Facile formation of tetrahydrofurans with multiple chiral centers using double iodoetherification of σ-symmetric diene acetals: short asymmetric total synthesis of rubrenolide and rubrynolide

Article abstract of DOI:10.1016/j.tet.2008.02.088

A novel double intramolecular iodoetherification of σ-symmetric diene acetals from (R,R)-hydrobenzoin occurred in highly diastereoselective manners to give tetrahydrofuran moieties with multiple chiral centers in a one-pot operation. The chemoselective di

Full text of DOI:10.1016/j.tet.2008.02.088

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4233e4245
www.elsevier.com/locate/tet
Facile formation of tetrahydrofurans with multiple chiral centers using
double iodoetherification of s-symmetric diene acetals: short
asymmetric total synthesis of rubrenolide and rubrynolide
y
*
Hiromichi Fujioka , Yusuke Ohba , Hideki Hirose, Kenji Nakahara,
*
y
Kenichi Murai , Yasuyuki Kita
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Received 22 January 2008; received in revised form 23 February 2008; accepted 26 February 2008
Available online 29 February 2008
Abstract
A novel double intramolecular iodoetherification of s-symmetric diene acetals from (R,R)-hydrobenzoin occurred in highly diastereoselec-
tive manners to give tetrahydrofuran moieties with multiple chiral centers in a one-pot operation. The chemoselective discrimination of the two
iodomethyl functions in the products was attained in various reactions. The reaction was applied to the concise asymmetric syntheses of
rubrenolide and rubrynolide, in which the unit from the chiral auxiliary worked as a template to achieve the chemoselectivity and as the protect-
ing group of the hydroxyl function.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Acyclic diene acetal; Intramolecular haloetherification; Asymmetric synthesis; Rubrenolide; Rubrynolide
1. Introduction
olefins of an acyclic s-symmetric diene with a chiral auxiliary
by asymmetric intramolecular halolactonization have already
been published,4 there is no domino-type reaction and chiral
auxiliaries are removed during the halolactonization by the
reported methods.
Tetrahydrofuran or g-lactone moieties with multiple chiral
centers are found in a large number of biologically active
natural products.1 Therefore, the methodology for synthesiz-
ing them in a concise manner is highly desirable.
We had recently developed a new asymmetric synthesis of
chiral non-racemic 1,4- and 1,5-diol by the intramolecular
haloetherification of ene acetals, prepared from ene aldehydes
and chiral hydrobenzoin (Eq. 1).2 As an extension of this reac-
tion, we next studied the reaction of s-symmetric diene acetals
from (R,R)-hydrobenzoin and found a novel double intramo-
lecular iodoetherification reaction to give tetrahydrofuran
moieties with multiple chiral centers. Furthermore, the unit
from the chiral auxiliary still remained in the products (Eq.
2).3 Although several reports on the discrimination of two
Ph
O
Ph
Ph
OH
*
O
*
RO
Ph
I+ , ROH
O
O
Nu1
O
Nu2
n
(1)
(2)
OH
(n = 1, 2)
I
Ph
Ph
Ph
O
double intramolecular
iodoetherification
H
Ph
O
O
O
(one-pot)
I
R'
R'
I
With our reaction, we can form four new asymmetric
centers in a single operation and the products still have the
unit from the chiral auxiliary. The reaction was then applied
to the concise asymmetric synthesis of rubrenolide hoping
that the unit from the chiral auxiliary worked as a template
* Corresponding authors. Tel.: þ81 6 6879 8225; fax: þ81 6 6879 8229.
E-mail addresses: fujioka@phs.osaka-u.ac.jp (H. Fujioka), kita@phs.
osaka-u.ac.jp (Y. Kita).
y
JSPS Research Fellow.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.088

4234
H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
to achieve the chemoselectivity in further transformations and
as the protecting group of the hydroxyl function. We have
quite recently communicated these results.3 We have now
studied the reaction in detail, and also succeeded in the asym-
metric synthesis of rubrynolide. We now present a full account
of our study on the double intramolecular iodoetherification of
the acyclic diene acetals and its application to the syntheses of
rubrenolide and rubrynolide (Fig. 1).
stereoisomers were obtained as a mixture in about 10% yield.
Even with the use of 0.5 equiv of NIS, only the two com-
pounds, the recovered 3c and 6c, were obtained (Scheme 2).
NIS (1.1 eqiv.)
MeOH (5 eqiv.)
no reaction
Ph
Ph
CH3CN
-40 °C~0 °C
O
O
Ph
O
H
O
Ph
O
O
O
NIS (1.1 eqiv.)
H2O (5 eqiv.)
O
O
OTMS
3c
8
8
HO
HO
I
TMSO
6c (61%)
CH3CN
-40 °C~0 °C
I
HO
HO
rubrenolide
rubrynolide
Scheme 2. Reaction of 3c with NIS in the presence of MeOH or H2O.
Figure 1. Structure of rubrenolide and rubrynolide.
2. Results and discussion
The structure of 6c was determined as follows. The rela-
tionship of the substituents on the five-membered ring was
determined by the NOE experiment between two protons, Ha
and Hb, and the Me group of the TMS function. The complete
structure of the product including the absolute configurations
of all of the asymmetric carbon centers was unambiguously
determined by X-ray analysis6 of the dimethyl compound 7
obtained by radical reduction using VA-0617 of 6c (Scheme 3).
The optimization of the reaction using H2O as a nucleophile
wasstudiedindetail.TheseresultsareshowninTable 1. NBSpro-
duced almost the same result as the one by NIS (entry 1). The
result in Scheme 2, a 61% yield of 6c, is shown in entry 2. The
use of a greater amount of NIS (2.5 equiv) increased the yield,
64% (entry 3). In entries 1e3, the concentration of the solution
is 0.1 M. A greater concentrated reaction mixture (0.5 M) gave
a better result, i.e., 73% of 6c (entry 4). However, the increase
in the concentration to 1.0 M resulted in the insolubility of NIS.
This novel reaction proved to be a general reaction.
Although the hydroxyl acetal 2 and acetoxy acetal 3a resulted
in decomposition, and the methoxy acetal 3a resulted in a low
yield (entries 1e3), various diene acetals 3cee, which have an
ether group next to the acetal function, and 5aec, which have
a hydrogen, a methyl, and a phenyl group, next to the acetal
function, respectively, afforded the double intramolecular
iodoetherification products 6ceh as major products in fair to
good yields (Table 2). The Rf values between the major stereo-
isomer and the mixture of other stereoisomers are different
2.1. Preparation of diene acetals
The chiral diene acetals (2 and 3) having oxygen functions
such as hydroxyl, ether, and ester groups were prepared as
follows: (1) the reaction of (R,R)-hydrobenzoin and dichloro-
acetic acid with the assist of NaH followed by the formation of
methyl ester producing 1; (2) the reaction of allylmagnesium
bromide to 1 leading to the hydroxy diene acetal 2; and (3)
protection of the tert-hydroxyl function of 2 by appropriate
methods producing compounds 3. The chiral diene acetals
5aec having a hydrogen, a phenyl, and a methyl substituent
were prepared by acetalization of the diallyl aldehyde 45
with (R,R)-hydrobenzoin (Scheme 1).
2.2. Intramolecular iodoetherification
We first studied the reactivity of substrate 3c by treatment
with NIS (1.1 equiv) and MeOH (5.0 equiv) in CH3CN at
ꢀ40 ꢁC to 0 ꢁC as we already established the conditions in
our previous reactions of the ene acetals.2 However, no reaction
occurred and the starting 3c was recovered. When the reaction
was done at rt, the product from the MeOH attack on the olefin
in an intermolecular fashion was obtained. We then changed
the nucleophile, MeOH, to H2O. The reaction smoothly pro-
ceeded to give 6c as the major product in a yield of 61%. Other
Cl
CO2H
1)
Ph
Ph
appropriate methods Ph
Ph
Cl
Ph
Ph
Ph
Ph
MgBr
NaH, THF
(see Experimental)
O
O
O
O
O
O
THF
(99%)
(51–99%)
HO
OH
2)
TMSCHN2
(2 steps, 85%)
CO2Me
OH
2
OR''
3a–e
1
a: R'' = Ac; b: R'' = Me;
c: R'' = TMS; d: R'' = TES;
e: R'' = TBS
Ph
O
Ph
Ph
Ph
CHO
R'
O
HO
OH
TMSOTf
TMSOMe
R'
5a-c
4a–c
(a: R' = H (83%); b: R' = Ph (54%); c: R' = Me (98%))
Scheme 1. Preparation of the various acyclic diene acetals.

H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4235
NOE
Ph
O
Ph
Hb
H
VA–061 (2 equiv.)
EPHP (20 equiv.)
O
O
Ha
Ph
Ph
O
O
O
NaHCO3 (20 equiv.)
I
H2O : EtOH = 1:1
TMSO
6c
TMSO
7 (97%)
I
80 °C, 1 h
VA–061 = 2,2'-azobis[2-(2-imidazolin-2-yl)propane]
EPHP = 1-ethylpiperidine hypophosphite
X-ray analysis of 7
Scheme 3. Radical reduction of 6c and the X-ray analysis of its reduced product 7.
from each other (ca. 0.1e0.2 on TLC using hexane/EtOAc as
a developing solvent) in every reaction. The isolation of the
major isomer as a pure product was easily conducted by usual
SiO2 column chromatography.
determined by the X-ray analysis of its reduction product 7
(see Scheme 4). The stereochemistries of 6feh were deter-
mined by their differential NOE spectra. Thus the presence
of NOE between the junctional substituents in each compound
showed their cis configuration. The NOEs between the acetal
proton and the benzyl proton and between the junctional sub-
stituent and the proton next to the iodomethyl group were also
observed in each compound. Furthermore, in the case of 6f, its
stereochemistry was unambiguously determined by converting
it to rubrenolide and rubrynolide as will be described later
(Fig. 2).
Stereochemistry of the major isomer in each reaction was
determined as follows. The stereochemistries of 6d,e were de-
1
termined by comparison of their H and 13C NMR data with
those of 6c, whose stereochemistry was unambiguously
Table 1
Optimization of the double iodoetherification using 3c
Ph
Ph
Ph
H
NXS
H2O (5.0 eqiv.)
O
2.3. Reaction mechanism
Ph
O
O
O
+ other isomers
O
CH3CN
X
A mechanistic rationale of the double intramolecular iodo-
etherification is shown in Scheme 5. The hemiacetal interme-
diate ii was obtained via the oxonium ion intermediate i, in
which another olefin is present at the proper position. The sec-
ond intramolecular iodoetherification then occurred to give 6
in good yields. The nucleophilic center of the intermediate i
is crowded. That is the reason why the larger MeOH than
H2O cannot react (see Scheme 2).
TMSO
6c (X = I)
–40 °C~0 °C
OTMS
I
3c
6'c (X = Br)
Entry
NXS
equiv
Concentration (M)
Yielda (%)
1
2
3
4
NBS
NIS
NIS
NIS
1.1
1.1
2.5
2.5
0.1
0.1
0.1
0.5
60
61
64
73
The occurrence of the second intramolecular iodoetherifica-
tion from the hemiacetal iv was unexpected, because the hemi-
acetal structure of the eight-membered ring usually opens to
give the hydroxy aldehyde. Thus the reaction of the ene acetal
8 produced the hydroxyl aldehyde 9 (unpublished result). That
is, the NIS treatment of the ene acetal 8 in the presence of H2O
afforded the hydroxyl aldehyde 9 in good yield possibly via
the oxonium ion iii and then the hemiacetal iv (Scheme 4).
The only difference between the diene acetals (2, 3, and 5)
and the ene acetal 8 is the presence or absence of one more
olefin, which plays an important role.
a
Yield of the isolated major diastereomer.
Table 2
Intramolecular iodoetherfication of the various diene acetals
Ph
Ph
Ph
H
O
NIS (2.5 eqiv.)
H2O (5.0 eqiv.)
Ph
O
O
O
O
+ other isomers
I
CH3CN
–40 °C~0 °C
R'
6
I
R'
Entry Diene acetal
Time (h) Total yield (%) dra
Major product
1
2
3
4
5
6
7
8
9
2 (R0¼OH)
d
d
12
Decomp.
Decomp.
d
d
3a (R0¼OAc)
3b (R0¼OMe)
2.4. Discrimination of two iodomethyl units and the
possibility for multi-substituted tetrahydrofurans
38
82
58
84
80
72
72
N.D.b
3c (R0¼OTMS) 1.5
8/1 6c
3d (R0¼OTES)
3e (R0¼OTBS)
5a (R0¼H)
3.5
3
11/1 6d
11/1 6e
3.5/1 6f
2/1 6g
Dreiding models and the X-ray structure of 7 showed that
compounds 6ceh have the conformations shown in Figure 3,
in which the spatial surrounding of the two iodomethyl func-
tions (a) and (b) is completely different. Namely, the iodo-
methyl group (b) bearing the eight-membered acetal ring is
less hindered than the iodomethyl group (a). We then
3
5b (R0¼Ph)
3
13
5c (R0¼Me)
1.5/1 6h
a
Major diastereomer/other diastereomers.
Not determined.
b

4236
H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
Ph
O
Ph
HO
Ph
Ph
Ph
Ph
I(coll)2Cl2
O
Br
(1.5 equiv.)
O
O
O
Br
O
HO
Br
Ph
H2O (5 equiv.)
O
Ph
H2O
O
CH2Cl2
-78 °C
9 (33% de)
iii
iv
8
Scheme 4. Intramolecular iodoetherification of the ene acetal 8 in the presence of H2O.
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
O
H
O
O
O
O
O
I
I
I
H
H
O
O
O
Ph
Me
nOe
nOe
nOe
I
I
I
6f
6g
6h
Figure 2. NOE study of compounds 6feh.
Ph
Ph
Ph
Ph
Ph
H
O
O
I
Ph
O
NIS (1.1 eqiv.)
H2O (5 eqiv.)
O
b
O
O
I
O
HO
a
Ph
via a
R'
O
O
Ph
I
R'
b
CH3CN
−40 °C~0 °C
R'
H2O
I
R'
6
i
ii
I+
3, 5
Scheme 5. Domino-type intramolecular iodoetherification of 3 and 5.
(b)
group (b), in good yield. The reaction of 6e and sodium ethyl
malonate9 also gave the product 11 in the same manner.
Furthermore, the deiodoetherification10 of 6e selectively
occurred on the side of iodine (b) to give 12 in good yield
(Scheme 6).
Less hindrance
(Highly reactive)
H
O
R
O
H
I
O
(a)
I
H
H
6
2.5. Application to total syntheses of natural products
Figure 3. Stereoview of 6.
As shown above, we succeeded in the remote asymmetric
induction of acyclic diene acetals and produced several types
of tetrahydrofuran or g-lactone equivalents with multiple chi-
ral centers in optically active forms. We also proved that the
reactivity of the two iodomethyl groups could be controlled
to selectively react at one position. We then applied the
method to the total syntheses of rubrenolide and rubrynolide.
considered that the chemoselective reactions on two positions
were possible.
We first examined the nucleophilic substitution reactions
using cyano or malonic ester anions. The reaction of 6c and
sodium cyanide8 gave the product 10, which was obtained
by the selective nucleophilic substitution on the iodomethyl
Ph
H
O
NaCN, DMSO
60 °C~70 °C for 6c
Ph
O
O
I
or
Ph
O
R''O
H
NaH, H2C(CO2Me)2
O
Nu
Ph
O
DMF : THF (5 : 1)
10 (88%, Nu = CN, R'' = TMS) from 6c
11 (73%, Nu = CH(CO2Me)2, R'' = TBS)
from 6e
80 °C for 6e
I
R''O
6c,e
I
Ph
H
O
Ph
OH
12 (73%) from 6e
O
Zn, Zn(OTf)2 for 6e
I
TBSO
Scheme 6. Regioselective reactions.

H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4237
replacement
First Plan
cleavage of C-O bond
Ph
by alkyl unit
Ph
O
Ph
Ph
O
O
H
H
O
O
R
O
Ph
Ph
O
I
HO
HO
rubrenolide (R =
O
O
O
OH
I
I
)
)
ent-13
I
7
7
ent-6f
ent-6a
rubrynolide (R =
conv. to OH
(from
(S,S)-hydrobenzoin)
Real Route
O
O
O
O
Ph
O
O
Ph
OH
-
I
1) R
rubrenolide
rubrynolide
I
O
O
,
6f
O
2) re-cyclization
(from
(R,R)-hydrobenzoin)
R
16
14
I
13
R =
7
7
Scheme 7. First plan and real route to the syntheses of rubrenolide and rubrynolide.
Rubrenolide and rubrynolidewere isolated from the trunk wood
of the Amazonian tree Nectandra rubra of the Lauraceae family.
They both have a remote asymmetric center in addition to a g-lac-
tone ring with two asymmetric centers. The only difference
between the two compounds is the kind of side chains (alkenyl
for rubrenolide and alkynyl for rubrynolide).11 Asymmetric
synthesis of rubrenolide had already been reported.12 On the other
hand, no report on the synthesis of rubrynolide has appeared.
We planned their syntheses from a single intermediate. Our
retro-synthetic analysis and abstract of real route are shown in
Scheme 7. First, we considered that the lactone ent-13, which
would be derived from ent-6f obtained by the intramolecular
etherification of the diene acetal with (S,S)-hydrobenzoin,
would be the key intermediate, and elongation of the alkenyl
or alkynyl unit from the iodo methyl group and conversion
of iodine to the hydroxyl group would give two natural
products (first plan). However, in fact, we found a novel and
easy recyclization of lactone iodide obtained by nucleophilic
oxiran ring opening of the epoxy lactone iodide 14 to give
the lactone epoxides 16, which were converted into natural
products (real route, vide infra). Compound 6f from the
(R,R)-hydrobenzoin was then used for the syntheses of the
two natural products.
hydroxyl lactone was rather labile. The hydroxyl lactone was
treated with Ag2O15 and the more stable epoxy lactone 14 was
obtained in good yield (86%).
Ph
Ph
Ph
H
NIS (2.5 eqiv.)
H2O (5.0 eqiv.)
O
Ph
O
+ other stereo-isomers
(18%)
O
O
O
(Table 1,
entry 7)
I
H
I
5a
6f (62%)
Ph
O
Ph
OH
O
Ph
OH
O
Ph
DDQ
CH3CN–H2O
I
I
6f
O
NaClO2
Ag2O
O
OH
I
I
13 (2 steps, 84%)
O
O
O
CAN
O
I
I
CH3CN–H2O
OH
O
14 (86%)
I
Scheme 8. Asymmetric synthesis of the key intermediate 14.
2.5.2. Completion of the syntheses of rubrenolide
and rubrynolide
Completion of the syntheses from 14 was achieved as
shown in Scheme 9. For the synthesis of rubrenolide, the intro-
duction of the alkenyl side chain was next studied. That is, the
reaction of 14 with Grignard reagent16 from 8-nonenyl
bromide in the presence of a catalytic amount of CuI afforded
the hydroxyl lactone iodide 15, which, to our surprise, tended
to give the epoxide 16a by recyclization. The treatment of the
hydroxyl lactone with K2CO3 then gave the more stable epoxy
lactone 16a in good yield. Opening of the epoxy ring of 16a
2.5.1. Synthesis of the key intermediate 14
Syntheses of both rubrenolide and rubrynolide were
achieved from the same intermediate 14. The synthesis of
the key intermediate 14 is shown in Scheme 8. Although the
intramolecular iodoetherification of the diene acetal 5a
produced a 62% yield of 6f and an 18% yield of the mixture
of other stereoisomers, 6f was easily purified by SiO2 column
chromatography (hexane/AcOEt¼20/1). The hydrolysis of 6f
by DDQ treatment13 afforded the lactol, which was oxidized
by NaClO2 to give the lactone 13. The removal of the hydro-
benzoin unit by the usual methods, such as hydrogenation and
Birch reduction, afforded unsuccessful results possibly due to
the presence of iodines. This conversion was attained by a new
method using CAN that was recently developed by us.14 Thus
the treatment of 13 with CAN (2.0 equiv) in CH3CN/H2O (1/
1) removed the hydrobenzoin unit in high yield. The obtained
17
with Bi(OTf)3 catalyst promoted nucleophilic replacement
of water at the primary carbon to give (þ)-rubrenolide ([a]D25
þ20.5 (c 0.29, CHCl3)) in good yield. The authentic rubreno-
lide was obtained by separation of the mixture of rubrenolide
and rubrynolide, which was a generous gift from Prof. B. Zwa-
nenburg and Dr. L. Thijs, according to Ref. 12b. The physical
1
data, [a]D, H NMR, 13C NMR, and IR, of the synthesized
(þ)-rubrenolide showed good agreement with the authentic
one ([a]2D2 þ22 (CHCl3) in Ref. 11c). Total yield of

4238
H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
O
O
O
O
O
RMgBr
CuI
O
K2CO3
AcOEt
I
I
OH
O
O
R
R
14
15a,b
16a: 63%, R =
TMS
7
16b: 55%, R =
7
O
Bi(OTf)3
CH3CN–H2O
O
R
O
O
R
HO
TBAF
treatment for
rubrynolide
O
HO
rubrenolide (73%, R =
rubrynolide (70%, R =
)
7
)
7
Scheme 9. Asymmetric total synthesis of rubrenolide and rubrynolide.
(þ)-rubrenolide from the commercially available compound
4a is 17.1% in nine steps. Since we clarified the reactivity
of 14, 15a, and 16a and succeeded in the total synthesis of
(þ)-rubrenolide, we next tried the synthesis of rubrynolide.
In this case, 8-nonynyl bromide was used in place of the 8-
nonenyl bromide and the corresponding alkynyl Grignard
reagent was prepared.18 Introduction of the side chain fol-
lowed by alkaline treatment afforded the epoxy lactone 16b.
The treatment of 16b with Bi(OTf)3 and TBAF produced the
rubrynolide ([a]2D4.5 þ21.0 (c 0.23, CHCl3)). The authentic
rubrynolide was obtained by separation of the mixture of rubre-
nolide and rubrynolide as described above. The physical data,
[a]D, 1H NMR, 13C NMR, and IR, of the synthesized (þ)-rubry-
nolide showed good agreement with the authentic one ([a]D22
þ21 (CHCl3) in Ref. 11c). Total yield of (þ)-rubrynolide
from commercially available compound 4a is 12.9% in 10 steps.
E. Merck pre-coated TLC plates, silica gel F254, for prepara-
tive thin-layer chromatography were used.
4.2. (4R,5R)-4,5-Diphenyl-2-methoxycarbonyl-1,3-
dioxolane (1)
A solution of (R,R)-hydrobenzoin (15.0 g, 0.07 mol) in THF
(100 mL) was added dropwise to a suspension of NaH (60% dis-
persion in mineral oiland washed with Et2O, 6.16 g, 0.24 mol)in
THF (40 mL) at 0 ꢁC under N2. The mixture was stirred for
30 min at the same temperature. Cl2CHCO2H (5.8 mL,
0.07 mol) was added dropwise to the solution at 0 ꢁC and the
resulting mixture was refluxed for 3 h. HCl (10%) aqueous solu-
tion was added to the solution at 0 ꢁC. The mixturewas extracted
with AcOEt. Organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. Purification of the residue
by SiO2 column chromatography (AcOEt as an eluent) gave
the carboxylic acid (16 g, 0.059 mol, 85%), whose structure
3. Conclusion
1
1
was determined by H NMR. H NMR (300 MHz, CDCl3) d:
4.78 (1H, d, J¼8.4 Hz), 5.03 (1H, d, J¼8.4 Hz), 5.81 (1H, s),
7.23e7.32 (10H, m). 13C NMR (67.8 MHz, CDCl3) d: 85.6,
86.7, 98.7, 126.6, 126.9, 128.5, 128.5, 134.7, 134.9, 174.1.
TMSCHN2 (2.0 M in hexane, 3.6 mL, 7.20 mmol) was added
dropwise to a solution of the above carboxylic acid (1.5 g,
5.60 mmol) in MeOH/benzene (v/v¼1/5, 60 mL) and the
mixture was stirred for 30 min at rt. The solvent was evaporated
in vacuo. Purification of the residue by SiO2 column chromatog-
raphy (hexane/AcOEt¼5/1 as an eluent) gave 1 (1.54 g,
5.50 mmol, 99%). Colorless crystals: mp 33.0e33.5 ꢁC. [a]D24.1
We have developed the unprecedented double intramolecu-
lar haloetherifications of the s-symmetric diene acetals. The
reactions proceeded in highly diastereoselective manner to
give the tetrahydrofuran units with multiple chiral centers in
a one-pot operation. The chemoselective discrimination of
the two iodomethyl functions in the products was attained in
various reactions. The reaction was applied to the short asym-
metric syntheses of (þ)-rubrenolide and (þ)-rubrynolide.
Tetrahydrofuran moieties with multiple chiral centers are
found in a large number of biologically active natural prod-
ucts. This method would then provide a useful tool to synthe-
size them in an enantiomeric form. Further extension of this
reaction is currently in progress in our laboratory.
1
þ51.4 (c 1.12, CHCl3). IR (KBr): 1755, 912, 743 cmꢀ1. H
NMR (300 MHz, CDCl3) d: 3.88 (3H, s), 4.76 (1H, d,
J¼8.4 Hz), 5.06 (1H, d, J¼8.4 Hz), 5.79 (1H, s), 7.21e7.33
(10H, m). 13C NMR (67.8 MHz, CDCl3) d: 52.5, 85.5, 86.6,
98.9, 126.6, 127.0, 128.4, 128.5, 135.0, 135.3, 168.9. Anal.
Calcd for C17H16O4: C, 71.82; H, 5.67. Found: C, 71.87; H, 5.73.
4. Experimental
4.1. General
4.3. (4R,5R)-2-(1-Allyl-1-hydroxy-3-butenyl)-4,5-diphenyl-
1,3-dioxolane (2)
The 1H NMR spectra were measured by 300 MHz or
270 MHz spectrometer with tetramethylsilane as the internal
standard at 20e25 ꢁC. IR spectra were recorded by a diffuse
reflectance measurement of samples dispersed in KBr powder.
E. Merck silica gel 60 for column chromatography and
Allylmagnesium bromide (1.0 M in hexane, 69 mL,
69 mmol) was added dropwise to a solution of 1 (3.90 g,
13.7 mmol) in THF (140 mL) at 0 ꢁC under N2. The mixture

H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4239
was stirred for 2 h at the same temperature. Satd NH4Cl aqueous
4.6. (4R,5R)-2-(1-Allyl-1-trimethylsilyloxy-3-butenyl)-4,5-
diphenyl-1,3-dioxolane (3c)
solution was added to the solution at 0 ꢁC. The mixture was
extracted with AcOEt. Organic layer was washed with brine,
dried over Na2SO4, and evaporated in vacuo. Purification of the
residue by SiO2 column chromatography (CH2Cl2 as an eluent)
gave 2 (4.60 g, 13.6 mmol, 99%). Colorless oil: [a]2D4.1 þ32.2
Et3N (0.22 mL, 1.60 mmol) and TMSCl (0.10 mL,
0.80 mmol) were added dropwise to a solution of 2 (147 mg,
0.40 mmol) and DMAP (4 mg, 0.040 mmol) in CH2Cl2
(0.8 mL) at 0 ꢁC under N2. The mixture was stirred for 12 h at
rt. Satd NaHCO3 aqueous solution was added to the solution at
0 ꢁC. The mixture was extracted with AcOEt. Organic layer
was washed with brine, dried over Na2SO4, and evaporated in
vacuo. Purification of the residue by SiO2 column chromatogra-
phy (hexane/AcOEt¼10/1 as an eluent) gave 3c (162 mg,
0.40 mmol, 99%). Colorless oil: [a]2D5.9 þ16.2 (c 1.04, CHCl3).
1
(c 1.06, CHCl3). IR (KBr): 3562, 912, 743 cmꢀ1. H NMR
(300 MHz, CDCl3) d: 2.10 (1H, s), 2.49e2.55 (4H, m), 4.78
(2H, s), 5.17e5.23 (4H, m), 5.38 (1H, s), 5.94e6.08 (2H, m),
7.19e7.36 (10H, m). 13C NMR (67.8 MHz, CDCl3) d: 39.4,
39.8, 74.4, 85.2, 87.0, 106.7, 118.6, 126.2, 126.7, 128.1, 128.4,
128.5, 128.5, 133.0, 135.9, 137.8. Anal. Calcd for C22H16O4:
C, 78.54; H, 7.19. Found: C, 78.44; H, 7.36.
1
IR (KBr): 1248, 912, 743 cmꢀ1. H NMR (300 MHz, CDCl3)
4.4. (4R,5R)-2-(1-Allyl-1-acetyloxy-3-butenyl)-4,5-diphenyl-
1,3-dioxolane (3a)
d: 0.15 (9H, s), 2.47e2.56 (4H, m), 4.67 (2H, s), 5.07e5.17
(4H, m), 5.32 (1H, s), 5.88e6.07 (2H, m), 7.16e7.31 (10H,
m). 13C NMR (67.8 MHz, CDCl3) d: 2.8 (3C), 40.3, 40.3, 78.5,
85.2, 86.9, 107.0, 117.5, 117.6, 126.3, 126.7, 128.0, 128.4,
134.1, 136.2, 138.1. Anal. Calcd for C25H32O3Si: C, 73.49; H,
7.89. Found: C, 73.66; H, 7.97.
Ac2O (0.14 mL, 14.3 mmol) was added dropwise to a
solution of 2 (100 mg, 0.30 mmol) and DMAP (3 mg,
0.030 mmol) in pyridine (0.3 mL) at 0 ꢁC under N2. The
mixture was stirred for 12 h at rt. The solvent was evaporated
in vacuo. Purification of the residue by SiO2 column chroma-
tography (hexane/AcOEt¼5/1 as an eluent) gave 3a (57 mg,
0.15 mmol, 51%). Colorless oil: [a]2D6.4 þ26.3 (c 1.09,
4.7. (4R,5R)-2-(1-Allyl-1-triethylsilyloxy-3-butenyl)-4,5-
diphenyl-1,3-dioxolane (3d)
CHCl3). IR (KBr): 1738, 912, 743 cmꢀ1
.
1H NMR
TESOTf (1.68 mL, 7.40 mmol) was added dropwise to a
(300 MHz, CDCl3) d: 2.06 (3H, s), 2.86e2.99 (4H, m), 4.70
(1H, A in ABq, J¼8.4 Hz), 4.75 (1H, B in ABq, J¼8.4 Hz),
5.10e5.21 (4H, m), 5.81 (1H, s), 5.93e6.06 (2H, m), 7.19e
7.36 (10H, m). 13C NMR (67.8 MHz, CDCl3) d: 22.2, 37.7,
37.8, 84.9, 85.0, 87.0, 105.2, 118.0, 118.2, 126.3, 126.7,
128.1, 128.5, 133.0, 133.0, 135.7, 137.7, 170.0. LRMS
(FAB) m/z 379 (MHþ). HRMS (FAB) Calcd for C24H27O4:
379.1909. Found: 379.1901.
solution of
2
(500 mg, 1.50 mmol) and 2,6-lutidine
(1.73 mL, 14.9 mmol) in CH2Cl2 (1.5 mL) at 0 ꢁC under N2.
The mixture was allowed to gradually warm to rt. Satd
NaHCO3 aqueous solution was added to the solution at 0 ꢁC.
The mixture was extracted with AcOEt. Organic layer was
washed with brine, dried over Na2SO4, and evaporated in
vacuo. Purification of the residue by SiO2 column chromatog-
raphy (hexane/AcOEt¼50/1 as an eluent) gave 3d (636 mg,
1.40 mmol, 93%). Colorless oil: [a]2D5.6 þ4.9 (c 1.12,
4.5. (4R,5R)-2-(1-Allyl-1-methoxy-3-butenyl)-4,5-diphenyl-
1,3-dioxolane (3b)
CHCl3). IR (KBr): 1240, 912 cmꢀ1 1H NMR (300 MHz,
.
CDCl3) d: 0.59 (6H, q, J¼8.4 Hz), 0.88 (9H, t, J¼8.4 Hz),
2.43e2.45 (4H, m), 4.57 (1H, d, J¼8.4 Hz), 4.61 (1H, d,
J¼8.4 Hz), 5.01e5.11 (4H, m), 5.27 (1H, s), 5.92e5.94 (2H,
m), 7.10e7.27 (10H, m). 13C NMR (67.8 MHz, CDCl3) d:
7.0 (3C), 7.3 (3C), 40.7, 40.7, 78.0, 85.0, 86.9, 107.2, 117.4,
117.5, 126.3, 126.7, 127.9, 128.3, 134.3, 136.2, 138.2. Anal.
Calcd for C28H38O3Si: C, 74.62; H, 8.50. Found: C, 74.45;
H, 8.56.
A solution of 2 (100 mg, 0.30 mmol) in THF (0.30 mL) was
added dropwise to a suspension of NaH (60% dispersion in
mineral oil and washed with Et2O, 22 mg, 0.55 mmol) in
THF (0.3 mL) at 0 ꢁC under N2. The mixture was stirred for
30 min at the same temperature. MeI (0.034 mL, 0.55 mmol)
was added dropwise to the solution at 0 ꢁC and the resulting
mixture was stirred for 7 h at rt. Satd NH4Cl aqueous solution
was added to the solution at 0 ꢁC. The mixture was extracted
with AcOEt. Organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. Purification of the residue
by SiO2 column chromatography (hexane/AcOEt¼20/1 as an
eluent) gave 3b (104 mg, 0.30 mmol, 100%). Colorless oil:
4.8. (4R,5R)-2-[1-Allyl-1-tert-butyldimethylsilyloxy-3-
butenyl]-4,5-diphenyl-1,3-dioxolane (3e)
TBSOTf (1.71 mL, 7.40 mmol) was added dropwise to a solu-
tion of 2 (500 mg, 1.50 mmol) and 2,6-lutidine (1.73 mL,
14.9 mmol) in CH2Cl2 (1.5 mL) at 0 ꢁC under N2. The mixture
was allowed to gradually warm to rt and stirred for 12 h at the
same temperature. Satd NaHCO3 aqueous solution was added
to the solution at 0 ꢁC. The mixture was extracted with AcOEt.
Organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo. Purification of the residue by SiO2 column
chromatography (hexane/AcOEt¼50/1 as an eluent) gave
3e (615 mg, 1.40 mmol, 90%). Colorless oil: [a]2D5.7 ꢀ13.8
[a]D25.7 þ18.6 (c 1.12, CHCl3). IR (KBr): 1084, 912 cmꢀ1
.
1H NMR (300 MHz, CDCl3) d: 2.53e2.70 (4H, m), 3.49
(3H, s), 4.70 (1H, d, J¼8.4 Hz), 4.72 (1H, d, J¼8.4 Hz),
5.12e5.23 (4H, m), 5.43 (1H, s), 5.97e6.08 (2H, m),
7.18e7.36 (10H, m). 13C NMR (67.8 MHz, CDCl3) d: 36.7,
36.8, 51.5, 78.7, 84.7, 86.9, 107.1, 117.7, 126.2, 126.8,
128.0, 128.4, 133.6, 136.1, 138.3. Anal. Calcd for C23H26O3:
C, 78.83; H, 7.48. Found: C, 78.75; H, 7.59.

4240
H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
(c 0.50, CHCl3). IR (KBr): 1252, 912 cmꢀ1. 1H NMR (300 MHz,
CDCl3) d: 0.01 (3H, s), 0.06 (3H, s), 0.79 (9H, s), 2.41e2.45 (4H,
m), 4.54 (1H, d, J¼8.3 Hz), 4.57 (2H, d, J¼8.3 Hz), 4.97e5.08
(4H, m), 5.23 (1H, s), 5.87e5.97 (2H, m), 7.07e7.24 (10H, m).
13C NMR (67.8 MHz, CDCl3) d: e2.0 (2C), 18.9, 26.2 (3C),
40.4, 40.7, 78.2, 85.0, 86.9, 107.1, 117.4, 117.6, 126.3, 126.6,
128.0, 128.4, 134.2, 136.0, 138.0. Anal. Calcd for C28H38O3Si:
C, 74.62; H, 8.50. Found: C, 74.60; H, 8.60.
4.11. (4R,5R)-2-(1-Allyl-1-methyl-3-butenyl)-4,5-diphenyl-
1,3-dioxolane (5c)
A solution of (R,R)-hydrobenzoin (1.0 g, 4.80 mmol) in
THF (2.0 mL) and TMSOMe (2.7 mL, 11.3 mmol) was added
dropwise to a solution of the known 4c (367 mg, 2.40 mmol)
in THF (3.0 mL) at ꢀ78 ꢁC under N2. TMSOTf (0.05 mL,
0.28 mmol) was added to the mixture and the resulting
solution was allowed to gradually warm to rt and stirred for
24 h. Satd NH4Cl aqueous solution was added to the solution.
The mixture was extracted with AcOEt. Organic layer was
washed with brine, dried over Na2SO4, and evaporated in
vacuo. Purification of the residue by SiO2 column chromatog-
raphy (hexane/AcOEt¼50/1 as an eluent) gave 5c (820 mg,
2.35 mmol, 98%). Colorless oil: [a]2D5.0 þ24.9 (c 1.34,
4.9. (4R,5R)-2-(1-Allyl-3-butenyl)-4,5-diphenyl-1,3-
dioxolane (5a)
A solution of (R,R)-hydrobenzoin (340 mg, 1.60 mmol) in
THF (1.0 mL) and TMSOMe (0.89 mL, 6.40 mmol) was
added dropwise to a solution of the known and commercially
available 4a (100 mg, 0.81 mmol) in THF (0.6 mL) at ꢀ78 ꢁC
under N2. TMSOTf (0.015 mL, 0.081 mmol) was added to the
mixture and the resulting solution was allowed to gradually
warm to rt and stirred for 24 h. Satd NH4Cl aqueous solution
was added to the solution. The mixture was extracted with
AcOEt. Organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. Purification of the residue
by SiO2 column chromatography (hexane/AcOEt¼30/1 as an
eluent) gave 5a (214 mg, 0.66 mmol, 83%). Colorless oil:
CHCl3). IR (KBr): 912, 749 cmꢀ1 1H NMR (300 MHz,
.
CDCl3) d: 1.09 (3H, s), 2.30e2.33 (4H, m), 4.64 (1H, d,
J¼8.4 Hz), 4.70 (1H, d, J¼8.4 Hz), 5.10e5.16 (4H, m), 5.26
(1H, s), 5.89e6.01 (2H, m), 7.18e7.36 (10H, m). 13C NMR
(67.8 MHz, CDCl3) d: 19.3, 39.5, 39.7, 40.7, 85.2, 86.9,
109.3, 117.6, 126.3, 126.8, 128.0, 128.5, 134.7, 136.6,
138.8. Anal. Calcd for C23H26O2: C, 82.60; H, 7.84. Found:
C, 82.68; H, 7.83.
[a]D23.5 ꢀ30.9 (c 1.19, CHCl3). IR (KBr): 912, 748 cmꢀ1. H
4.12. General procedure for an intramolecular
haloetherification
1
NMR (300 MHz, CDCl3) d: 2.00 (1H, m), 2.21e2.28 (2H,
m), 2.36e2.38 (2H, m), 4.62 (1H, d, J¼8.4 Hz), 4.66 (1H,
d, J¼8.4 Hz), 4.99e5.09 (4H, m), 5.42 (1H, d, J¼3.3 Hz),
5.80e5.89 (2H, m), 7.12e7.28 (10H, m). 13C NMR
(67.8 MHz, CDCl3) d: 33.0, 33.1, 41.8, 85.0, 86.8, 106.4,
116.4, 126.2, 126.7, 127.9, 128.4, 136.5, 136.6, 138.5. Anal.
Calcd for C22H24O2: C, 82.46; H, 7.55. Found: C, 82.40; H,
7.69.
NIS (5 mmol) was added to a solution of the diene acetal
(1 mmol) in CH3CN (2 mL) at ꢀ40 ꢁC under N2 and the
mixture was stirred for 30 min at the same temperature. H2O
(5 mmol) was added to the resulting mixture, which was
allowed to warm to 0 ꢁC for over 40 min. Satd Na2S2O3 aque-
ous solution was added to the mixture, which was extracted
with Et2O. The organic layer was washed with brine, dried
over MgSO4, and evaporated in vacuo. The residue was puri-
fied by SiO2 column chromatography using hexane/AcOEt to
give the product and other diastereomixture.
4.10. (4R,5R)-2-(1-Allyl-1-phenyl-3-butenyl)-4,5-diphenyl-
1,3-dioxolane (5b)
A solution of (R,R)-hydrobenzoin (2.8 g, 13.0 mmol) in THF
(5.0 mL) and TMSOMe (7.2 mL, 52.0 mmol) was added dropwise
to a solution of the known 4b (1.3 g, 6.50 mmol) in THF (8.0 mL)
at ꢀ78 ꢁC under N2. TMSOTf (0.12 mL, 0.65 mmol) was added to
the mixture and the resulting solution was allowed to gradually
warm to rt and stirred for 24 h. Satd NH4Cl aqueous solution
was added to the solution. The mixture was extracted with AcOEt.
Organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo. Purification of the residue by SiO2 column
chromatography (hexane/AcOEt¼50/1 as an eluent) gave 5b
(1.4 g, 3.50 mmol, 54%). Colorless oil: [a]2D6.1 þ25.7 (c 1.09,
CHCl3). IR (KBr): 912, 743 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d: 2.94 (4H, t, J¼7.5 Hz), 4.26 (1H, d, J¼8.4 Hz), 4.66 (1H, d,
J¼8.4 Hz), 5.14e5.35 (4H, m), 5.65 (1H, s), 5.82e6.01 (2H, m),
7.00e7.94 (15H, m); 13C NMR (67.8 MHz, CDCl3) d: 37.3,
37.9, 47.8, 84.8, 86.8, 108.1, 117.8, 117.9, 126.2, 126.3, 127.0,
127.6, 127.9, 128.2, 128.3, 128.8, 134.2, 136.0, 138.2, 140.9.
LRMS (FAB) m/z 419 (MNaþ). HRMS (FAB) Calcd for
C28H28NaO2: 419.1987. Found: 419.1983.
4.12.1. (1S,3R,4R,6S,8S,10R)-6,10-Bis(iodomethyl)-3,4-
diphenyl-8-trimethylsilyloxy-2,5,11-trioxabicyclo[6.3.0]-
undecane (6c)
Compound 6c (62 mg, 0.092 mmol) and other diastereo-
meric mixture (8 mg, 0.011 mmol) were obtained in total 82%
from 3c (51 mg, 0.13 mmol), NIS (141 mg, 0.63 mmol), and
H2O (0.011 mL, 0.63 mmol). Hexane/AcOEt¼20/1. Amor-
phous: [a]2D4.8 þ50.4 (c 1.04, CHCl3). IR (KBr): 1016, 912,
741 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 1.82 (1H, dd,
.
J¼13.5, 4.5 Hz), 2.38e2.94 (2H, m), 2.48 (1H, dd, J¼13.5,
6.0 Hz), 3.03 (1H, dd, J¼9.3, 9.2 Hz), 3.12 (1H, d, J¼7.5 Hz),
3.34 (1H, dd, J¼9.3, 4.8 Hz), 4.38e4.41 (4H, m), 4.39 (1H, d,
J¼8.4 Hz), 4.54 (1H, d, J¼8.4 Hz), 5.69 (1H, s), 6.81e6.89
(4H, m), 7.07e7.13 (6H, m). 13C NMR (67.8 MHz, CDCl3) d:
2.3 (3C), 5.7, 10.8, 37.8, 44.2, 74.6, 78.1, 79.8, 85.1, 87.0,
111.3, 127.2, 127.3, 127.5, 127.6, 127.7, 127.8, 138.2, 139.0.
LRMS (FAB) m/z 679 (MHþ). HRMS (FAB) Calcd for
C25H33I2O4Si: 679.0267. Found: 679.0267.

H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4241
4.12.2. (1S,3R,4R,6S,10R)-6,10-Bis(iodomethyl)-3,4-
4.12.5. (1S,3R,4R,6S,8R,10R)-6,10-Bis(iodomethyl)-3,4-
diphenyl-8-methoxy-2,5,11-trioxabicyclo[6.3.0]-
undecane (6b)
diphenyl-2,5,11-trioxabicyclo[6.3.0]undecane (6f)
Compound 6f (114 mg, 0.19 mmol, 62%) and other
diastereomeric mixture (33 mg, 0.056 mmol, 18%) were
obtained from 5a (100 mg, 0.31 mmol), NIS (351 mg,
1.60 mmol), and H2O (0.028 mL, 1.60 mmol). Hexane/
AcOEt¼20/1. Amorphous: [a]2D3.9 þ65.4 (c 1.12, CHCl3). IR
Compound 6b (18 mg, 0.029 mmol, diastereomeric mix-
ture, total 38%) was obtained from 3b (27 mg, 0.077 mmol),
NIS (87 mg, 0.39 mmol), and H2O (0.007 mL, 0.39 mmol).
Colorless crystals: mp 175.5e176.0 ꢁC. [a]D25.7 þ44.2 (c
1.07, CHCl3). IR (KBr): 1096, 912, 740 cmꢀ1
.
1H NMR
(KBr): 1042, 912, 743 cmꢀ1. H NMR (300 MHz, CDCl3) d:
1
(300 MHz, CDCl3) d: 1.60 (1H, dd, J¼13.8, 9.3 Hz), 2.17
(1H, dd, J¼15.6, 12.0 Hz), 2.63e2.74 (2H, m), 3.05e3.15
(3H, m), 3.15e3.38 (1H, m), 3.35 (3H, s), 4.30e4.43 (2H,
m), 4.42 (1H, d, J¼8.4 Hz), 4.57 (1H, d, J¼8.4 Hz), 5.73
(1H, s), 6.84e6.89 (4H, m), 7.09e7.26 (6H, m). 13C NMR
(67.8 MHz, CDCl3) d: 5.8, 10.7, 31.9, 37.7, 50.0, 74.4, 77.8,
79.9, 87.3, 110.4, 127.1, 127.5, 127.5, 127.6, 127.7, 137.9,
138.7. LRMS (FAB) m/z 621 (MHþ). HRMS (FAB) Calcd
for C23H27I2O4: 620.9999. Found: 620.9974.
1.98e2.03 (2H, m), 2.10e2.23 (1H, m), 2.40e2.42 (2H, m),
3.00e3.07 (3H, m), 3.28 (1H, dd, J¼9.3, 4.5 Hz), 4.03e4.25
(2H, m), 4.32 (1H, d, J¼8.4 Hz), 4.44 (1H, d, J¼8.4 Hz),
5.89 (1H, d, J¼4.5 Hz), 6.79e6.72 (4H, m), 7.04e7.19 (6H,
m). 13C NMR (67.8 MHz, CDCl3) d: 6.3, 32.5, 35.4, 38.2,
65.3, 76.7, 77.4, 87.8, 127.0, 127.1, 127.8, 127.9, 128.0,
128.1, 128.3, 128.4, 128.5, 128.6, 128.7, 138.7, 139.4,
178.0. LRMS (FAB) m/z 591 (MHþ). HRMS (FAB) Calcd
for C22H25I2O3: 590.9893. Found: 590.9875.
4.12.6. (1S,3R,4R,6S,8R,10R)-6,10-Bis(iodomethyl)-3,4,8-
triphenyl-2,5,11-trioxabicyclo[6.3.0]undecane (6g)
4.12.3. (1S,3R,4R,6S,8S,10R)-6,10-Bis(iodomethyl)-3,4-
diphenyl-8-triethylsilyloxy-2,5,11-trioxabicyclo[6.3.0]-
undecane (6d)
Compound 6g (167 mg, 0.25 mmol) and its diastereomeric
mixture (83 mg, 0.13 mmol) in total 72% were obtained from 5b
(207 mg, 0.52 mmol), NIS (587 mg, 2.61 mmol), and H2O
(0.047 mL, 2.61 mmol). Colorless amorphous: [a]2D5.9 þ58.5 (c
Compound 6d (67 mg, 0.15 mmol) and other diastereomeric
mixture (5 mg, 0.007 mmol) were obtained in total 58% from 3d
(67 mg, 0.15 mmol), NIS (166 mg, 0.74 mmol), and H2O
(0.013 mL, 0.74 mmol). Hexane/AcOEt¼20/1. Amorphous:
[a]2D4.5 þ35.2 (c 1.12, CHCl3). IR (KBr): 1170, 912,
1.00, CHCl3). IR (KBr): 1076, 912, 739 cmꢀ1 1H NMR
.
(300 MHz, CDCl3) d: 2.48e2.60 (4H, m), 2.96e3.05 (3H, m),
3.23 (1H, dd, J¼9.6, 5.1 Hz), 3.68e3.90 (2H, m), 4.39 (1H, d,
J¼8.4 Hz), 4.61 (1H, d, J¼8.4 Hz), 6.3 (1H, s), 6.80e7.47 (15H,
m). 13C NMR (67.8 MHz, CDCl3) d: 5.9, 10.5, 38.7, 45.8, 55.6,
75.8, 80.0, 87.4, 109.1, 126.5, 126.9, 127.2, 127.3, 127.5, 127.6,
127.7, 128.8, 138.3, 138.8, 141.1. LRMS (FAB) m/z 667 (MHþ).
HRMS (FAB) Calcd for C28H29I2O3: 667.0206. Found: 667.0211.
743 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 0.65 (6H, q,
.
J¼7.8 Hz), 0.96 (9H, t, J¼7.8 Hz), 1.78 (1H, dd, J¼13.8,
5.1 Hz), 2.24e2.43 (3H, m), 2.96 (1H, t, J¼9.3 Hz), 3.05 (2H,
d, J¼6.9 Hz), 3.27 (1H, dd, J¼9.3, 4.8 Hz), 4.32e4.46 (2H,
m), 4.34 (1H, d, J¼8.4 Hz), 4.47 (1H, d, J¼8.4 Hz), 5.60 (1H,
s), 6.75e6.82 (4H, m), 7.02e7.18 (6H, m). 13C NMR
(67.8 MHz, CDCl3) d: 7.3 (3C), 8.0 (3C), 12.1, 39.2, 45.5,
75.2, 78.9, 80.4, 85.6, 87.7, 112.0, 127.8, 127.9, 128.1, 128.2,
128.4, 138.9, 139.6. Anal. Calcd for C28H38I2O4Si: C, 46.68;
H, 5.32; I, 35.23. Found: C, 46.69; H, 5.21; I, 35.18.
4.12.7. (1S,3R,4R,6S,8R,10R)-6,10-Bis(iodomethyl)-3,4-
diphenyl-8-methyl-2,5,11-trioxabicyclo[6.3.0]undecane
(6h)
Compound 6h (74 mg, 0.12 mmol) and its diastereomeric
mixture (48 mg, 0.079 mmol) in total 72% yield were obtained
from 5c (94 mg, 0.28 mmol), NIS (316 mg, 1.41 mmol), and
H2O (0.025 mL, 1.41 mmol). Colorless amorphous: [a]D24.3
ꢀ17.2 (c 1.15, CHCl3). IR (KBr): 1041, 912, 743 cmꢀ1. H
4.12.4. (1S,3R,4R,6S,8S,10R)-6,10-Bis(iodomethyl)-3,4-
diphenyl-8-tert-butyldimethylsilyloxy-2,5,11-trioxabicyclo-
[6.3.0]undecane (6e)
1
NMR (300 MHz, CDCl3) d: 1.34 (3H, s), 1.68 (1H, dd, J¼10.9,
5.4 Hz), 1.83 (1H, dd, J¼14.9, 10.6 Hz), 2.04e2.17 (2H, m),
2.76e2.77 (2H, m), 3.17 (1H, dd, J¼9.7, 7.8 Hz), 3.27 (1H, dd,
J¼4.6, 2.3 Hz), 4.15e4.22 (2H, m), 4.69 (1H, d, J¼9.3 Hz),
4.91 (1H, d, J¼9.34 Hz), 5.80 (1H, s), 7.01e7.09 (10H, m).
13C NMR (67.8 MHz, CDCl3) d: 9.4, 12.0, 22.8, 40.3, 44.5,
45.9, 73.0, 74.0, 81.4, 84.1, 109.2, 127.4, 127.6, 127.7, 127.9,
128.0, 128.2. LRMS (FAB) m/z 605 (MHþ). HRMS (FAB) Calcd
for C23H27I2O3: 605.0050. Found: 605.0048.
Compound 6e (67 mg, 0.093 mmol) and other diastereomeric
mixture (6 mg, 0.009 mmol) were obtained in total 84% from 3e
(55 mg, 0.12 mmol), NIS (137 mg, 0.61 mmol), and H2O
(0.011 mL, 0.61 mmol). Hexane/AcOEt¼20/1. Amorphous:
[a]D24.3 þ40.9 (c 1.01, CHCl3). IR (KBr): 1015, 912, 740 cmꢀ1
.
1H NMR (300 MHz, CDCl3) d: 0.23 (6H, s), 0.93 (9H, s), 1.84
(1H, dd, J¼13.5, 4.8 Hz), 2.30 (1H, dd, J¼12.0, 2.0 Hz), 2.41e
2.51 (2H, m), 3.02 (1H, t, J¼9.3 Hz), 3.10 (2H, d, J¼7.2 Hz),
3.32 (1H, dd, J¼9.3, 4.5 Hz), 4.39 (1H, d, J¼8.4 Hz), 4.55
(1H, d, J¼8.4 Hz), 4.38e4.55 (2H, m), 5.68 (1H, s), 6.81e6.88
(4H, m), 7.08e7.12 (6H, m). 13C NMR (67.8 MHz, CDCl3) d:
ꢀ1.6, ꢀ1.6, 6.5, 12.0, 19.2, 26.7 (3C), 38.9, 45.3, 75.1, 77.9,
80.4, 85.8, 87.7, 111.8, 127.8, 127.9, 128.1, 128.2, 128.3,
128.4, 138.9, 139.6. Anal. Calcd for C28H38I2O4Si: C, 46.68;
H, 5.32; I, 35.23. Found: C, 46.46; H, 5.34; I, 34.98.
4.13. (1R,3R,4R,6R,8S,10S)-6,10-Bismethyl-3,4-diphenyl-8-
trimethylsilyloxy-2,5,11-trioxabicyclo[6.3.0]undecane (7)
(reaction in Scheme 3)
NaHCO3 (74 mg, 0.88 mmol), EPHP (158 mg, 0.88 mmol),
and VA-061 (29 mg, 0.088 mmol) were added successively to

4242
H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
a solution of 6c (30 mg, 0.044 mmol) in EtOH/H2O (v/v¼1/1,
1.0 mL) at rt under N2, and the mixture was stirred for 1 h at
80 ꢁC. The reaction mixture was extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2 col-
umn chromatography (benzene as an eluent) to give 7 (18 mg,
0.043 mmol, 97%). Colorless crystals: mp 95.0e95.5 ꢁC.
washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by SiO2 column chromatography (hex-
ane/AcOEt¼5/1 as an eluent) to give 11 (23 mg, 0.032 mmol,
73%). Colorless oil: [a]2D5.2 þ96.0 (c 1.01, CHCl3). IR (KBr):
1
1736, 1436, 1037, 773 cmꢀ1. H NMR (300 MHz, CDCl3) d:
0.03 (3H, s), 0.06 (3H, s), 0.71 (9H, s), 1.60e1.73 (2H, m),
1.83e1.93 (2H, m), 2.13e2.26 (2H, m), 2.79e2.87 (2H, m),
3.10e3.15 (1H, m), 3.20 (3H, s), 3.46 (3H, s), 4.00e4.08 (1H,
m), 4.12e4.23 (1H, m), 4.13 (1H, d, J¼8.4 Hz), 4.34 (1H, d,
J¼8.4 Hz), 5.49 (1H, s), 6.62e6.69 (4H, m), 6.87e6.89 (6H,
m). 13C NMR (67.8 MHz, CDCl3) d: ꢀ2.7, ꢀ2.4, 11.2, 18.5,
25.9 (3C), 31.6, 40.0, 44.6, 47.7, 52.3, 52.5, 70.9, 77.0, 77.5,
79.0, 85.0, 87.0, 111.2, 127.1, 127.5, 138.3, 138.7, 169.3,
139.5. Anal. Calcd for C32H43IO8Si: C, 54.69; H, 6.26; I,
17.51. Found: C, 54.70; H, 6.17; I, 17.59.
[a]D25.6 þ38.5 (c 1.10, CHCl3). IR (KBr): 1146, 912 cmꢀ1
.
1H NMR (300 MHz, CDCl3) d: 0.01 (9H, s), 0.89 (3H, d,
J¼6.8 Hz), 1.09 (3H, d, J¼6.2 Hz), 1.50e1.60 (2H, m), 1.96
(1H, dd, J¼13.1, 5.6 Hz), 2.16 (1H, dd, J¼14.9, 12.3 Hz),
4.19 (1H, d, J¼8.8 Hz), 4.08e4.27 (2H, m), 4.35 (1H, d,
J¼8.8 Hz), 5.36 (1H, s), 6.64e6.74 (4H, m), 6.86e6.90 (6H,
m). 13C NMR (67.8 MHz, CDCl3) d: 2.4 (3C), 19.0, 23.0,
41.3, 45.2, 69.1, 73.8, 78.9, 85.6, 86.8, 110.8, 127.0, 127.2,
127.3, 127.6, 138.9, 140.1. Anal. Calcd for C25H34O4Si: C,
70.38; H, 8.03. Found: C, 70.48; H, 8.05.
4.16. (1R,2R)-2-[(2S,3S,5R)-3-Allyl-3-tert-butyldimethyl-
silyloxy-5-iodomethyl-2-tetrahydrofuranyloxy]-1,2-
diphenylethanol (12) (reaction in Scheme 6)
4.14. (1S,3R,4R,6R,8S,10R)-6-Cyanomethyl-10-iodomethyl-
3,4-diphenyl-8-trimethylsilyloxy-2,5,11-trioxabicyclo-
[6.3.0]undecane (10) (reaction in Scheme 6)
Zn(OTf)2 (20 mg, 0.055 mmol) was added to a solution of 6e
(31 mg, 0.043 mmol) in THF (0.5 mL) under N2. The mixture
was stirred for 30 min at 50 ꢁC. Zn (34 mg, 0.34 mmol) was
added to the resulting solution, which was additionally stirred
for 5 h at 70 ꢁC. Et2O was added to the mixture. Precipitated
salt was filtered. The filtrate was washed with brine, dried
over MgSO4, and evaporated in vacuo. The residue was purified
by SiO2 column chromatography (hexane/AcOEt¼20/1 as an
eluent) to give 12 (19 mg, 0.031 mmol, 73%). Colorless oil:
[a]2D6.6 þ104.4 (c 1.09, CHCl3). IR (KBr): 1068, 1011,
NaCN (4 mg, 0.088 mmol) was added to a solution of 6c
(40 mg, 0.059 mmol) in DMSO (1.2 mL) at rt under N2 and
the mixture was stirred for 2 h at 60e70 ꢁC. After completion
of the reaction (TLC check), satd Na2S2O3 aqueous solution
was added to the mixture, which was extracted with EtOAc.
The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified
by SiO2 column chromatography (hexane/AcOEt¼5/1 as an
eluent) to give 10 (30 mg, 0.052 mmol, 88%). Colorless crys-
tals: mp 112.0e112.5 ꢁC. [a]D25.2 þ70.3 (c 1.07, CHCl3). IR
1
698 cmꢀ1. H NMR (300 MHz, CDCl3) d: 0.09 (6H, s), 0.85
(9H, s), 1.57 (1H, dd, J¼13.0, 9.6 Hz), 2.18e2.24 (2H, m),
2.42e2.45 (1H, m), 2.63 (2H, d, J¼6.4 Hz), 4.22e4.33 (1H,
m), 4.52 (1H, d, J¼7.9 Hz), 4.69 (1H, d, J¼7.9 Hz), 5.10 (1H,
s), 5.23e5.28 (2H, m), 6.07e6.13 (1H, m), 7.01e7.04 (4H,
m), 7.13e7.17 (6H, m). 13C NMR (67.8 MHz, CDCl3) d:
ꢀ2.4, ꢀ2.3, 8.7, 18.4, 25.8 (3C), 40.4, 43.7, 77.0, 78.6, 79.7,
85.0, 85.8, 109.8, 117.6, 127.0, 127.5, 127.6, 127.8, 134.9,
139.5. LRMS (FAB) m/z 379 (MHþ). HRMS (FAB) Calcd for
C28H40IO4Si: 617.1560. Found: 617.1556.
(KBr): 2358, 1252, 912, 743 cmꢀ1 1H NMR (300 MHz,
.
CDCl3) d: 0.24 (9H, s), 1.84 (1H, dd, J¼13.5, 4.5 Hz), 2.08
(1H, dd, J¼14.7, 2.1 Hz), 2.45e2.53 (4H, m), 3.04 (1H, t,
J¼9.3 Hz), 3.34 (1H, dd, J¼9.6, 4.8 Hz), 4.38e4.47 (1H,
m), 4.53e4.60 (1H, m), 4.46 (1H, d, J¼8.4 Hz), 4.54 (1H,
d, J¼8.4 Hz), 5.65 (1H, s), 6.81e6.88 (4H, m), 7.08e7.13
(6H, m). 13C NMR (67.8 MHz, CDCl3) d: 2.2, 10.6, 22.2,
38.6, 44.1, 69.3, 78.1, 80.2, 84.9, 87.0, 111.4, 117.0, 127.2,
127.3, 127.6, 127.7, 127.8, 128.0, 137.9, 138.1. Anal. Calcd
for C26H32INO4Si: C, 54.07; H, 5.58; N, 2.43; I, 21.97. Found:
C, 54.22; H, 5.63; N, 2.36; I, 21.88.
4.17. (3R,5R)-3-{2-(S)-[(1R,2R)-2-Hydroxy-1,2-
diphenylethoxy]-3-iodopropyl}-5-iodomethyl-
dihydrofuran-2-one (13)
4.15. (1S,3R,4R,6R,8S,10R)-6-[2,2-Bis(methoxycarboyl)-
ethyl]-10-iodomethyl-3,4-diphenyl-8-tert-butyldimethyl-
silyloxy-2,5,11-trioxabicyclo[6.3.0]undecane (11)
(reaction in Scheme 6)
DDQ (58 mg, 0.25 mmol) was added to a solution of 6f
(100 mg, 0.17 mmol) in CH3CN/H2O (v/v¼10/1, 1.8 mL).
The mixture was stirred for 2 h at 60 ꢁC. Satd NaHCO3 aque-
ous solution was added to the mixture, which was extracted
with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, and evaporated in vacuo. The residue was puri-
fied by SiO2 column chromatography (hexane/AcOEt¼2/1 as
an eluent) to give 6f (36 mg, 0.061 mmol) and the hemiacetal
(60 mg, 0.099 mmol, 58% (91% based on the consumed 6f)).
Dimethyl malonate (0.025 mL, 0.21 mmol) was added drop-
wise to a solution of NaH (9 mg, 0.211 mmol, 60% dispersion in
mineral oil, washed with dry Et2O) in DMF (0.5 mL) at 0 ꢁC un-
der N2. The mixture was stirred for 30 min at the same tempera-
ture. A solution of 6e (32 mg, 0.044 mmol) in THF (0.1 mL) was
added to a resulting solution at 0 ꢁC and the mixture was stirred
for 4 h at 80 ꢁC. Satd NH4Cl aqueous solution was added to the
mixture, which wasextractedwith EtOAc. The organiclayerwas
Amorphous: IR (KBr): 3400, 1020, 748 cmꢀ1 1H NMR
.
(300 MHz, CDCl3) d: 1.17e2.23 (8H, m), 2.99e3.51 (4H,
m), 4.00e4.11 (1H, m), 4.22, 4.23 (total 1H, d, J¼8.4 Hz),

H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4243
4.77, 4.79 (total 1H, d, J¼8.4 Hz), 5.15, 5.37 (total 1H, d,
J¼4.3 Hz), 7.02e7.24 (10H, m).
mixture was stirred for additional 30 min at the same tempera-
ture. NH4Cl aqueous solution was added to the mixture, which
was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and evaporated invacuo. The res-
idue was purified by SiO2 column chromatography (hexane/
AcOEt¼4/1 as an eluent) to give 15a (20 mg, 0.049 mmol,
63%). Colorless oil: [a]2D1.3 þ15.7 (c 0.35, CHCl3). IR (KBr):
NaH2PO4
(36 mg,
0.30 mmol),
2-methyl-2-butene
(0.051 mL, 0.49 mmol), and NaClO2 (18 mg, 0.15 mmol) were
added to the solution of the above hemiacetal (60 mg,
0.99 mmol) in tert-BuOH/H2O (v/v¼5/1, 1.0 mL), and the mix-
ture was stirred for 3 h at rt. HCl (10%) aqueous solution was
added to the mixture and the solution was stirred for 3 h. The
mixture was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by SiO2 column chromatography (hex-
ane/AcOEt¼2/1 as an eluent) to give 13 (55 mg, 0.091 mmol,
92%). Colorless amorphous: [a]2D3.8 ꢀ32.1 (c 0.88, CHCl3). IR
(KBr): 3285, 1774, 1173, 912, 743 cmꢀ1. 1H NMR (300 MHz,
CDCl3) d: 1.00 (1H, q, J¼11.1 Hz), 1.15e1.54 (2H, m), 2.20e
2.23 (1H, m), 2.50e2.66 (1H, m), 2.99e3.05 (2H, m), 3.10e
3.82 (4H, m), 4.01e4.08 (1H, m), 4.17 (1H, d, J¼8.4 Hz), 4.78
(1H, d, J¼8.4 Hz), 7.21e7.98 (10H, m). 13C NMR (67.8 MHz,
CDCl3) d: 6.3, 32.5, 35.4, 38.2, 65.3, 76.9, 77.4, 78.4, 87.8,
127.0, 127.1, 127.9, 127.9, 128.0, 128.1, 128.3, 128.4, 128.5,
128.5, 128.6, 138.7, 178.0. Anal. Calcd for C22H24I2O4: C,
43.59; H, 3.99; I, 41.87. Found: C, 43.55; H, 4.03; I, 41.44.
1
3416, 1759, 1186, 742 cmꢀ1. H NMR (300 MHz, CDCl3) d:
1.22e1.78 (16H, m), 1.89e2.00 (3H, m), 2.41e2.51 (1H, m),
2.78e2.91 (1H, m), 3.17e3.29 (3H, m), 3.62 (1H, br s, OH),
4.31e4.38 (1H, m), 4.84e4.95 (2H, m), 5.69e5.79 (1H, m).
13C NMR (67.8 MHz, CDCl3) d: 14.8, 25.2, 28.9, 29.1, 29.3,
29.4, 29.4, 33.8, 35.4, 35.9, 37.1, 39.2, 69.6, 79.8, 114.1,
139.0, 179.5. Anal. Calcd for C17H29IO3: C, 50.01; H, 7.16; I,
31.08. Found: C, 50.18; H, 6.98; I, 30.75.
4.20. (3S,5R,20R)-5-Dec-9-enyl-3-oxiranylmethyldihydro-
furan-2-one (16a)
K2CO3 (203 mg, 1.47 mmol) was added to a solution of 15a
(20 mg, 0.049 mmol) in AcOEt (0.6 mL). The mixture was
stirred for 3 h at rt. After completion of the reaction (TLC check),
AcOEt was added to the mixture and precipitate was filtered
through Celite pad. The filtrate was concentrated in vacuo to
give the residue. The residue was purified by SiO2 column chro-
matography (hexane/AcOEt¼4/1 as an eluent) to give 16a
(14 mg, 0.049 mmol, 100%). Colorless oil: [a]2D6.0 þ29.8 (c
4.18. (3R,5R,20S)-5-Iodomethyl-3-oxiranylmethyldihydro-
furan-2-one (14)
CAN (90 mg, 0.17 mmol) was added to a solution of 13
(50 mg, 0.083 mmol) in CH3CN/H2O (v/v¼1/1, 0.8 mL). The
mixture was stirred for 1 h at rt. After completion of the reaction
(TLC check), H2O was added to the mixture, which was
extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and evaporated in vacuo to give the residue.
Ag2O (10 mg, 0.040 mmol) was added to a solution of the resi-
due in CH3CN (0.8 mL) under N2 and the mixturewas stirred for
3 h at 0e10 ꢁC. Addition of AcOEt to the mixture formed pre-
cipitate, which was filtered through Celite pad. The filtrate
was evaporated in vacuo to give the residue. The residue was
purified by SiO2 column chromatography (hexane/AcOEt¼
1/1 as an eluent) to give 14 (20 mg, 0.071 mmol, 86%). Color-
less oil: [a]2D5.5 ꢀ9.7 (c 2.74, CHCl3). IR (KBr): 1771, 1167,
1
0.82, CHCl3). IR (KBr): 1769, 1182, 912, 742 cmꢀ1. H NMR
(300 MHz, CDCl3) d: 1.29e2.01 (19H, m), 2.50e2.59 (2H, m),
2.78e2.83 (2H, m), 2.99e3.02 (1H, m), 4.35e4.41 (1H, m),
4.92e5.03 (2H, m), 5.77e5.86 (1H, m). 13C NMR (67.8 MHz,
CDCl3) d: 25.2, 28.9, 29.0, 29.3, 29.4, 32.6, 33.8, 35.1, 35.4,
38.6, 46.8, 49.8, 77.2, 79.2, 114.1, 139.1, 178.1. Anal. Calcd
for C17H28O3: C, 72.82; H, 10.06. Found: C, 72.85; H, 10.10.
4.21. Rubrenolide
Bi(OTf)3 (5 mg, 0.007 mmol) was added to a solution of 16a
(10 mg, 0.036 mmol) in THF/H2O (v/v¼4/1, 0.5 mL). The
mixture was stirred under reflux for 6 h. After completion of
the reaction (TLC check), K2CO3 was added to quench the
acid. AcOEt was added to the mixture and the precipitate was
filtered through Celite pad. The filtrate was concentrated in
vacuo to give the residue. The residue was purified by SiO2
column chromatography (hexane/AcOEt¼1/2 as an eluent) to
give rubrenolide (8 mg, 0.026 mmol, 73%). Colorless crystal:
mp 98.0e100.0 ꢁC. [a]D24.7 þ20.5 (c 0.29, CHCl3). IR (KBr):
1
912, 743 cmꢀ1. H NMR (300 MHz, CDCl3) d: 1.75 (1H, q,
J¼13.5 Hz), 1.88e1.92 (2H, m), 2.48e2.51 (1H, m),
2.67e2.94 (4H, m), 3.21e3.37 (1H, m), 3.38e3.42 (1H, m),
4.30e4.38 (1H, m). 13C NMR (67.8 MHz, CDCl3) d: 6.6,
32.6, 35.5, 38.9, 46.9, 49.7, 76.8, 176.9. Anal. Calcd for
C8H11IO3: C, 34.06; H, 3.93; I, 44.99. Found: C, 34.07; H,
3.93; I, 44.66.
3310, 1747, 1190, 912, 742 cmꢀ1 1H NMR (300 MHz,
.
4.19. (3R,5R,20R)-3-(2-Hydroxydodec-11-enyl)-5-iodo-
methyldihydrofuran-2-one (15a)
CDCl3) d: 1.27e2.03 (21H, m), 2.47e2.55 (1H, m), 2.86e
2.93 (1H, m), 3.45e3.52 (1H, m), 3.60e3.65 (1H, m),
3.80e3.82 (1H, m), 4.38e4.42 (1H, m), 4.90e5.00 (2H, m),
5.75e5.84 (1H, m). 13C NMR (67.8 MHz, CDCl3) d: 25.2,
28.9, 29.0, 29.3, 33.8, 35.3, 36.0, 39.5, 66.8, 70.6, 80.0, 114.1,
139.1, 180.4. LRMS (EIþ) m/z 298. HRMS (EIþ) Calcd for
Grignard reagent (1.62 mL, 0.41 mmol, 0.25 M in Et2O),
prepared from 9-bromonon-1-ene16 and Mg metal, was added
to a solution of CuI (38 mg, 0.20 mmol) in Et2O (0.8 mL) at
ꢀ35 ꢁC under N2. The mixture was stirred for 30 min at the
same temperature. Compound 14 (23 mg, 0.078 mmol) in
Et2O (0.5 mL) was added to the resulting solution and the
1
C17H30O4: 298.2144. Found: 298.2141. The [a]D, H and 13C
NMR, IR, and HRMS spectrum showed good agreement with
those of authentic sample.

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H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4.22. (3R,5R,20R)-3-(2-Hydroxy-12-trimethylsilanyl-dodec-
11-ynyl)-5-iodomethyldihydrofuran-2-one (15b)
25.2, 28.4, 28.7, 29.0, 29.3, 29.3, 33.9, 35.4, 36.0, 39.3,
66.7, 68.1, 70.5, 79.9, 84.7, 180.2. LRMS (FAB) m/z 297
(MHþ). HRMS (FAB) Calcd for C17H29O4: 297.2066. Found:
297.2089. The [a]D, 1H and 13C NMR, IR, and HRMS
spectrum showed good agreement with those of authentic
sample.
In the same procedure for 15a, 15b (25 mg, 0.053 mmol,
50%) was obtained from Grignard reagent (1.3 mL,
0.64 mmol, 0.5 M in THF/TBME (v/v¼1/1)), prepared from
9-bromo-1-trimethylsilylnon-1-yne18 and Mg metal, CuI
(61 mg, 0.32 mmol), and 14 (30 mg, 0.11 mmol) (SiO2 col-
umn chromatography (hexane/AcOEt¼4/1 as an eluent)). Col-
orless oil: [a]2D2.4 þ13.1 (c 1.23, CHCl3). IR (KBr): 3420,
Acknowledgements
The authors gratefully appreciate Prof. B. Zwanenburg and
Dr. L. Thijs for the generous gift of the mixture of natural
rubrenolide and rubrynolide. This work was supported by
Grant-in-Aid for Scientific Research (A) and Grant-in-Aid
for Scientific Research for Exploratory Research from Japan
Society for the Promotion of Science and by Grant-in-Aid
for Scientific Research on Priority Areas (17035047) from
the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
1
1749, 1247, 748 cmꢀ1. H NMR (300 MHz, CDCl3) d: 0.12
(9H, s), 1.16e1.82 (17H, m), 1.94e2.00 (1H, m), 2.19 (1H,
t, J¼6.9 Hz), 2.50e2.55 (1H, m), 2.80e2.95 (1H, m), 3.22e
3.34 (3H, m), 3.65 (1H, br s, OH), 4.31e4.90 (1H, m). 13C
NMR (67.8 MHz, CDCl3) d: 0.0 (3C), 14.5, 19.6, 24.9, 28.3,
28.5, 28.7, 29.0, 29.1, 35.1, 35.6, 36.8, 38.9, 69.3, 79.5,
84.0, 107.3, 179.2. Anal. Calcd for C20H35IO3Si: C, 50.20;
H, 7.37; I, 26.52. Found: C, 50.29; H, 7.21; I, 26.04.
4.23. (3S,5R,20R)-3-Oxiranylmethyl-5-(10-trimethylsilanyl-
dec-9-ynyl)dihydrofuran-2-one (16b)
References and notes
1. For some recent reviews, see: (a) Bermejo, A.; Figadere, B.; Zafra-Polo,
M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005,
269e303; (b) Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S.
Nat. Prod. Rep. 2005, 696e716; (c) Faul, M. M.; Huff, B. E. Chem.
Rev. 2000, 100, 2407e2474; (d) Kang, E. J.; Lee, E. Chem. Rev. 2005,
105, 4348e4378; (e) Wolf, J. P.; Hay, M. B. Tetrahedron 2007, 63,
261e290.
2. (a) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita, Y. J. Org. Chem. 1996,
61, 7309e7315; (b) Fujioka, H.; Matsunaga, N.; Kitagawa, H.; Nagatomi,
Y.; Kita, Y. Tetrahedron Lett. 1996, 37, 2245e2248.
In the same procedure for 16a, 16b (22 mg, 0.062 mmol,
99%) was obtained from K2CO3 (260 mg, 1.88 mmol) and
15b (30 mg, 0.063 mmol) (SiO2 column chromatography
(hexane/AcOEt¼4/1 as an eluent). Colorless oil: [a]D24.3
1
þ26.3 (c 0.76, CHCl3). IR (KBr): 1773, 1180, 842 cmꢀ1. H
NMR (300 MHz, CDCl3) d: 0.12 (9H, s), 1.23e1.98 (17H,
m), 2.19 (2H, t, J¼6.9 Hz), 2.48e2.57 (2H, m), 2.72e2.81
(2H, m), 2.96e2.99 (1H, m), 4.32e4.38 (1H, m). 13C NMR
(67.8 MHz, CDCl3) d: 0.0 (3C), 19.6, 25.1, 28.4, 28.5, 28.7,
29.1, 29.1, 32.4, 34.9, 35.2, 38.4, 46.6, 49.7, 79.0, 84.5,
107.5, 177.9. Anal. Calcd for C20H34O3Si: C, 68.52; H,
9.78. Found: C, 68.42; H, 9.64.
3. Fujioka, H.; Ohba, Y.; Hirose, H.; Murai, K.; Kita, Y. Angew. Chem., Int.
Ed. 2005, 44, 734e737.
4. For asymmetric desymmetrization of acyclic s-symmetric dienes, see: (a)
Takano, S.; Murakata, C.; Imamura, Y.; Tamura, N.; Ogasawara, K.
Heterocycles 1981, 16, 1291e1294; (b) Yokomatsu, T.; Iwasawa, H.;
Shibuya, S. J. Chem. Soc., Chem. Commun. 1992, 728e729; (c)
Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Tetrahedron Lett. 1992, 33,
6999e7002; (d) Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.;
Taguchi, T. J. Chem. Soc., Chem. Commun. 1992, 1005e1007; (e)
Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett.
1999, 40, 8827e8831.
4.24. Rubrynolide
Bi(OTf)3 (13 mg, 0.02 mmol) was added to a solution of
16b (33 mg, 0.094 mmol) in THF/H2O (v/v¼4/1, 0.9 mL).
The mixture was stirred under reflux for 6 h. After completion
of the reaction (TLC check), K2CO3 was added to quench the
acid. AcOEt was added to the mixture and precipitate was
filtered through Celite pad. The filtrate was concentrated in
vacuo to give the residue. TBAF (1.0 M in THF, 0.14 mL,
0.14 mmol) was added to a solution of the obtained residue
in THF (0.9 mL) under N2 and the resulting solution was
stirred for 30 min at rt. After completion of the reaction
(TLC check), the reaction mixture was concentrated in vacuo
to give the residue. The residue was purified by SiO2 column
chromatography (hexane/AcOEt¼1/2 as an eluent) to give ru-
brynolide (19 mg, 0.066 mmol, 70%). Colorless crystal: mp
84.0e85.0 ꢁC. [a]D24.5 þ21.0 (c 0.23, CHCl3). IR (KBr):
5. For 4a, see: (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687e9688; For 4b, see: (b) Ciganek, E. J. Org. Chem. 1995, 60,
5803e5807. Diallylmethyl aldehyde 4c was prepared from the known
diallyl ester 17 ((c) Snider, B. B.; Smith, R. B. Tetrahedron 2002, 58,
25e34) in two steps: (1) reduction of ester with DiBAL-H and (2) PDC
oxidation.
CO2Me
Me
17
6. CCDC-244868 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 CB2 1EZ, UK; fax: þ44 1223
336 033; or e-mail: deposit@ccdc.cam.ac.uk.
3285, 1747, 913 cmꢀ1 1H NMR (300 MHz, CDCl3) d:
.
7. (a) Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.; Matsugi, M. Org.
Lett. 2001, 3, 1157e1160; (b) Nambu, H.; Anilkumar, G.; Matsugi, M.;
Kita, Y. Tetrahedron 2003, 59, 77e85; For the radical reduction using
VA-061 in water including this transformation, see: (c) Nambu, H.;
Alinejad, A. H.; Hata, K.; Fujioka, H.; Kita, Y. Tetrahedron Lett. 2004,
45, 8927e8929.
1.19e1.80 (19H, m), 1.81e1.99 (2H, m), 2.01e2.12 (2H,
m), 2.40e2.49 (1H, m), 2.80e2.86 (1H, m), 3.43 (1H, dd,
J¼9.5, 7.2 Hz), 3.57e3.60 (1H, m), 3.68e3.75 (1H, m),
4.28e4.38 (1H, m). 13C NMR (67.8 MHz, CDCl3) d: 18.4,

H. Fujioka et al. / Tetrahedron 64 (2008) 4233e4245
4245
8. Kametani, T.; Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983, 48,
2311e2314.
12. For asymmetric total synthesis, see: (a) Saito, T.; Thijs, L.; Ettema, G.-J.;
Zwanenburg, B. Tetrahedron Lett. 1993, 34, 3589e3592; (b) Thijs, L.;
Zwanenburg, B. Tetrahedron 2004, 60, 5237e5252.
9. Fujioka, H.; Nagatomi, Y.; Kitagawa, H.; Kita, Y. J. Am. Chem. Soc. 1997,
119, 12016e12017.
´
13. Fernandes, J. M. G.; Mellet, C. O.; Marın, A. M.; Fuentes. J. Carbohydr.
´
10. Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Heterocycles 1950, 16,
951e954.
Res. 1995, 274, 263e268.
14. (a) Fujioka, H.; Ohba, Y.; Hirose, H.; Murai, K.; Kita, Y. Org. Lett. 2005,
7, 3303e3306; (b) Fujioka, H.; Hirose, H.; Ohba, Y.; Murai, K.; Nakahara,
K.; Kita, Y. Tetrahedron 2007, 63, 638e643.
15. Although K2CO3 was used in our communication (Ref. 3), Ag2O was
better for large-scale reaction.
11. For isolation and structural elucidation, see: (a) Franca, N. C.; Gottlieb,
O. R.; Coxon, D. T.; Ollis, W. D. An. Acad. Bras. Cienc. 1971, 43,
123e125; (b) Franca, N. C.; Gottlieb, O. R.; Coxon, D. T.; Ollis, W. D.
J. Chem. Soc., Chem. Commun. 1972, 514e515; (c) Franca, N. C.;
Gottlieb, O. R.; Coxon, D. T. Phytochemistry 1977, 16, 257e262; For total
synthesis, see: (d) Taylor, S. K.; Hopkins, J. A.; Spangenberg, K. A.;
McMillen, D. W.; Grutzner, J. B. J. Org. Chem. 1991, 56, 5951e5955.
Although wrong stereochemical structure of rubrenolide was originally
proposed, the correct one was reported by Zwanenburg et al. (see Ref. 12).
16. Patwardhan, A. P.; Thompson, D. H. Langmuir 2000, 16, 10340e10350.
17. Although BiCl3 is used in the literature [Mohammadpoor-Baltork, I.;
Tangestaninejad, S.; Aliyan, H.; Mirkhani, V. Synth. Commun. 2000, 30,
2365e2374], Bi(OTf)3 was also effective.
18. Organ, M. G.; Ghasemi, H. J. Org. Chem. 2004, 69, 695e700.