Synthesis and absolute configuration of annuionone A

Article abstract of DOI:10.1016/j.tet.2005.07.017

Synthesis of both enantiomers of annuionone A (1), an allelopathic agent isolated from Helianthus annuus (sunflower), was accomplished. The absolute configuration of the naturally occurring 1 was determined to be 1S,5R,8R.

Full text of DOI:10.1016/j.tet.2005.07.017

Tetrahedron 61 (2005) 8830–8835
Synthesis and absolute configuration of annuionone A
*
Hirosato Takikawa, Makiko Tobe, Kazuhiko Isono and Mitsuru Sasaki
Department of Biosystems Science, Graduate School of Science and Technology, Kobe University, Rokkodai, Nada-ku,
Kobe 657-8501, Japan
Received 2 June 2005; revised 6 July 2005; accepted 7 July 2005
Available online 26 July 2005
Abstract—Synthesis of both enantiomers of annuionone A (1), an allelopathic agent isolated from Helianthus annuus (sunflower), was
accomplished. The absolute configuration of the naturally occurring 1 was determined to be 1S,5R,8R.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Annuionone A and its relatives (annuionones B–G) have
´
been isolated from Helianthus. annuus (sunflower) by Macıas
and his co-workers as allelopathic agents.1 Although, the
initially proposed structure of annuionones A was
structurally unique ionone-type bisnorsesquiterepenes with
an exo-epoxide moiety,1a the correct structure has been
confirmed by our racemate synthesis to be 1 as depicted in
Scheme 1.2,3 However, the absolute configurations of the
naturally occurring 1 and other annuionones have still
remained unsolved. Thus, we initiated the synthesis of
optically active annuionone A (1) to determine its absolute
stereochemistry. Herein, we report the synthesis of both
enantiomers of 1 in detail.
Our synthetic plan for 1 is illustrated in Scheme 1. The
target compound 1 was obtainable by Wacker oxidation of
the intermediate A. For construction of the 6-oxabicyclo-
[3.2.1]octane framework of A, we adopted oxy-Michael
reaction as an appropriate methodology. The intermediate B
should be available from the known compound C, which
was prepared from D. This synthetic plan was completely
based on our racemate synthesis.2 Thus, the remaining
problem was how to prepare the optically active form. In
other words, there was a need to carry out optical resolution
or asymmetric reaction at an appropriate stage.
Scheme 1. Structure of annuionone A (1) and its synthetic plan.
2. Results and discussion
First, the known ketoester 2 was prepared according to the
reported procedure.4 The chemoselective reduction of the
ester group of 2 was achieved by treatment with LDA and
then DIBAL, furnishing 3 (86%). The hydroxyl group of 3
was protected as the t-butyldimethylsilyl (TBS) ether to give
4 (91%). For installation of the 3-oxobutyl side-chain, we
first attempted homoallylation of 4, because a homoallyl
group was thought to be convertible into a 3-oxobutyl group
with ease by Wacker oxidation.5 Unfortunately, however,
the conversion of 4 into 5 was not so successful. Even after
an in-depth study of the reaction conditions, the observed
Keywords: Sesquiterpene; Allelochemical; Absolute configuration; Optical
resolution.
*
Corresponding author. Tel./fax: C81 78 803 5958;
e-mail: takikawa@kobe-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.017

H. Takikawa et al. / Tetrahedron 61 (2005) 8830–8835
8831
best yield was only 18% under the following conditions:
LDA, THF, HMPA, 4-iodo-1-butene, K78 8C to room
temperature. Thus, we then turned to crotylation of 4, which
was performed by treatment with LDA and crotyl bromide
in the presence of HMPA, furnishing a chromatographically
inseparable mixture of 6a and 6b (90%; 6a:6bZca. 5:1,
8 (86%). The relative configuration of 8 was confirmed by
the observation of NOE as depicted in Scheme 2.
As mentioned before, there was a need to secure an optically
active intermediate. We envisioned adopting optical
resolution. For the purpose of conventional optical
resolution, (G)-8 was converted into the corresponding
secondary alcohol (G)-9 by diastereoselective reduction
with L-Selectridew (78%). Our first attempts to resolve (G)-
9 by enzymatic resolution did not succeed, even after
screening of over ten hydrolytic enzymes such as Lipase PS,
Lipase AK, Chirazyme L-2, etc. The next attempt was the
so-called classical resolution using a chiral derivatizing
reagent. To our delight, we found that the corresponding
(R)-a-methoxy-a-(trifluoromethyl)phenylacetates [(R)-
MTPA esters, 10a/b] were chromatographically separable.8
By careful chromatography, we obtained the less polar
diastereomer 10a (41%) and the more polar 10b (40%),
respectively. Application of a modified Mosher’s method9
made it possible to determine the absolute configurations of
10a/b, because the crucial Dd (10aK10b) values were
clearly observed in 1-Me, 5-Me and 7-H as shown in
Figure 1. The obtained diastereomerically pure 10a was
subjected to reductive cleavage of the resolving auxiliary to
furnish (C)-9 (76%). This was then oxidized with
o-iodoxybenzoic acid (IBX)10 to give (C)-8 (86%). Finally,
1
based on H NMR analysis). Although, it could be easily
deduced that the major diastereomer should be the b-isomer
(6a) by consideration of the steric factor, its relative
configuration could not be determined by NOE studies,
because the signals assigned as 6- and 10-H were poorly
resolved. At this stage, we have also found that 6a
contained its (Z)-isomer (w10%),6 that was derived from
geometrically impure crotyl bromide (commercially avail-
able). However, we continued our synthesis without further
purification, because we already knew that the (Z)-isomer
was inseparable but would not impede our tasks all through
the steps. From now on, thus, the presence of (Z)-isomer is
not mentioned to avoid difficulty of description and also
unnecessary confusion. Treatment with MeLi and the
following work-up could convert 6a/b into a mixture of 7
and its 4-epimer (85%). At this stage, diastereomers with
regard to C-4 were separated by careful chromatography to
give the diastereomerically pure 7.7 After removal of the
TBS protecting group of 7, subsequent intramolecular oxy-
Michael addition took place to give the desired adduct (G)-
Scheme 2. Synthesis of both enantiomers of 1. Reagents and conditions: (a) LDA, THF, DIBAL, toluene (86%); (b) TBSCl, imidazole, DMF (91%); (c) LDA,
THF, crotyl bromide, HMPA (90%); (d) MeLi, Et2O, satd aq NH4Cl (85%); (e) TBAF, THF (86%); (f) L-Selectridew, THF, K78 8C (78%); (g) (S)-MTPACl,
DMAP, pyridine, 40 8C (41% for 10a and 40% for 10b); (h) LiAlH4, THF (76%); (i) IBX, DMSO (86%); (j) PdCl2, CuCl, O2, aq DMF (64% for 1 and 6% for
11).

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H. Takikawa et al. / Tetrahedron 61 (2005) 8830–8835
in anhydrous THF (10 mL) was added at K78 8C. After
stirring for 30 min with warming to K15 8C gradually,
DIBAL (1.5 M in toluene; 7.4 mL, 11 mmol) was added at
K78 8C. After the mixture was stirred for 1 h at room
temperature, it was quenched with MeOH and saturated
aqueous Rochelle’s salt, and extracted with EtOAc. The
organic layer was dried with MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give 3 (0.73 g, 86%) as a colorless oil:
IR (neat) 3400 (s, O–H), 1650, 1630, 1600 (each s, C]O,
C]C) cmK1; 1H NMR d 1.02 (s, 3H, 5-Me), 2.09 (dd, JZ
1.2, 16.5 Hz, 1H, 6-H), 2.10 (dd, JZ1.2, 17.4 Hz, 1H, 4-H),
2.42 (d, JZ16.5 Hz, 1H, 6-H), 2.60 (d, JZ17.4 Hz, 1H,
4-H), 2.75 (br s, 1H, OH), 3.40 (s, CH2OH, 2H), 3.68 (s,
OMe, 3H), 5.34 (s, 1H, 2-H); 13C NMR d 22.6, 37.1, 37.4,
45.4, 55.8, 69.5, 101.0, 177.2, 199.5; HRMS (EI) m/z calcd
for C9H14O3: 170.0943, found 170.0939.
Figure 1. Absolute configurations of 10a/b.
Wacker oxidation5 of (C)-8 was followed by SiO2 column
chromatography to furnish (1S,5R,8R)-(C)-1 (64%), [a]2D2 C
16.9 (cZ0.50 in CHCl3), {lit.1a [a]D25 C12.3 (cZ0.4 in
CHCl3)}, and its regioisomer 11 (6%). The various spectral
data of synthetic (1S,5R,8R)-(C)-1 are in good accord with
those of the naturalproduct. Similarly, 10b was also converted
into (1R,5S,8S)-(K)-1, [a]2D3K17.6 (c 0.35 in CHCl3).
Therefore, the absolute configuration of the naturally
occurring annuionone A (1) was determined as 1S,5R,8R.
4.1.2. 5-t-Butyldimethylsilyloxymethyl-3-methoxy-5-
methyl-2-cyclohexen-1-one (4). Imidazole (0.86 g,
13 mmol) and TBSCl (1.9 g, 13 mmol) were added to a
solution of 3 (1.44 g, 8.46 mmol) in DMF (15 mL) at room
temperature. After stirring overnight, the reaction mixture
was quenched with saturated aqueous NH4Cl and extracted
with EtOAc. The organic layer was washed with water and
brine, dried with MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromato-
graphy to give 4 (2.18 g, 91%) as a colorless oil: IR (neat)
1660 (s, C]O), 1610 (s, C]C), 1255 (m, SiMe) cmK1; 1H
NMR d 0.01 (s, 3H, SiMe), 0.02 (s, 3H, SiMe), 0.87 (s, 9H,
But), 0.98 (s, 3H, 5-Me), 2.01 (dd, JZ1.5, 17.1 Hz, 1H,
4-H), 2.04 (dd, JZ1.5, 16.5 Hz, 1H, 6-H), 2.44 (d, JZ
16.5 Hz, 1H, 6-H), 2.65 (d, JZ17.1 Hz, 1H, 4-H), 3.30 (d,
JZ9.9 Hz, 1H, CH2OTBS), 3.35 (d, JZ9.9 Hz, 1H,
CH2OTBS), 3.68 (s, 3H, OMe), 5.34 (br s, 1H, 2-H); 13C
NMR d K5.65, K5.61, 18.2, 22.5, 25.8, 37.1, 37.7, 45.6,
55.7, 69.9, 101.0, 177.0, 199.4; HRMS (EI) m/z calcd for
C15H28O3Si: 284.1808, found 284.1798.
3. Conclusion
In conclusion, we have accomplished the first synthesis of
both enantiomers of annuionone A (1), which enabled us to
determine the absolute configuration of naturally occurring
annuionones A to be 1S,5R,8R. Furthermore, it can be easily
deduced that other annuionones such as B, E and F must
have the same absolute configuration.
4. Experimental
4.1. General
4.1.3. (5S*,6S*,20E)-6-(20-Butenyl)-5-t-butyldimethyl-
silyloxymethyl-3-methoxy-5-methyl-2-cyclohexen-1-one
(6a). n-BuLi (1.58 M in hexane; 10.4 mL, 16.4 mmol) was
added to a solution of (i-Pr)2NH (2.5 mL, 18 mmol) in
anhydrous THF (20 mL) at 0 8C under Ar. After stirring for
30 min at 0 8C, a solution of 4 (3.62 g, 12.7 mmol) in
anhydrous THF (20 mL) was added at K78 8C. After
stirring for 30 min with warming to K15 8C gradually, a
solution of crotyl bromide (Aldrich; 2.64 g, 16.6 mmol) in
anhydrous HMPA (5 mL) was added at K15 8C. After the
mixture was stirred for 30 min with warming to room
temperature gradually, the reaction mixture was quenched
with saturated aqueous NH4Cl and extracted with EtOAc.
The organic layer was washed with water and brine, dried
with MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give a
mixture of 6a and 6b (3.90 g, 90%; 6a:6bZca. 5:1) as a
colorless oil.
IR spectra were measured on a Shimadzu IR-408
spectrophotometer. 1H NMR spectra were recorded at
300 MHz on a JEOL JNM-AL300 spectrometer. The peak
for CHCl3 in CDCl3 (at d 7.26) was used for the internal
standard. Chemical shifts are reported in ppm on the d scale
and J-values are given in Hz. 13C NMR spectra were
recorded at 75 MHz on a JEOL JNM-AL300 spectrometer.
The peak for CDCl3 (at d 77.0) was used for the internal
standard. Optical rotations were taken with a HORIBA
SEPA-300 polarimeter. Mass spectra were measured with a
JEOL JMS-SX102A spectrometer. Column chromato-
graphy was carried out on Kanto Chemical Co. Inc. Silica
Gel 60 N (spherical, neutral, 63–210 mm). Flash chroma-
tography was carried out on Kanto Chemical Co. Inc. Silica
Gel 60 N (spherical, neutral, 40–50 mm). Analytical HPLC
was carried out with a Shimadzu LC-10A system. TLC
analyses were performed on Merck silica gel plates 60 F254
.
4.1.1. 5-Hydroxymethyl-3-methoxy-5-methyl-2-cyclo-
hexen-1-one (3). n-BuLi (1.59 M in hexane; 3.8 mL,
6.0 mmol) was added to a solution of (i-Pr)2NH (0.97 mL,
6.6 mmol) in anhydrous THF (6 mL) at 0 8C under Ar. After
stirring for 30 min at 0 8C, a solution of 2 (0.98 g, 4.9 mmol)
Compound 6a: IR (neat) 1660 (s, C]O), 1620 (s, C]C),
1255 (m, SiMe) cmK1; 1H NMR d 0.01 (s, 3H, SiMe), 0.02
(s, 3H, SiMe), 0.87 (s, 12H, But, 5-Me), 1.61 (d, 3H, JZ
6.0 Hz, 40-H3), 1.99 (d, 1H, JZ17.4 Hz, 4-H), 2.01–2.37
(m, 3H, 6-H, 10-H2), 2.71 (d, 1H, JZ17.4 Hz, 4-H), 3.19 (d,

H. Takikawa et al. / Tetrahedron 61 (2005) 8830–8835
8833
1H, JZ9.9 Hz, CH2OTBS), 3.52 (d, 1H, JZ9.9 Hz,
CH2OTBS), 3.66 (s, 3H, OMe), 5.29 (s, 1H, 2-H), 5.35–
5.54 (m, 2H, 20-, 30-H); 13C NMR d K5.6, 17.9, 18.2, 18.7,
25.8, 25.8, 28.4, 37.2, 40.9, 51.6, 55.5, 68.4, 100.6, 125.5,
130.3, 175.1, 201.5; HRMS (EI) m/z calcd for C19H34O3Si:
338.2277, found 338.2279.
aqueous NH4Cl and extracted with EtOAc. The organic
layer was washed with water and brine, dried with MgSO4,
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give (G)-9 (87 mg,
1
78%) as a colorless oil: IR (neat) 3400 (s, O–H) cmK1; H
NMR d 0.93 (s, 3H, 5-Me), 1.23 (s, 3H, 1-Me)0, 1.50 (t, JZ
7.5 Hz, 1H, 8-H), 1.61–1.91 (m, 5H, 2-, 4-H2, 1 -H), 1.63 (br
d, JZ5.7 Hz, 3H, 40-H3), 2.06–2.15 (m, 1H, 10-H), 3.43 (d,
JZ9.0 Hz, 1H, OH), 3.45 (dd, JZ2.4, 7.5 Hz, 1H, 7-H),
3.88–3.95 (m, 1H, 3-H), 3.93 (d, JZ7.5 Hz, 2H, 7-H), 5.30–
5.49 (m, 2H, 20-, 30-H); 13C NMR d 17.7, 20.9, 25.9, 28.5,
39.2, 39.5, 42.1, 53.1, 66.3, 76.8, 84.5, 125.9, 129.7; HRMS
(EI) m/z calcd for C13H22O2: 210.1620, found 210.1621.
1
Compound 6b: H NMR (only clearly observed peaks) d
1.06 (s, 5-Me), 2.44 (d, JZ17.4 Hz, 4-H), 3.21 (d, JZ
9.9 Hz, CH2OTBS), 5.27 (s, 2-H).
4.1.4. (4S*,5S*,20E)-4-(20-Butenyl)-5-t-butyldimethyl-
silyloxymethyl-3,5-dimethyl-2-cyclohexen-1-one (7).
MeLi (1.20 M in Et2O; 18.3 mL, 15.3 mmol) was added to
a solution of 6 (1.85 g, 5.48 mmol) in anhydrous Et2O
(10 mL) at 0 8C under Ar. After stirring overnight with
warming to room temperature gradually, the reaction
mixture was quenched with saturated aqueous NH4Cl and
extracted with EtOAc. The organic layer was washed with
water and brine, dried with MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give a diastereomeric mixture of 7 and
its a-isomer (1.50 g, 85%). This mixture was then carefully
separated by flash chromatography to afford pure 7 (0.53 g,
30%) and the remaining diastereomeric mixture (0.72 g,
41%).
4.1.7. (1S,3R,5R,8R,20E)-8-(20-Butenyl)-1,5-dimethyl-6-
oxabicyclo[3.2.1]octan-3-yl (R)-a-methoxy-a-(trifluoro-
methyl)phenylacetate (10a) and (1R,3S,5S,8S,20E)-8-(20-
butenyl)-1,5-dimethyl-6-oxabicyclo[3.2.1]octan-3-yl (R)-
a-methoxy-a-(trifluoromethyl)phenylacetate (10b). (S)-
MTPACl (0.41 mL, 2.2 mmol) and DMAP (89 mg,
0.73 mmol) were added to a solution of (G)-9 (154 mg,
0.732 mmol) in pyridine (10 mL) at 40 8C under Ar. After
stirring for 5 days at 40 8C, the reaction mixture was
quenched with water and extracted with EtOAc. The
organic layer was washed with water and brine, dried with
MgSO4, and concentrated under reduced pressure. The
residue was purified by flash silica gel chromatography to
give the more polar 10a (129 mg, 41%) and the less polar
10b (126 mg, 40%).
Compound 7: IR (neat) 1670 (s, C]O), 1630 (s, C]C),
1
1260 (m, SiMe) cmK1; H NMR d K0.03 (s, 3H, SiMe),
K0.02 (s, 3H, SiMe), 0.86 (s, 9H, But), 1.02 (s, 3H, 5-Me),
1.62 (d, JZ5.7 Hz, 3H, 40-H3), 1.95 (s, 3H, 3-Me), 2.12 (d,
JZ17.7 Hz, 1H, 6-H), 2.030 (d, JZ17.7 Hz, 1H, 6-H), 2.27–
2.45 (m, 3H, 4-H, 1 -H2), 3.22 (d, JZ9.6 Hz, 1H,
CH2OTBS), 3.34 (d, JZ9.6 Hz, 1H, CH2OTBS), 5.33–
5.52 (m, 2H, 20-, 30-H), 5.86 (s, 1H, 2-H); 13C NMR d K5.7,
K5.6, 17.9, 18.2, 21.9, 24.4, 25.8, 32.3, 41.0, 43.5, 44.8,
69.4, 126.0, 127.0, 128.8, 164.5, 199.2; HRMS (EI) m/z
calcd for C19H34O2Si: 322.2328, found 322.2336.
Compound 10a: [a]2D5 C82.8 (cZ1.02, CHCl3): IR (neat)
1740 (s, C]O) cmK1; 1H NMR d 0.90 (s, 3H, 1-Me), 1.21
(s, 3H, 5-Me), 1.48–1.53 (m, 2H, 2-, 8-H), 1.64 (d, JZ
5.7 Hz, 3H, 40-H3), 1.70–1.94 (m, 4H, 2-, 10-H, 4-H2), 2.05–
2.14 (m, 1H, 10-H), 3.32 (dd, JZ2.4, 7.8 Hz, 1H, 7-H), 3.62
(d, JZ7.08 Hz, 1H, 7-H), 3.64 (s, 3H, OMe), 5.25–5.52 (m,
3H, 3-, 2 -, 30-H), 7.36–7.41 (m, 3H, Ar), 7.64–7.69 (m, 2H,
Ar); 13C NMR d 17.8, 21.5, 25.5, 28.5, 36.0, 37.1, 41.3,
53.1, 55.6, 71.3, 75.8, 81.6, 84.1 (q, JZ27.4 Hz), 123.4 (q,
JZ287.9 Hz), 126.1, 127.2, 128.3, 129.4, 129.6, 132.7,
166.1; HRMS (EI) m/z calcd for C23H29F3O4: 426.2018,
found 426.2020.
4.1.5. (1S*,5R*,8R*,20E)-8-(20-Butenyl)-1,5-dimethyl-6-
oxabicyclo[3.2.1]octan-3-one (G)-8. TBAF (1.0 M in
THF; 7.4 mL, 7.4 mmol) was added to a solution of 7
(2.00 g, 6.20 mmol) in THF (20 mL). After stirring for 4 h at
room temperature, the reaction mixture was quenched with
saturated aqueous NH4Cl and extracted with EtOAc. The
organic layer was washed with water and brine, dried with
MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography to give
(G)-8 (1.11 g, 86%) as a colorless oil: IR (neat) 1710 (s,
Compound 10b: [a]2D2 C1.57 (cZ1.02, CHCl3): IR (neat)
1740 (s, C]O) cmK1; 1H NMR d 0.93 (s, 3H, 1-Me), 1.16
(s, 3H, 5-Me), 1.48–1.70 (m, 3H, 2-, 4-, 8-H), 1.63 (d, JZ
4.8 Hz, 3H, 40-H3), 1.81–1.96 (m, 3H, 2-, 4-, 10-H), 2.03–
2.13 (m, 1H, 10-H), 3.35 (dd, JZ2.4, 7.5 Hz, 1H, 7-H), 3.51
(s, 3H, OMe), 3.75 (d, JZ7.5 Hz, 1H, 7-H), 5.29–5.47 (m,
3H, 3-H, 20-, 30-H), 7.37–7.42 (m, 3H, Ar), 7.53–7.60 (m,
2H, Ar); 13C NMR d 17.8, 21.5, 25.5, 28.5, 36.4, 37.2, 41.4,
53.1, 55.2, 71.2, 76.0, 81.5, 84.5 (q, JZ27.4 Hz), 123.3 (q,
JZ287.9 Hz), 126.1, 127.8, 128.4, 129.5, 129.7, 131.8,
166.2; HRMS (EI) m/z calcd for C23H29F3O4: 426.2018,
found 426.2020.
1
C]O) cmK1; H NMR d 1.05 (s, 3H, 1-Me), 1.28 (s, 3H,
5-Me), 1.67 (d, JZ5.1 Hz, 3H, 40-H3), 1.78 (t, JZ7.2 Hz,
1H, 8-H), 2.02–2.40 (m, 6H, 2-, 4-, 10-H2), 3.56 (dd, JZ2.4,
7.8 Hz, 1H, 7-H), 3.62 (d, JZ7.8 Hz, 1H, 7-H), 5.38–5.57
(m, 2H, 20-, 30-H); 13C NMR d 17.8, 20.6, 24.9, 28.8, 43.1,
48.7, 49.5, 53.0, 78.3, 83.2, 126.8, 129.1, 209.7; HRMS (EI)
m/z calcd for C13H20O2: 208.1463, found 208.1466.
4.1.8. Determination of the diastereomeric purities of
10a and 10b. The diastereomeric purities of 10a/b were
estimated by HPLC analysis [column: Kanto Mightysil Si
60 250-3.0 column (5 mm); solvent: hexane/EtOAcZ50:1;
flow rate: 1.0 mL/min; detection: at 254 nm]: 10a tR/min
26.8 (w100%, 10a), 38.0 (w0%, 10b). The diastereomeric
purity of 10a was estimated to be w100% de: 10b tR/min
4.1.6. (1S*,3R*,5R*,8R*,20E)-8-(20-Butenyl)-1,5-dimethyl-
6-oxabicyclo[3.2.1]octan-3-ol (G)-9. L-Selectridew
(1.02 M in THF; 0.60 mL, 0.61 mmol) was added to a
solution of (G)-8 (0.11 g, 0.53 mmol) in anhydrous THF
(4 mL) at K78 8C under Ar. After stirring for 30 min at
K78 8C, the reaction mixture was quenched with saturated

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H. Takikawa et al. / Tetrahedron 61 (2005) 8830–8835
26.8 (0.35%, 10a), 38.0 (99.65%, 10b). The diastereomeric
purity of 10b was estimated to be 99.3% de.
Compound (C)-1: [a]2D2 C16.9 (cZ0.50, CHCl3): IR (neat)
1720 (s, C]O) cmK1; 1H NMR d 1.07 (s, 3H, 1-Me), 1.31
(s, 3H, 5-Me), 1.58–1.72 (m, 2H, 10-H2), 1.76–1.88 (m, 1H,
8-H), 2.18 (s, 3H, 40-H3), 2.24 (br s, 1H, 4-H), 2.35–2.43 (m,
3H, 2-H2, 4-H), 2.63–2.68 (m, 2H, 20-H2), 3.55 (dd, JZ2.7,
8.1 Hz, 1H, 7-H), 3.62 (d, JZ7.8 Hz, 1H, 7-H); 13C NMR d
18.5, 20.7, 24.9, 30.1, 42.6, 43.4, 48.5, 49.3, 53.0, 78.2,
83.4, 207.5, 209.0; HRMS (EI) m/z calcd for C13H20O3:
224.1412, found 224.1402.
4.1.9. (1S,3R,5R,8R)-8-(20-Butenyl)-1,5-dimethyl-6-oxa-
bicyclo[3.2.1]octan-3-ol (C)-9. LiAlH4 (11 mg,
0.29 mmol) was added to a solution 10a (117 mg,
0.274 mmol) in anhydrous THF (3 mL). After stirring for
1 h at room temperature, the reaction mixture was quenched
with 1 M HCl and extracted with EtOAc. The organic layer
was washed with water and brine, dried with MgSO4, and
concentrated under reduced pressure. The residue was
purified by silica gel chromatography to give (C)-9 (44 mg,
76%) as a colorless oil: [a]2D5 C10.4 (cZ0.88, MeOH);
HRMS (EI) m/z calcd for C13H22O2: 210.1620, found
210.1624. NMR and IR spectra of (C)-9 were identical to
those of (G)-9.
1
Compound 11: H NMR d 0.99 (s, 3H, 1-Me), 1.11 (t, JZ
7.5 Hz, 3H, 40-H3), 1.24 (s, 3H, 5-Me), 2.27–2.64 (m, 9H, 2-,
4-, 10-H2, 40-H), 3.64–3.70 (m, 2H, 7-H2).
4.1.14. (1R,5S,8S)-1,5-Dimethyl-8-(30-oxobutyl)-6-oxa-
bicyclo[3.2.1]octan-3-one (K)-1. In the same manner as
described above, (K)-8 (34 mg, 0.16 mmol) was converted
to (K)-1 (17 mg, 48%): [a]2D3 K17.6 (cZ0.35, CHCl3);
HRMS (EI) m/z calcd for C13H20O3: 224.1412, found
224.1412. NMR and IR spectra of (K)-1 were identical to
those of (C)-1.
4.1.10. (1R,3S,5S,8S)-8-(20-Butenyl)-1,5-dimethyl-6-oxa-
bicyclo[3.2.1]octan-3-ol (K)-9. In the same manner as
described above, 10b (115 mg, 0.269 mmol) was converted
to (K)-9 (41 mg, 71%): [a]2D3 K9.45 (cZ0.81, MeOH);
HRMS (EI) m/z calcd for C13H22O2: 210.1620, found
210.1609. NMR and IR spectra of (K)-9 were identical to
those of (G)-9.
Acknowledgements
4.1.11. (1S,5R,8R)-8-(20-Butenyl)-1,5-dimethyl-6-oxa-
We thank Professor Emeritus Kenji Mori (The University of
Tokyo) for giving us the opportunity to start this project. We
also thank Dr. T. Tashiro (RIKEN) for his generous support
of this work. This work was financially supported by Grant-
in-Aid for Scientific Research from Japan Society for the
Promotion of Science.
bicyclo[3.2.1]octan-3-one
(C)-8.
IBX
(65 mg,
0.23 mmol) was added to a solution (C)-9 (44 mg,
0.21 mmol) in DMSO (5 mL). After stirring for 1.5 h
at room temperature, the reaction mixture was quenched
with water and filtered through Celite. The filtrate was
and diluted with EtOAc. The organic layer was washed
with water and brine, dried with MgSO4, and con-
centrated under reduced pressure. The residue was
purified by silica gel chromatography to give (C)-8
(37 mg, 86%) as a colorless oil: [a]2D3 C12.0 (cZ0.94,
CHCl3); HRMS (EI) m/z calcd for C13H20O2: 208.1463,
found 208.1456. NMR and IR spectra of (C)-8 were
identical to those of (G)-8.
References and notes
´
1. (a) Macıas, F. A.; Varela, R. M.; Torres, A.; Oliva, R. M.;
Molinillo, J. M. G. Phytochemistry 1997, 48, 631–636. (b)
´
Macıas, F. A.; Oliva, R. M.; Varela, R. M.; Torres, A.;
Molinillo, J. M. G. Phytochemistry 1999, 52, 613–621. (c)
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Macıas, F. A.; Torres, A.; Galindo, J. L. G.; Varela, R. M.;
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Alvarez, J. A.; Molinillo, J. M. G. Phytochemistry 2002, 61,
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4.1.12. (1R,5S,8S)-8-(20-Butenyl)-1,5-dimethyl-6-oxa-
bicyclo[3.2.1]octan-3-one (K)-8. In the same manner as
described above, (K)-9 (41 mg, 0.19 mmol) was converted
to (K)-8 (34 mg, 85%): [a]2D4 K12.8 (cZ0.68, CHCl3);
HRMS (EI) m/z calcd for C13H20O2: 208.1463, found
208.1457. NMR and IR spectra of (K)-8 were identical to
those of (G)-8.
A.; Molinillo, J. M. G. Phytochemistry 2004, 65, 3057–3063.
´
2. Takikawa, H.; Isono, K.; Sasaki, M.; Macıas, F. A.
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´
3. Macıas’ and his co-workers have also reached the same
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of our synthetic work. Ref. 1d.
4.1.13. (1S,5R,8R)-1,5-Dimethyl-8-(30-oxobutyl)-6-oxa-
bicyclo[3.2.1]octan-3-one (C)-1. PdCl2 (4 mg,
0.02 mmol) and CuCl (18 mg, 0.18 mmol) were added to
a mixture of DMF and water (7:1; 0.5 mL). After stirring
for 40 min under oxygen at room temperature, a solution of
(C)-8 (37 mg, 0.18 mmol) in a mixture of DMF and water
(7:1; 1 mL) was added, and the reaction mixture was stirred
for 3 days at room temperature. It was then quenched with
1 M HCl and extracted with EtOAc. The organic layer was
washed with saturated aqueous NaHCO3, water and brine,
dried with MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromato-
graphy to give (C)-1 (25 mg, 64%) and its regioisomer 11
(2 mg, 6%).
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not attempted.
8. It was noted that Harada’s derivatizing reagent did not work in
this case. (a) Ichikawa, A.; Hiradate, S.; Sugio, A.; Kuwahara,
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8835
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