Synthesis of NH006 - A photostable fungicide effective against Botrytis cinerea - According to the asymmetric total synthesis of MK8383

Article abstract of DOI:10.1039/b924096a

MK8383, isolated from Phoma sp. T2526 in 1993, exhibits potent antibiotic activities against a variety of phytopathogens and has been considered a promising fungicide against Botrytis cinerea. Unfortunately, MK8383 is a photosensitive compound and it undergoes irreversible decomposition. Although much effort has been devoted to improving the photostability of MK8383 by chemical modification of its structure by a research group organized by Meiji Seika Kaishya, Ltd. and Mitsubishi Chemical Corporation, a photostable MK8383 derivative has never been prepared. We have found that a C13-14 double bond of MK8383 and (+)-phomopsidin is responsible for the photosensitivity, and herein, we report the synthesis of NH006, an MK8383 derivative with a saturated C13-14 double bond and (S) configuration at C14, based on the asymmetric total synthesis of MK8383. NH006 exhibits good photostability and potent antifungal activity against B. cinerea.

Full text of DOI:10.1039/b924096a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of NH006—a photostable fungicide effective against Botrytis
cinerea—according to the asymmetric total synthesis of MK8383†
Nobuyuki Hayashi,a Kentaro Yamamoto,b Nobuto Minowa,b Masaaki Mitomib and Masahisa Nakada*a
Received 18th November 2009, Accepted 22nd January 2010
First published as an Advance Article on the web 15th February 2010
DOI: 10.1039/b924096a
MK8383, isolated from Phoma sp. T2526 in 1993, exhibits potent antibiotic activities against a variety
of phytopathogens and has been considered a promising fungicide against Botrytis cinerea.
Unfortunately, MK8383 is a photosensitive compound and it undergoes irreversible decomposition.
Although much effort has been devoted to improving the photostability of MK8383 by chemical
modification of its structure by a research group organized by Meiji Seika Kaishya, Ltd. and Mitsubishi
Chemical Corporation, a photostable MK8383 derivative has never been prepared. We have found that
a C13-14 double bond of MK8383 and (+)-phomopsidin is responsible for the photosensitivity, and
herein, we report the synthesis of NH006, an MK8383 derivative with a saturated C13-14 double bond
and (S) configuration at C14, based on the asymmetric total synthesis of MK8383. NH006 exhibits
good photostability and potent antifungal activity against B. cinerea.
porcine brains. However, the antibiotic activity of MK8383 against
Introduction
a variety of phytopathogens, especially against Botrytis cinerea,
In 1993, a research group organized by Meiji Seika Kaishya, Ltd.
is more potent than that of (+)-phomopsidin. The activity of
and Mitsubishi Chemical Corporation isolated MK8383 (Fig. 1)
MK8383 is comparable to that of the commercially available
from Phoma sp. T2526 as a new fungicide.1 This compound has a
cis-fused dehydrodecalin ring with two characteristic substituents,
(E,E)-pentadienoic acid and a (Z)-trisubstituted alkene. The struc-
ture of MK8383 is almost the same as that of (+)-phomopsidin2
(Fig. 1), except for the geometry of the trisubstituted side-chain
alkene.
fungicides.1
B. cinerea is a facultative phytopatogenic fungus that attacks
flowers, fruits, leaves, and stems of more than 200 plant species,
causing grey mould disease.3 Dicarboximide, benzimidazole, and
several fungicides are known to be effective against B. cinerea;
however, the continuous use of such commercially available
fungicides has resulted in the development of highly resistant
strains of B. cinerea as well as the contamination of soil and water.4
Some natural products have been reported to show antifungal
activity against B. cinerea; therefore, such compounds are expected
to be used as alternative fungicides to the commercial ones.5
MK8383 and its derivatives are considered promising fungi-
cides against B. cinerea;1 however, MK8383 is a light-sensitive
compound and it undergoes irreversible decomposition (Fig. 2,
Table 1). Although much effort has been devoted to finding pho-
tostable derivatives of MK8383 that show high antifungal activity
against B. cinerea, no MK8383 derivatives with photostability have
been prepared. Thus, the development of a new fungicide derived
from MK8383 is desired.
Fig. 1 Structures of MK8383 and (+)-phomopsidin.
In comparison with (+)-phomopsidin (IC50 of 5.7 mM),2
MK8383 shows relatively weak inhibitory activity (IC50 of 8.0
mM) against an assembly of microtubule proteins derived from
Table 1 Residual ratio (%) after irradiation of artificial sunlight lampa
Time (h)
MK8383
(+)-phomopsidin
12b
16b
NH006b
aDepartment of Chemistry and Biochemistry, School of Advanced Science
and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo,
169-8555, Japan. E-mail: mnakada@waseda.jp; Fax: +81352863240;
Tel: +81352863240
0
1
2
4
100.0
99.7
99.0
94.4
78.7
51.4
30.1
107.0
100.0
88.9
89.9
77.4
59.8
39.2
19.5
100.0
100.0
98.9
106.2
103.4
100.0
99.6
100.0
103.2
102.1
102.9
101.5
101.1
103.0
99.8
100.0
99.4
99.6
100.4
101.8
96.2
bAgricultural & Veterinary Research Labs Meiji Seika Kaisha, Ltd.,
760 Morooka-cho, Kohoku-ku, Yokohama, Japan; Fax: +81455453198;
Tel: +81455412521
8
16
24
Control
94.2
100.2
87.5
106.0
† Electronic supplementary information (ESI) available: Data of new com-
pounds and experimental procedures. CCDC reference number 751813.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b924096a
a See experimental. b Average value of three tests.
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Table 2 Protective value (%) against Botrytis cinerea evaluated by cab-
bage disk testa
Conc (ppm)
MK8383 (+)-Phomopsidin
12
16
NH006
100
25
6.25
1.56
0.39
0
90.9
100.0
90.9
63.6
36.4
0.0
100.0
72.3
63.1
16.9
16.9
0.0
8.3
16.7
0.0
8.3
0.0
0.0
83.3 100.0
50.0 91.7
25.0 75.0
16.7 25.0
8.3
0.0
0.0
0.0
a See experimental. Protective value was calculated using the average value
of four tests.
carried out the hydrogenation of compound 1, which was a
synthetic intermediate in our asymmetric total syntheses of (+)-
phomopsidin and MK8383. However, hydrogenation of 1 gave a
mixture of diastereomers under all reaction conditions. Therefore,
1 was converted to the corresponding triisopropyl (TIPS) ether.
This was followed by removal of the ethoxyethyl group to give
alcohol 2, which was subjected to hydrogenation in the presence
of Rh/Al2O3 catalyst to successfully afford compound 3 as a single
product (84%, 86% conv.) (Scheme 1). Dess–Martin oxidation8 of
compound 3, subsequent treatment of the resulting aldehyde 4
with tetrabutylammonium fluoride (TBAF) to remove the TIPS
group, and Dess–Martin oxidation for a second time afforded
lactone 5.
Fig. 2 Results of the photostability test of MK8383, (+)-phomopsidin,
12, 16, and NH006.
In 2003, we reported on the first total synthesis of (+)-
phomopsidin based on the construction of a cis-fused dehy-
drodecaline skeleton by a stereoselective transannular Diels–Alder
(TADA) reaction.6 Recently, we also achieved the asymmetric
total synthesis of MK8383 via the iron-mediated stereoselective
construction of a (Z)-trisubstituted alkenyl side chain.7a As
the number of derivatives obtained from a natural product is
limited, we focused on the preparation of MK8383 derivatives
with photostability and high antifungal activity based on the
total syntheses of (+)-phomopsidin and MK8383. Recently, we
succeeded in the preparation of NH006, a promising fungicide
against B. cinerea with photostability. In this paper, we discuss
its preparation and its properties such as photostability and
antifungal activity.
We surmised that the photosensitivity of MK8383 could be
attributed to the double bonds existing in the dehydrodecalin core
and side chains. However, previous studies on the relationship
between the structure of MK8383 and its photostability have sug-
gested that the photosensitivity of MK8383 cannot be attributed
to the double bonds in the side chains.1 Thus, the C13-C14 double
bond in the dehydrodecalin core has been suspected to be a
primary cause for the photosensitivity of MK8383.
The selective modification of a C13-C14 double bond was
difficult in the presence of side chain double bonds; therefore,
an MK8383 derivative with a modified C13-C14 double bond has
never been prepared.1 Hence, we decided to modify the C13-C14
double bond on the basis of the asymmetric total syntheses of
(+)-phomopsidin and MK8383.
Scheme 1 Reagents and conditions: a) TIPSOTf, DBU, CH2Cl2, -78 ◦C,
96%; b) AcOH/EtOH (1/5, v/v), 60 ◦C, 75%; c) H2 (1 atm), Rh-Al2O3,
MeOH/AcOH (5/1, v/v), rt, 84% (86% conv.); d) Dess–Martin periodi-
nane, CH2Cl2, rt, 95%; e) TBAF, THF, reflux; f) Dess–Martin periodinane,
CH2Cl2, rt, 40% (2 steps).
(+)-Phomopsidin exhibits relatively weak antifungal activity
against B. cinerea in comparison with MK8383, but it can be
synthesized more easily than MK8383 (Fig. 4, Table 2). Hence, we
prepared (+)-phomopsidin derivatives with a modified C13-C14
double bond and then studied the effect of structural modification
on the photostability and antifungal activity of the derivative in
order to develop a method for preparing an MK8383 derivative.
Lactone 5 was crystalline, and the single crystal formed
was suitable for the X-ray crystallographic analysis. The X-ray
structure9 shown in Fig. 3 indicates that epimerization occurred
during the transformation of aldehyde 4 to lactone 5; moreover,
the configuration of C14 was unambiguously confirmed. This X-
ray crystallographic analysis suggested that the hydrogenation
of 2 with Rh/Al2O3 catalyst occurred opposite to the C15 hy-
droxymethyl group. Therefore, this stereoselectivity would be well
explained by the reaction occurring at the less hindered side rather
than the reaction directed by the adjacent C15 hydroxymethyl
group.
Results and discussion
Synthesis, antifungal activity, and photo-stability of compound 12
A (+)-phomopsidin derivative with a saturated C13-C14 bond
was expected to show the desired photostability. Therefore, we
Aldehyde 4 was subjected to the Corey–Fuchs protocol10 to
afford alkyne 6. Carboalumination of 6 under Wipf’s conditions11
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Fig. 3 X-Ray structure of 5. Displacement ellipsoids are drawn at the
50% probability level.
and in situ trapping of the product with iodine gave iodide
7. Negishi coupling of iodide 7 with dimethylzinc12 and the
subsequent treatment of the product with TBAF afforded diol 8,
followed by selective TBS ether formation and benzoylation to give
compound 9. The treatment of 9 with TBAF and subsequent Dess–
Martin oxidation afforded aldehyde 10. Then, 10 was subjected to
the Horner–Wadsworth–Emmons reaction with phosphonate 11.
Hydrolysis of the resultant ethyl ester with concomitant removal
of the benzoyl group afforded compound 12.
Expectedly, 12 remained almost intact after irradiation by
artificial light for 24 h (Fig. 2, Table 1), but it exhibited almost
no antifungal activity even at a concentration of 100 ppm
(Fig. 4, Table 2). Thus, hydrogenation of the C13-14 double
bond was found to greatly improve the photostability of the
(+)-phomopsidin derivative. Molecular modeling of 12 showed
that its three-dimensional structure is considerably different from
that of (+)-phomopsidin, but the C14 epimer of 12 has a three-
dimensional structure that is similar to that of (+)-phomopsidin.
As a result, we focused on the total synthesis of the C14 epimer of
12.
Scheme 2 Reagents and conditions: a) CBr4, PPh3, CH2Cl2, rt, 84%; b)
n-BuLi, THF, -78 ◦C, 88%; c) Cp2ZrCl2, Me3Al, CH2Cl2, H2O, -30 ◦C,
then, I2, THF, -30 ◦C, 83%; d) Me2Zn, PdCl2(PPh3)2, THF, rt, 96%;
e) TBAF, THF, reflux, 100%; f) TBSCl, imidazole, CH2Cl2, rt, 71%; g)
Bz2O, DMAP, CH2Cl2, rt, 100%; h) TBAF, THF, rt, 98%; i) Dess–Martin
=
periodinane, CH2Cl2, rt, 90%; j) (EtO)2P(O)CH2CH CHCO2Et (11),
LHMDS, THF, -78 to 0 ◦C, 91%; k) LiOH·H2O, EtOH/H2O (4/1, v/v),
89%.
Scheme 3 Reagents and conditions: a) H2 (1 atm), [Ir(cod)pyr(PCy3)]PF6
(20 mol%), (CH2Cl)2 (degassed), 60 ◦C, 84%; b) Dess–Martin periodinane,
CH2Cl2, rt, 95%; c) see ESI.
Fig. 4 Results of the antifungal activity test of MK8383, (+)-phomop-
sidin, 12, 16, and NH006.
give 14 as the sole product. Although 14 and 3 have different
protective groups on hydroxyls, the spectroscopic data of 14 was
very different from that of 3, suggesting that the C14 configuration
of 14 was different from that of 3. Therefore, we continued the
synthesis of the (+)-phomopsidin derivative from 14.
To synthesize the C14 epimer of 12, we had to establish a
method for preparing compound 14 (Scheme 3) on the basis of the
stereoselective hydrogenation of 13, which was also a synthetic in-
termediate in the asymmetric total syntheses of (+)-phomopsidin
and MK8383. We expected that the hydroxymethyl group in 13
would direct the hydrogenation to afford the desired product
with high stereoselectivity. Indeed, stereoselective hydrogenation
was successfully realized by the use of Crabtree’s catalyst13 to
Synthesis, antifungal activity, and photo-stability of compound 16
Dess–Martin oxidation of 14 afforded aldehyde 15 that was
successfully converted to compound 16 according to the method
used for the preparation of 12, which is shown in Scheme 2.
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16 also showed excellent photostability (Fig. 2, Table 1); its
antifungal activity was stronger than that of 12 (Fig. 4, Table 2),
but weaker than that of (+)-phomopsidin.
CBr4 and PPh3 resulted in the isomerization of the trisubstituted
side-chain alkene; however, the use of PBr3 in the presence of
pyridine successfully suppressed the isomerization and converted
the allylic alcohol to the desired bromide. The reaction of the
allylic bromide with LiAlH4 gave compound 19, and subsequent
treatment of 19 with TBAF afforded a diol. The primary and
secondary hydroxyls of the diol were protected as TBS ether and
benzoate, respectively, to give compound 20. The TBS group of 20
was removed with TBAF, and subsequent Dess–Martin oxidation
afforded aldehyde 21. The Horner–Wadsworth–Emmons reaction
of 21 with phosphonate 11 and hydrolysis of the resultant ethyl
ester with concomitant removal of the benzoyl group furnished
NH006.
Although NH006 slightly decomposed after 24 h irradiation
(ca. 12.5%), NH006 showed excellent photostability, which was
expected from the results of compounds 12 and 16 (Fig. 2,
Table 1). Comparing the relationships between the structure and
photostablity of 12, 16, and NH006, the slight decomposition of
NH006 after 24 h irradiation could be attributed to the relatively
photosensitive (Z)-trisubstituted side-chain alkene in NH006.
The antifungal activity of NH006 was also slightly reduced as
compared to that of MK8383 (Fig. 4, Table 2), but it was better
than that of (+)-phomopsidin. Thus, NH006 is sufficiently potent
as a fungicide against B. cinerea.
Synthesis, antifungal activity, and photo-stability of NH006
The above results prompted us to further pursue the synthesis,
photostability test, and antifungal activity test of a derivative of
MK8383 because the antifungal activity of MK8383 is stronger
than that of (+)-phomopsidin, and the sole structural difference
between MK8383 and (+)-phomopsidin is the geometry of
the trisubstituted side-chain alkene. Therefore, we initiated the
synthesis of NH006, a derivative of MK8383 with a saturated
C13-14 bond and whose C14 configuration is the same as that of
16.
Conclusions
We successfully prepared NH006 that showed good photosta-
bility and potent antifungal activity against B. cinerea. The
stereoselective hydrogenation of the C13-14 double bond of the
intermediates in the total synthesis of (+)-phomopsidin and
MK8383 was successfully achieved. Hydrogenation was carried
out by the reaction occurring at the less hindered side using
Rh/Al2O3 catalyst or by the reaction directed by the hydroxyl
group using Crabtree’s catalyst to give both diastereomers as
the sole product in the respective reaction. Starting from the
products thus prepared, two C13-14-saturated (+)-phomopsidin
derivatives were synthesized, and the C13-14 double bond was
found to be essentially responsible for the photosensitivity of (+)-
phomopsidin and MK8383. The derivatives with a saturated C13-
14 bond prepared in this study showed high antifungal activity
when the C14 configuration was (S). The (Z) configuration of the
trisubstituted side-chain alkene of NH006 was also found to play
an important role in the high antifungal activity. As NH006 is a
promising fungicide with good photostability, a field test of the
antifungal activity of NH006 against B. cinerea is now underway,
and the results will be reported in due course.
Scheme 4 Reagents and conditions: a) LDA, AcOMe, THF, -78 ◦C; b)
Dess–Martin periodinane, CH2Cl2, rt, 84% (2 steps); c) Et3N, HMPA,
0
0
◦C, then ClP(O)(OPh)2, DMAP, rt, 98%; d) MeMgCl, Fe(acac)3, NMP,
◦C, 91%; e) DIBAL, CH2Cl2, -78 ◦C, 98%; f) PBr3, pyridine, Et2O,
rt,; g) LiAlH4, Et2O, rt, 73% (2 steps); h) TBAF, THF, reflux, 92%; i)
TBSCl, imidazole, CH2Cl2, rt, 97%; j) Bz2O, DMAP, CH2Cl2, rt, 90%; k)
TBAF, THF, rt, 100%; l) Dess–Martin periodinane, CH2Cl2, rt, 88%; m)
11, LHMDS, THF, -78 to 0 ◦C, 98%; n) LiOH·H2O, EtOH/H2O (10/1,
v/v), 82%.
Experimental
The total synthesis of NH006 was carried out starting from
aldehyde 15 on the basis of the asymmetric total synthesis of
MK8383.7 Thus, an aldol reaction of methyl acetate with 15
and subsequent Dess–Martin oxidation of the product afforded
a b–keto ester, which was converted to enol phosphate 17. A
coupling reaction of 17 with methylmagnesium bromide in a mixed
solvent composed of THF and NMP in the presence of Fe(acac)3
afforded compound 18 in 91% yield.14 Reduction of 18 with
DIBAL and subsequent treatment of the resultant alcohol with
Photostability test
500 mL of 200 mg/mL test compound in acetone was dispensed in
glass dishes (50 mm in diameter) and dried in the dark. The dishes
were exposed to artificial sunlight lump for 24 h in a chamber
(25 ◦C, 60% RH). The illumination and ultraviolet intensity
was 30,000 lux and 300–400 mW/cm2, respectively. The dried
compound was washed with 500 mL of methanol. The methanol
solution was analyzed by HPLC on an XTerra C18 column
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Disease index
Lesioned area on leaf disk
Notes and references
1 F. Wakui, K. Harimaya, M. Iwata, R. Sashita, N. Chiba and T. Mikawa,
Jpn. Kokai Tokkyo Koho, JP 07,126,211, May 16, 1995, Appl. Oct. 29,
1993; Chem. Abstr., 1995, 123, 105272b.
2 (a) H. Kobayashi, S. Meguro, T. Yoshimoto and M. Namikoshi,
Tetrahedron, 2003, 59, 455; (b) M. Namikoshi, H. Kobayashi, T.
Yoshimoto, S. Megro and K. Akano, Chem. Pharm. Bull., 2000, 48,
1452; (c) M. Namikoshi, H. Kobayashi, T. Yoshimoto and T. Hosoya,
J. Antibiot., 1997, 50, 890.
3 (a) B. Williamson, B. Tudzynski, P. Tudzynski and J. A. L. Van
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Phytopathology, 1995, 85, 637.
4 B. A. Latorre, V. Flores, A. M. Sara and A. Roco, Plant. Dis., 1994, 78,
990.
5 R. J. Grayer and T. Kokubun, Phytochemistry, 2001, 56, 253.
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Lett., 2004, 6, 553; (b) N. Hayashi, T. Suzuki, K. Usui and M. Nakada,
Tetrahedron, 2009, 65, 888.
7 (a) N. Hayashi and M. Nakada, Tetrahedron Lett., 2009, 50, 232Also see
the asymmetric total synthesis of (+)-carneic acid A: (b) S. Yamakoshi,
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5372.
0
1
2
3
No lesioned area was recognized.
Lesioned area was very small.
Lesioned area was formed less than control.
Lesioned area was formed as same as control.
(dimensions: 4.5 ¥ 50 mm) using 15%–100% CH3CN in H2O over
10 min (flow rate: 0.8 mL/min) to evaluate the residual ratio. The
residual ratio was calculated by using following equation. rediual
ratio (%) = (area exposed for 24 h)/(area not exposed)
Cabbage leaf disk test
A cabbage leaf disk test was carried out by using four disks cut
from cabbage leafs (cv. Kinkei 201 EX) with a cork borer (14 mm
in diameter); the leaves were grown in a greenhouse for 1 month.
The leaf disks were placed in a 24-well plate (Cellstarꢀ, No.
R
662160, Greiner Bio-One GmbH). The test compound solution
containing 10% acetone and 0.05% v/v spreader (Neoesterin,
Kumiai Chemical Industry Co., Ltd.) was sprayed on the four
cabbage leaf disks (8 mL/disk), and the disks were allowed to dry
naturally. A conidia suspension (1 ¥ 105 conidia/mL) of B. cinerea
containing 10% w/v potato tuber extract, 2.5% w/v dextrose, and
0.125% w/v inosine was inoculated into the leaf disks using a spray
gun (2 mL per 24-well plate). After incubation for 3 days at 21 ◦C
in a humid and dark chamber, the disks were assessed visually
for lesioned areas and the disease index was obtained from the
following table below.
8 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155; (b) M.
Frigerio, M. Santagostino and S. Sputore, J. Org. Chem., 1999, 64,
4537.
9 Crystallographic data for 5. C14H20O3, M = 236.31, orthorhombic,
3
˚
˚
a = 7.4309(10), b = 10.1138(12), c = 16.7778(18)A, V = 1260.9(3)A ,
T = 123.1 K, P21 (#19), Z = 4, Dx = 1.245 g cm-3, Mo-Ka radiation,
12303 measured reflections, 2884 independent reflections (Rint = 0.038),
R1 = 0.0488 for 2254 data with I > 2s(I), wR2 = 0.1278 (all data).
Fig. 2 shows the relative stereochemistry of 5. Crystallographic data
(excluding structure factors) for the structure in this paper have
been deposited with the Cambridge Crystallographic Data centre as
supplementary publication numbers CCDC 751813. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 IEZ, UK [fax: +44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk]. The atom numbers in Fig. 2 do not
correspond to those in Fig. 1 and Schemes 1–4.
Protective value: The protective value was calculated by using
the following equation. The disease index is the mean of the disease
indices of the four leaf disks. Protective value = ((disease index
of control)–(disease index of test compound))/(disease index of
control) ¥ 100.
10 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 13, 3769.
11 P. Wipf and S. Lim, Angew. Chem., Int. Ed. Engl., 1993, 32, 1068.
12 E. Negishi, Pure Appl. Chem., 1981, 53, 2333and references therein.
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14 (a) Reviews, see: B. D. Sherry and A. Fu¨rstner, Acc. Chem. Res., 2008,
41, 1500; (b) A. Fu¨rstner and R. Martin, Chem. Lett., 2005, 34, 624;
(c) C. Bolm, J. Legros, J. L. Paih and L. Zani, Chem. Rev., 2004, 104,
6217; (d) G. Cahiez and H. Avedissian, Synthesis, 1998, 1199. The
first report regarding the iron-catalyzed coupling reactions of Grignard
reagents with alkenyl halides: (e) M. Tamura and J. K. Kochi, J. Am.
Chem. Soc., 1971, 93, 1487.
Acknowledgements
This work was supported in part by a Waseda University Grant for
Special Research Projects, a Grant-in-Aid for Scientific Research
(B), and the Global COE program “Center for Practical Chemical
Wisdom” by MEXT.
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The Royal Society of Chemistry 2010
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