Co-catalyzed C(sp3)-H oxidative coupling of glycine and peptide derivatives

Article abstract of DOI:10.1021/acs.orglett.7b02567

Cobalt-catalyzed selective a-alkylation and a-heteroarylation processes of a-amino esters and peptide derivatives are described. These cross-dehydrogenative reactions occur under mild conditions and allow for the rapid assembly of structurally diverse a-amino carbonyl compounds. Unlike enolate chemistry, these methods are distinguished by their site-specificity, occur without racemization of the existing chiral centers, and exhibit total selectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modifications.

Full text of DOI:10.1021/acs.orglett.7b02567

Letter
pubs.acs.org/OrgLett
Co-Catalyzed C(sp3)−H Oxidative Coupling of Glycine and Peptide
Derivatives
Marcos San Segundo, Itziar Guerrero, and Arkaitz Correa*
Department of Organic Chemistry-I, University of the Basque Country (UPV-EHU), Joxe Mari Korta R&D Center, Av. Tolosa 72,
20018 Donostia-San Sebastian, Spain
́
S
* Supporting Information
ABSTRACT: Cobalt-catalyzed selective α-alkylation and α-
heteroarylation processes of α-amino esters and peptide derivatives
are described. These cross-dehydrogenative reactions occur under
mild conditions and allow for the rapid assembly of structurally
diverse α-amino carbonyl compounds. Unlike enolate chemistry,
these methods are distinguished by their site-specificity, occur
without racemization of the existing chiral centers, and exhibit total
selectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modifications.
Conventional approaches for the preparation of aryl glycine
wing to the emergence of peptides and peptidomimetics at
Othe forefront of pharmaceutical research and the limited compounds involve the Strecker synthesis,10 the Petasis
reaction,11 and the Ugi reaction.12 However, the direct
functionalization of glycine or glycine-containing peptides
through metal-catalyzed CDC processes clearly represents a
practical, yet challenging, alternative.13 Li and co-workers
elegantly introduced efficient Cu-catalyzed α-functionalizations
of glycine and peptide derivatives with a variety of highly reactive
nucleophiles (boronic acids, alkynes and indoles).13k,l Despite
the remarkable importance of the method, the success of the
oxidative process was limited to the particular use of p-
methoxyphenyl glycine amides and related α-amino esters were
found unreactive. Herein we report on the development of an
unprecedented Co-catalyzed site-selective alkylation and hetero-
arylation reaction with cyclic ethers and indoles, respectively.
Our method features the use of a combination of cobalt salts as
practical cost-efficient catalysts along with an aqueous solution of
tert-butyl hydroperoxide as inexpensive oxidant. Remarkably, it
represents a versatile synthetic tool of utmost importance for the
assembly of a wide variety of substituted N-aryl α-amino esters
and short peptides hence broadening the synthetic scope of
existing methodologies to produce molecular diversity from
inexpensive biomass in a selective and rapid manner.
availability of amino acids genetically encoded,1 the development
of new methodologies for the straightforward chemical
modification of α-amino carbonyl compounds represents a
challenging task of prime scientific interest.2 Although most
classical α-functionalization methods are hitherto limited to
carbanion chemistry,3 and solid phase techniques,4 the last years
have witnessed the upsurge of catalytic C−H functionalization
approaches as atom-economic and environmentally friendly
means for the direct modification of glycine and peptide
derivatives.5 Of particular importance are cross-dehydrogenative
couplings (CDCs) pioneered by Li which involve the dual
oxidation of two distinct C−H bonds in a catalytic fashion.6
These types of reactions are mostly catalyzed by copper and iron
salts, and hence the implementation of alternative metal catalysts
could open up new horizons in the realm of organic chemistry. In
this respect, cobalt catalysis7 has recently received a great deal of
attention and provides new dogmas for achieving practical and
unconventional bond-disconnections that were beyond reach
using other metals. Despite the existence of various Co-catalyzed
CDC reactions,8 Co-catalyzed functionalization of amino esters
and peptide derivatives remains virtually unexplored.
Given the prevalence of ethers in a plethora of natural products
and drugs together with their appealing use in CDC reactions,14
we first analyzed the viability of using Co catalysis in the
dehydrogenative alkylation of N-phenyl glycine ester (1a) with
THF. After systematically evaluating the reaction parameters,15
we found that a combination of Co(acac)2·H2O (5 mol %) and
an aqueous solution of TBHP in the presence of 1,2-
dichoroethane as solvent afforded α-alkylated glycinate 2a in
78% yield (Table 1, entry 1). Control experiments revealed that
all the reaction parameters were critical for success (entries 2−3).
Aryl glycines are important nonproteogenic amino acids
prevalent in a vast array of glycopeptide antibiotics and common
key intermediates in the production of β-lactam antibiotics.9
Some relevant examples are vancomycin, amoxicillin, and
ampicillin which contain aryl glycine residues (Figure 1).
Received: August 18, 2017
Figure 1. Importance of aryl glycines in medicinal chemistry.
© XXXX American Chemical Society
A
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Letter
a
a b
,
Table 1. Co-catalyzed C(sp3)−H Alkylation of 1a with THF
Scheme 1. Co-catalyzed C−H Alkylation with Cyclic Ethers
b
entry
change from standard conditions
none
2a (%)
1
78
0
2
without Co(acac)2·H2O
3
without TBHP(aq)
0
4
TBHP(dec) instead of TBHP(aq)
without DCE
48
61
54
0
5
6
under air
7
K2S2O8 instead of TBHP(aq)
DCP instead of TBHP(aq)
Co(OAc)2 instead of Co(acac)2·H2O
Co(acac)3 instead of Co(acac)2·H2O
CoBr2 instead of Co(acac)2·H2O
CoCl2 instead of Co(acac)2·H2O
8
0
9
69
64
77
71
10
11
12
a
Reaction conditions: 1a (0.5 mmol), Co(acac)2·H2O (5 mol %),
TBHP(aq) (2.0 equiv), THF (1.0 mL), DCE (1.0 mL) at 60 °C for 24
b
h under argon. Yield of isolated product after column chromatog-
raphy. TBHP (aq) = tBuOOH 70% in H2O; TBHP (dec) = tBuOOH
5.0−6.0 M in decane; DCP = dicumyl peroxide.
a
b
As for Table 1, entry 1. Yield of isolated product after column
c
chromatography; average of at least two independent runs. Reaction
performed at 80 °C.
Importantly, an aqueous solution of TBHP was found superior
than its analogue in decane (entry 4), which represents a practical
bonus in terms of economics and sustainability; other related
oxidants were shown unreactive (entries 7−8). A variety of metal
sources were tested (entries 9−12), but the easy-to-handle and
cheap Co(acac)2·H2O provided slightly better yields. Remark-
ably, a competitive double-oxidative dehydrogenative cyclization
toward the formation of quinolone-fused lactones16 was not
observed, thus evidencing the significant subtleties of our Co-
based catalytic system vs the use of other metals.
a b
,
Scheme 2. Co-catalyzed C−H Heteroarylation with Indoles
With optimal conditions in hand, we next examined the
generality of our transformation by exploring a variety of N-aryl
α-amino carbonyl compounds with ethers as feedstock
substrates. Not only α-amino esters (1a−c) but also amides
(1d) underwent the desired alkylation in good yields. As shown
in Scheme 1, the process turned out to be widely applicable
regardless of the nature of the aryl ring. Importantly, several
functional groups were perfectly accommodated such as halides
(2e−f, 2i−j, 2n, 2p−q), ketones (2g), nitriles (2k), ethers (2l),
and heterocycles (2m). Notably, even sterically demanding α-
amino ester 1h also smoothly underwent alkylation reaction. Of
paramount significance is the use of 1,3-dioxolane as coupling
partner due to the fact that its CDC would provide a masked
formyl derivative upon a practical and aldehyde-free synthetic
protocol. In this regard, the reaction turned out to be exclusively
selective toward the C2 position providing 2o−r as single
regioisomers. We next envisioned the application of our Co-
based method to the use of more powerful nucleophiles such as
indoles. To our delight, after slight modification of the reaction
conditions,15 the use of cobalt catalysis allowed for the efficient
coupling process of numerous α-amino esters 1a−l and indole
derivatives 3 under mild reaction conditions. As depicted on
Scheme 2, N-methyl and N-benzyl indoles as well as versatile
free-NH indoles underwent the target heteroarylation, regardless
of the electronic nature of the N-aryl glycinate.17 Notably,
sterically hindered 2-substituted indole 3j reacted to give the
corresponding product 4j in good yield. Besides, other
heteroaromatic substrates such as less reactive simple pyrroles
could be also utilized to produce heteroarylated glycinate 4l,
a
Reaction conditions: 1a (1.0 mmol), 3 (0.5 mmol), Co(acac)2·H2O
(10 mol %), TBHP(aq) (2.0 equiv), MeCN (1.0 mL) at 40 °C for 24
b
h under argon. Yield of isolated product after column chromatog-
raphy; average of at least two independent runs.
albeit in moderate yield. Noteworthy, the method was found
tolerant with the presence of synthetically valuable functional
groups such as nitriles (4i, 4k).
Encouraged by these promising results, we decided to tackle
the more challenging task of selectively functionalizing short
peptides, which are typically prone to undergo oxidative
cleavage18 and hence difficult to manipulate. Importantly, simple
dipeptides 5a−k and tripeptides 5l−n underwent the desired α-
functionalization reaction both with ethers and indoles to furnish
the corresponding products 6a−n in moderate to excellent yields
B
DOI: 10.1021/acs.orglett.7b02567
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Organic Letters
Letter
(Scheme 3). Whereas the heteroarylation event can be achieved
upon copper catalysis13k,l or through aerobic auto-oxidative
operative. On the other hand, when glycinate 1a was submitted
to the coupling conditions in the absence of THF the α-tert-
butyldioxyl intermediate 7 was isolated in 23% yield [Scheme 4,
ab
,
Scheme 3. Co-catalyzed α-Functionalization of Peptides
Scheme 4. Control Experiments
eq (1)]; the latter species was found to be stable and could be
fully characterized by NMR spectroscopy.19 Interestingly,
peroxide derivative 7 provided the corresponding alkylated
product 2a in 88% yield under the optimized conditions [Scheme
4, eq (2)], thus evidencing its possible key role as a competent
reaction intermediate within our catalytic cycle. Conversely, it
did not react with indole [Scheme 4, eq (3)]. Curiously, whereas
treatment of imine 8 with indole furnished the corresponding
coupling product 4c in 99% yield at room temperature in the
absence of cobalt and oxidant [Scheme 4, eq (4)], such imine 8
remained unreactive under our oxidative alkylation conditions
with THF [Scheme 4, eq (5)], thus revealing that a distinct
mechanistic scenario could be operative in each case.
Furthermore, our Co-catalyzed C−H functionalization processes
upon tertiary amine 9 were unsuccessful [Scheme 4, eq (6)],
which highlights the crucial role of the free-NH aryl group.
On the basis of the above results and previous literature
reports,8,13 a plausible reaction mechanism is proposed in
Scheme 5. The reaction would start with the Co(II)/Co(III)-
induced decomposition of tBuOOH to produce tert-butoxy
radical A.20 Subsequently, the corresponding aryl glycine would
a
b
As for Table 1, entry 1. Yield of isolated product after column
c
chromatography; average of at least two independent runs. Reaction
performed at 80 °C. Reaction conditions as for Scheme 2.
d
conditions,16c to the best of our knowledge, our Co-catalyzed
functionalization with cyclic ethers represents the first example of
a highly selective alkylation of peptides featuring the use of
feedstock substrates.13d In all cases, the N-aryl group directed the
CDC to occur exclusively on the terminal Gly unit even in the
presence of other Gly residues and not even traces of the
functionalization of other residues were observed. Interestingly,
dipeptides bearing valine and proline units also delivered the
coupling products 6f, 6h, and 6i, respectively, in 52−92% yields.
Remarkably, in the latter cases HLPC analysis verified the full
preservation of the chiral integrity of the existing stereocenters.15
Accordingly, our method scores over enolate chemistry which
not only suffers from lack of regioselectivity in cases where the
peptide contains multiple Gly residues, but also because of the
often observed racemization due to the strong basic conditions
required to deprotonate α-protons to the adjacent carbonyl
moiety. Notably, unlike Cu-based system,13k,l the success of the
process was not limited to the use of activated N-PMP-Gly-Gly-
OEt but also peptides bearing N-Ph (6a, 6d, 6f−h) and even N-
m-chlorophenyl group (6c) provided the corresponding
products in good yields. As a result, our Co-catalyzed approach
outperforms known methods for the site-selective functionaliza-
tion of small peptides.
Scheme 5. Proposed Reaction Mechanism
To gain some insights into the reaction mechanism, we carried
out the following experiments. On one hand, we found that the
CDC of amino ester 1a with both indole and THF were entirely
inhibited in the presence of radical traps such as TEMPO and
BHT, which indicated that a radical mechanism may be
C
DOI: 10.1021/acs.orglett.7b02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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undergo Hydrogen Atom Transfer (HAT) by radical species A to
furnish alkyl radical intermediate B, which would be likely
converted to the more stable carbocation C through a Single
Electron Transfer (SET) event assisted by Co(III). Such
carbocation C could be further stabilized as the corresponding
iminium ion D. According to experimental evidence, the latter
would be trapped by highly nucleophilic indoles to produce the
target product. In contrast, when using less reactive ethers, prior
nucleophilic attack of tBuOOH would deliver peroxide
intermediate E,21 which could eventually react with the in situ
generated α-oxy radical F14 to produce the corresponding
coupling product.
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and indoles can be selectively introduced in a variety of glycine
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modifications which was found to be applicable to the assembly
of a vast array of α-functionalized glycine derivatives of
paramount importance in proteomics. We anticipate that our
experimental results could lead to acquiring new knowledge in
catalyst design, thus opening up new vistas in cobalt-catalyzed
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02567.
Detailed screening processes, experimental procedures,
and spectral data (PDF)
́
(k) Zhao, L.; Basle, O.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2009, 106,
AUTHOR INFORMATION
4106. (l) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075.
(14) (a) Liu, S.; Liu, A.; Zhang, Y.; Wang, W. Chem. Sci. 2017, 8, 4044.
■
Corresponding Author
*E-mail: arkaitz.correa@ehu.es.
ORCID
́
(b) Correa, A.; Fiser, B.; Gomez-Bengoa, E. Chem. Commun. 2015, 51,
13365. (c) Wan, M.; Meng, Z.; Lou, H.; Liu, L. Angew. Chem., Int. Ed.
2014, 53, 13845.
(15) For more details, see the Supporting Information.
(16) (a) Huo, C.; Xie, H.; Chen, F.; Tang, J.; Wang, Y. Adv. Synth.
Catal. 2016, 358, 724. (b) Huo, C.; Chen, F.; Yuan, Y.; Xie, H.; Wang, Y.
Org. Lett. 2015, 17, 5028. (c) Huo, C.; Yuan, Y.; Wu, M.; Jia, X.; Wang,
X.; Chen, F.; Tang, J. Angew. Chem., Int. Ed. 2014, 53, 13544.
(17) As expected, less nucleophilic N-tosyl- and N-phenylindole
derivatives remained unreactive under our reaction conditions.
(18) Dean, R. T.; Fu, S.; Stocker, R.; Davies, M. J. Biochem. J. 1997, 324,
1.
Arkaitz Correa: 0000-0002-9004-3842
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge technical and human support provided by
SGIker of UPV/EHU and European funding (ERDF and ESF).
We are grateful to G. V. (ELKARTEK_KK-2015/0000101;
IT_1033-16) and MINECO (CTQ2016-78395-P) for financial
(19) For a recent C(sp3)−H peroxidation, see: Xia, Q.; Wang, Q.; Yan,
C.; Dong, J.; Song, H.; Li, L.; Liu, Y.; Wang, Q.; Liu, X.; Song, H. Chem. -
Eur. J. 2017, 23, 10871.
́
support. A.C. thanks MINECO for a Ramon y Cajal contract.
Cost-CHAOS action is also acknowledged.
(20) (a) Watanabe, E.; Kaiho, A.; Kusama, H.; Iwasawa, N. J. Am.
Chem. Soc. 2013, 135, 11744. (b) Turra, N.; Neuenschwander, U.;
̀
Baiker, A.; Peeters, J.; Hermans, I. Chem. - Eur. J. 2010, 16, 13226.
(21) At this stage, a distinct reaction pathway where the direct radical
reaction of alkyl intermediate B with tBuOOH could occur to produce E
cannot be entirely ruled out. There, the resulting peroxide species E
would alternatively release tBuOOH to furnish iminium ion D and
subsequently undergo a nucleophilic attack to afford the target product.
(a) Boess, E.; Wolf, L. M.; Malakar, S.; Salamone, M.; Bietti, M.; Thiel,
W.; Klussmann, M. ACS Catal. 2016, 6, 3253. (b) Boess, E.; Schmitz, C.;
Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317.
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DOI: 10.1021/acs.orglett.7b02567
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