Enantioselective divergent approaches to both (-)-platensimycin and (-)-platencin

Article abstract of DOI:10.1016/j.tet.2010.10.076

Enantioselective divergent approaches to (-)-platencin and (-)-platensimycin have been developed. A rationally designed chiral synthetic intermediate, possessing a useful α,β-unsaturated sulfone functionality, which served as a masked ketone as well as a good Michael acceptor, was successfully prepared via the highly enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) developed in our laboratory. Copyright

Full text of DOI:10.1016/j.tet.2010.10.076

Tetrahedron 67 (2011) 518e530
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective divergent approaches to both (ꢀ)-platensimycin
and (ꢀ)-platencin
*
Sho Hirai, Masahisa Nakada
Department of Chemistry and Biochemistry, ASE Graduate School, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2010
Received in revised form 23 October 2010
Accepted 26 October 2010
Available online 12 November 2010
Enantioselective divergent approaches to (ꢀ)-platencin and (ꢀ)-platensimycin have been developed.
A rationally designed chiral synthetic intermediate, possessing a useful a,b-unsaturated sulfone func-
tionality, which served as a masked ketone as well as a good Michael acceptor, was successfully prepared
via the highly enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) de-
veloped in our laboratory.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Cyclopropanation
Divergent approaches
Enantioselective synthesis
1. Introduction
inhibitor of FabF, the condensing enzyme, which catalyzes elon-
gation in bacterial fatty acid synthesis.1 (ꢀ)-Platencin (2) is a mod-
The emerging threat of multi-resistant bacteria, such as methi-
cillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant
enterococci (VRE), penicillin-resistant Streptococcus pneumonia
(PRSP), and so on, has made researchers find new antibiotics having
a new mode of action. Under such situation, the research group at
Merck isolated new class antibiotics, (ꢀ)-platensimycin (1)1 (Fig. 1)
and (ꢀ)-platencin (2)2 from Streptomyces platensis MA 7327 and
7339, respectively. (ꢀ)-Platensimycin (1) is a potent and selective
erate inhibitor of both FabF and FabH, the enzyme catalyzing the
initial condensation in bacterial fatty acid synthesis.2 Because of
their new modes of action, 1 and 2 show potent, broad-spectrum
Gram-positive antibacterial activity, and also exhibit no cross-re-
sistance to antibiotic-resistant bacteria, including MRSA and VRE.1,2
These compounds have a same side-chain including 3-amino-
2,4-dihydroxybenzoic acid as the common structure; however,
both compounds have unique structural features in their polycyclic
moieties. (ꢀ)-Platensimycin (1) has a tetracyclic framework in-
cluding a cyclic ether while (ꢀ)-platencin (2) has a tricyclic
framework, which consists of only carbons.
O
O
R
R
The new modes of action and unique structural features of these
new antibiotics 1 and 2 have attracted much interest of synthetic
chemists and medicinal scientists, and a number of research groups
have reported total syntheses3e6 and SAR studies.7 Because of their
novelty in the structure and biological activity, we were also in-
terested in the enantioselective total synthesis of compounds 1, 2,
and their new derivatives. The structural similarities between 1 and
2 led us to develop enantioselective divergent approaches to these
antibiotics, and recently, we completed a formal total synthesis of 2.5
During the synthesis of 2,5 we found that the intermediate in the
total synthesis of 2 would be used for the total synthesis of 1, too.
Therefore, we started the total syntheses of 1 via the same key in-
termediate, and herein report the full detail of the enantioselective
formal total synthesis of 2 and a new enantioselective formal total
synthesis of 1 via the enantioselective divergent approaches.
O
(–)-platensimycin (1)
(–)-platencin (2)
OH
O
R=
HO2C
HO
N
H
Fig. 1. Structures of (ꢀ)-platensimycin (1) and (ꢀ)-platencin (2).
* Corresponding author. Tel.: þ81352863240; e-mail address: mnakada@wase-
da.jp (M. Nakada).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.076

S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
519
2. Results and discussions
2.2. Retrosynthetic analysis of 3
2.1. Retrosynthetic analysis of 1 and 2
In our retrosynthetic analysis of 3 (Scheme 3), compound 3 would
be formed by the acid-catalyzed intramolecular ether formation of
the corresponding alcohol, which would be obtained by the stereo-
selective reduction of ketone 8. Ketone 8 could be derived from keto-
aldehyde 9 by converting the aldehyde group to the exo-methylene.
We proposed that tricyclic keto-aldehyde 9 could be obtained by the
acid-catalyzed intramolecular Michael reaction of ketone 10 or the
corresponding aldehyde, which would be obtained from compound
In the course of the retrosynthetic analysis of 1 and 2, we
identified a common carbon framework, a cis-dehydrodecalin
skeleton possessing a bridgehead stereogenic quaternary carbon,
which was hidden within their structures (Scheme 1). The cis-
dehydrodecalin skeleton was also found in intermediates reported
earlier by other research groups, including Snider’s intermediate
33b for 1 and Nicolaou’s intermediate 44a for 2. Therefore, we set 3
and 4 as targets of our formal total synthesis.
11 since an a,b-unsaturated sulfone can be converted to a ketone and
a C-1 elongation of the bridgehead substituent of 11 would furnish
the methyl alkenyl ether moiety in 10. Compound 11 was thought to
be prepared via the ring-opening reaction of cyclopropane 12 and
following appropriate transformations.
R1
cis-dehydrodecalin
H
skeleton
stereoselective
ether
reduction
formation
O
O
8
3
(–)-platensimycin (1)
(–)-platencin (2)
O
intramolecular
Michael
MeO
addition
Snider's
H
intermediate (3)
O
H
CHO
O
9
O
10
TBDPSO
TBDPSO
O
Nicolaou' s
intermediate (4)
H
Scheme 1. cis-Dehydrodecalin skeleton hidden in 1 and 2.
H
PhO2S
SPh
PhO2S
H
11
12
We have reported a highly enantioselective catalytic asymmet-
Scheme 3. Retrosynthetic analysis of 3.
ric intramolecular cyclopropanation (CAIMCP) of
a-diazo-b-keto
sulfones with CuOTf and bisoxazoline ligand 6.8 The cyclopropanes
thus prepared have been successfully utilized for the enantiose-
lective total synthesis of some natural products in our laboratory.9
Indeed, tricyclo[4.4.0.0]decene derivatives 7 have been easily pre-
pared in a highly enantioselective manner from 5 by the CAIMCP
(Scheme 2).
2.3. Retrosynthetic analysis of 4
Our retrosynthetic analysis of 4 is shown in Scheme 4. Com-
pound 4 was thought to be formed from alcohol 13 via oxidation,
Wittig olefination, deprotection of the TBS group, and oxidation of
the resulting alcohol. Alcohol 13 would be obtained from 14 by
reductive removal of all the sulfur-containing functional groups at
the same time, followed by allylic oxidation to introduce the hy-
R1
R1
CuOTf
(10 mol %)
droxy group, and selective TBS ether formation. As an
a,b-un-
H
H
saturated sulfone is a good Michael acceptor, tricyclic compound 14
could be formed by the intramolecular Michael addition of alde-
hyde 15. Finally, aldehyde 15 would be easily prepared from
6a or 6b
(15 mol %)
96-97% ee
O
O
ArO2S
N2
SO2Ar
5 (Ar = Ph, Mes)
7 (Ar = Ph, Mes)
R2 R2
O
TBSO
O
O
6a (R2=Me)
6b (R2=Bn)
N
N
HO
Scheme 2. Preparation of 7 by catalytic asymmetric intramolecular cyclopropanation
4
13
(CAIMCP).
CHO
SPh
intramolecular
Michael
Compounds 7 can serve as key synthetic intermediates because
they possess useful functional groups including a cyclopropane, an
alkene, and a ketone. As compounds 7 incorporate the above
mentioned cis-dehydrodecalin skeleton with a quaternary stereo-
genic center; hence, we surmised that 7 would be suitable for the
synthesis of 3 and 4, and undertook retrosynthetic analysis of 3 and
4 starting from 7.
addition
11
PhO2S
HO
SPh
14
H
PhO2S
15
Scheme 4. Retrosynthetic analysis of 4.

520
S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
compound 11, which is the same intermediate appeared in the
retrosynthetic analysis of 3 (Scheme 3).
not determined at this stage but was provisionally assigned as
shown in Table 1 according to our transition state model.8a As
shown in Table 1, the CAIMCPs with other ligands, 6b and 6c, were
also examined. The ees were almost the same as that in entry 1, but
the reactions proceeded slowly, required heating, and yields were
lowered. These reduced reaction rate and yields were probably
attributed to the crowded transition states that arose from the
bulky substituent in the ligands 6b and 6c.
It should be noted that the attempted CAIMCP of compound 18a
(Fig.2) afforded the corresponding cyclopropane in low yield be-
cause a certain amount of by-products formed. This result indicates
that the alkenylsilane in 18a could be involved in the intra- or inter-
2.4. Preparation of a-diazo-b-keto sulfone 18
On the basis of the retrosynthetic analyses of 3 and 4 (Schemes 3
and 4), we first prepared -diazo- -keto sulfone 18, which would
a
b
afford cyclopropane 12 by the CAIMCP (Scheme 5). Birch reduction of
benzoic acid to afford cyclohexa-2,5-dienecarboxylic acid A, forma-
tion of the methyl ester B, and subsequent alkylation of the enolate
with tert-butyl bromoacetate afforded compound 16. Reduction of
diester 16 with LiAlH4 afforded the corresponding diol 16a, followed
by selective TBDPS ether 16b formation and then Swern oxidation to
1) Li, liq. NH3, t-BuOH
THF, -78 ºC
1) LiAlH4, Et2O, 0 ºC, 93%
2) TBDPSCl, Et3N, CH2Cl2
room temp, 92%
t
BuO2C
2) MeOH, C6H6
HO2C
c.H2SO4 (cat.), reflux
MeO2C
3) BrCH2CO2Bu-t, LDA
THF, -78 ºC
3) (COCl)2, DMSO, Et3N, CH2Cl2
-78 ºC to room temp, 93%
16
96% (3 steps)
TBDPSO
OTBDPS
OHC
1) (EtO)2P(O)CH2CO2Et, t-BuOK
THF, -78 ºC to room temp, 91%
2) NaBH4 , NiCl2-6H2O, MeOH, 0 ºC, 96%
O
N2
SO2Ph
18
3) CH3SO2Ph, n-BuLi, THF, -78 ºC, 95%
4) TsN3, Et3N, MeCN, room temp, 79%.
17
Scheme 5. Preparation of a-diazo-b-keto sulfone 18.
afford aldehyde 17. Aldehyde 17 was subjected to Hor-
nereWadswortheEmmons reaction to afford the -unsaturated
molecular reaction of the carbene complex formed from 18a. The
product obtained by the CAIMCP of 18a was a potent candidate for
the synthesis of 4, but the low yield turned our attention to use
compound 12.
a,b
ester 17a, followed by reduction with NaBH4 in the presence of NiCl2
to give the corresponding alcohol 17b10 formation of a keto sulfone
17c, and diazo transfer reaction to afford
2.5. CAIMCP of -diazo- -keto sulfone 18
The CAIMCP of -diazo- -keto sulfone 18 was examined using
CuOTf and ligand 6aec. The CAIMCP of compound 18 with ligand 6a
proceeded at room temperature to successfully afford cyclopropane
12 (72%) with 95% ee (Table 1). The absolute configuration of 12 was
a-diazo-b-keto sulfone 18.
a
b
TMS
O
a
b
N2
SO2Ph
Table 1
18a
CAIMCP of a-diazo-b-keto sulfone 18
Fig. 2. Structure of 18a.
TBDPSO
TBDPSO
O
CuOTf
(10 mol %)
2.6. Preparation of key intermediate 11
O
ligand
(15 mol %)
toluene
H
N2
SO2Ph
PhO2S
H
We first attempted the ring-opening reaction of cyclopropane
12 without removing the phenyl sulfonyl group; however, all the
reactions with various reducing agents provided a mixture of
products that lacked the phenyl sulfonyl group. Consequently, we
conducted the ring-opening reaction of cyclopropane 12 with
lithium thiophenoxide9a with the intention of removing the
phenyl sulfide at a later stage. The ring-opening reaction with
lithium thiophenoxide afforded the keto sulfide 19 in high yield
(Scheme 6), and subsequent reduction with NaBH4 afforded the
corresponding alcohol 19a. Dehydration of the resultant alcohol
was attempted under various conditions, but unfortunately,
a mixture of regioisomeric alkenes was always obtained. After
several attempts, we found that careful treatment of its mesylate
19b with potassium tert-butoxide at ꢀ78 ꢁC successfully afforded
alkene 11.
18
12
R2 R2
6a (R2=Me)
6b (R2=Bn)
6c (R2=Et)
O
O
N
N
Entry
Temp (ꢁC)
Time (h)
Yielda (%)
Eeb (%)
1
2
3
rt
11
72
50
42
95
93
93
rt, 50c
rt, 50c
3.5, 15c
3.5, 13c
a
Isolated yields.
b
c
Ee determined by HPLC. For HPLC conditions, see Supplementary data.
Reaction was carried out at the indicated temperatures for the indicated times,
respectively.

S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
521
2.8. Formal total synthesis of (L)-platensimycin (1)
TBDPSO
PhSLi, THF
reflux, 96%
TBDPSO
O
We next examined the formal total synthesis of (ꢀ)-platensi-
mycin (1). Synthesis of compound 3 commenced with compound
O
PhO2S
11 because the
a,b-unsaturated sulfone was thought to be con-
H
H
SPh
SPh
PhO2S
H
verted to enone 24 via epoxide 23 (Scheme 8). The chemoselective
epoxidation of compound 11 was realized using lithium tert-butyl
hydroperoxide to afford the epoxide 23; however, treatment of
epoxide 23 with base caused no reaction. The reaction of 23 with
lithium bromide induced epoxide-opening reaction at the less-
12
19
TBDPSO
1) NaBH4, MeOH, THF
0 ºC, 100%
hindered side to afford the corresponding
a-bromo ketone, but
which was not suffered from base-induced dehydrobromination.
Fortunately, treatment of epoxide 23 with magnesium iodide11
afforded ketone 25 in 82% yield (Scheme 9). Removal of the sul-
fide with Raney-nickel and removal of the TBDPS group with TBAF
gave alcohol 26, followed by Swern oxidation and Wittig reaction to
afford compound 27.
Introduction of the double bond into compound 27 was success-
fully achieved by Nicolaou’s protocol12 to afford enone 10. We initially
attempted to convert compound 10 to the corresponding aldehyde by
hydrolysis under acidic conditions; however, we found that a mixture
of products including compound 9 was obtained. After several at-
tempts, the reaction of enone 10 in the presence of p-toluenesulfonic
acid in a mixed solvent system (acetone and toluene) at room tem-
perature was found to efficiently afford desired tricyclic compound 9.
2) MsCl, Et3N, ClCH2CH2Cl
50 ºC, 98%
3) t-BuOK, THF, -78 ºC, 92%
H
PhO2S
11
Scheme 6. Preparation of 11 from 12.
2.7. Formal total synthesis of (L)-platencin (2)
With the key compound 11 in hand, we first examined synthesis
of compound 4 prior to the synthesis of 3, because we thought that 4
would be more easily accessed from compound 11 (Scheme 7). Not
only did removal of the TBDPS group in compound 11 with TBAF
cause migration of the double bond, but use of TBAF with acidic
additive was unsuccessful. Fortunately, the reaction with HF$py
OHC
SmI2, MeOH
THF, 0 ºC
1) HF-py, THF
TBDPSO
Li, naphthalene
room temp, 87%
PhO2S
HO
THF, -20 ºC
69%
SPh
14
95%
2) (COCl)2, DMSO
Et3N, CH2Cl2
-78 ºC to room temp
88%
H
H
PhO2S
SPh
11
PhO2S
SPh
15
TBSO
HO
1) DMP, CH2Cl2
room temp, 95%
SeO2, dioxane
reflux, 100%
TBSCl, imidazole
DMF, -20 ºC, 69%
HO
2) Ph3PCH=CH2
THF, 50 ºC
HO
HO
20
13
21
1) TBAF, THF, 60 ºC
95% (2 steps)
O
TBSO
ref. 4a
(–)-platencin (2)
2) DMP, NaHCO3, CH2Cl2
room temp, 82%.
22
4
Scheme 7. Formal total synthesis of (ꢀ)-platencin (2).
proceeded cleanly afforded the desired alcohol and kept the alkene
intact, and subsequent Swern oxidation afforded aldehyde 15.
The key reductive radical cyclization of aldehyde 15 with SmI2
proceeded smoothly at 0 ꢁC to afford compound 14, which pos-
sessed the tricyclic core of (ꢀ)-platencin (2) as a single isomer.
Treatment of compound 14 with lithium naphthalenide removed
the sulfide and sulfone simultaneously without problem. Sub-
sequent allylic oxidation with selenium dioxide followed by se-
lective protection of the reactive allylic hydroxyl with TBSCl at
ꢀ20 ꢁC afforded TBS ether 13. DesseMartin oxidation of alcohol 13,
Wittig methylenation, removal of the TBS group, and DesseMartin
oxidation in the presence of sodium bicarbonate successfully
afforded compound 4.
TBDPSO
TBDPSO
t-BuO2Li, THF
-78 to 40 ºC
100%
O
H
H
PhO2S
SPh
PhO2S
SPh
11
23
TBDPSO
H
base or
The synthesized compound was proved to be identical in all
LiBr, then, base
respects to the intermediate 4 described by Nicolaou (1H and 13C
O
SPh
NMR, IR, MS, and [a
]D).4f This fact established the absolute structure
24
of cyclopropane 12 and verified the formal enantioselective total
synthesis of (ꢀ)-platencin (2).
Scheme 8. Attempted preparation of ketone 24 via epoxide 23.

522
S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
TBDPSO
TBDPSO
O
HO
1) Raney-Ni, MeOH, THF
MgI2, Et2O
room temp, 84%
H
O
H
O
2) TBAF, THF, 50 ºC, 92%
room temp, 82%
H
SPh
PhO2S
SPh
23
25
26
MeO
MeO
1) (COCl)2, DMSO, Et3N, CH2Cl2
-78 ºC to room temp, 91%
1) LDA, TMSCl, Et3N, THF, 0 ºC
H
O
H
2) IBX, MPO, DMSO, room temp
70% (2 steps)
2) Ph3PCH=CHOMe, THF
-78 ºC to room temp, 90%
27
O
10
1) NaBH4, EtOH, CH2Cl2, -78 ºC, 93%
2) I2, PPh3, imidazole, benzene, 83%
TsOH, toluene/acetone=10/1
room temp, 96%
O
O
H
CHO
9
3) DBU, DMF, 50 ºC, 81%
8
Scheme 9. Preparation of 8.
Conversion of aldehyde 9 to ketone 8 via the enol triflate of 9
was very difficult because of the instability of the enol triflate.
Therefore, following three steps sequence were employed. Thus,
selective reduction of the aldehyde 9 in the presence of the ketone
was achieved with NaBH4 at ꢀ78 ꢁC to provide the corresponding
alcohol 9a, which was converted to the iodide 9b, and subsequent
treatment with DBU furnished ketone 8.
H
HO
TFA, CH2Cl2
0 ºC, 86%
O
28
3
ref. 3b
(–)-platensimycin (1)
Reduction of ketone 8 was expected to afford 28 in a stereo-
selective manner due to the cage-like structure of 8 (Table 2).
However, reduction with sodium borohydride gave 28a as the
major product (entry 1), and the ratio of 28a increased in the re-
duction with DIBAL-H (entry 2). To deliver a hydride to the less-
hindered side of the carbonyl group in 8, more bulky reducing
agents were examined. The ratio of 28/28a was expectedly im-
proved by use of L-Selectride, but the 28/28a ratio was 1/1 (entry 3).
Use of K-Selectride in THF further improved the 28/28a ratio to 5/1
(entry 4), and finally, the reduction with K-Selectride in CH2Cl2
successfully afforded 28 as the sole product in high yield (entry 5).
The obtained alcohol 28 was treated with TFA in CH2Cl2 to fur-
nish the required ether bond, affording compound 3 (Scheme 10).
The synthesized compound was proved to be identical with Snid-
er’s intermediate 33b in all respects (1H and 13C NMR, IR, and MS).13
Compound 3 was synthesized from compound 11, absolute struc-
ture of which had been determined in the synthesis of 4, and ab-
solute structures between 1 and 2 have been correlated; hence,
formal enantioselective total synthesis of (ꢀ)-platensimycin (1) has
been achieved.
Scheme 10. Formal total synthesis of (ꢀ)-platensimycin (1).
3. Conclusion
In summary, enantioselective divergent approaches to both
(ꢀ)-platensimycin (1) and (ꢀ)-platencin (2) have been developed
via the rationally designed common chiral synthetic intermediate
11, possessing a useful a,b-unsaturated sulfone functionality, which
served as a masked ketone as well as a good Michael acceptor. This
intermediate 11 was derived from compound 12, which was suc-
cessfully prepared via the highly enantioselective CAIMCP we have
developed. Therefore, the formal enantioselective total syntheses
reported herein prove the applicability of uniquely functionalized
tricyclo[4.4.0.0]decene derivative 12 as well as the usefulness of the
CAIMCP in natural product synthesis. Although the enantiose-
lective approaches to 1 and 2 described herein are not the shortest
ones among the total syntheses reported to date, the chiral in-
termediate prepared by us enabled total syntheses of both 1 and 2;
therefore, it would be useful for the preparation of their new de-
rivatives as well as for the enantioselective total synthesis of their
congeners including the cis-dehydrodecaline skeleton that could
emerge in the future.
Table 2
Stereoselective reduction of ketone 8
HO
H
H
HO
conditions
+
O
4. Experimental
28a
28
8
4.1. General procedures
Entry Reagent (equiv) Solvent Temp (ꢁC) Time (h) Yielda (%)
Ratiob
1H and 13C NMR spectra were recorded on a JEOL AL-400
spectrometer or Bruker AVANCE 600 spectrometer. 1H and 13C
chemical shifts are reported in parts per million downfield from
28:28a
1
2
3
4
NaBH4 (10.0)
DIBAl-H (2.0)
L-Selectride (1.5) THF
K-Selectride (6.0) THF
MeOH
CH2Cl2 ꢀ78
0
0.5
0.5
quant
quant
92
quant
(at 72% conv)
quant
1:2
1:10
1:1
5:1
ꢀ78 to 0 1.5
tetramethylsilane (TMS,
d scale) with the solvent resonances as
ꢀ78 to 0 3.5
internal standards. The following abbreviations were used to ex-
plain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; band, several overlapping signals; br, broad. IR
spectra were recorded on a JASCO FT/IR-8300. Optical rotations
5
K-Selectride (5.0) CH2Cl2 ꢀ78 to 0 1.5
Isolated yields.
1:0
a
b
Ratio determined by 400 MHz 1H NMR.

S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
523
were measured using a 2 mL cell with a 1 dm path length on
a JASCO DIP-1000. Mass spectra and elemental analyses were
provided at the Materials Characterization Central Laboratory,
Waseda University. All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. All reactions were monitored
by thin-layer chromatography carried out on 0.25 mm E. Merck
silica gel plates (60F-254) using UV light as visualizing agent and
phosphomolybdic acid and heat as developing agents. E. Merck
silica gel (60, particle size 0.040e0.063 mm) was used for flash
chromatography. Preparative thin-layer chromatography (PTLC)
separations were carried out on self-made 0.3 mm E. Merck silica
gel plates (60F-254). THF and Et2O were distilled from sodium/
benzophenone ketyl. Toluene was distilled from sodium. MeOH
was distilled with a small amount of magnesium and I2. Benzene
and CH3CN were distilled from CaH2, and all other reagents were
purchased from commercial sources.
(780 mL) was added 16 (55.8 g, 0.23 mol) at 0 ꢁC and the reaction
mixture was stirred at this temperature for 1 h. The reaction was
quenched with saturated aqueous Na2SO4 and 2 N-HCl (100 mL),
and the aqueous layer was extracted with Et2O (100 mLꢂ2). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼1/1) to afford diol 16a (36.1 g, 93%) as
a
white solid; Rf 0.11 (hexane/ethyl acetate¼1/1); 1H NMR
(400 MHz, CDCl3)
d
6.01 (2H, ddd, J¼10.4, 3.4, 3.4 Hz), 5.52 (2H, ddd,
J¼10.4, 2.0, 2.0 Hz), 3.69 (2H, t, J¼6.6), 3.38 (2H, s), 2.72e2.68 (2H,
m), 1.61 (2H, t, J¼6.6 Hz); 13C NMR (100 MHz, CDCl3)
d 129.5, 126.8,
70.2, 59.5, 41.4, 39.8, 26.4; IR (KBr) nmax 3312, 2943, 2861, 1633,
1039, 1004 cmꢀ1; FAB HRMS [MþH]þ calcd for C9H15O2: 155.1072,
found: 155.1067; mp 72e75 ꢁC.
4.2.4. (1-(2-(tert-Butyldiphenylsilyloxy)ethyl)cyclohexa-2,5-dienyl)
methanol (16b). To a stirred solution of 16a (228 mg, 1.48 mmol) in
CH2Cl2 (15 mL) were added Et3N (0.41 mL, 2.96 mmol) and TBDPSCl
(3.8 mL, 1.48 mmol) at room temperature. Then the reaction mix-
ture was stirred at this temperature for 12 h. The reaction was
quenched with saturated aqueous NH4Cl (5 mL), and the aqueous
layer was extracted with CH2Cl2 (5 mLꢂ2). The combined organic
layer was dried over Na2SO4, filtered, and evaporated. The residue
was purified by flash column chromatography (hexane/ethyl
acetate¼20/1) to afford silyl ether 16b (534 mg, 92%) as a colorless
oil; Rf 0.44 (hexane/ethyl acetate t¼4/1); 1H NMR (400 MHz, CDCl3)
4.2. Cyclohexa-2,5-dienecarboxylic acid (A)
To a stirred solution of benzoic acid (30.0 g, 0.25 mol) and t-
BuOH (26.1 mL, 0.27 mol) in dry THF (65 mL) and liq. NH3 (120 mL)
at ꢀ78 ꢁC was added lithium (5.11 g, 0.74 mol) in small pieces. The
dark blue mixture was stirred at this temperature for 1 h. After the
reaction was completed, to the reaction mixture was added to solid
NH4Cl until the blue color was disappeared, and the resulting
mixture was slowly warmed to room temperature to remove NH3.
Then, H2O (500 mL) and 2 N-HCl were added and the aqueous layer
was extracted with Et2O (200 mLꢂ2) under acidic conditions (pH
2). The combined organic layer was dried over Na2SO4, filtered, and
evaporated. The crude carboxylic acid A was used for the next step
without further purification.
d
7.66e7.64 (4H, m), 7.44e7.35 (6H, m), 5.84 (2H, ddd, J¼10.4, 3.4,
3.4 Hz), 5.37 (2H, ddd, J¼10.4, 2.0, 2.0 Hz), 3.66 (2H, t, J¼7.1 Hz), 3.34
(2H, s), 2.68e2.46 (2H, m), 1.60 (2H, t, J¼7.1 Hz), 1.03 (9H, s); 13C
NMR (100 MHz, CDCl3)
d 135.6, 133.7, 129.6, 127.6, 127.0, 70.2, 60.8,
41.6, 40.0, 26.8, 26.5, 19.1; IR (neat) nmax 3409, 2956, 2858, 1589,
1111, 1086, 823, 739, 702 cmꢀ1; FAB HRMS [MþH]þ calcd for
C25H33O2Si: 393.2250, found: 393.2233.
4.2.1. Methyl cyclohexa-2,5-dienecarboxylate (B). To a stirred solu-
tion of crude A in benzene (818 mL) were added MeOH (38.9 mL,
0.98 mol) and H2SO4 (3.6 mL, 67.5 mmol), and the reaction mixture
was refluxed for 5.5 h. The reaction was quenched with saturated
aqueous Na2CO3 (20 mL), and the aqueous layer was extracted with
Et2O (200 mLꢂ2). The combined organic layer was dried over
Na2SO4, filtered, and evaporated. The residue was purified by short
column chromatography (hexane/ethyl acetate¼3/1) to afford ester
B, which was used for the next step without further purification.
4.2.5. 1-(2-(tert-Butyldiphenylsilyloxy)ethyl)cyclohexa-2,5-dien-
ecarbaldehyde (17). To a stirred solution of oxalyl chloride (18.5 mL,
0.212 mol) in CH2Cl2 (950 mL) was added DMSO (20.5 mL,
0.289 mol) at ꢀ78 ꢁC and the reaction solution was stirred at this
temperature for 15 min. Then, to the mixture was added a solution
of 16b (75.7 g, 0.193 mol) in CH2Cl2 (50 mL) via a cannula. After
stirred at ꢀ78 ꢁC for 15 min, Et3N (67.2 mL, 0.483 mol) was added at
this temperature and the mixture was stirred at room temperature
for 30 min. The resulting mixture was quenched with brine
(200 mL). The aqueous layer was extracted with CH2Cl2
(200 mLꢂ2). The combined organic layer was dried over Na2SO4,
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼20/1) to afford aldehyde 17
(69.9 g, 93%) as a colorless oil. Rf 0.51 (hexane/ethyl acetate¼4/1);
4.2.2. Methyl 1-(2-tert-Butoxy-2-oxoethyl)cyclohexa-2,5-dienecarbox-
ylate (16). To a stirred solution of DIPA (37.9 mL, 0.27 mol) in THF
(818 mL) was added n-BuLi (1.59 M in hexane, 170 mL, 0.27 mol) at
0 ꢁC and the solution was stirred at this temperature for 15 min. Then,
the solution was cooled to ꢀ78 ꢁC and a solution of crude B in THF
(20 mL) was added via a cannula. After the reaction mixture was
stirred at ꢀ78 ꢁC for 30 min, tert-butyl bromoacetate (36.3 mL,
0.25 mol) was added, and the mixture was stirred at this temperature
for 1 h. The reaction was quenched with saturated aqueous NH4Cl
(20 mL), and the aqueous layer was extracted with Et2O (200 mLꢂ2).
The combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatogra-
phy (hexane/ethyl acetate¼30/1) to afford diester 16 (56.4 g, 96%
(three steps)) as a colorless oil; Rf 0.36 (hexane/ethyl acetate¼10/1);
1H NMR (400 MHz, CDCl3)
d 9.33 (1H, s), 7.66e7.57 (4H, m),
7.44e7.36 (6H, m), 5.95 (2H, ddd, J¼10.5, 3.2, 3.2 Hz), 5.45 (2H, d,
J¼10.5 Hz), 3.67 (2H, t, J¼6.8 Hz), 2.72e2.60 (2H, m), 1.93 (2H, t,
J¼6.8 Hz), 1.02 (9H, 2); 13C NMR (100 MHz, CDCl3)
d 199.0, 135.6,
133.6, 129.6, 128.1, 127.6, 124.6, 60.3, 52.4, 37.8, 26.7, 26.5, 19.1; IR
(neat) nmax 2931, 2858, 2817, 2703, 1722, 1589, 1111, 823, 373,
702 cmꢀ1; FAB HRMS [MþH]þ calcd for C25H31O2Si: 391.2093,
found: 391.2093.
1H NMR (400 MHz, CDCl3)
(2H, ddd, J¼10.5, 2.0, 2.0 Hz), 3.72 (3H, s), 2.70e2.65 (2H, m), 2.65 (2H,
s), 1.42 (9H, s); 13C NMR (100 MHz, CDCl3)
174.0, 169.5, 126.5, 126.0,
d
5.90 (2H, ddd, J¼10.5, 3.3, 3.3 Hz), 5.80
4.2.6. (E)-Ethyl 3-(1-(2-(tert-Butyldiphenylsilyloxy)ethyl)cyclohexa-
2,5-dienyl)acrylate (17a). To a stirred suspension of t-BuOK (33.1 g,
0.251 mol) in THF (850 mL) were added ethyl dieth-
ylphosphnoacetate (56.8 mL, 0.286 mol) at ꢀ78 ꢁC, and then, 17
(69.9 g, 0.180 mol). After the addition, a cooling bath was removed
and the reaction mixture was stirred at room temperature for 1 h.
The reaction was quenched with saturated aqueous NH4Cl
(100 mL), and the aqueous layer was extracted with Et2O
(50 mLꢂ2). The combined organic layer was dried over Na2SO4,
d
80.8, 52.3, 45.9, 45.7, 27.9, 25.9; IR (neat) nmax 2979, 2952, 1732, 1637,
1153 cmꢀ1; FAB HRMS [MþH]þ calcd for C14H21O4: 253.1440, found:
253.1441.
4.2.3. 2-(1-(Hydroxymethyl)cyclohexa-2,5-dienyl)ethanol (16a). To
a stirred suspension of LiAlH4 (80%, 23.3 g, 0.49 mol) in Et2O

524
S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼50/1) to afford -un-
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼10/1) to afford diazo compound 18
(71.3 mg, 79%) as a pale yellow oil; Rf 0.49 (hexane/ethyl acetate¼4/
a,b
saturated ester 17a (74.6 mg, 91%) as a colorless oil; Rf 0.29 (hexane/
ethyl acetate¼30/1); 1H NMR (400 MHz, CDCl3)
d 7.65e7.63 (4H,
m), 7.43e7.26 (6H, m), 6.83 (1H, d, J¼15.9 Hz), 5.73 (2H, ddd, J¼10.2,
3.2, 3.2 Hz), 5.68 (1H, d, J¼15.9 Hz), 5.38 (2H, d, J¼10.2 Hz), 4.16 (2H,
q, J¼7.1 Hz), 3.65 (2H, t, J¼7.6 Hz), 2.56e2.51 (2H, m), 1.77 (2H, t,
J¼7.6 Hz), 1.27 (3H, t, J¼7.1 Hz) 1.02 (9H, s); 13C NMR (100 MHz,
1); 1H NMR (400 MHz, CDCl3)
d 7.95e7.93 (2H, m), 7.67e7.61 (5H,
m), 7.57e7.53 (2H, m), 7.42e7.33 (6H, m), 5.65 (2H, ddd, J¼10.2, 3.2,
3.2 Hz), 5.08 (2H, ddd, J¼10.2, 1.7, 1.7 Hz), 3.58 (2H, t, J¼7.4 Hz),
2.47e2.43 (2H, m), 2.37 (2H, t, J¼8.0 Hz), 1.59 (2H, t, J¼7.4 Hz), 1.53
CDCl3)
d
167.0, 154.1, 135.6, 133.8, 129.5, 128.8, 127.6, 125.0, 119.0,
(2H, t, J¼8.0 Hz), 1.01 (9H, s); 13C NMR (100 MHz, CDCl3)
d 188.8,
60.9, 42.7, 41.3, 26.8, 26.0, 19.0, 14.2; IR (neat) nmax 2931, 2858, 1716,
1644, 1589, 1110, 823, 741, 702 cmꢀ1; FAB HRMS [MþNa]þ calcd for
C29H36O3SiNa: 483.2331, found: 483.2334.
141.9, 135.5, 134.1, 134.0, 131.1, 129.5, 129.3, 127.5, 127.5, 125.5, 61.2,
44.5, 38.5, 35.3, 35.1, 26.8, 26.3,19.1; IR (neat) nmax 2931, 2856, 2106,
1666, 1589, 1344, 1155, 1111, 1086, 823, 756, 704 cmꢀ1; FAB HRMS
[MþH]þ calcd for C34H39O4N2SiS: 599.2400, found: 599.2375.
4.2.7. Ethyl 3-(1-(2-(tert-Butyldiphenylsilyloxy)ethyl)cyclohexa-2,5-
dienyl)propanoate (17b). To a stirred solution of 17a (250 mg,
0.545 mmol) in MeOH (6 mL) were added NiCl2$6H2O (19.4 mg,
0.0817 mmol) and NaBH4 (22.7 mg, 0.599 mmol) at 0 ꢁC succes-
sively, and stirred at this temperature for 15 min. The reaction was
quenched with saturated aqueous NH4Cl (5 mL), and the aqueous
layer was extracted with Et2O (5 mLꢂ2). The combined organic
layer was dried over Na2SO4, filtered, and evaporated. The residue
was purified by flash column chromatography (hexane/ethyl
acetate¼50/1) to afford saturated ester 17b (241.3 mg, 96%) as
a colorless oil; Rf 0.29 (hexane/ethyl acetate¼30/1); 1H NMR
4.2.10. (1R,5S,6S,7R)-1-(2-(tert-Butyldiphenylsilyloxy)ethyl)-7-phe-
nylsulfonyltricyclo[4.4.0.05,7]dec-2-ene-8-one (12). To a stirred so-
lution of toluene azeotroped [CuOTf]2PhMe (813 mg, 0.0945 mmol)
in toluene (315 mL) was added a solution of toluene azeotroped
ligand 6a (1.23 g, 0.284 mmol) in toluene (5 mL) via a cannula, and
the mixture was stirred at room temperature for 30 min. Then, to
the solution was added toluene azeotroped 18 (18.9 g, 31.6 mmol)
in toluene (5 mL) via a cannula, and the reaction mixture was
stirred at this temperature for 11 h. The reaction was quenched
with NH4OH (3 mL) and H2O (50 mL), and the aqueous layer was
extracted with Et2O (20 mLꢂ2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash column chromatography (hexane/ethyl acetate¼20/1)
to afford 12 (12.9 g, 72%, 95% ee) as a colorless oil; Rf 0.38 (hexane/
(400 MHz, CDCl3) d 7.65e7.63 (4H, m), 7.42e7.24 (6H, m), 5.67 (2H,
ddd, J¼10.4, 3.4, 3.4 Hz), 5.17 (2H, ddd, J¼10.4, 2.0, 2.0 Hz), 4.07 (2H,
q, J¼7.1 Hz), 3.61 (2H, t, J¼7.6 Hz), 2.46e2.45 (2H, m), 2.15 (2H, t,
J¼8.2 Hz), 1.64 (2H, t, J¼7.6 Hz), 1.59 (2H, t, J¼8.2 Hz), 1.21 (3H, t,
J¼7.1 Hz), 1.02 (9H, s); 13C NMR (100 MHz, CDCl3)
d
174.3, 135.6,
ethyl acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d 7.81e7.79 (2H, m),
134.1, 129.4, 127.5, 125.4, 61.3, 60.1, 44.5, 38.5, 36.7, 30.1, 26.8, 26.3,
19.1, 14.2; IR (neat) nmax 2931, 3858, 1736, 1589, 1113, 1086, 823, 737,
702 cmꢀ1; FAB HRMS [MþH]þ calcd for C29H39O3Si: 463.2668,
found: 463.2660.
7.68e7.62 (5H, m), 7.55e7.51 (2H, m), 7.45e7.39 (6H, m), 5.50 (1H,
ddd, J¼10.4, 3.4, 3.4 Hz), 5.05 (1H, d, J¼10.4 Hz), 3.83e3.69 (2H, m),
2.62 (1H, d, J¼9.8 Hz), 2.28e2.11 (3H, m), 2.07e1.98 (3H, m),
1.95e1.90 (1H, m), 1.82e1.76 (1H, m), 1.57e1.52 (1H, m), 1.07 (9H,
s); 13C NMR (100 MHz, CDCl3)
d 201.4, 139.4, 135.6, 135.5, 133.7,
4.2.8. 4-(1-(2-(tert-Butyldiphenylsilyloxy)ethyl)cyclohexa-2,5-di-
enyl)-1-(phenylsulfonyl)butan-2-one (17c). To a stirred solution of
methyl phenyl sulfone (38.4 mg, 0.247 mmol) in THF (2 mL) was
added n-BuLi (1.66 M in hexane, 0.296 mL, 0.494 mmol) at 0 ꢁC and
the solution was stirred at this temperature for 1 h. Then, to the
reaction mixture was added a solution of 17b (104 mg, 0.225 mmol)
in THF (1 mL) via a cannula and the mixture was stirred at this
temperature for 30 min. The reaction was quenched with saturated
aqueous NH4Cl (5 mL), and the aqueous layer was extracted with
Et2O (5 mLꢂ2). The combined organic layer was dried over Na2SO4,
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼4/1) to afford saturated
ester 17c (121 mg, 95%) as a colorless oil; Rf 0.26 (hexane/ethyl
130.3, 129.7, 128.9, 128.8, 127.7, 127.7, 125.6, 60.8, 47.9, 44.1, 36.4,
35.9, 31.7, 28.4, 26.8, 22.5, 19.2, 19.1; IR (neat) nmax 2929, 2858, 1707,
1589, 1307, 1149, 1113, 1088, 822, 756, 704 cmꢀ1; FAB HRMS
[MþNa]þ calcd for C34H38O4SiSNa: 593.2158, found: 593.2166;
25
[a
]
þ71.3 (c 0.83, CHCl3); Daicel CHIRALCEL OD-H 0.46 ꢂ25 cm,
4
D
hexane/isopropanol¼9/1, flow rate¼0.4 mL/min, retention time:
18.6 min for the minor, 22.2 min for the major.
4.2.11. (1R,4aS,8R,8aR)-4,4a,8,8a-Tetrahydro-4a-(2-(tert-butyldiphe-
nylsiloxy)ethyl)-1-(phenylsulfonyl)-8-(phenylthio)naphthalen-2
(1H,3H,7H)-one (19). To a stirred solution of PhSH (7.17 mL,
69.5 mmol) in THF (210 mL) was added n-BuLi (1.59 M in hexane,
42.3 mL, 67.3 mmol) at 0 ꢁC, and the mixture was stirred at this
temperature for 10 min. To the mixture was added a solution of 12
(12.8 g, 22.4 mmol) in THF (10 mL) at 0 ꢁC via a cannula, the reaction
mixture was refluxed for 9 h. The reaction was quenched with
saturated aqueous NH4Cl (30 mL) and the aqueous layer was
extracted with Et2O (20 mLꢂ2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash column chromatography (hexane/ethyl acetate¼20/1)
to afford 19 (14.7 g, 96%) as a colorless oil; Rf 0.57 (benzene/ethyl
acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d 7.87e7.85 (2H, m),
7.69e7.62 (5H, m), 7.58e7.54 (2H, m), 7.43e7.34 (6H, m), 5.68 (2H,
ddd, J¼10.2, 3.2, 3.2 Hz), 5.11 (2H, d, J¼10.2 Hz), 4.09 (2H, s), 3.59
(2H, t, J¼7.1 Hz), 2.50 (2H, t, J¼7.8 Hz), 2.50e2.45 (2H, m), 1.61 (2H,
t, J¼7.8 Hz), 1.52 (2H, t, J¼7.1 Hz), 1.01 (9H, s); 13C NMR (100 MHz,
CDCl3)
d 198.7, 138.8, 135.6, 134.2, 134.0, 131.1, 129.5, 129.3, 128.3,
127.5, 125.6, 66.9, 61.3, 44,5, 40.4, 38.4, 34.9, 26.8, 19.1; IR (neat)
nmax 2931, 2856, 1720, 1587, 1524, 1155, 1111, 1085, 823, 742,
704 cmꢀ1; FAB HRMS [MþNa]þ calcd for C34H40O4SiSNa: 595.2314,
found: 595.2291.
acetate¼40/1); 1H NMR (600 MHz, CDCl3)
d 7.90e7.86 (2H, m),
7.73e7.69 (3H, m), 7.67e7.64 (1H, m), 7.57e7.53 (2H, m), 7.44e7.36
(6H, m), 7.33e7.29 (2H, m), 7.29e7.22 (4H, m), 5.56 (1H, ddd,
J¼10.2, 5.1, 2.6 Hz), 5.47 (1H, d, J¼10.2 Hz), 4.93 (1H, s), 3.95 (1H,
ddd, J¼10.5, 6.4, 6.4 Hz), 3.82 (1H, ddd, J¼10.8, 6.4, 6.4 Hz), 3.14 (1H,
d, J¼10.8 Hz), 2.96 (1H, ddd, J¼10.8, 9.7, 5.1 Hz), 2.85 (1H, ddd,
J¼16.4, 10.5, 5.6 Hz), 2.48 (1H, ddd, J¼14.3, 6.4, 6.4 Hz), 2.39 (1H,
ddd, J¼17.7, 5.1, 5.1 Hz), 2.28 (1H, ddd, J¼16.4, 5.8, 4.1 Hz), 2.22e2.15
(3H, m), 1.76 (1H, ddd, J¼14.6, 10.5, 4.1 Hz), 1.06 (9H, s); 13C NMR
4.2.9. 4-(1-(2-(tert-Butyldiphenylsilyloxy)ethyl)cyclohexa-2,5-di-
ethyl)-1-diazo-1-phenylsulfonylbutan-2-one (18). To a stirred solu-
tion of 17c (85.9 mg, 0.150 mmol) in CH3CN (1.5 mL) were added
Et3N (0.0818 mL, 0.300 mmol) and TsN3 (45.6 mg, 0.450 mmol)
successively at 0 ꢁC, and the reaction mixture was stirred at this
temperature over night. After the reaction was completed, CH3CN
was evaporated. Then, to the residue was added 2N-KOH (10 mL)
and the aqueous layer was extracted with Et2O (5 mLꢂ2). The
(150 MHz, CDCl3)
d 202.2, 146.8, 139.8, 135.7, 134.4, 133.9, 133.7,
133.6, 133.0, 129.5, 129.2, 129.1, 128.5, 127.8, 127.7, 127.6, 124.1, 74.7,

S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
525
60.3, 49.1, 43.4, 41.0, 37.4, 36.3, 33.3, 32.1, 26.8, 19.1; IR (neat) nmax
acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d
7.79e7.74 (2H, m),
2929, 2856, 1712, 1585, 1309, 1147, 1111, 823, 754, 704 cmꢀ1; FAB
7.61e7.55 (4H, m), 7.46e7.31 (11H, m), 7.30e7.19 (3H, m), 7.10 (1H,
dd, J¼5.4, 2.7 Hz), 5.59 (1H, ddd, J¼10.2, 3.7, 3.7 Hz), 5.37 (1H, d,
J¼10.2 Hz), 3.77 (1H, ddd, J¼7.0, 7.0, 7.0 Hz), 3.56e3.44 (2H, m), 2.87
(1H, d, J¼7.0), 2.29e2.17 (3H, m), 2.07e1.98 (1H, m), 1.65e1.53 (3H,
m), 1.40e1.34 (1H, m), 1.00 (9H, s); 13C NMR (100 MHz, CDCl3)
HRMS [MþNa]þ calcd for C40H44O4SiS2Na: 703.2348, found:
28
703.2354; [
a]
ꢀ17.7 (c 0.52, CHCl3).
D
4.2.12. (1R,4aS,8R,8aR)-1,2,3,4,4a,7,8,8a-Octahydro-4a-(2-(tert-bu-
tyldiphenylsiloxy)ethyl)-1-(phenylsulfonyl)-8-(phenylthio)naph-
thalen-2-ol (19a). To a stirred solution of 19 (13.9 g, 20.4 mmol) in
THF/MeOH (1/2) (210 mL) was added NaBH4 (42.3 mL, 67.3 mmol)
at 0 ꢁC, and the reaction mixture was stirred at this temperature for
30 min. The reaction was quenched with saturated aqueous NH4Cl
(30 mL) and the aqueous layer was extracted with Et2O (20 mLꢂ2).
The combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼2/1) to afford 19a (13.9 g, 100%) as
a colorless oil; Rf 0.21 (hexane/ethyl acetate¼4/1); 1H NMR
d
143.6, 143.4, 141.4, 136.3, 135.5, 135.5, 134.0, 133.7, 133.6, 132.9,
131.8, 129.6, 129.0, 128.8, 127.7, 127.6, 126.8, 124.9, 59.9, 47.0, 42.3,
40.6, 38.8, 31.5, 30.4, 26.8, 23.3,19.1; IR (neat) nmax 2931, 2858,1633,
1585, 1305, 1147, 1111, 823, 756, 704 cmꢀ1; FAB HRMS [MþNa]þ
31
calculated for C40H44O3SiS2Na: 687.2399, found: 687.2380; [
a]
D
ꢀ77.8 (c 1.4, CHCl3).
4.2.15. 2-((1R,4aS,8aR)-1,2,4a,5,6,8a-Hexahydro-8-(phenylsulfonyl)-
1-(phenylthio)naphthalen-4a-yl)ethanol (11a). To a stirred solution
of 11 (469 mg, 0.705 mmol) in THF (7 mL) was added HF$Py
(0.240 mL, 14.1 mmol) at room temperature, and the reaction
mixture was stirred at the same temperature for 12 h. The reaction
was quenched with saturated aqueous NaHCO3 (2 mL) at 0 ꢁC and
the aqueous layer was extracted with Et2O (5 mLꢂ2). The combined
organic layer was dried over Na2SO4, filtered, and evaporated. The
residue was purified by flash column chromatography (hexane/
ethyl acetate¼10/1) to afford 11a (263 mg, 87%) as a colorless oil; Rf
0.17 (hexane/ethyl acetate¼1/1); 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3) d 7.97e7.90 (2H, m), 7.75e7.67 (4H, m), 7.62e7.56
(1H, m), 7.55e7.47 (2H, m), 7.45e7.32 (8H, m), 7.30e7.22 (3H, m),
5.50 (1H, ddd, J¼10.2, 4.3, 2.9 Hz), 5.43 (1H, d, J¼10.2 Hz), 4.33 (1H,
br), 3.93 (1H, ddd, J¼10.2, 6.6, 6.6 Hz), 3.88e3.78 (2H, m), 3.74e3.66
(1H, m), 2.93 (1H, dd, J¼8.2, 5.2 Hz), 2.50e2.34 (3H, m), 2.23 (1H,
dddd, J¼18.3, 7.3, 2.4, 2.4 Hz), 2.11e1.95 (2H, m), 1.88e1.80 (1H, m),
1.60e1.58 (1H, m), 1.44e1.34 (1H, m), 1.04 (9H, s); 13C NMR
(100 MHz, CDCl3)
d 142.6, 135.7, 135.5, 134.1, 133.2, 131.9, 129.4,
129.1, 129.0, 127.8, 127.6, 127.5, 127.3, 123.0, 67.3, 67.1, 60.5, 45.3,
42.2, 42.0, 38.4, 32.7, 32.2, 28.0, 26.9, 19.1; IR (neat) nmax 3513, 2929,
2858, 1585, 1304, 1140, 1082, 823, 754, 704 cmꢀ1; FAB HRMS
d 7.86e7.82 (2H, m), 7.59e7.54 (1H, m), 7.50e7.44 (2H, m),
7.43e7.38 (2H, m), 7.31e7.20 (3H, m), 7.14 (1H, dd, J¼5.0, 2.8 Hz),
5.67 (1H, ddd, J¼10.0, 3.7, 3.7 Hz), 5.44 (1H, d, J¼10.0 Hz), 3.75 (1H,
ddd, J¼7.0, 7.0, 7.0 Hz), 3.54e3.42 (2H, m), 3.02 (1H, d, J¼7.0),
2.40e2.17 (4H, m), 1.70e1.62 (1H, m), 1.60e1.53 (2H, m), 1.46e1.30
[MþNa]þ calcd for C40H46O4SiS2Na: 705.2505, found: 705.2514;
28
[
a]
þ11.7 (c 0.60, CHCl3).
D
(2H, m); 13C NMR (100 MHz, CDCl3)
d 143.4, 143.3, 141.1, 136.1, 134.2,
4.2.13. (1R,4aS,8R,8aR)-1,2,3,4,4a,7,8,8a-Octahydro-4a-(2-(tert-bu-
tyldiphenylsiloxy)ethyl)-1-(phenylsulfonyl)-8-(phenylthio)naph-
thalen-2-ylmethanesulfonate (19b). To a stirred solution of 19a
(14.5 g, 21.3 mmol) in 1,2-dichloro ethane (210 mL) were added
Et3N (14.8 mL, 0.107 mol) and MsCl (2.50 mL, 32.0 mmol), and the
reaction mixture was stirred at 50 ꢁC for 17 h. The reaction was
quenched with saturated aqueous NH4Cl (30 mL) and the aqueous
layer was extracted with CH2Cl2 (20 mLꢂ2). The combined organic
layer was dried over Na2SO4, filtered, and evaporated. The residue
was purified by flash column chromatography (hexane/ethyl
acetate¼20/1) to afford 19b (15.8 g, 98%) as a colorless oil; Rf 0.21
133.0, 131.6, 129.0, 128.9, 128.0, 126.8, 125.4, 58.9, 47.0, 41.3, 40.8,
39.0, 31.7, 31.3, 23.3; IR (neat) nmax 3749, 2933, 2889, 1635, 1583,
1304, 1146, 1089, 752, 690 cmꢀ1; FAB HRMS [MþH]þ calcd for
C24H27O3S2: 427.1402, found: 427.1418; [
a
]
D
33 þ115.2 (c 0.98, CHCl3).
4.2.16. 2-((1R,4aS,8aR)-1,2,4a,5,6,8a-Hexahydro-8-(phenylsulfonyl)-
1-(phenylthio)naphthalen-4a-yl)acetaldehyde (15). To a stirred so-
lution of oxalyl chloride (0.0579 mL, 0.665 mmol) in CH2Cl2 (5 mL)
was added DMSO (0.129 mL, 1.82 mmol) at ꢀ78 ꢁC and the reaction
solution was stirred at this temperature for 15 min. Then, to the
mixture was added a solution of 11a (258 mg, 0.605 mmol) in
CH2Cl2 (2 mL) via a cannula. After stirred at ꢀ78 ꢁC for 15 min, Et3N
(0.153 mL, 1.51 mmol) was added at the same temperature and the
mixture was stirred at room temperature for 30 min. The resulting
mixture was quenched with saturated aqueous brine (5 mL). The
aqueous layer was extracted with CH2Cl2 (5 mLꢂ2). The combined
organic layer was dried over Na2SO4, filtered, and evaporated. The
residue was purified by flash column chromatography (hexane/
ethyl acetate¼10/1) to afford aldehyde 15 (224 mg, 88%) as a whte
solid; Rf 0.60 (hexane/ethyl acetate¼1/1); 1H NMR (400 MHz,
(hexane/ethyl acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d 7.96e7.91
(2H, m), 7.72e7.65 (4H, m), 7.63e7.57 (1H, m), 7.54e7.44 (2H, m),
7.44e7.23 (11H, m), 5.47e5.40 (2H, m), 3.95 (1H, ddd, J¼10.2, 6.5,
6.5 Hz), 3.78 (1H, J¼10.2, 6.6, 6.6 Hz), 3.40e3.32 (1H, m), 3.06 (1H,
dd, J¼9.6, 3.0 Hz), 2.72e2.60 (1H, m), 2.54e2.44 (1H, m), 2.36 (3H,
s), 2.25e2.10 (2H, m), 2.05e1.95 (1H, m), 1.92e1.83 (1H, m),
1.74e1.70 (1H, m), 1.60e1.50 (2H, m), 1.04 (9H, s); 13C NMR
(100 MHz, CDCl3)
d 143.2, 135.6, 135.2, 133.9, 133.8, 133.6, 133.2,
132.6, 129.4, 129.4, 129.1, 128.1, 127.8, 127.6, 127.5, 122.8, 64.4, 60.4,
60.3, 60.1, 45.8, 43.0, 38.0, 37.9, 26.8, 25.8, 21.0, 19.1, 14.2; IR (neat)
nmax 29,931, 2856, 1583, 1308, 1145, 1111, 823, 754, 704 cmꢀ1; FAB
CDCl3)
d
9.49 (1H, t, J¼2.0 Hz) 7.76e7.71 (2H, m), 7.60e7.54 (1H, m),
7.50e7.42 (4H, m), 7.37e7.25 (3H, m), 7.22 (1H, dd, J¼6.2, 2.6 Hz),
5.81 (1H, ddd, J¼10.2, 3.9, 3.9 Hz), 5.44 (1H, d, J¼10.2 Hz), 4.09 (1H,
ddd, J¼5.3, 5.3, 5.3 Hz), 3.12 (1H, d, J¼5.3 Hz), 2.71 (1H, dd, J¼16.6,
2.0 Hz), 2.54 (1H, dd, J¼16.6, 2.0 Hz), 2.39e2.30 (2H, m), 2.26e2.12
HRMS [MꢀH]þ calcd for C41H47O6SiS3: 759.2304, found: 759.2328;
32
[
a]
ꢀ9.6 (c 2.1, CHCl3).
D
4.2.14. (2-((1R,4aS,8aR)-1,2,4a,5,6,8a-Hexahydro-8-(phenyl-
sulfonyl)-1-(phenylthio)naphthalen-4a-yl)ethoxy)(tert-butyl)diphe-
nylsilane (11). To a stirred solution of 19b (141 mg, 0.186 mmol) in
THF (2 mL) was added slowly a solution of t-BuOK (1.0 M in THF,
0.186 mL, 0.186 mmol) at ꢀ78 ꢁC, and the reaction mixture was
stirred at this temperature for 30 min. The reaction was quenched
with saturated aqueous NH4Cl (2 mL) and the aqueous layer was
extracted with CH2Cl2 (5 mLꢂ2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash column chromatography (hexane/ethyl acetate¼20/1)
to afford 11 (113.4 mg, 92%) as a colorless oil; Rf 0.42 (hexane/ethyl
(2H, m), 1.66e1.52 (2H, m); 13C NMR (100 MHz, CDCl3)
d 200.9,
143.8, 142.7, 140.5, 135.4, 133.2, 131.8, 129.1, 129.0, 127.8, 127.1, 126.6,
52.2, 45.6, 41.4, 38.3, 31.7, 29.4, 22.9; IR (KBr) nmax 2915, 2896, 2838,
1739, 1716, 1633, 1586, 1304, 1146, 739, 687 cmꢀ1; FAB HRMS
[MþH]þ calcd for C24H25O3S2: 425.1245, found: 425.1251; mp
109e110 ꢁC; [
a
]
D
33 þ119.5 (c 0.99, CHCl3).
4.2.17. (1S,6R,8R)-7-(Phenylsulfonyl)-5-(phenylthio)tricyclo
[6.2.2.01,6]dodec-2-en-9-ol (14). To
solution of 15 (4.68 g,
a
11.0 mmol) and MeOH (0.84 mL, 22.0 mmol) in degassed THF
(1100 mL) was added a THF solution of SmI2 (prepared with Sm

526
S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
(11.6 g, 77.3 mmol) and 1,2-diiodoethane (10.5 g, 38.5 mmol)) in
degassed THF (350 mL) at 0 ꢁC until the color of the mixture turned
to blue. Then, the reaction mixture was stirred at 0 ꢁC for 1 h. The
reaction was quenched with saturated aqueous NH4Cl (200 mL) and
the aqueous layer was extracted with Et2O (200 mLꢂ2). The com-
bined organic layer was dried over Na2SO4, filtered, and evaporated.
The residue was purified by flash column chromatography (hexane/
ethyl acetate¼5/1) to afford 14 (4.48 g, 95%) as a white solid; Rf 0.48
stirred at ꢀ20 ꢁC for 2 h. The reaction was quenched with saturated
aqueous NH4Cl (5 mL) and the aqueous layer was extracted with
Et2O (5 mLꢂ2). The combined organic layer was dried over Na2SO4,
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼100/1) to afford silyl ether
13 (11.9 mg, 69%) as a white solid and bis silyl ether 130 (4.74 mg,
20%). Bis silyl ether 130 was converted to 21 (TBAF, THF, 84%) and
reused; Rf 0.40 (hexane/ethyl acetate¼4/1); 1H NMR (400 MHz,
(hexane/ethyl acetate¼1/1); 1H NMR (400 MHz, CDCl3)
d
7.82e7.76
CDCl3)
d
5.57 (1H, ddd, J¼9.8, 4.9, 1.0 Hz), 5.36 (1H, d, J¼9.8 Hz),
(2H, m), 7.45e7.39 (1H, m), 7.33e7.15 (7H, m), 5.53 (1H, ddd, J¼9.8,
5.1, 2.9 Hz), 5.29 (1H, d, J¼9.8 Hz), 4.48 (1H, ddd, J¼9.5, 3.8, 1.0 Hz),
4.24 (1H, ddd, J¼11.7, 8.8, 6.1 Hz), 4.18 (1H, dd, J¼8.5, 5.1 Hz),
2.68e2.65 (1H, m), 2.55e2.42 (3H, m), 2.19e2.07 (2H, m), 1.91 (2H,
dd, J¼13.9, 8.5 Hz), 1.79 (1H, br), 1.36e1.22 (3H, m); 13C NMR
4.10e4.08 (1H, m), 4.02 (1H, dd, J¼9.0, 4.1 Hz), 2.16e2.01 (2H, m),
1.88 (1H, dd, J¼13.9, 9.0 Hz), 1.78e1.73 (1H, m), 1.63e1.50 (4H, m),
1.45e1.30 (2H, m), 1.27e1.21 (1H, m), 1.09e1.01 (1H, m), 0.89 (9H,
s), 0.06 (3H, s), 0.05 (3H, s); 13C NMR (100 MHz, CDCl3)
d 137.3,
127.6, 69.8, 64.6, 44.7, 36.0, 33.0, 31.6, 29.2, 27.4, 26.0, 24.3, 24.1,
(100 MHz, CDCl3)
d
144.6, 134.5, 133.4, 132.2, 130.5, 128.7, 128.3,
18.3, ꢀ4.4, ꢀ4.6; IR (KBr) nmax 3301, 2936, 2857, 1648, 1471, 1250,
126.3, 126.2, 123.3, 68.5, 61.4, 44.8, 44.6, 39.1, 35.1, 33.3, 26.5, 20.1;
IR (KBr) nmax 3465, 2918, 2876, 1735, 1583, 1300, 1283, 1136, 728,
688 cmꢀ1; FAB HRMS [M]þ calcd for C24H26O3S2: 426.1323, found:
1051, 1032, 833 cmꢀ1; FAB HRMS [MþH]þ calcd for C18H31O2Si:
25
307.2093, found: 307.2096; mp 108e111 ꢁC; [
CHCl3).
a
]
ꢀ159.5 (c 0.39,
D
426.1338; mp 61e65 ꢁC; [
a
]
34 ꢀ26.5 (c 0.99, CHCl3).
D
4.2.21. (1R,6S,8S)-4-(tert-Butyldimethylsiloxy)tricyclo[6.2.2.01,6]do-
dec-2-en-9-one (13a). To stirred solution of 13 (510 mg,
4.2.18. (1R,6R,8S)-Tricyclo[6.2.2.01,6]dodec-2-en-9-ol (20). To a stir-
red solution of 14 (191.3 mg, 0.448 mmol) in THF (4.5 mL) was
added a solution of lithium napthalenide (prepared with Li dis-
persion (30%) (311 mg, 13.5 mmol) and naphthalene (1.72 g,
13.5 mmol) in THF (30 mL)) at ꢀ78 ꢁC until the color of the mixture
turned to dark green. After stirred at ꢀ78 ꢁC for 1 h, the reaction
mixture was stirred at ꢀ20 ꢁC for 1 h. The reaction was quenched
with saturated aqueous NH4Cl (10 mL) and the aqueous layer was
extracted with Et2O (5 mLꢂ2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash column chromatography (hexane/ethyl acetate¼100/
1) to afford 20 (55.1 mg, 69%) as a white solid; Rf 0.48 (hexane/ethyl
a
1.65 mmol) in CH2Cl2 (20 mL) was added DesseMartin periodinane
(3.51 g, 8.27 mmol) and the mixture was stirred at room temper-
ature for 30 min. The reaction was quenched with saturated
aqueous NaHCO3 (5 mL) and saturated aqueous Na2S2O3 (5 mL). The
aqueous layer was extracted with Et2O (5 mLꢂ2). The combined
organic layer was dried over Na2SO4, filtered, and evaporated. The
residue was purified by flash column chromatography (hexane/
ethyl acetate¼1/1) to afford 13a (482 mg, 95%) as a colorless oil; Rf
0.67 (hexane/ethyl acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d 5.56
(1H, dd, J¼10.0, 4.9 Hz), 5.47 (1H, d, J¼10.0 Hz), 4.18e4.14 (1H, m),
2.32e2.25 (2H, m), 2.12e1.96 (3H, m), 1.80e1.61 (5H, m), 1.46e1.37
(1H, m),1.28e1.21 (1H, m), 0.88 (9H, s), 0.07 (3H, s), 0.06 (3H, s); 13C
acetate¼1/1); 1H NMR (600 MHz, CDCl3)
d
5.56 (1H, ddd, J¼10.0,
2.8, 1.5 Hz), 5.24 (1H, ddd, J¼10.0, 2.3, 2.3 Hz), 4.02 (1H, dd, J¼10.0,
9.0, 4.4 Hz), 2.13e2.08 (1H, m), 2.05e1.94 (2H, m), 1.88 (1H, dd,
J¼14.0, 8.8 Hz),1.75e1.69 (2H, m), 1.62e1.56 (2H, m), 1.53e1.48 (1H,
m), 1.45e1.40 (1H, m), 1.36e1.31 (1H, m), 1.18e1.15 (1H, m), 1.09
(1H, dddd, J¼13.1, 11.3, 2.0, 2.0 Hz), 0.92 (1H, dd, J¼13.7, 8.7 Hz); 13C
NMR (100 MHz, CDCl3) d 216.4, 135.2, 128.3, 64.5, 50.0, 43.0, 36.3,
35.5, 31.1, 30.5, 25.9, 24.3, 24.0, 18.2, ꢀ4.4, ꢀ4.7; IR (neat) nmax 2951,
2858, 1728, 1471, 1254, 1254, 1055, 835 cmꢀ1; FAB HRMS [MꢀH]þ
calcd for C18H29O2Si: 305.1937, found: 305.1939; [
CHCl3).
a
]
D
26 ꢀ114.6 (c 1.1,
NMR (150 MHz, CDCl3)
d 134.7, 125.9, 70.2, 45.1, 35.3, 32.7, 31.6,
27.8, 26.2, 26.1, 25.7, 24.3; IR (KBr) nmax 3314, 2917, 2858, 1646, 103,
4.2.22. (1R,8S)-4-(tert-Butyldimethylsiloxy)-9-methylidenetricyclo
[6.2.2.01,6]dodec-2-ene(22). To a stirred solution of toluene azeo-
troped methyl triphenylphosphomiumbromide (2.02 g, 5.65 mmol)
in THF (12 mL) was added n-BuLi (1.66 M in hexane, 3.07 mL,
5.09 mmol) at 0 ꢁC and the mixture was stirred at this temperature
for 10 min. Then, a toluene azeotroped 13a (347 mg,1.13 mmol) was
added at 0 ꢁC, and the reaction mixture was stirred at 50 ꢁC for 1.5 h.
The reaction was quenched with saturated aqueous NH4Cl (5 mL)
and the aqueous layer was extracted with Et2O (5 mLꢂ2). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by short column chroma-
tography (hexane only) to afford crude silyl ether 22 and this was
used for the next step without further purification.
700 cmꢀ1; FAB HRMS [MꢀOH]þ calcd for C12H17: 161.1330, found:
34
161.1323; mp 65e67 ꢁC; [
a
]
ꢀ171.0 (c 0.49, CHCl3).
D
4.2.19. (1R,6S,8S)-Tricyclo[6.2.2.01,6]dodec-2-ene-4,9-diol
(21). To
a stirred solution of 20 (42.1 mg, 23.6 mmol) in 1,4-dioxane (3 mL)
was added SeO2 (78.6 mg, 70.8 mmol). The mixture was refluxed
for 1.5 h. The reaction was quenched with saturated aqueous
NaHCO3 (5 mL) and the aqueous layer was extracted with Et2O
(5 mLꢂ2). The combined organic layer was dried over Na2SO4, fil-
tered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼1/1) to afford 21 (45.8 mg,
100%) as a colorless oil; Rf 0.16 (hexane/ethyl acetate¼1/1); 1H NMR
(400 MHz, CDCl3)
d
5.73 (1H, ddd, J¼9.8, 4.9, 1.5 Hz), 5.46 (1H, d,
J¼9.8 Hz), 4.09 (1H, ddd, J¼4.9, 4.9, 1.5 Hz), 4.04 (1H, dd, J¼9.0,
4.3 Hz), 2.19e2.12 (1H, m), 2.03e1.95 (1H, m), 1.90 (1H, dd, J¼13.9,
9.0 Hz), 1.81e1.73 (2H, m), 1.64 (1H, dd, J¼13.9, 4.4 Hz), 1.48e1.30
(3H, m), 1.25e1.19 (1H, m), 1.12e1.04 (1H, m), 0.96e0.89 (1H, m);
4.2.23. (1R,6S,8S)-9-Methylidenetricyclo[6.2.2.01,6]dodec-2-en-4-ol
(22a). To a stirred solution of crude 22 in THF (12 mL) was added
TBAF (1.0 M in THF, 9.04 mL, 9.04 mmol), and the solution was
stirred at 60 ꢁC for 1 h. The reaction was quenched with saturated
aqueous NH4Cl (5 mL), and the aqueous layer was extracted with
Et2O (5 mLꢂ2). The combined organic layer was dried over Na2SO4,
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼20/1) to afford 22a
(205 mg, 95% (two steps)) as a colorless oil; Rf 0.41 (hexane/ethyl
13C NMR (100 MHz, CDCl3)
d 139.1, 126.7, 69.6, 64.3, 44.4, 35.1, 33.2,
31.5, 29.3, 27.3, 24.1, 23.9; IR (neat) nmax 3400, 2933, 2861, 1647,
1441, 1024, 756 cmꢀ1; FAB HRMS [MꢀOH]þ calcd for C12H17O:
177.1279, found: 177.1285; [
a]
24 ꢀ178.8 (c 0.62, CHCl3).
D
4.2.20. (1R,6S,8S)-4-(tert-Butyldimethylsiloxy)tricyclo[6.2.2.01,6]do-
dec-2-ene-9-ol (13). To stirred solution of 21 (10.9 mg,
acetate¼4/1); 1H NMR (400 MHz, CDCl3)
5.73 (1H, ddd, J¼9.8, 4.9,
d
a
1.2 Hz), 5.54 (1H, d, J¼9.8 Hz), 4.78 (1H, d, J¼2.4 Hz), 4.63 (1H, d,
J¼2.4 Hz), 4.13e4.12 (1H, m), 2.30 (1H, dt, J¼16.3, 2.7 Hz), 2.23 (1H,
br), 2.07e2.02 (1H, m), 1.94e1.87 (1H, m), 1.85e1.73 (2H, m), 1.67
0.0561 mmol) in DMF (1 mL) were added imidazole (11.5 mg,
0.168 mmol) and TBSCl (33.9 mg, 0.225 mmol), and the mixture was

S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
527
(1H, dd, J¼13.4, 4.1 Hz), 1.64e1.49 (3H, m), 1.32e1.25 (1H, m), 1.11
mixture was quenched with a mixture of saturated aqueous
NaHCO3 (5 mL) and saturated aqueous Na2S2O3 (5 mL). The aqueous
layer was extracted with Et2O (10 mLꢂ2). The combined organic
layer was dried over Na2SO4, filtered, and evaporated. The residue
was purified by flash column chromatography (hexane/ethyl
acetate¼10/1) to afford ketone 25 (53.7 mg, 82%) as a colorless oil;
Rf¼0.52 (hexane/ethyl acetate¼4/1); 1H NMR (400 MHz, CDCl3)
(1H, ddd, J¼12.2, 8.0, 1.0 Hz); 13C NMR (100 MHz, CDCl3)
d 151.1,
139.3, 126.5, 105.8, 64.4, 41.6, 35.9, 34.9, 34.7, 34.5, 30.6, 26.7, 25.3;
IR (neat) nmax 3324, 2933, 2862, 1646, 1429, 1167, 1045, 1001, 875,
756 cmꢀ1; FAB HRMS [MꢀH]þ calcd for C13H17O: 189.1279, found:
27
189.1278; [
a
]
ꢀ163.2 (c 1.1, CHCl3).
D
4.2.24. (1R,6S,8S)-9-Methylidenetricyclo[6.2.2.01,6]dodec-2-en-4-one
(4). To a stirred solution of 22a (20.3 mg, 0.107 mmol) in CH2Cl2
(1 mL) were added NaHCO3 (86.0 mg, 1.07 mmol) and DesseMartin
periodinane (226 mg, 0.530 mmol), and the mixture was stirred at
room temperature for 1 h. The reaction was quenched with satu-
rated aqueous NaHCO3 (5 mL) and saturated aqueous Na2S2O3
(5 mL). The aqueous layer was extracted with Et2O (5 mLꢂ2). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼4/1) to afford 4 (16.4 mg, 82%) as
a colorless oil; Rf 0.56 (hexane/ethyl acetate¼4/1); 1H NMR
d 7.65e7.63 (2H, m), 7.48e7.46 (4H, m), 7.45e7.34 (6H, m),
7.31e7.27 (3H, m), 5.49e5.47 (2H, m), 3.71 (1H, ddd, J¼10.2, 7.8,
6.1 Hz), 3.60 (1H, ddd, J¼10.2, 7.3, 6.1 Hz), 3.53 (1H, ddd, J¼12.0,
11.2, 5.4 Hz), 2.44e2.34 (3H, m), 2.30e2.23 (1H, m), 2.02 (1H, dd,
J¼17.6, 11.2 Hz), 1.88e1.80 (1H, m), 1.80e1.66 (3H, m), 1.64e1.54
(2H, m), 1.01 (9H, s); 13C NMR (100 MHz, CDCl3)
d 212.1, 135.6, 135.5,
134.3, 134.2, 133.6, 133.6, 132.5, 129.6, 128.9, 127.9, 127.7, 127.6,
124.0, 60.1, 59.8, 44.1, 43.1, 39.1, 38.6, 33.5, 33.0, 26.8, 22.3, 19.0; IR
(neat) nmax 2929, 2856, 1708, 1587, 1473, 1427, 823, 752, 701 cmꢀ1
;
FAB HRMS [MþNa]þ calcd for C34H40O2SiSNa: 563.2416, found:
28
563.2403; [
a
]
þ41.5 (c 0.70, CHCl3).
D
(400 MHz, CDCl3)
d
6.57 (1H, d, J¼10.0 Hz), 5.88 (1H, d, J¼10.0 Hz),
4.83 (1H, d, J¼1.7 Hz), 4.69 (1H, d, J¼1.7 Hz), 2.48e2.40 (2H, m),
2.36e2.29 (2H, m), 2.19e2.08 (2H, m), 2.03e1.96 (1H, m), 1.82e1.68
(3H, m), 1.55e1.48 (1H, m), 1.20 (1H, ddd, J¼12.6, 7.8, 1.2 Hz); 13C
4.2.27. (4aS,8aS)-4a-2-(tert-Butyldiphenylsilyloxyethyl)-
2,3,4,4a,8,8a-hexahydronaphthalen-1(7H)-one (25a). To a stirred
solution of 25 (4.3 g, 7.88 mmol) in MeOH/THF (2/1) (100 mL) was
added a excess amount of Raney-Ni under an atmosphere of Ar, and
the reaction mixture was stirred at room temperature for 6 h. After
the reaction was completed, to the reaction mixture was added
acetone (100 mL) and stirred over night. Then the mixture was
filtered through a plug of Celite, and the filtrate was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼10/1) to afford ketone 25a
(3.4 g, 84%) as a colorless oil; Rf¼0.52 (benzene/ethyl acetate¼40/
NMR (100 MHz, CDCl3)
d 200.1, 156.7, 148.9, 127.7, 106.9, 41.6, 40.8,
36.0, 35.5, 35.4, 34.8, 26.3, 24.5; IR (neat) nmax 2939, 2866, 1684,
1429, 1273, 1236, 1167, 877, 765 cmꢀ1; FAB HRMS [MþH]þ calcd for
C13H17O: 189.1279, found: 189.1288; [
a
]
25 þ21.2 (c 0.1, CHCl3) (lit.4f
D
25
[
a]
þ21.2 (c 1.0, CHCl3)).
D
4.2.25. tert-Butyldiphenyl(2-((3aS,7R,7aR)-7b-(phenylperoxythio)-7-
(phenylthio)-1a,2,3,3a,6,7,7a,7b-octahydronaphtho[2,1-b]oxiren-3a-
yl)ethoxy)silane (23). To a stirred solution of TBHP (2.38 mL,
13.1 mmol) in THF (75 mL) was added a solution of n-BuLi (1.65 M in
hexane, 7.45 mL, 12.2 mmol) dropwise at ꢀ78 ꢁC, and the reaction
mixture was stirred at this temperature for 15 min. Then, to the
reaction mixture was added a solution of 11 (5.45 g, 8.19 mmol) in
THF (5 mL) via a cannula at ꢀ78 ꢁC, and the mixture was stirred at
40 ꢁC for 30 min. The resulting mixture was quenched with brine
(20 mL). The aqueous layer was extracted with Et2O (10 mLꢂ2). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼20/1) to afford epoxide 23 (5.58 g,
100%) as a colorless solid as a colorless oil; Rf¼0.31 (hexane/ethyl
1); 1H NMR (400 MHz, CDCl3)
d 7.67e7.64 (4H, m), 7.45e7.36 (6H,
m), 5.60 (1H, ddd, J¼10.2, 3.4, 3.4 Hz), 5.54 (1H, ddd, J¼10.2, 2.2,
2.2 Hz), 3.74 (2H, dd, J¼7.1, 7.1 Hz), 2.38e2.27 (2H, m), 2.20e2.00
(3H, m), 1.93e1.83 (1H, m), 1.79e1.59 (1H, m), 1.03 (9H, s); 13C NMR
(100 MHz, CDCl3)
d 212.9, 135.6, 135.5, 133.7, 133.7, 133.6, 129.6,
127.6, 127.5, 60.2, 52.5, 43.1, 40.3, 40.3, 34.4, 26.8, 22.6, 21.7, 19.9,
19.0; IR (neat) nmax 2931, 2856, 1707, 1589, 1471, 1427, 1110, 823,
701 cmꢀ1; FAB HRMS [MþNa]þ calcd for C28H36O2SiNa: 455.2382,
found: 455.2392; [
a
]
29 þ62.5 (c 0.40, CHCl3).
D
4.2.28. (4aS,8aS)-4a-(2-Hydroxyethyl)-2,3,4,4a,8,8a-hexahy-
dronaphthalen-1(7H)-one (26). To a stirred solution of 25a (510 mg,
1.18 mmol) in THF (12 mL) was added a solution of tetra-n-buty-
lammonium fluoride (1.0 M in THF, 1.8 mL, 1.77 mmol), and the
reaction mixture was stirred at 50 ꢁC for 30 min. The resulting
mixture was quenched with saturated aqueous NH4Cl (2 mL). The
aqueous layer was extracted with Et2O (5 mLꢂ2). The combined
organic layer was dried over Na2SO4, filtered, and evaporated. The
residue was purified by flash column chromatography (hexane/
ethyl acetate¼2/1) to afford alcohol 26 (210 mg, 92%) as a colorless
oil; Rf¼0.11 (hexane/ethyl acetate¼1/1); 1H NMR (400 MHz, CDCl3)
acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d 8.02e7.98 (2H, m),
7.71e7.66 (4H, m), 7.65e7.60 (1H, m), 7.54e7.49 (2H, m), 7.48e7.37
(8H, m), 7.29e7.18 (3H, m), 5.43 (1H, ddd, J¼10.0, 5.4, 2.2 Hz), 5.38
(1H, d, J¼10.0 Hz), 3,82 (1H, ddd, J¼13.7, 7.8, 7.0 Hz), 3.65 (1H, ddd,
J¼13.7, 7.1, 7.1 Hz), 3.56e3.52 (1H, m), 3.12 (1H, ddd, J¼11.0, 11.0,
5.4 Hz), 2.87 (1H, d, J¼11.0 Hz), 2.36 (1H, ddd, J¼17.8, 5.4, 5.4 Hz),
2.28 (1H, ddd, J¼17.8, 11.0, 2.2 Hz), 1.91 (1H, dd, J¼16.3, 5.36 Hz),
1.83e1.74 (2H, m), 1.66e1.53 (1H, m), 1.30 (1H, ddd, J¼19.3, 14.1,
5.6 Hz), 1.17e1.10 (1H, m), 1.05 (9H, s); 13C NMR (100 MHz, CDCl3)
d
136.3, 135.7, 135.6, 134.2, 133.6, 133.5, 133.1, 132.7, 130.3, 129.6,
d
5.71 (1H, ddd, J¼10.2, 3.7, 3.7 Hz), 5.46 (1H, ddd, J¼10.2, 2.2,
129.6, 128.8, 128.8, 127.7, 127.7, 127.1, 124.2, 74.9, 59.9, 56.7, 44.3,
39.9, 38.4, 37.4, 35.0, 26.8, 26.0, 20.0, 19.1; IR (neat) nmax 2931, 2857,
1585, 1473, 1427, 1216, 1153, 1110, 823, 757, 703 cmꢀ1; FAB HRMS
[MþNa]þ calcd for C40H44O4SiS2Na: 703.2348, found: 703.2327;
2.2 Hz), 3.75 (2H, dd, J¼7.3, 7.3 Hz), 2.45e2.36 (1H, m), 2.34e2.31
(1H, m), 2.29e2.04 (3H, m), 2.00e1.91 (1H, m), 1.88e1.79 (3H, m),
1.77e1.60 (5H, m); 13C NMR (100 MHz, CDCl3)
d 213.0, 133.4, 128.1,
59.2, 52.8, 43.5, 40.4, 40.0, 34.7, 22.8, 21.7, 20.3; IR (neat) nmax 3419,
[
a]
27 þ47.3 (c 0.78, CHCl3).
2937, 2869, 1558, 1051 cmꢀ1; FAB HRMS [MþNa]þ calcd for
D
C12H18O2Na: 217.1204, found: 217.1206; [
a]
27 þ90.4 (c 0.34, CHCl3).
D
4.2.26. (4aS,8R,8aS)-4a-2-(tert-Butyldiphenylsilyloxyethyl)-8-phe-
nylthio-2,3,4,4a,8,8a-hexahydronaphthalen-1(7H)-one (25). To
4.2.29. 2-((4aS,8aS)-1-Oxo-1,2,3,4,4a,7,8,8a-octahydronaphthalen-
4a-yl)acetaldehyde (26a). To a stirred solution of oxalyl chloride
(0.330 mL, 3.76 mmol) in CH2Cl2 (20 mL) at ꢀ78 ꢁC was added
DMSO (0.534 mL, 7.53 mmol) and the reaction solution was stirred
at this temperature for 15 min. Then, to the mixture was added
a solution of 26 (487 mg, 2.51 mmol) in CH2Cl2 (5 mL). After stirred
at ꢀ78 ꢁC for 30 min, Et3N (0.874 mL, 6.27 mmol) was added and
a stirred suspension of dry Mg turnings (14.7 mg, 6.03 mmol) in
anhydrous Et2O (10 mL) was added 1,2-diiodoethane (197.4 mg,
7.24 mmol) and the solution was stirred at room temperature for
20 min (disappearance of Mg was observed). To neat 23 (80.2 mg,
0.121 mmol) was added this reaction mixture via a cannula and the
mixture was stirred at room temperature for 24 h. The resulting

528
S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
the mixture was stirred at room temperature for 30 min. The
resulting mixture was quenched with saturated aqueous brine
(5 mL). The aqueous layer was extracted with CH2Cl2 (5 mLꢂ2). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼20/1) to afford aldehyde 26a (438 mg,
91%) as a colorless oil; Rf¼0.36 (hexane/ethyl acetate¼1/1); 1H NMR
NaHCO3 (1 mL). The aqueous layer was extracted with Et2O
(5 mLꢂ2). The combined organic layer was dried over Na2SO4, fil-
tered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼20/1) to afford enone 10
(12.0 mg, 70% (two steps), E/Z¼1/2 mixture) as a colorless oil;
Rf¼0.58 (hexane/ethyl acetate¼2/1); 1H NMR (400 MHz, CDCl3)
d
6.80 (1.5H, ddd, J¼10.2, 4.1, 4.1 Hz), 6.21 (1H, d, J¼12.4 Hz),
(400 MHz, CDCl3)
d
9.81 (1H, dd, J¼2.9, 2.4 Hz), 5.80 (1H, ddd,
6.04e5.96 (2.5H, m), 5.75e5.66 (1.5H, m), 5.49 (1.5H, ddd, J¼10.4,
2.2, 2.2 Hz), 4.63 (0.5H, ddd, J¼12.7, 7.8, 7.8 Hz), 4.29 (1H, ddd, J¼7.8,
7.8, 7.8 Hz), 3.54 (3H, s), 3.51 (1.5H, s), 2.44e2.27 (5H, m), 2.19e2.03
J¼10.2, 3.4, 3.4 Hz), 5.53 (1H, ddd, J¼10.2, 2.2, 2.2 Hz), 2.63 (1H, dd,
J¼15.4, 2.4 Hz), 2.46 (1H, dd, J¼15.4, 2.9 Hz), 2.47e2.38 (2H, m),
2.31e2.14 (3H, m), 2.04e1.62 (6H, m); 13C NMR (100 MHz, CDCl3)
(5H, m), 1.97e1.73 (3.5H, m); 13C NMR (100 MHz, CDCl3)
d 202.2,
d
211.0, 201.8, 131.7, 129.7, 54.4, 52.2, 40.7, 40.4, 35.2, 22.2, 21.6, 19.4;
202.1, 149.4, 148.4, 147.3, 147.1, 134.0, 133.5, 128.7, 128.5, 127.4, 127.3,
101.3, 97.4, 59.4, 56.1, 49.8, 49.5, 39.8, 39.7, 37.4, 35.5, 35.2, 33.3,
24.0, 21.7; IR (neat) nmax 2933, 2838, 1668, 1455, 1388, 1211, 1106,
937 cmꢀ1; FAB HRMS [MþH]þ calcd for C14H19O2: 219.1385, found:
IR (neat) nmax 2938, 2867, 2732, 1716, 1708, 1455, 1170 cmꢀ1; FAB
HRMS [MþH]þ calcd for r C12H17O2: 193.1229, found: 193.1229;
[
a
]
26 þ118.3 (c 0.49, CHCl3).
D
219.1394; [
a
]
25 þ129.5 (c 0.60, CHCl3).
D
4.2.30. (4aS,8aS)-4a-(3-Methoxyallyl)-2,3,4,4a,8,8a-hexahydronaph-
thalen-1(7H)-one (27). To a stirred suspension of toluene azeo-
troped (methoxymethyl)triphenyl phosphonium chloride (83.0 mg,
0.242 mmol) in THF (1 mL) was added NaHMDS (1.07 M in THF,
0.181 mL, 0.193 mmol) at 0 ꢁC and the mixture was stirred at this
temperature for 1 h min. Then, to the reaction solution was added
a solution of 26a (30.1 mg, 0.161 mmol) in THF (0.5 mL) via a can-
nula. After stirred at ꢀ78 ꢁC for 10 min, cooling bath was removed
and the mixture was stirred for 10 min. The resulting solution was
quenched with saturated aqueous NH4Cl (2 mL). The aqueous layer
was extracted with Et2O (5 mLꢂ2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash column chromatography (hexane/ethyl acetate¼50/1)
to afford methyl enol ether 27 (32.1 mg, 90%, E/Z¼1/2 mixture) as
a colorless oil; Rf¼0.47 (hexane/ethyl acetate¼4/1); 1H NMR
4.2.33. (1S,9S,10S)-7-Oxotricyclo[7.2.1.01,6]dodec-2-ene-10-carbalde-
hyde (9). To a stirred solution of 10 (2.0 mg, 9.14ꢂ10ꢀ3 mmol) in
acetone (0.1 mL) and toluene (1 mL) was added PTSA$H2O (5.2 mg,
2.74ꢂ10ꢀ2 mmol) and the mixture was stirred at room temperature
for 1.5 days. The reaction was quenched with saturated aqueous
NaHCO3. The aqueous layer was extracted with Et2O (2 mLꢂ2). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼20/1) to afford aldehyde 9 (1.8 mg,
96%) as a white solid; Rf¼0.47 (hexane/ethyl acetate¼2/1); 1H NMR
(400 MHz, CDCl3)
d
9.65 (1H, d, J¼1.0 Hz), 5.72 (1H, ddd, J¼10.2, 3.4,
3.4 Hz), 5.46 (1H, d, J¼10.2 Hz), 2.77 (1H, dd, J¼8.0, 4.4 Hz),
2.73e2.65 (1H, m), 2.52 (1H, dd, J¼17.3, 3.7 Hz), 2.47e2.38 (1H, m),
2.34e2.24 (1H, m), 2.15e2.07 (2H, m), 2.00 (1H, dd, J¼13.9, 6.3 Hz),
(400 MHz, CDCl3)
d
6.27 (0.5H, d, J¼12.7 Hz), 6.01 (1H, d, J¼6.6 Hz),
1.84e1.48 (5H, m); 13C NMR (100 MHz, CDCl3)
d 214.2, 200.8, 132.7,
5.67 (1.5H, ddd, J¼10.2, 3.4, 3.4 Hz), 5.42e5.38 (1.5H, m), 4.70 (0.5H,
ddd, J¼12.7, 7.8, 7.8 Hz), 4.35 (1H, ddd, J¼6.6, 6.6, 6.6 Hz), 3.57 (3H,
s), 3.53 (3H, s), 2.47e1.66 (19.5H, m); 13C NMR (100 MHz, CDCl3)
128.0, 57.8, 55.0, 47.6, 45.3, 39.1, 38.2, 35.0, 25.4, 24.9; IR (neat) nmax
2940, 2869, 2717, 1720, 1704, 1454, 1224, 756, 705 cmꢀ1; FAB HRMS
[MþH]þ calcd for C13H17O2: 205.1229, found: 205.1229; [
a]
24 þ41.3
D
d
213.7, 213.4, 149.3, 148.2, 134.1, 133.9, 127.7, 127.5, 101.5, 97.5 59.5,
(c 0.30, CHCl3); mp 75.7e77.3 ꢁC.
56.1, 51.7, 51.6, 41.7, 41.5, 40.4, 40.3, 38.9, 34.8, 33.7, 33.7, 22.8, 22.7,
21.6, 21.6, 20.0, 19.8; IR (neat) nmax 2935, 2856, 1705, 1662, 1652,
1455, 1209, 1106 cmꢀ1; FAB HRMS [MþH]þ calcd for C14H21O2:
4.2.34. (1S,9S,10S)-10-(Hydroxymethyl)tricyclo[7.2.1.01,6]dodec-2-
en-7-one (9a). To a suspension of NaBH4 (7.5 mg, 0.198 mmol) in
EtOH/CH2Cl2 (1/3) (1 mL) at ꢀ78 ꢁC was added a solution of 9
(2.7 mg, 1.32ꢂ10ꢀ2 mmol) in EtOH/CH2Cl2 (1/3) (0.5 mL) and the
mixture was stirred this temperature for 1.5 h. The reaction was
quenched with saturated aqueous NH4Cl (2 mL). The aqueous layer
was extracted with Et2O (2 mLꢂ2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash column chromatography (hexane/ethyl acetate¼2/1)
to afford alcohol 9a (2.5 mg, 93%) as a colorless oil; Rf¼0.14 (hexane/
221.1542, found: 221.1544; [
a]
27 þ120.6 (c 0.90, CHCl3).
D
4.2.31. ((4aS,8aS)-4a-(3-Methoxyallyl)-3,4,4a,7,8,8a-hexahy-
dronaphthalen-1-yloxy)trimethylsilane (27a). To a stirred solution
of diisopropylamine (0.0343 mL, 0.245 mmol) in THF (1 mL) was
added
a solution of n-BuLi (1.57 M in hexane, 0.151 mL,
0.270 mmol) at 0 ꢁC, and the reaction solution was stirred at this
temperature for 15 min. Then, to the reaction mixture was added
a solution of 27 (17.4 mg, 0.0790 mmol) in THF (1 mL) via a can-
nula, and the mixture was stirred at 0 ꢁC for 30 min. After Et3N
(0.0330 mL, 0.270 mmol) and TMSCl (0.0302 mL, 0.270 mmol)
were added, the solution was stirred 0 ꢁC for 10 min. The resulting
mixture was quenched with saturated aqueous NH4Cl (2 mL). The
aqueous layer was extracted with Et2O (5 mLꢂ2). The combined
organic layer was dried over Na2SO4, filtered, and evaporated. The
crude silyl enol ether 27a was used for the next step without
further purification.
ethyl acetate¼2/1); 1H NMR (400 MHz, CDCl3)
d 5.70 (1H, ddd,
J¼10.2, 3.7, 3.7 Hz), 5.44 (1H, ddd, J¼10.2, 2.0, 2.0 Hz), 3.51 (1H, dd,
J¼10.5, 6.1 Hz), 3.45 (1H, dd, J¼10.4, 8.0 Hz), 2.47 (1H, dd, J¼16.8,
3.9 Hz), 2.43e2.39 (1H, m), 2.38e2.32 (1H, m), 2.29e2.22 (1H, m),
2.17e2.07 (2H, m), 2.05e1.95 (1H, m), 1.84e1.75 (2H, m), 1.75e1.64
(4H, m), 1.25 (1H, dd, J¼13.4, 6.6 Hz); 13C NMR (100 MHz, CDCl3)
d
215.9, 133.6, 127.3, 66.6, 57.6, 48.5, 45.4, 45.1, 42.6, 38.8, 36.4, 25.5,
24.9; IR (neat) nmax 3386, 2939, 2865, 1670, 1452, 1228 cmꢀ1; FAB
HRMS [MþH]þ calcd for C13H19O2: 207.1385, found: 207.1382; [
þ74.0 (c 0.73, CHCl3).
a]
25
D
4.2.32. (4aS,8aS)-4a-(3-Methoxyallyl)-4,4a,8,8a-tetrahydronaph-
thalen-1(7H)-one
(10). 4-Methoxypyridine-N-oxide
(MPO)
4.2.35. (1S,9S,10S)-10-(Iodomethyl)tricyclo[7.2.1.01,6]dodec-2-en-7-
one (9b). To a stirred solution of 9a (47.4 mg, 0.230 mmol) in
benzene (2.5 mL) were added imidazole (62.5 mg, 0.919 mmol),
triphenylphospine (129.7 mg, 0.460 mmol), and I2 (116.6 mg,
0.460 mmol) at room temperature, and the solution was stirred at
this temperature for 2 h. The reaction was quenched with a mixture
of saturated aqueous NaHCO3 (1 mL) and saturated aqueous Na2SO3
(1 mL). The aqueous layer was extracted with Et2O (5 mLꢂ2). The
(44.0 mg, 0.158 mmol) and IBX (19.8 mg, 0.158 mmol) were added
to DMSO (0.1 mL) and the resulting mixture was stirred at room
temperature for 30 min (disappearance of MPO and IBX was ob-
served and the mixture turned to clear solution.). Then, to a neat
27a was added the MPO-IBX complex solution in DMSO (0.2 mL) via
a cannula and the solution was stirred at room temperature for 2 h.
The resulting mixture was quenched with saturated aqueous

S. Hirai, M. Nakada / Tetrahedron 67 (2011) 518e530
529
combined organic layer was dried over Na2SO4, filtered, and
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate¼20/1) to afford 9b (60.0 mg, 83%) as
a colorless oil; Rf¼0.72 (hexane/ethyl acetate¼2/1); 1H NMR
1448, 1377, 1326, 1090, 1039, 997, 823 cmꢀ1; EI HRMS [M]þ calcd for
C13H18O: 190.1358, found: 190.1352; [
a
]
20 ꢀ35.1 (c 0.09, CHCl3).
D
Acknowledgements
(400 MHz, CDCl3)
d
5.72 (1H, ddd, J¼10.0, 3.7, 3.7 Hz), 5.44 (1H, ddd,
J¼10.0, 2.2, 2.2 Hz), 3.16 (1H, d, J¼7.3 Hz), 2.49e2.39 (2H, m),
2.34e2.28 (1H, m), 2.28e2.19 (2H, m), 2.15e2.08 (2H, m), 1.96 (1H,
ddd, J¼13.4, 8.3, 2.2 Hz), 1.84e1.62 (4H, m), 1.25 (1H, dd, J¼13.7,
This work was financially supported in part by a Waseda Uni-
versity Grant for Special Research Projects, a Grant-in-Aid for Sci-
entific Research on Innovative Areas (No. 21106009), and the Global
COE program ‘Center for Practical Chemical Wisdom’ by MEXT.
6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 214.9, 133.3, 127.6, 57.3, 48.3,
47.9, 46.4, 46.0, 40.5, 38.5, 25.5, 24.9,13.3; IR (neat) nmax 2935, 2856,
1704, 1450, 1228, 1186 cmꢀ1; FAB HRMS [MþH]þ calcd for C13H18OI:
Supplementary data
317.0402, found: 317.0410; [
a
]
26 þ49.6 (c 0.63, CHCl3).
D
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.10.076.
4.2.36. (1S,9S)-10-Methylidenetricyclo[7.2.1.01,6]dodec-2-en-7-one
(8). To a stirred solution of 9b (53.2 mg, 0.168 mol) in DMF (1.7 mL)
was added DBU (0.0264 mL, 0.177 mmol) and the mixture was
stirred at 50 ꢁC for 24 h. The reaction was quenched with saturated
aqueous NH4Cl (1 mL). The aqueous layer was extracted with Et2O
(5 mLꢂ2). The combined organic layer was dried over Na2SO4, fil-
tered, and evaporated. The residue was purified by flash column
chromatography (hexane/ethyl acetate¼50/1) to afford 8 (25.5 mg,
84% (96% conv.)) and recover 9b (2.3 mg) as a colorless oil; Rf¼0.60
References and notes
1. (a) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.; Galgoci, A.; Painter,
R.; Parthasarathy, G.; Tang, Y. S.; Cummings, R.; Ha, S.; Dorso, K.; Motyl, M.;
Jayasuriya, H.; Ondeyka, J.; Herath, K.; Zhang, C.; Hernandez, L.; Allocco, J.;
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(hexane/ethyl acetate¼4/1); 1H NMR (400 MHz, CDCl3)
d 5.73 (1H,
ddd, J¼10.2, 3.7, 3.7 Hz), 5.48 (1H, ddd, J¼10.2, 2.0, 2.0 Hz), 4.98 (1H,
s), 4.94 (1H, s), 2.94e2.87 (1H, m), 2.52 (1H, dd, J¼17.3, 3.7 Hz),
2.46e2.22 (4H, m), 2.19e2.09 (2H, m), 1.90e1.65 (4H, m); 13C NMR
(100 MHz, CDCl3)
d 214.9, 152.8, 133.3, 127.5, 108.4, 57.0, 49.9, 47.0,
44.2, 40.8, 40.7, 25.6, 25.1; IR (KBr) nmax 2952, 2883, 1702, 1650,
1330 cmꢀ1; EI HRMS [M]þ calcd for C13H18O: 188.1201, found:
188.1203; [
a
]
20 þ93.5 (c 0.55, CHCl3).
D
4.2.37. (1S,7S,9S)-10-Methylidenetricyclo[7.2.1.01,6]dodec-2-en-7-ol
(28). To a stirred solution of 8 (1.0 mg, 5.32 10ꢀ3 mmol) in CH2Cl2
(1 mL) was added K-Selectride (1.0
M in THF 0.0226 mL,
2.66ꢂ10ꢀ2 mmol) at ꢀ78 ꢁC and the reaction mixture was warmed
up to 0 ꢁC and stirred for 1.5 h. The reaction was quenched with
saturated aqueous NH4Cl (1 mL). The aqueous layer was extracted
with CH2Cl2 (5 mLꢂ2). The combined organic layer was dried over
Na2SO4, filtered, and evaporated. The residue was purified by flash
column chromatography (hexane/ethyl acetate¼20/1) to afford
alcohol 28 (1.0 mg, quant) as a colorless oil; Rf¼0.37 (hexane/ethyl
acetate¼4/1); 1H NMR (400 MHz, CDCl3)
5.65 (1H, ddd, J¼9.8, 4.9,
d
2.2 Hz), 5.42 (1H, ddd, J¼9.8, 2.0, 2.0 Hz), 5.10 (1H, s), 4.96 (1H, s),
3.68e3.60 (1H, m), 2.72e2.63 (1H, m), 2.48e2.44 (1H, m), 2.29 (1H,
ddd, J¼16.6, 2.9, 2.9 Hz), 2.22e2.05 (2H, m), 1.97 (1H, ddd, J¼14.6,
5.4, 2.7 Hz), 1.94e1.89 (2H, m), 1.69e1.41 (5H, m); 13C NMR
(100 MHz, CDCl3)
d 156.5, 135.4, 126.9, 106.6, 73.7, 49.0, 46.1, 43.7,
41.3, 41.2, 40.8, 26.4, 25.7; IR (neat) nmax 2925, 1725, 1650, 1434,
1041, 991, 887, 827 cmꢀ1; EI HRMS [M]þ calcd for C13H18O:
190.1358, found: 190.1357; [
a]
18 ꢀ93.5 (c 0.11, CHCl3).
D
4.2.38. (1S,3S,4S,5aS,9aS)-1,4,5,8,9,9a-Hexahydro-3-methyl-3H-
1,4:3,5a-dimethano-2-benzoxepine (3). To a stirred solution of 28
(3.5 mg, 0.0184 mmol) in CH2Cl2 (1 mL) was added TFA (0.2 mL) at
0
ꢁC and the mixture was stirred at the same temperature for
15 min. The reaction was quenched with saturated aqueous
NaHCO3 (3 mL) at 0 ꢁC. The aqueous layer was extracted with
CH2Cl2 (3 mLꢂ2). The combined organic layer was dried over
Na2SO4, filtered, and evaporated. The residue was purified by flash
column chromatography (hexane/ethyl acetate¼50/1) to afford 3
(3.0 mg, 86%) as a colorless oil; Rf¼0.54 (hexane/ethyl acetate¼4/1);
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d
5.60 (1H, ddd, J¼9.8, 3.7, 3.7 Hz), 5.33
(1H, ddd, J¼9.8, 2.0, 2.0 Hz), 4.14 (1H, dd, J¼3.4, 3.4 Hz), 2.17e2.07
(3H, m), 1.92e1.73 (4H, m), 1.62e1.42 (5H, m), 1.39 (3H, s); 13C NMR
(100 MHz, CDCl3)
d 133.2, 126.8, 86.8, 80.6, 52.7, 45.6, 44.9, 44.6,
43.6, 38.3, 26.3, 23.4, 22.3; IR (neat) nmax 2925, 2863, 1727, 1432,

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a] value of 3 has not been reported since the total synthesis of racemic
D
1 by Snider.