A study toward a total synthesis of fostriecin

Article abstract of DOI:10.1016/S0040-4039(02)00403-3

In order to synthesize the major C(3)-C(12) part of fostriecin, asymmetric dihydroxylation of several dienes 5a-f, prepared by cross-coupling reactions of several types, was studied, thus providing high dependency on the hydroxyl groups at C(5) and C(11). The best regioselectivity was obtained with 5d to produce diol 23, which was later transformed into the advanced intermediate 26.

Full text of DOI:10.1016/S0040-4039(02)00403-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2725–2729
A study toward a total synthesis of fostriecin
Yohei Kiyotsuka, Junji Igarashi and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501,
Japan
Received 17 December 2001; revised 7 February 2002; accepted 22 February 2002
Abstract—In order to synthesize the major C(3)ꢀC(12) part of fostriecin, asymmetric dihydroxylation of several dienes 5a–f,
prepared by cross-coupling reactions of several types, was studied, thus providing high dependency on the hydroxyl groups at C(5)
and C(11). The best regioselectivity was obtained with 5d to produce diol 23, which was later transformed into the advanced
intermediate 26. © 2002 Elsevier Science Ltd. All rights reserved.
Biological investigation of fostriecin has disclosed a
variety of biological properties, such as inhibition of
cell cycles and that of DNA, RNA and protein synthe-
sis.1 Due to high efficiency of these properties, fostriecin
has attracted much interest as a lead compound for
developing a new drug.2 In order to gain deep under-
standing on these biological properties, investigation
using fostriecin and its analogues is a convenient and
efficient way. The absolute structure of fostriecin was
determined by Boger3 recently in 1997, who later suc-
ceeded in the first total synthesis in 2001.4 Shortly after
this publication, a synthesis of the C(1)ꢀC(12) (fos-
triecin numbering) part was reported by Cossy,5 and
then synthesis of the full structure by Jacobsen.6 How-
ever, there still seems an urgent demand to develop a
new synthetic method in order to provide analogues of
fostriecin. Herein, we report a study toward a synthesis
of fostriecin.7
by the coupling reaction of alkenyl halide 3 and a
dienyl metal 4. Recently, alkenyl and aryl borates with
the 2,2-dimethyl-1,3-propanediol and the Me ligands
were developed in order to secure coupling reactions
with alkenyl halides of steric hindrance and/or less
reactivity to be successful.8 Halide 3 is one such com-
pound, and thence borate 4 is selected as a reagent in
our fostriecin synthesis, and was found to be successful
in a model study.9 With regard to this coupling reac-
tion, Jacobsen also accomplished a similar reaction
with dienyl stannane 4 (M=SnBu3) under the ligand-
free palladium catalysis. For preparation of the key
intermediate 3, we chose a sequence involving the
Sharpless asymmetric dihydroxylation (AD reaction)10
of diene 5 at the C(8)ꢀC(9) double bond and a subse-
quent one-carbon elongation, because numerous meth-
ods are available for preparation of dienes, for instance,
the Sonogashira reaction of 7 and halide 6 followed by
reduction of enyne, cross-coupling reaction of
organometallic 8 and halide 6, and vise versa, etc.
O
(HO)2P
O
OH
12
According to the results previously obtained from the
AD reactions of dienes,11 an olefin part of higher
electron density and/or less steric hindrance is the reac-
tion site for the oxidation. In our case, however, the
regioselectivity seemed to be disrupted by the alkoxy
groups close to the diene moiety of 5. Consequently,
dienes 5a–f (Table 1) of related structures were chosen
in order to find the structural factor indispensable for
the high regioselectivity in the AD reaction.
8
OH
O
O
6
OH
fostriecin (1)
Our approach to fostriecin (1) is illustrated in Scheme
1. Alcohol 2, which is transferred to 1 by selective
phosphorylation at C(9) by Boger,4 would be prepared
Keeping asymmetric synthesis in mind, substrates and
organometallics for construction of dienes 5a–f were
prepared by methods summarized in Schemes 2 and 3.
Epoxide ring opening of TBS ether of glycidol12 with
Keywords: fostriecin; asymmetric dihydroxylation; coupling reactions;
regioselection.
* Corresponding author. Tel.: +81-45-924-5789; fax: +81-45-924-5789;
e-mail: ykobayas@bio.titech.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00403-3

2726
Y. Kiyotsuka et al. / Tetrahedron Letters 43 (2002) 2725–2729
R1O
R2O
OR3 OR4
X
OH OH
1
8
OH
+
O
O
M
OR6
OR3
6
12
OH
4
3
2
O
O
M =
Me
Me
B
Me
R1O
R2O
"HO + OH"
(AD-mix-β)
OR4
R1O
R2O
OR4
7
one carbon
elongation
X
(or m)
or
+
R1O
R2O
OR5
8
6
OR5
6
5
m (or X)
X = I
m = Zn
8
m: Sn, Zn
X = I
Scheme 1. Retrosynthesis of fostriecin.
Table 1. AD reaction of diene with AD-mix-b
diol
yield of
entry
1
conditions
rt., 2 days
6,7- : 8,9-
major isomer
diene
8
PMBO
EEO
OTBS
52%
(83% conversion)
1 : 1
OPMB
11
6
5a
5b
TBSO
EEO
OTBS
< 42%
(80% conversion)
rt., 2 days
rt., 2 days
2
3
1 : 1
OPMB
TBSO
HO
OTBS
OPMB
< 20%
(complex mixture)
1 : < 1
5c
PMBO
THPO
OMOM
OTBS
rt., 2 days
or 0 °C, 3 days
90–93%
85%
4
5
1 : 10
5d
5e
PMBO
EEO
rt., 2 days
rt., 2 days
1 : > 17
OTBS
OEE
PMBO
TBSO
6
1 : 3.6
66%
5f
a Reactions were carried out under the conditions specified using AD-mix-β with five-fold more
K2OsO6 and the DHQD in the reagent.
propyne according to the procedure of Yamaguchi13
followed by protection of the resulting alcohol 11 with
MOMCl provided 12 in good yield. In order to prepare
6b by iodination at C(8), hydrozirconation of acetylene
12 was carried out under the thermodynamic control
using excess Cp2Zr(H)Cl (2–2.5 equiv.) at 50°C accord-
ing to Panek14 and the resulting intermediate was
quenched with I2. When Cp2Zr(H)Cl generated in situ
from Cp2ZrCl2 and LiBEt3H was used,15 a mixture of
6b and minor impurities was produced after iodination

Y. Kiyotsuka et al. / Tetrahedron Letters 43 (2002) 2725–2729
2727
(1) Preparation of 6a and 6b
MeC≡CLi
BF3·OEt2
Cp2ZrCl2, DIBAL
Me
OR
Cl
Cp2Zr
OMOM
OMOM
I2
O
THF / hexane
I
50 °C
80%
79%
OR
9: R = H
10: R = TBS
OTBS
OTBS
OTBS
6a
6b
11: R = H
12: R =MOM
MOMCl
Pr2NEt
TBSCl
imidazole
90%
82%
(2) Preparation of 6c
1) PMBCl/ NaI/ TBAI
NaH, DMF
1) K2CO3
MeOH
R
OTBS
OTBS
TMS
OH
Cp2ZrCl2, DIBAL
then NIS
I
9
2) TMSC≡CLi
BF3·OEt2
2) TBSCl
C3H4N2
OPMB
14: R = H
15: R = Me
OPMB
OPMB
13
6c
1) BuLi
2) MeI
38% from 9
regioselectivity
97%
(3) Preparation of models 18a and 18b
I
Cp2ZrCl2, DIBAL
then NIS
1) BuLi
OR
2) MeI
OR
OR
51%
18a: R = TBS
18b: R = EE
16a: R = TBS
16b: R = EE
17a: R = TBS, 90%
17b: R = EE, 86%
regioselectivity
80–98%
Scheme 2. Preparation of the C(8)ꢀC(12) intermediates 6a–c and model compounds 18a,b.
Coupling reactions between the C(3)ꢀC(7) and the
C(8)ꢀC(12) parts to produce the dienes 5a–f were
accomplished by sequences or reactions summarized in
Scheme 4. Sonogashira reaction19 of acetylene 7a and
iodide 6c using Pd(PPh3)4 and CuI as catalysts and
Et3N as a base in DMF at room temperature proceeded
smoothly to afford acetylene 20 in 59% yield, and
subsequent hydroalumination with LiAlH4 produced
with I2, though 6b was isolated in 53% yield with a 7:1
ratio of 6b and the regioisomer (structure not shown).
In contrast, the use of DIBAL as a reducing agent of
Cp2ZrCl2 resulted in clean production of 6b in 80%
yield. The exclusive formation of 6b is surprising since
Zr species sensitively recognized the small steric differ-
ence between the methyl and methylene parts attached
to the acetylene moiety. Moreover, this result encour-
ages direct use of the presumed zirconium intermediate
6a in the formation of diene by the coupling reaction,
which is mentioned later.
(1) Preparation of 7a and 8a
PMBO
RO
1) TMSC≡CLi
PMBO
In a similar manner, glycidol 9 was converted into
acetylene 15 in good yield, and submitted to the
hydrozirconation/iodination (by NIS)16 as mentioned
above, to afford iodide 6c with 97% regioselectivity in
68% yield (38% overall yield). Regioselective formation
of 6c and 6b strongly indicates the efficiency of
Cp2ZrCl2 and DIBAL as a hydrozirconation agent.
CHO
2) K2CO3
78%
DHP, H+
65%
19a
7a: R = H
7b: R = THP
3
Cp2ZrCl2, LiBEt3H
PMBO
7
THPO
I
then I2
85%
8a
We also prepared iodides 18a and 18b as shown in
Scheme 2 for construction of model dienes 5e and 5f
(Table 1). Once again, combination of Cp2ZrCl2 and
DIBAL as described above provided a good result in
the transformation of 17a,b into iodides 18a,b.
(2) Preparation of 8b and 8c
Bu3Sn
TBSO
HO
Li
TBSO
SnBu3
47%
CHO
Preparation of the C(3)ꢀC(7) parts 7a and 8a–c in
racemic forms is presented in Scheme 3. For the
hydrozirconation of 7b, the conventional protocol was
used with success. Note that these intermediates in
optically active forms will be available by the reliable
methods such as asymmetric reduction of the corre-
sponding ketones,17 the kinetic resolution of racemic
g-stannyl or g-iodo allylic alcohols by using the Sharp-
less reagents,18 etc.
19b
8b
TBSO
THPO
1) I2
2) DHP, H+
91%
I
8c
Scheme 3. Preparation of the C(3)ꢀC(7) intermediates 7a and
8a–c.

2728
Y. Kiyotsuka et al. / Tetrahedron Letters 43 (2002) 2725–2729
50% yield.21 Reaction of 5c with CH2ꢁCHOEt gave
another diene 5b in good yield. Use14 of the zirconium
intermediate 6a (Scheme 2) in the coupling with iodide
8a in the presence of Pd(PPh3)4 was successful to afford
diene 5d in 73% yield.
Although asymmetric dihydroxylation of diene 5a using
AD-mix-b was quite slow under the standard condi-
tions, use of the forcing conditions with the catalyst-
rich reagent22 forwarded the reaction. Unfortunately,
almost no regioselectivity was observed. Diene 5b with
the TBS protection at C(3), which is similar to diene 5a
except for PMB protecting group, afforded the same
ratio of diols, while 5c with the hydroxyl group at C(5)
furnished worse selectivity with low yield. These results
suggest that the size of hydroxyl groups at C(5) and/or
C(11) is more important than the inductive effect of the
alkoxy group at C(5) or C(11) on the density of olefin
in the fostriecin case, and diene 5d with a smaller
MOM-oxy group at C(11) was found to be an ideal
substrate to afford the desired diol 23 (structure, see
Scheme 5) with a high regioselectivity in good yield.
Conversion of diol 23 to the advanced intermediate 26
was accomplished easily as shown in Scheme 5. After
protection of the diol moiety as acetonide, the TBS
group at C(12) was removed and oxidation of the
resulting alcohol furnished aldehyde 25 in good yield.
Finally, Stork–Wittig reaction produced cis iodide 26 in
50% yield.
Scheme 4. Preparation of dienes 5a–d. (Model dienes 5e and
5f were prepared similarly to 5a.)
In conclusion, we have figured out the diene 5d that
provides diol 23, the key intermediate for fostriecin
synthesis, with high regioselectivity. The starting com-
pounds of the sequence disclosed herein are available as
optically active forms,23 and thence asymmetric synthe-
sis of fostriecin and analogues would be in our hand. In
addition, efficiency of various coupling reactions were
assessed for the formation of the diene moiety and the
results would be useful in the synthesis of other
molecules with a similar diene moiety.
diene 21 stereoselectively. Finally, protection of the
hydroxyl group at C(5) as an EE group furnished diene
5a in 72%.20 This two-step formation of diene was
successfully applied to coupling between acetylene 7a
and iodides 18a,b to produce dienes 5e and 5f in good
yields after protection as EE and TBS ethers, respec-
tively (equation not shown). Cross-coupling of stan-
nane 8b and iodide 6c was found to proceed under the
ligand-free Pd catalysis conditions, thus furnishing 5c in
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Scheme 5. Synthesis of the fostriecin intermediate 26.

Y. Kiyotsuka et al. / Tetrahedron Letters 43 (2002) 2725–2729
2729
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