Chemoenzymatic synthesis of (+)-totarol, (+)-podototarin, (+)-sempervirol, and (+)-jolkinolides E and D

Article abstract of DOI:10.1016/j.tetasy.2007.11.024

The enzymatic resolution products [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-7 (98% ee) and {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-9 (>99% ee)] obtained by the lipase-catalyzed enantioselective acetylation of (±)-7 in the presence of vinyl acetate as an acyl donor were converted to the α,β-unsaturated ketones (8aR)-6 and (8aS)-6, respectively. Concise syntheses of (+)-totarol 1, (+)-podototarin 2 and (+)-sempervirol 3 were achieved based on Michael reactions between (8aS)-6 and the appropriate β-keto ester followed by aldol condensation. The first chiral syntheses of (+)-jolkinolides E 4 and D 5 were achieved from (5R,10R,12R)-12-hydroxypodocarpa-8(14)-en-13-one 15 derived from (8aR)-6.

Full text of DOI:10.1016/j.tetasy.2007.11.024

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2915–2922
Chemoenzymatic synthesis of (+)-totarol, (+)-podototarin,
(+)-sempervirol, and (+)-jolkinolides E and D
Takahiro Miyake,a,b Hideo Kigoshic and Hiroyuki Akitaa,*
aFaculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
bTsukuba Research Institute, Novartis Pharma K.K., 8 Ohkubo, Tsukuba-shi, Ibaraki 300-2611, Japan
cDepartment of Chemistry, University of Tsukuba 1-1-1 Tsukuba-shi, Ibaraki 305-8571, Japan
Received 31 October 2007; accepted 19 November 2007
Abstract—The enzymatic resolution products [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-
1-methanol-2-ethylene acetal (8aR)-7 (98% ee) and {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-
trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-9 (>99% ee)] obtained by the lipase-catalyzed enantioselective acetylation of
( )-7 in the presence of vinyl acetate as an acyl donor were converted to the a,b-unsaturated ketones (8aR)-6 and (8aS)-6, respectively.
Concise syntheses of (+)-totarol 1, (+)-podototarin 2 and (+)-sempervirol 3 were achieved based on Michael reactions between (8aS)-6
and the appropriate b-keto ester followed by aldol condensation. The first chiral syntheses of (+)-jolkinolides E 4 and D 5 were achieved
from (5R,10R,12R)-12-hydroxypodocarpa-8(14)-en-13-one 15 derived from (8aR)-6.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Many natural products contain the podocarpane skeleton,
including (+)-totarol 1,1 (+)-podototarin 2,2 (+)-sempervi-
rol 3,3 and (+)-jolkinolides E 44 and D 54 (Scheme 1). To
synthesize these compounds, the construction of the C-ring
of the chiral podocarpane skeleton is necessary. This can be
achieved by a Michael reaction between chiral a,b-unsatu-
rated ketone 6 and a b-keto ester followed by an aldol con-
densation. We previously reported that the lipase-assisted
resolution of racemic primary alcohol ( )-7, derived from
( )-b-keto ester 8, gave (8aS)-acetate 9 (49%, >99% ee)
and (8aR)-primary alcohol 7 (49%, 98% ee).5 This enzy-
matic resolution method was found to be effective, with
an estimated E-value of 921. Chiral (8aS)- and (8aR)-6
could be obtained from (8aS)-9 and (8aR)-7, respectively.
Herein we report concise syntheses of (+)-1, (+)-2, (+)-3
from (8aS)-9, and the first synthesis of (+)-4 and (+)-5
from (8aR)-7.
2.1. Syntheses of (+)-totarol 1 and (+)-podototarin 2
(+)-Totarol 1,1 a rare tricyclic diterpene phenol possessing
an isopropyl group at the C(14) position, was first isolated
as a major constituent of the heartwood of Podocarpus tot-
ara G. Benn and can also be isolated from a variety of other
sources. It has been shown to have antibacterial activity
against gram-positive bacteria, particularly methicillin-
resistant Staphylococcus aureus (MRSA), with an MIC of
2.7 lM in vitro.6 The structure of 1 was deduced on the
basis of chemical and spectroscopic analysis,7 while the
absolute structure was determined by ORD measurement
and by direct correlation with dehydroabietic acid.8 (+)-
Podototarin 2 was also isolated from the heartwood of
Podocarpus totara,2 and its structure was determined based
on the synthesis from natural (+)-1.9 The total synthesis of
(+)-1 was achieved by intramolecular cyclization of a chiral
phenethylcyclohexene congener derived from (R)-(ꢀ)-a-
cyclocitral10 and also by conversion of natural products
such as manool11 or zamoranic acid.12 Straightforward
syntheses of (+)-1 and (+)-2 are shown in Scheme 2.
*
The consecutive treatment of the previously reported (8sS)-
75 with 10% HCl and p-TsOH gave a,b-unsaturated ketone
Corresponding author. Tel.: +81 047 472 1805; fax: +81 047 472 1825;
e-mail: akita@phar.toho-u.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.024

2916
T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
OH
H
O
O
H
H
(+)-1
O
O
HO
OH
OH
OH
H
H
4
(+)-
(+)-5
H
(+)-2
(+)-3
R
1) Michael reaction
2) Aldol condensation
C
O
+
R1COCH2COOR2
B
A
H
H
6
OAc
O
OH
O
COOMe
O
8a
isopropenyl acetate
lipase PL-266
O
O
7
( )-
+
in (i-Pr)2O, 33 °C
H
H
H
( )-8
(8aS)-9
(8aR)-7
49%, 98 %ee
49%, >99 %ee
OH
O
O
O
ref. 5
O
9
(8aS)-
(8aR)-7
H
H
H
7
6
(8aS)-
(8aS)-
(8aR)-6
Scheme 1.
COOMe
O
O
O
O
d
c
a
b
e
7
(8aS)-
1
(+)-
(+)-2
H
H
H
(10S)-11
10
OH
(8aS)-6
f
OR3
O
g
O
h
R3 = H (+)-3
i
H
H
H
3
14
12
(10S)-13
R = Ac (+)-
Scheme 2. Reagents and conditions: (a) (1) 10% HCl/MeOH, (2) p-TsOH/PhH; (b) methyl 5-methyl-3-oxohexanoate/NaOMe/MeOH; (c) (1) 1 M NaOH/
MeOH, (2) 5 M HCl, 100 °C; (d) CuBr2/LiBr/MeCN; (e) aq KOH/K3[Fe(CN)6]/PhH; (f) (1) methyl acetoacetate/NaOMe/MeOH, (2) 5 M NaOH, (3) 5 M
HCl; (g) (1) LDA/THF, (2) acetone/0.5 M ZnCl2/THF; (h) CeCl3ꢂ7H2O/NaI/MeCN (i) Ac2O/pyridine.
(8aS)-6 in quantitative yield; this was used for the subse-
quent reaction without further purification. A Michael
reaction of (8aS)-6 with the anion obtained from the reac-
tion of methyl 5-methyl-3-oxohexanoate13 with NaOMe
gave a 2:1 diastereomeric mixture of 10 in quantitative
yield. Alkaline hydrolysis of 10 followed by treatment with
5 M HCl gave the aldol condensation product (10S)-11 in
55% overall yield. Treatment of 11 with CuBr2 and LiBr
gave the product (+)-totarol 1 in 76% yield. The physical
data of synthetic (+)-1 (mp 123–124 °C and 1H NMR)
were in agreement with those of the reported (+)-1 (mp
129–130 °C and 1H NMR).12 The specific rotation
27
{½aꢁD ¼ þ41:9 (c 1.0, CHCl3)} of synthetic (+)-1 was also
in accordance with that of the previously reported sample
25
{½aꢁD ¼ þ41:2 (c 0.4, CHCl3)}.12 Oxidation of (+)-1 with
alkaline potassium ferricyanide [K3Fe(CN)6] by the re-
ported procedure9b gave (+)-2 in 45% yield. The specific
27
rotation (½aꢁD ¼ þ73:5 (c 1.0, CHCl3)) of the synthetic

T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
2917
(+)-2 was in accordance with that of natural (+)-2
sis followed by treatment with 5 M HCl to afford the aldol
condensation product (10R)-13 in 46% overall yield. Lithi-
ation of (10R)-13 followed by treatment with trimethylsilyl
chloride gave a silyl enol ether, which underwent treatment
with m-chloroperbenzoic acid (MCPBA) followed by
desilylation with tetrabutylammonium fluoride (TBAF)
to afford a-hydroxy ketone 15 in 51% overall yield. Esteri-
fication of 15 with 2-(diethylphosphono)propanoic acid in
the presence of 4-dimethylaminopyridine (DMAP) and
1,3-dicyclohexylcarbodiimide (DCC), as reported previ-
ously,16 gave ester 16, which was treated with NaH to
afford (+)-jolkinolide E 4 in 48% yield. The 1H NMR data
24
f½aꢁD ¼ þ76:1 (c 1.0, CHCl3)}.2c
2.2. Syntheses of (+)-sempervirol 3
(+)-Sempervirol 2,3 a rare tricyclic diterpene phenol pos-
sessing an isopropyl group at the C(12) position, was iso-
lated from Cupressus sempervirens. Total syntheses of
racemic 3 and its acetate ( )-12 have been achieved by
intramolecular cyclization of an a,b-unsaturated ketone
congener obtained by condensation of b-cyclocitral with
4-isopropyl-3-methoxybenzyl chloride,14 while the synthesis
of natural (+)-3 was accomplished by a novel conversion of
of synthetic (+)-4 were identical to those of the previously
21
methyl 12-bromodehydroabietate.15
A
straightforward
reported sample4 and the specific rotation f½aꢁD ¼ þ337 (c
synthesis of (+)-3 from (8aS)-6 is shown in Scheme 2. A
Michael reaction of (8aS)-6 with the anion obtained from
the reaction of methyl acetoacetate with NaOMe gave a
Michael addition product, which was subjected to alkaline
hydrolysis followed by treatment with 5 M HCl to afford
the aldol condensation product (10S)-13 in 46% overall
yield. Lithiation of (10S)-13 followed by treatment with ace-
tone in the presence of 0.5 M ZnCl2 gave aldol product 14 in
59% overall yield. Finally, treatment of 14 with a combina-
tion of CeCl3 and NaI, followed by dehydration and aroma-
tization, afforded (+)-3 in 82% overall yield. The 1H NMR
0.6, CHCl3)} of the synthetic (+)-4 was also in agreement
20
with that previously reported f½aꢁD ¼ þ340 (c 0.45,
CHCl3)}.4 Silylation of 15 followed by treatment with a
dianion derived from 2-iodoallyl alcohol, as reported
previously,17 gave (ꢀ)-18 27% overall yield from 15,
28
½aꢁD ¼ ꢀ40:7 (c 0.15, CHCl3) and (ꢀ)-19 (32% overall yield
30
1
from 15, ½aꢁD ¼ ꢀ27:3 (c 0.64, CHCl3)), whose H NMR
data were identical with those of the previously reported
samples of 18 and 19.17 Desilylation of the obtained prod-
30
uct (ꢀ)-19 gave triol (ꢀ)-20 (93% yield, ½aꢁD ¼ ꢀ76:8 (c
0.1,CHCl3)), which was treated with MnO2 to afford jolk-
inolode D (5) in 82% yield. The physical data (mp
190.5 °C and 1H NMR) of the synthetic (+)-5 were in
agreement with those of the previously reported sample
data of synthetic (+)-3 were identical to those reported for
23
the natural sample.14b The specific rotation f½aꢁD ¼ þ54:2
(c 1.0, CHCl3)} of synthetic (+)-3 was also in accordance
with that of natural (+)-3 ([a]D = +60.2 (CHCl3)).14b Acet-
ylation of (+)-3 gave its acetate (+)-12 in quantitative yield;
1
(mp 200–201 °C and H NMR).4 and the specific rotation
21
f½aꢁD ¼ þ301 (c 0.5, CHCl3)} of synthetic (+)-5 was in
20
1
the physical data of synthetic (+)-12 (mp 88 °C and H
agreement with that of natural (+)-5 f½aꢁD ¼ þ360 (c
NMR) were in agreement with those of the previously
0.28, CHCl3)}.4
reported sample of (+)-12 (mp 92–94 °C and 1H NMR).14b
23
In addition, the specific rotation f½aꢁD ¼ þ49:7 (c 1.0,
CHCl3)} of synthetic (+)-12 was in agreement with that
of the previously reported sample {[a]D = +55.4
(CHCl3)}.14b
3. Conclusion
The enzymatic resolution products [(1R,4aR,8aR)-1,2,3,4,
4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naph-
thalene-1-methanol-2-ethylene acetal (8aR)-7 (98% ee)
and {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahy-
dro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-
2-ethylene acetal} (8aS)-9 (>99% ee)] were obtained based
on the lipase-catalyzed enantioselective acetylation of ( )-7
in the presence of vinyl acetate as an acyl donor. The
obtained (8aS)-9 and (8aR)-7 were converted to a,b-unsat-
urated ketones (8aS)-6 and (8aR)-6, respectively. Concise
syntheses of (+)-totarol 1, (+)-podototarin 2, and (+)-sem-
pervirol 3 were achieved based on Michael reactions
between (8aS)-6 and the appropriate b-keto ester followed
by aldol condensation. The first chiral syntheses of (+)-
jolkinolides E 4 and D 5 were achieved using (5R,10R,
12R)-12-hydroxypodocarpa-8(14)-en-13-one 15 derived
from (8aR)-6.
2.3. Syntheses of (+)-jolkinolides E 4 and D 5
Jolkinolides A, B, C, D 5 and E 4 are diterpenoids, which
were originally isolated from the roots of Euphorbia Jolkini
Boiss.4 The absolute structures of these compounds were
determined by a chemical transformation to ferruginol,
which possesses an abietane-type skeleton; the stereostruc-
ture of 5 was also confirmed by X-ray crystallographic
analysis.15 Jolkinolide D 5 exhibits cytotoxicity, inhibits
tumor invasion into the basement membrane, and induces
apoptosis in tumor cells.15 A total synthesis of racemic 4
was achieved based on the intramolecular Wittig–Horner
reaction.16 We carried out the first total synthesis of the
enantiomer of 5 from abietic acid.17 Total syntheses of nat-
ural jolkinolodes 4 and 5 have not been reported. Straight-
forward syntheses of (+)-4 and (+)-5 from (8aR)-6 are
shown in Scheme 3.
4. Experimental
4.1. General
Consecutive treatment of the previously reported com-
pound (8aR)-75 with 10% HCl and p-TsOH gave a,b-unsat-
urated ketone (8aR)-6 in quantitative yield. A Michael
reaction of (8aR)-6 with the anion obtained from the reac-
tion of methyl acetoacetate with NaOMe gave a Michael
addition product, which was subjected to alkaline hydroly-
All melting points were measured on a Buchi 535 melting
¨
point apparatus and are uncorrected. H and 13C NMR
1
spectra were recorded on Bruker AV400M digital NMR

2918
T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
OR4
O
O
O
b
a
c
e
7
(8aR)-
(+)-4
H
H
H
13
(10R)-
(8aR)-6
R4 = H
15
d
R4 = COCH(Me)P(OEt)2 16
O
OH
+
OH
OR4
TBDMSO
OR4
O
OH
i
OH
g
5
(+)-
H
H
H
R4 = H
18
R4 = TBDMS
15
19
h
f
R4 = SiMe2But (TBDMS)
R4 = H
17
20
Scheme 3. Reagents and conditions: (a) (1) 10% HCl/MeOH, (2) p-TsOH/PhH; (b) (1) methyl acetoacetate/NaOMe/MeOH, (2) 1 M NaOH/MeOH, (3)
5 M HCl; (c) (1) LDA/TMSCl/THF, (2) MCPBA/CH2Cl2; (d) 2-(diethylphosphono)propanoic acid/DMAP/DCC/CH2Cl2; (e) 60% NaH/DME; (f)
TBDMSCl/imidazole/DMF; (g) 2-iodoallyl alcohol/tBuLi/Et2O; (h) TBAF/THF; (i) MnO2/CH2Cl2.
spectrometer in CDCl3. High-resolution mass spectra
(HRMS) and the fast atom bombardment mass spectra
(FAB MS) were obtained with a JEOL JMS 600H
spectrometer and JEOL GC-Mate spectrometer (matrix;
m-nitrobenzylalcohol). IR spectra were recorded with a
JASCO FT/IR-4100 spectrometer. Optical rotations were
measured with a JASCO P-1020 digital polarimeter. All
evaporations were performed under reduced pressure.
For column chromatography, silica gel (KANTO Silica
Gel 60N, spherical, neutral, 40–50 mM) was employed.
(ii) To a solution of methyl 5-methyl-3-oxohexanoate13
(0.693 g, 4.4 mmol) and NaOMe (0.237 g, 44 mmol) in
MeOH (5 mL) was added dropwise a solution of (8aS)-6
(0.753 g) in MeOH (5 mL) at rt and the reaction mixture
was stirred for 16 h at the same temperature. The reaction
mixture was diluted with ice-water and extracted with
AcOEt. The organic layer was dried over Na2SO4 and
evaporated to give a residue, which was chromatographed
on silica gel (50 g, n-hexane–AcOEt = 4:1) to give a 2:1 dia-
stereomeric mixture of 10 (1.330 g, quantitative yield) as a
pale yellow oil. 10 (major product): IR (KBr): 2958, 1748,
1712, 1463, 1435, 1366, 1238, 1189 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 3.70 (3H, s), 3.51–3.46 (1H, m),
2.49 (1H, d, J = 6.6 Hz), 2.47–2.37 (2H, m), 2.33–1.96
(5H, m), 1.93–1.87 (1H, m), 1.87–1.79 (1H, m), 1.71–1.58
(1H, m), 1.57–1.49 (2H, m), 1.47–1.41 (2H, m), 1.31–1.19
(2H, m), 0.95 (3H, d, J = 3.0 Hz), 0.94 (3H, d,
J = 3.0 Hz), 0.92 (3H, s), 0.85 (3H, s), 0.73 (3H, s); 13C
NMR (100 MHz, CDCl3) d 212.0, 205.4, 170.4, 61.4,
57.4, 54.0, 52.1, 50.9, 42.6, 42.3, 41.7, 38.8, 33.7, 33.4,
24.3, 23.8, 22.3, 22.3, 21.7, 20.9, 18.9, 14.6; (minor product)
1H NMR (400 MHz, CDCl3) d 3.71 (3H, s), 3.58–3.53 (1H,
m), 2.49 (1H, d, J = 6.6 Hz), 2.47–2.37 (2H, m), 2.33–1.96
(5H, m), 1.93–1.87 (1H, m), 1.87–1.79 (1H, m), 1.71–1.58
(1H, m), 1.57–1.49 (2H, m), 1.47–1.41 (2H, m), 1.31–1.19
(2H, m), 0.95 (3H, d, J = 3.5 Hz), 0.94 (3H, d,
J = 2.0 Hz), 0.93 (3H, s), 0.84 (3H, s), 0.73 (3H, s);
HREI-MS: m/z: calcd for C22H36O4: 364.2614. Found:
364.2616.
4.2. (+)-Totarol 1
(i) To a solution of (8aS)-7 (0.98 g, 3.65 mmol) in MeOH
(50 mL) was added 10% aqueous HCl (15 mL) at 0 °C
and the reaction mixture was stirred for 2 h at 0 °C. The
reaction mixture was diluted with ice-water and extracted
with AcOEt. The organic layer was washed with saturated
NaHCO3 and brine, and dried over Na2SO4, after which it
was evaporated to give a crude oil. To a solution of the
crude oil in benzene (50 mL) was added p-toluenesulfonic
acid (p-TsOH, 0.14 g, 0.73 mmol) and the reaction mixture
was stirred for 1 h at 50 °C. The reaction mixture was di-
luted with ice-water and extracted with AcOEt. The organ-
ic layer was washed with saturated NaHCO3 and brine,
and dried over Na2SO4, and evaporated to give a crude
oil (8aS)-6 (0.753 g, quantitative yield), which was used
for the next reaction without further purification. (8aS)-6:
1H NMR: d 0.92 (3H, s), 0.96 (3H, s), 1.02 (3H, s), 1.25
(1H, dd, J = 12.6, 5.0 Hz), 1.40 (1H, dd, J = 12.6,
3.0 Hz), 1.44–1.53 (2H, m), 1.57–1.64 ( 2H, m), 1.73–1.80
(2H, m), 1.93–2.00 (1H, m), 2.33 (1H, ddd, J = 17.0,
12.6, 7.6 Hz), 2.67 (1H, ddd, J = 17.0, 5.5, 2.0 Hz), 5.01
(1H, d, J = 1.2 Hz), 5.54 (1H, d, J = 1.2 Hz).
(iii) To a solution of 10 (1.1 g, 3.0 mmol) in MeOH (50 mL)
was added 1 M aqueous NaOH (9 mL) and the reaction
mixture was stirred for 4 h at 100 °C. After cooling, to
the above reaction mixture was added 5 M aqueous HCl
(5 mL) and the reaction mixture was stirred for 6 h at
100 °C. The reaction mixture was diluted with ice-water

T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
2919
and extracted with AcOEt. The organic layer was washed
with saturated NaHCO3 and brine, and dried over Na2SO4.
Evaporation of the organic solvent gave a crude oil, which
was chromatographed on silica gel (50 g, n-hexane–
AcOEt = 4:1) to give (10S)-11 (4.476 g, 55%) as a pale yel-
low oil. (10S)-11: IR (KBr): 2924, 2868, 1712, 1663, 1459,
20.2, 21.6, 25.3, 27.7, 28.8, 33.2, 33.3, 37.8, 39.8, 41.6,
49.6, 120.8, 124.4, 132.0, 135.0, 143.3, 150.0. HREI-MS:
m/z: calcd for C40H58O2: 570.4437. Found: 570.4418. Anal.
Calcd for C40H58O2ꢂ1.5H2O: C, 80.35; H, 10.28. Found: C,
80.58; H, 9.86.
1366, 1238, 1189 cmꢀ1
;
1H NMR: d 0.74 (3H, s), 0.86
4.4. (+)-Sempervirol 3
(3H, s), 0.92 (3H, s), 0.80–1.11 (3H, m), 1.13 (3H, d,
J = 7.0 Hz), 1.19 (3H, d, J = 7.0 Hz), 1.38–1.69 (6H, m),
1.75–1.83 (1H, m), 1.86–1.96 (2H, m), 2.07 (1H, dd,
J = 9.6, 5.5 Hz), 2.17 (1H, ddd, J = 14.6, 14.6, 5.6 Hz),
2.33 (1H, ddd, J = 9.6, 9.6, 4.6 Hz), 3.08–3.20 (2H, m).
13C NMR: d 14.6, 18.9, 19.7, 20.4, 21.8, 22.0, 22.5, 26.6,
31.4, 33.4, 33.5, 37.9, 38.7, 39.9, 41.8, 52.9, 54.5, 140.1,
157.0, 199.6. HREI-MS: m/z: calcd for C20H32O:
288.2453. Found: 288.2453.
(i) To a solution of methyl acetoacetate (2.1 g, 18 mmol)
and NaOMe (0.973 g, 18 mmol) in MeOH (40 mL) were
added dropwise a solution of (8aS)-6 (3.09 g, 15 mmol) in
MeOH (10 mL) for 2 h at rt and the reaction mixture
was stirred for 16 h at the same temperature. To the above
reaction mixture was added 5 M aqueous NaOH (11 mL)
at rt and the reaction mixture was stirred for 10 h at the
same temperature. After cooling, to the above reaction
mixture were added 5 M aqueous HCl (15 mL) at rt and
the reaction mixture was stirred for 1 h at the same temper-
ature. The reaction mixture was diluted with ice-water
(200 mL) and extracted with AcOEt. The organic layer
was washed with saturated NaHCO3 and brine, and dried
over Na2SO4. Evaporation of the organic solvent gave a
crude oil, which was chromatographed on silica gel (50 g,
(iv) To a solution of (10S)-11 (0.07 g, 0.24 mmol) in MeCN
(2.4 mL) were added CuBr2 (0.108 g, 0.48 mmol) and LiBr
(0.021 g, 0.24 mmol) and the reaction mixture was stirred
for 6 h at rt. The reaction mixture was diluted with water
and extracted with AcOEt. The organic layer was washed
with brine, and dried over Na2SO4. Evaporation of the
organic solvent gave a crude oil, which was chromatographed
on silica gel (20 g, n-hexane–AcOEt = 5:1) to give (+)-1
n-hexane–AcOEt = 4:1) to give (10S)-13 (1.7 g, 46%) as a
22
pale brown oil. (10S)-13: ½aꢁD ¼ þ39:7 (c 1.0, CHCl3); IR
1
(0.053 g, 76%) as a colorless solid. (+)-1: mp 123–124 °C
(KBr): 2908, 1659, 1613, 1457, 1387, 1220, 1173 cmꢀ1; H
27
(n-hexane); ½aꢁD ¼ þ41:9 (c 1.0, CHCl3); IR (KBr): 3587,
NMR: d 0.81 (3H, s), 0.88 (3H, s), 0.93 (3H, s), 1.07–1.25
(3H, m), 1.42–1.58 (4H, m) 1.70–1.78 (3H, m), 1.97–2.09
(2H, m), 2.17–2.32 (2H, m), 2.40 (1H, ddd, J = 15.6, 4.2,
4.2 Hz), 2.54 (1H, dd, J = 15.1, 4.5 Hz), 5.88 (1H, s). 13C
NMR: d 15.3, 18.7, 20.5, 22.0, 22.0, 33.4, 33.6, 35.6, 36.8,
39.0, 39.3, 41.8, 51.7, 53.9, 125.8, 165.8, 199.9. HREI-
MS: m/z: calcd for C17H26O: 246.1984. Found: 246.1987.
1
3460, 2940, 1586, 1455, 1372, 1266, 1176 cmꢀ1; H NMR:
d 0.91 (3H, s), 0.95 (3H, s), 1.17 (3H, s), 1.22 (1H, dd,
J = 13.6, 4.5 Hz), 1.26 (1H, dd, J = 12.6, 2.0 Hz), 1.30–
1.38 (1H, m), 1.33 (3H, d, J = 7.0 Hz), 1.35 (3H, d,
J = 7.0 Hz), 1.44–1.48 (1H, m), 1.56–1.75 (3H, m), 1.88–
1.94 (1H, m), 2.19–2.26 (1H, m), 2.74 (1H, ddd, J = 19.2,
11.1, 7.6 Hz), 2.94 (1H, dd, J = 17.1, 6.6 Hz), 3.29 (1H,
ddd, J = 21.1, 14.1, 7.0 Hz), 4.41 (1H, s), 6.51 (1H, d,
J = 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz). 13C NMR: d 19.4,
19.5, 20.3, 20.4, 21.6, 25.2, 27.1, 28.7, 33.2, 33.3, 37.7,
39.6, 41.6, 49.6, 114.3, 123.0, 131.0, 134.0, 143.2, 151.9.
HREI-MS: m/z: calcd for C20H30O: 286.2297. Found:
286.2302. Anal. Calcd for C20H30O: C, 83.86; H, 10.56.
Found: C, 83.49; H, 10.58.
(ii) To a solution of diisopropylamine (83 lL, 0.6 mmol) in
THF (1 mL) was added 1.6 M n-BuLi in n-hexane solution
(380 lL, 0.6 mmol) at ꢀ78 °C and the reaction mixture was
stirred for 30 min at the same temperature. To the gener-
ated lithium diisopropylamide (LDA) solution was added
a solution of (10S)-13 (0.123 g, 0.5 mmol) in THF (1 mL)
at ꢀ78 °C and the reaction mixture was stirred for
20 min at the same temperature. To the above reaction
mixture was added 0.5 M ZnCl2 in THF solution (1 mL),
acetone (0.1 mL) and THF (0.5 mL) at ꢀ48 °C and the
reaction mixture was stirred for 20 min at ꢀ48 °C and
for 1 h at 0 °C. The reaction mixture was diluted with sat-
urated NH4Cl solution (30 mL) and extracted with AcOEt.
The organic layer was washed with brine, and dried over
Na2SO4. Evaporation of the organic solvent gave a crude
oil, which was chromatographed on silica gel (10 g) to
afford the recovery (10S)-13 (0.026 g, 21%) from n-hex-
ane–AcOEt = 4:1 elution and 14 (0.090 g, 59%) as a color-
4.3. (+)-Podototarin 2
To a solution of (+)-1 (0.04 g, 0.14 mmol) in benzene
(1 mL) was added KOH solution (KOH; 0.039 g, H2O;
1.5 mL) and K3[Fe(CN)6] solution (K3[Fe(CN)6]; 0.077 g,
H2O; 1.5 mL) and the reaction mixture was stirred for
1 h at rt and 40 min at 100 °C. The reaction mixture was
diluted with 5 M aqueous HCl (5 mL) and extracted with
AcOEt. The organic layer was washed with brine, and
dried over Na2SO4. Evaporation of the organic solvent
gave a crude oil, which was chromatographed on silica
gel (10 g, n-hexane–AcOEt = 10:1) to give (+)-2 (0.018 g,
less oil from n-hexane–AcOEt = 2:1 elution. 14:
23
½aꢁD ¼ ꢀ125:2 (c 1.0, CHCl3); IR (KBr): 3452, 2924,
1
45%) as
a
colorless solid. (+)-2: mp 210.0 °C;
½aꢁD ¼ þ73:5 (c 1.0, CHCl3); IR (KBr): 3532, 2934, 1453,
1359, 1223, 1118 cmꢀ1 1H NMR: d 0.92 (6H, s), 0.96
1647, 1460, 1389, 1230, 1167 cmꢀ1; H NMR: d 0.86 (3H,
27
s), 0.92 (3H, s), 0.96 (3H, s), 1.17 (3H, s), 1.21 (3H, s),
1.13–1.25 (3H, m), 1.42–1.64 (4H, m), 1.74–1.83 (1H, m),
1.84–1.93 (2H, m), 2.12–2.32 (3H, m), 2.49 (1H, ddd,
J = 13.6, 4.3, 2.2 Hz), 2.57 (1H, dd, J = 12.1, 5.6 Hz),
4.75 (1H, br s), 5.89 (1H, s). 13C NMR: d 16.1, 19.0,
21.8, 23.1, 23.9, 24.6, 28.4, 33.5, 33.7, 36.7, 40.0, 41.9,
42.2, 50.4, 52.2, 55.0, 73.0, 125.4, 166.9, 203.3. HREI-
;
(6H, s), 1.20 (6H, s), 1.35 (6H, d, J = 7.8 Hz), 1.37 (6H,
d, J = 7.8 Hz), 1.15–1.76 (14H, m), 1.91–1.97 (2H, m),
2.16–2.23 (2H, m), 2.80 (1H, ddd, J = 18.6, 11.0, 8.6 Hz),
2.99 (1H, dd, J = 17.1, 6.0 Hz), 3.15–3.40 (2H, m), 5.07
(2H, br s), 7.00 (2H, s). 13C NMR: d 19.3, 19.4, 20.2,

2920
T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
MS: m/z: calcd for C20H32O2: 304.2402 (M+). Found:
304.2412.
over Na2SO4, and evaporated to give a crude oil (8aR)-6
(0.753 g, quantitative yield), which was used for the next
reaction without further purification.
(iii) A mixture of CeCl3ꢂ7H2O (0.335 g, 0.9 mmol) and NaI
(0.135 g, 0.9 mmol) in MeCN (3 mL) was stirred for 14 h at
100 °C. After cooling, to the reaction mixture was added a
solution of 14 (0.090 g, 0.3 mmol) in MeCN (2 mL) and the
reaction mixture was stirred for 30 h at the same tempera-
ture. The reaction mixture was diluted with ice-water
(200 mL) and extracted with Et2O. The organic layer was
washed with brine, and dried over Na2SO4. Evaporation
of the organic solvent gave a crude oil, which was chro-
matographed on silica gel (10 g, n-hexane–AcOEt = 3:1)
(ii) To a solution of methyl acetoacetate (2.1 g, 18 mmol)
and NaOMe (0.973 g, 18 mmol) in MeOH (40 mL) was
added dropwise a solution of (8aR)-6 (3.09 g, 15 mmol)
in MeOH (10 mL) for 2 h at rt and the reaction mixture
was stirred for 16 h at the same temperature. To the above
reaction mixture was added 5 M aqueous NaOH (11 mL)
at rt and the reaction mixture was stirred for 10 h at the
same temperature. After cooling, to the above reaction
mixture was added 5 M aqueous HCl (15 mL) at rt and
the reaction mixture was stirred for 1 h at the same temper-
ature. The reaction mixture was worked up in the same
to give (+)-3 (0.07 g, 82%) as a colorless oil. (+)-3:
23
½aꢁD ¼ þ54:2 (c 1.0, CHCl3); IR (KBr): 3399, 2924, 1616,
1
1508, 1460, 1416, 1241, 1160 cmꢀ1; H NMR: d 0.92 (3H,
way as for (8aS)-6 to afford (8aR)-13 (1.7 g, 46%) as a pale
29
s), 0.93 (3H, s), 1.17 (3H, s), 1.24 (6H, d, J = 7.0 Hz),
1.20–1.28 (1H, m), 1.32 (1H, dd, J = 12.6, 2.5 Hz), 1.39
(1H, dd, J = 13.1, 4.0 Hz), 1.44–1.50 (1H, m), 1.56–1.88
(4H, m), 2.28 (1H, d, J = 13.1 Hz), 2.71–2.88 (2H, m),
3.13 (1H, ddd, J = 20.6, 14.1, 7.0 Hz), 4.43 (1H, s), 6.42
(1H, s), 7.07 (1H, s). 13C NMR: d 19.0, 19.3, 21.6, 22.7,
22.8, 25.0, 27.2, 30.0, 33.3, 33.4, 37.5, 39.1, 41.7, 50.7,
114.9, 122.4, 131.8, 133.7, 142.8, 150.2. HREI-MS: m/z:
calcd for C20H30O: 286.2297. Found: 286.2299.
brown oil. (8aR)-13: ½aꢁD ¼ ꢀ41:7 (c 0.22, CHCl3). Spectral
1
data (IR, H and 13C NMR) of (8aR)-13 were identical
with those of (8aS)-13.
(iii) To a solution of diisopropylamine (0.68 mL, 4.8 mmol)
in THF (2 mL) was added 1.6 M n-BuLi in n-hexane solu-
tion (3 mL, 4.8 mmol) at ꢀ78 °C and the reaction mixture
was stirred for 30 min at the same temperature. To the gen-
erated lithium diisopropylamide (LDA) solution was added
a solution of (8aR)-13 (0.222 g, 0.9 mmol) in THF (2 mL)
at ꢀ78 °C and the reaction mixture was stirred for 1 h at
the same temperature. To the above reaction mixture was
added trimethylsilyl chloride (TMSCl; 0.8 mL, 4.6 mmol)
and the reaction mixture was stirred for 2 h at rt. The reac-
tion mixture was diluted with Et2O (20 mL) and the organ-
ic layer was washed with saturated NaHCO3 and brine,
and dried over Na2SO4. Evaporation of the organic solvent
gave a crude enol ether (0.7 g), which was used for the next
reaction without further purification. To a solution of a
crude enol ether (0.7 g) in CH2Cl2 (20 mL) was added
65% m-chloroperbenzoic acid (MCPBA; 0.8 g, 3 mmol) at
ꢀ40 °C and the reaction mixture was stirred for 3 h at
the same temperature. The reaction mixture was filtered
and the filtrate was condensed to afford a residue. To a
solution of this residue in CH2Cl2 (10 mL) was added
1 M tetrabutylammonium fluoride (TBAF) in THF solu-
tion (6 mL) at rt and the reaction mixture was stirred for
6 h at rt. The reaction mixture was diluted with saturated
NaHCO3 and CH2Cl2 and the organic layer was washed
with 1 M aqueous HCl and brine, and dried over Na2SO4.
Evaporation of the organic solvent gave a crude oil, which
was chromatographed on silica gel (10 g, n-hexane–
(iv) To a solution of (+)-3 (0.02 g, 0.07 mmol) in pyridine
(0.5 mL) was added Ac2O (0.009 g, 0.08 mmol) and the
reaction mixture was stirred for 16 h at rt. The reaction
mixture was diluted with water and extracted with AcOEt.
The organic layer was washed with 1 M aqueous HCl,
saturated NaHCO3 and brine, and dried over Na2SO4.
Evaporation of the organic solvent gave a crude oil, which
was chromatographed on silica gel (5 g, n-hexane–
AcOEt = 4:1) to give (+)-12 (0.023 g, quantitative yield)
23
as colorless prisms. (+)-12: mp 88.0 °C; ½aꢁD ¼ þ49:7 (c
1.0, CHCl3); IR (KBr): 2932, 1760, 1497, 1462, 1368,
1
1216, 1190 cmꢀ1; H NMR: d 0.92 (3H, s), 0.94 (3H, s),
1.178 (3H, d, J = 7 Hz), 1.178 (3H, s), 1.182 (3H, d,
J = 7 Hz), 1.20–1.28 (1H, m), 1.33 (1H, dd, J = 12.4,
2.3 Hz), 1.38 (1H, dd, J = 13.1, 3.8 Hz), 1.42–1.50 (1H,
m), 1.54–1.88 (4H, m), 2.29 (3H, s), 2.74–2.90 (2H, m),
2.93 (1H, ddd, J = 20.7, 13.6, 6.8 Hz), 6.64 (1H, s), 7.16
(1H, s). 13C NMR: d 19.0, 19.3, 21.0, 21.6, 23.0, 23.2,
25.0, 27.6, 29.9, 33.3, 33.4, 37.8, 38.9, 41.7, 50.2, 121.7,
122.6, 134.0, 136.8, 145.5, 148.0, 169.9. HREI-MS: m/z:
calcd for C22H32O2: 328.2402. Found: 328.2403.
4.5. (+)-Jolkinolide E 4
AcOEt = 3:2) to give 15 (0.12 g, 51%) as a pale yellow
30
oil. 15: ½aꢁD ¼ þ159:8 (c 1.0, CHCl3). IR (KBr): 3397,
1
(i) To a solution of (8aR)-7 (0.98 g, 3.65 mmol) in MeOH
(50 mL) was added 10% aqueous HCl (15 mL) at 0 °C
and the reaction mixture was stirred for 2 h at 0 °C. The
reaction mixture was diluted with ice-water and extracted
with AcOEt. The organic layer was washed with saturated
NaHCO3 and brine, and dried over Na2SO4, and evapo-
rated to give a crude oil. To a solution of the crude oil in
benzene (50 mL) was added p-toluenesulfonic acid (p-
TsOH, 0.14 g, 0.73 mmol) and the reaction mixture was
stirred for 1 h at 50 °C. The reaction mixture was diluted
with ice-water and extracted with AcOEt. The organic
layer was washed with saturated NaHCO3 and brine, dried
2929, 1613, 1265, 1068, 871 cmꢀ1; H NMR: d 0.86 (3H,
s), 0.92 (3H, s), 1.00 (3H, s), 1.13–1.30 (3H, m), 1.42–1.65
(4H, m), 1.78–2.02 (3H, m), 2.23–2.31 (1H, m), 2.48–2.56
(1H, m), 3.55 (1H, s), 4.31 (1H, dd, J = 13.0, 6.5 Hz),
5.92 (1H, s). 13C NMR: d 16.4, 19.1, 21.7, 24.0, 29.4,
33.6, 33.8, 37.1, 40.0, 42.0, 42.3, 51.5, 55.0, 69.3, 121.5,
167.6, 199.8. HREI-MS: m/z: calcd for C20H32O:
288.2453. Found: 288.2453.
(iv) To a solution of 15 (0.055 g, 0.21 mmol) in CH2Cl2
(1 mL) was added 4-dimethylaminopyridine (DMAP;
0.029 g, 0.24 mmol), 2-(diethylphosphono)propanoic acid

T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
2921
(0.046 g, 0.22 mmol) and 1,3-dicyclohexylcarbodiimide
(DCC; 0.05 g, 0.24 mmol) and the reaction mixture was
stirred for 30 min at rt. The reaction mixture was diluted
with ice-water and extracted with AcOEt. The organic
layer was washed with 1 M aqueous HCl, saturated NaH-
CO3, brine, and dried over Na2SO4. Evaporation of the or-
ganic solvent gave the crude oil 16 (0.1 g), which was used
for the next reaction without further purification.
was chromatographed on silica gel (10 g, n-hexane–
AcOEt = 3:1) to give (ꢀ)-18 (0.041 g, 36%) as a colorless
oil and (ꢀ)-19 (0.05 g, 43%) as a colorless prism in elution
28
order. 18; ½aꢁD ¼ ꢀ40:7 (c 0.15, CHCl3); IR (KBr): 3420,
1
2931, 2858, 1461, 1387, 1251, 1085, 835 cmꢀ1; H NMR:
d 0.12 (6H, s), 0.75 (3H, s), 0.86 (3H, s), 0.91 (12H, s),
1.07 (1H, dd, J = 12.6, 2.5 Hz), 1.10–1.75 (11H, m), 1.83–
1.90 (1H, m), 2.05–2.16 (1H, m), 2.38 (1H, ddd, J = 14.4,
4.5, 1.5 Hz), 3.33 (1H, br s), 3.99 (1H, dd, J = 5.0,
1.5 Hz), 4.09 (1H, d, J = 12.6 Hz), 4.34 (1H, d,
J = 12.6 Hz), 5.12 (1H, d, J = 1.5 Hz), 5.20 (1H, d,
J = 1.5 Hz), 5.27 (1H, d, J = 1.5 Hz). 13C NMR: d ꢀ5.0,
ꢀ4.2, 15.0, 18.2, 18.9, 22.1, 22.2, 25.4, 25.9 (3C), 33.4,
33.7, 35.0, 37.8, 39.1, 42.0, 46.6, 54.6, 64.6, 71.2, 76.2,
117.7, 123.5, 140.8, 150.0. HREI-MS: m/z: calcd for
(v) To a solution of 16 (0.1 g) in DME (2 mL) was added
60% NaH (0.01 g, 0.25 mmol) at 0 °C and the reaction mix-
ture was stirred for 3 h at rt. The reaction mixture was di-
luted with saturated NH4Cl and extracted with AcOEt.
The organic layer was washed with saturated NaHCO3,
brine, and dried over Na2SO4. Evaporation of the organic
solvent gave a crude oil, which was chromatographed on
silica gel (10 g, n-hexane–AcOEt = 5:1) to give (+)-4
C26H46O3:Si 434.3216. Found: 434.3222. 19; mp 105.3 °C;
30
½aꢁD ¼ ꢀ27:3 (c 0.64, CHCl3); IR (KBr): 3421, 2928,
1
(0.030 g, 48% from 15) as colorless prism. (+)-4: mp
2856, 1461, 1254, 1092, 835 cmꢀ1; H NMR: d 0.03 (3H,
21
182.3 °C; ½aꢁD ¼ þ337 (c 0.6, CHCl3); IR (KBr): 2958,
s), 0.08 (3H, s), 0.83 (3H, s), 0.85 (3H, s), 0.86 (9H, s),
0.90 (3H, s), 1.09–1.83 (12H, m), 1.90 (1H, t, J = 6.5 Hz),
2.07–2.17 (1H, m), 2.36 (1H, ddd, J = 14.0, 4.0, 1.5 Hz),
2.45 (1H, br s), 2.90 (1H, br s), 3.91 (1H, dd, J = 7.6,
3.5 Hz), 4.14 (1H, d, J = 12.6 Hz), 4.30 (1H, d,
J = 12.6 Hz), 4.97 (1H, d, J = 1.0 Hz), 5.22 (1H, d,
J = 1.0 Hz), 5.40 (1H, s). 13C NMR: d ꢀ4.6, ꢀ4.4, 15.4,
18.2, 19.1, 22.1, 22.5, 25.9 (3C), 26.4, 28.1, 29.8, 33.4,
33.7, 35.4, 38.6, 39.4, 42.1, 48.4, 54.6, 65.1, 73.7, 76.3,
116.6, 124.3, 142.0, 149.0. HREI-MS: m/z: calcd for
C26H46O3SiNa 457.3114 (M++Na). Found: 457.3116.
1748, 1670, 1607, 1368, 1086, 1020 cmꢀ1 1H NMR: d
;
0.86 (3H, s), 0.92 (3H, s), 0.93 (3H, s), 1.05–1.25 (3H, m),
1.36–1.63 (5H, m), 1.84 (3H, s), 1.80–1.88 (1H, m), 1.89–
1.97 (1H, m), 2.15–2.25 (2H, m), 2.51 (1H, ddd, J = 13.4,
4.0, 2.3 Hz), 2.58 (1H, dd, J = 13.4, 6.2 Hz), 4.88 (1H,
ddd, J = 13.4, 6.2, 1.5 Hz), 6.27 (1H, br s). 13C NMR: d
8.3, 16.8, 19.1, 21.8, 23.9, 27.6, 33.6, 33.9, 37.2, 39.7,
41.7, 42.0, 51.9, 55.3, 76.1, 113.9, 116.2, 152.3, 156.3,
175.4. HREI-MS: m/z: calcd for C20H28O2: 300.2089.
Found: 300.2095.
4.6. (+)-Jolkinolide D 5
(iii) To a solution of 19 (0.085 g, 0.2 mmol) in THF (2 mL)
was added 1 M tetrabutylammonium fluoride (TBAF) in
THF solution (4 mL) at 0 °C and the reaction mixture
was stirred for 1 h at rt. The reaction mixture was diluted
with saturated NH4Cl and extracted with AcOEt. The or-
ganic layer was washed with brine and dried over Na2SO4.
Evaporation of the organic solvent gave a crude oil, which
was chromatographed on silica gel (10 g, n-hexane–
(i) To a solution of 15 (0.105 g, 0.4 mmol) in DMF (2 mL)
were added imidazole (0.17 g, 2.5 mmol) and tbutyldimeth-
ylsilyl chloride (TBDMSCl; 0.19 g, 1.25 mmol) at rt and
the reaction mixture was stirred for 2 h at rt. The reaction
mixture was diluted with H2O and extracted with Et2O.
The organic layer was washed with brine and dried over
Na2SO4. Evaporation of the organic solvent gave a crude
oil, which was chromatographed on silica gel (10 g, n-hex-
AcOEt = 1:1) to give 20 (0.058 g, 93%) as colorless plates.
30
20: mp 130.4 °C; ½aꢁD ¼ ꢀ76:8 (c 0.1, CHCl3); IR (KBr):
1
ane–AcOEt = 50:1) to give (+)-17 (0.113 g, 75%) as a pale
3191, 2948, 2841, 1486, 1364, 1046, 902 cmꢀ1; H NMR:
30
yellow oil. Compound 17; ½aꢁD ¼ þ16:7 (c 0.1, CHCl3); IR
d 0.81 (3H, s), 0.86 (3H, s), 0.90 (3H, s), 1.00–1.74 (11H,
m), 1.85 (2H, dd, J = 8.0, 4.5 Hz), 2.00 (1H, t,
J = 8.0 Hz), 2.12–2.22 (1H, m), 2.37 (1H, ddd, J = 14.3,
4.5, 2.0 Hz), 3.86 (1H, ddd, J = 8.0, 4.0, 1.0 Hz), 4.23
(1H, d, J = 12.3 Hz), 4.34 (1H, d, J = 12.3 Hz), 5.09 (1H,
d, J = 1.5 Hz), 5.35 (1H, d, J = 1.0 Hz), 5.46 (1H, d,
J = 1.0 Hz). 13C NMR: d 14.8, 18.9, 22.1, 22.4, 24.2,
33.4, 33.7, 35.5, 38.3, 39.0, 42.0, 46.7, 54.6, 64.4, 70.6,
75.1, 116.5, 122.6, 144.7, 149.9. HREI-MS: m/z: calcd for
C20H32O3: 320.2352. Found: 320.2354.
(KBr): 2938, 1676, 1471, 1262, 1123, 840 cmꢀ1; 1H NMR: d
0.05 (3H, s), 0.08 (3H, s), 0.82 (3H, s), 0.87 (12H, s), 0.93
(3H, s), 1.06–1.28 (3H, m), 1.40–1.55 (4H, m), 1.72–1.90
(3H, m), 1.99–2.07 (1H, m), 2.24–2.35 (2H, m), 2.52 (1H,
ddd, J = 15.0, 4.5, 1.8 Hz), 4.07–4.15 (1H, m), 5.78 (1H,
t, J = 2 Hz). 13C NMR: d ꢀ5.1, ꢀ4.7, 14.2, 15.4, 18.9,
22.0, 22.5, 25.8 (3C), 30.1, 33.5, 33.7, 36.0, 39.4 (2C),
41.9, 48.9, 54.2, 71.8, 122.9, 165.6, 197.8. FAB-MS: m/z:
377 (M++1).
(ii) To a solution of 2-iodoallyl alcohol (0.04 g, 2.2 mmol)
in Et2O (2.5 mL) was added 1.5 M BuLi in pentane solu-
(iv) To a solution of 20 (0.032 g, 0.1 mmol) in CHCl3
(2 mL) was added MnO2 (Aldrich, 0.086 g, 0.1 mmol) at
rt and the reaction mixture was stirred for 16 h at rt. To
the above reaction mixture was again added MnO2 (Al-
drich, 0.086 g, 0.1 mmol) at rt and the reaction mixture
was stirred for 8 h at rt. The reaction mixture was filtered
with the aid of Celite and the filtrate was condensed to give
a crude oil, which was chromatographed on silica gel (10 g,
t
tion (3.5 mL, 5.3 mmol) at ꢀ78 °C and the reaction mix-
ture was stirred for 10 min at 0 °C. To the anion
generated was added a solution of 17 (0.1 g, 0.27 mmol)
in Et2O (2.5 mL) and the reaction mixture was stirred for
3 h at 0 °C. The reaction mixture was diluted with MeOH
(1 mL), H2O and extracted with AcOEt. The organic layer
was washed with brine and dried over Na2SO4. Evapora-
tion of the organic solvent gave a crude oil, which
n-hexane–AcOEt = 1:1) to give (+)-5 (0.026 g, 82%) as col-
21
orless prisms. (+)-5: mp 190.5 °C; ½aꢁD ¼ þ301 (c 0.5,

2922
T. Miyake et al. / Tetrahedron: Asymmetry 18 (2007) 2915–2922
4. Uemura, D.; Hirata, Y. Chem. Lett. 1974, 819–822.
5. Amano, Y.; Kinoshita, M.; Akita, H. J. Mol. Catal. B:
Enzym. 2005, 32, 141–148.
6. Muroi, H.; Kubo, I. Biosci. Biotchnol. Biochem. 1994, 58,
1925–1926.
7. Barltrop, J. A.; Rogers, N. A. J. J. Chem. Soc. 1958, 2566–
2572.
8. (a) Chow, Y.-L.; Erdtmann Acta Chem. Scand. 1960, 14,
1852; (b) Chow, Y.-L.; Erdtmann Acta Chem. Scand. 1962,
16, 1305.
9. (a) Cambie, R. C.; Simpson, W. R. J.; Colebrook, L. D.
Tetrahedron 1963, 19, 209–217; (b) Falshaw, C. P.; Johnson,
A. W.; King, T. J. J. Chem. Soc. 1963, 2422–2428; (c) Day, A.
G. J. Chem. Soc. 1964, 3001–3005.
10. Matsumoto, T.; Suetsugu, A. Bull. Chem. Soc. Jpn. 1979, 52,
1450–1453.
11. Evans, G. B.; Furneaux, R. H.; Gravestock, M. B.; Lynch, G.
P.; Scott, G. K. Bioorg. Med. Chem. 1999, 7, 1953–1964.
12. Marcos, I. S.; Cubillo, M. A.; Moro, R. F.; Carballares, S.;
Diez, D.; Basabe, P.; Llamazartes, C. F.; Beneitez, A.; Sanz,
F.; Broughton, H. B.; Urones, J. G. Tetrahedron 2005, 61,
977–1003.
CHCl31); IR (KBr): 3450, 2936, 2837, 1748, 1382, 1273, 982
cmꢀ1; H NMR: d 0.80 (3H, s), 0.86 (3H, s), 0.90 (3H, s),
1.07–1.51 (7H, m), 1.59–1.67 (1H, m), 1.67–1.75 (2H, m),
1.92–1.99 (1H, m), 2.02 (1H, br s), 2.06–2.16 (1H, m),
2.22 (1H, ddd, J = 15.0, 6.0, 4.0 Hz), 2.28–2.35 (1H, m),
4.42–4.46 (1H, m), 5.15 (1H, d, J = 1.5 Hz), 5.81 (1H, s),
6.21 (1H, s). 13C NMR: d 15.1, 18.8, 21.3, 21.7, 22.1,
33.4, 33.6, 35.1, 37.6, 39.5, 41.8, 44.6, 53.9, 72.9, 81.1,
120.1, 120.8, 142.8, 145.0, 171.5. HREI-MS: m/z: calcd
for C20H28O3: 316.2039. Found: 316.2032.
Acknowledgments
The authors are grateful to Mr. Takayanagi Y. and Mr.
Yamaura M., Department of Chemistry, University of
Tsukuba for their technical assistance.
References
13. Domon, K.; Mori, K. Eur. J. Org. Chem. 1999, 979–980.
14. (a) Matsumoto, T.; Usui, S.; Fukui, K. Chem. Lett. 1976,
241–244; (b) Matsumoto, T.; Usui, S. Bull. Chem. Soc. Jpn.
1979, 52, 212–215.
15. Kigoshi, H.; Ichino, T.; Yamada, K.; Ijuin, Y.; Makita, S. F.;
Uemura, D. Chem. Lett. 2001, 518–519.
16. Katsumura, S.; Isoe, S. Chem. Lett. 1982, 1689–1692.
17. Suenaga, K.; Takayanagi, Y.; Yamamura, M.; Kigoshi, H.
Chem. Lett. 2004, 33, 918–919.
1. Easterfield, T. H.; McDowell, J. C. Trans. New Zealand Inst.
1915, 48, 578.
2. (a) Brandt, C. W.; Thomas, B. R. New Zealand J. Sci.
Technol. 1951, 33B, 950; (b) Cambie, R. C.; Mander, L. N.
Tetrahedron 1962, 18, 465–475; (c) Cambie, R. C.; Simpson,
W. R. J.; Colebrook, L. D. Tetrahedron 1963, 19, 209–217.
3. Mangoni, L.; Caputo, R. Tetrahedron Lett. 1967, 8,
673–675.