Site-Selective Modification of α-Amino Acids and Oligopeptides via Native Amine-Directed γ-C(sp3)-H Arylation

Article abstract of DOI:10.1021/acs.orglett.9b03607

Site-selective modification of chemically and biologically valuable α-amino acids and peptides is of great importance for biochemical study and pharmaceutical development. Few methods based on remote C(sp³)-H functionalization of aliphatic side-chains of peptides has been disclosed in recent years. In this report, we developed a novel approach for γ-C(sp³)-H and γ-/δ-C(sp²)-H arylation of α-amino acids with α-hydrogen by native amine-directed C-H functionalization and further realized the γ-C(sp³)-H arylation of N-terminally unprotected peptides.

Full text of DOI:10.1021/acs.orglett.9b03607

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Site-Selective Modification of α‑Amino Acids and Oligopeptides via
Native Amine-Directed γ‑C(sp3)‑H Arylation
Feipeng Yuan, Zhen-Lin Hou, Pranab K. Pramanick, and Bo Yao*
MOE Key Laboratory of Cluster Science, Beijing Key Laboratory of Photoelectronic-Electrophotonic Conversion Materials, School
of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, P. R. China
S
* Supporting Information
ABSTRACT: Site-selective modification of chemically and biologically
valuable α-amino acids and peptides is of great importance for biochemical
study and pharmaceutical development. Few methods based on remote
C(sp3)-H functionalization of aliphatic side-chains of peptides has been
disclosed in recent years. In this report, we developed a novel approach for
γ-C(sp3)-H and γ-/δ-C(sp2)-H arylation of α-amino acids with α-
hydrogen by native amine-directed C−H functionalization and further
realized the γ-C(sp3)-H arylation of N-terminally unprotected peptides.
eptides have gained more and more interest as
therapeutics in recent years.1 The postsynthetic mod-
1ii).12 In addition, 8-aminoquinoline-derived amides were also
used to promote β-C(sp3)-H arylation13 and macrocyclization
(Scheme 1iii).14 However, all of these transformations required
the protection of the N-terminus (NH2). In particular,
auxiliaries were even needed to form powerful directing groups
at the N-terminus to promote the γ- or δ-C(sp3)-H
functionalization (Scheme 1iv).15−19 Although a variety of
efficient transformations such as δ-alkylation,17 γ-silylation,18
and γ-arylation/macrocyclization19 have been developed, the
additional steps for the preinstallation and the removal of these
groups reduce the atom- and step-economy of these methods.
Therefore, the use of the native amino group of peptides as the
monodentate directing group for γ- or δ-C(sp3)-H function-
alization would be challenging but also appealing.
Compared with other N-containing functional groups, free
amino groups have been far less utilized as directing groups in
transition-catalyzed C−H functionalization.20,21 Successful
examples were mainly restricted to the C(sp2)-H functionaliza-
tion of anilines,22 benzyl amines,23 and arylethylamines,24 as
well as the C(sp3)-H functionalization of sterically bulky
secondary amines.25 So far, there have been only three reports
on the NH2-directed γ- or δ-C(sp3)-H functionalization of
primary aliphatic amines and amino esters (Scheme 2B).26−28
As for the scope of α-amino acids, only α,α-disubstitued α-
amino esters were compatible with the conditions. The
reaction of α-amino esters having α-hydrogen was met with
such problems as low yield and serious racemization.27 In the
meantime, in recent years, transient directing strategies have
been developed to solve the problems in the remote C(sp3)-H
functionalization of primary aliphatic amines.29−31 Although
the efficient γ-C(sp3)-H arylation of α-amino esters with α-
hydrogen was enabled by an aldehyde-type transient ligand,
the reaction was susceptible to full racemization.30 In another
P
ification of bioactive peptides provides one of the most
efficient and straightforward approaches for the synthesis of
peptide drug candidates. Compared with traditional methods
relying on the chemistry of amine, thiol, alcohol, carboxylic
acid, and others, the direct functionalization of inert C−H
bonds of peptides is much more challenging.2 Selective C(sp2)-
H functionalization such as arylation,3 vinylation,4 allylation,5
and alkynylation6 at Trp and Phe residues of peptides has also
been developed in the past decade. In contrast, methods based
on the remote C(sp3)-H functionalization of the aliphatic side
chains of peptides are rare. Using the backbone functional
groups (amide and carboxyl) as bidentate directing groups, Yu
developed the β-C(sp3)-H arylation7 and alkynylation8 of
peptides at the N-terminus (Scheme 1i), and Noisier/
Albericio9 and Wang10 later reported intramolecular β-
C(sp3)-H arylation/macrocyclization (Scheme 1i). With the
peptide−isosteric triazole and amide as bidentate directing
groups, Ackermann developed the β-C(sp3)-H arylation of
peptidomimetics at internal residues11 and applied this
protocol to the BODIPY labeling of peptidomimetics (Scheme
Scheme 1. Directing Groups for Remote C(sp3)-H
Functionalization of Peptides
Received: October 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 2. NH2-Directed γ-C(sp3)-H Functionalization of α-
Amino Acids and Oligopeptides
reactivity of α-amino esters having α-hydrogen (Scheme 2A).
Herein we report a novel method of native amine-directed γ-
C(sp3)-H arylation for the site-selective modification of α-
amino acids and oligopeptides (Scheme 2C). The key features
and contributions of this work are as follows: (1) The use of
TfOH and AgOAc as additives considerably improved the
reactivity and led to the first NH2-directed γ-C(sp3)-H
arylation of α-amino acids containing α-hydrogen. (2) The
observation of the complete retention of the α-stereocenter’s
configuration in α-amino amide led to the development of the
first C(sp3)-H late-stage modification of N-unprotected
oligopeptides. (3) The conjugation with the natural product,
fluorophore, and the amino acid showcased the synthetic
utility of the established method.
The study commenced with conditions optimized for the γ-
C(sp3)-H arylation of ethyl L-tert-leucinate 1a with PhI 2a by
mainly screening anions (Table 1). First, the counteranions of
silver additives were examined by performing the reaction with
diverse silver salts or oxide in the presence of 10 mol %
Pd(OAc)2 in HFIP/AcOH (6/1) at 100 °C (entries 1−6 in
Table 1). Among the tested silver additives, AgOTf gave the
best result and yielded a mixture of γ-mono- and diarylation
products (3a) in 55% yield and with a 2.58:1 ratio (entry 6 in
Table 1). However, the further addition of 1.0 equiv of TsOH
to the reaction with AgOTf led to a poor yield (entry 7 in
Table 1). By contrast, the combination of 1.5 equiv of AgOAc
with 1.0 equiv of TsOH resulted in a slightly higher yield
(59%) and a larger turnover number (TON = 8) (entry 8 in
Table 1). Notably, a similar yield and TON were retained
when conducting the reaction without AcOH as the cosolvent
(entry 9 in Table 1). These results suggested that the higher
reactivity was attributed to the effect of anions rather than the
acidity. Then, several protic acids with different pKa values and
steric bulks were tested (entries 10−13 in Table 1). Both
work on CO2-mediated γ-C(sp3)-H arylation, ethyl L-valinate
underwent monoarylation to give the product with 3.3:1 dr
and with the retention of the S-configuration of α-stereo-
centers.31
In this context and in continuation with our project on NH2-
directed C−H functionalization,27 we envisioned that the
anion exchange of the key complex B with a suitable anion
might afford a more reactive complex and thereby improve the
a
Table 1. Conditions Optimization for the γ-Arylation of Ethyl L-tert-Leucine Ester with PhI
b
b
entry
[Ag]
acid (equiv)
ratio of 3aa-mono/di/tri
yield (%) (TON)
1
2
AgOAc
AgTFA
Ag2CO3
Ag2O
1.22/1/−
1.35/1/−
1.45/1/−
1.83/1/−
n.d.
2.58/1/−
1/−/−
1.26/1/−
1.92/1/−
1/1.3/0.44
1/0.68/−
1/0.61/0.14
1/0.76/0.13
1/0.81/0.13
1/0.65/0.11
1/1.14/0.39
1/0.14/−
39
44
41
50
trace
55 (7)
15
59 (8)
58 (8)
49 (9)
64 (9)
63 (9)
62 (10)
77 (12)
69 (12)
c
3
4
c
5
6
7
8
AgNO3
AgOTf
AgOTf
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
TsOH (1.0)
TsOH (1.0)
TsOH (1.0)
CF3CO2H (1.0)
o-NO2-C6H4CO2H (1.0)
PivOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.2)
d
9
10
11
12
13
14
15
e
e
e
f
16
17
TfOH (0.8)
TfOH (0.8)
80 (14)
23
g
a
Conditions: 1a (0.3 mmol), PhI 2a (0.9 mmol), Pd(OAc)2 (10 mol %), [Ag] (1.5 equiv), acid, HFIP/AcOH (6/1, 3 mL), air, 100 °C, 24 h.
b
1
Total yield and ratios of mono/di/triarylation products were obtained based on the H NMR spectra of crude samples. Turnover numbers
c
d
e
f
g
(TON) are provided in parentheses. 0.75 equiv of Ag2O or Ag2CO3. HFIP (3 mL). 80 °C. Isolated yield. 60 °C.
B
DOI: 10.1021/acs.orglett.9b03607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
strong acid and sterically bulky acids exhibited a positive effect,
and TfOH led to the largest TON (entry 13 in Table 1). To
further improve the reactivity and reduce the degradation, we
optimized the amount of TfOH and the temperature (entries
14−17) and finally determined the optimal conditions to be
ethyl L-tert-leucinate 1a (0.3 mmol), PhI (3.0 equiv), 10 mol %
Pd(OAc)2, 1.5 equiv AgOAc, 0.8 equiv TfOH in HFIP/AcOH
(6/1 v/v, 3 mL) at 80 °C, air, 24 h (entry 16 in Table 1). The
reaction under the optimal conditions afforded a mixture of
mono-, di-, and triarylation products in 80% total yield (TON
= 14) by flash chromatographic purification without the
protection of the amino group. It is worth noting that the yield
based on AgOAc was ∼94%.
Scheme 4. Scope of α-Amino Acids
With the optimal conditions in hand, we first investigated
the scope of aryl iodides for the γ-C(sp3)-H arylation of ethyl
L-tert-leucinate 1a (Scheme 3). Both electron-rich and
Scheme 3. Scope of Aryl Iodides in the γ-Arylation of Ethyl
a b
,
L-tert-Leucine Ester
a
Standard conditions: 1 (0.3 mmol), ArI (0.9 mmol), Pd(OAc)2 (10
mol %), AgOAc (1.5 equiv), TfOH (0.8 equiv), HFIP/AcOH (6/1, 3
b
mL), air, 100−120 °C, 24 h. ee was determined by the HPLC
c
analysis of the acetamides. (See the details in the SI.) Acyl-protection
d
by AcCl or BzCl. AgTFA (1.5 equiv).
(3ba−ga, 37−83%). The extent of racemization/epimerization
varied according to the steric and electronic properties of side-
chains: Ethyl (S)-2-aminobutanoate 1b (smallest side-chain)
and L-phenylglycinate 1e (aromatic side-chain) underwent
serious racemization to give the products as almost racemic
mixtures (3ba, 5% es; 3ea, 0% es), whereas the reaction of ethyl
L-phenylalaninate 1f (benzylic side-chain) gave the diarylation
product in 70% es, even under 110 °C. Both the ethyl L-
valinate 1c and L-isoleucinate 1d yielded the products with
moderate dr (3ca-mono, 2.4 dr; 3cb-mono: 3.4:1 dr; 3db,
1.4:1 dr). The ee and optical rotation data of 3cb-mono (two
diastereomers) and 3cb-di showed that the epimerization at
the α-stereocenter took place but was slower than the first C−
H arylation. Furthermore, free α-amino acid and α-amino
amide were also examined. L-tert-Leucine 1h exhibited no
reactivity, probably due to the formation of the inactive η2-
Pd(II)−amino acid complex. By contrast, α-amino amide 1i
displayed moderate reactivity, yielding the mono- and
diarylation products 3ia in 46% yield and with 3.5:1 ratio as
well as >99% es. The inhibition of the racemization in the
reaction of 1i might be attributed to the faster tautomerization
of the amide group than the enolization related to α-hydrogen
(Scheme 2A).32
a
Standard conditions: 1a (0.3 mmol), ArI (0.9 mmol), Pd(OAc)2 (10
mol %), AgOAc (1.5 equiv), TfOH (0.8 equiv), HFIP/AcOH (6/1, 3
mL), air, 80 °C, 24 h. Yield and ratio of mono-, di-, and triarylation
products were based on chromatographic purification. Enantiomeric
excess (ee) was determined by HPLC analysis of the corresponding
acetamides. (See the details in the SI.)
b
c
electron-poor aryl groups were successfully installed in the γ-
positions, yielding the γ-arylation products in moderate to
good yield (3aa−ae, 60−84% total yield). Meta- and ortho-
substituted aryl iodides gave a similar result as para-substituted
aryl iodides, indicating that the reaction was not sensitive to
steric hindrance. Gratifyingly, the HPLC analysis of the
acetamides of the monoarylation products showed that the
racemization was largely inhibited (3aa-mono: 94% es; 3ab-
mono: 92% es). However, the ee erosion took place as more
aryl groups were installed (3aa-di: 75% es, 3aa-tri: 56% es),
suggesting that the racemization process was related to
palladium (Scheme 2A).
Then, we continued to investigate the scope of α-amino
acids (Scheme 4). The ethyl esters of six α-amino acids were
submitted to the optimal conditions. At various temperatures
(100−120 °C), these reactions afforded the desired γ-C(sp3)-
H or γ/δ-C(sp2)-H arylation products in moderate yield
Inspired by the result above, we wondered if the NH2-
directed γ-C(sp3)-H arylation method could be applied to the
postsynthetic modification of N-terminus unprotected peptides
(Scheme 5). Surprisingly, a series of dipeptides (4a−j)
underwent γ-C(sp3)-H arylation at the N-terminal Tle
residues, delivering arylation products in moderate yield with
the complete retention of the configuration of all α-
stereocenters (5a−j). A wide range of α-amino acid residues
C
DOI: 10.1021/acs.orglett.9b03607
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Letter
a
Scheme 5. Scope for the γ-C(sp3)-H Arylation of
Oligopeptides
Scheme 6. Synthetic Application
a b
,
a
Conditions for (A−C): 4a (0.2 mmol), 6 (0.6 mmol), Pd(OAc)2
(10 mol %), AgOAc (1.5 equiv), TfOH (0.8 equiv), HFIP/AcOH (6/
1, 2 mL), 100 °C, air, 24 h. For (D): 5n, 7 (1.0 equiv), DCC (1.1
equiv), HOBt (1.1 equiv), iPr2EtN (1.0 equiv), CH2Cl2 (5 mL), rt, 12
h.
a
Standard conditions: peptide 4 (0.2 mmol), ArI (0.6 mmol),
Pd(OAc)2 (10 mol %), AgOAc (1.5 equiv), TfOH (0.8 equiv),
HFIP/AcOH (6/1, v/v, 2 mL), air, 100 °C, 24 h; then, SOCl2 (10
b
equiv), EtOH (2 mL), reflux, 5 h. Yield and ratio were based on the
In conclusion, we have developed a new protocol of native
amine-directed C−H functionalization and realized the first
NH2-directed γ-C(sp3)-H arylation of diverse chiral α-amino
acids having α-hydrogen. The extent of the racemization of the
α-stereocenters was found to be dependent on the properties
of side-chains and functional groups at the C-terminus. On the
basis of this observation, we further established the first γ-
C(sp3)-H arylation of N-terminus unprotected oligopeptides.
The synthetic application of this protocol was demonstrated by
the conjugation with natural D-(+)-menthol and fluorescent
1,8-naphthalimide as well as the two-fold peptide ligation to
prepare a trigeminal peptide. In view of the ubiquitous feature
of the L-tert-leucine moiety in many peptide-based drugs and
chiral ligands, the present method will find applications in the
future. Our present project is to develop new protocols of
native functional-group-directed C−H functionalization for the
selective late-stage modification of complex peptides at diverse
residues.
result of chromatographic purification. (See the details in the SI.)
such as Val (5a−c), Ala (5d), Phe (5e), Ile (5f), Leu (5g), Tle
(5k), and other unnatural amino acids (5h−j) at the C-
terminus were compatible. Functional groups such as
carboxamide, carboximide, ester, chloro, ether, nitro, and
amino groups were well tolerated, providing opportunities for
further transformations of the products and late-stage
conjugation with functional molecules. In addition, tripeptide
4k was also successfully arylated at the N-terminus at 80 °C,
delivering the γ-monoarylation product 5k in 24% yield.
Notably, all of these products and unreacted substrates were
practically isolated by chromatographic purification without
the protection of the amino group. In addition, the excellent
repeatability and scale-up reaction also exhibited the
practicality of the method.
Finally, the synthetic application of the method for peptide
modification was investigated (Scheme 6). With ester and
carboximide functional groups as linkers, natural D-(+)-men-
thol and fluorescent 1,8-naphthalimide were installed to
dipeptide 4a via the C−H arylation method to give the
conjugates 5l and 5m in 31 and 38% yield, respectively
(Scheme 2A,B). In addition, combining the C−H arylation
method with the amide formation reaction, a two-fold peptide
ligation strategy was established (Scheme 2C,D). The
sequential reaction of 4a with amino acid 6c and dipeptide 7
afforded the trigeminal peptide 8 in 22% yield (two steps).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03607.
Detailed experimental procedures, complete optimiza-
tion table, characterization data of prepared starting
1
materials and products, and copies of H and 13C NMR
spectra of these compounds (PDF)
D
DOI: 10.1021/acs.orglett.9b03607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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́
(16) Hernando, E.; Villalva, J.; Martínez, A. M.; Alonso, I.;
AUTHOR INFORMATION
■
́
́
Rodríguez, N.; Gomez Arrayas, R.; Carretero, J. C. ACS Catal.
Corresponding Author
*E-mail: yaobo@bit.edu.cn
ORCID
2016, 6, 6868−6882.
(17) Zhan, B. B.; Li, Y.; Xu, J. W.; Nie, X. L.; Fan, J.; Jin, L.; Shi, B.
F. Angew. Chem., Int. Ed. 2018, 57, 5858−5862.
(18) Zhan, B.-B.; Fan, J.; Jin, L.; Shi, B.-F. ACS Catal. 2019, 9,
3298−3303.
Bo Yao: 0000-0002-8709-7989
Notes
(19) Li, B.; Li, X.; Han, B.; Chen, Z.; Zhang, X.; He, G.; Chen, G. J.
Am. Chem. Soc. 2019, 141, 9401−9407.
The authors declare no competing financial interest.
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We gratefully acknowledge the National Natural Science
Foundation of China (21502006), Beijing National Laboratory
for Molecular Sciences, and Beijing Institute of Technology
(BIT) for financial support. We also thank the Analysis and
Testing Centre of BIT for the NMR and HRMS analysis and
Yu-Fei Ao at the Institute of Chemistry, Chinese Academy of
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DOI: 10.1021/acs.orglett.9b03607
Org. Lett. XXXX, XXX, XXX−XXX