Degradation of the side chain of (-)-sclareol: A very short synthesis of nor-ambreinolide and ambrox

Article abstract of DOI:10.1081/SCC-200031056

The synthesis of nor-Ambreinolide (8) from (-)-sclareol (1) was carried out by treatment with KMnO₄-Ac₂O and further alkaline hydrolysis. 8 was directly transformed into (-)-ambrox (11) by reduction with metal borohydride in the presence of Lewis acids.

Full text of DOI:10.1081/SCC-200031056

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Degradation of the Side Chain
of (-)‐Sclareol: A Very Short
Synthesis of nor‐Ambreinolide
and Ambrox
A. F. Barrero a , E. J. Alvarez‐Manzaneda a , R.
Chahboun a & A. F. Arteaga a
a Departamento de Química Orgánica, Facultad de
Ciencias, Instituto de Biotecnología , Universidad
de Granada , 18071, Granada, Spain
Published online: 10 Jan 2011.
To cite this article: A. F. Barrero , E. J. Alvarez‐Manzaneda , R. Chahboun & A. F.
Arteaga (2004) Degradation of the Side Chain of (-)‐Sclareol: A Very Short Synthesis
of nor‐Ambreinolide and Ambrox, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:19, 3631-3643,
DOI: 10.1081/SCC-200031056
To link to this article: http://dx.doi.org/10.1081/SCC-200031056
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 19, pp. 3631–3643, 2004
Degradation of the Side Chain of
(2)-Sclareol: A Very Short Synthesis of
nor-Ambreinolide and Ambrox
*
A. F. Barrero, E. J. Alvarez-Manzaneda, R. Chahboun,
and A. F. Arteaga
´ ´
Departamento de Quımica Organica, Facultad de Ciencias, Instituto de
´
Biotecnologıa, Universidad de Granada, 18071, Granada, Spain
ABSTRACT
The synthesis of nor-Ambreinolide (8) from (-)-sclareol (1) was carried
out by treatment with KMnO4-Ac2O and further alkaline hydrolysis. 8
was directly transformed into (-)-ambrox (11) by reduction with metal
borohydride in the presence of Lewis acids.
Key Words: Terpenes; Ambergris; Odorants.
*
´ ´
Correspondence: E. J. Alvarez-Manzaneda, Departamento de Quımica Organica,
´
Facultad de Ciencias, Instituto de Biotecnologıa, Universidad de Granada, 18071
Granada, Spain; E-mail: eamr@ugr.es.
3631
DOI: 10.1081/SCC-200031056
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3632
Barrero et al.
INTRODUCTION
Since ancient times, ambergris has been a highly valued material due to its
olfactive[1] and aphrodisiac properties.[2] Ambergris is a metabolic product of
the sperm whale (Physeter macrocephalus L.) that accumulates as concretions
in the intestinal tract. (2)-Ambrox (11), the commercially most important con-
stituent of the scarce natural ambergris, is recognized as the prototype of all
ambergris odorants and is used in perfumery as a valuable ingredient of many
fine fragrances because of its unique scent and fixative properties. This fact
has prompted chemists to develop synthetic routes for the production of (2)-
ambrox (11) as well as for the racemic compound (þ/ 2 )-ambrox, whose
odor is somewhat different from that of the natural product. Total syntheses of
(þ/ 2 )-ambrox, mainly based on biogenetic-type cyclizations, starting from
farnesic and monocyclic farnesic acids, have been reported.[3] The present
authors have described a synthesis of (þ/ 2 )-ambrox from E-nerolidol and
b-ionone.[4] Nevertheless, in most cases, natural sesquiterpenes[5] as well as
abietane[6] and labdane[7] diterpenes have been used as starting materials.
(2)-Sclareol (1), a labdane diterpene that constitutes the main component of
the hexane extract of Salvia sclarea, has been extensively used for preparing
(2)-ambrox (11).[8] Because of its widespread natural occurrence, 1 is the
raw material used industrially for this purpose.[9] Our group has reported very
efficient synthesis of 11 from 1.[10] We have also synthesized a great variety
of interesting compounds, such as bioactive drimanes, monocarbocyclic
terpenes or marine metabolites starting from (2)-sclareol (1).[11]
In all cases, the transformation of (2)-sclareol (1) into the different valuable
compounds involves the oxidative degradation of the labdane side chain. Most
of the processes reported use expensive or toxic reagents, and sometimes the
reaction conditions require arduous workup, which restricts their industrial utili-
zation. Therefore, it becomes necessary to investigate new methodologies using
cheap and less contaminating reagents. Potassium permanganate could be a suit-
able oxidant from this point of view. The oxidation of (2)-sclareol (1) with this
reagent has been reported,[8a,b] although this reaction has not yet been studied.
In this paper we report the results of our research on this subject and
its application to the synthesis of ambergris compounds starting from
(2)-sclareol (1).
RESULTS AND DISCUSSION
The degradative oxidation of (2)-sclareol (1) to ambergris compounds,
such as (2)-ambrox (11) and related substances, is outlined in Sch. 1. The
homodrimane skeleton is formed by rupture of the C12-C-13 bond of the

Synthesis of nor-Ambreinolide and Ambrox
3633
Scheme 1.
enol ether 3, which is in equilibrium with the methylketone 2, resulting from
the oxidation of (2)-sclareol (1) with potassium permanganate.
This process has been studied with a view to improving on the unsatisfac-
tory yields reported in the literature for the conversion of 1 into 2. The reaction
was carried out under the reported conditions, [8a,b] after modification of some
parameters. The low yield of 2 did not change when the reaction time was
longer, or when the temperature or the oxidant proportion were increased.
In all cases, 50–60% of 2 was obtained, this methyl ketone being the only
product detected by chromatographic or spectroscopic analysis of the crude
reaction. The same results were obtained after exhaustive washing of the pre-
cipitated manganese dioxide. A significant influence of the solvent purity on
the methyl ketone yield was observed, this latter increasing when the
solvent was dried. This behavior can be understood by taking into account
the reaction mechanism (Sch. 2).
The presence of water in the basic reaction medium must favor the
formation of the salt of acid 5. These polar compounds would be solubilized
in the aqueous phase during the workup.
In order to confirm this hypothesis, oxidation of (2)-sclareol (1) with
potassium permanganate using different acetone-water mixtures as the solvent
was carried out (Table 1). In all cases, a mixture of methyl ketone 2 and acid
5 was obtained, the yield of 2 decreasing whereas that of 5 increased when

3634
Barrero et al.
Scheme 2.
the proportion of water was raised. When the reaction was carried out in anhy-
drous acetone under an argon atmosphere for 1 h, methyl ketone 2 in high yield
was obtained. Polyol 6 was not detected. Acid 5 remained unaltered after treat-
ment with potassium permanganate under the reaction conditions described.
The oxidation of methyl ketone 2 was then studied under different reac-
tion conditions. The most representative results are summarized in Table 2.
Acetoxyaldehyde 9 was obtained in high yield when the Jones reagent was
used (entry 3); overoxidation of 2 to the acetoxyacid 7 under these conditions
Table 1. Oxidation of 1 with KMnO4.
Entry
Solvent
Reaction time
Products (%)
1
2
3
4
Commercial acetone
Acetone-H2O (3 : 1)
Acetone- H2O(3 : 2)
Anhydrous acetone
45 min
35 min
25 min
1 h
2 (73%), 5 (21%)
2 (63%), 5 (33%)
2 (55%), 5 (39%)
2 (90%), 5 (5%)

Synthesis of nor-Ambreinolide and Ambrox
Table 2. Oxidation of 2 with some common reagents.
3635
Products
(%)
Entry
1
Oxidant
PDC
Solvent
CH2Cl2
Temp.
r.t.
Time
5 h
7 (41%),
8 (45%)
8 (5%),
9 (71%)
9 (80%)
8 (83%)
2
PCC
CH2Cl2
r.t.
3 h
3
4
Jones
Na2CrO4
Acetone
Benzene-
2158C
708C
45 min
4 h
Ac2O-AcOH
Acetone-Ac2O
5
KMnO4
288C
2 h
7 (91%)
was difficult. Entry 5 shows an interesting result, which allowed us to make the
direct transformation from (2)-sclareol (1) into homodrimane compounds.
Acetoxyacid 7 was obtained in high yield by treating 2 with potassium per-
manganate in acetone-acetic acid. In the acid medium, the methyl ketone 2
was isomerized to the enol ether 3, which underwent oxidative rupture to
produce the homodrimane derivative (Sch. 1).
In the light of the above results, the direct degradation of (2)-sclareol (1)
was accomplished. The treatment of a solution of 1 in a 4 : 1 acetone-acetic
anhydride mixture with potassium permanganate at 08C gave acetoxyacid 7
and nor-ambreinolide (8), a valued ambergris odorant, in a 4 : 1 proportion
(94% yield). The reaction is exothermic, the formation of 8 being favored
when the temperature was raised (Sch. 3).
Finally, (2)-ambrox(11) wasobtained following twoalternativeroutes. The
treatment of the mixture of 7 and 8 with lithium aluminum hydride gave the diol
10, which was stereoselectively cyclized to 11 with bromotrichloromethane and
triphenylphosphine. In an alternative procedure, the alkaline hydrolysis of the
mixture of 7 and 8 gave, after acidification, the lactone 8 as the only product. 8
was converted directly, or via diol 10, into 11. Treatment of 8 with zinc iodide
and sodium borohydride or with boron trifluoride etherate and potassium borohy-
dride gave 11 in high yield. 10 was prepared from 8 in two alternative ways. The
treatment of 8 with potassium borohydride produced 10 in 95% yield, this diol
resulting in almost quantitative yield when 8 was refluxed with red-Al in toluene.
EXPERIMENTAL
Infrared (IR) spectra were obtained on Perkin-Elmer Models 782 and 983G
spectrometers with samples between sodium chloride plates or as potassium

3636
Barrero et al.
Scheme 3.
bromide pellets. Proton nuclear magnetic resonance spectra were taken on a
Bruker AMX 300 (300MHz) or Bruker ARX 400 (400MHz) spectrometer
using CDCl3 and D2O as solvent, and TMS or residual protic solvent CHCl3
(dH ¼ 7.25ppm) as internal reference, and the multiplicity of a signal is a
singlet unless otherwise stated, when the following abbreviations are used: s,
singlet; bs, broad singlet; d, doublet; bd, broad doublet; dd, double doublet; t,
triplet; m, multiplet. 13C NMR spectra were run on a Bruker AMX 300
(75MHz) Bruker ARX 400 (100MHz) instrument. Chemical shifts are in ppm
(d scale) and the coupling constants are in Hertz. Carbon substitution degrees
were established by DEPT pulse sequence. The MS were recorded on a
Hewlett-Packard 5988A spectrometer using an ionizing voltage of 70eV. For
analytical TLC Merck silica gel 60G in 0.25mm thick layers was used. Chroma-
tographic separations were carried out by conventional column on Merck silica
gel 60 (70–230 mesh) and by flash column on Merck silica gel 60
(230–400 mesh) using hexane-MeOtBu (H-E) mixtures of increasing polarity.
Routinely, dry organic solvents were stored under argon, over freshly activated
molecular sieves. Ether, benzene, and THF were dried over sodium-benzophe-
none ketyl, HMPA from Na, and dichloromethane over calcium hydride.

Synthesis of nor-Ambreinolide and Ambrox
3637
Reaction of sclareol (1) with Potassium Permanganate
To a solution of 1 (10.0 g, 32.4 mmol) in acetone (200 mL), cooled at 08C,
KMnO4 (16.0 g, 113.6 mmol) was added in several portions for 15 min and the
mixture was stirred at room temperature for 45 min. NaHSO3 (5.0 g) in H2O
(20 mL) was added and the stirring was continued for 15 min. The mixture
was filtered, washing with acetone (100 mL), and diluted with t-butyl
methyl ether (50 mL). The resulting solution was washed with H2O
(2 ꢀ 50 mL) and brine (2 ꢀ 50 mL), dried and evaporated to give 14,15-
dinor-8a-hydroxy-13-labdanone (2) (9.2 g, 90%). Oil; [a]D þ 6.7, (c, 1). IR
1
(neat): n 3489, 1774, 1048. H NMR (300 MHz): d 0.75 (3 H, s, Me-10),
0.77 (3H, s, Meb-4), 0.83 (3 H, s, Mea-4), 1.12 (3 H, s, Meb-8), 1.83 (1 H,
dt, 3.1, 12.2, Heq-7), 2.10 (3 H, s, Me-13), 2.54 (1 H, ddd, 5.7, 7.8, 17.8,
H-12), 2.66 (1 H, dd, 7.8, 17.8, H0-12). 13C NMR (75 MHz): d 39.98 (C-1),
18.68 (C-2), 41.82 (C-3), 33.14 (C-4), 55.97 (C-5), 20.41 (C-6), 44.43 (C-
7), 73.79 (C-8), 60.53 (C-9), 39.21 (C-10), 18.36 (C-11), 46.19 (C-12),
210.56 (C-13), 29.94 (C-16), 24.03 (C-17), 33.34 (C-18), 21.44 (C-19),
15.13 (C-20); MS m/z (rel. int.): 280 (Mþ, 0.7), 262 (Mþ-H2O, 3.2), 191
(5.1), 177 (6.5), 135 (5.5), 109 (19.7), 43 (100). The aqueous phase was acidi-
fied with 2N HCl and extracted with t-butyl methyl ether (2 ꢀ 30 mL), and the
organic phase dried and evaporated to give 15-nor-8a,13-dihydroxy-14-lab-
danoic acid (5) (0.5 g, 5%). White crystals. IR (nujol): n 3250–2500, 1715,
1
1120. H NMR (400 MHz, D2O): d 1.18 (3 H, s, Me-10), 1.20 (3 H, s,
Meb-4), 1.26 (3 H, s, Mea-4), 1.78 (3 H, s, Me-13). 13C NMR (100 MHz,
D2O): d 39.41 (C-1), 18.08 (C-2), 41.59 (C-3), 32.56 (C-4), 55.53 (C-5),
20.90 (C-6), 42.81 (C-7), 75.61 (C-8), 60.81 (C-9), 39.14 (C-10), 19.92
(C-11), 43.31 (C-12), 76.69 (C-13), 171.11 (C-14), 25.56 (C-16), 22.76 (C-
17), 32.76 (C-18), 20.91 (C-19), 14.91 (C-20).
Reaction of 2 with Pyridinium Dichromate
To a stirred solution of 2 (0.5 g, 1.8 mmol) in anhydrous CH2Cl2 (20 mL)
was added pyridinium dichromate (1.2 g) and the mixture was stirred for 5 h.
It was filtered over Florisil and flushed with t-butyl methyl ether. The solvent
was evaporated to afford a crude which by flash column chromatography on
silicagel (7 : 3 hexane-t-BuOMe) gave nor-ambreinolide (8) (0.20 g, 45%)
and 8a-acetoxy-13,14,15,16,tetranor-12-labdanoic acid (7) (0.23 g, 45%).
7. Oil. IR (neat): n 3450, 1727, 1703, 1240, 941. 1H NMR (300 MHz): d
0.78 (3 H, s, Me-10), 0.82 (3 H, s, Meb-4), 0.87 (3 H, s, Mea-4), 1.50 (3 H, s,
Meb-8), 1.86 (3 H, s, AcO-8). 13C NMR (75 MHz): d 39.07 (C-1), 18.27 (C-2),
41.60 (C-3), 33.11 (C-4), 55.35 (C-5), 19.78 (C-6), 38.85 (C-7), 86.27 (C-8),

3638
Barrero et al.
55.35 (C-9), 38.62 (C-10), 30.26 (C-11), 180.10 (C-12), 22.46 (C-17), 33.27
(C-18), 21.34 (C-19), 15.65 (C-20), 169.88 (C-21), 19.87 (C-22). MS m/z
(rel. int.): 295 (M þ 1þ, 0.4), 251 (M-MeC0-, 100), 191 (21.8).
8. IR: 1775, 1193, 1128, 1080, 914 cm21. 1H NMR (CDCl3, 300 MHz): d
0.82 (3 H, s, Me-10), 0.87 (3 H, s, Meb-4), 0.89 (3 H, s, Mea-4), 1.04 (1 H, dd,
12.6 y 3.5, H-5) 1.31 (3 H, s, Meb-8), 1.86 (1 H, dq, J ¼ 14.0 y 3.5 Hz, H-6eq),
1.95 (1 H, dd, J ¼ 14.8 y 6.5 Hz, H-9), 2.06 (1 H, dt, J ¼ 11.7 y 3.3 Hz,
H-7eq), 2.21 (1H, dd, J ¼ 12.2 y 6.5 Hz, H-11), 2.39 (1H, dd, J ¼ 16.2 y
14.8 Hz, H-11). 13C NMR (CDCl3, 75 MHz): d 39.5 (C-1), 18.0 (C-2), 42.1
(C-3), 33.1 (C-4), 56.6 (C-5), 20.5 (C-6), 38.7 (C-7), 86.3 (C-8), 59.1 (C-9),
36.0 (C-10), 28.7 (C-11), 176.8 (C-12), 20.9 (C-17), 33.1 (C-18), 21.5
(C-19), 15.0 (C-20). MS m/z (rel. int): 250 (0.6), 235 (12), 206 (15), 191
(13), 150 (15), 123 (49), 67 (77), 55 (66), 43 (100).
Reaction of 2 with pyridinium chlorochromate
To a stirred solution of 2 (1.0 g, 3.6 mmol) in anhydrous CH2Cl2 (25 mL),
pyridinium chlorochromate (1.1 g) was added and the mixture was stirred at
room temperature for 3 h. The mixture was filtered through Florisil and
flushed with t-butyl methyl ether. The solvent was evaporated giving a
crude reaction that by flash column chromatography on silicagel (8 : 2
hexane-t-BuOMe) afforded 8a-acetoxy-13,14,15,16-tetranor-12-labdanal
(9) (0.75 g, 71%) and 8 (0.0.5 g, 5%). 9 Oil; [a]D 230.78, (c, 0.09). IR
1
(neat): n 2870, 1724, 1246, 937. H NMR (300 MHz): d 0.77 (3 H, s, Me-
10), 0.83 (3 H, s, Meb-4), 0.86 (3 H, s, Mea-4), 1.48 (3 H, s, Meb-8), 1.85
(3 H, s, AcO-8), 9.64 (1 H, dd, 1.8, 3.4, H-12). 13C NMR (75 MHz): d
39.81 (C-1), 18.27 (C-2), 41.82 (C-3), 33.11 (C-4), 55.59 (C-5), 19.73 (C-
6), 40.28 (C-7), 86.08 (C-8), 53.59 (C-9), 38.44 (C-10), 28.95 (C-11),
202.42 (C-12), 22.52 (C-17), 33.25 (C-18), 21.31 (C-19), 15.88 (C-20),
169.66 (C-21), 20.06 (C-22). MS m/z (rel. int.): 295 (M þ 1þ, 1), 251 (M-
MeC0-, 100), 235 (45), 191 (78).
Reaction of 2 with Jones Reagent
To a stirred solution of 2 (20.0 g, 71.4 mmol) in acetone (300 mL) was
added dropwise Jones reagent (20 mL) at 2158C for 30 min and the mixture
was stirred for an additional 15 min. A sat. NaHCO3 solution was slowly
added and stirring was continued at 08C for 5 min. The mixture was filtered,
the solvent was evaporated, and the residue was diluted with t-BuOMe
(200 mL), and successively washed with H2O (2 ꢀ 50 mL) and brine

Synthesis of nor-Ambreinolide and Ambrox
3639
(2 ꢀ 50 mL). After working up as described for the above oxidations, 9
(17.0 g, 80%) was obtained.
Reaction of 2 with Sodium Chromate
To a solution of 2 (5.0 g, 17.8 mmol) in benzene (80 mL), sodium chro-
mate (17.0 g, 35 mmol), acetic anhydride (10 mL), and glacial acetic acid
(10 mL) was added and the mixture was stirred at 708C for 4 h. It was
poured into ice and extracted with t-BuOMe (2 ꢀ 50 mL). The combined
organic phases were washed with sat. NaHCO3 solution (3 ꢀ 30 mL), H2O
(2 ꢀ 50 mL), and brine (2 ꢀ 50 mL). Usual work-up gave lactone 8 (3.6 g,
80%).
Reaction of 2 with Potassium Permanganate
KMnO4 (12.0 g, 75.9 mmol) was slowly added to a solution of ketone 2
(10.0 g, 35.7 mmol) in acetone (200 mL) and acetic acid (30 mL), cooled at
288C, and the mixture was stirred at this temperature for 2 h. A 10%
NaHSO3 solution (100 mL) was added and the mixture was filtered. The
solvent was evaporated to give a precipitate, which was filtered and dried,
affording 7 (10.1 g, 91%).
Reaction of 1 with Potassium Permanganate
KMnO4 (16.0 g, 101.2 mmol) was slowly added for 20 min to a solution of
1 (5.0 g, 16.2 mmol) in acetone (120 mL) and acetic anhydride (30 mL),
cooled at 08C, and the mixture was further stirred at this temperature for 2
h. Then a solution of Na2CO3 (10 g) in H2O (150 mL) was added and the
mixture was stirred for 15 min. It was filtered and the acetone was evaporated
to give a precipitate, which was filtered washed with cold water and dried,
affording a mixture of 7 and 8 (94% total yield).
nor-Ambreinolide (8)
A mixture (4.0 g) of 7 and 8 in 2N NaOH (15 mL) was refluxed for 2 h.
Then it was acidified with 2N HCl (16 mL) and the precipitate was filtered
washing with cold water. After drying under vacuum lactone 8 (3.5 g, 97%)
was obtained.

3640
Barrero et al.
13,14,15,16-Tetranor-8a,12-labdanediol (10)
LiAlH4 (1.8 g, 52 mmol) was added to a solution of the mixture (5.0 g) of
7 and 8 in THF (30 mL), cooled at 08C, and the mixture was stirred at room
temperature for 2 h. It was poured into ice and sat. NH4Cl was added until
pH 7. Then it was diluted with t-BuOMe (100 mL) and washed with brine
(2 ꢀ 20 mL). The solvent was dried and evaporated to give 10 (4.4 g, 97%).
White crystals; [a]D 2158, (c, 1). IR (nujol): n 3244, 1052. 1H NMR
(300 MHz): d 0.77 (6 H, s, Me-10, Meb-4), 0.85 (3 H, s, Mea-4), 1.16 (3 H,
s, Meb-8), 1.87 (1 H, dt, 3.20, 12.2, Heq-7), 3.42 (1 H, dt, 6.9, 10.3, H-12), 3.75
(1 H, dt, 4.3, 10.3, H0-12). 13C NMR (75 MHz): d 39.31 (C-1), 18.38 (C-2),
41.87 (C-3), 33.24 (C-4), 55.99 (C-5), 20.42 (C-6), 44.15 (C-7), 72.94 (C-
8), 59.22 (C-9), 38.93 (C-10), 27.85 (C-11), 63.98 (C-12), 24.56 (C-17),
33.38 (C-18), 21.48 (C-19), 15.29 (C-20). MS m/z (rel. int.): 254 (Mþ,
0.41), 236 (Mþ-H2O, 25), 177 (26.3), 151 (18.1), 95 (48.8), 43 (100).
Synthesis of 10 from nor-Ambreinolide (8)
Procedure A: KBH4 (0.56 g) was added to a solution of 8 (1.0 g, 4.0 mmol)
in EtOH (20 mL) and the mixture was stirred under reflux for 10 h. The solvent
was evaporated and the mixture was fractionated into H2O (30 mL) – t-BuOMe
(30 mL) and extracted with t-BuOMe (3 ꢀ 30 mL). The combined organic
phases were washed with brine (3 ꢀ 30 mL), dried, and evaporated to give
10 (0.96 g, 95%).
Procedure B: A solution of red-Al in toluene (2.5 eq) was added to a
solution of 8 (5.0 g, 20.0 mmol) in toluene (50 mL) and the mixture was
refluxed for 12 h. The solvent was evaporated and the residue was fractionated
into H2O (100 mL) – t-BuOMe (200 mL). The organic phase was washed with
2 N HCl (3 ꢀ 30 mL), dried, and evaporated to afford 10 (4.8 g, 95%).
(2)-Ambrox (11)
CBrCl3 (0.47 g, 2.3 mmol), Ph3P (0.33 g, 1.2 mmol) and NaHCO3 (0.4 g)
was added to a solution of diol 10 (20.0 g, 0.8 mmol) in CH2Cl2 (10 mL) and
the mixture was refluxed for 6 h. The solvent was evaporated and the residue
was dissolved in t-BuOMe (30 mL) and washed with H2O (2 ꢀ 20 mL) and
brine (2 ꢀ 20 mL). The organic phase was dried and evaporated to give a
residue that after crystallization from petroleum ether yielded (2)-ambrox
(11) (0.17 g, 92%). White cristals; [a]D 222.18 (c, 0.68). IR (KBr): n
1
1083, 1006, 978, 915 (ether). H NMR (300 MHz): d 0.81 (3 H, s, Meb-4

Synthesis of nor-Ambreinolide and Ambrox
3641
or Me-10), 0.82 (3 H, s, Me-10 or Meb-4), 0.86 (3 H, s, Mea-4), 1.07 (3 H,
s, Me-8), 3.81 (1 H, q, 8.3, H-12), 3.90 (1 H, td, 8.3, 4.3, H0-12). 13C NMR
(75 MHz): d 39.95ꢁ (C-1), 18.39 (C-2), 42.43 (C-3), 33.06 (C-4), 57.25 (C-
5), 20.64 (C-6), 39.73 (C-7)ꢁ, 79.91 (C-8), 60.11 (C-9), 36.18 (C-10), 22.62
(C-11), 64.97 (C-12), 21.13 (C-17), 33.58 (C-18), 21.13 (C-19), 15.03 (C-
20). MS m/z (rel. int.): 236 (Mþ, 2%), 221 (Mþ-CH3, 100), 205 (5), 203
(4), 177 (3), 137 (C10Hþ17, 15), 109 (5), 97 (13), 81 (7), 67 (6), 55 (5), 43 (8).
Synthesis of 11 from 8
Procedure A: ZnI2 (7.7 g, 24 mmol) was slowly added to a stirred
mixture of 8 (4.0 g, 16 mmol) and NaBH4 (1.2 g, 32 mmol) in THF
(50 mL), cooled at 08C. The mixture was further stirred at room temperature
for h and then under reflux for 1 h. It was filtered through Celite, washing
with t-BuOMe (30 mL). After evaporating the solvent 11 (3.2 g, 85%) was
obtained.
Procedure B: BF3-Et2O (5.6 g, 40 mmol) was added in portions to a stirred
solution of 8 (5.0 g, 20 mmol) and KBH4 (2.1 g, 40 mmol) in THF (50 mL),
cooled at 08C, and the mixture was stirred at room temperature for 50 min
and then under reflux for 2 h. Following the same work-up described for the
procedure A, 11 (3.7 g, 80%) was obtained.
ACKNOWLEDGMENTS
We should like to thank the CICYT (Projet 1FD97-1103) for financial
support.
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*
These assignments may be interchanged.

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Received in the UK July 29, 2003