Synthesis of an ambergris-type ketal from abietic acid

Article abstract of DOI:10.1055/s-2006-926392

Abietic acid, the main component of pine rosin, was used as starting material for the hemisynthesis of the ambergris-type ketal. The key intermediate step consisted of the synthesis of an exocyclic olefin through appropriate handling of a very sensitive aldehyde generated as an intermediate precursor. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926392

PAPER
1171
Synthesis of an Ambergris-Type Ketal from Abietic Acid
S
ynthesisof anAmber
.
gris-Type
K
e
C
tal from
A
bietic
éAcid u Costa,* S. P. Alves, M. Eduarda Correia, M. João Marcelo-Curto
Instituto Nacional de Engenharia Tecnologia e Inovação, Estrada do Paço do Lumiar, Ed. F, 1649-038 Lisbon, Portugal
Fax +351(21)7168100; E-mail: ceu.costa@mail2.ineti.pt
Received 21 October 2005
the early 1980s by Buchbauer et al.8 and Ohno et al.9 Lat-
er, Cambie et al.6,7 described the conversion of abietic acid
into several analogues of ambergris perfumes.
Abstract: Abietic acid, the main component of pine rosin, was used
as starting material for the hemisynthesis of the ambergris-type ket-
al. The key intermediate step consisted of the synthesis of an exocy-
clic olefin through appropriate handling of a very sensitive aldehyde
generated as an intermediate precursor.
The strategy described herein for the stereoselective syn-
thesis of a new potential ambergris-type ketal 2 starting
from abietic acid 3 (Scheme 1) was based on the oxidative
degradation of the C-ring to the labdan-13-one side chain
and subsequent regiospecific construction of a C-7 exocy-
clic double bond to achieve the desired final intramolecu-
lar d,e-epoxyketone cyclization to a spiroketal.
Key words: ambergris perfume, rosin, abietic acid, ketalization
Ambergris is a metabolic product of the sperm whale and
is considered one of the most valuable animal perfumes
besides civet, musk, and castreum.1a–1e Like all aromatic
substances of animal origin, ambergris may be considered
a pheromone that acts through a proposed 3D amber ol-
factophore at the sensorial receptor of ambery smell.1e
From ancient times ambergris tincture has been used as a
fixative for rare perfumes since it has the effect of making
other fragrances last much longer than they would other-
wise. Ambergris is rarely used anymore because of its
very high price due to enforced whale protection; thus,
chemists have been looking for new, commercially viable,
synthetic substitutes.2 Among the most expensive synthet-
ic equivalents of the scarce natural ambergris source is the
ambraketal 1 which possesses a strong and tenacious am-
bergris-type odor.1a The natural chiral pool of precursors
include manool,3 sclareol,4 and the resinic acids, antico-
palic,5 and podocarpic,6,7 for the synthesis of ambraketals,
but in all cases the synthesis of ambraketals or its ana-
logues was undertaken from (–)-abietic acid 3.
O
O
O
O
OH
COOMe
COOMe
COOMe
2
9
7
COOH
3
Scheme 1 Retrosynthesis of the ketal 2.
As different structure–activity concepts have been inves-
tigated to explain the presence or absence of ambergris
scent,10 its presence in ketal 2 was expected to be influ-
enced by the slight structural difference at C-13 and C-14,
where an isopropyl and a methyl ester group are present
instead of the methyl substituents shown in the ambraketal
skeleton.
O
O
O
O
COOMe
COOH
3
1
2
The first step in our strategy aimed at building a labdan-
13-one side chain was inspired by the route described by
Ohno et al.9 for the synthesis of (–)-Ambrox®. Abietic
acid 3 was readily converted to the corresponding methyl
ester 4 with diazomethane in 50% yield or alternatively
with dimethyl sulfate, in quantitative yield (Scheme 2).
Treatment of 4 with a catalytic amount of osmium tetrox-
ide in refluxing tert-butanol, pyridine, and water in the
presence of trimethylamine N-oxide as co-oxidant, pro-
duced diol 5 (74%) as a mixture of b-diol and a-diol in a
ratio of 7:3, which is comparable to that previously report-
ed.9 Diol 5 could also be prepared in the same ratio using
the NMO–acetone system at room temperature. The NMR
Figure 1
In this paper we report the synthesis of new ambergris-
type analogue 2 from abietic acid 3, using Portuguese
Pinus pinaster Ait. rosin as a readily available renewable
source.
The use of abietic acid 3 as a precursor for compounds
possessing an ambergris-type fragrance was reported in
SYNTHESIS 2006, No. 7, pp 1171–1175
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-926392; Art ID: P17005SS
x
x
.
x
x
.2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

1172
M. C. Costa et al.
PAPER
OH
OH
b
O O
a
c
H
COOH
COOMe
COOMe
COOMe
3
4
5
6
Scheme 2 Reagents and conditions: a) acetone, K2CO3, Me2SO4, stirred overnight, 99%; b) OsO4 (cat.), Me3NO·2H2O, py–H2O–t-BuOH,
reflux, 22 h, 74%; c) NaIO4, EtOH–H2O, 98%.
data recorded after regioselective attack on the C-ring of firmed the presence of the aldehyde group with chemical
methyl abietate 4 is in accordance with that reported pre- shifts at 9.36 and 194.82 ppm, respectively.
viously.9,11 The 13C NMR data of 5 revealed typical sig-
The next, and key, step in the synthesis of ketal 2 involved
nals for an abietane skeleton, but also significant upfield
the conversion of aldehyde 6 into exocyclic olefin 9. Ini-
tially we attempted the selective thioketalization of alde-
hyde 6 with 1,2-ethanedithiol and p-toluenesulfonic acid
at room temperature, followed by Raney nickel reduction
in ethanol which afforded a mixture of unsaturated com-
pounds 6b (60%) in a 3:1 ratio (endo/exo) (Scheme 3).
We then attempted to adopt a strategy which had been
successfully applied to the TBS derivative of our sub-
shifts for C-13 at 76.26 ppm (b-diol) and 75.01 ppm (a-
diol) and for C-14 at 73.29 ppm (b-diol) and 77.30 ppm
(a-diol); these should be compared with 145.33 ppm (C-
13) and 120.62 ppm (C-14) for methyl abietate 4, indicat-
ing the hydroxylation of these positions accompanied by
the absence of a double bond in 5. The aldehyde 69 was
subsequently produced by adopting alternative conditions
for oxidative cleavage at room temperature to the not-so-
strate, however, when we applied the photo-induced
environment-friendly lead(IV) acetate in benzene report-
isomerization,9 in order to obtain exclusively the desired
ed by Ohno et al.9 Thus, a mixture of diol 5 was treated
exo-olefin, unreacted starting material was always recov-
ered (Scheme 3).
with sodium periodate in water and ethanol (Scheme 2) to
1
give aldehyde 6 (98%). The H and 13C NMR data con-
O
S
O
S/A
b
S
S/A
COOMe
COOMe
6b
c
a
6a
O O
O
O
O
H
d
g
OH
h
OTs
COOMe
COOMe
COOMe
COOMe
9
6
7
8
f
i
e
O
O
O
I
COOMe
COOMe
7a
2
Scheme 3 a) 1,2-ethanedithiol, EtOH, p-TsOH; b) Raney Ni, EtOH–AcOH, 60% (2 steps; endo/exo, 3: 1); c) hn, xylene, i-PrOH; d) Raney
Ni, THF, 78%; e) I2, imidazole, PPh3, CH3CN–toluene (1:2), reflux; f) t-BuOK, THF; g) p-TsCl, py, 70%; h) DBU, glyme, NaI, reflux, 54%;
i) OsO4 (cat.), Me3NO·2H2O, py–H2O–t-BuOH, reflux, 34%.
Synthesis 2006, No. 7, 1171–1175 © Thieme Stuttgart · New York

PAPER
Synthesis of an Ambergris-Type Ketal from Abietic Acid
1173
R1
R1
OH
O
O
R1
14
O
O
OH
R
9
R
R
2
R = COOMe
R1 = CH(CH3)2
Scheme 4 Tentative mechanism for the synthesis of ketal 2.
A second route for the synthesis of the exo-olefin 9 was achieved using a reported procedure by the reaction of the
studied, consisting of the selective reduction of both the primary tosylate with DBU in the presence of sodium
conjugated double bond and the aldehyde group in the iodide17 in glyme under reflux. The presence of the unsat-
1
presence of the ketone group with Raney nickel, as de- urated compound was confirmed by H NMR spectral
scribed by Barrero et al.12,13 Using this approach the alde- analysis, where two olefinic hydrogens were assigned at
hyde 6 was treated with an aqueous suspension of Raney 4.47 and 4.83 ppm along with the signals of the sp2 car-
nickel in THF, at room temperature, to afford alcohol 7 bons which were unequivocally located at 147.73 (C-8)
1
(78%) (Scheme 3). The structure was established by H and 106.89 ppm (C-14) in the 13C NMR spectrum. This re-
and 13C NMR spectroscopy with the aid of 2D experi- sult is particularly remarkable since Barrero et al.12 report-
ments. The 13C NMR data of 7 showed significant upfield ed no reaction when 14,15-dinorlabdan-8,17-on-4-al was
shifts for C-7 to 28.84 ppm and C-8 to 39.74 ppm, com- subjected to these conditions, thus we can unequivocally
pared to 152.28 and 144.27 ppm, respectively, in aldehyde state that Raney nickel is indeed an efficient reagent to
6, indicating reduction of the conjugated double bond. achieve the chemoselective 1,4-hydrogenation of a,b-un-
The conversion of the aldehyde into an alcohol group was saturated carbonyl labdanes according to the method de-
also observed by the appearance of the C-14 signal at scribed by Barrero et al.13 Finally the new ambergris type
61.36 ppm in the 13C NMR spectrum.
analogue 2 was obtained by treatment of the exo-olefin 9
with a catalytic amount of osmium tetroxide in refluxing
tert-butanol, pyridine, water, and trimethylamine N-
oxide2c,2d under reflux in moderate yield (34%).
In order to produce the exo-olefin 9, alcohol 7 was sub-
jected to nucleophilic substitution with iodide followed by
dehydrohalogenation with potassium tert-butoxide. The
conversion of the hydroxyl on 7 into a iodide group was The formation of ketal 2 with the most desired stereo-
carried out using a reagent system reported in the litera- chemistry is due to the intramolecular hydroxycarbonyl
ture for carbohydrates14,15 and used in the total synthesis rearrangement which occurs by attack of the primary hy-
of (+)-pumiliotoxin A.16 Triphenylphosphine, imidazole, droxyl group on the electron-deficient carbon C-13,
and iodine in toluene converted all chromatographically whose carbonyl oxygen then reacts at C-8 in order to build
homogeneous pure starting material into a crude mixture the trans-fused spiroketal ring of 2 as shown in Scheme 4.
which was readily subjected to dehalogenation with po- The d,e-epoxycarbonyl rearrangement has been exten-
tassium tert-butoxide in THF at room temperature. Taking sively studied by the authors and will be published later.
into account the instability of iodide compounds, it is per- Compound 2 was fully characterized by 1H NMR spectral
haps not surprising that this failed to produce olefin 9 as analysis where the chemical shift for H-14 was observed
desired (Scheme 3).
as two doublets at 3.25 (J = 7 Hz) and 4.30 ppm (J = 7
Hz), which is in good agreement with the data reported for
the ambraketal5 and its C-4 methyl ester analogues previ-
ously synthesized by Barrero et al.2c,d The structure of
ketal 2 was further elucidated by 13C NMR, COSY,
HETCOR, and MS analysis. An unequivocal characteris-
tic amber-type fragrance was empirically detected, show-
ing that the substitution of a methyl by an isopropyl group
at C-13 in the ambraketal skeleton, leaving an ester group
at C-4, still retains ambergris unique olfactory scent.
Finally, we attempted a third route for the synthesis of
exo-olefin 9 (Scheme 3) which proved to be successful.
We converted the alcohol 7, previously obtained, into tos-
ylate 8 (70%) following the standard procedure with p-tol-
uenesulfonyl chloride in pyridine at room temperature.
The structure of the tosylate 8 was elucidated by 1H, 13C,
DEPT, HETCOR, and COSY spectroscopy. The presence
1
of two aromatic signals at 7.35 and 7.78 ppm in the H
NMR spectrum showed the presence of the tosylate
group, which was also confirmed by the assignment of
four aromatic carbon signals at 127.79, 129.85, 133.05,
and 144.79 ppm in the 13C NMR spectrum. From the
COSY spectrum two methyl groups at 1.08 ppm (d,
J = 6.6 Hz) both coupled with a septet (J = 6.9 Hz) cen-
tred at 2.55 ppm indicating the presence of an isopropyl
group. The H-14 signal was clearly coupled with one pro-
ton resonance centred at 2.06 ppm assigned to H-8. A re-
The solvents used in the reactions were dried by standard proce-
dures. FTIR spectra were recorded on a Perkin-Elmer 1725X. NMR
spectra were run on a Bruker AMX 300 MHz or Bruker 400 MHz
using CDCl3 as solvent and TMS as internal reference; structure
elucidation was performed with the aid of DEPT, HETCOR, and
COSY NMR methods. The chemical shifts are reported in ppm, and
coupling constants (J) in Hz. TLC was performed using silica gel
(Merck silica gel GF254). Chromatographic separations were car-
gioselective elimination to produce the exo-olefin 9 was ried out by flash column on Merck silica gel 60 (230–400 mesh).
Synthesis 2006, No. 7, 1171–1175 © Thieme Stuttgart · New York

1174
M. C. Costa et al.
PAPER
Methyl Abietadien-19-oate (4)
73.29 (C-14), 76.26 (C-13), 120.00 (C-7), 137.92 (C-8), 179.23 (C-
19).
HRMS-EI: m/z calcd for C21H34O4 [M]+: 350.24516; found:
To a stirred solution of abietic acid 3 (2.45 g, 8.1 mmol), acetone
(75 mL), and K2CO3 (1.2 equiv, 1.34 g, 9.7 mmol) was added
Me2SO4 (0.8 mL) and the resulting solution was stirred overnight at
r.t. After removing the solvent the mixture was diluted with CH2Cl2
(20 mL), washed with H2O (20 mL), dried over MgSO4, filtered,
and concentrated. The residue was filtered through a pad of silica
gel, washed with CH2Cl2, and the filtrate was concentrated to afford
methyl abietadien-19-oate 4 (2.22 g, 99%) as an oil.
1H NMR (300 MHz): d = 0.82 (s, 3 H, H-20), 1.00 (d, J = 6.9 Hz, 3
H, H-16 or H-17), 1.01 (d, J = 6.9 Hz, 3 H, H-17 or H-16), 1.25 (s,
1 H, H-18), 2.16–2.29 (m, 1 H, H-15), 3.63 (s, 3 H, CH3-21), 5.33–
5.41 (m, 1 H, H-7), 5.77 (s, 1 H, H-14).
13C NMR (75.6 MHz): d = 14.03 (C-20), 17.01 (C-18), 18.14 (C-2),
20.85 (C-16 or C-17), 21.42 (C-17 or C-16), 22.46 (C-11), 25.68
(C-6), 27.48 (C-12), 34.53 (C-10), 34.88 (C-15), 37.12 (C-3), 38.33
(C-1), 45.10 (C-5), 46.59 (C-4), 50.94 (C-9), 51.85 (C-21), 120.62
(C-14), 122.36 (C-7), 135.53 (C-8), 145.33 (C-13), 179.01 (C-19).
350.24535.
Methyl Abiet-7-en-13-one-8-al-19-oate (6)
A solution of NaIO4 (1.5 equiv, 0.618 mmol, 132 mg) in H2O (0.7
mL) was added to a solution of diol 5 (144.2 mg, 0.412 mmol) in
EtOH (3 mL). The reaction mixture was stirred for 5 h at r.t. After
removing the solvent under vacuum, the crude product was dis-
solved in EtOAc (10 mL), washed with H2O (7 mL), dried over
MgSO4, filtered, and concentrated. The concentrate was filtered
through a pad of silica gel to afford 6 (142.7 mg, 98%) as a colorless
oil. This material was used directly in the next reaction.
1H NMR (300 MHz): d = 1.08 (d, J = 6.9 Hz, 6 H, H-16 and H-17),
1.25 (s, 3 H, H-18), 3.64 (s, 3 H, CH3-21), 6.74 (qt, J = 2.1, 2.4 Hz,
1 H, H-7), 9.36 (s, 1 H, H-14).
13C NMR (75.6 MHz): d = 14.19 (C-20), 18.24 (C-16 or C-17),
18.36 (C-17 or C-16), 17.02 (C-18), 17.67 (C-2), 20.74 (C-11),
26.76 (C-6), 36.36 (C-10), 37.00 (C-3), 37.71 (C-1), 40.68 (C-15),
42.48 (C-12), 44.11 (C-5), 46.21 (C-4), 49.88 (C-9), 52.09 (C-21),
144.27 (C-8), 152.28 (C-7), 178.54 (C-19), 194.82 (C-14), 215.37
(C-13).
APCI-MS: m/z (%) = 317.2 (100) [M+ 1]+, 315.2 (77), 313.2 (47),
257.2 (25).
Methyl 13,14-Dihydroxyabiet-7-en-19-oate (5a and 5b)
Methyl abietate 4 (500 mg, 1.58 mmol) was added to a stirred mix-
ture of Me3NO·2H2O (1.5 equiv, 178 mg, 2.37 mmol), H2O (1 mL),
t-BuOH (3 mL), pyridine (0.13 mL), and OsO4 (2.5% wt in t-BuOH,
0.08 equiv, 0.13 mmol, 0.13 mL) which was then heated at reflux
under argon. When the reaction was complete (TLC, 50 h), the re-
action mixture was cooled, treated with an aq solution of NaHSO3
(15 mL), concentrated under vacuum to remove t-BuOH, saturated
with NaCl, and extracted with Et2O (4 × 20 mL). The combined or-
ganic layers were dried over MgSO4, filtered, and concentrated, the
residue was purified by flash column chromatography (CH2Cl2–
MeOH, 99:1) to afford methyl 13a,14a-dihydroxyabiet-7-en-19-
oate 5a and methyl 13b,14b-dihydroxyabiet-7-en-19-oate 5b in a
total yield of 74% (408 mg, 7:3 b/a ratio).
Methyl 14-Hydroxyabiet-13-one-19-oate (7)
An aqueous suspension of Raney Ni (520 mg) was added to a stirred
solution of aldehyde 6 (55 mg, 0.158 mmol) in THF (10 mL) and
the mixture was stirred at r.t. overnight. The mixture was diluted
with Et2O (10 mL), filtered through silica, and the solvent was evap-
orated. The residue was purified by flash column chromatography
(hexane–EtOAc, 4:1Š1:1Š1:4) to afford alcohol 7 (43 mg, 78%)
as a colorless oil.
IR (film): 3435, 1724, 1458, 1249 cm–1.
1H NMR (300 MHz): d = 0.74 (s, 3 H, H-20), 0.94–1.02 (m, 2 H, H-
1ax, H-6ax), 1.10 (d, J = 6.9 Hz, 6 H, H-16, H-17), 1.14 (s, 3 H, H-
18), 1.24–1.33 (m, 1 H, H-9), 1.40–1.56 (m, 6 H, H-2, H-3, H-6eq,
H-7ax), 1.59–1.77 (m, 4 H, H-1eq, H-11, H-5), 1.78–1.88 (m, 1 H, H-
8), 1.89–2.01 (m, 1 H, H-7eq), 2.34–2.57 (m, 2 H, H-12), 2.60 (sept,
J = 6.9 Hz, 1 H, H-15), 3.40 (t, J = 9.9 Hz, 10.2, 1 H, H-14), 3.65 (s,
3 H, CH3-21), 3.65 (m, 1 H, H-14).
13C NMR (75.6 MHz): d = 15.96 (C-20), 16.39 (C-18), 17.84 (C-2),
18.28 (C-16 or C-17), 18.38 (C-17 or C-16), 19.27 (C-11), 20.66
(C-6), 28.84 (C-7), 36.86 (C-3), 37.58 (C-10), 38.21 (C-1), 38.94
(C-12), 39.74 (C-8), 40.98 (C-15), 47.74 (C-4), 50.79 (C-5), 51.89
(C-21), 52.77 (C-9), 61.36 (C-14), 179.31 (C-19), 215.19 (C-13).
Methyl 13a,14a-Dihydroxyabiet-7-en-19-oate (5a)
IR (KBr): 3448, 1733, 1718, 1458, 1250, 1145, 1011 cm–1.
1H NMR (300 MHz): d = 0.82 (s, 3 H, H-20), 0.89 (d, J = 7 Hz, 3
H, H-16 or H-17), 0.90 (d, J = 6.7 Hz, 3 H, H-17 or H-16), 1.25 (s,
3 H, H-18), 3.63 (s, 3 H, CH3-21), 4.01 (s, 1 H, H-14), 5.70 (m, 1 H,
H-7).
13C NMR (75.6 MHz): d = 15.24 (C-20), 15.93 (C-16 or C-17),
16.17 (C-17 or C-16), 17.44 (C-18), 18.06 (C-2), 20.15 (C-11),
25.28 (C-6), 28.64 (C-12), 29.78 (C-15), 34.70 (C-10), 36.90 (C-3),
38.80 (C-1), 44.75 (C-5), 46.53 (C-4), 46.72 (C-9), 52.08 (C-21),
75.01 (C-13), 77.30 (C-14), 127.56 (C-7), 138.00 (C-8), 179.06 (C-
19).
HRMS-EI: m/z calcd for C21H36O4 [M + Na]+: 375.25057; found:
375.25045.
Methyl 14-(p-Toluenesulfonate)abiet-13-one-19-oate (8)
p-TsCl (1.2 equiv, 0.532 mmol, 102 mg) was added, at 0 °C under
nitrogen, to a solution of alcohol 7 (156 mg, 0.443 mmol) in freshly
distilled pyridine (3 mL), the reaction mixture was stirred for 4 h un-
der nitrogen. Pyridine was removed under vacuum, the crude was
diluted with H2O (10 mL) and Et2O (10 mL), and washed with HCl
(4%). The combined organic layers were dried over MgSO4, fil-
tered, and concentrated to afford tosylate 8 (185 mg, 70%) as a col-
orless oil.
Methyl 13b,14b-Dihydroxyabiet-7-en-19-oate (5b)
IR (KBr): 3448, 1733, 1718, 1458, 1250, 1145, 1011 cm–1.
1H NMR (300 MHz): d = 0.85 (s, 3 H, H-20), 0.90 (d, J = 7 Hz, 3
H, H-16 or H-17), 0.93 (d, J = 6.7 Hz, 3 H, H-17 or H-16), 1.06–
1.16 (m, 1 H, H-1ax), 1.25 (s, 3 H, H-18), 1.31 (dd, J = 13.2, 2.8 Hz,
1 H, H-12ax), 1.37 (d, J = 3.16 Hz, 1 H, H-11), 1.40 (d, J = 3.48 Hz,
1 H, H-11eq), 1.48–1.59 (m, 2 H, H-2), 1.59–1.71 (m, 1 H, H-6ax),
1.59–1.81 (m, 2 H, H-3), 1.66–1.81 (m, 1 H, H-12eq), 1.71–1.81 (m,
1 H, H-9), 1.86 (d, J = 11.7 Hz, 1 H, H-1eq), 1.88 (dd, J = 12, 3.6 Hz,
1 H, H-5), 1.93–2.05 (m, 1 H, H-6eq), 2.14 (sept, J = 6.9 Hz, 1 H, H-
15), 3.62 (s, 3 H, CH3-21), 3.94 (s, 1 H, H-14), 5.87 (m, 1 H, H-7).
13C NMR (75.6 MHz): d = 15.59 (C-20), 16.42 (C-16 or C-17),
17.52 (C-18), 17.87 (C-17 or C-16), 18.04 (C-2), 19.29 (C-11),
25.02 (C-6), 26.43 (C-12), 33.07 (C-15), 35.25 (C-10), 36.93 (C-3),
39.13 (C-1), 44.69 (C-5), 46.52 (C-4), 51.26 (C-9), 52.02 (C-21),
IR (film): 2928, 1717, 1457, 1362, 1176 cm–1.
1H NMR (300 MHz): d = 0.66 (s, 3 H, H-20), 0.83–0.94 (m, 2 H, H-
6), 0.94–1.03 (m, 1 H, H-1ax), 1.08 (d, J = 6.6, 6 H, H-16, H-17),
1.09 (s, 3 H, H-18), 1.09–1.28 (m, 1 H, H-11ax), 1.28–1.32 (m, 1 H,
H-9), 1.32–1.44 (m, 1 H, H-7ax), 1.46–1.60 (m, 4 H, H-2, H-3), 1.69
(d, J = 12.3 Hz, 2 H, H-1eq, H-5), 1.75–1.88 (m, 2 H, H-7eq, H-11eq),
2.00–2.12 (m, 1 H, H-8), 2.19–2.29 (m, 1 H, H-12ax), 2.46 (s, 3 H,
Synthesis 2006, No. 7, 1171–1175 © Thieme Stuttgart · New York

PAPER
Synthesis of an Ambergris-Type Ketal from Abietic Acid
1175
H-28), 2.47–2.52 (m, 1 H, H-12eq), 2.55 (sept, J = 6.9 Hz, 1 H, H-
15), 3.64 (s, 3 H, CH3-21), 3.92–4.08 (m, 2 H, H-14), 7.36 (d, 2 H,
J = 8.4 Hz, H-25, H-26), 7.78 (d, J = 8.1 Hz, 2 H, H-23, H-24).
13C NMR (75.6 MHz): d = 15.99 (C-20), 16.25 (C-18), 17.68 (C-2),
18.20 (C-16 or C-17), 18.30 (C-17 or C-16), 18.92 (C-11), 20.15
(C-6), 21.62 (C-28), 28.30 (C-7), 35.71 (C-8), 36.68 (C-3), 37.31
(C-10), 37.91 (C-1), 38.02 (C-12), 40.93 (C-15), 47.54 (C-4), 50.38
(C-5), 51.90 (C-21), 51.90 (C-9), 69.66 (C-14), 127.79 (C-23, C-
24), 129.85 (C-25, C-26), 133.05 (C-22), 144.79 (C-27), 179.03 (C-
19), 214.49 (C-13).
13C NMR (75.6 MHz): d = 14.99 (C-20), 16.63 (C-18), 16.88 (C-2),
17.25 (C-16, C-17), 17.37 (C-11), 22.71 (C-6), 30.72 (C-12), 34.84
(C-15), 35.45 (C-7), 36.76 (C-3, C-10), 37.93 (C-1), 47.32 (C-4),
49.85 (C-5), 51.95 (C-21), 53.95 (C-9), 73.65 (C-14), 82.33 (C-8),
109.76 (C-13), 179.06 (C-19).
HRMS-EI: m/z calcd for C21H34O4 [M]+: 350.245161; found:
350.24486.
References
HRMS-EI: m/z calcd for C28H42O6SK [M + K]+: 545.233368;
found: 545.23265.
(1) (a) Ohloff, G. The Fragrance of Ambergris, In Fragrance
Chemistry; Theimer, E. T., Ed.; Academic Press: New York,
1982, 535–573. (b) Bajgrowicz, J. A.; Broger, C. In
Procedures of the 13th International Congress of Flavours,
Fragrances and Essential Oils; Baser, K. H. C., Ed.; AREP
Publications: Istanbul, 1995, 1–15. (c) Dimoglo, A. S.;
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Manzaneda, E.; Altarejos, J.; Salido, S.; Ramos, J. M.
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Coste-Maniére, I.; Martres, P.; Perfetti, P.; Waegell, B. Bull
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E.; Petrzilka, M. Tetrahedron Lett. 1993, 34, 8081.
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University of Lisbon: Portugal, 1992. (b) Costa, M. C.;
Tavares, R.; Motherwell, W. B.; Marcelo Curto, M. J.
Tetrahedron Lett. 1994, 35, 8839.
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Methyl Abiet-8(14)-en-13-one-19-oate (9)
A stirred solution of tosylate 8 (0.1 M; 0.162 mg, 0.32 mmol) in
glyme (3.2 mL) containing NaI (3 equiv, 144 mg, 0.96 mmol) and
DBU (2 equiv, 0.1 mL, 0.64 mmol), was refluxed for 7 h. Additional
portions of NaI (2 equiv, 96 mg, 0.64 mmol) and DBU (2 equiv, 0.1
mL, 0.64 mmol) were added and the resulting solution was refluxed
for 3 h. The solution was cooled to r.t., diluted with Et2O (5 mL) and
H2O (5 mL), and stirred for 10 min. The layers were separated and
the aqueous phase was extracted with Et2O (2 × 10 mL). The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated. The residue was purified by flash column chromatography
(hexane–Et2O, 3:1) to afford olefin 9 (58 mg, 54%) as a colorless
oil.
IR (film): 1716, 1657, 1458 cm–1.
1H NMR (300 MHz): d = 0.72 (s, 3 H, H-20), 1.07 (d, J = 6.9 Hz, 6
H, H-16, H-17), 1.14 (s, 3 H, H-18), 1.94 (dd, J = 12.3, 2.7 Hz, 1 H,
H-5ax), 2.29–2.39 (m, 2 H, H-3), 2.34–2.39 (m, 1 H, H-12ax), 2.55
(sept, J = 6.9 Hz, 1 H, H-15), 2.53–2.64 (m, 1 H, H-12eq), 3.66 (s, 3
H, CH3-21), 4.47 (d, J = 0.9 Hz, 1 H, H-14), 4.83 (d, J = 1.2 Hz, 1
H, H-14).
13C NMR (75.6 MHz): d = 14.55 (C-20), 16.54 (C-18), 17.24 (C-2),
18.19 (C-16 or C-17), 18.23 (C-17 or C-16), 18.41 (C-11), 26.81
(C-6), 36.97 (C-7), 37.78 (C-3), 37.85 (C-1), 39.09 (C-10, C-12),
40.91 (C-15), 47.73 (C-4), 49.77 (C-5), 51.86 (C-21), 56.19 (C-9),
106.89 (C-14), 147.73 (C-8), 179.28 (C-19), 215.24 (C-13).
HRMS-EI: m/z calcd for C21H34O3 [M]+: 334.250246; found:
334.25017.
Methyl (8R,13S)-8a,13:13,14-Diepoxiabiet-19-oate (2)
A stirred mixture of olefin 9 (22 mg, 0.07 mmol), Me3NO·2H2O
(4.5 equiv, 22 mg, 0.29 mmol), H2O (0.2 mL), t-BuOH (0.6 mL),
pyridine (0.03 mL), and OsO4 (2.5 wt% in t-BuOH, 0.01 equiv, 0.7
mmol, 0.03 mL) was kept overnight at reflux under nitrogen. The re-
action mixture was cooled, treated with an aq solution of NaHSO3
(5 mL), concentrated under vacuum to remove t-BuOH, saturated
with NaCl, and extracted with Et2O (3 × 7 mL). The combined or-
ganic layers were dried over MgSO4, filtered, and concentrated, the
residue was purified by flash column chromatography (hex-
ane→hexane–Et2O, 3:1→1:1) to afford pure ketal 2 (8 mg, 34%) as
a colorless oil.
(8) Buchbauer, G.; Heneis, V. M.; Krejci, V.; Talsky, C.;
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Meneses, R. Synlett 2000, 197.
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Meneses, R. Synlett 1999, 1663.
IR (film): 1728, 1454, 1245, 1171 cm–1.
1H NMR (400 MHz): d = 0.91 (s, 3 H, H-20), 0.94 (d, J = 6.9 Hz, 6
H, H-16, H-17), 0.96–1.02 (m, 1 H, H-1ax), 1.13 (s, 3 H, H-18),
1.14–1.23 (m, 2 H, H-6), 1.48–1.56 (m, 1 H, H-9), 1.51–1.60 (m, 2
H, H-3), 1.56–1.63 (m, 1 H, H-12eq), 1.67–1.77 (m, 1 H, H-12ax),
1.70 (d, J = 11.8 Hz, 1 H, H-1eq), 1.77–1.91 (m, 2 H, H-7), 1.81–
1.91 (m, 1 H, H-15), 1.84–1.91 (m, 1 H, H-5), 3.25 (d, J = 7 Hz, 1
H, H-14), 3.65 (s, 3 H, CH3-21), 4.30 (d, J = 7 Hz, 1 H, H-14).
(14) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866.
(15) Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson, B. J.
Chem. Soc., Perkin Trans. 1 1982, 681.
(16) Aoyagi, S.; Hirashima, S.; Saito, K.; Kibayashi, C. J. Org.
Chem. 2002, 67, 5517.
(17) Phukan, P.; Bauer, M.; Maier, M. Synthesis 2003, 1324.
Synthesis 2006, No. 7, 1171–1175 © Thieme Stuttgart · New York