Synthesis of (4R,5S)-melithiazols F and I

Article abstract of DOI:10.1002/ejoc.200500568

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (8) derived from the (2R,3S)-epoxybutanoate 7 followed by methylation gave the tetrahydro-2-furylidene acetate (-)-9, which was converted into 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 (+)-(4R,5S)- melithiazol F (1), whose spectroscopic data were identical with those of the natural product 1. Moreover, the synthesis of (+)-(4R,5S)-melithiazol I (2), was achieved by the same synthetic strategy as that of (+)-(4R,5S)-melithiazol F (1). The antifungal activity of the synthetic melithiazols F (1) and I (2) against the phytopathogenic fungus, Phytophthora capsici, was evaluated by using a paper disc assay method. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500568

FULL PAPER
DOI: 10.1002/ejoc.200500568
Synthesis of (4R,5S)-Melithiazols F and I
Hiroyuki Takayama,[a] Keisuke Kato,[a] and Hiroyuki Akita*[a]
Keywords: Asymmetric synthesis / Antibiotic / Melithiazol / Antifungal activity / Natural products
Palladium-catalyzed cyclization-methoxycarbonylation of
(2R,3S)-3-methylpenta-4-yne-1,2-diol (8) derived from the
(2R,3S)-epoxybutanoate 7 followed by methylation gave the
tetrahydro-2-furylidene acetate (–)-9, which was converted
into 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 (+)-(4R,5S)-melithiazol F (1), whose spectro-
scopic data were identical with those of the natural product
1. Moreover, the synthesis of (+)-(4R,5S)-melithiazol I (2), was
achieved by the same synthetic strategy as that of (+)-
(4R,5S)-melithiazol F (1). The antifungal activity of the syn-
thetic melithiazols F (1) and I (2) against the phytopathogenic
fungus, Phytophthora capsici, was evaluated by using a pa-
per disc assay method.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Melithiazols F (1) and I (2) have been isolated from melithiazols B and C based on transformation from natural
myxobacterium, Myxococcus stipitatus, strain Mx s64, and myxothiazol A was reported,[6,7] while earlier reports have
exhibit antifungal and cytotoxic activities, and inhibition of documented the independent total synthesis of cystothi-
NADH oxidation.[1] The structures of F (1) and I (2) were azoles A,[8–10] B,[10,11] C,[8,9] E[12] and G.[13] This paper de-
established on the basis of spectroscopic analysis, and the scribes the synthesis of (4R,5S)-melithiazols F (1) and I (2)
absolute configurations of F (1) and I (2) were deduced as and the antifungal activity of melithiazols F (1) and I (2).
(4R,5S) by similarity to melithiazol E (3).[1] Compound 3
Retrosynthetically, the synthesis of 1 can be achieved by
was found to be identical to an antifungal substance named Wittig condensation of the left-half aldehyde 4 and the
cystothiazole A (3)[1] from the myxobacterium Cystobacter right-half phosphonium iodide 5 (Scheme 1). The synthesis
fuscus strain AJ-13278 by using an inhibition assay against of chiral aldehyde 4 was achieved in the total synthesis of
the phytopathogenic fungus, Phytophthora capsici.[2,3] cystothiazole A (3).[4,5] Palladium-catalyzed cyclization-
Meanwhile, we reported the total synthesis of cystothiazole methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-
A (3) based on a chemoenzymatic method.[4,5] Synthesis of diol (8) derived from the (2R,3S)-epoxybutanoate 7 fol-
Scheme 1.
lowed by methylation gave the tetrahydro-2-furylidene ace-
tate (9), which was converted into the left-half aldehyde (+)-
4.[4,5] The synthesis of 5, the right part, is shown in
Scheme 2.
[a] School of Pharmaceutical Sciences, Toho University,
2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
644
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 644–649

Synthesis of (4R,5S)-Melithiazols F and I
FULL PAPER
Scheme 2.
Commercially available phenylacetyl chloride (10) was
Treatment of commercially available isobutylamide 20
treated with NH3/THF to give the corresponding amide 11. with P4S10 gave the corresponding thioamide 21, which was
Treatment of 11 with P4S10 gave the corresponding thio- reacted with α-bromopyruvate to afford the mono-thiazole
amide 12, which was reacted with α-bromopyruvate to af- ester 22 in 43% overall yield from 20. Treatment of 22 with
ford a mono-thiazole ester 13 in 51% overall yield from 10. NH3/MeOH followed by thioamidation with Lawesson’s
Treatment of 13 with NH3/MeOH followed by thioamid- reagent yielded thioamide 24, which was reacted with α-
ation with Lawesson’s reagent yielded thioamide 15, which bromopyruvate to afford the bithiazole ester 2 in 61% over-
was reacted with α-bromopyruvate to afford the 2,4Ј-bithi- all yield from 22. LiBH4 reduction (alcohol 26: 83% yield)
azole ester 16 in 56% overall yield from 13. LiBH4 re- of 25 followed by treatment with I2/Ph3P/imidazole pro-
duction [alcohol 17: 86% yield] of 16 followed by treatment vided the iodide 27 in 90% yield. The reaction of 27 and
with I2/Ph3P/imidazole provided the iodide 18 in 92% yield. triphenylphosphane gave the phosphonium salt 6 in 97%
The reaction of 18 and triphenylphosphane gave the phos- yield, which was condensed with (+)-4 in the presence of
phonium salt 5 in 96% yield, which was condensed with lithium bis(trimethylsilyl)amide in THF to afford a mixture
(+)-4 in the presence of lithium bis(trimethylsilyl)amide in [(+)-(E)-2/(+)-(Z)-28 = 2.83:1] of olefins in 92% yield. Both
THF to afford a mixture [(+)-(E)-1/(+)-(Z)-19 = 2.33:1] of isomers were isolated by means of preparative HPLC to
olefins in 92% yield. Both isomers were isolated by means provide (+)-2 as a colorless oil {[α]D +91.6 (c = 0.63,
of preparative HPLC to provide (+)-1 as a colorless oil CHCl3)} and (+)-28 as a colorless oil {[α]D +245.7 (c =
{[α]D +79.9 (c = 0.925, CHCl3)} and (+)-19 as a colorless 1.46, CHCl3)}. The (Z)-geometry of (+)-28 was confirmed
oil {[α]D +231.4 (c = 1.41, CHCl3)}. The (Z)-geometry of by the coupling constant (J = 12.0 Hz) of the olefinic pro-
(+)-19 was confirmed by the coupling constant (J = tons. The physical data [1H NMR(CDCl3)] of the synthetic
12.0 Hz) of the olefinic protons. The physical data [1H (+)-2 were identical with those of the reported melithiazol
NMR (CDCl3)] of the synthetic (+)-1 were identical with I (2). The antifungal activity of the synthetic melithiazols F
those of the reported melithiazol (+)-1. Then the synthesis (1) and I (2) against the phytopathogenic fungus, Phyto-
of melithiazol I (2) was carried out. Retrosynthetically, the phthora capsici, was evaluated by using a paper disc assay
synthesis of 2 can be achieved by Wittig condensation of method as reported previously.[3,4] The minimum dose ap-
the left-half aldehyde 4 and the right-half phosphonium plied on a paper disc to inhibit the fungal growth was 1 µg/
iodide 6. The synthesis of 6, the right part, is shown in disc. The synthetic melithiazols F (1) and I (2) also showed
Scheme 3.
the activities at a similar level of dosage (0.2 µg/disc and
Eur. J. Org. Chem. 2006, 644–649
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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645

H. Takayama, K. Kato, H. Akita
FULL PAPER
Scheme 3.
0.04 µg/disc, respectively) in comparison to that (0.2 µg/
disc) of cystothiazole A (3).[14] According to the recent
studies on antifungal tests using the phytopathogenic fun-
gus, Phytophthora capsici, synthetic cystothiazole A (3)
[(4R,5S)-3] showed activity up to a dose of 0.04 µg/disc.
However, not only the enantiomer (4S,5R)-3, but also the
two diastereomers, (4S,5S)-3 and (4R,5R)-3, showed no an-
tifungal activity up to 100 µg/disc. This result was not ex-
pected at all, because all the stereoisomers possess the β-
methoxyacrylate unit that is regarded as the binding site to
the target molecules.[15]
In conclusion, palladium-catalyzed cyclization–methoxy-
carbonylation of (2R,3S)-3- methylpenta-4-yne-1,2-diol (8)
derived from the (2R,3S)-epoxybutanoate 7 followed by
methylation gave the tetrahydro-2-furylidene acetate (–)-9,
which was converted into the left-half aldehyde (+)-4. Wit-
tig reaction between (+)-4 and the phosphoranylide derived
Experimental Section
General: All melting points were measured on a Yanaco MP-3S
micro melting point apparatus and are uncorrected. 1H- and 13C
NMR spectra were recorded with a JEOL AL 400 spectrometer in
CDCl3. Carbon substitution degrees were established by DEPT
pulse sequence experiments. High-resolution mass spectra (HRMS)
and fast atom bombardment mass spectra (FAB MS) were ob-
tained with a JEOL JMS 600H spectrometer. IR spectra were re-
corded with a JASCO FT/IR-300 spectrometer. The preparative
HPLC system was composed of a detector (Shodex RI-1) and a
pump (JASCO PU-2080 Plus). HPLC analysis conditions were as
follows; column: YMC-Pack ProC18 [150×20 mm and Precolumn
(50×20 mm)], solvent: MeOH/H2O (80:20), flow rate: 5 mL/min.
Optical rotations were measured with a JASCO DIP-370 digital
polarimeter. All evaporations were performed under reduced pres-
sure. For column chromatography, silica gel (Kieselgel 60) was em-
ployed.
from the bithiazole-type phosphonium iodide 5 using lith- Ethyl 2-Phenethylthiazole-4-carboxylate (13): 1) NH3 gas was
bubbled into a solution of commercially available 10 (1.0 g,
6.46 mmol) in anhydrous THF (20 mL) for 10 min at room temp.
The reaction mixture was diluted with H2O and extracted with Ac-
OEt. Evaporation of the organic solvent gave a crude amide (11),
which was used without further purification. 2) To a solution of
phosphorus pentasulfide (P4S10; 0.288 g, 0.65 mmol) in benzene
(35 mL) was added crude 11 and the whole mixture was stirred for
2 h at room temperature. The reaction mixture was diluted with
brine and extracted with AcOEt. The organic layer was dried with
MgSO4 and evaporated to give crude 12. 3) A mixture of crude 12
and ethyl α-bromopyruvate (1.22 g, 6.47 mmol) in EtOH (20 mL)
ium bis(trimethylsilyl)amide afforded (+)-(4R,5S)-melithi-
azol F (1), the spectroscopic data of which were identical
with those of the natural product. Moreover, the synthesis
of (+)-(4R,5S)-melithiazol I (2) was achieved by the same
synthetic strategy as that of (+)-(4R,5S)-melithiazol F (1).
The absolute structure of natural melithiazols F (1) and I
(2) might be confirmed as (4R,5S)-configuration because
both natural products and synthetic products indicate anti-
fungal activity, although the tested microorganisms were
different.
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Eur. J. Org. Chem. 2006, 644–649

Synthesis of (4R,5S)-Melithiazols F and I
FULL PAPER
was refluxed for 60 min. The reaction mixture was evaporated, di-
luted with AcOEt, and washed with 7% aqueous NaHCO3. The
organic layer was dried with MgSO4 and evaporated to give a crude
oil, which was purified by chromatography on silica gel (20 g, n-
hexane/AcOEt, 10:1) to afford 13 as a pale yellow oil (0.816 g, 51%
H) ppm. 13C NMR: δ = –1.60, 39.7, 116.7, 116.8, 127.4, 128.9 (2
C), 129.1 (2 C), 137.4, 148.7, 154.1, 162.9, 171.5 ppm.
C14H11IN2S2: calcd. C 42.22, H 2.78, N 7.03; found C 42.27, H
2.81, N 6.50. MS (FAB): m/z = 399 [M+ + 1].
[2Ј-Phenethyl-2,4Ј-bithiazolyl-4-yl)methyl]triphenylphosphonium Io-
dide (5): A mixture of 18 (0.507 g, 1.27 mmol) and triphenylphos-
phane (0.368 g, 1.4 mmol) in benzene (10 mL) was refluxed for
15 h. After cooling, the resulting colorless powder 5 (0.81 g, 96%)
overall yield from 10). 13: IR (KBr): ν = 1719 cm–1. 1H NMR: δ =
˜
1.41 (t, J = 7.2 H, 3 H), 4.39 (s, 2 H), 4.43 (q, J = 7.2 Hz, 2 H),
7.27–7.37 (m, 5 H), 8.05 (s, 1 H) ppm. 13C NMR: δ = 14.4, 39.9,
61.5, 127.5, 127.8, 129.0 (2 C), 129.2 (2 C), 137.3, 146.9, 161.5,
171.9 ppm. MS (FAB): m/z = 248 [M+ + 1].
1
was obtained by filtration. 5: m.p. 224–226 °C. H NMR: δ = 4.32
(s, 2 H), 5.52 (d, J = 13.6 Hz, 2 H), 7.25 (s, 1 H), 7.27–7.37 (m, 5
H), 7.26–7.66 (m, 6 H), 7.75–7.84 (m, 9 H), 8.11 (s, 1 H) ppm.
C32H26IN2PS2: calcd. C 58.18, H 3.97, N 4.24; found C 58.13, H
3.92, N 3.63. MS (FAB): m/z = 533 (M+ – I).
Ethyl 2Ј-Phenethyl-2,4Ј-bithiazolyl-4-carboxylate (16): 1) A mixture
of 13 (0.78 g, 3.5 mmol) and NH3-saturated MeOH (100 mL) in a
sealed tube stood for 2 d at room temp. After cooling, the reaction
mixture was evaporated to afford crude amide 14. To a solution of
crude 14 in benzene (10 mL) was added Lawesson’s reagent (0.65 g,
1.6 mmol) and the whole mixture was refluxed for 1 h. The reaction
mixture was diluted with H2O and extracted with AcOEt. The or-
ganic layer was washed with brine and dried with MgSO4. The
organic layer was evaporated to give crude thioamide 15. A solu-
tion of 15 and ethyl α-bromopyruvate (0.62 g, 3.1 mmol) in abso-
lute EtOH (10 mL) was stirred for 1.5 h at reflux. The reaction
mixture was evaporated, diluted with 7% aqueous NaHCO3, and
extracted with AcOEt. The organic layer was washed with brine
and dried with MgSO4. The organic layer was evaporated to give
a crude residue, which was purified by chromatography on silica
gel (20 g, n-hexane/AcOEt, 10:1) to afford 16 (0.581 g, 56%).
Wittig Condensation of (+)-4 and 5: To a solution of 5 (0.608 g,
0.92 mmol) in THF (5 mL) was added lithium bis(trimethylisilyl)-
amide (1 m in THF, 0.92 mL, 0.92 mmol) at 0 °C under argon and
the mixture was stirred for 20 min. A solution of (+)-4 (0.10 g,
0.46 mmol) in THF (2 mL) was added to the above reaction mix-
ture at 0 °C and the whole mixture was stirred for 20 min at the
same temperature. The reaction mixture was diluted with H2O and
extracted with AcOEt. The organic layer was dried with MgSO4
and evaporated to afford a crude product which was purified by
chromatography on silica gel (5 g, n-hexane/AcOEt, 20:1) to give a
mixture [(E)/(Z) = 2.33:1] of isomers of 1 (0.20 g, 92%). This mix-
ture was subjected to preparative HPLC to afford (+)-1 (0.140 g,
58%) as a colorless oil and (+)-19 (0.06 g, 27%) as a colorless oil.
Recrystallization of 16 from n-hexane/AcOEt provided colorless
(+)-1: [α]2D8 = +79.9 (c = 0.925, CHCl ). IR (KBr): ν = 2925, 1711,
˜
1
needles. 16: m.p. 92–94 °C. IR (KBr): ν = 1721 cm–1. H NMR: δ
3
˜
1627, 1450, 1146 cm–1. 1H NMR: δ = 1.21 (d, J = 7.0 Hz, 3 H),
3.30 (s, 3 H), 3.60 (s, 3 H), 3.66 (s, 3 H), 3.81 (t, J = 7.6 Hz, 1 H),
4.16 (dq, J = 7.6, 7.0 Hz, 1 H), 4.38 (s, 2 H), 4.96 (s, 1 H),6.41 (dd,
J = 15.8, 7.6 Hz, 1 H), 6.58 (d, J = 15.8 Hz, 1 H), 7.10 (s, 1 H),
7.28–7.40 (m, 5 H), 7.85 (s, 1 H) ppm. 13C NMR: δ = 14.0, 39.7,
39.8, 50.8, 55.5, 57.0, 84.4, 91.1, 115.0, 116.3, 125.5, 127.4, 128.9
(2 C), 129.1 (2 C), 131.8, 137.4, 149.2, 154.5, 162.2, 167.7, 171.4,
176.7 ppm. HRMS (FAB): (m/z) calcd. for C24H26N2O4S2:
471.1412 [M+ + 1]; found 471.1431. (+)-19: [α]2D9 = +231.4 (c =
= 1.43 (t, J = 7.2 Hz, 3 H), 4.37 (s, 2 H), 4.44 (q, J = 7.2 Hz, 2 H),
7.27–7.37 (m, 5 H), 8.03 (s, 1 H), 8.17 (s, 1 H) ppm. 13C NMR: δ
= 14.4, 39.6, 61.5, 117.6, 127.4, 127.7, 128.9 (2 C), 129.1 (2 C),
137.2, 147.9, 148.2, 161.5, 163.4, 171.5 ppm. C16H14N2O2S2: calcd.
C 58.16, H 4.27, N 8.48; found C 58.19, H 4.26, N 8.10. MS (FAB):
m/z = 331 [M+ + 1].
4-Hydroxymethyl-2Ј-phenethyl-2,4Ј-bithiazol (17): A mixture of 16
(1.54 g, 5.45 mmol) and LiBH4 (0.51 g, 2.72 mmol) in THF
(20 mL) was stirred for 1.5 h at room temperature. The reaction
mixture was diluted with H2O (10 mL) and the whole mixture was
stirred for 5 h at the same temperature. The reaction mixture was
extracted with AcOEt, washed with brine, and the organic layer
dried with MgSO4. The organic layer was evaporated to give a
crude residue, which was purified by chromatography on silica gel
(16 g, n-hexane/AcOEt, 1:1) to afford 17 (1.16 g, 86%). Recrystalli-
zation of 17 from n-hexane/AcOEt provided colorless needles. 17:
1.41, CHCl ). IR (KBr): ν = 2925, 1710, 1621, 1449, 1378, 1267,
˜
3
1146, 925, 817, 703 cm–1. H NMR: δ = 1.24 (d, J = 7.2 Hz, 3 H),
1
3.32 (s, 3 H), 3.34 (s, 3 H), 3.67 (s, 3 H), 4.22 (dq, J = 9.4, 7.2 Hz,
1 H), 4.39 (s, 2 H), 4.92 (s, 1 H), 5.08 (t, J = 9.4 Hz, 1 H), 5.60
(dd, J = 12.0, 9.4 Hz, 1 H), 6.59 (d, J = 12.0 H, 1 H), 7.24 (s, 1
H), 7.28–7.40 (m, 5 H), 7.83 (s, 1 H) ppm. 13C NMR (CD3OD): δ
= 14.8, 39.3, 39.7, 50.8, 55.1, 56.3, 78.5, 91.1, 116.0, 117.9, 125.4,
127.4, 128.9 (2 C), 129.1 (2 C), 132.7, 137.4, 149.2, 153.6, 161.3,
m.p. 121–123 °C. IR (KBr): ν = 3391, 3114 cm–1. 1H NMR: δ = 167.8, 171.6, 176.6 ppm. HRMS (FAB): (m/z) calcd. for C24H26N2
˜
4.37 (s, 2 H), 4.81 (s, 2 H), 7.20 (s, 1 H), 7.28–7.36 (m, 5 H), 7.83
(s, 1 H) ppm. 13C NMR: δ = 39.7, 61.0, 115.2, 116.4, 127.4, 128.9
(2 C), 129.1 (2 C), 137.3, 148.9, 157.2, 163.3, 171.6 ppm.
C14H12N2OS2: calcd. C 58.31, H 4.19, N 9.71; found C 58.38, H
4.20, N 9.58. MS (FAB): m/z = 289 [M+ + 1].
O4S2 [M+ + 1]: 471.1412; found 471.1372.
Ethyl 2-Isobutyl-1,3-thiazole-4-carboxylate (22): 1) To a solution of
phosphorus pentasulfide (P4S10; 0.872 g, 1.9 mmol) in Et2O
(20 mL) was added commercially available isobutylamide 20 (1.98 g
19.6 mmol), and the mixture was stirred for 2 h at room tempera-
ture. The reaction mixture was diluted with brine and extracted
with Et2O. The organic layer was dried with MgSO4 and evapo-
rated to give crude thioamide 21, which was used for the next reac-
tion without further purification. 2) A mixture of crude 21 and
ethyl α-bromopyruvate (3.82 g, 19.6 mmol) in EtOH (30 mL) was
refluxed for 2 h. The reaction mixture was evaporated, diluted with
AcOEt, and washed with 7% aqueous NaHCO3. The organic layer
was dried with MgSO4 and evaporated to give a crude oil, which
4-Iodomethyl-2Ј-phenethyl-2,4Ј-bithiazol (18): To a mixture of 17
(0.40 g, 1.38 mmol), triphenylphosphane (0.40 g, 1.52 mmol), and
imidazole (0.141 g, 2.0 mmol) in THF (10 mL) was added I2
(0.383 g, 1.52 mmol) under argon and the mixture was stirred for
10 min at room temperature. The reaction mixture was diluted with
H2O and extracted with AcOEt. The organic layer was washed with
brine and dried with MgSO4. The organic layer was evaporated to
give a crude residue, which was purified by chromatography on
silica gel (10 g, n-hexane/AcOEt, 5:1) to afford 18 (0.507 g, 92%). was purified by chromatography on silica gel (40 g, n-hexane/Ac-
Recrystallization of 18 from n-hexane provided pale yellow needles.
OEt, 10:1) to afford 22 as a pale yellow oil (1.99 g, 48% overall
1
18: m.p. 129–131 °C. IR (KBr): ν = 1499 cm–1. H NMR: δ = 4.37
yield from 20). 22: IR (KBr): ν = 1728 cm–1. 1H NMR: δ = 1.00
˜
˜
(s, 2 H), 4.56 (s, 2 H), 7.26–7.36 (m, 5 H), 7.27 (s, 1 H), 7.89 (s, 1
(d, J = 6.8 Hz, 6 H), 1.40 (t, J = 7.2 Hz, 3 H), 2.14 (m, 1 H), 2.93
Eur. J. Org. Chem. 2006, 644–649
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H. Takayama, K. Kato, H. Akita
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(d, J = 7.2 Hz, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 8.06 (s, 1 H) ppm. 20 h. After cooling, the resulting colorless powder 6 (1.34 g, 97%)
13C NMR: δ = 14.4, 22.3 (2 C), 29.9, 42.4, 61.4, 126.9, 146.8, 161.5,
171.2 ppm. MS (FAB): m/z = 214 [M+ + 1].
was obtained by filtration. 6: m.p. 222–223 °C. 1H NMR: δ = 0.99
(d, J = 6.8 Hz, 6 H), 2.10 (m, 1 H), 2.85 (d, J = 7.2 Hz, 2 H), 5.44
(d, J = 13.6 Hz, 2 H), 7.25 (s, 1 H), 7.63–7.66 (m, 6 H), 7.75–7.81
(m, 9 H), 8.01 (s, 1 H) ppm. C29H28IN2PS2: calcd. C 55.59, H 4.50,
N 4.47; found C 55.52, H 4.44, N 3.99. MS (FAB): m/z = 499 (M+ –
I).
Ethyl 2Ј-Isobutyl-2,4Ј-bithiazolyl-4-carboxylate (25): 1) A mixture
of 22 (1.99 g, 9.3 mmol) and NH3-saturated MeOH (100 mL) in a
sealed tube stood for 2 d at room temperature. After cooling, the
reaction mixture was evaporated to afford crude amide 23. To a
solution of crude 23 in benzene (25 mL) was added Lawesson’s rea-
gent (1.72 g, 4.3 mmol) and the mixture was refluxed for 20 min.
The reaction mixture was diluted with H2O and extracted with Ac-
OEt. The organic layer was washed with brine and dried with
MgSO4. The organic layer was evaporated to give crude thioamide
24. A solution of crude thioamide 24 and ethyl α-bromopyruvate
(1.82 g, 9.3 mmol) in absolute EtOH (40 mL) was refluxed for 1 h.
The reaction mixture was evaporated, diluted with 7% aqueous
NaHCO3, and extracted with AcOEt. The organic layer was
washed with brine and dried with MgSO4. The organic layer was
Wittig Condensation of (+)-4 and 6: To a solution of 6 (0.463 g,
0.74 mmol) in THF (45 mL) was added lithium bis(trimethylisilyl)-
amide (1 m in THF, 0.74 mL, 0.74 mmol) at 0 °C under argon and
the mixture was stirred for 20 min. A solution of (+)-4 (0.08 g,
0.37 mmol) in THF (2 mL) was added at 0 °C and the whole mix-
ture was stirred for 20 min at the same temperature. The reaction
mixture was diluted with H2O and extracted with AcOEt. The or-
ganic layer was dried with MgSO4 and evaporated to afford a crude
product which was purified by chromatography on silica gel (10 g,
n-hexane/AcOEt, 20:1) to give a mixture [(E)/(Z) = 2.5:1] of iso-
mers of 2 (0.151 g, 93%). This mixture was subjected to preparative
HPLC to afford (+)-2 (0.108 g, 66%) as a colorless oil and (+)-28
(0.043 g, 26%) as a colorless oil. (+)-2: [α]2D6 = +91.6 (c = 0.63,
evaporated to give
a crude residue, which was purified by
chromatography on silica gel (40 g, n-hexane/AcOEt, 10:1) to af-
ford 25 (1.6981 g, 61%). Recrystallization of 25 from n-hexane pro-
vided colorless needles. 25: m.p. 83–84 °C. IR (KBr):
ν
=
CHCl ). IR (KBr): ν = 2925, 1711, 1626, 1457, 1376, 1146 cm–1.
˜
˜
3
1722 cm–1. 1H NMR: δ = 1.03 (d, J = 6.8 Hz, 6 H), 1.43 (t, J =
7.2 Hz, 3 H), 2.16 (m, 1 H), 2.91 (d, J = 7.2 Hz, 2 H), 4.44 (q, J =
7.2 Hz, 1 H), 8.03 (s, 1 H), 8.16 (s, 1 H)ppm. 13C NMR: δ = 14.4,
1H NMR: δ = 1.02 (d, J = 6.4 Hz, 6 H), 1.22 (d, J = 6.8 Hz, 3 H),
2.10–2.20 (m, 1 H), 2.92 (d, J = 7.2 Hz, 2 H), 3.33 (s, 3 H), 3.60
(s, 3 H), 3.67 (s, 3 H), 3.81 (t, J = 7.6 Hz, 1 H), 4.17 (dq, J = 7.6,
22.3 (2 C), 29.7, 42.2, 61.5, 116.7, 127.6, 147.9, 148.0, 161.5, 163.7, 6.8 Hz, 1 H), 4.97 (s, 1 H),6.41 (dd, J = 16.0, 7.6 Hz, 1 H), 6.57
171.1 ppm. C13H16N2O2S2: calcd. C 52.68, H 5.44, N 9.45; found
(d, J = 16.0 Hz, 1 H), 7.09 (s, 1 H), 7.86 (s, 1 H) ppm. 13C NMR:
δ = 14.1, 22.3 (2 C), 29.7, 39.8, 42.2, 50.8, 55.5, 57.0, 84.4, 91.1,
115.0, 115.4, 125.6, 131.7, 149.0, 154.5, 162.5, 167.7, 171.0,
176.7 ppm. HRMS (FAB): (m/z) calcd. for C21H28N2O4S2:
437.1569 [M+ + 1]; found 437.1576. (+)-28: [α]2D9 = +245.7 (c =
C 52.54, H 5.36, N 9.17. MS (FAB): m/z = 297 [M+ + 1].
4-Hydroxymethyl-2Ј-isobutyl-2,4Ј-bithiazol (26): A mixture of 25
(1.0 g, 4.4 mmol) and LiBH4 (0.486 g, 22.3 mmol) in THF (30 mL)
was stirred for 2 h at room temperature. The reaction mixture was
diluted with H2O (20 mL) and stirred for 15 h at the same tempera-
ture. The reaction mixture was extracted with AcOEt, washed with
brine, and the organic layer was dried with MgSO4. The organic
layer was evaporated to give a crude residue, which was purified by
chromatography on silica gel (20 g, n-hexane/AcOEt, 2:1) to afford
26 (0.92 g, 83%). Recrystallization of 26 from n-hexane/AcOEt pro-
1.46, CHCl ). IR (KBr): ν = 2925, 1711, 1628, 1457, 1146 cm–1. 1H
˜
3
NMR: δ = 1.03 (d, J = 6.8 Hz, 6 H), 1.25 (d, J = 6.8 Hz, 3 H),
2.10–2.23 (m, 1 H), 2.93 (d, J = 7.2 Hz, 2 H), 3.33 (s, 3 H), 3.34
(s, 3 H), 3.67 (s, 3 H), 4.23 (dq, J = 9.4, 6.8 Hz, 1 H), 4.92 (s, 1 H),
5.09 (t, J = 9.4 Hz, 1 H), 5.60 (dd, J = 12.0, 9.4 Hz, 1 H), 6.59 (d,
J = 12.0 Hz, 1 H), 7.23 (s, 1 H), 7.83 (s, 1 H) ppm. 13C NMR
(CDCl3): δ = 14.8, 22.3 (2 C), 29.7, 39.3, 42.3, 50.8, 55.1, 56.3,
78.6, 91.1, 115.1, 117.8, 125.4, 132.7, 149.0, 153.5, 161.6, 167.8,
171.2, 176.6 ppm. HRMS (FAB): (m/z) calcd. for C21H28N2O4S2
[M+ + 1]: 437.1569; found 437.1595.
vided colorless needles. 26: m.p. 118–119 °C. IR (KBr): ν = 3402,
˜
1
2925 cm–1. H NMR: δ = 1.02 (d, J = 6.8 Hz, 6 H), 2.15 (m, 1 H),
2.91 (d, J = 7.2 Hz, 2 H), 3.49 (br. s, 1 H), 4.81 (s, 2 H), 7.20 (s, 1
H), 7.85 (s, 1 H) ppm. 13C NMR: δ = 22.3 (2 C), 29.7, 42.2, 60.8,
115.3, 115.5, 148.6, 157.2, 163.6, 171.2 ppm. C11H14N2OS2: calcd.
C 51.94, H 5.55, N 11.01; found C 51.87, H 5.49, N 10.86. MS
(FAB): m/z = 255 [M+ + 1].
Supporting Information Available (see footnote on the first page of
this article): NMR charts for (+)-(4R,5S,6E)-melithiazol F (1), (+)-
(4R,5S,6Z)-melithiazol F (19), (+)-(4R,5S,6E)-melithiazol I (2),
and (+)-(4R,5S,6Z)-melithiazol I (28) are available on the WWW
under http://www.eurjoc.org.
4-Iodomethyl-2Ј-isobutyl-2,4Ј-bithiazol (27): To a mixture of 26
(0.77 g, 3.0 mmol), triphenylphosphane (0.875 g, 3.33 mmol), and
imidazole (0.309 g, 4.54 mmol) in THF (15 mL) was added I2
(0.847 g, 3.33 mmol) under argon and the mixture was stirred for
10 min at room temp. The reaction mixture was diluted with H2O
and extracted with AcOEt. The organic layer was washed with
brine and dried with MgSO4. The organic layer was evaporated to
give a crude residue, which was purified by chromatography on
silica gel (10 g, n-hexane/AcOEt, 5:1) to afford 27 (0.99 g, 90%).
Acknowledgments
The authors are grateful to Professor Makoto Ojika at Nagoya
University in Japan for performance of a biological experiment
using the synthetic products. We also thank Dr. K. Koike at Toho
University in Japan for preparative HPLC separation of the syn-
thetic products performed in his laboratory. This work was sup-
ported by a Grant-in Aid for Scientific Research (C) (No. 14572016
to H.A.) from The Ministry of Education, Culture, Sports, Science
and Technology.
Recrystallization of 27 from n-hexane provided pale yellow needles.
1
27: m.p. 116–117 °C. IR (KBr): ν = 1500 cm–1. H NMR: δ = 1.01
˜
(d, J = 6.8 Hz, 6 H), 2.15 (m, 1 H), 2.91 (d, J = 7.2 Hz, 2 H), 4.56
(s, 2 H), 7.25 (s, 1 H), 7.87 (s, 1 H) ppm. 13C NMR: δ = –1.50,
22.3 (2 C), 29.7, 42.2, 115.8, 116.7, 148.5, 154.0, 163.2, 171.1 ppm.
C11H13IN2S2: calcd. C 36.27, H 3.60, N 7.69; found C 36.15, H
3.58, N 7.26. MS (FAB): m/z = 365 [M+ + 1].
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648
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 644–649

Synthesis of (4R,5S)-Melithiazols F and I
FULL PAPER
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Received: July 27, 2005
Published Online: November 25, 2005
Eur. J. Org. Chem. 2006, 644–649
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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