Synthesis and olfactoric activity of side-chain modified β-santalol analogues

Article abstract of DOI:10.1016/S0223-5234(01)01271-5

Three osmophoric points have been postulated to be necessary for the sandalwood scent of β-santalol derivatives. One of these points, close to the hydroxyl group, is highly specific on the stereochemistry and, in particular, on the molecular shape. The ro

Full text of DOI:10.1016/S0223-5234(01)01271-5

Eur. J. Med. Chem. 36 (2001) 673–683
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© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01271-5/FLA
Original article
Synthesis and olfactoric activity of side-chain modified b-santalol analogues
Gerhard Buchbauera,*, Aneta Sunaraa, Petra Weiss-Greilerb, Peter Wolschannb
aInstitute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
bInstitute of Theoretical Chemistry and Molecular Structural Biology, University of Vienna, Wa¨hringer Strasse 17,
A-1090 Vienna, Austria
Received 21 March 2001; revised 7 August 2001; accepted 7 August 2001
With our best wishes, dedicated to Professor Dr W. Fleischhacker on the occasion of his 70th birthday
Abstract – Three osmophoric points have been postulated to be necessary for the sandalwood scent of b-santalol derivatives. One
of these points, close to the hydroxyl group, is highly specific on the stereochemistry and, in particular, on the molecular shape. The
role of the 2-methyl group in the side chain of b-santalol derivatives was studied by replacement through a hydrogen atom, an ethyl
or an isopropyl group. It turns out that any change at the 2-methyl substituent leads to the complete loss of sandalwood odour.
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS
structure–odour relationship / sandalwood odorant / b-santalol
1. Introduction
In this model, one of the important regions of the
molecule is the functional group (A), mainly repre-
sented by a hydroxyl group. A second, very specific
osmophoric point (B) occurs in the neighbourhood of
this functional group. The third point (C) includes the
bulky hydrophobic residue. The relative position of
these osmophoric points, the distance between them
and the stereospecifity are very important for the
fragrance [11].
For the refinement of the model the osmophoric
points were analysed in more detail taking into ac-
count both steric as well as electronic properties. The
bulky substituent was already modified in several
studies [6, 8, 9, 19–22], also investigations on the
influence of the side-chain geometry on the sandal-
wood scent have been performed [12, 19, 23, 24].
Modifications of the functional group (A) [25–27]
and of the substituent at the a-C-atom were studied,
too [7].
(−)-(Z)-b-Santalol (1), the main constituent of nat-
ural sandalwood oil, is an odour compound with
typical sandalwood fragrance and is described as
warm-woody, creamy and sweet with an animalic
tonality [1–4]. The structure–odour properties of this
compound and a series of derivatives were topics of
interest in many investigations [5–18]. The structures
of odour receptors and the corresponding mecha-
nisms of interaction between the receptor protein and
the odour molecules are more or less unknown.
Therefore, the determination of essential structure
elements can be only performed by molecular similar-
ity studies within a series of sandalwood odour com-
pounds and structurally similar, but non-odorous
molecules. In a general study on sandalwood odour
substances three osmophoric centres, which are im-
portant for this specific odour impression were found
by ‘Active Analog Approach’ investigations [11].
These osmophoric parts of 1 are depicted in figure 1.
The importance of the osmophoric centre B in this
class of compounds was not proven up to now. The
results obtained from ‘Active Analog Approach’ in-
vestigations showed that this substituent plays an
important role for the odour of the compound, either
* Correspondence and reprints
E-mail address: gerhard.buchbauer@univie.ac.at
(G. Buchbauer).

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G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
exerting a steric (=shielding) effect on the neighbour-
ing hydroxyl group, or as a sort of anchor group
directing the essential hydroxyl moiety into the ap-
propriate position for the necessary contact with the
receptor. It may also act as a hydrophobic counter-
part to the hydrophilic functional group. To answer
this question, if the methyl group in this position is
really essential for the sandalwood scent, derivatives
with various substituents at the osmophoric point B
have been synthesised: compound 2 with a smaller
substituent—a hydrogen atom instead of the methyl
group—and compounds 3 and 4 with larger sub-
stituents, an ethyl and an isopropyl group. The influ-
ence of the size of the substituents is discussed in the
present work based on the olfaction of these newly
synthesised b-santalol derivatives. Interestingly,
within the class of campholenic aldehyde derivatives
the replacement of the methyl neighbouring group by
a bigger ethyl group has no influence on the odour
impression [28].
accordance with the findings of Corey et al. [30], the
more space demanding side chain assumes the exo-posi-
tion, whereas the relatively small methyl group is forced
into the cavity of the bicyclus, thus being endo at C-3. In
case the order of sequence of the two alkylating steps is
reversed, a mixture of both epimers is obtained. Cleav-
age of the acetals with diluted sulphuric acid—this more
or less drastic condition furnishes better yields and a
cleaner product—leads to the corresponding aldehyde
7, as a suitable synthon for the following ‘Wittig–
Horner’ reaction using 18-crown-6, potassium-bis-
(trimethylsilyl)-amide and the appropriate alkyl
phosphone esters1 [32, 33]. Normally, this procedure
provides threefold substituted olefinic esters with a high
Z-selectivity (>80:20 [32]). However, we obtained 8 as a
33:67-, 9 as a 40:60- and 10 only as a 83:17-mixture of
the corresponding Z/E-isomers. In comparison to 10,
which was used as the isomeric mixture for the next
step, 8 and 9 could be separated into the pure Z- and
1
E-compounds. In the H-NMR spectrum of these com-
In order to study the influence of the specific posi-
tion of the osmophoric group B relative to the other
centres, the (E)- and (Z)-configurated compounds are
included.
pounds the signal of the olefinic proton at C-3% shown as
a multiplet in Z-8, triplet in Z-9 and Z-10, could always
be found characteristically upfield shifted compared to
the same signal of the C-3%ꢀH of E-8, E-9 and E-10. In
the case of both isomers of 8 and 9, transformation of
the ketone function at C-2 into the exocyclic methylene
group was accomplished by ‘Nozaki’s’ method with zinc
dust and TiCl4 as Lewis acid [34]. For the sterically
more voluminous molecule 10 the TEBBE-reagent [35,
36] had to be used. Column chromatography followed
by preparative TLC led to Z-13 only in a very moderate
yield. Finally, the last step, the reduction of the esters
Z-11, E-11, Z-12, E-12 and Z-13 with DIBAH fur-
nished the target products, namely the allylic alcohols
Z- and E-2, Z- and E-3 and Z-4 (figure 2).
2. Results: syntheses and olfactoric evaluation
2.1. Syntheses
As a starting substance for the preparation of the
bicyclic alcohols 2–4, we have chosen the commercially
available bicyclic ketone 5, which could be alkylated in
a two-step process according to the procedure of Krotz
et al. [29], first with bromomethyldioxolane and subse-
quently with methyl iodide leading to the ketone 6. In
2.2. Olfactoric evaluation
An extensive odour evaluation was performed for all
the newly synthesised compounds. The results are given
in table I. As shown in the table, the scent of the
compounds differs significantly and allows, therefore, to
draw conclusions about the structure–activity
relationships.
1 The side-chain synthons for 8 and 9 are commercially avail-
able, the appropriate one for 10 had to be prepared from
2-bromo-3-methyl-butyric acid via esterification, followed by
an ‘Arbuzov’ reaction [31] with phosphoric acid triethyl ester.
Figure 1. Osmophoric centres found for sandalwood odour
compounds by ‘Active Analog Approach’ investigations
shown for 1.

G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
675
Figure 2. Syntheses of compounds Z-2–Z-4 and E-2 and E-3.
As already postulated before [11], this hydrophobic re-
gion is indeed very sensitive to changes. The absence of
the allylic methyl group deprives the b-santalol
derivative from the sandalwood odour, the insertion of a
more bulky substituent, such as ethyl or even isopropyl as
well. The decrease of odour strength in E-3 and Z-4 is
probably caused by an increase of molecular mass, thus
reducing the volatility, a phenomenon, which is well
known in fragrance chemistry. Based on these results it is
ascertained that only the allylic methyl group possesses
the suitable dimension allowing a close contact with the
corresponding receptor.
3. Discussion
Following the model of sandalwood odour devel-
oped by the ‘Active Analog Approach’ study [11], a lot
of structurally modified b-santalol derivatives have
been synthesised in the past with the intention to get
more information about the detailed structural require-
ments and the importance of the osmophoric parts for
the association at the receptor site. Besides steric mod-
ifications, also the influence of the electronic parame-
ters has been a centre of interest. A survey of the most
important synthetic modifications is given in figure 3.

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G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
Table I. Odour description of side-chain modified b-santalol
only (−)-(Z)-b-santalol (1) possesses sandalwood fra-
grance. Such a stereoselectivity was also found for
(+)-tert-butyl-bicyclo[4.4.0]decan-3-ol [37], (−)-(1%S)-
Madrol® [38] and another more rigid campholenic
aldehyde derivative, namely [1-methyl-2-(1,2,2-
trimethylbicyclo[3.1.0]hex-3-yl-methyl)-cyclopropyl]-
methanol [28], three synthetic compounds with clear
sandalwood odour.
In figure 3, the modifications of b-santalol are
drawn together with their contributions to sandal-
wood odour. Compounds with solid line arrows show
no sandalwood scent anymore; this means that there
might be a steric hindrance at the receptor, which
disables the association of the odour molecule. Com-
pounds with broken line arrows show sandalwood
fragrance or at least a somewhat weaker sandalwood
odour compared to b-santalol.
analogues.
Compound Odour
Z-1
pure sandalwood, warm, woody, creamy,
sweet, animalic
E-1
Z-2
woody, medicinal
olibanum-like, leathery, reminiscent of
castoreum, woody, very volatile
spicy, olibanum-like, galbanum note, very
volatile
E-2
Z-3
E-3
Z-4
spicy, herbaceous, later cedar wood note
faint odour, like Z-3
very faint odour, soft woody, neither
reminiscent to cedar wood nor to sandalwood
First of all, it has to be mentioned that the receptor
odour molecule interaction is stereospecific. Investiga-
tions done by Krotz and Helmchen [29] show that
Figure 3. Structural and electrostatic modifications of b-santalol derivatives and their fragrance (sandalwood odour molecules are
depicted with broken line arrows, non-sandalwood odour compounds with arrows drawn with solid lines). Derivatives with
electrostatic modifications are indicated by squares.

G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
677
Some modifications have been done at the func-
tional group, the hydroxyl group, which, e.g. can be
substituted by a carbonyl group (compound 11 [25,
27]). Esterification with formic acid (compound 12),
acetic acid (compound 13) or propionic acid (com-
pound 14) forms sandalwood fragrant substances [26].
The use of higher carbonic acids, like butyric acid
(yields compound 15) or aromatic carbonic acids
causes the loss of sandalwood scent. It is evident that
this region is not very sensitive against structural
changes as long as not too large groups are intro-
duced. Methylation at the a-carbon atom (compound
16) changes the odour to be aromatic, woody, with
still some residual of the sandalwood note [7]. This
again is an indication for a weaker steric influence of
this part of the molecule, as long as the possibility to
form a hydrogen bond remains. Also slight modifica-
tions in the bulky residue are without consequences
for the odour quality. Substitution of the methylene
bridge by an ethano bridge (yields compound 17) [20],
etheno bridge (compound 18) [19], or by the larger
propano bridge (compound 19) [21], or even removal
of the methyl group at the chiral carbon atom (com-
pound 20) [12, 22], does not influence the fragrance
(see figure 3). (+)-(Z)-a-Santalol (21) [39], which
shows differences in the ring-skeleton, possesses weak
sandalwood odour. More complex is the situation in
the case of side-chain modifications. Pure hydrogena-
tion of the CꢁC double bond (compound 22) does not
affect the odour at all [23, 24], whereas the hydro-
genation of both, the side-chain double bond and the
exocyclic double bond (compound 23), completely
removes the sandalwood fragrance [24]. Generally,
the trans (E)-double bond substituted compounds do
not behave like sandalwood odorants, the cis-(Z)-
configured derivatives show this odour [13, 29].
for the association of the odour molecule at the
specific receptor site. Generally, modifications of the
electrostatic potential lead to the lack of sandalwood
fragrance, the influence of the sterical changes de-
pends on the region at the molecule. The osmophoric
point A is not very sensitive to changes, similar as the
bulky substituent C, but here some more sensitive
molecule parts can be detected. Side-chain modifica-
tions are somewhat divergent, as some modifications
have strong influence on the odour impression, some
not. On the contrary, the stereospecific position of the
osmophoric point B is very important for the fra-
grance. Referring to the newly synthesised com-
pounds it could be shown that this osmophoric point
is extremely sensitive to structural changes, because
here only rather small modifications have a strong
influence on the sandalwood scent. Replacement of
the methyl group by a smaller substituent (a hydrogen
atom) as well as by larger substituents (an ethyl or an
isopropyl-residue) causes the complete loss of the
sandalwood odour impression.
Evidently, only the methyl substituted compound
fulfils all requirements for an association at a very
sensitive and specific site of the receptor.
Van der Waals contacts of the methyl group may
be necessary for the association of the compound at
the receptor site, or the methyl group may force the
hydroxyl moiety in a proper position to obtain a
stronger interaction with the receptor protein.
5. Experimental protocols
GC analyses were carried out in a Shimadzu GC-
14A, 30 m fused silica capillary column permabond
SE-30-DF-0.25 (purity for the odour analysis: 99%).
Mass spectra were recorded in a Hewlett–Packard
MSD (GC: 5890; MS: 5970) spectrometer. IR spectra
were acquired using a Perkin–Elmer-237 spectrome-
ter as well as a Perkin–Elmer FT-IR spectrum 2000
Changes of the electrostatic potential at the bulky
residue (see figure 3) generally lead to compounds
without sandalwood fragrance. Substitution of the
methylene group by an oxygen atom in the norbor-
nane skeleton (compound 24) [6], or in the exocyclic
CꢁC double bond (compound 25) [8] as well as the
substitution of this double bond by a methoxy group
(compound 26) destroys the scent [8].
1
spectrometer (bands are assigned in cm−1). H-NMR
spectra were recorded in a Bruker AM 400 WB
(400.13 MHz) using TMS as internal standard (at
room temperature (r.t.) and in CDCl3 if not otherwise
indicated, l values are given in ppm). 13C-NMR spec-
tra were recorded in the same spectrometer (Bruker
AM 400 WB, 100.61 MHz) using the same conditions
(J-modulated). For TL-chromatography, alumina
sheets coated with silica gel 60 F254 (20×20 cm, layer
thickness 0.2 mm, Merck no. 5554) were used. Prepar-
4. Conclusions
As shown in the general overview (figure 3), both
sterical as well as electronic properties are important

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G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
ative TLC was performed on PSC plates silica gel 60
F254S with concentration zone (20×20 cm, 2 mm layer
thickness, Merck no. 13 793). Column chromatogra-
phy for purification was performed with silica gel 60
filled glass columns (Merck no. 1.09385, particle size
0.040–0.063 mm).
(trimethylsilyl)-amide (0.5 M in toluene) (7 mL, 3.5
mmol). Afterwards, a solution of the aldehyde 7 (600
mg, 3.3 mmol) in THF was added dropwise and the
mixture stirred for 4 h at −80 °C. Upon quenching with
saturated NH4Cl solution, extraction with diethyl ether
followed. Afterwards, the combined ethereal extracts
were dried with MgSO4 and freed from the solvent by
evaporation. The residue was distilled (kugelrohr) and
yielded 1 g of the raw Wittig product (two isomers, 33%
Z:67% E) which was purified by preparative TLC with
ligroin–ethyl acetate (85:15) and some drops of MeOH
(twofold development). Yield: zone 1 Z-8=82 mg
(30%), zone 2 E-8=266 mg (48% relative to the amount
used for this separation). C15H22O3 (250.16). Z-8: IR
5.1. 3-[2-(1,3-Dioxolan-2-yl)-ethyl]-3-methyl-
bicyclo[2.2.1]heptan-2-one (6)
(1) A mixture of sodium amide (2.13 g, 54.54 mmol),
hexamethyldisilazane (11.51 mL, 54.54 mmol) in 46 mL
xylene was refluxed for 5 h and finally allowed to cool.
Then, norbornan-2-one (5) (5 g, 45.45 mmol) was added
and stirred for another 2 h at r.t. Upon addition of
2-(2-bromoethyl)-1,3-dioxolane (11.21 mL, 95.45 mmol)
the mixture was refluxed for 1 h, allowed to cool and
quenched with water followed by extraction with diethyl
ether. The combined ethereal extracts were dried with
magnesium sulphate. Evaporation of the solvent and
subsequent distillation (kugelrohr) of the residue af-
forded 7.1 g of raw 3-[2-(1,3-dioxolan-2-yl)-ethyl]-bicy-
clo[2.2.1]heptan-2-one which were purified by column
chromatography using ligroin–ethyl acetate=80:20.
Yield: 5.2 g (54.5%). C12H18O3 (210.13).
1
(NaCl, liquid film): 1742, 1721, 1655, 1175; H-NMR
(CDCl3): 1.0 (s, 3H, CH3), 1.21 (t, 3H, CH3), 1.25–1.9
(m, 8H), 2.28 (m, 1H), 2.50 (m, 1H, HꢀC-1), 2.60 (m,
2H), 4.10 (q, 2H, OCH2), 5.69 (d, 1H, ꢁCHCOOR), 6.10
(m, 1H, ꢁCHR); 13C-NMR (CDCl3): 14.1 (CH3), 19.0
(CH3), 22.9 (CH2), 23.7 (CH2), 24.7 (CH2), 33.3 (CH2),
34.7 (CH2/C-7), 43.7 (CH/C-4), 49.8 (C/C-3), 49.96
(CH/C-1), 59.7 (OCH2), 119.8 (ꢁCHCOOR), 149.4
(ꢁCHR), 166.1 (CꢁO, ester), 221.8 (CꢁO, ketone). MS
(m/z, relative intensity): 250, ([M+], 23), 204 (100), 176
(46), 137 (22), 124 (32), 114 (35), 107 (76), 96 (60), 81
1
(2) 3-[2-(l,3-Dioxolan-2-yl)-ethyl]-bicyclo[2.2.1]heptan-
2-one (5.9 g, 28.09 mmol) was alkylated with methyl
iodide (3.53 mL, 56.68 mmol) using the same procedure
as above. Yield: 4.84 g (77%) of a colourless oil. Data:
see Ref. [8].
(53), 67 (84), 55 (44). E-8: H-NMR (CDCl3): 1.05 (s,
3H, CH3), 1.28 (t, 3H, CH3), 1.32–1.98 (m, 8H), 2.17
(m, 1H), 2.32 (m, 2H), 2.58 (m, 1H, HꢀC-1), 4.18 (q,
2H, OCH2), 5.84 (d, 1H, ꢁCHCOOR), 6.96 (m, 1H,
ꢁCHR); 13C-NMR (CDCl3): 14.1 (CH3), 18.9 (CR3),
22.9 (CH2), 24.5 (CH2), 26.8 (CH2), 32.4 (CH2), 34.6
(CH2/C-7), 43.8 (CH/C-4), 49.4 (C/C-3), 49.8 (CH/C-1),
59.9 (OCH2), 121.2 (ꢁCHCOOR), 148.2 (ꢁCHR), 166.2
(CꢁO, ester), 221.1 (CꢁO, ketone).
5.2. 3-(2-Methyl-3-oxo-bicyclo[2.2.1]heptan-2-yl)-
propanal (7) (‘2-keto-ekasantalal’)
An amount of 4.84 g (21.6 mmol) of 6 was dissolved
in 10 mL of diethyl ether and stirred overnight with 72
mL 2 N H2SO4. Upon extraction of this mixture with
diethyl ether, the combined organic phases were washed
with water, dried with sodium sulphate and finally evap-
orated. With this residue the hydrolysis reaction was
repeated. Yield: 3.04 g (78.2%) of 7 as a colourless,
viscous oil. Data: see Ref. [8].
5.4. (E)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-
2-yl)-2-pentenoic acid ethyl ester (E-11)
To a suspension of zinc dust (929.6 mg, 14.22 mmol)
and dibromomethane (0.33 mL, 4.74 mmol) in THF (8
mL) was added a 1 M solution of TiCl4 in CH2Cl2 (74
mL, 1.74 mmol) at 25 °C dropwise. A rapid, exothermic
discolouring to dark brown could be observed. After 15
min a solution of ketoester E-8 (395 mg, 1.58 mmol) in
THF was added dropwise and stirred for another 60 h
at r.t.. Upon dilution with diethyl ether and subsequent
quenching with 1 M HCl the mixture was extracted with
diethyl ether. The combined ethereal extracts were
washed with brine, dried with MgSO4 and evaporated.
The residue was purified by preparative TLC with
5.3. (Z)/(E)-5-(3-Oxo-2-methyl-bicyclo[2.2.1]hept-2-
yl)-2-pentenoic acid ethyl ester (Z/E-8)
A solution of 2-phosphonoacetic acid triethyl ester
(0.68 mL, 3.41 mmol) and freshly recrystallised 18-
Crown-6 (4.43 g, 16.75 mmol) in 68 mL THF was
cooled down to −80 °C and mixed with potassium-bis-

G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
679
ligroin–ethyl acetate (95:5) and some drops of MeOH.
filtered through Celite®. The residue was washed with
ethyl acetate and the filtrate freed from the solvent by
evaporation. Purification of this residue was performed
by preparative TLC with ligroin–ethyl acetate (70:30)
and some drops of MeOH (twofold development).
Yield: 94 mg (29.4%). C14H22O (206.15). IR (NaCl,
Yield: 96 mg (24.5%). C16H24O2 (248.17). IR (NaCl,
1
liquid film): 3070, 1735, 1655, 1180, 970, 880; H-NMR
(CDCl3): 1.01 (s, 3H, CH3), 1.29 (t, 3H, CH3), 1.25–1.8
(m, 8H), 2.01 (m, 1H, C-4), 2.1 (m, 1H), 2.25 (m, 1H),
2.69 (m, 1H, C-1), 4.18 (q, 2H, OCH2), 4.48 (s, 1H,
exocyl. ꢁCH2), 4.74 (s, 1H, exocycl. ꢁCH2), 5.84 (d, 1H,
ꢁCHCOOR), 6.97 (m, 1H, ꢁCHR); 13C-NMR (CDCl3):
14.3 (CH3), 23.7 (CH2), 25.2 (CH3), 28.2 (CH2), 28.97
(CH2), 37.03 (CH2/C-7), 37.14 (CH2), 44.6 (C/C-3), 45.1
(CH/C-4), 46.7 (CH/C-1), 60.1 (OCH2), 99.7 (exocycl.
ꢁCH2), 120.9 (ꢁCHCOOR), 149.5 (ꢁCHR), 166.1 (ꢁCR2/
C-2), 166.7 (CꢁO). MS (m/z, relative intensity): 248
([M+], 17), 220 (11), 180 (39), 160 (28), 135 (48), 119
(32), 107 (47), 93 (99), 91(100), 79 (87), 77 (55).
1
liquid film): 3360, 3080,1665, 1375, 970, 880; H-NMR
(CDCl3): 1.0 (s, 3H, CH3), 1.2–1.8 (m, 8H), 1.99 (m,
2H, HꢀC-4), 2.1 (m, 1H), 2.67 (m, 1H, C-1), 4.08 (d,
2H, CH2OH), 4.47 (s, 1H, exocycl. ꢁCH2), 4.72 (s, 1H,
exocycl. ꢁCH2), 5.68 (2m, 2H, RCHꢁCHR); 13C-NMR
(CDCl3): 23.6 (CH2), 25.2 (CH3), 28.05 (CH2), 28.99
(CH2), 37.0 (CH2/C-7), 38.4 (CH2), 44.7 (C/C-3), 45.1
(CH/C-4), 46.7 (CH/C-1), 63.7 (CH2OH), 99.3 (exocycl.
ꢁCH2), 128.5 (RCHꢁ), 133.6 (ꢁCHR), 166.5 (ꢁCR2/C-2);
MS (m/z, relative intensity): 188 ([M+−18], 5), 173 (5),
159 (6), 145 (8), 133 (9), 121(21), 105 (27), 94 (100), 93
(67), 79 (58), 67 (27).
5.5. (Z)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-
2-yl)-2-pentenoic acid ethyl ester (Z-11)
The same procedure as above, but this time using
680.1 mg (10.4 mmol) zinc dust, 0.24 mL (3.5 mmol)
dibromomethane in 6 mL THF and 1.3 mL (1.27 mmol)
TiCl4 solution in methylene chloride yielded after
preparative TLC 58 mg (20.2%) of Z-11. C16H24O2
5.7. (Z)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-pent-2-enol (Z-2) (‘2%-desmethyl-i-santalol’)
The same procedure as above using 290 mg (1.17
mmol) ester Z-11 and 5.2 mL (7.27 mmol) DIBAH in
n-hexane yielded after preparative TLC 81 mg (33.6%)
of Z-2. C14H22O (206.15). Anal. Calc. C, 81.56; H,
1
(248.17). H-NMR (CDCl3): 1.05 (s, 3H, CH3), 1.29 (t,
3H, CH3), 1.2–1.75 (m, 8H), 2.05 (m, 1H, C-4), 2.59 (m,
1H), 2.68 (m, 2H, HꢀC-1), 4.18 (q, 2H, OCH2), 4.48 (s,
1H, exocycl. ꢁCH2), 4.73 (s, 1H, exocycl. ꢁCH2), 5.72 (d,
1H, ꢁCHCOOR), 6.22 (m, 1H, ꢁCHR); 13C-NMR
(CDCl3): 14.3 (CH3), 23.6 (CH2), 25.21 (CH2), 25.25
(CH3), 29.1 (CH2), 37.1 (CH2/C-7), 38.1 (CH2), 44.9
(C/C-3), 45.1 (CH/C-4), 46.7 (CH/C-1), 59.8 (OCH2),
99.4 (exocycl. ꢁCH2), 119.3 (ꢁCHCOOR), 150.5
(ꢁCHR), 166.7 (CꢁO); MS (m/z, relative intensity): 248
([M+], 17), 220 (11), 180 (39), 160 (28), 135 (48), 119
(32), 107(47), 93 (99), 91(100), 79 (87), 77 (55).
1
10.76. Found: C, 81.78; H, 10.89%. H-NMR (CDCl3):
1.02 (s, 3H, CH3), 1.2–1.75 (m, 8H), 1.98 (m, 2H,
HꢀC-4), 2.13 (m, 1H), 2.68 (m, 1H, C-1), 4.21 (d, 2H,
CH2OH), 4.47 (s, 1H, exocycl. ꢁCH2), 4.72 (s, 1H,
exocycl. ꢁCH2), 5.58 (2m, 2H, RCHꢁCHR); 13C-NMR
(CDCl3): 23.5 (CH2), 23.7 (CH2), 25.2 (CH3), 29.0
(CH2), 37.0 (CH2/C-7), 38.9 (CH2), 44.8 (C/C-3), 45.1
(CH/C-4), 46.6 (CH/C-1), 58.5 (CH2OH), 99.4 (exocycl.
ꢁCH2), 128.03 (RCHꢁ), 133.3 (ꢁCHR), 166.4 (ꢁCR2/C-
2); MS (m/z, relative intensity): 188 ([M+−18], 5), 173
(5), 159 (6), 145 (8), 133 (9), 121(21), 105 (27), 94 (100),
93 (67), 79 (58), 67 (27).
5.6. (E)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-
2-yl)-pent-2-enol (E-2)
5.8. (Z)/(E)-5-(3-Oxo-2-methyl-bicyclo[2.2.1]hept-2-
yl)-2-ethyl-2-pentenoic acid ethyl ester (Z-9, E-9)
A solution of 385 mg (1.55 mmol) of ester E-11 in dry
methylene chloride was cooled down to −78 °C and
mixed with a 20% solution of diisobutylaluminiumhy-
dride (DIBAH) (6.86 mL, 9.65 mmol) in n-hexane.
Stirring overnight caused a warming up of the reaction
mixture to r.t. and afforded another cooling, but this
time only to −20 °C. Then 2 mL of a methanol–water
(1:1) mixture was added and stirring proceeded for
another 3 h, this time at r.t., as long as the precipitation
of a thick, white sediment could be noticed, which was
A solution of 2-phosphonobutyric acid triethyl ester
(0.67 mL, 2.84 mmol) and freshly recrystallised 18-
Crown-6 (3.7 g, 13.96 mmol) in 57 mL THF was cooled
down to −80 °C and mixed with potassium-bis-
(trimethylsilyl)-amide (0.5 M in toluene) (5.8 mL, 2.92
mmol). Afterwards, a solution of the aldehyde 7 (500
mg, 2.78 mmol) in THF was added dropwise and the
reaction continued as already described above. The raw

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G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
5.10. (E)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-2-ethyl-2-pentenoic acid ethyl ester (E-12)
Wittig product was purified by preparative TLC with
pentane–ethyl acetate (90:10) and some drops of MeOH.
Yield: zone 1 (Z-9)=82 mg (26.5%), zone 2 (E-9)=
186 mg (40.2% relative to the amount used for this
Zinc dust (863.5 mg, 13.21 mmol), dibromomethane
(0.31 mL, 4.40 mmol) in 7.3 mL THF, a 1 M solution of
TiCl4 in CH2Cl2 (1.6 mL, 1.61 mmol) and keto ester E-9
(408 mg, 1.47 mmol) in THF were used and processed
as described above. Purification was performed by
preparative TLC with pentane–ethyl acetate (98:2) and
some drops of MeOH (twofold development). Yield: 135
mg (33.4%). C18H28O2 (276.2). IR (NaCl, liquid film):
1
separation). C17H26O3 (278.18). Z-9: H-NMR (CDCl3):
1.02 (t, 3H, CH3), 1.05 (s, 3H, CH3), 1.31 (t, 3H, CH3),
1.3–2 (m, 8H), 2.26 (q, 2H, allyl. CH2), 2.32–2.5 (m,
3H), 2.58 (m, 1H, C-1), 4.22 (q, 2H, OCH2), 5.80 (t, 1H,
ꢁCH); 13C-NMR (CDCl3): 13.5 (CH3), 14.3 (CH3), 19.1
(CH3), 23.1 (CH2), 24.3 (CH2), 24.7 (CH2), 27.4 (CH2),
33.9 (CH2), 34.8 (CH2/C-7), 43.8 (CH/C-4), 49.9 (C/C-3),
50.04 (CH/C-1), 59.99 (OCH2), 133.9 (ꢁCR2), 139.5
(ꢁCHR), 168.03 (CꢁO, ester), 222.1 (CꢁO, ketone); MS
(m/z, relative intensity): 278 ([M+], 2), 232 (58), 205 (8),
163 (11), 137 (14), 124 (12), 109 (100), 96 (49), 81(36), 67
1
3070, 1720,1650, 1040, 880; H-NMR (CDCl3): 1.04 (t,
3H, CH3), 1.05 (s, 3H, CH3), 1.29 (t, 3H, CH3), 1.22–
1.75 (m, 8H), 2.03 (m, 1H, C-4), 2.05–2.25 (m, 2H), 2.33
(q, 2H, allyl. CH2), 2.69 (m, 1H, C-1), 4.19 (q, 2H,
OCH2), 4.48 (s, 1H, exocycl. CH2), 4.73 (s, 1H, exocycl.
CH2), 6.72 (t, 1H, ꢁCH); 13C-NMR (CDCl3): 14.1
(CH3), 14.3 (CH3), 20.04 (CH2), 23.7 (CH2), 24.5 (CH2),
25.2 (CH3), 29.02 (CH2), 37.1 (CH2), 38.02 (CH2), 44.8
(C/C-3), 45.1 (CH/C-4), 46.7 (CH/C-1), 60.3 (OCH2),
99.6 (exocycl. ꢁCH2), 133.7 (ꢁCR2), 142.0 (ꢁCHR),
166.2 (ꢁCR2, C-2), 167.9 (CꢁO); MS (m/z, relative inten-
sity): 277 ([M++1], 3), 276 (18), 247 (4), 230 (14), 202
(9), 162 (23), 135 (37), 107 (31), 94 (100), 79 (55), 67
(39).
1
(42), 55 (22). E-9: H-NMR (CDCl3): 1.02 (t, 3H, CH3),
1.07 (s, 3H, CH3), 1.29 (t, 3H, CH3), 1.3–2.4 (m, 11H),
2.32 (m, 2H, allyl. CH2), 2.59 (m, 1H, C-1), 4.19 (q, 2H,
OCH2), 6.68 (t, 1H, ꢁCH); 13C-NMR (CDCl3): 13.95
(CH3), 14.2 (CH3), 19.1 (CH3), 19.97 (CH2), 23.07 (CH2),
23.13 (CH2), 24.6 (CH2), 33.4 (CH2), 34.7 (CH2/C-7),
43.9 (CH/C-4), 49.7 (C/C-3), 50.0 (CH/C-1), 59.96
(OCH2), 134.2 (ꢁCR2), 140.8 (ꢁCHR), 167.6 (CꢁO, es-
ter), 221.6 (CꢁO, ketone).
5.9. (Z)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-2-ethyl-2-pentenoic acid ethyl ester (Z-12)
5.11. (Z)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-2-ethyl-pent-2-enol (Z-3) (‘2%-ethyl-i-santalol’)
Zinc dust (535.4 mg, 8.19 mmol), dibromomethane
(0.19 mL, 2.73 mmol) in 4.5 mL THF, a 1 M solution of
TiCl4 in CH2Cl2 (1 mL, 1.001 mmol) and keto ester Z-9
(253 mg, 0.91 mmol) in THF were used and processed as
described above. Purification was performed by prepara-
tive TLC with pentane–ethyl acetate (98:2) and some
drops of MeOH (twofold development). Yield: 63 mg
(25.2%). C18H28O2 (276.2). IR (NaCl, liquid film): 3070,
As already described above ester Z-12 (244 mg, 0.88
mmol) and a 20% solution of DIBAH in n-hexane (3.91
mL, 5.5 mmol) were processed. Preparative TLC with
pentane–ethyl acetate (85:15) and some drops of MeOH
furnished finally 42 mg (20.3%) of the target product.
C16H26O (234.18). Anal. Calc. C, 82.06; H, 11.19. Found:
C, 82.26; H, 11.27%. IR (NaCl, liquid film): 3326, 3070,
1
1720,1660, 1040, 880; H-NMR (CDCl3): 1.03 (t, 3H,
1
1656, 1017, 878; H-NMR (CDCl3): 1.02 (s, 3H, CH3),
CH3), 1.03 (s, 3H, CH3), 1.31 (t, 3H, CH3), 1.25–1.75
(m, 8H), 2.02 (m, 1H, C-4), 2.27 (m, 3H, allyl. CH2 also
q), 2.5 (m, 1H), 2.67 (m, 1H, C-1), 4.22 (q, 2H, OCH2),
4.48 (s, 1H, exocycl. CH2), 4.72 (s, 1H, exocycl. CH2),
5.83 (t, 1H, ꢁCH); 13C-NMR (CDCl3): 13.6 (CH3), 14.3
(CH3), 23.7 (CH2), 25.3 (CH3), 25.6 (CH2), 27.6 (CH2),
29.1 (CH2), 37.1 (CH2), 38.6 (CH2), 44.9 (C/C-3), 45.2
(CH/C-4), 46.7 (CH/C-1), 60.0 (OCH2), 99.3 (exocycl.
ꢁCH2), 133.3 (ꢁCR2), 140.2 (ꢁCHR), 166.7 (ꢁCR2, C-2),
168.4 (CꢁO); MS (m/z, relative intensity): 277 ([M++1],
4), 276 (23), 247 (5), 230 (21), 202 (14), 162 (25), 135 (38),
107 (35), 94 (100), 79 (57), 67 (36).
1.04 (t, 3H, CH3), 1.2–1.7 (m, 8H), 1.9–2.2 (m, 2H), 2.02
(m, 1H, C-4), 2.14 (q, 2H, allyl. CH2), 2.67 (m, 1H, C-1),
4.17 (s, 2H, CH2OH), 4.47 (s, 1H, exocycl. CH2), 4.72 (s,
1H, exocycl. CH2), 5.32 (t, 1H, ꢁCH); 13C-NMR
(CDCl3): 12.8 (CH3), 23.5 (CH2), 23.7 (CH2), 25.2 (CH3),
27.8 (CH2), 29.1 (CH2), 37.1 (CH2), 38.5 (CH2), 44.9
(C/C-3), 45.2 (CH/C-4), 46.7 (CH/C-1), 60.4 (CH2OH),
99.3 (exocycl. ꢁCH2), 127.8 (ꢁCHR), 139.6 (ꢁCR2), 166.6
(ꢁCR2, C-2); MS (m/z, relative intensity): 216 ([M+−18],
5), 203 (1), 187 (7), 161(4), 148 (7), 133 (5), 122 (24), 107
(13), 94 (100), 79 (35), 67 (18).

G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
681
5.12. (E)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-2-ethyl-pent-2-enol (E-3)
was cooled down to −80 °C and mixed with potassium-
bis-(trimethylsilyl)-amide (0.5 M in toluene) (5.8 mL,
2.92 mmol). Afterwards, a solution of the aldehyde 7
(500 mg, 2.78 mmol) in THF was added dropwise and
the reaction continued as already described above. The
raw Wittig product was purified by preparative TLC
with pentane–ethyl acetate (90:10) and some drops of
MeOH. Yield: 93 mg (11.5%) (mixture of Z-10 and
E-10). GC: isomeric ratio=83:17 (Z/E), reaction
time=14.1 and 14.5 min. C18H28O3 (292.22). IR (NaCl,
liquid film): 2966, 1743, 1713, 1638, 1178, 1055; 1H-
NMR (CDCl3): 0.96–0.99 (m, 9H, 3CH3), 1.1–1.9 (m,
9H), 1.24 (t, 3H, CH3), 2.24 (m, 2H, allyl. CH2), 2.51
(m, 1H, C-1), 2.60 (m, 1H, allyl. CH), 4.16 (q, 2H,
OCH2), 5.59 (t, 1H, ꢁCH), [6.48 (t, ꢁCH) of E-10];
13C-NMR (CDCl3): 14.3 (CH3), 19.1 (CH3), 21.7
(2CH3), 23.1 (CH2), 24.3 (CH2), 24.6 (CH2), 31.3 (allyl.
CH), 33.96 (CH2), 34.8 (CH2), 43.9 (CH/C-4), 49.91
(C/C-3), 49.99 (CH/C-1), 60.02 (OCH2), 134.3 (ꢁCH/Z-
10), 138.1 (ꢁCR2/E-10), 139.2 (ꢁCR2/Z-10), 139.7 (ꢁCH/
E-10), 167.6 (CꢁO, ester, E-10), 168.8 (CꢁO, ester,
Z-10), 222.01 (CꢁO, ketone); MS (m/z, relative inten-
sity): 292 ([M+], 4), 277 (3), 246 (74), 231 (7), 219 (19),
203 (13), 177 (4), 151 (7), 137 (14), 123 (60), 95 (100).
Ester E-12 (407 mg, 1.47 mmol), 6.52 mL (9.17 mmol)
of a 20% solution of DIBAH in n-hexane in dry CH2Cl2
were processed as described above. Finally, the same
purification procedure furnished 105 mg (30.4%) of the
allylic alcohol E-3. C16H26O (234.18). IR (NaCl, liquid
1
film): 3330, 3070, 1656, 1014, 877; H-NMR (CDCl3):
1.03 (s, 3H, CH3), 1.03 (t, 3H, CH3), 1.2–1.7 (m, 8H),
1.9–2.2 (m, 2H), 2.02 (m, 1H, C-4), 2.13 (q, 2H, allyl.
CH2), 2.67 (m, 1H, C-1), 4.04 (s, 2H, CH2OH), 4.47 (s,
1H, exocycl. CH2), 4.72 (s, 1H, exocycl. CH2), 5.38 (t,
1H, ꢁCH); 13C-NMR (CDCl3): 13.4 (CH3), 21.01 (CH2),
23.2 (CH2), 23.7 (CH2), 25.2 (CH3), 29.04 (CH2), 37.02
(CH2), 39.1 (CH2), 44.8 (C/C-3), 45.1 (CH/C-4), 46.7
(CH/C-1), 66.8 (CH2OH), 99.3 (exocycl. ꢁCH2), 126.6
(ꢁCHR), 140.2 (ꢁCR2), 166.6 (ꢁCR2, C-2); MS (m/z,
relative intensity): 216 ([M+−18], 8), 203 (3), 187 (11),
161 (6), 148 (10), 133 (8), 122 (25), 107 (16), 94 (100), 79
(38), 67 (19).
5.13. 2-Phosphono-(3-methyl-butyric acid)-triethyl ester
2-Bromo-3-methyl-butyric acid ethyl ester (2.5 g,
11.96 mmol, freshly prepared by azeotropic esterifica-
tion of 2-bromo-isovaleric acid and ethanol) under ar-
gon atmosphere was refluxed with phosphoric acid
triethyl ester (2.05 mL, 11.96 mmol) overnight (oil bath,
200 °C). Purification of the mixture was performed by
distillation (kugelrohr, 70 °C, 0.2 Torr) and then by
preparative TLC with diethyl ether–ethyl acetate
(70:30). C11H23O5P (266.10). IR (NaCl, liquid film):
5.15. (Z)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-2-isopropyl-2-pentenoic acid ethyl ester (Z-13)
A solution of the ketoester mixture Z/E-10 (210 mg,
0.72 mmol) in dry THF (6.3 mL) was cooled down to
0 °C. Then TEBBE reagent (0.5 M in toluene, 1.75 mL)
was added dropwise and stirred for 30 min at 0 °C.
Stirring was carried out for 24 h at r.t. Afterwards, the
mixture was quenched by the addition of 10–20 mL
diethyl ether and as many drops of dry methanol re-
quired till no reaction could be observed anymore. Then
the suspension was filtered through Celite®. Finally, the
filtrate was washed with diethyl ether and freed from the
solvent. The deep orange–red coloured, very viscous
residue was roughly purified by column chromatography
over Al2O3. The final purification of this mixture (GC:
isomeric ratio=85:15 Z/E, reaction time=13.9 and
14.3 min) was performed by preparative TLC with
ligroin–diethyl ether (97:3) and some drops of MeOH
(fourfold development). Yield: 44 mg (21.1%) pure Z-
13. C19H30O2 (290.24). IR (NaCl, liquid film): 3063,
1
1735,1392, 1369, 1257, 1029; H-NMR (CDCl3): 1.10 (d,
3H, CH3), 1.15 (d, 3H, CH3), 1.27–1.35 (m, 9H,
3OCH2CH3), 2.38 (m, 1H, i-PrꢀCH), 2.72 (m, 1H,
PꢀCH), 4.12–4.25 (m, 6H, 3OCH2); 13C-NMR (CDCl3):
14.07 (CH3), 16.2 (CH3), 16.3 (CH3), 21.4 (CH3), 21.6
(CH3), 28.2 (i-PrꢀCH), 52.4 and 52.2 (PꢀCH), 61.01
(OCH2), 62.2 (OCH2), 62.3 (OCH2), 169.2 (CꢁO); MS
(m/z, relative intensity): 267 ([M++1], 2), 251 (9), 224
(100), 197 (77), 179 (48), 169 (28), 152 (71), 137 (27), 123
(80), 105 (30), 81 (43).
5.14. (Z)/(E)-5-(3-Oxo-2-methyl-bicyclo[2.2.1]hept-2-
yl)-2-isopropyl-2-pentenoic acid ethyl ester (Z/E-10)
1
1716, 1656, 1052, 878; H-NMR(CDCl3): 0.94–0.99 (m,
A solution of 2-phosphono-3-(methylbutyric acid)-tri-
ethyl ester (755.3 mg, 2.84 mmol) and freshly recrys-
tallised 18-Crown-6 (3.7 g, 13.96 mmol) in 57 mL THF
9H, 3 CH3), 1.11–1.62 (m, 8H), 1.25 (t, 3H, CH3), 1.93
(m, 1H, C-4), 2.09–2.4 (m, 2H), 2.61 (m, 2H, allyl. CH,
HꢀC-1), 4.16 (q, 2H, OCH2), 4.41 (s, 1H, exocycl.

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G. Buchbauer et al. / European Journal of Medicinal Chemistry 36 (2001) 673–683
ꢁCH2), 4.65 (s, 1H, exocycl. ꢁCH2), 5.60 (t, 1H, ꢁCH);
13C-NMR (CDCl3): 14.3 (CH3), 21.75 (CH3), 21.80
(CH3), 23.7 (CH2), 25.3 (CH3), 25.6 (CH2), 29.1 (CH2),
31.4 (allyl. CH), 37.1 (CH2), 38.7 (CH2), 44.9 (C/C-3),
45.2 (CH/C-4), 46.7 (CH/C-1), 60.04 (OCH2), 99.4 (exo-
cycl. ꢁCH2), 135.04 (ꢁCH), 138.7 (ꢁCR2), 166.6 (ꢁCR2,
C-2), 169.1 (CꢁO); MS (m/z, relative intensity): 290
([M+], 1), 275 (1), 244 (2), 229 (3), 201 (2), 176 (8), 135
(18), 122 (21), 107 (19), 94 (100), 79 (44).
References
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5.16. (Z)-5-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-
yl)-2-isopropyl-pent-2-enol (Z-4)
(‘2%-isopropyl-i-santalol’)
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As already described above ester Z-13 (174 mg, 0.6
mmol) in dry CH2Cl2 and a 20% solution of DIBAH in
n-hexane (2.65 mL, 3.73 mmol) were processed. Prepar-
ative TLC with pentane–diethyl ether (65:35) and some
drops of MeOH furnished 140 mg of a still impure
target compound which could be completely purified by
another TLC, but this time on alumina sheets coated
with silica gel 60 F254 (20×20 cm, layer thickness 0.2
mm, Merck no. 5554) with ligroin–diethyl ether (70:30)
(and some drops of MeOH, threefold development).
Yield: 26 mg (17.5) pure Z-4. C17H28O (248.21). Anal.
Calc. C, 82.26; H, 11.37. Found: C, 82.49; H, 11.48%.
IR (NaCl, liquid film): 3350, 3063, 1656, 1018, 878;
1H-NMR (CDCl3): 0.96–0.99 (m, 9H, 3CH3), 1.11–1.62
(m, 8H), 1.89–2.16 (m, 2H), 1.95 (m, 1H, C-4), 2.35 (m,
1H, allyl. CH), 2.60 (m, 1H, C-1), 4.1 (s, 2H, CH2OH),
4.41 (s, 1H, exocycl. ꢁCH2), 4.65 (s, 1H, exocycl. ꢁCH2),
5.28 (t, 1H, ꢁCH); 13C-NMR (CDCl3): 22.0 (2 CH3),
23.6 (CH2), 23.8 (CH2), 25.3 (CH3), 29.1 (CH2), 32.9
(allyl. CH), 37.1 (CH2), 39.5 (CH2), 44.9 (C/C-3), 45.2
(CH/C-4), 46.7 (CH/C-1), 59.6 (CH2OH), 99.3 (exocycl.
ꢁCH2), 127.4 (ꢁCH), 144.1 (ꢁCR2), 166.7 (ꢁCR2, C-2);
MS (m/z, relative intensity): 230 ([M+−18], 1), 215 (1),
187 (4), 167 (3), 147 (2), 135 (3), 122 (22), 105 (11), 94
(100), 79 (41), 67 (25).
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J.M., J. Phys. Org. Chem. 10 (1997) 612–622.
8
[19] Buchbauer G., Spreitzer H., Ockher B., Pretterklieber C.,
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