DOI: 10.1002/chem.201600351
Communication
&
Synthetic Methods
Synthesis of Triarylpyridines in Thiopeptide Antibiotics by Using
a CÀH Arylation/Ring-Transformation Strategy
Herein, we describe a new method for the synthesis of 2,3,6-
Abstract: We have described a CÀH arylation/ring-trans-
triarylpyridines by using a CÀH arylation/ring transformation
formation strategy for the synthesis of triarylpyridines,
strategy (Figure 1B):[6] this consists of a sequence of CÀH aryla-
which form the core structure of thiopeptide antibiotics.
tion and [4+2] cycloaddition (Kondrat’eva reaction)[7] with suit-
This synthetic method readily gave 2,3,6-triarylpyridines in
able alkenes. Such a sequence would begin with 4-aryloxazoles
a regioselective manner by a two-phase approach: CÀH
as starting material, which in turn would be prepared by decar-
arylation (a nickel-catalyzed decarbonylative Suzuki–
bonylative coupling of a phenyl ester with arylboronic acid de-
Miyaura cross-coupling and decarbonylative CÀH coupling
for the synthesis of 2,4-diaryloxazoles) and ring transfor-
mation ([4+2] cycloaddition of 2,4-diaryloxazoles with
(hetero)arylacrylic acids). To showcase these methods, we
have accomplished the formal synthesis of thiopeptide an-
tibiotics GE2270 s and amythiamicins.
rivatives (Figure 1B).[8] Recently, transition-metal-catalyzed
direct CÀH arylation has attracted much attention as a next-
generation coupling method for the construction of (hetero)-
biaryl frameworks.[9,10] But although the CÀH arylation of five-
membered heteroarenes is well established with controlled re-
gioselectivity, the CÀH arylation of six-membered (hetero)aro-
matics, such as pyridine, has considerable room for further in-
vestigation in terms of overcoming challenges in reactivity and
regioselectivity.[11] One way to access diverse multi-arylated
pyridines would be to diarylate five-membered heteroaromat-
ics by decarbonylative arylation and CÀH arylation, followed by
a ring transformation from a five-membered ring to a six-mem-
bered ring.
Many recently emerging thiopeptide antibiotics, such as
GE2270s and amythiamicins, are composed of a 2,3,6-triarylpyr-
idine moiety and a macrocyclic oligopeptide (Figure 1A).[1] Bio-
logical assays of these compounds have shown that they are
protein-synthesis-inhibitor candidates against Gram-positive
bacteria, and one of these derivatives LFF571, developed by
Novartis, is now undergoing phase II clinical trials.[2] Owing to
their interesting structures and remarkable biological activities,
these compounds have attracted considerable attention as
synthetic targets.[1c,3–5] To date, a number of strategies toward
these molecules, particularly the synthesis of their core 2,3,6-
triarylpyridine structure, have been devised, which includes
a hetero-Diels–Alder/dimerization process, a Bohlmann–Rahtz
or Hantzsch pyridine synthesis and a cross-coupling reaction of
organometallic compounds with aryl halides. Although excel-
lent strategies and syntheses have been reported, the develop-
ment of a diverse method to form and derivatize the core
structure of these heterocyclic oligopeptides is in high
demand.
To realize this plan, we first synthesized a variety of 2,4-diary-
loxazoles that can undergo [4+2] cycloaddition. Although 4-ar-
yloxazoles can be prepared by using a known method, the
yields were moderate to low.[12] Therefore, we prepared them
by developing a coupling method (Scheme 1).[8] To this end,
phenyl oxazole-4-carboxylate was coupled with arylboroxines
in the presence of Ni(OAc)2/P(nBu)3 catalyst and Na2CO3 in tolu-
ene at 1508C to give 4-aryloxazoles 1a–d in 45–57% yield.
Next, 1a–d were coupled with phenyl esters 2a and b using
our CÀH coupling method under the following conditions:
[Ni(cod)2]/dcype (cod=1,5-cyclooctadiene; dcype=1,2-bis(di-
cyclohexylphosphino)ethane; 1:2 molar ratio; 10 mol% Ni),
K3PO4 (2.0 equiv), 1,4-dioxane, 1508C, 24 h.[13] Phenyl 2-phenyl-
thiazole-4-carboxylate (2a) and phenyl thiophene-2-carboxyl-
ate (2b) were coupled with 4-phenyloxazole (1a) to give 2,4-
diaryloxazoles 3a and b, respectively, in excellent yield. The
coupling of 4-(4-methoxyphenyl)oxazole (1b) and 2a gave the
product 3c in moderate yield. Compounds 4-(p-tolyl)oxazole
(1c) and 4-(2-naphthyl)oxazole (1d) were reacted with 2a
under the same conditions to produce the corresponding cou-
pling products 3d and e in good to excellent yields.
[a] K. Amaike, Prof. Dr. K. Itami, Prof. Dr. J. Yamaguchi
Institute of Transformative Bio-Molecules (WPI-ITbM)
Nagoya University, Chikusa, Nagoya, 464-8601 (Japan)
[b] K. Amaike, Prof. Dr. K. Itami, Prof. Dr. J. Yamaguchi
Department of Chemistry, Graduate School of Science
Nagoya University, Chikusa, Nagoya, 464-8602 (Japan)
Next, we examined the [4+2] cycloaddition of 2,4-diaryloxa-
zoles 3 with (hetero)arylalkenes to generate triarylpyridines by
ring transformation. When thiazolylacrylic acid 4a was used as
the dienophile, cycloaddition with 3a proceeded in o-dichloro-
benzene at 1508C to give 2,3,6-triarylpyridine 5a in 71% yield
with virtually complete regioselectivity, structure of which was
[c] Prof. Dr. K. Itami
JST, ERATO, Itami Molecular Nanocarbon Project
Chikusa, Nagoya, 464-8602 (Japan)
Supporting information and the ORCID identification number(s) for the au-
Chem. Eur. J. 2016, 22, 4384 – 4388
4384
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Amaike, Kazuma
