Site-selective C(sp3)-H functionalization of di-, tri-, and tetrapeptides at the N-terminus

Article abstract of DOI:10.1021/ja510233h

Although the syntheses of novel and diverse peptides rely mainly on traditional coupling using unnatural amino acids, postsynthetic modification of peptides could provide a complementary method for the preparation of nonproteinogenic peptides. Site select

Full text of DOI:10.1021/ja510233h

Article
pubs.acs.org/JACS
3
Site-Selective C(sp )−H Functionalization of Di‑, Tri‑, and
Tetrapeptides at the N‑Terminus
†
†
Wei Gong, Guofu Zhang, Tao Liu, Ramesh Giri, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
*
ABSTRACT: Although the syntheses of novel and diverse
peptides rely mainly on traditional coupling using unnatural
amino acids, postsynthetic modification of peptides could
provide a complementary method for the preparation of
nonproteinogenic peptides. Site selectivity of postsynthetic
modification of peptides is usually achieved by targeting
reactive moieties, such as the thiol group of cysteine or the
C-2 position of tryptophan. Herein, we report the development
3
of site-selective functionalizations of inert C(sp )−H bonds of
N-terminal amino acids in di-, tri-, and tetrapeptides without
installing a directing group. The native amino acid moiety
within the peptide is used as a ligand to accelerate the C−H activation reaction. In the long run, this newly uncovered reactivity
3
could provide guidance for developing site-selective C(sp )−H activation toward postsynthetic modification of a broader range of
peptides.
1. INTRODUCTION
Peptide therapeutics have recently attracted broad attention
from the pharmaceutical industry because of their superior
1
−3
specificity for their targets over small molecules.
The
number of approved peptide drugs has also steadily increased
1
in the past decade. Therefore, postsynthetic modification of
peptides has emerged as a significant task of current
4
−9
interests.
For example, the “tag-and-modify” approach has
been developed by Davis to covalently modify peptides and
proteins through a diverse range of transition metal-catalyzed
6
,10
2
C−C bond-forming reactions.
Direct C(sp )−H function-
alization of inherent phenylalanine and tryptophan moieties has
also been elegantly exploited to modify the structures of
11−13
bioactive small peptides.
It has been long recognized that
3
site-selective functionalization of various inert C(sp )−H bonds
in a peptide side chain will greatly enrich the toolbox for
postsynthetic modification of peptides. Despite the significant
progress in developing C(sp )−H activation reactions of amino
acids using directed C−H activation (Figure 1a),
3
3
Figure 1. Site-selective C−H functionalization. (a) C(sp )−H
14−24
functionalization of amino acids using specifically designed directing
groups. (b) C−H activation by Pd(II)/amino acid complexes. (c)
site-
selective functionalizations of alkyl side chains in peptides
without installing an external auxiliary remains to be developed,
an attribute that is essential for postsynthetic modification of a
broad range of peptides.
3
C(sp )−H activation of peptides at the N-terminus. Phth = phthaloyl,
DG = directing group, Subs = substrate, NPG = protected amino
group.
We recently discovered that monoprotected amino acid
report the successful implementation of this approach, through
which site-selective arylation and acetoxylation of C(sp )−H
bonds at the N-terminus of various peptides are accomplished
ligands coordinated to Pd(II) complexes in a bisdentate
3
2
manner can drastically accelerate both C(sp )−H and
3
25−31
C(sp )−H activation reactions (Figure 1b).
This finding
without installing a directing group. Postsynthetic modification
prompted us to investigate whether native amino acids
embedded in the peptide backbone could bind to Pd(II),
leading to analogous complexes that activate proximate C−H
bonds in the adjacent amino acid unit (Figure 1c). Herein, we
Received: October 5, 2014
©
XXXX American Chemical Society
A
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,
ab
Table 1. Scope of Aryl Iodides for the C−H Arylation of Dipeptide 1
a
Reaction conditions: substrate (0.2 mmol), Pd(OAc) (2.5 mol %), ArI (1.5 equiv), AgOAc (1.2 equiv), KF (3 equiv), HFIP (0.2 M), air, 100 °C,
2
b
1
c
2
0 h. Ratio of mono- to diarylated product based on analysis of crude H NMR spectra. Combined yield of mono- and diarylated products.
d
e
Isolated yield of monoarylated products. Isolated yield of a 5 mmol scale reaction with 5 mol % Pd(OAc) . HFIP, hexafluoroisopropanol.
2
of a wide range of di-, tri-, and tetrapeptides using these C−H
in 88% NMR yield, along with the formation of 8% diarylated
product (see SI for detailed screening of reaction conditions).
We also discovered that selective monoarylation of 1 could
be achieved in the absence of KF, although with lower yields
activation reactions are thus made possible, demonstrating
3
potential applications of Pd-catalyzed C(sp )−H activation
reactions in peptide synthesis.
(
54−73% with various aryl iodides, mono-/diarylation product
20:1). The Pd catalyst loading can be reduced to 1 mol % in a
gram-scale reaction, albeit lowering the combined yield to 77%
mono/di = 10:1, see SI). The relatively low catalyst loading
demonstrates the high efficiency of this C−H activation
reaction directed by the C-terminal amino acid moiety. The
protection of C-terminal carboxylic acid as a benzyl ester led to
a complete loss of reactivity supporting the involvement of the
free carboxylate in the active complex, as is proposed in Figure
>
2
. RESULTS AND DISCUSSION
We have previously discovered that mono-N-protected amino
acids (MPAAs) can enable or accelerate a diverse range of C−
H bond activation/carbon−carbon and carbon-heteroatom
bond-forming reactions.
studies
coordinated by a monoprotected amino acid in a bisdentate
manner is highly reactive for cleaving inert C−H bonds. We
reasoned that the C-terminus of a dipeptide is a native
monoprotected amino acid that can coordinate to Pd(II)
species, thus forming a reactive complex that could potentially
activate the proximate C−H bonds in the N-terminus. If
successful, this strategy could be potentially expanded to longer
peptides (for example, tripeptides and tetrapeptides), which
may form analogous N,N-biscoordinated complexes with
Pd(II) catalyst and promote the C−H activation process.
To test these hypotheses, we initially focused on the direct β-
(
2
5−31
Kinetic and computational
3
2−34
suggest that the monomeric Pd(II) complex
1
c. The conservation of the two chiral centers without
1
epimerization is verified by H NMR and HPLC analysis of
the arylation product in comparison with a standard sample
prepared using known procedure (see SI). It is noteworthy that
this reaction could tolerate up to 20% water in HFIP (v/v) to
give the desired arylation product in 55% NMR yield with 10%
Pd(OAc) , potentially a useful feature when solubility of
2
peptide in pure organic solvent is poor.
With the optimized conditions in hand, dipeptide 1 was
arylated at the N-terminus with a wide range of aryl iodides in
good yields (Table 1). Both electron-donating (Me− and
3
C(sp )−H functionalization of N- phthaloyl protected
dipeptide 1, which is readily synthesized from optically pure
Phth−Ala−OH (99% ee) via a two-step sequence at 20-g
scale (see Supporting Information (SI) for details). We chose
the arylation reaction because it can provide rapid access to
peptides containing modified phenylalanine moiety. After
MeO−) and electron-withdrawing (F−, Cl−, Br−, CF −,
3
35
CN−, NO −, and CO Me−) groups at either the para or meta
2
2
position of the aryl iodide are well tolerated (72−90% yield).
The bromo group in 2f and 2o can be used for further coupling
6
using Davis’ conditions developed for peptide chemistry. Aryl
extensive experimentation, we found that with Pd(OAc) (2.5
mol %) as the catalyst, KF (3 equiv) as the base and AgOAc
iodides with various ortho substituents were also compatible
with the reaction condition (69−83% yield). The dipeptide 1
could be smoothly arylated with disubstitued iodide to give 2q
in 86% yield. A gram-scale synthesis of the dipeptide 2m with
an ortho substituent (MeO) on the phenyl ring was conducted
to afford the desired product in 85% isolated yield when 5 mol
2
(
1.2 equiv) as the additive, the arylation of the dipeptide 1 with
phenyl iodide in tert-amyl alcohol at 100 °C could afford the
monoarylation product 2a in 56% NMR yield. Further
optimization revealed that the reaction could reach full
conversion when hexafluoroisopropyl alcohol (HFIP) is used
as the solvent. Thus, 2a was obtained as a single diastereomer
% Pd(OAc) was employed. A few heteroaryl iodides, such as 4-
2
iodopyridine, 3-iodopyridine, 3-iodothiophene, 2-iodo-5-meth-
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yl-thiophene, 5-iodo-1H-indole, and 5-iodo-1-tosyl-1H-indole,
were tested as the coupling partner in the arylation of dipeptide
Table 3. Scope of Amino Acids at the N-Terminus of
a b
,
Dipeptides
1; however, only the reaction with 5-iodo-1-tosyl-1H-indole
gave ∼30% NMR yield of the desired product using 20 mol %
Pd(OAc) at 120 °C. Reactions with other heteroaryl iodides
2
did not give any product.
To examine the scope of peptides, dipeptides 3 containing
various amino acids at the C-terminus were prepared in high
purity from Phth−Ala−OH and the corresponding natural or
unnatural amino acid derivatives (Table 2). Dipeptides 3a−3d
Table 2. Scope of Amino Acids at the C-Terminus of
,
a b
Dipeptides
a
Reaction conditions: substrate (0.2 mmol), Pd(OAc) (10 mol %),
2
ArI (2.5 equiv), AgOAc (2.5 equiv), KF (3 equiv), HFIP (0.2 M), air,
b
c
d
1
20 °C, 20 h. Isolated yield. Racemic substrate was used. Methyl
ester was synthesized directly from crude acid product with SOCl in
2
e
1
MeOH. Diastereomeric ratio = 9:1 determined by crude H NMR.
5
6
g were also arylated with phenyl iodide and tolyl iodide to give
g and 6g , respectively, albeit providing the products in lower
1
2
yields. For the ease of purification, the arylation product with
phenyl iodide was converted to the corresponding methyl ester
6
g1 in one pot (see SI). The arylation of dipeptide 5g with tolyl
iodide afforded two diasteremoers (d.r. = 9:1), with 6g as the
2
a
Reaction conditions: substrate (0.2 mmol), Pd(OAc) (2.5 mol %),
major product.
2
4
-CN-C H I (1.5 equiv), AgOAc (1.2 equiv), KF (3 equiv), HFIP (0.2
In these dipeptide substrates, the C-terminus essentially
provides a native coordinating ligand that is structurally
analogous to our monoprotected amino acid ligand (MPAA).
It would be synthetically useful and mechanistically interesting
to test how tripeptides or even tetrapeptides behave under
these conditions. The key question is whether the amino acid
moiety embedded in longer peptides could form a N,N-
biscoordinated complex with Pd(II) in a manner similar to the
N,O-bisdentate coordination in the dipeptides and still be
6
4
b
c
M), air, 100 °C, 20 h. Ratio of mono- to diarylated product. Isolated
yield of monoarylated products. Combined yield of mono- and
diarylated products. 5 mol % Pd(OAc) was used. Racemic substrate
was used.
d
e
f
2
with alkyl substituents at the C-terminus reacted smoothly with
4
-CN-phenyl iodide to provide the desired products in high
yields under standard conditions (81−91%). Arylation of
dipeptides derived from glycine and 2-aminoisobutyric acid (3e,
3
reactive toward C(sp )−H activation (Figure 1c). To
3
f) also proceeded in good to high yields using 5 and 2.5 mol %
investigate this fundamental question, tripeptide 7a was
prepared in high purity via direct coupling of dipeptide 1
with the corresponding alanine derivative. Although the free
carboxylic acid at the C-terminus inhibited the arylation of
tripeptides and resulted in a low yield (20%), we found that the
benzyl ester substrate 7a was arylated in 1,2-dichloroethane
Pd(OAc) , respectively. Phenylalanine and tyrosine in the
2
dipeptides 3g and 3h were also tolerated. Interestingly, the
dipeptide 3i containing D-valine also proved to be a good
substrate for this arylation reaction, affording the mono- and
diarylation products in 89% combined yield.
The scope of the amino acids at the N-terminus was also
surveyed. Dipeptide 5a was prepared from 2-aminoisobutyric
acid and valine. Arylation of 5a under the standard conditions
gave a mixture of mono- and diarylated products. Diarylation
product 6a was obtained as a major product in 60% yield by
(DCE) to give the desired product 8a in 86% isolated yield.
1
Importantly, a wide range of amino acids, including alanine,
valine, leucine, isoleucine, proline, phenylalanine, glycine,
aspartic acid, threonine, tryptophan, or 2-aminoisobutyric
acid, embedded in the tripeptides are compatible with these
conditions (8a−r, Table 4). A variety of aryl iodides possessing
electron-donating or electron-withdrawing groups in para,
meta, or ortho position are used as the coupling partners to
provide the desired products in moderate to high yields (51%
to 89%). To demonstrate that the site selectivity at the N-
terminus of the tripeptide is not specific to alanine, but rather
using 10 mol % Pd(OAc) ), along with small amount of
2
monoarylation product. Similarly, peptides 5b−5f derived from
1
-aminocyclopropanecarboxylic acid or 1-aminocyclobutane-
carboxylic acid were also arylated to give the diarylation
products 6b−6f in reasonable to good yields (50−88%, Table
3
6
3
3
). Benzylic C(sp )−H bonds in phenylalanine of dipeptide
C
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,
a b
Table 4. C−H Arylation of Tripeptides
a
b
c
Reaction conditions: Pd(OAc) (5 mol %), ArI (1.5 equiv), AgOAc (1.2 equiv), DCE (0.2 M), air, 100 °C, 20 h. Isolated yield. 10 mol %
2
d
e
f
Pd(OAc) was used. A mixture of inseperable rotamers (ratio = 1.5:1). Racemic substrate was used. Reaction conditions: Pd(OAc) (10 mol %),
2
ArI (2.5 equiv), AgOAc (2.5 equiv), DCE (0.2 M), air, 120 °C, 20 h. DCE, dichloroethane.
controlled by the N,N-biscoorindation of the peptide backbone
Figure 1c), tripeptide 7j consisting of three alanine moieties
isolated yield to give 2.20 g of tripeptide 8a ; see the SI for
details).
1
(
was selectively arylated at the N-terminus. Tripeptides
containing C -disubstituted amino acids at the N-terminus
The selective arylation of tripeptides demonstrates that N,N-
α,α
biscoordinated Pd (II) complexes can activate proximate
3
(
7q and 7r) could also undergo arylation using slightly
C(sp )−H bonds; however, we were concerned that the
modified conditions to give mono- and diarylation products.
We were pleased to find that the current protocol for arylation
of tripeptide is also suitable for gram-scale synthesis of novel
tripeptides (arylation of 7a in 5 mmol scale proceeded in 77%
additional coordinative amide bonds in longer peptides could
inhibit the reaction in a manner similar to that of the C-
terminus carboxylic acid. Remarkably, minor modification of
the reaction conditions (10% Pd(OAc) , 2 equiv. of ArI and 2
2
D
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,
a b
Table 5. C−H Arylation of Tetrapeptides
a
b
Reaction conditions: substrate (0.2 mmol), Pd(OAc) (10 mol %), ArI (2 equiv), AgOAc (2 equiv), DCE (0.2 M), air, 100 °C, 20 h. Isolated
2
c
yield. NMR yield based on internal standard (1,3,5-trimethoxybenzene) when 20% water (v/v) was added as a cosolvent.
,
a b
Table 6. C−H Acetoxylation of Tripeptides
a
b
c
Reaction conditions: substrate (0.2 mmol), Pd(OAc) (10 mol %), PhI(OAc) (4 equiv), Ac O (0.066 M), air, 100 °C. Isolated yield. Reaction
2
2
2
d
time. Racemic substrate was used.
equiv of AgOAc, Table 5) allows the selective arylation of
tetrapeptides 9a−9e at the N-terminus end to provide the
desired products in good yields (60−76%). To vigorously
demonstrate that this method is site-selective at the N-
terminus, tetrapeptide 9e containing four alanine units was
also arylated to give 10e as the major product in 60% yield.
Further arylation of another methyl group in Ala(2) of 10e also
occurred to give a diarylated product in 10% yield. Arylation of
the degree of Pd contamination in the peptide products, ICP
analysis of product 10d was performed, and the residual Pd
content was 280 ppm.
Next, we examined the feasibility of using this approach to
convert C−H bonds in the N-terminus into other functional
groups. Considering that site-selective oxidation of peptide-
based drug molecules could increase the hydrophilicity of the
peptide as well as facilitate the study of the undesired metabolic
1
−3
9d could occur in the presence of water (20% v/v) as a
oxidation pathway,
we sought to develop C−H oxidation
37
cosolvent to give 10d in 54% NMR yield. The reactivity
observed with tetrapeptides demonstrates the feasibility of
applying this reaction to even longer peptides. To determine
reactions of peptides using previously reported conditions.
We found tripeptide 7a was selectively acetoxylated at the N-
terminus with 10 mol % Pd(OAc)2 as the catalyst and
E
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PhI(OAc) as the oxidant in acetic anhydride at 100 °C to give
was stirred for 20 h at 100 °C. Upon completion, the reaction mixture
2
was cooled to room temperature. To the mixture was added acetic acid
the acetate 11a in 55% isolated yield. A number of tripeptides
containing alanine, valine, leucine, isoleucine, glycine, or proline
residues are selectively acetoxylated at the N-terminus in
moderate yields (45−66%, Table 6). Although the N-terminus
is limited to alanine for this acetoxylation at this stage, further
optimization could lead to selective oxidation of other amino
acids at the N-terminus.
(0.3 mL) and EtOAc (3 mL). The mixture was filtered through a short
Celite pad, and the filtrate was concentrated under reduced pressure.
The resulting mixture was purified by preparative TLC, typically using
hexane/ethyl acetate/HOAc mixtures as the eluent, to give the
arylated product as a solid. The arylated product was typically obtained
1
as a single diastereomer (d.r. > 20:1), as evidenced by H NMR and
13
C NMR.
Although C−H functionalization of peptides using this
method occurs exclusively at the N-terminus, we envision that
multiple structural modifications on other sites can be achieved
by performing sequential C−H functionalizations of peptides of
different lengths. Thus, gram-scale arylation of 1 was carried
out to give 1.8 g of modified dipeptide 2m (Scheme 1).
General Procedure for the Arylation of Tripeptides (Table
4). To a microwave tube (5 mL) was added the substrate (0.2 mmol),
Pd(OAc) (0.01 mmol), AgOAc (0.24 mmol), ArI (0.3 mmol), and
2
DCE (1 mL) in air. The tube was sealed and heated to 100 °C. The
mixture was stirred for 20 h at 100 °C. Upon completion, the reaction
mixture was cooled to room temperature. To the mixture was added
acetic acid (0.3 mL) and EtOAc (3 mL). The mixture was filtered
through a short Celite pad, and the filtrate was concentrated under
reduced pressure. The resulting mixture was purified by preparative
TLC, typically using hexane/ethyl acetate/CH Cl mixtures as the
Scheme 1. Synthesis of a Novel Tripeptide via Sequential C−
H Arylation
2
2
eluent, to give the arylated product as a solid. The arylated product
was typically obtained as a single diastereomer (d.r. > 20:1), as
1
13
evidenced by H NMR and C NMR.
General Procedure for the Acetoxylation of Tripeptides
Table 6). To a microwave tube (5 mL) was added the substrate (0.2
(
mmol), Pd(OAc) (0.02 mmol), PhI(OAc) (0.8 mmol), and acetic
2
2
anhydride (3 mL) in air. The tube was sealed and heated to 100 °C.
The mixture was stirred at 100 °C until the color of the solution
turned black, typically after 12−23 h. The reaction mixture was cooled
to room temperature. The mixture was filtered through a short Celite
pad, and the filtrate was concentrated under reduced pressure. The
resulting mixture was purified by preparative TLC, typically using
hexane/ethyl acetate/CH Cl2 mixtures as the eluent, to give the
2
acetate as a solid. The acetate was typically obtained as a single
1
13
diastereomer (d.r. > 20:1), as evidenced by H NMR and C NMR.
ASSOCIATED CONTENT
■
*
S
Supporting Information
Detailed experimental procedures and characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Dipeptide 2m was then converted to 13 and subsequently
coupled with Phth−Ala−OH to give the tripeptide 14 in 69%
overall yield. The second modification was then performed on
AUTHOR INFORMATION
1
4 to give tripeptide 15 with two unnatural phenylalanine
■
moieties at different sites (Scheme 1). Tripeptide 15 could be
potentially incorporated into longer peptide sequences via
deprotection-coupling steps.
Corresponding Author
*
yu200@scripps.edu.
Author Contributions
†
W.G. and G.Z. contributed equally to this work.
3. CONCLUSION
In summary, we have developed a method for site-selective
Notes
3
functionalization of C(sp )−H bonds in peptides at the N-
The authors declare no competing financial interest.
terminus. Di-, tri-, and tetrapeptides could be arylated with a
broad range of arylating reagents to provide peptides with
ACKNOWLEDGMENTS
3
■
modified phenylalanine residues. Acetoxylation of C(sp )−H
This work was supported by The Scripps Research Institute
and the NIH (NIGMS, 2R01GM084019). G.Z. gratefully
acknowledges the visiting scholar award organized by the China
Scholarship Council (No.201208330026). We are grateful to
Professor Reza Ghadiri and Phil Dawson for their insightful
suggestions during our preparation of this manuscript.
bonds in tripeptides is also demonstrated. This study illustrates
that the amino acid moiety of peptides can coordinate with
Pd(II) via N,O- or N,N-bisdentate coordination and promote
3
functionalization of proximate C(sp )−H bonds. We anticipate
that these preliminary results could facilitate further develop-
ment of C−H bond functionalization of peptide aliphatic side
chain in the context of postsynthetic modification of peptides.
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(
7
(
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(
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