Intramolecular Diels-Alder reaction leading to tricyclic derivatives as intermediates of natural products synthesis

Article abstract of DOI:10.1016/S0040-4020(03)01013-5

Tricyclic compounds 4a and 4b possessing a bicyclo[4.3.0] moiety, were successfully synthesized by using the intramolecular Diels-Alder reaction. The siloxy- rather than acyloxy-substituents increased the ratio of the endo-cylcoadducts 10 and 12. The oxygen substitution of 9 influenced conformation of the transition state, which was stereochemically restricted by the butenolide moiety. In addition, 9b carrying a hydroxyl group also produced 10b in a similar ratio to 9a. Compound 11 was the only exo-adduct produced in all of the entries.

Full text of DOI:10.1016/S0040-4020(03)01013-5

Tetrahedron 59 (2003) 6039–6044
Intramolecular Diels–Alder reaction leading to tricyclic
derivatives as intermediates of natural products synthesis
*
Junichi Shiina and Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
Received 21 May 2003; accepted 23 June 2003
Abstract—Tricyclic compounds 4a and 4b possessing a bicyclo[4.3.0] moiety, were successfully synthesized by using the intramolecular
Diels–Alder reaction. The siloxy- rather than acyloxy-substituents increased the ratio of the endo-cylcoadducts 10 and 12. The oxygen
substitution of 9 influenced conformation of the transition state, which was stereochemically restricted by the butenolide moiety. In addition,
9b carrying a hydroxyl group also produced 10b in a similar ratio to 9a. Compound 11 was the only exo-adduct produced in all of the entries.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
[4.3.0] ring system, as well as the typical cis-fused
substitutions (Fig. 1).
Among powerful tools in organic synthesis towards
bioactive natural products, the intramolecular Diels–Alder
reactions have promised effective access to a variety of
complicated carbon-frameworks.1 An advantage of the
reaction is the simultaneous assembly of the carbon
framework, coupled with stereogenic centers. An example
of appropriate target molecules by the Diels–Alder reaction
might be a family of such terpenoids as punctatin A 1,2
fukinolide 2,3 and chiloscyphone 3,4 sharing the bicyclo-
Synthetic access to these terpenoids has been known:5 one
method is introduction of substitutions into cyclized
derivatives produced in advance. Another way is cyclization
of acyclic precursors with appropriate substitutions. In this
context, we investigated construction of the common
structure of the above-mentioned terpenoids with the cis-
oriented continuous substitutions by the intramolecular
Diels–Alder reaction. We describe herein progress of the
intramolecular Diels–Alder reaction, along with a stereo-
chemical assessment.
2. Results and discussion
2.1. Synthesis of triene 9a–9e
The Diels–Alder substrates 9a–9e, were synthesized from
diacetonide 5, readily available from D-mannitol (Scheme
1).6 Selective removal of an acetonide of 5 using p-TsOH
gave the corresponding diol in 74% yield, which was
reacted with n-Bu2SnO, followed by oxidation to give
ketone 6 in 96% yield in two steps.7 Exposure of 6 to
Ph3PCvCvO,8 and removal of an acetonide gave 7, after
protection with a TIPS group. Selective acid hydrolysis
gave the corresponding primary alcohol, which was
oxidized by Swern oxidation, and the resulting aldehyde
was submitted to the Wittig reaction with Ph3PCHCHO to
yield unsaturated aldehyde 8. Reaction of 8 with TMSCH2
MgCl, followed by desilylation furnished triene 9a. After
removal of the TIPS group of 9a, the resultant 9b could be
utilized for synthesis of 9c–9e by appropriate silylation and
acylation (Scheme 2).
Figure 1. The natural product possessed bicyclo[4.3.0] ring system.
Keywords: intramolecular Diels–Alder reaction; 1,3-allylic strain;
bicyclo[4.3.0] ring derivatives; terpenoid.
*
Corresponding author. Tel./fax: þ81-45-566-1717;
e-mail: nisiyama@chem.keio.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01013-5

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J. Shiina, S. Nishiyama / Tetrahedron 59 (2003) 6039–6044
Scheme 1. Reagents and conditions: (a) p-TsOH, CHCl3, MeOH, room temperature, 74%; (b) nBu2SnO, toluene, reflux; (c) NBS, CHCl3, room temperature,
96% in two steps; (d) Ph3PCvCvO, THF, reflux; (e) AcOH, H2O, THF, room temperature; (f) TIPSOTf, 2,6-lutidine, ClCH2CH2Cl, 08C, 50% in three steps;
(g) HCl, EtOH, room temperature, 88%; (h) (COCl)2, DMSO, Et3N, CHCl3, 2608C; (i) Ph3PCHCHO, THF, reflux, 72% in two steps; (j) TMSCH2MgCl, Et2O,
08C; (k) 1 M HCl, THF, 08C, 53% in two steps; (l) 3 M HCl, THF, room temperature, 100%; (m) TBSCl, imidazole, DMF, room temperature, 52%; (n) Ac2O,
pyridine, room temperature, 94%; (o) BzCl, pyridine, room temperature, 56%.
(Fig. 2).10 Roush has reported a similar intramolecular
Diels–Alder reaction of the triene derivatives: the main
product II, was obtained in the endo manner as in the case of
12a, bearing no 1,3-allylic strain between the substituent
at C-6 and a proton at C-8 in the reaction conformation
(Fig. 3).11
Furthermore, the circumstance of an OH group at C-6 would
control product distribution: upon employing bulky silyl
groups, I was obtained, while an acyl group provided II.
Based on such observation, 9b–9e were submitted to the
same reaction conditions, as in the case of 9a, to confirm the
reaction outcome by altering the function at the C-3
position. Contrary to expectation, the major product was
type-10 in all of the entries. There was no obvious influence
of the protective group at C-3. The reason might be that the
butenolide moiety in 9 decreased the flexibility of the
transition state. The transition state adopts conformations
to get rid of the stereochemical influence of a substituent at
C-3 (Fig. 4). Accordingly, 10a via the transition state
carrying less 1,3-diaxial strain (pre10a), was preferentially
produced to avoid the strain, which is observed in pre12a
(entry 1). Cyclization of 9c provided 10c as a major product
similar to the case of 9a (entry 3). In addition, even 9b
carrying a small volume of a hydroxyl group provided a
comparable result (entry 2) to the siloxy case.12 In the case
of the acylated derivatives (9d and 9e), the endo-adducts
10d and 10e decreased (entries 4 and 5), while 12d and
12e were produced in a similar ratio. Elucidation of these
results might show that the relatively compact acyl group
of 12 is more favorable than a bulky siloxy group in
the sterically hindered transition state. In addition, only
the type-11 products among possible exo-adducts, were
Scheme 2.
2.2. Intramolecular Diels–Alder reaction
The triene 9a in hand was submitted to the Diels–Alder
reaction (0.15 M concentration at 1658C in a sealed tube).9
As can be seen in Table 1, cyclization of 9a afforded a
55:19:26 mixture of the adducts 10a, 11a, and 12a, and their
stereochemistry was determined by the NOESY correlation
Table 1. The intramolecular Diels–Alder reaction of the butenolide
derivatives 9
Entry
Substrate
R
Yield (%)a
Product ratio 10:11:12b
1
2
3
4
5
9a
9b
9c
9d
9e
TIPS
H
TBS
Ac
90
72
73
90
73
55:19:26
56:16:28
60:16:24
43:21:36
49:23:28
Bz
a
Isolated yields.
Determined by 1H NMR analysis. Compounds 10 and 11 would be
converted into the same 4a, while 12 provided 4b.
b
Figure 2. The NOESY correlation of the cycloadducts 10a, 11a, and 12a.

J. Shiina, S. Nishiyama / Tetrahedron 59 (2003) 6039–6044
6041
Scheme 3. Reagents and conditions: (a) 6 M HCl, THF, room temperature,
95%; (b) SO3·py, DMSO, Et3N, room temperature, 95%.
3. Experimental
3.1. General
Figure 3. Transition state of Roush’s cycloaddition.
IR spectra were recorded on a JASCO Model A-202
1
spectrophotometer. H NMR and 13C NMR spectra were
obtained on JEOL JNM GX-400 spectrometers in a
deuteriochloroform (CDCl3) solution using tetramethyl-
silane as an internal standard. High-resolution mass spectra
were obtained on a Hitachi M-80 B GC-MS spectrometer
operating at the ionization energy of 70 eV. Optical
rotations were recorded at the sodium D line and ambient
temperatures with a JASCO DIP-360. Melting points were
measured on a Yanaco MP-S3 and uncorrected. Silica gel-
column chromatography was carried out using Katayama
K.K. Silica (60–200 mesh). Thin-layer chromatography
(TLC) was carried out on 0.25 mm precoated silica gel
plates of Silica Gel 60 F254 (E. Merck, Darmstadt).
Reaction progress was monitored by either UV (254 nm)
or stained with 5% phosphomolybdic acid in ethanol as
developing agent, followed in the latter case by heating on
an electric plate.
3.1.1. (5S)-1,5,6-Trihydroxy-5,6-O-isopropylidene-
hexan-2-one (6). To a solution of 5 (18.06 g, 78.4 mmol)
in CHCl3 (600 mL) and MeOH (60 mL) was added p-TsOH
(0.75 g, 3.9 mmol): the solution was stirred at room
temperature for 15 h. After addition of NaHCO3 (5 g), the
solvent was removed in vacuo. Purification of the crude
product by column chromatography on silica-gel (CHCl3–
MeOH, 20:1!5:1) to give diol (4.20 g, 74% conversion
yield) as a colorless oil and unreacted 5 (11.23 g): [a]2D0¼
211.2 (c 1.00, MeOH); IR (film) 3357, 2935 cm21; dH 4.13
(1H, m), 4.06 (1H, dd, J¼5.9, 8.1 Hz), 3.73 (1H, m), 3.63
(1H, dd, J¼3.4, 11.2 Hz), 3.53 (1H, t, J¼7.3 Hz), 3.45 (1H,
dd, J¼7.3, 11.2 Hz), 1.72–1.67 (2H, complex), 1.59–1.52
(2H, complex), 1.41 (3H, s), 1.35 (3H, s); dC 109.1, 76.1,
72.0, 69.4, 66.8, 30.1, 29.9, 26.9, 25.7. HRMS calcd for
C8H15O4 ([M2CH3]þ) m/z 175.0970, found 175.0987.
Figure 4. Transition state of cycloadducts.
produced, owing to lack of the two kinds of strains above-
mentioned.
Compound 4a and 4b were obtained from the Diels–Alder
cycloadducts 10a, 11a, and 12a. Thus, removal of the TIPS
group of 10a, 11a using 6 M HCl gave the corresponding
secondary alcohol in 95% yield. The resultant alcohol was
oxidized and isomerized under the SO3·py in DMSO to give
4a in 95% yield. Cycloadduct 12a was converted into
enantiomeric 4b by essentially the same procedure as 4a
(Scheme 3).
In conclusion, we have synthesized 4a and 4b using the
intramolecular Diels–Alder reaction, and demonstrated the
selectivity of cycloadducts 10–12. The product distribution
of the cycloadducts was controlled by their transition state:
the main product 10 was obtained in all of the entries, upon
carrying a more bulky silyl protecting group rather than the
acyl substrate. Further investigation of this synthetic
approach to natural products is in progress.
To a solution of the diol (8.23 g, 43.3 mmol) in toluene
(300 mL) was added dibutyltin oxide (11.30 g, 45.4 mmol):
the mixture was stirred at 1108C for 21 h in an apparatus
equipped with a Dean–Stark trap. The reaction mixture was
cooled to room temperature and concentrated in vacuo, and
the residue was dissolved in CHCl3 (200 mL). To this
mixture was added NBS (8.18 g, 45.4 mmol). The mixture
was stirred at room temperature for 30 min, concentrated in

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J. Shiina, S. Nishiyama / Tetrahedron 59 (2003) 6039–6044
vacuo, and a slurry was filtered through Celite pad. The
filtrate was concentrated in vacuo. Purification by column
chromatography on silica-gel (hexane–EtOAc, 1:1) to give
6 (7.84 g, 96% from diol) as a colorless oil: [a]2D0¼28.0 (c
1.00, CHCl3); IR (film) 3408, 2935, 1709 cm21; dH 4.27
(2H, s), 4.11 (1H, m), 4.04 (1H, dd, J¼6.0, 7.8 Hz), 3.54
(1H, dd, J¼6.6, 7.8 Hz), 2.75–2.48 (2H, complex), 1.95
(1H, m), 1.82 (1H, m), 1.38 (3H, s), 1.32 (3H, s); dC 208.9,
109.1, 74.7, 69.0, 68.1, 34.4, 27.4, 26.9, 25.5. HRMS calcd
for C8H13O4 ([M2CH3]þ) m/z 173.0814, found 173.0785.
To a solution of oxalyl chloride (0.41 mL, 4.7 mmol) in
CHCl3 (10 mL) was added a solution of DMSO (0.67 mL,
9.5 mmol) in CHCl3 (2 mL) dropwise at 2608C; the
resulting solution was stirred at the same temperature for
15 min. To this solution was added a solution of the above
alcohol (778 mg, 2.4 mmol) in CHCl3 (5 mL) dropwise at
the same temperature. The mixture was stirred at the same
temperature for 1 h. To this reaction mixture was added
Et3N (2.6 mL, 19 mmol) and stirred at 08C for 15 min. The
mixture was quenched by the addition of saturated aqueous
NH4Cl at 08C, and then resulting slurry was partitioned
between EtOAc and H2O. The combined organic layer was
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The crude oil was used directly for the next reaction
without further purification.
3.1.2. 3-[(3S)-Butanyl-3,4-bis(triisopropylsilyloxy)]-2-
buten-4-olide (7). To a solution of 6 (11.54 g, 61.3 mmol)
in THF (200 mL) was added Bestman’s Ylide (20.51 g,
67.8 mmol). The mixture was stirred at 658C for 9 h. The
resulting mixture was concentrated in vacuo, and the residue
was partitioned between EtOAc and H2O. The combined
organic layer was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The crude oil was used directly for
the next reaction without further purification.
To a solution of the above product in THF (20 mL) was
Ph3PCHCHO (1.45 g, 4.8 mmol). The mixture was stirred at
refluxing temperature for 12 h. The reaction mixture was
cooled to room temperature, concentrated in vacuo and
filtered. The filtrate was concentrated in vacuo. Purification
by column chromatography on silica-gel (hexane–EtOAc,
3:1!1:1) to afford 8 (605 mg, 72% in two steps) as a
colorless oil: [a]2D1¼þ22.8 (c 1.00, CHCl3); IR (film) 2943,
2866, 1780, 1749, 1691 cm21; dH (C6D6) 9.46 (1H, d, J¼
7.8 Hz), 6.27 (1H, ddd, J¼1.2, 7.8, 15.6 Hz), 6.06 (1H, dd,
J¼4.8, 15.6 Hz), 5.47 (1H, t, J¼1.4 Hz), 4.17 (1H, m), 3.87
(2H, d, J¼1.4 Hz), 1.81 (1H, m), 1.53 (1H, m), 1.38 (1H,
m), 1.20 (1H, m), 1.02–0.96 (21H, bs); dC (C6D6) 191.7,
168.4, 156.5, 132.0, 115.6, 72.2, 70.7, 34.0, 22.3, 18.2, 12.6.
HRMS calcd for C16H25O4Si ([M2C3H7]þ) m/z 309.1522,
found 309.1472.
To a mixture of the above product in water (30 mL) and
THF (30 mL) was added AcOH (90 mL). The mixture was
stirred at room temperature for 36 h. The mixture was
concentrated to a half volume, and passed through on silica-
gel (CHCl3–MeOH, 5:1), and the eluent was concentrated
in vacuo. The crude oil was used directly for the next
reaction without further purification.
To a solution of the above product in 1,2-dichloroethane
(100 mL) were added 2,6-lutidine (17.9 mL, 154 mmol) and
TIPSOTf (20.6 mL, 77 mmol) at 08C; the resulting mixture
was stirred at the same temperature for 1.5 h. The mixture
was quenched by the addition of 1 M HCl at 08C, and then
resulting slurry was partitioned between EtOAc and
H2O. The combined organic layer was washed with
saturated aqueous NaHCO3, brine, dried over Na2SO4 and
concentrated in vacuo. Purification by column chroma-
tography on silica-gel (hexane–EtOAc, 10:1) to give 7
(14.87 g, 50% from 6) as a colorless oil: [a]2D1¼215.5 (c
1.00, CHCl3); IR (film) 2943, 2866, 1782, 1751 cm21; dH
5.84 (1H, t, J¼1.4 Hz), 4.74 (2H, d, J¼1.4 Hz), 3.95 (1H,
m), 3.77 (1H, dd, J¼4.8, 9.0 Hz), 3.47 (1H, dd, J¼9.0 Hz),
2.57–2.52 (2H, complex), 1.99–1.83 (2H, complex), 1.05
(42H, bs); dC 170.9, 115.1, 73.1, 71.5, 66.0, 31.7, 23.1, 18.2,
18.1, 18.0, 17.8, 12.6, 12.4, 11.9. HRMS calcd for
C23H45O4Si2 ([M2C3H7]þ) m/z 441.2856, found 441.2842.
3.1.4. 3-[(3S,4E,6E)]-4,6-Heptadienyl-3-triisopropylsilyl-
oxy]-2-buten-4-olide (9a). To a solution of 8 (219 mg,
0.62 mmol) in Et2O (2 mL) was added TMSCH2MgCl
1.0 M solution in Et2O (1.2 mL, 1.2 mmol) dropwise at 08C.
The mixture was stirred at the same temperature for 20 min.
The mixture was quenched by the addition of saturated
aqueous NH4Cl at 08C, and then resulting slurry was
partitioned between EtOAc and H2O. The combined organic
layer was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The crude oil was used directly for
the next reaction without further purification.
To a solution of the above product in THF (3 mL) was added
1 M HCl (1.5 mL) at 08C. The mixture was stirred at the
same temperature for 3.5 h. The mixture was quenched by
the addition of saturated aqueous NaHCO3 at 08C, and then
resulting slurry was partitioned between EtOAc and
H2O. The combined organic layer was washed with brine,
dried over Na2SO4 and concentrated in vacuo. Purification
by column chromatography on silica-gel (hexane–EtOAc,
4:1) to give 9a (116 mg, 53% from 8) as a colorless oil:
[a]2D2¼þ3.4 (c 1.00, CHCl3); IR (film) 2943, 2866, 1782,
1751, 1637 cm21; dH 6.33 (1H, m), 6.18 (1H, dd, J¼10.7,
15.2 Hz), 5.83 (1H, t, J¼1.5 Hz), 5.65 (1H, dd, J¼6.8,
15.2 Hz), 5.20 (1H, d, J¼16.6 Hz), 5.11 (1H, d, J¼10.3 Hz),
4.73 (2H, d, J¼1.5 Hz), 4.41 (1H, m), 2.53–2.38 (2H,
complex), 1.89–1.84 (2H, complex), 1.05 (21H, bs); dC
170.4, 136.0, 135.7, 131.1, 117.5, 115.2, 73.1, 71.9, 35.6,
23.5, 18.1, 12.4. HRMS calcd for C20H34O3Si ([M]þ) m/z
350.2277, found 350.2254.
3.1.3. 3-[(3S,4E)-4-(6-Oxohexenyl)-3-triisopropylsilyl-
oxy]-2-buten-4-olide (8). To a solution of 7 (6.76 g,
13.9 mmol) in EtOH (50 mL) was added conc. HCl
(1 mL). The resulting solution was stirred at room
temperature for 5 h. The reaction mixture was concentrated
in vacuo, purification by column chromatography on silica-
gel (hexane–EtOAc, 1:1) to give alcohol (1.01 g, 88%
conversion yield) as a colorless oil and unreacted 7 (5.08 g):
[a]2D1¼þ7.6 (c 1.00, CHCl3); IR (film) 3454, 2943, 2866,
1780, 1747 cm21; dH 5.85 (1H, t, J¼1.6 Hz), 4.75 (2H, d,
J¼1.6 Hz), 3.98 (1H, m), 3.68–3.55 (2H, complex), 2.50
(2H, t, J¼8.1 Hz), 2.02–1.78 (2H, complex), 1.08 (21H,
bs); dC 169.9, 115.3, 73.0, 71.5, 65.4, 31.6, 24.1, 18.1, 12.6.
HRMS calcd for C14H25O4Si ([M2C3H7]þ) m/z 285.1522,
found 285.1559.

J. Shiina, S. Nishiyama / Tetrahedron 59 (2003) 6039–6044
6043
3.1.5. 3-[(3S,4E,6E)-4,6-Heptadienyl-3-hydroxy]-2-
buten-4-olide (9b). To a solution of 9a (68.3 mg,
0.20 mmol) in THF (1 mL) was added 3 M HCl (1 mL);
the mixture was stirred at room temperature for 8 h. The
mixture was quenched by the addition of saturated aqueous
NaHCO3 at 08C, and then resulting slurry was partitioned
between EtOAc and H2O. The combined organic layer was
washed with brine, dried over Na2SO4 and concentrated in
vacuo. Purification by column chromatography on silica-gel
(hexane–EtOAc, 1:1) to give 9b (19.3 mg, 100% conver-
sion yield) as a colorless oil and unreacted 9a (34.1 mg):
[a]2D2¼21.7 (c 1.00, CHCl3); IR (film) 3419, 2927, 1780,
1745, 1635 cm21; dH 6.37–6.21 (2H, complex), 5.84 (1H, t,
J¼1.6 Hz), 5.70 (1H, dd, J¼7.0, 15.2 Hz), 5.24 (1H, d, J¼
15.2 Hz), 5.14 (1H, d, J¼8.8 Hz), 4.75 (2H, d, J¼1.6 Hz),
4.22 (1H, m), 2.55–2.48 (2H, complex), 1.86–1.80 (2H,
complex); dC 170.0, 135.7, 135.0, 131.8, 118.4, 115.4, 73.1,
71.3, 34.2, 24.5. HRMS calcd for C11H14O3 ([M]þ) m/z
194.0943, found 194.0906.
layer was washed with saturated aqueous NaHCO3, brine,
dried over Na2SO4 and concentrated in vacuo. Purification
by column chromatography on silica-gel (hexane–EtOAc,
3:1) to give 9e (8.8 mg, 56%) as a colorless oil: [a]2D0¼
þ28.5 (c 0.77, CHCl3); IR (film) 2927, 1780, 1749, 1714,
1639 cm21; dH 8.04 (2H, d, J¼8.3 Hz), 7.59 (1H, m), 7.46
(2H, dd, J¼7.8 Hz), 6.40–6.28 (2H, complex), 5.89 (1H, d,
J¼1.5 Hz), 5.74 (1H, dd, J¼6.8, 14.2 Hz), 5.61 (1H, dd,
J¼6.8, 13.2 Hz), 5.30 (1H, m), 5.19 (1H, d, J¼10.3 Hz),
4.75 (2H, d, J¼1.5 Hz), 2.54–2.50 (2H, complex), 2.18–
2.01 (2H, complex); dC 168.8, 165.5, 135.4, 134.0, 133.2,
130.0, 129.8, 129.5, 128.4, 119.4, 115.7, 73.5, 73.0, 31.9,
24.5. HRMS calcd for C18H18O4 ([M]þ) m/z 298.1205,
found 298.1167.
3.1.9. (1R,5S,9R,10S)-10-Triisopropylsilyloxy-3-oxatri-
cyclo[7.3.0.01,5]dodec-7-ene-4-one (10a), (1R,5S,9S,10S)-
10-triisopropylsilyloxy-3-oxatricyclo[7.3.0.01,5]dodec-7-
ene-4-one (11a), (1S,5R,9S,10S)-10-triisopropylsilyloxy-
3-oxatricyclo[7.3.0.01,5]dodec-7-ene-4-one (12a). A solu-
tion of 9a (372 mg, 1.06 mmol) in dry toluene (7 mL) was
heated at 1658C for 32 h in a sealed tube. After being cooled
to room temperature, the tube was opened, and mixture was
concentrated in vacuo. Analysis of the crude product by 1H
NMR spectroscopy indicated that the TIPS ether 10a, 11a,
12a were present in the ratio of 55:19:26. The crude
products were purified by column chromatography on silica-
gel (hexane–EtOAc, 10:1) to give 10a, 11a, and 12a
(334 mg, 90%) as diastereomeric mixture. A part of the
mixture was submitted to chromatographic separation to
obtain the following data.
3.1.6. 3-[(3S,4E,6E)-3-tert-Butyldimethylsilyloxy-4,6-
heptadienyl]-2-buten-4-olide (9c). To a solution of 9b
(16.2 mg, 0.083 mmol) in DMF (0.8 mL) was added
imidazole (35.0 mg, 0.51 mmol) and TBSCl (35.0 mg,
0.23 mmol). The resulting solution was stirred at room
temperature for 6 h. The reaction mixture was purified by
column chromatography on silica-gel (hexane–EtOAc,
10:1) to give 9c (13.3 mg, 52%) as a colorless oil:
[a]2D2¼þ1.0 (c 1.00, CHCl3); IR (film) 2929, 2856, 1780,
1751, 1637 cm21; dH 6.32 (1H, m), 6.16 (1H, m), 5.82 (1H,
t, J¼1.6 Hz), 5.62 (1H, dd, J¼6.4, 15.2 Hz), 5.20 (1H, d,
J¼17.2 Hz), 5.10 (1H, d, J¼9.6 Hz), 4.73 (2H, d, J¼
1.6 Hz), 4.25 (1H, m), 2.46–2.42 (2H, complex), 1.81–1.76
(2H, complex), 0.89 (9H, s), 0.04 (3H, s), 0.03 (3H, s); dC
170.3, 136.0, 135.7, 130.9, 117.5, 115.2, 73.1, 71.8, 35.3,
25.9, 24.1, 18.2, 24.2, 24.8. HRMS calcd for C17H28O3Si
([M]þ) m/z 308.1808, found 308.1785.
Compound 10a. [a]2D2¼þ9.1 (c 1.00, CHCl3); mp 104–
1058C (toluene–MeOH); IR (disk) 2943, 2866, 1755 cm21
;
dH 6.20 (1H, m), 5.97 (1H, m), 4.53 (1H, t, J¼5.0 Hz), 4.22
(1H, dd, J¼2.0, 9.9 Hz), 3.98 (1H, d, J¼9.9 Hz), 2.67 (1H,
dd, J¼3.0, 10.2 Hz), 2.43 (1H, m), 2.36–2.30 (2H, com-
plex), 2.16 (1H, m), 2.07 (1H, bs), 1.83 (1H, m), 1.53 (1H,
m), 1.06 (21H, bs); dC 180.9, 129.0, 127.7, 76.5, 71.7, 51.6,
49.0, 43.7, 36.4, 35.6, 26.4, 18.2, 18.1, 12.3. HRMS calcd
for C17H27O3Si ([M2C3H7]þ) m/z 307.1729, found
307.1727.
3.1.7. 3-[(3S,4E,6E)-3-Acetoxy-4,6-heptadienyl]-2-
buten-4-olide (9d). To a solution of 9b (19.3 mg,
0.099 mmol) in pyridine (1 mL) was added Ac2O (1 mL)
at 08C. The resulting solution was stirred at room
temperature for 16 h. This reaction mixture was concen-
trated in vacuo, purification by column chromatography on
silica-gel (hexane–EtOAc, 2:1) to give 9d (22.0 mg, 94%)
as a colorless oil: [a]D22¼26.3 (c 1.00, CHCl3); IR (film)
2931, 1780, 1747, 1637, 1238 cm21; dH 6.35–6.20 (2H,
complex), 5.86 (1H, t, J¼1.8 Hz), 5.60 (1H, dd, J¼7.2,
14.4 Hz), 5.34–5.25 (2H, complex), 5.17 (1H, m), 4.74 (2H,
d, J¼1.8 Hz), 2.46–2.42 (2H, complex), 2.06 (3H, s), 2.03–
1.87 (2H, complex); dC 170.0, 168.9, 135.4, 134.0, 129.9,
119.4, 115.6, 73.1, 72.9, 31.7, 24.5, 21.2. HRMS calcd for
C13H16O4 ([M]þ) m/z 236.1049, found 236.1031.
Compound 11a. dH 5.73 (1H, m), 5.58 (1H, m), 4.45 (1H, d,
J¼8.2 Hz), 4.14 (1H, bs), 4.01 (1H, d, J¼8.2 Hz), 2.55–
2.54 (2H, complex), 2.45 (1H, bs), 2.25 (1H, m), 2.04 (1H,
m), 1.79–1.68 (3H, complex), 1.06 (21H, bs); dC 180.0,
127.8, 125.1, 80.0, 78.6, 50.7, 46.7, 43.1, 33.7, 31.5, 20.6,
18.1, 12.1.
Compound 12a. dH 6.13 (1H, m), 5.98 (1H, m), 4.03 (1H,
m), 3.92 (1H, d, J¼8.8 Hz), 3.82 (1H, d, J¼8.8 Hz), 2.70
(1H, dd, J¼3.4, 9.4 Hz), 2.44–2.41 (2H, complex), 2.26
(1H, m), 1.92 (1H, m), 1.86–1.75 (2H, complex), 1.07
(21H, bs); dC 180.5, 129.6, 128.3, 75.4, 73.2, 51.0, 49.5,
43.8, 34.3, 32.6, 26.4, 18.1, 12.3.
3.1.8. 3-[(3S,4E,6E)-3-Benzoyloxy-4,6-heptadienyl]-2-
buten-4-olide (9e). To a solution of 9b (10.3 mg,
0.053 mmol) in pyridine (1 mL) was added BzCl (0.2 mL,
1.7 mmol). The resulting solution was stirred at room
temperature for 12 h. To this reaction mixture was added
MeOH (0.1 mL) at room temperature, and then stirred at the
same temperature for 30 min. The mixture was quenched by
the addition of 1 M HCl at 08C, then resulting slurry was
partitioned between EtOAc and H2O. The combined organic
3.2. Intramolecular Diels–Alder reaction of 9b–9e
A solution of substrate in dry toluene (0.15 M) was heated
at 1658C for 32 h in a sealed tube. After being cooled
to room temperature, the tube was opened, and the
mixture was concentrated in vacuo. Purification by column

6044
J. Shiina, S. Nishiyama / Tetrahedron 59 (2003) 6039–6044
chromatography on silica-gel to give the tricyclic compound
as diastereomeric mixture. Protecting groups were removed
by aqueous HCl or K2CO3 in MeOH, and the resulting
alcohols were treated with TIPSOTf and 2,6-lutidine to give
a crude mixture, which was spectroscopically analyzed to
determine a ratio of 10, 11, and 12.
References
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3.2.1. (1S,5S)-3-Oxatricyclo[7.3.0.01,5]dodec-8-ene-4,10-
dione (4a). To a solution of 10a (9.3 mg, 0.027 mmol) in
THF (0.5 mL) was added 6 M HCl (0.5 mL). The resulting
solution was stirred at room temperature for 12 h. The
mixture was quenched by the addition of saturated aqueous
NaHCO3 at 08C, then resulting slurry was partitioned
between EtOAc and H2O. The combined organic layer was
washed with brine, dried over Na2SO4 and concentrated in
vacuo. Purification by column chromatography on silica-gel
(hexane–EtOAc, 1:2) to give alcohol (4.9 mg, 95%) as a
colorless oil: dH 6.13 (1H, dt, J¼2.8, 9.6 Hz), 6.02 (1H, m),
4.47 (1H, t, J¼5.2 Hz), 4.20 (1H, dd, J¼1.8, 10.0 Hz), 4.01
(1H, d, J¼10.0 Hz), 2.69 (1H, dd, J¼3.8, 9.4 Hz), 2.45 (1H,
m), 2.35 (1H, m), 2.19 (1H, m), 2.15 (1H, bs), 1.86–1.70
(2H, complex), 1.51 (1H, m).
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To a solution of above alcohol (4.9 mg, 0.025 mmol) in
DMSO (0.2 mL) and Et3N (0.2 mL) was added SO3·py
(50 mg, 0.31 mmol). The resulting solution was stirred at
room temperature for 4 h. The mixture was quenched by the
addition of saturated aqueous NH4Cl at 08C, then resulting
slurry was partitioned between EtOAc and H2O. The
combined organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo. Purification by column
chromatography on silica-gel (hexane–EtOAc, 1:2) to give
4a (4.6 mg, 95%) as a colorless oil: [a]2D4¼25.4 (c 0.26,
CHCl3); IR (film) 2950, 1772, 1720, 1651 cm21; dH 6.90
(1H, t, J¼4.4 Hz), 4.28 (1H, d, J¼9.2 Hz), 4.13 (1H, dd,
J¼1.0, 9.2 Hz), 2.54 (1H, dd, J¼5.2, 8.8 Hz), 2.43–2.40
(2H, complex), 2.39–2.31 (3H, complex), 2.02 (1H, m),
1.92 (1H, m), 1.69 (1H, m); dC 203.2, 177.9, 139.2, 134.5,
76.3, 46.3, 43.6, 35.6, 32.8, 23.7, 21.4. HRMS calcd for
C11H12O3 ([M]þ) m/z 192.0786, found 192.0781.
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dione (4b). [a]2D2¼þ4.6 (CHCl3), its spectroscopic data was
superimposable to those of 4a.
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Acknowledgements
This work was supported by Grant-in-Aid for the 21st
Century COEprogram ‘Keio Life Conjugate Chemistry’
from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
12. A possibility of electrostatic effect by the polaritic hydroxyl
group is also considered.