Synthetic studies toward miroestrols: trials for elongation of the methyl group of 5-substituted 2-methyl-2-cyclohexanone to 3-methyl-2-butenyl function

Article abstract of DOI:10.1016/j.tet.2008.11.055

Toward total synthesis of miroestrols (miroestrol and deoxymiroestrol), 3-methyl-2-butenyl function (endo-C5 unit) on D ring as a carbon chain for C and E rings was prepared by elongation of the methyl group in α-methyl-α,β-unsaturated ketone unit, and 3,

Full text of DOI:10.1016/j.tet.2008.11.055

Tetrahedron 65 (2009) 771–785
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies toward miroestrols: trials for elongation of the methyl group
of 5-substituted 2-methyl-2-cyclohexanone to 3-methyl-2-butenyl function
,
,
b
a,
*
Fumihiro Ito a b, Takuya Kumamoto a , Kentaro Yamaguchi , Tsutomu Ishikawa
*
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
b Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2008
Received in revised form 19 November 2008
Accepted 20 November 2008
Available online 25 November 2008
Toward total synthesis of miroestrols (miroestrol and deoxymiroestrol), 3-methyl-2-butenyl function
(endo-C5 unit) on D ring as a carbon chain for C and E rings was prepared by elongation of the methyl
group in a-methyl-a,b-unsaturated ketone unit, and 3,5-dinitrobenzoyl group was introduced as a po-
tential leaving group for the construction of B ring. The former was accomplished through a sequence of
epoxide ring-opening, microwave-irradiated siloxy-Cope rearrangement, and isomerization of 3-methyl-
3-butenyl function (exo-C5 unit) to endo-C5 unit.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
preparation of key intermediate 8, which possesses an endo-C5
unit, an oxygen functionality on position 17, and 3,5-dinitrobenzoyl
A medicinal plant ‘kwao keur’ has been locally considered to be
a rejuvenating drug in Thailand and was identified as Pueraria
mirifica (Leguminosae).1 The relationship between the chemical
constituents and estrogenic activity has been widely studied and
(þ)-miroestrol (1) was isolated as an active principle.2 We have
independently investigated the analysis and the total synthesis of
chemical components of P. mirifica3 and (þ)-deoxymiroestrol (2)
was successfully isolated as a new active component, which pos-
sesses ten times stronger activity than miroestrol (1).4 Therefore,
even though the first total synthesis of (þ)-miroestrol (1) had al-
ready been achieved by Corey and Wu,5 synthetic studies of these
strong phytoestrogens via new strategy is much valuable for further
pharmacological studies. We have reported synthetic approaches
toward these compounds, in which A ring was introduced via boron
trichloride-mediated regioselective Claisen rearrangement of res-
orcinol carvonyl ether 7, derived from (R)-(ꢀ)-carvone (4b), to
phenol 66 and the synthesis of methoxyethoxymethyl (MEM) ether
4a was achieved via oxygenative isomerization of allylbenzene 5.7
As next stages, the following reactions have been studied toward
the synthesis of key diol 3: (1) conversion of methyl group of 4a to
3-methyl-2-butenyl (endo-C5) unit as a carbon chain for the con-
struction of C and E rings, (2) introduction of oxygen functionality
at positions 15 and 17,8 and (3) displacement of the MEM function
to leaving group for B ring formation. In this study, we achieved the
(DNB) group as a potential leaving group (Scheme 1).
2. Results and discussion
For the construction of endo- or 3-methyl-3-butenyl (exo-C5)
unit on D ring, we planned three routes as follows; (1) siloxy-Cope
rearrangement of diene 9a followed by Cope rearrangement of 11,
after oxidative dehydrosilylation of 10a, to enone 12 (rearrange-
ment route), (2) double epoxidationdring-opening sequence from
4a to dihydroxy ketone 16 through epoxides 13c and 15 (ring-
opening route), and (3) a combination of ring-opening of epoxide
17 and siloxy-Cope rearrangement of 18 to enone 12 via 19 (com-
bination route) (Scheme 2).
2.1. Rearrangement route
At first, rearrangement route was examined with (R)-(ꢀ)-car-
vone (4b) as a model substrate. Grignard reaction of 4b with 2-
methylallylmagnesium chloride afforded carbinol (18S)-20b9 in
77% as a 95:5 diastereomeric mixture. Next, the carbinol 20b and
the corresponding TMS ether 9b were subjected to oxy- and siloxy-
Cope rearrangements.10 Under conventional thermal conditions
with 20b, no reaction occurred in the case of without solvent and
decomposition to (R)-(ꢀ)-carvone (4b) (10%) was observed via
retro-oxy-ene (retro-allyl-Grignard) type reaction11 when N,N-
diethylaniline (PhNEt2) was used as a solvent. On the other hand,
microwave (MW) irradiation12 of silyl ether 9b without solvent
gave the desired 10b (31%) (Scheme 3). However, application of this
reaction condition to a fully functionalized silyl ether 9a, derived
* Corresponding authors.
E-mail addresses: tkuma@faculty.chiba-u.jp (T. Kumamoto), benti@p.chiba-u.
ac.jp (T. Ishikawa).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.055

772
F. Ito et al. / Tetrahedron 65 (2009) 771–785
6
O
X
H
OMEM TBDPSO
H
OP
4
5
HO
7
OH
O
A
H
3
2
B
8 R
Ar
Ar
A
15
15
17
9
16
17
10
H
OH
14
D18OH
1
C
11
13
12
OH
HE
20
O
O
O
21
19
4a
5: P = Bn
6: P = H
R = OH: (+)-miroestrol (1)
R = H: (+)-deoxymiroestrol (2)
3 (X = leaving group)
ODNB
H
TBDPSO
OBn
O
H
regioselective
Claisen
H
Ar
rearrangement
OH
D
7
O
O
O
4b
8
TBDPSO
Ar =
Bn = benzyl, DNB = 3,5-dinitrobenzoyl,
MEM = methoxyethoxymethoxy, TBDPS = tert-butyldiphenylsilyl.
Scheme 1. Retrosynthesis of miroestrols (1 and 2).
from 4a, gave a complex mixture. Anionic oxy-Cope rearrange-
ment13 of carbinol 20a led to the formation of only desilylated
product 21 in 26% yield.
diethylaluminum amide 26,14 instead of Al(Oi-Pr)3, afforded
a complex mixture.
2.3. Combination route
2.2. Ring-opening route
Finally, combination route was examined (Scheme 6). Dienes 28
and 18 were prepared as substrates for oxy- and siloxy-Cope rear-
rangement. Grignard reaction of 13c with 2-methylallylmagnesium
chloride afforded homoallyl alcohol 27 as a 1:1 mixture of di-
astereoisomers. Next, the carbinol 27 and the corresponding TMS
ether 17 were subjected to ring-opening reaction (Table 1). Treat-
ment of 27 with Al(Oi-Pr)3 in refluxed xylenes gave desired allylic
alcohol 28 (9%) together with small amount of cyclohexene 29 (6%)
(run 1, Table 1). NOE enhancements of 28 and 29 (Fig. 1a) showed
that these were derived from (18S)- and (18R)-27, respectively.
Reaction of siloxy epoxide 17 under the same reaction conditions as
run 1 afforded desired silyl ether 18 in better yield (27%) and un-
desired isopropyl ether 30 (13%) (run 2), and the latter was sup-
posed to be formed by SN20 type reaction of 18 with isopropoxide
anion. Absolute configurations of position 18 of 18 obtained above
Next, ring-opening route was attempted (Scheme 4). Stereo-
selective epoxidation14 of enone 4a with cumene hydroperoxide
(CHP) in the presence of TritonÒ B afforded epoxy ketone 13c in 87%
yield as a single diastereoisomer. Ring-opening of epoxide 13c did
not proceed with lithium diisopropylamide (LDA) even under
refluxed condition, and reaction with boron trifluoride etherate
gave
a complex mixture. Treatment with trimethylsilyl tri-
fluoromethanesulfonate in the presence of 2,6-lutidine15 gave
enone 22 in 34%, which was supposed to be formed by Favorskii-
type reaction of the silyl ether 23 followed by cyclization of 24
(Scheme 5), and that with aluminum triisopropoxide [Al(Oi-Pr)3]16
afforded diol 2517 in 19% via ring-opening of epoxide followed by
undesired Meerwein–Ponndorf–Verley reduction of ketone. Use of
1. Rearrangement route
H
H
H
siloxy-Cope
rearrangement
Cope
rearrangement
H
TMSO
TMSO
O
11
O
12
9a
10a
2. Ring-opening route
OMEM
H
epoxide
epoxide
ring-
opening
H
H
H
H
ring-
Ar
OH
OH
O
OH
OH
[O]
[O]
opening
O
O
O
13c
O
O
O
4a
14
15
16
3. Combination route
epoxide
H
H
H
OH
OH
siloxy-Cope
rearrangement
O
ring-opening
12
TMSO
17
TMSO
18
TMSO
19
Scheme 2. Plans for introduction of endo- and exo-C5 units as a carbon chain for C and E rings.

F. Ito et al. / Tetrahedron 65 (2009) 771–785
773
R2
H
R2
H
HO
OBn OMEM
H
H
R1
R1
b)
a)
c)
(from 9b)
18
R3O
HO
TMSO
10b
21
O
4
a: R1 = Ar, R2 = OMEM
b: R1 = R2 = H
20: R3 = H
9: R3 = TMS
Scheme 3. Synthesis and trials for the Cope rearrangement carbinols 20 and TMS ethers 9 on the rearrangement route. Reagents and conditions: (a) 2-methylallylmagnesium
chloride, ꢀ78 ꢁC, 75% for 20a, 77% for 20b; (b) TMSCl, imidazole, DMF, rt, 83% for 9a, 98% for 9b; (c) MW, 250 ꢁC, 5 min, 31%.
H
H
H
Ar
H
OH
OH
a)
b)
4a
O
N
AlEt2
O
i-Pr
H
O
O
OH
O
22
25
26
13c
14
Scheme 4. Trials for ring-opening of epoxide 13c on the ring-opening route. Reagents and conditions: (a) CHP, TritonÒ B, toluene, 0 ꢁC, 87%; (b) see text.
O
Siloxy-Cope rearrangement of 18 with an activated allylic hy-
droxyl group as 32 (X¼leaving group) was also examined (Table 3).
Rearrangement of 18 in the presence of methanesulfonyl chloride
(MsCl) in refluxed dichloromethane (CH2Cl2) gave desired 12 (25%)
and a bicyclic byproduct 34 (16%) (run 1). The use of Burgess
reagent18 afforded an aromatized byproduct 35 (13%) without im-
provement of the formation of 12 (26%) (run 2). Although yields in
these trials were still low, the acceleration of reaction was observed.
O
OMEM
H
O
H
Ar
Ar
OTMS
TMSOTf
13c
22
O
TMS
O
O
TMS
23
24
Scheme 5. Supposed mechanism for the formation of enone 22.
2.4. Trials for the introduction of oxygen functionality at
positions 15 and 17
was determined as S by NOE enhancements (Fig. 1b). Utilization of
aluminum amide reagents 26 and 31 improved the yield of 18: the
reaction with dimethylaluminum amide 31 afforded 18 in 50% yield
as a 1:3 mixture of diastereoisomers together with a small amount
of TMS-deprotected (18R)-28 (run 3). When diethylaluminum re-
agent 26 was used, the yield of 18 was greatly improved up to 74%
from 13c, obtained as a 1:2 mixture of diastereoisomers (run 4).
Siloxy-Cope rearrangement of 18 was examined (Table 2). The
rearrangement of diastereomerically pure (18S)- and (18R)-18
under conventional thermal condition without solvent gave desired
enone 12 in 24–28% yields after dehydrosilylation of intermediate
19 (runs 1 and 2). Similar result was obtained when a di-
astereomeric mixture of 18 was used (run 3). The reaction was
accelerated by MW irradiation and completed within 6 min in neat
condition; however, yield of 12 was still low (22%) (run 4). Yield
was not improved with using PhNEt2 (28%) (run 5) and a complex
mixture was obtained in dimethylsulfoxide (DMSO) (run 6). Prod-
uct was increased (56%) when xylenes were used (run 7). Reaction
in N,N-dimethylformamide (DMF) gave the best result with shorter
reaction period (run 8).
Toward the introduction of oxygen functionality at positions 15
and 17 on enone 12, model reactions using the methyl epoxide 13c
were examined. After the stereoselective reduction14 of epoxide
13c, ring-opening of 36c with Al(Oi-Pr)3 gave allylic alcohol 37c.
Hydrogen bond-directed epoxidation19 of 37c with m-chloro-
perbenzoic acid (m-CPBA) gave smoothly epoxide 38c even
contamination with diepoxide 38c0. Reductive ring-opening of the
epoxide 38c and the corresponding TBS ether 39c under several
conditions were examined; however, the desired 15-OH isomer 40
was not produced in all cases: only regioisomeric 16-OH derivative
41 was obtained when alcohol 38c was treated with lithium
aluminum hydride (LiAlH4). Similar transformation of epoxide 13d
with exo-C5 unit, prepared by epoxidation and simultaneous
desilylation of 12 to 13d0 followed by re-silylation, gave key allylic
alcohol 37d in moderate yield; however, epoxidation of this
compound to the corresponding epoxide 38d was low yield (13%)
(Scheme 7). Thus, we gave up to introduce oxygen functionality on
position 15 in this strategy, and decided to proceed our synthetic
study with 15-deoxygenated compounds.
H
H
H
H
OH
OH
Oi-Pr
see
Table 1
a)
13c
OH
O
18
N
AlMe2
R3O
R3O
HO
i-Pr
27: R3 = H
17: R3 = TMS
28: R3 = H
b)
29
30
31
18: R3 = TMS
Scheme 6. Preparation of allyl alcohols 28 and 18 as substrates for oxy-Cope rearrangement. Reagents and conditions: (a) 2-methylallylmagnesium chloride, THF, ꢀ78 ꢁC; (b)
TMSCl, imidazole, DMF, rt, 92% from 13c, dr¼1:1.

774
F. Ito et al. / Tetrahedron 65 (2009) 771–785
Table 1
Ring-opening of epoxides 27 and 17
Run
Substratea
R3
Reagent
Solvents
Conditions
Results
1
2
3
4
27
17
17
17
H
Al(Oi-Pr)3
Al(Oi-Pr)3
31
Xylenes
Xylenes
Benzene
Benzene
115 ꢁC to reflux, 9 h
Reflux, 7 h
rt, 22 h
30 ꢁC, 4 h
(18S)-28 (9%), 29 (6%)
TMS
TMS
TMS
(18S)-18 (27%), 30 (13%), (18R)-17 recovery (27%)
18b (50%), (18R)-28 (7%), 17a recovery (23%)
18c (74%)d
26
a
b
c
dr¼1:1.
Ratio: (18R)-18/(18S)-18¼1:3.
Ratio: (18R)-18/(18S)-18¼1:2.
From 13c.
d
(III),28 resulted in the formation of complex mixtures. Only in the
case when Wilkinson’s catalyst [ClRh(PPh3)3]27 was applied, de-
sired 46 was obtained in 88% yield as a 10:1 inseparable mixture
with 45. Deprotection of the acetonide function29 in 46 followed by
IBX oxidation of diol 47 gave ketone 48, MEM group of which was
removed with PPTS under MW condition to afford diol 49 (30%)
together with recovery of 48 (48%).
7.0%
(a)
(b)
HO
2.6%
3.2%
H
H
OH
H
OH
H
H
OH
OH
H
O
TMS
H
4.2%H
H
MEMO
Ar
3.9%
H
H
13.5%
H
3.4%
14.5%
3.4%
6.2%
Finally, DNB group was smoothly introduced at allylic hydroxyl
group to give desired 8 (Scheme 8).
(18S)-28
(18S)-18
29
Figure 1. Selected NOE enhancements of (18S)-28, 29, and (18S)-18.
3. Conclusion
As a model substrate for the removal of MEM group, a-hydroxy
In conclusion, toward total synthesis of strongly phytoestro-
genic miroestrols we accomplished the synthesis of key in-
termediate 8, which possesses endo-C5 unit as a side chain which
will constitute the C and E rings, one hydroxyl group at position 17,
and DNB group as a potential leaving group. On the construction of
exo-C5 unit by siloxy-Cope rearrangement of allylic alcohol 18, MW
irradiation was effective to give key enone 12. Oxygen functionality
at position 17 was introduced via epoxidation and reductive ring-
opening of 12. Isomerization of exo-C5 unit by Wilkinson catalyst
was successful to give desired endo one. Removal of MEM group
with PPTS gave low yield; however, the yield was slightly improved
by MW irradiation. Further approaches to the construction of C and
E rings and total synthesis of miroestrols are under investigation.
ketone 42 was synthesized by regioselective reduction of epoxide
36c followed by o-iodoxybenzoic acid (IBX)20 oxidation of sec-
ondary alcohol. Unfortunately, trials for the removal of MEM group
of a
-hydroxyl ketone 42 under reported conditions (10% HCl aq,3c
TiCl4,21 CeCl3,22 CBr423) gave no desired allylic alcohol 43. Only in
the case when pyridinium p-toluenesulfonate (PPTS) in tert-butyl
alcohol24 was used, 43 was obtained in 21% yield. Replacement of
the solvent to methyl ethyl ketone (MEK)25 slightly increased the
yield [31%: recovery of 42 (18%)]. Irradiation of MW effectively ac-
celerated the reaction and gave better yield (43: 42%), in which 42
was recovered in 32% (Scheme 7).
2.5. Isomerization of exo- to endo-C5 unit
4. Experimental section
4.1. General
Next, we tried isomerization of the exo-C5 unit to the endo one
in 36d. The substrate 45 for the isomerization was prepared via
reductive ring-opening of epoxide 36d and ketalization of 1,2-diol
44. Initial trials for isomerization of 45 under reported conditions,
such as iodine,26 p-toluenesulfonic acid,27 and rhodium chloride
IR spectra were recorded on a JASCO FT/IR-300E and FT/IR-6300
spectrophotometer; ATR¼attenuated total reflectance system. 1H
NMR spectra were recorded in CDCl3 on JEOL JNM-GSX400A
(400 MHz), JNM-ECP400 (400 MHz), JNM-ECX400 (400 MHz),
JNM-GSX500A (500 MHz), JNM-ECP600 (600 MHz) or Bruker Bio-
spin-AVANCE 400 (400 MHz) using tetramethylsilane (0.00 ppm)
Table 2
Construction of exo-C5 unit by siloxy-Cope rearrangement of 18
H
H
OH
OH
or residual chloroform (CHCl3) (7.26 ppm) as internal standard. 13
C
NMR spectra were recorded in CDCl3 on JEOL JNM-ECP400
(100 MHz), JNM-ECX400 (100 MHz), JNM-GSX500A (125 MHz),
JNM-ECP600 (150 MHz) or Bruker Biospin-AVANCE 400 (100 MHz)
using the middle resonance of CDCl3 (77.0 ppm) as an internal
solvents
180 °C
time
TMSO
TMSO
O
18
19
12
standard;
d
in parts per million, J in hertz, dif.¼diffused. Optical
Run
18
Solvent
Time
12 (%)
rotations were measured with a Jasco DIP-140 or P-1030 polarim-
eter as a chloroform solution. EIMS were recorded on a JEOL GC-
Mate with direct inlet. FABMS were recorded on a JEOL JMS-HX110
with m-nitrobenzyl alcohol as a matrix. FT-ICR-MS were recorded
on a Bruker Daltonics apex-Qe 9.4 T with direct inlet. For TLC was
used TLC plates Silica gel 60 F254 (Merck No. 5715) and for column
Conventional (h)
MW (min)
1
2
3
4
5
6
7
8
S only
None
None
None
None
PhNEt2
DMSO
Xylenes
DMF
1.5
1.5
2.0
d
d
d
d
6
6
5
24
28
22
22
28
CMb
56
69
R only
a
a
a
a
a
a
d
chromatography Silica gel 60, spherical, particle size 63–210 mm
d
(Kanto Chemical No. 37564-85 for normal, No. 37565-84 for neu-
tral). Microwave (MW) irradiation was done in a CEM Discover
system in a sealed tube. Biotage Horizon system was used for flash
chromatography. Anhydrous dichloromethane (CH2Cl2) and diethyl
d
16
4
d
a
Ratio: (18R)-18/(18S)-18¼1:2.
b
A complex mixture.

F. Ito et al. / Tetrahedron 65 (2009) 771–785
775
Table 3
Trials for Cope rearrangement of 18 under dehydration conditiona
H
H
X
H
H
X
reagents
12
18
solvents
conditions
TMSO
HO
O
TMS
32
33
34
35
Run
Reagents
Solvent
CH2Cl2
Conditions
Results
1
2
MsCl, Et3N, DMAP
Burgess reagent
ꢀ20 ꢁC to reflux, 6 h
12 (25%), 34 (16%)
12 (26%), 35 (13%)
Benzene
rt, 18 h
a
A diastereomeric mixture of 18 (18R/18S¼1:2) was used as a substrate.
ether (Et2O) were purchased from Kanto Chemicals and Wako Pure
Chemical. Anhydrous tetrahydrofuran (THF) was purchased from
Wako Pure Chemical. Anhydrous N,N-dimethylformamide (DMF)
was purchased from Kanto Chemicals. Burgess reagent [(C2H5)3
2.33–2.40 (1H, m, H-5), 2.45 (1H, d, J¼13.7 Hz, one of CH2), 4.73 (2H,
br s, ]CH2), 4.77 (1H, br s, one of ]CH2), 4.94 (1H, dq, J¼2.4, 1.5 Hz,
one of ]CH2), 5.44 (1H, ddq, J¼5.1, 2.6, 1.4 Hz, H-3). 13C NMR
(100 MHz) d: 17.0, 20.4, 24.7, 30.9, 39.5, 40.3, 45.7, 73.9, 109.1, 114.9,
NþSO2NꢀCO2CH3],
a
THF solution of 2-methylallylmagnesium
123.2, 138.7, 142.6, 148.7. LRFABMS m/z:205 [(MꢀH)þ].
chloride, a hexane solution of potassium bis(trimethylsilyl)amide
(KHMDS), a THF solution of lithium triethylborohydride (LiEt3BH), and
a heptane solution of diethylaluminum chloride (Et2AlCl) were
purchased from Aldrich. A hexane solution of dimethylaluminum
chloride (Me2AlCl) was purchased from Kanto Chemicals.
4.1.2. (4S,6R)-4-Isopropenyl-1-methyl-6-(2-methyl-2-propen-1-yl)-
6-trimethylsilanlyloxycyclohexene (9b)
Chlorotrimethylsilane (TMSCl) (0.27 mL, 2.13 mmol) was added
to a solution of 20b (293 mg, 1.42 mmol) and imidazole (192 mg,
2.82 mmol) in DMF (1 mL) and the whole was stirred at rt for 1 h.
Satd aq NH4Cl was added and the whole was extracted with Et2O.
The organic layer was washed with H2O and brine, successively, and
dried over MgSO4. The solvent was evaporated in vacuo and the
residue was purified by CC (neutral SiO2, hexane/Et2O¼20:1) to
4.1.1. (1S,5R)-5-Isopropenyl-2-methyl-1-(2-methyl-2-propen-1-yl)-
2-cyclohexen-1-ol (20b)
2-Methylallylmagnesium chloride (0.5 M solution in THF,
8.90 mL, 4.45 mmol) was added to a solution of (R)-carvone (4b,
556 mg, 4.70 mmol) in THF (2 mL) at ꢀ78 ꢁC and the whole was
stirred at ꢀ78 ꢁC for 30 min. Satd aq NH4Cl and H2O were added
and the whole was extracted with Et2O. The organic layer was
washed with H2O and brine, successively, and dried over MgSO4.
The solvent was evaporated in vacuo and the residue was purified
by column chromatography (CC, n-hexane/AcOEt¼11:1) to give 20b
give 9b as a colorless oil (388 mg, 98%).
23
[a
]
ꢀ45.5 (c 1.1). IR (neat, cmꢀ1): 1645. 1H NMR (400 MHz)
d:
D
0.09 (9H, s, TMS), 1.53 (1H, ddd, J¼12.7, 12.7, 1.3 Hz, H-5), 1.71 (3H,
ddd, J¼2.5, 1.6, 1.6 Hz, Me), 1.72 (3H, br s, Me), 1.82 (3H, br s, Me),
1.92 (1H, dddq, J¼17.2, 12.7, 2.5, 2.5 Hz, H-3), 2.05 (1H, ddddq,
J¼17.2, 5.1, 5.1, 1.6, 1.6 Hz, H-3), 2.15 (1H, ddd, J¼12.7, 2.1, 2.1 Hz, H-
5), 2.24 (1H, d, J¼13.6 Hz, one of CH2), 2.27–2.35 (1H, m, H-4),
2.44 (1H, d, J¼13.6 Hz, one of CH2), 4.66 (1H, m, one of ]CH2),
4.70–4.72 (2H, m, ]CH2), 4.85 (1H, dq, J¼2.8, 1.4 Hz, one of
]CH2), 5.36 (1H, ddq, J¼5.1, 3.4, 1.6 Hz, H-2). 13C NMR (100 MHz)
as
a colorless oil (586 mg, 77%) and the corresponding di-
astereoisomer (32 mg, 4%).
23
[
a]
ꢀ59.6 (c 1.0). IR (neat, cmꢀ1): 3452. 1H NMR (400 MHz)
d:
D
1.48 (1H, ddd, J¼12.5, 12.5, 1.1 Hz, H-6), 1.68 (1H, s, OH, exchange-
able with D2O), 1.73 (3H, br s, Me), 1.75 (3H, ddd, J¼2.6, 1.4, 1.4 Hz,
Me),1.85 (3H, br s, Me),1.97 (1H, dddq, J¼17.8,10.7, 2.6, 2.6 Hz, H-4),
2.05–2.14 (2H, m, H-4 and 6), 2.31 (1H, d, J¼13.7 Hz, one of CH2),
d
: 2.05, 17.5, 20.9, 24.3, 31.1, 39.9 (overlapped), 47.6, 77.7, 108.7,
114.3, 122.1, 140.0, 143.8, 149.1. LREIMS m/z: 279 [(MþH)þ], 277
[(MꢀH)þ].
H
O
H
H
H
g)
c)
b)
f)
a)
OH
R4
OH
R4
O
O
12
13d'
(for 13d)
R4
R4
OR
OH
37
O
13
OH
36
38: R = H
39: R = TBS
c: R4 = Me
d)
h)
d: R4 = CH2CH2C(=CH2)Me
(from 38c)
(from 36c)
e)
(from 39c)
OR5
H
OH
H
H
HO
OBn OMEM
H
Ar
OMEM
OH
OH
15
17
OH
i)
O
H
O
OH
Ar
O
OH
O
R4
OH
41
OR
42: R5 = MEM
38c'
13d'
40 (R = H or TBS)
O
OH
43: R5 = H
Scheme 7. Trials of introduction of oxygen functionality on positions 15 and 17 and removal of MEM group of 42. Reagents and conditions: (a) LiBEt3H, THF, 0 ꢁC, 30 min, 90% for
36c, 93% for 36d; (b) Al(Oi-Pr)3, toluene, reflux, 1.5 h, 86% for 37c, 66% for 37d; (c) m-CPBA, CH2Cl2, ꢀ30 ꢁC, 16 h, 90% (as a 5:1 mixture of 38c and 38c0), 13% for 38d; (d) TBSOTf, 2,6-
lutidine, CH2Cl2, ꢀ78 ꢁC, 30 min, 60%; (e) LiAlH4, THF, rt, 5 h, 31% for 41c; (f) TBHP, TritonÒ B, toluene, rt; (g) TBDPSCl, imidazole, DMF, rt, two steps 90%; (h) (1) LiAlH4, THF, rt, 92%,
(2) IBX, DMSO, 60 ꢁC, 90%; (i) PPTS, MEK, MW, 90 ꢁC, 20 min, 42% for 43, recovery of 42 (32%).

776
F. Ito et al. / Tetrahedron 65 (2009) 771–785
H
H
H
H
c)
a)
b)
O
OH
17
O
O
OH
36d
OH
O
O
44
45
46
OR5
48: R5 = MEM
H
H
(+ isomer)
49: R5 = H
8: R5 = DNB
f)
Ar
d)
e)
OH
OH
g)
OH
O
47 (+ isomer)
Scheme 8. Isomerization of exo 45 to endo olefin 46 and introduction of DNB group. Reagents and conditions: (a) LiAlH4, THF, rt, 89%; (b) 2,2-dimethoxypropane, TsOH$H2O, CH2Cl2,
rt, 97%; (c) ClRh(PPh3)3, 10% aq EtOH, reflux, 24 h, 88%, 46/45¼10:1; (d) AcOH/H2O/THF (4:1:1), rt, 92%; (e) IBX, DMSO, 60 ꢁC, 90%; (f) PPTS, MEK, MW, 90 ꢁC, 30% for 49; recovery for
48 (48%); (g) DNBCl, NEt3, CH2Cl2, 0 ꢁC, 96%.
4.1.3. (3S,5R)-5-Isopropenyl-2-methyl-3-(2-methyl-2-propen-1-yl)-
1-trimethylsilanyloxycyclohexene (10b)
156.0, 156.7. HRFABMS: m/z 785.3627 (calcd for C47H58KO6Si:
785.3640).
Compound 9b (120 mg, 0.43 mmol) was irradiated under MW
condition (300 W) at 250 ꢁC for 5 min. The residue was purified by
CC (neutral SiO2, n-hexane/benzene¼20:1) to give 10b as a color-
4.1.5. (4R,6S,Z)-4-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
1-methyl-6-(2-methyl-2-propen-1-yl)-6-trimethyl-
silanyloxycyclohexene (9a)
Compound 9a was prepared from 20a by the same procedure for
9b and was obtained as a colorless oil in 83%.
less oil (38 mg, 31%).
21
[a
]
þ31.1 (c 1.3). IR (ATR, cmꢀ1): 1648. 1H NMR (400 MHz)
d:
D
0.18 (9H, s, TMS), 1.32 (1H, dddd, J¼12.8, 12.8, 5.5, 0.8 Hz, H-4), 1.61
(3H, dif. dd, J¼1.9, 1.6 Hz, Me), 1.68–1.73 (1H, m, H-4), 1.71–1.73 (6H,
m, 2ꢂMe), 1.94 (1H, dd, J¼13.7, 11.1 Hz, one of CH2), 2.02 (2H, dif. d,
J¼8.1 Hz, H-6), 2.16–2.23 (1H, m, H-3), 2.28 (1H, dif. dd, J¼13.7,
2.8 Hz, one of CH2), 2.32–2.40 (1H, m, H-5), 4.67–4.69 (1H, m, one of
]CH2), 4.70–4.73 (2H, m, ]CH2), 4.76–4.78 (1H, m, one of ]CH2).
20
[
a
]
D
ꢀ29.6 (c 1.0). IR (ATR, cmꢀ1): 1603. 1H NMR (400 MHz)
d:
0.06 (9H, s, TMS), 1.10 (9H, s, t-Bu), 1.66 (1H, m, H-5), 1.70 (3H, br s,
Me), 1.78 (3H, s, Me), 1.98 (1H, dddq, J¼17.0, 11.5, 2.9, 2.9 Hz, H-3),
2.14–2.23 (2H, m, H-3 and 5), 2.24, 2.42 (each 1H, d, J¼13.4 Hz,
CH2), 2.61 (1H, dif. ddd, J¼11.5, 11.5, 4.8 Hz, H-4), 3.33 (3H, s, OMe),
13C NMR (100 MHz)
d: 0.7, 14.9, 20.8, 22.1, 30.4, 35.5, 36.9 (over-
lapped), 41.4, 108.7, 112.0, 114.8, 143.4, 144.9, 149.4. LRFABMS m/z:
3.44 (2H, t, J¼4.7 Hz, OCH2CH2OMe), 3.59–3.68 (2H, m, OCH2
-
277 [(MꢀH)þ].
CH2OMe), 4.06, 4.10 (each 1H, d, J¼10.8 Hz, CH2OMEM), 4.63–4.66
(1H, m, one of ]CH2), 4.65 (2H, s, OCH2O or CH2Ph), 4.67, 4.69 (each
1H, d, J¼7.0 Hz, CH2Ph or OCH2O), 4.75 (1H, dq, J¼1.3, 1.3 Hz, one of
]CH2), 5.34–5.36 (1H, m, H-2), 6.32 (1H, d, J¼2.3 Hz, Ar H-3), 6.35
(1H, dd, J¼8.2, 2.3 Hz, Ar H-5), 6.54 (1H, s, ]CH), 7.06 (1H, d,
J¼8.2 Hz, Ar H-6), 7.23–7.32 (5H, m, Ph), 7.37 (4H, dif. t, J¼7.2 Hz,
Ph), 7.44 (2H, dif. t, J¼7.3 Hz, Ph), 7.71 (4H, dif. d, J¼8.1 Hz, Ph). 13C
4.1.4. (1S,5R,Z)-5-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
2-methyl-1-(2-methyl-2-propen-1-yl)-2-cyclohexenol (20a)
To a solution of 4a (1.86 g, 2.70 mmol) in Et2O (20 mL), 2-
methylallylmagnesium chloride30 (0.9 M solution in Et2O, 9.00 mL,
8.10 mmol) was added at ꢀ78 ꢁC under Ar and the mixture was
stirred at ꢀ78 ꢁC for 30 min. After the mixture was poured into
satd aq NH4Cl, the whole was diluted with H2O and extracted
with Et2O. The organic layer was washed with H2O and brine,
dried over MgSO4, and evaporated in vacuo. The residue was
purified by CC (n-hexane/AcOEt¼3:1) to give 20a as a colorless oil
NMR (100 MHz) d: 2.0, 17.5, 19.4, 24.3, 26.5, 32.1, 38.2, 40.2, 47.5,
58.9, 65.8, 66.9, 69.7, 71.6, 77.9, 95.3, 104.3, 111.4, 114.3, 119.4, 122.2,
124.1, 126.9, 127.6, 127.8, 128.3, 129.9, 130.4, 132.9, 135.5, 136.9,
139.8, 140.2, 143.6, 155.9, 156.7. HRFABMS m/z 857.4030 (calcd for
C50H66KO6Si2: 857.4035).
(1.51 g, 75%).
4.1.6. Trial for the synthesis of 10a: (1S,5R,Z)-5-{3-[2-benzyloxy-4-
hydroxyphenyl]-1-[(2-methoxyethoxy)methoxy]2-propen-2-yl}-2-
methyl-1-(2-methyl-2-propen-1-yl)-2-cyclohexenol (21)
21
[a
]
ꢀ34.1 (c 1.0). IR (ATR, cmꢀ1): 3485. 1H NMR (400 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.64 (1H, dd, J¼12.4, 12.4 Hz, H-6), 1.74 (3H,
ddd, J¼2.2, 2.2, 1.4 Hz, Me), 1.80 (3H, br s, Me), 1.82 (1H, s, OH,
exchangeable with D2O), 2.03–2.23 (3H, m, 2ꢂH-4 and ꢀ6), 2.31,
2.44 (each 1H, d, J¼13.7 Hz, CH2), 2.64–2.71 (1H, m, H-5), 3.34
(3H, s, OMe), 3.45–3.47 (2H, m, OCH2CH2OMe), 3.63–3.66 (2H, m,
OCH2CH2OMe), 4.06, 4.10 (each 1H, d, J¼10.5 Hz, CH2OMEM), 4.66
(2H, s, OCH2O or CH2Ph), 4.67 (2H, s, CH2Ph or OCH2O), 4.75 (1H,
br s, one of ]CH2), 4.85 (1H, dq, J¼2.6, 1.3 Hz, one of ]CH2), 5.44
(1H, dq, J¼4.6, 1.4 Hz, H-3), 6.29 (1H, d, J¼2.4 Hz, Ar H-3), 6.34
(1H, dd, J¼8.2, 2.4 Hz, Ar H-5), 6.55 (1H, s, ]CH), 7.04 (1H, d,
J¼8.2 Hz, Ar H-6), 7.22 (2H, dif. d, J¼8.1 Hz, Ph), 7.30 (3H, dif. t,
J¼8.0 Hz, Ph), 7.37 (4H, dif. t, J¼7.2 Hz, Ph), 7.43 (2H, dif. t,
To a solution of 20a (116 mg, 0.16 mmol) and 18-crown-6
(247 mg, 0.94 mmol) in toluene (1 mL), KHMDS (0.5 M in hexane,
1.00 mL, 0.50 mmol) was added and whole was stirred at ꢀ78 ꢁC
for 1 h. The temperature was gradually warmed up to refluxed
condition within 5 h and the whole was refluxed for further
15.5 h. After cooling to rt, the reaction mixture was poured into
satd aq NH4Cl. The whole was diluted with H2O and extracted
with AcOEt. The organic layer was washed with satd aq NH4Cl and
brine, dried over MgSO4, and evaporated in vacuo. The residue
was purified by CC (n-hexane/AcOEt¼3:2) to give 21 as a colorless
oil (21 mg, 26%).
J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼8.1 Hz, Ph). 13C NMR (100 MHz)
d
:
IR (ATR, cmꢀ1): 3413. 1H NMR (400 MHz)
d
: 1.70 (1H, dd, J¼12.3,
17.1, 19.5, 24.7, 26.6, 31.9, 37.8, 40.6, 45.8, 59.0, 65.7, 67.1, 69.8,
71.7, 73.8, 95.4, 104.5, 111.5, 114.9, 119.4, 123.5, 124.8, 127.0, 127.6,
127.8, 128.4, 129.9, 130.4, 132.9, 135.5, 137.0, 138.7, 140.0, 142.8,
12.3 Hz, H-6), 1.75 (3H, br s, Me), 1.81 (3H, s, Me), 1.99 (1H, br s, OH,
exchangeable with D2O), 2.09–2.24 (3H, m, 2ꢂH-4 and H-6), 2.33,
2.45 (each 1H, d, J¼13.7 Hz, CH2), 2.68–2.76 (1H, m, H-5), 3.35 (3H,

F. Ito et al. / Tetrahedron 65 (2009) 771–785
777
s, OMe), 3.52 (2H, dif. t, J¼4.6 Hz, OCH2CH2OMe), 3.68 (2H, dif. t,
4.1.9. Trial for the ring-opening of 13c with Al(Oi-Pr)3: (1R,3R,Z)-c-
J¼4.6 Hz, OCH2CH2OMe), 4.12, 4.16 (each 1H, d, J¼10.7 Hz, CH2O-
MEM), 4.70 (2H, s, OCH2O or CH2Ph), 4.77, 4.87 (each 1H, s, ]CH2),
4.99 (2H, s, CH2Ph or OCH2O), 5.47 (2H, br s, H-3 and Ar 4-OH,
exchangeable with D2O), 6.35 (1H, dd, J¼8.2, 2.3 Hz, Ar H-5), 6.42
(1H, d, J¼2.3 Hz, Ar H-3), 6.60 (1H, s, ]CH), 7.12 (1H, d, J¼8.2 Hz, Ar
5-[3-{2-benzyloxy-4-(tert-butyldiphenylsilanyloxy)phenyl}-1-{(2-
methoxyethoxy)methoxy}-2-propen-2-yl]-2-methylenecyclo-
hexane-r-1,3-diol (25)
A mixture of 13c (156 mg, 0.22 mmol) and Al(Oi-Pr)3 (100 mg,
0.49 mmol) in toluene (2 mL) was stirred at rt for 1 h, 70 ꢁC for 1 h,
and then refluxed for 6 h under Ar. After cooling to rt, 10% aq NaOH
was added and the mixture was extracted with Et2O. The organic
layer was washed with 10% aq NaOH and brine, dried over MgSO4,
and evaporated in vacuo. The residue was purified by CC (n-hexane/
H-6), 7.28–7.38 (5H, m, Ph). 13C NMR (100 MHz)
d: 17.1, 24.7, 31.7,
37.5, 40.6, 45.9, 59.0, 65.7, 67.1, 70.0, 71.7, 74.0, 95.4, 100.3, 107.0,
115.0,118.9, 123.6, 125.0, 127.1, 127.8, 128.5, 130.9, 137.0, 138.6, 139.9,
142.8, 156.4, 157.3. HRFABMS m/z: 531.2687 (calcd for C31H40NaO6:
531.2723).
acetone¼3:1) to give 25 as a light yellow oil (30 mg, 19%).
24
[a
]
ꢀ15.5 (c 0.5). IR (ATR, cmꢀ1): 3415. 1H NMR (500 MHz)
d:
D
4.1.7. (2R,3R,5R,Z)-5-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
2,3-epoxy-2-methylcyclohexanone (13c)
1.09 (1H, s, t-Bu), 1.38 (1H, ddd, J¼12.1, 12.1, 12.1 Hz, H-6), 1.53 (1H,
ddd, J¼13.5, 13.5, 2.8 Hz, H-4), 1.76 (1H, br d, J¼5.2 Hz, OH), 1.92
(1H, br s, OH), 2.11 (1H, ddd, J¼13.5, 5.3, 2.8 Hz, H-4), 2.27–2.32 (1H,
m, H-6), 3.04 (1H, dddd, J¼12.1, 12.1, 2.8, 2.8 Hz, H-5), 3.36 (3H, s,
OMe), 3.51 (2H, t, J¼4.6 Hz, OCH2CH2OMe), 3.63–3.67, 3.71–3.75
(each 1H, m, OCH2CH2OMe), 4.12 (2H, s, ]CH), 4.56 (1H, dd, J¼2.8,
2.8 Hz, H-1 or 3), 4.55–4.60 (1H, m, H-3 or 1), 4.67 (4H, s, OCH2O
and CH2Ph), 5.02, 5.11 (each 1H, d, J¼1.5, 1.5 Hz, ]CH2), 6.29 (1H, d,
J¼2.3 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.3 Hz, Ar H-5), 6.52 (1H, s,
]CH), 6.99 (1H, d, J¼8.2 Hz, Ar H-6), 7.20 (2H, dif. d, J¼8.2 Hz, Ph),
7.23–7.30 (3H, m, Ph), 7.36 (4H, t, J¼7.8 Hz, Ph), 7.43 (2H, dif. t,
A solution of 4a (1.05 g, 1.51 mmol), CHP (3.5 M solution in tol-
uene, 4.30 mL, 15.1 mmol), and TritonÒ B (40% solution in MeOH,
0.13 mL, 0.34 mmol) in toluene (2 mL) was stirred at 0 ꢁC for 1 day.
TritonÒ B (40% solution in MeOH, 0.10 mL, 0.26 mmol) was added at
0 ꢁC and the mixture was stirred at 0 ꢁC for 1 day. After the addition
of 10% aq Na2S2O3 at 0 ꢁC, NaCl was added until the aqueous layer
was saturated and the mixture was extracted with AcOEt. The
organic layer was washed with brine, dried over MgSO4 and
evaporated in vacuo. The residue was purified by CC (n-hexane/
J¼7.5 Hz, Ph), 7.68 (4H, dif. d, J¼8.0 Hz, Ph). 13C NMR (100 MHz)
d:
acetone¼8:1) to give 13c as a colorless oil (928 mg, 87%).
19.5, 26.6, 35.2, 39.8, 42.4, 59.1, 65.9, 67.2, 69.0, 69.8, 71.9, 73.5, 95.3,
104.8,107.4,111.7, 119.5,124.5,126.8, 127.6,127.8,128.4,129.9, 130.4,
133.0, 135.5, 137.0, 139.4, 152.2, 156.0, 156.7. HRFABMS m/z
733.3544 (calcd for C43H54O7Si: 733.3536).
22
[
a]
þ14.3 (c 1.0). IR (ATR, cmꢀ1): 1709. 1H NMR (400 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.39 (3H, s, Me), 2.03 (1H, ddd, J¼14.8, 11.5, 1.1 Hz,
H-4), 2.16 (1H, dd, J¼17.8, 11.5 Hz, H-6), 2.43 (1H, dif. ddd, J¼14.8,
4.5, 4.5 Hz, H-4), 2.67 (1H, ddd, J¼17.8, 4.5, 1.1 Hz, H-6), 3.04 (1H,
dddd, J¼11.5, 11.5, 4.5, 4.5 Hz, H-5), 3.34 (3H, s, OMe), 3.43 (1H, dif.
dd, J¼4.5, 1.1 Hz, H-3), 3.47 (2H, m, OCH2CH2OMe), 3.64 (2H, m,
OCH2CH2OMe), 4.06, 4.09 (each 1H, d, J¼11.0 Hz, CH2OMEM), 4.66
(4H, s, OCH2O and CH2Ph), 6.29 (1H, d, J¼2.3 Hz, Ar H-3), 6.35 (1H,
dd, J¼8.2, 2.3 Hz, Ar H-5), 6.49 (1H, s, ]CH), 6.96 (1H, d, J¼8.2 Hz,
Ar H-6), 7.20 (2H, dif. dd, J¼7.8, 1.8 Hz, Ph), 7.29 (3H, dif. t, J¼8.0 Hz,
Ph), 7.36 (4H, dif. t, J¼7.8 Hz, Ph), 7.43 (2H, dif. t, J¼7.3 Hz, Ph), 7.69
4.1.10. (1R,2R,3R,5R,Z)- and (1S,2R,3R,5R,Z)-5-{3-[2-Benzyloxy-4-
(tert-butyldiphenylsilanyloxy)phenyl]-1-[(2-methoxyethoxy)-
methoxy]-2-propen-2-yl}-2,3-epoxy-2-methyl-1-(2-methyl-2-
propen-1-yl)cyclohexanol (27)
2-Methylallylmagnesiumchloride (0.5 M solution inTHF, 8.90 mL,
4.45 mmol) was added to a solution of 13c (322 mg, 0.46 mmol) in
THF (1 mL) at ꢀ78 ꢁC and the whole was stirred at ꢀ78 ꢁC for 30 min.
Satd aq NH4Cl and H2O were added and the whole was extracted with
Et2O. The organic layer was washed with H2O and brine, dried over
MgSO4, and evaporated in vacuo. The residue was purified by CC (n-
hexane/Et2O¼3:1) to give 27 as a colorless oil (282 mg, 81%, dr 1:1).
(4H, dif. d, J¼8.0 Hz, Ph). 13C NMR (100 MHz)
d: 15.3,19.4, 26.5, 29.3,
33.2, 42.6, 58.7, 58.9, 61.4, 65.7, 67.1, 69.8, 71.6, 95.4, 104.6, 118.7,
125.4, 126.9, 127.7, 127.8, 128.5, 129.9, 130.3, 132.8, 135.5, 136.8,
137.8, 156.2, 156.7, 205.6. HREIMS m/z 706.3263 (calcd for
C42H50O7Si: 706.3326).
An aliquot was further purified by CC to give (18R)- and (18S)-27.
24
Compound (18R)-27: a colorless oil. [
a
]
þ7.5 (c 1.1). IR (ATR,
D
4.1.8. Trial for the ring-opening of 13c with TMSOTf: (3aS,Z)-3-[2-
benzyloxy-4-(tert-butyldiphenylsilanyloxy)benzylidene]-6-methyl-
2,3,3a,7a-tetrahydro-4H-benzo[b]furan-7-one (22)
cmꢀ1): 3480. 1H NMR (400 MHz)
d: 1.09 (9H, s, t-Bu), 1.33 (1H, m H-
6), 1.37 (each 3H, s, Me), 1.67–1.74 (2H, m, H-4 and 6), 1.82 (3H, s,
Me), 2.20 (1H, d, J¼14.1 Hz, one of CH2), 2.30 (1H, br d, J¼14.7 Hz, H-
4), 2.47 (1H, d, J¼14.1 Hz, one of CH2), 2.55 (1H, br t, J¼12.3 Hz, H-5),
2.87 (1H, s, OH, exchangeable with D2O), 3.30 (1H, br d, J¼1.8 Hz, H-
To a solution of 13c (117 mg, 0.17 mmol) in CH2Cl2 (1 mL), 2,6-
lutidine (0.06 mL, 0.52 mmol) and TMSOTf (0.06 mL, 0.33 mmol)
were added at ꢀ78 ꢁC under Ar and the mixture was stirred at
ꢀ78 ꢁC for 1 h, ꢀ40 ꢁC for 1 h, and then 0 ꢁC for 2 h. Satd aq NH4Cl
was added and the mixture was extracted with AcOEt. The organic
layer was washed with brine, dried over MgSO4, and evaporated in
vacuo. The residue was purified by CC (n-hexane/acetone¼8:1) to
give 22 as a colorless oil (34 mg, 34%).
3), 3.36 (3H, s, OMe), 3.48–3.50, 3.65–3.68 (each 2H, s, OCH2
-
CH2OMe), 4.04, 4.07 (each 1H, d, J¼10.9 Hz, CH2OMEM), 4.65 (1H,
br s, one of ]CH2), 4.66, 4.67 (each 2H, s, CH2Ph or OCH2O), 4.81
(1H, br t, J¼1.6 Hz, one of ]CH2), 6.30 (1H, d, J¼2.2 Hz, Ar H-3), 6.34
(1H, dd, J¼8.2, 2.2 Hz, Ar H-5), 6.48 (1H, s, ]CH), 7.00 (1H, d,
J¼8.2 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.9 Hz, Ph), 7.29 (3H, dif. t,
J¼7.9 Hz, Ph), 7.36 (4H, dif. t, J¼7.2 Hz, Ph), 7.43 (2H, dif. t, J¼7.4 Hz,
IR (ATR, cmꢀ1): 1676. 1H NMR (400 MHz)
d: 1.09 (9H, s, t-Bu),
1.75 (3H, dd, J¼3.2, 1.7 Hz, Me), 2.61–2.79 (2H, m, H-4), 3.38 (1H,
br s, H-3a), 4.37 (1H, d, J¼7.0 Hz, H-7a), 4.48 (1H, ddd, J¼14.0, 2.1,
2.1 Hz, H-2), 4.59 (1H, ddd, J¼14.0, 2.4, 1.4 Hz, H-2), 4.67 (2H, s,
CH2Ph), 6.32 (1H, d, J¼2.4 Hz, Ar H-3), 6.37 (1H, dd, J¼8.4, 2.4 Hz,
Ar H-5), 6.56–6.59 (2H, m, H-5 and ]CH), 6.70 (1H, d, J¼8.4 Hz, Ar
H-6), 7.22 (2H, dif. d, J¼7.8 Hz, Ph), 7.31 (3H, dif. t, J¼7.5 Hz, Ph),
7.37 (2H, dif. t, J¼7.1 Hz, Ph), 7.43 (2H, dif. t, J¼7.3 Hz, Ph), 7.69 (4H,
Ph), 7.69 (4H, dif. d, J¼8.0 Hz, Ph). 13C NMR (100 MHz)
d: 19.0, 19.5,
24.4, 26.5, 30.8, 31.3, 41.2, 47.5, 59.0, 62.8, 65.0, 66.2, 67.0, 69.8, 71.2,
71.7, 95.3, 104.6, 111.6, 114.2, 119.3, 124.5, 126.9, 127.0, 127.6, 127.8,
128.4, 129.9, 130.4, 132.9, 135.5, 136.9, 139.7, 142.6, 156.0, 156.7.
HRFABMS m/z 801.3622 (calcd for C47H58KO7Si: 801.3589).
24
Compound (18S)-27: a colorless oil. [
a]
ꢀ14.6 (c 1.9). IR (ATR,
D
cmꢀ1): 3480. 1H NMR (400 MHz)
d
: 1.09 (9H, s, t-Bu), 1.32 (each 3H,
dif. d, J¼6.6 Hz, Ph). 13C NMR (100 MHz)
d
: 15.9, 19.5, 25.8, 26.5,
s, Me), 1.43 (1H, dd, J¼12.9, 11.9 Hz, H-6), 1.81 (1H, br d, J¼12.9 Hz,
H-6), 1.85 (3H, s, Me), 1.88 (1H, dif. ddd, J¼14.8, 10.2, 2.0 Hz, H-4),
2.20 (1H, dif. dd, J¼14.8, 4.5 Hz, H-4), 2.25 (1H, d, J¼13.4 Hz, one of
CH2), 2.35 (1H, s, OH, exchangeable with D2O), 2.42 (1H, m, H-5),
2.52 (1H, d, J¼13.4 Hz, one of CH2), 3.09 (1H, dd, J¼2.0, 2.0 Hz, H-3),
43.6, 69.3, 70.0, 78.8, 104.8, 112.1, 114.7, 119.0, 127.0, 127.78, 127.84,
128.4, 128.6, 130.0, 132.8, 135.1, 135.5, 136.9, 138.0, 143.5, 156.0,
156.4, 196.8. HRFABMS m/z 600.2728 (calcd for C39H40O4Si
600.2696).

778
F. Ito et al. / Tetrahedron 65 (2009) 771–785
3.34 (3H, s, OMe), 3.46–3.48, 3.64–3.66 (each 2H, m, OCH2-
CH2OMe), 4.03, 4.07 (each 1H, d, J¼10.6 Hz, CH2OMEM), 4.66, 4.67
(each 2H, s, CH2Ph or OCH2O), 4.82 (1H, br s, one of ]CH2), 4.95
(1H, br dd, J¼1.3, 1.3 Hz, one of ]CH2), 6.29 (1H, d, J¼2.2 Hz, Ar H-
3), 6.34 (1H, dd, J¼8.2, 2.2 Hz, Ar H-5), 6.52 (1H, s, ]CH), 7.01 (1H,
d, J¼8.2 Hz, Ar H-6), 7.21 (2H, dif. d, J¼7.9 Hz, Ph), 7.28 (3H, dif. t,
J¼7.7 Hz, Ph), 7.36 (4H, dif. t, J¼7.9 Hz, Ph), 7.43 (2H, dif. t, J¼7.3 Hz,
and the mixture was extracted with AcOEt. The organic layer was
washed with 5% aq NaOH and brine, dried over MgSO4, and evap-
orated in vacuo. The residue was purified by CC (n-hexane/
acetone¼4:1) to give (18S)-28 (14 mg, 9%) and 29 (4 mg, 6%) as
a colorless oil, respectively.
22
Compound (18S)-28: [
NMR (400 MHz)
a]
ꢀ9.5 (c 1.2). IR (ATR, cmꢀ1): 3496. 1H
D
d
: 1.08 (9H, s, t-Bu),1.53 (1H, dd, J¼12.7,12.7 Hz, H-
Ph), 7.69 (4H, dif. d, J¼7.9 Hz, Ph). 13C NMR (100 MHz)
d
: 18.9, 19.5,
6), 1.55–1.68 (1H, m, H-4), 1.82 (4H, s, Me and OH, exchangeable
with D2O), 2.09 (2H, m, H-4 and 6), 2.22 (1H, s, OH, exchangeable
with D2O), 2.61, 2.78 (each 1H, d, J¼13.5 Hz, CH2), 3.04 (1H, m, H-5),
3.35 (3H, s, OMe), 3.49–3.53, 3.64–3.74 (each 2H, m, OCH2CH2OMe),
4.10 (2H, s, CH2OMEM), 4.58 (1H, br s, H-3), 4.68 (4H, s, OCH2O and
CH2Ph), 4.82, 4.92 (each 1H, br s, ]CH2), 5.09, 5.29 (each 1H, d,
J¼1.4 Hz, ]CH2), 6.28 (1H, d, J¼2.2 Hz, Ar H-3), 6.34 (1H, dd, J¼8.3,
2.2 Hz, Ar H-5), 6.55 (1H, s, ]CH), 7.02 (1H, d, J¼8.3 Hz, Ar H-6),
7.19–7.30 (5H, m, Ph), 7.36 (4H, dif. t, J¼7.3 Hz, Ph), 7.43 (2H, dif. t,
25.1, 26.5, 31.5, 33.1, 40.5, 43.9, 59.0, 61.7, 62.9, 65.9, 67.1, 69.8, 71.7,
71.9, 95.4, 104.5, 111.6, 115.7, 119.1, 125.1, 127.0, 127.7, 127.8, 128.4,
129.9, 130.3, 132.9, 135.5, 136.9, 139.6, 142.6, 156.1, 156.7. HRFABMS
m/z 762.3927 (calcd for C47H58O7Si: 762.3952).
4.1.11. (1R,2RS,4R,6R,Z)-4-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
1,6-epoxy-1-methyl-2-(2-methyl-2-propen-1-yl)-2-
trimethylsilanyloxylcyclohexane (17)
J¼7.2 Hz, Ph), 7.68 (4H, dif. d, J¼7.3 Hz, Ph). 13C NMR (100 MHz)
d:
To a solution of 13c (2.55 g, 3.64 mmol) in Et2O (30 mL), 2-
methylallylmagnesium chloride (0.9 M solution in Et2O, 16.0 mL,
14.4 mmol) was added at ꢀ78 ꢁC under Ar and the mixture was
stirred at ꢀ78 ꢁC for 30 min. Satd aq NH4Cl was added and the
mixture was extracted with Et2O. The organic layer was washed
with H2O and brine, dried over MgSO4, and evaporated in vacuo to
give a crude 27 (3.0 g). TMSCl (1.00 mL, 7.88 mmol) was added to
a solution of the crude 27 and imidazole (735 mg, 10.8 mmol) in
DMF (10 mL) and the whole mixture was stirred at rt for 4 h. Satd aq
NH4Cl was added and extracted with AcOEt. The organic layer was
washed with H2O and brine, dried over MgSO4, and evaporated in
vacuo. The residue was purified by CC (n-hexane/AcOEt¼8:1) to
give 17 as a colorless oil (2.76 g, 92%, dr 1:1).
19.5, 24.8, 26.6, 34.8, 40.1, 46.5, 48.2, 59.1, 65.8, 67.1, 69.8, 71.9, 74.0,
74.2, 95.3, 104.7, 111.6, 112.4, 115.3, 119.5, 124.8, 126.8, 127.6, 127.8,
128.4, 129.9, 130.4, 133.0, 135.5, 137.0, 139.5, 143.8, 152.9, 156.0,
156.7. HRFABMS m/z 801.3622 (calcd for C47H58KO7Si: 801.3589).
Compound 29: IR (ATR, cmꢀ1): 3494. 1H NMR (400 MHz)
d: 1.10
(9H, s, t-Bu), 1.20 (3H, s, Me), 1.55 (1H, dd, J¼14.0, 10.7 Hz, H-6), 1.87
(3H, s, Me), 2.07 (1H, d, J¼13.3 Hz, one of CH2), 2.22 (1H, dd, J¼14.0,
5.6 Hz, H-6), 2.35 (1H, s, 1-OH, exchangeable with D2O), 2.64 (1H, d,
J¼13.3 Hz, one of CH2), 2.80 (1H, s, 2-OH, exchangeable with D2O),
3.23–3.28 (1H, m, H-5), 3.34 (3H, s, OMe), 3.48, 3.66 (each 2H, dif. t,
J¼4.5 Hz, OCH2CH2OMe), 4.04, 4.12 (each 1H, d, J¼10.6 Hz, CH2O-
MEM), 4.65, 4.68 (2H, s, OCH2O or CH2Ph), 4.79, 5.01 (each 1H, s,
]CH2), 5.58 (1H, dd, J¼10.2, 2.4 Hz, H-3), 5.65 (1H, br d, J¼10.2 Hz,
H-4), 6.31 (1H, d, J¼2.2 Hz, Ar H-3), 6.36 (1H, dd, J¼8.2, 2.2 Hz, Ar H-
5), 6.55 (1H, s, ]CH), 7.06 (1H, d, J¼8.2 Hz, Ar H-6), 7.24–7.32 (5H,
m, Ph), 7.37 (4H, dif. t, J¼7.5 Hz, Ph), 7.44 (2H, dif. t, J¼7.3 Hz, Ph),
IR (ATR, cmꢀ1): 1603. 1H NMR (400 MHz)
d: 0.10, 0.15 (each 9H,
s, 2ꢂTMS), 1.10 (18H, s, 2ꢂt-Bu), 1.31–1.47 (1H, m, H-5), 1.33 (6H, s,
2ꢂMe), 1.61–1.75 (5H, m, 2ꢂH-5 and 3ꢂH-3), 1.77, 1.82 (each 3H, s,
2ꢂMe), 2.03(1H,dif. dd, J¼12.6,1.7,1.7 Hz,H-5), 2.11(1H, d,J¼13.8 Hz,
one of CH2), 2.22 (1H, d, J¼13.3 Hz, one of CH2), 2.24 (1H, dif. d,
J¼14.5 Hz, H-3), 2.37 (1H, m, H-4), 2.39 (1H, d, J¼13.8 Hz, one of CH2),
2.45 (1H, d, J¼13.3 Hz, one of CH2), 2.75 (1H, dddd, J¼12.0, 12.0,
3.2, 3.2 Hz, H-4), 3.08 (1H, dif. d, J¼1.1 Hz, H-6), 3.09 (1H, dif. d,
J¼2.4 Hz, H-6), 3.33, 3.34 (each 3H, s, 2ꢂOMe), 3.45–3.47 (4H, m,
2ꢂOCH2CH2OMe), 3.63–3.66 (4H, m, 2ꢂOCH2CH2OMe), 3.99, 4.035,
4.043, 4.07(each1H, d,J¼10.7 Hz, 2ꢂCH2OMEM), 4.61(1H,brs,oneof
]CH2), 4.64, 4.67 (each 4H, m, 2ꢂCH2Phand 2ꢂOCH2O), 4.73 (1H, dif.
d,J¼1.8 Hz, one of ]CH2),4.77(1H,dif.dd, J¼1.9,1.9 Hz,oneof]CH2),
4.85 (1H, dif. dd, J¼2.6, 1.4 Hz, one of ]CH2), 6.30, 6.31 (each 1H, d,
J¼2.5 Hz, Ar H-3), 6.35, 6.34 (each 1H, dd, J¼8.3, 2.5 Hz, 2ꢂAr H-5),
6.47, 6.49 (each 1H, s, 2 ]CH), 7.02, 7.03 (each 1H, d, J¼8.3 Hz, 2ꢂAr
H-6), 7.23 (4H, dif. d, J¼7.7 Hz, Ph), 7.25–7.30 (6H, m, Ph), 7.37 (8H, dif.
t, J¼7.2 Hz, Ph), 7.43 (4H, dif. t, J¼7.2 Hz, Ph), 7.70 (8H, dif. d, J¼8.0 Hz,
7.71 (4H, dif. d, J¼6.8 Hz, Ph). 13C NMR (100 MHz)
d: 19.5, 24.6, 25.7,
26.5, 38.1, 38.9, 42.2, 59.0, 66.2, 67.0, 69.7, 71.7, 72.5, 74.5, 95.4,
104.4, 111.6, 116.0, 119.1, 126.1, 126.9, 127.7, 127.8, 128.3, 129.1, 129.9,
130.1, 132.9, 134.6, 135.5, 136.9, 139.6, 142.8, 156.1, 156.7. HRFABMS
m/z 801.3533 (calcd for C47H58KO7Si: 801.3589).
4.1.13. Ring-opening of 17 with Al(Oi-Pr)3 (run 2 in Table 1):
(1R,3S,5R,Z)-5-{3-[2-benzyloxy-4-(tert-butyldiphenylsilanyloxy)-
phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-3-(2-
methyl-2-propen-1-yl)-2-methylene-3-trimethylsilanyloxy-1-
cyclohexanol [(18S)-18] and (1R,5S,2E,Z)-5-{3-[2-benzyloxy-4-
(tert-butyldiphenylsilanyloxy)phenyl]-1-[(methoxyethoxy)meth-
oxy]-2-propen-2-yl}-2-isopropyloxymethyl-3-(2-methyl-2-
propen-1-yl)-2-cyclohexen-1-ol (30)
A mixture of 17 (108 mg, 0.13 mmol) and Al(Oi-Pr)3 (161 mg,
0.79 mmol) in xylenes (1 mL) was refluxed for 7 h under Ar. After
cooling to rt, satd aq NH4Cl was added and the mixture was
extracted with AcOEt. The organic layer was washed with brine,
dried over MgSO4, and evaporated in vacuo. The residue was
purified by CC (n-hexane/AcOEt¼4:1 to 2:1) to give (18S)-18
(29 mg, 27%) and 30 (13 mg, 13%) as a colorless oil, respectively,
Ph).13C NMR (100 MHz)
d: 2.5, 2.7,19.5,19.6,19.9, 24.5, 25.1, 26.6, 31.2,
32.2, 32.3, 33.2, 41.2, 41.3, 44.2, 51.2, 59.0, 61.4, 61.5, 62.3, 62.6, 66.1,
66.2, 66.9, 67.0, 69.76, 69.80, 71.7, 75.8, 76.5, 95.5, 95.6, 104.4, 104.5,
111.5, 111.6, 114.3, 115.3, 119.2, 119.5, 124.5, 124.6, 127.0, 127.1, 127.6,
127.7,127.79,127.80,128.35,128.40,130.0,130.4,130.5,132.95,132.96,
135.5, 136.9, 137.0, 139.6, 140.1, 142.8, 143.0, 156.0, 156.1, 156.69,
156.72. HRFABMS m/z 834.4418 (calcd for C50H66O7Si2: 834.4347).
with recovery of (18R)-17 (29 mg, 27%).
20
Compound (18S)-18: [
a
]
ꢀ9.5 (c 1.3). IR (ATR, cmꢀ1): 3466. 1H
D
4.1.12. Ring-opening of 27 with Al(Oi-Pr)3 (run 1 in Table 1):
(1S,3R,5R,Z)-5-{3-[2-benzyloxy-4-(tert-butyldiphenylsilanyloxy)-
phenyl]-1-[(methoxyethoxy)methoxy]-2-propen-2-yl}-2-
methylene-1-(2-methyl-2-propen-1-yl)-1,3-cyclohexadiol [(18S)-
28] and (1R,2R,5S,Z)-5-{3-[2-benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(methoxyethoxy)methoxy]-2-propen-2-yl}-2-
methyl-1-(2-methyl-2-propen-1-yl)-3-cyclohexen-1,2-diol (29)
A mixture of 27 (150 mg, 0.12 mmol) and Al(Oi-Pr)3 (241 mg,
1.18 mmol) in xylenes (2 mL) was stirred at 115 ꢁC for 3 h and then
refluxed for 6 h under Ar. After cooling to rt, 5% aq NaOH was added
NMR (400 MHz) d: 0.08 (9H, s, TMS), 1.09 (9H, s, t-Bu), 1.45 (1H, ddd,
J¼13.5,13.5, 2.7 Hz, H-6), 1.64 (1H, dd, J¼12.3,12.3 Hz, H-4), 1.74 (1H,
s, OH), 1.80 (3H, s, Me), 2.09 (1H, ddd, J¼13.5, 5.3, 2.7 Hz, H-6), 2.16
(1H, ddd, J¼12.3, 2.3, 2.3 Hz, H-4), 2.55, 2.61 (each 1H, d, J¼13.8 Hz,
CH2), 3.00 (1H, m, H-5), 3.34 (3H, s, OMe), 3.45–3.52 (2H, m, OCH2
-
CH2OMe), 3.62–3.74 (2H, m, OCH2CH2OMe), 4.09, 4.13 (each 1H, d,
J¼10.6 Hz, CH2OMEM), 4.52 (1H, br d, J¼2.7, 2.7 Hz, H-1), 4.66–4.70
(1H, m, one of ]CH2), 4.66 (2H, s, CH2Ph), 4.70 (2H, s, OCH2O), 4.79
(1H, br dd, J¼2.7, 1.3 Hz, one of ]CH2), 5.08 (1H, d, J¼2.3 Hz, one of
]CH2), 5.27 (1H, d, J¼2.3 Hz, one of ]CH2), 6.31 (1H, d, J¼2.3 Hz, Ar

F. Ito et al. / Tetrahedron 65 (2009) 771–785
779
H-3), 6.35 (1H, dd, J¼8.3, 2.3 Hz, Ar H-5), 6.53 (1H, s, ]CH), 7.04 (1H,
d, J¼8.3 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.7 Hz, Ph), 7.25–7.31 (3H, m,
Ph), 7.37 (4H, dif. t, J¼7.4 Hz, Ph), 7.43 (2H, dif. t, J¼7.3 Hz, Ph), 7.70
(125 MHz) d: 2.4, 19.5, 25.2, 26.5, 32.9, 41.1, 45.2, 47.0, 59.0, 65.9,
66.9, 69.8, 71.7, 75.0, 79.7, 95.4, 104.5,111.6, 112.6, 115.5,119.4, 124.9,
127.0, 127.6, 127.8, 128.3, 129.9, 130.4, 132.9, 135.5, 137.0, 139.8,
140.1, 148.2, 156.0, 156.7. HRFABMS m/z 873.3956 (calcd for
C50H66KO7Si2: 873.3984).
(4H, dif. d, J¼6.4 Hz, Ph). 13C NMR (100 MHz)
d: 2.7, 19.5, 24.7, 26.6,
35.0, 39.4, 45.6, 49.7, 59.0, 66.0, 67.0, 69.7, 71.8, 73.6, 79.1, 95.4, 104.5,
111.5, 113.8, 114.0, 119.4, 124.4, 127.0, 127.6, 127.8, 128.4, 129.9, 130.5,
132.9, 135.5, 136.9, 139.8, 145.0, 152.3, 156.0, 156.7. HRFABMS m/z
834.4340 (calcd for C50H66O7Si2: 834.4347).
Compound (18R)-28: IR (ATR, cmꢀ1): 3411. 1H NMR (400 MHz)
d:
1.09 (9H, s, t-Bu), 1.37 (1H, dd, J¼13.4, 13.4 Hz, H-6), 1.52–1.58 (1H,
m, H-4), 1.83 (3H, s, Me), 2.12 (1H, ddd, J¼13.3, 2.8, 2.8 Hz, H-4),
2.22 (1H, dddd, J¼13.4, 2.9, 2.9, 2.9 Hz, H-6), 2.32, 2.63 (each 1H, d,
J¼13.5 Hz, CH2), 3.17 (1H, m, H-5), 3.36 (3H, s, OMe), 3.51 (2H, t,
J¼4.5 Hz, OCH2CH2OMe), 3.64–3.76 (2H, m, OCH2CH2OMe), 4.10,
4.13 (each 1H, d, J¼10.5 Hz, CH2OMEM), 4.46 (1H, br s, H-3), 4.67,
4.68 (each 2H, s, CH2Ph or OCH2O), 4.77 (1H, br s, one of ]CH2),
4.94 (1H, dq, J¼1.4, 1.4 Hz, one of ]CH2), 5.09, 5.11 (each 1H, s,
]CH2), 6.29 (1H, d, J¼2.3 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.3 Hz, Ar
H-5), 6.52 (1H, s, ]CH), 7.02 (1H, d, J¼8.2 Hz, Ar H-6), 7.22 (2H, dif.
d, J¼7.9 Hz, Ph), 7.26–7.31 (3H, m, Ph), 7.36 (4H, dif. t, J¼7.2 Hz, Ph),
7.43 (2H, dif. t, J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼8.0 Hz, Ph). 13C NMR
Compound 30: IR (ATR, cmꢀ1): 3471. 1H NMR (400 MHz)
d: 1.09
(9H, s, t-Bu), 1.17, 1.20 (each 3H, d, J¼6.1 Hz, Me2CH), 1.60 (1H, ddd,
J¼13.3,13.3, 3.9 Hz, H-6), 1.67 (3H, s, Me), 1.94–2.08 (2H, m, H-4 and
6), 2.23 (1H, dd, J¼7.4, 4.6 Hz, H-4), 2.76, 2.81 (each 1H, d,
J¼14.9 Hz, CH2), 2.79–2.83 (1H, m, H-5), 3.13 (1H, br s, OH), 3.34
(3H, s, OMe), 3.44–3.51 (2H, m, OCH2CH2OMe), 3.60–3.67 (2H, m,
OCH2CH2OMe), 3.94 (1H, dd, J¼10.5, 2.0 Hz, one of CH2), 4.11 (2H, s,
CH2OMEM), 4.29 (1H, d, J¼10.5 Hz, one of CH2), 4.35 (1H, br s,
Me2CH), 4.65 (1H, br s, one of ]CH2), 4.65–4.70 (1H, m, H-1), 4.67
(2H, s, CH2Ph), 4.68 (2H, s, OCH2O), 4.73 (1H, br s, one of ]CH2),
6.29 (1H, d, J¼2.3 Hz, Ar H-3), 6.35 (1H, dd, J¼8.3, 2.3 Hz, Ar H-5),
6.54 (1H, s, ]CH), 7.04 (1H, d, J¼8.3 Hz, Ar H-6), 7.22 (2H, m Ph),
7.25–7.30 (3H, m, Ph), 7.36 (4H, dif. t, J¼7.2 Hz, Ph), 7.43 (2H, dif. t,
(100 MHz) d: 19.5, 25.4, 26.6, 31.9, 40.6, 43.8, 46.7, 59.1, 66.1, 67.0,
69.8, 71.9, 74.0, 75.7, 95.2, 104.7, 111.5, 111.6, 115.6, 119.5, 124.5,
126.9, 127.6, 127.8, 128.4, 129.9, 130.4, 132.9, 135.5, 137.0, 139.9,
142.0, 149.7, 156.0, 156.7. HRFABMS m/z 762.3942 (calcd for
C47H58O7Si: 762.3952).
J¼6.9 Hz, Ph), 7.69 (4H, dif. d, J¼6.6 Hz, Ph). 13C NMR (100 MHz)
d:
19.5, 22.0, 22.2, 22.6, 26.6, 34.0, 36.3, 36.9, 41.4, 59.0, 66.3, 66.9,
67.8, 68.1, 69.8, 71.8, 71.9, 95.4, 104.7, 111.5, 111.6, 119.7, 124.2, 126.8,
127.6, 127.8, 128.3, 129.9, 130.4, 133.0, 135.6, 136.7, 137.1 (over-
lapped),140.6,142.8,155.9,156.7. HRFABMS m/z 843.4005 (calcd for
C50H64KO7Si: 843.4058).
4.1.15. Ring-opening of 17 with diethylaluminum amide 26: three-
step procedure from 13c (run 4 in Table 1)
To a solution of 13c (279 mg, 0.39 mmol) in Et2O (3 mL), 2-
methylallylmagnesium chloride (0.9 M solution in Et2O, 1.80 mL,
1.62 mmol) was added at ꢀ78 ꢁC under Ar and the mixture was
stirred at ꢀ78 ꢁC for 30 min. Satd aq NH4Cl was added and the
mixture was extracted with Et2O. The organic layer was washed
with H2O and brine, dried over MgSO4, and evaporated in vacuo to
give crude 27 as a colorless oil (390 mg). To a solution of crude 27
and imidazole (82 mg, 1.20 mmol) in DMF (1 mL), TMSCl (0.12 mL,
0.95 mmol) was added at rt under Ar and the mixture was stirred
for 4 h. Satd aq NH4Cl was added and the whole was extracted with
AcOEt. The organic layer was washed with H2O and brine, dried
over MgSO4, and evaporated in vacuo to give crude 17 as a colorless
oil (349 mg). To a solution of N-cyclohexyl-N-isopropylamine
(0.39 mL, 2.37 mmol) in benzene (0.5 mL), n-BuLi (1.3 M solution in
n-hexane, 1.8 mL, 2.36 mmol) was slowly added at 0 ꢁC under Ar
and the solution was stirred at 0 ꢁC for 10 min. Et2AlCl (1 M solution
in heptanes, 2.4 mL, 2.40 mmol) was slowly added and the solution
was stirred at 0 ꢁC for 30 min. To the solution, a solution of crude 17
in benzene (1.5 mL) was slowly added at 0 ꢁC and the mixture was
stirred at 30 ꢁC for 3 h. 2% Aq HCl was added at 0 ꢁC and the mixture
was extracted with AcOEt. The organic layer was washed with 2% aq
HCl and brine, dried over MgSO4, and evaporated in vacuo. The
residue was purified by CC (neutral SiO2, n-hexane/AcOEt¼3:1) to
give 18 as a light yellow oil (242 mg, 74%, dr 1:2).
4.1.14. Ring-opening of 17 with dimethylaluminum amide 31 (run 3
in Table 1): (1R,3RS,5R,Z)-5-{3-[2-benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
3-(2-methyl-2-propen-1-yl)-2-methylene-3-trimethylsilanyloxy-1-
cyclohexanol (18) and (1R,3R,5R,Z)-5-{3-[2-benzyloxy-4-(tert-
butyldiphenylsilanyloxy)phenyl]-1-[(methoxyethoxy)methoxy]-2-
propen-2-yl}-2-methylene-1-(2-methyl-2-propen-1-yl)-1,3-
cyclohexadiol [(R)-28]
To
a solution of N-cyclohexyl-N-isopropylamine (0.12 mL,
0.73 mmol) in benzene (0.5 mL), n-BuLi (1.3 M solution in n-hex-
ane, 0.57 mL, 0.75 mmol) was slowly added at 0 ꢁC under Ar and the
solution was stirred at 0 ꢁC for 10 min. Me2AlCl (0.94 M in n-hex-
ane, 0.80 mL, 0.75 mmol) was slowly added and the solution was
stirred at 0 ꢁC for 30 min. To the solution, a solution of 17 (104 mg,
0.13 mmol, dr 1:1) in benzene (1.5 mL) was slowly added at 0 ꢁC
and the mixture was stirred at rt for 22 h. Satd aq NH4Cl was added
at 0 ꢁC and the mixture was extracted with AcOEt. The organic layer
was washed with satd aq NH4Cl and brine, dried over MgSO4, and
evaporated in vacuo. The residue was purified by CC (neutral SiO2,
n-hexane/AcOEt¼3:1) to give 18 as a light yellow oil (52 mg, 50%, dr
1:3) and (18R)-28 as a brown oil (7 mg, 7%) with recovery of 17
(24 mg, 23%, dr 1:1). An aliquot of 18 was further purified by CC to
give (18R)-18 as a colorless oil.
23
Compound (18R)-18: [
NMR (600 MHz)
a
]
D
ꢀ3.1 (c 1.0). IR (ATR, cmꢀ1): 3494. 1H
4.1.16. MW-irradiated Cope rearrangement of 18 in DMF (run 8 in
Table 2): (R,Z)-5-{3-[2-benzyloxy-4-(tert-butyldiphenylsilanyloxy)-
phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-2-(3-
methyl-3-buten-1-yl)-2-cyclohexen-1-one (12)
5-mL portions of a solution of 18 (7.50 g, 8.97 mmol, dr 1:2) in
DMF (100 mL) were irradiated under MW condition (300 W) at
180 ꢁC for 4 min. After cooling to rt, the portions were combined.
H2O was added and the mixture was extracted with AcOEt. The or-
ganic layer was washed with H2O and brine, dried over MgSO4, and
evaporated in vacuo. The residue was purified by CC (neutral SiO2,
d: 0.16 (9H, s, TMS), 1.10 (9H, s, t-Bu), 1.57 (1H, ddd,
J¼13.2, 13.2, 2.8 Hz, H-6), 1.64 (1H, dd, J¼13.7, 12.6 Hz, H-4), 1.93
(1H, ddd, J¼13.7, 2.8, 2.8 Hz, H-4), 2.16 (1H, ddd, J¼13.2, 5.8, 3.6 Hz,
H-6), 2.40, 2.61 (each 1H, d, J¼16.7 Hz, CH2), 3.17 (1H, dddd, J¼12.6,
12.6, 3.3, 3.3 Hz, H-5), 3.33 (3H, s, OMe), 3.46 (2H, t, J¼4.7 Hz,
OCH2CH2OMe), 3.62–3.68 (2H, m, OCH2CH2OMe), 4.05 (1H, d,
J¼8.7 Hz, OH, exchangeable with D2O), 4.08, 4.10 (each 1H, d,
J¼10.8 Hz, CH2OMEM), 4.33 (1H, ddd, J¼8.7, 3.3, 3.3 Hz, H-1), 4.33,
4.68 (each 2H, s, OCH2O or CH2Ph), 4.87, 4.90 (each 1H, s, ]CH2),
5.10 (1H, d, J¼0.8 Hz, one of ]CH2), 5.13 (1H, s, one of ]CH2), 6.30
(1H, d, J¼2.4 Hz, Ar H-3), 6.35 (1H, dd, J¼8.3, 2.4 Hz, Ar H-5), 6.54
(1H, s, ]CH), 7.02 (1H, d, J¼8.3 Hz, Ar H-6), 7.22 (2H, dif. d,
J¼8.2 Hz, Ph), 7.26–7.30 (3H, m, Ph), 7.37 (4H, t, J¼7.3 Hz, Ph), 7.43
(2H, dif. t, J¼7.3 Hz, Ph), 7.70 (4H, dif. d, J¼8.2 Hz, Ph). 13C NMR
n-hexane/Et2O¼2:1) to give 12 as a light yellow oil (4.60 g, 69%).
22
[a
]
ꢀ19.1 (c 1.0). IR (ATR, cmꢀ1): 1672. 1H NMR (400 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.72 (3H, s, Me), 2.09–2.13 (2H, m, CH2), 2.31–2.36
(2H, m, CH2), 2.39–2.46 (1H, m, H-4), 2.45 (1H, dd, J¼16.2, 13.8 Hz,
H-6), 2.53 (1H, br ddd, J¼18.0, 4.9, 4.9 Hz, H-4), 2.66 (1H, br dd,

780
F. Ito et al. / Tetrahedron 65 (2009) 771–785
J¼16.2, 3.1 Hz, H-6), 2.94–3.02 (1H, m, H-5), 3.31 (3H, s, OMe), 3.46
(2H, dif. t, J¼4.6 Hz, OCH2CH2OMe), 3.64 (2H, dif. t, J¼4.6 Hz,
OCH2CH2OMe), 4.12 (2H, s, CH2OMEM), 4.65 (1H, br s, one of
]CH2), 4.67 (4H, s, CH2Ph and OCH2O), 4.70 (1H, br s, one of ]CH2),
6.30 (1H, d, J¼2.3 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.3 Hz, Ar H-5),
6.55 (1H, s, ]CH), 6.72 (1H, dif. d, J¼3.8 Hz, H-3), 6.98 (1H, d,
J¼8.2 Hz, Ar H-6), 7.21 (2H, dif. d, J¼6.4 Hz, Ph), 7.26–7.32 (3H, m,
Ph), 7.37 (4H, dif. t, J¼7.1 Hz, Ph), 7.43 (2H, dif. t, J¼7.1 Hz, Ph), 7.69
6.37 (1H, dd, J¼8.2, 2.1 Hz, Ar H-5), 6.57 (1H, s, ]CH), 6.88 (1H,
s, H-8), 6.91 (1H, d, J¼7.8 Hz, H-6), 6.97(1H, d, J¼7.8 Hz, H-5),
7.04 (1H, d, J¼8.2 Hz, Ar H-6), 7.22 (2H, dif. d, J¼8.2 Hz, Ph), 7.27–
7.31 (3H, m, Ph), 7.37 (4H, t, J¼7.3 Hz, Ph), 7.43 (2H, dif. t,
J¼7.4 Hz, Ph), 7.70 (4H, dif. d, J¼7.9 Hz, Ph). 13C NMR (125 MHz)
d
: 19.5, 21.0, 26.6, 28.8, 29.3, 35.9, 39.5, 59.0, 66.2, 67.0, 69.8, 71.7,
95.5, 104.7, 111.6, 119.7, 124.1, 126.4, 126.9, 127.6, 127.8, 128.4,
128.7, 129.6, 129.9, 130.4, 133.0, 133.4, 134.9, 135.6, 136.7, 137.1,
140.9, 155.9, 156.7. HRFABMS m/z 765.3381 (calcd for
C47H54KO5Si: 765.3378).
(4H, dif. d, J¼7.9 Hz, Ph). 13C NMR (125 MHz)
d: 19.4, 22.4, 26.5, 27.5,
32.1, 36.6, 40.5, 43.9, 59.0, 65.6, 67.1, 69.8, 71.6, 95.4, 104.6, 110.2,
111.6, 118.8, 125.2, 126.8,127.7, 127.7, 128.4, 129.9, 130.4, 132.8,135.5,
136.8, 138.0, 138.8, 144.6, 145.3, 156.2, 156.7, 199.4. HRFABMS m/z
783.3537 (calcd for C47H56KO6Si: 783.3483).
4.1.19. (1S,2S,3R,5S,Z)-5-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
2,3-epoxy-2-methylcyclohexanol (36c)
4.1.17. Trial for Cope rearrangement of 18 in the presence of MsCl
(run 1 in Table 3): (R,Z)-6-[3-{2-benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-3-methyl-1,4,4a,5,6,7-hexahydronaphthalen-4a-ol (34)
To a solution of 18 (81 mg, 96 mmol, dr 1:2) in CH2Cl2 (1 mL),
To a solution of 13c (535 mg, 0.76 mmol) in THF (5 mL),
LiEt3BH (1 M solution in THF, 1.10 mL, 1.10 mmol) was added at
0 ꢁC under Ar and the mixture was stirred at 0 ꢁC for 30 min.
Satd aq NaHCO3 was added and the mixture was extracted with
CH2Cl2. The organic layer was washed with H2O and brine, dried
over MgSO4, and evaporated in vacuo. The residue was purified
pyridine (25
added at 0 ꢁC under Ar and the mixture was stirred at 0 ꢁC for 3.5 h
and rt for 7 h. Pyridine (25 L, 0.31 mmol) and MsCl (15 L,
mL, 0.31 mmol) and MsCl (15 mL, 0.19 mmol) were
by CC (n-hexane/AcOEt¼3:2) to give 36c as
a colorless oil
m
m
(482 mg, 90%).
ꢀ15.4 (c 1.0). IR (ATR, cmꢀ1): 3464. 1H NMR (600 MHz)
d:
24
0.19 mmol) was added at 0 ꢁC and the mixture was stirred at rt for
14 h. Aq CuSO4 (10%) was added and the mixture was extracted
with AcOEt. The organic layer was washed with 10% aq CuSO4, satd
aq NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo.
The residue was purified by CC (neutral SiO2, n-hexane/AcOEt¼6:1
to 4:1) to give 12 (18 mg, 25%) and 34 (12 mg, 16%) as a colorless oil,
[
a
]
D
1.09 (9H, s, t-Bu), 1.37 (3H, s, Me), 1.48 (1H, ddd, J¼13.8, 11.5, 4.9 Hz,
H-6), 1.76 (1H, dif. dd, J¼15.0, 2.2 Hz, H-4), 1.77 (1H, dif. dd, J¼13.8,
2.1 Hz, H-6), 2.24 (1H, dif. ddd, J¼15.0, 2.2, 2.2 Hz, H-4), 2.34 (1H, d,
J¼10.4 Hz, OH, exchangeable with D2O), 2.55 (1H, m, H-5), 3.26 (1H,
dd, J¼2.2, 2.2 Hz, H-3), 3.35 (3H, s, OMe), 3.49 (2H, dd, J¼5.2, 4.1 Hz,
OCH2CH2OMe), 3.67 (2H, m, OCH2CH2OMe), 3.91 (1H, ddd, J¼10.4,
4.2, 4.2 Hz, H-1), 4.05, 4.08 (each 1H, d, J¼10.7 Hz, CH2OMEM), 4.67
(4H, s, OCH2O and CH2Ph), 6.30 (1H, d, J¼2.3 Hz, Ar H-3), 6.36 (1H,
dd, J¼8.3, 2.3 Hz, Ar H-5), 6.45 (1H, s, ]CH2), 6.99 (1H, d, J¼8.3 Hz,
Ar H-6), 7.21 (2H, dif. d, J¼7.2 Hz, Ph), 7.25–7.31 (3H, m, Ph), 7.36
(4H, t, J¼7.3 Hz, Ph), 7.43 (2H, dif. t, J¼7.4 Hz, Ph), 7.69 (4H, dif. d,
respectively.
24
Compound 34: [
(500 MHz)
a
]
ꢀ26.5 (c 0.6). IR (ATR, cmꢀ1): 3477. 1H NMR
D
d: 1.09 (9H, s, t-Bu), 1.68 (3H, s, Me), 1.90 (1H, dd, J¼12.7,
12.7 Hz, H-5), 1.99–2.12 (3H, m, H-4, 5, and 7), 2.08 (1H, s, OH), 2.21
(1H, dif. ddd, J¼16.9, 5.3, 5.3 Hz, H-7), 2.48–2.59 (3H, m, H-1, H-4
and 6), 3.07 (1H, br d, J¼16.9 Hz, H-1), 3.34 (3H, s, OMe), 3.48 (2H, t,
J¼4.8 Hz, OCH2CH2OMe), 3.62–3.70 (2H, m, OCH2CH2OMe), 4.09,
4.13 (each 1H, d, J¼10.7 Hz, CH2OMEM), 4.69 (4H, s, CH2Ph and
OCH2O), 5.45 (1H, br s, H-2), 5.53 (1H, ddd, J¼5.3, 1.9, 1.9 Hz, H-8),
6.29 (1H, d, J¼2.2 Hz, Ar H-3), 6.35 (1H, dd, J¼8.4, 2.2 Hz, Ar H-5),
6.56 (1H, s, ]CH), 7.01 (1H, d, J¼8.4 Hz, Ar H-6), 7.22 (2H, dif. d,
J¼8.2 Hz, Ph), 7.25–7.31 (3H, m, Ph), 7.37 (4H, t, J¼7.3 Hz, Ph), 7.43
(2H, dif. t, J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼7.9 Hz, Ph). 13C NMR
J¼8.3 Hz, Ph). 13C NMR (150 MHz)
d: 19.4, 21.3, 26.5, 30.0, 30.7, 36.1,
59.0, 59.7, 63.0, 66.1, 67.0, 68.2, 69.8, 71.7, 95.3, 104.6, 111.6, 119.2,
124.5, 126.9, 127.6, 127.7, 128.3, 129.9, 130.3, 132.9, 135.5, 136.9,
139.3, 156.0, 156.6. HREIMS m/z 708.3463 (calcd for C43H52O7Si:
708.3482).
4.1.20. (1R,2S,4R,Z)-4-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-1-methyl-5-cyclohexen-1,2-diol (37c)
A mixture of 36c (301 mg, 0.425 mmol) and Al(Oi-Pr)3 (133 mg,
0.651 mM) in toluene (3 mL) was refluxed for 1.5 h. After cooling to
rt, 10% aq HCl was added and the whole was extracted with CH2Cl2.
The organic layer was washed with 10% aq HCl and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by CC
(125 MHz) d: 19.5, 23.5, 26.5, 31.2, 32.0, 38.8, 42.5, 45.4, 59.0, 65.9,
67.1, 69.8, 71.1, 71.7, 95.5, 104.7,111.6, 119.4,120.4, 121.4, 124.6,126.8,
127.6, 127.8, 128.4, 129.9, 130.4, 131.8, 132.9, 135.5, 136.96, 136.99,
139.8, 156.0, 156.7. HRFABMS m/z 783.3458 (calcd for C47H56KO6Si:
783.3483).
4.1.18. Trial for Cope rearrangement of 18 in the presence of Burgess
reagent (run 2 in Table 3): (R,Z)-2-{3-[2-benzyloxy-4-(tert-butyl-
diphenylsilanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-
propen-2-yl}-7-methyl-1,2,3,4-tetrahydronaphthalene (35)
(n-hexane/AcOEt¼2:3) to give 37c as a colorless oil (259 mg, 86%).
24
[
a
]
ꢀ86.1 (c 1.0). IR (ATR, cmꢀ1): 3435. 1H NMR (500 MHz)
d:
D
1.10 (9H, s, t-Bu), 1.16 (3H, s, Me), 1.77 (1H, ddd, J¼13.4, 5.8, 2.8 Hz,
H-3), 2.04 (1H, ddd, J¼13.4, 8.2, 5.5 Hz, H-3), 2.24 (1H, s, OH, ex-
changeable with D2O), 2.26 (1H, d, J¼6.4 Hz, OH, exchangeable with
D2O), 3.31 (1H, br t, J¼6.6 Hz, H-4), 3.35 (1H, s, OMe), 3.50 (2H, t,
J¼4.7 Hz, OCH2CH2OMe), 3.62–3.73 (3H, m, OCH2CH2OMe and H-
2), 4.08, 4.17 (each 1H, d, J¼11.9 Hz, CH2OMEM), 4.61, 4.63 (each 1H,
d, J¼11.6 Hz, OCH2O), 4.69, 4.70 (each 1H, d, J¼7.0 Hz, CH2Ph), 5.68
(1H, dd, J¼10.0, 1.7 Hz, H-6), 5.72 (1H, dd, J¼10.0, 3.4 Hz, H-5), 6.30
(1H, d, J¼2.3 Hz, Ar H-3), 6.36 (1H, dd, J¼8.3, 2.3 Hz, Ar H-5), 6.42
(1H, s, ]CH), 7.01 (1H, d, J¼8.3 Hz, Ar H-3), 7.23–7.33 (5H, m, Ph),
7.37 (4H, dif. t, J¼7.2 Hz, Ph), 7.44 (2H, dif. t, J¼7.3 Hz, Ph), 7.71 (4H,
A solution of 18 (90 mg, 0.11 mmol) and Burgess reagent (69 mg,
0.29 mmol) in benzene (1 mL) was stirred at rt for 17.5 h under Ar.
Satd aq NH4Cl was added and the mixture was extracted with
AcOEt. The organic layer was washed with satd aq NH4Cl, H2O, and
brine, dried over MgSO4, and evaporated in vacuo. The residue was
purified by CC (n-hexane/AcOEt¼9:1) to give 12 (21 mg, 26%) and
35 (10 mg, 13%) as a colorless oil, respectively.
24
Compound 34: [
NMR (500 MHz)
a
]
D
ꢀ26.5 (c 0.6). IR (ATR, cmꢀ1): 1603. 1H
d
: 1.10 (9H, s, t-Bu), 1.72 (1H, dddd, J¼11.1, 11.1,
11.1, 6.2 Hz, H-4), 2.07 (1H, m, H-3), 2.28 (3H, s, Me), 2.65 (1H,
dif. t, J¼11.6 Hz, H-2), 2.77 (1H, m, H-1), 2.80–2.87 (2H, m, H-3
and 4), 2.94 (1H, dd, J¼16.3, 3.9 Hz, H-1), 3.32 (3H, s, OMe), 3.45
dif. d, J¼7.9 Hz, Ph). 13C NMR (125 MHz)
d: 19.4, 26.4, 26.5, 32.7,
38.0, 58.9, 65.9, 66.9, 69.5, 69.7, 71.3, 71.7, 95.3, 104.3, 111.5, 119.1,
126.2, 127.0, 127.65, 127.72, 128.3, 129.9, 130.1, 130.9, 132.79, 132.80,
135.4, 136.8, 138.2, 156.0, 156.6. HRFABMS m/z: 731.3337 (calcd for
C43H52NaO7Si: 731.3380).
(2H, t, J¼4.7 Hz, OCH2CH2OMe), 3.64 (2H, t, J¼4.7 Hz, OCH2
-
CH2OMe), 4.15, 4.17 (each 1H, d, J¼11.2 Hz, CH2OMEM), 4.67 (2H,
s, CH2Ph), 4.69 (2H, s, OCH2O), 6.30 (1H, d, J¼2.1 Hz, Ar H-3),

F. Ito et al. / Tetrahedron 65 (2009) 771–785
781
4.1.21. (1S,2R,3R,4R,6S,Z)-4-[3-{2-Benzyloxy-4-(tert-butyl-
diphenylsilanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-
propen-2-yl]-2,3-epoxy-1-methylcyclohexan-1,6-diol (38c)
The organic layer was washed with 10% aq HCl and brine, dried
over Na2SO4, and evaporated in vacuo. The residue was purified
by CC (n-hexane/acetone¼1:1) to give 41 as a colorless oil
(32 mg, 31%).
To a solution of 37c (440 mg, 0.62 mmol) in CH2Cl2 (4 mL), m-
CPBA (65%, 182 mg, 0.69 mmol) was added at ꢀ30 ꢁC and the whole
was stirred at ꢀ30 ꢁC for 16 h. Aq Na2S2O3 (10%) was added and the
whole was extracted with CH2Cl2. The organic layer was washed
with 10% aq Na2S2O3, satd aq NaHCO3, and brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by CC (neutral
SiO2, benzene/AcOEt¼3:2) to give 38c as a colorless oil (406 mg,
IR (ATR, cmꢀ1): 3383. 1H NMR (500 MHz)
d: 1.10 (9H, s, t-Bu),1.19
(3H, s, Me), 1.74 (2H, br dd, J¼12.5, 12.5 Hz, H-3 and 5), 2.11 (2H, br
d, J¼14.3 Hz, H-3 and 5), 2.99 (1H, dddd, J¼12.5, 12.5, 3.3, 3.3 Hz, H-
4), 3.36 (3H, s, OMe), 3.43 (2H, br d, J¼4.2 Hz, 2- and 6-OH, ex-
changeable with D2O), 3.52 (2H, dif. t, J¼4.6 Hz, OCH2CH2OMe),
3.60 (1H, br s, 1-OH, exchangeable with D2O), 3.69 (2H, dif. t,
J¼4.6 Hz, OCH2CH2OMe), 3.79 (2H, br s, H-2 and 6), 4.14 (2H, s,
CH2OMEM), 4.68 (4H, s, OCH2O and CH2Ph), 6.30 (1H, d, J¼2.1 Hz,
Ar H-3), 6.36 (1H, dd, J¼8.2, 2.1 Hz, Ar H-5), 6.55 (1H, s, ]CH), 6.98
(1H, d, J¼8.2 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.9 Hz, Ph), 7.26–7.31
(3H, m, Ph), 7.37 (4H, t, J¼7.2 Hz, Ph), 7.43 (2H, dif. t, J¼7.3 Hz, Ph),
90%, 38c/38c0¼5:1).
24
[
a]
ꢀ48.9 (c 1.1). IR (ATR, cmꢀ1): 3462. 1H NMR (500 MHz)
d:
D
1.11 (9H, s, t-Bu), 1.13 (3H, s, Me), 1.65 (1H, ddd, J¼14.0, 7.3, 3.0 Hz,
H-5), 1.90 (1H, ddd, J¼14.0, 7.0, 7.0 Hz, H-5), 2.73 (1H, d, J¼11.0 Hz,
6-OH, exchangeable with D2O), 3.05 (1H, s, 1-OH, exchangeable
with D2O), 3.16–3.19 (2H, m, H-2 and 4), 3.34 (3H, s, OMe), 3.43–
3.47 (2H, m, H-3 and 6), 3.49 (2H, t, J¼4.6 Hz, OCH2CH2OMe), 3.65–
3.67 (2H, m, OCH2CH2OMe), 4.12, 4.21 (each 1H, d, J¼11.3 Hz,
CH2OMEM), 4.61, 4.62 (each 1H, d, J¼11.0 Hz, CH2Ph), 4.70 (2H, s,
OCH2O), 6.33 (1H, d, J¼2.2 Hz, Ar H-3), 6.38 (1H, dd, J¼8.3, 2.2 Hz,
Ar H-5), 6.47 (1H, s, ]CH), 6.99 (1H, d, J¼8.3 Hz, Ar H-6), 7.21 (2H,
dif. d, J¼7.9 Hz, Ph), 7.28–7.36 (3H, m, Ph), 7.38 (4H, dif. t, J¼7.7 Hz,
Ph), 7.44 (2H, dif. t, J¼7.3 Hz, Ph), 7.71 (4H, dif. d, J¼7.9 Hz, Ph). 13C
7.70 (4H, dif. d, J¼7.9 Hz, Ph). 13C NMR (100 MHz)
d: 19.4, 23.0, 26.5,
28.9, 35.1, 59.1, 65.9, 67.1, 69.8, 71.3, 71.9, 75.8, 95.2, 104.7, 111.7,
119.3, 124.3, 126.8, 127.6, 127.8, 128.3, 129.9, 130.3, 132.9, 135.5,
137.0, 139.4, 156.0, 156.7. HRFABMS m/z 726.3599 (calcd for
C43H54O8Si: 726.3588).
4.1.24. (2R,3R,5R,Z)-5-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
2,3-epoxy-2-(3-methyl-3-buten-1-yl)cyclohexanone (13d)
NMR (125 MHz) d: 19.5, 22.9, 26.5, 30.5, 36.1, 59.0, 59.6, 61.1, 66.2,
67.1, 68.6, 70.0, 71.57, 71.64, 95.4, 104.3, 111.6, 118.3, 126.7, 127.4,
127.8, 127.9, 128.5, 130.0, 130.1, 132.8, 135.5, 136.6, 136.8, 156.4,
156.8. LREIMS 724 (Mþ).
A solution of 12 (845 mg, 1.13 mmol), TBHP (2.6 M solution in
toluene, 3.0 mL, 7.74 mmol), and TritonÒ B (40% solution in
MeOH, 0.95 mL, 2.27 mmol) was stirred at rt for 22 h. Aq Na2S2O3
(10%) was added at 0 ꢁC and the mixture was extracted with
AcOEt. The organic layer was washed with 10% aq Na2S2O3 and
brine, dried over MgSO4, and evaporated in vacuo to give crude
13d0 as a yellow oil (945 mg). To a solution of crude 13d0 and
imidazole (243 mg, 3.6 mmol) in DMF (5 mL), TBDPSCl (0.44 mL,
1.69 mmol) was added at rt and the mixture was stirred at rt for
7 h. Satd aq NH4Cl was added and the mixture was extracted
with AcOEt. The organic layer was washed with H2O and brine,
dried over MgSO4, and evaporated in vacuo. The residue was
purified by CC (n-hexane/AcOEt¼5:1) to give 13d as a colorless
4.1.22. (1R,2R,3R,4R,6S,Z)-4-[3-{2-Benzyloxy-4-(tert-butyl-
diphenylsilanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-
propen-2-yl]-6-tert-butyldimethylsilanyloxy-2,3-epoxy-1-methyl-
1-cyclohexanol (39c)
To a solution of 38c (114 mg, 0.16 mmol, 38c/38c0¼5:1) in
CH2Cl2 (2 mL), 2,6-lutidine (0.03 mL, 0.26 mmol) and TBSOTf
(0.046 mL, 0.20 mmol) were added at ꢀ78 ꢁC and the whole was
stirred at ꢀ78 ꢁC for 30 min. Satd aq NH4Cl and H2O were added
and the whole was extracted with AcOEt. The organic layer was
washed with satd aq NH4Cl and brine, dried over MgSO4, and
evaporated in vacuo. The residue was purified by CC (neutral SiO2,
oil (776 mg, 90%).
24
Compound 13d: [
a
]
þ17.0 (c 1.0). IR (ATR, cmꢀ1): 1709. 1H NMR
D
n-hexane/AcOEt¼3:1) to give 39c as a colorless oil (79 mg, 60%).
(500 MHz)
d
: 1.09 (9H, s, t-Bu),1.63 (1H, ddd, J¼13.8, 9.4, 6.8 Hz, one
25
[
a]
ꢀ58.2 (c 1.0). IR (ATR, cmꢀ1): 3548. 1H NMR (400 MHz)
d:
of CH2),1.71 (3H, s, Me),1.98 (1H, ddd, J¼14.8,11.7, 0.8 Hz, H-4), 2.06
(1H, dd, J¼9.4, 6.2 Hz, one of CH2), 2.07 (1H, dd, J¼9.4, 6.8 Hz, one of
CH2), 2.12 (1H, dd, J¼17.6, 12.1 Hz, H-6), 2.25 (1H, ddd, J¼13.8, 8.7,
6.2 Hz, one of CH2), 2.45 (1H, ddd, J¼14.8, 3.0, 3.0 Hz, H-4), 2.66 (1H,
ddd, J¼17.6, 4.4, 1.1 Hz, H-6), 2.99 (1H, dddd, J¼11.7, 11.7, 4.3, 4.3 Hz,
H-5), 3.34 (3H, s, OMe), 3.44 (1H, d, J¼2.5 Hz, H-3), 3.47 (2H, dif. t,
J¼4.7 Hz, OCH2CH2OMe), 3.64 (2H, dif. t, J¼4.7 Hz, OCH2CH2OMe),
4.07, 4.10 (each 1H, d, J¼11.0 Hz, CH2OMEM), 4.64 (1H, br s, one of
]CH2), 4.66 (2H, s, OCH2O), 4.67 (2H, s, CH2Ph), 4.69 (1H, br s, one
of ]CH2), 6.29 (1H, d, J¼2.2 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.2 Hz,
Ar H-5), 6.49 (1H, s, ]CH), 6.96 (1H, d, J¼8.2 Hz, Ar H-6), 7.20 (2H,
dif. d, J¼8.2 Hz, Ph), 7.27–7.32 (3H, m, Ph), 7.37 (4H, t, J¼7.4 Hz, Ph),
7.43 (2H, dif. t, J¼7.4 Hz, Ph), 7.69 (4H, dif. d, J¼8.2 Hz, Ph). 13C NMR
D
ꢀ0.03, ꢀ0.02 (each 3H, s, Me-TBS), 0.86 (9H, s, t-Bu), 1.09 (9H, s, t-
Bu),1.10 (3H, s, Me),1.47 (1H, ddd, J¼13.3, 3.8, 3.8 Hz, H-5), 1.85 (1H,
ddd, J¼13.3, 10.4, 5.3 Hz, H-5), 3.04 (1H, d, J¼3.7 Hz, H-2), 3.05 (1H,
s, OH, exchangeable with D2O), 3.19 (1H, br t, J¼4.6 Hz, H-4), 3.30
(1H, br d, J¼4.6 Hz, H-3), 3.35 (3H, s, OMe), 3.47–3.50 (3H, m,
OCH2CH2OMe and H-6), 3.65–3.68 (2H, m, OCH2CH2OMe), 4.11,
4.20 (each 1H, d, J¼10.8 Hz, CH2OMEM), 4.66 (2H, s, CH2Ph), 4.71,
4.72 (each 1H, d, J¼7.2 Hz, OCH2O), 6.31 (1H, d, J¼2.3 Hz, Ar H-3),
6.38 (1H, dd, J¼8.3, 2.3 Hz, Ar H-5), 6.46 (1H, s, ]CH), 7.02 (1H, d,
J¼8.3 Hz, Ar H-6), 7.18 (2H, dif. d, J¼7.3 Hz, Ph), 7.26–7.29 (3H, m,
Ph), 7.37 (4H, dif. t, J¼7.8 Hz, Ph), 7.44 (2H, t, J¼7.3 Hz, Ph), 7.70 (4H,
dif. d, J¼8.1 Hz, Ph). 13C NMR (100 MHz)
: ꢀ5.0, ꢀ4.4, 17.9, 19.4,
d
25.7, 25.8, 26.5, 28.3, 37.6, 56.8, 58.3, 58.9, 66.5, 67.0, 68.2, 70.0,
70.8, 71.6, 95.4, 104.4, 111.6, 118.5, 126.7, 127.2, 127.8, 127.9, 128.4,
129.9, 130.2, 132.8, 135.5, 136.3, 136.6, 156.3, 156.8. HRFABMS m/z
764.4060 (calcd for C47H60O7Si: 764.4108).
(125 MHz) d: 19.4, 22.3, 26.5, 27.3, 29.6, 32.7, 32.9, 43.3, 59.0, 60.1,
60.8, 65.8, 67.1, 69.8, 71.6, 95.4, 104.6, 110.4, 111.6, 118.7, 125.4, 126.9,
127.7, 127.8, 128.4, 129.9, 130.3, 132.8, 135.5, 136.8, 137.7, 145.0,
156.2, 156.7, 204.9. HRFABMS m/z 799.3465 (calcd for C47H56KO7Si:
799.3432).
4.1.23. (2S,6R,Z)-t-4-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-1-methylcyclohexan-r-1,c-2,c-6-triol (41)
To a solution of 38c (105 mg, 0.14 mmol, 38c/38c0¼5:1) in
THF (1 mL), LiAlH4 (29 mg, 0.70 mmol) was added and the
whole was stirred at rt for 4 h. LiAlH4 (29 mg, 0.70 mM) was
added and the whole was stirred at rt for further 1 h. Aq HCl
(10%) was added under ice-cooling and the whole was CH2Cl2.
4.1.25. (1S,2S,3R,5S,Z)-5-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
2,3-epoxy-2-(3-methyl-3-buten-1-yl)cyclohexanol (36d)
Compound 36d was prepared from 13d by the same procedure
as for 36c and was obtained as a colorless oil in 93%.
24
[a
]
ꢀ8.0 (c 1.0). IR (ATR, cmꢀ1): 3450. 1H NMR (500 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.39 (1H, ddd, J¼13.2, 13.2, 4.1 Hz, H-6), 1.65–1.74

782
F. Ito et al. / Tetrahedron 65 (2009) 771–785
(2H, m, H-4 and one of CH2), 1.71 (3H, s, Me), 1.83 (1H, d, J¼13.2 Hz,
H-6), 1.94 (1H, ddd, J¼13.8, 10.2, 5.4 Hz, H-4), 2.09–2.19 (2H, m,
CH2), 2.29 (1H, br d, J¼14.6 Hz, one of CH2), 2.46 (1H, d, J¼10.4 Hz,
OH, exchangeable with D2O), 2.54 (1H, dd, J¼11.5, 11.5 Hz, H-5),
3.30 (1H, br s, H-3), 3.36 (3H, s, OMe), 3.49 (2H, dif. t, J¼4.5 Hz,
OCH2CH2OMe), 3.67 (2H, dif. t, J¼4.5 Hz, OCH2CH2OMe), 4.05 (1H br
s, H-1), 4.07 (2H, s, CH2OMEM), 4.67 (4H, s, OCH2O and CH2Ph), 4.67,
4.71 (each 1H, s, ]CH2), 6.29 (1H, d, J¼2.3 Hz, Ar H-3), 6.35 (1H, dd,
J¼8.3, 2.3 Hz, Ar H-5), 6.47 (1H, s, ]CH), 6.99 (1H, d, J¼8.3 Hz, Ar H-
6), 7.22 (2H, dif. d, J¼7.0 Hz, Ph), 7.25–7.32 (3H, m, Ph), 7.36 (4H, t,
J¼7.3 Hz, Ph), 7.43 (2H, dif. t, J¼7.4 Hz, Ph), 7.69 (4H, dif. d, J¼7.6 Hz,
4.1.28. (2R,5R,Z)-5-[3-{2-Benzyloxy-4-(tert-butyldiphenylsilanyloxy)-
phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-yl]-2-hydroxy-
2-methylcyclohexan-1-one (42)
LiAlH4 (36 mg, 0.88 mmol) was placed in a flask and a solution of
36c (637 mg, 0.90 mmol) in THF (7 mL) was added at 0 ꢁC under Ar.
The mixture was stirred at rt for 1 h. Aq HCl (10%) was added and
the mixture was extracted with CH2Cl2. The organic layer was
washed with 10% aq HCl and brine, dried over Na2SO4, and evap-
orated in vacuo. The residue was purified by CC (n-hexane/
AcOEt¼5:12) to give diol as a colorless oil (585 mg, 92%).
25
[
a
]
þ8.2 (c 1.0). IR (ATR, cmꢀ1): 3417. 1H NMR (500 MHz)
d:
D
Ph). 13C NMR (125 MHz)
d
: 19.4, 22.5, 26.5, 29.5, 31.1, 32.6, 33.5,
1.10 (9H, s, t-Bu), 1.23 (3H, s, Me), 1.42 (1H, dddd, J¼12.6, 12.6, 12.6,
3.6 Hz, H-5), 1.57 (1H, dif. dd, J¼12.6, 2.9 Hz, H-6), 1.60 (1H, ddd,
J¼14.2, 11.9, 2.4 Hz, H-3), 1.77–1.82 (1H, m, H-5), 1.84 (1H, dif. ddd,
J¼12.6, 12.6, 3.6 Hz, H-6), 2.02 (1H, ddd, J¼14.2, 5.7, 3.5 Hz, H-3),
2.57 (1H, br s, 1-OH or 2-OH, exchangeable with D2O), 2.68 (1H,
dddd, J¼11.9, 11.9, 3.3, 3.3 Hz, H-4), 2.97 (1H, br s, 2-OH or 1-OH,
exchangeable with D2O), 3.35 (3H, s, OMe), 3.48–3.54 (2H, m,
OCH2CH2OMe), 3.62–3.65 (1H, m, one of OCH2CH2OMe), 3.64–3.65
(1H, m, H-2), 3.71–3.75 (1H, m, one of OCH2CH2OMe), 4.09, 4.12
(each 1H, d, J¼10.4 Hz, CH2OMEM), 4.68 (4H, s, OCH2O and, CH2Ph),
6.30 (1H, d, J¼2.2 Hz, Ar H-3), 6.36 (1H, dd, J¼8.2, 2.2 Hz, Ar H-5),
6.53 (1H, s, ]CH), 7.01 (1H, d, J¼8.2 Hz, Ar H-6), 7.23 (2H, dif. d,
J¼7.0 Hz, Ph), 7.26–7.30 (3H, m, Ph), 7.36 (4H, t, J¼7.3 Hz, Ph), 7.42
(2H, dif. t, J¼7.3 Hz, Ph), 7.70 (4H, dif. d, J¼7.9 Hz, Ph). 13C NMR
37.0, 59.0, 62.0, 66.2, 66.5, 67.0, 69.8, 71.7, 95.3, 104.6, 110.2, 111.6,
119.2, 124.5, 126.8, 127.6, 127.8, 128.3, 129.9, 130.4, 132.9, 135.5,
137.0, 139.4, 145.0, 156.0, 156.6. HRFABMS m/z 762.3939 (calcd for
C47H58O7Si: 762.3952).
4.1.26. (1R,2S,4S,Z)-4-{3-[2-Benzyloxy-4-(tert-butyl-
diphenylsilanyloxy)phenyl]-1-[(2-methoxyethoxy)-
methoxy]-2-propen-2-yl}-1-(3-methyl-3-buten-1-yl)-
5-cyclohexen-1,2-diol (37d)
Compound 37d was prepared from 36d by the same procedure
as for 37c and was obtained as a colorless oil in 66%.
24
[a
]
ꢀ62.6 (c 1.0). IR (ATR, cmꢀ1): 3417. 1H NMR (500 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.66 (3H, s, Me), 1.66–1.70 (2H, m, CH2), 1.81 (1H,
ddd, J¼13.4, 5.6, 2.8 Hz, H-3), 2.03–2.10 (3H, m, H-3 and CH2), 2.28
(1H, d, J¼6.2 Hz, 2-OH, exchangeable with D2O), 2.32 (1H, s, 1-OH,
exchangeable with D2O), 3.30–3.35 (1H, m, H-4), 3.35 (3H, s,
OMe), 3.49 (2H, t, J¼4.6 Hz, OCH2CH2OMe), 3.60–3.65, 3.67–3.72
(each 1H, m, OCH2CH2OMe), 3.77 (1H, ddd, J¼6.2, 6.2, 2.5 Hz, H-2),
4.08, 4.16 (each 1H, d, J¼10.8 Hz, CH2OMEM), 4.62, 4.65 (each 1H,
br s, ]CH2), 4.65 (2H, s, CH2Ph), 4.69 (2H, s, OCH2O), 5.73 (1H, dd,
J¼10.1, 1.7 Hz, H-6), 5.81 (1H, dd, J¼10.1, 3.5 Hz, H-5), 6.28 (1H, d,
J¼2.2 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.2 Hz, Ar H-5), 6.43 (1H, s,
]CH), 6.98 (1H, d, J¼8.2 Hz, Ar H-6), 7.20 (2H, dif. d, J¼8.1 Hz, Ph),
7.25–7.31 (3H, m, Ph), 7.36 (4H, t, J¼7.2 Hz, Ph), 7.43 (2H, dif. t,
(125 MHz) d: 19.4, 24.0, 26.5, 28.6, 34.4, 35.1, 35.4, 58.9, 65.9, 66.9,
69.7, 71.7, 71.8, 73.7, 95.2,104.6,111.6,119.5,123.9,126.7,127.5,127.7,
128.3, 129.9, 130.3, 132.8, 135.5, 137.0, 140.2, 155.8, 156.6. HREIMS
m/z 710.3624 (calcd for C43H54O7Si: 710.3639).
A solution of diol (276 mg, 0.39 mmol) and IBX (162 mg,
0.58 mmol) in DMSO (3 mL) was stirred at 60 ꢁC for 1 h. After
cooling to rt, H2O was added and the mixture was filtered. The
filtrate was extracted with AcOEt. The organic layer was washed
with satd aq NaHCO3 and brine, dried over MgSO4, and evaporated
in vacuo. The residue was purified by CC (n-hexane/AcOEt¼4:3) to
give 42 as a colorless oil (246 mg, 90%).
25
J¼7.3 Hz, Ph), 7.68 (4H, dif. d, J¼8.1 Hz, Ph). 13C NMR (125 MHz)
d
:
[
a
]
D
þ8.2 (c 1.0). IR (ATR, cmꢀ1): 3494, 1711. 1H NMR (400 MHz)
19.4, 22.5, 26.5, 31.5, 32.2, 37.2, 38.1, 59.0, 66.0, 67.0, 69.4, 69.7,
71.5, 71.7, 95.4, 104.5, 109.8, 111.6, 119.2, 126.2, 126.8, 127.6, 127.7,
128.3, 129.9, 130.2, 131.3, 132.1, 132.9, 135.5, 136.9, 138.3, 145.9,
156.0, 156.6. HRFABMS m/z 801.3570 (calcd for C47H58KO7Si:
801.3589).
d: 1.10 (9H, s, t-Bu), 1.41 (3H, s, Me), 1.70–1.85 (2H, m, H-3 and 4),
1.99 (1H, dif. d, J¼14.1 Hz, H-4), 2.17 (1H, ddd, J¼12.4, 2.7, 2.7 Hz, H-
3), 2.59–2.69 (3H, m, H-5 and 2ꢂH-6), 3.33 (3H, s, OMe), 3.47 (2H,
dif. t, J¼4.6 Hz, OCH2CH2OMe), 3.64 (2H, dif. t, J¼4.6 Hz, OCH2-
CH2OMe), 3.99 (1H, s, OH, exchangeable with D2O), 4.13 (2H, s,
CH2OMEM), 4.67(each 2H, s, OCH2O or CH2Ph), 4.68 (each 2H, s,
CH2Ph or OCH2O), 6.31 (1H, d, J¼2.4 Hz, Ar H-3), 6.37 (1H, dd, J¼8.2,
2.4 Hz, Ar H-5), 6.56 (1H, s, ]CH), 6.97 (1H, d, J¼8.2 Hz, Ar H-6),
7.22 (2H, dif. d, J¼7.5 Hz, Ph), 7.26–7.32 (3H, m, Ph), 7.37 (4H, dif. t,
J¼7.8 Hz, Ph), 7.43 (2H, dif. t, J¼7.3 Hz, Ph), 7.70 (4H, dif. d, J¼8.2 Hz,
4.1.27. (1S,2R,3R,4R,6S,Z)-4-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-yl]-
2,3-epoxy-1-(3-methyl-3-buten-1-yl)cyclohexan-1,6-diol (38d)
Compound 38d was prepared from 37d by the same procedure
as for 38c and was obtained as a colorless oil in 13%.
Ph). 13C NMR (100 MHz)
d: 19.5, 25.0, 26.5, 29.0, 40.7, 43.1, 45.1,
IR (ATR, cmꢀ1): 3485. 1H NMR (500 MHz)
d: 1.09 (9H, s, t-Bu),
59.0, 65.7, 67.1, 69.8, 71.7, 76.1, 95.4, 104.7, 111.7, 118.7, 124.9, 126.8,
127.7, 127.8, 128.4, 130.0, 130.3, 132.8, 135.5, 136.9, 138.2, 156.3,
156.8, 213.7. HRFABMS m/z 708.3473 (calcd for C43H52O7Si:
708.3482).
1.66 (3H, s, Me), 1.66–1.75 (3H, m, CH2), 1.88 (1H, ddd, J¼14.1, 7.1,
7.1 Hz, H-5), 2.09–2.16 (2H, m, H-5 and one of CH2), 2.73 (1H, d,
J¼11.0 Hz, 6-OH, exchangeable with D2O), 2.97 (1H, s, 1-OH, ex-
changeable with D2O), 3.21 (1H, m, H-3), 3.26 (1H, m, H-2), 3.34
(3H, s, OMe), 3.45–3.49 (3H, m, OCH2CH2OMe and H-6), 3.55 (1H,
ddd, J¼15.7, 7.9, 3.5 Hz, H-4), 3.63–3.66 (2H, m, OCH2CH2OMe),
4.14, 4.20 (each 1H, d, J¼11.4 Hz, CH2OMEM), 4.61, 4.65 (each 1H,
br s, ]CH2), 4.66 (2H, s, CH2Ph), 4.68 (2H, s, OCH2O), 6.29 (1H, d,
J¼2.2 Hz, Ar H-3), 6.37 (1H, dd, J¼8.2, 2.2 Hz, Ar H-5), 6.48 (1H, s,
]CH), 6.95 (1H, d, J¼8.2 Hz, Ar H-6), 7.16 (2H, dif. d, J¼7.9 Hz,
Ph), 7.26–7.28 (3H, m, Ph), 7.37 (4H, dif. t, J¼7.7 Hz, Ph), 7.44 (2H,
dif. t, J¼7.3 Hz, Ph), 7.68 (4H, dif. d, J¼8.1 Hz, Ph). 13C NMR
4.1.29. (2R,5R,Z)-5-{3-[2-Benzyloxy-4-(tert-butyldiphenylsilanyloxy)-
phenyl]-1-hydroxy-2-propen-2-yl}-2-hydroxy-2-methylcyclohexan-
1-one (43)
5-mL portions of a mixture of 42 (2.70 g, 3.77 mmol) and PPTS
(4.70 g, 18.8 mmol) in MEK (30 mL) were irradiated under MW
condition (300 W) at 90 ꢁC for 10 min. After cooling to rt, the por-
tions were combined. Aq HCl (10%) was added and the mixture was
extracted with CH2Cl2. The organic layer was washed with 10% aq
HCl and brine, dried over MgSO4, and evaporated in vacuo to give
a light yellow crude oil (3.1 g). 5-mL portions of a mixture of crude
oil and PPTS (4.70 g, 18.8 mmol) in MEK (30 mL) were irradiated
under MW condition (300 W) at 90 ꢁC for 10 min. After cooling to
rt, the portions were combined. Aq HCl (10%) was added and the
(125 MHz)
d: 19.5, 22.6, 26.6, 29.8, 30.7, 33.8, 36.3, 59.0, 59.7,
60.1, 66.3, 67.1, 69.5, 69.9, 70.1, 71.7, 95.5, 104.6, 110.0, 111.7, 118.5,
126.7, 126.9, 127.8, 127.8, 128.5, 130.0, 130.3, 132.8, 135.5, 136.8,
145.4, 156.4, 156. HRFABMS m/z 778.3930 (calcd for C47H58O8Si:
778.3901).

F. Ito et al. / Tetrahedron 65 (2009) 771–785
783
mixture was extracted with CH2Cl2. The organic layer was washed
with 10% aq HCl and brine, dried over MgSO4, and evaporated in
vacuo. The residue was purified by flash CC (n-hexane/Et2O¼2:3) to
give 43 as a light yellow oil (973 mg, 42%) with recovery of 42
dd, J¼6.4, 3.7 Hz, OCH2CH2OMe), 3.67 (2H, dd, J¼5.8, 3.7 Hz,
OCH2CH2OMe), 3.99 (1H, dd, J¼2.7, 2.7 Hz, H-2), 4.07, 4.11 (each
1H, d, J¼10.7 Hz, CH2OMEM), 4.68 (2H, s, CH2Ph), 4.69 (2H, s,
OCH2O), 4.70, 4.72 (each 1H, br s, ]CH2), 6.29 (1H, d, J¼2.3 Hz,
Ar H-3), 6.35 (1H, dd, J¼8.3, 2.3 Hz, Ar H-5), 6.53 (1H, s, ]CH),
7.01 (1H, d, J¼8.3 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.0 Hz, Ph), 7.24–
7.35 (3H, m, Ph), 7.36 (4H, t, J¼7.5 Hz, Ph), 7.43 (2H, dif. t,
(841 mg, 32%).
23
[
a
]
ꢀ0.68 (c 1.0). IR (ATR, cmꢀ1): 3452, 1711. 1H NMR
D
(400 MHz)
d
: 1.11 (9H, s, t-Bu), 1.41 (3H, s, Me), 1.49 (1H, t, J¼5.5 Hz,
CH2OH, exchangeable with D2O), 1.72 (1H, ddd, J¼12.8, 12.8, 3.5 Hz,
H-3), 1.80–1.87, 1.93–1.99 (each 1H, m, H-4), 2.16 (1H, ddd, J¼12.8,
2.9, 2.9 Hz, H-3), 2.57 (1H, dd, J¼9.0, 2.1 Hz, H-6), 2.69–2.71 (2H, m,
H-5 and 6), 3.96 (1H, s, 2-OH, exchangeable with D2O), 4.10 (2H, d,
J¼5.5 Hz, CH2OH), 4.66 (2H, s, CH2Ph), 6.36 (1H, d, J¼2.3 Hz, Ar H-3),
6.38 (1H, s, ]CH), 6.40 (1H, dd, J¼8.3, 2.3 Hz, Ar H-5), 6.88 (1H, d,
J¼8.3 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.3 Hz, Ph), 7.30 (3H, dif. t,
J¼6.2 Hz, Ph), 7.37 (4H, dif. t, J¼7.1 Hz, Ph), 7.44 (2H, dif. t, J¼7.3 Hz,
J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼6.7 Hz, Ph). 13C NMR (125 MHz)
d:
19.5, 22.8, 26.5, 27.1, 28.6, 28.9, 31.6, 32.5, 33.2, 34.4, 36.9, 59.0,
66.0, 66.9, 69.8, 71.7, 77.3, 80.3, 95.3, 104.7, 106.9, 109.5, 111.6,
119.5, 124.2, 126.8, 127.6, 127.8, 128.3, 129.9, 130.4, 132.9, 135.5,
137.0, 140.5, 145.9, 155.9, 156.7. HRFABMS m/z 804.4449 (calcd for
C50H64O7Si: 804.4421).
4.1.32. (1S,2S,4R,Z)-4-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-1,2-dimethylmethylenedioxy-1-(3-methyl-2-buten-1-
yl)cyclohexane (46)
A mixture of 45 (97 mg, 0.12 mmol) and ClRh(PPh3)3 (23 mg,
25 mM) in degassed 10% aq EtOH (2 mL) was refluxed for 24 h under
Ph), 7.70 (4H, dif. d, J¼7.8 Hz, Ph). 13C NMR (100 MHz)
d: 19.4, 25.0,
26.5, 29.2, 40.7, 43.2, 45.1, 60.5, 70.3, 76.1 105.1 112.1, 118.7, 123.8
126.8 127.8, 128.1 128.5, 129.98, 130.44, 132.7, 135.5, 136.4, 141.8,
156.1, 156.4, 213.7. HRFTMS m/z 643.2863 (calcd for C39H44NaO5Si:
643.2850).
N2. After cooling to rt, the mixture was filtered through a Celite pad
and the filtrate was extracted with AcOEt. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by CC (neutral SiO2, n-hexane/AcOEt¼6:1)
4.1.30. (1R,2S,4S,Z)-4-{3-[2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl]-1-[(2-methoxyethoxy)methoxy]-2-propen-2-yl}-
1-(3-methyl-3-buten-1-yl)-cyclohexan-1,2-diol (44)
LiAlH4 (76 mg, 1.84 mmol) was placed in a flask and a solution of
36d (378 mg, 0.49 mmol) in THF (3 mL) was added at 0 ꢁC under Ar.
The mixture was stirred at rt for 1.5 h. Aq HCl (10%) was added and
the mixture was extracted with CH2Cl2. The organic layer was
washed with 10% aq HCl and brine, dried over Na2SO4, and evap-
orated in vacuo. The residue was purified by CC (n-hexane/
to give 46 as a brown oil (85 mg, 88%, as 10:1 mixture of 46 and 45).
23
[a
]
ꢀ4.3 (c 1.0). IR (ATR, cmꢀ1): 1603. 1H NMR (400 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.22–1.33 (1H, m, H-5), 1.33, 1.50 (each 3H, s,
CMe2),1.56–1.60 (1H, m, H-6),1.58 (3H, s, Me),1.73 (3H, s, Me),1.70–
1.77 (3H, m, 2ꢂH-3 and H-5), 2.25–2.33 (3H, m, H-6 and CH2), 2.60
(1H, dd, J¼12.1, 12.1 Hz, H-4), 3.34 (3H, s, OMe), 3.47 (2H, dif. t,
J¼4.7 Hz, OCH2CH2OMe), 3.67 (2H, dif. t, J¼4.7 Hz, OCH2CH2OMe),
3.95 (1H, br s, H-2), 4.07, 4.11 (each 1H, d, J¼11.0 Hz, CH2OMEM),
4.67 (2H, s, CH2Ph), 4.68 (2H, s, OCH2O), 5.29 (1H, t, J¼7.3 Hz, ]CH),
6.29 (1H, d, J¼2.0 Hz, Ar H-3), 6.35 (1H, dd, J¼8.3, 2.0 Hz, Ar H-5),
6.52 (1H, s, ]CH), 7.01 (1H, d, J¼8.3 Hz, Ar H-6), 7.22 (2H, dif. d,
J¼7.8 Hz, Ph), 7.26–7.31 (3H, m, Ph), 7.36 (4H, t, J¼7.3 Hz, Ph), 7.43
(2H, t, J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼7.8 Hz, Ph). 13C NMR
AcOEt¼2:3) to give 44 as a colorless oil (335 mg, 89%).
22
[
a]
þ6.6 (c 1.0). IR (ATR, cmꢀ1): 3442. 1H NMR (500 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.40 (1H, dif. ddd, J¼12.8, 12.8, 12.8 Hz, H-5), 1.57–
1.68 (3H, m, H-3, 6 and one of CH2), 1.74 (3H, s, Me), 1.71–1.79 (3H,
m, H-5, 6 and one of CH2), 2.05 (1H, br d, J¼15.1 Hz, H-3), 2.11 (2H, t,
J¼8.2 Hz, CH2), 2.28 (1H, s, 1-OH, exchangeable with D2O), 2.70 (1H,
br t, J¼15.1 Hz, H-4), 2.74 (1H, s, 1-OH, exchangeable with D2O),
3.36 (3H, s, OMe), 3.48–3.55 (2H, m, OCH2CH2OMe), 3.61–3.65 (1H,
(100 MHz) d: 18.1, 19.6, 26.0, 26.7, 27.0, 28.7, 29.2, 32.8, 33.8, 34.9,
m, OCH2CH2OMe), 3.71 (1H, br s, H-2), 3.71–3.79 (1H, m, OCH2
36.9, 59.1, 66.2, 67.1, 69.9, 71.9, 77.1, 81.0, 95.4, 104.8, 107.1, 111.7,
119.5, 119.7, 124.2, 126.9, 127.7, 127.9, 128.4, 130.0, 130.5, 133.1, 134.2,
135.6, 137.2, 140.7, 156.0, 156.8. HRFTMS m/z 827.4312 (calcd for
C50H64NaO7Si: 827.4314).
-
CH2OMe), 4.09, 4.12 (each 1H, d, J¼10.6 Hz, CH2OMEM), 4.67 (2H, s,
CH2Ph), 4.68 (2H, s, OCH2O), 4.70, 4.72 (each 1H, br s, ]CH2), 6.30
(1H, d, J¼2.2 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.2 Hz, Ar H-5), 6.52
(1H, s, ]CH), 6.99 (1H, d, J¼8.2 Hz, Ar H-6), 7.23 (2H, dif. d,
J¼7.9 Hz, Ph), 7.25–7.31 (3H, m, Ph), 7.37 (4H, t, J¼7.5 Hz, Ph), 7.43
(2H, dif. t, J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼7.3 Hz, Ph). 13C NMR
4.1.33. (1S,2S,4R,Z)-4-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-1-(3-methyl-2-buten-1-yl)-cyclohexane-1,2-diol (47)
(125 MHz) d: 19.4, 22.7, 26.5, 28.1, 30.7, 31.8, 33.7, 35.1 (overlapped),
59.0, 66.0, 67.0, 69.7, 71.8, 72.7, 73.3, 95.3, 104.6, 109.8, 111.6, 119.5,
124.0, 126.8, 127.6, 127.8, 128.3, 129.9, 130.3, 132.9, 135.50, 137.0,
140.2, 146.1, 155.9, 156.6. HRFABMS m/z 764.4060 (calcd for
C47H60O7Si: 764.4108).
A solution of 46 (733 mg, 0.91 mmol) in a mixture of AcOH, THF,
and H2O (4:1:1, 14 mL) was stirred at 40 ꢁC for 11 h. After cooling to
rt, satd aq NaHCO3 was added at 0 ꢁC and the mixture was extracted
with CH2Cl2. The organic layer was washed with satd aq NaHCO3
and brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by CC (neutral SiO2, n-hexane/AcOEt¼2:3) to give 47
4.1.31. (1S,2S,4R,Z)-4-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-1,2-(dimethylmethylenedioxy)-1-(3-methyl-3-buten-1-yl)-
cyclohexane (45)
A mixture of 44 (1.1 g, 1.47 mmol) and TsOH$H2O (86 mg,
0.45 mmol) in CH2Cl2 (10 mL) was stirred at rt for 30 min. Satd aq
NaHCO3 was added and the mixture was extracted with AcOEt. The
organic layer was washed satd aq NaHCO3 and brine, dried over
MgSO4, and evaporated in vacuo. The residue was purified by CC (n-
as a colorless oil (639 mg, 92%).
23
[a
]
þ7.9 (c 1.0). IR (ATR, cmꢀ1): 3428. 1H NMR (400 MHz)
d:
D
1.09 (9H, s, t-Bu), 1.42 (1H, dif. dd, J¼11.9, 3.2 Hz, H-5), 1.59–1.65
(2H, m, H-3 and 6), 1.62 (3H, s, Me), 1.71–1.82 (2H, m, H-5 and 6),
1.74 (3H, s, Me), 2.03 (1H, dif. d, J¼14.2 Hz, H-3), 2.12 (1H, s, 1-OH,
exchangeable with D2O), 2.24 (1H, dd, J¼14.3, 7.3 Hz, one of CH2),
2.29 (1H, dd, J¼14.3, 7.6 Hz, one of CH2), 2.67 (1H, s, 2-OH, ex-
changeable with D2O), 2.70 (1H, dif. dd, J¼12.6, 12.6 Hz, H-4), 3.35
(3H, s, OMe), 3.50 (2H, dif. t, J¼4.4 Hz, OCH2CH2OMe), 3.62–3.67
hexane/AcOEt¼8:1) to give 45 as a colorless oil (1.10 g, 97%).
18
[
a]
ꢀ3.2 (c 1.0). IR (ATR, cmꢀ1): 1603. 1H NMR (500 MHz)
d:
(1H, m, one of OCH2CH2OMe), 3.69–3.78 (2H, m, one of OCH2
D
-
1.09 (9H, s, t-Bu), 1.35, 1.52 (each 3H, s, CMe2), 1.54–1.83 (7H, m,
2ꢂH-3, 2ꢂH-5, 6 and CH2), 1.74 (3H, s, Me), 2.10, 2.19 (each 1H,
ddd, J¼13.3, 13.3, 4.7 Hz, CH2), 2.28 (1H, br d, J¼15.0 Hz, H-6),
2.62 (1H, br dd, J¼12.1, 12.1 Hz, H-4), 3.34 (3H, s, OMe), 3.47 (2H,
CH2OMe and H-2), 4.09, 4.12 (each 1H, d, J¼11.4 Hz, CH2OMEM),
4.67 (2H, s, CH2Ph), 4.68 (2H, s, OCH2O), 5.25 (1H, t, J¼7.6 Hz, ]CH),
6.30 (1H, d, J¼2.3 Hz, Ar H-3), 6.35 (1H, dd, J¼8.2, 2.3 Hz, Ar H-5),
6.53 (1H, s, ]CH), 7.00 (1H, d, J¼8.2 Hz, Ar H-6), 7.23 (2H, dif. d,

784
F. Ito et al. / Tetrahedron 65 (2009) 771–785
J¼7.8 Hz, Ph), 7.25–7.31 (3H, m, Ph), 7.36 (4H, t, J¼7.1 Hz, Ph), 7.43
(2H, dif. t, J¼7.3 Hz, Ph), 7.69 (4H, dif. d, J¼8.3 Hz, Ph). 13C NMR
added at 0 ꢁC and the mixture was extracted with AcOEt. The or-
ganic layer was washed with 10% aq HCl, satd aq NaHCO3 and brine,
dried over Na2SO4, and evaporated in vacuo. The residue was pu-
rified by CC (neutral SiO2, n-hexane/AcOEt¼5:1) to give 8 as yellow
(100 MHz) d: 18.2, 19.6, 26.2, 26.7, 28.4, 32.4, 34.6, 35.1, 35.3, 59.1,
66.2, 67.1, 69.9, 71.9, 72.5, 73.9, 95.4, 104.8, 111.7, 118.1, 119.7, 124.1,
126.9,127.7,127.9,128.4,130.0,130.5,133.1,135.6,135.9,137.2,140.5,
156.0, 156.8. HRFTMS m/z 787.4006 (calcd for C47H60NaO7Si:
787.4001).
amorphous (193 mg, 96%).
23
[
a
]
þ27.3 (c 1.0). IR (KBr, cmꢀ1): 3494, 1732, 1712. 1H NMR
D
(400 MHz) d: 1.09 (9H, s, t-Bu), 1.58 (3H, s, Me), 1.60–1.70 (1H, m,
H-5), 1.68 (3H, s, Me), 1.83 (1H, dif. ddd, J¼11.8, 11.8, 11.8 Hz, H-6),
2.03 (1H, dif. d, J¼11.8 Hz, H-6), 2.27 (1H, ddd, J¼13.4, 3.1, 3.1 Hz,
H-5), 2.39 (1H, dd, J¼14.8, 7.5 Hz, one of CH2), 2.53 (1H, dd,
J¼14.8, 6.8 Hz, one of CH2), 2.59–2.68 (3H, m, H-1 and 2ꢂH-2),
3.84 (1H, br s, OH, exchangeable with D2O), 4.69 (2H, s, CH2Ph),
4.95, 5.01 (each 1H, d, J¼12.1 Hz, CH2ODNB), 4.97–5.02 (1H, m,
]CH), 6.34 (1H, br s, Ar H-3), 6.36 (1H, dd, J¼9.7, 2.3 Hz, Ar H-5),
6.73 (1H, s, ]CH), 6.89 (1H, d, J¼9.7 Hz, Ar H-6), 7.21 (2H, dif. d,
J¼8.2 Hz, Ph), 7.25–7.32 (3H, m, Ph), 7.36 (4H, t, J¼7.1 Hz, Ph), 7.43
(2H, dif. t, J¼7.3 Hz, Ph), 7.67 (4H, dif. d, J¼7.8 Hz, Ph), 9.02 (2H, d,
J¼2.3 Hz, DNB-ortho), 9.20 (1H, t, J¼2.3 Hz, DNB-para). 13C NMR
4.1.34. (2S,5R,Z)-5-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-{(2-methoxyethoxy)methoxy}-2-propen-2-
yl]-2-hydroxy-2-(3-methyl-2-buten-1-yl)-cyclohexan-1-one (48)
Compound 48 was prepared from 47 by the same procedure for
42 and was obtained as a colorless oil in 90%.
20
[a
]
þ19.5 (c 1.0). IR (ATR, cmꢀ1): 3480, 1710. 1H NMR
D
(400 MHz) d: 1.07 (9H, s, t-Bu), 1.59 (3H, s, Me), 1.64 (1H, ddd,
J¼12.9, 12.9, 5.5 Hz, H-3), 1.69 (3H, s, Me), 1.82 (1H, dddd, J¼14.3,
14.3, 14.3, 3.2 Hz, H-4), 1.96 (1H, dif. d, J¼14.3 Hz, H-4), 2.24 (1H,
ddd, J¼12.9, 2.8, 2.8 Hz, H-3), 2.38 (1H, dd, J¼15.6, 7.1 Hz, one of
CH2), 2.55 (1H, dd, J¼15.6, 8.0 Hz, one of CH2), 2.58–2.71 (3H, m, H-
(100 MHz) d: 18.1, 19.4, 25.9, 26.4, 28.9, 35.9, 38.7, 43.2, 44.6, 64.9,
5 and 2ꢂH-6), 3.33 (3H, s, OMe), 3.47 (2H, dif. t, J¼4.7 Hz, OCH2
69.9, 78.7, 104.8, 112.0, 116.4, 117.8, 122.4, 126.8, 127.8, 127.8, 128.0,
128.4, 129.2, 129.9, 130.0, 132.6, 133.4, 135.0, 135.4, 135.9, 136.6,
148.5, 156.8, 156.8, 162.3, 212.4. HRFTMS m/z 891.3271 (calcd for
C50H52N2NaO10Si: 891.3283).
-
CH2OMe), 3.64 (2H, dif. t, J¼4.7 Hz, OCH2CH2OMe), 3.90 (1H, s, OH,
exchangeable with D2O), 4.12 (2H, s, CH2OMEM), 4.31 (4H, s, CH2Ph
and OCH2O), 5.02 (1H, dd, J¼7.3, 7.3 Hz, ]CH), 6.31 (1H, d, J¼2.2 Hz,
Ar H-3), 6.37 (1H, dd, J¼8.4, 2.2 Hz, Ar H-5), 6.54 (1H, s, ]CH), 6.97
(1H, d, J¼8.4 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.8 Hz, Ph), 7.26–7.32
(3H, m, Ph), 7.37 (4H, t, J¼7.3 Hz, Ph), 7.44 (2H, dif. t, J¼7.3 Hz, Ph),
Acknowledgements
7.69 (4H, dif. d, J¼7.8 Hz, Ph). 13C NMR (100 MHz)
d: 18.3, 19.6, 26.1,
The Sasakawa Scientific Research Grant from The Japan Science
Society was acknowledged (F.I.) for the financial support.
26.7, 29.0, 36.1, 39.1, 43.6, 45.1, 59.1, 66.0, 67.2, 70.0, 71.8, 78.9, 95.5,
104.8, 111.8, 116.9, 118.8, 125.0, 127.0, 127.9, 127.9, 128.5, 130.1, 130.5,
132.9, 135.6, 135.7, 137.0, 138.4, 156.4, 156.9, 213.5. HRFTMS m/z
785.3855 (calcd for C47H58NaO7Si: 785.3844).
References and notes
1. Ingham, J. L.; Tahara, S.; Pope, G. Chemical Components and Pharmacology of
the Rejuvenating Plant Pueraria mirifica. In Pueraria; Keung, W. M., Ed.; Taylor &
Francis: London, 2002; pp 97–118.
4.1.35. (2S,5R,Z)-5-[3-{2-Benzyloxy-4-(tert-butyldiphenyl-
silanyloxy)phenyl}-1-hydroxy-2-propen-2-yl]-2-hydroxy-2-(3-
methyl-2-buten-1-yl) cyclohexan-1-one (49)
2. (a) Cain, J. C. Nature 1960, 188, 774–777; (b) Jones, H. E.; Pope, G. S. J. Endocrinol.
1960, 20, 229–235; (c) Jones, H. E.; Waynforth, H. B.; Pope, G. S. J. Endocrinol.
1961, 22, 293–302; (d) Jones, H. E.; Pope, G. S. J. Endocrinol. 1961, 22, 303–312.
3. (a) Chansakaow, S.; Ishikawa, T.; Sekine, K.; Okada, M.; Higuchi, Y.; Kudo, M.;
Chaichantipyuth, C. Planta Med. 2000, 66, 572–575; (b) Iwasaki, M.; Watanabe,
T.; Ishikawa, T.; Chansakaow, S.; Higuchi, Y.; Tahara, S. Heterocycles 2004, 63,
1375–1392; (c) Ito, F.; Iwasaki, M.; Watanabe, T.; Ishikawa, T.; Higuchi, Y. Org.
Biomol. Chem. 2005, 3, 674–681.
3-mL portions of a mixture of 48 (2.1 g, 2.71 mmol) and PPTS
(2.2 g, 8.79 mmol) in MEK (21 mL) were irradiated under MW
condition (300 W) at 90 ꢁC for 6 min. After cooling, the portions
were combined. 10% aq HCl was added and the mixture was
extracted with CH2Cl2. The organic layer was washed with 10% aq
HCl and brine, dried over MgSO4, and evaporated in vacuo. The
residue was purified by flash CC (n-hexane/Et2O¼2:1) to give 49 as
4. Chansakaow, S.; Ishikawa, T.; Seki, H.; Sekine, K.; Okada, M.; Chaichantipyuth, C.
J. Nat. Prod. 2000, 63, 173–175.
5. Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327–9328.
6. Ito, F.; Kumamoto, T.; Ishikawa, T. Tetrahedron Lett. 2005, 46, 7765–7767.
7. Ito, F.; Fusegi, K.; Kumamoto, T.; Ishikawa, T. Synthesis 2007, 1785–1796.
8. The numberings of the following compounds are based on those of miroestrols.
9. Majidi, L.; Fihi, R.; El Idrissi, M.; Kharchouf, S. Phys. Chem. News 2005, 25,
127–129.
10. Reviews: Paquette, L. A. Tetrahedron 1997, 53, 13971–14020.
11. As examples of metal-mediated retro-oxy-ene (retro-allyl-Grignard) type re-
actions, see: (a) Holm, T. Acta Chem. Scand., Ser. B 1976, B30, 985–990; (b)
Snowden, R. L.; Schulte-Elte, K. H. Helv. Chim. Acta 1981, 64, 2193–2202; (c)
Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Organomet. Chem. 2007, 692,
505–513; (d) Zhang, W.; Li, C. J. Org. Chem. 2000, 65, 5831–5833.
12. (a) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM:
Matthews, NC, 2000; (b) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005; (c) Tierney, J. P.; Lidstrom, P.
Microwave Assisted Organic Synthesis; Blackwell: Oxford, 2005; (d) Loupy, A.
Microwaves in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
a light yellow oil (539 mg, 30%) with recovery of 48 (1.00 g, 48%).
21
[a
]
þ7.0 (c 1.0). IR (ATR, cmꢀ1): 3460, 1709. 1H NMR (400 MHz)
D
d
: 1.10 (9H, s, t-Bu), 1.47 (1H, t, J¼5.3 Hz, CH2OH, exchangeable with
D2O), 1.60 (3H, s, Me), 1.65 (1H, dif. ddd, J¼13.8, 13.8, 5.4 Hz, H-3),
1.69 (3H, s, Me),1.80–1.95 (2H, m, 2ꢂH-4), 2.23 (1H, ddd, J¼13.8, 3.1,
3.1 Hz, H-3), 2.39 (1H, dd, J¼14.8, 7.5 Hz, one of CH2), 2.54–2.73 (4H,
m, H-5, 2ꢂH-6 and one of CH2), 3.89 (1H, s, 2-OH, exchangeable
with D2O), 4.10 (2H, br d, J¼5.3 Hz, CH2OMEM), 4.66 (2H, s, CH2Ph),
5.02 (1H, dd, J¼7.2, 7.2 Hz, ]CH), 6.35 (1H, d, J¼2.1 Hz, Ar H-3), 6.38
(1H, s, ]CH), 6.40 (1H, dd, J¼8.2, 2.1 Hz, Ar H-5), 6.88 (1H, d,
J¼8.2 Hz, Ar H-6), 7.22 (2H, dif. d, J¼7.9 Hz, Ph), 7.28–7.34 (3H, m,
Ph), 7.37 (4H, t, J¼7.3 Hz, Ph), 7.44 (2H, dif. t, J¼7.4 Hz, Ph), 7.70 (4H,
dif. d, J¼7.6 Hz, Ph). 13C NMR (100 MHz)
d: 18.3,19.6, 26.1, 26.6, 29.2,
13. Smith, A. B., III; Nolen, E. G.; Shirai, R.; Blase, F. R.; Ohta, M.; Chida, N.;
Hartz, R. A.; Fitch, D. M.; Clark, W. M.; Sprengeler, P. A. J. Org. Chem. 1995,
60, 7837–7848.
14. Kirsch, S.; Bach, T. Synthesis 2003, 1827–1836.
15. Murata, S.; Suzuki, M.; Noyori, R. Bull. Chem. Soc. Jpn. 1982, 55, 247–254.
16. Mischne, M. P.; Sierra, M. G.; Ruveda, E. A. J. Org. Chem. 1984, 49, 2035–2037.
36.1, 39.1, 43.7, 45.1, 60.7, 70.5, 78.9, 105.2, 112.2, 116.9, 118.9, 123.9,
127.3, 127.9, 128.2, 128.6, 130.1, 130.6, 132.9, 135.6, 135.8, 136.6,
142.0, 156.3, 156.5, 213.4. HRFTMS m/z 697.3329 (calcd for
C43H50NaO5Si: 697.3320).
17. The stereochemistry of 27 was determined as dl form, not meso form, because
24
of its optical rotation ([
a
]
ꢀ15.5).
D
4.1.36. (1R,4S,Z)-3-{2-Benzyloxy-4-(tert-butyldiphenylsilanyloxy)-
phenyl}-2-{4-hydroxy-4-(3-methyl-2-buten-1-yl)-3-
oxocyclohexyl}-2-propenyl 3,5-dinitrobenzoate (8)
A mixture of 49 (156 mg, 0.23 mmol), 3,5-dinitrobenzoyl chlo-
ride (136 mg, 0.59 mmol), and Et3N (0.10 mL, 0.72 mmol) in CH2Cl2
(1 mL) was stirred at 0 ꢁC for 30 min under N2. Aq HCl (10%) was
18. Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Am. Chem. Soc. 1970, 92, 5224–5226.
19. Hembest, H. B.; Wilson, A. J. Chem. Soc. 1957, 1958–1965.
20. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60,
7272–7276.
21. Corey, E. J.; Gras, J.; Ulrich, P. Tetrahedron Lett. 1976, 17, 809–812.
22. Sabitha, G.; Babu, R. S.; Rajkumar, M.; Srividya, R.; Yadav, J. S. Org. Lett. 2001, 3,
1149–1151.

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23. Shih-Yuan Lee, A.; Hu, Y.; Chu, S. Tetrahedron 2001, 57, 2121–2126.
27. Mace, L. H. M.; Shanmugham, S.; White, J. D.; Drew, M. G. B. Org. Biomol. Chem.
2006, 4, 1020–1031.
´
24. Monti, H.; Leandri, G.; Klos-ringuet, M.; Corriol, C. Synth. Commun. 1983, 13,
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28. Mehta, G.; Murthy, A. N. J. Org. Chem. 1987, 52, 2875–2881.
29. Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960–15961.
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