Versatile Ru-Photoredox-Catalyzed Functionalization of Dehydro-Amino Acids and Peptides

Article abstract of DOI:10.1002/cctc.201900446

A versatile photoredox-catalyzed synthesis of unnatural amino acids and peptides is presented. Commercially available Ru(bpy)₃(PF₆)₂ was efficiently used as visible light photocatalyst in combination with a broad number of

Full text of DOI:10.1002/cctc.201900446

Accepted Article
Title: Versatile Ru-Photoredox-Catalyzed Functionalization of Dehydro-
Amino Acids and Peptides
Authors: Tobias Brandhofer and Olga García Mancheño
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ChemCatChem
10.1002/cctc.201900446
COMMUNICATION
Versatile Ru-Photoredox-Catalyzed Functionalization of Dehydro-
Amino Acids and Peptides
Tobias Brandhofer, [a],[b] and Olga García Mancheño*[a]
Abstract: A versatile photoredox-catalyzed synthesis of unnatural
limit their general application. More recently, the photoredox
catalyzed cross-coupling of -dehydroamino acid derivatives,
such as dehydroalanine (Dha), have attracted a great attention
(Figure 1b).[10] -Dehydroamino acids are naturally occurring
non-coded amino acids present in a large number of peptides.[
They are very useful synthetic building blocks for the synthesis of
unnatural amino acids and peptides, since they allow the coupling
with different radicals at their olefinic moieties. Thus, pioneer work
employing iridium(III) photoredox catalysis has been made in this
field in the past few years. However, these methods are restricted
to the Karady-Beckwith alkene[10a,b] or, for the more valuable
amino acids and peptides is presented. Commercially available
3 6 2
Ru(bpy) (PF ) was efficiently used as visible light photocatalyst in
combination with a broad number of different types of radical
precursors in the coupling with several dehydrogenated amino acid
residues. This method provides new entries to the mild, selective and
direct modification of both simple and complex peptide-like
compounds towards novel structures with improved or unusual
properties. Hence, (fluorinated)alkyl halides, arylsulfonyl chlorides or
various N-(acyloxy)phthalimides (NHPI esters) were effectively
reacted with a series of natural and unnatural -dehydroamino acids
and dipeptides. Moreover, the applicability of the process was also
proved by the late stage functionalization of the naturally occurring
peptide thiostrepton.
11]
[
10a]
acyclic -dehydroamino acids, to the use of halopyridines,
10b]
N-alkyl
tertiary
amines,[
potassium
as radical precursors and/or
phenoxymethyl
trifluoroborates[
10c]
and imines
[10d]
coupling partners. Aiming at a more general and less costly
Amino acids and peptides play a key role in chemistry and biology, method, we herein present a ruthenium(II) photoredox-catalyzed
being important chiral building blocks for the construction of
biomolecules, as well as synthetic catalysts and drugs.[1]
Moreover, they present an unlimited potential for the discovery of
new bioactive targets with extremely diverse activities upon
chemical alteration of their structures. However, there are still
substantial challenges in peptide drug design,[2] for which the
straightforward modification of naturally occurring amino acid
residues would overcome some of these constraints. As a
consequence, catalytic site-selective functionalization methods of
amino acids and peptides under mild, biocompatible conditions
towards novel drug candidates and therapeutics are of current
growing demand.
functionalization of dehydroamino acids and peptides with a
broad variety of alkyl radical precursors, which allows to easily
introduce fluorinated and fatty acid-derived chain groups, as well
as carrying on late stage peptide functionalization (Figure 1c).
a) Decarboxylative couplings:
R2
PG
O
O
Ir or Ru photocatalyst
or
EWG
N
R1
R
R2
n
OPht
OMe
R
PG
OH
or
N
R1
or PG
R
O
N
hn
- CO2
O
n
PG
PG
OMe
R1 = PG, H
N
PG
b) Ir-catalyzed coupling with dehydroalanines (Dha) and Karady-Beckwith alkene:
In this regard, visible-light photoredox catalysis has recently
emerged as a powerful strategy for the activation of organic
molecules under mild conditions, while enabling unprecedented
transformations.[3] Indeed, due to its mildness, photocatalysis
presents an intrinsic large functional group tolerance, being
compatible with highly functionalized compounds such as amino
acids or peptides. Based on this, several procedures for the
photocatalytic modification of amino acid derivatives have been
recently developed. Besides the derivatization of functional
groups of amino acid residues such as sulfur-containing
O
R
Ir(III)]+
R
O
[
PG
R2
O
hn
PG
R2
or
or
O
N
R1
N
N
R1
N
Cbz
R
O
O
Cbz
tBu
tBu
Jui
Roelfes
R''' ArO
Dixon
NR''
PG = Boc, Ac, Pept.
R1 = H, PG
R2 = OR, NH-Pept.
R''
N
X
BF3K
[
4]
R'
R'
N
R'
H
R
c) This work:
Ru(bpy)3]2+
blue LEDs
reductant
[
R2
R2
Ø Ru-catalyzed
Ø broad scope
PG
PG
cysteine[ and methionine or aromatic rests such as in tyrosine
5]
[6]
[7]
N
H
N
O
H
O
and tryptophan,[8] an interesting alternative approach is based on
Ø fluorinated & fatty acid rests
Ø late stage functionalization
of complex peptides
O
O
O
O
O
decarboxylative couplings (Figure 1a).[9] In this case, the amino
acid structure is lost[9b,c] or aspartic or glutamic acid units suffer
FAlk-X
Alk
ArSO2-Cl
F3C
I
R
X
N
the decarboxylation/functionalization at the side-chain,[9d] which
O
Scheme 1. Visible Light photocatalytic functionalization of amino acid
derivatives.
[
[
a]
b]
T. Brandhofer, Prof. Dr. O. García Mancheño
Organic Chemistry Institute, Münster University
Corrensstrasse 40, 48149 Münster
E-mail: olga.garcia@uni-muenster.de
T. Brandhofer
We started our study by optimizing the reaction of
dehydroaniline 1a as model substrate with CBrCl
precursor using 2 mol% of commercially available Ru(bpy)
3
as radical
6 2
(PF )
Institute for Organic Chemistry, Regensburg University
Universitätsstrasse 31, 93053 Regensburg
3
as photoredox catalyst in a blue LED’s photoreactor at room
temperature (Table 1, see S.I. for the complete screening).
Several common reducing agents such as diisopropylethylamine
Supporting information for this article is given via a link at the end of
the document.
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ChemCatChem
10.1002/cctc.201900446
COMMUNICATION
Table 2. Reaction scope with dehydroamino acids 1.[a],[b]
(
DIPEA), 1-benzyl-1,4-dihydronicotinamide (BNAH) or the
Hantzsch ester (HE) were initially tested in acetonitrile as solvent
entries 1-3). Among them, the Hantzsch ester showed the best
performance, providing the desired coupling product 2a in a good
9% yield (entry 3). This result could be enhanced when using
O as co-solvent (65%, entry 4). Under these conditions, a
similar good 64% yield was obtained with the N-methyl HE (entry
), which facilitated in this case the purification of the product.
R
X
or
(
Ru(bpy)3(PF6)2 (2 mol%)
R
O
O
PG
Ac
OMe
O
O
HE or Me-HE (2 eq.)
N
H
+
PG
OMe
N
N
5
H
CH CN:H O (5:1)
O
R
3
2
H
blue LEDs, 18 h
1
O
2
2
CCl3
OMe
CCl3
CCl3
CBr3
OMe
5
Boc
OMe
Cbz
OMe
Ac
N
H
N
N
N
Instead, the absence of the Ru-catalyst or use of the
organophotocatalyst Eosin Y[12] provided lower conversions
H
H
H
O
O
O
O
2a, 65%
2b, 88%
2c, <10%
2d, n.r.
X = Br
X = Br
X = Br
X = Br
(
entries 6 and 7). Moreover, other solvent mixtures (entries 8-9),
as well as by carrying out the reaction under air atmosphere (entry
0) or without reductant and/or light irradiation (entry 11), led to
CF3
C4F9
OMe
C8F17
CF2CO2Et
OMe
Ac
OMe
Ac
Ac
OMe
Ac
1
N
N
N
N
H
H
H
H
low amounts of 2a or no reaction.
O
O
O
O
2
e, 63%[
c]
2f, 67%
2g, 38%
2h, 57%
X = I
X = I
X = Br
Table 1. Screening of the reaction conditions with 1a as model substrate.[a]
NO2
Br
O
Ph
CCl3
photocatalyst (2 mol%)
O
O
reductant (2 eq.)
N
CO2Me
N
CO2Me
Ac
OMe
SO2
OMe
SO2
SO2
OMe
H
CBrCl3 (3 eq.)
solvent, 18 h
blue LEDs
H
N
H
O
Ac
Ac
OMe
Ac
N
1
a
2a
N
H
N
H
H
O
O
O
2
i, 56%
2j, 74%
X = Cl
2k, 66%
X = Cl
2l, 45%
X = Cl
Yield (%)[b]
X = Br
Entry
Catalyst
Red.
Solvent
Ph
Ph
C8H17
1
2
3
4
5
6
7
8
9
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
3
3
3
3
(PF
(PF
(PF
(PF
(PF
6
6
6
6
6
)
)
)
)
)
2
2
2
2
2
DIPEA
BNAH
HE
MeCN
MeCN
MeCN
37
55
59
65
64
4
tBu
4
C12H25
7
Ac
OMe Boc
OMe Cbz
OMe Boc
OMe Ac
OMe
N
N
N
N
N
H
H
H
H
H
O
O
O
O
O
2m, 74%
2n, 72%
2o, 48%
2p, 39%
2q, 29%
HE
Me-HE
HE
MeCN/H
2
2
2
2
O (5:1)
O (5:1)
O (5:1)
O (5:1)
[a] Conditions: Ru(bpy)
mmol, 2 eq.) and the coupling partner (0.6 mmol, 3 eq.) were reacted in
MeCN/H O (5:1) at r.t. for 18 h. [b] Isolated yield. [c] Togni’s reagent was used.
3 6 2
(PF ) (2 mol%), 1 (0.2 mmol, 1 eq.), HE or Me-HE (0.4
MeCN/H
MeCN/H
MeCN/H
MeOH/H
2
--
Eosin Y
the corresponding trifluoromethylated product 2e in a good 63%
yield. Fluorinated alkylhalides with various chain lengths were
effectively enrolled under the standard reaction conditions. The
desired coupling products 2f-h were obtained in moderate to good
yields (38-67%), depending on the introduced chain (i.e. longer
chains led to lower conversions).[14] Other alkylhalides bearing
carbonyl groups, as well as arylsulfonyl chlorides, were employed
as radical precursors, leading to the corresponding alkylated and
sulfonylated products 2i and 2j-l, respectively. Finally, a series of
N-(acyloxy)phthalimides (NHPI esters)[15] with branched (tBu,
product 2m) and linear rests (products 2n-q) were also efficiently
coupled, including the more challenging reaction with derivatives
from fatty acids and olefin-containing moieties.
HE
17
35
57
Ru(bpy)
3
3
3
3
(PF
6
6
6
6
)
2
)
2
)
2
)
2
HE
2
O (5:1)
Ru(bpy)
Ru(bpy)
Ru(bpy)
(PF
(PF
(PF
HE
DMSO/H
2
O (5:1)
O (5:1)
O (5:1)
1
0
1
HE
MeCN/H
MeCN/H
2
16[c]
--[d]
1
--
2
[
(
[
a] Conditions: Photocatalyst (2 mol%), 1a (0.2 mmol, 1 eq.), HE or Me-HE
0.4 mmol, 2 eq.) and CBrCl (0.6 mmol, 3 eq.) were reacted at r.t. for 18 h.
b] Isolated yield. [c] Reaction under air. [d] Reaction without reductant or
3
without light irradiation led to no reaction or traces of 2a.
This method was then extended to other natural and unnatural
amino acids such as dehydro-2-methyl--alanine, dehydro-
phenylalanine and dehydrobutyrine derivatives (Scheme 2, top).
In all these cases presenting a substituted olefin group, we could
observe an important steric effect, which notable hindered the
Having identified the optimal reaction conditions
(
Ru(bpy)
MeCN:H
reaction with various alkyl radical precursors was investigated
Table 2). First, different N-protected Dha derivatives were
explored in the reaction with Cl CBr. Whereas the N-Boc
3
6 2
(PF ) as catalyst and HE or Me-HE as reductant in
2
O (5:1) at room temperature for 18 h), the scope of the
(
reaction with CBrCl
3
(e.g. 3a, 15%). Therefore, to overcome this
CCF -Br as
3
issue, the reactions were performed with EtO
2
2
protected Dha led to the product 2b in an excellent 88% yield,
other protecting groups such as Cbz proved less effective.
Choosing 1a as model substrate for next studies, analogous
trihalogenated C1-precursors were reacted. Under these
coupling partner, leading then to the desired products 3b, 4 and 5
in good yields (up to 91%). Furthermore, an itaconic acid derivate
and dipeptides with dissimilar substitution pattern and protecting
groups were also effectively alkylated to the corresponding
products 6 and 7a-b with moderate to good diastereomeric ratios.
Finally, this method was also employed for the late stage
conditions, CBr
4
did not participate in the reaction, while Togni’s
reagent (1-trifluormethyl-1,2-benziodoxol-3(1H)-on)[13] delivered
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ChemCatChem
10.1002/cctc.201900446
COMMUNICATION
functionalization of a naturally occurring peptide such as the
natural cyclic oligopeptide antibiotic thiostrepton (8),[16] which
present four dehydroamino acid residues (in blue) and a further
unreactive cyclic olefin in its structure (orange) (Scheme 2,
bottom). In this case, a different product distribution could be
obtained by varying the stoichiometries of the reactants and,
especially, the reaction time. Thus, in the reaction with the tert-
butyl NHPI ester we could observe a low conversion of 8 into the
mono to tri-alkylated derivatives 9-12 (entry 1), while by
increasing the reaction time to 18 or 36 h favored the formation of
the tri- (11) and tetra-substituted (12) products, respectively
pathway does not involve a radical chain propagation process (Φ
≤1). Based on these observations and previous reports in the
literature,[19] a plausible reaction mechanism implying a catalyst
reductive quenching with the HE is outlined in Scheme 3
(bottom).[20] Accordingly, the excitation of the catalyst in its ground
+
2
state Ru(bpy)
3
(PC) by absorption of visible light generates the
photoexcited state PC*. The PC* is able to oxidize the Hantzsch
ester (A) by a single electron transfer (SET) to form the HE-radical
–
•
–•
cation (B) and the reduced catalyst PC . The PC species reacts
then with the reagent partner R-X, forming the radical
•
intermediate R and regenerating the photocatalyst PC in its
(
(
entries 2 and 3). Similarly, the 18 h reaction with EtO
entry 4) led to a product distribution in favor of the tri-substituted
2
CCF
2
-Br
ground state. The generated carbon radical adds to the double
bond of the -dehydroamino acid 1a to form the radical I. Then,
a SET from the HE-radical cation to I led to the anionic
intermediate II and the pyridine/pyridinium species C. Finally, the
products 11 (43%).
co-solvent H
2
O protonates II to form the product 2a.
Hantzsch ester (2 eq.)
CBrCl3 (3 eq.)
>
90% Deuteration
CH3CN:D2O (5:1)
CCl3
H/D
O
Ru(bpy) (PF )
O
3
6
2
(
2 mol%)
N
H
CO2Me
N
2
CO Me
blueLED, 18 h
H
2
1
a
D -Hantzsch ester (2 eq.)
CBrCl3 (3 eq.)
2a/2a-D
9
% Deureartion
CH3CN:H2O (5:1)
EtO2C
CO2Et
EtO C
2
CO Et
EtO2C
CO2Et
2
N
N
N
R'
R'
R'
C
A
B
R' = H, Me
R
O
R
-
H+
SET
Ac
O
SET
Ac
O
N
N
H
H
PC*
O
I
II
PC
H2O
visible
light
R + X-
R
H
PC
Ac
O
Ac
N
O
N
H
R-X
H
O
O
1
a
2a
Scheme 3. Deuteriation studies and proposed mechanism.
1
,2
,15
,1
1
y = 0,9736x + 1,0055
1
1
,05
1
Scheme 2. Functionalization of different dehydroamino acids and peptides.
0,95
,9
0
0
0,02
0,04
[Hantzsch ester] (M)
0,06
0,08
Lastly, in order to get some insights into the mechanism of this
transformation, deuteration and quenching studies were carried
2
out. Hence, whereas the use of D O as co-solvent led to a >90%
of deuteration, the deuterated labelled Hantzsch ester provided
the product within a low 9% of deuteration level (Scheme 3, top).
Furthermore, a notable fluorescence quenching of the catalyst
was observed with the Hantzsch ester (Figure 1), not being
significant for the -dehydroamino acid 1a (see S.I. for the
complete quenching study).[17,18] Moreover, the quantum yield
was determined as 0.4 (see S.I.), which suggests that the main
(4·10-4
3 6 2
Figure 1. Stern-Volmer Plot: Fluorescence quenching of Ru(bpy) (PF )
q
M in MeCN) with HE. k M s .
= 1.09·106
-1
-1
In conclusion, we have developed a versatile photoredox-
catalyzed synthesis of unnatural amino acids and peptides by
coupling of -dehydroamino amino acids and peptides with a
broad number of different types of radical precursors using
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ChemCatChem
10.1002/cctc.201900446
COMMUNICATION
commercially available Ru(bpy)
3
(PF
6
)
2
as visible light
46, 5193-5203; j) I. K. Sideri, E. Voutyritsaa, C. G. Kokotos, Org. Biomol.
Chem. 2018, 16, 4596-4614. See also: k) Special Issue on photoredox
catalysis: Eur. J. Org. Soc. 2017, issue 15, 1978-2204.
photocatalyst. Accordingly, (fluorinated)alkyl halides, arylsulfonyl
chlorides or various N-(acyloxy)phthalimides (NHPI esters) were
effectively reacted. Moreover, the applicability of the process was
also proved by the late stage functionalization of the naturally
occurring peptide thiostrepton. In addition, the determination of
the quantum yield, quenching and deuterium experiments were
performed to enlighten the reaction mechanism. Moreover, we
[
4]
5]
C. Bottecchia, T. Noël, Chem. Eur. J. 2019, 25, 26-42.
[
a) C. A. DeForest, K. S. Anseth, Angew. Chem. Int. Ed. 2012, 51, 1816-
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2
found that the co-solvent H O is more prompt than the HE to
participate in the final protonation step.
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3 6 2
General catalytic procedure: In a screw cap vial, Ru(bpy) (PF ) (3.4 mg,
0.004 mmol, 2 mol%), dehydroamino acid 1 or peptide (0.2 mmol, 1 eq.),
HE or Me-HE (0.4 mmol, 2 eq.) and the coupling partner 2 (0.6 mmol, 3
eq.) were added and the vial was degassed three times by evacuating and
refilling with Argon. 2 mL of a 5:1 mixture of MeCN/H
2
O was added and
[8]
[9]
a) Y. Yu, L.-K. Zhang, A. V. Buevich, G. Li, H. Tang, P. Vachal, S. L.
Colletti, Z.- C. Shi, J. Am. Chem. Soc. 2018, 140, 6797-6800; b) Y. Wang,
J. Wang, G.-X. Li, G. He, G. Chen, Org. Lett. 2017, 19, 1442-1445.
a) M. Jiang, Y. Jin, H. Yang, H. Fu, Sci. Reports 2016, 6, 26161. For C-
terminal couplings, see: b) S. Bloom, C. Liu, D. K. Kölmel, J. X. Qiao, Y.
Zhang, M. A. Poss, W. R. Ewing, D. W. C. MacMillan, Nat. Chem. 2017,
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911. For side-chain modifications, see: d) M. Jiang, H. Yang, H. Fu, Org.
Lett. 2016, 18, 1968-1971.
the vial was degassed by three freeze-pump-thaw cycles. The reaction
mixture was stirred at room temperature for 18 h under irradiation of blue
light. Then, the mixture was transferred in a separation funnel and 5mL
DCM and 5 mL water was added. The phases were separated and the
aqueous phase was extracted three times with DCM. The combined
organic layers were washed with brine, dried over MgSO , filtered, and
4
concentrated under reduced pressure. The residue was purified by flash
column chromatography.
[
10] a) R. A. Aycock, D. B. Vogt, N. T. Jui, Chem. Sci. 2017, 8, 7998-8003; b)
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Acknowledgements
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INTERREG V A, ETZ 2014-2020 – Bayern-Czech Republic
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Synthesis 1988, 159-172.
(
project 41) is gratefully acknowledged for generous support.
[
[
[
12] D. P. Hari, B. König, Chem. Commun. 2014, 50, 6688-6699.
13] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579-2586.
14] For the inclusion of fluorinated moieties into cysteine-containing amino
acids, see: C. Bottecchia, X.-J. Wei, K. P. L. Kuijpers, V. Hessel, T. Noël,
J. Org. Chem. 2016, 81, 7301-7307.
Keywords: Photoredox catalysis • Dehydroamino acids •
Peptides • Visible light • Ruthenium
[
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[20] Though presenting a lower K
q
, a fluorescence quenching of the Ru-
catalyst with Cl CBr could also be observed (see S.I.). Therefore, an
3
alternative mechanism implying an oxidative quenching by the coupling
reagent could not be excluded.
This article is protected by copyright. All rights reserved.

ChemCatChem
10.1002/cctc.201900446
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Tobias Brandhofer, Olga García
Mancheño*
R
O
Ø Ru-catalyzed
OR'/Peptide Ø broad scope
[
Ru(bpy)3]2+
HE
Peptide/PG
OR'/Peptide
Peptide/PG
N
H
N
H
Ø fluorinated & fatty acid rests
Ø peptide late stage
O
Page No. – Page No.
(F)Alk-X
O
ArSO2-Cl
R
O
NHPI
functionalization
Versatile Ru-Photoredox-Catalyzed
Functionalization of Dehydro-Amino
Acids and Peptides
A versatile photoredox-catalyzed synthesis of unnatural amino acids and peptides by
coupling of -dehydroamino amino acids and peptides with a broad number of
different types of radical precursors using commercially available Ru(bpy)
3 6 2
(PF ) as
visible light photocatalyst is presented.
This article is protected by copyright. All rights reserved.