Stereoselective synthesis of 19-hydroxytaxoid by utilizing samarium(II) iodide-mediated double aldol cyclization

Article abstract of DOI:10.1246/bcsj.78.677

The stereoselective synthesis of new 19-hydroxytaxoid 36, possessing a double-aldol skeleton was achieved by way of B to BC to ABC ring construction. Optically active 8-membered ring 6 corresponding to the B-ring of 19-hydroxytaxol has been synthesized in high yield from epoxyketo aldehyde 8 by intramolecular samarium(II) iodide-mediated double aldol cyclization. The bicyclic compound 5 corresponding to the BC ring system was prepared from the 8-membered ring 6 by successive trimethylaluminium-assisted stereoselective conjugated addition and intramolecular samarium(II) iodide-mediated double aldol cyclization. The ABC-ring system 4 was constructed by stereoselective homoallylation and pinacol coupling cyclization with low-valent titanium. The synthesis of new 19-hydroxytaxoid 36 was accomplished from ABC ring system 4 by olefination of vicinal diol unit.

Full text of DOI:10.1246/bcsj.78.677

ꢁ 2005 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 78, 677–697 (2005)
677
Stereoselective Synthesis of 19-Hydroxytaxoid by Utilizing
Samarium(II) Iodide-Mediated Double Aldol Cyclization
ꢀ;1;2
Yasuyuki Ogawa,1 Kiichi Kuroda,1 Jun-ichi Matsuo,1 and Teruaki Mukaiyama
1The Kitasato Institute, Center for Basic Research, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
2Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
Received October 13, 2004; E-mail: mukaiyam@abeam.ocn.ne.jp
The stereoselective synthesis of new 19-hydroxytaxoid 36, possessing a double-aldol skeleton was achieved by
way of B to BC to ABC ring construction. Optically active 8-membered ring 6 corresponding to the B-ring of 19-hy-
droxytaxol has been synthesized in high yield from epoxyketo aldehyde 8 by intramolecular samarium(II) iodide-medi-
ated double aldol cyclization. The bicyclic compound 5 corresponding to the BC ring system was prepared from the 8-
membered ring 6 by successive trimethylaluminium-assisted stereoselective conjugated addition and intramolecular sa-
marium(II) iodide-mediated double aldol cyclization. The ABC-ring system 4 was constructed by stereoselective homo-
allylation and pinacol coupling cyclization with low-valent titanium. The synthesis of new 19-hydroxytaxoid 36 was
accomplished from ABC ring system 4 by olefination of vicinal diol unit.
Taxolꢀ (1, paclitaxel)1 is currently considered as one of the
most important drugs used in chemotherapy, and is actually the
agent of choice for the treatment of ovarian, breast, and lung
cancer. However, lack of sufficient solubility in water (0.25
mg/mL)2 was one of taxol’s most-concerned problems associ-
ated with its formulation for clinical applications. During our
preparing of a new anticancer agent by chemical modification
of taxol, 19-hydroxytaxol (2) was chosen so as to improve its
pharmacological profile, especially its water-solubility, by the
introducing a hydrophilic molecule such as sugar onto the
newly-introduced C-19 hydroxy group3 of 2 (Fig. 1).
prepared from an optical active polyoxy unit 7 followed by
construction of the A and C ring systems on this framework.
The major difference between 19-hydroytaxol and taxol in
chemical behavior is that the 19-hydroxytaxol has an unstable
double-aldol (ꢀ,ꢀ0-dihydroxy ketone) skeleton. Taking this in-
to consideration, the synthesis of 19-hydroxytaxoid was stud-
ied by utilizing the newly-developed samarium(II) iodide
(SmI2)-mediated double aldol reaction6 as a key step.
OH
R
AcO
O
AcO
O
OH
OH
19
19
Although 19-hydroxybaccatin III (3) can be isolated from
natural resources,4 the quantities of the isolated 3 are not suf-
ficient to prepare its derivatives 2 to develop new biological
activities. Therefore, it was planned to synthesize 2 based on
our strategy for the total synthesis of 1.
Retrosynthetic analysis of 2 is shown in Scheme 1. The syn-
thesis of taxane’s basic skeleton according to our strategy for
the total synthesis of 15 was tried by starting from the B ring
B
BzHN
O
C
A
D
O
O
HO
H
O
H
HO BzO
HO BzO
OAc
OAc
OH
Taxol(1, paclitaxel): R = H
19-Hydroxytaxol (2): R = OH
19-Hydroxybaccatin III (3)
Fig. 1.
OH
OH
O
O
BnO
HO
O
BnO
OMOM
HO
TBSO
19-Hydroxytaxol (2)
H
c-HexMe2SiO OBn
PMBO OBn
4
5
BnO
O
BnO
OBn
TBSO
OH
OH
OTBS
OH
TBS
O
OPMB
PMBO OBn
6
7
Scheme 1. Retrosynthetic analysis.
Published on the web April 8, 2005; DOI 10.1246/bcsj.78.677

678 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
In previous papers, the SmI2-mediated intramolecular aldol
reaction of ꢁ,ꢀ-epoxyketo aldehyde had already been reported
(Scheme 6).6,7 It was shown there that a mixture of cis-syn and
cis-anti diasteromers of the eight-membered double-aldol
products was obtained in 78% yield when 3 equiv of water
were used as additives.
The above method was further applied to the synthesis of a
key intermediate 6, a polyoxy eight-membered ring compound
corresponding to the B ring of 19-hydroxytaxol. As shown in
Scheme 7, ꢁ,ꢀ-epoxyketo aldehyde 8 was obtained from alde-
hyde 9 that was prepared from D-pantolactone according to our
original procedure.10 Vinylation of aldehyde 9 with vinylmag-
nesium bromide gave allylic alcohol 10 in 98% yield as a mix-
ture of two diastereomers. In order to remove the t-butyldi-
methylsilyl (TBS) group at the primary hydroxy group selec-
tively, a diastereomeric mixture of allylic alcohol 10 was treat-
Results and Discussion
Synthesis of the B Ring of 19-Hydroxytaxol.7 In the first
place, construction of a polyoxy eight-membered ring inter-
mediate 6 that contained a double-aldol skeleton was exam-
ined. However, very few examples are known that involve
the synthesis of double aldols, in spite of remarkable recent de-
velopments of aldol chemistry.8 The undesired enolate IV is
generally known to be liberated from ꢀ-hydroxy ketone I by
deprotonation at ꢁ0-carbon with strong bases such as lithium
diisopropylamide (LDA). The thus formed IV reacts with alde-
hyde to afford dihydroxy ketone V (Scheme 2).9
For example, a dihydroxy ketone VII was obtained in 60%
yield by deprotonation of ꢀ-hydroxy ketone VI with LDA,
followed by aldol reaction with 3-phenylpropionaldehyde
(Scheme 3).
In order to overcome these synthetic difficulties, it was tried
to find a new and useful method for the synthesis of unsym-
metrical double-aldols. Eventually, the desired SmI2-mediated
aldol reaction of aldehydes with aryl or alkyl oxiranyl ketones
was established recently in our laboratory (Scheme 4).6
Then, it was considered that the intermediate 6 would be
prepared from ꢁ,ꢀ-epoxyketo aldehyde 8 by the above-
mentioned double-aldol reaction (Scheme 5).
O
OH
O
I SmO
OSmI
2
2
O
R CHO
3
2 SmI
2
R
1
R
2
R
R
2
1
R
1
R
2
HO
R
3
disamarium -oxido
enolate tetraiodide
β
double-aldol
Scheme 4.
BnO
O
OBn
OBn
O
OH
TBSO
O
OH
OH
O
O
α
RCHO
CHO
OPMB
β
O
O
HO
R
TBS
O
OH
PMBO OBn
II
III: double aldol
α
6
8
β
α'
I
Scheme 5.
O
O
OH
O
OH
RCHO
α
α'
β
β'
O
O
I2Sm
SmI2
IV
V
O
O
SmI2, H2O
THF
Ph
Scheme 2.
Ph
Ph
CHO
CHO
O
OH
1) LDA
O
O
OH
OH
CHO
OH
H
H
2)
Ph
Ph
VI
O
OH
+
OH
cis, anti
OH
cis, syn
Ph
VII
(60%)
(78%)
Scheme 6. The eight-membered ring formation by the SmI2-
mediated aldol reaction.
Scheme 3.
OBn
OBn
OH
OBn
OBn
a
OTBS
Ref. 10
OTBS
OHC
TBSO
O
O
OH
TBS
O
OPMB
OPMB
D-Pantolactone
9
10
OBn
OBn
OBn
OBn
O
b
c
OH
CHO
OPMB
OH
TBS
O
OPMB
O
O
TBS
11
8
ꢁ
ꢁ
Scheme 7. Reagents and conditions: a) vinyl-MgBr, THF, 0 C (98%). b) 1 M HCl, THF, rt (88%). c) m-CPBA, CH2Cl2, 50 C
ꢁ
ꢁ
(96%); (COCl)2, DMSO, Et3N, CH2Cl2, ꢂ78 C to 0 C (96%).

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Table 1. Formation of the Eight-Membered Ring (6) by the SmI2-Mediated Aldol Reaction
679
BnO
O
BnO
O
OH
OH
OBn
OBn
O
SmI (2.5 eq.)
10
10
2
TBSO
TBSO
CHO
OPMB
+
THF
O
TBS
O
OH
OH
−78 °C
8
PMBO OBn
PMBO OBn
6a
6b
Yield %
O
OH
Entry Additive equiv
OBn
O
OBn
6 (a b)
12
13
10
TBSO
1
2
3

83 (50 50) 10

12
CHO
OPMB
OH
OH
O
H2O 3.0
76 (39 61)


PMBO OBn
TBS
i-PrOH 2.0 91 (49 51)
trace
12
13
ed with 1 M HCl under high-diluted reaction conditions to give
diol 11 in 88% yield. After epoxydation of terminal olefin with
m-chloroperoxybenzoic acid (m-CPBA), Swern oxidation af-
forded the desired ꢁ,ꢀ-epoxyketo aldehyde 8 as a mixture of
two diastereomers in 92% yield in two steps.
OBn
BnO
O
OH
OH
OH
OH
OH
TBSO
8
8
TBSO
a
1
O
3
3
1
H
PMBO OBn
OBn
Since the precursor for the eight-membered double-aldol 6
was prepared, the following SmI2-mediated intramolecular al-
dol reaction of ꢁ,ꢀ-epoxyketo aldehyde 8 was investigated in
detail. In the first place, 8 was treated with 2.5 equiv of SmI2 in
THF at ꢂ78 ꢁC, and the cyclized products 6a and 6b were ob-
tained in 83% yields (Table 1, Entry 1). Under the conditions
of Entry 1, the by-products 12 which were formed by cleavage
of benzyloxy group at 10-position of 6a and 6b were obtained
at the same time. It was considered that the debenzyloxygena-
tion might take place by further reduction of 6 with SmI2. In
order to inhibit the reductive elimination of benzyloxy group
with SmI2, the reactivity of SmI2 was controlled by the use
of additives. When 3 equiv of water were used as additives,
the aldol reaction of 8 proceeded smoothly to give the cyclized
products 6a and 6b in 76% yield, along with a small amount of
13, which was formed by ring opening of epoxide 8 (Entry 2).
There, hydrolysis of disamarium ꢀ-oxido enolate tetraiodide
with water was thought to take place competitively with the
desired cyclization. It was further found that the yield of the
cyclized product increased up to 91% when i-PrOH was used
as additives (Entry 3). In this case, debenzyloxygenation and
ring opening of the epoxide were not observed. The diaster-
eomer ratio (6a/6b) was not influenced by the stereochemistry
of epoxide 8: that is, SmI2-mediated aldol reaction of each of
diastereomers of 8 gave the same diastereomer ratio (6a/6b).
In order to clarify the structure of these eight-membered ring
compounds, 6a and 6b were transformed into bicyclic deriva-
tives 14a and 14b on treatment with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) and the structures of the formed rig-
id bicyclic skeletons were determined by NOE analysis
(Scheme 8). The NOEs between C-3 proton and C-8 proton,
and C-3 proton and C-1 proton of 14a indicated that both C-
8 hydroxymethyl group and C-3 hydroxy group had ꢀ-config-
urations. On the other hand, the NOEs between C-3 proton and
C-8 proton, and C-3 proton and C-2 proton of 14b indicated
that both C-8 hydroxymethyl group and C-3 hydroxy group
had ꢁ-configurations.
6a
14a
OBn
BnO
O
OH
OH
OH
OH
OH
TBSO
8
8
TBSO
b
3
O
3
2
H
PMBO OBn
OBn
6b
14b
8
3
8
3
2
1
14a
14b
: NOE
Scheme 8. Reagents and conditions: a) DDQ, H2O, CH2Cl2,
rt (51%). b) DDQ, H2O, CH2Cl2, rt (64%).
compounds 6a and 6b were converted into the corresponding
cyclooctenone derivative 17 (Scheme 9). Selective protection
of the primary hydroxy group of 6a and 6b with triethylsilyl
(TES) group followed by acetylation of the remaining secon-
dary hydroxy group gave 15a and 15b. At this point, the
crystalline 15a was subjected to X-ray crystallographic analy-
sis to confirm the assigned stereochemistry (Fig. 2).11 Then,
successive treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)–benzene (4/1) gave enone 16 in 59% yield along with
17 in 26% yield. Conversion of 16 to 17 was carried out by de-
protection of TES group of 16 under acidic conditions.
Synthesis of the BC Ring System of 19-Hydroxytaxol.12,13
In the strategy of total synthesis of 2, the construction of the C-
ring is most important because a double aldol unit is stereose-
For installation of C-ring segment, eight-membered ring

680 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
BnO
O
BnO
O
BnO
O
OH
OH
OTES
OAc
OR
TBSO
TBSO
TBSO
a
b
PMBO OBn
PMBO OBn
PMBO OBn
6a, 6b
15a, 15b
16 : R = TES
17 : R = H
c
ꢁ
Scheme 9. Reagents and conditions: a) TESCl, pyridine, 0 C (95%); Ac2O, DMAP, pyridine, rt (96%). b) DBU, benzene, rt (16:
ꢁ
59%, 17: 26%). c) 0.1 M HCl, THF, 0 C (95%).
lization of epoxyketo aldehyde.
In order to construct the C-ring on the eight-membered ring
compound, the conjugated addition to enone 16 using a higher
order cuprate reagent, generated in situ from 10 equiv of 2-bro-
mo-5-(triethylsilyloxy)pentene with 20 equiv of t-BuLi and 5
equiv of CuCN, was attempted first (Table 2, Entry 1).12 How-
ever, the desired 1,4-adduct was not obtained at all. Then, non-
protected hydroxymethyl enone 17 was employed since this
conjugated addition was probably prevented by the protecting
group because of its steric hindrance. The desired conjugated
addition proceeded by using 5 equiv of cuprate reagent, yet
the yield of 1,4-adduct still remained low (Entry 3). To im-
prove the yield of the desired 1,4-adduct and to reduce the
amount of cuprate reagent, use of a suitable activating agent
was considered necessary for the promotion of the reaction.
Trimethylaluminium was found to work effectively as an acti-
vating agent (Scheme 10). When 1.1 equiv of trimethylalumi-
nium and only 2.5 equiv of the cuprate reagent were used, the
reaction proceeded smoothly and the desired ꢀ-substituted
eight-membered ring ketone 18 having the C-3,C-8-cis config-
Fig. 2. ORTEP drawing of compound 15a.
uration (71% yield) and dehydrated compound 19 (22% yield)
were obtained with perfect diastereoselectivity (Entry 4).
Next, preparation of the key intermediate, epoxyketo alde-
hyde 21, is illustrated in Scheme 11:13 namely, hydroxymethyl
ketone 18, prepared by the above-mentioned 1,4-addition of
lectively prepared during this stage. The synthetic plan for the
construction of the C-ring is similar to that of B-ring; that is,
its preparation is attained by SmI2-mediated double aldol cyc-
Table 2. Trimethylaluminium-Assisted Conjugated Addition to Enone
BnO
O
OR
OTES
TBSO
AlMe , t-BuLi, CuCN
3
+
Br
Et O
2
−23 °C
PMBO OBn
16: R = TES
17: R = H
BnO
O
BnO
O
OH OTES
+
OTES
TBSO
TBSO
PMBO OBn
PMBO OBn
18
19
Entry
R
Cuprate reagent/equiv
AlMe3/equiv
18
19
1aÞ
2bÞ
3
4
5
TES
H
H
H
H
5.0
2.0
5.0
2.5
3.5
—
—
—
1.1
1.1
NDcÞ
ND
55
71
67
ND
ND
26
22
21
a) 16 was 85% recovered. b) 17 was 83% recovered. c) Not detected.

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
681
BnO
O
BnO
O
OH OTES
OTES
Me Me
Al
BnO
O
a
OH
TBSO
TBSO
O
O
BnO
TBSO
AlMe3
TBSO
PMBO OBn
PMBO OBn
18
19
PMBO OBn
PMBO OBn
17
BnO
O
BnO
O
OH
O
O
O
TBSO
TBSO
b
c
OTES
BnO
O
OH
OTES
TBSO
PMBO OBn
PMBO OBn
Li2(NC)Cu
20
21
2
Scheme 11. Reagents and conditions: a) Ac2O, DMAP, pyr-
idine, rt (89%); DBU, CH2Cl2, rt (85%); b) 0.5 M HCl,
THF, ꢂ20 C (91%); H2O2, NaOH, MeOH, 0 C (82%);
c) PhSNHt-Bu, NCS, K2CO3, MS4A, CH2Cl2, rt (95%).
PMBO OBn
18
ꢁ
ꢁ
Scheme 10. Trimethylaluminium-assisted conjugate addition.
Table 3. SmI2-Mediated Intramolecular Cyclization of Epoxyketo Aldehyde (21)
OH
OH
BnO
O
O
BnO
O
O
TBSO
TBSO
SmI2
additive
THF
H
PMBO OBn
PMBO OBn
21
5a
OH
OH
OH
OH
OH
OH
O
O
O
BnO
BnO
BnO
TBSO
TBSO
TBSO
H
H
H
PMBO OBn
PMBO OBn
PMBO OBn
5b
5c
5d
SmI2
Additive
equiv
Temp.
/ꢁC
Yield/%
5b
Entry
/equiv
5a
5c
5d
1
2
3
4
5
6
7
8
3.0
3.0
3.0
5.0
4.0
4.0
3.0
3.0
—
—
—
—
ꢂ100
ꢂ78
ꢂ45
ꢂ23
ꢂ78
ꢂ78
ꢂ78
ꢂ78
71
59
42
24
45
27
41
45
NDaÞ
ND
ND
ND
ND
ND
ND
ND
10
9
3
15
16
20
16
6
7
9
17
2
H2O/3.0
MeOH/3.0
iPrOH/3.0
HMPA/3.0
44
38
35
24
a) The product was not detected.
higher order cyanocuprate, was acetylated first. This was fol-
lowed by the formation of ꢁ,ꢀ-unsaturated ketone 19 by regio-
selective elimination of the formed ꢁ-acetoxymethyl ketone
with DBU. After deprotection of TES group, epoxidation of
enone using H2O2 and NaOH gave ꢁ-epoxy ketone 20 as a
1:1 mixture of diastereomers. Swern oxidation and tetrapropyl-
ammonium perruthenate (TPAP)-catalyzed oxidation of the
primary hydroxy group of a diastereomixture of 20 did not
give the desired aldehyde 21, whereas sulfenamide-catalyzed
oxidation14 of 20 with N-chlorosuccinimide (NCS) proceeded
smoothly to give 21 in 95% yield.
selective construction of C-ring (Table 3). In the first place, the
reaction was carried out at temperatures ranging from ꢂ100 ꢁC
ꢁ
to ꢂ23 C in the absence of additives (Entries 1–4). The de-
sired isomer 5a was obtained in 71% yield along with diaster-
eomers 5c (10%) and 5d (15%) at ꢂ100 ꢁC. On the other hand,
the yields of diastereomers 5a and 5c decreased at the elevated
reaction temperatures. In these experiments, a 1:1 diastereo-
mixture of 21 was employed, since the results were the same
whether a mixture of two isomers or the single isomer was em-
ployed. Therefore, it is assumed that the desired facial selectiv-
ity of the formed samarium enolate and an aldehyde moiety
could be controlled if the reaction temperature was lowered.
Then, SmI2-mediated cyclization of 21 was tried for stereo-

682 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
Next, our investigation on the effects of additives revealed
that, contrary to our expectations, the addition of additives
such as H2O, MeOH, i-PrOH, or hexamethylphosphoric tri-
amide (HMPA) did not improve the yield of the desired prod-
uct 5a, while that of diastereomer 5c increased. No formation
of diastereomer 5b was detected throughout the above-
mentioned trials. The stereochemistry of compound 5a was
clearly identified by X-ray crystal structure analysis of a
methoxymethyl (MOM) ether 22, which was obtained by pro-
tecting the primary hydroxy group of 5a with MOM group
(Scheme 12, Fig. 3).15
The stereochemistry of 5d was determined in the following
way: the primary alcohol of 5d was protected with TBS group
first and then the p-methoxybenzyl (PMB) group was depro-
tected with DDQ to form a bridged tricyclic compound 23.
The stereochemistry of 23 was determined by NOE analysis.
The NOE between C-5ꢀ proton and C-7 proton of 23 indicated
that the C-7 hydroxy group had ꢁ-configuration. As for C-8 (t-
butyldimethylsilyloxy)methyl group, the NOEs between C-19
proton and C-3 proton as well as C-6ꢁ proton revealed that
C-8 (t-butyldimethylsilyloxy)methyl group had ꢁ-configura-
tion. Thus, the stereochemistry of 5d was determined as shown
in Scheme 13. Furthermore, in order to determine the structure
of 5c, structurally-defined 5d was oxidized by Dess–Martin pe-
riodinane to give ketone 24, which was also formed by oxida-
tion of 5c. Thus, it was noted that 5c had the opposite stereo-
chemistry concerning a hydroxy group at 7-position.
the desired isomer 5a was examined. However, after protection
of primary hydroxy group of 5c and 5d with TBS group, an
isomerization experiment using NaOMe in MeOH–THF did
not give any isomerized product which had the desired stereo-
chemistry for synthesis of 2.
Synthesis of the ABC Ring System of 19-Hydroxytaxol.16
The conversion of 22, prepared by the SmI2-mediated double
aldol reaction, to a tricyclic compound 4 is shown in
Scheme 14.
In the first place, MOM-protected double aldol 22 was dia-
stereoselectively reduced with AlH3 to afford the correspond-
ing C-7,C-9-cis-diol; protection of thus formed cis-diol with
isopropylidene acetal provided tricyclic compound 25. Then,
25 was converted to 8-membered ring ketone 26 by oxidative
deprotection of PMB group, followed by successive oxidation
of C-1 hydroxy group with Dess–Martin periodinane. Alkyla-
tion of 26 at C-1 position with homoallyllithium5 in benzene
afforded the desired ꢀ-alcohol in high yield with perfect dia-
stereoselectivity. Deprotection of TBS group resulted in the
formation of cis-diol 27 and successive treatment of 27 with
Next, isomerization of undesired diastereomers 5c and 5d to
OH
OH
OMOM
OH
O
O
BnO
BnO
TBSO
TBSO
a
H
H
PMBO OBn
PMBO OBn
5a
22
Scheme 12. Reagents and conditions: a) MOMCl, n-Bu4NI,
i-Pr2NEt, CH2Cl2, rt (76%).
Fig. 3. ORTEP drawing of compound 22.
OH
OH
OTBS
OBn
O
BnO
TBSO
OH
HO
19
TBSO
a
7
8
3
O
5
H
H
H
OBn
PMBO OBn
7
19
8
5d
23
5
b
3
OTBS
O
OH
O
O
BnO
TBSO
BnO
OH
c
TBSO
7
23
: NOE
H
H
PMBO OBn
PMBO OBn
24
5c
ꢁ
Scheme 13. Reagents and conditions: a) TBSOTf, pyridine, rt (65%); DDQ, H2O, CH2Cl2, 0 C (96%). b) TBSOTf, pyridine, rt
(65%); Desꢁs–Martin periodinane, NaHCO3, CH2Cl2 (91%). c) TBSOTf, pyridine, rt (82%); Dess–Martin periodinane, NaHCO3,
CH2Cl2, 0 C (82%).

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
683
OMOM
OH
O
BnO
TBSO
O
O
BnO
TBSO
O
O
BnO
TBSO
OMOM
OMOM
9
9
7
a
7
c
b
1
H
H
H
OBn
PMBO OBn
O
PMBO OBn
22
25
26
O
O
BnO
HO
O
O
BnO
O
O
O
BnO
OMOM
OMOM
OMOM
HO
d
e
11
12
1
1
c-Hex Si
H
H
H
O
Me
HO OBn
OBn
c-HexMe SiO OBn
2
27
28
29
O
O
O
O
BnO
BnO
HO
OMOM
OMOM
O
HO
f
g
11
12
O
H
H
c-HexMe SiO OBn
c-HexMe SiO OBn
2
2
30
4
Scheme 14. Reagents and conditions: a) AlH3, THF, ꢂ23 ꢁC (81%); 2,2-dimethoxypropane, CSA, CH2Cl2, rt (92%). b) DDQ, phos-
phate buffer, CH2Cl2, 0 ꢁC (quant); Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 ꢁC (95%). c) homoallyllithium, benzene, ꢂ23
ꢁ
ꢁC (97%); TBAF, THF, 50 C (80%). d) dichloro(cyclohexyl)methylsilane, imidazole, DMF, rt (quant). e) MeLi, THF–HMPA,
ꢂ78 ꢁC (99%). f) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 ꢁC (97%); PdCl2, DMF–H2O, rt (83%). g) TiCl2, LiAlH4, THF,
ꢁ
40 C (64%).
dichlorocyclohexylmethylsilane yielded silylenedioxy deriva-
tive 28 in high yield. Alkylation of 28 with methyllithium fur-
nished 29, which had the desired C-1 silyloxy group. Oxida-
tion of the thus formed secondary hydroxy group at C-11 with
Dess–Martin periodinane gave the corresponding ketone in
good yield. The terminal olefin of 29 was then oxidized by us-
ing PdCl2 in DMF–H2O to afford the desired diketone 30 in
good yield. By the above sequence of experiments, compound
30, a precursor of ABC-ring system, was efficiently synthe-
sized from BC-ring units. Intramolecular pinacol coupling of
diketone 30 using low-valent titanium reagent,17 prepared
from TiCl2 and LiAlH4, gave ABC-ring system of 4 as a main
product. Under the pinacol coupling conditions, the MOM
group of C-19 hydroxy group was not cleaved. On the other
hand, the same pinacol coupling reaction using SmI2 did not
give the desired coupling product. The stererochemistry of 4
: NOE
was confirmed by NOE experiments (Fig. 4).
The conversion of 4 to 19-hydroxytaxoid 36 is shown in
Scheme 15. After deprotections of benzyl groups of 4 with
Na/NH3 and of a cyclohexyldimethylsilyl group with tetra-
butylammonium fluoride (TBAF), regioselective protection
of the thus formed pentol with bis(trichloromethyl) carbonate
afforded C-1,C-2 carbonate 31 in high yield. Deprotection of
both MOM group and isopropylidene acetal under acidic con-
ditions was tried at this point. Unexpectedly, acid hydrolysis
with 6 M HCl followed by protection with diisopropylsilane-
diyl bis(trifloromethanesulfonate) (i-Pr2Si(OTf)2) gave cyclic
ether 32 in moderate yield. Through careful observation, it
was revealed that the deprotection of MOM group and the in-
Fig. 4. Stable conformation of pinacol 4 generated by calu-
culation. Some atoms have been omitted for clarity.
tramolecular ether formation took place rapidly while depro-
tection of isopropylidene acetal did not proceed completely.
Since it was difficult to suppress the undesired formation of cy-
clic ether, C-19 hydroxy group, which was formed by selective
deprotection of MOM group, was protected by the intramolec-
ular bromo ether formation procedure18 using N-bromosuccin-
imide (NBS). After the five-membered ether ring was formed,
the deprotection of isopropylidene acetal moiety under acidic
conditions proceeded smoothly, and regoiselective protection

684 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
iPr iPr
Si
O
O
O 19 O
BnO
HO
HO
HO
O
O
HO
HO
OMOM
OMOM
HO
HO
HO
b
a
c
O
1
2
1
2
H
H
O
H
O
O
c-HexMe2SiO OBn
O
4
O
31
O
32
OTBS
OH
OTES
OH
HO
HO
AcO
HO
O 19
O
O
HO
HO
OTES
7
7
e
d
10
HO
10
HO
HO
O
H
O
H
O
H
O
O
O
O
Br
Br
O
O
O
33
34
35
OTBS
OH OTES
AcO
f
H
O
O
36
O
Scheme 15. Reagents and conditions: a) Na, liq. NH3, THF, ꢂ78 ꢁC to ꢂ45 ꢁC; TBAF, THF, rt (94%); triphosgene, pyridine,
CH2Cl2, ꢂ45 ꢁC (quant). b) 6 M HCl, THF, 60 ꢁC; i-Pr2Si(OTf)2, pyridine, CH2Cl2, ꢂ45 ꢁC (37%). c) 6 M HCl, THF, rt (quant);
NBS, CH2Cl2, rt (quant). d) 3 M HCl, THF; TESOTf, pyridine, ꢂ23 ꢁC (91%). e) Zn–Ag, AcOH, EtOH, 90 ꢁC (81%); TBSOTf,
pyridine, ꢂ23 ꢁC (83%); Ac2O, DMAP, pyridine, rt (77%). f) thiophosgene, DMAP, CHCl3, 80 ꢁC; P(OMe)3, 110 ꢁC (43% based
on 35% conversion).
of hydroxy group at C-7 with triethylsilyl trifluoromethanesul-
fonate (TESOTf) afforded tetrol 34. Deprotection of cyclic
bromo ether 34 with zinc–silver couple in EtOH,19 protection
of the formed primary hydroxy group with t-butyldimethylsilyl
trifluoromethanesulfonate (TBSOTf), and the following selec-
tive acetylation of hydroxy group at C-10 gave acetate 35. A
novel 19-hydroxytaxoid 36 was synthesized from acetate 35
by a two-step procedure. Namely, conversion of the vicinal di-
ol unit to the corresponding thiocarbonate using thiophosgene,
followed by heating the thiocarbonate with trimethyl phos-
phite,20 afforded 19-hydroxytaxoid 36.
be employed not only as a precursor of 19-hydroxytaxol but
also as a starting material in developing new chemotherapeutic
agents.
Experimental
General.
All melting points were determined on a
Yanagimoto micro melting point apparatus (Yanaco MP-S3) and
are not corrected. Infrared (IR) spectra were recorded on a JASCO
FT-IR-8900 spectrometer. 1H NMR spectra were recorded on a
JEOL JNM EX270L (270 MHz) spectrometer; chemical shifts
(ꢂ) are reported in parts per million relative to tetramethylsilane.
Splitting patterns are designated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. 13C NMR spectra were recorded
on an EX270L (68 MHz) spectrometer with complete proton de-
coupling. Chemical shifts are reported in parts per million relative
to tetramethylsilane, with the solvent resonance as the internal
standard (CDCl3; ꢂ ¼ 77:0 ppm, C6D6; ꢂ ¼ 128:0 ppm). High
resolution mass spectra (HRMS) were recorded on a JEOL
JMS-AX-505HA or a JMS-700 mass spectrometer. Analytical
TLC measurements were performed on Merck preparative TLC
plates (silica gel 60 GF254, 0.25 mm). Column chromatography
was carried out on Merck silica gel 60 (0.063–0.200 mm). Prepa-
rative thin-layer chromatography (pTLC) was carried out on silica
gel Wakogel B-5F. All reactions were carried out under an argon
atmosphere in dried glassware, unless otherwise noted. Dichloro-
methane was distilled from diphosphorus pentaoxide, then from
calcium hydride, and finally dried over MS 4A; benzene and tol-
uene were distilled from diphosphorus pentaoxide and dried over
MS 4A; DMF, HMPA, and DMSO were distilled from calcium
Conclusion
Stereoselective synthesis of 19-hydroxytaxoid was accom-
plished by starting from D-pantolactone. The synthesis of the
eight-membered ring compound corresponding to the B ring
of 19-hydroxytaxol was achieved by intramolecular SmI2-
mediated double aldol cyclization. The ABC ring system of
19-hydroxytaxol was constructed on the B ring by successive
trimethylaluminium-assisted stereoselective conjugated addi-
tion, intramolecular SmI2-mediated double aldol cyclization,
stereoselective homoallylation, and pinacol coupling cycliza-
tion. Thus, the synthesis of 19-hydroxytaxoid from ABC ring
system by olefination was performed. The advantage of our
previously reported synthetic strategy for the synthesis of taxol
was proved by the present experiment to synthesize taxol-ana-
logs having additional functional groups. This is the first report
on the synthesis of 19-hydroxytaxoid,21 which is expected to

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
685
hydride, and dried over MS 4A; and THF and diethyl ether were
distilled from sodium/benzophenone immediately prior to use. All
reagents were purchased from Tokyo Kasei Kogyo, Kanto Chemi-
cal, Kokusan Chemical, Wako Pure Chemical Industries, or Al-
drich Chemical, and were used without further purification unless
otherwise noted.
Et2O, and the organic layer was washed with H2O and brine, dried
over MgSO4, and then filtered. The filtrate was concentrated under
reduced pressure and the crude product was purified by column
chromatography (silica gel, 20–30% EtOAc–hexane) to afford a
diastereomeric mixture of diol 11 (1.55 g, 88%) as a colorless
oil. A part of the diastereomeric mixture of 11 (145 mg) was sep-
(4S,5R,7R,8S)-4,8-Bis(benzyloxy)-5,9-bis(t-butyldimethylsi-
lyloxy)-7-(4-methoxybenzyloxy)-6,6-dimethylnon-1-en-3-ol (10).
To a solꢁution of aldehyde 9 (9.22 g, 12.3 mmol) in THF (100 mL)
at ꢂ78 C was added vinylmagnesium bromide (1.0 M in THF,
24.6 mL, 24.6 mmol); the reaction mixture was stirred for 1 h.
The temperature was allowed to rise to 0 ꢁC, and then the reaction
was quenched with saturated aqueous NH4Cl. The mixture was
extracted with Et2O and the combined organic layers were washed
with H2O and brine, dried over MgSO4, and then filtered. The fil-
trate was concentrated under reduced pressure and the crude prod-
uct was purified by column chromatography (silica gel, 5%
EtOAc–hexane) to afford a 1:1 diastereomeric mixture of allylic
alcohol 10 (9.61 g, 96%) as a colorless oil. A part of the diaster-
eomeric mixture of 10 (157 mg) was separated by preparative
TLC (15% EtOAc–hexane) to isolate 10a (74.6 mg) and 10b
arated by preparative TLC (30% EtOAc–hexane) to isolate 11a
21
(68.5 mg) and 11b (74.4 mg). 11a (less-polar isomer): ½ꢁꢃD
¼
ꢂ15:1 (c 0.91, CHCl3); IR (neat) 3355, 3116, 1620, 1519, 1095
1
cmꢂ1; H NMR (CDCl3) ꢂ 7.35–7.25 (m, 12H), 6.91 (d, J ¼ 8:4
Hz, 2H), 5.92 (ddd, J ¼ 16:7, 10.8, 5.7 Hz, 1H), 5.30 (d, J ¼
17:0 Hz, 1H), 5.12 (d, J ¼ 10:3 Hz, 1H), 4.78 (d, J ¼ 10:5 Hz,
1H), 4.57 (s, 2H), 4.52 (d, J ¼ 6:5 Hz, 1H), 4.48 (d, J ¼ 6:5
Hz, 1H), 4.42 (d, J ¼ 11:1 Hz, 1H), 4.24 (d, J ¼ 1:9 Hz, 1H),
3.97–3.75 (m, 3H), 3.80 (s, 3H), 3.72–3.67 (m, 1H), 3.61–3.48
(m, 2H), 2.02 (brs, 1H), 1.14 (s, 3H), 1.12 (s, 3H), 0.93 (s, 9H),
0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3) ꢂ 159.2, 138.9,
137.9, 137.8, 130.5, 129.1, 128.6, 128.2, 127.9, 127.9, 127.6,
127.2, 115.7, 113.8, 83.1, 82.7, 80.9, 78.1, 74.6, 73.9, 73.3,
71.7, 61.7, 55.3, 43.5, 26.3, 21.8, 19.5, 18.7, ꢂ3:3, ꢂ4:5; HRMS
(EI) calcd for C39H56O7Si ½Mꢃþ 664.3795, found 664.3822. 11b
21
17
(78.3 mg). 10a (less-polar isomer): ½ꢁꢃD ¼ ꢂ7:87 (c 1.01,
(more-polar isomer): ½ꢁꢃD ¼ ꢂ32:3 (c 0.90, CHCl3); IR (neat)
1
CHCl3); IR (neat) 3056, 1612, 1510, 1260, 1061 cmꢂ1; H NMR
3370, 3108, 1596, 1511, 1095 cmꢂ1 1H NMR (CDCl3) ꢂ 7.32–
;
(CDCl3) ꢂ 7.35–7.21 (m, 12H), 6.87 (d, J ¼ 8:6 Hz, 2H), 5.98
(ddd, J ¼ 17:0, 10.3, 6.2 Hz, 1H), 5.31 (d, J ¼ 17:0 Hz, 1H),
5.11 (d, J ¼ 10:3 Hz, 1H), 4.72 (d, J ¼ 11:1 Hz, 1H), 4.63 (d, J ¼
10:5 Hz, 1H), 4.58–4.52 (m, 1H), 4.52 (d, J ¼ 10:5 Hz, 1H), 4.46
(d, J ¼ 11:1 Hz, 1H), 4.32 (d, J ¼ 1:9 Hz, 1H), 4.23 (s, 2H), 4.16–
4.12 (brs, 1H), 4.11–4.03 (m, 1H), 3.87 (dd, J ¼ 11:7, 3.8 Hz,
1H), 3.80 (s, 3H), 2.72 (d, J ¼ 5:9 Hz, 1H), 3.62–3.52 (m, 2H),
1.22 (s, 3H), 1.09 (s, 3H), 0.95 (s, 9H), 0.90 (s, 9H), 0.02 (s,
3H), 0.02 (s, 3H), 0.01 (s, 3H), ꢂ0:01 (s, 3H); 13C NMR (CDCl3)
ꢂ 159.0, 139.3, 138.8, 138.1, 130.9, 129.1, 128.4, 128.2, 128.1,
127.7, 127.4, 127.2, 114.3, 113.7, 85.9, 82.6, 81.5, 78.1, 73.9,
73.2, 72.4, 72.2, 63.0, 55.2, 44.1, 26.3, 26.0, 22.3, 19.8, 18.5,
18.3, ꢂ3:2, ꢂ3:5, ꢂ4:8, ꢂ5:3; HRMS (EI) calcd for C45H70O7Si2
½Mꢃþ 778.4660, found 778.4612. 10b (more-polar isomer):
7.21 (m, 12H), 6.85 (d, J ¼ 8:5 Hz, 2H), 6.09 (ddd, J ¼ 17:0,
10.5, 5.1, 1H), 5.31 (d, J ¼ 17:0 Hz, 1H), 5.14 (d, J ¼ 10:8 Hz,
1H), 4.77 (d, J ¼ 10:8 Hz, 1H), 4.60 (d, J ¼ 11:6 Hz, 1H), 4.55
(s, 2H), 4.53 (d, J ¼ 11:3 Hz, 1H), 4.45 (d, J ¼ 11:3 Hz, 1H),
4.41–4.33 (m, 1H), 4.25 (d, J ¼ 1:9 Hz, 1H), 3.98–3.80 (m,
3H), 3.79 (s, 3H), 3.75–3.68 (m, 1H), 3.58 (dd, J ¼ 6:5, 1.9 Hz,
1H), 2.55 (brs, 1H), 2.20 (brs, 1H), 1.14 (s, 3H), 1.07 (s, 3H),
0.94 (s, 9H), 0.11 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3) ꢂ
159.1, 138.9, 138.5, 137.8, 130.5, 129.3, 128.5, 128.2, 127.8,
127.8, 127.4, 127.2, 115.0, 113.8, 84.9, 82.7, 81.1, 78.4, 74.7,
72.9, 72.5, 71.5, 61.4, 55.2, 43.9, 26.3, 22.2, 19.9, 18.5, ꢂ3:1,
ꢂ4:5; HRMS (EI) calcd for C39H56O7Si ½Mꢃþ 664.3795, found
664.3766.
(2S,3R,5R,6S)-2,6-Bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-
5-(4-methoxybenzyloxy)-4,4-dimethyl-1-oxiranylheptane-1,7-
diol. To a stirred solution of 11 (2.28 g, 3.44 mmol) in CH2Cl2
21
½ꢁꢃD ¼ ꢂ22:7 (c 1.10, CHCl3); IR (neat) 3054, 1610, 1510,
1
1250, 1054 cmꢂ1; H NMR (CDCl3) ꢂ 7.36–6.83 (m, 12H), 6.85
ꢁ
(d, J ¼ 8:6 Hz, 2H), 6.10 (ddd, J ¼ 17:0, 10.5, 4.9 Hz, 1H),
5.28 (d, J ¼ 17:0 Hz, 1H), 5.09 (d, J ¼ 10:5 Hz, 1H), 4.78 (d, J ¼
11:1 Hz, 1H), 4.62 (d, J ¼ 10:8 Hz, 1H), 4.56 (d, J ¼ 12:2 Hz,
1H), 4.47 (d, J ¼ 11:3 Hz, 1H), 4.41–4.32 (m, 1H), 4.30 (d, J ¼
11:3 Hz, 1H), 4.26 (d, J ¼ 1:4 Hz, 1H), 4.07 (d, J ¼ 11:6, 1.9 Hz,
1H), 3.87 (d, J ¼ 11:6, 4.6 Hz, 1H), 3.83 (d, J ¼ 6:2 Hz, 1H), 3.79
(s, 3H), 3.70–3.62 (m, 1H), 3.56 (d, J ¼ 6:8 Hz, 1H), 2.74 (d, J ¼
5:4 Hz, 1H), 1.16 (s, 3H), 1.02 (s, 3H), 0.94 (s, 9H), 0.92 (s, 9H),
0.09 (s, 3H), 0.08 (s, 3H), 0.03 (s, 3H), ꢂ0:02 (s, 3H); 13C NMR
(CDCl3) ꢂ 159.1, 138.6, 138.3, 138.0, 130.6, 129.1, 128.4, 127.9,
127.8, 127.7, 127.3, 127.2, 115.7, 113.7, 82.1, 81.1, 80.9, 79.7,
74.3, 73.9, 73.4, 72.2, 62.0, 55.2, 43.6, 26.2, 26.0, 22.1, 19.3,
18.7, 18.3, ꢂ3:4, ꢂ3:5, ꢂ5:0, ꢂ5:3; HRMS (EI) calcd for
C45H70O7Si2 ½Mꢃþ 778.4660, found 778.4683.
(50 mL) at 0 C was added m-CPBA (1.78 g, 10.32 mmol) and
ꢁ
then the mixture was heated to reflux at 50 C. After the reaction
mixture was stirred for 8 h, it was cooled to 0 ꢁC and then the re-
action was quenched with saturated aqueous Na2SO3. The mixture
was extracted with CH2Cl2 and the combined organic layers
were washed with saturated aqueous NaHCO3, H2O, and brine,
dried over MgSO4, and then filtered. The filtrate was concentrated
under reduced pressure and the residue was purified by column
chromatography (silica gel, 25–35% EtOAc–hexane) to give
(2S,3R,5R,6S)-2,6-bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-5-
(4-methoxybenzyloxy)-4,4-dimethyl-1-oxiranylheptane-1,7-diol (a
mixture of 4 diastereomers, 2.24 g, 96%) as colorless oils. IR
1
(neat) 3559, 3112, 1023, 1252, 1103 cmꢂ1; H NMR (CDCl3) ꢂ
7.29–7.12 (m, 12H), 6.82–6.78 (m, 2H), 4.75–4.20 (m, 7H),
3.81–3.62 (m, 8H), 3.42–1.98 (m, 4H), 1.08–1.03 (m, 6H),
0.88–0.85 (m, 9H), 0.60–0.00 (m, 6H).
(2R,3R,5R,6R)-2,6-Bis(benzyloxy)-5-(t-butyldimethylsilyloxy)-
3-(4-methoxybenzyloxy)-4,4-dimethyl-7-oxiranyl-7-oxoheptanal
(8). To a solution of oxalyl chloride (0.94 mL, 10.8 mmol) in
CH2Cl2 (40 mL) at ꢂ78 ꢁC was added DMSO (1.28 mL, 18.0
mmol). After the reaction mixture was stirred for 15 min at ꢂ78
ꢁC, a solution of a diastereomeric mixture of (2S,3R,5R,6S)-2,6-
bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-5-(4-methoxybenzyl-
(2S,3R,5R,6S)-2,6-Bis(benzyloxy)-5-(t-butyldimethylsilyloxy)-
3-(4-methoxybenzyloxy)-4,4-dimethylnon-8-ene-1,7-diol (11).
To a solution of a diastereomeric mixture of allylic alcohol 10
(2.07 g, 2.67 mmol) in THF (100 mL) at 0 ꢁC was added HCl
(1 M, 160 mL, 160 mmol). The reaction mixture was stirred for
ꢁ
1 h at 0 C and then the temperature was allowed to rise to room
temperature. After the reaction mixture was stirred for 2 h, it was
diluted with hexane at room temperature and neutralized with sat-
urated aqueous NaHCO3 at 0 ꢁC. The mixture was extracted with

686 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
oxy)-4,4-dimethyl-1-oxiranylheptane-1,7-diol (2.45 g, 3.60 mmol)
in CH2Cl2 (30 mL) was added. The stirring was continued at ꢂ78
ꢁC for 30 min and then triethylamine (3.52 mL, 25.2 mmol) was
added. The reaction mixture was allowed to warm to room tem-
perature and then the reaction was quenched with H2O. The mix-
ture was extracted with CH2Cl2, and the combined organic layers
were washed with brine, and dried over MgSO4. After filtration of
the mixture and evaporation of the solvent, the crude product was
purified by column chromatography (silica gel, 10–20% EtOAc–
hexane) to afford a 1:1 diastereomeric mixture of ꢁ,ꢀ-epoxyketo
aldehyde 8 (2.33 g, 96%) as a colorless oil. A part of the diaster-
eomeric mixture of 8 (170 mg) was separated by preparative TLC
(20% EtOAc–hexane) to isolate 8a (91.1 mg) and 8b (77.2 mg).
Hz, 2H), 4.95–4.20 (m, 5H), 4.18–3.70 (m, 6H), 3.81 (s, 3H),
3.57 (brs, 1H), 3.15–3.05 (m, 1H), 1.90–1.81 (m, 1H), 1.13–
0.76 (m, 9H), 0.74 (s, 6H), ꢂ0:02 (s, 6H); 13C NMR (CDCl3) very
broadened spectra; HRMS (FAB) calcd for C39H54NaO8 [M +
22
Na]þ 701.3486, found 701.3486. 6b: ½ꢁꢃD ¼ þ25:4 (c 0.95,
CHCl3); IR (neat) 3454, 1708 cmꢂ1 1H NMR (CDCl3) ꢂ 7.38–
;
7.18 (m, 12H), 6.84 (d, J ¼ 8:1 Hz, 2H), 4.94 (d, J ¼ 3:4 Hz,
1H), 4.78–4.45 (m, 5H), 4.16–3.79 (m, 5H), 3.77 (s, 3H), 3.70–
3.31 (m, 2H), 2.96 (brs, 1H), 2.15–2.05 (m, 1H), 1.17 (s, 3H),
1.14 (s, 3H), 0.88 (s, 9H), 0.00 (s, 3H), ꢂ0:12 (s, 3H); 13C NMR
(CDCl3) very broadened spectra; HRMS (FAB) calcd for
C39H54NaO8 [M + Na]þ 701.3486, found 701.3482.
(1R,2S,3R,4S,5R,7R,8R)-4,8-Bis(benzyloxy)-7-(t-butyldimeth-
ylsilyloxy)-2-hydroxymethyl-6,6-dimethyl-9-oxabicyclo[3.3.1]-
nonane-1,3-diol (14a). To a solution of bis-aldol 6a (15 mg, 0.04
22
8a (less-polar isomer): ½ꢁꢃD ¼ þ20:0 (c 1.06, CHCl3); IR (neat)
3116, 1712, 1079 cmꢂ1; 1H NMR (CDCl3) ꢂ 9.59 (d, J ¼ 2:2 Hz,
1H), 7.26–7.12 (m, 12H), 6.80 (d, J ¼ 8:9 Hz, 2H), 4.52 (d, J ¼
11:6 Hz, 1H), 4.51 (d, J ¼ 11:1 Hz, 1H), 4.41 (s, 1H), 4.37 (s,
1H), 4.31 (d, J ¼ 9:5 Hz, 1H), 4.27 (d, J ¼ 11:3 Hz, 1H), 4.16
(s, 3H), 3.98–3.93 (m, 2H), 3.85 (d, J ¼ 4:3 Hz, 1H), 3.72 (s,
3H), 2.84 (dd, J ¼ 7:0, 4.3 Hz, 1H), 2.79 (dd, J ¼ 6:8, 2.4 Hz,
1H), 0.89 (s, 3H), 0.87 (s, 3H), 0.84 (s, 9H), 0.02 (s, 3H), 0.00
(s, 3H); 13C NMR (CDCl3) ꢂ 206.9, 201.3, 159.2, 136.9, 136.8,
129.9, 129.3, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.1,
113.7, 86.1, 83.9, 83.4, 77.9, 73.7, 73.2, 72.5, 55.2, 51.7, 47.7,
44.3, 26.3, 21.4, 18.9, 18.6, ꢂ3:0, ꢂ4:7; HRMS (EI) calcd for
C39H52O8Si ½Mꢃþ 676.3431, found 676.3468. 8b (more-polar iso-
ꢁ
mmol) in CH2Cl2 (7 mL) at 0 C were added H2O (1.3 mL) and
DDQ (13 mg, 0.057 mmol). The reaction mixture was stirred at
room temperature for 1 h and then H2O was added. The mixture
was extracted with CH2Cl2 and the combined organic layers were
washed with H2O and brine, and dried over Na2SO4. After filtra-
tion of the mixture and evaporation of the solvent, the crude prod-
uct was purified by preparative TLC (50% EtOAc–hexane) to
25
afford hemiacetal 14a (11.4 mg, 51%) as a colorless oil. ½ꢁꢃD
¼
þ9:39 (c 1.15, benzene); IR (neat) 3378, 3023, 1697, 1079 cmꢂ1
;
1H NMR (CDCl3) ꢂ 7.49–7.33 (m, 10H), 6.09 (t, J ¼ 3:5 Hz, 1H),
6.02 (s, 1H), 5.12 (d, J ¼ 10:5 Hz, 1H), 4.81 (d, J ¼ 11:1 Hz, 1H),
4.74 (d, J ¼ 11:1 Hz, 1H), 4.46 (d, J ¼ 11:1 Hz, 1H), 4.36 (t, J ¼
3:5 Hz, 1H), 4.23 (d, J ¼ 4:3 Hz, 1H), 4.15–4.07 (m, 1H), 3.85 (d,
J ¼ 4:3 Hz, 1H), 3.69–3.58 (m, 2H), 3.02 (dd, J ¼ 4:3, 8.1 Hz,
1H), 1.98–1.90 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 0.90 (s, 9H),
0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3) ꢂ 138.3, 137.7,
129.0, 128.4, 128.4, 128.2, 127.9, 127.7, 95.8, 82.4, 81.1, 77.9,
76.7, 76.0, 71.5, 67.8, 60.7, 49.9, 40.1, 31.4, 26.2, 23.5, 18.9,
ꢂ4:3, ꢂ4:6; HRMS (FAB) calcd for C31H46NaO7Si [M + Na]þ
581.2911, found 581.2910.
23
mer): ½ꢁꢃD ¼ ꢂ7:00 (c 0.96, CHCl3); IR (neat) 3124, 1704,
1
1050 cmꢂ1; H NMR (CDCl3) ꢂ 9.61 (d, J ¼ 1:9 Hz, 1H), 7.27–
7.11 (m, 12H), 6.79 (d, J ¼ 8:9 Hz, 2H), 4.54 (d, J ¼ 11:3 Hz,
1H), 4.49 (d, J ¼ 10:8 Hz, 1H), 4.39 (d, J ¼ 11:1 Hz, 1H), 4.29
(d, J ¼ 11:3 Hz, 1H), 4.26–4.14 (m, 2H), 4.09 (d, J ¼ 4:9 Hz,
1H), 4.01–3.93 (m, 2H), 3.87 (d, J ¼ 4:6 Hz, 1H), 3.72 (s, 3H),
3.70 (d, J ¼ 8:1 Hz, 1H), 2.76 (dd, J ¼ 6:8, 4.9Hz, 1H), 2.52
(dd, J ¼ 6:8, 2.4 Hz, 1H), 1.00 (s, 3H), 0.92 (s, 3H), 0.86 (s,
9H), 0.03 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3) ꢂ 206.9,
201.3, 159.2, 136.9, 136.8, 130.0, 129.3, 128.6, 128.5, 128.4,
128.3, 128.3, 128.1, 128.1, 113.7, 86.2, 83.9, 83.5, 77.9, 73.8,
73.3, 72.5, 55.2, 51.7, 47.7, 44.3, 26.3, 21.5, 18.9, 18.6, ꢂ2:9,
ꢂ4:8; HRMS (EI) calcd for C39H52O8Si ½Mꢃþ 676.3431, found
676.3396.
(1R,2R,3S,4S,5R,7R,8R)-4,8-Bis(benzyloxy)-7-(t-butyldimeth-
ylsilyloxy)-2-hydroxymethyl-6,6-dimethyl-9-oxabicyclo[3.3.1]-
nonane-1,3-diol (14b). To a solution of bis-aldol 6b (10 mg,
0.027 mmol) in CH2Cl2 (5 mL) at 0 ꢁC were added H2O (1
mL) and DDQ (8.7 mg, 0.057 mmol). The reaction mixture was
stirred at room temperature for 1 h and then H2O was added.
The mixture was extracted with CH2Cl2 and the combined organic
layers were washed with H2O, brine and, dried over Na2SO4. Af-
ter filtration of the mixture and evaporation of the solvent, the
crude product was purified by preparative TLC (50% EtOAc–hex-
ane) to afford hemiacetal 14b (14.3 mg, 64%) as a colorless oil.
(2R,3R,5R,6S,7R,8S)-2,6-Bis(benzyloxy)-3-(t-butyldimethyl-
silyloxy)-7-hydroxy-8-hydroxymethyl-5-(4-methoxybenzyloxy)-
4,4-dimethylcyclooctanone (6a) and (2R,3R,5R,6S,7S,8R)-
2,6-Bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-7-hydroxy-8-hy-
droxymethyl-5-(4-methoxybenzyloxy)-4,4-dimethylcycloocta-
none (6b). To a solution of a diastereomeric mixture of ꢁ,ꢀ-ep-
oxyketo aldehyde 8 (1.54 g, 2.38 mmol) in THF (100 mL) were
added a solution of SmI2 in THF (0.1 M, 71.4 mL, 7.14 mmol)
and iꢁ-PrOH (300 mg, 4.76 mmol) immediately in succession at
ꢂ78 C. The reaction mixture was stirred for 30 min at the same
temperature and then saturated aqueous NH4Cl was added. The
mixture was filtered through a short pad of Celite and the filtrate
was extracted with Et2O. The combined organic layers were wash-
ed with H2O and brine, and dried over MgSO4. After filtration of
the mixture and evaporation of the solvent, the crude product was
purified by column chromatography (silica gel, 20–45% EtOAc–
hexane) to afford a 1:1 diastereomeric mixture of the cyclized
product 6 (1.47 g, 91%) as a colorless oil. A part of the diastereo-
meric mixture of 6 (45.5 mg) was separated by preparative TLC
(40% EtOAc–hexane) to isolate 6a (24.7 mg) and 6b (20.3 mg).
25
½ꢁꢃD ¼ ꢂ33:6 (c 0.50, benzene); IR (neat) 3394, 3077, 1704,
1033 cmꢂ1; 1H NMR (CDCl3) ꢂ 7.37–7.24 (m, 10H), 5.40 (t, J ¼
9:7 Hz, 1H), 4.84 (d, J ¼ 11:3 Hz, 1H), 4.76 (d, J ¼ 4:6 Hz, 1H),
4.73 (d, J ¼ 11:1 Hz, 1H), 4.72 (d, J ¼ 11:1 Hz, 1H), 4.68 (d, J ¼
11:3 Hz, 1H), 4.33 (dd, J ¼ 3:5, 11.1 Hz, 1H), 3.85 (dd, J ¼ 8:8,
11.1 Hz, 1H), 3.70–3.60 (m, 3H), 3.57 (d, J ¼ 4:6 Hz, 1H), 3.10–
3.04 (m, 1H), 2.83 (ddd, J ¼ 3:2, 8.9, 12.2 Hz, 1H), 1.30 (s, 3H),
1.09 (s, 6H), 0.99 (s, 9H), 0.07 (s, 3H), 0.00 (s, 3H); 13C NMR
(CDCl3) ꢂ 138.8, 137.7, 129.0, 128.4, 128.4, 128.2, 127.9,
127.7, 95.8, 82.4, 81.1, 77.9, 76.7, 76.0, 71.5, 67.8, 60.7, 49.9,
40.1, 31.4, 26.2, 23.5, 18.9, ꢂ2:8, ꢂ5:1; HRMS (FAB) calcd
for C31H46NaO7Si [M + Na]þ 581.2911, found 581.2910.
(2R,3R,5R,6S,7R,8S)-2,6-Bis(benzyloxy)-3-(t-butyldimethyl-
silyloxy)-7-hydroxy-5-(4-methoxybenzyloxy)-4,4-dimethyl-8-
(triethylsilyloxymethyl)cyclooctanone and (2R,3R,5R,6S,7S,
8R)-2,6-Bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-7-hydroxy-
21
6a: ½ꢁꢃD ¼ ꢂ4:16 (c 0.99, CHCl3); IR (neat) 3480, 1699
1
cmꢂ1; H NMR (CDCl3) ꢂ 7.40–7.15 (m, 12H), 6.88 (d, J ¼ 8:6

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
687
5-(4-methoxybenzyloxy)-4,4-dimethyl-8-(triethylsilyloxymeth-
yl)cyclooctanone. To a solution of a diastereomeric mixture of
6a and 6b (2.36 g, 3.48 mmol) in pyridine (20 mL) at 0 C was
quenched with phosphate buffer (pH ¼ 7). The mixture was ex-
tracted with EtOAc and the combined organic extracts were wash-
ed with saturated aqueous CuSO4, H2O, and brine, and then dried
over MgSO4. After filtration, the filtrate was concentrated under
reduced pressure and the obtained crude product was purified by
column chromatography (silica gel, 5–15% EtOAC–hexane) to
give a mixture of 15a and 15b (7.76 g, 96%) as colorless oils.
A part of the diastereomeric mixture of 15 (83.0 mg) was separat-
ed by preparative TLC (20% EtOAc–hexane) to isolate 15a (38.7
ꢁ
added TESCl (0.64 mL, 3.82 mmol) dropwise. After the reaction
mixture was stirred for 1 h, the reaction was quenched with phos-
phate buffer (pH ¼ 7) and the mixture was extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
CuSO4, H2O, and brine, and then dried over MgSO4. After filtra-
tion, the filtrate was concentrated under reduced pressure and the
obtained crude product was purified by column chromatography
(silica gel, 10–15% EtOAc–hexane) to give a mixture of (2R,3R,
5R,6S,7R,8S)-2,6-bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-7-hy-
droxy-5-(4-methoxybenzyloxy)-4,4-dimethyl-8-(triethylsilyloxy-
methyl)cyclooctanone and (2R,3R,5R,6S,7S,8R)-2,6-bis(benzyl-
oxy)-3-(t-butyldimethylsilyloxy)-7-hydroxy-5-(4-methoxybenzyl-
oxy)-4,4-dimethyl-8-(triethylsilyloxymethyl)cyclooctanone (2.63
g, 95%) as a colorless oil. A part of the diastereomeric mixture
of TES ethers (62.3 mg) was separated by preparative TLC
(20% EtOAc–hexane) to isolate (2R,3R,5R,6S,7R,8S)-2,6-bis-
(benzyloxy)-3-(t-butyldimethylsilyloxy)-7-hydroxy-5-(4-methoxy-
benzyloxy)-4,4-dimethyl-8-(triethylsilyloxymethyl)cyclooctanone
(29.2 mg) and (2R,3R,5R,6S,7S,8R)-2,6-bis(benzyloxy)-3-(t-bu-
tyldimethylsilyloxy)-7-hydroxy-5-(4-methoxybenzyloxy)-4,4-di-
methyl-8-(triethylsilyloxymethyl)cyclooctanone (30.3 mg). (2R,
3R,5R,6S,7R,8S)-2,6-bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-
7-hydroxy-5-(4-methoxybenzyloxy)-4,4-dimethyl-8-(triethylsilyl-
20
mg) and 15b (41.2 mg). 15a: mp 140–142 ꢁC; ½ꢁꢃD ¼ þ44:4 (c
0.50, benzene); IR (neat) 3162, 3076, 1718, 1049 cmꢂ1; 1H NMR
(CDCl3) ꢂ 7.37–7.23 (m, 10H), 7.19 (d, J ¼ 8:4 Hz, 2H), 6.87 (d,
J ¼ 8:4 Hz, 2H), 6.05 (s, 1H), 4.83 (d, J ¼ 11:6 Hz, 1H), 4.73 (d,
J ¼ 12:2 Hz, 1H), 4.66 (d, J ¼ 11:6 Hz, 1H), 4.50 (d, J ¼ 11:3
Hz, 1H), 4.45 (d, J ¼ 12:2 Hz, 1H), 4.35 (d, J ¼ 3:3 Hz, 1H),
4.18 (d, J ¼ 11:3 Hz, 1H), 3.81 (s, 3H), 3.80–3.75 (m, 2H),
3.53 (s, 1H), 3.31 (s, 1H), 2.03 (s, 3H), 0.99 (t, J ¼ 7:8 Hz,
9H), 0.97 (s, 3H), 0.85 (s, 3H), 0.80 (s, 9H), 0.63 (q, J ¼ 7:8
Hz, 6H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3) very broad-
ened spectra; HRMS (EI) calcd for C47H70O9Si2 ½Mꢃþ 834.4558,
20
found 834.4537. 15b: ½ꢁꢃD ¼ ꢂ5:81 (c 0.50, benzene); IR (neat)
3154, 3077, 1718, 1033 cmꢂ1; 1H NMR (CDCl3) ꢂ 7.13–6.87 (m,
10H), 6.82 (d, J ¼ 8:4 Hz, 2H), 6.52 (d, J ¼ 8:4 Hz, 2H), 4.66 (d,
J ¼ 3:8 Hz, 1H), 4.53 (d, J ¼ 11:3 Hz, 1H), 4.38 (d, J ¼ 11:1 Hz,
1H), 4.33 (d, J ¼ 11:1 Hz, 1H), 4.23–4.15 (m, 1H), 4.05 (d, J ¼
11:3 Hz, 1H), 3.90 (d, J ¼ 10:5 Hz, 1H), 3.80 (d, J ¼ 10:5 Hz,
1H), 3.70–3.64 (m, 2H), 3.46 (s, 3H), 3.36 (d, J ¼ 9:5 Hz, 1H),
2.80 (s, 1H), 1.80 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H), 0.64 (t, J ¼
7:8 Hz, 9H), 0.57 (s, 9H), 0.27 (q, J ¼ 7:8 Hz, 6H), ꢂ0:34 (s, 3H),
ꢂ0:46 (s, 3H); 13C NMR (CDCl3) very broadened spectra; HRMS
(EI) calcd for C47H70O9Si2 ½Mꢃþ 834.4558, found 834.4527.
(4S,5R,7R,8R)-4,8-Bis(benzyloxy)-7-(t-butyldimethylsilyl-
oxy)-5-(4-methoxybenzyloxy)-6,6-dimethyl-2-(triethylsilyloxy-
methyl)cyclooct-2-enone (16). To a solution of a diastereomeric
mixture of 15 (1.61 g, 2.08 mmol) in benzene (2 mL) at room tem-
perature was added DBU (8 mL) dropwise. The reaction mixture
was stirred for 30 min at room temperature. The mixture was di-
luted with EtOAc (10 mL) and the reaction was quenched with
phosphate buffer (pH ¼ 7) at 0 ꢁC. The mixture was extracted
with EtOAc and the combined organic layers were washed with
saturated aqueous NH4Cl, H2O, and brine, and then dried over
MgSO4. After filtration, the filtrate was concentrated under re-
duced pressure and the crude product was purified by column
chromatography (silica gel, 10–40% EtOAc–hexane) to afford
16 (0.86 g, 59%) as a colorless oil and 17 (0.33 g, 26%) as a col-
21
oxymethyl)cyclooctanone: ½ꢁꢃD ¼ þ0:75 (c 0.50, benzene); IR
1
(neat) 3332, 3023, 1712, 1042 cmꢂ1; H NMR (CDCl3) ꢂ 7.38–
7.08 (m, 12H), 6.83 (d, J ¼ 8:6 Hz, 2H), 4.94–4.29 (m, 7H),
4.16–3.83 (m, 4H), 3.75 (s, 3H), 3.73–3.60 (m, 2H), 2.77 (d, J ¼
11:1 Hz, 1H), 0.98–0.75 (m, 18H), 0.66 (s, 6H), 0.55 (q, J ¼ 7:8
Hz, 6H), 0.03 (s, 3H), ꢂ0:08 (s, 3H); 13C NMR (CDCl3) very
broadened spectra; HRMS (EI) calcd for C45H68O8Si2 ½Mꢃþ
792.4453, found 792.4412. (2R,3R,5R,6S,7S,8R)-2,6-bis(ben-
zyloxy)-3-(t-butyldimethylsilyloxy)-7-hydroxy-5-(4-methoxyben-
zyloxy)-4,4-dimethyl-8-(triethylsilyloxymethyl)cyclooctanone:
22
½ꢁꢃD ¼ þ17:4 (c 0.83, benzene); IR (neat) 3185, 3085, 1720,
1095 cmꢂ1; 1H NMR (CDCl3) ꢂ 7.40–7.08 (m, 12H), 6.80 (d, J ¼
8:6 Hz, 2H), 4.90 (d, J ¼ 3:2 Hz, 1H), 4.68 (d, J ¼ 11:3 Hz, 1H),
4.67 (d, J ¼ 11:1 Hz, 1H), 4.63–4.39 (m, 3H), 4.33 (d, J ¼ 11:3
Hz, 1H), 4.16–3.98 (m, 2H), 3.94–3.82 (m, 2H), 3.74 (s, 3H),
3.72–3.65 (brm, 1H), 3.54–3.40 (brm, 1H), 3.34 (d, J ¼ 8:10
Hz, 1H), 2.91 (s, 1H), 1.20 (s, 3H), 1.13 (s, 3H), 0.91 (t, J ¼
7:8 Hz, 9H), 0.84 (s, 9H), 0.55 (q, J ¼ 7:8 Hz, 6H), ꢂ0:03 (s,
3H), ꢂ0:14 (s, 3H); 13C NMR (CDCl3) very broadened spectra;
HRMS (EI) calcd for C45H68O8Si2 ½Mꢃþ 792.4453, found
792.4409.
28
orless oil. ½ꢁꢃD ¼ þ34:9 (c 1.03, benzene); IR (neat) 3162,
1
3065, 1720, 917 cmꢂ1; H NMR (CDCl3) ꢂ 7.34–7.12 (m, 12H),
(1R,2S,3R,5R,6R,8S)-2,6-Bis(benzyloxy)-5-(t-butyldimethyl-
silyloxy)-3-(4-methoxybenzyloxy)-4,4-dimethyl-7-oxo-8-(tri-
ethylsilyloxymethyl)cyclooctyl Acetate (15a) and (1S,2S,3R,5R,
6R,8R)-2,6-Bis(benzyloxy)-5-(t-butyldimethylsilyloxy)-3-(4-
methoxybenzyloxy)-4,4-dimethyl-7-oxo-8-(triethylsilyloxymeth-
yl)cyclooctyl Acetate (15b). To a solution of a mixture of (2R,
3R,5R,6S,7R,8S)-2,6-bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-
7-hydroxy-5-(4-methoxybenzyloxy)-4,4-dimethyl-8-(triethylsilyl-
6.84 (d, J ¼ 8:4 Hz, 2H), 6.52 (s, 1H), 5.46 (s, 1H), 4.63 (d, J ¼
11:3 Hz, 1H), 4.60 (d, J ¼ 11:6 Hz, 1H), 4.47–4.22 (m, 5H), 4.07
(s, 1H), 4.01 (d, J ¼ 12:2 Hz, 1H), 3.90 (s, 1H), 3.81 (s, 3H), 3.41
(s, 1H), 1.10–0.86 (m, 24H), 0.65 (q, J ¼ 7:8 Hz, 6H), 0.07 (s,
6H); 13C NMR (CDCl3) very broadened spectra; HRMS (EI) calcd
for C45H66O7Si2 ½Mꢃþ 774.4347, found 774.4348.
(4S,5R,7R,8R)-4,8-Bis(benzyloxy)-7-(t-butyldimethylsilyloxy)-
2-hydroxymethyl-5-(4-methoxybenzyloxy)-6,6-dimethylcyclo-
oct-2-enone (17). To a solution of TES-protected enone 16 (633
oxymethyl)cyclooctanone
and (2R,3R,5R,6S,7S,8R)-2,6-bis-
ꢁ
(benzyloxy)-3-(t-butyldimethylsilyloxy)-7-hydroxy-5-(4-methoxy-
benzyloxy)-4,4-dimethyl-8-(triethylsilyloxymethyl)cyclooctanone
(7.78 g, 9.81 mmol) in pyridine (50 mL) at 0 ꢁC were added
DMAP (119.8 mg, 0.98 mmol) and acetic anhydride (27.8 mL,
294.2 mmol). After the reaction mixture was stirred for 30 min
at 0 ꢁC and for 30 min at room temperature, the reaction was
mg, 0.82 mmol) in THF (50 mL) at 0 C was added HCl (0.1 M,
9.0 mL, 0.90 mmol) dropwise. After the reaction mixture was stir-
red for 40 min, hexane (20 mL) was added and then the reaction
was quenched with saturated aqueous NaHCO3. The mixture was
extracted with Et2O and the combined organic layers were washed
with brine and dried over MgSO4. After filtration, the solvent was

688 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
3085, 2949, 1705, 1245, 995 cmꢂ1 1H NMR (CDCl3) ꢂ 7.38–
7.01 (m, 12H), 6.77 (d, J ¼ 8:7 Hz, 2H), 5.12–3.90 (m, 14H),
3.74 (s, 3H), 3.53 (s, 1H), 3.50 (t, J ¼ 6:3 Hz, 2H), 2.78 (brs,
1H), 2.24–1.73 (m, 2H), 1.82 (s, 3H), 1.71–1.58 (m, 2H), 1.07
(s, 3H), 1.04 (s, 3H), 0.96–0.82 (m, 18H), 0.61 (q, J ¼ 7:8 Hz,
6H), 0.04 (s, 6H); 13C NMR (CDCl3) very broadened spectra;
HRMS (FAB) calcd for C52H78NaO9Si2 [M + Na]þ 925.5082,
found 925.5112.
(2R,3R,5R,6S,7R)-2,6-Bis(benzyloxy)-3-(t-butyldimethylsilyl-
oxy)-5-(4-methoxybenzyloxy)-4,4-dimethyl-8-methylene-7-[1-
methylene-4-(triethylsilyloxy)butyl]cyclooctanone (19). To a
solution of (1R,3R,4R,6R,7S,8S)-3,7-bis(benzyloxy)-4-(t-butyldi-
methylsilyloxy)-6-(4-methoxybenzyloxy)-5,5-dimethyl-8-[1-meth-
removed under reduced pressure and the crude product was puri-
fied by preparative TLC (30% EtOAc–hexane) to afford 17 (514
;
28
mg, 95%) as a colorless oil. ½ꢁꢃD ¼ þ52:3 (c 1.17, benzene);
IR (liquid film) 3453, 1672 cmꢂ1 1H NMR (CDCl3) ꢂ 7.34–
;
7.14 (m, 10H), 7.08 (d, J ¼ 8:7 Hz, 2H), 6.76 (d, J ¼ 8:7 Hz,
2H), 6.39 (brs, 1H), 5.37 (brs, 1H), 4.57 (d, J ¼ 11:7 Hz, 1H),
4.50–4.06 (brm, 6H), 4.01 (d, J ¼ 11:7 Hz, 1H), 3.90 (s, 1H),
3.79 (s, 3H), 3.43 (s, 1H), 2.40 (t, J ¼ 5:4 Hz, 1H), 0.99 (s,
3H), 0.95 (s, 3H), 0.85 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3)
ꢂ 201.7, 158.8, 139.8, 137.9, 137.5, 135.9, 129.5, 129.3, 128.5,
128.4, 128.3, 127.9, 127.8, 127.6, 113.4, 93.6, 90.7, 77.0, 75.5,
74.4, 71.6, 70.8, 65.1, 55.1, 43.9, 30.3, 25.8, 19.5, 18.0, ꢂ4:2,
ꢂ5:1; HRMS (EI) calcd for C39H52O7Si ½Mꢃþ 660.3482, found
660.3474.
ylene-4-(triethylsilyloxy)butyl]-2-oxocyclooctylmethyl
acetate
(2R,3R,5R,6S,7S,8R)-2,6-Bis(benzyloxy)-3-(t-butyldimethyl-
silyloxy)-8-hydroxymethyl-5-(4-methoxybenzyloxy)-4,4-dimeth-
yl-7-[1-methylene-4-(triethylsilyloxy)butyl]cyclooctanone (18).
To a solution of 2-bromo-5-(triethylsilyloxy)pentene (212 mg,
0.76 mmol) in Et2O (8 mL) was added t-butyllithium (1.51 M
(133 mg, 0.15 mmol) in CH2Cl2 (4 mL) was added DBU (0.44
mL, 2.94 mmol) dropwise. After the reaction mixture was stirred
for 1.5 h, the reaction was quenched with phosphate buffer
(pH ¼ 7) and the mixture was extracted with CH2Cl2. The com-
bined organic extracts were washed with H2O and brine, and then
dried over MgSO4. After filtration, the solvent was removed under
reduced pressure and the crude product was purified by prepara-
tive TLC (10% EtOAc–hexane) to afford 19 (105 mg, 85%) as
ꢁ
in pentane, 1.0 mL, 1.51 mmol) at ꢂ78 C. The reaction mixture
was stirred for 30 min and then it was added to a suspension of
CuCN (33.9 mg, 0.38 mmol) in Et2O (12 mL) at ꢂ78 ꢁC. The re-
action mixture was allowed to warm to ꢂ23 ꢁC and stirred for 20
min to give a clear solution of cuprate. To a solution of cyclo-
octenone 17 (100 mg, 0.15 mmol) in Et2O (3 mL) was added tri-
methylaluminium (1.08 M in hexane, 0.15 mL, 0.17 mmol) at 0
ꢁC. After the reaction mixture was stirred for 30 min, it was
cooled down to ꢂ23 ꢁC and then the above cuprate was added
throuꢁgh cannula. The reaction mixture was stirred for 1 h at
23
a colorless oil. ½ꢁꢃD ¼ ꢂ6:24 (c 1.00, CHCl3); IR (neat) 3487,
3108, 2954, 1696, 1231, 1046 cmꢂ1 1H NMR (CDCl3) ꢂ 7.28–
;
7.09 (m, 12H), 6.80 (d, J ¼ 8:4 Hz, 2H), 6.13 (brs, 1H), 5.32 (s,
1H), 4.99–4.93 (m, 2H), 4.83 (brs, 1H), 4.81 (s, 1H), 4.67 (d, J ¼
11:9 Hz, 1H), 4.42 (d, J ¼ 12:7 Hz, 1H), 4.38 (d, J ¼ 12:3 Hz,
1H), 4.35 (d, J ¼ 11:1 Hz, 1H), 4.24 (d, J ¼ 11:9 Hz, 1H), 3.95
(d, J ¼ 10:5 Hz, 1H), 3.74 (s, 3H), 3.62 (brs, 1H), 3.49 (brs,
1H), 3.42 (t, J ¼ 6:5 Hz, 2H), 3.02 (d, J ¼ 10:5 Hz, 1H), 1.98–
1.60 (m, 2H), 1.58–1.33 (m, 2H), 1.11 (s, 6H), 0.93 (s, 9H),
0.88 (t, J ¼ 7:6 Hz, 9H), 0.48 (q, J ¼ 7:6 Hz, 6H), 0.16 (s, 3H),
0.01 (s, 3H); 13C NMR (CDCl3) very broadened spectra; HRMS
(FAB) calcd for C50H74NaO7Si2 [M + Na]þ 865.4871, found
865.4902.
ꢁ
ꢂ23 C and then i-PrOH (0.5 mL) was added at ꢂ78 C. The re-
action was quenched with saturated aqueous NH4Cl with vigorous
stirring. The mixture was extracted with Et2O and the combined
organic layers were washed with H2O and brine, and then dried
over MgSO4. After filtration, the solvent was removed under re-
duced pressure and the obtained residue was purified by prepara-
tive TLC (20% EtOAc–hexane) to give the 18 (102 mg, 71%) as a
colorless oil and the dehydrogenated product 19 (37.1 mg, 22%)
(2R,3R,5R,6S,7R)-2,6-Bis(benzyloxy)-3-(t-butyldimethylsilyl-
oxy)-7-(4-hydroxy-1-methylenebutyl)-5-(4-methoxybenzyloxy)-
22
as a colorless oil. ½ꢁꢃD ¼ þ8:05 (c 1.13, CHCl3); IR (neat)
4,4-dimethyl-8-methylenecyclooctanone.
To a solution of
3440, 3124, 1718, 1249, 1079 cmꢂ1
;
1H NMR (CDCl3) ꢂ 7.42–
enone 19 (187 mg, 0.22 mmol) in THF (35 mL) at 0 ꢁC was added
HCl (0.5 M, 0.49 mL, 0.24 mmol) dropwise. After the reaction
mixture was stirred for 15 min at 0 ꢁC, the reaction was quenched
with saturated aqueous NaHCO3. The mixture was extracted with
Et2O and the combined organic layers were washed with H2O and
brine, dried over MgSO4, and then filtered. The solvent was re-
moved under reduced pressure and the crude product was purified
by preparative TLC (30% EtOAc–hexane) to give (2R,3R,5R,6S,
7R)-2,6-bis(benzyloxy)-3-(t-butyldimethylsilyloxy)-7-(4-hydroxy-
7.03 (m, 12H), 6.77 (d, J ¼ 8:7 Hz, 2H), 5.01–3.75 (m, 11H),
3.72 (s, 3H), 3.70 (s, 1H), 3.52–3.45 (m, 4H), 2.74 (brs, 1H),
2.16 (brm, 1H), 1.92 (brm, 2H), 1.62–1.50 (m, 3H), 1.02 (s,
3H), 0.98 (s, 3H), 0.87 (t, J ¼ 7:8 Hz, 9H), 0.79 (s, 9H), 0.48
(q, J ¼ 7:8 Hz, 6H), 0.02 (s, 6H); 13C NMR (CDCl3) very broad-
ened spectra; HRMS (FAB) calcd for C50H76NaO8Si2 [M + Na]þ
883.4976, found 883.4953.
(1R,3R,4R,6R,7S,8S)-3,7-Bis(benzyloxy)-4-(t-butyldimethyl-
silyloxy)-6-(4-methoxybenzyloxy)-5,5-dimethyl-8-[1-methylene-
4-(triethylsilyloxy)butyl]-2-oxocyclooctylmethyl Acetate. To a
solution of ketone 18 (150 mg, 0.17 mmol) in pyridine (3 mL)
were added DMAP (2.1 mg, 17.4 mmol) and Ac2O (0.16 mL,
1.74 mmol) at 0 ꢁC; the reaction mixture was stirred for 1 h.
The reaction was quenched with phosphate buffer (pH ¼ 7) and
the mixture was extracted with EtOAc. The combined organic lay-
ers were washed with saturated aqueous CuSO4, H2O, and brine,
and then dried over MgSO4. After filtration, the filtrate was con-
centrated under reduced pressure and the crude product was puri-
fied by preparative TLC (20% EtOAc–hexane) to afford (1R,3R,
4R,6R,7S,8S)-3,7-bis(benzyloxy)-4-(t-butyldimethylsilyloxy)-6-(4-
methoxybenzyloxy)-5,5-dimethyl-8-[1-methylene-4-(triethylsilyl-
oxy)butyl]-2-oxocyclooctylmethyl acetate (139 mg, 89%) as a
1-methylenebutyl)-5-(4-methoxybenzyloxy)-4,4-dimethyl-8-meth-
22
ylenecyclooctanone (146.3 mg, 91%) as a colorless oil. ½ꢁꢃD
¼
ꢂ6:85 (c 1.09, CHCl3); IR (neat) 3509, 3065, 2981, 1687, 1373,
1044 cmꢂ1; 1H NMR (CDCl3) ꢂ 7.34–7.17 (m, 12H), 6.87 (d, J ¼
8:6 Hz, 2H), 6.20 (brs, 1H), 5.38 (s, 1H), 5.05 (d, J ¼ 11:1 Hz,
1H), 4.98 (s, 1H), 4.89 (s, 2H), 4.74 (d, J ¼ 12:4 Hz, 1H), 4.49
(d, J ¼ 12:4 Hz, 1H), 4.44 (d, J ¼ 12:4 Hz, 1H), 4.40 (d, J ¼
8:1 Hz, 1H), 4.35 (d, J ¼ 9:2 Hz, 1H), 4.00 (dd, J ¼ 2:2, 8.5
Hz, 1H), 3.82 (s, 3H), 3.69 (brs, 1H), 3.60–3.51 (m, 1H), 3.46
(t, J ¼ 6:4 Hz, 2H), 3.10 (d, J ¼ 10:7 Hz, 1H), 2.17–1.38 (m,
4H), 1.18 (s, 6H), 0.91 (s, 9H), 0.23 (s, 3H), 0.07 (s, 3H);
13C NMR (CDCl3) ꢂ 196.6, 159.9, 149.7, 146.3, 140.1, 138.4,
130.9, 130.1, 129.9, 128.6, 128.3, 128.0, 127.4, 125.4, 114.2,
113.9, 109.1, 85.2, 83.6, 80.3, 76.4, 73.7, 71.8, 62.3, 61.5, 54.8,
47.4, 45.0, 34.5, 31.2, 29.5, 26.7, 26.4, 26.1, 23.5, 18.8, ꢂ2:8,
22
colorless oil. ½ꢁꢃD ¼ þ3:10 (c 0.98, CHCl3); IR (neat) 3100,

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
689
ꢂ4:7; HRMS (FAB) calcd for C44H60NaO7Si [M + Na]þ
751.4006, found 751.4035.
(5R,6R,8R,9S,10S)-5,9-Bis(benzyloxy)-6-(t-butyldimethylsi-
lyloxy)-10-(4-hydroxy-1-methylenebutyl)-8-(4-methyoxyben-
Hz, 1H), 7.27–6.79 (m, 12H), 6.59 (d, J ¼ 8:7 Hz, 2H), 5.07 (s,
1H), 4.84 (brs, 1H), 4.76 (d, J ¼ 11:4 Hz, 1H), 4.50 (s, 1H),
4.41 (d, J ¼ 10:9 Hz, 1H), 4.29–4.16 (m, 4H), 3.90 (d, J ¼ 11:2
Hz, 1H), 3.79 (d, J ¼ 10:9 Hz, 1H), 3.31 (s, 1H), 3.05 (s, 3H),
2.82 (d, J ¼ 11:1 Hz, 1H), 2.47 (d, J ¼ 4:8 Hz, 1H), 2.40–2.29
(m, 1H), 2.19–2.12 (m, 1H), 2.01–1.90 (m, 1H), 1.83–1.74 (m,
2H), 0.99 (s, 6H), 0.79 (s, 9H), 0.00 (s, 3H), ꢂ0:03 (s, 3H);
13C NMR (C6D6) very broadened spectra; HRMS (FAB) calcd
for C44H58NaO8Si [M + Na]þ 765.3799, found 765.3834. 21b
zyloxy)-7,7-dimethyl-1-oxaspiro[2.7]decan-4-one (20).
To a
solution of (2R,3R,5R,6S,7R)-2,6-bis(benzyloxy)-3-(t-butyldi-
methylsilyloxy)-7-(4-hydroxy-1-methylenebutyl)-5-(4-methoxy-
benzyloxy)-4,4-dimethyl-8-methylenecyclooctanone (146 mg,
0.20 mmol) in MeOH were added H2O2 (30%, 0.12 mL, 1.00
mmol) and NaOH (6 M, 0.17 mL, 1.00 mmol) dropwise; the reac-
tion mixture was stirred at 0 ꢁC for 12 h. The reaction was
quenched with saturated aqueous NH4Cl and then MeOH was re-
moved under reduced pressure. The aqueous layer was extracted
with Et2O and the combined organic extracts were washed with
brine and dried over MgSO4. After filtration, the filtrate was con-
centrated under reduced pressure and the obtained residue was pu-
rified by preparative TLC (30% EtOAc–hexane) to afford a dia-
stereomeric mixture of 20 (123 mg, 82%) as a colorless oil. A part
of the diastereomeric mixture of 20 (38.3 mg) was separated by
16
(more-polar isomer): ½ꢁꢃD ¼ þ10:5 (c 1.00, EtOH); IR (neat)
3355, 3054, 2908, 2815, 1712, 1095 cmꢂ1 1H NMR (C6D6) ꢂ
;
9.19 (t, J ¼ 1:3 Hz, 1H), 7.36–6.82 (m, 12H), 6.64 (d, J ¼ 8:6
Hz, 2H), 4.97 (d, J ¼ 11:3 Hz, 1H), 4.78 (s, 1H), 4.74–3.93 (m,
8H), 3.68 (s, 1H), 3.50 (s, 1H), 3.12 (s, 3H), 3.11–2.88 (m, 1H),
2.54 (brs, 1H), 2.28 (s, 2H), 2.17–1.86 (m, 2H), 1.79 (brs, 1H),
0.97 (s, 3H), 0.93 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.00 (s,
3H); 13C NMR (C6D6) very broadened spectra; HRMS (FAB)
calcd for C44H58NaO8Si [M + Na]þ 765.3799, found 765.3852.
(1R,3R,4R,6R,7S,8R,12S)-3,7-Bis(benzyloxy)-4-(t-butyldi-
methylsilyloxy)-12-hydroxy-1-hydroxymethyl-6-(4-methoxy-
benzyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]dodecan-2-
one (5a) and (1S,3R,4R,6R,7S,8R,12S)-3,7-Bis(benzyloxy)-
4-(t-butyldimethylsilyloxy)-12-hydroxy-1-hydroxymethyl-6-(4-
methoxybenzyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]do-
decan-2-one (5c) and (1S,3R,4R,6R,7S,8R,12R)-3,7-Bis(benzyl-
oxy)-4-(t-butyldimethylsilyloxy)-12-hydroxy-1-hydroxymeth-
yl-6-(4-methoxybenzyloxy)-5,5-dimethyl-9-methylenebicyclo-
[6.4.0]dodecan-2-one (5d). To a solution of a diastereomeric
mixture of aldehyde 21 (20.0 mg, 26.9 mmol) in THF (2.7 mL)
at ꢂ100 ꢁC was added SmI2 (0.1 M in THF, 81.0 mmol, 0.81
mL) dropwise; the reaction mixture was stirred for 1 h. The reac-
tion was quenched with saturated aqueous NH4Cl (0.5 mL) and
then the resulting mixture was filtered through a short pad of silica
gel. The filtrate was concentrated under reduced pressure and the
residue was purified by preparative TLC (30% EtOAc–hexane) to
give bicyclic diols 5a (14.2 mg, 71%), 5c (2.0 mg, 10%), and 5d
preparative TLC (30% EtOAc–hexane) to obtained 20a (20.0
15
mg) and 20b (15.4 mg). 20a (less-polar isomer): ½ꢁꢃD
¼
ꢂ24:0 (c 0.5, EtOH); IR (neat) 3247, 3062, 1712, 1095 cmꢂ1
;
1H NMR (C6D6) ꢂ 7.28–6.88 (m, 12H), 6.61 (d, J ¼ 8:8 Hz,
2H), 5.16 (s, 1H), 4,83 (d, J ¼ 10:7 Hz, 1H), 4.77 (s, 1H), 4.45
(d, J ¼ 11:2 Hz, 1H), 4.32–4.20 (m, 5H), 4.04 (d, J ¼ 11:2 Hz,
1H), 3.86 (d, J ¼ 10:7 Hz, 1H), 3.36 (s, 1H), 3.21 (brs, 2H),
3.08 (s, 3H), 2.92 (d, J ¼ 11:2 Hz, 1H), 2.53 (d, J ¼ 3:1 Hz,
1H), 2.26–2.19 (m, 2H), 2.00–1.93 (m, 1H), 1.43–1.36 (m, 2H),
1.01 (s, 6H), 0.82 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H); 13C NMR
(C6D6) very broadened spectra; HRMS (FAB) calcd for
C44H60NaO8Si [M + Na]þ 767.3955, found 767.3986. 20b
16
(more-polar isomer): ½ꢁꢃD ¼ þ19:9 (c 1.00, EtOH); IR (neat)
3216, 3062, 2962, 1720, 1095 cmꢂ1 1H NMR (C6D6) ꢂ 7.18–
;
6.84 (m, 12H), 6.61 (d, J ¼ 8:6 Hz, 2H), 4.98 (d, J ¼ 11:3 Hz,
1H), 4.81 (brs, 1H), 4.79 (d, J ¼ 11:0 Hz, 1H), 4.67 (s, 1H),
4.64–4.43 (m, 2H), 4.38 (d, J ¼ 11:0 Hz, 1H), 4.24 (d, J ¼ 11:3
Hz, 2H), 4.14 (d, J ¼ 11:0 Hz, 1H), 4.08 (d, J ¼ 10:7 Hz, 1H),
3.94 (d, J ¼ 11:6 Hz, 1H), 3.49 (s, 1H), 3.28 (s, 1H), 3.10 (s,
3H), 2.54 (brs, 1H), 2.30 (d, J ¼ 7:3 Hz, 2H), 2.23–1.81 (m,
2H), 1.51–1.40 (m, 2H), 1.20 (s, 3H), 0.94 (s, 3H), 0.86 (s, 9H),
0.01 (s, 3H), ꢂ0:02 (s, 3H); 13C NMR (C6D6) very broadened
spectra; HRMS (FAB) calcd for C44H60NaO8Si [M + Na]þ
767.3955, found 767.4000.
22
(3.1 mg, 15%) as colorless oils. 5a: ½ꢁꢃD ¼ ꢂ2:15 (c 0.81,
CHCl3); IR (KBr pellet) 3466, 1696 cmꢂ1 1H NMR (CDCl3) ꢂ
;
7.43 (d, J ¼ 7:0 Hz, 2H), 7.35–7.10 (m, 10H), 6.90 (d, J ¼ 8:4
Hz, 2H), 5.17 (d, J ¼ 11:6 Hz, 1H), 5.04 (brs, 1H), 4.71–4.59
(m, 4H), 4.55 (d, J ¼ 11:1 Hz, 1H), 4.47 (d, J ¼ 11:1 Hz, 1H),
4.35 (d, J ¼ 11:6 Hz, 1H), 4.28 (d, J ¼ 10:3 Hz, 1H), 4.03–3.90
(m, 2H), 3.80 (s, 3H), 3.80–3.70 (m, 2H), 3.64 (d, J ¼ 11:3 Hz,
1H), 3.34 (s, 1H), 3.27 (dd, J ¼ 10:5, 3.2 Hz, 1H), 2.83 (d, J ¼
10:0 Hz, 1H), 2.59–2.43 (m, 1H), 2.30–2.07 (m, 2H), 1.95–1.77
(m, 1H), 1.19 (s, 3H), 1.15 (s, 3H), 0.85 (s, 9H), 0.01 (s, 3H),
ꢂ0:01 (s, 3H); 13C NMR (CDCl3) ꢂ 213.9, 159.1, 141.9, 138.6,
130.2, 129.3, 127.9, 127.9, 127.9, 127.5, 127.1, 126.9, 126.8,
113.7, 110.0, 84.6, 83.1, 79.1, 74.4, 73.6, 73.3, 72.5, 63.5, 58.1,
55.3, 50.0, 46.4, 35.4, 33.0, 29.8, 25.9, 21.7, 21.7, 18.2, ꢂ3:6,
ꢂ4:5; HRMS (FAB) calcd for C44H60NaO8Si [M + Na]þ
4-[(4S,5S,6R,8R,9R)-5,9-Bis(benzyloxy)-8-(t-butyldimethyl-
silyloxy)-6-(4-methoxybenzyloxy)-7,7-dimethyl-10-oxo-1-oxa-
spiro[2.7]dec-4-yl]pent-4-enal (21). To a suspension of MS4A
(281 mg), K2CO3 (388 mg, 2.81 mmol), and NCS (41.2 mg,
0.31 mmol) in CH2Cl2 (2.5 mL) were successively added a solu-
tion of alcohol 20 (209 mg, 0.28 mmol) in CH2Cl2 (3 mL) and a
solution of N-t-butylbenzenesulfenamide (10.2 mg, 0.06 mmol) in
CH2Cl2 (0.5 mL) at room temperature. After the reaction mixture
was kept stirring for 2 h, it was filtered through a Celite pad, and
the filtrate was extracted with 10% aqueous Na2CO3. The organic
layers were washed with H2O and brine, dried over MgSO4, and
then filtered. The solvent was removed under reduced pressure
and the crude product was purified by preparative TLC (25%
EtOAc–hexane) to afford a diastereomeric mixture of 21 (198
mg, 95%) as a colorless oil. A part of the diastereomeric mixture
of 21 (58.3 mg) was separated by preparative TLC (20% EtOAc–
hexane) to obtain 21a (30.9 mg) and 21b (25.4 mg). 21a (less-po-
22
767.3955, found 767.3945. 5c: ½ꢁꢃD ¼ þ38:3 (c 0.69, CHCl3);
1
IR (KBr pellet); 3448, 1695 cmꢂ1; H NMR (CDCl3) ꢂ 7.44 (d,
J ¼ 7:0 Hz, 2H), 7.39–7.18 (m, 10H), 6.85 (d, J ¼ 8:6 Hz, 2H),
4.93–4.87 (m, 2H), 4.83 (d, J ¼ 11:1 Hz, 1H), 4.75 (d, J ¼ 4:9
Hz, 1H), 4.73–4.61 (m, 2H), 4.57 (d, J ¼ 11:6 Hz, 1H), 4.50 (d,
J ¼ 10:8 Hz, 1H), 4.47–4.31 (m, 4H), 4.28 (d, J ¼ 10:3 Hz,
1H), 3.79 (s, 3H), 3.79–3.62 (m, 2H), 3.36 (d, J ¼ 3:0 Hz, 1H),
3.33 (d, J ¼ 1:6 Hz, 1H), 3.07 (d, J ¼ 9:7 Hz, 1H), 2.63–2.47
(m, 1H), 2.14–1.89 (m, 2H), 1.85–1.68 (m, 1H), 1.21 (s, 3H),
1.18 (s, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR
(CDCl3) ꢂ 212.6, 158.6, 144.3, 139.3, 138.5, 131.2, 128.5,
16
lar isomer): ½ꢁꢃD ¼ ꢂ33:0 (c 1.00, EtOH); IR (neat) 3424, 3070,
2954, 2892, 1720, 1087 cmꢂ1; 1H NMR (C6D6) ꢂ 9.04 (t, J ¼ 1:3

690 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
127.9, 127.8, 127.7, 126.9, 126.8, 114.5, 113.5, 113.5, 88.4, 83.8,
79.3, 75.2, 74.3, 74.1, 72.3, 66.3, 59.6, 55.3, 51.8, 46.4, 32.0, 29.4,
26.1, 25.3, 22.6, 22.3, 18.3, ꢂ3:3, ꢂ4:6; HRMS (FAB) calcd for
C44H60NaO8Si [M + Na]þ 767.3955, found 767.3953. 5d:
brine, dried over MgSO4, and then filtered. The filtrate was
concentrated under reduced pressure and the crude product was
purified by preparative TLC (25% EtOAc–hexane) to afford (1S,
3R,4R,6R,7S,8R,12R)-3,7-bis(benzyloxy)-4-(t-butyldimethylsilyl-
oxy)-1-(t-butyldimethylsilyloxymethyl)-12-hydroxy-9-(4-methoxy-
benzyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]dodecan-2-one
21
½ꢁꢃD ¼ ꢂ24:1 (c 1.00, CHCl3); IR (KBr pellet) 3466, 1693
cmꢂ1 1H NMR (CDCl3) (1:1 conformer mixture) ꢂ 7.50–7.21
;
21
(m, 11H), 7.18 (d, J ¼ 8:6 Hz, 1H), 6.92 (d, J ¼ 8:6 Hz, 1H),
6.82 (d, J ¼ 8:9 Hz, 1H), 4.91–4.62 (m, 5H), 4.52–4.25 (m,
5H), 3.91 (brs, 0.5H), 3.82 (s, 1.5H), 3.79 (s, 1.5H), 3.78–3.48
(m, 2.5H), 3.32 (brs, 0.5H), 3.07–2.95 (m, 1.5H), 2.78–2.71 (m,
1H), 2.31–2.05 (m, 2H), 1.91–1.63 (m, 2H), 1.23 (s, 1.5H), 1.20
(s, 1.5H), 1.18 (s, 1.5H), 1.15 (s, 1.5H), 0.97 (s, 4.5H), 0.88 (s,
4.5H), 0.12 (s, 1.5H), 0.07 (s, 1.5H), 0.06 (s, 1.5H), 0.04 (s,
1.5H); 13C NMR (CDCl3) (1:1 conformer mixture) ꢂ 214.9,
214.0, 159.3, 158.9, 142.2, 142.1, 138.7, 138.1, 132.0, 130.2,
130.2, 130.1, 129.9, 128.9, 128.8, 128.3, 128.1, 127.9, 127.9,
127.8, 127.7, 127.5, 127.1, 127.1, 126.8, 126.6, 115.3, 115.2,
113.7, 113.3, 86.3, 81.8, 80.0, 79.6, 75.2, 75.1, 74.1, 73.5, 72.8,
71.9, 71.6, 70.9, 70.8, 67.6, 65.6, 60.2, 57.5, 56.9, 55.4, 55.2,
53.8, 53.3, 46.6, 45.9, 31.8, 30.2, 29.3, 29.2, 28.1, 28.0, 26.4,
26.0, 25.8, 22.3, 22.1, 21.5, 18.6, 18.3, ꢂ3:3, ꢂ3:6, ꢂ4:5, ꢂ5:0;
HRMS (FAB) calcd for C44H60NaO8Si [M + Na]þ 767.3955,
found 767.3954.
(7.0 mg, 65%) as colorless oil. ½ꢁꢃD ¼ þ7:66 (c 1.19, CHCl3);
IR (KBr pellet) 3537, 1694 cmꢂ1 1H NMR (CDCl3) (1:1 con-
;
former mixture) ꢂ 7.34–7.05 (m, 12H), 6.82 (d, J ¼ 8:6 Hz,
1H), 6.74 (d, J ¼ 8:6 Hz, 1H), 5.03 (brs, 0.5H), 4.90–4.78 (m,
2H), 4.77 (s, 0.5H), 4.65–4.45 (m, 2H), 4.40–4.23 (m, 3H),
4.19–4.10 (m, 1H), 3.96–3.80 (m, 2H), 3.84 (s, 1.5H), 3.75 (s,
1.5H), 3.72–3.55 (m, 3H), 3.20 (s, 0.5H), 2.87 (d, J ¼ 10:1 Hz,
0.5H), 2.15–1.60 (m, 4H), 1.47 (s, 1.5H), 1.21 (s, 1.5H), 1.10 (s,
1.5H), 1.05 (s, 1.5H), 0.85 (s, 4.5H), 0.82 (s, 4.5H), 0.81 (s,
4.5H), 0.78 (s, 4.5H), 0.04 (s, 1.5H), 0.02 (s, 1.5H), 0.02 (s,
1.5H), 0.00 (s, 1.5H), ꢂ0:01 (s, 1.5H), ꢂ0:02 (s, 1.5H), ꢂ0:03
(s, 1.5H), ꢂ0:04 (s, 1.5H); 13C NMR (CDCl3) (1:1 conformer
mixture) ꢂ 218.1, 215.7, 159.2, 158.5, 142.6, 142.4, 138.8,
138.1, 130.4, 130.3, 129.7, 129.5, 128.8, 128.3, 128.1, 128.0,
127.9, 127.8, 127.7, 127.4, 127.3, 127.2, 127.1, 127.0, 126.7,
126.3, 115.1, 114.8, 113.7, 113.3, 88.4, 82.4, 79.9, 79.2, 75.0,
74.9, 74.6, 74.0, 73.4, 72.7, 71.7, 71.3, 70.1, 69.7, 69.6, 65.2,
64.8, 58.9, 57.5, 55.4, 55.2, 52.7, 46.0, 45.5, 29.9, 27.7, 26.4,
26.3, 26.2, 26.0, 25.9, 25.8, 25.7, 22.1, 22.0, 21.5, 19.5, 18.9,
18.7, 18.6, 18.3, 18.1, ꢂ3:2, ꢂ3:3, ꢂ4:7, ꢂ4:9, ꢂ5:0, ꢂ5:2,
ꢂ5:4, ꢂ6:0; HRMS (FAB) calcd for C50H74NaO8Si2 [M +
Na]þ 881.4820, found 881.4821.
(1R,3R,4R,6R,7S,8R,12S)-3,7-Bis(benzyloxy)-4-(t-butyldi-
methylsilyloxy)-12-hydroxy-1-methoxymethoxymethyl-6-(4-
methoxybenzyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]do-
decan-2-one (22). To a solution of 5a (7.7 mg, 0.01 mmol) in
CH2Cl2 (1 mL) was added N,N-diisopropylethylamine (99 mg,
0.773 mmol), tetrabutylammonium iodide (190 mg, 0.515 mmol),
and a solution of chloromethyl methyl ether (41 mg, 0.52 mmol)
(1R,2S,3R,7R,8S,9R,11R,12R)-8,12-Bis(benzyloxy)-11-(t-bu-
tyldimethylsilyloxy)-2-(t-butyldimethylsilyloxymethyl)-10,10-di-
methyl-6-methylene-13-oxatricyclo[7.3.1.02,7]tridecane-1,3-
diol (23). To a solution of alcohol (1S,3R,4R,6R,7S,8R,12R)-3,7-
bis(benzyloxy)-4-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsi-
lyloxymethyl)-12-hydroxy-6-(4-methoxybenzyloxy)-5,5-dimeth-
yl-9-methylenebicyclo[6.4.0]dodecan-2-one (6.0 mg, 0.00698
mmol) in CH2Cl2 (5 mL) at 0 ꢁC were added H2O (0.5 mL)
and DDQ (5.0 mg, 0.0222 mmol). The reaction mixture was stir-
red at room temperature for 1 h and then H2O was added. The
mixture was extracted with CH2Cl2 and the combined organic lay-
ers were washed with H2O and brine, and dried over Na2SO4. Af-
ter filtration of the mixture and evaporation of the solvent, the
crude product was purified by preparative TLC (20% EtOAc–hex-
ꢁ
in CH2Cl2 (1 mL) at 0 C. After the reaction mixture was stirred
for 5 h at room temperature, the reaction was quenched with satu-
rated aqueous sodium hydrogencarbonate and the mixture was ex-
tracted with CH2Cl2. The combined organic layers were washed
with water and brine, dried over MgSO4, and then filtered. The fil-
trate was concentrated under reduced pressure and the crude prod-
uct was purified by preparative TLC (30% EtOAc–hexane) to
afford 22 (6.2 mg, 76%) as a crystalline solid. mp 131–133 ꢁC;
21
½ꢁꢃD ¼ þ43:1 (c 1.30, benzene); IR (KBr pellet) 3497, 1710
cmꢂ1
;
1H NMR (CDCl3) ꢂ 7.46 (d, J ¼ 6:9 Hz, 2H), 7.38–7.17
(m, 10H), 6.90 (d, J ¼ 8:7 Hz, 2H), 5.20 (d, J ¼ 11:4 Hz, 1H),
5.09 (s, 1H), 4.80–4.53 (m, 7H), 4.40 (d, J ¼ 11:0 Hz, 1H),
4.38 (d, J ¼ 11:4 Hz, 1H), 4.27 (d, J ¼ 11:4 Hz, 1H), 4.07 (d, J ¼
10:1 Hz, 1H), 3.99 (d, J ¼ 9:9 Hz, 1H), 3.87 (d, J ¼ 10:1 Hz, 1H),
3.82 (s, 3H), 3.46 (s, 3H), 3.37 (s, 1H), 3.24 (d, J ¼ 9:9 Hz, 1H),
2.95 (d, J ¼ 10:4 Hz, 1H), 2.60–2.46 (m, 1H), 2.38–2.19 (m, 1H),
2.15–2.02 (m, 1H), 1.80–1.71 (m, 1H), 1.20 (s, 3H), 1.14 (s, 3H),
0.87 (s, 9H), 0.33 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3) ꢂ 207.8,
159.1, 142.8, 138.9, 130.8, 129.1, 128.0, 127.9, 127.9, 127.6,
127.1, 127.0, 126.8, 113.7, 110.1, 97.1, 84.6, 83.8, 79.1, 78.3,
74.3, 73.5, 73.4, 72.5, 67.1, 58.7, 55.2, 50.7, 46.3, 35.4, 32.7,
29.8, 25.9, 21.6, 21.5, 18.1, ꢂ3:7, ꢂ4:7; HRMS (FAB) calcd
for C46H64NaO9Si [M + Na]þ 811.4217; found 811.4202.
21
ane) to afford 23 (5.0 mg, 96%) as a colorless oil. ½ꢁꢃD ¼ þ15:4
1
(c 0.29, CHCl3); IR (liquid film) 3441 cmꢂ1; H NMR (C6D6) ꢂ
7.38 (d, J ¼ 7:0 Hz, 2H), 7.19–6.95 (m, 8H), 6.73 (s, 1H), 5.20
(brs, 1H), 5.10 (dt, J ¼ 11:0, 5.0 Hz, 1H), 5.01 (d, J ¼ 10:0 Hz,
1H), 4.95 (brs, 1H), 4.89 (d, J ¼ 9:5 Hz, 1H), 4.83 (d, J ¼ 10:5
Hz, 1H), 4.73 (d, J ¼ 3:5 Hz, 1H), 4.69 (dd, J ¼ 12:5, 5.5 Hz,
1H), 4.63 (d, J ¼ 10:0 Hz, 1H), 4.57 (d, J ¼ 10:0 Hz, 1H), 4.21
(d, J ¼ 5:0 Hz, 1H), 4.09 (d, J ¼ 9:3 Hz, 1H), 3.72 (d, J ¼ 4:5
Hz, 1H), 3.66 (d, J ¼ 3:5 Hz, 1H), 3.55 (d, J ¼ 11:5 Hz, 1H),
2.58–2.48 (m, 1H), 2.29–2.21 (m, 1H), 2.10–2.01 (m, 1H),
1.76–1.64 (m, 1H), 1.11 (s, 3H), 1.06 (s, 3H), 1.00 (s, 9H), 0.96
(s, 9H), 0.11 (s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H);
13C NMR (C6D6) ꢂ 145.6, 139.6, 136.7, 130.1, 128.7, 128.4,
128.3, 127.9, 127.6, 115.5, 104.9, 84.5, 84.1, 78.6, 76.8, 74.2,
72.0, 67.3, 63.8, 53.4, 49.2, 38.6, 31.2, 30.5, 27.8, 26.7, 25.9,
22.6, 18.9, 18.2, ꢂ3:1, ꢂ5:0, ꢂ5:3, ꢂ5:7; HRMS (FAB) calcd
for C42H67O7Si2 [M + H]þ 739.4425, found 739.4421.
(1S,3R,4R,6R,7S,8R,12R)-3,7-Bis(benzyloxy)-4-(t-butyldi-
methylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)-12-hydroxy-
6-(4-methoxybenzyloxy)-5,5-dimethyl-9-methylenebicyclo-
[6.4.0]dodecan-2-one. To a solution of a diol 5d (9.4 mg, 0.0126
ꢁ
mmol) in pyridine (1 mL) at 0 C was added TBSOTf (0.03 mL,
0.131 mmol) dropwise. After the reaction mixture was stirred for
1.5 h, the reaction was quenched with phosphate buffer (pH ¼ 7)
and the mixture was extracted with EtOAc. The combined organic
layers were washed with saturated aqueous CuSO4, H2O, and
(1S,3R,4R,6R,7S,8R)-3,7-Bis(benzyloxy)-4-(t-butyldimethyl-
silyloxy)-1-(t-butyldimethylsilyloxymethyl)-6-(4-methoxyben-
zyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]dodecane-2,12-

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
691
dione (24). To a solution of (1S,3R,4R,6R,7S,8R,12R)-3,7-bis-
(benzyloxy)-4-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyl-
oxymethyl)-12-hydroxy-9-(4-methoxybenzyloxy)-5,5-dimethyl-9-
methylenebicyclo[6.4.0]dodecan-2-one (51.3 mg, 0.0597 mmol)
in CH2Cl2 (5 mL) were added NaHCO3 (50.2 mg, 0.597 mmol)
and Dess–Martin periodinane (127 mg, 0.299 mmol) at room tem-
perature. After the reaction mixture was stirred for 50 min, the re-
action was quenched with 10% aqueous Na2SO3 (2 mL) and satu-
rated aqueous NaHCO3. The mixture was extracted with CH2Cl2
and the combined organic layers were washed with brine, dried
over MgSO4, and then filtered. The filtrate was concentrated under
reduced pressure and the crude product was purified by prepara-
tive TLC (15% EtOAc–hexane) to afford ketone 24 (46.6 mg,
methylsilyloxy)-6-(4-methoxybenzyloxy)-1-(methoxymethoxy-
methyl)-5,5-dimethyl-9-methylenebicyclo[6.4.0]dodecane-2,12-
diol. To a solution of lithium aluminium hydride in THF (1.0 M,
ꢁ
75 mL, 75 mmol) at 0 C was added sulfuric acid (98%, 2.0 mL,
37.5 mmol). The reaction mixture was stirred for 1 h at room tem-
perature and then it was allowed to stand. The clear solution of tet-
rahydridoaluminium in THF (1.0 M) was instantly used in the fol-
lowing reaction without further purification. To a solution of alco-
ꢁ
hol 22 (4.30 g, 5.45 mmol) in toluene (110 mL) at ꢂ23 C was
added tetrahydridoaluminium in THF (1.0 M, 54.5 mL, 54.5
ꢁ
mmol). The reaction mixture was stirred for 2 h at ꢂ23 C and
then saturated aqueous potassium sodium tartrate was added.
The mixture was extracted with ethyl acetate, and the organic lay-
er was washed with brine and dried over anhydrous sodium sul-
fate. After filtration of the mixture and evaporation of the solvent,
the crude product was purified by column chromatography (silica
gel, 10–20% EtOAc–hexane) to afford (1R,2S,3S,4R,6R,7S,
8R,12S)-3,7-bis(benzyloxy)-4-(t-butyldimethylsilyloxy)-6-(4-me-
thoxybenzyloxy)-1-(methoxymethoxymethyl)-5,5-dimethyl-9-meth-
ylenebicyclo[6.4.0]dodecane-2,12-diol (3.48 g, 81%) as a color-
22
91%) as a colorless oil. ½ꢁꢃD ¼ ꢂ43:0 (c 1.13, CHCl3); IR (thin
1
film) 1719, 1689 cmꢂ1; H NMR (CDCl3) ꢂ 7.60–7.51 (m, 2H),
7.50–7.28 (m, 10H), 6.98 (d, J ¼ 8:4 Hz, 2H), 5.12 (d, J ¼ 9:2
Hz, 1H), 5.01 (s, 1H), 4.94 (d, J ¼ 1:9 Hz, 1H), 4.88 (d, J ¼
10:5 Hz, 1H), 4.77 (d, J ¼ 9:2 Hz, 1H), 4.59 (d, J ¼ 9:2 Hz,
1H), 4.49 (d, J ¼ 9:2 Hz, 1H), 4.36 (d, J ¼ 11:1 Hz, 1H), 4.29
(s, 1H), 4.27 (d, J ¼ 11:1 Hz, 1H), 4.11 (s, 1H), 3.95 (s, 1H),
3.91 (s, 3H), 3.69 (s, 1H), 3.65 (d, J ¼ 9:5 Hz, 1H), 2.84 (d, J ¼
10:5 Hz, 1H), 2.29–2.21 (m, 2H), 2.16–1.95 (m, 2H), 1.44 (s, 3H),
1.11 (s, 3H), 1.07 (s, 9H), 0.88 (s, 9H), 0.35 (s, 3H), 0.26 (s, 3H),
0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3) ꢂ 206.6, 204.8,
158.7, 143.5, 138.9, 136.9, 130.0, 129.6, 128.9, 128.2, 128.2,
128.0, 127.5, 127.2, 115.5, 113.4, 93.6, 90.4, 78.4, 78.2, 76.0,
75.8, 72.4, 69.4, 66.0, 55.2, 53.7, 43.8, 42.1, 30.0, 28.8, 26.1,
25.9, 20.3, 18.3, 18.2, ꢂ3:4, ꢂ5:1, ꢂ5:7, ꢂ5:7; HRMS (FAB)
calcd for C50H72NaO8Si2 [M + Na]þ 879.4663, found 879.4674.
(1S,3R,4R,6R,7S,8R,12S)-3,7-Bis(benzyloxy)-4-(t-butyldi-
methylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)-12-hydroxy-
6-(4-methoxybenzyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]-
dodecan-2-one. To a solution of a diol 5c (21.1 mg, 0.0283
mmol) in pyridine (2 mL) at 0 ꢁC was added TBSOTf (22.4
mg, 0.0849 mmol) dropwise. After the reaction mixture was stir-
red for 1.5 h, the reaction was quenched with phosphate buffer
(pH ¼ 7) and the mixture was extracted with EtOAc. The com-
bined organic layers were washed with saturated aqueous CuSO4,
H2O, and brine, dried over MgSO4, and then filtered. The filtrate
was concentrated under reduced pressure and the crude product
was purified by preparative TLC (25% EtOAc–hexane) to afford
(1S,3R,4R,6R,7S,8R,12S)-3,7-bis(benzyloxy)-4-(t-butyldimethyl-
silyloxy)-1-(t-butyldimethylsilyloxymethyl)-12-hydroxy-6-(4-me-
thoxybenzyloxy)-5,5-dimethyl-9-methylenebicyclo[6.4.0]dodecan-
23
less oil. ½ꢁꢃD ¼ þ29:3 (c 0.45, benzene); IR (neat) 3492
1
cmꢂ1; H NMR (CDCl3) ꢂ 7.36–7.11 (m, 12H), 6.80 (d, J ¼ 8:1
Hz, 2H), 5.78 (s, 1H), 5.26 (s, 1H), 4.98–4.88 (m, 3H), 4.80–
4.62 (m, 1H), 4.60–4.48 (m, 6H), 4.48–4.40 (m, 1H), 4.37 (s,
2H), 4.03–3.97 (m, 1H), 3.94–3.60 (m, 3H), 3.80 (s, 3H), 3.39
(s, 3H), 3.40–3.31 (m, 1H), 2.40–2.27 (m, 2H), 2.10–1.98 (m,
1H), 1.95–1.85 (m, 1H), 1.39 (s, 3H), 1.37 (s, 3H), 0.98 (s, 9H),
0.30 (s, 3H), 0.18 (s, 3H); 13C NMR (CDCl3) very broadened
spectra; HRMS (FAB) calcd for C46H66NaO9Si [M + Na]þ
813.4374; found 813.4348.
(1R,2S,3S,4R,6R,7S,8R,12S)-3,7-Bis(benzyloxy)-4-(t-butyldi-
methylsilyloxy)-2,12-(isopropylidenedioxy)-6-(4-methoxyben-
zyloxy)-1-(methoxymethoxymethyl)-5,5-dimethyl-9-methylene-
bicyclo[6.4.0]dodecane (25). To a solution of (1R,2S,3S,4R,6R,
7S,8R,12S)-3,7-bis(benzyloxy)-4-(t-butyldimethylsilyloxy)-6-(4-
methoxybenzyloxy)-1-(methoxymethoxymethyl)-5,5-dimethyl-9-
methylenebicyclo[6.4.0]dodecane-2,12-diol (3.48 g, 4.4 mmol) in
CH2Cl2 (220 mL) were added 2,2-dimethoxypropane (220 mL)
and CSA (205 mg, 0.88 mmol) at 0 ꢁC. The reaction mixture
was allowed to warm to room temperature and stirred for 5 h.
The reaction was quenched with Et3N and the solvent was re-
moved under reduced pressure. The obtained residue was purified
by column chromatography (silica gel, 10–20% EtOAc–hexane)
24
to afford 25 (3.35 g, 92%) as a colorless oil. ½ꢁꢃD ¼ þ27:3 (c
20
2-one (20.0 mg, 82%) as a colorless oil. ½ꢁꢃD ¼ þ35:5 (c 1.23,
0.50, benzene); IR (thin film) 2952, 2858 cmꢂ1; 1H NMR (CDCl3)
ꢂ 7.46–7.18 (m, 12H), 6.84 (d, J ¼ 8:6 Hz, 2H), 4.90–4.08 (m,
9H), 4.37–4.26 (m, 4H), 4.24 (d, J ¼ 2:2 Hz, 1H), 4.02 (s, 1H),
3.97 (d, J ¼ 2:7 Hz, 1H), 3.79 (s, 3H), 3.78–3.71 (m, 1H), 3.63
(d, J ¼ 2:7 Hz, 1H), 3.35 (s, 3H), 3.04–2.85 (m, 1H), 2.43 (d, J ¼
11:1 Hz, 1H), 2.24–2.08 (m, 1H), 2.01–1.66 (m, 2H), 1.48 (s, 3H),
1.44 (s, 3H), 1.22 (s, 3H), 1.18 (s, 3H), 0.97 (s, 9H), 0.10 (s, 3H),
0.07 (s, 3H); 13C NMR (CDCl3) ꢂ 158.6, 144.4, 139.7, 139.0,
131.7, 128.6, 128.0, 128.0, 127.9, 127.8, 127.3, 126.6, 115.4,
113.5, 98.9, 97.7, 92.6, 83.3, 81.9, 78.3, 77.2, 76.8, 75.8, 73.3,
72.1, 64.5, 56.5, 55.2, 50.3, 46.1, 43.0, 29.8, 27.7, 26.9, 25.9,
25.4, 21.3, 19.0, 18.0, ꢂ4:2, ꢂ4:7; HRMS (FAB) calcd for
C49H70NaO9Si [M + Na]þ 853.4687; found 853.4730.
CHCl3); IR (KBr pellet) 3548, 1698 cmꢂ1 1H NMR (CDCl3) ꢂ
;
7.35–7.10 (m, 12H), 6.75 (d, J ¼ 8:6 Hz, 2H), 4.77 (d, J ¼ 9:2
Hz, 1H), 4.74 (d, J ¼ 8:1 Hz, 1H), 4.67 (d, J ¼ 6:8 Hz, 1H),
4.60 (d, J ¼ 5:7 Hz, 1H), 4.55 (d, J ¼ 10:8 Hz, 1H), 4.52–4.46
(m, 1H), 4.31 (d, J ¼ 5:7 Hz, 1H), 4.28 (d, J ¼ 10:8 Hz, 1H),
4.25–4.10 (m, 2H), 3.81 (d, J ¼ 10:8 Hz, 1H), 3.68 (s, 3H),
3.56 (d, J ¼ 10:8 Hz, 1H), 3.42 (d, J ¼ 3:0 Hz, 1H), 3.28 (s,
1H), 2.72 (d, J ¼ 10:3 Hz, 1H), 2.60–2.42 (m, 1H), 2.05–1.83
(m, 2H), 1.75–1.55 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.81 (s,
9H), 0.77 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H), ꢂ0:05 (s, 3H),
ꢂ0:07 (s, 3H); 13C NMR (CDCl3) ꢂ 211.7, 158.6, 144.2, 139.2,
138.7, 131.1, 128.7, 128.0, 127.7, 127.7, 127.2, 126.8, 126.5,
114.4, 113.5, 87.2, 83.4, 79.1, 75.4, 74.3, 73.9, 72.3, 68.4, 66.1,
59.3, 53.2, 46.6, 28.9, 26.1, 26.0, 25.8, 25.7, 22.5, 22.5, 18.3,
18.2, ꢂ3:4, ꢂ4:5, ꢂ5:4, ꢂ5:5; HRMS (FAB) calcd for
C50H74NaO8Si2 [M + Na]þ 881.4820, found 881.4854.
(1R,2S,3R,5R,6S,7S,8R,9S)-2,6-Bis(benzyloxy)-5-(t-butyldi-
methylsilyloxy)-7,9-(isopropylidenedioxy)-8-(methoxymethoxy-
methyl)-4,4-dimethyl-12-methylenebicyclo[6.4.0]dodecan-3-ol.
To a solution of 25 (3.35 g, 4.03 mmol) in CH2Cl2 (400 mL) at 0
ꢁC were added phosphate buffer (pH ¼ 7, 20 mL) and DDQ (1.37
(1R,2S,3S,4R,6R,7S,8R,12S)-3,7-Bis(benzyloxy)-4-(t-butyldi-

692 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
g, 6.05 mmol). After the reaction mixture was stirred for 1 h, DDQ
(0.46 g, 2.01 mmol) was added, and this mixture was stirred at 0
ꢁC for 30 min. The reaction was quenched with a 1:1 mixture of
10% aqueous Na2SO3 and saturated aqueous NaHCO3 and then
the mixture was extracted with CH2Cl2. The combined organic
layers were washed with H2O and brine, dried over MgSO4, and
then filtered. The filtrate was concentrated under reduced pressure
and the crude product was purified by column chromatography
(silica gel, 10% EtOAc–hexane) to afford (1R,2S,3R,5R,6S,7S,
8R,9S)-2,6-bis(benzyloxy)-5-(t-butyldimethylsilyloxy)-7,9-(iso-
propylidenedioxy)-8-(methoxymethoxymethyl)-4,4-dimethyl-12-
methylenebicyclo[6.4.0]dodecan-3-ol (2.87 g, quant) as a color-
min at ꢂ23 ꢁC, a solution of ketone 26 (600 mg, 0.846 mmol)
in benzene (50 mL) was added. The reaction mixture was stirred
for 1 h at 0 ꢁC and then saturated aqueous ammonium chloride
was added. The mixture was extracted with diethyl ether. The or-
ganic layer was washed with 10% aqueous sodium thiosulfate and
brine, and dried over anhydrous sodium sulfate. After filtration of
the mixture and evaporation of the solvent, the crude product was
purified by column chromatography (silica gel, 1–2% Et2O–ben-
zene) to afford (1R,2S,3S,5R,6S,7S,8R,9S)-2,6-bis(benzyloxy)-
3-(3-butenyl)-5-(t-butyldimethylsilyloxy)-7,9-(isopropylidenedi-
oxy)-8-(methoxymethoxymethyl)-4,4-dimethyl-12-methylenebi-
cyclo[6.4.0]dodecan-3-ol (630 mg, 97%) as a colorless oil.
19
24
less oil. ½ꢁꢃD ¼ þ90:1 (c 0.50, benzene); IR (thin film) 3568
½ꢁꢃD ¼ þ32:0 (c 1.10, CHCl3); IR (liquid film) 3403 cmꢂ1
;
cmꢂ1
;
1H NMR (CDCl3) ꢂ 7.36–7.20 (m, 10H), 4.86 (s, 2H),
1H NMR (CDCl3) ꢂ 7.50–7.11 (m, 10H), 6.02–5.41 (brm, 2H),
5.11–3.98 (brm, 14H), 3.77–3.49 (brm, 2H), 3.45–3.11 (brm,
3H), 3.03–2.88 (brm, 1H), 2.87–1.70 (brm, 8H), 1.51–1.33 (brm,
6H), 1.31–1.15 (brm, 6H), 0.95 (s, 9H), 0.09 (s, 6H); 13C NMR
(CDCl3) very broadened spectra; HRMS (FAB) calcd for
C45H68NaO8Si [M + Na]þ 787.4581; found 787.4564.
4.75–4.52 (m, 6H), 4.47 (dd, J ¼ 3:0, 10.8 Hz, 1H), 4.38–4.25
(m, 2H), 4.17 (d, J ¼ 11:6 Hz, 1H), 4.02 (s, 1H), 3.90 (d, J ¼
2:7 Hz, 1H), 3.76 (t, J ¼ 7:8 Hz, 1H), 3.62 (d, J ¼ 2:7 Hz, 1H),
3.36 (s, 3H), 2.98–2.78 (m, 1H), 2.52 (d, J ¼ 11:6 Hz, 1H),
2.20–2.12 (m, 1H), 1.95–1.72 (m, 2H), 1.44 (s, 3H), 1.41 (s,
3H), 1.17 (s, 3H), 1.04 (s, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.03
(s, 3H); 13C NMR (CDCl3) ꢂ 144.9, 138.8, 138.6, 128.3, 128.1,
128.0, 127.3, 127.3, 127.1, 115.4, 99.2, 97.2, 91.9, 82.0, 78.2,
77.1, 76.0, 74.1, 73.3, 72.1, 64.0, 55.8, 49.8, 45.6, 43.2, 29.7,
27.8, 27.4, 25.9, 24.1, 21.2, 19.0, 18.0, ꢂ4:1, ꢂ4:8; HRMS
(FAB) calcd for C41H62NaO8Si [M + Na]þ 733.4112; found
733.4122.
(1R,2S,5R,6S,7S,8R,9S)-2,6-Bis(benzyloxy)-5-(t-butyldimeth-
ylsilyloxy)-7,9-(isopropylidenedioxy)-8-(methoxymethoxymeth-
yl)-4,4-dimethyl-12-methylenebicyclo[6.4.0]dodecan-3-one (26).
To a solution of (1R,2S,3R,5R,6S,7S,8R,9S)-2,6-bis(benzyloxy)-5-
(t-butyldimethylsilyloxy)-7,9-(isopropylidenedioxy)-8-(methoxy-
methoxymethyl)-4,4-dimethyl-12-methylenebicyclo[6.4.0]dode-
can-3-ol (2.24 g, 3.15 mmol) in CH2Cl2 (315 mL) were added
NaHCO3 (2.65 g, 31.5 mmol) and Dess–Martin periodinane
(6.68 g, 15.8 mmol) at room temperature. After the reaction mix-
ture was stirred for 20 min, the reaction was quenched with 10%
aqueous Na2SO3 and saturated aqueous NaHCO3. The mixture
was extracted with CH2Cl2 and the combined organic layers were
washed with brine, dried over MgSO4, and then filtered. The fil-
trate was concentrated under reduced pressure and the crude prod-
uct was purified by column chromatography (silica gel, 5–10%
(1R,2S,3S,5R,6R,7S,8R,9S)-2,6-Bis(benzyloxy)-3-(3-butenyl)-
7,9-(isopropylidenedioxy)-8-(methoxymethoxymethyl)-4,4-di-
methyl-12-methylenebicyclo[6.4.0]dodecane-3,5-diol (27). To
a solution of (1R,2S,3S,5R,6S,7S,8R,9S)-2,6-bis(benzyloxy)-3-(3-
butenyl)-5-(t-butyldimethylsilyloxy)-7,9-(isopropylidenedioxy)-8-
(methoxymethoxymethyl)-4,4-dimethyl-12-methylenebicyclo[6.4.0]-
dodecan-3-ol (301 mg, 0.393 mmol) in THF (53 mL) at room tem-
perature was added TBAF in THF (1.0 M, ꢁ12 mL, 12 mmol). The
reaction mixture was stirred for 1 h at 50 C and then phosphate
buffer (pH ¼ 7) was added at 0 ꢁC. The mixture was extracted
with diethyl ether, and the organic layer was washed with brine
and dried over anhydrous sodium sulfate. After filtration of the
mixture and evaporation of the solvent, the crude product was pu-
rified by preparative TLC (25% EtOAc–hexane) to afford alcohol
18
27 (204 mg, 80%) as a colorless oil. ½ꢁꢃD ¼ þ36:8 (c 1.00,
CHCl3); IR (thin film) 3472 cmꢂ1 1H NMR (CDCl3) ꢂ 7.50–
;
7.12 (m, 10H), 5.88–5.72 (brm, 1H), 5.41–5.30 (brm, 1H), 5.09–
4.25 (brm, 12H), 4.21–4.03 (brm, 1H), 3.95–3.51 (brm, 3H),
3.34 (s, 3H), 3.30–2.92 (brm, 1H), 2.60–2.45 (brm, 1H), 2.38–
2.01 (brm, 4H), 2.00–1.61 (brm, 3H), 1.52 (s, 3H), 1.46 (s, 3H),
1.26 (brs, 3H), 1.17 (brs, 3H); 13C NMR (CDCl3) very broadened
spectra; HRMS (FAB) calcd for C39H54NaO8 [M + Na]þ
673.3716; found 673.3727.
EtOAc–hexane) to afford ketone 26 (2.13 g, 95%) as a colorless
20
oil. ½ꢁꢃD ¼ ꢂ19:0 (c 1.00, CHCl3); IR (thin film) 1687 cmꢂ1
;
(1R,2S,3S,4R,6S,7S,8R,12S)-3,7-Bis(benzyloxy)-6-(3-buten-
yl)-4,6-(cyclohexylmethylsilylenedioxy)-2,12-(isopropylidene-
dioxy)-1-(methoxymethoxymethyl)-5,5-dimethyl-9-methylene-
bicyclo[6.4.0]dodecane (28). To a solution of diol 27 (1.20 g,
1.84 mmol) and imidazole (12.6 g, 106 mmol) in DMF (102
1H NMR (CDCl3) ꢂ 7.23–7.10 (m, 10H), 4.90 (s, 1H), 4.78 (s,
1H), 4.64 (d, J ¼ 11:3 Hz, 1H), 4.56 (d, J ¼ 11:3 Hz, 1H),
4.42–4.33 (m, 5H), 4.22 (d, J ¼ 11:6 Hz 1H), 4.07 (d, J ¼ 11:3
Hz, 1H), 3.98 (d, J ¼ 11:1 Hz, 1H), 3.78–3.67 (m, 2H), 3.58 (d,
J ¼ 2:2 Hz, 1H), 3.30 (s, 3H), 2.72 (d, J ¼ 11:9 Hz, 1H), 2.49–
2.33 (m, 1H), 2.03–1.90 (m, 1H), 1.85–1.66 (m, 2H), 1.31 (s,
6H), 1.24 (s, 3H), 1.22 (s, 3H), 0.82 (s, 9H), 0.00 (s, 3H),
ꢂ0:05 (s, 3H); 13C NMR (CDCl3) ꢂ 210.4, 143.4, 138.9, 138.1,
128.8, 128.5, 128.5, 128.1, 127.9, 127.6, 115.9, 99.6, 97.3, 91.0,
82.8, 82.0, 76.5, 74.0, 71.7, 64.3, 55.9, 54.6, 48.1, 43.9, 30.2,
29.1, 29.0, 28.7, 26.2, 26.1, 20.3, 19.5, 18.4, ꢂ3:7, ꢂ4:4; HRMS
(FAB) calcd for C41H60NaO8Si [M + Na]þ 731.3955; found
731.3968.
ꢁ
mL) at 0 C was added dichloro(cyclohexyl)methylsilane (7.3 g,
36.8 mmol). The reaction mixture was stirred for 10 min at room
temperature and then saturated aqueous sodium hydrogencarbon-
ate was added. The mixture was extracted with diethyl ether, and
the organic layer was washed with brine and dried over anhydrous
sodium sulfate. After filtration of the mixture and evaporation of
the solvent, the crude product was purified by column chromatog-
raphy (silica gel, 2–10% EtOAc–hexane) to afford alcohol 28
18
(1.49 g, quant) as a colorless oil. ½ꢁꢃD ¼ ꢂ3:72 (c 1.07, CHCl3);
(1R,2S,3S,5R,6S,7S,8R,9S)-2,6-Bis(benzyloxy)-3-(3-butenyl)-
5-(t-butyldimethylsilyloxy)-7,9-(isopropylidenedioxy)-8-(me-
thoxymethoxymethyl)-4,4-dimethyl-12-methylenebicyclo[6.4.0]-
dodecan-3-ol. To a solution of s-butyllithium in cyclohexane
IR (thin film) 2922, 2849 cmꢂ1 1H NMR (CDCl3) ꢂ 7.46–7.35
;
(m, 2H), 7.33–7.10 (m, 8H), 5.88–5.71 (m, 1H), 5.65 (brs, 1H),
4.98 (d, J ¼ 11:3 Hz, 1H), 4.90 (d, J ¼ 16:1 Hz, 1H), 4.84 (s,
1H), 4.80 (s, 1H), 4.75–4.65 (m, 2H), 4.62 (d, J ¼ 5:9 Hz, 1H),
4.57 (d, J ¼ 3:0 Hz, 1H), 4.54 (d, J ¼ 3:0 Hz, 1H), 4.50 (d, J ¼
3:0 Hz, 1H), 4.47 (d, J ¼ 3:0 Hz, 1H), 4.44 (d, J ¼ 16:1 Hz, 1H),
ꢁ
(0.97 M, 17.5 mL, 17.0 mmol) at 0 C was added 4-iodobutene
(3.09 g, 17 mmol). After the reaction had been stirred for 25

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
693
4.25 (s, 1H), 4.16 (d, J ¼ 8:9 Hz, 1H), 4.07 (d, J ¼ 8:9 Hz, 1H),
3.74 (dd, J ¼ 11:1, 4.3 Hz, 1H), 3.37 (s, 3H), 2.65–2.12 (m, 6H),
1.92–1.52 (m, 4H), 1.44 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.38 (s,
3H), 1.25–0.95 (m, 9H), 0.70–0.55 (m, 1H), 0.10 (s, 3H);
13C NMR (CDCl3) ꢂ 144.3, 140.9, 139.8, 138.1, 129.1, 127.9,
127.8, 127.5, 126.6, 126.5, 113.1, 114.1, 99.6, 96.5, 86.2, 83.8,
82.0, 79.6, 78.4, 76.9, 71.2, 66.5, 55.5, 49.5, 47.3, 42.0, 37.7,
31.5, 31.4, 30.0, 29.6, 29.2, 28.1, 27.9, 27.8, 27.5, 27.3, 27.0,
26.9, 19.9, ꢂ0:1, ꢂ1:4; HRMS (FAB) calcd for C46H66NaO8Si
[M + Na]þ 797.4425; found 797.4458.
811.4598.
(1R,2S,3S,6S,7S,8R,12S)-3,7-Bis(benzyloxy)-6-(cyclohexyldi-
methylsilyloxy)-2,12-(isopropylidenedioxy)-1-(methoxymethoxy-
methyl)-5,5-dimethyl-9-methylene-6-(3-oxobutyl)bicyclo[6.4.0]-
dodecan-4-one (30). To a solution of (1R,2S,3S,6S,7S,8R,12S)-
3,7-bis(benzyloxy)-6-(3-butenyl)-6-(cyclohexyldimethylsilyloxy)-
2,12-(isopropylidenedioxy)-1-(methoxymethoxymethyl)-5,5-di-
methyl-9-methylenebicyclo[6.4.0]dodecan-4-one (205 mg, 0.26
mmol) in DMF (71 mL) and water at 0 ꢁC was added palla-
dium(II) chloride (230 mg, 1.3 mmol). The reaction mixture
was stirred for 3.5 h at room tꢁemperature and then phosphate buff-
er (pH ¼ 7) was added at 0 C. The mixture was extracted with
ethyl acetate. Then the organic layers were washed with water
and brine, and dried over anhydrous sodium sulfate. After filtra-
tion of the mixture and evaporation of the solvent, the crude prod-
(1R,2S,3R,4R,6S,7S,8R,12S)-3,7-Bis(benzyloxy)-6-(3-buten-
yl)-6-(cyclohexyldimethylsilyloxy)-2,12-(isopropylidenedioxy)-
1-(methoxymethoxymethyl)-5,5-dimethyl-9-methylenebicyclo-
[6.4.0]dodecan-4-ol (29). To a solution of silylene 28 (1.49ꢁg,
1.92 mmol) in THF (192 mL) and HMPA (19.2 mL) at ꢂ78 C
was added methyllithium in diethyl ether (1.02 M, 37.6 mL,
38.4 mmol). The reaction mixture was stirred for 30 min at ꢂ78
ꢁC and then saturated aqueous ammonium chloride was added.
The mixture was extracted with diethyl ether, and the organic lay-
er was washed with brine and dried over anhydrous sodium sul-
fate. After filtration of the mixture and evaporation of the solvent,
the crude product was purified by column chromatography (silica
gel, 10–20% EtOAc–hexane) to afford alcohol 29 (1.51 g, 99%) as
uct was purified by preparative TLC (20% EtOAc–hexane) to
18
afford diketone 30 (174 mg, 83%) as a colorless oil. ½ꢁꢃD
¼
þ33:4 (c 1.04, CHCl3); IR (KBr pellet) 1716, 1673 cmꢂ1
;
1H NMR (CDCl3) ꢂ 7.41–7.05 (m, 10H), 4.98 (d, J ¼ 12:4 Hz,
1H), 4.89 (s, 1H), 4.86 (d, J ¼ 12:4 Hz, 1H), 4.68 (s, 2H), 4.67
(d, J ¼ 11:6 Hz, 1H), 4.63 (s, 1H), 4.59 (d, J ¼ 11:6 Hz, 1H),
4.45–4.37 (m, 2H), 4.36 (d, J ¼ 1:9 Hz, 1H), 4.24 (d, J ¼ 3:5
Hz, 1H), 3.85 (d, J ¼ 3:5 Hz, 1H), 3.78 (t, J ¼ 9:2 Hz, 1H),
3.57–3.41 (m, 1H), 3.40 (s, 3H), 2.74–2.57 (m, 1H), 2.55–2.40
(m, 1H), 2.22–1.95 (m, 4H), 2.01 (s, 3H), 1.95–1.47 (m, 6H),
1.65 (s, 3H), 1.46 (s, 3H), 1.41 (s, 3H), 1.21 (s, 3H), 1.20–0.90
(m, 6H), 0.72–0.60 (m, 1H), 0.09 (s, 3H), ꢂ0:16 (s, 3H); 13C NMR
(CDCl3) ꢂ 214.8, 208.7, 147.8, 140.0, 137.3, 127.9, 127.5, 127.4,
127.2, 125.7, 124.6, 112.4, 99.7, 97.0, 91.9, 88.9, 82.6, 80.2, 75.4,
74.0, 72.2, 64.1, 56.6, 55.8, 47.3, 44.6, 40.6, 30.1, 29.6, 29.5, 28.3,
27.8, 27.6, 27.0, 26.6, 25.8, 23.7, 21.2, 19.5, 0.0, ꢂ1:5; HRMS
(FAB) calcd for C47H68NaO9Si [M + Na]þ 827.4530; found
827.4567.
18
a colorless oil. ½ꢁꢃD ¼ þ18:9 (c 1.05, CHCl3); IR (KBr pellet)
3469 cmꢂ1 1H NMR (CDCl3) ꢂ 7.45–6.98 (m, 10H), 5.88–5.61
;
(brm, 2H), 4.99–3.92 (brm, 14H), 3.73–3.52 (brm, 2H), 3.31–
3.05 (brm, 3H), 2.80–2.60 (brm, 1H), 2.51–0.88 (brm, 18H),
1.57 (s, 3H), 1.38 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H), 0.58–0.51
(brm, 1H), 0.02 (s, 3H), ꢂ0:30 (s, 3H); 13C NMR (CDCl3) very
broadened spectra; HRMS (FAB) calcd for C47H70NaO8Si [M
+ Na]þ 813.4738; found 813.4729.
(1R,2S,3S,6S,7S,8R,12S)-3,7-Bis(benzyloxy)-6-(3-butenyl)-6-
(cyclohexyldimethylsilyloxy)-2,12-(isopropylidenedioxy)-1-(me-
thoxymethoxymethyl)-5,5-dimethyl-9-methylenebicyclo[6.4.0]-
dodecan-4-one. To a solution of alcohol 29 (225 mg, 0.284
mmol) in CH2Cl2 (14 mL) were added NaHCO3 (477 mg, 5.68
mmol) and Dess–Martin periodinane (603 mg, 1.42 mmol) at
room temperature. After the reaction mixture was stirred for 20
min, the reaction was quenched with 10% aqueous Na2SO3 (2
mL) and saturated aqueous NaHCO3. The mixture was extracted
with CH2Cl2 and the combined organic layers were washed with
brine, dried over MgSO4, and then filtered. The filtrate was con-
centrated under reduced pressure and the crude product was puri-
fied by preparative TLC (20% EtOAc–hexane) to afford (1R,2S,
3S,6S,7S,8R,12S)-3,7-bis(benzyloxy)-6-(3-butenyl)-6-(cyclohex-
yldimethylsilyloxy)-2,12-(isopropylidenedioxy)-1-(methoxyme-
thoxymethyl)-5,5-dimethyl-9-methylenebicyclo[6.4.0]dodecan-4-
(4S,4aR,5S,6S,7R,8R,11S,12S,12aR)-6,12-Bis(benzyloxy)-11-
(cyclohexyldimethylsilyloxy)-4,5-(isopropylidenedioxy)-4a-(me-
thoxymethoxymethyl)-8,13,13-trimethyl-1-methylenetetradeca-
hydro-7,11-methanobenzocyclodecene-7,8-diol (4).
Titani-
um(II) chloride was prepared from titanium(IV) chloride and
hexamethyldisilane by the procedure of Paul et al.17 To a solution
ofꢁthis titanium(II) chloride (1.23 g, 10.3 mmol) in THF (20 mL) at
0 C was added lithium aluminium hydride in THF (1.0 M, 2.29
mL, 2.29 mmol). The reaction mixture was refluxed for 20 min
and then THF (12 mL) was added at room temperature. The sus-
pension of low-valent titanium in THF (0.2 M) thus prepared
was immediately used in the following reaction. To a solution of
diketone 30 (186 mg, 0.231 mmol) in THF (84 mL) at 35 ꢁC
was added the suspension of low-valent titanium in THF (0.2 M,
28.9 mL, 5.78 mmol). The reaction mixture was stirred for 20
min at 40 ꢁC and then saturated aqueous sodium hydrogencarbon-
ate was added at 0 ꢁC. The mixture was stirred for 10 min at room
temperature and then it was extracted with ethyl acetate. The or-
ganic layers were washed with water and brine, and dried over an-
hydrous sodium sulfate. After filtration of the mixture and evapo-
ration of the solvent, the crude product was purified by preparative
TLC (30% EtOAc–hexane) to afford diol 4 (119 mg, 64%) as a col-
19
one (217 mg, 97%) as a colorless oil. ½ꢁꢃD ¼ þ19:2 (c 1.04,
CHCl3); IR (KBr pellet) 1673 cmꢂ1 1H NMR (CDCl3) ꢂ 7.41–
;
7.05 (m, 10H), 5.78 (ddt, J ¼ 16:2, 10.3, 5.9 Hz, 1H), 5.04–
4.82 (m, 5H), 4.68 (s, 2H), 4.65–4.56 (m, 3H), 4.55 (d, J ¼ 1:6
Hz, 1H), 4.42 (d, J ¼ 12:2 Hz, 1H), 4.34 (d, J ¼ 1:6 Hz, 1H),
4.22 (d, J ¼ 3:8 Hz, 1H), 3.84 (d, J ¼ 3:8 Hz, 1H), 3.78 (d, J ¼
9:5 Hz, 1H), 3.41 (s, 3H), 2.97–2.82 (m, 1H), 2.51–2.37 (m, 1H),
2.23–2.09 (m, 1H), 2.05–1.61 (m, 10H), 1.66 (s, 3H), 1.46 (s, 3H),
1.42 (s, 3H), 1.25 (s, 3H), 1.25–0.85 (m, 6H), 0.70–0.58 (m, 1H),
0.13 (s, 3H), ꢂ0:15 (s, 3H); 13C NMR (CDCl3) ꢂ 215.6, 147.0,
140.4, 139.5, 137.6, 128.2, 127.7, 127.6, 127.5, 125.9, 125.0,
113.6, 113.1, 99.9, 97.3, 92.3, 89.5, 82.9, 80.6, 75.6, 74.3, 72.6,
64.4, 57.0, 56.0, 47.6, 44.9, 29.9, 29.8, 29.7, 29.1, 28.7, 28.1,
27.9, 27.3, 27.3, 27.0, 26.2, 21.5, 19.9, ꢂ0:0, ꢂ1:4; HRMS
(FAB) calcd for C47H68NaO8Si [M + Na]þ 811.4581; found
21
orless oil. ½ꢁꢃD ¼ þ28:4 (c 1.00, CHCl3); IR (KBr pellet) 3559
1
cmꢂ1; H NMR (C6D6) ꢂ 7.58 (d, J ¼ 7:5 Hz, 2H), 7.38 (d, J ¼
7:5 Hz, 2H), 7.28 (t, J ¼ 7:5 Hz, 2H), 7.24 (t, J ¼ 7:5 Hz, 2H),
7.13 (t, J ¼ 7:5 Hz, 1H), 7.10 (t, J ¼ 7:5 Hz, 1H), 5.25 (d, J ¼
10:5 Hz, 1H), 5.19 (brs, 1H), 5.02 (d, J ¼ 13:0 Hz, 1H), 4.98
(brs, 1H), 4.97 (d, J ¼ 13:0 Hz, 1H), 4.94 (d, J ¼ 12:0 Hz, 1H),
4.49 (d, J ¼ 12:0 Hz, 1H), 4.39 (d, J ¼ 4:0 Hz, 1H), 4.39 (d, J ¼

694 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
19
6:0 Hz, 1H), 4.38 (d, J ¼ 10:5 Hz, 1H), 4.36 (d, J ¼ 6:0 Hz, 1H),
3.95 (d, J ¼ 2:5 Hz, 1H), 3.84 (t, J ¼ 9:0 Hz, 1H), 3.82 (d, J ¼
2:5 Hz, 1H), 3.33 (d, J ¼ 4:5 Hz, 1H), 3.20 (s, 1H), 3.11 (s,
3H), 3.02–2.94 (m, 2H), 2.56–2.47 (m, 1H), 2.38 (dd, J ¼ 14:0,
5.5 Hz, 1H), 2.27–2.14 (m, 2H), 2.13–1.95 (m, 4H), 1.85–1.78
(m, 1H), 1.76–1.70 (m, 1H), 1.68–1.62 (m, 1H), 1.62 (s, 3H),
1.46 (s, 3H), 1.45–1.41 (m, 1H), 1.39 (s, 3H), 1.36–1.25 (m,
1H), 1.30 (s, 3H), 1.24–1.06 (m, 2H), 1.17 (s, 3H), 0.98–0.87
(m, 1H), 0.80–0.72 (m, 1H), 0.24 (s, 3H), 0.22 (s, 3H); 13C NMR
(CDCl3) ꢂ 147.6, 141.7, 139.5, 129.4, 128.8, 128.6, 128.2, 127.3,
127.0, 112.8, 99.6, 98.1, 93.5, 84.5, 83.1, 82.7, 80.6, 78.3, 75.4,
73.4, 73.4, 73.2, 64.2, 56.1, 51.1, 45.6, 45.4, 38.4, 31.4, 30.6,
29.7, 29.2, 29.1, 28.9, 28.5, 28.4, 28.3, 28.2, 28.0, 23.7, 19.4,
0.9, 0.4; HRMS (FAB) calcd for C47H70NaO9Si [M + Na]þ
829.4687; found 829.4691.
6,9,10,11-pentol (75.3 mg, 98%) as a colorless oil. ½ꢁꢃD
þ22:3 (c 1.04, CHCl3); IR (KBr pellet) 3483 cmꢂ1
¼
;
1H NMR
(CDCl3) ꢂ 5.27 (s, 1H), 4.97 (s, 1H), 4.66 (d, J ¼ 6:5 Hz, 1H),
4.62 (d, J ¼ 6:5 Hz, 1H), 4.44 (d, J ¼ 8:9 Hz, 1H), 4.40 (d, J ¼
10:5 Hz, 1H), 4.22 (brs, 1H), 4.12 (d, J ¼ 1:6 Hz, 1H), 4.03 (d,
J ¼ 9:2 Hz, 1H), 3.93 (dd, J ¼ 8:9, 1.6 Hz, 1H), 3.76 (d, J ¼
10:5 Hz, 1H), 3.74 (t, J ¼ 5:7 Hz, 1H), 3.60 (s, 1H), 3.41 (s,
3H), 3.30 (brs, 1H), 2.90 (brs, 1H), 2.65–2.55 (m, 1H), 2.53 (d,
J ¼ 8:9 Hz, 1H), 2.32–2.15 (m, 1H), 2.12–1.58 (m, 6H), 1.50
(s, 3H), 1.44 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H), 1.23 (s, 3H);
13C NMR (CDCl3) ꢂ 148.8 110.9, 99.1, 97.2, 82.4, 79.4, 78.7,
77.2, 77.1, 73.4, 72.4, 64.0, 56.4, 50.4, 47.6, 47.3, 34.9, 34.7,
29.8, 29.7, 27.1, 27.0, 25.1, 20.5, 19.3; HRMS (FAB) calcd for
C25H42NaO9 [M + Na]þ 509.2727; found 509.2729.
(4S,4aR,5S,6S,7R,8R,11S,12S,12aR)-11,12-(Carbonyldioxy)-
4,5-(isopropylidenedioxy)-4a-(methoxymethoxymethyl)-8,13,13-
trimethyl-1-methylenetetradecahydro-7,11-methanobenzocy-
clodecene-6,7,8-triol (31). To a solution of (1S,4aR,5S,6S,9R,
10R,11S,12S,12aR)-1,12-(isopropylidenedioxy)-12a-(methoxyme-
thoxymethyl)-9,13,13-trimethyl-4-methylenetetradecahydro-6,10-
methanobenzocyclodecene-5,6,9,10,11-pentol (65.2 mg, 0.134
mmol) in dichloromethane (76 mL) and pyridine (530 mg, 6.70
mmol) at ꢂ45 ꢁC was added bis(trichloromethyl) carbonate
(199 mg, 0.67 mmol). The reaction mixture was stirred for 70
(1S,4aR,5S,6S,9R,10R,11S,12S,12aR)-6-(Cyclohexyldimeth-
ylsilyloxy)-1,12-(isopropylidenedioxy)-12a-(methoxymethoxy-
methyl)-9,13,13-trimethyl-4-methylenetetradecahydro-6,10-
methanobenzocyclodecene-5,9,10,11-tetrol. To a solution of
ꢁ
diol 4 (133 mg, 0.164 mmol) in THF (12.6 mL) at ꢂ78 C were
added liquid ammonia (29.3 mL) and sodium (37.6 mg, 1.64
mmol). After the reaction mixture was stirred for 15 min at ꢂ78
ꢁC, it was allowed to warm to ꢂ45 ꢁC. The reaction mixture
was stirred for 30 min at ꢂ45 ꢁC and then solid ammonium chlo-
ride was added. After evaporation of liquid ammonia at room tem-
perature, the residue was diluted with diethyl ether and dried over
anhydrous sodium sulfate. After filtration of the mixture and evap-
oration of the solvent, the crude product was purified by prepara-
tive TLC (50% EtOAc–hexane) to afford (1S,4aR,5S,6S,9R,
10R,11S,12S,12aR)-6-(cyclohexyldimethylsilyloxy)-1,12-(isopro-
pylidenedioxy)-12a-(methoxymethoxymethyl)-9,13,13-trimethyl-
4-methylenetetradecahydro-6,10-methanobenzocyclodecene-5,9,
ꢁ
min at ꢂ45 C and then saturated aqueous sodium hydrogencar-
bonate was added. The mixture was extracted with diethyl ether,
and the organic layer was washed with saturated aqueous cop-
per(II) sulfate, water, and brine and dried over anhydrous sodium
sulfate. After filtration of the mixture and evaporation of the sol-
vent, the crude product was purified by preparative TLC (75%
EtOAc–hexane) to afford carbonate 31 (73.2 mg, quant) as a col-
17
orless oil. ½ꢁꢃD ¼ ꢂ5:99 (c 1.03, CHCl3); IR (KBr pellet) 3425,
18
1
10,11-tetrol (98.7 mg, 96%) as a colorless oil. ½ꢁꢃD ¼ þ18:9 (c
1797 cmꢂ1; H NMR (CDCl3) ꢂ 5.55 (d, J ¼ 11:1 Hz, 1H), 5.32
1.01, CHCl3); IR (KBr pellet) 3535 cmꢂ1
;
1H NMR (CDCl3) ꢂ
(s, 1H), 4.87 (s, 1H), 4.70 (d, J ¼ 6:5 Hz, 1H), 4.66 (d, J ¼ 6:5
Hz, 1H), 4.65–4.52 (m, 1H), 4.29 (brs, 1H), 4.23 (d, J ¼ 10:3
Hz, 1H), 3.92 (d, J ¼ 10:3 Hz, 1H), 3.76 (dd, J ¼ 11:3, 4.6 Hz,
1H), 3.48 (brs, 1H), 3.42 (s, 3H), 2.75 (brs, 1H), 2.52–2.25 (m,
3H), 2.23–1.97 (m, 3H), 1.94–1.70 (m, 2H), 1.69–1.50 (m, 1H),
1.51 (s, 3H), 1.45 (s, 3H), 1.45 (s, 3H), 1.34 (s, 3H), 1.26 (s,
3H); 13C NMR (CDCl3) ꢂ 152.4, 141.2, 114.1, 99.2, 97.3, 93.0,
81.7, 80.5, 79.0, 78.0, 76.7, 73.2, 64.0, 56.9, 48.2, 45.8, 44.9,
36.0, 33.0, 31.2, 29.5, 27.5, 26.5, 22.5, 21.2, 19.3; HRMS
(FAB) calcd for C26H41O9 [M + H]þ 513.2700; found 513.2681.
(1S,2S,3R,4R,7S,8R,9S,10S,11R,12R)-1,2-(Carbonyldioxy)-
4,19-epoxy-7,9-(diisopropylsilylenedioxy)taxane-10,11,12-triol
(32). 1) To a solution of carbonate 31 (5.0 mg, 0.00975 mmol) in
THF (1 mL) at room temperature was added hydrochloric acid (6
M, 0.5 mL). The reaction mixture was stirred for 5 h at 60 ꢁC and
then solid sodium hydrogencarbonate was added at 0 ꢁC. The mix-
ture was diluted with ethyl acetate, and dried over anhydrous so-
dium sulfate. Filtration of the mixture through a short pad of silica
gel and evaporation of the solvent afforded crude pentaol.
2) To a solution of the above crude pentaol in CH2Cl2 (2 mL) at
ꢂ23 ꢁC was added 2,6-lutidine (47 mg, 0.439 mmol) and diisopro-
pylsilanediyl bistriflate (32.0 mg, 0.0975 mmol). The reaction
mixture was stirred for 40 min at ꢂ23 ꢁC and then saturated aque-
ous sodium hydrogencarbonate was added. The mixture was ex-
tracted with ethyl acetate, and the organic layer was washed with
saturated aqueous copper(II) sulfate, water, and brine and dried
over anhydrous sodium sulfate. After filtration of the mixture
and evaporation of the solvent, the crude product was purified
by preparative TLC (10% MeOH–CH2Cl2) to afford silylene 32
4.87 (s, 1H), 4.62 (s, 2H), 4.58 (s, 1H), 4.39 (d, J ¼ 5:9 Hz,
1H), 4.37 (d, J ¼ 11:9 Hz, 1H), 3.98 (d, J ¼ 11:9 Hz, 1H), 3.89
(dd, J ¼ 5:4, 2.7 Hz, 1H), 3.78 (s, 1H), 3.71 (d, J ¼ 2:7 Hz,
1H), 3.64 (dd, J ¼ 10:8, 7.0 Hz, 1H), 3.46 (d, J ¼ 5:4 Hz, 1H),
3.36 (s, 3H), 2.92 (brs, 1H), 2.89 (d, J ¼ 7:0 Hz, 1H), 2.67 (s,
1H), 2.61–2.47 (m, 1H), 2.11–1.68 (m, 7H), 1.67–1.50 (m, 4H),
1.41 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H), 1.25–0.88 (m, 6H), 1.27
(s, 3H), 1.11 (s, 3H), 0.63–0.51 (m, 1H), ꢂ0:01 (s, 3H), ꢂ0:02
(s, 3H); 13C NMR (CDCl3) ꢂ 144.6, 113.5, 99.1, 97.1, 81.8,
79.8, 78.9, 78.1, 77.1, 73.9, 73.3, 64.0, 56.3, 47.6, 47.0, 45.1,
36.7, 31.1, 29.8, 28.0, 27.9, 27.8, 27.7, 27.7, 27.2, 27.1, 27.0,
26.9, 21.2, 19.3, 18.7, ꢂ2:8, ꢂ3:1; HRMS (FAB) calcd for
C33H58NaO9Si [M + Na]þ 649.3748; found 649.3773.
(1S,4aR,5S,6S,9R,10R,11S,12S,12aR)-1,12-(Isopropylidene-
dioxy)-12a-(methoxymethoxymethyl)-9,13,13-trimethyl-4-meth-
ylenetetradecahydro-6,10-methanobenzocyclodecene-5,6,9,10,
11-pentol.
To a solution of (1S,4aR,5S,6S,9R,10R,11S,12S,
12aR)-6-(cyclohexyldimethylsilyloxy)-1,12-(isopropylidenedioxy)-
12a-(methoxymethoxymethyl)-9,13,13-trimethyl-4-methylenetet-
radecahydro-6,10-methanobenzocyclodecene-5,9,10,11-tetrol (98.7
mg, 0.157 mmol) in THF (24.5 mL) at room temperature was add-
ed TBAF in THF (1.0 M, 0.98 mL, 0.98 mmol). The reaction mix-
ture was stirred for 30 min at room temperature and then a small
amount of methanol was added. After the solvent was evaporated,
the crude product was purified by preparative TLC (75% EtOAc–
hexane) to afford (1S,4aR,5S,6S,9R,10R,11S,12S,12aR)-1,12-(iso-
propylidenedioxy)-12a-(methoxymethoxymethyl)-9,13,13-trimeth-
yl-4-methylenetetradecahydro-6,10-methanobenzocyclodecene-5,

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
695
24
(2.0 mg, 37%) as a colorless oil. ½ꢁꢃD ¼ þ0:77 (c 0.41, CHCl3);
IR (thin film) 3479, 1791 cmꢂ1; 1H NMR (CDCl3) ꢂ 5.15 (d, J ¼
10:0 Hz, 1H), 4.43 (d, J ¼ 9:5 Hz, 1H), 4.34 (d, J ¼ 3:0 Hz, 1H),
4.26 (d, J ¼ 9:5 Hz, 1H), 4.15 (dd, J ¼ 3:0, 2.5 Hz, 1H), 4.09 (dd,
J ¼ 10:5, 5.5 Hz, 1H), 3.27 (s, 1H), 2.99 (d, J ¼ 2:5 Hz, 1H), 2.53
(s, 1H), 2.48–2.41 (m, 1H), 2.08–2.01 (m, 1H), 2.00–1.92 (m, 2H),
1.91–1.78 (m, 2H), 1.70–1.62 (m, 2H), 1.50 (s, 3H), 1.49 (s, 3H),
1.49–1.42 (m, 1H), 1.37 (s, 3H), 1.30 (s, 3H), 1.08–1.00 (m, 14H);
13C NMR (CDCl3) ꢂ 152.7, 91.0, 86.9, 85.0, 81.9, 79.5, 79.1, 75.7,
73.2, 68.2, 58.1, 50.4, 46.5, 40.1, 31.3, 29.9, 26.9, 26.4, 26.2, 23.3,
22.0, 17.5, 17.2, 17.1, 16.9, 13.0, 12.5; HRMS (FAB) calcd for
C27H44KO9 [M + K]þ 579.2391; found 579.2382.
(ESI) calcd for C24H35BrNaO9 [M + Na]þ 569.1362; found
569.1393.
(1S,2S,3R,4R,7S,8S,9S,10S,11R,12R)-20-Bromo-1,2-(carbon-
yldioxy)-4,19-epoxy-7-(triethylsilyloxy)taxane-9,10,11,12-tetrol
(34). 1) To a solution of bromo ether 33 (60.0 mg, 0.106 mmol)
in THF (10 mL) at room temperature was added hydrochloric acid
(3 M, 5 mL). The reaction mixture was stirred for 5 h at 60 ꢁC and
then solid sodium hydrogencarbonate was added at 0 ꢁC. The mix-
ture was diluted with ethyl acetate, and dried over anhydrous so-
dium sulfate. Filtration of the mixture through a short pad of silica
gel and evaporation of the solvent afforded crude pentol.
2) To a solution of the above crude pentol in pyridine (3 mL) at
ꢂ23 ꢁC was added triethylsilyl triflate (0.1 mL, 0.442 mmol). The
(4S,4aR,5S,6S,7R,8R,11S,12S,12aR)-11,12-(Carbonyldioxy)-
4a-hydroxymethyl-4,5-(isopropylidenedioxy)-8,13,13-trimeth-
yl-1-methylenetetradecahydro-7,11-methanobenzocyclodecene-
6,7,8-triol. To a solution of carbonate 31 (73.2 mg, 0.143 mmol)
in THF (16 mL) at room temperature was added hydrochloric acid
(6 M, 8 mL). The reaction mixture was stirred for 4 h at room tem-
perature and then saturated aqueous sodium hydrogencarbonate
was added. The mixture was extracted with ethyl acetate, and
the organic layer was washed with water and brine and dried over
anhydrous sodium sulfate. After filtration of the mixture and evap-
oration of the solvent, the crude product was purified by prepara-
tive TLC (35% acetone–CHCl3) to afford (4S,4aR,5S,6S,7R,8R,
11S,12S,12aR)-11,12-(carbonyldioxy)-4a-hydroxymethyl-4,5-(iso-
propylidenedioxy)-8,13,13-trimethyl-1-methylenetetradecahydro-
7,11-methanobenzocyclodecene-6,7,8-triol (67.0 mg, quant) as a
ꢁ
reaction mixture was stirred for 30 min at ꢂ23 C and then satu-
rated aqueous sodium hydrogencarbonate was added. The mixture
was extracted with ethyl acetate, and the organic layer was washed
with saturated aqueous copper(II) sulfate, water, and brine and
dried over anhydrous sodium sulfate. After filtration of the mix-
ture and evaporation of the solvent, the crude product was purified
by preparative TLC (30% acetone–CHCl3) to afford triethylsilyl
22
ether 34 (60.0 mg, 91%) as a colorless oil. ½ꢁꢃD ¼ þ41:7 (c
1.00, CHCl3); IR (KBr pellet) 3454, 1795 cmꢂ1
;
1H NMR
(CDCl3) ꢂ 5.39 (d, J ¼ 7:8 Hz, 1H), 4.93 (s, 1H), 4.51 (d, J ¼
10:0 Hz, 1H), 4.38 (d, J ¼ 10:0 Hz, 1H), 4.37 (d, J ¼ 9:2 Hz,
1H), 4.19 (s, 1H), 4.09 (s, 1H), 3.90–3.81 (m, 1H), 3.24 (d, J ¼
9:2 Hz, 1H), 3.24–3.17 (brs, 1H), 3.15–3.05 (brs, 1H), 2.75–
2.54 (m, 1H), 2.50–2.26 (m, 3H), 2.07–1.81 (m, 4H), 1.60–1.42
(m, 2H), 1.47 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H), 0.97 (t, J ¼
8:7 Hz, 9H), 0.69 (q, J ¼ 8:7 Hz, 6H); 13C NMR (CDCl3) ꢂ
153.2, 88.3, 88.1, 85.3, 80.1, 79.3, 77.8, 74.8, 73.2, 71.4, 58.9,
49.3, 47.5, 38.8, 37.3, 31.2, 28.8, 26.3, 24.9, 24.8, 20.5, 6.9,
5.1; HRMS (ESI) calcd for C27H45BrNaO9Si [M + Na]þ
643.1914; found 643.1905.
24
colorless oil. ½ꢁꢃD ¼ ꢂ28:6 (c 1.00, CHCl3); IR (KBr pellet)
3402, 1791 cmꢂ1
;
1H NMR (CDCl3) ꢂ 5.81 (d, J ¼ 10:8 Hz,
1H), 5.34 (s, 1H), 5.00 (s, 1H), 4.25 (d, J ¼ 12:7 Hz, 1H), 4.23
(s, 1H), 4.08 (d, J ¼ 12:7 Hz, 1H), 3.75 (d, J ¼ 1:6 Hz, 1H),
3.73 (dd, J ¼ 11:3, 5.1 Hz, 1H), 2.49–2.28 (m, 3H), 2.25–2.01
(m, 3H), 1.95–1.78 (m, 2H), 1.72–1.64 (m, 1H), 1.51 (s, 3H),
1.45 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.29 (s, 3H); 13C NMR
(CDCl3) ꢂ 152.4, 140.7, 114.4, 99.1, 92.8, 82.1, 80.6, 79.0,
77.9, 77.1, 73.3, 58.0, 48.9, 45.9, 44.8, 36.0, 33.1, 31.2, 29.4,
27.4, 26.5, 22.4, 21.5, 19.3; HRMS (FAB) calcd for C24H37O9
[M + H]þ 469.2438; found 469.2462.
(4S,4aS,5S,6S,7R,8R,11S,12S,12aR)-11,12-(Carbonyldioxy)-
4a-(hydroxymethyl)-8,13,13-trimethyl-1-methylene-4-(trieth-
ylsilyloxy)tetradecahydro-7,11-methanobenzocyclodecene-5,6,
7,8-tetrol. To a solution of triethylsilyl ether 34 (27.1 mg, 0.0436
mmol) in EtOH (7.5 mL) and AcOH (0.1 mL) at room tempera-
ture was added zinc–silver (160 mg). The reaction mixture was
stirred for 1 h at 90 ꢁC. After filtration of the reaction mixture
through a short pad of celite and evaporation of the solvent, the
crude product was purified by preparative TLC (50% EtOAc–hex-
ane) to afford (4S,4aS,5S,6S,7R,8R,11S,12S,12aR)-11,12-(carbon-
yldioxy)-4a-(hydroxymethyl)-8,13,13-trimethyl-1-methylene-4-
(triethylsilyloxy)tetradecahydro-7,11-methanobenzocyclodecene-
(1S,2S,3R,4R,7S,8R,9S,10S,11R,12R)-20-Bromo-1,2-(carbon-
yldioxy)-4,19-epoxy-7,9-(diisopropylidenedioxy)taxane-10,11,
12-triol (33). To a solution of (4S,4aR,5S,6S,7R,8R,11S,12S,
12aR)-11,12-(carbonyldioxy)-4a-hydroxymethyl-4,5-(isopropyli-
denedioxy)-8,13,13-trimethyl-1-methylenetetradecahydro-7,11-
methanobenzocyclodecene-6,7,8-triol (53.0 mg, 0.106 mmol) in
dichloromethane (20 mL) at room temperature was added N-bro-
mosuccinimide (20.8 mg, 0.117 mmol). The reaction mixture was
stirred for 1 h at room temperature and then water was added. The
mixture was extracted with ethyl acetate, and the organic layer
was washed with water and brine and dried over anhydrous so-
dium sulfate. After filtration of the mixture and evaporation of
the solvent, the crude product was purified by preparative TLC
(10% MeOH–CHCl3) to afford bromo ether 33 (60.0 mg, quant)
22
5,6,7,8-tetrol (19.2 mg, 81%) as a colorless oil. ½ꢁꢃD ¼ ꢂ4:57 (c
1.00, CHCl3); IR (KBr pellet) 3390, 1794 cmꢂ1
;
1H NMR
(CDCl3) ꢂ 6.50 (brs, 1H), 5.82 (d, J ¼ 9:7 Hz, 1H), 5.29 (s,
1H), 5.07 (s, 1H), 4.25–4.10 (m, 4H), 3.89 (dd, J ¼ 11:1, 4.9
Hz, 1H), 3.40 (brs, 1H), 2.62 (brs, 1H), 2.50 (d, J ¼ 9:7 Hz,
1H), 2.43–2.25 (m, 2H), 2.20–1.91 (m, 5H), 1.82–1.58 (m, 2H),
1.48 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H), 0.97 (t, J ¼ 7:8 Hz,
9H), 0.69 (q, J ¼ 7:8 Hz, 6H); 13C NMR (CDCl3) ꢂ 152.6,
140.5, 115.3, 91.7, 83.3, 82.7, 79.7, 79.3, 77.2, 73.2, 57.6, 53.9,
46.1, 45.5, 35.4, 34.2, 32.8, 26.9, 26.6, 23.3, 21.8, 6.8, 5.1; HRMS
(ESI) calcd for C27H46NaO9Si [M + Na]þ 565.2809; found
565.2786.
(4S,4aS,5S,6S,7R,8R,11S,12S,12aR)-4a-(t-Butyldimethylsilyl-
oxymethyl)-11,12-(carbonyldioxy)-8,13,13-trimethyl-1-methyl-
ene-4-(triethylsilyloxy)tetradecahydro-7,11-methanobenzocy-
clodecene-5,6,7,8-tetrol. To a solution of (4S,4aS,5S,6S,7R,8R,
11S,12S,12aR)-11,12-(carbonyldioxy)-4a-(hydroxymethyl)-8,13,
25
as a colorless oil. ½ꢁꢃD ¼ þ5:64 (c 1.00, CHCl3); IR (KBr pel-
let) 3469, 1790 cmꢂ1
;
1H NMR (CDCl3) ꢂ 5.20 (d, J ¼ 9:5 Hz,
1H), 4.57 (d, J ¼ 9:2 Hz, 1H), 4.43 (d, J ¼ 9:2 Hz, 1H), 4.23
(s, 1H), 4.08 (s, 1H), 4.06 (d, J ¼ 10:0 Hz, 1H), 3.82 (dd,
J ¼ 8:1, 6.2 Hz, 1H), 3.54 (d, J ¼ 10:0 Hz, 1H), 3.28 (brs, 1H),
2.65–2.57 (m, 2H), 2.56–2.38 (m, 1H), 2.20 (d, J ¼ 9:5 Hz,
1H), 2.17–1.51 (m, 8H), 1.46 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H),
1.34 (s, 3H), 1.25 (s, 3H); 13C NMR (CDCl3) ꢂ 152.4, 100.4,
90.9, 86.0, 84.5, 79.2, 79.1, 75.1, 73.3, 73.1, 68.9, 62.0, 53.9,
48.3, 47.1, 40.8, 35.8, 32.3, 29.6, 25.7, 23.4, 21.6, 20.0; HRMS

696 Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
Synthesis of 19-Hydroxytaxoid
13-trimethyl-1-methylene-4-(triethylsilyloxy)tetradecahydro-7,11-
methanobenzocyclodeceꢁne-5,6,7,8-tetrol (32.9 mg, 0.0606 mmol)
in pyridine (3 mL) at 0 C was added t-butyldimethylsilyl triflate
(0.1 mL, 0.434 mmol). The reaction mixture was stirred for 30
(1 mL) were added thiophosgene (17 mg, 0.148 mmol) and
DMAP (72.3 mg, 0.592 mmol). The reaction mixture was stirred
for 48 h at 80 ꢁC and then it was diluted with ethyl acetate at room
temperature. Filtration of the mixture through a short pad of silica
gel and evaporation of the solvent afforded a crude thionocarbon-
ate (2.0 mg).
ꢁ
min at ꢂ23 C and then saturated aqueous sodium hydrogencar-
bonate was added. The mixture was extracted with ethyl acetate,
and the organic layer was washed with saturated aqueous cop-
per(II) sulfate, water, and brine and dried over anhydrous sodium
sulfate. After filtration of the mixture and evaporation of the sol-
vent, the crude product was purified by preparative TLC (50%
EtOAc–hexane) to afford (4S,4aS,5S,6S,7R,8R,11S,12S,12aR)-
4a-(t-butyldimethylsilyloxymethyl)-11,12-(carbonyldioxy)-8,13,
13-trimethyl-1-methylene-4-(triethylsilyloxy)tetradecahydro-7,11-
methanobenzocyclodecene-5,6,7,8-tetrol (33.1 mg, 83%) as a col-
2) To the above crude thionocarbonate was added trimethyl
phosphite (1 mL) at room temperature. The reaction mixture
ꢁ
was stirred for 5 h at 110 C and then the crude product was pu-
rified by preparative TLC (40% EtOAc–hexane) to afford olefin
36 (0.4 mg, 43% based on 35% conversion) as a colorless oil
20
and recovered acetate 35 (1.3 mg, 65%). ½ꢁꢃD ¼ ꢂ22:3 (c
1
0.27, CHCl3); IR (KBr pellet) 3451, 3370, 1797 cmꢂ1; H NMR
(CDCl3) ꢂ 6.11 (d, J ¼ 6:0 Hz, 1H), 5.52 (s, 1H), 5.33 (d, J ¼
2:0 Hz, 1H), 5.24 (s, 1H), 4.89 (d, J ¼ 2:0 Hz, 1H), 4.63 (s,
1H), 4.77 (d, J ¼ 11:0 Hz, 1H), 4.54 (d, J ¼ 11:0 Hz, 1H), 3.41
(dd, J ¼ 10:5, 5.0 Hz, 1H), 2.75 (d, J ¼ 6:0 Hz, 1H), 2.70–2.64
(m, 2H), 2.54–2.47 (m, 2H), 2.29 (dd, J ¼ 11:5, 6.0 Hz, 1H),
2.16 (s, 3H), 2.15 (s, 3H), 2.01–1.87 (m, 2H), 1.71–1.63 (m,
1H), 1.40 (s, 3H), 1.34 (s, 3H), 0.95 (t, J ¼ 8:0 Hz, 9H), 0.89
(s, 9H), 0.58 (q, J ¼ 8:0 Hz, 6H), 0.11 (s, 3H), 0.10 (s, 3H);
13C NMR (CDCl3) ꢂ 170.6, 152.9, 141.2, 140.1, 130.6, 116.2,
92.0, 78.4, 76.7, 75.4, 72.5, 64.0, 55.3, 49.7, 45.4, 37.2, 36.8,
33.6, 30.1, 27.1, 25.7, 24.8, 23.9, 20.4, 18.0, 6.9, 5.2, ꢂ5:9,
ꢂ5:9; HRMS (ESI) calcd for C35H60NaO8Si2 [M + Na]þ
687.3724; found 687.3739.
24
orless oil. ½ꢁꢃD ¼ þ11:9 (c 0.83, CHCl3); IR (KBr pellet) 3392,
1795 cmꢂ1; 1H NMR (CDCl3) ꢂ 6.14 (s, 1H), 5.46 (d, J ¼ 6:2 Hz,
1H), 5.12 (s, 1H), 4.98 (s, 1H), 4.41 (d, J ¼ 11:3 Hz, 1H), 4.22 (d,
J ¼ 11:3 Hz, 1H), 4.14 (s, 1H), 4.04 (s, 1H), 3.92 (s, 1H), 3.89
(dd, J ¼ 10:8, 5.9 Hz, 1H), 3.70 (brs, 1H), 2.83 (d, J ¼ 6:2 Hz,
1H), 2.68–2.54 (m, 1H), 2.45–2.33 (m, 2H), 2.19–2.03 (m, 2H),
2.00–1.94 (m, 2H), 1.89–1.65 (m, 2H), 1.48 (s, 3H), 1.35 (s,
3H), 1.28 (s, 3H), 1.02–0.93 (m, 18H), 0.68 (q, J ¼ 7:0 Hz,
6H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (CDCl3) ꢂ 153.1,
141.5, 115.1, 90.9, 83.1, 81.8, 80.6, 80.4, 77.8, 73.0, 58.7, 51.8,
46.6, 43.2, 34.1, 32.8, 32.4, 27.4, 26.1, 26.0, 24.4, 21.5, 18.6,
6.8, 5.2, ꢂ5:3, ꢂ5:7; HRMS (ESI) calcd for C33H61O9Si2 [M +
H]þ 657.3854; found 657.3826.
(4S,4aS,5S,6S,7R,8R,11S,12S,12aR)-4a-(t-Butyldimethylsilyl-
oxymethyl)-11,12-(carbonyldioxy)-5,7,8-trihydroxy-8,13,13-tri-
methyl-1-methylene-4-(triethylsilyloxy)tetradecahydro-7,11-
methanobenzocyclodecen-6-yl Acetate (35). To a solution of
(4S,4aS,5S,6S,7R,8R,11S,12S,12aR)-4a-(t-butyldimethylsilyloxy-
methyl)-11,12-(carbonyldioxy)-8,13,13-trimethyl-1-methylene-4-
(triethylsilyloxy)tetradecahydro-7,11-methanobenzocyclodecene-
5,6,7,8-tetrol (29.3 mg, 0.0446 mmol) and DMAP (3.0 mg, 0.0245
mmol) in pyridine (3 mL) at 0 ꢁC was added acetic anhydride (0.2
mL). The reaction mixture was stirred for 30 min at room temper-
ature and then saturated aqueous sodium hydrogencarbonate was
added. The mixture was extracted with ethyl acetate, and the or-
ganic layer was washed with saturated aqueous copper(II) sulfate,
water, and brine and dried over anhydrous sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT).
The authors wish to thank Dr. Youji Furukawa, Sankyo Co.,
Ltd., for his support in X-ray crystal structure analysis.
References
1
M. C. Wani, H. L. Talor, M. E. Wall, P. Coggon, and A. T.
McPhail, J. Am. Chem. Soc., 93, 2325 (1971).
D. M. Vyas, H. Wong, A. R. Croswell, A. M. Casazza,
2
J. O. Knipe, S. W. Mamber, and T. W. Doyle, Bioorg. Med. Chem.
Lett., 3, 1357 (1993).
3
The numbers on each carbon atom of all compounds are
according to IUPAC taxane skeleton nomenclature.
J. L. McLaughlin, R. W. Miller, R. G. Powell, and C. R.
Smith, Jr., J. Nat. Prod., 44, 312 (1981).
a) T. Mukaiyama, I. Shiina, H. Iwadare, H. Sakoh, Y. Tani,
product was purified by preparative TLC (50% EtOAc–hexane) to
20
4
afford acetate 35 (24.1 mg, 77%) as a colorless oil. ½ꢁꢃD
¼
þ4:07 (c 0.35, CHCl3); IR (KBr pellet) 3468, 3379, 1798 cmꢂ1
;
5
1H NMR (CDCl3) ꢂ 5.97 (s, 1H), 5.38 (d, J ¼ 4:9 Hz, 1H), 5.31
(d, J ¼ 2:7 Hz, 1H), 4.98 (s, 1H), 4.78 (s, 1H), 4.57 (d, J ¼
12:2 Hz, 1H), 4.24 (d, J ¼ 12:2 Hz, 1H), 3.90 (dd, J ¼ 10:0,
6.5 Hz, 1H), 3.84 (d, J ¼ 2:7 Hz, 1H), 3.44 (s, 1H), 3.06 (s,
1H), 3.01 (d, J ¼ 4:9 Hz, 1H), 2.82–2.68 (m, 1H), 2.50–1.83
(m, 7H), 2.19 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H),
1.02–0.81 (m, 18H), 0.68 (q, J ¼ 7:4 Hz, 6H), 0.13 (s, 6H);
13C NMR (CDCl3) ꢂ 173,4, 153.2, 141.6, 113.6, 90.0, 84.4,
83.3, 82.2, 79.1, 77.2, 73.1, 57.9, 51.2, 46.7, 41.5, 34.3, 31.6,
31.1, 27.1, 25.9, 24.8, 24.7, 21.2, 21.1, 18.4, 6.8, 5.3, ꢂ5:5,
ꢂ5:6; HRMS (ESI) calcd for C35H62O10NaSi2 [M + Na]þ
721.3779; found 721.3790.
M. Hasegawa, and K. Saitoh, Proc. Jpn. Acad., 73B, 95 (1997). b)
T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T. Nishimura,
N. Ohkawa, H. Sakoh, K. Nishimura, Y. Tani, M. Hasegawa, K.
Yamada, and K. Saitoh, Chem.—Eur. J., 5, 121 (1999).
6
a) T. Mukaiyama, H. Arai, and I. Shiina, Chem. Lett., 2000,
580. b) T. Mukaiyama, K. Pudhom, K. Yamane, and H. Arai, Bull.
Chem. Soc. Jpn., 76, 413 (2003).
7 K. Pudhom, H. Arai, K. Yamane, and T. Mukaiyama,
Chem. Lett., 2002, 82.
8
a) G. P. Luke and J. Morris, J. Org. Chem., 60, 3013
(1995). b) P. A. McCarhy and M. Kageyama, J. Org. Chem.,
57, 4681 (1987). c) A. Abiko, J.-F. Liu, D. C. Buske, S.
Moriyama, and S. Masamune, J. Am. Chem. Soc., 121, 7168
(1999).
(4S,4aS,5S,6R,11S,12S,12aR)-4a-(t-Butyldimethylsilyloxy-
methyl)-11,12-(carbonyldioxy)-5-hydroxy-8,13,13-trimethyl-1-
methylene-4-(triethylsilyloxy)-1,2,3,4,4a,5,6,9,10,11,12,12a-do-
decahydro-7,11-methanobenzocyclodecen-6-yl Acetate (36).
1) To a solution of acetate 35 (2.0 mg, 0.00295 mol) in CHCl3
9
a) D. A. Evans, K. T. Chapman, and E. M. Carreira, J. Am.
Chem. Soc., 110, 3560 (1986). b) I. Paterson and C. K. McClure,
Tetrahedron Lett., 28, 1229 (1987).

Y. Ogawa et al.
Bull. Chem. Soc. Jpn., 78, No. 4 (2005)
697
10 I. Shiina, J. Shibata, R. Ibuka, Y. Imai, and T. Mukaiyama,
Bull. Chem. Soc. Jpn., 74, 113 (2001).
16 T. Mukaiyama, Y. Ogawa, K. Kuroda, and J. Matsuo,
Chem. Lett., 33, 1412 (2004).
11 Crystal data: C47H70N3O9Si2 (FW ¼ 877:26), monoclinic,
17 TiCl2 was prepared from TiCl4 and Me3SiSiMe3 by a lit-
erature method: a) R. C. Paul, A. Arneja, and S. P. Narula, Inorg.
Nucl. Chem. Lett., 5, 1013 (1969). b) S. P. Narula and H. K.
Sharma, Inorg. Synth., 24, 181 (1986). c) T. Mukaiyama, A.
Kagayama, and I. Shiina, Chem. Lett., 1998, 1107.
18 J. Ishihara, R. Nonaka, Y. Terasawa, R. Shiraki, K. Yabu,
H. Kataoka, Y. Ochiai, and K. Tadano, J. Org. Chem., 63, 2679
(1998).
ꢀ
C2, a ¼ 21:015ð5Þ, b ¼ 10:563ð5Þ, c ¼ 21:068ð4Þ A, ꢀ ¼
ꢁ
ꢀ 3
92:85ð2Þ , V ¼ 4670ð2Þ A , Z ¼ 4, Dx ¼ 1:247 g cmꢂ3, T ¼ 123
K. X-ray intensities were measured on Rigaku AFC7R diffractom-
ꢀ
eter with Cu Kꢁ radiation (ꢃ ¼ 1:54178 A), and R ¼ 0:067 for
3323 observed reflections.
12 K. Pudhom, J. Matsuo, and T. Mukaiyama, Heterocycles,
59, 445 (2003).
13 J. Matsuo, Y. Ogawa, K. Pudhom, and T. Mukaiyama,
Chem. Lett., 33, 124 (2004).
19 a) J. M. Denis, C. Girard, and J. M. Conia, Synthesis, 1972,
549. b) T. Tokoroyama, K. Matsuo, and R. Kanazawa, Bull.
Chem. Soc. Jpn., 53, 3383 (1980).
20 a) E. Block, Org. React., 30, 457 (1984). b) E. J. Corey, F.
A. Carey, and R. A. E. Winter, J. Am. Chem. Soc., 87, 934 (1965).
c) E. J. Corey and P. B. Hopkins, Tetrahedron Lett., 23, 1979
(1982).
21 H. Kusama, R. Hara, S. Kawahara, T. Nishimori, H.
Kashima, N. Nakamura, K. Morihira, and I. Kuwajima already
reported this taxoid as an intermediate for synthesis of taxol;
J. Am. Chem. Soc., 122, 16, 3811 (2000).
14 a) J. Matsuo, D. Iida, H. Yamanaka, and T. Mukaiyama,
Tetrahedron, 59, 6739 (2003). b) T. Mukaiyama, J. Matsuo, D.
Iida, and H. Kitagawa, Chem. Lett., 2001, 846.
15 Crystal data: C46H64O9Si (FW ¼ 789:09), monoclinic,
ꢀ
P21, a ¼ 16:051ð3Þ, b ¼ 12:914ð4Þ, c ¼ 10:915ð3Þ A, ꢀ ¼
ꢁ
ꢀ 3
93:73ð2Þ , V ¼ 2257ð1Þ A , Z ¼ 2, Dx ¼ 1:161 g cmꢂ3, T ¼ 298
K. X-ray intensities were measured on Rigaku AFC7R diffractom-
ꢀ
eter with Cu Kꢁ radiation (ꢃ ¼ 1:54178 A), and R ¼ 0:052 for
4209 observed reflections.