Total synthesis of (+)-myxothiazols A and Z

Article abstract of DOI:10.1016/j.tetasy.2008.12.031

The first synthesis of (+)-myxothiazol A 1 was achieved based on a modified Julia olefination between (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenamide 3, corresponding to the left side of the final molecule, and 4-(2″-benzothiazolyl)sulfonylmethyl-2′-[(

Full text of DOI:10.1016/j.tetasy.2008.12.031

Tetrahedron: Asymmetry 20 (2009) 298–304
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of (+)-myxothiazols A and Z q
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:
The first synthesis of (+)-myxothiazol A 1 was achieved based on a modified Julia olefination between
(3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenamide 3, corresponding to the left side of the final mol-
ecule, and 4-(200-benzothiazolyl)sulfonylmethyl-20-[(1000R),6000-dimethylhepta-(2000E),(4000E)-dienyl]-2,40-
bithiazole 6, corresponding to the right side. The synthesis of (+)-myxothiazol Z 2 was also achieved
based on modified Julia olefination between (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenoate 4, cor-
responding to left side of the final molecule, and (S)-sulfone 6.
Received 18 November 2008
Accepted 15 December 2008
Available online 11 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Myxothiazols A 1 and Z 2 possessing a bithiazole skeleton as
well as a b-methoxyacrylate moiety were isolated from the myxo-
bacterium Myxococcus fulvus strain Mxf161 and M. fulvus, respec-
tively. Feeding experiments with labeled precursors established
biosynthesis of 2 from 1.2 Myxothiazol A 1 is active against many
filamentous fungi, and completely inhibits growth of Mucor hie-
2.1. Synthesis of left half (4R,5R)-3 and (4R,5R)-4
The synthesis of ( )-3 was achieved in 1% overall yield (9 steps)
based on a condensation reaction between cinnamaldehyde and
the dianion derived from methyl 3-oxopentanoate followed by
several synthetic steps.6 In this case, the preparation of a chiral
form of 3 could be possible due to the resolution of an intermedi-
ate. On the other hand, the synthesis of (4R,5R)-4 was reported
based on an Evans asymmetric aldol condensation procedure.6b
The preparation of (4R,5R)-3 and (4R,5R)-4 was achieved by the fol-
lowing synthetic route as shown in Scheme 2.
malis at a concentration of 2 l
g/mL.1 The fungicidal activity of
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.3 Myx-
othiazol Z 2 was reported to exhibit potent cytotoxicity against hu-
man tumor cell.4 The structure of myxothiazol A 1 was established
by a combination of chemical degradation and NMR study, and its
absolute configuration at C(14)-carbon was determined by X-ray
analysis of its degradation product.5 The synthesis of a diastereo-
meric mixture of 1 was achieved based on a Wittig coupling be-
tween racemic aldehyde ( )-3 corresponding to the left half and
chiral phosphonium salt (S)-5 corresponding to the right half.6
Meanwhile, the synthesis of (+)-2 was reported by a Wittig cou-
pling between chiral aldehyde (4R,5R)-4 and (S)-5.6 (Scheme 1)
The chiral synthesis of 1 has not been achieved to date, and we
now report the first synthesis of (+)-1 based on modified Julia olef-
ination between the chiral aldehyde (4R,5R)-3 and the chiral ben-
zothiazole sulfone (S)-6. Furthermore, we describe the synthesis of
(+)-2 based on modified Julia olefination between a (4R,5R)-4 and a
(S)-6.
By applying the previously reported procedure,7 the reaction of
(2R,3S)-epoxy butanoate 78 and lithium silyl-acetylide in the pres-
ence of Et2AlCl gave the diastereomerically pure compound 8
{½a 2D4
¼ ꢁ7:6 (c 1.09, CHCl3)} in 72% yield. Methylation of 8 fol-
ꢀ
lowed by consecutive desilylation and reduction afforded 10
{½a 2D7
¼ ꢁ27:6 (c 1.05, CHCl3)} in 59% overall yield. Silylation of
ꢀ
10 afforded the silyl ether 11 {93%, ½a D25
¼ ꢁ4:7 (c 1.06, CHCl3)},
ꢀ
which was treated with n-BuLi and methyl chloroformate to give
an acetylenecarboxylate 12 {½a D24
¼ ꢁ15:1 (c 0.86, CHCl3)} in 88%
ꢀ
yield. By applying the reported procedure,9 conjugate addition of
MeOH to acetylenecarboxylate 12 in the presence of a catalytic
amount of Bu3P afforded a single isomer, (Z)-b-methoxy-
a
,b-unsat-
urated ester 13 {½a D25
ꢀ
¼ ꢁ15:6 (c 0.96, CHCl3)} in 86% yield. The (Z)-
geometry of 13 was confirmed by the NOE enhancement for the
olefinic proton and the methine proton (8.6%). The formation of
(Z)-13 from 12 could be explained as shown in Scheme 3. Addition
of tributyl phosphine to 12 followed by MeOH attack would give
intermediates TS-A and TS-B. Intermediate TS-B could lead to
(Z)-form 13 because TS-B is more stable than TS-A due to stereo-
chemical repulsion in TS-A.
q
A part of this work was already reported as a preliminary communication (see
Ref. 12).
* Corresponding author. Tel.: +81 047 472 1805; fax: +81 047 472 1825.
E-mail address: akita@phar.toho-u.ac.jp (H. Akita).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.031

Y. Iwaki et al. / Tetrahedron: Asymmetry 20 (2009) 298–304
Me
299
S
OMe OMe
(S)
N
(R)
(S)
Me
N
Me
S
Me
R1
O
right-half
left-half
R
1 = NH2 : myxothiazol A 1
R1 = OMe : myxothiazol Z 2
Me
S
OMe OMe
(S)
N
R1
N
Me
CHO
+
Me
S
Me
O
R1 = NH2 : ( )-3
1 = NH2 : (4R,5R)-3
R1
R1 = I- Ph3P+- (S)-5
N
R
R1
=
SO2
(S)-6
(BT-SO2-)
R1 = OMe : (4R,5R)-4
S
Scheme 1.
OR2
(2R)
COOBu
TMS
OMe
O
(2R)
OR3
(3S)
Me
a
c
COOBu
(3S)
(2R,3S)-7
Me
Me
R2 = H: (2R,3S)-8 (72%)
R2 = Me: (2R,3S)-9 (82%)
3
10
R = H :
(84%)
d
b
R3= TBDMS : 11 (93%)
TBDMS: -SiMe2But
MeOOC
OMe
OMe OMe
OTBDMS
(86%)
OTBDMS
MeOOC
e
f
H
Me
i
Me
H
12 (88%)
13
n.O.e 8.6%
OMe OMe
OMe OMe
g
OR3
OTBDMS
h
(4R,5R)-3 (32%)
Me
O
Me
O
MeO
j
H2N
15
(39%)
R3= TBDMS : 14 (95%)
k
3
(4R,5R)-4 (89%)
16
R = H :
(94%)
Scheme 2. Reagents: (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 MꢁHCl 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; (j) Et3N(HF)3/CH2Cl2; (k) Dess–Martin periodinane.
Isomerization of (Z)-13 to (E)-14 was carried out by the follow-
ing procedure. When a solution of (Z)-13 in aged CDCl3 (see Section
4) was stood for 3 d at room temperature, (E)-14 was obtained
exclusively in 95% yield. 1H NMR spectra of (E)-14 were identical
with those of the previously reported (E)-14.10 Meanwhile, a solu-
tion of (Z)-13 in CHCl3 containing EtOH as stabilizer was treated
with a small amount of 4 M HCl in dioxane to give a mixture of
(E)-14 and a trace amount of (4R,5R)-6-tert-butyldimethylsiloxy-
3-ethoxy-5-methoxy-4-methyl-2(E)-hexenoate. This experiment
indicated that proton (H+)-assisted isomerization of (Z)-13 to (E)-
14 to seek the thermodynamically more stable (E)-14 from (Z)-13
had occurred as shown in Scheme 4.
of 4-methylmorpholine N-oxide (NMO) and MS-4A afforded the
desired aldehyde (4R,5R)-3 in 32% overall yield. 1H NMR data of
the synthetic (4R,5R)-3 were consistent with those of the reported
( )-3.6b This aldehyde 3 was used in the next reaction without fur-
ther purification after passing through silica gel pad to remove the
reagents. Desilylation of 14 with Et3Nꢂ(HF)3 followed by oxidation
with Dess–Martin reagent gave the desired aldehyde (4R,5R)-4 in
84% yield from 14.
2.2. Synthesis of right half (S)-6, myxothiazols A 1 and Z 2
The starting chiral alcohol (S)-17 was previously obtained
based on lipase-assisted asymmetric hydrolysis of racemic acetate
of 17.11 Treatment of (S)-17 with 2-mercaptobenzothiazole (BTSH)
in the presence of Ph3P and diethyl azodicarboxylate (DEAD) gave
Conversion of the ester group to an amide was carried out by
the following procedure. Alkaline hydrolysis of the crude (E)-14
followed by acid treatment gave a carboxylic acid. Treatment of
this acid with water-soluble carbodiimide hydrochloric acid salt
(WSCDꢂHCl) in the presence of 1-hydroxy-7-aza-benzotriazole
(HOAt) followed by addition of aqueous NH3 gave the desired
the corresponding sulfide (S)-18 {½a D26
¼ ꢁ92:9 (c 1.48, CHCl3)} in
ꢀ
93% yield. Then, LiBH4 reduction of (S)-18 followed by oxidation
with 35% H2O2 in the presence of Mo7O24(NH4)6ꢂ4H2O provided
the corresponding sulfone-alcohol, which was again treated with
2-mercaptobenzothiazole (BTSH) in the presence of Ph3P and
amide 15 {½a 2D7
¼ þ35:7 (c 0.84, CHCl3)} in 39% overall yield from
ꢀ
(E)-14. Desilylation of 15 with HFꢂpyridine followed by oxidation
with tetrapropylammonium perruthenate (TPAP) in the presence
DEAD to afford the corresponding sulfide (S)-19 {½a D26
¼ ꢁ74:4
ꢀ

300
Y. Iwaki et al. / Tetrahedron: Asymmetry 20 (2009) 298–304
Addition of MeOH to compound 12
:PBu3
-O
P+Bu3
R
MeOH
O
MeOOC
H
P+Bu3
R
R
C
R
MeO
MeO
12
MeO-
-
R
H
OMe
R
OMe
MeOOC
OMe
P+Bu3
MeOOC
H
MeOOC
H
(E)-form (13)
P+Bu3
TS-A
-
R
R
OMe
MeOOC
OMe
R
OMe
P+Bu3
H
H
H
COOMe
MeOOC
13
(Z)-f orm (
)
TS-B
P+Bu3
OMe
OTBDMS
R =
Me
Scheme 3.
Acid-catalysed isomerization
H+
OH
H
O
-H+
MeO
OMe
H
O
OMe
R
MeO
OMe
R
H
OMe
R
MeO
H
MeOOC
(E)-form
R
H
(Z )-form
Scheme 4.
(c 0.77, CHCl3)} in 66% overall yield. The reaction of (S)-19 and
(2E)-4-methylpentenal in the presence of lithium bis(trimethyl-
silyl)amide (LHMDS) in THF gave a mixture (E/Z = 3.3/1) of cou-
pled products, which were separated chromatographically to
chiral benzothiazole sulfone (S)-6 in the presence of LHMDS affor-
ded (+)-myxothiazol A (1) {½a D27
¼ þ33:5 (c 0.70, MeOH)} in 61%
ꢀ
yield. The spectral data of the synthetic 1 were identical with
those of natural (+)-myxothiazol
A
1
{½a 2D5
¼ þ43:4 (c 6.0,
ꢀ
give (E)-20 {½a 2D7
ꢀ
¼ þ7:8 (c 0.525, CHCl3)} (59%) and (Z)-21
MeOH)}1 including the sign of a specific rotation, although the
concentration of both samples was different. Julia coupling be-
tween a chiral aldehyde (4R,5R)-4 and a chiral benzothiazole sul-
fone (S)-6 in the presence of LHMDS afforded (+)-myxothiazol Z
{½a 2D7
¼ ꢁ82:3 (c 0.81, CHCl3)} (18%). Oxidation of (E)-20 under
ꢀ
the same condition as preparation of (S)-19 provided the desired
(S)-6 (½a 2D5
¼ ꢁ3:6 (c 0.6, CHCl3)) in 77% yield. The overall yield
ꢀ
of (S)-6 from the reported (S)-17 was 28% (4 steps). In contrast,
the overall yield of (S)-5 from the commercially available (2R)-
3-hydroxy-2-methylpropanoate was 1% (19 steps).6 Finally, mod-
ified Julia coupling between the chiral aldehyde (4R,5R)-3 and the
(2) {½a 2D7
¼ þ85:7 (c 1.66, MeOH)} in 73% yield. The spectral data
ꢀ
of the synthetic 2 were identical with those of natural (+)-myx-
othiazol Z 2 {½a 2D2
ꢀ
¼ þ79:2 (c 1.4, MeOH)}2 including the sign of
a specific rotation (Scheme 5).
S
S
(S)
N
(S)
N
EtOOC
a
EtOOC
b
OH
SBT
N
N
Me
Me
(S)-18 (93%)
S
S
(S)-17
Me
S
S
2
(S)
N
S
N
d
c
SO2BT
Me
BTS
N
HBTS
N
(S)-6
77%
(E:Z=3.3:1)
77%
Me
Me
S
(S)-19 (66%)
(1S,2E)-20
(1S,2Z)-21
e
e
(S)-6
(S)-6
(4R,5R)-3
(4R,5R)-4
+
+
myxothiazol A 1 (61%)
myxothiazol Z 2 (73%)
Scheme 5. Reagents: (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.

Y. Iwaki et al. / Tetrahedron: Asymmetry 20 (2009) 298–304
301
for 48 h at room temperature. The reaction mixture was diluted with
EtOAc (30 mL) and filtered off with the aid of Celite. The filtrate was
diluted with H2O and extracted with n-hexane. The organic layer
was dried over MgSO4. Concentration of the organic layer gave a
crude residue, which was chromatographed on silica gel (50 g, n-
hexane/EtOAc = 60:1) to provide (2R,3S)-9 (1.819 g, 82% yield) as a
3. Conclusion
In conclusion, first synthesis of (+)-myxothiazol A 1 was
achieved based on a modified Julia olefination between the func-
tionalized aldehydes (4R,5R)-3, corresponding to the left side of
the final molecule, and chiral benzothiazole sulfone (S)-6, bearing
a bithiazole moiety corresponding to right side. (+)-Myxothiazol
Z 2 was also synthesized based on a modified Julia coupling be-
tween the functionalized aldehyde (4R,5R)-4 and (S)-6. The desired
aldehyde (4R,5R)-3 was obtained from the starting epoxy ester
(2R,3S)-7 in 4% total overall yield (9 steps). Furthermore, the de-
sired aldehyde (4R,5R)-4 was obtained from the starting epoxy es-
ter (2R,3S)-7 in 27% total overall yield (9 steps). Meanwhile, chiral
benzothiazole sulfone (S)-4 was obtained from (S)-4-ethoxycar-
bonyl-20-(1-hydroxymethylethyl)-2,40-bithiazole 14 in 28% overall
yield (4 steps). Finally, a modified Julia olefination between
(4R,5R)-3 and (S)-6 afforded (+)-myxothiazol A 1 in 61% yield,
and coupling of (4R,5R)-4 and (S)-6 provided (+)-myxothiazol Z 2
in 73% yield The present coupling yield (61%) was better in com-
parison to the reported Wittig procedure (22% yield for (+)-1).6b
colorless oil. (2R,3S)-9: ½a D24
¼ þ0:8 (c 1.54, CHCl3); IR (neat): 2175,
ꢀ
1748 cmꢁ1 1H NMR (400 MHz, CDCl3): d 0.13 (9H, s), 0.95 (3H, t,
;
J = 7.2 Hz), 1.23 (3H, d, J = 6.8 Hz), 1.36–1.46 (2H, m), 1.63–1.70
(2H, m), 2.91 (1H, dq, J = 6.8, 6.8 Hz), 3.44 (3H, s), 3.68 (1H, d,
J = 6.8 Hz), 4.18 (2H, t, J = 11.2 Hz), 4.18 (1H, dq, J = 6.8, 6.8 Hz). 13C
NMR (101 MHz, CDCl3): d 0.3 (3C), 13.6, 16.4, 19.1, 30.5, 30.6, 58.8,
64.8, 84.0, 86.4, 106.6, 170.9. HRMS (FAB) (m/z): calcd for C14H27O3Si
(M+H)+: 271.1729, found: 271.1730.
4.4. (2R,3S)-3-Methyl-2-methoxy-5-trimethylsilyl-4-pentyn-1-
ol 10
To a solution of (2R,3S)-9 (1.66 g, 7.3 mmol) in THF (20 mL) was
added 1 M tetrabutylammonium fluoride (TBAF) in THF solution
(3.7 mL, 3.7 mmol) at 0 °C, and the whole mixture was stirred for
10 min at 0 °C. The reaction mixture was diluted with H2O and ex-
tracted with EtOAc. The organic layer was dried over MgSO4 and
evaporated to give a crude residue, which was used for the next reac-
tion without further purification. To a solution of the above 2-meth-
oxy ester in THF (20 mL) was added LiBH4 (0.641 g, 29.4 mmol) at
0 °C, and the whole mixture was stirred for 60 min at room temper-
ature. The reaction mixture was diluted with MeOH (2 mL), H2O
(100 mL) and Et2O (100 mL), and the whole mixture was stirred for
12 h at the same temperature. The generated precipitate was filtered
off with the aid of Celite to afford the filtrate. The filtrate was ex-
tracted with Et2O. The organic layer was dried over MgSO4. Evapora-
tion of the filtrate gave a crude residue, which was chromatographed
on silica gel (20 g, n-hexane/EtOAc = 5:1) to provide a colorless oil
4. Experimental
4.1. General
All melting points were measured on a Büchi 535 melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were re-
corded on Bruker AV400 M digital NMR spectrometer in CDCl3.
Electrosprey ionization-mass spectrometry (ESI-MS) and fast atom
bombardment mass spectra (FAB-MS) were performed with JEOL
JMS-T100LP or JEOL JMS SX-102A (matrix; m-nitrobenzyl alcohol)
mass spectrometers. IR spectra were recorded with a JASCO FT/IR-
4100 spectrometer. Optical rotations were measured with a JASCO
P-1020 digital polarimeter. All evaporations were performed under
reduced pressure. For column chromatography, silica gel (KANTO
silica gel 60 N, spherical, neutral, 40–50) was employed.
(ꢁ)-10 (0.66 g, 84%). Compound (ꢁ)-10: ½a D27
ꢀ
¼ ꢁ27:6 (c 1.05,
CHCl3); IR (neat): 3429, 3296, 2113 cmꢁ1
;
1H NMR (400 MHz,
CDCl3): d 1.25 (3H, d, J = 6.8 Hz), 2.11 (1H, d, J = 2.4 Hz), 2.38 (1H,
br s), 2.76 (1H, ddq, J = 2.4, 6.8, 6.8 Hz), 3.16 (1H, ddd, J = 3.2, 5.6,
6.8 Hz), 3.80 (2H, dq, J = 12, 5.6 Hz). 13C NMR (101 MHz, CDCl3): d
17.1, 27.3, 58.4, 61.9, 70.3, 84.5, 85.5. HRMS (FAB) (m/z): calcd for
C7H13O2 (M+H)+: 129.0916, found 129.0919.
4.2. n-Butyl (2R,3S)-2-hydroxy-3-methyl-5-trimethylsilyl-4-pe-
ntynoate 8
To a solution of trimethylsilylacetylene (9.82 g, 99.7 mmol) in
toluene (100 mL) at ꢁ40 °C under argon atmosphere was added
2.6 M solution of n-BuLi in n-hexane (38.5 mL, 99.7 mmol), and
the reaction mixture was stirred for 10 min. To the above reaction
mixture was added 1 M solution of Et2AlCl in n-hexane (62.5 mL,
99.7 mmol), and the reaction mixture was stirred for 1 h at 0 °C.
To the above reaction mixture was added (2R,3S)-7 (12.64 g,
80 mmol) at 0 °C, and the reaction mixture was stirred for 1 h.
After addition of H2O (100 mL) to the reaction mixture, the reac-
tion mixture was filtered off with the aid of Celite to give a filtrate.
The filtrate was dried over MgSO4 and evaporated to afford a crude
oil, which was purified by chromatography on silica gel (310 g, n-
hexane/EtOAc = 40:1) to provide (2R,3S)-8 (14.8 g 72%) as a color-
4.5. (2R,3S)-1-tert-Butyldimethylsiloxy-3-methyl-2-methoxy-4-
pentyn 11
A solution of (ꢁ)-10 (0.452 g, 3.5 mmol), imidazole (0.492 g,
7.1 mmol), and tbutyldimethylsilyl chloride (TBDMSCl, 0.797 g,
5.3 mmol) in DMF (2 mL) was stirred for 1 h at room temperature.
The reaction mixture was diluted with brine and extracted with
EtOAc/n-hexane (1:1). The organic layer was dried over MgSO4 and
evaporated to give a crude 11, which was chromatographed on silica
gel (30 g, n-hexane/EtOAc = 30:1) to afford 11 (0.801 g, 93%) as a col-
orless oil. Compound (ꢁ)-11: ½a D25
¼ ꢁ4:7 (c 1.06, CHCl3); IR (neat):
ꢀ
less oil. (2R,3S)-8: ½a D24
¼ ꢁ7:6 (c 1.09, CHCl3); IR (neat): 3487,
ꢀ
2115 cmꢁ1 1H NMR (400 MHz, CDCl3): d 0.06 (6H, s), 0.89 (9H, s),
;
2168, 1733 cmꢁ1 1H NMR (400 MHz, CDCl3): d 0.14 (9H, s), 0.95
;
1.21 (3H, d, J = 7.2 Hz), 2.05 (1H, d, J = 2.4 Hz), 2.68 (1H, ddq,
J = 2.4, 7.2, 6.4 Hz), 3.16 (1H, ddq, J = 4.4, 5.6, 6.4 Hz), 3.71 (1H, dd,
J = 5.6, 10.8 Hz), 3.82 (1H, dd, J = 4.4, 10.8 Hz). 13C NMR (101 MHz,
CDCl3): d ꢁ5.46, ꢁ5.41, 16.4, 18.3, 25.9(3C), 27.4, 59.0, 63.3, 69.4,
84.6, 86.5. HRMS (FAB) (m/z): calcd for C13H27O2Si (M+H)+:
243.1781, found: 243.1785.
(3H, t, J = 7.6 Hz), 1.21 (3H, d, J = 7.2 Hz), 1.36–1.45 (2H, m),
1.63–1.70 (2H, m), 2.94 (1H, dq, J = 3.2, 7.2 Hz), 4.15–4.26 (3H,
m). 13C NMR (101 MHz, CDCl3): d ꢁ0.06 (3C), 13.6, 15.8, 19.1,
30.6, 32.3, 65.7, 73.4, 86.7, 106.4, 172.9. HRMS (FAB) (m/z): calcd
for C13H25O3Si (M+H)+: 257.1573, found: 257.1539.
4.3. n-Butyl (2R,3S)-3-methyl-2-methoxy-5-trimethylsilyl-4-pe-
4.6. Methyl (4S,5R)-6-tert-butyldimethylsiloxy-4-methyl-5-met-
ntynoate 9
hoxy-2-hexynoate 12
A
mixture of
8 (2.105 g, 9.8 mmol), methyl iodide (18 g,
To a solution of 11 (3.9 g, 11.4 mmol) in THF (40 mL) at ꢁ78 °C,
1.59 M solution of n-butyllithium in n-hexane (8.6 mL, 13.6 mmol)
127 mmol), and Ag2O (3.2 g, 13.8 mmol) in DMF (6 mL) was stirred

302
Y. Iwaki et al. / Tetrahedron: Asymmetry 20 (2009) 298–304
was added. The mixture was stirred at ꢁ78 °C for 0.5 h, and then
methyl chloroformate (1.06 mL, 13.7 mmol) was added. After being
warmed to room temperature and stirred for 1 h, the reaction was
quenched with aqueous saturated NH4Cl at ꢁ78 °C. The mixture
was diluted with EtOAc, the separated organic layer was washed
with brine, dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by flash silica gel column chromatogra-
phy (80 g, n-hexane/EtOAc = 9:1) to afford 12 (4.24 g, 88%) as a col-
stirring at 50 °C for 0.5 h, additional WSCDꢂHCl (0.202 g,
1.05 mmol), HOAt (0.123 g, 0.90 mmol), Et3N (0.147 mL, 1.05
mmol), and 28% aqueous NH3 (0.5 mL) were added and then stirred
for further 0.5 h. The reaction mixture was diluted with H2O and
extracted with EtOAc. The organic layer was dried over Na2SO4,
concentrated, and purified with silica gel column chromatography
(silica gel 40 g, EtOAc/n-hexane = 1:2?1:0) to give 15 as a white
wax (0.187 g, 39% for 2 steps). Compound 15: ½a D27
ꢀ
¼ þ35:7 (c
orless oil. Compound 12: ½a D24
ꢀ
¼ ꢁ15:1 (c 0.86, CHCl3); IR (neat):
0.84, CHCl3); IR (KBr): 2930, 1672, 1590 cmꢁ1
;
1H NMR
2236, 1717 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 0.06 (6H, s), 0.89
(400 MHz, CDCl3): d 0.056 (3H, s), 0.069 (3H, s), 0.90 (9H, s), 1.16
(3H, d, J = 6.8 Hz), 3.27–3.32 (1H, m), 3.46 (3H, s), 3.54–3.60 (1H,
m), 3.58 (3H, s), 3.76 (1H, dd, J = 11.4, 2.8 Hz), 3.85–3.92 (1H, m),
4.93 (1H, s). 13C NMR (101 MHz, CDCl3): d ꢁ5.43, ꢁ5.27, 15.08,
18.47, 25.97 (3C), 36.79, 55.04, 59.09, 64.16, 84.62, 94.22, 169.05,
171.59. HRMS (FAB) (m/z): calcd for C15H32NO4Si: 318.2101
(M+H)+, found: 318.2135.
(9H, s), 1.25 (3H, d, J = 7.2 Hz), 2.86 (1H, dq, J = 7.2, 6.8 Hz), 3.23–
3.27 (1H, m), 3.47 (3H, s), 3.68–3.77 (2H, m), 3.74 (3H, s). 13C
NMR (101 MHz, CDCl3): d ꢁ5.52, ꢁ5.47, 15.0, 18.2, 25.8 (3C),
27.5, 52.5, 59.0, 62.7, 73.7, 83.6, 91.3, 154.1. HRMS (FAB) (m/z):
calcd for C15H29O4Si: 301.1836 (M+H)+ Found: 301.1837.
4.7. Methyl (4R,5R)-6-tert-butyldimethylsiloxy-3,5-dimethoxy-
4-methyl-2(Z)-hexenoate 13
4.10. (3,5R)-Dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenamide 3
A mixture of (ꢁ)-12 (1.25 g, 4.2 mmol), (n-Bu)3P (0.254 g,
1.25 mmol), and MeOH (0.335 g, 10.5 mmol) in CH2Cl2 (25 mL)
was stirred for 4 h at room temperature. The reaction mixture
was evaporated to give a crude residue, which was chromato-
graphed on silica gel (30 g, n-hexane/EtOAc = 50:1) to afford (ꢁ)-
To a solution of 15 (0.040 g, 0.126 mmol) in THF (1.5 mL) was
treated HFꢂPy (0.1 mL) at 0 °C. After stirring at room temperature
for 0.5 h, the reaction was quenched with saturated aqueous NaH-
CO3 at 0 °C. The mixture was extracted with EtOAc, washed with
brine, dried over Na2SO4, and concentrated. The residue was dis-
solved in CH2Cl2 (1.5 mL) and treated with TPAP (tetrapropylam-
monium perruthenate) (0.004 g, 0.0114 mmol), NMO (0.030 g,
0.256 mmol), and MS-4 Å (0.020 g) at 0 °C. After stirring for
5 min, additional NMO (0.020 g, 0.171 mmol) and MS-4 Å
(0.020 g) were added and stirred for further 5 min. Completion of
the reaction was confirmed by TLC, the reaction mixture was
passed through silica gel pad to remove the reagents (silica gel
2 g, EtOAc). The filtrate was concentrated to give (4R,5R)-3
(0.008 g containing slight impurities, 32% for 2 steps), which was
used for the next reaction quickly without further purification.
13 (1.19 g, 86%) as
a
colorless oil. Compound (ꢁ)-13:
½
a 2D4
ꢀ
¼ ꢁ15:6 (c 0.96, CHCl3); IR (neat): 1717, 1630 cmꢁ1
;
1H
NMR (400 MHz, CDCl3): d0.05 (6H, s), 0.89 (9H, s), 1.11 (3H, d,
J = 7.2 Hz), 2.59 (1H, dq, J = 6.8, 6.8 Hz), 3.30 (1H, dd, J = 5.6,
6.8 Hz), 3.41 (3H, s), 3.61 (2H, d, J = 5.6 Hz), 3.66 (3H, s), 3.91
(3H, s), 5.07 (1H, s). 13C NMR (101 MHz, CDCl3): d ꢁ5.45, ꢁ5.38,
13.4, 18.3, 25.9(3C), 40.5, 50.9, 59.3, 60.2, 62.9, 83.1, 95.8, 165.9,
174.7. HRMS (FAB) (m/z): calcd for C16H33O5Si (M+H)+: 333.2097,
found: 332.2120.
4.8. Methyl (4R,5R)-6-tert-butyldimethylsiloxy-3,5-dimethoxy-
4-methyl-2(E)-hexenoate 14
(4R,5R)-3: IR (neat): 2940, 1731, 1662 cmꢁ1 1H NMR (400 MHz,
;
CDCl3): d 1.19 (3H, d, J = 7.3 Hz), 3.44 (3H, s), 3.55 (1H, dd, J = 6.7,
2.7 Hz), 3.60 (3H, s), 3.54 (1H, dq, J = 7.3, 6.7 Hz), 5.00 (1H, s),
5.45 (2H, br s ꢃ 2), 9.59 (1H, d, J = 2.7 Hz). 13C NMR (101 MHz,
CDCl3): d 13.9, 36.4, 55.3, 58.5, 87.6, 93.9, 168.5, 171.1, 202.1.
HRMS (FAB) (m/z): calcd for C9H16NO4: 202.1079 (M+H)+, found:
202.1098.
(1) A solution of (ꢁ)-13 (0.103 g, 0.45 mmol) in CDCl3 (2 mL; D,
99.8% including 1% V/V TMS, silver foil, available from Cambridge
Isotope Laboratories Inc.) was stood for 2 weeks at room tempera-
ture. Evaporation of the solvent gave 14 as a colorless oil (0.098 g,
95%), which was used for the next reaction without further purifi-
cation. Compound 14: 1H NMR (400 MHz, CDCl3): d 0.03 (6H, s),
0.87 (9H, s), 1.15 (3H, d, J = 7.2 Hz), 3.33 (1H, dq, J = 3.0, 7.2 Hz),
3.46 (3H, s), 3.54 (1H, dd, J = 7.2, 11.2 Hz), 3.61 (3H, s), 3.61–3.65
(1H, m), 3.65 (3H, s), 3.97–4.04 (1H, m), 4.96 (1H, s). (2) To a solu-
tion of (ꢁ)-13 (0.205 g, 0.617 mmol) in CHCl3 (5 mL) was added
one drop of 4 N HCl in dioxane. After stirring for 3 min, saturated
aqueous NaHCO3 was added. The mixture was extracted with
CH2Cl2, dried over Na2SO4, and concentrated. The residue was puri-
fied by silica gel column chromatography to give 14 (0.166 g, 81%)
as a colorless oil.
4.11. Methyl (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexeno-
ate 4
A mixture of 14 (0.253 g, 0.76 mmol) and Et3Nꢂ(HF)3 (1.3 g,
7.6 mmol) in CH2Cl2 (4 mL) was stirred for 12 h at room tempera-
ture. The reaction mixture was diluted with CH2Cl2 and washed
with 7% aqueous NaHCO3. The organic layer was dried over MgSO4.
Evaporation of the organic solvent gave a crude residue, which was
chromatographed on silica gel (5 g, n-hexane/EtOAc = 3:1) to afford
(+)-16 (0.156 g, 94%) as
¼ þ91:4 (c 0.64, CHCl3); IR (KBr): 3450, 1711, 1623,
1150 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.19 (3H, d, J = 6.8 Hz),
a colorless oil. Compound (+)-16:
½ ꢀ
a 2D7
4.9. Methyl (4R,5R)-6-tert-butyldimethylsiloxy-3,5-dimethoxy-
4-methyl-2(E)-hexenamide 15
;
3.24–3.32 (1H, m), 3.44–3.48 (1H, m), 3.45 (3H, s), 3.63 (3H,
s),3.67–3.73 (1H, m), 3.69 (3H, s), 4.07–4.15 (1H, m), 5.05 (1H, s).
13C NMR (101 MHz, CDCl3): d14.5, 36.0, 51.2, 55.6, 58.1, 61.4,
83.6, 91.4, 168.6, 176.6. HRMS (FAB) calcd for C10H19O5 (M+H)+:
A solution of 14 (0.50 g, 1.50 mmol) in MeOH (8 mL) was heated
with Ba(OH)2ꢂ8H2O (1.90 g, 6.01 mmol) at 70 °C. After 4 h, the reac-
tion mixture was filtered to remove precipitate. The filtrate was di-
luted with EtOAc and washed with 0.5 N HCl and brine. The organic
layer was dried over Na2SO4 and concentrated. The residue was
dissolved in DMF (5 mL) and treated with WSCDꢂHCl (water-solu-
ble carbodiimide hydrochloric acid salt) (0.432 g, 2.26 mmol),
HOAt (1-hydroxy-7-aza-benzotriazole) (0.246 g, 1.80 mmol), and
Et3 N (0.315 mL, 2.26 mmol). The mixture was stirred at 50 °C for
0.5 h, and then 28% aqueous NH3 (0.5 mL) was then added. After
219.1232, found: 219.1191.
A mixture of (+)-16 (0.142 g,
0.65 mmol) and Dess–Martin reagent (0.708 g, 1.67 mmol) in
CH2Cl2 (6 mL) was stirred for 2 h at room temperature. The reac-
tion mixture was diluted with ether. The organic layer was washed
with 7% aqueous NaHCO3 and dried over MgSO4. Evaporation of the
organic solvent gave a crude residue, which was chromatographed
on silica gel (5 g, n-hexane/EtOAc = 9:1) to provide a colorless oil
(+)-4 (0.125 g, 89%). Compound (+)-4: ½a D27
¼ þ104:7 (c 0.55,
ꢀ

Y. Iwaki et al. / Tetrahedron: Asymmetry 20 (2009) 298–304
303
CHCl3); IR (KBr): 1712, 1628, 1441, 1149, 1095 cmꢁ1
;
1H NMR
ther 10 min. The reaction was quenched with saturated aqueous
NH4Cl and warmed to room temperature. The mixture was ex-
tracted with EtOAc and washed with brine. The organic layer was
dried over Na2SO4 and concentrated. The residue was purified by
silica gel column chromatography (silica gel 20 g, EtOAc/n-hex-
ane = 1:4) to afford a mixture of 20 and 21 (3.3:1 mixture of E:Z
by 1H NMR, 0.122 g, 77%) as a colorless amorphous. The (Z)-isomer
21 was removed by careful silica gel chromatography before the
(400 MHz, CDCl3): d 1.20 (3H, d, J = 7.2 Hz), 3.43 (3H, s), 3.56 (1H,
dd, J = 2.4, 6.8 Hz), 3.64 (3H, s), 3.68 (3H, s), 4.48 (1H, dq, J = 6.8,
7.2 Hz), 5.07 (1H, s), 9.59 (1H, q, J = 2.4 Hz). 13C NMR (101 MHz,
CDCl3): d 13.9, 36.5, 51.0, 55.7, 58.6, 87.4, 91.9, 167.6, 174.4,
202.1. HRMS (FAB) (m/z): calcd for C10H17O5 (M+H)+: 217.1076,
found: 217.1079.
4.12. (S)-4-Ethoxycarbonyl-20-(1-benzothiazolylsulfanylmethyl-
next step. (E)-isomer 20: ½a D27
¼ þ7:8 (c 0.525, CHCl3); IR (KBr):
ꢀ
ethyl)-2,40-bithiazole 18
2959, 1459, 1426 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.00 (6H, d,
;
J = 6.8 Hz), 1.53 (3H, d, J = 6.8 Hz), 2.29–2.38 (1H, m), 3.90–3.97
(1H, m), 4.76 (2H, s), 5.67 (1H, dd, J = 15.2, 6.8 Hz), 5.78 (1H, dd,
J = 15.2, 7.6 Hz), 6.01 (1H, ddd, J = 15.6, 10.4, 0.8 Hz), 6.17 (1H,
dd, J = 15.6, 10.4 Hz), 7.24–7.30 (1H, m), 7.34 (1H, s), 7.40–7.46
(1H, m), 7.73–7.76 (1H, m), 7.83 (1H, s), 7.89–7.91 (1H, m). 13C
NMR (101 MHz, CDCl3): d 20.8, 22.2, 22.2, 31.0, 33.0, 41.2, 112.2,
117.6, 121.0, 121.3, 121.5, 124.3, 124.6, 126.0, 126.5, 127.1,
131.9, 132.4, 135.4, 142.4, 153.0, 176.4, 190.8. HRMS (ESI) (m/z):
calcd for C23H23N3S4: 469.0775 (M)+, found: 469.0775 (Z)-isomer
To a solution of (S)-17 (0.540 g, 1.81 mmol), 2-mercaptobenzo-
thiazole (0.363 g, 2.17 mmol) and triphenylphosphine (0.665 g,
2.53 mmol) in THF (10 mL) was added DEAD (40% toluene solution,
0.86 mL). After stirring for 0.5 h, the reaction mixture was concen-
trated and purified by silica gel column chromatography (silica gel
50 g, EtOAc/n-hexane = 1:95?1:1) to afford (S)-18 (0.754 g, 93%)
as a colorless oil. Compound (S)-18: ½a D26
¼ ꢁ92:9 (c 1.48, CHCl3);
ꢀ
IR (KBr): 1720 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.42 (3H, t,
;
J = 7.2 Hz), 1.61 (3H, d, J = 6.8 Hz), 3.71–3.80 (2H, m), 3.85–3.94
(1H, m), 4.44 (2H, q, J = 7.2 Hz), 7.27 (1H, ddd, J = 8.4, 7.2, 1.2 Hz),
7.40 (1H, ddd, J = 8.4, 7.2, 1.2 Hz), 7.72 (1H, ddd, J = 8.0, 1.2,
0.4 Hz), 7.86 (1H, ddd, J = 8.0, 1.2, 0.4 Hz), 8.05 (1H, s), 8.16 (1H,
s). 13C NMR (101 MHz, CDCl3): d 14.3, 20.3, 38.3, 39.2, 61.4,
116.7, 120.9, 121.4, 124.2, 125.9, 127.6, 135.2, 147.8, 147.9,
153.0, 161.3, 163.3, 166.1, 174.1. HRMS (FAB) (m/z): calcd for
C19H18N3O2S4: 448.0282 (M+H)+, found: 448.0273.
21:
½
a 2D7
ꢀ
¼ ꢁ82:3 (c 0.81, CHCl3); IR (neat): 2959, 1457,
1427 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 1.01 (6H, dd, J = 6.8,
2.0 Hz), 1.51 (3H, d, J = 7.0 Hz), 2.31–2.42 (1H, m), 4.29–4.38 (1H,
d-sep, J = 6.8, 1.0 Hz), 4.76 (2H, s), 5.47 (1H, dd, J = 10.1, 10.1 Hz),
5.77 (1H, dd, J = 15.1, 6.5 Hz), 6.10 (1H, dd, J = 11.0 Hz), 6.33 (1H,
dd, J = 15.1, 11.0 Hz), 7.28–7.32 (1H, m), 7.33 (1H, s), 7.40–7.44
(1H, m), 7.74 (1H, d, J = 8.1 Hz), 7.82 (1H, s), 7.90 (1H, d,
J = 8.1 Hz). 13C NMR (101 MHz, CDCl3): d 21.7, 22.2, 22.3, 31.4,
33.1, 36.9, 115.6, 117.5, 121.0, 121.6, 121.9, 124.3, 126.1, 130.4,
130.7, 135.5, 144.6, 148.7, 152.2, 153.1, 163.2, 166.0, 176.3. HRMS
(ESI) (m/z): calcd for C23H23N3S4: 469.0775 (M)+, found: 469.0746.
4.13. (S)-4-Benzothiazolylsulfanylmethyl-20-(1-benzothiazolyl-
sulfonylmethylethyl)-2,40-bithiazole 19
To a solution of (S)-18 (0.754 g, 1.69 mmol) in THF (10 mL) was
added LiBH4 (0.048 g, 2.19 mmol). After stirring for 2 h, the reac-
tion was quenched with H2O. The mixture was extracted with
EtOAc and washed with brine. The organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was dissolved in
EtOH (10 mL) and treated with 35% H2O2 (3 mL) and Mo7O24(N-
H4)6ꢂ4H2O (0.208 g, 0.168 mmol). After stirring for 3 h, the mixture
was diluted with EtOAc and washed with H2O, 10% aqueous
Na2S2O3, and brine. The organic layer was dried over Na2SO4 and
concentrated. The residue was passed through silica gel pad (elu-
ent; EtOAc) and again concentrated. The solution of the residue,
2-mercaptobenzothiazole (0.318 g, 1.90 mmol), and triphenyl-
phosphine (0.569 g, 2.17 mmol) in THF (10 mL) was treated with
DEAD (40% toluene solution, 0.855 mL). After stirring for 0.5 h,
the mixture was concentrated and purified by silica gel column
chromatography (silica gel 40 g, EtOAc/n-hexane = 5:95?8:92) to
afford (S)-19 (0.650 g, 66% for 3 steps) as a colorless amorphous so-
4.15. 4-(200-Benzothiazolyl)sulfonylmethyl-20-[(1000S),6000-dime
thylhepta-(2000E),(4000E)-dienyl]-2,40-bithiazole 6
A solution of 20 (0.062 g, 0.132 mmol) in EtOH (3 mL) was
treated with 35% H2O2 (1 mL) and Mo7O24(NH4)6ꢂ4H2O (0.033 g,
0.0264 mmol). The reaction mixture was stirred for 10 h and then
diluted with H2O. The mixture was extracted with EtOAc and
washed with 10% aqueous Na2S2O3 and brine. The organic layer
was dried over Na2SO4 and concentrated. The residue was puri-
fied by silica gel column chromatography (silica gel 15 g, EtOAc/
n-hexane = 10:90?80:20) to afford (S)-6 (0.051 g, 77%) as color-
less amorphous. Compound (S)-6: ½a D25
¼ ꢁ3:6 (c 0.60, CHCl3);
ꢀ
IR (CCl4): 1338, 1155 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.00
;
(6H, d, J = 6.8 Hz), 1.50 (3H, d, J = 7.2 Hz), 2.29–2.38 (1H, m),
3.83–3.90 (1H, m), 4.98 (2H, s), 5.68 (1H, dd, J = 15.6, 7.2 Hz),
5.74 (1H, dd, J = 15.6, 7.6 Hz), 6.00 (1H, dd, J = 15.6, 9.2 Hz), 6.15
(1H, dd, J = 15.6, 10.4 Hz), 7.18 (1H, s), 7.35 (1H, s), 7.54–7.58
(1H, m), 7.62–7.66 (1H, m), 7.91–7.93 (1H, m), 8.26–8.28 (1H,
m). 13C NMR (101 MHz, CDCl3): d 20.7, 22.2, 22.4, 31.1, 41.1,
57.0, 115.7, 121.4, 122.2, 123.1, 125.6, 126.4, 127.6, 127.9,
131.9, 132.3, 137.3, 142.4, 142.7, 152.7, 163.3, 171.8, 176.3. HRMS
(ESI) (m/z): calcd for C23H23N3O2S4: 501.0670 (M)+, found:
501.0673.
lid. Compound (S)-19: ½a D27
¼ ꢁ74:4 (c 0.77, CHCl3); IR (KBr): 3102,
ꢀ
2971, 2915 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 1.62 (3H, d,
J = 7.1 Hz), 3.77 (1H, dd, J = 14.7, 6.1 Hz), 3.98–4.06 (1H, m), 4.49
(1H, dd, J = 14.7, 7.1 Hz), 4.70 (1H, s), 7.26 (1H, s), 7.30–7.34 (1H,
m), 7.39–7.51 (3H, m), 7.68 (1H, s), 7.75–7.81 (2H, m), 7.91–7.95
(1H, m), 8.03–8.08 (1H, m). 13C NMR (101 MHz, CDCl3): d 22.1,
33.0, 33.7, 60.1,115.7, 117.8, 121.1, 121.6, 122.1, 124.4, 125.5,
126.1, 127.4, 128.0, 135.4, 136.9, 148.6, 152.1, 152.5, 153.1,
162.1, 165.6, 165.9, 171.9. HRMS (ESI) (m/z): calcd for
C24H18N4O2S6: 585.9754 (M)+, found: 585.9769.
4.16. Myxothiazol A 1
To a solution of (S)-6 (0.047 g, 0.0929 mmol) in THF (1 mL) was
added LHMDS (1.06 M THF solution, 0.092 mL) at ꢁ78 °C under a
N2 atmosphere. The mixture was gradually warmed to ꢁ30 °C over
30 min, then cooled to ꢁ78 °C and (4R,5R)-3 (0.017 g,
0.0845 mmol) in THF (0.5 mL) was added. The reaction mixture
was gradually warmed to ꢁ40 °C, and then quenched with satu-
rated aqueous NH4Cl. The mixture was extracted with EtOAc,
washed with brine, dried over Na2SO4, and concentrated. The res-
idue was purified by silica gel column chromatography (silica gel
4.14. 4-(200-Benzothiazolyl)sulfanylmethyl-20-[(1000S),6000-dimeth-
ylhepta-(2000E),(4000E)-dienyl]-2,40-bithiazole 20
To a solution of (S)-19 (0.198 g, 0.337 mmol) and (2E)-4-meth-
ylpentenal (0.066 g, 0.675 mmol) in THF (2 mL) was added LHMDS
(1.06 M THF solution, 0.65 mL) at ꢁ78 °C. After 5 min, additional
LHMDS (0.05 mL) was added, and the mixture was stirred for fur-

304
Y. Iwaki et al. / Tetrahedron: Asymmetry 20 (2009) 298–304
10 g, EtOAc/n-hexane = 1:1?1:0) to give myxothiazol A 1 (0.025 g,
7.6 Hz), 6.57 (1H, d, J = 15.6 Hz), 7.09 (1H, s), 7.85 (1H, s). 13C
NMR (101 MHz, CDCl3): d 14.1, 20.9, 22.3 (2C), 31.1, 39.9, 41.3,
50.8, 55.5, 57.0, 84.4, 91.1, 115.0, 115.5, 125.6, 126.6, 131.7,
131.9, 132.6, 142.4, 149.0, 154.5, 162.5, 167.7, 176.2, 176.7. HRMS
(ESI) (m/z): calcd for C26H34N2O4S2: 502.1960 (M)+, found:
502.1966.
61% from (4R,5R)-3) as colorless oil. myxothiazol A 1: ½a D26
ꢀ
¼ þ33:5
(c 0.70, MeOH); IR (neat): 2963, 1667, 1598 cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
d 1.01 (6H, d, J = 6.8 Hz), 1.17 (3H, d,
J = 6.8 Hz), 1.55 (3H, d, J = 6.8 Hz), 2.30–2.39 (1H, m), 3.34 (3H, s),
3.58 (3H, s), 3.79–3.83 (1H, m), 3.94 (1H, dq, J = 6.8, 6.8 Hz), 4.10
(1H, dq, J = 6.8, 6.8 Hz), 4.94 (1H, s), 5.69 (1H, dd, J = 15.1,
6.8 Hz), 5.80 (1H, dd, J = 15.1, 7.4 Hz), 6.02 (1H, dd, J = 15.1,
10.4 Hz), 6.19 (1H, dd, J = 15.1, 10.4 Hz), 6.42 (1H, dd, J = 15.6,
8.1 Hz), 6.57 (1H, d, J = 15.6 Hz), 7.12 (1H, s), 7.86 (1H, s). 13C
NMR (101 MHz, CDCl3): d 14.3, 20.9, 22.3, 31.1, 39.7, 41.3, 55.1,
56.8, 85.2, 94.3, 115.2, 115.6, 126.0, 126.6, 131.3, 131.9, 132.6,
142.4, 149.0, 154.4, 162.6, 169.1, 171.7, 176.3. HRMS (ESI) (m/z):
calcd for C25H33N3O3S2: 487.1963 (M)+, found: 487.1986.
Acknowledgment
We would like to thank Dr. Ryoichi Akaishi of Osaka Yuki Kaga-
ku Kogyo Co., Ltd (Japan) for providing n-butyl (2R,3S)-epoxybut-
anoate 7.
References
1. Gerth, K.; Irschik, H.; Reichenbach, H.; Trowitzsch, W. J. Antibiot. 1980, 33,
1474–1479.
4.17. Myxothiazol Z 2
2. Steinmetz, H.; Forche, E.; Reichenbach, H.; Höfle, G. Tetrahedron 2000, 56,
1681–1684.
3. Thierbach, G.; Reichenbach, H. Biochim. Biophys. Acta 1981, 638, 282–289.
4. Ahn, J.-W.; Woo, S.-H.; Lee, C.-O.; Cho, K.-Y.; Kim, B.-S. J. Nat. Prod. 1999, 62,
495–496.
5. (a) Trowitzsch, W.; Reifenstahl, G.; Wray, V.; Gerth, K. J. Antibiot. 1980, 33,
1480–1490; (b) Trowitzsch, W.; Höfle, G.; Sheldrick, W. S. Tetrahedron Lett.
1981, 22, 3829–3832.
6. (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, G.;
Reddy, K. S.; Waldron, I. R. Org. Biomol. Chem. 2006, 4, 2906–2911.
7. Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett. 1986, 27, 5397–5400.
8. Chemoenzymatic synthesis of methyl (2R,3S)-epoxybutanoate 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 butanoate 7 is commercially available from Osaka Yuki
Kagaku Kogyo Co., Ltd (Japan). Japan Kokai Tokkyo Koho JP 3095539.
9. Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241–244.
10. Akita, H.; Sutou, N.; Sasaki, T.; Kato, K. Tetrahedron 2006, 62, 11592–
11598.
11. (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)-17 and (R)-17 were obtained by optical resolution
of ( )-17 using HPLC separation {Chiralcel OD-H (2 ꢃ 25 cm), eluent; 20% 2-
propanol in hexane, 10 mL/min, (S)-17; tR = 30 min, (R)-17; tR = 50 min}.
12. Iwaki, Y.; Kaneko, M.; Akita, H. Tetrahedron Lett. 2008, 49, 7024–7026.
To a solution of (S)-6 (0.096 g, 0.191 mmol) in THF (1.5 mL) was
added LHMDS (1.06 M THF solution, 0.19 mL) at ꢁ78 °C under N2
atmosphere. The reaction mixture was gradually warmed up to
ꢁ20 °C over 30 min and then cooled to ꢁ60 °C. To this mixture
was added (4R,5R)-4 (0.050 g, 0.230 mmol) in THF (0.5 mL). After
stirring at ꢁ60 °C for 10 min, the reaction was quenched with sat-
urated aqueous NH4Cl at ꢁ15 °C. The mixture was extracted with
EtOAc and washed with brine. The organic layer was dried over
Na2SO4 and concentrated. The residue was purified by silica gel
chromatography (silica gel 15 g, EtOAc/n-hexane = 17:83?25:75)
to afford myxothiazol Z 2 (9:1 of E:Z mixture by 1H NMR,
0.070 g, 73%). The (6Z) isomer was carefully removed by prepara-
tive TLC (EtOAc/toluene). myxothiazol Z (2): ½a D27
ꢀ
¼ þ85:7 (c
1.66, MeOH); IR (neat): 2963, 1711, 1624 cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
d 1.01 (6H, d, J = 6.5 Hz), 1.22 (3H, d,
J = 7.0 Hz), 1.55 (3H, d, J = 7.0 Hz), 2.31–2.41 (1H, m), 3.33 (3H, s),
3.60 (3H, s), 3.66 (3H, s), 3.81 (1H, dd, J = 8.1, 8.1 Hz), 3.91–3.98
(1H, m), 4.14–4.21 (1H, m), 4.96 (1H, s), 5.68 (1H, dd, J = 15.1,
6.5 Hz), 5.80 (1H, dd, J = 15.1, 7.0 Hz), 6.02 (1H, dd, J = 14.6,
10.2 Hz), 6.18 (1H, dd, J = 15.1, 10.2 Hz), 6.40 (1H, dd, J = 15.6,