Oxidative Routes to the Heterocyclic Cores of Benzothiazole Natural Products

Article abstract of DOI:10.1055/s-0035-1560722

Methyl 6-(2-acetylaminoethyl)-4-hydroxy-benzothiazole-2-carboxylate, the benzothiazole core of the natural product violatinctamine, was prepared in a biomimetic oxidative route from N-acetyldopamine and cysteine methyl ester. In an alternative oxidative cyclization, ethyl 6-benzyloxy-5-methoxybenzo[d]thiazole-2-carboxylate, the heterocyclic core of erythrazole A, was also prepared.

Full text of DOI:10.1055/s-0035-1560722

SYNLETT
0
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0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 37–40
letter
37
C. E. Blunt et al.
Letter
Synlett
Oxidative Routes to the Heterocyclic Cores of Benzothiazole Natu-
ral Products
OH
Christopher E. Blunt
OH
HN
C
OH
N
S
Christopher C. Nawrat
Lucille LeBozec
Mantas Liutkus
Yang Liu
1. Ag2O (2 equiv), Na2SO4
HCO2H, MeOH
N
S
OH
CO2Me
Me2N
NH2⋅HCl
2.
HS
CO2Me
MeOH
3. FeCl3, H2O
NR1R2
violatinctamine
NR1R2
O
William Lewis
Christopher J. Moody*
MeO
HO
O
N
S
School of Chemistry, University of Nottingham,
University Park, Nottingham NG7 2RD, UK
c.j.moody@nottingham.ac.uk
HN
Me
H
MeO
N
S
MeO
N
CO2Et
CAN
CO2H
CO2Et
MeCN
(52%)
S
BnO
R
BnO
Dedicated to Professor Steve Ley FRS in celebration of
his 70th birthday, and of his many outstanding con-
tributions to organic synthesis
Me
R = CH2CH=CMe(CH2)3CHMeCO2H
erythrazole A
Received: 20.08.2015
Accepted after revision: 25.09.2015
Published online: 09.10.2015
Me
Me
Me
CO2H
N
N
S
HO
DOI: 10.1055/s-0035-1560722; Art ID: st-2015-d0651-l
S
OH
HO
AcO
MeO
O
Me
Abstract Methyl 6-(2-acetylaminoethyl)-4-hydroxy-benzothiazole-2-
carboxylate, the benzothiazole core of the natural product violatinct-
amine, was prepared in a biomimetic oxidative route from N-acetyldo-
pamine and cysteine methyl ester. In an alternative oxidative cycliza-
tion, ethyl 6-benzyloxy-5-methoxybenzo[d]thiazole-2-carboxylate, the
heterocyclic core of erythrazole A, was also prepared.
luciferin (1)
OH OH
Me
NH
OH
Me
O
HN
N
S
S
O
N
O
Key words heterocycles, natural products, amino acids, quinones, ox-
idation
Me
NMe2
rifamycin P (2)
O
violatinctamine (3)
Amino acids serve as precursors to a wide range of nat-
urally occurring substances including alkaloids and antibi-
otics, many of which contain heterocyclic rings. One inter-
esting subset of these heterocyclic natural products is bio-
synthesized from cysteine, and therefore contains both
nitrogen and sulfur atoms. Whilst the simplest N,S-hetero-
cycle – thiazole – is relatively common in nature, benzothi-
azoles, on the other hand, are relatively rare as natural
products, possibly because the biosynthetic route to the
ring system is more complex than for thiazoles themselves.
Nevertheless, well-known examples include firefly luciferin
(1) and rifamycin P (2, Figure 1). We now report oxidative
routes to the heterocyclic core of two more recently isolat-
ed benzothiazoles, violatinctamine (3),1 and erythrazole A
(4, Figure 1).2
MeO
O
N
erythrazole A (4)
S
HN
Me
HO
CO2H
Me
Me
Me
Figure 1 Some naturally occurring benzothiazoles
CO2H
isolation chemists suggested that the benzothiazole core of
violatinctamine (3) could derive by addition of cysteine to a
benzoquinone.1 In this proposal, cysteine adds to the ortho-
quinone, formed by oxidation of DOPA, to give 5-S-cyste-
inyl-DOPA (5), which upon further oxidation gives the ben-
zothiazine 6 that undergoes ring contraction to the key
benzothiazole 7 (X = CHO or CO2H, Scheme 1). Therefore,
inspired by the possibility of a biomimetic route to violat-
inctamine (3), we undertook the preparation and oxidation
of a number of dopamine derivatives.
Violatinctamine (3) was isolated from the Kenyan ma-
rine tunicate Cystodytes cf. violatinctus and exists as a mix-
ture of two tautomers, the amino quinone methide (shown)
and the iminophenol. By analogy with the biosynthesis of
luciferin,3 and of the red hair pigments pheomelanins,4 the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 37–40

38
C. E. Blunt et al.
Letter
Synlett
OH
OH
R1
OH
R1
OH
OH
OH
OH
S
N
S
[O]
1. Ag2O (2 equiv), Na2SO4
HCO2H, MeOH
CO2Me
NH2
CO2H
NH2
CO2H
R
R
HS
NH2⋅HCl
CO2Me
2.
HS
5
N
R2
N
R2
DOPA
R = CH2CH(NH2)CO2H
OH
MeOH
[O]
3. FeCl3, H2O
8
R1 = H, R2 = Ac
10 R1 = H, R2 = Boc
12 R1 = Me, R2 = Boc
9
R1 = H, R2 = Ac (37%)
11 R1 = H, R2 = Boc (22%)
13 R1 = Me, R2 = Boc (10%)
OH
N
CO2H
N
S
3
Scheme 2 Biomimetic oxidative route to benzothiazole core of violat-
inctamine (3)
X
R
R
S
7
6
Scheme 1 Proposed biosynthesis of violatinctamine (3)1
A range of ten N-protected derivatives of dopamine was
prepared (see Supporting Information), and their oxidation
in the presence of cysteine methyl ester investigated. A
number of reagents are reported to oxidize DOPA deriva-
tives to the corresponding ortho-quinones, including ceri-
um(IV) ammonium nitrate (CAN),5 DDQ,6 and tyrosinase,7
but we elected to use silver(I) oxide.8 Thus, silver(I) oxide
was added to N-acetyldopamine (8) in methanol; after 15
minutes the black suspension was filtered to give a red
solution of the ortho-quinone that was immediately added
to a solution of cysteine methyl ester in methanol to give
the corresponding cysteinyl dopamine. The oxidative cy-
clization of such compounds is often carried out using po-
tassium ferricyanide,4 but in our hands this was unsatisfac-
tory. In the event, the intermediate cysteinyl acetyldopa-
mine was not isolated, but treated with aqueous iron(III)
chloride to give the desired benzothiazole 9 in 37% yield
from dopamine 8 (Scheme 2),9 the structure being con-
firmed by X-ray crystallography (Figure 2). The intermedi-
ate benzothiazine analogous to compound 6 was not ob-
served. Similarly, N-Boc dopamine (10) and N-Boc epinine
(12) gave the corresponding benzothiazoles 11 and 13, but
in poor yield (Scheme 2), whilst the remaining dopamine
derivatives (see Supporting Information) did not deliver the
required heterocycles. Nevertheless, despite the modest
37% yield, this biomimetic oxidative route does give access
to the benzothiazole core 9 of violatinctamine (3) in a fasci-
nating sequence of reactions from simple, readily available
starting materials, and paved the way for a similar approach
to the benzothiazole core of erythrazole A (4).
Figure 2 X-ray crystal structure of methyl 6-(2-acetylaminoethyl)-4-
hydroxybenzothiazole-2-carboxylate (9)
fore seemed an ideal starting point for a biomimetic syn-
thesis of the benzothiazole core of erythrazole A (4). Addi-
tion of cysteine ethyl ester hydrochloride to 2-methoxy-
1,4-benzoquinone proceeded smoothly but the isolated
yield of the cysteine adduct 14 was extremely poor (14%).
Therefore the sequence was repeated without isolation of
the intermediate 14 by direct oxidation of the reaction mix-
ture with potassium ferricyanide, the preferred oxidant for
such reactions,3,10 giving an inseparable mixture of benzo-
thiazine 15 and the desired benzothiazole 16 (Scheme 3).
Treatment of the mixture with hydrochloric acid10 led to
the ring contraction of the benzothiazine 15 to giving the
desired benzothiazole 16 in an overall of 9% over three
steps from 2-methoxy-1,4-benzoquinone. Although the
yield of the benzothiazole core of erythrazole A (4) is poor,
the sequence does establish the viability of a biomimetic
oxidative route.
Erythrazole A (4) was isolated from an Erythrobacter
strain of marine-derived bacteria as a 1.0:0.6 mixture of en-
antiomers.2 Again, by analogy with the biosynthesis of lu-
ciferin,3 it was proposed that the natural product arose
from addition of cysteine to a 6-substituted 2-methoxy-1,4-
benzoquinone.2 Indeed the addition of cysteine ethyl ester
to 1,4-benzoquinone itself is a well-established route to
ethyl 6-hydroxybenzothiazole-2-carboxylate,3,10 and there-
In view of the poor yield in the above biomimetic route
to benzothiazole 16, we investigated an alternative oxida-
tive cyclization from a thioamide. The cyclization of thio-
amides to benzothiazoles does have some precedent, and
was used in the first synthesis of firefly luciferin.11 The
route started from 4-benzyloxy-3-methoxynitrobenzene
(17) that was reduced and acylated to give the oxalamide
18. Conversion into the corresponding thioamide 19 pro-
ceeded in excellent yield, and the key oxidative cyclization
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 37–40

39
C. E. Blunt et al.
Letter
Synlett
Supporting Information
NH2
HS
MeO
OH
S
MeO
O
O
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560722.
CO2Et
HO
NH2
CO2Et
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
aq MeOH
14
References and Notes
K3Fe(CN)6
aq EtOH
(1) Chill, L.; Rudi, A.; Benayahu, Y.; Kashman, Y. Tetrahedron Lett.
2004, 45, 7925.
(2) Hu, Y.; MacMillan, J. B. Org. Lett. 2011, 13, 6580.
(3) McCapra, F.; Razavi, Z. J. Chem. Soc., Chem. Commun. 1975, 42.
(4) Napolitano, A.; Panzella, L.; Leone, L.; D’Ischia, M. Acc. Chem. Res.
2013, 46, 519.
MeO
HO
MeO
HO
N
S
CO2Et
N
S
aq HCl
EtOH
CO2Et
OEt
16
15
(5) Chioccara, F.; Novellino, E. Synth. Commun. 1986, 16, 967.
(6) Land, E. J.; Perona, A.; Ramsden, C. A.; Riley, P. A. Org. Biomol.
Chem. 2005, 3, 2387.
Scheme 3 Biomimetic oxidative route to benzothiazole core of eryth-
razole A (4)
(7) Greco, G.; Panzella, L.; Napolitano, A.; d’Ischia, M. Tetrahedron
Lett. 2009, 50, 3095.
(8) Prota, G.; Scherillo, G.; Nicolaus, R. A. Gazz. Chim. Ital. 1968, 98,
496.
(9) Methyl 6-(2-Acetylaminoethyl)-4-hydroxy-benzothiazole-2-
carboxylate (9)
step was attempted using potassium ferricyanide as report-
ed in the firefly luciferin synthesis.11 Unfortunately, this
failed to deliver the desired benzothiazole, and therefore a
change in oxidant was instigated. Two alternatives were
considered – cerium(IV) ammonium nitrate and phenylio-
dine(III)diacetate – but based on a recent comparative
study,12 we elected to use CAN. Treatment of the thioamide
19 with CAN in acetonitrile at 0 °C resulted in cyclization to
the benzothiazole 20 in 52% yield (Scheme 4),13 thereby
completing a practical route to the heterocyclic core of
erythrazole A (4).
Ag2O (256 mg, 1.1 mmol) and Na2SO4 (251 mg, 1.8 mmol) were
added to a solution of N-acetyldopamine (8, 60 mg, 0.3 mmol)
and formic acid (42 μL, 1.1 mmol) in MeOH (4 mL), and the
black suspension was stirred for 15 min in the dark at r.t. then
filtered through a pad of Celite®. The filter cake was washed
with MeOH (2 × 6 mL), and the combined red filtrates were
immediately added dropwise to a solution of cysteine methyl
ester hydrochloride (57 mg, 0.3 mmol) in MeOH (2 mL). After
addition had completed the pale green solution was concen-
trated to give the cysteine adduct as a pale yellow–green foam
that was used directly without purification {HRMS: m/z calcd
for C14H21N2O5S+: 329.1166; found [M + H+]: 329.1160}. The
above foam was dissolved in H2O (0.7 mL) and a solution of
FeCl3·6H2O (442 mg, 1.6 mmol) in H2O (1.8 mL) was slowly
added dropwise with vigorous stirring. The mixture was stirred
for 72 h at r.t., then diluted with H2O (10 mL), and extracted
with EtOAc (3 × 10 mL). The combined organic extracts were
washed with H2O (30 mL) and brine (30 mL), dried (Na2SO4),
and concentrated. The residue was subjected to flash column
chromatography on silica gel, eluting with EtOH–AcOH (1:9) to
give the title compound as yellow solid (34 mg, 37% over two
steps); mp 143–144 °C. HRMS: m/z calcd for C13H15N2O4S+:
295.0747; found [M + H+]: 295.0742. IR (CHCl3): νmax = 3522,
H
MeO
BnO
NO2
MeO
BnO
N
CO2Et
1. H2, Pt/C, THF
2.
O
Cl
CO2Et
17
O
18
Lawesson's
reagent
toluene
(92%)
Et3N, CH2Cl2
(52%, 2 steps)
H
MeO
BnO
MeO
BnO
N
CO2Et
N
S
CAN
CO2Et
S
MeCN
(52%)
20
19
3011, 2414, 1722, 1603, 1497, 1192 cm–1. UV-Vis (MeCN): λmax
=
Scheme 4 Oxidative cyclization of thioamide to benzothiazole core of
erythrazole A (4)
264 (log ε 3.15), 312 (log ε 3.58) nm. 1H NMR (400 MHz,
acetone-d6): δ = 9.44 (1 H, br s), 7.79 (1 H, br s), 7.46 (1 H, s),
6.94 (1 H, s), 4.01 (3 H, s), 3.57–3.53 (2 H, m), 2.96–2.93 (2 H,
m), 2.02 (3 H, s). 13C NMR (100 MHz, acetone-d6): δ = 172.8 (C),
161.5 (C), 155.5 (C), 153.7 (C), 143.0 (C), 124.9 (C), 139.1 (C),
113.9 (CH), 113.6 (CH), 53.7 (Me), 41.8 (CH2), 36.4 (CH2), 20.9
(Me).
Hence we have developed routes to the heterocyclic
cores of two naturally occurring benzothiazoles – violat-
inctamine and erythrazole A – based on oxidative cycliza-
tion reactions. Further studies towards a total synthesis of
the natural products are in progress.
(10) Lowik, D.; Tisi, L. C.; Murray, J. A. H.; Lowe, C. R. Synthesis 2001,
1780.
(11) White, E. H.; McCapra, F.; Field, G. F. J. Am. Chem. Soc. 1963, 85,
337.
(12) Zhu, J.; Xie, H.; Li, S.; Chen, Z.; Wu, Y. J. Fluorine Chem. 2011,
132, 306.
Acknowledgment
We thank the University of Nottingham for a China Science Research
Scholarship to Y.L., and the EPSRC for support.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 37–40

40
C. E. Blunt et al.
Letter
Synlett
(13) Ethyl 6-Benzyloxy-5-methoxybenzo[d]thiazole-2-carboxyl-
beige solid (1.28 g, 52%); mp 116 °C. HRMS: m/z calcd for
ate (20)
C
18H18NO4S: 344.0951; found [M + H]+: 344.0961. IR (CHCl3):
To
a
solution of ethyl 2-(4-benzyloxy-3-methoxyphe-
ν
max = 3009, 1714, 1607, 1497 cm–1. 1H NMR (400 MHz, CDCl3):
nyl)amino)-2-thioxoacetate (19, 2.5 g, 7.2 mmol) in MeCN (175
mL) at 0 °C was added CAN (9.86 g, 18 mmol) in H2O (175 mL).
The reaction mixture was stirred for 1.5 h, then diluted with
H2O (200 mL) and extracted with EtOAc (3 × 100 mL). The
organic extracts were combine, washed with brine (2 × 200
mL), then dried over MgSO4 to give the title compound as a
δ = 7.66 (1 H, s), 7.45–7.31 (6 H, m), 5.24 (2 H, s), 4.52 (2 H, q, J =
7.1 Hz), 3.97 (3 H, s), 1.47 (3 H, t). 13C NMR (100 MHz, CHCl3): δ
= 160.7 (C), 156.2 (C), 150.9 (C), 149.9 (C), 148.2 (C), 136.1 (C),
129.8 (C), 128.7 (CH), 128.2 (CH), 127.3 (CH), 106.0 (CH), 104.1
(CH), 71.3 (CH2), 62.8 (CH2), 56.2 (Me), 14.3 (Me).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 37–40