Visible-Light-Driven, Copper-Catalyzed Decarboxylative C(sp3)?H Alkylation of Glycine and Peptides

Article abstract of DOI:10.1002/anie.201809400

Despite a well-developed and growing body of work in Cu catalysis, the potential of Cu to serve as a photocatalyst remains underexplored. Reported herein is the first example of visible-light-induced Cu-catalyzed decarboxylative C(sp³)?H alkylation of glycine for preparing α-alkylated unnatural α-amino acids. It merits mentioning that the mild conditions and the good functional-group tolerance allow the modification of peptides using this method. The mechanistic studies revealed that a radical–radical coupling pathway is involved in the reaction.

Full text of DOI:10.1002/anie.201809400

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Visible-Light-Driven, Copper-Catalyzed Decarboxylative C(sp3)-H
Alkylation of Glycine and Peptides
Authors: Chao Wang, Mengzhun Guo, Rupeng Qi, Qinyu Shang,
Qiang Liu, Shan Wang, Long Zhao, Rui Wang, and Zhaoqing
Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809400
Angew. Chem. 10.1002/ange.201809400
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10.1002/anie.201809400
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Visible-Light-Driven, Copper-Catalyzed Decarboxylative C(sp3)-H
Alkylation of Glycine and Peptides
Chao Wang, Mengzhun Guo, Rupeng Qi, Qinyu Shang, Qiang Liu, Shan Wang, Long Zhao, Rui
Wang,* and Zhaoqing Xu*
Abstract: Despite a well-developed and growing body of work in Cu
catalysis, the potential of Cu to serve as a photocatalyst remains
underexplored. We here report the first example of visible-light-
induced Cu-catalyzed decarboxylative C(sp3)-H alkylation of glycine
for preparing α-alkylated unnatural α-amino acids. It merits
mentioning that the mild conditions and the good functional group
tolerance allow the modification of peptides using this method. The
mechanistic studies revealed that a radical-radical coupling pathway
was involved in the reaction.
application in alkylated modification of peptides and
pharmaceutical compounds.[7] In the reactions, the precious
transition-metal photocatalysts, e.g. Ir or Pd, were used to
mediate the single electron transfer. Compared with Ir and Ru,
the using of Cu as photoredox catalyst is uncommon.[9] In 2017,
Fu reported the first visible-light-induced Cu-catalyzed
intramolecular sp3 C-N coupling via the decarboxylation of alkyl
NHP ester (Figure 1b).[6] Despite of this achievement, the visible-
light-induced Cu-catalyzed intermolecular decarboxylative
C(sp3)-C(sp3) cross-coupling, especially the C(sp3)-H alkylation,
is still not realized.
The cross-coupling between two sp3 C remains a significant
challenge in synthetic organic chemistry. In the past few
decades, great progress has been made in transition-metal-
catalyzed alkyl-alkyl cross-coupling between organometallic
reagents and alkyl halides.[1] A series of significant achievements
have been made by Noller, Tamura, Fu, Suzuki, Knochel,
Kambe, and many others.[2] However, the frequent toxicity and
limited abundance of alkyl halides restrict their applied value in
alkyl-alkyl cross-couplings. Compared with alkyl halides, alkyl
carboxylic acids are presented in numerous natural products
and medicines. The carboxylic acids derived redox active esters,
namely N-hydroxyphthalimide (NHP) esters or their analogues,
have recently been intensively investigated as precursors for
organic radical couplings.[3] In 2016, Baran’s group pioneered a
general alkyl-alkyl cross-coupling using alkyl NHP esters, which
provided new opportunities for choosing alkyl electrophiles in sp3
C-C bond formations (Figure 1a).[4a] In the same year, Fu[4b] and
Weix[4c]
reported
Ni-catalyzed
decarboxylative
alkene
hydroalkylation and decarboxylative C(sp2)-C(sp3) cross-
coupling using alkyl NHP esters, respectively. Although several
approaches have been reported for photo activation of alkyl
NHP esters, such as UV light irradiation[5a,b] and visible-light-
induced photo catalysis using precious metal photocatalyst (Ru,
Ir, or Pd)[5c-h, 5k-q] or organic dye catalysts[5i-j], the using of earth-
abundant Cu as visible-light photosensitizer to promote the
generation of alkyl radicals from alkyl NHP esters is still not
easily accessible.[6]
Figure 1. Decarboxylative of alkyl redox-active esters and alkylated
modification of peptides.
Introduction of unnatural amino acids or modifying the
residues in natural peptides are the most important strategies in
peptide drug discovery.[10] Glycine possesses the basic skeleton
of α-amino acids. α-C(sp3)-H alkylation of glycine represents the
most straight forward way to synthesis unnatural α-amino acid.
Unfortunately, the reported methods for direct C(sp3)-H
alkylation of glycine were either merely restricted to
benzylation[11] or using strong oxidants with high temperature,
which led to poor regio-selectivities and functional group
tolerance.[11,12] Importantly, the harsh conditions or limited
substrate scopes restrict their further applications in late-stage
modification of bioactive peptides.
The direct alkylation of C(sp3)-H provide
a convenient
alternation for C(sp3)-C(sp3) cross-coupling. Very recently, the
photoinduced alkylations of C(sp3)-H have been developed by
MacMillan[7] and Yu[8], using alkyl bromides or benzyl chlorides
as electrophiles. MacMillan and co-workers also reported its
Continued with our interest in photoinduced alkylations[13] and
peptides synthesis,[14] we here report the first example of visible-
light-induced Cu-catalyzed C(sp3)-H decarboxylative alkylation
(Figure 1c). The mild conditions provided good functional group
tolerance and broad substrate scopes, in which the primary,
secondary, and tertiary carboxylic acids, as well as amino acids
and oligopeptides, all served as the alkylation reagents with
uniformly good yields. It merits mentioning that peptides could
also be highly site-selectively alkylated with very good yields
under standard reaction conditions.
[*]
C. Wang, M. Guo, R. Qi, Q. Shang, S. Wang, L. Zhao, Prof. Dr. R.
Wang, Prof. Dr. Z. Xu
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, School of Basic Medical Sciences, Lanzhou University,
199 West Donggang Road, Lanzhou 730000(China)
E-mail: wangrui@lzu.edu.cn, zqxu@lzu.edu.cn
Prof. Dr. Q. Liu
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, 222 South Tianshui Road, Lanzhou 730000 (China)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201809400
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COMMUNICATION
Table 1. Optimization of reaction conditions.
provide a better yield than DMF (entry 14). Other NHP type
esters (2a’ and 2a’’) gave negative results (entries 15 and 16).
Light sources screening showed that only blue LED light was
effective for this reaction (entry 17). Reducing the amount of 2a,
Cu(MeCN)4PF6, and ligands resulted in the substantial drop of
yields (entries 18-20). In addition, the coupling reaction was
sensitive to the oxygen (entry 21).
Table 2. Scope of alkyl NHP esters.[a]
Our investigation was initiated by using ethyl 2-
(phenylamino)acetate 1a and cyclohexyl NHP ester 2a as model
substrates under blue LED light irradiation (Table 1). After
screening of the reaction parameters (e.g. copper catalysts,
ligands, basic additives, and solvents), the desired product 3aa
was obtained in 93% NMR yield (88% yield of isolated product)
in the presence of 10 mol% Cu(MeCN)4PF6, 15 mol% dmp, 15
mol%
xantphos,
2.0
equivalent
DABCO
(1,4-
diazabicyclo[2.2.2]octane), and DMF (N,N-dimethylformamide,
entry 1, see the SI for details). Control experiments showed that
blue LED irradiation, copper catalyst, ligands, and DABCO were
indispensable for the reaction (entries 2-4). Compared to cupric
catalysts, cuprous catalysts furnished a better yield of the
product (entries 5 and 6). When dmp and xantphos were
replaced with other ligands, the reaction proceeded inefficiently
To explore the substrate scopes, various alkyl NHP esters
were investigated under optimal conditions. As summarized in
Table 2, the strategy was successfully applied to primary,
secondary, and tertiary alkyl NHP esters with good to excellent
yields (3ab-3ak, 53-90%). Importantly, the substrates bearing
various substituent groups, such as halogen, ester, and ether
group were all tolerant (3ac, 3ad, and 3ae-3ag). Furthermore,
NHP esters of α-amino acids (2l, 2m, and 2n) were smoothly
decarboxylative coupled with 1a in excellent yields, which
provided an efficient method for the preparation of 1,2-di-amine
compounds (3al-3an). Notably, dipeptide (2o) derived NHP
(entries 7-10). Cu(dap)2Cl (dap
phenanthrolin) was also not effective for our reaction either
under blue light or green light (530 nm) irradiation (entry 11)[15]
=
2,9-bis(p-anisyl)-1,10-
.
Replacing DABCO with other bases, including organic bases
(HMPA = hexamethylphosphoric triamide) and inorganic bases,
led to significantly lower yields (entries 12 and 13). Furthermore,
other solvents, such as dichloromethane (DCM), could not
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esters coupled with 1a in 81% yield of isolated product, which
protected dipeptide 1k was successfully coupled with primary
and secondary alkyl NHP esters in excellent yields (3ka and
3kd). For the alkylation of tripeptide and tetrapeptide (fragment
of enkephalin) bearing sensitive functional group (-CH2SCH3),
the reactions absolutely selective proceeded at α-position of
glycine carbonyl, rather than α-position of thiomethyl (3lc, 3ma,
and 3mi, PMP = p-methoxyphenyl).
rendered
a versatile application of our reaction in the
modification of bioactive peptides (3ao). Naturally occurring
carboxylic acids such as palmitic acid (2p), arachidic acid (2q),
and deoxycholic acid (2r) were also amenable to this C(sp3)-H
alkylation.
Table 3. Scope of glycine derivatives.[a]
Scheme 1. Synthetic application of product 3da.
The α-alkylated product was easily converted to α-unnatural
amino acid via removing N-protecting group (Scheme 1, 3da).
The PMP protection could be removed by CAN (ammonium
cerium nitrate, 6 equiv) and used in peptide synthesis without
further purifications. Collagen tripeptides are important skin care
products. With our strategy, the condensation of the deprotected
intermediate 3da’ and dipeptide proceeded smoothly and
provided the analogue of collagen tripeptide 4 in 76% overall
yield (1:1d.r.).
Further expansion of the substrate scopes was focused on
glycine derivatives (Table 3). The esters of glycine bearing both
electron-rich and electron-poor groups on the aromatic ring were
well tolerated (3aa-3ea, 78-88%). In addition, the yield of 3da
was maintained when the reaction was conducted on a gram
scale (82%, 10 mmol scale and 36 h). Besides esters, the
amides of glycine with N-mono-substituent and N-bis-
substituents all went smoothly (3fa-3ha). Furthermore, α-amino
ketone 1i and N-aryl tetrahydroisoquinoline 1j were also suitable
substrates for this transformation.
Table 4. Site-selective modification of peptides.[a]
Scheme 2. Mechanistic studies.
The applied value of our reaction was demonstrated by
alkylated modification of peptides (Table 4). The N-phenyl
To gain some information of the reaction mechanism, radical
trapping experiments and radical clock experiments were
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5
4.5
4
conducted (Scheme 2). When 2.0 equiv of TEMPO (2,2,6,6-
tetramethylpiperidin-1-oxyl)
or
BHT
(2,6-di-tert-butyl-4-
methylphenol) was added, the reaction was shut down,
respectively (eq 1 and 2). The TEMPO trapping product 5 was
isolated in 40% yield (eq 1). When ethene-1,1-diyldibenzene
was added instead of 1a, Heck-type product 6 was obtained in
65% yield (eq 3). In the presence of 1a, 2a, and ethene-1,1-
diyldibenzene, the product of three-component reaction was
observed (eq 4). Furthermore, the radical clock experiment with
6-heptenoic acid derived NHP ester 2s led to the formation of
cyclization product 3as in 62% yield (eq 5). In addition, the
3.5
3
y = 0.5749x + 1
R² = 0.9707
2.5
2
1.5
1
0.5
0
0
2
4
6
8
quencher concentration （10-4 M）
Figure 2. Stern-Volmer plot for the emission quenching of
Cu(dmp)(xantphos)PF6 by various concentrations of quencher 2a.
homo-coupling product
8 from glycine derivative 1a was
obtained in 2.7% yield of isolated product (eq 6). These results
suggested that the alkyl radical and the glycine derivative radical
were generated in the reaction system.
On the basis of above investigations and previous reports,[16]
a
possible reaction mechanism was proposed in Scheme 3. Under
blue LED light irradiation, cuprous-based complex [CuIL] was
excited to its excited state [CuIL]* (E1/2[CuII/CuI*] = -1.86 V versus
SCE (saturated calomel electrode) in MeCN), which underwent
a single electron transfer (SET) process with alkyl NHP ester 2
(Ep0/-1(2) = -1.28 to -1.37 V versus SCE in MeCN)[16c,18], followed
by the generation of alkyl radical A, CO2, phthalimide anion, and
[CuIIL]. [CuIIL] (E1/2[CuII/CuI] = 0.38 V versus SCE in MeCN)
oxidized glycine derivatives 1 (Ep0/+1(1a) = 0.31 V versus SCE in
MeCN) to form radical cation intermediate B, along with
regeneration of [CuIL]. On the other hand, intermediate B was
deprotonated and followed by a 1,2-H shift process under basic
conditions (DABCO or phthalimide anion) to provide a stable α-
carbon radical C. Finally, the radical-radical cross-coupling
between alkyl radical A and α-carbon radical C was proposed
and provided alkyl-alkyl cross-coupling product 3.
Table 5. Control experiments.
To further understand the interactional manners between
copper salt and ligands, control experiments were carried out
(Table 5). In the absence of dmp and xantphos, or either of them,
the reaction was not proceeded (entries 1-3). The results
suggested that a heteroleptic copper(I)-based complex might
formed in the system and acted as the photosensitizer. When
Cu(dmp)(xantphos)PF6 was prefabricated[16] and employed in
the reaction (10 mol %), a similar result was obtained to the
using of in situ generated catalyst (entries 4-6). Furthermore,
HRMS analysis of the mixture in the standard reaction (Table 1,
entry 1) indicated the formation of Cu(dmp)(xantphos)BF6 in the
reaction system.[17]
In UV-Vis absorption experiments, the absorption spectrum of
the in situ generated Cu catalyst (Cu(MeCN)4PF6:dmp:xantphos
=
1:1.5:1.5) was consistent with the prefabricated
[Cu(dmp)(xantphos)]PF6 (see the SI for details, Figure S3).
When cyclohexyl NHP ester 2a was combined with Cu salt and
ligands, an obvious bathochromic-shift and broader absorption
region were observed (Figure S4). The results indicated that the
Cu complex might also increase the reactivity of NHP ester
under blue light irradiation. In addition, Stern-Volmer plot results
indicated that the alkyl NHP ester 2a quenched the excited state
of Cu(dmp)(xantphos)PF6, where it presumably engaged in SET
event in the reaction (Figure 2). Finally, the quantum yield Φ =
0.74 indicated a radical chain process might not involve in the
reaction (see the SI for details)
Scheme 3. Proposed mechanism.
In summary, we disclosed the first photo-induced Cu-
catalyzed
site-selective
alkylation
of
C(sp3)-H
via
decarboxylative of alkyl NHP esters. A series of glycine
derivatives and N-aryl tetrahydroisoquinoline were tolerant with
uniformly good yields. A variety of alkyl NHP esters proceeded
the alkyl-alkyl cross-coupling in good to excellent yields. The
strategy was successfully applied in the preparation of unnatural
α-amino acids and the alkylated modification of peptides.
Furthermore, with a simple operation, the α-alkylated unnatural
amino acid could be directly used for the preparation peptide-
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tripeptide.
[5]
Acknowledgements
We are grateful for the grants from the NSFC (No. 21432003)
and Fundamental Research Funds for the Central Universities
(lzujbky-2017-127 and lzujbky-2018-k9). The authors thanks
Prof. Yong Ding, Prof. Yawen Wang, Dr. Junqi Lin, Dr. Xu Feng,
and Dr. Baojun Wang for helpful discussion and technical
assitance.
Keywords: alkylation • decarboxylative • C(sp3)-C(sp3) cross-
coupling • copper • peptide
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[17] When Cu(MeCN)4PF6 was in situ combined with different diamine and
bisphosphine ligands, and used in the standard reaction, only some of
them showed catalytic activities.The HRMS analysis of the reaction
mixtures indicated that the Cu(diamine)(bisphosphine)PF6 complexes
[4]
a) T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura,
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were
formed.
In
addition,
the
prefabricated
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10.1002/anie.201809400
Angewandte Chemie International Edition
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Cu(diamine)(bisphosphine)PF6 complexes with various diamine and
bisphosphine ligands were also applied in the standard reactions. With
the same ligands, the prefabricated complex and the in situ generated
catalyst gave the similar results. See the SI for details.
[18] K. Okada, K. Okamoto, M. Oda, J. Am. Chem. Soc. 1988, 110, 8736 –
8738.
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