Expedient synthesis of eumelanin-inspired 5,6-dihydroxyindole-2-carboxylate ethyl ester derivatives

Article abstract of DOI:10.1039/c8ra06148c

Dihydroxyindoles such as 5,6-dihydroxyindole-2-carboxylic acid (DHICA) are the main monomer units of eumelanin, the black to brown pigment in humans, and have emerging biological roles beyond melanin. Elaboration of commercially available 5,6-dimethoxy-2-

Full text of DOI:10.1039/c8ra06148c

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Expedient synthesis of eumelanin-inspired 5,6-
dihydroxyindole-2-carboxylate ethyl ester
derivatives†
Cite this: RSC Adv., 2018, 8, 28323
Andrew H. Aebly, Jeffrey N. Levy, Benjamin J. Steger, Jonathan C. Quirke
*
and Jason M. Belitsky
Received 20th July 2018
Accepted 28th July 2018
Dihydroxyindoles such as 5,6-dihydroxyindole-2-carboxylic acid (DHICA) are the main monomer units of
eumelanin, the black to brown pigment in humans, and have emerging biological roles beyond melanin.
Elaboration of commercially available 5,6-dimethoxy-2-carboxylate ethyl ester provides ready access to
DHICA-inspired small molecules, including 3-(hetero)aryl-indoles and 4,7-di-(hetero)aryl-indoles.
DOI: 10.1039/c8ra06148c
rsc.li/rsc-advances
Eumelanin, the brown to black pigment found in the human Similar structures recently emerged as hits in a large scale
body, has been the subject of investigation for nearly 100 years.1 virtual inhibition screening of inuenza virus RNA-dependent
This natural pigment, comprised of heterogeneous oligomers of RNA polymerase complex (RdRp).19 As DHICA itself is prone
5,6-dihydroxyindoles that vary in both length and oxidation to auto-oxidation,2 we identied 5,6-dimethoxy-2-carboxylate
state, is formed through the oxidative polymerization of tyro- ethyl ester 1 (DMICE) (Fig. 1) as a promising scaffold for the
sine via the catechol L-dopa.2,3 The most abundant monomers generation of DHICA-inspired small molecules.
are 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-
DHICA derivatives have been of interest to synthetic chem-
carboxylic acid (DHICA) (Fig. 1). The oxidative polymerization ists since the 1960's, and have been produced via classical
of dopamine to a DHI-containing material, polydopamine,3,4 organic and biomimetic routes.1 Palladium-catalyzed chem-
has sparked an explosion of interest in the natural pigment and istry, so widely used with other indoles,20 has been applied only
its analogs from the materials science community.5 Natural sporadically toward dihydroxyindoles.10ꢀ13,21 En route to the
eumelanin, synthetic eumelanin derived from L-dopa, and pol- formation of DHI oligomers, d'Ischia and co-workers have
ydopamine are being investigated for a wide variety of applica- investigated Sonogashira couplings.11,12 The Nelson group has
tions from batteries6,7 and organic electronics to water developed a six-step sequence from vanillin to create a 4,7-
purication agents8 to bioadhesives and drug delivery dibromo-DHICA scaffold 3 (Fig. 2b)21 and utilized a Sonogashira
systems.3–5 While the majority of work in this area has focused cross-coupling to elicit promising small molecule building
on the oxidative polymerization of L-dopa, dopamine, and other blocks for organic semiconductors,10 and a polymerizable
catechols,7,9 well-dened small molecule model systems1,2,10–13 monomer.21 This work is of particular interest because DHICA is
can provide insight into these complex and heterogeneous
polymeric systems.
Small molecule models can also help elucidate the natural
functions of free DHICA. It was long thought that free dihy-
droxyindoles were conned to the melanin-producing organelle
known as the melanosome, but there is growing evidence that
DHICA, in particular, has independent biological roles,14
including as a possible natural agonist of GPR35, an orphan G
protein-coupled receptor (GPCR).15 A series of 3-aryl-DHICA
derivatives 2 have been synthesized and tested as GPR35
agonists (Fig. 2a).16 The DHICA scaffold has also drawn interest
for HIV-1 integrase inhibition, with bis- and hyperbranched
DHICA esters showing potential as integrase inhibitors.17,18
Department of Chemistry and Biochemistry, Oberlin College, 119 Woodland St.,
Oberlin, OH 44074, USA. E-mail: Jason.Belitsky@Oberlin.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra06148c
Fig. 1 Eumelanin monomers DHI and DHICA and analog DMICE.
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Fig. 2 Previous synthetic approaches to DHICA/DMICE derivatives.
linked primarily through the 4,7-positions in natural aldehydes (4a) via a Cadogan-type cyclization of intermediates
eumelanin.1,2
(4b) to the indoles (4c), is shown in Fig. 2c. In order to generate
Suzuki cross-coupling with alcohol- and nitrogen-protected potential GPR35 agonists, Deng and Fang used a strategy of
DHICA derivatives was rst reported in 2008 by Huleatt, Chai, halogenation and subsequent palladium-catalyzed coupling
and co-workers.13 These authors developed multiple synthetic (Fig. 2a).16 DMICE (1), obtained from 2-bromo-4,5-dimethoxy-
schemes for the bromination of the 3-, 4- and 7-positions of the benzaldehyde, was regioselectively brominated to 3-bromo-
protected DHICA scaffold utilizing different starting mate- DMICE (5). Suzuki cross-coupling of 5 with ten boronic acids,
rials.22,23 The synthetic route, from commercially available yielded eight 3-aryl derivatives, as well as was 3-pyridin-3-yl and
Scheme 1 Halogenation of 1.
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3-thiophen-3-yl derivatives. Removal of the ethyl and methyl position is more reactive than the 4-position (see ESI†). Triple
groups generated the corresponding 3-aryl-DHICA analogs (2). bromination to 3,4,7-tribromo-DMICE (6) could be readily
Now commercially available, 1 is an attractive scaffold for the achieved with four equivalents of NBS at 65 ꢁC for 24 h. The
generation of DHICA-inspired compounds. We explored the reactivity of the system is such that 4,7-dibromo-DMICE (7) is
halogenation of DMICE and ultimately developed rapid routes not a viable product directly from NBS halogenation. Never-
to both 3- and 4,7-substituted aryl and heteroaryl derivatives theless, 7 could be accessed in a two-step global halogenation/
without the need for protection of the indole nitrogen. Di-aryl/ selective de-halogenation sequence, inspired by the work of
indole trimers and di-heteroaryl/indole trimers are accessible Murakami et al.24 From 6, selective debromination at the 3-
in three steps from DMICE with two purications. The key position is achieved by utilizing m-dimethoxybenzene under
advance toward these trimers was facile global bromination acidic conditions to trap the in situ generated bromine, giving 7
followed by regioselective debromination to selectively func- in a good yield over two steps (Scheme 1).24 The reactivity of the
tionalize the eumelanin-relevant 4,7 positions. Suzuki coupling 3-position also allows for selective iodination with iodine under
of the DMICE scaffold was optimized for 3- and 4,7-halogenated basic conditions to yield 3-iodo-DMICE (8).25
derivatives. Interestingly, 4,7-di-coupling proceeds more readily
The Suzuki cross-coupling conditions were initially opti-
than coupling solely at the 3-position. The optimized mono- mized with 5 and a substantial excess of 4-methoxyphenylbor-
and di-Suzuki couplings proceeded in high yields with both onic acid (Table 1, entry 1) utilizing XPhos Pd G2 as the catalyst
electron-rich and electron-withdrawing substituents on the aryl in a THF/H2O mixture at 50 ꢁC at 4% catalyst loading.26
A
boronic acid partners. We could thus generate a set of reduction in the equivalence of the boronic acid led to
eumelanin-inspired model compounds with a wide range of decreased conversion (entry 2). Switching the halogen from
substituents for future structure–activity relationship studies. bromo-indole 5 to iodo-indole 8 (entry 3) and decreasing the
The modularity, short linear sequences, and substrate tolerance amount of water in the reaction (entry 4) did not improve the
of the synthetic approach suggest that it could ultimately serve conversion. Remaining with 8 and 1.25 equivalents of boronic
as a platform for eumelanin oligomer synthesis. As a rst step acid, the reactivity was improved by switching to dioxane as the
toward that goal and an exploration of DHICA-inspired organic component of majority organic mixture and increasing
compounds beyond the eumelanin context, here we describe the reaction temperature (entry 5). Further decreasing either the
the synthesis of twenty-six aryl- and heteroaryl DMICE deriva- catalyst loading (entry 6) or the equivalence of the boronic acid
tives, twenty-four of which have not been previously reported.
(entry 7) resulted in incomplete conversion. The optimized
The functionalization of 1 began by exploring its reactivity conditions (Table 1, entry 5) improve upon the existing litera-
with N-bromosuccinimide (NBS)16 under a variety of solvent and ture, reducing both the catalyst loading and the equivalence of
temperature conditions. Selective bromination at the 3-position the boronic acid coupling partner.16
occurs rapidly in acetonitrile at room temperature with a single
Having determined the appropriate conditions for the cross-
equivalent of NBS to produce 5 (Scheme 1). With excessꢁNBS at coupling, a series of aryl boronic acids were examined to explore
intermediate times and elevated temperature (2 h, 65 C) 3,7- the scope of the reaction (Table 2). Yields were uniformly good
dibromo-DMICE is the major product, suggesting that the 7- for electron-rich and electron-poor boronic acids as well as the
Table 1 Optimization of Suzuki coupling of 5 and 8a
Entry
X
Boronic acid (eq.)
Conditions
Conversionb
(Yield)c
(94%)
1
2
3
4
Br
Br
I
I
I
2.0
THF/H2O (1 : 1), 50 ꢁ
THF/H2O (1 : 1), 50 ꢁ
THF/H2O (1 : 1), 50 ꢁ
C
C
C
100%
70%
71%
70%
100%
76%
95%
1.25
1.25
1.25
1.25
1.25
1.1
THF/H2O (11 : 1), 50 ꢁ
C
5
Dioxane/H2O (11 : 1), 75 ꢁ
Dioxane/H2O (11 : 1), 75 ꢁ
Dioxane/H2O (11 : 1), 75 ꢁ
C
C
C
(99%)
(94%)
6d
7
I
I
a
Reaction conditions: 5 or 8 (0.04 mmol), 4-methoxyphenylboronic acid (0.044–0.080 mmol), XPhos Pd G2 (0.0016 mmol), K3PO4 (0.18 mmol),
solvent (0.083 M) at 75 ꢁC. b Determined from crude 1H-NMR. c Isolated yield. d XPhos Pd G2 (1 mol%).
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sterically hindered 1-naphthaleneboronic acid. A variety of
heteroatom boronic acids also provided good yields including
the unsubstituted indoles at both the 4- and 6-positions.
However, some heteroaryl boronic acids were unsuccessful
under these conditions. 4-Pyridineboronic acid and 4-pyr-
azoleboronic acid gave no desired product, presumably through
deleterious coordination to the active Pd0 catalyst,27 while 2-
furanboronic acid and 2-thiopheneboronic acid did not react,
possibly as a result of competitive protodeborylation.28 Notably,
9e and 9j were synthesized in higher yields than the previously
reported procedure,16 and the rest of the derivatives are novel
compounds.
Table 2 Substrate scope of Suzuki coupling of 8a
Having shown the efficacy of the Suzuki cross-coupling on
the simpler 3-I-DMICE (8), conditions for a double coupling of
4,7-diBr-DMICE (7) were explored. Upon monitoring the reac-
tion with 4-methoxyphenyl boronic acid under the optimized
conditions for the mono coupling, it became apparent that the
substrate reacted much more rapidly in comparison to 8,
providing a quantitative conversion in 3.5 hours (see ESI, Table
S1†). Standard conditions26 established for the XPhos Pd G2
catalyst also supported a rapid reaction in excellent yield,
particularly with 2.5 equivalents of the boronic acid partner.
With the optimized conditions determined, a set of boronic
acids was analyzed to explore the robustness of the reaction
(Table 3). Again, both electron-rich and electron-poor substrates
performed similarly, with the exception of 4-cyanophenylbor-
onic acid which gave only a modest yield. Sulfur and oxygen-
containing heterocycles also gave good to excellent yields. The
indole trimer (10l) generated in three steps from commercially
available DMICE 1 highlights the ability of this chemistry to
generate model compounds with increasing relevance to
eumelanin.
Having access to 26 DMICE derivatives with a range of aryl/
heteroaryl substituents will allow us to systematically explore
structure–activity relationships using these DHICA-inspired
compounds. As
a preliminary example, the unprotected
indole–nitrogen in these compounds affords a proton in an
1
uncluttered region of their H NMR spectra. Comparing the 3-
aryl series, the chemical shi of this proton is clearly sensitive
to remote substituents on the aryl ring in a Hammett fashion,29
varying from d ¼ 8.74 ppm for the dimethylamino substituent to
d ¼ 9.05 ppm for the cyano substituent (see ESI, Table S2†). The
4,7-aryl series falls in much narrower range of d ¼ 8.64–
8.73 ppm, perhaps indicating that steric interactions with the
70-aryl ring are more signicant than electronic differences of
the remote aryl substituents. The 4,7-heteroaryl series have
chemical shis in a similar range, with the pronounced
exception of 2-benzofuran at d ¼ 10.34 ppm, which is signi-
cantly deshielded compared to 3-furan (d ¼ 8.84 ppm) or 6-
indole (d ¼ 8.72 ppm). This is potentially indicative of an
intramolecular hydrogen bond with the indole NH as the donor
and benzofuran O as the acceptor, although other factors such
as ring current and anisotropy could also be responsible for the
large chemical shi.30
a
Reaction conditions: 8 (0.06 mmol), boronic acid (0.075 mmol), XPhos
Pd G2 (0.0024 mmol), K3PO4 (0.18 mmol), solvent (0.083 M) at 75 ꢁC.
Isolated yields shown.
In summation, regioselective halogenation and de-
halogenation of commercially available DMICE (1) has been
developed, providing access to two different DMICE scaffolds
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Table 3 Substrate scope of Suzuki coupling of 7a
a
Reaction conditions: 7 (0.04 mmol), boronic acid (0.096 mmol), XPhos Pd G2 (0.0016 mmol), 0.5 M K3PO4 (0.17 M), THF (0.17 M) at 50 ꢁC. Isolated
yields shown.
for derivatization. Exploration of additional substitution
patterns (i.e., 3,7-) is ongoing. Successful Suzuki cross-coupling
conditions have been determined for 3-I-DMICE (8) and 4,7-
diBr-DMICE (7) to produce 24 novel eumelanin-inspired
compounds. Examination of the optical properties of these
model compounds is underway. Also, this modular strategy is
currently being explored for the synthesis of eumelanin dimers
and trimers.
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