Practical synthesis of the C-ring precursor of paclitaxel from 3-methoxytoluene

Article abstract of DOI:10.1038/ja.2016.6

The practical synthesis of the C-ring precursor of paclitaxel starting from 3-methoxytoluene is described. Lipase-catalyzed kinetic resolution of a substituted cyclohexane-1,2-diol, derived from 3-methoxytoluene in three steps, successfully afforded a desired enantiomer with >99% ee, which was transformed to a cyclohexenone. 1,4-Addition of a vinyl metal species, followed by Mukaiyama aldol reaction with formalin in the presence of a Lewis acid provided the known C-ring precursor of paclitaxel in a 10 g scale.

Full text of DOI:10.1038/ja.2016.6

The Journal of Antibiotics (2016), 1–7
2016 Japan Antibiotics Research Association All rights reserved 0021-8820/16
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&
ORIGINAL ARTICLE
Practical synthesis of the C-ring precursor of paclitaxel
from 3-methoxytoluene
Keisuke Fukaya1, Yu Yamaguchi1, Ami Watanabe1, Hiroaki Yamamoto1, Tomoya Sugai1, Takeshi Sugai2,
Takaaki Sato1 and Noritaka Chida1
The practical synthesis of the C-ring precursor of paclitaxel starting from 3-methoxytoluene is described. Lipase-catalyzed kinetic
resolution of a substituted cyclohexane-1,2-diol, derived from 3-methoxytoluene in three steps, successfully afforded a desired
enantiomer with 499% ee, which was transformed to a cyclohexenone. 1,4-Addition of a vinyl metal species, followed by
Mukaiyama aldol reaction with formalin in the presence of a Lewis acid provided the known C-ring precursor of paclitaxel in a
10 g scale.
The Journal of Antibiotics advance online publication, 10 February 2016; doi:10.1038/ja.2016.6
INTRODUCTION
reaction of 5 by Mukaiyama aldol reaction under various conditions
Paclitaxel (taxol, 1) is a well-known natural diterpenoid that has been are also described.
used as an anticancer drug.1–3 The challenging structure as well as
RESULTS AND DISCUSSION
important biological activities of 1 have attracted much attention from
the synthetic community,4,5 and nine successful total and formal
syntheses of 1 have been documented so far.6–14 For the creation of
novel anticancer agents, development of an efficient synthetic way to
chiral 1 and its derivatives starting from readily available materials is
still an important issue in the field of organic and medicinal chemistry.
In 2015, our group reported the formal synthesis of 1, in which
Takahashi’s oxetane intermediate 4 was synthesized using the novel
SmI2-mediated cyclization as the key transformation (Figure 1).15,16
For the synthesis of 4, we adopted the convergent approach based on
the coupling of A ring 2 with C ring 3 by the Shapiro reaction.7 The
densely functionalized C ring 3 was constructed in a homochiral form
from C-ring precursor 6, which was prepared by the three-component
For the practical synthesis of C-ring precursor 6, we chose readily
available 3-methoxytoluene as the starting material. Birch reduction of
3-methoxytoluene, followed by treatment with ethylene glycol and
formic acid cleanly afforded ketal derivative 8,18–21 which, without
isolation, was reacted with catalytic amount of OsO4 in the presence of
N-methylmorpholine N-oxide to give racemic diol rac-9 in 83% yield
from 3-methoxytoluene (Scheme 1).
For the resolution of rac-9, we chose lipase-catalyzed enantioselec-
tive acylation of racemic secondary alcohol in organic solvent,22–24 in
the standpoint of facile experimental operation. After the proper
progress of reaction, catalysts are filtered off, and the simple
chromatographic separation of ester and unreacted alcohol in the
crude residue can provide enantiomerically enriched forms. First,
rac-9 was treated with vinyl acetate in the presence of various lipases.
Although reactions with lipase AS, lipase AYS and lipase from wheat
germ at 40 °C resulted in the no reaction, when rac-9 was treated with
lipase PS at 40 °C, enantiomerically enriched (− )-9 was obtained in
43% yield with modest enantiomeric excess (ee) (Table 1, entry 1). It
was found that a use of lipase AK gave better results, providing (− )-9
in 41% yield with 499% ee (entry 2). After screening the reaction
parameters, it was shown the reaction at 35 °C for 85 h gave ( − )-9 in
46% yield with 499% ee (entry 3). However, it was not easy to
separate ( − )-9 from (+)-10a by silica-gel chromatography due to
their similar polarities (SiO2 TLC: Rf = 0.26 for 9 and 0.41 for 10a and
EtOAc–hexane, 2:1 (v/v)), and repeated chromatographic operations
were required for their complete separation. To facilitate the separa-
tion step, introduction of an acyl group with longer chain have been
coupling reaction of
5
with
a
vinyl metal species and
formaldehyde.15,17 The pivotal intermediate, cyclohexenone 5, was
prepared starting from commercially available tri-O-acetyl-D-glucal
utilizing Hg2+-mediated Ferrier carbocyclization reaction as the key
reaction.17 This chiral pool approach successfully provided chiral
C-ring precursor 6 in good overall yield (29% from tri-O-acetyl-D-
glucal), however, for the preparation of 5, the relatively long-step
reaction sequence (10 steps) and the time- and cost-consuming
chromatographic purification processes (nine chromatographic
separations) were required. For the large-scale synthesis and the
development of more effective second-generation synthesis of 1, it is
necessary to establish the practical synthetic way to 6. In this paper, we
report a chiral and large-scale (10 g scale) synthesis of 6 utilizing the
lipase-catalyzed kinetic resolution of a racemic cyclohexane-diol
derived from 3-methoxytoluene. Results of three-component coupling examined.25,26 Thus, treatment of rac-9 with vinyl laurate, instead of
1Department of Applied Chemistry, Keio University, Yokohama, Japan and 2Department of Pharmaceutical Science, Keio University, Tokyo, Japan
Correspondence: Professor N Chida, Department of Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
E-mail: chida@applc.keio.ac.jp
Received 3 December 2015; revised 12 January 2016; accepted 15 January 2016

Synthesis of C-ring precursor of paclitaxel from 3-methoxytoluene
K Fukaya et al
2
O
O
OAc
TBDPSO
O
OBn
BzHN
Ph
O
OTES
O
known
steps
OH
steps
O
A
B
1
+
C
(ref. 13)
OH
O
O
H
HO
HO
H
D
N
NHSO2R
H
BzO
O
O
OMOM
AcO
paclitaxel (1)
A-ring (2)
C-ring (3)
Takahashi's oxetane
intermediate (4)
R = 2,4,6-triisopropylphenyl
AcO
AcO
AcO
10 steps and nine
column chromatographic
separations
O
OBn
MgCl
1.
OBn
CuI, TMEDA, THF
then Me3SiCl, Et3N
7 steps
tri-O-acetyl-D-glucal
C-ring 3
2. formalin
Lewis acid
THF
H
HO
O
O
C-ring precursor (6)
this study
5
(more practical synthesis)
OMe
3-methoxytoluene
Figure 1 Outline of our first-generation synthesis of paclitaxel and the aim of this study (THF, tetrahydrofuran). A full color version of this figure is available
at The Journal of Antibiotics journal online.
OH
HO
O
O
Li
OH
Enzymatic
resolution
HO
liq. NH3
EtOH
OsO4 (0.3 mol%)
NMO
(–)-9
HCO2H
+
(CH2OH)2
–78 to –55 °C
t-BuOH–H2O
83% for 3 steps
Table 1
O
O
OR
OMe
OMe
HO
O
O
3-methoxytoluene
8
7
rac-9
O
O
(+)-10a: R = Ac
(+)-10b: R = -C-(CH2)10CH3
OBn
OBn
NaH
BnBr
Bu4NI
HO
O
p-TsOH•H2O
(–)-9
acetone–H2O
60 °C
THF
88%
(>99% ee)
p-TsOH•H2O
acetone–H2O
60 °C
O
O
O
90%
11
5
80%
(>99% ee, from (–)-9)
(97% ee, from (+)-10b)
O
OBn
O
OH
OBn
1. NaBH(OAc)3
CH2Cl2
0 to 15 °C
HO
HO
HO
HO
K2CO3
SO3•pyridine
MeOH
+
(+)-10b
then
crystalization
33%
CH2Cl2
86%
2. NaH, BnBr
Bu4NI
(75% ee)
O
O
O
O
O
O
O
DMF–THF
(+)-9
(97% ee)
12
13
ent-11
12% from 12
52% from 12
Scheme 1 Synthesis of cyclohexenone 5 from 3-methoxytoluene (THF, tetrahydrofuran).
vinyl acetate, in the presence of lipase AK was attempted. Gratifyingly, 60 °C to give ( − )-9 in 49% yield with 499% ee in shorter reaction
the kinetic acylation smoothly took place to give ( − )-9 and (+)-10b in time (entry 7). By comparing the enantioselectivities (E values22)
good yields with high ees, although longer reaction time was required between entry 5 (E = 32, with vinyl acetate) and entry 7 (E = 99, with
(entry 6). As expected, (+)-10b was less polar than (+)-10a, and the vinyl laurate), the selectivity depended upon the length of carbon
separation of ( − )-9 from (+)-10b could be done without difficulty chain in acylating agent, as had been observed in the literature.27 On a
(SiO2 TLC: Rf = 0.26 for 9, 0.84 for 10b and EtOAc–hexane, 2:1 (v/v)). 20 g scale (entry 8), the reaction at 60 °C afforded ( − )-9 with high
To accelerate the reaction rate, the same reaction was carried out at enantiomeric purity (499% ee) in 42% yield and (+)-10b (58% yield,
The Journal of Antibiotics

Synthesis of C-ring precursor of paclitaxel from 3-methoxytoluene
K Fukaya et al
3
Table 1 Enzymatic resolution of rac-9a
Yield % (ee %)b
Entry
Amount of rac-9
Reagent
Lipase
T (°C)
Time (h)
( − )-9
(+)-10a
(+)-10b
1
2
3
4
5
6
7
8
50 mg
51 mg
53 mg
51 mg
50 mg
48 mg
2.11 g
20.3 g
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl laurate
Vinyl laurate
Vinyl laurate
Amano PS
Amano AK
Amano AK
Amano AK
Amano AK
Amano AK
Amano AK
Amano AK
40
40
35
45
60
35
60
60
145
147
85
43 (56)
41 (99)
46 (99)
54 (82)
38 (86)
48 (99)
49 (99)
42 (99)
52 (41)
59 (64)
54 (82)
46 (87)
54 (84)
–
–
–
–
30
–
19
–
168
48
50 (98)
51 (90)
58 (75)
–
156
–
Compound ( − )-9 was converted to ( − )-10a by acetylation (Ac2O, Et3N and N,N-dimethyl-4-aminopyridine in CH2Cl2, at room temperature), and compound (+)-10b was converted to (+)-10a by
basic methanolysis (K2CO3, MeOH), followed by acetylation. For detail, see the Experimental section.
aCompound rac-9 in i-Pr2O (0.1 M solution) was treated with reagent (3 equivalent) in the presence of enzyme (ca. 20 wt% to rac-9). Yield refers to the isolated yield after chromatographic
separation.
bEe was determined by HPLC analyzes with chiral stationary phase of (+)-10a and ( − )-10a.
formalin (5 equiv)
Lewis acid (5 mol%)
THF, T °C
OBn
O
OBn
OBn
OBn
OBn
MgCl
CuI, TMEDA
TMSCl
+
+
THF, –78 °C
then TMSCl, Et3N
Table 2
H
H
HO
O
HO
O
O
OTMS
C-ring precursor (6)
5
14
15
16
(>99% ee)
(>99% ee)
K2CO3, MeOH
6: 31%, 15: 55%
Scheme 2 Preparation of C-ring precursor 6 by three-component coupling reaction (TMS, trimethylsilyl; THF, tetrahydrofuran).
75% ee), and ( − )-9 could be isolated in pure form by a single-step respectively. Acid treatment of 13 provided additional amount of 5 in
silica-gel chromatography.
80% yield (97% ee, 6% overall yield from 3-methoxytoluene).
The secondary alcohol function in ( − )-9 was protected as a benzyl
Finally, three-component coupling reaction of 5 with vinyl metal
ether to give 11 in 88% yield. Treatment of 11 with p-toluenesulfonic species and formalin was carried out. In the early stage of our
acid in aqueous acetone cleanly afforded cyclohexenone 528 in 90% paclitaxel synthesis, we adopted the three-component coupling
yield. The HPLC analysis with chiral stationary phase of 5 showed that reaction of 5 with higher order vinylcuprate and formaldehyde, which
the ee of 5 was 499%. By this procedure, the desired cyclohexenone 5 afforded 6 and 15 in 62% and 33% yields, respectively.17 However,
was synthesized in six-step reactions from 3-methoxytoluene with this procedure required strictly anhydrous conditions as well as a use
four-column chromatographic separations, affording ample quantities of freshly prepared gaseous formaldehyde (generated by pyrolysis of
(over 15 g) of optically pure 5 (28% overall yield from 3-methox- paraformaldehyde), thus it was technically unsuitable for the larger-
ytoluene). This route was superior to the so far reported one, based on scale synthesis. We investigated the Mukaiyama aldol reaction of a silyl
the esterase-catalyzed enantioselective hydrolysis of the corresponding enol ether in the presence of rare earth metal triflates as the reaction
acetate28 in terms of scaled-up preparation.
could be conducted in aqueous media.31,32
Next, convergence of the undesired enantiomer (+)-10b to 5 was
Treatment of 5 (499% ee) with vinyl magnesium chloride in the
investigated. Basic methanolysis of (+)-10b afforded (+)-9 in 96% presence of CuI and N,N,N′,N′,-tetramethylethylenediamine cleanly
yield (75% ee) as a mixture of oily product and crystalline residue, afforded a 1,4-addition product, which was trapped with trimethylsilyl
which was suspended in EtOAc–hexane, 1:20 (v/v). After removal of (TMS) chloride to give TMS enol ether 14 (Scheme 2). Without
the crystals by filtration, the filtrate was concentrated to give purification, enol ether 14 was subjected to conditions for the
enantiomerically enriched (+)-9 (97% ee) as an oil in 33% yield. Mukaiyama aldol reaction with commercially available 35% formalin
Oxidation of (+)-9 with SO3-pyridine29 gave ketone 12 in 86% yield. as an electrophile. Lanthanoid and scandium triflates were examined
Hydroxy-directed reduction of 12 with NaBH(OAc)3,30 followed by as the promoter and the results are shown in Table 2. Reactions with
33
O-benzylation afforded 13 in 52% yield and ent-11 in 12% yield, Gd(OTf)3 or Yb(OTf)3 were found to be sluggish and gave the
The Journal of Antibiotics

Synthesis of C-ring precursor of paclitaxel from 3-methoxytoluene
K Fukaya et al
4
Table 2 Mukaiyama aldol reaction of silyl enol ether 14 with
formalina
recorded with JEOL ECA-500 spectrometer (JEOL Ltd., Tokyo, Japan), or 1H at
400 MHz and 13C NMR at 100 MHz were recorded with JEOL ECS-400
spectrometer (JEOL Ltd.). Chemical shifts are reported in p.p.m. with reference
to solvent signals (1H NMR: CDCl3 (7.26); 13C NMR: CDCl3 (77.16)). Optical
rotations were measured with a JASCO P-2100 polarimeter (JASCO Corpora-
tion, Tokyo, Japan) with 0.5 dm tube and values of [α]D are recorded in units
of 10–1 deg·cm2·g–1. IR spectra were recorded using a BRUKER ALPHA FT-IR
spectrometer (Bruker Corporation, Billerica, MA, USA). Mass spectra (EI) were
measured with a JEOL GC-Mate spectrometer (JEOL Ltd.). Mass spectra
(ESI–TOF) were measured with a Waters, LCT Premier XE (Waters Corpora-
tion, Milford, MA, USA). Melting points were measured with a Mitamura-
Riken microhot stage.
Yield %b
Entry
Amount of 5
Lewis acid
T (°C)
Time (h)
6
15
16
c
1
2
3
4
5
6
33 mg
33 mg
31 mg
31 mg
31 mg
15.2 g
Gd(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
0
0
96
96
3
15
22
53
51
49
60
17
19
20
15
21
27
–
c
–
0
25
27
29
12
−20
rtd
0
8
0.5
3.5
(7RS,8SR)-7-methyl-1,4-dioxaspiro[4.5]decane-7,8-diol
(rac-9):
Lithium
(18.9 g, 2.72 mol) was added in portions to a solution of 3-methoxytoluene
(50 ml, 397 mmol) in EtOH (300 ml, 5.2 mol) and liquid NH3 (1.0 l) at
− 78 °C. After stirring for 20 min, the mixture was allowed to warm to − 55 °C.
After the blue color of the reaction mixture disappeared, the reaction mixture
was cooled to − 78 °C and quenched by the addition of solid NH4Cl (20 g) at
− 78 °C. The mixture was allowed to warm to room temperature. After being
stirred vigorously for 10 h, the resulting mixture was diluted with H2O and
extracted with pentane (3 × ). The combined organic extracts were washed with
brine and dried over Na2SO4. The resulting solution was concentrated at 40 °C
under atmospheric pressure to give crude 1-methoxy-5-methylcyclohexa-1,4-
diene (7), which was used in the next reaction without purification: a colorless
oil; IR νmax (film) cm− 1 3048, 2997, 2965, 2946, 2888, 2824, 1701, 1666, 1439,
1390, 1224, 1135, 1023, 958, 771, 701; 1H NMR (400 MHz, CDCl3) δ 5.44–5.37
(m, 1H, 4-H), 4.67–4.61 (m, 1H, 2-H), 3.56 (s, 3-H, OCH3), 2.83–2.73
(m, 2-H, 6-H2 or 3-H2), 2.65–2.57 (m, 2-H, 3-H2 or 6-H2), 1.73–1.67 (m, 3-H,
CH3); 13C NMR (100 MHz, CDCl3) δ 153.0 (C), 130.5 (C), 118.9 (CH),
90.3 (CH), 53.8 (CH3), 33.3 (CH2), 26.9 (CH2), 22.9 (CH3); MS (EI) m/z 124
(M+, 74%), 109 (M–CH3, 100); HR-MS (EI): M+ = 124.0883 m/z. Calcd for
C8H12O 124.0888 m/z.
aCompound 14 in tetrahydrofuran (0.16 M solution) was reacted with 35% formalin (5
equivalent) in the presence of Lewis acid (5 mol%).
bIsolated yield from 5 after chromatographic purification.
cA mixture of 14 and 16 was obtained in ca. 50% yield.
dRoom temperature.
desired product 6 in low yields with low stereoselectivities (entries 1
34
and 2). A reaction with Sc(OTf)3 at 0 °C, however, proceeded
smoothly to afford 6, 15, and protonated product 16 in 53%, 20% and
25% yields, respectively (entry 3). In a 15 g scale reaction (entry 6), the
same reaction conditions afforded desired product 6 in 60% yield
along with 15 (27%). Treatment of 15 with K2CO3 in MeOH provided
6 in 31% yield (8% from 5): thus the desired isomer 6 was obtained in
68% combined yield after one-cycle epimerization of 15. HPLC
analysis with chiral stationary phase of 6 showed that compound 6
has 499% ee, indicating that the reaction proceeded without loss of
enantiomeric purity. Compound 6 was transformed to C-ring 3 by the
known procedure15 to provide 3 in over 5 g scale.
In summary, a new and efficient synthetic way to the C-ring
precursor 6 of paclitaxel, employing 3-methoxytoluene as the starting
material and utilizing the effective lipase-catalyzed kinetic resolution,
has been established. Compared with the previous chiral pool
approach to 6 starting from tri-O-acetyl-D-glucal,15,17 the present
enzymatic procedure, although the overall yield of 6 was not improved
(chiral pool approach: 29% yield, from tri-O-acetyl-D-glucal →
enzymatic approach: 17% yield with 499% ee, 20% yield with
497% ee, from 3-methoxytoluene), reduced the reaction steps
(12 →8) and number of chromatographic purification processes
(10 → 5). By this procedure, it is now possible to conduct the
large-scale synthesis and prepare ample quantities of enantiomerically
pure 6 in a short-term period. Further efforts for the development
of the second-generation synthesis of paclitaxel 1 and its derivatives
based on the procedure reported in this paper are ongoing in our
laboratory.
Formic acid (16 ml, 410 mmol) was added to a solution of crude 7 in
ethylene glycol (550 ml) at room temperature. After being stirred for 14 h, the
reaction mixture was quenched by saturated aqueous NaHCO3 (350 ml). The
resulting mixture was extracted with pentane (3 × ). The combined organic
extracts were washed with H2O and brine, and dried over Na2SO4. The
resulting solution was concentrated at 40 °C (at 980 hPa) to give crude
7-methyl-1,4-dioxaspiro[4.5]dec-7-ene (8), which was used in the next reaction
without purification: a colorless oil; IR νmax (film) cm− 1 2881, 1441, 1366,
1254, 1172, 1103, 1064, 949, 861, 805; 1H NMR (400 MHz, CDCl3) δ 5.45–5.39
(m, 1H, 8-H), 4.01–3.96 (m, 4-H, OCH2CH2O), 2.24–2.15 (m, 4-H, 6-H2,
9-H2), 1.75–1.65 (m, 5-H, CH3, 10-H2); 13C NMR (100 MHz, CDCl3) δ 131.7
(C), 120.3 (CH), 108.5 (C), 64.4 (2 × CH2), 40.4 (CH2), 30.6 (CH2), 24.1
(CH2), 23.4 (CH3); HR-MS (ESI): (M+H)+ = 155.1071 m/z. Calcd for C9H15O2
155.1072 m/z.
Osmium tetraoxide (0.20 M solution in t-BuOH, 6.0 ml, 1.2 mmol) was
added to a solution of crude 8 in H2O (140 ml) and t-BuOH (650 ml) at room
temperature. Then, 4-methylmorpholine N-oxide (60.4 g, 516 mmol) was
added to the solution at 0 °C. After stirring for 24 h at room temperature,
the reaction mixture was quenched by solid NaHSO3 (19.0 g). The resulting
mixture was extracted with tetrahydrofuran–EtOAc, 1:1 (v/v), (7 × ). The
combined organic extracts were washed with brine, dried over Na2SO4 and
concentrated. The residue was purified by silica-gel column chromatography
(EtOAc–hexane, 1:10–1:5 (v/v), silica gel 1.5 kg) to give 21.2 g of pure rac-9
(28%) and 44.7 g of impure material. A part of impure material (39.1 g) was
dissolved in a minimum of EtOAc (about 20 ml) at 60 °C. After standing for
12 h at room temperature, colorless crystals were separated by filtration to give
27.1 g of rac-9 (36%). The mother liquor was concentrated to give 12.1 g of the
residue. It was purified by recrystallization in the same way to give 7.56 g of rac-
9 (10%). The second filtrate (4.15 g) and the impure material (5.64 g) in the
first chromatography were combined and repurified by silica-gel column
chromatography to give 5.93 g of rac-9 (8%) (61.79 g, 83% yield in total):
Rf = 0.26 (EtOAc–hexane, 2:1 (v/v)); colorless crystals, m.p. 85.0–86.0 °C; IR
EXPERIMENTAL PROCEDURE
General information
Anhydrous reactions were performed in oven-dried glassware fitted with rubber
septa under an argon atmosphere. All distilled solvents, CH2Cl2 and MeOH
were dried over activated 3-Å molecular sieves. Tetrahydrofuran (dehydrated,
stabilizer free) was purchased from Kanto Chemical Co., Inc (Tokyo, Japan).
Commercial reagents were used without further purification. Lipases were
purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan) or Sigma-
Aldrich Corporation (St Louis, MO, USA): Lipase AK Amano from Pseudo-
monas fluorescens (Wako), Lipase AS Amano from Aspergillus niger (Wako),
Lipase AYS Amano from Candida rugosa (Wako), Lipase PS Amano SD from
Burkholderia cepacia (Wako) and Lipase from wheat germ (Sigma-Aldrich).
TLC was performed on Merck 60 F254 precoated silica-gel plates. Flash column
chromatography was performed on silica gel (Silica Gel 60N; 63–210 mesh,
ν
max (KBr) cm− 1 3476, 3398, 2986, 2950, 2931, 2895, 1448, 1419, 1397, 1356,
Kanto Chemical Co., Inc or Wakogel 60N, 63–212 μm, Wako Pure Chemical 1229, 1120, 1083, 1060, 1013, 952, 840, 696; 1H NMR (500 MHz, CDCl3) δ
Industries, Ltd.). NMR spectra (1H at 500 MHz and 13C at 125 MHz) were
4.02–3.91 (m, 4-H, OCH2CH2O), 3.73 (brs, 1H, 7-OH), 3.33 (ddd, J = 10.7,
The Journal of Antibiotics

Synthesis of C-ring precursor of paclitaxel from 3-methoxytoluene
K Fukaya et al
5
10.6, 4.9 Hz, 1H, 8-H), 2.03 (d, J = 10.6 Hz, 1H, 8-OH), 1.94–1.86 (m, 2-H, 6- 128.4 (2 × CH), 127.9 (2× CH), 127.7 (CH), 108.6 (C), 80.9 (CH), 72.2 (C),
H and 9-H), 1.78–1.56 (m, 4-H, 6-H, 9-H, 10-H2), 1.25 (d, J = 0.9 Hz, 3-H, 71.2 (CH2), 64.4 (CH2), 64.2 (CH2), 44.6 (CH2), 31.6 (CH2), 26.0 (CH3),
CH3); 13C NMR (125 MHz, CDCl3) δ 108.7 (C), 74.0 (CH), 72.5 (C), 64.7 23.0 (CH2); HR-MS (ESI): (M+Na)+ = 301.1403 m/z. Calcd for C16H22O4Na
(CH2), 64.4 (CH2), 44.1 (CH2), 33.2 (CH2), 28.4 (CH2), 26.2 (CH3); HR-MS 301.1416 m/z.
(ESI): (M+Na)+ =211.0936 m/z. Calcd for C9H16O4Na 211.0946 m/z.
(S)-4-benzyloxy-3-methylcyclohex-2-en-1-one (5): p-Toluenesulfonic acid
(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decane-7,8-diol [(− )-9] and (7S,8R)-7- monohydrate (14.9 g, 78.3 mmol) was added to a solution of 11 (21.8 g,
hydroxy-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl dodecanoate [(+)-10b]: Vinyl 78.4 mmol) in acetone (390 ml) and H2O (390 ml) at room temperature. After
laurate (84 ml, 320 mmol) was added to a mixture of rac-9 (20.3 g, 108 mmol)
stirred for 72 h at 60 °C, the reaction solution was quenched by solid NaHCO3
and lipase AK (4.06 g) in i-Pr2O (1.08 l) at room temperature. After stirring for (28 g) at 0 °C. The resulting mixture was extracted with EtOAc (3 × ). The
7 days at 60 °C, the reaction mixture was filtered through a pad of silica gel. The combined organic extracts were washed with H2O and brine, dried over
pad was washed with EtOAc (3 l). The resulting solution was concentrated, and Na2SO4 and concentrated. The residue was purified by silica-gel column
the residue was purified by silica-gel column chromatography (EtOAc–hexane, chromatography (EtOAc–hexane, 1:7 (v/v), silica gel 510 g) to give 15.2 g of 5
1:9–4:1 (v/v), silica gel 400 g) to give 8.62 g of ( − )-9 (42%, 99% ee) and 23.1 g (90%): 499% ee by HPLC (CHIRALCEL OD-H, 250× 4.6 mm, UV 254 nm,
of (+)-10b (58%, 75% ee). ( − )-9: A colorless oil; [α]27D − 15.3 (c 0.94, CHCl3); i-PrOH–hexane, 1:22 (v/v), 1.0 ml min− 1, ent-5: room temperature= 16.1 min
IR νmax (film) cm− 1 3451, 2950, 2887, 1120, 1086, 1062, 1011, 981, 951; (peak area: 0.3%), 5: room temperature= 18.6 min (peak area: 99.7%));
HR-MS (ESI): (M+Na)+ = 211.0938 m/z. Calcd for C9H16O4Na 211.0946 m/z. a colorless oil; [α]26 +8.1 (c 1.01, CHCl3); IR νmax (film) cm− 1 2951, 2869,
D
Other spectral data, see the preparation of rac-9. (+)-10b: Rf = 0.84 1672, 1092, 1068, 740, 699; 1H NMR (500 MHz, CDCl3) δ 7.40–7.29 (m, 5-H,
(EtOAc–hexane, 2:1 (v/v)); white crystals, m.p. 47.9–49.8 °C; [α]25 +2.5 C6H5), 5.86 (q, J = 0.9 Hz, 1H, 2-H), 4.74 (d, J =11.7 Hz, 1H, PhCHHO–),
D
(c 1.08, CHCl3); IR νmax (film) cm− 1 3520, 2926, 2855, 1732, 1462, 1361, 1227, 4.56 (d, J = 11.7 Hz, 1H, PhCHHO–), 4.11–4.05 (m, 1H, 4-H), 2.64–2.56
1153, 1118, 1067; 1H NMR (500 MHz, CDCl3) δ 4.67 (dd, J = 11.2, 4.6 Hz, (m, 1H, 6-H), 2.35–2.22 (m, 2-H, 5-H, 6-H), 2.16–2.06 (m, 1H, 5-H), 2.02
1H, 8-H), 4.04–3.90 (m, 4-H, OCH2CH2O), 3.86 (brs, 1H, OH), 2.42–2.31 (dd, J = 1.2, 0.9 Hz, 3-H, CH3); 13C NMR (125 MHz, CDCl3) δ 198.8 (C),
(m, 2-H, OCOCH2), 1.95–1.51 (m, 8-H, 6-H2, 9-H2, 10-H2, CH2), 1.36–1.20 161.4 (C), 138.0 (C), 128.6 (2× CH), 128.1 (CH), 128.0 (2 × CH), 127.8 (CH),
(m, 16H, 8 × CH2), 1.17 (s, 3-H, 7-CH3), 0.87 (t, J = 6.9 Hz, 3-H, CH3); 75.1 (CH), 71.9 (CH2), 34.5 (CH2), 27.7 (CH2), 21.2 (CH3); HR-MS (ESI):
13C NMR (125 MHz, CDCl3) δ 173.9 (C), 108.5 (C), 76.0 (CH), 71.5 (C), (M+Na)+ = 239.1040 m/z. Calcd for C14H16O2Na 239.1048 m/z.
64.8 (CH2), 64.3 (CH2), 44.6 (CH2), 34.6 (CH2), 33.1 (CH2), 32.0 (CH2),
(7S,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-7,8-diol [(+)-9]: Potassium bicar-
29.7 (2× CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 26.0 (CH3), bonate (5.39 g, 39.0 mmol) was added to the solution of (+)-10b (2.89 g,
25.2 (CH2), 24.3 (CH2), 22.8 (CH2), 14.2 (CH3); HR-MS (ESI): (M+Na) 7.80 mmol, 75% ee) in MeOH (78 ml) at room temperature. After stirring for
+ = 393.2615 m/z. Calcd for C21H38O5Na 393.2617 m/z.
18 h, the reaction mixture was diluted with H2O (20 ml). The resulting mixture
(7R,8S)-7-hydroxy-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl acetate [(− )-10a] was extracted with EtOAc (11 × ). The combined organic extracts were washed
from ( − )-9 and determination of its ee: N,N-dimethyl-4-aminopyridine with brine, dried over Na2SO4 and concentrated. The residue was purified by
(3.2 mg, 28 μmol) was added to a solution of ( − )-9 (49.1 mg, 261 μmol), silica-gel column chromatography (EtOAc/hexane 1:8–2:1, silica gel 29 g) to
triethylamine (89 μl, 0.64 mmol) and Ac2O (62 μl, 0.65 mmol) in CH2Cl2 give 1.41 g of (+)-9 (96%) as a mixture of slightly yellow crystals and oil, which
(5.2 ml) at room temperature. After maintaining for 4 h, the reaction mixture was co-distilled twice with hexane (5 ml). The resulting residue was suspended
was quenched by saturated aqueous NH4Cl (3 ml). The resulting mixture was in EtOAc–hexane (1:20 (v/v), 21 ml) and gently stirred for 30 s. The crystals
extracted with CHCl3 (2× ). The combined organic extracts were washed with were removed by filtration and washed with hexane (5 ml). The filtrate was
brine, dried over Na2SO4 and concentrated. The residue was filtered through a concentrated to give 478 mg of enantiomerically enriched (+)-9 (33%, 97% ee):
pad of silica gel (1.0 g). The pad was washed with EtOAc (30 ml). The resulting a colorless oil; [α]24 +13.7 (c 1.01, CHCl3); HR-MS (ESI): (M+Na)+
D
solution was concentrated. The residue was purified by HPLC (PEGASIL Silica
=211.0938 m/z. Calcd for C9H16O4Na 211.0946 m/z. Other spectral data, see
the preparation of rac-9. Compound (+)-9 was converted to (+)-10a by the
120–5, 250 ×20 mm, UV 210 nm, i-PrOH–hexane, 1:5 (v/v), 10 ml min− 1
,
room temperature= 15.1 min) to give 54.3 mg of (− )-10a (90%): 499% ee by same procedure as described for the preparation of (− )-10 from ( − )-9, and ee
HPLC (CHIRALCEL OJ-H, 250×4.6 mm, UV 210 nm, i-PrOH–hexane, 1:6 of (+)-10a was determined by HPLC analysis (CHIRALCEL OJ-H,
(v/v), 1.0 ml min− 1, (+)-10a: room temperature= 8.6 min (not detected), 250 ×4.6 mm, UV 210 nm, i-PrOH–hexane, 1:6 (v/v), 1.0 ml min− 1).
(− )-10a: room temerature= 11.1 min); Rf =0.41 (EtOAc–hexane, 2:1 (v/v));
(S)-7-hydroxy-7-methyl-1,4-dioxaspiro[4.5]decan-8-one (12): Sulfur trioxide–
a colorless oil; [α]27 − 6.6 (c 0.98, CHCl3); IR νmax (film) cm− 1 3504, 2958, pyridine complex (2.50 g, 15.7 mmol) was added to a solution of (+)-9 (1.52 g,
D
2887, 1734, 1368, 1243, 1121, 1087, 1045, 949, 842; 1H NMR (500 MHz, 8.08 mmol) and triethylamine (6.5 ml, 47 mmol) in DMSO (10 ml) and
CDCl3) δ 4.67 (dd, J = 11.2, 4.9 Hz, 1H, 8-H), 4.04–3.88 (m, 5-H, OCH2CH2O, CH2Cl2 (71 ml) at room temperature. After maintaining for 17 h, the solution
OH), 2.12 (s, 3-H, OCOCH3), 1.96–1.65 (m, 6-H, 6-H2, 9-H2, 10-H2), 1.18 was quenched by H2O (30 ml). The resulting mixture was extracted with
(s, 3-H, 7-CH3); 13C NMR (125 MHz, CDCl3) δ 171.2 (C), 108.5 (C), 76.4 CHCl3 (3× ). The combined organic extracts were dried over Na2SO4 and
(CH), 71.5 (C), 64.8 (CH2), 64.4 (CH2), 44.6 (CH2), 33.2 (CH2), 26.0 (CH3), concentrated. The residue was purified by silica-gel column chromatography
24.2 (CH2), 21.4 (CH3); HR-MS (ESI): (M+Na)+ = 253.1049 m/z. Calcd for (EtOAc–hexane, 1:9 to 1:4 (v/v), silica gel 150 g) to give 1.29 g of 12 (86%):
C11H18O5Na 253.1052 m/z.
a slightly yellow oil; [α]26 − 32.6 (c 0.98, CHCl3); IR νmax (film) cm− 1 3482,
D
(7R,8S)-8-benzyloxy-7-methyl-1,4-dioxaspiro[4.5]decan-7-ol (11): Tetrabutyl- 2967, 2934, 2890, 1720, 1110, 1069, 1027; 1H NMR (400 MHz, CDCl3) δ 4.09
ammonium iodide (3.28 g, 8.88 mmol) was added to a mixture of (− )-9 (s, 1H, OH), 4.08–3.96 (m, 4-H, OCH2CH2O), 2.75–2.60 (m, 2-H, 9-H2),
(16.7 g, 88.7 mmol), benzyl bromide (12 ml, 98 mmol) and sodium hydride 2.18 (dd, J = 13.9, 2.5 Hz, 1H, 6-H), 2.11–1.95 (m, 3-H, 6-H, 10-H2),
(63%, 10.1 g, 265 mmol) in tetrahydrofuran (240 ml) at 0 °C. The solution was 1.41 (s, 3-H, CH3); 13C NMR (125 MHz, CDCl3) δ 212.1 (C), 107.4 (C),
allowed to warm up to room temperature. After stirring for 1 day, the reaction 74.9 (C), 64.9 (CH2), 64.6 (CH2), 47.7 (CH2), 35.4 (CH2), 33.9 (CH2),
mixture was quenched with brine (200 ml) at 0 °C. The resulting mixture was 25.8 (CH3); HR-MS (ESI): (M+H)+ = 187.0968 m/z. Calcd for C9H15O4
extracted with EtOAc (3× ). The combined organic extracts were dried over 187.0970 m/z.
Na2SO4 and concentrated. The residue was purified by silica-gel column
(7S,8S)-8-(benzyloxy)-7-methyl-1,4-dioxaspiro[4.5]decan-7-ol (13): Sodium
chromatography (EtOAc–hexane, 1:7 (v/v), silica gel 740 g) to give 21.8 g of 11 triacetoxyborohydride (128 mg, 0.605 mmol) was added to a solution of 12
(88%): a colorless oil; [α]26D +48.7 (c 0.99, CHCl3); IR νmax (film) cm− 1 3518, (74.4 mg, 400 μmol) in CH2Cl2 (8.0 ml) at 0 °C. After stirring for 3 h at 15 °C,
2952, 2879, 1125, 1085, 739, 699; 1H NMR (500 MHz, CDCl3) δ 7.39–7.25 (m, further sodium triacetoxyborohydride (127 mg, 0.599 mmol) was added to the
5-H, C6H5), 4.70 (d, J =11.7 Hz, 1H, PhCHHO-), 4.49 (d, J = 11.7 Hz, 1H, reaction mixture at 0 °C. After stirring for 2 h at 15 °C, further sodium
PhCHHO–), 4.01–3.88 (m, 4-H, OCH2CH2O), 3.42 (s, 1H, OH), 3.22 triacetoxyborohydride (84.7 mg, 400 μmol) was added to the reaction mixture
(dd, J = 8.0, 4.0 Hz, 1H, 8-H), 1.94–1.77 (m, 4-H, 6-H, 9-H2, 10-H), 1.68 at 0 °C. After stirring for 2 h at 15 °C, the reaction mixture was quenched by
(dd, J = 14.0, 0.9 Hz, 1H, 6-H), 1.52 (dddd, J =12.9, 9.4, 4.3, 0.9 Hz, 1H, saturated aqueous NaHCO3 (8 ml) at 0 °C. The resulting mixture was extracted
10-H), 1.26 (s, 3-H, 7-CH3); 13C NMR (125 MHz, CDCl3) δ 138.5 (C), with EtOAc (10 × ). The combined organic extracts were washed with H2O
The Journal of Antibiotics

Synthesis of C-ring precursor of paclitaxel from 3-methoxytoluene
K Fukaya et al
6
and brine, dried over Na2SO4 and concentrated. The residue was purified by (d, J = 11.7 Hz, 1H, PhCHHO–), 3.92 (dd, J = 11.6, 8.6 Hz, 1H, CHHOH),
silica-gel column chromatography (EtOAc/hexane 1:4–2:1, silica gel 2.3 g) 3.64 (dd, J = 10.6, 4.3 Hz, 1H, 4-H), 3.49 (dd, J = 11.6, 2.9 Hz, 1H, CHHOH),
to give an inseparable mixture of (7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan- 2.49 (ddd, J = 8.6, 2.9, 1.2 Hz, 1H, 2-H), 2.48 (brs, 1H, OH), 2.46 (ddd,
7,8-diol and its 8-epimer, which was used in the next reaction without further J = 15.6, 5.4, 3.4 Hz, 1H, 6-H), 2.39 (dddd, J =15.6, 12.8, 6.4, 1.2 Hz, 1H, 6-H),
purification. Benzyl bromide (52 μl, 440 μmol) was added to a solution
of a mixture of (7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-7,8-diol and its
8-epimer, tetrabutylammonium iodide (14.7 mg, 39.8 μmol) and sodium
hydride (64%, 44.6 mg, 1.19 mmol) in DMF–tetrahydrofuran (1:5, 1.1 ml) at
0 °C. The solution was allowed to warm to room temperature. After stirring for
12 h, the reaction mixture was quenched with brine (3 ml) at 0 °C. The
resulting mixture was extracted with EtOAc (6× ). The combined organic
extracts were dried over Na2SO4 and concentrated. The residue was purified by
silica-gel column chromatography (EtOAc/hexane 1:8, silica gel 7.5 g) to give
58.1 mg of 13 (52% from 12) and 13.1 mg of ent-11 (12% from 12): 13: a
2.23 (dddd, J = 13.5, 6.4, 4.3, 3.4 Hz, 1H, 5-H), 1.88 (dddd, J = 13.5, 12.8, 10.6,
5.4 Hz, 1H, 5-H), 0.98 (s, 3-H, 3-CH3); 13C NMR (125 MHz, CDCl3) δ 212.4
(C), 143.8 (CH), 138.4 (C), 128.4 (2× CH), 127.8 (CH), 127.7 (2× CH), 115.2
(CH2), 81.1 (CH), 72.4 (CH2), 58.9 (CH2), 58.0 (CH), 47.9 (C), 38.8 (CH2),
26.6 (CH2), 13.1 (CH3); HR-MS (ESI): (M+Na)+ = 297.1460 m/z. Calcd for
C17H22O3Na 297.1467 m/z. 15: a colorless oil; [α]24D +14.4 (c 0.99, CHCl3); IR
νmax (film) cm− 1 3469, 2968, 2941, 2882, 1702, 1071, 1038, 1029, 739, 698;
1H NMR (500 MHz, CDCl3) δ 7.42–7.29 (m, 5-H, C6H5), 5.64 (dd, J = 17.3,
10.9 Hz, 1H, CH = CH2), 5.11 (dd, J = 10.9, 0.9 Hz, 1H, CH =CHH), 5.06
(dd, J = 17.3, 0.9 Hz, 1H, CH = CHH), 4.72 (d, J = 11.5 Hz, 1H, PhCHHO–),
4.54 (d, J = 11.5 Hz, 1H, PhCHHO–), 3.91 (ddd, J = 11.8, 9.2, 3.4 Hz, 1H,
CHHOH), 3.51 (ddd, J = 11.8, 10.3, 3.4 Hz, 1H, CHHOH), 3.24 (dd, J = 2.0,
2.0 Hz, 1H, 4-H), 3.05 (ddd, J = 9.2, 3.4, 0.9 Hz, 1H, 2-H), 2.73 (ddd, J =14.2,
14.0, 6.9 Hz, 1H, 6-H), 2.62 (dd, J = 10.3, 3.4 Hz, 1H, OH), 2.28 (dddd,
J = 14.2, 5.2, 3.2, 0.9 Hz, 1H, 6-H), 2.20 (dddd, J = 14.3, 6.9, 3.2, 2.0 Hz, 1H,
5-H), 2.00 (dddd, J = 14.3, 14.0, 5.2, 2.0 Hz, 1H, 5-H), 1.32 (s, 3-H, 3-CH3);
13C NMR (125 MHz, CDCl3) δ 215.3 (C), 140.6 (CH), 138.5 (C), 128.6
(2 × CH), 127.9 (CH), 127.6 (2× CH), 116.2 (CH2), 81.8 (CH), 71.8 (CH2),
59.0 (CH2), 56.0 (CH), 48.8 (C), 36.8 (CH2), 25.2 (CH2), 21.2 (CH3); HR-MS
(ESI): (M+Na)+ = 297.1462 m/z. Calcd for C17H22O3Na, 297.1467 m/z. 16:
colorless oil; [α]24 +67.8 (c 0.92, CHCl3); IR (film) 3509, 2962, 2932, 2882,
D
1195, 1089, 966, 738, 699 cm− 1
;
1H NMR (500 MHz, CDCl3) δ 7.36–7.25
(m, 5-H, C6H5), 4.62 (d, J = 11.7 Hz, 1H, PhCHHO–), 4.44 (d, J = 11.7 Hz, 1H,
PhCHHO–), 4.07 (brs, 1H, OH), 4.01–3.92 (m, 4-H, OCH2CH2O), 3.28 (dd,
J = 2.6, 2.6 Hz, 1H, 8-H), 2.00 (d, J = 13.8 Hz, 1H, 6-H), 1.97–1.81 (m, 3-H,
9-H2, 10-H), 1.60 (ddd, J = 13.8, 2.6, 0.9 Hz, 1H, 6-H), 1.53 (dddd, J = 12.0,
3.7, 3.2, 2.6 Hz, 1H, 10-H), 1.26 (s, 3-H, 7-CH3); 13C NMR (125 MHz, CDCl3)
δ 138.9 (C), 128.4 (2xCH), 127.6 (3xCH), 109.7 (C), 79.9 (CH), 73.0 (C), 71.3
(CH2), 64.5 (CH2), 64.2 (CH2), 41.1 (CH2), 28.9 (CH2), 26.0 (CH3), 21.9
(CH2); HR-MS (ESI): (M+Na)+ =301.1419 m/z. Calcd for C16H22O4Na
301.1416 m/z. ent-11: a colorless oil; [α]25 –47.5 (c 1.14, CHCl3).
a colorless oil; [α]25 +41.3 (c 1.07, CHCl3); IR νmax (film) cm− 1 2958, 2870,
D
D
1710, 1092, 1073, 739, 698; 1H NMR (500 MHz, CDCl3) δ 7.41–7.28
(m, 5-H), 5.71 (dd, J = 17.5, 10.6 Hz, 1H, CH = CH2), 5.05 (d, J =10.6 Hz,
1H, CH= CHH), 5.04 (d, J = 17.5 Hz, 1H, CH= CHH), 4.71 (d, J =11.7 Hz,
1H, PhCHHO–), 4.54 (d, J = 11.7 Hz, 1H, PhCHHO–), 3.44 (dd, J = 4.0,
2.3 Hz, 1H, 4-H), 2.61 (d, J = 14.6 Hz, 1H, 2-H), 2.51 (dddd, J = 14.8, 12.0, 6.3,
0.9 Hz, 1H, 6-H), 2.40–2.34 (m, 1H, 2-H), 2.22–2.15 (m, 1H, 6-H), 2.10
(dddd, J = 14.3, 6.3, 4.6, 4.0 Hz, 1H, 5-H), 1.95 (dddd, J = 14.3, 12.0, 5.2,
2.3 Hz, 1H, 5-H), 1.16 (s, 3-H, 3-CH3); 13C NMR (125 MHz, CDCl3) δ 211.2
(C), 144.0 (CH), 138.6 (C), 128.5 (2× CH), 127.8 (CH), 127.6 (2× CH), 114.3
(CH2), 79.2 (CH), 71.6 (CH2), 47.3 (CH2), 46.1 (C), 36.1 (CH2), 25.0 (CH2),
24.2 (CH3); HR-MS (ESI): (M+H)+ = 245.1532 m/z. Calcd for C16H21O2
245.1542 m/z.
Base-induced epimerization of 15: To a solution of 15 (4.66 g, 17.0 mmol) in
MeOH (140 ml) at room temperature was added K2CO3 (305 mg, 2.21 mmol),
and the resulting mixture was stirred for 2.5 h. After addition of 1M HCl
(100 ml), products were extracted with EtOAc (3× ). The combined organic
extracts were washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4 and concentrated. The residue was purified by silica-gel column
chromatography (EtOAc–hexane, 1:7–1:4 (v/v), silica gel 230 g) to give 1.45 g
of 6 (31%) and 2.56 g of the starting material (15, 55%).
(S)-4-(benzyloxy)-3-methylcyclohex-2-en-1-one (5) from 13: p-Toluenesulfo-
nic acid monohydrate (90.7 mg, 477 μmol) was added to a solution of 13
(130 mg, 466 μmol) in acetone (2.3 ml) and H2O (2.3 ml) at room tempera-
ture. After stirred for 3 days at 60 °C, the reaction solution was quenched by
solid NaHCO3 (123 mg) at 0 °C. The resulting mixture was extracted with
EtOAc (3 × ). The combined organic extracts were washed with H2O and brine,
dried over Na2SO4 and concentrated. The residue was purified by silica-gel
column chromatography (EtOAc–hexane, 1:6 (v/v), silica gel 10 g) to give
80.7 mg of 5 (80%): 97% ee by HPLC (CHIRALCEL OD-H, 250× 4.6 mm,
UV 254 nm, i-PrOH–hexane, 1:22 (v/v), 1.0 ml min− 1).
(2R,3S,4S)-4-benzyloxy-2-(hydroxymethyl)-3-methyl-3-vinylcyclohexan-1-one
(6), its (2R,3S,4S)-isomer (15) and (3R,4S)-4-benzyloxy-3-methyl-3-vinylcyclo-
hexan-1-one (16): Vinyl magnesium chloride (1.5 M in tetrahydrofuran, 82 ml,
120 mmol) was added to a mixture of 5 (15.2 g, 70.3 mmol), CuI (4.02 g,
21.1 mmol), N,N,N’,N’-tetramethylethylenediamine (21 ml, 140 mmol) and
trimethylsilyl chloride (22 ml, 180 mmol, neutralized over 10 mg of poly-4-
vinyl-pyridine) in tetrahydrofuran (230 ml) at − 78 °C. After maintaining for
30 min, trimethylsilyl chloride (31 ml, 250 mmol) and Et3N (34 ml, 250 mmol)
were added to the solution at − 78 °C. This solution was allowed to warm to
room temperature. After maintaining for 14 h, the solution was cooled to − 78 °
C and then quenched by saturated aqueous NH4Cl (200 ml). The resulting
mixture was extracted with hexane (3 × ). The combined organic extracts were
washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4.
The solution was filtered through a pad of Celite (300 cm3). The pad was
washed with hexane (1.5 l). The resulting solution was concentrated to give a
crude TMS enol ether 14, which was used in the next reaction without
purification.
Scandium trifluoromethanesulfonate (1.73 g, 3.52 mmol) was added to a
solution of crude 14 and formalin (35%, 28 ml, 350 mmol) in tetrahydrofuran
(440 ml) at 0 °C. After maintaining for 3.5 h, the reaction solution was
quenched by saturated NaHCO3 (300 ml) at 0 °C. The resulting mixture was
extracted with EtOAc (3× ). The combined organic extracts were washed with
brine, dried over Na2SO4 and concentrated. The residue was purified by silica-
gel column chromatography (EtOAc–hexane, 1:10–1:1 (v/v), silica gel 580 g) to
give 11.5 g of 6 (60%), 5.29 g of 15 (27%) and 2.08 g of 16 (12%): 6: 499% ee
by HPLC (CHIRALCEL OD-H, 250 × 4.6 mm, UV 254 nm, i-PrOH–hexane,
1:30 (v/v), 1.0 ml min− 1, ent-6: room temperature = 21.5 min (not detected),
6: room temperature =23.2 min); a colorless oil; [α]26D +10.3 (c 0.99, CHCl3);
IR νmax (film) cm− 1 3447, 2947, 1711, 1100, 1025, 738, 698; 1H NMR
(500 MHz, CDCl3) δ 7.36–7.26 (m, 5-H, C6H5), 5.80 (dd, J = 17.5, 10.6 Hz,
1H, CH = CH2), 5.23 (dd, J = 10.6, 0.6 Hz, 1H, CH= CHH), 5.12 (dd, J = 17.5,
0.6 Hz, 1H, CH = CHH), 4.62 (d, J =11.7 Hz, 1H, PhCHHO–), 4.54
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This research was supported by the MEXT-supported Program for the Strategic
Research Foundation at Private Universities, 2012–2016, from the Ministry of
Education, Culture, Sports, Science and Technology of Japan (MEXT). Authors
also acknowledge the financial support (Grant-in Aid for Scientific Research
(B), 26288018) from Japan Society for the Promotion of Science (JSPS).
1
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