Highly stereoselective total synthesis of PM-Toxin B, a corn host-specific pathotoxin

Article abstract of DOI:10.1039/b007617l

The highly stereoselective total synthesis of PM-toxin B, a corn host-specific toxin produced by the fungal pathogen Phyllosticta maydis, has been achieved by a convergent synthetic strategy which involves cross-aldol coupling of four key segments and the

Full text of DOI:10.1039/b007617l

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Highly stereoselective total synthesis of PM-Toxin B, a corn
host-specific pathotoxin
Mitsuru Hosaka, Hiroyuki Hayakawa and Masaaki Miyashita*
1
Division of Chemistry, Graduate School of Science, Hokkaido University, Hokkaido 060-0810,
Japan. E-mail: miyasita@sci.hokudai.ac.jp
Received (in Cambridge, UK) 19th September 2000, Accepted 30th October 2000
First published as an Advance Article on the web 9th November 2000
The highly stereoselective total synthesis of PM-toxin B, a
corn host-specific toxin produced by the fungal pathogen
Phyllosticta maydis, has been achieved by a convergent
synthetic strategy which involves cross-aldol coupling of
four key segments and the regioselective reductive cleavage
of three ꢀ,ꢁ-epoxy ketone functionalities by an organo-
selenium reagent as key steps.
corn pathotoxins as well as their marked host-specific toxicity
have elicited much attention from biologists and synthetic
chemists.4,5 So far, only the synthesis of an isomeric mixture of
PM-toxin B in a racemic form by Daly and co-workers has been
reported.6 Recently, we reported the first asymmetric total
synthesis of PM-toxin A, containing a characteristic sequence
of four aldol structures, by a linear synthetic strategy which
involves four tandem aldol reactions as key steps;7 however,
the yield of the cross aldol reactions was greatly reduced as the
carbon chain length of the substrate became longer.7
We describe herein the first and highly stereoselective total
synthesis of PM-toxin B (1) by a convergent synthetic strategy
which involves cross-aldol coupling of four key segments and
the organoselenium-mediated regioselective reductive cleavage
of three α,β-epoxy ketone units as key steps.
The cause of major epidemics of Northern T-corn leaf blight
disease in the United States in 1970 has been shown to be PM-
toxin, a corn host-specific pathotoxin produced by the fungal
pathogen Phyllosticta maydis.1 PM-toxin2 and HMT-toxin3
produced by the fungal pathogen Helminthosporium maydis,
race T, are representative corn host-specific toxins.4 Among
10–15 PM-toxin components, the four major ones, PM-toxin A,
B, C, and D, have been isolated so far and found to be linear
C33 and C35 compounds containing a number of characteristic
β-ketol (aldol) structures.2 The unique structures of these
The retrosynthetic analysis for 1 is shown in Scheme 1.
Taking into consideration chemically labile aldol structures,
we designed a synthetic route which involves construction of
Scheme 1 The retrosynthetic analysis for the synthesis of 1.
DOI: 10.1039/b007617l
J. Chem. Soc., Perkin Trans. 1, 2000, 4227–4230
This journal is © The Royal Society of Chemistry 2000
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Scheme 2 Reagents: i, Ac2O, DMAP, pyridine; ii, Bu4NF, THF; iii, MCPBA, CH2Cl2, 0 ЊC; iv, NH3, MeOH; v, (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC,
then Et3N.
Scheme 3 Reagents: i, PMBOCH(᎐NH)CCl3, PPTS, CH2Cl2; ii, Bu4NF, THF; iii, MCPBA, CH2Cl2, 0 ЊC; iv, (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC,
᎐
then Et3N.
three aldol structures by regioselective reductive cleavage of
tris-epoxy ketone 2 at the final stage of the synthesis. For the
synthesis of the key tris-epoxy ketone 2, 2 was divided into the
left-half segment, bis-epoxy ketone 3, and the right-half seg-
ment, epoxy aldehyde 4, and both segments were designed to be
assembled from the key fragments 5 and 6, 7 and 8, respectively.
Furthermore, all these key fragments were designed to be syn-
thesized from the same starting material, i.e., methyl -lactate
(9), as shown in Scheme 1. The first epoxy ketone fragment 5
was efficiently and highly stereoselectively synthesized from
9 according to our previous route (63% overall yield for 6
steps).7 Similarly, the second epoxy aldehyde 6 was also stereo-
selectively synthesized from 9 employing a modified procedure7
as shown in Scheme 2. Thus, the (Z)-alkenyl alcohol 10 readily
obtainable from 9 was converted to the acetate 11, which was
then treated with Bu4NF in THF to give the (Z)-allylic alcohol
12 in 97% overall yield from 10. Upon epoxidation of the allylic
alcohol 12 with MCPBA in CH2Cl2 the α-epoxy alcohol 13
was produced exclusively and quantitatively. The epoxy alcohol
13 thus obtained was converted to the epoxy aldehyde 6 by the
two-step reaction sequence: (1) hydrolysis of the acetate with
NH3 in MeOH (93%) and (2) Swern oxidation (85%).
On the other hand, the third key fragment 7 was prepared
from the common intermediate 10 as shown in Scheme 3.
Protection of the primary hydroxy group of 10 with 4-methoxy-
benzyl (PMB) trichloroacetimidate followed by treatment of the
resulting TBDMS ether 15 with Bu4NF in THF furnished the
allyl alcohol 16 in 75% overall yield. Subsequent epoxidation
of 16 with MCPBA in CH2Cl2 proceeded cleanly giving rise to
the single α-epoxy alcohol 17 in 88% yield. The epoxy alcohol
17 thus obtained was converted to the epoxy ketone 7 by Swern
oxidation (90%).
selenium reduction.8 Thus, on treatment of 18 with sodium
(phenylseleno)triethylborate (Na[PhSeB(OEt)3])8 (2.5 equiv.)
in ethanol in the presence of AcOH (3 equiv.) at 0 ЊC, the regio-
selective reductive cleavage of the epoxide moiety occurred
to give the β-hydroxy ketone 19 as a single product in 94%
isolated yield. It should be noted that the chemo- and regio-
selective reduction of an epoxy ketone moiety is possible
by organoselenium reduction.8 Construction of the requisite
syn-1,3-diol 20 from the resulting β-hydroxy ketone 19 was
successfully performed by diethylmethoxyborane–sodium
borohydride reduction9 in THF–MeOH (5:1) in excellent yield,
and no diastereomer was detected, although other reducing
agents inevitably formed a mixture of diastereomers in variable
ratios. The 1,3-diol 20 thus obtained was converted to the
fourth key segment 8 by the three-step reaction sequence:
(1) protection of syn-1,3-diol with 2,2-dimethoxypropane
(93%); (2) hydrolysis of the acetate with NH3 in MeOH (98%);
(3) Swern oxidation (92%).
With the four key fragments 5–8 in hand, we next focused on
the cross-aldol reaction in the synthesis of the left segment
3 and the right segment 4, respectively. Initially, the left seg-
ment 3 was synthesized by the aldol reaction of 5 and 6 as in
the synthesis of PM-toxin A7 (Scheme 5). On the other hand,
the right segment 4 was successfully synthesized according to
Scheme 5. Thus, the cross-aldol reaction of 7 (1.3 equiv.) and 8
(1 equiv.) by the use of lithium hexamethyldisilazide (LiHMDS,
1.3 equiv.) as base smoothly proceeded in THF at Ϫ78 ЊC
giving rise to the hydroxy ketone 23 as a diastereomeric mixture
in 63% yield. Subsequent treatment of 23 with methanesulfonyl
chloride in CH2Cl2 in the presence of DMAP directly afforded
the enone 24 in 77% yield, which was submitted to catalytic
hydrogenation over 10% Pd-C in ethyl acetate followed by
treatment with DDQ to give the epoxy alcohol 25 in 79%
overall yield. Swern oxidation of the resulting alcohol 25
furnished the desired segment 4 in 94% yield.
The fourth fragment 8 containing a syn-1,3-diol moiety was
efficiently and highly stereoselectively synthesized according
to Scheme 4. First, the epoxy alcohol 13 used in the synthesis
of the fragment 6 was transformed into the epoxy ketone 18
by Swern oxidation, which was then subjected to the organo-
With the left and right segments 3 and 4 in hand, we set out
the final coupling reaction in the total synthesis of PM-toxin B
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Scheme 4 Reagents: i, (COCl)2, DMSO, CH2Cl2, Et3N; ii, Na[PhSeB(OEt)3], AcOH, EtOH, 0 ЊC, 1 h; iii, (CH3CH2)2BOCH3, NaBH4,
THF–MeOH; iv, (CH3)2C(OCH3)2, PPTS, CH2Cl2; v, NH3, MeOH.
Scheme 5 Reagents: i, LiHMDS (1.3 equiv.), THF, Ϫ78 ЊC, then 8; ii, CH3SO2Cl, DMAP, CH2Cl2; iii, H2, 10% Pd-C, AcOEt; iv, DDQ,
CH2Cl2–H2O (10:1); v, (COCl)2, DMSO, CH2Cl2, Et3N.
(1) (Scheme 6). Fortunately, the key aldol reaction of 3 and 4
cleanly occurred with the use of LiHMDS in THF at Ϫ78 ЊC,
giving rise to the β-hydroxy ketones 26 as a diastereomeric
mixture in 72% isolated yield, although we were afraid that the
yield of this cross-aldol reaction might decrease greatly as in
the synthesis of PM-toxin A.7 We were pleased, therefore, to
obtain optimal results. The products 26 thus obtained were
converted to the tris-epoxy ketone 2 by the two-step reaction
sequence: (1) mesylation (79%) and (2) hydrogenation (87%).
Thus, the key tris-epoxy ketone 2 for the synthesis of 1 was
secured in an optically pure form based on the convergent
aldol strategy. The critical organoselenium reduction of 2
was successfully performed by treatment with benzeneselenol
(PhSeH) generated in situ from Na[PhSeB(OEt)3] (15 equiv.)8
and acetic acid (18 equiv.) in EtOH at 0 ЊC, whereupon the
reductive cleavage of three epoxy ketone moieties occurred
regioselectively at the α-position, giving rise to the crystalline
tris-β-ketol 27 in 93% yield. Finally, on treatment of the
resulting tris-β-hydroxy ketone 27 with 1 M HCl in THF at
0 ЊC, PM-toxin B (1) was obtained as crystals in 82% yield.
Physical properties of the synthetic compound: mp 126–
126.5 ЊC (from acetone); [α]D24 Ϫ29.7 (c 0.38, CHCl3), Ϫ6.8
J. Chem. Soc., Perkin Trans. 1, 2000, 4227–4230
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Scheme 6 Reagents: i, LiHMDS (1.3 equiv.), THF, Ϫ78 ЊC, then 4; ii, CH3SO2Cl, DMAP, CH2Cl2; iii, H2, 10% Pd-C, AcOEt; iv, Na[PhSeB(OEt)3],
AcOH, EtOH; v, 1 M HCl, THF, 0 ЊC.
3 Y. Kono, S. Takeuchi, A. Kawarada, J. M. Daly and H. W. Knoche,
Tetrahedron Lett., 1980, 21, 1537; Y. Kono, S. Takeuchi,
A. Kawarada, J. M. Daly and H. W. Knoche, Agric. Biol. Chem.,
1980, 44, 2613; Y. Kono, S. Takeuchi, A. Kawarada, J. M. Daly
and H. W. Knoche, Bioorg. Chem., 1981, 10, 206.
4 J. M. Daly, Y. Kono, Y. Suzuki and H. W. Knoche, in Pesticide
Chemistry, ed. J. Miyamoto, Pergamon Press, Oxford, 1983, p. 11;
Y. Kono, Y. Suzuki and S. Takeuchi, J. Synth. Org. Chem. Jpn., 1985,
43, 980.
(c 0.35, MeOH); UV λmax 280 nm (ε 108, MeOH); CD λmax 281
nm (∆ε 0.36, MeOH); FD-MS m/z 587 (M ϩ Hϩ), m/z 609
(M ϩ Naϩ), 625 (M ϩ Kϩ). These results are in agreement
with the reported data except melting point 97 ЊC, [α]D25 Ϫ10
(MeOH), UV λmax 275 nm (ε 138, MeOH), CD λmax 281 nm
(∆ε 0.36, MeOH)).2b 1H NMR and 13C NMR spectra of the
synthetic compound were identical with those of natural
PM-toxin B.6,10
In conclusion, the highly stereoselective total synthesis of
PM-toxin B (1) has been achieved by a convergent strategy
involving cross-aldol reactions and the regioselective reductive
cleavage of α,β-epoxy ketone units as key steps.
This work was supported by a Grant-in-Aid for JSPS Fellows
(No. 2709) and a Grant-in-Aid for Scientific Research on
Priority Areas (No. 706: Dynamic Control of Stereochemistry)
from the Ministry of Education, Science, Sports and Culture
of Japan.
5 Y. Suzuki, H. W. Knoche and J. M. Daly, Bioorg. Chem., 1982, 11,
300; Y. Suzuki, S. J. Danko, Y. Kono, S. Takeuchi, J. M. Daly and
H. W. Knoche, Agric. Biol. Chem., 1984, 48, 2321.
6 Y. Suzuki, S. J. Danko, Y. Kono, J. M. Daly and S. Takeuchi,
Agric. Biol. Chem., 1985, 49, 149.
7 H. Hayakawa, M. Ohmori, K. Takamichi, F. Matsuda and
M. Miyashita, Chem. Commun., 1997, 1219.
8 M. Miyashita, T. Suzuki, M. Hoshino and A. Yoshikoshi,
Tetrahedron, 1997, 53, 12469; T. Suzuki and M. Miyashita, J. Synth.
Org. Chem. Jpn., 1998, 56, 736.
9 K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic and
M. J. Shapiro, Tetrahedron Lett., 1987, 28, 155.
1
10 H NMR (500 MHz, C5D5N): 0.82 (t, J = 7.0 Hz, 3H), 1.12–1.78
Notes and references
(m, 38H), 1.37 (d, J = 6.2 Hz, 3H), 1.87 (dt, J = 13.8, 9.5 Hz,
1H), 2.54 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.3 Hz, 4H), 2.61
(dd, J = 15.0, 4.1 Hz, 1H), 2.62 (dd, J = 15.0, 4.1 Hz, 1H), 2.63
(dd, J = 15.0, 4.1 Hz, 1H), 2.79 (dd, J = 15.0, 8.6 Hz, 2H), 2.81
(dd, J = 15.0, 8.6 Hz, 1H), 4.01–4.12 (m, 1H), 4.24–4.47 (m, 4H);
13C NMR (125 MHz, C5D5N): 210.3, 210.3, 210.3, 71.3, 67.8,
67.7, 67.7, 67.6, 51.3, 51.3, 51.3, 46.5, 43.8, 43.8, 43.8, 38.6, 38.3,
38.1, 38.1, 32.0, 29.6, 29.5, 29.5, 25.9, 25.9, 25.8, 25.7, 24.6, 23.9,
23.9, 23.9, 22.9, 14.1.
1 J. C. Comstock, C. A. Martinson and B. C. Gegenbach, Phyto-
pathology, 1973, 63, 1357; O. C. Yoder, Phytopathology, 1973, 63,
1361.
2 (a) Y. Kono, S. J. Danko, Y. Suzuki, S. Takeuchi and J. M. Daly,
Tetrahedron Lett., 1983, 24, 3803; (b) S. J. Danko, Y. Kono,
J. M. Daly, Y. Suzuki, S. Takeuchi and D. A. McCrery,
Biochemistry, 1984, 23, 759; (c) Y. Kono, Y. Suzuki, S. Takeuchi,
H. W. Knoche and J. M. Daly, Agric. Biol. Chem., 1985, 49, 559.
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