Total synthesis of xanthanolides

Article abstract of DOI:10.1016/j.tet.2010.08.061

The total synthesis and determination of the absolute configuration of (+)- and (-)-sundiversifolide have been achieved via intramolecular acylation and Wittig-lactonization as the key steps. The xanthanolide sesquiterpene lactones, 8-epi-xanthatin (1), d

Full text of DOI:10.1016/j.tet.2010.08.061

Tetrahedron 66 (2010) 8407e8419
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of xanthanolides
Kazumasa Matsuo a, Keiko Ohtsuki a, Takashi Yoshikawa a, Kozo Shishido b, Kaori Yokotani-Tomita c,
,
Mitsuru Shindo d
*
a Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga 816-8580, Japan
b Graduate School of Pharmaceutical Sciences, The University of Tokushima, Shomachi, Tokushima 770-8505, Japan
c Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
d Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2010
Received in revised form 26 August 2010
Accepted 26 August 2010
Available online 18 September 2010
The total synthesis and determination of the absolute configuration of (þ)- and (ꢀ)-sundiversifolide have
been achieved via intramolecular acylation and Wittig-lactonization as the key steps. The xanthanolide
sesquiterpene lactones, 8-epi-xanthatin (1), dihydroxanthatin (2), and xanthatin (3) were also prepared,
starting from a common intermediate derived from the synthesis of sundiversifolide.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Xanthanolides
Natural products
Sesquiterpene lactones
Total synthesis
1. Introduction
carbocycle by an intramolecular acylation and a one-pot Wittig-
lactonization as the key steps. This synthesis afforded useful in-
The xanthanolide sesquiterpene lactones are a class of natural
products isolated from the plants of the genus Xanthium (family
Composite). They have a bicyclic 5,7-fused ring system, and are
known to exhibit allelopathic,1 antitumor,2 antimalarial,3 and an-
timicrobial activity.4 Accordingly, their intriguing biological profile
has attracted the interest of medicinal chemists and biochemists as
well as organic chemists. An efficient synthesis of these sesquiter-
penes therefore would be extremely useful in order to identify bi-
ological targets and develop related drugs. Xanthatin (3), isolated
from Xanthium strumarium5 and other Xanthium families, has
shown potent antibacterial activity against methicillin-sensitive
and methicillin-resistant Staphylococcus aureus.6 8-epi-Xanthatin
(1), which is found in the extracts of the aerial parts of various
species in the genus Xanthium,7 has also been reported to exhibit
antitumor activity2a and in vitro inhibitory activity on farnesyl-
transferase,2d insect development,7b and auxin-induced growth of
sunflower hypocotyls.1b,c In spite of these attractive bioactivities,
only a few synthetic studies of the xanthanolides and their related
natural products have been reported (Fig. 1).8,9 Recently, we have
achieved an efficient total synthesis of a dinorxanthanolide,
(þ)-sundiversifolide (4),9b which was isolated from the exudate of
germinating sunflowers (Helianthus annuus L.) as an allelopathic
compound,1a via a novel construction of the seven-membered
termediates having a bicyclic 5,7-fused ring system for the syn-
thesis of the xanthanolides. Herein, we report the total synthesis of
(þ)-8-epi-xanthatin (1), (ꢀ)-dihydroxanthatin (2), and (ꢀ)-xan-
thatin (3) starting from the common key intermediate 5 as well as
full details of the total synthesis of (þ)-sundiversifolide.
* Corresponding author. Fax: þ81 92 583 7875; e-mail address: shindo@
cm.kyushu-u.ac.jp (M. Shindo).
Fig. 1. Xanthanolide natural products.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.061

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K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
2. Results and discussion
protonation, and mesylationeiodination. The diastereoselective al-
kylation of Evans’ oxazolidinone 11 with 12 provided 13 in good yield
2.1. Synthesis of sundiversifolide and the key intermediate
for the xanthanolides
with excellent stereoselectivity.11 The stereocontrolled dihydroxylation
of 13 with AD-mix-b
Ò12 was accompanied by spontaneous lactoniza-
tion of the intermediate diol to afford the lactone 14 as a single isomer.
Protection of the secondary alcohol with MOMCl and deprotection of
the TBDPS ether with TBAF in THF,13 followed by mesylationeiodina-
tion, furnished the iodolactone 17 in good yield (Scheme 2).
Our synthetic strategy for the key intermediate 5 is illustrated
in Scheme 1. The
g-lactone moiety would be formed by acyla-
tioneolefination of the hydroxyketone 6, followed by hydroge-
nation. The vinyl side chain on C-1 would then be introduced by
alkylation of the ketone 7. The seven-membered ring construc-
tion is much more challenging than the six-membered ring, due
to the entropically unfavorable ring size and/or non-bonded in-
teractions in the transition state. To overcome these issues, we
envisioned an intramolecular acylation of a carbanion on the
g-
lactone 9 leading to the 8-oxabicyclo[3.2.1]octane skeleton 8 via
a six-membered ring formation. Since the fused oxabicycle 8 is
a hemiacetal, the hydroxycycloheptanone 7 would be easily
provided. The relevant strategy has been reported by Molander
and co-workers utilizing SmI2.10 The asymmetric centers on 9
would be obtained by a diastereoselective alkylation using the
chiral oxazolidinone 11, followed by stereocontrolled dihydrox-
ylation of the resulting 10.
Scheme 2. Asymmetric synthesis of the g-lactone 17.
The pivotal intramolecular acylation forming the seven-mem-
bered ring was first attempted with SmI2 under various conditions
and resulted in no reaction. Instead, lithiation of the iodide 17 using
t-BuLi successfully provided the seven-membered ring in excellent
yield.13 The NMR spectra showed that the product is in equilibrium
between the hemiacetal 18 and the cycloheptanone 19 in CDCl3.
Treatment of the product with TBDPSCl and imidazole gave the
trisubstituted cycloheptanone 20 in good yield (Scheme 3).
With the seven-membered skeleton in hand, we next attempted
the introduction of the vinyl unit along with the formation of the
C1eC5 endocyclic-olefin (Scheme 4). The vinyl Grignard reagent
Scheme 1. Retro synthesis of the key intermediate for the xanthanolides.
The alkylating reagent 12 was prepared from 3-butyn-1-ol in
five steps via protection, hydroxymethylation, hydroaluminatione
Scheme 3. Intramolecular acylation of the alkyllithium to give the cycloheptanone.
Scheme 4.

K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
8409
added stereoselectively to the ketone to give 21 in good yield as
a single isomer. According to the conformational analysis of 20,14
using various kinds of acid, but resulted in low yield, and the
oxabicyclic compound 30 was again obtained. The tertiary carbo-
cation at C-1 would be easily generated to form this product.
In place of the MOM ether, a TBS ether was selected as the
protecting group of the hydroxyl group at C-7. Treatment of 14 with
TBSCl gave 31, the primary TBDPS ether of which should be selec-
tively deprotected. Although the usual protocol (TBAF, AcOH in
THF)15 gave mainly the diol 37, in the presence of CH2Cl2 as a co-
solvent,16 the desired partially deprotected alcohol 32 was obtained
in good yield. However, on a scale larger than 10 g of substrate, the
yield of 32 decreased to 60% and more of the diol 37 was generated.
The alcohol 32 was converted into the iodide 33 quantitatively. The
diol 37 also can be transformed into the iodide 33 via selective
iodination followed by protection of the secondary alcohol with
TBSOTf. The iodide 33 was treated with t-BuLi to afford the hemi-
acetal 34 and the cycloheptanone 35 in excellent yield. Although
MOMCl reacted with the hydroxyl groups on both 34 and 35,
TBDPSCl protected only the secondary alcohol of 35 to afford 36 in
good yield (Scheme 6).
the nucleophile would attack the
a-face as an equatorial attack
(Fig. 2). Attempts to dehydrate with thionyl chloride gave the
chlorinated compound 22 via an SN20 reaction, and the Burgess
reagent resulted in formation of the oxabicyclic compound 23.
The Shapiro reaction was carried out on the corresponding
hydrazone 37 to give the doubly iodinated compound 38 in low
yield after treatment with iodine (Scheme 7).
Hence, we then attempted the nucleophilic vinylation of 36 with
a Grignard reagent as in the previous case.17 Vinylmagnesium
bromide added to the ketone to afford the adduct 39 in excellent
yield as a single isomer. Since dehydration of the tertiary alcohol of
39 to afford the endocyclic-olefin was unsuccessful at this stage as
shown in Scheme 8, we decided to assemble the lactone first. Se-
lective deprotection of the TBS group of 39, TPAP oxidation of 40,
and removal of the TBDPS group of 41 provided the hydroxy
hemiacetal 42 in nearly quantitative yield. We next tried to con-
struct the lactone moiety from 42, which is equivalent to an
Fig. 2. Calculated conformation of 20 (TBDPS group was replacedby TMSfor simplification).
We then tried the enol triflation of the ketone 20, which gave
only recovered starting material, but the Shapiro reaction of the
corresponding p-toluenesulfonyl hydrazone 24 afforded the alkenyl
iodide 25 in 77% yield after trapping of the alkenyllithium with
iodine (Scheme 5). Stille coupling with 25 and tributylvinyltin
provided the vinylcycloheptene 26. Since we first intended to
achieve the synthesis of sundiversifolide, the vinyl compound 26
was subjected to hydroboration with thexylborane to provide pri-
mary alcohol 27 after oxidative treatment. After protection of the
hydroxyl group, deprotection of the MOM ether was attempted by
a-hydroxyketone. In order to carry out the intramolecular Hor-
nereEmmons reaction, condensation with the carboxylic acid of
the phosphonate ((EtO)2P(O)CH(CH3)CO2H) and 42 gave a 1:1
mixture of 43 and 44. On the contrary, reaction of 42 with the
Scheme 5.

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K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
Scheme 6.
Wittig reagent (Ph3P]C(CH3)CO2C2H5) under reflux in xylene for
9 h directly provided the butenolide 46 in 91% yield, the structure of
which was unambiguously assigned by X-ray diffraction study. In
contrast to Garner’s report on the Wittig reaction of
a-hydroxy
ketones giving E-olefins,18 this reaction was exclusively Z-selective.
The mechanism of this direct lactonization could be postulated as
transesterification giving the intermediate 45, followed by intra-
molecular olefination, because the ketone in 42 was masked by
hemiacetalization. The reaction using the Wittig reagents with the
trifluoroethyl ester (R¼CH2CF3) and the phenyl ester (R¼Ph), which
Scheme 7.
Scheme 8.

K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
8411
have better leaving groups, was completed in only 4 h (92% yield)
and 2.5 h (74% yield), also suggesting that the intramolecular ole-
fination had occurred (Scheme 8).
oxazolidinone derived from
L
-Phe in the asymmetric alkylation and
AD-mix-aÒ in the asymmetric dihydroxylation, which also gave
a single isomer. HPLC analysis using chiral column (Daicel Chiralpak
IA, detector: UV 207 nm, hexane/isopropanol 93:7, flow¼1.0 mL/min;
(ꢀ)-sundiversifolide tr¼31 min; (þ)-sundiversifolide tr¼38 min,
30 ꢁC) indicated that the natural 4 is identical with the synthetic
(þ)-4 (Fig. 3). This study therefore determined that the absolute
configuration of the naturally occurring sundiversifolide isolated
from the sunflower is that shown in 1.
With the carbon skeleton in hand, we then investigated the less
substituted endocyclic alkene formation. Dehydration using MsCl/
Et3N gave the SN20 products 47 and not the desired compound.
Since the double bond on the allylic alcohol had to be protected
prior to dehydration, 46 was treated with m-CPBA to give the ep-
oxide 48, which was subjected to hydrogenation with the nickel
boride reagent derived from NiCl2 and NaBH419 to afford a separa-
ble mixture of 49 (81%) and its C11-epimer (14%). After numerous
attempts, the best results for a kinetically controlled dehydration of
49 were obtained using a protocol involving slow addition of a so-
lution of freshly distilled SOCl2 (2 equiv) and pyridine (4 equiv) in
CH2Cl2 at ꢀ20 ꢁC. Under these conditions, the desired endocyclic
alkene 50 was successfully obtained in yields ranging of 68e87%.
Finally, the epoxide in 50 was regioselectively reduced with
NaBH3CN in the presence of ZnI220 to provide sundiversifolide (4) in
2.2. Synthesis of (D)-8-epi-xanthatin (1)
The key intermediate 5 for construction of xanthanolide has
a cis-fused cycloheptene-g-butyrolactone skeleton bearing a vinyl
substituent, which has been converted into the butenone moiety
via cross metathesis.8 Attempts to reduce the epoxide in 50 to an
21
22
alkene using SmI2 or P2I4 resulted in a complex mixture, but
KSeCN successfully reduced the epoxide to give 5 in good yield
(Scheme 10).23 With the key intermediate in hand, we tried to
convert 5 to xanthanolides. In order to prepare 8-epi-xanthatin (1)
85% yield. The synthetic 4 {[
a
]
22 þ33.0 (c 0.44, CHCl3)} was found to
D
be identical to the natural 4 according to spectroscopic properties
(1H and 13C NMR, IR, and MS) (Scheme 9). Since the optical rotation
data of the natural product has not been reported due to a limited
amount of the natural product, the enantiomer ent-1 {[
0.46, CHCl3)} was synthesized in a similar manner, using the chiral
from 5, conversion of the a-methyl group on the g-butyrolactone
into an exo-methylene was examined. According to Ando’s pro-
tocol,24 bromination at C-11 was employed with LDA/CBr4 to give
a 1:1.4 diastereomeric mixture of 51 and 52, the stereochemistry of
which was determined by NOE experiments as shown in Scheme
10. After separation of these diastereomers, each isomer was sub-
a
]
22 ꢀ33.7 (c
D
jected to dehydrobromination with base. The
was easily converted into the desired exo-olefin 53 by using TBAF in
THF. The -bromo isomer 52, on the other hand, after being treated
a-bromo isomer 51
b
with various bases (TBAF, KHMDS, DBU, or Triton B) only gave the
conjugated endo-olefin 55, probably due to the anti-periplanar re-
lationship between the bromide and the b-proton on C-11. Thus, for
isomerization of 52 to 51, formation of the enolate of 52 via lith-
iumehalogen exchange, followed by bromination, was attempted
using n-, sec- or tert-butyllithium, but the desired bromo lactone 51
was not obtained. Unexpectedly, LDA worked well to generate the
enolate 56 via lithiumehalogen exchange, affording a 1:1.4e1:2.5
mixture of 51 and 52 after bromination by CBr4. Finally, 53 was
subjected to cross metathesis8 using the second generation Hov-
eydaeGrubbs catalyst (54)25 to give 8-epi-xanthatin (1) in good
yield. The spectra of the synthetic 1 were identical with those of the
natural compound.8a
Scheme 9. Synthesis of sundiversifolide (4).
2.3. Synthesis of (L)-dihydroxanthatin (2)
In order to synthesize dihydroxanthatin (2) from the intermediate
5, a stereochemical inversion at C-8 was necessary. As we reported in
the synthesis of diversifolide,9d the lactone moiety was opened by
diethylamine and aluminum trichloride to give the hydroxy amide 57
quantitatively. Since the inversion at C-8 by the Mitsunobu reaction
was unsuccessful, probably due to steric reasons,26 the oxida-
tionereduction protocol was examined. TPAP oxidation of the sec-
ondary alcohol at C-8, followed by thermodynamically controlled
reduction with SmI2,27 provided a 4:1 mixture of the desired trans-
isomer 59 and the cis-isomer 57, quantitatively. After separation of
these isomers, the trans-isomer 59 was cyclized by acid to furnish the
trans-fused lactone 60, which was subjected to cross metathesis with
methyl vinyl ketone as described previously to yield (ꢀ)-dihydrox-
anthatin (2). All the spectra were identical with those of the reported
compound8c (Scheme 11).
2.4. Synthesis of (L)-xanthatin (3)
Xanthatin (3) could be synthesized by ‘dehydrogenation’ of the
methyl moiety on dihydroxanthatin (2). According to the pro-
cedure described above, the precursor 60 was deprotonated by
Fig. 3. HPLC analysis of natural and unnatural sundiversifolide using a chiral column
(Daicel Chiralpak IA, detector: UV 207 nm, hexane/isopropanol 93:7, flow¼1.0 mL/min;
(ꢀ)-sundiversifolide tr¼31 min; (þ)-sundiversifolide tr¼38 min, 30 ꢁC).

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K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
Scheme 10. Synthesis of (þ)-8-epi-xanthatin (1).
LDA induced lithiation to give the lithium enolate. Since the trans-
fused lactone would have a planar structure, bromination would
occur from the -face of the enolate rather than the -face to
b
a
avoid steric hindrance with H-7. We then decided to carry out the
stereochemical inversion of C-8 in 53, since it already had the exo-
methylene on the lactone. According to the stereochemical in-
version procedure described above, the lactone was opened to
give the hydroxy amide 63, which was oxidized by TPAP to afford
the ketone 64. This compound was treated with SmI2 in the same
way, but gave 66, resulting from reduction of the enoate as well as
the ketone. After screening several reducing reagents, we found
that DIBAL reduced only the ketone to give a 1:1.2 ratio of the
epimers (65:63). After lactonization with acid, cross metathesis
was employed to provide (ꢀ)-xanthatin (3) (Scheme 12). The
spectra of the synthetic 3 were identical with those of the
reports.29
2.5. Conclusion
We have achieved the total synthesis of 8-epi-xanthatin (1),
dihydroxanthatin (2), and xanthatin (3) starting from a common
intermediate, prepared according to our original method, in-
cluding an intramolecular acylation and a one-pot Wittig-lacto-
nization, used in the synthesis of sundiversifolide. Since these
xanthanolides have shown promising bioactivity, this work would
be useful for the preparation of these compounds and the de-
velopment of novel bioactive compounds derived from the natural
products.
Scheme 11. Synthesis of (ꢀ)-dihydroxanthatin (2).
LDA, followed by bromination with CBr4, to give selectively the
brominated compound 61 with the undesired stereochemistry.28
The elimination reaction with base (TBAF, KHMDS) resulted in the
formation of the endo-olefin 62, as was seen with 52 (Scheme 10).

K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
8413
nitrogen atmosphere unless otherwise noted, and dichloromethane
(CH2Cl2), diethyl ether (Et2O), and tetrahydrofuran (THF) were
purchased from Kanto Chemical Co., Inc., and the other solvents
were distilled. Unless otherwise noted, reagents were obtained from
chemical sources and used without further purification.
3.2. Synthesis of sundiversifolide (4)
3.2.1. (E)-5-(tert-Butyldiphenylsiloxy)-1-iodo-2-pentene 12. To a so-
lution of 5-(tert-butyldiphenylsiloxy)pent-2-en-1-ol (5.00 g,
14.7 mmol)30 in CH2Cl2 (150 mL) at 0 ꢁC were added Et3N (5.1 mL,
36.7 mmol) and MsCl (2.3 mL, 29.4 mmol). The mixture was stirred
for 0.5 h at room temperature, and then cooled to 0 ꢁC. After ad-
dition of H2O, the resulting mixture was extracted with CH2Cl2,
washed with 5% HCl, saturated aqueous NaHCO3, and brine, and
dried over MgSO4. The crude product was dissolved in acetone
(150 mL) and NaI (6.60 g, 44.0 mmol) was added. The resulting
suspension was stirred for 0.5 h at room temperature, and the
solvent was removed in vacuo. After addition of H2O, the mixture
was extracted with CH2Cl2, washed with saturated aqueous
Na2S2O4 and brine, and dried over Na2SO4. After the mixture was
evaporated, the residue was purified by silica gel column chroma-
tography (10% EtOAc/hexane) to give 12 as a yellow oil (6.53 g, 99%).
1H NMR (400 MHz, CDCl3)
d
: 1.06 (s, 9H), 2.28 (dt, J¼6.6, 6.6 Hz, 2H),
3.70 (t, J¼6.6 Hz, 2H), 3.86 (d, J¼7.4 Hz, 2H), 5.72 (dt, J¼6.6, 15.2 Hz,
1H), 5.78 (dt, J¼7.4, 15.2 Hz,1H), 7.47 (m, 6H), 7.70 (m, 4H); 13C NMR
(100 MHz, CDCl3) d: 6.4 (t), 19.3 (s), 26.9 (q), 35.4 (t), 63.1 (t), 127.5
(d), 129.5 (d), 129.7 (d), 131.5 (d), 133.7 (s), 135.5 (d). IR (KBr, neat):
3070, 3048, 2955, 2930, 2857, 1471, 1427 cmꢀ1; MS (FAB) m/z: 473
(MþþNa), 135 (100%); HRMS (FAB) calcd for C21H27IOSiNa (MþþNa)
473.0774, found: 473.0784.
3.2.2. (4R,20S)-4-Benzyl-3-[70-(tert-butyldiphenylsiloxy)-20-methyl-
hept-40-enoyl]oxazolidin-2-one 13. To a solution of diisopropyl-
amine (1.08 mL, 7.73 mmol) inTHF (21 mL) at ꢀ78 ꢁC was added BuLi
in pentane (1.55 M, 4.9 mL, 7.73 mmol). The mixture was stirred for
20 min at ꢀ78 ꢁC, and a solution of 11 (1.50 g, 6.44 mmol) in THF
(10 mL) was added. After the reaction stirred for 1 h at ꢀ78 ꢁC,
a solution of 6 (4.35 g, 9.66 mmol) in THF (10 mL) was added to the
mixture, which was stirred for 6 h at ꢀ40 ꢁC. After addition of sat-
urated aqueous NH4Cl (3 mL), the resulting mixture was extracted
with EtOAc. The combined organic layers were washed with brine
(10 mL), and dried over MgSO4. After the mixture was evaporated,
the residue was purified by silica gel column chromatography (30%
EtOAc/hexane) to give 13 as a colorless oil (3.29 g, 92%, >99%de).
Scheme 12. Synthesis of (ꢀ)-xanthatin (3).
3. Experimental
3.1. General procedures
1H NMR and 13C NMR spectra were measured in a CDCl3 solution
using JEOL JNM AL-400 (1H NMR at 400 MHz, 13C NMR at 100 MHz),
and a JNM ECA-600 spectrometer (1H NMR at 600 MHz, 13C NMR at
[
a
]
26.4 ꢀ20.1 (c 1.07, CHCl3), enantiomer; [
a
]
20 þ20.37 (c 1.08, CHCl3);
D
D
1H NMR (400 MHz, CDCl3)
d
: 1.05 (s, 9H), 1.17 (d, J¼6.8 Hz, 3H), 2.18
150 MHz) as the reference standards (1H NMR at 0.00 ppm (TMS),13
C
(ddd, J¼7.2, 7.2, 12.8 Hz, 1H), 2.28 (dt, J¼6.4, 6.4 Hz, 2H), 2.48 (ddd,
J¼6.4, 6.4,12.8 Hz,1H), 2.65 (dd, J¼10.4,12.8 Hz,1H), 3.26 (dd, J¼2.8,
12.8 Hz, 1H), 3.69 (t, J¼7.2 Hz, 2H), 3.81 (tq, J¼6.8, 6.8 Hz, 1H), 4.13
(dd, J¼3.2, 7.6, 10.4 Hz, 1H), 5.47 (dt, J¼6.4, 14.8 Hz, 1H), 5.54 (ddd,
J¼7.2, 6.4, 14.8 Hz, 1H), 7.20e7.40 (m, 11H), 7.64e7.70 (m, 4H); 13C
NMR at 77.0 ppm (CDCl3)) unless otherwise noted. Chemical shifts
are reported in parts per million. Peak multiplicities used the fol-
lowing abbreviation: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. IR spectra were recorded on JASCO FT/IR-410
and Shimazu FT/IR-8300 spectrometers. Mass spectra and high
resolution mass spectra were obtained on JMS-K9, JMS-AMSUN200/
300, JMS-SX102A, JMS-DX303, and Waters LCT Premier mass spec-
trometers. Elemental analyses were performed with a Yanaco MT-3,
MT-5, MT-6 CHN-Corde. Melting points were measured with
a Yanaco MP-500D apparatus and a Seki Technotron Corp. Opti Melt
MPA 100 apparatus and are uncorrected. Optical rotations were
recordedonJASCOP-1010 andHORIBASEPA-200. AnalyticalTLC was
performed on precoated plates (0.25 mm, silica gel Merck 60 F254).
Column chromatography was performed on silica gel (Kanto
Chemical Co., Inc.). Preparative HPLC was performed on Kanto
Mightysil Si60 and Merck LiChrosorb Si60, and performed with
a gradient solvent system of hexane and ethyl acetate and a UV
detector at 254 nm. All reactions were performed under argon or
NMR (100 MHz, CDCl3) d: 16.4 (q), 19.2 (s), 26.9 (q), 36.6 (t), 36.9 (t),
37.6 (d), 38.1 (t), 55.3 (d), 63.8 (t), 66.0 (t), 127.2 (d), 127.5 (d), 127.6
(d), 128.8 (d), 129.3 (d), 129.4 (d), 133.9 (s), 135.4 (s), 135.5 (d), 152.9
(s), 176.5 (s). IR (KBr, neat): 2931, 2858, 1781, 1698 cmꢀ1; MS (FAB)
m/z: 578 (MþþNa),135 (100%); HRMS (FAB) calcd for C13H43NO4SiNa
(MþþNa) 556.2883, found: 556.2888.
3.2.3. (3S,5R,10R)-5-[30(tert-Butyldiphenylsiloxy)-10-hydroxypropyl-
3-methyldihydrofuran-2-one 14. To a solution of AD-mix b
Ò (16.33 g)
in 50% t-BuOH/H2O (30 mL) was added MeSO2NH2 (1.00 g,
10.4 mmol), and the mixture was stirred for 0.5 h at room temper-
ature. The resulting mixture was cooled to 0 ꢁC, and a solution of 13
(2.33 g, 4.17 mmol) in 50% t-BuOH/H2O (30 mL) was added. The
mixture was stirred for 10 h at 0 ꢁC, and Na2SO3 (3.15 g, 25.06 mmol)

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K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
was added. The resulting mixture was stirred for 0.5 h at room
temperature, extracted with CHCl3 (100 mL), and the combined or-
ganic layer was washed with satd NaHCO3 aq (50 mL), brine (50 mL),
and driedover MgSO4. Afterthe mixturewas evaporated, the residue
was purified by silica gel column chromatography (30% EtOAc/
hexane) to give 14 (1.67 g, 97%): colorless needles(benzene/hexane):
aqueous NaHCO3, and was dried over MgSO4. The solvent was re-
moved in vacuo and the residue was dissolved in acetone (128 mL).
NaI (11.5 g, 76.8 mmol) was added to the resulting mixture, which
was stirred for 0.5 h at room temperature. The solvent was removed
and water was added. The resulting mixture was extracted with
CH2Cl2, and the combined organic layers were washed with satu-
rated aqueous Na2S2O4 and brine, then dried over MgSO4. After
removal of the solvent in vacuo, the residue was purified by column
chromatography (10% EtOAc/hexane) to give a colorless oil 33
mp 93 ꢁC. [
a
]
26 ꢀ33.19 (c 0.97, CHCl3); 1H NMR (400 MHz, CDCl3)
d:
D
1.05 (s, 9H), 1.27 (d, J¼7.2 Hz, 3H), 1.68 (ddt, J¼3.2, 3.2, 14.8 Hz, 1H),
1.94 (m,1H),1.96 (m,1H), 2.44 (ddd, J¼3.6, 9.6,12.4 Hz,1H), 2.89 (td,
J¼7.2,12.4 Hz,1H), 3.94 (m,1H), 4.39 (dt, J¼3.6, 8.4 Hz,1H), 7.26e7.47
26
20
(5.10 mg, quant.). [
a
]
ꢀ18.1 (c 1.06, CHCl3), enantiomer; [
a]
D
D
(m, 6H), 7.66e7.68 (m, 4H); 13C NMR (100 MHz, CDCl3)
d: 16.3 (q),
þ18.62 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 0.13 (s, 6H),
19.1 (s), 26.8 (q), 32.5 (t), 34.1 (t), 62.5 (t), 73.1 (d), 80.2 (d),127.2 (d),
127.7 (d),129.7 (d),132.6 (s),132.9 (s),135.4 (d),180.4 (s). IR (CHCl3):
3459, 1769 cmꢀ1; MS (FAB) m/z: 435 (MþþNa, 100%). Anal. Calcd for
C24H32O4Si: C, 69.86; H, 7.82. Found: C, 69.72; H, 7.85.
0.89 (s, 9H), 1.28 (d, J¼7.6 Hz, 3H), 1.90e2.01 (m, 2H), 2.08e2.16 (m,
1H), 2.30 (ddd, J¼4.4, 9.6, 12.8 Hz, 1H), 2.68e2.78 (m, 1H),
3.19e3.28 (m, 2H), 3.85 (dt, J¼4.4, 6.8 Hz,1H), 4.47 (dt, J¼4.0, 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d: ꢀ4.4 (q), ꢀ4.3 (q), 1.7 (t), 16.5 (q),
18.0 (s), 25.8 (q), 31.8 (t), 34.1 (d), 36.4 (t), 74.0 (d), 78.3 (d),179.6 (s).
IR (KBr, neat): 1774 cmꢀ1. MS (EI) m/z: 398 (Mþ), 283 (100%); HRMS
(EI) calcd for C14H27O3SiI (Mþ) 398.0774, found: 398.0780.
3.2.4. (3S,5R,10R)-5-[1-(tert-Butyldimethylsiloxy)-3-(tert-butyldiphe-
nylsiloxy)propyl]-3-methyldihydrofuran-2-one 31. To a solution of
14 (1.37 g, 3.33 mmol) in CH2Cl2 (6.7 mL) were added imidazole
(793 mg, 11.7 mmol), 4-DMAP (40.3 mg, 0.33 mmol), and TBSCl
(1.50 g, 9.99 mmol) at room temperature. The mixture was heated
for 10 h under reflux. After addition of water, the resulting mixture
was extracted with CH2Cl2, and the combined organic layers were
washed with brine, and dried over MgSO4. After the mixture was
evaporated, the residue was purified by silica gel column chro-
matography (10e30% EtOAc/hexane) to give 31 as a colorless oil
3.2.7. (1R,4R,5R,7S)-4-(tert-Butyldimethylsilyloxy)-7-methyl-8-oxa-
bicyclo[3.2.1]octan-1-ol 34. To a solution of 33 (5.10 g,12.8 mmol) in
THF (213 mL) was added t-BuLi (1.45 M in pentane, 21.2 mL,
30.7 mmol) at ꢀ78 ꢁC. The mixture was stirred for 30 min, and sat-
urated aqueous NH4Cl was added. The resulting mixture was
extracted with EtOAc, and the combined organic layers werewashed
with brine and dried over MgSO4. The solvent was removed in vacuo
and the residue was purified by column chromatography (15%
EtOAc/hexane) to give 34 (3.29 mg, 94%) as a colorless solid.1H NMR
26
20
(1.75 g, quant.). [
a
]
ꢀ15.6 (c 1.16, CHCl3), enantiomer; [
a]
D
D
þ13.09 (c 0.84, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 0.05 (s, 3H),
0.09 (s, 3H), 0.86 (s, 9H), 1.05 (s, 9H), 1.24 (d, J¼7.2 Hz, 3H),
1.66e1.74 (m, 1H), 1.78e1.89 (m, 2H), 2.21 (ddd, J¼4.4, 9.2, 12.8 Hz,
1H), 2.65e2.75 (m, 1H), 3.76 (t, J¼6.0 Hz, 2H), 3.92 (dt, J¼4.0,
6.4 Hz, 1H), 4.43 (dt, J¼4.4, 8.4 Hz, 1H), 7.36e7.46 (m, 6H), 7.64 (dd,
(400 MHz, CDCl3) d:0.03 (s,1.5H), 0.04 (s,1.5H), 0.155 (s,1.5H), 0.12(s,
1.5H), 0.86 (s, 4.5H), 0.91 (s, 4.5H), 1.00 (d, J¼6.8 Hz, 1.5H), 1.10 (d,
J¼6.8 Hz, 1.5H), 1.43e1.52 (m, 2H), 1.69e1.85 (m, 2H), 1.94 (tt, J¼3.2,
14.4 Hz, 1H), 2.08e2.15 (m, 0.5H), 2.34 (dd, J¼9.2, 13.2 Hz, 0.5H),
2.36e2.43 (m, 0.5H), 2.49 (dd, J¼3.6,12.8, 0.5 Hz), 2.56 (s, 0.5H), 2.70
(s, 0.5H), 3.40 (dt, J¼3.6, 10.4 Hz, 0.5H), 3.50 (ddd, J¼3.2, 7.6, 11.2 Hz,
J¼1.2, 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3)
: ꢀ4.5 (q), ꢀ4.4 (q),
d
16.6 (q), 18.1 (s), 19.2 (s), 25.9 (q), 26.9 (q), 32.2 (t), 34.3 (d), 35.7 (t),
60.1 (t), 71.5 (d), 79.1 (d), 127.6 (d), 129.6 (d), 129.7 (d), 133.4 (s),
133.5 (s), 135.4 (d), 180.1 (s). IR (KBr, neat): 1779 cmꢀ1. MS (EI) m/z:
526 (Mþ), 135 (100%); HRMS (EI) calcd for C30H46O4Si2 (Mþ)
526.2935, found: 526.2915.
0.5H), 3.96e4.00 (m, 0.5H); 13C NMR (100 MHz, CDCl3)
d
: ꢀ4.7 (q),
ꢀ4.7 (q), ꢀ4.6 (q), ꢀ4.1 (q),17.3 (q),17.6 (q),18.0 (s), 25.8 (q), 27.1 (t),
29.7 (t), 32.5 (t), 35.3 (t), 36.5 (t), 36.6 (d), 37.6 (t), 41.7 (d), 68.0 (d),
76.0 (d), 76.4 (d), 78.6 (d),104.1 (s), 214.0 (s). IR (0.2 mm KBr, CHCl3):
3590,1701 cmꢀ1; MS (EI) m/z: 272 (Mþ), 215 (100%); HRMS (EI) calcd
for C14H28O3Si (Mþ) 272.1808, found: 398.0780.
3.2.5. (3S,5R,10R)-5-[1-(tert-Butyldimethylsiloxy)-3-hydroxypropyl]-
3-methyldihydrofuran-2-one 32. TBAF (1.0 M in THF, 0.02 mL,
0.02 mmol) and AcOH (0.01 mL, 0.019 mmol) were added to a solu-
tion of 31 (10 mg, 0.02 mmol) in THF (0.1 mL) and CH2Cl2 (0.1 mL).
The resulting mixture was refluxed for 6 h, and saturated aqueous
NaHCO3 was added to neutralize the mixture to a pH of 7. The
aqueous phase was saturated with NaCl and extracted with EtOAc.
The combined organic layers were dried over MgSO4. The solvent
was removed in vacuo and the residue was purified by column
chromatography (30e75% EtOAc/hexane) to give 32 as a colorless oil
3.2.8. 5-(tert-Butyldimethylsiloxy)-4-(tert-butyldiphenylsiloxy)-2-
methylcycloheptanone 36. To a solution of 34 (11.4 mg, 0.04 mmol)
in CH2Cl2 (0.08 mL) were added imidazole (5.1 mg, 0.07 mmol),
4-DMAP (catalytic amount), and TBDPSCl (0.01 mL, 0.05 mmol) at
room temperature. The mixture was stirred for 2 days, and after
addition of H2O, the resulting mixture was extracted with CH2Cl2.
The combined organic layers were washed with brine and dried
over MgSO4. The solvent was removed in vacuo and the residue
(4.6 mg, 84%). [
a
]
26 ꢀ23.7 (c 1.00, CHCl3), enantiomer; [
a
]
20 þ17.24 (c
was purified by column chromatography (3% EtOAc/hexane) to
D
D
26
1.45, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 0.11 (s, 3H), 0.12 (s, 3H),
give a colorless oil 36 (20 mg, 94%). [
a
]
ꢀ0.75 (c 1.06, CHCl3),
D
20
0.90 (s, 9H), 1.28 (d, J¼7.2 Hz, 3H), 1.68e1.76 (m, 2H), 1.84e1.97 (m,
2H), 2.28 (ddd, J¼4.4, 9.6,13.2 Hz,1H), 2.68e2.78 (m,1H), 3.73e3.83
(m, 2H), 3.94 (dt, J¼6.4, 10.8 Hz, 1H), 4.55 (dt, J¼4.4, 8.8 Hz, 1H); 13C
enantiomer; [
CDCl3)
a
]
þ0.96 (c 1.04, CHCl3); 1H NMR (400 MHz,
D
d
: ꢀ0.31 (s, 3H), ꢀ0.20 (s, 3H), 0.77 (s, 9H), 1.05 (s, 9H), 1.15
(d, J¼6.8 Hz, 3H), 1.59e1.69 (m, 2H), 1.98e2.06 (m, 1H), 2.28e2.35
(m, 2H), 2.51e2.60 (m, 1H), 2.72 (ddd, J¼3.2, 11.6, 12.8 Hz, 1H),
3.51 (dt, J¼2.4, 5.6 Hz, 1H), 3.94 (ddd, J¼2.0, 4.8, 7.2 Hz, 1H),
7.35e7.47 (m, 6H), 7.65 (dd, J¼1.2, 8.0 Hz, 4H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3)
d
: ꢀ4.6 (q), ꢀ4.5 (q),16.5 (q),18.0 (s), 25.8 (q),
32.0 (t), 34.3 (d), 35.4 (t), 58.8 (t), 71.9 (d), 79.4 (d), 180.1 (s). IR (KBr,
neat) 3444,1770 cmꢀ1. MS (EI) m/z: 288 (Mþ),157 (100%); HRMS (EI)
calcd for C14H28O4Si (Mþ) 288.1757, found: 288.1744.
CDCl3)
d
: ꢀ5.1 (q), ꢀ5.0 (q), 17.9 (q), 18.2 (s), 19.2 (s), 25.7 (q), 27.2
(q), 27.2 (t), 32.1 (t), 36.6 (t), 42.6 (d), 71.7 (d), 74.8 (d), 127.6 (d),
127.7 (d), 129.7 (d), 129.7 (d), 133.8 (s), 133.9 (s), 135.7 (d), 135.8
(d), 213.5 (s). IR (KBr, neat) 1711 cmꢀ1; MS (EI) m/z: 510(Mþ), 193
(100%); HRMS (EI) calcd for C30H46O3Si2 (Mþ) 510.2986, found:
510.3013.
3.2.6. (3S,5R,10R)-5-[1-(tert-Butyldimethylsiloxy)-3-iodopropyl]-3-
methyldihydrofuran-2-one 33. To
a solution of 32 (3.70 g,
12.8 mmol) in CH2Cl2 (128 mL) were added Et3N (3.6 mL,
25.6 mmol) and MsCl (1.9 mL, 19.2 mmol). The mixture was stirred
for 30 min at room temperature, and then cooled to 0 ꢁC. Water was
added to the resulting mixture, which was diluted with CH2Cl2. The
organic layer was washed with 5% aqueous HCl and saturated
3.2.9. (1S,2S,4R,5R)-5-(tert-Butyldimethylsilyloxy)-4-(tert-butyldi-
phenylsilyloxy)-2-methyl-1-vinylcycloheptanol 39. To a 1.0 M THF

K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
8415
solution of vinylmagnesium bromide (3.5 mL, 3.51 mmol) was
added 36 (0.89 g, 1.75 mmol) in THF (6.0 mL), and the mixture was
refluxed for 6 h. After cooling to room temperature, the mixture
was poured into 0.3 M HCl at 0 ꢁC. The mixture was extracted with
EtOAc, and the combined organic layers were washed with satu-
rated aqueous NaHCO3, and brine, and dried over MgSO4. The sol-
vent was removed in vacuo and the residue was purified by column
chromatography (5% EtOAc/hexane), to give 39 as a colorless oil
room temperature for 30 min, and the solvent was removed in
vacuo. The residue was purified with column chromatography
(30e60% EtOAc/hexane) to give 42 as colorless needles (0.26 g,
25
quant.). Colorless needles (EtOAc/hexane): mp 63e64 ꢁC; [
a]
D
ꢀ50.98 (c 1.02, CHCl3), enantiomer; [
a
]
20 þ64.38 (c 0.73, CHCl3); 1H
D
NMR (400 MHz, CDCl3)
d
: 1.11 (d, J¼7.2 Hz, 3H), 1.60 (m, 1H), 1.76
(m, 1H), 1.84e2.00 (m, 4H), 2.04 (m, 1H), 2.16 (m, 1H), 3.60 (m, 1H),
3.88 (s, 1H), 5.08 (dd, J¼1.2, 11.2 Hz, 1H), 5.26 (dd, J¼1.2, 18 Hz, 1H),
(0.90 g, 96%). [
a
]
26 ꢀ12.58 (c 1.04, CHCl3), enantiomer; [
a
]
20 þ14.96
5.90 (dd, J¼11.2, 18 Hz); 13C NMR (150 MHz, CDCl3)
d: 18.1 (q), 32.1
D
D
(c 1.47, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: ꢀ0.23 (s, 3H), ꢀ0.12 (s,
(t), 32.9 (t), 34.4 (t), 35.1 (d), 70.9 (d), 85.4 (s), 104.5 (s), 112.1 (t),
140.5 (d). IR (0.1 mm NaCl, CHCl3):3537 cmꢀ1; MS (FAB) m/z: 185
(Mþþ1), 154 (100%). Anal. Calcd for C10H16O3: C, 65.19; H, 8.75.
Found: C, 65.11; H, 8.72.
3H), 0.80 (s, 9H), 1.09 (s, 9H), 1.41e1.52 (m, 2H), 1.65e1.75 (m, 3H),
1.87 (m, 1H), 2.17 (m, 1H), 2.91 (s, 1H), 3.62 (m, 1H), 3.86 (m, 1H),
4.95 (dd, J¼1.6, 10.8 Hz, 1H), 5.17 (dd, J¼1.6, 17.2 Hz, 1H), 5.77 (dd,
J¼10.8, 17.2 Hz, 1H), 7.34e7.45 (m, 6H), 7.67e7.71 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d
: ꢀ4.8 (q), ꢀ4.7 (q), 17.9 (q), 18.5 (s), 19.1 (s), 25.8
3.2.13. (6S,7S,8aR)-6-Hydroxy-3,7-dimethyl-6-vinyl-4,5,6,7,8,8a-hexa-
hydro-2H-cyclohepta[b]furan-2-one 46. To a solution of 42 (0.10 g,
0.54 mmol) in xylene (10.8 mL) was added the Wittig reagent (Ph3PC
(CH3)CO2CH2CF3, 1.80 g, 4.32 mmol). The resulting mixture was
refluxed for 4 h. The solvent was removed and the crude residue was
purified with column chromatography (50% EtOAc/hexane) to give
46 as colorless prisms (0.112 g, 92%): (EtOAc/hexane): mp 151 ꢁC;
(q), 26.0 (t), 27.1 (q), 35.1 (t), 36.2 (t), 38.4 (d), 73.8 (d), 75.7 (s), 76.6
(d), 109.8 (t), 127.5 (d), 127.6 (d), 129.6 (d), 129.7 (d), 133.5 (s), 133.7
(s), 135.8 (d), 135.9 (d), 146.2 (d). IR (KBr, neat): 3464, 1704 cmꢀ1
;
MS (ESI) m/z: 561 (MþþNa); HRMS (ESI) calcd for C32H50O3NaSi2
(MþþNa) 561.3196, found: 561.3192.
25
20
3.2.10. (1S,4R,5R,7S)-5-(tert-Butyldiphenylsilyloxy)-7-methyl-1-vi-
nylcycloheptane-1,4-diol 40. To a solution of 39 (1.35 g, 1.61 mmol)
in THF (14.2 mL) was added 6 M HCl (1.8 mL). The mixture was
stirred for 18 h at room temperature, and then extracted with
EtOAc. The combined organic layers were washed with saturated
aqueous NaHCO3 and brine, and dried over MgSO4. The solvent was
removed in vacuo and the residue was purified by column chro-
[a]
ꢀ140.27 (c 1.08, CHCl3), enantiomer; [
a
]
þ133.11 (c 1.54,
D
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 0.93 (d, J¼6.8 Hz, 3H), 1.61 (m,
1H), 1.775 (m, 1H), 1.779 (s, 3H), 1.86 (m, 2H), 2.11 (m, 1H), 2.53 (m,
1H), 2.89 (m, 1H), 4.87 (br d, J¼12.4 Hz, 1H), 5.09 (d, J¼10.8 Hz, 1H),
5.19 (d, J¼17.6 Hz, 1H), 5.93 (dd, J¼10.8, 17.6 Hz, 1H); 13C NMR
(150 MHz, CDCl3) d: 8.2 (q),17.1 (q), 20.8 (t), 36.0 (t), 36.3 (t), 39.9 (d),
75.3 (s), 82.1 (d), 110.4 (t), 120.8 (d), 146.3 (d), 164.8 (s), 174.5 (s). IR
(CHCl3): 3471, 1741, 1672 cmꢀ1. MS (EI) m/z: 222 (Mþ), 204 (100%);
Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.05; H, 8.12.
CCDC-629263 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts.retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (þ44)1223 336 033; or deposit@ccdc.cam.ac.uk).
matography (30% EtOAc/hexane) to give 40 as colorless needles
25
(0.62 g, 91%): (EtOAc/hexane): mp 110 ꢁC; [
a
]
ꢀ49.55 (c 1.12,
D
20
CHCl3), enantiomer;
(400 MHz, CDCl3)
[a
]
þ53.19 (c 0.94, CHCl3); 1H NMR
D
d
: 0.51 (d, J¼6.8 Hz, 3H), 1.04 (s, 9H), 1.13 (m, 3H),
1.36 (m, 1H), 1.55e1.60 (m, 1H), 1.76e1.83 (m, 2H), 1.90 (m, 1H), 2.42
(s, 1H), 3.53 (m, 1H), 3.64 (m, 1H), 4.96 (dd, J¼1.2, 11.2 Hz, 1H), 5.079
(dd, J¼1.2, 17.2 Hz, 1H), 5.75 (dd, J¼11.2, 17.2 Hz, 1H), 7.40 (m, 6H),
7.66 (m, 4H); 13C NMR (150 MHz, CDCl3)
d: 16.1 (q), 19.3 (s), 25.3 (t),
27.0 (q), 35.5 (t), 35.7 (t), 36.5 (d), 75.5 (s), 78.5 (d), 81.1 (d), 110.9
(d), 127.6 (d), 127.8 (d), 129.7 (d), 129.8 (d), 133.7 (s), 135.6 (d), 135.7
(d), 145.3 (d). IR (0.1 mm NaCl, CHCl3): 3427, 1633 cmꢀ1; MS (FAB)
m/z: 425 (Mþþ1). Anal. Calcd for C26H36O3Si: C, 73.54; H, 8.54.
Found: C, 73.47; H, 8.49.
3.2.14. (6R,7S,8aR)-6-Hydroxy-3,7-dimethyl-6-(oxiran-2-yl)-
4,5,6,7,8,8a-hexahydro-2H-cyclohepta[b]furan-2-one 48. To a solu-
tion of 46 (50 mg, 0.22 mmol) in CH2Cl2 (2.2 mL) was added
m-chloroperbenzoic acid (155.3 mg, 0.90 mmol). The mixture was
stirred for 10 h at room temperature, and then saturated aqueous
NaHCO3 and brine were added. The mixture was extracted with
CH2Cl2, and the combined organic layers were washed with brine
and dried over MgSO4. The solvent was removed and the crude
residue was purified with column chromatography (60% EtOAc/
3.2.11. (1S,2R,4S,5S)-2-(tert-Butyldiphenylsilyloxy)-4-methyl-5-vi-
nyl-8-oxabicyclo[3.2.1]octan-1-ol 41. To a solution of 40 (0.62 g,
1.46 mmol) in CH2Cl2 (10 mL) were added 4-methylmorpholine
N-oxide (0.85 g, 7.30 mmol) and molecular sieves 4 Å (0.73 g). The
mixture was stirred at room temperature for 10 min, and tetra-
propylammonium perruthenate (0.02 g, 0.07 mmol) was added.
The mixture was stirred for 1 h, and filtered through a pad of
Celite. The solvent was removed from the filtrate and the crude
product was purified with column chromatography (30% EtOAc/
hexane) to give 48 (50.2 mg, 96%) as colorless prisms; (CH2Cl2/
22
hexane); mp 220 ꢁC; [
a
]
D
ꢀ99.25 (c 1.35, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
: 1.01 (d, J¼6.8 Hz, 3H), 1.39 (s, 1H), 1.67 (ddd,
J¼11.2, 12, 14 Hz, 1H), 1.77 (s, 3H), 1.81e1.89 (m, 2H), 2.59 (m, 1H),
2.81 (m, 1H), 2.91 (d, J¼4 Hz, 2H), 2.98 (t, J¼4 Hz, 1H), 4.89 (br d,
J¼11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d: 8.3 (q), 16.7 (q), 20.7
hexane) to give 41 as a colorless oil (0.61 g, quant.). [
a
]
25 ꢀ40.62 (c
(t), 34.0 (t), 36.7 (t), 38.5 (d), 46.5 (t), 58.0 (d), 71.3 (s), 81.9 (d), 121.1
(s), 164.4 (s), 174.4 (s). IR (CHCl3): 3018, 1743 cmꢀ1. MS (EI) m/z: 238
(Mþ), 177 (100%); Anal. Calcd for C13H18O4: C, 66.53; H, 7.61. Found:
C, 65.26; H, 7.58.
D
20
1.35, CHCl3), enantiomer; [
(400 MHz, CDCl3)
a
]
þ54.54 (c 0.33, CHCl3); 1H NMR
D
d
: 1.09 (s, 9H), 1.13 (d, J¼6.8 Hz, 3H), 1.46 (m,
2H), 1.69e1.95 (m, 5H), 3.72 (s, 1H), 3.77 (m, 1H), 5.04 (dd, J¼1.48,
11 Hz, 1H), 5.23 (dd, J¼1.48, 17.5 Hz, 1H), 5.93 (dd, J¼11, 17.5 Hz,
1H), 7.40 (m, 6H), 7.70 (m, 4H); 13C NMR (150 MHz, CDCl3)
d
: 17.4
3.2.15. (3S,3aR,6R,7S,8aR)-6-Hydroxy-3,7-dimethyl-6-(oxiran-2-yl)
octahydro-2H-cyclohepta[b] furan-2-one 49. To a suspension of 48
(139 mg, 0.58 mmol) and NiCl2 (19 mg, 0.14 mmol) in MeOH
(10 mL) was added NaBH4 (88 mg, 2.34 mmol) at 0 ꢁC. The mixture
was stirred at 0 ꢁC for 2 h, and then saturated aqueous NH4Cl (5 mL)
was added. The resulting mixture was diluted with CH2Cl2 and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine and dried over MgSO4. The solvent
was removed and the crude residue was purified by HPLC (60%
EtOAc/hexane) to give 49 as colorless prisms (114 mg, 81%, 4:1
(q), 19.3 (s), 27.1 (q), 32.0 (t), 32.4 (t), 34.3 (t), 35.5 (d), 72.2 (d),
85.2 (s), 104.3 (s), 112.0 (t), 127.7 (d), 127.9 (d), 129.8 (d), 129.9 (d),
133.1 (s), 133.4 (d), 135.8 (d), 136.2 (d), 141.3 (d). IR (KBr
neat):3551 cmꢀ1; MS (FAB) m/z: 422 (Mþ); HRMS (FAB) calcd for
C26H34O3Si (MþþNa) 422.2277, found: 422.2278.
3.2.12. (1S,2R,4S,5S)-4-Methyl-5-vinyl-8-oxabicyclo[3.2.1]octane-
1,2-diol 42. To a solution of 41 (0.l6 g, 1.46 mmol) in THF (15 mL)
was added TBAF (1.0 M in THF, 1.7 mL). The mixture was stirred at

8416
K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
mixture of diastereomers of the oxirane) and C11-isomer (14%).
7.2, 3.6 Hz, 1H), 4.96 (d, J¼11.4 Hz, 1H), 5.12 (d, J¼11.4 Hz, 1H), 5.74
(dd, J¼9.0, 5.4 Hz, 1H), 6.17 (dd, J¼17.4, 11.4 Hz, 1H); 13C NMR
Major isomer of 49: colorless prisms (CH2Cl2/hexane); mp 150 ꢁC;
22
[
a]
ꢀ5.00 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 1.00 (d,
(150 MHz, CDCl3) d: 12.2 (q), 21.7 (q), 22.2 (t), 31.1 (d), 36.7 (t), 38.1
D
J¼7.2 Hz, 3H), 1.20 (d, J¼7.2 Hz, 3H), 1.45e1.59 (m, 2H), 1.72 (m, 3H),
2.02 (ddd, J¼7.6, 7.6, 8.0 Hz,1H), 2.35 (ddd, J¼10.4,11.2,14.8 Hz,1H),
2.58 (m, 1H), 2.78e2.87 (m, 3H), 2.93 (dd, J¼2.8, 5.2 Hz, 1H), 4.67
(d), 40.5 (d), 80.5 (d), 111.9 (t), 127.1 (d), 139.8 (d), 144.2 (s), 179.6 (s).
IR (KBr): 2933, 1743 cmꢀ1; MS (EI) m/z: 206 (Mþ), 91 (100%); HRMS
(EI) calcd for C13H18O2: 206.1307, found: 206.1311.
(ddd, J¼6.6, 12 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d: 11.1 (q), 17.3
(t), 17.8 (q), 33.2 (t), 34.5 (d), 38.9 (d), 40.9 (t), 43.4 (d), 45.1 (t), 58.3
3.4. Synthesis of (D)-8-epi-xanthatin (1)
(d), 71.2 (s), 80.8 (r), 179.1 (s). IR (0.1 mm NaCl, CHCl3): 1762 cmꢀ1
;
MS (FAB) m/z: 241 (Mþþ1). Anal. Calcd for C13H20O4: C, 64.98; H,
3.4.1. (3R,3aS,7S,8aR)-3-Bromo-3,7-dimethyl-6-vinyl-3,3a,4,7,8,8a-
hexahydro-2H-cyclohepta [b]furan-2-one 51. To a solution of 5
(70.0 mg, 0.34 mmol) in THF (3.4 mL) was added LDA (0.61 M)
(0.72 mL, 0.44 mmol) at ꢀ78 ꢁC. The mixture was stirred for 1 h at
ꢀ78 ꢁC, and then CBr4 (225 mg, 0.68 mmol) in THF (1.0 mL) was
added dropwise at ꢀ78 ꢁC. After 20 min at ꢀ78 ꢁC, the reaction was
quenched with aqueous saturated NH4Cl, and the mixture was
extracted with CH2Cl2. The combined organic layers were washed
with brine and dried over MgSO4. After the mixture was evapo-
rated, the residue was purified by silica gel column chromatogra-
phy (5% EtOAc/Hex) to give 51 (37.4 mg, 39%) as a colorless oil and
8.39. Found: C, 64.93; H, 8.36.
3.2.16. (3S,3aR,7S,8aR)-3,7-Dimethyl-6-(oxiran-2-yl)-3,3a,4,7,8,8a-
hexahydro-2H-cyclohepta[b] furan-2-one 50. To a solution of 49
(3.0 mg, 0.0125 mmol) in CH2Cl2 (1.2 mL) was added dropwise
a solution of freshly distilled thionyl chloride (1.8 mL, 0.025 mmol)
and pyridine (4
m
L) in CH2Cl2 (0.3 mL) at ꢀ20 ꢁC. The resulting
mixture was stirred at ꢀ20 ꢁC for 10 min then saturated aqueous
NaHCO3 was added. The resulting mixture was extracted with
CH2Cl2, and the combined organic layer was washed with aqueous
CuSO4 and dried over MgSO4. The solvent was removed in vacuo
and the residue was purified by column chromatography (20%
52 (53%) as a white solid.
25
Compound 51: [
CDCl3)
a
]
ꢀ44.4 (c 0.27, CHCl3); 1H NMR (600 MHz,
D
EtOAc/hexane) to give 50 as a colorless oil (2.5 mg, 87%); Major
d
: 1.19 (d, J¼7.2 Hz, 3H), 1.87 (s, 3H), 2.00e2.06 (m, 1H),
22
isomer: mp 71.5e72 ꢁC (hexane-EtOAc); [
a
]
D
ꢀ16.22 (c 0.31,
2.15e2.24 (m, 2H), 2.37e2.42 (m, 1H), 2.67e2.73 (m, 1H), 3.10 (ddd,
J¼13.2, 7.2, 3.0 Hz, 1H), 4.94 (ddd, J¼11.4, 6.6, 4.8 Hz, 1H), 4.99 (d,
J¼10.8 Hz, 1H), 5.13 (d, J¼18.0 Hz, 1H), 5.73 (dd, J¼9.0, 4.2 Hz, 1H),
CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 1.16 (d, J¼7.2 Hz, 3H), 1.20 (d,
J¼6.8 Hz, 3H), 1.95e2.19 (m, 4H), 2.47 (dd, J¼6.4, 3.2 Hz, 1H), 2.48
(m, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 2.91 (dd, J¼6.4, 4.4 Hz, 1H), 3.23
(br s,1H), 4.65 (m, 1H), 5.73 (br d, J¼9.6 Hz,1H); 13C NMR (100 MHz,
6.17 (dd, J¼18.0, 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d: 22.1 (q),
22.9 (t), 24.1 (q), 30.9 (d), 35.8 (t), 52.5 (d), 57.3 (s), 79.4 (d),112.8 (t),
125.2 (d), 139.6 (d), 145.2 (s), 174.3 (s). IR (CHCl3): 2958, 1774,
1207 cmꢀ1; MS (EI) m/z: 286 ([MþH]þ), 284 ([Mꢀ1]þ), 79 (100%);
CDCl3) d: 10.6 (q), 21.0 (q), 31.8 (t), 36.9 (d), 38.9 (d), 42.3 (t), 50.4
(d), 52.7 (d), 53.2 (d),80.1 (t), 121.4 (d), 141.2 (s), 178.8 (s). IR (NaCl,
neat): 1770 cmꢀ1. MS (EI) m/z: 222 (Mþ), 60 (100%); HRMS (EI) calcd
for C13H18O3 (Mþ) 222.1256, found: 222.1258.
HRMS (EI) calcd for C13H17O2Br: 284.0412, found: 284.0411.
25
Compound 52: mp 86e87.5 ꢁC; [
a]
ꢀ16.7 (c 0.18, CHCl3); 1H
D
NMR (600 MHz, CDCl3)
d
: 1.19 (d, J¼6.6 Hz, 3H), 1.93 (s, 3H), 2.16
3.2.17. Sundiversifolide (4). To
a
solution of 50 (18.6 mg,
(ddd, J¼14.4, 7.8, 1.8 Hz, 1H), 2.25 (ddd, J¼13.8, 9.0, 4.8 Hz, 1H),
2.43e2.49 (m, 2H), 2.79e2.88 (m, 2H), 4.51 (ddd, J¼12.6, 8.4, 1.8 Hz,
1H), 5.00 (d, J¼10.8 Hz, 1H), 5.15 (d, J¼17.4 Hz, 1H), 5.74 (dd, J¼9.0,
6.0 Hz,1H), 6.16 (dd, J¼17.4, 10.8 Hz,1H); 13C NMR (150 MHz, CDCl3)
0.0837 mol) in CH2Cl2 (1.5 mL) and THF (0.1 mL) were added ZnI2
(80.1 mg, 0.25 mmol) and NaBH3CN (16.5 mg, 0.25 mmol). The
mixture was stirred for 2 h at room temperature, and 1 M aqueous
HCl (0.1 mL) was added at 0 ꢁC. The resulting mixture was saturated
with NaCl and extracted with CH2Cl2. The organic layer was dried
over MgSO4. The solvent was removed in vacuo and the residue was
purified by column chromatography (70% EtOAc/hexane) to give 4
d: 21.2 (q), 25.9 (t), 27.8 (q), 31.2 (d), 33.0 (t), 47.1 (d), 58.5 (s), 79.1
(d), 112.0 (t),125.5 (d), 139.6 (d), 143.9 (s), 174.8 (s). IR (CHCl3): 2941,
1762, 1236, 1209, 1105, 979 cmꢀ1; MS (EI) m/z: 286 ([MþH]þ), 284
([Mꢀ1]þ), 91 (100%); HRMS (EI) calcd for C13H17O2Br: 284.0412,
found: 284.0417.
as a colorless solid (15.9 mg, 85%). Mp 42e47 ꢁC; [
a
]
20 þ33.0 (c 0.44,
D
CHCl3), enantiomer; [
a
]
20 ꢀ33.7 (c 0.46, CHCl3); 1H NMR (400 MHz,
Conversion of 52 to 51: To a solution of 52 (7.7 mg, 27.0 mmol) in
D
CD3OD)
d
: 1.11 (d, J¼7.3 Hz, 3H), 1.15 (d, J¼7.1 Hz, 3H), 1.87e1.99 (m,
THF (300
m
L) was added LDA (0.61 M, 66
m
L, 40.5
m
mol) at ꢀ78 ꢁC.
2H), 2.01e2.04 (m, 2H), 2.10e2.23 (m, 2H), 2.72e2.80 (m, 1H),
2.86e2.94 (m, 1H), 3.50e3.63 (m, 2H), 4.67e4.73 (m, 1H),
The mixture was stirred for 1 h at ꢀ78 ꢁC, then CBr4 (17.9 mg,
54
mmol) in THF (200
m
L) was added dropwise at ꢀ78 ꢁC. After
5.53e5.55 (m, 1H); 13C NMR (150 MHz, CD3OD)
d: 10.9, 21.8, 22.8,
20 min at ꢀ78 ꢁC, the reaction was quenched with aqueous satu-
rated NH4Cl, and the mixture was extracted with CH2Cl2. The
combined organic layers were washed with brine, then dried over
MgSO4. After the mixture was evaporated, the residue was purified
by silica gel column chromatography (5% EtOAc/Hex) to give 51
(3.3 mg, 43%) as a colorless oil and 52 (4.4 mg, 57%) as a white solid.
33.9, 38.2, 40.1, 41.2, 43.5, 62.1, 82.5, 125.3, 143.6, 181.8. IR (neat):
3415, 1651, 1732 cmꢀ1; HRMS (EI) calcd for C13H20O3 (Mþ) 224.1412,
found: 224.1405.
3.3. Synthesis of 5
3.3.1. (3S,3aR,7S,8aR)-3,7-Dimethyl-6-vinyl-3,3a,4,7,8,8a-hexahy-
3.4.2. (3aR,7S,8aR)-7-Methyl-3-methylene-6-vinyl-3,3a,4,7,8,8a-
dro-2H-cyclohepta[b]furan-2-one 5. To a solution of the epoxide 50
hexahydro-2H-cyclohepta[b] furan-2-one 53. To a solution of 51
(6.2 mg, 27.9
mmol) in H2O/methanol (1:10, 0.3 mL) was added
(3.9 mg,13.7
mmol) in THF (0.35 mL) was added TBAF (1.0 M, 27.4 mL,
potassium selenocyanate (16.1 mg, 111.6
mmol). The mixture was
27.4 mol) at room temperature. The reaction was stirred for
m
stirred for 10 h at room temperature. The reaction was filtered,
diluted with water, and extracted with Et2O. The combined organic
layers were washed with brine and dried over MgSO4. After the
mixture was evaporated, the residue was purified by silica gel
30 min at room temperature before the reaction was quenched
with aqueous saturated NH4Cl. The mixture was extracted with
CH2Cl2, and the combined organic layers were washed with brine,
and dried over MgSO4. After the mixture was evaporated, the res-
idue was purified by silica gel column chromatography (10% AcOEt/
Hex) to give 53 (2.8 mg) as colorless needles: mp 74.5e75.5 ꢁC
column chromatography (10% EtOAc/Hex) to give 5 (5.2 mg, 90%) as
21
colorless prisms: mp 53.0e54.0 ꢁC (EtOAc/Hex); [
a]
ꢀ21.21 (c
D
0.33, CHCl3); 1H NMR (600 MHz, CDCl3)
d
: 1.19 (d, J¼6.6 Hz, 3H),
(EtOAc/Hex); [
a
]
25 þ14.8 (c 0.27, CHCl3); 1H NMR (600 MHz, CDCl3)
D
1.23 (d, J¼4.8 Hz, 3H), 1.98e2.05 (m, 2H), 2.16 (ddd, J¼13.8, 5.4,
3.6 Hz,1H), 2.43e2.48 (m, 1H), 2.71e2.86 (m, 3H), 4.63 (ddd, J¼11.4,
d
: 1.18 (d, J¼6.6 Hz, 3H), 1.84e1.90 (m, 1H), 2.13 (ddd, J¼13.8, 7.2,
2.4 Hz, 1H), 2.37 (ddd, J¼13.8, 8.4, 4.8 Hz, 1H), 2.51 (ddd, J¼13.8,

K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
8417
13.8, 6.0 Hz, 1H), 2.80e2.87 (m, 1H), 3.36e3.42 (m, 1H), 4.66 (ddd,
J1¼12.0, 8.4, 2.4 Hz, 1H), 5.00 (d, J¼11.4 Hz, 1H), 5.14 (d, J¼17.4 Hz,
1H), 5.54 (d, J¼3.0 Hz, 1H), 5.77 (dd, J¼9.0, 6.6 Hz, 1H), 6.16 (dd,
J¼17.4, 11.4 Hz, 1H), 6.29 (d, 1H, J¼3.0 Hz); 13C NMR (150 MHz,
3H), 1.13 (t, J¼7.2 Hz, 3H), 1.20 (t, J¼6.6 Hz, 3H), 2.06 (ddd, J¼16.2,
12.0, 6.6 Hz, 1H), 2.28 (ddd, J¼15.0, 9.6, 3.6 Hz, 1H), 2.63 (d,
J¼6.0 Hz, 2H), 2.84 (ddd, J¼12.6, 10.2, 3.6 Hz, 1H), 3.00e3.07 (m,
2H), 3.32e3.45 (m, 4H), 4.96 (d, J¼10.8 Hz, 1H), 5.13 (d, J¼17.4 Hz,
1H), 5.83 (dd, J¼9.0, 4.8 Hz, 1H), 6.23 (dd, J¼17.4, 10.8 Hz, 1H); 13C
CDCl3) d: 21.5 (q), 26.3 (t), 31.3 (d), 36.4 (t), 41.6 (d), 78.8 (d), 112.1
(t), 122.1 (d), 126.4 (s), 138.6 (d), 139.6 (d), 143.9 (s), 170.2 (s). IR
(CHCl3): 2931, 1747, 1272, 977 cmꢀ1; MS (EI) m/z: 204 (Mþ), 93
(100%); HRMS (EI) calcd for C13H16O2: 204.1150, found: 204.1153.
NMR (150 MHz, CDCl3) d: 13.2 (q), 15.1 (q), 17.2 (d), 18.4 (t), 27.9 (t),
29.8 (d), 36.4 (d), 40.6 (t), 42.2 (t), 49.1 (t), 56.2 (d), 111.0 (t), 129.7
(d), 140.2 (d), 145.0 (q), 174.2 (q), 212.3 (q). IR (CHCl3): 2975, 1701,
1627, 1463, 1220 cmꢀ1; MS (FAB) m/z: 278 ([MþH]þ); HRMS (FAB)
calcd for C17H28NO2 ([MþH]þ): 278.2120, found: 278.2117.
3.4.3. (þ)-8-epi-Xanthatine 1. To a solution of 53 (1.7 mg, 8.3
in dry CH2Cl2 (1.5 mL), the second generation HoveydaeGrubbs
catalyst 54 (0.5 mg, 0.83 mol) was added. Freshly distilled methyl
vinyl ketone (13.4 L, 166.4 mol) was added to the mixture using
a syringe pump over 8 h at 45 ꢁC. Upon completion, the mixture
was cooled to room temperature before DMSO (15.0 L) was added.
mmol)
m
3.5.3. (S)-N,N-Diethyl-2-((1R,5S,7S)-7-hydroxy-5-methyl-4-vinyl-
cyclohept-3-enyl)propanamide 59. To a solution of 58 (2.0 mg,
m
m
7.2
(1
m
mol) in THF (0.8 mL) were added Et3N (5.0
m
L, 36
mmol), H2O
m
mL, 45 mol), and SmI2 (0.1 M in THF, 180 L, 18.0 m
m
m
mol) at 0 ꢁC.
After 6 h at room temperature, the mixture was evaporated, and the
residue was purified by silica gel column chromatography (30%
EtOAc/Hex) to give 8-epi-xanthatin (1) (1.7 mg, 85%) as a colorless
The mixture was stirred for a few seconds at 0 ꢁC, whereupon the
reaction was quenched with saturated aqueous NH4Cl, and then
extracted with EtOAc. The combined organic layers were washed
with saturated aqueous NaHCO3 and brine, and dried over MgSO4.
After the mixture was evaporated, the residue was purified by silica
gel column chromatography (50% AcOEt/Hex) to give 59 (1.6 mg,
80%) and the C8-isomer (20%) as colorless oils. Major isomer 59:
oil. [
a
]
D
23 þ44.0 (c 0.25, CHCl3); 1H NMR (600 MHz, CDCl3)
d: 1.18 (d,
J¼6.6 Hz, 3H), 1.88e1.94 (m, 1H), 2.17 (ddd, J¼13.8, 7.2, 2.4 Hz, 1H),
2.30 (s, 3H), 2.57e2.65 (m, 1H), 2.50 (ddd, J¼13.8, 9.0, 4.8 Hz, 1H),
2.61 (ddd, J¼13.8, 13.8, 6.0 Hz, 1H), 2.80e2.86 (m, 1H), 3.39e3.44
(m, 1H), 4.65 (ddd, J¼12.0, 8.4, 2.4 Hz, 1H), 5.57 (d, J¼2.4 Hz, 1H),
6.13 (d, J¼16.2 Hz, 1H), 6.20 (dd, J¼9.0, 6.0 Hz,1H), 6.32 (d, J¼3.6 Hz,
[a
]
23 ꢀ80.0 (c 0.25, CHCl3); 1H NMR (600 MHz, CDCl3)
d: 1.11e1.23
D
(m, 6H), 1.21 (t, J¼7.2 Hz, 3H), 1.27 (d, J¼7.2 Hz, 3H), 1.59e1.69 (m,
2H), 2.00e2.38 (m, 1H), 2.40 (ddd, J¼16.2, 12.0, 4.8 Hz, 1H), 2.78
(ddd, J¼14.4, 7.2, 2.4 Hz, 1H), 2.87e2.92 (m, 1H), 3.28e3.36 (m, 2H),
3.39e3.399 (m, 2H), 3.95e3.99 (m, 1H), 4.92 (d, J¼10.8 Hz, 1H), 5.15
(d, J¼17.4 Hz, 1H), 5.16 (s, 1H), 5.72 (dd, J¼9.6, 4.8 Hz, 1H), 6.21 (dd,
1H), 6.97 (d, J¼16.2 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d: 21.5 (q),
27.0 (q), 27.7 (d), 31.7 (q), 36.3 (t), 41.1 (d), 78.2 (d), 122.5 (t), 125.8
(d), 135.7 (d), 138.1 (s), 142.9 (s), 146.4 (d), 169.8 (s), 198.5 (s). IR
(CHCl3): 3018,1758,1668,1593,1274,1207 cmꢀ1; MS (FAB) m/z: 247
([MþH]þ); HRMS (FAB) calcd for C15H19O3 ([MþH]þ): 247.1334,
found: 247.1337.
J¼17.4, 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d: 12.7 (q), 13.0 (q),
14.9 (q), 17.1 (q), 28.6 (d), 31.1 (t), 40.9 (t), 41.5 (d), 42.0 (t), 42.5 (t),
46.5 (d), 69.5 (d), 110.2 (t), 129.3 (d), 140.1 (d), 146.7 (s), 177.1 (s). IR
3.5. Synthesis of (L)-dihydroxanthatin (2)
(CHCl3): 2974, 2933, 1608, 1456 cmꢀ1
; MS (FAB) m/z: 280
([MþH]þ); HRMS (FAB) calcd for C17H30NO2 ([MþH]þ): 280.2277,
3.5.1. (S)-N,N-Diethyl-2-((1R,5S,7R)-7-hydroxy-5-methyl-4-vinyl-
found: 280.2276.
cyclohept-3-enyl)propanamide 57. To a solution of 5 (20.0 mg,
97.9
293.7
m
m
mol) in CH2Cl2 (1.0 mL) were added AlCl3 (39.1 mg,
3.5.4. (3S,3aR,7S,8aS)-3,7-Dimethyl-6-vinyl-3,3a,4,7,8,8a-hexahy-
mol) and Et2NH (30.6 mL, 293.7 mol) at room temperature.
m
dro-2H-cyclohepta[b]furan-2-one 608c. To a solution of 59 (16.5 mg,
After 30 min at room temperature, the reaction was quenched with
1 M HCl, whereupon the mixture was extracted with CH2Cl2. The
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, and dried over MgSO4. After the mixture was
evaporated, the residue was purified by silica gel column chroma-
tography (50% AcOEt/Hex) to give 57 (27.4 mg) as a colorless oil.
59.1 mmol) in THF (0.47 mL) was added 3 M HCl (0.11 mL). The
mixture was refluxed for 30 min. The reaction was quenched with
saturated aqueous NaHCO3, and extracted with Et2O. The combined
organic layers were washed with brine, and dried over MgSO4. After
the mixture was evaporated, the residue was purified by silica gel
column chromatography (10% AcOEt/Hex) to give 60 (10.5 mg, 86%)
[
a]
23 ꢀ75.0 (c 0.40, CHCl3); 1H NMR (600 MHz, CDCl3)
d: 1.12e1.20
as colorless prisms. Mp 82.5e83.5 ꢁC; [
a
]
D
23 ꢀ103.1 (c 0.32, CHCl3);
D
(m, 6H), 1.19 (t, J¼7.2 Hz, 3H), 1.28 (d, J¼7.2 Hz, 3H), 1.72 (dd, J¼15.0,
9.0 Hz,1H), 1.82 (dt, J¼15.0, 3.6 Hz, 1H),1.86 (br s, 1H), 1.93e1.97 (m,
1H), 2.02 (dt, J¼15.0, 5.4 Hz, 1H), 2.61 (ddd, J¼15.6, 11.4, 4.8 Hz, 1H),
2.75e2.84 (m, 2H), 3.30e3.45 (m, 4H), 4.31 (br s, 1H), 4.87 (d,
J¼10.8 Hz, 1H), 5.07 (d, J¼16.8 Hz, 1H), 5.78 (dd, J¼9.0, 4.2 Hz, 1H),
1H NMR (600 MHz, CDCl3)
d: 1.13 (d, J¼7.8 Hz, 3H), 1.22 (d, J¼7.8 Hz,
3H), 1.70 (ddd, J¼12.6, 12.6, 3.6 Hz, 1H), 2.07e2.16 (m, 2H),
2.28e2.34 (m, 2H), 2.69 (dq, J¼7.8, 7.8 Hz, 1H), 3.07 (ddq, J¼7.8, 4.2,
4.2 Hz, 1H), 4.53 (ddd, J¼12.6, 10.2, 3.0 Hz, 1H), 4.96 (d, J¼10.8 Hz,
1H), 5.17 (d, J¼17.4 Hz, 1H), 5.81 (dd, J¼9.6, 3.6 Hz, 1H), 6.23 (dd,
6.21 (dd, J¼16.8, 10.2 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d
: 13.1 (q),
J¼17.4, 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d: 10.2 (q), 18.4
15.0 (q), 15.9 (q), 19.8 (t), 26.0 (t), 30.6 (d), 38.2 (d), 40.0 (t), 40.6 (t),
42.1 (t), 43.9 (q), 71.5 (d), 109.6 (d), 131.3 (d), 140.5 (d), 145.8 (s),
176.1 (s). IR (CHCl3): 2985, 2358, 1731, 1618, 1462, 1434 cmꢀ1; MS
(FAB) m/z: 280 ([MþH]þ); 280 (100%); HRMS (FAB) calcd for
C17H30NO2 ([MþH]þ): 280.2277, found: 280.2276.
(q),25.0 (t), 28.1 (d), 36.5 (t), 40.0 (d), 46.2 (d), 81.4 (d), 110.3 (t),
129.8 (d), 141.4 (d), 145.4 (s), 180.0 (s). IR (KBr): 2958, 2929, 1766,
1627, 1465, 1450, 1211, 1039, 989, 887 cmꢀ1; MS (EI) m/z: 206 (Mþ),
79 (100%); HRMS (EI) calcd for C13H18O2: 206.1307, found:
206.1302.
3.5.2. (S)-N,N-Diethyl-2-((1R,5S)-5-methyl-7-oxo-4-vinylcyclohept-
3.5.5. (ꢀ)-Dihydroxanthatin 28c. To a solution of 60 (6.2 mg,
3-enyl)propanamide 58. To a solution of 57 (12.3 mg, 44.0
mmol) in
30 mmol) in dry CH2Cl2 (6.0 mL) were added the second generation
CH2Cl2 (0.44 mL) were added N-methylmorpholine oxide (NMO,
25.8 mg, 0.22 mmol) and molecular sieves 4 Å (22 mg) at room
temperature. After 10 min at room temperature, tetrapropy-
HoveydaeGrubbs catalyst 54 (1.9 mg, 3.0 mmol), and freshly dis-
tilled methyl vinyl ketone (49
mL, 0.60 mmol). The mixture was
stirred at 45 ꢁC for 1 h. Upon completion, the mixture was evapo-
lammonium perruthenate (TPAP,1.5 mg, 4.4
mmol) was added. After
rated, and the residue was purified by column chromatography
30 min, the mixture was filtered and concentrated. The residue was
purified by silica gel column chromatography (40% AcOEt/Hex) to
(30% EtOAc/Hex) to give dihydroxanthatin (2) (6.6 mg, 89%) as
23
colorless prisms. Mp 121.0e124.0 ꢁC (CH2Cl2/hexane); [
a
]
ꢀ75.0
D
give 58 (9.9 mg, 81%) as a colorless oil. [
a
]
23 þ44.9 (c 0.29, CHCl3);
(c 0.32, CHCl3); 1H NMR (CDCl3, 600 MHz)
1.23 (d, J¼7.8 Hz, 3H),1.72 (ddd, J¼12.6,12.6, 3.6 Hz,1H), 2.13 (dddd,
d
: 1.15 (d, J¼7.8 Hz, 3H),
D
1H NMR (600 MHz, CDCl3)
d
: 1.06 (d, J¼7.2 Hz, 3H), 1.10 (d, J¼6.6 Hz,

8418
K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
J¼12.6,12.6, 7.8, 2.4 Hz,1H), 2.21 (ddd, J¼12.0,12.0, 3.0 Hz,1H), 2.30
(s, 3H), 2.35 (ddd, J¼12.6, 4.2, 4.2 Hz, 1H), 2.45 (ddd, J¼16.2, 9.0,
2.4 Hz, 1H), 2.72 (dq, J¼7.8, 7.8 Hz, 1H), 3.05 (ddq, J¼7.8, 4.2, 4.2 Hz,
1H), 4.54 (ddd, J¼12.6, 10.8, 3.0 Hz, 1H), 6.18 (d, J¼16.2 Hz, 1H), 6.25
(dd, J¼9.6, 3.0 Hz, 1H), 7.05 (d, J¼16.2 Hz, 1H); 13C NMR (CDCl3,
J¼13.2, 4.8, 2.4 Hz, 1H), 2.17e2.22 (m, 2H), 2.27e2.33 (m, 1H),
2.93e2.96 (m, 1H), 3.40 (dd, J¼15.6 Hz, 1H), 2.61 (dd, J¼10.8,
5.4 Hz, 1H), 2.75e2.80 (m, 1H), 2.92e3.01 (m, 2H), 3.40 (dq,
J¼14.4, 7.2 Hz, 2H), 3.49e3.57 (m, 2H), 3.9 (br t, J¼10.8 Hz, 1H),
4.64 (d, J¼3.0 Hz, 1H), 4.95 (d, J¼10.8 Hz, 1H), 5.15 (s, 1H), 5.17 (d,
J¼17.4 Hz, 1H), 5.29 (s, 1H), 5.71 (dd, J¼9.6, 4.2 Hz, 1H), 6.22 (dd,
J¼17.4, 10.8 Hz, 1H).
150 MHz) d: 10.2 (q), 18.4 (q), 25.7 (t), 27.9 (q), 29.0 (d), 36.4 (t), 39.9
(d), 45.9 (d), 80.8 (d), 124.4 (d), 139.3 (d), 144.5 (s), 148.4 (d), 179.0
(s), 198.6 (s). IR (KBr): 2968,1768, 1679,1585, 1357, 1282, 1205, 1180,
981 cmꢀ1; MS (EI) m/z: 248 (Mþ), 248 (100%); HRMS (EI) calcd for
C15H20O3: 248.1412, found: 248.1417.
To a solution of the diastereomeric mixture (65 and 63)
(16.0 mmol) in THF (320 mL) was added 3 M HCl (80 mL). The mixture
was refluxed for 30 min. The reaction was quenched with saturated
aqueous NaHCO3 and extracted with Et2O. The combined organic
layers were washed with brine and dried over MgSO4. After the
mixture was evaporated, the residue was purified by silica gel
column chromatography (10% AcOEt/Hex) to give 67 (1.3 mg, 27%
3.6. Synthesis of (L)-xanthatin (3)
3.6.1. N,N-Diethyl-2-((1R,5S,7R)-7-hydroxy-5-methyl-4-vinyl-
cyclohept-3-enyl)acrylamide 63. To a solution of 53 (6.4 mg,
for two steps) and 53 (33% for two steps) as colorless needles.
23
31.3
and Et2NH (6.5
m
mol) in CH2Cl2 (0.5 mL) were added AlCl3 (8.4 mg, 62.7
mmol)
Compound 67: mp 77.2e77.7 ꢁC (hexane); [
a
]
ꢀ40.0 (c 0.05,
D
mL, 62.7
m
mol) at 0 ꢁC. The mixture was stirred for
CHCl3); 1H NMR (600 MHz, CDCl3)
d
: 1.14 (d, J¼7.8 Hz, 3H), 1.83
30 min at room temperature, whereupon the reactionwas quenched
with 1 M HCl, and the mixture was extracted with CH2Cl2. The
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, and dried over MgSO4. After the mixture was
evaporated, the residue was purified by silica gel column chroma-
(ddd, J¼12.6, 12.6, 3.6 Hz, 1H), 2.14 (ddd, J¼16.2, 11.4, 3.6 Hz, 1H),
2.35 (ddd, J¼13.2, 4.2, 3.6 Hz, 1H), 2.51e2.56 (m, 1H), 2.67 (ddd,
J¼16.2, 9.0, 2.4 Hz, 2H), 3.11 (dq, J¼3.6, 3.6 Hz, 1H), 4.29 (ddq,
J¼12.6, 10.2, 2.4 Hz, 1H), 4.99 (d, J¼11.4 Hz, 1H), 5.20 (d, J¼17.4 Hz,
1H), 5.47 (dd, J¼9.0, 3.0 Hz, 1H), 6.18 (d, J¼3.0 Hz, 1H), 6.26 (dd,
tography (50% AcOEt/Hex) to give 63 (8.4 mg, 97%) as a colorless oil.
J¼17.4, 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d: 18.9 (q), 26.6 (t),
20
[
a]
ꢀ58.3 (c 0.06, CHCl3); 1H NMR (600 MHz, CDCl3)
d
: 1.18 (t,
28.3 (d), 36.7 (t), 47.9 (d), 82.1 (d), 110.7 (t), 118.6 (t), 128.9 (d), 139.7
D
J¼7.2 Hz, 6H),1.25 (d, J¼7.2 Hz, 3H),1.78 (ddd, J¼14.4, 4.8, 2.4 Hz,1H),
1.86 (ddd, J¼14.4, 9.6, 2.4 Hz, 1H), 2.07 (ddd, J¼14.4, 7.2, 7.2 Hz, 1H),
2.68 (br d, J¼12.0 Hz, 6H), 2.78 (ddd, J¼14.4, 14.4, 4.2 Hz, 1H), 2.83
(dq, J¼7.2, 7.2 Hz, 1H), 3.339 (dq, J¼14.4, 7.2 Hz, 1H), 3.343 (dq,
J¼14.4, 7.2 Hz, 1H), 3.55 (dq, J¼14.4, 7.2 Hz, 2H), 4.15e4.17 (m, 1H),
4.91 (d, J¼10.8 Hz,1H), 4.96 (br s, 1H), 5.126 (d, J¼16.8 Hz, 1H), 5.132
(s, 1H), 5.26 (s, m), 5.73 (dd, J¼9.6, 4.8 Hz, 1H), 6.21 (dd, J¼16.8,
(s), 141.5 (d), 145.7 (s), 170.1 (s). IR (CHCl3): 3005, 1764, 1600 cmꢀ1
;
MS (EI) m/z: 204 (Mþ), 204 (100%); HRMS (EI) calcd for C13H16O2:
204.1150, found: 204.1151.
3.6.4. (ꢀ)-Xanthatin 329. To a solution of 67 (3.0 mg, 14.7
mmol) in
dry CH2Cl2 (3.0 mL) were added the second generation Hovey-
daeGrubbs catalyst 54 (0.9 mg, 1.5
m
mol), and freshly distilled
10.8 Hz,1H); 13C NMR (150 MHz, CDCl3)
d: 12.6 (q),14.2 (q), 20.3 (q),
methyl vinyl ketone (11.9 L, 147
m
mmol). The mixture was stirred
25.0 (t), 31.4 (d), 38.4 (t), 39.0 (t), 43.3 (t), 48.5 (d), 74.4 (d), 110.4 (t),
115.8 (t), 129.0 (d), 140.4 (d), 146.5 (s), 146.7 (s), 172.2 (s). IR (CHCl3):
2927, 1596, 1458 cmꢀ1; MS (FAB) m/z: 278 ([MþH]þ); HRMS (FAB)
calcd for C17H28NO2 ([MþH]þ): 278.2120, found: 278.2120.
at 45 ꢁC for 1 h. Upon completion, the mixture was evaporated,
and the residue was purified by column chromatography (30%
EtOAc/Hex) to give xanthatin (3) (3.0 mg, 83%) as colorless nee-
dles. Mp 112.1e113.1 ꢁC (Et2O/hexane); lit.8d mp 114.5e115.2 ꢁC
(EtOH); [
a
]
25 ꢀ20.0 (c 0.15, CHCl3); lit.8d
[
a
]
D ꢀ17.8 (c 0.14, CHCl3);
D
3.6.2. N,N-Diethyl-2-((1R,5S)-5-methyl-7-oxo-4-vinylcyclohept-3-
1H NMR (600 MHz, CDCl3)
d
: 1.17 (d, J¼7.8 Hz, 3H), 186 (ddd,
enyl)acrylamide 64. To a solution of 63 (7.1 mg, 25.6
CH2Cl2 (0.3 mL) were added NMO (15.0 mg, 128.0
molecular sieves 4 Å (12.8 mg) at room temperature. The mixture
was stirred for 10 min, and then TPAP (0.9 mg, 2.6 mol) was added.
mmol) in
J¼12.6, 12.6, 3.6 Hz, 1H), 2.22 (ddd, J¼12.6, 9.6, 3.6 Hz, 1H), 2.31 (s,
3H), 2.38 (ddd, J¼12.6, 4.2, 2.4 Hz, 1H), 2.53e2.58 (m, 1H), 2.80
(ddd, J¼16.2, 8.4, 2.4 Hz, 1H), 2.80e2.86 (m, 1H), 3.39e3.44 (m,
1H), 4.65 (ddd, J¼12.0, 8.4, 2.4 Hz, 1H), 3.09 (ddq, J¼8.4, 4.2,
4.2 Hz, 1H), 4.30 (ddd, J¼12.6, 9.6, 2.4 Hz, 1H), 5.49 (d, J¼3.0 Hz,
1H), 6.207 (d, J¼16.2 Hz, 1H), 6.212 (d, J¼3.0 Hz, 1H), 6.29 (dd,
J¼9.6, 2.4 Hz, 1H), 7.08 (d, J¼16.2 Hz, 1H); 13C NMR (150 MHz,
mmol) and
m
The mixture was stirred for 30 min. After filtration, the filtrate was
purified by silica gel column chromatography (40% AcOEt/Hex) to
20
give 64 as a colorless oil. [
a
]
þ11.6 (c 0.17, CHCl3); 1H NMR
D
(600 MHz, CDCl3)
d
: 1.15e1.17 (m, 9H), 2.43 (ddd, J¼15.6, 9.6, 4.2 Hz,
CDCl3) d: 18.9, 27.2, 27.9, 29.2, 36.6, 47.5, 81.5, 119.0, 124.7, 138.1,
1H), 2.61 (dd, J¼10.8, 5.4 Hz, 1H), 2.75e2.80 (m, 1H), 2.92e3.01 (m,
2H), 3.4 (br s, 3H), 3.47 (dd, J¼13.2, 4.2, 4.2 Hz, 1H), 3.52 (br s, 1H),
4.98 (d, J¼10.8 Hz, 1H), 5.13 (d, J¼17.4 Hz, 1H), 5.22 (s, 1H), 5.26 (d,
J¼1.2 Hz, 1H), 5.86 (dd, J¼9.6, 4.8 Hz, 1H), 6.20 (dd, J¼17.4, 10.8 Hz,
139.2, 144.8, 148.5, 169.7, 198.5. IR (KBr): 2927, 1760, 1685, 1587,
1402, 1353, 1247, 1178, 1137, 977 cmꢀ1; MS (EI) m/z: 246 (Mþ), 91
(100%); HRMS (EI) calcd for C15H18O3 (Mþ): 246.1256, found:
246.1258.
1H); 13C NMR (150 MHz, CDCl3)
d: 12.6 (q),14.2 (q), 20.0 (q), 27.6 (t),
31.2 (d), 38.8 (d), 43.0 (d), 47.3 (t), 57.1 (d), 111.8 (t), 115.3 (t), 128.4
(d), 139.7 (d), 142.9 (s), 144.6 (s), 170.3 (s), 210.3 (s). IR (CHCl3):
2999, 1703, 1610, 1461 cmꢀ1; MS (FAB) m/z: 276 ([MþH]þ); HRMS
(FAB) calcd for C17H26NO2 ([MþH]þ): 276.1964, found: 276.1966.
Acknowledgements
This research was partially supported by a Grant-in-Aid for Sci-
entific Research on (B) (19390007, 22390002) and the Program for
Promotion of Basic and Applied Research for Innovations in the Bio-
oriented Industry (BRAIN). K.M. additionally acknowledges the
support of the JSPS. We are also grateful to Ms. C. Moriya for
experimental contribution in the early stage of this project.
3.6.3. (3aR,7S,8aS)-7-Methyl-3-methylene-6-vinyl-3,3a,4,7,8,8a-
hexahydro-2H-cyclohepta[b] furan-2-one 67. To a solution of 64
(4.4 mg, 16.0
(18.9 L, 17.6 mmol). The resulting mixture was stirred for 0.5 h at
m
mol) in THF (0.3 mL) at 0 ꢁC was added DIBAL-H
m
room temperature, then cooled to 0 ꢁC, whereupon water was
added. The mixture was filtered and the filtrate was dried over
MgSO4. The crude product (a mixture of the diastereomers,
Supplementary data
65:63¼1:1.2) was used directly in the next step. Compound 65:
20
[
a
]
ꢀ141.7 (c 0.06, CHCl3); 1H NMR (600 MHz, CDCl3)
d
: 1.12 (d,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.08.061.
D
J¼7.8 Hz, 3H), 1.18 (t, J¼6.6 Hz, 6H), 1.59e1.61 (m, 1H), 2.14 (ddd,

K. Matsuo et al. / Tetrahedron 66 (2010) 8407e8419
8419
see: (c) Hashimoto, T.; Tashiro, T.; Sasaki, M.; Takikawa, H. Biosci. Biotechnol.
Biochem. 2007, 71, 2046e2051 (ꢀ)-diversifolide, see: (d) Matsuo, K.; Yokoe, H.;
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15. Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama, H.; Nakata,
M. Synlett 2000, 1306e1308.
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Ref. 15.
17. The keto group on 36 was inert to olefinations, such as the Wittig or the Pe-
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18. Garner, P.; Ramakanth, S. J. Org. Chem. 1987, 52, 2629e2631.
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