Stereoselective and Site-Specific Allylic Alkylation of Amino Acids and Small Peptides via a Pd/Cu Dual Catalysis

Article abstract of DOI:10.1021/jacs.7b05460

We report a stereoselective and site-specific allylic alkylation of Schiff base activated amino acids and small peptides via a Pd/Cu dual catalysis. A range of noncoded α,α-dialkyl α-amino acids were easily synthesized in high yields and with excellent enantioselectivities (up to >99% ee). Furthermore, a direct and highly stereoselective synthesis of small peptides with enantiopure α-alkyl or α,α-dialkyl α-amino acids residues incorporated at specific sites was accomplished using this dual catalyst system.

Full text of DOI:10.1021/jacs.7b05460

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Communication
Stereoselective and Site-specific Allylic Alkylation of
Amino Acids and Small Peptides via a Pd/Cu Dual Catalysis
Xiaohong Huo, Rui He, Jingke Fu, Jiacheng Zhang, Guoqiang Yang, and Wanbin Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b05460 • Publication Date (Web): 07 Jul 2017
Downloaded from http://pubs.acs.org on July 7, 2017
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Stereoselective and Site-specific Allylic Alkylation of Amino
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Xiaohong Huo,†,‡ Rui He,† Jingke Fu,† Jiacheng Zhang,† Guoqiang Yang,† and Wanbin Zhang*,†,‡
†School of Chemistry and Chemical Engineering and ‡School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
Supporting Information Placeholder
Scheme 1. Bimetallic Catalysis for Stereoselective Modification of
Amino Acids and Peptides
ABSTRACT: We report a stereoselective and siteꢀspecific allylic
alkylation of Schiff base activated amino acids and small peptides via a
Pd/Cu dual catalysis. A range of noncoded α,αꢀdialkyl αꢀamino acids
were easily synthesized in high yields and with excellent enantioselecꢀ
tivities (up to >99% ee). Furthermore,
a direct and highly
stereoselective synthesis of small peptides with enantiopure αꢀalkyl or
α,αꢀdialkyl αꢀamino acids residues incorporated at specific sites was
accomplished using this dual catalyst system.
The transitionꢀmetalꢀcatalyzed asymmetric allylic alkylation reaction
serves as a versatile and powerful tool for enantioselective CꢀC bond
formation and is widely employed in the synthesis of biologically
important molecules.1 The development of increasingly elaborate
nucleophiles to facilitate this process is a major research area. The
introduction of a second catalyst to this process, which is responsible
for generating active nucleophiles in a catalytic manner, would provide
an effective and reliable strategy for promoting this reaction.2 Despite
achieving remarkable progress in this area using a combination of
transitionꢀmetals and organocatalysts,3ꢀ6 cooperative bimetallic catalyst
systems consisting of two distinct chiral metal complexes have not been
widely reported, an attribute that is expected to provide a series of
unprecedented asymmetric transformations.7
reaction conditions; (2) the steric effect of peptides on the reactivity
and stereoselectivity; (3) the presence of multiple reactive functional
groups in various peptides. Despite great advances in metalꢀcatalyzed
asymmetric reactions, the stereoselective and siteꢀspecific modification
of peptides using transitionꢀmetalꢀbased reactions has not been reportꢀ
ed yet.13
Herein, we report a Pd/Cu dual catalyst system, which was applied
not only to the asymmetric synthesis of nonꢀnatural α,αꢀdialkyl αꢀAAs
but also to the highly stereoselective Nꢀterminal αꢀallylation of small
peptides (Scheme 1). Under the assistance of a copper complex and a
weak base, an aldimine Schiff base could be easily converted to
Nonꢀproteinogenic, optically active α,αꢀdisubstituted αꢀamino acids
(αꢀAAs) are present in numerous biologically active compounds and
are frequently utilized as building blocks in organic synthesis and new
drug discovery.8 The development of efficient methods for the rapid
generation of enantiopure α,αꢀdialkyl αꢀAAs has thus attracted a great
deal of attention.9 Among various methodologies, the Pdꢀcatalyzed
asymmetric allylic alkylation of aldimine Schiff bases derived from the
corresponding αꢀAAs represents an attractive and powerful catalytic
process in terms of starting material availability, operational simplicity
and derivation convenience. However, this transformation suffered
from low reactivity and enantioselectivity,10 mainly because of the
congested threeꢀdimensional configuration11 and challenging
stereocontrol of prochiral nucleophiles.1 On the other hand, the
postsynthetic modification of peptides represents an essential and
flexible synthetic concept for the conformational control and design of
peptidomimetics for biomedical applications.12 In particular, the apꢀ
propriate incorporation of noncoded αꢀAAs into peptides has proven
to induce significant conformational constraints and has allowed for
the preparation of peptides with new functionalities for use in pharmaꢀ
ceutics.8 However, the regioꢀ and stereoselective modification of a
given peptide is far from trivial, mainly due to (1) the demand for harsh
nucleophiles possessing greater stability (Nꢀmetalated azomethine
ylides I).14 The rigid structure of the five membered N,Oꢀbidentate
metalated azomethine ylide I facilitates the asymmetric induction from
the chiral ligand. Furthermore, the ylide I generated in situ and in cataꢀ
lytic amounts may also have a positive influence on the enantioꢀ
determining step.15 Additionally, the cooperative use of two chiral
reactive species, I and πꢀallypalladium II, may allow for the ready
control of the stereocenter. We envisioned that the proposed
stereoselective and siteꢀspecific αꢀallylation of amino acids and small
peptides via this bimetallic catalysis strategy would take advantage of
preexisting structures and provide a convienent method to rapidly
generate large arrays of amino acids and peptides for biological studies.
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Table 1. Optimization of Reaction Conditionsa Table 2. The Substrate Scope of Allylic Acetatesa
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1
2
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5
6
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9
yield
ee
(%)b
entry
1
R1
R2
(%)b
88
82
85
85
92
93
90
91
85
89
86
92
74
82
85
84
1
1a
1b
1c
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
98 (
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
)
2
(Z
)ꢀC6H5
98 (
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
3
2ꢀMeC6H4
88 (
4
1d 2ꢀFC6H4
97 (
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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59
60
5
1e 3ꢀMeC6H4
98 (
6
1f
3ꢀFC6H4
98 (
yield
(%)b
ee
(%)b
7
1g 3ꢀClC6H4
1h 4ꢀMeC6H4
>99 (
97 (
entry
L for Pd
L for Cu
t (h)
8
1c
2c
3
L1
L2
L3
L4
L2
ꢀꢀ
L1
L2
L3
L4
ꢀꢀ
12
12
12
12
24
24
12
12
91
88
89
86
<10
0
76 (
98 (
75 (
97 (
26 (
ꢀꢀ
S
)
)
)
)
)
9
1i
1j
4ꢀOMeC6H4
4ꢀFC6H4
>99 (
99 (
10
11
12
13
14
15
16
S
S
S
S
1k 4ꢀClC6H4
99 (
1l
4ꢀCF3C6H4
4ꢀNO2C6H4
99 (
4
1
m
>99 (
99 (
5
1n 2,4ꢀMe2C6H3
1o 3,4ꢀMe2C6H3
1p 3,5ꢀCl2C6H3
6
L2
L5
L2
95 (
7
L2
L5
92
91
40 (
S
)
)
>99 (
8
52 (
S
aConditions: 2a (0.25 mmol), 1a (1.2 equiv), Cu/L (1 mol%), Pd/L (1
mol%), Cs2CO3 (1.0 equiv), THF (2 mL), rt. The isolated yields and
ee values of the desired products were measured following hydrolysis
to the unprotected αꢀAAs. The absolute configurations of 3a were deꢀ
3,4ꢀ(methyꢀ
1q
17
H
86
98 (
S)
b
lenedioxy)
18
19
20
21c
1r
1s
1t
1ꢀnaphthyl
2ꢀnaphthyl
2ꢀfuryl
H
67
84
65
88
>99 (
>99 (
95 (
S)
S)
S)
)
H
termined to be
S by comparison of its optical rotation with the literaꢀ
H
ture value.16 c0.5 mol% L for 0.5 mol% [Pd(allyl)Cl]2 and 1.0 mol%
Cu(OTf)2.
1u C6H5
C6H5
95 (S,R
bConditions: see Table 1, entry 2. c6:1 dr.
a
,
Initially, cinnamyl acetate 1a was selected as an electrophilic precurꢀ
sor for the asymmetric allylation of the aldimine Schiff base 2a (Table
1). A bimetallic catalysts library was created via random combination
of any two of the Pd/Lm17 and Cu/Ln14 complexes using the
phosphinoꢀoxazoline (PHOX) ligands (L1ꢀL4).18,19 After primary
screening, the [Pd/L2+Cu/L2] catalyst was found to be outstanding,
affording the desired product in 88% yield and with 98% ee (entries 1ꢀ
4). The use of identical ligands in the optimal combinations avoids the
troublesome problem of ligand exchange. In order to gain insight into
the nature of the cooperative effect, control experiments were
conducted. The reaction proceeded with substantially lower reactivity
and enantioselectivity (<10% yield, 26% ee) when only the Pd/L2
catalyst was used (entry 5). No reaction occurred using only the
Cu/L2 catalyst (entry 6). The Cu and Pd complex activated the reacꢀ
tion in a synergistic manner. To further probe the relative role of the
chiral environments, bimetallic catalyst systems consisting of a chiral
metal complex and an achiral metal complex were created to give
products with much lower enantioselectivities (entries 7 and 8). Altꢀ
hough the underlying mechanism requires further clarification, the
combined use of two chiral metal complexes seems to be important for
the reactivity and stereocontrol of the reaction.
Next, an array of aldimine Schiff bases derived from αꢀsubstituted αꢀ
AAs were treated with 1a under the optimized conditions (Table 3).
To our delight, the aldimine Schiff bases derived from both natural and
nonꢀnatural αꢀAAs gave the corresponding α,αꢀdialkyl αꢀAAs in good to
high yields and with excellent enantioselectivities (up to >99% ee).
Table 3. The Substrate Scope of Aldimine Schiff Basesa
yield
(%)b
88
ee
entry
2
R3
R4
(%)b
98 (
94 (
96 (
98 (
94 (
1
2a
2b
2c
2d
2e
2f
Me
Me
Me
Et
tꢀBu
S
S
S
S
S
)
)
)
)
)
)
)
)
)
)
)
)
)
2
Me
87
3
i
ꢀPr
88
4
tꢀBu
tꢀBu
tꢀBu
86
5
i
ꢀBu
84
6
Bn
69
84 (R
7
2g
2h
2i
CH2CH2Ph
allyl
Et
85
93 (
S
S
8
t
t
t
t
t
t
ꢀBu
85
96 (
9
CH2O
tꢀBu
ꢀBu
ꢀBu
ꢀBu
ꢀBu
ꢀBu
89
98 (
R
R
The allylic electrophile scope was explored using the aldimine Schiff
base 2a as a representive substrate (Table 2). A range of allylic acetates
substituted with arenes bearing electronꢀdonating and electronꢀ
withdrawing substituents all furnished the corresponding products
with high reactivities and excellent selectivities (entries 1ꢀ17). Reacꢀ
tions involving naphthylꢀ and furylꢀsubstituted allyl acetates also proꢀ
ceeded well to deliver their desired products in good to high yields and
with excellent enantioselectivities (entries 18ꢀ20). Furthermore, 1,3ꢀ
diphenylꢀsubstituted substrate 1u proved to be compatible with the
reaction conditions, providing the product 3u in 88% yield, 6:1 dr, and
95% ee (entry 21).
10
11
12
13
2j
CH2CO2tꢀBu
86
97 (
2k
2l
CH2CH2CO2tꢀBu
CH2CH2SMe
82
98 (
S
S
S
89
94 (
2m
(CH2)4NHCbz
78
>99 (
bConditions: see Table 1, entry 2.
a
,
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catalyst system (Table 4). To verify this transformation, a dipeptide
Alaꢀ ꢀAla derivative 5a was first subjected to our bimetallic catalyst
system to furnish the desired product 7a in 62% yield and >20:1 dr.
The reaction of dipeptide ꢀAlaꢀ ꢀPro derivative 5b also proceeded
Lꢀ
Scheme 2. Stereoselective Double Alkylations of Aldimine Schiff
Base Derived from Glycinea
1
2
3
L
L
L
smoothly, providing the cyclization product in 58% yield and >20:1 dr.
In a similar manner, a variety of dipeptide derivatives 6aꢀ6e could also
be employed in this alkylation, where excellent stereoselectivities were
uniformly observed. These results clearly demonstrate that the effiꢀ
ciency of the transmission of stereochemical information is not affected
by the sideꢀchain structure of the preexisting amino acid residues. Enꢀ
couraged by these results, we extended the bimetallic catalyst system to
4
5
6
7
8
9
aThe reaction was performed by the sequential treatment of aldimine
Schiff base 2n (0.25 mmol) with 1v (1 equiv) and 1a (1.2 equiv) in the
presence of Cu/L2 (2 mol%), Pd/L2 (2 mol%), Cs2CO3 (2.0 equiv),
THF (2 mL), rt, 18 h.
10
11
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With the feasibility of this stereoselective quaternization method
established, a oneꢀpot asymmetric double alkylation of 2n derived from
the simple amino acid, glycine, was conducted under the optimized
reaction conditions (Scheme 2). The desired product 4n was obtained
in 61% yield and 96% ee.
the stereoselective
derivative 6f, GlyꢀGlyꢀ
Glyꢀ ꢀAlaꢀGly derivative 6h. To our delight, the desired peptides were
N
ꢀterminal alkylation of the tripeptides GlyꢀGlyꢀGly
L
ꢀAla derivative 6g, and even tetrapeptide Glyꢀ
L
all obtained in good yields and with high stereoselectivities, thus verifyꢀ
ing the feasibility of this bimetallic catalysis for the stereoselective and
siteꢀspecific incorporation of nonꢀnatural αꢀAAs residues in long pepꢀ
tides.
The successful development of a stereoselective process for the αꢀ
allylation of aldimine Schiff bases prompted us to question whether αꢀ
AAs embedded in long peptide chains could be modified using our
Table 4. The Substrate Scope of Small Peptidesa
aConditions: see Table 1, entry 2; ratio of dr was determined by 1H NMR integration. bK2CO3 (1.0 equiv).
easily synthesized in high yields and with excellent enantioselectivities
Scheme 3. Synthesis of a Novel Tripeptide via Sequential Asymꢀ
metric Allylations
under mild conditions. Furthermore, a highly stereoselective and siteꢀ
specific construction of enantiopure αꢀAAs embedded small peptides
was realized using this dual catalyst system. We believe that this bimeꢀ
tallic catalysis strategy will provide new opportunities for other chalꢀ
lenging asymmetric reactions.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all reactions and
products, including 1H and 13C NMR spectra, HPLC spectra, crystal
data, and crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Based on the results above, we envisioned that sequential Cꢀ
functionalizations of peptides of different lengths may provide multiple
structural modifications of peptides at other sites. Indeed, the
tripeptide 13 was readily prepared from simple glycine by employing
three asymmetric allylations and by introducing two new glycine
subunit using the wellꢀestablished methods (Scheme 3). The tripeptide
13 can be potentially incorporated into longer peptide sequences using
the steps described above.
Corresponding Author
wanbin@sjtu.edu.cn.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NSFC (No. 21232004, 21472123 and 21672142),
STCSM (No. 14XD1402300 and 15JC1402200) and China Postdocꢀ
toral Science Foundation (No. 2017M610249) for financial support.
In summary, we have developed a Pd/Cu dual catalyst system for
the asymmetric αꢀallylation of Schiff base activated amino acids and
small peptides. A range of noncoded α,αꢀdialkyl αꢀamino acids were
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zilleri, R. M.; Poss, M. A.; Eastgate, M. D.; Miller, M. M.; MacMillan, D. W. C.
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