Enantioselectivity in odor perception: Synthesis and olfactory properties of iso-β-bisabolol, a new natural product

Article abstract of DOI:10.1002/hlca.200390219

The odorous trace constituent iso-β-bisabolol (4) was isolated from East Indian and Western Australian sandalwood oil and synthesized by using the (E/Z)-triene 12 (iso-γ-bisabolene) as a key intermediate. Only one of four stereoisomeric forms of 4, (6R,7R)-4a, is odor active, having a strong floral, muguet-like, very pleasant scent.

Full text of DOI:10.1002/hlca.200390219

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Helvetica Chimica Acta Vol. 86 (2003)
Enantioselectivity in Odor Perception: Synthesis and Olfactory Properties
of Iso-b-Bisabolol, a New Natural Product
by Norbert A. Braun*, Manfred Meier, Gerhard Schmaus, Bernd Hˆlscher, and Wilhelm Pickenhagen*
Symrise GmbH & Co. KG1), Research & Development, D-37603 Holzminden
(phone: ‡49-5531-90-3832, e-mail:norbert.braun@symrise.com; phone: ‡49-5531-90-3270,
e-mail:wilhelm.pickenhagen@symrise.com)
The odorous trace constituent iso-b-bisabolol (4) was isolated from East Indian and Western Australian
sandalwood oil and synthesized by using the (E/Z)-triene 12 (iso-g-bisabolene) as a key intermediate. Only one
of four stereoisomeric forms of 4, (6R,7R)-4a, is odor active, having a strong floral, muguet-like, very pleasant
scent.
Introduction. Odor perception is initiated by an interaction of a volatile stimulant
with a proteinaceous receptor [1]. Different diastereoisomers and enantiomers of the
same molecular structure can elicit different odor impressions, both qualitative and
quantitative [2]. In our continuous search for new natural trace constituents with high
odor impact, we analyzed sandalwood oils of East Indian as well as Western Australian
origin [3]. The oils are obtained from wood, trunk butt, or roots of Santalum album L.
and Santalum spicatum (R. Br.) A. DC. by different extraction and/or distillation
techniques [4].
Among a broad range of compounds, the odorless sesquiterpene alcohols a-
bisabolol (1) and b-bisabolol (2) were detected by GC-MS analysis in both Santalum
species [3a][3b]. The corresponding iso-a-bisabolol (3)2) and iso-b-bisabolol (4),
however, have, to the best of our knowledge, neither been found in nature nor
synthesized so far.
Here, we report the isolation, total synthesis, and olfactory properties of a new,
odor-active trace constituent of East Indian and Western Australian sandalwood oil
iso-b-bisabolol (4).
1
)
)
Former company name: DRAGOCO Gerberding & Co. AG.
2
Iso-a-bisabolol (3) was detected together with 1 in a distillate of Candeia oil (Vanillosmopsis erythropappa
Schultz-Bip.) by GC/MS in a ratio 1/3 99.2:0.8 (N. A. Braun, B. Kohlenberg, unpublished results from
our laboratory).

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Results and Discussion. Gas chromatographic (GC) olfactometry [5] of East
Indian and Western Australian sandalwood oil led to the detection of a trace
component (<0.001%) with a strong floral, muguet-like, very pleasant odor. The
compound, which turned out to be 4, was enriched up to 0.8% by fractional distillation,
followed by repeated column chromatography and preparative two-dimensional GC.
‡
‡
Its mass spectrum showed at m/z 222 and 204 the M and [M À H2O] signals,
respectively, very similar to that of b-bisabolol (2). Compound 4 was accompanied by
alcohol 2 during the entire isolation process and displayed similar retention indices
(RI) on two GC columns: DBWax (2:2160; 4:2134) and HP5 (2:1670; 4:1651). This
pointed to a sesquiterpene alcohol closely related to b-bisabolol (2).
During our investigations, we obtained a distillation fraction from the acid-
catalyzed cyclization of nerolidol (5) [6], having an odor that was very reminiscent of 4.
We could not only detect, but also isolate alcohol 4 from this mixture. The mass
spectrum and gas chromatogram (co-injection on two different GC-columns) strongly
suggested that this compound was, indeed, identical to the one isolated from East
Indian and Western Australian sandalwood oil.
The GC-FTIR spectrum of 4 showed a characteristic OH absorption band at
3629 cmÀ1, and two bands at 3079 and 1646 cmÀ1, respectively, pointing to an exocyclic
1
double bond. Also, the corresponding H- and the 13C-NMR spectra clearly indicated
the presence of the diastereomeric pairs 4a vs. 4b (Fig. 1).
Fig. 1. The four possible stereoisomers of iso-b-bisabolol (4; stereoid-type numbering). Dashed lines indicate
mirror planes of racemic couples.
1
The H- and 13C-NMR spectra of separated 4a and 4b were very similar. The
13C-NMR spectra of 4a and 4b respectively, showed a tertiary alcohol function (s at
72.2 ppm), one exo-CH2 group (109.7 (t) and 146.0 (s)), and a trisubstituted double
1
bond (118.4 (d), 133.9 (s)). The H-NMR spectra showed three down-field-shifted
olefinic H-atoms at 4.67 (m, 1 H, ˆCH2), 4.69 (m, 1 H, ˆCH2), and 5.30 (m, HÀC(3)),
and three Me groups, two located at the double bonds (1.69 (s) and 1.71 (s)), and one at
a secondary C-atom (4a:0.91 ( d); 4b:0.95 ( d)).
The structure of iso-b-bisabolol (4) was further corroborated by synthesis. Although
compound 4 was isolated from a fraction of the acid-catalyzed cyclization of nerolidol
(ˆ 3,7,11-trimethyl-dodeca-1,6,10-trien-3-ol; 5), it seemed more obvious from a
chemical point of view to use isonerolidol (6) [7] as a starting material. Cyclization
of alcohol 6 led, indeed, to the formation of iso-a-bisabolol (3) and iso-b-bisabolol (4)
in a ratio of 1/2 and 3/4 of 96 :4 each ( Scheme 1).

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Scheme 1. Acid-Catalyzed Cyclization of Nerolidol (5) and Isonerolidol (6)
a) HCOOH, hexane, 43% (1/2 and 3/4 96 :4).
Our results indicated that 4 was probably formed from impurities of isonerolidol (6)
present in commercially available nerolidol (5). However, we could not completely
rule out that 4 could also be formed directly from 5, either by isomerization or via an
unknown intermediate.
Unfortunately, the cyclization of isonerolidol (6) led to only trace amounts of iso-b-
bisabolol (4). We, thus, tried a Grignard-type coupling of cyclic ketone 7 [8] with bromo
compound 8 [9]. However, the reaction of 7 with the Mg reagent of 8 [10] or with the
corresponding lithiated compound [11] afforded 4 in very low yields only (Scheme 2).
Scheme 2. Synthesis of Iso-b-bisabolol (4) via Grignard-Type Reactions
a) Mg, Et2O, < 2%; b) Li, THF, 11%.
Next, we tested iso-g-bisabolene ((E/Z)-12) as a starting material for the synthesis
of 4 (Scheme 3). (E/Z)-12 was prepared via a two-step procedure:allyl rearrangement
of 1-isopropenyl-4-methylcyclohex-3-en-1-ol (9) [12] led to acetate 10 ((E/Z) 60 : 40),
which was coupled with the Cu reagent of 4-bromo-2-methylbut-1-ene (11) [13] to
yield (E/Z)-123) in 12% overall yield [14]. Alternatively, (E/Z)-12 was synthesized
analogously to the procedure of Faulkner and co-workers from acid 14 [15] and ketone
15 [16]. Aldol reaction of the dianion of 14 with ketone 15 led to b-hydroxy acid 16. The
best yield (76%) was obtained in a 4 :1 mixture of THF and TMEDA (ˆ N,N,N',N'-
tetramethylethane-1,2-diamine) [17]. Compound 16 was transformed to (E/Z)-12
(64% overall yield) via b-lactone 17, followed by thermal decarboxylation. The
configuration of 12 was determined as described by Negishi et al. for (E/Z)-g-
bisabolene [18].
3
)
A side product of this reaction is the SN1-type product 12* formed at temperatures ꢀ 08.

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Scheme 3. Synthesis of Iso-b-bisabolol (4) via (E/Z)-Triene 12. For abbreviations, see text.
a) Ac2O, AcONa, H2WO4, 25%; b) Mg, Li2[CuCl4], Et2O/THF, 48%; c) BuLi, THF/TMEDA, 76%; d) TsCl,
pyridine, CH2Cl2, 89%; e) D, 95%; f) MCPBA, CH2Cl2, 81%; g) LiALH4, THF, 22% (3), 70% (4), ratio: 4/3
76 :24.
Compound (E/Z)-12 was converted immediately after purification, due to its
sensitivity to polymerization, to the epoxide 13 by means of 3-chloroperbenzoic acid
(MCPBA). Reductive opening of the epoxide with LiAlH4 [19] gave iso-b-bisabolol
(4) together with iso-a-bisabolol (3) in a ratio of 76 :24 in good yield. Synthetic 4 was,
in all respects (1H- and 13C-NMR, GC/FTIR, and GC/MS), identical to the natural
product.
It is known that diastereoisomers and even enantiomers can have different
olfactory properties [2][20]. Having established the structure of 4, we used a chiral GC
column (2,3-di-O-acetyl-6-O-(tert-butyl)dimethylsilyl-b-cyclodextrin [3b][21]) to de-
termine the olfactory properties of 4a and 4b. The gas chromatogram of synthetic 4
showed three peaks in a ratio of 2 :1:1, the first corresponding to a strong floral,
muguet-like, very pleasant odor (the others were odorless; Fig. 2,a). Separation of the
diastereoisomers by HPLC showed that the first peak contained 4a and 4b, only the
former being odor-active (Fig. 2,b vs. 2,c).
The relative configurations of 4a and 4b at C(6) and C(7) were determined by
1H-NMR analogously to the stereochemical assignment of b-bisabolol (2):the Me
group (d) at C(7) had a chemical shift d of 0.91 ppm for (6S*,7S*)-2 and 0.95 ppm for
the corresponding diastereoisomeric (6R*,7S*)-2 [22]. Similar shifts were observed for

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Fig. 2. Gas chromatograms of synthetic and natural samples of 4. Odorous substances are marked with a plus
(‡), odorless ones with a minus (À). a) Synthetic probe (before HPLC separation); b) racemic 4a (after
HPLC); c) racemic 4b (after HPLC); d) natural probe from Santalum album L.
(6S*,7S*)-4a and (6S*,7R*)-4b:0.91 and 0.95 ppm, respectively. The odor-active
compound 4a showed a signal at 0.91 ppm, pointing to a (6S*,7S*) configuration. To
determine the absolute configuration of 4a, one could envisage several methods, e.g.,
enantioselective synthesis starting from (E)-12 and using enantioselective epoxidation
or separation of the racemic mixture of 4a by chiral HPLC [23], followed by
derivatization and X-ray diffractometry. However, all attempts were, so far, unsuc-
cessful. Therefore, we compared the retention times of racemic 4a on two chiral GC
columns (2,3-di-O-acetyl-6-O-(tert-butyl)dimethylsilyl-b-cyclodextrine and 2,3-di-O-
acetyl-6-O-(tert-butyl)dimethylsilyl-b-cyclodextrine, resp.) with those of the corre-
sponding racemic b-bisabolol (2a). The retention order of 2a was determined by using
enantiomerically pure b-bisabolol samples as references [3b][22]:(6 R,7R)-2a was
followed by (6S,7S)-2a. Assuming that the retention order is identical for iso-b-
bisabolol (4a), the odor-active enantiomer of 4a has the (6R,7R)-configuration.
One could envisage from a biogenetic point of view that b-bisabolol (2) could be
transformed into iso-b-bisabolol (4) with the help of a double-bond isomerase.
Although more iso-b-bisabolol (4) is present in S. spicatum, the odor impression is
weaker than in S. album, pointing to a higher concentration of the odor-active (6R,7R)-
isomer in S. album. This assumption is supported by the observation that only in S.
album the main isomer of 2 has (6R,7R)-configuration (see Fig. 2,d), while in S.
spicatum the (6R,7S)-isomer of 2 is dominant. Moreover, different ratios of the
corresponding b-bisabolol isomers 2 are present in both Santalum species:(6 R,7S)/
(6R,7R)/(6S,7R)/(6S,7S) 21:55 :19 :5 in S. album vs. 61:19 :5 :15 in S. spicatum,

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respectively [3a][3b]. It seems likely, that natural 4 from S. album and S. spicatum also
consists of all four possible stereoisomers.
Finally, the odor-detection threshold [24] of 4a in H2O (0.785 mg/l) and air
(0.081 mg/l) was measured. It seems noteworthy that some people in the test panels
showed an anosmia for alcohol 4a.
Conclusions. Iso-b-bisabolol (4) was isolated for the first time from Western
Australian and East Indian sandalwood oil and synthesized in five steps with an overall
yield of 36%. Of the four possible stereoisomer of 4, only the (6R,7R)-isomer 4a is
¾
odor active. This is in contrast to other powerful chiral odorants (e.g., Hedione [25],
(Z)-methyl jasmonate [26]), where at least two stereoisomeric forms are active [20a].
Apart from the steroid androstenone, a pig pheromone [27], iso-b-bisabolol (4) is, to
the best of our knowledge, the first rigorously diastereo- as well as enantiospecific
odorant, i.e., only one isomer elicits a strong odor, whereas the other three are odorless.
Stereoselective synthesis of alcohols 4a d will have to corroborate our results.
Moreover, the chiral fragrant 4 nicely confirms the enantioselectivity of odor
¬
perception put forward by Kraft and Frater [28].
Experimental Part
1. General. All reagents and solvents were commercial products (Fluka, Aldrich, or Lancaster) and used as
received. All reactions were performed under N2, monitored by TLC. East Indian sandalwood oil was purchased
from Frey & Lau GmbH (Henstedt, Germany) and Australian sandalwood oil from Mt. Romance Australia Pty.
Ltd. (Albany, Australia) [3a][3b]. Column chromatography (CC): Merck silica gel 60 (63 200 mm). HPLC:
Knauer HPLC-pump 64 (column: Eurospher 100 Si, 5 mm, 250  20 mm; flow rate:10 ml/min; detection: l ˆ
220 nm). Two-dimensional preparative GC: Hewlett-Packard 6890 with Gerstel trapping unit (I: DB-1, 15 m Â
0.53 mm  1.2 mm; II: DB-Wax: 27 m  0.53 mm  2 mm; 1208 2208 at 48/min; He]. Chiral GC: Hewlett-
Packard 6890 with FID and GC-sniffing-port (column: Ivadex-3 ˆ 2,3-di-O-acetyl-6-O-[(tert-butyl)dimethylsil-
yl]-b-cyclodextrine (30%) and PS 086 (70%):25 m  0.25 mm  0.15 mm; 80 1508 with 18/min, He). GC/FTIR:
Hewlett-Packard 5890B with Hewlett-Packard 5965B IR detector (DB-Wax column:60 m  0.32 mm  0.50 mm;
60 2408 at 48/min; He); n in cmÀ1. NMR: Varian VXR-300 (1H:300 MHz; 13C:75.45 MHz) or Varian Mercury
Plus AS-400 (1H-NMR:400 MHz; 13C-NMR:100.70 MHz), unless otherwise noted, in CDCl with TMS as
3
internal standard; chemical shift (d) in ppm, coupling constants (J) in Hz. GC-MS: Hewlett-Packard 5973N
(DB-Wax column:60 m  0.25 mm  0.25 mm; 60 2408 at 48/min; carrier gas:He), EI mode (70 eV); data in m/
z (%). LC-MS: Bruker Esquire-LCMS (injection with syringe pump; flow rate 240 ml/h), ESI mode (negative or
positive). HR-MS:EI mode (70 eV), Institut f¸r Organische Chemie, Georg-August-Universit‰t Gˆttingen.
2. Enrichment of Iso-b-bisabolol (4) from S. album and S. spicatum. East Indian sandalwood oil (2 kg) was
rectified via Sulzer distillation under reduced pressure [3a]. During the isolation process, fractions were
combined according to their composition as assessed by GC olfactometry; alternatively, alcohol 2 was used as a
GC marker substance. Alcohol 4 was enriched by repeated CC of a Sulzer fraction: a) SiO2, hexane/Et2O 100 :0
in 1%-steps to 85 :15; b) SiO2 containing 15% AgNO3 [29], hexane/Et2O 80 :20. Further separation was carried
out by two-dimensional preparative GC, leading to an enriched fraction of 4 (0.2%) used for GC-MS and a pure
fraction of b-bisabolol (2). The same procedure was used to enrich alcohol 4 (0.8%) from Australian
sandalwood oil (1.5 kg).
(1S/R)-1-[(1S/R)-1,5-Dimethylhex-4-enyl]-4-methylcyclohex-3-en-1-ol (ˆ b-Bisabolol; 2) [3b]. Colorless,
highly viscous oil, odorless. GC/RI:2160 ( DBWax), 1670 (HP5). 1H-NMR (300 MHz):0.91, 0.95 ( d, J ˆ 6.8,
MeÀC(1')); 1.06 (m, 1 H); 1.45 (m, 1 H); 1.55 1.63 (m, 3 H); 1.56 (s, Me(6')); 1.68 (s, MeÀC(4) and
MeÀC(5')); 1.76 (s, OH); 1.85 1.97 (m, 3 H); 2.04 2.24 (m, 3 H); 5.11 (m, HÀC(4')); 5.28 (m, HÀC(3)).
13C-NMR (75 MHz):13.4 (2 q, MeÀC(1')); 17.5 (q, MeÀC(6')); 23.1 (2q, C(4)); 25.5 (q, MeÀC(5')); 26.4, 26.5
(t, C(6)); 26.8, 26.9 (t, C(2')), 30.6, 30.7 (t, C(5)); 30.8 (2t, C(3')); 34.0, 34.6 (t, C(2)); 41.6, 41.9 (d, C(1')); 71.8,
71.9 (s, C(1)); 118.3 (d, C(3)); 124.6, 124.7 (d, C(4')); 131.0 (2s, C(5')); 133.6, 133.7 (s, C(4)). GC-MS:222 (1),

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207 (1), 204 (25), 189 (2), 161 (11), 154 (4), 140 (9), 139 (6), 126 (2), 121 (36), 119 (37), 111 (46), 107 (14), 93
(69), 83 (34), 82 (100), 72 (33), 69 (44), 67 (41), 57 (23), 55 (43), 43 (39), 41 (69).
(1S/R)-1-[(1S/R)-1,5-Dimethylhex-5-enyl]-4-methylcyclohex-3-en-1-ol (ˆ Iso-b-bisabolol; 4):GC/RI:2134
‡
(DBWax), 1651 (HP5). GC-MS:222 (4, M ), 207 (1), 204 (8), 189 (1), 161 (5), 154 (10), 153 (9), 140 (22), 139
(24), 126 (5), 121 (23), 119 (31), 111 (100), 93 (67), 83 (50), 82 (93), 72 (50), 69 (68), 55 (57), 43 (34), 41 (35).
3. Isolation of Iso-b-bisabolol (4) from a Distillation Fraction of the Acid Catalyzed Nerolidol Cyclization.
The isolation started from a forerun fraction (10 kg) of a production-scale distillation, which was rectified via
Sulzer distillation under reduced pressure. Fractions were combined according to their composition, as assessed
by GC olfactometry or GC. Alcohol 4 was further enriched from a Sulzer fraction by repeated CC as described
in Sect. 2 and purified by two-dimensional prep. GC. Colorless, highly viscous oil, 4a/4b 1:1. GC/FT-IR: 3629,
‡
3079, 2972, 2932, 1646, 1449, 1379, 889. GC-MS:222 (4, M ), 207 (1), 204 (8), 189 (1), 161 (5), 154 (10), 153 (9),
140 (22), 139 (24), 126 (5), 121 (23), 119 (31), 111 (100), 93 (67), 83 (50), 82 (93), 72 (50), 69 (68), 55(57), 43
(34), 41 (35). 1H-NMR (300 MHz):0.91, 0.95 ( d, J ˆ 6.9, MeÀC(1')); 1.02 (m, 1 H); 1.33 (m, 1 H); 1.36 (s, OH);
1.46 (m, 1 H); 1.53 1.65 (m, 4 H); 1.69 (s, MeÀC(4)); 1.71 (s, MeÀC(5')); 1.80 2.07 (m, 4 H); 2.12 2.24
(m, 2 H); 4.67, 4.69 (m, 1 H, CH2(6')); 5.30 (m, HÀC(3)). 13C-NMR (300 MHz):13.6, 13.7 ( q, MeÀC(1')); 22.3
(2q, MeÀC(5')); 23.2, 23.3 (q, MeÀC(4)); 26.2, 26.3 (t, C(6)); 27.0 (2t, C(2')); 30.3 (t, C(3')); 30.6, 30.9 (t, C(5));
34.2, 34.8 (t, C(2)); 38.0 (t, C(4')); 42.1, 42.4 (d, C(1')); 72.2 (2s, C(1)); 109.7 (2t, C(6')); 118.4 (2d, C(3)); 133.8,
133.9 (s, C(4)); 146.0 (2s, C(5')). HR-MS:222.1983 (C 15H26O).
4. Synthesis of 4 via Li-Grignard-Reaction of Ketone 7 and bromide 8. 4-Methylcyclohex-3-en-1-one (7) was
synthesized from terpinolene in three steps in 60% overall yield according to [8]. Colorless oil. 1H-NMR
(300 MHz):1.78 ( m, MeÀC(4)); 2.38 2.42 (m, CH2(5)); 2.47 2.52 (m, CH2(6)); 2.81 2.84 (m, CH2(2)); 5.44
(m, HÀC(3)). 13C-NMR (75 MHz):22.6 ( q, Me); 29.9 (t, C(5)); 38.0 (t, C(2)); 39.1 (t, C(2)); 117.8 (d, C(3));
134.2 (s, C(4)); 210.4 (s, C(1)).
6-Bromo-2-methyl-hept-1-ene (8) was prepared from ethyl 3-oxobutanoate in five steps according to [9]
(overall yield:35%). Colorless oil. 1H-NMR (300 MHz):1.49 1.59 ( m, 2 H); 1.70 (d, J ˆ 6.6, Me(7)); 1.71
(s, Me(2)); 1.72 1.83 (m, 2 H); 2.02 (tq, J ˆ 0.7, 7.2, 2 H); 4.13 (m, HÀC(6)); 4.68, 4.70 (m, J ˆ 0.7, 2  1 H,
H2C(1)). 13C-NMR (75 MHz):22.1 ( q, MeÀC(2)); 25.5 (t, C(4)); 26.4 (q, C(7)); 36.9 (t, C(5)); 40.5 (t, C(3));
51.3 (d, C(6)); 110.3 (t, C(1)); 144.9 (s, C(2)).
(1S/R)-1-[(1S/R)-1,5-Dimethylhex-5-enyl]-4-methylcyclohex-3-en-1-ol (ˆ Iso-b-bisabolol; 4). To a suspen-
sion of Li pellets (0.15 g, 22 mmol) in THF (10 ml) was slowly added a mixture of 7 (1.21 g, 11 mmol) and 8
(1.91 g, 10 mmol) in THF (10 ml) at À 108. Stirring was continued for 30 min at that temp., then the mixture was
warmed to r.t. over 2 h and stirred for 8 h. The suspension was carefully hydrolyzed with aq. NH4Cl soln. (10 ml)
and extracted with Et2O (4 Â 15 ml). The org. layers were dried (Na2SO4), concentrated, and the residue was
purified by a) CC (SiO2, hexane/Et2O 100 :0 ! 85 :15 in 1%-steps, then 80 :20, 75 :25), b) prep. TLC (SiO2,
hexane/Et2O 8 :2) to yield 0.24 g (11%) of alcohol 4. Colorless oil, 4a/4b 1:1. The synthetic material was
identical in all respects (TLC, GC, IR, NMR, MS) to the natural product. HR-MS (C15H26O, 220.1984, calc.:
222.1984).
5. Synthesis of 4 via Cu-Grignard-Reaction of Acetate 10 and Bromide 11. 4-Bromo-2-methylbut-1-ene (11)
was prepared from commercial 3-methylbut-3-en-1-ol in 2 steps according to [13] (overall yield:87%). Pale
yellow oil. 1H-NMR (300 MHz):1.74 ( d, J ˆ 0.9, MeÀC(2)); 2.57 (tt, J ˆ 1.6, 7.4, H2C(3)); 3.47 (t, J ˆ 7.4,
H2C(4)); 4.77 (q, J ˆ 0.9, HÀC(1)); 4.85 (t, J ˆ 1.6, HÀC(1)). 13C-NMR (75 MHz):21.8 ( q, MeÀC(2)); 30.6
(t, C(4)); 40.8 (t, C(3)); 112.5 (t, C(1)); 142.2 (s, C(2)).
2-[(E/Z)-4-Methylcyclohex-3-en-1-ylidene]propyl Acetate (10). Ac2O (61.0 g, 0.6 mmol), AcONa (3.0 g,
36 mmol), and H2WO4 (1.25 g, 5 mmol) was placed in a 500-ml 3-necked round-bottom flask equipped with a
thermometer, reflux condenser, and dropping funnel. The mixture was heated to 130 1408. Then, 4-methyl-1-
isopropenylcyclohex-3-en-1-ol (ˆ p-mentha-1,8-dien-4-ol; 9) (90.0 g, 0.5 mol) was added dropwise over 30 min,
and heating was continued for 1 h. The mixture was cooled to 808, H2O (100 ml) was added, and stirring was
continued for 30 min at 808. After cooling, the mixture was extracted with Et2O (3 Â 50 ml). The org. layers were
washed with H2O (3 Â 40 ml), dried (Na2SO4), evaporated, and the residue was purified by fractional
1
distillation to afford 24.06 g (25%) of 10. Pale yellow liquid. (E)/(Z) 60 :40. B.p. 1158/5 mbar [30]. H-NMR
(300 MHz):1.66 ( d, J ˆ 1.3, MeÀC(4)); 1.72, 1.75 (s, Me); 1.99 2.08 (m, H2C(5)); 2.05 (s, 3 H, Ac); 2.36 (t, J ˆ
6.4, 2 H, H2C(6)) and 2.41 (dt, J ˆ 1.0, 6.3, 2 H, H2C(6)); 2.77, 2.83 (m, H2C(2)); 4.60, 4.64 (s, CH2O); 5.34
(m, HÀC(3)). 13C-NMR (75 MHz):15.9, 16.6 ( q, Me); 20.8, 20.9 (q, MeCO); 23.1 (q, MeÀC(4)); 26.7, 27.0
(t, C(6)); 29.1, 29.8 (t, C(5)); 30.9, 31.5 (t, C(2)); 65.0, 65.1 (t, CH2O); 119.7, 119.9 (d, C(3)); 120.6, 120.8
(s, C(1)); 134.0, 134.2 (s, C(4)); 135.4, 136.0 (s, ˆC); 171.1 (s, COO). GC-MS ((E)-isomer):151 (0.1, [ M À
‡
‡
C2H3O] ), 134 (100, [M À C2H4O2] ), 119 (65), 105 (30), 93 (31), 92 (21), 91 (38), 79 (21), 77 (16), 43 (33), 41

Helvetica Chimica Acta Vol. 86 (2003)
2705
‡
‡
(10). GC/MS ((Z)-isomer):151 (0.1, [ M À C2H3O] ), 134 (100, [M À C2H4O2] ), 119 (72), 105 (27), 93 (26), 92
(18), 91 (37), 79 (19), 77 (15), 43 (30), 41 (10).
4-[(E/Z)-1,5-Dimethylhex-5-enylidene]-1-methylcyclohex-1-ene (ˆ Iso-g-bisabolene; 12). Bromide 11
(2.24 g, 15 mmol) was slowly added to Mg metal shavings (0.40 g, 16.5 mmol) in Et2O (15 ml) and THF
(5 ml). The suspension was refluxed for 30 min and then cooled to À 208. A 0.1m soln. of Li2[CuCl4] (5 ml,
0.5 mmol) in THF was slowly added, and stirring was continued for 30 min at À 208. Then, acetate 10 (1.94 g,
10 mmol) in THF (5 ml) was added dropwise at a temp. below À 108 to avoid formation of 12*. The mixture was
stirred for 2 h at À 208, then slowly warmed to 08, and carefully quenched with H2O (10 ml), followed by 1m
H2SO4 (15 ml). Once extracted with Et2O (3 Â 40 ml), the org. layers were washed with brine (10 ml), dried
(Na2SO4), and purified by CC (SiO2, hexane) to afford 0.98 g (48%) of 12. Colorless oil. (E)/(Z) 60 :40. GC-
FT-IR:3080, 2974, 2935, 2915, 2869, 1648, 1451, 1380, 890. 1H-NMR (300 MHz):1.44 1.54 ( m, 2 H); 1.65
(m, MeÀC(4), MeÀC(1')); 1.72 (s, MeÀC(5')); 1.96 2.09 (m, 6 H); 2.31 (t, J ˆ 6.3, H2C(6)); 2.73 (s, H2C(2));
4.67, 4.69 (m, 2 Â 1 H, H2C(6')); 5.36 (m, HÀC(3)). 13C-NMR (75 MHz):17.7, 18.3 ( q, MeÀC(1')); 22.5
(q, MeÀC(5')); 23.4 (q, MeÀC(4)); 26.1, 26.5 (t, C(6)); 26.7, 26.9 (t, C(2')); 29.3, 29.7 (t, C(5)); 31.6, 31.8
(t, C(3')); 33.6, 33.9 (t, C(2)); 37.8 (t, C(4')); 109.6 (t, C(6')); 120.7, 120.8 (d, C(3)); 125.8, 126.0 (s, C(1)); 128.21
(s, C(1')); 134.2 (s, C(4)); 146.1 (s, C(5')). GC/MS ((Z)-isomer):204 (39), 189 (9), 161 (18), 148 (12), 147 (17),
134 (38), 133 (49), 121 (85), 119 (100), 109 (10), 107 (33), 106 (29), 105 (57), 93 (75), 91 (60), 79 (39), 77 (32),
55 (19), 41 (23). GC-MS ((E)-isomer):204 (27), 189 (10), 161 (14), 148 (28), 147 (12), 134 (23), 133 (52), 121
(100), 119 (94), 109 (16), 107 (40), 106 (42), 105 (64), 93 (91), 91 (70), 79 (47), 77 (38), 55 (27), 41 (32). HR-
24
MS:calc.:204.1878 (C
H
15
).
‡
4-Isopropenyl-1-methyl-4-(3-methylbut-3-enyl)cyclohex-1-ene (12*). Colorless oil. GC/FT-IR:3081, 2973,
2937, 1639, 1451, 1379, 892. 1H-NMR (300 MHz):1.33 ( m, 1 H); 1.56 1.68 (m, 2 H); 1.62 (s, Me); 1.69 1.71
(m, 6 H, MeÀC(4), MeÀC(3')); 1.76 2.04 (m, 6 H); 2.16 (m, 1 H); 4.64 4.68 (m, CH2(4'), HÀCˆ); 4.86
(m, HÀCˆ); 5.30 (m, HÀC(3)). 13C-NMR (75 MHz):18.9 ( q, MeÀC(1)); 22.8 (q, MeÀC(3')); 23.3 (q, Me);
27.7 (t, C(5)); 31.1 (t, C(1')); 32.1 (t, C(6)); 35.4 (t, C(3)); 35.5 (t, C(2')); 40.2 (s, C(4)); 109.0 (t, ˆCH2); 111.3
(t, C(4')); 119.3 (d, C(2)); 133.0 (s, C(1)); 146.9 (s, Cˆ); 148.5 (s, C(3')). GC-MS:204 (6), 189 (28), 176 (18), 175
(11), 161 (8), 148 (14), 133 (28), 121 (69), 119 (25), 108 (40), 107 (93), 105 (42), 93 (100), 91 (46), 81 (25), 79
(65), 77 (31), 67 (23), 55 (33), 53 (22), 41 (48), 39 (22).
2,6-Dimethyl-2-(4-methylpent-4-enyl)-1-oxaspiro[2.5]oct-5-ene (13). A soln. of (E/Z)-12 (0.31 g, 1.5 mmol)
in CH2Cl2 (15 ml) was cooled to 08, and 70% MCPBA (0.41 g, 1.65 mmol) was added. The mixture was slowly
warmed to r.t., stirred for 8 h, and filtered under suction. The remaining solid was rinsed with CH2Cl2 (20 ml).
The organic layers were successively washed with solns. of 10% NaHSO3 (10 ml), sat. K2CO3 (10 ml), and brine
(10 ml), dried (Na2SO4), and purified by CC (SiO2, hexane/Et2O 3 :1) to yield 0.22 g (81%) of 13. Colorless oil.
Two diastereoisomers [(S*,S*)/(S*,R*) ˆ 60 :40]. 1H-NMR (300 MHz):1.30, 1.34 ( s, MeÀC(2)); 1.43 1.65
(m, 4 H); 1.69 (m, MeÀC(6)); 1.71 (s, MeÀC(4')); 1.70 1.89 (m, 2 H); 1.94 2.10 (m, 3 H); 2.12 2.30
(m, 2 H); 2.35 (m, J ˆ 17.6, 1 H); 4.66, 4.70 (m, 3  1 H, CH2(5')); 5.33 (m, 1 H, CH2(5)). 13C-NMR
(75 MHz):17.9, 18.3 ( q, MeÀC(2)); 22.2 (2q, MeÀC(4')); 23.1, 23.2 (q, MeÀC(6)); 23.3, 23.6 (t, C(8)); 26.5,
27.3 (t, C(1')); 28.6, 29.1 (t, C(2')); 30.5, 31.1 (t, C(7)); 34.0, 34.3 (t, C(4)); 37.8 (2t, C(3')); 64.0, 64.3 (s, C(2));
64.6, 64.7 (s, C(3)); 109.9 (2t, C(5')); 118.9, 119.0 (d, C(5)); 133.9 (2s, C(6)); 144.8 (s, C(4')). GC/MS ((S*,R*)-
isomer):220 (2), 205 (6), 202 (4), 187 (3), 159 (3), 152 (5), 151 (4), 147 (5), 138 (10), 137 (14), 132 (8), 119
(10), 111 (14), 110 (43), 109 (17), 107 (7), 105 (10), 95 (100), 94 (25), 93 (28), 91 (22), 81 (17), 79 (63), 77 (24),
69 (14), 68 (16), 67 (22), 55 (23), 43 (19), 41 (19). GC/MS ((S*,S*)-isomer):220 (1), 205 (4), 202 (4), 187 (2),
159 (3), 152 (6), 147 (5), 138 (9), 137 (13), 132 (7), 119 (9), 111 (16), 110 (47), 109 (16), 107 (6), 105 (9), 95
(100), 94 (25), 93 (27), 91 (19), 81 (18), 79 (64), 77 (22), 69 (14), 68 (16), 67 (22), 55 (24), 43 (20), 41 (21). HR-
MS:220.1826 (C 15H24O; calc. 220.1827).
Mixture of 4 and 6-Methyl-2-(4-methylcyclohex-3-enyl)hept-6-en-2-ol (ˆ Iso-a-bisabolol; 3). LiAlH4
(0.12 g, 3 mmol) was added slowly to a soln. of 13 (0.44 g, 2.0 mmol) in anh. THF (15 ml), and the mixture
was heated under reflux for 2 h. The suspension was cooled to 08, and H2O (2 ml) was carefully added. The
mixture was filtered over glass wool, the residue was rinsed with Et2O (40 ml), and the org. layers were washed
with brine (10 ml), dried (Na2SO4) and evaporated. CC (SiO2, hexane/Et2O 8 :2) afforded 311.6 mg (70%) of 4
and 98.4 mg (22%) of 3 in a ratio of 76 :24. Iso-b-bisabolol (4), a colorless oil, ((S*,S*)/(S*,R*) 60 :40) matched
the natural product in all respects.
Iso-a-bisabolol (3):Colorless oil, odorless. Diastereoisomer ratio:( S*,S*)/(S*,R*) 60 :40. GC/FT-IR:3641,
1
3080, 2972, 2930, 1648, 1453, 1379, 891. H-NMR (300 MHz):1.11, 1.14 ( s, Me(1)); 1.20 1.36 (m, 2 H); 1.40
1.61 (m, 5 H); 1.44 (s, OH); 1.62 (s, MeÀC(4')); 1.72 (s, MeÀC(6)); 1.75 1.94 (m, 2 H); 1.95 2.05 (m, 4 H);
4.69, 4.71 (s, 1 H, CH2(7)); 5.39 (m, HÀC(3')). 13C-NMR (75 MHz):21.1, 21.4 ( t, C(4)); 22.3 (q, C(1)); 23.2

2706
Helvetica Chimica Acta Vol. 86 (2003)
(t, C(6')); 23.3 (2q, MeÀC(6)); 23.8 (t, C(6')); 24.0 (q, MeÀC(4')); 26.0, 26.8 (t, C(3)); 30.9, 31.0 (t, C(5')); 38.2
(2t, C(2')); 39.0, 39.8 (t, C(5)); 42.8, 43.1 (d, C(1')); 74.2 (2s, C(2)); 109.9 (t, C(7)); 120.5, 120.7 (d, C(3')); 133.7,
‡
134.0 (s, C(2')); 145.6 (s, C(6)). GC-MS:222 (0.2, M ), 207 (0.4), 204 (10), 189 (4), 161 (5), 139 (19), 133 (7),
121 (36), 119 (81), 109 (100), 105 (11), 95 (26), 94 (24), 93 (40), 81 (29), 71 (35), 69 (60), 55 (17), 43 (63), 41
(22). HR-MS:222.1984 (C 15H26O; calc. 222.1984).
6. Synthesis of 4 via Nucleophilic Addition of 14 to 15. 4-Methyl-cyclohex-3-encarboxylic Acid (14) was
prepared in 71% overall yield according to [15]. Colorless crystals. M.p. 97 998. 1H-NMR (400 MHz):1.65
(d, J ˆ 0.7, MeÀC(4)); 1.72 (m, 1 H); 1.97 2.06 (m, 3 H); 2.18 2.25 (m, 2 H); 2.52 (m, 1 H); 5.37
(m, HÀC(3)); 11.24 (m, COOH). 13C-NMR (100 MHz):23.4 ( q, MeÀC(4)); 25.2 (t, C(6)); 27.4 (t, C(5));
29.1 (t, C(2)); 39.1 (d, C(1)); 118.8 (d, C(3)); 133.5 (s, C(4)); 182.4 (s, COO).
6-Methyl-hept-6-en-2-one (15) was prepared in an overall yield of 42% according to [9a]. Colorless oil. B.p.
1
638/18 mbar. H-NMR (300 MHz):1.67 1.77 ( m, CH2(4)); 1.71 (m, MeÀC(6)); 2.01 (t, J ˆ 7.4, CH2(5)); 2.14
(s, Me(1)); 2.42 (t, J ˆ 7.4, CH2(3)); 4.67, 4.73 (m, 2  1 H, CH2(7)). 13C-NMR (300 MHz):21.4 ( t, C(4)); 22.1
(q, MeÀC(6)); 29.9 (q, C(1)); 36.9 (t, C(5)); 42.9 (t, C(3)); 110.5 (t, C(7)); 144.9 (s, C(6)); 208.9 (s, C(2)).
1-(1-Hydroxy-1,5-dimethylhex-5-enyl)-4-methylcyclohex-3-enecarboxylic Acid (16). To a soln. of (i-Pr)NH
(6.02 g, 60 mmol) in anh. THF (120 ml) and TMEDA (30 ml) was added a 1.83m soln. of BuLi in hexane
(32.7 ml, 60 mmol) at À 408. After stirring for 30 min, a soln. of 14 (4.2 g, 30 mmol) in THF (20 ml) was added
dropwise at a temp. below À 208. The mixture was stirred for 15 min at À 208 and then heated to 508 for 3 h. The
soln. was cooled to À 408, and 15 (3.78 g, 30 mmol) was slowly added. Stirring was continued for 3 h at À 408,
the mixture was poured onto ice and extracted with Et2O (3 Â 50 ml). The org. layers were discarded. The aq.
layer was acidified with 1.5m H2SO4 to pH ꢁ 3 and extracted with Et2O (4 Â 75 ml). The org. layers were dried
(Na2SO4), and the solvent was removed to yield 6.10 g (76%) of 16. Highly viscous colorless oil (solidifies upon
standing). Diastereoisomer ratio:1:1. 1H-NMR (400 MHz):1.18, 1.20 ( s, MeÀC(1')); 1.40 1.58 (m, 3 H); 1.64
(m, MeÀC(4)); 1.60 1.72 (m, 2 H); 1.70 (s, MeÀC(5')); 1.92 2.02 (m, 3 H); 2.03 2.22 (m, 3 H); 2.49
(m, 1 H); 4.66, 4.69 (m, 2 Â 1 H, H2C(6')); 5.37 (m, HÀC(3)). 13C-NMR (100 MHz):21.1 ( q, MeÀC(1'));
21.3, 21.5 (t, C(3')); 21.5 (q, MeÀC(1')); 22.3 (2q, MeÀC(5')); 23.2 (q, MeÀC(4)); 25.3, 25.4 (t, C(2')); 28.1, 28.2
(t, C(6)); 28.6, 28.7 (t, C(5)); 36.6, 37.1 (t, C(2)); 38.1, 38.2 (t, C(4')); 53.7 (2s, C(1)); 75.5, 75.6 (s, C(1')); 109.8,
1
109.9 (t, C(6')); 119.1, 119.3 (d, C(3)); 132.8, 133.1 (s, C(4)); 145.2 (s, C(5')); 180.2, 180.3 (s, COO). H-NMR
(400 MHz, (D6)acetone):1.19, 1.20 ( s, MeÀC(1')); 1.45 1.57 (m, 3 H); 1.58 (m, MeÀC(4)); 1.62 1.72
(m, 2 H); 1.69 (s, MeÀC(5')); 1.90 (m, 1 H); 1.98 2.03 (m, 2 H); 2.09 2.23 (m, 3 H); 2.51 (m, 1 H); 4.66
(m, H2C(6')); 5.34 (m, HÀC(3)). 13C-NMR (100 MHz, (D6) acetone):21.7, 22.1 ( q, MeÀC(1')); 22.2, 22.3
(t, C(3')); 22.4 (q, MeÀC(5')); 23.3 (q, MeÀC(4)); 25.8, 25.9 (t, C(2')); 28.8, 28.9 (t, C(6)); 29.1, 29.4 (t, C(5));
37.3, 37.6 (t, C(2)); 38.9 (2t, C(4')); 54.1, 54.2 (s, C(1)); 74.9, 75.1 (s, C(1')); 110.0 (t, C(6')); 120.7 (2d, C(3));
132.9, 133.0 (s, C(4)); 146.2 (2s, C(5')); 176.6, 176.7 (s, COO). LC-MS (neg.):265 (100, [ M À H]À), 139 (15,
‡
‡
[C8H11O2]À). LC-MS (pos.):305 (19, [ M ‡ K] ), 289 (100, [M ‡ Na] ). HR-MS:248.1776 (C 16H26O3; [M À
‡
‡
H2O] ; calc. for M :266.1882).
3,7-Dimethyl-3-(4-methylpent-4-enyl)-2-oxa-spiro[3.5]non-6-en-1-one (17). Hydroxy acid 16 (5.32 g,
20 mmol) was dissolved in anh. pyridine (80 ml) and CH2Cl2 (80 ml). After cooling to À 58, p-toluenesulfonyl
chloride (11.43 g, 60 mmol) was added with stirring. The mixture was stirred at 08 for 18 h, then poured on ice,
and extracted with Et2O (4 Â 50 ml). The org. layers were washed with 10% H2SO4 (2 Â 30 ml), neutralized with
aq. NaHCO3 soln. (4 Â 50 ml), and dried (Na2SO4) to yield 4.43 g (89%) of 17, which was used without further
purification. Colorless oil. Diastereoisomer ratio:1 :1. 1H-NMR (400 MHz):1.45, 1.51 ( s, MeÀC(3)); 1.48 1.60
(m, 3 H); 1.67 (m, MeÀC(7)); 1.70, 1.71 (s, MeÀC(5')); 1.69 1.93 (m, 2 H); 1.96 2.12 (m, 3 H); 2.14 2.44
(m, 4 H); 4.67, 4.71 (m, H2C(5')); 5.33 (m, 1 H, CH2(6)). 13C-NMR (100 MHz):19.6, 19.7 ( q, MeÀC(3)); 21.8,
21.9 (t, C(2')); 22.1 (q, MeÀC(4')); 23.0 (2q, MeÀC(7)); 24.2, 24.9 (t, C(1')); 26.9, 27.0 (t, C(9)); 27.5, 28.1
(t, C(8)); 35.1, 35.5 (t, C(5)); 37.7 (2t, C(3')); 56.5, 56.7 (s, C(4)); 84.7, 85.2 (s, C(3)); 110.2 (2t, C(5')); 116.5,
116.8 (d, C(6)); 133.7, 134.0 (s, C(7)); 144.4 (2s, C(4')); 174.1, 174.3 (s, C(1)). HR-MS:248.1776 (C 16H24O2 ; calc.:
248.1776).
Decarboxylation of 17 to give 12. The crude b-lactone 17 (3.72 g, 15 mmol) was heated to 150 1608 under
N2 for 2 h (evolution of CO2) and then cooled. The crude brown oil was distilled in a bulb-to-bulb apparatus
under reduced pressure and further purified by CC (SiO2, hexane) to obtain 2.92 g (95%) of (E/Z)-12. Colorless
oil. Diastereomer ratio:11:. This material had properties identical to those of another sample of iso- g-
bisabolene prepared synthetically (cf. Sect. 5 of the Exper. Part).
7. Separation of Iso-b-bisabolol Isomers (4a,b). The mixture of 4a,b was separated via HPLC (hexane/Et2O
9 :1, injection: 150 ml of a 25% solution) to obtain two fractions.

Helvetica Chimica Acta Vol. 86 (2003)
2707
(1S*)-1-[(1S*)-1,5-Dimethyl-hex-5-enyl]-4-methylcyclohex-3-en-1-ol (4a). Colorless oil, strong floral,
muguet-like, very pleasant odor. 1H-NMR (300 MHz):0.91 ( d, J ˆ 6.9, MeÀC(1')); 1.02 (m, 1 H); 1.26
(s, OH); 1.33 (m, 1 H); 1.46 (m, 1 H); 1.53 1.65 (m, 4 H); 1.69 (s, MeÀC(4)); 1.71 (s, MeÀC(5')); 1.80 1.98
(m, 2 H); 1.98 2.06 (m, 2 H); 2.12 2.24 (m, 2 H); 4.67, 4.69 (m, H2C(6')); 5.30 (m, HÀC(3). 13C-NMR
(75 MHz):13.7 ( q, MeÀC(1')); 22.3 (q, MeÀC(5')); 23.3 (q, MeÀC(4)); 26.3 (t, C(6)); 27.0 (t, C(2')); 30.3
(t, C(3')); 30.9 (t, C(5)); 34.2 (t, C(2)); 38.0 (t, C(4')); 42.4 (d, C(1')); 72.2 (s, C(1)); 109.7 (t, C(6')); 118.4
(d, C(3)); 133.8 (s, C(4)); 146.0 (s, C(5')).
(1S*)-1-[(1R*)-1,5-Dimethylhex-5-enyl]-4-methylcyclohex-3-en-1-ol (4b). Colorless oil. Odorless. 1H-NMR
(300 MHz):0.95 ( d, J ˆ 6.9, MeÀC(1')); 1.03 (m, 1 H); 1.34 (s, OH); 1.35 (m, 1 H); 1.43 1.63 (m, 5 H); 1.69
(s, MeÀC(4)); 1.71 (s, MeÀC(5')); 1.83 2.05 (m, 4 H); 2.13 2.24 (m, 2 H); 4.67 (m, 1 H); 4.69 (m, 1 H); 5.29
(m, 1 H). 13C-NMR (75 MHz):13.6 ( q, MeÀC(1')); 22.3 (q, MeÀC(5')); 23.2 (q, MeÀC(4)); 26.2 (t, C(6)); 27.0
(t, C(2')); 30.3 (t, C(3')); 30.6 (t, C(5)); 34.8 (t, C(2)); 38.0 (t, C(4')), 42.1 (d, C(1')); 72.2 (s, C(1)); 109.7
(t, C(6')); 118.4 (d, C(3)); 133.9 (s, C(4)); 146.0 (s, C(5')).
We are especially grateful to Prof. Dr. Lutz F. Tietze (Georg-August-Universit‰t Gˆttingen) for HR-MS
and helpful discussions. We thank Birgit Kohlenberg, Stephan Seilwind, and Nicole K¸hne (Dragoco Gerberding
& Co. AG) for MS, NMR and GC-FTIR measurements. The authors express their gratitude to Benjamin Rost
(Dragoco Gerberding & Co. AG) and Dr. Anja Finke (Haarmann & Reimer GmbH) for odor-threshold
determinations.
REFERENCES
[1] H. Hatt, Zoology 1999/2000, 102, 120; P. Mombaerts, Science 1999, 286, 707; K. Mori, H. Nagao, Y.
Yoshihara, Science 1999, 286, 711; J. Krieger, H. Breer, Science 1999, 286, 720.
[2] G. Ohloff, −Scent and Fragrances×, Springer Verlag, Berlin, 1994; W. Pickenhagen, in −Flavor Chemistry
Trends and Developments×, Eds. R. Teranishi, R. G. Buttery, F. Shahidi, American Chemical Society,
Washington, 1989, p. 151.
[3] a) C. Valder, M. Neugebauer, M. Meier, B. Kohlenberg, F.-J. Hammerschmidt, N. A. Braun, J. Essent. Oil
Res. 2003, 15, 178; b) N. A. Braun, M. Meier, W. Pickenhagen, J. Essent. Oil Res. 2003, 15, 63; c) E.-J.
Brunke, K.-G. Fahlbusch, G. Schmaus, J. Vollhardt, Revista Italiana EPPOS 1997, 01/97, 49 (special issue).
[4] M. J. Piggott, E. L. Ghisalberti, R. D. Trengove, Flav. Fragr. J. 1997, 12, 43; E.-J. Brunke, W. Rojahn,
Dragoco Rep. 1980, 127.
[5] A. R. Mayol, T. E. Acree, in −Gas Chromatography-Olfactometry. The State of the Art×, Eds. J. V. Leland,
P. Schieberle, A. B¸ttner, T. E. Acree, American Chemical Society, Washington, 2001, p. 1.
[6] C. D. Gutsche, J. R. Maycock, C. T. Chang, Tetrahedron 1968, 24, 859.
[7] H. Pasedach, R. Fischer, W. Hoffmann (BASF AG), DE Pat. 1,289,043, 1967.
[8] R. M. Carman, A. C. Rayner, Aust. J. Chem. 1994, 47, 2087; P. S. Engel, D. M. Robertson, J. N. Scholz, H. J.
Shine, J. Org. Chem. 1992, 57, 6178; A. F. Thomas, R. Bubini, Helv. Chim. Acta 1974, 57, 2084.
[9] a) A. C. Jackson, B. E. Goldman, B. B. Snider, J. Org. Chem. 1984, 49, 3988; b) C. Walling, A. Cioffari, J.
Am. Chem. Soc. 1972, 94, 6059.
[10] S. D. Sharma, S. Singh, S. S. Bari, Indian J. Chem. 1976, 14B, 379.
[11] E. J. Corey, N. N. Girotra, C. T. Mathew, J. Am. Chem. Soc. 1969, 91, 1557.
[12] E. Klein (DRAGOCO Gerberding & Co. AG), DE Pat. 1,235,306, 1965.
[13] L. A. Paquette, D. R. Sauer, D. G. Cleary, M. A. Kinsella, C. M. Blackwell, L. G. Anderson, J. Am. Chem.
Soc. 1992, 114, 7375.
[14] G. Fouquet, M. Schlosser, Angew. Chem., Int. Ed. 1974, 13, 82.
[15] T. Inukai, M. Kasai, J. Org. Chem. 1965, 30, 3567; T. Inukai, T. Kojima, J. Org. Chem. 1966, 31, 1121.
[16] L. E. Wolinsky, D. J. Faulkner, J. Finer, J. Clardy, J. Org. Chem. 1976, 41, 697; D. J. Faulkner, L. E. Wolinsky,
J. Org. Chem. 1975, 40, 389.
[17] D. B. Collum, Acc. Chem. Res. 1992, 25, 448.
[18] L. Anastasia, Y. R. Dumond, E.-I. Negishi, Eur. J. Org. Chem. 2001, 3039.
[19] J. March, −Advanced Organic Chemistry×, 5th edn., John Wiley & Sons, New York, 1992, p. 443; P. Gosselin,
D. Joulain, P. Laurin, F. Rouessac, Tetrahedron Lett. 1989, 30, 2775.
[20] a) E. Brenna, C. Fuganti, S. Serra, Tetrahedron Asym. 2003, 14, 1; b) M. H. Boelens, H. Boelens, L. J. van
Gemert, Perfum. Flavor. 1993, 18(6), 1.

2708
Helvetica Chimica Acta Vol. 86 (2003)
[21] W. A. Kˆnig, B. Gehrcke, D. Icheln, P. Evers, J. Dˆnnecke, W. Wang, J. HighResol. Chromatogr . 1992, 15,
367.
¬
[22] G. Frater, U. M¸ller, Helv. Chim. Acta 1989, 72, 653; G. Ohloff, W. Giersch, R. N‰f, F. Delay, Helv. Chim.
Acta 1986, 69, 698.
[23] K. G¸nther, R. Carle, I. Fleischhauer, S. Merget, Fresenius J. Anal. Chem. 1993, 345, 787; E. Francotte, A.
Junker-Buchheit, J. Chromatogr. 1992, 576, 1.
[24] L. F. W¸nsche, C. Vuilleurmier, U. Keller, M. P. Byfield, I. P. May, M. J. Kearney, in −Proceedings of the
13th International Congress of Flavours, Fragrances and Essential Oils×, Ed. K. H. C. Baser, AREP
Publications, Istanbul, 1995, Vol. 3, p. 295; J. C. Leffingwell, D. Leffingwell, Perfum. Flavor. 1991, 16(1), 1.
¬
[25] P. Kraft, J. A. Bajgrowicz, C. Denis, G. Frater, Angew. Chem., Int. Ed. 2000, 39, 2980; V. Rautenstrauch, J.-J.
Riedhauser (FirmenichS.A. ), WO Pat. 96/00206, 1994.
[26] T. E. Acree, R. Nishida, H. Fukami, J. Agric. Food Chem. 1985, 33, 425.
[27] G. Ohloff, B. Maurer, B. Winter, W. Giersch, Helv. Chim. Acta 1983, 66, 192.
¬
[28] P. Kraft, G. Frater, Chirality 2001, 13, 388.
[29] C. M. Williams, L. N. Mander, Tetrahedron 2001, 57, 425.
[30] A. C. Oehlschlager, P. Mishra, S. Dhami, Can. J. Chem. 1984, 62, 791; E. Klein, W. Rojahn Dragoco Rep.
1967, 139.
Received May 2, 2003