Asymmetric total synthesis of 9-methoxystrobilurin K

Article abstract of DOI:10.1016/S0040-4039(01)00812-7

Asymmetric total synthesis of a potent antifungal and cytostatic 9-methoxystrobilurin K was achieved by developing a convergent and versatile synthetic route.

Full text of DOI:10.1016/S0040-4039(01)00812-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4531–4534
Asymmetric total synthesis of 9-methoxystrobilurin K
Hiromi Uchiro, Koh Nagasawa, Yasuyuki Aiba, Tomoya Kotake, Daiju Hasegawa and
Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 5 April 2001; revised 8 May 2001; accepted 11 May 2001
Abstract—Asymmetric total synthesis of a potent antifungal and cytostatic 9-methoxystrobilurin K was achieved by developing
a convergent and versatile synthetic route. © 2001 Elsevier Science Ltd. All rights reserved.
9-Methoxystrobilurin K (1) was first isolated from a
mycelial culture of the Favolaschia by Anke and co-
workers in 19951 as a new and potent analogue of
b-methoxyacrylate antibiotics (MOAs). The compound
was originally proposed as another structure;1 however,
Blunt and Munro et al. claimed a benzodioxepin-type
structure 1 in 1997.2 Recently, Anke and Steglich et al.
formally revised the structure to 1 by the comparison of
the synthetic benzodioxepin moiety with the degrada-
tion product of natural strobilurin K.3
the structure–activity relationship on the side-chain
moiety is expected for the development of new anti-
tumor agents; however, asymmetric synthesis of 9-
methoxystrobilurin K or its derivative has not yet been
developed.
In our previous paper, a total synthesis of 9-methoxy-
strobilurin A (2), which is the simplest 9-methoxy-
strobilurin-type MOA, was reported.5 In this communi-
cation, we would like to describe the first total synthesis
OMe
OMe
O
O
OMe
OMe
MeOOC
MeOOC
O
9-Methoxystrobilurin K (1)
9-Methoxystrobilurin A (2)
9-Methoxystrobilurin K (1) exhibits strong antifungal
activities toward a wide variety of fungi by specific
binding to the Qo-center of cytochrome b and inhibit-
ing mitochondrial respiration in a similar manner as
other natural and artificial MOAs. In addition, 1 shows
remarkable cytostatic activity toward human-derived
tumor cell lines at very low concentration without
showing any significant cytotoxity. The interesting cyto-
static property of 9-methoxystrobilurin K would be
closely related to the structure of an extended side-
chain moiety from the 1,5-benzodioxepin ring system
because strobilurin D and E having similar part on
aromatic ring also exhibit cytostatic activities.4 Study of
of the more complicated and potent analogue 9-
methoxystrobilurin K by a convergent and applicable
method including efficient construction of an enan-
tiomerically pure 1,5-benzodioxepin ring system having
a hindered and acid-sensitive allylic tertiary-secondary
ether linkage.
Our synthetic strategy for the benzodioxepin-type 9-
methoxystrobilurin analogue is shown in Scheme 1. A
convergent synthetic route was strongly desired for
future studies of the structure–activity relationships of
the side-chain moiety. A key-step of our approach is
the Heck reaction of aryl bromide with vinyl ketone,
and optically active 7-bromo-4,4-dimethyl-3,4-dihydro-
1,5-benzodioxepin-3-ol 6 was decided as the first syn-
thetic target. The 1,5-benzodioxepin skeleton in 6 might
be constructed by a Lewis acid-mediated intramolecular
cyclization6 of the chiral epoxy phenol 5.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00812-7

4532
H. Uchiro et al. / Tetrahedron Letters 42 (2001) 4531–4534
OMe OMe
O
O
O
O
O
O
RO
RO
RO
OMe
MeOOC
MeOOC
O
MeOOC
Ac
O
O
Br
Br
Br
HO
Br
RO
HO
Heck
Reaction
HO
O
O
O
O
+
O
6
5
O
HOOC
Cl
COOMe
COOMe
MeOOC
Scheme 1. Synthetic strategy for benzodioxepin-type 9-methoxystrobilurins.
The desired chiral epoxy phenol 5 was successfully
prepared from prenyl alcohol 3 using Sharpless asym-
metric epoxidation (Scheme 2). However, in the synthe-
sis of 7-bromo-type benzodioxepin, the yield of the
and isoprene under acidic conditions were unsuccessful
because of exclusive polymerization of isoprene; there-
fore,
a
stepwise approach was attempted.
A
Williamson-type coupling reaction of methyl 2-bromo-
propionate with sodium alkoxide of 6 smoothly pro-
ceeded to give the corresponding a-alkoxyester 8 in
good yield. The thus-obtained a-monomethylester 8
was further methylated with sodium bis(trimethyl-
silyl)amide-methyl iodide to afford the corresponding
a,a-dimethylester 9 and the desired secondary-tertiary
ether linkage was successfully constructed. The ester 9
was converted to the corresponding aldehyde 10, and
the following Wittig reaction gave the 7-bromo-4,4-
dimethyl-1,5-benzodioxepin 11 equipped with the natu-
ral-type side-chain moiety (Scheme 3).
desired 7-endo-cyclized product
6
significantly
decreased because of several undesirable side reactions.
The major side reaction was tin(IV) chloride-mediated
1,2-hydride migration of epoxy phenol 5 followed by an
intramolecular acetalization resulting in the corre-
sponding hemiketal of isopropyl ketone. This is proba-
bly due to the lowering of nucleophilicity of the
phenolic hydroxyl group on the bromo-substituted aro-
matic ring.
Therefore, several reaction conditions for the 7-endo
selective cyclization were examined and the yield was
greatly improved by use of diethyl ether as solvent at
0°C. Interestingly, a major by-product under these con-
ditions was a chlorohydrin 7 produced by ring-opening
and chlorine-transfer from tin(IV) chloride. It is noted
that the chlorohydrin 7 was efficiently converted in high
yield to the starting epoxy phenol 5 by a treatment with
potassium tert-butoxide at 0°C.
Heck reaction of the above 7-bromo-4,4-dimethyl-1,5-
benzodioxepin 11 with 2 equivalents of vinyl ketone 125
prepared from methyl itaconate was tried to obtain the
corresponding a,b-unsaturated ketone 13 (Scheme 4).
The reaction proceeded smoothly, and the desired cou-
pling product 13 was prepared in high yield (81%). The
conversion of enone 13 to the corresponding methyl
enol ether 15 was then examined; however, the allylic
and tertiary ether linkage was completely cleaved under
the acidic condition employed for the synthesis of 9-
methoxystrobilurin A.5 On the other hand, O-alkyla-
Next, construction of a hindered and allylic secondary–
tertiary ether linkage was studied. Several attempts for
direct ether synthesis utilizing 1,5-benzodioxepin-3-ol 6
(i)
(ii), (iii)
(iv), (v)
O
O
O
OH
OH
Op-NO2Bz
OTs
3 steps 75%
85%ee
>98%ee
3
O
Br
HO
O
O
62%
>99%ee
O
Br
HO
Br
(vii), (viii)
2 steps 75%
(ix)
(vi)
6
+
HO
O
Br
3 steps 87%
O
O
Cl
5
O
OH
7
26%
(x)
94%
Scheme 2. Synthesis of optically active 7-bromo-1,5-benzodioxepin-3-ol. (i) TBHP, Ti(OiPr)4, (+)-DIPT, CH2Cl2, −40°C; (ii)
p-NO2BzCl, Et3N, 0°C; (iii) recryst. from Et2O; (iv) NaOMe, MeOH, Et2O, 0°C; (v) TsCl, DMAP, CH2Cl2, Et3N, 0°C; (vi)
K2CO3, 5-bromo-2-hydroxyacetophenone 3, DMF, rt; (vii) mCPBA, benzene, 60°C; (viii) DIBAH, THF, −78°C; (ix) SnCl4, Et2O,
0°C; (x) KOtBu, THF, −15°C.

H. Uchiro et al. / Tetrahedron Letters 42 (2001) 4531–4534
4533
O
O
O
O
Br
Br
O
O
Br
(ii)
(i)
HO
MeOOC
O
MeOOC
O
82%
62%
6
8
9
O
O
O
O
Br
Br
(v)
OHC
O
O
94%
(iii)
10
11
70%
(iv)
96%
+
O
O
Br
HO
O
21%
Scheme 3. Construction of hindered allylic tertiary-secondary ether linkage. (i) NaH, methyl 2-bromopropionate, THF, 0°C; (ii)
NaHMDS, MeI, THF, −78°C; (iii) DIBAH, CH2Cl2, −78°C; (iv) (COCl)2, DMSO, Et3N, CH2Cl2, −60°C; (v) Ph3PꢀCH2,
DMSO–THF, rt.
O
OMe
O
O
O
O
O
O
O
Br
(i)
(iii)
84%
O
O
O
+
81%
ROOC
MeOOC
MeOOC
11
12
13 : R = Me
14 : R = H
15 (E / Z = 1 : 4)
(ii)
90%
OMe
OMe
OMe COOMe
O
O
O
O
O
(iv) ~ (v)
+
+
O
OMe
OMe
MeOOC
MeOOC
O
OMe
9-methoxystrobilurin K (1)
3 steps 23% (Total 41%)
unseparable mixture
3 steps 57%
(vi)
33%
Scheme 4. Total synthesis of 9-methoxystrobilurin K. (i) 20 mol% Pd(OAc)2, PPh3, Et3N, 100°C; (ii) aq. NaOH–MeOH, rt then
HCl; (iii) KOtBu, MeI, DMF, −45 to −15°C; (iv) NaH, HCOOMe, rt; (v) K2CO3, Me2SO4, HCOOMe, rt; (vi) hw (u: 365 nm),
acetone–benzene, rt.
tion of enolate under several basic conditions (e.g.
potassium bis(trimethylsilyl)amide-methyl triflate) gave
complex mixtures. We assumed that an undesirable side
reaction occurred after intramolecular lactonization of
the enolic hydroxyl group. In order to prevent the
intramolecular reaction, a stepwise double methylation
was attempted. First, the ester 13 was hydrolyzed to
afford the corresponding carboxylic acid 14. A dianion
was generated by treatment of the carboxylic acid 14
with potassium tert-butoxide in dimethylformamide at
−45°C. By the addition of excess dimethyl sulfate to the
dianion at −45 to −15°C, the double methylation pro-
ceeded successively and methyl enol ether 15 was
obtained in good yield. Treatment of the enol ether 15
with sodium hydride–methyl formate, followed by the
addition of dimethyl sulfate and potassium carbonate
gave a mixture of the geometrical isomers of 9-
methoxystrobilurin K (1). The mixture was isomerized
twice by irradiation with an ultraviolet lamp (u: 365
nm) and the desired 1 was successfully obtained (three
steps total 41% yield) along with other isomerization-
incomplete isomers.7 The physical data of the synthetic
9-methoxystrobilurin K8 were in good accordance with
those of the natural product reported by Anke’s group.1
Thus, the first asymmetric total synthesis of 9-
methoxystrobilurin K was successfully achieved. It
should be emphasized that the present methodology
could be applied to the synthesis of various 9-
methoxystrobilurin-type b-MOAs. Further investiga-
tion into the structure–activity relationships and
development of a new and pharmacologically superior
analogue are now in progress.
References
1. Zapf, S.; Werle, A.; Anke, T.; Klostermeyer, D.; Steffan,
B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1995, 34,
196–198.
2. Nicholas, G. M.; Blunt, J. W.; Cole, A. L. J.; Munro, M.
H. G. Tetrahedron Lett. 1997, 38, 7465–7468.
3. Hellwig, V.; Dasenbrock, J.; Klostermeyer, D.; Kroiß, S.;
Sindlinger, T.; Spiteller, P.; Steffan, B.; Steglich, W.;
Engler-Lohr, M.; Semar, S.; Anke, T. Tetrahedron 1999,
55, 10101–10118.
4. (a) Weber, W.; Anke, T.; Bross, M.; Steglich, W. Planta.
Med. 1990, 56, 446–450; (b) Weber, W.; Anke, T.; Steffan,
B.; Steglich, W. J. Antibiot. 1990, 43, 207–212.

4534
H. Uchiro et al. / Tetrahedron Letters 42 (2001) 4531–4534
5. Uchiro, H.; Nagasawa, K.; Aiba, Y.; Kobayashi, S. Tetra-
hedron Lett. 2000, 41, 4165–4168.
6. Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J.
Am. Chem. Soc. 1996, 118, 557–579.
7. The irradiation condition has not yet been optimized in
terms of the light density.
8. Physical data of synthesized 9-methoxystrobilurin K (1):
1H NMR (l, 300 MHz, CDCl3) 1.23 (s, 3H), 1.32 (s, 6H),
1.43 (s, 3H), 1.89 (s, 3H), 3.65 (s, 3H), 3.68 (dd, 1H,
J=3.3, 7.9 Hz), 3.71 (s, 3H), 3.81 (s, 3H), 3.98 (dd, 1H,
J=7.7, 12.3 Hz), 4.22 (dd, 1H, J=3.3, 12.3 Hz), 5.15 (d,
1H, J=10.6 Hz), 5.17 (d, 1H, J=17.6 Hz), 5.88 (dd, 1H,
J=10.8, 17.6 Hz), 6.37 (d, 1H, J=15.8 Hz), 6.63 (d, 1H,
J=15.9 Hz), 6.82 (d, 1H, J=8.6 Hz), 6.93 (dd, 1H, J=2.0,
8.8 Hz), 6.94 (d, 1H, J=2.0 Hz), 7.39 (s, 1H); 13C NMR
(l, 75.5 MHz, CDCl3) 16.3, 21.8, 26.3, 26.7, 28.1, 51.5,
59.5 61.8, 71.8, 75.5, 76.1, 81.6, 110.5, 114.4, 118.1, 120.1,
120.3, 121.5, 122.5, 126.8, 132.9, 143.5, 146.4, 150,6, 152.6,
159.4, 168.1; [h]2D4=−8.87 (c=0.860, CHCl3); HRMS calcd
for C27H36O7 (M+) 472.2461, found 472.2437.
.