Oxidative functionalization of aliphatic and aromatic amino acid derivatives with H2O2 catalyzed by a nonheme imine based iron complex

Article abstract of DOI:10.1039/c8ra02879f

The oxidation of a series of N-acetyl amino acid methyl esters with H₂O₂ catalyzed by a very simple iminopyridine iron(ii) complex 1 easily obtainable in situ by self-assembly of 2-picolylaldehyde, 2-picolylamine, and Fe(OTf)₂ was investigated. Oxidation of protected aliphatic amino acids occurs at the α-C-H bond exclusively (N-AcAlaOMe) or in competition with the side-chain functionalization (N-AcValOMe and N-AcLeuOMe). N-AcProOMe is smoothly and cleanly oxidized with high regioselectivity affording exclusively C-5 oxidation products. Remarkably, complex 1 is also able to catalyze the oxidation of the aromatic N-AcPheOMe. A marked preference for the aromatic ring hydroxylation over Cα-H and benzylic C-H oxidation was observed, leading to the clean formation of tyrosine and its phenolic isomers.

Full text of DOI:10.1039/c8ra02879f

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Oxidative functionalization of aliphatic and
aromatic amino acid derivatives with H2O2
Cite this: RSC Adv., 2018, 8, 19144
catalyzed by a nonheme imine based iron complex†
a
Barbara Ticconi,a Arianna Colcerasa,a Stefano Di Stefano,
a
*
Osvaldo Lanzalunga,
Andrea Lapi,a Marco Mazzonnaa and Giorgio Olivob
The oxidation of a series of N-acetyl amino acid methyl esters with H2O2 catalyzed by a very simple
iminopyridine iron(II) complex easily obtainable in situ by self-assembly of 2-picolylaldehyde,
1
2-picolylamine, and Fe(OTf)2 was investigated. Oxidation of protected aliphatic amino acids occurs at
the a-C–H bond exclusively (N-AcAlaOMe) or in competition with the side-chain functionalization (N-
AcValOMe and N-AcLeuOMe). N-AcProOMe is smoothly and cleanly oxidized with high regioselectivity
affording exclusively C-5 oxidation products. Remarkably, complex 1 is also able to catalyze the
oxidation of the aromatic N-AcPheOMe. A marked preference for the aromatic ring hydroxylation over
Ca–H and benzylic C–H oxidation was observed, leading to the clean formation of tyrosine and its
phenolic isomers.
Received 3rd April 2018
Accepted 17th May 2018
DOI: 10.1039/c8ra02879f
rsc.li/rsc-advances
environmentally friendly H2O2 as the terminal oxidant. These
species can be considered simple models of iron oxygenases,
Introduction
and were found to efficiently catalyze aliphatic C–H hydroxyl-
ation with high selectivity.6 Thus, they represent good candi-
dates as catalysts for the side-chain functionalization of amino
acid residues in proteins. A signicant advantage lies in the
possibility of nely tuning their oxidation by varying the nature
of the ligand. For example, the two aminopyridine nonheme
Fe(PDP) and Fe(CF3PDP) complexes (PDP ¼ [N,N0-bis(2-pyr-
idylmethyl)]-2,20-bipyrrolidine) catalyze the oxidative modica-
tion of aliphatic amino acids proline, leucine, valine, and
norvaline triggered by C–H oxidation with preservation of the
stereocenters.3e,7
Along with aminopyridine iron catalysts, an interesting yet
underdeveloped class of nonheme models is represented by
imine iron complexes where the central iron metal is coordi-
nated to an imine based ligand.8 These catalysts have received
a minor attention with respect to their amine analogues since
they are considered less robust and stable under the oxidizing
conditions employed, yet some of these complexes proved
particularly efficient as oxidation catalysts.
Oxidative functionalization of amino acids has received a great
deal of attention in recent years. This interest has its roots in the
great signicance for human health of the reactions of amino
acids and peptides with reactive oxygen species (ROS), which
are implicated in various disease states and aging processes.1
Reactions of ROS with amino acids are also important in
structural analysis and protein targeting.2 Finally, oxidations of
amino acid derivatives and oxidative postsynthetic modica-
tions of peptides have found interesting applications in the
production of useful synthetic intermediates for the prepara-
tion of medicinal agents3 and chiral auxiliaries in asymmetric
reactions.4
Product analysis of the oxidation of amino acids and
peptides have been carried out by several research groups using
both metal based or organic oxidants.5 Such studies clearly
showed that these reactions may lead to oxidation of amino acid
side chains, backbone cleavage, cross-linking, unfolding and
loss of enzymatic activity.
A growing interest has been recently devoted to sustainable
oxidations catalyzed by nonheme iron complexes and
For example, we found that the nonheme iron complex 1,
easily and quantitatively obtained by spontaneous self-assembly
of cheap and commercially available 2-picolylaldehyde, 2-pico-
a
`
Dipartimento di Chimica, Universita degli Studi di Roma “La Sapienza” and Istituto
lylamine, and Fe(OTf)2 in a 2 : 2 : 1 ratio (Fig. 1) is able to
CNR di Metodologie Chimiche (IMC-CNR), Sezione Meccanismi di Reazione, c/o
9,10
`
Dipartimento di Chimica, Universita degli Studi di Roma “La Sapienza”, P.le A.
catalyze aliphatic C–H hydroxylation with H2O2
with yields
Moro 5, I-00185 Rome, Italy. E-mail: osvaldo.lanzalunga@uniroma1.it
and turnover numbers comparable to those reported for far
more sophisticated nonheme aminopyridine iron-complexes.
Remarkably, we found clear evidence that no free radical
processes are involved in the C–H hydroxylation process and
b
´
`
´
Institut de Quımica Computacional i Catalisi (IQCC) and Departament de Quımica,
Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain
† Electronic supplementary information (ESI) available: Other experimental
details, selected GC and GC-MS chromatograms and characterization of the
products of some oxidation reactions. See DOI: 10.1039/c8ra02879f
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Fig. 1 Oxidation of aliphatic and aromatic hydrocarbons with H2O2 promoted by the nonheme imine-based iron complex 1.
that a metal based oxidant is responsible for the C–H and aromatic substrates9–11 at 25 C for 30–90 min in the pres-
functionalization.10
ence of 1 mol% catalyst and 2.5 molar equivalents of H2O2
ꢀ
Moreover, we recently found that the imine complex 1 also slowly added over 30 minutes through a syringe pump. The
catalyzes the hydroxylation of aromatic rings with H2O2 under results are shown in Table 1. Reaction products were identied
mild conditions with good efficiency.11 It has to be remarked by GC-MS and 1H NMR analyses (see ESI†). In all cases the mass
that in the oxidation of alkylaromatics and benzylic alcohols, balance was satisfactory (>80%).
the 1/H2O2 system has a striking preference for aromatic
Control experiments showed that no oxidation of amino
hydroxylation over side-chain oxidation.11,12 The above results acids occurred in the absence of iron catalyst, nor when using
obtained in the oxidation of aliphatic and aromatic hydrocar- H2O2 and Fe(OTf)2 as catalyst. Moreover similar product yields
bons catalyzed by imine complex 1 prompted us to investigate were observed in the reactions carried out under air or nitrogen,
the oxidation of a-amino acids containing both aliphatic and thus reinforcing the idea that autoxidation processes are not
aromatic side-chains in order to obtain information on the responsible of products formation.
reactivity and selectivity patterns in these oxidative processes.
The results are reported herewith.
The oxidation of the alanine substrate 2 leads to the
formation of methyl piruvate as the exclusive reaction product
in 13% yield. Methyl piruvate likely derives from decomposition
of a-hydroxyalanine produced aer initial hydroxylation of the
Ca–H bond by the iron based oxidant (Scheme 1). No compet-
itive side chain oxidation is observed due to the low reactivity of
the strong methyl C–H bonds.
Results and discussion
A series of methyl esters of N-acetylated amino acids (2–8, Fig. 2)
were prepared to model individual residues within a poly-
peptide chain. Both the carboxylic acid and the amino function
have been protected in order to avoid their coordination to the
iron ion, which could affect the reactivity of the oxidizing spe-
cies.6k,7 Substrates 2–8 were synthesized from the corresponding
L-amino acids according to a literature procedure13 (see Exper-
imental section).
A competition between the side-chain and Ca–H oxidation is
instead observed with other aliphatic amino acids 3–5 con-
taining more reactive secondary and tertiary C–H bonds.
Oxidation of N-AcValOMe (3) furnished methyl 3-methyl-2-
oxobutanoate as the major product (8%) via initial Ca–H
hydroxylation accompanied by N-acetyl-b-hydroxyvaline methyl
ester (4%) which in turn derives from hydroxylation of the
tertiary C–H bond. Ca–H hydroxylation is also the preferred
reaction pathway in the oxidation of N-AcLeuOMe (4) with 4-
methyl-2-oxo-pentanoic acid methyl ester and 2-acetylamino-
4,4-dimethyl-4-butanolide formed in 10% and 5% yields,
respectively. The latter is obtained aer lactonization of the rst
formed N-acetyl-g-hydroxyleucine methyl ester (Scheme 2).
In the likely hypothesis of a hydrogen atom transfer (HAT)
mechanism from the substrate to the oxidizing species, ‡ the
observed preference for Ca–H hydroxylation is in accordance
with a relatively late transition state structure where the stability
of the incipient a-carbon centered radical plays a major role
even though in the case of substituted amino acids such as Ala,
Oxidations with the 1/H2O2 system were carried out in
acetonitrile in the conditions previously adopted for aliphatic
‡ The structure of the active species is still unknown, the hypothetical formation
of an imine based nonheme iron-oxo complex (see ref. 10) is currently under
investigation.
Fig. 2 N-acetyl amino acids methyl esters (2–8) investigated in this
work.
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Table 1 Oxidation of amino acids 2–8 by H2O2 in CH3CN at room temperature catalyzed by complex 1a
Substrate
Unreacted substrateb
Productsb (Yields%)
72
70
73
64
73
65
98
a
Reaction conditions: 250 mol% H2O2, 1 mol% catalyst 1, CH3CN at 25 ꢀC, reaction time 30–90 minutes, oxidant added by syringe pump (30 min).
b
Recovered substrates and product yields (%), determined by GC and 1H NMR analysis using bibenzyl as an internal standard, are referred to the
initial amount of substrate. Average of at least two runs (error ꢁ 5%).
Scheme 1 Formation of methyl piruvate in the oxidation of N-AcAlaOMe Scheme 2 Formation of Ca–H and side-chain oxidation products in
(2) with the 1/H2O2 system.
the reaction of N-AcLeuOMe (4) with the 1/H2O2 system.
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Val and Leu, a nonbonding interaction between the amide
carbonyl and side chain R group destabilizes the coplanar
conformation of the radical formed which does not benet of
captodative stabilization.14
Thus, the catalytic behavior of the 1/H2O2 system is different
from what observed in the oxidations of aliphatic amino acids
promoted by aminopyridine nonheme iron catalysts. Exclusive
side-chain functionalization was observed as in the oxidation of
leucine and valine promoted by Fe(PDP) and Fe(CF3PDP) com-
plexes.3e On the other hand, no products have been observed in
the oxidation of amino acids Ala, Val, Leu with KHSO5
promoted by the pentadentate nonheme complex [FeII(N4Py)]2+
with the active species iron(IV)-oxo complex [FeIV(O)(N4Py)]2+
decaying at a rate faster than the hydrogen abstraction from
these substrates.15
Scheme 3 Formation of N-formyl-N-acetylkynurenine methyl ester
in the oxidation of N-AcTrpOMe (6) with the 1/H2O2 system.
The selectivity pattern observed with the 1/H2O2 system
resembles that of the cumyloxyl radical (CumOc) where exclu-
sive HAT from a-C–H bond with Ala and a competition between
side-chain vs. Ca–H bond cleavage for N-AcLeuOMe (4) were
observed.16 However, no HAT reaction from the tertiary b-C-H
bond of N-AcValOMe (3) has been observed with CumOc, thus
indicating that our system is less sensitive to steric effects in the
HAT process.
N-AcProOMe (5) was the most reactive substrate with the 1/
H2O2 system. N-Ac-5-hydroxyproline methyl esters (mixture of
diastereomers) and N-Ac-5-oxoproline methyl ester were formed
as oxidation products in a combined 35% yield (36% conver-
sion). Selective C-5 functionalization well matches the expected
high reactivity of the C5–H bonds on the basis of the intrinsi-
cally high HAT reactivity due to polar effects of the C–H bonds
in the d-carbon atom.3e,5c,14,16a, Similar results were found in the
oxidations promoted by aminopyridine nonheme Fe(PDP) and
Fe(CF3PDP) complexes.3e However, it has to be remarked that
the lower yields of C-5 proline oxidation with the 1/H2O2 system
when compared to those obtained with the Fe(PDP) system
(77%) are obtained at a considerably lower catalyst loading (1%
vs. 25%).
C–H functionalization of phenylalanine and other aromatic
amino acids are particularly attractive transformations and
have been exploited for the preparation of unnatural amino
acids and structural modication of small peptides.3c,17 Oxida-
tion of N-AcTrpOMe (6) with the 1/H2O2 system led to small
amounts of side chain functionalization products (see ESI† for
details). The major one, formed in 6% yield, was N-formyl-N-
acetylkynurenine methyl ester deriving from the oxidative
cleavage of the indole ring. The same product had been
observed in the oxidation of N-AcTrpOMe (6) with singlet oxygen
or with N3c in g-radiolysis experiments18 and its formation may
be rationalized according to the mechanism reported in
Scheme 3 where the rst step involves the abstraction of
hydrogen from the indole N–H bond.
The high chemoselectivity for the aromatic hydroxylation
with respect to the oxidation of a-CH and b-CH bonds is
a noteworthy feature of this transformation and is in line with
the preference for aromatic over aliphatic alcohol oxidation
previously reported.11,12 The 1/H2O2 system indeed revealed
especially suitable for the hydroxylation of aromatic rings11 and it
does not suffer the irreversible phenol binding to the iron center
that generally prevents catalytic turnover with nonheme iron
catalysts.19 Moreover with this system the oxidation tends to stop
at the phenol stage without quinone formation. The latter is an
undesired overoxidation product that aws other iron-catalyzed
oxidations20 as reported for example in the oxidation of phenyl-
alanine with the iron(IV)-oxo complex [FeIV(O)(N4Py)]2+ where
orthoquinone was the main product.21
It is worth to note that while direct phenylalanine to tyrosine
oxidation can be easily accomplished by enzymes (in particular
the nonheme iron enzyme phenylalanine hydroxylase22), few
chemical oxidants are competent for this transformation. For
example, the oxidation of Phe by hydroxyl radicals produced by
Fenton reactions or g-radiolysis also leads to a mixture of o-, m-,
p-hydroxyphenylalanines but suffers the limitation of a low
positional selectivity and partial overoxidation to 2,3- and 3,4-
dihydroxyphenylalanines.23 The higher o-, m-, p- positional
selectivity observed with our system is in accordance with
a metal based SEAr mechanism proposed in a previous study for
the oxidation of aromatic compounds.11
In accordance with the high selectivity for p-hydrox-
yphenylalanine, no products were observed in the 1/H2O2
promoted oxidation of N-AcTyrOMe (8), with the substrate being
recovered almost quantitatively. This result is somewhat
surprising since phenolic O–H bond is particularly activated
towards HAT reagents, including high-valent iron–oxo species.
For instance, [FeIV(O)(N4Py)]2+ reacts much faster with the
electron-rich phenol moiety of N-AcTyrNHtBu than with the
aromatic ring of N-AcPheNHtBu.15
In view of the relevance of the Phe to Tyr transformation,
reaction conditions were subsequently screened varying the
amounts of catalyst and oxidant in order to optimize the Tyr
yields. The results are shown in Table 2.
Oxidation of N-AcPheOMe (7) with the 1/H2O2 system leads
to the formation of N-AcTyrOMe (8) as the main reaction
product (14%) accompanied by the two isomeric o-OH and m-
OH phenolic derivatives. No products deriving from Ca–H or
benzylic hydroxylation have been observed.
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Table 2 Oxidation of N-AcPheOMe (7) by H2O2 in CH3CN at room temperature catalyzed by complex 1a
Yields of
hydroxyphenylalanines
Entry
Cat. (mol%)
H2O2 (eq)
Cosolv H2O
Conv. (%)
o
m
p
1
2
3
4
5
6b
7
8
9
1
3
5
3
3
1
3
3
3
2.5
2.5
2.5
3.5
5
2.5
2.5
2.5
2.5
—
—
—
—
—
—
7%
14%
21%
35
47
36
45
37
69
45
42
40
11
13
9
11
4
9
6
6
7
3
9
6
9
6
2
10
10
10
13
24
16
24
9
20
24
20
20
a
b
Yields (%) are referred to the initial amount of substrate. Reaction time 75 minutes. Reaction time 120 min.
A pleasant improvement in Tyr yield was observed on investigate further the high preference for aromatic hydroxyl-
increasing catalyst loading from 1 to 3% (entry 2). A further ation through intermolecular competitive oxidation experi-
increase in catalyst loading led to a lower substrate conversion ments of N-AcPheOMe (7) and other aliphatic amino acids. To
(entry 3). With the optimal amount of catalyst (3%) the effi- this purpose, equimolar mixtures of N-AcPheOMe (7) and N-
ciency decreased by increasing the added oxidant to 3.5 and 5 AcValOMe (3), N-AcLeuOMe (4) or N-AcProOMe (5) were sub-
molar equiv. (entries 4 and 5). By increasing reaction time from jected to the standard oxidation conditions (see Table 1), and
75 to 120 min lower yields of phenolic products and mass the results are reported in Fig. 3. Quite surprisingly, in the
balance were observed likely due to formation of overoxidation competitive oxidation experiments of N-AcPheOMe (7) with N-
products (entry 6). Interestingly, the catalyst activity and selec- AcValOMe (3) or N-AcLeuOMe (4) formation of a mixture of o-,
tivity are maintained in the presence of water as cosolvent. m-, p-hydroxyphenylalanines was accompanied by trace
Substrate conversions and Tyr yields are almost unaffected up amounts of products deriving from the oxidation of aliphatic
to 20% (v/v) water content (entries 7–9).
amino acids. Phe aryl oxidation also well competes with the C-5
The high chemoselectivity displayed by the 1/H2O2 system oxidation of reactive N-AcProOMe (5), with product yields
for the aromatic hydroxylation in Phe prompted us to comparable with those observed in the oxidation of N-
Fig. 3 Oxidation products and yields in the competitive experiments of N-AcPheOMe (7) with N-AcValOMe (3), N-AcLeuOMe (4) and N-
AcProOMe (5).
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AcPheOMe (7) alone. These results conrm the marked prefer-
ence for the electrophilic aromatic substitution over the HAT
process displayed by the active species formed in the 1/H2O2
system, a property that makes this catalyst unique and partic-
ularly attractive in comparison with other nonheme iron
complexes.
ꢂ 60 mL), and brine (3 ꢂ 60 mL), dried over anhydrous Na2SO4
and ltered. Substrates 2–8 were puried by recrystallization or
by column chromatography. Spectral data are in accordance
with those reported in the literature (see ESI†).
Such a clear preference for the aromatic hydroxylation pave
the way to the possible selective oxidative functionalization of
the Phe aryl rings in polypeptide chains, which is currently
under investigation in our laboratories.
Product analysis of the oxidation of 2–8 with the 1/H2O2
system
In
a typical oxidation experiment Fe(CF3SO3)2(CH3CN)2
(1.09 mg, 2.50 mmol), picolylamine (50 mL of a solution 0.1 M in
CH3CN 5.0 mmol) and picolylaldehyde (50 mL of a solution 0.1 M
in CH3CN, 5.0 mmol) were mixed in a vial at 25 ꢀC. Substrate (250
mmol) and CH3CN were then added up to a total volume of 700
mL. A solution of H2O2 in CH3CN (1.74 M diluted from a 30% w/
w H2O2) was added over 30 minutes by syringe pump under
vigorous stirring, and le reacting for additional 5 minutes
(Pro), 45 minutes (Phe), 60 minutes (Ala, Val, Leu, Trp). At this
point an internal standard was added (bibenzyl, 25 mmol) and
the reaction mixture was ltered over a short pad of SiO2 with
10 mL of AcOEt. The ltered solution was subjected to GC and
GC-MS analysis or evaporated to furnish the product mixture for
the 1H NMR analysis. The following oxidation products were
identied by comparison with authentic specimens or by
comparison of their spectral data with those reported in the
literature: methyl piruvate,24 methyl 3-methyl-2-ketobuta-
noate,25 (3S)-N-acetyl-hydroxyvaline methyl ester,5j 4-methyl-2-
oxo-pentanoic acid methyl ester,26 (2S)-2-acetylamino-4,4-
Conclusion
The readily available iminopyridine iron(II) complex 1 was
found to promote the a-C–H or side-chain oxidation of aliphatic
amino acids with H2O2 and a regioselectivity dictated by the
substrate structure. In the oxidation of N-AcPheOMe (7) it
showed a marked preference for aromatic hydroxylation over
Ca–H and benzylic C–H oxidation unlocking the key conversion
of Phe to Tyr with a sustainable oxidant and a cheap and easily
obtainable iron catalyst. Extension of this methodology to the
site-specic modication and/or cleavage of peptides and
proteins is current underway in our laboratory.
Experimental
Instruments and general methods
GC analyses were carried out on a gas chromatograph equipped
with a capillary methylsilicone column (30 m ꢂ 0.25 mm ꢂ 25
mm). GC-MS analyses were performed with a mass detector (EI at
70 eV) coupled with a gas chromatograph equipped with a melted
silica capillary column (30 m ꢂ 0.2 mm ꢂ 25 mm) covered with
a methylsilicone lm (5% phenylsilicone, OV5). NMR spectra
were recorded on a 300 MHz spectrometer and were internally
referenced to the residual proton solvent signal.
dimethyl-4-butanolide,5j
(2S,5S)-
and
(2S,5R)-N-Ac-5-
hydroxyproline methyl esters (mixture of diastereomers),27
(2S)–N-acetyl-5-oxoproline methyl ester,28 (2S)–N-acetyl-m-
hydroxyphenylalanine methyl ester,29 N-formyl-N-acetylkynur-
enine methyl ester.18 (2S)–N-acetyl-o-hydroxyphenylalanine
methyl ester was isolated from the crude reaction mixture by
column chromatography and characterized as follows:
1H NMR (300 MHz, CDCl3): d ¼ 7.17–7.11 (dt, 1H), 7.00–6.97
(dd, 1H), 6.86–6.78 (m, 2H), 6.62–6.60 (m, 1H), 4.65–4.59 (m,
1H), 3.73 (s, 3H), 3.21–3.15 (dd, 1H), 2.99–2.92 (dd, 1H), 2.04 (s,
3H). 13C NMR (75 MHz, CDCl3): d ¼ 172.6, 171.0, 154.9, 131.1,
128.6, 122.3, 119.9, 115.9, 53.6, 52.4, 33.3, 22.8. HR-MS (ESI-
TOF): m/z ¼ 260.0897 [M + Na]+ calcd. for C12H15NO4Na,
found 260.0899.
Materials
All reagents and solvents employed were of the highest purity
available and used without further purication. Methyl esters of
N-acetylated amino acids 2–8 were prepared as reported in the
literature.13 In a typical procedure L-amino acid (17 mmol) was
dissolved in acetic anhydride (44 mmol) in methanol (7.6 mL).
The mixture was stirred under reux for 6 h, aer cooling to
room temperature the solvent was evaporated under reduced
pressure and the residue was triturated with ethyl acetate, l-
trated and dried in vacuo. With this procedure it was possible to
isolate directly the methyl esters 5–8 and the N-acetylated amino
acids N-Ac-Ala, N-Ac-Val and N-Ac-Leu. Methyl esters 2–4 were
prepared by adding potassium carbonate (30 mmol) to a solu-
tion of N-acetylated amino acids (10 mmol) in DMF (36 mL). The
reaction was kept at room temperature for 24 h. Aer this time,
iodomethane (30 mmol) was added and stirring was continued
Conflicts of interest
There are no conicts to declare.
Acknowledgements
`
for additional 24 h. The solvent was evaporated under reduced Thanks are due to the Ministero dell’Istruzione, dell'Universita
pressure and the reaction mixture was extracted with ethyl e della Ricerca (MIUR), for nancial support and to the CIRCC,
acetate (2 ꢂ 50 mL). The combined organic layers were Interuniversity Consortium of Chemical Catalysis and
successively washed with H2O (60 mL), 5% aqueous Na2S2O3 (3 Reactivity.
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W. N. Oloo and L. Que Jr, Acc. Chem. Res., 2015, 48, 2612–
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