A short and enantioselective preparation of taxol A-ring fragment

Article abstract of DOI:10.1016/j.tetlet.2013.01.115

Two short preparations of the taxol A-ring fragment are described: one via organocatalyzed α-aminoxylation and the other via Sharpless asymmetric dihydroxylation (SAD). The former approach affords the A-ring fragment in 10 steps, and the latter approach involves eight steps to afford the new A-ring fragment in 91% ee, which is made enantiomerically pure through recrystallization. The new A-ring fragment bearing a bromoalkene is confirmed to be useful to form the carbocyclic eight-membered ring of a taxol model compound by palladium-catalyzed intramolecular alkenylation. The preparation of the new A-ring fragment will be beneficial for the total synthesis of taxol as well as other natural products.

Full text of DOI:10.1016/j.tetlet.2013.01.115

Tetrahedron Letters 54 (2013) 1888–1892
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A short and enantioselective preparation of taxol A-ring fragment
⇑
Sho Hirai, Naoko Urushizako, Masayuki Miyano, Tomohiro Fujii, Masahisa Nakada
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Two short preparations of the taxol A-ring fragment are described: one via organocatalyzed a-aminoxy-
Received 12 December 2012
Revised 21 January 2013
Accepted 28 January 2013
Available online 4 February 2013
lation and the other via Sharpless asymmetric dihydroxylation (SAD). The former approach affords the
A-ring fragment in 10 steps, and the latter approach involves eight steps to afford the new A-ring frag-
ment in 91% ee, which is made enantiomerically pure through recrystallization. The new A-ring fragment
bearing a bromoalkene is confirmed to be useful to form the carbocyclic eight-membered ring of a taxol
model compound by palladium-catalyzed intramolecular alkenylation. The preparation of the new A-ring
fragment will be beneficial for the total synthesis of taxol as well as other natural products
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dihydroxylation
Enantioselective
Organocatalysis
Stereoselective
Taxol
Taxol (Fig. 1) is an intriguing and synthetically challenging com-
pound because of its complex structure and clinically important
anticancer activity.1–7 Although six total syntheses and one formal
synthesis have been reported thus far, the distinguished structure
and bioactivity of taxol still draw the attention of synthetic
chemists.8,9
We have reported the enantioselective synthesis of compound 2
(Scheme 1),8a which contains the taxol A–B ring system, via the
construction of an eight-membered ring through the palladium-
catalyzed intramolecular alkenylation of methyl ketone 1, which
proceeded with excellent yield (96%). Although a benzene ring
was used as a substitute for the C-ring moiety of taxol, this reaction
would be potentially useful for the construction of the taxol B-ring.
However, one problem to be solved in this strategy is how to
decrease the number of steps in preparing the A-ring fragment 4
(Scheme 2), because this requires 16 steps from the commercially
available compound 3.8b
co-workers14a described the (S)-proline-catalyzed
tion of an -branched aldehyde (58%, 37% ee) in their report on
prolinamide-catalyzed direct nitroso aldol reactions. Kim et al.14b
reported the catalytic asymmetric -hydroxyamination and
-aminoxylation of -branched aldehydes using (S)-proline and
its derivatives, and obtained -hydroxyamination adducts with
up to 90% ee. However, they obtained a mixture of -hydroxyam-
ination and -aminoxylation products, and the ee of the -amin-
a-aminoxyla-
a
a
a
a
a
a
a
a
oxylation products did not exceed 45%, probably because the
enamine formed in situ through the organocatalytic reaction
would be a mixture of geometric isomers. Recently, List and
co-workers14c reported the organocatalytic asymmetric
a
-benzoyl-
-branched aldehydes and enals, which afford
-benzoyloxy aldehydes in good yields and enantioselectivity.
oxylation of
a
a
Unfortunately, this protocol cannot be applied for the preparation
of 5 from 6, because 5 decomposes via fragmentation under the
reaction conditions for the removal of benzoate.
Compound 4 was expected to be prepared from 5 (Scheme 3),
The enamine of aldehyde 6 with (R)-proline would prefer the
E-isomer 8 (Scheme 4) owing to the steric repulsion between the
which could be obtained through
Recent progress in organocatalysis suggests that chiral
yaldehydes can be obtained via the proline- or its derivative-cata-
lyzed -aminoxylation of aldehyde with nitrosobenzene in high
ee.10 For example, the catalytic asymmetric
-aminoxylations of
a-oxygenation of aldehyde 6.
a-hydrox-
a
AcO
O
OH
C
a
aldehydes using proline and nitrosobenzene, which were reported
B
independently by Zhong,11 MacMillan,12 and Hayashi,13 are useful
A
O
methods for the preparation of chiral
ever, to the best of our knowledge, the organocatalytic asymmetric
-oxygenation of -branched aldehydes is limited. Jang and
a-hydroxyaldehydes. How-
O
H
OBz
OAc
HO
OH
O
a
a
BzHN
Taxol
Ph
⇑
Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
Figure 1. Structure of taxol.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.115

S. Hirai et al. / Tetrahedron Letters 54 (2013) 1888–1892
1889
Table 1
(R)-Proline-catalyzed
O
O
a-aminoxylation of 6 with nitrosobenzene
I
Pd(PPh3)4 (30 mol %)
PhOK (3.0 equiv)
I
I
I
PhNO (3.0 equiv)
toluene, 100 °C, 2 h
96%
15
1
+
BnO
BnO
(R)-proline (mol %)
conditions, rt, 48 h
OTBS
OTBS
CHO
CHO
CHO
PhHNO
HO
1
2
6
9
5
Scheme 1.
I
I
CSA
NaBH4
I
O
O
acetone
rt, 30 min
93%
MeOH, rt, 10 min
16 steps
O
HO
10
O
OH
11
CHO
BnO
Entry
Catalyst (mol %)
Solvent
Yielda (%)
10
eeb (%)
11
3
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
10
30
100
30 + 30c
30
DMSO
DMSO
DMSO
DMSO
DMSOd
11
45
45
25
51
23
22
20
11
Trace
5
52
86
86
84
75
—
75
79
16
—
38
—
—
—
—
Scheme 2.
DMSO, additivee
DMF
I
I
I
I
30
30
30
30
30
30
30
30
NMP
MeCN
MeNO2
CH2Cl2
CHCl3
(CH2Cl)2
1,4-Dioxane
THF
CHO
CHO
CHO
O
BnO
HO
0
0
0
0
4
5
6
7
30
30
30
Scheme 3.
EtOAc
0
—
a
I
Isolated yields.
b
I
ee determined by HPLC (254 nm); CHIRALPAK OD-H, 0.46 cm
u ꢀ 25 cm, hex-
15
ane/i-PrOH = 300:1, 0.2 mL/min, 23.7 min (ent-11), 25.5 (11).
(R)-proline
c
Another 30 mol % of (R)-proline was added after 24 h.
The reaction was carried out at 50 °C.
d
1
e
1-(2-(Dimethylamino)ethyl)-3-phenylurea (30 mol %) was used.
CHO
N
OH
O
6
to obtain the desired enantiomer. The reaction of 6 with nitroso-
benzene (3.0 equiv) in the presence of 10 mol % of (R)-proline in
DMSO at room temperature for 48 h afforded a mixture of 9 and
5 (entry 1). An extended reaction time did not improve the yield.
The obtained mixture was reduced with NaBH4 in a one-pot man-
ner to give 10 in 11% yield (two steps). The ee of the product was
52%, as determined by HPLC analysis of the corresponding aceto-
nide 11. The use of 30 mol % of (R)-proline improved the yield
and ee to 45% and 86%, respectively (entry 2), but the yield was
not improved by an extended reaction time. The use of 100 mol %
of (R)-proline did not change the yield and ee (entry 3), and the
addition of another 30 mol % of (R)-proline after 24 h reduced the
yield (entry 4). The reaction at 50 °C improved the yield slightly,
but reduced the ee (entry 5). The use of the additive (1-(2-(dimeth-
ylamino)ethyl)-3-phenylurea),15 which was reported to increase
( )-enamine (8)
E
Scheme 4.
I
I
MeOCH2PPh3Cl, KHMDS, THF, rt
then, THF/ 2 M HCl (3:1), rt, 67%
O
CHO
7
6
Scheme 5.
organocatalyst and the C15 quaternary carbon, and high enantiose-
lectivity is expected. However, the -aminoxylation of 6 is sus-
a
the rate of proline-catalyzed a-aminoxylations, was also ineffec-
pected to be slow because the C1 position is sterically hindered
by the adjacent C15 quaternary carbon. Nonetheless, the enantio-
selective direct installation of an oxygen atom at the C1 position
is attractive. Hence, for the exploration of the possibility of utiliz-
tive (entry 6). The reactions were also examined in a variety of sol-
vents; however, no improvement was observed (entries 7–16).
The organocatalyzed asymmetric a-aminoxylation of 6 was fur-
ther examined using other catalysts (Table 2). The yield and the ee
of the products were determined according to the method used in
Table 1. The reactions in the presence of 30 mol % of 12,16a 13,16b
14,16c and 1516e gave no products (entries 1–4). The reactions using
1616e and 1716d afforded the desired products, but the yield and the
ee were low (entries 5 and 6). The reaction with 18,16e,17 the acidity
of which in a polar solvent is comparable to that of carboxylic acid,
and subsequent reduction afforded 10 in 53% yield and with 85% ee
(entry 7). Although the ee (85%) was almost the same as that in
ing the
a-aminoxylation of 6 to establish short access to 4, the
organocatalyzed asymmetric
a-aminoxylation of 6 was examined.
Aldehyde 6 was obtained by the reaction of 7 with methoxyme-
thylidene triphenylphosphorane and subsequent one-pot acid
hydrolysis in 67% yield (Scheme 5). With 6 in hand, the organocat-
alyzed catalytic asymmetric
(Table 1). Considering the mechanism of the proline-catalyzed
-aminoxylation of 6 with nitrosobenzene, (R)-proline was used
a-aminoxylation of 6 was examined
a

1890
S. Hirai et al. / Tetrahedron Letters 54 (2013) 1888–1892
Table 2
Organocatalyzed
We first examined the Sharpless asymmetric dihydroxylation
a-aminoxylation of 6 with nitorosobenzene using 12–19
(SAD) of 24 (Table 3), which was prepared by the Wittig reaction
of 7 (Ph3P@CH2, THF, reflux, 83%). The SAD of 24 using a catalytic
amount of (DHQ)2PHAL and K2OsO2ꢁ2H2O afforded 25 in 83% yield,
but the ee was low (45% ee) (entry 1). The SAD of 24 using DHQ-
PHN improved the ee; however, 76% ee was unsatisfactory (entry
2). Therefore, we decided to examine the SAD of silyl enol ether
of 6, which was expected to give good results, because the highly
enantioselective SAD of a similar compound has been reported
by Kuwajima and co-workers.21
In addition, we examined the SAD of silyl enol ether of 23
because 23 was prepared in three steps from commercially avail-
able compounds. That is, the Diels–Alder reaction of commercially
available 20 and acryloyl chloride afforded 21,22 which was con-
verted into aldehyde 23 via 22 (Scheme 6).23
TIPS enol ether 24a was prepared as a single and stable
(E)-isomer from 6.24 The SAD of 24a using a catalytic amount of
(DHQ)2PHAL (Fig. 2) and K2OsO2ꢁ2H2O under the conditions given
in Table 3 afforded 25a in 86% yield and with 24% ee (entry 3). The
use of an increased amount of (DHQ)2PHAL (10.0 mol %) did not
improve the ee (entry 4), and reaction at 0 °C reduced the yield
(entry 5).
The use of (DHQ)2PHAL resulted in a low ee; hence, the reaction
using another ligand, Q-PHN (Fig. 2), was performed. As a result,
the reaction proceeded faster than that using (DHQ)2PHAL and
was completed after 26 h to afford 25a in 71% yield with 85% ee
(entry 6).
The SAD of a similar TIPS enol ether using DHQ-PHN (Fig. 2) was
reported to afford the product with high yield and ee.21 Hence, the
SAD of 24a using a catalytic amount of DHQ-PHN and K2OsO2ꢁ2H2O
was examined. The yield and the ee were slightly improved (entry
7) and the reaction was completed faster (12.5 h) than that with
Q-PHN (26 h). The SAD of 24a using DHQ-PHN (15.0 mol %) and
K2OsO2ꢁ2H2O (5.0 mol %) gave 25a with 91% ee, but the yield was
64% (entry 8).
The SAD of 24b was also examined using DHQ-PHN (15.0 mol %)
and K2OsO2ꢁ2H2O (5.0 mol %). The reaction was completed after
20 h to afford 25b in 78% yield and with 88% ee (entry 9). Finally,
the reaction with DHQ-PHN (10.0 mol %) and K2OsO2ꢁ2H2O
(5.0 mol %) afforded 25b in 92% yield and with 91% ee (entry 10),
which was reproducible in a gram-scale reaction.
Compound 25b was subjected to benzylidene formation to af-
ford 26 (Scheme 7), followed by regioselective cleavage of benzyl-
idene acetal by DIBAL-H, and subsequent Dess–Martin oxidation
gave 27. Gratifyingly, 27 was crystalline and an enantiomerically
pure compound was obtained through recrystallization.25
Compound 27 was prepared from 20 in eight steps. Hence, the
preparation of 27 via SAD could be the shortest preparation of our
A-ring fragment. However, we must confirm whether methyl
ketone 31 (Scheme 8), which could be prepared from 27, is con-
verted into 2 via palladium-catalyzed intramolecular alkenylation.
Compound 27 was converted into 31 and its palladium-cata-
lyzed reaction was examined as follows. The reaction of 27 with
lithiated 28 afforded 29 as a single isomer. This was followed by
TBS formation, removal of ethoxyethyl ether, and Dess–Martin oxi-
dation to give aldehyde 30. The reaction of 30 with methylmagne-
sium bromide and subsequent Dess–Martin oxidation afforded
methyl ketone 31. The palladium-catalyzed intramolecular alkeny-
lation of 31 was performed under the same conditions used for the
reaction of compound 1. As a result, 31 was converted successfully
into 2 in 95% yield, which was comparable to the yield of the reac-
tion of 1, though the reaction required 4 h for completion.
In summary, two short preparations of the A-ring fragment of
I
I
I
PhNO (3.0 equiv)
catalyst (30 mol %)
+
DMSO
conditions, rt, 48 h
CHO
CHO
CHO
PhHNO
HO
6
9
5
I
I
CSA
NaBH4
MeOH, rt, 10 min
acetone
rt, 30 min
93%
O
HO
10
O
OH
11
eeb (%)
Entry
Catalyst (30 mol %)
Yielda (%)
10
11
OH
1
2
12
13
0
0
—
N
H
S
S
—
—
—
CO2H
N
H
3
4
5
14
15
16
0
0
CO2H
N
H
H
N
S
N
H
O2
O
O
H
N
15
59
S
N
H
O2
NO2
H
N
6
17
21
20
85
S
N
H
O2
O
N
7c
8
18
19
53
28
N
N
H
HN N
NHTf
ꢂ94d
N
H
a
Isolated yields.
b
ee determined by HPLC. For the conditions, see footnote to Table 1. For the
determination of absolute configuration of 11, see Ref. 19.
c
100 mol % of catalyst was used.
Minus sign means ent-11.
d
entry 2 of Table 1, the yield (53%) was improved from 45%. The ee
of the reaction catalyzed by 1918 afforded the product with 94% ee,
but the yield was only 28%.
Considering both the yield and the ee of 10, the conditions in
entry 7 could be utilized for the preparation of the A-ring fragment
because compound 10 has been converted into 4, which is crystal-
line and its ee can be improved by recrystallization.19 Compound 7
(Scheme 5) was prepared from commercially available compounds
in five steps;20 therefore, the number of synthetic steps required
for the preparation of 4 was reduced to 10 steps from commercially
available compounds, because compound 10 is converted into 4 in
three steps (benzylidene formation, reductive cleavage of the
benzylidene by DIBAL-H, and Dess–Martin oxidation).8b
The yield of the organocatalyzed
a
-aminoxylation of 6 with
taxol, via organocatalyzed a-aminoxylation and Sharpless asym-
nitrosobenzene is unsatisfactory. Hence, we explored another
metric dihydroxylation (SAD), were studied. The former approach
possibility for the short preparation of the A-ring fragment 4.
afforded the A-ring fragment in 10 steps and the latter in eight

S. Hirai et al. / Tetrahedron Letters 54 (2013) 1888–1892
1891
Table 3
Sharpless asymmetric dihydroxylation of 24, 24a, and 24b
.
X
X
X
K2OsO2 2H2O, Ligand
K3Fe(CN)6 (3.0 equiv)
TIPSOTf, DBU
DMAP, CH2Cl2
I
K2CO3 (3.0 equiv)
MeSO2NH2 (1.0 eqiv)
0 ° to rt
CHO
CHO
HO
OTIPS
t-BuOH/H2O = 1:1
6
(X = I)
23 (X = Br)
24a (X = I)
25 (X = H)
25a (X = I)
25b (X = Br)
24
78%
97%
24b (X = Br)
Entry
Substrate
Ligand (mol %)
K2OsO2ꢁ2H2O (mol %)
Temp (°C)
Time (h)
Yielda (%)
ee (%)
1
2
3
4
5
6
7
8
9
24
24
(DHQ)2PHAL (15.0)
DHQ-PHN (15.0)
(DHQ)2PHAL (5.0)
(DHQ)2PHAL (10.0)
(DHQ)2PHAL (10.0)
Q-PHN (10.0)
DHQ-PHN (10.0)
DHQ-PHN (15.0)
DHQ-PHN (15.0)
DHQ-PHN (10.0)
5.0
5.0
2.5
2.5
2.5
2.5
2.5
5.0
5.0
5.0
0
0
rt
rt
0
0
0
0
0
0
3
1.5
14
15
50
26
12.5
18
20
83
96
86
99
59
71
73
64
78
92
45b,c
76b,c
24c,d
33c,d
45c,d
85c,d
87c,d
91c,d
88e
24a
24a
24a
24a
24a
24a
24b
24b
10
35
91e
a
Isolated yields.
b
The product was oxidized to 25a by Dess–Martin periodinane, which was used to determine the ee by HPLC. The HPLC (254 nm) analysis also confirmed the absolute
configuration of 25 as shown above.
c
CHIRALPAK IC, 0.46 cm
u
ꢀ 25 cm, hexane/i-PrOH = 19:1, 0.3 mL/min, 20.2 (ent-25a), 22.0 (25a).
d
Compound 25a was converted into compound 11 to determine its absolute configuration by HPLC, which also confirmed the absolute configuration of 25a shown above.
For the conditions, see footnote to Table 1.
e
Compound 25b was converted into 27 for HPLC (254 nm); CHIRALCEL AS-H, 0.46 cm
u
ꢀ 25 cm, hexane/i-PrOH = 19:1, 0.3 mL/min, 17.8 (27), 21.7 (ent-27). For the
determination of absolute configuration of 27, see Ref. 25.
Br
Br
Br
Br
MeNH2OMeCl
neat
CSA, PhCH(OMe)2
CH2Cl2, reflux
+
COCl
reflux, 87%
Et3N, CH2Cl2
rt, 94 %
O
OMe
26
COCl
CHO
HO
25b
20
21
O
Ph
Br
Br
LiAlH4
Br
1) DIBAL-H, toluene
100 °C
THF, –40 °C, 91%
CON(OMe)Me
CHO
22
23
2) DMP, CH2Cl2
rt, 62% (3 steps)
CHO
BnO
27
Scheme 6.
steps. The organocatalyzed
a-aminoxylation afforded the desired
Scheme 7.
product with up to 86% ee (94% ee when ent-19 is used), but the
yield requires improvement. The SAD approach afforded the new
A-ring fragment with 91% ee, which was made enantiomerically
pure through recrystallization. The new A-ring fragment bearing
a bromoalkene was confirmed to be useful for the palladium-cata-
lyzed intramolecular alkenylation to form the carbocyclic eight-
membered ring. The preparation of the new A-ring fragment will
be beneficial to the total synthesis of taxol as well as other natural
products.
Acknowledgments
This work was financially supported in part by The Grant-in-Aid
for Scientific Research on Innovative Areas ‘Organic Synthesis
based on Reaction Integration. Development of New Methods and
Creation of New Substances’ (No. 2105).
N
N
N
N
N
N
O
O
O
O
H
H
H
H
OMe
MeO
MeO
MeO
N
N
N
N
(DHQ)2-PHAL
Q-PHN
Figure 2. Structures of (DHQ)2-PHAL, Q-PHN, and DHQ-PHN.
DHQ-PHN

1892
S. Hirai et al. / Tetrahedron Letters 54 (2013) 1888–1892
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Br
Br
OEE
I
28, n-BuLi
THF, –78 °C
+
then 27, –78 °C
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96%
CHO
BnO
27
BnO
OH
29
28
O
1) TBSOTf, DIPEA
CH2Cl2, 0 °C, 99%
1) MeMgI, THF
0 °C, 94 %
Br
2) p-TsOH, MeOH
rt, 84%
3) DMP, CH2Cl2, rt, 95%
2) DMP, CH2Cl2
rt, 95%
BnO
11. Zhong, G.; Tejero, T. Angew. Chem., Int. Ed. 2003, 42, 4247–4250.
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OTBS
30
O
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O
Br
Pd(PPh3)4 (30 mol %)
PhOK (3.0 equiv)
toluene, 100 °C, 4 h
95%
BnO
BnO
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D. T. J. Org. Chem. 2009, 74, 1574–1580.
OTBS
OTBS
31
2
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Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141–1146; (e) Cobb,
A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem.
2005, 3, 84–96.
17. (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558–560; (b) Hartikka, A.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831–1834; (c) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808–1809; (d)
Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983–1986.
Scheme 8.
References and notes
1. (a) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang,
S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116,
1597–1598; (b) Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. J.;
Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao,
C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem.
Soc. 1994, 116, 1599–1600.
18. Wang, W.; Lia, H.; Wang, J. Tetrahedron Lett. 2005, 46, 5077–5079.
19. Compound 4: mp = 104–105 °C (recrystallization from hexane); Rf = 0.63
(hexane/EtOAct = 4/1); IR (KBr) mmax 1724, 1458, 1094, 1049, 899, 739 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d 9.84 (s, 1H), 7.39–7.26 (m, 5H), 4.56 (d,
2. (a) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.;
Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J.
Nature 1994, 367, 630–634; (b) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy,
R. K.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1995, 117, 624–633; (c)
Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy,
R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117,
634–644; (d) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claiborne, C.
F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995, 117, 645–652; (e)
Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, P. G.; Yang, Z.; Renaud, J.;
Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995, 117, 653–659.
3. (a) Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1723–1726; (b) Danishefsky, S. J.; Masters, J. J.;
Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.;
Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Grandi, M. J. D. J. Am. Chem. Soc.
1996, 118, 2843–2859.
4. (a) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.;
Gränicher, C.; Houze, J. B.; Jänichen, J.; Lee, D.; Marquess, D. G.; McGrane, P. L.;
Meng, W.; Mucciaro, T. P.; Mühlebach, M.; Natchus, M. G.; Paulsen, H.; Rawlins,
D. B.; Satkofsky, J.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E.; Tomooka, K. J. Am.
Chem. Soc. 1997, 119, 2755–2756; (b) Wender, P. A.; Badham, N. F.; Conway, S.
P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Krauss, N. E.; Lee, D. S.; Marquess,
D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A. J.; Sutton, J. C.;
Taylor, R. E. J. Am. Chem. Soc. 1997, 119, 2757–2758.
5. (a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Sakoh, H.; Tani, Y.; Hasegawa, M.;
Saitoh, K. Proc. Jpn. Acad., Ser. B 1997, 73, 95–100; (b) Mukaiyama, T.; Shiina, I.;
Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.;
Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem. Eur. J. 1999, 5, 121–161.
6. (a) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama,
H.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980–12981; (b) Kusama, H.;
Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.;
Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 3811–3820.
J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 2.35–2.21 (m, 2H), 2.17–2.09 (m,
1H), 2.04–1.98 (m, 1H), 1.91 (s, 3H), 1.38 (s, 3H), 1.10 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 204.7, 138.2, 137.1, 128.3, 127.5, 126.8, 114.2, 83.4, 66.2,
45.6, 30.9, 29.4, 27.5, 26.6, 20.8; HRMS (FAB) [M+H]+ calcd for C17H22O2I,
385.0664, found 385.0676; ½a D32
ꢃ
+57.7 (c 1.03, CHCl3, >99% ee). The plus sign in
specific rotation of 4, which was derived from 10, was the same as that of the
previously prepared
4
via baker’s yeast reduction,8b indicating that the
absolute configuration of 10 is as shown in Table 1.
20. Young, W. B.; Masters, J. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5228–
5234.
21. Nakamura, T.; Waizumi, N.; Horiguchi, Y.; Kuwajima, I. M. Tetrahedron Lett.
1994, 35, 7813–7816.
22. Frost, C.; Linnane, P.; Magnus, P.; Spyvee, M. Tetrahedron Lett. 1996, 37, 9139–
9142.
23. Rosemund reduction of 21 afforded 23. However, the yield (71%) was inferior
to the two-step sequence in Scheme 6 (86%, two steps) because reduction of
the C–Br bond in 21 took place during the palladium-catalyzed reduction.
24. (E)-TBDPS enol ether of 6 was also prepared and subjected to the SAD, but the
reaction proceeded very slowly at room temperature and only 17% of 25a with
28% ee was formed after 12 h.
25. Compound 27: mp = 92–93 °C (recrystallization from hexane, 39% from 27 (91%
ee)); IR (neat) mmax 2196, 1980, 1728, 1458, 1365, 1092, 1028, 904, 735, 696,
580 cmꢂ1;1H NMR (400 MHz, CDCl3): d 9.87 (s, 1H), 7.41–7.20 (m, 5H), 4.56 (d,
J = 11.7 Hz 1H), 4.40 (d, J = 11.7 Hz 1H), 2.29–2.17 (m, 2H), 2.17–2.07 (m, 1H),
2.07–1.95 (m, 1H), 1.83 (s, 3H), 1.42 (s, 3H), 1.14 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 204.8, 138.5, 129.0, 128.5, 127.7, 127.0, 84.5, 66.3, 45.2, 29.1, 25.2,
24.5, 20.7; HRMS (ESI) [M+Na]+ calcd for C17H21O2BrNa, 359.0623, found,
359.0622; ½a 1D6
ꢃ
+90.0 (c 1.72, CHCl3, >99% ee). Compounds 4 (>99% ee)8b and 27
(91% ee) were converted into compound 32 as shown below. Both compounds
were found to have the same plus sign in specific rotation, confirming the
absolute configuration of 27 as shown here.
7. Formal total synthesis of taxol: Doi, T.; Fuse, S.; Miyamoto, S.; Nakai, K.; Sasuga,
D.; Takahashi, T. Chem. Asian J. 2006, 1, 370–383.
1) NaBH4
2) nBuLi
3) DMP
Br
1) NaBH4
2) nBuLi
3) DMP
I
H
8. (a) Utsugi, M.; Kamada, Y.; Miyamoto, H.; Nakada, M. Tetrahedron Lett. 2008, 49,
4754–4757; (b) Utsugi, M.; Kamada, Y.; Miyamoto, H.; Nakada, M. Tetrahedron
Lett. 2007, 48, 6868–6872; (c) Utsugi, M.; Miyano, M.; Nakada, M. Org. Lett.
2006, 8, 2973–2976; (d) Iwamoto, M.; Miyano, M.; Utsugi, M.; Kawada, H.;
Nakada, M. Tetrahedron Lett. 2004, 45, 8647–8651; (e) Kawada, H.; Iwamoto,
M.; Utsugi, M.; Miyano, M.; Nakada, M. Org. Lett. 2004, 6, 4491–4494; (f)
Nakada, M.; Kojima, E.; Iwata, Y. Tetrahedron Lett. 1998, 39, 313–316.
9. (a) Uttaro, J.-P.; Audran, G.; Monti, H. J. Org. Chem. 2005, 70, 3484–3489; (b)
Gao, Z.-H.; Liu, B.; Li, W.-D. Z. Tetrahedron 2005, 61, 10734–10737; (c)
Chouraqui, G.; Petit, M.; Phansavath, P.; Aubert, C.; Malacria, M. Eur. J. Org.
Chem. 2006, 1413–1421; (d) Kreilein, M. M.; Hofferberth, J. E.; Hart, A. C.;
Paquette, L. A. J. Org. Chem. 2006, 71, 7329–7336; (e) Kaliappan, K. P.;
CHO
8%
(3 steps)
CHO
CHO
46%
(3 steps)
BnO
BnO
BnO
32
4 (>99% ee)8b
27 (91% ee)
[α]D22 +38.0 (c 0.10, CHCl3)
[α]D22 +35.3 (c 0.17, CHCl3)
from 4:
from 27: