Pd-catalyzed intramolecular C(sp2)-H amination of phenylalanine moieties in dipeptides: Synthesis of indoline-2-carboxylate-containing dipeptides

Article abstract of DOI:10.1039/c8ob00207j

A palladium-catalyzed intramolecular C(sp²)-H amination of phenylalanine moieties in dipeptides is described. By this protocol, a series of indoline-2-carboxylate-containing dipeptides were synthesized from dipeptides. The N-protected amino aci

Full text of DOI:10.1039/c8ob00207j

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Pd-catalyzed intramolecular C(sp2)–H amination
of phenylalanine moieties in dipeptides: synthesis
of indoline-2-carboxylate-containing dipeptides†
Cite this: DOI: 10.1039/c8ob00207j
Received 25th January 2018,
Accepted 13th March 2018
Yong Zheng, Weibin Song, Yefu Zhu, Bole Wei and Lijiang Xuan
*
DOI: 10.1039/c8ob00207j
rsc.li/obc
A
palladium-catalyzed intramolecular C(sp2)–H amination of
phenylalanine moieties in dipeptides is described. By this protocol,
a series of indoline-2-carboxylate-containing dipeptides were syn-
thesized from dipeptides. The N-protected amino acid moiety
within the peptide is used as an intrinsic bidentate directing group.
This intramolecular C–H amination reaction provides an appealing
strategy for the post-synthetic modification of peptides.
Peptides and peptidomimics have attracted considerable atten-
tion in medicinal chemistry research due to their high target
specificity and low toxicity.1 As a consequence, a number of
peptide-based drugs have been approved in the past decades.1c
However, natural peptides often suffer from poor pharmaco-
logical properties and the lack of structural diversity, which
hampers access of these agents to extracellular target space.2
Thus, post-synthetic modification of peptides which overcomes
these disadvantages has become a hot research topic.3 Peptides
containing indoline-2-carboxylate moieties are an important
class of modified peptides, which are found in many pharma-
ceutically active molecules, such as enzyme tripeptidyl pepti-
dase II inhibitors, β-amyloid peptide release inhibitors, ACE
inhibitors, etc. (Fig. 1).4–11 The classical method is achieved by
coupling indoline-2-carboxylates with amino acid derivatives.
However, examples of the preparation for indoline-2-carboxy-
lates are rare. The existing methods often suffer from limit-
ations such as inaccessible starting materials, use of expensive
chiral catalysts, and tedious procedures.12 Therefore, develop-
ment of a straightforward approach toward such structures
from dipeptides is highly desirable.
Fig. 1 Bioactive peptides containing indoline-2-carboxylate moieties.
forward and powerful strategy for the construction of chiral
indoline-2-carboxylates from phenylalanine derivatives. Various
directing groups, such as trifluoromethanesulfonyl (Tf), picoli-
namide (PA), pyridinylsulfonyl (TS), 1,2,3-triazole-4-carboxylic
acid (TAA), and oxalyl amide (OA), were successfully employed
in intramolecular amination for the construction of indolines
(Scheme 1A).14–18 However, the installation and removal of the
directing group increases the number of synthetic steps and
harsh conditions are always required for removal of the
directing group. Recently, Ma reported a Pd-catalyzed intra-
molecular dehydrogenative cyclization of 2-methoxyiminoacyl-
protected phenylalanine derivatives (Scheme 1B).19 The cyclized
products can be converted into indoline-2-carboxylate-embodied
dipeptides upon hydrogenation. However, two diastereoisomers
In the past decades, transition-metal-catalyzed C–H amin-
ation has become an appealing method for the formation of
C–N bonds.13 Particularly, the Pd-catalyzed directing group
assisted intramolecular C–H amination provides a straight-
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai
201203, China. E-mail: ljxuan@mail.shcnc.ac.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob00207j
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amination (Scheme 1). Herein, we report the synthesis of indo-
line-2-carboxylate-containing dipeptides via the Pd-catalyzed
intramolecular C(sp2)–H amination of phenylanine moieties in
dipeptides. The amino acid moieties in dipeptides are used as
intrinsic directing groups, which avoid removing after C–H
amination. This protocol offers a versatile tool for the post
modification of phenylalanine-containing dipeptides.
To test these hypotheses, we initially started our C–H amin-
ation by treating 1a with 2 equiv. PhI(OAc)2 in the presence of
5% Pd(OAc)2 in DCE at 120 °C for 20 h (Table 1, entry 1). As
expected, the desired product 2a was obtained in 30% yield.
Screening of different solvents showed that toluene was the
best solvent (entries 2 and 3). Lower or higher reaction temp-
eratures led to lower reaction yields (entries 4 and 5).
Increasing oxidant loading from 2 equiv. to 3 equiv. did not
lead to any improvement (entry 6). We then screened various
Table 2 Scope of the protected-amino acid moieties in the dipetidesa,b
Scheme 1 Pd-catalyzed intramolecular C–H amination.
were formed after hydrogenation, which must be separated by
column chromatography (Scheme 1B).
Recently, inexpensive and environmentally friendly amino
acid moieties have been employed as bidentate directing
groups in C–H functionalization.20 Inspired by these pioneer-
ing studies, we envisioned that the N-protected amino acid
moiety within peptides might be utilized as an intrinsic biden-
tate directing group to facilitate the intramolecular C(sp2)–H
Table 1 Optimization of reaction conditionsa,b
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
K2S2O8
H2O2
TBHP
PhI(OAc)2
DCE
HFIP
30
22
64
44
60
62
<5
<5
<5
0
3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
4c
5d
6e
7
8
9
10
11
Pd(OAc)2
0
a Reaction conditions: 1a (0.3 mmol), oxidant (0.6 ml), Pd(OAc)2
(5 mol%), solvent (2 ml), 120 °C, 20 h. b Isolated yields. c 80 °C. d 150 °C. a Reaction conditions: 1 (0.3 mmol), PhI(OAc)2 (0.6 mmol), Pd(OAc)2
e 3 equiv. of PhI(OAc)2.
(5 mol%), toluene (2 ml), 120 °C, air, 20 h. b Isolated yields.
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oxidants, including K2S2O8, H2O2, and TBHP (entries 7–9). The
results showed that PhI(OAc)2 was the best oxidant.
Furthermore, the reaction did not proceed without the use of
Pd(OAc)2 or PhI(OAc)2 (entries 10 and 11).
With the optimized conditions in hand, the scope of the
Boc-amino acids in the peptides was surveyed (Table 2). The
peptides bearing Boc-L-alanine, Boc-L-phenylalanine, Boc-L-
leucine, Boc-L-isoleucine, Boc-L-valine, Boc-L-serine and Boc-L-
tryptophan afforded the desired products in moderate to good
yields (2b–2h). Notably, no racemisation was observed for 2a
(99% ee) and 2b (99% ee). Besides L-amino acids, the substrate
containing Boc-D-alanine also underwent C–H amination to
afford product 2i in 58% yield. Furthermore, Cbz-, Fmoc-, and
Ac-protected dipeptides could also deliver the corresponding
cyclization products 2j–2l in moderate yields. A low yield was
observed for peptide 2m, presumably due to the steric hin-
drance from the tert-butyl group. Attempt at the synthesis of
the tetrahydroquinoline derivative 2n was not successful,
because of the formation of an unfavorable seven-membered
palladacycle intermediate during the catalytic cycle. The cycli-
zation of 1o and 1p failed under the standard conditions
because the palladium complex via a bidentate coordination
could not be formed during the catalytic cycle, indicating that
the bidentate directing group is crucial to this amination.
Scheme 2 Plausible mechanism.
Next, peptides with different substituents on the phenyl
ring were examined (Table 3). Both electron-donating (OAc and
4a–4d) and electron-withdrawing (Cl, F, Br, NO2, and 4e–4i)
groups on the phenyl rings were compatible under the stan-
dard conditions, affording the cyclization products. Notably,
the halogen groups were intact after the C–H amination,
which provided the possibility for further useful transform-
ations (4e–4g). Furthermore, indolines 4j and 4k were also
obtained under the standard conditions, which expanded the
versatility of this C–H amination protocol.
Table 3 Scope of substitutes on phenyl ringsa,b
On the basis of the above observations and literature
reports, a plausible mechanism for this Pd-catalyzed intra-
molecular C–H amination reaction is depicted in
Scheme 2.15–18 Dipeptide 1a coordinates with Pd(OAc)2 to
generate the palladium complex 5. Complex 5 then undergoes
C–H insertion to afford the intermediate 6. Next, the oxidation
of 6 using PhI(OAc)2 provides an intermediate Pd(IV) species 7,
which could then form the new C–H bond via selective C–N
reductive elimination, thus yielding 2a and regenerating the
active palladium catalyst.
In summary, we have developed a novel Pd-catalyzed intra-
molecular C–H amination for the synthesis of indoline-2-
carboxylate-containing dipeptides. The protected-amino acid
moiety in the dipeptide not only acts as the intrinsic bidentate
directing group, but also is an indispensable part of the entire
molecule. This protocol would provide a diverse library of
indoline-2-carboxylate-containing dipeptides for preclinical
drug candidates.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
a Reaction conditions: 3 (0.3 mmol), PhI(OAc)2 (0.6 mmol), Pd(OAc)2
We gratefully acknowledge the National Natural Science
Foundation of China (Grants 81602995) for financial support.
(5 mol%), toluene (2 ml), 120 °C, air, 20 h. b Isolated yields.
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