Resolution of sclareolide as a key intermediate for the synthesis of Ambrox

Article abstract of DOI:10.1016/S0957-4166(98)00404-2

Sclareolide was efficiently resolved by a diastereomeric salt formation method using homochiral erythro-2-amino-1,2-diphenylethanol (ADPE) as a resolving agent.

Full text of DOI:10.1016/S0957-4166(98)00404-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3819–3823
Resolution of sclareolide as a key intermediate for the synthesis
of Ambrox®
Tsukasa Koga, Yoshio Aoki, Takuji Hirose and Hiroyuki Nohira ∗
Department of Applied Chemistry, Faculty of Engineering, Saitama University, 255 Shimo-Ohkubo, Urawa,
Saitama 338-8570, Japan
Received 18 August 1998; accepted 2 October 1998
Abstract
Sclareolide was efficiently resolved by a diastereomeric salt formation method using homochiral erythro-2-
amino-1,2-diphenylethanol (ADPE) as a resolving agent. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
In recent years, it has become more and more difficult to obtain many kinds of animal perfumes
because of the reduction in the world’s resources and the conservation movement with regard to wild
animals.1 Ambergris, a metabolite of the sperm whale, is one of the most valuable animal perfumes,
taking rank with civet and musk.1,2 The major constituent of ambergris is a triterpene alcohol ambrein 1
with an amber-like odor. During drifting in the sea for many years, 1 is oxidatively decomposed by the
action of seawater, air, and sunlight to give some odorous compounds (Scheme 1).2,3 In these compounds,
Ambrox® 2 in particular has a very strong amber-like odor and it is reported that the odor of (−)-2 is
much stronger than that of (+)-2.1,3 Although considerable effort has been paid to the total asymmetric
syntheses of 2 for a long time, some reports have been known to prepare enantiomerically pure 2.3–7 In
two of them,5,6 resolution was applied in key steps to obtain enantiomerically pure intermediates.
Based on our previous work,8 a diastereomeric salt formation method seems effective for the resolution
of sclareolide 3, one of the key intermediates of Ambrox®, and is economical when the resolving agents
are recovered. In this paper, we report the resolution of 3 using various homochiral amines as resolving
agents. Synthesis of enantiomerically pure 2 is demonstrated by the use of resolved 3 (Scheme 2).
∗
Corresponding author. Fax: +81-48-858-9534; e-mail: nohira@apc.saitama-u.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00404-2

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T. Koga et al. / Tetrahedron: Asymmetry 9 (1998) 3819–3823
Scheme 1. Decomposition of ambrein (1)
Scheme 2. Leading to Ambrox® (2*) from sclareolide (3*)
2. Results and discussion
The racemic sclareolide 3 was prepared from β-ionone in 3 steps (17% overall yield) with a slight
modification of the method reported by Oritani et al.2,4,6 The racemate, (ꢀ)-3, was hydrolyzed with
sodium hydroxide in methanol to give a hydroxy acid sodium salt 4. Treatment of 4 with various
homochiral amines as resolving agents gave diastereomeric salts 5. A diastereomerically pure salt
was afforded by recrystallization of 5 from various solvents. Enantiomerically pure 3 was obtained by
liberation of recrystallized 5* with sodium hydroxide, and by following lactonization with hydrochloric
acid (Scheme 3). The enantiomeric purity of resolved 3* was determined using HPLC equipped with a
chiral column (Daicel Chiralpak AD).
Scheme 3. Preparation of enantiomerically pure sclareolide (3*)
Seven homochiral amines, α-methylbenzylamine (MBA) 6, cis-2-(benzylamino)-cyclohexane-
methanol (cis-amine) 7, 1-(1-naphthyl)ethylamine (NEA) 8, 1-phenyl-2-(p-tolyl)ethylamine (PTE) 9,

T. Koga et al. / Tetrahedron: Asymmetry 9 (1998) 3819–3823
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Table 1
Resolution of (ꢀ)-3 by a diastereomeric salt formation method
1-(p-tolyl)ethylamine (TEA) 10, 2-amino-1-butanol (2AB) 11, and erythro-2-amino-1,2-diphenylethanol
(ADPE) 12, were examined as resolving agents. The results of resolution of (ꢀ)-3 are summarized in
Table 1. Among those various amines, ADPE was found to be the most efficient resolving agent to give
the enantiomerically pure 3 (>99% ee) after a single recrystallization of the less soluble diastereomeric
salt 5, while MBA and cis-amine were ineffective in this case. (−)-Ambrox®; m.p. 75.0–76.5°C (lit.9
m.p. 77.0–77.5°C), [α]D −25.0 (c 1.0 CHCl3) {lit.9 [α]D −24.7 (in CHCl3)} was prepared from
enatiomerically pure (+)-3 without racemization. Thus, a practical synthetic route of enatiomerically
pure (−)-2 was established.
In summary, the resolution of sclareolide 3 was efficiently achieved by the diastereomeric salt
formation method using homochiral ADPE as the resolving agent, and highly pure (+)- and (−)-3 were
obtained as the key intermediates of both enantiomers of Ambrox®.

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T. Koga et al. / Tetrahedron: Asymmetry 9 (1998) 3819–3823
3. Experimental
3.1. General
All melting point (m.p.) values were uncorrected. Specific rotations were measured with a JASCO
DIP-370 polarimeter.
3.2. (ꢀ)-Sclareolide [(3aR*,5aS*,9aS*,9bR*)-1,2,3a,4,5,5a,6,7,8,9,9a,9b-dodecahydro-3a,6,6,9a-
tetramethylnaphtho[2,1-b]furan-2-one] (ꢀ)-3
The preparation of (ꢀ)-3 was based on the method reported by Oritani et al.6
Dihydro-β-ionone: to β-ionone (203 mg, 1.06 mmol) was added a solution of Raney nickel (W-2 type)
(780 mg) in EtOH (5 ml). After stirring for 2 days at 75°C, the mixture was filtered with Celite and the
filtrate was concentrated to give the product (195 mg, 0.95 mmol, 90% yield).
β-Monocyclofarnesyl acid: to a suspension of carboxyethyl triphenyl phosphonium chloride (22.7 g,
61.1 mmol) in THF (200 ml) was added n-BuLi (74 ml of 1.66 M hexane soln, 122.8 mmol) at −78°C.
The mixture was stirred for 1.5 h, warmed to room temperature for a few minutes, and again cooled to
−78°C. To the solution was added, dropwise, a solution of dihydro-β-ionone (6.0 g, 30.7 mmol) in THF
(5 ml). The mixture was then stirred for 6.5 h at this temperature, then for a further 3 h at −45°C, before
being allowed to warm to room temperature gradually. The next day, after adding 1 N HCl aq. (90 ml), the
mixture was extracted with AcOEt (100 ml×3). The combined organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by column chromatography (silica gel,
hexane:AcOEt=12:1–2:3) to give β-monocyclofarnesyl acid, 4-methyl-6-(20,60,60-trimethylcyclohex-10 -
enyl)-3-hexanoic acid (4.0 g, 15.4 mmol, 50% yield).
(ꢀ)-Sclareolide (ꢀ)-3: to a solution of chlorosulfuric acid (0.53 ml, 8.0 mmol) in 2-nitropropane (8 ml)
was added a solution of the β-monocyclofarnesyl acid (501 mg, 2.0 mmol) in 2-nitropropane (8 ml) at
−78°C. After stirring for 45 min, sat. aq. NaHCO3 (10 ml) was added and the mixture was extracted with
Et2O (10 ml×3). The combined organic layer was dried over MgSO4 and concentrated under reduced
pressure. After purification by column chromatography (silica gel, hexane:AcOEt=5:1), recrystallization
from hexane gave (ꢀ)-3 (198 mg, 0.79 mmol, 40% yield) in 17% overall yield.
3.3. (+)-Sclareolide [(3aR,5aS,9aS,9bR)-(+)-1,2,3a,4,5,5a,6,7,8,9,9a,9b-dodecahydro-3a,6,6,9a-tetra-
methylnaphtho[2,1-b]furan-2-one] (+)-3
The optimum procedure using (+)-ADPE is described as follows. To a solution of (ꢀ)-3 (470 mg, 1.88
mmol) in methanol (3 ml) at 60°C, was added a solution of NaOH (306 mg, 7.65 mmol) in methanol (10
ml). The mixture was stirred for 2 h at the same temperature, and then 2 N HCl aq. was added until pH 7–8
at room temperature was reached. A solution of (+)-ADPE (403 mg, 1.89 mmol) in methanol (6 ml) was
added to the mixture, then 2 N HCl aq. was added until pH 6–7 was reached. After stirring for 40 min, the
mixture became muddy, while the mixtures with other amines remained clear. Following the replacement
of solvent from the mixture of water and methanol to ethanol, most of the precipitated sodium chloride
was filtered off, and then the diastereomeric salt 5 was obtained as a white powder. The diastereomeric
salt 5 (897 mg; containing a small quantity of sodium chloride) was recrystallized from the mixture of
ethanol (6 ml) and methanol (4 ml) to give the less soluble salt (175 mg, 0.36 mmol) as colorless prisms;
m.p. 176.0–177.0°C, [α]D +66.7 (c 1.0 MeOH). The less soluble salt was then decomposed by 1 M aq.
sodium hydroxide solution (2 ml) and the resolving agent (+)-ADPE was extracted with diethyl ether.

T. Koga et al. / Tetrahedron: Asymmetry 9 (1998) 3819–3823
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The remaining hydroxy acid sodium salt 5 was transformed to the lactone by addition of 2 N HCl aq. (2
ml), and following stirring for 4 h at 60°C. After sodium chloride was separated in the same manner as
described earlier, the residual solid was purified by preparative TLC (hexane:AcOEt=4:1) to give (+)-3
(45 mg, 0.18 mmol), which was recrystallized from hexane to yield colorless plates; m.p. 121.0–124.0°C,
[α]D +47.3 (c 1.0 MeOH). By HPLC analysis {column, Daicel Chiralpak AD (250×4.6 mm ID); eluent,
3% 2-propanol in hexane; flow rate, 0.4 ml/min; detection, 220 nm UV; retention time, (+)-3, 31 min,
(−)-3, 37 min}, the enantiomeric purity of (+)-3 was over 99% ee.
3.4. (−)-Ambrox® [(3aR,5aS,9aS,9bR)-(−)-1,2,3a,4,5,5a,6,7,8,9,9a,9b-dodecahydro-3a,6,6,9a-tetra-
methylnaphtho[2,1-b]furan] (−)-2
(−)-2 was prepared according to the literature2,4,6 as follows. To a suspension of LiAlH4 (78 mg, 2.06
mmol) in THF (4 ml) was added a solution of enantiomerically pure (+)-3 (500 mg, 2.00 mmol) in THF
(2 ml) at 0°C. After stirring for 4 h at room temperature, the reaction was quenched by adding satd
aq. Na2SO4 and the organic layer was concentrated. The residue was recrystallized from AcOEt to give
the corresponding (−)-diol (see Scheme 2) as colorless needles (379 mg, 1.50 mmol, 75% yield); m.p.
132.0–133.5°C, [α]D −16.8 (c 1.0 CHCl3).3 Its enatiomeric purity of more than 99% ee was determined
by HPLC analysis using its mono-(R)-MTPA (α-methoxy-α-(trifluoromethyl)phenylacetic acid) ester of
the primary hydroxyl group {column, Daicel Chiralcel OD-H (250×4.6 mm ID); eluent, 5% 2-propanol
in hexane; flow rate, 0.5 ml/min; detection, 254 nm UV; retention time, (−)-isomer, 18 min, (+)-isomer,
20 min}. The (−)-diol (255 mg, 1.00 mmol) was cyclized by p-toluenesulfonyl chloride (384 mg, 2.01
mmol) in pyridine (15 ml) at 0°C. After stirring for 14 h at room temperature, water (30 ml) was added
and the mixture was extracted with Et2O (30 ml×3). The combined organic layer was washed with
satd aq. NaHCO3 and brine, dried over MgSO4, and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel (hexane:AcOEt=20:1) and recrystallized from
EtOH·H2O to yield colorless plates (174 mg, 0.75 mmol, 75% yield); m.p. 75.0–76.5°C, [α]D −25.0
(c 1.0 CHCl3) (56% overall yield).
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