First total synthesis and absolute stereochemical assignment of vittarilide-A, an antioxidant extractive component isolated from Vittaria anguste-elongata Hayata

Article abstract of DOI:10.1016/j.tet.2012.06.105

The first stereocontrolled synthesis of vittarilide-A and its C5-epimer was completed from d-glucuronolactone. Comparison with the spectroscopic properties reported for authentic material has given a clear indication as to the absolute stereochemistry of the natural vittarilide-A.

Full text of DOI:10.1016/j.tet.2012.06.105

Tetrahedron 68 (2012) 7997e8002
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Tetrahedron
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First total synthesis and absolute stereochemical assignment of vittarilide-A, an
antioxidant extractive component isolated from Vittaria anguste-elongata Hayata
*
Masaki Takahashi, Yusuke Murata, Yuki Hakamata, Kohei Suzuki, Tetsuya Sengoku, Hidemi Yoda
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2012
Received in revised form 25 June 2012
Accepted 26 June 2012
Available online 4 July 2012
The first stereocontrolled synthesis of vittarilide-A and its C5-epimer was completed from D-glucur-
onolactone. Comparison with the spectroscopic properties reported for authentic material has given
a clear indication as to the absolute stereochemistry of the natural vittarilide-A.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Vittarilide-A
Natural product
Total synthesis
D
-Glucuronolactone
Vittaria anguste-elongata Hayata
1. Introduction
no synthetic challenges associated with this natural product have
been reported previously, and hence its absolute stereochemistry at
C5 has remained unspecified. Accordingly, total synthesis is
expected to offer beneficial opportunities to gain complete un-
derstanding of the chemical structure as well as to address the
supply problem leading to broader exploration of its biological
function and further development of clinically superior analogs.
From this basis, we set out to develop a stereocontrolled route to
access this new natural product from commercially available
Vittaria anguste-elongata Hayata, family Vittariaceae, is a very
rare linear grass-like fern distributed in Taiwan, Philippines, and
Pacific Islands.1 In 2005, Wu and co-workers have identified 12 new
and 20 known compounds in a crude methanol extract from this
plant and have shown one of the components can exhibit signifi-
cant cytotoxic activity against human cancer cell lines.2 Vittarilide-
A serves as one constituent of the new extractive components with
D
-glucuronolactone as an inexpensive chiral pool material.3,4 In this
publication, we report the success in the first total synthesis and
absolute stereochemical assignment of vittarilide-A.
2. Results and discussion
We commenced our synthetic approach with protection of
potent antioxidant property (IC50 value of 91
-picrylhydrazyl free radical (DPPH) scavenging assay), whose
structure consisting of trans-caffeoyl (3,4-dihydroxycinnamoyl)
mM, a,a-diphenyl-
D-glucuronolactone (Scheme 1). As reported in our previous work,
b
this substrate was readily protected through treatment with ace-
tone and concd H2SO4 at room temperature and the resulting
acetonide 1a could be further converted to the corresponding
benzyl ether 1b (95% for two steps).4 Subsequently, we attempted
the stepwise reduction of the remaining lactone moiety with
DIBALeH and NaBH4 to furnish the corresponding diol, whose
primary and secondary hydroxyl groups were then chemo-
selectively protected as the TBS and MOM ethers, respectively, to
obtain 2 in 87% (for four steps). At this stage, we replaced the TBS
group in 2 with benzyl substituent from the viewpoint of functional
group tolerance. As a matter of fact, the benzyl functionality
moiety and D-gluconate skeleton has been established on the basis
of spectroscopic studies.2 As a promising candidate for potential
biological applications, vittarilide-A can be an appealing synthetic
target due to the fact that the low abundance of the natural source
has limited its availability, impeding a more detailed investigation
of its unique biological properties. Nevertheless, to our knowledge,
* Corresponding author. Tel./fax: þ81 53 478 1150; e-mail address: tchyoda@
ipc.shizuoka.ac.jp (H. Yoda).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.105

7998
M. Takahashi et al. / Tetrahedron 68 (2012) 7997e8002
introduced through the desilylationebenzylation sequence was
tolerant to acidic treatment with methanolic HClaq, allowing for
removal of the acetonide and MOM groups to the corresponding
methyl glycoside. Further acidic hydrolysis of this product
employing HClaq in 1,4-dioxane at 90 ꢀC led to efficient production
of the corresponding lactol (75% for four steps), which underwent
chemoselective Fetizon oxidation5 to give the expected lactone 3 in
83% yield. Protection of all the hydroxyl groups in 3 with TBSCl and
subsequent deprotective hydrogenolysis of all the benzyl groups in
the presence of palladium hydroxide on carbon afforded the de-
sired gluconate segment 4 in 77% for two steps, which can be
considered to have R-configuration at the C5 stereocenter. Having
the gluconate intermediate in hand, our next objective was in-
troduction of trans-caffeoyl moiety onto the hydroxyl group located
at the terminal position of the gluconate structure. The site-
selective introduction was successfully achieved by EDCI coupling
of 4 with a TBS-protected substrate 5, which was readily derived
from caffeic acid (71% yield), to give 6 in 56%. Removal of all the TBS
groups, although challenging for the polyhydroxylated system and
initially problematic,6 was finally accomplished through treatment
with BF3$OEt2 in acetonitrile at 0 ꢀC,7 giving rise to the synthetic
target (5R)-7 in 50% yield, which could be purified by silica gel
column chromatography.
preparation of substantial quantities of the reference compound in
analytically pure form (see Supplementary data)8.
Scheme 2. Reagents and conditions: (a) (i) Tf2O, pyridine, CH2Cl2, 0 ꢀC, (ii) AcOK,
18-crown-6, DMF, 0 ꢀC; 99% (two steps), (iii) K2CO3, MeOH, 0 ꢀC, (iv) PPTS, (CH2Cl)2,
80 ꢀC; 71% (two steps); (b) see Supplementary data.
The structural identity of the synthetic and natural products was
confirmed by comparison of 1H and 13C NMR spectral data with
those in the literature.2,9 Fig. 1 depicts the 1H NMR spectra of (5R)-
and (5S)-7. As can be seen in this figure, these two compounds
showed remarkably different patterns for resonances attributed to
the gluconate segments in the higher magnetic fields, whereas
similar spectral shapes were given for resonances attributed to the
trans-caffeoyl moieties in the lower magnetic fields. Additionally,
chemical shift deviations estimated from the root-mean-square
(rms) of
data (Dd values) are shown in Table 1. From inspection of these data,
it appears that values of (5R)-7 closely match those for vittarilide-
d value differences between the reported and observed
d
In order to obtain precise determination of the absolute con-
figuration of the naturally occurring vittarilide-A, we decided to
A, giving 0.064 ppm of the rms for the gluconate segment much
less than 0.396 ppm for that of (5S)-7, while no impressive differ-
ences in the d value deviations were observed for the trans-caffeoyl
moieties of these two compounds (0.040 ppm for (5R)-7 and
0.020 ppm for (5S)-7). From these observations along with identity
of all coupling constants (J values) for (5R)-7 with those reported in
the literature, it is evident that (5R)-7 can be assigned as the nat-
urally occurring vittarilide-A and (5S)-7 should be its C5-epimer.
Furthermore, the 13C NMR spectra of (5R)- and (5S)-7 showed
similar trends observed in the 1H NMR spectra, which gave signifi-
cant difference in resonance patterns attributed to the gluconate
segments in the higher magnetic fields as well as similarity of reso-
nance patterns attributed to the trans-caffeoyl moieties in the lower
magnetic fields (Fig. 2). In view of Table 2 that lists chemical shift
deviations estimated from the rms of
reported and observed data (Dd values), one can clearly see that
values of (5R)-7 closely match those for vittarilide-A, giving
d value differences between the
d
0.173 ppm of the rms for the gluconate segment much less than
2.52 ppm for that of (5S)-7 besides 0.224 ppm for the trans-caffeoyl
moieties of (5R)-7 significantly less than 1.15 ppm for (5S)-7. From
these observations, it is evident that (5R)-7 can be assigned as the
naturally occurring vittarilide-A and (5S)-7 should be its C5-epimer,
inagreement with theconclusiondrawnfrom the data analysisof the
1H NMR. Therefore, the obvious conclusion that can be drawn from
the comparison of the NMR data is that the unspecified C5
Scheme 1. Reagents and conditions: (a) see Ref. 4; (b) (i) DIBALeH, CH2Cl2, ꢁ40 ꢀC, (ii)
NaBH4, MeOH, rt, (iii) TBSCl, Et3N, DMAP, CH2Cl2, rt; 91% (three steps), (iv) MOMCl,
DIPEA, CH2Cl2, rt; 87% (four steps), (c) (i) TBAF, THF, rt, (ii) BnBr, NaH, THF, rt, (iii) HClaq
,
MeOH, 50 ꢀC, (iv) HClaq, 1,4-dioxane, 90 ꢀC; 75% (four steps), (v) Ag2CO3, Celite, toluene,
80 ꢀC; 83%; (d) (i) TBSCl, imidazole, DMF, rt, (ii) H2, Pd(OH)2/C, EtOH, rt; 77% (two
steps); (e) (i) TBSCl, imidazole, DMF, rt, (ii) K2CO3, MeOH/H2O (1:1), rt; 71% (two steps);
(f) EDCI, DMAP, CH2Cl2, 0 ꢀC; 56%; (g) BF3$OEt2, CH3CN, 0 ꢀC; 50%.
pursue synthesis of C5-epimeric counterpart of (5R)-7. The requi-
site chiral substrate for the synthesis could be prepared by in-
version of the stereogenic center at a-position of the lactone ring in
1a (Scheme 2). Indeed, 1a was treated with triflic anhydride in the
presence of pyridine to give triflate, which was subjected to re-
action with potassium acetate in the presence of 18-crown-6,
providing the corresponding acetate with complete inversion of the
relevant stereochemistry in 99% yield for two steps. Hydrolysis of
this compound under basic conditions resulted in removal of the
acetyl moiety and concomitant lactone ring opening to generate
hydroxyl acid, which was readily cyclized to 1a0 (71% yield for two
steps) by treatment with pyridinium p-toluenesulfonate (PPTS). As
expected, transformation of 1a0 into (5S)-7 was achieved by fol-
lowing the established above strategy for (5R)-7, allowing for the
Fig. 1. Comparison of 1H NMR spectra of (5R)- and (5S)-7 in acetone-d6.

M. Takahashi et al. / Tetrahedron 68 (2012) 7997e8002
7999
Table 1
by a range of analytical experiments, this pronounced difference in
absolute value of the optical rotation observed for (5R)-7 can hardly
be explained otherwise than that the extractive sample of natural
vittarilide-A would contain several impurities.11
Observed chemical shifts (dH) and their deviations from the reported data
H9c
H15c
H11c
H12c
H8c
rmsb
Naturala
(5R)-7
DdH
(5S)-7
DdH
7.58
7.15
7.17
7.03
7.05
6.86
6.87
6.30
d
7.59
þ0.01
7.59
þ0.01
6.31
þ0.01
6.30
0
d
þ0.02
þ0.03
þ0.01
0.040
d
3. Conclusions
7.16
7.05
6.87
þ0.01
þ0.02
þ0.01
0.020
In conclusion, we have achieved the stereocontrolled synthesis
of vittarilide-A and its C5-epimer. The stereochemistry of this
natural product has been unequivocally established, with the
convincing spectroscopic evidence demonstrated by comparison
with the two possible synthetic candidates. To the best of our
knowledge, this report represents the first example of synthetic
elaboration of vittarilide-A, providing an indication of a need for
revision in the optical rotation value, as well as the initial disclosure
of the complete absolute stereochemistry of this natural product.
c
H4c
H3c
H6c
H60
H2c
4.33
4.38
H5c
rmsb
Naturala
(5R)-7
DdH
(5S)-7
DdH
4.63
4.49
4.46
4.34
4.35
4.30
d
4.64
þ0.01
4.62
ꢁ0.01
4.52
þ0.03
4.54
þ0.05
4.48
þ0.02
4.30
ꢁ0.16
4.31
þ0.01
4.41
þ0.11
d
þ0.01
þ0.05
0.064
d
4.22
4.65
ꢁ0.12
þ0.32
0.396
a
Spectral data for the natural vittarilide-A are reported in Ref. 2.
Root-mean-square of DdH values.
b
c
For the numbering scheme, see below.
4. Experimental section
4.1. General
Allsolventsand reagentswereofreagent gradequalityfrom Wako
Pure Chemicals and Tokyo Chemical Industry (TCI), and used without
further purification. The 1H and 13C nuclear magnetic resonance
(NMR) spectra operating at the frequencies of 300 and 75 MHz, re-
spectively, were recorded on a JEOL JNM-AL300 spectrometer in
chloroform-d (CDCl3) and acetone-d6 unless otherwise noted.
Chemical shifts are reported in parts per million (ppm) relative to
TMS and the solvent used as internal standards, and the coupling
constants are reported in hertz (Hz). Optical rotations were measured
in 1 dm path length cell of 2 mL capacity using a JASCO Model DIP-
1000 polarimeter at a wavelength of 589 nm. Reactions were moni-
tored by thin layer chromatography (TLC) using 0.25 mm Merck silica
gel 60-F254 precoatedsilicagelplates by irradiationwithUVlightand/
or by treatment with a solution of phosphomolybdic acid in ethanol
followed by heating. Column chromatography was performed on
Kanto Chemical silica gel 60N eluting with the indicated solvent
system. Fourier transform infrared (FTIR) spectra were recorded on
a JASCO FT/IR-550 spectrometer. Elemental analyses were performed
stereocenter in the naturally occurring vittarilide-A should have R-
configuration. Unexpectedly, we noted that (5R)-7 gave a much
greater optical rotation of [
a
]
þ49.8 (c 1.80, MeOH) than the
D
reported value of [
a]
D þ5.1 (c 1.075, MeOH),10 besides a comparable
optical rotation of [a]D þ45.3 (c 0.830, MeOH) was given for (5S)-7.
Considering the chemical integrity of the synthetic products ensured
by JSL Model JM 10 instruments. Samples of D-glucuronolactone de-
rivatives 1a and 1b were prepared by the procedures reported in the
literature.4 Their physical properties and spectroscopic data were in
full agreement with those reported earlier.
4.2. Preparation and characterization of new compounds
4.2.1. Synthesis and characterization of 2 and all the related com-
pounds. To a solution of 1b (3.43 g, 11.2 mmol) in anhydrous CH2Cl2
(37.3 mL) was added diisobutylaluminum hydride (DIBALeH,
Fig. 2. Comparison of 13C NMR spectra of (5R)- and (5S)-7 in acetone-d6.
Table 2
Observed chemical shifts (dC) and their deviations from the reported data
C1c
C7c
C13c
C12c
C9c
C10c
C15c
C14c
C8c
C11c
rmsb
Naturala
(5R)-7
DdC
(5S)-7
DdC
175.3
175.3
0
176.0
ꢁ0.7
167.5
167.4
0
167.6
þ0.1
148.7
148.8
þ0.1
146.4
146.3
ꢁ0.1
146.0
146.0
0
146.4
þ0.4
127.5
127.6
þ0.1
122.5
122.5
0
122.8
þ0.3
116.3
116.3
0
116.6
þ0.3
115.3
115.3
0
115.5
þ0.2
115.1
115.2
þ0.1
d
d
0.040
d
149.1
þ0.4
146.6
þ0.2
127.8
þ0.3
115.5
þ0.4
0.020
C4c
C2c
C3c
C5c
C6c
rmsb
Naturala
(5R)-7
DdC
(5S)-7
DdC
80.1
80.1
0
79.2
ꢁ0.9
74.5
74.5
0
75.4
þ0.9
74.5
74.4
ꢁ0.1
73.8
ꢁ0.7
69.0
68.9
ꢁ0.1
67.1
ꢁ1.9
66.4
66.3
ꢁ0.1
65.6
ꢁ0.8
0.173
2.52
a
Spectral data for the natural vittarilide-A are reported in Ref 2.
Root-mean-square of DdC values.
For the numbering scheme, see Table 1.
b
c

8000
M. Takahashi et al. / Tetrahedron 68 (2012) 7997e8002
21.5 mL, 22.4 mmol, 1.04 M n-hexane solution) at ꢁ78 ꢀC. The re-
action mixture was warmed to ꢁ40 ꢀC, stirred at this temperature
for additional 2 h, quenched by addition of saturated aqueous
Rochelle salt (potassium sodium tartarate, 30 mL), and warmed to
room temperature. After stirring for 17 h, the resulting mixture was
extracted with CH2Cl2 (70 mL), washed with brine (40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to provide crude
hemiacetal intermediate. To a solution of the hemiacetal (3.53 g) in
methanol (37.3 mL) was added sodium borohydride (NaBH4,
508 mg, 13.4 mmol) at room temperature. The reaction mixture
was stirred for 1.5 h, quenched by addition of water (15 mL),
extracted with AcOEt (70 mL), washed with brine (40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to provide a crude
diol intermediate. To a solution of the diol (3.58 g) in anhydrous
CH2Cl2 (11.2 mL) were added triethylamine (Et3N, 2.83 g,
28.0 mmol), N,N-dimethyl-4-aminopyridine (DMAP, 684 mg,
5.60 mmol), and tert-butyldimethylsilyl chloride (TBSCl, 3.38 g,
22.4 mmol) at room temperature. The reaction mixture was stirred
for 45 min, quenched by addition of water (20 mL) at room tem-
perature, extracted with CH2Cl2 (40 mL), washed with brine
(20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to
provide a crude residue. Purification of the residue by column
chromatography on silica gel (eluent: hexane/AcOEt, 9:1 to 4:1)
water (15 mL), extracted with AcOEt (50 mL), washed with brine
(20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to
provide a crude alcohol intermediate. To a solution of the alcohol
(1.56 g) in anhydrous THF (4.10 mL) were added in small portions
sodium hydride (NaH, 711 mg, ca. 16.3 mmol, 55e56% dispersion
in mineral oil), benzyl bromide (BnBr, 5.58 g, 32.6 mmol) at 0 ꢀC
over a period of 10 min. After warming to room temperature, the
reaction mixture was stirred for 17 h, quenched by addition of
saturated aqueous NH4Cl (20 mL), extracted with AcOEt (40 mL),
washed with brine (20 mL), dried over Na2SO4, filtered, and con-
centrated in vacuo to provide a crude residue. Purification of the
residue by column chromatography on silica gel (eluent: hexane/
acetone, 50:1 to 8:1) gave the benzyl ether (1.36 g, 3.06 mmol, 94%
for two steps) as colorless oil: Rf¼0.54 (silica gel, hexane/
22
AcOEt¼2:1); [
a
]
D
ꢁ9.08 (c 1.18, CHCl3); IR (NaCl): nmax 3018
(CeH), 2935 (CeH), 2896 (CeH), 2867 (CeH), 757 (C]C) cmꢁ1; 1H
NMR (300 MHz, CDCl3): 7.38e7.24 (m, 10H, ArH), 5.89 (d,
d
J¼3.6 Hz, 1H, CH), 4.86 (d, J¼11.4 Hz, 1H, CH2), 4.61 (d, J¼3.6 Hz,
1H, CH), 4.60 (s, 2H, CH2), 4.59 (s, 2H, CH2), 4.52 (d, J¼11.4 Hz, 1H,
CH2), 4.30 (dd, J¼3.0, 9.0 Hz, 1H, CH), 4.18 (d, J¼3.0 Hz, 1H, CH),
3.97 (ddd, J¼1.8, 5.7, 9.0 Hz, 1H, CH), 3.94 (dd, J¼1.8, 10.8 Hz, 1H,
CH2), 3.70 (dd, J¼5.7, 10.8 Hz, 1H, CH2), 3.34 (s, 3H, OCH3), 1.48 (s,
3H, CH3), 1.31 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 138.7 (C),
gave the TBS ether (4.33 g, 10.2 mmol, 91% for three steps) as col-
138.6 (C), 128.40 (CH), 128.39 (CH), 127.73 (CH), 127.66 (CH), 127.62
(CH), 127.5 (CH), 111.9 (C), 105.0 (CH), 97.2 (CH2), 83.2 (CH), 81.1
(CH), 78.7 (CH), 75.3 (CH), 73.4 (CH2), 72.1 (CH2), 70.9 (CH2), 55.9
(CH3), 26.7 (CH3), 26.3 (CH3). Anal. Calcd for C25H32O7: C, 67.55; H,
7.26. Found: C, 67.16; H, 7.11.
23
orless oil: Rf¼0.34 (silica gel, hexane/AcOEt¼3:1); [
a
]
ꢁ10.1 (c
D
1.31, CHCl3); IR (NaCl): nmax 3450 (OeH), 3018 (CeH), 2955 (CeH),
2930 (CeH), 2858 (CeH) cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
7.49e7.40 (m, 5H, ArH), 6.11 (d, J¼3.6 Hz, 1H, CH), 4.93 (d,
J¼11.7 Hz, 1H, CH2), 4.87 (d, J¼11.7 Hz, 1H, CH2), 4.63 (d, J¼3.6 Hz,
1H, CH), 4.45 (t, J¼2.7 Hz, 1H, CH), 4.37 (dd, J¼2.7, 5.1 Hz, 1H, CH),
4.17 (q, J¼5.1 Hz, 1H, CH), 4.05 (d, J¼2.7 Hz, 1H, OH), 3.99 (dd, J¼5.1,
10.5 Hz, 1H, CH2), 3.91 (dd, J¼5.1, 10.5 Hz, 1H, CH2), 1.61 (s, 3H, CH3),
1.45 (s, 3H, CH3),1.04 (s, 9H, CH3), 0.21 (s, 3H, CH3), 0.20 (s, 3H, CH3);
To a solution of the benzyl ether (1.16 g, 2.61 mmol) in methanol
(17.4 mL) was added concd HClaq (1.28 g, 13.1 mmol) at 0 ꢀC. After
warming to 50 ꢀC, the reaction mixture was stirred for 3 h, cooled to
0 ꢀC, quenched by addition of saturated aqueous NaHCO3 (25 mL),
extracted with AcOEt (20 mL), washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to provide a crude methyl glycoside (1.01 g) as
colorless oil. A solution of the crude methyl glycoside (1.01 g) in a 1:1
mixture of 3% w/w HClaq and 1,4-dioxane (12.3 mL) was heated at
90 ꢀC. This reaction mixture was stirred for 5 h, cooled to 0 ꢀC,
quenched by addition of saturated aqueous NaHCO3 (15 mL),
extracted with AcOEt (20 mL), washed with brine (20 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to provide a crude
residue. Purification of the residue by column chromatography on
silica gel (eluent: hexane/AcOEt, 1:1) gave the lactol (756 mg,
13C NMR (75 MHz, CDCl3):
d 138.0 (C), 128.7 (CH), 128.20 (CH),
128.19 (CH), 111.6 (C), 104.7 (CH), 85.4 (CH), 79.3 (CH), 78.7 (CH),
75.7 (CH), 74.0 (CH2), 63.3 (CH2), 26.8 (CH3), 26.2 (CH3), 25.9 (CH3),
18.2 (C), ꢁ5.46 (CH3), ꢁ5.53 (CH3). Anal. Calcd for C22H36O6Si: C,
62.23; H, 8.55. Found: C, 62.25; H, 8.20.
To a solution of the TBS ether (1.44 g, 3.39 mmol) in anhydrous
CH2Cl2 (2.30 mL) were added methoxymethyl chloride (MOMCl,
2.73 g, 33.9 mmol) and N,N-diisopropylethylamine (DIPEA, 4.38 g,
33.9 mmol) at 0 ꢀC. After warming to room temperature, the re-
action mixture was stirred for 23 h, quenched by addition of water
(20 mL), extracted with CH2Cl2 (40 mL), washed with brine (20 mL),
dried over Na2SO4, filtered, and concentrated in vacuo to provide an
orange oily residue. Purification of the residue by column chro-
matography on silica gel (eluent: hexane/AcOEt, 10:1) gave 2
(1.53 g, 3.26 mmol, 96%) as colorless oil: Rf¼0.43 (silica gel, hexane/
2.10 mmol, 80% for two steps) as colorless oil: Rf¼0.23 (silica gel,
17
hexane/AcOEt¼1:2); [
a]
ꢁ13.8 (c 0.490, CHCl3); IR (NaCl): nmax
D
3408 (OeH), 3019 (CeH), 2927 (CeH), 2870 (CeH), 758 (C]C)
cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
7.33e7.22 (m, 20H, ArH), 5.44
(m, 1H, CH), 5.12 (m, 1H, CH), 4.72e4.40 (m, 8H, CH2), 4.26e4.14 (m,
2H, CH), 4.04e3.94 (m, 4H, CH), 3.84e3.76 (m, 2H, CH), 3.72e3.57
AcOEt¼3:1); [
a
]
D
20 þ1.12 (c 1.37, CHCl3); IR (NaCl): nmax 3019 (CeH),
2954 (CeH), 2931 (CeH), 2894 (CeH) cmꢁ1
;
1H NMR (300 MHz,
(m, 4H, CH2); 13C NMR (75 MHz, CDCl3):
d 138.2 (C),138.0 (C),137.96
CDCl3):
d
7.45e7.35 (m, 5H, ArH), 6.00 (d, J¼3.6 Hz, 1H, CH), 5.02 (d,
(C),137.94 (C),128.7 (CH),128.6 (CH),128.19 (CH),128.18 (CH),128.15
(CH), 128.11 (CH), 128.0 (CH), 127.96 (CH), 127.93 (CH), 127.90 (CH),
103.2 (CH), 96.8 (CH), 81.2 (CH), 80.0 (CH), 78.0 (CH), 77.5 (CH), 77.43
(CH), 77.41 (CH), 77.37 (CH), 76.6 (CH), 76.2 (CH), 73.6 (CH2), 73.5
(CH2), 73.4 (CH2), 73.1 (CH2), 70.1 (CH2), 69.9 (CH2). Anal. Calcd for
C20H24O6: C, 66.65; H, 6.71. Found: C, 66.96; H, 7.01.
J¼11.4 Hz, 1H, CH2), 4.73 (d, J¼3.6 Hz, 1H, CH), 4.72 (s, 2H, CH2), 4.65
(d, J¼11.4 Hz, 1H, CH2), 4.35 (dd, J¼3.0, 8.4 Hz, 1H, CH), 4.28 (d,
J¼3.0 Hz, 1H, CH), 4.19 (m, 1H, CH), 3.98e3.90 (m, 2H, CH2), 3.45 (s,
3H, OCH3), 1.58 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.04 (s, 9H, CH3), 0.20
(s, 6H, CH3); 13C NMR (75 MHz, CDCl3):
d 139.1 (C), 128.5 (CH), 127.8
(CH), 127.7 (CH), 111.9 (C), 105.2 (CH), 97.4 (CH2), 83.3 (CH), 81.4
(CH), 78.6 (CH), 77.0 (CH), 72.5 (CH2), 64.1 (CH2), 56.0 (CH3), 26.8
(CH3), 26.4 (CH3), 26.0 (CH3), 18.3 (C), ꢁ5.36 (CH3), ꢁ5.42 (CH3).
Anal. Calcd for C24H40O7Si: C, 61.51; H, 8.60. Found: C, 61.14; H, 8.25.
To a solution of the lactol (25.3 mg, 0.0702 mmol) in toluene
(0.7 mL) were added silver carbonate (Ag2CO3, 38.6 mg,
0.140 mmol) and Celite (40 mg) at room temperature. After
warming to 80 ꢀC, the reaction mixture was stirred for 6 h, cooled
to room temperature, filtered through a pad of Celite followed by
successive washings with AcOEt (40 mL), and concentrated in
vacuo to provide a crude residue. Purification of the residue by
column chromatography on silica gel (eluent: hexane/AcOEt, 2:1)
4.2.2. Synthesis and characterization of 3 and all the related com-
pounds. To a solution of 2 (1.53 g, 3.26 mmol) in anhydrous THF
(11.0 mL) was added tetra(n-butyl)ammonium fluoride (TBAF, 1 M
THF solution, 8.20 mL, 8.20 mmol) at room temperature. The re-
action mixture was stirred for 4.5 h, quenched by addition of
gave 3 (21.0 mg, 0.0586 mmol, 83%) as colorless oil: Rf¼0.49 (silica
22
gel, hexane/AcOEt¼1:2); [
a
]
þ18.1 (c 0.790, CHCl3); IR (NaCl):
D

M. Takahashi et al. / Tetrahedron 68 (2012) 7997e8002
8001
nmax 3434 (OeH), 3019 (CeH), 2926 (CeH), 2871 (CeH), 1782 (C]
O), 758 (C]C) cmꢁ1 1H NMR (300 MHz, CDCl3):
7.36e7.23 (m,
(CH3), ꢁ4.00 (CH3). Anal. Calcd for C21H36O4Si2: C, 61.72; H, 8.88.
;
d
Found: C, 62.11; H, 9.05.
10H, ArH), 4.68 (d, J¼11.4 Hz, 1H, CH2), 4.62 (dd, J¼3.6, 6.0 Hz, 1H,
CH), 4.54 (d, J¼11.4 Hz, 1H, CH2), 4.51 (s, 2H, CH2), 4.44 (q, J¼6.0 Hz,
1H, CH), 4.44 (br s, 1H, OH), 4.11 (br s, 1H, OH), 4.04 (dd, J¼3.6,
5.1 Hz, 1H, CH), 3.89 (d, J¼6.0 Hz, 1H, CH), 3.75 (dd, J¼5.1, 10.5 Hz,
1H, CH2), 3.68 (dd, J¼5.1, 10.5 Hz, 1H, CH2); 13C NMR (75 MHz,
4.2.5. Synthesis and characterization of 6. To a solution containing 4
(355 mg, 0.873 mmol) and 5 (392 mg, 0.960 mmol) in anhydrous
CH2Cl2 (8.80 mL) were successively added 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 201 mg,
1.05 mmol) and N,N-dimethyl-4-aminopyridine (DMAP, 138 mg,
1.13 mmol) at 0 ꢀC. The reaction mixture was stirred for 4 h,
quenched by addition of water (15 mL), extracted with AcOEt
(40 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to provide a crude residue. Purification of the
residue by column chromatography on silica gel (eluent: hexane/
AcOEt, 20:1) gave 6 (391 mg, 0.490 mmol, 56%) as colorless oil:
CDCl3): d 175.5 (C]O), 137.6 (C), 137.4 (C), 128.83 (CH), 128.76 (CH),
128.42 (CH), 128.39 (CH), 128.2 (CH), 128.0 (CH), 79.4 (CH), 78.1
(CH), 74.7 (CH), 73.8 (CH), 73.7 (CH2), 73.6 (CH2), 69.0 (CH2). Anal.
Calcd for C20H22O6: C, 67.03; H, 6.19. Found: C, 67.11; H, 6.25.
4.2.3. Synthesis and characterization of 4. To a solution of
3
(406 mg, 1.13 mmol) in DMF (0.380 mL) were added tert-butyldi-
methylsilyl chloride (TBSCl, 1.70 g, 11.3 mmol) and imidazole
(846 mg, 12.4 mmol) at room temperature. The reaction mixture
was stirred for 17 h, quenched by addition of water (10 mL),
extracted with AcOEt (40 mL), washed with brine (40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to provide a crude
TBS ether. To a solution of the TBS ether (1.26 g) in ethanol
(2.30 mL) was added palladium hydroxide on carbon (Pd(OH)2/C,
94.5 mg), and the resulting mixture was hydrogenated at room
temperature. After 1 h, the reaction mixture was filtrated through
a pad of Celite followed by successive washings with AcOEt
(100 mL). The filtrate was concentrated in vacuo and the residue
was purified by column chromatography on silica gel (eluent:
hexane/AcOEt, 5:1) to give 4 (355 mg, 0.873 mmol, 77% for two
Rf¼0.51 (silica gel, hexane/AcOEt¼4:1); [
a
]
23 þ31.0 (c 0.875, CHCl3);
D
IR (NaCl): nmax 3465 (OeH), 3020 (CeH), 2956 (CeH), 2931 (CeH),
2897 (CeH), 2886 (CeH), 2859 (CeH), 1789 (C]O), 1705 (C]O)
cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.63 (d, J¼15.9 Hz, 1H, CH]CH),
7.03 (dd, J¼2.1, 8.7 Hz, 1H, ArH), 7.03 (d, J¼2.1 Hz, 1H, ArH), 6.83 (d,
J¼8.7 Hz, 1H, ArH), 6.29 (d, J¼15.9 Hz, 1H, CH]CH), 4.62 (dd, J¼2.4,
12.0 Hz, 1H, CH2), 4.54 (dd, J¼3.9, 8.4 Hz, 1H, CH), 4.37 (dd, J¼5.7,
12.0 Hz, 1H, CH2), 4.32 (dd, J¼2.4, 3.9 Hz, 1H, CH), 4.21 (dddd, J¼2.4,
5.1, 5.7, 8.4 Hz, 1H, CHOH), 4.10 (d, J¼2.4 Hz, 1H, CH), 2.97 (d,
J¼5.1 Hz,1H, OH),1.00 (s, 9H, CH3), 0.99 (s, 9H, CH3), 0.91 (s, 9H, CH3),
0.91 (s, 9H, CH3), 0.23 (s, 6H, CH3), 0.22 (s, 6H, CH3), 0.17 (s, 6H, CH3),
0.16 (s, 3H, CH3), 0.15 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 174.1
(C]O), 168.6 (C]O), 150.1 (C), 147.6 (C), 146.4 (C), 128.0 (CH), 122.8
(CH), 121.4 (CH), 120.8 (CH), 114.9 (CH), 80.5 (CH), 75.1 (CH), 74.9
(CH), 67.8 (CH), 66.6 (CH2), 26.02 (CH3), 25.99 (CH3), 25.77 (CH3),
25.72 (CH3), 18.61 (C), 18.56 (C), 18.21 (C), 18.09 (C), ꢁ3.97 (CH3),
ꢁ4.01 (CH3), ꢁ4.65 (CH3), ꢁ4.94 (CH3), ꢁ4.96 (CH3). Anal. Calcd for
C39H72O9Si4: C, 58.75; H, 9.10. Found: C, 58.48; H, 9.41.
steps) as a white solid: Rf¼0.17 (silica gel, hexane/AcOEt¼4:1); mp
20
71e72 ꢀC; [
a]
þ34.6 (c 1.31, CHCl3); IR (KBr): nmax 3494 (OeH),
D
3397 (OeH), 2953 (CeH), 2930 (CeH), 2887 (CeH), 2858 (CeH),
1786 (C]O) cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
4.52 (dd, J¼4.2,
8.4 Hz, 1H, CH), 4.31 (dd, J¼3.0, 4.2 Hz, 1H, CH), 4.10 (d, J¼3.0 Hz,
1H, CH), 4.01 (dddd, J¼3.6, 4.5, 5.4, 8.4 Hz, 1H, CHOH), 3.90 (dt,
J¼3.6, 11.1 Hz, 1H, CH2), 3.79 (dt, J¼4.5, 11.1 Hz, 1H, CH2), 2.78 (d,
J¼5.4 Hz, 1H, OH), 2.18 (dd, J¼3.6, 4.5 Hz, 1H, OH), 0.91 (s, 18H,
CH3), 0.17 (s, 6H, CH3), 0.16 (s, 3H, CH3), 0.15 (s, 3H, CH3); 13C NMR
4.2.6. Synthesis and characterization of (5R)-7. To a solution of 6
(383 mg, 0.480 mmol) in anhydrous CH3CN (2.40 mL) was added
boron trifluoride ethyl ether complex (BF3$OEt2, 300 mg,
2.11 mmol) at 0 ꢀC. After stirring for 20 min at this temperature, the
reaction mixture was quenched by addition of water (0.5 mL) and
powders of NaHCO3 (1 g), dried over Na2SO4, filtered through cot-
ton followed by successive washings with AcOEt (100 mL), and
concentrated in vacuo to provide a crude residue. Purification of the
residue by column chromatography on silica gel (eluent: hexane/
AcOEt, 1:3) gave (5R)-7 (81.0 mg, 0.238 mmol, 50%) as pale yellow
(75 MHz, CDCl3):
d 174.4 (C]O), 80.5 (CH), 75.0 (CH), 74.9 (CH),
68.6 (CH), 63.9 (CH2), 25.71 (CH3), 25.67 (CH3), 18.1 (C), 18.0 (C),
ꢁ4.69 (CH3), ꢁ4.71 (CH3), ꢁ5.0 (CH3). Anal. Calcd for C18H38O6Si2:
C, 53.16; H, 9.42. Found: C, 52.93; H, 9.29.
4.2.4. Synthesis and characterization of 5. To a solution of caffeic
acid (585 mg, 3.25 mmol) in DMF (1.10 mL) were added tert-
butyldimethylsilyl chloride (TBSCl, 1.62 g, 10.7 mmol) and imidaz-
ole (1.46 g, 21.5 mmol) at room temperature. The reaction mixture
was stirred for 6 h, quenched by addition of water (10 mL),
extracted with AcOEt (40 mL), washed with brine (40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to provide a crude
mixture. To a solution of this mixture in 50% v/v aqueous methanol
(11.0 mL) was added potassium carbonate (K2CO3, 449 mg,
3.25 mmol) at room temperature. The reaction mixture was stirred
for 1 h, quenched by addition of 3% w/w HClaq (35 mL), extracted
with AcOEt (40 mL), washed with brine (40 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to provide a crude residue.
Purification of the residue by column chromatography on silica gel
(eluent: hexane/AcOEt, 4:1) gave 5 (948 mg, 2.32 mmol, 71% for
two steps) as a white solid: Rf¼0.43 (silica gel, hexane/AcOEt¼2:1);
mp 158e159 ꢀC; IR (KBr): nmax 3422 (OeH), 2962 (CeH), 2930
(CeH), 2859 (CeH), 1685 (C]O), 1629 (C]C), 1508 (C]C) cmꢁ1; 1H
oil: Rf¼0.42 (silica gel, AcOEt); [
a
]
25 þ49.8 (c 1.80, MeOH); IR (KBr):
D
nmax 3359 (OeH), 2964 (CeH), 1698 (C]O), 1632 (C]C), 1601 (C]
C), 1523 (C]C) cmꢁ1 1H NMR (300 MHz, acetone-d6):
; d 7.59 (d,
J¼15.9 Hz, 1H, CH]CH), 7.17 (d, J¼2.1 Hz, 1H, ArH), 7.05 (dd, J¼2.1,
8.4 Hz, 1H, ArH), 6.87 (d, J¼8.4 Hz, 1H, ArH), 6.31 (d, J¼15.9 Hz, 1H,
CH]CH), 4.64 (dd, J¼5.4, 6.6 Hz, 1H, CH), 4.52 (dd, J¼4.5, 5.4 Hz,1H,
CH), 4.48 (dd, J¼2.7, 10.8 Hz, 1H, CH2), 4.38 (d, J¼4.5 Hz, 1H, CH),
4.35 (dd, J¼2.7,10.8 Hz,1H, CH2), 4.31 (dd, J¼2.7, 6.6 Hz,1H, CH); 13
C
NMR (75 MHz, acetone-d6):
d 175.3 (C]O), 167.4 (C]O), 148.8 (C),
146.3 (CH), 146.0 (CH), 127.6 (C), 122.5 (CH), 116.3 (C), 115.3 (CH),
115.2 (CH), 80.1 (CH), 74.5 (CH), 74.4 (CH), 68.9 (CH), 66.3 (CH2).
Anal. Calcd for C15H16O9: C, 52.94; H, 4.74. Found: C, 53.18; H, 5.07.
4.2.7. Synthesis and characterization of 1a0 and all the related
compounds. To a solution of 1a (1.77 g, 8.19 mmol) in anhydrous
CH2Cl2 (8.20 mL) were added pyridine (842 mg, 10.6 mmol) and
triflic anhydride (Tf2O, 2.77 g, 9.83 mmol) at 0 ꢀC. After stirring at
this temperature for 10 min, the reaction mixture was quenched by
addition of saturated aqueous NaHCO3 (10 mL), extracted with
CH2Cl2 (100 mL), washed with brine (40 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to provide a crude triflate
(7.46 g). To a solution of the crude triflate (7.46 g) in DMF (8.20 mL)
were added 18-crown-6 (216 mg, 0.819 mmol) and potassium
NMR (300 MHz, CDCl3):
d
7.67 (d, J¼15.9 Hz, 1H, CH]CH), 7.05 (dd,
J¼2.1, 8.4 Hz, 1H, ArH), 7.05 (d, J¼2.1 Hz, 1H, ArH), 6.84 (d, J¼8.4 Hz,
1H, ArH), 6.25 (d, J¼15.9 Hz, 1H, CH]CH), 1.00 (s, 9H, CH3), 0.99 (s,
9H, CH3), 0.23 (s, 3H, CH3), 0.23 (s, 3H, CH3), 0.22 (s, 3H, CH3), 0.22
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 172.2 (C]O), 150.3 (C),
147.6 (C), 147.3 (C), 128.0 (CH), 123.0 (CH), 121.5 (CH), 120.9 (CH),
114.9 (CH), 26.05 (CH3), 26.02 (CH3), 18.64 (C), 18.59 (C), ꢁ3.95

8002
M. Takahashi et al. / Tetrahedron 68 (2012) 7997e8002
acetate (AcOK, 965 mg, 9.83 mmol) at 0 ꢀC. After stirring at this
temperature for 1 h, the reaction mixture was quenched by addi-
tion of water (10 mL), extracted with AcOEt (100 mL), washed with
brine (40 mL), dried over Na2SO4, filtered, and concentrated in
vacuo to provide a crude residue. Purification of the residue by
column chromatography on silica gel (eluent: hexane/AcOEt, 6:1)
gave acetate (2.09 g, 8.09 mmol, 99% for two steps) as colorless oil:
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Supplementary data
Details of the transformation of 1a0 into (5S)-7, experimental
details and characterization data for all the new compounds related
to this transformation. Supplementary data associated with this
article can be found in the online version at http://dx.doi.org/
10.1016/j.tet.2012.06.105.
Rf¼0.57 (silica gel, hexane/AcOEt¼1:1); [
a
]
19 þ104 (c 1.17, CHCl3); IR
D
(NaCl): nmax 2992 (CeH), 2940 (CeH), 1800 (C]O), 1759 (C]O),
1376 (CeH) cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
5.98 (d, J¼3.6 Hz,
1H, CH), 5.09 (d, J¼3.6 Hz, 1H, CH), 4.95 (d, J¼0.3 Hz, 1H, CH), 4.86
(d, J¼3.6 Hz, 1H, CH), 4.82 (dd, J¼0.3, 3.6 Hz, 1H, CH), 2.16 (s, 3H,
CH3), 1.49 (s, 3H, CH3), 1.35 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
References and notes
d
170.9 (C]O), 169.6 (C]O), 113.0 (CH3), 106.1 (CH), 85.2 (CH), 82.0
1. Shieh, W. C.; Chiou, W. L.; Oevol, C. E. In Flora of Taiwan; Epoch: Taipei, 1994;
Vol. 1, p 259.
2. Wu, P. L.; Hsu, Y. L.; Zao, C. W.; Damu, A. G.; Wu, T. S. J. Nat. Prod. 2005, 68,
1180e1184.
(CH), 81.3 (CH), 72.5 (CH), 26.9 (CH3), 26.4 (CH3), 19.9 (C). Anal.
Calcd for C11H14O7: C, 51.16; H, 5.46. Found: 51.17; H, 5.75.
To a solution of the acetate (4.77 g, 18.5 mmol) in methanol
(37.0 mL) was added potassium carbonate (K2CO3, 256 mg,
1.85 mmol) at ꢁ10 ꢀC. After stirring at this temperature for 2 h, the
reaction mixture was quenched by addition of saturated aqueous
NH4Cl (5 mL), extracted with AcOEt (150 mL), washed with brine
(70 mL), dried over Na2SO4, filtered, and concentrated in vacuo to
provide a crude ester (4.49 g). To a solution of the ester (4.49 g) in
1,2-dichloroethane ((CH2Cl)2, 18.5 mL) was added pyridinium p-
toluenesulfonate (PPTS, 4.65 g, 18.5 mmol) at 80 ꢀC. After stirring at
this temperature for 6 h, the reaction mixture was cooled to room
temperature, quenched by addition of saturated aqueous NaHCO3
(10 mL), extracted with CH2Cl2 (150 mL), washed with brine
(70 mL), dried over Na2SO4, filtered, and concentrated in vacuo to
provide a crude residue (3.74 g). Purification of the residue by re-
crystallization from toluene gave 1a0 (2.81 g, 13.0 mmol, 71% for
3. (a) Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler, H. J. Am.
Chem. Soc. 1996, 118, 10156e10167; (b) Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett
2002, 1532e1534; (c) Yoda, H.; Nakaseko, Y.; Takabe, K. Tetrahedron Lett. 2004,
45, 4217e4220; (d) Matsuura, D.; Nojiri, T.; Suzuki, Y.; Takabe, K.; Yoda, H.
Synlett 2005, 287e288; (e) Matsuura, D.; Takabe, K.; Yoda, H. Tetrahedron Lett.
2006, 47, 1371e1374.
4. Matsuura, D.; Mitsui, T.; Sengoku, T.; Takahashi, M.; Yoda, H. Tetrahedron 2008,
64, 11686e11696.
5. (a) Fetizon, M.; Golfier, M.; Mourgues, P. Tetrahedron Lett. 1972, 13, 4445e4448;
(b) Mckillop, A.; Young, D. W. Synthesis 1979, 401e422.
6. Our initial attempts to deprotect the TBS groups using TBAF, methanolic PTSA
or HClaq failed to afford any desired product.
7. King, S. A.; Pipik, B.; Thompson, A. S.; DeCamp, A.; Verhoeven, T. R. Tetrahedron
Lett. 1995, 36, 4563e4566.
8. Characterization data for (5S)-7 (5-epi-vittarilide-A): Rf¼0.14 (silica gel,
20
AcOEt); [
a
]
þ45.3 (c 0.830, MeOH); IR (KBr): nmax 3393 (OeH), 2961(CeH),
D
1722 (C]O), 1602 (C]C) cmꢁ1 1H NMR (300 MHz, acetone-d6):
; d 7.59 (d,
J¼15.9 Hz, 1H, CH]CH), 7.16 (d, J¼2.1 Hz, 1H, ArH), 7.05 (dd, J¼2.1, 7.8 Hz, 1H,
ArH), 6.87 (d, J¼7.8 Hz, 1H, ArH), 6.30 (d, J¼15.9 Hz, 1H, CH]CH), 4.65 (d, J¼7.
5 Hz, 1H, CH), 4.62 (dd, J¼1.8, 7.5 Hz, 1H, CH), 4.54 (t, J¼7.5 Hz, 1H, CH), 4.41
(ddd, J¼1.8, 6.3, 6.9 Hz, 1H, CHOH), 4.30 (dd, J¼6.9, 10.5 Hz, 1H, CH2), 4.22 (dd,
two steps) as a white solid: Rf¼0.29 (silica gel, hexane/AcOEt¼2:1);
26
mp 134e135 ꢀC; [
a
]
D
þ109 (c 1.07, CHCl3); IR (KBr): nmax 3406
J¼6.3, 10.5 Hz, 1H, CH2); 13C NMR (75 MHz, acetone-d6):
d 176.0 (C]O), 167.6
(OeH), 2987 (CeH), 2944 (CeH), 2859 (CeH), 1767 (C]O) cmꢁ1; 1H
NMR (300 MHz, CDCl3):
(C]O), 149.1 (C), 146.6 (C), 146.4 (CH), 127.8 (C), 122.8 (CH), 116.6 (CH), 115.58
(CH), 115.54 (CH), 79.2 (CH), 75.4 (CH), 73.8 (CH), 67.1 (CH), 65.6 (CH2). Anal.
Calcd for C15H16O9: C, 52.94; H, 4.74. Found: C, 53.29; H, 5.12.
d
5.93 (d, J¼3.6 Hz, 1H, CH), 5.06 (d,
J¼3.0 Hz, 1H, CH), 4.84 (d, J¼3.6 Hz, 1H, CH), 4.80 (dd, J¼0.3, 3.0 Hz,
1H, CH), 4.33 (d, J¼0.3 Hz, 1H, CH), 1.52 (s, 3H, CH3), 1.35 (s, 3H,
9. High purities of the synthetic samples were secured on the basis of the in-
tegrities of the spectral shapes and well-resolved sets of 1H NMR signals, al-
lowing for complete understanding of all coupling interactions encountered
with the molecular systems as well as for precise analyses of the coupling
constants rather than those of the natural sample (see Ref. 2).
CH3); 13C NMR (75 MHz, CDCl3):
d 175.1 (C]O),113.5 (C),106.4 (CH),
85.3 (CH), 82.6 (CH), 82.2 (CH), 71.9 (CH), 27.1 (CH3), 26.9 (CH3).
10. In fact, we observed that the optical rotation value of (5R)-7 fell off seriously
Anal. Calcd for C9H12O6: C, 50.00; H, 5.59. Found: 49.62; H, 5.33.
after a period of an hour ([
a
]D þ33.6) probably due to occurrence of undesirable
ring-opening reaction with methanol yielding acyclic ester.
11. In our experiments, we found that (5R)- and (5S)-7 were unstable and degraded
upon long-term exposure to air at ambient temperature, making them very
difficult to isolate. Considering this, it cannot be excluded that the optical ro-
tation value reported for the natural sample would be much lower than that of
the intrinsic property due to unexpected decomposition of the extract during
experimental treatment.
Acknowledgements
We thank Mr. Shuhei Nishio for partial support of this research.
This research was supported by a Grant-in-Aid for Scientific