A concise approach towards the synthesis of WS75624 a and WS75624 B via the cross-metathesis of vinyl-functionalized thiazoles

Article abstract of DOI:10.1016/j.tetlet.2011.01.027

Synthetic approach towards precursors of WS75624 A and WS75624 B, two potent endothelin converting enzyme (ECE) inhibitors and potential antihypertensive agents, is reported featuring a key cross-metathesis between a vinyl-functionalized thiazole and a terminal olefin. As the two natural products only differ by the nature of their hydroxyalkyl side-chain, our convergent strategy enable the synthesis of key intermediates of both molecules in a limited amount of steps.

Full text of DOI:10.1016/j.tetlet.2011.01.027

Tetrahedron Letters 52 (2011) 2246–2249
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A concise approach towards the synthesis of WS75624 A and WS75624 B via
the cross-metathesis of vinyl-functionalized thiazoles
⇑
⇑
Jyotirmayee Dash , Bruno Melillo, Stellios Arseniyadis , Janine Cossy
Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084, 10 rue Vauquelin, 75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic approach towards precursors of WS75624 A and WS75624 B, two potent endothelin converting
enzyme (ECE) inhibitors and potential antihypertensive agents, is reported featuring a key cross-metath-
esis between a vinyl-functionalized thiazole and a terminal olefin. As the two natural products only differ
by the nature of their hydroxyalkyl side-chain, our convergent strategy enable the synthesis of key inter-
mediates of both molecules in a limited amount of steps.
Received 4 November 2010
Revised 22 December 2010
Accepted 7 January 2011
Available online 13 January 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Cross-metathesis
Natural products
Alkene
Thiazole
Pyridine
Natural products bearing a 2,4-disubstituted thiazole ring, such
as the epothilones,1 the melithiazoles,2 thiostrepton3 and micro-
coccin P14 have attracted considerable attention over the past
two decades due to their astounding pharmacological properties.
In 1995, Okuhara and co-workers isolated WS75624 A and B, two
potent endothelin converting enzyme (ECE) inhibitors with IC50
OMe
N
OMe
N
OMe
N
OMe
N
HO
HO
O
O
S
S
OH
WS75624 A 1
WS75624 B 2
values of 0.03 lg/mL from the fermentation broth of Saccharothrix
HO
sp. No. 75624.5,6 These two natural products, which both bear a
tetra-substituted pyridine ring, a thiazole ring, and a seven-carbon
hydroxyalkyl side-chain (Fig. 1) also exhibited some other metallo-
protease (collagenase and neutral endopeptidase) inhibitory activ-
Figure 1. Structure of WS75624 A and WS75624 B.
Due to the promising biological properties of WS75624 A and B,
to the rather limited number of syntheses reported so far,14,15 and
to our recent results pertaining to olefin cross-metathesis, we be-
came particularly interested in devising a straightforward access
to A and B (Scheme 1), two key intermediates in the synthesis of
these natural products and to various analogues thereof. The re-
sults of our efforts in this field are reported herein.
Our convergent strategy for the synthesis of A and B, which is
depicted in Scheme 1, relied on two main disconnections: a Stille
coupling between a 2-iodo pyridine and a 2,4-disubstituted thia-
zole bearing a trimethyltin unit at the 4-position in order to link
the two heterocycles together, and a one-pot cross-metathesis/
hydrogenation sequence to introduce the hydroxyalkyl side-chain.
Hence, the choice of the appropriate olefinic coupling partner in the
cross-metathesis step, which will be derived from either hexen-5-
one (20) (WS75624 A) or (R)-propylene oxide (21) (WS75624 B)
sets the stage for the synthesis of either intermediates.
ity (IC50 = 1
lg/mL) as well as a weak antifungal activity against
Candida albicans (IC50 = 50
lg/mL).
In the past few years, our group has been particularly interested
in implementing the cross-metathesis reaction with new coupling
partners with the idea of being able to access structurally intrigu-
ing molecules in a more efficient and straightforward manner. In
this context, we were able to develop effective cross-metathesis
conditions that allowed to couple
a-methylene-c-butyrolactone
with a variety of terminal olefins7 and apply them to the formal
synthesis of leustroducsin B.8 Later, we reported the first examples
of olefin cross-metatheses involving vinyl-functionalized oxazoles9
and thiazoles10 which led to the total syntheses of melithiazole C11
and cystothiazole A,12 as well as to the synthesis of the C12–C34
fragment of mycalolide A.13
⇑
Corresponding authors. Tel.: +33 0 1 40 79 44 29; fax: +33 01 40 79 46 60.
E-mail addresses: stellios.arseniyadis@espci.fr (S. Arseniyadis), janine.cossy@
espci.fr (J. Cossy).
The synthesis of B (P = TIPS) began by the preparation of the 2-
iodo pyridine unit 8 common to the two natural products following
a six-step procedure and starting from 3-hydroxy pyridine (3)
Present address: Department of Chemistry, IISER, Kolkata, India.
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.01.027

J. Dash et al. / Tetrahedron Letters 52 (2011) 2246–2249
2247
pared in four steps and 50% overall yield starting from the
commercially available thiazolidine-2,4-dione (Scheme 3).
OMe
9
WS75624 A 1
WS75624 B 2
OMe
N
Compound 9 was thus first converted into the corresponding 2,4-
bis(triflate), [Tf2O, Et3N, CH2Cl2, À78 °C, 82%] which was later en-
N
gaged in
a Stille coupling with vinyltributyltin [Pd(PPh3)4
Structural
analogues
S
R
R'
(5 mol %), LiCl (5 equiv), dioxane, 80 °C] to afford the correspond-
ing 2-vinyl-functionalized thiazole 11 in 76% yield.
Stille
n
PO
In order to establish the best cross-metathesis conditions, com-
pound 11 was then subjected to a series of experiments in the
presence of carbene ruthenium complex [Ru]-I and various olefinic
coupling partners, 15–18. The results are reported in Table 1. As a
general trend, all the reactions that were carried out with olefins
bearing a free hydroxyl group, such as 15 and 17,17 were more
sluggish and afforded the corresponding disubstituted olefins in
both lower yields (33–67%) and lower stereoselectivities (E/
Z = 4:1–5:1) (Table 1, entries 1–3 and 5). Comparatively, all the
reactions which were performed using olefins bearing a protected
hydroxyl group such as 16 and 1818 led to considerably higher
yields (up to 84%) and excellent stereoselectivities (E/Z >20:1) (Ta-
ble 1, entries 4 and 6). In addition, when the reactions were carried
out under microwave irradiation [400 W, 100 °C, sealed tube] or
with a higher catalyst loading (10 mol % instead of 5 mol %), the
rates of the reaction were found to be accelerated and the yields
were slightly improved (Table 1, entries 2 and 3).
A (n = 2; R = R' = Me)
B (n = 3; R = H; R' = Me)
OMe
CM/Hydrogenation
Me3Sn
N
OMe
+
S
n
R
N
8
I
PO
R'
C and D
OH
X
N
S
+
n
R
N
3
PO
R'
11 (X = OTf); 19 (X = Br)
E and F
It is worth pointing out that the analogous 4-bromo thiazole
derivative 1919 also gave satisfactory results with yields upto 91%
(Table 2, entry 2), however, the resulting disubstituted olefin could
not be used in the context of the synthesis as the subsequent pal-
ladium-catalysed hydrogenation inevitably led to the reduction of
the olefin with concomitant loss of the bromide.
X
N
O
X
O
S
10 (X = OTf); 22 (X = Br)
20
21
Scheme 1. Retrosynthetic analysis of A and B.
In order to limit the amount of steps and thus circumvent the
time- and yield-loss generally associated with the isolation and
purification of synthetic intermediates in multistep sequences,
we applied a previously developed10 one-pot Stille coupling/
cross-metathesis sequence starting from 2,4-bis-trifloylthiazole
10.20 Hence, by subjecting 10 to PdCl2(PPh3)2 (5 mol %), LiCl
(4 equiv), CuI (10 mol %) and vinyltributyltin (1.0 equiv) in toluene
at 80 °C followed, after complete conversion of the starting mate-
rial, by [Ru]-I (5 mol %) and 18 (1.5 equiv) (12 h at 40 °C), we were
able to isolate the desired product 12 in 62% yield. The latter was
then engaged in hydrogenation using Pd/C (30 mol %) in AcOEt at
rt21 to afford the corresponding reduced product in nearly quanti-
tative yield.
(Scheme 2). Hence, the latter was first protected as a methoxy-
methyl (MOM) ether [t-BuOK, MOMCl, THF/DMF (3:8), À15 °C to
rt, 86%] in order to direct the subsequent chlorination at the 4-po-
sition of the pyridine ring [t-BuLi, hexachloroethane, Et2O, À78 °C].
The resulting 4-chloro derivative 5 was then treated with NaOMe
in MeOH to effect an aromatic nucleophilic substitution and afford
the corresponding 4-methoxy pyridine derivative 6 in 68% overall
yield (2 steps). The cleavage of the MOM group [TFA, CH2Cl2, re-
flux] followed by the protection of the resulting free hydroxyl as
methoxy ether [TMSCH2N2, benzene/MeOH (1:1), 71% from 6] then
led to 3,4-dimethoxy pyridine (7), which was finally subjected to a
selective ortho-lithiation/iodination sequence to afford the desired
2-iodo pyridine derivative 8 in 58% overall yield (3 steps).16
With the 2-iodo pyridine derivative 8 in hand, we next turned
our attention to the synthesis of the 2,4-disubstituted thiazole unit
bearing the hydroxylalkyl side chain. The latter was easily pre-
With compound 13 in hand, the stage was finally set for the key
Stille coupling, which was envisioned to join the two heterocycles
together. In order to prevent any protodestannylation, which could
occur upon column chromatography, the palladium-catalysed
Cl
OH
OMOM
OMOM
t-BuOK
t-BuLi
MOMCl
Hexachloroethane
Et2O, -78 °C
N
3
N
4
N
5
THF/DMF (3:8)
-15 °C to rt
86%
Na, MeOH
reflux
68% (from 4)
OMe
OMe
OMe
1)
TFA
CH2Cl2, reflux
OMe
I
OMe
OMOM
n-BuLi
I2
81%
2) TMSCH2N2
Benzene/MeOH (1:1)
-15 °C to rt
N
N
N
8
7
6
71%
Scheme 2. Synthesis of the common 2-iodo pyridine derivative 8.

2248
J. Dash et al. / Tetrahedron Letters 52 (2011) 2246–2249
TfO
TfO
O
N
N
NH
Bu3Sn
Tf2O, Et3N
OTf
O
PdCl2(PPh3)2, LiCl, CuI
Toluene, 80 °C
CH2Cl2, -78 °C
82%
S
S
S
9
10
11
N
N
18, [Ru]-I
Cl
Cl
Ru
CH2Cl2, reflux
O
62% (from 10)
[Ru]-I
1)
Me3SnSnMe3
PdCl2(PPh3)2, LiCl
Dioxane, 100 °C
OMe
TfO
TfO
OMe
N
N
H2, Pd/C
5
OMe
OMe
2)
AcOEt, rt
98%
S
S
N
S
N
3
OTIPS
5
14
13
12
OTIPS
N
I
(E/Z > 20:1)
TIPSO
8
43% (from 13)
Scheme 3. Synthesis of 14.
Table 1
Table 2
Cross-metathesis of 2-vinyl thiazole 11a
Cross-metathesis of 2-vinyl thiazole 19a
TfO
TfO
N
N
S
Br
Br
[Ru]-I (5-10 mol %)
CH2Cl2, 40 °C
N
S
N
[Ru]-I (5-10 mol %)
CH2Cl2, 40 °C
R
R
S
R
S
R
11
15-18
19
15-18
Methodb/Yieldc (%)
E:Zd
R
Entry
(15-18)
Methodb/Yieldc (%)
E:Zd
R
Entry
(15-17)
OH
1
2
3
A/47 (24 h)
A/53e (2 h)
B/64 (12 h)
4:1
4:1
4:1
OH
1
2
15
16
A/67 (12 h)
A/91 (8 h)
5:1
15
OTES
>20:1
OTES
OH
4
16
17
A/84 (12 h)
>20:1
3
17
B/36 (18 h)
7:1
OH
5
6
B/33 (18 h)
A/83 (18 h)
5:1
a
All the reactions were carried out using 1 equiv of vinyl thiazole 19, and 1.5
equiv of olefin 15, 16 or 17 in CH2Cl2 at 40 °C.
18
>20:1
TIPSO
b
Method A: 5 mol % of [Ru]-I, Method B: 10 mol % of [Ru]-I.
a
c
All the reactions were carried out using 1 equiv of vinyl thiazole 11, and 1.5
equiv of olefin 15, 16, 17 or 18 in CH2Cl2 at 40 °C.
Isolated yield.
E/Z ratio determined by 1H NMR of the crude reaction mixtures.
d
b
Method A: 5 mol % of [Ru]-I, Method B: 10 mol % of [Ru]-I.
c
Isolated yield.
E/Z ratio determined by 1H NMR of the crude reaction mixtures.
Reaction run under microwave irradiation [sealed tube, 400 W, 100 °C].
d
After completing the synthesis of 14, a key intermediate in the
preparation of WS75624 B, we next turned our attention to the
synthesis of 26, an analogue of WS75624 A, using the same
strategy (Scheme 4). 2-Vinyl thiazole 11 was thus engaged in a
cross-metathesis with 16, and the resulting disubstituted olefin
was reduced using Pd/C (30 mol %) under a hydrogen atmosphere
[AcOEt, rt, 84%]. Interestingly, the reduction occurred with
concomitant cleavage of the TES protecting group thus affording
alcohol 23 in 97% yield. The latter was then converted into the
e
Stille coupling was performed in a one-pot fashion with in situ
generation of the tin species intermediate [hexamethylditin
(2 equiv), PdCl2(PPh3)2 (10 mol %), LiCl (15 equiv), dioxane,
100 °C, then 8 (1.2 equiv), 100 °C]. This practical procedure allowed
to isolate the desired compound 14 in 43% overall yield (Scheme 3).
TfO
TfO
TfO
N
N
N
16, [Ru]-I
H2, Pd/C
5
CH2Cl2, reflux
84%
AcOEt, rt
97%
S
S
S
3
HO
22
23
11
TESO
Me3SnSnMe3
PdCl2(PPh3)2, LiCl
Dioxane, 100 °C
OMe
OMe
N
N
N
I
SnMe3
Cl
Cl
N
Ru
O
25
N
S
N
5
S
61% (from 23)
5
[Ru]-I
HO
26
24
HO
Scheme 4. Synthesis of 26.

J. Dash et al. / Tetrahedron Letters 52 (2011) 2246–2249
10. Dash, J.; Arseniyadis, S.; Cossy, J. Adv. Synth. Catal. 2007, 349, 152–156.
2249
corresponding tin species intermediate and directly used in the
palladium-catalysed Stille coupling with the 2-iodopyridine deriv-
ative 25 to afford the desired coupled product 26 in 61% yield.
In summary, we have prepared a key intermediate in the syn-
thesis of WS75624 B as well as an analogue of WS75624 A using
a convergent strategy based on a Stille coupling between a 2-iodo
pyridine and a 4-trimethyltin-disubstituted thiazole to link the
two heterocycles together, and a one-pot cross-metathesis/hydro-
genation sequence to introduce the hydroxyalkyl side chain.
Compound 14 is particularly interesting as deprotection of the
secondary hydroxyl group15d followed by the introduction of the
carboxylic acid moiety15c (via a Reissert–Henze reaction22) or any
other substituent should allow to complete the synthesis
WS75624 B and generate a library of potentially useful synthetic
analogues.
11. Gebauer, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 3425–3427.
12. Gebauer, J.; Arseniyadis, S.; Cossy, J. Eur. J. Org. Chem. 2008, 2701–2704.
13. Hoffman, T. J.; Kolleth, A.; Rigby, J. H.; Arseniyadis, S.; Cossy, J. Org. Lett. 2010,
12, 3348–3351.
14. For the total synthesis of WS75624 A, see: Bach, T.; Heuser, S. Synlett 2002,
2089–2091.
15. For the total synthesis of WS75624 B, see: (a) Patt, W. C.; Massa, M. A.
Tetrahedron Lett. 1997, 38, 1297–1300; (b) Massa, M. A.; Patt, W. C.; Ahn, K.;
Sisneros, A. M.; Herman, S. B.; Doherty, A. Bioorg. Med. Chem. Lett. 1998, 8,
2117–2122; (c) Huang, S.-T.; Gordon, D. M. Tetrahedron Lett. 1998, 39, 9335–
9338; (d) Stangeland, E. L.; Sammakia, T. J. Org. Chem. 2004, 69, 2381–2385.
16. (a) Trecourt, F.; Mallet, M.; Mongin, O.; Gervain, B.; Queguiner, G. Tetrahedron
1993, 37, 8373–8380; (b) Mongin, F.; Trecourt, F.; Mongin, O.; Queguiner, G.
Tetrahedron 2002, 58, 309–314.
17. Olefins 15 and 17 were prepared in respectively one and two steps starting
from commercially available hexen-5-one (20). The latter was first subjected to
methylmagnesium bromide [Et2O, 0 °C, 93%] to afford 15 which was then
converted to the corresponding triethylsilyl ether [TESOTf, 2,6-lutidine, CH2Cl2,
À78 °C, 96%].
18. Olefin 17 was prepared starting from commercially available (R)-propylene
oxide (21) according to a reported procedure, see: Yu, M.; Alonso-Galicia, M.;
Sun, C.-W.; Roman, R. J.; Ono, N.; Hirano, H.; Ishimoto, T.; Reddy, Y. K.;
Katipally, K. R.; Reddy, K. M.; Gopal, V. R.; Yu, J.; Takhi, M.; Falck, J. R. Bioorg.
Med. Chem. 2003, 11, 2803–2821. Olefin 17 was then converted to the
corresponding triethylsilyl ether 18 [TIPSOTf, 2,6-lutidine, CH2Cl2, À78 °C,
95%].
Acknowledgements
The authors would like to thank the Ministère Français des Af-
faires Etrangères for financial support to B.M.
19. 4-Bromo-2-vinyl-thiazole 19 was prepared in high yield starting from 2,4-
dibromo thiazole 22, see: Colaou, K. C.; King, N. P.; Finlay, M. R. V.; He, Y.;
Roschangar, S.; Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic, S.; Sarabia,
F.; Hepworth, D. Bioorg. Med. Chem. 1999, 7, 665–697.
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20. General procedure for the one-pot Stille coupling/cross-metathesis: A mixture of
freshly flame dried LiCl (4 equiv), Pd(PPh3)4 (4 mol %), 2,4-bistriflate 10
(1 mmol), vinyltributyltin (1 mmol) in 5 mL of toluene was heated at 80 °C
for 8 h. After complete conversion of the starting material (reaction monitored
by tlc analysis), the reaction mixture was cooled before the terminal olefin
(1.5 equiv) was added along with the ruthenium carbene catalyst [Ru]-I
(10 mol %). The reaction mixture was then stirred at 40 °C for an additional
12 h and then cooled back to rt and concentrated in under reduced pressure.
Filtration of the reaction mixture followed by purification using flash
chromatography on silica gel afforded the corresponding disubstituted olefin.
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lost the triflate moiety.
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