Reactivity and stereoselectivity of the Diels-Alder reaction using cyclic dienophiles and siloxyaminobutadienes

Article abstract of DOI:10.1016/j.tet.2011.01.019

Several bicyclic compounds were synthesized by the Diels-Alder reaction using aminodiene and a cyclic dienophile. The stereochemistries of the obtained adducts were determined by X-ray crystallography or NMR analysis. The stereoselectivity of this Diels-A

Full text of DOI:10.1016/j.tet.2011.01.019

Tetrahedron 67 (2011) 1893e1906
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Tetrahedron
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Reactivity and stereoselectivity of the DielseAlder reaction using cyclic
dienophiles and siloxyaminobutadienes
*
Toshiyuki Ohfusa, Atsushi Nishida
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2011
Received in revised form 5 January 2011
Accepted 6 January 2011
Available online 13 January 2011
Several bicyclic compounds were synthesized by the DielseAlder reaction using aminodiene and a cyclic
dienophile. The stereochemistries of the obtained adducts were determined by X-ray crystallography or
NMR analysis. The stereoselectivity of this DielseAlder reaction was based on the interaction of
molecular orbitals between the diene and dienophile. The reactivities of these DielseAlder reactions
were estimated, and the generality of this reaction is discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
DielseAlder reaction
Siloxyaminobutadiene
Cyclic dienophile
Stereoselectivity
Reactivity
1. Introduction
Many natural compounds contain a six-membered ring system.
In the synthesis of this ring system, stereo-control is an important
issue. In 1997, Rawal and Kozmin introduced 1-amino-3-siloxy-bu-
tadiene (aminodiene) as a highly reactive diene in the DielseAlder
(DA) reaction (Scheme 1).1a They also reported a diastereoselective
DA reaction using a chiral aminodiene1b,1c and an enantioselective
DA reaction in the presence of a chiral Cr-salen-SbF6 catalyst.1de1f
These highly reactive DA reactions using aminodienes are power-
ful tools for constructing cyclohexene derivatives and have been
applied tothe synthesis of natural products.1c,2ꢀ7 However, there are
few reports of the use of aminodiene and a cyclic dienophile to
construct a bicyclic system.1d,1e,6,8 Rawal reported the DA reaction
using carboxaldehyde 4 with aminodiene 5 and obtained endo ad-
duct 6 (Scheme 2),1d although the stereochemistry of 6 was only
Scheme 2.
estimated based on the reaction mechanism. Furthermore, in most
of these examples, an amino group is immediately removed to
transform the product into an enone (Scheme 3).9
On the other hand, we previously reported the enantioselective
DA reaction of 10 and 11 with 50 mol % of a chiral Cr-Salen-F
complex, which has fluoride anion as a counter ion.10 The reaction
Scheme 1.
Scheme 3.
* Corresponding author. E-mail address: nishida@p.chiba-u.ac.jp (A. Nishida).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.019

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T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
proceeded smoothly to give a hydroisoquinoline 12 with high endo
selectivity (Scheme 4), in which the formyl group and amino group
have a syn stereochemistry. Isoquinoline 12 should be a potential
intermediate for the total synthesis of manzamine B (13).
Fig. 1. Natural products possessing bicyclic system like 15.
2.1. Synthesis of dienophiles
Carboxaldehydes 20, 21, and 22, enone 23, and doubly activated
ketoesters 24 and 25 were used as dienophiles to investigate carbo-
cyclic dienophiles (Fig. 2). Lactam dienophile 26 was also designed to
compare its reactivity to that of 10 in Scheme 4. Dienophiles 20, 24,
and 25 were synthesized by a known procedure.15,16 Carboxaldehyde
22 was synthesized from known alcohol 33,17 via protection of the
secondary alcohol and halogenelithium exchange followed by for-
mylation with DMF. The known compound 3518 was converted to
enoen dienophile 23 by protection with a PMB group under acidic
conditions. Lactam-type dienophile 26 was synthesized from
N-benzenesulfonyl lactam 38 in 2 steps.19 Dienes 11 and 39 were
prepared by an established procedure.10 Cyclohexenecarboxalde
hyde 21 is available from Aldrich (Fig. 3).
Scheme 4.
Thus, further study on the stereoselectivity of the DA reaction
using aminodienes has been required. In this paper, we report
a systematic study of the reactivity and stereoselectivity of the DA
reaction using aminodienes and cyclic dienophiles.
2. Results and discussion
We studied DA reactions using aminodienes and cyclic dien-
ophiles as shown in Scheme 5, with particular focus on the ster-
eoselectivity of the amino function. If the stereoselectivity is
controlled by an electron-withdrawing group X or Y on the dien-
ophile, the reaction may be useful for constructing skeletons in
natural compounds, such as 13 and 17e19,11e14 which have an
amino pendant group on a bicyclic skeleton with different stereo-
chemical requirements (Fig. 1).
Fig. 2. Designed dienophiles.
2.2. DA reaction and determination of stereochemistry
We began to study the DA reaction using cycloalkeneecarbo
xaldehyde-type dienophiles 20, 21, and 22 under the influence of
50 mol % CreSaleneF complex (Table 1). These results show endo
addition to a formyl carbonyl group. In the reaction of dienophile 22,
Scheme 5.
Fig. 3. Preparation of dienophile.

T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
1895
Table 1
DA reaction of carboxaldehyde-type dienophiles
Entry
Dienophile
Time (h)
Result
1
2
3
20: n¼1, R¼H
1
50
5
40: 86%, 79% ee
41: 69%, 81% ee
42: 73%a, 59% eeb
21: n¼2, R¼H
22: n¼1, R¼OPMB
a
Diastereomer ratio at the C7 position was 7.3:1.
ee of major isomer.
b
Table 2
DA reaction of substituted cyclopentenone
Fig. 4. X-ray crystallography of 48.
reactive. The DA reaction of 23 and 39 gaveadduct 43 in only 4% yield
in the presence of 50 mol % CreSaleneF complex at 100 ꢁC for 4 days
(Table 2, entry 1). However, microwave irradiation accelerated the
reaction to give adduct in 61% yield (Table 2, entry 2). Adduct 43 has
anti stereochemistry, which is explained by an endo transition state
to a ketone carbonyl group.
Entry
Conditions
Yield
1
2
CreSaleneF (50 mol %), 100 ꢁC, 4 d
Microwave (<300 W, 150 ꢁC, <3.0 atm, 36 h)
4%
61%
The DA adducts were converted into derivatives to determine
their stereochemistries by X-raycrystallographic or 2D-NMR analysis
and NOE correlation. Adduct 42 was converted into tricyclic com-
pound 45 by Rawal’s procedure.2 Deprotection followed by reduction
of the ketone gave a mixture of diastereomeric secondaryalcohols, 47
and 48. Separated 48 wasa crystalline compound, which was suitable
for X-ray analysis (Scheme 6 and Fig. 4). Adducts 40 and 41 were
converted to cyclic carbamates 49 and 50 by reduction of a formyl
group followed by cyclization (Scheme 7). Their stereochemistries
which has a stereogenic center in the cyclopentene ring, a mixture of
adducts was smoothly obtained with high diastereoselectivity
(7.3:1) at the C7 position. When dienophile 22 was used, C5 proton,
which occupies the pseudo axial position, blocked
tion state as shown in A. Therefore, diene 39 attacked from
a
face in transi-
face.
b
Cyclopentenecarboxaldehyde 20 was more reactive than cyclo-
hexenecarboxaldehyde 21 and 10 (Table 1, entries 1 and 2). In all of
the reactions, the face selectivity was perfectly controlled to give
a syn adduct. On the other hand, cyclopentenone 23 was less
Scheme 6.
Scheme 7.

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T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
Table 4
DA reaction using ketoester dienophiles 24 and 25
Entry Dienophile Conditions
Yield % (ee%)a
anti syn
Fig. 5. Stereochemistries of 49 and 50 determined by NMR analysis.
1
2
3
4
5
6
7
24
24
24
24
25
25
25
CreSaleneF (50 mol %), 0 ꢁC, 4.5 h
CreSaleneF (50 mol %), rt, 2 h
CreSaleneF (50 mol %), 60 ꢁC, 1 h
23 (18) 24 (23)
38 (16) 31 (15)
43 (16) 44 (13)
were determined by a combination of 2D-NMR analysis and NOE
experimentation (Fig. 5). DA adduct 43 was converted to crystalline
compound 52 by deprotection of both the TBS enol ether and PMB
groupfollowed byacylationofaprimaryalcoholusingp-nitrobenzoyl
chloride. The stereochemistry of 52 was determined by X-ray analy-
sis, and the crystal was confirmed to be a dimer (Scheme 7 and Fig. 6).
Microwave (<300W, 150 ꢁC), 5 min 39
24
CreSaleneF (50 mol %), rt, 4 d
CreSaleneF (50 mol %), 60 ꢁC, 6 h
Microwave (<300W, 150 ꢁC), 2 h
23 (48) 26 (5)
21 (40) 25 (12)
35
20
a
Absolute stereochemistry was determined from a mechanistic point of view.
25 gave a mixture of syn/anti DA adducts with low enantiose-
lectivity (Table 4). Although the isolated yield of both adducts is
almost equal, we found that the isolated anti isomer isomerized to
syn isomer under Lewis acidic conditions (Table 5). However, the
isomerization did not proceed under microwave irradiation.
Table 5
Isomerization of DA adduct 55-anti and 56-anti
Entry SM
Conditions
Result
1
2
3
4
55-anti CreSaleneF (50 mol %), rt, 21 h
55-syn: quant
55-anti Microwave (<300 W, 150 ꢁC), 5 min no reaction
56-anti CreSaleneF (50 mol %), rt, 5 d
56-anti Microwave (<300 W, 150 ꢁC), 2 h
56-anti:56-syn ca. 1:1
no reaction
A plausible mechanismfor this isomerizationisshowninScheme8.
Fig. 6. X-ray crystallography of 52.
By a retro-Mannich pathway, zwitterionic intermediate 57 is gener-
ated, which should be recyclized to the more stable syn adduct.8 While
the anti adduct was a major adduct when the dienophile 24 or 25 was
irradiated by microwave with diene 39, the selectivity was poor (Table
4, entries 4 and 7).
Next, we were interested in the reaction using doubly activated
cyclic dienophiles. When the lactam dienophile 26 was reacted
with aminodienes, anti-adduct 53 or 54 was obtained as a single
racemic isomer (Table 3). On the other hand, both ketoester 24 and
Table 3
DA reaction using lactam-type dienophile 26
Scheme 8.
Silyl enoletherof 53was convertedto aketone, whichwasin turn
reduced to b-alcohol 59 (Scheme 9). Methanolysis of 59 followed by
Entry
Diene
Conditions
Result
intramolecular lactonization (via 60) gave crystalline compound 61,
which has an oxabicyclo[2.2.2]octanone skeleton. The structure of
61 was confirmed by X-ray crystallographic analysis (Fig. 7).
DA adducts 55-anti and 55-syn, synthesized from ketoester
dienophile 24, were exposed to LiBH4 reduction. As a result, cyclic
1
2
3
4
11
11
39
39
CreSaleneF (50 mol %), CHCl3, reflux, 3 d
Microwave (<300 W, 150 ꢁC), 2 h
CreSaleneF (50 mol %), CHCl3, reflux, 3 d
Microwave (<300 W, 150 ꢁC), 2 h
53: 75%
53: 46%
54: 61%
54: 19%

T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
1897
Scheme 9.
Fig. 9. X-ray crystallography of 64.
Fig. 7. X-ray crystallography of 61.
carbamate 62 (from 55-anti) and diol 64 (from 55-syn) were
obtained (Scheme 10). Cyclic carbamate 62 was oxidized to alde-
hyde 63, and its stereochemistry was determined by 2D-NMR
analysis and NOE experiments (Fig. 8). Diol 64 is a crystalline
compound, and its stereochemistry was determined by X-ray
analysis (Fig. 9). Although the methoxycarbonyl group at the ring-
juncture was less reactive, adduct 56-anti was converted to diol 66,
which was a crystalline compound suitable for X-ray analysis
(Scheme 11 and Fig. 10). The crystal was determined to be a dimer.
Scheme 11.
Fig. 10. X-ray crystallography of 66.
Reduction of 56-syn at 45 ꢁC gave a diol, which was converted to
cyclic carbamate 67 under basic conditions. Compound 67 was then
oxidized to ketone 68 and its stereochemistry was determined by
2D-NMR analysis and NOE experiments (Scheme 11 and Fig. 11).
Scheme 10.
Fig. 8. Stereochemistry of 63.
Fig. 11. Stereochemistry of 68.

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T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
2.3. Stereoselectivity
2.4. Reactivity
The results of the DA reaction using aminodiene and a cyclic
dienophile are summarized in Table 6. These data show that the
orbital interaction between a carbonyl group and diene affects the
stereoselectivity to give DA adducts via an endo transition state to
a carbonyl group. Therefore, syn adducts 12, 40, 41, and 42 were
obtained from a carboxaldehyde-type dienophile. On the other
hand, enone-type dienophile 23 gave anti adduct 43.
When a ketoester was used, both carbonyl groups would acti-
vate the reaction to give a syn/anti mixture. We confirmed that the
endo adduct to a ketone, which has a larger LUMO orbital, was the
major product under thermal conditions using microwave irradi-
ation. Due to the instability of the ketoaldehyde-type dienophile,
69 could not be used for this study.
The structure of the dienophile clearly affected reactivity. The
enone-type dienophile 23 was less reactive than cyclo-
pentenecarboxaldehyde 22, due to the steric hindrance between
aminodiene and the cyclopentenone ring (Schemes 12). A similar
difference in reactivity was observed in the reaction of 10 and 26.
While the lactam-type dienophile 26 required heating for 3 days to
complete the reaction, carboxaldehyde 10 and diene 11 gave adduct
12 under rt in 20 h (Scheme 4 and Table 3, entry 1).
To consider the case of lactam dienophile 26, the LUMO of dien-
ophiles was calculated using computational chemistry. Lactam car-
bonylhasalargerLUMOorbitalthananester(Fig.12). Therefore, endo
addition to a lactam carbonyl should give anti adduct 53 (Table 3).
However, it is unclear why the reaction of 26 showed higher selec-
tivity than those of dienophiles 24 and 25.
Table 6
Stereoselectivity of DA reaction using cyclic dienopile and aminodiene
Entry
Dienophile
Adduct
Stereoselectivity
Scheme 12.
The ring size of the dienophile also influenced the reactivity
(Scheme 13). In the case of 24 and 25, five-membered ring dien-
ophile 24 was more reactive than six-membered ring dienophile 25
(Table 2).20 In a comparison of transition states, pseudo axial pro-
tons at C4 and C6 on the ring of 25 shield both faces of the dien-
ophile (shown in E) and slow the reaction of 25 more than that of
24. The reactivities of all the dienophiles are summarized in Fig. 13.
Although dienophiles 22 and 24 are synthetic equivalents of each
other, 24 is less effective for the DA reaction using aminodiene.
1
2
3
4
5
6
Poor selectivity
Dienophile 69 was too unstable. ND
Scheme 13.
Fig. 12. Calculated LUMO of 26.
Fig. 13. Reactivity of dienophiles.

T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
1899
3. Conclusion
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Center,12, Union Road, Cambridge,
CB21EZ, UK;Fax: þ441223336033;email:deposit@ccdc.cam.ac.uk).
In this study, the stereoselectivity of the DA reaction using
aminodienes and cyclic dienophiles was established. We have
consolidated the stereoselective syntheses of bicyclic skeletons
possessing an amino group.
This reaction should be useful for the synthesis of natural
products. For example, DA adduct 430, which has anti stereo-
chemistry, seems to be suitable as a building block for constructing
the skeleton of lycoposerramine-R (Scheme 14).13 In addition, as
well as 430, syn adduct 420 may be a precursor of lycoposerramine-
Q.12 We are now studying these syntheses and hope to demonstrate
the efficiency of the DA reaction using aminodiene and cyclic
dienophiles.
4.1.1. (1-Cyclopentenyl)methanol, 28. To
a solution of methyl-
cyclopentene-1-carboxylate (0.73 mL, 5.35 mmol) in toluene
(67 mL) was added dropwise Red-AlÒ (3.34 M in toluene, 3.6 mL,
11.7 mmol) at 0 ꢁC. The resulting mixture was stirred for 3 h at the
same temperature. Ice-cold H2O (20 mL) was added to quench the
reaction. The separated water layer was extracted with Et2O, and
the combined organic layers were dried over Na2SO4. After volatile
material was removed under reduced pressure, the resulting resi-
due was purified by column chromatography (SiO2, hexane/
AcOEt¼9/1) to give 28 (419 mg, yield 80%) as a colorless oil. Spectral
data were identical to the reported data.21
4.1.2. Cyclopentene-1-carboxaldehyde, 20. To
a solution of 28
(419 mg, 4.27 mmol) in pentane (14.2 mL) was added MnO2 (2.1 g,
500 w/w %) at rt. The resulting mixture was stirred for 29 h at the
same temperature. The mixture was filtered through a pad of Cel-
iteÒ and the pad was washed with Et2O. The combined filtrates
were distilled (at 35 ꢁC, 1 atm) to remove pentane and Et2O to give
20 (391 mg, yield 95%) as a light yellow oil. The resulting residue
was used in the next step without purification. Spectral data were
identical to the reported data.22
4.1.3. Methyl cyclopentenone-2-carboxylate, 24. To a solution of
PhSeCl (850 mg, 4.44 mmol) and pyridine (0.49 mL, 6.05 mmol) in
CH2Cl2 (24 mL) was added dropwise methyl 2-cyclopentanon
ecarboxylate (0.5 mL, 4.03 mmol) at 0 ꢁC. After stirring for 1.5 h, 1 N
HCl (5 mL) was added to quench the reaction. The separated or-
ganic layer was washed with saturated aqueous NaHCO3 and dried
over Na2SO4. After volatile material was removed under reduced
pressure, the resulting residue was used in the next step without
purification.
Scheme 14.
4. Experimental section
4.1. General
To a solution of crude product in CH2Cl2 (81 mL) was added
dropwise 35% H2O2 aq (1.2 mL,12.1 mmol) at 0 ꢁC over 30 min. After
stirring at the same temperature for further 2 h, the resulting
mixture was washed with H2O and saturated aqueous NaHCO3 and
dried over Na2SO4. After volatile material was removed under
reduced pressure, the resulting residue was purified by Kugelrohr
distillation (0.12 mmHg, 150e152 ꢁC) to give 24 (445 mg, yield 78%,
95% purity) as a yellow oil. Spectral data were identical to the
reported data.23
All reactions were performed under an argon atmosphere. Sol-
vents and reagents were purified prior to use by the usual methods.
Analytical thin-layer chromatography was performed on Merck
Japan Limited silica gel 60 F254 plates, and on Merck DC-Platten
Aluminiumoxid 60 F254 plates. Silica gel column chromatography
was performed using Fuji Silysia Chemical Ltd silica gel PSQ 60B.
Alumina column chromatography was performed using Merck
Aluminiumoxid 90 aktivbasisch. Melting points were determined
on a Yanagimoto micro melting point apparatus. Infrared (IR)
spectra were recorded on a JASCO FT/IR-230 spectrometer. 1H NMR
spectra were taken on 400 or 600 MHz instruments (JEOL JNM-GSX
4.1.4. Methyl cyclohexanone-2-carboxylate, 25. To a solution of
PhSeCl (850 mg, 4.44 mmol) and pyridine (0.49 mL, 6.05 mmol) in
CH2Cl2 (24 mL) was added dropwise methyl 2-cyclohexanon
ecarboxylate (0.64 ml, 4.03 mmol) at 0 ꢁC. After stirring for 1.5 h,1 N
HCl (5 mL) was added to quench the reaction. The separated or-
ganic layer was washed with saturated aqueous NaHCO3 and dried
over Na2SO4. After volatile material was removed under reduced
pressure, the resulting residue was used in the next step without
purification.
To a solution of crude product in CH2Cl2 (81 mL) was added
dropwise 35% H2O2 aq (1.2 mL,12.1 mmol) at 0 ꢁC over 30 min. After
stirring at the same temperature for further 2 h, the resulting
mixture was washed with H2O and saturated aqueous NaHCO3 and
dried over Na2SO4. After volatile material was removed under
reduced pressure, the resulting residue was purified by Kugelrohr
distillation (0.12 mmHg, 155e157 ꢁC) to give 25 (575 mg, yield 93%,
95% purity) as a yellow oil. Spectral data were identical to the
reported data.18
400a, JEOL JMN-ECP 400, JEOL JMN-ECP 600) in the indicated sol-
vent at rt unless otherwise stated. 13C NMR spectra were taken at
100 or 150 MHz in the indicated solvent. Mass spectrometry was
performed on a JEOL JMS-AX500 (LRFABMS), JEOL JMS-AX505
(LRFABMS), JEOL JMS-HX100 (HRFABMS), and JEOL JMS-T100LP
(HRESIMS). X-ray crystallographic analyses were performed on
a BRUKER SMART APEX II. Optical rotations were measured on
a JASCO P-1000 polarimeter at 589 nm. Data are reported as fol-
lows: [a]l
temp, concentration (c g/100 ml), and solvents.
Dienophile 20 was available from Aldrich. Diene 11 and 39 were
prepared as described in the literature.10 Microwave reactions were
performed in a CEM Discover LabMate microwave reactor under
the condition indicated.
Crystallographic data have been deposited with Cambridge
Crystallographic Data Center: Deposition number CCDC-784190 for
compound 48, CCDC-784193 for compound 52, CCDC-784189 for
compound 61, CCDC-784191 for compound 64, and CCDC-784192
forcompound66. Copiesof thedatacanbeobtainedfreeofchargevia
4.1.5. 2-Bromo-2-cyclopentenone, 32. To
a solution of cyclo-
pentenone (500 mg, 6.09 mmol) and pyridine-N-oxide (870 mg,

1900
T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
9.14 mmol) in CH3CN (30 mL) was added NBS (1.08 g, 6.09 mmol) at
ꢁC. The resulting mixture was warmed to rt and stirred for 24 h.
After volatile material was removed under reduced pressure, the
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt¼7/1) to give 32 (967 mg, yield 99%) as a brown oil.
Spectral data were identical to the reported data.24
added dropwise a solution of CSA (207 mg, 0.892 mmol) in CH2Cl2
(6 mL) at 0 ꢁC. After stirring for 10 min, the resulting mixture was
warmed to rt and stirred for 3 h. Saturated aqueous NaHCO3 (10 mL)
was added to quench the reaction. The separated water layer was
extracted with AcOEt, and the combined organic layers were washed
with brine and dried over Na2SO4. After volatile material was re-
moved under reduced pressure, the resulting residue was purified by
columnchromatography(SiO2, hexane/AcOEt¼3/1)togive 23(1.55g,
0
4.1.6. 1-((2-Bromocyclopent-2-enyloxy)methyl)-4-methoxybenzene,
34. To a solution of 32 (100 mg, 0.62 mmol) and CeCl3$7H2O
(278 mg, 0.75 mmol) in MeOH (6.2 mL) was added NaBH4 (35 mg,
0.93 mmol) at 0 ꢁC. The resulting mixture was stirred for 20 min at
the same temperature. Saturated aqueous NH4Cl (3 mL) was added
to quench the reaction. The separated water layer was extracted
with AcOEt, and the combined organic layers were washed with
brine and dried over Na2SO4. After volatile material was removed
under reduced pressure, the resulting residue was used in the next
step without purification.
yield 75%) as a colorless oil: 1H NMR (400 MHz, CDCl3):
d 2.43 (ddd,
J¼2.4, 2.4, 4.8 Hz, 2H), 2.62 (ddt, J¼2.4, 2.4, 4.8 Hz, 2H), 3.80 (s, 3H),
4.17 (dd, J¼2.4, 8.0 Hz, 2H), 4.51 (s, 2H), 6.89e90 (m, 2H), 7.26e7.31
(m, 2H), 7.61 (tt, J¼1.6, 2.4 Hz,1H); 13C NMR (100 MHz, CDCl3):
d 26.7,
34.7, 55.1, 63.6, 72.6, 113.6, 128.3, 129.2, 143.2, 159.1, 159.6, 208.3; IR
(ATR):
HRMS (EI) m/z calcd for C14H16O3 (M) 232.1099, found 232.1095.
n
2931, 2857, 2836, 1690, 1612 cmꢀ1; LRMS (EI) m/z 232 (M);
4.1.10. (1-Benzensulfonyl)piperidin-2-one, 38. To
a solution of
Toasolution ofcrudeproduct andNaI(138mg, 0.92 mmol)inTHF
(6.1 mL) was added NaH (60% in oil, 37 mg, 0.92 mmol) at 0 ꢁC. After
stirring for 10 min, PMBCl (0.12 mL, 0.92 mmol) was added dropwise
at 0 ꢁC and the resulting mixturewas warmed tort and stirredfor 8 h.
Saturated aqueous NH4Cl (4 mL) was added to quench the reaction.
The separated water layer was extracted with AcOEt, and the com-
bined organic layers were washed with brine and dried over Na2SO4.
After volatile material was removed under reduced pressure, the
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt¼5/1) to give 34 (151 mg, yield 87%) as a brown oil: 1H
piperidin-2-one (5.0 g, 50.4 mmol) inTHF(250 mL)was added n-BuLi
(1.6 M in hexane, 37.8 mL, 60.5 mmol) at ꢀ78 ꢁC. After stirring for 1 h
at the same temperature, benzenesulfonyl chloride (9.7 mL,
75.7 mmol) was added dropwise at ꢀ78 ꢁC and the resulting mixture
was stirred for4 h at the same temperature. Saturated aqueous NH4Cl
(30 mL) was added to quench the reaction. The separated water layer
was extracted with AcOEt, and the combined organic layers were
washed with brine and dried over Na2SO4. After volatile material was
removed under reduced pressure, the resulting residue was purified
by column chromatography (SiO2, hexane/AcOEt/CH2Cl2¼1/1/1) to
give 38 (12.05 g, yield quant) as a colorless oil. Spectral data were
identical to the reported data.19
NMR (400 MHz, CDCl3):
d 1.92e2.00 (m, 1H), 2.17e2.29 (m, 2H),
2.39e2.49 (m, 1H), 3.80 (s, 3H), 4.49e4.54 (m, 1H), 4.56 (s, 2H), 6.10
(dt, J¼0.6, 1.2 Hz, 1H), 6.88 (dt, J¼2.0, 7.2 Hz, 2H), 7.30e7.34 (m, 2H);
13C NMR (100 MHz, CDCl3):
129.2, 130.3, 135.2, 159.0; IR (ATR):
d
29.3, 30.5, 55.1, 70.3, 85.2, 113.6, 122.4,
4.1.11. Methyl 1-(benzensulfonyl)-2-oxo-1,2,5,6-tetrahydropyridine-
3-carboxylate, 26. To a solution of 38 (7.0 g, 29.25 mmol) in THF
(250 mL) was added LHMDS (1.0 M in THF, 73.1 mL, 73.1 mmol) at
ꢀ78 ꢁC. After stirring for 30 min at the same temperature, methyl
chloroformate (2.5 mL, 32.2 mmol) was added dropwise at ꢀ78 ꢁC.
After stirring for 1 h at the same temperature, a solution of PhSSO2Ph
(8.06 g, 32.2 mmol) in THF (10 mL) was added dropwise at ꢀ78 ꢁC
and the mixture was warmed to rt and stirred for 17.5 h. Saturated
aqueous NH4Cl (30 mL) was added to quench the reaction. The
separated water layer was extracted with AcOEt, and the combined
organic layers were washed with brine and dried over Na2SO4. After
volatile material was removed under reduced pressure, the resulting
residue was used in the next step without purification.
n ;
2934, 2852, 1612, 1585 cmꢀ1
LRMS (FAB) m/z 321 (MþK); HRMS (FAB) m/z calcd for C13H15O2BrK
(MþK) 320.9892, found 320.9986.
4.1.7. 5-(4-Methoxybenzyloxy)cyclopent-1-enecarbaldehyde, 22. To
a solution of 34 (20 mg, 0.071 mmol) in THF (0.71 mL) was added
dropwise n-BuLi (1.65 M, in hexane) at ꢀ78 ꢁC. After stirring for
30 min, dropwise DMF (7.8 mg, 0.106 mmol) in THF (0.1 mL) was
added at ꢀ78 ꢁC and the resulting mixture was stirred for 1.5 h at the
same temperature. Saturated aqueous NH4Cl (2 mL) was added to
quench the reaction. The separated water layer was extracted with
AcOEt, and the combined organic layers were washed with brine and
dried over Na2SO4. After volatile material was removed under re-
duced pressure, the resulting residue was purified by column chro-
matography (SiO2, hexane/AcOEt¼1/1) to give 22 (14.2 mg, yield 86%)
To a solution of mCPBA (10.82 g, 43.8 mmol) in CH2Cl2 (192 mL)
and saturated aqueous NaHCO3 (292 mL) was added dropwise
a solution of crude product in CH2Cl2 (100 mL) at 0 ꢁC over 30 min.
The resulting mixture was warmed to rt and stirred vigorously for
15 h. Saturated aqueous sodium thiosulfate (50 mL) was added at
as a colorless solid: 1H NMR (400 MHz, CDCl3):
d 2.00e2.18 (m, 2H),
2.46 (ddt, J¼2.8, 8.4,19.6 Hz,1H), 2.70e2.80 (m,1H), 3.76 (s, 3H), 4.55
(s, 2H), 4.83(d, J¼7.2 Hz,1H), 6.85 (d, J¼8.8 Hz, 2H), 7.02e7.05 (m,1H),
0
ꢁC and the mixture was stirred at rt for 30 min. The separated
7.28 (d, J¼8.8 Hz, 2H), 9.82 (s,1H); 13C NMR (100 MHz, CDCl3):
d
30.8,
water layer was extracted with AcOEt, and the combined organic
layers were washed with brine and dried over Na2SO4. After volatile
material was removed under reduced pressure, the resulting resi-
due was purified by column chromatography (SiO2, hexane/
AcOEt¼1/2) to give 26 (6.10 g, yield 75%, in two steps) as a colorless
31.4, 55.0, 71.4, 79.3, 113.5, 129.1, 130.5, 147.2, 156.2, 158.8, 189.0; IR
(ATR):
n
2936, 2834, 1679, 1612 cmꢀ1; LRMS (FAB) m/z 271 (MþK);
HRMS(FAB)m/zcalcdforC14H16O3K(MþK)271.0737, found271.0735.
4.1.8. 2-(Hydroxymethyl)cyclopent-2-enone, 35. To a solution of
cyclopentenone (1 g,12.2 mmol) in CHCl3 (14.6 mL) andMeOH (9.8 mL)
was added dropwise 37% HCHO aq (1.2 mL, 14.6 mmol) and n-Bu3P
(0.15 mL, 0.61 mmol) at rt. The resulting mixture was stirred for 1 h.
After volatile material was removed under reduced pressure, the
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt¼1/3) to give 35 (1.10 g, yield 89%) as a colorless oil.
Spectral data were identical to the reported data.18
oil: 1H NMR (400 MHz, CDCl3):
d
2.68 (dt, J¼4.4, 6.4 Hz, 2H), 3.76 (s,
3H), 4.12 (t, J¼6.4 Hz, 2H), 7.50e7.56 (m, 2H), 7.59e7.66 (m, 2H),
8.05 (dd, J¼1.2, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 25.4, 43.3,
52.4, 128.5, 128.74, 128.78, 133.8, 138.5, 151.3, 159.4, 163.4; IR (ATR):
n
2952, 1738, 1687 cmꢀ1; HRMS (ESI) m/z calcd for C13H13NO5SNa
(MþNa) 318.0412, found 318.0431.
4.2. General procedure for the DielseAlder reaction using
SaleneCreF complex (1 mmol-scale experiments)10
4.1.9. 2-((4-Methoxybenzyloxy)methyl)cyclopentenone, 23. To a so-
lution of 35 (1.0 g, 8.92 mmol) and 4-methoxybenzyl 2,2,2-tri-
chloroacetimidate 36 (6.85 g, 24.4 mmol) in CH2Cl2 (30 mL) was
After a mixture of SaleneCreF complex (50 mol %, based on
dienophile) and oven-dried powdered 4A MS (0.8 g) was dried
ꢀ

T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
1901
under vacuum for 20 min, a solution of dienophile (1 mmol) in PhCF3
(5 ml) was added and the mixture was stirred for 30 min at rt. To this
mixture was added aminodiene (2 mmol), and the resulting mixture
was stirred at the temperature indicated. The reaction mixture was
then filtered through a pad of CeliteÒ, the pad was washed with
CH2Cl2, and volatile material was removed under reduced pressure.
The resulting residue was purified bycolumn chromatography (SiO2,
hexane/AcOEt¼7/1) to give DielseAlder adduct.
1H), 2.45 (ddt, J¼2.4, 6.8, 16.4 Hz, 1H), 2.60 (ddt, J¼2.4, 6.8, 13.2 Hz,
1H), 3.41 (s, 3H), 3.55 (s, 3H), 3.58 (dd, J¼8.4, 17.6 Hz, 2H), 3.64 (br s,
1H), 3.79 (br d, J¼8.8 Hz, 1H), 3.89 (br d, J¼12.4 Hz, 1H), 4.34 (dd,
J¼11.6, 20.4 Hz, 1H), 4.66 (br s, 1H), 4.90 (t, J¼2.4 Hz, 1H), 5.01 (dd,
J¼1.2, 10.4 Hz, 1H), 5.08 (dd, J¼1.2, 17.2 Hz, 1H), 5.85 (ddt, J¼5.2, 5.2,
22.0 Hz, 1H), 6.80 (d, J¼8.4 Hz, 2H), 7.16 (dd, J¼8.4 Hz, 2H); 13C NMR
(C6D6, 100 MHz, 75 ꢁC):
d
ꢀ4.16, ꢀ4.14, 18.2, 25.9, 26.5, 32.1, 38.0,
38.3, 45.5, 52.1, 54.9, 56.1, 56.9, 73.6, 75.2, 114.3, 115.4, 128.5, 129.4,
131.1, 136.4, 151.6, 156.9, 160.0, 216.0; IR (ATR):
n 2929, 1736,
1702 cmꢀ1; LRMS (FAB) m/z 552 (MþNa); HRMS (FAB) m/z calcd for
C29H43NO6SiNa (MþNa) 552.2757, found 552.2737.
4.3. General procedure for the DielseAlder reaction using
microwave irradiation (1 mmol-scale experiments)
4.3.5. DA adduct 53. 1H NMR (400 MHz, CDCl3):
d
ꢀ0.01 (s, 3H),
Oven-dried powdered 4A MS (0.8 g) was added to a solution of
dienophile (1 mmol) in PhCF3 (5 mL) and the mixture was stirred for
5 min at rt. To this mixture was added aminodiene (2 mmol), and the
resulting mixture was irradiated by microwave (<300 W, 150 ꢁC, in
a sealed tube) in a CEM. Discover LabMate microwave reactor. The re-
action mixture was then filtered through a pad of CeliteÒ, the pad was
washed with CH2Cl2, and volatile material was removed under reduced
pressure. The resulting residue was purified by column chromatogra-
phy (SiO2, hexane/AcOEt¼7/1) to give DielseAlder adduct.
0.04 (s, 3H), 0.85 (s, 9H), 1.71e1.85 (m, 2H), 2.02 (dd, J¼4.8, 17.6 Hz,
1H), 2.20e2.27 (m, 1H), 2.92 (br td, J¼5.6, 11.6 Hz, 1H), 3.30 (br td,
J¼8.8, 14.4 Hz, 1H), 3.55 (s, 3H), 3.88 (d, J¼12.8 Hz, 1H), 4.03 (d,
J¼12.8 Hz, 1H), 4.12 (br d, J¼19.6 Hz, 1H), 4.39 (ddd, J¼2.0, 8.8,
13.6 Hz, 1H), 4.47 (br d, J¼2.0 Hz, 1H), 4.61 (br s, 1H), 5.02 (d,
J¼17.2 Hz, 1H), 5.19 (d, J¼10.4 Hz, 1H), 5.85 (ddt, J¼3.6, 9.6, 16.8 Hz,
1H), 7.52 (t, J¼7.6 Hz, 2H), 7.62 (t, J¼7.6 Hz, 2H), 7.97 (d, J¼7.6 Hz,
2H); 13C NMR (100 MHz, CDCl3):
34.5, 41.9, 42.2, 49.5, 53.6, 56.5, 59.2, 60.4, 100.2, 115.3, 128.4, 128.6,
d
ꢀ4.8, ꢀ4.5, 14.2, 17.8, 21.0, 33.6,
1
4.3.1. DA adduct 40. H NMR (CDCl3, 400 MHz, 55 ꢁC):
d
0.14 (s, 6H),
133.7, 136.7, 138.4, 151.0, 166.9, 166.9, 168.7, 169.3; IR (ATR): n 2991,
1754, 1724, 1698 cmꢀ1; LRMS (FAB) m/z 649 (MþK); HRMS (FAB)
m/z calcd for C28H39ClN2O7SSiK (MþK) 649.1573, found 649.1588.
0.92 (s, 9H), 1.41e1.56 (m, 2H), 1.67e1.79 (m, 4H), 2.11 (t, J¼10.0 Hz,
1H), 2.31 (dd, J¼8.0, 18.0 Hz, 1H), 2.57e2.64 (m, 1H), 3.53e3.64 (m,
1H), 3.67 (s, 3H), 3.74 (dd, J¼5.6, 16.0 Hz, 1H), 4.66 (d, J¼4.8 Hz, 1H),
5.03 (d, J¼8.4, 17.6 Hz, 1H), 5.05 (d, J¼9.6 Hz, 1H), 5.09 (br s, 1H),
5.73 (ddd, J¼5.6, 10.4, 23.2 Hz, 1H), 9.51 (s, 1H); 13C NMR (CDCl3,
4.3.6. DA adduct 54. 1H NMR (400 MHz, CDCl3, 55 ꢁC):
d 0.01 (s,
3H), 0.06 (s, 3H), 0.86 (s, 9H), 1.74e1.94 (m, 2H), 2.02 (dd, J¼6.4,
18.0 Hz, 1H), 2.15 (dt, J¼3.2, 14.0 Hz, 1H), 2.84 (ddd, J¼4.0, 6.4,
10.4 Hz, 1H), 3.40 (ddd, J¼6.8, 9.2, 13.6 Hz, 1H), 3.56 (s, 3H), 3.61 (s,
3H), 3.94e3.99 (m, 1H), 4.33 (ddd, J¼3.6, 8.4, 13.6 Hz, 1H), 4.70 (br s,
1H), 4.97 (br d, J¼17.2 Hz, 1H), 5.00 (br d, J¼10.4 Hz, 1H), 5.29 (d,
J¼2.0 Hz, 1H), 5.72 (ddd, J¼5.2, 10.4, 17.2 Hz, 1H), 7.50 (t, J¼7.6 Hz,
2H), 7.60 (t, J¼7.6 Hz, 2H), 7.98 (d, J¼7.6 Hz, 2H); 13C NMR (100 MHz,
100 MHz, 55 ꢁC):
d
ꢀ4.51, ꢀ4.28, 17.9, 19.4, 25.6, 31.1, 32.1, 32.3, 34.7,
46.9, 52.5, 54.8, 60.1,100.3,115.8,135.4,153.3, 157.2, 203.3; IR (ATR):
n
2953, 2930, 2883, 2857, 1726, 1697, 1671 cmꢀ1; HRMS (ESI) m/z
calcd for C42H70N2O8Si2Na (2MþNa) 809.4568, found 809.4545;
HPLC: DAICEL CHIRALCEL OD-H, 210 nm, flow rate 1.0 mL/min,
25
hexane/i-PrOH¼99:1, retention time: 6.4 min and 7.1 min; [
a]
D
CDCl3, 55 ꢁC):
d
ꢀ4.7, ꢀ4.5, 17.9, 25.4, 25.6, 33.8, 34.2, 42.5, 49.2,
52.4, 53.1, 57.9, 60.2, 102.0, 114.2, 128.55, 128.60, 133.5, 136.9, 139.1,
149.7, 160.8, 166.7, 169.8; IR (ATR):
2950, 1745, 1711, 1697 cmꢀ1
36.4 (c 1.00, CHCl3, 79% ee).
1
4.3.2. DA adduct 41. H NMR (C6D6, 400 MHz, 75 ꢁC):
d
0.21 (s, 6H),
n
;
HRMS (ESI) m/z calcd for C28H40N2O8SSiNa (MþNa) 615.2172, found
1.06 (s, 9H), 1.27 (br s, 4H), 1.51e1.84 (m, 4H), 2.07 (br d, J¼18.0 Hz,
1H), 2.23 (br d, J¼18.0 Hz,1H), 2.48 (br s,1H), 3.57 (br s, 3H), 3.74 (br
d, J¼16.0 Hz,1H), 3.96 (br d, J¼16.0 Hz,1H), 4.81 (br s,1H), 5.11 (br d,
J¼18.0 Hz, 3H), 5.80e5.97 (m, 1H), 9.80 (br s, 1H); 13C NMR (C6D6,
615.2162.
1
4.3.7. DA adduct 55-anti. H NMR (400 MHz, CDCl3, 55 ꢁC):
d 0.14
100 MHz, 75 ꢁC):
30.9, 31.6, 47.8, 52.3, 53.3, 57.3, 101.2, 115.2, 136.6, 153.5, 157.3,
d
ꢀ4.29, ꢀ4.13, 18.1, 21.4, 22.7, 25.8, 27.6, 28.6,
(s, 6H), 0.91 (s, 9H), 1.94e2.02 (m, 3H), 2.22e2.25 (m, 0.5H),
2.27e2.30 (m, 0.5H), 2.31e2.40 (m, 2H), 2.94e3.01 (m, 1H), 3.61 (s,
3H), 3.73 (s, 3H), 3.79e3.93 (m, 2H), 4.77 (d, J¼1.6 Hz, 1H), 5.10 (dd,
J¼1.6, 5.6 Hz, 1H), 5.13 (dt, J¼1.6, 13.2 Hz, 1H), 5.19 (br s, 1H), 5.76
204.0; IR (ATR):
n
2928, 2857, 1723, 1695, 1674 cmꢀ1; HRMS (ESI)
m/z calcd for C22H37NO4SiNa (MþNa) 430.2389, found 430.2408;
13
(ddd, J¼5.6, 10.4, 22.4 Hz, 1H); C NMR (100 MHz, CDCl3, 55 ꢁC):
HPLC: DAICEL CHIRALCEL OD-H, 210 nm, flow rate 1.0 mL/min,
25
d
ꢀ4.36, 18.0, 25.6, 26.0, 31.1, 37.6, 41.3, 50.0, 52.2, 52.9, 55.7, 62.4,
hexane/i-PrOH¼99:1, retention time: 6.1 min and 7.1 min; [
a]
D
103.6, 115.8, 135.3, 149.7, 156.6, 172.8, 211.4; IR (ATR):
n 2952, 2930,
43.7 (c 0.83, CHCl3, 81% ee).
2857, 1734, 1701, 1678 cmꢀ1
;
HRMS (ESI) m/z calcd for
C44H70N2O12Si2Na (2MþNa) 897.4365, found 897.4339; HPLC:
DAICEL CHIRALPAK IA, 210 nm, flow rate 0.5 mL/min, hexane/i-
PrOH¼95:5, retention time: 12.2 min and 13.3 min; [
a]
25 9.6 (c 1.00,
D
CHCl3, 16% ee).
1
4.3.8. DA adduct 55-syn. H NMR (CDCl3, 400 MHz, 55 ꢁC):
d 0.09
(s, 3H), 0.10 (s, 3H), 0.87 (s, 9H), 1.50e1.73 (m, 2H), 1.96e2.09 (m,
1H), 2.18 (dt, J¼9.6, 19.2 Hz, 1H), 2.37 (dt, J¼9.6, 19.2 Hz, 2H), 3.27
(dd, J¼8.4, 14.4 Hz, 1H), 3.60e3.66 (m, 1H), 3.64 (s, 3H), 3.67 (s,
3H), 3.78 (dd, J¼6.0, 16.0 Hz, 1H), 4.69 (dd, J¼1.2, 4.8 Hz, 1H), 5.06
(br d, J¼8.8 Hz, 1H), 5.09 (br d, J¼16.4 Hz, 1H), 5.36 (br s, 1H), 5.76
4.3.3. DA adduct 42. Adduct 42 was obtained as inseparable
diastereomixtures at C7 position. Good 1H and 13C NMR spectra
were difficult to obtain due to the presence of rotamers and di-
astereomers, even at elevated temperatures. The structure of 42
was determined after it was converted to 48 or 70 via 45.
13
(ddd, J¼6.0, 11.2, 22.4 Hz, 1H); C NMR (CDCl3, 100 MHz, 55 ꢁC):
d
ꢀ4.58, ꢀ4.33, 17.9, 25.6, 25.9, 31.0, 32.2, 35.0, 48.3, 52.4, 52.5,
54.0, 64.8, 101.8, 115.8, 135.32, 151.9, 156.5, 168.6, 208.7; IR (ATR):
n
1
4.3.4. DA adduct 43. H NMR (C6D6, 400 MHz, 75 ꢁC):
d
0.15 (s, 3H),
2949, 2932, 2857, 1750, 1728, 1695, 1677 cmꢀ1; HRMS (ESI) m/z
calcd for C22H35NO6SiNa (MþNa) 460.2131, found 460.2142; HPLC:
DAICEL CHIRALPAK IA, 210 nm, flow rate 0.5 mL/min, hexane/i-
0.16 (s, 3H), 0.98 (s, 9H), 1.63e1.72 (m, 1H), 1.77 (br s, 1H), 1.94 (dt,
J¼9.2, 19.2 Hz, 1H), 1.99 (br d, J¼17.6 Hz,1H), 2.26 (dd, J¼7.6, 17.6 Hz,

1902
T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
PrOH¼95:5, retention time: 14.1 min and 17.3 min; [
a
]
26 ꢀ28.4 (c
flow rate 1.0 mL/min, hexane/i-PrOH¼97:3, retention time: 5.9 min
D
1.00, CHCl3, 15% ee).
and 6.3 min.
1
4.3.9. DA adduct 56-anti. H NMR (CDCl3, 400 MHz, 55 ꢁC):
d 0.117
(s, 3H), 0.126 (s, 3H), 0.90 (s, 9H), 1.54 (br d, J¼9.6 Hz,1H), 1.80e2.05
(m, 5H), 2.26 (br d, J¼13.6 Hz,1H), 2.55e2.63 (m,1H), 2.96e3.04 (m,
1H), 3.60 (s, 3H), 3.75 (s, 3H), 4.10 (br d, J¼17.6 Hz, 1H), 4.32 (dd,
J¼3.2, 17.6 Hz,1H), 4.78 (br s,1H), 5.00 (br d, J¼16.0 Hz,1H), 5.04 (br
d, J¼10.0 Hz, 1H), 5.21 (br s, 1H), 5.76 (ddd, J¼4.8, 10.0, 22.4 Hz, 1H);
13C NMR (CDCl3, 100 MHz, 55 ꢁC):
26.6, 30.5, 39.8, 41.1, 48.4, 52.4, 52.6, 58.1, 64.8, 101.7, 113.8, 137.4,
d
ꢀ4.65, ꢀ4.38, 17.9, 23.4, 25.6,
149.8, 157.8, 171.7, 205.6; IR (ATR):
n 2950, 2930, 2858, 1743, 1717,
Good 1H and 13C NMR spectra were difficult to obtain due to the
presence of rotamers and inseparable impurity. The structure of 450
was determined after it was converted to diketone 70 (Scheme 15).
1682 cmꢀ1; HRMS (ESI) m/z calcd for C46H74N2O12Si2Na (2MþNa)
925.4678, found 925.4674; HPLC: DAICEL CHIRALPAK IA, 210 nm,
flow rate 0.5 mL/min, hexane/i-PrOH¼95:5, retention time:
25
13.6 min and 18.4 min; [
a]
59.9 (c 0.60, CHCl3, 48% ee).
D
1
4.3.10. DA adduct 56-syn. H NMR (CDCl3, 400 MHz, 55 ꢁC):
d 0.13
(s, 6H), 0.91 (s, 9H), 1.57 (br d, J¼14.0 Hz, 1H), 1.85e1.97 (m, 4H),
2.08e2.19 (m, 1H), 2.37e2.44 (m, 2H), 3.13 (br s, 1H), 3.64 (s, 3H),
3.65 (br s, 1H), 3.66 (s, 3H), 3.79 (br s, 1H), 4.71 (d, J¼4.4 Hz, 1H),
5.05 (br d, J¼10.4 Hz, 1H), 5.05 (br d, J¼16.4 Hz, 1H), 5.67e5.80 (m,
13
2H); C NMR (CDCl3, 100 MHz, 55 ꢁC):
d
ꢀ4.59, ꢀ4.24, 17.9, 22.7,
Scheme 15.
25.6, 26.4, 30.1, 40.2, 47.8, 52.2, 52.4, 53.4, 64.8, 101.8, 115.6, 135.6,
151.5, 156.5, 170.3, 204.0; IR (ATR):
n 2950, 2929, 2898, 2857, 1745,
1717, 1682 cmꢀ1; HRMS (ESI) m/z calcd for C23H37NO6SiNa (MþNa)
474.2288, found 474.2306; HPLC: DAICEL CHIRALPAK IA, 210 nm,
flow rate 0.5 mL/min, hexane/i-PrOH¼95:5, retention time:
4.3.13. Diketone 70. To a solution of 450 (25 mg, <50
in CH3CN (0.5 mL) was added HF$Py (20
L, 0.75 mmol) at 0 ꢁC. The
mmol, impure)
m
resulting mixture was warmed to rt and stirred for 19 h at the same
temperature. Saturated aqueous NaHCO3 (1 mL) was added to
quench the reaction at 0 ꢁC. The separated water layer was
extracted with AcOEt, and the combined organic layers were dried
over Na2SO4. Volatile material was removed under reduced pres-
sure, and the resulting residue was used in the next step without
purification.
14.3 min and 25.3 min; [a]
25 52.5 (c 0.615, CHCl3, 12% ee).
D
4.3.11. Diene 44. To a solution of Ph3PþCH3$Brꢀ (2.02 g, 5.66 mmol)
in THF (10 mL) was added KHMDS (0.5 M in toluene, 11.3 mL,
5.66 mmol) at 0 ꢁC. After stirring for 1 h at rt, a solution of 42 (1.0 g,
1.89 mmol) in THF (9 mL) was added dropwise to the mixture at
0
ꢁC and the mixture was stirred for 1.5 h at rt. Saturated NH4Cl
To a solution of crude product in CH2Cl2 (0.5 mL) was added
DesseMartin periodinane (69 mg, 0.15 mmol) at 0 ꢁC. The resulting
mixture was warmed to rt and stirred for 18 h at the same tem-
perature. Saturated aqueous NaHCO3 (1 mL) and sodium thiosulfate
(1 mL) were added and the mixture stirred for 30 min to quench the
reaction. The separated water layer was extracted with AcOEt, and
the combined organic layers were washed with brine and dried
over Na2SO4. Volatile material was removed under reduced pres-
sure. The resulting residue was purified by column chromatography
(SiO2, hexane/AcOEt¼1/3) to give 70 (7 mg, yield 54%, in two steps)
(10 mL) were added to quench the reaction at 0 ꢁC. The separated
water layer was extracted with AcOEt, and the combined organic
layers were washed with brine and dried over Na2SO4. Volatile
material was removed under reduced pressure. The resulting resi-
due was purified by column chromatography (SiO2, hexane/
AcOEt¼5/1) to give inseparable mixture of 44 (874 mg, yield 88%)
and its stereoisomer as a colorless oil, which was used in the next
step without purification.
4.3.12. RCM of 44. To a solution of 44 (691 mg, 1.31 mmol) in
CH2Cl2 (131 mL) was added Grubbs’ second cat. (111 mg,
0.131 mmol) at rt. The resulting mixture was warmed to reflux
temperature and stirred for 6 h. The mixture was filtered through
a pad of CeliteÒ and volatile material was removed under reduced
pressure. The resulting residue was purified by column chroma-
tography (SiO2, hexane/AcOEt¼7/1) to give 45 (545 mg, yield 84%)
and 450 (<75 mg, yield 11%, with impurities derived from Grubbs’
second cat.).
as a colorless foam: 1H NMR (400 MHz, C6D6, 75 ꢁC):
d 1.19e1.33 (m,
1H), 1.34e1.48 (m, 1H), 1.77e1.92 (m, 2H), 2.02e2.18 (m, 2H),
2.19e2.37 (m, 3H), 3.30 (ddd, J¼2.4, 4.8, 19.2 Hz, 1H), 3.54 (s, 3H),
4.44 (br s, 1H), 4.72 (br s, 1H), 5.06 (br d, J¼10.0 Hz, 1H), 5.72 (dd,
13
J¼2.4, 10.0 Hz, 1H); C NMR (100 MHz, C6D6, 75 ꢁC):
d 24.4, 35.8,
40.5, 40.9, 42.4, 43.5, 48.7, 52.5, 53.2, 124.5, 128.5, 138.3, 204.8,
211.1; IR (ATR):
n ;
3365, 2922, 2851, 1735, 1682, 1457, 1363 cmꢀ1
LRMS (FAB) m/z 268 (MþH); HRMS (ESI) m/z calcd for
C28H34N2O8Na (2MþNa) 549.2213, found 549.2239.
Compound 45 (103 mg, 0.206 mmol) was also converted to 70
(44 mg, yield 81%, in two steps) by the same method as shown
above.
Compound 45 (mixture of rotamers): 1H NMR (400 MHz,
CDCl3):
d 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.59e1.75 (m, 3H),
1.75e1.95 (m, 2H), 2.04e2.2.20 (m, 2H), 3.50e3.56 (m, 1H), 3.57 (s,
3H), 3.74 (s, 3H), 3.74e3.83 (m, 1H), 4.19e4.36 (m, 1H), 4.38e4.53
(m, 3H), 5.07 (br s, 0.5H), 5.24 (br s, 0.5H), 5.38 (t, J¼9.6 Hz,1H), 5.73
(ddd, J¼1.6, 4.0, 10.0 Hz, 0.5H), 5.81 (ddd, J¼1.6, 4.0, 10.0 Hz, 0.5H),
6.78e6.83 (m, 2H), 7.12e7.16 (m, 2H); 13C NMR (100 MHz, CDCl3,
4.3.14. Secondary alcohol 46. To a solution of 45 (1.20 g, 2.4 mmol)
in CH3CN (24 mL) was added HF$Py (0.31 mL, 7.2 mmol) at 0 ꢁC. The
resulting mixture was warmed to rt and stirred for 17.5 h at the
same temperature. Saturated aqueous NaHCO3 (1 mL) was added to
quench the reaction at 0 ꢁC. The separated water layer was
extracted with AcOEt, and combined organic layers were dried over
Na2SO4. Volatile material was removed under reduced pressure,
and the resulting residue was purified by column chromatography
(SiO2, hexane/AcOEt¼1/4) to give 46 (529 mg, yield 85%) as
55 ꢁC):
47.2, 47.5, 52.2, 53.4, 55.2, 71.7, 72.1, 86.5, 86.7, 104.1, 113.7, 125.2,
d
ꢀ4.6, ꢀ4.3, 18.0, 25.7, 25.9, 28.1, 28.4, 29.4, 39.6, 42.8, 45.4,
125.7, 128.5, 128.9, 131.2, 131.4, 131.6, 150.6, 159.1; IR (ATR): n 2952,
2931, 1699, 1671, 1512, 1445, 1324, 1246 cmꢀ1; LRMS (FAB) m/z 522
(MþNa); HRMS (FAB) m/z calcd for C28H41NO5SiNa (MþNa)
522.2652, found 522.2639; HPLC: DAICEL CHIRALPAK IB, 254 nm,

T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
1903
1
a colorless oil: H NMR (400 MHz, CDCl3, 55 ꢁC):
d
1.67 (br s, 1H),
5.87 (ddd, J¼5.4, 9.6, 16.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz):
1.80e1.90 (m, 1H), 1.90e1.99 (m, 1H), 2.04 (br s, 2H), 2.31 (dd, J¼4.4,
16.4 Hz, 1H), 2.35e2.42 (m, 1H), 2.45 (dd, J¼4.8, 15.2 Hz, 1H), 2.55
(dd, J¼13.2, 16.0 Hz, 1H), 3.18 (br s, 1H), 3.55 (t, J¼2.0 Hz, 0.5H), 3.60
(t, J¼2.0 Hz, 0.5H), 3.75 (s, 3H), 3.94 (br s, 1H), 4.32 (br d, J¼18.8 Hz,
1H), 4.98 (br d, J¼10.4 Hz 1H), 5.48 (ddd, J¼2.0, 3.6, 10.0 Hz, 1H),
d
ꢀ4.51, ꢀ4.35, 18.0, 20.8, 25.5, 30.6, 31.3, 34.0, 39.5, 41.5, 50.3, 56.4,
71.5, 101.9, 118.2, 133.0, 150.6, 153.5; IR (ATR):
n 2952, 2928, 2857,
1695, 1666 cmꢀ1; HRMS (ESI) m/z calcd for C20H33NO3SiNa (MþNa)
386.2127, found 386.2142.
5.75 (br s, 1H); 13C NMR (100 MHz, CDCl3, 55 ꢁC):
d
29.0, 31.2, 40.1,
4.3.19. Cyclic carbamate 50. To a solution of 41 (40 mg, 98.1 mmol)
40.4, 41.7, 44.4, 47.0, 49.9, 53.0, 79.6, 123.4, 131.3, 156.4, 209.0; IR
in THF (0.98 mL) were added MeOH (1 drop) and NaBH4 (7.4 mg,
0.196 mmol) at 0 ꢁC. The resulting mixture was warmed to rt and
stirred for 14 h at the same temperature. Saturated aqueous NH4Cl
(1 mL) was added to quench the reaction at rt. The separated water
layer was extracted with AcOEt, and the combined organic layers
were washed with brine and dried over Na2SO4. Volatile material
was removed under reduced pressure, and the resulting residue
was purified by column chromatography (SiO2, hexane/AcOEt¼3/1)
to give 50 (18 mg, yield 49%) as a colorless foam: 1H NMR (CDCl3,
(ATR):
n
3442, 2953, 1699, 1681, 1448, 1239 cmꢀ1; LRMS (FAB) m/z
266 (MþH); HRMS (FAB) m/z calcd for C14H20NO4 (MþH) 266.1392,
found 266.1394.
4.3.15. Reduction of 46. To a solution of 46 (50 mg, 0.188 mmol) in
THF (24 mL) were added MeOH (1 drop) and NaBH4 (29 mg,
0.754 mmol) at 0 ꢁC. The resulting mixture was warmed to rt and
stirred for 3.5 h at the same temperature. Then reaction mixture
was added NaBH4 (29 mg, 0.745 mmol) again at 0 ꢁC and stirred
1.5 h at rt H2O (10 mL) was added to quench the reaction at 0 ꢁC. The
separated water layer was extracted with AcOEt, and combined
organic layers were dried over Na2SO4. Volatile material was re-
moved under reduced pressure, and the resulting residue was pu-
rified by column chromatography (SiO2, AcOEt) to give 47 (27 mg,
yield 55%) as a colorless solid and 48 (23 mg, yield 45%) as a col-
orless foam. Then 48 was recrystallized from i-Pr2O. The stereo-
chemistry of 48 was determined by X-ray crystallography.
600 MHz): d 0.14 (s, 3H), 0.15 (s, 3H), 0.92 (s, 9H), 1.10e1.15 (m, 1H),
1.25e1.39 (m, 3H), 1.46e1.53 (m, 1H), 1.59e1.69 (m, 3H), 1.72e1.79
(m, 1H), 2.00 (d, J¼9.6 Hz, 1H), 2.31 (dt, J¼3.0, 18.0 Hz, 1H), 3.56 (dd,
J¼7.2, 15.0 Hz, 1H), 3.60 (dd, J¼1.8, 10.8 Hz, 1H), 3.97 (br s, 1H),
4.35e4.40 (m, 2H), 4.89 (br s, 1H), 5.21 (d, J¼9.6 Hz, 1H), 5.22 (d,
J¼16.2 Hz, 1H), 5.86 (ddd, J¼5.4, 9.6, 16.2 Hz, 1H); 13C NMR (CDCl3,
150 MHz):
d
ꢀ4.46, ꢀ4.29, 18.0, 20.9, 25.6, 25.6, 29.4, 30.2, 33.5,
33.7, 36.3, 50.1, 52.7, 72.2, 101.1, 118.2, 133.3, 149.8, 153.1; IR (ATR):
2927, 2856, 1693, 1667 cmꢀ1
HRMS (ESI) m/z calcd for
C21H35NO3SiNa (MþNa) 400.2284, found 400.2274.
n
;
4.3.16. Diol 47 (a mixture of rotamers). 1H NMR (400 MHz, CDCl3,
55 ꢁC):
d
1.59 (dt, J¼3.6, 14.0 Hz, 1H), 1.61 (dt, J¼3.6, 14.0 Hz, 1H),
4.3.20. Diketone 51. To a solution of 43 (200 mg, 0.378 mmol) in
CH3CN (3.8 mL) was added HF$Py (29
L, 1.13 mmol) at 0 ꢁC. The
1.69 (t, J¼4.8 Hz, 3H), 1.81e1.92 (m, 4H), 1.92e2.00 (m, 1H),
2.08e2.16 (m, 1H), 3.52 (t, J¼2.4 Hz, 0.5H), 3.57 (t, J¼2.4 Hz, 0.5H),
3.73 (s, 3H), 3.83 (t, J¼6.4 Hz, 1H), 4.12e4.17 (m, 1H), 4.25 (dt, J¼2.4,
18.8 Hz, 1H), 4.82 (dd, J¼3.6, 12.0 Hz, 1H), 5.39 (ddd, J¼2.0, 3.6,
10.0 Hz, 1H), 5.73 (br d, J¼4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
m
resulting mixture was warmed to rt and stirred for 4 h at the same
temperature. Saturated aqueous NaHCO3 (1 mL) was added to
quench the reaction at 0 ꢁC. The separated water layer was
extracted with AcOEt, and the combined organic layers were dried
over Na2SO4. Volatile material was removed under reduced pres-
sure, and the resulting residue was purified by column chroma-
tography (SiO2, hexane/AcOEt¼3/2) to give 51 (152 mg, yield 96%)
55 ꢁC):
d 27.5, 31.0, 33.6, 33.8, 40.4, 42.0, 44.1, 47.0, 48.8, 52.9, 67.3,
80.7, 123.7, 131.9, 156.6; IR (ATR):
n 3393, 3015, 2969, 2938, 2921,
2886, 2857, 1738, 1661 cmꢀ1; HRMS (ESI) m/z calcd for C28H43N2O8
(2MþH) 535.3019, found 535.3044.
as a colorless oil: 1H NMR (C6D6, 400 MHz, 75 ꢁC):
d 1.53 (br s, 1H),
1.65e1.74 (m, 1H), 1.98 (dt, J¼9.6, 16.4 Hz, 1H), 2.38 (dd, J¼2.4,
17.2 Hz, 1H), 2.43e2.58 (m, 3H), 2.65 (dd, J¼5.2, 17.2 Hz, 1H), 3.43
(m, 2H), 3.45 (s, 3H), 3.49 (s, 3H), 3.68 (d, J¼9.2 Hz, 1H), 3.71 (br s,
1H), 4.00 (br s, 2H), 4.35 (s, 2H), 5.01 (dq, J¼1.6, 10.4 Hz, 1H), 5.06
(dq, J¼1.6, 17.2 Hz, 1H), 5.76 (ddt, J¼5.6, 10.4, 17.2 Hz, 1H), 6.88 (dt,
J¼2.4, 8.8 Hz, 2H), 7.20 (dt, J¼2.4, 8.8H, 2H); 13C NMR (C6D6,
1
4.3.17. Diol 48. H NMR (400 MHz, CDCl3, 55 ꢁC):
d
1.35 (ddd, J¼5.2,
10.8, 24.0 Hz, 2H), 1.48e189 (m, 8H), 1.99e2.09 (m, 1H), 2.10e2.20
(m, 1H), 3.54 (t, J¼2.0 Hz, 0.5H), 3.59 (t, J¼2.0 Hz, 0.5H), 3.73 (s, 3H),
3.87 (t, J¼8.8 Hz, 1H), 3.97 (tt, J¼4.8, 10.8, 21.6 Hz, 1H), 4.26 (br d,
J¼2.4, 18.0 Hz, 1H), 4.45 (br d, J¼11.6 Hz, 1H), 5.39 (dd, J¼1.6,
10.4 Hz, 1H), 5.86 (br d, J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
100 MHz, 75 ꢁC):
d
27.2, 38.1, 40.2, 41.5, 42.9, 52.1, 52.9, 54.8, 55.0,
56.3, 73.7, 75.1, 114.5, 116.6, 129.6, 130.6, 135.4, 156.7, 160.3, 207.4,
215.7; IR (ATR):
2952, 1692, 1611 cmꢀ1; LRMS (FAB) m/z 438
55 ꢁC):
130.8, 156.4; IR (ATR):
d 24.4, 30.3, 34.5, 36.3, 40.1, 43.0, 46.9, 47.1, 52.8, 80.6, 125.5,
n
3365, 2922, 2851, 1735, 1682, 1457,
n
1363 cmꢀ1; LRMS (FAB) m/z 268 (MþH); HRMS (FAB) m/z calcd for
C14H22NO4 (MþH) 268.1549, found 268.1543; mp: 70e71.5 ꢁC (from
i-Pr2O).
(MþNa); HRMS (FAB) m/z calcd for C23H29NO6Na (MþNa) 438.1893,
found 438.1903.
4.3.21. p-Nitorobenzoate 52. To
a solution of 51 (152 mg,
4.3.18. Cyclic carbamate 49. To
a
solution of 40 (40 mg,
0.366 mmol) in CH2Cl2 (5.9 mL) and H2O (1.5 mL) was added DDQ
(166 mg, 0.732 mmol) at 0 ꢁC. The resulting mixture was warmed to
rt and stirred for 1 h at the same temperature. Saturated aqueous
sodium thiosulfate (3 mL) was added and the resulting mixture was
stirred for 30 min at rt. The separated water layer was extracted
with CH2Cl2, and the combined organic layers were dried over
Na2SO4. Volatile material was removed under reduced pressure,
and the resulting residue was purified by column chromatography
(SiO2, hexane/AcOEt¼1/3) to give deprotected alcohol (105 mg,
0.102 mmol) in THF (1.0 mL) were added MeOH (1 drop) and NaBH4
(7.7 mg, 0.203 mmol) at 0 ꢁC. The resulting mixture was warmed to
rt and stirred for 14 h at the same temperature. Saturated aqueous
NH4Cl (1 mL) was added to quench the reaction at rt. The separated
water layer was extracted with AcOEt, and combined organic layers
were washed with brine and dried over Na2SO4. Volatile material
was removed under reduced pressure, and the resulting residue
was purified by column chromatography (SiO2, hexane/AcOEt¼3/1)
to give 49 (19 mg, yield 51%) as a colorless foam: 1H NMR (CDCl3,
yield 97%) as a colorless oil: 1H NMR (C6D6, 400 MHz, 75 ꢁC):
d 1.24
600 MHz):
d
0.14 (s, 3H), 0.15 (s, 3H), 0.92 (s, 9H), 1.43 (dt, J¼9.6,
(br s, 1H), 1.69 (br s, 1H), 1.82e1.94 (m, 1H), 2.12 (br d, J¼15.6 Hz,
2H), 2.35e2.47 (m, 2H), 2.55 (br s,1H), 2.68 (br s,1H), 3.34 (br s,1H),
3.48 (s, 3H), 3.65 (br d, J¼10.8 Hz, 2H), 3.80 (br d, J¼15.6 Hz, 1H),
4.04 (br d, J¼16.4 Hz, 1H), 4.40 (br s, 1H), 5.00 (br d, J¼12.0 Hz, 2H),
19.2 Hz, 1H), 1.59e1.65 (m, 1H), 1.66e1.77 (m, 2H), 1.78e1.82 (m,
1H), 1.86e1.96 (m, 2H), 1.95 (d, J¼19.2 Hz, 1H), 2.16 (dd, J¼7.2,
17.4 Hz, 1H), 3.59 (dd, J¼7.8, 15.0 Hz, 1H), 3.62 (br s, 1H), 3.69 (dd,
J¼1.8, 10.2 Hz, 1H), 4.21 (d, J¼10.2 Hz, 1H), 4.32 (dd, J¼4.8, 15.0 Hz,
1H), 4.88 (br s, 1H), 5.21 (d, J¼5.4 Hz, 1H), 5.22 (d, J¼16.2 Hz, 1H),
5.62e5.76 (m, 1H); 13C NMR (C6D6, 100 MHz, 75 ꢁC):
d 26.5, 37.6,
38.0, 42.4, 49.9, 50.9, 52.6, 54.4, 57.9, 65.2, 116.1, 135.8, 158.2, 206.4,

1904
T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
217.5; IR (ATR):
n
3430, 2953, 1712, 1691 cmꢀ1; HRMS (ESI) m/z
128.4, 128.6, 133.8, 136.3, 138.2, 168.0, 168.5, 169.0; IR (ATR): n 3447,
calcd for C30H42N2O10Na (2MþNa) 613.2737, found 613.2728.
To a solution of the alcohol (105 mg, 0.356 mmol) in CH2Cl2
(3.6 mL) was added Et3N (0.15 mL,1.07 mmol) at rt. After stirring for
5 min, p-nitrobenzoyl chloride (79 mg, 0.427 mmol) and DMAP
2928, 1707, 1652 cmꢀ1; LRMS (FAB) m/z 499 (MþH); HRMS (FAB)
m/z calcd for C22H28ClN2O7S (MþH) 499.1306, found 499.1281; mp
157.5e159 ꢁC (MeOH).
(4.4 mg, 35.6
m
mol) were added at 0 ꢁC. The resulting mixture was
4.3.24. Cyclic carbamate 62. To a solution of 55-anti (20 mg,
warmed to rt and stirred for 1.5 h at the same temperature. Satu-
rated aqueous NH4Cl (2 mL) was added to quench the reaction. The
separated water layer was extracted with AcOEt, and the combined
organic layers were dried over Na2SO4. Volatile material was re-
moved under reduced pressure, and the resulting residue was pu-
rified by column chromatography (SiO2, hexane/AcOEt/CH2Cl2¼1/
1/1) to give 52 (100 mg, yield 63%) as a colorless solid. Then 52 was
recrystallized from benzene. The Stereochemistry of 52 was de-
termined by X-ray crystallography: 1H NMR (C6D6, 400 MHz,
45.7
46.0
mmol) in THF (0.46 mL) was added LiBH4 (2.0 M in THF, 23 mL,
m
mol) at ꢀ78 ꢁC. After stirring for 30 min at the same tempera-
ture, MeOH(1drop)wasaddedandthemixturewaswarmedtortand
then stirred for 1 h. After addition of water (3 mL) at 0 ꢁC, the sepa-
rated water layer was extracted with AcOEt, and the combined or-
ganic layers were washed with brine and dried over Na2SO4. Volatile
material was removed under reduced pressure. The resulting residue
was purified by column chromatography (SiO2, hexane/AcOEt¼1/3)
to give 62 (16 mg, yield quant) as a colorless oil: 1H NMR (CDCl3,
75 ꢁC):
d
1.54 (br s, 1H), 1.62e1.74 (m, 1H), 1.98 (dt, J¼9.2, 18.8 Hz,
600 MHz): d 0.14 (s, 6H), 0.91 (s, 9H),1.67e1.73 (m,1H),1.82e1.93 (m,
1H), 2.23e2.34 (m, 2H), 2.37 (d, J¼6.0 Hz, 1H), 2.40e2.44 (m, 1H),
2.52 (br s, 1H), 3.18e3.51 (br s, 1H), 3.48 (s, 3H), 3.88 (m, 3H), 4.49
(dd, J¼11.2, 20.0 Hz, 2H), 5.01 (d, J¼3.2 Hz, 2H), 5.04 (d, J¼11.2 Hz,
3H), 2.00e2.05 (m, 1H), 2.04 (dd, J¼4.0, 10.4 Hz, 1H), 2.17 (dd, J¼4.4,
6.6 Hz, 1H), 2.24 (dt, J¼4.4, 9.6 Hz,1H), 3.45 (d, J¼6.4 Hz, 1H), 3.53 (d,
J¼6.4 Hz, 1H), 3.59 (dd, J¼5.2, 10.0 Hz, 1H), 3.86 (d, J¼1.2 Hz, 1H),
4.28e4.35 (m, 2H), 4.78 (d, J¼2.4 Hz, 1H), 5.23 (d, J¼6.8 Hz, 1H), 5.26
(d, J¼11.6 Hz, 1H), 5.85 (dddd, J¼4.0, 5.2, 6.8, 18.0 Hz, 1H); 13C NMR
1H), 5.74 (ddd, J¼5.6, 10.8, 22.4 Hz, 1H), 7.27e7.31 (m, 2H), 7.84 (dd,
13
J¼8.8, 12.8 Hz, 2H); C NMR (C6D6, 100 MHz, 75 ꢁC):
d 26.9, 37.9,
38.0, 38.9, 40.9, 42.5, 52.3, 54.2, 56.6, 68.7, 116.9, 123.7, 128.5, 135.0,
(CDCl3, 150 MHz):
d
ꢀ4.35, ꢀ4.21, 18.1, 25.6, 25.7, 31.0, 31.3, 33.0, 41.1,
135.1, 151.1, 156.8, 164.4, 206.2, 212.2; IR (ATR):
n
2958, 1727, 1706,
49.5, 52.5, 54.5, 66.9, 84.9, 101.5, 118.7, 133.5, 154.5, 157.4; IR (ATR): n
1694 cmꢀ1; HRMS (ESI) m/z calcd for C22H24N2O8Na (MþNa)
3409, 2951, 2928, 2888, 2859,1708,1665 cmꢀ1; HRMS (ESI) m/z calcd
for C40H67N2O8Si2 (2MþH) 759.4436, found 759.4424.
467.1430, found 467.1446; mp 137.5e139.5 ꢁC (benzene).
4.3.22. Ketone 58. To a solution of 53 (26 mg, 42.5
m
mol) in CH3CN
4.3.25. Aldehyde 63. To a solution of 62 (14 mg, 36.9
(0.4 mL) was added DesseMartin periodinane (34 mg, 79
m
mol) in CH2Cl2
(0.5 mL) was added HF$Py (2 mg, 98.2
m
mol) at 0 ꢁC. After stirring
mmol) at
for 10 min, the resulting mixture was warmed to rt and stirred for
13 h. Saturated aqueous NaHCO3 (10 mL) was added to quench the
reaction. The separated water layer was extracted with AcOEt, and
the combined organic layers were washed with brine and dried
over Na2SO4. Volatile material was removed under reduced pres-
sure. The resulting residue was purified by column chromatography
(SiO2, hexane/AcOEt¼1/3) to give 58 (19 mg, yield 90%) as a color-
0 ꢁC. After stirring for 10 min, the resulting mixturewas warmed tort
and stirred for 1.5 h. Saturated aqueous NaHCO3 (2 mL) and aqueous
sodium thiosulfate (2 mL) were added and the mixture was stirred
for 30 min. The separated water layer was extracted with AcOEt, and
the combined organic layers were washed with brine and dried over
Na2SO4. Volatile material was removed under reduced pressure. The
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt¼2/1) togive 63(11 mg, yield 79%) as a colorlessoil: 1H
less foam: 1H NMR (C6D6, 400 MHz, 75 ꢁC):
d 1.42 (br s, 1H), 1.74 (br
s, 1H), 1.92 (br t, J¼14.0 Hz, 1H), 2.07 (br d, J¼15.2 Hz, 1H), 2.38 (br d,
J¼15.2 Hz, 1H), 2.58 (br s, 1H), 3.03 (br t, J¼14.0 Hz, 1H), 3.33 (br s,
1H), 3.43 (s, 3H), 3.69 (br d, J¼12.4 Hz, 1H), 3.79 (br d, J¼12.4 Hz,
1H), 3.84e3.96 (m, 1H), 4.11e4.30 (m, 2H), 4.88 (br t, J¼9.2 Hz, 2H),
5.08 (br s, 1H), 5.43 (br s, 1H), 7.14 (br s, 3H), 8.05 (br d, J¼5.2 Hz,
NMR (CDCl3, 600 MHz):
d
0.15 (s, 6H), 0.92 (s, 9H), 1.78 (dt, J¼7.8,
13.2 Hz, 2H), 2.00e2.07 (m,1.5H), 2.08e2.14 (m,1.5H), 2.16 (dt, J¼6.6,
16.8 Hz,1H), 2.59 (dt, J¼6.6,13.2 Hz,1H), 3.60 (dd, J¼7.2,15.0 Hz,1H),
4.25 (d, J¼3.6 Hz, 1H), 4.30 (ddt, J¼1.8, 5.4, 15.6 Hz, 1H), 4.80 (dd,
J¼3.0, 6.6 Hz,1H), 4.86 (d, J¼3.6 Hz,1H), 5.25 (d, J¼17.4 Hz,1H), 5.26
(dd, J¼0.6, 8.4 Hz,1H), 5.80 (ddd, J¼4.8, 8.4,17.4 Hz,1H), 9.52 (s,1H);
2H); 13C NMR (100 MHz, C6D6, 75 ꢁC):
d 26.5, 35.5, 41.6, 42.2, 43.0,
44.3, 48.8, 53.2, 55.9, 61.7, 116.3, 128.6, 128.9, 133.4, 135.6, 139.7,
13C NMR (CDCl3,150 MHz):
d
ꢀ4.52, ꢀ4.36,18.0, 25.5, 30.5, 31.3, 31.9,
167.7, 168.3, 169.4, 202.4; IR (ATR):
n
2924, 1710, 1661 cmꢀ1; LRMS
39.4, 49.2, 51.8, 61.7, 81.9, 100.2, 118.8, 133.0, 154.5, 156.5, 198.7; IR
(FAB) m/z 535 (MþK); HRMS (FAB) m/z calcd for C22H25ClN2O7SK
(MþK) 535.0708, found 535.0715.
(ATR):
n
2930, 2857, 1716, 1665 cmꢀ1; HRMS (ESI) m/z calcd for
C20H31NO4SiNa (MþNa) 400.1920, found 400.1939.
4.3.23. Oxabicyclo[2.2.2]octanone 61. To a solution of 58 (14 mg,
28.2 mmol) in THF (0.3 mL) was added NaBH4 (2 mg, 56.3 mmol) at
4.3.26. Diol 64. To a solution of 55-syn (151 mg, 0.345 mmol) in
THF (3.5 mL) was added LiBH4 (2.0 M in THF, 0.35 mL, 0.70 mmol) at
ꢀ78 ꢁC. After stirring for 1 h at the same temperature, MeOH
(1 drop) was added and the mixture was warmed to rt and stirred
for 2 h. Saturated aqueous NH4Cl (3 mL) was added to quench the
reaction at 0 ꢁC. The separated water layer was extracted with
AcOEt, and the combined organic layers were dried over Na2SO4.
Volatile material was removed under reduced pressure. The
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt¼1/2) to give 64 (121 mg, yield 85%) as a colorless
solid. Then 64 was recrystallized from AcOEt/hexane. The stereo-
chemistry of 64 was determined by X-ray crystallography: 1H NMR
0 ꢁC. After stirring for 35 min at the same temperature, water (1 mL)
was added to quench the reaction. The separated water layer was
extracted with AcOEt, and the combined organic layers were
washed with brine and dried over Na2SO4. Volatile material was
removed under reduced pressure. Crude 59 was dissolved in MeOH
for 2 days to give 61 (10 mg, yield 71%) as a colorless crystal. The
stereochemistry of 61 was determined by X-ray crystallography: 1H
NMR (400 MHz, CDCl3):
d
1.04 (dd, J¼13.2, 24.8 Hz, 1H), 1.66 (dddt,
J¼2.4, 7.2, 9.6, 12.0 Hz, 1H), 1.83 (dd, J¼12.0, 24.0 Hz, 1H), 1.88e2.01
(m, 3H), 2.28e2.38 (m, 1H), 2.72e2.2.82 (m, 1H), 3.33 (ddd, J¼6.4,
9.6, 14.4 Hz, 1H), 3.53 (s, 3H), 3.77 (tt, J¼4.0, 15.2 Hz, 1H), 3.98 (d,
J¼13.2 Hz, 1H), 4.04 (d, J¼13.2 Hz, 1H), 4.16 (dt, J¼2.0, 18.8 Hz, 1H),
4.27 (ddd, J¼4.0, 7.6, 14.0 Hz, 1H), 4.55 (dd, J¼4.8, 19.2 Hz, 1H), 4.75
(dd, J¼3.2, 13.2 Hz, 1H), 5.03 (d, J¼17.2 Hz, 1H), 5.09 (d, J¼10.4 Hz,
1H), 5.65 (ddd, J¼4.8, 10.4, 17.2 Hz, 1H), 7.56 (t, J¼8.0 Hz, 2.6H), 7.67
(t, J¼7.2 Hz,1.4H), 7.97 (d, J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
(CDCl3, 400 MHz): d 0.13 (s, 3H), 0.14 (s, 3H), 0.91 (s, 9H), 1.50e1.62
(m, 1H), 1.62e1.86 (m, 3H), 1.94e2.09 (m, 1H), 2.15 (ddd, J¼4.4, 9.6,
18.4 Hz, 1H), 2.21e2.38 (m, 1H), 2.78 (br s, 1H), 3.51e3.62 (m, 2H),
3.65e3.85 (m, 2H), 3.73 (s, 3H), 3.99 (dd, J¼4.8,15.2 Hz,1H), 4.33 (br
s, 1H), 4.74 (tt, J¼2.4, 14.0 Hz, 1H), 5.03e5.19 (m, 3H), 5.85 (ddt,
J¼5.2, 10.0, 16.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d
ꢀ4.46, 17.9,
d
27.1, 34.4, 34.9, 40.0, 42.1, 42.2, 47.7, 53.6, 55.0, 61.4, 68.0, 115.6,
25.5, 26.0, 29.2, 30.5, 37.2, 47.8, 48.9, 53.1, 53.2, 64.4, 77.9, 102.3,

T. Ohfusa, A. Nishida / Tetrahedron 67 (2011) 1893e1906
1905
115.3, 135.8, 152.1, 159.2; IR (ATR):
n
3396, 2956, 2928, 2857, 1736,
quench the reaction at 0 ꢁC. The separated water layer was
extracted with AcOEt, and the combined organic layers were dried
over Na2SO4. Volatile material was removed under reduced pres-
sure and the resulting residue was purified by column chroma-
tography (SiO2, hexane/AcOEt¼2/3) to give 67 (37 mg, yield 62%, in
1660 cmꢀ1; HRMS (ESI) m/z calcd for C42H74N2O10Si2Na (2MþNa)
845.4780, found 845.4762; mp 116e118.5 ꢁC (AcOEt/n-hexane).
4.3.27. Diol 66. To a solution of 56-anti (93 mg, 0.206 mmol) in THF
(3.5 mL) was added LiBH4 (2.0 M in THF, 0.10 mL, 0.20 mmol) at 0 ꢁC.
After stirring for 1 h at the same temperature, ice-cold H2O (3 mL)
was added to quench the reaction at 0 ꢁC. The separated water layer
was extracted with AcOEt, and the combined organic layers were
dried over Na2SO4. Volatile material was removed under reduced
pressure. The resulting residue was purified by column chroma-
tography (SiO2, hexane/AcOEt¼4/1) to give secondary alcohol
(77 mg, yield 83%) as a colorless oil: 1H NMR (C6D6, 400 MHz, 75 ꢁC):
two steps) colorless oil: 1H NMR (CDCl3, 400 MHz):
d 0.14 (s, 3H),
0.15 (s, 3H), 0.91 (s, 9H), 1.22e1.39 (m, 2H), 1.41e1.55 (m, 2H),
1.56e1.66 (m, 1H), 1.65 (d, J¼18.0 Hz, 1H), 1.70e1.82 (m, 2H),
2.02e2.14 (m,1H), 2.15e2.27 (m,1H), 3.06 (br s,1H), 3.54 (dd, J¼8.0,
15.2 Hz, 1H), 3.91 (br s, 1H), 3.94 (br s, 1H), 4.16 (d, J¼10.4 Hz, 1H),
4.27 (d, J¼10.4 Hz, 1H), 4.34 (dt, J¼1.2, 4.8 Hz, 1H), 4.87 (t, J¼1.6 Hz,
1H), 5.20e5.27 (m, 1H), 5.83 (dtt, J¼4.8, 9.6, 11.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz):
33.3, 37.7, 50.0, 53.8, 63.8, 66.9, 101.0, 118.4, 133.0, 150.5, 153.9; IR
(ATR):
3404, 2932, 2857, 1734, 1654 cmꢀ1; HRMS (ESI) m/z calcd
for C21H35NO4SiNa (MþNa) 416.2233, found 416.2242.
d
ꢀ4.44, ꢀ4.29, 17.9, 19.3, 25.5, 28.6, 28.9, 30.3,
d
0.36 (s, 6H), 1.11 (s, 9H), 1.27e1.59 (m, 2.8H), 1.59e1.74 (d, 1.2H),
1.80e2.10 (m, 3H), 2.18 (br s, 1H), 2.87 (br s, 1.3H), 3.10 (br s, 1.7H),
3.50 (br s, 7H), 4.31 (brd, J¼16.0 Hz,1H), 4.69 (br s,1H), 5.00e5.16 (m,
n
3H), 5.80 (br s, 1H); 13C NMR (C6D6, 100 MHz, 75 ꢁC):
d
ꢀ4.2, ꢀ4.0,
15.6,18.2, 26.0, 28.6, 31.8, 33.5, 34.4, 51.4, 52.5, 52.9, 65.6, 67.9,104.3,
4.3.29. Ketone 68. To a solution of 67 (30 mg, 76.2 mol) in CH2Cl2
m
116.2, 134.8, 152.3, 157.4, 175.6; IR (ATR):
n
3447, 2929, 2856, 1727,
(0.76 mL) was added NaHCO3 (13 mg, 0.152 mmol) and
DesseMartin periodinane (65 mg, 0.152 mmol) at 0 ꢁC. After stir-
ring for 10 min, the resulting mixture was warmed to rt and stirred
for 5.5 h. Saturated aqueous sodium thiosulfate (2 mL) was added
and the mixture was stirred for 30 min. The separated water layer
was extracted with AcOEt, and the combined organic layers were
washed with brine and dried over Na2SO4. Volatile material was
removed under reduced pressure. The resulting residue was puri-
fied by column chromatography (SiO2, hexane/AcOEt¼1/1) to give
68 (21 mg, yield 78%) as a colorless oil: 1H NMR (CD3CN, 600 MHz):
1702 cmꢀ1; HRMS (ESI) m/z calcd for C46H78N2O12Si2Na (2MþNa)
929.4991, found 929.4973. Broad peaks were observed in 13C NMR
spectra due to the presence of rotamers, even at elevated tempera-
tures. Three carbons were not observed separately.
To a solution of the alcohol (70 mg, 0.154 mmol) in CH3CN
(1.5 mL) was added HF$Py (20 m
L, 0.772 mmol) at 0 ꢁC. After stirring
for 10 min, the resulting mixture was warmed to rt and stirred for
16 h. Saturated aqueous NaHCO3 (2 mL) was added to quench the
reaction at 0 ꢁC. The separated water layer was extracted with
AcOEt, and the combined organic layers were dried over Na2SO4.
Volatile material was removed under reduced pressure to give
crude 65, which was used in the next step without purification.
To a solution of crude 65 in THF (1.5 mL) was added MeOH (1
drop) and LiBH4 (2.0 M in THF, 0.15 mL, 0.30 mmol) at ꢀ78 ꢁC. After
stirring for 1 h at the same temperature, ice-cold H2O (3 mL) was
added at ꢀ78 ꢁC. The resulting mixture was slowly warmed to rt to
quench the reaction. The separated water layer was extracted with
AcOEt, and the combined organic layers were dried over Na2SO4.
Volatile material was removed under reduced pressure and the
resulting residue was purified by column chromatography (SiO2,
hexane/AcOEt¼2/3) to give 66 (24 mg, yield 52%, in two steps) as
a colorless solid. Then 66 was recrystallized from AcOEt/i-PrOH. The
stereochemistry of 66 was determined by X-ray crystallography: 1H
d
0.18 (s, 3H), 0.19 (s, 3H), 0.94 (s, 9H), 1.66e1.75 (m, 2H), 1.77e1.87
(m, 2H), 2.03e2.09 (m, 2H), 2.25 (br d, J¼9.6 Hz, 1H), 2.33 (ddt,
J¼2.0, 4.4, 12.4 Hz, 1H), 2.71 (dt, J¼4.4, 17.2 Hz, 1H), 3.61 (dd, J¼4.4,
10.4 Hz, 1H), 4.13 (d, J¼7.6 Hz, 2H), 4.17 (ddt, J¼0.8, 3.2, 14.0 Hz, 1H),
4.33 (dd, J¼0.8, 7.6 Hz, 1H), 4.45 (br s, 1H), 5.00 (dt, J¼0.8, 1.2 Hz,
1H), 5.17 (dd, J¼1.2, 3.2 Hz, 1H), 5.19 (ddd, J¼0.8, 1.6, 7.6 Hz, 1H); 13C
NMR (CD3CN, 150 MHz):
d
ꢀ4.5, ꢀ4.3, 18.5, 25.8, 26.3, 28.4, 33.0,
38.3, 38.6, 49.9, 50.7, 54.4, 67.0, 102.9, 118.17, 134.4, 150.8, 152.7,
210.8; IR (ATR):
n
2928, 2856, 1697, 1660 cmꢀ1; HRMS (ESI) m/z
calcd for C42H66N2O8Si2Na (2MþNa) 805.4255, found 805.4223.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search (B) from MEXT, Japan (project number; 21390002).
NMR (DMSO-d6, 400 MHz, 100 ꢁC):
d
1.33 (dt, J¼3.2, 12.8 Hz, 1H),
1.41e1.65 (m, 4H), 1.74e1.84 (m, 2H), 1.93 (ddt, J¼4.4, 13.2, 26.4 Hz,
2H), 2.36 (t, J¼7.6 Hz, 1H), 2.59 (dd, J¼11.2, 24.4 Hz, 1H), 3.41 (br s,
2H), 3.66 (s, 3H), 3.67 (s, 3H), 3.67e3.77 (m, 1H), 4.15 (dd, J¼4.0,
15.6 Hz,1H), 4.30 (dd, J¼4.0,15.6 Hz,1H), 4.47 (dd, J¼5.6,16.4 Hz,1H),
4.55 (br s,1H), 5.15 (dd, J¼1.6, 7.6 Hz,1H), 5.19 (dd, J¼1.6,14.4 Hz,1H),
5.94 (ddt, J¼5.6, 10.4, 17.6 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz,
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.01.019.
100 ꢁC):
d 14.1, 28.8, 31.5, 33.7, 35.7, 36.5, 45.7, 51.0, 51.6, 52.3, 58.9,
References and notes
67.0, 67.9, 114.2, 136.4, 155.8, 173.7; IR (ATR):
n 3437, 3324, 2926,
2860, 1695 cmꢀ1; HRMS (ESI) m/z calcd for C17H27NO6Na (MþNa)
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1906
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€
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