Total synthesis of the antitumor acetogenin mosin B: Desymmetrization approach to the stereodivergent synthesis of threo/trans/erythro-type acetogenins

Article abstract of DOI:10.1002/chem.200390040

A total synthesis of the threo/trans/erythro-type acetogenin mosin B and one of its diastereomers has been achieved. The carbon skeleton is assembled in a convergent fashion from two segments (a THF ring segment and a γ-lactone segment) through the Nozaki

Full text of DOI:10.1002/chem.200390040

T. Tanaka, M. Monden et al.
Chem. Eur. J. 2003, 9, No. 2
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389

FULL PAPER
Total Synthesis of the Antitumor Acetogenin Mosin B: Desymmetrization
Approach to the Stereodivergent Synthesis of threo/trans/erythro-Type
Acetogenins
Naoyoshi Maezaki,[a] Naoto Kojima,[a] Atsunobu Sakamoto,[a] Hiroaki Tominaga,[a]
Chuzo Iwata,[a] Tetsuaki Tanaka,*[a] Morito Monden,*[b] Bazarragchaa Damdinsuren,[b] and
Shoji Nakamori[b]
Abstract: A total synthesis of the threo/trans/erythro-type acetogenin mosin B and
one of its diastereomers has been achieved. The carbon skeleton is assembled in a
convergent fashion from two segments (a THF ring segment and a g-lactone
segment) through the Nozaki Hiyama Kishi reaction. The THF ring segment was
stereoselectively constructed by a stereodivergent synthesis starting from a common
intermediate (4-cyclohexene-1,2-diol) based on a desymmetrization strategy. The g-
lactone segment was synthesized by coupling a triflate and a chiral a-sulfenyl g-
lactone. By virtue of these synthetic results, we suggest that the absolute
configuration of natural mosin B is 1a. Antiproliferative effects of 1a and 1b were
also investigated.
Keywords: annonaceous acetogenins
asymmetric desymmetrization
mosin B ¥ structure elucidation ¥
¥
¥
total synthesis
of natural resources, more samples are required for further
biological and clinical studies and for precise structural
determination.
Mosin B (1) (Scheme 1) is a threo/trans/erythro-type mono-
THF acetogenin isolated in 1997 from the bark of Annona
squamosa by McLaughlin and co-workers.[4, 5] This natural
product has selective and potent cytotoxic activity against the
human pancreatic tumor cell line. The structure of 1 was
Introduction
Annonaceous acetogenins[1] are a new class of natural
products which have attracted worldwide attention in recent
years because of their potent biological activities such as
cytotoxic, antitumor, immunosuppressive, pesticidal, antifee-
dant, and antimalarial effects. Inhibition of mitochondrial
complex I (NADH ubiquinone oxoreductase) is considered
to be one mode of action for acetogenins, leading to a lack of
ATP in the tumor cell and the subsequent apoptosis.[2] Some
acetogenins inhibit multidrug-resistant cancer cells with an
ATP-driven transporter system.[3] Furthermore, although
more than 250 acetogenins have been isolated from various
Annonaceae plants, the absolute configuration of many
acetogenins have not been determined. In view of the scarcity
trans
Me
34
erythro
threo
OH
4
nC12H25
9
O
20
O
15
OH
O
HO
O
mosin B (1)
20
HO
15
20
HO
15
O
O
OH
OH
1a
1b
[a] Prof. Dr. T. Tanaka, Dr. N. Maezaki, N. Kojima, Dr. A. Sakamoto,
H. Tominaga, Prof. Dr. C. Iwata
Scheme 1. Possible structures of mosin B.
Graduate School of Pharmaceutical Sciences
Osaka University, 1-6 Yamadaoka, Suita
Osaka 565-0871 (Japan)
assigned mainly on the basis of 1H and 13C NMR spectroscopy
and MS data. Although the absolute configuration of the g-
lactone moiety was established as (4R,34S) and the relative
stereochemistry of the THF part was determined as threo/
trans/erythro,[1a] the absolute configuration remained un-
known. Differentiation of the two possible structures 1a and
Fax : (‡81)6-6879-8214
E-mail: t-tanaka@phs.osaka-u.ac.jp
[b] Prof. Dr. M. Monden, Dr. B. Damdinsuren, Dr. S. Nakamori
Department of Surgery and Clinical Oncology
Graduate School of Medicine, Osaka University, E2
2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax : (‡81)6-6879-3259
1
1b would be difficult by H or 13C NMR spectroscopic data,
since two stereogenic regions, that is, the THF ring core part
(C15 C20) and the g-lactone segment (C4 and C34), are
separated by a long carbon chain. Moreover, the absolute
E-mail: monden@surg2.med.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://www.chemeurj.org or from the author.
390
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Chem. Eur. J. 2003, 9, No. 2

Antitumor Acetogenin Mosin B
389 399
stereochemical assignment of the threo/trans/erythro-type
acetogenin by the advanced Mosher ester methodology is
generally difficult because the protons of the THF part are
affected by the shielding from the two methoxy(trifluorome-
thyl)phenylacetate (MTPA) esters flanking both sides of the
THF ring.[4, 6] X-ray analysis is also very difficult due to the
waxy nature of this compound. To establish the absolute
configuration of mosin B, we planned to synthesize the two
candidate structures (1a and 1b) by a stereodivergent syn-
thesis based on a desymmetrization strategy starting from the
common intermediate 4-cyclohexene-1,2-diol (3).[7]
In a preliminary communication,[8] we reported the first
total synthesis of 1a and 1b, and suggested that compound 1a
is the correct structure of mosin B. In this paper, we describe
full details of the synthesis of 1a and 1b including an
investigation of an appropriate alkylating agent for an a-
sulfenylated g-lactone 9. Furthermore, precise comparison of
the 13C NMR spectral data of the natural mosin B, 1a, and 1b
afforded additional evidence that mosin B is identical with 1a
rather than 1b. The antiproliferative effects of 1a and 1b
against several anticancer cells are also reported.
blocks for the construction of stereogenic centers at the C19
and C20 positions in both 1a and 1b.
Scheme 3 shows a retrosynthetic analysis of the candidate
1a. Compound 1a is divided into the two key building blocks 5
and 6. The THF core segment 5 is stereoselectively con-
structed by iodoetherification[9] of the E allylic alcohol 7,
which is prepared from the chiral alcohol 4a.[7] The g-lactone
segment 6 is synthesized by a-alkylation of known a-sulfenyl
g-lactone 9[10] with an alkyne 8 prepared from an iodide 10.[11]
C-C bond formation
Me
OH
8
9
nC12H25
HO
O
O
OH
O
O
1a
C-Alkylation
Me
OP
nC12H25
PO
O
CHO
O
3
+
PhS
OP
H
O
6
Iodoetherification
5
Me
OP
C-Alkylation
L
+
O
PhS
nC12H25
H
8
O
9
O
O
OH
7
Results and Discussion
Me
O
O
O
I
We have recently developed an efficient method for the
asymmetric desymmetrization of cyclic meso-1,2-diols by
using C2-symmetric bis-sulfoxide 2 (Scheme 2).[7] After ace-
talization of the meso-1,2-diols with the chiral auxiliary 2, the
resulting acetals were subjected to base-promoted acetal
10
(S)-propylenoxide
HO
OBn
OH
CO2H
4a
HO2C
(R)-malic acid
Scheme 3. Retrosynthetic analysis of mosin B.
O
O
O
O
S
S
S
S
O
O
Acetalization
X
O
+
X
The synthesis of the allylic alcohol 7 from the optically pure
alcohol 4a is summarized in Scheme 4. Alcohol 4a was
converted into a lactol 11 by dihydroxylation of the double
bond followed by oxidative cleavage of the resulting 1,2-diol.
HO OH
2
O
S
Acid
Hydrolysis
1) Acetal Fission
2) Protection
O
X
+
2
X
S
HO OR
RO
O
BnO
OHC
BnO
e
a, b
c, d
4a
using (S,S)-2
OH
OH
OH
nC9H19
O
1a
12
HO
OBn
11
4a (>98% ee)
Asymmetric
g, h
f
Desymmetrization
nC12H25
OH
OH
nC12H25
OH
HO
OH
O
OH
O
O
3
1b
using (R,R)-2
13
14
BnO
OH
4b (>98% ee)
j
i
nC12H25
I
nC12H25
O
O
O
OTBS
Scheme 2. Our asymmetric desymmetrization protocol for cyclic meso-1,2-
16
15
diols.
k
nC12H25
nC12H25
O
O
fission followed by benzylation to give the desymmetrized
diol derivatives with high diastereoselectivity. The chiral
auxiliary 2 was readily removed by acid hydrolysis and can be
recovered without loss of enantiomeric excess. Based on this
methodology, 4-cyclohexene-1,2-diol (3) can be converted to
the desymmetrized alcohols 4a and 4b (>98% ee); the
stereochemistry for both compounds was confirmed by a
modified Mosher method. These are versatile chiral building
O
O
OH
OH
7
17
Scheme 4. Synthesis of allylic alcohol 7. a) cat. OsO4, N-methylmorpholine
N-oxide, acetone/THF, RT; b) NaIO4, acetone/H2O, RT; c) Ph3PC10H21Br,
KHMDS, THF, À78 to 08C; d) NaBH4, MeOH, RT, 20% over four steps;
e) H2, Pd/C, 3 atm, MeOH, RT, quant.; f) pTsOH, acetone, RT, 93%;
g) MsCl, Et3N, CH2Cl2, RT; h) NaI, NaHCO3, acetone, reflux, 88% over
two steps; i) 1-tert-butyldimethylsilyloxy-2-propyne, nBuLi, THF/HMPA,
08C, 74%; j) TBAF, THF, RT, quant.; k) LiAlH4, THF, reflux, 90%.
Chem. Eur. J. 2003, 9, No. 2
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391

T. Tanaka, M. Monden et al.
FULL PAPER
Wittig reaction proceeded selectively on the free aldehyde
moiety of lactol 11, and the lactol itself was then reduced with
NaBH4 in MeOH at room temperature to give diol 12 in
overall 20% yield from 4a. Hydrogenation of the double
bond accompanied by debenzylation afforded a triol 13 in
quantitative yield. The 1,2-diol was selectively protected as an
acetonide to give 14 in 93% yield.[12] Mesylation of 14
followed by iodination gave an iodide 15 (88% in two steps).
The iodide 15 was coupled with the acetylide generated from
the tert-butyldimethylsilyl (TBS) ether of propargyl alcohol[13]
on treatment with nBuLi to give alkyne 16 in 74% yield.
Alkylation of 15 with the acetylide generated from an
unprotected propargyl alcohol afforded no desired product,
and instead, elimination of the iodide occurred due to the
basicity of the alkoxide. The alkyne 16 was converted into the
E allylic alcohol 7 by deprotection of the TBS ether to give
alcohol 17 followed by an E-selective reduction of the triple
bond with LiAlH4. Attempted Birch reduction of 16 afforded
an E-selective reduction product, but the TBS ether was lost.
Upon treatment of 7 with I(collidine)2ClO4,[9] iodoether-
ification proceeded highly stereoselectively to give epoxide 18
Figure 1. Differences between the characteristic chemical shifts of the
carbon atoms of 19 and those of Fujimoto×s model compounds. The x and y
axes represent the carbon position and Dd (d19 À dmodel compound), respectively.
O
a
O
b
O
as
a single isomer after subsequent base treatment
O
I
(Scheme 5). The epoxide 18 was subjected to nucleophilic
ring opening[9b, 14] with 5-hexenylmagnesium bromide in the
TMS
23
10
OH
OTBS
f
OH
d, e
OTs
R
H
24: R = TMS
25: R = H
26
e
c
d
a
c
a, b
nC12H25
nC12H25
(
)
3
O
c
O
b
O
7
OH
RO
d
OR
19: R = H
20: R = TBS
Me
OTBS
I
OTBS
PhS
g
18
O
H
O
H
28
f
27
nC12H25
TBSO
nC12H25
(
)
3
( )
3
OH
O
CHO
O
Scheme 6. Synthesis of g-lactone segment 28. a) Trimethylsilylacetylene,
nBuLi, THF/HMPA, À78 to 08C, 85%; b) AcOH, H2O, RT, 92 %;
c) TBAF, THF, RT, 90%; d) pTsCl, pyridine, RT; e) TBSCl, imidazole,
DMF, RT, 69% over two steps; f) NaI, NaHCO3, acetone, reflux, 88%;
g) 9, KHMDS, THF/HMPA, 08C to reflux, 16%.
OTBS
21
TBSO
OTBS
OH
22
Scheme 5. Synthesis of THF core segment 22. a) I(collidine)2ClO4, MeCN/
H2O, RT; b) K2CO3, MeOH, RT, 80% over two steps; c) 6-bromo-1-
hexene, Mg, CuBr, THF, 08C, 89%; d) TBSOTf, 2,6-lutidine, CH2Cl2, RT,
83%; e) cat. OsO4, N-methylmorpholine N-oxide, THF/acetone/H2O, RT,
79%; f) NaIO4, CH2Cl2/acetone/H2O, RT, 75 %.
the presence of potassium hexamethyldisilazane (KHMDS)
in THF/HMPA (hexamethylphosphoramide) gave the sulfide
28 in only 16% yield.[17, 18] We suggest that the bulky TBS
ether adjacent to the iodo substituent prevents the alkylation,
since alkylation of 9 with 1-iodohexane proceeded in good
yield (74%) under the same conditions. Thus, we investigated
an appropriate protecting and leaving group for the a-
alkylation of 9.
We selected a methoxymethyl (MOM) group as a less bulky
protecting group, and triflate (OTf) and chloromethanesulfo-
nate (OMc)[19] as more efficient leaving groups. The MOM-
protected iodide 30 was synthesized from the diol 25 by the
same procedure as that described for 27 (Scheme 7). The
alkylating agents 36 39 with OTf or OMc as the leaving
group were prepared as follows: selective esterification of the
primary alcohol of 25 to a pivaloyl ester 31 followed by
protection of the secondary alcohol as the TBS or MOM ether
afforded 32 or 33, respectively. Deprotection of the pivaloyl
ester of 32 or 33 with diisobutylaluminum hydride (DIBALH)
was carried out in 98% and 92% yield, respectively.
Conversion of the primary alcohol in 34 or 35 into the leaving
group gave four alkylating agents 36 39. The alkylating agent
presence of CuBr to give diol 19 regioselectively in 89%
yield.[15] The stereochemistry around the THF ring was
assigned as threo/trans/erythro by comparison of the
13C NMR spectral data of 19 with those of Fujimoto×s
synthetic model compounds.[16] As shown in Figure 1, the
13C NMR spectral data around the THF ring of 19 nicely
matched those of the model compound with threo/trans/
erythro stereochemistry. The THF core segment 22 was then
synthesized by silylation of the diol 19 followed by oxidative
cleavage of the terminal olefin via the intermediate diol 21.
Preparation of the g-lactone segment 28 is summarized in
Scheme 6. The known iodide 10[11] prepared from (R)-malic
acid was converted into an alkyne 23 on treatment with
lithium trimethylsilyl acetylide. Deacetonization of 23 with
AcOH to give diol 24 was followed by desilylation to give
acetylenic diol 25 in 90% yield. Selective tosylation of the
primary alcohol in 25 and subsequent silylation of the
secondary alcohol gave tosylate 26 in 69% yield in two steps.
Iodination of 26 with NaI gave the iodide 27 in 88% yield.
Unfortunately, alkylation of the known lactone 9[10] with 27 in
392
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Antitumor Acetogenin Mosin B
389 399
Table 2. Effect of HMPA in coupling reaction of lactone and triflate.
OMOM
OMOM
I
c
a, b
OTs
25
Me
Me
H
H
OTBS
O
29
30
OPG
OTBS
OTf
O
PhS
9
PhS
O
O
H
OH
d
e or f
KHMDS
HMPA
36
28
H
OPv
OPv
25
H
H
32 (PG = TBS)
33 (PG = MOM)
Entry
HMPA [equiv]
Conditions
Yield [%]
31
1
2
3
4
5
0
1
5
5
14
08C to RT
08C
08C
10 (20)[a]
OPG
OPG
48
69
65
26
OR
h or i
g
OH
H
À 20 to À108C
H
36 (PG = TBS, R = Tf)
37 (PG = TBS, R = Mc)
38 (PG = MOM, R = Tf)
39 (PG = MOM, R = Mc)
34 (PG = TBS)
35 (PG = MOM)
08C
[a] Yield in parentheses based on the consumed triflate.
Table 3. Coupling reaction of aldehyde and acetylide.
Scheme 7. Synthesis of alkylating agents 30 and 36 39. a) pTsCl, pyridine,
RT; b) MOMCl, iPr2NEt, CH2Cl2, RT, 67% over two steps; c) NaI,
NaHCO3, acetone, reflux, 79%; d) pivaloyl chloride, pyridine, CH2Cl2, 08C
to RT, 89%; e) TBSCl, imidazole, DMF, RT, quant.; f) MOMCl, iPr2NEt,
CH2Cl2, 08C to RT, 93%; g) DIBALH, CH2Cl2, À788C, 98% for 34 and
92% for 35; h) Tf2O, 2,6-lutidine, CH2Cl2, 08C, 91% for 36; i) McCl,
2,6-lutidine, CH2Cl2, 08C, 90% for 37 and 84% for 39.
Me
OTBS
PhS
H
O
+
28
O
O
40
OH
41
Entry
Base
Additive
Yield [%]
38 was used immediately in the next reaction without further
purification due to its instability.
1
2
3
4
5
6
nBuLi
nBuLi
tBuLi
tBuLi
tBuLi
20
HMPA
complex mixture
23
20
complex mixture
trace
The results of the coupling reaction of the alkylating agents
30 and 36 39 with the lactone 9 are summarized in Table 1.
For substrates bearing a MOM ether, the reaction resulted in
decomposition and gave the coupling product in poor yield
(entries 1 3). For the substrates with a TBS ether, triflate was
the best leaving group (entries 4 6). Thus, the product 28 was
obtained in 26% yield.
BF3 ¥ OEt2
CeCl3
KHMDS
The corresponding cerium acetylide has a low basicity;
however, coupling with this also failed because of the
decomposition of the sulfide 28 (entry 5). We therefore
abandoned the coupling reaction of the aldehyde with the
acetylide and planned an alternative route with the Nozaki
Hiyama Kishi reaction.[21]
Synthesis of the g-lactone segment 47 started from the
known aldehyde 42[22] prepared from d-glutamic acid, which
was converted into a diol 43 by Takai×s olefination[23] followed
by deacetalization. Selective triflation of the primary alcohol
in 43 with Tf2O at À508C and subsequent silylation of the
secondary alcohol with TBSOTf at 08C were carried out in a
one-pot reaction.[24] In contrast to 36, the coupling reaction of
Table 1. Coupling reaction of lactone and alkylating agents.
Me
Me
O
OPG
PhS
OPG
PhS
O
9
O
L
O
KHMDS
HMPA
H
H
28 (PG = TBS)
30, 36–39
Entry
Compound
PG
L
Conditions
Yield [%]
1
2
3
4
5
6
30
38
39
27
36
37
MOM
MOM
MOM
TBS
TBS
TBS
I
08C to RT
08C
08C to RT
08C to reflux
08C
trace
decomp.
trace
16
26
trace
OTf
OMc
I
OTf
OMc
08C to reflux
OH
e, f
a, b
c
OTBS
OTf
O
OH
O
I
I
OHC
d
42
43
Me
44
OTBS
Next, we examined the effect of HMPA on the yield of
alkylation (Table 2). We found that the yield was optimized at
69% when five equivalents of HMPA were used. The correct
combination of the protecting group (TBS) and the leaving
group (OTf) in the alkylating agent, and the amount of
HMPA were therefore important to achieve high yields. This
procedure will be useful for the synthesis of other acetogenins
with an hydroxy group at the C4-position.[20]
Me
OTBS
PhS
O
O
I
I
O
O
45
47
OTBS
SPh
I
46
We investigated the reaction of the acetylide derived from
28 with 1-pentanal (40) as a model study (Table 3). Although
an adduct 41 was obtained, the yield was low. All efforts to
improve the yield were unsuccessful and led to decomposition
of 40 probably as a result of the high basicity of the acetylide.
Scheme 8. Synthesis of g-lactone segment 47. a) CrCl2, CHI3, THF, RT;
b) Dowex 50W, MeOH, RT, 58% over two steps; c) Tf2O, 2,6-lutidine,
CH2Cl2, À508C then TBSOTf, 08C, 92%; d) 9, KHMDS, THF, 08C then
39, RT, 79%; e) mCPBA, CH2Cl2, 08C; f) toluene, reflux, 85% over two
steps.
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393

T. Tanaka, M. Monden et al.
FULL PAPER
44 with lactone 9[10] in the presence of HMPA (5 equiv) gave
the desired product 45 in poor yield (13%) along with the by-
product 46 in 12% yield. In this case, the yield was improved
up to 79% when the reaction was carried out without HMPA.
Oxidation of the sulfide 45 into sulfoxide followed by thermal
elimination afforded the g-lactone segment 47.
Assembly of the two segments 22 and 47 was performed
with the Nozaki Hiyama Kishi reaction (Scheme 9). Treat-
ment of 47 with CrCl2 (5 equiv) in the presence of catalytic
other candidate 1b was synthesized from 4b by using the same
procedure as for 1a.
The specific rotations of the two synthetic samples 1a and
1b were very different. While the specific rotation of synthetic
1a ([a]2D5 ˆ ‡18.7, c ˆ 0.50, CH2Cl2) is higher than the
reported value of the naturally occurring mosin B[4] ([a]D23
‡11.5, c ˆ 0.005, CH2Cl2), the specific rotation of 1b ([a]D26
ˆ
ˆ
‡2.2, c ˆ 0.39, CH2Cl2) was very small. Due to the unavail-
ability of mosin B, a comparison of our synthetic samples with
the authentic natural product was not possible. However,
taking into account the fact that the reported optical rotations
of acetogenins are sometimes smaller than their actual values
when they are measured at low concentrations, presumably
owing to experimental error or the presence of impuri-
ties,[5c, d, 27] the synthetic compound 1a was assumed to be the
natural mosin B.
Me
OTBS
c
a
22
nC12H25
TBSO
O
(
)
3
O
OTBS
R
O
48 (R = OH, H)
49 (R = O)
b
Me
OTBS
d
Compounds 1a and 1b could not be differentiated by
1H NMR spectral data. The 13C NMR spectral data of 1a and
1b were also very close to those of natural mosin B. It would
therefore be difficult to distinguish which compound was
identical to the natural mosin B unless both 1a and 1b were
available. We compared the 13C NMR spectral data more
precisely by plotting the difference between the chemical
shifts of natural mosin B and those of each candidate 1a and
1b as shown in Figure 2. The chemical shifts of 1a were almost
identical to the reported values of mosin B, and the differ-
ences in the chemical shifts were within 0.04 ppm except for
one carbon. In contrast, the differences in 1b exceeded more
than 0.04 ppm for many carbons. From this evidence, we
concluded that natural mosin B is 1a and not 1b.
nC12H25
TBSO
O
(
)
3
1a
O
OTBS
O
O
50
a
nC12H25
CHO
O
4b
TBSO
OTBS
ent-22
Me
O
OTBS
c
nC12H25
(
)
3
O
TBSO
OTBS
R
O
51 (R = OH, H)
52 (R = O)
b
Me
OTBS
d
nC12H25
TBSO
O
(
)
3
1b
O
OTBS
O
O
53
Scheme 9. Synthesis of mosin B 1a and the diastereomer 1b. a) 47, CrCl2,
cat. NiCl2, DMF/Me2S, RT, 71% from 22, 70% from ent-22; b) SO3 ¥ pyri-
dine, DMSO, Et3N, CH2Cl2, 08C to RT, 72% from 48, 83% from 51; c) H2,
[(Ph3P)3RhCl], benzene, RT, 78% from 49, 74% from 52; d) aq. HF,
MeCN/THF, RT, 72% from 50, 78% from 53.
Biological evaluation of 1a and 1b: Comparison of the
antiproliferative effects of mosin B (1a) and the unnatural
diastereomer 1b is of great interest. Thus, we evaluated their
antiproliferative effects by using adriamycin as a positive
control. The results are shown in Figure 3. Both compounds
1a and 1b inhibited proliferation of two pancreatic cancer cell
lines (PaCa-2 and PSN-1) in a dose-dependent manner. In the
growth-inhibitory assay (for 4 d), they had approximately
sixfold greater ED50 values than adriamycin against PaCa-2
and PSN-1.[28] Unexpectedly, the growth-inhibitory effect of
1b is almost the same as that of 1a (the differences were not
statistically significant, p > 0.05). The growth-inhibitory as-
says with 1a, 1b, and adriamycin were also performed on HT-
29(colon adenocarcinoma) and MCF-7 (breast adenocarci-
noma) cell lines. Compounds 1a and 1b did not have superior
NiCl2 in DMF afforded 48 in low yield, although rapid
consumption of aldehyde 22 was observed. With the DMF/
Me2S solvent system,[25] the yield was remarkably improved
and gave 48[26] in 59% yield and recovered aldehyde 22 in
35% yield. Moreover, the alcohol 48 was obtained in 71%
yield when ten equivalents of CrCl2 were used. Oxidation of
48 with SO3 ¥ pyridine complex and DMSO followed by
selective reduction of the resulting enone 49 with Wilkinson×s
catalyst afforded the tri-TBS ether 50. Finally, deprotection of
all the TBS ethers with HF afforded the candidate 1a. The
Figure 2. Differences between the characteristic chemical shifts of the carbon atoms of natural mosin B and those of each candidate 1a (left) and 1b (right)
(75 MHz, CDCl3). The x and y axes represent the carbon number and Dd (d1a,b À dmosin B), respectively.
394
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Chem. Eur. J. 2003, 9, No. 2

Antitumor Acetogenin Mosin B
389 399
Figure 3. Antiproliferative effect of 1a, 1b, and adriamycin in PaCa-2 and PSN-1 cells: a) Growth-inhibitory assay for 4 d (average data from four
independent experiments). b) Growth-inhibitory assay for 7 d (average data from four independent experiments).
adsorbent for column chromatography. Known compounds 4a,[7] 4b,[7] 9,[10]
growth-inhibition effects relative to adriamycin in those cells
or in the KMP-5 (pancreatic adenocarcinoma) cell line (data
not shown).
10,[11] and 42[22] were synthesized according to the literature methods.
Experimental procedures and characterization data of 23 39 and 41 are
included in the Supporting Information.
(6Z,3R,4S)-3-Benzyloxy-6-hexadecene-1,4-diol (12): N-Methylmorpholine
N-oxide (2.15 g, 18.4 mmol) and OsO4 (31.1 mg, 0.122 mmol) were added
successively to a stirred solution of 4a (1.25 g, 6.12 mmol) in acetone/water
Conclusion
(1:1, 60 mL) at RT. After 3 h, the reaction was quenched with saturated
Na2S2O3. Celite was added to the mixture and stirring was continued for
1 h. The Celite was filtered off, and the filtrate was concentrated under
reduced pressure. NaIO4 (1.57 g, 7.24 mmol) was added to a stirred solution
of the crude diol in acetone/water (3:1, 40 mL) at RT. The stirring was
The total synthesis of mosin B (1a) and the diastereomer 1b
was accomplished by using asymmetric desymmetrization of
the s-symmetric diol 3 and the Nozaki Hiyama Kishi
reaction as key steps. The overall yield was 1.1% for 20 steps
from the desymmetrized alcohol 4a. Based on the spectral
data, we suggest that mosin B is 1a and not 1b. Diastereomer
1b exhibited a higher antiproliferative effect than adriamycin
and had a similar profile of growth inhibition as 1a against
used cancer cells.
continued at the same temperature for 10 min. After filtration through
Celite, the solvent was evaporated under reduced pressure. The residue was
extracted with EtOAc prior to drying and solvent evaporation. KHMDS
(0.5m in toluene, 10.6 mL, 5.31 mmol) was added slowly to a stirred
suspension of Ph3P(nC10H21)Br (2.57 g, 5.31 mmol) in THF (10 mL) at 08C.
A solution of the crude aldehyde in THF (10 mL) was added to the mixture
at À788C, and this was stirred at 08C for 2 h. The reaction was quenched
with water, and the mixture was extracted with EtOAc. The combined
organic phases were washed with brine prior to drying and solvent
evaporation. NaBH4 (183 mg, 4.83 mmol) was added to a stirred solution of
the crude lactol in MeOH (48 mL) at RT. After 5 min, the reaction was
quenched with water, and the solvent was concentrated under reduced
pressure. The residue was extracted with EtOAc, and the extract was
washed with water and brine prior to drying and solvent evaporation. The
residue was purified by chromatography (hexane/EtOAc 3:1) to give 12
(435 mg, 20% in four steps) as a colorless oil. [a]2D7 ˆ ‡3.1 (c ˆ 0.92,
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.0 Hz, 3H), 1.26
1.35 (m, 14H), 1.78 1.84 (m, 1H), 1.88 1.95 (m, 1H), 2.05 (dt, J ˆ 7.3,
6.7 Hz, 2H), 2.22 2.27 (m, 1H), 2.30 2.36 (m, 1H), 2.38 (m, 2H), 3.62 (dt,
J ˆ 7.3, 3.7 Hz, 1H), 3.72 3.76 (m, 1H), 3.82 (ddd, J ˆ 11.0, 7.3, 3.7 Hz, 1H),
3.89(dt, J ˆ 8.5, 4.3 Hz, 1H), 4.58 (d, J ˆ 11.6 Hz, 1H), 4.64 (d, J ˆ 11.6 Hz,
1H), 5.37 5.43 (m, 1H), 5.56 (dt, J ˆ 10.4, 7.3 Hz, 1H), 7.30 7.38 (m, 5H);
13C NMR (67.8 MHz, CDCl3): d ˆ 14.1, 22.6, 27.5, 29.3 (2C), 29.5, 29.56,
29.60, 30.6, 31.2, 31.9, 59.5, 71.7, 71.8, 80.0, 124.7, 127.9 (3C), 128.5 (2C),
Experimental Section
General: Melting points are uncorrected. Optical rotations were measured
with a JASCO DIP-360 digital polarimeter. IR spectra were measured with
an Horiba FT-210 IR spectrometer. 1H NMR spectra were measured with a
JEOL JNM-GX500 spectrometer (500 MHz) or a JEOL JNM-AL300
spectrometer (300 MHz). 13C NMR spectra were measured with a JEOL
JNM-AL300 spectrometer (75 MHz) or a JEOL JNM-EX270 spectrometer
(67.8 MHz). All signals are expressed as ppm downfield from tetramethyl-
silane used as an internal standard. The following abbreviations are used:
singlet (s), doublet (d), triplet (t), quartet (q), quintet (qn), multiplet (m).
Mass spectra were recorded on a Shimadzu QP-1000 mass spectrometer, a
JEOL JMS-D300, or a JEOL JMS-600 mass spectrometer. High-resolution
mass spectra were obtained with a JEOL JMS-D300 or a JEOL JMS-600
mass spectrometer. FAB mass spectra were measured with a JEOL-JMS-
700 mass spectrometer. Unless otherwise stated, all solvents were dry and
all extracts were dried over MgSO4. Merck Kieselgel 60 was used as an
‡
133.4, 138.0; IR (KBr): nÄ ˆ 3358 cmÀ1; MS (EI): m/z (%): 362 (0.2) [M] ,
253 (4.1), 177 (18.2), 91 (100); elemental analysis calcd (%) for C23H38O3: C
76.20, H 10.56; found: C 76.01, H 10.50.
Chem. Eur. J. 2003, 9, No. 2
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395

T. Tanaka, M. Monden et al.
FULL PAPER
(3R,4S)-1,3,4-Hexadecanetriol (13): Pd/C (4.0 mg) was added to a solution
of 12 (37.8 mg, 0.104 mmol) in MeOH (1 mL). The mixture was stirred
under 3 atm pressure of hydrogen at RT for 6.5 h. The Pd/C was filtered off
and the filtrate was concentrated under reduced pressure. The residue was
purified by chromatography (hexane/EtOAc 1:1) to give 13 (28.7 mg,
100%) as a colorless powder. M.p. 109.5 110.08C (EtOAc/MeOH);
[a]2D8 ˆ ‡0.58 (c ˆ 1.00, MeOH); 1H NMR (500 MHz, [D4]MeOH): d ˆ 0.90
(t, J ˆ 7.0 Hz, 3H), 1.29 1.37 (m, 20H), 1.52 1.63 (m, 3H), 1.80 1.86 (m,
1H), 3.34 3.44 (m, 1H), 3.52 3.55 (m, 1H), 3.67 3.76 (m, 2H); 13C NMR
(67.8 MHz, [D4]MeOH): d ˆ 14.4, 23.7, 27.0, 30.5, 30.8 (5C), 30.9, 33.1, 33.7,
35.9, 60.4, 73.5, 76.0; IR (KBr): nÄ ˆ 3263 cmÀ1; MS (FAB): m/z: 275
residue was purified by chromatography (hexane/EtOAc 3:1) to give 17
(28.8 mg, 100%) as a colorless oil. [a]3D0 ˆ ‡23.1 (c ˆ 1.05, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.0 Hz, 3H), 1.26 1.40 (m, 20H), 1.34 (s,
3H), 1.42 (s, 3H), 1.50 1.60 (m, 3H), 1.67 (dddd, J ˆ 12.8, 10.4, 8.2, 5.0 Hz,
1H), 2.32 (dtt, J ˆ 17.1, 8.2, 2.1 Hz, 1H), 2.44 (dddt, J ˆ 17.1, 7.8, 5.0, 2.4 Hz,
1H), 4.08 (dt, J ˆ 10.4, 4.3 Hz, 1H), 4.12 (ddd, J ˆ 10.4, 6.1, 3.1 Hz, 1H),
4.25 (brs, 2H); 13C NMR (67.8 MHz, CDCl3): d ˆ 14.1, 15.5, 22.7, 25.9, 26.4,
28.6, 29.1, 29.3, 29.4, 29.5, 29.57, 29.61 (2C), 29.65, 29.68, 31.9, 51.3, 76.5,
77.8, 78.8, 85.6, 107.6; IR (KBr): nÄ ˆ 3381, 2224 cmÀ1; MS (FAB): m/z: 353
‡
[M‡H] ; elemental analysis calcd (%) for C22H40O3: C 74.95, H 11.44;
found: C 74.79, H 11.39.
‡
[M‡H] ; elemental analysis calcd (%) for C16H34O3: C 70.02, H 12.49;
(E,6R,7S)-6,7-O-Isopropylidene-2-nonadecene-1,6,7-triol (7): LiAlH4
(22.0 mg, 0.579mmol) was added to a stirred solution of 17 (102 mg,
0.289mmol) in Et 2O (3 mL) at RT. The mixture was heated at reflux for
3 h. Saturated Rochelle salt was gradually added to the vigorously stirred
mixture. After 10 min, the mixture was extracted with EtOAc, and the
extract was washed with water and brine prior to drying and solvent
evaporation. The residue was purified by chromatography (hexane/EtOAc
3:1) to give 7 (92.4 mg, 90%) as a colorless oil. [a]2D8 ˆ ‡4.3 (c ˆ 1.02,
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.7 Hz, 3H), 1.26
1.63 (m, 24H), 1.34 (s, 3H), 1.43 (s, 3H), 2.06 2.13 (m, 1H), 2.45 2.32 (m,
1H), 4.01 4.06 (m, 2H), 4.09 4.11 (m, 2H), 5.66 5.76 (m, 2H); 13C NMR
(67.8 MHz, CDCl3): d ˆ 14.1, 22.6, 26.0, 26.2, 28.6, 28.7, 29.3 (2C), 29.5,
29.56, 29.60 (3C), 29.63, 29.7, 31.9, 63.5, 77.3, 78.0, 107.4, 129.5, 132.2; IR
found: C 69.64, H 12.21.
(3R,4S)-3,4-O-Isopropylidene-1,3,4-hexadecanetriol (14): A mixture of 13
(54.7 mg, 0.199 mmol) and pTsOH ¥ H2O (0.8 mg) in acetone (4 mL) was
stirred at RT for 24 h. The reaction was quenched with NaHCO3. After
filtration, the solvent was concentrated under reduced pressure. The
residue was purified by chromatography (hexane/EtOAc 1:1) to give 14
(58.0 mg, 93%) as a colorless oil. [a]2D8 ˆ ‡16.3 (c ˆ 1.13, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.0 Hz, 3H), 1.23 1.58 (m, 23H), 1.35 (s,
3H), 1.46 (s, 3H), 1.74 1.81 (m, 1H), 2.35 2.36 (m, 1H), 3.80 3.85 (m,
2H), 4.07 4.11 (m, 1H), 4.24 (ddd, J ˆ 11.0, 5.8, 2.7 Hz, 1H); 13C NMR
(67.8 MHz, CDCl3): d ˆ 14.1, 22.7, 25.9, 26.3, 28.4, 29.3, 29.49, 29.54, 29.6
(5C), 31.9, 31.9, 61.3, 77.3, 78.0, 107.8; IR (KBr): nÄ ˆ 3410 cmÀ1; MS (FAB):
‡
‡
m/z: 315 [M‡H] ; elemental analysis calcd (%) for C19H38O3: C 72.56, H
(KBr): nÄ ˆ 3396 cmÀ1; MS (FAB): m/z: 355 [M‡H] ; elemental analysis
12.18; found: C 72.46, H 12.00.
calcd (%) for C22H42O3: C 74.52, H 11.94; found: C 74.46, H 11.85.
(3R,4S)-1-Iodo-3,4-O-isopropylidene-3,4-hexadecanediol (15): Methane-
sulfonyl chloride (0.144 mL, 1.86 mmol) was added to a stirred mixture of
14 (488 mg, 1.55 mmol) and Et3N (0.260 mL, 1.86 mmol) in CH2Cl2 (16 mL)
at RT. After 5 min, the reaction was quenched with water. The mixture was
extracted with EtOAc, and the extract was washed with brine prior to
drying and solvent evaporation. NaHCO3 (1.04 g, 12.4 mmol) and NaI
(698 mg, 4.65 mmol) were added to the mixture of the residue in acetone
(16 mL), and the mixture was heated at reflux for 11 h. Water was added
and the mixture was extracted with EtOAc. The extract was washed with
brine prior to drying and solvent evaporation. The residue was purified by
chromatography (hexane/EtOAc 4:1) to give 15 (578 mg, 88% in two
(2R,3R,6R,7S)-1,2:3,6-Diepoxy-7-hydroxynonadecane (18): I(collidine)2-
ClO4 (552 mg, 1.18 mmol) was added to a stirred solution of 7 (348 mg,
0.981 mmol) in MeCN/water (100:1, 9.8 mL) at RT. After 5 min, water was
added and the mixture was extracted with EtOAc. The organic phase was
washed with water and brine prior to drying and solvent evaporation.
K2CO3 (814 mg, 5.89mmol) was added to a stirred solution of the residue in
MeOH (10 mL) at RT. After 30 min, water was added and the mixture was
extracted with CHCl3. The extract was washed with saturated NH4Cl,
water, and brine prior to drying and solvent evaporation. The residue was
purified by chromatography (hexane/EtOAc 3:1) to give 18 (244 mg, 80%
in two steps) as a colorless powder. M.p. 52.0 52.58C (hexane); [a]D28
ˆ
steps) as
a
colorless oil. [a]D29 ˆ ‡31.6 (c ˆ 1.02, CHCl3); 1H NMR
‡1.5 (c ˆ 1.04, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.0 Hz,
3H), 1.25 1.51 (m, 22H), 1.83 1.94 (m, 3H), 2.01 (brs, 1H), 2.05 2.16 (m,
1H), 2.70 (dd, J ˆ 5.2, 2.7 Hz, 1H), 2.79(t, J ˆ 4.5 Hz, 1H), 2.98 (dt, J ˆ 4.5,
2.7 Hz, 1H), 3.82 (dt, J ˆ 6.1, 3.1 Hz, 1H), 3.87 (dd, J ˆ 12.2, 6.7 Hz, 1H),
3.94 (ddd, J ˆ 8.9, 5.8, 3.1 Hz, 1H); 13C NMR (67.8 MHz, CDCl3): d ˆ 14.1,
22.6, 24.6, 25.9, 29.0, 29.3, 29.5, 29.56, 29.60 (2C), 29.62 (2C), 31.9, 32.5,
44.2, 54.2, 71.5, 79.2, 83.0; IR (KBr): nÄ ˆ 3421 cmÀ1; MS (FAB): m/z: 319
(500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 7.0 Hz, 3H), 1.23 1.54 (m, 22H), 1.35
(s, 3H), 1.42 (s, 3H), 1.81 1.87 (m, 1H), 1.92 1.99 (m, 1H), 3.24 (dt, J ˆ
9.2, 7.3 Hz, 1H), 3.37 (ddd, J ˆ 9.2, 7.3, 4.3 Hz, 1H), 4.07 4.13 (m, 2H);
13C NMR (67.8 MHz, CDCl3): d ˆ 2.8, 14.1, 22.7, 25.9, 26.3, 28.6, 29.3, 29.5
(2C), 29.56, 29.62 (2C), 29.7 (2C), 31.9, 34.2, 77.5, 77.6, 107.8; IR (KBr): nÄ ˆ
‡
1092 cmÀ1; MS (FAB): m/z: 425 [M‡H] ; elemental analysis calcd (%) for
‡
C19H37IO2: C 53.77, H 8.79, I 29.90; found: C 53.73, H 8.56, I 29.57.
[M‡Li] ; elemental analysis calcd (%) for C19H36O3: C 73.03, H 11.61;
found: C 72.86, H 11.22.
(6R,7S)-1-(tert-Butyldimethylsilyloxy)-6,7-O-isopropylidene-2-nonade-
cyne-6,7-diol (16): nBuLi (1.54m in n-hexane, 2.88 mL, 4.44 mmol) was
added to a stirred solution of 1-(tert-butyldimethylsilyloxy)-2-propyne
(756 mg, 4.44 mmol) in THF (19mL) at 0 8C. After 5 min, a solution of 15
(942 mg, 2.22 mmol) in HMPA (3.2 mL) was added to the mixture at the
same temperature, and the stirring was continued for 10 min. The reaction
was quenched with saturated NH4Cl, and the solvent was concentrated
under reduced pressure. The residue was extracted with EtOAc, and the
extract was washed with saturated NH4Cl, water, and brine prior to drying
and solvent evaporation. The residue was purified by chromatography
(8R,9R,12R,13S)-9,12-Epoxy-8,13-dihydroxy-1-pentacosene (19): 6-Bro-
mo-1-hexene (0.090 mL, 0.672 mmol) was added to a stirred mixture of
Mg (17.2 mg, 0.706 mmol) in THF (0.3 mL) at RT. After 1.5 h, THF
(0.3 mL) was added to the mixture. The mixture was cooled at À308C, and
CuBr (9.6 mg, 0.067 mmol) was added. After 5 min, 18 (10.5 mg,
0.034 mmol) in THF (0.34 mL) was added, and the mixture was stirred at
08C for 1 h. The reaction was quenched with saturated NH4Cl, and the
solvent was concentrated under reduced pressure. The residue was
extracted with EtOAc, and the extract was washed with water and brine
prior to drying and solvent evaporation. The residue was purified by
chromatography (hexane/EtOAc 2:1) to give 19 (11.8 mg, 89%) as a
colorless powder. M.p. 55.0 56.08C (hexane); [a]2D8 ˆ ‡14.0 (c ˆ 1.03,
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.7 Hz, 3H), 1.26
1.43 (m, 28H), 1.50 1.53 (m, 2H), 1.62 1.67 (m, 1H), 1.82 1.94 (m, 2H),
1.97 2.01 (m, 1H), 2.03 2.07 (m, 3H), 2.37 (brs, 1H), 3.38 3.39 (m, 1H),
3.79 3.89(m, 3H), 4.93 (dd, J ˆ 10.4, 1.8 Hz, 1H), 4.99 (dq, J ˆ 17.1, 1.8 Hz,
1H), 5.81 (ddt, J ˆ 17.1, 10.4, 6.7 Hz, 1H); 13C NMR (67.8 MHz, CDCl3):
d ˆ 14.1, 22.6, 25.2, 25.4, 26.0, 28.6, 28.8, 29.1, 29.3, 29.5, 29.57, 29.60 (2C),
29.63, 29.7, 31.9, 32.5, 33.0, 33.7, 71.4, 74.3, 82.3, 83.3, 114.2, 139.0; IR (KBr):
(hexane/EtOAc 50:1) to give 16 (763 mg, 74%) as a colorless oil. [a]D29
ˆ
‡17.1 (c ˆ 1.04, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.11 (s, 6H), 0.88
(t, J ˆ 7.0 Hz, 3H), 0.91 (s, 9H), 1.26 1.40 (m, 20H), 1.33 (s, 3H), 1.42 (s,
3H), 1.45 1.58 (m, 3H), 1.63 1.70 (m, 1H), 2.26 2.32 (m, 1H), 2.39 2.45
(m, 1H), 4.06 (dt, J ˆ 8.5, 4.3 Hz, 1H), 4.12 (ddd, J ˆ 10.4, 5.5, 3.1 Hz, 1H),
4.29(t, J ˆ 2.1 Hz, 2H); 13C NMR (67.8 MHz, CDCl3): d ˆ À5.1 (2C), 14.1,
15.6, 18.3, 22.7, 25.9 (3C), 26.0, 26.3, 28.6, 29.1, 29.3, 29.5 (2C), 29.59 (2C),
29.65 (2C), 29.71, 31.9, 52.0, 76.6, 77.8, 79.1, 84.6, 107.5; IR (KBr): nÄ ˆ
‡
‡
2233 cmÀ1; MS (EI): m/z (%): 465 (3.6) [M À H] , 451 (31.5) [M À CH3] ,
‡
351 (100) [M À TBS] ; elemental analysis calcd (%) for C28H54O3Si: C
‡
72.04, H 11.66; found: C 72.24, H 11.36.
nÄ ˆ 3425 cmÀ1; MS (FAB): m/z: 39 7 [M‡H] ; elemental analysis calcd (%)
for C25H48O3: C 75.70, H 12.20; found: C 75.62, H 11.95.
(6R,7S)-6,7-O-Isopropylidene-2-nonadecyne-1,6,7-triol (17): TBAF (1.0m
in THF, 0.163 mL, 0.163 mmol) was added to a stirred solution of 16
(38.0 mg, 0.081 mmol) in THF (0.8 mL) at RT. After 10 min, water was
added and the mixture was extracted with EtOAc. The organic phase was
washed with water and brine prior to drying and solvent evaporation. The
(8R,9R,12R,13S)-8,13-Bis(tert-butyldimethylsilyloxy)-9,12-epoxy-1-penta-
cosene (20): TBSOTf (17.9 mL, 0.078 mmol) was added to a stirred mixture
of 19 (10.3 mg, 0.026 mmol) and 2,6-lutidine (12.1 mL, 0.104 mmol) in
CH2Cl2 (0.3 mL) at RT. After 10 min, the reaction mixture was quenched
396
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0902-0396 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 2

Antitumor Acetogenin Mosin B
389 399
with saturated NH4Cl. The mixture was extracted with EtOAc, and the
extract was washed with water and brine prior to drying and solvent
evaporation. The residue was purified by chromatography (hexane) to give
20 (13.5 mg, 83%) as a colorless oil. [a]2D6 ˆ ‡13.6 (c ˆ 1.03, CHCl3);
1H NMR (500 MHz, CDCl3): d ˆ 0.05 (s, 9H), 0.06 (s, 3H), 0.88 (m, 21H),
1.26 1.51 (m, 30H), 1.59 1.66 (m, 1H), 1.78 1.89(m, 3H), 2.02 2.06 (m,
2H), 3.52 3.55 (m, 1H), 3.69 3.72 (m, 1H), 3.81 (td, J ˆ 7.0, 4.3 Hz, 1H),
3.88 (td, J ˆ 8.5, 6.1 Hz, 1H), 4.91 4.94 (m, 1H), 4.99 (ddd, J ˆ 17.1, 3.7,
1.8 Hz, 1H), 5.81 (tdd, J ˆ 17.1, 10.4, 6.7 Hz, 1H); 13C NMR (67.8 MHz,
CDCl3): d ˆ À4.6, À4.5, À4.24, À4.18, 14.1, 18.2, 18.3, 21.5, 22.7, 25.2, 25.5,
26.0 (6C), 26.7, 27.7, 28.9, 29.36, 29.42, 29.6 (2C), 29.7 (2C), 29.9, 31.9, 32.9,
33.8, 34.7, 73.8, 75.1, 81.9, 82.0, 114.1, 139.2; IR (KBr): nÄ ˆ 1088 cmÀ1; MS
20:1) to give 44 (243 mg, 92%) as a colorless oil. The triflate was unstable
and was therefore used immediately in the next step.
(3RS,5S)-3-[(EZ,2R)-2-(tert-Butyldimethylsilyloxy)-6-iodo-5-hexenyl]-5-
methyl-3-(phenylsulfenyl)tetrahydrofuran-2-one (45) and (5R)-5-(tert-Bu-
tyldimethylsilyloxy)-1-iodo-6-phenylsulfenyl-1-hexene (46): KHMDS
(0.5m in toluene, 6.42 mL, 3.21 mmol) was added to a stirred solution of
9 (669mg, 3.21 mmol) in THF (3 mL) at 0 8C. After 5 min, a solution of 44
(1.57 g, 3.21 mmol) in THF (3 mL) was added to the mixture at 08C. After
stirring at RT for 2 h, saturated NH4Cl was added, and the mixture was
extracted with EtOAc. The organic phase was washed with saturated
NH4Cl, water, and brine prior to drying and solvent evaporation. The
residue was purified by chromatography (hexane/EtOAc 20:1) to give 45
(1.38 g, 79%) as a colorless oil along with 46.
‡
(FAB): m/z: 624 [M‡H] ; elemental analysis calcd (%) for C37H76O3Si2: C
71.08, H 12.25; found: C 71.04, H 12.04.
Compound 45: [a]2D4 ˆ À49.9 (c ˆ 0.85, CHCl3); 1H NMR (500 MHz,
CDCl3) (major): d ˆ 0.12 (s, 3H), 0.17 (s, 3H), 0.87 (s, 9H), 1.25 (d, 3H,
J ˆ 6.1 Hz), 1.48 1.65 (m, 2H), 1.86 (dd, 1H, J ˆ 14.0, 6.7 Hz), 1.90 (dd,
2H, J ˆ 7.6, 3.1 Hz), 1.95 (td, 2H, J ˆ 7.3, 4.9Hz), 3.00 (dd, 1H, J ˆ 14.0,
7.3 Hz), 4.27 4.31 (m, 1H), 4.53 (qd, 1H, J ˆ 14.0, 6.1 Hz), 5.98 (d, 1H, J ˆ
14.6 Hz), 6.44 (td, 1H, J ˆ 14.6, 7.3 Hz), 7.34 7.44 (m, 3H), 7.53 7.58 (m,
2H); 13C NMR (75 MHz, CDCl3) (major): d ˆ À4.0 (2C), 17.9, 21.3, 25.9
(3C), 30.8, 36.7, 39.5, 41.0, 54.9, 68.3, 73.2, 75.1, 129.0 (2C), 129.7, 130.0,
136.6 (2C), 145.4, 177.2; IR (KBr): nÄ ˆ 1767 cmÀ1; MS (FAB): m/z: 547
(2RS,8R,9R,12R,13S)-8,13-Bis(tert-butyldimethylsilyloxy)-9,12-epoxypen-
tacosan-1,2-diol (21): A catalytic amount of OsO4 was added to a stirred
mixture of 20 (330 mg, 0.528 mmol) and N-methylmorpholine N-oxide
(92.8 mg, 0.792 mmol) in THF/acetone/water (1:1:1, 8 mL) at RT. After
stirring at RT for 17 h, saturated Na2S2O3 was added and the mixture was
stirred for a further 1 h. The mixture was extracted with EtOAc, and the
extract was washed with brine prior to drying and solvent evaporation. The
residue was purified by chromatography (hexane/EtOAc 1:1) to give 21
(274 mg, 79%) as a colorless oil. [a]2D5 ˆ ‡10.2 (c ˆ 1.06, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.04 (s, 3H), 0.05 (s, 6H), 0.07 (s, 3H), 0.88 (brs,
21H), 1.26 1.43 (m, 32H), 1.63 (td, J ˆ 10.4, 8.5 Hz, 1H), 1.78 1.89(m,
3H), 2.40 (brs, 2H), 3.43 (dd, J ˆ 11.0, 7.9Hz, 1H), 3.51 3.54 (m, 1H), 3.64
(dd, J ˆ 11.0, 3.1 Hz, 1H), 3.68 3.73 (m, 2H), 3.82 (td, J ˆ 7.0, 4.3 Hz, 1H),
3.88 (td, J ˆ 7.9, 6.1 Hz, 1H); 13C NMR (67.8 MHz, CDCl3): d ˆ À4.6, À4.5,
À4.3, À4.2, 14.1, 18.16, 18.22, 22.7, 25.2, 25.5, 25.6, 26.0 (9C), 26.6, 27.7, 29.3,
29.58, 29.63 (2C), 29.9, 31.9, 32.8, 33.1, 34.7, 66.8, 72.3, 73.7, 75.0, 81.9, 82.0;
‡
[M‡H] ; HRMS (FAB): m/z: calcd for C23H36IO3SSi: 547.1199; found:
‡
547.1170 [M‡H] .
Compound 46: [a]2D2 ˆ ‡38.0 (c ˆ 0.53, CHCl3); 1H NMR (300 MHz,
CDCl3) (major): d ˆ 0.00 (s, 3H), 0.03 (s, 3H), 0.87 (s, 9H), 1.58 1.71
(m, 1H), 1.75 1.88 (m, 1H), 2.01 2.21 (m, 2H), 2.91 (dd, J ˆ 13.1, 7.3 Hz,
1H), 3.03 (dd, J ˆ 13.4, 5.0 Hz, 1H), 3.76 3.88 (m, 1H), 5.98 (d, J ˆ
14.0 Hz, 1H), 6.50 (td, J ˆ 14.3, 7.0 Hz, 1H), 7.14 7.22 (m, 1H), 7.28 7.37
(m, 4H); 13C NMR (75 MHz, CDCl3) (major): d ˆ À4.7, À4.4, 18.0, 25.8
(3C), 31.5, 34.5, 40.7, 70.5, 74.8, 126.2, 128.9(2C), 129.6 (2C), 136.5, 146.0;
‡
IR (KBr): nÄ ˆ 3356 cmÀ1; MS (FAB) m/z: 660 [M‡H] ; HRMS (FAB):
‡
m/z: calcd for C37H79O5Si2: 659.5466; found: 659.5464 [M‡H] .
‡
IR (KBr): nÄ ˆ 1585, 1080 cmÀ1; MS (FAB): m/z: 455 [M‡Li] ; HRMS
‡
(8R,9R,12R,13S)-8,13-Bis(tert-butyldimethylsilyloxy)-9,12-epoxytetaraco-
sanal (22): NaIO4 (187 mg, 0.876 mmol) was added to a stirred solution of
21 (274 mg, 0.416 mmol) in CH2Cl2/acetone/water (10:6:1, 9mL) at 0 8C.
After stirring at RT for 12 h, Et2O was added to the mixture. The organic
layer was separated, dried, and evaporated. The residue was purified by
chromatography (hexane/EtOAc 3:1) to give 22 (196 mg, 75%) as a
colorless oil. The aldehyde was unstable and was therefore used immedi-
ately in the next step.
(FAB): m/z: calcd for C18H29INaOSSi: 471.0651; found: 471.0633 [M‡Na] .
(5S)-3-[(EZ,2R)-2-(tert-Butyldimethylsilyloxy)-6-iodo-5-hexenyl]-5-meth-
yl-2,5-dihydrofuran-2-one (47):
A
solution of mCPBA (10.5 mg,
0.061 mmol) in CH2Cl2 (0.6 mL) was added to a stirred solution of 45
(27.7 mg, 0.051 mmol) in CH2Cl2 (0.6 mL) at 08C. After 20 min, the mixture
was partitioned between Et2O and saturated NaHCO3. The organic layer
was separated, and washed with saturated NaHCO3 and brine prior to
drying and solvent evaporation. The residue was dissolved in toluene
(2 mL), and the mixture was stirred at 1308C for 20 min. The solvent was
concentrated under reduced pressure. The residue was purified by
chromatography (hexane/EtOAc 20:1) to give 47 (9:1 E/Z mixture,
18.8 mg, 85% in two steps) as a colorless oil. [a]2D5 ˆ ‡15.1 (c ˆ 1.33,
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.04 (s, 27³10 H), 0.05 (s, 3³10 H), 0.06
(EZ,R)-6-Iodo-5-hexene-1,2-diol (43):
A solution of 42 (97.3 mg,
0.615 mmol) and iodoform (484 mg, 1.23 mmol) in THF (6 mL) was added
to a slurry of flame-dried chromium chloride (567 mg, 4.61 mmol) in THF
(4 mL) at RT. The resulting suspension was stirred at RT for 15 h. After
water was added, the mixture was extracted with EtOAc. The organic phase
was washed with saturated Na2S2O3 and brine prior to drying and solvent
evaporation. The residue was filtered through a short plug of silica gel,
eluted with hexane/EtOAc (10:1), and the combined filtrates were
concentrated under reduced pressure. The residue was dissolved in MeOH
(4 mL), and Dowex 50W (100 mg) was added to the solution. The mixture
was stirred at RT for 4.5 h, filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography (EtOAc) to
give 43 (9:1 E/Z mixture, 85.8 mg, 58% in two steps) as a colorless oil.
[a]2D5 ˆ ‡6.8 (c ˆ 0.88, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 1.54 (q,
3
(s, 27³10 H), 0.09(s, ³10 H), 0.88 (s, 8H), 0.89(s, 1H), 1.42 (d, J ˆ 6.7 Hz, 3H),
1.53 (td, J ˆ 7.9, 6.1 Hz, 2H), 2.05 2.28 (m, 2H), 2.40 (dd, J ˆ 14.6, 5.5 Hz,
9
³10 H), 2.41 (dd, J ˆ 14.6, 5.5 Hz, 1³10 H), 2.46 (dd, 9³10 H, J ˆ 14.6, 5.5 Hz), 2.50
(dd, J ˆ 14.6, 6.1 Hz, 1³10 H), 3.97 (qn, J ˆ 5.8 Hz, 9³10 H), 4.02 (qn, J ˆ 5.8 Hz,
1
³10 H), 5.02 (qd, J ˆ 6.7, 1.2 Hz, 1H), 6.02 (td, 9³10 H, J ˆ 14.0, 1.5 Hz), 6.16
6.21 (m, 2³5 H), 6.49(td, J ˆ 14.0, 7.3 Hz, 9³10 H), 7.12 (d, J ˆ 1.2 Hz, 9³10 H), 7.15
(d, J ˆ 1.2 Hz, 1³10 H); 13C NMR (75 MHz, CDCl3) (major): d ˆ À4.6, À4.5,
17.9, 18.9, 25.8 (3C), 31.7, 32.6, 35.2, 69.2, 74.9, 77.5, 130.3, 145.8, 151.8,
173.8; (minor): d ˆ À4.6, À4.5, 17.9, 18.9, 25.8 (3C), 30.5, 32.6, 34.7, 69.4,
77.5, 82.8, 130.4, 140.6, 151.8, 173.8; IR (KBr): nÄ ˆ 1755 cmÀ1; MS (EI): m/z
9
9
J ˆ 7.3 Hz, 1H), 2.17 (qn, J ˆ 7.5 Hz, ³10 H), 2.24 (qn, J ˆ 7.8 Hz, ³10 H),
2.13 2.33 (m, 6³5 H), 3.42 3.48 (m, 1H), 3.63 3.67 (m, 1H), 3.68 3.73 (m,
‡
(%): 436 (2.3) [M] , 379(100); HRMS (EI): m/z: calcd for C17H29IO3Si:
9
1
‡
1H), 6.06 (d, J ˆ 14.6 Hz, ³10 H), 6.18 6.26 (m, ³5 H), 6.52 (td, J ˆ 14.0,
7.3 Hz, 9³10 H); 13C NMR (75 MHz, CDCl3) (major): d ˆ 31.4, 32.0, 66.5, 71.1,
75.4, 145.5; (minor): d ˆ 31.0, 31.1, 66.5, 71.5, 83.3, 140.4; IR (KBr): nÄ ˆ
436.0931; found: 436.0928 [M] .
(5S)-3-[(E,2R,7RS,13R)-2,13-Bis(tert-butyldimethylsilyloxy)-13-
[(2R,5R)-5-[(1S)-1-(tert-butyldimethylsilyloxy)tridesyl]tetrahydrofuran-2-
yl]-7-hydroxytridec-5-enyl]-5-methyl-2,5-dihydrofuran-2-one (48): CrCl2
(291 mg, 2.37 mmol) and NiCl2 (1.5 mg, 0.012 mmol) were added to a
stirred mixture of 22 (149mg, 0.237 mmol) and 47 (207 mg, 0.447 mmol) in
DMF/Me2S (2:1, 4 mL) at RT. After 20 h, EtOAc and saturated NH4Cl
were added and the mixture was stirred for 10 min. The mixture was
extracted with EtOAc, and the organic phase was washed with water and
brine prior to drying and solvent evaporation. The residue was purified by
chromatography (hexane/EtOAc 5:1) to give 48 (1:1 diastereomeric
mixture, 158 mg, 71%) and 22 (27.6 mg, 19%) each as a colorless oil.
[a]1D9 ˆ ‡16.9( c ˆ 0.93, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.02 (s,
3H), 0.03 (s, 3H), 0.035 (s, 3H), 0.039(s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.88
3331 cmÀ1; MS (EI): m/z (%): 242 (0.2) [M] , 224 (23.4) [M À H2O] , 115
‡
‡
‡
‡
(9.6) [M À I] , 97 (27.2) [M À H2O À I] , 55 (100); HRMS (EI): m/z: calcd
‡
for C6H11IO2: 241.9804; found: 241.9796 [M] .
(EZ,R)-2-(tert-Butyldimethylsilyloxy)-6-iodo-5-hexenyl trifloromethane-
sulfonate (44): Tf2O (0.106 mL, 0.647 mmol) was added to a mixture of
43 (131 mg, 0.539mmol) and 2,6-lutidine (0.314 mL, 2.70 mmol) in CH 2Cl2
(5 mL) at À508C. After 15 min, TBSOTf (0.210 mL, 0.916 mmol) was
added and the mixture was stirred for 5 min at 08C. Saturated NH4Cl was
added, and the mixture was extracted with Et2O. The extract was washed
with saturated NH4Cl, water, and brine prior to drying and solvent
evaporation. The residue was purified by chromatography (hexane/EtOAc
Chem. Eur. J. 2003, 9, No. 2
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0902-0397 $ 20.00+.50/0
397

T. Tanaka, M. Monden et al.
FULL PAPER
(brs, 30H), 1.25 1.31 (m, 32H), 1.41 (d, J ˆ 6.7 Hz, 3H), 1.49 1.58 (m,
2H), 1.62 (td, J ˆ 11.6, 8.5 Hz, 1H), 1.77 1.84 (m, 2H), 1.86 (td, J ˆ 6.7,
4.3 Hz, 1H), 2.02 2.17 (m, 2H), 2.43 2.45 (m, 2H), 3.50 3.53 (m, 1H),
3.70 (td, J ˆ 6.1, 4.3 Hz, 1H), 3.81 (td, J ˆ 7.3, 4.3 Hz, 1H), 3.87 (td, J ˆ 8.5,
6.1 Hz, 1H), 3.98 (tdd, J ˆ 11.6, 8.5, 3.1 Hz, 1H), 4.02 (q, J ˆ 6.7 Hz, 1H),
5.01 (qd, J ˆ 6.7, 1.2 Hz, 1H), 5.47 (dd, J ˆ 15.3, 7.0 Hz, 1H), 5.60 (td, J ˆ
6.7 Hz, 3H), 1.26 (brs, 30H), 1.35 1.41 (m, 4H), 1.44 (d, J ˆ 6.7 Hz, 3H),
1.46 1.51 (m, 2H), 1.56 1.65 (m, 1H), 1.82 1.94 (m, 2H), 1.97 2.02 (m,
1H), 2.38 2.43 (m, 1H), 2.40 (t, J ˆ 7.3 Hz, 2H), 2.42 (t, J ˆ 7.3 Hz, 2H),
2.52 (ddd, J ˆ 15.3, 3.1, 1.8 Hz, 1H), 3.36 3.40 (m, 1H), 3.79 3.84 (m, 2H),
3.85 3.89(m, 2H), 5.06 (qd, J ˆ 6.7, 1.2 Hz, 1H), 7.19(d, J ˆ 1.2 Hz, 1H);
13C NMR (75 MHz, CDCl3): d ˆ 14.1, 19.1, 22.7, 23.4, 23.6, 25.1, 25.2, 25.3,
26.0, 28.6, 29.2, 29.3, 29.5, 29.59, 29.63 (2C), 29.7 (2C), 31.9, 32.5, 32.9, 33.4,
37.0, 42.5, 42.7, 69.6, 71.5, 74.2, 78.0, 82.1, 83.2, 131.0, 152.0, 174.7, 211.4; IR
(KBr): nÄ ˆ 3444, 1767, 1755, 1743, 1703 cmÀ1; MS (EI): m/z (%): 325, 307,
1
1
15.9, 6.7 Hz, 1H), 7.12 (d, J ˆ 1.2 Hz, ³2 H), 7.13 (d, J ˆ 1.2 Hz, ³2 H);
13C NMR (75 MHz, CDCl3): d ˆ À4.6, À4.5, À4.4 (2C), À4.24, À4.19, 14.1,
18.0, 18.17, 18.24, 18.9(0.5C), 19.0 (0.5C), 22.7, 25.2, 25.5, 25.6, 25.7, 25.8
(3C), 25.97 (3C), 25.99 (3C), 26.7, 27.7, 27.9, 29.3, 29.59, 29.64 (2C), 29.7
(2C), 29.9, 31.9, 32.6 (0.5C), 32.7 (0.5C), 32.9, 34.7, 36.2, 37.3, 69.5 (0.5C),
69.6 (0.5C), 73.0 (0.5C), 73.0 (0.5C), 73.7, 75.1, 77.5, 81.9, 82.0, 130.6 (0.5C),
130.7 (0.5C), 131.1 (0.5C), 131.2 (0.5C), 133.5 (0.5C), 133.6 (0.5C), 151.7,
‡
289, 225, 207; MS (FAB): m/z: 59 5 [M‡H] 595; HRMS (FAB): m/z: calcd
‡
for C35H63O7: 595.4574; found: 595.4556 [M‡H] .
(5S)-3-[(E,2R,7RS,13S)-2,13-Bis(tert-butyldimethylsilyloxy)-13-[(2S,5S)-
5-[(1R)-1-(tert-butyldimethylsilyloxy)tridesyl]tetrahydrofuran-2-yl]-7-hy-
droxytridec-5-enyl]-5-methyl-2,5-dihydrofuran-2-one (51): The procedure
was the same as that used for preparation of 48. [a]2D8 ˆ À0.16 (c ˆ 1.01,
‡
174.0; IR (KBr): nÄ ˆ 3502, 1759cm À1; MS (FAB): m/z: 960 [M‡Na] ;
HRMS (FAB): m/z: calcd for C53H104NaO7Si3: 959.6987; found: 959.6962
‡
[M‡Na] .
1
CHCl3); H NMR (500 MHz, CDCl3): d ˆ 0.01 (s, 3H), 0.02 (s, 3H), 0.025
(s, 3H), 0.030 (s, 3H), 0.04 (s, 3H), 0.05 (s, 3H), 0.86 (brs, 30H), 1.23 1.30
(m, 32H), 1.40 (d, 3H, J ˆ 6.7 Hz), 1.49 1.56 (m, 2H), 1.61 (td, J ˆ 11.0,
8.9Hz, 1H), 1.76 1.87 (m, 3H), 2.01 2.16 (m, 2H), 2.42 2.44 (m, 2H),
3.49 3.51 (m, 1H), 3.68 3.71 (m, 1H), 3.80 (td, J ˆ 7.0, 4.3 Hz, 1H), 3.86
(td, J ˆ 7.9, 6.1 Hz, 1H), 3.94 3.99 (m, 1H), 4.02 (td, 1H, J ˆ 6.7, 3.1 Hz),
5.00 (qd, J ˆ 6.7, 1.2 Hz, 1H), 5.46 (dd, J ˆ 15.3, 7.0 Hz, 1H), 5.59(td, J ˆ
(5S)-3-[(E,2R,13R)-2,13-Bis(tert-butyldimethylsilyloxy)-13-[(2R,5R)-5-
[(1S)-1-(tert-butyldimethylsilyloxy)tridesyl]tetrahydrofuran-2-yl]-7-oxo-
tridec-5-enyl]-5-methyl-2,5-dihydrofuran-2-one (49): SO3 ¥ pyridine com-
plex (58.6 mg, 0.368 mmol) was added to a mixture of 48 (86.3 mg,
0.092 mmol), DMSO (52.2 mL, 0.736 mmol), and Et3N (0.154 mL,
1.10 mmol) in CH2Cl2 (0.3 mL) at 08C. After stirring at RT for 4 h, water
was added to the reaction mixture. The mixture was extracted with EtOAc,
and the organic phase was washed with water and brine prior to drying and
solvent evaporation. The residue was purified by chromatography (hexane/
EtOAc 5:1) to give 49 (61.7 mg, 72%) as a colorless oil. [a]2D5 ˆ ‡13.8 (c ˆ
1
1
14.6, 6.7 Hz, 1H), 7.11 (d, J ˆ 1.2 Hz, ³2 H), 7.12 (d, J ˆ 1.2 Hz, ³2 H);
13C NMR (75 MHz, CDCl3): d ˆ À4.6, À4.53 (2C), À4.47, À4.3, À4.2, 14.1,
18.0, 18.1, 18.2, 18.89(0.5C), 18.92 (0.5C), 22.6, 25.1, 25.47, 25.48, 25.6, 25.8
(3C), 25.9 (3C), 26.0 (3C), 26.6, 27.7, 27.9, 29.3, 29.56 (2C), 29.61 (2C),
29.64, 29.9, 31.9, 32.6 (0.5C), 32.7 (0.5C), 32.8, 34.7, 36.2, 37.2, 69.4 (0.5C),
69.6 (0.5C), 72.9 (0.5C), 73.0 (0.5C), 73.7, 75.1, 77.5, 81.9, 82.0, 130.5 (0.5C),
130.6 (0.5C), 131.0 (0.5C), 131.1 (0.5C), 133.5 (0.5C), 133.6 (0.5C), 151.7,
1
0.26, CHCl3); H NMR (500 MHz, CDCl3): d ˆ 0.01 (s, 3H), 0.02 (s, 3H),
0.038 (s, 3H), 0.044 (s, 3H), 0.05 (s, 3H), 0.07 (s, 3H), 0.86 0.89(m, 30H),
1.25 1.31 (m, 30H), 1.43 (d, J ˆ 7.3 Hz, 3H), 1.57 1.63 (m, 3H), 1.78 1.87
(m, 3H), 2.22 2.36 (m, 2H), 2.44 (d, 1H, J ˆ 6.1 Hz), 2.48 (d, 1H, J ˆ
6.1 Hz), 2.52 (t, J ˆ 7.3 Hz, 2H), 3.50 3.54 (m, 1H), 3.71 (td, J ˆ 6.1, 4.3 Hz,
1H), 3.81 (td, J ˆ 7.3, 4.3 Hz, 1H), 3.87 (td, J ˆ 7.9, 5.5 Hz, 1H), 4.02 (qn,
J ˆ 5.5 Hz, 1H), 5.02 (qd, J ˆ 6.7, 1.2 Hz, 1H), 6.09(d, J ˆ 15.9Hz, 1H),
6.80 (td, J ˆ 15.9, 6.7 Hz, 1H), 7.13 (d, J ˆ 1.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d ˆ À4.63, À4.57, À4.53, À4.47, À4.3, À4.2, 14.1, 17.9, 18.1, 18.2,
18.9, 22.6, 24.1, 25.1, 25.5, 25.8, 25.9 (4C), 26.0 (5C), 26.6, 27.6, 28.0, 29.3,
29.55 (2C), 29.59, 29.60, 29.63, 29.9, 31.9, 32.67, 32.71, 34.7, 35.0, 40.1, 69.4,
73.7, 75.0, 77.5, 81.8, 82.0, 130.3, 130.4, 146.3, 151.8, 173.8, 200.6; IR (KBr):
‡
174.0; IR (KBr): nÄ ˆ 3437, 1759cm À1; MS (FAB): m/z: 960 [M‡Na] ;
HRMS (FAB): m/z: calcd for C53H104NaO7Si3: 959.6987; found: 959.6963
‡
[M‡Na] .
(5S)-3-[(E,2R,13S)-2,13-Bis(tert-butyldimethylsilyloxy)-13-[(2S,5S)-5-
[(1R)-1-(tert-butyldimethylsilyloxy)tridesyl]tetrahydrofuran-2-yl]-7-oxo-
tridec-5-enyl]-5-methyl-2,5-dihydrofuran-2-one (52): The procedure was
the same as that used for preparation of 49. [a]2D7 ˆ À1.6 (c ˆ 0.58, CHCl3);
1H NMR (500 MHz, CDCl3): d ˆ 0.02 (s, 3H), 0.025 (s, 6H), 0.031 (s, 3H),
0.05 (s, 6H), 0.86 (brs, 30H), 1.24 1.31 (m, 30H), 1.40 (d, J ˆ 6.7 Hz, 3H),
1.55 1.63 (m, 3H), 1.76 1.87 (m, 3H), 2.19 2.34 (m, 2H), 2.41 (dd, J ˆ
14.0, 5.5 Hz, 1H), 2.46 (d, 1H, J ˆ 5.5 Hz), 2.50 (t, 2H, J ˆ 7.3 Hz), 3.49
3.52 (m, 1H), 3.69(td, J ˆ 6.1, 4.3 Hz, 1H), 3.79(td, J ˆ 7.3, 4.3 Hz, 1H),
3.85 (td, J ˆ 7.9, 6.1 Hz, 1H), 4.00 (qn, J ˆ 5.5 Hz, 1H), 5.00 (qd, J ˆ 6.7,
1.2 Hz, 1H), 6.07 (d, J ˆ 15.9Hz, 1H), 6.78 (td, J ˆ 15.3, 6.7 Hz, 1H), 7.12
(d, J ˆ 1.2 Hz, 1H); 13C NMR (67.8 MHz, CDCl3): d ˆ À4.5, À4.40, À4.37,
À4.3, À4.12, À4.06, 14.2, 18.1, 18.2, 18.3, 19.0, 22.7, 24.2, 25.2, 25.6, 25.8
(3C), 26.0 (3C), 26.1 (3C), 26.7, 27.7, 28.1, 29.4, 29.6 (2C), 29.68 (2C), 29.72
(2C), 29.9, 32.0, 32.79, 32.81, 34.8, 35.1, 40.2, 69.4, 73.7, 75.0, 77.5, 81.8, 82.0,
130.2, 130.3, 146.2, 151.6, 173.6, 200.4; IR (KBr): nÄ ˆ 1759, 1697 cmÀ1; MS
‡
nÄ ˆ 1759, 1697 cmÀ1; MS (FAB): m/z: 958 [M‡Na] ; HRMS (FAB): m/z:
‡
calcd for C53H102NaO7Si3: 957.6831; found: 957.6827 [M‡Na] .
(5S)-3-[(2R,13R)-2,13-Bis(tert-butyldimethylsilyloxy)-13-[(2R,5R)-5-
[(1S)-1-(tert-butyldimethylsilyloxy)tridesyl]tetrahydrofuran-2-yl]-7-oxo-
tridecyl]-5-methyl-2,5-dihydrofuran-2-one (50): [(Ph3P)3RhCl] (28.4 mg,
0.031 mmol) was added to a solution of 49 (57.2 mg, 0.061 mmol) in
benzene (0.6 mL). The mixture was stirred under H2 at RT for 27 h. The
solution was purified by chromatography (hexane/EtOAc 5:1) to give 50
(44.5 mg, 78%) as a colorless oil. [a]2D6 ˆ ‡11.9( c ˆ 0.55, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.02 (s, 3H), 0.038 (s, 3H), 0.044 (s, 6H), 0.05 (s,
3H), 0.06 (s, 3H), 0.88 (brs, 30H), 1.26 1.40 (m, 32H), 1.42 (d, J ˆ 6.7 Hz,
3H), 1.53 1.68 (m, 5H), 1.78 1.81 (m, 1H), 1.83 (td, J ˆ 6.7, 4.3 Hz, 1H),
1.87 (td, J ˆ 6.1, 4.3 Hz, 1H), 2.376 (t, J ˆ 7.3 Hz, 2H), 2.382 (t, J ˆ 7.3 Hz,
2H), 2.41 (dd, J ˆ 2.4, 1.2 Hz, 1H), 2.42 (dd, J ˆ 3.1, 1.2 Hz, 1H), 3.50 3.55
(m, 1H), 3.71 (td, J ˆ 6.1, 4.0 Hz, 1H), 3.81 (td, J ˆ 7.3, 4.3 Hz, 1H), 3.87 (td,
J ˆ 8.5, 6.1 Hz, 1H), 3.95 (qn, J ˆ 5.5 Hz, 1H), 5.01 (qd, J ˆ 6.7, 1.2 Hz, 1H),
7.12 (d, J ˆ 1.2 Hz, 1H); 13C NMR (67.8 MHz, CDCl3): d ˆ À4.6 (2C), À4.5
(2C), À4.3, À4.2, 14.1, 18.0, 18.1, 18.2, 18.9, 22.6, 23.8, 23.9, 24.7, 25.1, 25.4,
25.8 (4C), 25.9 (5C), 26.6, 27.7, 29.3, 29.56 (3C), 29.60 (3C), 29.9, 31.9, 32.6,
32.7, 34.7, 36.7, 42.6, 42.8, 69.9, 73.7, 75.0, 77.5, 81.8, 82.0, 130.7, 151.5, 173.9,
‡
(FAB): m/z: 958 [M‡Na] ; HRMS (FAB): m/z: calcd for C53H102NaO7Si3:
‡
957.6831; found: 957.6830 [M‡Na] .
(5S)-3-[(2R,13S)-2,13-Bis(tert-butyldimethylsilyloxy)-13-[(2S,5S)-5-[(1R)-
1-(tert-butyl-dimethylsilyloxy)tridesyl]tetrahydrofuran-2-yl]-7-oxotridec-
yl]-5-methyl-2,5-dihydrofuran-2-one (53): The procedure was the same as
that used for preparation of 50. [a]2D5 ˆ À1.9( c ˆ 0.57, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.01 (s, 3H), 0.026 (s, 6H), 0.032 (s, 6H), 0.05 (s,
3H), 0.87 (brs, 30H), 1.24 1.47 (m, 32H), 1.40 (d, J ˆ 6.7 Hz, 3H), 1.51
1.63 (m, 5H), 1.77 1.87 (m, 3H), 2.365 (t, J ˆ 7.3 Hz, 2H), 2.371 (t, J ˆ
7.3 Hz, 2H), 2.40 2.41 (m, 2H), 3.49 3.53 (m, 1H), 3.68 3.71 (m, 1H),
3.80 (td, J ˆ 7.0, 4.3 Hz, 1H), 3.85 (td, J ˆ 8.5, 6.1 Hz, 1H), 3.94 (qn, J ˆ
5.5 Hz, 1H), 5.00 (qd, J ˆ 6.7, 1.2 Hz, 1H), 7.11 (d, 1H, J ˆ 1.2 Hz);
13C NMR (75 MHz, CDCl3): d ˆ À4.6, À4.5 (3C), À4.3, À4.2, 14.1, 18.0,
18.1, 18.2, 18.9, 22.7, 23.8, 23.9, 24.7, 25.1, 25.5, 25.8 (3C), 25.9 (3C), 26.0
(3C), 26.6, 27.6, 29.3, 29.5, 29.56 (2C), 29.62 (2C), 29.6, 29.9, 31.9, 32.6, 32.7,
34.7, 36.7, 42.7, 42.8, 69.9, 73.7, 75.0, 77.5, 81.8, 82.0, 130.7, 151.6, 174.0, 211.2;
‡
211.1; IR (KBr): nÄ ˆ 1759, 1716 cmÀ1; MS (FAB): m/z: 960 [M‡Na] ;
HRMS (FAB): m/z: calcd for C53H104NaO7Si3: 959.6988; found: 959.6993
‡
[M‡Na] .
(5S)-3-[(2R,13R)-2,13-Dihydroxy-13-[(2R,5R)-5-[(1S)-1-hydroxytridesyl]-
tetrahydrofuran-2-yl]-7-oxotridecyl]-5-methyl-2,5-dihydrofuran-2-one
(1a): Four drops of 48% aqueous HF was added to a stirred solution of 50
(84.9mg, 0.091 mmol) in MeCN/THF (1.5:1, 1.5 mL) at RT. After stirring
at RT for 2.5 h, the reaction mixture was partitioned between CH2Cl2 and
brine. The organic layer was separated and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed with brine prior to
drying and solvent evaporation. The residue was purified by chromatog-
‡
IR (KBr): nÄ ˆ 1759, 1714 cmÀ1; MS (FAB): m/z: 960 [M‡Na] ; HRMS
(FAB): m/z: calcd for C53H104NaO7Si3: 959.6988; found: 959.6981
‡
[M‡Na] .
(5S)-3-[(2R,13S)-2,13-Dihydroxy-13-[(2S,5S)-5-[(1R)-1-hydroxytridesyl]-
tetrahydrofuran-2-yl]-7-oxotridecyl]-5-methyl-2,5-dihydrofuran-2-one
(1b): The procedure was the same as that used for preparation of 1a.
[a]2D6 ˆ ‡2.2 (c ˆ 0.39, CH2Cl2); 1H NMR (500 MHz, CDCl3): d ˆ 0.86 (t,
raphy (EtOAc) to give 1a (39.0 mg, 72%) as a white waxy solid. [a]D25
ˆ
‡18.7 (c ˆ 0.50, CH2Cl2); 1H NMR (500 MHz, CDCl3): d ˆ 0.88 (t, J ˆ
398
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Chem. Eur. J. 2003, 9, No. 2

Antitumor Acetogenin Mosin B
389 399
¬
ƒ
J ˆ 7.0 Hz, 3H), 1.23 (brs, 30H), 1.33 1.38 (m, 4H), 1.41 (d, J ˆ 6.7 Hz,
3H), 1.45 1.49 (m, 2H), 1.51 1.64 (m, 1H), 1.79 1.92 (m, 2H), 1.94 2.00
(m, 1H), 2.29(br, 1H), 2.38 (t, J ˆ 7.3 Hz, 2H), 2.39(t, J ˆ 7.3 Hz, 2H),
2.36 2.41 (m, 1H), 2.47 2.51 (m, 1H), 2.56 (br, 1H), 2.72 (br, 1H), 3.34
3.38 (m, 1H), 3.76 3.83 (m, 2H), 3.84 3.87 (m, 2H), 5.04 (qd, J ˆ 6.7,
1.2 Hz, 1H), 7.18 (d, J ˆ 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 14.1,
19.0, 22.6, 23.4, 23.6, 25.1, 25.16, 25.23, 26.0, 28.5, 29.1, 29.3, 29.5, 29.55,
29.59 (2C), 29.61, 29.64, 31.9, 32.5, 32.9, 33.3, 37.0, 42.5, 42.6, 69.5, 71.5, 74.2,
78.0, 82.2, 83.2, 131.0, 152.0, 174.6, 211.4; IR (KBr): nÄ ˆ 3439, 1740, 1720,
1716, 1705 cmÀ1; MS (EI): m/z: 325, 307, 289, 225, 207; MS (FAB): m/z: 59 5
[6] J. M. Seco, E. Quinoa, R. Riguera, Tetrahedron: Asymmetry 2000, 11,
2781 2791.
[7] a) N. Maezaki, A. Sakamoto, N. Nagahashi, M. Soejima, Y.-X. Li, T.
Imamura, N. Kojima, H. Ohishi, K. Sakaguchi, C. Iwata, T. Tanaka, J.
Org. Chem. 2000, 65, 3284 3291; b) N. Maezaki, A. Sakamoto, M.
Soejima, I. Sakamoto, Y.-X. Li, T. Tanaka, H. Ohishi, K. Sakaguchi, C.
Iwata, Tetrahedron: Asymmetry 1996, 7, 2787 2790.
[8] N. Maezaki, N. Kojima, A. Sakamoto, C. Iwata, T. Tanaka, Org. Lett.
2001, 3, 429 432.
[9] a) H. Zhang, M. Seepersaud, S. Seepersaud, D. R. Mootoo, J. Org.
Chem. 1998, 63, 2049 2052; b) H. Zhang, D. R. Mootoo, J. Org.
Chem. 1995, 60, 8134 8135.
[10] J. D. White, T. C. Somers, G. N. Reddy, J. Org. Chem. 1992, 57, 49 9 1
4998.
[11] K. Mori, H. Watanabe, Tetrahedron 1986, 42, 295 304.
[12] H. Hayashi, K. Nakanishi, C. Brandon, J. Marmur, J. Am. Chem. Soc.
1973, 95, 8749 8757.
‡
[M‡H] ; HRMS (FAB): m/z: calcd for C35H63O7: 595.4574; found:
‡
595.4561 [M‡H] .
Biological assay: The two human pancreatic cancer cell lines, PaCa-2 and
PSN-1, were purchased from the Japanese Cancer Research Resources
Bank (Tokyo, Japan). The KMP-5 cell line was a gift from Prof. M.
Imamura (Kyoto University, Kyoto, Japan).[29] They were maintained in
Dulbecco×s Modified Eagle Medium supplemented with 10% fetal bovine
serum, 100 unitsmLÀ1 penicillin and 100 mgmLÀ1 streptomycin at 378C in a
humidified incubator with 5% CO2 in air.
[13] Y. Araki, T. Konoike, J. Org. Chem. 1997, 62, 5299 5309.
[14] H. Naito, E. Kawahara, K. Maruta, M. Maeda, S. Sasaki, J. Org. Chem.
1995, 60, 4419 4427.
Growth inhibitory assays: Cells with a density of 3 Â 103 per well were
added in triplicate to a 96-well microplate. After 24 h, the medium was
replaced by fresh medium (0.1 mL) containing various concentrations of
mosin B (1a), its diastereomer 1b, or adriamycin. The concentrations of 1a
and 1b tested were 0.0002 0.05 mgmLÀ1; those of adrimycin were 0.001
1 mgmLÀ1. Tumor cells suspended in complete medium were used as a
control for cell viability. The medium was changed every 72 h, and 3 or 6 d
after the addition of drugs, the numbers of viable cells were assessed by
MTT (Sigma Co, St.Louis, MO) assay. Briefly, 10 mL (50 mg) of MTT was
added to each well. The plate was incubated for 4 h at 378C. Unreacted
MTT was then removed, leaving the resultant formazan crystals at the
bottom of the well. Then, 2-propanol (0.1 mL) was added to each well to
dissolve the crystals. The absorbance of the plate was measured in a
microplate reader at a wavelength of 570 nm. These assays were repeated
four times, and similar results were obtained.
[15] In the presence of CuI, the epoxide 18 was opened by iodide to give an
iodohydrin rather than the coupling product 19.
[16] Y. Fujimoto, C. Murasaki, H. Shimada, S. Nishioka, K. Kakinuma, S.
Singh, M. Singh, Y. Gupta, M. Sahai, Chem. Pharm. Bull. 1994, 42,
1175 1184.
[17] a) S. E. Schaus, J. Branalt, E. N. Jacobsen, J. Org. Chem. 1998, 63,
4876 4877; b) H. Avedissian, S. C. Sinha, A. Yazbak, A. Sinha, P.
Neogi, S. C. Sinha, E. Keinan, J. Org. Chem. 2000, 65, 6035 6051.
[18] In this coupling reaction, we observed a by-product in which SPh was
substituted for the iodide.
[19] T. Shimizu, S. Hiranuma, T. Nakata, Tetrahedron Lett. 1996, 37, 6145
6148.
[20] During the course of our study, Kitahara reported another solution
employing a less hindered MeS group instead of a PhS group as an
anion-stabilizing group: a) W.-Q. Yang, T. Kitahara, Tetrahedron Lett.
1999, 40, 7827 7830; b) W.-Q. Yang, T. Kitahara, Tetrahedron 2000,
56, 1451 1461.
[21] a) H. Jin, J. Uenishi, W. J. Christ, Y. Kishi, J. Am. Chem. Soc. 1986,
108, 5644 5646; b) K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K.
Utimoto, H. Nozaki, J. Am. Chem. Soc. 1986, 108, 6048 6050.
[22] A. B. Smith, III, T. A. Rano, N. Chida, G. A. Sulikowski, J. L. Wood, J.
Am. Chem. Soc. 1992, 114, 8008 8022.
The inhibitory activities (ED50, mgmLÀ1) of mosin B, its diastereomer, and
adriamycin against used cell growth were evaluated by using the growth-
inhibitory curves and the results represent the averages from four
independent experiments.
Acknowledgement
[23] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108, 7408
7410.
[24] Y. Mori, T. Sawada, H. Furukawa, Tetrahedron Lett. 1999, 40, 731
734.
We thank Prof. J. L. McLaughlin and Dr. D. C. Hopp for providing spectral
data of mosin B.
[25] M. Rowley, M. Tsukamoto, Y. Kishi, J. Am. Chem. Soc. 1989, 111,
2735 2737.
[1] For reviews of annonaceous acetogenins, see: a) F. Q. Alali, X.-X. Liu,
J. L. McLaughlin, J. Nat. Prod. 1999, 62, 504 540; b) L. Zeng, Q. Ye,
N. H. Oberlies, G. Shi, Z.-M. Gu, K. He, J. L. McLaughlin, Nat. Prod.
Rep. 1996, 13, 275 306; c) J. K. Rupprecht, Y.-H. Hui, J. L. McLaugh-
[26] Although a 9:1 mixture of (E/Z)-45 isomers was used for the Nozaki
Hiyama Kishi reaction, the coupling reaction gave only the E allylic
alcohol 46 presumably due to E/Z isomerization of the organo-
chromium reagent and the low reactivity of the Z isomer.
[27] S. C. Sinha, S. C. Sinha, E. Keinan, J. Org. Chem. 1999, 64, 7067 7073.
[28] McLaughlin and co-workers reported that the ED50 value of mosin B
against PaCa-2 cells was 72-fold higher than that of adriamycin
(ref. [4]). The discrepancy from our results was probably caused by a
difference in the passage of cancer cells or in the bioassay protocol.
However, we cannot prove this at the present time, since the natural
mosin B is not available.
¬
¬
lin, J. Nat. Prod. 1990, 53, 237 278; d) A. Cave, B. Figadere, A.
Laurens, D. Cortes, Progress in the Chemistry of Organic Natural
Products: Acetogenins from Annonaceae, Vol. 70 (Ed.: W. Herz),
Springer, New York, 1997, pp. 81 288.
[2] E. Wolvetang, K. L. Johnson, K. Kramer, A. W. Linnane, FEBS Lett.
1994, 339, 40 44.
[3] N. H. Oberlies, V. L. Croy, M. L. Harrison, J. L. McLaughlin, Cancer
Lett. 1997, 15, 73 79.
[4] D. C. Hopp, L. Zeng, Z.-M. Gu, J. F. Kozlowski, J. L. McLaughlin, J.
Nat. Prod. 1997, 60, 581 586.
[29] M. Kato, Y. Shimada, H. Tanaka, R. Hosotani, G. Ohshio, K. Ishizaki,
M. Imamura, Cancer 1999, 85, 832 840.
[5] For recent total syntheses of mono-THF acetogenins, see: H. Makabe,
Y. Hattori, A. Tanaka, T. Oritani, Org. Lett. 2002, 4, 1083 1085 and
references therein.
Received: September 16, 2002 [F4425]
Chem. Eur. J. 2003, 9, No. 2
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0902-0399 $ 20.00+.50/0
399