Construction of the ABC ring system of taxanes via stereoselective one-pot three-component coupling and intramolecular alkylation of a protected cyanohydrin ether

Article abstract of DOI:10.1246/bcsj.20090341

Construction of the ABC ring system of taxanes via one-pot three-component coupling and intramolecular alkylation is accomplished. The 1,4-addition of a protected cyanohydrin ether to 2-methyl-2-cyclohexenone and subsequent addition of the resulting enolate to formaldehyde proceeded stereoselectively to provide the AC ring in 90% yield. The stereoselective reduction of the 2-keto group was achieved by using hydroxy-directed hydride reduction with LiAlH₄. The intramolecular alkylation of the protected cyanohydrin ether furnished the ABC ring system of taxanes in 43% yield.

Full text of DOI:10.1246/bcsj.20090341

942
Bull. Chem. Soc. Jpn. Vol. 83, No. 8, 942–949 (2010)
© 2010 The Chemical Society of Japan
Construction of the ABC Ring System of Taxanes via Stereoselective
One-Pot Three-Component Coupling and Intramolecular
Alkylation of a Protected Cyanohydrin Ether
Takayuki Serizawa,1 Shigeru Miyamoto,1 Shinichiro Fuse,1 Takayuki Doi,1,2 and Takashi Takahashi*1
1Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552
2Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578
Received December 24, 2009; E-mail: ttak@apc.titech.ac.jp
Construction of the ABC ring system of taxanes via one-pot three-component coupling and intramolecular alkyla-
tion is accomplished. The 1,4-addition of a protected cyanohydrin ether to 2-methyl-2-cyclohexenone and subsequent
addition of the resulting enolate to formaldehyde proceeded stereoselectively to provide the AC ring in 90% yield. The
stereoselective reduction of the 2-keto group was achieved by using hydroxy-directed hydride reduction with LiAlH4. The
intramolecular alkylation of the protected cyanohydrin ether furnished the ABC ring system of taxanes in 43% yield.
The taxanes paclitaxel (1) and docetaxel (2) are highly
potent agents in the treatment of breast, ovarian, lung, head,
and neck cancers (Figure 1).1 Inspired by the potent biological
activity, in addition to the synthetic challenges offered by the
structure,2-7 our group has focused on the total synthesis of this
natural product. We have already reported an efficient method
for the construction of A, B, and C rings.8-11 In addition, we
have also reported a formal total synthesis of paclitaxel (1) via
the stereoselective coupling of the highly functionalized A
and C rings and the intramolecular alkylation of the protected
cyanohydrin ether.12 However, the preparation of the highly
functionalized C ring was laborious in this case. Recently, we
have reported the stereoselective one-pot three-component
coupling13-17 of protected cyanohydrin ether 8 with 2-methyl-
2-cyclohexenone (7), and formaldehyde to provide the desired
AC ring system of taxanes in high yield (Scheme 1).18 Here we
wish to report the construction of the ABC ring system of
taxanes via the stereoselective one-pot three-component cou-
pling and the intramolecular cyclization of the protected
cyanohydrin ether.
Our synthetic strategy to construct the ABC ring system of
taxanes is shown in Scheme 1. The intramolecular alkylation
of the protected cyanohydrin ether 4 is the crucial step in the
construction of the highly strained 8-membered ring. We
planned to introduce the protected cyanohydrin ether group at
the 10-position via the oxidation of the ¦10,(11) double-bond of
the diene 5. The protected tetraol 5 could be obtained from 6 by
stereoselective reductions of the 7-keto group18 and the 2-keto
group which is derived from the protected cyanohydrin ether
group, followed by the stereoselective oxidation of the ¦1,(14)
double-bond. The second key step is the stereoselective one-pot
three-component coupling of the protected cyanohydrin ether 8
with 2-methyl-2-cyclohexenone (7) and formaldehyde.18 The
coupling reaction could introduce the trans-stereochemistry
between C(3) H and C(8) methyl. The triene 8 should be
readily accessible from the A ring 9.19
O
R2O
O
OH
C
R1
NH
O
A
Ph
O
B
D
O
OH
H
OBz
HO
OAc
R1 = Ph, R2 = Ac: Paclitaxel (1)
R1 = Ot-Bu, R2= H: Docetaxel (2)
Figure 1. Structures of paclitaxel and docetaxel.
Treatment of the chloronitrile 919 with DBU afforded triene
10 (Scheme 2). Reduction of nitrile 10 to the corresponding
aldehyde and subsequent formation of a protected cyanohydrin
afforded the desired compound 8 in 95% yield from 9. The key
reaction, stereoselective one-pot three-component coupling,
was carried out to provide the desired coupling product 6 in
90% yield. Stereoselective reduction of the ketone at the 7-
position in 6, followed by conversion of the cyanohydrin ether
at the 2-position into the corresponding ketone provided 12 as a
single diastereomer.18 The relative stereochemistry at the 3-, 4-,
7-, and 8-positions was determined to be the desired config-
uration based on the NOE observation of benzylidene acetal 13
derived from the diol 12 (Scheme 3).18
We prepared the ketone 14 to examine the effect of a
protecting group at the 9-OH group on the stereoselective
reduction of the 2-keto group (Scheme 3). Several reducing
reagents were examined in the reduction of ketones 13 and 14
(Table 1). Ketone 13, containing benzylidene acetal protection
on the 7-OH and 9-OH groups, was reduced with LiAlH4
(Entry 1) or LiBH4 (Entry 4) to afford alcohol 15¢, whereas no
reaction occurred with NaBH4 (Entry 2) or Zn(BH4)2 (Entry 3).
The stereochemistry of the 2-OH group was speculated to be
the undesired ¢-configuration based on the coupling constant
Published on the web July 24, 2010; doi:10.1246/bcsj.20090341

T. Serizawa et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
943
CN
OTs
H
O
10
OBOM
OBOM
Intramolecular
Alkylation
OBOM
OTs
EEO
MeO
11
H
OMe
5
H
OMe
3
MeO
MeO
OMe
4
O
O
H
OH
O
H
OAc
3-Component
Coupling
7
8
3
2
CN
14
1
H
Cl
EEO CN
EEO CN
9
8
7
6
Scheme 1. Synthetic strategy for the ABC ring system of taxanes.
OAc
a
b
CN
CN
CHO
Cl
9
10
11
O
O
HO
OH
HO
g, h, i
c, d, e
f
+
H
H
EEO CN
EEO CN
O
8
7
6
12
Scheme 2. Preparation of the AC ring 12. (a) DBU, benzene, reflux, quant; (b) i-Bu2AlH, toluene, ¹78 °C, quant; (c) TMSCN,
KCN¢DC-18-Cr-6; (d) 1 M HCl, THF; (e) EVE, CSA, CH2Cl2, 0 °C, 3 steps 95%; (f) i-Pr2NLi, THF then HCHO, ¹78 °C, 90%;
(g) NaBH4, MeOH; (h) CuSO4, MeOH/H2O; (i) 1 M NaOH aq. Et2O, 3 steps 61%.
Ph
Table 1. Reduction of the Ketones 13 and 14 with Several
Kinds of Reducing Reagents
O
O
1 OR2
1 OR2
OR
OR
a
Conditions
9
7
12
13 or 14
H
H
H
O
13
OH
desired
OH
undesired
OBOM
OH
15α: R1 = R2 = -CH(Ph)-
16α: R1 = H, R2 = BOM
15β: R1 = R2 = -CH(Ph)-
16β: R1 = H, R2 = BOM
b, c, d
Temperature
Product
(yield/%)
Entry Substrate Reagent Solvent
H
/°C
O
1
2
3
4
5
6
7
13
13
13
13
14
14
14
LiAlH4
NaBH4 MeOH
Zn(BH4)2 Et2O
LiBH4
LiAlH4
Et2O
¹78
0
¹78 to 0
¹78 to 0
¹78
15¢ (64)
n.r.
n.r.
15¢
16¡ (59)
n.r.
14
Scheme 3. Preparation of ketones 13 and 14. (a) PhCH-
(OMe)2, CSA, CH2Cl2, 52%; (b) TBSCl, imidazole,
CH2Cl2; (c) BOMCl, i-Pr2NEt, CH2Cl2; (d) TBAF, THF,
3 steps 47%.
Et2O
Et2O
Zn(BH4)2 Et2O
LiBH4 Et2O
¹78 to 0
¹78 to 0 decomposed
(9.9 Hz) of H2 and H3. Calculation of coupling constants by
Carplus equation based on conformational analysis using MM2
(MacroModel 6.0, Monte Carlo) suggested J2,3 = 0.5 Hz for
15¡ and J2,3 = 10.0 Hz for 15¢. On the other hand, the
reduction of ketone 14, containing a free hydroxy group at the
9-position, afforded the desired isomer, 16¡ (Entry 5). It is
conceivable that hydride approached from the sterically less
hindered Si face in the case of ketone 13 containing protection
on the 9-OH group (Figure 2). On the other hand, hydroxy-

944
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
Synthesis of the ABC Ring System of Taxanes
directed hydride reduction from the Re-face would take place
in the case of ketone 14 containing a free hydroxy group at the
9-position.
Unexpectedly, intramolecular etherification of the alcohol
16¡ occurred in CDCl3 (Scheme 4). Stereochemistry of the 2-
OH group was speculated to be desired ¡-configuration based
on the coupling constant (10.2 Hz) of H2 and H3. Calculation
of coupling constants by Carplus equation based on conforma-
tional analysis using MM2 (MacroModel 6.0, Monte Carlo)
suggested J2,3 = 1.1 Hz for 16¡ and J2,3 = 11.0 Hz for 17¡.
The observed J values were small for 16¡ and 10.2 Hz for 17¡.
These comparisons also supported the above speculations.
Construction of the ABC ring 3 was performed as follows
(Scheme 5). Protection of the primary hydroxy group in 16¡
with a TBS group afforded the corresponding silyl ether 18.
Hydroxy-directed stereoselective epoxidation, regioselective
ring opening of the epoxide with LiAlH4,12 protection of diol
20 with methyl groups, followed by conversion of the TBS
group to a Ts group provided 23. The epoxidation of ¦10,(11)
Hydroxy-directed
Re face attack
Al
Me
Me
H
Ph
H
O
O
OBOM
O
O
O
7
7
8
8
3
3
Si face attack
13
H
14
Figure 2. Proposed mechanism in the stereoselective re-
duction of the ketones 13 and 14.
OBOM
OBOM
CDCl3
HO
Me
H
OBOM
8
O
8
3
O
2
OH
2
3
H
H
H
17α
HO
17α
J2,3 = 11.0 Hz (calc.)
2,3 = 10.2 Hz (obs.)
OH
16α
J
2,3 = 1.1 Hz (calc.)
2,3 = broad singlet (obs.)
J
J
Scheme 4. Stereochemical assignment of the 2-OH group in 17¡.
R3O
10
OBOM
OBOM
OBOM
RO
TBSO
11
b
c
H
H
H
R1O
O
OR2
OH
OH
16α: R = H
19
20: R1 = R2 = H, R3 = TBS
21: R1 = R2 = Me, R3 = TBS
22: R1 = R2 = Me, R3 = H
23: R1 = R2 = Me, R3 = Ts
a
d
e
f
18: R = TBS
O
O
O
OBOM
OBOM
OBOM
OBOM
TsO
TsO
TsO
TsO
O
g
h
+
+
H
H
H
H
MeO
MeO
MeO
OMe
OMe
OMe
OMe
24
25
26
27
acidic or basic conditions
CN
OTs
H
O
OBOM
OBOM
H
EEO
MeO
O
O
H
H
8
i, j, k
l, m, n
7 OBOM
H
25
2
3
H
MeO
O
OMe
OMe
3
H
4
NOEs
Scheme 5. Construction of the ABC ring 3. (a) TBSCl, imidazole, CH2Cl2, quant; (b) VO(acac)2, TBHP, benzene, 4 °C; (c) LiAlH4,
Et2O, 0 °C; (d) NaH, MeI, THF; (e) TBAF, THF; (f) TsCl, DMAP, ¦, 5 steps 31%; (g) dimethyldioxirane, CH2Cl2, 72%; (h) p-
TsOH, benzene, 75% (25:26:27 = 4:3:3); (i) TMSCN, KCN•DC-18-Cr-6; (j) HCl, THF; (k) EVE, CSA, CH2Cl2, 0 °C, 3 steps 83%;
(l) LiN(TMS)2 dioxane, ¦, 43%; (m) CSA, MeOH; (n) NaOH, Et2O, 2 steps 42%.

T. Serizawa et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
945
double-bond and subsequent treatment of the diene mono-
epoxide with p-TsOH afforded the desired enal 25 with
undesired aldehydes 26 and 27 in 75% combined yield
(25:26:27 = 4:3:3).20-22 The ¢,£-unsaturated aldehyde 26
could not be converted to the desired enal 25 in either acidic
(CSA in MeOH) or basic (DBU in CH2Cl2) conditions. The
enal 25 was converted to the protected cyanohydrin ether 4.
The crucial step, the intramolecular alkylation of the protected
cyanohydrin ether was carried out.12 Treatment of 4 with
LiN(TMS)2 in refluxing dioxane for 7 h afforded the desired
cyclization product in 43% yield. Hydrolysis of the cyanohy-
drin furnished the desired ABC ring 3. The stereochemistry of
compound 3 was confirmed by NOE experiments (Scheme 5).
In conclusion, we developed an efficient synthetic route for
3. One-pot stereoselective three-component coupling of the
protected cyanohydrin ether 8 with 2-methyl-2-cyclohexenone
(7) and formaldehyde afforded the desired coupling product
6 in 90% yield. The stereoselective reduction of the 2-keto
group was achieved by hydroxy-directed hydride reduction
with LiAlH4. The crucial intramolecular cyclization of the
protected cyanohydrin ether 4 afforded the desired ABC ring 3
in 43% yield. This synthetic strategy allowed us to construct
the ABC ring system of taxanes from structurally simple A and
C rings.
Nitrile 10. To a solution of chloronitrile 9 (19.6 g,
76.7 mmol) in benzene (100 mL) was added DBU (23.0 mL,
153 mmol) at room temperature under an argon atmosphere.
The reaction mixture was heated to reflux. After being stirred
under reflux for 10 h, the reaction mixture was poured into
water and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by
flash chromatography (Silica, 10% Et2O in hexane) to give the
nitrile 10 (18.6 g, 76.7 mmol, quant) as a pale yellow oil.
1H NMR (270 MHz, CDCl3): ¤ 6.59 (d, J = 6.3 Hz, 1H), 5.85
(d, J = 6.3 Hz, 1H), 5.38 (brs, 1H), 5.32 (d, J = 2.0 Hz, 1H),
1.98 (s, 3H), 1.35 (s, 6H). 13C NMR (67.8 MHz, CDCl3): ¤
151.2, 139.0, 135.5, 119.8, 119.7, 118.9, 114.0, 38.3, 30.6,
20.0. IR (neat): 2966, 2202, 1560, 1459, 1408, 1361, 897,
¹1
840 cm
.
Aldehyde 11. To a solution of nitrile 10 (12.2 g, 76.7
mmol) in toluene (70 mL) was added dropwise i-Bu2AlH
(100 mL, 1.01 M in toluene, 100 mmol) at ¹78 °C. After being
stirred at the same temperature for 3 h, the reaction mixture was
carefully quenched with saturated aqueous Na2SO4 solution
and 1 M HCl aqueous solution. The aqueous layer was
extracted with Et2O. The combined organic layers were washed
with saturated aqueous NaHCO3, brine and dried over MgSO4
and concentrated in vacuo. The residue was purified by flash
chromatography (Silica, 10% Et2O in hexane) to give the
aldehyde 11 (16.0 g, 76.7 mmol, quant) as a pale yellow oil.
1H NMR (270 MHz, CDCl3): ¤ 9.32 (s, 1H), 6.67 (d, J =
6.3 Hz, 1H), 6.05 (d, J = 6.3 Hz, 1H), 5.33 (brs, 2H), 2.01 (s,
3H), 1.43 (s, 6H). 13C NMR (67.8 MHz, CDCl3): ¤ 192.3,
Experimental
General Procedures. 1H NMR spectra were recorded on a
JEOL Model EX-270 (270 MHz) instrument in the indicated
solvent. Chemical shifts were recorded in parts per million
(ppm) relative to Me4Si (0.0 ppm) or chloroform (7.26 ppm) as
an internal standard. NMR multiplicities were reported using
the following abbreviations. s: singlet, d: doublet, t: triplet, q:
quartet, m: multiplet, br: broad, J: coupling constant in Hertz.
13C NMR spectra were recorded on a JEOL Model EX-270
(67.8 MHz). Chemical shifts were recorded in a part per
million (ppm) relative to chloroform (77.1 ppm) as an internal
standard. Infrared spectra (IR) were recorded on a Perkin-Elmer
Spectrum One. Only the strongest and/or structurally important
signals were reported as the IR data given in cm¹1. The
reactions were monitored by thin layer chromatography (TLC)
carried out on Merck precoated TLC plates (60F-254) with
indicator. Visualization of the spots was UV-light and 5% p-
anisaldehyde/sulfuric acid/ethanol solution, phosphomolybdic
acid/ethanol solution, ceric sulfate/water solution or iodine.
Column chromatography separations were performed using
silica gel (Merk silicagel). Flash column chromatography
separations were performed using silica gel (KANTO,
Silica Gel 60N, spherical, neutral, 40-100 ¯m). ESI-TOF
mass spectra were measured with P. E. Biosystems TK-3500
Biospectrometry Workstation. All reactions were carried out
under an argon atmosphere in dried glassware unless otherwise
noted. Dry THF, dry hexane, dry benzene, dry Et2O, and dry
dioxane were distilled from sodium wire containing a catalytic
amount of benzophenone, dry CH2Cl2 was distilled from
P2O5. Dry i-Pr2NH, dry pyridine and dry (TMS)2NH were
distilled from CaH2. Dry acetone was distilled from CaSO4
(DRIERITE·). Dry MeOH was distilled from Mg(OMe)2. All
reagents were purchased at highest commercial quality and
used as received unless otherwise noted.
154.7, 146.0, 143.1, 141.7, 120.9, 112.5, 38.7, 29.9, 20.3. IR
¹1
(neat): 2962, 2706, 1674, 1559, 1233, 1131 cm
Protected Cyanohydrin 8.
.
To the enal 11 (16.0 g,
76.7 mmol) was added TMSCN (12.5 mL, 92.1 mmol) and a
catalytic amount of DC-18-crown-6 KCN complex at 0 °C
under an argon atmosphere. After being stirred at room
temperature for 1 h, the reaction mixture was diluted with
THF (20 mL) and 1 M HCl was carefully added at 0 °C
(Caution: HCN is generated). After being stirred at the same
temperature for 30 min, the reaction mixture was diluted with
Et2O and washed with brine. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The residue was
used for the next reaction without further purification.
To a mixture of the crude cyanohydrin and CSA (178 mg,
0.77 mmol) in CH2Cl2 (20 mL) was added dropwise ethyl
vinyl ether (8.80 mL, 92.1 mmol) at 0 °C under an argon
atmosphere. After being stirred at the same temperature for 1 h,
the reaction mixture was poured into ice-cooled saturated
aqueous NaHCO3 and the aqueous layer was extracted with
Et2O. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography (Silica, 10% Et2O in hexane)
to give the protected cyanohydrin 8 (9.0 g, 3 steps 95%) as a
yellow oil.
Three-Component Coupling of Protected Cyanohydrin
Ether 8 with 2-Methyl-2-cyclohexenone (7) and Formalde-
hyde. To a solution of i-Pr2NH (0.98 mL, 7.5 mmol) in dry
THF (40 mL) was added n-BuLi (4.50 mL, 1.65 M in hexane,
7.40 mmol) at 0 °C under argon. After being stirred at 0 °C for

946
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
Synthesis of the ABC Ring System of Taxanes
1 h, to the mixture was added dropwise a solution of the
protected cyanohydrin 8 (1.31 g, 5.00 mmol, azeotropically
dried with toluene) in dry THF (10 mL) at ¹78 °C over 30 min.
After being stirred at ¹78 °C for 2 h, a solution of 2-methyl-2-
cyclohexenone (7) (500 mg, 4.50 mmol) in dry THF (10 mL)
was added dropwise to the reaction mixture at ¹78 °C over
10 min. After stirring at ¹78 °C for 30 min, formaldehyde
(50 mL, ca. 0.1 M in THF, 5.0 mmol)23 was added to the
reaction mixture at ¹78 °C. Then the mixture was poured into
ice-cooled saturated aqueous NH4Cl and the aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography
(Silica, 70% EtOAc in hexane) to give the coupling product 6
(1.65 g, 90%) as a colorless oil.
1H NMR (270 MHz, CDCl3): ¤ 7.58-7.27 (m, 5H), 6.71 (d,
J = 6.3 Hz, 1H), 5.90 (d, J = 6.3 Hz, 1H), 5.54 (s, 1H), 5.24 (d,
J = 1.3 Hz, 1H), 5.22 (s, 1H), 3.87 (d, J = 10.9 Hz, 1H), 3.65
(d, J = 10.9 Hz, 1H), 3.61 (dd, J = 4.6, 10.9 Hz, 1H), 2.92 (dd,
J = 3.3, 12.2 Hz, 1H), 2.00 (d, J = 1.3 Hz, 3H), 2.00-1.20 (m,
6H), 1.44 (s, 3H), 1.38 (s, 6H), 1.26 (s, 3H). 13C NMR
(67.8 MHz, CDCl3): ¤ 201.7, 155.2, 146.6, 140.2, 138.4, 131.2,
128.9, 128.3, 126.2, 120.0, 111.6, 102.6, 84.3, 78.9, 48.8, 41.1,
37.7, 31.5, 26.3, 26.0, 23.8, 23.1, 20.2, 11.8. IR (neat): 3020,
¹1
2949, 2862, 1655, 1560 cm
.
Alcohol 14. To a mixture of diol 12 (624 mg, 2.05 mmol)
and imidazole (600 mg, 8.81 mmol) in dry CH2Cl2 (20 mL) was
added TBSCl (620 mg, 4.11 mmol) at 0 °C under an argon
atmosphere. After being stirred at room temperature for 3 h, the
reaction mixture was poured into saturated aqueous NaHCO3
and the aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4,
concentrated in vacuo and passed through a short pad of silica
gel (5% EtOAc in hexane). After removal of the solvent, the
residue was used for the next reaction without further
purification. To a solution of alcohol and i-Pr2NEt (3.0 mL,
17.7 mmol) in dry CH2Cl2 (20 mL) was added BOMCl (1.2 mL,
8.7 mmol) at room temperature under an argon atmosphere.
After being stirred at 40 °C for 17 h, the reaction was quenched
by addition of MeOH (1.40 mL, 34.5 mmol). The mixture was
poured into ice-cooled saturated aqueous NaHCO3, and the
aqueous layer was extracted with hexane. The combined
organic layers were washed with brine, dried over Na2SO4,
concentrated in vacuo and passed through a short pad of silica
gel (3% EtOAc in hexane). The residue was used for the next
reaction without further purification.
Trienone 12.
To a solution of the ketone 6 (1.65 g,
4.10 mmol) in MeOH (20 mL) was added NaBH4 (500 mg,
12.5 mmol) at 0 °C under argon. After being stirred at room
temperature for 1 h, the reaction mixture was poured into
aqueous 1 M HCl solution and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with
saturated aqueous NaHCO3 and brine, dried over MgSO4 and
concentrated in vacuo. The residue was used for the next
reaction without further purification.
To a solution of the crude protected cyanohydrin in MeOH
(30 mL) and H2O (10 mL) was added a catalytic amount of
copper(II) sulfate. After being stirred at 40-50 °C for 2 h, the
reaction mixture was poured into brine and the aqueous layer
was extracted with EtOAc. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The residue was
used for the next reaction without further purification.
To a solution of the crude cyanohydrin in Et2O (10 mL) was
added 0.5 M NaOH aqueous solution at 0 °C. After being
stirred at room temperature for 30 min, the mixture was poured
into brine and the aqueous layer was extracted with EtOAc.
The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash
chromatography (Silica, 70% EtOAc in hexane) to give the
To a solution of the TBS ether in dry THF (30 mL) was
added TBAF¢nH2O (4.2 g, 16.1 mmol) at 0 °C under an argon
atmosphere. After being stirred at room temperature for 22 h,
the reaction mixture was poured into saturated aqueous
NaHCO3. The aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by flash chromatography (Silica, 20% EtOAc in hexane) to
1
trienone 12 (760 mg, 3 steps 61%) as a yellow oil. H NMR
1
(270 MHz, CDCl3): ¤ 6.83 (d, J = 6.3 Hz, 1H), 5.88 (d,
J = 6.3 Hz, 1H), 5.23 (s, 1H), 5.20 (s, 1H), 3.65 (dd, J = 3.6,
10.2 Hz, 1H), 3.57 (d, J = 10.9 Hz, 1H), 3.36 (d, J = 10.9 Hz,
1H), 3.04 (dd, J = 3.6, 11.2 Hz, 1H), 1.97 (s, 3H), 1.80-1.20
(m, 6H), 1.42 (s, 3H), 1.36 (s, 3H), 0.97 (s, 3H). 13C NMR
(67.8 MHz, CDCl3): ¤ 203.6, 155.6, 146.8, 140.1, 131.6, 120.4,
111.4, 74.9, 69.6, 47.2, 44.0, 43.0, 41.0, 30.1, 29.9, 28.2, 25.0,
24.8, 23.6, 22.6, 20.3. IR (neat): 3384, 2928, 2862, 1711, 1648,
1558, 1444, 1379, 1237, 1129, 1053 cm¹1. HRMS (ESI-TOF):
calcd for [C19H29O3 + H]+ 305.2111, found: 305.2110.
give the alcohol 14 (408 mg, 47%) as a yellow oil. H NMR
(270 MHz, CDCl3): ¤ 7.36-7.29 (m, 5H), 7.03 (d, J = 6.4 Hz,
1H), 5.91 (d, J = 6.4 Hz, 1H), 5.23 (d, J = 1.7 Hz, 1H), 5.20
(brs, 1H), 4.78 (dd, J = 6.8, 15.3 Hz, 2H), 4.70 (d, J = 12.1 Hz,
1H), 4.58 (d, J = 12.1 Hz, 1H), 3.62 (dd, J = 4.0, 11.9 Hz, 1H),
3.61 (d, J = 11.9 Hz, 1H), 3.20 (d, J = 11.9 Hz, 1H), 3.27-3.15
(m, 1H), 1.97 (s, 3H), 1.57 (s, 3H), 1.44 (s, 3H), 1.81-1.20 (m,
6H), 0.90 (s, 3H). 13C NMR (67.8 MHz, CDCl3): ¤ 203.4,
155.8, 146.9, 139.6, 137.4, 132.0, 128.7, 128.0, 127.9, 120.8,
111.1, 94.2, 78.8, 70.4, 65.6, 46.7, 43.6, 40.9, 35.5, 29.3, 29.1,
Benzylidene Acetal 13. To a mixture of diol 12 (750 mg,
2.46 mmol) and a catalytic amount of CSA in CH2Cl2 (10 mL)
was added benzaldehyde dimethylacetal (0.44 mL, 3.0 mmol) at
0 °C under argon. After being stirred at room temperature for
24 h, the mixture was poured into saturated aqueous NaHCO3
and the aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash
chromatography (Silica, 5% EtOAc in hexane) to give the
benzylidene acetal 13 (500 mg, 52%) as a colorless oil.
26.8, 25.2, 23.7, 20.3, 11.1. IR (neat): 3510, 3033, 2941, 1652,
¹1
1563, 1497, 1471, 1455 cm
.
Allylic Alcohol 15¢. To a solution of ketone 13 (52.5 mg,
0.134 mmol) in dry Et2O (3.0 mL) was added LiAlH4 (10.2 mg,
0.270 mmol) at 0 °C under an argon atmosphere. After being
stirred at room temperature for 30 min, the reaction was
quenched by slow addition of a saturated aqueous solution
of Na2SO4. The organic layer was dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash
chromatography (Silica, 10% EtOAc in hexane) to give the

T. Serizawa et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
947
allylic alcohol 15¢ (33.8 mg, 64%) as a colorless oil. 1H NMR
(270 MHz, CDCl3): ¤ 7.60-7.30 (m, 5H), 6.01 (d, J = 6.3 Hz,
1H), 5.81 (d, J = 6.3 Hz, 1H), 5.58 (s, 1H), 5.18 (s, 1H), 5.15
(d, J = 1.7 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.20 (d, J = 9.9
Hz, 1H), 3.77 (d, J = 11.6 Hz, 1H), 3.61 (dd, J = 4.3, 10.9 Hz,
1H), 1.92 (s, 3H), 1.80-1.20 (m, 7H), 1.34 (s, 3H), 1.29 (s, 3H),
1.15 (s, 3H). 13C NMR (67.8 MHz, CDCl3): ¤ 155.0, 150.1,
139.0, 132.3, 128.9, 128.4, 126.4, 121.1, 119.0, 110.0, 102.3,
11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 3.64 (s, 2H), 3.56 (dd,
J = 3.5, 8.7 Hz, 1H), 1.94 (s, 3H), 1.80-1.20 (m, 7H), 1.21
(s, 3H), 1.19 (s, 3H), 1.07 (s, 3H), 0.91 (s, 9H), 0.06 (s, 6H).
13C NMR (67.8 MHz, CDCl3): ¤ 156.6, 149.4, 138.0, 131.2,
128.5, 127.9, 127.7, 121.7, 119.8, 108.5, 95.5, 80.0, 70.5, 70.0,
69.7, 66.4, 44.1, 41.6, 40.7, 29.3, 27.8, 27.5, 26.3, 26.2, 26.1,
25.7, 22.0, 20.0, 19.0, 18.4, ¹5.31, ¹5.34. IR (neat): 3460,
¹1
3032, 2930, 1584, 1498, 1472, 1387, 1255, 1149 cm
.
84.7, 80.0, 47.3, 40.6, 38.6, 30.2, 27.0, 26.9, 25.6, 23.7, 19.8,
Epoxide 19. To a mixture of allylic alcohol 18 (101 mg,
0.190 mmol) and TBHP (0.12 mL, 5 M in decane, 0.60 mmol)
in dry benzene (3.0 mL) was added vanadyl acetoacetonate
(3.1 mg, 9.0 ¯mol) at 0 °C under an argon atmosphere. After
being stirred at the same temperature for 2 h, the reaction
mixture was poured into ice-cooled saturated aqueous NaHCO3
and 10% aqueous Na2S2O3 and the aqueous layer was extracted
with Et2O. The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography (Silica, 5%
EtOAc in hexane) to give the epoxide 19 (97 mg, 93%) as a
colorless oil. 1H NMR (270 MHz, CDCl3): ¤ 7.40-7.20 (m,
5H), 5.82 (brs, 1H), 5.08 (d, J = 1.7 Hz, 1H), 5.03 (brs, 1H),
4.85 (d, J = 6.9 Hz, 1H), 4.81 (d, J = 6.9 Hz, 1H), 4.74 (d,
J = 11.9 Hz, 1H), 4.45 (d, J = 11.9 Hz, 1H), 4.43 (brs, 1H),
3.71 (d, J = 9.9 Hz, 1H), 3.60 (d, J = 9.9 Hz, 1H), 3.53 (dd,
J = 4.3, 11.7 Hz, 1H), 3.48 (d, J = 4.3 Hz, 1H), 2.10-1.20
(m, 7H), 1.88 (s, 3H), 1.55 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H),
0.92 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (67.8 MHz,
CDCl3): ¤ 153.3, 139.9, 138.2, 128.5, 127.9, 119.5, 108.8,
95.5, 81.0, 69.4, 67.4, 66.7, 64.1, 53.8, 46.3, 44.4, 40.8, 39.1,
31.1, 28.6, 26.8, 26.4, 21.9, 21.0, 20.5, 18.4, 14.2, 12.4, 11.6,
¹1
11.6. IR (neat): 3481, 2942, 2861, 1584, 1456 cm
.
Diol 16¡. To a solution of ketone 14 (500 mg, 1.18 mmol)
in dry Et2O (2.0 mL) was added LiAlH4 (100 mL, ca. 0.1 M in
Et2O, 10 mmol) at ¹78 °C under an argon atmosphere. After
being stirred at the same temperature for 5 h, the reaction was
quenched by slow addition of 1 M NaOH aqueous solution.
The mixture was diluted with saturated aqueous potassium
sodium tartrate and EtOAc. After being stirred at room
temperature for 1 h, the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The residue was
used for the next reaction without further purification. 1H NMR
(270 MHz, CDCl3): ¤ 7.36-7.29 (m, 5H), 6.02 (d, J = 6.1 Hz,
1H), 5.83 (d, J = 6.1 Hz, 1H), 5.13 (d, J = 1.7 Hz, 1H), 5.11 (s,
1H), 4.81 (d, J = 6.6 Hz, 1H), 4.80-4.75 (brs, 1H), 4.75 (d,
J = 6.6 Hz, 1H), 4.72 (d, J = 12.1 Hz, 1H), 4.60 (d, J = 12.1
Hz, 1H), 3.76 (d, J = 11.7 Hz, 1H), 3.70 (d, J = 11.7 Hz, 1H),
3.56 (dd, J = 3.8, 11.4 Hz, 1H), 1.93 (s, 3H), 1.26 (s, 3H), 1.21
(s, 3H), 1.80-1.20 (m, 7H), 0.96 (s, 3H). 13C NMR (67.8 MHz,
CDCl3): ¤ 156.3, 150.5, 137.5, 131.6, 128.7, 128.0, 127.9,
121.4, 119.4, 109.0, 94.1, 80.1, 70.5, 69.1, 65.0, 44.0, 42.0,
40.6, 28.4, 27.6, 27.0, 23.4, 20.0, 18.2, 12.5. IR (neat): 3469,
¹5.2, ¹5.4. IR (neat): 3509, 3033, 2930, 1679, 1648, 1472,
1389, 1362, 1254 cm .
¹1
¹1
2941, 2872, 1596, 1454, 1383 cm
.
Tricyclic Ether 17¡. The alcohol 16¡ (1.0 mg, 2.3 ¯mol)
was dissolved in CDCl3 (3 mL, pH ca. 4.0). After 30 min,
formation of ether 17¡ was observed by NMR. 1H NMR
(270 MHz, CDCl3): ¤ 7.35-7.25 (m, 5H), 6.00 (d, J = 9.9 Hz,
1H), 5.90 (d, J = 9.9 Hz, 1H), 4.78 (d, J = 6.9 Hz, 1H), 4.63 (d,
J = 6.9 Hz, 1H), 4.58 (dd, J = 11.9, 15.8 Hz, 2H), 3.83 (d, J =
10.9 Hz, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.54 (d, J = 11.4 Hz,
1H), 3.32 (dd, J = 4.13, 11.4 Hz, 1H), 1.71 (s, 3H), 1.70 (s,
3H), 1.16 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H), 1.83-0.80 (m, 7H).
13C NMR (67.8 MHz, CDCl3): ¤ 138.7, 137.9, 132.5, 128.5,
127.9, 127.7, 123.4, 120.0, 92.8, 80.4, 79.9, 70.4, 69.7,
69.5, 44.3, 42.9, 40.8, 29.8, 26.4, 23.7, 21.5, 20.7, 20.1, 18.1,
Diol 20. To a solution of epoxide 19 (202 mg, 0.360 mmol,
azeotropically dried with toluene) in dry Et2O (1.0 mL) was
added LiAlH4 (16 mL, 0.1 M in Et2O, 1.6 mmol) at ¹78 °C
under an argon atmosphere. After being stirred at 0 °C for 1.5 h,
the reaction was quenched by addition of 1 M NaOH aqueous
solution. The mixture was diluted with saturated aqueous
potassium sodium tartrate and chloroform. The mixture was
stirred at room temperature for 2 h and the aqueous layer was
extracted with chloroform. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue (270 mg) was purified by flash chromatog-
raphy to give the diol 20 (58.7 mg, 50%) as a white solid.
1H NMR (270 MHz, CDCl3): ¤ 7.40-7.20 (m, 5H), 5.48 (brs,
1H), 5.13 (s, 1H), 5.11 (s, 1H), 4.88 (d, J = 6.9 Hz, 1H), 4.78
(d, J = 6.9 Hz, 1H), 4.69 (d, J = 11.9 Hz, 1H), 4.52 (d, J =
11.6 Hz, 1H), 3.91 (d, J = 5.9 Hz, 1H), 3.60-3.50 (m, 3H),
2.40-1.40 (m, 9H), 1.84 (s, 3H), 1.16 (s, 3H), 1.08 (s, 3H), 0.92
(s, 3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR
(67.8 MHz, CDCl3): ¤ 156.2, 137.9, 132.3, 128.5, 128.5,
127.9, 127.8, 127.7, 127.6, 123.1, 110.0, 95.1, 79.9, 69.7,
69.4, 68.9, 65.9, 45.1, 43.5, 39.3, 34.3, 31.7, 26.1, 22.7, 20.8,
20.3, 18.3, 14.2, ¹5.3, ¹5.5. IR (neat): 3509, 2954, 2930,
13.4, 11.1. IR (neat): 3557, 3032, 2933, 2863, 1740, 1596,
¹1
1497 cm
.
TBS Ether 18.
To a mixture of diol 16¡ (172 mg,
0.403 mmol) and imidazole (165 mg, 2.42 mmol) in dry CH2Cl2
(6 mL) was added TBSCl (182 mg, 1.21 mmol) at 0 °C under an
argon atmosphere. After being stirred at room temperature for
2 h, the reaction mixture was poured into saturated aqueous
NaHCO3 and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography (Silica, 7% EtOAc in hexane) to give the
TBS ether 18 (218 mg, quant) as a colorless oil. 1H NMR
(270 MHz, CDCl3): ¤ 7.36-7.28 (m, 5H), 6.06 (d, J = 5.9 Hz,
1H), 5.85 (d, J = 5.9 Hz, 1H), 5.10 (s, 2H), 4.81 (brs, 1H), 4.87
(d, J = 6.9 Hz, 1H), 4.81 (d, J = 6.9 Hz, 1H), 4.71 (d, J =
2883, 2858, 1679, 1610, 1472, 1388, 1362, 1254, 1149,
¹1
1107 cm
.
Dimethyl Ether 21. To a suspension of sodium hydride
(101 mg, 55% dispersion in mineral oil, 4.20 mmol), washed
with dry hexane (5 mL © 3 times) in dry THF (0.5 mL), was

948
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
Synthesis of the ABC Ring System of Taxanes
added dropwise a solution of the diol 20 (58.7 mg, 0.110 mmol)
in dry THF (3.0 mL) at 0 °C under an argon atmosphere. After
being stirred for 30 min, methyl iodide (0.69 mL, 1.1 mmol)
was added to the mixture at 0 °C. After being stirred at room
temperature for 7 h, the reaction was quenched by addition of
MeOH. The mixture was poured into saturated aqueous NH4Cl
and the aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash
chromatography to give the dimethyl ether 21 (50.8 mg, 79%)
3H), 0.85 (s, 3H). 13C NMR (67.8 MHz, CDCl3): ¤ 153.7,
144.8, 138.1, 133.3, 132.1, 129.8, 128.5, 128.4, 128.2, 127.8,
127.7, 107.3, 95.2, 85.2, 83.5, 80.5, 72.0, 69.5, 61.0, 53.3,
44.2, 43.5, 42.7, 28.6, 26.8, 23.7, 23.1, 21.7, 20.2, 11.1. IR
(neat): 2935, 2829, 1739, 1658, 1600, 1496, 1464, 1455, 1367,
1242, 1149, 1100, 1044 cm¹1. HRMS (ESI-TOF): calcd for
[C36H50O7S + Na]+ 649.3169, found: 649.3167.
Epoxide 24.
To a solution of diene 23 (68.0 mg,
0.106 mmol) in dry CH2Cl2 (2.0 mL) was added dimethyldiox-
irane (1.5 mL, ca. 0.1 M in acetone, 0.15 mmol) at 0 °C under
an argon atmosphere. After being stirred at the same temper-
ature for 3 h, the reaction mixture was poured into saturated
aqueous NaHCO3 and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with
saturated aqueous Na2S2O3 and brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by flash
chromatography to give the epoxide 24 (50 mg, 72%) as a
colorless oil.
Enal 25. To a solution of the epoxide 24 (50 mg, 78 ¯mol)
in dry benzene (2.0 mL) was added a catalytic amount of p-
TsOH at 0 °C under an argon atmosphere. After being stirred at
the same temperature for 13 h, the mixture was poured into ice-
cooled saturated aqueous NaHCO3 and the aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, and concentration in
vacuo. The residue was purified by flash chromatography to
give the enal 25 (15 mg, 30%) as a colorless oil. 1H NMR
(270 MHz, CDCl3): ¤ 10.1 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H),
7.40-7.20 (m, 7H), 4.63 (d, J = 12.2 Hz, 1H), 4.46 (brs, 2H),
4.40 (d, J = 12.2 Hz, 1H), 4.17 (d, J = 9.9 Hz, 1H), 3.95 (d,
J = 9.9 Hz, 1H), 3.56 (brs, 1H), 3.41 (s, 3H), 3.36 (s, 3H),
3.40-3.30 (m, 1H), 2.41 (s, 3H), 2.40-2.10 (m, 2H), 2.06 (s,
3H), 1.90-1.10 (m, 9H), 1.30 (s, 3H), 1.26 (s, 3H), 1.09 (s, 3H).
13C NMR (67.8 MHz, CDCl3): ¤ 193.0, 151.7, 145.1, 139.9,
138.1, 133.0, 129.9, 128.5, 128.2, 127.8, 127.7, 95.3, 83.0,
81.5, 80.3, 71.7, 69.5, 59.9, 53.0, 43.8, 42.6, 42.5, 33.0, 28.7,
1
as a colorless oil. H NMR (270 MHz, CDCl3): ¤ 7.40-7.20
(m, 5H), 5.52 (brs, 1H), 5.01 (s, 1H), 4.93 (s, 1H), 4.81 (d,
J = 6.9 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 4.67 (d, J = 11.9 Hz,
1H), 4.52 (d, J = 11.9 Hz, 1H), 3.89 (brs, 1H), 3.65 (d, J =
10.2 Hz, 1H), 3.48 (d, J = 10.2 Hz, 1H), 3.43 (s, 3H), 3.39 (s,
3H), 3.20-3.10 (m, 1H), 2.70-2.40 (m, 2H), 2.00-1.20 (m, 7H),
1.83 (s, 3H), 1.24 (s, 3H), 1.08 (s, 3H), 0.92 (s, 9H), 0.89 (s,
3H), 0.07 (s, 3H), 0.04 (s, 3H). 13C NMR (67.8 MHz, CDCl3): ¤
154.8, 138.2, 132.0, 127.8, 124.3, 106.5, 94.6, 85.2, 83.4, 81.0,
69.6, 67.2, 60.6, 53.2, 44.4, 44.2, 31.7, 28.3, 26.3, 24.2, 23.3,
22.7, 18.5, 14.2, 10.9, ¹5.1, ¹5.4. IR (neat): 2931, 1605, 1472,
¹1
1377, 1255, 1102 cm
.
Alcohol 22. To a solution of the TBS ether 21 (24.8 mg,
40.0 ¯mol) in THF (1.0 mL) was added TBAF¢nH2O (110 mg,
0.400 mmol) at room temperature under an argon atmosphere.
After being stirred at 50 °C for 10 h, the reaction mixture was
poured into saturated aqueous NaHCO3 and the aqueous layer
was extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash chromatography to
give the alcohol 22 (17.4 mg, 87%) as a colorless oil. 1H NMR
(270 MHz, CDCl3): ¤ 7.40-7.20 (m, 5H), 5.59 (brs, 1H), 5.04
(brs, 1H), 4.95 (brs, 1H), 4.82 (d, J = 6.6 Hz, 1H), 4.78 (d,
J = 6.6 Hz, 1H), 4.63 (s, 2H), 3.65-3.25 (m, 3H), 3.40 (s, 3H),
3.38 (s, 3H), 3.24 (brs, 1H), 2.80-2.60 (m, 1H), 2.50-2.30 (m,
1H), 2.10-1.40 (m, 7H), 1.84 (d, J = 1.3 Hz, 3H), 1.21 (s, 3H),
1.13 (s, 3H), 0.80 (s, 3H). 13C NMR (67.8 MHz, CDCl3): ¤
154.9, 137.9, 132.2, 128.5, 128.0, 127.8, 124.1, 106.8, 94.0,
85.2, 83.6, 79.8, 69.9, 65.4, 61.0, 53.2, 44.3, 43.8, 40.6, 31.7,
24.5, 23.5, 22.7, 22.1, 21.7, 19.2, 11.1. IR (neat): 2927, 1672,
¹1
1599, 1455, 1364, 1177 cm
.
Protected Cyanohydrin 4. To enal 25 (15 mg, 20 ¯mol)
was added TMSCN (0.50 mL, 4.9 mmol) and a catalytic
amount of KCN-DC-18-crown-6 complex at 0 °C under an
argon atmosphere. The mixture was stirred at the same
temperature for 30 min. The reaction mixture was diluted with
THF (2.0 mL), and then 1 M HCl was added at 0 °C (Caution:
HCN is generated). After being stirred at the same temperature
for 30 min, the reaction mixture was diluted with Et2O and
washed with brine. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The residue was used
for the next reaction without further purification.
To a mixture of cyanohydrin and a catalytic amount of CSA
in dry CH2Cl2 (2.0 mL) was added ethyl vinyl ether (0.1 mL,
1.0 mmol) at 0 °C under an argon atmosphere. After being
stirred at the same temperature for 1 h, the reaction mixture was
poured into ice-cooled saturated aqueous NaHCO3 and the
aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash
chromatography (Silica, 25% Et2O in hexane) to give the
protected cyanohydrin 4 (13 mg, 3 steps 83%) as a yellow oil.
27.0, 23.9, 23.3, 22.7, 20.3, 14.2, 11.3. IR (neat): 3494, 2942,
¹1
2828, 2244, 1605, 1471, 1455, 1380 cm
Tosylate 23.
.
To a mixture of alcohol 22 (17.4 mg,
37.0 ¯mol) and DMAP (460 mg, 3.75 mmol) in dry chloroform
(filtrated through alumina, 1.0 mL) was added TsCl (373 mg,
1.95 mmol) at room temperature under an argon atmosphere.
The reaction mixture was heated to reflux. After being stirred
under reflux for 12 h, the reaction mixture was poured into
saturated aqueous NaHCO3 and the aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash chromatography to
1
give the tosylate 23 (35.3 mg, 96%) as a yellow oil. H NMR
(270 MHz, CDCl3): ¤ 7.79 (d, J = 8.3 Hz, 2H), 7.40-7.20 (m,
7H), 5.45 (brs, 1H), 4.92 (s, 1H), 4.88 (s, 1H), 4.62 (d,
J = 11.9 Hz, 1H), 4.53 (d, J = 6.9 Hz, 1H), 4.50 (d, J = 6.9 Hz,
1H), 4.40 (d, J = 11.9 Hz, 1H), 4.12 (d, J = 9.9 Hz, 1H), 3.94
(d, J = 9.9 Hz, 1H), 3.39 (brs, 1H), 3.37 (s, 6H), 3.22 (dd,
J = 11.6, 4.3 Hz, 1H), 2.60-2.40 (m, 2H), 2.41 (s, 3H), 2.10-
1.20 (m, 7H), 1.80 (d, J = 1.0 Hz, 3H), 1.10 (s, 3H), 1.02 (s,

T. Serizawa et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 8 (2010)
949
MS (ESI-TOF): calcd for [C41H59O9SN + NH4]+ 759.4, found:
2
R. A. Holton, C. Somoza, H. B. Kim, F. Liang, R. J.
Biediger, P. D. Boatman, M. Shindo, C. C. Smith, S. C. Kim, H.
Nadizadeh, Y. Suzuki, C. L. Tao, P. Vu, S. H. Tang, P. S. Zhang,
K. K. Murthi, L. N. Gentile, J. H. Liu, J. Am. Chem. Soc. 1994,
116, 1597.
759.4.
ABC Ring 3.
To a solution of (TMS)2NH (0.6 mL,
2.90 mmol) in dry dioxane (2.0 mL) was added n-BuLi
(1.80 mL, 1.57 M in hexane, 2.80 mmol) at 0 °C and stirred at
room temperature for 30 min under an argon atmosphere. A
solution of the protected cyanohydrin 4 (45 mg, 60 ¯mol,
azeotropically dried with toluene) in dry dioxane (3.0 mL) was
added dropwise to the lithiated mixture under reflux over 2 h.
After being stirred under reflux for 5 h, the reaction mixture
was poured into ice-cooled saturated aqueous NH4Cl and the
aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine and dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash
chromatography to give the cyclized product (15 mg, 27 ¯mol,
43%) as a brown oil.
To a solution of the protected cyanohydrin (15 mg,
0.027 mmol) in MeOH (2.0 mL) was added a catalytic amount
of CSA. After being stirred at 0 °C for 4 h, the reaction mixture
was poured into brine and the aqueous layer was extracted with
Et2O. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was used for the next
reaction without further purification.
3
K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G.
Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud, E. A.
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5
6
Floreancig, T. E. Glass, J. B. Houze, N. E. Krauss, D. S. Lee,
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K. Morihira, R. Hara, S. Kawahara, T. Nishimori, N.
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8
T. Takahashi, H. Iwamoto, K. Nagashima, T. Okabe, T. Doi,
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K. Nakai, M. Kamoshita, T. Doi, H. Yamada, T. Takahashi,
9
Tetrahedron Lett. 2001, 42, 7855.
To a solution of the crude cyanohydrin in Et2O (2.0 mL) was
added 0.5 M NaOH aqueous solution (1.0 mL) at 0 °C. After
being stirred at room temperature for 3 h, the mixture was
poured into brine and the aqueous layer was extracted with
Et2O. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography to give the ABC ring 3 (5.5 mg, 2 steps 42%)
as a colorless oil. 1H NMR (270 MHz, CDCl3): ¤ 7.40-7.20 (m,
5H), 4.88 (d, J = 6.9 Hz, 1H), 4.81 (d, J = 6.9 Hz, 1H), 4.70 (d,
J = 11.9 Hz, 1H), 4.63 (d, J = 11.9 Hz, 1H), 3.51 (s, 3H), 3.43
(s, 3H), 3.38 (d, J = 4.6 Hz, 1H), 3.06 (dd, J = 11.2, 4.6 Hz,
1H), 2.90 (d, J = 11.4 Hz, 1H), 2.80-2.60 (m, 1H), 2.49 (d,
J = 11.4 Hz, 1H), 2.10-0.80 (m, 10H), 1.70 (s, 3H), 1.26 (s,
3H), 1.08 (s, 3H), 0.93 (s, 3H). 13C NMR (67.8 MHz, CDCl3):
¤ 204.2, 147.3, 138.3, 137.6, 128.4, 128.0, 127.6, 95.0, 85.4,
83.6, 81.6, 69.8, 60.5, 53.9, 50.4, 45.5, 43.6, 40.6, 32.1, 29.8,
28.6, 27.5, 24.6, 23.5, 23.4, 21.7, 19.9, 16.2. IR (neat): 2929,
1733, 1675, 1621, 1119, 1041 cm¹1. HRMS (ESI-TOF): calcd
for [C29H42O5 + Na]+ 493.2924, found: 493.2923.
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