Pd/Cu dual catalysis: Highly enantioselective access to α-substituted α-amino acids and α-amino amides

Article abstract of DOI:10.1039/c7cc08732b

The asymmetric allylation of glycine iminoesters has been accomplished through a synergistic Pd/Cu catalyst system, affording a range of α-substituted α-amino acids in high yields and with excellent enantioselectivities (88 → 99% ee). The introduction of a Cu-P,N-metallocenyl complex-activated glycine iminoester to the chiral palladium-catalyzed allylic allylation process is crucial owing to its high reactivity and excellent enantioselectivities. Importantly, this Pd/Cu dual catalysis strategy can be used for the asymmetric allylic alkylation of prochiral glycine amide derivatives, which could be further utilized to synthesize biologically important vicinal diamines.

Full text of DOI:10.1039/c7cc08732b

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
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3
N@C2n (2n
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68 and 80). Synthesis of the
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Pd/Cu Dual Catalysis: Highly Enantioselective Access to α-
Substituted α-Amino Acids and α-Amino Amides
Received 00th January 20xx,
Accepted 00th January 20xx
a,†
a,†
a
a
a
ab
Xiaohong Huo, Jingke Fu, Xiaobo He, Jianzhong Chen, Fang Xie, and Wanbin Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The asymmetric allylation of glycine iminoesters has been
accomplished through synergistic Pd/Cu catalyst system,
a
affording a range of α-substituted α-amino acids in high yields and
with excellent enantioselectivities (94->99% ee). The introduction
of a Cu-P,N-metallocenyl complex-activated glycine iminoester to
the chiral palladium-catalyzed allylic allylation process is crucial
for its high reactivity and excellent enantioselectivities.
Importantly, this Pd/Cu dual catalysis strategy can be used for the
asymmetric allylic alkylation of prochiral glycine amide derivatives,
which could be further utilized to synthesize biologically
important vicinal diamines.
Scheme 1 Bimetallic catalysis for the asymmetric allylation of
glycine iminoesters/amides to get access to α-substituted α-
amino acids/amides.
by the research groups of Gong and Takemoto, the
enantioselectivity of the allylic alkylation of glycine iminoesters
Non-proteinogenic, optically active α-substituted α-amino
5
was greatly improved. Compared with synergistic transition-
acids (α-AAs) are valuable structural motifs in biological and
1
5-8
metal and organocatalyst strategy, cooperative bimetallic
pharmacological
compounds.
Accordingly,
the
catalysis consisting of two distinct metal complexes possesses
distinct advantages: (a) an amount of available chiral ligands
enantioselective construction of α-substituted α-AAs is of
great importance and has sparked considerable synthetic
2
interest. Among various methodologies, the asymmetric
9
and metal catalysts could be employed; (b) a variety of metal-
10
catalyzed asymmetric reactions exist; and (c) a versatile
allylic alkylation (AAA) of readily available glycine iminoesters
is one of the most straightforward methods for the synthesis
3
of enantioenriched α-substituted α-AAs. Unfortunately, the
bimetallic catalyst library could be generated via combinatorial
chemistry, which thus has accommodated a broad range of
11
challenging asymmetric transformations. Very recently, we
stereocontrol of prochiral glycine iminoesters represents a
great challenge owing to the long distance between the
reported a Pd/Cu bimetallic catalyst system for the highly AAA
11h
of aldimine esters. However, glycine-based aldimine esters
3
nucleophile and the chiral environment of the ligand.
always give biallylated products. In order to obtain the highly
enantiopure α-substituted α-AAs, several problems must be
overcome: (a) the internal contradictions of keeping the high
reactivity of the bimetallic catalysis and lowering the reactivity
of glycine-based aldimine esters to avoid the biallylated
products, must be addressed; (b) the stereocontrol of the
prochiral nucleophile; and (c) the potential enolization of α-
substituted α-AAs in the presence of a Lewis acid or under
basic conditions. Herein, we describe a new development in
cooperative bimetallic catalysis: a chiral Cu-P,N-metallocenyl
complex was introduced to the chiral Pd complex-catalyzed
allylic alkylation process, which leads to the construction of α-
substituted α-AAs with high reactivity and excellent
enantioselectivity (Scheme 1). It was anticipated that the two
chiral metal complexes could work in tandem to activate the
Consequently, novel catalysts or catalytic strategies for the
asymmetric allylation of prochiral glycine iminoesters in a
highly enantioselective manner are greatly required.
Synergistic catalysis is gaining increasing attention due to
its advantages, such as improved catalytic activity, wide
4
substrate scope, increased selectivity, and cost efficiency.
Indeed, through the combination of a chiral-phase transfer
catalyst (PTC) and an achiral palladium(0) complex developed
a.
Shanghai Key Laborotary for Molecular Engineering of Chiral Drugs, School of
Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, China. Email: wanbin@sjtu.edu.cn
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
b.
Shanghai 200240, P. R. China.
X. Huo and J. Fu contributed equally
†
†
Electronic Supplementary Information (ESI) available. See DOI: allyl and glycine susbtrates and contribute to the reaction
0.1039/x0xx00000x
1
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efficiency and the enantioselectivity of the prochiral Table 2 Allylic substrates scope of alkylation of glycine
a
iminoesters
nucleophile. Compared with the PTC-mediated allylic
alkylation of glycine iminoesters, this homogeneous Pd/Cu co-
catalyzed AAA reaction proceeded under mild conditions and
thus provided much better substrate compatibility.
R
O
5 mol% Pd/L2
mol% Cu/L2
Cs2CO3, THF, -10 o
tBuO
5
Ph2C=N
+
R
OAc
N=CPh2
t
O Bu
C
1
2
O
3
On the other hand, despite the significant progress in
expanding the scope of applicable carbon nucleophiles in AAA
reactions, α-amino amide deriatives are still difficult to enolize
and thus have not been used as nucleophiles in catalytic
allylation reactions. Based on the potential advantages of the
bimetallic catalysis strategy, this Pd/Cu catalytic system was
Entry
2
Yield [%]b ee [%]c
1
2
3
4
2a (R = H)
2b (R = Me)
2c (R = F)
2d (R = Cl)
96% yield, 97% ee
96% yield, 99% ee
97% yield, 99% ee
98% yield, 99% ee
OAc
OAc
R
2e (R = Me)
2f (R = F)
95% yield, 97% ee
94% yield, 96% ee
97% yield, 97% ee
5
6
7
1
2
used for the AAA of prochiral glycine amide deriatives.
A
2g (R = Cl)
range of α-substituted α-amino amides could be smoothly
obtained in high yields and with excellent enantioselectivity,
which could be utilized to further synthesize biologically
R
2h (R = Me)
96% yield, 94% ee
97% yield, 98% ee
96% yield, 97% ee
97% yield, 98% ee
96% yield, 98% ee
8
9
2i (R = OMe)
OAc
2j (R = F)
10
1
3
important vicinal diamines by simple transformation.
The investigation was initiated by the asymmetric allylation
of the diphenylimino glycinate with the cinnamyl acetate 2a
in the presence of a weak base (K CO ) using Pd/Cu bimetallic
11
R
2k (R = Cl)
l (R = CF3)
2
12
OAc
OAc
1
13
2m
2n
95% yield, 96% ee
98% yield, 99% ee
Me
Cl
Me
2
3
catalysis (Table 1). In order to evaluate the effect of the
bimetallic catalyst system, a bimetallic catalyst library was
3
created by the combination of metal precursors {[Pd(ƞ -
14
Cl
allyl)Cl]
2
and Cu(OTf)
2
} and chiral P,N-metallocenyl ligands (L1-
15d
1-naphthyl
OAc
2o
2p
96% yield, 94% ee
97% yield, 98% ee
92% yield, 95% ee
L8). To our delight, almost quantitative yields and good to high
16
2-naphthyl
O
OAc
OAc
a
Table 1 Optimization of the reaction conditions
2q
.5 mol% [Pd( 3-allyl)Cl]2
17
2
Ph
O
+
5 mol% Lm
tBuO
Ph2C=N
Ph
OAc
t
O Bu
5 mol% Cu(OTf)2
5 mol% Ln, THF, base
N=CPh2
S
OAc
O
3a
1
8
9
2r
90% yield, 97% ee
1
2a
Metal
Chiral metallocene-based P,N ligands
1
OAc
2s
2t
98% yield, 98% ee
65% yield, 88% ee
O
O
O
O
R
R
R
Cu
R
R
N
N
0d
N
PPh2
PPh2
2
OAc
OAc
N
PPh2
PPh2
Ru
Fe
PPh2
N
PPh2
N
Ru
Fe
R
2
1e
2u
95% yield, 96% ee
Pd
O
O
Ph
L1: i-Pr; L2: t-Bu
L3: i-Pr; L4: t-Bu
L5: i-Pr; L6: t-Bu
L7: i-Pr; L8: t-Bu
a
c
b
Reaction conditions: see Table 1, entry 11. Isolated yields.
Determined by HPLC using chiral columns. At room
e
temperature. 18 h.
d
Pd
Cu
o
T ( C) t (h) Yield (%)
b
c
Entry
Base
ee (%)
/
Lm
L1
L2
L3
L4
L5
L6
L7
L8
L2
L4
L2
L4
L2
-
/
Ln
L1
L2
L3
L4
L5
L6
L7
L8
L2
L4
1
2
3
4
5
6
7
8
9
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
rt
rt
4
4
94
93
94
93
95
94
93
92
NR
NR
96
25
18
NR
76
94
88
94
75
92
80
84
ND
ND
97
ND
ND
NR
enantioselectivities were uniformly obtained under all the
[
[
Pd/Lm+Cu/Ln
] catalyst combinations. In particular, the
rt
4
Pd/L2+Cu/L2] and the [Pd/L4+Cu/L4] catalysts were the best,
rt
4
affording the desired product 3a in 93% yield and with 94% ee
Table 1, entries 1-8). It was found that the substituent R on
rt
4
(
rt
4
the oxazolinyl ring had much effect on the enantioselectivity
and a bulkier group gave a better ee value. We assumed that
the enantioselectivity may be further improved by reducing
the reaction temperature. However, the catalytic reaction did
rt
4
rt
4
-10
-10
-10
-10
-10
-10
12
12
12
12
12
12
1
0
1
2
3
4
0
not proceed at -10 C, even with a prolonged reaction time
1
1
1
1
L2 Cs
L4 Cs
2
2
2
2
CO
CO
CO
CO
3
3
3
3
(
entries 9 and 10). Interestingly, this situation could be
reversed by using Cs CO as the base, delivering the desired
product 3a in 96% yield and with 97% ee under the
Pd/L2+Cu/L2 catalyst combination (entry 11). It was
reasoned that the better solubility and stronger basicity of the
Cs CO may help to promote the reactivity and the
2
3
-
Cs
L2 Cs
[
]
a
Reaction conditions:
mol%), Cu/Ln* (5 mol%), base (1.0 equiv), THF (2 mL); Isolated
1 (0.25 mmol), 2a (1.2 equiv), Pd/Lm* (5
b
2
3
c
yield; The ee values were determined by HPLC using chiral
columns. NR = not reaction, ND = not determined.
enantioselectivity of the reaction. In an effort to probe the
cooperative interplay of the bimetallic catalyst system, control
experiments were conducted. It turned out that the Pd-
2
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catalyzed allylic substitution reaction furnished only a trace Table 3 Allylic substrates scope of alkylation of glycine amide
a
amount of products (18% yield) without the participation of
the Cu catalyst (entry 13). Additionally, no products were
obtained using only the Cu catalyst (entry 14). These results
suggested the synergistic role of the bimetallic catalysts in
improving both the reactivity and enantioselectivity of the
reaction.
s
With the optimized reaction conditions in hand, we then
explored the substrate scope of the allylic electrophiles (Table
2). Allylic acetates substituted with arenes bearing alkyl,
halogen, electron-donating and electron-withdrawing
substituents at different positions were all tolerated in this
transformation, affording their respective products in high
yields and with high enantioselectivities (Table 2, entries 1-14).
Notably, allylic acetates containing naphthalene, furan and
thiophene substituents, were also compatible with this
reaction (entries 15-18). To our delight, simple allyl acetate,
prenylacetate, and branched 1-phenyl-2-propenyl acetate also
proved to be good substrates, affording the desired
high yields and enantioselectivities (entries 19-21).
α-AAs in
Additionally, the allylic allylation of
1 with the symmetrical
1,3-disubstitued allyl acetate 2v was examined under the
optimized conditions (Scheme 2). The desired product with
two contiguous stereocenters was successfully obtained in
a
98% yield, 98% ee, and >20:1 dr.
Reaction conditions: see Table 1, entry 12.
diphenylimino glycinate
1
delivered 3s in 91% yield with 98%
was obtained after
ee (Scheme 3). Then the key intermediate
8
hydrolysis and benzoylation of 3s. We anticipate that the
enantioselective construction of α-substituted α-AAs is
attractive for their use in medicinal chemistry.
Scheme 2 Allylic alkylation of the diphenylimino glycinate with
,3-disubstitued allyl acetate 2v
1
.
Having established the feasibility of enantioselective
construction of α-substituted α-AAs with high reactivity, we
then set out to verify the high catalytic efficiency of the
bimetallic catalyst system by applying this methodology to the
asymmetric allylation of prochiral glycine amide derivatives
(Table 3). The allylation reactions of N-benzylglycinamide 5a
and diphenylmethyl derivative 5b with the cinnamyl acetate 2a
proceeded smoothly, furnishing the corresponding alkylation
products 6a and 6b in high yields and with 93%->99% ee. The
generality of allylic substrates was then investigated using 5b
as the representative prochiral nucleophile. A range of allylic
Scheme 3 Synthetic utility of methodology.
In summary, we have developed a synergistic Pd/Cu
acetates with substituents at the ortho-, meta-, or para- catalyst system for the asymmetric allylation of glycine
position of the phenyl ring were all well employed in this iminoesters. A range of noncoded α-substituted α-amino acids
transformation, affording their desired products (6c
high yields and enantioselectivities (99->99% ee). Importantly, enantioselectivities under mild conditions (94->99% ee).
simple allyl acetate and allylic acetates bearing furan Additionally, highly enantioselective construction of
substituent were also good substrates, affording the desired enantiopure α-substituted α-amino amides was achieved using
products (6n and 6o) in high yields with 98% ee.
this Pd/Cu dual catalyst system, which were expected to
-
6m) in were efficiently synthesized in high yields and with excellent
a
Finally, in order to demonstrate the synthetic utility of this further synthesize biologically important vicinal diamines. We
bimetallic catalytic process, we endeavored to apply the envision that this bimetallic catalysis strategy will allow access
to more difficult asymmentric transformations.
allylation product 3s to the synthesis of a stable intermediate
8,
which is a versatile intermediate used for the construction of
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21702134, 21572129, and
penicillin. The Pd/Cu catalyzed allylation of 2s with
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C7CC08732B
Pd/Cu Dual Catalysis: Highly Enantioselective Access to α-Substituted α-Amino Acids
and α-Amino Amides
a,†
a,†
a
a
a
ab
Xiaohong Huo, Jingke Fu, Xiaobo He, Jianzhong Chen, Fang Xie, and Wanbin Zhang*
In this paper, we have developed a synergistic Pd/Cu catalyst system for the asymmetric allylation
of glycine iminoesters/amides, affording a range of α-substituted α-amino acids/amides in high
yields and with excellent enantioselectivities (94->99% ee).