Asymmetric total synthesis of MK8383: the iron-mediated coupling reaction is the only effective method for the construction of the (Z)-trisubstituted side-chain alkene

Article abstract of DOI:10.1016/j.tetlet.2008.10.138

The first asymmetric total synthesis of MK8383 through the iron-mediated coupling reaction is described. In this total synthesis, the key step was clearly the stereoselective construction of the (Z)-trisubstituted side-chain alkene. Although this problem

Full text of DOI:10.1016/j.tetlet.2008.10.138

Tetrahedron Letters 50 (2009) 232–235
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Asymmetric total synthesis of MK8383: the iron-mediated coupling
reaction is the only effective method for the construction of the
(Z)-trisubstituted side-chain alkene
*
Nobuyuki Hayashi, Masahisa Nakada
Department of Chemistry and Biochemistry, Advanced School of 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:
The first asymmetric total synthesis of MK8383 through the iron-mediated coupling reaction is described.
In this total synthesis, the key step was clearly the stereoselective construction of the (Z)-trisubstituted
side-chain alkene. Although this problem was seemingly easy to resolve, in fact it presented us an oppor-
tunity to evaluate the coupling reactions reported to date, and the iron-mediated coupling reaction was
found to be the only effective method for the stereoselective construction of the (Z)-trisubstituted side-
chain alkene.
Received 5 October 2008
Revised 23 October 2008
Accepted 28 October 2008
Available online 3 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
MK8383 (Fig. 1) was isolated from Phoma sp. T2526 by a joint
research group organized by Meiji Seika Kaishya, Ltd, and Mitsubi-
shi Chemical Corporation.1 This compound comprises a cis-fused
dehydrodecalin ring with (E,E)-pentadienoic acid and a (Z)-trisub-
stituted alkene as characteristic substituents. The structure of
MK8383 is almost the same as that of (+)-phomopsidin2 (Fig. 1),
except for the geometry of the alkene side chain.
We reported the first total synthesis of (+)-phomopsidin based
on the construction of the cis-fused dehydrodecaline skeleton by
a
stereoselective transannular Diels–Alder (TADA) reaction.3
Accordingly, we started to investigate the asymmetric total synthe-
sis of MK8383 through the stereoselective construction of the (Z)-
trisubstituted alkenyl side chain. However, although the construc-
tion of the (Z)-trisubstituted alkenyl side chain was considered
easy since many methods for the stereoselective construction of
(Z)-trisubstituted alkenes have been reported to date, this seem-
ingly easy challenge presented us an opportunity to evaluate the
coupling reactions reported so far. We herein report the first
asymmetric total synthesis of MK8383 based on the iron-mediated
coupling reaction, which was the only effective method for the
construction of the (Z)-trisubstituted alkene side chain.
Clearly, the stereoselective construction of the (Z)-trisubsti-
tuted alkene side chain presented a problem in the total synthesis
of MK8383, as we reported the synthesis of the cis-fused dehyd-
rodecaline skeleton. Among various methods, the cis-addition of
organometallic reagents to alkynes4a,5 and the coupling reaction
of alkenes incorporating a leaving group with organometallic re-
agents4b have been employed in the synthesis of natural products
due to their wide applicability. Therefore, a carbometallation–pro-
tonation sequence of the alkyne 1 (method A) affording the product
2 and a transition-metal catalyzed coupling reaction of the alkene
3 incorporating a leaving group with an organometallic reagent
(method B) affording the product 4 were promising methods for
this purpose (Scheme 1).
MK8383 shows inhibitory activity against the assembly of
microtubule proteins derived from the porcine brain at an IC50 of
8.0
of 5.7
l
M, which is comparable with that of (+)-phomopsidin (IC50
l
M).2 MK8383 also exhibits antibacterial activities against
a variety of phytopathogens (e.g., gray mold Botrytis cinerea).1
Therefore, MK8383 and its derivatives are regarded as promising
fungicides. Due to the above structures and biological activities,
we are interested in the structure–activity relations of MK8383
and (+)-phomopsidin.
CO2H
CO2H
H
H
H
H
OH
OH
(+)-phomopsidin
MK8383
First, we conceived that a carbometallation–protonation se-
quence of alkyne 1 (R = Me) would be a straight-forward method;
hence, we first examined the reaction using the model compound 5
(Scheme 2). However, the carbometallation of the alkyne 55 gave
the products 6 and 7 in low yield with almost no regioselectivity,
Figure 1. Respective structures of MK8383 and (+)-phomopsidin.
* Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.138

N. Hayashi, M. Nakada / Tetrahedron Letters 50 (2009) 232–235
233
method A
OTBDPS
OTBDPS
CO2Me
OTBDPS
OTBDPS
n-BuLi, THF
-78 oC; then
H
H
H
R
Br
H
H
H
Me
Br
ClCO2Me
R
H
TIPSO
TIPSO
9
8
H
TIPSO
1
2
TIPSO
OTBDPS
methodB
H
H
Me2CuLi
OTBDPS
L
OTBDPS
R
THF, -78 oC
CO2Me
H
H
H
Me
TIPSO
10
Scheme 3.
R
H
TIPSO
TIPSO
L=leaving group
3
4
Scheme 1.
1) MeOAc, LDA
THF, -78 oC, 89%
OTBDPS
CO2Me
OTBDPS
2) Dess-Martin
Oxidn, CH2Cl2
room temp, 79%
CHO
11
Cp2ZrCl2 (1.0 equiv)
Me3Al (10.0 equiv)
CH2Cl2, rt, 30 min
O
12
OTBDPS
Et3N, HMPA, 0 oC;
then ClP(O)(OPh)2
OTBDPS
then H2O (1.0 equiv)
-30 oC to -10 oC, 10 min
OP(O)(OR)2
5
then 5, -30 oC to 0 oC, 17 h
DMAP (cat.)
room temp, 18 h
87%, single isomer
MeO2C
13 (R=Ph)
13' (R=Et)
OTBDPS
OTBDPS
+
Scheme 4.
7 (11%)
6 (13%)
Scheme 2.
Then, we turned our attention to method B in Scheme 1.
Although the stereoselective preparation of compound
3
(R = Me), incorporating an energetically unfavorable alkene, was
thought to be difficult, compound 3 (R = ester) was expected to
be readily obtainable from the corresponding b-keto ester. For
example, the stereoselective preparation of both geometrical iso-
mers of enol phosphates from the corresponding b-keto esters
has been reported.8
We prepared the (E)-enol phosphate 13 (R = Ph) as the model
compound in order to examine the coupling reaction (Scheme 4).
The aldol reaction of the aldehyde 11 with the lithium enolate of
methyl acetate afforded the desired product (89%), followed by
suggesting that this protocol would be unsuitable for the synthesis
of the side chain.
Therefore, although transformations of the functional group
after the coupling reaction would be inevitable, we examined the
cis-addition of a cuprate6 with the alkyne 9 incorporating an ester
group at the alkyne terminal, which was readily prepared from the
known alkenyl dibromide 83 (Scheme 3) by the Corey–Fuchs proto-
col.7 To our surprise, however, no products were formed in the
reaction of the alkyne 9 with lithium dimethyl cuprate.
Table 1
Coupling reaction of enol phosphates 13 and 130
OTBDPS
OTBDPS
OTBDPS
OP(O)(OR)2
conditions
CO2Me
+
O
MeO2C
R1 R2
12
14
14
Z
E
(R1=CO2Me, R2=H)
(R1=H, R2=CO2Me)
13 (R=Ph)
13' (R=Et)
Entry
Substrate
Reagents (equiv)
Solvent
Temperature (°C)
Time (h)
Yielda (%)
14Z
13
12
1
2
3
4
5
6
7
13
13
13
13
13
130
130
Ni(acac)2 (0.9), Me3Al (6.0)
Me2CuMgCl (8.0)
Me3FeLi (3.0)
THF
THF
THF
0
0
0
0
0
1.5
3.5
1.5
1.5
1
0
—
26
2
26b
—
0
0
88
25
65
0
—
c
c
c
60
52
12
37
28
Me3FeLi (3.0)
THF/NMP = 20/1
THF/NMP = 20/1
(CH2Cl)2
Fe(acac)3 (0.6), MeMgCld (9.0)
Pd(PPh3)4 (0.3), Me3Al (6.0)
Fe(acac)3 (0.9), MeMgCld (12)
0
80
0
16
2
0e
0e
THF/NMP = 20/1
a
Isolated yields.
30% of 14E was formed.
No reaction.
THF solution was used.
Recovered yield of 13.
b
c
d
e

234
N. Hayashi, M. Nakada / Tetrahedron Letters 50 (2009) 232–235
reaction provided compound 14Z in 65% yield (entry 7). The yield
OTBDPS
CHO
OTBDPS
O
1) LDA, AcOMe
THF, -78 o
94%
C
obtained by using the enol phosphate 13 (R = Ph) was higher, and
therefore we decided to employ the iron-mediated coupling
reaction of the diphenyl enol phosphate in order to pursue the
effective and stereoselective construction of the side chain in
MK8383.
We prepared the requisite enol phosphate 17 as shown in
Scheme 5 starting from the aldol reaction of the known aldehyde
153 with an enolate of methyl acetate (94%). The resultant alcohol
was subjected to the Dess–Martin oxidation to provide the b-keto
ester 16 (80%), which was successfully converted into the enol
phosphate 17, stereoselectively (99%), under the conditions de-
scribed in Scheme 5.
H
H
CO2Me
2) Dess-Martin
Oxidn, CH2Cl2
room temp
80%
H
H
15
OTIPS
16
OTIPS
OTBDPS
OP(O)(OPh)2
Et3N, HMPA, 0 oC;
then ClP(O)(OPh)2
H
CO2Me
DMAP (cat.), room temp
99% (single isomer)
H
17
OTIPS
The coupling reactions of the enol phosphate 17 are summa-
rized in Table 2. The reaction of the enol phosphate 17 with MeM-
gCl (5.0 equiv) in the presence of a catalytic amount of Fe(acac)3
(0.2 equiv) in the mixed solvent system (THF/NMP = 20/1) afforded
the desired product in only 12% yield, the b-keto ester 16 was
formed in 22% yield, and a certain amount of the enol phosphate
17 remained (64%, entry 1). Interestingly, compared with the suc-
cessful coupling reaction of the model compound 13 under the cat-
alytic conditions (Table 1, entry 5), the reaction with 10 equiv of
MeMgCl in the presence of 1 equiv Fe(acac)3 did not improve the
results (entry 2). However, the reaction with 30 equiv of MeMgCl
and 3 equiv of Fe(acac)3 provided the desired product 18 in 26%
yield (entry 3). Therefore, large amounts of the reagents were used
for this reaction, and 60 equiv of MeMgCl and 5 equiv of Fe(acac)3
were found to effectively afford product 18 in 82% yield (entry 4).14
In this case, the starting material 17 disappeared, and the b-keto
ester 16 was not formed.
Scheme 5.
Dess–Martin oxidation9 to give the b-keto ester 12 (79%), which
was treated with ClP(O)(OPh)2 in the presence of triethylamine,
providing the enol phosphate 13 (R = Ph), stereoselectively (87%).
The enol phosphate 130 (R = Et) was also prepared by the same
method as the single isomer (89%).
The coupling reaction of the enol phosphate 13 (R = Ph) with
10
Me3Al in the presence of Ni(acac)2 produced a geometrical mix-
ture of compounds 14E and 14Z (Table 1, entry 1). The reaction
with Me2CuMgCl11 gave no products (entry 2). Although Corey
and Seibel reported the reaction of an enol phosphate with lithium
trimethyl ferrate,12 the reaction of the enol phosphate 13 afforded
the b-keto ester 12 (entries 3 and 4). On the other hand, the reac-
tion of MeMgCl in the presence of a catalytic amount of Fe(acac)3 in
the mixed solvent system (THF/NMP = 20/1)13 successfully pro-
vided the desired product 14Z in 88% yield without the formation
of its isomer, 14E, and the b-keto ester 12 was formed in only 12%
yield (entry 5). The reaction of the enol phosphate 130 (R = Et) with
Me3Al in the presence of a catalytic amount of Pd(PPh3)4 gave
compound 14Z in low yield (25%, entry 6), and the iron-mediated
In addition to the iron-mediated reaction, we surveyed other
frequently used reagents for this type of coupling reaction. How-
ever, organocopper reagents (entries 5 and 6) and palladium-med-
iated reactions (entries 7–9) yielded disappointing results, and
nickel-mediated reactions (entries 11, 12, and 15) afforded product
17 in low yield.
Table 2
Coupling reaction of enol phosphates 17
OTBDPS
OTBDPS
OTBDPS
OP(O)(OPh)2
O
H
H
H
CO2Me
conditions
+
CO2Me
CO2Me
H
H
H
17
OTIPS
18
OTIPS
16
OTIPS
Entry
Reagents (equiv)
Solvent
Temperaturea (°C)
Timea (h)
Yieldb (%)
17
18
16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Fe(acac)3 (0.2), MeMgClc (5.0)
Fe(acac)3 (1.0), MeMgClc (10)
Fe(acac)3 (3.0), MeMgClc (30)
Fe(acac)3 (5.0), MeMgClc (60)
Me2CuMgCl (3.0)
THF/NMP = 20/1
THF/NMP = 20/1
THF/NMP = 20/1
THF/NMP = 20/1
THF
0
0
0
0
1
1
1
1
64
76
61
—
12
5
26
82
—
22
16
10
—
ꢀ30, 0, rt
ꢀ30, 0, rt
rt, 50, 80
rt, 50, 80
rt, 50
0, rt
0, rt
0
rt
rt
2, 1, 1
2, 1, 1
1, 1, 1
1, 1, 1
1, 1
1, 1
1, 1
1
87
21
57
9
11
55
12
—
Me2Cu(CN)Li2 (4.0)
THF
—
—
Pd(PPh3)4 (0.1), Me3Al (2.0)
Pd(PPh3)4 (1.0), Me3Al (10)
Pd(PPh3)4 (5.0), Me3Al (60)
Ni(acac)2 (0.1), MeMgClc (2.5)
Ni(acac)2 (1.0), MeMgClc (10)
Ni(acac)2 (5.0), MeMgClc (60)
NiCl2(dppe) (0.1), MeZnCl (2.5)
NiCl2(dppe) (1.0), MeZnCl (10)
NiCl2(dppe) (5.0), MeZnCl (60)
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
Et2O
Et2O
Et2O
Benzene
Benzene
Benzene
Trace
d
d
d
—
—
—
67
63
—
—
Trace
20
10
12
20
0
—
19
1
1
1
NRe
93
31
0
Trace
Trace
rt
a
The reaction was carried out at the indicated temperatures for the indicated times.
Isolated yields.
THF solution was used.
Decomposition occurred.
No reaction.
b
c
d
e

N. Hayashi, M. Nakada / Tetrahedron Letters 50 (2009) 232–235
235
In the case of the enol phosphate 13 (Table 1, entry 5), the reac-
tion was completed by use of a catalytic amount of Fe(acac)3
(0.6 equiv), although the amount was relatively large. On the other
hand, the reaction of the enol phosphate 17 required a large excess
of the reagents. This can be attributed to the steric hindrance de-
rived from the two adjacent substituents (a tert-butyldiphenyl-
silyloxymethyl group and a methyl group), which were placed at
both sides of the enol phosphate substituent. That is, the steric hin-
drance retarded the coupling reaction, and therefore large amounts
of the reagents were required. Furthermore, the reactive species
generated in the reaction mixture to provide product 18 were
not clear, although it could be possible to exclude the ironate com-
plex since Me3FeLi provided no coupling products in the reaction
with the enol phosphate 13 (Table 1, entries 3 and 4).
After we had established the synthetic route to compound 18,
we examined its transformation into MK8383 (Scheme 6). The es-
ter 18 was reduced by DIBAL to provide the allylic alcohol (97%),
which was subjected to bromination. Although a mixture of the
geometrical isomers was formed by the use of PPh3 and CBr4, no
isomerization was observed when PBr3 was used. The allylic bro-
mide 19 thus obtained was subjected to a reaction with LiAlH4
(71%, two steps), followed by treatment with TBAF to provide the
diol 20 (quant). The primary and secondary hydroxyls of the diol
were protected as a TBS ether (89%) and a benzoate (96%), respec-
tively, and product 21 was treated with TBAF to give the alcohol
(99%), which was oxidized with Dess–Martin periodinane9 to pro-
vide the aldehyde 22 (98%). The Horner–Wadsworth–Emmons
reaction of the aldehyde 22 with the phosphonate 23 successfully
afforded the (E,E)-dienoate 24 (94%) as a single isomer, which was
subjected to the hydrolysis under basic conditions to accomplish
the total synthesis of MK8383 (83%). The synthetic MK8383 was
spectroscopically identical in all respects with the naturally occur-
ring MK8383,1 thereby confirming the asymmetric total synthesis
of MK8383.
In conclusion, we accomplished the first asymmetric total syn-
thesis of MK8383 by utilizing the iron-mediated coupling reaction.
In this total synthesis, the problem with the synthesis was clearly
the stereoselective construction of the (Z)-trisubstituted side-chain
alkene. However, although this problem was seemingly easy to re-
solve, in fact it presented us an opportunity to evaluate the cou-
pling reactions reported to date, and the iron-mediated coupling
reaction was found to be the only effective method for the stereo-
selective construction of the (Z)-trisubstituted side-chain alkene of
MK8383. Although the iron-mediated coupling reaction has not
been extensively applied to the synthesis of natural products,13 it
is considered relatively more reliable than other coupling reac-
tions, which failed to give the desired product as described above.
Acknowledgments
We thank Dr. Nobuto Minowa (Meiji Seika Kaishya, Ltd, Japan)
for kindly providing a sample of MK8383. This work was finan-
cially supported in part by a Waseda University Grant for Special
Research Projects, a Grant-in-Aid for Scientific Research (B), and
the Global COE program ‘Center for Practical Chemical Wisdom’
by MEXT.
References and notes
1. Wakui, F.; Harimaya, K.; Iwata, M.; Sashita, R.; Chiba, N.; Mikawa, T. Jpn. Kokai
Tokkyo Koho JP 07,126, 211, May 16, 1995, Appl. Oct. 29, 1993; Chem. Abstr.
1995, 123, 105272b.
2. (a) Kobayashi, H.; Meguro, S.; Yoshimoto, T.; Namikoshi, M. Tetrahedron 2003,
59, 455–459; (b) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro, S.;
Akano, K. Chem. Pharm. Bull. 2000, 48, 1452–1457; (c) Namikoshi, M.;
Kobayashi, H.; Yoshimoto, T.; Hosoya, T. J. Antibiot. 1997, 50, 890–892.
3. Suzuki, T.; Usui, K.; Miyake, Y.; Namikoshi, M.; Nakada, M. Org. Lett. 2004, 6,
553–556.
4. (a) Knochel, P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 865–911 and references cited therein; (b)
Tamao, K.. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, pp 435–480 and references cited therein.
5. Negishi, E. Pure Appl. Chem. 1981, 53, 2333–2356. and references cited therein.
6. Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91, 1851–1852.
7. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
8. Alderdice, M.; Spino, C.; Weiler, L. Tetrahedron Lett. 1984, 25, 1643–1646.
9. (a) Dess, D. E.; Martin, J. C. J. Org. Chem. 1991, 56, 7277–7287; (b) Frigerio, M.;
Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537–4538.
OTBDPS
1) DIBAL, CH2Cl2
H
-78 oC, 97%
18
2) PBr3, pyridine
Br
Et2O, room temp
H
19
OTIPS
OH
1) TBSCl, imidazole
CH2Cl2, room temp
89%
1) LiAlH4, Et2O
room temp
71% (2 steps)
H
10. Hayashi, T.; Katsuro, Y.; Okamoto, Y.; Kumada, M. Tetrahedron Lett. 1981, 22,
4449–4452.
2) Bz2O, DMAP
CH2Cl2, room temp
96%
2) TBAF, THF
reflux, quant
H
11. The reaction with Me2CuLi provided the b-keto ester 15 only.
12. Corey, E. J.; Seibel, W. L. Tetrahedron Lett. 1986, 27, 905–908.
13. (a) Reviews, see: Sherry, B. D.; Fürstner, A. Acc. Chem. Res., in press; (b)
Fürstner, A.; Martin, R. Chem. Lett. 2005, 34, 624–629; (c) Bolm, C.; Legros, J.;
Paih, J. L.; Zani, L. Chem. Rev. 2004, 104, 6217–6254; (d) Cahiez, G.; Avedissian,
A. Synthesis 1998, 1199–1205. The first report regarding the iron-catalyzed
coupling reactions of Grignard reagents with alkenyl halides: (e) Tamura, M.;
Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487–1489.
OH
20
OTBS
H
CHO
H
1) TBAF, THF
reflux, 99%
2) Dess-Martin
Oxidn, CH2Cl2
room temp
98%
H
14. Preparation of compound 18: To a stirred solution of the enol phosphonate 17
(0.0152 g, 0.0162 mmol) and Fe(acac)3 (0.0288 g, 0.0815 mmol) in a mixed
solvent (THF/NMP = 20/1, 3.15 mL) was added MeMgCl (0.324 mL, 3.0 M in
THF) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was
quenched with saturated aqueous NH4Cl (10 mL) and the aqueous layer was
extracted with Et2O (20 mL ꢁ 3). The combined organic layer was dried over
MgSO4, filtered, and evaporated. The residue was purified by silica gel
chromatography (hexane/ethyl acetate = 50/1) to give the ester 18 (0.0093 g,
H
22
OBz
21
OBz
CO2Et
(EtO)2(O)P
CO2Et
23
H
82%) as
a
colorless oil: Rf = 0.52 (hexane/ethyl acetate = 10/1); 1H NMR
(400 MHz, CDCl3) d 7.65–7.57 (4H, m), 7.44–7.39 (6H, m), 5.75 (1H, s), 5.65
(1H, s), 4.46–4.39 (1H, m), 3.75 (1H, ddd, J = 11.7, 4.4, 4.4 Hz), 3.70 (3H, s), 3.64
(1H, d, J = 9.8 Hz), 3.50 (1H, dd, J = 9.8, 5.4 Hz), 2.72–2.64 (1H, m), 2.56–2.47
(1H, m), 1.78–1.70 (1H, m), 1.68–1.60 (2H, m), 1.59 (3H, s), 1.52 (3H, s), 1.50–
1.36 (1H, m), 1.13–0.94 (35H, m); 13C NMR (100 MHz, CDCl3) d 166.2, 161.7,
135.5, 135.4, 134.1, 133.8, 132.5, 129.5, 127.6, 127.5, 124.0, 118.9, 73.6, 63.3,
50.8, 42.1, 42.0, 40.7, 37.6, 33.8, 31.6, 28.2, 26.7, 23.0, 22.1, 19.2, 19.2, 18.2,
12.4; IR (neat) mmax 2936, 2868, 1716, 1632, 1464, 1430, 1374, 1362, 1208,
1150, 1112, 1088, 1010, 998, 882, 862, 824, 762, 740, 702 cmꢀ1; FAB-MS
LiHMDS, THF
-78 oC to 0 oC
94%
H
OBz
24
LiOH-H2O
MK8383
EtOH / H2O (4 / 1)
83%
[M+H]+ calculated for C43H67O4Si2: 703.4578, found: 703.4599; ½a D18
ꢂ
+51.6 (c
0.4, CHCl3).
Scheme 6.