The first total synthesis and structural determination of actinopyrone A

Article abstract of DOI:10.1016/j.tetlet.2006.05.028

Actinopyrone A (1) has been synthesized by using our developed remote stereoinduction, Kocienski olefination, Horner-Wadsworth-Emmons olefination, and reductive de-conjugation of the vinylpyrone. A concise method of O-methylation to obtain the γ-pyrone ha

Full text of DOI:10.1016/j.tetlet.2006.05.028

Tetrahedron Letters 47 (2006) 5415–5418
The first total synthesis and structural determination
of actinopyrone A
Seijiro Hosokawa,* Kazuya Yokota, Keisuke Imamura, Yasuaki Suzuki,
Masataka Kawarasaki and Kuniaki Tatsuta*
Department of Applied Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
Received 11 April 2006; revised 2 May 2006; accepted 8 May 2006
Available online 12 June 2006
Abstract—Actinopyrone A (1) has been synthesized by using our developed remote stereoinduction, Kocienski olefination, Horner–
Wadsworth–Emmons olefination, and reductive de-conjugation of the vinylpyrone. A concise method of O-methylation to obtain
the c-pyrone has also been established.
Ó 2006 Elsevier Ltd. All rights reserved.
Actinopyrone A (1) was isolated from Streptomyces pac-
tum S12538 as a relatively unstable compound possess-
ing coronary vasodilating activity and antimicrobial
activity.1 Later, it was found to exhibit potent anti-
Helicobacter pylori activity.2
the synthesis of actinopyrone A (1) has been required
to be established. Herein, we present the first total syn-
thesis of actinopyrone A (1), which is applicable to a
variety of derivatives.3
Our synthetic plan is shown in Scheme 1. To avoid insta-
bility of actinopyrone A (1), the conjugated pyrone 2
was set up as the precursor. The precursor 2 would be
subjected to the reductive de-conjugation of the conju-
gated pyrone moiety in the final stage of the synthesis.
The conjugated pyrone 2 might be synthesized by
In addition to multi-bioactivity, little toxicity makes
actinopyrone A (1) to be an attractive candidate of a
drug for chemotherapy. However, instability of 1 makes
it difficult to promote further research and even the
absolute structure has not been disclosed yet. Thus,
Me Me Me
Me
Me Me Me
Me
8
15
14
Me
O
O
OMe
Me
15
14
Me
O
O
OMe
Me
10
6
8
18
18
10
6
11
7
7
11
X
OH
OR
Me
Me
Actinopyrone A (1)
2
Me
P(O)(OEt)2
O
Ph
14
OMe
Me
6
Me
N
N
Me
CHO
O
N
11
O
N
Me
8
10
Me
S
N
18
Me
7
15
O
O
TBSO
O
O
5
6
3
4
Scheme 1. Retrosynthetic analysis of actinopyrone A (1).
Keywords: Actinopyrone A; Total synthesis; Structural determination; Remote stereoinduction; 4-Pyrone; Reductive de-conjugation.
*
Corresponding authors. Tel./fax: +81 3 3200 3203 (K.T.); e-mail: tatsuta@waseda.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.028

5416
S. Hosokawa et al. / Tetrahedron Letters 47 (2006) 5415–5418
connection of the compounds 3–6. The chiral centers
C14 and C15 should be constructed by our developed
methodology using the chiral vinylketene N,O-acetal
4,4 which was prepared from D-valine.
was converted to tetrazole 9 under Mitsunobu condi-
tions. Both olefin and sulfide of 9 were oxidized to give
epoxy-sulfone 5 by treatment with m-CPBA in the pres-
ence of NaHCO3.5,6 On the other hand, during the syn-
thesis of the c-pyrone moiety 6, we found a concise and
economical method of methylation to convert 4-hydr-
oxy-2-pyrone to 2-methoxy-4-pyrone. Treatment of the
Compounds 5 and 6 were synthesized from 7 and 10,
respectively (Scheme 2). The commercially available 7
Ph
N
SH
N
Ph
Ph
Me
N
N
Me
N
N
Me
N
N
O
8
b
N
N
HO
S
N
S
N
a
O
O
7
9
5
Cl
P(O)(OEt)2
O
Me
Me
O
O
Me
Me
O
OMe
Me
O
OMe
Me
OMe
Me
c
d
e
Me
Me
Me
OH
O
O
O
10
11
12
6
Scheme 2. Reagents and conditions: (a) DEAD, PPh3, THF, rt, 2 h, 92%; (b) m-CPBA, NaHCO3, CH2Cl2, 0 °C, 4 d, 87%; (c) CaCO3, Me2SO4,
acetone, 50 °C, 3 d, 56%; (d) LHMDS, NCS, THF, 0 °C, 1 h, 67%; (e) P(OEt)3, 140 °C, 6.5 h, 80%.
Me
Me
Me
CHO
Me Me Me
Me Me Me
15
3
b
c
15
11
N
O
N
O
Me
N
O
Me
14
18
14
Me
TBSO
a
OH
O
O
O
OTBS
O
O
13
14
4
Ph
Me
N
N
O
N
S
N
Me Me Me
O
O
Me Me Me
Me
Me Me Me
Me
O
H
e
5
Me
Me
Me
OH
10
11
OMe
d
OTBS
O
OTBS
OTBS
15
16
17
O
O
OMe
Me
(EtO)2(O)P
Me
Me Me Me
OTBS
Me
7
Me
O
O
OMe
Me
Me Me Me
Me
6
8
6
f
OMe
Me
Me
CHO
MeO
g
OTBS
19
18
Me Me Me
Me
Me Me Me
OH
Me
8
15
14
Me
O
O
OMe
Me
Me
O
O
OMe
Me
i
h
8
6
18
11
7
OMe
Me
OH
Me
20
Actinopyrone A (1)
Scheme 3. Reagents and conditions: (a) TiCl4, CH2Cl2, ꢀ60 °C, 4 d, 82%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 1.5 h, 93%; (c) DIBAL, CH2Cl2,
ꢀ78 °C, 1 h, 68%; (d) NaHMDS, DME, ꢀ60 to 0 °C, 18 h; (e) CSA, MeOH, 0 °C, 1 h, 67% (two steps); (f) SO3ÆPy, DMSO, Et3N, rt, 30 min, 94%; (g)
LHMDS, THF, ꢀ78 to 0 °C, 5.5 h, 96%; (h) CSA, MeOH, rt, 18 h, 70%; (i) SmI2, 2-propanol, THF, ꢀ78 to ꢀ20 °C, 30 min, 70%.

S. Hosokawa et al. / Tetrahedron Letters 47 (2006) 5415–5418
5417
known a-pyrone 107 with calcium carbonate and di-
methylsulfate in acetone at 50 °C promoted 2-O-methyl-
ation to give c-pyrone 118 as a major product. The
regioselectivity of the O-methylation was 2-O-methyl-
ation/4-O-methylation = 3:1.9 The isolated yield of c-
pyrone 11 (56%) is comparable to the yield under condi-
tions with MeSO3F (53%).10 The regioselective chlorina-
tion of c-pyrone 11 to obtain chloromethylpyrone 12
was realized with lithium hexamethyldisilazide and
NCS, and followed by substitution with triethylphosph-
ite to afford phosphonate 6.6,11
information including spectral data and properties.
K.I. thanks JSPS Research Fellowships for Young Sci-
entists. The authors are also grateful for financial sup-
port to 21COE ‘Center for Practical Nano-Chemistry’,
Consolidated Research Institute for Advanced Science
and Medical Care, and Grant-in-Aid for Scientific
Research (A), Scientific Research (C), and Scientific
Research on Priority Areas 16073220 from The Ministry
of Education, Culture, Sports, Science and Technology
(MEXT).
References and notes
The total synthesis of actinopyrone A (1) was accom-
plished as shown in Scheme 3. Stereoselective construc-
tion of C11–C18 unit 13 was achieved by our remote
stereocontrol methodology.4 Coupling of silyl dienolate
44c and tiglic aldehyde 3 in the presence of TiCl4 gave
C14–C15 anti-adduct 13 as a single isomer. Protection
of 13 as the TBS ether afforded the crystalline 14, of
which stereochemistry was determined to be the
(14R,15R)-isomer by X-ray crystallography as expected
from our previous works.4,12 The chiral auxiliary of 14
was removed to give aldehyde 15 by treatment with DI-
BAL at ꢀ78 °C.4b The aldehyde 15 was converted to tri-
ene 16 (10,11-E:10,11-Z = 93:7) by Kocienski’s method5
using sulfone 5. The epoxide 16 was transformed under
the acidic conditions to primary alcohol 17, which was
separated from 10,11-Z-isomer by silica gel column
chromatography. The alcohol 17 was submitted to oxi-
dation to afford aldehyde 18. The pyrone moiety was
introduced by Horner–Wadsworth–Emmons reaction
of 18 with phosphonate 6 to afford the stable vinylpy-
rone 19. De-O-silylation of 19 under the acidic condi-
tions proceeded in good yield to provide 20 (2: R = H,
X = OMe). The final and key step was settled. Treat-
1. (a) Yano, K.; Yokoi, K.; Sato, J.; Oono, J.; Kouda, T.;
Ogawa, Y.; Nakashima, T. J. Antibiot. 1986, 39, 32–37; (b)
Yano, K.; Yokoi, K.; Sato, J.; Oono, J.; Kouda, T.;
Ogawa, Y.; Nakashima, T. J. Antibiot. 1986, 39, 38–43.
2. Taniguchi, M.; Watanabe, M.; Nagai, K.; Suzumura, K.;
Suzuki, K.; Tanaka, A. . J. Antibiot. 2000, 53, 844–847.
3. Recently, piericidin A1 possessing the same side chain of
actinopyrone A was synthesized. Schnermann, M. J.;
Boger, D. L. J. Am. Chem. Soc. 2005, 127, 15704–15705.
4. (a) Tatsuta, K.; Hosokawa, S. Chem. Rev. 2005, 105,
4707–4729; (b) Hosokawa, S.; Ogura, T.; Togashi, H.;
Tatsuta, K. Tetrahedron Lett. 2005, 46, 333–337; (c)
Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada,
M.; Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 13604–13605.
5. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28.
6. Selected data; Compound 5: prisms recrystallized from 2-
1
propanol, mp 88.3–88.7 °C; H NMR (400 MHz, CDCl3)
d 1.40 (3H, s), 2.21 (1H, ddd, J = 14.4, 10.8, 5.4 Hz), 2.32
(1H, ddd, J = 14.4, 10.8, 5.6 Hz), 2.66 (1H, d, J = 4.0 Hz),
2.71 (1H, d, J = 4.0 Hz), 3.75 (1H, ddd, J = 14.8, 10.8,
5.4 Hz), 3.83 (1H, ddd, J = 14.8, 10.8, 5.6 Hz), 7.56–7.64
(3H, m), 7.65–7.73 (2H, m); 13C NMR (100 MHz, CDCl3)
d 21.0, 28.9, 52.1, 53.3, 54.8, 125.1, 129.8, 131.5, 133.0,
153.3; MS (FAB+) m/z 295 [M+H]+, HRMS (FAB+)
calcd for C12H15O3N4S1 [M+H]+ 295.0865, found
295.0863. Anal. Calcd for C12H14O3N4S1: C, 48.97; H,
4.79; N, 19.04. Found: C, 48.92; H, 4.78; N, 18.91; IR
(KBr) 3072, 3056, 2981, 2967, 2927, 1949, 1348, 1324,
1155, 894, 765, 694. Compound 6: prisms recrystallized
from diisopropyl ether, mp 70.0–70.4 °C; 1H NMR
(400 MHz, CDCl3) d 1.32 (6H, t, J = 7.1 Hz), 1.85 (3H,
s), 1.98 (3H, d, J = 3.7 Hz), 3.14 (2H, d, J = 22.0 Hz), 3.99
(3H, s), 4.08–4.17 (4H, m); 13C NMR (100 MHz, CDCl3) d
6.9, 10.4 (d, J = 3 Hz), 16.5 (d, J = 6 Hz), 30.1 (d,
J = 140 Hz), 55.7, 62.6 (d, J = 6 Hz), 99.8, 120.8 (d,
J = 9 Hz), 149.4 (d, J = 12 Hz), 162.3, 180.4 (d, J = 3 Hz);
MS (FAB+) m/z 305 [M+H]+, HRMS (FAB+) calcd for
C13H22O6P1 [M+H]+ 305.1154, found 305.1158; IR (KBr)
2985, 2967, 2927, 1672, 1602, 1463, 1328, 1253, 1238, 1020,
977, 792. Compound 18 (the value in bracket is data of the
isomer at C8 position): 1H NMR (400 MHz, CDCl3) d
ꢀ0.09 (3H, s), ꢀ0.07 (3H, s), 0.75 (3H, d, J = 6.9 Hz), 0.80
(9H, s), 1.21 [1.22] (3H, s), 1.55 (3H, s), 1.58 (3H, d,
J = 6.7 Hz), 1.71 (3H, s), 2.33–2.52 (2H, m), 2.55–2.66
(1H, m), 3.32 (3H, s), 3.62 (1H, d, J = 8.0 Hz), 5.20 (1H, d,
J = 10.1 Hz), 5.31 (1H, q, J = 6.7 Hz), 5.41 (1H, dt,
J = 15.3, 7.5 Hz), 6.09 (1H, d, J = 15.3 Hz), 9.58 [9.59]
(1H, s); 13C NMR (100 MHz, CDCl3) d ꢀ5.1, ꢀ4.8, 10.79
[10.81], 12.9 [13.0], 17.4, 17.47 [17.49], 18.1, 25.7, 37.3, 38.0
[38.2], 51.89 [51.93], 82.35 [82.39], 83.5 [83.6], 118.9, 121.29
[121.32], 132.7,136.70 [136.73], 137.1, 139.5 [139.6], 205.0
[205.1]; MS (FAB+) m/z 393 [MꢀH]+, 365 [MꢀCHO]+,
13
ment of the vinylpyrone 20 with SmI2 in the presence
of 2-propanol promoted the reductive de-conjugation
to give actinopyrone A (1) accompanied with the 7,8-
Z-isomer in the ratio of 88:12. These isomers were easily
separated by silica gel column chromatography to iso-
late 1 in 70% yield. The synthetic 1 was identical in all
respects with the natural product including the optical
25
rotation (synthetic 1: ½aꢁD +31.3 (c 0.43, CH2Cl2), natu-
26
ral: ½aꢁD +30.8 (c 0.42, CH2Cl2)).6 Thus, the absolute
structure of actinopyrone A (1) was determined to be
(14R,15R)-configuration. We also synthesized the enan-
tiomer of actinopyrone A showing the opposite optical
23
rotation (½aꢁD ꢀ31.7 (c 0.43, CH2Cl2)) by starting from
the enantiomer of 44c derived from L-valine.
In conclusion, the first total synthesis and structural
determination of actinopyrone A (1) were accomplished
by coupling of four units (3, 4, 5, and 6) and reductive
de-conjugation of the vinylpyrone 20. This route is
applicable to synthesize a variety of analogs of actino-
pyrones to produce anti-H. pylori drugs.
Acknowledgments
Special thanks to Drs. T. Adachi, A. Kawashima, and
Y. Terui in Taisho Pharmaceutical Co. Ltd. to give us
an authentic sample of actinopyrone A (1) and useful

5418
S. Hosokawa et al. / Tetrahedron Letters 47 (2006) 5415–5418
363 [MꢀOMe]+; HRMS (FAB+) calcd for C23H41O3Si1
138.0, 156.9, 162.1, 181.0; MS (FAB+) m/z 401 [M+H]+,
HRMS (FAB+) calcd for C25H37O4 [M+H]+ 401.2692,
found 401.2673; IR (KBr) 3407, 3023, 2958, 2923, 2863,
1666, 1587, 1463, 1378, 1326, 1251, 1164.
[MꢀH]+ 393.2825, found 393.3827; IR (KBr) 3031, 2956,
2929, 2856, 2829, 2800, 2701, 1737, 1471, 1461, 1247, 1079,
1056, 860, 836, 773. Compound 20: (the value in bracket is
1
data of the isomer at C8 position): H NMR (400 MHz,
7. (a) Suzuki, E.; Sekizaki, H.; Inoue, S. J. Chem. Res. Syn.
1977, 200; (b) Ishibashi, Y.; Ohba, S.; Nishiyama, S.;
Yamamura, S. Tetrahedron Lett. 1996, 37, 2997–3000.
8. Suzuki, E.; Hamajima, R.; Inoue, S. Synthesis 1975, 192–
194.
9. In the case of K2CO3 as a base, the ratio of 2-O-
methylation/4-O-methylation was ꢂ1/1. Hatakeyama, S.;
Ochi, N.; Takano, S. Chem. Pharm. Bull. 1993, 41, 1358–
1361.
10. Under the conditions using excess amount (3 equiv) of
MeSO3F, 2-O-methylation proceeded selectively, however,
starting material 10 did not consumed completely and
isolated yield of 11 was 53%. Beak, P.; Lee, J.; McKinnie,
B. G. J. Org. Chem. 1978, 43, 1367–1372.
11. Analogous transformation to a phosphonate via a mesy-
late: Moses, J. E.; Baldwin, J. E.; Adlington, R. M.
Tetrahedron Lett. 2004, 45, 6447–6448.
12. Crystallographic data (excluding structure factors) for the
structures of 14 has been deposited with the Cambridge
Crystallographic Data Center as supplementary publica-
tion numbers CCDC 602830. Copies of the data can be
obtained, free charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
13. For reduction of c-acetoxy-a,b-unsaturated ester: Otaka,
A.; Yukimasa, A.; Watanabe, J.; Sasaki, Y.; Oishi, S.;
Tamamura, H.; Fuji, N. Chem. Commun. 2003, 1834–
1835.
CDCl3) d 0.81 (3H, d, J = 6.9 Hz), 1.35 (3H, s), 1.60–1.68
(7H, m), 1.81 (3H, s), 1.87 (3H, s), 2.05 (3H, s), 2.44 (2H,
d, J = 7.2 Hz), 2.68 (1H, ddq, J = 9.6, 9.1, 6.9 Hz), 3.246
[3.252] (3H, s), 3.63 (1H, d, J = 9.1 Hz), 3.998 [4.001] (3H,
s), 5.26 (1H, d, J = 9.6 Hz), 5.49 (1H, q, J = 6.2 Hz), 5.53–
5.63 (1H, m), 6.13 [6.14] (1H, d, J = 15.7 Hz), 6.36 (1H, d,
J = 16.0 Hz), 6.50 [6.51] (1H, d, J = 16.0 Hz); 13C NMR
(100 MHz, CDCl3) d 6.9, 9.6, 10.5, 13.1, 13.2, 17.4, 22.16
[22.23], 36.8, 43.5 [43.6], 50.5, 55.3, 77.2, 82.8, 99.6, 119.1,
119.49 [119.52], 122.4 [122.5], 123.6, 134.08 [134.14],
135.49 [135.53], 135.6, 138.0 [138.1], 140.0, 151.2, 161.7,
181.0; MS (FAB+) m/z 431 [M+H]+; HRMS (FAB+)
calcd for C26H39O5 [M+H]+ 431.2797, found 431.2769; IR
(KBr) 3423, 3029, 2971, 2925, 2863, 2829, 1666, 1631,
1602, 1577, 1465, 1417, 1376, 1336, 1259, 1168, 968.
25
Actinopyrone A (1) (synthetic): ½aꢁD +31.3 (c 0.43,
26
1
CH2Cl2) [natural ½aꢁ +30.8 (c 0.42, CH2Cl2)] H NMR
(400 MHz, CDCl3) dD0.81 (3H, d, J = 6.9 Hz), 1.63 (3H, d,
J = 6.0 Hz), 1.64 (3H, s), 1.67 (1H, br), 1.73 (3H, s), 1.81
(3H, s), 1.84 (3H, s), 1.96 (3H, s), 2.68 (1H, ddq, J = 9.6,
9.1, 6.9 Hz), 2.80 (2H, d, J = 6.9 Hz), 3.31 (2H, d,
J = 7.3 Hz), 3.63 (1H, d, J = 9.1 Hz), 3.92 (3H, s), 5.24
(1H, d, J = 9.6 Hz), 5.26 (1H, t, J = 7.3 Hz), 5.49 (1H, q,
J = 6.0 Hz), 5.56 (1H, dt, J = 15.5, 6.9 Hz), 6.10 (1H, d,
J = 15.5 Hz); 13C NMR (100 MHz, CDCl3) d 6.9, 9.9,
10.5, 13.1, 13.2, 16.6, 17.4, 30.0, 36.9, 42.9, 55.2, 82.8, 99.3,
118.0, 118.1, 123.6, 125.6, 133.8, 135.57, 135.61, 136.4,