Site-Selective δ-C(sp3)?H Alkylation of Amino Acids and Peptides with Maleimides via a Six-Membered Palladacycle

Article abstract of DOI:10.1002/anie.201801445

The site-selective functionalization of unactivated C(sp³)?H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site-selective δ-C(sp³)?H alkylation of amino acids and peptides with maleimides

Full text of DOI:10.1002/anie.201801445

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Accepted Article
Title: Site-Selective δ-C(sp3)−H Alkylation of Amino Acids and
Peptides with Maleimides via a Six-Membered Palladacycle
Authors: Bei-Bei Zhan, Ya Li, Jing-Wen Xu, Xing-Liang Nie, Jun Fan,
Liang Jin, and Bing-Feng Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801445
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Site-Selective δ-C(sp3)−H Alkylation of Amino Acids and Peptides with
Maleimides via a Six-Membered Palladacycle
Bei-Bei Zhan,[a] Ya Li,[a] Jing-Wen Xu,[a] Xing-Liang Nie,[a] Jun Fan,[a] Liang Jin,[a] and Bing-Feng Shi*[a,b]
Abstract: The site-selective functionalization of unactivated C(sp3)-
H bonds remains one of the greatest challenges in organic synthesis. significantly fast, the selectivity might originate from a Curtin-
reversible and the interconversion of INT-A and INT-B is
Herein, we report a site-selective δ-C(sp3)−H alkylation of amino
acids and peptides with maleimides via a kinetically less favored six-
membered palladacycle in the presence of more accessible γ-
C(sp3)−H bonds. Experimental studies revealed that C-H bond
cleavage occurs reversibly and preferentially at γ-methyl over δ-
methyl C-H bonds, while the subsequent alkylation proceed
exclusively at six-membered palladacycle that generated via δ-C-H
activation. The selectivity can be explained by the Curtin-Hammett
principle. The exceptional compatibility of this alkylation with various
oligopeptides renders this protocol valuable for late-stage
modification of peptides. Notably, this also represents the first Pd(II)-
catalyzed Michael-type alkylation reaction via C(sp3)-H activation.
Hammett situation.[5] Thereafter, we assumed that under certain
conditions, δ-selectivity could be achieved via the
functionalization of INT-B if the functionalization of INT-A could
not occur due to high energy barrier (Figure 1A, path b, the
functionalization step is the SDS). Guided by this hypothesis, we
have realized the first site-selective alkenylation of δ-methyl C−H
bonds in the presence of more accessible γ-methyl C−H bonds
by using picolinamide (PA) as the directing group.[4]
Unfortunately, this proof-of-concept study was far from practical,
due to the narrow substrate scope and low yields. Thus, it would
be highly desirable to make this complementary site-selective
protocol to be general for
a broad range of densely
functionalized substrates, such as peptides.
The direct functionalization of unactivated C(sp3)-H bonds offers
new strategic approaches for the synthesis of useful molecular
entities.[1] However, the realization of this promising strategy
requires the ability to achieve the selective activation of a single
aliphatic C-H bond among many others on the substrates, since
C-H bonds are ubiquitous in organic molecules.[2] The
introduction of a directing group that coordinates with palladium
catalyst and facilitates the cleavage of a proximal C-H bond has
become one of the most successful strategies. Typically,
selective functionalization of γ-methyl C-H was favored over
those of a C(sp3)-H bond at other positions (eg, γ-methylene and
δ-methyl) through the preferencial formation of a kinetically
favored five-membered palladacycle INT-A (Figure 1A, path a).[1]
A fundamental challenge is whether an exclusively site-selective
functionalization of δ-methyl C-H bonds in the presence of γ-
methyl C-H bonds can be achieved via a kinetically less favored
six-membered palladacycle?[3,4] The availability of such
a
strategy would enrich our toolkit for streamlining synthesis of
complex molecules, particularly bioactive natural products and
pharmaceutical targets.
Regardless of the detailed elementary reactions of the whole
catalytic process, the selectivity for Pd-catalyzed C-H
functionalization might arise from each of the following two steps
or both: i) C-H activation to generate a palladacycle, and ii)
functionalization of the resulting palladacycle (Figure 1A).[2a]
Previous γ-selectivity resulted from the fast functionalization of
kinetically favored INT-A (path a, the C-H activation step is the
Figure 1. Pd-catalyzed site-selective C(sp3)−H functionalization
Peptides, being the building blocks of proteins and drug
candidates, have attracted broad attention in biochemistry and
pharmaceuticals.[6] On several occasions, unnatural peptides are
found to shown enhanced biological activities and improved
pharmacokinetic properties when compared to their natural
counterparts.[7] Motivated by the need for postassembly peptide
modification, it is highly desirable to develop new strategies
which are capable of site-specific funcationalization of amino
acids and peptides. Thus far, only scattered examples of site-
selective C(sp3)−H functionalization of peptides have been
achieved. [8,9] Yu reported the late-stage β-C(sp3)−H arylation[9a]
and alkynylation[9b] at the N-terminal amino acid of short
peptides by choosing peptide backbones as directing groups.
Noisier and Albericio achieved the Pd-catalyzed C(sp3)-H
selectivity-determining step (SDS)),
which was
well
established.[1] We reasoned that if the C-H activation step is
[a]
[b]
B.-B. Zhan, Y. Li, J.-W. Xu, X.-L. Nie, Dr. J. Fan, L. Jin, Prof. Dr. B.-
F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
E-mail: bfshi@zju.edu.cn.
Homepage: http://mypage.zju.edu.cn/en/bfshi/.
Prof. Dr. B.-F. Shi
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071 (China)
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10.1002/anie.201801445
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peptide macrocyclization based on Yu’s backbone-enabled
C(sp3)-H activation.[10] Carretero and coworkers demonstrated
the Pd-catalyzed γ-C(sp3)-H carbonylation of amino acids and
peptides.[11a] More recently, Ackermman developed a site-
selective C(sp3)−H arylation of amino acids and peptides by
using internal 1,2,3-triazole moieties as directing group.[12]
However, site-selective δ-C(sp3)−H functionalization of peptides
via a kinetically less favored six-membered palladacycle has not
been realized. In continuation of our ongoing research on
modification of amino acids via C(sp3)−H functionalization,[4,13]
herein, we report the first example of Pd-catalyzed site-selective
δ-methyl C−H alkylation of amino acids and peptides with
maleimides in the presence of more accessible γ-methyl C−H
bonds (Figure 1B). It is worth noting that maleimides were
frequently used in C-H alkylation catalyzed by Ru(II), Rh(III),
Cu(II), Co(III), and Mn(0) complexes.[14] This reaction represents
the first Pd(II)-catalyzed C(sp3)-H alkylation with maleimides
(Figure 1C).[15,16]
general, δ-selectivities were obtained exclusively in good to
excellent yields under the optimized conditions. The phenyl, N-
2,4,6-trichlorophenyl, N-4-ethylphenyl and N-4-hydroxyphenyl
maleimides reacted smoothly with 1 to give the desired
products in good to excellent yields (1a−1d, 72%−88%).
Maleimides bearing N-4-bromophenyl, N-4-acetylphenyl and N-
(3-chloro-4-methyl)phenyl groups were also compatible with this
protocol, albeit in slightly lower yields (1e−1f, 53%−63%). We
were pleased to find that N-4-phenyldiazenylphenyl maleimides
2h, whose derivates can be used as bioprobes to control the
enzyme activity of a bacterial histone[18] also react with 1 to
afford the product 1h in good yields. Eventually, the N-alkyl
maleimides, including benzyl, cyclohexyl, methyl, ethyl, and tert-
butyl, also displayed high reactivity to give the corresponding
products in high yields (1i−1m, 78%−85%).
We further examined the scope of other amines (Table 2).
Gratifyingly, other isoleucine derivatived esters, such as ethyl (3),
benzyl (4), and allyl (5), were also viable, giving the desired
products in good yields. Isoleucinols that masked by
synthetically useful protecting group, such as acetyl (6), benzoyl
(7), and benzyl (8) were also applicable with this reaction. γ-
Arylated isoleucine derivative 9 reacted with 2a to provide the
desired site-specific alkylation product 9a in 59% isolated
yield.[17a] Moreover, γ-alkoxylated[17b] (10 and 11) and γ-
alkylated[3c] (12 and 13) isoleucine derivatives also reacted
smoothly with 2a to furnish the δ-alkylation products in
acceptable yields. Notably, γ-arylated, γ-alkoxylated and γ-
alkylated isoleucine derivatives (9-13) were all synthesized
through γ-C(sp3)-H functionalization of 1,[3c,17] showcasing this
protocol might be valuble for derivatization of α-amino acid via
sequencial C(sp3)-H functionalization. In addition, the L-
norvaline derivative 14 was also reactive (14a, 31%). The
presence of another amide bond in isoleucine derivative didn’t
affect the reaction, affording the target product in moderate
yield (15a, 40%; 16a, 52%). These results were extremely
attractive, since these kind of substrates were known to be
incompatible with our previous δ-alkenylation reaction[4] due to
the competing N,N-coordination.[9,10]
Encouraged by these results, we rationalized that the reaction
conditions could also be amenable to peptides. To our delight,
various dipeptides with an isoleucine at the N-terminus were well
tolerated. As shown in Table 2, dipeptide with L-tert-leucine
methyl ester at the C-terminus proceed smoothly to give 17a in
62% yield in a mixture of 1,1,2,2-tetrachloroethane (TCE) and
trifluoroethanol without adding any base. Moreover, dipeptides
containing valine (18), proline (19) and isoleucine (20) reacted
with 2a to give the alkylated products 18a-20a in slightly lower
yields (36-45%). Dipeptide with norvaline at the N-terminus was
also tolerated, albeit in low yield (21a, 28%).
The direct C(sp3)-H functionalization of longer peptides would
be more challenging because additional amide bonds in longer
peptides could deactivate the palladium catalyst by the formation
of a N,N-biscoordinating complex.[9] The robustness of this
protocol was shown by the site-selective δ-alkylation of tri- and
tetrapeptides (Table 2). Four representative tripeptides bearing
tert-leucine, isoleucine, cyclohexylglycine, or proline residues
reacted smoothly with 2a under slightly modified conditions
(22a−25a, 42%−47%). Remarkably, δ-alkylation of isoleucine at
the N-terminus of tetrapeptides, as exemplified by 26 (Ile-Pro-
Tle-Ala-OMe) and 27 (Ile-Pro-Tle-Val-OMe), also proceeded in
reasonable yields (26a, 55%; 27a, 48%). It was worth
mentioning that the alkylation occurred exclusively at the δ-
methyl C-H bond among all substrates listed above.
Table 1. The Scope of the Maleimides.[a]
[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv), maleimide 2 (2.5 equiv),
Pd(OAc)2 (10 mol %), 1-AdCOOH (0.2 equiv), BQ (0.3 equiv), Na2CO3 (2.0
equiv) in 1,1,2-trichloroethane (1 mL) at 100 °C for 24 h, isolated yields.
Diastereomeric ratio was determinated by HPLC. [b] Pd(OAc)2 (15 mol %).
We initiated our investigation by choosing picolinamide (PA) -
protected isoleucine methyl ester 1 as the model substrate and
N-phenylmaleimide 2a as the alkylation reagent (Table S1).[17]
Preliminary screenings led to the formation of δ-selective
alkylation product 1a in 44% yield (entry 2). The yield was
slightly improved to 52% when 1,1,2-trichloroethane was used
as solvent, probably due to its better solubility of catalyst and
additives (entry 5). The subsequent investigation of additive led
to an exciting finding that, benzoquinone (BQ) could promote the
reaction, which may act both as a ligand and a co-oxidant (entry
7). 1a was obtained in 75% yield when the amount of BQ was
increased to 0.3 equivalent (entry 9). After further optimization,
we finalized the conditions for the δ-selective alkylation of 1 with
2a as follows: 10 mol% Pd(OAc)2, 30 mol% BQ, 20 mol% 1-
AdCOOH, 2.0 equiv Na2CO3, with 1,1,2-trichloroethane as
solvent at 100 o C for 24 h (entry 10, 88%, dr = 1.4:1). Various
directing groups were evaluated under the optimized conditions,
the unmodified PA was found to be the optimal (Table S8).
Other types of olefins were also tested, however, no alkylation
products at either positions were detected (Table S9, see
Supporting Information).
Having optimized the reaction conditions, we next turned to
the evaluation of the scope of the maleimides (Table 1). In
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Table 2. The Scope of α-Amino Acids and Peptides. [a]
[a] Standard conditions, isolated yields. [b] PivOH (0.3 equiv) instead of 1-AdCOOH. [c] Pd(OAc)2 (15 mol %),110 °C. [d] MesCOOH (0.2 equiv) instead of 1-
AdCOOH, NaOAc (2.0 equiv) instead of Na2CO3, 110 °C. [e] Pd(OAc)2 (15 mol %), TCE:TFE = 2:1 (1 mL) at 120 °C for 24 h. [f] Pd(OAc)2 (15 mol %), 1-AdCOOH
(0.3 equiv). [g] TCE as solvent. [h] TCE as solvent without Na2CO3. [i] 2, 5-DiPhBQ instead of BQ, L-Boc-Ser-OH (0.2 equiv) as additive, Na2CO3 (3.0 equiv). [j]
Na2HPO4 (2.0 equiv) instead of Na2CO3, PivOH (0.3 equiv) instead of 1-AdCOOH. [k] Li3PO4 (2.0 equiv) instead of Na2CO3. [l] NaHCO3 (2.0 equiv) instead of
Na2CO3.
The easy removal of the PA group under mild conditions and
further transformation of product were conducted to demonstrate
the versatility of this reaction. The PA group was readily
replaced with synthetically more useful protecting group Fmoc
(fluorenylmethyloxycarbonyl) by treating 1a with excess zinc in a
mixture of THF and aqueous hydrochloric acid at room
temperature and subsequent protecting with FmocCl (95% yield,
Scheme 1a).[19] Reduction of 1a using B2H6 gave
tetrahydropyrrole 29 in 66% yield (Scheme 1b).
only trace of deuterium incorporation into δ-C-H bonds was
observed in the presence of 2a (Scheme S1b, δ, <5% D; γ, 50%
D). Furthermore, the reaction of PA-protected valine derivative
23 with 2a resulted in significant deuteration of γ-C-H bonds
(Scheme S1c, 62% D). However, no γ-alkylation product was
detected. Similar results were observed form the isotope
exchange study of L-2-aminobutyric acid derivative 24 (Scheme
S1d). These results indicated that: 1) both γ- and δ-C-H
activation is reversible with the cleavage of γ-C-H bonds favored
under the reaction conditions; 2) the subsequent
functionalization of δ-palladacycle B is significantly faster than
the back reaction of the δ-C-H activation; 3) although γ-C-H
activation is kinetically favored, the subsequent alkylation of γ-
palladacycle B1 couldn’t occur. Overall, the selectivity can be
explained by Curtin-Hammett principle.[5] Notably, only γ-arylated
product 46 was observed when methyl 4-iodobenzoate was
used as reactant instead of maleimide 2a (Scheme S1f),
suggesting that the δ-selectivity is resulted from the selectivity-
determining migratory insertion of maleimides.[20]
Scheme 1. Application of the Alkylation Reaction
On the basis of deuteration experiments and earlier
precedents, a putative mechanistic pathway was proposed
(Scheme 2).[4] Complexation of amide 1 with Pd(OAc)2 affords a
Pd(II) complex A, which could undergo reversible C-H cleavage
to form the kinetically favored five-membered palladacycles (B1
and B2, via γ-C−H activation) and the kinetically less favored
six-membered palladacycles (B, via δ-C−H activation), which
were proved by deuteration experiments. However, subsequent
migratory insertion of palladacycles B1 and B2 with maleimide
To gain information on the origin of the selectivity, several H/D
exchange experiments were conducted. Previous experimental
studies indicated that both γ- and δ-methyl C-H activation steps
are reversible.[3a,b,4] Consistent with these precedents, we also
observed appreciable amounts of deuterium incorporation into γ-,
and δ-C-H bonds of 1 under the standard conditions in the
absence of 2a, with a significant lower incorporation into the δ-
position (Scheme S1a, γ, 57% D; δ, 29% D). In sharp contrast,
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134,7; c) S.-Y. Zhang, G. He, W. A. Nack, Y. Zhao, Q. Li, G. Chen, J.
Am. Chem. Soc. 2013,135, 2124; d) W. Cui, S. Chen, J.-Q. Wu, X.
Zhao, W. Hu, H.-G. Wang, Org. Lett. 2014, 16, 4288.
2a to form C1 and C2 is less favored, while palladacycle B
undergoes a fast migratory insertion with maleimide 2a to form a
eight-membered
intermediate
C,
which
undergoes
[4]
[5]
[6]
[7]
J.-W. Xu, Z.-Z. Zhang, W.-H. Rao, B.-F. Shi, J. Am. Chem. Soc. 2016,
138, 10750.
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Chem. Rev. 1983, 83, 83.
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[8]
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Ed. 2017, 56, 314.
Scheme 2. Proposed Mechanism for δ-Selective C–H Alkylation
In conclusion, the first site-selective δ-C(sp3)−H alkylation of
amino acids and peptides with maleimides via a kinetically less
favored six-membered palladacycle in the presence of more
accessible γ-C(sp3)−H bonds was reported. The exceptional
compatibility with various oligopeptides and the facile removal of
the PA group renders this protocol valuable for late-stage
modification of peptides. Notably, this also represents the first
Pd(II)-catalyzed Michael-type alkylation reaction via C(sp3)-H
activation. Experimental studies indicated that the selectivity
originated from a Curtin-Hammett situation. We anticipate that
this new mode of selectivity might offer a unique opportunity for
reaction development.
[11] a) E. Hernando, J. Villalva, Á. M. Martínez, I. Alonso, N. Rodríguez, R.
G. Arrayás, J. C. Carretero, ACS, Catal. 2016, 6, 6868; b) N. Rodríguez,
J. A. Romero-Revilla, M. A. Fernández-Ibáñez, J. C. Carretero, Chem.
Sci. 2013, 4, 175.
[12] M. Bauer, W. Wang, M.M, Lorion, C. Dong, L. Ackermann, Angew.
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Yin, K. Chen, Q. Zhang, S.-Q. Zhang, B.-F. Shi, Nat. Commun. 2016, 7,
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Shi, Angew. Chem. Int. Ed. 2016, 55, 13859.
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Prabhu, Org. Lett. 2015, 17, 4658; b) S. Han, J. Park, S. Kim, S. H. Lee,
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W. Miura, K. Hirano, M. Miura, Org. Lett. 2015, 17, 4034; e) Z. Zhang, S.
Han, M. Tang, L. Ackermann, J. Li, Org. Lett. 2017, 1 9, 3315; f) S.-L.
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[15] Few examples of chelation-assisted addition of C(sp3)-H across alkenes
or alkynes have been reported, see: a) Y. Xu, M. C. Young, G. Dong, J.
Am. Chem. Soc. 2017, 139, 5716; b) M. Li, Y. Yang, D. Zhou, D. Wan,
J. You, Org. Lett. 2015, 17, 2546; c) S. Maity, S. Agasti, A. M. Earsad,
A. Hazra, D. Maiti, Chem.-Eur. J. 2015, 21, 11320; d) N. Chatani, T.
Asaumi, S. Yorimitsu, T. Ikeda, F. Kakiuchi, S. Murai, J. Am. Chem.
Soc. 2001, 123,10935. And refs. 4 and 14c.
Acknowledgements
Financial support from the NSFC (21772170, 21422206,
21572201), the National Basic Research Program of China
(2015CB856600), the Fundamental Research Funds for the
Central
Universities
and
Zhejiang
Provincial
NSFC
(LR17B020001) is gratefully acknowledged.
Keywords: Site-selective • alkylation • six-membered
palladacycle • peptides • palladium
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[20] The underlying factors controlling the selectivity-determining migratory
insertion of maleimides remain unclear at that stage. We assumed that
the ring strain of the resulting palladacycle (C1 and C2 vs C) might
account for the unusual selectivity. Previously, the Pd(II)-catalyzed site-
selective
δ-C(sp3)–H
alkenylation
has
been
investigated
[2]
[3]
a) J. F. Hartwig, Chem. Soc. Rev. 2011, 40, 1992; b) J. F. Hartwig, Acc.
Chem. Res. 2017, 50, 549; c) Z. Huang, G. Dong, Acc. Chem. Res.
2017, 50, 465.
For selected examples of δ-C(sp3)-H functionalization when the γ-
C(sp3)-H bonds were sterically or conformationally less accessible, see:
a) G. He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am. Chem. Soc.
2012,134, 3; b) E. T. Nadres, O. Daugulis, J. Am. Chem. Soc. 2012,
computationally, and the site-selectivity was proposed to originate from
the electronic effect in the migratory insertion transition states: Y.-Y.
Xing, J.-B. Liu, G.-Z. Sun, F. Huang, D.-Z. Chen, Dalton Trans. 2017,
46, 9430.
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10.1002/anie.201801445
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
R
O
Bei-Bei Zhan, Ya Li, Jing-Wen Xu, Xing-
Liang Nie, Jun Fan, Liang Jin, and Bing-
Feng Shi*
NHPA
cat.
Pd(OAc)2
R
N
N
NHPA
H
H
O
O
O
+
H
-
methyl C-H alkylation in the presence of -methyl C-H bonds
Page No. – Page No.
- selectivity originated from a Curtin-Hammett situation
- late stage modification of pepetides
Site-Selective δ-C(sp3)−H Alkylation of
α-Amino Acids and Peptides with
- compatible with oligopeptides containing Ile, Nva, Tle, Pro, Val, Chg
- the first Pd(II)-catalyzed addition of C(sp3) H bonds across maleimides
Maleimides
Palladacycle
via
a
Six-Membered
Site-selective δ-C(sp3)−H alkylation of amino acids and peptides with maleimides via a
kinetically less favored six-membered palladacycle in the presence of more accessible
γ-C(sp3)−H bonds was reported. Experimental studies revealed that C-H bond cleavage
occurs reversibly and preferentially at γ-methyl over δ-methyl C-H bonds, while the
subsequent alkylation procced exclusively at six-membered palladacycle that generated
via δ-C-H activation. The selectivity can be explained by the Curtin-Hammett principle.
The exceptional compatibility of this alkylation with various oligopeptides renders this
protocol valuable for late-stage modification of peptides. Notably, this also represents
the first Pd(II)-catalyzed Michael-type alkylation reaction via C(sp3)-H activation.
This article is protected by copyright. All rights reserved.