New total synthesis of (+)-cystothiazole A

Article abstract of DOI:10.1016/S0040-4039(01)02207-9

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (7) derived from (2R,3S)-epoxy butanoate 8 followed by methylation gave the tetrahydro-2-furylidene acetate (-)-9, which was converted to the left-half aldehyde (

Full text of DOI:10.1016/S0040-4039(01)02207-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 643–645
New total synthesis of (+)-cystothiazole A
Keisuke Kato, Akira Nishimura, Yasuhiro Yamamoto and Hiroyuki Akita *
a
a
b
a,
a
School of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
b
Department of Chemistry, Faculty of Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 22 October 2001; accepted 16 November 2001
Abstract—Palladium-catalyzed cyclization–methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (7) derived from
(
2R,3S)-epoxy butanoate 8 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-9, which was converted to the
left-half aldehyde (+)-4. A Wittig reaction between (+)-4 and the phosphoranylide derived from the bithiazole-type phosphonium
iodide 5 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole A (2). © 2002 Elsevier Science Ltd. All rights reserved.
1
Antifungal substances, myxothiazole (1) and cystothia-
theleft-halfpartof1startingfrombenzyloxyacetaldehyde
2
8
zole A (2), were isolated from different strains of
myxobacterium Myxococcus fulvus and Cystobacter fus-
cus, respectively. They are related to the oudemansins A
is also reported. In this paper, we describe a new total
synthesis of (+)-cystothiazole A (2) based on a catalytic
9
synthesis of the b-methoxyacrylate moiety.
3
4
5
(
3a), B (3b), C (3c), which are also naturally occurring
congeners of b-methoxyacrylic acid produced by Oude-
mansiella mucida, Xerula species, Oudemansiella radicata,
respectively. The fungicidal activity of these b-methoxy-
acrylate (MOA) inhibitors (1, 2, 3a,b,c) has been shown
to be due to their ability to inhibit mitochondrial
respiration by blocking electron transfer between
Retrosynthetically, the synthesis of 2 can be achieved by
Wittig condensation of the left-half aldehyde 4 and the
right-half phosphonium iodide 5 by applying Martin’s
7
approach in the total synthesis of myxothiazole (1). The
aldehyde 4 can be derived from the tetrahydro-2-furyli-
dene acetate 6, which can be obtained by oxidative
6
cytochrome b and cytochrome c. The absolute structure
cyclization–methoxycarbonylation
of
(2R,3S)-3-
of cystothiazole A (2) was established by a combination
methylpenta-4-yne-1,2-diol (7) in the presence of Pd(II)/
p-benzoquinone in MeOH under a carbon monoxide
atmosphere. The synthesis of the chiral diol 7 can be
of spectroscopic analysis and chemical degradation of the
2
natural product. Although a number of chiral syntheses
1
0
of the b-methoxyacrylate moiety including the adjacent
achieved by the reaction of (2R,3S)-epoxy butanoate 8
3
b,4b,5b
chiral centers have been achieved,
a catalytic
and silyl-acetylide followed by reduction. An important
chiral synthon (2R,3S)-8 has been synthesized by us based
onthelipase-catalyzedasymmetrichydrolysisof(±)-(2,3)-
synthesis of the b-methoxyacrylate system has not been
reported so far. Total synthesis of a diastereomeric
mixture of myxothiazole (1) has been achieved, but chiral
synthesis of the left-half part possessing two chiral centers
10
anti-3-acetoxy-2-chloro-butanoate. A catalytic conver-
sion of 7 into 6 is a key step in this total synthesis, and
7
11
has not been carried out. Another racemic synthesis of
this type of reaction was previously reported.
OMe OMe
R
S
MeOOC
OMe
N
R1
Me
S
X
N
S
S
left half
OMe Me
X = Y = H
right half
R2
S
Y
Oudemansin A 3a
X = OMe Y = Cl Oudemansin B 3b
X = H Y = OMe Oudemansin X 3c
R = CONH2
Me
1
R2=
S
Me
Myxothiazole 1
Me
R = COOMe R = CHMe2
1
2
Cystothiazole A
2
*
0
Corresponding author.
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02207-9

6
44
K. Kato et al. / Tetrahedron Letters 43 (2002) 643–645
I- Ph3+P
N
OMe OMe
R
2
4
R
CHO
+
S
N
Me
MeOOC
O
Me
5
4
S
Me
O
HC
OH
R
2R
C
R
S
OH
Me
OH
R
COOMe
3S
MeOOC
Me
Me
6
7
(2R,3S)-8
O
a
b
OMe
-)-9
(
2R,3S)-8
(-)-7
76%
51%
MeOOC
HO
Me
Me
(
O
O
c
MeOOC
OMe
OMe
+
Me
H
H
MeOOC
(
+)-10 (5%)
11 (68%)
n.O.e. 8%
OMe
n.O.e. 6%
O
OMe OMe
d
e
H
t
CH OSiMe Bu
R3
84%
2
2
50%
MeOOC
Me
MeOOC
Me
(-)-12
R = CH OH (+)-13
3
2
f
R = CHO
3
(+)-4 (89%)
a; 1) Li+ -C
C
SiMe3 / Et AlCl 2) Bu N F 3) LiBH4
2 4
+
-
b; 1) Pd(OAc) (5 mol %) / CO (balloon) / p-benzoquinone / MeOH 2) MeI / Ag O
c; dil. HCl / THF
2
2
t
d; BuMe SiCl / imidazole / DMF
e; 1) Me SO / K CO / acetone 2) Et N(HF) / CH Cl
2 4 2 3 3 3 2 2
2
f; Dess-Martin periodinane
4
b
By applying the previously reported procedure, the
monoxide atmosphere (balloon) gave crude secondary
1
0
reaction of (2R,3S)-epoxy butanoate 8 and lithium
silyl-acetylide in the presence of Et AlCl, followed by
alcohol 6, which was immediately subjected to methyla-
tion using MeI in the presence of Ag O to afford the
2
2
the consecutive desilylation and reduction gave (−)-7
methoxy compound (−)-9 ([h] −69.9 (c=1.06, CHCl ))
D
3
12
13
(
[h]D −36.8 (c=0.93, CHCl )) in 76% overall yield.
in 51% overall yield. Acid treatment of (−)-9 provided
a hemiketal 11 (68%) along with the isomerized product
(+)-10 (5%). The geometry of (+)-10 was confirmed to
be Z-form because of NOE enhancement for the
olefinic proton and methine proton (8%); thence, that
of (−)-9 was deduced to be E-form. Silylation of 11 in
DMF at 80°C gave a silyl ether (−)-12 ([h]D −18.8
3
The synthesis of an alcohol (±)-13 corresponding to the
11
left-half part from (±)-7 was briefly reported, total
yield of (+)-13 from (−)-7 was improved in the chiral
synthesis.
The oxidative cyclization–methoxycarbonylation of (−)-
7
in the presence of Pd(OAc)2 (5 mol%)/p-benzo-
quinone (1.1 equiv.) in MeOH at 0°C under a carbon
(c=1.02, CHCl )) in 84% yield, which was subjected to
3
consecutive methylation (Me SO /K CO ) and desilyla-
2
4
2
3
R6
N
R5
MeOOC
N
N
N
S
c
e
Me
Me
R4
S
94%
S
S
Me
Me
R = COCH3
14
R = CONH
17
18
(96% from 15)
R = COOEt 19
6
4
5
2
a
b
d
f
R = CSNH
R = C(=CH )CH 15 (93%)
5
2
R = CH OH 20
6 2
4
2
3
g
h
4
R = CHMe2
16
R = CH I
21 (70% from 19)
R = CH P Ph I- 5 (80%)
6 2
+
6
2
3

K. Kato et al. / Tetrahedron Letters 43 (2002) 643–645
645
OMe OMe R7
N
i
R
R7=
5
(+)-2
+
S
S
N
8
2% (2/22 = 4/1)
Me
MeOOC
Me
S
(+)-22
Me
+
-
a; Ph P -Me Br / t-BuOK / toluene
b; H / 5% Pd-C / MeOH
c; NH / MeOH
3
2
3
d; Lawesson's reagent / benzene
e; BrCH2COCOOEt / EtOH
f; LiBH4
+
-
g; I / Ph P / imidazole
h; Ph P / benzene
i; Li N (SiMe ) / (+)-4 / THF
3 2
2
3
3
tion (Et N(HF) ) to afford an alcohol (+)-13 ([h] +76.1
witzsch, W.; Reifenstahl, G.; Wray, V.; Gerth, K. J.
Antibiot. 1980, 33, 1480–1490; (c) Trowitzsch, W.;
H o¨ fle, G.; Sheldrick, W. S. Tetrahedron Lett. 1981, 22,
3829–3832.
3
3
D
(
c=0.7, CHCl )) in 50% overall yield. The (E)-geometry
3
of (+)-13 was confirmed by the NOE enhancement for
the olefinic proton and the methoxyl group (6%). Dess–
Martin periodinane oxidation of (+)-13 afforded the
desired aldehyde (+)-4 ([h] +104.7 (c=0.55, CHCl )) in
2. Ojika, M.; Suzuki, Y.; Tsukamoto, A.; Sakagami, Y.;
Fudou, R.; Yoshimura, T.; Yamanaka, S. J. Antibiot.
1998, 51, 275–281.
3. (a) Isolation: Anke, T.; Hecht, H. J.; Schramm, G.;
Steglich, W. J. Antibiot. 1979, 32, 1112–1117; (b) chiral
synthesis: Akita, H.; Koshiji, H.; Furuichi, A.;
Horikoshi, K.; Oishi, T. Tetrahedron Lett. 1983, 24,
2009–2010.
D
3
8
9% yield, whose NMR spectra were identical with those
8
of the reported (±)-4.
1
4
Wittig olefination of methyl ketone 14 gave an exo-
olefin 15 in 93% yield. A catalytic hydrogenation of 15
followed by consecutive treatment with NH /MeOH and
3
Lawesson’s reagent yielded a thioamide 18 in 96% overall
yield form 15. The reaction of 18 and a-bromopyruvate
gave a bithiazole 19 in 94% yield, which was subjected
to consecutive treatment with LiBH and I /Ph P/imida-
4. (a) Isolation: Anke, T.; Besl, H.; Mocek, U.; Steglich,
W. J. Antibiot. 1983, 36, 661–666; (b) chiral synthesis:
Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett.
1986, 27, 5397–5400.
5. (a) Isolation: Anke, T.; Werle, A.; Bross, M.; Steglich,
W. J. Antibiot. 1990, 43, 1010–1011; (b) chiral synthe-
sis: Chida, N.; Yamada, K.; Ogawa, S. Chem. Lett.
1992, 687–690; (c) Akita, H.; Umezawa, I.; Nozawa,
M.; Nagumo, S. Tetrahedron: Asymmetry 1993, 4, 757–
760.
4
2
3
zole to provide an iodide 21 in 70% overall yield from
9. The reaction of 21 and triphenylphosphine gave a
1
phosphonium salt 5 in 80% yield, which was condensed
with (+)-4 in the presence of lithium bis(trimethylsil-
yl)amide in THF to afford a mixture ((+)-(E)-2/(+)-(Z)-
2
2=4/1) of olefins in 82% yield. Both isomers were
isolated by silica gel column chromatography to provide
+)-2 (colorless needles from n-hexane/AcOEt (20/1), mp
10–111°C, [h]D +109.3 (c=0.53, CHCl )) and (+)-22
6. Thierbach, G.; Reichenbach, H. Biochim. Biophys. Acta
1981, 638, 282–289.
(
1
7. Martin, B. J.; Clough, J. M.; Pattenden, G.; Waldron,
I. R. Tetrahedron Lett. 1993, 34, 5151–5154.
8. Backhaus, D. Tetrahedron Lett. 2000, 41, 2087–2090.
9. According to a private communication from Professor
M. Ojika (Nagoya University, Japan), his group
recently achieved the total synthesis of (+)-cystochiazole
A based on Evans’ asymmetric aldol condensation
strategy.
10. Kato, K.; Ono, M.; Akita, H. Tetrahedron: Asymmetry
1997, 8, 2295–2298.
11. Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita, H.
Tetrahedron Lett. 2001, 42, 4203–4205.
12. Satisfactory analytical data were obtained for all new
compounds.
3
(
[h] +240.5 (c=0.65, CHCl )). The physical data of the
D 3
synthetic (+)-2 were identical with those (mp 111–112°C,
[
h]D +109 (c=0.24, CHCl ), NMR) of the reported
3
2
natural product (+)-2.
In conclusion, palladium-catalyzed cyclization–methoxy-
carbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol
10
(
7) derived from (2R,3S)-epoxy butanoate 8 followed
by methylation gave the tetrahydro-2-furylidene acetate
−)-9, which was converted to the left-half aldehyde (+)-4.
(
A Wittig reaction between (+)-4 and the phosphoranylide
derived from the bithiazole-type phosphonium iodide 5
using lithium bis(trimethylsilyl)amide afforded the (+)-
cystothiazole A (2), whose spectral data were identical
with those of the natural product (+)-2.
13. A secondary alcohol 6 was found to decompose gradu-
ally during silica gel column chromatography. In a
small scale experiment, short column treatment gave
pure (−)-6 ([h]D −51.6 (c=0.91, CHCl )) in 76% yield,
3
References
which was subjected to methylation to provide (−)-9 in
87% yield.
1
. (a) Gerth, K.; Irschik, H.; Reichenbach, H.; Trow-
itzsch, W. J. Antibiot. 1980, 33, 1474–1479; (b) Trowi-
14. Akita, H.; Nozawa, M.; Nagumo, S. Chem. Pharm.
Bull. 1994, 42, 1208–1212.