Asymmetric synthesis of (-)- and (+)-eutipoxide B using a base-catalyzed Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4020(01)00032-1

The asymmetric synthesis of eutipoxide B, a metabolite of the phytopathogenic fungus Eutypa lata, is described. Quick and efficient synthesis of each enantiomer was achieved through base-catalyzed asymmetric Diels-Alder reactions with 3-hydroxy-2-pyrone and chiral acrylates.

Full text of DOI:10.1016/S0040-4020(01)00032-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1903±1908
Asymmetric synthesis of (2)- and (1)-eutipoxide B using a
base-catalyzed Diels±Alder reaction
Hideki Shimizu, Hiroaki Okamura,p Tetsuo Iwagawa and Munehiro Nakatani
Department of Chemistry, Faculty of Science, Kagoshima University, 1-21-35 Korimoto, Kagoshima 890-0065, Japan
Received 28 November 2000; accepted 4 January 2001
AbstractÐThe asymmetric synthesis of eutipoxide B, a metabolite of the phytopathogenic fungus Eutypa lata, is described. Quick and
ef®cient synthesis of each enantiomer was achieved through base-catalyzed asymmetric Diels±Alder reactions with 3-hydroxy-2-pyrone and
chiral acrylates. q 2001 Elsevier Science Ltd. All rights reserved.
Eutipoxide B (1, Fig. 1) is a secondary metabolite of the
phytopathogenic fungus Eutypa lata, which is responsible
for `vineyard die-back' disease. The ®rst isolation of eutip-
oxide B and its ®rst synthesis in racemic form were reported
in 1992 by Tabacchi et al.1 This compound features a highly
oxygenated cyclohexene oxide, an important component
of various biologically active compounds. For example,
(1)-crotepoxide2 (isolated from the fruit of Croton
dienophile.10 The DA adducts arising from the base-
catalyzed reaction have various functional groups on the
ridged bicyclolactone framework and are considered to be
attractive starting materials for syntheses of complex
molecules. In our continuing efforts to improve the synthetic
utility of this reaction, we have further examined the base-
catalyzed asymmetric DA reaction of 2.8,9 In particular, the
reaction of 2 and the optically active acrylate derivative 3 to
give 4 appears to be a useful method for preparing highly
functionalized six-membered rings, due to the ready avail-
ability of the substrates and the near-complete stereo-
selectivity. Indeed, the ef®cient asymmetric synthesis of
pseudo-sugars that have four oxygen functional groups
and one alkyl substituent on a cyclohexane ring has been
achieved from the optically active adduct 4.9
macrostachys), (1)-cyclophellitol3 (obtained from
a
Phellinus sp. mushroom) and eupenoxide4 (produced by a
fungus of the genus Eupenicilliu) are typical naturally
occurring cyclohexene oxides displaying various, strong
biological activities. Although the biological functions and
the absolute stereochemistry of 1 are not known at this time,
a strong interest in the synthesis of 1 has developed, in part
because of its structural resemblance to the biologically
active compounds described above and in part because of
a general interest in methods for synthesis of highly substi-
tuted cyclohexene oxides. After the ®rst synthesis of dl-1,1
asymmetric syntheses of (2)- and (1)-1 were reported by
Ogasawara et al. in 19935 and Maycock et al. in 1997,6
respectively. The former asymmetric synthesis was
achieved by an ef®cient asymmetric induction using lipase
hydrolysis of a meso substrate with a rigid tricyclic structure
and the latter synthesis was attained by stereoselective 1,4-
addition on an optically active cyclohexene derivative
obtained from (2)-quinic acid.
An important consideration in achieving ef®cient asym-
metric synthesis of 1 is the choice of the chiral starting
material, which should have appropriate functional groups
at appropriate positions. Since 1 contains four oxygen func-
tional groups and one alkyl substituent, its structural
features are essentially the same as those of pseudo-sugars.
Therefore, we again choose 4 as the starting material for this
asymmetric synthesis. Indeed, each functionality of 4
potentially corresponds to a functional group on 1. For
example, the oxygen functional groups at C-1 and C-4 and
the double bond at C-5,6 of 4 potentially correspond to the
epoxide and two hydroxyl groups of 1, respectively. In
We have previously reported a base-catalyzed Diels±Alder
(DA) reaction of 3-hydroxy-2-pyrone (2) with electron-
de®cient dienophiles.7±9 The mechanism of this reaction,
which involves activation of the diene moiety by a base,
is completely opposite to that of an ordinary DA reaction,
which is generally catalyzed by a Lewis acid that activates a
Keywords: eutipoxide B; Diels±Alder reaction; asymmetric synthesis.
Corresponding author. Fax: 181-99-285-8117;
e-mail: okam@sci.kagoshima-u.ac.jp
p
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00032-1

1904
H. Shimizu et al. / Tetrahedron 57 (2001) 1903±1908
Table 1. Stereoselective DA reaction of 2 and 3 in practical scale
was approximately equal to that of the above-described
reaction yielding (1)-4.
Dienophile
Catalyst (equiv.)
Cinchonine (0.2)
Yield (%) % de [(1)- or (2)-4]
With suf®cient quantities of optically pure starting materials
in hand, we began the synthesis of (2)-1 from (1)-4a
(Scheme 2). First, methanolysis and subsequent TBS protec-
tion for the resulting secondary alcohol yielded silyl ether 5.
Then, reduction of two carbomethoxy groups of 5 and
oxidative cleavage of the resulting 1,2-diol resulted in the
desired unsaturated ketone 6 in good yield. Next, stereo-
selective reduction of the carbonyl group of 6 was achieved
by NaBH(OAc)3, and the 1,3-diol having the appropriate
stereochemistry 7 was obtained as a single isomer.12
74
.95 (1)-4
.95 (2)-4
Cinchonidine (0.2) 82
The next step was stereoselective epoxidation of the C±C
double bond and chemoselective oxidation of the primary
hydroxyl group to an aldehyde that could be a footing for
introduction of the side-chain. Normally, direct and chemo-
selective oxidation of a 1,3-diol to give a hydroxyl aldehyde
is dif®cult. Frequently, the reiteration of protection±depro-
tection processes is needed, such as (1) selective protection
of the primary alcohol using a bulky reagent, (2) protection
of the secondary alcohol, (3) selective deprotection of the
primary group and (4) oxidation of the primary alcohol.
Recently, however, Rodriguez et al.13 reported chemoselec-
tive Swern oxidation of a primary silyl ether to an aldehyde
in the presence of secondary silyl ethers. Using this method,
the desired aldehyde could be prepared from a trisilyl ether
that is easily derived from 7. Furthermore, the bulky silyl
ether neighboring the double bond was expected to promote
stereoselective epoxidation. Indeed, epoxidation and subse-
quent Swern oxidation of silyl ether 8 resulted in epoxy
aldehyde 10, with complete stereoselectivity and in good
yield.
addition, the carbonyl group at C-8 of 4 provides a suitable
footing to introduce the alkyl substituent of 1. In this paper,
we present this new ef®cient asymmetric synthesis of (1)-
and (2)-1 from 4.
Before beginning the synthesis, we ®rst sought a practical
method of obtaining optically pure 4 in quantity (Scheme 1).11
Fortunately, we found a very simple and practical method for
obtaining (1)-4, as shown in Table 1. To a ®ne suspension of
(2)-3 (10.3 g, 47.4 mmol) and 2 (6.35 g, 56.7 mmol) in
aqueous 2-propanol (i-PrOH/H2Oˆ95:5, 177 mL) at 08C,
powdered cinchonine (2.78 g, 9.44 mmol) was added. The
mixture was continuously stirred for 2 h at 08C, and the
resulting precipitate was collected by vacuum ®ltration
and washed with 2-propanol (ca. 30 mL£3). The washed
precipitate was dried under vacuum for 3 h to yield (1)-4
as a slightly yellow powder (11.5 g, 74%, single isomer).
Consequently, (2)-4 was also obtained from (1)-3 by a
similar method, in which the catalyst was cinchonidine
rather than cinchonine. The stereoselectivity of this reaction
Introduction of the C4 side-chain and deprotection of the
Scheme 1.
Scheme 2. (a) MeONa, MeOH; (b) TBSCl, imidazole; (c) LiAlH4, THF; (d) NaIO4, THF/H2O; (e) NaBH (OAc)3; (f) TMSCl, Imidazole; (g) mCPBA;
(h) DMSO, (COCl)2, Et3N; (i) 2-methylpropenyl magnesiumbromide.

H. Shimizu et al. / Tetrahedron 57 (2001) 1903±1908
1905
Scheme 3.
remaining TMS ether were achieved by treatment with the
corresponding Grignard reagent and subsequent acidic
work-up, and diol 11 was obtained as a 1:1 diastereomeric
mixture. This mixture was used for oxidation of the result-
ing hydroxyl group without separation.
these adducts, which are readily available at high optical
purity, for synthesis of various biologically active molecules
including cyclohexane oxides. Further applications of (1)-
and (2)-4a are currently being examined in our laboratory.
Since the target hydroxyl group was an allylic alcohol,
effective and selective oxidation was expected (Scheme
3). Surprisingly, Fetizone oxidation14 of 11 afforded only
a trace amount of 12 and the starting material was not
recovered, probably due to its decomposition. Active-
MnO2 oxidation15 of 11 was complete within 15 min, but
provided an inseparable mixture of 12 and an alternative
ketone 13, which was obtained as a single isomer of
undetermined stereochemistry. Although PDC oxidation16
of 12 was relatively slow compared to MnO2 oxidation,
the desired ketone 12 was obtained along with a trace
amount of dehydrated 14, which could be removed by
SiO2 column chromatography. Therefore, we chose PDC
as the oxidant for this step.
1. Experimental
1.1. General
All reagents and solvents were used as supplied commer-
cially, except for THF and CH2Cl2, which were distilled
from Na/Ph2CO and CaH2, respectively. Melting points
were determined on a Yanagimoto micro melting point
apparatus and were uncorrected. Infrared spectra were
measured by JASCO FT/IR 5300 spectrophotometer: only
diagnostic absorptions in the infrared spectrum were
reported. 1H and 13C NMR spectra were measured by
JEOL GSX400 spectrometer at 400 and 100 MHz, respec-
tively. All chemical shifts (d) were recorded in ppm,
relative to tetramethylsilane (TMS). Mass spectra were
recorded on a Shimazu QP-5000 mass spectrometer. High-
resolution FAB mass spectra were obtained from JEOL
JMX-SX/SX 102A spectrometer using m-nitrobenzyl
alcohol matrix. Optical rotation was measured with a
JASCO DIP-370S Digital Polarimeter. All reactions were
carried out under inert atmosphere, if necessary. TLC analy-
sis was performed on Silica gel 60 F254-coated aluminum
sheets (Merck). Visualization was accomplished with
254 nm UV light and phosphomolybdic acid ethanol
solution as an indicator.
Finally, deprotection of the TBS ether of 12 yielded the
target compound (2)-1, which was obtained as a colorless
oil. Its spectroscopic properties, including optical rotation
24
([a]D ˆ260 (c 0.82, CHCl3), lit.5 [a]D ˆ256.6 (c 0.68,
CHCl3)), were fully identical to those previously
reported.1,5,6
23
Since the enantiomeric starting material (2)-4a, as well as
(1)-4a, was available, synthesis of the opposite enantiomer
was also examined. This enantiomer was successfully
produced with (2)-4a, using a procedure identical to that
24
described above, with an optical rotation of [a]D ˆ155 (c
1.1.1. (1S,4R,8S)-4-Hydroxy-3-oxo-8-[(4S)-4-phenyloxa-
zolidin-2-one-3-carbonyl]-2-oxabicyclo[2.2.2]oct-5-ene
[(2)-4a]. See text. Rf 0.51 (hexane/AcOEt, 3:7). Mp 120.0±
0.20, CHCl3), lit.6 [a]D ˆ157.3 (c 0.84, CHCl3).
23
20
In conclusion, the ef®cient asymmetric synthesis of both
enantiomers of 1 has been achieved from (1)- and (2)-
4a, which were themselves obtained from a base-catalyzed
asymmetric DA reaction of 2 and (2)- and (1)-3a, respec-
tively. This synthesis demonstrates the synthetic utility of
121.58C. [a]D ˆ173 (c 0.45, CHCl3). IR (KBr): 3478,
3416, 1775, 1707, 1638, 1618, 766, 702 cm21. H NMR
1
(CDCl3): d 7.27±7.40 (m, 5H); 6.35±6.38 (m, 2H); 5.43
(dd, Jˆ8.8 Hz, 1H); 5.26 (d, Jˆ4.0 Hz, 1H); 4.73 (t,
Jˆ8.8 Hz, 1H); 4.29±4.33 (m, 2H); 3.77 (s, ±OH); 2.71

1906
H. Shimizu et al. / Tetrahedron 57 (2001) 1903±1908
(ddd, Jˆ13, 9.5, 3.7 Hz, 1H); 1.83 (dd, Jˆ13, 3.3 Hz, 1H).
13C NMR (CDCl3): d 173.9, 169.8, 153.8, 138.8, 135.0,
129.3, 129.2, 128.9, 125.9, 75.8, 74.0, 70.1, 58.1, 40.2,
32.5. Anal. Calcd for C17H15NO6: C 62.00, H 4.59, N
4.25. Found: C 62.01, H 4.56, N 4.29.
38.8, 32.6, 25.8, 18.2, 24.56, 24.68. Anal. Calcd for
C14H28O4Si: C 58.29, H 9.78. Found: C 58.30, H 9.77.
To a stirring solution of the triol (2.25 g, 7.80 mmol) in
THF/H2O (1:1, 40 mL) NaIO4 (1.84 g, 8.58 mmol) was
added. The reaction was complete within 20 min. The
resulting mixture was quenched with a few drops of ethyl-
ene glycol, extracted with ethyl acetate (25 mL) for three
times, and the combined organic layer was washed with
brine, dried over MgSO4, ®ltered through a glass ®lter and
concentrated under reduce pressure. The resulting residue
was puri®ed by silica gel column chromatography to give
a,b -unsaturated ketone 6 (1.61 g, 80%) as a colorless oil. Rf
1.1.2. Dimethyl (1S,2R,5S)-5-tert-butyldimethylsilyloxy-
2-hydroxy-3-cyclohexene-1,2-dicarboxylate (5). To a
solution of adduct (1)-4a (5.00 g, 15.2 mmol) in MeOH
(100 mL), a solution of NaOMe 4.9 M in MeOH (9.3 mL,
45.6 mmol) at 08C was added dropwise. The reaction was
complete for approximately 30 min. The resulting solution
was quenched with aqueous diluted H3PO4 (5.0%, 50 mL)
and water (50 mL), evaporated under reduce pressure to
remove MeOH. The resulting solution was extracted with
ethyl acetate (40 mL) for three times, and the combined
organic layer was washed with aqueous saturated
solution of NaHCO3, and brine, evaporated to give crude
product which was used without further puri®cation in the
next step.
20
0.36 (hexane/AcOEt, 7:3). [a]D ˆ2137 (c 0.88, CHCl3).
IR (neat): 3445, 1678, 1385, 1254, 1076, 999, 777 cm21. 1H
NMR (CDCl3): d 6.80 (ddd, Jˆ9.9, 4.8, 1.1 Hz, 1H); 5.94
(d, Jˆ9.9 Hz, 1H); 4.48 (dd, Jˆ8.4, 4.0 Hz, 1H); 3.84±3.72
(m, 2H); 2.98 (ddd, Jˆ16, 6.6, 4.8 Hz, 1H); 2.68 (dd, Jˆ8.1,
4.8 Hz, ±OH); 2.10±1.97 (m, 2H); 0.91 (s, 9H); 0.11 and
0.12 (each s, 3H). 13C NMR (CDCl3): d 202.6, 148.7, 129.0,
63.3, 63.2, 43.8, 34.1, 25.7, 18.1, 24.64, 24.82.
HRFABMS m/z. Calcd for C13H25O3Si (M1H)1:
257.1575. Found 257.1573.
To a solution of the above product (4.95 g) in DMF (30 mL)
at 608C imidazole (1.14 g, 16.7 mmol) and TBDMSCl
(2.30 g, 15.2 mmol) were added. After stirring for 10 h at
the same temperature, the reaction mixture was poured into
water and extracted with ethyl acetate (30 mL) for three
times. The combined organic layer was dried over
MgSO4, ®ltered through a glass ®lter, and evaporated
under reduce pressure. Puri®cation by column chromato-
graphy gave 5 (3.80 g, 74% from (1)-4a) as a colorless
1.1.4. (1S,4S,6R)-4-tert-Butyldimethylsilyloxy-6-hydro-
xymethyl-2-cyclohexenol (7). To a solution of ketone 6
(120 mg,
0.468 mmol)
in
CH3COOH
(4.7 mL)
NaBH(OAc)3 was added at room temperature. After stirring
for 30 min, the reaction mixture was poured into aq. satu-
rated solution of NaHCO3 (20 mL) and the whole mixture
was extracted with AcOEt (20 mL) for three times. The
combined organic layer was dried over MgSO4, ®ltered
through a glass ®lter, and evaporated. The resulting residue
was puri®ed by silica gel column chromatography, and
alcohol 7 (115 mg, 95%) was obtained as a colorless oil.
Rf 0.38 (hexane/AcOEt, 3:7). Mp 70.0±71.58C.
20
oil. Rf 0.33 (hexane/AcOEt, 7:3). [a]D ˆ269 (c 0.76,
CHCl3). IR (neat): 3495, 2955, 2888, 2859, 1746, 1439,
1
1256, 1065, 837, 777 cm21. H NMR (CDCl3): d 5.97 (dd,
Jˆ9.9, 5.1 Hz, 1H); 5.61 (d, Jˆ9.5 Hz, 1H); 4.29 (brs, 1H);
3.85 (s, ±OH); 3.84 and 3.70 (each s, 3H); 3.59 (dd, Jˆ12,
4.4 Hz, 1H); 2.04±2.13 (m, 2H); 0.90 (s, 9H); 0.084 and
0.096 (each s, 3H). 13C NMR (CDCl3): d 175.5, 173.2,
132.5, 127.7, 72.1, 63.1, 53.4, 52.0, 42.1, 29.5, 25.8, 18.1,
24.52, 24.78. HRFABMS m/z. Calcd for C16H29O6Si
(M1H)1: 345.1761. Found 345.1733.
21
[a]D ˆ292 (c 0.55, CHCl31). IR (KBr): 3252, 1618,
1470, 1254, 941, 880 cm21. H NMR (CDCl3): d 5.73
(brd, Jˆ10 Hz, 1H); 5.71 (brd, Jˆ10 Hz, 1H); 4.18 (brd,
Jˆ2.6 Hz, 1H); 4.08 (dd, Jˆ8.4, 5.1 Hz, 1H); 3.78 (ddd,
Jˆ10, 5.9, 4.4 Hz, 1H); 3.68 (dt, Jˆ10, 4.0 Hz, 1H); 3.11
(d, Jˆ5.5 Hz, ±OH); 2.73 (dd, Jˆ5.5, 4.4 Hz, ±OH); 2.13±
2.06 (m, 1H); 1.59 (br d, Jˆ14 Hz, 1H); 1.41 (dt, Jˆ4.0,
14 Hz, 1H); 0.89 (s, 9H); 0.71 (s, 6H). 13C NMR (CDCl3): d
132.8, 129.6, 72.5, 67.7, 63.7, 38.3, 32.4, 25.9, 18.2, 24.57,
24.76. Anal. Calcd for C13H26O3Si: C, 60.42; H, 10.14.
Found: C 60.37, H 10.27.
1.1.3. (4S,6R)-4-tert-Butyldimethylsilyloxy-6-hydroxy-
methyl-2-cyclohexenone (6). To a solution of 5 (3.66 g,
10.6 mmol) in THF (50 mL) was carefully added lithium
aluminum hydride (LAH) (806 mg, 21.2 mmol) at 08C,
and after stirring for 3 h, the reaction mixture was quenched
with water (1.0 mL), aqueous NaOH (15%, 1.0 mL) and
H2O (3.0 mL). A diluted H3PO4 (5.0%, 50 mL) was added
to the resulting suspension to dissolve the precipitate. The
clear solution was extracted with ether (30 mL) for three
times, the extracts were washed with brine, and dried over
MgSO4. After ®ltered through a glass ®lter, the residue was
evaporated under reduce pressure to give triol (2.72 g, 89%)
as a white solid. Rf 0.47 (AcOEt). Mp. 72.5±73.58C.
1.1.5. (1S,2S,3R,4R,5R)-1-tert-Butyldimethylsilyloxy-2,3-
epoxy-4-trimethylsilyloxy-5-trimethylsilyloxymethyl-
cyclohexane (9). To a solution of diol 7 (405 mg,
1.57 mmol) and Et3N (656 mL, 4.71 mmol) in CH2Cl2
(15 mL) TMSCl (500 mL, 3.92 mmol) was added at room
temperature, and the mixture was stirred for 30 min. The
reaction solution was poured into a mixture of aq. saturated
solution of NaHCO3 and H2O (10 mL), and the whole
mixture was extracted with ether (25 mL) for three times.
The combined organic layer was washed with brine, dried
over MgSO4, ®ltered through a glass ®lter, and evaporated
to give crude TMS ether 8 (ca. 640 mg) as a colorless oil.
20
[a]D ˆ2120 (c 0.55, CHCl3). IR (KBr): 3416, 2955,
1
2888, 1638, 1618, 1472, 1399, 837, 775 cm21. H NMR
(CDCl3): d 5.85 (dd, Jˆ10, 4.4 Hz, 1H); 5.60 (d,
Jˆ10 Hz, 1H); 4.21 (brq, Jˆ4.4 Hz, 1H); 3.80 (dd, Jˆ11,
8.1 Hz, 1H); 3.74 (dd, Jˆ11, 2.9 Hz, 1H); 3.69 (d, Jˆ11 Hz,
1H); 3.47 (d, Jˆ11 Hz, 1H); 3.25±3.83 (br, 3H); 2.17 (m,
1H); 1.87 (ddd, Jˆ14, 9.5, 4.4 Hz, 1H); 1.56 (dt, Jˆ14,
4.4 Hz, 1H); 0.88 (s, 9H); 0.067 and 0.071 (each s, 3H).
13C NMR (CDCl3): d 133.1, 130.9, 72.2, 68.9, 64.3, 64.2,
To a solution of 8 in CH2Cl2 (10 mL) was added mCPBA
(541 mg, 3.17 mmol), and the solution was heated under

H. Shimizu et al. / Tetrahedron 57 (2001) 1903±1908
1907
1
re¯ux. After 7 h, the excess mCPBA was quenched with aq.
saturated solution of Na2S2O3 and the mixture was extracted
with ether (20 mL) for three times. The combined organic
layer was washed with aq. saturated solution of NaHCO3
and brine, dried over MgSO4, ®ltered through a glass ®lter,
and evaporated under reduced pressure. The residual oil was
puri®ed by silica gel column chromatography to give epox-
ide 9 (507 mg, 1.21 mmol, 77% from 7) as a colorless oil. Rf
1725, 1678, 1445, 1256, 1196, 1078, 912, 837 cm21. H
NMR (CDCl3): d 5.10 (dd, Jˆ9.2, 1.1 Hz, 1H); 4.24±4.21
(m, 3H); 3.90 (d, Jˆ9.2 Hz, 1H); 3.17 (d, Jˆ3.3 Hz, 1H);
3.09 (s, 1H); 2.00 (brs, ±OH); 1.83±1.70 (m, 1H); 1.73 (d,
Jˆ1.1 Hz, 3H); 1.66 (d, Jˆ1.1 Hz, 3H); 1.25 (dt, Jˆ13,
2.6 Hz, 1H); 1.10 (dt, Jˆ2.6, 13 Hz, 1H); 0.91 (s, 9H);
0.083 and 0.064 (each s, 3H). 13C NMR (CDCl3): d 137.4,
126.5, 74.3, 70.7, 65.3, 56.9, 55.0, 39.8, 26.6, 25.7, 25.6,
18.4, 18.1, 24.75, 25.00. Anal. Calcd for C17H32O4Si: C
62.15, H 9.82. Found: C 62.05, H 9.82. Second diastereomer
(white solid). Rf 0.33 (hexane/AcOEt, 6:4). Mp 129±1308C.
23
0.55 (hexane/ether, 10:1). [a]D ˆ14.3 (c 0.76, CHCl3). IR
1
(neat): 2957, 2859, 1472, 1254, 1088, 841 cm21. H NMR
(CDCl3): d 4.24 (brd, Jˆ2.2 Hz, 1H); 3.69 (d, Jˆ9.9 Hz,
1H); 3.55 (dd, Jˆ9.9, 2.9 Hz, 1H); 3.45 (dd, Jˆ9.9, 5.9 Hz,
1H); 3.08 (d, Jˆ3.3 Hz, 1H); 3.05 (brd, Jˆ1.1 Hz, 1H);
1.84±1.77 (m, 1H); 1.49 (brd, Jˆ14 Hz, 1H); 1.34 (dt,
Jˆ14, 13, 2.9 Hz, 1H); 0.90 (s, 9H); 0.18 (s, 9H); 0.093
and 0.087 (each s, 3H); 0.073 (s, 9H). 13C NMR (CDCl3):
d 67.0, 65.5, 63.1, 58.3, 55.5, 37.0, 28.3, 25.8, 18.1, 0.15,
20.57, 24.78, 24.82. HRFABMS m/z. Calcd for
C19H43O4Si3 (M1H)1: 419.2471. Found 419.2469.
21
[a]D ˆ246 (c 0.50, CHCl3). IR (KBr): 3457, 2932, 1736,
1676, 1462, 1254, 1184, 1078, 905, 837 cm21. H NMR
1
(CDCl3): d 5.32 (dt, Jˆ9.2, 1.5 Hz, 1H); 4.52 (dd, Jˆ9.2,
3.7 Hz, 1H); 4.25 (dd, Jˆ5.1, 2.6 Hz, 1H); 4.00 (brd,
Jˆ9.9 Hz, 1H); 3.63 (brs, ±OH); 3.17 (d, Jˆ3.7 Hz, 1H);
3.08 (t, Jˆ2.6 Hz, 1H); 2.13 (ddd, Jˆ9.9, 5.1, 4.8 Hz, 1H);
1.96 (brs, ±OH); 1.74 (d, Jˆ1.1 Hz, 3H); 1.68 (d, Jˆ1.1 Hz,
3H); 1.22±1.18 (m, 2H); 0.91 (s, 9H); 0.10 and 0.092 (each
s, 3H). 13C NMR (CDCl3): d 137.3, 123.6, 71.6, 66.7, 65.4,
57.2, 54.9, 39.2, 26.8, 26.0, 25.8, 18.4, 18.1, 24.76, 24.87.
Anal. Calcd for C17H32O4Si: C 62.15, H 9.82. Found: C
61.92, H 9.78.
1.1.6. (1R)-1-[(1R,2R,3S,4S,5S)-5-tert-Butyldimethylsilyl-
oxy-3,4-epoxy-2-hydroxycyclohexyl]-3-methyl-2-butenol
and (1S)-1-[(1R,2R,3S,4S,5S)-5-tert-butyldimethylsilyl-
oxy-3,4-epoxy-2-hydroxy-cyclohexyl]-3-methyl-2-butenol
(11). To a solution of oxalyl chloride (42 mL, 0.48 mmol) in
CH2Cl2 (3.0 mL) was dropwisely added DMSO (68 mL,
0.96 mmol) at 2788C, and the solution was stirred for
30 min. A solution of 9 (134 mg, 0.32 mmol) in CH2Cl2
(0.5 mL) was then dropwisely added to the above solution
at that temperature. After stirring for another 30 min, Et3N
(355 mL, 0.48 mmol) was added to the solution, and the
resulting mixture was stirred and gradually warmed to
room temperature for 2 h. The reaction solution was
quenched with water (1.0 mL), the whole mixture was
extracted with ether (10 mL) for three times. The combined
organic layer was washed with brine, dried over MgSO4,
®ltered through a glass ®lter, and evaporated under reduced
pressure to give crude product. The residue was puri®ed by
silica gel column chromatography to afford recovered 9
(19 mg, 14%), deprotected hydroxyaldehyde (5.0 mg,
7.2%), and aldehyde 10 (72 mg, 66%) as a colorless oil.
1.1.7. 1-[(1S,2R,3S,4R,5S)-5-tert-Butyldimethylsilyloxy-
3,4-epoxy-2-hydroxycyclohexyl]-3-methyl-2-buten-1-one
(12). To a solution of 11 (65 mg, 0.20 mmol) in CH2Cl2
(2.0 mL) was added PDC (89 mg, 0.24 mmol) at 08C. The
reaction mixture was stirred and gradually warmed to rt for
2 h. The resulting mixture was ®ltered through a pad of
silica gel and the pad was washed with ethyl acetate. The
®ltrate was evaporated under reduced pressure, and the resi-
due was puri®ed by silica gel column chromatography to
give the starting material 11 (7.0 mg, 11%) and the desired
product 12 (32 mg, 50%) as a colorless oil. Rf 0.40 (hexane/
24
AcOEt, 7:3). [a]D ˆ281 (c 0.15, CHCl3). IR (neat): 3463,
2930, 1686, 1618, 1445, 1254, 1076, 837 cm21. H NMR
1
(CDCl3): d 6.06 (t, Jˆ1.1 Hz, 1H); 4.30 (dd, Jˆ5.1, 2.6 Hz,
1H); 4.21 (dd, Jˆ9.5, 4.4 Hz, 1H); 3.23 (d, Jˆ3.7 Hz, 1H);
3.09 (brs, 1H); 2.73 (ddd, Jˆ13, 9.5, 2.6 Hz, 1H); 2.61 (d,
Jˆ4.4 Hz, ±OH); 2.16 (d, Jˆ1.1 Hz, 3H); 1.91 (d,
Jˆ1.1 Hz, 3H); 1.65 (dt, Jˆ14, 2.2 Hz, 1H); 1.44 (ddd,
Jˆ14, 13, 2.9 Hz, 1H); 0.95 (s, 9H); 0.142 and 0.138
(each s, 3H). 13C NMR (CDCl3): d 202.3, 157.8, 122.4,
66.0, 65.3, 56.9, 54.8, 48.4, 28.4, 28.0, 25.7, 21.0, 18.1,
24.70, 24.89. Anal. Calcd for C17H30O4Si: C 62.54, H
9.26. Found: C 62.71, H 9.20.
23
Rf 0.52 (hexane/ether, 8:2). [a]D ˆ25.9 (c 0.91, CHCl3).
IR (neat): 2932, 1728, 1472, 1362, 1254, 1100, 839 cm21
.
1H NMR (CDCl3): d 9.70 (d, Jˆ1.5 Hz, 1H); 4.28 (t,
Jˆ3.3 Hz, 1H); 4.16 (d, Jˆ9.2 Hz, 1H); 3.12±3.09 (m,
2H); 2.70 (dddd, Jˆ12, 9.2, 2.9, 1.5 Hz, 1H); 1.65 (dt,
Jˆ14, 3.3 Hz, 1H); 1.45 (ddd, Jˆ14, 12.1, 2.9 Hz, 1H);
0.92 (s, 9H); 0.20 (s, 9H); 0.12 and 0.11 (each s, 3H). 13C
NMR (CDCl3): d 202.8, 65.8, 64.3, 57.1, 55.4, 48.1, 25.8,
25.1, 18.1, 0.156, 24.81, 24.85.
1.1.8. (2)-Eutipoxide B ((2)-1). To a solution of 12
(69 mg, 0.21 mmol) in THF (2.0 mL), was added tetrabutyl-
ammonium ¯uoride (1.0 M in THF, 0.42 mmol) at room
temperature. After stirring for 30 min, the reaction mixture
was concentrated under reduced pressure, and the resulting
residue was puri®ed by silica gel column chromatography to
give (2)-eutipoxide B (1) (42 mg, 94%) as a very viscous
and hygroscopic colorless oil. Rf 0.45 (AcOEt).
To a solution of 10 (160 mg, 0.46 mmol) in THF (5.0 mL)
was added dropwise 2-methyl-1-propenylmagnesium
bromide (1.0 M in THF, 0.69 mmol) at 08C. After stirring
for 2 h, the reaction was quenched with diluted HCl (5.0%,
2.0 mL), and the whole mixture was extracted with ethyl
acetate (20 mL) for three times. The combined organic layer
was washed with brine, dried over MgSO4, ®ltered through a
glass ®lter, and evaporated to give crude product. Puri®ca-
tion by column chromatography gave 11 as an almost 1:1
mixture of two isomers (total 146 mg, 96%). First diastereo-
mer (white solid). Rf 0.48 (hexane/AcOEt, 6:4). Mp 100.5±
24
[a]D ˆ260 (c 0.82, CHCl3). IR (neat): 3418, 2932,
1680, 1615, 1445, 1383, 1250, 1115, 1044, 838,
1
799 cm21. H NMR (CDCl3): d 6.15 (d, Jˆ1.1 Hz, 1H);
4.38 (brd, Jˆ2.2 Hz, 1H); 4.26 (dd, Jˆ9.5, 4.4 Hz, 1H);
3.26 (d, Jˆ3.3 Hz, 1H); 3.22 (br d, Jˆ1.1 Hz, 1H); 2.87
(d, Jˆ4.8 Hz, 1H); 2.67 (ddd, Jˆ13, 9.5, 2.6 Hz, 1H);
2.20 (d, Jˆ4.8 Hz, ±OH); 2.16 (d, Jˆ1.1 Hz, 3H); 1.92
18
1028C. [a]D ˆ259 (c 0.50, CHCl3). IR (KBr): 3385, 2930,

1908
H. Shimizu et al. / Tetrahedron 57 (2001) 1903±1908
10. This type of reaction is very rare, and only one precedent, a
base-catalyzed reaction of anthrone with electron de®cient
dienophile, was known at that present; (a) Koerner, M.;
Rickborn, B. J. Org. Chem. 1989, 54, 6. (b) Koerner, M.;
Rickborn, B. J. Org. Chem. 1990, 55, 2662±2672. (c) Riant,
O.; Kagan, H. B.; Ricard, L. Tetrahedron 1994, 50, 4543±
4554.
(d, Jˆ1.1 Hz, 3H); 1.80 (dt, Jˆ13, 2.6 Hz, 1H); 1.50 (dt,
Jˆ2.6, 13 Hz, 1H). 13C NMR (CDCl3): d 201.9, 158.4,
122.4, 65.8, 64.6, 56.7, 54.3, 48.3, 27.9, 27.7, 21.2.
HRFABMS m/z. Calcd for C11H17O4 (M1H)1: 213.1131.
Found 213.1127.
1.1.9. (1)-Eutipoxide B ((1)-1). In according to the above
mentioned procedure, (1)-eutipoxide B ((1)-1) was also
synthesized from (2)-4a. All the spectra showed
completely identical with those of (2)-1, except for optical
11. We have already reported a stereoselective synthesis of (1)-
40, which has essentially the same stereochemistry as (1)-4,
by a reaction using (1)-30. In this reaction, the resulting (1)-
40 was obtained as a slightly gummy, intractable white
powder, and thus (1)-4 was used as a starting material
(Scheme 4).
24
rotation. [a]D ˆ155 (c 0.20, CHCl3).
Acknowledgements
The authors thank Dr Ryo Irie, Kyushu University, for
elemental analyses and measurements of HRMS. We are
also grateful to Professor Kunio Ogasawara, Tohoku
University, for helpful advice to measure [a]D of
eutipoxide B.
References
1. Defrancq, E.; Gordon, J.; Brodard, A.; Tabacchi, R. Helv.
Chim. Acta 1992, 75, 276±281.
2. Kupchan, S. M.; Hemingway, R. J.; Coggon, P.; Mcphail, A. T.
J. Am. Chem. Soc. 1968, 90, 2982±2983. Kupchan, S. M.;
Hemingway, R. J.; Smith, R. M. J. Org. Chem. 1969, 34,
3898±3902.
3. Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.;
Nakamura, H.; Iitaka, Y.; Takeuchi, T. J. Antibiot. 1990, 43,
49±53.
Scheme 4.
4. Duke, R. K.; Richards, R. W. J. Org. Chem. 1984, 49, 1898±
1904.
12. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560±3578.
5. Takano, S.; Moriya, M.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1993, 614±615.
13. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1999, 40, 5161±5164.
6. Teresa Barros, M.; Maycock, C. D.; Venture, M. R. J. Org.
Chem. 1997, 62, 3984±3988.
14. Fetizone, M.; Gol®er, M. C. R. Acad. Sci. (C) 1968, 267, 900±
903.
7. Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett.
1995, 36, 5939±5942.
15. Fieser, L.; Fieser, M. In Reagents for Organic Synthesis, Vol.
1, Wiley: New York, 1967; pp 637.
8. Okamura, H.; Nakamura, Y.; Iwagawa, T.; Nakatani, M.
Chem. Lett. 1996, 193±194.
16. Fieser, M.; Danheiser, R. L.; Roush, R. In Reagents for
Organic Synthesis; Wiley: New York, 1981; Vol. 9, pp 399.
9. Okamura, H.; Morishige, H.; Iwagawa, T.; Nakatani, M.
Tetrahedron Lett. 1998, 39, 1211±1214.