Synthesis of all possible isomers corresponding to the proposed structure of montanacin E, and their antitumor activity

Article abstract of DOI:10.1021/jo901150h

(Chemical Equation Presented) Total synthesis of 4 and its three diastereomers is described. The key steps involve stereoselective formation of the tetrahydrofuran ring by a cascade cyclization of hydroxy tosylate 7 and an intermolecular cross metathesis

Full text of DOI:10.1021/jo901150h

pubs.acs.org/joc
mono-THF, the adjacent bis-THF, and the nonadjacent bis-
Synthesis of All Possible Isomers Corresponding to
the Proposed Structure of Montanacin E, and Their
Antitumor Activity
THF acetogenins. Recently, several nonclassical acetogenins
have been discovered bearing a tetrahydropyran (THP) ring.2
Shunya Takahashi,*,† Ryotaro Takahashi,† Yayoi Hongo,†
Hiroyuki Koshino,† Kazunori Yamaguchi,‡ and
Taeko Miyagi‡
†RIKEN, Wako, Saitama 351-0198, Japan, and ‡Division of
Biochemistry, Miyagi Cancer Center Research Institute,
Natori 981-1293, Japan.
shunyat@riken.jp
Received May 31, 2009
FIGURE 1. Structures of acetogenins from Annona montana.
Montanacin E was isolated as a minor component from
the ethanolic extract of the leaves of Annona montana along
with montanacins C (2) and D (3).3 The structure of mon-
tanacin E was elucidated by spectroscopic methods to be
1 possessing a 4,8-cis THP ring4 along with a 16,19-cis THF
ring (Figure 1).5 The relative stereochemistry from C-15 to
C-20 was suggested to be threo/cis/threo by comparison
of the NMR data of 2. However, the absolute configuration
of the cyclic ether moieties in 1 was not determined because
of the lack of a sufficient amount of sample.6 The antitumor
activity was also not evaluated although 1 showed significant
cytotoxic activity in a brine shrimp lethality test. As part of
our continuing efforts toward synthesis of anticancer THP
acetogenins,7 we describe here total synthesis of all possible
isomers corresponding to the proposed structure of monta-
nacin E, and their antitumor activities.
Total synthesis of 4 and its three diastereomers is de-
scribed. The key steps involve stereoselective formation
of the tetrahydrofuran ring by a cascade cyclization of
hydroxy tosylate 7 and an intermolecular cross metathesis
between a tetrahydrofuran 5 and a γ-lactone 6. Spectro-
scopic data of 4 and biosynthetic hypothesis strongly
suggest it to be montanacin E. Inhibitory activities of
4 and its isomers against six human solid tumor cell lines
were also evaluated.
(3) (a) Wang, L.-Q.; Zhao, W.-M.; Qin, G.-W.; Cheng, K.-F.; Yang,
R.-Z. Nat. Prod. Lett. 1999, 14, 83–90. (b) Wang, L.-Q.; Nakamura, N.;
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G.-W. Chem. Pharm. Bull. 2000, 48, 1109–1113.
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Hwang, C. H.; Keum, G.; Sohn, K.; Lee, D. H.; Lee, E. Tetrahedron Lett.
The rapidly expanding family of annonaceous acetogenins
from the Annonaceae plants has recently attracted much
attention because of a remarkably broad spectrum of biologi-
cal properties such as anticancer, antiinfective, immunosup-
pressive, pesticidal, and antifeedant activities.1 Structurally,
most of these compounds belong to several classic types
with an unsubstituted tetrahydrofuran (THF) ring: the
€
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(5) The numbering system of the carbon follows the one employed in ref 3.
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mainly determined by the modified Mosher’s method: Ohtani, I.; Kusumi,
T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4093.
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shi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025–2028. (d)
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S.; Hongo, Y.; Tsukagoshi, Y.; Koshino, H. Org. Lett. 2008, 10, 4223–4226.
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Published on Web 07/10/2009
DOI: 10.1021/jo901150h
r
2009 American Chemical Society

Takahashi et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis of Acetogenin 45
SCHEME 2. Synthesis of THF Segment 5
In an analogy with the case of montanacin D (3), we
hypothesized that montanacin E might be biosynthetically
obtained from 2. Hence we initially started synthesis of
4 with the stereochemistry of 4R,8S,15R,20S. Our synthetic
strategy directed toward 4 was based on a convergent process
that involved intermolecular metathesis8 of olefin 5 and
enone 67l as illustrated in Scheme 1. The THF ring in 5 might
be constructed by an intramolecular cascade cyclization
of tosylate 7. Oxidative cleavage of the one-carbon unit in
7 leads to γ-lactone 8. This would be obtained by the
Sharpless AD reaction9 with unsaturated ester 9. By chan-
ging the chiral reagent, preparation of ent-5 is also feasible.
Since we have already developed the method for preparation
of 6 and its diastereomer 21, this strategy also enables us to
synthesize diastereomers of 4 in regard to the cyclic-ether
moieties easily.
Synthesis of 5 began with preparation of lactone 10 by
Sinha and Keinan’s method (Scheme 2).10 The hydroxyl
groups in 10 were protected as methoxymethyl (MOM)
ether. The MOM ether 8 obtained was treated with DI-
BAL-H and the resulting hemiacetal was reacted with
methylenetriphenyl phosphorane to give olefin 11. Sulfony-
lation of 11 with p-TsCl and triethylamine in the presence
of DMAP gave the corresponding tosylate 12. Upon treat-
ment with HCl in methanol-dichloromethane, 12 afforded
7, which was treated with sodium methoxide in methanol.
The key cyclization proceeded nicely to provide THF ether
13 in good yield. Both hydroxyl groups in 13 were silylated,
giving bis TBS ether 5.
gave 4 after treatment with HF pyridine complex in good
3
overall yield.
After establishing the method for the synthesis of 4,
we next turned to preparation of other diastereomers of
4. Initially, ent-5 was synthesized from ent-1010 according to
the method described above. The coupling reaction of ent-5
with 6 led to 15. Hydrogenation of 15 afforded 17 from which
18 was synthesized through a butenolide formation and
deprotection reaction. Similarly, both 5 and ent-5 were
coupled with lactone 21,7l giving 22 and 23, respectively
(Scheme 4). These compounds were transformed into a
couple of acetogenins 26 and 27 via 24 and 25, respectively.
The four isomers thus obtained were submitted to exten-
sive NMR analyses and the results are shown in Table 1. The
1H and 13C NMR data of both 4 and 18 were consistent with
those reported for montanacin E. On the other hand, the
data of 26 and 27 were not so consistent. The characteristic
difference is in the chemical shift of protons in the terminal
1
butenolide residue: the H NMR spectra of 26 and 27 in
CDCl3 showed an olefinic proton of C-33 at 7.17 ppm,
whereas H-33 of the natural montanacin E was observed
at δ 7.14. The methyl group at C-34 of 26 and 27 showed
a slight upfield shift rather than that of natural montanacin
E (1.38 ppm vs. 1.41 ppm). Since we could not discriminate
1
between 4 and 18 in the H and 13C NMR spectra,11 the
corresponding MTPA derivatives 19 and 20 were prepared.
As shown in Table 1, each MTPA ester showed clearly
different spectra. It should be mentioned that the chemical
shifts of H-15-21, -33, and -34 were markedly different.
Due to the unavailability of natural product,12 a direct
comparison of our samples with a natural type was impos-
sible. If derivation of a natural sample into the correspond-
ing MTPA ester is possible, an unambiguous assignment of
absolute stereochemistry of montanacin E can be performed.
Construction of the complete carbon backbone was
accomplished by our previously reported method.7l Thus,
a mixture of 5 and enone 6 in dichloromethane was heated
at 40 °C in the presence of Grubbs catalyst second generation
to give E-olefin 14 in high yield (Scheme 3). This compound
was hydrogenated over 5% PtO2 to provide ketone 16.
Oxidation of the SPh group followed by elimination reaction
(8) Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH: New York,
2003; Vols. 1-3.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547.
(10) Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 115, 4891–4892.
(11) Comparison of [R]D between 4 or 18 and natural montanacin E
provided no reliable information because of the small values and low
concentrations reported.
(12) Private communication from Prof. G. W. Qin.
J. Org. Chem. Vol. 74, No. 16, 2009 6383

Takahashi et al.
SCHEME 4. Total Synthesis of Acetogenins 26 and 275
JOCNote
SCHEME 3. Total Synthesis of Acetogenins 4 and 185
However, we propose that natural montanacin E might be 4
rather than 18 based on the standpoint of biosynthesis.
The antitumor activities of 3, 4, 18, 26, 27, and the 4S,
8R-epimer 287l of 3 were evaluated. As shown in Table 2, all
compounds employed showed significant cytotoxicity to-
ward six human solid tumor cell lines13 with adriamycin as
the positive control. No remarkable difference of inhibitory
activity between 4 and 18 was observed.
In conclusion, the synthesis of all possible isomers corre-
sponding to montanacin E was achieved. The analysis of the
data allowed diastereomers 26 and 27 to be eliminated, and
that biosynthetic considerations favored structure 4 as the
natural product.
J=15.9, 6.8 Hz), 6.08 (1H, d, J=15.9 Hz), 4.37 (1H, m), 3.89 (1H,
m), 3.85-3.75 (2H, m), 3.73 (1H, m), 3.66 (1H, m), 3.61 (1H, m),
2.79 (1H, dd, J=16.4, 7.6 Hz), 2.76 (1H, J=14.2, 7.6 Hz), 2.46
(1H, J=16.4, 4.9 Hz), 2.35 (1H, m), 2.24 (1H, m), 2.00 (1H, dd,
J=14.2, 10.0 Hz), 1.85-1.20 (36H, m), 1.18 (3H, d, J=6.1 Hz),
0.88 (9H, s), 0.87 (12H, m), 0.07 (3H, s), 0.06 (3H, s), 0.04 (6H, s);
13C NMR (125 MHz, CDCl3) δ 198.5, 177.6, 148.2, 137.0, 130.8,
130.4, 129.7, 128.9, 81.7, 81.5, 74.3, 74.2, 74.0, 73.8, 73.2, 54.4,
45.8, 41.6, 38.6, 32.8, 31.9, 31.3, 31.2, 30.9, 29.8, 29.7, 29.6,
29.3, 28.8, 26.9, 26.8, 25.9, 25.7, 23.4, 22.7, 21.3, 18.2, 18.1, 14.1,
-4.2, -4.3, -4.6, -4.7; HRMS (ESI) calcd for C53H92O7Si2SNa
[M+Na]+ 951.6000, found 951.5959.
(3S,5S,20R,60S,130R,140R,170S,180S)-[130,180-Di(tert-butyldi-
methylsilyloxy)-20,60:140,170-dioxido-80-oxo-triacontanyl]-5-
methyl-3-(phenylthio)tetrahydrofuran-2-one (16). A mixture of
14 (23.2 mg, 24.9 μmol) and PtO2 (6.8 mg) in THF
(1.2 mL) was vigorously stirred at rt under H2 atmosphere for
12 h, filtered through a pad of Celite, and concentrated. The
residue was purified by preparative TLC (n-hexane-ethyl
acetate 8:1, 6 developments) to give 16 (17.4 mg, 75%) as a
Experimental Section
(3S,5S,20R,60S,130R,140R,170S,180S)-[130,180-Di(tert-butyldi-
methylsilyloxy)-20,60:140,170-dioxido-80-oxo-90-triacontenyl]-5-
methyl-3-(phenylthio)tetrahydrofuran-2-one (14). To a stirred
mixture of 5 (50.1 mg, 85.9 μmol) and 6 (20.0 mg, 53.4 μmol) in
dichloromethane (2.0 mL) was added Grubbs’ second-generation
catalyst (8.3mg, 9.8μmol). The mixture was stirred at rt for 10 min
and at 40 °C for 2 h, then cooled to rt. Florisil was added with
stirring, and the resulting mixture was filtered through a pad of
Celite. The filtrate was concentrated to give a syrup, which was
chromatographed on silica gel (n-hexane-ethyl acetate=20:1 f
colorless syrup; [R]22 -16.8 (c 0.32, CHCl3); IR (ZnSe) 2925,
D
2854, 1772, 1716, 1456, 1376, 1233, 1187, 1081, 835 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.56-7.53 (2H, m), 7.39-7.31
(3H, m), 4.35 (1H, m), 3.86 (1H, m), 3.81-3.76 (2H, m), 3.67 (1H,
m), 3.61 (2H, m), 2.71 (1H, dd, J=14.2, 7.6 Hz), 2.63 (1H, dd,
J=16.1, 8.5 Hz), 2.51-2.37 (2H, m), 2.25 (1H, dd, J=16.1, 3.9
Hz), 2.03 (1H, dd, J=14.2, 10.3 Hz), 1.87-1.20 (40H, m), 1.19
(3H, d, J=6.4 Hz), 0.88 (9H, s), 0.87 (12H, m), 0.05 (9H, s), 0.04
(3H, s);13C NMR(125 MHz, CDCl3) δ 209.3, 177.4, 137.0, 130.5,
129.6, 128.8, 81.8, 81.7, 74.4, 74.3, 74.1, 73.7, 73.0, 54.1, 48.6, 44.3,
42.3, 38.6, 32.8, 32.7, 31.9, 31.2, 30.7, 29.8, 29.7, 29.6, 29.3, 27.0,
26.9, 25.9, 25.7, 25.3, 23.7, 23.3, 22.7, 21.4, 18.2, 14.1, -4.3, -4.6;
HRMS (ESI) calcd for C53H94O7Si2SNa [M+Na]+ 953.6157,
found 953.6137.
4:1) to give 14 (42.1 mg, 85% from 6) as a colorless syrup; [R]24
-
D
18.9 (c 0.12, CHCl3); IR (ZnSe) 2924, 2853, 1767, 1671, 1629,
1
1461, 1340, 1250, 1185, 1068, 834 cm-1; H NMR (500 MHz,
CDCl3) δ 7.56-7.52 (2H, m), 7.41-7.30 (3H, m), 6.82 (1H, dt,
(13) Shi, G.; Zeng, L.; Gu, Z.-M.; MacDougal, J. M.; McLaughlin, J. L.
Heterocycles 1995, 41, 1785–1796.
6384 J. Org. Chem. Vol. 74, No. 16, 2009

Takahashi et al.
JOCNote
TABLE 1. 1H NMR (600 or 500 MHz) Data (δ) for Compounds 1, 4, 18, 19, 20, 26, and 27
a
b
no.a
natural 1b
2.36 d (6.0)
3.59 m
4
18
26
27
19
20
3
4
2.35 m
3.58 m
2.36 m
3.58 m
2.35 m
3.56 m
2.35 m
3.56 m
2.36 m
3.58 m
2.36 m
3.56 m
5-7 1.26-1.64 m
1.23-1.84 m
3.83 m
1.23-1.84 m
3.83 m
1.23-1.84 m
3.82 m
1.23-1.84 m
3.83 m
1.25-1.84 m
3.83 m
1.23-1.84 m
3.80 m
2.60 dd (15.9, 8.8)
2.35 m
2.31-2.37 m
1.48 m
1.28 m
8
9
3.85 m
2.63 dd (15.0, 9.0) 2.62 dd (15.6, 9.1) 2.63 dd (15.6, 9.1) 2.63 dd (15.6, 9.1) 2.63 dd (15.6, 9.1) 2.61 dd (15.9, 8.8)
c
2.37c dd (15.0, 6.6) 2.37 dd (15.6, 3.5) 2.37 dd (15.6, 4.0) 2.37 dd (15.6, 4.0) 2.37 dd (15.6, 4.0) 2.37 dd (15.9, 4.0)
11 2.41cc m
12 1.26-1.87 m
13 1.26-1.87 m
14 1.47 m
2.41 t (7.1)
1.52 m, 1.58 m
1.35 m, 1.48 m
1.46 m
2.41 t (7.3)
1.52 m, 1.58 m
1.34 m, 1.46 m
1.46 m
2.41 t (7.3)
1.52 m, 1.56 m
1.35 m, 1.48 m
1.46 m
2.41 t (7.3)
1.52 m, 1.58 m
1.36 m, 1.48 m
1.46 m
2.30 t (7.6)
1.38 m, 1.52 m
1.12 m, 1.17 m
1.34 m
1.66 m, 1.71 m
15 3.40 m
16 3.80 m
17 1.75 m, 1.95 m
18 1.75 m, 1.95 m
19 3.80 m
20 3.40 m
21 1.47 m
32 0.88 t (7.0)
33 7.14 d (1.6)
34 4.99 dq (1.6, 6.8)
35 1.41 d (6.8)
3.40 m
3.81 m
1.75 m, 1.93 m
1.75 m, 1.93 m
3.81 m
3.42 m
1.46 m
0.87 t (7.1)
7.14 m
3.41 m
3.81 m
1.76 m, 1.93 m
1.76 m, 1.93 m
3.81 m
3.42 m
1.46 m
0.88 t (6.8)
7.14 m
3.41 m
3.81 m
1.75 m, 1.93 m
1.75 m, 1.93 m
3.81 m
3.42 m
1.46 m
0.87 t (7.1)
7.17 m
3.41 m
3.81 m
1.76 m, 1.93 m
1.76 m, 1.93 m
3.81 m
3.42 m
1.46 m
0.88 t (7.1)
7.17 m
5.06 ddd (8.0, 7.5, 3.5) 4.91 ddd (7.0, 6.5, 3.0)
3.87 m
4.08 ddd (7.0, 4.6, 3.5)
1.36 m, 1.82 m
0.86 m, 1.44 m
3.87 ddd (8.1, 8.0, 7.0)
5.07 ddd (9.1, 8.0, 3.5)
1.27 m, 1.35 m
0.89 t (7.1)
0.90 m, 1.48 m
1.38 m, 1.82 m
4.09 m
4.93 m
1.64 m, 1.68 m
0.88 t (7.1)
7.13 m
7.14 m
4.96 m
1.39 d (7.1)
4.98 dq (1.5, 6.6) 4.98 dq (1.5, 6.6) 4.98 dq (1.4, 6.6) 4.98 dq (1.5, 6.6) 4.94 m
1.40 d (6.6) 1.40 d (6.6) 1.39 d (6.6) 1.39 d (6.6) 1.38 d (7.1)
aReference 5. bReference 3b (500 MHz). cObtained from the copies of the original NMR spectra kindly provided by Prof.
Qin. The original data denoted in ref 3b were opposite.
TABLE 2. ED50 (μg/mL) Values of 3, 4, 18, 26, 27, and 28 against Six Human Tumor Cell Linesa
ACHN
5.8 ꢀ 10-1
MCF-7
7.2 ꢀ 10-1
PC-3
8.8 ꢀ 10-1
HT-29
PACA
3.3
4.7
3.3
6.0
A-549
1.3
3.1
4
18
26
27
3.2
1.4
4.4 ꢀ 10-1
5.4
1.6
1.3
>10
>10
8.4
4.3 ꢀ 10-1
2.6
1.0
7.5 ꢀ 10-1
1.6
1.0
7.9 ꢀ 10-1
3.2
1.6
3 (montanacin D)
28
4.5 ꢀ 10-1
3.7 ꢀ 10-1
9.0 ꢀ 10-2
3.2
2.1
3.5
3.2
5.4 ꢀ 10-1
1.0 ꢀ 10-2
7.8 ꢀ 10-1
1.2 ꢀ 10-1
9.6 ꢀ 10-1
Adrb
3.0 ꢀ 10-2
3.7 ꢀ 10-3
9.0 ꢀ 10-3
aACHN (renal carcinoma), MCF-7 (breast carcinoma), PC-3 (prostate adenocarcinoma), HT-29 (colon adenocarcinoma),
PACA (pancreas carcinoma), and A-549 (lung carcinoma). bAdriamycin was used for the standard positive control.
(5S,20R,60S,130R,140R,170S,180S)-[130,180-Dihydroxy-20,60:140,
170-dioxido-80-oxotriacontanyl]-5-methylfuran-2(5H)-one (4).
To a stirred solution of 16 (14.1 mg, 15.1 μmol) in dichloro-
methane (1.0 mL) was added mCPBA (70-75% assay; 3.7 mg, ca.
15.1 μmol) at 0 °C. After 30 min, aqueous saturated NaHCO3/
Na2S2O3 (1:1) was added, and the resulting mixture was extracted
with ether. The extracts were washed with aqueous saturated
Na2S2O3, water, and brine, dried, and concentrated. The residue
was dissolved in toluene (1.0 mL). The solution was heated at
100-105 °C for 1 h with stirring, then concentrated to give a
crude butenolide (22.9 mg). To a stirred solution of the butenolide
(2H, t, J=7.2 Hz), 2.37 (1H, dd, J=15.6, 3.5 Hz), 2.35 (2H, m),
1.93 (2H, m), 1.84 (1H, m), 1.75 (2H, m), 1.58 (3H, m), 1.56
(1H, m), 1.52 (1H, m), 1.48 (2H, m), 1.46 (4H, m), 1.40 (3H, d,
J=6.6 Hz), 1.35 (2H, m), 1.28 (2H, m), 1.25 (17H, m), 1.23 (1H,
m), 0.87 (3H, t, J=7.1 Hz); 13C NMR (150 MHz, CDCl3) δ209.37,
174.17, 151.32, 130.56, 82.66, 82.60, 77.81, 75.55, 74.29, 74.05,
74.00, 49.13, 43.72, 34.15, 33.81, 31.91, 31.79, 31.15, 31.05, 29.68,
29.65, 29.62, 29.60, 29.33, 28.10, 25.71, 25.27, 23.50, 23.28, 22.67,
19.08, 14.09; HRMS (ESI) calcd for C35H60O7Na [M+Na]+
615.4237, found 615.4209.
(22.9 mg) in dichloromethane (0.7 mL) was added a HF pyridine
Acknowledgment. We are grateful to Prof. G. W. Qin
(Shanghai Institute of Materia Medica) for providing us
copies of the original spectra of natural montanacin E. This
work was supported by a Grant-in-Aid for Scientific Re-
search from MEXT and by the Chemical Genomics Project
(RIKEN).
3
complex (50 μL) at 0 °C, then the mixture was stirred at 0 °C for
30 min. After addition of aqueous saturated NaHCO3, the result-
ing mixture was stirred at 0 °C for 10 min and extracted with ethyl
acetate. The extracts were washed with water and brine, dried, and
then concentrated. The residue was purified by preparative TLC
(ethyl acetate, 2 developments) to give 4 (7.4 mg, 83% from 16) as
a white powder; [R]22D +1.6 (c 0.32, methanol); IR (ZnSe) 3407,
2916, 2848, 1756, 1734, 1698, 1461, 1405, 1318, 1300, 1196, 1139,
1018 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.14 (1H, m), 4.98 (1H,
brdq, J=1.5, 6.6 Hz), 3.83 (1H, m), 3.81 (2H, m), 3.58 (1H, m),
3.42 (1H, m), 3.40 (1H, m), 2.62 (1H, dd, J=15.6, 9.1 Hz), 2.41
Supporting Information Available: Experimental proce-
dures and NMR spectra of 4, 5, 7, 8, 10-18, and 22-27. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6385