Reductant-Induced Free Radical Fluoroalkylation of Nitrogen Heterocycles and Innate Aromatic Amino Acid Residues in Peptides and Proteins

Article abstract of DOI:10.1002/chem.201902944

A series of fluoroalkylated cyclic λ³-iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition-metal-free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.

Full text of DOI:10.1002/chem.201902944

A Journal of
Accepted Article
Title: Reductant-Induced Free Radical Fluoroalkylation of Nitrogen
Heterocycles and Innate Aromatic Amino Acid Residues in
Peptides and Proteins
Authors: Kherironnesae Rahimidashaghoul, Iveta Klimánkoá, Martin
Hubálek, Michal Korecký, Matúš Chvojka, Daniel Pokorný,
Václav Matoušek, Lukáš Fojtík, Daniel Kavan, Zdeněk
Kukačka, Petr Novák, and Petr Beier
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To be cited as: Chem. Eur. J. 10.1002/chem.201902944
Link to VoR: http://dx.doi.org/10.1002/chem.201902944
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10.1002/chem.201902944
Chemistry - A European Journal
RESEARCH ARTICLE
Reductant-Induced Free Radical Fluoroalkylation of Nitrogen
Heterocycles and Innate Aromatic Amino Acid Residues in
Peptides and Proteins
Kheironnesae Rahimidashaghoul,[a,b] Iveta Klimánková,[a] Martin Hubálek,[a] Michal Korecký,[a] Matúš
Chvojka,[c] Daniel Pokorný,[c] Václav Matoušek,[c] Lukáš Fojtík,[d] Daniel Kavan,[d] Zdeněk Kukačka,[d]
Petr Novák,*[d] and Petr Beier*[a]
Abstract: A series of fluoroalkylated cyclic 3-iodanes and their
hydrochloride salts was prepared and used in a combination with
sodium ascorbate in buffer or aqueous methanol mixtures for radical
fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan
or its derivatives, and Trp residues in peptides. As demonstrated on
several peptides, aromatic amino acid residues Trp, Tyr, Phe and His
are targeted with high selectivity to Trp. The functionalization method
is biocompatible, mild, rapid and transition metal-free. Proteins
myoglobin, ubiquitin and human carbonic anhydrase I were also
successfully functionalized.
bioconjugation
trifluoromethylation
trifluoromethanesulfinate (CF3SO2Na) and t-butylhydroperoxide
allowed the preparation of fluorinated protein constructs for 19F
NMR studies.[9] However, there are no biocompatible and rapid
methods targeting His and Phe residues.
was
of
reported
Trp residues
recently.[8]
using
Radical
sodium
Trifluoromethylated cyclic 3-iodanes (Togni reagents) and
their tetrafluoroethylene-containing analogues 1 have been
previously used as electrophilic fluoroalkylating species in
reactions with various sulfur-, oxygen-, phosphorus- and carbon-
centered nucleophiles and also sulfur-centered biomolecules
including bioconjugations of Cys residues (Figure 1A).[10-12] The
concept of reductive trifluoromethylation of small molecules such
as alkenes or aromatics using Togni reagents and transition-
metal (Cu, Fe and photochemically using Ru or Ir) or non-metallic
(NaI, TEMPONa) reductants has been realized successfully on
number of examples (Figure 1B).[13-14] However, reported
conditions did not allow to perform this functionalization with
biomolecules in aqueous environment under ambient conditions.
Here we describe the development of a radical functionalization
method based on the reduction of 3-iodanes with water-soluble
and biocompatible reductant targeting small molecules (indoles,
pyrroles) and peptides or proteins on aromatic amino acid
residues with high selectivity to tryptophan (Figure 1C). The
reactions operate in water under ambient conditions, at
micromolar concentration and with high reaction rates, thus
expanding the protein functionalization toolbox. Related to this
work is the report of ethynylation of Trp-containing peptides (in
acetonitrile and trifluoroacetic acid) using an ethynyl-containing
3-iodane and a gold catalyst.[15]
Introduction
Selective methods for late-stage functionalization of organic
molecules and biomolecules are highly sought after. Of special
interest for basic biological research and drug development are
methods that allow fast and selective protein functionalization
targeting specific amino acid residues.[1-4] Typical standard
methods
include
lysine
functionalization
with
N-
hydroxysuccinimide ester of carboxylic acid, a reaction of highly
nucleophilic cysteine in alkylation with haloaceamides or reaction
with maleimides or related Michael acceptors. In comparison,
methods that enable direct functionalization of aromatic amino
acids are less common. Examples include ene-type
functionalization of tyrosine residues with triazolodiones[5] or azo-
coupling using aryldiazonium reagents.[6] Tryptophan residues
were selectively modified using metallocarbenes in aqueous
media. A carbene derived from a vinyl diazo compound and a
rhodium catalyst reacted with nitrogen and C(2) of tryptophan
indole ring.[7] A transition metal-free procedure based on
stabilized
aminoxyl
radical
for
tryptophane-selective
[a]
K. Rahimidashaghoul, I. Klimánková, Dr. M. Hubálek, M. Korecký,
Dr. P. Beier
Institute of Organic Chemistry and Biochemistry of the Czech
Academy of Sciences, Flemingovo nám. 2, 166 10 Prague 6, Czech
Republic. E-mail: beier@uochb.cas.cz
[b]
[c]
[d]
K. Rahimidashaghoul
Department of Organic Chemistry, Faculty of Science, Charles
University, Hlavova 2030/8. 128 43 Prague 2, Czech Republic.
M. Chvojka, D. Pokorný, Dr. V. Matoušek
CF Plus Chemicals s.r.o., Karásek 1767/1, 62100 Brno-Řečkovice,
Czech Republic.
L. Fojtík, D. Kavan, Z. Kukačka, Dr. P. Novák
Institute of Microbiology of the Czech Academy of Sciences,
Vídeňská 1083, 142 00 Prague 4, Czech Republic. E-mail:
pnovak@biomed.cas.cz
Figure 1. Previously reported (A, B) and hereby presented (C) fluoroalkylations
of small organic substrates and biomolecules using 3-iodanes.
Supporting information for this article is given via a link at the end of
the document.
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Results and Discussion
For optimization study, an electron-rich aromatic substrate
3-methylindole (skatole) was used. It has been previously
fluoroalkylated using 1a-1c activated by Zn(NTf2)2, ZnBr2,
TMSOTf, CuOAc or MeReO3 (20–80 °C).[11,17-19] We evaluated
reagent 1f with skatole and a number of reductants in methanol
or ethanol (with minimum water when necessary). While
reductants such as Na2SO3, FeCl2, CuOAc, NaH2PO3 and Et3B
afforded the product 2e in maximum 5–10% 19F NMR yields, the
use of sodium ascorbate afforded 2e in 42% 19F NMR yield (Table
1, entry 1). Optimization of solvent, reaction time, temperature,
amount of reagent, and ascorbate revealed that the best
conditions were a slight excess of 1f and 50 mol% of sodium
ascorbate in aqueous methanol (Table 1). The reaction was
finished in less than 5 min at ambient temperature and delivered
Structures of 3-iodanes used in this study are shown in
Figure 2. They are all stable compounds and include commercial
Togni reagents 1a and 1b, previously reported tetrafluoroethyle-
containing iodanes 1c, 1d and 1i and reagents 1e, 1f and salts
1g, 1h, 1j. The salt 1i was shown to undergo functionalization on
the amino group using acyl chlorides or sulfonyl chlorides for late-
stage customization with a functional group (demonstrated by an
attachment
of
fluorescent
groups,
biotin,
short
oligo(ethyleneglycol) chain, and various functional groups,
including CHO, I, Bpin, N3, ethynyl, and other).[12] Iodanes 1e-1h
and 1j were prepared by umpolung reactions of appropriate
fluoroalkylsilanes with fluoro- or acetoxyiodanes followed by
protonation with HCl or reaction with acetyl chloride (Scheme
1).[16]
Table 1. Optimization of radical fluoroalkylation of 3-methylindole with
hypervalent iodine reagents 1 and sodium ascorbate.
Entry
1
Na Asc.
(equiv.)
Solvent
Yield
(%)[a]
(equiv.)
1[b]
1f (1.0)
1f (1.0)
1f (1.2)
1f (1.0)
1f (1.2)
1f (1.5)
1f (1.2)
1f (1.2)
1f (1.2)
1f (1.2)
1f (1.2)
1e (1.2)
1a (1.2)
1b (1.2)
1c (1.2)
1d (1.2)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
0.05
0.5
0.5
0.5
0.5
0.5
0.5
EtOH
2e, 42
2e, 44
2e, 30
2e, 49
2e, 53
2e, 59
2e, 53
2e, 32
2e, 46
2e, 39
2e, 98
2e, 91
2a, 34
2a, 53
2c, 63
2c, 54
2
3
4
5
EtOH/H2O (1:1)
Dioxane/H2O (1:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
MeOH/H2O (6:1)
Figure 2. Structures of 3-iodanes 1 used in this study.
6
7[c]
8[d]
9
10
11[e]
12[e]
13[e]
14[e]
15[e]
16[e]
Scheme 1. Synthesis of new reagents 1.
[a] 19F NMR yield using (2,2,2-trifluoroethanol) as an internal standard. [b]
Reaction time was 1 h. [c] Reaction temperature was –78 °C. [d] Reaction
temperature was 40 °C. [e] Slow addition (over 5 min) of a solution of 1 in MeOH
to the solution of skatole and sodium ascorbate in aq. MeOH.
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2e in high yields, while for 1a-d the yields were somewhat
reduced. The order of addition was very important for achieving
high product yields. Hypervalent iodine reagents 1 needed to be
added last to achieve the best results.
methylthiophene were resistant to fluoroalkylation under the
applied reaction conditions (not shown in Scheme 2).
Evaluation of aromatic amino acid derivatives in trifluoro-
methylation with a small excess of 1b revealed that Trp was much
more reactive than Tyr, Phe or His. Conducting the reaction in
basic buffer increased the initially low reactivity of Tyr and His
which is consistent with the formation of more electron-rich
substrates by the deprotonation of aromatic OH group of Tyr or
imidazolium ring of His (Table 2). A clear correlation between
electron density of aromatic amino acid derivative and reactivity
in trifluoromethylation with 1b was found.
When exploring the scope of radical fluoroalkylation of
indole derivatives under optimal reaction conditions (Table 1,
Entry 11), it was found that indoles with alkyl, cycloalkyl or other
electron-rich groups in position 1, 2 or 3 underwent smooth
conversion to indoles fluoroalkylated in position 2 or 3 (Scheme
2). Indoles substituted with electron-acceptor groups (such as
formyl or nitro) afforded fluoroalkylated products in low yields.
Table 2. Fluoroalkylation of amino acid derivatives with 1b.
Entry
Amino acid deriv.
N-Ac Trp
N-Ac Tyr
Phe[d]
Product yield (%)[a]
56 + 6[b][c]
1
2
3
4
11[b], 18 (pH 9)
0 (pH 5), 4 (pH 9)
2 (pH 5), 11 (pH 9)
His.HCl
[a] 19F NMR yield using (trifluoroethanol) as an internal standard. [b] Water
instead of buffer was used. [c] Mono- and bis(trifluoromethylation), respectively.
[d] Phenylalanine ethyl ester hydrochloride was used.
In a competitive experiment, an equimolar mixture of all
natural amino acids (5 mM, pH 7.5) was used for
trifluoromethylation with 1a and of sodium ascorbate (10 equiv. to
each amino acid) and half the amount of sodium ascorbate.
Semiquantitative LCMS analysis showed reactivity order as
follows: Trp >> Cystine > Tyr > Phe > His (Figure 3). Other amino
acids were not reactive. Extracted ion chromatograms indicated
that with a large excess of 1a, Trp afforded mono(trifluoro-
methylated) product and two isomers of the bis(trifluoro-
methylated) product and Phe provided two isomers of
mono(trifluoromethylated) product. Reactivity of cystine can be
explained by the presence of trifluoromethyl radicals (mechanism
of the process vide infra) which cause homolytic cleavage of the
S-S bond followed by radical recombination. When only reactive
aromatic amino acids were evaluated in a competitive experiment
using moderate excess of 1b and 1d and a large preference for
the reaction with Trp to mono- or bis(fluoroalkylated) product was
observed (Table 3).
Scheme 2. Fluoroalkylation of indoles and pyrroles with 1f. Isolated yields are
shown. [a] 19F NMR yield using (2,2,2-trifluoroethanol) as an internal standard.
Next, several short peptides containing aromatic amino
acids were evaluated. A small peptide with the amino acid
sequence AFRIPLYWGRI was fluoroalkylated with excess of 1e,
1f or 1h (10 equiv.) and sodium ascorbate in aqueous acetonitrile.
MALDI MS analysis showed the formation of conjugates with one
fluoroalkyl modification (major product) and two modification
(minor product) (Figure 4 and Figures S1-S3). The subsequent
A similar outcome was observed with unsubstituted indole
and N-methyl pyrroles. N-Methyl indole afforded two isomers in a
65:35 ratio. The major isomer 10e was isolated in 35% yield.
Protected tryptophan was fluoroalkylated in position
2 in
moderate yield. A number of substrates such as caffeine,
adenosine monophosphate, but also electron-rich phenol or 2-
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Table 3. MS conversions of fluoroalkylated aromatic aminoacids in reactions
with 1b and 1d and sodium ascorbate.[a]
Entry
Reagent
MS conversion (%)
Trp-RF + Trp-(RF)2 Tyr-RF Phe-RF His-RF
1
2
3
4
1b (10 equiv.)
1b (50 equiv.)
1d (10 equiv.)
1d (50 equiv.)
75 + 8
38 + 62
72 + 14
0 + 100
12
40
19
26
2
10
5
<1
7
0
9
0
[a] Sodium ascorbate (5 or 25 equiv.), buffer (pH 7.5), rt, 5 min.
MS/MS analysis confirmed that both modifications took place
exclusively on the Trp residue (Figures S4 and S5). Formation of
small amount of oxidized fluoroalkylated product (probably
oxindole of the Trp residue) was often observed. The formation of
this side-product was minimized by using an additive methionine
or using one half of sodium ascorbate relative to hypervalent
iodine reagent. Peptide TEVNAWLVHRDP in reaction with 1g (10
or
100
equiv.)
afforded
mono(fluoroalkylation)
and
bis(fluoroalkylation) on the Trp residue (Figures S6-S9). The
efficiency of fluoroalkylation was concentration dependent; at
higher concentrations a complete fluoroalkylation was observed
even with lower excess of 1g.
Peptide bradykinin (RPPGFSPFR), an inflammatory mediator,
causing dilatation of blood vessels required a large excess of 1j
for the fluoroalkylation to take place. This is consistent with the
observed low reactivity of Phe residues and no reactivity of other
amino acid residues present in bradykinin. MS analysis indicated
partial formation of fluoroalkylated bradykinin on Phe residues
(not selective) and only traces of bis(fluoroalkylated) bradykinin
(Figure 4 and Figures S10 and S11). Cyclic peptide somatostatin
is a hormone regulating human endocrine system, for example, it
inhibits the secretion of insulin and glucagon. Somatostatin in
reaction with 1j afforded products of hydrogen substitution (not
addition to the disulfide bridge): mono(fluoroalkylated)
somatostatin as the main product, bis(fluoroalkylated)
somatostatin as the minor product and traces of
tris(fluoroalkylated) somatostatin (Figure 4 and Figure S12).
Another investigated peptide was bombesin. It is a 14-amino acid
peptide capable of stimulating gastrin release from G-cells. It is
also a tumor marker for small cell carcinoma of lung, gastric
cancer, pancreatic cancer, and neuroblastoma. Again, with a
large excess of 1j fluoroalkylation on Trp residue took place and
the main products were mono- and bis(functionalized) with some
traces of tris(fluoroalkylated) product and oxidized products
(Figure 4 and Figures S13-S15).
Figure 3. Extracted ion chromatograms of HPLC-MS analysis of a mixture of all
natural amino acids in trifluoromethylation with 1a (10 equiv. calculated to each
amino acid) and sodium ascorbate (5 equiv. calculated to each amino acid) in
buffer (pH 7.5), rt, 15 min. Reactive amino acids are shown on the left,
unreactive amino acids are shown on the right.
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the ‘acid type’ reagent 1d provided a deeper degree of
fluoroalkylation (up to 8 modifications) than the ‘alcohol type’
reagent 1c (Figures S16 and S17). Furthermore, at pH 9 the
extent of fluoroalkylation was higher than at pH 7 or 8 for both
reagents 1i and 1j (Figure S18), which is consistent with a higher
degree of ionization of Tyr residues at higher pH and therefore
creation of more electron rich reactive sites. Again, no signal
corresponding to addition to the disulfide bridge was observed by
MS.
To test the potential of fluoroalkylated hypervalent iodine
compounds for the introduction of a specific tag on proteins, horse
heart myoglobin and ubiquitin from bovine erythrocytes were
selected as model proteins. Myoglobin (16.9 kDa) contains a
number of aromatic amino acids (2 Trp, 2 Tyr, 7 Phe and 11 His).
Fluoroalkylation of myoglobin with 1h (100 equiv.) followed by
product separation by gel filtration and click reaction with a
dibenzocyclooctyne-amine (DBCO-amine) afforded myoglobin
containing one and two fluoroalkyl-triazole modifications (Figure
5). Bottom-up approach revealed the site of modification being
primarily on Trp14 residue and to a lesser degree also on Trp7
residue (Figure S19).
Since all above mentioned data show only modification of
Trp residues, to shed light on the behavior of other aromatic
amino acids, we carried out similar experiment with ubiquitin, a
small (8.6 kDa) regulatory protein found in most eucaryotes. As
far as aromatic amino acid residues are concerned, it contains
one Tyr, one His, two Phe and no Trp residue. Ubiquitin was
modified with 1h (100 equiv.) and sodium ascorbate (50 equiv.) in
50 mM ammonium bicarbonate buffer (pH 7.5), followed by a click
reaction with
a DBCO-amine derivative. The extent of
modification was similar to myoglobin. Prevalently,
a
mono(fluoroalkylated) protein was observed in MS data (Figure
S20). Subsequent, top-down analysis determined the
modification to take place on Tyr59 (Figure S21).
Figure 4. Structures of peptides AFRIPLYWGRI, TEVNAWLVHRDP,
bradykinin, somatostatin and bombesin with aromatic amino acid residues
highlighted in blue and their observed major and minor sites of functionalization
using sodium ascorbate and
functionalization are not shown.
1 depicted by blue arrows. Sites of trace
Human recombinant insulin in HEPES or TRIS buffer (pH 7-
9) was subjected to fluoroalkylation with reagents 1c, 1d, 1i and
1j (20-100 equiv. to aromatic AA). This larger system consist of
several aromatic amino acid residues (4 Tyr, 3 Phe, 2 His);
however, no Trp residue. Comparison of 1c and 1d revealed that
Figure 5. Structure of myoglobin with highlighted Trp7 and Trp14 residues,
which underwent fluoroalkylation with 1h, followed by the click reaction with
DBCO and simplified fluoroalkylation reaction scheme of modification of
myoglobin.
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Finally, carbonic anhydrase I from human erythrocyces
(hCA I) (cca 29 kDa) at cca 17 M concentration in ammonium
bicarbonate buffer (pH 7.5) was fluoroalkylated with reagents 1a
(200 equiv.) and sodium ascorbate (150 equiv.). To determine the
sites of fluoroalkylation, the reaction side products were removed
using a polyacrylamide electrophoresis and the separated protein
was analyzed using a bottom-up approach. Bands of interest were
excised, digested by trypsin, and analyzed by LC-MS/MS.
Fluoroalkylated residues were identified using Mascot search
against hCA I sequence. For example, the analysis revealed that
in the reaction with 1a the residues Trp123, Tyr88, Phe84 and
His67 were modified with one trifluoromethyl group (Figure S22).
All modified residues are solvent accessible using 1hcb structural
model of hCA I (Figure 6), which clearly demonstrated that after
radical fluoroalkylation with 1a the native structure of the protein
was not perturbed.
control experiment in which N-acetyl tryptophan with 1b in the
presence of TEMPO provided TEMPO-CF3 adduct in 43% 19F
NMR yield and no product of trifluoromethylation of the tryptophan
derivative (Figure S23).
Scheme 3. Proposed simplified reaction mechanism for sodium ascorbate-
mediated fluoroalkylation of 3-methylindole with hypervalent iodine reagent 1f.
Conclusion
In conclusion, we have demonstrated that sodium ascorbate
acts as an efficient, biocompatible and mild reductant towards
fluoroalkyl-substituted cyclic 3-iodanes for rapid fluoroalkylation
(functionalization with the trifluoromethyl or RCF2CF2 groups) of
small molecules (indoles, pyrroles), aromatic amino acids or
aromatic amino acid residues in peptides and proteins with a high
selectivity to tryptophan. With a small excess of 3-iodanes, Trp
residues were selectively fluoroalkylated in position two. With a
large excess of 3-iodanes, the second fluoroalkylation of the Trp
residue and fluoroalkylation of other aromatic amino acid residues
(Tyr, Phe and His) in peptides and proteins was observed. The
reaction is rapid (less than 15 min), operates in water or buffer of
a wide pH range (at least pH 5–9) at ambient temperature. A
mechanism involving free-radical intermediates was proposed.
The presented method is expected to find applications in Trp
bioconjugation and construction of protein-small molecule
conjugates, antibody-drug conjugates and post-translational
protein modification in general. Further investigations in
application of the method for protein surface and epitope mapping
and protein crosslinking are underway.
Figure 6. Structural model (1hcb) of hCA I with Trp123, Tyr88, Phe84 and His67
residues, which underwent fluoroalkylation highlighted in red.
The proposed simplified mechanism of sodium ascorbate-
mediated fluoroalkylation of indole derivatives is shown in
Scheme 3 (in the reaction of 1f with 3-methylindole). Ascorbate is
an efficient two-electron donor; however, under the conditions it
donates one electron to the iodine reagent 1f forming the transient
radical anion A, which decomposes to 2-iodobenzoate and
fluoroalkyl radical B. Radical addition of B to 3-methylindole leads
to the formation of a stabilized benzylic radical C, which transfers
proton to 2-iodobenzoate or any other base present in the reaction
mixture to give the radical anion D. Finally, the reactive
intermediate D is oxidatively aromatized by another SET process
to afford the product 2e, closing the catalytic cycle involving
electron as the catalyst as proposed by Curran and Studer.[20] The
oxidant involved in oxidative aromatization step of D to 2e is either
oxygen from air, 1f (in the case of low ascorbate loading) or
semidehydroascorbate radical (in the case of high ascorbate
loading). Fluoroalkyl radical B is a relatively electron-poor
species,[21] which prefers to react with electron-rich substrates,
such as indoles or pyrroles. Further evidence for fluoroalkylation
to proceed via radical pathway was obtained by performing a
Acknowledgements
This work was financially supported by the Czech Science
Foundation (17-00598S and 19-16084S). Additional institutional
and facility support from the Academy of Sciences of the Czech
Republic (RVO: 61388963 and 61388971); the Ministry of
Education of the Czech Republic (LM2015043 CIISB) and
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10.1002/chem.201902944
Chemistry - A European Journal
RESEARCH ARTICLE
European Regional Development Funds (CZ.1.05/1.1.00/02.0109
BIOCEV) are gratefully acknowledged.
Keywords: bioconjugation • radical • fluorine • iodine •
tryptophan
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10.1002/chem.201902944
Chemistry - A European Journal
RESEARCH ARTICLE
Layout 2:
RESEARCH ARTICLE
Kheironnesae Rahimidashaghoul, Iveta
Klimánková, Martin Hubálek, Michal
Korecký, Matúš Chvojka, Daniel
Pokorný, Václav Matoušek, Lukáš Fojtík,
Daniel Kavan, Zdeněk Kukačka, Petr
Novák,* Petr Beier*
Page No. – Page No.
Text for Table of Contents
Reductant-Induced Free Radical
Fluoroalkylation of Nitrogen
Heterocycles and Innate Aromatic
Amino Acid Residues in Peptides and
Proteins
Sodium ascorbate-induced radical fluoroalkylation of indoles, pyrroles and aromatic amino acids in peptides and proteins using cyclic
hypervalent iodine reagents is reported.
This article is protected by copyright. All rights reserved.