An enantioselective total synthesis of aspergillides A and B

Article abstract of DOI:10.1016/j.tet.2010.07.062

An enantioselective total synthesis of aspergillides A and B has been accomplished on the basis of a unified synthetic strategy that exploits stereodivergent intramolecular oxa-conjugate cyclization and Yamaguchi macrolactonization.

Full text of DOI:10.1016/j.tet.2010.07.062

Tetrahedron 66 (2010) 7492e7503
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An enantioselective total synthesis of aspergillides A and B
*
Haruhiko Fuwa , Hiroshi Yamaguchi, Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2010
Received in revised form 21 July 2010
Accepted 21 July 2010
Available online 27 July 2010
An enantioselective total synthesis of aspergillides A and B has been accomplished on the basis of
a unified synthetic strategy that exploits stereodivergent intramolecular oxa-conjugate cyclization and
Yamaguchi macrolactonization.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
of 2.0e71 mg/mL render these naturally occurring substances
intriguing targets for the synthetic community.5e7 Herein, we
describe in detail our enantioselective total synthesis of aspergil-
lides A and B on the basis of a unified synthetic strategy that
exploits stereodivergent intramolecular oxa-conjugate cyclization
and Yamaguchi lactonization.8
Kusumi and co-workers have recently reported the isolation and
structure characterization of aspergillides AeC.1 These naturally
occurring substances are the secondary metabolites of the marine
fungus Aspergillus ostianus strain 01F313, cultured in a bromine-
modified medium. On the basis of extensive 2D NMR studies and
application of the modified Mosher’s method, the initially proposed
structures of aspergillides AeC were represented by 1e3,
respectively (Fig. 1). However, total synthesis of the proposed
structure 1 of aspergillide A by Hande and Uenishi disclosed non-
identity of the synthetic material with natural aspergillide A.2 They
instead revealed that the spectroscopic properties of synthetic 1
matched exactly those of natural aspergillide B. Thus, the structure
14
14
Me
Me
O
O
O
O
1
1
O
O
7
7
3
3
HO
HO
of aspergillide
A once again fell into the mystery. On the
other hand, the absolute stereostructure of aspergillide C (3) was
unambiguously confirmed by a total synthesis by Nagasawa and
Kuwahara.3 Finally, the Kusumi group unequivocally established
the structures of aspergillides A and B to be represented by 4 and 1,
respectively, through X-ray crystallographic analysis of the corre-
sponding 3-bromobenzoate derivatives.4 The molecular archi-
tecture of aspergillides A (4) and B (1) is characterized by
a 14-membered macrolactone embedded with a tetrahydropyran
ring. Aspergillide B (1) has a 2,6-trans-substituted tetrahydropyran
ring, which is a quite rare structure in natural products. Moreover,
as evident from the X-ray crystallographic analysis by Kusumi and
co-workers, the tetrahydropyran ring of these natural products is in
an axial-rich chair conformation presumably due to the constraint
of the macrocyclic framework. Although aspergillide A (4) is the C3-
epimer of aspergillide B (1), Kusumi and co-workers reported that
interconversion between 1 and 4 was not possible.4 These unique
structural aspects combined with the cytotoxic activity against
mouse lymphocytic leukemia cells (L1210) with LD50 values
1
2
14
Me
14
Me
O
O
O
O
1
1
O
O
7
7
3
3
HO
HO
4
3
Figure 1. Proposed and correct structures of aspergillides AeC.
2. Results and discussion
2.1. Synthesis plan
Olefin metathesis reaction has emerged as a powerful and ver-
satile tool for the synthesis of macrocycles.9 There are an increasing
number of total syntheses of macrolide natural products, which
relied on esterification/ring-closing metathesis (RCM) strategy.10 In
* Corresponding author. E-mail address: hfuwa@bios.tohoku.ac.jp (H. Fuwa).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.062

H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
7493
view of the structural resemblance, we planned
a unified
Ph
TBS
O
total synthesis of aspergillides A (4) and B (1), as summarized in
Scheme 1. We envisioned that the 14-membered macrocyclic
framework of 4 and 1 could be forged via RCM of dienes 5 and 6,
respectively. The dienes 5 and 6 would in turn be synthesized from
the respective tetrahydropyrans cis-7 and trans-7 through esteri-
fication. We planned to construct the tetrahydropyrans cis-7 and
trans-7 from a common precursor 8 by means of stereodivergent
intramolecular oxa-conjugate cyclization.11,12 Specifically, we
expected that energetically more favored cis-7 would be obtained
under thermodynamic conditions, while trans-7 would be selec-
tively produced under kinetic conditions.11 Enoate 8 would be
derived from allylic alcohol 9 via chemoselective olefin cross-
metathesis (CM),13 where the C9 phenyl and C7 silyloxy groups
would reduce the reactivity of the C8eC9 double bond toward
initiation of olefin metathesis.14 Finally, allylic alcohol 9 could be
traced back to homoallylic alcohol 10.15
L = MesN
NMes
HO
9
G-II
L
Cl
H
H
Ru
Ph
Cl
O
MeO2C TBS
O
H
CM
CO2Me
OTBS
Ph
HO
16
A
conformational
constraint
breaking
H-bonding
L
Cl
Ph
HO
H
Ru
Cl
RCM
[Ru]
O
14
Me
OTBS
Me
Ph
or
Figure 2. Plausible rationale for chemoselective olefin CM.
P
MeO2C
MOMO
OTBS
O
O
Ph
O
O
H
HO
O
1
B
C
OTBS
O
O
7
3
MOMO
HO
cis-7
5
by Hoye and Zhao18 and the recent disclosure from the Hoveyda
group,19 reaction of allylic alcohol 9 with G-II catalyst would gen-
erate ruthenium alkylidene complex A, wherein an H-bonding
between the hydroxy group and one of the two chlorine atoms of G-
II is formed. We envision that this H-bonding would act as a con-
formational constraint that renders the possible RCM pathway
unfavorable. Thus, the CM reaction of 9 would proceed via the ru-
thenium alkylidene complex A in a usual manner, while the ring-
closing metathesis of 9 would have to take place via ruth-
( )-aspergillide A (4)
Ph
Ph
Ph
9
TBS
O
MeO2C
MOMO
HO
HO
8
HO
10
9
common intermediate 8
14
Me
Me
enacyclobutane
B by breaking the H-bonding and/or highly
Ph
MeO2C
MOMO
O
O
Ph
O
O
strained ruthenacyclobutane C. Thus, RCM would be energetically
less favored than CM in the present case.20 Protection of enoate 16
as its MOM ether proceeded in 90% yield. Subsequent desilylation
using TBAF buffered with AcOH afforded hydroxy enoate 8, the
common intermediate, in 89% yield.
1
O
O
O
7
3
MOMO
HO
6
trans-7
( )-aspergillide B (1)
2.3. Intramolecular oxa-conjugate cyclization of 8
Scheme 1. Synthesis plan toward aspergillides A and B.
With the common intermediate 8 available in a gram-scale, we
focused our attention to stereodivergent intramolecular oxa-con-
jugate cyclization (Table 1). It was quickly revealed that the for-
mation of 2,6-trans-tetrahydropyran trans-7 could be efficiently
achieved in a highly stereoselective manner. Thus, exposure of 8 to
0.05 equiv of KOt-Bu in THF at ꢀ78 ꢁC for 30 min furnished trans-7
in 96% yield with an approximately 17:1 diastereoselectivity. In
contrast, stereoselective synthesis of 2,6-cis-tetrahydropyran cis-7
(entry 1) proved to be difficult than anticipated. In principle, the
energetically more favored cis-7 could be produced provided that
an efficient thermodynamic equilibration between cis-7 and trans-
7 exists. We initially thought that such equilibrium would be pos-
sible simply by elevating the reaction temperature. However, we
were surprised to find that running the reaction at 0 ꢁC for 2 h only
gave a 2.5:1 mixture of trans-7 and cis-7 (entry 2). Extending the
reaction time did not improve the stereochemical outcome, and
elevating the reaction temperature above 0 ꢁC resulted in low mass
recovery due to degradation of the material. Reacting 8 with NaH
(1.5 equiv) in THF at room temperature for 2 h gave a 1.4:1 mixture
of trans-7 and cis-7 in 98% yield (entry 3), and decomposition of the
material was observed on forcing the reaction conditions (e.g.,
extended reaction times and/or raising the reaction temperature
above room temperature). Treatment of 8 with DBU (0.3 equiv) in
2.2. Synthesis of common intermediate 8
Our synthesis started with silylation of the known homoallylic
alcohol 10, available in one step from (E)-cinnamaldehyde via
asymmetric allylation,15 giving silyl ether 11 in quantitative yield
(Scheme 2). Chemoselective hydroboration of 11 with dis-
iamylborane followed by oxidative workup delivered alcohol 12.
16
One-pot oxidation/Wittig homologation of 12 (TEMPO, PhI(OAc)2
then Ph3P]CHCO2Et) afforded enoate 13 in high yield and ster-
eoselectivity (95% yield, E/Z>20:1), which was reduced with
DIBALH to afford allylic alcohol 14. Asymmetric epoxidation of 14
using (þ)-diethyl tartrate (DET) as a chiral auxiliary produced ep-
oxy alcohol 15 (89%) as a single diastereomer (judged by 600 MHz
1H NMR). Iodination of 15 followed by zinc reduction cleanly gave
secondary allylic alcohol 9 quantitatively. Upon treatment of 9 with
methyl acrylate in the presence of 5 mol % of the Grubbs second-
generation catalyst (G-II)17 in toluene at room temperature, olefin
CM reaction proceeded cleanly to afford enoate 16 in 90% yield as
a sole isolable product. It is of particular interest that the possible
RCM reaction to yield the corresponding cyclohexene derivative did
not take place at all. The plausible rationale for this intriguing re-
activity of 9 is summarized in Figure 2. According to the early report

7494
H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
Thus, exposure of 8 to DBU (10 equiv) in toluene at 100 ꢁC (sealed
Ph
Ph
Ph
TBSCl
tube) afforded cis-7 in 85% yield with 7:1 diastereoselectivity. This
result indicated that sufficient thermodynamic equilibration be-
tween cis-7 and trans-7 could be achieved under these conditions
(entry 5). Further improvement was possible by running the re-
action at 135 ꢁC in a sealed tube, giving rise to cis-7 in 81% yield
with diastereomer ratio of 11:1 (entry 6). Fortunately, cis-7 and
trans-7 could be easily separated by flash chromatography on silica
gel. Thus, stereodivergent synthesis of 2,6-cis- and 2,6-trans-
substituted tetrahydropyrans, cis-7 and trans-7, respectively, from
the common intermediate 8 was realized simply by switching the
reaction conditions. The stereochemistry of cis-7 and trans-7 was
unequivocally established by NOE experiments as shown.
(Sia)2BH; then
aq NaHCO3
HO
TBSO
imidazole
TBSO
TBSO
100%
H2O2
HO
88%
10
11
12
TEMPO
Ph
Ph
PhI(OAc)2;
DIBALH
100%
HO
TBSO
then
Ph3P=CHCO2Et
95%
EtO2C
13
14
Ph
Ph
Ph
Ti(Oi-Pr)4, (+)-DET
t-BuOOH, 4 MS
TBS
O
1. I2, PPh3
imidazole
TBSO
O
89%
HO
2. Zn, AcOH
100%
2.4. Construction of the 14-membered macrocyclic
framework by esterification/RCM strategy
HO
9
15
(2 steps)
With both cis-7 and trans-7 in hand, we proceeded to construct
the macrocyclic framework of aspergillides A and B (Scheme 3).
Saponification of cis-7 with potassium trimethylsilanolate
(TMSOK)21 followed by coupling of the derived carboxylic acid with
Ph
G-II
MeO2C TBS
MeO2C TBS
O
MOMCl
i-Pr2NEt
CO2Me
toluene, rt
90%
O
90%
16
17
HO
MOMO
Me
Ph
1. TMSOK
MeO2C
MOMO
2. 2,4,6-Cl3C6H2COCl
Et3N; then DMAP
O
O
Ph
O
Ph
MesN
Cl
NMes
Ph
MeO2C
MOMO
TBAF
O
Me
AcOH
HO
Ru
Cl
OH
89%
cis-7
MOMO
PCy3
G-II
18
5
77% (2 steps)
8
Me
Me
Scheme 2. Synthesis of common intermediate 8.
G-II (10 mol%)
O
O
O
O
Table 1
Screening of the reaction conditionsa
CH2Cl2, 40 C
O
O
69%
MOMO
MOMO
Ph
(Z)-19
(E)-19
Me
O
1. TMSOK
MeO2C
MOMO
2. 2,4,6-Cl3C6H2COCl
Et3N; then DMAP
O
Ph
O
O
Me
OH
MOMO
18
trans-7
81% (2 steps)
6
Me
O
Me
O
G-II (10 mol%)
O
O
CH2Cl2, 40 C
Entry Reagents and conditions
Yield cis-7/trans-7b
O
O
(%)a
17%
1
2
KOt-Bu (0.05 equiv), THF, ꢀ78 ꢁC, 30 min
96
89
98
1:17
1:2.5
1:1.4
1:1.4
7:1
MOMO
MOMO
KOt-Bu (0.2 equiv), THF, 0 ꢁC, 2 h
(E)-20
(Z)-20
3
NaH (1.5 equiv), THF, room temperature, 2 h
4
DBU (0.3 equiv), CH2Cl2, room temperature, 99 h 93
OMOM
5c
6c
DBU (10 equiv), toluene, 100 ꢁC, 54 h
DBU (10 equiv), toluene, 135 ꢁC, 36 h
85
81
11:1
O
a
Isolated yield of a purified mixture of cis-7 and trans-7.
b
The diastereomer ratio was determined on the basis of 1H NMR analysis
Ph
O
O
(500 MHz, CDCl3) on crude reaction mixture.
Me
c
Me
Performed in a sealed tube.
O
O
Ph
21
CH2Cl2 at room temperature also resulted in an unsatisfactory
diastereoselectivity (entry 4). In contrast to the recent report from
the Murga/Marco group,5b after several experiments, we were
delighted to find that DBU efficiently converted trans-7 into cis-7
under forcing conditions without a sign of material decomposition.
O
MOMO
Scheme 3. RCM of dienes 5 and 6.

H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
7495
alcohol 1822 under Yamaguchi conditions23 gave diene 5 in 77%
yield for the two steps. RCM of 5 took place smoothly by the action
of 10 mol % of G-II catalyst in CH2Cl2 at 40 ꢁC. However, (Z)-isomer
(Z)-19 was exclusively isolated in 69% yield; no trace amount of the
desired (E)-19 was detected. A similar result was obtained when the
reaction was carried out in toluene at 70 ꢁC.5b,24 On the other hand,
RCM of diene 6, similarly prepared from trans-7, also produced (Z)-
isomer (Z)-20 in low yield (17%), along with several unidentified
products. Changing the solvent to toluene did not improve the
result, and the use of the Grubbs first-generation catalyst (G-I)25
only provided dimer 21 in 23% yield (38% based on recovered 6).
Here, we attempted to account for the outcome of the RCM of
diene 5 on the basis of conformational analysis by NOE experiments
and theoretical calculations.26 First, the conformational property of
diene 5 and macrolactone (Z)-19 was analyzed on the basis of NOE
experiments. As illustrated in Figure 3, it was found that both of the
tetrahydropyran rings of 5 and (Z)-19 exist in a stable chair con-
formation with all the substituents being equatorially disposed (i.e.,
‘equatorial-rich’ chair conformer), suggesting that the conforma-
tion of the tetrahydropyran did not change during the RCM process.
In contrast, according to the X-ray crystallographic analysis by
Kusumi and co-workers, the tetrahydropyran ring of aspergillide
A (4) is in a chair conformation, where all of the substituents are
axially oriented (i.e., ‘axial-rich’ chair conformer). Molecular
modeling by conformational searches (MMFF) and geometry opti-
mization (HF/6-31G //PM3) suggested that the tetrahydropyran
*
ring of (E)-19 adopts essentially the same conformation as that of 4,
possibly because of the constraint of the macrocycle (Fig. 4). Thus, it
is likely that the configuration of the C8eC9 double bond plays
a critical role in defining the conformation of the tetrahydropyran
ring of (E)-19 and (Z)-19, and vice versa. The formation of (Z)-19
would be preferred under kinetic conditions, because the pathway
to (E)-19 should suffer from an energetic penalty arising from
conformational flipping of the tetrahydropyran ring (i.e., ‘equato-
rial-rich’ chair conformer/‘axial-rich’ chair conformer). In addi-
tion, (Z)-19 would be also thermodynamically more favored than
(E)-19 because repulsive interactions between the substituents on
the tetrahydropyran are present within (E)-19,25 and this is also
Figure 4. Geometrically optimized structures of (E)-19, (Z)-19, (E)-20, and (Z)-20 at
HF/6-31G //PM3 level of theory.
*
We have also investigated the conformation of diene 6 and
macrolactones (E)-20 and (Z)-20. On the basis of 3JH,H values and an
NOE experiment, the tetrahydropyran ring of 6 would be in a chair
conformation with the C4 and C7 substituents being equatorially
oriented (i.e., ‘equatorial-rich’ chair conformer). By contrast, NOE
experiments on macrolactone (Z)-20 showed that the tetrahy-
dropyran ring of (Z)-20 adopts a chair conformation with the C4
and C7 substituents being axially disposed (i.e., ‘axial-rich’ chair
conformer), presumably due to the macrocyclic constraint. Thus,
the tetrahydropyran ring of diene 6 would have to flip to ‘axial-rich’
chair conformer during the RCM process, which makes the RCM of
6 difficult to achieve and may account for the low yield of (Z)-20.
Interestingly, theoretical calculations at HF/6-31G*//PM3 level
revealed that (E)-20 is energetically more stable than (Z)-20
supported by calculations at HF/6-31G
*
//PM3 level, which in-
dicated that (Z)-19 is considerably more stable than (E)-19
(
D
E¼13.0 kcal/mol). Thus, the kinetic product (Z)-19 would not
isomerize to (E)-19 under the reaction conditions.
(
D
E¼13.0 kcal/mol) (Fig. 4). The preferential formation of
energetically less stable (Z)-20 suggests that the RCM of 6 pro-
ceeded under kinetic control. We think that isomerization of (Z)-20
to the energetically more stable (E)-isomer was retarded
presumably because the C8eC9 double bond is sterically encum-
bered and could not react with ruthenium methylidene complex,
an active propagation catalyst of RCM.
2.5. Completion of the total synthesis of aspergillides A and B
by SuzukieMiyaura coupling/macrolactonization strategy
Based on the disappointing results of the RCM of dienes 5 and 6,
we envisaged that a prerequisite for the success of the total syn-
thesis of aspergillides A and B would be the formation of the C8eC9
double bond with correct configuration prior to the construction of
the macrocyclic framework. Accordingly, we thought that it would
be possible to construct the macrocycle via macrolactonization
(Scheme 4). Thus, 4 and 1 would be synthesized from cis-7 and
trans-7, respectively, via the formation of the C9eC10 double bond
Figure 3. Conformations of the tetrahydropyran rings of 5, 6, (Z)-19, and (Z)-20.

7496
H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
PdCl2(dppf), Ph3As, THF/DMF, rt)30 proceeded without incident to
14
Me
Me
Me
deliver trans-olefin 27 in 73% yield. Hydrolysis of 27 gave hydroxy
acid 23 in 88% yield, which was cyclized under Yamaguchi condi-
tions (2,4,6-Cl3C6H2COCl, Et3N, THF, rt; then slow addition (6.5 h) to
DMAP, toluene (1 mM), 100 ꢁC) to provide macrolactone 28 in 73%
yield. Finally, deprotection of the MOM group using LiBF4 (aqueous
CH3CN, 72 ꢁC)6c furnished synthetic aspergillide B (1), whose
spectroscopic properties and optical rotation value were in full
accordance with those of the natural product.
The total synthesis of aspergillide A (4) was similarly completed
as depicted in Scheme 6. The spectroscopic data and specific rotation
of synthetic 4 matched exactly those reported for the natural
product. However, we found it difficult to forge the macrolactone 30
OBz
26
10
OH
I
O
O
9
HO2C
MeO2C
1
O
O
24
O
O
7
3
MOMO
MOMO
HO
( )-aspergillide A (4)
22
Ph
Ph
MeO2C
MOMO
MeO2C
MOMO
O
cis-7
I
trans-7
Ph
MeO2C
MOMO
MeO2C
Me
I
O
14
Me
O
1. O3; then Ph3P
2. CrCl2, CHI3
Me
OBz 26
MOMO
OH
O
O
71% (2 steps)
MeO2C
MOMO
HO2C
1
E:Z = 3:1
24
cis-7
O
O
O
7
3
Me
MOMO
HO
( )-aspergillide B (1)
26, 9-BBN-H
THF, rt; then
aq Cs2CO3
OBz
23
25
aq NaOH
91%
O
Scheme 4. Revised synthesis plan for aspergillides A and B.
MeO2C
PdCl2(dppf)
Ph3As, DMF, rt
94%
by means of SuzukieMiyaura coupling27 and subsequent macro-
lactonization to forge the whole framework (i.e., SuzukieMiyaura
coupling/macrolactonization strategy).
Completion of the total synthesis of aspergillide B (1) is sum-
marized in Scheme 5. Ozonolysis of the double bond of trans-7
followed by Takai olefination (CrCl2, CHI3, THF/1,4-dioxane, rt)28
gave (E)-vinyl iodide 25 in 65% yield (E/Z¼ca. 5:1) for the two
steps. SuzukieMiyaura coupling of 25 with an alkylborane derived
from olefin 2629 under Johnson conditions (aqueous Cs2CO3,
MOMO
29
Me
Me
OH
O
O
see Table 2
O
O
HO2C
MOMO
MOMO
30
22
Me
Ph
I
MeO2C
MeO2C
MOMO
O
O
O
O
1. O3; then Ph3P
2. CrCl2, CHI3
LiBF4, aq MeCN, 72 C
82%
O
MOMO
65% (2 steps)
E:Z = 5:1
HO
4: aspergillide A
trans-7
25
Me
Scheme 6. Completion of the total synthesis of aspergillides A.
26, 9-BBN-H
THF, rt; then
aq Cs2CO3
OBz
due to competitive formation of dimeric product 31 and degradation
of the material. We examined several reaction conditions as sum-
marized in Table 2. Our first attempt was to perform the macro-
lactonizationunderessentially the sameconditions as those usedfor
23 (2,4,6-Cl3C6H2COCl, Et3N, THF, room temperature; then slow
addition (5 h) to DMAP, toluene (1 mM), 100 ꢁC), but unfortunately
the only isolable product was dimer 31 (entry 1). Only a trace
amount of 30 was detected by LC/MS analysis of a crude mixture. To
suppress the undesired dimerization, a solution of a mixed anhy-
dride generated in situ from hydroxy acid 22 was added slowly over
a period of 8.5 h to a solution of DMAP in toluene at 100 ꢁC, resulting
in the formation of the desired lactone 30 in 12% yield, along with
dimer 31 in 28% yield (entry 2). This result suggested that the
macrolactonization had to be performed under high-dilution con-
ditions (<1 mM) with careful slow addition technique. Further
optimization of the reaction conditions (2,4,6-Cl3C6H2COCl, Et3N,
THF, room temperature; then slow addition (13 h) to DMAP, toluene
(0.2 mM), 80 ꢁC) improved the yield of 30 up to 20% (entry 3).
However, at the same time, a significant amount of 22 was decom-
posed under these conditions, resulting in low mass recovery. The
difficulties associated with the macrolactonization of 22 can be
aq NaOH
88%
O
MeO2C
MOMO
PdCl2(dppf)
Ph3As, DMF, rt
73%
27
Me
O
Me
OH
O
2,4,6-Cl3C6H2COCl
Et3N, THF, rt; then
DMAP, toluene (1 mM)
O
O
HO2C
MOMO
100 C, 6.5 h
73%
MOMO
28
23
Me
O
O
LiBF4, aq MeCN, 72 C
94%
O
HO
1: aspergillide B
Scheme 5. Completion of the total synthesis of aspergillide B.

H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
7497
Table 2
was stirred at room temperature for 1.5 h before the reaction was
quenched with H2O. The resultant mixture was extracted with
diethyl ether, and the combined organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography on
Screening of the reaction conditions of Yamaguchi macrolactonization
OMOM
Me
Me
O
silica gel (3% EtOAc/hexanes) gave silyl ether 11 (4.29 g, 100%) as
O
O
OH
O
O
HO2C
18
a colorless clear oil: [
a
]
þ28.4 (c 1.00 in CHCl3); IR (film) 2955,
D
O
O
2929, 2856, 1254, 1071, 966, 836, 776 cmꢀ1
CDCl3)
;
1H NMR (600 MHz,
Me
+
Me
d
7.36 (d, J¼7.8 Hz, 2H), 7.30 (dd, J¼7.8, 7.8 Hz, 2H), 7.21 (dd,
MOMO
MOMO
O
O
J¼7.8, 7.8 Hz, 1H), 6.50 (d, J¼15.6 Hz, 1H), 6.19 (dd, J¼15.6, 6.0 Hz,
1H), 5.83 (m, 1H), 5.10e5.02 (m, 2H), 4.31 (ddd, J¼6.0, 6.0, 6.0 Hz,
1H), 2.39e2.29 (m, 2H), 0.91 (s, 9H), 0.075 (s, 3H), 0.051 (s, 3H); 13C
22
30
O
NMR (125 MHz, CDCl3)
d
137.1, 134.9, 132.8, 129.1, 128.5 (ꢂ2), 127.3,
MOMO
31
126.4 (ꢂ2), 117.0, 73.3, 43.1, 25.9 (ꢂ3), 18.3, ꢀ4.3, ꢀ4.7; HRMS (ESI)
calcd for C18H28OSiNa [(MþNa)þ] 311.1802, found 311.1804.
Entry
1
Reagents and Conditions
Yield (%)
30
31
4.1.2. Alcohol 12. To a solution of 2-methyl-2-butene (4.10 mL,
38.7 mmol) in THF (100 mL) cooled to 0 ꢁC was added BH3$SMe2
(1.9 M solution in THF, 10.1 mL, 19.2 mmol), and the resultant
solution was stirred at 0 ꢁC for 1 h. To this solution was added
a solution of silyl ether 11 (4.26 g, 14.8 mmol) in THF (20þ10 mL
rinse). The resultant solution was stirred at 0 ꢁC for 1 h before it was
treated with saturated aqueous NaHCO3 solution (20 mL) and 30%
aqueous H2O2 solution (10 mL). The resultant mixture was stirred
at room temperature for 1 h. The reaction mixture was extracted
with EtOAc, and the combined organic layer was washed with
saturated aqueous Na2SO3, and then brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on silica
2,4,6-Cl3C6H2COCl, Et3N, THF, room temperature;
then DMAP, toluene (1 mM), 100 ꢁC
(added over 5 h)a
2,4,6-Cl3C6H2COCl, Et3N, THF, room temperature;
then DMAP, toluene (0.8 mM), 100 ꢁC
(added over 8.5 h)a
2,4,6-Cl3C6H2COCl, Et3N, THF, room temperature;
then DMAP, toluene (0.2 mM), 80 ꢁC
(added over 13 h)a
Trace
29
2
3
12
20
28
Trace
a
Syringe pump addition.
reasoned by the fact that the energetically favored ‘all-equatorial’
chair conformer of the tetrahydropyran ring of 22 would have to flip
to the energetically disfavored ‘all-axial’ chair conformer during the
macrolactonization process.
gel (10e15% EtOAc/hexanes) gave alcohol 12 (3.98 g, 88%) as
25
a colorless clear oil: [
a]
þ42.2 (c 1.00 in CHCl3); IR (film) 3349,
D
2952, 2928, 2884, 2856, 1254, 1058, 836, 775, 692 cmꢀ1
(600 MHz, CDCl3)
;
1H NMR
3. Conclusion
d
7.35 (d, J¼7.2 Hz, 2H), 7.30 (dd, J¼7.2, 7.2 Hz,
2H), 7.21 (dd, J¼7.2, 7.2 Hz, 1H), 6.48 (d, J¼15.8 Hz, 1H), 6.16 (dd,
J¼15.8, 6.5 Hz, 1H), 4.35 (m, 1H), 3.68e3.59 (m, 2H), 1.87 (br m, 1H),
1.73e1.59 (m, 4H), 0.91 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR
We have successfully completed the enantioselective total
synthesis of aspergillides A and B by exploiting a unified strategy.
Highly chemoselective olefin CM of secondary allylic alcohol 9 with
methyl acrylate was realized by the assistance of the H-bonding
formed within the ruthenium alkylidene species A. Stereodivergent
synthesis of 2,6-cis- and 2,6-trans-substituted tetrahydropyrans
(cis-7 and trans-7, respectively) was achieved simply by switching
the reaction conditions. Due to the unique strained molecular ar-
chitecture, the esterification/RCM strategy has proven to be un-
suitable for the construction of the macrocyclic framework of these
natural products. The total synthesis of aspergillides A and B was
eventually accomplished by exploiting SuzukieMiyaura coupling/
macrolactonization strategy.
(125 MHz, CDCl3)
d
136.9, 132.7, 129.4, 128.5 (ꢂ2), 127.4, 126.3 (ꢂ2),
73.3, 63.0, 34.9, 28.3, 25.9 (ꢂ3), 18.2, ꢀ4.3, ꢀ4.8; HRMS (ESI) calcd
for C18H30O2SiNa [(MþNa)þ] 329.1907, found 329.1917.
4.1.3. Enoate 13. To a solution of alcohol 12 (3.95 g, 12.9 mmol) in
CH2Cl2 (100 mL) were added PhI(OAc)2 (5.40 g, 16.8 mmol) and
TEMPO (0.40 g, 2.6 mmol), and the resultant solution was stirred at
room temperature for 8 h. To this solution was added Ph3P]
CHCO2Et (6.74 g, 19.3 mmol), and the resultant solution was stirred
at room temperature for 15 h. The reaction mixture was diluted
with EtOAc and washed with a 1:1 mixture of saturated aqueous
NaHCO3 solution/saturated aqueous Na2S2O3 solution, and then
brine. The organic layer was dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (3% EtOAc/hexanes) gave enoate
4. Experimental section
4.1. General remarks
13 (4.61 g, 95%) as a colorless clear oil: [
a]
28 þ19.7 (c 0.40 in CHCl3);
D
All reactions sensitive to moisture and/or air were carried out
under an atmosphere of argon in dry, freshly distilled solvents under
anhydrous conditions using oven-dried glassware unless otherwise
noted. Chemical shift values of 1H and 13C NMR spectra are reported
IR (film) 2954, 2929, 2856, 1720, 1257, 836, 776 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d
7.34 (d, J¼8.4 Hz, 2H), 7.30 (dd, J¼8.4, 8.4 Hz,
2H), 7.22 (dd, J¼8.4, 8.4 Hz, 1H), 6.97 (ddd, J¼15.6, 6.8, 6.8 Hz, 1H),
6.48 (d, J¼15.6 Hz, 1H), 6.12 (dd, J¼15.6, 6.8 Hz, 1H), 5.81 (d,
J¼15.6 Hz, 1H), 4.29 (ddd, J¼6.8, 6.8, 6.8 Hz, 1H), 4.16 (q, J¼6.8 Hz,
2H), 2.34e2.22 (m, 2H), 1.78e1.64 (m, 2H), 1.26 (t, J¼6.8 Hz, 3H),
0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
in parts per million (d) downfield from tetramethylsilane with ref-
erence to internal residual solvent [1H NMR, CHCl3 (7.24), C6HD5
(7.15); 13C NMR, CDCl3 (77.0), C6D6 (128.0)] unless otherwise noted.
Coupling constants (J) are reported in hertz (Hz). The following ab-
breviations were used to designate the multiplicities: s¼singlet;
d¼doublet; t¼triplet; m¼multiplet; br¼broad.
d
166.7,149.0,136.9,132.6, 129.6, 128.6 (ꢂ2),127.5,126.4 (ꢂ2),121.4,
72.7, 60.1, 36.5, 27.8, 25.9 (ꢂ3), 18.2, 14.3, ꢀ4.2, ꢀ4.8; HRMS (ESI)
calcd for C22H34O3SiNa [(MþNa)þ] 397.2169, found 397.2176.
4.1.1. Silyl ether 11. To a solution of homoallylic alcohol 10 (2.59 g,
14.9 mmol) in DMF (50 mL) were added imidazole (2.03 g,
29.8 mmol) and TBSCl (3.14 g, 20.8 mmol). The reaction mixture
4.1.4. Allylic alcohol 14. To a solution of enoate 13 (4.58 g,
12.2 mmol) in CH2Cl2 (100 mL) cooled to ꢀ78 ꢁC was added DIBALH
(1.02 M solution in hexanes, 35.0 mL, 35.7 mmol). The resultant

7498
H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
solution was stirred at ꢀ78 ꢁC for 1 h before the reaction was
quenched with MeOH. The resultant mixture was diluted with
EtOAc and saturated aqueous potassium sodium tartrate solution
and stirred vigorously at room temperature until the layers became
clear. The organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash chromato-
graphy on silica gel (10e15% EtOAc/hexanes) gave allylic alcohol 14
[
a
]
28 þ49.8 (c 1.00 in CHCl3); IR (film) 3364, 2953, 2928, 2885, 2856,
D
1070, 967, 836, 775 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
7.35 (d,
J¼7.2 Hz, 2H), 7.30 (dd, J¼7.2, 7.2 Hz, 2H), 7.21 (dd, J¼7.2, 7.2 Hz,1H),
6.47 (d, J¼15.8 Hz, 1H), 6.16 (dd, J¼15.8, 6.5 Hz, 1H), 5.85 (ddd,
J¼17.0, 10.3, 5.3 Hz, 1H), 5.21 (dd, J¼17.0, 1.2 Hz, 1H), 5.08 (d,
J¼10.3 Hz, 1H), 4.32 (ddd, J¼5.3, 5.3, 5.3 Hz, 1H), 4.10 (m, 1H), 2.07
(br s, 1H), 1.74e1.56 (m, 4H), 0.90 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H);
13C NMR (125 MHz, CDCl3)
d
141.1, 137.0, 132.8, 129.4, 128.5 (ꢂ2),
127.4, 126.4 (ꢂ2), 114.6, 73.5, 73.2, 34.3, 32.6, 25.9 (ꢂ3), 18.3, ꢀ4.3,
ꢀ4.8; HRMS (ESI) calcd for C20H32O2SiNa [(MþNa)þ] 355.2064,
found 355.2059.
(4.10 g, 100%) as a colorless clear oil: [
a
]
27 þ24.7 (c 1.00 in CHCl3); IR
D
(film) 3341, 2952, 2928, 2855, 1087, 966, 835, 775, 692 cmꢀ1
;
1H
NMR (600 MHz, CDCl3)
d
7.35 (d, J¼7.3 Hz, 2H), 7.30 (dd, J¼7.3,
7.3 Hz, 2H), 7.21 (dd, J¼7.3, 7.3 Hz, 1H), 6.47 (d, J¼15.8 Hz, 1H), 6.14
(dd, J¼16.1, 6.5 Hz, 1H), 5.70 (m, 1H), 5.64 (m, 1H), 4.27 (ddd, J¼6.5,
6.5, 6.5 Hz, 1H), 4.07 (dd, J¼5.6, 5.6 Hz, 2H), 2.19e2.05 (m, 2H),
1.72e1.56 (m, 2H), 1.25 (m, 1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s,
4.1.7. Enoate 16. To a solution of allylic alcohol 9 (150.2 mg,
0.4517 mmol) in toluene (4.5 mL) and methyl acrylate (2.5 mL) was
added the Grubbs second-generation catalyst (14.3 mg,
0.0228 mmol). After being stirred at room temperature for 2 h, the
reaction mixture was exposed to air for 1.5 h, treated with Et3N (10
drops), and then filtered through a pad of silica gel. The filtrate was
concentrated under reduced pressure. Purification of the residue by
3H); 13C NMR (125 MHz, CDCl3)
d 137.0, 133.1, 133.0, 129.2, 129.1,
128.5 (ꢂ2), 127.3, 126.3 (ꢂ2), 73.0, 63.8, 37.7, 27.9, 25.9 (ꢂ3), 18.2,
ꢀ4.2, ꢀ4.8; HRMS (ESI) calcd for C20H32O2SiNa [(MþNa)þ]
355.2064, found 355.2077.
flash chromatography on silica gel (5e20% EtOAc/hexanes) gave
28
enoate 16 (158.7 mg, 90%) as a colorless oil: [
a
]
þ55.2 (c 1.00 in
D
4.1.5. Epoxy alcohol 15. To a solution of allylic alcohol 14 (1.13 g,
CHCl3); IR (film) 3444, 2952, 2928, 2856, 1725, 1256, 1070, 836,
ꢀ
3.40 mmol) in CH2Cl2 (30 mL) were added 4 A molecular sieves
776 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
7.36e7.32 (m, 2H),
(1.00 g) and (þ)-DET (0.18 g, 0.87 mmol), and the resultant mixture
was cooled to ꢀ25 ꢁC. To this mixture was added Ti(Oi-Pr)4
(0.200 mL, 0.676 mmol), and the resultant mixture was stirred at
ꢀ25 ꢁC for 30 min. To this mixture was added t-BuOOH (5.0 M so-
lution in isooctane, 1.40 mL, 7.00 mmol), and the resultant mixture
was stirred at ꢀ25 ꢁC for 24 h. The reaction was quenched with
saturated aqueous Na2SO4 solution. The resultant mixture was
allowed to warm to room temperature with vigorous stirring and
then filtered through a pad of Celite. The filtrate was extracted with
EtOAc. The combined organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
7.32e7.27 (m, 2H), 7.22 (m, 1H), 6.93 (dd, J¼15.5, 4.5 Hz, 1H), 6.47
(d, J¼16.0 Hz, 1H), 6.14 (dd, J¼15.5, 6.0 Hz, 1H), 6.06 (dd, J¼16.0,
1.0 Hz,1H), 4.40e4.28 (m, 2H), 3.72 (s, 3H), 2.68 (br d, J¼3.5 Hz,1H),
1.80e1.58 (m, 4H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d
167.0, 150.4, 136.7, 132.2, 129.8, 128.6 (ꢂ2),
127.5, 126.4 (ꢂ2), 119.7, 73.4, 71.0, 51.6, 34.2, 32.0, 25.9 (ꢂ3), 18.3,
ꢀ4.3, ꢀ4.8; HRMS (ESI) calcd for C22H34O4SiNa [(MþNa)þ]
413.2119, found 413.2128.
4.1.8. MOM ether 17. To
a solution of enoate 16 (146.5 mg,
0.3751 mmol) in ClCH2CH2Cl (5 mL) were added i-Pr2NEt (1.29 mL,
7.50 mmol) and MOMCl (0.285 mL, 3.75 mmol), and the resultant
solution was stirred at 50 ꢁC for 7.25 h. After cooling to room
temperature, the reaction mixture was diluted with EtOAc and
washed successively with H2O, 1 M aqueous HCl solution, saturated
aqueous NaHCO3 solution, and then brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on silica
gel (3e10% EtOAc/hexanes) gave MOM ether 17 (147.0 mg, 90%) as
(10e20% EtOAc/hexanes) gave epoxy alcohol 15 (1.05 g, 89%) as
27
a colorless clear oil: [
a]
þ19.9 (c 1.00 in CHCl3); IR (film) 3419,
D
2953, 2928, 2856, 967, 836, 776, 692 cmꢀ1
CDCl3)
;
1H NMR (600 MHz,
d
7.34 (d, J¼7.2 Hz, 2H), 7.30 (dd, J¼7.2, 7.2 Hz, 2H), 7.21 (dd,
J¼7.2, 7.2 Hz, 1H), 6.48 (d, J¼15.8 Hz, 1H), 6.13 (dd, J¼15.8, 6.2 Hz,
1H), 4.31 (m, 1H), 3.89 (ddd, J¼12.6, 5.3, 2.6 Hz, 1H), 3.60 (ddd,
J¼12.6, 7.2, 4.8 Hz, 1H), 2.97 (m, 1H), 2.91 (m, 1H), 1.78e1.54 (m,
5H), 0.90 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz,
a colorless clear oil: [
a]
26 þ1.3 (c 1.0 in CH2Cl2); IR (film) 2952, 2929,
D
CDCl3)
d
136.9, 132.8, 129.4, 128.5 (ꢂ2), 127.4, 126.3 (ꢂ2), 73.0, 61.6,
2887, 2856, 1728, 1257, 1037, 836, 776 cmꢀ1
;
1H NMR (500 MHz,
58.4, 55.9, 34.5, 27.4, 25.9 (ꢂ3), 18.2, ꢀ4.2, ꢀ4.8; HRMS (ESI) calcd
CDCl3) d 7.36e7.32 (m, 2H), 7.32e7.27 (m, 2H), 7.21 (m, 1H), 6.80
for C20H32O3SiNa [(MþNa)þ] 371.2013, found 371.2023.
(dd, J¼15.5, 6.5 Hz, 1H), 6.46 (d, J¼15.5 Hz, 1H), 6.12 (dd, J¼16.0,
7.0 Hz, 1H), 5.97 (dd, J¼16.0, 1.0 Hz, 1H), 4.60 (d, J¼6.5 Hz, 1H), 4.56
(d, J¼6.5 Hz,1H), 4.27 (m,1H), 4.20 (m,1H), 3.72 (s, 3H), 3.34 (s, 3H),
1.77e1.52 (m, 4H), 0.89 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR
4.1.6. Allylic alcohol 9. To a solution of epoxy alcohol 15 (1.02 g,
2.93 mmol) in THF (25 mL) were added imidazole (0.40 g,
5.9 mmol), Ph3P (1.15 g, 4.38 mmol), and I2 (1.12 g, 4.41 mmol). The
reaction mixture was stirred at room temperature for 20 min before
the reaction was quenched with saturated aqueous Na2S2O3 solu-
tion. The resultant mixture was extracted with EtOAc, and the
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude iodo-
epoxide was used in the next reaction without further purification.
To a solution of the above iodo-epoxide in EtOH (25 mL) were
added zinc powder (1.92 g, 29.4 mmol) and AcOH (0.335 mL,
5.85 mmol). The reaction mixture was stirred at room temperature
for 30 min before the reaction was quenched with saturated
aqueous NaHCO3 solution. The mixture was filtered through a pad
of Celite, and extracted with EtOAc. The combined organic layer
was washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Purification of the residue by flash
chromatography on silica gel (5e15% EtOAc/hexanes) gave allylic
alcohol 9 (0.97 g, 100% for the two steps) as a colorless clear oil:
(125 MHz, CDCl3)
d
166.6, 148.1, 136.9, 132.9, 129.3, 128.5 (ꢂ2),
127.4, 126.4 (ꢂ2), 121.5, 94.6, 75.2, 73.3, 55.7, 51.6, 33.7, 30.4, 25.9
(ꢂ3), 18.2, ꢀ4.2, ꢀ4.8; HRMS (ESI) calcd for C24H38O5SiNa
[(MþNa)þ] 457.2381, found 457.2389.
4.1.9. Alcohol 8. To
a solution of MOM ether 17 (127.8 mg,
0.2940 mmol) in THF (0.5 mL) were added TBAF (1.0 M solution in
THF, 4.40 mL, 4.40 mmol) and AcOH (0.265 mL, 4.63 mmol), and
the resultant solution was stirred at 35 ꢁC overnight. The reaction
mixture was diluted with EtOAc and washed successively with
saturated aqueous NaHCO3 solution, saturated aqueous NH4Cl
solution, and then brine. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash chromatography on silica gel (10e30% EtOAc/
hexanes) gave alcohol 8 (83.6 mg, 89%) as a colorless clear oil:
[a
]
28 ꢀ35.3 (c 1.00 in CHCl3); IR (film) 3422, 2949, 1720, 1276, 1149,
D
1031 cmꢀ1
; d 7.37e7.32 (m, 2H),
1H NMR (500 MHz, CDCl3)

H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
7499
7.32e7.27 (m, 2H), 7.22 (m, 1H), 6.81 (dd, J¼15.5, 6.5 Hz, 1H), 6.55
(d, J¼15.5 Hz,1H), 6.18 (dd, J¼16.5, 7.0 Hz,1H), 5.98 (br d, J¼15.5 Hz,
1H), 4.62 (d, J¼7.0 Hz,1H), 4.58 (d, J¼7.0 Hz,1H), 4.30e4.22 (m, 2H),
3.72 (s, 3H), 3.36 (s, 3H), 1.94 (br s, 1H), 1.80e1.55(m, 4H); 13C NMR
Cl3C6H2COCl (0.075 mL, 0.48 mmol). The resultant mixture was
stirred at room temperature for 80 min. The solvent was removed
under reduced pressure, and the residue was taken up in benzene
(3 mL). To this mixture was added a solution of alcohol 18 (62.0 mg,
0.544 mmol) and DMAP (132.8 mg, 1.087 mmol) in benzene (2 mL),
and the resultant mixture was stirred at room temperature for
90 min. The reaction mixture was diluted with EtOAc, washed
successively with 1 M aqueous HCl solution, saturated aqueous
NaHCO3 solution, and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (10%
EtOAc/hexanes) gave ester 5 (112.9 mg, 77% for the two steps) as
(125 MHz, CDCl3)
d
166.6,147.8,136.5,132.0,130.5,128.6 (ꢂ2),127.7,
126.4 (ꢂ2), 121.7, 94.7, 75.0, 72.7, 55.8, 51.7, 32.6, 30.7; HRMS (ESI)
calcd for C18H24O5Na [(MþNa)þ] 343.1516, found 343.1518.
4.1.10. Tetrahydropyran trans-7. To a solution of alcohol 8 (107.1 mg,
0.3343 mmol) inTHF (4.5 mL) cooled to ꢀ78 ꢁC was added dropwise
a solution of KOt-Bu (1.9 mg, 0.017 mmol) in THF (0.3 mL). After
being stirred at ꢀ78 ꢁC for 0.5 h, the reaction mixture was quenched
with saturated aqueous NH4Cl solution and extracted with EtOAc.
The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (10e30%
EtOAc/hexanes) gave a 17:1 mixture of trans-7 and cis-7 (102.4 mg,
96%). Separation of these diastereomers was achieved by flash
a colorless oil: [
a
]
26 þ78.5 (c 0.92 in benzene); IR (film) 2937, 1732,
D
1451, 1377, 1298, 1191, 1107, 1038, 966, 915, 747, 695 cmꢀ1; 1H NMR
(600 MHz, CDCl3)
d
7.33 (d, J¼7.2 Hz, 2H), 7.27 (dd, J¼7.9, 7.2 Hz,
2H), 7.19 (dd, J¼7.9, 7.9 Hz, 1H), 6.54 (d, J¼16.1 Hz, 1H), 6.15 (dd,
J¼16.1, 5.5 Hz, 1H), 5.72 (m, 1H), 5.00e4.91 (m, 2H), 4.88 (m, 1H),
4.72 (d, J¼6.8 Hz,1H), 4.60 (d, J¼6.8 Hz,1H), 4.02 (m,1H), 3.77 (ddd,
J¼8.6, 8.6, 3.8 Hz, 1H), 3.37 (s, 3H), 3.35 (m, 1H), 2.83 (dd, J¼15.1,
4.1 Hz, 1H), 2.48 (dd, J¼15.1, 8.6 Hz, 1H), 2.27 (m, 1H), 2.01e1.96 (m,
2H), 1.84 (m, 1H), 1.61e1.32 (m, 6H), 1.19 (d, J¼6.5 Hz, 3H); 13C NMR
chromatography on silica gel (1% diethyl ether/benzene) to give
18
tetrahydropyran trans-7 (96.4 mg, 90%) as a colorless clear oil: [a]
þ3.4 (c 1.0 in CHCl3); IR (film) 2948, 1738, 1149, 1104, 1035 cmꢀ1; 1DH
NMR (500 MHz, CDCl3)
d
7.40e7.35 (m, 2H), 7.32e7.27 (m, 2H), 7.21
(150 MHz, CDCl3)
d
171.1, 138.5, 136.8, 130.2, 129.5, 128.4 (ꢂ2), 127.5,
(m, 1H), 6.61 (dd, J¼16.5, 1.5 Hz, 1H), 6.21 (dd, J¼16.0, 4.5 Hz, 1H),
4.70 (d, J¼7.0 Hz, 1H), 4.62 (d, J¼7.5 Hz, 1H), 4.50 (m, 1H), 4.38 (ddd,
J¼8.0, 5.0, 3.5 Hz, 1H), 3.73e3.66 (m, 4H), 3.37 (s, 3H), 2.78 (dd,
J¼15.5, 9.0 Hz, 1H), 2.60 (dd, J¼15.5, 5.5 Hz, 1H), 2.08 (m, 1H),
126.4 (ꢂ2), 114.6, 95.2, 77.64, 77.61, 75.2, 70.8, 55.6, 38.7, 35.4, 33.4,
31.1, 29.9, 24.6, 20.0, 14.2; HRMS (ESI) calcd for C24H34O5Na
[(MþNa)þ] 425.2298, found 425.2302.
1.94e1.76 (m, 2H), 1.60 (m, 1H); 13C NMR (125 MHz, CDCl3)
d
172.0,
4.1.13. (Z)-Olefin 19. To a solution of ester 5 (16.3 mg, 0.0405 mmol)
in CH2Cl2 (38 mL) was added G-II (3.4 mg, 0.0040 mmol) in CH2Cl2
(2 mL), and the resultant solution was stirred at 40 ꢁC for 20 h. After
being cooled to room temperature, the resultant solution was ex-
posed to air with stirring at room temperature for a while and then
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (4e10% EtOAc/hexanes) gave (Z)-
136.7,131.4,128.9,128.5 (ꢂ2),127.6,126.4 (ꢂ2), 95.3, 71.8, 71.5, 70.3,
55.7, 51.7, 34.9, 25.9, 23.9; HRMS (ESI) calcd for C18H24O5Na
[(MþNa)þ] 343.1516, found 343.1518.
4.1.11. Tetrahydropyran cis-7. To
a
solution of
8
(61.1 mg,
0.191 mmol) in toluene (3.0 mL) placed in a tube was added DBU
(0.285 mL,1.91 mmol). The tube was sealed and heated at 135 ꢁC for
36 h. The reaction mixture was cooled to 0 ꢁC and neutralized with
saturated aqueous NH4Cl solution. The resultant mixture was
extracted with EtOAc, and the organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on silica
gel (10e20% EtOAc/hexanes) gave an 11:1 mixture of cis-7 and
trans-7 (49.7 mg, 81%) as a colorless clear oil. Further purification
by flash chromatography on silica gel (1.5% diethyl ether/benzene)
olefin 19 (8.3 mg, 69%) as a colorless oil: [
a
]
26 þ63.4 (c 0.74 in ben-
D
zene); IR (film) 2930, 1726, 1452, 1373, 1334, 1301, 1245, 1220, 1190,
1137, 1104, 1071, 1038, 916 cmꢀ1 1H NMR (600 MHz, CDCl3)
; d 5.61
(ddd, J¼10.7, 5.9, 2.5 Hz, 1H), 5.16 (dd, J¼10.7, 2.8 Hz, 1H), 5.01 (m,
1H), 4.70 (d, J¼6.5 Hz, 1H), 4.55 (d, J¼6.5 Hz, 1H), 4.06 (m, 1H), 3.66
(ddd, J¼11.3, 9.3, 2.4 Hz, 1H), 3.33 (s, 3H), 3.28 (ddd, J¼10.3, 9.7,
4.4 Hz,1H), 2.81 (dd, J¼12.1, 2.8 Hz,1H), 2.31 (dd, J¼12.1,11.3 Hz,1H),
2.28e2.17 (m, 2H), 1.77 (m, 1H),1.68e1.45 (m, 6H), 1.40 (m, 1H), 1.23
(d, J¼6.2 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d 173.3, 135.5, 128.1,
gave pure tetrahydropyran cis-7 (42.7 mg, 70%) as a colorless clear
95.0, 79.8, 75.04, 74.97, 69.7, 55.5, 39.2, 34.5, 31.7, 30.3, 28.0, 25.9,
20.9; HRMS (ESI) calcd for C16H26O5Na [(MþNa)þ] 321.1672, found
321.1662.
24
oil: [
a
]
D
þ88.5 (c 1.00 in CHCl3); IR (film) 2948, 1740, 1150, 1107,
1037 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.34 (d, J¼7.5 Hz, 2H), 7.27
(dd, J¼7.5, 7.5 Hz, 2H), 7.20 (dd, J¼7.5, 7.5 Hz,1H), 6.53 (d, J¼16.0 Hz,
1H), 6.15 (dd, J¼16.0, 5.5 Hz, 1H), 4.71 (d, J¼7.0 Hz, 1H), 4.60 (d,
J¼7.0 Hz, 1H), 4.04 (m, 1H), 3.78 (ddd, J¼8.5, 8.5, 4.0 Hz, 1H), 3.68 (s,
3H), 3.40e3.29 (m, 4H), 2.83 (dd, J¼15.5, 4.0 Hz, 1H), 2.51 (dd,
J¼15.5, 8.5 Hz,1H), 2.27 (m,1H), 1.85 (m,1H), 1.62e1.48 (m, 2H); 13C
4.1.14. Ester 6. To a solution of 2,6-trans-tetrahydropyran trans-7
(19.3 mg, 0.0602 mmol) in diethyl ether (1.5 mL) was added TMSOK
(23.2 mg, 0.181 mmol). The resultant mixture was stirred at room
temperature for 3 h before being quenched with H2O and acidified
with 1 M aqueous HCl solution (pH¼ca. 2). The resultant mixture
was extracted with CHCl3, and the combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was passed through a pad of silica gel (eluted with
40% EtOAc/hexanes) to give a carboxylic acid (17.8 mg), which was
used in the next reaction without further purification.
To a solution of the above material (17.8 mg) in THF (1.3 mL)
cooled to 0 ꢁC were added Et3N (0.040 mL, 0.29 mmol) and 2,4,6-
Cl3C6H2COCl (0.018 mL, 0.12 mmol). The resultant mixture was
stirred at room temperature for 80 min. The solvent was removed
under reduced pressure, and the residue was taken up in toluene
(0.8 mL). To this mixture was added a solution of alcohol 18
(21.2 mg, 0.186 mmol) and DMAP (21.3 mg, 0.174 mmol) in toluene
(0.8 mL), and the resultant mixture was stirred at room tempera-
ture for 1.5 h. The reaction mixture was diluted with EtOAc, washed
with saturated aqueous NH4Cl solution and brine, dried over
NMR (125 MHz, CDCl3)
d
172.0, 136.7, 130.3, 129.4, 128.4 (ꢂ2), 127.5,
126.4 (ꢂ2), 95.2, 77.7, 77.3, 75.2, 55.6, 51.6, 38.1, 31.1, 29.9; HRMS
(ESI) calcd for C18H24O5Na [(MþNa)þ] 343.1516, found 343.1519.
4.1.12. Ester 5. To
a solution of 2,6-cis-tetrahydropyran cis-7
(117.6 mg, 0.3675 mmol) in THF (4 mL) was added TMSOK
(141.4 mg, 1.102 mmol). The resultant mixture was stirred at room
temperature for 4 h before being quenched with H2O and acidified
with 1 M aqueous HCl solution (pH¼ca. 4). The resultant mixture
was extracted with EtOAc, and the organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was passed through a pad of silica gel (eluted
with 30e50% EtOAc/hexanes) to give a carboxylic acid (110.9 mg),
which was used in the next reaction without further purification.
To a solution of the above material (110.9 mg) in THF (4 mL)
cooled to 0 ꢁC were added Et3N (0.100 mL, 0.717 mmol) and 2,4,6-

7500
H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (5e10%
EtOAc/hexanes) gave ester 6 (19.3 mg, 81% yield for the two steps)
excess ozone, triphenylphosphine (227.8 mg, 0.8684 mmol) was
added. The resultant mixture was allowed to warm to room tem-
perature overnight and then concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(10e30% EtOAc/hexanes) gave an aldehyde (99.8 mg, 93%) as
as a colorless oil: [
a]
26 þ7.5 (c 1.29 in benzene); IR (film) 2937, 1730,
D
1446, 1377, 1281, 1148, 1105, 1037, 966, 915, 748, 695 cmꢀ1; 1H NMR
(600 MHz, CDCl3)
d
7.37 (d, J¼7.2 Hz, 2H), 7.29 (dd, J¼7.9, 7.2 Hz,
a colorless oil: [
a]
18 ꢀ16.5 (c 1.0 in CHCl3); IR (film) 2951, 1734, 1149,
D
2H), 7.22 (dd, J¼7.9, 7.9 Hz, 1H), 6.60 (dd, J¼16.1, 1.7 Hz, 1H), 6.22
(dd, J¼16.1, 5.2 Hz, 1H), 5.75 (m, 1H), 4.99e4.89 (m, 3H), 4.70 (d,
J¼6.9 Hz, 1H), 4.63 (d, J¼6.9 Hz, 1H), 4.48 (m, 1H), 4.39 (ddd, J¼9.3,
4.8, 4.1 Hz, 1H), 3.73 (m, 1H), 3.37 (s, 3H), 2.76 (dd, J¼15.1, 9.3 Hz,
1H), 2.57 (dd, J¼15.1, 4.8 Hz, 1H), 2.09e1.98 (m, 3H), 1.90e1.77 (m,
2H), 1.62e1.33 (m, 5H), 1.20 (d, J¼6.2 Hz, 3H); 13C NMR (150 MHz,
1106, 1034 cmꢀ1; 1H NMR (500 MHz, C6D6)
d
9.65 (br s, 1H), 4.32 (d,
J¼7.0 Hz, 1H), 4.25 (d, J¼7.0 Hz, 1H), 4.14 (m, 1H), 3.63 (m, 1H), 3.34
(s, 3H), 3.26 (m, 1H), 3.04 (s, 3H), 2.77 (dd, J¼16.0, 9.0 Hz, 1H), 2.41
(dd, J¼16.0, 5.0 Hz, 1H), 1.67 (m, 1H), 1.48e1.36 (m, 2H), 1.18 (m,
1H); 13C NMR (125 MHz, C6D6)
d 203.1, 171.2, 95.4, 77.6, 73.0, 71.2,
55.3, 51.2, 35.8, 24.1, 19.5; HRMS (ESI) calcd for C11H18O6Na
CDCl3)
d
171.2, 138.4, 136.8, 131.2, 129.1, 128.5 (ꢂ2), 127.5, 126.4
[(MþNa)þ] 269.0996, found 269.1006.
(ꢂ2), 114.7, 95.3, 72.0, 71.2, 71.0, 70.7, 55.7, 35.3, 35.0, 33.4, 26.5,
24.6, 24.1, 20.0; HRMS (ESI) calcd for C24H34O5Na [(MþNa)þ]
425.2298, found 425.2313.
To a mixture of CrCl2 (470.6 mg, 3.829 mmol) and CHI3
(452.4 mg, 1.149 mmol) in THF (1 mL) cooled to 0 ꢁC was added
a solution of the above aldehyde (94.3 mg) in 1,4-dioxane (6 mL).
The resultant mixture was stirred at room temperature for 2 h
before the reaction was quenched with saturated aqueous Na2S2O3
solution. The resultant mixture was extracted with diethyl ether,
and the combined organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (5e10%
EtOAc/hexanes) gave an approximately 5:1 mixture of (E)-vinyl
iodide 25 and the corresponding (Z)-isomer (98.6 mg, 70%). Further
purification by flash chromatography on silica gel (1% diethyl ether/
benzene) gave pure (E)-vinyl iodide 25 (70.8 mg, 50%) along with
4.1.15. (Z)-Olefin 20. To a solution of ester 6 (8.1 mg, 0.020 mmol)
in CH2Cl2 (3.5 mL) was added
a solution of G-II (1.7 mg,
0.0020 mmol) in CH2Cl2 (0.5 mL), and the resultant solution was
stirred at 40 ꢁC for 9 h. The reaction mixture was exposed to air
with stirring at room temperature for 1.5 h, treated with Et3N
(0.8 mL), and stirred further at room temperature for 1 h. The re-
sultant solution was concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (5e15%
EtOAc/hexanes) gave (Z)-olefin 20 (1.0 mg, 17%) as a colorless oil:
26
[
a]
ꢀ49.6 (c 0.16 in benzene); IR (film) 2926, 1730, 1449, 1371,
a 1.5:1 mixture of E/Z isomers (11.7 mg, 8%). Data for 25: [
a
]
29 þ18.9
D
D
1277, 1192, 1148, 1098, 1035, 917 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
(c 1.00 in CHCl3); IR (film) 2948, 1737, 1148, 1103, 1034 cmꢀ1
;
1H
d
5.69 (m, 1H), 5.46 (m, 1H), 4.86 (m, 1H), 4.74 (d, J¼6.9 Hz,1H), 4.63
NMR (500 MHz, CDCl3)
d
6.55 (dd, J¼14.5, 4.5 Hz, 1H), 6.42 (dd,
(m,1H), 4.59 (d, J¼6.9 Hz,1H), 4.19 (ddd, J¼11.7, 2.8,1.7 Hz,1H), 3.51
(m, 1H), 3.37 (s, 3H), 2.78 (dd, J¼15.5, 11.7 Hz, 1H), 2.30 (dd, J¼15.5,
2.8 Hz, 1H), 2.12 (m, 1H), 1.95e1.87 (m, 2H), 1.78 (m, 1H), 1.75e1.51
(m, 5H), 1.33 (m, 1H), 1.18 (d, J¼6.2 Hz, 3H); 13C NMR (150 MHz,
J¼14.5, 2.0 Hz, 1H), 4.67 (d, J¼7.0 Hz, 1H), 4.59 (d, J¼6.5 Hz, 1H),
4.33e4.25 (m, 2H), 3.70e3.64 (m, 4H), 3.36 (s, 3H), 2.72 (dd, J¼15.5,
8.5 Hz, 1H), 2.54 (dd, J¼16.0, 5.0 Hz, 1H), 2.00 (m, 1H), 1.83e1.72 (m,
2H), 1.47 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 171.8, 144.9, 95.3,
CDCl3)
d
170.4, 138.7, 128.0, 95.0, 72.4, 71.2, 69.5, 69.2, 55.8, 38.7,
78.7, 73.4, 71.5, 70.3, 55.7, 51.8, 35.0, 25.0, 23.6; HRMS (ESI) calcd for
32.6, 27.3, 24.5, 24.3, 23.2, 21.8; HRMS (ESI) calcd for C16H26O5Na
C12H19O5INa [(MþNa)þ] 393.0169, found 393.0157.
[(MþNa)þ] 321.1672, found 321.1669.
4.1.18. Olefin 26. To a suspension of CuI (327.6 mg, 1.72 mmol) in
THF (30 mL) cooled to ꢀ20 ꢁC were added vinylmagnesium bro-
mide (1.0 M solution in THF, 34.4 mL, 34.4 mmol) and (S)-propylene
oxide (1.20 mL, 17.2 mmol). The resultant mixture was stirred at
ꢀ20 ꢁC overnight. The reaction was quenched with saturated
aqueous NH4Cl, and the mixture was extracted with diethyl ether.
The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude (S)-4-penten-2-ol was used in the next reaction without
further purification.
4.1.16. Dimer 21. To a solution of ester 6 (11.0 mg, 0.0273 mmol) in
CH2Cl2 (5.0 mL) was added a solution of G-I (2.3 mg, 0.0027 mmol)
in CH2Cl2 (0.5 mL), and the resultant solution was stirred at 40 ꢁC
for 18 h. The reaction mixture was exposed to air with stirring at
room temperature for 1 h, treated with Et3N (0.3 mL), and stirred
further at room temperature for 30 min. The resultant solution was
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (10e20% EtOAc/hexanes) gave
dimer 21 (4.9 mg, 23% yield) as a mixture of E/Z isomers along with
recovered 6 (4.4 mg). Data for 21: [
a
]
D
26 þ3.9 (c 0.60 in benzene); IR
To a solution of the above (S)-4-penten-2-ol in diethyl ether
(35 mL) cooled to 0 ꢁC were added pyridine (2.09 mL, 25.8 mmol) and
benzoyl chloride (2.97 mL, 25.8 mmol). The resultant mixture was
allowed to warm to room temperature and stirred overnight. The
reaction was quenched with N,N0-dimethylethylenediamine at 0 ꢁC,
and the mixture was extracted with diethyl ether. The combined
organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (20e30% CH2Cl2/hexanes) gave
(film) 2932, 1729, 1452, 1376, 1281, 1186, 1148, 1104, 1036, 966, 918,
748, 694 cmꢀ1; 1H NMR (600 MHz, CDCl3, signals for major isomer)
d
7.37 (d, J¼7.2 Hz, 4H), 7.28 (dd, J¼7.6, 7.2 Hz, 4H), 7.21 (dd, J¼7.6,
7.6 Hz, 2H), 6.60 (d, J¼16.1 Hz, 2H), 6.22 (dd, J¼16.1, 4.8 Hz, 2H),
5.34e5.25 (m, 2H), 4.92 (m, 2H), 4.69 (d, J¼6.8 Hz, 2H), 4.63 (d,
J¼6.8 Hz, 2H), 4.47 (m, 2H), 4.39 (m, 2H), 3.72 (m, 2H), 3.37 (s, 6H),
2.76 (dd, J¼15.1, 8.9 Hz, 2H), 2.56 (dd, J¼15.1, 4.8 Hz, 2H), 2.09e1.77
(m, 10H), 1.62e1.22 (m, 10H), 1.19 (d, J¼6.5 Hz, 6H); 13C NMR
(150 MHz, CDCl3, signals for major isomer)
d
171.2 (ꢂ2), 136.8 (ꢂ2),
olefin26(2.83 g, 87%forthetwosteps)asapaleyellowoil:[
a
]
29 þ18.9
D
131.2 (ꢂ2),130.2 (ꢂ2), 129.1 (ꢂ2),128.5 (ꢂ4), 127.6 (ꢂ2), 126.4 (ꢂ4),
95.3 (ꢂ2), 72.0 (ꢂ2), 71.2 (ꢂ2), 71.1 (ꢂ2), 70.8 (ꢂ2), 55.7 (ꢂ2), 35.4
(ꢂ2), 35.1 (ꢂ2), 32.3 (ꢂ2), 26.9 (ꢂ2), 25.3 (ꢂ2), 24.1 (ꢂ2), 20.0 (ꢂ2);
HRMS (ESI) calcd for C46H64O10Na [(MþNa)þ] 799.4392, found
799.4413.
(c 1.00 in CHCl3); IR (film) 2979, 2933, 1717, 1273, 1112, 712 cmꢀ1; 1H
NMR (500 MHz, CDCl3) d 8.05e8.00 (m, 2H), 7.53 (m, 1H), 7.44e7.39
(m, 2H), 5.82 (m, 1H), 5.20 (m, 1H), 5.15e5.04 (m, 2H), 2.51e2.36 (m,
2H), 1.34 (d, J¼6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 166.0, 133.6,
132.7, 130.7, 129.5 (ꢂ2), 128.3 (ꢂ2), 117.8, 70.7, 40.3, 19.5; HRMS (ESI)
calcd for C12H15O2 [(MþH)þ] 191.1067, found 191.1068.
4.1.17. (E)-Vinyl iodide 25. Ozone was bubbled through a solution
of tetrahydropyran trans-7 (139.1 mg, 0.4342 mmol) in CH2Cl2
(10 mL) cooled to ꢀ78 ꢁC until pale blue color persisted (ca.15 min).
After O2 gas was bubbled through the reaction mixture to remove
4.1.19. (E)-Olefin 27. To
a solution of olefin 26 (55.3 mg,
0.291 mmol) in THF (2 mL) cooled to 0 ꢁC was added a solution of
9-BBN-H dimer (85.1 mg, 0.349 mmol) in THF (1 mL). After being

H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
7501
stirred at room temperature for 105 min, the reaction mixture was
treated with 3 M aqueous Cs2CO3 solution (0.180 mL, 0.520 mmol)
and stirred at room temperature for 35 min. To this mixture were
added PdCl2(dppf)$CH2Cl2 (14.1 mg, 0.0173 mmol), Ph3As (21.2 mg,
0.0693 mmol), and a solution of (E)-vinyl iodide 25 (64.1 mg,
0.173 mmol) in DMF (1 mL). After being stirred at room tempera-
ture for 11.5 h, the reaction mixture was diluted with diethyl ether
and H2O. The aqueous layer was extracted with diethyl ether, and
the combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (5e30%
70.0, 68.8, 55.6, 39.9, 31.7, 30.6, 24.7, 24.1, 23.0,19.0; HRMS (ESI) calcd
for C16H26O5Na [(MþNa)þ] 321.1672, found 321.1668.
4.1.22. Aspergillide B (1). A mixture of macrolactone 28 (2.0 mg,
0.0067 mmol) and LiBF4 (65.4 mg, 0.698 mmol) in CH3CN (2.0 mL)
and H2O (0.04 mL) was heated at 72 ꢁC for 9.25 h. After being
cooled to room temperature, the reaction mixture was poured into
H2O and extracted with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
matography on silica gel (10e50% EtOAc/hexanes) gave aspergillide
26
EtOAc/hexanes) gave (E)-olefin 27 (53.0 mg, 73%) as a pale yellow
B (1) (1.6 mg, 94%) as a colorless clear oil: [
a
]
D
ꢀ88.1 (c 0.10 in
27
oil: [
a
]
D
ꢀ7.5 (c 1.0 in benzene); IR (film) 2938, 1740, 1715, 1276,
MeOH); IR (film) 3420, 2929, 2854, 1732, 1277, 1193, 1086, 1025,
1110, 1036, 714 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
8.04e7.99 (m,
970 cmꢀ1; 1H NMR (500 MHz, C6D6)
d
6.14 (dddd, J¼15.6, 10.7, 4.4,
2H), 7.52 (m, 1H), 7.44e7.38 (m, 2H), 5.64 (m, 1H), 5.47 (dd, J¼15.5,
4.5 Hz, 1H), 5.14 (m, 1H), 4.66 (d, J¼7.0 Hz, 1H), 4.59 (d, J¼7.0 Hz,
1H), 4.30 (ddd, J¼9.0, 5.5, 4.0 Hz, 1H), 4.24 (m, 1H), 3.70e3.62 (m,
4H), 3.35 (s, 3H), 2.71 (dd, J¼15.5, 9.0 Hz, 1H), 2.57 (dd, J¼15.0,
5.0 Hz, 1H), 2.12e2.03 (m, 2H), 1.93 (m, 1H), 1.82e1.56 (m, 4H),
1.55e1.38 (m, 3H),1.31 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
1.5 Hz, 1H), 5.33 (dd, J¼15.6 4.4 Hz, 1H), 5.04 (m, 1H), 4.25 (br s, 1H),
4.03 (br d, J¼11.2 Hz, 1H), 3.16 (br s, 1H), 2.66 (dd, J¼13.7, 11.7 Hz,
1H), 2.07 (dd, J¼13.7, 2.0 Hz, 1H), 1.99 (dddd, J¼13.2, 10.8, 4.9,
2.4 Hz, 1H), 1.78e1.66 (m, 2H), 1.62e1.44 (m, 3H), 1.36e1.22 (m,
4H), 1.01 (d, J¼6.4 Hz, 3H), 0.93 (dddd, J¼13.7, 4.9, 2.4, 1.0 Hz, 1H);
13C NMR (125 MHz, C6D6)
d 169.8, 138.2, 129.0, 71.5, 69.8, 69.6, 67.2,
d
172.0, 166.1, 132.7, 132.5, 130.8, 129.5 (ꢂ2), 129.5, 128.2 (ꢂ2), 95.2,
39.9, 32.0, 30.7, 27.8, 25.3, 22.6, 19.1; HRMS (ESI) calcd for
71.8, 71.4, 71.2, 70.2, 55.6, 51.6, 35.5, 34.6, 32.2, 26.1, 24.9, 23.8, 20.0;
HRMS (ESI) calcd for C24H34O7Na [(MþNa)þ] 457.2197, found
457.2193.
C14H22O4Na [(MþNa)þ] 277.1410, found 277.1404.
4.1.23. (E)-Vinyl iodide 24. Ozone was bubbled through a solution of
tetrahydropyran cis-7 (43.3 mg, 0.135 mmol) in CH2Cl2 (8 mL) cooled
to ꢀ78 ꢁC until pale blue color persisted. The excess ozone was
removed by bubbling O2 gas through the reaction mixture. The
reaction mixture was treated with triphenylphosphine (71 mg,
0.27 mmol), and the resultant solution was allowed to warm to room
temperature over a period of 2 h. The resultant mixture was con-
centrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (20e30% EtOAc/hexanes) gave an
4.1.20. Hydroxy acid 23. To a solution of (E)-olefin 27 (23.3 mg,
0.0557 mmol) in MeOH (5.0 mL) was added a solution of NaOH
(79.1 mg) in H2O (0.5 mL). After being stirred at room temperature
overnight, the reaction mixture was cooled to 0 ꢁC and acidified
with 1 M aqueous HCl solution (pH¼ca. 2). The resultant mixture
was extracted with CHCl3. The combined organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(0.5% MeOH/CHCl3) gave hydroxy acid 23 (15.5 mg, 88%) as a col-
aldehyde (27.2 mg, 82%): [
a
]
18 þ114.9 (c 1.0 in C6H6); IR (film) 2952,
D
2891, 1739, 1105, 1038 cmꢀ1; 1H NMR (500 MHz, C6D6)
d
9.38 (s, 1H),
orless oil: [
a
]
17 ꢀ21.1 (c 0.570 in CHCl3); IR (film) 3422, 2933, 1716,
4.38 (d, J¼6.5 Hz, 1H), 4.28 (d, J¼6.5 Hz, 1H), 3.77 (ddd, J¼9.0, 9.0,
3.0 Hz, 1H), 3.37 (s, 3H), 3.22 (dd, J¼11.5, 2.5 Hz, 1H), 3.10e2.97 (m,
4H), 2.83 (dd, J¼15.5, 3.0 Hz, 1H), 2.49 (dd, J¼15.5, 9.0 Hz, 1H), 1.82
(m, 1H), 1.46 (m, 1H), 1.09e0.93 (m, 2H); 13C NMR (125 MHz, C6D6)
D
1148, 1104, 1034 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
5.70 (m, 1H),
5.53 (dd, J¼15.5, 5.5 Hz, 1H), 4.70 (d, J¼7.0 Hz,1H), 4.60 (d, J¼7.5 Hz,
1H), 4.35 (m, 1H), 4.23 (ddd, J¼12.0, 4.0, 4.0 Hz, 1H), 3.78 (m, 1H),
3.65 (m, 1H), 3.37 (s, 3H), 2.75 (dd, J¼16.0, 9.0 Hz, 1H), 2.54 (dd,
J¼16.0, 4.0 Hz, 1H), 2.10 (m, 1H), 2.06e1.97 (m, 2H), 1.84e1.76 (m,
2H), 1.56e1.34 (m, 4H), 1.17 (s, 3H), 1.6 (s, 3H); 13C NMR (125 MHz,
d
200.0, 171.2, 95.2, 80.8, 77.6, 74.6, 55.2, 51.2, 37.9, 29.2, 25.4; HRMS
(ESI) calcd for C11H18O6Na [(MþNa)þ] 269.0996, found 269.0994.
To a mixture of CrCl2 (135.0 mg, 1.098 mmol) in THF (0.5 mL)
cooled to 0 ꢁC was added a solution of the above aldehyde (27.2 mg)
and CHI3 (130.0 mg, 0.3315 mmol) in 1,4-dioxane (3.0 mL), and the
resultant mixture was stirred at room temperature for 2.5 h. The
reaction mixture was diluted with diethyl ether and quenched with
saturated aqueous Na2S2O3 solution. The resultant mixture was
extracted with diethyl ether. The combined organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
matography on silica gel (10e20% EtOAc/hexanes) gave an approx-
imately 3:1 mixture of (E)-vinyl iodide 24 and the corresponding (Z)-
isomer (35.4 mg, 87%). Further purification of the mixture by flash
CDCl3)
d 198.1, 175.4, 133.7, 128.8, 95.2, 71.9, 71.8, 69.8, 68.1, 55.7,
38.2, 35.3, 32.1, 24.8, 23.6, 23.1; HRMS (ESI) calcd for C16H27O7
[(MꢀH)ꢀ] 315.1813, found 315.1814.
4.1.21. Macrolactone 28. To a solution of hydroxy acid 23 (14.6 mg,
0.0462 mmol) in THF (2 mL) cooled to 0 ꢁC were added Et3N
(0.039 mL, 0.28 mmol)
and
2,4,6-Cl3C6H2COCl
(0.029 mL,
0.18 mmol). After being stirred at room temperature for 3.5 h, the
reaction mixture was diluted with toluene (15 mL) and added
dropwise to a solution of DMAP (169.2 mg, 1.385 mmol) in toluene
(32 mL) at 100 ꢁC over a period of 6.5 h. The reaction mixture was
cooled to room temperature, washed successively with 0.5 M
aqueous HCl solution, saturated aqueous NaHCO3 solution, and then
brine. The organic layer was dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (5e10% EtOAc/CH2Cl2) gave
chromatography on silica gel (1% diethyl ether/benzene) gave 24
16
(23.4 mg, 57%) as a yellow oil: [
a
]
þ115.6 (c 0.66 in benzene); IR
D
(film) 2946, 1740, 1108, 1037 cmꢀ1; 1H NMR (500 MHz, C6D6)
d 6.30
(dd, J¼15.0, 5.5 Hz,1H), 6.13 (dd, J¼15.0,1.0 Hz,1H), 4.43 (d, J¼6.5 Hz,
1H), 4.32 (d, J¼6.5 Hz, 1H), 3.81 (ddd, J¼8.5, 8.5, 3.5 Hz, 1H),
3.35e3.29 (m, 4H), 3.10e3.03 (m, 4H), 2.83 (dd, J¼15.0, 3.5 Hz, 1H),
2.47 (dd, J¼15.0, 8.5 Hz, 1H), 1.83 (dddd, J¼12.0, 4.0, 4.0, 4.0 Hz, 1H),
macrolactone 28 (10.0 mg, 73%) as a colorless clear oil: [
a
]
28 ꢀ57.2 (c
1.00 in CHCl3); IR (film) 2931, 1733, 1248, 1148, 1032 cmꢀ1D; 1H NMR
(500 MHz, CDCl3)
d
6.17 (dddd, J¼15.5, 10.5, 4.5, 1.5 Hz, 1H), 5.63 (dd,
1.17e1.02 (m, 2H), 0.95 (m, 1H); 13C NMR (125 MHz, C6D6)
d 171.4,
J¼16.0, 4.5 Hz, 1H), 5.06 (m, 1H), 4.73 (d, J¼7.5 Hz, 1H), 4.59 (d,
J¼7.0 Hz, 1H), 4.47 (br s, 1H), 4.23 (d, J¼11.0 Hz, 1H), 3.56 (br s, 1H),
3.36 (s, 3H), 2.58 (dd, J¼14.5, 11.5 Hz, 1H), 2.27 (dd, J¼14.0, 1.5 Hz,
1H), 2.19 (m, 1H), 2.12 (m, 1H), 1.99e1.88 (m, 2H), 1.88e1.77 (m, 2H),
1.72 (m, 1H), 1.66e1.54 (m, 1H), 1.48e1.34 (m, 2H), 1.17 (d, J¼6.0 Hz,
145.9, 95.2, 78.8, 77.7, 77.4, 74.9, 55.2, 51.2, 38.1, 30.3, 29.7; HRMS
(ESI) calcd for C12H19O5Na [(MþNa)þ] 393.0169, found 393.0176.
4.1.24. (E)-Olefin 29. To a solution of 26 (19.2 mg, 0.101 mmol) in
THF (0.9 mL) cooled to 0 ꢁC was added a solution of 9-BBN-H dimer
(29.6 mg, 0.121 mmol) in THF (0.5 mL), and the resultant solution
3H); 13C NMR (125 MHz, CDCl3)
d 170.4, 138.0, 128.6, 95.0, 72.1, 71.2,

7502
H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
was stirred at room temperature for 70 min. In a separate flask,
a solution of (E)-vinyl iodide 24 (21.3 mg, 0.0575 mmol) in DMF
(0.7 mL) was prepared. To this solution were added PdCl2(dppf)$
CH2Cl2 (4.7 mg, 0.0058 mmol), Ph3As (7.0 mg, 0.023 mmol), and
3 M aqueous Cs2CO3 solution (0.060 mL, 0.18 mmol). The resultant
mixture was stirred at room temperature for 15 min before it was
treated with the above alkylborane solution. After being stirred at
room temperature overnight, the resultant mixture was diluted
with diethyl ether and washed with H2O. The aqueous layer was
extracted with diethyl ether. The combined organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
(m, 1H), 1.97e1.85 (m, 2H), 1.85e1.70 (m, 2H), 1.58e1.46 (m, 2H),
1.37 (m, 1H), 1.20 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
170.1, 136.7, 132.5, 94.6, 71.6, 71.4, 71.3, 71.1, 55.5, 40.8, 32.3, 31.1,
23.7, 22.7, 19.9, 18.6; HRMS (ESI) calcd for C16H26O5Na [(MþNa)þ]
321.1672, found 321.1667.
4.1.27. Dimer 31. To a solution of carboxylic acid 22 (11.9 mg,
0.0376 mmol) in THF (1.5 mL) cooled to 0 ꢁC were added Et3N
(0.030 mL, 0.22 mmol) and 2,4,6-Cl3C6H2COCl (0.025 mL,
0.16 mmol). The resultant mixture was stirred at room temperature
for 2.25 h before being diluted with toluene (12 mL). This mixed
anhydride solution was added dropwise to a solution of DMAP
(137.8 mg,1.128 mmol) in toluene (23 mL) at 100 ꢁC over a period of
5 h, and the resultant mixture was stirred at 100 ꢁC for additional
1.25 h. After being cooled to room temperature, the reaction mix-
ture was diluted with EtOAc and washed successively with 0.5 M
aqueous HCl solution, saturated aqueous NaHCO3 solution, and
brine. The organic layer was dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification of the residue by
matography on silica gel (10e20% EtOAc/hexanes) gave (E)-olefin
16
29 (22.7 mg, 94%) as a yellow oil: [
a
]
D
þ55.8 (c 0.80 in CHCl3); IR
(film) 2937, 1741, 1715, 1276, 1111, 1037, 714 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d
8.01 (d, J¼7.5 Hz, 2H), 7.52 (dd, J¼7.5, 7.5 Hz,
1H), 7.41 (dd, J¼7.5, 7.5 Hz, 2H), 5.60 (ddd, J¼15.5, 6.5, 6.5 Hz, 1H),
5.41 (dd, J¼15.5, 6.5 Hz, 1H), 5.13 (m, 1H), 4.68 (d, J¼6.5 Hz, 1H),
4.57 (d, J¼6.5 Hz,1H), 3.80 (m,1H), 3.70 (ddd, J¼8.0, 8.0, 4.0 Hz,1H),
3.64 (s, 3H), 3.34 (s, 3H), 3.26 (ddd, J¼8.0, 8.0, 4.0 Hz, 1H), 2.77 (dd,
J¼15.0, 4.0 Hz, 1H), 2.46 (dd, J¼15.0, 8.0 Hz, 1H), 2.21 (m, 1H), 2.02
(dt, J¼7.5, 7.5 Hz, 2H), 1.76e1.64 (m, 2H), 1.64e1.54 (m, 2H),
1.54e1.36 (m, 3H),1.31 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
flash chromatography on silica gel (5% EtOAc/CH2Cl2) gave dimer 31
26
(6.5 mg, 29%) as a colorless oil: [
a]
þ37.8 (c 0.68 in benzene); IR
D
(film) 2935, 1730, 1453, 1377, 1294, 1191, 1105, 1037, 984, 917 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
5.56 (ddd, J¼15.5, 8.2, 6.2 Hz, 2H), 5.39
d
172.0, 166.2, 132.7, 131.7, 130.8, 130.4, 129.5 (ꢂ2), 128.3 (ꢂ2), 95.2,
(dd, J¼15.5, 5.2 Hz, 2H), 5.03 (m, 2H), 4.71 (d, J¼6.9 Hz, 2H), 4.57 (d,
J¼6.9 Hz, 2H), 3.77 (m, 2H), 3.69 (m, 2H), 3.34 (s, 6H), 3.25 (ddd,
J¼10.3, 10.0, 4.5 Hz, 2H), 2.84 (dd, J¼14.0, 2.4 Hz, 2H), 2.33 (dd,
J¼14.0, 10.3 Hz, 2H), 2.21 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H), 1.76
(m, 2H), 1.59e1.31 (m, 12H), 1.18 (d, J¼6.2 Hz, 6H); 13C NMR
77.7, 77.2, 75.4, 71.5, 55.6, 51.6, 38.1, 35.5, 32.1, 31.0, 29.9, 24.8, 20.0;
HRMS (ESI) calcd for C24H34O7Na [(MþNa)þ] 457.2197, found
457.2197.
4.1.25. Carboxylic acid 22. To a solution of (E)-olefin 29 (17.3 mg,
0.0413 mmol) in MeOH (3 mL) was added 4 M aqueous NaOH so-
lution (0.3 mL, 1.2 mmol), and the resultant solution was stirred at
room temperature for 19 h. The reaction mixture was cooled to 0 ꢁC
and acidified with 1 M aqueous HCl solution. The resultant mixture
was extracted with CHCl3, and the organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (1e3%
(150 MHz, CDCl3)
d
172.1 (ꢂ2), 131.3 (ꢂ2), 129.9 (ꢂ2), 95.0 (ꢂ2),
78.2 (ꢂ2), 77.4 (ꢂ2), 74.9 (ꢂ2), 70.4 (ꢂ2), 55.6 (ꢂ2), 38.5 (ꢂ2), 35.8
(ꢂ2), 32.2 (ꢂ2), 31.0 (ꢂ2), 29.9 (ꢂ2), 24.5 (ꢂ2), 20.3 (ꢂ2); HRMS
(ESI) calcd for C32H52O10Na [(MþNa)þ] 619.3453, found 619.3447.
4.1.28. Aspergillide A (4). A stock solution of LiBF4 in aqueous CH3CN
was prepared by mixing LiBF4 (72.1 mg, 0.769 mmol), CH3CN
(2.0 mL), and H2O (0.080 mL). A mixture of macrolactone 30 (1.0 mg,
0.0034 mmol) and 1.5 mL of the above stock solution was heated at
72 ꢁC for 7 h. After being cooled to room temperature, the reaction
mixture was poured into H2O and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification of the residue by flash
MeOH/CHCl3) gave carboxylic acid 22 (11.9 mg, 91%) as a colorless
28
oil: [a
]
þ59.8 (c 1.00 in CHCl3); IR (film) 3420, 2934, 1715, 1107,
D
1036 cmꢀ1
;
1H NMR (500 MHz, C6D6)
d
5.64 (ddd, J¼15.0, 7.0,
7.0 Hz, 1H), 5.42 (dd, J¼15.0, 6.5 Hz, 1H), 4.70 (d, J¼7.0 Hz, 1H), 4.57
(d, J¼7.0 Hz, 1H), 3.84 (m, 1H), 3.77 (m, 1H), 3.68 (ddd, J¼9.0, 9.0,
3.5 Hz, 1H), 3.34 (s, 3H), 3.28 (m, 1H), 2.84 (dd, J¼15.5, 3.5 Hz, 1H),
2.51 (dd, J¼15.5, 8.0 Hz, 1H), 2.22 (m, 1H), 2.06e1.96 (m, 2H), 1.74
(m, 1H), 1.54e1.32 (m, 6H), 1.16 (d, J¼6.5 Hz, 3H); 13C NMR
chromatography on silica gel (30e50% EtOAc/hexanes) gave asper-
16
gillide A (4) (0.7 mg, 82%) as a colorless oil: [
a
]
ꢀ66.7 (c 0.12 in
D
CHCl3); IR (film) 3365, 2927, 1733, 1717, 1558, 1541, 1507, 1457,
(125 MHz, CDCl3)
d
175.0, 132.6, 129.9, 95.1, 78.1, 76.9, 74.9, 68.0,
1050 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
5.80 (ddd, J¼15.0, 8.0, 2.0 Hz,
55.7, 38.6, 37.8, 32.1, 30.8, 29.7, 25.0, 23.4; HRMS (ESI) calcd for
1H), 5.71 (ddd, J¼15.0, 9.5, 3.0 Hz, 1H), 4.96 (m, 1H), 4.29e4.22 (m,
2H), 3.58 (m, 1H), 2.64 (dd, J¼15.0, 12.5 Hz, 1H), 2.39 (dd, J¼15.0,
4.5 Hz,1H), 2.30 (m,1H), 2.21 (m,1H), 2.11 (m,1H),1.99e1.88 (m, 2H),
1.82 (m, 1H), 1.72 (m, 1H), 1.62e1.46 (m, 3H), 1.40 (m, 1H), 1.20 (d,
C16H27O6 [(MꢀH)ꢀ] 315.1813, found 315.1811.
4.1.26. Macrolactone 30. To
a solution of carboxylic acid 22
(13.3 mg, 0.0420 mmol) in THF (5.0 mL) cooled to 0 ꢁC were added
Et3N (0.045 mL, 0.32 mmol) and 2,4,6-Cl3C6H2COCl (0.035 mL,
0.22 mmol), and the reaction mixture was stirred at room tem-
perature for 1.5 h. The resultant mixture was diluted with toluene
(70 mL) and added to a solution of DMAP (770 mg, 6.30 mmol) in
toluene (140 mL) over a period of 13 h. The reaction mixture was
cooled to room temperature and washed with 0.5 M aqueous HCl
solution, saturated NaHCO3 solution, and then brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Purification of the residue by flash chromatography
on silica gel (10e20% diethyl ether/benzene) gave macrolactone 30
J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 170.0, 137.1, 132.1, 74.0,
71.5, 71.2, 66.8, 40.5, 32.1, 31.1, 23.7, 22.0, 21.7, 18.6; HRMS (ESI) calcd
for C14H22O4Na [(MþNa)þ] 277.1410, found 277.1421.
Acknowledgements
We thank Professors Shigefumi Kuwahara (Tohoku University)
and Takenori Kusumi (Tokyo Institute of Technology) for providing
us with copies of 1H and 13C NMR spectra of aspergillides A and B.
This work was funded in part by a Grant-in-Aid for Scientific Re-
search from MEXT, Japan.
(2.5 mg, 20%) as a colorless clear oil: [
a
]
28 ꢀ58.7 (c 0.20 in CHCl3); IR
(film) 2929, 1732, 1717, 1148, 1038 cmꢀ1D; 1H NMR (500 MHz, CDCl3)
d
5.81 (dd, J¼15.0, 8.0 Hz, 1H), 5.71 (ddd, J¼15.0, 9.0, 3.0 Hz, 1H),
Supplementary data
4.96 (m, 1H), 4.70 (s, 2H), 4.35 (dd, J¼13.0, 4.5 Hz, 1H), 4.26 (dd,
J¼6.5, 6.5 Hz, 1H), 3.47 (m, 1H), 3.37 (s, 3H), 2.63 (dd, J¼15.0,
13.0 Hz, 1H), 2.36 (dd, J¼15.0, 4.5 Hz, 1H), 2.33e2.18 (m, 2H), 2.11
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.062.

H. Fuwa et al. / Tetrahedron 66 (2010) 7492e7503
7503
15. Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K. Chem.dEur.
J. 2003, 9, 4405e4413. Alternatively, homoallylic alcohol 10 could also be
prepared in an enantiopure form by enzymatic resolution of the corre-
sponding racemate (Amano AK, i-Pr2O, 40 ꢁC, 47%, >99% ee, determined by
chiral HPLC analysis) followed by methanolysis of the resultant acetate
(K2CO3, MeOH, rt, 93%).
16. Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974e6977.
17. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953e956.
18. Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123e1125.
References and notes
1. Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi, T. Org. Lett.
2008, 10, 225e228.
2. Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009, 50, 189e192.
3. Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761e764.
4. Ookura, R.; Kito, K.; Saito, Y.; Kusumi, T.; Ooi, T. Chem. Lett. 2009, 38, 384.
5. Total synthesis of aspergillide A: (a) Nagasawa, T.; Kuwahara, S. Tetrahedron
Lett. 2010, 51, 875e877; (b) Díaz-Oltra, S.; Angulo-Pachón, C. A.; Murga, J.;
Carda, M.; Marco, J. A. J. Org. Chem. 2010, 75, 1775e1778; Formal synthesis of
aspergillide A: Sabitha, G.; Reddy, D. V.; Rao, A. S.; Yadav, J. S. Tetrahedron Lett.
2010, 51, 4195e4198.
6. Total synthesis of aspergillide B: (a) Díaz-Oltra, S.; Angulo-Pachón, C. A.;
Kneeteman, M. N.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2009, 50,
3783e3785; (b) Nagasawa, T.; Kuwahara, S. Biosci. Biotechnol. Biochem. 2009,
73, 1893e1894; (c) Liu, J.; Xu, K.; He, J.; Zhang, L.; Pan, X.; She, X. J. Org. Chem.
2009, 74, 5063e5066; (d) Hendrix, A. J. M.; Jennings, M. Tetrahedron Lett. 2010,
51, 4260e4262. See also Ref. 2.
7. Formal synthesis of aspergillide C: Panarese, J. D.; Waters, S. P. Org. Lett. 2009,
11, 5086e5088.
8. For a preliminary communication of this work, see: Fuwa, H.; Yamaguchi, H.;
Sasaki, M. Org. Lett. 2010, 12, 1848e1851.
9. For recent selected reviews, see: (a) Hoveyda, A. H.; Zhugralin, A. R. Nature
2007, 450, 243e251; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490e4527; (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199e2238; (d) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012e3043 and
references cited therein.
19. Hoveyda, A. H.; Lombardi, P. J.; O’Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc.
2009, 131, 8378e8379.
20. A highly chemoselective olefin CM of a homoallylic alcohol based on H-
bonding has also been reported by us: Fuwa, H.; Saito, A.; Sasaki, M. Angew.
Chem., Int. Ed. 2010, 49, 3041e3044; See also: Moosophon, P.; Baird, M. C.;
Kanokmedhakul, S.; Pyne, S. G. Eur. J. Org. Chem. 2010, 3337e3344.
21. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831e5834.
22. Kim, M.-Y.; Kim, H.; Tae, J. Synlett 2009, 1303e1306.
23. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989e1993.
24. During the time this work is in progress, Marco and co-workers reported
that RCM of a related compound resulted in a similar stereochemical out-
come. They also showed that isomerization of the C8eC9 double bond is
possible by photoirradiation, albeit in a low conversion yield. For details, see
Ref. 5b.
25. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100e110.
26. All calculations were performed on Spartan ’08, Wavefunction, Inc., USA. The
structures for compounds (E)-19, (Z)-19, (E)-20, and (Z)-20 were generated by
10. For a review, see: Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
6086e6101.
11. For discussions on the stereochemical outcome of intramolecular oxa-conjugate
addition, see: (a) Betancort, J. M.; Martín, V. S.; Padrón, J. M.; Palazón, J. M.;
Ramírez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570e4583; (b) Schneider, C.;
Schuffenhauer, A. Eur. J. Org. Chem. 2000, 73e82.
MMFF conformational searches and geometrically optimized at HF/6-31G
*
//
PM3 level of theory.
27. For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2483; (b)
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4544e4568; (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633e9695; (d) Suzuki, A. Chem. Commun. 2005, 4759e4763.
28. (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408e7410; (b)
Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497e4513.
29. Prepared from (S)-propylene oxide in two steps (vinylMgBr, THF, ꢀ20 ꢁC; then
BzCl, pyridine, Et2O, room temperature, 87% yield for the two steps). For details,
see Experimental section.
€
12. For a review of oxa-conjugate reactions, see: Nising, C. F.; Brase, S. Chem. Soc.
Rev. 2008, 37, 1218e1228.
13. For a review, see: Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900e1923.
14. (a) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465e3467; (b)
Marvin, C. C.; Voight, E. A.; Suh, J. M.; Paradise, C. L.; Burke, S. D. J. Org. Chem.
2008, 73, 8452e8457.
30. Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014e11015.