Highly efficient borylation Suzuki coupling process for 4-bromo-2-ketothiazoles: Straightforward access to micrococcinate and saramycetate esters

Article abstract of DOI:10.1021/ol901525t

Image Presented The first palladium-catalyzed borylation of 4-bromo-2-ketothiazoles followed by a Suzuki cross-coupling reaction with haloheteroaromatics using Buchwald's Cy-JohnPhos and XPhos ligands is reported. The methodology has allowed the fast preparation of highly valuable 4-pyridinyl- and 4-thiazolyl-2-ketothiazoles as common subunits of thiopeptide antibiotics. As direct applications, novel concise syntheses of a sulfomycinamate thio-analogue as well as micrococcinate and saramycetate esters are described.

Full text of DOI:10.1021/ol901525t

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3690-3693
Highly Efficient Borylation Suzuki
Coupling Process for 4-Bromo-2-
ketothiazoles: Straightforward Access to
Micrococcinate and Saramycetate Esters
Thibaut Martin, Claire Laguerre, Christophe Hoarau,* and Francis Marsais
UMR 6014 COBRA, CNRS, INSA de Rouen et UniVersite´ de Rouen, Institut de Chimie
Organique Fine (IRCOF) INSA de Rouen, BP08, 76131 Mont Saint Aignan, France
christophe.hoarau@insa-rouen.fr
Received July 3, 2009
ABSTRACT
The first palladium-catalyzed borylation of 4-bromo-2-ketothiazoles followed by a Suzuki cross-coupling reaction with haloheteroaromatics
using Buchwald’s Cy-JohnPhos and XPhos ligands is reported. The methodology has allowed the fast preparation of highly valuable 4-pyridinyl-
and 4-thiazolyl-2-ketothiazoles as common subunits of thiopeptide antibiotics. As direct applications, novel concise syntheses of a
sulfomycinamate thio-analogue as well as micrococcinate and saramycetate esters are described.
Thiopeptide antibiotics are a class of highly modified sulfur-
containing peptides with at least 77 structures from 29
distinct families.1 Most of them inhibit protein synthesis
through two main modes of action, by binding to the complex
of 23S rRNA with ribosomal protein L11 or inhibiting the
action of elongation factors Tu. The important d series of
thiopeptides, exemplified by the first micrococcin P1 isolated
in 1948 from the city of Oxford, are characterized by two
main blocks: a peptide chain, derived amino acid including
modifications of many cysteine and serine units to thiazole-
(line) and oxazole(line) rings and connected to a common
complex di- or triazolylpyridine heterocyclic core. As a result
of their important biological activity, many groups including
Moody, Bagley, Bach, Nicolaou, Hashimoto-Nakata, and
Ciufolini have been actively involved in the total synthesis
of thiopeptides.1a,b,2 One of the multiple synthetic challenges
is the development of concise synthetic routes toward the
complex heterocyclic cores (three main examples are de-
(1) For reviews: (a) Hughes, R. A.; Moody, C. Angew. Chem., Int. Ed.
2007, 46, 2–27. (b) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X.
Chem. ReV. 2005, 105, 685–714. (c) Roy, R. S.; Gehring, A. M.; Milne,
J. C.; Belshaw, P. J.; Walsh, C. T. Nat. Prod. Rep. 1999, 16, 249–263. (d)
Li, Y.-M.; Milne, J. C.; Madison, L. L.; Kolter, R.; Walsh, C. T. Science
1996, 274, 1188–1193. For recent reports on thiopeptide antibiotics, see:
(e) Zhang, C.; Occi, J.; Masurekar, P.; Barrett, J. F.; Zink, D. L.; Smith, S.;
Onishi, R.; Ha, S.; Salazar, O.; Genilloud, O.; Basilio, A.; Vicente, F.; Gill,
C.; Hickey, E. J.; Dorso, K.; Motyl, M.; Singh, S. B. J. Am. Chem. Soc.
2008, 130, 12102–12110. (f) Morris, R. P.; Leeds, J. A.; Naegeli, H. U.;
Oberer, L.; Memmert, K.; Weber, E.; LaMarche, M. J.; Parker, C. N.; Burrer,
N.; Esterow, S.; Hein, A. E.; Schmitt, E. K.; Krastel, P. J. Am. Chem. Soc.
2009, 131, 5946–5955.
(2) For recent total synthesis of thiopeptides, see: (a) Lefranc, D.;
Ciufolini, M. A. Angew. Chem., Int. Ed. 2009, 48, 4198–4201. (b) Nicolaou,
K. C.; Dethe, D. H.; Chen, D. Y.-K. Chem. Commun. 2008, 2632–2634.
(c) Nicolaou, K. C.; Dethe, D. H.; Leung, G. Y. C.; Zou, B.; Chen, D. Y.-
K. Chem. Asian J. 2008, 3, 413–429. (d) Mu¨ller, H. M.; Delgado, O.; Bach,
¨
T. Angew. Chem., Int. Ed. 2007, 46, 4771–4774. (e) Delgado, O.; M; uller,
H. M.; Bach, T. Chem.sEur. J. 2008, 14, 2322–2339. (f) Mori, T.;
Higashibayashi, S.; Goto, T.; Kohno, M.; Satouchi, Y.; Shinko, K.; Suzuki,
K.; Suzuki, S.; Tohmiya, H.; Hashimoto, K.; Nakata, M. Chem. Asian J.
2008, 3, 1013–1025. (g) Merritt, E. A.; Bagley, M. C. Synlett 2007, 954–
958
.
10.1021/ol901525t CCC: $40.75
Published on Web 07/22/2009
 2009 American Chemical Society

picted in Figure 1). An attractive approach would consist of
direct interconnections of the heterocyclic subunits, mainly
thiazole, pyridine, and sometimes oxazole, using heteroaryl-
heteroaryl coupling reactions.
pharmaceutics. As a first example, a synthesis of the ethyl
saramycetate subunit of the cyclothiazomycin thiopeptide was
proposed.
Scheme 1. Study of Single-Step BSC Protocol for Introduction
of 2-Ketothiazol-4-yl Unit in Our Previously Reported tert-Butyl
Sulfomycinamate Thio-analogue 1 Synthesis
Figure 1. Three main common bi- or triazolylpyridine cores of d
series thiopeptide antibiotics.
Such a strategy was initially explored by Kelly some 20
years ago3a,b and remained largely unexplored until the recent
remarkable Bach synthesis of the GE2270A central core
based upon a three-step sequence of cross-coupling reactions
starting from 2,3,6-tribromopyridine, as reported in 2005.3c
In this context, we have recently reported a palladium-
catalyzed direct connection of the common oxazole and
thiazole-4-carboxylate blocks to a central pyridine unit, thus
avoiding the intermediary preparation of thiazolyl- or py-
ridinylmetals classically used in cross-coupling methodolo-
gies.4 The method was directly applied to a neat synthesis
of a tert-butyl sulfomycinamate thio-analogue through a
three-step direct arylation, chlorination, and Stille cross-
coupling sequence (Scheme 1). Following this work, we
focused on a novel friendly protocol for the direct introduc-
tion of the 2-ketothiazole unit at position-4 to the central
pyridine core. Indeed, the Stille cross-coupling methodology,
currently employed for this last connection, requires prior
preparation of the 4-stannyl intermediate 3 using a two-step
keto-protection, transmetalation-stannylation protocol4c fol-
lowed by a coupling step and a final hydrolysis as depicted
in Scheme 1. Herein we report the borylation Suzuki coupling
(BSC) of 4-bromo-2-ketothiazoles 4a,b with 2-halopyridines
to give direct access to 4-pyridinyl-2-ketothiazoles. These
are common features of the heterocyclic cores of thiopeptide
antibiotics. The methodology was directly applied to an
innovative synthesis of the tert-butyl sulfomycinamate thio-
analogue 1 and the micrococcinate 13 ester. The scope of
this novel BSC protocol for ketothiaozles 4a,b, using various
coupling partners, was also evaluated for the further synthesis
of 4-substituted 2-ketothiazole-based natural products and
The 4-bromo-2-ketothiazoles 4a,b were ready prepared in
high yield from the commercially available 2,4-dibromothia-
zole via regioselective lithium-bromide exchange and
quenching with N-acetyl and propionylmorpholines.5
A first set of palladium-catalyzed borylations of 4-bromo-
2-acetyl and propionylthiazoles 4a,b was carried out under
the Masuda and Baudoin processes using pinacolborane as
a cheaper borylating agent.6 In both cases, production of
borylated thiazoles was not observed. We then turned to
bis(pinacol)borane as employed by Miyaura,7g and we
decided to check the nature of the ligand as the main
borylation parameter using Pd2(dba)3 as recently suggested
by Buchwald,7a KOAc as base, and dioxane as solvent (Table
1).7 Except for the bidentate ligand dppf (entry 1), we were
pleased to observe that all Buchwald ligands, as well as the
carbene ligand IMes, allowed good conversion of the starting
material as measured by GC monitoring to give the expected
4-borylated thiazoles 8a,b in short reaction time (0.5-3 h).
We then immediately evaluated the performance of the
same catalyst systems that proved efficient in the prior
borylation reaction8 for a subsequent Suzuki coupling of
2-chloropyridine using the K3PO4 base, following the
(5) Gebauer, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 3425–
3427.
(6) For palladium-catalyzed borylation of aromatics methods using
pinacolborane, see: (a) Broutin, P.-E.; Cerna, I.; Campaniello, M.; Leroux,
F.; Colobert, F. Org. Lett. 2004, 6, 4419–4422. (b) Baudoin, O.; Gue´nard,
D.; Gue´ritte, F. J. Org. Chem. 2000, 65, 9268–9271. (c) Murata, M.;
Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458–6459.
(7) For palladium-catalyzed borylation of aromatics methods using
bis(pinacol)borane, see: (a) Billingsley, K. L.; Barder, T. E.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2007, 46, 5359–5363. (b) Zhu, L.; Duquette,
J.; Zhang, M. J. Org. Chem. 2003, 68, 3729–3732. (c) Fu¨rstner, A.; Seidel,
G. Org. Lett. 2002, 4, 541–543. (d) Ishiyama, T.; Ishida, K.; Miyaura, N.
Tetrahedron 2001, 57, 9813–9816. (e) Ishiyama, T.; Itoh, Y.; Kitano, T.;
Miyaura, N. Tetrahedron Lett. 1997, 38, 3447–3450. (f) Giroux, A.; Han,
Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841–3844. (g) Ishiyama, T.;
Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
(8) Both borylated thiazoles 8a,b proved to be highly unstable under
usual isolating procedures.
(3) (a) Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Lett. 1991, 32,
4263–4266. (b) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623–4633.
(c) First synthesis of a heterocyclic core of a thiopeptide antibiotic
(GE2270A) in a complete cross-coupling approach: Heckmann, G.; Bach,
T. Angew. Chem., Int. Ed 2005, 44, 1199–1201.
(4) (a) Martin, T.; Verrier, C.; Hoarau, C.; Marsais, F. Org. Lett. 2008,
10, 2909–2912. (b) Verrier, C.; Martin, T.; Hoarau, C.; Marsais, F. J. Org.
Chem. 2008, 73, 7383–7386. (c) Direct palladium-catalyzed stannylation
of 4a using bistrimethystannane is penalized by the side production of 2,2′-
acetyl-4,4′-bithiazole (35% GC yield), which could not be isolated from
the expected 2-acetylthiazol-4-ylstannane (51% GC yield).
Org. Lett., Vol. 11, No. 16, 2009
3691

Table 1. Evaluation of 4-Bromo-2-ketothiazoles 4a,b in
Table 2. Scope of BSC of 4a,b Procedure Using Various
Palladium-Catalyzed BSC Methodologya
Bromo and Chlorohetaromaticsa
time (min)b
yield of 9a,b (%)c
from
from
from
from
entry
ligand
4a
4b
8a
8b
1
2
3
4
5
6
dppf
1000f
40
180
120
90
1000f
30
60
JohnPhosd
SPhos
90 (84)g
68
100 (97)g
99 (96)g
94(90)g
52
XPhos
30
84 (81)g
30
DavePhos
45
180
IMese
150
n.r.
n.r.
h
a Reaction run on sealed vials under N2 from 0.25 mmol of ketothiazole.
b Time to 100% completion of starting material followed by GC analysis.
c GC yield using n-eicosane as an internal standard. d Cy-JohnPhos )
2-(dicyclohexylphosphino)-biphenyl. e IMes ) 1,3-bis-(mesitylimidazolyl)-
carbene. f <10% of 8a,b. g Isolated yield. h 80% of completion of 4b.
Baudoin6b and Buchwald7a BSC procedures (Table 1). Under
these conditions, the IMes-based catalyst system proved to
be completely ineffective for subsequent Suzuki reaction
(entry 6), whereas all Buchwald ligand-based catalysts
provided 4-pyridin-2-ylthiazoles 9a,b in fair to quantitative
yield (entries 2-5) without any notable R-arylation reaction
of the ketones. Nevertheless, the Cy-JohnPhos- and XPhos-
based catalysts proved to be slightly more effective than the
SPhos- and DavePhos-based catalysts for the Suzuki coupling
of both ketothiazoles 4a,b, providing 9a,b in a range of
81-97% isolated yields. These good results probably came
from a better preservation of the active catalyst in the prior
clean and fast palladium-catalyzed borylation reaction.
With the aim to include this BSC protocol of 4a,b as a
novel synthetic tool for the construction of heterocyclic cores
of thiopeptides, various 2-halopyridines were next evaluated
as coupling partners.
The results depicted in Table 2 (entries 1-4) clearly
showed that the BSC protocol applied to 4a,b allowed fair
to good yield couplings with various 2-halopyridines bearing
electron-attractive or electron-donating group. We then
reinvestigated the last connection of the 2-acetylthiazol-4-
yl unit to 6-chlorothiazolylpicolinate 5a in order to simplify
our previous synthesis of tert-butyl sulfomycinamate thio-
analogue 14 as depicted in Scheme 1. Pleasingly, the direct
coupling of 4a with 5a could be achieved using the novel
BSC protocol, affording 1 in an excellent 87% yield (Table
2, entry 7). Finally, the tert- butylsulfomycinamate thio-
analogue 1 is prepared from tert-butyl-5-bromopicolinate 6a
in an excellent 47% overall yield. We then immediately
a Reaction run on usual glassware fitted with a condenser under N2 from
1 mmol of ketothiazole. b Yield of isolated product. c Coupling with
2-iodopyridine. d XPhos as ligand. e Isolated yield of saramycetic acid after
hydrolysis (see Supporting Information).
focused on an extension of this strategy to the synthesis of
micrococcinate 13 mainly by modulating the tert-butyl ester
group to a 4-(4′-ethoxycarbonylthiazol-2′-yl)thiazol-2-yl
subunit (Scheme 2). With this purpose in mind, the ethyl-
tert-butyl pyridinylthiazolecarboxylate 5b was first produced
through a palladium-catalyzed direct coupling of 4-thiazole-
carboxylate 7 with picolinate 6b followed by R-chlorination
of the pyridine. The latter was then submitted to a modified
Shin procedure.9 Thus, treatment of 5b with aqueous
3692
Org. Lett., Vol. 11, No. 16, 2009

procedure with Cy-JohnPhos and Xphos as ligands. Thus,
interestingly, while the Cy-JohnPhos ligand appeared poorly
or completely inefficient in the BSC reaction, the XPhos
ligand allowed attainment of fair to good yields of coupling
products (Table 2, entries 5, 8-9, 15). As an application,
the commercially available ethyl 2-bromothiazole-4-car-
boxylate was used as a coupling partner to prepare the ethyl
saramycetate subunit of cyclothiazomycin thiopeptide 21
recently identified by Bagley.10,11
Scheme 2. Innovative Synthesis of
ethyl-tert-Butylmicrococcinate 13
Moreover, two first direct vinylations of 4a,b with bro-
moalkene derivatives (Table 1, entries 14 and 15) were also
achieved in good yield using the BSC procedure. This
methodology could be directly used for novel synthetic
approaches to 4-vinylated-2-ketothiazole-based natural prod-
ucts, as exemplified by melithiazole C.12
In summary, we have developed here a highly efficient
borylation Suzuki coupling process of 4-bromo-2-ketothia-
zoles with various haloheteroaromatics and bromoalkenes.
This methodology is suitable to simplify current syntheses
or to design concise routes to 4-substituted 2-ketothiazole-
based natural products and pharmaceutics. As examples, in
the current context of active research in the design of concise
routes toward complex heterocyclic units of d thiopeptide
antibiotics, innovative syntheses of sulfomycinamate thio-
analogue 1, micrococcinate 13, and saramycetate 21 esters
are described here.
Acknowledgment. This work has been supported by the
CNRS, the interregional CRUNCH network, INSA and
University of Rouen (I.U.T.).
ammonia followed by subsequent thioamidation with the
Lawesson’s reagent and a final Hantzsch condensation under
mild conditions (EtOH/THF 1:1 mixture) provided 11 in 40%
overall yield. Pleasingly, the final connection of 2-acetylthi-
azole unit to the highly substituted 2-chloropyridine 11 was
achieved using the BSC protocol of 4b to give the ethyl-
tert-butylmicrococcinate ester 13 in 87% yield.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (IR, analytical
1
analysis, H, 13C data) of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
As the last part of this work and to design novel synthetic
routes toward 4-substituted 2-ketothiazole-based natural
products and pharmaceutics, various other coupling partners
were also evaluated in the BSC process of 4a,b (Table 2,
entries 5, 6, 8-15). Remarkably, several haloheteroaromatics
could be directly introduced to 4a,b to produce the 4-het-
eroaryl-2-ketothiazoles 16-20 in high yields using the BSC
OL901525T
(10) Bagley and co-workers recently reported the first and unique
synthesis of ethyl saramycetate in 8 steps and 11% overyield from
diethoxyacetonitrile: Glover, C.; Merritt, E. A.; Bagley, M. C. Tetrahedron
Lett. 2007, 48, 7027–7030
.
(11) For a general access to 2′-substituted 4-bromo-2,4′-bithiazoles using
regioselective Negishi and Stille cross-coupling reactions, see: Bach, T.;
Heuser, S. J. Org. Chem. 2002, 67, 5789–5795
.
(12) (a) Gebauer, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 3425–
3427. (b) Bo¨hlendorf, B.; Hermann, M.; Hecht, H. J.; Sasse, F.; Forche,
E.; Kunze, B.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem. 1999, 10,
2601–2608.
(9) Yasuchika, S. S.; Yonezawa, Y.; Shin, C. Chem. Lett. 2004, 33, 814–
815.
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