Assembly of indoline-2-carboxylate-embodied dipeptides via Pd-catalyzed C(sp2)-H bond direct functionalization

Article abstract of DOI:10.1021/ol503514t

Intramolecular dehydrogenative cyclization of 2-methoxyiminoacyl-protected phenylalanine derivatives proceeded at 110 ?°C under catalysis of Pd(OAc)₂ in the presence of 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate to afford substituted

Full text of DOI:10.1021/ol503514t

Letter
pubs.acs.org/OrgLett
Assembly of Indoline-2-carboxylate-Embodied Dipeptides via Pd-
Catalyzed C(sp2)−H Bond Direct Functionalization
Yu-Peng He,† Chao Zhang,† Mengyang Fan,‡ Zhijie Wu,‡ and Dawei Ma*,‡
†College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1,
Fushun 113001, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Intramolecular dehydrogenative cyclization of
2-methoxyiminoacyl-protected phenylalanine derivatives pro-
ceeded at 110 °C under catalysis of Pd(OAc)2 in the presence
of 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate to
afford substituted indoline-2-carboxylates that were converted
into indoline-2-carboxylate-embodied dipeptides via Raney Ni-
catalyzed hydrogenation.
eptidomimetics containing the indoline-2-carboxylate
moiety have been found to have a variety of biological
reported that amine protecting groups play a key role for this
transformation because the corresponding amides can serve as
directing groups to facilitate C−H cleavage for C(sp2)−H
functionalization. In 2005, palladium-catalyzed arylation of
amine derivatives employing aminoquinoline and picolinamide
auxiliary as the directing group was disclosed by Daugulis and
co-workers.5 Until now, (trifluoromethyl)sulfonyl, picolina-
mides, and 2-pyridylsulfonyl have been proven to be suitable
protecting groups for this purpose. However, after intra-
molecular dehydrogenative cyclization, they must be removed
for further conversions to prepare useful molecules.
P
activities,1 including inhibiting zinc metalloproteases angioten-
sin converting enzyme (ACE) and neutral endopeptidase
(NEP)2 that was displayed by tripeptide 1 (Scheme 1, IC50
=
Scheme 1. Bioactive Peptidomimetics Containing an
Indoline-2-carboxylate Moiety
In 2013, we reported that 2-methoxyiminoacyl (MIA) was a
powerful amine auxiliary for palladium-catalyzed direct γ-
arylation of 2-aminobutanoic acid derivatives.6 The amine
auxiliary in resultant γ-arylation products 6 could be easily
removed under mild conditions to provide protected amino
acids 7 or converted into dipeptides 8 via simple hydrogenation
(Scheme 2). In order to further explore the synthetic usage of
this amine auxiliary, we attempted palladium-catalyzed aerobic
intramolecular dehydrogenative cyclization of 2-methoxyimi-
noacyl-protected phenylalanines 9 and were pleased that the
C−H amination proceeded smoothly under the catalysis of
Pd(OAc)2 to afford the substituted indoline-2-carboxylates 10,
which could be transformed into indoline-2-carboxylate-
embodied dipeptides 11 and 12 upon hydrogenation. Herein,
we disclose our results.
13 nM and 50 nM respectively);1a antagonizing dopamine D2/
D4 receptor demonstrated by dipeptide 2;1b blocking the
activity of farnesyltransferase (FT) shown by tetrapeptide 3
(IC50 = 37 nM;)1c and inhibiting β-amyloid peptide release
exhibited by dipeptide 4.1d,e Therefore, developing new
synthetic methodologies that allow efficient and convenient
assembly of indoline-2-carboxylate-embodied peptidomimetics
has been an important goal in recent years.3
As indicated in Table 1, we chose amide 9a as a model
substrate for exploring suitable cyclization conditions. Under
the catalysis of 10 mol % of Pd(OAc)2, the reaction took place
at 110 °C and in the presence of 2.0 equiv of PhI(OAc)2,
providing the desired cyclization product 10a in 30% yield,
together with overoxidized product3d,7 13a in 28% yield (entry
Recent progress in transition-metal-catalyzed C(sp2)−H
bond functionalization4 has provided an alternative approach
for assembling substituted indoline-2-carboxylates in which the
key transformation is a palladium-catalyzed aerobic intra-
molecular dehydrogenative cyclization of phenylalanine de-
rivatives through C(sp2)−H functionalization.3b,c,f It was
Received: December 5, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503514t
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Organic Letters
Letter
Scheme 2. Synthesis of Dipeptides via Pd-Catalyzed C(sp3)−
H and C(sp2)−H Bond Functionalization
Table 1. Pd(OAc)2-Catalyzed Intramolecular
Dehydrogenative Cyclization of Amide 9a
yield (%)
Pd(OAc)2
time
(h)
a
entry (mol %)
additives/atm
solvent
PhMe
10a
13a
1
2
3
10
10
10
2.0 equiv of
PhI(OAc)2,
air
16
16
2
30
28
2.0 equiv of
PhI(OAc)2,
Ar
PhMe
Ac2O
32
35
26
b
2.0 equiv of
PhI(OAc)2,
Ar
32
4
5
6
7
8
9
10
10
10
10
10
10
10
10
5
2.0 equiv of
K2S2O8, air
PhMe
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
16
16
16
16
16
8
<1
30
<1
48
65
73
74
65
80
2.0 equiv of
Ce(SO4)2, air
1). Little improvement was observed when reaction was carried
out at an argon atmosphere or using acetic anhydride as the
c
c
c
c
2.0 equiv of
F+(A), air
6,8
solvent (entries 2 and 3). Changing the oxidant to K2S2O8
3b
2.0 equiv of
and Ce(SO4)2 resulted in no or poor conversion (entries 4
F+(B), air
and 5). In light of recent developments using bystanding F+
oxidants to promote selective reductive elimination of high-
valent metal centers,9 we examined several F+ (A−C) sources10
as the oxidants and were pleased that overoxidization could be
avoided and F+(C) could give the cyclization product in a
satisfactory yield (entries 6−8). In this case, addition of 1.25
equiv of DMF was crucial to ensure good conversion.3b The
reaction proceeded more efficiently under an argon atmosphere
(compare entries 8 and 9), indicating that oxygen has some
inhibitory effect to the present transformation. Reducing the
loading of F+(C) from 2 equiv to 1.5 equiv did not alter the
reaction yield; however, further reduction decreased the
reaction yield significantly (entries 9−11). Interestingly,
reducing the catalyst loading even gave better results (entries
12 and 13), and the best result (86% yield) was obtained when
5 mol % of Pd(OAc)2 and 1.5 equiv of F+(C) were adopted
(compare entry 14 with entries 9−13). More importantly, the
high enantiopurity of the cyclization product 10a (97% ee)
indicated that no racemization occurred during the reaction
course. Additionally, further reduction of the loading of
Pd(OAc)2 and F+(C) resulted in incomplete conversion,
leading to decreased yields (entries 15 and 16).
2.0 equiv of
F+(C), air
2.0 equiv of
F+(C), Ar
c
c
c
c
c
c
c
10
11
12
13
14
15
16
1.5 equiv of
8
F+(C), Ar
1.0 equiv of
8
F+(C), Ar
2.0 equiv of
8
F+(C), Ar
2
2.0 equiv of
8
77
F+(C), Ar
b
5
1.5 equiv of
8
86 (88)
F+(C), Ar
5
1.2 equiv of
8
80
73
F+(C), Ar
2
1.5 equiv of
8
F+(C), Ar
a
1
Yields are based on H NMR analysis of the reaction mixture using
1,3,5-trimethoxybenzene as an internal standard on a 0.1 mmol scale.
Yields based on isolated products on a 0.5 mmol scale. With 1.25
equiv of DMF.
b
c
giving the corresponding cyclization products in good to
excellent yields. Interestingly, the yield of a substrate possessing
forced electron-donating functional group OBn (10i) was
relatively low, and the corresponding indole products were
isolated in 12% yield, while similar overoxidation was not
observed for substrates with an OTf or OAc group (10g and
10h). It is noteworthy that some functional groups such as
OAc, OTf, nitro, and halogens including chloro, bromo, and
even iodo were preserved under these reaction conditions.
Furthermore, the orientation of substituents has a weak
With the optimal reaction conditions in hand, we next
examined the reaction scope by varying the directing groups
and the substituents on the aromatic ring of phenylalanines,
and the results are summarized in Scheme 3. It was found that
three other directing groups also worked well, leading to the
formation of 10b−d in 78−86% yields. Further investigations
revealed that a wide range of phenylalanine derivatives bearing
either electron-donating or electron-withdrawing groups were
compatible with this C−H functionalization protocol, thus
B
DOI: 10.1021/ol503514t
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 3. Synthesis of Substituted Indoline-2-carboxylate
via Pd-Catalyzed Direct Amination
Scheme 4. Possible Reaction Mechanism
a
H insertion to give the double palladium chelate 15. After an
oxidative process of the two-electron oxidant (F+), the resultant
complex 16 with a Pd(IV) center11 undergoes reductive
elimination to deliver the product 10a through the intermediate
17. Noteworthy is that for this transformation a mechanism via
Pd(III) intermediate12,13 is also possible.
To demonstrate the synthetic usage of the present cyclization
reaction, we attempted further transformations of the
cyclization products 10. To our delight, hydrogenation of the
oxime moiety in 10b proceeded smoothly under the catalysis of
Raney Ni at ordinary pressure and temperature to afford
dipeptide 11a in 93% yield after protection with Boc anhydride
(Scheme 5). For other substrates, a new chiral center was
Scheme 5. Transformation into the Boc-Protected
a
Dipeptides
a
a
b
Yields based on isolated products on a 0.5 mmol scale.
Corresponding indole product was isolated in 12% yield.
Isolated yield. Solvent: 20% THF in MeOH.
b
created after hydrogenation, leading to formation of two
diastereoisomers that could be easily separated by column
chromatography. There is a moderate asymmetric induction
during hydrogenation as about 3:1 diastereomeric ratio for 11
and 12 were observed. To determine the relative stereo-
chemistry of the diastereomers, we removed the Boc protecting
group in 11 and 12 and then treated then with triethylamine to
deliver tricyclic compounds 18 and 19, whose structures were
established by NOESY studies.
In summary, we have developed an effective protocol for the
synthesis of dipeptides containing indoline-2-carboxylate via
palladium-catalyzed direct amination of phenylalanine deriva-
tives. The key for this success is employing substituted
influence on the reactivity (compare 10l with 10m and 10q
with 10p). This unique combination of reactivity and functional
group compatibility provided a convenient and efficient route
for the formation of various chiral indoline-2-carboxylates. In
addition, the structure of 10p was unambiguously confirmed by
X-ray diffraction crystallography.
Although a detailed mechanistic investigation of the present
amination process awaits further experimental evaluation, our
tentative hypothesis is outlined in Scheme 4. Based on the
studies by the Ritter9c,e and Yu3b groups, we speculated that the
amide 9a might react with a Pd(II) species to form the
palladium amidate 14 and therefore facilitate a subsequent C−
C
DOI: 10.1021/ol503514t
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Organic Letters
Letter
methoxyiminoacyl (MIA) as the directing groups and a F+
source as the oxidant. This method features high efficiency and
wide functional group tolerance. Applications of these directing
groups to other coupling reactions, together with detailed
mechanistic studies, are being explored in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectra data and copies of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) (a) Grushin, V. V. Chem.−Eur. J. 2002, 8, 1006−1014. (b) Kaspi,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: madw@mail.sioc.ac.cn.
Notes
(10) (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
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1737−1755. (b) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent,
S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192−212.
(c) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed.
2011, 50, 1478−1491.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) (a) Xu, L. M.; Li, B. J.; Yang, Z.; Shi, Z. J. Chem. Soc. Rev. 2010,
39, 712−733. (b) Sehnal, P.; Taylor, R. J. K; Fairlamb, I. J. S. Chem.
Rev. 2010, 110, 824−889.
We are grateful to the Chinese Academy of Sciences, National
Natural Science Foundation of China (Grant Nos. 21132008
and 21202077) and the Scientific Research Foundation of
Liaoning Science and Technology Agency (Grant No.
20121047) for their financial support.
(12) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J.
Am. Chem. Soc. 2009, 131, 17050−17051.
(13) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131,
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