A concise total synthesis of melithiazole C+

Article abstract of DOI:10.1021/ol701459j

A short and convergent synthesis of the myxobacterial antibiotic melithiazole C is described featuring a highly E-selective cross-metathesis as the key step.

Full text of DOI:10.1021/ol701459j

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3425-3427
A Concise Total Synthesis of
Melithiazole C†
Julian Gebauer, Stellios Arseniyadis, and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 rue Vauquelin,
F-75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received June 20, 2007
ABSTRACT
A short and convergent synthesis of the myxobacterial antibiotic melithiazole C is described featuring a highly E-selective cross-metathesis
as the key step.
The thiazole subunit is found in many natural and synthetic
compounds with a wide range of interesting bioactivities.1
The melithiazoles A-N represent a group of fungicidal
â-methoxy acrylate (MOA) metabolites which have been
isolated from different strains of myxobacteria.2 As a
common structural motif they share either a bisthiazole or a
thiazole-thiazoline ring system linked via a double bond to
a highly pharmacophoric polypropionate moiety that selec-
tively inhibits mitochondrial respiration by binding to the
cytochrome bc1 complex (Figure 1).3
and additionally occurs as a mixture of E/Z isomers at C6-
C7 (6E/6Z ) 7/2)2 with only the trans-isomer being biologi-
cally active.4 On the other hand, derivatization of the acetyl
group in 1 was found to selectively enhance its biological
activities.4 Whereas simple transformation of the carbonyl
group into an oxime functionality reduces the antifungal
properties and increases the cytotoxicity, an exceptionally
high antifungal activity is observed with a methoxime or
vinyl derivative. Thus, melithiazole C (1) has attracted great
attention as a potential lead for the development of agro-
chemical fungicides.5
Despite its very limited natural availability arising from
the low efficiency of the fermentation process, only one total
synthesis of 1 has been reported proceeding via a moderately
stereoselective Wittig reaction (E/Z ≈ 6/1) to introduce the
C6-C7 double bond (14 steps, 15% overall yield).6 On the
basis of our recent work on the cross-metathesis (CM) of
vinyl substituted thiazoles,7 we present herein a short and
Figure 1. Melithiazoles A-N.
(3) Thierbach, G.; Reichenbach, H. Biochim. Biophys. Acta 1981, 638,
282-289.
(4) So¨ker, U.; Sasse, F.; Kunze, B.; Ho¨fle, G. Eur. J. Org. Chem. 2000,
11, 2021-2026.
(5) (a) Meyer, O.; Simon, W.; Ho¨fle, G.; So¨ker, U. PCT Int. Appl. WO
2001038317 A2 20010531, 2001 (32 pp). (b) Simon, W.; Carter, P.; Ho¨fle,
G.; So¨ker, U. PCT Int. Appl. WO 2001012615 A2 20010222, 2001 (41
pp). (c) Ho¨fle, G.; So¨ker, U. Ger. Offen. DE 19715290 A1 19981015, 1998
(14 pp).
(6) Takayama, H.; Kato, K.; Kimura, M.; Akita, H. Heterocycles 2007,
71, 75-85.
Isolated in only minor quantities from Melittangium
lichenicola, melithiazole C (1) contains a single thiazole ring
† Dedicated to the memory of Charles Mioskowski (1946-2007).
(1) de Souza, M. V. N. J. Sulfur Chem 2005, 26, 429-449.
(2) Bo¨hlendorf, B.; Herrmann, M.; Hecht, H. J.; Sasse, F.; Forche, E.;
Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem. 1999, 10, 2601-
2608.
10.1021/ol701459j CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/18/2007

highly stereoselective synthesis of 1 that, at the same time,
should allow rapid access to structural derivatives5c as well
as various heterocyclic analogues.5b
formate gave the desired â-methoxy acrylate 2 as a single
stereoisomer in 50% overall yield from 4.10
Concerning the preparation of the vinyl thiazole 3, the
thiazolyl bromide 9 was considered a suitable precursor since
it is readily available from 2,4-dibromothiazole (5) via
regioselective metalation (n-BuLi, Et2O, -78 °C) and
treatment with N-acetylmorpholine.11 In our approach, a
change of solvent from Et2O to THF furnished the known
bromide 9 in a significantly improved yield (81% vs 66%).11
The latter was then subjected to a Stille cross-coupling
reaction with vinyl tributyltin (1.1 equiv) under standard
conditions [2 mol % of PdCl2(PPh3)2, dioxane, 100 °C]12 to
efficiently afford the desired vinyl thiazole 3 (Scheme 3).
Retrosynthetically, 1 was therefore fragmented into the
common â-methoxy acrylate 2 and the vinyl thiazole 3 which
would both be readily accessible in a few steps from the
commercially available Evans’ propionate 4 and the dibro-
mothiazole 5, respectively (Scheme 1).
Scheme 1. Retrosynthesis of Melithiazole C (1)
Scheme 3. Synthesis of the Vinyl Thiazole 3
With both fragments in hand, the conditions for the final
metathesis reaction were investigated. While Grubbs first
generation catalyst (G I)13 proved completely ineffective
(Table 1, entry 1), CM of an equimolar mixture of 2 and 3
As depicted in Scheme 2, the synthesis of the â-methoxy
acrylate 2 began with a previously described asymmetric
aldol reaction between 4 and acrolein (dr >95:5)8 followed
by O-methylation with methyl triflate in the presence of 2,6-
ditertbutylpyridine (DTBP). While initial attempts to directly
Table 1. Optimization of the CM Reaction
Scheme 2. Synthesis of the â-Methoxy Acrylate 2
mol equiv
%
temp time conversionb,c
entry [Ru]
of 3 solventa (°C)
(h)
(%)
1
2
3
4
5
6
7
8
G I
10
1
1
1
2
2
2
2
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C6H6
CH2Cl2
CH2Cl2
CH2Cl2
40
40
40
40
60
20
40
40
48
48
48
60
60
72
60
60
0
27
18
50
26
5
68 (56)d
72
G II 10
H-G 10
G II 20
G II 20
G II 20
G II 30
G II 40
transform the resulting oxazolidinone 7 into the required
â-keto ester 8 under Reformatsky conditions failed (BrCH2-
CO2Me, Zn, THF, reflux),9 activation of the corresponding
carboxylic acid with use of carbonyl diimidazole (CDI) and
direct condensation with the lithium enolate of methyl acetate
at -78 °C in THF proceeded smoothly to produce 8 in 75%
yield (3 steps). Finally, acid-catalyzed methyl enol ether
formation with MeOH in the presence of trimethyl ortho-
a 0.05 M. b Ratio of 1:2 determined by 1H NMR. c E/Z > 20/1. d Isolated
yield.
in refluxing CH2Cl2 with 10 mol % of Grubbs second
generation catalyst (G II)14 or with Hoveyda-Grubbs catalyst
(H-G)15 resulted mainly in homodimerization of the vinyl
(10) Shao, J.; Panek, J. S. Org. Lett. 2004, 6, 3083-3085.
(11) Ung, A. T.; Pyne, S. G. Tetrahedron: Asymmetry 1998, 9, 1395-
1407.
(12) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 1363-1365.
(13) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(7) Dash, J.; Arseniyadis, S.; Cossy, J. AdV. Synth. Catal. 2007, 349,
152-156.
(8) Nicolaou, K. C.; Brenzovich, W. E.; Bulger, P. G.; Francis, T. M.
Org. Biomol. Chem. 2006, 4, 2119-2157.
(9) Kashima, C.; Huang, X. C.; Harada, Y.; Hosomi, A. J. Org. Chem.
1993, 58, 793-794.
3426
Org. Lett., Vol. 9, No. 17, 2007

thiazole 3 while 2 was consumed only slowly (Table 1,
entries 2 and 3).
In conclusion we have described a short and convergent
synthesis of melithiazole C (1), which was obtained in 6 steps
and 28% overall yield starting from the commercially
available Evans’ propionate 4. The key feature of this novel
approach consists of a highly E-selective CM reaction
between a vinyl thiazole and a polypropionate fragment.
Further applications of this strategy to the synthesis of related
natural products are currently under investigation.
Since protected allylic alcohols such as 2 do not undergo
any self-metathesis (Type III olefins),16 better results were
obtained under more forcing conditions by employing 20
mol % of G II and an excess of thiazole 3, whereas higher
or lower temperatures were detrimental (Table 1, entries
4-6). Finally, CM was best effected with 30 mol % of G II
in the presence of 2 equiv of 3 at 40 °C in CH2Cl2 (Table 1,
entry 7) affording melithiazole C (1) as a single diastereo-
isomer (E/Z > 20/1) in 56% isolated yield. The spectroscopic
and physical data of 1 were identical with those reported
Acknowledgment. J.G. thanks the CNRS for a grant.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
for the natural product {[R]20 +167 (c 0.3, MeOH); lit.
D
[R]22 +169 (c 0.3, MeOH)}.2,4
D
(15) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
(16) Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360-11370.
OL701459J
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