Construction of the taxane skeleton via the stereoselective conjugate addition of cyanide and the intramolecular B-alkyl Suzuki-Miyaura coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2007.07.179

Construction of the taxane skeleton via the stereoselective conjugate addition of cyanide and the intramolecular B-alkyl Suzuki-Miyaura coupling reaction is described. A conjugate addition of cyanide to enone 17 proceeded diastereoselectively to provide t

Full text of DOI:10.1016/j.tetlet.2007.07.179

Tetrahedron Letters 48 (2007) 6868–6872
Construction of the taxane skeleton via the stereoselective
conjugate addition of cyanide and the intramolecular
B-alkyl Suzuki–Miyaura coupling reaction
Masayuki Utsugi, Yasuaki Kamada, Hidetoshi Miyamoto and Masahisa Nakada*
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
Received 9 July 2007; revised 25 July 2007; accepted 26 July 2007
Available online 31 July 2007
Abstract—Construction of the taxane skeleton via the stereoselective conjugate addition of cyanide and the intramolecular B-alkyl
Suzuki–Miyaura coupling reaction is described. A conjugate addition of cyanide to enone 17 proceeded diastereoselectively to pro-
vide the desired 18 incorporating the correct C3 stereogenic center in the taxol C-ring. The intramolecular B-alkyl Suzuki–Miyaura
coupling reaction of 22, which was derived from 18, successfully furnished the taxol B-ring in 81% yield.
Ó 2007 Elsevier Ltd. All rights reserved.
Since its discovery, taxol (Fig. 1) has been a fascinating
and synthetically challenging target because of its
complex structure and clinically important anticancer
activity.1–7 We have reported asymmetric synthesis of
a taxol model 4 (Scheme 1) via the intramolecular B-
alkyl Suzuki–Miyaura coupling reaction of 3,8 which
was prepared from the enantiopure fragments, 1 and
2. Although compound 4 incorporates a taxane skele-
ton, stereoselective introduction of a hydrogen to the
C3 position from its concave a-side is necessary to com-
plete the total synthesis of taxol. However, construction
of the C3 tertiary stereogenic center with C3a-H in 4 was
surmised to be difficult because of the cage-like structure
of 4.
group in 5 would be axial in the transition state from
model A, providing enolate C. Then, the axial proton-
ation of enolate C would occur because the large
RCO– group could hardly be axial, affording the desired
product 6 as the major diastereomer. Another possible
axial attack of cyanide (model B, Fig. 2) would lead to
the more energetically unfavored transition state as
mentioned above, resulting in the formation of enolate
D, which would afford the undesired product.
Consequently, we undertook to examine the conjugate
addition of cyanide to enone 17 possessing the A-ring
moiety of taxol.
OBn
I
I
OBn
We report herein a method for constructing the C3 ste-
reogenic center of the taxol C-ring via the stereoselective
conjugate addition of cyanide to enone 17, which was
composed of the A- and C-rings of taxol.9
+
Li
MOMO
MOMO
OBn
O
3
1
2
We expected that a conjugate addition of cyanide to
enone 5 (Scheme 2) would provide stereoselectively the
desired product 6 because the transition state derived
from model B (Fig. 2) would be energetically unfavored
due to the three axial substituents (–CN, –OBn, and
–CH@CH2) existing in the transition state. The methyl
OBn
1) 9-BBN, THF
reflux, 3 h
2) Pd(PPh3)4 (30 mol%)
NaOH (4.0 equiv)
CH3CN/H2O (10:1)
3
MOMO
OBn
reflux, 72 h, 85%
4
*
Scheme 1. Preparation of 4 via the intramolecular B-alkyl Suzuki–
Miyaura coupling reaction.8
Corresponding author. Tel./fax: +813 5286 3240; e-mail: mnakada@
waseda.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.179

M. Utsugi et al. / Tetrahedron Letters 48 (2007) 6868–6872
6869
AcO
HO
O
OH
1) t-BuLi, THF
OH
O
Si
-78 oC, 5 min
I
2) H2O2, KHCO3
KF, THF/MeOH
1/1, rt, 10 h
O
O
HO
H
O
OH
OAc
OBz
O
8
7
OH
BzHN
O
1) TMSOTf, DIPEA
CH2Cl2, -20 oC, 2 h
Ph
1) cat. CSA, acetone
rt, 1 h
Taxol
Figure 1. Structure of taxol.
2) Dess-Martin
Periodinane
CH2Cl2, rt, 2 h
2) MeLi, THF, rt, 30 min;
MeI, 0 oC to rt, 9 h
O
O
9
85% (4 steps)
O
OBn
OBn
CN
I
1) H2NNH2, Et3N
EtOH, 110 oC, 5 d
R
1,4-addition
axial attack
R
R
O
O
CN
2) I2, DBU, Et2O
0 oC to rt, 20 min;
benzene, reflux, 2 h
5
O
O
O
O
OBn
10
80% (4 steps)
11
H
diastereoselective
protonation
I
PhCH(OMe)2
cat. CSA
H
PTSA
O
CN
6
MeOH/H2O 5/1
reflux, 12 h
CH2Cl2, rt, 1 h
100%
HO
Scheme 2. Construction of the C3 stereogenic center via the stereo-
selective axial conjugate addition of cyanide to 5.
OH
94%
12
I
1) DIBAL-H
CH2Cl2, rt, 4 h
I
CN
2) Dess-Martin
Periodinane
axial attack
BnO
CHO
O
BnO
14
O
CH2Cl2, rt, 2 h
H3C
H
H3C
91% (2 steps)
Ph 13
R
BnO
R
O
O
Scheme 3. Preparation of 14 from 7.
H
A
B
CN
axial attack
OBn
n
-BuLi, THF, -78 oC, 15 min;
H3C
O
BnO
R
H
OBn
CN
H
14, THF, 1 h
99%
I
H3C
H
15
R
CN
O
OBn
OBn
I
I
6
C
D
IBX, DMSO
Figure 2. Expected diastereoselective formation of 6 via model A.
70 oC, 4 h
97%
BnO
BnO
OH
16
Single detectable isomer
O
17
To prepare enone 17 (Scheme 4), fragments 14 and 15
were required. Since 15 is a known compound,8 prepara-
tion of 14 was started for the preparation of enone 17
(Scheme 3). The silicon-tethered intramolecular alkyl-
ation of 7,10,11 followed by Tamao oxidation,12 aceto-
nide formation, and Dess–Martin oxidation afforded
ketone 9. Mono-methylation of 9 was troublesome; that
is, use of LDA and methyl iodide was unreproducible,
and use of methyl iodide and sodium hydride provided
10 with concomitant formation of the corresponding
a,a-dimethylated ketone. After surveying various condi-
tions, however, methylation of the lithium enolate
Scheme 4. Coupling reaction of 14 with 15.
generated from the silyl enol ether of 913 successfully
provided 10, which was converted to iodide 11 via a
hydrazone of 10.14 Acetonide in 11 was replaced by a
benzylidene acetal; that is, diol 12 generated by removal
of the acetonide in 11 under acidic conditions was then
treated with benzaldehyde dimethyl acetal to afford 13.
Finally, regioselective reduction of benzylidene acetal

6870
M. Utsugi et al. / Tetrahedron Letters 48 (2007) 6868–6872
Table 1. The conjugate addition of cyanide to enone 17
OBn
OBn
CN
I
I
Conditions
H
O
BnO
O
BnO
17
18
Entry
Reagents (equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
17
18
19
20
1
2
3
4
5
6
7
8
9
KCN (10), NH4Cl (7.5)
AlMe3 (4.0), TMSCN (8.0)
Et2AlCN (5.0)
DMF/H2O (2:1)
Hexane
Benzene
THF
DMF
DMF
DMF
DMF
DMSO
n-PrOH
Toluene
DMF
100
60
80
60
70
100
100
100
100
Reflux
100
100
24
24
24
12
72
48
72
24
24
24
24
24
100
100
100
100
10
0
20
0
22
0
0
0
0
0
0
0
3
6
0
6
0
0
0
6
0
0
0
0
7
4
0
5
0
0
0
4
Yb(CN)3 (1.0)
0
NCCO2Me (7.5), AcOK (5.0), TEA (5.0)
NCCO2Me (7.5), AcOK (5.0), TEA (5.0)
NCCO2Me (7.5), TEA (10.0)
57
71
23
65
45
0
NCCO2Me (7.5), AcOK (10.0)
NCCO2Me (7.5), AcOK (5.0), TEA (5.0)
NCCO2Me (7.5), AcOK (5.0), TEA (5.0)
NCCO2Me (7.5), AcOK (5.0), TEA (5.0)
KCN (7.5)
10
11
12
100
100
0
0
70
a Isolated yield.
13 and the subsequent Dess–Martin oxidation afforded
14.
The coupling reaction of 14 with 15 was successfully car-
ried out (Scheme 4). That is, the alkenyllithium gener-
ated in situ from 15 using n-BuLi was reacted with 14
to afford 16 as the single detectable diastereomer. This
selectivity would be well explained by the chelation con-
trol. IBX oxidation15 of 16 at 70 °C in DMSO success-
fully provided 17 with excellent yield (97%).
With enone 17 in hand, a conjugate addition of cyanide to
17 was examined (Table 1). Reaction of the in situ gener-
ated hydrogen cyanide16 with 17 gave no product (entry
1). Then we examined the reaction with various reagents,
but no reaction occurred by AlMe3 and TMSCN17 (entry
2), Et2AlCN18 (entry 3), and Yb(CN)319 (entry 4).
Figure 4. X-ray crystal structure of 18.
were the diastereomers of 18, as shown in Figures 3
and 5.
The conjugate addition carried out at 100 °C (entry 6)
shortened the reaction time to 48 h, improving the yield
to 71%. This result indicated that diastereoselectivity of
the conjugate addition was in a ratio of 77:4. The reac-
tions in the absence of AcOK (entry 7) or Et3N (entry 8)
decreased the yield and suggested that AcOK played an
important role in this reaction. Change of the solvent to
DMSO lowered the yield, too (entry 9). No reaction
Fortunately, reaction of 17 with methyl cyanoformate,
potassium acetate, and triethylamine in DMF at 70 °C
for 72 h (entry 5), which were the conditions reported
by Shimizu et al.,20 provided 18 in 57% along with 19
(3%), 20 (7%) (Fig. 3), and 17 (10%). X-ray crystallo-
graphic analysis of 18 clearly determined the structure
as shown in Fig. 4,21 indicating that the conjugate addi-
tion of cyanide proceeded stereoselectively, as expected.
NOESY spectra of 19 and 20 suggested that 19 and 20
BnO
Me
H
OBn
H
O
H
OBn
OBn
Me
CN
I
I
R
R
H
H
CN
H
H
H
O
H
H
CN
CN
O
O
BnO
BnO
19
20
19
20
Figure 5. NOE correlations in the NOESY spectra of 19 and 20. R is
Figure 3. Structure of 19 and 20.
A-ring moiety.

M. Utsugi et al. / Tetrahedron Letters 48 (2007) 6868–6872
6871
occurred in either n-propanol (entry 10) or toluene (en-
MeO
MeO
try 11). The former would arise from solvation and the
latter from insolubility of KCN, which would generate
in situ. Finally, we found that the reaction of 17 with
potassium cyanide in DMF at 100 °C for 24 h provided
18 in 70% yield along with 19 (6%) and 20 (4%) (entry
12). This result was comparable with that in entry 6,
suggesting that the conditions in entry 6 probably gener-
ated KCN in situ, which reacted with 17 to afford the
products. To the best of our knowledge, a conjugate
addition of cyanide has been widely used in a polycyclic
system,18 and the successful example in cyclohexenyl
carbonyl compounds is rare.22
O
H
Me
O
O
O
H
O
Ph
Ph
Me
H
H
Figure 6. NOE correlations in the NOESY spectrum of 23.
Consequently, 22 was subjected to the intramolecular B-
alkyl Suzuki–Miyaura coupling reaction (Scheme 5),
and gratifyingly, the product 23 was obtained in high
yield (81%).24 The structure of 23 was confirmed by ana-
lyzing its NOESY spectrum (Fig. 6). Although 23 pos-
sesses an a-hydrogen adjacent to the ketone, no
epimerization was observed during the ring-closing cou-
pling reaction.
Next we examined the transformation of 18 (Scheme 5)
for the intramolecular B-alkyl Suzuki–Miyaura coupling
reaction to construct the taxol B-ring.8 The ketone in 18
was inert to various reducing reagents probably due to
its steric hindrance and the nitrile group in 18 was re-
duced faster to provide the corresponding keto-alde-
hyde. However, the yield varied depending on the
work-up procedure, and the concomitant epimerization
at the a position of the aldehyde occurred in part. For-
tunately, quenching the DIBAL-H reduction of 18 with
THF/AcOH/H2O (2:1:1) and following silica-gel treat-
ment of the product (a mixture of the aldehyde and its
hydrate) reproducibly provided the desired aldehyde.
The aldehyde was reduced with NaBH4 to afford 21 in
53% (three steps).
In conclusion, we found that the diastereoselective con-
jugate addition of cyanide to enone 17, which was pre-
sumed to proceed in an axial attack manner,
succeeded in the stereoselective construction of the C3
stereogenic center. The intramolecular B-alkyl Suzuki–
Miyaura coupling reaction of ketone 22 was found to
provide 23 incorporating the taxane skeleton without
epimerization in high yield, demonstrating its applicabil-
ity to the eight-membered ring synthesis as well as its
mild reaction conditions. The stereoselective reduction25
and allylic oxidation of 23 are the problems to be solved
and now in progress in our laboratory.
The hydroxyl in 21 was protected as a DMBM (3,4-
dimethoxybenzyloxymethyl) ether 22.23 Reduction of
ketone 22 did not occur even using LiAlH4 probably
due to the steric hindrance, resulting in the reduction
of the alkenyliodide.
Acknowledgments
This work was financially supported in part by a Wase-
da University Grant for Special Research Projects and a
Grant-in-Aid for Scientific Research (C) and Scientific
Research on Priority Areas (Creation of Biologically
Functional Molecules (No. 17035082)) from MEXT, Ja-
pan. We are also indebted to GCOE ‘Practical Chemical
Wisdom’.
1) DIBAL-H, DME
-90 oC to rt, 1 h
2) SiO2, CH2Cl2
rt, 2.5 h
OBn
CN
OBn
I
I
3) NaBH4, MeOH
rt, 5 min
H
H
O
O
BnO
BnO
OBn
OH
References and notes
18
53% (3 steps)
(dr ~10:1)
21
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Suzuki–Miyaura coupling reaction.

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1360, 1266, 1160, 1140, 1068, 1030 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 7.36–7.19 (m, 10H), 6.90 (d,
J = 1.7 Hz, 1H), 6.81 (dd, J = 8.1, 1.7 Hz, 1H), 6.76
(d, J = 8.1 Hz, 1H), 4.72 (d, J = 6.6 Hz, 1H), 4.71
(d, J = 6.6 Hz, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.48 (d,
J = 11.5 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.44 (d,
J = 11.7 Hz, 1H), 4.44 (d, J = 11.2 Hz, 1H), 4.27
(d, J = 11.7 Hz, 1H), 4.10 (d, J = 9.8 Hz, 1H), 3.85 (s,
3H), 3.85 (s, 3H), 3.67 (dd, J = 9.8, 9.3 Hz, 1H), 3.28 (d,
J = 3.9 Hz, 1H), 3.25 (dd, J = 11.2, 4.2 Hz, 1H), 2.73 (m,
1H), 2.33 (ddd, J = 13.9, 13.9, 5.4 Hz, 1H), 2.20 (ddd,
J = 14.6, 9.8, 4.9 Hz, 1H), 2.10–1.79 (m, 8H), 1.73–1.24
(m, 2H), 1.56 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H), 0.97 (s,
3H); 13C NMR (100 MHz, CDCl3): d 211.7, 148.8, 148.5,
139.9, 139.3, 138.7, 130.7, 130.2, 128.3, 128.0, 128.0, 127.6,
126.8, 126.7, 120.4, 111.1, 110.8, 94.6, 91.0, 78.1, 70.5,
69.2, 67.7, 66.0, 55.9, 55.8, 52.4, 43.7, 43.2, 37.8, 34.7, 33.2,
30.5, 28.0, 27.4, 26.0, 25.2, 24.9, 22.7, 22.6, 22.0, 20.6,
20.1; HRMS(FAB)[M]+ calcd for C44H56O7, 696.4026,
22
found, 696.4031; ½aꢁD +69.7 (c 0.81, CHCl3); Rf = 0.48
(hexane/AcOEt = 2:1).
25. Reduction of the ketone at C2 position in the taxane
model compounds, see: (a) Wender, P. A.; Mucciaro, T. P.
´
J. Am. Chem. Soc. 1992, 114, 5878–5879; (b) Vazquez, A.;
Williams, R. M. J. Org. Chem. 2000, 65, 7865–7869.