A convenient synthesis of (+)-albicanol based on enzymatic function: Total syntheses of (+)-albicanyl acetate, (-)-albicanyl 3,4- dihydroxycinnamate, (-)-drimenol, (-)-drimenin and (-)-ambrox

Article abstract of DOI:10.1016/S0957-4166(00)00076-8

By using lipase 'PL-266' from Alcaligenes sp. enantioselective acetylation of (±)-albicanol 4 with isopropenyl acetate gave the enantiomerically pure (+)-albicanyl acetate 3 and (+)-albicanol 4. Deprotection of (+)-3 afforded the natural (+)-albicanol 4 which was converted to the natural products (-)-albicanyl 3,4-dihydroxycinnamate 7, (- )-drimenol 8, (-)-drimenin 9 and (-)-ambrox 10. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00076-8

Tetrahedron: Asymmetry 11 (2000) 1375±1388
A convenient synthesis of (+)-albicanol based on enzymatic
function: total syntheses of (+)-albicanyl acetate,
(^)-albicanyl 3,4-dihydroxycinnamate, (^)-drimenol,
(^)-drimenin and (^)-ambrox
Hiroyuki Akita,* Masako Nozawa, Ayumi Mitsuda and Hitomi Ohsawa
School of Pharmaceutical Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 27 January 2000; accepted 21 February 2000
Abstract
By using lipase `PL-266' from Alcaligenes sp. enantioselective acetylation of (þ)-albicanol 4 with iso-
propenyl acetate gave the enantiomerically pure (+)-albicanyl acetate 3 and (+)-albicanol 4. Deprotection
of (+)-3 a€orded the natural (+)-albicanol 4 which was converted to the natural products (^)-albicanyl
3,4-dihydroxycinnamate 7, (^)-drimenol 8, (^)-drimenin 9 and (^)-ambrox 10. # 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The wide variety of biological activities of some drimane sesquiterpenes1 has focused on the
development of general synthetic routes to this class of compounds.2 Due to the potent anti-
feedant activity of several members of these groups, including polygodial 1, warburganal 2 and
albicanyl acetate 3, much attention has been paid to their synthesis both in racemic and optically
active forms.3 While some asymmetric syntheses of 1 and 2 have been achieved by the conversion
of higher terpenes such as sclareol,3 abietic acid4 and mannol,2 asymmetric syntheses of 3 and
albicanol 4 were carried out by employing enantiomerically pure Wieland±Miescher ketone.5 A
short and ecient synthesis of 1 from 3 has been reported3a and drimenyl acetate 5 corresponding
to the C7±C8 double bond isomer of 3 has been used in the preparation of 1,6 27 and ugandensi-
dial 6.8 In this paper, enantioselective syntheses of (^)- and (+)-albicanols 4, and (+)-albicanyl
acetate 3, based on the enzymatic preparation and application of (+)-4 into the syntheses of
(^)-albicanyl 3,4-dihydroxycinnamate 7, (^)-drimenol 8, (^)-drimenin 9 and (^)-ambrox 10, are
described (Scheme 1).
* Corresponding author. E-mail: akita@phar.toho-u.ac.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00076-8

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H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
Scheme 1.
2. Results and discussion
2.1. Synthesis of the substrate for enzymatic resolution
Jones oxidation of the b-hydroxy ester (þ)-119 gave the b-keto ester (þ)-12 in 96% yield. The
Wittig reaction of 12 with Ph3PˆCH2, by applying the reported procedure,9 provided a 22:1
epimeric mixture of the 8b-methoxycarbonyl-7-methylene compound (þ)-13 and (þ)-8a-14 in
98% yield. The minor epimer (þ)-14 could not be separated by conventional chromatography.
LiAlH4 reduction of a 22:1 mixture of (þ)-13, followed by chromatographic puri®cation, a€orded
a 37:1 mixture of (þ)-4, which was recrystallized to provide pure (þ)-albicanol 4 in 87% overall
.
yield. Conversion of (þ)-4 into (þ)-drimenol 8 was carried out using BF3 Et2O to provide (þ)-8 in
93% yield (Scheme 2).
Scheme 2.
2.2. Enantioselective acetylation of (þ)-4 and (þ)-8
At ®rst, for the purpose of determining the enantiomeric excess (ee) of the enzymatic reaction
products, two racemates [(þ)-4 and (þ)-8] were treated with (S)-a-methoxy-a-tri¯uoromethyl-

H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
1377
phenylacetyl chloride [(S)-MTPACl]10 in pyridine to a€ord the corresponding (R)-MTPA esters.
In every case, the signals due to C8-methylene protons appeared in distinctly di€erent ®elds [(R)-
MTPA esters from (þ)-4: ꢀ 4.58 dd and 4.23 dd, ꢀ 4.45 dd and 4.37 dd; (R)-MTPA esters from
(þ)-8: ꢀ 4.22 dd and 4.55 dd, ꢀ 4.17 dd and 4.63 dd] of the 400 MHz NMR spectrum. From a
screening experiment using various kinds of lipase, the e€ective lipases were as follows: `OF-360'
from Candida rugosa, `MY-30' from Candida rugosa, `Amano P' from Pseudomonas sp. and `PL-
266' from Alcaligenes sp. Enzymatic acetylation of (þ)-4 in the presence of isopropenyl acetate
was performed in diisopropyl ether at 33ꢀC and selected data are shown in Table 1. In the cases
of `OF-360' and `MY-30', (^)-acetate 3 and unchanged (+)-4 were obtained (entries 1 and 2),
while `Amano P' and `PL-266' a€orded (+)-acetate 3 and unchanged (^)-4 (entries 3±6). When
the alcohol (þ)-4 was exposed to `PL-266' in the presence of isopropenyl acetate, an acetate (+)-3
(56%, 67% ee) and unchanged (^)-4 (38%, >99% ee) were obtained (entry 5). Optically active
(+)-3 possessing 67% ee was reduced with LiAlH4 to give an alcohol (+)-4, which was again
subjected to the same enzymatic acetylation to a€ord the enantiomerically pure albicanyl acetate
(+)-3 ([ꢁ]D +33.9 (c 1.34, CHCl3)) in 53% yield (entry 6). The spectral data of synthetic (+)-3
were identical with those ([ꢁ]D +24.0 (c 0.5, CHCl3)) of natural (8aS)-(+)-3.11 The enantiomeric
purity of the enzymatic reaction products was determined by NMR measurement of the corre-
sponding (R)-MTPA ester derived from each enzymatic reaction product. The absolute con®g-
uration at the C8a-position of (^)-4 ([ꢁ]D ^12.7 (c 0.74, CHCl3)) was determined to be R by direct
comparison with the sign of the speci®c rotation of the natural (8aS)-(+)-albicanol 4 ([ꢁ]D +13
(c 0.6, CHCl3)).11 The enantiomerically pure (+)-3 was treated with LiAlH4 to provide enantio-
merically pure (+)-albicanol 4 (mp 70ꢀC, [ꢁ]D +12.8 (c 1.14, CHCl3)) whose physical data were
identical with those (mp 68±69ꢀC,12 [ꢁ]D) of the natural (8aS)-(+)-albicanol 4. Then enantio-
selective acetylation of (þ)-8 was carried out and selected data are shown in Table 2. When
alcohol (þ)-8 was exposed to `PL-266' in the presence of isopropenyl acetate, acetate (+)-5
(53%, 61% ee) and unchanged (+)-8 (40%, 80% ee) were obtained (entry 2). The ee of (+)-8
Table 1
Asymmetric acetylation of (þ)-4 with enzymes

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H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
Table 2
Asymmetric acetylation of (þ)-8 with enzymes
(80%) was improved to 88% by repeating enzymatic acetylation (entry 3). On the other hand, the
ee of (+)-5 (61%) was improved to 85% by repeating enzymatic acetylation of (^)-8 (61% ee)
prepared by LiAlH4 reduction of (+)-5 (61% ee) (entry 4). The enantiomeric purity of the enzym-
atic reaction products was determined by NMR measurement of the corresponding (R)-MTPA
esters derived from enzymatic reaction products. The absolute con®guration at the C8a-position
of (+)-8 (entry 3; [ꢁ]D +15.8 (c 1.2, benzene); corresponds to 88% ee) was con®rmed to be R by
direct comparison with the sign of the speci®c rotation ([ꢁ]D ^18 (c 3.55, benzene)) of the natural
(8aS)-(^)-drimenol 8.13 When using `Amano P', 88% ee of (+)-5 was obtained in 41% yield (entry 5).
Finally, enantiomerically pure (^)-drimenol 8 ([ꢁ]D ^18.2 (c 1.19, benzene)) was obtained in 90%
.
yield by treatment of the above-mentioned enantiomerically pure (+)-albicanol 4 with BF3 Et2O.
The physical data ([ꢁ]D and NMR) of the synthetic (^)-5 were identical with those ([ꢁ]D and
NMR) of the natural (^)-drimenol 8.13
2.3. Synthesis of (^)-albicanyl 3,4-dihydroxycinnamate 7
Albicanyl 3,4-dihydroxycinnamate 7 was isolated from Bazzania japonica and Bazzania pom-
peana as the major component.14 Attempts to synthesize it directly by the reaction of (þ)-4 and
3,4-dihydroxycinnamic acid 15 in the presence of dicyclohexylcarbodiimide (DCC)-4-dimethyl-
aminopyridine (DMAP) were unsuccessful. The reaction of (þ)-4 and 3,4-dimethoxycinnamic acid
16 in the presence of DCC±DMAP gave (þ)-albicanyl 3,4-dimethoxycinnamate 17 in 94% yield,
whose spectra (1H NMR) were identical with those reported for 17.14 Treatment of (þ)-17 with
BBr3 provided an inseparable 1:1 mixture of 3-hydroxy-4-methoxycinnamate 18 and the 4-
hydroxy-3-methoxycinnamate 19 in 62% yield (Scheme 3).
Then esteri®cation of (þ)-4 and 3,4-diacetoxycinnamic acid 20 was carried out. Acetylation of
15 gave the desired acid 20 in 93% yield, which was subjected to the esteri®cation of (+)-4 under
the following reaction conditions (the results are shown in Table 3). When using DCC without an
additive, the trans-acetylation product, (þ)-albicanyl acetate 3, was obtained in 26% yield along

H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
1379
Scheme 3.
Table 3
The reaction of (þ)- or (^)-4 and 20
with the starting material (þ)-4 (60%) (entry 1). The same reaction as for entry 1 was carried out
in the presence of DMAP to a€ord (þ)-3 (78%) and the desired (þ)-3,4-diacetoxycinnamate 21
(1%) (entry 2). Surprisingly, the same reaction as for entry 2 in the presence of (+)-camphor-
sulfonic acid ((+)-CSA) furnished (þ)-21 (49%) and (þ)-3 (34%). This reaction condition was
applied for the reaction of (+)-4 and 20, and (^)-albicanyl 3,4-diacetoxycinnamate 21 ([ꢁ]D ^5.6
(c 1.18, CHCl3)) was obtained in 50% yield. Finally, enzymatic hydrolysis of (^)-21 using the
lipase `Amano P' in water-saturated isopropyl ether provided the (^)-albicanyl-3,4-dihydroxy-
cinnamate (7; mp 179±180ꢀC, [ꢁ]D ^29.3 (c 0.89, MeOH)) quantitatively, which was consistent
with the natural 7 with respect to the physico-chemical data (mp 179±180ꢀC, [ꢁ]D ^18.3 (c 3.2,
MeOH) and 13C NMR).14
2.4. Synthesis of (^)-drimenin 9
(^)-Drimenin 9 was isolated from the stem bark of the South American Drimys species,15 and
(^)-9 was converted to potent antifeedants such as polygodial 1 and warburganal 2.2 Epoxidation
of (+)-albicanol 4 gave the diastereomerically pure epoxide 22 (mp 60.5±61ꢀC, [ꢁ]D ^24.4 (c 1.24,
CHCl3)) in 99% yield. Jones oxidation of 22 provided an epoxy acid 23 followed by treatment

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H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
with p-toluenesulfonic acid to yield (^)-drimenin 9 (mp 128.5±129ꢀC, [ꢁ]D ^58.6 (c 0.85, benzene))
in an overall 46% yield from (^)-22 (Scheme 4). The spectral data of the synthetic (^)-9 were
identical with those (mp 129±130ꢀC, [ꢁ]D ^54.5 (c 1, benzene)) of the natural (^)-9.12
Scheme 4.
2.5. Synthesis of (^)-ambrox 10
Ambergris is a metabolite product found in the gut of some blue sperm whales and used in
perfumery as a valuable ingredient of many ®ne fragrances. (^)-Ambrox 10 is one of the con-
stituents of the ambergris tincture and possesses a powerful amber-type aroma. In order to
achieve homologation of the primary alcohol group of (^)-8, the following synthetic sequence was
developed (Scheme 5). Tosylation of (þ)-8 in pyridine gave the tosylate (þ)-24 (88%), while
mesylation of (^)-8 in pyridine provided the mesylate (+)-25 ([ꢁ]D +12.0 (c 1.26, CHCl3))
quantitatively. Treatment of (þ)-24 with NaCN in DMSO gave the nitrile compound (þ)-26
(53%) and exo-ole®n (þ)-27 (34%), while the reaction of (+)-25 and NaCN in DMSO furnished
(^)-26 (45%, [ꢁ]D ^7.5 (c 1.14, CHCl3)) and (^)-27 (37%, [ꢁ]D ^185.4 (c 0.22, CHCl3)). Reduc-
tion of (^)-26 with diisobutylaluminum hydride (DIBAL-H) in toluene furnished an aldehyde
(^)-28 ( [ꢁ]D ^27.4 (c 0.55, CHCl3)) in 81% yield. NaBH4 reduction of (^)-28 provided the alcohol
(^)-29 ([ꢁ]D ^9.6 (c 1.51, CHCl3)) in quantitative yield. Treatment of (^)-29 with p-TsOH in
acetonitrile gave (^)-ambrox 10 ([ꢁ]D ^23.8 (c 1.13, CHCl3)) in 55% yield, which was consistent
with the reported (^)-10 ( [ꢁ]D ^22.3 (c 1.30, CHCl3)).16
Scheme 5.

H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
1381
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. High-resolution mass
spectra (HRMS) and the fast atom bombardment mass spectra (FAB MS) were obtained with a
JEOL JMS-DX 303 spectrometer. IR spectra were recorded using a JASCO FT/IR-300 spectrometer.
The HPLC system was composed of two SSC instruments (ultraviolet (UV) detector 3000B and
¯ow 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. (þ)-Methyl (1R*,4aS*,8aS*)-decahydro-5,5,8a-trimethyl-2-oxonaphthalene-1-carboxylate 12
Jones reagent (6 ml) was added to a solution of (þ)-11 (3.75 g, 14.7 mmol) in acetone (30 ml) at
0ꢀC and the reaction mixture was stirred at room temperature for 90 min. After iso-PrOH (6 ml)
was added to the reaction mixture, the whole was condensed and diluted with H2O, and extracted with
ether. The ether layer was washed in brine and dried over MgSO4. The ether layer was evaporated
to give a crude residue, which was chromatographed on silica gel (50 g, n-hexane:AcOEt=20:1)
to give (þ)-12 (3.58 g, 96%). Crystallization of (þ)-12 from n-hexane provided colorless plates: mp
84.5±85ꢀC; IR (KBr): 1747, 1708 cm^1 (COOMe, ketone); H NMR: ꢀ 0.90 (3H, s), 0.97 (3H, s),
1
1.16 (3H, s), 1.19±1.30 (2H, m), 1.43 (1H, dd, J=3, 13 Hz), 1.45±1.69 (4H, m), 1.75 (1H, dddd,
J=5.5, 13, 14, 14 Hz), 2.03 (1H, dddd, J=2, 3, 7, 14 Hz), 2.33 (1H, ddd, J=7, 14, 14 Hz), 2.51
(1H, ddd, J=2, 2.5, 14 Hz), 3.22 (1H, s), 3.69 (3H, s). 13C NMR: ꢀ 14.8 (q), 18.6 (t), 21.7 (q), 23.0
(t), 33.5 (q), 33.6 (s), 39.2 (t), 41.3 (t), 41.9 (t), 42.0 (s), 51.4 (q), 53.3 (d), 70.0 (d), 168.7 (s), 205.6
(s). Anal. found: C, 71.67; H, 9.35. Calcd for C15H24O3: C, 71.39; H, 9.59%. EI MS m/z: 252
(M+).
3.3. (þ)-Albicanol 4
(1) A solution of Ph3P+MeBr^ (9.45 g, 26.5 mmol) and NaNH2 (972 mg, 24.9 mmol) in toluene
(100 ml) was heated under re¯ux for 6 h under argon. After the suspension had settled, the decanted
yellow solution (Ph3PˆCH2) was poured into (þ)-12 (1.32 g, 5.23 mmol) at 0ꢀC. The whole was
stirred for 1 h at room temperature. The reaction mixture was diluted with H2O and extracted
with ether. The ether layer was washed in brine and dried over MgSO4. The organic layer
was evaporated to give a crude residue, which was chromatographed on silica gel (60 g, n-
hexane:AcOEt=50:1) to give a 22:1 mixture (1.288 g, 98%) of (þ)-13 and (þ)-14. Compound
(þ)-13: IR (neat): 1737 cm^1 (COOMe); 1H NMR: ꢀ 0.84 (3H, s), 0.87 (3H, s), 1.05 (3H, s), 1.06±
1.73 (9H, m), 2.02±2.12 (1H, m), 2.42 (1H, ddd, J=2, 5, 13 Hz), 2.80 (1H, s), 3.65 (3H, s), 4.64
(1H, d, J=1.5 Hz), 4.83 (1H, d, J=1.5 Hz). EI MS m/z: 250 (M+). (2) To a solution of the above
mixture (1.236 g, 4.97 mmol) in Et2O (20 ml) at 0ꢀC was added LiAlH4 (256 mg, 6.76 mmol) and
the whole was stirred for 1 h at room temperature. The reaction mixture was diluted with H2O,
acidi®ed with 2 M aqueous HCl and extracted with ether. The ether layer was washed in brine and
dried over MgSO4. Evaporation of the organic layer gave a crude residue. This was chromatographed

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H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
on silica gel (50 g, n-hexane:AcOEt=5:1) to give a colorless oil whiꢀch was crystallized from
n-hexane to provide colorless needles (þ)-4 (953 mg, 87%): mp 67±68 C; IR (KBr): 3358 cm^1
1
(OH); H NMR: ꢀ 0.72 (3H, s), 0.80 (3H, s), 0.88 (3H, s), 1.11±2.45 (12H, m), 3.75 (1H, dd,
J=9.5, 11 Hz), 3.82 (1H, dd, J=4, 11 Hz), 4.64 (1H, d, J=1.5 Hz), 4.93 (1H, d, J=1.5 Hz). 13C
NMR: ꢀ 15.4 (q), 19.4 (t), 21.9 (q), 24.3 (t), 33.6 (s), 33.7 (q), 38.0 (t), 39.0 (s), 39.1 (t), 42.1 (t),
55.2 (d), 58.8 (t), 59.2 (d), 106.2 (t), 147.7 (s). Anal. found: C, 81.19; H, 11.97. Calcd for C15H26O:
C, 81.02; H, 11.79%. EI MS m/z: 222 (M+).
3.4. (þ)-Albicanyl acetate (þ)-3
A solution of (þ)-4 (1.013 g, 4.56 mmol) in pyridine (20 ml) and 4-dimethylaminopyridine
(50 mg, 0.42 mmol) was treated with Ac2O (0.66 ml, 6.47 mmol) and the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture was diluted with H2O and extracted
with ether. The ether layer was washed with 2 M aqueous HCl, 7% aqueous NaHCO3, saturated
brine and dried over MgSO4. Evaporation of the organic layer gave a crude residue, which was
chromatographed on silica gel (20 g, n-hexane:AcOEt=30:1) to give (þ)-3 as a colorless oil (1.161
1
g, 96%): IR (neat): 1738 cm^1 (OAc); H NMR: ꢀ 0.73 (3H, s), 0.80 (3H, s), 0.86 (3H, s), 1.10±
2.41 (12H, m), 2.00 (3H, s), 4.17 (1H, dd, J=9, 11 Hz), 4.32 (1H, dd, J=4, 11 Hz), 4.49 (1H, d,
J=1 Hz), 4.83 (1H, d, J=1 Hz). 13C NMR: ꢀ 15.3 (q), 19.3 (t), 21.3 (q), 21.9 (q), 24.0 (t), 33.6 (s),
33.7 (q), 37.7 (t), 39.1 (s), 39.2 (t), 42.0 (t), 54.8 (d), 55.1 (d), 61.6 (t), 107.1 (t), 146.7 (s), 171.1 (s).
Anal. found: C, 77.51; H, 10.69. Calcd for C17H28O2: C, 77.22; H, 10.67%. FAB MS m/z: 265
(M++1).
3.5. (þ)Drimenol (þ)-8
.
To a solution of (þ)-4 (2.125 g, 9.39 mmol) in CH2Cl2 (20 ml) was added BF3 Et2O (3.3 ml, 11
mmol) at ^20ꢀC. The whole was stirred for 30 min at 0ꢀC and allowed to stand for 12 h in a
refrigerator. The reaction mixture was diluted with 7% aqueous NaHCO3 and extracted with
ether. The organic layer was washed with saturated brine and dried over MgSO4. Evaporation of
the organic layer gave a crude residue, which was chromatographed on silica gel (45 g, n-hex-
ane:AcOEt=20:1) to give a homogeneous oil (þ)-8 (1.983 g, 93%): IR (KBr): 3335 cm^1 (OH);
1H NMR: ꢀ 0.79 (3H, s), 0.80 (3H, s), 0.82 (3H, s), 0.94±1.18 (3H, m), 1.32±1.56 (3H, m), 1.71
(3H, br s), 1.74±1.97 (4H, m), 3.66 (1H, dd, J=5, 11.5 Hz), 3.79 (1H, dd, J=3, 11.5 Hz), 5.46±
5.48 (1H, m). 13C NMR: ꢀ 14.9 (q), 18.8 (t), 22.0 (q), 22.1 (q), 23.6 (t), 32.9 (s), 33.4 (q), 36.1 (s),
39.9 (t), 42.2 (t), 49.9 (d), 57.3 (d), 60.9 (t), 124.1 (d), 132.9 (s). Anal. found: C, 80.77; H, 11.86.
Calcd for C15H26O: C, 81.02; H, 11.79%. EI MS m/z: 222 (M+).
3.6. (þ)-Drimenyl acetate (þ)-5
A solution of (þ)-8 (743 mg, 3.28 mmol) in pyridine (5 ml) and 4-dimethylaminopyridine (30
mg, 0.2 mmol) was treated with Ac2O (0.64 ml, 6.75 mmol) and the reaction mixture was stirred
for 4 h at room temperature. The reaction mixture was diluted with H2O and extracted with
ether. The ether layer was washed with 2 M aqueous HCl, 7% aqueous NaHCO3, saturated brine
and dried over MgSO4. Evaporation of the organic layer gave a crude residue, which was chrom-
atographed on silica gel (30 g, n-hexane:AcOEt=50:1) to give (þ)-5 as a colorless oil (840 mg,
95%): IR (neat): 1740 cm^1 (OAc); 1H NMR: ꢀ 0.82 (3H, s), 0.86 (3H, s), 0.89 (3H, s), 1.09 (1H, dt,

H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
1383
J=4, 13 Hz), 1.13±1.23 (2H, m), 1.39±1.58 (3H, m), 1.67 (3H, br s), 1.82±2.01 (4H, m), 2.04 (3H,
s), 4.09 (1H, dd, J=6.5, 12 Hz), 4.25 (1H, dd, J=3, 12 Hz), 5.50 (1H, br s). 13C NMR: ꢀ 14.6 (q),
18.9 (t), 21.4 (q), 21.8 (q), 22.1 (q), 23.7 (t), 33.1 (s), 33.4 (q), 36.1 (s), 39.6 (t), 42.2 (t), 49.9
(d),53.4 (d), 63.2 (t), 123.5 (d), 132.3 (s), 170.9 (s). Anal. found: C, 77.02; H, 10.67. Calcd for
C17H28O2: C, 77.22; H, 10.67%. FAB MS m/z: 265 (M++1).
3.7. (R)-MTPA ester formation from (þ)-albicanol 4
To a stirred solution of (þ)-4 (51 mg, 0.23 mmol) in pyridine (2 ml) was added (S)-MTPACl (65
mg, 0.25 mmol) and the whole was stirred for 12 h at room temperature. The reaction mixture
was diluted with H2O and extracted with ether. The ether layer was washed with 2 M aqueous
HCl, 7% aqueous NaHCO3 and saturated brine, and dried over MgSO4. Evaporation of the
organic layer gave a crude residue, which was chromatographed on silica gel (10 g, n-hex-
ane:AcOEt=50:1) to give a diastereomeric mixture of (8aS)-(R)- and (8aR)-(R)-MTPA esters
1
(100 mg, 99%): H NMR: ꢀ 4.37 (1H, dd, J=9, 11 Hz) and 4.45 (1H, dd, J=4, 11 Hz), ꢀ 4.22
(1H, dd, J=9.5, 11 Hz) and 4.58 (1H, dd, J=3.5, 11 Hz). FAB MS m/z: 439 (M++1).
3.8. (R)-MTPA ester formation from (þ)-drimenol 8
To a stirred solution of (þ)-8 (120 mg, 0.54 mmol) in pyridine (1 ml) was added (S)-MTPACl
(160 mg, 0.64 mmol) and the whole was stirred for 12 h at room temperature. The reaction mix-
ture was worked up in the same way as in Section 3.7 to a€ord a diastereomeric mixture of (8aS)-
1
(R)- and (8aR)-(R)-MTPA esters (237 mg, 99%): H NMR: ꢀ 4.17 (1H, dd, J=6, 11.5 Hz) and
4.63 (1H, dd, J=3, 11.5 Hz), ꢀ 4.22 (1H, dd, J=6.5, 11.5 Hz) and 4.55 (1H, dd, J=3, 11.5 Hz).
FAB MS m/z: 439 (M++1).
3.9. Enantioselective acetylation of (þ)-4
(1) Table 1, entry 1: A suspension of (þ)-4 (100 mg), isopropenyl acetate (100 mg) and lipase
OF-360 (100 mg) in diisopropyl ether (10 ml) was incubated at 33ꢀC for 0.5 day. After the reac-
tion mixture was ®ltered, the precipitate was washed with diisopropyl ether. The combined
organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica
gel (10 g) to give (^)-3 (59 mg, 50%, 76% ee) from n-hexane:AcOEt=50:1 eluate and (+)-4 (46
mg, 46%, 75% ee) from n-hexane:EtOAc=20:1 eluate, respectively. (2) Table 1, entry 2: A sus-
pension of (þ)-4 (700 mg), isopropenyl acetate (700 mg) and lipase MY-30 (700 mg) in diiso-
propyl ether (70 ml) was incubated at 33ꢀC for 1 day. The reaction mixture was worked up in the
same way as for entry 1 to give (^)-3 (358 mg, 43%, 56% ee) and (+)-4 (350 mg, 50%, 60% ee).
(3) Table 1, entry 3: A suspension of (þ)-4 (231 mg), isopropenyl acetate (230 mg) and lipase
Amano-P (200 mg) in diisopropyl ether (40 ml) was incubated at 33ꢀC for 12 days. The reaction
mixture was worked up in the same way as for entry 1 to give (+)-3 (115 mg, 42%, 82% ee) and
(^)-4 (132 mg, 57%, 61% ee). (4) Table 1, entry 4: A suspension of (þ)-4 (233 mg), isopropenyl
acetate (230 mg) and lipas PL-266 (200 mg) in diisopropyl ether (40 ml) was incubated at 33ꢀC for
1 day. The reaction mixture was worked up in the same way as for entry 1 to give (+)-3 (161 mg,
58%, 68% ee) and (^)-4 (93 mg, 40%, >99% ee). (5) Table 1, entry 5: A suspension of (þ)-4
(2.469 g), isopropenyl acetate (2.5 g) and lipase PL-266 (2.5 g) in diisopropyl ether (100 ml) was
incubated at 33ꢀC for 1 day. The reaction mixture was worked up in the same way as for entry 1

1384
H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
24
D
to give (+)-3 (1.647 g, 56%, 67% ee) and (^)-4 (938 mg, 38%, ‰ꢁŠ ^12.7 (c 0.74, CHCl3);
corresponds to >99% ee). (6) Table 1, entry 6: LiAlH4 (372 mg) reduction of (+)-3 (67% ee, 1.647 g)
in Et2O (20 ml) gave (+)-4 (1.33 g, 96%, 67% ee) in the same way as that in Section 3.3. A
suspension of (+)-4 (67% ee, 1.268 g), isopropenyl acetate (1.26 g) and lipase PL-266 (1.26 g)
in diisopropyl ether (150 ml) was incubated at 33ꢀC for 1 day. The reaction mixture was worked up
in the same way as for entry 1 to give (+)-3 (799 mg, 53%, ‰ꢁŠ21 +33.9 (c 1.34, CHCl3); corresponds
D
to >99% ee) and (+)-4 (449 mg, 35%, 19% ee).
3.10. (8aS)-(+)-Albicanol 4
LiAlH4 (241 mg, 6.3 mmol) reduction of (+)-3 (>99% ee, 799 mg, 3 mmol) in Et2O (20 ml)
gave (+)-4 (638 mg, 95%) in the same way as in Section 3.3. Recrystallization of (+)-4 from
26
D
n-hexane a€orded colorless needles: mp 70ꢀC; ‰ꢁŠ +12.8 (c 1.14, CHCl3). Physical data of (+)-4
were identical with those of (þ)-4.
3.11. Enantioselective acetylation of (þ)-8
(1) Table 2, entry 1: A suspension of (þ)-8 (235 mg), isopropenyl acetate (200 mg) and lipase
PL-266 (200 mg) in diisopropyl ether (40 ml) was incubated at 33ꢀC for 1 day. After the reaction
mixture was ®ltered, the precipitate was washed with diisopropyl ether. The combined organic
layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel (10
g) to give (+)-5 (134 mg, 48%, 72% ee) from n-hexane:AcOEt=50:1 eluate and (+)-8 (113 mg,
48%, 73% ee) from n-hexane:AcOEt=20:1 eluate, respectively. (2) Table 2, entry 2: A suspension
of (þ)-4 (669 mg), isopropenyl acetate (670 mg) and lipase PL-266 (670 mg) in diisopropyl ether
(80 ml) was incubated at 33ꢀC for 1 day. The reaction mixture was worked up in the same way as
for entry 1 to give (+)-5 (422 mg, 53%, 61% ee) and (+)-8 (267 mg, 40%, 80% ee). (3) Table 2,
entry 3: A suspension of (+)-8 (247 mg, 80% ee), isopropenyl acetate (240 mg) and lipase PL-266
(200 mg) in diisopropyl ether (60 ml) was incubated at 33ꢀC for 1 day. The reaction mixture was
worked up in the same way as for entry 1 to give (^)-5 (53 mg, 18%, 57% ee) and (+)-8 (198 mg,
26
D
80%, ‰ꢁŠ +15.8 (c 1.2, benzene); corresponds to 88% ee). (4) Table 2, entry 4: LiAlH4 (122 mg)
25
D
reduction of (+)-5 (61% ee, 442 mg) in Et2O (10 ml) gave (^)-8 (356 mg, 96%, ‰ꢁŠ ^10.8 (c 1.09,
benzene); corresponds to 61% ee) in the same way as in Section 3.3. A suspension of (^)-8 (61%
ee, 322 mg), isopropenyl acetate (320 mg) and lipase PL-266 (320) in diisopropyl ether (60 ml)
was incubated at 33ꢀC for 1 day. The reaction mixture was worked up in the same way as for
26
D
entry 1 to give (+)-5 (278 mg, 73%, ‰ꢁŠ +8.7 (c 1.88, CHCl3); corresponds to 85% ee) and (þ)-8
(83 mg, 26%). (5) Table 2, entry 5: A suspension of (þ)-8 (216 mg), isopropenyl acetate (200 mg)
and lipase PL-266 (200 mg) in diisopropyl ether (40 ml) was incubated at 33ꢀC for 5.5 days. The
reaction mixture was worked up in the same way as for entry 1 to give (+)-5 (107 mg, 41%, 88% ee)
and (+)-8 (115 mg, 53%, 68 ee).
3.12. General procedure of (R)-MTPA ester formation from enzymatic reaction products (alcohol
and acetate)
(1) To a stirred solution of alcohol (ca. 10 mg) in pyridine (0.5 ml) was added (S)-MTPACl (ca.
30 mg), and the whole was stirred for 1 h at room temperature. The reaction mixture was worked
up in the same way as in Section 3.7 to give the corresponding (R)-MTPA ester quantitatively.

H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
1385
The ee of the resulting (R)-MTPA ester was determined by NMR analysis. (2) LiAlH4 (10±16 mg)
reduction of acetate (59±100 mg) in Et2O (15 ml) gave the corresponding alcohol quantitatively.
To a stirred solution of the resulting alcohol (ca. 10 mg) in pyridine (0.5 ml) was added (S)-
MTPACl (ca. 30 mg), and the whole was stirred for 1 h at room temperature. The reaction mix-
ture was worked up in the same way as in (1) to give the corresponding (R)-MTPA ester quant-
itatively. The ee of the resulting (R)-MTPA ester was determined by NMR analysis.
3.13. Conversion of (+)-albicanol 4 into (^)-drimenol 8
.
To a solution of (+)-4 (1.418 g, 6.38 mmol) in CH2Cl2 (15 ml) was added BF3 Et2O (2.4 ml,
8.24 mmol) at ^20ꢀC, and the whole was stirred for 12 h at 0ꢀC. The reaction mixture was worked
up in the same way as in Section 3.5 to give (^)-8 (1.278 g, 90%). Recrystallization of (^)-8
24
D
from n-hexane a€orded colorless needles: mp 86ꢀC; ‰ꢁŠ ^18.2 (c 1.19, benzene). Physical data of
(^)-8 were identical with those of (þ)-8.
3.14. (þ)-Albicanyl 3,4-dimethoxycinnamate 17
A mixture of (þ)-4 (48 mg, 0.22 mmol), 3,4-dimethoxycinnamic acid 16 (111 mg, 0.54 mmol),
DCC (108 mg, 0.52 mmol) and DMAP (64 mg, 0.53 mmol) in CH2Cl2 (1 ml) was stirred for 12 h
at room temperature. The reaction mixture was diluted with saturated brine and extracted with
ether. The organic layer was dried over MgSO4. Evaporation of the organic layer gave a crude
residue, which was chromatographed on silica gel (15 g, n-hexane:AcOEt=10:1) to provide
crystals (þ)-17 (84 mg, 94%). Recrystallization of (þ)-17 from n-hexane±AcOEt gave colorless
ꢀ
1
(þ)-17: mp 118.5 C; IR (KBr): 1710 cm^1 (ester); H NMR data of (þ)-17 were identical with
those of the reported 17.14 13C NMR: ꢀ 15.3 (q), 19.3 (t), 21.9 (q), 24.0 (t), 33.6 (s), 33.7 (q), 37.7
(t), 39.1 (s), 39.2 (t), 42.0 (t), 55.0 (d), 55.2 (d), 55.9 (q), 56.0 (q), 61.5 (t), 107.2 (t), 109.5 (d), 110.9
(d), 115.9 (d), 122.5 (d), 127.3 (s), 144.3 (d), 146.7 (s), 149.0 (s), 150.8 (s), 167.2 (s). Anal. found:
C, 75.82; H, 8.32. Calcd for C26H36O4: C, 75.69; H, 8.80%. EI MS m/z: 412 (M+).
3.15. 3,4-Diacetoxycinnamic acid 20
A solution of ca€eic acid 15 (1.0 g, 5.5 mmol) in pyridine (10 ml) was treated with Ac2O (2.83
g, 27.7 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction
mixture was diluted with H2O and extracted with ether. The ether layer was washed with 2 M
aqueous HCl and saturated brine, and dried over MgSO4. Evaporation of the organic layer gave
a crude residue, which was chromatographed on silica gel (20 g, n-hexane:AcOEt=1:1) to give
crystals 20 (1.368 g, 93%). Recrystallization of 20 from MeOH gave a colorless powder: mp 206±
207ꢀC; IR (KBr): 1763, 1683, 1682 cm^1 (OAc, CˆC±COOH); 1H NMR (DMSO-d6): ꢀ 2.28 (3H,
s), 2.29 (3H, s), 6.53 (1H, d, J=16 Hz), 7.31 (1H, d, J=8 Hz), 7.58 (1H, d, J=16 Hz), 7.63 (1H,
dd, J=2, 8 Hz), 7.66 (1H, d, J=2 Hz), 12.45 (1H, br s). Anal. found: C, 58.81; H, 4.61. Calcd for
C13H12O6: C, 59.09; H, 4.58%. EI MS m/z: 264 (M+).
3.16. (^)-Abicanyl 3,3-dihydroxycinnamate 7
(1) To a solution of (+)-4 (226 mg, 1.02 mmol) in CH2Cl2 (15 ml) was added 20 (506 mg, 1.92
mmol), DCC (494 mg, 2.4 mmol), DMAP (282 mg, 2.31 mmol) and (+)-CSA (229 mg, 1.88 mmol)

1386
H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
at 0ꢀC, and the whole was stirred for 12 h at ambient temperature. The reaction mixture was
directly ®ltered with the aid of Celite and the ®ltrate was condensed. The residue was subjected to
chromatography on silica gel (30 g) to give (^)-3 (22 mg, 8%) from n-hexane:AcOEt=50:1 eluate
and (^)-albicanyl 3,4-diacetoxycinnamate 21 (240 mg, 50%) from n-hexane:AcOEt=5:1 eluate.
Recrystallization of 21 from n-hexane±AcOEt gave a colorless powder 21. (^)-21: mp 103ꢀC; IR
27
D
(KBr): 1768, 1702 cm^1 (OAc, CˆC±COOR); ‰ꢁŠ ^5.6 (c 1.18, CHCl3); 1H NMR: ꢀ 0.79 (3H, s),
0.83 (3H, s), 0.89 (3H, s), 1.14±2.15 (11H, m), 2.29 (3H, s), 2.30 (3H, s), 2.40±2.46 (1H, m), 4.31
(1H, dd, J=9, 11.5 Hz), 4.50 (1H, dd, J=3, 11.5 Hz), 4.57 (1H, d, J=1.5 Hz), 4.88 (1H, d, J=1.5
Hz), 6.36 (1H, d, J=16 Hz), 7.21 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=2.5 Hz), 7.39 (1H, dd,
J=2.5, 8.5 Hz), 7.58 (1H, d, J=16 Hz). 13C NMR: ꢀ 15.2 (q), 19.2 (t), 20.6 (q), 20.6 (q), 21.8 (q),
23.9 (t), 33.5 (s), 33.6 (s), 37.6 (t), 39.0 (s), 39.1 (t), 42.0 (t), 54.9 (d), 55.1 (d), 61.8 (t), 107.3 (t),
119.6 (d), 122.7 (d), 123.9 (d), 126.4 (d), 133.4 (s), 142.4 (s), 142.6 (d), 143.4 (s), 146.8 (s), 166.8
(s), 167.9 (s), 168.0 (s). Anal. found: C, 71.70; H, 7.88. Calcd for C28H36O6: C, 71.77; H,
7.74%. FAB MS m/z: 469 (M++1). (2) A suspension of (^)-21 (105 mg, 0.22 mmol) and Amano P
(100 mg) in H2O saturated isopropyl ether (10 ml) was stirred for 1 h at 35ꢀC and the reaction
mixture was dried over MgSO4. Evaporation of the organic solvent gave a residue, which was
chromatographed on silica gel (15 g, n-hexane:AcOEt=2:1) to give (^)-7 (85 mg, 99%).
Recrystallization of (^)-7 from AcOEt a€orded colorless needles: mp 179±180ꢀC; IR (CHCl3):
1696 cm^1 (CˆC±COOR); ‰ꢁŠ23 ^29.3 (c 0.89, MeOH); 1H NMR and 13C NMR data of (^)-7 were
D
identical with those of the reported (^)-7.14 Anal. found: C, 75.32; H, 8.42. Calcd for C24H32O4:
C, 74.97; H, 8.39%.
3.17. (^)-Drimenin 9
(1) A mixture of (+)-4 (473 mg, 2.13 mmol) and MCPBA (444 mg, 2.58 mmol) in CH2Cl2 (8 ml)
was stirred for 20 min at room temperature. The reaction mixture was diluted with ether and
the organic layer was washed with 10% aqueous Na2S2O3, 7% aqueous NaHCO3 and dried over
MgSO4. Evaporation of the organic solvent gave a residue, which was chromatographed on silica
gel (20 g, n-hexane:AcOEt=50:1) to give (^)-22 (507 mg, 99%). Recrystallization of (^)-22 from
24
D
n-hexane provided colorless plates (^)-22: mp 60.5±61ꢀC; IR (KBr): 3514 cm^1 (OH); ‰ꢁŠ ^24.4
1
(c 1.24, CHCl3); H NMR: ꢀ 0.83 (3H, s), 0.85 (3H, s), 0.91 (3H, s), 1.07 (1H, dd, J=2, 12 Hz),
1.17±2.02 (11H, m), 2.72 (1H, d, J=4 Hz), 3.11 (1H, d, J=10.5 Hz, disappeared with D2O, OH),
3.41 (1H, dd, J=10, 10.5 Hz), 3.63 (1H, dd, J=3, 10.5 Hz). 13C NMR: ꢀ 15.6 (q), 18.6 (t), 21.6
(q), 21.6 (t), 33.3 (s), 33.5 (q), 36.2 (t), 38.8 (t), 39.1 (s), 41.7 (t), 51.8 (t), 54.3 (d), 54.6 (d), 58.8 (t),
61.7 (s). Anal. found: C, 75.67; H, 11.03. Calcd for C15H26O2: C, 75.58; H, 11.00%. FAB MS m/z:
239 (M++1). (2) Jones reagent (0.65 ml) was added to a solution of (^)-22 (322 mg, 1.35 mmol) in
acetone (10 ml) at 0ꢀC and the reaction mixture was stirred for 1 h at room temperature. After
iso-PrOH (0.5 ml) was added to the reaction mixture, the whole was condensed and diluted with
H2O, and extracted with ether. The ether layer was washed in brine and dried over MgSO4. The
ether layer was evaporated to give a crude residue, which was chromatographed on silica gel (15
g, n-hexane:AcOEt=1:1) to give 23 as a colorless oil (311 mg, 91%): IR (neat): 1711 cm^1
(COOH); 1H NMR: ꢀ 0.86 (3H, s), 0.91 (3H, s), 1.03 (1H, dd, J=2.5, 12 Hz), 1.14 (3H, s), 1.12±
1.97 (10H, m), 2.62 (1H, d, J=5 Hz), 2.69 (1H, s), 3.37 (1H, dd, J=2, 5 Hz). FAB MS m/z: 253
+
.
(M +1). (3) A mixture of 23 (160 mg, 0.63 mmol) and TsOH H2O (13 mg, 0.07 mmol) in CHCl3
(5 ml) was stirred for 1 h at re¯ux. The reaction mixture was diluted with saturated brine and
extracted with ether. The organic layer was dried over MgSO4. Evaporation of the organic solvent

H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
1387
gave a residue, which was chromatographed on silica gel (15 g, n-hexane:AcOEt=20:1) to give
(^)-9 (69 mg, 46%). Recrystallization of (^)-9 from MeOH provided colorless plates: mp 128.5±
24
D
129ꢀC; IR (KBr): 1762 cm^1 (lactone); ‰ꢁŠ ^58.6 (c 0.85, benzene); 1H NMR: ꢀ 0.87 (3H, s), 0.89
(3H, s), 0.91 (3H, s), 1.17±1.29 (2H, m), 1.36 (1H, dd, J=5, 11.5 Hz), 1.46±1.65 (3H, m), 1.93±
2.04 (1H, m), 2.16±2.25 (1H, m), 2.50 (1H, J=3.5, 5, 13.5 Hz), 2.78 (1H, br s), 4.61±4.71 (2H, m),
5.73 (1H, br s). 13C NMR: ꢀ 14.0 (q), 18.3 (t), 21.4 (q), 23.4 (t), 33.0 (q), 33.1 (s), 34.4 (s), 38.5 (t),
42.4 (t), 49.7 (d), 53.7 (d), 69.8 (t), 121.2 (d), 129.9 (s), 175.3 (s). Anal. found: C, 76.84; H, 9.53.
Calcd for C15H22O2: C, 76.84; H, 9.46%. EI MS m/z: 234 (M++1).
3.18. (^)-Ambrox 10
(1) To a solution of (^)-8 (1.051 g, 1.02 mmol) in pyridine (10 ml) was added a solution of
MsCl (795 mg, 1.92 mmol) in pyridine (5 ml), and the whole was stirred for 1 h at room tem-
perature. The reaction mixture was diluted with saturated brine and extracted with ether. The
organic layer was washed with 2 M aqueous HCl, 7% aqueous NaHCO3 and dried over MgSO4.
Evaporation of the organic solvent gave a residue, which was chromatographed on silica gel (20
g, n-hexane:AcOEt=20:1) to give (+)-25 as a colorless oil (1.406 g, 99%): IR (neat): 1354 cm^1;
24
1
‰ꢁŠ +12.0 (c 1.26, CHCl3); H NMR: ꢀ 0.84 (3H, s), 0.87 (3H, s), 0.89 (3H, s), 1.09±2.13 (10H,
D
m), 1.73 (3H, br s), 3.00 (3H, s), 4.23 (1H, dd, J=6, 10 Hz), 4.42 (1H, dd, J=3, 10 Hz), 5.54 (1H,
br s). 13C NMR: ꢀ 14.6 (q), 18.6 (t), 21.6 (q), 21.9 (q), 23.4 (t), 32.9 (s), 33.2 (s), 36.0 (s), 37.4 (q),
41.8 (t), 49.6 (d), 53.6 (d), 67.9 (t), 124.3 (d), 130.8 (s). EI MS m/z: 204 (M+^OMs). (2) A mixture of
(+)-25 (443 mg, 1.48 mmol) and NaCN (382 mg, 7.8 mmol) in DMSO (6 ml) was stirred for 12 h
at room temperature, and the reaction mixture was dried over MgSO4. The reaction mixture was
diluted with saturated brine and extracted with ether. The organic layer was dried over MgSO4.
Evaporation of the organic solvent gave a residue, which was chromatographed on silica gel (15
g) to give (^)-27 as a colorless oil (106 mg, 37%) from n-hexane eluate and (^)-26 as a colorless oil
(155 mg, 45%) from n-hexane:AcOEt=100:1 eluate. Compound (^)-26: IR (neat): 2243 cm^1
24
1
(CN); ‰ꢁŠ ^7.5 (c 1.14, CHCl3); H NMR: ꢀ 0.84 (3H, s), 0.87 (3H, s), 0.89 (3H, s), 1.04±2.19
D
(10H, m), 1.79 (3H, br s), 2.24 (1H, dd, J=7, 17 Hz), 2.48 (1H, dd, J=4, 17 Hz), 5.56 (1H, br s).
13C NMR: ꢀ 13.8 (q), 15.0 (t), 18.6 (t), 21.6 (q), 21.9 (q), 23.5 (t), 32.9 (s), 33.2 (q), 36.5 (s), 39.6
(t), 41.9 (t), 49.7 (d), 51.6 (d), 121.0 (s), 125.0 (d), 131.2 (s). Anal. found: C, 83.07; H, 11.08; N,
5.91. Calcd for C16H25N: C, 83.05; H, 10.89; N, 6.05%. FAB MS m/z: 232 (M++1). Compound
20
D
1
(^)-27: IR (neat): 1601 cm^1; ‰ꢁŠ ^185.4 (c 0.22, CHCl3); H NMR: ꢀ 0.87 (3H, s), 0.93 (3H, s),
0.97 (3H, s), 1.18±2.19 (9H, m), 1.80 (3H, br s), 4.80 (1H, br s), 4.84 (1H, br s), 5.65 (1H, br s).
13C NMR: ꢀ 19.1 (t), 20.6 (q), 21.1 (q), 22.1 (q), 24.3 (t), 32.9 (q), 33.4 (s), 37.7 (t), 37.8 (s), 42.2
(t), 48.7 (d), 103.7 (t), 126.5 (d), 131.2 (s), 158.2 (s). Anal. found: C, 88.60; H, 12.02. Calcd for
C15H24: C, 88.16; H, 11.84%. EI MS m/z: 204 (M+). (3) To a solution of (^)-26 (390 mg, 1.69
mmol) in toluene (10 ml) was added 1 M DIBAL in toluene (3.7 ml, 3.7 mmol) at ^78ꢀC, and the
whole was stirred for 30 min at the same temperature. After addition of acetone (0.5 ml), the
reaction mixture was diluted 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=50:1) to a€ord (^)-28
24
as a colorless oil (322 mg, 81%): IR (neat): 1724 cm^1 (CHO); ‰ꢁŠ ^27.4 (c 0.55, CHCl3); H
1
D
NMR: ꢀ 0.77 (3H, s), 0.88 (3H, s), 0.89 (3H, s), 1.52 (3H, br s), 1.03±2.06 (9H, m), 2.35±2.46 (2H,
m), 2.53 (1H, br s), 5.43 (1H, br s), 9.85 (1H, J=1.5, 2 Hz). 13C NMR: ꢀ 14.2 (q), 18.7 (t), 21.8
(q), 22.5 (q), 23.7 (t), 32.9 (s), 33.2 (q), 36.0 (s), 39.5 (t), 42.1 (t), 42.4 (t), 48.6 (d), 49.8 (d), 123.4

1388
H. Akita et al. / Tetrahedron: Asymmetry 11 (2000) 1375±1388
(d), 132.9 (s), 203.5 (d). Anal. found: C, 81.85; H, 11.20. Calcd for C16H26O: C, 81.99; H, 11.18%.
(4) To a solution of (^)-28 (298 mg, 1.27 mmol) in MeOH (4 ml) was added NaBH4 (69 mg, 1.8
mmol) at 0ꢀC, and the whole was stirred for 30 min at the same temperature. After addition of
acetone (0.3 ml), the reaction mixture was diluted with saturated brine and extracted with ether.
The organic layer was dried over MgSO4. Evaporation of the organic solvent gave a residue,
which was chromatographed on silica gel (15 g, n-hexane:AcOEt=10:1) to a€ord (^)-29 as a
colorless oil (300 mg, 99%): IR (neat): 3324 cm^1 (OH); ‰ꢁŠ23 ^9.6 (c 1.51, CHCl3); 1H NMR: ꢀ 0.76
D
(3H, s), 0.85 (3H, s), 0.88 (3H, s), 0.96±2.02 (12H, m), 1.67 (3H, br s), 3.53±3.60 (1H, m), 3.76±
3.83 (1H, m), 5.42 (1H, br s). 13C NMR: ꢀ 13.6 (q), 18.8 (t), 21.8 (q), 22.1 (q), 23.8 (t), 30.5 (s),
33.0 (t), 33.2 (q), 36.5 (s), 39.2 (t), 42.3 (t), 50.1 (d), 50.8 (d), 64.4 (t), 122.7 (d), 134.6 (s). Anal.
found: C, 81.27; H, 12.04. Calcd for C16H28O: C, 81.29; H, 11.94%. FAB MS m/z: 237 (M++1).
(5) To a solution of (^)-29 (300 ꢀmg, 1.27 mmol) in MeCN (8 ml) was added a solution of p-
.
TsOH H2O in MeCN (2 ml) at 0 C, and the whole was stirred for 12 h at ambient temperature.
The reaction mixture was diluted with 7% aqueous NaHCO3 and extracted with ether. The
organic layer was dried over MgSO4. Evaporation of the organic solvent gave a residue, which
was chromatographed on silica gel (20 g, n-hexane:AcOEt=50:1) to a€ord (^)-10 as a colorless
25
D
oil (165 mg, 55%): ‰ꢁŠ ^23.8 (c 1.13, CHCl3). FAB MS m/z: 342 (M+). Spectral data (1H NMR
23
and 13C NMR) were identical with those (‰ꢁŠ ^22.3 (c 1.3, CHCl3)) of reported (^)-10.16
D
Acknowledgements
This work was supported by a grant for the Biodesign Research Program from the Institute of
Physical and Chemical Research (RIKEN) to H.A. and a Grant-in-Aid for Scienti®c Research
(No. 10672002) from the Ministry of Education, Science and Culture of Japan to H.A.
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