Synthesis of decalin type chiral synthons based on enzymatic functionalisation and their application to the synthesis of (-)-ambrox and (+)-zonarol

Article abstract of DOI:10.1016/S0957-4166(98)00172-4

Stereoselective syntheses of (-)-ambrox 2 and (+)-zonarol 3 were achieved based on the enzymatic syntheses of (8aS)- and (8aR)-decalin-type 1,3-diols 1, respectively. Non-racemic intermediates such as (8aS)-1 and (8aR)-1 were obtained based on the enantioselective hydrolyses of the phenolic acetal derivative (±)-7 by acylase I.

Full text of DOI:10.1016/S0957-4166(98)00172-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1789–1799
Synthesis of decalin type chiral synthons based on enzymatic
functionalisation and their application to the synthesis of
(−)-ambrox and (+)-zonarol
Hiroyuki Akita,∗ Masako Nozawa and Hiroyo Shimizu
School of Pharmaceutical Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 30 March 1998; accepted 27 April 1998
Abstract
Stereoselective syntheses of (−)-ambrox 2 and (+)-zonarol 3 were achieved based on the enzymatic syntheses
of (8aS)- and (8aR)-decalin-type 1,3-diols 1, respectively. Non-racemic intermediates such as (8aS)-1 and (8aR)-1
were obtained based on the enantioselective hydrolyses of the phenolic acetal derivative (ꢀ)-7 by acylase I. © 1998
Elsevier Science Ltd. All rights reserved.
1. Introduction
In the field of the synthesis of optically and biologically active drimane sesquiterpenes and their
related compounds, the use of the optically active and functionalized decalin derivatives is known to be
advantageous.1 The optically active 1,3-diols (8aS)-1 and (8aR)-1 seem to be important chiral synthons
for the synthesis of ambergris-fragrance (−)-ambrox 22 and fungitoxic hydroquinone (+)-zonarol 3,3
respectively.
Enantioselective and regioselective acetylation of (ꢀ)-1 with the lipase ‘Godo E-4’ from Pseudomonas
sp. in the presence of isopropenyl acetate was reported to give four kinds of optically active compounds
(8aS)-4, (8aS)-5, (8aS)-6 and (8aR)-1 because (ꢀ)-1 has two reaction sites for acetylation.4 This problem
could be overcome by converting two reaction sites to one reaction site in the substrate. This synthetic
strategy could be realised by the formation of a phenolic acetal (ꢀ)-7 which corresponds to the masked
1,3-diol structure. The newly introduced bulky naphthyl group in the substrate (ꢀ)-7 is situated with the
thermodynamically stable equatorial conformation shown in Scheme 1. We now report the stereoselective
synthesis of the phenolic acetal (ꢀ)-7 (Scheme 2) followed by chiral induction using an enzyme and
∗
Corresponding author. E-mail: akita@phar.toho-u.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00172-4

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asymmetric synthesis of (−)-2 and (+)-3 from the enzymatic reaction products, (8aS)-1 and (8aR)-1,
respectively.
Scheme 1.
Scheme 2.
2. Results and discussion
The reaction of (ꢀ)-1 and 2-hydroxy-1-naphthaldehyde gave the phenolic acetal (ꢀ)-(7) as a single
diastereomer in quantitative yield whose acetylation afforded the corresponding acetate (ꢀ)-8 in 99%
yield (Scheme 2). The stereochemistry of (ꢀ)-7 was confirmed by difference nuclear Overhauser effect
(NOE) spectra. The observation of NOE enhancement for the newly generated methine proton C3-axial
proton/C4a-axial proton (13.4%) and C3-axial proton/C1-axial proton (6.5%) as shown in Scheme 1
indicated that the newly introduced naphthyl group is located in the equatorial position. From a screening
experiment using various kinds of lipase and acylase, a commerically available acylase I (No. A-2156)
from Aspergillus melleus was found to be effective. When the phenolic acetate (ꢀ)-8 was exposed to the
acylase I in water-saturated diisopropyl ether, hydrolyzed product (+)-7 (47%, 80% ee) and unchanged
(+)-8 (40%, 92% ee) were obtained. An enantiomeric excess of both materials was improved to give

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 1789–1799
1791
enantiomerically pure (+)-7; [α]D +10.3 (c=1.10, CH2Cl2) and (+)-8; [α]D +9.0 (c=1.15, CHCl3) by
recrystallization. The enantiomeric purity of the enzymatic reaction products was determined by HPLC
on a Chiralcel AD column (250 mm×4.6 mm). In order to confirm the absolute configurations of (+)-8,
it was subjected to a catalytic hydrogenation to provide the (−)-1,3-diol 1 ([α]D −2.8 (c=1.61, MeOH)),
whose sign of [α]D was the same as that ([α]D −2.26 (c=1.06, MeOH)) of the known (−)-(8aS)-1,3-diol
(1) previously reported.4 The phenol (+)-7 was also converted into the (+)-1,3-diol 1 ([α]D +2.8 (c=1.04,
MeOH)). Consequently, absolute configurations at the C10a-position of (+)-8 and (+)-7 were determined
to be S and R, respectively.
Treatment of (8aS)-1 with benzaldehyde in the presence of a catalytic amount of conc. H2SO4 afforded
acetal 9 exclusively in 98% yield, which was reduced with a mixed reducing reagent [LiAlH4 (1
equiv.)–AlCl3 (4 equiv.)]5 to provide selectively primary alcohol 10 (93% yield) along with a small
amount of secondary alcohol 11 (5% yield) (Scheme 3). The structure of both alcohols was confirmed by
derivation to the corresponding acetates 12 and 13, respectively. Conversion of 10 by treatment with CBr4
and Ph3P into the bromide 14 (98% yield) followed by catalytic reduction gave the 1,3-bromohydrin 15
(99% yield). Treatment of 15 with NaCN provided nitrile 16 (97% yield), which was oxidized with Jones
reagent to afford keto-nitrile 17 (96% yield).6 Hydrolysis of 17 gave the β-keto-acid 18 (89% yield),
which was reacted with MeLi followed by treatment with p-TsOH to provide the δ-lactone 19 (65%
yield). Reduction of 19 yielded the diol 20 (76% yield) which was reacted with p-TsOH in MeNO2
to provide the (−)-ambrox 2 (45% yield, mp 75–76°C, [α]D −22.3 (c=1.30, CHCl3)) whose spectral
1
data (mp, [α]D, H NMR and 13C NMR) were identical to those (mp 75–76°C,2n [α]D −22.1 (c=0.68,
CHCl3),2i 1H NMR2i and 13C NMR2i) reported for (−)-2.2i
Scheme 3.
A formal total synthesis of (+)-zonarol 3 from (8aR)-1 was then carried out. The (8aR)-1 was converted
into the 1,3-bromohydrin (8aR)-15 in 79% overall yield in the same way as in the conversion of (8aS)-
1 to (8aS)-15. Oxidation of (8aR)-15 gave the bromo-ketone 21 (97% yield) which was treated with

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1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the desired α,β-unsaturated ketone 22 (86% yield).
Michael addition of 22 with the 2,5-dimethoxyphenyl Grignard reagent in the presence of CuI followed
by treatment with Ac2O provided an enol acetate 23 (82% yield), which was hydrolyzed to the ketone 24
(95% yield, [α]D +56.3 (c=1.37, CHCl3)). Wittig reaction of 24 with phosphonium salt in the presence of
n-BuLi afforded the exo-olefin 25 (73% yield, [α]D +27.9 (c=1.06, CHCl3)) whose spectral data ([α]D,
NMR) were identical with those ([α]D +28.9 (c=0.89, CHCl3),3c NMR3c) of the reported olefin (+)-25.3c
The total synthesis of (+)-zonarol 3 from (8aR)-25 has been already achieved by Mori (Scheme 4).3c
Scheme 4.
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-3S micro melting point apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded on a JEOL EX 400 spectrometer in CDCl3. Carbon
substitution degrees were established by DEPT pulse sequence. The fast atom bombardment mass spectra
(FAB MS) were obtained using a JEOL JMS-DX 303 spectrometer. IR spectra were recorded on a JASCO
FT/IR-300 spectrometer. The HPLC system was composed of two SSC instruments (ultraviolet (UV)
detector 3000B and flow system 3100). Optical rotations were measured with a JASCO DIP-370 digital
polarimeter. All evaporations were performed under reduced pressure. For column chromatography, silica
gel (Kieselgel 60) was employed.
3.2. 1-[(3S*,4aR*,6aS*,10aS*,10bS*)-Decahydro-7,7,10a-trimethyl-1H-naphtho-[2,1-d][1,3]-dioxin-
3-yl]-2-naphthol (ꢀ)-7
A small amount of conc. H2SO4 (2 ml) was added to a solution of (ꢀ)-14 (513 mg, 2.27 mmol),
2-hydroxy-1-naphthaldehyde (428 mg, 2.48 mmol) in DMSO (20 ml) at 0°C, and the whole mixture
was stirred at rt for 1 h, and then diluted with saturated brine and extracted with ether. The organic
layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel (25 g, n-
hexane:AcOEt=10:1) to give (ꢀ)-7 as crystals. Recrystallization from n-hexane:CHCl3 gave (ꢀ)-7 (863

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 1789–1799
1793
mg, 99%) as colorless plates. (ꢀ)-7: Mp 229°C; IR (KBr): 3274 cm−1 (OH); 1H NMR: δ 0.86 (3H, s),
0.91 (3H, s), 0.99 (3H, s), 1.04–1.66 (10H, m), 1.76–1.82 (1H, m), 2.14–2.20 (1H, m), 3.94 (1H, t, J=11
Hz), 4.02 (1H, dt, J=5, 11 Hz), 4.32 (1H, dd, J=4, 11 Hz), 6.33 (1H, s), 7.10 (1H, d, J=9 Hz), 7.30 (1H,
dt, J=1, 8 Hz), 7.45 (1H, dt, J=1, 8 Hz), 7.70 (1H, d, J=9 Hz), 7.71 (1H, d, J=8 Hz), 7.76 (1H, d, J=8
Hz), 9.19 (1H, s). 13C NMR: δ 15.0 (q), 18.2 (t), 20.3 (t), 21.7 (q), 32.8 (t), 33.1 (s), 33.4 (q), 36.3 (s),
38.3 (t), 41.8 (t), 52.2 (d), 54.6 (d), 67.8 (t), 77.8 (d), 101.0 (d), 111.6 (s), 119.7 (d), 121.4 (d), 122.9
(d), 126.8 (d), 128.6 (d), 128.6 (s), 131.1 (d), 131.8 (s), 154.6 (s). Anal. found: C, 79.07; H, 8.37. Calcd.
for C25H32O3: C, 78.91; H, 8.48%. FAB MS m/z: 381 (M++1). The racemate (ꢀ)-7 was analyzed to
provide well separated peaks (16 and 18 min) of each enantiomer using a Chiralcel AD column under
the following analytical conditions (eluent, n-hexane:EtOH=50:1); detection, UV at 254 nm; flow rate,
1.0 ml/min).
3.3. 2-Acetoxy-1-[(3S*,4aR*,6aS*,10aS*,10bS*)-decahydro-7,7,10a-trimethyl-1H-naphtho-[2,1-d]-
[1,3]-dioxin-3-yl]-2-naphthalene (ꢀ)-8
A mixture of (ꢀ)-7 (665 mg, 1.75 mmol), Ac2O (814 mg, 7.98 mmol), p-dimethylaminopyridine
(DMAP, 33 mg, 0.27 mmol) in pyridine (15 ml) was stirred at rt for 1 h, and then diluted with
saturated brine and extracted with ether. The organic layer was washed with 2 M aqueous HCl, saturated
aqueous NaHCO3, saturated brine and dried over MgSO4. The organic layer was evaporated and
chromatographed on silica gel (25 g, n-hexane:AcOEt=20:1) to afford crystals which were recrystallized
from n-hexane:AcOEt to provide (ꢀ)-8 (738 mg, 99%) as colorless needles. (ꢀ)-8: Mp 139°C; IR (KBr):
1759 cm−1 (OAc); 1H NMR: δ 0.85 (3H, s), 0.92 (3H, s), 0.99 (3H, s), 1.11–1.82 (11H, m), 2.08–2.16
(1H, m), 2.39 (3H, s), 3.80 (1H, t, J=11 Hz), 3.88 (1H, dt, J=5, 11 Hz), 4.28 (1H, dd, J=4, 11 Hz), 6.10
(1H, s), 7.13 (1H, d, J=9 Hz), 7.42 (1H, dt, J=1, 8 Hz), 7.50 (1H, dt, J=1, 8 Hz), 7.76 (1H, dd, J=1, 8 Hz),
7.79 (1H, d, J=8 Hz), 8.75 (1H, dd, J=1, 9 Hz). 13C NMR: δ 15.1 (q), 18.3 (t), 20.4 (t), 21.1 (q), 21.7 (q),
32.9 (t), 33.2 (s), 33.5 (q), 36.3 (s), 38.4 (t), 41.9 (t), 52.4 (d), 54.8 (d), 68.1 (t), 77.7 (d), 97.9 (d), 121.3
(d), 123.8 (s), 125.5 (d), 126.4 (d), 126.7 (d), 128.1 (d), 130.8 (d), 131.5 (s), 132.5 (s), 146.3 (s), 169.3 (s).
FAB MS m/z: 423 (M++1). Anal. found: C, 76.36; H, 8.23. Calcd. for C27H34O4: C, 76.07; H, 8.35%.
The racemate (ꢀ)-8 was analyzed to provide well separated peaks (8 and 13 min) of each enantiomer
using a Chiralcel AD column under the following analytical conditions (eluent, n-hexane:EtOH=10:1);
detection, UV at 254 nm; flow rate, 1.0 ml/min).
3.4. Enantioselective hydrolysis of (ꢀ)-8
A suspension of (ꢀ)-8 (ca. 100 mg) and acylase I (ca. 100 mg) in water-saturated diisopropyl ether
(20 ml) was incubated at 33°C for 2 days. This reaction was carried out seventeen times (total amount of
(ꢀ)-8 was 1.748 g, 4.14 mmol). After the reaction mixture was filtered, the precipitate was washed with
diisopropyl ether. The combined organic layer was dried over MgSO4 and evaporated. The residue was
chromatographed on silica gel (50 g) to give phenol (+)-(10aR)-7 (740 mg, 47%, 80% ee) from n-hexane:-
AcOEt (20:1) eluate and acetate (+)-(10aS)-8 (699 mg, 40%, 92% ee) from n-hexane:AcOEt (10:1)
eluate, respectively. Both fractions were recrystalized from n-hexane:AcOEt to give enantiomerically
pure (+)-(10aR)-7 as colorless needles and enantiomerically pure (+)-(10aS)-8 as colorless plates. (+)-
27
29
(10aR)-7: Mp 232–233°C; [α]D +10.3 (c=1.1, CH2Cl2). (+)-(10aS)-8: Mp 142–142.5°C; [α]D +9.0
(c=1.15, CHCl3). The retention times of (+)-(10aR)-7 and (+)-(10aS)-8 were 18 and 8 min by means of
HPLC analysis, respectively.

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3.5. (−)-(1S,2R,4aS,8aS)-2-Hydroxy-decahydro-5,5,8a-trimethyl-1-naphthylmethanol (−)-(8aS)-1
A mixture of (+)-(10aS)-8 (1.835 g, 4.34 mmol) and 20% Pd(OH)2–C (900 mg) in MeOH (20 ml)
was subjected to catalytic hydrogenation at ambient temperature and the reaction mixture was filtered
with the aid of Celite. The filtrate was evaporated to give a crude product, which was chromatographed
on silica gel (30 g, n-hexane:AcOEt=1:1) to provide (8aS)-1 (947 mg, 96%). Recrystallization from n-
27
hexane gave (8aS)-1 as colorless plates. (−)-(8aS)-1: Mp 84.5–85°C; [α]D −2.8 (c=1.61, MeOH). The
spectral data of (−)-(8aS)-1 were identical to those of the reported (−)-(8aS)-1.4
3.6. (+)-(1R,2S,4aR,8aR)-2-Hydroxy-decahydro-5,5,8a-trimethyl-1-naphthylmethanol (+)-(8aR)-1
A mixture of (+)-(10aR)-7 (983 mg, 2.58 mmol) and 20% Pd(OH)2–C (980 mg) in AcOEt (10 ml) was
subjected to catalytic hydrogenation at ambient temperature. The reaction mixture was worked up in the
same way as for the preparation of (−)-(8aS)-1 and gave (+)-(8aR)-1 (541 mg, 92%) as colorless plates.
21
(+)-(8aR)-1: Mp 86.5°C; [α]D +2.8 (c=1.04, MeOH). The spectral data of (+)-(8aR)-1 were identical
to those of the reported (−)-(8aS)-1.4
3.7. (−)-[(3S,4aR,6aS,10aS,10bS)-Decahydro-7,7,10a-trimethyl-1H-naphtho-[2,1-d][1,3]-dioxin-
3-yl]-benzene (−)-9
A small amount of conc. H2SO4 (15 drops) was added to a solution of (−)-(8aS)-1 (338 mg, 1.5 mmol),
benzaldehyde (462 mg, 4.36 mmol) in DMSO (3 ml) at 0°C and the whole mixture was stirred at rt for
30 min, and then diluted with H2O and extracted with ether. The organic layer was washed with saturated
brine and dried over MgSO4. The organic layer was evaporated to give a residue. To a solution of the
residue in a mixed solvent [H2O (1 ml)–DMSO (1 ml)] was added NaHSO3 (548 mg, 5.27 mmol) at rt
and the whole mixture was stirred at rt for 12 h. The reaction mixture was diluted with H2O and extracted
with ether. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed
on silica gel (15 g, n-hexane:AcOEt=20:1) to afford (−)-(10aS)-9 as crystals. Recrystallization from n-
23
hexane gave (−)-(10aS)-9 (463 mg, 98%) as colorless needles. (−)-(10aS)-9: Mp 98.5–99°C; [α]D
−9.5 (c=1.12, CHCl3); IR (KBr): 1041 cm−1; H NMR: δ 0.85 (3H, s), 0.89 (3H, s), 0.94 (3H, s),
1
1.01–1.62 (10H, m), 1.73–1.79 (1H, m), 2.09–2.14 (1H, m), 3.78 (1H, t, J=11 Hz), 3.85 (1H, dt, J=5,
11 Hz), 4.21 (1H, dd, J=4, 11 Hz), 5.46 (1H, s), 7.28–7.34 (3H, m), 7.46–7.49 (2H, m). Anal. found: C,
80.58; H, 9.39. Calcd. for C21H30O2: C, 80.21; H, 9.62%. FAB MS m/z: 315 (M++1).
3.8. (−)-(1S,2R,4aS,8aS)-2-Benzyloxy-decahydro-5,5,8a-trimethyl-1-naphthylmethanol (−)-(8aS)-10
and (+)-(1R,2R,4aS,8aS)-1-benzyloxy-2-hydroxy-decahydro-5,5,8a-trimethylnaphthalene (+)-(8aS)-11
To a solution of (−)-(10aS)-9 (359 mg, 1.14 mmol) in Et2O (10 ml) at −20°C was added LiAlH4 (51
mg, 1.35 mmol) and the whole mixture was stirred for 10 min. AlCl3 (734 mg, 5.52 mmol) was added
to the above mixture which was then stirred at −20°C for 30 min. The reaction mixture was diluted
with H2O, acidified with 2 M aqueous HCl and extracted with ether. The organic layer was washed
with saturated brine and dried over MgSO4. Evaporation of the organic solvent gave a residue which
was chromatographed on silica gel (15 g, n-hexane:AcOEt=20:1) to give (−)-(8aS)-10 (336 mg, 93%) as
crystals and (+)-(8aS)-11 (18 mg, 5%) as a colorless oil, respectively. Recrystallization of the former from
23
n-hexane gave (−)-(8aS)-10 as colorless plates. (−)-(8aS)-10: Mp 110.5–111°C; [α]D −67.0 (c=1.08,
CHCl3); IR (KBr): 3479 cm−1 (OH); 1H NMR: δ 0.75 (3H, s), 0.79 (3H, s), 0.88 (3H, s), 0.90–1.58 (9H,

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 1789–1799
1795
m), 1.71–1.85 (2H, m), 2.30–2.36 (1H, m), 3.39 (1H, d, J=11 Hz, OH), 3.59 (1H, dd, J=8, 11 Hz), 3.64
(1H, dt, J=5, 11 Hz), 3.78 (1H, t, J=11 Hz), 4.44 (1H, d, J=11.5 Hz), 4.70 (1H, d, J=11.5 Hz), 7.26–7.37
(5H, m). Anal. found: C, 79.98; H, 10.04. Calcd. for C21H32O2: C, 79.70; H, 10.19%. FAB MS m/z: 317
(M++1). (+)-(8aS)-11: [α]D22 +32.5 (c=1.36, CHCl3); IR (KBr): 3480 cm−1 (OH); 1H NMR: δ 0.80 (3H,
s), 0.81 (3H, s), 0.88 (3H, s), 0.91–1.75 (11H, m), 2.05–2.12 (1H, m), 3.61 (1H, t, J=9 Hz), 3.82 (1H, dt,
J=5, 10.5 Hz), 3.85 (1H, dd, J=3, 9 Hz), 4.05 (1H, br s), 4.51 (2H, s), 7.26–7.36 (5H, m). Anal. found:
C, 79.73; H, 10.08. Calcd. for C21H32O2: C, 79.70; H, 10.19%. FAB MS m/z: 317 (M++1).
3.9. Acetylation of (−)-(8aS)-10
The primary hydroxyl group of (−)-(8aS)-10 (95 mg, 0.3 mmol) was acetylated with Ac2O (45 mg,
0.44 mmol) in pyridine (2 ml) in the usual manner to give (8aS)-12 (103 mg, 96%) as a colorless oil.
(8aS)-12: IR (KBr): 1738 cm−1 (OAc); 1H NMR: δ 0.82 (3H, s), 0.86 (3H, s), 0.88 (3H, s), 0.90–1.77
(11H, m), 1.95 (3H, s), 2.32–2.37 (1H, m), 3.42–3.50 (1H, m), 4.26 (1H, dd, J=4, 11 Hz), 4.30 (1H,
dd, J=3, 11 Hz), 4.38 (1H, d, J=12 Hz), 4.63 (1H, d, J=12 Hz), 7.22–7.35 (5H, m). FAB MS m/z: 359
(M++1).
3.10. Acetylation of (+)-(8aR)-11
The secondary hydroxyl group of (+)-(8aR)-11 (95 mg, 0.3 mmol) was acetylated with Ac2O (45 mg,
0.44 mmol), DMAP (12 mg, 0.1 mmol) in pyridine (2 ml) in the usual manner to give (8aR)-13 (106 mg,
99%) as a colorless oil. (8aR)-13: IR (neat): 1736 cm−1 (OAc); 1H NMR: δ 0.81 (3H, s), 0.87 (3H, s),
0.91 (3H, s), 0.92–1.83 (11H, m), 2.09–2.15 (1H, m), 1.91 (3H, s), 3.39 (1H, dd, J=3.5, 10 Hz), 3.52 (1H,
dd, J=4, 10 Hz), 4.38 (1H, d, J=11 Hz), 4.42 (1H, d, J=11 Hz), 4.95 (1H, dt, J=5.5, 11 Hz), 7.23–7.34
(5H, m). Anal. found: C, 77.32; H, 9.09. Calcd. for C23H34O3: C, 77.05; H, 9.56%. FAB MS m/z: 359
(M++1).
3.11. (−)-(1R,2S,4aS,8aS)-2-Benzyloxy-1-bromomethyl-decahydro-5,5,8a-trimethylnaphthalene
(−)-(8aS)-14
To a solution of (−)-(8aS)-10 (316 mg, 1 mmol) in THF (5 ml) at 0°C was added CBr4 (657 mg,
1.98 mmol) and Ph3P (521 mg, 1.99 mmol) and the whole mixture was stirred at rt for 15 min. The
reaction mixture was diluted with H2O and extracted with ether. The organic layer was washed with
saturated brine and dried over MgSO4. Evaporation of the organic solvent gave a residue which was
chromatographed on silica gel (10 g, n-hexane:AcOEt=50:1) to give (−)-(8aS)-14 (370 mg, 98%) as
crystals. Recrystallization from n-hexane afforded (−)-(8aS)-14 as colorless needles. (−)-(8aS)-14: Mp
67.5–68°C; [α]D −45.7 (c=1.16, CHCl3); IR (neat): 1071 cm−1; 1H NMR: δ 0.82 (3H, s), 0.87 (3H, s),
21
0.94 (3H, s), 0.87–1.61 (10H, m), 1.66–1.74 (1H, m), 1.80–1.86 (1H, m), 2.01–2.05 (1H, m), 2.43–2.48
(1H, m), 3.42–3.50 (1H, m), 3.56 (1H, dd, J=2.5, 10.5 Hz), 3.66 (1H, dd, J=4, 10.5 Hz), 7.24–7.43
(5H, m). Anal. found: C, 66.85; H, 7.73. Calcd. for C21H31OBr: C, 66.49; H, 8.24%. FAB MS m/z: 379
(M++1).

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3.12. (−)-(1R,2R,4aS,8aS)-1-Bromomethyl-2-hydroxy-decahydro-5,5,8a-trimethylnaphthalene
(−)-(8aS)-15
A mixture of (−)-(8aS)-14 (1.123 g, 2.96 mmol) and 20% Pd(OH)2–C (1 g) in AcOEt (10 ml) was
subjected to catalytic hydrogenation at ambient temperature and the reaction mixture was worked up
in the same way as (8aS)-1 to give a residue which was chromatographed on silica gel (20 g, n-
24
hexane:AcOEt=20:1) to provide (−)-(8aS)-15 (855 mg, 99%) as a colorless oil. (−)-(8aS)-15: [α]D
−16.3 (c=1.36, CHCl3); IR (neat): 3351 cm−1 (OH); 1H NMR: δ 0.81 (3H, s), 0.87 (3H, s), 0.89 (3H, s),
1.08–1.61 (8H, m), 1.67–1.71 (2H, m), 1.79–1.84 (1H, m), 2.11–2.17 (1H, m), 3.58 (1H, dd, J=3.5, 11
Hz), 3.63 (1H, dd, J=4, 11 Hz), 3.68 (1H, ddd, J=5, 11, 11 Hz). Anal. found: C, 58.77; H, 8.44. Calcd.
for C14H25OBr: C, 58.13; H, 8.71%. FAB MS m/z: 271 (M++1–H2O).
3.13. (−)-(1R,2R,4aS,8aS)-2-Hydroxy-decahydro-5,5,8a-trimethyl-1-naphthaleneacetonitrile
(−)-(8aS)-16
To a solution of (−)-(8aS)-15 (199 mg, 0.68 mmol) in DMSO (2 ml) was added NaCN (51 mg,
1.04 mmol) and the mixture was stirred at 40°C for 12 h. The reaction mixture was diluted with H2O
and extracted with ether. The organic layer was washed with saturated brine and dried over MgSO4.
Evaporation of the organic layer gave a residue which was chromatographed on silica gel (10 g, n-
hexane:AcOEt=5:1) to yield (−)-(8aS)-16 (156 mg, 97%) as crystals. Recrystallization from n-hexane
22
afforded (−)-(8aS)-16 as colorless plates. (−)-(8aS)-16: Mp 59°C; [α]D −17.6 (c=1.50, CHCl3); IR
(neat): 3433 cm−1 (OH), 2245 cm−1 (CN); 1H NMR: δ 0.82 (3H, s), 0.88 (3H, s), 0.89 (3H, s), 0.90–1.75
(11H, m), 2.13–2.18 (1H, m), 2.48 (2H, d, J=5 Hz), 3.57–3.66 (1H, m). Anal. found: C, 76.82; H, 10.79;
N, 5.64. Calcd. for C15H25NO: C, 76.55; H, 10.71; N, 5.95%. FAB MS m/z: 236 (M++1).
3.14. (−)-(1R,4aS,8aS)-2-Oxo-decahydro-5,5,8a-trimethyl-1-naphthaleneacetonitrile (−)-(8aS)-17
A mixture of (−)-(8aS)-16 (172 mg, 0.73 mmol) in acetone (5 ml) at 0°C was oxidized with Jones
reagent (20 drops) in the usual manner to give (−)-(8aS)-17 (165 mg, 96%) as a colorless oil. (−)-(8aS)-
23
1
17: [α]D −43.4 (c=1.11, CHCl3). The spectral data (IR and H NMR) were identical to those of the
reported (−)-(8aS)-17.4
3.15. (−)-(1R,4aS,8aS)-2-Oxo-decahydro-5,5,8a-trimethyl-1-naphthaleneacetic acid (−)-(8aS)-18
A mixture of (−)-(8aS)-17 (165 mg, 0.708 mmol), 6 M aqueous NaOH (2 ml) in MeOH (2 ml) was
refluxed for 1 h. The reaction mixture was acidified with 2 M aqueous HCl and extracted with ether.
The organic layer was washed with saturated brine and dried over MgSO4. Removal of the solvent gave
a residue which was chromatographed on silica gel (10 g, n-hexane:AcOEt=1:1) to give (−)-(8aS)-18
(159 mg, 89%) as crystals. Recrystallization from n-hexane afforded (−)-(8aS)-18 as colorless needles.
22
(−)-(8aS)-18: Mp 124°C; [α]D −81.9 (c=1.30, CHCl3); IR (KBr): 1712 cm−1 (COOH); 1H NMR: δ
0.73 (3H, s), 0.86 (3H, s), 0.98 (3H, s), 1.21–1.72 (8H, m), 2.02–2.50 (4H, m), 2.70–2.78 (2H, m). Anal.
found: C, 71.17; H, 9.46. Calcd. for C15H24O3: C, 71.40; H, 9.59%. FAB MS m/z: 251 (M+−1).

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 1789–1799
1797
3.16. (−)-(3aS,5aS,9aS,9bR)-3a,4,5,5a,6,7,8,9,9a,9b-Decahydro-3a,6,6,9a-tetramethyl-naphtho-
[1,2-d]furan-2(1H)-one (−)-(9aS)-19
To a solution of (−)-(8aS)-18 (227 mg, 0.90 mmol) in a mixed solvent (Et2O (1 ml) and THF (2 ml))
at −70°C was added MeLi (1.4 M in Et2O, 1.3 ml, 1.82 mmol) and the whole mixture was stirred at
−70°C for 1 h and at 0°C for 30 min. The reaction mixture was diluted with saturated brine and acidified
with 2 M aqueous HCl, extracted with ether. The organic layer was dried over MgSO4 and evaporated.
A mixture of the residue and p-TsOH·H2O (150 mg, 0.87 mmol) in toluene (3 ml) was refluxed for
30 min. The reaction mixture was diluted with saturated brine and extracted with ether. The organic
layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel (10 g, n-
hexane:AcOEt=10:1) to yield (−)-(9aS)-19 (148 mg, 65%) as crystals. Recrystallization from n-hexane
24
afforded (−)-(9aS)-19 as colorless plates. (−)-(9aS)-19: Mp 106°C; [α]D −163.9 (c=0.213, CHCl3);
1
IR (KBr): 1767 cm−1 (γ-lactone); H NMR: δ 0.87 (3H, s), 0.90 (3H, s), 0.91 (3H, s), 0.85–1.65 (10H,
m), 1.32 (3H, s), 1.76 (1H, d, J=8 Hz), 2.31 (1H, ddd, J=3, 5, 15 Hz), 2.38 (1H, d, J=18 Hz), 2.72 (1H,
dd, J=8, 18 Hz). Anal. found: C, 76.82; H, 10.35. Calcd. for C16H26O2: C, 76.75; H, 10.47%. FAB MS
m/z: 251 (M++1).
3.17. (+)-(1R,2S,4aS,8aS)-2-Hydroxy-decahydro-2,5,5,8a-tetramethyl-1-naphthaleneethanol
(−)-(8aS)-20
A mixture of (9aS)-19 (148 mg, 0.593 mmol), LiAlH4 (57 mg, 1.49 mmol) in Et2O (3 ml) was stirred
at rt for 30 min. The reaction mixture was quenched with saturated brine and acidified with 2 M aqueous
HCl, extracted with ether. The organic layer was dried over MgSO4 and evaporated. The residue was
chromatographed on silica gel (10 g, n-hexane:AcOEt=1:1) to provide (−)-(8aS)-20 (114 mg, 76%) as
crystals. Recrystallization from AcOEt gave (−)-(8aS)-20 as colorless needles. (−)-(8aS)-20: Mp 186°C;
[α]D +15.1 (c=1.06, CHCl3); IR (KBr): 3338 cm−1 (OH); 1H NMR: δ 0.83 (6H, s), 0.87 (3H, s), 0.97
22
(3H, s), 1.14 (3H, s), 0.78–1.78 (14H, m), 3.54–3.69 (2H, m). 13C NMR: δ 15.1 (q), 18.1 (t), 18.3 (t),
21.7 (q), 28.7 (t), 30.7 (q), 33.3 (s), 33.4 (q), 38.5 (s), 39.3 (t), 42.0 (t), 42.3 (t), 54.7 (d), 55.9 (d), 64.9
(t), 72.9 (s). Anal. found: C, 75.57; H, 11.64. Calcd. for C16H30O2: C, 75.54; H, 11.89%.
3.18. (−)-Ambrox (−)-2
A mixture of (8aS)-20 (112 mg, 0.44 mmol) and p-TsOH·H2O (14.4 mg, 0.08 mmol) in MeNO2 (2
ml) was stirred at 40°C for 5 min. The reaction mixture was diluted with saturated brine and extracted
with ether. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed
on silica gel (10 g, n-hexane:AcOEt=50:1) to give (−)-2 (47 mg, 45%) as crystals. Recrystallization from
23
EtOH gave (−)-2 as colorless plates. (−)-2: Mp 75–76°C; [α]D −22.3 (c=1.30, CHCl3). FAB MS m/z:
221 (M+−Me, 20). 13C NMR: δ 15.1 (q), 18.4 (t), 20.7 (t), 21.2 (q), 21.2 (q), 22.7 (t), 33.1 (s), 33.6
(q), 36.2 (s), 39.8 (t), 40.0 (t), 42.4 (t), 57.3 (d), 60.1 (d), 65.0 (t), 79.9 (s). The spectral data (IR and 1H
NMR) were identical with those of the reported (−)-2.
3.19. (+)-(1S,2S,4aR,8aR)-1-Bromomethyl-2-hydroxy-decahydro-5,5,8a-trimethylnaphthalene
(+)-(8aR)-15
The bromohydrin (8aR)-15 was obtained in 79% overall yield from (8aR)-1 in the same way as for the
conversion of (8aS)-1 to (8aS)-15. (8aR)-15: [α]D22 +16.1 (c=1.34, CHCl3).

1798
H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 1789–1799
3.20. (+)-(1S,4aR,8aR)-1-Bromomethyl-2-oxo-decahydro-5,5,8a-trimethylnaphthalene (+)-(8aR)-21
A mixture of (+)-(8aR)-15 (465 mg, 1.61 mmol) in acetone (10 ml) at 0°C was oxidized with Jones
reagent (1 ml) in the usual manner to give (+)-(8aR)-21 (448 mg, 97%) as a colorless oil. (+)-(8aR)-21:
[α]D +16.8 (c=1.30, CHCl3); IR (neat): 1718 cm−1 (ketone); H NMR: δ 0.72 (3H, s), 0.84 (3H, s),
0.96 (3H, s), 1.23–1.78 (7H, m), 1.65 (1H, dq, J=5, 13 Hz), 2.08 (1H, ddt, J=2, 7, 13 Hz), 2.38 (1H, ddd,
J=1, 7, 13 Hz), 2.50 (1H, ddd, J=2, 5, 13 Hz), 2.74 (1H, dd, J=2.5, 9.5 Hz), 3.33 (1H, dd, J=2.5, 9.5 Hz),
3.73 (1H, t, J=9.5 Hz).
25
1
3.21. (−)-(4aR,8aR)-1-(2,5-Dimethoxyphenyl)methyl-2-acetoxy-3,4,4a,5,6,7,8,8a-octahydro-5,5,8a-
trimethylnaphthalene (−)-(8aR)-23
(i) A mixture of (+)-(8aR)-21 (428 mg, 1.49 mmol), DBU (455 mg, 3 mmol) in benzene (5 ml) was
stirred at rt for 30 min. The reaction mixture was diluted with saturated brine and extracted with ether.
The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel
(5 g, n-hexane:AcOEt=20:1) to give (8aR)-22 (263 mg, 86%) as a colorless oil. (ii) A mixture of Mg (154
mg, 6.33 mmol) and 2,5-dimethoxybromobenzene (1.399 g, 6.45 mmol) in THF (15 ml) was refluxed for
2 h under Argon. The generated Grignard reagent was added dropwise to CuI (364 mg, 1.91 mmol) at
0°C under Ar and the whole miture was stirred at 0°C for 10 min. A solution of (8aR)-22 (263 mg, 1.28
mmol) in THF (5 ml) was added stepwise to the above cuprate reagent at 0°C for 15 min and the whole
mixture was stirred at rt for 1 h. After cooling, Ac2O (1 ml, 10.9 mmol) was added to the stirred mixture
to quench the enolate and stirring was continued for 20 min at rt. The reaction mixture was diluted with
saturated aqueous NH4Cl, saturated aqueous NaHCO3 and extracted with ether. The organic layer was
washed with saturated brine and dried over MgSO4. Removal of the organic solvent gave a residue which
was chromatographed on silica gel (50 g, n-hexane:AcOEt=30:1) to give (8aR)-23 (404 mg, 82%) as a
26
pale yellow oil. (−)-(8aR)-23: [α]D −102.4 (c=1.42, CHCl3); IR (neat): 1747 cm−1 (OAc); 1H NMR:
δ 0.84 (3H, s), 0.92 (3H, s), 1.07 (3H, s), 0.95–1.85 (9H, m), 1.90 (3H, s), 2.21 (1H, dd, J=7, 17 Hz),
2.49 (1H, ddd, J=10, 11, 17 Hz), 3.24 (1H, d, J=18 Hz), 3.30 (1H, d, J=18 Hz), 3.75 (3H, s), 3.79 (3H,
s), 6.65 (1H, dd, J=3, 8.5 Hz), 6.73 (1H, d, J=8.5 Hz), 6.77 (1H, d, J=3 Hz). 13C NMR: δ 18.7 (t), 18.7
(t), 20.5 (q), 20.9 (q), 21.7 (q), 24.2 (t), 28.0 (t), 33.3 (q), 33.3 (s), 35.9 (t), 38.7 (s), 41.6 (t), 51.2 (d), 55.7
(q), 56.0 (d), 110.5 (d), 110.8 (d), 115.6 (d), 130.2 (s), 132.2 (s), 145.0 (s), 151.1 (s), 153.5 (s), 169.3 (s).
Anal. found: C, 74.52; H, 8.68. Calcd. for C24H34O4: C, 74.58; H, 8.87%. FAB MS m/z: 386 (M+).
3.22. (+)-(1S,4aR,8aR)-1-(2,5-Dimethoxyphenyl)methyl-2-oxo-5,5,8a-decahydro-trimethylnaphtha-
lene (+)-(8aR)-24
A mixture of (8aR)-23 (371 mg, 0.96 mmol) and KOH (1 g) in MeOH (9 ml) was stirred at rt
for 6 h. The reaction mixture was diluted with saturated brine and extracted with ether. The organic
layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel (15 g, n-
hexane:AcOEt=20:1) to afford (8aR)-24 (314 mg, 95%) as crystals. Recrystallization from n-hexane gave
24
(8aR)-24 as colorless prisms. (+)-(8aR)-24: Mp 108°C; [α]D +56.3 (c=1.37, CHCl3); IR (KBr): 1709
1
cm−1 (ketone); H NMR: δ 0.80 (3H, s), 0.86 (3H, s), 0.96 (3H, s), 1.22–1.67 (7H, m), 1.93–2.06 (2H,
m), 2.23 (1H, ddt, J=1, 6, 13 Hz), 2.36 (1H, ddd, J=2.5, 5, 13 Hz), 2.47 (1H, br. d, J=9 Hz), 2.66 (1H,
dd, J=1, 13 Hz), 2.88 (1H, dd, J=9, 13 Hz), 3.74 (3H, s), 3.76 (3H, s), 6.64 (1H, dd, J=3, 8.5 Hz), 6.70
(1H, d, J=8.5 Hz), 6.90 (1H, d, J=3 Hz). 13C NMR: δ 14.6 (q), 19.1 (t), 21.7 (q), 22.9 (t), 24.2 (t), 33.5
(q), 33.8 (s), 38.9 (t), 42.0 (t), 42.7 (t), 43.4 (s), 54.3 (d), 55.6 (q), 55.8 (q), 64.2 (d), 110.0 (d), 111.2 (d),

H. Akita et al. / Tetrahedron: Asymmetry 9 (1998) 1789–1799
1799
117.7 (d), 131.7 (s), 151.6 (s), 153.2 (s), 211.6 (s). Anal. found: C, 77.19; H, 9.02. Calcd. for C22H32O3:
C, 76.71; H, 9.36%. FAB MS m/z: 344 (M+).
3.23. (+)-Zonarol dimethyl ether (+)-(8aR)-25
n-BuLi (1.6 M in n-hexane, 0.6 ml, 0.96 mmol) was added to a suspension of Ph3P+MeBr− (685 mg,
1.92 mmol) in THF (10 ml) at −78°C under Argon and the whole mixture was stirred for 30 min. A
solution of (8aR)-24 (263 mg, 0.76 mmol) in THF (2 ml) was added to the above reaction mixture at 0°C
and the whole mixture was stirred at 80°C for 2 days. The reaction mixture was diluted with saturated
brine and extracted with ether. The organic layer was dried over MgSO4 and evaporated. The residue
was chromatographed on silica gel (15 g, n-hexane:AcOEt=50:1) to afford (8aR)-25 (190 mg, 73%) as a
colorless oil. (+)-(8aR)-25: [α]D +27.9 (c=1.06, CHCl3); 1H NMR: δ 0.82 (3H, s), 0.84 (3H, s), 0.89
26
(3H, s), 1.12–1.67 (7H, m), 1.71–1.76 (1H, m), 1.85–1.91 (1H, m), 2.00 (1H, dt, J=5, 13 Hz), 2.20 (1H,
d, J=7 Hz), 2.35 (1H, ddd, J=2.5, 6.5, 13 Hz), 2.74 (2H, d, J=7 Hz), 3.73 (3H, s), 3.78 (3H, s), 4.61 (1H,
d, J=1.5 Hz), 4.74 (1H, d, J=1.5 Hz), 6.63 (1H, dd, J=3, 9 Hz), 6.73 (1H, d, J=9 Hz), 6.72 (1H, d, J=3
Hz). 13C NMR: δ 14.6 (q), 19.5 (t), 21.8 (q), 23.3 (t), 24.4 (t), 33.7 (q), 33.7 (s), 38.3 (t), 39.2 (t), 39.9 (s),
42.2 (t), 55.6 (q), 55.7 (d), 55.9 (q), 56.0 (d), 107.7 (t), 109.7 (d), 110.8 (d), 116.3 (d), 132.1 (s), 148.3
(s), 151.8 (s), 153.3 (s). Anal. found: C, 80.93; H, 9.88. Calcd. for C23H34O2: C, 80.65; H, 10.00%. FAB
MS m/z: 342 (M+).
Acknowledgements
This work was supported by a grant for the ‘Biodesign Research Program’ from The Institute of
Physical and Chemical Research (RIKEN, Japan) to H. A.
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6. The overall yield of (8aS)-17 was improved to 82% in 6 steps from (8aS)-1 in the present case while that of (8aS)-17 was
39% in 4 steps from (8aS)-1 in the previously reported synthetic route.4