Total synthesis of marine sesquiterpenoid sinularianin b and 8-epi-sinularianin b

Article abstract of DOI:10.3987/COM-14-S(K)42

The enantioselective total synthesis of marine sesquiterpenoid sinularianin B, isolated from the Formosan soft coral Sinularia sp., has been accomplished in 16 steps based on a highly concise synthetic strategy. The synthesis features two highly stereoselective sulfone-mediated reactions, including a key tandem intermolecular-intramolecular alkylation developed in our laboratory, and a palladium-catalyzed desulfonylation of an allyl sulfone through ?-allyl palladium complex formation.

Full text of DOI:10.3987/COM-14-S(K)42

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HETEROCYCLES, Vol. 90, No. 1, 2015
HETEROCYCLES, Vol. 90, No. 1, 2015, pp. 442 - 461. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 26th June, 2014, Accepted, 29th July, 2014, Published online, 4th August, 2014
DOI: 10.3987/COM-14-S(K)42
TOTAL SYNTHESIS OF MARINE SESQUITERPENOID SINULARIANIN
B AND 8-EPI-SINULARIANIN B
Koichiro Ota and Hiroaki Miyaoka*
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan; E-mail: miyaokah@toyaku.ac.jp
Dedicated to Professor Dr. Isao Kuwajima on his 77th birthday
Abstract – The enantioselective total synthesis of marine sesquiterpenoid
sinularianin B, isolated from the Formosan soft coral Sinularia sp., has been
accomplished in 16 steps based on a highly concise synthetic strategy. The
synthesis features two highly stereoselective sulfone-mediated reactions, including
a key tandem intermolecular−intramolecular alkylation developed in our laboratory,
and a palladium-catalyzed desulfonylation of an allyl sulfone through -allyl
palladium complex formation.
INTRODUCTION
Sinularianin B (1) is a structurally unique valerenane sesquiterpenoid first isolated in 2006 from extracts of
the Formosan soft coral Sinularia sp. by Sheu and co-workers (Figure 1).1 The structure of this unique
tricyclic sesquiterpenoid was determined by detailed NMR spectroscopic analysis to comprise a highly
strained trans-5,6-fused ring appended to -spirolactone. Although the overall relative configuration of
sinularianin B was assigned on the basis of spectral analysis, the absolute configuration had not been
determined. Furthermore, sesquiterpenoids possessing a valerenane skeleton have been isolated mostly
from terrestrial plants, e.g. Valeriana officinalis,2 although one report has described the isolation of
valerenane sesquiterpenoid from soft coral.3 Recently, we were first to report on the asymmetric total
synthesis of sinularianin B (1) using our developed method involving sulfone-mediated highly
stereoselective tandem intermolecular−intramolecular alkylation. 4 In this paper, we wish to report on the
detailed synthesis of sinularianin B and 8-epi-sinularianin B.

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443
Figure 1. Structure of sinularianin B (1)
Our initial retrosynthetic analysis for the synthesis of sinularianin B (1) is outlined in Figure 2. We
envisioned that the trans-5,6-fused ring moiety should be constructed in the latter stages due to potential
isomerization of the double bond between C-5 and C-6 under both acidic and basic conditions. Therefore,
we set triene A for further elaboration toward 1. Triene A was expected to be generated from aldehyde B
through stepwise double alkylation at C-8. Aldehyde B could be generated from sulfonylcyclopentane C by
stereoselective palladium-mediated hydrogenolysis and oxidation. Key intermediate sulfonylcyclopentane
C would be constructed by our developed tandem intermolecular−intramolecular alkylation of epoxide D
and methallyl phenyl sulfone.5 Optically active epoxide D could be derived from known allylic alcohol 2.6
H
5
H
5
6
H
4
9
5
1
8
8
12
13
6
8
H
H
HO
CHO
O
PO
OH
H
HO
PO
14
14
B
O
1
A
PhO2S
3
4
3
1
3
9
9
1
X
OP
1
OP
MPMO
OH
9
O
8
H
HO
D
2
C
+
PhO2S
Figure 2. Retrosynthetic analysis of sinularianin B (1)
RESULTS AND DISCUSSION
The first stage involved construction of the sulfonylcyclopentane possessing a tertiary hydroxy group at
C-1 (sinularianin B numbering). The asymmetric synthesis of sulfonylcyclopentane 5 from epoxyiodide 4
and methallyl phenyl sulfone-mediated tandem intermolecular−intramolecular alkylation is shown in
Scheme 1. According to the known three-step procedure, 4-hydroxybutan-2-one was elaborated to allylic

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alcohol 2,6 which was then converted to epoxyalcohol 3 in 97% yield using Sharpless asymmetric
epoxidation under standard conditions.7 The optical purity of epoxyalcohol 3 was determined as >95% ee,
which was estimated from the 1H NMR spectra in the presence of chiral shift reagent “Chirabite-AR”.8 To
demonstrate the practical utility of Chirabite-AR, at first, synthetic racemic epoxyalcohol rac-3 was tested.
Prior to the comparison between synthetic (−)-epoxyalcohol 3 and rac-3 with Chirabite-AR, we examined
the effect of differing amounts of Chirabite-AR regarding rac-3, in an effort to determine sufficient signal
separations between (+)- and (−)-3. Consequently, a mixture of rac-3 with 75 mol% of Chirabite-AR was
1
measured sequentially by 400 MHz H NMR at 25 °C in CDCl3. The methine proton at C-9 signal
separations were observed between 3.32 to 3.14 ppm, and good enantiomeric discrimination was achieved
for (+)- and (−)-3. NMR analysis of (−)-epoxyalcohol 3 under the same conditions indicated that separated
signals exhibited >39/1 ratio in numerical integration value. Therefore, the optical purity of (−)-3 was
determined as >95 % ee. Epoxyiodide 4, required for the key tandem intermolecular−intramolecular
alkylation necessary for the construction of sulfonylcyclopentane 5, was obtained by protection of the
primary hydroxy group in chiral epoxyalcohol 3 with benzyl bromide, sodium hydride, and TBAI, selective
deprotection with DDQ, and iodination of the primary hydroxy group with I2, Ph3P and imidazole in 91%
yield for the three steps and in multigram quantities. The sulfonylcarbanion prepared from methallyl phenyl
n
sulfone (1.30 equiv.) and BuLi (1.25 equiv.) was treated with epoxyiodide 4 at −45 °C. Following
n
confirmation of the disappearance of the starting material by TLC, BuLi (2.00 equiv.) and Me3Al (1.50
equiv.) were added sequentially at −78 °C, and allowing the reaction mixture to warm to −55 °C cleanly
promoted 5-endo cyclization to give sulfonylcyclopentane 5 as the sole product in 99% yield.
Scheme 1
The relative configuration of sulfonylcyclopentane 5 was determined by NOESY analysis (Figure 3). The
trans-configuration of the isopropenyl and benzyloxymethyl groups in sulfonylcyclopentane 5 was
determined by NOE correlation between the -methylene proton at C-3 and the sp2-methine proton at the
ortho position of the phenylsulfonyl group, the -methylene proton at C-3 and the methine proton at C-9,

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445
the methylene protons at C-8 and the methyl protons at C-10, and the methine proton at C-9 and the methyl
protons at C-11.
Figure 3. Selected NOE correlations of sulfonylcyclopentane 5
The complete diastereoselectivity associated with the tandem intermolecular−intramolecular alkylation
was attributed to the stability of the transition state in the intramolecular alkylation from the
sulfonylcarbanion intermediate. The carbanion of methallyl phenyl sulfone reacted with epoxyiodide 4 to
form epoxysulfone 6, which is rapidly converted into corresponding sulfonylcarbanion 6a. Furthermore,
activation of the epoxide that followed the addition of Me3Al as a Lewis acid, shifted the equilibrium
between sulfonylcarbanions 6b and 6c. In the equilibrium state, intramolecular cyclization mostly
proceeded from sulfonylcarbanion 6c, as a result of transition state destabilization due to steric hindrance
between the phenylsulfonyl group and the benzyloxymethyl group in sulfonylcarbanion 6b. Consequently,
sulfonylcyclopentane 5 was generated by acidic workup of alkoxyaluminum anionic species 6d.
Figure 4. A plausible mechanism for the formation of sulfonylcyclopentane 5
We next focused on removal of the phenylsulfonyl group in sulfonylcyclopentane 5. We conceived a
9
hydrogenolysis approach via a -allyl palladium complex (Table 1). Initially, we applied NaBH4 or
LiBHEt310 as a standard hydride source for the palladium-mediated hydrogenolysis, however, the desired
cyclopentane 7 was not generated, and isomerization proceeded to the corresponding internal olefin 9
(entries 1 and 2). A solution to this problem was found by using in situ-generated ammonium formate as the
hydride source,11 where treatment of sulfonylcyclopentane 5 with triethylamine (8.0 equiv.), formic acid

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(8.0 equiv.), and PdCl2(dppp) (0.005 equiv.) in THF at rt facilitated regioselective hydrogenolysis and
provided cyclopentane 7 in 16% yield and 4-epimer 8 in 18% yield with low diastereoselectivity (entry 3).
After some optimization, optimal reaction conditions included a reagent combination comprising
Pd2(dba)3·CHCl3 (0.08 equiv.), nBu3P (0.20 equiv.), triethylamine (8.0 equiv.), and formic acid (8.0 equiv.)
in 1,4-dioxane (0.05 M) under reflux, and these conditions generated cyclopentane 7 in 91% yield with high
stereoselectivity at C-4 (>20 : 1 d.r.) (entry 8).
Table 1. Palladium catalyst screening in the desulfonylation of sulfonylcyclopentane 5
Pd cat.
phosphine
PhO2S
H
hydride source
4
4
4
+
OBn
OBn
OBn
solvent
H
H
H
HO
HO
HO
5
9
7 : -H
8 : -H
yield (%)
entry
Pd catalyst
equiv. phosphine hydride source
temperature
solvent
7
8
9
-
PdCl2(dppp)
PdCl2(dppp)
NaBH4
1
2
3
4
5
6
7
8
0.005
0.005
0.005
0.08
THF
THF
0
0
44
98
0
rt
-
LiBHEt3
0
rt
0
-
PdCl2(dppp)
Et3N, HCO2H
Et3N, HCO2H
Et3N, HCO2H
Et3N, HCO2H
Et3N, HCO2H
Et3N, HCO2H
THF
16
57
73
78
83
91
18
38
18
21
13
4
rt
nBu3P
nBu3P
nBu3P
nBu3P
nBu3P
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
THF
0
40 °C
reflux
40 °C
80 °C
reflux
0.08
THF
0
0.08
1,4-dioxane
1,4-dioxane
1,4-dioxane
0
0.08
0
0.08
0
The relative configurations of cyclopentane 7 were determined by NOE correlation between the methine
proton at C-4 and the methyl protons at C-10, the methylene protons at C-8 and the methyl protons at C-10,
and the methine proton at C-9 and the methyl protons at C-11 (Figure 5). Similarly, the relative
configurations of 4-epimer 8 were determined by NOE correlation between the methine proton at C-4 and
the methine proton at C-9, the methylene protons at C-8 and the methyl protons at C-10, and the methylene
protons at C-8 and the methyl protons at C-11.
Figure 5. Selected NOE correlations of cyclopentanes 7 and 8

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447
In order to account for the observed improvement in the reaction outcome, a possible mechanism of the
regio- and stereoselective hydrogenolysis has been outlined in Figure 6. In palladium-catalyzed
hydrogenolysis, it is well-established that the initial step in -allyl palladium complex formation involves
inversion of stereochemistry. The resulting -allyl palladium complex 10a rapidly rearranges to the -allyl
palladium formate 10b, and subsequently the single bond rotation, which was caused by the non-bonding
interactions between the oxygen atom and the cationic palladium species, generated 10c. Subsequent
migration of the hydride from the -allyl palladium formate on the more substituted end of the allylic
system afforded cyclopentane 7.
Figure 6. A plausible mechanism for desulfonylation following decarboxylation
As shown in Scheme 2, removal of the benzyl group in cyclopentane 7 with Na/liq.NH3 did not affect the
terminal olefin and proceeded smoothly to give the primary hydroxy group. Subsequent treatment of the
derived diol with IBX12 in DMSO/THF oxidized the primary alcohol to corresponding aldehyde 11 in 96%
yield for the two steps. Next, according to the synthetic plan, we introduced two different allylic groups at
C-8. Thus, zinc-mediated Barbier−Grignard type allylation13 of aldehyde 11 with 2-(bromomethyl)allyl
acetate in saturated NH4Cl aqueous/THF furnished corresponding diol 12 as diastereomeric mixtures.
Oxidation of diol 12 with IBX in DMSO/THF afforded the ,-unsaturated ketone in 87% yield for the two
steps. To the resulting ketone was introduced an allyl group using allyl magnesium bromide, giving triene
13 in 85% yield as a single diastereomer. Although it was not possible to determine the configuration of the
tertiary hydroxy group at C-8 in triene 13 at this stage, the presence of an opposite configuration to that of
the natural sinularianin B was determined by NOESY analysis at a later step. Oxidation of the allylic
hydroxy group in stereochemically-undefined triene 13 with manganese dioxide14 led to
-methylene--lactone 14 in quantitative yield. Isomerization with rhodium chloride trihydrate,15 and
ring-closing metathesis (RCM) of the resulting ,-unsaturated lactone gave tricyclic compound 15 in 30%

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yield for the two steps.
H
H
H
H
1) Na, liq.NH3,
THF, –78 °C
2-(bromomethyl)allyl acetate,
Zn (powder)
1) IBX, DMSO/THF, rt,
87% (2 steps)
8
8
OBn
2) IBX, DMSO/THF,
rt, 96% (2 steps)
8
sat.NH4Cl aq., THF, rt
2) allylmagnesium bromide,
Et2O, 0 °C, 85%
CHO
HO
H
H
HO
AcO
12
HO
HO
11
7
H
H
5
H
5
6
4
1) RhCl3·3H2O,
EtOH, reflux
9
MnO2
1
8
8
6
12
H
H
2) Grubbs 2nd catalyst,
toluene, rt,
30% (2 steps)
CH2Cl2, rt,
quant.
H
HO
HO
O
O
HO
13
HO
HO
14
14
14
O
O
14
13
8-epi-sinularianin B (15)
Scheme 2
Since the 1H- and 13C NMR data of synthetic 15 and the natural product did not match,1 the aforementioned
determination of the relative configuration at C-8 was performed at this stage as shown in Figure 7. The
relative configurations of 15 were determined by NOE correlation between the methine proton at C-4 and
the methyl protons at C-10, the methine proton at C-4 and the olefin proton at C-12, the-methylene proton
at C-7 and the olefin proton at C-12, the -methylene proton at C-7 and the methine proton at C-9, and the
methyl protons at C-10 and the olefin proton at C-12. Therefore, synthetic compound 15 was determined to
be 8-epi-sinularianin B.
Figure 7. Selected NOE correlations of 8-epi-sinularianin B (15)
Given the above results, a second synthetic attempt was performed whereby the order of introducing the
side chain was altered. Zinc-mediated Barbier−Grignard type allylation13 of aldehyde 11 with
3-bromoprop-1-ene in saturated NH4Cl aqueous/THF furnished the corresponding diol as diastereomeric
mixtures (Scheme 3). Subsequent treatment of the derived diol with IBX12 in DMSO/THF oxidized the
secondary alcohol to ,-unsaturated ketone 16 in 92% yield for the two steps. Although metal-mediated
allylation of ,-unsaturated ketone 16 with various hydroxy group protected allylic bromides (R = Bn,
MPM, THP, TBS) was negligible, ,-unsaturated ketone 16 underwent decomposition.

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449
Scheme 3
On the basis of this unsatisfactory result, an alternative strategy had to be implemented (Figure 8). We
envisaged that the -spirolactone moiety of sinularianin B (1) could be assembled from precursor E.
Construction of the cyclohexene ring of E from the O-silylated cyanohydrin F would involve sequential
RCM, conversion of the nitrile to the aldehyde, and deprotection. O-Silylated cyanohydrin F could be
generated from aldehyde 11 by cyanohydrin formation and stereoselective alkylation with allyl halide at
C-8.
Figure 8. Modified retrosynthetic analysis
As shown in Scheme 4, for the pivotal construction of the trans-5,6-fused ring, aldehyde 11 was treated
with TBSCN in the presence of a catalytic amount of bis(triphenylphosphoranylidene)ammonium chloride
(PNPCl).16 Following confirmation of the disappearance of 11 by TLC, TMSCN was added, which
promoted silylation of the bulky tertiary hydroxy group at C-1 to afford -siloxynitrile 18 as the
diastereomeric mixture at C-8. Initially, allylation of crude -siloxynitrile 18 with allyl bromide was
negligible given the steric bulkiness of the nucleophile. However, following extensive optimization, it was
found that generation of the carbanion of -siloxynitrile 18 with LDA in THF at 0 °C followed by cooling
to −78 °C and addition of allyl bromide premixed with HMPA gave -siloxynitrile 18 as an inseparable
diastereomeric mixture at C-8 and acceptable selectivity (5 : 1). After considerable optimization, RCM of a
mixture comprising -siloxynitrile 18 and C-8 epimer cleanly generated the trans-5,6-fused ring using
Grubbs 2nd generation catalyst,17 with high catalyst loading (10 mol%). Reduction of the cyano group with
DIBAH led to the -siloxyaldehyde. The reaction proceeded in good yields, based on careful monitoring of
the weak acidic workup conditions and a minimal excess of DIBAH. Interestingly, degradation of the C-8
epimer occurred concurrently with DIBAH reduction. Deprotection with TBAF/AcOH afforded

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-siloxyaldehyde 20 as a sole product in 67% yield for the five steps from 11. The desired R configuration
at C-8 of -siloxyaldehyde 20 was determined by single-crystal X-ray diffraction (Figure 9).
Scheme 4
Figure 9. ORTEP drawing of -siloxyaldehyde 20
The final critical step, involving assembly of sinularianin B (1), was executed via the ,-unsaturated
seven-membered lactone. -Siloxyaldehyde 20 was coupled with 2-(diethoxyphosphoryl)propanoic acid
using carbodiimide18 to give the phosphate as shown in Scheme 5. The resultant phosphate was utilized in
an intramolecular Horner-Wadsworth-Emmons reaction19 to give ,-unsaturated seven-membered lactone
21 in 78% yield for the two steps from 20. The last transformation was best achieved by one-pot
desilylation/methanolysis/re-lactonization methodologies, and where it was imperative to remove the TBS
group from lactone 21 with TBAF to generate -hydroxylactone. Following confirmation of the
disappearance of lactone 21 by TLC, treatment with K2CO3 in MeOH at 40 °C for 2 days cleanly promoted
methanolysis and rapid re-lactonization to give sinularianin B (1) as the sole product in 99% yield. The 1H
and 13C NMR spectroscopic data of synthetic 1 matched those reported for sinularianin B. Comparison of

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451
the specific optical rotation data {[]D −111 (c 1.55, CHCl3); lit.1 []D −27 (c 1.04, CHCl3)} enabled us to
establish the absolute configuration of natural sinularianin B as being identical to that of synthetic product 1.
Despite the discrepancy in magnitude, the match of all other data has confirmed that the constitution and
stereochemistry of sinularianin B (1) assigned by previously determined spectroscopic analyses are correct.
Scheme 5
In conclusion, a highly stereoselective total synthesis of sinularianin B (1) was accomplished by a concise
strategy. The procedure comprises 16 steps (longest linear sequence) with 39.5% yield starting from known
allylic alcohol 2. Furthermore, this work has unambiguously established the absolute configuration. Our
synthetic strategy can be highlighted by the use of sulfone-mediated tandem intermolecular−intramolecular
alkylation for construction of the cyclopentane core, palladium-catalyzed hydrogenolysis of allyl sulfone
through -allyl palladium complex formation, ring-closing metathesis to build the highly strained
trans-5,6-fused ring, and an intramolecular Horner-Wadsworth-Emmons reaction for conversion of the
seven-membered lactone into -spirolactone by an apparent acyl rearrangement.
EXPERIMENTAL
All reagents (Aldrich, Kanto, TCI and Wako) and solvents were of commercial quality and were used as
received. Reactions were monitored by thin layer chromatography on glass plates coated with a fluorescent
indicator with a 254 nm excitation wavelength (Merck Merck-5554-7). Flash column chromatography was
performed using Kanto Chemical Silica Gel 60N (spherical, natural) 40−50 m. Melting points (mp) were
measured using the Yanaco melting point apparatus MP-S3 and are uncorrected. Optical rotations were
measured with a JASCO P-1030 polarimeter. IR spectra were recorded with a JASCO FT-IR/620
spectrometer. UV spectra were recorded using a SHIMADZU UV-1200 spectrophotometer. Single crystal
1
13
X-ray diffraction was recorded using a MacScience Co., Ltd DIP 2020 Image Plate. H- and C NMR
spectra were recorded on a Bruker AVANCE III HD Nanobay or Bruker Biospin AV-600 spectrometer.
Chemical shifts are given on the  (ppm) scale using tetramethylsilane (TMS) as the internal standard (s,
singlet; d, doublet; t, triplet; q, quartet; quint., quintet; m, multiplet; br, broad). High resolution ESIMS

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HETEROCYCLES, Vol. 90, No. 1, 2015
(HRESIMS) spectra were obtained using a Micromass LCT spectrometer. Elemental analysis data were
obtained using an Elementar Vario EL.
((2R,3R)-3-(2-(4-Methoxybenzyloxy)ethyl)-3-methyloxiran-2-yl)methanol (3): To a cold (−20 °C)
suspension of 4Å molecular sieves (8.44 g) in CH2Cl2 (38.0 mL) were added D-(−)-DIPT (1.50 mL, 7.13
mmol), Ti(OiPr)4 (1.10 mL, 3.73 mmol) and TBHP (5.55 M solution in CH2Cl2, 38.6 mL, 214 mmol). After
stirring for 30 min at the same temperature, a solution of allylic alcohol 2 (16.9 g, 71.5 mmol) in CH2Cl2
(200 mL) was added over 10 h. After stirring at −20 °C for 2 h, NaOH (30% solution in brine, 3.25 mL) was
added. The mixture was diluted with Et2O, warmed to room temperature, and stirred for 10 min. MgSO4
(2.90 g) and Celite (0.35 g) were then added, and after stirring for 15 min the mixture was passed through a
pad of Celite and then concentrated in vacuo. The residue was purified with flash column chromatography
on silica gel (hexane/AcOEt = 1:1) to give epoxyalcohol 3 (17.5 g, 97% yield) as a colorless oil. Rf = 0.20
(hexane/AcOEt 1:1); []D25 +0.29 (c 1.06 in CHCl3); 1H NMR (400 MHz, CDCl3): 7.24 (d, J = 8.6 Hz,
2H), 6.87 (d, J = 8.6 Hz, 2H), 4.43 (d, J = 14.7 Hz, 1H), 4.40 (d, J = 14.7 Hz, 1H), 3.80 (m, 1H), 3.79 (s, 3H),
3.65 (m, 1H), 3.57−3.51 (m, 2H), 3.02 (dd, J = 4.4, 6.5 Hz, 1H), 2.15 (brs, 1H), 1.94 (ddd, J = 5.9, 6.0, 14.3
Hz, 1H), 1.78 (ddd, J = 6.6, 7.1, 14.3 Hz, 1H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3): 159.1 (s),
130.2 (s), 129.2 (d)×2, 113.8 (d)×2, 72.6 (t), 66.0 (t), 62.8 (d), 61.2 (t), 59.6 (s), 55.2 (q), 38.2 (t), 17.2 (q);
IR (neat): 3441, 2932 cm−1; HRMS (ESI): m/z calcd for C14H20O4+Na+: 275.1259 [M+Na+]; found:
275.1247; Anal. Calcd for C14H20O4: C 66.65, H 7.99; found: C 66.64, H 8.14.
Determination of optical purity of synthetic (−)-epoxyalcohol 3: Before comparison between synthetic
(−)-epoxyalcohol 3 and synthetic racemic epoxyalcohol rac-3 with Chirabite-AR, we examined the effect
of differing amounts of Chirabite-AR regarding rac-3, to determine sufficient signal separations between
(+)- and (−)-3. Consequently, a mixture of rac-3 with 75 mol% of Chirabite-AR was measured sequentially
1
by 400 MHz H NMR at 25 °C in CDCl3, the methine proton at C-9 signal separations were observed
between 3.32 to 3.14 ppm, and good enantiomeric discrimination was achieved for (+)- and (−)-3. NMR
analysis of (−)-epoxyalcohol 3 under the same conditions as used to obtain the results indicated that
separated signals exhibited >39/1 ratio in numerical integration value. Therefore, the optical purity of
synthetic (−)-3 was determined as >95 %ee.
(2R,3R)-3-Benzyloxymethyl-2-(2-iodoethyl)-2-methyloxirane (4): To a stirring solution of epoxyalcohol
3 (16.5 g, 65.4 mmol) in THF (109 mL) were added NaH (55%, 5.70 g, 432 mmol), BnBr (11.7 mL, 98.5
mmol) and TBAI (2.40 g, 6.50 mmol) at 0 °C and then allowed to warm to room temperature. After stirring
for 7 h, MeOH (10.0 mL) was slowly added at 0 °C. The mixture was then allowed to warm to room
temperature. After stirring for 1 h, the mixture was diluted with Et2O, washed with saturated aqueous
NaHCO3 solution, H2O and brine, and then concentrated in vacuo. The residue was passed through a pad of

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453
silica gel (hexane/AcOEt = 4:1) and then concentrated in vacuo to give a crude product.
To a stirring suspension of the crude product in CH2Cl2/saturated aqueous NaHCO3 solution (10:1, 127 mL)
were added DDQ (22.3 g, 98.2 mmol) over 10 min at room temperature. After stirring for 30 min, the
reaction mixture was diluted with Et2O, washed with saturated aqueous NH4Cl solution, H2O and brine,
dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was passed through a pad of
silica gel (hexane/AcOEt = 2:1) and then concentrated in vacuo to give a crude product.
To a cold (0 °C) solution of the crude product in CH2Cl2 (211 mL) were added Ph3P (19.9 g, 75.9 mmol),
imidazole (6.47 g, 95.0 mmol). After stirring for 5 min at the same temperature, I2 (19.4 g, 76.4 mmol) was
slowly added. The mixture was then allowed to warm to room temperature. After stirring for 10 min, the
solvent was removed in vacuo. The residue was passed through a pad of silica gel (hexane/Et2O = 6:1) and
then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel
(hexane/AcOEt = 9:1) to give epoxyiodide 4 (19.8 g, 91% yield for 3 steps) as a colorless oil. Rf = 0.60
(hexane/AcOEt 2:1); []D25 +7.19 (c 1.53 in CHCl3); 1H NMR (400 MHz, CDCl3): 7.37-7.30 (m, 5H),
4.64 (d, J = 11.9 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 3.75 (dd, J = 4.2, 11.3 Hz, 1H), 3.55 (dd, J = 6.2, 11.3
Hz, 1H), 3.20 (ddd, J = 5.3, 8.6, 9.2 Hz, 1H), 3.15 (ddd, J = 1.9, 7.7, 8.6 Hz, 1H), 3.10 (dd, J = 4.2, 6.2 Hz,
1H), 2.24 (ddd, J = 5.3, 8.6, 14.3 Hz, 1H), 2.04 (ddd, J = 7.7, 9.2, 14.3 Hz, 1H), 1.26 (s, 3H); 13C NMR (100
MHz, CDCl3): 137.8 (s), 128.4 (d)×2, 127.7 (d), 127.7 (d)×2, 73.2 (t), 68.5 (t), 61.1 (d), 60.1 (s), 42.2 (t),
16.2 (q), −1.2 (t); IR (neat): 2925, 2857 cm−1; HRMS (ESI): m/z calcd for C13H17IO2+H+: 333.0352
[M+H+]; found: 333.0335; Anal. Calcd for C13H17IO2: C 47.00, H 5.16; found: C 46.94, H 5.27.
(1R,2S,3R)-2-Benzyloxymethyl-1-methyl-3-phenylperoxythio-3-prop-1-en-2-ylcyclopentanol (5): To
a solution of methallyl phenyl sulfone (1.45 g, 7.39 mmol) in THF (24.0 mL) were added nBuLi (1.58 M
solution in hexane, 4.50 mL, 7.11 mmol) at −78 °C. After stirring for 30 min at the same temperature, a
solution of epoxyiodide 4 (1.89 g, 5.69 mmol) in THF (90.0 mL) was added and then allowed to warm to
−45 °C over 18 h. After cooling to −78 °C, nBuLi (1.58 M solution in hexane, 7.20 mL, 11.4 mmol). After
stirring for 15 min at the same temperature, Me3Al (1.07 M solution in hexane, 8.00 mL, 8.56 mmol) was
introduced and then allowed to warm to −55 °C. After stirring for 2.5 h, the reaction mixture was diluted
with Et2O, washed with saturated aqueous NH4Cl solution, 1.0 M aqueous HCl solution, H2O and brine,
dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt = 2:1) to give cyclopentane 5 (2.26 g, 99% yield) as a white
needle-like crystalline solid. Rf = 0.15 (hexane/AcOEt 2:1); mp 108−109 °C (recrystallized from
hexane/AcOEt); []D25 −45.7 (c 1.16 in CHCl3); 1H NMR (400 MHz, CDCl3): 7.73−7.72 (m, 2H), 7.59
(m, 1H), 7.47−7.44 (m, 2H), 7.36−7.29 (m, 5H), 4.99 (s, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.61 (s, 1H), 4.59 (d,
J = 11.6 Hz, 1H), 4.46 (dd, J = 4.8, 9.5 Hz, 1H), 4.41 (dd, J = 9.5, 11.4 Hz, 1H), 3.07 (brs, 1H), 2.75 (dd, J

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= 4.8, 11.4 Hz, 1H), 2.41 (dt, J = 6.4, 12.9 Hz, 1H), 1.98 (s, 3H), 1.92−1.81 (m, 2H), 1.71 (dt, J = 6.4, 12.9
Hz, 1H), 1.60 (s, 3H); NOE correlations (H/H): H-3 (H 2.41)/ortho-H (H 7.73), H-3 (H 2.41)/H-10 (H
1.60), H-3 (H 1.71)/H-9 (H 2.75), H-8 (H 4.46)/H-10 (H 1.60), H-8 (H 4.41)/H-11 (H 1.98), H-9 (H
13
2.75)/H-11 (H 1.98); C NMR (100 MHz, CDCl3): 142.2 (s), 137.8 (s), 136.0 (s), 133.5 (d), 130.3
(d)×2, 128.4 (d)×2, 128.0 (d)×2, 127.7 (d), 127.7 (d)×2, 118.1 (t), 80.4 (s), 77.5 (s), 73.6 (t), 68.8 (t), 57.9
(d), 38.0 (t), 31.4 (t), 22.9 (q), 20.8 (q); IR (KBr): 3363, 2975, 2931, 1291, 1135 cm−1; HRMS (ESI):
m/z calcd for C23H28O4S+Na+: 423.1606 [M+Na+]; found: 423.1591; Anal. Calcd for C23H27O4S: C 68.97,
H 7.05; found: C 69.17, H 7.00.
(1R,2S,3S)-2-(Benzyloxymethyl)-1-methyl-3-(prop-1-en-2-yl)cyclopentanol (7) and (1R,2S,3R)-2-
n
(benzyloxymethyl)-1-methyl-3-(prop-1-en-2-yl)cyclopentanol (8): Bu3P (0.82 mL, 3.28 mmol) was
added to a solution of Pd2(dba)3·CHCl3 (1.36 g, 1.31 mmol) in 1,4-dioxane (200 mL) at room temperature
and the mixture was stirred for 10 min. Et3N (18.3 mL, 131 mmol) and HCO2H (4.95 mL, 131 mmol) were
added to the mixture at the same temperature. After stirring for 10 min, the mixture was refluxed. Asolution
of cyclopentane 5 (6.56 g, 16.4 mmol) in 1,4-dioxane (128 mL) was added to the mixture and the mixture
was stirred for 15 min. The reaction mixture was concentrated in vacuo. The residue was purified with flash
column chromatography on silica gel (hexane/AcOEt = 5:1) to give trans-cyclopentane 7 (3.89 g, 91%
yield) as a colorless oil and cis-cyclopentane 8 (171 mg, 4% yield) as a colorless oil. trans-cyclopentane 7:
Rf = 0.40 (hexane/AcOEt 3:1); []D25 +31.9 (c 1.23 in CHCl3); 1H NMR (400 MHz, CDCl3): 7.37−7.29
(m, 5H), 4.68 (s, 1H), 4.68 (s, 1H), 4.52 (d, J = 11.8 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H), 3.55 (dd, J = 4.0, 9.4
Hz, 1H), 3.43 (t, J = 9.4 Hz, 1H), 2.85 (brs, 1H), 2.28−2.16 (m, 2H), 1.87−1.59 (m, 4H), 1.72 (s, 3H), 1.24
(s, 3H); 1H NMR (400 MHz, C6D6):  7.31−7.16 (m, 5H), 4.84 (s, 1H), 4.81 (s, 1H), 4.33 (d, J = 11.9 Hz,
1H), 4.26 (d, J = 11.9 Hz, 1H), 3.55 (dd, J = 4.4, 9.4 Hz, 1H), 3.38 (t, J = 9.4 Hz, 1H), 2.72 (brs, 1H), 2.40
(dt, J = 4.4, 10.7 Hz, 1H), 2.24 (dt, J = 10.7, 8.7 Hz, 1H), 2.05 (dt, J = 11.0, 7.4 Hz, 1H), 1.78−1.64 (m, 3H),
1.71 (s, 3H), 1.33 (s, 3H); NOE correlations (H/H): H-4 (H 2.24)/H-10 (H 1.33), H-8 (H 3.55 and
3.38)/H-10 (H 1.33), H-9 (H 2.40)/H-11 (H 1.71); 13C NMR (100 MHz, CDCl3): 146.7 (s), 138.0 (s),
128.4 (d)×2, 127.7 (d), 127.7 (d)×2, 110.5 (t), 80.1 (s), 73.5 (t), 70.8 (t), 51.5 (d), 47.6 (d), 39.4 (t), 27.2 (t),
23.5 (q), 18.7 (q); 13C NMR (100 MHz, C6D6): 147.2 (s), 138.6 (s), 128.6 (d)×2, 128.5 (d), 127.8 (d)×2,
110.6 (t), 80.0 (s), 73.5 (t), 70.9 (t), 52.5 (d), 48.4 (d), 40.4 (t), 27.8 (t), 24.1 (q), 18.8 (q); IR (neat):
3446, 2962, 2871, 1645, 1098 cm−1; HRMS (ESI): m/z calcd for C17H24O2+Na+: 283.1674 [M+Na+];
found: 283.1677; Anal. Calcd for C17H24O2: C 78.42, H 9.29; found: C 78.26, H 9.03. cis-cyclopentane 8:
Rf = 0.35 (hexane/AcOEt 3:1); []D25 −15.6 (c 1.27 in CHCl3); 1H NMR (400 MHz, CDCl3): 7.35−7.27
(m, 5H), 4.85 (s, 1H), 4.74 (s, 1H), 4.40 (s, 2H), 3.40 (dd, J = 3.4, 9.8 Hz, 1H), 3.26 (dd, J = 7.7, 9.8 Hz, 1H),
3.08 (dd, J = 8.2, 16.2 Hz, 1H), 2.15 (dt, J = 3.4, 7.7 Hz, 1H), 1.89−1.73 (m, 4H), 1.76 (s, 3H), 1.62 (m, 1H),

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1.41 (s, 3H); NOE correlations (H/H): H-4 (H 3.08)/H-9 (H 2.15), H-8 (H 3.40 and 3.26)/H-10 (H 1.41),
H-8 (H 3.40 and 3.26)/H-11 (H 1.76); 13C NMR (100 MHz, CDCl3): 145.7 (s), 138.5 (s), 128.3 (d)×2,
127.4 (d)×2, 127.4 (d), 110.5 (t), 81.9 (s), 73.2 (t), 68.7 (t), 52.7 (d), 47.0 (d), 39.3 (t), 26.3 (t), 25.5 (q), 23.7
(q); IR (neat): 3387, 2963, 2936, 2871, 1646, 1070 cm−1; HRMS (ESI): m/z calcd for C17H24O2+Na+:
283.1674 [M+Na+]; found: 283.1669; Anal. Calcd for C17H24O2: C 78.42, H 9.29; found: C 78.18, H 9.29.
(1R,2R,5S)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentanecarbaldehyde (11): A solution of
trans-cyclopentane 7 (2.63 g, 10.1 mmol) in THF (50.5 mL) was added to a pre-prepared Na (2.53 g, 110
mmol)/liquid ammonia (50.5 mL) at −78 °C. After stirring for 20 min, NH4Cl (10.1 g, 189 mmol) was
added to the mixture and excess NH3 was removed by warming. The reaction mixture was diluted with
Et2O, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The
residue was passed through a pad of silica gel (hexane/AcOEt = 3:2) and then concentrated in vacuo to give
a crude product.
To a solution of IBX (5.66 g, 20.2 mmol) in DMSO (50.5 mL) was added a solution of the above crude
product in THF (50.5 mL). After stirring for 2.5 h at room temperature, H2O was added to the mixture.
After diluting with Et2O, the mixture was filtered through celite, washed with H2O and brine, dried over
anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt = 2:1) to give aldehyde 11 (1.64 g, 96% yield for 2 steps) as a
colorless oil. Rf = 0.30 (hexane/AcOEt 2:1); []D25 −29.5 (c 1.27 in CHCl3); 1H NMR (400 MHz, CDCl3):
9.72 (d, J = 2.8 Hz, 1H), 4.74 (s, 1H), 4.73 (s, 1H), 2.99 (m, 1H), 2.75 (dd, J = 2.8, 9.8 Hz, 1H), 2.12 (brs,
1H), 1.95−1.67 (m, 4H), 1.72 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3): 203.7 (d), 145.7 (s),
110.5 (t), 81.3 (s), 65.8 (d), 45.7 (d), 41.9 (t), 28.0 (t), 25.3 (q), 20.3 (q); IR (neat): 3416, 2968, 1717,
1652, 1104 cm−1; HRMS (ESI): m/z calcd for C10H16O2+Na+: 191.1048 [M+Na+]; found: 191.1041; Anal.
Calcd for C10H16O2: C 71.39, H 9.59; found: C 71.49, H 9.50.
4-((1R,2R,5S)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)-2-methylene-4-oxobutyl acetate:
To a stirring solution of aldehyde 11 (22.7 mg, 0.135 mmol) in THF (1.4 mL) were added
2-(bromomethyl)allyl acetate (65.2 mg, 0.338 mmol), Zn powder (44.2 mg, 0.675 mmol) and saturated
aqueous NH4Cl solution (2.7 mL) at room temperature. After stirring for 2 h, H2O (1.4 mL) was slowly
added. After stirring for 30 min, the mixture was diluted with Et2O, passed through a pad of celite (Et2O).
The resulting solution was washed with H2O and brine, dried over anhydrous Na2SO4, and then
concentrated in vacuo to give a crude product.
To a solution of IBX (133 mg, 0.405 mmol) in DMSO (1.4 mL) was added a solution of the above crude
product in THF (1.4 mL). After stirring for 10 h at room temperature, H2O was added to the mixture. After
diluting with Et2O, the mixture was filtered through celite, washed with H2O and brine, dried over

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anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt = 3:1) to give ketone (32.9 mg, 87% yield for 2 steps) as a
colorless oil. Rf = 0.30 (hexane/AcOEt 3:1); []D25 −52.3 (c 1.17 in CHCl3); 1H NMR (400 MHz, CDCl3):
5.24 (s, 1H), 5.03 (s, 1H), 4.69 (s, 2H), 4.60 (d, J = 13.2 Hz, 1H), 4.52 (d, J = 13.2 Hz, 1H), 3.39 (d, J =
16.9 Hz, 1H), 3.25 (d, J = 16.9 Hz, 1H), 3.08 (d, J = 10.6 Hz, 1H), 2.98 (dd, J = 7.8, 16.2 Hz, 1H), 2.06 (s,
3H), 1.78−1.89 (m, 3H), 1.70 (s, 3H), 1.65 (m, 1H), 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3): 208.3,
170.8, 146.4, 137.2, 117.4, 110.2, 81.3, 66.6, 64.9, 49.2, 47.2, 42.2, 27.3, 25.2, 20.9, 20.1; IR (neat):
3481, 3080, 2964, 1737, 1652, 1237 cm−1; HRMS (ESI): m/z calcd for C16H24O4+H+: 281.1753
[M+H+]; found: 281.1748; Anal. Calcd for C16H24O4: C 68.54, H 8.63; found: C 68.32, H 8.61.
(R)-4-((1R,2R,5S)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)-2-methylenehept-6-ene-1,4-
diol (13): To a stirring solution of above ketone (32.9 mg, 0.117 mmol) in Et2O (2.3 mL) were added
allylmagnesium bromide (1.0 M solution in Et2O, 0.35 mL, 0.35 mmol) at 0 °C. After stirring for 30 min,
the mixture was diluted with Et2O, washed with saturated aqueous NH4Cl solution, H2O and brine, dried
over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt = 3:2) to give triol 13 (27.8 mg, 85% yield) as a white scaly
25
1
crystal. mp 103−104 °C; Rf = 0.25 (hexane/AcOEt 3:2); []D +38.4 (c 1.33 in CHCl3); H NMR (400
MHz, CDCl3): m, 1H), 5.19 (s, 1H), 5.15 (d, J = 10.3 Hz, 1H), 5.05 (d, J = 16.2 Hz, 1H), 4.89 (s,
1H), 4.78 (s, 1H), 4.73 (s, 1H), 4.14 (d, J = 12.3 Hz, 1H), 4.07 (d, J = 12.3 Hz, 1H), 3.92−4.02 (m, 3H), 2.74
(d, J = 13.6 Hz, 1H), 2.67 (m, 1H), 2.45 (m, 1H), 2.34 (d, J = 13.6 Hz, 1H), 2.28 (d, J = 11.6 Hz, 1H), 2.01
13
(dd, J = 8.1, 14.8 Hz, 1H), 1.51−1.81 (m, 4H), 1.72 (s, 3H), 1.48 (s, 3H); C NMR (100 MHz, CDCl3):
147.8, 144.8, 134.8, 118.6, 118.4, 112.1, 81.5, 75.6, 67.3, 53.6, 46.1, 43.6, 41.9, 40.8, 26.0, 25.0, 17.4;
IR (KBr): 3292, 3075, 2959, 1699, 1653 cm−1; HRMS (ESI): m/z calcd for C17H28O3+H+: 303.1936
[M+H+]; found: 303.1947; Anal. Calcd for C17H28O3: C 72.82, H 10.06; found: C 72.83, H 10.07.
(R)-5-Allyl-5-((1R,2R,5S)-2-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)-3-methylenedihydro-
furan-2(3H)-one (14): To a stirring solution of triol 13 (27.8 mg, 0.099 mmol) in CH2Cl2 (5.0 mL) was
added manganese dioxide (556 mg, 6.40 mmol) at room temperature. After stirring for 1 h, the mixture was
diluted with Et2O, passed through a pad of silica gel (hexane/AcOEt = 3:1), and then concentrated in vacuo.
The residue was purified with flash column chromatography on silica gel (hexane/AcOEt = 3:1) to give
-methylene-lactone 14 (27.4 mg, quantitative yield) as a colorless oil. Rf = 0.30 (hexane/AcOEt 3:1);
25
1
[]D +3.81 (c 0.93 in CHCl3); UV max (MeOH) nm (): 208 (8900, sh); H NMR (400 MHz, CDCl3):
t, J = 3.0 Hz, 1H), 5.74 (ddt, J = 9.2, 17.0, 7.0 Hz, 1H), 5.58 (t, J = 2.5 Hz, 1H), 5.15 (d, J = 9.2 Hz,
1H), 5.12 (d, J = 17.0 Hz, 1H), 4.75 (s, 1H), 4.70 (s, 1H), 3.05 (dt, J = 17.6, 3.1 Hz, 1H), 2.69 (dt, J = 17.6,
2.3 Hz, 1H), 2.45−2.62 (m, 3H), 2.42 (d, J = 10.2 Hz, 1H), 2.17 (brs, 1H), 1.77−1.89 (m, 2H), 1.75 (s, 3H),

HETEROCYCLES, Vol. 90, No. 1, 2015
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1.52−1.68 (m, 2H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3): 169.8, 148.3, 135.0, 131.5, 122.4, 120.7,
111.8, 86.9, 81.0, 56.2, 46.4, 45.4, 41.9, 34.6, 27.6, 24.9, 18.4; IR (neat): 3444, 3075, 2955, 1746, 1649,
1272 cm−1; HRMS (ESI): m/z calcd for C17H24O3+Na+: 299.1627 [M+Na+]; found: 299.1623; Anal. Calcd
for C17H24O3: C 73.88, H 8.75; found: C 73.78, H 8.74.
(2R,3'R,3a'R,7a'S)-3'-Hydroxy-3',4,7'-trimethyl-1',2',3',3a',5',7a'-hexahydro-5H-spiro[furan-2,4'-
inden]-5-one (8-epi-sinularianin B, 15): To a stirring solution of -methylene-lactone 14 (27.4 mg, 0.099
mmol) in EtOH (19.8 mL) was added rhodium chloride trihydrate (26.1 mg, 0.099 mmol) at room
temperature and then refluxed for 5 h. The mixture was cooled to room temperature, diluted with EtOH,
passed through a pad of silica gel (Et2O), and then concentrated in vacuo to give a crude product.
To a stirring solution of the above crude ,-unsaturated lactone in degassed toluene (19.8 mL) was added
Grubbs 2nd generation catalyst (17.0 mg, 0.020 mmol) at room temperature. After stirring for 12 h, the
reaction mixture was diluted with Et2O and the residue was passed through a pad of silica gel
(hexane/AcOEt = 12:1) and then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt = 2:1) to give 8-epi-sinularianin B (15) (7.4 mg, 30% yield
25
for 2 steps) as a colorless oil. Rf = 0.30 (hexane/AcOEt 2:1); []D −52.2 (c 0.24 in CHCl3); UV max
(MeOH) nm (): 213 (5400, sh); 1H NMR (400 MHz, CDCl3): d, J = 1.5 Hz, 1H), 5.23 (s, 1H),
2.81 (m, 1H), 2.46 (d, J = 13.1 Hz, 1H), 2.33 (m, 1H), 1.89−1.99 (m, 4H), 1.91 (d, J = 1.5 Hz, 3H), 1.71 (s,
3H), 1.70 (m, 1H), 1.51 (m, 1H), 1.06 (s, 3H); 13C NMR (100 MHz, CDCl3):
; IR (neat):
3435, 2963, 2925, 2849, 1747, 1645 cm−1; HRMS (ESI): m/z calcd for C15H20O3+Na+: 271.1310
[M+Na+]; found: 271.1317; Anal. Calcd for C15H20O3: C 72.55, H 8.12; found: C 72.26, H 8.13.
1-((1R,2R,5S)-2-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentyl)but-3-en-1-one (16): To a stirring
solution of aldehyde 11 (432 mg, 2.57 mmol) in THF (25.7 mL) were added 3-bromoprop-1-ene (777 mg,
6.42 mmol), Zn powder (841 mg, 12.9 mmol) and saturated aqueous NH4Cl solution (51.4 mL) at room
temperature. After stirring for 2 h, H2O (25.7 mL) was slowly added. After stirring for 30 min, the mixture
was diluted with Et2O, passed through a pad of celite (Et2O). The resulting solution was washed with H2O
and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude product.
To a solution of IBX (1.44 g, 5.14 mmol) in DMSO (12.9 mL) was added a solution of the above crude
product in THF (12.9 mL). After stirring for 3 h at room temperature, H2O was added to the mixture. After
diluting with Et2O, the mixture was filtered through celite, washed with H2O and brine, dried over
anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt = 2:1) to give ,-unsaturated ketone 16 (493 mg, 92% yield
for 2 steps) as a colorless oil. Rf = 0.25 (hexane/AcOEt 2:1); []D25 −65.5 (c 1.00 in CHCl3); 1H NMR (400

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MHz, CDCl3): 5.92 (dddd, J = 6.8, 7.0, 10.2, 17.2 Hz, 1H), 5.17 (d, J = 10.2 Hz, 1H), 5.12 (d, J = 17.2
Hz, 1H), 4.69 (s, 2H), 3.35 (dd, J = 6.8, 17.1 Hz, 1H), 3.23 (dd, J = 7.0, 17.1 Hz, 1H), 3.05 (d, J = 10.4 Hz,
1H), 2.98 (d, J = 7.8 Hz, 1H), 1.95 (brs, 1H), 1.70−1.89 (m, 3H), 1.62−1.71 (m, 1H), 1.69 (s, 3H), 1.18 (s,
3H); 13C NMR (100 MHz, CDCl3): 209.4, 146.4, 130.4, 118.8, 110.0, 81.3, 65.2, 49.4, 47.2, 42.3, 27.6,
25.5, 20.4; IR (neat): 3446, 3080, 1966, 1699, 1646 cm−1; HRMS (ESI): m/z calcd for C13H20O2+Na+:
231.1361 [M+Na+]; found: 231.1370; Anal. Calcd (%) for C13H20O2: C 74.96, H 9.68; found: C 75.23, H
9.80.
(3R,3aR,4R,7aS)-4-(tert-Butyldimethylsilyloxy)-3-hydroxy-3,7-dimethyl-2,3,3a,4,5,7a-hexahydro-
1H-indene-4-carbaldehyde (20): To a stirring solution of aldehyde 11 (121 mg, 0.718 mmol) in THF (109
mL) were added TBSCN (122 mg, 0.862 mmol), and PNPCl (41.3 mg, 0.0718 mmol) at room temperature.
After stirring for 2 h, TMSCN (0.14 mL, 1.12 mmol) was added at the same temperature. The mixture was
concentrated in vacuo, and the residue was passed through a pad of silica gel (hexane/AcOEt = 15:1) and
then concentrated in vacuo to give a crude TMS-protected cyanohydrin 18.
A solution of the above crude TMS-protected cyanohydrin 18 in THF (4.00 mL) was added to a
pre-prepared LDA (0.39 M solution in THF, 4.97 mL, 1.94 mmol) at −78 °C and then allowed to warm to
0 °C. After stirring for 40 min, the mixture was cooled to −78 °C, and then pre-mixed allyl bromide (0.31
mL, 3.59 mmol) and HMPA (0.31 mL, 1.80 mmol) was introduced to the mixture. After stirring for 15 min
at the same temperature, the reaction mixture was diluted with Et2O, washed with saturated aqueous NH4Cl
solution, H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was
passed through a pad of silica gel (hexane/AcOEt = 30:1) and then concentrated in vacuo to give a crude
diene 19.
To a stirring solution of the above crude diene 19 in degassed 1,2-dichloroethane (144 mL) was added
Grubbs 2nd generation catalyst (61.0 mg, 0.0718 mmol) at room temperature, and then refluxed. After
stirring for 6 h, cooled to room temperature, and then added DMSO (0.51 mL, 7.18 mmol). After stirring for
12 h, the solvent was removed in vacuo, the residue was diluted with Et2O and the residue was passed
through a pad of silica gel (hexane/AcOEt = 12:1) and then concentrated in vacuo to give a crude product.
To a stirring solution of the above crude product in toluene (14.4 mL) was added DIBAH (1.02 M solution
in hexane, 1.41 mL, 1.44 mmol) at −78 °C and then allowed to warm to 0 °C. After stirring for 30 min, the
mixture was cooled to −78 °C, and then Et2O (14.4 mL), saturated aqueous NH4Cl solution (7.18 mL), and
0.5 M aqueous H2SO4 solution (14.4 mL) were introduced to the mixture. The mixture was then allowed to
warm to room temperature and then the reaction mixture was diluted with Et2O, washed with saturated
aqueous NH4Cl solution, H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo.
The residue was passed through a pad of silica gel (hexane/AcOEt = 15:1) and then concentrated in vacuo

HETEROCYCLES, Vol. 90, No. 1, 2015
459
to give a crude product.
To a stirring solution of the above crude product in THF (7.18 mL) were added acetic acid (0.82 mL, 14.4
mmol) and TBAF (1.0 M solution in THF, 7.18 mL, 7.18 mmol) at room temperature, and then allowed to
warm to 40 °C. After stirring for 5 h, the reaction mixture was diluted with Et2O, washed with saturated
aqueous NaHCO3 solution, H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo.
The residue was purified with flash column chromatography on silica gel (hexane/AcOEt = 4:1) to give
-siloxyaldehyde 20 (156 mg, 67% yield for 5 steps) as a white needle-like crystalline solid. Rf = 0.60
(hexane/AcOEt 2:1); mp 77−78 °C (recrystallized from hexane/AcOEt); []D25 +9.70 (c 1.51 in CHCl3); 1H
NMR (400 MHz, CDCl3): 9.77 (s, 1H), 5.21 (s, 1H), 2.58 (m, 1H), 2.43 (m, 1H), 1.99 (d, J = 12.6 Hz,
1H), 1.96−1.73 (m, 4H), 1.69 (3H, s), 1.45 (m, 1H), 1.30 (s, 3H), 0.85 (s, 9H), 0.18 (s, 3H), 0.02 (s, 3H);13C
NMR (100 MHz, CDCl3): 204.0 (d), 137.4 (s), 116.5 (d), 81.3 (s), 78.4 (s), 58.9 (d), 41.5 (t), 39.8 (d),
35.3 (t), 27.9 (q), 25.8 (q)×3, 25.6 (t), 20.2 (q), 18.6 (s), −2.5 (q), −3.1 (q); IR (KBr): 3420, 2956, 2931,
2857, 1733, 1653 cm−1; HRMS (ESI): m/z calcd for C10H16O2+Na+: 347.2018 [M+Na+]; found: 347.2023;
Anal. Calcd for C18H32O3Si: C 66.62, H 9.94; found: C 66.54, H 9.90.
(4aS,4a1R,7aS,9aR)-4a-(tert-Butyldimethylsilyloxy)-3,7,9a-trimethyl-4a,5,7a,8,9,9a-hexahydro-
indeno[1,7-bc]oxepin-2(4a1H)-one (21): To a stirring solution of -siloxyaldehyde 20 (101 mg, 0.311
mmol) in CH2Cl2 (6.22 mL) were added 2-(diethoxyphosphoryl)propanoic acid (211 mg, 0.933 mmol), and
WSC (179 mg, 0.933 mmol) at room temperature. After stirring for 30 min, the mixture was diluted with
Et2O, washed with saturated aqueous NaHCO3 solution, H2O and brine, and then concentrated in vacuo.
The residue was passed through a pad of silica gel (hexane/AcOEt = 3:2) and then concentrated in vacuo to
give a crude product.
To a stirring solution of the above crude product in THF (62.4 mL) was added KOtBu (48.9 mg, 0.435
mmol) at room temperature and then allowed to warm to 60 °C. After stirring for 2 h, the mixture was
cooled to room temperature and then the reaction mixture was diluted with Et2O, washed with saturated
aqueous NH4Cl solution, H2O and brine, and then concentrated in vacuo. The residue was purified with
flash column chromatography on silica gel (hexane/AcOEt = 12:1) to give ,-unsaturated lactone 21 (88.1
mg, 78% yield for 2 steps) as a colorless oil. Rf = 0.35 (hexane/AcOEt 12:1); []D25 +162 (c 1.29 in CHCl3);
1H NMR (400 MHz, CDCl3): 6.20 (s, 1H), 5.14 (s, 1H), 2.46 (m, 1H), 2.31 (dd, J = 11.4, 13.8 Hz, 1H),
2.24 (m, 1H), 2.13 (m, 1H), 2.08 (d, J = 12.7 Hz, 1H), 2.05 (s, 3H), 1.96 (m, 1H), 1.86 (dt, J = 14.8, 8.8 Hz,
13
1H), 1.68 (s, 3H), 1.51 (s, 3H), 1.49 (m, 1H), 0.83 (s, 9H), 0.11 (s, 6H); C NMR (100 MHz, CDCl3):
167.9 (s), 140.7 (d), 137.0 (s), 127.7 (s), 117.7 (d), 85.8 (s), 73.1 (s), 58.7 (d), 41.3 (d), 41.1 (t), 40.7 (t),
26.5 (t), 25.7 (q)×3, 24.6 (q), 24.1 (q), 20.1 (q), 18.4 (s), −2.1 (q), −2.4 (q); IR (neat): 2957, 2930, 2857,
1698, 1684, 1254 cm−1; UV/Vis: max (MeOH)/nm 215sh ( /dm3 mol−1 cm−1 9100); HRMS (ESI): m/z

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calcd for C21H34O3Si+H+: 363.2355 [M+H+]; found: 363.2350; Anal. Calcd for C21H34O3Si: C 69.56, H
9.45; found: C 69.39, H 9.49.
Sinularianin B (1): To a stirring solution of ,-unsaturated lactone 21 (71.0 mg, 0.196 mmol) in THF
(1.96 mL) was added TBAF (1.0 M solution in THF, 0.49 mL, 0.490 mmol) at room temperature. After
stirring for 2 h, a suspension of 4Å molecular sieves (14.0 mg) and K2CO3 (271 mg, 1.96 mmol) in MeOH
(9.80 mL) was added and the mixture was warmed to 40 °C. After stirring for 36 h, the solvent was removed
in vacuo. The residue was passed through a pad of silica gel (Et2O) and then concentrated in vacuo. The
residue was purified with flash column chromatography on silica gel (hexane/AcOEt = 2:1) to give
sinularianin B (1) (48.0 mg, 99% yield) as a colorless oil. Rf = 0.15 (hexane/AcOEt 2:1); []D25 −111 (c 1.55
in CHCl3); 1H NMR (500 MHz, CDCl3): 7.16 (d, J = 1.5 Hz, 1H), 5.24 (dd, J = 1.9, 2.3 Hz, 1H), 2.57 (m,
1H), 2.53 (m, 1H), 1.98 (d, J = 12.8 Hz, 1H), 1.95−1.75 (m, 4H), 1.93 (d, J = 1.5 Hz, 3H), 1.71 (s, 3H), 1.47
(brs, 1H), 1.43 (m, 1H), 1.12 (s, 3H); 13C NMR (125 MHz, CDCl3): 173.7 (s), 152.2 (d), 137.3 (s), 129.1
(s), 117.2 (d), 85.4 (s), 78.4 (s), 56.6 (d), 41.8 (t), 40.9 (d), 39.7 (t), 26.0 (q), 25.3 (t), 20.2 (q), 10.6 (q); IR
(neat): 3445, 2962, 1734, 1658 cm−1; UV/Vis max (MeOH)/nm 213sh ( /dm3 mol−1 cm−1 9600);
HRMS (ESI): m/z calcd for C15H20O3+Na+: 271.1310 [M+Na+]; found: 271.1313; Anal. Calcd for
C15H20O3: C 72.55, H 8.12; found: C 72.37, H 7.93.
ACKNOWLEDGEMENT
The authors are grateful to Professor Jyh-Horng Sheu, National Sun Yat-sen University, for providing the
NMR spectra of sinularianin B.
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