Total synthesis of myxothiazols, novel bis-thiazole β-methoxyacrylate- based anti-fungal compounds from myxobacteria

Article abstract of DOI:10.1039/b603433k

Convergent total syntheses of myxothiazols A and Z are described. The syntheses are based on elaboration of the (S)-E,E-diene thioamide 22, conversion of 22 into the bis-thiazole 27 and Wittig reactions between 27c and the aldehyde 30. The substituted β-m

Full text of DOI:10.1039/b603433k

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Total synthesis of myxothiazols, novel bis-thiazole b-methoxyacrylate-based
anti-fungal compounds from myxobacteria†
John M. Clough, Henry Dube, Bruce J. Martin, Gerald Pattenden,* K. Srinivasa Reddy and Ian R. Waldron
Received 7th March 2006, Accepted 9th June 2006
First published as an Advance Article on the web 29th June 2006
DOI: 10.1039/b603433k
Convergent total syntheses of myxothiazols A and Z are described. The syntheses are based on
elaboration of the (S)-E,E-diene thioamide 22, conversion of 22 into the bis-thiazole 27 and Wittig
reactions between 27c and the aldehyde 30. The substituted b-methoxyacrylate aldehyde 30 was
produced via an Evans asymmetric aldol protocol or via the 2H-pyran-2-one 31. An E-selective Wittig
reaction between the ylide derived from the phosphonium salt 27c and the (+)-aldehyde 30 led to
(+)-myxothiazol Z (1b), and a corresponding reaction with the ( )-acrylamide aldehyde 44 gave
( )-myxothiazol A (1a). Complementary studies led to synthesis of the ester 47b, corresponding to
myxothiazol R and myxothiazol S.
in 1 is further substituted on the right-hand side by a conjugated
E,E-heptadienyl unit, viz. 8, carrying a third stereogenic centre.
The presence of these structural units in the myxothiazols 1
suggested a straightforward strategy to their synthesis based on
Introduction
Myxothiazol is the generic name used to describe a family of
fungicides isolated from myxobacteria, e.g. Myxococcus fulvus,
Angiococcus disciformis, and characterised by the presence of a
(i) synthesis of the E,E-heptadienyl side chain, 8, followed by
novel and unusual b-methoxyacrylate pharmacophore linked to
(ii) conversion into the substituted bis-thiazole 7, and finally (iii)
a 2,4-disubstituted bis-thiazole unit. Myxothiazol A (1a) was the
linking the left-hand side b-methoxyacrylate residue 6. In our
first member to be isolated, in 1980,1 and myxothiazol Z (1b) was
described in the primary literature in 1999.2 In 1988, Ho˝fle and
Sakagami and their respective co-workers3 reported a different
group of b-methoxyacrylate fungicides from various species of
myxobacteria which were named melithiazols, e.g. melithiazol A
(2), and cystothiazols, e.g. 3a and 3b. Interestingly, the secondary
metabolites 1, 2, and 3 are related to the strobilurins, e.g. 4, and
the oudemansins, e.g. 5, produced by various fungi.4
All of the aforementioned b-methoxyacrylates act as inhibitors
of mitochondrial respiration by blocking electron transfer between
cytochrome b and cytochrome c1.5 An exciting range of synthetic
analogues of strobilurin has now been brought to the market
as agricultural fungicides,6 and synthetic studies within the
melithiazols and cystothiazols have been vigorous in recent years.7
Before these recent endeavours, however, in 1993, we described the
first, and only, synthesis of ( )-myxothiazol A (1a).8 Since this
time, we have carried out further synthetic investigations towards
the myxothiazols, and in this paper we draw together these studies,
culminating in total syntheses of several of their members.
Results and discussion
Synthetic strategies
The myxothiazol structure 1 accommodates a substituted b-
methoxyacrylate left-hand side, viz. 6, linked to a bis-thiazole by an
E-butenyl unit, carrying two stereogenic centres. The bis-thiazole
School of Chemistry, University of Nottingham, University Park, Notting-
ham, UK NG7 2RD
† Electronic supplementary information (ESI) available: experimental
details. See DOI: 10.1039/b603433k
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The (S)-E,E-heptadienyl side chain 8
The heptadienyl side chain in the myxothiazols, appropriately
functionalised as a thioamide, i.e. 22, was conveniently synthesised
starting from commercially available (R) methyl 3-hydroxy-2-
methylpropionate 15a (Scheme 1). Thus, protection of 15a as its
TBDPS ether, followed by reduction of the ester group in 15b,
to the corresponding carbinol 16a and oxidation first gave the
aldehyde 17a as a low-melting solid. A Julia olefination reaction9
between the aldehyde 17a and the E-benzothiazole sulfone 18 de-
rived from E-4-methylpent-2-en-1-ol,10 in the presence of sodium
bis(trimethylsilylamide) at −78 ◦C next led to the conjugated
diene 19a, which was produced as a 4 : 1 mixture of E- and Z-
isomers at the newly introduced alkene bond. Deprotection of the
TBDPS group in 19a, followed by treatment of the resulting diene
alcohol 19b (4 : 1 mixture of E-3, E-5 and Z-3, E-5 isomers) with
iodine in refluxing diethyl ether under ultraviolet light irradiation,
and chromatography, gave the geometrically pure E-3, E-5 diene
alcohol 20 as a colourless liquid. A Mosher’s ester analysis gave
an ee > 98%,11 and the E-3, E-5 geometry of the conjugated
diene followed conclusively from examination of the magnitude
earlier studies,8 we synthesised the bis-thiazole unit 7 and attached
the left-hand side chain in the structure 1 using a Wittig reaction
between the ylide derived from the bis-thiazole phosphonium
salt 7 and the aldehyde 6 (R = CHO). This strategy was later
applied by Charette and Deroy7b and by Akita and co-workers7a
in their syntheses of cystothiazols A (3a) and B (3b) using the
phosphonium salt 9. In other studies Bach and Heuser7d developed
a Suzuki cross-coupling reaction from the 4-bromo bis-thiazole
10a to synthesise cystothiazol E, and Shao and Panek,7e in 2004,
applied the Stille cross-coupling reaction between 10b and 11
in their synthesis of cystothiazols. By contrast, Williams et al.7c
produced the left-hand side chain in their synthesis of cystothiazols
A and C using an asymmetric aldol reaction between the a,b-
unsaturated aldehyde 12 and the Evans oxazolidinone 13, leading
ultimately to 14. This general strategy was also later used by Ojika
et al.7f in another synthesis of cystothiazol A.
1
of the vicinal couplings for the olefinic protons in the H NMR
spectrum of 20. The same diene alcohol 20 was also obtained via a
Wittig reaction between the l-ethoxyethyl derivative 17b, and the
phosphonium salt 23, using n-BuLi in diethyl ether at −10 ◦C,
which first gave the conjugated diene 19c, also as a 4 : 1 mixture
of E-3, E-5 and Z-3, E-5 isomers. Deprotection of 19c, followed
by iodine-catalysed equilibration of the resulting diene alcohol
then gave the E-3, E-5 diene alcohol 20 in a similar overall yield
as the alternative Julia olefination protocol. The E-3, E-5 diene
alcohol 20 was next smoothly converted into the corresponding
thioamide 22 in four straightforward steps, i.e. oxidation to the
carboxylic acid 21b using Dess–Martin periodinane followed by
buffered sodium chlorite; conversion of the acid 21b into the
amide 21c and, finally, treatment of 21c with Lawesson’s reagent in
THF.
The substituted bis-thiazole 7
A useful variety of methods is now available for making 2,4-
disubstituted thiazoles, including the Hantzsch method12 de-
scribed as early as 1887, and a more biomimetic approach which
proceeds via thiazoline intermediates produced from cysteinyl
peptide precursors.13 Both of these general methods can be used
in an iterative manner to make bis-thiazoles of the type found
in myxothiazols and the related natural products 2 and 3. More
recently, Pd-catalysed cross-coupling reactions between 4-bromo-
, 4-stannyl, and 4-triflyl thiazoles7 have been used to synthesise
bis-thiazoles en route to cystothiazols.
In our own studies we examined a variety of complementary
routes to the bis-thiazole unit 7 in the myxothiazols.14 Ultimately,
we found that a Hantzsch condensation between the thioamide 22
and the 2,4-disubstituted thiazole bromoketone 24b, carried out
under the conditions described by Holzapfel and Bredenkamp,15
provided the most reliable procedure for preparing the particular
substituted bis-thiazole 25.
The thiazole a-bromoketone 24b is a known compound ob-
tained by bromination of the corresponding methyl ketone 24a
using NBS in refluxing CCl4.16 We experienced difficulty in
In our own studies, we explored a number of comple-
mentary pathways to elaborate the interesting substituted b-
methoxyacrylate side chain, viz. 6, in the myxothiazols. These
methods, alongside procedures to synthesise the right-hand side
chain 8 attached to the bis-thiazole unit 7, together with the
assembly of these units leading to syntheses of myxothiazol A
(1a) and Z (1b), and also the methyl ester corresponding to
myxothiazols R and S, will now be described.
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Scheme 1 Reagents and conditions: i) tBuMe2SiCl, imidazole (95%); ii) LiBH4, THF (85%); iii) DMSO, (COCl)2, −78 ◦C (60%); iv) LiHMDS, 17, −78 ◦C
(75%); v) Bu4NF, THF (94%); vi) I2, Et2O, hm (74%); vii) Dess–Martin periodinane, NaHCO3, then viii) NaClO2, NaHPO4 (61%); ix) (COCl)2 then NH3
(74%); x) Lawesson’s reagent, THF (87%).
obtaining reproducible yields using these conditions, and ulti-
mately produced the bromoketone 24b by bromination of the
intermediate enol silyl ether 26 derived from 24a, using NBS in
With the overall intention of linking the b-methoxyacrylate side
chain 6 to the bis-thiazole unit 7 using a Wittig reaction, we next
treated the alcohol 27a with I2/PPh3/imidazole at 0 ◦C under
a nitrogen atmosphere, which led to the corresponding iodide
27b, as a solid, in 78% yield. Treatment of the iodide 27b with
triphenylphosphine in benzene at room temperature then gave the
corresponding phosphonium salt 27c, which was obtained as a
colourless powder.
◦
THF at 0 C (Scheme 2). The bis-thiazole ester 25 was obtained
as colourless prisms, with [a]2D5 +1.96 (c 1.53 in CHCl3). Reduction
of the ester 25 using DIBAL-H in THF next gave the primary
carbinol 27a. Analysis of the corresponding Mosher’s ester of 27a
gave an ee > 95%.
The substituted b-methoxyacrylate unit 6, and end game
We discussed earlier the variety of synthetic approaches that
have been applied, by others, to introduce the substituted b-
methoxyacrylate left-hand side chain, viz. 6, in endevours towards
the related cystothiazols, i.e. 2 and 3. We examined a number
of complementary synthetic routes to the b-methoxyacrylate side
chain in myxothiazols in our studies, including those based on
regioselective ring opening of chiral epoxides, i.e. 29, by both
substituted lithium acetylides and vinyl anions e.g. 28, but to
no avail. Ultimately, we decided to synthesise the aldehyde 30
and carry out a Wittig reaction with 27c leading to 1b. A
synthetic approach to the b-methoxyacrylate aldehyde 30 that
was attractive was via the 2H-pyran-2-one 31 (Scheme 3). The
pyranone 31 was chosen since it incorporated a masked d-hydroxy
ester functionality, in addition to a b-methoxyacrylate residue with
the required E-configuration. Furthermore, the styryl side chain
in 31b acted as precursor to the sensitive aldehyde functionality in
the b-methoxyacrylate aldehyde 30.
Thus, a condensation between cinnamaldehyde and the dianion
produced from methyl 3-oxopentanoate,17 using NaH and n-
BuLi in THF at 0 ◦C, first gave the pyran-2-one 31a which, on
methylation with Me2SO4–K2CO3, produced a 1 : 1 mixture of
Scheme 2 Reagents and conditions: i) NBS, CCl4 or NBS, THF then 26
(54%); ii) 24b and 22, NaHCO3 at −20 ◦C, then TFA, pyridine (59%); iii)
DIBAL-H, THF, −78 ◦C (56%); iv) I2, PPh3, imidazole, 0 ◦C (78%); v)
PPh3, C6H6 (80%).
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MeI and Ag2O in diethyl ether finally led to the 3RS, 5RS methyl
ether diastereoisomer 34 as a colourless oil. Oxidative cleavage
of 34 via the corresponding isolated intermediate vicinal diol,
using OsO4–NMO, followed by NaIO4, finally gave the ( )-b-
methoxyacrylate aldehyde 30, as a labile liquid.
The same b-methoxyacrylate aldehyde 30 was later synthesised
by Backhaus19 using aldol chemistry starting from benzyloxy-
acetaldehyde, and Deroy and Charette7b developed an Evans
enantiopure asymmetric aldol protocol to afford the (+)-aldehyde
30. Akita et al.7a also developed a route to enantiopure 30 from
the chiral acetylenic alcohol 36 produced from ring opening
of the 2R, 3S epoxy butanoate 35. We also synthesised the
enantiopure b-methoxyacrylate aldehyde 30 by first using an Evans
aldol reaction between the auxiliary 37 and cinnamaldehyde,
which gave the syn-aldol 38a with >98% ee (Scheme 4).20 O-
Methylation of 38a, followed by conversion of the intermediate
methyl ether 38b into the corresponding carboxylic acid 39 and
treatment of the latter with LiCH2CO2Me next led to the b-
ketoester 40. Deprotonation of the b-ketoester 40, using NaH
in DMPU, followed by addition of dimethyl sulfate then led to the
enantiopure (+)-b-methoxyacrylate 34. Oxidative cleavage of the
styryl alkene bond in 34, using the same conditions as those used
with the racemic material, finally gave the (+) b-methoxyacrylate
aldehyde 30, as an oil [a]2D5 +105 (c 0.55 in CHCl3).
Scheme 3 Reagents and conditions: i) Me2SO4, K2CO3 (65%); ii) KOH,
H2O, 100 ◦C, then CH2N2, then chromatography (9%); iii) MeI, Ag2O
(55%); iv) OsO4, NMO, Me2CO–H2O (9 : 1), then NaIO4, THF–H2O (1 :
3) (65%).
syn- and anti-diastereoisomers of the corresponding methyl ether
31b. The diastereoisomers of 31b could be separated by HPLC
and their relative stereochemistries followed from inspection of
the magnitude of their vicinal coupling between C5 and C6 in
1
the H NMR spectra, and comparison of these data with those
obtained for similar compounds in the literature.18 Thus, the syn-
diasteroisomer of 31b displayed vicinal coupling of 3.6 Hz between
the hydrogen atoms at C5 and C6 whereas the corresponding
anti-diastereoisomer showed vicinal coupling of 7.1 Hz between
the same hydrogens. For the related compound kawain-5-ol the
corresponding vicinal couplings have been recorded as 3.0 Hz (syn-
diastereoisomer) and 7.0 Hz (anti-diastereoisomer).18 Preparative
HPLC separation of the diastereoisomers of 31b was avoided in the
synthetic scheme at this point, however, and instead the mixture
of diastereoisomers was heated with 1.2 equivalents of KOH in
H2O at 100 ◦C followed by treatment with diazomethane leading
to the syn and anti b-methoxyacrylate secondary alcohols 32 and
33 respectively, which could be easily separated by routine column
chromatography. Methylation of the syn-diastereoisomer 32 using
Scheme
4
Reagents and conditions: i) n-Bu2BOTf, 37, then
t
=
PhCH CH·CHO (90%); ii) 2,6- Bu2C5H3N, MeOTf (72%); iii) LiOH,
H2O2 (98%); iv) NNCD, then LiCH2CO2Me, −78 ◦C (85%); v) NaH,
Me2SO4, DMPU (66%); vi) OsO4, NMO, Me2CO–H2O (9 : 1), then
NaIO4, THF–H2O (1 : 3) (65%). (DMPU = N,Nꢀ-dimethylpropylene urea;
NNCD = 2-chloro-4-nitro-1-benzenediazonium 2-naphthalenesulfonate.)
With both the phosphonium salt 27c, and racemic and enan-
tiopure b-methoxyacrylate aldehyde 30 in hand, we were now in
a position to examine their coupling to give myxothiazol Z (1b).
This Wittig reaction between 27c and 30 proved to be somewhat
temperamental. Fo◦r example, when the salt 27c was treated with
KOBut in THF at 0 C followed by addition of the ( )-aldehyde 30,
only the product 27d resulting from hydrolysis of the phosphonium
salt was isolated. Furthermore, when a mixture of 27c and ( )-30
was treated with KOBut in THF only the positional isomer 41
of myxothiazol Z and the di-t-butyl acetal 42 of the aldehyde 30
were isolated. After more experimentation, use of the less basic
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methoxyacrylamide aldehyde 44. Gratifyingly, a Wittig reaction
between this aldehyde and the phosphonium salt 27c using
LiHMDS in THF at 0 ◦C was found to be E-selective and led
to 7R, 18SR, 19RS myxothiazol A (1a), albeit in only 12% yield.
The synthetic myxothiazol A showed spectroscopic data which
were completely superimposable on those of the natural product
derived from M. fulvus.
As a corollary to the aforementioned synthetic work, we also
examined a synthetic approach to the bis-thiazole metabolites 48a
and 48b known as myxothiazol R and myxothiazol S respectively,
which co-occur with the b-methoxyacrylate myxothiazols A and
Z in myxobacteria.21 Thus, a Wittig reaction between the bis-
thiazole aldehyde 45a produced from the alcohol 27a, and (formyl-
methylene) triphenylphosphorane first gave the corresponding a,
b-unsaturated aldehyde 45b as a pale yellow solid in 72% yield
(Scheme 6). An Evans aldol condensation between 37 and the
aldehyde 45b in the presence of n-Bu2BOTf next gave the b-hydroxy
amide 46, which was then converted into the methyl ester 47a using
◦
sodium methoxide in THF at 0 C finally delivered myxothiazol
Z (1b), which was obtained as a single alkene geometrical isomer
after HPLC purification, in 11% yield. The synthetic myxothiazol
showed spectroscopic data which were identical to those described
for myxothiazol Z isolated from myxobacteria, even though this
structure was not published as a natural product until some time
after the completion of this work. A corresponding Wittig reaction
between the bis-thiazole salt 27c and the enantiopure (+)-aldehyde
30, using lithium hexamethyldisilazide as the base in THF at 0 ◦C,
proceeded much more smoothly and led to (+)-myxothiazol Z in
74% yield. A small amount of the corresponding Z-alkene was
produced concurrently during the condensation which could be
largely removed by HPLC. The synthetic myxothiazol Z had [a]D25
+118.8 (c 1.44 in CHC13) whereas Ahn et al. give [a]2D5 +152, and
Ho˝fle and co-workers [a]2D2 +79.2 for naturally derived material.2
Attempts were now made to convert myxothiazol Z (1b) into
myxothiazol A (1a) using Weinreb’s conditions, i.e. Me2AlNH2
in CH2Cl2. However, these attempts failed, and instead only
starting material was recovered. However, treatment of the b-
methoxyacrylate 34 with Me2AlNH2 gave the corresponding
amide 43 in 40% yield (Scheme 5). Oxidative cleavage of the
styryl alkene bond in 43, using OsO4–NaIO4 then gave the b-
◦
MeMgBr in MeOH at 0 C. Treatment of 47a with NaOH–MeI
gave the corresponding methyl ether 47b which is the methyl ester
analogue of the amide 48a, i.e. myxothiazol R, and the carboxylic
Scheme 5 Reagents and conditions: i) Me2AlNH2, CH2Cl2 (40%); ii) OsO4,
Me2CO–H2O (9 : 1), then NaIO4, THF–H2O (1 : 3) (32%); iii) LiHMDS,
THF added to 44 and 27c (22%).
◦
=
Scheme 6 Reagents and conditions: i) PDC, CH2Cl2 (58%); ii) OHC·CH PPh3, C6H6 (72%); iii) 37, n-Bu2BOTf, Et3N, 0 C, then 45 (93%); iv) MeMgBr,
MeOH, 0 ◦C (52%); v) MeI, NaOH, DMSO–H2O (2 : 1) (45%).
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acid 48b, i.e. myxothiazol S. Unfortunately, the dearth of synthetic
materials did not allow us to realise the syntheses of myxothiazols
R and S from the methyl ester 47b.
Bartlett, J. M. Clough, C. R. A. Godfrey, J. R. Godwin, A. A. Hall, S. P.
Heaney and S. J. Maund, Pestic. Outlook, 2001, 12, 143–148; H. Sauter,
W. Steglich and T. Anke, Angew. Chem., Int. Ed., 1999, 38, 1328–1349.
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Acknowledgements
We thank the SERC (now EPSRC) for studentships (CASE awards
to B. J. M. and I. R. W.) and the Commonwealth Scholarship
Commission for a scholarship (to H. D.). We also thank Dr
G. Ho¨fle (GBF, Braunshweig, Germany) for correspondence and
exchange of information on natural myxothiazols.
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