Effect of stereochemistry of Δlac-acetogenins on the inhibition of?mitochondrial complex I (NADH-ubiquinone oxidoreductase)

Article abstract of DOI:10.1016/j.tet.2006.11.057

Δlac-Acetogenins are a new type of inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase). We synthesized a series of Δlac-acetogenins in which the stereochemistry around the hydroxylated tetrahydrofuran (THF) ring moiety was

Full text of DOI:10.1016/j.tet.2006.11.057

Tetrahedron 63 (2007) 1127–1139
Effect of stereochemistry of Dlac-acetogenins on the inhibition
of mitochondrial complex I (NADH-ubiquinone oxidoreductase)
*
Naoya Ichimaru, Naoko Yoshinaga, Takaaki Nishioka and Hideto Miyoshi
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
Received 12 October 2006; revised 20 November 2006; accepted 21 November 2006
Available online 12 December 2006
Abstract—Dlac-Acetogenins are a new type of inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase). We
synthesized a series of Dlac-acetogenins in which the stereochemistry around the hydroxylated tetrahydrofuran (THF) ring moiety was sys-
tematically modified, and examined their inhibitory effect on complex I. The present results revealed that the inhibitory effects of the bis-THF
ring analogs are much more potent than those of the mono-THF ring analogs and that the stereochemistry around the bis-THF ring moiety
significantly influences the inhibitory effect. The profiles of the structure–activity relationship observed for Dlac-acetogenins were entirely
different from those for natural-type acetogenins.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
nanomolar level.7 Several lines of evidence, e.g., competi-
tion tests using a fluorescent ligand and the effect on super-
oxide production from complex I, revealed that the site of
inhibition by Dlac-acetogenins is different from that by nat-
ural acetogenins as well as ordinary complex I inhibitors
such as rotenone and piericidin A.8,9 Thus Dlac-acetogenins
were shown to be a new type of inhibitors acting at the
terminal electron transfer step in complex I. Accordingly,
a detailed analysis of their inhibitory action would provide
valuable insights into the functional features of complex I.
Acetogenins isolated from the plant family Annonaceae
have potent and diverse biological effects such as antitumor,
antimalarial, and insecticidal activities.1,2 Their inhibitory
effect on mitochondrial NADH-ubiquinone oxidoreductase
(complex I) is of particular importance since the diverse
biological activities of acetogenins are thought to be attri-
butable to this effect.1 Their unique structural features and
multiple chiral centers, especially the four or more in the
tetrahydrofuran (THF) portion, make acetogenins challeng-
ing synthetic targets.3 On the other hand, structural simplifi-
cation while maintaining all the essential functionalities of
acetogenins may facilitate the task of synthesizing a variety
of acetogenin mimics, which may be used not only as possi-
ble chemotherapeutic agents, but also as molecular probes to
investigate the functional features of mitochondrial complex
I,4–6 one of the largest known membrane protein complexes.
To elucidate the mode of inhibitory action of Dlac-acetoge-
nins, identification of the crucial structural factors required
for the inhibition is needed. A previous structure–activity
study concerning Dlac-acetogenins indicated that the num-
ber of carbon atoms (i.e., hydrophobicity) of the alkyl side
chains remarkably affects the inhibitory potency.7 In addi-
tion, the balance of the hydrophobicity of the two chains at-
tached to the C2-symmetric bis-THF portion was also an
important structural factor of these inhibitors.10 This is prob-
ably because the side chains decide the precise location of
the hydrophilic THF moiety at or close to the membrane in-
terface. On the other hand, information about the effect of
both the number of THF rings and the stereochemistry
around the THF ring including flanking OH groups is limited
since we have examined solely bis-THF analogs having
R-configurations at all chiral centers like compound 1. To
examine these subjects, we here synthesized a series of
Dlac-acetogenins in which the stereochemistry around
the hydroxylated THF moiety was systematically modified
(Fig. 1), and examined their inhibitory effect on bovine
mitochondrial complex I.
In the course of the synthesizing simplified acetogenin
mimics, we deleted a a,b-unsaturated g-methylbutyrolac-
tone ring, which is a structural feature common to a large
number of natural acetogenins,1,2 from the mother skeleton
of the natural products and named the resultant compounds
‘Dlac-acetogenins’. Unexpectedly, some Dlac-acetogenins
(e.g., compound 1 in Fig. 1) exhibited a strong inhibitory
effect on bovine heart mitochondrial complex I at the
Keywords: Stereoselective synthesis; Acetogenin; Respiratory inhibitor;
Mitochondrial complex I.
* Corresponding author. Tel.: +81 75 753 6119; fax: +81 75 753 6408;
e-mail: miyoshi@kais.kyoto-u.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.057

1128
N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
6
6
6
HO
threo
HO
HO
erythro
O
O
O
threo
erythro
threo
5
5
5
trans
trans
cis
cis
O
O
cis
cis
O
1
2
3
2
2
2
threo
threo
erythro
erythro
(2R, 2'R, 5R, 5'R, 6R, 6'R)
2'
2'
2'
(2R, 2'S, 5S, 5'R, 6S, 6'R)
(2R, 2'S, 5S, 5'R, 6R, 6'S)
O
5'
O
5'
O
5'
O
O
O
HO
HO
6'
HO
6'
6'
6
6
HO
threo
HO
threo
O
O
5
5
α'
HO
threo
O
cis
cis
trans
trans
O
O
5
5
4
2
2
6
threo
threo
threo
threo
(2S, 2'S, 5S, 5'S, 6S, 6'S)
cis
2'
O
5'
2'
O
5'
O
2
(2S, 2'S, 5R, 5'R, 6R, 6'R)
(2R, 5S, R, 'S)
threo
HO
O
α
O
O
HO
HO
6'
6'
α'
α'
α'
HO
threo
HO
erythro
HO
erythro
O
O
O
5
5
5
9
8
7
trans
trans
cis
O
2
O
2
O
2
(2R, 5R, αR, α'S)
(2R, 5R, αR, α'R)
(2R, 5S, αR, α'R)
threo
HO
threo
HO
threo
HO
O
O
O
α
α
α
R
HO
threo
C13
C11
R
R
HO
threo
HO
threo
C13
trans
trans
O
O
10
12
trans
trans
O
O
threo
threo
11
threo
HO
threo
HO
C13
R
R
C13
C11
HO
R
Figure 1. Structures of Dlac-acetogenins studied in the present study. Compounds 1, 10 and 11 are the same samples as used previously.8
2. Results and discussion
available 1,6-hexanediol, as shown in the bottom of
Scheme 1. Allyldimethylphenylsilane 14 was synthesized
by the Grignard reaction of a commercially available chloro-
dimethylphenylsilane with allylmagnesium chloride. The
absolute configurations and enantiopurity of 16a and its
enantiomer 16b were determined through a Mosher ester
analysis of the corresponding secondary alcohols 15a (R
configuration, 96% ee) and 15b (S configuration, 96% ee),
as shown in Figure 2.11,14
2.1. Synthesis of diastereomeric Dlac-acetogenins
To synthesize small libraries of stereochemically diverse
bis-THF systems, Roush and colleagues recently reported
double asymmetric [3+2]-annulation reaction of chiral
b-silyloxyallylsilanes with chiral 2-tetrahydrofuranyl carb-
aldehydes, leading to the stereocontrolled synthesis of dia-
stereomeric bis-THF structures.11–13 This excellent strategy
is a highly useful way to synthesize diastereomeric Dlac-
acetogenins to elucidate the effect of the stereochemistry
of the hydroxylated bis-THF moiety on the inhibitory action.
We therefore synthesized the following test compounds, ex-
cept compound 5, largely according to their procedures. The
side chains of all test compounds were fixed as identical to
that of compound 1 since this inhibitor is the most potent
Dlac-acetogenin to be synthesized in our laboratory.7,8
A BF3$Et2O-catalyzed [3+2]-annulation reaction between
16a and a-(benzyloxy)acetoaldehyde gave the 2,5-cis-THF
17 in 56% yield with 17:1 ds. The relative stereochemistry
1
at the C2 and C5 positions in 17 was assigned using a H
NOE analysis (Fig. 3).11 As closely studied by Roush’s
group,11–13 the relative configuration about the C2–Ca
bond in 17 was assigned as threo on the basis of the finding
that the threo relationship at this position results from [3+2]-
annulation reactions of b-silyloxyallylsilanes with anti rela-
tive stereochemistry, such as 16a and 16b. The 2,5-cis-THF
17 was converted to the aldehyde 18 in 72% yield by
Pd(OH)2/C-catalyzed debenzylation and subsequent Swern
oxidation. The BF3$Et2O-catalyzed [3+2]-annulation reac-
tion of 16b with 18 afforded the cis–threo–cis bis-THF struc-
ture 19 as 16:1 ds. Subsequent treatment with TBAF gave the
compound 2 in 63% yield (two steps). The stereochemistry
For the synthesis of compounds 2–4, we prepared chiral
allylsilanes 16a and 16b through the reaction of aldehyde
13 with (E)-g-[(dimethylphenysilyl)allyl]diisopinocam-
pheylbornane, which was derived from allyldimethylphenyl-
silane 14 and (ꢀ)-Ipc2BOMe (for 16a) or (+)-Ipc2BOMe
(for 16b), respectively (Scheme 1).11–13 Aldehyde 13 was
synthesized by four reaction steps from a commercially

N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
1129
OH
OTBS
O
O
O
O
R
R
O
H
SiMe2Ph
SiMe2Ph
Bu
Bu
Bu
16a
15a
Bu
a
b
13
or
or
+
OTBS
OH
O
S
S
Si
14
SiMe2Ph
SiMe2Ph
Bu
16b
15b
OTBS
OTBS
OTBS
O
O
O
O
O
O
H
d
c
R
R
R
SiMe2Ph
OBn
Bu
Bu
Bu
PhMe2Si
PhMe2Si
16a
18
17
Bu
Bu
Bu
6S
6R
TBSO
PhMe2Si
HO
HO
HO
HO
O
O
O
O
5
5
O
O
2
2'
O
5'
O
2
2'
O
5'
g
e
f
16b + 18
19
2
3
O
PhMe2Si
O
O
TBSO
6'R
6'S
Bu
Bu
Bu
Partial NMR data for 2 and 3
h
i
OH
OH
position
6'
6
5
2
2'
5'
HO
TBSO
1H (δ, ppm) for 2
1H (δ, ppm) for 3
3.40 3.82 4.05 4.05 3.82 3.40
3.85 3.89 4.12 4.12 3.89 3.85
20
j
O
k
O
TBSO
HO
13
13C (δ, ppm) for 2
13C (δ, ppm) for 3
74.2 82.7 81.1 81.1 82.7 74.2
72.1 82.9 80.7 80.7 82.9 72.1
21
Bu
22
Bu
Scheme 1. Reagents and conditions: (a) t-BuOK, n-BuLi, BF3$Et2O, (ꢀ)-Ipc2BOMe for 15a, (+)-Ipc2BOMe for 15b, THF, ꢀ78 ꢁC, 4 h, 51% for 15a, 55% for
ꢁ
ꢁ
˚
15b; (b) TBSCl, imidazole, DMF, 50 C, 48 h, 98% for 16a, 94% for 16b; (c) a-(benzyloxy)acetaldehyde, BF3$Et2O, 4 A MS, CH2Cl2, ꢀ78 to ꢀ45 C, 22 h,
ꢁ
ꢁ
˚
56%; (d) (i) 20% Pd(OH)2/C, H2, THF, rt, 2 h, 86%, (ii) oxalyl chloride, DMSO, Et3N, CH2Cl2, ꢀ78 C, 1 h, 84%; (e) BF3$Et2O, CH2Cl2, 4 A MS, ꢀ78 C, 1 h;
(f) TBAF, DMF, 90 ꢁC, 6.5 h, 63% (two steps); (g) (i) 4-nitrobenzoic acid, PPh3, DIAD, toluene, 100 ꢁC, 2 h, (ii) K2CO3, MeOH, 35 ꢁC, 1.5 h, 23%; (h) NaH,
TBSCl, THF, 0 ꢁC, 2 h, 58%; (i) 4-butylphenol, PPh3, DIAD, THF, 0 ꢁC to rt, 3 h; (j) TBAF, THF, 0 ꢁC to rt, 3.5 h, 82% (two steps); (k) oxalyl chloride, DMSO,
Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h, 84%.
PhMe2Si
Ha
PhMe2Si
Ha
Hc
Hc
of 2 was assigned through inspection of its 1H and 13C NMR
spectral data, which exhibit only three nonequivalent
methine resonances, indicating that 2 has a C2-symmetric
structure. The R absolute configuration of C60 in 2 is known
from the stereochemistry of the parent allylsilane 16a.
Likewise, the S configuration of C6 is known from allyl-
silane 16b. We also know that one THF ring in 2 possesses
the 20,50-cis stereochemistry present in aldehyde 18, and
a threo relationship exists between the C50 and C60 substitu-
ents. Thus, there is no symmetric structure other than the
threo–cis–erythro–cis–threo structure that can be assigned
for 2.
R
S
R
Hd
R
Hd
MTPAO
Hb
Hb
MTPAO
MTPA ester of 15a
MTPA ester of 15b
position
a
b
c
d
Δδ (ppm) for 15a
-0.11
-0.02
-0.07
-0.06
(2.14-2.25) (5.71-5.73) (4.79-4.86) (4.93-4.99)
+0.09 +0.02 +0.07 +0.06
(2.22-2.13) (5.73-5.71) (4.86-4.79) (4.99-4.93)
Δδ (ppm) for 15b
Figure 2. Determination of the absolute configurations of 15a and 15b. Dif-
ferences in chemical shifts [DS–R values in d (400 MHz, CDCl3)] between
(S)- and (R)-MTPA esters of 15a and 15b are shown.
Compound 3, in which the relative configurations about
C5–C6 and C50–C60 bonds are the erythro relationship,
cannot be obtained by Roush’s procedures since the threo
relationship at these positions selectively results from
[3+2]-annulation reactions of b-silyloxyallylsilanes.11–13
Therefore compound 3 was synthesized from 2 through Mit-
sunobu inversion (Scheme 1). The relative configuration was
determined by the application of Born’s rule to H and 13
1
C
Figure 3. NOEs observed for 17 and 30.
NMR spectral data of 3.15,16 The spectral data still exhibit

1130
N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
OH
OAc
OAc
b
O
O
O
O
O
O
O
H
a
c
R
R
R
17
OBn
OBn
Bu
Bu
Bu
25
23
24
Bu
Bu
R
AcO
HO
O
O
O
O
O
O
d
e
16a + 25
4
26
PhMe2Si
TBSO
O
O
HO
R
Bu
Bu
Scheme 2. Reagents and conditions: (a) TBAF, DMF, 90 ꢁC, 5.5 h, 96%; (b) AcCl, DMAP, CH2Cl2, 0 ꢁC to rt, 1 h, 92%; (c) (i) 20% Pd(OH)2/C, H2, THF, rt, 2 h,
ꢁ
ꢁ
ꢁ
˚
92%, (ii) oxalyl chloride, DMSO, Et3N, CH2Cl2, ꢀ78 C, 1 h, 89%; (d) SnCl4, 4 A MS, CH2Cl2, ꢀ78 C, 6 h, 67%; (e) (i) K2CO3, MeOH, 35 C, 1.5 h, (ii)
TBAF, DMF, 90 ꢁC, 3.5 h, 54%.
only three nonequivalent methine resonances, indicating that
there is no symmetric structure other than the erythro–cis–
erythro–cis–erythro structure that can be assigned for 3.
afford 4, a bis-THF with 1H and 13C NMR spectral data in-
dicating a symmetric product. The R configuration at the C6
and C60 positions in 4 is known from allylsilane 16a, and one
2,5-cis-tetrahydrofuran ring must be present in the structure.
There are no other possible symmetric stereochemical as-
signments for 4 other than the cis–threo–cis structure.
The SnCl4-catalyzed [3+2]-annulation reaction between
allylsilane 16a and aldehyde 25 was successful (6.5:1 ds,
67% yield) for construction of a bis-THF skeleton in 26,
which was the key reaction step in the synthesis of com-
pound 4 (Scheme 2). The diastereomers (26 and its epimer)
were separated by chromatography on silica gel. Aldehyde
25 was synthesized from 17 through protiodesilylation
with TBAF, protection of alcohol 23 by an acetate group,
Pd(OH)2/C-catalyzed debenzylation, and subsequent Swern
oxidation in 72% yield (four steps). The acetate protecting
group adjacent to the tetrahydrofuran ring of 25, rather
than a TBS group, is likely favorable for construction of
the cis–threo–cis stereochemistry of 26.11 The cis–threo–
cis stereochemistry of 26 was established upon hydrolysis
with K2CO3/MeOH and protiodesilylation with TBAF to
The synthesis of mono-THF ring analogs (6–9) was accom-
plished by alkyne addition to chiral 2-tetrahydrofuranyl
carbaldehydes (Schemes 3 and 4). The reaction of aldehyde
18 with the lithium acetylide derived from 27 in the presence
of anhydrous CeCl317 gave alkynyl compounds 28a and 28b
as a 1:2.2 mixture (Scheme 3), which could be separated by
chromatography on silica gel. Hydrogenation of 28a and
28b with catalytic 10% Pd/C and subsequent protiodesilyla-
tion with TBAF provided 6 and 7. The stereochemistry of 6
1
was assigned through inspection of its H and 13C NMR
spectral data, which exhibit only two nonequivalent methine
resonances, indicating that 6 has a C2-symmetric structure.
Bu
Bu
Bu
'S
O
HO
HO
HO
HO
O
O
O
5
c
b
28a
O
O
2
O
6
29a
PhMe2Si
PhMe2Si
O
O
TBSO
TBSO
R
Bu
Bu
Bu
Bu
Bu
Bu
a
18 +
O
27
Bu
O
'R
HO
HO
HO
HO
O
O
O
5
b
c
28b
O
O
2
O
7
29b
PhMe2Si
PhMe2Si
TBSO
O
O
TBSO
R
Bu
Bu
Bu
Partial NMR data for 6
Partial NMR data for 7
position
2
5
α'
2
5
α'
α
position
α
1H (δ, ppm) 3.44 3.82 3.82 3.44
1H (δ, ppm) 3.44 3.82 3.90 3.85
13C (δ, ppm) 74.3 82.6 82.2 72.2
13C (δ, ppm) 74.3 82.6 82.6 74.3
Scheme 3. Reagents and conditions: (a) n-BuLi, CeCl3, THF, ꢀ78 to ꢀ23 ꢁC, 5 h, 18% for 28a, 40% for 28b; (b) 10% Pd/C, H2, EtOH, rt, 3 h, 87% for 29a, 91%
for 29b; (c) TBAF, DMF, 90 ꢁC, 4 h, 44% for 6, 28% for 7.

N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
1131
OBn
O
H
OH
5
16a
+
a
b
c
O
2
O
30
O
32
31
PhMe2Si
TBSO
PhMe2Si
TBSO
α-(benzyloxy)acetaldehyde
PhMe2Si
TBSO
O
O
O
Bu
Bu
Bu
Bu
Bu
Bu
f
O
O
α'
HO
HO
HO
HO
O
O
O
Bu
d
e
33
O
O
O
34
32 +
O
PhMe2Si
TBSO
PhMe2Si
TBSO
O
27
R
Bu
Bu
Bu
8 (α'R), 9 (α'S)
ꢁ
˚
Scheme 4. Reagents and conditions: (a) SnCl4, 4 A MS, CH2Cl2, ꢀ45 C, 20 h, 81%; (b) 20% Pd(OH)2/C, H2, THF, rt, 2 h, 92%; (c) oxalyl chloride, DMSO,
Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h, 88%; (d) n-BuLi, CeCl3, THF, ꢀ78 to ꢀ23 ꢁC, 5 h, 74%; (e) 10% Pd/C, H2, EtOH, rt, 12 h, 91%; (f) (i)TBAF, DMF, 90 ꢁC, 6 h,
57%, (ii) AcCl, DMAP, CH2Cl2, 0 ꢁC, 2 h, (iii) K2CO3, MeOH, 24% for 8, 50% for 9.
The R absolute configuration of Ca in 6 is known from the
stereochemistry of the parent allylsilane 16a. We also know
that the THF ring in 6 possesses the 2,5-cis stereochemistry
present in aldehyde 18 and a threo relationship exists be-
tween the C2 and Ca substituents. Thus, there is no symmet-
ric structure other than the threo–cis–threo one that can be
assigned for 6. The 1H and 13C NMR spectral data of 7 exhibit
four different methine resonances, indicating that 7 has an
asymmetric structure. We know that the THF ring in 7 pos-
sesses the 2,5-cis stereochemistry present in aldehyde 18
and a threo relationship also exists between the C2 and Ca
substituents. Thus, there is no asymmetric structure other
than the erythro–cis–threo one that can be assigned for 7.
and AD-mix-a in place of (+)-DET and AD-mix-b, respec-
tively. The 1H and 13C NMR spectral data of 5 were identical
to those of 1. Optical rotations ([a]D) of 1 and 5 were +17
(c 0.41, EtOH) and ꢀ19 (c 0.21, EtOH) at 16 ꢁC, respectively.
The total synthesis of stereoisomer library of bis- and mono-
THF acetogenins has been disclosed in Refs. 11 and 20,
1
respectively. The H and 13C NMR spectral data of the
bis-THF portion of 1–5 and mono-THF portion of 6–9
matched the data published in these papers.
2.2. Biological activity
The inhibition of complex I in bovine heart submitochon-
drial particles was investigated by NADH oxidase assay.
The inhibitory potencies of the test compounds, in terms
of IC50 values, are listed in Table 1, taking bullatacin and
piericidin A as references. Compound 1 was the most potent
inhibitor among the Dlac-acetogenins synthesized so far in
our laboratory.8,10 All modifications of the stereochemistry
around the THF moiety of 1 (i.e., all R isomer) significantly
reduced the inhibitory potency, but none resulted in drastic
changes such as a 103–104 fold loss in activity. The threo ste-
reochemistry about the C2–C20 bond seems to be slightly
better for the activity than the erythro stereochemistry.
To synthesize compounds 8 and 9, the 2,5-trans THF struc-
ture was constructed for compound 30 through a SnCl4-cat-
alyzed [3+2]-annulation reaction between allylsilane 16a
and a-(benzyloxy)acetaldehyde with complete diastereo-
selectivity in 81% yield (Scheme 4). The relative stereo-
chemistry at the C2 and C5 positions in 30 was assigned
using a 1H NOE analysis (Fig. 3).11 The relative configura-
tion about the C2–Ca bond in 30 was assigned as threo, as
described above. Debenzylation of 30 catalyzed by 10%
Pd(OH)2/C and subsequent Swern oxidation gave the alde-
hyde 32, which was coupled with the alkyne 27 to afford
the alkynyl compound 33 as a 4:5 mixture of diastereoiso-
mers. Although the mixture was hydrogenated and protio-
desilylated only to give a mixture of 8 and 9 without any
success in separation by chromatography on silica gel, we
found that the diacetate derivatives could be separated by
chromatography on silica gel. Hydrolysis of the resultant di-
acetate provided 8 (and 9). The stereochemistry of 8 and 9
was assigned through the application of Born’s rule to their
1H and 13C NMR spectral data,15,16 indicating that the threo-
trans-threo and erythro-trans-threo structures can be as-
signed for 8 and 9, respectively.
With respect to the mono-THF analogs, it was revealed
that their inhibitory effects are much weaker than those of
Table 1. Summary of the inhibitory potencies (IC50) of the test compoundsa
Compound no.
IC50 (nM)
Compound no.
IC50 (nM)
1
2
3
4
5
6
7
0.90 (ꢂ0.05)
16 (ꢂ1)
8
9
10
11
12
47 (ꢂ2)
38 (ꢂ2)
9.0 (ꢂ0.7)b
308 (ꢂ13)
1.3 (ꢂ0.05)b
0.85 (ꢂ0.03)b
9.0 (ꢂ1.4)
5.2 (ꢂ0.5)
3.8 (ꢂ0.3)
39 (ꢂ8)
>25,000b
Piericidin A
Bullatacin
In previous studies,18,19 the six stereogenic centers in com-
pound 1 were constructed by sequential double Sharpless
asymmetric epoxidation and dihydroxylation (AD) using
(+)-diethyl tartrate (DET) and AD-mix-b, respectively. Com-
pound 5, an enantiomer of 1, was synthesized following the
procedure used for the synthesis of 1, but using (ꢀ)-DET
41 (ꢂ3)
a
The IC50 value is the molar concentration needed to reduce the control
NADH oxidase activity (0.60–0.65 mmol NADH/min/mg of protein)
in submitochondrial particles by half. Values are meansꢂSD of three
independent experiments.
b
From Ref. 8.

1132
N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
compound 1 and that the changes among them due to the
modification of stereochemistry are negligibly small. We
previously showed that a mono-THF derivative possessing
two tridecyl groups in the side chain portion (compound
10, IC50>25,000 nM) drastically lost inhibitory activity
compared to the corresponding bis-THF analog (compound
11, IC50¼9.0 nM).7,8 No such drastic loss in activity was ob-
served for the present set of mono-THF analogs, indicating
that the physicochemical properties of the side chains mark-
edly affect the molecular interaction of the polar hydroxyl-
ated mono-THF with the enzyme. In particular, the drastic
reduction in the activity of 10 may be due to an excessive in-
crease in hydrophobicity of the alkyl tails, which results in
some sort of trapping in the hydrophobic lipid bilayer of
mitochondrial membrane. This phenomenon is generally ob-
served for largely hydrophobic inhibitors.7 To address this
possibility, we newly synthesized compound 12 possessing
two undecyl groups in place of tridecyl groups and examined
its inhibitory effect. Expectedly, 12 (IC50¼308ꢂ13 nM) sig-
nificantly recovered the inhibitory effect compared to 10, but
still much weaker than the corresponding bis-THF analog
(compound 3 in Ref. 7: IC50¼1.6ꢂ0.2 nM) as well as 11.
Taken together, it is obvious that the mono-THF skeleton
is much less favorable for the inhibition than bis-THF.
at the same temperature. A CH2Cl2 solution (50 mL) of alco-
hol 22 (4.9 g, 20 mmol) was added slowly. After stirring for
30 min, the mixture was quenched with Et3N (14 mL) at
ꢀ78 ꢁC. The reaction mixture was slowly warmed to 0 ꢁC
over 1 h and then saturated aqueous NH4Cl was added.
The organic layer was removed and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and con-
centrated. The crude product was purified by Wako silica
gel chromatography (10% EtOAc/hexane) to give aldehyde
1
13 (4.1 g, 17 mmol, 84%) as a pale yellow oil: H NMR
(400 MHz, CDCl3) d 9.78 (t, J¼1.7 Hz, 1H), 7.07 (d,
J¼8.6 Hz, 2H), 6.80 (d, J¼8.6 Hz, 2H), 3.93 (t, J¼6.3 Hz,
2H), 2.54 (t, J¼7.6 Hz, 2H), 2.46 (dt, J¼7.4, 1.7 Hz, 2H),
1.79 (tt, J¼7.1, 6.3 Hz, 2H), 1.70 (quint, J¼7.7 Hz, 2H),
1.56–1.51 (m, 4H), 1.34 (tq, J¼7.5, 7.3 Hz, 2H), 0.91 (t,
J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 202.53,
157.08, 134.84, 129.19 (2C), 114.25 (2C), 67.77, 34.72,
34.31, 33.91, 29.21, 25.87, 23.30, 13.96; ESI-HRMS (m/z)
calcd for C16H25O2 [M+H]+ 249.1848, observed 249.1844.
3.2.2. Allyldimethylphenylsilane (14). To a solution of
chlorodimethylphenylsilane (5.0 g, 29.3 mmol) in anhy-
drous Et2O (40 mL) was added allylmagnesium chloride
(14.6 mL of a 2.0 M solution in THF, 29.3 mmol) slowly
over 20 min and the resulting mixture was refluxed at
60 ꢁC for 18.5 h. The mixture was cooled to room tempera-
ture, quenched with saturated aqueous NH4Cl, and parti-
tioned between H2O and Et2O. The organic layer was
washed with saturated NaHCO3 and brine, dried over anhy-
drous MgSO4, and concentrated. The crude product was
purified by YMC silica gel chromatography (5% CHCl3/
hexane) to give 14 (4.4 g, 25 mmol, 84%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) d 7.52–7.49 (m, 2H),
7.36–7.33 (m, 3H), 5.77 (ddt, J¼16.8, 10.1, 8.0 Hz, 1H),
4.86 (dd, J¼16.8, 2.6 Hz, 1H), 4.83 (dd, J¼10.1, 2.6 Hz,
1H), 1.75 (d, J¼8.0 Hz, 2H), 0.27 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 138.67, 134.63, 133.61 (2C), 129.00,
127.74 (2C), 113.38, 23.67, ꢀ3.48 (2C); ESI-MS (m/z)
177.2 [M+H]+.
The structure–activity studies for natural-type acetogenins
including mono- and bis-THF acetogenins showed that the
stereochemistry around the THF moiety including flanking
OH groups does not significantly affect the inhibitory activ-
ity and that mono-THF analogs are just about 2-fold less po-
tent than bis-THF analogs if other structural factors, such as
the length of the alkyl spacer linking g-lactone and THF
moieties, are identical among them.21–24 Thus, the structural
factors governing the inhibitory effect are appreciably differ-
ent between Dlac-acetogenins and natural acetogenins. This
result also supports our previous view derived from various
biochemical experiments; namely, that the site of inhibition
by Dlac-acetogenins in complex I is different from that by
natural acetogenins.
3. Experimental
3.2.3. (3S,4R)-9-(4-Butylphenyloxy)-3-dimethylphenyl-
silyl-4-hydroxy-1-nonene (15a). To a solution of t-BuOK
(0.86 g, 7.7 mmol) in THF (15 mL) at ꢀ78 ꢁC was added
14 (1.5 g, 8.5 mmol). The mixture was stirred for 5 min,
then n-BuLi (1.57 M in hexane, 4.9 mL, 7.7 mmol) was
added slowly via a syringe over 5 min. The mixture was
stirred at ꢀ78 ꢁC for 10 min and then warmed to ꢀ45 ꢁC
and stirred for 1 h. The mixture was recooled to ꢀ78 ꢁC
and (ꢀ)-Ipc2BOMe (2.4 g, 7.7 mmol) was added as a solu-
tion in THF (9 mL) slowly over 5 min. The mixture was
stirred for 30 min and then BF3$Et2O (1.5 g, 10.2 mmol)
was added in one portion. After 5 min, aldehyde 13
(2.32 g, 9.4 mmol) was added as a solution in THF
(15 mL) slowly over 5 min. The mixture was stirred at
ꢀ78 ꢁC for 4 h and then diluted with KOH/KH2PO4 buffer
(1.0 M solution of KH2PO4, adjusted to pH 6.0 with KOH,
7.5 mL) and warmed to room temperature. H2O2 (30%,
1.4 mL) was added and then the two-phase mixture was
stirred at ambient temperature for 16 h. The reaction mixture
was partitioned between saturated aqueous NaHCO3 and
Et2O. The organic layer was dried over anhydrous MgSO4,
and concentrated, and the residue was dissolved in MeOH
3.1. General procedures
1H NMR spectra were recorded at 500 or 400 MHz with
a Bruker ARX500 or Bruker AVANCE400 spectrometer
using tetramethylsilane as the internal standard. 13C NMR
spectra were recorded at 100 MHz. The ESI-MS and HR
ESI-MS spectra were recorded with a Perkin–Elmer Sciex
API165 and Shimadzu LCMS-IT-TOF, respectively. Optical
rotations were measured with a JASCO P-1010 polarimeter.
Column chromatography was performed on Wako silica gel
(C-200, 75–150 mm) or YMC silica gel (SIL-60-S75, 42–
105 mm). Dry solvents were either used as purchased or
freshly distilled using common practices where appropriate.
3.2. Synthesis of compound 2
3.2.1. 6-(4-Butylphenyloxy)-1-hexanal (13). To a cooled
solution of oxalyl chloride (2.6 mL, 30 mmol) in anhydrous
CH2Cl2 (60 mL) at ꢀ78 ꢁC was added dropwise DMSO
(4.0 mL, 56 mmol) and the mixture was stirred for 15 min

N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
1133
(20 mL) for subsequent reduction of the excess aldehyde 13.
This reduction step enabled the product 15a to be isolated as
a pure form on purification by silica gel chromatography.
NaBH4 (0.13 g, 3.4 mmol) was added at 0 ꢁC and the mix-
ture was stirred at 0 ꢁC for 1.5 h. The reaction mixture was
poured into 15 mL of saturated aqueous NH4Cl, and the re-
sulting suspension was extracted with Et2O, washed with
brine, dried over anhydrous MgSO4, and concentrated. The
crude product was purified by YMC silica gel chromato-
graphy (10% EtOAc/hexane) to give allylsilane 15a (1.7 g,
3.9 mmol, 51%) as a colorless oil: [a]2D1 +2.3 (c 0.26,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.54–7.52 (m,
2H), 7.35–7.34 (m, 3H), 7.07 (d, J¼8.6 Hz, 2H), 6.78 (d,
J¼8.6 Hz, 2H), 5.82 (ddd, J¼17.0, 10.4, 10.4 Hz, 1H),
5.05 (dd, J¼10.4, 2.0 Hz, 1H), 4.91 (dd, J¼17.0, 2.0 Hz,
1H), 3.87 (t, J¼6.5 Hz, 2H), 3.75–3.69 (m, 1H), 2.53 (t,
J¼7.7 Hz, 2H), 1.91 (dd, J¼10.4, 4.5 Hz, 1H), 1.75–1.67
(m, 2H), 1.57–1.53 (m, 2H), 1.56 (br s, 1H), 1.40–1.30 (m,
9H), 0.91 (t, J¼7.3 Hz, 3H), 0.35 (s, 3H), 0.32 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 157.0, 137.9, 135.1, 134.8,
134.0 (2C), 129.1 (2C), 129.0, 127.7 (2C), 115.6, 114.2
(2C), 71.34, 67.80, 42.12, 37.03, 34.72, 33.91, 29.22,
25.93, 25.46, 22.30, 13.97, ꢀ3.37, ꢀ3.97; ESI-HRMS
(m/z) calcd for C27H40SiO2Na [M+Na]+ 447.2685, observed
447.2690.
3.85–3.82 (m, 1H), 2.54 (t, J¼7.6 Hz, 2H), 2.00 (dd,
J¼10.4, 3.4 Hz, 1H), 1.75–1.67 (m, 2H), 1.56–1.54 (m,
2H), 1.45–1.31 (m, 8H), 0.91 (t, J¼7.3 Hz, 3H), 0.86 (s,
9H), 0.34 (s, 3H), 0.29 (s, 3H), 0.01 (s, 3H), ꢀ0.01 (s,
3H); 13C NMR (100 MHz, CDCl3) d 157.10, 138.79,
136.01, 134.84, 134.07 (2C), 129.20 (2C), 128.74, 127.52
(2C), 114.44, 114.25 (2C), 73.29, 67.85, 40.68, 36.79,
34.73, 33.92, 29.29, 26.13 (3C), 25.70, 25.21, 22.31,
18.23, 13.97, ꢀ3.01, ꢀ3.66, ꢀ3.74, ꢀ3.87; ESI-HRMS
(m/z) calcd for C33H54Si2O2Na [M+Na]+ 561.3546,
observed 561.3545.
3.2.6. (3R,4S)-4-(tert-Butyldimethylsilyloxy)-9-(4-butyl-
phenyloxy)-3-dimethylphenylsilyl-1-nonene (16b). Com-
pound 16b was synthesized by the same procedure used
for the synthesis of 16a in a 94% yield as a colorless oil:
[a]2D2 ꢀ1.4 (c 0.27, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.50–7.48 (m, 2H), 7.33–7.31 (m, 3H), 7.07 (d, J¼8.6 Hz,
2H), 6.78 (d, J¼8.6 Hz, 2H), 5.83 (ddd, J¼17.2, 10.4,
10.2 Hz, 1H), 4.94 (dd, J¼10.2, 2.2 Hz, 1H), 4.74 (dd,
J¼17.2, 2.2 Hz, 1H), 3.87 (t, J¼6.5 Hz, 2H), 3.85–3.82
(m, 1H), 2.54 (t, J¼7.6 Hz, 2H), 2.00 (dd, J¼10.4, 3.4 Hz,
1H), 1.75–1.67 (m, 2H), 1.56–1.54 (m, 2H), 1.45–1.31 (m,
8H), 0.91 (t, J¼7.3 Hz, 3H), 0.86 (s, 9H), 0.34 (s, 3H),
0.29 (s, 3H), 0.01 (s, 3H), ꢀ0.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 157.10, 138.79, 136.01, 134.84,
134.07 (2C), 129.20 (2C), 128.74, 127.52 (2C), 114.44,
114.25 (2C), 73.29, 67.85, 40.68, 36.79, 34.73, 33.92,
29.29, 26.13 (3C), 25.70, 25.21, 22.31, 18.23, 13.97,
ꢀ3.01, ꢀ3.66, ꢀ3.74, ꢀ3.87; ESI-HRMS (m/z) calcd for
C33H54Si2O2Na [M+Na]+ 561.3546, observed 561.3546.
3.2.4. (3R,4S)-9-(4-Butylphenyloxy)-3-dimethylphenyl-
silyl-4-hydroxy-1-nonene (15b). Compound 15b was syn-
thesized by the same procedure used for the synthesis of
15a, except that (+)-Ipc2BOMe was used in place of (ꢀ)-
Ipc2BOMe, in a 55% yield as a colorless oil: [a]2D1 ꢀ2.3
1
(c 0.17, CHCl3); H NMR (400 MHz, CDCl3) d 7.54–7.52
(m, 2H), 7.35–7.34 (m, 3H), 7.06 (d, J¼8.6 Hz, 2H), 6.79
(d, J¼8.6 Hz, 2H), 5.82 (ddd, J¼17.0, 10.4, 10.4 Hz, 1H),
5.05 (dd, J¼10.4, 2.0 Hz, 1H), 4.91 (dd, J¼17.0, 2.0 Hz,
1H), 3.87 (t, J¼6.5 Hz, 2H), 3.74–3.70 (m, 1H), 2.53 (t,
J¼7.7 Hz, 2H), 1.90 (dd, J¼10.4, 4.5 Hz, 1H), 1.75–1.67
(m, 2H), 1.57–1.53 (m, 2H), 1.56 (br s, 1H), 1.40–1.30 (m,
9H), 0.91 (t, J¼7.3 Hz, 3H), 0.35 (s, 3H), 0.32 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 157.0, 137.9, 135.1, 134.8,
134.0 (2C), 129.1 (2C), 129.0, 127.7 (2C), 115.6, 114.2
(2C), 71.34, 67.79, 42.12, 37.02, 34.72, 33.91, 29.22,
25.93, 25.46, 22.30, 13.96, ꢀ3.37, ꢀ3.98; ESI-HRMS
(m/z) calcd for C27H40SiO2Na [M+Na]+ 447.2685, observed
447.2685.
3.2.7. (2S,3R,5S)-5-Benzyloxymethyl-2-[(1R)-1-(tert-
butyldimethylsilyloxy)-6-(4-butylphenyloxy)hexyl]-3-di-
methylphenylsilyltetrahydrofuran (17). To a ꢀ78 ꢁC
mixture of allylsilane 16a (0.50 g, 0.93 mmol), a-(benzyl-
oxy)acetaldehyde (0.13 mL, 0.93 mmol), CH2Cl2 (2.0 mL),
ꢁ
˚
and oven-dried powdered 4 A molecular sieves (130 C,
12 h, 8.6 mg) was added BF3$Et2O (59 mL, 0.47 mmol)
dropwise from a syringe. The resulting mixture was stirred
for 22 h, warming slowly from ꢀ78 to ꢀ45 ꢁC. The reaction
mixture was quenched through addition of Et3N (0.3 mL)
and warmed to room temperature. The mixture was parti-
tioned between EtOAc and saturated aqueous NaHCO3,
washed with brine, dried over anhydrous MgSO4, and con-
centrated. The crude product was purified by YMC silica
gel chromatography (5% EtOAc/hexane) to give tetrahydro-
furan 17 (0.36 g, 0.52 mmol, 56%) as a colorless oil contain-
ing a 17:1 mixture of diastereomers (favoring 17) as
determined by 1H NMR analysis: [a]2D3 ꢀ15 (c 0.15,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.50–7.44 (m,
2H), 7.35–7.33 (m, 3H), 7.31–7.30 (m, 4H), 7.27–7.23 (m,
1H), 7.07 (d, J¼8.6 Hz, 2H), 6.81 (d, J¼8.6 Hz, 2H), 4.55
(d, J¼12.2 Hz, 1H), 4.47 (d, J¼12.2 Hz, 1H), 4.04–3.99
(m, 1H), 3.91 (m, 1H), 3.90 (t, J¼6.4 Hz, 2H), 3.41 (dd,
J¼9.6, 5.6 Hz, 1H), 3.36–3.32 (dd, J¼9.6, 6.6 Hz, 1H),
3.35–3.33 (m, 1H), 2.54 (t, J¼7.7 Hz, 2H), 1.89–1.86 (m,
2H), 1.75–1.70 (m, 2H), 1.70–1.61 (m, 2H), 1.60–1.52 (m,
2H), 1.40–1.30 (m, 7H), 0.91 (t, J¼7.3 Hz, 3H), 0.85 (s,
9H), 0.33 (s, 3H), 0.33 (s, 3H), ꢀ0.02 (s, 3H), ꢀ0.03 (s,
3H); 13C NMR (100 MHz, CDCl3) d 157.1, 138.5, 137.7,
134.8, 133.9 (2C), 129.2 (3C), 128.3 (2C), 127.8 (2C),
127.6 (2C), 127.4, 114.2 (2C), 83.32, 73.29, 73.18, 72.87,
3.2.5. (3S,4R)-4-(tert-Butyldimethylsilyloxy)-9-(4-butyl-
phenyloxy)-3-dimethylphenylsilyl-1-nonene (16a). To
a solution of allylsilane 15a (0.77 g, 1.81 mmol) in DMF
(3 mL) was added TBSCl (0.55 g, 3.62 mmol) and imid-
azole (0.25 g, 3.62 mmol) at room temperature. The reaction
flask was flushed with N2, sealed with a septum, and heated
to 50 ꢁC for 48 h. The mixture was cooled to room tem-
perature and partitioned between H2O and Et2O. The org-
anic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated. The crude product was purified
by YMC silica gel chromatography (5% EtOAc/hexane) to
give allylsilane 16a (0.96 g, 1.8 mmol, 98%) as a colorless
oil: [a]2D1 +1.3 (c 0.64, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.50–7.48 (m, 2H), 7.33–7.31 (m, 3H), 7.07 (d,
J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 5.83 (ddd,
J¼17.2, 10.4, 10.2 Hz, 1H), 4.94 (dd, J¼10.2, 2.2 Hz, 1H),
4.74 (dd, J¼17.2, 2.2 Hz, 1H), 3.87 (t, J¼6.5 Hz, 2H),

1134
N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
67.84, 34.72, 34.55, 33.92, 32.15, 29.36, 26.32, 26.09 (3C),
25.69, 24.46, 22.30, 18.22, 13.97, ꢀ3.84, ꢀ4.06, ꢀ4.24,
ꢀ4.33; ESI-HRMS (m/z) calcd for C42H64Si2O4Na
[M+Na]+ 711.4224, observed 711.4253.
gel chromatography (5% EtOAc/hexane) twice to give 19
(175 mg) as a colorless oil still containing the excess allyl-
silane 16b, which was brought to the next reaction step with-
out further purification. The product was a 16:1 mixture of
diastereomers (favoring 19) as determined through 1H
NMR analysis: [a]D22 ꢀ5.2 (c 0.31, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.47–7.45 (m, 4H), 7.32–7.30 (m,
6H), 7.07 (d, J¼8.6 Hz, 4H), 6.81 (d, J¼8.6 Hz, 4H), 3.89
(t, J¼6.5 Hz, 4H), 3.77 (dd, J¼9.6, 2.0 Hz, 2H), 3.62 (m,
2H), 3.29 (m, 2H), 2.54 (t, J¼7.6 Hz, 4H), 2.04 (m, 2H),
1.84–1.81 (m, 2H), 1.78–1.70 (m, 4H), 1.60–1.54 (m, 8H),
1.36–1.26 (m, 10H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H), 0.91 (t,
J¼7.3 Hz, 6H), 0.84 (s, 18H), 0.31 (s, 6H), 0.30 (s, 6H),
ꢀ0.04 (s, 6H), ꢀ0.06 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 157.13 (2C), 137.94 (2C), 134.82 (2C), 133.95
(4C), 129.21 (4C), 129.07 (2C), 127.78 (4C), 114.24 (4C),
83.51 (2C), 79.45 (2C), 73.17 (2C), 67.88 (2C), 34.74
(4C), 33.93 (2C), 32.01 (2C), 29.41 (2C), 26.33 (2C),
26.10 (6C), 25.67 (2C), 24.20 (2C), 22.31 (2C), 18.22
(2C), 13.97 (2C), ꢀ3.89 (2C), ꢀ3.93 (2C), ꢀ3.98 (2C),
ꢀ4.44 (2C); ESI-HRMS (m/z) calcd for C68H110Si4O6Na
[M+Na]+ 1157.7248, observed 1157.7262.
3.2.8. (2S,4R,5S)-5-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-4-dimethylphenylsilyltetra-
hydrofuran-2-carbaldehyde (18).
A mixture of 17
(150 mg, 0.22 mmol), THF (13 mL), and 20% Pd(OH)2 on
carbon (37 mg) was stirred at room temperature under a hy-
drogen gas atmosphere for 2 h. The reaction mixture was
then filtered through a Celite layer. The Celite layer was
washed with 10 mL of EtOAc. The combined filtrates
were concentrated and purified by YMC silica gel chromato-
graphy (10% EtOAc/hexane) to give 113 mg of alcohol as
a colorless oil. Then, to a cooled solution of oxalyl chloride
(22 mL, 0.25 mmol) in anhydrous CH2Cl2 (0.50 mL) at
ꢀ78 ꢁC was added dropwise DMSO (34 mL, 0.47 mmol)
and the mixture was stirred for 5 min at the same tempera-
ture. A CH2Cl2 solution (1.2 mL) of the alcohol (0.10 g,
0.17 mmol) was added slowly. After stirring for 15 min,
the mixture was quenched with Et3N (0.12 mL) at ꢀ78 ꢁC.
The reaction mixture was slowly warmed to 0 ꢁC over 1 h
and then saturated aqueous NH4Cl (2 mL) was added. The
mixture was extracted with EtOAc, washed with brine, dried
over anhydrous MgSO4, and concentrated. The crude prod-
uct was purified by Wako silica gel chromatography (10%
EtOAc/hexane) to give aldehyde 18 (85 mg, 0.14 mmol,
84%, two steps) as a pale yellow oil: [a]2D1 ꢀ35 (c 0.25,
CHCl3); 1H NMR (400 MHz, CDCl3) d 9.73 (s, 1H), 7.47–
7.44 (m, 2H), 7.37–7.33 (m, 3H), 7.07 (d, J¼8.6 Hz, 2H),
6.81 (d, J¼8.6 Hz, 2H), 4.11–4.07 (m, 2H), 3.92 (t,
J¼6.4 Hz, 2H), 3.26 (dd, J¼8.9, 4.5 Hz, 1H), 2.54 (t, J¼
7.6 Hz, 2H), 2.36 (ddd, J¼12.7, 8.9, 2.4 Hz, 1H), 1.93 (m,
1H), 1.90–1.82 (m, 1H), 1.76–1.72 (m, 2H), 1.57–1.31 (m,
8H), 1.34 (tq, J¼7.5, 7.3 Hz, 2H), 0.91 (t, J¼7.3 Hz, 3H),
0.84 (s, 9H), 0.35 (s, 3H), 0.34 (s, 3H), ꢀ0.05 (s, 3H),
ꢀ0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d 206.50,
157.08, 136.73, 134.90, 133.84 (2C), 129.51, 129.23 (2C),
128.03 (2C), 114.24 (2C), 83.97, 83.02, 73.36, 67.78,
35.26, 34.73, 33.92, 31.78, 29.36, 26.35, 25.98 (3C), 25.57,
25.43, 22.30, 18.15, 13.96, ꢀ4.20, ꢀ4.25, ꢀ4.37, ꢀ4.57;
ESI-HRMS (m/z) calcd for C35H56Si2O4Na [M+Na]+
619.3600, observed 619.3605.
3.2.10. (2R,20S,5S,50R)-5-[(1S)-6-(4-Butylphenyloxy)-1-
hydroxyhexyl]-50-[(1R)-6-(4-butylphenyloxy)-1-hydr-
oxyhexyl]octahydro-2,20-bifuran (2). To a solution of
crude bis-tetrahydrofuran 19 (131 mg) in DMF (1.0 mL)
was added TBAF (0.20 mL of a 1.0 M solution in THF,
0.20 mmol). The resulting solution was stirred at 90 ꢁC for
6.5 h. The mixture was cooled to room temperature and di-
luted with EtOAc. The resulting solution was washed with
1.0 M HCl, saturated aqueous NaHCO3, and brine, dried
over anhydrous MgSO4, and concentrated. The crude prod-
uct was purified by YMC silica gel chromatography (30–
70% EtOAc/hexane) to give 2 (34 mg, 53 mmol, 63%, two
steps from 18) as a white solid: [a]2D5 +6.7 (c 0.12, EtOH);
mp 83–84 ꢁC; 1H NMR (400 MHz, CDCl3) d 7.06 (d,
J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 4.05 (m, 2H), 3.91
(t, J¼6.5 Hz, 4H), 3.82 (m, 2H), 3.40 (m, 2H), 2.78 (br s,
2H), 2.53 (t, J¼7.6 Hz, 4H), 1.99–1.95 (m, 4H), 1.79–1.75
(m, 8H), 1.57–1.51 (m, 16H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H),
0.91 (t, J¼7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 157.09 (2C), 134.79 (2C), 129.19 (4C), 114.23 (4C),
82.76 (2C), 81.18 (2C), 74.23 (2C), 67.85 (2C), 34.27
(2C), 34.15 (2C), 33.91 (2C), 29.32 (2C), 28.04 (2C),
27.04 (2C), 26.13 (2C), 25.55 (2C), 22.30 (2C), 13.97
(2C); ESI-HRMS (m/z) calcd for C40H62O6Na [M+Na]+
661.4428, observed 661.4400.
3.2.9. (2R,20S,4S,40R,5R,50S)-5-[(1S)-1-(tert-Butyldime-
thylsilyloxy)-6-(4-butylphenyloxy)hexyl]-50-[(1R)-1-(tert-
butyldimethylsilyloxy)-6-(4-butylphenyloxy)hexyl]-4,40-
bis-dimethylphenylsilyloctahydro-2,20-bifuran (19). A
solution of allylsilane 16b (0.11 g, 0.20 mmol), aldehyde
3.3. Synthesis of compound 3
˚
18 (70 mg, 0.12 mmol), and oven-dried powdered 4 A
molecular sieves (130 ꢁC, 12 h, 16 mg) in anhydrous CH2Cl2
(2.0 mL) was cooled to ꢀ78 ꢁC. BF3$Et2O (18 mL,
0.14 mmol) was added slowly dropwise to the cold solution
and the reaction mixture was stirred at ꢀ78 ꢁC for 1 h. The
mixture was quenched cold by dropwise addition of Et3N
(0.8 mL) and the resulting mixture was warmed to room
temperature. A 1:1 EtOAc/hexane solution (5 mL) and
saturated aqueous NaHCO3 (5 mL) were added to form a
cloudy white suspension, which was stirred at room temper-
ature for 12 h. The suspension was extracted with EtOAc,
washed with brine, dried over anhydrous MgSO4, and con-
centrated. The crude product was purified by YMC silica
3.3.1. (2R,20S,5S,50R)-5-[(1R)-6-(4-Butylphenyloxy)-1-
hydroxyhexyl]-50-[(1S)-6-(4-butylphenyloxy)-1-hydroxy-
hexyl]octahydro-2,20-bifuran (3). A solution of 2 (30 mg,
47 mmol), PPh3 (123 mg, 0.47 mmol), 4-nitrobenzoic acid
(79 mg, 0.47 mmol) and DIAD (91 mL, 0.47 mmol) in tolu-
ene (0.2 mL) was stirred at 100 ꢁC for 2 h. The reaction mix-
ture was cooled to room temperature and directly subjected
to silica gel chromatography (30% EtOAc/hexane) to give
a crude product. To a MeOH (3 mL) solution of the product
was added K2CO3 (39 mg, 0.28 mmol) and then the resulting
mixture was stirred at 35 ꢁC for 1.5 h. The mixture was
quenched with saturated aqueous NH4Cl, extracted with

N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
1135
EtOAc, washed with brine, dried over anhydrous MgSO4,
and concentrated. The crude product was purified by YMC
silica gel chromatography (30–70% EtOAc/hexane) to give
3 (7 mg, 11 mmol, 23%) as a colorless oil: [a]2D5 +44 (c
0.18, EtOH); 1H NMR (400 MHz, CDCl3) d 7.07 (d,
J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 4.12 (m, 2H), 3.91
(t, J¼6.5 Hz, 4H), 3.89 (m, 2H), 3.85 (m, 2H), 2.53 (t,
J¼7.6 Hz, 4H), 2.50 (br s, 2H), 1.99–1.95 (m, 4H), 1.80–
1.75 (m, 8H), 1.57–1.46 (m, 16H), 1.34 (tq, J¼7.5, 7.3 Hz,
4H), 0.91 (t, J¼7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 157.08 (2C), 134.83 (2C), 129.20 (4C), 114.24 (4C),
82.94 (2C), 80.73 (2C), 72.19 (2C), 67.84 (2C), 34.72
(2C), 33.91 (2C), 32.74 (2C), 29.26 (2C), 26.54 (2C),
26.14 (2C), 25.84 (2C), 23.96 (2C), 22.31 (2C), 13.97
(2C); ESI-HRMS (m/z) calcd for C40H62O6Na [M+Na]+
661.4428, observed 661.4404.
75.38, 73.34, 72.77, 67.76, 34.73, 33.91, 30.99, 29.21,
28.41, 27.42, 26.03, 25.22, 22.30, 21.16, 13.96; ESI-
HRMS (m/z) calcd for C30H42O5Na [M+Na]+ 505.2919, ob-
served 505.2937.
3.4.3. (2S,5R)-5-[(1R)-1-Acetyloxy-6-(4-butylphenyloxy)-
hexyl]tetrahydrofuran-2-carbaldehyde (25). Compound
25 was synthesized by the same procedure used for the syn-
thesis of 18 in a 82% yield as a pale yellow oil: [a]2D0 ꢀ8.3 (c
0.12, CHCl3); 1H NMR (400 MHz, CDCl3) d 9.72 (d,
J¼1.3 Hz, 1H), 7.07 (d, J¼8.6 Hz, 2H), 6.80 (d, J¼8.6 Hz,
2H), 4.92 (ddd, J¼8.0, 4.8, 4.8 Hz, 1H), 4.25 (ddd, J¼6.7,
6.7, 1.3 Hz, 1H), 4.18 (ddd, J¼7.0, 7.0, 4.8 Hz, 1H), 3.92
(t, J¼6.4 Hz, 2H), 2.53 (t, J¼7.6 Hz, 2H), 2.12–2.10 (m,
2H), 2.09 (s, 3H), 2.07–1.99 (m, 1H), 1.78–1.75 (m, 2H),
1.72–1.66 (m, 2H), 1.57–1.39 (m, 7H), 1.34 (tq, J¼7.5,
7.3 Hz, 2H), 0.91 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 203.78, 170.74, 157.04, 134.92, 129.22 (2C),
114.24 (2C), 83.40, 81.34, 75.11, 67.70, 34.72, 33.91,
31.34, 29.18, 27.76, 27.66, 26.01, 25.16, 22.30, 21.12,
13.96; ESI-HRMS (m/z) calcd for C23H34O5Na [M+Na]+
413.2295, observed 413.2313.
3.4. Synthesis of compound 4
3.4.1. (2R,5S)-5-Benzyloxymethyl-2-[(1R)-6-(4-butyl-
phenyloxy)-1-hydroxyhexyl]tetrahydrofuran (23). Com-
pound 23 was synthesized by protiodesilylation of 17
according to the procedure used for the synthesis of 2 in
a 96% yield as a colorless oil: [a]2D0 +1.7 (c 0.12, CHCl3);
1H NMR (400 MHz, CDCl3) d 7.36–7.33 (m, 4H), 7.30–
7.28 (m, 1H), 7.07 (d, J¼8.6 Hz, 2H), 6.80 (d, J¼8.6 Hz,
2H), 4.58 (d, J¼12.2 Hz, 1H), 4.55 (d, J¼12.2 Hz, 1H),
4.15 (m, 1H), 3.92 (t, J¼6.5 Hz, 2H), 3.84 (ddd, J¼6.5,
5.3, 5.3 Hz, 1H), 3.58 (dd, J¼10.0, 3.8 Hz, 1H), 3.45 (dd,
J¼10.0, 4.7 Hz, 1H), 3.38 (m, 1H), 2.67 (br s, 1H), 2.53 (t,
J¼7.6 Hz, 2H), 1.94–1.76 (m, 6H), 1.56–1.43 (m, 8H),
1.34 (tq, J¼7.5, 7.3 Hz, 2H), 0.91 (t, J¼7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 157.11, 138.00, 134.82, 129.20
(3C), 128.43 (2C), 127.74 (2C), 114.26 (2C), 82.80, 78.46,
74.29, 74.38, 72.43, 67.88, 34.73, 34.25, 33.92, 29.34,
28.13, 28.05, 26.15, 25.59, 22.31, 13.97; ESI-HRMS (m/z)
calcd for C28H40O4Na [M+Na]+ 463.2814, observed
463.2813.
3.4.4. (2S,20S,40R,5R,50S)-5-[(1R)-1-Acetyloxy-6-(4-butyl-
phenyloxy)hexyl]-50-[(1R)-1-(tert-butyldimethylsilyl-
oxy)-6-(4-butylphenyloxy)hexyl]-40-dimethylphenylsilyl-
octahydro-2,20-bifuran (26). A solution of aldehyde 25
˚
(57 mg, 0.15 mmol) and oven-dried powdered 4 A molecu-
lar sieves (130 ꢁC, 12 h, 4 mg) in anhydrous CH2Cl2
(0.8 mL) was cooled to ꢀ78 ꢁC. SnCl4 (0.15 mL of 1.0 M
solution in CH2Cl2, 0.15 mmol) was added dropwise to the
cold solution and the reaction mixture was stirred at
ꢀ78 ꢁC for 20 min. A solution of allylsilane 16a (79 mg,
0.15 mmol) in 0.4 mL of CH2Cl2 was added slowly drop-
wise to the reaction mixture and stirring at ꢀ78 ꢁC pro-
ceeded for 6 h. The reaction mixture was quenched at
ꢀ78 ꢁC by the dropwise addition of Et3N (0.1 mL) and the
resulting mixture was warmed to room temperature. EtOAc
(5 mL) and saturated aqueous NaHCO3 (5 mL) were added
to form a cloudy white suspension, which was stirred at
room temperature overnight. The organic layer was removed
and the aqueous layer was extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over an-
hydrous MgSO4, and concentrated. The crude product was
purified by YMC silica gel chromatography (10% EtOAc/
hexane) to give a mixture of 26 and its epimer (91 mg,
98 mmol, 67%). The product was a 6.5:1 mixture of dia-
3.4.2. (2R,5S)-2-[(1R)-1-Acetyloxy-6-(4-butylphenyloxy)-
hexyl]-5-benzyloxymethyltetrahydrofuran (24). A solu-
tion of 23 (100 mg, 0.22 mmol) and DMAP (107 mg,
0.88 mmol) in anhydrous CH2Cl2 (3.0 mL) was cooled to
0 ꢁC. AcCl (39 mL, 0.55 mmol) was added slowly dropwise
to the solution and the resulting mixture was warmed to
35 ꢁC. After stirring for 1 h, the mixture was recooled to
0 ꢁC and quenched with H2O. The resulting mixture was ex-
tracted with EtOAc, washed with brine, dried over anhy-
drous MgSO4, and concentrated. The crude product was
purified by silica gel chromatography (20% EtOAc/hexane)
to give 24 (98 mg, 0.20 mmol, 92%) as a colorless oil: [a]D20
+1.8 (c 0.11, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.34–
7.33 (m, 4H), 7.28–7.27 (m, 1H), 7.07 (d, J¼8.6 Hz, 2H),
6.80 (d, J¼8.6 Hz, 2H), 4.90 (ddd, J¼6.9, 5.6, 5.6 Hz,
1H), 4.59 (d, J¼12.2 Hz, 1H), 4.55 (d, J¼12.2 Hz, 1H),
4.12 (dddd, J¼6.6, 6.0, 5.7, 5.1 Hz, 1H), 3.98 (ddd, J¼6.9,
6.9, 5.3 Hz, 1H), 3.90 (t, J¼6.5 Hz, 2H), 3.51 (dd, J¼9.9,
5.7 Hz, 1H), 3.44 (dd, J¼9.9, 5.1 Hz, 1H), 2.53 (t,
J¼7.6 Hz, 2H), 2.03 (s, 3H), 1.99–1.91 (m, 2H), 1.76–1.53
(m, 8H), 1.46–1.34 (m, 4H), 1.34 (tq, J¼7.5, 7.3 Hz, 2H),
0.91 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 170.88, 157.07, 138.48, 134.87, 129.21 (2C), 128.34
(2C), 127.66 (2C), 127.52, 114.25 (2C), 80.13, 78.54,
1
stereomers (favoring 26) as determined through H NMR
analysis. Chromatography was repeated under the same con-
ditions to give pure 26 as a colorless oil: [a]2D1 +4.4 (c 0.09,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.50–7.48 (m, 2H),
7.35–7.33 (m, 3H), 7.07 (d, J¼8.6 Hz, 2H), 7.06 (d,
J¼8.6 Hz, 2H), 6.81 (d, J¼8.6 Hz, 2H), 6.80 (d, J¼8.6 Hz,
2H), 4.88 (ddd, J¼8.0, 4.8, 4.8 Hz, 1H), 3.95 (m, 1H),
3.92 (m, 1H), 3.90 (t, J¼6.5 Hz, 4H), 3.80 (ddd, J¼8.7,
6.7, 6.7 Hz, 1H), 3.67 (ddd, J¼7.1, 7.1, 7.1 Hz, 1H), 3.48
(m, 1H), 2.53 (t, J¼7.6 Hz, 4H), 2.01 (s, 3H), 1.88–1.68
(m, 8H), 1.62–1.53 (m, 9H), 1.36–1.30 (m, 10H), 1.34 (tq,
J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz, 6H), 0.87 (s, 9H),
0.34 (s, 3H), 0.33 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 170.84, 157.13, 157.09,
138.04, 134.84, 133.90 (2C), 133.04, 129.66, 129.20 (2C),
129.13 (2C), 127.92 (2C), 127.85 (2C), 114.25 (2C),

1136
N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
83.80, 82.15, 81.19, 79.51, 75.21, 74.14, 67.90, 67.80, 34.73
(2C), 33.92 (2C), 33.57, 31.22, 30.56, 29.38, 29.25, 27.58,
27.46, 26.34, 26.13 (3C), 26.04, 25.91, 25.32, 25.15, 22.31
(2C), 21.17, 18.27, 13.97 (2C), ꢀ3.34, ꢀ3.92, ꢀ4.30,
ꢀ4.41; ESI-HRMS (m/z) calcd for C56H88Si2O7Na
[M+Na]+ 951.5943, observed 951.5955.
12 mmol), and 4-butylphenol (1.3 g, 8.8 mmol) in THF
(9.0 mL) was added DIAD (2.3 mL, 12 mmol) dropwise
from a syringe over 5 min. The mixture was stirred at
room temperature for 1 h and concentrated. The crude prod-
uct was purified by silica gel chromatography (5% EtOAc/
hexane) twice to give 27 (1.2 g, 5.6 mmol, 95%) as a color-
1
less oil: H NMR (400 MHz, CDCl3) d 7.08 (d, J¼8.5 Hz,
3.4.5. (2S,20S,5R,50R)-5,50-Bis-[(1R)-6-(4-butylphenyl-
oxy)-1-hydroxyhexyl]octahydro-2,20-bifuran (4). To a so-
lution of 26 (90 mg, 97 mmol) in MeOH (1 mL) and THF
(2 mL) was added K2CO3 (40 mg, 0.29 mmol) and the
resulting mixture was stirred at 35 ꢁC for 3 h. The mixture
was quenched with saturated aqueous NH4Cl, extracted
with EtOAc, washed with brine, dried over anhydrous
MgSO4, and concentrated. The crude product was purified
by silica gel chromatography (10% EtOAc/hexane) to give
67 mg of colorless oil, which was dissolved in DMF
(1 mL). To this solution was added TBAF (0.29 mL of
a 1.0 M solution in THF, 0.29 mmol) and the resulting mix-
ture was stirred at 90 ꢁC for 3.5 h. The mixture was cooled to
room temperature and diluted with EtOAc. The resulting
solution was washed with 1 N HCl, saturated aqueous
NaHCO3, and brine, dried over anhydrous MgSO4, and con-
centrated. The crude product was purified by YMC silica gel
chromatography (50–70% EtOAc/hexane) to give 4 (33 mg,
52 mmol, 54%, two steps) as a colorless oil: [a]2D5 +26 (c
0.14, EtOH); 1H NMR (400 MHz, CDCl3) d 7.06 (d,
J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 3.91 (t, J¼6.5 Hz,
4H), 3.89 (m, 2H), 3.83 (m, 2H), 3.41 (m, 2H), 2.89 (br s,
2H), 2.53 (t, J¼7.6 Hz, 4H), 1.99–1.96 (m, 4H), 1.79–1.75
(m, 8H), 1.57–1.46 (m, 16H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H),
0.91 (t, J¼7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 157.10 (2C), 134.79 (2C), 129.19 (4C), 114.24 (4C),
82.71 (2C), 81.07 (2C), 73.89 (2C), 67.86 (2C), 34.73
(2C), 34.25 (2C), 33.92 (2C), 29.33 (2C), 28.34 (2C),
27.96 (2C), 26.14 (2C), 25.60 (2C), 22.31 (2C), 13.97
(2C); ESI-HRMS (m/z) calcd for C40H62O6Na [M+Na]+
661.4428, observed 661.4417.
2H), 6.82 (d, J¼8.5 Hz, 2H), 4.04 (t, J¼6.1 Hz, 2H), 2.54
(t, J¼7.6 Hz, 2H), 2.40 (dt, J¼7.0, 2.6 Hz, 2H), 2.00 (tt, J¼
7.0, 6.1 Hz, 2H), 1.96 (t, J¼2.6 Hz, 1H), 1.55 (tt, J¼7.6,
7.5 Hz, 2H), 1.34 (tq, J¼7.5, 7.3 Hz, 2H), 0.91 (t, J¼
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 156.89,
135.11, 129.25 (2C), 114.30 (2C), 83.61, 68.76, 66.14,
34.73, 33.91, 28.28, 22.30, 15.21, 13.96; ESI-HRMS (m/z)
calcd for C15H20ONa [M+Na]+ 239.1407, observed
239.1472.
3.6.2. (2S,3R,5S)-2-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-5-[(1S)-6-(4-butylphenyl-
oxy)-1-hydroxy-2-hexynyl]-3-dimethylphenylsilyltetra-
hydrofuran (28a) and (2S,3R,5S)-2-[(1R)-1-(tert-
butyldimethylsilyloxy)-6-(4-butylphenyloxy)hexyl]-5-
[(1R)-6-(4-butylphenyloxy)-1-hydroxy-2-hexynyl]-3-di-
methylphenylsilyltetrahydrofuran (28b). To a stirred so-
lution of alkyne 27 (30 mg, 173 mmol) in THF (1.4 mL)
was added dropwise n-BuLi (1.57 M in hexane, 0.10 mL,
163 mmol) at ꢀ78 ꢁC and stirred for 1 h. To the resulting
solution was added anhydrous cerium chloride (40 mg,
163 mmol) and stirring was continued for 1 h at ꢀ78 ꢁC.
A solution of aldehyde 18 (61 mg, 102 mmol) in THF
(0.6 mL) was added dropwise at ꢀ78 ꢁC and the mixture
was stirred at ꢀ78 ꢁC for 2 h and warmed to ꢀ23 ꢁC over
3 h with stirring. After being quenched with saturated aque-
ous NH4Cl, the resulting suspension was warmed to room
temperature and extracted with Et2O, washed with 1 M
HCl, saturated aqueous NaHCO3, and brine, dried over
anhydrous MgSO4, and concentrated. The crude product
was purified by YMC silica gel chromatography (5–30%
EtOAc/hexane) to give 28a (14 mg, 18 mmol, 18%) and
28b (31 mg, 41 mmol, 40%) as a colorless oil. 28a: [a]D22
ꢀ17 (c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.45–7.44 (m, 2H), 7.36–7.33 (m, 3H), 7.08 (d,
J¼8.6 Hz, 2H), 7.06 (d, J¼8.6 Hz, 2H), 6.80 (d,
J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 4.03 (m, 2H),
4.00 (t, J¼6.1 Hz, 2H), 3.98 (m, 1H), 3.93 (m, 1H), 3.91
(t, J¼6.5 Hz, 2H), 3.36 (br s, 1H), 3.20 (dd, J¼9.4,
3.6 Hz, 1H), 2.54 (t, J¼7.6 Hz, 2H), 2.53 (t, J¼7.6 Hz,
2H), 2.40 (dt, J¼7.0, 1.7 Hz, 2H), 2.01–1.89 (m, 4H),
1.80–1.67 (m, 4H), 1.56–1.53 (m, 4H), 1.38–1.31 (m,
4H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz, 6H),
0.87 (s, 9H), 0.33 (s, 3H), 0.32 (s, 3H), ꢀ0.02 (s, 3H),
ꢀ0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) d 157.07,
156.92, 136.97, 134.97, 134.88, 133.89 (2C), 129.47,
129.21 (4C), 128.02 (2C), 114.29 (2C), 114.24 (2C),
84.56, 82.94, 81.53, 79.62, 73.06, 67.77, 66.35, 65.19,
35.58, 34.73 (2C), 33.91 (2C), 31.95, 29.38, 28.39, 26.30,
26.02 (3C), 25.31, 25.28, 22.30 (2C), 18.19, 15.61, 13.96
(2C), ꢀ3.93, ꢀ4.11, ꢀ4.66, ꢀ4.72; ESI-HRMS (m/z)
calcd for C50H76Si2O5Na [M+Na]+ 835.5109, observed
835.5129. 28b: [a]2D2 ꢀ36 (c 1.48, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.47–7.45 (m, 2H), 7.35–7.33 (m,
3H), 7.08 (d, J¼8.6 Hz, 2H), 7.07 (d, J¼8.6 Hz, 2H),
6.81 (d, J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 4.54 (m,
3.5. Synthesis of compound 5
3.5.1. (2S,20S,5S,50S)-5,50-Bis-[(1S)-6-(4-butylphenyl-
oxy)-1-hydroxyhexyl]octahydro-2,20-bifuran (5). Com-
pound 5 was synthesized following the procedure used
for the synthesis of 1, but using (ꢀ)-DET and AD-mix-
a in place of (+)-DET and AD-mix-b, respectively:8 [a]D16
1
ꢀ19 (c 0.21, EtOH); H NMR (400 MHz, CDCl3) d 7.07
(d, J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 3.92 (t,
J¼6.5 Hz, 4H), 3.87–3.81 (m, 4H), 3.39 (m, 2H), 2.53 (t,
J¼7.6 Hz, 4H), 2.48 (br s, 2H), 1.99–1.96 (m, 4H), 1.80–
1.75 (m, 4H), 1.69–1.43 (m, 20H), 1.33 (tq, J¼7.5, 7.3 Hz,
4H), 0.91 (t, J¼7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 157.09 (2C), 134.82 (2C), 129.20 (4C), 114.24 (4C),
83.14 (2C), 81.80 (2C), 73.94 (2C), 67.84 (2C), 34.72
(2C), 33.92 (2C), 33.36 (2C), 29.31 (2C), 28.98 (2C),
28.35 (2C), 26.15 (2C), 25.44 (2C), 22.30 (2C), 13.97
(2C); ESI-HRMS (m/z) calcd for C40H62O6Na [M+Na]+
661.4428, observed 661.4411.
3.6. Synthesis of compound 6
3.6.1. 5-(4-Butylphenyloxy)-1-pentyne (27). To a 0 ꢁC
solution of 4-pentyne-1-ol (0.5 g, 5.9 mmol), PPh3 (3.1 g,

N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
1137
2H), 4.00 (m, 1H), 3.99 (t, J¼6.4 Hz, 2H), 3.97 (m, 1H),
3.91 (t, J¼6.4 Hz, 2H), 3.86 (br s, 1H), 3.27 (dd, J¼9.9,
3.7 Hz, 1H), 2.54 (t, J¼7.6 Hz, 2H), 2.53 (t, J¼7.6 Hz,
2H), 2.41 (m, 1H), 2.40 (dt, J¼7.0, 1.7 Hz, 2H), 1.95
(quint, J¼6.6 Hz, 2H), 1.94–1.74 (m, 5H), 1.56 (tt,
J¼7.6, 7.5 Hz, 4H), 1.40–1.32 (m, 4H), 1.34 (tq, J¼7.5,
7.3 Hz, 4H), 1.18 (m, 1H), 0.91 (t, J¼7.3 Hz, 6H), 0.87
(s, 9H), 0.33 (s, 3H), 0.32 (s, 3H), 0.00 (s, 3H), ꢀ0.12 (s,
3H); 13C NMR (100 MHz, CDCl3) d 157.06, 156.91,
137.12, 135.00, 134.89, 133.97 (2C), 129.40, 129.23
(4C), 127.99 (2C), 114.26 (2C), 114.23 (2C), 85.32,
82.77, 81.26, 78.78, 73.02, 67.76, 66.36, 66.00, 35.46,
34.73 (2C), 33.91, 33.90, 29.75, 29.37, 28.30, 26.64,
26.30, 26.10 (3C), 25.33, 22.30 (2C), 18.21, 15.68, 13.96
(2C), ꢀ3.78, ꢀ3.87, ꢀ4.86, ꢀ5.10; ESI-HRMS (m/z)
calcd for C50H76Si2O5Na [M+Na]+ 835.5109, observed
835.5127.
(m/z) calcd for C36H56O5Na [M+Na]+ 591.4011, observed
591.3992.
3.7. Synthesis of compound 7
3.7.1. (2S,3R,5S)-2-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-5-[(1R)-6-(4-butylphenyl-
oxy)-1-hydroxyhexyl]-3-dimethylphenylsilyltetrahydro-
furan (29b). Compound 29b was synthesized from 28b by
the same procedure used for the synthesis of 29a in a 91%
yield as a colorless oil: [a]2D2 ꢀ14 (c 1.32, CHCl3); H
1
NMR (400 MHz, CDCl3) d 7.48–7.46 (m, 2H), 7.35–7.33
(m, 3H), 7.08 (d, J¼8.6 Hz, 2H), 7.06 (d, J¼8.6 Hz, 2H),
6.81 (d, J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 3.92 (m,
1H), 3.91 (t, J¼6.5 Hz, 2H), 3.90 (t, J¼6.4 Hz, 2H), 3.79
(m, 2H), 3.29 (dd, J¼9.1, 4.0 Hz, 1H), 3.25 (br s, 1H),
2.54 (t, J¼7.6 Hz, 2H), 2.53 (t, J¼7.6 Hz, 2H), 2.13 (m,
1H), 1.81–1.68 (m, 7H), 1.56–1.53 (m, 6H), 1.38–1.16 (m,
11H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz, 6H),
0.87 (s, 9H), 0.33 (s, 3H), 0.32 (s, 3H), 0.00 (s, 3H),
ꢀ0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d 157.10,
157.08, 137.35, 134.87, 134.78, 133.92 (2C), 129.33,
129.22 (2C), 129.18 (2C), 127.96 (2C), 114.25 (2C),
114.24 (2C), 81.74, 81.65, 73.94, 73.23, 67.88, 67.78,
35.32, 34.73 (2C), 33.92 (2C), 32.74, 29.38, 29.26, 27.60,
26.62, 26.30, 26.21, 26.05 (3C), 25.79, 25.42, 22.30 (2C),
18.26, 13.97 (2C), ꢀ4.00, ꢀ4.05, ꢀ4.55, ꢀ4.65; ESI-
HRMS (m/z) calcd for C50H80Si2O5Na [M+Na]+ 839.5421,
observed 839.5434.
3.6.3. (2S,3R,5S)-2-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-5-[(1S)-6-(4-butylphenyl-
oxy)-1-hydroxyhexyl]-3-dimethylphenylsilyltetrahydro-
furan (29a). A mixture of 28a (14 mg, 18 mmol), EtOH
(2 mL), and catalytic 10% Pd on carbon was stirred at
room temperature under a hydrogen gas atmosphere for
3 h. The reaction mixture was then filtered through a Celite
layer. The Celite layer was washed with 5 mL of EtOAc. The
combined filtrates were concentrated and purified by YMC
silica gel chromatography (5% EtOAc/hexane) to give 29a
(12 mg, 16 mmol, 87%) as a colorless oil: [a]2D2 ꢀ11 (c
1
0.24, CHCl3); H NMR (400 MHz, CDCl3) d 7.47–7.45
(m, 2H), 7.35–7.33 (m, 3H), 7.08 (d, J¼8.6 Hz, 2H), 7.06
(d, J¼8.6 Hz, 2H), 6.81 (d, J¼8.6 Hz, 2H), 6.79 (d,
J¼8.6 Hz, 2H), 3.93 (m, 1H), 3.90 (t, J¼6.6 Hz, 4H), 3.74
(m, 1H), 3.27 (br s, 1H), 3.25 (m, 1H), 3.24 (m, 1H), 2.54
(t, J¼7.6 Hz, 2H), 2.53 (t, J¼7.6 Hz, 2H), 1.93 (m, 2H),
1.83–1.75 (m, 6H), 1.58–1.53 (m, 6H), 1.43–1.32 (m,
10H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H), 1.20 (m, 1H), 0.91 (t,
J¼7.3 Hz, 6H), 0.87 (s, 9H), 0.34 (s, 3H), 0.32 (s, 3H),
0.00 (s, 3H), ꢀ0.08 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 157.13, 157.08, 137.28, 134.88, 134.76, 133.90 (2C),
129.38, 129.22 (2C), 129.17 (2C), 127.98 (2C), 114.24
(4C), 82.25, 81.09, 74.16, 73.64, 67.93, 67.80, 35.62,
34.73 (2C), 34.59, 33.92 (2C), 32.45, 29.39, 29.36, 26.33,
26.20, 26.00 (3C), 25.74, 25.67, 25.35, 22.30 (2C), 18.18,
13.96 (2C), ꢀ3.98, ꢀ4.08, ꢀ4.58, ꢀ4.76; ESI-HRMS
(m/z) calcd for C50H80Si2O5Na [M+Na]+ 839.5421, ob-
served 839.5420.
3.7.2. (2R,5S)-2,5-Bis-[(1R)-6-(4-butylphenyloxy)-1-hy-
droxyhexyl]tetrahydrofuran (7). Compound 7 was synthe-
sized by protiodesilylation of 29b according to the procedure
used for the synthesis of 2 in a 28% yield as a waxy oil: [a]D25
+2.5 (c 0.24, EtOH); 1H NMR (400 MHz, CDCl3) d 7.07 (d,
J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 3.92 (t, J¼6.5 Hz,
4H), 3.90 (m, 1H), 3.85 (m, 1H), 3.82 (m, 1H), 3.44 (m,
1H), 2.53 (t, J¼7.6 Hz, 4H), 2.39 (br s, 2H), 1.99–1.91 (m,
2H), 1.79–1.72 (m, 6H), 1.59–1.49 (m, 16H), 1.34 (tq,
J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz, 6H); 13C NMR
(100 MHz, CDCl3) d 157.07 (2C), 134.87 (2C), 129.21
(4C), 114.24 (4C), 82.67, 82.22, 74.34, 72.27, 67.80 (2C),
34.72 (2C), 34.11, 33.91 (2C), 32.99, 29.26 (2C), 28.39,
26.13 (2C), 25.74, 25.50, 24.39, 22.30, 13.97 (2C); ESI-
HRMS (m/z) calcd for C36H56O5Na [M+Na]+ 591.4011, ob-
served 591.3985.
3.8. Synthesis of compounds 8 and 9
3.6.4. (2R,5S)-2-[(1R)-6-(4-Butylphenyloxy)-1-hydroxy-
hexyl]-5-[(1S)-6-(4-butylphenyloxy)-1-hydroxyhexyl]-
tetrahydrofuran (6). Compound 6 was synthesized by
protiodesilylation of 29a according to the procedure used
for the synthesis of 2 in a 44% yield as a waxy oil: [a]D25
3.8.1. (2S,3R,5R)-5-Benzyloxymethyl-2-[(1R)-1-(tert-
butyldimethylsilyloxy)-6-(4-butylphenyloxy)hexyl]-3-di-
methylphenylsilyltetrahydrofuran (30). To a ꢀ45 ꢁC
solution of allylsilane 16a (0.3 g, 0.56 mmol), a-(benzyl-
oxy)acetaldehyde (126 mg, 0.84 mmol), and oven-dried
powdered 4 A molecular sieves (130 C, 12 h, 150 mg) in
CH2Cl2 (1.3 mL) was added SnCl4 (0.28 mL of a 1.0 M
solution of CH2Cl2, 0.28 mmol) dropwise from a syringe
over 2 min. The reaction mixture was stirred at ꢀ45 ꢁC for
20 h and then quenched with Et3N (0.3 mL) and warmed
to room temperature. The mixture was diluted with Et2O
(3 mL) and saturated aqueous NaHCO3 (3 mL), and then
stirred for 24 h. The layers were separated and the aqueous
layer was extracted with Et2O. The combined organic layers
1
ꢀ1.4 (c 0.14, EtOH); H NMR (400 MHz, CDCl3) d 7.07
ꢁ
˚
(d, J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 3.93 (t,
J¼6.5 Hz, 4H), 3.82 (m, 2H), 3.44 (m, 2H), 2.53 (t,
J¼7.6 Hz, 4H), 2.33 (br s, 2H), 1.99–1.93 (m, 2H), 1.80–
1.70 (m, 6H), 1.57–1.45 (m, 16H), 1.34 (tq, J¼7.5, 7.3 Hz,
4H), 0.91 (t, J¼7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 157.08 (2C), 134.86 (2C), 129.21 (4C), 114.24 (4C),
82.66 (2C), 74.27 (2C), 67.83 (2C), 34.73 (2C), 34.03
(2C), 33.92 (2C), 29.31 (2C), 28.12 (2C), 26.14
(2C), 25.49 (2C), 22.31 (2C), 13.97 (2C); ESI-HRMS

1138
N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
were washed with brine, dried over anhydrous MgSO4, and
concentrated. The crude product was purified by YMC silica
gel chromatography (5% EtOAc/hexane) to give tetrahydro-
furan 30 (0.31 g, 0.45 mmol, 81%) as a colorless oil: [a]D21
+2.6 (c 1.23, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.48–
7.46 (m, 2H), 7.35–7.31 (m, 7H), 7.25 (m, 1H), 7.07 (d, J¼
8.6 Hz, 2H), 6.80 (d, J¼8.6 Hz, 2H), 4.56 (d, J¼12.2 Hz,
1H), 4.52 (d, J¼12.2 Hz, 1H), 4.05 (dddd, J¼10.0, 5.0,
5.0, 5.0 Hz, 1H), 3.93 (dd, J¼8.7, 1.7 Hz, 1H), 3.89 (t,
J¼6.5 Hz, 2H), 3.51 (dd, J¼10.1, 5.4 Hz, 1H), 3.43 (dd,
J¼10.1, 4.7 Hz, 1H), 3.25 (m, 1H), 2.54 (t, J¼7.6 Hz, 2H),
2.02 (m, 1H), 1.73–1.69 (m, 4H), 1.57–1.47 (m, 3H),
1.37–1.30 (m, 5H), 1.34 (tq, J¼7.5, 7.3 Hz, 2H), 0.91 (t,
J¼7.3 Hz, 3H), 0.87 (s, 9H), 0.32 (s, 3H), 0.31 (s, 3H),
0.00 (s, 6H); 13C NMR (100 MHz, CDCl3) d 157.22,
138.68, 137.87, 134.80, 133.89 (2C), 129.27, 129.23 (2C),
128.32 (2C), 127.92 (2C), 127.69 (2C), 127.48, 114.31
(2C), 82.84, 78.58, 74.74, 73.22, 72.67, 67.87, 34.78,
34.67, 34.01, 33.20, 29.40, 26.55, 26.33, 26.10 (3C),
25.69, 22.34, 18.25, 13.99, ꢀ3.93, ꢀ4.20, ꢀ4.28, ꢀ4.32;
ESI-HRMS (m/z) calcd for C42H64Si2O4Na [M+Na]+
711.4224, observed 711.4242.
(0.44C), 81.59, 78.37 (0.56C), 74.44 (0.56C), 74.32
(0.44C), 67.83 (1.44C), 66.28 (0.56C), 65.93 (0.44C),
63.28 (0.56C), 34.74 (2C), 34.60 (0.56C), 34.53 (0.44C),
33.92 (2C), 29.67 (0.44C), 29.34 (1.56C), 28.41, 26.66
(0.44C), 26.49 (0.56C), 26.26, 26.03 (3C), 25.60, 22.31
(2C), 18.19, 15.59, 13.97 (2C), ꢀ3.90, ꢀ4.30, ꢀ4.33,
ꢀ4.43; ESI-HRMS (m/z) calcd for C50H76Si2O5Na
[M+Na]+ 835.5109, observed 835.5120.
3.8.4. (2S,3R,5R)-2-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-5-[6-(4-butylphenyloxy)-1-
hydroxyhexyl]-3-dimethylphenylsilyltetrahydrofuran
(34). Compound 34 was synthesized by the same procedure
used for the synthesis of 29a in a 91% yield as a colorless oil:
1H NMR (400 MHz, CDCl3) d 7.48–7.46 (m, 2H), 7.35–7.33
(m, 3H), 7.08 (d, J¼8.6 Hz, 2H), 7.06 (d, J¼8.6 Hz, 2H),
6.81 (d, J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 3.91 (t,
J¼6.5 Hz, 4H), 3.90 (m, 1H), 3.87 (m, 0.56H), 3.86 (m,
0.44H), 3.73 (m, 0.56H), 3.33 (m, 1H), 3.21 (m, 0.44H),
3.18 (br s, 0.44H), 2.54 (t, J¼7.6 Hz, 2H), 2.53 (t,
J¼7.6 Hz, 2H), 2.24 (br s, 0.56H), 1.93 (m, 0.56H), 1.79–
1.61 (m, 5.44H), 1.57–1.51 (m, 8H), 1.47–1.23 (m, 15H),
0.91 (t, J¼7.3 Hz, 6H), 0.87 (s, 9H), 0.32 (s, 6H), 0.00
(s, 6H).
3.8.2. (2R,4R,5S)-5-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-4-dimethylphenylsilyl-2-
carbaldehyde (32). Compound 32 was synthesized via
alcohol 31 by the same procedure used for the synthesis of
18 in a 81% yield as a pale yellow oil: [a]2D1 +13 (c 0.27,
3.8.5. (2R,5R)-2,5-Bis-[(1R)-6-(4-butylphenyloxy)-1-hy-
droxyhexyl]tetrahydrofuran (8) and (2R,5R)-2-[(1R)-6-
(4-butylphenyloxy)-1-hydroxyhexyl]-5-[(1S)-6-(4-butyl-
phenyloxy)-1-hydroxyhexyl]tetrahydrofuran (9). A mix-
ture of 8 and 9 was synthesized by protiodesilylation of 34
according to the procedure used for the synthesis of 2 in
a 57% yield (a 5:4 mixture of 8 and 9) as a colorless oil,
26 mg (41 mmol) of which was dissolved in anhydrous
CH2Cl2 (0.5 mL). DMAP (75 mg, 0.61 mmol) was added
and the mixture was cooled to 0 ꢁC. To this solution was
added AcCl (30 mL, 0.41 mmol) and the resulting mixture
was stirred at room temperature for 2 h. The mixture was
then quenched with H2O and extracted with Et2O, washed
with brine, dried over anhydrous MgSO4, and concentrated.
The crude product was purified by YMC silica gel chroma-
tography twice (20% EtOAc/hexane and then 10% EtOAc/
hexane) to give a diacetate derivative of 8 (10 mg,
15 mmol, 37%) and 9 (15 mg, 23 mmol, 56%) as a colorless
oil. Then, to a solution of the diacetate derivative of 8 (7 mg,
11 mmol) in MeOH (1 mL) was added K2CO3 (4 mg,
30 mmol) and the resulting mixture was stirred at 35 ꢁC for
1 h. The mixture was quenched with saturated aqueous
NH4Cl, extracted with EtOAc, washed with brine, dried
over anhydrous MgSO4, and concentrated. The crude prod-
uct was purified by YMC silica gel chromatography (50%
EtOAc/hexane) to give 8 (4 mg, 7 mmol, 64%) as a waxy
oil: [a]2D5 +14 (c 0.18, EtOH); 1H NMR (400 MHz, CDCl3)
d 7.07 (d, J¼8.6 Hz, 4H), 6.80 (d, J¼8.6 Hz, 4H), 3.93 (t,
J¼6.5 Hz, 4H), 3.79 (m, 2H), 3.42 (m, 2H), 2.53 (t,
J¼7.6 Hz, 4H), 2.34 (br s, 2H), 1.99–1.93 (m, 2H), 1.80–
1.72 (m, 4H), 1.70–1.63 (m, 2H), 1.57–1.44 (m, 16H),
1.34 (tq, J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d 157.06 (2C), 134.85 (2C),
129.20 (4C), 114.22 (4C), 82.62 (2C), 73.92 (2C), 67.80
(2C), 34.72 (2C), 33.91 (2C), 33.38 (2C), 29.29 (2C),
28.73 (2C), 26.14 (2C), 25.38 (2C), 22.30 (2C), 13.97
(2C); ESI-HRMS (m/z) calcd for C36H56O5Na [M+Na]+
591.4011, observed 591.4006.
1
CHCl3); H NMR (400 MHz, CDCl3) d 9.53 (d, J¼2.6 Hz,
1H), 7.48–7.45 (m, 2H), 7.36–7.33 (m, 3H), 7.08 (d,
J¼8.6 Hz, 2H), 6.81 (d, J¼8.6 Hz, 2H), 4.20 (m, 1H), 4.06
(dd, J¼8.9, 1.4 Hz, 1H), 3.91 (t, J¼6.5 Hz, 2H), 3.25 (m,
1H), 2.54 (t, J¼7.6 Hz, 2H), 2.20 (m, 1H), 1.82–1.51 (m,
6H), 1.44–1.21 (m, 6H), 1.34 (tq, J¼7.5, 7.3 Hz, 2H), 0.91
(t, J¼7.3 Hz, 3H), 0.87 (s, 9H), 0.34 (s, 6H), ꢀ0.01 (s,
6H); 13C NMR (100 MHz, CDCl3) d 202.56, 157.09,
136.86, 134.90, 133.77 (2C), 129.51, 129.23 (2C), 128.03
(2C), 114.24 (2C), 84.11, 83.63, 74.20, 67.80, 34.74 (2C),
33.93, 31.86, 29.33, 26.54, 26.28, 25.98 (3C), 25.52,
22.31, 18.14, 13.97, ꢀ3.85, ꢀ4.34, ꢀ4.44 (2C); ESI-
HRMS (m/z) calcd for C35H56Si2O4Na [M+Na]+ 619.3600,
observed 619.3619.
3.8.3. (2S,3R,5R)-2-[(1R)-1-(tert-Butyldimethylsilyloxy)-
6-(4-butylphenyloxy)hexyl]-5-[6-(4-butylphenyloxy)-1-
hydroxy-2-hexynyl]-3-dimethylphenylsilyltetrahydro-
furan (33). Compound 33 was synthesized by the same pro-
cedure used for the synthesis of 28a and 28b, except that 32
was used in place of 18, in a 74% yield as a colorless oil,
which was an unseparable 4:5 mixture of alcohols: 1H
NMR (500 MHz, CDCl3) d 7.48–7.46 (m, 2H), 7.34–7.33
(m, 3H), 7.08 (d, J¼8.6 Hz, 2H), 7.07 (d, J¼8.6 Hz, 2H),
6.80 (d, J¼8.6 Hz, 2H), 6.79 (d, J¼8.6 Hz, 2H), 4.50 (m,
0.56H), 4.11 (m, 0.44H), 3.99 (t, J¼6.1 Hz, 2H), 3.96
(m, 2H), 3.89 (t, J¼6.5 Hz, 2H), 3.24 (m, 0.44H), 3.20 (m,
0.56H), 2.54 (t, J¼7.6 Hz, 4H), 2.39 (t, J¼7.1 Hz, 2H),
2.32 (br s, 0.44H), 2.22 (br s, 0.56H), 1.95–1.82 (m, 3H),
1.73–1.70 (m, 3H), 1.57–1.47 (m, 7H), 1.36–1.24 (m, 4H),
1.34 (tq, J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz, 6H), 0.87
(s, 9H), 0.32 (s, 6H), 0.00 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 157.10, 156.89, 137.70, 135.05, 134.87, 133.82
(2C), 129.24 (4C), 129.22 (2C), 127.88, 114.27 (2C),
114.24 (2C), 85.44 (0.44C), 83.66, 83.37 (0.56C), 82.46

N. Ichimaru et al. / Tetrahedron 63 (2007) 1127–1139
1139
Compound 9 was prepared from the diacetate derivative of 9
by the same procedure used for the synthesis of 8 in a 90%
References and notes
1
yield as a waxy oil: [a]2D5 +4.7 (c 0.30, EtOH); H NMR
1. Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999,
62, 504–540.
(400 MHz, CDCl3) d 7.07 (d, J¼8.6 Hz, 4H), 6.80 (d,
J¼8.6 Hz, 4H), 3.92 (t, J¼6.5 Hz, 4H), 3.87 (ddd, J¼9.4,
6.0, 3.4 Hz, 1H), 3.82 (m, 2H), 3.40 (m, 1H), 2.53 (t,
J¼7.6 Hz, 4H), 2.37 (br s, 1H), 2.06 (br s, 1H), 1.99–1.93
(m, 1H), 1.90–1.85 (m, 1H), 1.83–1.72 (m, 4H), 1.58–1.46
(m, 18H), 1.34 (tq, J¼7.5, 7.3 Hz, 4H), 0.91 (t, J¼7.3 Hz,
6H); 13C NMR (100 MHz, CDCl3) d 157.06 (2C), 134.85
(2C), 129.20 (4C), 114.22 (4C), 83.22, 82.13, 74.23,
71.45, 67.80 (2C), 34.72 (2C), 33.91 (2C), 33.13, 32.46,
29.29, 29.26, 28.57, 26.15 (2C), 25.79, 25.36, 25.28, 22.30
(2C), 13.97 (2C); ESI-HRMS (m/z) calcd for C36H56O5Na
[M+Na]+ 591.4011, observed 591.3990.
2. Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303.
3. Nattrass, G. L.; Diez, E.; McLachlan, M. M.; Dixon, D. J.; Ley,
S. V. Angew. Chem., Int. Ed. 2005, 44, 580–584. In this article,
a number of papers concerning the total synthesis of natural
acetogenins are listed in chronological order.
4. Huang, G.-R.; Jiang, S.; Wu, Y.-L.; Jin, Y.; Yao, Z.-J.; Wu, J.-R.
ChemBioChem 2003, 4, 1216–1221.
5. Liu, H.-X.; Yao, Z.-J. Tetrahedron Lett. 2005, 46, 3525–3528.
6. Fujita, D.; Ichimaru, N.; Abe, M.; Murai, M.; Hamada, T.;
Nishioka, T.; Miyoshi, H. Tetrahedron Lett. 2005, 46, 5775–
5779.
3.9. Synthesis of compound 12
7. Hamada, T.; Ichimaru, N.; Abe, M.; Fujita, D.; Kenmochi, A.;
Nishioka, T.; Zwicker, K.; Brandt, U.; Miyoshi, H.
Biochemistry 2004, 43, 3651–3658.
8. Ichimaru, N.; Murai, M.; Abe, M.; Hamada, T.; Yamada, Y.;
Makino, S.; Nishioka, T.; Makabe, H.; Makino, A.;
Kobayashi, T.; Miyoshi, H. Biochemistry 2005, 44, 816–825.
9. Murai, M.; Ichimaru, N.; Abe, M.; Nishioka, T.; Miyoshi, H.
Biochemistry 2006, 45, 9778–9787.
10. Ichimaru, N.; Abe, M.; Murai, M.; Senoh, M.; Nishioka, T.;
Miyoshi, H. Bioorg. Med. Chem. Lett. 2006, 16, 3555–3558.
11. Mertz, E.; Tinsley, J. M.; Roush, W. R. J. Org. Chem. 2005, 70,
8035–8046.
12. Tinsley, J. M.; Mertz, E.; Chong, P. K.; Rarig, R. F.; Roush,
W. R. Org. Lett. 2005, 7, 4245–4248.
3.9.1. (2R,5R)-2,5-Bis-[(1R)-1-hydroxyundecyl]tetra-
hydrofuran (12). Compound 12 was synthesized by the
same procedure used for the synthesis of 8 as a waxy
oil: [a]2D6 +22 (c 0.10, EtOH); 1H NMR (400 MHz,
CDCl3) d 3.82–3.87 (m, 2H), 3.42–3.38 (m, 2H), 2.32 (br
s, 2H), 1.99–1.93 (m, 2H), 1.71–1.65 (m, 2H), 1.52–1.49
(m, 2H), 1.43–1.41 (m, 4H), 1.35–1.26 (m, 30H), 0.87 (t,
J¼6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 82.62
(2C), 74.04 (2C), 33.51 (2C), 31.91 (2C), 29.72 (2C),
29.62 (2C), 29.60 (2C), 29.34 (2C), 28.74 (2C), 28.60
(2C), 25.61 (2C), 22.69 (2C), 14.12 (2C); ESI-HRMS
(m/z) calcd for C26H52O3Na [M+Na]+ 435.3801, observed
435.3814.
13. Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127,
10818–10819.
3.10. Measurement of complex I activity
14. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–
519; Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H.
J. Am. Chem. Soc. 1991, 113, 4092–4096.
Bovine heart submitochondrial particles were prepared
by the method of Matsuno-Yagi and Hatefi25 using a
sonication medium containing 0.25 M sucrose, 1 mM
succinate, 1.5 mM ATP, 10 mM MgCl2, 10 mM MnCl2,
and 10 mM Tris–HCl (pH 7.4), and stored in a buffer con-
taining 0.25 M sucrose and 10 mM Tris–HCl (pH 7.4)
at ꢀ84 ꢁC. The NADH oxidase activity in submitochon-
drial particles was followed spectrometrically with a
Shimadzu UV-3000 (340 nm, 3¼6.2 mMꢀ1 cmꢀ1) at 30 ꢁC.
The reaction medium (2.5 mL) contained 0.25 M sucrose,
1 mM MgCl2, and 50 mM phosphate buffer (pH 7.4).
The final mitochondrial protein concentration was 30 mg
of protein/mL. The reaction was started by adding 50 mM
NADH after the equilibration of SMP with an inhibitor
for 4 min.
15. Born, L.; Lieb, F.; Lorentzen, J. P.; Moeschler, H.; Nonfon, M.;
€
Sollner, R.; Wendisch, D. Planta Med. 1990, 56, 312–316.
16. Fujimoto, Y.; Murasaki, C.; Shimada, H.; Nishioka, S.;
Kakinuma, K.; Singh, S.; Singh, M.; Gupta, Y. K.; Sahai, M.
Chem. Pharm. Bull. 1994, 42, 1175–1184.
17. Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67, 5739–5752.
18. Motoyama, T.; Yabunaka, H.; Miyoshi, H. Bioorg. Med. Chem.
Lett. 2002, 12, 2089–2092.
19. Yabunaka, H.; Abe, M.; Kenmochi, A.; Hamada, T.; Nishioka,
T.; Miyoshi, H. Bioorg. Med. Chem. Lett. 2003, 13, 2385–2388.
20. Curran, D. P.; Zhang, Q.; Richard, C.; Lu, H.; Gudipati, V.;
Wilcox, C. S. J. Am. Chem. Soc. 2006, 128, 9561–9573. In
this paper, the total syntheses of 28-member libraries of muri-
solin (mono-THF acetogenin) stereoisomers are reported.
21. Degli Esposti, M.; Ghelli, A.; Ratta, M.; Cortes, D.; Estornell,
E. Biochem. J. 1994, 301, 161–167.
Acknowledgements
22. Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura,
H.; McLaughlin, J. L. Biochim. Biophys. Acta 1998, 1365,
443–452.
23. Makabe, H.; Miyawaki, A.; Takahashi, R.; Hattori, Y.; Konno,
H.; Abe, M.; Miyoshi, H. Tetrahedron Lett. 2004, 45, 973–977.
24. Makabe, H.; Hattori, Y.; Kimura, Y.; Konno, H.; Abe, M.;
Miyoshi, H.; Tanaka, A.; Oritani, T. Tetrahedron 2004, 60,
10651–10657.
We thank Dr. Naoki Mori in our Division for the HRMS
analysis. Piericidin A and bullatacin were generous gifts
from Drs. S. Yoshida (The Institute of Physical and Chemi-
cal Research, Saitama, Japan) and J. McLaughlin (Purdue
University, West Lafayette, USA), respectively. This work
was supported in part by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of
Science (Grant 17380073 to H.M.).
25. Matsuno-Yagi, A.; Hatefi, Y. J. Biol. Chem. 1985, 260, 14424–
14427.