The synthesis of (-)-Ambrox starting from labdanolic acid

Article abstract of DOI:10.1016/S0040-4020(01)00493-8

Iododecarboxylation of labdanolic acid (1), followed by dehydrohalogenation led to alkenes 4 and 12. Both compounds were converted into (1R,2R,4aS,8aS)-1-(2-hydroxyethyl)-2,5,5,8a-tetramethyldecahydro-2- naphthalenol (8), which was transformed via cyclization into (-)-Ambrox (9).

Full text of DOI:10.1016/S0040-4020(01)00493-8

TETRAHEDRON
Pergamon
Tetrahedron 57 $2001) 5657±5662
The synthesis of ꢀ2)-Ambroxw starting from labdanolic acid
Marjon G. Bolster, Ben J. M. Jansen and Aede de Grootp
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, HB 6703 Wageningen, The Netherlands
Received 23 January 2001; revised 17 April 2001; accepted 3 May 2001
AbstractÐIododecarboxylation of labdanolic acid $1), followed by dehydrohalogenation led to alkenes 4 and 12. Both compounds were
converted into $1R,2R,4aS,8aS)-1-$2-hydroxyethyl)-2,5,5,8a-tetramethyldecahydro-2-naphthalenol $8), which was transformed via cycliza-
tion into $2)-Ambroxw $9). q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
because the carboxyl group is the only available functional
group in the side chain. Several studies to break down the
side chain of labdanolic acid $1) or its methyl ester have
been reported in the literature.10a Lead tetraacetate is mostly
used as decarboxylating reagent10b,c and acetates are
obtained in rather irreproducible yields.11 We now report
on the iododecarboxylation of labdanolic acid as the key
step in the synthesis of $2)-Ambroxw $Scheme 1).
Since ancient times, ambergris has been one of the most
highly valued perfumery materials.1 Ambergris is a meta-
bolic product of the spermwhale $Physeter macrocephalus
L.) which accumulates as concretions in the gut. $2)-
Ambroxw $9), the commercially most important constituent
of the scarce natural ambergris, is recognized as the proto-
type of all ambergris odorants2 and the release of ambergris
scent proved to be strongly related to structural elements of
the tetra-nor-labdane skeleton.3 Several synthetic routes to
$2)-Ambroxw and its racemate have been developed4 and
many are based on naturally occuring sesqui-5 or diterpenes6
as starting material. Nowadays $2)-sclareol is the
industrially used starting material for the preparation of
$2)-Ambroxw.7 The price of $2)-Ambroxw is relatively
high, which induces an ongoing search for new syntheses
starting from cheap, abundantly available labdanes.
Labdanolic acid $1) is one of the labdanes that has the
potential to ful®ll this role because it is easily available
from Nature8. Labdanolic acid $1) is the main component
$ca. 40%) in the acidic fraction of the n-hexane extract of
Cistus ladaniferus L. $`Rock-rose')8b±9 and after oxidative
degradation of the C$9) side chain of labdanolic acid suit-
able synthons for the synthesis of $2)-Ambroxw become
available.
2. Results and discussion
The commercial extract from C. ladaniferus L.,12 is obtained
by steam distillation of the twigs and leaves of the plants, or
by treatment of the plant material with hot water or aqueous
base. These conditions may cause elimination of the tertiary
hydroxyl group which results in formation of a mixture of
labdenic acids. To prevent this dehydration the air dried
twigs and leaves of the C. ladaniferus L. were soaked
with n-hexane and evaporation of the solvent gave rise to
a sticky labdanum gum. Partial puri®cation was performed
by extracting the acid from an etheral solution into water by
base and upon acidi®cation crude labdanolic acid $1) was
obtained. Further puri®cation of this crude labdanolic acid
$1) appeared to be dif®cult, but after conversion of the C$8)
tertiary hydroxyl group in its acetate, the puri®cation of the
acetate 2 proved to be relatively easy, and pure acetate 2
The degradation of labdanolic acid is not an easy task
Keywords: Ambroxw; labdanolic acid; iododecarboxylation.
Corresponding author. Tel.: 131-317-482370; fax: 131-317-484914; e-mail: aede.degroot@bio.oc.wag-ur.nl
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020$01)00493-8

5658
M. G. Bolster et al. / Tetrahedron 57 02001) 5657±5662
Scheme 2. Reagents and conditions: $a) AcCl, N,N-dimethylaniline; $b) IBDA, I2, CCl4, hn, D, 76%; $c) tBuOK, THF, 74%; $d) O3, MeOH/CH2Cl2 1:5,
2788C, PPh3, 44%; $e) O3, CH2Cl2, py, 2788C; $f) LiAlH4, THF, 60%; $g) pTsOH, CH3NO2, 87%.
could be obtained in 35±45% based upon crude acidic mate-
rial.
ozonolysis. So the tertiary hydroxyl group of 4 was
protected again as its acetate and the ozonolysis product
of 11 was subjected to Criegee rearrangement. After reduc-
tion of the obtained intermediate with lithium aluminum
hydride $LiAlH4) compound 8 was obtained in 89% overall
yield from compound 11 $Scheme 3). This diol was trans-
formed into $2)-Ambroxw 9 as shown in Scheme 2.
The iododecarboxylation13 of acetate 2 with iodobenzene-
diacetate $IBDA) and iodine could be achieved under
irradiation with a 100 W tungsten lamp and the iodide 3
was obtained in 76% yield. Because this iodide 3 proved
to be a rather unstable compound and because it was
contaminated with iodobenzene, the product was treated
immediately with potassium tert-butoxide $tBuOK) in
THF at room temperature to give dehydroiodination and
hydrolysis of the acetate group to compound 4 in 74% yield.
In the ®rst route it was shown that treatment of 3 with
tBuOK at room temperature afforded compound 4. When
this dehydroiodonation was performed using the same base
in re¯uxing THF $or in DMSO at room temperature), the
intermediate 4 was in situ isomerized to 12 $Scheme 4).
Ozonolysis of the double bond and reduction with sodium
borohydride $NaBH4) of the intermediate ozonides gave
diol 8 in 92% overall yield and this diol again was trans-
formed into $2)-Ambroxw 9 according to Scheme 2.
Ozonolysis of the double bond of compound 4 and reduction
of the intermediate ozonides gave the methyl ketone
which immediately cyclized into sclareol oxide $6). The
irreproducible yield of 45±90% in the conversion of 4 to
sclareol oxide $6) is due to the fact that this compound is
fairly unstable. Therefore, the enol ether in sclareol oxide
$6) was ozonolyzed immediately, and reduction of the alde-
hyde and acetate group in intermediate 7 afforded the diol 8
in 60% overall yield starting from 4. Stirring of this diol 8 in
nitromethane in the presence of p-toluenesulfonic acid
gave the cylized product $2)-Ambroxw $9) in 87% yield
$Scheme 2).14
The results of these three synthetic routes of acetate 2 to
$2)-Ambroxw are summarized in Table 1. From this table, it
is clear that $2)-Ambroxw $9) can be obtained in a short
An obvious way to circumvent the unstable sclareol oxide
was the synthesis of acetate ester 10 via a Criegee rearrange-
ment15 of the ozonide of alkene 4, but this approach was
unsuccessful. The rearranged product 10 was not observed
upon treatment of the ozonide under the usual Criegee
conditions $acetic anhydride, triethylamine, and N,N-
dimethylaminopyridine), probably because an unfavourable
seven membered ring intermediate cannot be formed, and
the reaction gave the normal ozonolysis product 5 which
cyclized as before to sclareol oxide.
Another way to circumvent the formation of sclareol oxide
was to apply the Criegee rearrangement but to prevent the
interference of the hydroxyl group at C$8) during the
Scheme 3. Reagents and conditions: $a) O3, MeOH/CH2Cl2 1:5, 2788C;
$b) Ac2O, NEt3, DMAP; $c) AcCl, N,N-dimethylaniline, 83%; $d) LiAlH4,
THF, 89%; $e) CH3NO2, pTsOH, 87%.

M. G. Bolster et al. / Tetrahedron 57 02001) 5657±5662
5659
Scheme 4. Reagents and conditions: $a) tBuOK, THF; $b) D, 78%; $c) O3, MeOH/CH2Cl2 3:1, 2788C; $d) NaBH4, 92%; $e) pTsOH, CH3NO2, 87%.
Table 1. Synthesis of $2)-Ambroxw, starting from 8-acetoxy-labdanolic
acid $2)
with helium as the carrier gas. The ratios m/e and relative
intensities $%) are indicated for the signi®cant peaks. MS
and HRMS data were obtained with a Finnigan MAT 95
spectrometer. The ratios m/z and relative intensities $%) are
indicated for signi®cant peaks. Elemental analyses were
performed on a Carlo Erba 1106 elemental analyser. Optical
rotations were recorded on a Perkin±Elmer 241 polarimeter
at 208C for chloroform solutions and concentrations are
speci®ed in units of g/100 mL. Gas chromatography was
performed on a 5890 Series II Hewlett Packard gas chroma-
tograph using a DB-17 fused silica bonded capillary column
$30 m£0.25 mm i.d.), programmed from 100±2508C at a
rate of 108C/min. For ¯ash chromatography, ICN Bio-
medicals silica gel mean pore size 60 $32±63 mm) was
used with mixtures of distilled light petroleum ether $bp
40±608C) $PE) and EtOAc $EA) as eluents unless reported
otherwise. Solvents were dried and freshly distilled by
common practice. Usual work up refers to washing of the
extract with brine, drying over anhydrous MgSO4, ®ltration
and evaporation of the solvent under reduced pressure.
Reactions were monitored by GC or by TLC on Merck silica
gel 60F254 plastic sheets plates. Compounds on TLC were
visualized by UV detection and by spraying with basic
KMnO4 or with an acidic anisaldehyde solution or with a
molybdate solution and subsequent heating.
Route depicted
in Schemes
Steps
Overall
yield $%)
Average step
yield $%)
2
3
4
5
5
4
13
36
47
65
80
85
four-step procedure in 47% overall yield starting from the
acetate of labdanolic acid 2. The main drawback of
the method is the application of IBDA and iodine in the
decarboxylation reaction. When a cheaper procedure can
be found for this reaction, labdanolic acid $1) will become
a good alternative as starting material for the industrial
preparation of $2)-Ambroxw $9).
3. Experimental
3.1. General information and instrumentation
All reagents used were purchased from Aldrich or Acros
Chimica and used without further puri®cation, unless other-
wise stated. Reactions under dry conditions were performed
under a steady stream of dry nitrogen or argon with glass-
ware pre-dried at 1408C. Sonication experiments were
performed using a 35 KHz Bandelin Sonorex TK 52
apparatus. Melting points were determined on a C. Reichert,
Vienna, hot stage apparatus and are not corrected. Infrared
spectra were recorded on a FT-IR, Biorad FTS-7 spectro-
3.1.1. ꢀ2)-ꢀ3S)-5-ꢀꢀ1R,2R,4aS,8aS)-2-Hydroxy-2,5,5,8a-
tetramethyldecahydro-1-naphthalenyl)-3-methylpenta-
noic acid ꢀlabdanolic acid ꢀ1)). The air dried twigs and
leaves of C. ladaniferus L. $300 g) were soaked with
n-hexane $5 L) at room temperature for three days. The
solution was separated from the solid material and the
solvent was evaporated to give a sticky labdanum gum.
The gum was stirred with ether and the etheral solution
was washed with a 4 M aqueous NaOH solution. The
basic solution was acidi®ed with aqueous 4 M HCl solution,
extracted with ether and dried. After evaporation of the
solvent a crude acidic fraction $30 g) was obtained. A
sample of the crude product was puri®ed by column
chromatography $eluent CH2Cl2/MeOH 9:1) to give pure
labdanolic acid $1) as a sticky solid compound. Mp 80±
828C $lit.10a: 82±838C); [a]Dˆ26.9 $c 0.9) $lit.10a: 27.2);
1
meter and only characteristic absorptions are reported. H
and 13C NMR spectra were, unless otherwise stated,
recorded at 200 and 50 MHz on a Bruker AC-E 200 spec-
trometer, respectively, using CDCl3 as solvent. The chemi-
cal shift values are expressed in ppm $parts per million) $d)
relative to the residual CHCl3 at 7.24 $1H) and 77.00 $13C) as
1
internal standard. The multiplicity of the H signals are
expressed as: sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet,
br sˆbroad singlet, mˆmultiplet. The multiplicity of the
13C signals were determined with the DEPT technique,
qˆquartet, tˆtriplet, dˆdoublet, sˆsinglet. GC-MS data
were determined at 70 eV on a Hewlett Packard 5890B
series Mass Selective Detector, coupled with a Hewlett
Packard 5973 GC provided with a DB-17 fused silica capil-
lary column, 30 m£0.25 mm i.d., ®lm thickness 0.25 mm
1
IR $KBr) nmax 3431, 2924, 1710 cm21; H NMR $CDCl3/
CD3OD) d 0.62 $s, 3H), 0.69 $s, 3H), 0.77 $d, Jˆ5.0 Hz,
3H), 1.01 $s, 3H), 1.08 $s, 3H), 1.10±1.84 $m, 17H), 2.06 $m,
2H), 4.37 $br s, 2H); 13C NMR $CDCl3/CD3OD) d 15.1 $q),
18.1 $t), 19.4 $q), 20.1 $t), 21.1 $q), 22.7 $t), 23.1 $q), 29.3 $t),

5660
M. G. Bolster et al. / Tetrahedron 57 02001) 5657±5662
30.9 $d), 31.0 $s), 32.9 $q), 38.8 $s), 39.4 $t), 40.3 $t), 41.6 $t),
43.3 $t), 55.8 $d), 61.7 $d), 73.9 $s), 176.7 $s); HRMS:
M1, found 324.2661. C20H36O3 requires 324.2664; MS m/e
$%) 324 $M1, 38), 312 $58), 235 $47), 177 $65), 171 $100),
148 $84), 123 $64), 109 $62), 69 $86); Anal. found C, 73.50;
H, 11.27%. C20H36O3 requires C, 74.02; H, 11.18%.
solution of 3 $1.61 g; 3.6 mmol) in THF $20 mL) under
nitrogen was added tBuOK $2.02 g; 18 mmol). After stir-
ring overnight at room temperature the mixture was
quenched with an aqueous saturated solution of NH4Cl,
and worked up as usual. The residue was puri®ed by ¯ash
column chromatography $eluent PE/EA 5:1) and 4 $0.74 g;
2.66 mmol; 74%) was obtained as a sticky solid compound.
[a]Dˆ10.6 $c 1.6); IR $liquid ®lm) nmax 3420, 3072, 2927,
3.1.2. ꢀ2)-ꢀ3S)-5-ꢀꢀ1R,2R,4aS,8aS)-2-ꢀAcetyloxy)-2,5,5,
8a-tetramethyldecahydro-1-naphthalenyl)-3-methylpen-
tanoic acid ꢀ2). To a stirred solution of crude labdanolic
acid $1) $10 g) in N,N-dimethylaniline $40 mL) was added
acetyl chloride $15 mL; 16.56 g; 210.9 mmol) and the
solution was left overnight. Dilute sulfuric acid was care-
fully added to the blue reaction mixture till the color had
disappeared. The mixture was extracted with ether and the
ethereal solution was washed with aqueous 1 M sulfuric
acid $150 mL), and worked up as usual. The residue was
puri®ed by ¯ash column chromatography on silica gel
$eluent PE/EA 7:1) to yield 2 $4.66 g; 12.73 mmol; 47%,
based upon the crude acidic fraction) as a light yellow sticky
gum. [a]Dˆ218.1 $c 1.8); IR $KBr) nmax 3449, 2925, 2852,
1
2868, 1457 cm21; H NMR d 0.76 $s, 3H), 0.78 $s, 3H),
0.84 $s, 3H), 1.11 $s, 3H), 1.71 $s, 3H), 0.87±2.36 $m, 17H),
4.67 $s, 2H); 13C NMR d 15.5 $q), 18.5 $t), 20.6 $t), 21.5 $q),
22.6 $q), 23.6 $t), 23.9 $q),, 33.3 $s), 33.4 $q), 39.2 $s), 39.7
$t), 41.3 $t), 42.0 $t), 44.6 $t), 56.1 $d), 61.5 $d), 74.1 $s),
109.7 $t), 147.1 $s); HRMS: M1, found 278.2605. C19H34O
requires 278.2610; MS m/e $%) 278 $M1, 6), 245 $36), 192
$100), 191 $71), 177 $75), 123 $39), 109 $45), 95 $50), 69
$58), 43 $32); Anal. found C, 82.18; H, 12.62%. C19H34O
requires C, 81.95; H, 12.31%.
3.1.5. ꢀ1)-ꢀ4aR,6aS,10aS)-3,4a,7,7,10a-Pentamethyl-4a,
5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]chromene
ꢀsclareol oxide ꢀ6)). A stirred solution of 4 $0.30 g;
1.08 mmol) in a mixture of MeOH and CH2Cl2 1:5
$20 mL) was purged through with ozone at 2788C until a
pale blue color appeared. The excess ozone was expelled
and PPh3 $0.57 g; 2.17 mmol) was added at 2788C. The
mixture was allowed to warm to room temperature. After
stirring overnight the solvent was evaporated. The residue
was puri®ed by ¯ash column chromatography $eluent PE/
EA 6:1) to yield sclareol oxide $6) $0.124 g; 0.47 mmol;
44%) as a light yellow oil. [a]Dˆ14.9 $c 1.3) $lit.16:
[a]Dˆ15.7, c 1.6); IR $liquid ®lm) nmax 3055, 2950,
1
1734, 1643, 1287 cm21; H NMR d 0.75 $s, 3H), 0.80 $s,
3H), 0.96 $d, Jˆ6.6 Hz, 3H), 1.20 $s, 3H), 1.90 $s, 3H),
0.65±2.38 $m, 20H), 2.62 $dt, Jˆ3.0, 12.4 Hz, 1H), 4.38
$br s, 2H); 13C NMR d 15.7 $q), 18.3 $t), 19.7 $q), 19.9 $t),
20.3 $q), 21.4 $q), 22.8 $q), 23.1 $t), 29.7 $t), 30.8 $d), 33.0
$s), 33.3 $q), 38.7 $t), 39.3 $s), 39.5 $t), 39.8 $t), 41.6 $t), 55.5
$d), 59.0 $d), 88.0 $s), 170.4 $s), 179.7 $s); HRMS:
$M1260), found 306.2557. C20H34O2 requires 306.2559;
MS m/e $%) 366 $M1, 1), 307 $29), 306 $100), 291 $66),
191 $98), 182 $65), 137 $40), 109 $42), 95 $33), 69 $36);
Anal. found C, 72.51; H, 10.49%. C22H38O4 requires C,
72.09; H, 10.45%.
2900, 2890, 1687, 1470, 1390, 1342, 1000 cm21 1H
;
NMR d 0.74 $s, 3H), 0.75 $s, 3H), 0.81 $s, 3H), 1.25 $s,
3H), 1.61 $s, 3H), 1.76±1.83 $m, 13H), 1.87 $dt, Jˆ4.3,
14.6 Hz, 1H), 4.30 $br s, 1H); 13C NMR d 19.3 $q), 18.2
$q), 18.6 $t), 19.8 $t), 20.7 $q), 21.0 $q), 26.6 $q), 28.6 $q),
33.1 $s), 36.7 $s), 39.3 $t), 41.1 $t), 41.9 $t), 52.4 $d), 55.2 $d),
76.2 $s), 94.6 $d), 147.8 $s); MS m/e $%) 262 $M1, 100), 191
$81), 177 $39), 123 $46), 109 $97), 95 $64), 81 $72), 43 $78).
3.1.3.
ꢀ1R,2R,4aS,8aS)-1-ꢀꢀ3S)-4-Iodo-3-methylbutyl)-
2,5,5,8a-tetramethyldecahydro-2-naphthalenyl acetate
ꢀ3). A solution of 2 $1.5 g; 4.10 mmol) in carbon tetra-
chloride $40 mL) containing iodobenzene diacetate
$IBDA) $0.72 g; 2.25 mmol) and iodine $0.52 g;
2.05 mmol) was irradiated with a 100 W tungsten ®lament
lamp for 45 min at re¯ux temperature. Then another portion
of IBDA $0.72 g; 2.25 mmol) and iodine $0.52 g;
2.05 mmol) was added, and the irradiation at re¯ux
temperature was continued for 45 min. The reaction mixture
was cooled to room temperature and was washed with
aqueous 1 M sodium thiosulfate solution $100 mL), water
and brine. Flash column chromatography of the residue
$eluent PE/EA 9:1) on silica gel gave the iodo compound
3 $1.40 g; 3.12 mmol; 76%) as an oil contaminated with
iodobenzene in a 1:1 molar ratio, determined via 1H
3.1.6. ꢀ2)-ꢀ1R,2R,4aS,8aS)-1-ꢀ2-Hydroxyethyl)-2,5,5,8a-
tetramethyldecahydro-2-naphthalenol ꢀ8). A solution of
sclareol oxide $6) $0.124 g; 0.47 mmol) in CH2Cl2 $35 mL)
and pyridine $0.35 mL) was ozonolyzed at 2788C. The
excess of ozone was expelled and the mixture was allowed
to come to room temperature. The mixture was acidi®ed
with an aqueous 1 M hydrochloric acid solution and worked
up as usual. The residue was dissolved in THF $20 mL),
cooled to 08C and LiAlH4 $137 mg; 3.60 mmol) was added
in portions. After stirring overnight at room temperature the
mixture was carefully acidi®ed with 1 M HCl. The aqueous
layer was extracted three times with ethyl acetate and
worked up as usual. The crude oil was puri®ed by ¯ash
column chromatography $eluent PE/EA 1:1) to give 8
$72 mg; 0.28 mmol; 60%) as a white crystalline solid. Mp
128±1308C; [a]Dˆ213.8 $c 1.1); IR $KBr) nmax 3410,
1
NMR. H NMR d 0.76 $s, 3H), 0.81 $s, 3H), 0.85 $s, 3H),
0.97 $d, Jˆ6.4 Hz, 3H), 1.05±1.81 $m, 19H), 1.96 $s, 3H),
2.63 $dt, Jˆ2.7, 12.3 Hz, 1H), 3.18 $d, Jˆ5.2 Hz, 2H); 13C
NMR d 15.7 $q), 17.8 $t), 18.4 $t), 20.0 $t), 20.4 $q), 20.8 $q),
21.5 $q), 23.2 $t), 23.3 $q), 29.7 $s), 33.1 $s), 33.4 $q), 35.7
$d), 38.8 $t), 39.4 $t), 39.6 $t), 41.9 $t), 55.6 $d), 58.9 $t), 87.8
$s), 170.3 $s); HRMS: M1, found 448.1844. C21H37O2I
requires 448.1838; MS m/e $%) 448 $M1, 1), 389 $25),
388 $100), 373 $37), 264 $44), 191 $60), 137 $33), 95 $28),
69 $31), 43 $29).
1
2926, 2894, 1458, 1243, 1051 cm21; H NMR d 0.80 $s,
6H), 0.89 $s, 3H), 1.16 $s, 3H), 0.92±1.70 $m, 13H), 1.92 $dt,
Jˆ4.5, 11.9 Hz, 1H), 2.67 $br s, 2H), 3.48 $dt, Jˆ6.5,
10.0 Hz, 1H), 3.81 $dt, Jˆ4.3, 10.0 Hz, 1H); 13C NMR d
15.3 $q), 18.4 $t), 20.5 $t), 21.5 $q), 24.7 $q), 27.9 $t), 33.3
$s), 33.4 $q), 39.0 $s), 39.3 $t), 41.9 $t), 44.3 $t), 56.0 $d), 59.1
3.1.4. ꢀ1)-ꢀ1R,2R,4aS,8aS)-2,5,5,8a-Tetramethyl-1-ꢀ3-
methyl-3-butenyl)-decahydro-2-naphthalenol ꢀ4). To a

M. G. Bolster et al. / Tetrahedron 57 02001) 5657±5662
5661
$d), 64.2 $t), 73.2 $s); HRMS: M1, found 254.2249.
C16H30O2 requires 254.2250; MS m/e $%) 254 $M1, 9),
221 $73), 195 $100), 177 $64), 151 $65), 109 $81), 95 $76),
69 $87), 43 $48); Anal. found C, 75.98; H, 12.27%. C16H30O2
requires C, 75.53; H, 11.89%.
3.1.10. ꢀ2)-ꢀ1R,2R,4aS,8aS)-2,5,5,8a-Tetramethyl-1-ꢀ3-
methyl-3-butenyl)-decahydro-2-naphthalenyl acetate ꢀ11).
To a stirred solution of 4 $0.53 g; 1.91 mmol) in N,N-
dimethylaniline $30 mL) was added acetyl chloride $8 mL;
8.83 g; 112.5 mmol) and left overnight. An aqueous 1 M sul-
furic acid solution was added carefully to the blue reaction
mixture till the color had disappeared. The mixture was
extracted with ether and worked up as usual. The residue
was puri®ed by ¯ash column chromatography on silica gel
$eluent PE/EA 10:1) to yield 11 $0.53 g; 1.58 mmol; 83%)
as a white crystalline solid. Mp 64±668C; [a]Dˆ223.1 $c
1.2); IR $KBr) nmax 3431, 2926, 2852, 1728, 1253 cm21; 1H
NMR d 0.76 $s, 3H), 0.81 $s, 3H), 0.84 $s, 3H), 1.91 $s, 3H),
1.05±2.03 $m, 21H), 2.61 $dt, Jˆ3.0, 12.4 Hz, 1H), 4.65 $s,
2H); 13C NMR d 15.7 $q), 18.3 $t), 20.4 $q), 21.4 $q), 22.5 $q),
22.9 $q), 24.5 $t), 29.7 $t), 33.1 $s), 33.3 $q), 38.7 $t), 39.3 $s),
39.4 $t), 41.1 $t), 41.9 $t), 55.6 $d), 58.6 $d), 88.0 $s), 109.3 $t),
146.9 $s), 170.1 $s); HRMS: M1, found 320.2715. C21H36O2
requires 320.2715; MS m/e $%) 320 $M1, 4), 245 $30), 192
$100), 191 $57), 177 $55), 123 $31), 109 $32), 95 $33), 81 $34),
69 $36), 43 $33); Anal. found C, 78.63; H, 11.45%. C21H36O2
requires C, 78.69; H, 11.32%.
3.1.7. ꢀ2)-ꢀ1R,2R,4aS,8aS)-1-ꢀ2-Hydroxyethyl)-2,5,5,8a-
tetramethyldecahydro-2-naphthalenol ꢀ8). A stirred solu-
tion of 11 $0.25 g; 0.78 mmol) in a mixture of MeOH and
CH2Cl2 1:5 $20 mL) was purged through with ozone at
2788C until a pale blue color appeared, then the solution
was purged with nitrogen to remove the excess of ozone.
This mixture was treated with acetic anhydride $1.16 mL;
10.5 mmol), triethylamine $0.53 mL; 7.16 mmol) and
4-N,N-dimethylaminopyridine $DMAP) $25 mg; 0.20
mmol). The reaction mixture was allowed to come to
room temperature and stirred overnight. The solution was
poured into an aqueous 1 M HCl solution and extracted with
ethyl acetate and worked up as usual. The residue was
dissolved in THF $10 mL), and cooled to 08C and LiAlH4
$84 mg; 2.22 mmol) was added. After stirring for 1 h at
room temperature the mixture was carefully diluted with
ethyl acetate, and treated with aqueous 1 M HCl solution.
The aqueous layer was extracted with ethyl acetate and
worked up as usual. The crude oil was puri®ed by ¯ash
column chromatography $PE/EA 1:1) to give 8 $0.17 g;
0.65 mmol; 89%) as a white crystalline solid. For analytical
data see the foregoing experiment.
3.1.11. ꢀ1)-ꢀ1R,2R,4aS,8aS)-2,5,5,8a-Tetramethyl-1-ꢀ3-
methyl-2-butenyl)-decahydro-2-naphthalenol ꢀ12). Under
an atmosphere of nitrogen iodide, 3 $0.56 g; 1.24 mmol) was
dissolved in DMSO $20 mL) and tBuOK $1.39 g;
12.4 mmol) was added. After stirring overnight at room
temperature the mixture was quenched with saturated
NH4Cl and worked up as usual. The residue was puri®ed
by ¯ash column chromatography $eluent PE/EA 5:1) and
12 $0.27 g; 0.97 mmol; 78%) was obtained as a yellow oil.
[a]Dˆ114.7 $c 1.6); IR $liquid ®lm) nmax 3446, 2924, 2867,
3.1.8. ꢀ2)-ꢀ1R,2R,4aS,8aS)-1-ꢀ2-Hydroxyethyl)-2,5,5,8a-
tetramethyldecahydro-2-naphthalenol ꢀ8). A solution of
12 $0.2 g; 0.72 mmol) in a mixture of MeOH and CH2Cl2
3:1 $30 mL) was ozonized at 2788C. The excess ozone was
expelled and NaBH4 $0.22 g; 5.79 mmol) was added at
2788C. The mixture was alllowed to warm to room
temperature. The excess of NaBH4 was destroyed with a
1 M aqueous HCl solution and diluted with water. The
mixture was extracted with ethyl acetate and worked up as
usual. The residue was puri®ed by ¯ash column chromato-
graphy $eluent PE/EA 2:1) to yield 8 $0.17 g; 0.66 mmol;
92%) as a white crystalline solid. The analytical data were
as mentioned before.
1
1457, 1387, 1083 cm21; H NMR d 0.72 $s, 3H), 0.75 $s,
3H), 0.80 $s, 3H), 1.12 $s, 3H), 1.60 $s, 6H), 0.83±2.26 $m,
15H), 5.18 $t, Jˆ4.5 Hz, 1H); 13C NMR d 15.4 $q), 17.9 $q),
18.6 $t), 20.2 $t), 21.6 $q), 23.7 $t), 24.7 $q), 25.9 $q), 33.3 $s),
33.5 $q), 38.7 $s), 40.0 $t), 41.9 $t), 56.1 $d), 61.6 $d), 74.3 $s),
127.2 $d), 130.8 $s); HRMS: $M1218), found 260.2500.
C19H32 requires 260.2504; HRMS: $M1215), found
263.2377. C18H31O requires 263.2374; MS m/e $%) 278
$M1, 1), 263 $2), 260 $13), 178 $11), 136 $9), 122 $100),
109 $11), 107 $19), 95 $10), 69 $19), 43 $9).
3.1.9.
ꢀ2)-ꢀ3aR,5aS,9aS,9bR)-3a,6,6,9a-Tetramethyl-
dodecahydronaphtho[2,1-b]furan ꢀꢀ2)-Ambroxw ꢀ9)). A
mixture of 8 $0.10 g; 0.39 mmol) and p-toluenesulfonic
acid $0.04 g; 0.19 mmol) in nitromethane $7 mL) was stir-
red at room temperature for 3 h. Ether was added and the
mixture was washed with a saturated aqueous sodium bicar-
bonate solution and brine, dried and evaporated. Flash
column chromatography $eluent PE/EA 6:1) gave Ambroxw
$9) $0.08 g; 0.34 mmol; 87%) as white crystals. Mp 74±
758C $lit.6a: 74±768C); [a]Dˆ223.8 $c 1.3) $lit.6a: 222.1,
c 0.7); IR $KBr) nmax 3441, 2922, 2884, 1130, 1120,
Acknowledgements
This work was ®nanced by the European Union $Fair CT96-
1781). We thank Dr L. de Vries of Destilaciones Bordas
Chinchurreta, S.A., Sevilla $Spain), for collecting twigs
and leaves of C. ladaniferus. We thank A. van Veldhuizen
for recording NMR spectra, C. J. Teunis and H. Jongejan for
mass spectral data, and M. van Dijk and E. J. C. v.d. Klift for
performing the elemental analyses.
1
1005 cm21; H NMR d 0.82 $s, 6H), 0.86 $s, 3H), 1.07 $s,
3H), 0.92±1.92 $m, 14H), 3.85 $m, 2H); 13C NMR d 15.1
$q), 18.4 $t), 20.7 $t), 21.2 $q), 21.3 $q), 22.6 $t), 33.1 $s),
33.6 $q), 36.2 $s), 39.7 $t), 40.0 $t), 42.4 $t), 57.3 $d), 60.1
$d), 65.0 $t), 79.9 $s); HRMS: M1, found 236.2143. C16H28O
requires 236.2140; MS m/e $%) 236 $M1, 3), 221 $100), 137
$15), 97 $10), 95 $4), 81 $4), 69 $5), 55 $4), 43 $4); Anal.
found C, 81.10; H, 11.95%. C16H28O requires C, 81.29; H,
11.94%.
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