Catalysis-based enantioselective total synthesis of myxothiazole Z, (14S)-melithiazole G and (14S)-cystothiazole F

Article abstract of DOI:10.1039/c2cc35721f

A common strategy for the stereoselective and protecting group-free total synthesis of the myxobacterial antibiotics myxothiazole Z, (14S)-melithiazole G and (14S)-cystothiazole F is described featuring an asymmetric organocatalytic transfer hydrogenation

Full text of DOI:10.1039/c2cc35721f

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COMMUNICATION
Catalysis-based enantioselective total synthesis of myxothiazole Z,
(14S)-melithiazole G and (14S)-cystothiazole Fw
Aude Colon,a Thomas J. Hoffman,ab Julian Gebauer,a Jyotirmayee Dash,a James H. Rigby,b
Stellios Arseniyadis*a and Janine Cossy*a
Received 7th August 2012, Accepted 5th September 2012
DOI: 10.1039/c2cc35721f
A common strategy for the stereoselective and protecting group-free
total synthesis of the myxobacterial antibiotics myxothiazole Z,
(14S)-melithiazole G and (14S)-cystothiazole F is described featuring
an asymmetric organocatalytic transfer hydrogenation, a palladium-
catalyzed Stille coupling and a cross-metathesis as the key steps.
families5 and several other myxothiazole derivatives.6 Although
synthetic studies within this intriguing class of natural products
have been vigorous, only one total synthesis of 27a and its side-
chain analogues 37b and 47c have been reported, respectively,
relying on a moderately E-selective Wittig reaction between a
homochiral bis-thiazolyl phosphonium salt and the appropriate
aldehyde. The synthesis of the polypropionate fragment, on the
other hand, was achieved by an asymmetric aldol reaction,
while the stereogenic center a to the bis-thiazole unit was
either introduced starting from the chiral pool7a or through
enzymatic kinetic resolution.7b
Myxobacteria belong to the d-subgroup of gram-negative proteo-
bacteria that predominantly inhabit the soil. Apart from their
distinct cooperative social behaviour and unusually complex life-
cycle, these unique microorganisms have gained attention as
proficient producers of biologically active secondary metabolites
with diverse chemical structures and unusual modes of action.1
In 1980, Reichenbach et al. and Hofle et al. reported the isolation
of a novel myxobacterial antibiotic named myxothiazole A, 1,2
whose structure is characterized by a central bis-thiazole unit linked
to a highly pharmacophoric chiral b-methoxy acrylate (MOA)
moiety and a heptadienyl side-chain bearing a stereogenic
center at the a-position of the thiazole ring (Fig. 1). Acting
as potent inhibitors of mitochondrial respiration,3 both 1 and
its corresponding methyl ester, myxothiazole Z, 2,4 exhibit
broad antifungal activity as well as significant cytotoxicity
against different human tumor cell lines with IC50 values
As an extension to our recently reported cross-metathesis-
based synthesis of melithiazole C8 and cystothiazole A,9 we
herein describe a highly convergent and catalysis-based total
synthesis of cystothiazole F, 4, its deshydroxy derivative
melithiazole G, 3, and the cytotoxic myxothiazole Z, 2, via a
common synthetic strategy featuring a key enantioselective
organocatalytic transfer hydrogenation to control the absolute
configuration of the stereogenic center a to the bis-thiazole
unit.10
reaching as low as 0.01 ng mLÀ1 4a
.
During the following three decades, more than 20 structurally
related fungicides have been isolated from various strains of
myxobacteria including the congeneric cysto- and melithiazole
Fig. 1 Selected myxobacterial antibiotics.
a Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS,
10 rue Vauquelin, 75231 Paris Cedex 05, France.
E-mail: stellios.arseniyadis@espci.fr, janine.cossy@espci.fr;
Fax: +33 (0)1 40 79 46 60; Tel: +33 (0)1 40 79 46 62
b Department of Chemistry, Wayne State University, Detroit,
Michigan 48202-3489, USA
w Electronic supplementary information (ESI) available: Details of
experimental procedures and 1H NMR, 13C NMR spectra for all new
compounds. See DOI: 10.1039/c2cc35721f
Scheme 1 Common strategy for the synthesis of myxothiazole Z, 2,
melithiazole G, 3, and cystothiazole F, 4.
c
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Scheme 2 Synthesis of the common bromothiazole intermediate 10.
Retrosynthetically, all three natural products were fragmented
into the advanced bromothiazole intermediate 108 and the
corresponding thiazolyl stannanes A (Schemes 1 and 2). The
latter were in turn envisioned to be derived from the same
a,b-unsaturated aldehyde intermediate 13 applying the asym-
metric organocatalytic conjugate reduction method previously
developed in our laboratory10 followed by side-chain elabora-
tion and palladium-catalyzed stannylation.
As reported previously,8 b-methoxy acrylate 8 was prepared
in six steps and 32% overall yield via an asymmetric Evans
aldol reaction between Evans’ propionate 5 and acrolein11
followed by O-methylation of the resulting allylic alcohol
using methyl triflate in the presence of 2,6-di-tert-butylpyri-
dine, cleavage of the chiral auxiliary using basic peroxide,
activation of the resulting carboxylic acid using carbonyl
diimidazole, condensation with LiCH2CO2Me to generate
the corresponding b-keto ester and H2SO4-mediated methyl
enol ether formation.12 The required 4-vinyl thiazole 9, on the
other hand, was prepared in one step and 53% yield starting
from commercially available 2-bromo-4-formylthiazole 2313
via a Wittig olefination using methylenetriphenylphosphorane.
In order to complete the synthesis of the common C1–C10
fragment, olefins 8 and 9 were eventually cross-coupled using
Grubbs’ second generation catalyst (30 mol%) under micro-
wave irradiation14 (400 W, 100 1C, CH2Cl2). Under these
conditions, the bromothiazole intermediate 10 was obtained
in 55% yield (17% yield over seven steps) as a single stereo-
isomer (E/Z > 20 : 1).
Scheme 3 Protecting-group free total synthesis of myxothiazole Z, 2.
three-step sequence featuring a proline-catalyzed a-chlorination17
of the aldehyde (N-chlorosuccinimide, CH2Cl2, 0 1C) followed
by an alkenyl homologation using (E)-3-methyl-l-butenyllithium18
(THF, À78 1C) and a final acetylation in the presence of acetic
anhydride, N-methylmorpholine and a catalytic amount of
DMAP (CH2Cl2, 0 1C). Elimination of the O-acetyl chlorohydrin
moiety through two consecutive single electron transfers mediated
by SmI2 eventually afforded diene 18 in 80% yield as a 1 : 1
mixture of stereoisomers.18 Fortunately, the separation of the two
isomers was possible by flash column chromatography over silica
gel thus allowing us to isolate the required (E,E)-diene, which was
subsequently taken up in toluene and heated in a sealed tube in
the presence of hexamethylditin and Pd(PPh3)4 to introduce the
stananne moiety. After purifying the crude residue over a short
plug of silica, the resulting 4-stannyl thiazole was finally
coupled with the bromothiazole intermediate 10 in the presence
of Pd(PPh3)4 (5 mol%) in refluxing toluene to afford the desired
natural product, myxothiazole Z, 2, in 73% yield.
The preparation of the thiazolyl stannane fragment of
myxothiazole Z is based on two key transformations: an
enantioselective organocatalytic transfer hydrogenation of a
b-thiazole-containing a,b-unsaturated aldehyde to control
the configuration of the C14 stereogenic center and a
SmI2-mediated O-acetyl chlorohydrin elimination to afford the
required (E,E)-diene moiety (Scheme 3). Accordingly, the synthesis
began with the preparation of a,b-unsaturated aldehyde 13 via a
palladium-catalyzed Stille coupling15 between 2,4-dibromothiazole
11 and vinylstannane 12 [PdCl2(PPh3)4 (5 mol%), CuCl (5 mol%),
dioxane, 90 1C] followed by a Dess–Martin periodinane-mediated
oxidation16 (CH2Cl2, rt) of the resulting allylic alcohol (72% yield
over two steps). The corresponding enal 13 was then reduced under
our optimized organocatalytic transfer hydrogenation conditions10
using Hantzsch ester I as the hydride donor and imidazolidinone II
as the chiral organocatalyst (toluene, À35 1C) thus affording the
saturated aldehyde 14 in 84% yield and 94% ee. The latter was then
converted to the corresponding O-acetyl chlorohydrin 17 via a
Gratifyingly, the spectroscopic and physical data of 2
were consistent with the ones reported in the literature for
the natural product, with an optical rotation {[a]2D0 + 111.5
(c 0.75, MeOH)} which was in the range of those reported by
Ahn et al. {[a]2D5 + 152.0 (c 0.67, MeOH)}4a and by Hofle et al.
{[a]2D5 + 79.2 (c 1.40, MeOH)}.4b
As depicted in Scheme 1, our strategy for the synthesis of
melithiazole G, 3, and cystothiazole F, 4, is based on the same
key disconnections as for myxothiazole Z, thus requiring the
synthesis of the corresponding thiazolyl stannanes. The latter
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together and a cross-metathesis to introduce the highly pharmaco-
phoric chiral b-methoxy acrylate fragment. This straightforward
and particularly flexible approach provides expedient access to
the cysto- and melithiazole families as well as a variety of
synthetic analogues thereof.
This work was supported by the Ministere de l’Education
Nationale, de l’Enseignement Superieur et de la Recherche and
by the Centre National de la Recherche Scientifique (CNRS).
Notes and references
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Scheme 4 Total synthesis of melithiazole G, 3, and cystothiazole F, 4.
were prepared starting from a-chloro aldehyde 15, which was
first reduced to the corresponding a-chlorohydrin (NaBH4,
MeOH) and acetylated under the exact same conditions
as previously described (Scheme 3). The resulting a-chloro
acetate 19 was then treated with SmI2 to afford olefin 20,
which was used as a common intermediate in the synthesis of
both natural products (Scheme 4). Hence, the double bond
was either reduced under a hydrogen atmosphere (PtO2,
MeOH, rt) to afford the saturated product 21 quantitatively
or converted to the corresponding silyl ether 22 via ozonolysis,
reduction and subsequent protection of the resulting primary
alcohol (64% overall yield). Both 4-bromo thiazole derivatives
21 and 22 were then stannylated [(SnMe3)2, Pd(PPh3)4, toluene,
110 1C] and engaged in the key Stille coupling with the
bromothiazole intermediate 10 [Pd(PPh3)4, toluene, 110 1C]19
to afford melithiazole G, 3, and, after TBAF-mediated depro-
tection of the primary alcohol, cystothiazole F, 4, in 51% and
63% yield respectively. Once again, the spectroscopic and
physical data of 3 and 4 were consistent with those reported
in the literature {(14S)-melithiazole G, 3: [a]2D0 + 106.6 (c 1.3,
CHCl3); ref. 7b [a]2D5 + 100.0 (c 0.9, CHCl3), (14S)-cystothiazole
F, 4: [a]2D0 + 89.8 (c 0.85, CHCl3); ref. 7c [a]2D5 + 86.2 (c 1.05,
CHCl3)}.
6 J.-W. Ahn, K. H. Jang, H.-C. Yang, K.-B. Oh, H.-S. Lee and
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13 Purchased from the Synthonix Corporation.
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2002, 8, 5585.
In summary, we have described a stereoselective and
protecting group-free total synthesis of the myxobacterial
antibiotic myxothiazole Z, 2, and two of its side-chain analogues
(14S)-melithiazole G, 3, and (14S)-cystothiazole F, 4, using a
common strategy which features an asymmetric organocatalytic
transfer hydrogenation to control the configuration of the C14
stereogenic center, a Stille coupling to link the two thiazole units
c
10510 Chem. Commun., 2012, 48, 10508–10510
This journal is The Royal Society of Chemistry 2012