Enantiospecific synthesis, separation and olfactory evaluation of all diastereomers of a homologue of the sandalwood odorant Polysantol

Article abstract of DOI:10.1016/j.tet.2005.09.023

The four stereoisomers of (5E)-4,4-dimethyl-6-(2′,2′,3′- trimethylcyclopent-3′-en-1′-yl)-hex-5-en-3-ol, a homologue of the valuable sandalwood-type odorant Polysantol, were enantiospecifically synthesized from (+)- and (-)-α-pinene, through (-)- and (+)-campholenic aldehyde, by aldol condensation with 3-pentanone, deconjugative α-methylation and reduction. The mixtures of epimeric alcohols obtained after reduction were separated by means of derivatization with (-)-(1S)-camphanic chloride. The enantiomerically pure final products were evaluated organoleptically.

Full text of DOI:10.1016/j.tet.2005.09.023

Tetrahedron 61 (2005) 11192–11203
Enantiospecific synthesis, separation and olfactory evaluation
of all diastereomers of a homologue of the
sandalwood odorant Polysantol
w
Juan M. Castro, Pablo J. Linares-Palomino, Sof ´ı a Salido, Joaqu ´ı n Altarejos,
and Adolfo S a´ nchez
*
Manuel Nogueras
Departamento de Qu ´ı mica Inorg a´ nica y Org a´ nica, Facultad de Ciencias Experimentales, Universidad de Ja e´ n, 23071 Ja e´ n, Spain
Received 27 May 2005; revised 2 September 2005; accepted 8 September 2005
Available online 27 September 2005
Dedicated to Professor Joaqu ´ı n Plumet on the occasion of his 60th birthday with admiration and friendship.
0
0
0
0
0
Abstract—The four stereoisomers of (5E)-4,4-dimethyl-6-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -yl)-hex-5-en-3-ol, a homologue of the
w
valuable sandalwood-type odorant Polysantol , were enantiospecifically synthesized from (C)- and (K)-a-pinene, through (K)- and (C)-
campholenic aldehyde, by aldol condensation with 3-pentanone, deconjugative a-methylation and reduction. The mixtures of epimeric
alcohols obtained after reduction were separated by means of derivatization with (K)-(1S)-camphanic chloride. The enantiomerically pure
final products were evaluated organoleptically.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
main constituents of sandalwood oil are unsaturated
alcohols, aldehydes and ketones consisting of a bulky
polycyclic hydrophobic moiety separated from the
oxygenated function by a 4–5 C-atoms chain (e.g., I–III,
Since olfactory receptors (OR) are peptides consisting of
L-amino acids, fragrance science frequently deals with the
phenomenon of chirality. Very often, diastereomers, and
enantiomers exhibit different olfactory profiles and inten-
4
Fig. 1).
1
sities. The optical purity and diastereomeric composition of
The search for their efficient synthetic substitutes has been
carried out over the last 50 years and, until now, the best
a mixture of chiral fragrances can also influence the odour
greatly. Enantiomeric chiral molecules interact differently
with other chiral molecules present in the different ORs
5
,6
ones found are trimethylcyclopentenyl alkenols IV–VII
Fig. 1) derived from campholenic aldehyde (1). However,
not much is known about the structure–odour relationship
SOR) of single stereoisomers of sandalwood-smelling
(
2
types since such interactions are diastereomeric. However,
(
it is often difficult to obtain large amounts of optically pure
chiral odour materials. Synthetic chemicals are often
racemic, or have a specific ratio of stereoisomers that is
related to either the optical purity of the starting material,
the stereoselectivity of the reaction, or both. The growing
awareness of the importance of chirality in fragrance
chemistry has resulted in both the development of
asymmetric synthesis of chiral chemicals and the search
for optically active natural starting materials.
mixtures because the structures of the specific ORs and
the corresponding mechanism of interaction between the
receptor protein and the odour molecules remain more or
7
less unknown. Nevertheless, some authors have postulated,
for the sandalwood-type odour, the importance of at least
three binding centres together with the relative position of
these points, that is, the distance among binding sites and
the stereospecificity is crucial for eliciting this specific type
of odour.
East India sandalwood oil belongs to the most appreciated
3
but unfortunately scarce perfumery raw materials. The
As a continuation of our previous studies on the synthesis of
odorants, we had contributed to develop a collection of
8
6
several substitutes of sandalwood scent. In that report, we
Keywords: a-Campholenic aldehyde derivatives; a-Pinene; Enantiospecific
synthesis; Organoleptic evaluation; Sandalwood; Odorants.
w
attained Polysantol (V) and other analogous molecules,
*
Corresponding author. Tel.: C34 953 212743; fax: C34 953 211876;
e-mail: jaltare@ujaen.es
taking the exact position of the binding site in consider-
ation, based on a selective and efficient magnesium-
7
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.023

J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
11193
Figure 1.
w
Scheme 1. Synthesis of Polysantol (V) from campholenic aldehyde (1). (i) Mg, Et
MeOH, 0 8C to rt.
2 2 3 4
O, 6; (ii) MsCl, Py, 0 8C to rt; LiBr, Li CO , DMF, 150 8C; (iii) NaBH ,
mediated aldol reaction of technical-grade campholenic
aldehyde and different a-bromoketones, dehydration of the
resulting secondary alcohols, and reduction of the carbonyl
group (Scheme 1).
an enantiospecific synthesis of the two enantiomeric
ketones, precursors of 5, was chosen. In this way, the
reduction of these ketones and esterification of the resulting
alcohols with an enantiomerically pure chiral reagent, the
subsequent chromatographic isolation of these new dia-
stereomeric derivatives and, finally, the removing of the
chiral auxiliary moiety, led to the enantiomerically pure
final products.
Among the whole range of compounds structurally related
w
6
to Polysantol prepared by us, the perfumers pointed out
compound 5 due to its interesting olfactory properties. Even
though, as a mixture of stereoisomers, compounds 5 showed
woody, leathery and spicy notes with a slight sweetness,
surprisingly, it was almost devoid of sandalwood scent.
Since great differences in the odour impression of
2. Results and discussion
2.1. Synthesis
9
enantiomers often exist, it was of interest to synthesize
all the possible stereoisomers and evaluate their odour
separately.
0
epimers of (5E)-4,4-dimethyl-6-(2 ,2 ,3 -trimethylcyclo-
In the following, we describe the syntheses of the two C-1
0
0
0
0
0
pent-3 -en-1 -yl)-hex-5-en-3-ones (10), which are suitable
to be transformed to alcohols 5 (Scheme 2). Starting with
the epoxidation and rearrangement of (C)- and (K)-a-
pinene (6) to afford the two enantiomers of campholenic
aldehyde (1) separately (as they are not optically pure
commercially available), we continued by aldol conden-
sation of each one with 3-pentanone, deconjugative
According to this, an approach based on the development of
0
0
0
0
0
Scheme 2. Retrosynthetic approach to (5E)-4,4-dimethyl-6-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -yl)-hex-5-en-3-ol (5).

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J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
2 2 2
Scheme 3. Syntheses of (K)- and (C)-campholenic aldehydes (1). (i) AcOOH, NaOAc, CH Cl , 0 8C; (ii) ZnBr , toluene, 6.
a-methylation of the respective enones (9) and reduction of
10 (in analogy to the route described by Firmenich,
Scheme 2) to achieve the two pairs of isomers 5, separately.
differences in boiling points between both oxygenated
monoterpenes, 7 and 1, are not sufficient to allow a complete
separation of them. As a result, the spectra set and [a] were
D
5
b
performed with the distilled mixture of 7 and 1. However,
these spectroscopic data are in accordance with those
already described.
In the synthesis of compounds 5 according to the above
described reactions, the configuration of the campholenic
aldehyde starting material depends on that of the a-pinene
used, which fixes the final product configuration at C-1 .
When (C)-(1R)-a-pinene (91% ee) is used to produce
1
3
0
With regard to the rearrangement of the two a-pinene
epoxide isomers (7), the reaction of these with ZnBr2
yielded, in both cases, the corresponding campholenic
campholenic aldehyde via pinene epoxide, the product is
0
0
0
(
K)-(1 S)-campholenic aldehyde (Scheme 3). These
aldehyde ((K)-(1 S)-1, 56% and (C)-(1 R)-1, 59%) with a
small amount of pinocamphone as by-product (11:1, in
processes involve an epoxidation of a-pinene (6) and a
stereospecific rearrangement of the epoxide 7 to
campholenic aldehyde (1) in the well-known modified
1
3
favour of 1, detected by GC).
1
0,11
0
0
Arbuzov preparation,
amount of ZnBr in refluxing toluene.
in the presence of a catalytic
The two aldehydes, (K)-(1 S)-1 and (C)-(1 R)-1, derived
from the two optically pure a-pinene samples (6), were
reacted with 3-pentanone, separately, using potassium
2
1
The epoxidation of 6 (AcOOH/NaOAc/CH Cl ) is a
2
14
hydroxide as catalyst (Scheme 4). In both cases, the
2
2
diastereoface-selective reaction. The electrophilic reagent
normally reacts on the sterically less hindered face.
Consequently, the reaction afforded the epoxide 7 with
excellent diastereofacial selectivity, in both a-pinenes
direct aldol reaction was carried out without low tempera-
ture conditions, because of the symmetry of 3-pentanone
does not lead to the formation of regioisomers in the enolate
ion of the ketone. The mixtures of the b-hydroxyketone
isomers (1 S)-8 and (1 R)-8 were identified by mass
spectrometry.
0
0
(
Scheme 3). Under the latter condition, the oxidation
reagent peracetic acid prompts the newly formed a-pinene
oxide (7) to the rearrangement into a-campholenic aldehyde
(
1) as well. A 10% amount of 1 was detected by GC, as a
Without previous purification, the crude products of the
aldol addition directly underwent dehydration by azeotropic
distillation in dry toluene and p-toluenesulfonic acid. Thus,
the a,b-unsaturated ketones 9 obtained were purified by
by-product of the epoxidation. Since the flash chromato-
graphy attempted led to the degradation of the a-pinene
oxide (7), a viable alternative based on the vacuum
distillation technique was tried. Nevertheless, the
0
reduced pressure distillation to afford (K)-(1 S)-9 (61%
Scheme 4. Aldol reaction of (K)- and (C)-campholenic aldehydes (1) with 3-pentanone and dehydration to the a,b-unsaturated ketones (K)-9 and (C)-9.
i) KOH, MeOH; (ii) p-TsOH, toluene, 6.
(

J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
11195
t
Scheme 5. Deconjugative a-methylation of 9 and reduction of 10 to 5. (i) K BuO, DMF, 20 8C, 30 min; (ii) MeI, 0 8C, 10 min; (iii) NaBH
4
, MeOH, 0 8C to rt.
0
addition-dehydration yield, [a] K1.6) and (C)-(1 R)-9
D
Finally, the b,d-unsaturated ketones 10 could be converted
into the corresponding homoallylic alcohols by reducing the
carbonyl group with sodium borohydride. As expected, a
mixture of diastereoisomeric alcohols 5 in 55:45 ratio was
obtained (95 and 94%) in both cases. The existence of the
diastereoisomeric pair was only revealed by their NMR
spectra and was especially clear in their camphanoate ester
derivatives gas chromatogram (vide infra).
(58% addition–dehydration yield, [a] C1.5). The examin-
D
ation of the H NMR and C NMR spectra of both
enantiomers (9), where two new sets of signals were
1
13
1
13
detected at d ( H) 1.10 (t) and 2.68 (q) together with d ( C)
.87 and 30.32 for C-1 and C-2, proved the presence of the
8
ethylketone moiety. Besides, the a,b-unsaturation (D )
could be unequivocally assigned as a result of the two
4
1
signals detected at d 136.92 and 141.87 in C NMR.
3
At that moment, a direct chromatography separation of the
0
0
pair of diastereoisomers (3S/3R,1 S)-5 and (3S/3R,1 R)-5
was envisaged. Unfortunately, these attempts were fruitless.
Different alternatives to the above more straightforward
method of separation of 5 were attempted, like the
preparation of acetate or benzoate esters. Nevertheless,
Once the ketones 9 were obtained, they could be converted
to the b,d-unsaturated ketones 10 by deconjugative
1
5
a-methylation reaction. This step relies on the initial
formation of an enolate, using a slight stoichiometric excess
of potassium t-butoxide, followed by the methylation of this
ion under conditions that provided the kinetically favoured
product in excess over the thermodynamically favoured
product. A 10 M excess of cool iodomethane was added
quickly over the cooled (0 8C) solution of the referred
1
6a
only the preparation of the camphanoate derivatives,
allowed us to separate them by chromatography. Hence, the
mixture of (3S/3R,1 S)-5 was reacted with (1S)-(K)-
using DMAP as nucleophilic
catalyst and proton scavenger. The mixture of the
camphanoate diastereoisomers 11a/11b was obtained in
86% yield (Fig. 2). Two successive chromatographies with
flash silica gel were necessary, because of the scarce
0
1
6b
camphanic chloride,
enolate in N,N-dimethylformamide. This procedure pro-
0
vided the two new chiral enones (C)-(1 S)-10 ([a] C28.5,
D
0
7
8%) and (K)-(1 R)-10 ([a] K26.6, 78%) (Scheme 5).
D
0
0
Figure 2. Diastereoisomers 11a–11d prepared by esterifying (1 S)-5 and (1 R)-5 with (K)-(1S)-camphanic chloride, and specific rotations measured for each
one after chromatographic purification.

11196
J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
4
Figure 3. Isomers 5 obtained by reduction of 11 with LiAlH , and specific rotations measured for each one after chromatographic purification.
difference in polarity exhibited by the two diastereomers
0
liberate the pure enantiomers of 5 by reducing 11a–11d,
separately, with LiAlH4 in THF at room temperature for
2 h (91% yield after silica-gel purification) (Fig. 3).
17
(
11a/11b). The less polar product was 11a-(3S,1 S). Both
compounds could not be obtained entirely pure but as a
mixture in a 9:1 ratio. Similar results over compounds
0
(
3S/3R,1 R)-5 were obtained yielding the stereoisomer
The stereoisomers of 5 were characterized by their NMR
and MS data. No spectroscopic differences were found
between the data corresponding to the separated isomers and
the initial mixtures of them, except the disappearance of
some duplicate signals in NMR.
compounds 11c/11d (Fig. 2). The behaviour of these
products on the silica-gel chromatography and their
retention times when analyzed by GC clearly show that
the separation is possible due to the diastereomeric
relationship between the camphanoate moiety and the C-3
0
centre, the stereochemical configuration at C-1 being
irrelevant for this purpose.
To determine the absolute configuration of enantiomers 5,
1
8
the modified Mosher’s method was selected. The isomer 5
obtained from 11a was treated with (K)-(2R)-MTPA
chloride and (C)-(2S)-MTPA chloride, separately, afford-
ing the esters 12A and 12B (Scheme 6).
These four compounds were structurally assigned by
1
standard spectroscopic analytical techniques (IR, MS, H
1
3
NMR, C NMR, 2D NMR). Their absolute configurations
at C-3 were deduced latter, after establishing those of the
four stereoisomers of 5.
1
After assigning the H NMR signals of 12A and 12B, and
obtaining Dd [d(S)Kd(R)] values for the protons, the
absolute configuration was then accomplished following
1
8
Next, we attempted the saponification of the esters 11 with
KOH in MeOH. Nevertheless, the strict condition of this
saponification (reflux for 4–5 days) was not enough to
complete the ester hydrolysis. We, therefore, decided to
the typical procedure referred in the literature. The results,
which support the assignment are summarized in Table 1.
Consequently, the absolute configuration at C-3 of the
0
Scheme 6. Esterification of (C)-(3S,1 S)-5 with (K)-(2R)- and (C)-(2S)-MTPA chlorides.

J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
11197
1
Table 1. Differences in the H NMR chemical shifts of the (S) and (R)-MTPA esters of (3S,1 S)-5 to define the stereochemistry at C-3
0
d(S)-MTPA (ppm)
d(R)-MTPA (ppm)
Dd [d(S)-MTPAKd(R)-MTPA] (Hz)
Assignation
0
0
1
1
1
.79
.99
.00
.41–1.54
.63–1.73
0.87
0.96
0.97
1.46–1.58
1.64–1.78
K24
C9
C9
ca. K15
ca. K9
H-1
Me-4
0
Me -4
H-2
0
H -2
alcohol 5 prepared from 11a is S, and accordingly, the
configuration of the isomer of 5 obtained from 11b on C-3
was necessarily R. Eventually, the absolute configuration at
the carbon C-3 of the two isomers of 5 obtained from 11c
and 11d, were assigned as S and R, respectively, by
sandalwood, woody and dry. Heart notes: weak
spicy and sandalwood. Base note: almost odourless.
(b) Compounds 5 were odour evaluated after injecting
them, separately, on a GC fitted with sniffing port. The
results achieved by this way are depicted on Table 2.
1
3
comparison of the C NMR spectra data of them with those
of 11a and 11b.
0
Therefore, the profile of the stereoisomer (K)-(3S,1 R)-5
was positioned as the most stimulating and full of
interesting qualities among the four diastereomers, though
its odour is not as intense as that of Polysantol (V). It iws
also interesting to emphasize that in the case of Polysantol
2
.2. Odour evaluation
w
The independent odour evaluation of each individual
optically active isomer 5 (over 98.5% of purity according
to GC) was carried out by a group of perfumers using two
different protocols.
(
V), the diastereomer, which triggers the strongest and most
substantive sandalwood type odour is that with the absolute
0
atoms. From this analogy, that somehow can be extended to
configuration alike to (K)-(3S,1 R)-5 on the same carbon
9
b
(
a) Compounds 5 were smelt at three moments from
blotting paper strips impregnated with them, pre-
viously diluted with Et O, at the beginning, after Et O
w
Ebanol (IV), some useful conclusions could be put forward
regarding the structure–odour relationship among the deriva-
tives of campholenic aldehyde sandalwood-type odorants.
2
2
evaporation (top note), after 3 h (heart note) and finally
after 24 h (base note):
0
†
†
†
†
(C)-(3S,1 S)-5: top notes: phenolic, leather, styrax,
sandalwood and woody. Heart notes: very clean
sandalwood and sandela scents. Base note: almost
odourless.
3. Experimental
3.1. General experimental conditions
0
(C)-(3R,1 S)-5: top notes: smoky, tarry, phenolic,
guaiacol, woody on cedar, sandal and benjui notes.
Heart notes: sandalwood and burnt scents. Base
note: weak sandalwood odour.
GC analyses were performed on a Varian CP-3800 gas
chromatograph fitted with a methyl silicone (CP-Sil 8 CB)
capillary column (30 m!0.25 mm!0.25 mm); carrier gas:
He; flow rate: 1 mL/min; oven temperature program:
50–200 8C at a rate of 3 8C/min, then 200–290 8C at a rate
of 12 8C/min, holding the final temperature for 5 min;
injector temperature: 250 8C; flame ionization detector
0
(K)-(3S,1 R)-5: top notes: sandalwood, polysantol-
type, woody and dry. Heart notes: sandalwood and
sandela very intense. Base note: mild but clear
sandalwood note.
0
(K)-(3R,1 R)-5: top notes: weak spicy,
temperature: 300 8C; retention times (R ) are expressed in
t
Table 2. Odour evaluation of compounds 5 using a GC fitted with sniffing port
Isomer
Odour
Sandalwood pure note
0
(
C)-(3S,1 S)-5
0
Very clean but less intense sandalwood scent than (C)-(3S,1 S)-5, with woody, borneol and cashmeran notes at the end
0
(
(
C)-(3R,1 S)-5
Very clean sandalwood odour, with a waxy note at the end
0
K)-(3S,1 R)-5
Sandalwood pure note, with a waxy note at the end
0
(
K)-(3R,1 R)-5

11198
J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
minutes. Sample size for each injection was approximately
mL in a 1:50 split mode. HRMS were obtained on a
(10 mL) was added dropwise to a refluxing solution of
ZnBr2 (44 mg, 0.19 mmol) in dry toluene (50 mL) for
10 min. The reaction flask was fitted with a Dean–Stark
apparatus to remove any trace of water. After that, reflux
was continued for a further 1 h. The solution was cooled
down to room temperature, diluted with Et O (200 mL)
2
and washed with a saturated aqueous NaHCO solution
3
(3!100 mL), 1 N AcOH solution (100 mL) and brine
(3!100 mL). The resulting organic solution was dried over
1
trisector EBE Waters Micromass AutoSpect NT spec-
trometer using EI (70 eV). Unless otherwise specified, the
other general aspects and instrumentation used on these
experiences and those previous reported by us on this same
8
a,b
journal
.2. Starting materials
C)-(1R)-a-pinene (6) ((1R,5R)-2,6,6-trimethyl-bi-
are alike.
3
anhydrous Na SO and the solvent evaporated under
2
4
(
reduced pressure. The crude oil (28.13 g) was purified
by reduced pressure distillation (bp at 0.3 Torr: 43–49 8C)
to afford (K)-(1 S)-campholenic aldehyde ((K)-1)
cyclo[3.1.1]hept-2-ene): [a] C47.1 (neat), 91% ee,
D
0
(16.76 g, 56%). In the same way, (C)-(1 R)-campholenic
Aldrich, 98%. (K)-(1S)-a-pinene (6) ((1S,5S)-2,6,6-tri-
methyl-bicyclo[3.1.1]hept-2-ene): [a] K45.0 (neat), 87%
ee, Aldrich, 99%. (K)-(1S)-camphanic chloride ((1S,4R)-
0
aldehyde ((C)-1) was obtained from (K)-7 in a 59%
yield.
D
4
bonyl chloride): [a] K18.0, 99% ee, Aldrich, 98%. (K)-
,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-car-
D
0 0 0 0 0 0
3.4.1. [(1 S)-(2 ,2 ,3 -Trimethylcyclopent-3 -en-1 -yl)]-
(
2
2R)-MTPA chloride ((K)-(2R)-3,3,3-trifluoro-2-methoxy-
-phenylpropionyl chloride): [a] K137.0, 99% ee,
FLUKA, 99%. (C)-(2S)-MTPA chloride ((C)-(2S)-3,3,3-
9
a,13a
acetaldehyde, (K)-1. Colourless liquid (lit.
); Rt
14.80; [a] K5.0 (c 1.08); 96.5% (GC purity); 91% ee; IR
D
D
trifluoro-2-methoxy-2-phenylpropionyl chloride): [a] C
D
(neat) n 2716 (CHO), 1727 (C]O), 3040, 800 (C]C) and
1
0
1438 (CH –C]C); H NMR d 0.80 (3H, s, Me -2 ), 1.01
3 ax
1
37.0, 99% ee, FLUKA, 99%.
0 0
3H, s, Me -2 ), 1.62 (3H, br s, Me-3 ), 1.83–1.96 (1H, m,
eq
H-1 ), 2.23–2.46 (3H, m, H-5 CH-2), 2.53 (1H, ddd, JZ
(
0
0
3
.3. Epoxidation of a-pinene to give 7
0 0
5.4, 4.1, 2.2 Hz, H -2), 5.24 (1H, br s, H-4 ) and 9.80 (1H, t,
1
1
3
A mixture of AcOOH (60 mL, 30%, 236.8 mmol) and
anhydrous NaOAc (1.56 g) was added dropwise to a
stirred solution of (C)-(1R)-a-pinene ((C)-6) (30.75 g,
JZ2.2 Hz, H-1); C NMR d 202.93 (C-1), 45.07 (C-2),
44.18 (C-1 ), 46.88 (C-2 ), 147.93 (C-3 ), 121.52 (C-4 ),
0
0
0
0
35.48 (C-5 ), 19.98 (Meax-2 ), 25.58 (Meeq-2 ) and 12.55
0
(Me-3 ); MS m/z 152 (M , 1%), 137 (M KMe, 1), 119
0
0
0
(M KMe–H
Me, 86), 77 (20), 67 (32), 53 (14) and 41 (30).
C
C
2
23.4 mmol) and anhydrous NaOAc (28.19 g, 343.6 mmol)
in CH Cl (250 mL) at 0 8C for 45 min. After the addition
C
C
C
O, 5), 108 (M KC H O, 100), 93 (108 K
2 4
2
2
2
was completed, the mixture was allowed to warm to room
temperature and stirring was continued for another 2 h.
Then, the organic solution was washed with saturated
aqueous Fe SO solution (4!100 mL), brine (3!100 mL)
0
0
0
0
0
0
3.4.2. [(1 R)-(2 ,2 ,3 -Trimethylcyclopent-3 -en-1 -yl)]-
acetaldehyde, (C)-1. All spectroscopic properties were
identical to those of (K)-1, except for [a] C3.0 (c 1.06);
2
4
and dried over anhydrous Na SO . Filtration and evapor-
2
4
D
ation gave 27.78 g of a crude, which was purified by
reduced pressure distillation (bp at 0.05 Torr: 22–28 8C) to
afford (C)-(1S)-a-pinene epoxide ((C)-7) (18.6 g, 52%
yield). GC analysis showed a 10% amount of (K)-1 as well.
In the same way, (K)-a-(1R)-pinene epoxide ((K)-7) was
obtained from (K)-(1S)-a-pinene ((K)-6) in a 54% yield.
97.5% (GC purity); 87% ee.
3.5. Aldol reaction of 1 to give 8
The aldehyde (K)-1 (22.98 g, 151.2 mmol) was added
dropwise to a stirred solution of 3-pentanone (53.04 g,
6
03.5 mmol) and KOH (499 mg, 7.6 mmol) in MeOH
3
1
.3.1. (1S,2S,4R,6S)-2,7,7-Trimethyl-3-oxatricyclo[4.1.
); R 13.62;
t
(12 mL) at 0 8C for 1 h. Then, the mixture was allowed to
warm to room temperature and stirring was continued for a
further 3 h. The reaction was quenched with a 1 N AcOH
aqueous solution (100 mL), the solvent was then partially
evaporated in vacuo and the resulting crude diluted with
2
.0. ]octane, (C)-7 Colourless liquid (lit.
,4
13a,b
[
2
a] C95.4 (c 1.18); 89.5% (GC purity); 91% ee; IR (neat) n
D
1
978 (CH), 1267, 857 and 767 (COC); H NMR d 0.94 (3H,
0
s, Me-7), 1.29 (3H, s, Me -7), 1.31 (3H, s, Me-2), 1.62 (1H,
d, JZ9.1 Hz, H-1), 1.68–1.76 (1H, m, H-6), 1.85–2.05 (4H,
Et O (25 mL) and washed with 1 N AcOH solution (25 mL)
2
1
3
m, H-5CH-8) and 3.07 (1H, dd, JZ4.0, 1.2 Hz, H-4);
NMR d 45.04 (C-1), 60.24 (C-2), 56.83 (C-4), 27.59 (C-5),
9.71 (C-6), 40.48 (C-7), 25.82 (C-8), 20.12 (Me-7), 22.36
C
and brine (3!25 mL). The crude was dried over anhydrous
Na SO and evaporated to yield 26.52 g (74%) of a yellow
2
4
3
residue, which was used in the next reaction without further
purification. The mixture of diastereoisomeric aldols (1 S)-8
0
C
0
was analyzed by mass spectrometry. In the same way, the
(
Me-2) and 26.67 (Me -7); MS m/z 152 (M , 0.3%), 137
C
M KMe, 16), 119 (M KMe–H O, 4), 109 (M K
C
C
(
C H O, 28), 95 (18), 83 (34), 67 (100), 55 (37) and 41 (90).
2
2
3
reaction of (C)-1 with 3-pentanone yielded a mixture of
aldols (1 R)-8 in a 72% yield.
0
3
1
.3.2. (1R,2R,4S,6R)-2,7,7-Trimethyl-3-oxatricyclo[4.1.
.0. ]octane, (K)-7 All spectroscopic properties were
2
,4
0 0 0 0
3.5.1. (4R/S,5R/S)-5-Hydroxy-4-methyl-6-[(1 S)-(2 ,2 ,3 -
trimethylcyclopent-3 -en-1 -yl)]-hexan-3-one, (1 S)-8. R :
0
0
0
identical to those of (C)-7, except for [a] K108.8 (c 1.24);
D
t
9
5.3% (GC purity); 87% ee.
37.14, 37.39 and 37.52 (three peaks); MS m/z (peak R
3
1), 205 (M KH O–Me, 0.9), 162 (2), 153 (2), 149 (2), 137
2
t
C
C
C
7.14) 238 (M , 2%), 220 (M KH O, 5), 209 (M KEt,
2
C
3
.4. Preparation of campholenic aldehyde (1)
(3), 128 (2), 122 (39), 108 (79), 93 (55), 86 (13), 79 (17), 67
(18), 57 (100) and 41 (41); MS m/z (peak R 37.39) 238
A solution of (C)-7 (30.12 g, 198.2 mmol) in dry toluene
t

J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
11199
C
M , 2%), 220 (M KH O, 6), 209 (M KEt, 1), 205
C
C
(
temperature for 30 min. After the addition was completed,
the reaction was stirred for 10 min and then cooled to 0 8C.
Pre-cooled MeI (22.81 g, 160.7 mmol) was added quickly
and stirred at that temperature for 10 min and the mixture
was allowed to warm to room temperature. Brine (10 mL)
and 1 N AcOH solution (10 mL) were added and the crude
2
C
M KH O–Me, 0.9), 162 (2), 153 (2), 149 (2), 137 (3), 128
(
2
(
(
2
4), 122 (28), 108 (78), 93 (53), 86 (15), 79 (15), 67 (19), 57
100) and 41 (34); MS m/z (peak R 37.52) 238 (M , 3%),
20 (M KH O, 5), 209 (M KEt, 2), 205 (M KH O–
2 2
C
t
C
C
C
Me, 1), 162 (2), 153 (3), 149 (2), 137 (4), 128 (7), 122 (28),
08 (90), 93 (55), 86 (18), 79 (18), 67 (22), 57 (100) and 41
49).
1
(
was extracted with hexane/Et O 1:1 (75 mL). The resulting
2
organic solution was washed with 1 N AcOH solution (2!
30 mL) and brine (3!30 mL), dried over anhydrous
Na SO and evaporated under reduced pressure to
0
trimethylcyclopent-3 -en-1 -yl)]-hexan-3-one, (1 R)-8.
0
0
0
3
.5.2. (4R/S,5R/S)-5-Hydroxy-4-methyl-6-[(1 R)-(2 ,2 ,3 -
2
4
0
0
0
The GC analysis and mass spectra were identical to those
afford 13.49 g of crude (C)-10. An aliquot sample of this
crude (621 mg) was chromatographed on flash silica gel
0
(eluent hexane/Et O 95:5) to afford pure (C)-10 (484 mg,
2
of (1 S)-8.
7
8% yield). The rest of the crude was used in the
following reaction without further purification. In the
same way, (K)-10 was obtained from (C)-9 in a 78%
yield.
3
.6. Dehydration of aldol 8 to give 9
A Dean–Stark apparatus was fitted to a flask containing a
solution of (1 S)-8 (25.68 g, 107.9 mmol) and TsOH$H O
0
282 mg, 1.4 mmol) in dry toluene (40 mL), and the mixture
2
0 0 0 0
3.7.1. (5E)-(4,4-Dimethyl-6-[(1 S)-(2 ,2 ,3 -trimethyl-
(
0
0
was refluxed for 30 min. Then, the solution was allowed to
cool down and washed with an aqueous saturated NaHCO3
solution (3!25 mL), 1 N AcOH solution (25 mL) and brine
(3!25 mL). The solution was dried over anhydrous
Na SO and evaporated in vacuo to yield an oil (22.07 g),
cyclopent-3 -en-1 -yl)]-hex-5-en-3-one, (C)-10. Colour-
less liquid; R 32.58; [a] C28.5 (c 1.16); 95.7% (GC
t
D
purity); 91% ee; IR (neat) n 1712 (C]O), 3038, 798 (C]C)
1
0
and 1463 (CH –C]C); H NMR d 0.74 (3H, s, Me -2 ),
3 ax
0
2
4
0.95 (3H, s, Me -2 ), 1.01 (3H, t, JZ7.3 Hz, H-1), 1.23
eq
0
(6H, s, Me-4), 1.61 (3H, br s, Me-3 ), 2.02–2.14 (1H, m,
which was purified by reduced pressure distillation (bp at
.06 Torr: 78–86 8C) to afford (K)-9 (14.55 g, 61% from
0
0
0
0
H-5 ), 2.20–2.31 (1H, m, H -5 ), 2.38 (1H, dt, JZ9.1,
†
K)-1). In the same way, (C)-9 was obtained from (1 R)-8
0
0
(
in a 58% yield (from (C)-1).
7.3 Hz, H-1 ), 2.49 (2H, q, JZ7.3 Hz, H-2), 5.23 (1H, br s,
0
5.6, 7.3 Hz, H-6); C NMR d 8.39 (C-1), 30.46 (C-2),
H-4 ), 5.50 (1H, d, JZ15.6 Hz, H-5) and 5.58 (1H, dd, JZ
1
3
1
214.21 (C-3), 49.97 (C-4), 135.20 (C-5), 131.17 (C-6),
0 0 0 0
.6.1. (4E)-4-Methyl-6-[(1 S)-(2 ,2 ,3 -trimethylcyclo-
3
0
0
0 0 0 0
54.10 (C-1 ), 48.31 (C-2 ), 147.95 (C-3 ), 121.41 (C-4 ),
35.29 (C-5 ), 24.29 (Me-4), 20.48 (Meax-2 ), 25.42
pent-3 -en-1 -yl)]-hex-4-en-3-one, (K)-9. Colourless
liquid; R 35.38; [a] K1.6 (c 1.02); 93.1% (GC purity);
0
0
t
D
0
0
C
9
1
(
1% ee; IR (neat) n 1673, 1641 (C]O), 3039, 798 (C]C),
(Meeq-2 ) and 12.62 (Me-3 ); MS m/z 234 (M , 0.8%),
1
0
C
C
461 (CH –C]C); H NMR d 0.83 (3H, s, Me -2 ), 1.02
219 (M KMe, 0.1), 177 (M KEtCO, 14), 161 (0.9), 149
(2), 135 (4), 126 (20), 109 (33), 91 (9), 79 (7), 69 (100), 57
(33) and 41 (53).
3
ax
0
3H, s, Me -2 ), 1.10 (3H, t, JZ7.4 Hz, H-1), 1.61 (3H, br
eq
0
0
s, Me-3 ), 1.80 (3H, br s, Me-4), 1.81–1.99 (2H, m, H-5 C
0
0
0
H-1 ), 2.15–2.42 (3H, m, H -5 CH-6), 2.68 (2H, q, JZ
0
.4 Hz, H-5); C NMR d 8.87 (C-1), 30.32 (C-2), 202.49
C-3), 136.92 (C-4), 141.87 (C-5), 29.78 (C-6), 49.82 (C-1 ),
7
1
(
.4 Hz, H-2), 5.23 (1H, br s, H-4 ) and 6.68 (1H, td, JZ7.3,
0 0 0 0
.7.2. (5E)-4,4-Dimethyl-6-[(1 R)-(2 ,2 ,3 -trimethyl-
3
1
3
0
0
cyclopent-3 -en-1 -yl)]-hex-5-en-3-one, (K)-10. All spec-
troscopic properties were identical to those of (C)-10,
except for [a] K26.6 (c 1.04); 97.7% (GC purity); 87% ee.
0
0
0
1.47 (Me-4), 19.76 (Me -2 ), 25.89 (Me -2 ) and 12.59
0
0
4
1
6.90 (C-2 ), 148.43 (C-3 ), 121.48 (C-4 ), 35.56 (C-5 ),
0
D
0
ax
C
eq
C
0
(
(
(
Me-3 ); MS m/z 220 (M , 4%), 205 (M KMe, 12), 191
C
C
M KEt, 4), 177 (5), 163 (M KEtCO, 3), 159 (3), 150
3.8. Reduction of 10 with NaBH to give 5
4
13), 138 (5), 121 (20), 112 (39), 93 (39), 79 (28), 67 (47),
7 (60) and 41 (100).
Solid NaBH (2.77 g, 71.8 mmol) was added portionwise to
4
5
a stirred solution of crude (C)-10 (12.80 g, ca. 54.7 mmol)
in MeOH (50 mL) at 0 8C. After 15 min the crude was
allowed to warm to room temperature and left to react for
45 min. Then, the solvent was partially evaporated under
reduced pressure and the resulting suspension was diluted
0
0
0
0
3
.6.2. (4E)-4-Methyl-6-[(1 R)-(2 ,2 ,3 -trimethylcyclo-
0
0
pent-3 -en-1 -yl)]-hex-4-en-3-one, (C)-9. All spectro-
scopic properties were identical to those of (K)-9, except
for [a] C1.5 (c 1.16); 98.8% (GC purity); 87% ee.
D
with hexane/Et O 1:2 (75 mL), cooled again to 0 8C and
2
neutralized with 1 N AcOH solution. The organic layer was
washed again with 1 N AcOH solution (50 mL) and brine
3
.7. Deconjugative a-methylation of 9 to give 10
(3!50 mL), then dried over anhydrous Na SO and the
solvent evaporated in vacuo to yield 12.64 g of a crude,
2 4
A solution of (K)-9 (13.31 g, 60.5 mmol) in dry DMF
t
(
(
4 mL) was added dropwise to a stirred solution of K BuO
6.98 g, 61.0 mmol) in dry DMF (30 mL) at room
which was purified by reduced pressure distillation (bp at
0
0
dimethyl-6-[(1 S)-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -
.15 Torr: 89–90 8C) to afford (1 S)-5 ((3R/S,5E)-4,4-
0
0
0
0
0
0
yl)]-hex-5-en-3-ol) (9.58 g, 95% yield). (1 S)-5 is a mixture
†
The synthesis of (K)-9 was also performed working with crude products
without further purification in order to avoid losing weight by evaporation
of the very volatile compounds 7 and 1. In that case, a four-step overall
yield of 36% from a-pinene was obtained (77% averaged yield per
reaction).
0
of diastereoisomers in ca. 1:1 ratio as its NMR spectra
showed. Colourless liquid; R 33.28; 98.5% (GC purity). In
t
0
the same way, a (1 R)-5 mixture was obtained from (K)-10

11200
J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
in a 94% yield, showing the same retention time in GC and
identical NMR spectra.
3.9.2. (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]
heptane-1-carboxylic acid, (3R,5E)-4,4-dimethyl-6-
0
0
0
0
0
0
[
(1 S)-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -yl)]-hex-5-en-
-yl ester, 11b. Colourless crystals; mp 104.6–106.1 8C
hexane); R 56.97; [a] C25.2 (c 1.01); 91.5% (GC purity;
3
3
.9. Esterification of 5 with (K)-(1S)-camphanic chloride
(
t
D
8
and 977 (C]C); H NMR d 0.74 (3H, s, Me -2 ), 0.89 (3H,
t, JZ7.3 Hz, H-1), 0.95 (3H, s, Me -2 ), 1.02 (3H, s, Me-
eq
.5% of 11a); IR (KBr) n 1793, 1741, 1172 (COO), 3031
Solid (K)-(1S)-camphanic chloride (1.08 g, 4.9 mmol) was
added to a stirred solution of (1 S)-5 (807 mg, 3.42 mmol)
1
0
0
ax
0
7camp), 1.03 (6H, s, Me-4), 1.10 (3H, s, Me -7camp), 1.12
and DMAP (595 mg, 4.8 mmol) in dry CH Cl (30 mL) at
2
0
), 1.42–1.56 (1H, m, H-2), 1.61 (3H, br s,
), 1.94 (1H, ddd,
2
0 8C under argon. The reaction crude was allowed to reach
room temperature and, after 2 h, the crude was diluted with
(3H, s, Me-4
Me-3 ), 1.65–1.76 (2H, m, H -2CH-5
camp
0
0
camp
Et O (50 mL) and washed with 1 N AcOH solution (3!
2
0
), 2.16–2.29 (1H, m, H -5 ), 2.30–2.37 (1H, m,
0
JZ13.3, 10.7, 4.5 Hz, H -5
H-6
camp
H-1 ), 2.43 (1H, ddd, JZ13.3, 10.7, 4.5 Hz, H -6
), 2.01–2.13 (2H, m, H-5 C
camp
2
and brine (2!25 mL). The resulting organic solution was
5 mL), saturated aqueous NaHCO solution (2!25 mL)
0
0
3
0
0
), 4.88
camp
0
dried over anhydrous Na SO and the solvent evaporated
2
4
(
1H, dd, JZ10.4, 2.5 Hz, H-3), 5.23 (1H, br s, H-4 ), 5.42
under reduced pressure to yield 1.31 g of a mixture of the
diastereoisomers 11a/11b. The mixture was flash chromato-
graphed on silica gel (eluent hexane to hexane/Et O 9:1) to
2
(
1H, d, JZ15.8 Hz, H-5) and 5.49 (1H, dd, JZ15.8, 6.7 Hz,
13
H-6); C NMR d 11.14 (C-1), 23.10 (C-2), 83.70 (C-3),
0
4
(
(
1
0.02 (C-4), 136.24 (C-5), 129.67 (C-6), 54.15 (C-1 ), 48.02
obtain 188 mg of 11a (less polar product), 853 mg of a 11a/
0
0
0
0
C-2 ), 147.98 (C-3 ), 121.42 (C-4 ), 35.30 (C-5 ), 23.16
1
1b mixture and 177 mg of 11b (more polar product) (total
recovered mass after column chromatography: 1218 mg,
6% reaction yield). In the same way, (1 R)-5 was esterified
0 0 0
Me-4), 25.03 (Me -4), 20.45 (Me -2 ), 25.35 (Me -2 ) and
ax eq
0
2.65 (Me-3 ), signals for the camphanoate moiety: 91.32
C-1), 178.18 (C-3), 54.84* (C-4), 28.98 (C-5), 31.12 (C-6),
0
8
(
with the same acid chloride to yield a mixture of the
diastereoisomers 11c/11d (84% yield), which were also
isolated using the same separation technique, the less polar
product being 11c and the more polar one 11d.
5
and 16.91 (Me -7) (*these signals may be interchanged);
3.84* (C-7), 167.41 (COO-1), 9.63 (Me-4), 16.84 (Me-7)
0
C C
MS m/z 218 (M KCampOH, 12%), 203 (M KCampOH–
C C
Me, 9), 189 (M KCampOH–Et, 3), 177 (M KCampO-
CHEt, 100), 161 (11), 149 (8), 135 (14), 121 (25), 109 (42),
9
7 (13), 83 (37), 69 (61), 55 (37) and 41 (40).
3.9.1. (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]
heptane-1-carboxylic acid, (3S,5E)-4,4-dimethyl-6-
0
-yl ester, 11a. Colourless crystals; mp 90.9–92.2 8C
0
0
0
0
0
[
3
(1 S)-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -yl)]-hex-5-en-
3.9.3. (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]
heptane-1-carboxylic acid, (3S,5E)-4,4-dimethyl-6-
‡
0
0
0
0
0
0
(
hexane); R 56.88; [a] K8.1 (c 1.05); 90.4% (GC purity;
t
[(1 R)-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -yl)]-hex-5-
en-3-yl ester, 11c. Colourless crystals; mp 67.6–72.2 8C
D
9
and 979 (C]C); H NMR d 0.74 (3H, s, Me -2 ), 0.87 (3H,
.6% of 11b); IR (KBr) n 1793, 1741, 1173 (COO), 3040
0
1
(hexane); R 56.85; [a] K26.8 (c 1.05 in CHCl ); 84.7%
t D 3
(GC purity; 8.5% of 11d); IR (KBr) n 1791, 1742, 1173
ax
0
t, JZ7.3 Hz, H-1), 0.94 (3H, s, Me -2 ), 1.01 (3H, s, Me-
eq
1
COO), 3040 and 979 (C]C); H NMR d 0.74 (3H, s, Me -
0
(
7camp), 1.037 (3H, s, Me-4), 1.044 (3H, s, Me -4), 1.11 (3H,
0
ax
0
), 1.03 (3H, s, Me-4), 1.04 (3H, s, Me -4),
0
3H, s, Me-7
2
), 0.86 (3H, t, JZ7.4 Hz, H-1), 0.95 (3H, s, Me -2 ), 1.01
s, Me -7
H-2), 1.61 (3H, br s, Me-3 ), 1.65–1.76 (2H, m, H -2CH-
), 1.12 (3H, s, Me-4
0
), 1.42–1.57 (1H, m,
0
0
), 2.16–2.28 (1H, m, H -
eq
camp
camp
0
(
camp
0
1H, m, H-2), 1.61 (3H, br s, Me-3 ), 1.63–1.75 (2H, m,
1
.11 (3H, s, Me -7
), 1.12 (3H, s, Me-4camp), 1.43–1.56
0
5camp), 1.93 (1H, ddd, JZ13.2, 10.7, 4.4 Hz, H -5
.99–2.12 (2H, m, H-5 CH-6
), 2.30–2.37 (1H, m, H-1 ), 2.43 (1H, ddd, JZ13.2, 10.7,
),
camp
camp
0
0
(
H -2CH-5
1
5
4
camp
0
0
0
.4 Hz, H -6
0
), 1.92 (1H, ddd, JZ13.3, 10.7, 4.4 Hz,
camp
0
0
H -5
), 1.99–2.13 (2H, m, H-5 CH-6camp), 2.15–2.27
), 4.89 (1H, dd, JZ10.6, 2.3 Hz, H-3), 5.23
camp
camp
0
13
0
0
3.3, 10.7, 4.4 Hz, H -6
0
(
1H, m, H -5 ), 2.30–2.37 (1H, m, H-1 ), 2.43 (1H, ddd, JZ
(
NMR d 11.03 (C-1), 22.78 (C-2), 83.56 (C-3), 40.15 (C-4),
1H, br s, H-4 ) and 5.39–5.53 (2H, m, H-5CH-6);
C
0
H-3), 5.23 (1H, br s, H-4 ) and 5.39–5.54 (2H, m, H-5CH-
1
), 4.88 (1H, dd, JZ10.4, 2.2 Hz,
camp
0
); C NMR d 11.11 (C-1), 22.94 (C-2), 83.77 (C-3), 40.11
C-4), 136.36 (C-5), 129.66 (C-6), 54.15 (C-1 ), 48.06
0 0
36.74 (C-5), 129.66 (C-6), 54.19 (C-1 ), 48.18 (C-2 ),
1
1
2
(
1
5
1
3
0
4.24 (Me -4), 20.44 (Me -2 ), 25.34 (Me -2 ) and 12.65
0
0
6
48.01 (C-3 ), 121.38 (C-4 ), 35.55 (C-5 ), 23.34 (Me-4),
0
0
0
0
0
(
(
(
ax
eq
0
0
0
0
78.35 (C-3), 54.82* (C-4), 28.92 (C-5), 31.08 (C-6),
C-2 ), 148.06 (C-3 ), 121.46 (C-4 ), 35.30 (C-5 ), 23.17
Me-3 ), signals for the camphanoate moiety: 91.35 (C-1),
0 0 0
Me-4), 24.98 (Me -4), 20.49 (Me -2 ), 25.39 (Me -2 ) and
ax eq
0
12.70 (Me-3 ), signals for the camphanoate moiety: 91.40
C-1), 178.42 (C-3), 54.87* (C-4), 28.96 (C-5), 31.09 (C-6),
3.77* (C-7), 167.53 (COO-1), 9.64 (Me-4), 16.79 (Me-7)
0
(
and 16.87 (Me -7) (*these signals may be interchanged);
MS m/z 218 (M KCampOH, 6%), 203 (M KCampOH–
C
C
53.81* (C-7), 167.59 (COO-1), 9.69 (Me-4), 16.83 (Me-7)
and 16.92 (Me -7) (*these signals may be interchanged);
0
MS m/z 218 (M KCampOH, 4%), 203 (M KCampOH–
C C
Me, 6), 189 (M KCampOH–Et, 3), 177 (M KCampO-
C
C
CHEt, 67), 161 (8), 149 (8), 135 (5), 121 (37), 109 (56), 97
20), 83 (57), 69 (100), 55 (58) and 41 (64).
C
C
Me, 3), 189 (M KCampOH–Et, 1), 177 (M KCampO-
CHEt, 37), 161 (4), 149 (4), 135 (7), 121 (16), 109 (26), 97
(10), 83 (26), 69 (75), 55 (69) and 41 (100).
(
‡
In order to avoid confusion, identification numbers for hydrogen and
carbon atoms in NMR are the same than in 5. Carbon atoms of the
camphanoate moiety are separately numbered from 1 to 7, following the
IUPAC nomenclature, with the subscript ‘camp’. Despite this, note that in
IUPAC nomenclature the camphanoate moiety is the main part of the
molecule. In the MS, ‘camp’ means (1S,4R)-4,7,7-trimethyl-3-oxo-2-
oxabicyclo[2.2.1]heptane-1-carbonyl. This moiety has a formula weight
of 181 amu.
3.9.4. (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]
heptane-1-carboxylic acid, (3R,5E)-4,4-dimethyl-6-
0 0 0 0 0 0
[
(1 R)-(2 ,2 ,3 -trimethylcyclopent-3 -en-1 -yl)]-hex-5-
en-3-yl ester, 11d. Colourless crystals; mp 106.2–109.4 8C
(hexane); R 56.99; [a] C0.4 (c 0.94); 79.0% (GC purity;
t
D

J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
11201
0
25.38 (Me -2 ) and 12.70 (Me-3 ); MS m/z 221 (M K
0
0
8
9
% of 11c); IR (KBr) n 1793, 1741, 1172 (COO), 3065 and
80 (C]C); H NMR d 0.74 (3H, s, Me -2 ), 0.89 (3H, t,
(C-5 ), 22.66 (Me-4), 23.94 (Me -4), 20.52 (Me -2 ),
ax
1
0
0
0
C
ax
0
eq
C
C
JZ7.4 Hz, H-1), 0.94 (3H, s, Me -2 ), 1.02 (3H, s,
Me, 0.1%), 218 (M KH O, 0.1), 207 (M KEt, 0.3),
2
eq
0
), 1.44–1.57 (1H,
C
C
Me-7camp), 1.03 (3H, s, Me-4), 1.04 (3H, s, Me -4), 1.10
), 1.12 (3H, s, Me-4
203 (M KH O–Me, 0.2), 178 (M KCH CH COH,
2 3 2
0
m, H-2), 1.61 (3H, br s, Me-3 ), 1.63–1.77 (2H, m, H -2CH-
C
20), 163 (178 KMe, 14), 149 (4), 135 (14), 121 (26),
(
3H, s, Me -7
camp
camp
0
0
109 (48), 93 (16), 79 (12), 69 (100), 59 (23) and 41 (62).
HRMS m/z, calcd for C H O, 236.2140 (M ), found
236.2116.
0
.00–2.11 (2H, m, H-5 CH-6camp), 2.17–2.29 (1H, m,
C
5camp), 1.93 (1H, ddd, JZ13.3, 10.7, 4.4 Hz, H -5camp),
2
16
28
0
0
0.7, 4.4 Hz, H -6
0
0
H -5 ), 2.30–2.37 (1H, m, H-1 ), 2.44 (1H, ddd, JZ13.3,
0
.23 (1H, br s, H-4 ) and 5.38–5.53 (2H, m, H-5CH-6);
0
cyclopent-3 -en-1 -yl)]-hex-5-en-3-ol, (K)-(3R,1 R)-5.
0
0
0
1
5
), 4.89 (1H, dd, JZ10.4, 2.2 Hz, H-3),
3.10.2. (3R,5E)-4,4-Dimethyl-6-[(1 R)-(2 ,2 ,3 -trimethyl-
camp
0
NMR d 11.15 (C-1), 23.00 (C-2), 83.56 (C-3), 40.15 (C-4),
13
0
0
Obtained from 11d. All spectroscopic properties were
0
C
0
0
48.05 (C-3 ), 121.44 (C-4 ), 35.58 (C-5 ), 23.29 (Me-4),
0
(c 1.00); 98.5% (GC purity); 66% de.
1
1
2
36.70 (C-5), 129.71 (C-6), 54.24 (C-1 ), 48.20 (C-2 ),
identical to those of (C)-(3S,1 S)-5, except for [a] K9.4
D
0
4.41 (Me -4), 20.48 (Me -2 ), 25.38 (Me -2 ) and 12.69
0
0
0
0
0
ax
eq
0
78.25 (C-3), 54.90* (C-4), 29.02 (C-5), 31.16 (C-6),
0 0 0 0
3.10.3. (3R,5E)-4,4-Dimethyl-6-[(1 S)-(2 ,2 ,3 -trimethyl-
(
Me-3 ), signals for the camphanoate moiety: 91.36 (C-1),
0
0
0
1
5
cyclopent-3 -en-1 -yl)]-hex-5-en-3-ol, (C)-(3R,1 S)-5.
Obtained from 11b, colourless liquid; R 33.28; [a] C
25.3 (c 1.26); 97.7% (GC purity); 64% de; IR (neat) n 3413
3.89* (C-7), 167.45 (COO-1), 9.68 (Me-4), 16.85 (Me-7)
0
t
D
and 16.91 (Me -7) (*these signals may be interchanged);
MS m/z 218 (M KCampOH, 4%), 203 (M KCampOH–
C
C
(OH), 1103 (C–O), 3037, 977 (C]C) and 1463 (CH –
3
C C
Me, 3), 189 (M KCampOH–Et, 1), 177 (M KCampO-
1
C]C); H NMR d 0.75 (3H, s, Me -2 ), 0.95 (3H, s, Me -
0
ax
eq
0
CHEt, 36), 161 (4), 149 (4), 135 (7), 121 (15), 109 (26), 97
(
2 ), 0.97–1.05 (9H, m, Me-4CH-1), 1.15–1.31 (1H, m,
0 0
H-2), 1.51–1.69 (1H, m, H -2), 1.61 (3H, br s, Me-3 ), 2.01–
9), 83 (31), 69 (80), 55 (65) and 41 (100).
0
0
0
2
.15 (1H, m, H-5 ), 2.20–2.31 (1H, m, H -5 ), 2.37 (1H, dt,
0
JZ8.9, 7.7 Hz, H-1 ), 3.14 (1H, d, JZ10.4 Hz, H-3), 5.24
3
.10. Reduction of 11 with LiAlH to give 5
4
0
(
(
2
(
(
2
1H, br s, H-4 ), 5.41 (1H, d, JZ15.8 Hz, H-5) and 5.50
1
3
1H, dd, JZ15.8, 7.7 Hz, H-6); C NMR d 11.66 (C-1),
4.28 (C-2), 80.25 (C-3), 41.00 (C-4), 137.74 (C-5), 130.26
Solid LiAlH (320 mg, 8.43 mmol) was added portionwise
4
to a stirred solution of 11a (270 mg, 0.65 mmol) in dry THF
0 0 0
C-6), 54.37 (C-1 ), 48.03 (C-2 ), 148.00 (C-3 ), 121.50
(15 mL) at 0 8C, and then allowed to react at room
temperature for 2 h. Then, the mixture was diluted wih
0
0
0
C-4 ), 35.56 (C-5 ), 22.68 (Me-4), 24.01 (Me -4),
0 0 0
0.53 (Me -2 ), 25.45 (Me -2 ) and 12.70 (Me-3 ); MS
ax eq
Et O (25 mL). The remaining hydride was destroyed by
2
C
C
m/z 221 (M KMe, 0.1%), 219 (M KOH, 0.1), 207,
adding brine (10 mL) and the aqueous solution neutralized
with 1 N HCl solution. The aqueous layer was extracted
with Et O (2!25 mL) and the resulting organic solution
C
M KEt, 0.3), 203 (M KH O–Me, 0.2), 178 (M K
C
C
(
CH CH COH, 23), 163 (178 KMe, 15), 149 (4), 135 (11),
2
C
3
2
2
122 (25), 109 (48), 93 (16), 79 (11), 69 (100), 59 (24) and 41
was washed with 5% NaHCO solution (25 mL) and brine
3
(62).
(
2!25 mL), then dried over anhydrous Na SO and the
2 4
solvent evaporated under reduced pressure to afford 250 mg
of a crude, which was purified by silica-gel flash
chromatography (eluent hexane/Et O 85:15) to yield (C)-
0 0 0 0
.10.4. (3S,5E)-4,4-Dimethyl-6-[(1 R)-(2 ,2 ,3 -trimethyl-
cyclopent-3 -en-1 -yl)]-hex-5-en-3-ol, (K)-(3S,1 R)-5.
3
0
0
0
2
0
Obtained from 11c. All spectroscopic properties were
identical to those of (C)-(3R,1 S)-5, except for [a] K
(
reduction of 11b, 11c and 11d, separately, (C)-(3R,1 S)-5,
3S,1 S)-5 (140 mg, 0.59 mmol, 91%). In the same way, by
0
2.1 (c 1.06); 97.0% (GC purity); 64% de. HRMS m/z, calcd
0
K)-(3S,1 R)-5 and (K)-(3R,1 R)-5 were obtained,
D
0
respectively.
0
2
for C H O, 236.2140 (M ), found 236.2144.
(
C
16 28
0
0 0 0 0
.10.1. (3S,5E)-4,4-Dimethyl-6-[(1 S)-(2 ,2 ,3 -trimethyl-
3.11. Esterification of (C)-(3S,1 S)-5 with (K)-(2R)- and
(C)-(2S)-MTPA chloride
3
0
0
0
cyclopent-3 -en-1 -yl)]-hex-5-en-3-ol, (C)-(3S,1 S)-5.
Obtained from 11a, colourless liquid; R 33.28; [a] C4.6
t
D
§
c 1.17); 94.2% (GC purity); 66% de; IR (neat) n 3412
A solution of (K)-(2R)-MTPA chloride (0.3 mL, 10%,
0.12 mmol) in dry CH Cl was added to a stirred solution of
(C)-(3S,1 S)-5 (13.5 mg, 0.057 mmol) and DMAP (23 mg,
3.3 mmol) in dry CH Cl (1 mL) at 0 8C under argon. Then,
the reaction crude was allowed to warm to room
temperature overnight. After that, the crude was diluted
(
(
2 2
OH), 1102 (C–O), 3036, 977 (C]C) and 1463 (CH –
3
0
1
0
), 0.97–1.04 (9H, m, Me-4CH-1), 1.15–1.32 (1H, m,
C]C); H NMR d 0.75 (3H, s, Me -2 ), 0.96 (3H, s, Me -
ax
eq
0
H-2), 1.53–1.70 (1H, m, H -2), 1.62 (3H, br s, Me-3 ), 2.02–
2
2
2
0
.15 (1H, m, H-5 ), 2.19–2.32 (1H, m, H -5 ), 2.37 (1H, q,
0
0
0
0
2
0
with Et
with 1 N AcOH solution (2!10 mL), saturated aqueous
NaHCO solution (15 mL) and brine (2!15 mL). The
resulting organic solution was dried over anhydrous Na SO
2
O (25 mL) and the organic solution was washed
JZ8.2 Hz, H-1 ), 3.14 (1H, d, JZ10.2 Hz, H-3), 5.24 (1H,
br s, H-4 ), 5.40 (1H, d, JZ15.9 Hz, H-5) and 5.50 (1H, dd,
JZ15.9, 7.7 Hz, H-6); C NMR d 11.66 (C-1), 24.27 (C-2),
0.15 (C-3), 41.02 (C-4), 137.77 (C-5), 130.20 (C-6), 54.28
0
1
3
3
2
4
8
0 0 0 0
C-1 ), 48.03 (C-2 ), 148.02 (C-3 ), 121.50 (C-4 ), 35.48
and the solvent evaporated under reduced pressure to yield
2 mg of a crude that was flash chromatographed on silica
gel (eluent hexane/Et O 95:5) to obtain pure 12A (23 mg,
89% yield). In the same way, the (R)-MTPA ester (12B) was
obtained after reacting (C)-(3S,1 S)-5 with (C)-(2S)-
MTPA chloride in an 89% yield.
(
3
§
2
Diastereomeric excess calculated through the integration of the duplicate
0
1
3
0
0
C NMR signals assigned to C-3, C-1 , C-5 and Me -4, for (C)-(3S,
S)-5 (major component) and its diastereomer (C)-(3R,1 S)-5 (minor
0
0
0
1
component).

11202
J. M. Castro et al. / Tetrahedron 61 (2005) 11192–11203
3.11.1. (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionic
acid, (3S,5E)-4,4-dimethyl-6-[(1 S)-(2 ,2 ,3 -trimethyl-
temperature: 250 8C; oven temperature program: 60 8C
(0 min) to 240 8C (20 min) at a rate of 4 8C/min. Sample
size for each injection was approximately 1 mL.
0
0
0
cyclopent-3 -en-1 -yl)]-hex-5-en-3-yl ester, 12A. Colour-
0
0
less liquid; R 54.90; 94% (GC purity); H NMR d 0.72 (3H,
0
¶
1
t
0
), 0.99 (3H, s, Me-4), 1.00 (3H, s, Me -4), 1.41–1.54 (1H,
s, Me -2 ), 0.79 (3H, t, JZ7.6 Hz, H-1), 0.93 (3H, s, Me -
ax
eq
0
m, H-2), 1.60 (3H, br s, Me-3 ), 1.63–1.73 (1H, m, H -2),
0
2
Acknowledgements
0
.99–2.09 (1H, m, H-5 ), 2.15–2.28 (1H, m, H -5 ), 2.28–
0
0
0
0
1
2
1
We wish to thank the Spanish Ministerio de Ciencia y
Tecnolog ´ı a for financial support (RCD project PPQ2000-
0
0.2, 2.5 Hz, H-3), 5.23 (1H, br s, H-4 ), 5.36–5.51 (2H, m,
.38 (1H, m, H-1 ), 3.54 (3H, br s, OMe), 4.93 (1H, dd, JZ
0
1
665; partial financial support from the FEDER funds of the
H-5CH-6), 7.36–7.43 (3H, m, o,p-Ph), 7.57–7.62 (2H, m,
m-Ph); C NMR d 10.91 (C-1), 23.17 (C-2), 85.33 (C-3),
European Union) and the Ministerio de Educaci o´ n, Cultura
y Deporte for a fellowship to J.M.C. We also greatly thank
to Carles Ib a´ n˜ ez, Fina Caballer and Meritxell Antich of
Lucta S. A. (Barcelona, Spain) for the odour evaluation.
1
3
0
4
4
2
2
0.33 (C-4), 136.64 (C-5), 129.66* (C-6), 54.19 (C-1 ),
0
3.41 (Me-4), 24.37 (Me -4), 20.44 (Me -2 ), 25.35 (Me -
0
0
0
8.16 (C-2 ), 148.06 (C-3 ), 121.45 (C-4 ), 35.42 (C-5 ),
0
), 12.69 (Me-3 ), signals for the MTPA moiety: 166.52
0
ax
eq
0
0
(
(
(
C-1), 84.50 (C-2), 125.35 (CF ), 55.33 (OMe), 131.95
3
C-1 ), 129.51* (C-2 ), 128.31 (C-3 ), 127.81 (C-4 )
Ph
Ph
Ph
Ph
*these signals may be interchanged).
References and notes
1. Fra
7633–7703.
2. Bajgrowicz, J. A.; Fra
´
ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54,
3
.11.2. (2R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-pro-
pionic acid, (3S,5E)-4,4-dimethyl-6-[(1 S)-(2 ,2 ,3 -tri-
0
0
0
0
methylcyclopent-3 -en-1 -yl)]-hex-5-en-3-yl ester, 12B.
0
Colourless liquid; R 54.85; 95% (GC purity); H NMR d
0
´
ter, G. Enantiomer 2000, 5, 225–234.
1
3. Shankaranarayana, K. H.; Parthasarathi, K. Perfum. Flavor.
1984, 9, 17–20.
4. Bajgrowicz, J. A.; Frank, I.; Frater, G.; Hennig, M. Helv.
´
t
0
3H, s, Me -2 ), 0.96 (3H, s, Me-4), 0.97 (3H, s, Me -4),
0
.72 (3H, s, Me -2 ), 0.87 (3H, t, JZ7.6 Hz, H-1), 0.93
ax
0
.46–1.58 (1H, m, H-2), 1.60 (3H, br s, Me-3 ), 1.64–1.78
0
(
eq
0
1H, m, H -2), 1.97–2.10 (1H, m, H-5 ), 2.13–2.24 (1H, m,
1
(
Chim. Acta 1998, 81, 1349–1358.
0
H -5 ), 2.27–2.37 (1H, m, H-1 ), 3.57 (3H, br s, OMe), 4.93
0
5. (a) Naipawer, R. E. U.S. Patent 4,696,766 (Priority, March 19,
1986, to Givaudan and CIE) [Chem. Abstr. 1987, 106, 175828].
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Patent 0,155,591 (Priority, March 23, 1984, to Firmenich S.A.)
[Chem. Abstr. 1985, 105, 191435q].
0
0
0
0
.50 (2H, m, H-5CH-6), 7.37–7.44 (3H, m, o,p-Ph), 7.58–
(
1H, dd, JZ9.7, 2.3 Hz, H-3), 5.23 (1H, br s, H-4 ), 5.35–
5
7
8
5
3
2
13
.64 (2H, m, m-Ph); C NMR d 11.24 (C-1), 23.44 (C-2),
5.38 (C-3), 40.30 (C-4), 136.34 (C-5), 129.76* (C-6),
4.22 (C-1 ), 48.14 (C-2 ), 148.05 (C-3 ), 121.46 (C-4 ),
6. Castro, J. M.; Linares-Palomino, P. J.; Salido, S.; Altarejos, J.;
nchez, A. Tetrahedron Lett. 2004, 45,
0
5.41 (C-5 ), 22.87 (Me-4), 24.68 (Me -4), 20.44 (Me -2 ),
0
0
0
Nogueras, M.; Sa
2619–2622.
´
0
0
0
5.36 (Me -2 ), 12.69 (Me-3 ), signals for the MTPA
ax
0
0
7. (a) Buchbauer, G.; Spreitzer, H.; Swatonek, H.; Wolschann, P.
Tetrahedron: Asymmetry 1992, 3, 197–198. (b) Buchbauer, G.;
Hillisch, A.; Mraz, K.; Wolschann, P. Helv. Chim. Acta 1994,
77, 2286–2296. (c) Buchbauer, G.; Sunara, A.; Weiss-Greiler,
P.; Wolschann, P. Eur. J. Med. Chem. 2001, 36, 673–683 and
references cited therein.
. (a) Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; S a´ nchez,
A. Tetrahedron Lett. 2003, 44, 6651–6655. (b) Castro, J. M.;
Salido, S.; Altarejos, J.; Nogueras, M.; S a´ nchez, A.
Tetrahedron 2002, 58, 5941–5949. (c) Linares, P.; Salido,
S.; Altarejos, J.; Nogueras, M.; S a´ nchez, A. In Chlorosulfonic
Acid as a Cyclization Agent for Preparing Cyclic Ether
Odorants; Lanzotti, V., Taglialatela-Scafati, O., Eds.; Flavour
and Fragrance Chemistry; Kluwer Academic: Dordrecht,
eq
moiety: 166.44 (C-1), 85.00 (C-2), 125.37 (CF ), 55.38
3
(
OMe), 132.13 (C-1 ), 129.49* (C-2 ), 128.28 (C-3 ),
Ph Ph Ph
1
27.62 (C-4 ) (*these signals may be interchanged).
Ph
3
.12. Sensory evaluation
8
Blotting paper strips were impregnated with compounds
a–5d, previously diluted with Et O (25 mg/200 mL) and
5
2
smelt by perfumers at that moment, 3 h later, and 24 h later.
The olfactory description in each session, therefore,
corresponded to the top, heart and base notes, respectively.
3
.13. GC sniffing analysis
2
000; pp 101–107.
9
. (a) Buchbauer, G.; Lebada, P.; Wiesinger, L.; Weiss-Greiler,
P.; Wolschann, P. Chirality 1997, 9, 380–385. (b) Brenna, E.;
Fuganti, C.; Serra, S. Tetrahedron: Asymmetry 2003, 14, 1–42.
Odour assessment by a group of perfumers was achieved
using a Hewlett–Packard Model 5890 Series II gas
chromatograph equipped with a thermal conductivity
detector (TCD) and a handmade sniffing port. Separation
was done with a 10% Carbowax 20M over Chromosorb
W/AW 80–100 mesh packed column (1.8 m!6 mm OD!
1
0. (a) Arbuzov, B. Ber. 1935, 68B, 1430–1435 [Chem. Abstr.
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1
A. F. A. J. Chem. Soc. 1964, 5494–5496. (c) Lewis, J. B.;
Hedrick, G. W. J. Org. Chem. 1965, 30, 4271–4275.
2
.2 mm ID); injector temperature: 250 8C; detector
1
1. Kane, B. J.; Sanders, G. P.; Snow, J. W.; Erman, M. B. U.S.
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2. Schulte-Elte, K. H.; Ohloff, G. Tetrahedron Lett. 1964,
¶
In order to avoid confusion, identification numbers for hydrogen and
carbon atoms in NMR are the same than in 5. Carbon atoms of the MTPA
moiety are separately numbered, following the IUPAC nomenclature.
Despite this, note that in IUPAC nomenclature the MTPA moiety is the
main part of the molecule.
1
1143–1146.
13. (a) Chapuis, C.; Brauchli, R. Helv. Chim. Acta 1992, 75,

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1
1
4. Naipawer, R. E.; Easter, W. M. U.S. Patent 4,052,341
(
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1
3
1
0
1, 1985, to Givaudan and CIE) [Chem. Abstr. 1986, 106,
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,841,318 (Priority, Nov 6, 1996, to Givaudan-Roure) [Chem.
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6. (a) Chapuis, C.; Gautier, A.; Blanc, P. -A. U.S. Patent 5,512,
1