2.28 (q, J=7.5, 2H),
1.83–1.62(m, 5H), 1.44 (m, 2H), 1.33–1.18 (m, 3H), 1.07
(t, J=7.5, 3H). 13C NMR: d 202.3 (s), 145.6 (s), 142.3
(d), 137.5 (d), 114.7 (t), 38.4 (d), 37.9 (t), 30.5 (2t), 28.6
(t), 26.9 (2t), 25.8 (t), 21.6 (t), 13.6 (q). MS: 220 (M+,
10), 191(43), 177(9), 165(100), 149(5), 137(11), 123(7),
109(12), 95(86), 81(72), 79(23), 67(34), 55(63), 41(26).
IR: nmax 2927vs, 2852s, 1672s, 1641w, 1450m, 911m.
HRMS: calcd for C15H24O: 220.1827. Found: 220.1816.
1
2-Cyclohexylmethylhepta-1,6-dien-3-one (8k). H NMR:
d 6.00 (s, 1H), 5.83 (ddt J=17.2, 10.3, 6.4, 1H), 5.67 (td,
J=1.0, 0.8, 1H), 5.04 (dq, J=17.2, 1.7, 1H), 4.98 (ddt,
J=10.2, 1.8, 1.3, 1H), 2.78 (m, 2H), 2.36 (dtt, J=7.8,
6.5, 1.4, 2H), 2.16 (dd, 7.0, 0.9, 2H), 1.72–1.55 (m, 5H),
1.35 (m, 1H), 1.25–1.06 (m, 3H), 0.91–0.79 (m, 2H). 13C
NMR: d 201.2 (s), 147.4 (s), 137.4 (d), 124.7 (t), 115.0 (t),
40.0 (t), 36.9 (t), 36.6 (d), 33.1 (2t), 28.4 (t), 26.4 (t), 26.2
(2t). MS: 206 (M+, 17), 191(3), 177(5), 165(20), 164(23),
151(26), 133(27), 123(46), 109(24), 95(47), 83(27), 81(43),
79(24), 69(33), 67(30), 55(100), 41(55). IR: nmax 2923vs,
2851s, 1680vs, 1641w, 1448m, 997w, 911m. HRMS: calcd
for C14H22O: 206.1671. Found: 206.1671.
2-Methyl-3-methyleneoct-7-en-4-one (8u). 1H NMR d
5.97 (s, 1H), 5.84 (ddt, J=17.1, 10.2, 6.6, 1H), 5.69 (d,
J=1.3, 1H), 5.04 (dq, J=17.1, 1.7, 1H), 4.97 (ddt,
J=10.2, 1.9, 1.3, 1H), 2.92 (spd, J=6.8, 1.0, 1H), 2.7
(m, 2H), 2.37 (dtt, J=8.0, 6.6, 1.4, 2H), 1.02 (d, J=6.8,
6H). 13C NMR: d 201.2(s), 155.2(s), 137.3 (d), 120.8
(t), 115.0 (t), 37.3 (t), 28.4 (t), 27.7 (d), 21.8 (2q). MS:
152(M +, 3), 137(34), 123(13), 109(14), 97(84), 83(13),
69(100), 55(62), 53(22), 43(12), 41(98), 39(32), 27(17).
IR: nmax 2963vs, 2873m, 1681vs, 1641s, 1464m, 1368s,
998m, 914s. Anal. calcd for C10H16O: C, 78.90; H,
10.59. Found: C, 78.73; H, 10.61%.
6-Methylenenon-1-en-5-one (8n). 1H NMR: d 5.99 (s,
1H), 5.83 (ddt, J=17.1, 10.2, 6.6, 1H), 5.72 (td, J=1.3,
0.5, 1H), 5.04 (dq, J=17.1, 1.7, 1H), 4.97 (ddt, J=10.2,
1.9, 1.3, 1H), 2.78 (m, 2H), 2.36 (dtt, J=7.8, 6.6, 1.4,
2H), 2.25 (m, 2H), 1.43 (sx, J=7.6, 2H), 0.91 (t, J=7.6,
3H). 13C NMR: d 200.9 (s), 148.6 (s), 137.2 (d), 123.4
(t), 114.8 (t), 36.7 (t), 32.8 (t), 28.2 (t), 21.4 (t), 13.6 (q).
MS: 152(M +, 7), 124(7), 123(40), 110(14), 97(100),
95(16), 81(9), 69(87), 67(12), 55(37), 41(81), 39(20). IR:
nmax 3080w, 2961vs, 2932s, 2873s, 1680vs, 1642s,
1
6-Methylenedodec-1-en-5-one (8v). H NMR d 5.98 (s,
1H), 5.83 (ddt, J=17.1, 10.2, 6.6, 1H), 5.71 (s, 1H), 5.03
(dq, J=17.1, 1.7, 1H), 4.97 (ddt, J=10.2, 1.8, 1.3, 1H),
2.78 (m, 2H), 2.36 (dtt, J=7.8, 6.4, 1.4, 2H), 2.26 (m,
2H), 1.44–1.20 (m, 8H), 0.88 (t, J=7.0, 3H). 13C NMR:
d 200.8 (s), 149.0 (s), 137.2 (d), 123.2 (t), 114.8 (t), 36.8

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2941
(t), 31.5 (t), 30.7 (t), 28.8 (t), 28.3 (t), 28.2 (t), 22.4 (t),
13.8 (q). MS: 194 (M+, 1), 179(2), 165(4), 151(8),
139(21), 123(24), 110(12), 109(19), 95(25), 83(11),
81(14), 69(100), 67(17), 55(66), 43(18), 41(34), 29(13).
IR: nmax 2956vs, 2927vs, 2857s, 1680vs, 1641m, 1437m,
1114w, 997m, 913s. Anal. calcd for C13H22O: C, 80.35;
H, 11.41. Found: C, 80.53; H, 11.25%.
37.3 (t), 31.2 (s), 30.0 (3q), 29.6 (d), 28.4 (t), 23.9 (q).
MS: 208 (M+, 1), 193(20), 179(7), 153(41), 151(32),
137(64), 123(40), 109(40), 97(25), 95(30), 83(50), 69(48),
67(26), 57(100), 55(87), 43(28), 41(47). IR: nmax 2956vs,
2906s, 2869s, 1679vs, 1642m, 1476m, 1364s, 927m, 913s.
Anal. calcd for C14H24O: C, 80.71; H, 11.61. Found: C,
80.69; H, 11.59%.
1
8,8-Dimethyl-6-methylenenon-1-en-5-one (8w). H NMR
(E)-2-Cyclohexylbut-2-enal (14b). A mixture of [(2-
cyclohexylethenyl)oxy)]trimethylsilane38 (19.8 g, 0.1 mol)
and acetaldehyde (4.4 g, 0.1 mol) was added slowly at
À70 ꢁC to a solution of titanium (IV) chloride (11 mL,
0.1 mol) and titanium (IV) isopropoxide (0.59 mL,
0.02mol) in CH 2Cl2 (50 mL). After stirring for 1 h at
À70 ꢁC the reaction was quenched with saturated
NH4Cl soln and extracted with Et2O (2 Â 100 mL). The
combined organic layers were washed with water to
neutral pH, dried (MgSO4) and concentrated in vacuo.
The crude aldol was dehydrated by distillation (120 ꢁC/
0.1 torr) in the presence of I2 (0.2g) using a 5 cm Wid-
mer column to give 14b39 that contained ꢃ12% of its
d 6.05 (d, J=0.5, 1H), 5.84 (ddt, J=17.1, 10.4, 6.6, 1H),
5.66 (m, 1H), 5.05 (dq, J=17.1, 1.7, 1H), 4.98 (ddt,
J=10.3, 1.8, 1.3, 1H), 2.80 (m, 2H), 2.37 (m, 2H), 2.28
(d, J=0.6, 2H), 0.83 (s, 9H). ). 13C NMR: d 201.3 (s),
147.1 (s), 137.3 (d), 125.8 (t), 114.9 (t), 43.1 (t), 36.8 (t),
31.1 (s), 29.2 (3q), 28.3 (t). MS: 180 (M+, 2), 165(9),
125(16); 124(20), 109(23), 96(26), 95(68), 81(16), 68(17),
57(100), 55(25), 41(31). IR: nmax 2953s, 2867w, 1682vs,
1642w, 1476w, 1365s, 1154m, 997m, 912s. HRMS: calcd
for C12H20O: 180.1514. Found: 180.1506.
(10R/S=2:1) - cis - 2 - (2,2,3 - Trimethylcyclopentyl)hepta -
1,6-dien-3-one (8x). Contained 10% of the trans-isomer.
1H NMR d 6.13 (s, 1H), 5.84 (ddt, J=17.1, 10.4, 6.4,
1H), 5.67 (d, J=0.6, 1H), 5.05 (dq, J=17.1, 1.7, 1H),
4.98 (ddt, J=10.2, 1.8, 1.3, 1H), 3.09 (dd, J=11.8, 8.6,
1H), 2.88 (dt, J=16.9, 7.5, 1H), 2.75 (dt, J=16.9, 7.5,
1H), 2.38 (m, 2H), 1.84 (m, 1H), 1.77–1.56 (m, 3H), 1.27
(m, 1H), 0.85 (d, J=6.7, 3H), 0.72(s, 3H), 0.48 (s, 3H).
13C NMR: d 202.2 (s), 149.2 (s), 137.4 (d), 123.6 (t),
115.1 (t), 48.3 (d), 45.3 (d), 43.2(s), 37.5 (t), 29.7 (t),
28.5 (t), 27.0 (t), 26.2 (q), 15.2 (q), 14.4 (q). MS: 220
(M+, 6), 205(16), 177(19), 165(39), 163(33), 149(26),
137(47), 121(30), 109(49), 107(29), 95(64), 84(42),
83(40), 81(77), 79(32), 69(89), 55(100), 53(39), 41(54).
IR: nmax 2958vs, 2871s, 1683vs, 1641w, 1468m, 1368m,
1208w, 997m, 912s. Anal. calcd for C15H24O: C, 81.76;
H, 10.98. Found: C, 81.94; H, 10.78%.
1
(Z)-isomer (7.7 g, 50%). H NMR: d 9.31 (d, J=1.5,
1H), 6.46 (q, J=7.2, 1H), 2.54 (ttd, J=12.1, 3.5, 1.5,
1H), 2.01 (d, J=7.2, 3H), 1.88–1.61 (m, 5H), 1.49–1.41
(m, 2H), 1.39–1.02 (m, 3H). 13C NMR: d 195.6 (d),
150.3 (d), 148.2 (s), 36.4 (d), 29.7 (2t), 26.8 (2t), 25.9 (t),
15.0 (q). MS: 152(M +, 72), 137(29), 134(14), 123(100),
119(24), 109(43), 105(25), 95(57), 91(37), 84(21), 81(68),
79(45), 77(24), 69(31), 67(72), 55(48), 41(50). IR: nmax
2927vs, 2853s, 2704w, 1689vs, 1634m, 1450m, 1213m,
1008w, 892m, 831m.
cis-
and
trans-2-(2-Methylcyclopentyl)acrylonitrile
(13c+13m). The methodology of Stetter and Kuhl-
mann40 for preparation of a-alkylacrylates was adapted.
KOH (16.3 g, 0.29 mol) in EtOH (200 mL) was added at
room temperature during 1 h to a solution of ethyl
cyano(2-methylcyclopentyl)acetate (56.5 g, 0.29 mol),
obtained as a 34:32:20:13 diast. rac. mixture according
to Herz,41 in EtOH (200 mL). The reaction mixture was
stirred at room temperature for 18 h, concentrated at
70 ꢁC/75 torr and dissolved in water (250 mL). Concd
HCl (250 mL) was added dropwise at 10 ꢁC under vig-
orous stirring and the mixture was extracted with
MTBE (500 mL). The organic layer was dried (MgSO4),
concentrated in vacuo and reacted with paraformalde-
hyde (7.2g), pyridine (46 mL) and piperidine (2.5 g,
29 mmol) at 130 ꢁC for 3 h. After cooling, the reaction
mixture was poured into ice/water, and extracted with
MTBE (2 Â 200 mL). The combined organic layers were
dried (MgSO4), concentrated in vacuo and distilled
using a 5 cm Vigreux column (31 ꢁC/0.08 torr) to give a
3:2mixture of 13c+13m (22.5 g, 58%). 13c: 1H NMR: d
5.90 (t, J=0.9, 1H), 5.68 (dd, J=1.3, 0.6, 1H), 2.69 (m,
1H), 2.28 (m, 1H, 1.90–1.79 (m, 3H), 1.75 (m, 1H), 1.60
(m, 1H), 1.24 (m, 1H), 0.89 (d, J=7.1, 3H). 13C NMR: d
130.0 (t), 125.3 (s), 119.2 (s), 47.9 (d), 37.1 (d), 33.2 (t),
27.9 (t), 23.0 (t), 15.6 (q). MS: 135 (M+, 15), 134(21),
120(20), 107(20), 106(27), 93(16), 80(100), 66(15),
56(94), 55(16), 53(20), 41(45), 39(25). HRMS: calcd for
(R/S=2:1) -2-(2,2,3-Trimethylcyclopent-3-enyl)hepta-
1
1,6-dien-3-one (8y). H NMR d 6.12(s, 1H), 5.85 (ddt,
J=17.1, 10.2, 6.6, 1H), 5.78 (d, J=0.8, 1H), 5.29 (m,
1H), 5.05 (dq, J=17.1, 1.7, 1H), 4.99 (ddt, J=10.2, 1.8,
1.4, 1H), 3.39 (td, J=8.1, 0.9, 1H), 2.87 (dt, J=16.9,
7.5, 1H), 2.78 (ddd, J=16.9, 7.8, 6.8, 1H), 2.39 (m, 2H),
2.37–2.20 (m, 2H), 1.59 (m, 3H), 1.00 (s, 3H), 0.67 (s,
3H). 13C NMR: d 202.0 (s), 150.2 (s), 147.1 (s), 137.4
(d), 123.6 (t), 121.4 (d), 115.1 (t), 48.1 (s), 47.9 (d), 37.3
(t), 34.9 (t), 28.5 (t), 26.6 (q), 21.5 (q), 12.8 (q). MS: 218
(M+, 20), 203(44), 177(26), 163(21), 161(65), 147(27),
135(38), 133(26), 121(35), 119(70), 109(31), 108(52),
107(48), 105(97), 93(77), 91(68), 79(43), 77(44), 55(100),
41(39). IR: nmax 3038w, 2957vs, 2932s, 2853m, 1682vs,
1641m, 1437m, 1361m, 997m, 913s. Anal. calcd for
C15H22O: C, 82.52; H, 10.16. Found: C, 82.67; H,
10.18%.
7,9,9-Trimethyl-6-methylenedec-1-en-5-one (8z). 1H
NMR d 6.00 (s, 1H), 5.84 (ddt, J=17.2, 10.2, 6.6, 1H),
5.75 (d, J=0.8, 1H), 5.04 (dq, J=17.2, 1.6, 1H), 4.98
(ddt, 10.2, 1.8, 1.3, 1H), 2.94 (m, 1H), 2.78 (m, 2H), 2.37
(m, 2H), 1.49 (dd, J=14.0, 6.7, 1H), 1.25 (dd, J=14.0,
5.2, 1H), 1.03 (d, J=7.0, 3H), 0.86 (s, 9H). 13C NMR: d
200.9 (s), 156.2 (s), 137.4 (d), 122.3 (t), 115.0 (t), 50.5 (t),
1
C9H13N: 135.1048. Found: 135.1039. 13m: H NMR: d
5.81 (d, J=0.9, 1H), 5.71 (t, J=0.7, 1H), 2.08 (m, 1H),
1.99–1.79 (m, 3H), 1.76–1.63 (m, 3H), 1.24 (m, 1H), 0.98

2942
J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
(d, J=6.4, 3H). 13C NMR: d 129.5 (t), 126.9 (s), 117.8
(s), 53.1 (d), 39.7 (d), 34.1 (t), 31.7 (t), 23.3 (t), 18.0 (q).
MS: 135 (M+, 13), 134(16), 120(21), 107(20), 106(19),
93(17), 80(100), 66(17), 56(94), 53(19), 41(41), 39(24).
HRMS: calcd for C9H13N: 135.1048. Found: 135.1036.
IR (13c+13m): nmax 2959vs, 2873s, 2221w, 1618w,
1458m, 1405w, 1379w, 936m.
107(22), 97(30), 95(37), 93(37), 91(36), 83(70), 81(36),
79(57), 67(66), 55(100), 43(31), 41(10), 39(25). IR: nmax
3359s, 3077w, 2952vs, 2869s, 1641m, 1451m, 1059m,
904s. Anal. calcd for C12H20O: C, 79.94; H, 11.18.
Found: C, 79.96; H, 11.10%.
General procedure for the synthesis of hepta-1,6-dien-3-
ones 8
cis-
and
trans-2-(2-Methylcyclopentyl)propenal
(14c+14m). 1 M solution of DIBAH in hexane
(200 mL, 0.2 mol) was added dropwise to 13c (13.5 g,
0.1 mol) in toluene (200 mL) at À73 ꢁC. The reaction
mixture was stirred for 1 h at the same temperature,
poured into ice-cold 5% H2SO4 (300 mL) and extracted
with MTBE (300 mL). The extract was dried (MgSO4)
and the solvents evaporated under reduced pressure to
give a 3:2mixture of 14c+14m (7.1 g, 51%) as yellowish
oil used in the next step without further purification.
Method B; via cyanohydrins 11. 2-Cycloheptyl-3-hydro-
xypropionitrile (11f). A solution of crude ethyl cyanocy-
cloheptylacetate42 (47.5 g, 0.23 mol), prepared in a
similar way as the starting material in the synthesis of
13c, in EtOH (200 mL) was added dropwise during 1 h
into a suspension of NaBH4 (7.44 g, 0.20 mol) in the
same solvent (50 mL) at 0 ꢁC and stirring continued for
18 h at room temperature. The reaction mixture was
concentrated in vacuo, diluted with MTBE (300 mL),
washed successively with ice/water (300 mL), 1 N HCl
(200 mL) and brine (2 Â 300 mL) and dried (MgSO4).
Evaporation of solvents under reduced pressure gave
11f (34.8 g, 91%) used in the next step without further
purification. 1H NMR d 3.85 (dd, J=10.9, 7.6, 1H),
3.78 (dd, J=10.9, 5.7, 1H), 2.71 (dt, J=7.6, 5.7, 1H),
2.14 (m broad, 1H), 1.91–1.66 (m, 5H), 1.65–1.37 (m,
8H). ). 13C NMR: d 120.4 (s), 61.3 (t), 42.3 (d), 37.9 (d),
33.1 (t), 31.0 (t), 27.9 (t), 27.8 (t), 26.3 (t), 26.2 (t). MS:
166 ([MÀH]+, 0.2), 148(2), 136(6), 122(5), 108(23),
97(92), 94(19), 81(20), 80(29), 67(17), 55(100), 41(25).
IR: nmax 3442s, 2926vs, 2856s, 2241w, 1461m, 1052m.
HRMS: [MÀH]+ calcd for C10H16NO: 166.1232.
Found: 166.1202.
1
14c: H NMR: d 9.55 (s, 1H), 6.20 (s, 1H), 6.07 (s, 1H),
2.95 (m, 1H), 2.37 (m, 1H), 1.90 (m, 1H), 1.80–1.51 (m,
4H), 1.30 (m, 1H), 0.57 (d, J=7.1, 3H). 13C NMR: d
195.1 (d), 151.6 (s), 134.0 (t), 41.5 (d), 34.7 (d), 33.3 (t),
27.5 (t), 22.6 (t), 16.4 (q). MS: 138 (M+, 29), 123(27),
110(17), 109(100), 95(74), 83(32), 81(50), 79(29), 67(70),
55(38), 53(32), 41(60), 39(42). HRMS: calcd for
1
C9H14O: 138.1045. Found: 138.1036. 14m: H NMR: d
9.56 (s, 1H), 6.25 (s, 1H), 5.99 (s, 1H), 2.41 (m, 1H),
2.05–1.83 (m, 3H), 1.74–1.62 (m, 2H), 1.42 (m, 1H), 1.27
(m, 1H), 0.92(d, J=6.2, 3H). 13C NMR: d 195.1 (d),
153.4 (s), 132.9 (t), 45.6 (d), 39.6 (d), 34.4 (t), 32.9 (t),
23.6 (t), 18.6 (q). MS: 138 (M+, 35), 123(42), 110(18),
109(100), 105(19), 95(58), 83(25), 81(47), 79(27), 67(73),
55(33), 53(28), 41(52), 39(38). HRMS: calcd for
C9H14O: 138.1045. Found: 138.1031. IR (14c+14m):
nmax 2955vs, 2870s, 2696w, 1695vs, 1624w, 1456m,
1377w, 1245w, 940m.
2-Cycloheptyl-3-trimethylsilyloxypropionitrile (12f). First
triethylamine (24.35 g, 0.24 mol), then chlorotrimethyl-
silane (26.2 g, 0.24 mol ) was added to a solution of 11f
(33.4 g, 0.20 mol) in THF (350 mL) at À5 to 0 ꢁC. After
additional 4 h stirring at room temperature, the pre-
cipitate was filtered off and the reaction mixture con-
centrated in vacuo, diluted with hexane (300 mL) and
washed successively with 1 N HCl, (100 mL), aqueous
sodium bicarbonate solution (100 mL) and brine (2 Â
200 mL) and dried (MgSO4). After evaporation of sol-
vents under reduced pressure, pure 12f (47.1 g, 98%)
2-Cyclohexyl-3-methylbut-2-enal (14q). Ethyl cyclohexyl-
acetate (25.5 g, 0.15 mol) in abs THF (25 mL) and
HMPA (50 mL) was added to a 1.6 M THF solution of
LDA (92mL, 0.15 mol) at À65 ꢁC. After 20 min of stir-
ring, acetone (8.7 g, 0.15 mol) in THF (10 mL) was
added and stirring continued for additional 4 h at
À65 ꢁC, and overnight in the ice/NaCl bath. The
reaction mixture was poured into ice-cold 2N HCl,
extracted (Et2O) dried (MgSO4) and concentrated in
vacuo. The crude ethyl 2-cyclohexyl-3-hydroxy-3-
methylbutyrate was distilled, reduced with LAH and
oxidised (MnO2) as usual to give a crude mixture of 14q
(unstable) and 2-cyclohexyl-3-hydroxy-3-methylbutanal
used without purification in the next step.
1
was obtained. H NMR d 3.76 (dd, J=10.1, 7.3, 1H),
3.70 (dd, J=10.1, 6.4, 1H), 2.65 (ddd, J=7.2, 6.3, 4.8,
1H), 1.89–1.67 (m, 5H), 1.65–1.39 (m, 8H), 0.14 (s, 9H).
13C NMR: d 120.4 (s), 61.1 (t), 42.2 (d), 37.6 (d), 33.3
(t), 30.5 (t), 28.0 (t), 27.8 (t), 26.5 (t), 26.2 (t), À0.6 (3q).
MS: 239 (M+, 0.04), 225(16), 224(100), 209(19),
194(16), 152(8), 121(9), 103(29), 101(12), 75(16), 73(44),
55(13). IR: nmax 2927vs, 2857s, 2240w, 1461m, 1252s,
1112s, 874s, 844vs, 751m. HRMS: [MÀCH3]+ calcd for
C12H22NSiO: 224.1471. Found: 224.1463.
2-Cyclopentylhepta-1,6-dien-3-ol (15e). Prepared in a
similar manner as 15a starting from cyclopentylace-
taldehyde: 1H NMR d 5.85 (ddt, J=17.1, 10.4, 6.6, 1H),
5.05 (ddt, J=17.1, 2.0, 1.6, 1H), 5.03 (t, J=1.0, 1H),
4.98 (ddt, J=10.3, 2.0, 1.1, 1H), 4.93 (t, J=1.0, 1H),
4.13 (dd, J=7.6, 4.8, 1H), 2.38 (ttd, J=9.7, 7.3, 0.8,
1H), 2.25–2.06 (m, 2H), 1.91–1.81 (m, 2H), 1.77–1.51
(m, 7H), 1.49–1.28 (m, 2H). 13C NMR: d 156.4 (s), 138.5
(d), 114.8 (t), 107.4 (t), 74.6 (d), 42.2 (d), 35.1 (t), 33.2
(t), 32.9 (t), 30.1 (t), 25.0 (2t). MS: 179 ([MÀH]+, 0.5),
162(5), 151(8), 133(10), 126(13), 125(21), 111(38),
2-Cycloheptylhepta-1,6-dien-3-one (8f). 4-Bromobut-1-
ene (36.5 g, 0.27 mol) in toluene (200 mL) was added to
magnesium turnings (6.0 g, 0.25 mol) suspended in
gently refluxing Et2O (35 mL). After additional 1 h stir-
ring at 70 ꢁC, a solution of 12f (38.3 g, 0.16 mol) in tol-
uene (160 mL) was slowly added at the same
temperature and stirring continued for 20 h at 75–80 ꢁC.
After cooling down to room temperature, concd HCl

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2943
(50 mL) was added dropwise and the reaction mixture
was concentrated (280 mL of liquids were distilled off
through a short Vigreux column), stirred at 110 ꢁC for
3 h, cooled down to room temperature, poured onto ice
(250 g) and extracted with MTBE (2 Â 250 mL). The
combined organic phases were washed successively with
2N HCl (200 mL), saturated sodium bicarbonate solu-
tion (200 mL) and brine (2 Â 200 mL), dried (MgSO4)
and concentrated in vacuo. The crude product was
flash-distilled and the resulting brown liquid (15.8 g)
was fractionated using a 5 cm Vigreux column (88–
90 ꢁC/0.07 torr) to give 8f (9.3 g, 28%). 1H NMR: d 5.95
(s, 1H), 5.84 (ddt, J=17.0, 10.2, 6.6, 1H), 5.68 (d,
J=1.0, 1H), 5.04 (dq, J=17.0, 1.7, 1H), 4.98 (ddt,
J=10.2, 1.7. 1.4, 1H), 2.77 (m, 3H), 2.36 (dtt, J=7.8,
6.5, 1.4, 2H), 1.77–1.41 (m, 10H), 1.40–1.28 (m, 2H).
13C NMR: d 201.3 (s), 155.8 (s), 137.4 (d), 121.3 (t),
115.0 (t), 39.3 (d), 37.2 (t), 34.7 (2t), 28.5 (t), 27.8 (2t),
26.9 (2t). MS: 206 (M+, 3), 191(2), 177(26), 165(9),
151(37), 149(22), 121(13), 109(21), 95(29), 81(100),
79(28), 69(20), 67(56), 55(97), 53(31), 41(52), 39(27). IR:
nmax 2924vs, 2855vs, 1680vs, 1641m, 1460m, 1445m,
997m, 912m. Anal. calcd for C14H22O: C, 81.50; H,
10.75. Found: C, 81.70; H, 10.80%.
37.4 (d), 32.4 (2t), 26.6 (t), 26.4 (2t), 26.1 (t), 22.2 (t),
13.7 (q). MS: 194 (M+, 19), 152(10), 151(19), 137(100),
112(12), 109(64), 85(11), 81(19), 79(12), 67(82), 57(20),
55(22), 41(39), 29(19). IR: nmax 2927vs, 2853s, 1680s,
1449m, 1032w, 930m. HRMS: calcd for C13H22O:
194.1671. Found: 194.1660.
2-Cyclohexylhept-6-en-3-one (21). Prepared following
the method A of the general procedure for the synthesis
of hepta-1,6-dien-3-ones 8 starting from 2-cyclohexyl-
propanal (19) obtained by catalytic (Pd/C) hydrogena-
tion of 14a according to Marshall et al.43 1H NMR d
5.81 (ddt, J=17.1, 10.2, 6.6, 1H), 5.03 (dq, J=17.1, 1.7,
1H), 4.96 (ddt, J=10.2, 1.8, 1.3, 1H), 2.52 (m, 2H),
2.39–2.27 (m, 3H), 1.77–1.51 (m, 6H), 1.30–1.09 (m,
3H), 1.08–0.96 (m, 1H), 1.00 (d, J=7.0, 3H), 0.96–0.85
(m, 1H). 13C NMR: d 213.8 (s), 137.2 (d), 114.8 (t), 51.9
(d), 41.1 (t), 39.9 (d), 31.6 (t), 29.1 (t), 27.4 (t) 26.2 (t), 26.1
(2t), 13.0 (q). MS: 194 (M+, 1), 151(1), 139(9), 113(11),
112(100), 111(67), 97(20), 83(36), 70(15), 69(81), 56(16),
55(82), 41(26). IR: nmax 2925vs, 2852vs, 1711vs, 1641m,
1449s, 1373m, 996m, 911m. Anal. calcd for C13H22O: C,
80.35; H, 11.41. Found: C, 80.42; H, 11.43%.
(10R/S=2:1)-1-(2,2,3-Trimethylcyclopent-3-enyl)cyclo-
propanecarbaldehyde (22a). DMSO (700 mL) was added
dropwise during 50 min to the mixture of tri-
methylsulfoxonium iodide (132.0 g, 0.6 mol) and sodium
hydride (14.5 g, 0.6 mol) at 10–15 ꢁC. After 2h of addi-
tional stirring at room temperature the hydrogen evo-
lution ceased and 2,2,3-trimethyl-a-methylene-3-
cyclopentene-1-acetaldehyde44 (14y, 100.0 g, 0.6 mol),
prepared in a similar manner as 14a starting from a-
campholenal (9y; R/S=1:2), in DMSO (150 mL) was
cis- and trans-2-(3-Methylcyclohexyl)hepta-1,6-dien-3-
one (8r+8t). Prepared according to the general proce-
dure, method B; 2:3 mixture, separated on DBTM-1 col-
umn. 8r (1st eluted): 1H NMR: d 5.96 (s, 1H), 5.83 (ddt,
J=17.0, 10.4, 6.5, 1H), 5.65 (d, J=1.1, 1H), 5.03 (dq,
J=17.0, 1.7, 1H), 4.97 (ddt, J=10.4, 1.8, 1.3, 1H), 2.77
(m, 2H), 2.61 (tt, J=11.9, 2.6, 1H), 2.36 (m, 2H), 1.80–
1.61 (m, 4H), 1.49 (m, 1H), 1.39 (m, 1H), 1.14 (m, 1H),
0.88 (d, J=6.6, 3H), 0.84 (m, 1H), 0.74 (q, J=12.1, 1H).
13C NMR: d 201.5 (s), 154.3 (s), 137.3 (d), 121.2 (t),
115.0 (t), 41.2 (t), 37.3 (d), 37.3 (t), 34.9 (t), 32.8 (d), 32.0
(t), 28.4 (t), 26.3 (t), 22.7 (q). MS: 206 (M+, 4), 191(6),
178(11), 177(29), 163(16), 151(47), 123(20), 110(21),
109(15), 95(33), 81(100), 79(22), 67(42), 55(61), 41(28).
ꢁ
added during 2h at 8–10 C. The reaction mixture was
poured into a mixture of ice/water and extracted with
MTBE (1 L). The extract was washed with brine (3 Â
500 mL), dried (MgSO4), concentrated in vacuo and
distilled using a Vigreux column (76–79 ꢁC/0.2torr) to
give 22a (62g, 58%). 1H NMR d 9.52(s, 1H), 5.26 (m,
1H), 2.41–2.31 (m, 1H), 2.24–2.15 (m, 1H), 2.11 (dd,
J=8.5, 7.8, 1H), 1.61 (m, 3H), 1.21 (m, 1H), 1.18 (m,
1H), 1.10 (s, 3H), 0.95 (s, 3H), 0.93–0.89 (m, 2H). 13C
NMR: d 203.3 (d), 148.1 (s), 121.1 (d), 51.2 (d), 48.7 (s),
33.2 (t), 32.3 (s), 28.3 (q), 22.4 (q), 15.2 (t), 14.6 (t), 12.4
(q). MS: 178 (M+, 71), 163(100), 149(23), 145(26),
135(67), 121(79), 119(78), 108(41), 107(63), 105(39),
95(47), 93(75), 91(69), 81(28), 79(50), 77(40), 55(37),
41(59), 39(32). IR: nmax 3038w, 2958vs, 2932s, 2868m,
1713vs, 1465m, 1361m, 1023w, 896w, 800w. HRMS:
calcd for C12H18O: 178.1358. Found: 206.1362.
1
8t (2nd eluted): H NMR: d 5.97 (s, 1H), 5.83 (ddt,
J=17.0, 10.4, 6.5, 1H), 5.66 (d, J=1.2, 1H), 5.03 (dq,
J=17.0, 1.7, 1H), 4.97 (ddt, J=10.4, 1.8, 1.3, 1H), 2.88
(tt, J=10.5, 3.4, 1H), 2.77 (m, 2H), 2.36 (m, 2H), 1.98
(m, 1H), 1.72–1.31 (m, 7H), 1.02 (d, J=7.2, 3H), 1.00
(m, 1H). 13C NMR: d 201.7 (s), 154.3 (s), 137.3 (d),
121.3 (t), 115.0 (t), 37.9 (t), 37.4 (t), 32.1 (t), 32.0 (t),
31.5 (d), 28.4 (t), 27.8 (d), 21.0 (t), 18.5 (q). MS: 206
(M+, 5), 191(13), 178(22), 177(60), 163(40), 151(39),
149(21), 133(31), 123(27), 110(21), 109(35), 107(28),
105(28), 95(69), 93(61), 91(29), 81(100), 79(39), 67(51),
55(98), 41(45). IR (8r+8t): nmax 2923vs, 2850s, 1681vs,
1641m, 1458m, 1446m, 997m, 913s. Anal. calcd for
C14H22O: C, 81.50; H, 10.75. Found: C, 81.40; H,
10.74%.
(10R/S=2:1)-1-[1-(2,2,3-Trimethylcyclopent-3-enyl)cy-
clopropyl]pent-4-en-1-one (24a). Prepared according to
the method A of the general procedure for the synthesis
1
2-Cyclohexylhept-1-en-3-one (18). Prepared according to
the method A of the general procedure for the synthesis
of hepta-1,6-dien-3-ones 8, using bromobutane instead
of hepta-1,6-dien-3-ones 8 starting from 22a. H NMR:
d 5.80 (ddt, J=17.1, 10.2, 6.6, 1H), 5.18 (m, 1H), 5.03
(dq, J=17.1, 1.7, 1H), 4.96 (ddt, J=10.2, 1.9, 1.3, 1H),
2.89 (t, J=8.8, 1H), 2.55–2.41 (m, 2H), 2.38–2.24 (m,
2H), 2.10 (m, 1H), 1.76 (m, 1H), 1.57 (dt, J=2.3, 1.7,
3H), 1.41 (ddd, J=9.8, 6.6, 5.4, 1H), 1.05 (s, 3H), 0.88
(ddd, J=9.0, 6.4, 5.4, 1H), 0.85 (s, 3H), 0.73 (ddd,
J=9.0, 6.4, 4.7, 1H), 0.62(ddd, J=9.8, 6.6, 4.7, 1H).
1
of 4-bromobut-1-ene. H NMR d 5.94 (s, 1H), 5.62(d,
J=1.1, 1H), 2.66 (t, J=7.5, 2H), 2.57 (ttd, J=11.9, 3.1,
0.8, 1H), 1.80–1.65 (m, 5H), 1.59 (m, 2H), 1.41–1.28 (m,
4H), 1.24–1.13 (m, 1H), 1.07 (m, 2H), 0.92 (t, J=7.3,
3H). 13C NMR: d 202.2 (s), 154.4 (s), 120.7 (t), 37.7 (t),

2944
J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
13C NMR: d 209.5 (s), 148.1 (s), 137.5 (d), 120.5 (d),
115.1 (t), 49.0 (s), 48.8 (d), 37.0 (t), 32.1 (s), 31.5 (t), 28.4
(t), 28.0 (q), 21.9 (q), 12.5 (q), 12.3 (t), 9.4 (t). MS: 232
(M+, 30), 217(51), 191(72), 177(23), 161(19), 149(23),
135(37), 134(21), 133(34), 121(47), 119(53), 109(38),
108(99), 107(48), 105(44), 93(66), 91(67), 83(36), 81(36),
79(45), 77(40), 67(23), 55(100), 41(43). IR: nmax 2958vs,
2866m, 1693vs, 1641m, 1465m, 1362s, 1179m, 1074m,
994m, 913s, 800m. Anal. calcd for C16H24O: C, 82.70;
H, 10.41. Found: C, 82.69; H, 10.42%.
nitrogen at 0 ꢁC to a mixture of KOH (47.5 g, 0.85 mol),
K2CO3 (6.5 g, 0.047 mol) and CuCl (4.4 g, 0.044 mol) in
MeOH (300 mL) and the reaction mixture was stirred
for additional 0.5 h at 0 ꢁC. Allyl bromide (102g,
0.85 mol) was added slowly over a period of 25 min and
stirring continued overnight at room temperature. After
quenching with NH4Cl and concentration in vacuo the
reaction mixture was taken up in NH4Cl (500 mL) and
extracted with MTBE (2 Â 400 mL). The combined
organic phases were washed with NH4Cl (500 mL), H2O
(2 Â 500 mL), saturated NaCl (500 L), dried (MgSO4)
and the solvent evaporated in vacuo. A solution of thus
obtained crude 2-(pent-4-en-1-yn-1-yl)decahydro-naph-
thalen-2-ol (27a, 120 g, 0.55 mol) in 80% aqueous
HCOOH (200 mL) was heated at 90ꢁ for 16 h, cooled
down to rt, neutralised with saturated Na2CO3 and
extracted with MTBE (2 Â 400 mL). The combined
organic phases were washed with NaHCO3 (2 Â
400 mL), H2O (2 Â 400 mL), dried (MgSO4) and con-
centrated in vacuo. The residue was distilled using a
Vigreux column (145–146 ꢁC/0.1 torr) to give a mixture
of five isomers (22+8+15+13+42%) of 1-(1, 4, 4a, 5,
6, 7, 8, 8a-octahydronaphthalen-2-yl)pent-4-ene-1-one
and 1-(3, 4, 4a, 5, 6, 7, 8, 8a-octahydronaphthalen-2-
yl)pent-4-ene-1-one (54.2g, 44%). The main isomer, cis-
1-(1,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)pent-4-
ene-1-one (7a) was isolated by sequential preparative
GLC using a multicapillary MC-1 (Alltech) and a
1-(1-Cyclohexylcyclopropyl)pent-4-en-1-one (24b). Pre-
1
pared in a similar manner as 24a starting from 14a. H
NMR d 5.79 (m, 1H), 5.01 (m, 1H), 4.95 (m, 1H), 2.30
(m, 4H), 1.85 (tt, J=11.9, 3.3, 1H), 1.77–1.61 (m, 3H),
1.59–1.51 (m, 2H), 1.33–0.95 (m, 7H), 0.83–0.76 (m,
2H). 13C NMR: d 209.8 (s), 137.5 (d), 115.0 (t), 38.1 (d),
36.4 (s), 36.1 (t), 29.9 (2t), 28.4 (t), 26.6 (2t), 26.3 (t),
11.8 (2t). MS: 206 (M+, 6), 177(22), 163(21), 151(100),
123(23), 109(18), 95(18), 83(21), 81(82), 79(23), 67(49),
55(84), 41(42). 39(22). IR: nmax 3078w, 2926vs, 2852s,
1721m, 1687vs, 1641w, 1450m, 1358m, 1068m, 996m,
910m. HRMS: calcd for C14H22O: 206.1671. Found:
206.1667.
General procedure for the synthesis of 1-cycloalk-
enylpent-4-en-1-ones 7 and 28
1
2-Ethynyldecahydronaphthalen-2-ol (26a). Acetylene was
t
DBTM-5 column. H NMR: d 6.85 (m, 1H), 5.84 (ddt,
bubbled for 4 h through a solution of BuOK (95.8 g,
J=17.1, 10.2, 6.6, 1H), 5.04 (dq, J=17.1, 1.6, 1H), 4.97
(ddt, J=10.2, 1.8, 1.2, 1H), 2.74 (m, 2H), 2.36 (m, 2H),
2.29 (m, 1H), 2.25–2.13 (m, 3H), 1.91–1.79 (m, 2H),
1.63–1.50 (m, 2H), 1.46–1.30 (m, 6H). 13C NMR: d
200.7 (s), 138.3 (d), 137.7 (d), 137.2 (s), 114.8 (t), 36.2
(t), 32.4 (d), 32.3 (d), 30.1 (t), 28.9 (t), 28.6 (t), 28.5 (t),
26.0 (t), 23.6 (t), 22.9 (t). MS: 218 (M+, 8), 177(2),
163(100), 145(4), 135(11), 107(12), 93(24), 91(16),
79(21), 67(21), 55(20), 41(11). HRMS: calcd for
C15H22O: 218.1671. Found: 218.1668. IR (isomer mix-
ture): nmax 2923vs, 2853s, 2704w, 1711w, 1668vs, 1640s,
1447m, 1185m, 910m.
0.85 mol) in THF (1 L) at 0 ꢁC. 2-Decalone (100 g,
0,66 mol, 4:1 cis/trans mixture) was added slowly at
room temperature and the reaction mixture was stirred
for additional 3.5 h, quenched with saturated NH4Cl
(500 mL) and extracted with MTBE (2 Â 700 mL). The
combined organic layers were washed with NH4Cl
(0.5 L), H2O (2 Â 500 mL) and saturated NaCl
(500 mL), dried (MgSO4) and concentrated in vacuo.
The residue was flash distilled (88–90 ꢁC/0.01 torr) to
1
give 26a (101 g, 86%) as a 17:8 cis/trans mixture. H
NMR cis-isomer: d 2.49 (s, 1H), 2.25 (bs, 1H), 2.04 (m,
1H), 1.88 (t, J=12.5, 1H), 1.83–1.48 (m, 11H), 1.46–
1.20 (m, 3H); trans-isomer: d 2.49 (s, 1H), 2.25 (bs, 1H),
2.01 (m, 1H), 1.89 (m, 1H), 1.68–1.48 (m, 4H), 1.39–1.16
(m, 7H), 1.05–0.80 (m, 3H). 13C NMR cis: d 87.5 (s),
72.5 (d), 70.2 (s), 39.6 (t), 35.4 (t), 34.9 (d), 33.6 (d), 31.6
(t), 29.3 (t), 26.5 (t), 25.6 (t), 21.1 (t); trans: d 87.7 (s),
72.5 (d), 69.4 (s), 47.1 (t), 42.4 (d), 40.2 (d), 40.0 (t), 33.3
(t), 33.0 (t), 31.1 (t), 26.5 (t), 26.2 (t). MS cis: 178 (M+,
0.4), 177(0.8), 163(6), 160(6), 152(16), 149(43), 145(16),
131(21), 121(38), 110(42), 108(44), 97(51), 95(65),
82(46), 81(88), 79(49), 67(79), 55(100), 53(59), 41(69),
39(50); trans: 178 (M+, 0.9), 177(1), 163(8), 160(5),
152(15), 149(46), 145(10), 135(28), 121(69), 110(62),
108(45), 97(48), 95(72), 82(77), 81(92), 79(51), 67(849),
55(100), 53(63), 41(73), 39(51). IR cis/trans mixture:
nmax 3380m, 3307s, 2922vs, 2856s, 1446m, 1276w,
1055m, 1030m, 1007w, 948w. Anal. calcd for C12H18O:
C, 80.85; H, 10.18. Found: C, 80.47; H, 10.32%.
The following 1-cycloalkenylpent-4-en-1-ones 28 were
prepared according to this general procedure.
(ꢂ)-1-(5-tert-Butylcyclohex-1-enyl)pent-4-en-1-one (28a)
and (ꢂ)1-(3-tert-Butylcyclohex-1-enyl)pent-4-en-1-one
(28b). 7:3 mixture separated on DBTM-1 column. 28a
(2nd eluted): 1H NMR d 6.91 (m, 1H), 5.84 (ddt,
J=17.1, 10.2, 6.6, 1H), 5.04 (dq, J=17.1, 1.6, 1H), 4.97
(ddt, J=10.2, 1.8, 1.3, 1H), 2.74 (m, 2H), 2.49 (m, 1H),
2.43–2.32 (m, 3H), 2.29–2.16 (m, 1H), 1.89–1.74 (m,
2H), 1.27–1.02 (m, 2H), 0.90 (s, 9H). 13C NMR: d 200.7
(s), 139.6 (s), 139.5 (d), 137.7 (d), 114.9 (t), 43.8 (d), 36.3
(t), 32.2 (s), 28.7 (t), 27.5 (t), 27.2 (3q), 24.8 (t), 23.0 (t).
MS: 220 (M+, 13), 205(6), 166(11), 165(100), 163(13),
109(15), 107(13), 95(18), 81(22), 79(11), 57(27), 55(14),
41(13). HRMS: calcd for C15H24O: 220.1827. Found:
220.1818. 28b (1st eluted): 1H NMR d 6.90 (m, 1H), 5.85
(ddt, J=17.1, 10.2, 6.6, 1H), 5.04 (dq, J=17.1, 1.6, 1H),
4.97 (ddt, J=10.2, 1.8, 1.3, 1H), 2.75 (m, 2H), 2.44–2.33
(m, 3H), 2.07 (m, 1H), 2.03–1.92 (m, 3H), 1.39 (m, 1H),
1.27–1.15 (m, 1H), 0.95 (s, 9H). 13C NMR: d 200.7 (s),
(ꢂ)-cis-1-(1, 4, 4a, 5, 6, 7, 8, 8a-Octahydronaphthalen-
2-yl)pent-4-ene-1-one (7a). A solution of 26a (101 g,
0.56 mol) in i-PrOH (300 mL) was added slowly under

J. A. Bajgrowicz et al. / Bioorg. Med. Chem. 11 (2003) 2931–2946
2945
141.5 (d), 140.0 (s), 137.7 (d), 115.0 (t), 47.0 (d), 36.3 (t),
33.3 (s), 28.7 (t), 27.5 (3q), 23.6 (t), 23.3 (t), 22.2 (t). MS:
220 (M+, 2), 205(2), 165(14), 164(100), 123(33), 108(49),
95(14), 79(13), 57(39), 41(15). HRMS: calcd for
C15H24O: 220.1827. Found: 220.1842. IR (28a+28b):
IR: nmax 2958vs, 2866s, 1670vs, 1642m, 1365m, 1240m,
1194m, 911m.
5. Called substantivity by perfumers and fragrance chemists.
6. Gimelbrant, A. A.; Haley, S. L.; McClintock, T. S. J. Biol.
Chem. 2000, 1, 1.
7. An eminent exception is constituted by the I7 rat olfactory
receptor (specific for C7À10 aliphatic aldehydes) assay, albeit it
is far from being straightforward and its meaningfulness to
humans has not been proven: Araneda, R. C.; Kini, A. D.;
Firestein, S. Nat. Neurosci. 2000, 3, 1248.
8. These approaches, based on slight structural changes of a
known lead (‘me-too’) or combining structural features of dif-
ferent molecules having similar pharmacologoical effects
(‘mecano’) are probably still the most successful approaches in
bringing new medicins to the market.
9. Bauer, K.; Garbe, D.; Surburg, H. Common Fragrance and
Flavor Materials; Wiley-VCH: Weinheim (Ger.), 2001; p 196,
and references cited therein.
10. (a) Teisseire, P.; Corbier, B.; Plattier, M. Recherches
(Paris) 1967, 16, 5. (b) Naf, F.; Decorzant, R.; Thommen, W.;
Willhalm, B.; Ohloff, G. Helv. Chim. Acta 1975, 58, 1016.
11. Berger, R. G.; Drawert, F.; Kollmannsberger, H.; Nitz, S.
J. Food Sci. 1985, 50, 1655.
12. Muller, D. G.; Clayton, M. N.; Gassmann, G.; Boland,
W.; Marner, F.-J.; Schotten, T.; Jaenicke, L. Natur-
wissenschaften 1985, 72, 97 and references therein.
13. (a) Morris, A. F.; Naf, F.; Snowden, R. L. Perfumer Fla-
vorist 1991, 16, 33. (b) Schulte-Elte, K.-H.; Willhalm, B.;
Gautschi, F. US Patent 4147672, 1979 (priority 1974, to Fir-
menich); Chem. Abstr. 1979, 91, 19986.
14. Arctander, S. Perfume and Flavor Chemicals (Aroma
Chemicals); Allured: Carol Stream, IL, USA, 1994; Vol. 1,
No 77.
15. Bauer, K.; Garbe, D.; Surburg, H. Common Fragrance and
Flavor Materials; Wiley-VCH: Weinheim (Ger.), 2001; p 23.
16. Sprecker, M., A. US Patent 4735932, 1988 (priority 1987,
to IFF); Chem. Abstr. 1988, 109, 169913.
17. Bauer, K.; Garbe, D.; Surburg, H. Common Fragrance
and Flavor Materials; Wiley-VCH: Weinheim (Ger.), 2001;
p 93.
18. Bourdin, B.; Frater, G.; Bajgrowicz, J. A. Eur. Pat. Appl.
913383, 1999 (priority 1997, to Givaudan); Chem. Abstr. 1999,
130, 338271.
1
1-(4-tert-Butylcyclohex-1-enyl)pent-4-en-1-one (28c). H
NMR: d 6.91 (m, 1H), 5.83 (ddt, J=17.1, 10.3, 6.6, 1H),
5.03 (dq, J=17.1, 1.7, 1H), 4.96 (ddt, J=10.2 , 1.8, 1.3,
1H), 2.73 (m, 2H), 2.55 (m, 1H), 2.40–2.24 (m, 3H), 2.09–
1.87 (m, 3H), 1.32–1.22 (m, 1H), 1.08 (m, 1H), 0.89 (s, 9H).
13C NMR: d 200.0 (s), 139.9 (d), 138.9 (s), 137.5 (d), 114.7
(t), 43.3 (d), 36.1 (t), 31.9 (s), 28.4 (t), 27.6 (t), 26.9 (3q),
24.5 (t), 23.3 (t). MS: 220 (M+, 8), 205(3), 192(3), 166(13),
165(100), 163(9), 149(4), 137(5), 123(6), 121(6), 109(9),
107(14), 95(20), 83(10), 81(30), 79(18), 77(12), 57(42),
55(22), 41(17). IR: nmax 2960vs, 2869s, 1669vs, 1643s,
1365s, 1166m, 911m. Anal. calcd for C15H24O: C, 81.76;
H, 10.98. Found: C, 81.97; H, 10.80%.
1-Cyclooct-1-enylpent-4-en-1-one (28d). 1H NMR: d 6.88
(t, J=8.3, 1H), 5.84 (ddt, J=17.1, 10.2, 6.6, 1H), 5.03
(dq, J=17.1, 1.7, 1H), 4.96 (ddt, J=10.2, 1.9, 1.3, 1H),
2.76 (m, 2H), 2.45 (m, 2H), 2.35 (m, 4H), 1.63 (m, 2H),
1.56–1.38 (m, 6H). 13C NMR: d 200.0 (s), 142.4 (s),
142.0 (d), 137.4 (d), 114.7 (t), 36.0 (t), 29.0 (t), 28.9 (t),
28.7 (t), 27.3 (t), 26.4 (t), 25.9 (t), 23.4 (t). MS: 192 (M+,
16), 177(3), 163(4), 151(4), 137(100), 135(6), 121(5),
109(24), 95(8), 91(9), 81(20), 79(17), 77(9), 67(79),
55(38), 53(14), 41(19). IR: nmax 2925vs, 2852s, 1667vs,
1639s, 1465m, 1446m, 1090m, 908m. Anal. calcd for
C13H20O: C, 81.20; H, 10.48. Found: C, 81.17; H,
10.33%.
Acknowledgements
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We thank Ms. I. Frank, Mr. H.-J. Vogeli and Mr. U.
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