Synthesis of (±)-sundiversifolide based on Lewis acid-mediated claisen rearrangement

Article abstract of DOI:10.1271/bbb.70283

A new and concise synthesis of (±)-sundiversifolide (1), an allelopathic bisnor-sesquiterpene lactone isolated from germinating sunflower (Helianthus annuus L.) seeds, was achieved by employing Lewis acid-mediated Claisen rearrangement as the key step.

Full text of DOI:10.1271/bbb.70283

Biosci. Biotechnol. Biochem., 71 (8), 2046–2051, 2007
Synthesis of (Æ)-Sundiversifolide Based on Lewis Acid-Mediated
Claisen Rearrangement
y
1;
Takashi HASHIMOTO,1 Takuya TASHIRO,2 Mitsuru SASAKI,1 and Hirosato TAKIKAWA
1Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University,
1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan
2Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology,
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Received May 9, 2007; Accepted May 28, 2007; Online Publication, August 7, 2007
[doi:10.1271/bbb.70283]
A new and concise synthesis of (Æ)-sundiversifolide
8
H
H
H
(1), an allelopathic bisnor-sesquiterpene lactone isolated
7
5
1
O
O
8a
3a
from germinating sunflower (Helianthus annuus L.)
seeds, was achieved by employing Lewis acid-mediated
Claisen rearrangement as the key step.
2
O
O
6
HO
3
HO
4
H
Sundiversifolide (1)
Diversifolide (2)
Key words: sundiversifolide; allelopathic agent; sesqui-
terpene; Claisen rearrangement
Claisen
In 2001, Tomita-Yokotani et al. isolated a structurally
interesting bisnor-xanthane sesquiterpene lactone from
germinating sunflower (Helianthus annuus L.) seeds and
named this lactone sundiversifolide.1) They have re-
ported that sundiversifolide (1) showed unique allelo-
pathic activities. In shoot and root growth tests of cat’s-
eyes (Veronica persica Poiret) seedlings, 1 promoted
root growth at a concentration of 1 ppm, while it
inhibited both shoot and root growth by ca. 50% at 30
ppm. This substance also showed interesting species-
specificity in its plant growth-regulating effects on
various tested plants.1) There exists one closely related
natural product, that is diversifolide (2), which was
isolated from Tinthonia diversifolia by Kuo and Lin.2) In
respect of the chemical synthesis of 1, Shishido et al.
have recently disclosed the first enantioselective syn-
thesis of (+)-1.3) However, the absolute configuration of
naturally occurring 1 has remained unknown, because
the specific rotation value of natural 1 has never been
reported.
O
PO
O
PO
B
A
(P = protecting group)
PO
MeO2C
O
OH
D (= 3)
C
Scheme 1. Structure and Retrosynthetic Analysis of Sundiversifolide
(1).
The target compound 1 should be obtainable from
intermediate A via the construction of a butanolide
moiety by regioselective installation of a propionate
unit. To prepare A, we envisaged adopting a Lewis acid-
mediated Claisen rearrangement as the key step. This
key reaction may enable the desired 4-cycloheptenone
framework to be concisely constructed from 2-methyl-
ene-5-vinyltetrahydrofuran derivative B. Key intermedi-
ate B would be preparable from acyclic precursor C.
Thus, known ꢀ-ketoester D was assigned as an appro-
priate starting material.
Inspired by its interesting biological activities and
unique structure, we initiated synthetic studies on 1 in a
continuation of our work on the syntheses of allelopathic
agents.4–6) We report here a new and concise synthesis
of (ꢀ)-1.
Results and Discussion
The first step was the reduction of starting ꢀ-ketoester
37) (= D) to corresponding 1,3-diol 4. Our first attempt
to reduce 3 with LiAlH4 was not successful, affording
Our synthetic plan for 1 is illustrated in Scheme 1.
y
To whom correspondence should be addressed. Tel/Fax: +81-78-803-5958; E-mail: takikawa@kobe-u.ac.jp

Synthesis of (ꢀ)-Sundiversifolide
2047
allylic alcohol 6 as the main product (31%), instead of
desired diol 4 (23%). Although the formation of 6 was
not expected in this case, this type of reaction has been
reported as a useful method for the preparation of allylic
alcohols and was intentionally performed by adding
a base.8) However, there was a need to optimize the
reduction conditions. The second option was Soai’s
method, by which the reduction of ꢀ-ketoesters to the
corresponding 1,3-diols has been successfully per-
formed.9,10) Although this gave desired diol 4 as the
major product, the isolated yield was less than 40%. We
thus turned to adopting a stepwise procedure. Reduction
of 3 with NaBH4 was followed by further reduction with
LiAlH4 to afford 4 in 89% yield.11) Selective protection
of a primary hydroxyl group of 4 as a TBDPS ether
afforded 5 (89%). It was noted that the less expensive
TBS protecting group was unable to survive under the
conditions of the later iodoetherification. Oxidation of 5
with PDC furnished corresponding ketone 7 (88%),
which was then treated with vinylmagnesium chloride to
give alcohol 8 (= C; 97%) as a diastereomeric mixture.
Iodoetherification of 8 was performed by the conven-
tional manner to yield iodoether 9 (87%). Although
yielded 9 was a complex mixture of all the possible
stereoisomers, we were not concerned about this,
because discussing diastereomeric isomerism was not
the object of this exercise. A treatment with t-BuOK
converted iodolactone 9 to key intermediate 10 (= B)
which was used in the next key step without purification
because of its instability.
The key 7-membered ring construction based on
Claisen rearrangement was originally disclosed by
Nozaki et al. in 1984.12) They reported that Claisen
rearrangement of 2-methylene-5-vinyltetrahydrofurans
was successfully mediated by triisobutylaluminum
(TIBAL) to furnish 4-cycloheptenols, which was derived
from the initial Claisen adduct by successive reduction
with aluminum hydride generated from TIBAL, in good
to outstanding yield. We first examined the originally
reported reaction conditions of TIBAL, CH2Cl2, ꢁ78 ꢂC
to room temperature. However, desired adduct 11 was
obtained in less than 40% yield based on 9. Therefore,
we changed the solvent from CH2Cl2 to toluene
according to the other reports,13,14) and the isolated
yield was improved to 61%. Oxidation of 11 with PDC
gave key 4-cycloheptenone 12 (= A; 87%).
perfect regioselectivity. It was noteworthy that consid-
erable amounts of regioisomers were yielded when the
reaction was conducted without HMPA. Since this
alkylation needed a higher temperature and longer time
in the absence of HMPA, partial scrambling of the
regiochemistry of the enolate anion might occur. It was
also noted that the use of other bases such as LDA,
KHMDS and NaHMDS had no positive effect on the
isolated yield and diastereoselectivity. Obtained 13
was diastereoselectively reduced with L-SelectrideÒ at
ꢁ78 ꢂC to give a mixture of 14a and 14b which was
purified by SiO2 column chromatography to give pure
14a (desired, 39%) and 14b (undesired, 38%). Under
these conditions, only cis-lactones (14a/b) were ob-
served, while a considerable quantity of trans-lactones
were obtained by reduction with NaBH4 at 0 ꢂC in
MeOH. The relative configurations of 14a/b were
tentatively established by the observation of a NOE
correlation in 14b, as depicted in Scheme 2, and con-
firmed by the later conversion of 14a into (ꢀ)-1. The
spectral data for our synthetic 14a are in good agreement
with those reported by Shishido.3) Although 14a was
known as the optically active form in Shishido’s syn-
thesis, we continued our synthesis of (ꢀ)-1. Methylation
of 14a was performed by treating with LiHMDS and
MeI to give 15 as the sole product in 66% yield.
Deprotection of the TBDPS group was achieved by
treating with TBAF to give 16 (quant.). Finally, the ꢁ-
oriented methyl group was successfully inverted by
protonation of the dianion of 16 from the convex face to
give a mixture of (ꢀ)-1 and 16 (ca. 1:1). This mixture
was chromatographically purified to give (ꢀ)-1 [51%,
(96% based on the recovered 16)]. The various spectral
data for synthetic (ꢀ)-1 are in good accord with those of
the natural product. The overall yield was 6.0% in 13
steps based on 3.
In conclusion, a new and concise synthesis of (ꢀ)-
sundiversifolide (1), an allelopathic substance isolated
from sunflower seeds, was accomplished by starting
from known ketoester 3. A detailed bioassay employing
our synthetic samples is now in preparation.
Experimental
IR spectra were measured with a Shimadzu IR-408
spectrometer, and 1H-NMR spectra were recorded
at 300 MHz with a Jeol JNM-AL300 spectrometer.
The residual solvent peak in CDCl3 (at ꢂH ¼ 7:26) or
CD3OD (at ꢂH ¼ 3:30) was used as the internal standard.
13C-NMR spectra were recorded at 75 MHz with the
Jeol JNM-AL300 spectrometer, the peak for CDCl3 (at
ꢂC ¼ 77:0) or CD3OD (at ꢂC ¼ 49:0) being used as the
internal standard. Mass spectra were measured with a
Jeol JMS-SX102A spectrometer.
The remaining objective was to construct the ꢁ-
substituted butanolide portion. One of the important
points was the regioselective installation of a propionate
unit. We first attempted a simple alkylation of the
kinetically-controlled enolate anion of 12 with ethyl 2-
bromopropanoate. However, the desired product could
not be obtained, probably due to steric hindrance of the
electrophile. We then turned our attention to the
installation of an acetate unit. Ketone 12 was treated
with LiHMDS and ethyl bromoacetate in the presence
of HMPA at ꢁ78 ꢂC to furnish 13 as a diastereomeric
mixture (ꢁ:ꢀ = ca. 1:1) in 78% yield with almost
4-Methyl-6-heptene-1,3-diol (4). To a stirred solution
of 3 (3.82 g, 22.4 mmol) in MeOH (60 ml) was added

2048
T. HASHIMOTO et al.
RO
b
a
MeO2C
O
OH
OH
6
3
4 R = H
5 R = TBDPS
c
TBDPSO
e
TBDPSO
d
OH
O
8
7
g
OH
TBDPSO
f
TBDPSO
I
O
O
TBDPSO
10
11
9
O
O
j
h
i
CO2Et
TBDPSO
TBDPSO
12
13
NOE
H
H
O
O
O
O
O
O
O
+
TBDPSO
TBDPSO
H
H
14b
14a
k
H
H
H
H
m
O
RO
HO
15 R = TBDPS
16 R = H
( )-Sundiversifolide (1)
l
Scheme 2. Synthesis of (ꢀ)-1.
Reagents and conditions: (a) i) NaBH4, MeOH ii) LiAlH4, THF (89%); (b) TBDPSCl, Et3N, DMF (89%); (c) PDC, MS 4A, CH2Cl2 (88%);
(d) vinylmagnesium chloride, THF (97%); (e) I2, K2CO3, CH3CN (87%); (f) t-BuOK, DMF; (g) TIBAL, toluene (61% in 2 steps); (h) PDC, MS
4A, CH2Cl2 (87%); (i) LiHMDS, BrCH2CO2Et, THF, HMPA, ꢁ78 ꢂC (78%); (j) L-SelectrideÒ, THF, ꢁ78 ꢂC (39% for 14a, 38% for 14b); (k)
LiHMDS, MeI, THF (66%); (l) TBAF, THF (quant.); (m) LiHMDS, NH4Cl aq., THF (51% for 1, 47% for 16).
NaBH4 (1.70 g, 44.8 mmol) at ꢁ10 ꢂC. After stirring for
10 min, the reaction mixture was quenched with 6 N HCl
and extracted with EtOAc. The organic layer was suc-
cessively washed with water and brine, dried (MgSO4),
and concentrated under reduced pressure to give a crude
product (3.50 g). To a stirred solution of this crude
product (3.50 g) in THF (50 ml) was carefully added
LiAlH4 (2.56 g, 67.3 mmol) portionwise at 0 ꢂC. After
stirring for 10 min, the reaction mixture was quenched
by the successive addition of water (2.6 ml), 1 N aq.
NaOH, (2.6 ml) and then water (7.6 ml). This mixture
was filtered, and the resulting filtrate was dried (MgSO4)
and concentrated under reduced pressure. The residue
was chromatographed on SiO2 to give 4 (2.88 g,
20.0 mmol, 89%) as an oil. It was noted that 4 was
obtained as a mixture of the two possible diastereomers
(ca. 1:1). IR ꢃmax (film) cmꢁ1: 3350 (s, O–H), 1645 (m,
C=C). NMR ꢂH (CDCl3): 0.88 and 0.89 (total 3H, 2 ꢃ d,
J ¼ 6:6 Hz), 1.50–1.82 (3H, m), 1.82–1.99 (1H, m),
2.17–2.30 (1H, m), 2.92 (1H, s), 3.01 (1H, br s), 3.62–
3.98 (3H, m), 4.97–5.07 (2H, m), 5.70–5.86 (1H, m).
NMR ꢂC (CDCl3): 14.1, 14.5, 29.0, 29.4, 36.6, 36.8,
38.0, 38.3, 62.3, 62.5, 75.5, 75.9, 116.1, 116.3, 136.8,
136.9. HREIMS m=z [M]þ: calcd. for C8H16O2,
144.1150; found, 144.1153.
1-(tert-Butyldiphenylsilyloxy)-4-methyl-6-hepten-3-ol
(5). To a stirred solution of 4 (4.88 g, 33.8 mmol) in

Synthesis of (ꢀ)-Sundiversifolide
2049
CH2Cl2 (30 ml) were added Et3N (4.45 g, 44.1 mmol)
and TBDPSCl (10.2 g, 37.1 mmol). After stirring over-
night at room temperature, the reaction mixture was
diluted with water and extracted with hexane. The
organic layer was successively washed with water and
brine, dried (MgSO4), and concentrated under reduced
pressure. The residue was chromatographed on SiO2 to
give 5 (11.5 g, 30.1 mmol, 89%) as an oil. IR ꢃmax (film)
cmꢁ1: 3450 (s, O–H), 1640 (m, C=C). NMR ꢂH
(CDCl3): 0.86 and 0.91 (total 3H, 2 ꢃ d, J ¼ 6:9 Hz),
1.06 (9H, s), 1.54–1.82 (3H, m), 1.86–2.00 (1H, m),
2.24–2.36 (1H, m), 3.69–3.95 (3H, m) 4.97–5.09 (2H,
m), 5.74–5.89 (1H, m), 7.37–7.48 (6H, m), 7.66–7.73
(4H, m). NMR ꢂC (CDCl3): 13.9, 15.0, 19.0, 26.8, 34.6,
35.5, 36.9, 37.5, 38.55, 38.60, 63.7, 63.8, 74.4, 75.4,
115.8, 127.8, 129.8, 133.0, 135.6, 137.6, 137.7.
HREIMS m=z [M-tBu]þ: calcd. for C20H25O2Si,
325.1622; found, 325.1617.
38.3, 42.45, 42.50, 62.0, 62.1, 78.3, 78.4, 114.5, 114.6,
115.4, 115.5, 127.7, 127.8, 129.6, 129.9, 132.6, 134.8,
135.5, 135.6, 138.5, 138.7, 140.8, 141.9. HREIMS m=z
[M-tBu]þ: calcd. for C22H27O2Si, 351.1779; found,
351.1786.
2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-iodomethyl-
3-methyl-2-vinyloxolane (9). To a stirred solution of 8
(4.13 g, 10.1 mmol) in CH3CN (30 ml) were added
iodine (5.15 g, 20.4 mmol) and K2CO3 (4.19 g, 30.3
mmol) at 0 ꢂC. After stirring for 1 h, the reaction mixture
was quenched with 10% aq. Na2S2O3 and extracted with
ether. The organic layer was successively washed with
water and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed on
SiO2 to give 9 (4.70 g, 8.79 mmol, 87%) as an oil.
Although 9 was obtained as a complex mixture of the
four possible diastereomers, the composition of these
diastereomers was not carefully analyzed. IR ꢃmax (film)
cmꢁ1: 1630 (w, C=C). NMR ꢂH (CDCl3): 0.93–1.01
(3H, m), 1.10–1.11 (9H, m), 1.10–2.35 (5H, m), 2.77–
3.37 (2H, m), 3.74–4.06 (3H, m), 4.94–5.28 (2H, m),
5.62–5.80 (1H, m), 7.36–7.48 (6H, m), 7.65–7.75 (4H,
m). NMR ꢂC (CDCl3, only clearly observed peaks): 9.3,
10.6, 13.4, 14.2, 14.3, 14.8, 19.1, 26.8, 26.9, 37.2, 37.8,
38.7, 40.2, 40.3, 41.3, 41.6, 42.2, 43.1, 44.1, 60.1, 60.3,
60.6, 76.5, 77.3, 77.6, 86.4, 87.2, 112.2, 112.9, 113.8,
114.2, 127.5, 129.5, 129.6, 133.9, 134.0, 135.5, 135.6,
138.2, 139.7, 141.6. HREIMS m=z [M-tBu]þ: calcd. for
C22H26O2SiI, 477.0746; found, 477.0740.
1-(tert-Butyldiphenylsilyloxy)-4-methyl-6-hepten-3-one
(7). To a stirred solution of 5 (1.10 g, 2.88 mmol) in
CH2Cl2 (10 ml) were added PDC (1.62 g, 4.31 mmol)
and MS 4A (powdered; 2.0 g). After stirring for 5.5 h,
the reaction mixture was filtered, and the resulting
filtrate was concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give 7 (970
mg, 2.55 mmol, 88%) as an oil. IR ꢃmax (film) cmꢁ1
:
1720 (s, C=O). NMR ꢂH (CDCl3): 1.04 (9H, s), 1.09
(3H, d, J ¼ 6:9 Hz), 2.03–2.14 (1H, m), 2.37–2.48 (1H,
m), 2.57–2.73 (3H, m), 3.95 (2H, t, J ¼ 6:3 Hz) 4.97–
5.08 (2H, m), 5.66–5.79 (1H, ddt, J ¼ 17:1, 9.9, 6.9 Hz),
7.36–7.47 (6H, m), 7.64–7.69 (4H, m). NMR ꢂC
(CDCl3): 15.6, 19.1, 26.7, 36.7, 43.8, 46.5, 59.5,
116.7, 127.7, 129.6, 133.5, 135.5, 135.7, 212.3.
HREIMS m=z [M-tBu]þ: calcd. for C20H23O2Si,
323.1466; found, 323.1471.
2-[2-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-5-meth-
ylene-2-vinyloxolane (10). To a stirred solution of 9
(4.11 g, 7.69 mmol) in DMF (30 ml) was added t-BuOK
(85%; 2.03 g, 15.4 mmol) at 0 ꢂC. After stirring for 30
min, the reaction mixture was diluted with water and
extracted with ether. The organic layer was successively
washed with water and brine, dried (K2CO3), and
concentrated under reduced pressure to give crude 10
(3.06 g). This was used in the next step without pur-
ification because of its instability. NMR ꢂH (CDCl3):
0.94 and 0.95 (total 3H, 2 ꢃ d, J ¼ 6:9 Hz), 1.04 and
1.05 (total 9H, 2 ꢃ s), 1.60–2.77 (5H, m), 3.69–4.18
(4H, m), 4.94–5.36 (2H, m), 5.61 and 5.69 (total 1H,
2 ꢃ dd, J ¼ 17:1, 10.8 Hz), 7.34–7.47 (6H, m), 7.64–
7.75 (4H, m).
3-[2-(tert-Butyldiphenylsilyloxy)ethyl]-4-methyl-1,6-
heptadien-3-ol (8). To a stirred solution of 7 (2.57 g,
6.75 mmol) in THF (20 ml) was added vinylmagnesium
chloride (1.47 M in THF; 9.18 ml, 13.5 mmol) at ꢁ15 ꢂC
under Ar. After stirring for 30 min, the reaction mixture
was quenched with saturated aq. NH4Cl and extracted
with hexane. The organic layer was successively washed
with water and brine, dried (MgSO4), and concentrated
under reduced pressure. The residue was chromato-
graphed on SiO2 to give 8 (2.65 g, 6.48 mmol, 97%) as
an oil. It was noted that 8 was obtained as a mixture of
the two possible diastereomers (ca. 1:1). IR ꢃmax (film)
cmꢁ1: 3500 (s, O–H), 1640 (w, C=C). NMR ꢂH
(CDCl3): 0.86 and 0.94 (total 3H, 2 ꢃ d, J ¼ 6:9 Hz),
1.05(10H, m), 1.52–1.89 (3H, m), 1.96–2.10 (1H, m),
2.36–2.60 (1H, m), 3.71–3.80 (1H, m), 3.86–3.96 (1H,
m), 4.95–5.06 (2H, m), 5.26 and 5.28 (total 1H, 2 ꢃ dd,
J ¼ 2:1 Hz, 10.8 Hz), 5.46 and 5.49 (total 1H, 2 ꢃ dd,
J ¼ 2:1 Hz, 17.1 Hz), 5.68–5.85 (2H, m), 7.35–7.48 (6H,
m), 7.65–7.74 (4H, m). NMR ꢂC (CDCl3): 13.0, 14.3,
18.7, 18.9, 25.6, 26.6, 26.7, 33.6, 35.1, 35.3, 36.1, 37.5,
4-[2-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-4-cy-
clohepten-1-ol (11). To a stirred solution of 10 (3.06 g)
in toluene (30 ml) was added TIBAL (0.5 M in hexane;
30.8 ml, 15.4 mmol) at 0 ꢂC. This solution was warmed
to room temperature and stirred for 30 min. The reaction
mixture was diluted with water, filtered, and the
resulting filtrate was extracted with EtOAc. The organic
layer was successively washed with water and brine,
dried (MgSO4), and concentrated under reduced pres-
sure. The residue was chromatographed on SiO2 to give
11 (1.91 g, 4.67 mmol, 61%) as an oil. It was noted that

2050
T. HASHIMOTO et al.
11 was obtained as a mixture of the two possible
diastereomers (ca. 2:1). IR ꢃmax (film) cmꢁ1: 3400 (s, O–
H). NMR ꢂH (CDCl3): 0.99–1.10 (12H, m), 1.10–2.40
(10H, m), 3.62–4.03 (3H, m), 5.41–5.53 (1H, m), 7.34–
7.46 (6H, m), 7.65–7.72 (4H, m). NMR ꢂC (CDCl3):
14.1, 17.4, 19.2, 19.8, 22.3, 22.6, 26.9, 31.5, 31.8, 33.8,
35.2, 36.9, 38.0, 41.9, 42.4, 43.7, 63.4, 64.2, 70.2, 73.9,
126.2, 126.7, 127.6, 129.5, 134.0, 135.6, 143.1.
HREIMS m=z [M-tBu]þ: calcd. for C22H27O2Si,
351.1779; found, 351.1776.
2-one (14a) and (3aSꢄ,7Sꢄ,8aSꢄ)-6-[2-(tert-butyldiphen-
ylsilyloxy)ethyl]-7-methyl-3,3a,4,7,8,8a-hexahydrocyclo-
hepta[2,1-b]furan-2-one (14b). To a stirred solution of
13 (295 mg, 0.592 mmol) in THF (10 ml) was added L-
SelectrideÒ (1.02 M in THF; 1.17 ml, 1.19 mmol) at
ꢁ78 ꢂC under Ar. After stirring for 10 min, the reaction
mixture was quenched with saturated aq. NH4Cl and
extracted with EtOAc. The organic layer was succes-
sively washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was
chromatographed on SiO2 to give 14a (103 mg, 0.229
mmol, 39%) and 14b (102 mg, 0.228 mmol, 38%).
14a: IR ꢃmax (film) cmꢁ1: 1780 (s, C=O). NMR ꢂH
(CDCl3): 1.05–1.08 (12H, m), 1.89–2.42 (8H, m) 2.60
(1H, dd, J ¼ 9:0 Hz, 17.7 Hz), 2.71–2.85 (1H, m), 3.69
(2H, t, J ¼ 6:9 Hz), 4.57 (1H, dd, J ¼ 8:1, 14.7 Hz),
5.38 (1H, dd, J ¼ 5:1 Hz, 8.7 Hz), 7.36–7.47 (6H, m),
7.64–7.69 (4H, m). NMR ꢂC (CDCl3): 19.1, 20.8, 26.8,
27.4, 34.5, 34.7, 35.6, 37.3, 39.5, 63.2, 81.4, 122.1,
127.6, 129.6, 133.7, 135.48, 135.51, 142.5, 176.6.
HREIMS m=z [M-tBu]þ: calcd. for C24H27O3Si,
391.1727; found, 391.1722.
14b: Mp 98–101 ꢂC. IR ꢃmax (nujol) cmꢁ1: 1780 (s,
C=O). NMR ꢂH (CDCl3): 1.03–1.06 (12H, m), 1.84
(1H, m), 2.07–2.46 (7H, m), 2.63–2.74 (1H, m), 2.82
(1H, dd, J ¼ 8:7 Hz, 17.4 Hz), 3.68 (2H, t, J ¼ 6:9 Hz),
4.79 (1H, dd, J ¼ 7:8 Hz, 14.4 Hz), 5.33 (1H, dd, J ¼
3:0 Hz, 8.4 Hz), 7.35–7.46 (6H, m), 7.64–7.68 (4H, m).
NMR ꢂC (CDCl3): 18.5, 19.1, 26.8, 28.7, 33.8, 34.1,
37.2, 39.0, 39.5, 63.5, 80.9, 123.0, 127.6, 129.6, 133.79,
133.83, 135.5, 143.7, 176.6. HREIMS m=z [M-tBu]þ:
calcd. for C24H27O3Si, 391.1727; found, 391.1724.
4-[2-(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-4-cy-
clohepten-1-one (12). To a stirred solution of 11 (4.00 g,
9.79 mmol) in CH2Cl2 (50 ml) were added PDC (5.52 g,
14.7 mmol) and MS 4A (powdered; 6.0 g). After stirring
for 6 h, the reaction mixture was filtered, and the
resulting filtrate was concentrated under reduced pres-
sure. The residue was chromatographed on SiO2 to give
12 (3.46 g, 8.50 mmol, 87%) as an oil. IR ꢃmax (film)
cmꢁ1: 1710 (s, C=O). NMR ꢂH (CDCl3): 1.01 (3H, d,
J ¼ 6:6 Hz), 1.05 (9H, s), 2.17–2.34 (4H, m), 2.34–2.48
(4H, m), 2.81 (1H, dd, J ¼ 3:6 Hz, 12.0 Hz), 3.71 (2H, t,
J ¼ 6:9 Hz), 5.55 (1H, t, J ¼ 6:0 Hz), 7.35–7.45 (6H,
m), 7.64–7.68 (4H, m). NMR ꢂC (CDCl3): 19.1, 19.3,
22.7, 26.8, 34.3, 40.5, 43.6, 48.5, 63.4, 125.1, 127.6,
129.6, 133.8, 135.5, 142.6, 213.0. HREIMS m=z [M-
tBu]þ: calcd. for C22H25O2Si, 349.1621; found,
349.1616.
Ethyl 2-{4-[2-(tert-butyldiphenylsilyloxy)ethyl]-5-meth-
yl-7-oxo-3-cyclohepten-1-yl}acetate (13). LiHMDS (1.6
M in THF; 1.9 ml, 3.0 mmol) was added to dry THF
(5 ml) under Ar at ꢁ78 ꢂC. To this solution, 12 (880 mg,
2.16 mmol) in THF (5 ml) was slowly added dropwise.
After stirring for 40 min, HMPA (0.83 ml, 4.8 mmol)
and BrCH2CO2Et (0.57 ml, 4.7 mmol) were added drop-
wise, and the mixture was stirred for 20 min. The
reaction mixture was quenched with saturated aq.
NH4Cl at ꢁ78 ꢂC and then extracted with EtOAc. The
organic layer was successively washed with water and
brine, dried (MgSO4), and concentrated under reduced
pressure. The residue was chromatographed on SiO2 to
give 13 (835 mg, 1.68 mmol, 78%) as an oil. IR ꢃmax
(film) cmꢁ1: 1740 (s, C=O), 1710 (s, C=O). NMR ꢂH
(CDCl3): 0.96 (3H, d, J ¼ 6:9 Hz), 1.05–1.06 (9H, m),
1.24 and 1.25 (total 3H, 2 ꢃ t, J ¼ 7:2 Hz), 1.97–2.99
(10H, m), 3.71 and 3.74 (total 2H, 2 ꢃ t, J ¼ 6:9 Hz),
4.12 and 4.13 (total 2H, 2 ꢃ q, J ¼ 7:2 Hz), 5.49–5.58
(1H, m), 7.35–7.46 (6H, m), 7.65–7.70 (4H, m). NMR
ꢂC (CDCl3): 14.0, 14.1, 17.6, 19.08, 19.11, 19.6, 26.8,
28.4, 28.9, 34.0, 34.6, 35.6, 35.9, 39.8, 41.9, 47.3, 48.0,
49.1, 49.4, 60.4, 63.1, 63.4, 123.5, 123.8, 127.6, 133.7,
135.5, 142.7, 144.3, 172.2, 172.4, 211.6, 212.0.
HREIMS m=z [M]þ: calcd. for C30H40O4Si, 492.2696;
found, 492.2690.
(3Rꢄ,3aRꢄ,7Sꢄ,8aRꢄ)-6-[2-(tert-Butyldiphenylsilyloxy)-
ethyl]-3,7-dimethyl-3,3a,4,7,8,8a-hexahydrocyclohepta-
[2,1-b]furan-2-one (15). LiHMDS (1.6 M in THF; 0.365
ml, 0.584 mmol) was added to dry THF (2 ml) under Ar
at ꢁ78 ꢂC. To this solution, 14a (187 mg, 0.417 mmol)
in THF (1 ml) was slowly added dropwise. After stirring
for 1 h, MeI (0.042 ml, 0.63 mmol) was added dropwise,
and the mixture was stirred for 15 min. The reaction
mixture was quenched with saturated aq. NH4Cl and
extracted with hexane. The organic layer was succes-
sively washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was
chromatographed on SiO2 to give 15 (127 mg, 0.274
mmol, 66%) as an oil. IR ꢃmax (film) cmꢁ1: 1770 (s,
C=O). NMR ꢂH (CDCl3): 1.05–1.07 (12H, m), 1.21
(3H, d, J ¼ 6:6 Hz), 1.78–2.42 (9H, m), 3.66–3.74 (2H,
m), 4.40–4.48 (1H, m) 5.38 (1H, dd, J ¼ 5:4 Hz,
8.4 Hz), 7.36–7.47 (6H, m), 7.65–7.68 (4H, m). NMR
ꢂC (CDCl3): 13.9, 19.1, 20.5, 26.3, 26.8, 35.1, 35.3, 39.2,
39.5, 45.0, 63.3, 79.2, 121.1, 127.6, 129.6, 133.7, 135.5,
142.8, 179.4. HREIMS m=z [M-tBu]þ: calcd. for
C25H29O3Si, 405.1884; found, 405.1880.
(3aRꢄ,7Sꢄ,8aRꢄ)-6-[2-(tert-Butyldiphenylsilyloxy)ethyl]-
7-methyl-3,3a,4,7,8,8a-hexahydrocyclohepta[2,1-b]furan-
(3Rꢄ,3aRꢄ,7Sꢄ,8aRꢄ)-6-(2-Hydroxyethyl)-3,7-dimethyl-
3,3a,4,7,8,8a-hexahydrocyclohepta[2,1-b]furan-2-one

Synthesis of (ꢀ)-Sundiversifolide
2051
S., and Hasegawa, K., A species-selective allelopathic
substance from germinating sunflower (Helianthus an-
nuus L.) seeds. Phytochemistry, 56, 577–581 (2001).
2) Kuo, Y.-H., and Lin, B.-Y., A new dinorxanthane and
chromone from the root of Tithonia diversifolia. Chem.
Pharm. Bull., 47, 428–429 (1999).
3) Yokoe, H., Sasaki, H., Yoshimura, T., Shindo, M.,
Yoshida, M., and Shishido, K., Total synthesis of (+)-
sundiversifolide. Org. Lett., 9, 969–971 (2007).
4) Takikawa, H., Tobe, M., and Sasaki, M., Synthesis and
absolute configuration of annuionone A. Tetrahedron,
61, 8830–8835 (2005).
5) Takikawa, H., Imamura, Y., and Sasaki, M., Synthesis
and absolute configuration of brevione B, an allelochem-
ical isolated from Penicillium sp. Tetrahedron, 62, 39–
48 (2006).
6) Takikawa, H., Synthetic studies on allelopathic terpe-
noids. Yuki Gosei Kagaku Kyokaishi (in Japanese), 64,
819–826 (2006).
(16). To a stirred solution of 15 (12 mg, 0.026 mmol)
in THF (1 ml) was added TBAF (1.0 M in THF;
0.026 ml, 0.026 mmol). After stirring for 1 h, the
reaction mixture was quenched with saturated aq.
NH4Cl and extracted with EtOAc. The organic layer
was successively washed with water and brine, dried
(MgSO4), and concentrated under reduced pressure.
The residue was chromatographed on SiO2 to give 16
(6.0 mg, quant.). IR ꢃmax (film) cmꢁ1: 3400 (s, O–H),
1760 (s, C=O). NMR ꢂH (CDCl3): 1.16 (3H, d, J ¼
6:9 Hz), 1.23 (3H, d, J ¼ 6:9 Hz), 1.54 (1H, br s),
1.82–2.09 (2H, m), 2.10–2.50 (7H, m), 3.59–3.72 (2H,
m), 4.44–4.53 (1H, m), 5.48 (1H, dd, J ¼ 5:4, 8.4 Hz).
NMR ꢂC (CDCl3): 13.9, 20.6, 26.3, 35.1, 35.2, 39.2,
39.5, 45.0, 61.0, 79.1, 121.7, 142.3, 179.4. HRFABMS
m=z ½M þ Hꢅþ: calcd. for C13H21O3, 225.1490; found,
225.1489.
7) Snider, B. B., and Patricia, J. J., Manganese(III)-based
oxidative free-radical cyclizations. Oxidative cyclization
and aromatization of 3-oxo-6-heptenoate esters. J. Org.
Chem., 54, 38–46 (1989).
8) Marshall, J. A., and Litsas, S. B., Reduction of ꢁ-
substituted acetoacetate enolates with lithium aluminum
hydride. J. Org. Chem., 37, 1840–1842 (1972).
9) Soai, K., Chemoselective reductions with sodium bor-
ohydride and lithium borohydride in mixed solvents.
Yuki Gosei Kagaku Kyokaishi (in Japanese), 45, 1148–
1156 (1987).
10) Soai, K., and Oyamada, H., A chemoselective one-pot
reduction of ꢀ-ketoesters to 1,3-diols. Synthesis, 605–
607 (1984).
11) Comin, M. J., Parrish, D. A., Deschamps, J. F., and
Marquez, V. E., Synthesis of bicyclo[3.1.0]hexanes
functionalized at the tip of the cyclopropane ring.
Application to the synthesis of carbocyclic nucleosides.
Org. Lett., 8, 705–708 (2006).
(3Sꢄ,3aRꢄ,7Sꢄ,8aRꢄ)-6-(2-Hydroxyethyl)-3,7-dimethyl-
3,3a,4,7,8,8a-hexahydrocyclohepta[2,1-b]furan-2-one:
(ꢀ)-sundiversifolide (1). LiHMDS (1.6 M in THF; 0.047
ml, 0.075 mmol) was added to dry THF (2 ml) under Ar
at ꢁ78 ꢂC. To this solution, 16 (7.0 mg, 0.031 mmol) in
THF (1 ml) was slowly added dropwise. After stirring
for 1 h, the reaction mixture was quenched with satu-
rated aq. NH4Cl and extracted with EtOAc. The organic
layer was successively washed with water and brine,
dried (MgSO4), and concentrated under reduced pres-
sure. The residue was chromatographed on SiO2 to give
(ꢀ)-sundiversifolide (1) [3.6 mg, 0.016 mmol, 51%
(96% based on the recovered 16)] and recovered 16
(3.3 mg, 0.015 mmol, 47%) as an oil. IR ꢃmax (film)
cmꢁ1: 3400 (s, O–H), 1760 (s, C=O). NMR ꢂH (CD3-
OD): 1.11 (3H, d, J ¼ 7:5 Hz), 1.15 (3H, d, J ¼ 7:2 Hz),
1.85–1.95 (1H, m), 1.98–2.05 (2H, m), 2.08–2.25 (2H,
m), 2.30–2.45 (2H, m), 2.70–2.81 (1H, m), 2.85–2.95
(1H, m), 3.49–3.65 (2H, m), 4.65–4.74 (1H, m), 5.53–
5.56(1H, m). NMR ꢂC (CD3OD): 11.0, 21.9, 22.9, 34.0,
38.2, 40.2, 41.2, 43.6, 62.2, 82.5, 125.4, 143.6, 181.9.
HRFABMS m=z ½M þ Hꢅþ: calcd. for C13H21O3,
225.1490; found, 225.1487.
12) Mori, I., Takai, K., Oshima, K., and Nozaki, H.,
Organoaluminium assisted rearrangements of five-mem-
bered ring enol ethers with vinyl substituents. Tetrahe-
dron, 40, 4013–4018 (1984).
13) Sisu, E., Sollogoub, M., Mallet, J.-M., and Sinay, P.,
¨
Cycloheptanic sugar mimetics, bridging the gap in the
homologous series of carbocyclic analogues. Tetrahe-
dron, 58, 10189–10196 (2002).
14) Jia, C., Zhang, Y., and Zhang, L., High stereoselective
synthesis of a seven-membered carbasugar via triisobu-
tylaluminium promoted Claisen rearrangement. Tetrahe-
dron: Asymmetry, 14, 2195–2199 (2003).
References
1) Ohno, S., Tomita-Yokotani, K., Kosemura, S., Node, M.,
Suzuki, T., Amano, M., Yasui, K., Goto, T., Yamamura,