The first total synthesis of (-)-solanapyrone E based on domino Michael strategy.

Article abstract of DOI:10.1021/ol006893h

[figure: see text] A phytotoxin, solanapyrone E, has been synthesized from the decalone prepared by the domino Michael reaction of the kinetic enolate of optically pure acetylcyclohexene with methyl crotonate. After several transformations on the decalone

Full text of DOI:10.1021/ol006893h

ORGANIC
LETTERS
2001
Vol. 3, No. 2
251-254
The First Total Synthesis of
(−)-Solanapyrone E Based on Domino
Michael Strategy
Hisahiro Hagiwara,*,†,‡ Katsuhiro Kobayashi,† Shigeki Miya,† Takashi Hoshi,§
Toshio Suzuki,§ and Masayoshi Ando§
Graduate School of Science and Technology and Faculty of Engineering,
Niigata UniVersity, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
hagiwara@gs.niigata-u.ac.jp
Received November 20, 2000
ABSTRACT
A phytotoxin, solanapyrone E, has been synthesized from the decalone prepared by the domino Michael reaction of the kinetic enolate of
optically pure acetylcyclohexene with methyl crotonate. After several transformations on the decalone ring, condensation of a methyl acetoacetate
equivalent installed a pyrone moiety and introduction of a hydroxymethyl unit into the pyrone ring furnished solanapyrone E.
Solanapyrones D (1)1 and E (2)2 are polyketide natural
products isolated with solanapyrones A (3), B (4), or C (5)3
by Oikawa and Ichihara from Altenaria solani, a causal
fungus of early blight disease to tomato and potato. Phyto-
toxic activity of these compounds was assayed on growth
inhibition of lettuce seedlings,4 and the formyl derivatives 1
and 3 exhibited complete inhibition at 250 ppm, stronger
activity than the hydroxyl analogue 2 and 4. The structure
of solanapyrones contains a characteristic cis or trans decalin
framework and a pyrone moiety with a 14-oxygenated methyl
group in common. Racemic solanapyrone A (3) has already
† Graduate School of Science and Technology.
‡ Tel/fax: +81-25-262-7368.
§ Faculty of Engineering.
(1) Oikawa, H.; Yokota, T.; Ichihara, A.; Sakamura, S. J. Chem. Soc.,
Chem. Commun. 1989, 1284.
(2) Oikawa, H.; Suzuki, Y.; Naya, A.; Katayama, K.; Ichihara, A. J.
Am. Chem. Soc. 1994, 116, 3605.
(3) Ichihara, A.; Tazaki, H.; Sakamura, S. Tetrahedron. Lett. 1986, 24,
5373.
been synthesized by an intramolecular Diels-Alder reaction
(4) Oikawa, H.; Yokota, T.; Sakano, C.; Suzuki, Y.; Naya, A.; Ichihara,
A. Biosci. Biotecnol. Biochem. 1998, 62, 2016.
(5) Ichihara, A.; Miki, M.; Tazaki, H.; Sakamura, S. Tetrahedron. Lett.
1987, 28, 1175 and earlier references therein.
(6) Oikawa, H.; Kobayashi, T.; Katayama, K.; Suzuki, Y.; Ichihara, A.
J. Org. Chem. 1998, 63, 8748.
as a key step5 in which solanapyrone D (1) was obtained as
a byproduct before isolation from the fungus.
Investigation of these compounds proved the existence of
Diels-Alderase for the first time2,6 and led to the recent
10.1021/ol006893h CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/05/2001

synthesis of the natural solanapyrone A (3) by an enzymatic
Diels-Alder reaction.6 These results prompted us to inves-
tigate chemical synthesis. We describe herein the first total
synthesis of solanapyrone E (2) based on our general strategy
employing the domino Michael reaction.
overall yield. It is important in the presence of 2 equiv of
hexamethylphosphortriamide (HMPA) to employ the kinetic
enolate of 6 generated by cleavage of the trimethylsilylenol
ether 7 by methyllithium. Rigorous NMR study of the
decalone 8 revealed that the ester group at C-1 still remained
in an R-axial position. The proton at C-1 appeared at δ 3.02
(t-like, J 2.1 Hz) and had a W-type long-range coupling with
the â-equatorial proton at C-3.
The initial part of the synthesis involving stereoselective
construction of trans-decalone is summarized in Scheme 1.
From the relative stereochemistry of the decalone 8, the
present domino Michael reaction is anticipated to proceed
according to the pathway shown in Scheme 2. The first
Scheme 1
Scheme 2
Michael addition occurred from the less hindered R-face of
the enolate to s-cis-crotonate which was connected by
chelation to the enolate. The second Michael addition
occurred from the same face, keeping chelation, to give
enolate 20. Axial protonation to the enolate 20 furnished the
decalone 21 having a cis-steroidal conformation. After the
usual aqueous workup procedure, an inseparable mixture of
the decalones 8 and 21 was isolated. It is worth noting that
the chiral center in 7 controls the stereochemistry of the first
Michael reaction and consequently subsequent reactions.
The chiral directing siloxy group at C-9 in the decalone 8
was removed prior to introduction of double bond at C-3.
Deprotection of the TBDMS group with aqueous hydrogen
fluoride (HF) gave alcohol 99 in 94% yield, and subsequent
solid-state reaction with thiocarbonyldiimidazole10 success-
fully provided thiocarbonylimidazolide 10 in 90% yield. The
reaction proceeded simply by grinding the substrate 9 and
thiocarbonyldimidazole with a pestle in a mortar under a
nitrogen atmosphere. Probably due to the proximity of the
hydroxy group at C-9 with the ester group at C-1, all
conventional attempts to prepare xanthate via alkoxide failed.
The imidazolide 10 was reduced with n-tributyltin hydride
in hot benzene to afford decalone 11 in 94% yield. To
introduce a double bond selectively at C-3 by syn elimination,
the carbonyl group at C-4 of the decalone 11 was reduced
with L-Selectride to give axial alcohol 12 in 90% yield.
The synthesis started from enantiomerically pure trimethyl-
silylenol ether 7 of (S)-acetylcyclohexene 6 obtained by
lipase-catalyzed enantioselective acylation.7,8 As previously
exemplified in the successful total synthesis of (+)-com-
pactin,8 domino Michael reaction between methyl crotonate
and the kinetic enolate of 6 provided stereoselectively a
decalone which was subsequently treated with base to ensure
isomerization into more stable trans-decalone 8 in 86%
(7) Hagiwara, H.; Nakano, T.; Uda, H. Bull. Chem. Soc. Jpn. 1993, 66,
3110.
(8) Hagiwara, H.; Kon-no, M.; Nakano, T.; Uda, H. J. Chem. Soc., Perkin
Trans. 1 1995, 777.
(9) All new compounds from 9 to 14 and 16 gave satisfactory combustion
analyses. Compounds 15 and 17 were used for further transformation without
purification. Compounds 22-27 were transformed soon after purification.
(10) Hagiwara, H.; Ohtsubo, S.; Kato, M. Tetrahedron 1997, 53, 2415.
252
Org. Lett., Vol. 3, No. 2, 2001

According to MM2 calculations11 of all plausible substrates
for the isomerization at C-1, the energy stabilization of the
decalone 12 was the largest after isomerization into 13. To
this end, the R-axial ester group of 12 was then isomerized
into the thermodynamically more stable â-equatorial orienta-
tion by treatment with potassium tert-butoxide (t-BuOK) in
dimethyl sulfoxide (DMSO) to furnish decalone 13 having
all the requisite stereocenters for solanapyrones D (1) and E
(2). Alcohol 13 was transformed into xanthate 14 in 91%
yield using t-BuOK as a base. Then a double bond was
selectively introduced at C-3 by xanthate pyrolysis. After
heating the xanthate 14 in 1-methylnaphthalene at 190 °C,
to the resulting solution of ester 15 was directly added lithium
aluminum hydride (LAH) to give alcohol 16 in 89% overall
yield over two steps. Pyridinium chlorochromate (PCC)
oxidation of alcohol 16 provided aldehyde 17 which was
used for the next transformation without further purification.
Installation of the pyrone ring is summarized in Scheme
3. Aldehyde 17 was reacted with the bistrimethylsilyl enol
Introduction of the hydroxymethyl group at C-14 was not
a trivial task. Model experiments of 4-hydroxypyrone with
formaldehyde provided dimeric compounds. Nucleophilicity
of the vinylic carbanion at C-2 of 4-methoxypyrone was low.
However, we found our original method which is sum-
marized in Scheme 4. The phenylthiomethyl group was
Scheme 4
Scheme 3
introduced to pyrone 24 with paraformaldehyde and thiophe-
nol (PhSH) according to the procedure of Moreno-Manas et
al.14 to give sulfide 25 in 84% yield. Conventional O-
methylation of sulfide 25 provided in 77% yield methyl ether
26 which was oxidized with MCPBA to give sulfoxide 27
in 88% yield. Final treatment of sulfoxide 27 with trifluo-
roacetic anhydride followed by basic workup completed the
total synthesis of solanapyrone E (2) in 62% yield. The
reaction is explained as methoxy group assisted substitution
of trifluoroacetoxysulfonium ion by trifluoroacetoxy anion.
No aldehydic product as a result of Pummerer reaction was
isolated. Detailed results on the introduction of a hydroxy-
ether of methyl acetoacetate12 in the presence of titanium
tetrachloride (TiCl4) to afford δ-hydroxy-â-ketoester 22 in
73% yield from alcohol 16. Jones oxidation provided â,δ-
diketoester 23 in 74% yield, and subsequent treatment with
DBU13 furnished pyrone 24 in 93% yield.
(14) (a) de March, P.; Moreno-Manas, M.; Pi, R.; Trius, A. J. Heterocycl.
Chem. 1982, 19, 335. (b) Moreno-Manas, M. Synthesis 1984, 430.
(15) The optical rotation of stable synthetic intermediates in CHCl3 at
20 °C were as follows: 8 [R]D +43.1 (c 1.01), 9 [R]D +43.8 (c 1.00), 10
[R]D +20.3 (c 1.00), 11 [R]D +27.1 (c 1.00), 12 [R]D +39.5 (c 1.00), 13
[R]D -31.2 (c 1.00), 14 [R]D -29.9 (c 1.10), 16 [R]D -126.8 (c 1.07), and
26 [R]D -121.7 (c 0.98).
(11) Molecular modeling was performed using PCMODEL (Serena
Software, Bloomington, IN).
(12) Hagiwara, H.; Kimura, K.; Uda, H. J. Chem. Soc., Perkin Trans. 1
1992, 693.
(13) Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron.
Lett. 1996, 37, 2997.
Org. Lett., Vol. 3, No. 2, 2001
253

methyl unit to the pyrone ring will be reported in due course.
NMR data (500 MHz) of synthetic solanapyrone E (2) were
completely identical with those of the natural product kindly
provided by Prof. Oikawa {[R]D -155° (CHCl3, c 0.93), lit.4
[R]D -76° (CHCl3, c 1.0)}.15
Kobayashi, T. Ohtsubo, and I. Yamamoto, Tohoku Univer-
sity, for preliminary experiments.
Supporting Information Available: NMR spectra (500
MHz) of both synthetic and natural compounds 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Prof. H. Oikawa, Hokkaido
University, for providing spectral data of natural solanapy-
rone E. Thanks are also due to Mr. T. Okamoto, M.
OL006893H
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Org. Lett., Vol. 3, No. 2, 2001