Asymmetric total synthesis of PM-toxin A, a corn host-specific pathotoxin

Article abstract of DOI:10.1039/a702208e

The first asymmetric total synthesis of PM-toxin A, a corn host-specific toxin produced by the fungal pathogen Phyllosticta maydis, starting from D-lactate is described.

Full text of DOI:10.1039/a702208e

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Asymmetric total synthesis of PM-toxin A, a corn host-specific pathotoxin
Hiroyuki Hayakawa, Makiko Ohmori, Kiyoko Takamichi, Fuyuhiko Matsuda and Masaaki Miyashita*
Division of Chemistry, Graduate School of Science, Hokkaido University, Hokkaido 060, Japan
The first asymmetric total synthesis of PM-toxin A, a corn
host-specific toxin produced by the fungal pathogen Phyllos-
ticta maydis, starting from d-lactate is described.
alcohol 6 in 93% overall yield after purification by silica gel
chromatography. Oxidation of the resulting alcohol 6 with
2 2
MCPBA in CH Cl gave rise to the a-epoxy alcohol 7 as the
sole product in 90% yield, which was submitted to the Swern
oxidation resulting in the formation of the desired epoxy ketone
8 in 79% yield. Thus a key compound for the synthesis of PM-
toxin A 1 was synthesized in a stereoselective manner.
The fungal pathogen Phyllosticta maydis produces a corn host-
specific pathotoxin, PM-toxin, which was revealed to be the
cause of major epidemics of Northern T-corn leaf blight disease
1
2
3
in the United States. PM-toxin and the HMT-toxin, produced
by the fungal pathogen Helminthosporium maydis, race T, are
representative corn host-specific toxins.4 PM-toxin consists of
Another key component 15 was synthesized according to
Scheme 2. The Wittig reaction of the aldehyde 4 with pent-
4-enyltriphenylphosphonium bromide gave the (Z)-alkene 9
along with a minor amount of the (E)-isomer. Since the alkenes
could not be separated at this stage, the mixture was treated with
9-borabicyclo[3.3.1]nonane (9-BBN) followed by treatment
1
0–15 components, of which the four major ones—PM-toxin A,
B, C and D—have been isolated so far and determined to be
linear C33 and C35 compounds containing a number of
2
characteristic b-ketol (aldol) structures. The unique structures
with alkaline H
mixture of isomers. Subsequent acetylation of 10 with Ac
followed by treatment of the resulting acetate 11 with Bu NF in
2 2
O to furnish the alcohol 10 as an inseparable
of these corn pathotoxins as well as their marked host-specific
toxicity have elicited much attention from biologists and
synthetic chemists.4
2
O
4
,5
THF gave rise to the desired (Z)-allylic alcohol 12 in 81%
overall yield from 3 after purification by silica gel column
chromatography.† Upon epoxidation of the allylic alcohol 12
OH
O
OH
O
2 2
with MCPBA in CH Cl the a-epoxy alcohol 13 was ex-
clusively formed in 88% yield. The epoxy alcohol 13 thus
obtained was converted to the keto aldehyde 15, the second key
intermediate, by the two step reaction sequence: (i) hydrolysis
of the acetate (97%) and (ii) Swern oxidation (72%).
O
OH
O
OH
PM-Toxin A 1
With the key compounds 8 and 15 in hand, we set about the
crucial tandem aldol reaction toward the synthesis of tetrakis-
epoxy ketone 22. The first aldol reaction of 8 and 15 with
lithium hexamethyldisilazide (LiHMDS) as base smoothly
proceeded in THF at 278 °C giving rise to the hydroxy ketone
We report here the first and highly stereoselective total
synthesis of PM-toxin A 1 starting from d-lactate, in which
three tandem aldol reactions and the regiospecific organoselen-
ium-mediated reduction of four consecutive a,b-epoxy ketone
1
6 as a diastereoisomeric mixture in 64% isolated yield
Scheme 3). Subsequent treatment of 16 with methanesulfonyl
chloride in CH Cl in the presence of DMAP directly afforded
units are involved as key steps.
(
t
The starting methyl d-lactate 2 was treated with Bu Me
and imidazole in DMF to give 3 in nearly quantitative yield
Scheme 1). Reduction of 3 with DIBAL-H cleanly produced
the aldehyde 4 which was subjected to the Wittig reaction with
hexyltriphenylphosphonium bromide to give the (Z)-alkene 5
along with a trace amount of the (E)-isomer. Subsequent
2
SiCl
2
2
(
OSiMe2But
OSiMe2But
i
OHC
4
9
4
treatment of 5 with Bu NF in THF afforded the (Z)-allylic
ii
OSiMe2But
OSiMe2But
OSiMe2But
OSiMe2But
OH
AcO
iii HO
i
8%
ii
MeO2C
MeO2C
OHC
9
11
10
2
3
4
iv 81% from 3
iii
OH
OH
v
OH
OSiMe2But
AcO
AcO
HO
iv
88%
9
3% from 3
O
6
5
1
2
13
v
90%
O
vi 97%
OH
O
O
OH
vi
vii
OHC
7
9%
7
2%
O
SiCl, imidazole, DMF; ii,
O
O
7
8
15
14
t
Scheme 1 Reagents and conditions: i, Bu Me
2
Scheme 2 Reagents and conditions: i, pent-4-enyltriphenylphosphonium
DIBAL-H, toluene, 278 °C; iii, hexyltriphenylphosphonium bromide,
BuLi, toluene; iv, Bu NF, THF; v, MCPBA, CH Cl , 0 °C; vi, (COCl)
DMSO, CH Cl , 278 °C, then Et
bromide, BuLi, toluene; ii, 9-BBN, THF, 0 °C, then 8 m NaOH, H ; iii,
Ac O, DMAP, pyridine; iv, Bu NF, THF; v, MCPBA, CH Cl , 0 °C; vi,
NH , MeOH; vii, (COCl) , DMSO, CH Cl , 278 °C, then Et
2 2
O
4
2
2
2
,
2
4
2
2
2
2
3
N
3
2
2
2
3
N
Chem. Commun., 1997
1219

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O
O
O
O
OH
O
O
O
O
i
ii
6
4%
85%
O
O
O
O
O
O
O
O
8
16
17
iii 84%
O
O
O
i
4
4%
O
OH
O
O
19
18
ii, iii 67%
O
O
O
i
O
20
28%
O
O
OH
O
O
O
O
O
O
21
ii, iii 68%
O
O
O
O
iv
1
46%
O
O
O
O
22
Scheme 3 Reagents and conditions: i, LiHMDS, THF, then 15, 278 °C; ii, MeSO
2 2 2 2 3
Cl, DMAP, CH Cl ; iii, H , 10% Pd–C, EtOAc; iv, Na[PhSeB(OEt) ]
(
16 equiv.), AcOH (24 equiv.), EtOH, 0 °C
the enone 17 in 85% yield, which was then submitted to
catalytic hydrogenation over 10% Pd–C in EtOAc, resulting in
the formation of the bis-epoxy ketone 18 in 84% yield. Thus the
bis-epoxy ketone 18 could be synthesized via a three step
reaction sequence. The second aldol reaction of 18 and 15 was
similarly performed using LiHMDS in THF at 278 °C giving
the b-hydroxy ketone 19‡ in 44% yield. Apparently, the yield of
the second aldol reaction is lower than that of the first. The
products 19 were similarly converted to the tris-epoxy ketone
tetraacetate. We are grateful to the Syourai Foundation and the
Hoansya Foundation for their financial support.
Footnotes
* E-mail: miyasita@schem.ec.hokudai.ac.jp
† At this stage, it was confirmed that no racemization of the aldehyde 4 had
1
taken place via H NMR analysis of the (S)-mandelate ester of 12.
‡
§
4
A diastereoisomeric mixture.
2
2
Selected data for PM toxin A 1: mp 117–119 °C (from acetone); [a]
D
2
2
0 by the two step reaction sequence of mesylation (80%) and
5 (c 0.16, CHCl ); UV lmax 275.2 nm (MeOH); CD lmax 281 nm (MeOH);
3
subsequent hydrogenation (84%). The third aldol reaction of 20
and 15 was, as anticipated, reluctant to proceed under similar
conditions, resulting in the formation of 21 in 28% yield. The
products 21‡ thus obtained were also converted to the tetrakis-
epoxy ketone 22 by the two step reaction sequence of
mesylation (90%) followed by catalytic hydrogenation (76%).
Although the final aldol reaction suffered from low yield, the
critical compound 22 for the synthesis of PM-toxin A 1 was
secured in an optically pure form via the tandem aldol strategy.
2
+ +
FAB-MS m/z 583 (M–H ); FD-MS m/z 607 (M + Na ), 623 (M + K ). The
a] was measured in CHCl since the synthetic pure compound was almost
insoluble in MeOH. Data for an authentic sample: mp 118–119 °C; [a]
282 nm (MeOH); FAB-
[
D
3
25
D
2 11 (MeOH); UV l
max
+
276 nm (MeOH); CD l
max
+
MS m/z 585 (M + H ); FD-MS m/z 607 (M + Na ) (ref. 2).
References
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6
Finally, the organoselenium-mediated reduction of the tetra-
2
Y. Kono, S. J. Danko, Y. Suzuki, S. Takeuchi and J. M. Daly,
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synthesis, was performed by treatment of 22 with benzenesele-
nol (PhSeH, 16 equiv.) generated in situ from sodium
7
59.
7
(
phenylseleno)triethylborate (16 equiv.) and acetic acid (24
3
4
Y. Kono, S. Takeuchi, A. Kawarada, J. M. Daly and H. W. Knoche,
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6,8
equiv.) in ethanol. The reduction of four consecutive epoxy
ketone moieties occurred regiospecifically at the a-position as
7
expected, and the crystalline PM-toxin A 1 was obtained in
4
6% isolated yield (68% based on the consumed substrate) after
purification by silica gel chromatography. The physical proper-
ties of the synthetic compound§ were identical with those of an
5 Y. Suzuki, S. J. Danko, Y. Kono, S. Takeuchi, J. M. Daly and
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1
13
authentic specimen. Furthermore, H and C NMR spectra of
the corresponding tetraacetate derived from the synthetic
compound were also identical with those of authentic PM-toxin
A tetraacetate. Thus the stereoselective asymmetric total
synthesis of PM-toxin A 1 has been achieved by employing
tandem aldol reactions and the regiospecific organoselenium-
mediated reduction of a,b-epoxy ketone units as key steps.
We acknowledge Professor Y. Kono (Ibaragi University) for
1
985, 49, 149.
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4
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1
providing us with a H NMR spectrum of authentic PM-toxin A
Received in Cambridge, UK, 2nd April 1997; Com. 7/02208E
1220
Chem. Commun., 1997