First total syntheses of the phytotoxins solanapyrones D and E via the domino Michael protocol

Article abstract of DOI:10.1021/jo0163602

The phytotoxins solanapyrones D (1) and E (2) have been synthesized from the decalone prepared by the domino Michael reaction of the kinetic enolate of optically pure acetylcyclohexene with methyl crotonate. The decalone was transformed into a solanapyrone core by equilibration into thermodynamically stable trans-decalone (11), dehydroxylation, and dehydration. Condensation of a methyl acetoacetate equivalent followed by cyclization installed a pyrone moiety. Introduction of a formyl or hydroxymethyl unit into the pyrone ring via Pummerer related reactions furnished solanapyrones D (1) and E (2).

Full text of DOI:10.1021/jo0163602

F ir st Tota l Syn th eses of th e P h ytotoxin s Sola n a p yr on es D a n d E
via th e Dom in o Mich a el P r otocol
Hisahiro Hagiwara,*,† Katsuhiro Kobayashi,† Shigeki Miya,† Takashi Hoshi,‡ Toshio Suzuki,‡
Masayoshi Ando,‡ Tetsuji Okamoto,§ Masaki Kobayashi,§ Isao Yamamoto,§ Satoru Ohtsubo,§
Michiharu Kato,§ and Hisashi Uda§
Graduate School of Science and Technology, Niigata University, 8050,
2-nocho, Ikarashi, Niigata 950-2181, J apan, Faculty of Engineering, Niigata University,
8050, 2-nocho, Ikarashi, Niigata 950-2181, J apan, and Institute for Chemical Reaction Science,
Tohoku University, Katahira, 2-1-1, Aoba-ku, Sendai 980-8577, J apan
hagiwara@gs.niigata-u.ac.jp
Received December 11, 2001
The phytotoxins solanapyrones D (1) and E (2) have been synthesized from the decalone prepared
by the domino Michael reaction of the kinetic enolate of optically pure acetylcyclohexene with methyl
crotonate. The decalone was transformed into a solanapyrone core by equilibration into thermo-
dynamically stable trans-decalone (11), dehydroxylation, and dehydration. Condensation of a methyl
acetoacetate equivalent followed by cyclization installed a pyrone moiety. Introduction of a formyl
or hydroxymethyl unit into the pyrone ring via Pummerer related reactions furnished solanapyrones
D (1) and E (2).
In tr od u ction
Solanapyrones D (1)1 and E (2)2 are polyketide natural
products isolated with solanapyrone 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
plants. Subsequently, Strange et al.4 discovered solanapy-
rones A (3) and C (5) from stationary cultures of Asco-
chyta rabiet on a Czapek-Dox medium, supplemented
with an extract of chickpea seed. Those fungi are known
to reduce large amounts of chickpea, tomato, or potato
crops by infecting the plants when the weather of their
growing season is cool and moist. Recently, during the
course of examination of the antialgal effects of fungal
metabolites, the isolation of cis-solanapyrones C (5), E
(6),5 F (7), and G (8), having an amino group in the pyrone
nucleus, was reported by Fenical et al.6 from the uni-
dentified marine organism isolated from the surface of
the green alga Halimedia monile (Figure 1). Distribution
of solanapyrones in terrestrial as well as marine organ-
isms is very interesting in view of the common biogenesis
among the different organisms. Their biological activities
are yet to be explored. Phytotoxic activities of solanapy-
rones A (3), B (4), C (5), D (1), and E (2) were assayed on
F IGURE 1.
the growth inhibition of lettuce seedlings,2 and the formyl
derivatives 1 and 3 exhibited complete inhibition at 250
ppm, stronger activity than those of the hydroxyl ana-
logues 2 and 4. In addition, solanapyrone C (5) exhibited
substantial antialgal activity at a concentration of 300
µM against marine unicellular alga Dunaliella sp.
Racemic solanapyrone A (3) has been synthesized by
an intramolecular Diels-Alder reaction as a key step7
in which solanapyrone D (1) was obtained as a byproduct
* Corresponding author. Telephone/fax: +81-25-262-7368.
† Graduate School of Science and Technology, Niigata University.
‡ Faculty of Engineering, Niigata University.
§ Institute for Chemical Reaction Science, Tohoku University.
(1) Oikawa, H.; Yokota, T.; Ichihara, A.; Sakamura, S. J . Chem. Soc.,
Chem. Commun. 1989, 1284-1285.
(2) Oikawa, H.; Yokota, T.; Sakano, C.; Suzuki, Y.; Naya, A.;
Ichihara, A. Biosci. Biotecnol. Biochem. 1998, 62, 2016-2022.
(3) Ichihara, A.; Tazaki, H.; Sakamura, S. Tetrahedron Lett. 1983,
24, 5373-5376.
(4) Alam, S. S.; Bilton, J . N.; Slawin, A. M. Z.; Williams, D. J .;
Sheppard, R. N.; Strange, R. Phytochemistry 1989, 28, 2627-2630.
(5) The name “solanapyrone E” has double structures.
(6) J enkins, K. M.; Toske, S. G.; J ensen, P. R.; Fenical, W. Phy-
tochemistry 1998, 49, 2299-2304.
(7) Ichihara, A.; Miki, M.; Tazaki, H.; Sakamura, S. Tetrahedron
Lett. 1987, 28, 1175-1178.
10.1021/jo0163602 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/10/2002
J . Org. Chem. 2002, 67, 5969-5976
5969

Hagiwara et al.
SCHEME 1
SCHEME 2a
prior to isolation from the fungus. This result implied
the intervention of Diels-Alderase in the biosynthetic
pathway, and Oikawa and co-workers unveiled the exist-
ence of Diels-Alderase for the first time through their
study of the biosynthesis of solanapyrone A (3).8 Actually,
by incubation of the achiral triene precursor in the crude
enzyme extract from A. solani, they obtained solanapy-
rone A (3) in 53% yield with 98% ee.
The success of the synthesis of natural solanapyrone
A (3) by an enzymatic Diels-Alder reaction8 prompted
us to investigate chemical synthesis, and we describe
herein the first total syntheses of solanapyrone D (1)9
and E (2).
a
Reagents and conditions: (i) MeLi, methyl crotonate, HMPA,
THF; (ii) MeONa, MeOH, 86% from 14; (iii) aq HF, CH3CN, 94%;
(iv) 1,1′-thiocarbonyldiimidazole, 90%; (v) AIBN, Bu3SnH, benzene,
93%; (vi) L-selectride, aq NaOH, H2O2, THF, 90%; (vii) t-BuOK,
t-BuOH, DMSO, 78%; (viii) t-BuOK, CS2, MeI, THF, 91%; (ix)
1-methylnaphthalene, 190 °C; (x) LAH, Et2O, 89% from 20.
the kinetic enolate 9 generated by cleavage of the
trimethylsilyl enol ether (14) by methyllithium provided
decalone 10, which was treated with base to ensure
isomerization into more stable trans-decalone 11 (in 86%
overall yield), whose relative structure was established
by intensive NMR study.11 In the decalone 11, the ester
group at C-1 still stayed in the R-axial position, contrary
to our expectation. The double Michael reaction pro-
ceeded via chelation control between the enolate and
Michael partners. Discussions on the reaction pathway
have already been described in our earlier literature.9
Before the introduction of a double bond at C-3 of the
decalone 11, the chiral directing alkoxy group at C-9 was
removed by radical cleavage. After deprotection of the
TBDMS group by hydrogen fluoride in 94% yield, the
solid-state reaction of the resulting alcohol 15 with
thiocarbonyl diimidazole provided thiocarbonylimida-
zolide 16 in 90% yield. The reaction in THF or dichlo-
romethane recovered a large amount of the alcohol 15,
even in the presence of DMAP. The present solid-state
reaction was carried out by simply grinding a mixture of
crystals of 15 and thiocarbonyldiimidazole with a mortar
and pestle in a nitrogen bag.12 All conventional attempts
via alkoxide of the alcohol 15 to prepare xanthate
resulted in decomposition, probably because of the prox-
imity of the hydroxy group at C-9 to the ester group at
Resu lts a n d Discu ssion
Our synthetic design is outlined in Scheme 1. The
decaline framework of 10, having requisite functional-
ities, would be obtained by a domino Michael reaction
between acetylcyclohexene (9) and methyl crotonate.
Base-catalyzed isomerization would lead to trans-deca-
lone 11, having a â-equatorial ester. After removal of the
alkoxy group at C-9 (solanapyrone numbering) followed
by introduction of a double bond at C-3, installation of a
pyrone group at C-1 would furnish solanapyrone D (1)
and E (2).
Syn t h esis of Deca lin P or t ion . The synthesis was
started from the enantiomerically pure trimethylsilyl enol
ether (14) of (S)-acetylcyclohexene obtained by lipase-
catalyzed enantioselective acylation (Scheme 2).10 The
domino Michael reaction between methyl crotonate and
(8) (a) Oikawa, H.; Yokota, T.; Abe, T.; Ichihara, A.; Sakamura, S.;
Yoshizawa, Y.; Vederas, J . C. J . Chem. Soc., Chem. Commun. 1989,
1282-1284. (b) Oikawa, H.; Suzuki, Y.; Naya, A.; Katayama, K.;
Ichihara, A. J . Am. Chem. Soc. 1994, 116, 3605-3606. (c) Oikawa, H.;
Katayama, K.; Suzuki, Y.; Ichihara, A. J . Chem. Soc., Chem. Commun.
1995, 1321-1322. (d) Oikawa, H.; Kobayashi, T.; Katayama, K.;
Suzuki, Y.; Ichihara, A. J . Org. Chem. 1998, 63, 8748-8756.
(9) Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.;
Ando, M. Org. Lett. 2001, 3, 251-254.
(10) Hagiwara, H.; Nakano, T.; Uda, H. Bull. Chem. Soc. J pn. 1993,
66, 3110-3112.
(11) Hagiwara, H.; Nakano, T.; Kon-no, M.; Uda, H. J . Chem. Soc.,
Perkin Trans. 1 1995, 777-783.
(12) Hagiwara, H.; Ohtsubo, S.; Kato, M. Tetrahedron 1997, 53,
2415-2420.
5970 J . Org. Chem., Vol. 67, No. 17, 2002

Solanapyrones D and E via Domino Michael Protocol
SCHEME 3a
C-1. The imidazolide 16 was reduced with n-tetrabutyltin
hydride to afford decalone 17 in 93% yield. To introduce
a double bond selectively at C-3 by syn elimination, we
reduced the carbonyl group at C-4 of the decalone 18 with
L-selectride to give axial alcohol 19 in 90% yield. Accord-
ing to the MM2 calculations13 of all plausible substrates
for the isomerization at C-1, the calculated energy of
stabilization of the decalone 19 was the largest after the
isomerization. Then, the R-axial ester group of 17 was
isomerized into the thermodynamically more stable
â-equatorial orientation to furnish decalone 18, having
all the requisite stereochemistry of solanapyrones D (1)
and E (2). The double bond was selectively introduced
at C-3 by xanthate pyrolysis at 190 °C in 1-methylnaph-
thalene to afford the unsaturated ester 12, which was
reduced with lithium aluminumhydride in situ to enable
easy separation from 1-methylnaphthalene. Alcohol 21
was obtained in 89% yield in two steps.
In sta lla tion of P yr on e Nu cleu s. The requisite py-
rone moiety was installed by DBU-mediated cyclization
of â,δ-diketoester 24 which was elaborated by two
alternative routes (Scheme 3). The alcohol 21 was
subjected to J ones oxidation to give carboxylic acid 22 in
91% yield. Treatment with thionyl chloride and subse-
quently with imidazole provided carbonylimidazolide 23,
which was condensed with a dianion of ethyl acetoacetate
to furnish â,δ-diketoester 24 in 45% yield in three steps.
However, this protocol lacked reproducibility, especially
in the condensation of ethyl acetoacetate. Consequently,
the alcohol 21 was oxidized by PCC to aldehyde 25, which
was reacted cleanly with the bis(trimethylsilyl) enol ether
of methyl actoacetate14 in the presence of titanium
tetrachloride (TiCl4) to give hydroxyketoester 26 in 75%
overall yield. The J ones oxidation furnished in 74% yield
the diketoester 24, which was cyclized with DBU to
pyrone 13 in 93% yield.15
In t r od u ct ion of a F or m yl or H yd r oxym et h yl
Gr ou p to P yr on e: Tota l Syn th eses of Sola n a p y-
r on es D (1) a n d E (2). Introduction of the formyl group
at C-14 (solanapyrone numbering) of the pyrone 13 was
troublesome. We investigated the solution of this issue
by model experiments (Scheme 4). Reaction of various
4-hydroxypyrone (pyrone numbering) derivatives 27 with
paraformaldehyde in the presence of Lewis bases or acids
afforded methylenebispyrone derivatives 28 in high
yields.16 Deprotonation of 4-methoxypyrone (29) with
LDA was successful to give the carbanion 31, as exempli-
fied by the 79% deuterium take up after quenching with
D2O.17 The carbanion 31 was reactive toward tributyltin
chloride in the presence of TMEDA to give 3-tributylt-
inpyrone (32), which was lithiated back to the carbanion
31 by treatment with n-butyllithium. However, the
nucleophilicity of 31 toward carbonyl compounds such as
DMF, ethyl formate, or even formaldehyde was too low
a
Reagents and conditions: (i) J ones reagent, acetone, 91%; (ii)
SOCl2; (iii) imidazole; (iv) NaH, n-BuLi, ethyl acetoacetate, 45%
from 22; (v) PCC, 4A-MS, CH2Cl2; (vi) methyl acetoacetate
bis(TMS) enol ether, TiCl4, CH2Cl2, 75% from 21; (vii) J ones
reagent, acetone, 74%; (viii) DBU, benzene, 93%.
to result in the recovery of 4-methoxypyrone (29). An
attempt at Pd-catalyzed CO insertion of tributyltin
derivative 32 also failed. One of the literature prece-
dents18 for our purpose is the reaction of 4-methoxypy-
rone (29) with dichloromethyl methyl ether in the pres-
ence of TiCl4 to give 3-formylpyrone (30), though we
found that the procedure lacked reproducibility by our
experiments.
Therefore, an alternative route was investigated by the
introduction of a heteroatom substituted C-1 unit fol-
lowed by the alteration of the oxidation state of the
carbon. We have found that a phenylthiomethyl group
was introduced according to the procedure of Moreno-
Manas et al.19 to afford phenylthiomethylpyrone 34 in
reproducible yields (Scheme 5). O-Methylation followed
(13) Molecular modeling was performed using PCMODEL (Serena
Software, Bloomington, IN).
(14) Hagiwara, H.; Kimura, K.; Uda, H. J . Chem. Soc., Perkin Trans.
1 1992, 693-700.
(15) (a) Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1996, 37, 2997-3000. (b) Cervello, J .; Marquet, J .;
Moreno-Manas, M. Tetrahedron 1990, 46, 2035-2046.
(16) (a) Hagiwara, H.; Fujimoto, N.; Suzuki, T.; Ando, M. Hetero-
cycles 2000, 53, 549-552. (b) Hagiwara, H.; Miya, S.; Suzuki, T.; Ando,
M.; Yamamoto, I.; Kato, M. Heterocycles 1999, 51, 493-496.
(17) Carpenter, T. A.; J enner, P. J .; Leeper, F. J .; Staunton, J . J .
Chem. Soc., Chem. Commun. 1980, 1227.
(18) Paulton, G. A.; Cyr, T. D. Can. J . Chem. 1982, 60, 2158-2160.
J . Org. Chem, Vol. 67, No. 17, 2002 5971

Hagiwara et al.
SCHEME 4a
SCHEME 5a
a
Reagents and conditions: (i) paraformaldehyde, PhSH, AcOH,
piperidine; (ii) Me2SO4, K2CO3; (iii) MCPBA; (iv) TMSOTf, TMS-
NEt2 then TBAF; (v) (CF3CO)2O then aq NaOH.
TABLE 1. F or m yla tion of P yr on e 27
entry
formylpyrone 30
yield (%)
1
2
3
a : R ) (CH2)8CH3
b: R ) cyclohexyl
c: R ) (CH2)2Ph
49
33
37
vided 3-hydroxymethylpyrone (33) in satisfactory yield,
contrary to our anticipation. Pummerer rearrangement
of the sulfoxides 36 did not proceed at all. This result is
understood by the higher electron-donating ability of the
methoxy group at C-4 to eliminate thiophenyl trifluoro-
acetate from the intermediate. Subsequent conjugate
addition of the trifluoroacetoxy anion followed by basic
hydrolysis furnished 3-hydroxymethylpyrone (33). A
detailed discussion and the scope of the reaction have
already been reported.20
Since we have acquired new protocols to introduce a
formyl or hydroxymethyl group at C-3 of a pyrone ring
simply by changing reagents starting from the same
sulfoxide 36, our attention turned to completion of the
total syntheses of the solanapyrones (Scheme 6). Intro-
duction of the phenylthiomethyl group to the pyrone 13
proceeded smoothly to afford sulfide 37 in 82% yield. Con-
ventional O-methylation with dimethyl sulfate proceeded
in 77% yield, and subsequent MCPBA oxidation afforded
sulfoxide 39 in 88% yield. Finally, treatment of the sul-
foxide 39 with TMSOTf and DEATMS provided solanapy-
rone D (1) in 69% yield ([R]D -148.7, lit.1 [R]D -125.2).
On the other hand, treatment of the sulfoxide 39 with
trifluoroacetic anhydride furnished solanapyrone E (2)
in 62%yield {[R]D -154.9, lit.2 [R]D -76.4}. The NMR data
(500 MHz) were completely identical with those of the
natural products kindly provided by Prof. Oikawa. The
large difference in specific rotations in solanapyrone E
(2) may be caused by impurities involved in the natural
product (see Supporting Information of ref 9).
a
Reagents and conditions: (i) paraformaldehyde, DBU; (ii)
paraformaldehyde, Et2AlCl; (iii) Me2SO4, K2CO3; (iv) Cl2CHOMe,
TiCl4, 43% (R′ ) cyclohexyl); (v) LDA, -78 °C; (vi) TMEDA,
Bu3SnCl, 100% (R′ ) C9H19); (vii) n-BuLi, HMPA; (viii) DMF,
HCO2Et or HCHO.
by MCPBA oxidation gave sulfoxide 3620 in good yield.
We envisaged that Pummerer rearrangement of the
sulfoxide 36 followed by hydrolysis would enable the
introduction of the formyl group at C-3 of the pyrone
nucleus.
After screening numerous reagents to activate the
phenylsulfinyl group, a combination of (trimethylsilyl)-
trifluoromethanesulfonate (TMSOTf) as an O-silylating
reagent and (diethylamino)trimethylsilane (DEATMS) as
a mild base provided 3-formylpyrone (30) after treatment
with tetrabutylammonium fluoride (Table 1). None of the
other silylating or acylating reagents gave any of the
desired products. Excess TMSOTf was required to get
better yields, probably because of the coordination to the
methyl ether at C-4, thus suppressing elimination of
phenyltrimethylsiloxysulfide from the reaction interme-
diate. Such elimination leads to a substitution reaction
to give hyroxymethylpyrone 33 (vide infra). DEATMS
was a better base than triethylamine or diethylamine.
On the other hand, treatment of the sulfoxides 36 with
trifluoroacetic anhydride followed by basic workup pro-
(19) (a) de March, P.; Moreno-Manas, M.; Pi, R.; Trius, A. J .
Heterocycl. Chem. 1982, 19, 335-336. (b) Moreno-Manas, M.; Pleixats,
R. Synthesis 1984, 430-431.
(20) Hagiwara, H.; Kobayashi, K.; Hoshi, T.; Suzuki, T.; Ando, M.
Tetrahedron 2001, 57, 5039-5043.
In summary, the first total syntheses of the phytotoxins
solanapyrones D (1) and E (2) have been achieved by a
5972 J . Org. Chem., Vol. 67, No. 17, 2002

Solanapyrones D and E via Domino Michael Protocol
SCHEME 6a
quenched by addition of H2O, and the reaction mixture was
extracted with EtOAc (×2). The combined organic layers were
washed with brine (×2) and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the residue
involving compound 10 was used in the next step without
further purification.
To a stirred solution of sodium methoxide prepared from
sodium (462 mg, 20 mmol) in methanol (15 mL) was added
crude domino Michael product 10 at 0 °C under nitrogen. The
resulting solution was heated at reflux for 5.5 h and cooled at
0 °C. After addition of 1 N aqueous HCl, the reaction mixture
was extracted with EtOAc (×2). The combined organic layers
were washed with brine (×2), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Treatment with
diazomethane followed by column chromatography (EtOAc/n-
hexane 1:5) of the residue provided trans-decalone (11) (4.57
20
g, 86%) as a colorless oil: [R]D ) +43.05 (c ) 1.01); IR 2953,
1723, 1709, 1449, 1437, 1388, 1370, 1315, 1309, 1156, 1138,
1
1092, 1046, 1007 cm-1; H NMR (200 MHz) δ -0.07 (s, 6H),
-0.03 (s, 3H), 0.80 (s, 9H), 0.98 (d, 3H, J ) 7.3 Hz), 1.05-
1.28 (m, 3H), 1.58-1.73 (m, 2H), 1.79-1.93 (m, 2H), 2.021 (m,
1H), 2.47-2.71 (m, 2H), 2.84-3.00 (m, 2H), 3.64 (s, 3H), 3.73
(m, 1H); 13C NMR (50 MHz) δ -5.4, -3.7, 17.8, 19.8, 22.2, 24.8,
25.7, 33.7, 35.9, 44.1, 44.4, 47.2, 48.3, 51.1, 71.5, 174.4, 211.1.
Meth yl (1S,2R,4a R,8S,8a R)-1,2,3,4a ,6,7,8,8a -Octa h yd r o-
8-h yd r oxy-2-m et h yln a p h t h a len -4(4a H )-on e-1-ca r b oxy-
la te (15). To a stirred solution of trans-decalone (11) (4.88 g,
14 mmol) in acetonitrile (40 mL) was added aqueous hydrogen
fluoride (46%, 6 mL) at room temperature. After it was stirred
for 2 h, the solution was neutralized with 2 N aqueous NaOH.
The reaction mixture was extracted with EtOAc (×2), and the
combined organic layers were washed with brine (×2) and
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography (EtOAc/n-hexane 2:3 then 2:1) to afford
20
alcohol 15 (3.12 g, 94%) as crystals: mp ) 88-89 °C; [R]D
+43.78 (c ) 1.00); IR 3488, 2953, 1728, 1709, 1451, 1437, 1309,
1173, 1150, 1067, 1040 cm-1; H NMR (500 MHz) δ 1.05 (d,
1
3H, J ) 7.3 Hz), 1.12-1.32 (m, 3H), 1.77-1.82 (m, 2H), 1.87-
2.00 (m, 2H), 2.09 (dd, 1H, J ) 13.9, 2.7 Hz), 2.24 (d, 1H, J )
4.7 Hz), 2.62 (m, 1H), 2.69 (td, 1H, J ) 12.0, 3.4 Hz), 3.03 (dd,
1H, J ) 13.9, 6.1 Hz), 3.05 (d, 1H, J ) 5.1 Hz), 3.58 (tdd, 1H,
J ) 10.0, 5.4, 4.7, Hz), 3.78 (s, 3H); 13C NMR (125 MHz) δ
20.1, 22.3, 24.8, 33.1, 34.9, 44.1, 44.6, 47.3, 48.2, 51.7, 71.4,
174.5, 211.3; MS m/z 240 (M+, 34%), 222 (53), 196 (34), 163
(100), 162 (53), 97 (63), 69 (45). Anal. Calcd for C13H20O4: C,
64.98; H, 8.39. Found: C, 64.82; H, 8.38.
a
Reagents and conditions: (i) paraformaldehyde, PhSH, AcOH,
piperidine, 82%; (ii) Me2SO4, K2CO3, acetone, 77%; (iii) MCPBA,
CH2Cl2, 88%; (iv) TMSOTf, TMSNEt2 then TBAF, 69%; (v)
(CF3CO)2O, CH2Cl2 then aq NaOH, THF, 62%.
double Michael protocol for the synthesis of the decalin
portion and by a Pummerer-related protocol for the
introduction of an oxygenated methyl group of the pyrone
moiety.
O-[(1S,2R,4a R,8S,8a R)-Meth yl-1,2,3,4a ,6,7,8,8a -octa h y-
dr o-8-h ydr oxy-2-m eth yln aph th alen -4(4aH)-on e-1-car box-
yla te-8-yl]th ioca r boxyim id a zolid e (16). A mixture of the
alcohol 15 (4.40 g, 18.3 mmol) and 1,1′-thiocarbonyldiimidazole
(97%, 5.06 g, 27.5 mmol) was ground well with a pestle in a
mortar at room temperature under nitrogen. The reaction
mixture was left for 2 h and diluted with EtOAc. Evaporation
of EtOAc followed by purification of the residue by column
chromatography (EtOAc/n-hexane 1:1) gave thiocarbonylimi-
Exp er im en ta l Section
Gen er a l. Mp’s are uncorrected. IR spectra and optical
1
rotations were recorded for solutions in chloroform. H NMR
20
(200 MHz) and 13C NMR (50 MHz) spectra were obtained for
solutions in deuteriochloroform with tetramethylsilane as
internal standard. 1H NMR (500 MHz) spectra were run for
solutions in deuteriochloroform. Mass spectra were measured
under EI conditions.
dazolide 16 (5.79 g, 90%) as crystals: mp ) 112-113 °C; [R]D
) +20.25 (c ) 1.00); IR 2868, 1726, 1713, 1462, 1389, 1333,
1283, 1100, 992 cm-1; H NMR (200 MHz) δ 1.09 (d, 3H, J )
1
7.3 Hz), 1.12-1.48 (m, 3H), 1.84-2.42 (m, 6H), 2.61 (m, 1H),
2.78 (m, 1H), 2.90-3.09 (m, 2H), 3.64 (s, 3H), 5.53 (td, 1H, J
) 10.4, 4.6 Hz), 7.06 (dd, 1H, J ) 1.6, 0.9 Hz), 7.62 (d, 1H, J
) 1.6 Hz), 8.32 (d, 1H, J ) 0.9 Hz); 13C NMR (50 MHz) δ 20.3,
21.8, 24.5, 30.5, 33.0, 44.0, 44.2, 44.8, 48.0, 52.1, 83.1, 117.8,
130.9, 136.6, 173.7, 183.3, 209.6; MS m/z 319 (M+ - MeO, 3%),
223 (89), 222 (64), 163 (100), 121 (45), 69 (50). Anal. Calcd for
Meth yl (1S,2R,4a R,8S,8a R)-1,2,3,4a ,6,7,8,8a -Octa h yd r o-
8-(ter t-bu tyldim eth ylsiloxy)-2-m eth yln aph th alen -4(4a H)-
on e-1-ca r boxyla te (11). To a stirred solution of TMS enol
ether 14 (4.87 g, 14.9 mmol) in THF (20 mL) was added
methyllithium (15.7 mL, 1.14 M in diethyl ether, 16.6 mmol)
dropwise at -78 °C under nitrogen. After it was stirred at -78
°C for 30 min and at 0 °C for 35 min, a solution of HMPA (5.2
mL, 29.9 mmol) and methyl crotonate (2.4 mL, 22.3 mmol) in
THF (15 mL) was added dropwise at -78 °C. The resulting
solution was stirred at -78 °C for 50 min, at 0 °C for 35 min,
and at room temperature for 70 min. The reaction was
C
17H22N2O4S: C, 58.27; H, 6.33; N, 7.99. Found: C, 58.45; H,
6.28; N, 7.98.
Meth yl (1S,2R,4a R,8S,8a R)-1,2,3,4a,6,7,8,8a-Octah ydr o-
2-m eth yln a p h th a len -4(4a H)-on e-1-ca r boxyla te (17). To a
stirred solution of thiocarbonylimidazolide 16 (2.45 g, 7 mmol)
in benzene (35 mL) were added AIBN (118 mg, 0.7 mmol) and
J . Org. Chem, Vol. 67, No. 17, 2002 5973

Hagiwara et al.
n-tributyltinhydride (2.8 mL, 11 mmol), and the solution was
stirred at 60 °C for 1 h under nitrogen atmosphere. After
addition of H2O at 0 °C, the reaction mixture was extracted
with EtOAc (×2). The combined organic layers were washed
with H2O and brine and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, purification
of the residue by column chromatography (EtOAc/n-hexane
1:1) afforded ketoester 17 (1.46 g, 93%) as a solid: mp ) 42-
butoxide (236 mg, 2.0 mmol) at -50 °C under nitrogen. After
the resulting solution was stirred for 40 min, carbon disulfide
(74 µL, 1.2 mmol) was added at -35 °C. After this solution
was stirred for 50 min, methyl iodide (79 µL, 1.2 mmol) was
added, and stirring was continued for 10 min. The reaction
was quenched by aqueous ammonium chloride, and the reac-
tion mixture was extracted with EtOAc (×2). The combined
organic layers were washed with H2O and brine and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by column chromatog-
raphy (EtOAc/n-hexane 1:9) to afford xanthate 20 (258.1 mg,
91%) as a yellow oil: [R]D20 ) -29.87 (c ) 1.10); IR 2936, 1730,
1449, 1435, 1298, 1252, 1169, 1144, 1055 cm-1; 1H NMR (200
MHz) δ 0.82 (m, 1H), 0.99 (d, 3H, J ) 7.3 Hz), 1.20-2.08 (m,
11H), 2.18-2.40 (m, 2H), 2.58 (s, 3H), 3.68 (s, 3H), 5.70 (m,
1H); 13C NMR (50 MHz) δ 17.1, 18.9, 25.9, 26.3, 29.0, 29.7,
31.7, 32.6, 35.1, 45.1, 51.3, 52.5, 82.8, 174.3, 215.6; MS m/z
316 (M+, 0.5%), 285 (2), 209 (19), 208 (11), 150 (16), 149 (100).
Anal. Calcd for C15H24O3S2: C, 56.93; H, 7.66; S, 20.26.
Found: C, 57.15; H, 7.66; S, 20.10.
20
43 °C; [R]D ) +27.09 (c ) 1.00); IR 2936, 1725, 1703, 1449,
1440, 1352, 1321, 1308, 1169, 1138 cm-1; 1H NMR (500 MHz)
δ 1.05 (d, 3H, J ) 7.1 Hz), 1.12-1.32 (m, 4H), 1.65-1.79 (m,
3H), 1.82 (tdd, 1H, J ) 12.0, 4.6, 3.2 Hz), 1.99 (m, 1H), 2.08
(ddd, 1H, J ) 13.7, 3.4, 1.7 Hz), 2.48-2.55 (m, 2H), 2.73 (td,
1H, J ) 11.2, 3.4 Hz), 3.06 (dd, 1H, J ) 13.7, 5.9 Hz), 3.73 (s,
3H); 13C NMR (125 MHz) δ 20.4, 25.0, 25.3, 26.0, 30.9, 33.5,
40.0, 44.4, 49.1, 49.7, 51.3, 174.8, 212.3; MS m/z 224 (M+, 9%),
147 (15), 124 (23), 85 (68), 83 (100), 58 (15), 47 (23). Anal. Calcd
for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.40; H, 8.75.
Met h yl (1S,2R,4a R,8S,8a R)-Deca h yd r o-4-h yd r oxy-2-
m eth yln a p h th a len e-1-ca r boxyla te (18). To a stirred solu-
tion of ketoester 17 (1.04 g, 4.6 mmol) in THF (30 mL) was
added L-selectride (1.0 M solution in THF, 7 mL, 7 mmol) at
0 °C under nitrogen, and stirring was continued for 1.5 h. After
addition of 1 N aqueous NaOH (24 mL) and hydrogen peroxide
(30 wt %, 10.5 mL, 93 mmol), the resulting solution was stirred
at room temperature for 11.5 h. The solution was neutralized
with 1 N aqueous HCl, and the reaction mixture was extracted
with EtOAc (×2). The combined organic layers were washed
with H2O and brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was treated
with diazomethane and purified by column chromatography
(EtOAc/n-hexane 1:5) to afford hydroxyester 18 (944 mg, 90%)
Meth yl (1R,2R,4aR,8S,8aR)-1,2,4a ,5,6,7,8,8a -Octa h yd r o-
2-m eth yln a p h th a len e-1-ca r boxyla te (12). A stirred solu-
tion of the xanthate 20 (43.6 mg, 0.14 mmol) in 1-methylnaph-
thalene (0.7 mL) was heated at 190 °C for 3 h under nitrogen.
After dilution with EtOAc, the solution was dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was used in the next step without further
purification.
(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -Oct a h yd r o-2-m e-
th yln a p h th a len e-1-m eth a n ol (21). To a stirred solution of
the ester 12 in diethyl ether (2.8 mL) was added lithium
aluminumhydride (17 mg, 0.41 mmol, 3 equiv) at 0 °C under
nitrogen. After this solution was stirred for 15 min, aq NH4Cl
was added. The organic layer was dried over anhydrous Na2-
SO4 and evaporated to dryness. The residue was purified by
column chromatography (EtOAc/n-hexane 1:6) to afford alcohol
21 (22 mg, 89% from 20) as an amorphous solid: mp ) 89-90
20
as crystals: mp ) 64-65 °C; [R]D ) +39.49 (c ) 1.00); IR
3488, 2994, 1725, 1449, 1435, 1388, 1327, 1294, 1167, 1146,
1105, 1003 cm-1; 1H NMR (500 MHz) δ 1.05 (qd, 1H, J ) 12.0,
3.7 Hz), 1.27 (d, 3Ha, J ) 7.6 Hz), 1.20-1.38 (m, 4Ha), 1.53
(m, 1H), 1.58-1.64 (m, 2H), 1.69-1.70 (m, 2H), 1.82-1.92 (m,
2H), 2.60 (qdt, 1H, J ) 7.6, 5.9, 1.7 Hz), 2.21 (ddd, 1H, J )
14.6, 5.9, 3.4 Hz), 2.42 (dd, 1H, J ) 2.7, 1.7 Hz), 3.63 (s, 3H),
3.84 (m, 1H); atotal 4H; 13C NMR (125 MHz) δ 22.7, 26.2, 26.6,
29.3, 29.9, 31.0, 31.1, 34.6, 39.6, 50.4, 50.8, 70.8, 175.7; MS
m/z 208 (M+ - H2O, 25%), 176 (29), 149 (100), 148 (85), 108
(66), 93 (34), 79 (36). Anal. Calcd for C13H22O3: C, 68.99; H,
9.80. Found: C, 68.91; H, 9.83.
20
°C; [R]D ) -126.82 (c ) 1.07); IR 3488, 2928, 1448, 1095,
1
1017, 1001 cm-1; H NMR (200 MHz) δ 0.93 (d, 3Ha, J ) 7.3
Hz), 0.89-1.48 (m, 6Ha), 1.52-1.84 (m, 6H), 2.42 (m, 1H), 3.53
(td, 1H, J ) 10.7, 5.6 Hz), 3.84 (td, 1H, J ) 10.7, 5.4 Hz), 5.38
(d, 1H, J ) 9.8 Hz), 5.60 (ddd, 1H, J ) 9.8, 4.7, 2.4 Hz); atotal
9H; 13C NMR (50 MHz) δ 15.5, 26.5, 26.8, 29.3, 31.5, 33.2, 37.7,
43.6, 44.1, 63.0, 131.2, 132.25; MS m/z 180 (M+, 13%), 162 (10),
150 (16), 149 (100), 147 (13), 107 (13), 105 (17), 91 (16), 81
(21), 79 (15). Anal. Calcd for C12H20O: C, 79.94; H, 11.18.
Found: C, 80.02; H, 10.98.
Met h yl (1R,2R,4a R,8S,8a R)-Deca h yd r o-4-h yd r oxy-2-
m eth yln a p h th a len e-1-ca r boxyla te (19). To a stirred solu-
tion of axial ester 18 (226 mg, 1 mmol) in DMSO (50 µL) were
added potassium tert-butoxide (116 mg, 1 mmol) and tert-butyl
alcohol (190 µL, 2 mmol) under nitrogen atmosphere, and
stirring was continued at room temperature for 23 h. After
addition of 1 N aqueous HCl, the reaction mixture was
extracted with EtOAc (×2). The combined organic layers were
washed with H2O and brine (×2), dried over anhydrous Na2-
SO4, and concentrated under reduced pressure. Treatment
with diazomethane followed by MPLC (EtOAc/n-hexane 2:3)
of the residue provided isomeric equatorial ester 19 (178 mg,
(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -Oct a h yd r o-2-m e-
th yln a p h th a len e-1-ca r boxylic Acid (22). To a solution of
the alcohol 21 (92 mg, 0.5 mmol) in acetone (2.6 mL) was added
J ones reagent dropwise at 0 °C until the orange color persisted.
After addition of H2O, the reaction mixture was extracted with
EtOAc (×2). The combined organic layers were washed with
H2O and brine and dried over anhydrous Na2SO4. Concentra-
tion under reduced pressure followed by column chromatog-
raphy (MeOH/CHCl3 1:10) of the residue afforded carboxylic
20
acid 22 (90 mg, 91%) as crystals: mp ) 142-143 °C; [R]D
)
20
78%) as a colorless oil: [R]D ) -31.16 (c ) 1.00); IR 3488,
-141 (c ) 0.2); IR 3099, 2920, 1709, 1448, 1292, 1222, 1143,
1111 cm-1; 1H NMR (200 MHz) δ 0.8-1.0 (m, 1H), 1.0 (d, 3H,
J ) 6.9 Hz), 1.05-1.5 (m, 5H), 1.68-1.85 (m, 4H), 1.95-2.10
(m, 1H), 2.55-2.70 (m, 2H), 5.4 (d, 1H, J ) 9.8 Hz), 5.51-
5.61 (m, 1H).
2857, 1730, 1449, 1437, 1298, 1265, 1169, 1146, 1009 cm-1
;
1H NMR (500 MHz) δ 0.81 (qd, 1H, J ) 12.3, 3.4 Hz), 1.09 (m,
1Ha), 1.10 (d, 3Ha, J ) 7.3 Hz), 1.22-1.34 (m, 2H), 1.38-1.44
(m, 2H), 1.54 (m, 1H), 1.70 (m, 1H), 1.74-1.82 (m, 2H), 1.84-
1.94 (m, 3H), 2.23 (qddd, 1H, J ) 7.3, 5.4, 4.9, 2.4 Hz), 2.28
Eth yl 5-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -Octa h y-
d r o-2-m eth yln a p h th yl]-3,5-d ioxop en ta n oa te (24a ). A so-
lution of the carboxylic acid 22 (23 mg, 0.12 mmol) in SOCl2
(357 µL, 4.9 mmol) was heated at 55 °C for 2 h. After
evaporation of SOCl2 in vacuo, a solution of imidazole (16 mg,
0.23 mmol) in THF (0.23 mL) was added and the resulting
solution was stirred at room temperature overnight. Evapora-
tion of the solvent provided imidazolide 23 as a solid which
was used immediately for the next reaction without further
purification.
a
(dd, 1H, J ) 11.0, 4.9 Hz), 3.67 (s, 3H), 3.78 (m, 1H); total
4H; 13C NMR (125 MHz) δ 17.9, 26.1, 26.5, 29.4, 30.1, 31.8,
39.0, 46.0, 51.1, 53.2, 70.6, 174.8; MS m/z 226 (M+, 7%), 208
(14), 149 (77), 148 (100), 81 (33), 43 (36), 41 (39). Anal. Calcd
for C13H22O3: C, 68.99; H, 9.80. Found: C, 68.94; H, 9.69.
O-[Met h yl (1R,2R,4a R,8S,8a R)-Deca h yd r o-2-m et h yl-
n a p h th a len e-1-ca r boxyla te-4-yl] S-Meth yl Dith ioca r bon -
a te (20). To a stirred solution of the equatorial ester 19 (185
mg, 0.8 mmol) in THF (8.2 mL) was added potassium tert-
5974 J . Org. Chem., Vol. 67, No. 17, 2002

Solanapyrones D and E via Domino Michael Protocol
Sodium hydride (9.4 mg, 60%, 0.23 mmol) was washed with
n-hexane twice. To a stirred suspension of NaH in THF (0.3
mL) was added ethyl acetoacetate (30 µL, 0.23 mmol) at 0 °C
under nitrogen atmosphere. After this mixture was stirred for
10 min, a solution of n-BuLi (144 µL, 1.6 M in n-hexane, 0.23
mmol) was added. Subsequently, after 10 min, a solution of
the imidazolide 23 in THF (0.26 mL) was added. Stirring was
continued for 1.5 h, and the reaction was quenched by addition
of aq NH4Cl. The reaction mixture was extracted with EtOAc
(×2). Combined organic layers were washed with H2O and
brine and dried over anhydrous Na2SO4. Removal of the
solvent under reduced pressure followed by column chroma-
tography (EtOAc/n-hexane 1:3) and MPLC (EtOAc/n-hexane
1:3) gave â,δ-diketoester 24a (16 mg, 45% from 22) as an oil
which was used immediately for the next transformation: IR
2967, 1736, 1599, 1448, 1376, 1311, 1158, 1033 cm-1; 1H NMR
(200 MHz) δ 0.75-2.0 (m, 11H), 0.94 (d, 3H, J ) 6.8 Hz), 1.29
(t, 3H, J ) 7.0 Hz), 2.35-2.50 (m, 2H), 3.34 (d, 2H, J ) 2.0
Hz), 4.2 (q, 2H, J ) 7.0 Hz), 5.35-5.47 (brd, 1H), 5.5-5.65
(m, 2H).
stirred solution of â,δ-diketoester 24 (20 mg, 0.068 mmol) in
benzene (1 mL) was added DBU (20 µL, 0.14 mmol) under
nitrogen, and the solution was stirred at 60 °C for 2.5 h. The
reaction was quenched by 1 N aqueous HCl at 0 °C, and the
reaction mixture was extracted with CH2
Cl2 (×3). The com-
bined organic layers were washed with H2O and brine. After
they were dried over anhydrous Na2SO4, the solvent was
removed under reduced pressure. The residue was purified by
column chromatography (MeOH/CHCl3 0:1 then 1:10) to give
4-hydroxy-2-pyrone 13 (16.3 mg, 93%) as crystals: 1H NMR
(200 MHz) δ 0.85 (m, 1Ha), 0.93 (d, 3Ha, J ) 7.1 Hz), 1.02-
1.82 (m, 10H), 2.47 (m, 1H), 2.68 (dd, 1H, J ) 11.2, 6.0 Hz),
5.42 (d, 1H, J ) 9.7 Hz), 5.52 (d, 1Hb, J ) 2.1 Hz), 5.56 (ddd,
a
1Hb, J ) 9.7, 4.2, 2.4 Hz), 5.94 (d, 1H, J ) 2.1 Hz); total 4H,
btotal 2H.
4-H yd r oxy-6-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -oc-
ta h yd r o-2-m eth yln a p h th yl]-3-p h en ylth iom eth yl-2H-p y-
r a n -2-on e (37). To a stirred suspension of paraformaldehyde
(3.0 mg, 0.095 mmol), thiophenol (0.05 mL, 0.19 mmol), acetic
acid (3 µL, 0.052 mmol), and piperidine (3 µL, 0.030 mmol) in
EtOH (2 mL) was added a solution of 4-hydroxy-2-pyrone 13
(16 mg, 0.063 mmol) in EtOH (3 mL) at 55 °C under nitrogen.
The resulting mixture was stirred for 17 h and concentrated
under reduced pressure. Purification of the residue by column
chromatography (MeOH/CHCl3 0:1 then 1:50) provided 3-phe-
nylthiomethyl-2-pyrone 37 (19.7 mg, 82%) as an amorphous
solid: 1H NMR (200 MHz) δ 0.80 (m, 1Ha), 0.85 (d, 3Ha, J )
7.2 Hz), 1.02-1.82 (m, 9H), 2.40 (m, 1H), 2.58 (dd, 1H, J )
11.1, 6.0 Hz), 4.11 (s, 2H), 5.39 (d, 1H, J ) 9.9 Hz), 5.56 (ddd,
1H, J ) 9.9, 4.1, 2.3 Hz), 5.86 (s, 1H), 7.12-7.54 (m, 5H), 8.84
(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -Oct a h yd r o-2-m e-
th yln a p h th a len e-1-ca r ba ld eh yd e (25). To a suspension of
PCC (65 mg, 0.3 mmol) and 4-Å molecular sieves powder (65
mg) in CH2Cl2 (2 mL) was added a solution of the alcohol 21
(18 mg, 0.1 mmol) in CH2Cl2 (3 mL) under nitrogen, and the
resulting mixture was stirred at room temperature for 30 min.
After dilution with EtOAc, the reaction mixture was subjected
to column chromatography (EtOAc/n-hexane 1:6) to give
aldehyde 25 (17 mg) which was immediately used for the next
step: 1H NMR (200 MHz) δ 1.05 (d, 3Ha, J ) 7.0 Hz), 0.80-
1.99 (m, 10Ha), 2.38 (m, 1H), 2.59 (m, 1H), 5.42 (d, 1H, J )
10.0 Hz), 5.55 (ddd, 1H, J ) 10.0, 4.2, 2.1 Hz), 9.75 (d, 1H, J
a
(brs, 1H); total 4H.
4-Met h oxy-6-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -oc-
ta h yd r o-2-m eth yln a p h th yl]-3-p h en ylth iom eth yl-2H-p y-
r a n -2-on e (38). A suspension of 4-hydroxypyrone 37 (127 mg,
0.33 mmol), dimethyl sulfate (157 mL, 1.66 mmol), and
potassium carbonate (231 mg, 1.66 mmol) in acetone (3.3 mL)
was stirred at room temperature for 30 min under nitrogen.
H2O (1.7 mL) was added, and the resulting solution was stirred
at room temperature for 14.5 h. After addition of aqueous
ammonium chloride, the reaction mixture was extracted with
CH2Cl2 (×2). Combined organic layers were washed with H2O
and brine and dried over anhydrous Na2SO4. Evaporation of
the solvent followed by MPLC (EtOAc/n-hexane 1:2) of the
residue provided 4-methoxy-2-pyrone 38 (101.5 mg, 77%) as a
a
) 4.4 Hz); total 13H.
Meth yl 5-Hyd r oxy-5-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,
8a -octa h yd r o-2-m eth yln a p h th yl]-3-oxop en ta n oa te (26).
To a stirred solution of the aldehyde 25 (17 mg) in CH2Cl2 (2
mL) were added a solution of methyl acetoacetate bis(TMS)
enol ether (127 µL, 0.5 mmol) in CH2Cl2 (3 mL) and TiCl4 (1.0
M in CH2Cl2, 22 µL, 0.2 mmol) at -78 °C under nitrogen
atmosphere, and the resulting solution was stirred for 1 h.
After addition of H2O, the reaction mixture was extracted with
EtOAc (×2). The combined organic layers were washed with
H2O and brine and dried over anhydrous Na2SO4. Concentra-
tion under reduced pressure followed by chromatography
(EtOAc/n-hexane 1:4) of the residue afforded a mixture of
methyl acetoacetate and hydroxyketoester 26 (22 mg, 75%
from the alcohol 21) which was used for the next step without
further purification: IR 3568, 2957, 1746, 1712, 1450, 1440,
20
viscous oil: [R]D ) -121.67 (c ) 0.98); IR 2932, 1703, 1640,
1563, 1464, 1406, 1358, 1261, 1125, 1026 cm-1; 1H NMR (200
MHz) δ 0.87 (m, 1Ha), 0.95 (d, 3Ha, J ) 7.1 Hz), 1.02-1.84 (m,
9H), 2.43 (m, 1H), 2.65 (dd, 1H, J ) 10.9, 6.0 Hz), 3.72 (s, 3H),
3.98 (s, 2H), 5.42 (d, 1H, J ) 9.9 Hz), 5.55 (ddd, 1H, J ) 9.9,
4.2, 2.3 Hz), 5.93 (s, 1H), 7.10-7.31 (m, 3H), 7.40-7.48 (m,
2H); atotal 4H; 13C NMR (50 MHz) δ 17.8, 26.4, 26.6, 28.3, 30.2,
33.0, 35.5, 36.5, 43.1, 49.7, 56.3, 95.8, 101.3, 126.5, 128.5, 130.9,
131.1, 131.4, 167.9.
1323, 1153, 1007 cm-1; 1H NMR (200 MHz) δ 0.99 (d, 1.6Ha,b
,
J ) 7.0 Hz), 1.08 (d, 1.4Ha,b, J ) 7.0 Hz), 0.95-1.48 (m, 6Hb),
1.50-1.88 (m, 4H), 2.03 (m, 1H), 2.22-2.50 (m, 2H), 2.58-
2.99 (m, 2H), 3.51 (s, 1.1Hc), 3.53 (s, 0.9Hc), 3.75 (s, 3H), 4.25
(m, 0.55Hd), 4.46 (m, 0.45d), 5.32 (d, 1H, J ) 9.7 Hz), 5.64 (ddd,
b
c
d
1H, J ) 9.7, 4.1, 2.0 Hz); atotal 3H, total 9H, total 2H, total
4-Met h oxy-6-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -oc-
ta h yd r o-2-m eth yln a p h th yl]-3-p h en ylsu lfin ylm eth yl-2H-
p yr a n -2-on e (39). To a stirred solution of the phenylthiom-
ethylpyrone 38 (69 mg, 0.17 mmol) in CH2Cl2 (2 mL) was added
m-CPBA (80%, 37 mg, 0.17 mmol) at 0 °C under nitrogen
atmosphere. After this solution was stirred for 15 min, aqueous
sodium hydrogencarbonate was added and the reaction mix-
ture was extracted with CH2Cl2 (×2). The combined organic
layers were washed with H2O and brine, dried over anhydrous
Na2SO4, and evaporated to dryness. The residue was purified
by MPLC (EtOAc/n-hexane 6:1) to afford 3-phenylsulfinyl-2-
pyrone 39 (less polar diastereomer 28 mg, more polar diaste-
reomer 34 mg, total 88%) as a viscous oil. Less polar diaste-
reomer: IR 2928, 1703, 1638, 1563, 1466, 1408, 1356, 1036
cm-1; 1H NMR (200 MHz) δ 0.90 (m, 1H), 0.95 (d, 3H, J ) 7.2
Hz), 1.02-1.83 (m, 9H), 2.45 (m, 1H), 2.67 (dd, 1H, J ) 10.8,
5.9 Hz), 3.75 (s, 3H), 3.90 (d, 1H, J ) 12.1 Hz), 4.13 (d, 1H, J
) 12.1 Hz), 5.42 (d, 1H, J ) 9.9 Hz), 5.56 (ddd, 1H, J ) 9.9,
4.1, 2.2 Hz), 5.97 (s, 1H), 7.42-7.51 (m, 3H), 7.60-7.68 (m,
1H.
Meth yl 4-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -Octa h y-
d r o-2-m eth yln a p h th yl]-3,5-d ioxobu ta n oa te (24b). To a
stirred solution of the hydroxyketoester 26 (27 mg, 0.09 mmol)
in acetone (1 mL) was added J ones reagent dropwise at 0 °C
until the orange color persisted. After addition of H2O, the
reaction mixture was extracted with EtOAc (×2). Combined
organic layers were washed with H2O and brine and dried over
anhydrous Na2SO4. Removal of the solvent under reduced
pressure followed by column chromatography (EtOAc/n-hexane
1:8) gave â,δ-diketoester 24 (20 mg, 74%) as a yellow oil: IR
2959, 1742, 1610, 1593, 1450, 1439, 1321, 1156, 1130, 1015
1
cm-1; H NMR (200 MHz) δ 0.93 (d, 3Ha, J ) 7.0 Hz), 0.80-
1.95 (m, 11Ha), 2.38-2.50 (m, 2H), 3.36 (s, 2H), 3.75 (s, 3H),
5.39 (d, 1H, J ) 9.8 Hz), 5.55 (ddd, 1Hb, J ) 9.8, 3.8, 2.5 Hz),
a
b
5.59 (s, 1Hb); total 14H, total 2H.
4-H yd r oxy-6-[(1R,2R,4a R,8S,8a R)-1,2,4a ,5,6,7,8,8a -oc-
ta h yd r o-2-m eth yln a p h th yl]-2H-p yr a n -2-on e (13). To a
J . Org. Chem, Vol. 67, No. 17, 2002 5975

Hagiwara et al.
2H). More polar diastereomer: IR 2857, 1703, 1638, 1563,
1466, 1408, 1356, 1256, 1037, 1030 cm-1; 1H NMR (200 MHz)
δ 0.88 (m, 1H), 0.95 (d, 3H, J ) 7.1 Hz), 1.03-1.89 (m, 9H),
2.48 (m, 1H), 2.67 (dd, 1H, J ) 10.9, 5.9 Hz), 3.74 (s, 3H), 3.88
(d, 1H, J ) 12.1 Hz), 4.13 (d, 1H, J ) 12.1 Hz), 5.43 (d, 1H, J
) 9.9 Hz), 5.56 (ddd, 1H, J ) 9.9, 4.1, 2.2 Hz), 5.97 (s, 1H),
7.42-7.51 (m, 3H), 7.60-7.71 (m, 2H).
°C, 1 N aqueous NaOH (1 mL) and THF (2 mL) were added
and stirring was continued for 40 min at room temperature.
The reaction mixture was extracted with CH2Cl2 (×2), and the
combined organic layers were washed with H2O and brine and
dried over anhydrous Na2SO4. Evaporation of the solvent
followed by MPLC (EtOAc/n-hexane 10:1) purification fur-
nished solanapyrone E (2) (2.2 mg, 62%) as an amorphous
20
Sola n a p yr on e D (1). To a stirred solution of the sulfoxide
39 (20 mg, 0.05 mmol) in CH2Cl2 (EtOH free, 3 mL) were added
DEATMS (36 µL, 0.19 mmol) and TMSOTf (25 µL, 0.14 mmol)
at -25 °C under nitrogen. After the solution was stirred for
90 min with gradual warming to -5 °C, TBAF (0.15 mL, 1 M
solution in THF) was added and stirring was continued for 20
min. The solution was diluted with EtOAc and passed through
a short column of silica gel. Evaporation of the solvent followed
by MPLC (EtOAc) purification furnished solanapyrone D (1)
(9.9 mg, 69%) as an oil: [R]D22.5 ) -148.66 (c ) 0.60); IR 2930,
2861, 1726, 1686, 1617, 1520, 1375, 1342, 1265 cm-1; 1H NMR
(500 MHz) δ 0.90 (m, 1H), 0.99 (d, 3H, J ) 7.1 Hz), 1.13 (m,
1H), 1.22-1.42 (m, 3H), 1.53-1.88 (m, 5H), 2.51 (m, 1H), 2.75
(dd, 1H, J ) 11.2, 5.9 Hz), 4.06 (s, 3H), 5.44 (d, 1H, J ) 9.9
Hz), 5.57 (ddd, 1H, J ) 9.8, 4.4, 2.4 Hz), 6.12 (s, 1H), 10.15 (s,
1H); 13C NMR (125 MHz) δ 17.7, 26.3, 26.4, 30.2, 32.9, 35.5,
36.5, 42.8, 50.7, 57.6, 95.9, 101.6, 130.6, 131.0, 162.3, 173.6,
176.2, 186.8.
solid: [R]D ) -154.88 (c ) 0.93); IR 3504, 2926, 2855, 1690,
1636, 1564, 1466, 1626, 1098, 1013 cm-1; 1H NMR (500 MHz)
δ 0.88 (qd, 1H, J ) 12.5, 3.2 Hz), 0.97 (d, 3H, J ) 7.1 Hz),
1.12 (qd, 1H, J ) 12.8, 3.1 Hz), 1.24-1.42 (m, 2H), 1.61-1.70
(m, 2H), 1.71-1.81 (m, 4H), 2.46 (m, 1H), 2.69 (dd, 1H, J )
11.2, 5.9 Hz), 2.97 (brs, 1H), 3.90 (s, 3H), 4.55 (s, 2H), 5.45 (d,
1H, J ) 10.0 Hz), 5.55 (ddd, 1H, J ) 10.0, 4.4, 2.6 Hz), 6.05 (s,
1H); 13C NMR (125 MHz) δ 17.8, 26.4, 26.5, 30.2, 33.0, 35.5,
36.6, 43.1, 49.8, 54.7, 56.4, 96.2, 103.7, 130.9, 131.0, 165.3,
166.5, 168.6.
Ack n ow led gm en t. We thank Prof. H. Oikawa,
Hokkaido University, for providing spectral data of
natural solanapyrones D (1) and E (2).
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds 1, 2, 13, 24b, 26, 37, 38, and 39 as well as natural
1 and 2 (PDF, 19 pages). This material is available free of
charge via the Internet at http://pubs.acs.org.
Sola n a p yr on e E (2). To a stirred solution of the sulfoxide
39 (4.7 mg, 0.01 mmol) in CH2Cl2 (EtOH free, 1.1 mL) was
added trifluoroacetic anhydride (7 µL, 0.04 mmol) at 0 °C
under nitrogen. After the solution was stirred for 30 min at 0
J O0163602
5976 J . Org. Chem., Vol. 67, No. 17, 2002