Visible-Light-Promoted C(sp3)?H Alkylation by Intermolecular Charge Transfer: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides

Article abstract of DOI:10.1002/anie.201914555

Disclosed herein is the visible-light-promoted deaminative C(sp³)?H alkylation of glycine and peptides using Katritzky salts as electrophiles. Simple reaction conditions and excellent functional-group tolerance provide a general strategy for th

Full text of DOI:10.1002/anie.201914555

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Accepted Article
Title: Visible-Light-Promoted C(sp3)-H Alkylation by Intermolecular
Charge Transfer: Preparation of Unnatural α-Amino Acids and
Late-stage Modification of Peptides
Authors: Chao Wang, Rupeng Qi, Hongxiang Xue, Yuxuan Shen, Min
Chang, Yaqiong Chen, Rui Wang, and Zhaoqing Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914555
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10.1002/anie.201914555
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COMMUNICATION
Visible-Light-Promoted C(sp3)-H Alkylation by Intermolecular
Charge Transfer: Preparation of Unnatural α-Amino Acids and
Late-stage Modification of Peptides
Chao Wang,+ Rupeng Qi,+ Hongxiang Xue, Yuxuan Shen, Min Chang, Yaqiong Chen, Rui Wang, and
Zhaoqing Xu*
Abstract: Disclosed herein is a visible-light promoted deaminative
C(sp3)-H alkylation of glycine and peptides using Katritzky salts as
electrophiles. Simple reaction conditions and excellent functional-
transition metal catalyzed photoredox radical-radical cross
coupling has become a practical way for construction of C(sp3)-
C(sp3) bonds.[9] We recently disclosed the first example of
photoinduced Cu-catalyzed alkylation of glycine C(sp3)-H for
preparation of unnatural α-amino acids and modification of
peptides by decarboxylative cross coupling of alkyl N-
hydroxyphthalimide esters (Scheme 1a).[10] In spite of this
progress, the transition-metal-free or catalyst-free strategy for this
transformation is highly desirable and still not realized.
group tolerance provided
a general strategy for the efficient
preparation of unnatural α-amino acids and precise modification of
peptide with unnatural α-amino acid residues. Mechanistic studies
suggest that visible-light promoted intermolecular charge transfer
within glycine-Katritzky salt EDA complex induced a SET process
without the assistance of photocatalyst.
Peptides play crucial roles in living process, such as cell
proliferation and differentiation, immune defense, and tumor
formation.[1] Furthermore, peptide drugs are widespreadly applied
in clinical therapeutics, such as the treatment of diabetes, AIDS,
and tumors.[2,3] Despite natural peptides continue to be of great
importance, modification of peptides by introduction of
nonproteinogenic amino acids can significantly improve their
activities and pharmacokinetics as compared to their natural
counterparts.[4] In the past decades, significant progress has been
made in late-stage modification of peptide, such as site-specific
C-H functionalization of aromatic residues (tryptophan, histidine,
and phenylalanine),[5] reactions of cysteine -SH group,[6] or
decarboxylative coupling of C-terminal acids.[7] In contrast, the
functionalizations of sp3 C-H in peptide amino acid residues were
limited, and the reactions mainly focused on arylation and
alkynylation.[8] The cross coupling of peptide sp3 C-H bond with
alkylation reagent is still underdeveloped, especially under mild
and catalyst free conditions.
Glycine is the basic skeleton of α-amino acids. Direct
functionalization of α-sp3 C-H of glycine or glycine residue in
peptide represents the most straightforward way for the synthesis
of unnatural α-amino acids or late-stage modification of peptide
with unnatural α-amino acid residues. Despite these advantages,
unnatural α-amino acid synthesis and site-specific modification of
polypeptide based on sp3 C-H alkylation of glycine (glycine
residue) have not been well studied.[8] In the past few years, with
the rapid development of photoinduced radical reactions, the
[*]
C. Wang,[+] R. Qi,[+] Y. Chen, Prof. Dr. R. Wang, Prof. Dr. Z. Xu
Institute of Drug Design & Synthesis, Institute of Pharmacology, Key
Laboratory of Preclinical Study for New Drugs of Gansu Province,
School of Basic Medical Science, Lanzhou University, 199 West
Donggang Road, Lanzhou 730000, China.
E-mail: zqxu@lzu.edu.cn
H. Xue, Y. Shen, Prof. Dr. M. Chang
Institute of Biochemistry and Molecular Biology, School of Life
Sciences, Lanzhou University, 222 South Tianshui Road, Lanzhou
730000, China.
Scheme 1. Visible-light induced alkylation of glycine and peptides.
Alkyl pyridinium salts (Katritzky salts) have recently been
applied to a number of radical reactions, in which the catalyst
mediated single-electron-transfer (SET) was essentially
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201914555
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required.[11] For example, Watson and co-workers disclosed the
first example of Ni-catalyzed radical alkylation reaction using
Katritzky salts as the alkylation reagents.[11a] In the past few years,
photoinduced radical reactions through intermolecular charge
transfer have attracted much attention.[12] Very recently, Glorius
and co-workers disclosed a novel photoinduced radical addition-
elimination process for alkylation of indole sp2 C-H bonds.[13] In
the reaction, photoactive Katritzky salt based EDA complex
mediated SET under catalyst-free conditions (Scheme 1b). In the
same time, Aggarwal group reported a series of Katritzky salt
based EDA complex induced photoredox reactions, such as
Giese type Michael addition and radical addition-elimination of
unsaturated sulfone reagents (Scheme 1b).[14] The deaminative
borylation though photoexcitation of Katritzky salt based EDA
complex was also achieved by Aggarwal and Glorius,
respectively.[15] In line with our interests on photoinduced radical
alkylation and peptide synthesis, we here report the first example
of visible-light promoted catalyst-free deaminative sp3 C-H
alkylation of glycine via EDA complex mediated radical-radical
cross coupling (Scheme 1c).
10). Control experiment revealed that visible-light irradiation and
DBU were indispensable for this transformation (entries 11 and
12).
Table 2. Substrate scopes respect to Katritzky salts and glycine derivatives.[a]
Table 1. Optimization of reaction conditions.
For our first attempt, we selected ethyl 2-(phenylamino)
acetate (1a, 0.1 mmol) and cyclohexyl pyridinium salt (2a, 0.15
mmol) as model substrates under blue LED light irradiation (Table
1). The desired product 3aa was obtained in 25% yield by using
DBU (0.20 mmol) as the additive and CH3CN (2 mL) as the
solvent (entry 1). Screening of light sources showed that violet
LED (395-400 nm) was optimal as compared to other lights
(entries 2-5). Replacing DBU with other bases, such as K3PO4,
Na2CO3, NaOAc, Cs2CO3, pyridine, and TMEDA did not improve
the yield (entry 6, see the Supporting Information for details).
Other solvents (THF, DMF, DMAc, CH2Cl2, and EtOAc et. al.) also
could promote this approach with 0-62% yields (entry 7). It was
worth noting that the yield of 3aa was influenced by the
concentration of reaction mixture (entry 8). Reducing the loading
of 2a or DBU resulted in a substantial drop of yields (entries 9 and
With the optimized conditions in hand (Table 1, entry 4), we
explored the scopes of Katritzky salts and glycine derivatives. As
summarized in Table 2, all kinds of cyclic (2a-2f) and secondary
acyclic (2g and 2h) alkyl substrates were successfully applied to
this reaction efficiently and gave the desired products in excellent
yields (3aa-3ah, 65-85%). Notably, we prepared several alkyl
pyridinium salts derived from pharmaceutical and natural product,
including mexiletine hydrochloride (2i) and 5α-cholestan-3-one
(2j). All these substrates proceeded well under standard
conditions with good yields (3ai and 3aj). However, the primary
alkyl substrates, including Katritzky salts derived from n-
butylamine (2k), benzylamine (2l-2n), and glycine (2o) failed to
give the desired coupling products (see the Supporting
Information).[16] Furthermore, the glycine derivatives bearing
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different N-aryl groups and glycine amide were well tolerated
(3ba-3ea, 80-88%).
Furthermore, a series of novel peptides derived from p-
aminophenylalanine were synthesized and precisely alkylated
with other sensitive functional groups untouched (Table 4).[17] The
PMP group in 3ba was easily removed by CAN (ammonium
cerium nitrate) and used in tetrapeptide (4, 72%, d.r. = 1:1)
synthesis without further purifications (Scheme 2).
A variety of peptides were prepared to test the regio- and
chemoselectivity of the reaction in the presence of other amino
acid residues. As shown in Table 3, the glycine derived dipeptides
(1f-1n) and polypeptides (1o-1u) efficiently coupled to pyridinium
salts with other amino acid residues untouched (3fa-3ua, 65-
87%).
Table 4. Site-specific modification of peptides derived from p-
aminophenylalanine.[a]
Table 3. Regio- and chemoselective modification of peptides.[a]
Scheme 2. Synthetic application of product 3ba.
To gain some mechanistic insight, several control
experiments
were
carried
out.
TEMPO
(2,2,6,6-
tetramethylpiperidin-1-oxyl, 3 equiv) could completely suppress
the standard reaction, indicating a radical pathway might be
involved (Scheme 3a). Addition of BHT (butylated hydroxytoluene,
3.0 equiv) led to a dramatical decrease of the yield (12%)
(Scheme 3b). When (E)-ethyl 2-(phenylimino)acetate 5 was used
instead of ethyl 2-(phenylamino)acetate, no product 3aa was
detected, which indicated that iminium 5 was not formed as the
intermediate for this transformation (Scheme 3c). Interestingly,
when 1.2 equiv of 2a was used, the homo-coupling product 8 was
isolated in 4% yield, suggesting the formation of glycine radical
(Scheme 3d).
In UV/Vis absorption experiments (see the Supporting
Information for details), 1a and 2a both have obvious absorption
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between 300 nm to 380 nm, whereas almost no absorption over
400 nm. We observed formation of a visibly yellow color solution
when two colorless substrates (Katritzky salt 1a and glycine ester
2a) were combined. Meanwhile, the mixture of 1a and 2a
displayed a significant red-shift in absorbance (from 380 nm to
470 nm). Furthermore, the combination of 1a, 2a, and DBU led to
a further red-shift of the absorption to 600 nm, which suggested
that the addition of DBU enhanced the formation of EDA
complex.[18] We also carried out the standard reaction under 460
nm blue LED irradiation (a wavelength that 1a and 2a have no
absorption, whereas the mixture of 1a and 2a has obvious
absorption), and the alkylation product 3aa was still formed in
25% yield. All these experimental results diagnosed the formation
of EDA complex. Finally, the quantum yield Φ=0.29 indicated a
radical-chain process might not be involved in the reaction (see
the Supporting Information for details).
unnatural α-amino acids and precise late-stage modification of
peptides with unnatural α-amino acid residues.
Scheme 4. Proposed mechanism.
Acknowledgements
We are grateful for the grants from the NSFC (No. 21432003 and
21971098) and the Fundamental Research Funds for the Central
Universities (lzujbky-2018-k9). The authors also thank Prof. Yong
Ding, Prof. Yawen Wang, and Prof. Qiang Liu at Lanzhou
University for helpful discussion and technical assistance.
Keywords: cross-coupling • peptide • alkylation • donor-
acceptor complexes • intermolecular charge transfer
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proposed a possible mechanism for this reaction (Scheme 4).
Firstly, colored EDA complex was formed in the presence of 1a
and 2a (a ternary EDA complex might form in the presence of
DBU). Under violet LED (395-400 nm) irradiation, SET occurred
between 1a and 2a followed by the formation of radical A and
radical cation B. Radical A was fragmented to form 2,4,6-
triphenylpyridine and an alkyl radical C. Radical cation B was
deprotonated under basic conditions to provide a stable α-carbon
radical D.[19] Finally, the radical-radical cross coupling between C
and D gave the alkylation product 3.[20]
In summary, we reported a visible-light promoted catalyst-
free deaminative C(sp3)-H alkylation of glycine and peptides using
Katritzky salts as electrophiles. In the reactions, visible-light
induced the intermolecular charge transfer within EDA complex of
Katritzky salt and glycine enabled the SET. The preliminary
mechanistic studies indicated that the C(sp3)-C(sp3) bond
formation proceeded through a radical-radical coupling pathway.
The simple reaction conditions and excellent functional-group
tolerance provided a general strategy for efficient preparation of
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Chao Wang,+ Rupeng Qi,+ Hongxiang
Xue, Yuxuan Shen, Min Chang, Yaqiong
Chen, Rui Wang, and Zhaoqing Xu*
Page No. – Page No.
Visible-Light-Promoted C(sp3)-H
Alkylation by Intermolecular Charge
Transfer: Preparation of Unnatural α-
Amino Acids and Late-stage
The title reaction is the visible-light promoted deaminative C(sp3)-H alkylation
of glycine and peptides using Katritzky salts as electrophiles. Simple reaction
conditions and excellent functional-group tolerance provided a general
strategy for the efficient preparation of unnatural α-amino acids and precise
modification of peptides.
Modification of Peptides
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