Studies of the asymmetric total synthesis of clavilactone D by the 'lariat' cyclization strategy

Article abstract of DOI:10.1055/s-0029-1216909

A route to the core structure of clavilactone D, a new member of the tyrosine kinase inhibitors, is reported. The route employs sequential cyclization initiated by iodo etherification followed by Friedel-Crafts cyclization to furnish a polycyclic lactone

Full text of DOI:10.1055/s-0029-1216909

PAPER
2963
Studies of the Asymmetric Total Synthesis of Clavilactone D by the ‘Lariat’
Cyclization Strategy
Asymmetric
To
a
tal Synthes
k
is of Clavilac
e
tone
D
hiko Yoshimitsu,* Shoji Nojima, Masashi Hashimoto, Koji Tsukamoto, Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68798214; E-mail: yoshimit@phs.osaka-u.ac.jp
Received 30 May 2009
ed with that of clavilactone B (2) (Figure 1). Therefore,
Abstract: A route to the core structure of clavilactone D, a new
member of the tyrosine kinase inhibitors, is reported. The route em-
ploys sequential cyclization initiated by iodo etherification fol-
lowed by Friedel–Crafts cyclization to furnish a polycyclic lactone
with a view to confirming the proposed structure, which
would enable us to undertake structure–activity relation-
ship studies and to devise powerful candidates for potent
fused with an aromatic ring, which is readily transformed into the anticancer agents, we initiated a research program direct-
proposed clavilactone scaffold.
ed at the enantioselective total synthesis of clavilactone D
(1). In the present paper, we report the asymmetric con-
struction of the clavilactone ring system through the ‘lar-
iat’ strategy, which is initiated by iodo etherification and
followed by Friedel–Crafts-type cyclization.
Key words: total synthesis, natural products, cyclizations, asym-
metric synthesis, alkylations
Clavilactone D (1), a new member of the tyrosine kinase
inhibitors, has attracted considerable attention owing to
the prospect that it would serve as a potent molecularly
targeted anticancer agent.1,2 This naturally occurring mol-
ecule belongs to the clavilactone family that includes the
various congeners A (3), B (2), C (4), and E (5), all of
which possess a unique constrained ten-membered ring
system attached to a 2,3-epoxy-g-lactone and a benzo-
quinone or a hydroquinone ring (Figure 1).3
The key transformations for producing the clavilactone
core are shown in Scheme 1. Iodo etherification of alkenyl
alcohol 10a led to tetrahydrofuran derivative i, whose
chiral menthyloxy auxiliary was extruded by reaction
with the resultant hydroiodic acid in situ, to afford oxocar-
benium intermediate ii. Intermediate ii was then captured
by the electron-rich aromatic ring to deliver polycyclic
compound 9. Highly fused-ring system 9 was then sub-
jected to reductive regeneration of Z-olefin, furnishing
clavilactone skeleton 8. Several chemical manipulations
were applied to 8 to finally yield the clavilactone D skel-
eton 6.
O
OH
R
R
Substrate 10 was prepared by the aldol reaction of known
chiral lactone 116 with aldehyde 127 (Scheme 2). The al-
dol reaction took place in good yield (92%), although the
diastereoselectivity of this process was found to be only
moderate (10a/10b/10c = 3:1:2).8 We then investigated
the ‘lariat’ cyclization of alcohol 10a (Table 1). Cycliza-
tion of alkenyl alcohol 10a with three equivalents of io-
dine was found to provide highly fused polycyclic
compound 9a in moderate yield along with diastereomeric
non-macrocyclic compounds 13a and 14a (entry 1). It was
revealed that neither reagent amount nor temperature had
any significant effect on the product yields and ratios (en-
tries 2–4). This reaction was considered to take place
through the initial generation of an iodonium intermediate
(shown in brackets) that underwent tetrahydrofuran for-
mation. The tetrahydrofuran-tethered system served as a
good molecular scaffold that increased the proximity of
the aromatic ring to the oxocarbenium center generated at
the lactone acetal, both being suitably positioned for their
connection. The importance of the tetrahydrofuran-teth-
ered system for successful cyclization was suggested by
the fact that the O-acetyl derivative of 10a gave no detect-
able macrocycles. It should also be emphasized that not
only alkenyl alcohol 10a, but also 10b and 10c similarly
underwent the cyclization irrespective of their relative ste-
O
O
O
O
O
O
OH
O
clavilactone A R = H (3)
clavilactone C R = OH (4)
clavilactone E R = OMe (5)
clavilactone D R = OH (1)
clavilactone B R = H (2)
Figure 1 Clavilactone D and its congeners (revised absolute struc-
ture, see ref. 4)
This intriguing structure and the biological significance
make this family an attractive target for synthesis. Barrett
and co-workers have recently established a concise route
to clavilactone B (2) through a highly convergent three-
component benzyne coupling strategy and confirmed the
absolute stereochemistry of the natural compound.4,5 We
are interested in clavilactone D (1), one of the most bioac-
tive congeners, because it exerts a significant inhibitory
effect on tyrosine kinase and has yet to be chemically pro-
duced. Its structure has been elucidated by an extensive
NMR study and its absolute stereochemistry was correlat-
SYNTHESIS 2009, No. 17, pp 2963–2969
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.07.2009
DOI: 10.1055/s-0029-1216909; Art ID: C02309SS
© Georg Thieme Verlag Stuttgart · New York

2964
T. Yoshimitsu et al.
PAPER
O
O
O
O
O
HO
O
O
O
O
OMe
OMe
O
O
O
O
O
7
6
clavilactone D (1)
I
I
O
O
O
O
O
O
O
O
OH
H
H
H
reductive
olefination
Friedel–Crafts
cyclization
MeO
OMe
OMe
O
O
O
O
O
O
8
9
ii
O
O
I
O
O
O
O
O
O
I2
11
H
O
O
CHO
O
HO
H
O
iodo
etherification
O
MeO
OR
R = l-menthyl
O
i
OMe
OMe
12
10a
RO
Scheme 1 Retrosynthesis of clavilactone D
reochemistry, giving rise to corresponding polycyclic lac- achieved by b-elimination of the hydroxyl group followed
tones 9b (from 10b) and ent-9a (from 10c).
by an olefin isomerization to provide butenolide 7. How-
ever, such attempts were unsuccessful. Therefore, com-
pound 8 was first converted into thionocarbonate 15,10
which, by radical reduction with tributyltin hydride, pro-
vided lactone 16 in good yield. Enolization of lactone 16
with lithium hexamethyldisilazide, followed by the cap-
ture of the resultant enolate with diphenyl disulfide, gave
a-thiophenylated lactone 17. Lactone 17 was then oxi-
dized with sodium periodate to give a sulfoxide, which
immediately underwent elimination of thiophenol under
gentle heating to afford butenolide 7 quantitatively. The
epoxide moiety of the clavilactone core was installed by
the reaction of butenolide 7 with tert-butyl hydroperoxide
Iodo ether 9a was then subjected to reductive olefination
in the presence of a metal reagent (Scheme 3). Although
initial attempts to regenerate the olefin functionality by
use of zinc metal led to low selectivity (Z/E = ca. 1:1), we
eventually found that indium metal afforded a high degree
of Z selectivity (Z/E = ca. 10:1).9 The origin of the good
selectivity in the latter case is still unclear, although it may
be attributed to the steric effect of the large organoindium
intermediate that could maintain stereospecificity during
the removal of the iodo ether functionality.
The next task was to convert alcohol 8 into butenolide 7
(Scheme 3). We envisaged that it would be readily
O
O
O
O
O
O
O
H
H
O
O
OR
O
CHO
HO
HO
11
O
O
LHMDS
THF, –78 °C
92%
OR
OR
OMe
OMe
OMe
10a
10b
12
O
10a/10b/10c = 3:1:2
O
H
R = l-menthyl
O
HO
O
OR
OMe
10c
Scheme 2 Synthesis of alkenyl alcohol 10
Synthesis 2009, No. 17, 2963–2969 © Thieme Stuttgart · New York

PAPER
Asymmetric Total Synthesis of Clavilactone D
2965
Table 1 ‘Lariat’ Cyclization of Alkenyl Alcohol 10a
I
I
O
O
O
O
O
H
O
O
H
O
O
I2
HO
HO
O
O
H
MeCN
OMe
O
O
OR
O
OMe
OR
OMe
10a
9a
I
R = l-menthyl
O
O
H
O
I
selected NOE correlations of 9a
OMe
O
O
O
H
H3C
H
O
13a
I
O
RO
I
HO
O
O
O
H
O
H
O
OR
OMe
H
O
MeO
H
H
H
O
O
O
OMe
O
14a
RO
Entry
I2 (equiv)
3.0
Temp
r.t.
Time (h)
Products (yield, %)
1
2
3
4
1
9a (27), 13a (13), 14a (8)
9a (28), 13a (12), 14a (8)
9a (28), 13a (11), 14a (6)
9a (25), 13a (10), 14a (8)
10.0
3.0
r.t.
2.5
1.5
1.5
0 °C to r.t.
0 °C to r.t.
1.5
in the presence of Triton B. The epoxidation took place optical purity of product 6 (ca. 82% ee). However, fortu-
smoothly to furnish compound 6, a lactone fused with an nately, the rigidity of the macrocyclic architecture of
aromatic ring, which constituted the proposed clavilac- butenolide 7 prevented the system from undergoing con-
tone scaffold (Scheme 3).
siderable racemization. Furthermore, the recrystallization
of product 6 allowed us to obtain an enantiomerically pure
epoxide 6 (100% ee as determined by HPLC analysis).
The relative structure of 6 was also confirmed by X-ray
It was revealed that during the epoxidation reaction under
basic conditions, epimerization at the g-position of the
butenolide occurred, which led to a slight decrease in the
I
O
O
O
O
O
In powder
AcOH
ClC(S)OPh
Py, DMAP
O
O
R
OH
MeOH
r.t.
CH2Cl2, r.t.
76%
H
H
H
OMe
O
OMe
O
OMe
9a
O
O
O
O
8
15 R = OC(S)OPh
16 R = H
n-Bu3SnH
AIBN, toluene
100 °C
89% (Z/E = 10 : 1)
LHMDS
94%
–78 °C
62%
(PhS)2
THF
O
O
O
O
TBHP
O
NaIO4
O
Triton B
O
THF
aq MeOH
–78 °C to r.t.
SPh
60 °C
quant
OMe
17
O
OMe
O
OMe
O
59%
O
O
O
7
6
Scheme 3 Synthesis of the clavilactone D core
Synthesis 2009, No. 17, 2963–2969 © Thieme Stuttgart · New York

2966
T. Yoshimitsu et al.
PAPER
crystallographic analysis of its racemic crystals,11 indicat-
ing that the epoxidation took place from the b-face, as ex-
pected, to furnish the desired relative stereochemistry that
matches that proposed for the natural product (Figure 2).12
mL). The organic layers were combined, dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography (silica gel, E2O–n-hexane, 1:2 to 2:1) to give alco-
hols 10a, 10b, and 10c, all as colorless oils.
10a
Yield: 390 mg (45%); colorless oil; [a]D27 –69.7 (c 3.00, CHCl3).
IR (neat): 3503, 2955, 2924, 1771 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.34 (d, J = 2.5 Hz, 1 H), 6.16 (d,
J = 2.5 Hz, 1 H), 5.87 (s, 2 H), 5.65 (d, J = 4.9 Hz, 1 H), 5.39 (t,
J = 7.3 Hz, 1 H), 3.79 (dt, J = 7.7, 4.3 Hz, 1 H), 3.70 (s, 3 H), 3.49
(dt, J = 10.7, 4.3 Hz, 1 H), 3.33 (d, J = 14.7 Hz, 1 H), 3.24 (d,
J = 14.7 Hz, 1 H), 2.87 (ddd, J = 10.7, 8.9, 7.7 Hz, 1 H), 2.50–2.36
(m, 2 H), 2.19 (dd, J = 12.8, 8.9 Hz, 1 H), 2.16–1.98 (m, 3 H), 1.69
(s, 3 H), 1.69–1.60 (m, 2 H), 1.36 (m, 1 H), 1.21 (m, 1 H), 0.93–0.84
(m, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3 H), 0.75
(d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 178.8, 154.9, 147.6, 139.7, 136.0,
121.5, 120.7, 106.0, 100.7, 98.7, 95.1, 77.2, 71.7, 55.9, 47.6, 43.0,
39.7, 34.2, 33.3, 32.8, 31.7, 31.3, 25.4, 23.5, 22.9, 22.2, 20.8, 15.4.
Figure 2 X-ray crystal structure of rac-6; thermal ellipsoids are
shown at the 50% probability level
MS (FAB): m/z (%) = 511 [M + Na]+, 83 (100).
HRMS–FAB: m/z [M + Na]+ calcd for C28H40O7Na: 511.2672;
found: 511.2678.
In conclusion, we have established an asymmetric ap-
proach to the clavilactone core. Our route to the core uti-
lized the ‘lariat’ cyclization of alkenyl alcohol triggered
by iodo etherification followed by a Friedel–Crafts-type
cyclization. The present versatile route exemplifies a nov-
el concept applicable not only to clavilactones, but also to
highly fused macrocyclic natural compounds. Further
studies are in progress to accomplish the total synthesis of
natural clavilactone D (1) and the results will be reported
in due course.
10b
Yield: 129 mg (15%); colorless oil; [a]D27 –80.4 (c 3.00, CHCl3).
IR (neat): 3495, 2955, 2922, 1771 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.36 (d, J = 2.4 Hz, 1 H), 6.14 (d,
J = 2.4 Hz, 1 H), 5.89 (s, 2 H), 5.67 (d, J = 5.7 Hz, 1 H), 5.31 (t,
J = 7.3 Hz, 1 H), 4.27 (m, 1 H), 3.72 (s, 3 H), 3.51 (dt, J = 10.4, 4.0
Hz, 1 H), 3.34 (d, J = 14.8 Hz, 1 H), 3.25 (d, J = 14.8 Hz, 1 H), 2.91
(ddd, J = 10.4, 8.8, 2.8 Hz, 1 H), 2.50 (ddd, J = 13.0, 10.4, 5.7 Hz,
1 H), 2.42–1.95 (m, 5 H), 1.72–1.59 (m, 2 H), 1.69 (s, 3 H), 1.41–
1.15 (m, 2 H), 1.04–0.78 (m, 3 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.87
(d, J = 6.9 Hz, 3 H), 0.77 (d, J = 6.9 Hz, 3 H).
Melting points are uncorrected. Chemicals were used as received
from commercial suppliers unless otherwise noted. 1H NMR spectra
(500, 300, or 270 MHz) and 13C NMR spectra (125, 75, or 67.5
MHz) were measured of samples dissolved in CDCl3 unless other-
wise stated. Chemical shifts are reported relative to the internal sol-
vent signal: CDCl3 (d = 7.26) for 1H NMR and CDCl3 (d = 77.0) for
13C NMR. The proton signal of TMS (d = 0.00) was also used in
13C NMR (75 MHz, CDCl3): d = 177.9, 154.9, 147.7, 139.6, 136.5,
121.5, 120.5, 106.1, 100.8, 99.1, 95.1, 76.4, 69.0, 55.8, 47.7, 44.2,
39.8, 34.2, 33.9, 31.9, 31.3, 28.7, 25.3, 23.4, 22.9, 22.2, 20.9, 15.5.
MS (FAB): m/z (%) = 511 [M + Na]+, 83 (100).
HRMS–FAB: m/z [M + Na]+ calcd for C28H40O7Na: 511.2672;
found: 511.2687.
1
some cases as the internal standard for H NMR spectra. FT-IR
spectra were recorded for samples loaded on NaCl or KBr. Mass
spectra were obtained according to the specified technique. Analyt-
ical TLC was performed on Kieselgel 60 F254, and compounds were
visualized with UV light, anisaldehyde soln, phosphomolybdic acid
in EtOH, I2, or KMnO4 soln.
10c
Yield: 282 mg (32%); colorless oil; [a]D27 –72.2 (c 3.50, CHCl3).
IR (neat): 3501, 2953, 2924, 1768 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.35 (d, J = 2.4 Hz, 1 H), 6.17 (d,
J = 2.4 Hz, 1 H), 5.89 (s, 2 H), 5.68 (t, J = 5.5 Hz, 1 H), 5.39 (t,
J = 7.3 Hz, 1 H), 3.93 (m, 1 H), 3.73 (s, 1 H), 3.71 (s, 3 H), 3.55 (dt,
J = 10.6, 4.2 Hz, 1 H), 3.32 (d, J = 14.6 Hz, 1 H), 3.27 (d, J = 14.6
Hz, 1 H), 2.72 (dt, J = 9.9, 8.9 Hz, 1 H), 2.49 (ddd, J = 13.5, 9.9, 5.5
Hz, 1 H), 2.49–2.33 (m, 2 H), 2.17–2.02 (m, 2 H), 1.86 (ddd,
J = 13.5, 8.9, 5.5 Hz, 1 H), 1.72–1.58 (m, 2 H), 1.70 (s, 3 H), 1.44–
1.18 (m, 2 H), 0.94–0.85 (m, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 0.89
(d, J = 6.9 Hz, 3 H), 0.79 (d, J = 6.9 Hz, 3 H).
(3R,5R)-3-[(1R,3Z)-1-Hydroxy-5-(6-methoxy-2H-1,3-benzo-
dioxol-4-yl)-4-methylpent-3-en-1-yl]-5-{[(1R,2S,5R)-2-isopro-
pyl-5-methylcyclohexyl]oxy}dihydrofuran-2(3H)-one (10a),
(3R,5R)-3-[(1S,3Z)-1-Hydroxy-5-(6-methoxy-2H-1,3-benzo-
dioxol-4-yl)-4-methylpent-3-en-1-yl]-5-{[(1R,2S,5R)-2-isopro-
pyl-5-methylcyclohexyl]oxy}dihydrofuran-2(3H)-one (10b),
and (3S,5R)-3-[(1S,3Z)-1-Hydroxy-5-(6-methoxy-2H-1,3-ben-
zodioxol-4-yl)-4-methylpent-3-en-1-yl]-5-{[(1R,2S,5R)-2-iso-
propyl-5-methylcyclohexyl]oxy}dihydrofuran-2(3H)-one (10c)
A 1.1 M soln of LHMDS in THF (1.62 mL, 1.78 mmol) was added
to a stirred soln of lactone 11 (428 mg, 1.78 mmol) in THF (8 mL)
at –78 °C. After 30 min, a soln of aldehyde 12 (442 mg, 1.78 mmol)
in THF (8 mL) was added over 20 min, and the mixture was stirred
for an additional 40 min. The reaction was quenched with sat.
NH4Cl (50 mL), and the mixture was poured into a separatory fun-
nel where it was partitioned between Et2O (2 × 20 mL) and brine (10
13C NMR (75 MHz, CDCl3): d = 177.2, 154.9, 147.6, 139.7, 135.9,
121.4, 120.7, 105.9, 100.8, 100.0, 95.0, 78.4, 71.7, 55.9, 47.6, 44.8,
39.9, 34.1, 33.0, 32.4, 31.6, 31.3, 25.2, 23.5, 22.6, 22.2, 20.9, 15.5.
MS (FAB): m/z (%) = 511 [M + Na]+, 83 (100).
HRMS–FAB: m/z [M + Na]+ calcd for C28H40O7Na: 511.2672;
found: 511.2678.
Synthesis 2009, No. 17, 2963–2969 © Thieme Stuttgart · New York

PAPER
Asymmetric Total Synthesis of Clavilactone D
2967
(2R,5S,16R,17R)-17-Iodo-7-methoxy-16-methyl-4,10,12,19-tet-
raoxapentacyclo[14.2.1.12,5.06,14.09,13]icosa-6,8,13-trien-3-one
(9a), (3R,5R)-3-{(4S)-4-Iodo-5-[(6-methoxy-2H-1,3-benzodiox-
ol-4-yl)methyl]-5-methyltetrahydrofuran-2-yl}-5-{[(1R,2S,5R)-
2-isopropyl-5-methylcyclohexyl]oxy}dihydrofuran-2(3H)-one
(13a) and (3R,5S)-3-{(4S)-4-Iodo-5-[(6-methoxy-2H-1,3-benzo-
dioxol-4-yl)methyl]-5-methyltetrahydrofuran-2-yl}-5-
{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}dihydrofu-
ran-2(3H)-one (14a); Typical Procedure for Iodine-Mediated
‘Lariat’ Cyclization (Table 1, entry 3)
Compounds ent-9a and 9b from 10c and 10b
The same protocol was applied to alkenyl alcohols 10b and 10c,
similarly affording the corresponding polycycles. The spectroscop-
ic data are given below.
(2S,5R,16S,17S)-17-Iodo-7-methoxy-16-methyl-4,10,12,19-tet-
raoxapentacyclo[14.2.1.12,5.06,14.09,13]icosa-6,8,13-trien-3-one
(ent-9a)
Treatment of 10c (97.6 mg, 0.200 mmol) by the protocol described
above for 10a afforded iodo ether ent-9a as a colorless solid.
I2 (156 mg, 0.614 mmol) was added to a stirred soln of alcohol 10a
(98.2 mg, 0.201 mmol) in MeCN (1 mL) at 0 °C. After 15 min, the
mixture was allowed to warm to r.t. and the stirring was continued
for 1 h further. The mixture was poured into a separatory funnel
where it was partitioned between Et2O (20 mL) and a mixture of sat.
NaHCO3 and sat. Na2SO3 (1:1, 20 mL). The organic extracts were
combined, washed with brine (5 mL), dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash column chro-
matography (silica gel, acetone–n-hexane, 1:20) to give iodo ether
13a as a colorless oil and iodo ether 14a as a colorless oil. Further
elution (acetone–n-hexane, 1:5) gave iodo ether 9a as a colorless
solid.
Yield: 24.3 mg (27%); colorless needles; mp 203–204 °C (dec.)
(EtOAc–n-hexane); [a]D22 –7.3 (c 0.85, CHCl3). The other spectral
data of this material were identical with those of lactone 9a.
(2R,5S,16S,17S)-17-Iodo-7-methoxy-16-methyl-4,10,12,19-tet-
raoxapentacyclo[14.2.1.12,5.06,14.09,13]icosa-6,8,13-trien-3-one
(9b) from 10b
Compound 10b (307 mg, 0.628 mmol) was also transformed into
the corresponding iodo ether 9b by the protocol described above for
10a.
26
Yield: 67.8 mg (24%); colorless amorphous; [a]D +55.9 (c 2.10,
CHCl3).
IR (neat): 2934, 1759 cm–1.
9a
Yield: 25.4 mg (28%); colorless needles; mp 203–204 °C (dec)
1H NMR (500 MHz, CDCl3): d = 6.54 (s, 1 H), 6.33 (d, J = 9.8 Hz,
1 H), 5.89 (s, 1 H), 5.87 (s, 1 H), 4.62 (dd, J = 9.2, 7.4 Hz, 1 H), 4.06
(dt, J = 12.5, 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.28 (d, J = 14.7 Hz, 1 H),
2.97 (m, 1 H), 2.89 (d, J = 14.7 Hz, 1 H), 2.74 (dt, J = 12.5, 7.4 Hz,
1 H), 2.72–2.62 (m, 2 H), 2.35 (dt, J = 12.5, 9.2 Hz, 1 H), 1.22 (s, 3
H).
(EtOAc–n-hexane); [a]D25 +7.3 (c 3.53, CHCl3).
IR (KBr): 2939, 1755 cm–1.
1H NMR (270 MHz, CDCl3): d = 6.49 (s, 1 H), 6.28 (d, J = 8.6 Hz,
1 H), 5.91 (d, J = 1.2 Hz, 1 H), 5.84 (d, J = 1.2 Hz, 1 H), 4.37 (dd,
J = 15.0, 6.9 Hz, 1 H), 3.99 (dd, J = 11.0, 9.2 Hz, 1 H), 3.78 (s, 3 H),
3.21 (d, J = 14.5 Hz, 1 H), 3.08 (ddd, J = 14.3, 11.0, 7.1 Hz, 1 H),
2.88–2.71 (m, 3 H), 2.59 (d, J = 14.5 Hz, 1 H), 2.51 (m, 1 H), 1.15
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 177.2, 156.1, 146.8, 141.3, 118.6,
117.9, 100.4, 94.2, 82.9, 77.7, 77.2, 57.1, 45.7, 39.7, 36.4, 27.9,
23.9, 22.2.
13C NMR (75 MHz, CDCl3): d = 178.8, 152.3, 146.1, 141.6, 120.4,
119.5, 100.4, 93.1, 82.7, 76.8, 75.3, 56.6, 44.9, 37.3, 34.9, 31.1,
27.6, 22.5.
MS (FAB): m/z (%) = 459 [M + H]+, 154 (100).
HRMS–FAB: m/z [M + H]+ calcd for C18H20O6I: 459.0305; found:
459.0299.
MS (FAB): m/z (%) = 459 [M + H]+, 154 (100).
HRMS–FAB: m/z [M + H]+ calcd for C18H20O6I: 459.0305; found:
459.0298.
(1S,12Z,15R,16R)-15-Hydroxy-3-methoxy-12-methyl-6,8,18-
trioxatetracyclo[14.2.1.02,10.05,9]nonadeca-2,4,9,12-tetraen-17-
one [(Z)-8] and (1S,12E,15R,16R)-15-Hydroxy-3-methoxy-12-
methyl-6,8,18-trioxatetracyclo[14.2.1.02,10.05,9]nonadeca-
2,4,9,12-tetraen-17-one [(E)-8]
13a
Yield: 14.0 mg (11%); colorless oil.
AcOH (3 mL) and In metal (956 mg, 8.34 mmol) were added to a
stirred soln of iodo ether 9a (190 mg, 0.415 mmol) in MeOH (50
mL) at r.t. After 3 h of vigorous stirring of the mixture, sat. NaHCO3
(50 mL) was added and the mixture was filtered through a Celite
pad. After concentration of the filtrate under reduced pressure, the
residue was extracted with Et2O (2 × 20 mL) and washed with brine
(10 mL). The organic extracts were combined, dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash column
chromatography (silica gel, EtOAc–n-hexane, 1:1) to give E-alco-
hol 8 (9%) as a colorless oil and Z-alcohol 8 (89%) as a colorless
amorphous.
1H NMR (300 MHz, CDCl3): d = 6.36 (d, J = 2.6 Hz, 1 H), 6.29 (d,
J = 2.6 Hz, 1 H), 5.87 (s, 1 H), 5.86 (s, 1 H), 5.62 (dd, J = 6.0, 2.0
Hz, 1 H), 4.21 (dd, J = 11.0, 6.6 Hz, 1 H), 4.15 (ddd, J = 11.0, 5.8,
4.0 Hz, 1 H), 3.75 (s, 3 H), 3.51 (dt, J = 10.6, 4.4 Hz, 1 H), 3.10 (m,
1 H), 3.08 (d, J = 13.5 Hz, 1 H), 2.84 (dt, J = 12.2, 11.0 Hz, 1 H),
2.67 (d, J = 13.5 Hz, 1 H), 2.51 (ddd, J = 12.2, 6.6, 5.8 Hz, 1 H),
2.39 (ddd, J = 13.0, 9.2, 6.0 Hz, 1 H), 2.22 (ddd, J = 13.0, 9.2, 2.0
Hz, 1 H), 2.16–1.91 (m, 2 H), 1.71–1.57 (m, 3 H), 1.40 (m, 1 H),
1.23 (s, 3 H), 1.01–0.74 (m, 12 H).
14a
Yield: 7.0 mg (6%); colorless oil.
Alcohol (Z)-8
Yield: 123 mg (89%); colorless amorphous; [a]D +14.9 (c 2.61,
CHCl3).
23
1H NMR (300 MHz, CDCl3): d = 6.38 (s, 2 H), 5.874 (s, 1 H), 5.870
(s, 1 H), 5.55 (t, J = 5.7 Hz, 1 H), 4.28 (dt, J = 9.7, 5.7 Hz, 1 H), 4.25
(dd, J = 9.7, 7.1 Hz, 1 H), 3.75 (s, 3 H), 3.41 (dt, J = 10.6, 4.2 Hz, 1
H), 3.10 (d, J = 13.7 Hz, 1 H), 3.04 (ddd, J = 9.4, 8.4, 5.7 Hz, 1 H),
2.73 (d, J = 13.7 Hz, 1 H), 2.60 (dt, J = 13.0, 9.7 Hz, 1 H), 2.54
(ddd, J = 13.7, 9.4, 5.7 Hz, 1 H), 2.22–1.98 (m, 2 H), 2.17 (ddd,
J = 13.7, 8.4, 5.7 Hz, 1 H), 2.06 (ddd, J = 13.0, 7.1, 5.7 Hz, 1 H),
1.68–1.55 (m, 3 H), 1.36 (m, 1 H), 1.22, (s, 3 H), 1.08–0.75 (m, 3
H), 0.92 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.78 (d,
J = 7.0 Hz, 3 H).
IR (neat): 3420, 2969, 2913, 1744 cm–1.
1H NMR (500 MHz, CDCl3, including rotamer): d = 6.45 (s, 0.6 H),
6.43 (s, 0.4 H), 6.33 (t, J = 9.8 Hz, 0.6 H), 6.22, (t, J = 9.2 Hz, 0.4
H), 5.92 (s, 1.2 H), 5.90 (s, 0.8 H), 5.48 (t, J = 8.0 Hz, 0.4 H), 5.05
(br d, J = 8.5 Hz, 0.6 H), 4.57 (m, 0.6 H), 4.41 (t, J = 5.5 Hz, 0.4 H),
3.93 (d, J = 15.9 Hz, 0.6 H), 3.80 (d, J = 14.0 Hz, 0.4 H), 3.73 (s,
1.8 H), 3.72 (s, 1.2 H), 3.40–3.31 (m, 0.4 H), 3.38 (d, J = 15.9 Hz,
0.6 H), 3.18 (d, J = 14.0 Hz, 0.4 H), 3.08 (ddd, J = 9.2, 8.6, 2.4 Hz,
Synthesis 2009, No. 17, 2963–2969 © Thieme Stuttgart · New York

2968
T. Yoshimitsu et al.
PAPER
(1S,12Z,16S)-3-Methoxy-12-methyl-6,8,18-trioxatetracyc-
lo[14.2.1.02,10.05,9]nonadeca-2(10),3,5(9),12-tetraen-17-one (16)
n-Bu3SnH (131 mL, 0.496 mmol) and AIBN (81.4 mg, 0.496 mmol)
were added to a stirred soln of thionoester 15 (75.4 mg, 0.161
mmol) in toluene (5 mL) at r.t. After being heated at 100 °C for 1 h,
the mixture was cooled to r.t. and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(silica gel, acetone–n-hexane, 1:10 to 1:3).
0.6 H), 2.81 (ddd, J = 14.1, 9.8, 9.2 Hz, 0.6 H), 2.76–2.63 (m, 1.4
H), 2.45–2.32 (m, 2 H), 1.61 (s, 1.2 H), 1.44 (s, 1.8 H).
13C NMR (125 MHz, CDCl3, rotamer *): d = 178.2*, 177.3, 154.9,
153.1*, 147.4, 147.2*, 142.4, 142.2*, 138.8*, 137.0, 121.1, 120.8*,
120.6*, 119.8, 118,8*, 116.4, 100.6 (overlapped), 93.9, 93.3*,
74.6*, 72.8, 72.3, 67.9*, 57.3, 57.0*, 47.9*, 46.9, 32.5, 30.4*, 29.7,
28.4*, 27.3*, 22.7, 22.23*, 22.15.
MS (FAB): m/z (%) = 355 [M + Na]+, 176 (100).
25
Yield: 47.8 mg (94%); colorless amorphous; [a]D +74.4 (c 0.90,
CHCl3).
HRMS–FAB: m/z [M + Na]+ calcd for C18H20O6Na: 355.1158;
found: 355.1159.
IR (neat): 2965, 2922, 1759 cm–1.
Alcohol (E)-8
Yield: 11.8 mg (9%); colorless oil; [a]D26 +81.5 (c 0.28, CHCl3).
1H NMR (500 MHz, CDCl3, including rotamer): d = 6.44 (s, 0.3 H),
6.43 (s, 0.7 H), 6.27 (m, 0.3 H), 6.14 (t, J = 9.2 Hz, 0.7 H), 5.91 (s,
1.4 H), 5.87 (s, 0.6 H), 5.35 (br s, 0.7 H), 5.13 (br d, J = 7.9 Hz, 0.3
H), 3.91 (m, 0.3 H), 3.90 (d, J = 14.6 Hz, 0.7 H), 3.74 (s, 0.9 H),
3.72 (s, 2.1 H), 3.40 (d, J = 15.9 Hz, 0.3 H), 3.20–2.00 (m, 7 H),
3.15 (d, J = 14.6 Hz, 0.7 H), 1.57 (s, 2.1 H), 1.47 (s, 0.9 H).
IR (neat): 3428, 3009, 2924, 1748 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.45 (s, 1 H), 6.08 (t, J = 9.2 Hz,
1 H), 5.95 (d, J = 1.5 Hz, 1 H), 5.88 (d, J = 1.5 Hz, 1 H), 5.23 (br d,
J = 11.6 Hz, 1 H), 4.74 (dt, J = 8.8, 2.8 Hz, 1 H), 3.75 (s, 3 H), 3.64
(d, J = 13.7 Hz, 1 H), 3.37 (d, J = 13.7 Hz, 1 H), 3.04 (ddd, J = 10.8,
9.2, 2.8 Hz, 1 H), 2.74 (m, 1 H), 2.46 (ddd, J = 13.2, 10.8, 9.2 Hz, 1
H), 2.22 (dt, J = 13.0, 8.8 Hz, 1 H), 1.85 (dt, J = 13.2, 9.2 Hz, 1 H),
1.37 (s, 3 H).
13C NMR 125 MHz, CDCl3): d = 180.6*, 180.3, 154.9*, 153.1,
147.2*, 147.0, 142.4*, 142.2, 136.0, 135.4*,126.3, 124.0*, 121.4*,
120.9, 119.3, 117.0*, 100.6 (overlapped), 93.9*, 93.2, 74.0, 71.9*,
57.5*, 57.0, 41.3, 38.7*, 30.9, 29.7*, 28.4*, 28.1, 25.8, 24.6*, 24.3,
23.2*, 21.9, 19.3*.
13C NMR (75 MHz, CDCl3): d = 178.9, 152.9, 146.6, 141.6, 136.8,
121.9, 121.0, 117.3, 100.6, 93.0, 75.0, 70.5, 56.8, 47.7, 36.4, 33.6,
26.2, 15.9.
MS (FAB): m/z (%) = 339 [M + Na]+, 339 (100).
HRMS–FAB: m/z [M + Na]+ calcd for C18H20O5Na: 339.1208;
found: 339.1209.
MS (FAB): m/z (%) = 333 [M + H]+, 69 (100).
HRMS–FAB: m/z [M + H]+ calcd for C18H21O6: 333.1338; found:
333.1325.
(1S,12Z,16R)-3-Methoxy-12-methyl-16-(phenylsulfanyl)-
6,8,18-trioxatetracyclo[14.2.1.02,10.05,9]nonadeca-
2(10),3,5(9),12-tetraen-17-one (17)
(1S,12Z,15R,16R)-3-Methoxy-12-methyl-15-[(phenoxycarbono-
thioyl)oxy]-6,8,18-trioxatetracyclo[14.2.1.02,10.05,9]nonadeca-
2(10),3,5(9),12-tetraen-17-one (15)
A 1.1 M soln of LiHMDS in THF (316 mL, 0.348 mmol) was added
to a stirred soln of lactone 16 (99.1 mg, 0.313 mmol) in THF (3 mL)
at –78 °C. After 30 min, a soln of (PhS)2 (75.9 mg, 0.348 mmol) in
THF (3 mL) was added over 15 min, and the mixture was stirred at
the same temperature for a further 45 min. The reaction was
quenched with sat. NH4Cl (30 mL), and the mixture was poured into
a separatory funnel where it was extracted with Et2O (2 × 20 mL).
The organic extract was washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by
flash column chromatography (silica gel, E2O–n-hexane, 1:3 to
1:1).
ClC(S)OPh (102 mL, 0.741 mmol), py (120 mL, 1.48 mmol), and
DMAP (90 mg, 0.741 mmol) were added to a stirred soln of alcohol
8 (121 mg, 0.364 mmol) in CH2Cl2 (10 mL) at r.t. After 18 h, the
mixture was poured into a separatory funnel where it was parti-
tioned between Et2O (2 × 40 mL) and H2O (200 mL). The organic
extract was washed with brine (20 mL), dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash column chro-
matography (silica gel, E2O–n-hexane, 1:2).
23
Yield: 130 mg (76%); colorless amorphous; [a]D +17.7 (c 2.14,
CHCl3).
Yield: 82.5 mg (62%); colorless amorphous; [a]D25 +131.4 (c 0.81,
CHCl3).
IR (neat): 2969, 2940, 1755 cm–1.
IR (neat): 3007, 2940, 1757 cm–1.
1H NMR (300 MHz, CDCl3, including rotamer): d = 7.45–7.10 (m,
5 H), 6.50 (s, 0.6 H), 6.47 (s, 0.4 H), 6.38 (t, J = 9.3 Hz, 0.6 H), 6.29
(t, J = 9.3 Hz, 0.4 H), 6.02 (m, 0.6 H), 5.95 (s, 1.2 H), 5.91 (s, 0.8
H), 5.81 (br t, J = 5.5 Hz, 0.4 H), 5.39 (t, J = 8.6 Hz, 0.4 H), 5.13 (br
d, J = 11.0 Hz, 0.6 H), 4.01 (d, J = 15.8 Hz, 0.6 H), 3.90 (m, 0.4 H),
3.85 (d, J = 14.6 Hz, 0.4 H), 3.78 (s, 1.8 H), 3.75 (s, 1.2 H), 3.48 (m,
0.6 H), 3.49 (d, J = 15.8 Hz, 0.6 H), 3.34 (dt, J = 14.1, 9.3 Hz, 0.4
H), 3.26 (d, J = 14.6 Hz, 0.4 H), 2.99 (dt, J = 14.1, 9.3 Hz, 0.6 H),
2.99–2.71 (m, 2 H), 2.60–2.38 (m, 1 H), 1.65 (s, 1.2 H), 1.52 (s, 1.8
H).
1H NMR (500 MHz, CDCl3): d = 7.65–7.37 (m, 5 H), 6.37 (s, 1 H),
5.90 (s, 1 H), 5.86 (s, 1 H), 5.41 (t, J = 9.2 Hz, 1 H), 5.33 (t, J = 7.3
Hz, 1 H), 3.75 (d, J = 14.7 Hz, 1 H), 3.65–3.60 (m, 1 H), 3.61 (s, 3
H), 3.11 (d, J = 14.7 Hz, 1 H), 2.52 (br dd, J = 14.0, 12.8 Hz, 1 H),
2.33 (dd, J = 15.3, 9.2 Hz, 1 H), 2.15 (m, 1 H), 2.11 (ddd, J = 14.0,
7.3, 6.7 Hz, 1 H), 1.76 (t, J = 12.8 Hz, 1 H), 1.58 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 177.6, 153.3, 147.2, 142.3,
137.52, 137.45, 130.0, 129.9, 129.0, 125.2, 120.9, 118.5, 100.7,
93.6, 72.4, 57.2, 57.0, 37.8, 32.3, 28.2, 25.0, 22.0.
MS (FAB): m/z (%) = 447 [M + Na]+, 154 (100).
13C NMR (75 MHz, CDCl3, rotamer *): d = 193.5, 193.4*, 176.5*,
175.1, 155.1 (overlapped), 153.2 (overlapped), 147.6, 147.4*,
142.5, 142.3*, 139.2*, 138.8, 129.5 (overlapped), 126.6 (over-
lapped), 121.8, 121.7*, 120.8, 120.4*, 120.2*, 118.7*, 118.1, 116.2,
100.7 (overlapped), 94.1, 93.4*, 83.7, 79.6*, 74.4*, 72.5, 57.4,
57.1*, 44.1*, 43.5, 29.9, 28.6*, 28.4, 27.5*, 27.3*, 23.2, 22.3,
22.2*.
HRMS–FAB: m/z [M + Na]+ calcd for C24H24O5SNa: 447.1242;
found: 447.1240.
(1S,12Z)-3-Methoxy-12-methyl-6,8,18-trioxatetracyc-
lo[14.2.1.02,10.05,9]nonadeca-2(10),3,5(9),12,16(19)-pentaen-17-
one (7)
A soln of NaIO4 (20.4 mg, 0.0954 mmol) in H2O (0.5 mL) was add-
ed to a stirred soln of sulfide 17 (13.8 mg, 0.0325 mmol) in MeOH
(5 mL) at r.t. Then the mixture was heated at 60 °C for 17 h. After
concentration of the mixture under reduced pressure, the residue
MS (FAB): m/z (%) = 491 [M + Na]+, 176 (100).
HRMS–FAB: m/z [M + Na]+ calcd for C25H24O7SNa: 491.1140;
found: 491.1145.
Synthesis 2009, No. 17, 2963–2969 © Thieme Stuttgart · New York

PAPER
Asymmetric Total Synthesis of Clavilactone D
2969
was extracted with Et2O (2 × 20 mL), the mixture was washed with
H2O (70 mL) and brine (10 mL), and the Et2O fraction was dried
over Na2SO4, filtered, and concentrated. The residue was purified
by flash column chromatography (silica gel, EtOAc–n-hexane, 1:5).
The HPLC analysis of 7 revealed that during this oxidation process
no racemization had occurred.
Culture, Sports, Science, and Technology, Japan. The authors thank
Professor Naoyoshi Maezaki for helpful discussions and Dr.
Naoyuki Kotoku of our institute for conducting HMBC experi-
ments.
References
Yield: 10.2 mg (quant); colorless amorphous; [a]D25 +61.5 (c 0.18,
CHCl3).
(1) (a) Merlini, L.; Nasini, G.; Scaglioni, L.; Cassinelli, G.;
Lanzi, C. Phytochemistry 2000, 53, 1039. (b)Cassinelli,G.;
Lanzi, C.; Pensa, T.; Gambetta, R. A.; Nasini, G.; Cuccuru,
G.; Cassinis, M.; Pratesi, G.; Polizzi, D.; Tortoreto, M.;
Zunino, F. Biochem. Pharmacol. 2000, 59, 1539.
(2) The absolute stereochemistry of natural clavilactone D
shown in this paper is provided on the basis of the revised
structure of clavilactone B (see ref. 4), a closely related
congener of clavilactone D.
IR (neat): 2963, 2938, 1749 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.75 (s, 1 H), 6.74 (s, 1 H), 6.50
(s, 1 H), 5.93 (d, J = 1.4 Hz, 1 H), 5.88 (d, J = 1.4 Hz, 1 H), 5.14
(dd, J = 9.8, 7.2 Hz, 1 H), 3.82 (s, 3 H), 3.02 (d, J = 14.7 Hz, 1 H),
2.82 (m, 1 H), 2.71 (d, J = 14.7 Hz, 1 H), 2.24 (ddt, J = 12.8, 7.2,
3.2 Hz, 1 H), 1.97 (ddt, J = 12.8, 9.8, 2.6 Hz, 1 H), 1.86 (ddd,
J = 12.8, 12.0, 3.2 Hz, 1 H), 1.59 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 174.9, 154.4, 149.7, 147.9, 142.3,
138.7, 129.1, 121.6, 121.4, 111.2, 100.8, 93.9, 76.2, 57.4, 28.2,
25.1, 24.7, 22.1.
(3) Arnone, A.; Cardillo, R.; Meille, S.; Nasini, G.; Tollazi, M.
J. Chem. Soc., Perkin Trans. 1 1994, 2165.
(4) Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko,
E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.;
Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042.
(5) For another approach to clavilactones, see: Yasui, H.;
Yamamoto, S.; Takao, K.; Tadano, K. Heterocycles 2006,
70, 135.
MS (FAB): m/z (%) = 337 [M + Na]+, 314 (100).
HRMS–FAB: m/z [M + Na]+ calcd for C18H18O5Na: 337.1052;
found: 337.1064.
(1R,4Z,16R,17R)-14-Methoxy-5-methyl-9,11,18,20-tetraoxa-
pentacyclo[14.2.2.01,17.07,15.08,12]icosa-4,7(15),8(12),13-tetraen-
19-one (6)
(6) Moradei, O. M.; Paquette, L. A. Org. Synth. 2003, 80, 66.
(7) This material was prepared in two steps (TBAF, Dess–
Martin oxidation) from tert-butyl[(Z)-5-(6-methoxyben-
zo[d][1,3]dioxol-4-yl)-4-methylpent-3-enyloxy]diphenyl-
silane, which was synthesized by Shair’s protocol utilizing a
palladium-mediated cross-coupling between (Z)-tert-
butyl(4-iodopent-3-enyloxy)diphenylsilane and a benzylic
zinc reagent derived from 4-(bromomethyl)-6-methoxy-
benzo[d][1,3]dioxole. For Shair’s protocol, see: Layton, M.
E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002,
124, 773. The alkenyl iodide was synthesized from propane-
1,3-diol in three steps [TBDPSCl, Swern oxidation,
Ph3P=C(I)Me], and the benzyl bromide was prepared from
6-methoxybenzo[d][1,3]dioxole-4-carbaldehyde in two
steps (LAH, Ph3P, CBr4).
A 5.5 M aq soln of TBHP (43 mL, 0.239 mmol) followed by a 40%
soln of Triton B in MeOH (50 mL, 0.119 mmol) were added to a
stirred soln of butenolide 7 (24.1 mg, 0.767 mmol) in THF (2 mL)
at –78 °C. Then the mixture was allowed to warm to r.t. over 1 h,
and the stirring was continued for an additional 2 h. Sat. NH4Cl (10
mL) and sat. Na2SO3 (10 mL) were added and the mixture was ex-
tracted with Et2O (2 × 10 mL). The organic extract was washed with
brine (5 mL), dried over Na2SO4, filtered, and concentrated. The
residue was purified by flash column chromatography (silica gel,
CH2Cl2–n-hexane, 3:1); this gave epoxide 6 as a colorless solid; re-
crystallization (CH2Cl2–Et2O) gave colorless plates.
Yield (colorless solid): 15.0 mg (59%); mp (colorless plates) 167–
168 °C (CH2Cl2–Et2O); [a]D24 +87.2 (c 0.46, CHCl3).
(8) For a related study on the aldol reaction using this lactone,
see: Lee, N.; Kim, Y.-W.; Chang, K.; Kim, K. H.; Jew, S.-S.;
Kim, D.-K. Tetrahedron Lett. 1996, 37, 2429.
IR (neat): 2963, 2922, 1770 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.50 (s, 1 H), 6.28 (s, 1 H), 5.98
(s, 1 H), 5.91 (s, 1 H), 5.29 (t, J = 8.3 Hz, 1 H), 3.92 (s, 1 H), 3.79
(s, 3 H), 3.30 (d, J = 15.3 Hz, 1 H), 3.19 (d, J = 15.3 Hz, 1 H), 2.72
(dd, J = 13.4, 2.1 Hz, 1 H), 2.46 (dddd, J = 14.2, 12.8, 8.3, 2.1 Hz,
1 H), 2.19 (m, 1 H), 1.56 (s, 3 H), 1.25 (ddd, J = 14.2, 13.4, 2.6 Hz,
1 H).
(9) For pertinent reviews, see: (a) Cintas, P. Synlett 1995,
1087. (b) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55,
11149. (c) Ranu, B. Eur. J. Org. Chem. 2000, 2347.
(d) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin Trans.
1 2000, 3015. (e) Pitts, M. R.; Harrison, J. R.; Moody, C. J.
J. Chem. Soc., Perkin Trans. 1 2001, 955. (f) Podlech, J.;
Maier, T. C. Synthesis 2003, 633. (g) Miyabe, H.; Naito, T.
Org. Biomol. Chem. 2004, 2, 1267. (h) Ueda, M. Yakugaku
Zasshi 2004, 124, 311. (i) Nair, V.; Ros, S.; Jayan, C. N.;
Pillai, B. S. Tetrahedron 2004, 60, 1959.
13C NMR (75 MHz, CDCl3): d = 172.2, 154.7, 148.3, 142.0, 136.6,
122.7, 121.7, 133.2, 101.0, 93.6, 74.9, 63.7, 61.5, 57.1, 28.6, 25.1,
22.6, 21.7.
MS (FAB): m/z (%) = 353 [M + Na]+, 176 (100).
(10) Barton, D.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(11) The racemic crystal was more suitable for X-ray
crystallographic analysis than the chiral one.
HRMS–FAB: m/z [M + Na]+ calcd for C18H18O6Na: 353.1001;
found: 353.1008.
(12) CCDC 733571 contains the supplementary X-ray
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas [no. 18032047] from the Ministry of Education,
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Synthesis 2009, No. 17, 2963–2969 © Thieme Stuttgart · New York