The chemical reactivities of DOPA and dopamine derivatives and their regioselectivities upon oxidative nucleophilic trapping

Article abstract of DOI:10.1016/j.tet.2016.08.068

The chemical reactivities of four catecholamines, N-acetyl dopamine (NADA) and its dehydro derivative (NAΔDA), N-acetyl 3,4-dihydroxy-phenylalanine methyl ester (NADOPAME) and its dehydro derivative (NAΔDOPAME), under oxidative nucleophilic trapping and p

Full text of DOI:10.1016/j.tet.2016.08.068

Tetrahedron xxx (2016) 1e8
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The chemical reactivities of DOPA and dopamine derivatives and
their regioselectivities upon oxidative nucleophilic trapping
Yong Shung Cheah a, Sridhar Santhanakrishnan a, Michael B. Sullivan b, Koon Gee Neoh c,
,
Christina L.L. Chai a
*
a Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore
b Institute of High Performance Computing, Agency for Science Technology and Research, 1 Fusionopolis Way, #16-16 Connexis, 138632, Singapore
c Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, 117585, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemical reactivities of four catecholamines, N-acetyl dopamine (NADA) and its dehydro derivative
Received 19 May 2016
Received in revised form 9 August 2016
Accepted 23 August 2016
Available online xxx
(NA
(NA
D
DA), N-acetyl 3,4-dihydroxy-phenylalanine methyl ester (NADOPAME) and its dehydro derivative
DDOPAME), under oxidative nucleophilic trapping and polymerisation conditions were compared
and contrasted. Despite their structural similarities, varying reactivities and regioselectivities for oxi-
dative nucleophilic trapping with ethanethiol were observed. This has possible implications on the use of
these natural building blocks and their derivatives in the design and synthesis of biomimetic materials.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Catecholamine
Oxidation
Regioselectivity
Semi-empirical
Polymerisation
1. Introduction
reactivities and selectivities towards nucleophiles, which in turn
may explain how these sclerotizing precursors can lead to materials
Nature is remarkable in its ability to develop various materials
for different functions and properties using seemingly simple
building blocks. Such materials have been a source of inspiration for
the design and synthesis of highly efficient and functional materials
for various applications, e.g., functional coatings that are scratch
resistant, materials for energy storage and so on. One of the most
widely studied biomimetic materials is the material derived from
dopamine (DA), a naturally occurring building block. The many
applications of polydopamine are a source of continual wonder and
have recently been reviewed.1e7 In nature, N-acetyl dopamine
of different hardness and strengths.
DOPA containing proteins have bioadhesive and sclerotizing
functions in a number of invertebrates. In the former, DOPA pro-
teins are known to be present in the attachment tendon of mus-
sels,2 and cements in certain Annelida species.12,13 Their roles as
sclerotizing precursors, e.g., in the egg case of parasitic trematodes,
is responsible for the strength and durability of many structural
materials found in nature.12,14
(NADA) and N-acetyl dehydro dopamine (NADDA) are implicated in
cuticular hardening.8e10 Interestingly, a related catecholamine,
dehydro 3,4-dihydroxy-phenylalanine is also a potential sclerotiz-
ing intermediate with its origin from L-3,4-dihydroxy-phenylala-
nine (L-DOPA).11 Nature is ‘economic’ in this regard as these
structurally related sclerotizing precursors can be derived from
a common precursor tyrosine, and yet each gives rise to cuticles
that have different hardness and colors.8 This raises the interesting
question as to how these catechols are different in terms of their
The oxidation chemistry of NADA15e18 and NA
been studied while that of NADOPAME23 and NA
D
D
DA19e22 has
DOPAME23 is
less explored. Despite these reports, the oxidation chemistry of
these catecholamines cannot be easily compared in view of the
varying conditions reported. Our interests stem from the desire
* Corresponding author. Fax: þ65 6779 1554; e-mail address: phacllc@nus.edu.sg
(C.L.L. Chai).
http://dx.doi.org/10.1016/j.tet.2016.08.068
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
Y.S. Cheah et al. / Tetrahedron xxx (2016) 1e8
to understand the chemistry of these catecholamines with the
future goal of exploiting this in biomimetic material engineering.
In this study, the reactivities of the four catecholamines towards
oxidation, followed by nucleophilic trapping by ethanethiol are
compared. The ease of polymerisation of these catecholamines
under oxidative conditions was also investigated.
which is the characteristic of a quinone methide22 e this quinone
methide imine amide is relatively unstable and decays rapidly over
a 60-minute period. The formation of the quinone methide imine
amide from the ortho-quinone of NA
DDA has been reported as
a rapid enzymatic22 as well as a chemical mediated isomerisation.20
The analogous quinone methide imine amide of NA
not observed. Schemes 1 and 2.
DDOPAME was
In the oxidative nucleophilic trapping studies with NADOPAME,
NADA and NA DOPAME using silver oxide as the oxidant and
2. Results and discussion
D
ethanethiol as the nucleophile, a small amount of the starting
catechol and the di-substituted adducts were isolated (Schemes 1
and 2). According to Huang et al., the oxidation potentials of
NADA, its mono-substituted adduct, and its di-substituted adduct
decrease in order of increasing substitution.16 Hence, the observa-
tion above is believed to arise from the re-oxidation of the mono-
substituted adduct by the intermediate catecholamine quinones,
followed by a second nucleophilic substitution onto the quinone of
the mono substituted adduct. To prove this, 1 equiv of 5-SEt NADA
adduct (6) was added to freshly prepared NADA quinone in deu-
terated acetone. An immediate colour change was observed and the
1H NMR spectrum of the reaction mixture after 3 min showed the
presence of NADA (2) and 5-SEt NADA quinone. This is consistent
with the notion of the redox reaction as shown in Scheme 3 and
potentially explains the similar observations for the other three
derivatives.
2.1. Oxidative nucleophilic trapping studies of
catecholamines
Our initial studies examined the oxidation of the catechol-
amines using three chemical oxidants, followed by in situ trapping
with five equiv of ethanethiol. Oxidation of the catecholamines
using sodium periodate was first attempted. Although this gave
nearly full conversion to quinone (for NADOPAME and NADA as
shown by NMR spectroscopy), the subsequent nucleophilic trap-
ping by ethanethiol led to the formation of multiple products which
could not be readily separated. In contrast, the use of silver oxide
and DDQ as oxidants followed by trapping with ethanethiol gave
cleaner reaction mixtures. Of the two oxidants, the use of silver
oxide is more convenient as the oxidant can be filtered off prior to
the addition of the nucleophile. This avoids complications associ-
ated with the presence of residual oxidants which may interfere in
the oxidative nucleophilic trapping studies. The results are sum-
marised in Table 1.
2.2. Semi-empirical calculations for predictions of
regioselectivity
To rationalise the observed regioselectivities, attempts were
made to identify the intermediates from oxidation. Thus, oxidation
of each of the four catecholamines using silver oxide as oxidant was
studied via spectrophotometric means (see ESD). For NADOPAME,
The semi-empirical method PM626 was used to calculate the
LUMO coefficients of the atoms of both the ortho-quinone and the
quinone methide or quinone methide imine amide for each of the
catecholamines as summarised in Table 2 using Gaussian09.27 In
the case of NADOPAME quinone and NADA quinone, the size of the
LUMO orbital coefficients are in the order of decreasing size, i.e., C-
NADA and NADDOPAME, the ortho-quinone was formed as evi-
denced by an absorption maximum of ca. 400 nm, as reported by
others.20,24,25 This ortho-quinone is relatively stable over 60 min. In
the case of NADDA, the absorption maximum occurs at 485 nm
Table 1
Reaction conditions, ratio and yields for DOPA and DA derivatives under different oxidation conditions followed by addition of 5 equiv of ethanethiol
Catechol derivatives
Reaction conditionsa
Ratio of compounds and isolated yield (recovered SM)
NADOPAME (1)
5 eq. Ag2O, acetone, RT, 30 m
1.2 eq. DDQ, THF, ꢀ40 ꢁC, 1 h
5 eq. Ag2O, acetone, RT, 30 m
1.2 eq. DDQ, THF, ꢀ40 ꢁC, 1 h
5 eq. Ag2O, acetone, RT, 30 m
1.2 eq. DDQ, THF, ꢀ40 ꢁC, 1 h
5 eq. Ag2O, acetone, RT, 10 m
1.2 eq. DDQ, THF, ꢀ40 ꢁC, 1 h
1 eq. Ag2O, MeOH, RT, 1 hb
5:7¼2:1, 80%, 9¼7% (1¼10%)
5:7¼2:1, 81% (1¼7%)
NADA (2)
6:8¼7:1, 70%, 10¼3% (2¼3%)
6:8¼6:1, 72%, 10¼1% (2¼4%)
11:12¼1:5, 18%, 13¼2% (3¼8%)
11:12¼3:7, 86% (3¼13%)
14:15:17:18¼1:2:2:3, 8% (4¼35%)
16:17:18¼3:2:3, 8%
NA
NA
D
D
DOPAME (3)
DA (4)
18¼40%
a
Ethanethiol was added after the specified time.
In the absence of ethanethiol, SM¼starting material.
b
Scheme 1. Oxidative nucleophilic trapping studies with NADA and NADOPAME.
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Y.S. Cheah et al. / Tetrahedron xxx (2016) 1e8
3
Scheme 2. Oxidative nucleophilic trapping studies with NADDA and NADDOPAME.
Table 2
LUMO coefficients of quinones and quinone methides calculated using PM6
Atom
NADOPAME (1)
NADA (2)
Quinone
QM
Quinone
QM
Scheme 3. Redox reaction between NADA quinone and its adduct.
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
0.38
ꢀ0.23
ꢀ0.21
0.22
0.35
0.25
0.37
ꢀ0.27
ꢀ0.24
0.30
0.36
0.30
ꢀ0.34
ꢀ0.32
ꢀ0.32
ꢀ0.35
0.35
ꢀ0.32
ꢀ0.32
ꢀ0.33
ꢀ0.35
0.36
1>C-6wC-5>C-2 and C-1>C-6>C-5>C-2, respectively. The differ-
ences in the size of the orbital coefficients between C-2 and C-5 are
slightly larger for NADA quinone than that for NADOPAME quinone
which is consistent with the improved selectivity as tabulated in
Table 1. However it should be noted that of the three available
positions of attack, C-6 has the highest orbital coefficient for both
ꢀ0.35
ꢀ0.38
ꢀ0.02
0.41
ꢀ0.01
0.47
0.06
0.06
0.05
ꢀ0.04
the quinones of NADA and NA
ducts were observed in our studies. In contrast with NADOPAME
and NADA, the C-2 of NA DOPAME quinone has the largest LUMO
DDOPAME but no C-6 addition ad-
D
coefficient and this is consistent with the observation that the
major adduct arises from addition of ethanethiol to the C-2 posi-
tion. From the spectrophotometric studies above, the quinone
methide imine amide of NADDA is the major intermediate from the
oxidation reaction. Considering the orbital coefficients of this, the
largest LUMO coefficient resides on the C-7 carbon. This is also
consistent with experimental observations in which the formation
Atom
NA
D
DOPAME (3)
NADDA (4)
Quinone
QMIM
Quinone
QMIM
of adducts 17 and 18 is only observed with NADDA.
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
ꢀ0.38
0.41
0.30
0.25
0.29
ꢀ0.26
ꢀ0.23
0.31
ꢀ0.35
ꢀ0.19
0.28
0.35
0.27
0.38
ꢀ0.32
ꢀ0.20
0.26
0.35
0.29
ꢀ0.35
ꢀ0.32
ꢀ0.31
ꢀ0.34
0.34
0.08
ꢀ0.28
2.3. Oxidative polymerisation reactions of catecholamines
In order to examine the reactivity of each of the catecholamines
under oxidative conditions, we examined the spectral changes of
each compound upon oxidation with sodium periodate. Consistent
with studies with silver oxide as the oxidant, the intermediates
ꢀ0.33
ꢀ0.34
0.40
0.42
0.25
0.25
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4
Y.S. Cheah et al. / Tetrahedron xxx (2016) 1e8
ortho-quinone
(
lmaxw400 nm) and/or quinone methide
within 2 min of formation. From these studies, the relative re-
activities of the oxidation intermediates can be identified as NA DA
DOPAME quinone>NADA
(lmaxw485 nm) are observed for NADOPAME, NADA, NA
D
DOPAME
D
and NA
DDA, respectively (Fig. 1).
quinone methide imine amide>NA
quinonezNADOPAME quinone.
D
From these curves, the kinetics of the depletion of these in-
termediates can be delineated. The UV studies suggest that NA
DOPAME quinone has shorter half-life as compared to
D
The products of oxidation with sodium periodate were analysed
by MALDI-TOF-TOF MS after 24 h. A dark brown suspension was
a
NADOPAME and NADA quinones. A separate study was carried out
using in situ 1H NMR monitoring at a concentration of 10 mM of the
derivatives in D2O, in the presence of 1 equiv of sodium periodate
(for an example, see Fig. 2a). The NMR studies confirmed the
identity of the ortho-quinones, and the disappearance of the qui-
none was measured relative to an internal standard i.e., DMSO.
Our studies show that the formation of all the ortho-quinones of
observed for the polymerisation of NA
white suspension was obtained for NA
D
DOPAME while a milky
DDA. In contrast, no pre-
cipitate was observed in the polymerisation of NADOPAME and
NADA and a clear reddish brown solution was observed instead. In
cases where solids are formed, water was replaced with DMF to
solubilize the solids formed, and filtered prior to analysis. Only the
solids formed from DOPA and DA polymerisation did not fully
dissolve in water and DMF or a mixture of both. The results are
summarised in Table 3. In the analysis, the most prominent peak
shown in the MALDI-TOF-TOF mass chromatogram was identified
to be the most abundant ‘oligomer’ comprising 3 to 6 monomer
units.
As the initial concentration of the monomers in the oxidative
polymerisation is constant, the comparison of the amount of olig-
omer can be made based on the intensity of the signals shown in
the MALDI-TOF-TOF MS analysis. The polymerisation of dopamine
and DOPA afforded the most amount of oligomers. This is followed
NADA, NADOPAME and NADDOPAME occur very rapidly, i.e., within
3 min upon addition of the oxidant (the limit of 1H NMR moni-
toring). For both NADA and NADOPAME, after an initial drop of the
amounts of starting material to ca. 10%, with prolonged reaction
time, the amounts of NADA and NADOPAME increased suggesting
that a redox reaction has occurred between the cross-linked adduct
and quinone that has regenerated the starting catecholamines
(Fig. 2b). This phenomenon is depicted in Scheme 3. At 30 min, the
amount of NADA was found to be 35% while NADOPAME was
formed to a lesser extent, i.e., 19%. In the case of NADDOPAME(data
not shown), only 50% of the quinone remained after ca. 3 min (with
little or no starting catecholamine remaining) suggesting that the
quinone had reacted more rapidly as compared to that of NADA and
NADOPAME. This is also consistent with the observation of multiple
signals in the 1H NMR spectrum which signifies the formation of
by NADDOPAME and NADDA while polymerisation of NADA and
NADOPAME gave the lowest amount of oligomers. This is consistent
with the observations that quinone intermediates that are more
reactive lead to more oligomers.
In view of the interests in the use of polydopamine as coating
materials, we also investigated the coating abilities of NADOPAME
multiple adducts. In the case of NA
DDA oxidation monitored via
UV-Vis spectroscopy, we observed a rapid isomerisation of the
and NA
the coatings resulting from treatment of the catecholamines with
1 equiv of sodium periodate show that both NADOPAME and NA
DOPAME are not able to coat on silicon wafer after oxidation. In
DDOPAME onto silicon wafer as substrate. AFM analysis of
ortho-quinone from NA
(
D
DA (lmax¼400 nm) to quinone methide
lmax¼485 nm) at neutral pH as was reported by Sugumaran et al.19
D
The quinone methide imine amide was completely consumed
Fig. 1. Ultraviolet-visible spectral changes of (a) 0.2 mM NADOPAME (1), (b) 0.2 mM NADA (2), (c) 0.1 mM NADDOPAME (3), (d) 0.1 mM NADDA (4) associated with 1 equiv of NaIO4-
induced oxidation in water over 24 h. (Broken lines represent the starting materials’ spectra and arrows indicate the spectral change over time).
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Y.S. Cheah et al. / Tetrahedron xxx (2016) 1e8
5
slightly larger difference in the orbital coefficients between C-5 and
C-2 in NADA quinone as compared to NADOPAME quinone.
However when considering PM6 calculations, the C-6 position
for NADA quinone is larger than that of C-5 and C-2 while that for C-
6 of NADOPAME quinone is comparable in size to C-5. Despite this,
C6 addition adducts were not detectable in our studies, although
the use of thiourea and nitrogen nucleophiles such as histidine in
oxidative nucleophilic trapping experiments have been reported to
give C-6 adducts as major products of reaction.16e18 Huang et al.
have attributed this to intramolecular base catalysis effects16 but as
discussed by Branco et al., this does not explain the differential
regioselectivity at C2 and C5 positions.18 What is evident is that the
trapping by thiols such as ethanethiol is very rapid while trapping
by nitrogen nucleophiles and thiourea are known to be much
slower. The presence of unsaturation in both NADA and NADOPAME
gives rise to more reactive oxidation intermediates than the cor-
responding saturated systems. Intriguingly, the quinone of NADDA
rapidly isomerises to the quinone methide imine amide which is
highly reactive and nucleophilic trapping occurs predominantly at
the
of NA
trapping of the quinone of NA
b
-positions i.e., the side chain. In contrast, the quinone methide
DOPAME is not observed in our experiments, and thiol
DOPAME favours C-2 ring addition
D
D
over C-5 ring addition. The latter is consistent with predictions
based on orbital coefficients from PM6 calculations.
The oxidative polymerisation studies of the four catecholamines
were compared to that of dopamine and DOPA. In all the cases,
oligomers ranging from 3 to 6 repeating units are detected in the
MALDI-TOF-TOF-MS with DA and DOPA giving the highest amount
of oligomers. This suggests that the presence of a free amine in the
catecholamines is critical for efficient oxidative polymerisation
reactions. This is also evident from the unsuccessful attempts to
coat silicon wafers with NADOPAME and NADDOPAME as com-
pared to DA and DOPA under sodium periodate oxidative
conditions.
Fig. 2. (a)1H NMR spectra monitoring of the oxidation of 10 mM NADOPAME with
1 equiv of NaIO4 in D2O (DMSO as the internal standard) for 2 h. (b) 1H NMR moni-
toring of the amounts of NADA and NADOPAME (SM) and their respective quinones (Q)
upon oxidation with NaIO4 quantified by integration relative to an internal standard,
DMSO.
3. Conclusions
The comparative chemical reactivity studies with the four cat-
echolamines under oxidative nucleophilic/polymerisation condi-
tions demonstrate the economy of nature’s building blocks.
Although the catecholamines are structurally very similar, the re-
activities and regioselectivities can vary under similar reaction
conditions, leading to different adducts/polymers. It is anticipated
that the positional isomers of adducts or polymers will have dif-
ferent properties due to the crosslinking and overall stacking of the
repeating units, affecting bulk properties of these materials. In this
context, one should be able to exploit these chemistries in de-
signing biomimetic functional materials as well as tune the prop-
erties of the materials through judicious choice of catecholamines,
conditions and nucleophiles.
Table 3
Molecular mass for the most prominent peak of each catecholamine derivatives with
their signal intensity, using MALDI-TOF-TOF MS analysis, after oxidation with
1 equiv of NaIO4 for 24 h
Monomers
Mass (monomer unitsa) Signal intensity (approx.)
Dopamine hydrochloride 877.0753 (w6)
DOPA
NADOPAME (1)
NADA (2)
66000
13000
900
1072.0661 (w5)
810.2063 (w3)
1020.3808 (w5)
1078.1127 (w4)
1078.1210 (w6)
1400
5200
4400
NA
NA
D
D
DOPAME (3)
DA (4)
a
Monomer units¼Mass/Mw of a monomer.
contrast, both DA and DOPA gave uneven coatings with 10e20 nm
thickness under similar conditions (results not shown).
4. Experimental
The four catecholamines are important precursors in oxidative
polymerisation reactions, which have relevance in the context of
structural materials, bioadhesives and even neurodegenerative
diseases. It is especially of interest to note that seemingly similar
catecholamines can give different reaction outcomes depending on
the conditions and nucleophiles present. Our study on the chemical
reactivities of these four catecholamines in oxidative nucleophilic
trapping with thiols shows that the regiochemical outcomes of
trapping can be significantly different. For example, the presence of
a carboxymethyl group in NADOPAME as compared to that of NADA
can affect the regioselectivity of thiol addition onto the quinone
resulting in decreased regioselectivity. This is reflected in the
4.1. Materials and methods
NADA,28 NA DA,29e31 NADOPAME32,33 and NA DOPAME34
D D
were synthesised following reported literature procedures. All
other reagents and solvents were purchased from Sigma Aldrich or
Alfa Aesar and were used without further purification unless oth-
erwise specified. Silver(I) oxide was freshly prepared by adding
1 equiv of silver nitrate solution to a solution of sodium hydroxide.
Reactions involving air or moisture sensitive reagents were per-
formed with dried glassware under a nitrogen atmosphere. Thin
layer chromatography (TLC) was performed on Merck precoated
silica gel plates. Visualization was accomplished with UV light.
Compounds were purified by flash chromatography on a column
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6
Y.S. Cheah et al. / Tetrahedron xxx (2016) 1e8
using Merck silica gel 60 (230e400 mesh) or semi-preparative
J¼13.5, 8.8 Hz, 1H), 2.85 (q, 2H), 2.77 (m, 2H), 1.90 (s, 3H), 1.24 (t,
3H), 1.18 (t, 3H). 13C NMR (101 MHz, CD3OD)
173.8, 173.0, 147.9,
144.5, 133.0, 124.9, 123.6, 119.8, 54.9, 52.6, 37.1, 30.3, 28.3, 22.3, 15.0,
14.9. HRMS (ESI): m/z calcd for C16H23NNaO5S2 [MþNa]þ 396.0910,
found 396.0921.
reversed-phase HPLC/PDA method using GeminiÒ
5
m
m C18
d
ꢀ
110 A, LC Column 150ꢂ10 mm. Mass spectra were recorded on an
Applied Biosystems MDS SCIEX API 2000 mass spectrometer. High
resolution mass spectra (HRMS) were recorded on an Agilent Mass
spectrometer or Bruker micrOTOFQII using ESI-TOF (electrospray
ionization-time of flight). NMR spectra were recorded on a Bruker
Avance III 400 MHz spectrometer at 400 MHz for 1H and at
100 MHz for 13C on a Bruker spectrometer with methanol-d4 or
acetone-d6 as solvent. The chemical shifts are given in ppm, using
4.3.4. N-(3-(Ethylthio)-4,5-dihydroxyphenethyl)acetamide (6). Oil;
Rf (10% CH3OH/CH2Cl2) 0.31; nmax (liquid film) 3299 (br), 2928,1631,
1428, 1372 cmꢀ1
;
1H NMR (400 MHz, CD3OD)
d
6.69 (d, J¼2.0 Hz,
1H), 6.60 (d, J¼2.0 Hz,1H), 3.33 (t, 2H), 2.82 (q, 2H), 2.62 (t, 2H),1.90
(s, 3H), 1.22 (t, 3H). 13C NMR (101 MHz, CD3OD)
173.2, 146.3, 144.7,
the proton solvent residue signal (CD3OD:
d
3.31, acetone-d6:
d
2.05)
d
as a reference in the 1H NMR spectrum. The deuterium coupled
132.0,125.0,122.0,116.3, 42.2, 35.8, 29.0, 22.5,15.0. HRMS (ESI): m/z
signal of the solvent was used as a reference in 13C NMR (CD3OD:
calcd for C12H17NNaO3S [MþNa]þ 278.0821, found 278.0823.
d
49.00). The following abbreviations were used to describe the
signals: s¼singlet, d¼doublet, t¼triplet, m¼multiplet, q¼quartet.
IR spectra were recorded on a PerkineElmer Spectrum 100 FTIR
spectrometer.
4.3.5. N-(2-(Ethylthio)-3,4-dihydroxyphenethyl)acetamide (8). Oil;
Rf (10% CH3OH/CH2Cl2) 0.34; nmax(liquid film) 3299 (br), 2927, 1627,
1554, 1480, 1426 cmꢀ1 1H NMR (400 MHz, CD3OD)
; d 6.74 (d,
J¼8.2 Hz, 1H), 6.65 (d, J¼8.2 Hz, 1H), 3.37e3.30 (m, 2H), 2.99e2.93
4.2. General procedure for oxidation nucleophilic trapping
study
(m, 2H), 2.76 (q, 2H), 1.90 (s, 3H), 1.17 (t, 3H). 13C NMR (101 MHz,
CD3OD)
d 173.3, 148.0, 144.7, 135.5, 121.6, 120.4, 116.8, 42.1, 34.8,
30.1, 22.6, 14.9. HRMS (ESI): m/z calcd for C12H17NNaO3S [MþNa]þ
5 equiv of Ag2O were added to a stirred solution of catechol-
amines in acetone at room temperature. After 30 min (10 min for
278.0821, found 278.0814.
NA
DDA), Ag2O was removed from the yellow reaction mixture via
4.3.6. N-(2,5-Bis(ethylthio)-3,4-dihydroxyphenethyl)aceta-mide
filtration. To the filtrate, 5 equiv of ethanethiol were added. Stirring
was continued for 1 h and then the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (5% MeOH/DCM) and/or semi-preparative re-
versed-phase HPLC/PDA method. All the purified compounds are
brown oil unless specified otherwise.
1.2 equiv of DDQ were added to a solution of catecholamines in
dry THF at ꢀ40 ꢁC under nitrogen. The reaction mixture was stirred
at ꢀ40 ꢁC for 1 h and then 5 equiv of ethanethiol were added.
Stirring was continued at same temperature for 1 h and at room
temperature for 2.5 h. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(5% MeOH/DCM) and/or semi-preparative reversed-phase HPLC/
PDA method.
(10). Oil; Rf (10% CH3OH/CH2Cl2) 0.42; nmax (liquid film) 3323 (br),
2961, 2927, 1643, 1448, 1374, 1269 cmꢀ1 1H NMR (400 MHz,
;
CD3OD)
(q, 2H), 2.75 (q, 2H), 1.91 (s, 3H), 1.25 (t, 3H), 1.17 (t, 3H). 13C NMR
(101 MHz, CD3OD) 173.2, 147.8, 143.9, 135.5, 124.2, 124.0, 119.3,
d 6.78 (s, 1H), 3.37e3.32 (m, 2H), 2.99e2.94 (m, 2H), 2.87
d
42.0, 34.8, 30.3, 28.2, 22.6, 14.9 (2C). HRMS (ESI): m/z calcd for
C
14H21NNaO3S2[MþNa]þ 338.0855, found 338.0854.
4.3.7. Methyl (Z)-2-acetamido-3-(3-(ethylthio)-4,5-dihydroxy-phe-
nyl)acrylate (11). Oil; Rf (10% CH3OH/CH2Cl2) 0.31; nmax (liquid
film) 3318 (br), 2955, 2927, 1705, 1664, 1484, 1436 cmꢀ1 1H
;
NMR (400 MHz, CD3OD)
(d, J¼1.9 Hz, 1H), 3.79 (s, 3H), 2.86 (q, 2H), 2.13 (s, 3H), 1.24 (t,
3H). 13C NMR (101 MHz, CD3OD)
173.3, 167.4, 148.3, 146.2,
d
7.31 (s, 1H), 7.13 (d, J¼1.9 Hz, 1H), 7.06
d
136.3, 127.2, 126.3, 124.0, 123.0, 116.7, 52.8, 28.5, 22.6, 14.9.
HRMS (ESI): m/z calcd for C14H17NNaO5S [MþNa]þ 334.0720,
found 334.0717.
4.3. Characterisation of adducts
4.3.1. Methyl (S)-2-acetamido-3-(3-(ethylthio)-4,5-dihydroxy-phe-
nyl)propanoate (5). Oil; Rf (10% CH3OH/CH2Cl2) 0.39; nmax (liquid
4.3.8. Methyl (Z)-2-acetamido-3-(2-(ethylthio)-3,4-dihydroxy-phe-
film) 3349 (br), 2960, 1735, 1649, 1430, 1364, 1220 cmꢀ1
;
1H NMR
nyl)acrylate (12). Oil; Rf (10% CH3OH/CH2Cl2) 0.34; nmax (liquid film)
(400 MHz, CD3OD)
d
6.66 (d, J¼2.0 Hz, 1H), 6.58 (d, J¼2.0 Hz, 1H),
3369 (br), 1701, 1636, 1437, 1364, 1231 cmꢀ1 1H NMR (400 MHz,
;
4.58 (dd, J¼8.4, 5.9 Hz,1H), 3.69 (s, 3H), 2.97 (dd, J¼13.9, 5.9 Hz,1H),
CD3OD)
3.81 (s, 3H), 2.76 (q, 2H), 2.04 (s, 3H),1.16 (t, 3H). 13C NMR (101 MHz,
CD3OD) 173.2, 167.6, 148.2, 147.6, 134.8, 129.9, 125.5, 122.3, 122.2,
d
7.97 (s, 1H), 7.11 (d, J¼8.4 Hz, 1H), 6.82 (d, J¼8.4 Hz, 1H),
2.88e2.72 (m, 3H), 1.92 (s, 3H), 1.21 (t, 3H). 13C NMR (101 MHz,
CD3OD)
d
173.6, 173.1, 146.3, 145.2, 129.4, 125.4, 122.1, 116.6, 55.5,
d
52.7, 37.8, 28.9, 22.3, 15.0. HRMS (ESI): m/z calcd for C14H19NNaO5S
116.6, 52.9, 30.5, 22.4, 15.1. HRMS (ESI): m/z calcd for C14H18NO5S
[MþNa]þ 336.0876, found 336.0878.
[MþH]þ 312.0901, found 312.0896.
4.3.2. Methyl (S)-2-acetamido-3-(2-(ethylthio)-3,4-dihydroxy-phe-
4.3.9. Methyl (Z)-2-acetamido-3-(2,5-bis(ethylthio)-3,4-dihy-drox-
nyl)propanoate (7). Oil; Rf (10% CH3OH/CH2Cl2) 0.43; nmax (liquid
yphenyl)acrylate (13). Oil; Rf (10% CH3OH/CH2Cl2) 0.41; nmax (liquid
film) 3355 (br), 2957, 1732, 1647, 1428, 1372, 1219 cmꢀ1
;
1H NMR
film) 3324 (br), 2957, 2924, 1708, 1665, 1436, 1228 cmꢀ1 1H NMR
;
(400 MHz, CD3OD)
d
6.71 (d, J¼8.0 Hz, 1H), 6.58 (d, J¼8.0 Hz, 1H),
(400 MHz, CD3OD)
2H), 2.74 (q, 2H), 2.05 (s, 3H), 1.27 (t, 3H), 1.16 (t, 3H). 13C NMR
(101 MHz, CD3OD) 173.1, 167.4, 147.8, 146.4, 134.6, 129.9, 125.8,
d 7.96 (s, 1H), 7.22 (s, 1H), 3.82 (s, 3H), 2.86 (q,
4.67 (dd, J¼8.6, 6.6 Hz,1H), 3.64 (s, 3H), 3.33e3.36 (m,1H), 3.05 (dd,
J¼13.5, 8.6 Hz, 1H), 2.78 (m, 2H), 1.90 (s, 3H), 1.17 (t, 3H). 13C NMR
d
(101 MHz, CD3OD)
d
173.9, 173.1, 148.2, 145.3, 132.9, 122.3, 120.8,
124.5, 123.7, 120.7, 52.9, 30.8, 27.9, 22.5, 15.1, 15.0. HRMS (ESI): m/z
116.5, 55.1, 52.5, 37.2, 30.1, 22.3, 14.9. HRMS (ESI): m/z calcd for
calcd for C16H21NNaO5S2[MþNa]þ 394.0753, found 394.0756.
C
14H19NNaO5S [MþNa]þ 336.0876, found 336.0880.
4.3.10. (E)-N-(3-(Ethylthio)-4,5-dihydroxystyryl)acetamide
4.3.3. Methyl (S)-2-acetamido-3-(2,5-bis(ethylthio)-3,4-dihy-drox-
yphenyl)propanoate (9). Oil; Rf (10% CH3OH/CH2Cl2) 0.50; nmax
(liquid film) 3351 (br), 2960, 2938, 1737, 1657, 1436, 1371,
(14). Oil; Rf (10% CH3OH/CH2Cl2) 0.27; nmax (liquid film) 3340 (br),
2962, 1636, 1260 cmꢀ1 1H NMR (400 MHz, CD3OD)
; d 7.24 (d,
J¼14.7 Hz, 1H), 6.77 (d, J¼1.8 Hz, 1H), 6.75 (d, J¼1.8 Hz, 1H), 6.03 (d,
1227 cmꢀ1
;
1H NMR (400 MHz, CD3OD)
d
6.74 (s, 1H), 4.70 (dd,
J¼14.7 Hz, 1H), 2.83 (q, 2H), 2.03 (s, 3H), 1.23 (t, 3H). 13C NMR
J¼8.8, 6.3 Hz,1H), 3.66 (s, 3H), 3.37 (dd, J¼13.5, 6.3 Hz,1H), 3.03 (dd,
(101 MHz, CD3OD)
d 170.7, 146.5, 145.5, 129.8, 122.7, 122.4, 122.2,
Please cite this article in press as: Cheah, Y. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.068

Y.S. Cheah et al. / Tetrahedron xxx (2016) 1e8
7
114.3, 112.3, 28.9, 22.5, 14.9. HRMS (ESI): m/z calcd for
C
with 0.2 mM of DMSO as an internal standard) at room temperature
in NMR tubes. An equal volume of 1 equiv of NaIO4 in D2O was
added to a solution of 20 mM of catecholamine derivatives. Sub-
sequently, the samples were analysed by 1H NMR spectroscopy at
various time points (3, 5, 10, 20, 30, 60, 120 min).
12H15NNaO3S [MþNa]þ 276.0665, found 276.0659.
4.3.11. (E)-N-(2-(Ethylthio)-3,4-dihydroxystyryl)acetamide (15). Oil;
Rf (10% CH3OH/CH2Cl2) 0.30; nmax (liquid film) 3360 (br), 2916,
2850, 1656, 1633, 1470, 1418 cmꢀ1 1H NMR (400 MHz, CD3OD)
;
d
7.26 (d, J¼14.7 Hz, 1H), 6.95 (d, J¼8.4 Hz, 1H), 6.87 (d, J¼14.7 Hz,
4.5.3. MALDI-TOF-TOF-MS. Oxidation of catecholamine derivatives
was carried out by mixing 0.5 ml of 20 mM monomers in water
with 0.5 ml of 20 mM NaIO4 in water. The reaction mixtures were
stirred for 24 h at room temperature and filtered. Those mixtures
with suspended solids were reconstituted with 1 ml of DMF prior to
1H), 6.77 (d, J¼8.4 Hz, 1H), 2.69 (q, 2H), 2.04 (s, 3H), 1.14 (t, 3H).
HRMS (ESI): m/z calcd for C12H15NNaO3S [MþNa]þ 276.0665, found
276.0668.
4.3.12. (E)-N-(2,5-Bis(ethylthio)-3,4-dihydroxystyryl)aceta-mide
the filtration. 0.5
mL of the filtrates was spotted on a 384 well target
(16). Oil; Rf (10% CH3OH/CH2Cl2) 0.40; nmax (liquid film) 3340 (br),
plate and crystallized with 0.5
m
L of -cyano-4-hydroxycinnamic
a
2962, 2922, 1635, 1260 cmꢀ1; 1H NMR (400 MHz, CD3OD)
d
7.28 (d,
acid (CHCA) in 0.1% (v/v) Trifluoroacetic Acid (TFA) and 50% (v/v)
Acetonitrile (ACN), which were subsequently subjected to MALDI-
TOF/TOF mass analysis (4800 MALDI TOF/TOF Analyzer from Ap-
plied Biosystems, Framingham, MA, USA). The m/z data was man-
ually acquired in the reflector mode by using the Reflectron Method
(Accelerating Voltage: 20000V, Laser Intensity: 3300e3600).
J¼14.7 Hz, 1H), 7.04 (s, 1H), 6.84 (d, J¼14.7 Hz, 1H), 2.91 (q, J¼7.4 Hz,
2H), 2.68 (q, 2H), 2.05 (s, 3H), 1.27 (t, 3H), 1.14 (t, 3H). 13C NMR
(101 MHz, CD3OD)
d 170.7, 147.6, 143.9, 133.4, 125.0, 123.6, 119.0,
117.7, 113.1, 30.4, 28.0, 22.6, 14.9, 14.8. HRMS (ESI): m/z calcd for
C
14H19NNaO3S2[MþNa]þ 336.0699, found 336.0694.
4.3.13. N-(1,2-Bis(ethylthio)-2-(3-(ethylthio)-4,5-dihydroxy-phenyl)
4.6. Coating studies
ethyl)acetamide (17). Oil; Rf (10% CH3OH/CH2Cl2) 0.50; nmax (liquid
film) 3260 (br), 2969, 2928, 1655, 1583, 1421 cmꢀ1 1H NMR
;
The substrate silicon wafer (size: 10 mmꢂ10 mm), was im-
mersed in 1.5 ml of reaction mixture consisting of 10 mM mono-
mers and in water for 24 h at room temperature. Subsequently, they
were subjected to AFM analysis. The characterization was carried
out on Bruker Dimension ICON.
(400 MHz, CD3OD)
d
6.83 (d, J¼2.1 Hz, 1H), 6.80 (d, J¼2.1 Hz, 1H),
5.34 (d, J¼8.8 Hz, 1H), 3.97 (d, J¼8.8 Hz, 1H), 2.83 (q, 2H), 2.54e2.26
(m, 4H), 1.99 (s, 3H), 1.27e1.08 (m, 9H). 13C NMR (101 MHz, CD3OD)
d
172.7, 146.2, 145.8, 131.9, 125.4, 121.7, 116.0, 59.2, 55.2, 28.8, 26.3,
25.9, 22.5, 15.2, 15.0, 14.8. HRMS (ESI): m/z calcd for
C
16H25NNaO3S3[MþNa]þ 398.0889, found 398.0887.
Acknowledgements
4.3.14. (E)-N-(2-(2-Acetamido-3-(3,4-dihydroxyphe-nyl)-2,3-dihy-
drobenzo[b][1,4]dioxin-6-yl)vinyl)acetamide (18). 1 equiv of Ag2O
was added to a stirred solution of NADDA in methanol at room
We thank SERC-A*STAR for financial support of this project
(Project no: 1321202069). The work by MBS was supported by the
A*STAR Computational Resource Centre through the use of its high
performance computing facilities.
temperature. After 1 h, Ag2O was removed from the yellow reaction
mixture via filtration. The residue was purified by silica gel column
chromatography (5% MeOH/DCM) to yield 40% of 18 as a solid. Mp
182e184 ꢁC; Rf (10% CH3OH/CH2Cl2) 0.23; nmax (liquid film) 3265,
Supplementary data
2924, 1642, 1498, 1371, 1260 cmꢀ1 1H NMR (400 MHz, CD3OD)
;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.08.068.
d
7.30 (d, J¼14.7 Hz, 1H), 6.92e6.70 (m, 6H), 6.10 (d, J¼14.7 Hz, 1H),
5.69 (d, J¼7.2 Hz,1H), 4.71 (d, J¼7.2 Hz,1H), 2.03 (s, 3H),1.87 (s, 3H).
13C NMR (101 MHz, CD3OD)
173.2, 170.6, 147.2, 146.5, 144.6, 142.6,
d
References and notes
131.9, 128.7, 122.1120.6, 120.3, 118.2, 116.1, 115.6, 114.7, 114.0, 78.4,
78.4, 22.6, 22.6. HRMS (ESI): m/z calcd for C20H20N2NaO6[MþNa]þ
407.1214, found 407.1218.
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