A practical synthesis of ambrox from sclareol using no metallic oxidant

Article abstract of DOI:10.1081/SCC-100103265

The commercial synthesis of Ambrox is modified so that the key intermediate, the sclareolide, results from an indirect Oxidative degradation of sclareol. This method allows to greatly alleviate the waste disposal problem and to raise the overall yield of Ambrox to 75%.

Full text of DOI:10.1081/SCC-100103265

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A PRACTICAL SYNTHESIS OF
AMBROX® FROM SCLAREOL
USING NO METALLIC OXIDANT
Jean Moulines a , Anne-Marie Lamidey a & Valérie
Desvergnes-Breuil a
a Université Bordeaux I , 351, Cours de la
Libération, Talence Cedex, F-33405, France
Published online: 16 Aug 2006.
To cite this article: Jean Moulines , Anne-Marie Lamidey & Valérie Desvergnes-
Breuil (2001) A PRACTICAL SYNTHESIS OF AMBROX® FROM SCLAREOL USING NO
METALLIC OXIDANT, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:5, 749-758, DOI: 10.1081/
SCC-100103265
To link to this article: http://dx.doi.org/10.1081/SCC-100103265
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SYNTHETIC COMMUNICATIONS, 31(5), 749–758 (2001)
A PRACTICAL SYNTHESIS OF AMBROXÕ
FROM SCLAREOL
USING NO METALLIC OXIDANT
Jean Moulines,* Anne-Marie Lamidey, and
Valerie Desvergnes-Breuil
Institut du Pin, Laboratoire de Chimie des Substances
Vegetales, Universite Bordeaux I, 351, Cours de la
Liberation, F-33405 Talence Cedex, France
ABSTRACT
The commercial synthesis of AmbroxÕ is modified so
that the key intermediate, the sclareolide, results from an
indirect oxidative degradation of sclareol. This method
allows to greatly alleviate the waste disposal problem and to
raise the overall yield of AmbroxÕ to 75%.
Among all the ambergris-type compounds, much sought after by
the perfume industries, the (-)-8, 12-epoxy-13,14,15,16-tetranorlabdane 1,
so-called Ambrox (a trade name of Firmenich S.A.),1,2 comes to the fore.
It has been identified as one of the most valuable odoriferous constituents of
tincture of ambergris,3 a substance excreted by the sperm whale (Physeter
catodon L.) and occasionally found washed ashore.
The industrial production of Ambrox 1 is based upon a hemisynthesis
from sclareol 2.4 This diterpenic alcohol is most suited as a starting material
because it is available from clary sage (Salvia sclarea L.) in sizeable amounts
* Corresponding author.
749
Copyright & 2001by Marcel Dekker, Inc.
www.dekker.com

750
MOULINES, LAMIDEY, AND DESVERGNES-BREUIL
and has the same stereochemical features as Ambrox 1. The last point
is crucial since any change in the configuration of the four chiral carbon
atoms (5,8,9,10) has a major effect on the odour properties, the profile as
well as the strength.5
Three distinct stags are involved in the hemisynthesis: (a) an oxidative
degradation of the sclareol 2 side chain resulting in sclareolide 3 and its
precursor, the acetoxy-acid 4,6 (b) a reduction of these compounds to
ambradiol 5, (c) a cyclodehydration of ambradiol 5 to give Ambrox 1.
Both the last stages are easily achieved but not the former in which are
successively formed three intermediates,6 namely the dihydroxy-acid 6,
the hydroxy-ketone 7 and the sclareoloxide 8. This cyclic enol-ether,
which arises from the ready cyclodehydration of the hydroxy-ketone 7,
quickly undergoes oxidative cleavage to sclareolide 3 and acetoxy-acid
4. The oxidation of sclareol 2 is currently carried out using potassium per-
manganate (7 moles per mole of sclareol), and gives only a 65% yield of

SYNTHESIS OF AMBROXÕ
751
sclareolide 3, after saponification and lactonisation of the acetoxy-acid 4.7
At the same time, manganese dioxide is produced as a sticky solid which is
almost twice the weight of the sclareol 2 being treated, and which is very
difficult to remove from the reaction mixture. Therefore, it is convenient to
convert the manganese dioxide to the water-soluble manganese salts by
reduction (sulfur dioxide, sodium hydrogen sulfite, oxalic acid) under
acidic conditions. However, this process suffers from the problem of aqu-
eous waste disposal. As catalytic oxidation offers, among other advantages,
that of generating aqueous effluents with a low metallic salts content, such
technology is a very attractive for achieving the first stage of the Ambrox 1
hemisynthesis. For this purpose, ruthenium tetraoxide (usually prepared in
situ from ruthenium chloride) in conjunction with common oxygen donors
has proved to be an efficient catalyst. Thus, when the sclareol 2 is reacted
with ruthenium chloride hydrate (0.023 mol/mol) and sodium periodate
(ꢀ 8 mol/mol) under typical Sharpless conditions,8 a mixture of the acet-
oxy-acid 4 and sclareolide 3 is obtained in an 88.5% overall yield.9,10 By
changing both sodium periodate for sodium hypochlorite and organic
solvent for water with an admixture of an emulsifier, the yield of sclareolide
3, after saponification and lactonisation of the acetoxy-acid 4, still amounts
to 75–78%.11 To our knowledge, none of these procedures has yet to be
applied on a technical scale, perhaps because the recovery of the ruthenium
salts is far from easy.
In an earlier communication, we have shown that the sclareol 2
afforded the 8,13-epoxylabdane-14,15-diol 9 through an epoxidation, a
Payne rearrangement and an acid cyclisation.12
We now wish to report a method for the degradation of this diol 9
to sclareolide 3 without the need for any transition metal oxidant. The
8,13-epoxylabdane-14,15-diol 9 is first cleaved by sodium periodate to
8,13-epoxy-15-norlabdan-14-al 10.13 When this aldehyde is reacted with
commercial peracetic acid at 50ꢁ–55ꢁC, sclareolide 3 is selectively produced
(the acetoxy-acid 4 is not detected). The Baeyer-Villiger oxidation14 of the
aldehyde 10 leads to the formate 11, which is likely to lose formic acid to
give the sclareoloxide 8. This cyclic enol-ether is known to be readily cleaved
upon treatment with peroxyacids.15,16

752
MOULINES, LAMIDEY, AND DESVERGNES-BREUIL
In practice, from sclareol 2 to sclareolide 3, the crude product from
each reaction is used in the next step. As hereafter discussed, all the side-
products expected to be formed, produce sclareolide 3 so that only this
compound has to be purified by recrystallization. Firstly, there are the
derivatives of 13-episclareol, which is present in the sclareol 2 from natural
sources; but both the aldelhyde 10 and its 13-epimer lose the 13-chiral
carbon in the last step. Then, there are the compounds arising from the
epoxy sclareol itself since the Payne rearrangement is an equilibrium reac-
tion (in this case with the equilibrium well over to the side of the rearranged
epoxy sclareol). It would appear that the remaining epoxy sclareol is
hydrated to give a tetrol with hydroxyl groups on three contiguous carbons
i.e. 13, 14 and 15. Splitting of this triolic sequence by sodium periodate results
in the hydroxy-ketone 7, which quickly yields the sclareoloxide 8; now, this
cyclic enol-ether is the postulated intermediate in the peracetic oxidation of
the aldehyde 10. Lastly, each of the five conversions from sclareol 2 being
almost complete, the overall yield of sclareolide 3 is around 80%.
The synthesis of Ambrox 1 continues as previously reported; the
reduction of sclareolide 3 yields almost quantitatively ambradiol 5, which
undergoes cyclodehydration to produce Ambrox 1. If the ring closure
involves the attack of the 12-carbon by the 8-oxygen, the configuration of
the 8-chiral carbon is bound to be retained. This condition is fulfilled when
the usual method of preparation of cyclic ethers from 1,4-diols using tosyl
chloride in pyridine17 is applied to ambradiol 5.18,19 Indeed, the tosyloxy
group, selectively formed from the primary 12-hydroxyl, is displaced by the
8-oxygen in a nucleophilic substitution process. However, it is better to
avoid the use of pyridine, the odour of which, detectable at very low con-
centrations, can interfere with the Ambrox 1 fragrance. Thus, pyridine has
been successfully replaced by other basic compounds, such as sodium
hydride and sodium tert-amyl alcoholate.10 For our part, we obtain
unadulterated Ambrox 1 in 96% yield (75% overall from sclareol) by react-
ing ambradiol 5 with butylllithium and tosyl chloride under definite
conditions.20
In short, the method of producing sclareolide 3 that we have devised
requires two oxidants, commercial peracetic acid and sodium periodate,

SYNTHESIS OF AMBROXÕ
753
the latter being only used in a molar ratio to sclareol 2 close to unity.
Therefore, the problem of the treatment and disposal of waste becomes
much smaller with regard to the use of potassium permanganate.
Moreover, the increase in the number of steps associated with the oxidant
change is not detrimental to the yields of sclareolide 3 and Ambrox 1, which
compare with the best routes so far reported. We believe that our method
provides an adequate answer to the constraints on the practical synthesis of
Ambrox 1.
EXPERIMENTAL SECTION
Sclareol was available from Biolandes Parfumerie, Le Sen-Labrit
(France), and had mp 104ꢁC; the 13-episclareol amounted to 5–6%.
Commercial 40% peracetic acid was supplied by Seppic, Paris. It was said
to have the following composition by weight: peracetic acid, 40%; acetic
acid, 40%; hydrogen peroxide, 5%; water, 14%; sulfuric acid, 1%. Titration
of this chemical by the iodometric method proposed by Sully and Williams21
showed 38% of peracetic acid (0.50 mol per 100 g). For epoxidation of
sclareol, the 1% sulfuric acid had to be neutralized by adding sodium acet-
ate to the reaction mixture.
All the reactions were monitored by HPLC-analyses, which were
carried out on a Waters system with a LichrosorbÕ RP18 (10 mm;
4.6 ꢂ 250 mm) column (flow ¼ 1.2 ml/min, eluent methanol/water) or a
PartisilTM Silica (10 mm; 4.6 ꢂ 250 mm) column (flow ¼ 2 ml/min, eluent
hexane/ether). Melting points were determined on a Reichert hot stage
microscope and are uncorrected. NMR spectra were obtained in CDCl3 on
Bruker AC200 and AC250 spectrometers (for 1H at 200.13 and 250.13 MHz,
for 13C at 50.32 and 62.89 MHz). Chemical shift values are assigned relative
1
to the residual CHCl3, 7.26 ppm for H and 77.0 for 13C.
(13S,14RS)-8,13-Epoxylabdane-14,15-diol (9)
Our previous procedure12 was repeated with the following modifica-
tions: ethyl acetate as a solvent was substituted for dichloromethane, chloro-
form and carbon tetrachloride; 3-chloroperbenzoic acid was replaced by
peracetic acid (at the expense of a longer epoxidation time); trifluoroacetic
acid as a catalyst was changed for sulfuric acid.
Epoxidation: Peracetic acid (20 g, 100 mmol) was added dropwise and
with stirring to a solution of sclareol (15.4 g, 50 mmol) in ethyl acetate
(150 ml) containing sodium acetate (0.3 g). After being stirred for 8 days

754
MOULINES, LAMIDEY, AND DESVERGNES-BREUIL
at room temperature, the reaction mixture was diluted with water (100 ml) in
order to take out acetic acid and unreacted peracid. The organic layer was
washed with 10% aqueous Na2CO3, brine and dried over Na2SO4. Upon
removal of the ethyl acetate by evaporation, the crude epoxy sclareol was
obtained as a white solid (16.0 g, nearly quantitative yield).
Payne rearrangement: The epoxy sclareol (16.0 g, 49.3 mmol) was dis-
solved in tert-butyl alcohol (125 ml) warmed to about 30ꢁC. This solution,
after addition of 1N aqueous NaOH (125 ml), was stirred overnight at room
temperature. The reaction mixture was neutralized with saturated aqueous
NH4Cl. The bulk of the tert-butyl alcohol was distilled off under reduced
pressure and an equal volume of water was added. The aqueous mixture was
extracted three times with ethyl acetate. The combined organic layers were
washed with water, brine and dried over Na2SO4. Upon removal of the ethyl
acetate by evaporation, the crude rearranged epoxy sclareol was obtained as
a white solid (15.9 g, nearly quantitative yield).
Acid cyclisation: Sulfuric acid (360 mg, 3.7 mmol) was added dropwise
to a cold (0ꢁC) stirred solution of the rearranged epoxy sclareol (15.9 g,
49 mmol) in ethyl acetate (140 ml). The reaction mixture was allowed to
warm to room temperature over ca 2 hours and was neutralized with satu-
rated aqueous NaHCO3. The organic layer was washed with brine and dried
over Na2SO4. Removal of the ethyl acetate by evaporation led to crude diol
9 as a white waxy solid (15.9 g, quantitative yield).
(13-S)-8,13-Epoxy-15-norlabdan-14-al (10)
The diol 9 (15.9 g, 49 mmol) was dissolved in tetrahydrofuran (150 ml)
or in warm methanol (150 ml) and a solution of sodium periodate (11.5 g,
53.9 mmol) in water (120 ml) was added at room temperature. The reaction
mixture was kept in darkness for 16 hours, and was then filtered to remove
the precipitate of sodium iodate. The filter cake was washed with ethyl
acetate, and the filtrate concentrated under reduced pressure. The aqueous
residue was extracted three times with ethyl acetate. The combined organic
extracts were washed with brine and dried over Na2SO4. Removal of the
ethyl acetate by evaporation led to the crude aldehyde 10 as a white solid
(13.9 g, 97%). A purified sample was obtained by flash column chromato-
graphy on silica gel (hexane/ether, 9:1) followed by recrystallization from
hexane: colourless needles, mp 94–96ꢁC, [ꢀ]D20 þ 67.2ꢁ(c ¼ 2.30, CHCl3).
Elemental analysis: C19H32O2, calcd C ¼ 78.03, H ¼ 11.03, O ¼ 10.94,
found C ¼ 78.01, H ¼ 11.04, O ¼ 10.86.
1H NMR ꢁ 9.57 (1H,s,H-14), 2.45–2.32 (1H,m), 1.12, 1.04 (6H,2s,
H3-16 and H3-17), 0.83 (3H,s,H3-18), 0.75, 0.67 (6H,2s,H3-19 and H3-20).

SYNTHESIS OF AMBROXÕ
755
13C NMR ꢁ 205.2 (C-14), 78.0 (C-13), 76.6 (C-8), 57.3, 56.3 (C-5 and
C-9), 42.3 (C-7), 42.0 (C-3), 39.2 (C-1), 36.8 (C-10), 33.3 (C-18), 33.3 (C-4),
31.5 (C-12), 24.7, 22.7 (C-16 and C-17), 21.2 (C-19), 20.0 (C-6), 18.5 (C-2),
15.7 (C-20), 15.7 (C-11).
(13S)-8,13-Epoxy-15-norlabdan-14-oic Acid
Prepared in 90% yield by the oxidation of the aldehyde 10 with the
Jones reagent according to the usual procedure. Colourless needles (hexane)
mp 148–149ꢁC (lit.,22 152–154ꢁC), ½ꢀŠ þ 49.0ꢁ (c ¼ 3.3, CHCl3), [lit.,22
23
D
25
D
½ꢀŠ þ 49.9ꢁ(CHCl3)]. 1H NMR ꢁ 2.56–2.48 (1H,m), 1.89–1.81 (1H,m),
1.37, 1.24 (6H,2s,H3-16 and H3-17), 0.85 (3H,s,H3-18), 0.77, 0.73
(6H,2s,H3-19 and H3-20).
13C NMR ꢁ 180.8 (C-14), 78.2 (C-13), 74.0 (C-8), 57.4, 56.3 (C-5 and
C-9), 42.3 (C-7), 42.0 (C-3), 39.2 (C-1), 36.8 (C-10), 34.3 (C-12), 33.3 (C-18),
33.2 (C-4), 29.8 (C-16), 21.2 (C-19), 20.9 (C-17), 19.9 (C-6), 18.5 (C-2), 16.0
(C-11), 15.9 (C-20).
13,14,15,16-Tetranorlabdan-8,12-olide (Sclareolide) (3)
In a 250 ml three-necked flask fitted with a mechanical stirrer, a ther-
mometer and a dropping funnel, was placed the aldehyde 10 (13.9 g,
47.5 mmol). The dropping funnel was charged with peracetic acid (47 g,
235 mmol), and a few milliliters were added to the flask. While stirring
gently a reaction occurred as evidenced by the rapid rise in the temperature.
The remainder of the peracetic acid was then added at such a rate that the
temperature was maintained at 50–55ꢁC (from time to time external cooling
was required). Towards the end of the addition, the temperature fell. After
being stirred overnight at room temperature, the reaction mixture was
diluted with water (200 ml). The aqueous mixture was extracted twice with
ethyl acetate. The combined organic layers were washed free of acidic
materials with cold 1N aqueous NaOH, then with brine and dried
over Na2SO4. Ethyl acetate was evaporated, and the crude sclareolide 3
(11.3 g, 95%) crystallized from hexane (35 ml). The pure sclareolide 3
(10.3 g, 82% overall from sclareol) separated as needles, mp 123–124ꢁC
(lit.,6 123–124ꢁC).
2
1H NMR ꢁ 2.45-2.15 (2H, AB part of an ABX system, J ¼ 16.1 Hz,
3J ¼ 14.9 and 6.7 Hz, H2-11), 1.31 (3H,s,H3-17), 0.89, 0.86, 0.81 (9H,3s,
H3-18, H3-19 and H3-20).

756
MOULINES, LAMIDEY, AND DESVERGNES-BREUIL
13C NMR ꢁ 176.8 (C-12), 86.3 (C-8), 59.0 (C-9), 56.5 (C-5), 42.0 (C-3),
39.4 (C-7), 38.6 (C-1), 35.9 (C-10), 33.0 (C-18), 33.0 (C-4), 28.6 (C-11), 21.5,
20.8 (C-17 and C-19), 20.4 (C-6), 18.0 (C-2), 15.0 (C-20).
The spectral data are in close agreement with those previously
reported.23
13,14,15,16-Tetranorlabdane-8,12-diol (Ambradiol) (5)
To a stirred suspension of lithium aluminium hydride (1.0 g,
26.3 mmol) in dry tetrahydrofuran (10 ml) was added dropwise a solution
of sclareolide 3 (10.3 g, 41.1 mmol) in dry tetrahydrofuran (40 ml). After
stirring for 3 hours at room temperature the reaction mixture was diluted
with ethyl acetate (100 ml)24 and acidified with cold 3 N aqueous HCl
(40 ml). The organic layer was washed with staturated aqueous NaHCO3,
brine and dried over Na2SO4. Upon removal of solvents by evaporation,
ambradiol 5 (10.1 g, 97%) was obtained as a white crystalline solid. Recrys-
tallization of a 0.5 g aliquot from hexane gave an analytical sample: colour-
less crystals, mp 132ꢁC (lit.,2 131–132ꢁC).
1H NMR (exchange with D2O) ꢁ 3.78–3.71(H1,
dt,2J ¼ 10.1 Hz,
3J ¼ 4.3 Hz, H-12), 3.46–3.37(1H,dt, J ¼ 10.1 Hz, J ¼ 6.9 Hz, H0-12), 1.91–
2
3
3
1.87 (1H,dt,2J ¼ 12.2 Hz, J ¼ 3.2 Hz), 1.16 (3H,s,H3-17), 0.85 (3H,s,H3-18),
0.77 (6H,s,H3-19 and H3-20).
13C NMR ꢁ 72.8 (C-8), 63.9 (C-12), 59.2 (C-9), 55.9 (C-5), 44.0 (C-7),
41.8 (C-3), 39.2 (C-1), 38.9 (C-10), 33.3 (C-18), 33.2 (C-4), 27.8 (C-11), 24.5
(C-17), 21.4 (C-19), 20.4 (C-6), 18.4 (C-2), 15.3 (C-20).
The spectral data are in close agreement with those previously
reported.19
8,12-Epoxy-13,14,15,16-tetranorlabdane (Ambrox) (1)
To a stirred solution of ambradiol 5 (10.1 g, 38.7 mmol) in dry tetra-
hydrofuran (100 ml) cooled at 0ꢁC under nitrogen, were added dropwise a
1.6 M hexanic n-butyllithium solution (26 ml, 41.6 mmol) and, 15 minutes
later, tosyl chloride (7.6 g, 39.7 mmol) dissolved in dry tetrahydrofuran.
After 15 minutes, a further addition of the 1.6 M hexanic n-butyllithium
solution (26 ml, 41.6 mmol) was done at 0ꢁC. When about one-third of
the n-butyllithium have been added, a white precipitate began to form.
The reaction mixture was allowed to stir at room temperature for 2 hours.
Most of the tetrahydrofuran was evaporated in vacuo and the residue was
partitioned between water (100 ml) and ethyl acetate (100 ml). The organic

SYNTHESIS OF AMBROXÕ
757
layer was washed with brine and dried over Na2SO4. Upon removal of the
ethyl acetate by evaporation, Ambrox 1 was obtained as a white crystalline
solid (9.0 g, 96%). Recrystallization of a 0.5 g aliquot from pentane gave an
analytical sample: colourless plates, mp 76ꢁC (lit.,1 76–77ꢁC).
1H NMR ꢁ 3.94-3.75 (2H,m,H2-12), 1.07 (3H,s,H3-17), 0.86 (3H,s,
H3-18), 0.82 (6H, unresolved 2s, H3-19 and H3-20).
13C NMR ꢁ 79.8 (C-8), 64.9 (C-12), 60.0 (C-9), 57.2 (C-5), 42.4 (C-3),
39.9, 39.7 (C-1 and C-7), 36.1 (C-10), 33.5 (C-18), 33.0 (C-4), 22.5 (C-11),
21.1 (C-19), 21.1 (C-17), 20.6 (C-6), 18.3 (C-2), 15.0 (C-20).
The spectral data are in close agreement with those previously
reported19.
ACKNOWLEDGMENTS
The authors thank Olivier Griffoul for having investigated some other
oxidants to degradate the aldehyde 10.
REFERENCES AND NOTES
1. Stoll, M.; Hinder, M. Helv. Chim. Acta 1950, 33, 1251.
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4. For a general review on the Ambrox preparation see: Frater, G.;
Bajgrowicz, J.A.; Kraft, P. Tetrahedron 1998, 54, 7633.
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Chim. Acta 1985, 68, 2022. (b) Escher, S.; Giersch, W.; Niclass, Y.;
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758
MOULINES, LAMIDEY, AND DESVERGNES-BREUIL
12. Moulines, J.; Lamidey, A.-M.; Bats, J.-P.; Morisson, V. Synth.
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13. This aldehyde was obtained by Ohloff, G. Ann. 1958, 617, 134, from
ozonolysis of epimanoyl oxide (as shown later by Hodges, R.; Reed,
R.I. Tetrahedron 1960, 10, 71) formed in minute amount during the
acetylation of sclareol.
14. Aldehydes are generally oxidized to carboxylic acids by peracids
because in the rearrangement step of the Baeyer-Villiger reaction, the
aldehydic hydrogen migrates in preference to the carbon-bearing
group; in the present case, the converse migration happens (formate
formation).
The Jones reagent oxidizes the aldehyde 10 to the corresponding 8,13-
epoxy 15-norlabdan-14-oic acid.
15. Cambie, R.C.; Joblin, K.N.; Preston, A.F.; Australian J. Chem. 1972,
25, 1767.
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19. Barrero, A.F.; Alvarez-Manzaneda, E.J.; Altarejos, J.; Salido, S.;
Ramos, J.M. Tetrahedron 1993, 49, 10405.
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22. Giles, J.A.; Schumacher, J.N.; Mims, S.S.; Bernasek, E. Tetrahedron
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Sexmero, M.J.; Lithgow, A.M. Tetrahedron 1992, 48, 9991.
24. Ambradiol 5 is sparingly soluble in pure ethyl acetate but it is easily
soluble in ethyl acetate mixed with tetrahydrofuran (e.g. 2/1).
Received in the U.K. March 27, 2000