Total synthesis of (+/-)-syn-copalol.

Article abstract of DOI:10.1271/bbb.66.2504

The labdane diterpene derivative, syn-copalol [(+)-5] is the alcohol part of syn-copalyl diphosphate [(+)-4]. In this paper, racemic (+/-)-5 was synthesized from a known racemic lactone in 8 steps. The current and our previous syntheses provide all four copalol derivatives [(+)-3, (-)-3 and (+/-)-5] which are required for the biosynthetic study of polycyclic diterpenes.

Full text of DOI:10.1271/bbb.66.2504

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Total Synthesis of (±)-syn-Copalol
Hiroaki TOSHIMAa, Hideaki OIKAWAb, Hiroshi YADAc, Hiroshi ONOc, Tomonobu TOYOMASUd
& Takeshi SASSAd
a Department of Bioresource Science, College of Agriculture, Ibaraki University Ami-
machi, Inashiki-gun, Ibaraki 300-0393, Japan
b Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University
Kita-ku, Sapporo 060-8589, Japan
c National Food Research Institute 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan
d Department of Bioresource Engineering, Faculty of Agriculture, Yamagata University
Tsuruoka, Yamagata 997-8555, Japan
Published online: 22 May 2014.
To cite this article: Hiroaki TOSHIMA, Hideaki OIKAWA, Hiroshi YADA, Hiroshi ONO, Tomonobu TOYOMASU & Takeshi SASSA
(2002) Total Synthesis of (±)-syn-Copalol, Bioscience, Biotechnology, and Biochemistry, 66:11, 2504-2510, DOI: 10.1271/
bbb.66.2504
To link to this article: http://dx.doi.org/10.1271/bbb.66.2504
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Biosci. Biotechnol. Biochem., 66 (11), 2504–2510, 2002
Note
±
Total Synthesis of ( )-syn-Copalol
† Hideaki OIKAWA,2 Hiroshi YADA,3 Hiroshi ONO
,
1,
3
Hiroaki TOSHIMA
,
Tomonobu TOYOMASU,4 and Takeshi SASSA
4
1Department of Bioresource Science, College of Agriculture, Ibaraki University, Ami-machi, Inashiki-gun,
Ibaraki 300-0393, Japan
2Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Kita-ku,
Sapporo 060-8589, Japan
3National Food Research Institute, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan
4Department of Bioresource Engineering, Faculty of Agriculture, Yamagata University, Tsuruoka,
Yamagata 997-8555, Japan
Received May 23, 2002; Accepted June 26, 2002
＋
The labdane diterpene derivative, syn-copalol [( )-5]
been proved by using (
synthase catalyzed the cyclization of (+)-4 to
aphidicolan-16 -ol (6). We describe here the total
synthesis of ( )-syn-copalol [( )-5] from a known
racemic lactone in 8 steps.
±
)-4 that aphidicolan-16 b-ol
is the alcohol part of syn-copalyl diphosphate [( )-4].
＋
±
In this paper, racemic ( )-5 was synthesized from a
known racemic lactone in 8 steps. The current and our
previous syntheses provide all four copalol derivatives
[( )-3, ( )-3 and ( )-5] which are required for the
biosynthetic study of polycyclic diterpenes.
b
±
±
We chose a known lactone (8)6) as the most ap-
＋
－
±
±
propriate substrate for the synthesis of ( )-5, be-
cause 8 has the three required stereogenic centers of
Key words: labdane; diterpene; biosynthesis; syn
copalyl diphosphate; syn-copalol
-
( )-5, C-5, C-9 and C-10. Reduction of 8 with sodi-
±
um borohydride in an alkaline medium gave a lac-
tone (9) in a 92 yield (Scheme). Reduction of 9 with
DIBAH in THF gave a lactol, which was treated with
z
We have recently reported the preparation of both
enantiomers of the labdane diterpene derivative,
copalol [(+)-3 and („)-3] (Fig. 1),1) whose
diphosphates [copalyl diphosphate, (+)-2 and („)-2]
are known as biosynthetic intermediates of polycyclic
diterpenes. Geranylgeranyl diphosphate (1) was enzy-
matically converted to (+)-2 and („)-2 via the chair-
chair transition state, whereas 1 was also cyclized to
syn-copalyl diphosphate [(+)-4] via the chair-boat
transition state by the other diterpene cyclase (syn-
thase).2) The C-9 epimer of (+)-2 (labdane number-
ing) is also a biosynthetic intermediate of polycyclic
diterpenes. To study the stereochemical course of the
polycyclic diterpene cyclization, we required (+)-4 in
addition to (+)-2 and („)-2.3)
＝
the Wittig reagent (Ph3P CH2) in DMSO to give a
C1-elongated oleˆn (10) in an 82 yield (2 steps). To
z
introduce the exo-methylene of 12a, regioselective
elimination was achieved via acetate (11).7) The ter-
tiary hydroxyl group of 10 was acetylated with acetic
anhydride, triethylamine and 4-dimethylaminopyri-
9 z
dine in toluene at 70 C to give 11 in a 91 yield.
Treatment of 11 in 2,4,6-collidine at re‰uxing tem-
perature8) regioselectively gave a 4.7:1 mixture of
diene 12a and its endo-isomer (C-7-ene, 12b) in a
93
z
yield. The 1H- and 13C-NMR spectra of the mix-
ture of 12a and 12b respectively showed the exo
-
oleˆn signals (1H: 4.52 and 4.69 ppm; 13C: 109.3 and
149.1 ppm) and endo-oleˆn signals (1H: 5.25 ppm;
13C: 119.7 and 136.6 ppm). Therefore, the ratio of
12a and 12b could be readily determined from the in-
tegral values of the respective oleˆn signals in the 1H-
NMR spectrum.
To date, Yee and Coates have only reported a
versatile total synthesis of (+)-syn-copalol [(+)-5]
which required relatively long steps.4) Our need for
the enzymatic conversion of (+)-5 to polycyclic
diterpenes prompted us to develop a more concise
Since resulting 12a corresponds to the C-9 epimer
of the synthetic intermediate of 3 previously report-
ed,1) the same protocol (Wacker oxidation, Horner-
Emmons oleˆnation and DIBAH reduction) as that
±
route to racemic 5. syn-Copalyl diphosphate ( )-4
has been used in the biosynthetic study of aphidicolin
(7), a speciˆc inhibitor of DNA polymerase a
.5) It has
†
To whom correspondence should be addressed. Fax: +81-298-88-8662; E-mail: toshima
＠
ipc.ibaraki.ac.jp
Abbreviations: DIBAH, diisobutylaluminumhydride; DMSO, dimethylsulfoxide; THF, tetrahydrofuran; PTLC, preparative thin-layer
chromatography; HSQC, heteronuclear single-quantum coherence; HMBC, heteronuclear multiple-bond coherence; DQFCOSY, double-
quantum ˆltered correlation spectroscopy; NOESY, nuclear Overhauser enhancement and exchange spectroscopy

±
Total Synthesis of ( )-syn-Copalol
2505
Fig. 1. Biosynthetic Pathway to Polycyclic Diterpenes.
Scheme. Reagents and Conditions: (a) NaBH4
3
z
NaOH, EtOH–CHCl3, 4
, 2 steps; (d) Ac2O, Et3N, DMAP toluene, 70
9
C-r.t., 30 min, 92
z
; (b) DIBAH THF, „78
9
C, 30 min; (c)
; (e) 2,4,6-collidine, re‰ux,
exo):13b endo 4.3:1; (g)
4.2:1; (h) DIBAH Et2O, 4 C, 1 h, 99
W M
C, 2 h, 82
4.7:1; (f) O2, PdCl2, CuCl DMF-H2O, r.t., 5 h, 82
W
Ph3PCH3Br, NaH DMSO, r.t.-70
9
＝
9
C, 2 d, 91
z
W
W
8 h, 93
z
,
12a
(
exo):12b
(
endo
)
z
,
13a
(
(
)
＝
9
W
(EtO)2P(O)CH2CO2Me, NaH THF, „78
(
9
C-r.t., overnight, 83
z
, 14a (exo):14b (endo
)
＝
z
,
W
W
)-5 (exo):endo-isomer 4.2:1.
± ＝
used for 3 would be applicable to the synthesis of
tions could be also determined from the integral
values of the respective oleˆn signals in the 1H-NMR
spectra.
Another characteristic of the reactivity of 13a was
found while keeping 13a in a CHCl3 solution. A more
polar spot apart for 13a appeared by TLC within
several hours, and the product could be separated by
PTLC. Its structure was determined to be that of 15
±
(
)-5. The mixture of 12a and 12b could not be sepa-
rated by silica gel column chromatography, and was
used as such in the three subsequent steps. Wacker
oxidation of 12a 12b gave a 4.3:1 mixture of
W
methylketone 13a and its endo-isomer (13b) in an
82
z yield. The ratio of the exo- and endo-isomers
from the Wacker oxidation and the subsequent reac-

2506
H. TOSHIMA et al.
Fig. 2. Structure of the Carbonyl-ene Reaction Product (15) and Similarity between Chemical and Enzymatic Cyclization.
as the sole isomer with respect to the position of the
double bond by NMR experiments (500 MHz and
800 MHz), including HSQC, HMBC, DQFCOSY,
and phase-sensitive NOESY. The gradient-selected
was scarcely aŠected in the last three steps. At this
stage, the endo-isomer derived from 12b could be
separated by HPLC. The spectral data (1H-NMR,
13C-NMR, and IR) are identical with those of 5.4)
In conclusion, we developed a practical new syn-
J
-HMBC experiment9) in particular gave structurally
3
＝
±
±
informative values for JCH (C-15 H-12eq. 2.2 Hz;
thetic route to ( )-syn-copalol [( )-5] via diene 12a
corresponding to the C-9 epimer of the synthetic in-
termediate of 3. The same protocol (Wacker oxida-
tion, Horner-Emmons oleˆnation and DIBAH
reduction) as that used for the synthesis of 3 was ap-
W
C-15 H-12ax.
1.2 Hz; and C-15 H-14eq. 1.5 Hz)
＝ ＝
W
W
which revealed a C-13 stereogenic center as shown in
3
Fig. 2. The typical values for diaxial JCH have been
reported to be in the range between 5–9 Hz.10) The
carbonyl-ene reaction11) would be promoted to give
15 in the presence of a trace amount of HCl generat-
ed from CHCl3. The corresponding C-9 epimer of
13a did not provide any cyclization products, sugges-
ting that the conformation of the transition state of
13a was signiˆcantly more stable than that of the C-9
epimer. It is noteworthy that this cyclization resem-
±
plicable to the synthesis of ( )-5. In addition to both
enantiomers of copalol (3 and ent-3), (
±
)-5 could be
obtained by this synthesis. These compounds are es-
sential for the biosynthetic study of polycyclic diter-
penes. The optical resolution of (
±
)-5 is in progress.
Experimental
bles the enzymatic cyclization of (+)-4 to 9b-pimara-
7,15-diene (16).4) The resulted tricyclic system of 15
might be useful as a synthetic intermediate and ana-
log of more complex diterpenes.
General methods. 1H- and 13C-NMR spectra were
recorded with Jeol JNM-EX-270 (1H at 270 MHz;
13C at 67.8 MHz), Bruker AMX 500 (1H at 500 MHz;
13C at 125 MHz) and Bruker AVANCE 800 (1H at
Horner-Emmons oleˆnation of 13a 13b with
W
1
diethyl methoxycarbonylmethyl phosphonate and
800 MHz) spectrometers. Chemical shifts in the H-
sodium hydride in THF gave a 4.2:1 mixture of (
E
)-
NMR spectra are reported as
to the residual proton [
7.15 ppm (C6D6)], and in the 13C-NMR spectra as
d
(ppm) values relative
a
,
b
-unsaturated ester 14a and its endo-isomer (14b)
in an 83 yield after chromatographic separation of
the corresponding exo- and endo-isomers of the ( )-
-unsaturated ester (13 yield). Reduction of 14a
14b with DIBAH in ether gave ( )-5 containing the
d
7.26 ppm (CDCl3) or
d
d
z
Z
(ppm) values relative to the 13C signal of the solvent
a
W
,
b
z
[d 77.0 ppm (CDCl3) or 128.0 ppm (C6D6)]. IR spec-
±
tra were measured with a Perkin Elmer 2000 FT-IR
spectrometer, and mass spectra were recorded with a
endo-isomer in a 99
z
yield. The ratio of endo exo
W

±
Total Synthesis of ( )-syn-Copalol
2507
Jeol JMS-AX500 or Jeol JMS-SX102A spectrome-
ter. Melting point (mp) values were obtained with
Yanaco micro-melting point apparatus and are un-
corrected. Analytical and preparative TLC were
respectively performed on precoated silica gel 60 F254
plates of Merck Art. 5715 and Art. 5744. Column
chromatography was carried out with 60 N silica gel
mosphere. To the resulting solution of dimsyl sodium
in DMSO was added methyltriphenylphosphonium
bromide (1.38 g, 3.87 mmol), and the mixture was
stirred at 709C for 30 min. To the resulting ylide so-
lution was added a solution of the crude lactol in dry
THF (4.0 ml) at room temperature. After being
stirred for 2 h, the reaction mixture was partitioned
between EtOAc (20 ml) and H2O (20 ml). The organ-
ic layer was successively washed with H2O (20 ml)
and brine (10 ml), and concentrated under reduced
pressure. The residue was puriˆed by column chro-
(spherical, neutral, 100–210
cal Co.
mm) from Kanto Chemi-
*
*
*
*
(4aR ,6aS ,10aS ,10bS )-4a,7,7,10a-Tetra-
methyldodecahydrobenzo[f]chromen-3-one ( ). To a
stirred solution of 86) (715 mg, 1.43 mmol) in 3
NaOH (1.0 ml), EtOH (7.0 ml) and CHCl3 (7.0 ml)
was added NaBH4 (108 mg, 2.86 mmol) at 4 C. After
being stirred for 30 min at room temperature, the
mixture was acidiˆed with 3 HCl and extracted
＝
matography (50 g of silica gel, hexane:EtOAc 10:1)
9
M
z
to give 10 (280 mg, 82 ) as a colorless oil. EIMS
m z: 265 (1.0, MH+), 264 (5.0, M+), 249 (5.0,
W
9
M+„CH3), 246 (6.2, M+„H2O), 231 (11.7), 221
(4.2), 206 (3.6), 195 (51.3), 192 (21.9), 177 (69.3), 137
(39.4), 136 (13.5), 123 (41.8), 109 (52.9), 95 (64.4), 81
(80.0), 69 (100), 55 (69.6), 43 (55.5), 41 (54.2);
M
×
with CHCl3 (3 10 ml). The combined extracts were
washed with brine (10 ml), dried over anhydrous
Na2SO4, and concentrated under reduced pressure.
The resulting crystalline residue was recrystallized
HRMS m z (M+): calcd. for C18H32O, 264.2453;
W
1
found, 264.2429; H-NMR (270 MHz, C6D6)
d
: 0.74
(3H, s), 0.81 (3H, s), 0.96 (3H, s), 1.27 (3H, s),
0.90–1.74 (14H, m), 1.94–2.26 (3H, m), 5.01 (1H,
from EtOAc hexane to give 9 (347 mg, 92
z) as
W
＝
＝
17.1, 1.3 Hz),
colorless needles. Mp 125–127
9
C; EIMS m z: 265
dq,
J
10.2, 1.3 Hz), 5.12 (1H, dq,
J
W
(9.9, MH+), 264 (31.9, M+), 249 (50.3, M+„CH3),
221 (6.0), 192 (50.0), 177 (54.8), 137 (90.6), 136
(100), 123 (67.7), 109 (64.9), 95 (59.9), 81 (68.7), 69
5.93 (1H, ddt,
(67.8 MHz, C6D6)
J
17.1, 10.2, 6.7 Hz); 13C-NMR
＝
d: 19.2, 21.2, 21.7, 25.1, 27.0,
32.5, 33.2, 33.5, 37.0, 38.1, 38.2, 39.0, 42.6, 46.9,
61.0, 72.9, 114.4, 139.8; IR nmax (ˆlm) cm„1: 3457,
3074, 2998, 2947, 2868, 1640, 1461, 1462, 1414, 1384,
1365, 1332, 1295, 1268, 1240, 1207, 1183, 1159, 1110,
1089, 1068, 1053, 1012, 999, 973, 936, 906, 889, 869,
853, 821, 779.
(53.0), 55 (43.7), 43 (52.9), 41 (59.2); HRMS m z
W
(M+): calcd. for C17H28O2, 264.2090; found,
1
264.2064; H-NMR (270 MHz, CDCl3)
d: 0.82 (6H,
s), 0.88 (3H, s), 1.16 (3H, s), 1.63 (3H, s), 1.07–2.10
＝
17.5, 13.4, 6.1 Hz), 2.61
(14H, m), 2.26 (1H, ddd,
(1H, ddd,
MHz, CDCl3)
J
J
17.5, 4.5, 2.5 Hz); 13C-NMR (67.8
: 18.8, 19.5, 20.8, 21.8, 24.5, 30.8,
＝
d
*
*
*
*
(1R ,2R ,4aS ,8aS )-2-Acetoxy-1-(but-3-enyl)-
2,5,5,8a-tetramethyldecahydronaphthalene (11).
31.4, 33.3, 33.4, 36.9, 37.6, 38.1, 42.2, 47.2, 54.1,
88.0, 171.0; IR nmax (ˆlm) cm„1: 2947, 2870, 1731,
1466, 1421, 1388, 1352, 1337, 1324, 1292, 1269, 1242,
1217, 1195, 1160, 1141, 1117, 1096, 1080, 1040, 1024,
1002, 975, 955, 896, 802, 753.
A
mixture of 10 (190 mg, 0.72 mmol), Et3N (1.0 ml,
7.18 mmol), DMAP (261 mg, 2.15 mmol), and Ac2O
(0.34 ml, 3.59 mmol) in dry toluene (7.0 ml) was
9
stirred for 2 days at 70 C. The reaction mixture was
concentrated under reduced pressure. The residue
was puriˆed by column chromatography (40 g of
*
*
*
*
(1S ,2R ,4aS ,8aS )-1-(But-3-enyl)-2,5,5,8a-
tetramethyldecahydronaphthalen-2-ol 10). To
stirred solution of 9 (340 mg, 1.29 mmol) in dry THF
(7.0 ml) at „78 C under an argon atmosphere was
added dropwise DIBAH (a 0.93 hexane solution,
＝
silica gel, hexane:EtOAc 10:1) to give 11 (200 mg,
(
a
91
z
) as a colorless oil. EIMS m z: 307 (0.3, MH+),
W
9
306 (1.2, M+), 291 (0.4, M+„CH3), 264 (6.0,
M+„C2H2O), 246 (18.0, M+„C2H4O2), 231 (39.1),
205 (14.9), 192 (28.9), 177 (40.4), 149 (25.0), 137
(60.5), 136 (31.9), 123 (63.2), 109 (87.7), 95 (76.0), 81
(100), 69 (77.7), 55 (60.2), 43 (82.9), 41 (56.4);
M
1.52 ml, 1.41 mmol). The mixture was stirred for
30 min at the same temperature. After successively
adding sat. aq. Rochelle salt (3.0 ml), H2O (3.0 ml),
and EtOAc (5.0 ml) at „78
9
C, the resulting mixture
HRMS m z (M+): calcd. for C20H34O2, 306.2559;
found, 306.2588; H-NMR (270 MHz, C6D6)
W
1
was stirred for 1 h at room temperature and then
ˆltered through a Celite pad. The resulting ˆltrate
was separated, and the aqueous layer was extracted
d
: 0.71
(3H, s), 0.78 (3H, s), 0.95 (3H, s), 1.75 (3H, s), 1.76
(3H, s), 1.00–1.74 (13H, m), 2.04–2.35 (3H, m), 4.98
×
＝
＝
17.1,
with EtOAc (2 10 ml). The combined organic layers
(1H, dq,
1.3 Hz), 5.87 (1H, ddt,
NMR (67.8 MHz, C6D6)
J
10.2, 1.3 Hz), 5.09 (1H, dq,
17.1, 10.2, 6.7 Hz); 13C-
: 19.0, 20.2, 21.6, 22.3,
J
were washed with brine (10 ml) and concentrated un-
der reduced pressure to give a crude lactol, which was
used for the next Wittig reaction without puriˆca-
J
＝
d
24.6, 27.6, 28.2, 33.1, 33.4, 36.4, 37.0, 37.2, 39.2,
42.5, 46.7, 57.3, 85.5, 114.1, 139.6, 169.4; IR nmax
(ˆlm) cm„1: 3075, 2991, 2946, 2901, 2869, 1732,
1640, 1460, 1449, 1385, 1366, 1320, 1277, 1251, 1206,
tion. A suspension of NaH (ca. 60
155 mg, 3.87 mmol) in dry DMSO (8.0 ml) was
stirred at 70 C for 30 min under an argon at-
z
in an oil,
9

2508
H. TOSHIMA et al.
1
1181, 1158, 1115, 1086, 1051, 1016, 974, 940, 908,
841, 820, 784.
for C18H30O, 262.2297; found, 262.2314; H-NMR
(270 MHz, C6D6) d: 0.79 (3H, s), 0.84 (3H, s), 0.95
(3H, s), 1.69 (3H, s), 0.98–2.19 (16H, m), 4.51 (1H,
2.5 Hz); 13C-
＝
*
*
*
＝
(1R ,4aS ,8aS )-1-(But-3-enyl)-2-methylene-
5,5,8a-trimethyldecahydronaphthalene (12a). A solu-
tion of 11 (152 mg, 0.50 mmol) in 2,4,6-collidine
(4.0 ml) was re‰uxed for 8 h. After being cooled, the
reaction mixture was diluted with Et2O (20 ml), and
dd,
NMR (67.8 MHz, C6D6)
24.1, 29.8, 31.9, 33.4, 33.8, 37.1, 38.4, 42.1, 42.9,
J
2.5, 1.5 Hz), 4.73 (1H, br. t,
J
d
: 19.7, 20.4, 22.6, 22.8,
46.0, 57.7, 110.1, 149.4, 206.2; IR nmax (ˆlm) cm„1
:
3065, 2939, 2868, 2845, 1718, 1645, 1459, 1409, 1389,
1379, 1365, 1253, 1226, 1159, 1115, 1044, 976, 888.
×
HCl (2 10 ml), sat.
successively washed with 0.5
M
1
aq. NaHCO3 (10 ml) and brine (10 ml). The organic
layer was concentrated under reduced pressure. The
residue was puriˆed by column chromatography
Partial NMR data were assigned for 13b. H-NMR
(270 MHz, C6D6) d: 0.82 (3H, s), 0.87 (3H, s), 0.93
(3H, s), 1.67 (3H, s), 5.30 (1H, m); 13C-NMR
(67.8 MHz, C6D6) : 19.3, 22.4, 24.0, 24.7, 25.4,
＝
(30 g of silica gel, hexane:EtOAc 50:1) to give a
d
4.7:1 mixture of 12a and 12b (114 mg, 93
z
) as a
29.6, 33.1, 33.5, 36.9, 37.2, 42.5, 43.1, 45.1, 54.2,
colorless oil. Data are given for 12a containing 12b.
120.9, 136.0, 205.7 (one 13C signal overlaps).
EIMS m z: 247 (2.2, MH+), 246 (11.1, M+), 231
W
(74.3, M+„CH3), 217 (4.1), 205 (13.5), 192 (22.3),
177 (31.8), 149 (34.6), 137 (89.3), 123 (45.9), 109
(83.4), 95 (76.6), 81 (100), 69 (62.4), 55 (52.0), 43
Methyl (9
[methyl syn-copalate
(EtO)2P(O)CH2CO2Me (291 mg, 1.38 mmol) in dry
THF (4.0 ml) was added NaH (60 in an oil,
56.0 mg, 1.38 mmol) at 4 C. The mixture was stirred
at room temperature for 30 min under an argon at-
b
H)-labda-8(17),13(E)-dien-15-oate
(
14a)]. To solution of
a
(15.9), 41 (61.5); HRMS m z (M+): calcd. for
z
W
C18H30, 246.2347; found, 246.2382; 1H-NMR
9
(270 MHz, CDCl3)
d: 0.81 (3H, s), 0.87 (3H, s), 0.92
＝
(3H, s), 1.00–2.26 (16H, m), 4.52 (1H, dd,
J
2.5,
9
mosphere. To the resulting solution at „78 C was
added a mixture of 13a 13b (90.2 mg, 0.34 mmol) in
＝
1.5 Hz), 4.69 (1H, br. t,
J
2.5 Hz), 4.94 (1H, dq,
W
J
＝
10.2, 1.3 Hz), 4.99 (1H, dq,
J
＝
17.1, 1.3 Hz),
dry THF (2.0 ml). The mixture was gradually allowed
to warm to room temperature and then stirred over-
night. After being diluted with sat. aq. NH4Cl (5 ml)
and water (10 ml), the reaction mixture was extracted
＝
5.82 (1H, ddt,
(67.8 MHz, CDCl3)
J
17.1, 10.2, 6.7 Hz); 13C-NMR
d: 19.3, 22.3, 22.4, 23.7, 25.8,
31.7, 32.5, 33.3, 33.6, 36.8, 42.8, 45.8, 57.7, 109.3,
114.0, 139.4, 149.1 (one 13C signal overlaps); IR nmax
(ˆlm) cm„1: 3068, 2939, 2868, 1642, 1460, 1443,
1415, 1389, 1380, 1366, 1340, 1279, 1260, 1225, 1209,
1169, 1143, 1101, 1043, 991, 978, 936, 909, 888, 852,
×
with EtOAc (2 10 ml). The combined organic layers
were washed with brine (10 ml), dried over anhy-
drous Na2SO4, and concentrated under reduced
pressure. The residue was puriˆed by PTLC (hexane:
832, 808, 755. Partial NMR data were assigned for
EtOAc
0.63, 14.1 mg, 13
14b (Rf 0.58, 90.7 mg, 83
z
＝
30:1) to give a mixture of (
) and a 4.2:1 mixture of 14a and
) as colorless oils. Data
Z )-isomers (Rf
＝
1
12b. H-NMR (270 MHz, CDCl3)
d
: 0.86 (3H, s),
z
0.90 (3H, s), 0.92 (3H, s), 5.25 (1H, m); 13C-NMR
(67.8 MHz, CDCl3) : 18.9, 22.08, 22.12, 23.6, 24.3,
＝
d
are given for 14a containing 14b. EIMS m z: 319
W
31.0, 32.9, 33.2, 35.9, 36.4, 38.0, 42.2, 42.9, 53.9,
114.1, 119.7, 136.6, 139.2.
(5.4, MH+), 318 (20.1, M+), 287 (6.8, M+„CH3O),
271 (11.6), 244 (16.6), 229 (9.7), 205 (36.7), 177
(40.8), 163 (11.9), 149 (30.3), 137 (64.3), 109 (90.9),
95 (77.5), 81 (100), 69 (69.9), 55 (57.8), 43 (21.1), 41
*
*
*
(1R ,4aS ,8aS )-2-Methylene-1-(3-oxobutyl)-
5,5,8a-trimethyldecahydronaphthalene (13a). A mix-
ture of 12a 12b (112 mg, 0.45 mmol), PdCl2 (8.1 mg,
(66.4); HRMS m z (M+): calcd. for C21H34O2,
W
318.2559; found, 318.2548; 1H-NMR (270 MHz,
W
0.05 mmol), and CuCl (45.1 mg, 0.05 mmol) in DMF
(3.5 ml) and H2O (0.5 ml) was stirred at room tem-
perature for 5 h under an oxygen atmosphere. The
C6D6) d: 0.79 (3H, s), 0.85 (3H, s), 0.93 (3H, s),
0.95–2.12 (16H, m), 2.22 (3H, br. s), 3.44, (3H, s),
4.55 (1H, dd,
J 2.5, 1.5 Hz), 4.75 (1H, br. t,
＝
2.5 Hz), 5.87 (1H, br. s); 13C-NMR (67.8 MHz,
＝
reaction mixture was acidiˆed with 0.5
M
HCl (10 ml)
J
×
and extracted with EtOAc (2 10 ml). The combined
organic layers were successively washed with water
(10 ml) and brine (10 ml), dried over anhydrous
Na2SO4, and concentrated under reduced pressure.
C6D6)
d
: 19.2, 19.7, 22.5, 22.7, 24.1, 24.6, 31.9,
33.5, 33.8, 37.1, 38.4, 39.9, 43.0, 46.2, 50.5, 58.0,
110.3, 115.8, 148.8, 160.6, 166.8; IR n :
max (ˆlm) cm„1
3067, 2945, 2869, 2845, 1723, 1651, 1457, 1435, 1388,
1381, 1359, 1323, 1279, 1224, 1204, 1188, 1148, 1115,
1060, 1034, 978, 922, 946, 888, 864, 809, 738. Partial
NMR data were assigned for 14b. 1H-NMR
＝
The residue was puriˆed by PTLC (hexane:EtOAc
15:1) to give a 4.3:1 mixture of 13a and 13b (97.3 mg,
82
z
) as a colorless oil. Data are given for 13a con-
taining 13b. EIMS m z: 263 (10.8, MH+), 262 (54.5,
(270 MHz, C6D6)
(3H, s), 1.61 (3H, br. s), 2.22 (3H, br. s), 3.43 (3H,
s), 5.26 (1H, m); 13C-NMR (67.8 MHz, C6D6)
d: 0.83 (3H, s), 0.86 (3H, s), 0.92
W
M+), 247 (14.2, M+„CH3), 244 (41.0), 229 (32.3),
204 (100), 189 (19.1), 177 (20.1), 137 (43.9), 123
(21.4), 109 (49.9), 95 (53.1), 81 (35.5), 69 (29.6), 55
d
:
19.24, 22.5, 22.4, 23.8, 24.1, 24.7, 29.9, 33.1, 33.4,
36.8, 37.2, 43.1, 43.2, 54.4, 115.8, 120.7, 136.0,
(26.5), 43 (54.1), 41 (33.9); HRMS m z (M+): calcd.
W

±
Total Synthesis of ( )-syn-Copalol
2509
160.2, 166.7 (two 13C signals overlap).
(13.9), 69 (13.9), 55 (13.5), 43 (19.1), 41 (15.4);
HRMS m z (M+): calcd. for C18H30O, 262.2296;
W
±
±
(
)-(9
b
H)-Labda-8(17),13(E)-dien-15-ol
[( )-
found, 262.2261; 1H-NMR (800 MHz, CDCl3)
d
:
±
syn-copalol, ( )-(
5
)]. To a solution of a mixture of
0.89 (3H, s), 0.91 (3H, s), 0.95 (3H, s), 1.16 (1H, m),
1.19 (1H, m), 1.22 (3H, s), 1.24 (1H, m), 1.25 (1H,
14a 14b (85.3 mg, 0.27 mmol) in dry Et2O (3.0 ml)
W
＝
12.6, 2.7 Hz), 1.42 (2H, m),
was added DIBAH (a 0.93
M
hexane solution, 0.86
m), 1.34 (1H, br. dd,
J
ml, 0.80 mmol) at 4 C under an argon atmosphere.
9
1.44 (2H, m), 1.57 (1H, m), 1.74 (1H, m), 1.75 (1H,
m), 1.88 (1H, m), 2.02 (1H, m), 2.02 (OH), 2.03 (1H,
The mixture was stirred at the same temperature for 1
h. After successively adding sat. aq. Rochelle salt
＝
m), 2.13 (1H, dt,
J
12.6, 1.6 Hz), 5.47 (1H, d,
: 18.7,
(3.0 ml), H2O (3.0 ml), and EtOAc (5.0 ml) at 4
9
C,
J
＝
5.4 Hz); 13C-NMR (125 MHz, CDCl3)
d
the reaction mixture was stirred for 1 h at room tem-
22.0, 22.6, 23.8, 25.4, 28.9, 32.8, 33.4, 35.1, 36.6,
39.3, 42.9, 43.2, 50.4, 52.6, 70.4, 122.1, 137.2; IR
×
perature and then extracted with EtOAc (2 10 ml).
The combined organic layers were washed with brine
(5 ml), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was puri-
ˆed by column chromatography (10 g of silica gel,
n
max (ˆlm) cm„1: 3482, 2930, 2867, 1456, 1378, 1365,
1317, 1296, 1238, 1186, 1159, 1124, 1106, 1085, 1033,
1018, 978, 922, 882, 870, 810, 796, 740.
＝
±
hexane:EtOAc 4:1) to give ( )-(5) containing the
Acknowledgments
＝
z
, exo:endo 4.2:1) as a
endo-isomer (77.0 mg, 99
colorless oil. The desired exo-isomer was obtained as
We are grateful to Mr. K. Watanabe and Dr. E.
Fukushi (Faculty of Agriculture at Hokkaido Univer-
sity) for measuring the MS and NMR (500 MHz)
data. Financial support by grant-aid for scientiˆc
research (No. 11460053) from the Ministry of Educa-
tion, Science, Sports and Culture of Japan is grate-
fully acknowledged.
the sole isomer by HPLC separation under the fol-
×
z
lowing conditions: column, Wakosil-5C18 (q5
250 mm, Wako); UV, 210 nm; solvent, 100
CH3CN; ‰ow rate, 1.5 ml min; tR
:
endo-isomer,
W
±
10.30 min; exo-isomer [( )-(5)], 10.42 min. Repeat-
ed separation gave (
±
)-(5) (44.6 mg) and a mixture
of both iomers (28.0 mg) as colorless oils. Data are
given for ( )-(5). EIMS m z: 291 (3.8, MH+), 290
±
References
W
(14.1, M+), 275 (37.0, M+„CH3), 272 (60.5,
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(35.9), 192 (49.6), 191 (53.6), 177 (65.4), 163 (15.7),
149 (39.6), 137 (55.7), 123 (46.5), 109 (100), 95
(81.6), 81 (86.1), 69 (63.1), 55 (47.4), 43 (17.9), 41
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290.2610; found, 290.2606; 1H-NMR (270 MHz,
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＝
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±
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±
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*
*
*
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W
262 (37.6, M+), 245 (5.5, M+„OH), 244 (22.3,
M+„H2O), 229 (24.1), 204 (100), 189 (12.8), 175
(5.0), 161 (16.3), 123 (8.7), 109 (43.7), 95 (30.5), 81

2510
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