First synthesis of (+)-myxothiazol A

Article abstract of DOI:10.1016/j.tetlet.2008.09.125

First convergent synthesis of (+)-myxothiazol A (1) was achieved based on modified (one-pot) Julia olefination between (3,5R)-dimethoxy-(4R)-methyl 6-oxo-(2E)-hexenamide (2), corresponding to left-side of the final molecule, and E-4-2′-(1S,6-dimethylheptadiene)-(2,4′-bis-thiazole)-4-methybenzothiazole sulfone (4) corresponding to right-side.

Full text of DOI:10.1016/j.tetlet.2008.09.125

Tetrahedron Letters 49 (2008) 7024–7026
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Tetrahedron Letters
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First synthesis of (+)-myxothiazol A
Yuki Iwaki a,b, Masahiro Kaneko a, Hiroyuki Akita a,
*
a Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
b Research Institute, Novartis Pharma K.K., 8 Ohkubo, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
First convergent synthesis of (+)-myxothiazol A (1) was achieved based on modified (one-pot) Julia olef-
ination between (3,5R)-dimethoxy-(4R)-methyl 6-oxo-(2E)-hexenamide (2), corresponding to left-side of
the final molecule, and E-4-20-(1S,6-dimethylheptadiene)-(2,40-bis-thiazole)-4-methybenzothiazole
sulfone (4) corresponding to right-side.
Received 28 August 2008
Accepted 22 September 2008
Available online 25 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Myxothiazol A
Antibiotic
Total synthesis
Asymmetric synthesis
Modified Julia olefination
1. Introduction
of 2 was possible due to the optical resolution of the intermediate.
The preparation of (4R,5R)-2 was achieved by the following syn-
Myxothiazol A (1) possessing a bithiazole skeleton as well as a
b-methoxyacrylate moiety was isolated from the myxobacterium
Myxococcus fulvus strain Mxf16.1 Myxothiazol A is active against
many filamentous fungi and completely inhibits growth of Mucor
thetic route. By applying the previously reported procedure,5 the
reaction of (2R,3S)-epoxy butanoate 56and lithium silyl-acetylide
in the presence of Et2AlCl gave 6 {½a D24
ꢁ7.57 (c 1.09, CHCl3)} in
ꢀ
72% yield. Methylation of 6 followed by consecutive desilylation
hiemalis at a concentration of 2
l
g/ml.1 The fungicidal activity of
and reduction afforded 8 {½a D27
ꢁ27.6 (c 1.05, CHCl3)} in 40% overall
ꢀ
the b-methoxyacrylate (MOA) inhibitors has been shown to be
due to their ability to inhibit mitochondrial respiration by blocking
electron transfer between cytochrome b and cytochrome c.2 The
structure of myxothiazol A (1) was established by a combination
of chemical degradation and NMR study, and its absolute configu-
ration at C(14)–carbon was determined by X-ray analysis of its
degradation product.3 The synthesis of a diasteromeric mixture
of 1 was achieved based on a Wittig coupling between racemic
aldehyde ( )-2 (left half) and chiral phosphonium salt (S)-3 (right
half)4 (Scheme 1). Chiral synthesis of 1 was not achieved so far,
and we now report the first synthesis of (+)-1 based on modified
(one-pot) Julia olefination between a chiral aldehyde (4R,5R)-2
and a chiral benzothiazole sulfone (S)-4.
yield.7 Silylation of 8 afforded the silyl ether 9 {93%, ½a 2D5
ꢁ4.74 (c
ꢀ
1.06, CHCl3)}, which was treated with n-BuLi and methyl chloro-
formate to give an acetylenecarboxylate 10 (½a D24
ꢁ 15.1 (c 0.86,
ꢀ
CHCl3)) in 88% yield. Conjugate addition of MeOH to acetylenecarb-
oxylate 10 in the presence of a catalytic amount of Bu3P afforded a
single isomer, (Z)-b-methoxy-
a
,b-unsaturated ester 11 {½a D25
ꢁ15.6
ꢀ
(c 0.96, CHCl3)} in 89% yield. The (Z)-geometry of 11 was confirmed
by the NOE enhancement for the olefinic proton and the methine
proton (8.6%). Isomerization of (Z)-11 to (E)-12 was carried out
by the following procedure. When a solution of (Z)-11 in CDCl3
(chloroform-d + 1% v/v TMS (D, 99.8%) + SILVER FOIL) from Cam-
bridge Isotope Laboratories, Inc.) was allowed to react for 3 d at
room temperature, (E)-12 was exclusively obtained in 95% yield.
The overall yield of (E)-12 from (2R,3S)-5 was 20% (7 steps), and
was found to be improved in comparison to that of the desilylated
12 from methyl (2R,3S)-epoxy butanoate (11% overall yield, 8
steps).8 In addition, a solution of (Z)-11 in CHCl3 was treated with
a small amount of 4 M HCl in dioxane to give (E)-12 in 81% yield.
This experiment indicates proton (H+)-assisted isomerization of
(Z)-11 to the thermodynamically more stable (E)-12. Conversion
of ester group to amide was carried out by the following procedure.
Alkaline hydrolysis of the crude (E)-12 followed by acid treatment
gave carboxylic acid. Treatment of this acid with water-soluble
carbodiimide hydrochloric acid salt (WSCDꢂHCl) in the presence
2. Synthesis of left-half (4R,5R)-2
The synthesis of ( )-2 was achieved in overall 1% yield (9 steps)
based on a condensation reaction between cinnamaldehyde and
the dianion derived from methyl 3-oxopentanoate followed by
several synthetic steps.4 In this case, the preparation of chiral form
* Corresponding author. Tel.: +81 474 72 1805.
E-mail address: akita@phar.toho-u.ac.jp (H. Akita).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.125

Y. Iwaki et al. / Tetrahedron Letters 49 (2008) 7024–7026
7025
Me
Me
S
OMe OMe
N
S
R
S
N
Me
Me
O
S
H2N
right-half
left-half
Myxothiazol A (1)
OMe OMe
Me
S
N
S
R1
N
Me
CHO
+
Me
S
Me
O
H2N
R1 = I- Ph3P+-
(
S
)-3
( )-2
N
(4R,5R)-2
R1 =
SO2
(
S)-4
(BT-SO2-)
S
Scheme 1.
OR2
OMe
TMS
O
2
R
2
R
Me
OR3
a
b
3S
c
COOBu
COOBu
3
S
Me
R2 =H : (2
R2 =M e: (2
Me
(2
R
,3
S
)-5
3
8
R
,3
S
)-6 (72%)
)-7 (64%)
TBDMS: -SiMe2But
R =H : (63%)
d
3
R
,3
S
9
R =TBDMS : (93%)
MeOOC
OMe
OMe OMe
OTBDMS
(89%)
OTBDMS
MeOOC
e
f
Me
Me
10 (88%)
11
OMe OMe
OMe OMe
g
OTBDMS
OTBDMS
i
h
(4R,5R)-2 (32%)
Me
O
Me
O
MeO
H2N
12
13
(39%)
(95%)
Scheme 2. Reagents and conditions: (a) trimethylsilylacetylene/n-BuLi/Et2AlCl/THF; (b) MeI/Ag2O/DMF; (c) (1) n-Bu4N+Fꢁ/THF, (2) LiBH4; (d) TBDMSCl/imidazole/DMF; (e) n-
BuLi/ClCOOMe; (f) Bu3P/MeOH; (g) CDCl3 or 4 M-HCl in dioxane/CHCl3; (h) (1) Ba(OH)2ꢂ8H2O/MeOH, 70 °C (2) 0.5 M HCl (3) WSCDꢂHCl/HOAt/Et3N/DMF; (4) 28% aqueous
NH3; (i) (1) HF–pyridine (2) TPAP/NMO/MS-4A/CH2Cl2.
of 1-hydroxy-7-aza-benzotriazole (HOAt) followed by addition of
alcohol, which was again treated with BTSH in the presence of
aqueous NH3 gave the desired amide 13 {½a D27
ꢀ
+35.7 (c 0.84, CHCl3)}
Ph3P and DEAD to afford the corresponding sulfide (S)-16 {½a D26
ꢀ
in 39% overall yield from (E)-12. Desilylation of 13 with HF–pyr-
idine followed by oxidation with tetrapropylammonium perruthe-
nate (TPAP) in the presence of 4-methylmorpholine N-oxide
(NMO) and MS-4A afforded the desired aldehyde (4R,5R)-2 in
32% overall yield. 1H NMR data of the synthetic (4R,5R)-2 were
consistent with those of the reported ( )-24b (see Scheme 2).
ꢁ74.4 (c 0.77, CHCl3)} in 66% overall yield. The reaction of (S)-16
and (2E)-4-methylpentenal in the presence of lithium bis(trimeth-
ylsilyl)amide (LHMDS) in THF gave a mixture (E/Z = 3.3/1) of cou-
pled products, which were separated to give (E)-17 {½a D27
ꢀ
+7.83 (c
0.525, CHCl3)} (59%) and (Z)-18 {½a D27
ꢁ82.3 (c 0.81, CHCl3)}
ꢀ
(18%). Oxidation of (E)-17 with 35% H2O2 in the presence of
Mo7O24(NH4)6ꢂ4H2O provided the desired (S)-4 {½a D25
ꢁ3.6 (c 0.6,
ꢀ
CHCl3)} in 77% yield. The overall yield of (S)-4 from the reported
(S)-14 was 28% (4 steps). In contrast, the overall yield of (S)-3 from
the commercially available (2R)-3-hydroxy-2-methylpropanoate
was 1% (19 steps).4 Finally, modified (one-pot) Julia olefination be-
tween the chiral aldehyde (4R,5R)-2 and the chiral benzothiazole
sulfone (S)-4 in the presence of LHMDS afforded (+)-myxothiazol
3. Synthesis of right-half (S)-4 and Myxothiazol A (1)
We previously obtained the starting chiral alcohol (S)-14 based
on lipase-assisted asymmetric hydrolysis of racemic acetate of 14.9
Treatment of (S)-14 with 2-mercaptobenzothiazole (BTSH) in the
presence of Ph3P and diethylazodicarboxylate (DEAD) gave the cor-
A (1) {½a 2D6
ꢀ
+33.5 (c 0.70, MeOH)} in 61% yield. The spectral data
responding sulfide (S)-15 {½a D26
ꢁ92.97 (c 1.48, CHCl3)} in 95%
ꢀ
of the synthetic 1 were identical with those of natural (+)-myx-
yield. LiBH4 reduction of (S)-15 followed by oxidation with 35%
H2O2 in the presence of hexaammonium heptamolybdate tetrahy-
trate {Mo7O24(NH4)6ꢂ4H2O} provided the corresponding sulfone-
othiazol A (1) {½a D25
ꢀ
+43.4 (c 6.0, MeOH)}
including the sign of
3a
a specific rotation (see Scheme 3).

7026
Y. Iwaki et al. / Tetrahedron Letters 49 (2008) 7024–7026
S
S
N
S
N
S
EtOOC
a
EtOOC
b
OH
SBT
N
N
Me
S
Me
)-15 (95%)
S
(S
(S)-14
S
Me
Me
S
2
N
S
S
N
d
c
SO2BT
BTS
N
(S)-4
BTS
N
77%
(E:Z=3.3:1)
77%
Me
S)-16 (66%)
Me
S
(
(1
(1
S
,2
E
)-17
)-18
S
,2
Z
e
(S)-4
(4
R
,5
R
)-2
+
Myxothiazol A (1) (61%)
Scheme 3. Reagents and conditions: (a) 2-mercaptobenzothiazol (BTSH)/DEAD/Ph3P/THF; (b) (1) LiBH4/THF (2) H2O2/Mo7O24(NH4)6ꢂ4H2O/EtOH (3) BTSH/DEAD/Ph3P/THF;
(c) LHMDS/(2E)-4-methylpentenal/THF; (d) H2O2/Mo7O24(NH4)6ꢂ4H2O/EtOH; (e) LHMDS/THF.
4. Conclusion
References and notes
1. Gerth, K.; Irschik, H.; Reichenbach, H.; Trowitzsch, W. J. Antibiotics 1980, 33,
1474–1479.
2. Thierbach, G.; Reichenbach, H. Biochim. Biophys. Acta 1981, 638, 282–289.
3. (a) Trowitzsch, W.; Reifenstahl, G.; Wray, V.; Gerth, K. J. Antibiotics 1980, 33,
1480–1490; (b) Trowitzsch, W.; Höfle, G.; Sheldrick, W. S. Tetrahedron Lett. 1981,
22, 3829–3832.
4. (a) Martin, B. J.; Clough, J. M.; Pattenden, G.; Waldron, I. R. Tetrahedron Lett.
1993, 34, 5151–5154; (b) Clough, J. M.; Dube, H.; Martin, B. J.; Pattenden Reddy,
K. S. G.; Waldron, I. R. Org. Biomol. Chem. 2006, 4, 2906–2911.
5. Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett. 1986, 27, 5397–5400.
6. Chemenzymatic synthesis of methyl (2R,3S)-epoxy butanoate was reported: (a)
Akita, H.; Kawaguchi, T.; Enoki, Y.; Oishi, T. Chem. Pharm. Bull. 1990, 38, 323–
328; (b) Kato, K.; Ono, M.; Akita, H. Tetrahedron 2001, 57, 10055–10062. Now, n-
butyl (2R,3S)-epoxy butyrate (5) is commercially available from Osaka Yuki
Kagaku Kogyo Co., Ltd (Japan). Japan Kokai Tokkyo Koho JP 3095539.
7. Satisfactory analytical data were obtained for all new compounds.
8. Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita, H. Tetrahedron 2003, 43, 643–645.
9. (a) Akita, H.; Nozawa, M.; Nagumo, S. Chem. Pharm. Bull. 1994, 42, 1208–1212;
(b) Akita, H.; Iwaki, Y.; Kato, K.; Qi, J.; Ojika, M. Tetrahedron: Asymmetry 2007, 18,
513–519. Now, both (S)-14 and (R)-14 were obtained by optical resolution of
( )-14 using HPLC separation {Chiralcel OD-H (2 ꢃ 25 cm), eluent; 20% 2-
propanol in hexane, 10 mL/min, (S)-14; tR = 30 min, (R)-14; tR = 50 min}.
The first convergent synthesis of (+)-myxothiazol A (1) was
achieved based on modified (one-pot) Julia olefination between
the chiral aldehyde (4R,5R)-2, corresponding to left-side of the final
molecule, and chiral benzothiazole sulfone (S)-4, bearing a bithiaz-
ole moiety corresponding to right-side, respectively. The desired
chiral aldehyde (4R,5R)-2 was obtained from the starting epoxy es-
ter (2R,3S)-5 in an overall 2.5% yield (9 steps). Moreover, the de-
sired chiral benzothiazole sulfone (S)-4 was obtained from (S)-4-
ethoxycarbonyl-20-(1-hydroxymethylethyl)-2,40-bithiazole (14) in
an overall yield of 28% (4 steps). Finally, modified (one-pot) Julia
olefination between (4R,5R)-2 and (S)-4 afforded (+)-myxothiazol
A (1) in 61% yield. The coupling yield was comparably better than
that of the reported Wittig procedure (22% yield).4b
Acknowledgments
We would like to thank Dr Ryoichi Akaishi of Osaka Yuki
Kagaku Kogyo Co., Ltd (Japan) for providing n-butyl (2R,3S)-epoxy
butyrate (5).