Synthesis of Ambrox from labdanolic acid

Article abstract of DOI:10.1016/S0040-4020(02)00571-9

A synthesis of the valuable amber-type odorant Ambrox from labdanolic acid (main diterpenoid of the acid fraction of non-polar extracts of Cistus ladaniferus L.) is reported. The conversion is based on (a) the α,β-dehydrogenation of methyl labdanolate using an organoselenium reagent, (b) subsequent oxidative degradations of the side chain, and (c) final acid-promoted cyclization of the resulting tetranorlabdan-8α,12-diol. The influence of the temperature and solvent in the cyclization of the diol with p-toluenesulfonic acid is also described. Thus, Ambrox has been obtained by a six-step procedure in 33% overall yield from methyl labdanolate.

Full text of DOI:10.1016/S0040-4020(02)00571-9

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5941±5949
Synthesis of Ambroxw from labdanolic acid
p
Juan M. Castro, Sofõa Salido, Joaquõn Altarejos, Manuel Nogueras and Adolfo Sanchez
Â
Â
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    Â
Departamento de Quõmica Inorganica y Organica, Facultad de Ciencias Experimentales, Universidad de Jaen, 23071 Jaen, Spain
Received 27December 2001; revised 28 February 2002; accepted 15 March 2002
AbstractÐA synthesis of the valuable amber-type odorant Ambroxw from labdanolic acid (main diterpenoid of the acid fraction of non-
polar extracts of Cistus ladaniferus L.) is reported. The conversion is based on (a) the a,b-dehydrogenation of methyl labdanolate using an
organoselenium reagent, (b) subsequent oxidative degradations of the side chain, and (c) ®nal acid-promoted cyclization of the resulting
tetranorlabdan-8a,12-diol. The in¯uence of the temperature and solvent in the cyclization of the diol with p-toluenesulfonic acid is also
described. Thus, Ambroxw has been obtained by a six-step procedure in 33% overall yield from methyl labdanolate. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
acid33 and its methyl ester34,35 have already been converted
into norambreinolide, a classic precursor of Ambroxw,3b
through an oxidative cyclization with lead tetraacetate.
Later, the 8-acetyl derivative of labdanolic acid was
converted into norambreinolide and ambroxdiol (another
precursor of Ambroxw), through an oxidative decarboxyl-
ation reaction promoted by lead tetraacetate/copper(II)
acetate.36
Since Ambroxw (1) was initially prepared in 1950 from
(2)-sclareol1,2 considerable synthetic work has been done
to obtain this valuable amber odorant.3±15 One of the reasons
for the steady interest is that 1 still remains the prototype of
what perfumers understand as an ambery note.16 It possesses
the character of the no longer used natural ambergris and it
plays a central role in fragrance creations. Thus, nowadays,
a considerable world consumption of this synthetic material
exists. It is also known that diterpene (2)-sclareol still
constitutes the only practical starting material for the
industrial preparation of 1 and, therefore, the available
quantity of Ambroxw is limited, and its price accordingly
high.3d This is another reason why efforts have been concen-
trated on the search of new syntheses starting from cheap
and abundant alternative natural products. In fact, several
syntheses of Ambroxw have been developed from diter-
penoids such as (2)-manoyl oxide,17 (2)-abietic acid,18
(2)-levopimaric acid,19 (1)-communic acids,20,21 (1)-cis-
abienol22 and (2)-labda-12,14-dien-7a,8a-diol,11 from
sesquiterpenoids such as (2)-drimenol,23,24 and also from
monoterpenoids such as (1)-carvone25 and thujone.7 In
addition to these compounds, the diterpene (2)-labdanolic
acid (2) is a suitable chiral synthon for the synthesis of 1,
because of its structural features and easy availability from
Nature. It has been found in different plants26±28 and it is the
main component of the acidic fraction of non-polar extracts
of Cistus ladaniferus L.,29±31 an abundant and widely
distributed plant in the Iberian Peninsula.32 Labdanolic
²
In this paper, we report on the synthesis of Ambroxw (1)
from labdanolic acid (2) based on the a,b-dehydrogenation
of methyl labdanolate (3), subsequent oxidative degradation
of the side chain and ®nal stereoselective formation of the
tetrahydrofurane ring (Scheme 1). While preparing this
manuscript, a formal synthesis of Ambrox from labdanolic
acid, by iododecarboxylation of 8-acetyl-labdanolic acid
with iodobenzenediacetate, had been published in this
journal.37
2. Results and discussion
The starting material for the synthesis of Ambroxw (1)
was obtained from an ethereal extract of wild-grown
Â
C. ladaniferus, harvested on the northwest of Jaen province.
An extract was prepared by simple soaking of the plant
material in Et2O for 1 day at room temperature. It was
then dewaxed and fractionated to afford an acidic fraction
from which labdanolic acid (2) was isolated by chromato-
graphy. The treatment of this acidic fraction with diazo-
methane gave a mixture of methyl esters that was puri®ed
by chromatography to afford pure methyl labdanolate (3) in
43% yield. For comparison, this isolation procedure of 3
was applied to a plant material extracted with n-hexane in
a Soxhlet apparatus as usual.38 The isolated yield of 3 was
similar in both cases but we found that a simple extraction
of the plant with cold Et2O was more convenient than a
Keywords: Ambroxw; labdanolic acid; a,b-dehydrogenation; oxidative
degradations; stereoselective cyclization.
Corresponding author. Tel.: 134-953-002743; fax: 134-953-012141;
e-mail: jaltare@ujaen.es
Registered trademark of Firmenich S.A. for (2)-8a,12-epoxy-
13,14,15,16-tetranorlabdane.
p
²
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00571-9

5942
J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
Scheme 1. Retrosynthetic analysis of Ambroxw (1) from labdanolic acid (2).
continuous extraction with n-hexane. In addition, the
application of that puri®cation protocol to a labdanum
gum sample assured us that the commercial product of
rock-rose does not contain the desired compound 3.
4a and b (Scheme 2). The use of hexamethylphosphoramide
in the selenenylation step improved the yields,40,42 allowing
the conversion of 3 into 4a and 4b in 94% yield (55:45 ratio
acc. GC). Alternatively, the a,b-dehydrogenation of
compound 3 was proved with the cheaper diphenyl
disul®de.43 However, the need to heat for the dehydro-
sulfenylation resulted in the undesired loss of the tertiary
hydroxyl group. This and the fact that the reaction of 3 with
Ph2Se2 had the added interest of allowing the recovery of the
reagent in good yields by reduction of the by-product
benzeneseleninic acid,41 made the procedure most appro-
priate for the preparation of compounds 4a and b.
As shown in Scheme 1, the degradation of the side chain of
methyl labdanolate (3) was achieved in two steps: (1)
cleavage of the C13±C14 bond, the initial formation of a
D13 double bond being needed, and (2) cleavage of the
C12±C13 bond, via Baeyer±Villiger reaction carried out on
the resulting methyl ketone. For performing the a,b-
dehydrogenation of compound 3, the method of Sharpless
and co-workers39 was chosen to prepare the a,b-unsaturated
esters with electrophilic organoselenium reagents.39±41
Thus, compound 3 was treated with 2 equiv. of lithium
diisopropilamide (LDA), and then with other 2 equiv. of
Ph2Se2 at low temperature. The resulting a-phenylseleno
esters were oxidized with hydrogen peroxide to give spon-
taneous elimination of benzeneselenenic acid at room
temperature giving mixtures of the a,b-unsaturated esters
Treatment of the a,b-unsaturated esters 4a/b with KMnO4
in acetone or THF/water mixtures44 for several hours
afforded the methyl ketone 5, which tended to cyclize to
sclareol oxide (6). The addition of anhydrous MgSO4 to
the reaction mixture in acetone45 ef®ciently shortened the
reaction times allowing the conversion of 4a/b into a
mixture of 5 and 6 (5:2 ratio) in 30 min (Scheme 2).
Scheme 2. Reagents and conditions: (a) LDA, THF, Ph2Se2, 2788C, H2O2; (b) KMnO4, MgSO4, acetone; (c) HCOOH±Ac2O; (d) m-CPBA, CH2Cl2; (e) KOH,
MeOH; (f) p-TsOH, MeNO2.

J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
Table 1. Cyclization reactions of 10 with p-toluenesulfonic acid under different experimental conditions
Entry 10a (mmol) p-TsOH (mmol) MeNO2 (mL) CH2Cl2 (mL) Temperature Reaction time (h)
5943
Products distribution (%)b
10
1
11
12
13 Others
1
2
3
4
5
6
0.28
0.28
0.28
0.28
0.28
0.28
0.175
0.175
0.175
0.175
0.175
0.175
±
±
±
±
±
±
r.t. (
r.t. (
r.t. (
r.t. (
r.t. (
r.t. (
,20 8C)
,20 8C)
,20 8C)
,20 8C)
,20 8C)
,20 8C)
1
2
3
7±
24
96
±
±
±
87.1
88.5
87.7
2.5 10.5 1.5
83.8
71.0 16.1
±
±
t
9.8 1.5
8.3 1.1
9.1 1.1
±
t
6.4 1.1
±
±
±
83.5
±
±
5.1.77 1.2
2.6
70.04
8
9
0.03
±
1
r.t. (
1
1
,20 8C)
r.t. (,20 8C)
r.t. (,20 8C)
1
3
21
10.4 65.2
t
±
±
±
16.8 7.6
11.2 4.9
±
±
0.04
0.04
0.03
0.03
±
±
83.8
88.7±
11.3
t
±
10
11
12
13
14
15
0.29
0.29
0.29
0.29
0.29
0.29
0.18
0.18
0.18
0.18
0.18
0.18
5
5
5
5
5
5
±
±
±
±
±
±
80±858Cc
80±858Cc
80±858Cc
80±858Cc
80±858Cc
80±858Cc
0.5
1
2
3
21
30
±
±
±
±
±
±
11.9 38.76.9 1.1 41.4
t
32.9
36.9
37.1
23.6
17.8
t
t
67.1
63.2
62.9
76.4
82.3
±
±
±
±
±
±
±
±
±
±
±
±
16
0.28
0.17
±
0.17±
0.17±
0.17±
±
5
re¯ux
1
0.5
85.9
8.6
67.4
11.9 2.1
±
±
16.8 7.2
±
170.28
18
19
0.17
5
re¯ux
re¯ux
±
±
84.5
0.28
0.28
0.28
5
5
5
2
3
30
±
±
±
3.0 10.5 2.0
86..43 0.59.4 ± 7
29.6 59.1 11.2
±
re¯ux
re¯ux
20
t
t
a
Starting material.
Percentages deduced from the GC analysis of the crude reactions; t means traces.
Oil bath temperature.
b
c
Attempts to separate both compounds by chromatography
on silica gel failed as only the cyclized 6 was eluated by
chromatography in 68% yield.
10 with reagents such as tosyl chloride, phosphorous
oxychloride, zinc halides, aluminum oxide-based catalysts
or sulfonic acids. The cyclization of 10 is a delicate step as
the con®guration at C-8 has to be retained. A way to avoid
epimerization at that stereocenter is to favor the intra-
molecular nucleophilic substitution of the tertiary hydroxyl
group over the primary at C-12, which can be easily accom-
plished by converting the primary hydroxyl group in a good
leaving group by reaction of 10 with p-toluenesulfonyl (or
methylsulfonyl) chloride in pyridine.10,22,48 However, this
effective method has the laborious elimination of the bad-
smelling pyridine as its main drawback, although an
ef®cient replacement of pyridine by other odorless bases
is already known.8 In addition, acidic reagents can be
employed. It is assumed49 that these acid-catalyzed cycliza-
tion reactions proceed by attack of the primary hydroxyl
group on the tertiary carbocation I. This means that the
risk of epimerization at C-8 remains, as the a-face attack
affords Ambrox (1) and the b-face attack gives iso-Ambrox
(11). p-Toluenesulfonic acid in nitromethane has been one
of the most often used systems.7,9,20,37,49±51 However, a
minor discrepancy concerning the suitable temperature at
which the experiment has to be carried out still exists as
both low20,37,50,51 and high7,9,49 temperature procedures
seem to give Ambrox. Our previous experience20 on the
cyclization of the 8-epi diol II with p-TsOH/MeNO2
showed that low temperatures favored the equatorial
approach of HO±C-12 to the tertiary carbocation while
high temperatures promoted the axial approach, which
agrees with the known statement1,2 that Ambrox (trans-
fused tetrahydrofuran ring) is the kinetic isomer, and
iso-Ambrox (cis-fused tetrahydrofuran ring) the thermo-
dynamic one. In order to examine the in¯uence of the
temperature and solvent on the cyclization of the diol 10
with p-TsOH, a series of experiments have been carried out
Aware of the dif®culties to isolate methyl ketone 5 and the
impossibility to carry out the planned Baeyer±Villiger on it,
we decided to prevent the interference of the hydroxyl group
at C-8 by protection as acetate. Thus, a mixture of 4a/b was
treated with Ac2O, triethylamine and N,N-dimethylamino-
pyridine (DMAP) for several days, with further additions of
Ac2O and DMAP. However, an unexpected low yield was
observed. Supposing a hindering effect of the side chain, a
less-hindered protecting group was chosen. The reaction of
compounds 4a/b with formic acid±acetic anhydride mixture
(FAM)46 afforded the formyl derivatives 7a/b in 93% yield.
These were directly oxidized with KMnO4 to give the corre-
sponding methyl ketone 8 in 88% yield (Scheme 2).
The Baeyer±Villiger reaction on compound 8 with
m-chloroperoxybenzoic acid (m-CPBA) at room tempera-
ture led to the desired acetoxy derivative 9 in 96% yield.
In order to avoid long reaction times, a modi®ed procedure
based on the use of mixtures of tri¯uoroacetic acid (TFA)
and m-CPBA was followed.47 Reaction times were shorter
than before, but side products were observed now, which
could be circumvented by the addition of phosphate buffer
to the reaction mixture (Method B in Section 3.3.4). The
reaction of 9 with a methanol/KOH solution afforded the
diol 10 (59% yield), which was conveniently cyclized with
p-toluenesulfonic acid (p-TsOH) in nitromethane at room
temperature to give Ambrox (1) in 75% yield after
chromatographic puri®cation (Scheme 2).
Several approaches to transform the diol 10 into 1 have been
reported in the literature. They are based on the treatment of

5944
J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
(Table 1). The reaction of 10 with p-TsOH/MeNO2 at room
temperature (entries 1±6) afforded reaction mixtures mainly
composed of 1 along with minor amounts of 11 (entries
3±6) and alkenols 12 and 13, the latter compounds being
identi®ed by GC±MS analysis. Mixtures of these ole®nic
alcohols have also been detected in similar studies on 10 and
a related stereoisomer.7 It can be seen how iso-Ambrox (11)
gradually increases with longer reaction times (entries 3±6).
It is thus expected that 11 will become the major product
under prolonged treatments. When MeNO2 was replaced by
a less polar solvent such as CH2Cl2 (entries 7±9) and the
reactions were carried out at room temperature a similar
steroselectivity in the cyclization was observed. In addition,
a marked decrease in the rate of the process was noted, a
reaction time of 21 h being required (entry 9) to get a
comparable yield to that obtained with MeNO2 after 2 h
(entry 2). However, the treatment of 10 with p-TsOH/
MeNO2 at 80±858C (entries 10±15) led to crude reactions
where 11 appears in higher percentage than 1 (entry 10). In
addition, a successive decrease of 11 (and 12 and 13) in
favor of other unidenti®ed components was observed
under prolonged reaction times. These components could
not be puri®ed and studies to clarify their identity were
not pursued. Finally, when 10 was re¯uxed with p-TsOH/
CH2Cl2 (entries 16±20), a stereoselective formation of 1
was still observed after 1 h reaction time (entry 17) whereas
it was lost in favor of 11 under longer reaction times (entry
20). This allowed us to deduce that the stereoselective acid-
promoted cyclization of the diol 10 to Ambrox (1) can be
ef®ciently accomplished both at room temperature (entries 2
and 9) and at high temperature (entry 17) in regard of the
solvent chosen; either MeNO2 or CH2Cl2 in the ®rst case or
CH2Cl2 in the second one.
pre-dried glassware under a positive pressure of argon.
Commercial reagent grade chemicals and solvents such as
Et2O and MeNO2 were used as received, unless otherwise
stated. THF was freshly distilled from sodium benzo-
phenone ketyl under argon and the hexane (H) and ethyl
acetate (EtOAc), used for chromatographic separations,
and MeOH, acetone and CH2Cl2, used as solvents, were
glass-distilled prior to use. Reactions were monitored by
gas chromatography (GC) and/or analytical thin-layer chro-
matography (TLC) and the reaction products were puri®ed
by conventional column chromatography (Merck silica gel
60, 70±230 mesh) using hexane/Et2O (H/E) mixtures of
increasing polarity, or by ¯ash chromatography (Scharlau
silica gel 60, 230±400 mesh) using the appropriated H/E
mixture, with air pressure to obtain a suitable ¯ow. These
column chromatographic separations were monitored by
GC and/or TLC. Analytical TLC was performed using
Merck precoated (0.25 mm) silica gel 60 F254 aluminum-
backed TLC plates, and compounds were visualized by
UV light and by spraying with a 10% solution of phospho-
molybdic acid in ethanol followed by heating until blue
spots developed. GC analyses were performed on a Varian
CP-3800 gas chromatograph ®tted with a methyl silicone
(CP-Sil
8
CB) capillary column (30 m£0.25 mm£
0.25 mm); carrier gas: He; ¯ow rate: 1 mL/min; oven
temperature program: 100±2908C at a rate of 88C/min;
injector temperature: 2508C; ¯ame ionization detector
temperature: 3008C; retention times (Rt) are expressed in
minutes. Melting points (mp) were determined on an
Electrothermal 9300 melting point apparatus and are uncor-
rected. Optical rotations ([a]D) were recorded on a Perkin±
Elmer 241 automatic polarimeter using quartz cells of 1 dm
path length, in CHCl3 solutions; concentration (c, expressed
in cg/mL) is given in parentheses. Infrared (IR) spectra were
recorded on a FT-IR Perkin±Elmer 1760X spectrometer
using a thin ®lm between KBr plates (neat) or as KBr
pellets; only characteristic absorptions (n, cm21) are
1
reported. H NMR spectra were recorded at 300 MHz on a
Bruker DPX 300 spectrometer using CDCl3 as solvent and
tetramethylsilane (TMS) as internal reference; chemical
shift values are reported in parts per million (ppm, d
scale) and coupling constants (J) are in hertz (Hz); multi-
plicity of signals are expressed as s: singlet, d: doublet, t:
triplet, q: quadruplet, m: multiplet, br s: broad singlet, dd:
double doublet, ddd: double double doublet, dt: double
triplet and td: triple doublet. 13C NMR spectra were
recorded at 75 MHz on the same instrument; chemical shifts
are reported in ppm relative to TMS; carbon substitution
degrees were established by DEPT multipulse sequence.
2D NMR experiments (DQF-COSY, HSQC, HMBC) were
carried out for compounds 6, 7a and b on the same
instrument. Mass spectra (MS) were recorded on a
Hewlett±Packard 5989B mass spectrometer using the
electron impact ionization method (70 eV); MS were
obtained in most cases by GC±MS analysis carried out on
a Hewlett±Packard 5890A II gas chromatograph coupled to
the mass spectrometer described above; the parameters for
the GC unit were the same than those described previously
for the GC analyses; ion source temperature of the MS unit:
2508C; scan range from m/z 35 to 400; the ratios m/z and
relative intensities (%) are indicated for the signi®cant and
major peaks. High-resolution mass spectra (HRMS) were
recorded on a Micromax VG Autospec spectrometer.
In conclusion, a novel route to Ambroxw has been
developed from an abundant natural product via a six-step
procedure in 33% overall yield. All reactions of this
synthesis were carried out with crude materials. Because
of the potential interest of this starting material for the
industrial preparation of Ambroxw, further work is in
progress.
3. Experimental
3.1. General and instrumentation
Reactions with exclusion of moisture were performed with

J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
5945
3.1.1. Labdanolic acid (2). Air-dried twigs of C. ladaniferus
L. (904.03 g), harvested in May 1999 in the Sierra de
(2.03 g, 6.00 mmol) in dry THF (18.0 mL) was added drop-
wise. The mixture was allowed to stir for 1 h at the same
temperature and, then, a solution of Ph2Se2 (4.50 g,
14.40 mmol) in dry HMPA (7.0 mL, stored over molecular
sieves) was slowly poured into. After further stirring for 1 h
at 2788C, the mixture was allowed to warm to room
temperature and a saturated aq. NH4Cl solution (40 mL)
was added. The mixture was extracted with Et2O
(3£50 mL) and the combined organic layers were washed
with 2N HCl (50 mL), saturated aq. NaHCO3 (50 mL) and
brine (50 mL). The organic layer was dried over anhydrous
Na2SO4 and the solvent evaporated under reduced pressure.
The crude reaction was re-solved in Et2O (15 mL) and THF
(5 mL) and a 30% aq. H2O2 solution (9.0 mL, 79.40 mmol)
was added in portions at 08C with continuous stirring. The
mixture was allowed to warm to room temperature and Et2O
(50 mL) was added 0.5 h later. It was washed with saturated
aq. Na2CO3 (50 mL) and this aqueous fraction was
re-extracted with Et2O (2£30 mL). The combined organic
layers were washed with 2N HCl (25 mL), saturated aq.
Na2SO3 (25 mL) and brine (25 mL). After drying the
organic phase with anhydrous Na2SO4 and evaporation of
the solvent under reduced pressure a crude (1.90 g,
5.65 mmol, 94%), formed by a mixture of 4a and b in a
55:45 ratio (according to the GC analysis), was obtained.
An aliquot sample (300 mg) of this residue was ¯ash chro-
matographed (eluent: H/E 6:4) to afford pure 4a (140 mg)
and 4b (115 mg).
Â
Â
Andujar Natural Park (province of Jaen, Spain), were pieced
and soaked in Et2O at room temperature for 24 h. The solu-
tion was removed from the plant material and the solvent
was evaporated under reduced pressure to give an extract
(84.91 g), which was dewaxed with MeOH (16.94 g) and by
formation of urea clathrate compounds (0.73 g). The result-
ing extract was re-solved in Et2O and washed with a 10% aq.
Na2CO3 solution (3£150 mL) to give a neutral fraction
(23.85 g) and an acid fraction (34.05 g). An aliquot sample
(4.68 g) of this acid fraction was puri®ed by conventional
column chromatography (eluents: from H to H/EtOAc 4:6)
to give 2 (1.40 g) as a sticky solid (lit.37); [a]Dˆ26.68 (c
1.06); IR (neat) n 3600±2500, 1708 (COOH), 3408, 1083
(OH); 1H NMR d 0.78 (6H, s, Meb-4, Me-10), 0.86 (3H, s,
Mea-4), 0.98 (3H, d, Jˆ6.6 Hz, Me-13), 1.15 (3H, s, Me-8),
1.85 (1H, dt, Jˆ12.3, 3.3 Hz, Hb-7), 2.19 (1H, dd, Jˆ14.8,
7.2 Hz, H-14), 2.30 (1H, dd, Jˆ14.8, 6.4 Hz, H0-14); 13C
NMR d 39.58 (C-1), 18.38 (C-2), 41.94 (C-3), 33.16 (C-4),
55.96 (C-5), 20.37 (C-6), 43.74 (C-7), 74.92 (C-8), 61.97
(C-9), 39.04 (C-10), 22.99 (C-11), 40.45 (C-12), 31.15
(C-13), 41.49 (C-14), 177.87 (C-15), 19.89 (C-16), 23.79
(C-17), 33.33 (C-18), 21.43 (C-19), 15.45 (C-20); MS m/z
324 (M1, 1%), 306 (M12H2O, 4), 291 (M12H2O±Me, 7),
266 (1), 253 (3), 235 (9), 217(4), 193 (5), 171 (21), 153
(15), 137 (13), 123 (24), 109 (27), 95 (30), 81 (36), 69 (79),
55 (74), 43 (100).
3.1.2. Methyl labdanolate (3). A sample (29.37g) of the
acid fraction prepared as described in Section 3.1.1 from C.
ladaniferus extract was treated with an ethereal diazo-
methane solution, generated in situ by adding a methanolic
2N KOH solution (175 mL) over a suspension of N-methyl-
From the aqueous phase obtained after washing the H2O2-
treated mixture with saturated aq. Na2CO3, Ph2Se2 (2.52 g,
56%) was recovered following the procedure described in
Ref. 41.
N-nitrosotoluene-4-sulfonamide
(40.30 g)
in
Et2O
3.2.1. Methyl 8a-hydroxy-labd-13Z-en-15-oate (4a).
Colorless crystals; Rt 20.65; mp 131.9±133.78C (hexane);
[a]Dˆ134.68 (c 0.68); IR (neat) n 3529, 1086, 1075 (OH),
(400 mL). The resulting mixture of methyl esters (30.41 g)
was puri®ed by conventional column chromatography
(eluents: from H to H/E 6:4) to give 3 (12.75 g) as light
green crystals (lit.38); Rt 20.54; mp 68.3±71.38C (hexane);
[a]Dˆ28.08 (c 1.11); IR (neat) n 3483, 1085 (OH), 1739,
1260, 1201, 1160 (COOMe); 1H NMR d 0.78 (6H, s, Meb-4,
Me-10), 0.86 (3H, s, Mea-4), 0.95 (3H, d, Jˆ6.7Hz,
Me-13), 1.14 (3H, s, Me-8), 1.86 (1H, dt, Jˆ12.0, 3.1 Hz,
Hb-7), 2.16 (1H, dd, Jˆ14.6, 8.0 Hz, H-14), 2.34 (1H, dd,
Jˆ14.6, 5.8 Hz, H0-14), 3.66 (3H, s, OMe); 13C NMR d
39.59 (C-1), 18.37(C-2), 41.90 (C-3), 33.15 (C-4), 56.01
(C-5), 20.43 (C-6), 44.16 (C-7), 74.13 (C-8), 62.15 (C-9),
39.01 (C-10), 22.74 (C-11), 40.60 (C-12), 31.21 (C-13),
41.35 (C-14), 173.83 (C-15), 19.83 (C-16), 23.91 (C-17),
33.33 (C-18), 21.42 (C-19), 15.42 (C-20), 51.35 (OMe); MS
m/z 338 (M1, 0.3%), 320 (M12H2O, 0.7), 307 (M12OMe,
0.5), 305 (M12H2O±Me, 1), 267(1), 235 (2), 217(1), 191
(1), 185 (3), 177 (5), 153 (4), 144 (16), 125 (24), 109 (26),
101 (31), 95 (25), 81 (36), 69 (83), 55 (73), 43 (100).
1
1703, 1237, 1175, 1145 (COOMe), 1641, 857 (CvC); H
NMR d 0.74 (3H, s, Meb-4), 0.76 (3H, s, Me-10), 0.84 (3H,
s, Mea-4), 1.15 (3H, s, Me-8), 1.83 (1H, dt, Jˆ12.4, 3.1 Hz,
Hb-7), 1.88 (3H, d, Jˆ1.4 Hz, Me-13), 2.14±2.26 (1H, m,
0
H-12), 2.84-2.97(1H, m, H -12), 3.30 (1H, br s, OH), 3.64
(3H, s, OMe), 5.63 (1H, br s, H-14); 13C NMR d 39.30
(C-1), 18.45 (C-2), 41.94 (C-3), 33.21 (C-4), 56.03 (C-5),
20.22 (C-6), 43.15 (C-7), 73.88 (C-8), 61.52 (C-9), 38.79
(C-10), 24.19 (C-11), 37.44 (C-12), 161.96 (C-13), 115.09
(C-14), 166.98 (C-15), 25.62 (C-16), 24.13 (C-17), 33.32
(C-18), 21.41 (C-19), 15.45 (C-20), 51.03 (OMe); MS m/z
336 (M1, 0.3%), 319 (M12OH, 0.2), 318 (M12H2O, 0.2),
304 (M12OH±Me, 6), 303 (M12H2O±Me, 0.6), 289
(30412Me, 0.9), 276 (M12HCOOMe, 4), 266 (11), 243
(27612H2O±Me, 1), 205 (3), 191 (3), 177 (8), 163 (3), 149
(6), 137(6), 123 (11), 114 (26), 110 (25), 95 (32), 81 (38),
69 (61), 55 (74), 43 (100). HRMS (M1), found 336.2700,
C21H36O3 requires 336.2664.
3.2. Reaction of 3 with Ph2Se2/H2O2 to give a,b-
unsaturated ester derivatives 4a and b
3.2.2. Methyl 8a-hydroxy-labd-13E-en-15-oate (4b).
Colorless crystals (lit.38); Rt 21.66; mp 88.0±89.08C
(hexane); [a]Dˆ113.78 (c 0.71); IR (neat) n 3553, 1074
i
To a stirred solution of dry Pr2NH (2.4 mL, 17.10 mmol,
1
(OH), 1714, 1224, 1149 (COOMe), 1646, 854 (CvC); H
distilled from CaH2 and stored over molecular sieves) and
dry THF (36.0 mL) was added dropwise a 2.5 M solution of
n-BuLi in hexane (6.0 mL, 15.00 mmol) at 2788C under
argon. After stirring for 0.7h at 2788C a solution of 3
NMR d 0.77 (6H, s, Meb-4, Me-10), 0.85 (3H, s, Mea-4),
1.13 (3H, s, Me-8), 1.85 (1H, dt, Jˆ12.0, 3.1 Hz, Hb-7),
2.15 (3H, d, Jˆ1.2 Hz, Me-13), 3.67(3H, s, OMe), 5.67

5946
J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
(1H, br s, H-14); 13C NMR d 39.72 (C-1), 18.40 (C-2), 41.89
(C-3), 33.22 (C-4), 56.07(C-5), 20.57(C-6), 44.33 (C-7),
reduced pressure to yield a residue (1.91 g, 5.25 mmol,
93%) formed by a mixture of 7a and b in a 55:45 ratio,
p
74.18 (C-8), 61.37 (C-9), 39.16 (C-10), 23.53 (C-11), 44.71p
(C-12), 161.35 (C-13), 114.70 (C-14), 167.35 (C-15), 19.09
(C-16), 23.98 (C-17), 33.36 (C-18), 21.46 (C-19), 15.40
(C-20), 50.76 (OMe) (p these signals may be interchanged);
MS m/z 304 (M12OH±Me, 0.6%), 303 (M12H2O±Me,
0.6), 289 (30412Me, 0.4), 276 (M12HCOOMe, 1), 266
(3), 243 (27612H2O±Me, 1), 205 (3), 191 (9), 177 (12),
163 (2), 149 (5), 135 (7), 123 (10), 114 (21), 109 (19), 95
(34), 82 (59), 69 (56), 55 (70), 43 (100).
1
according to the H NMR spectrum. An aliquot sample
(453 mg) of this residue was puri®ed by ¯ash chromato-
graphy (eluent: H/E 8:2) to afford pure 7a (161 mg) and
7b (131 mg).
3.4.1. Methyl 8a-formyloxy-labd-13Z-en-15-oate (7a).
Colorless crystals; mp 58.0±59.68C (hexane); [a]Dˆ
212.78 (c 1.02); IR (KBr) n 1728, 1193 (OOCH), 1705,
1241, 1171 (COOMe), 1649, 875 (CvC); 1H NMR d
0.77 (3H, s, Meb-4), 0.82 (3H, s, Me-10), 0.86 (3H, s,
Mea-4), 1.49 (3H, s, Me-8), 1.88 (3H, d, Jˆ1.4 Hz,
Me-13), 2.53 (1H, dt, Jˆ12.5, 3.3 Hz, Hb-7), 2.59±2.76
(2H, m, H-12), 3.65 (3H, s, OMe), 5.60 (1H, br s, H-14),
8.04 (1H, s, OOCH); 13C NMR d 39.36p (C-1), 18.35 (C-2),
41.80 (C-3), 33.13 (C-4), 55.52 (C-5), 20.01 (C-6), 39.32p
(C-7), 89.08 (C-8), 58.91 (C-9), 39.53 (C-10), 24.10 (C-11),
36.13 (C-12), 160.49 (C-13), 115.44 (C-14), 166.53 (C-15),
25.16 (C-16), 21.24 (C-17), 33.29 (C-18), 21.42 (C-19),
15.69 (C-20), 50.78 (OMe), 160.65 (OOCH) (p these signals
may be interchanged); MS m/z 364 (M1, 0.1%), 349
(M12Me, 0.2), 319 (M12OOCH, 12), 318 (M12HCOOH,
4), 304 (M12HCOOMe, 1), 303 (31812Me, 4), 287
(M12HCOOH±OMe, 4), 259 (31812COOMe, 4), 205
(12), 192 (21), 177 (19), 149 (11), 136 (21), 121 (23), 109
(27), 95 (39), 81 (41), 69 (55), 55 (70), 41 (100). HRMS (M1),
found 364.2615, C22H36O4 requires 364.2614.
3.3. 8a,13-Epoxy-14,15-dinorlabd-12-ene (6)
To a stirred solution of crude 4a/b (205 mg, 0.60 mmol,
55:45 ratio) in acetone (15 mL) was added a mixture of
KMnO4 (333 mg, 2.20 mmol) and anhydrous MgSO4
(290 mg) at room temperature. After stirring for 0.5 h the
reaction mixture was ®ltered over Celite and the solvent
evaporated under reduced pressure at room temperature.
The residue was solved in Et2O (20 mL) and washed with
H2O (3£10 mL). After drying the organic layer with anhy-
drous Na2SO4 and evaporation of the solvent under reduced
pressure at room temperature, a residue (164 mg) was
obtained which was composed of 5 and 6 in a 5:2 ratio,
according to the 1H NMR spectrum (GC analysis only
showed a single peak at Rt 15.08). 1H NMR data correspond-
ing to 5 (lit.22): d 0.79 (3H, s, Meb-4), 0.80 (3H, s, Me-10),
0.86 (3H, s, Mea-4), 1.15 (3H, s, Me-8), 1.87(1H, dt,
Jˆ12.2, 3.1 Hz, Hb-7), 2.13 (3H, s, Me-13), 2.57 (1H,
ddd, Jˆ17.8, 7.8, 5.7 Hz, H-12), 2.68 (1H, dt, Jˆ17.8,
7.8 Hz, H0-12).
3.4.2. Methyl 8a-formyloxy-labd-13E-en-15-oate (7b).
(hexane);
Colorless
crystals;
mp
89.1±91.08C
[a]Dˆ218.98 (c 1.06); IR (KBr) n 1716, 1184 (OOCH),
1
1716, 1218, 1148 (COOMe), 1651, 854 (CvC); H NMR
d 0.79 (3H, s, Meb-4), 0.84 (3H, s, Me-10), 0.88 (3H, s,
Mea-4), 1.50 (3H, s, Me-8), 2.17(3H, s, Me-13), 2.60 (1H,
dt, Jˆ12.1, 3.1 Hz, Hb-7), 3.69 (3H, s, OMe), 5.67 (1H, br s,
H-14), 8.01 (1H, s, OOCH); 13C NMR d 39.50 (C-1), 18.21
(C-2), 41.72 (C-3), 33.07 (C-4), 55.52 (C-5), 19.95 (C-6),
39.37(C-7), 89.00 (C-8), 58.46 (C-9), 39.50 (C-10), 23.87
(C-11), 43.62 (C-12), 160.77 (C-13), 114.83 (C-14), 167.23
(C-15), 19.02 (C-16), 21.03 (C-17), 33.22 (C-18), 21.36
(C-19), 15.60 (C-20), 50.74 (OMe), 160.28 (OOCH); MS
m/z 364 (M1, 0.5%), 349 (M12Me, 0.7), 319 (M12OOCH,
5), 318 (M12HCOOH, 4), 304 (M12HCOOMe, 1), 303
(31812Me, 7), 287 (M12HCOOH±OMe, 5), 259
(31812COOMe, 3), 205 (17), 192 (62), 177 (40), 149
(17), 137 (24), 123 (38), 109 (41), 95 (57), 81 (67), 69
(77), 55 (84), 41 (100). HRMS (M1), found 364.2606,
C22H36O4 requires 364.2614.
That residue was ¯ash chromatographied (eluent: H/E 8:2)
to yield pure 6 (107mg, 0.41 mmol, 68%) as a pale yellow
oil (lit.22); Rt 15.08; mp 34.0±36.08C (MeOH); [a]Dˆ11.28
1
(c 0.95); IR (neat) n 3054, 1683 (CvC), 1127(C±O±C); H
NMR d 0.82 (6H, s, Meb-4, Me-10), 0.88 (3H, s, Mea-4),
1.16 (3H, s, Me-8), 1.68 (3H, br s, Me-13), 1.94 (1H, dt,
Jˆ12.3, 3.2 Hz, Hb-7), 4.43 (1H, br s, H-12); 13C NMR d
39.29 (C-1), 18.56 (C-2), 41.91 (C-3), 33.14 (C-4), 56.17
(C-5), 19.74 (C-6), 41.12 (C-7), 76.17 (C-8), 52.43 (C-9),
36.66 (C-10), 18.26 (C-11), 94.54 (C-12), 147.83 (C-13),
20.43 (C-16), 20.07(C-17), 33.43 (C-18), 21.55 (C-19),
15.00 (C-20); MS m/z 263 (M111, 7%), 262 (M1, 35),
247(M 12Me, 8), 244 (7), 229 (M12Me±H2O, 16), 219
(3), 204 (4), 201 (5), 191 (42), 177 (25), 163 (5), 149 (9),
135 (16), 123 (29), 109 (73), 95 (50), 81 (55), 69 (32), 55
(40), 43 (100).
3.4. Reaction of 4a/b with FAM to give formate esters 7a
and b
3.5. 8a-Formyloxy-14,15-dinorlabdan-13-one (8)
To a stirred solution of crude 7a/7b (286 mg, 0.78 mmol,
55:45 ratio) in acetone (18 mL) was added a mixture of
KMnO4 (632 mg, 4.00 mmol) and anhydrous MgSO4
(600 mg) at room temperature. After stirring for 0.75 h the
reaction mixture was worked-up, as for compound 6, to
afford crude 8 (214 mg, 0.68 mmol, 88%). An aliquot
sample (107mg) of crude 8 was puri®ed by ¯ash chromato-
graphy (eluent: H/E 4:6) to give pure 8 (89 mg) as a color-
less solid; mp 66.0±67.48C (hexane); [a]Dˆ222.38 (c
1.01); IR (KBr) n 1722, 1198, 1165 (OOCH), 1696 (CO);
1H NMR d 0.79 (3H, s, Meb-4), 0.86 (3H, s, Me-10), 0.88
A sample (3.8 mL, 29.00 mmol) of formic acid±acetic
anhydride mixture (FAM), prepared from Ac2O and formic
acid as described in the literature,46 was slowly added for
15 min to a mixture of 4a and b (1.90 g, 5.65 mmol, 55:45
ratio) at 108C. After stirring for 48 h at room temperature,
water (50 mL) was added and the mixture extracted with
Et2O (3£50 mL). The combined organic layers were
washed with 2N HCl (50 mL), saturated aq. Na2CO3
(50 mL) and brine (50 mL). The organic phase was dried
over anhydrous Na2SO4 and the solvent evaporated under

J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
5947
(3H, s, Mea-4), 1.52 (3H, s, Me-8), 2.13 (3H, s, Me-13),
3.7. 13,14,15,16-Tetranorlabdan-8a,12-diol (10)
2.43±2.69 (3H, m, Hb-7, H-12), 8.02 (1H, s, OOCH); 13C
NMR d 39.48 (C-1), 18.17(C-2), 41.67(C-3), 33.04 (C-4),
55.50 (C-5), 19.87 (C-6), 39.48 (C-7), 88.99 (C-8), 57.95
(C-9), 39.48 (C-10), 19.26 (C-11), 46.37(C-12), 208.98 (C-
13), 29.78 (C-16), 21.03 (C-17), 33.21 (C-18), 21.32 (C-19),
15.42 (C-20), 160.28 (OOCH); MS m/z 263 (M12OOCH,
0.7%), 262 (M12HCOOH, 0.9), 245 (M12OOCH±H2O,
7), 244 (M12HCOOH±H2O, 1), 229 (26212H2O±Me, 2),
219 (26212CH3CO, 0.2), 204 (26212Me±CH3CO, 3), 191
(2), 177 (2), 161 (1), 149 (1), 136 (6), 121 (5), 109 (6), 95
(8), 81 (8), 67(10), 55 (13), 43 (100). HRMS
(M12HCOOH), found 262.2296, C18H30O requires
262.2297.
A mixture of crude 9 (525 mg, 1.62 mmol) and 10% metha-
nol KOH (10 mL, 17.90 mmol) was stirred at room
temperature for 10 min. The crude reaction was concen-
trated under reduced pressure to remove MeOH, re-
suspended in water (50 mL) and extracted with Et2O
(3£40 mL). The combined organic extracts were washed
with brine (2£20 mL), dried over anhydrous Na2SO4 and
the solvent evaporated under reduced pressure to yield
crude 10 (244 mg, 0.96 mmol, 59%). An aliquot sample
(130 mg) of this crude product was ¯ash-chromatographied
(eluent: E) to afford pure 10 (95 mg) as a colorless solid
(lit.22,37); Rt 17.10; mp 130.6±132.28C (hexane);
[a]Dˆ215.88 (c 1.01); IR (KBr) n 3270, 1054, 1033
1
(OH); H NMR d 0.79 (6H, s, Meb-4, Me-10), 0.87(3H,
3.6. 12-Acetoxy-8a-formyloxy-13,14,15,16-tetranorlab-
dane (9)
s, Mea-4), 1.19 (3H, s, Me-8), 1.90 (1H, dt, Jˆ12.2, 3.2 Hz,
Hb-7), 3.44 (1H, dt, Jˆ10.1, 6.9 Hz, H-12), 3.77 (1H, dt,
Jˆ10.1, 4.3 Hz, H0-12); 13C NMR d 39.31 (C-1), 18.38 (C-
2), 41.86 (C-3), 33.24 (C-4), 55.99 (C-5), 20.42 (C-6), 44.15
(C-7), 72.94 (C-8), 59.23 (C-9), 38.94 (C-10), 27.82 (C-11),
63.98 (C-12), 24.56 (C-17), 33.38 (C-18), 21.45 (C-19),
15.29 (C-20); MS m/z 254 (M1, 0.3%), 239 (M12Me, 4),
236 (M12H2O, 3), 221 (M12H2O±Me, 8), 195 (21), 177
(45), 165 (8), 151 (22), 139 (10), 123 (15), 109 (44), 95 (50),
81 (41), 69 (61), 55 (57), 43 (100).
Method A. m-Chloroperoxybenzoic acid (348 mg,
2.02 mmol, prepared from technical grade m-CPBA by
washing with saturated aq. NaHCO3) was added to a solu-
tion of crude 8 (529, 1.72 mmol) in CH2Cl2 (20 mL), and the
mixture was left to stand in the dark at room temperature for
12 days. During this period, additional portions of the
enriched m-CPBA (170 mg, 0.99 mmol) were added every
day to complete the reaction. The mixture was washed with
10% aq. Na2SO3 (3£15 mL), saturated aq. Na2CO3
(3£15 mL) and brine (15 mL). The organic layer was
dried over anhydrous Na2SO4 and the solvent evaporated
under reduced pressure to afford crude 9 (532 mg,
1.64 mmol, 96%). An aliquot sample (148 mg) of this
crude was puri®ed by ¯ash chromatography (eluent: H/E
6:4) to afford pure 9 (93 mg) as a colorless oil;
[a]Dˆ223.88 (c 0.93) IR (neat) n 1738, 1248, 1235
3.8. 8a,12-Epoxy-13,14,15,16-tetranorlabdane
(Ambroxw (1))
A mixture of crude 10 (244 mg, 0.96 mmol) and p-toluene-
sulfonic acid monohydrate (113 mg, 0.58 mmol) in MeNO2
(17mL) was stirred at room temperature for 1 h. The reac-
tion mixture was diluted with Et2O (65 mL), washed with
saturated aq. NaHCO3 (2£20 mL) and brine (20 mL). The
organic layer was dried with anhydrous Na2SO4, and the
solvent evaporated under reduced pressure to afford a resi-
due (230 mg), which after ¯ash chromatography (eluent: H/
E 7:3) yielded pure 1 (170 mg, 0.72 mmol, 75%) as a color-
less solid (lit.20); Rt 13.49; mp 73.6±75.48C (hexane);
[a]Dˆ224.68 (c 0.68); IR (KBr) n 1069, 1007, 979, 916
(C±O±C); 1H NMR d 0.83 (3H, s, Meb-4), 0.84 (3H, s, Me-
10), 0.88 (3H, s, Mea-4), 1.09 (3H, s, Me-8), 1.94 (1H, dt,
Jˆ11.4, 3.1 Hz, Hb-7), 3.82 (1H, q, Jˆ8.2 Hz, H-12), 3.91
(1H, td, Jˆ8.2, 4.3 Hz, H0-12); 13C NMR d 39.72p (C-1),
18.37(C-2), 42.41 (C-3), 33.03 (C-4), 57.23 (C-5), 20.62
(C-6), 39.93p (C-7), 79.84 (C-8), 60.10 (C-9), 36.16 (C-10),
22.60 (C-11), 64.92 (C-12), 21.10 (C-17), 33.55 (C-18),
21.10 (C-19), 15.00 (C-20) (p these signals may be inter-
1
(OAc), 1719, 1200, 1179 (OOCH); H NMR d 0.79 (3H,
s, Meb-4), 0.85 (3H, s, Me-10), 0.88 (3H, s, Mea-4), 1.52
(3H, s, Me-8), 2.04 (3H, s, OAc), 2.64 (1H, dt, Jˆ12.5,
3.3 Hz, Hb-7), 4.10 (2H, t, Jˆ7.8 Hz, H-12), 8.00 (1H, s,
OOCH); 13C NMR d 39.27p (C-1), 18.18 (C-2), 41.66 (C-3),
33.08 (C-4), 55.46 (C-5), 19.88 (C-6), 39.41p (C-7), 88.36
(C-8), 54.91 (C-9), 39.03 (C-10), 24.69 (C-11), 65.74
²
(C-12), 20.91 (C-17), 33.20 (C-18), 21.34 (C-19), 15.49
²
(C-20), 160.15 (OOCH), 170.96 (OAc), 20.99 (OAc) (p,²
these signals may be interchanged); MS m/z 278
(M12HCOOH, 8%), 219 (M12HCOOH±OAc, 7), 218
(M12HCOOH±HOAc, 34), 203 (21812Me, 22), 190 (6),
175 (9), 161 (6), 149 (12), 136 (59), 123 (28), 109 (37), 94
(70), 81 (36), 69 (23), 55 (19), 43 (100).
changed); MS m/z 236 (M1, 1%), 221 (M12Me, 62), 203
Method B. m-Chloroperoxybenzoic acid (135 mg,
0.78 mmol, prepared from technical grade m-CPBA by
washing with saturated aq. NaHCO3) and a phosphate buffer
(2.5 mL, pH 7.4) were added to a stirred solution of 8
(92 mg, 0.30 mmol) in CH2Cl2 (2.5 mL). The reaction
¯ask was protected from light and the suspension cooled
to 08C. Then, tri¯uoroacetic acid (0.025 mL, 0.32 mmol)
was added, and the mixture allowed to stir at room
temperature for 4 days. An additional portion of enriched
m-CPBA (135 mg, 0.78 mmol) was added for complete
consumption of the starting material. Finally, the mixture
was worked-up as in Method A to afford 9 (78 mg,
0.24 mmol, 81%).
(M12Me±H2O, 3), 177 (2), 165 (1), 151 (2), 137 (C10H17
22), 121 (6), 109 (12), 97(51), 81 (38), 67(50), 55 (62), 41
(100).
,
1
3.9. Cyclization reactions of 10 with p-TsOH
A mixture of 10 and p-toluenesulfonic acid monohydrate in
MeNO2 or CH2Cl2 was stirred at room or high temperature
for different period of times (Table 1). Aliquot samples were
diluted with Et2O, washed with saturated aq. NaHCO3 and
brine. The organic layers were dried over anhydrous Na2SO4
and directly monitored by GC.

5948
J. M. Castro et al. / Tetrahedron 58 (2002) 5941±5949
15. Moulines, J.; Lamidey, A.-M.; Desvergnes-Breuil, V. Synth.
Commun. 2001, 31, 749±758.
Â
16. Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Frater, G. Angew.
3.9.1. 8b,12-Epoxy-13,14,15,16-tetranorlabdane (iso-
Ambrox (11)). Rt 12.82; MS m/z 221 (M12Me, 55%),
203 (M12Me±H2O, 3), 17(3), 165 (1), 147(2), 137
(C10H171, 17), 121 (6), 109 (7), 97 (28), 81 (20), 67 (24),
55 (42), 41 (100).
Chem., Int. Ed. Engl. 2000, 39, 2980±3010.
17. Cambie, R. C.; Joblin, K. N.; Preston, A. F. Aust. J. Chem.
1971, 24, 583±591.
3.9.2. 13,14,15,16-Tetranorlabd-8-en-12-ol (12). Rt 14.68;
MS m/z 236 (M1, 3%), 221 (M12Me, 5), 203 (M12Me±
H2O, 2), 191 (M12C2H5O, 9), 177 (6), 163 (4), 151 (4), 135
(6), 121 (C9H131, 13), 107(20), 95 (31), 81 (20), 69 (25), 55
(49), 41 (100).
18. Koyama, H.; Kaku, Y.; Ohno, M. Tetrahedron Lett. 1987, 28,
2863±2866.
19. Nishi, Y.; Ishihara, H. J. Jpn. Oil Chem. Soc. 1989, 38, 27 6±
279.
20. Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.;
Ramos, J. M.; Salido, S. Tetrahedron 1993, 49, 6251±6262.
21. Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.;
Ramos, J. M.; Salido, S. Tetrahedron 1993, 49, 9525±9534.
22. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Altarejos, J.; Salido,
S.; Ramos, J. M. Tetrahedron 1993, 49, 10405±10412.
3.9.3. 13,14,15,16-Tetranorlabd-7-en-12-ol (13). Rt 15.07;
MS m/z 236 (M1, 2%), 221 (M12Me, 0.9), 203 (M12Me±
H2O, 0.6), 192 (1), 191 (M12C2H5O, 1), 177 (2), 163 (0.6),
149 (2), 136 (3), 124 (C9H161, 15), 112 (M12124, 27), 109
(12412Me, 66), 94 (22), 81 (11212OMe, 32), 69 (25), 55
(56), 41 (100).
  Â
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