Synthesis to determine the absolute configuration of (-)-pyricuol, a phytotoxin isolated from rice blast disease fungus Magnaporthe grisea

Article abstract of DOI:10.1016/j.tetlet.2005.08.099

The absolute configuration of (-)-pyricuol, a phytotoxin isolated from rice blast disease fungus Magnaporthe grisea, was determined to be R by synthetic studies.

Full text of DOI:10.1016/j.tetlet.2005.08.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7107–7109
Synthesis to determine the absolute configuration of
(ꢀ)-pyricuol, a phytotoxin isolated from rice blast disease fungus
Magnaporthe grisea
Yoko Nakamura, Hiromasa Kiyota,* Rumi Ueda and Shigefumi Kuwahara
Department of Applied Bioorganic Chemistry, Division of Bioscience and Biotechnology for Future Bioindustry,
Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Received 27 July 2005; revised 18 August 2005; accepted 22 August 2005
Available online 6 September 2005
Dedicated to Professor Steven V. Ley, FRS CBE, on the occasion of his 60th birthday
Abstract—The absolute configuration of (ꢀ)-pyricuol, a phytotoxin isolated from rice blast disease fungus Magnaporthe grisea,
was determined to be R by synthetic studies.
Ó 2005 Elsevier Ltd. All rights reserved.
(ꢀ)-Pyricuol (1) was isolated from the culture filtrate of
rice blast disease fungus, Magnaporthe grisea (Hebert)
Barr, which induced a typical disease symptom stronger
than pyriculol (2).1 Compound 1 possesses a unique
branched side chain, which was confirmed by our race-
mic synthesis,2 however, the stereochemistry had
remained unknown. Determination of the absolute
configuration was essential for its biosynthetic studies
and for further pest managements. In this letter, we
describe a synthesis and the absolute configuration of
1 (Fig. 1).
(S)-1
OH
HO
C
Ar
O
O
D
racemic synthesis
M
X
+
(R)-lactate
RO
E
O
F
O
As for the synthesis, we targeted (S)-1 and evolved a new
scheme because of the low reproducibility of our previ-
ous one (Scheme 1).2 (R)-a,b;c,d-Dienol C is a key inter-
Scheme 1. Retrosynthetic analysis of (S)-1.
mediate of the racemic synthesis. Since the semi-
reduction of the triple bond of D was troublesome,
metal-mediated coupling reactions of E and F are suit-
able to construct E,Z-diene. The chirality of F is derived
from (R)-lactate.
OH
14
OH
8
12
6
10
7
5
4
9
11
13
OH
2
1
3
pyricuol 1
pyriculol 2
OH
O
OH O
As shown in Scheme 2, the known aldehyde 3,3 also the
starting compound of racemic synthesis, was converted
to alkyne 4 (= E) using Ohira–Bestmann reagent4 in
98% yield. While Z-alkenyl iodide 6 (= F)5 was prepared
from aldehyde 56 by Z-selective Wittig reaction (Z/
E = 25:1).7 E-Isomer of 6 was removed by silica gel col-
umn chromatography.
Figure 1. Pyricuol (1) and pyriculol (2).
Keywords: (ꢀ)-Pyricuol; Magnaporthe grisea; Stille reaction; [2,3]-
Wittig rearrangement; Total synthesis; Natural products.
*
Corresponding author. Tel.: +81 22 717 8785; fax: +81 22 717
8783; e-mail: kiyota@biochem.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.099

7108
Y. Nakamura et al. / Tetrahedron Letters 46 (2005) 7107–7109
absolute configuration of the natural pyricuol is deter-
O
mined to be R. Synthesis of natural (R)-1 and compari-
son of the biological activities of both enantiomers are
underway.
a
b
67%
98%
O
O
O
O
4
3
O
c
Acknowledgements
5
40-69%
TBSO
Sn(n-Bu)3
We thank Professor J.-C. Kim (KRICT) for kindly
sending us the natural sample. This work was partially
supported by Grant-in-Aid for Scientific Research from
Japan Society for the Promotion of Science (No.
14760069 and 17580092), The Agricultural Chemical
Research Foundation, Intelligent Cosmos Foundation
and The Naito Foundation.
I
6
12R
TBSO
RO
O
O
O
O
78%
d
8: R = TBS
9: R = H
OH
7
e
94%
OH
10S
g
f
58%
92%
References and notes
O
O
OH OH
10
dihydropyricuol 11
1. Kim, J.-C.; Min, J.-Y.; Kim, H.-T.; Cho, K.-Y.; Yu, S.-H.
Biosci. Biotechnol. Biochem. 1998, 62, 173–174.
2. Kiyota, H.; Ueda, R.; Oritani, T.; Kuwahara, S. Synlett
2003, 219–220.
3. Suzuki, M.; Sugiyama, T.; Watanabe, M.; Yamashita, K.
Agric. Biol. Chem. 1986, 50, 2159–2160, and a reference
cited therein; Suzuki, M.; Sugiyama, T.; Watanabe, M.;
Murayama, T.; Yamashita, K. Agric. Biol. Chem. 1987,
51, 1121–1127.
OH
natural 1
[α]D22 -17.4˚
h
quant
(S)-pyricuol 1
[α]D22 +19˚
unnatural
(R)-pyricuol
OH
O
Scheme 2. Synthesis of (S)-pyricuol: (a) dimethyl 1-diazo-2-
oxopropylphosphonate (2 equiv), K2CO3 (2.5 equiv), MeOH; (b) (n-
Bu)3SnH (2.3 equiv), CuCN (1.16 equiv), n-BuLi (2.3 equiv), THF
ꢀ76 °C; then 4, ꢀ37 °C; (c) (Ph3P+CH2I)Iꢀ (4 equiv), NaHMDS
(4 equiv), HMPA (1 equiv), THF, ꢀ78 °C; (d) 7 (4 equiv), Pd2dba3
(0.05 equiv), AsPh3 (0.1 equiv), CuI (0.1 equiv), DMF, rt; (e) TBAF
(excess), THF, rt, 2 h; (f) (i) KH (2.5 equiv), ICH2Sn(n-Bu)3
(1.5 equiv), THF, rt; (ii) n-BuLi (1.5 equiv), THF, ꢀ79 °C; (g) p-
TsOH (cat.), MeOH–dil HCl; (h) MnO2 (10 equiv), DMSO, 60 °C, 1 h.
4. Ohira, S. Synth. Commun. 1989, 19, 561–564; Muller, S.;
¨
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521–522.
5. Chackalamannil, S.; Davies, R. J.; Wang, Y.; Asberom,
T.; Doller, D.; Wong, J.; Leone, D. J. Org. Chem. 1999,
64, 1932–1940.
6. Wakabayashi, S.; Ogawa, H.; Ueno, N.; Kunieda, N.;
Mandai, T.; Nokami, J. Chem. Lett. 1987, 875–878.
7. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–
2174.
Then, metal-mediated coupling reactions were exam-
ined. Although Sonogashira coupling reaction8 gave
an enyne product in good yield, trials of its transforma-
tion were unsuccessful.9 Then, we chose Stille coupling
reaction. Hydrostannylation of 4 by stannylcuprate10
gave E-alkenylstannane 7. This compound was partly
decomposed to the corresponding stylene derivative dur-
ing silica gel column chromatography. Stille reaction11
with Z-vinyl iodide 6 gave the desired E,Z-diene 8 in
78% yield. Deprotection of TBS group afforded alcohol
9 (= C), which was the intermediate of our racemic syn-
thesis. The following steps were done according to our
previous report.2 [2,3]-Wittig rearrangement of an inter-
mediate stannyl ether gave the desired 10 in 58% yield
accompanied by 8% of [1,2]-rearranged product. The
corresponding Z-isomer was not detected by 1H
NMR. The R-chirality of lactate was to be exclusively
transferred to the 10S-position according to Still and
Mitra.12 Acetonide group of 10 was removed to afford
dihydropyricuol 11, which would be the biosynthetic
precursor, and selective oxidation of benzyl hydroxyl
group with MnO2 gave (S)-pyricuol 1.13 Overall yield
8. Crisp, G. T.; Turner, P. D. Tetrahedron 2000, 56, 407–415.
9. In our preliminary studies, alkaline treatment of Sono-
gashira coupling product 12 gave furan 13, or reduction
afforded allene 14.
I
a
HO
12
83%
•
EEO
75%
4
O
O
c
b
67%
O
O
O
O
O
OH
13
14
(a) (i) Pd(PPh3)4, Et3N, CuI, DMF; (ii) PPTS, MeOH, (b)
KH, THF; (c) Red Al, THF.
10. Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.;
Prunet, J. J. Org. Chem. 1997, 62, 7768–7780, and
references cited therein.
11. The conditions were modifications of the reported proce-
dures: Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991,
113, 9585–9595; Farina, V.; Kapadia, S.; Krishnan, B.;
Wang, C.; Liebeskind, L. J. Org. Chem. 1994, 59, 5905–
5911; Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.;
1
was 25% from 3 in seven steps. The H NMR spectral
datum was in good agreement with that reported,1 how-
22
ever, the sign of optical rotation value {½aꢁD +19 (c
0.070, CHCl3)} was reversed to that of natural com-
22
pound1 {½aꢁD ꢀ17.4 (c 0.03, CHCl3)}. Accordingly, the

Y. Nakamura et al. / Tetrahedron Letters 46 (2005) 7107–7109
7109
Gilmore, T. D.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267–
3270; Kuwahara, S.; Imada, S. Tetrahedron Lett. 2005, 46,
547–549.
(m), 1193 (m), 1163 (m), 967 (m), 722 (m). 1H NMR
(500 MHz, CDCl3): d 1.76 (3H, dd, J = 6.4, 1.0 Hz,
H-13), 3.15 (1H, pseudo-quint, J = 7.3 Hz, H-10), 3.63
(1H, m, H-14), 3.68 (1H, m, H-14), 5.43 (1H, ddq,
J = 15.1, 7.8, 1.5 Hz, H-11), 5.68 (1H, dq, J = 15.1,
6.3 Hz, H-12), 6.04 (1H, dd, J = 15.6, 7.3 Hz, H-9), 6.87
(1H, d, J = 8.3 Hz, H-6), 6.93 (1H, d, J = 7.3 Hz, H-4),
6.96 (1H, d, J = 15.6 Hz, H-8), 7.44 (1H, t, J = 8.0 Hz,
H-5), 10.31 (1H, s, CHO), 11.87 (1H, s, ArOH). HRMS
(FAB+): m/z calcd for C14H17O3, 233.1178; found,
233.1179.
12. Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1987, 100, 1927–
1928. For a recent review of the [2,3]-Wittig rearrange-
ment, see: Nakai, T.; Mikami, K. Org. React. 1994, 46,
105–209.
22
13. (S)-Pyricuol, a pale yellow oil, ½aꢁD +19 (c 0.30, CHCl3)
25
{lit.1 ½aꢁD ꢀ17.4 (c 0.7, CHCl3)}. IR (ATR, ZnSe) mmax
cmꢀ1: 3390 (s, O–H), 3025 (w), 2923 (s), 2854 (s), 1642 (s,
C@O), 1609 (s), 1569 (m, Ar), 1450 (s), 1327 (m), 1311