Stereoselective Oxidative Bioconjugation of Amino Acids and Oligopeptides to Aldehydes

Article abstract of DOI:10.1002/anie.202008513

The first stereoselective, near-equimolar, and metal-free oxidative bioconjugation of amino acids and oligopeptides to aldehydes is presented. Based on a newly developed organocatalytic oxidative concept, the C-terminal and side-chain carboxylic acid functionalities of amino acids and oligopeptides are shown to couple in a stereoselective manner to α-branched aldehydes catalyzed by a chiral primary amine and a quinone as oxidizing agent. The oxidative coupling generally proceeds in high yield. For aspartic acid, selective coupling of the side-chain, or the C-terminal carboxylic acid, is demonstrated depending on the protection strategy. The stereoselective, oxidative bioconjugation concept is extended to a series of oligopeptides where coupling to carboxylic acid functionalities is presented. Bioorthogonal linker molecules for further functionalization are obtained by merging the oxidative coupling strategy with the click concept. It is demonstrated that the configuration of the new stereocenter is determined exclusively by the organocatalyst.

Full text of DOI:10.1002/anie.202008513

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Accepted Article
Title: Stereoselective Oxidative Bioconjugation of Amino Acids and
Oligopeptides to Aldehydes
Authors: Henriette N Tobiesen, Lars A Leth, Marc V Iversen, Line
Næsborg, Søren Bertelsen, and Karl Anker Jørgensen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008513
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10.1002/anie.202008513
Angewandte Chemie International Edition
COMMUNICATION
Stereoselective Oxidative Bioconjugation of Amino Acids and
Oligopeptides to Aldehydes
Henriette N. Tobiesen,[a,b] Lars A. Leth,[a] Marc V. Iversen,[a] Line Næsborg,[a] Søren Bertelsen,[b] Karl
Anker Jørgensen[a]*
Abstract: The first stereoselective, near-equimolar, and metal-free
oxidative bioconjugation of amino acids and oligopeptides to
aldehydes is presented. Based on a newly developed organocatalytic
oxidative concept, the C-terminal and side chain carboxylic acid
functionalities of amino acids and oligopeptides are shown to couple
in a stereoselective manner to -branched aldehydes catalyzed by a
chiral primary amine and a quinone as oxidizing agent. The oxidative
coupling generally proceeds in high yield. For aspartic acid, selective
coupling of the side-chain, or the C-terminal carboxylic acid, is
demonstrated depending on the protection strategy. The
stereoselective, oxidative bioconjugation concept is extended to a
series of oligopeptides where coupling to carboxylic acid
functionalities are presented. Bioorthogonal linker-molecules for
further functionalization are obtained by merging the oxidative
coupling strategy with the click concept. It is demonstrated that the
configuration of the new stereocenter is determined exclusively by the
organocatalyst.
thiols and amines as nucleophilic partners, while the carboxylic
acid moiety is underdeveloped.
Carbodiimide-mediated activation is an extensively applied
methodology for modification of carboxylic acids in proteins with
amines by activated acylisoureas (Scheme 1a).[6] The reaction is
fast, quantitative, and proceeds under mild conditions, and is
therefore the strategy of choice in solid-phase peptide synthesis.
Due to the efficient reaction, orthogonal protection strategies of
side chain residues are necessary for obtaining selective
functionalization. In recent years, decarboxylative strategies have
also been developed to afford cross-coupled products at either
side-chain or C-terminal positions depending on the protection
strategy (Scheme 1b).[7] Through photoredox catalysis, selective
C-terminal functionalization has been achieved due to the
difference in oxidation potential relative to side-chain residues
(Scheme 1c).[8]
Esterification of carboxylic acids is a well-established prodrug
strategy and recently Raines et al. demonstrated how
esterification with diazo compounds can enable the translocation
of a putative therapeutic agent across the plasma membrane
(Scheme 1d).[9]
Nature makes post-translational modifications to peptides and
proteins to increase functional diversity. Such modifications play
a vital role in regulating the activity of the biomolecules within the
organism.[1,2] From a chemical biology perspective, chemical
modifications of biomolecules provide novel opportunities in the
study of biological systems, and for the pharmaceutical industry
to alter the pharmacodynamic properties allowing for new
important
developments
and
understanding
of
biopharmaceuticals.[3]
The biological and pharmaceutical significance of modified
peptides and proteins pushes for continued development of new
reactivity and selectivity concepts for their functionalization. In the
present work, we outline our initial efforts to develop the first
stereoselective metal-free, oxidative bioconjugation strategy for
late stage functionalization of amino acids and oligopeptides.
Amino acids and oligopeptides are inherently chiral, and despite
examples of Pd-catalyzed diastereoselective functionalization of
amino acids,[4] the majority of bioconjugation strategies that
generate a new stereocenter do not normally proceed in a
stereoselective manner.[5] Most bioconjugations are based on
[a]
[b]
H. N. Tobiesen, Dr. L. A. Leth, M. V. Iversen, Dr. L. Næsborg, Prof.
Dr. K. A. Jørgensen
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
H. N. Tobiesen, Dr. S. Bertelsen
Research Chemistry, Global Research Technologies
Novo Nordisk A/S
Scheme 1. a) C-Terminal peptide bond formation through carbodiimide-
mediated activation. b) Decarboxylative functionalization of carboxylic acid
moieties. c) Site-selective decarboxylative C-terminal functionalization by
photo-redox catalysis. d) Translocation of proteins across the cell membrane by
esterification. e) This work: Stereoselective metal-free functionalization of the
carboxylic acid functionality in amino acids and oligopeptides.
2760 Maaloev (Denmark)
This work was financially supported by Aarhus University and
Carlsberg Foundation. H.N.T. thanks Novo Nordisk for a PhD grant.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202008513
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COMMUNICATION
Peptides and proteins are already highly complex molecules with
several stereocenters, and adding additional complexity through
a stereoselective bioconjugation strategy could lead to higher
selectivity towards the chiral environment present in receptors.[10]
For reactions with peptides and proteins several obstacles have
to be resolved. Besides the challenges in controlling site- and
stereoselectivity many contemporary strategies for peptide and
protein modifications often require up to several hundred
equivalents of one of the reagents.[2]
Gratifyingly, substituting Ag2CO3 for the organic oxidant 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ)[12] afforded 3a in 56%
yield and 6:1 d.r. (entry 2). Less activated quinones, chloranil and
fluoranil, were not able to deliver the desired product (entries 3,
4). As the biomolecule is often the more expensive reagent, the
stoichiometry was changed making 1a the limiting reagent;
resulting in both increased yield and diastereoselectivity (entry 5).
Next, a series of different solvents were evaluated; toluene
diminished both the yield and diastereoselectivity of 3a (entry 6).
To enhance solubility of the biomolecules, more polar solvents
were considered. For the polar, protic solvents, methanol afforded
the methoxy-coupled product by outcompeting the amino acid as
the reactive nucleophile by its higher concentration. 1,1,1,3,3,3-
Hexafluoro-2-propanol (HFIP) gave 3a in 75% yield, but in a 1:1
d.r. (entries 7, 8). A control experiment revealed that the reaction
runs efficiently in the absence of an aminocatalyst when
performed in HFIP. Polar, aprotic solvent, such as acetonitrile,
offered high diastereoselectivity with a 13:1 d.r., but decreased
the yield of 3a to 45% (entry 9). In CH3NO2, 3a was formed in 78%
yield and 17:1 d.r. (entry 10). A control experiment omitting
aminocatalyst demonstrated a very slow coupling of 1a and no
control of the diastereoselectivity (entry 11). In summary, CH2Cl2
and CH3NO2 were chosen as solvents.
Herein we present our efforts towards
a
metal-free,
stereoselective, and highly atom-economical bioconjugation
strategy by applying oxidative enamine catalysis to functionalize
carboxylic acid moieties in amino acids and oligopeptides
generating tert-alkyl carboxylates (Scheme 1e).
Recently, we disclosed the first enantioselective oxidative
addition of aromatic and aliphatic carboxylic acids to the -
position of aldehydes applying a primary amine organocatalyst
and Ag2CO3 as oxidant.[11] Inspired by this work, we first tried to
extend this concept for the coupling of N-Boc-L-alanine 1a to
aldehyde 2a under oxidative conditions using the primary amine
catalyst A and Ag2CO3 as oxidant. Unfortunately, these reaction
conditions offered poor product selectivity and the desired amino
acid coupling product 3a was observed in low yield and isolated
in trace amounts (Table 1, entry 1).
To test the potential of the oxidative bioconjugation, a series of
different N-Boc protected amino acids, representative of the
different reactive functionalities found in the 20 proteogenic amino
acids were investigated (Table 2).
Table 1. Optimization of reaction conditions.
Table 2. Stereoselective oxidative bioconjugation of amino acid derivatives to
2a.[a]
Entry[a]
1[d]
2[d]
3[d]
4[d]
5
1a / 2a
1.5 / 1.0
1.5 / 1.0
1.5 / 1.0
1.5 / 1.0
1.0 / 1.5
1.0 / 1.5
1.0 / 1.5
1.0 / 1.5
1.0 / 1.5
1.0 / 1.5
1.0 / 1.5
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
MeOH
HFIP
Oxidant
Ag2CO3
DDQ
3a [%][b]
36[e]
56
d.r.[c]
4:1
6:1/6:1
-
Chloranil
Fluoranil
DDQ
0
0
-
85
8:1/10:1
4:1/4:1
-
6
DDQ
41
7
DDQ
0
8
DDQ
75
1:1/1:1
13:1/16:1
15:1/17:1
1:1
9
CH3CN
CH3NO2
CH3NO2
DDQ
45
10
11[f]
DDQ
78
DDQ
36[g]
[a] Reactions were performed on 0.1 mmol scale. [b] Isolated yields of 3a unless
otherwise noted. [c] The diastereomeric ratio of 3a was measured by 1H NMR
analysis of isolated product (red) and crude reaction mixture (blue). [d] Reaction
performed with 1.5 equiv. of oxidant and 5-22 h reaction time. [e] Yield
measured by 1H NMR analysis of the crude reaction mixture relative to internal
standard (1,3,5-tris(trifluoromethyl)benzene) at full consumption of 2a. [f] No
aminocatalyst. [g] Yield measured by 1H NMR analysis of the crude reaction
mixture relative to internal standard (1,3,5-tris(trifluoromethyl)benzene) at full
consumption of 2a and quinol intermediate after 120 h.
[a] Reactions were performed on a 0.1 mmol scale (see Supporting Information).
The diastereomeric ratio was determined by 1H NMR analysis of isolated
product (red) and crude reaction mixture (blue). The enantiomeric excess (3b)
was determined by a chiral stationary phase UPC2. For determination of the
absolute stereochemistry see Supporting Information. [b] The reaction was
performed using CH3NO2 as solvent. [c] 24 h reaction time.
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Table 3. Stereoselective oxidative bioconjugation of oligopeptide derivatives to
aldehydes 2a and 2c.[a]
With N-Boc-L-alanine, the acid coupled product 3a was isolated
in 85% yield and 10:1 d.r. The only non--branched amino acid
N-Boc-L-glycine delivered 3b in slightly lower yield (76%) and
77% ee. The cyclic amino acid derivative N-Boc-L-proline
provided product 3c in a moderate yield of 51% and low
diastereomeric ratio of 1.2:1. Methionine serves as an important
cellular antioxidant through reversible oxidation and reduction of
its thioether functionality,[13] however, these redox properties were
tolerated under the oxidative conditions and 3d was isolated in
67% yield and 6:1 d.r. Aromatic amino acids, N-Boc-L-
phenylalanine and N-Boc-L-tryptophan, provided comparable
results with 72% and 73% yield, and 13:1 and 11:1 d.r. of 3e and
3f, respectively. For N-Boc-L-tryptophan it was also necessary to
Boc-protect the indole moiety. The basic amino acids N-Boc-L-
lysine and N-Boc-L-histidine also needed protection of their basic
moieties to give products 3g and 3h respectively in moderate
yields and diastereomeric ratios. N-Boc-L-Serine has an
additional oxygen nucleophile in its hydroxymethyl side chain.
With the free alcohol, the reaction conditions afforded the acid
coupled product 3i in 64% yield and 8:1 d.r. With protection of the
side chain both yield and diastereoselectivity were significantly
increased to 86% and >20:1 d.r. (3j). L-Aspartic acid and L-
glutamic acid both have acidic side chains. In proteins their
reactivity is highly dependent on the microenvironment, and their
pKa can span across a wide range.[14] Due to the various acidic
sites development of a regioselective method was pursued by
selective protection of various amino acid functionalities. Coupling
through the -carboxylic acid of N-Boc-L-aspartic acid, afforded
the product 3k in 74% yield and 10:1 d.r. For coupling through the
side chain carboxylic acid (3l), similar yield was obtained (71%),
but with a slightly lower diastereomeric ratio (6:1). N-Boc-L-
asparagine with protected side chain also reacted smoothly
providing the desired product 3m in 73% yield and 11:1 d.r.
The methodology was extended to dipeptides and a tripeptide
under the same reaction conditions (Table 3). Glycine and alanine
both delivered products as single amino acids, and as the
dipeptide Boc-NH-Gly-Ala-OH, the product 3n was isolated in
80% yield and 12:1 d.r. Side-chain protected dipeptide Boc-NH-
Asp(Bn)-Phe-OH afforded 3o in a lower yield of 36%, but with a
high diastereomeric ratio of 19:1. Dipeptide Boc-NH-Lys(Boc)-
Gly-OH provided 3p in 45% yield and >20:1 d.r. Tripeptide Boc-
NH-Met-Leu-Phe-OH was attempted and product 3q obtained in
51% yield and >20:1 d.r. For C-terminal phenylalanine and glycine,
the oligopeptides react with a higher stereoselectivity than their
corresponding single amino acids indicating an increased
stereoeffect of the aminocatalyst for larger systems.
[a] Reactions were performed on a 0.1 mmol scale (see SI). The diastereomeric
ratio was determined by 1H NMR analysis of isolated product (red) and crude
reaction mixture (blue). For determination of the absolute stereochemistry see
Supporting Information. [b] The reaction was performed using CH3NO2 as
solvent.
For applicability in biochemical assays, aldehydes were
synthesized with biorthogonal handles for click chemistry,[15] such
as aldehydes 2b and 2c, with an azide and alkyne handle,
respectively. Side-chain protected L-serine was coupled to
1
aldehyde 2b with a 15:1 d.r. observed by H NMR spectroscopy
and isolated in 51% yield, 20:1 d.r. (3s). For aldehyde 2c the
desired product 3t was isolated in 84% yield and 13:1 d.r. The
product was further subjected to a click reaction with benzyl azide
affording 4 in 82% yield (Table 4) clearly demonstrating the role
of the -branched aldehydes as linker-molecules facilitating
various conjugations to the biomolecule.
A model oligopeptide 1r was synthesized and as a proof-of-
principle coupled to aldehyde 2a to afford bioconjugate 3r (Table
3, bottom). To the left is shown an HPLC run of purified product
3r supported by MS data to the right (see Supporting Information
for specification).
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Table 4. Stereoselective oxidative bioconjugation of aldehydes to amino acid
1j[a] and subsequent CuAAC with 3t and benzyl azide to give 4.[b]
Scheme 2. Stereochemistry determined by aminocatalyst A.
[a] Reactions were performed on a 0.1 mmol scale (see Supporting Information).
The diastereomeric ratio was determined by 1H NMR analysis of isolated
product (red) and crude reqction mixture (blue). [b] Reaction was performed on
a 0.069 mmol scale (see Supporting Information).
The chiral primary amine catalyst A induces the stereoselectivity
in the coupling step, however, since all amino acids, except
glycine, are chiral, they pose an opportunity for match and
mismatch combinations with the catalyst. A series of experiments
were therefore designed in order to evaluate the role of the
catalyst. With the (S)-enantiomer of catalyst A, a diastereomeric
ratio 12:1 was observed by reaction with N-Boc-L-Ser(Bn)-OH
(Scheme 2). We were pleased to observe, when performing the
reaction with the opposite enantiomer of the catalyst, the coupled
product was obtained in 1:12 d.r., showing that there is not a
substantial mismatch combination between catalyst and amino
acid. Thus, the diastereomeric outcome of the reaction is
controlled by the catalyst, and the stereocenter in the amino acid
has no influence on the stereochemical outcome of the reaction.
Furthermore, only two diastereoisomers are observed, indicating
that the stereocenter of the amino acid is stable during the
reaction conditions.
Reactions were performed on a 0.1 mmol scale (see SI). Diastereomeric ratios
were determined by 1H NMR analysis of crude reaction mixtures (blue) and for
isolated products, see Supporting Information.
In an attempt to gain further insight into the stereoinduction for the
bioconjugation step, the progression of the reaction was
1
monitored by H NMR analysis (see Supporting Information). It
was observed that within 15 min, the starting aldehyde 2a by
reaction with the O-benzyl-N-Boc-L-serine is fully consumed
generating a quinol-intermediate II and only a minor amount of 3j
(Scheme 3). The control experiment in Table 1, entry 11 shows
that the catalyst, under these reaction conditions, needs to be
present in order to activate II for the coupling to the amino acid
nucleophile. This is further supported when subjecting the N,N-
dimethylated version of the catalyst to the standard reaction
conditions. No oxidative coupling was observed supporting that
condensation of the primary amine with the aldehyde is necessary
for the reaction to proceed. Generating intermediate II without the
catalyst present and then adding catalyst A along with N-Boc-L-
glycine as the amino acid afforded the coupling product 3b with
67% ee, indicating that the stereochemistry is determined in the
second step (see Supporting Information).
Based on these results, we propose the catalytic cycle outlined in
Scheme 3. The first step is a condensation of aldehyde 2 with
aminocatalyst A, followed by a coupling reaction with DDQ
leading to intermediate I. Release of A from I forms a quinol-
intermediate II, which we propose to be an off-catalytic cycle
resting state. Intermediate II can enter the catalytic cycle by
reaction with aminocatalyst A, and release of the quinol form of
DDQ under formation of intermediate III. Intermediate III is
suggested to react with the carboxylic acid functionality in amino
acids and oligopeptides as outlined in IV in order to account for
the observed generated stereochemistry in the aldehyde moiety.
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Scheme 3. Proposed catalytic cycle for the stereoselective oxidative coupling
of the carboxylic acid functionality of amino acids and oligopeptides to
aldehydes.
[8]
[9]
a) S. Bloom, C. Liu, D. K. Kölmel, J. X. Qiao, Y. Zhang, M. A. Poss, W.
R. Ewing, D. W. C. MacMillan, Nat. Chem. 2018, 10, 205-211. b) M.
Garreau, F. Le Vaillant, J. Waser, Angew. Chem. Int. Ed. 2019, 58, 8182-
8186.
a) K. A. Mix, R. T. Raines, Org. Lett. 2015, 17, 2358-2361. b) N. A.
McGrath, K. A. Andersen, A. K. F. Davis, J. E. Lomax, R. T. Raines,
Chem. Sci. 2015, 6, 752-755. c) K. A. Mix, J. E. Lomax, R. T. Raines, J.
Am. Chem. Soc. 2017, 139, 14396-14398. d) V. T. Ressler, K. A. Mix, R.
T. Raines, ACS Chem. Biol. 2019, 14, 599-602.
[10] Y. Amako, C. M. Woo, Nat. Chem. 2019, 11, 1080-1082.
[11] L. A. Leth, L. Næsborg, G. J. Reyes-Rodríguez, H. N. Tobiesen, M. V.
Iversen, K. A. Jørgensen, J. Am. Chem. Soc. 2018, 140, 12687-12690.
[12] a) A. E. Wendlandt, S. S. Stahl, Angew. Chem. Int. Ed. 2015, 54, 14638-
14658. b) X. Guo, H. Mayr, J. Am. Chem. Soc. 2014, 136, 11499-11512.
c) N. M. Rezayee, V. H. Lauridsen, L. Næsborg, T. V. Q. Nguyen, H. N.
Tobiesen, K. A. Jørgensen, Chem. Sci. 2019, 10, 3586-3591. d) J. Blom,
G. J. Reyes-Rodríguez, H. N. Tobiesen, J. N. Lamhauge, M. V. Iversen,
C. L. Barløse, N. Hammer, M. Rusbjerg, K. A. Jørgensen, Angew. Chem.
Int. Ed. 2019, 58, 17856-17862.
[13] G. Kim, S. J. Weiss, R. L. Levine, Biochim. Biophys. Acta 2014, 1840,
901-905.
[14] G. R. Grimsley, J. M. Scholtz, C. N. Pace, Protein Sci. 2009, 18, 247-
251.
In conclusion, the first stereoselective oxidative bioconjugation of
the carboxylic acid functionality in amino acids and oligopeptides
to aldehydes has been developed. The concept relies on an
organocatalytic oxidative concept by which -branched
aldehydes combined with a chiral primary amine catalyst and
quinone as oxidizing agent allows for the stereoselective coupling
with C-terminal and side chain carboxylic acid functionalities of
amino acids and oligopeptides. Highly selective couplings are
demonstrated with both amino acids and oligopeptides under
atom-economic conditions. It is also demonstrated that this
stereoselective oxidative bioconjugation provides linker
molecules with biorthogonal handles for further functionalization
by merging the oxidative coupling strategy with the click concept.
Further effort towards a bioconjugation strategy are ongoing and
directed at optimizing conditions for larger biomolecules.
[15] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew.
Chem. Int. Ed. 2002, 41, 2596-2599. b) C. W. Tornøe, C. Christensen,
M. Meldal, J. Org. Chem. 2002, 67, 3057-3064.
Keywords: Bioconjugation • Amino acids • Oligopeptides•
Organocatalysis • Stereoselectivity • Oxidative coupling
[1]
[2]
N. Krall, F. P. da Cruz, O. Boutureira, G. J. L. Bernardes, Nat. Chem.
2016, 8, 103-113.
E. A. Hoyt, P. M. S. D. Cal, B. L. Oliveira, G. J. L. Bernardes, Nat. Rev.
Chem. 2019, 3, 147-171.
[3]
[4]
O. Koniev, A. Wagner, Chem. Soc. Rev. 2015, 44, 5495-5551.
a) B. Mondal, B. Roy, U. Kazmaier, J. Org. Chem. 2016, 81, 11646-
11655. b) B. V. S. Reddy, L. R. Reddy, E. J. Corey, Org. Lett. 2006, 8,
3391-3394. c) S.-Y. Zhang, Q. Li, G. He, W. A. Nack, G. Chen, J. Am.
Chem. Soc. 2013, 135, 12135-12141. d) D. P. Affron, O. A. Davis, J. A.
Bull, Org. Lett. 2014, 16, 4956-4959.
[5]
a) J. M. J. M. Ravasco, H. Faustino, A. Trindade, P. M. P. Gois, Chem.
Eur. J. 2019, 25, 43-59. b) S. Mahesh, V. Adebomi, Z. P. Muneeswaran,
M. Raj, Angew. Chem. Int. Ed. 2020, 59, 2793-2801. c) Y. Seki, T.
Ishiyama, D. Sasaki, J. Abe, Y. Sohma, K. Oisaki, M. Kanai, J. Am. Chem.
Soc. 2016, 138, 10798-10801.
[6]
[7]
a) D. G. Hoare, D. E. Koshland Jr., J. Am. Chem. Soc. 1966, 88, 2057-
2058. b) D. G. Hoare, D. E. Koshland Jr., J. Biol. Chem. 1967, 242, 2447-
2453. c) A. El-Faham, F. Albericio, Chem. Rev. 2011, 111, 6557-6602.
a) J. N. deGruyter, L. R. Malins, P. S. Baran, Biochemistry 2017, 56,
3863-3873. b) T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S.
Kawamura, B. D. Maxwell, M. D. Eastgate, P. S. Baran, Science 2016,
352, 801-805.
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Entry for the Table of Contents
RESEARCH ARTICLE
Henriette N. Tobiesen, Lars A. Leth,
Marc V. Iversen, Line Næsborg, Søren
Bertelsen, Karl Anker Jørgensen*
Page No. – Page No.
Stereoselective Oxidative
Bioconjugation of Amino Acids and
Oligopeptides to Aldehydes
The first stereoselective and atom-economical stereoselective oxidative
bioconjugation of carboxylic acid functionalities in amino acids and
oligopeptides to aldehydes is demonstrated.
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