One Stone Two Birds—Enantioselective Bimetallic Catalysis for α-Amino Acid Derivatives with an Allene Unit

Article abstract of DOI:10.1002/cjoc.202100002

A highly enantioselective 2,3-allenylation of acyclic and cyclic α-imino carboxylates via a synergistic bimetallic Pd/Cu catalysis with the same commercially available (R,R_p)-ⁱPr-FOXAP (also as Phosferrox, (R,R)-[2-(4’-i-propyloxazolin-2’-yl)ferrocenyl]diphenyl phosphine) ligand for both metals affording optically active 2,3-butadienyl α-amino acid derivatives in high to excellent yields with excellent enantioselectivities has been developed. The synthetic versatility of this reaction has been demonstrated by gram-scale synthesis, a catalytic enantioselective synthesis of naturally occurring (S)-2-amino-4,5-hexadienoic acid A, and conversions to several useful chemicals, such as optically active α-amino acids, β-amino alcohols, potential chiral oxazoline ligands bearing an allenic moiety, and bicyclic ketone compounds. A mechanism involving the roles of two metals and the single chiral ligand has been extensively studied based on the isolation of key palladium pre-catalyst and control experiments.

Full text of DOI:10.1002/cjoc.202100002

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: One Stone Two Birds – Enantioselective Bimetalic Catalysis for a-Amino Acid
Derivatives with An Allene Unit
Authors: Junzhe Xiao, Haibo Xu, Xiaohong Huo, Wanbin Zhang* and Shengming
Ma*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100002.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202100002
ISSN 1001-604X • CN 31-1547/O6
mc.manuscriptcentral.com/cjoc
www.cjc.wiley-vch.de

Ma Shengming (Orcid ID: 0000-0002-2866-2431)
Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
One Stone Two Birds – Enantioselective Bimetalic Catalysis for α-
Amino Acid Derivatives with An Allene Unit
Junzhe Xiao,a,b Haibo Xu,a,b Xiaohong Huo,d Wanbin Zhang*d and Shengming Ma*a,c
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 345 Lingling Lu,
Shanghai 200032 (P. R. China)
b University of Chinese Academy of Sciences, Beijing 100049 (P. R. China)
c Research Centre for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433
(P. R. China)
d Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering and School of Pharmacy,
Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (P. R. China)
Keywords
Amino acids | allene | synergistic bimetallic Pd/Cu catalysis | enantioselective synthesis | mechanism
Main observation and conclusion
A highly enantioselective 2,3-allenylation of acyclic and cyclic α-imino carboxylates via a synergistic bimetallic Pd/Cu catalysis with
the same commercially available (R,Rp)-iPr-FOXAP ligand for both metals affording optically active 2,3-butadienyl α-amino acid deriva-
tives in high to excellent yields with excellent enantioselectivities has been developed. The synthetic versatility of this reaction has been
demonstrated by gram-scale synthesis, a catalytic enantioselective synthesis of naturally occurring (S)-2-amino-4,5-hexadienoic acid A,
and conversions to several useful chemicals, such as optically active α-amino acids, β-amino alcohols, potential chiral oxazoline ligands
bearing an allenic moiety, and bicyclic ketone compounds. A mechanism involving the roles of two metals and the single chiral ligand
has been extensively studied based on the isolation of key palladium pre-catalyst and control experiments.
Comprehensive Graphic Content
O
PPh2
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d
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R2O2C
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*E-mail:
View HTML Article
Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX©
2021
SIOC,
CAS,
Shanghai,
&
WILEY-VCH
GmbH
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202100002
This article is protected by copyright. All rights reserved.

Scheme 1 The importance of allene-substituted amino acids
Background and Originality Content
O
•
•
H
CO2
Amino acids show widespread applications in human nutrition,
pharmaceutical arena, and the production of chiral catalysts.[1] Be-
sides enzymatic methods in biosynthesis, enantioselective catalytic
synthesis for diverse functionalized optically active non-natural
amino acids is an alternative pathway. [2] On the other hand, during
the last two decades, allenes have become more and more irre-
placeable in organic chemistry and medicinal chemistry due to their
unique physical,[3] biological,[4] and chemical properties.[5] Not only
widely present in naturally occurring molecules,[4] allenic structures
have been also demonstrated to be very useful building blocks in
synthetic transformation and construction of complex molecules. [5]
In fact, molecules possessing both allene and amino acid units are
extremely useful and attractive due to their highly functionalized
properties for synthetic organic chemists and biology-related scien-
tists: allene-substituted amino acids are widely distributed in many
fungi and considered a common intermediate in the biosynthesis of
various norleucine-type amino acids. [6] For example, (S)-2-amino-
4,5-hexadienoic acid (Scheme 1, A) was first reported and isolated
from the fruiting bodies of Amanita solitaria in 1968. [6a] In addition,
allenic amino acids indeed exhibit potent bioactivity: O-(buta-2,3-
dienoyl)-L-serine (Scheme 1, B) shows anti-tumor activity against
murine L1210 leukemia; [7] there are also some allenic amino acids
proved to be enzyme inhibitors, such as a GABA-T inhibitor[8]
COOH
NH2
O
NH2
A
B
acid
-serine
L
S
O
(
)-2-amino-4,5-hexadienoic
isolated from Amanita solitaria
-(buta-2,3-dienoyl)-
Anti-tumor
H2N
COOH
•
R1
NH2
•
COOH
R2
D
C
R1
R2
Me
=
=
H,
H,
acid
S
(
)-4-amino-5,6-heptadienoic
GABA-T inhibitor
3,4-dihydroxy
3-hydroxy,
AADC inhibitors
Results and Discussion
We began our study with acyclic α-imino carboxylate 1a and
buta-2,3-dienyl methyl carbonate 2 as model substrates. With
Cs2CO3 as the base and tetrahydrofuran (THF) as the solvent, a
[Pd/L*+Cu/L*] catalyst combination was applied to identify the op-
timal single chiral ligand for both metals. The most commonly used
ligands for enantioselective allenylation reactions failed to give sat-
isfactory results: the use of Trost ligand (R,R)-L1 gave (R)-3a in only
18% yield with 27% ee (Table 1, entry 1), and biphenyl ligand (S)-L2
resulted in a higher yield, but still with a low ee (Table 1, entry 2). It
was gratifying to observe that the enantiocontrol was getting better
by using phosphine oxazoline (PHOX) ligands: The (R)-L3 resulted in
32% yield with 36% ee (Table 1, entry 3). By tuning the steric effect,
it was observed that (R)-L4 improved the ee to 49% (Table 1, entry
4). To our delight, phosferrox (R,Rp)-L5 was able to provide 87%
yield and 93% ee of (R)-3a with no recovery of 1a as monitored by
1H NMR analysis (Table 1, entry 5). Next, the effect of base was in-
vestigated. A series of inorganic carbonates were screened to show
that the reactivity was improved by the increasing radius of the cat-
ion (Table 1, entries 5-9). The solvent effect was also studied: ethyl
ether failed to give (R)-3a with nearly quantitative recovery of 1a
(Table 1, entry 10); in methyl tert-butyl ether (MTBE) the reaction
exhibited a very low reactivity and enantioselectivity (Table 1, entry
11). Excitingly, the reaction in dichloromethane (DCM) afforded (R)-
3a in 97% ee with a yield of 86% (Table 1, entry 12). Toluene was
not effective for the transformation (Table 1, entry 13)
(Scheme 1, C) and aromatic amino acid decarboxylase inhibitors
[8,9]
(Scheme 1, D).
Thus, development of powerful methods for
highly enantioselective synthesis of optically active molecules con-
taining both amino acid unit and allene moiety is of great interest.
We reasoned that the reaction of methylene-π-allyl palla-
dium[10] with α-imino carboxylates[11] in the presence of a base
would be a straightforward strategy to afford α-imino-α-allenylcar-
boxylates, which are precursors for α-amino acids bearing an allene
moiety. When we were developing such a reaction, Wang et al. re-
ported such a reaction with two different ligands for two metals. [12]
After facing the Covid-19 and addressing some data discrepancy,
herein, we wish to report a highly active synergistic Pd/Cu dual ca-
talysis[13-15] for enantioselective 2,3-butadienylation of acyclic and
cyclic α-imino carboxylates with a single chiral ligand, i.e., commer-
cially available (R,Rp)-iPr-FOXA P, for both metals with a very wide
scope. The roles of each metal and the chiral ligand has been care-
fully unveiled based on the isolation of key palladium pre-catalyst.
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim

Running title
Chin. J. Chem.
Table 1 The effect of Ligands, bases, and solventsa
transformation affording (R)-3i and (S)-3k in ee of 92% and 94%, re-
spectively. Substrate 1j with an electron-deficient C=C bond also
gave (R)-3j in 62% yield and 91% ee. Last but not the least, a series
of synthetically attractive functional groups, such as ester ((S)-3l
and (R)-3m), cyano ((R)-3n), ether ((S)-3o), acetal ((S)-3p), tert-
butoxycarbonyl amino ((R)-3q), and methyl thioether ((R)-3r), were
well tolerated, proving the protocol a viable tool for further synthe-
ses of complicate bioactive compounds bearing an allenic moiety.
However, the reaction of phenylglycine methyl ester derived α-
imino carboxylate resulted in the formation of 3s in 87% yield with
4% ee. The practicality was also demonstrated by applying 8.0
mmol of 1a and 9.6 mmol of 2, affording 1.4206 g of (R)-3a in 90%
yield and 96% ee under 40 oC for 48 h.
O
O
•
0.5 mol%
1M HCl
[Pd(allyl)Cl]2
•
Ph
N
+
OtBu
OCO2Me
1.0 mol%
2.0 mol%
OtBu
Me NH2
R 3a
)-
Et
rt, 0.5 h
2O,
Cu(OTf)2
L*
Me
1a
0.25
2
1.0
Solvent,
Base
equiv.
(
mmol
1.2
equiv.
rt, 24
N
2
h,
O
O
PPh2
N
O
O
O
O
O
O
N
PPh2
PPh2
NH HN
PPh2 Ph2P
L1
PPh2
N
PPh2
Fe
iPr
tBu
O
,
R R L5
L2
R
(
L3
R
L4
S
(
R,R
(
)-
)-
)-
(
)-
(
p)-
1a
R 3a
)-
(
b
ee
(%)
Entry
1c
2
L*
Base
Solvent
NMR Recovery
Yield
18
(%)
(%)
L1
THF
74
6
27
22
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
R,R
)-
(
(
(
(
(
(
(
(
(
(
(
(
(
In addition, ketimine Schiff base 4 with R1 = H also reacted
smoothly with buta-2,3-dienyl methyl carbonate 2 under the
standard condition to afford (S)-5 in 87% yield with 94% ee (Scheme
2a). After removing both protecting groups with aqueous hydrogen
chloride solution (1 M HCl) and trifluoroacetic acid (TFA) subse-
quently, the naturally occurring (S)-2-amino-4,5-hexadienoic acid (A)
listed in Scheme 1 was formed and isolated easily via simple recrys-
tallization in 73% yield.The ee value was carefully determined by
HPLC to be 92% by its conversion to the corresponding methyl ester
(S)-6.
Furthermore, we performed the reduction of (R)-3a to afford
amino alcohol (R)-7, which was further reacted with 2-bromoben-
zoyl chloride, yielding (R)-8 with an aryl bromide unit in 80% yield
with 97% ee. Luckily, the absolute configuration of (R)-8 was even-
tually established by the X-ray crystallography, which also unambig-
uously established the stereochemistry of this reaction (Scheme 2b).
Oxazolination of (R)-8 was successfully realized in the presence of
methanesulfonyl chloride (MsCl) to afford the oxazolinyl allene
product (R)-9 (95% yield and 98% ee), which may be used as chiral
ligand directly or further transformed to chiral phosphine oxazoline
(PHOX) ligands bearing allenic structure as a coordinative regulator
due to its unique coordination behaviour. [16] Furthermore, we per-
formed hydrolysis and tosylation of (R)-3a to afford amino acid (R)-
10 and tosylamide (R)-12, respectively, in high yields with excellent
ee. In addition,
L2
L3
THF
70
S
)-
3
R
R
THF
48
32
-36
-49
)-
4
L4
THF
50
32
)-
-
5
Cs2CO3
Li
THF
87
93
R,R
p)-L5
-
-
,
L5
THF
6
R R
2CO3
Na2CO3
98
p)-
-
-
,
>
7
R R L5
THF
99
69
42
99
p)-
,
L5
L5
K
THF
25
8
R R
2CO3
95
p)-
p)-
,
9
R R
Rb
2CO3
THF
46
-
89
-
,
10
11
12
R R L5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et2O
MTBE
DCM
Toluene
p)-
,
R R L5
78
18
72
p)-
-
-
L5
86
97
R,R
)
p
-
-
,
13
R R L5
87
p)-
a
and
mmol),
1
2
L
L
mol%), Cu/
*
(1.0
Reaction conditions:
mmol),
mmol), Pd/
*
mol%), Base
(0.25
(0.3
(1.0
for 24 h. Isolated
(0.25
chiral HPLC
analysis
ee were
solvent
mL) at rt under N
The
determined
2 atmosphere
separation
yield.
b Determined
the internal standard. c 1 mol% of
R,R
( )-
by
(0.5
on
after column chromatographic
silica
1H NMR
before workup with 1M HCl
gel.
by
analysis
.
as
was used
L1
using CH3NO2
With the optimized conditions in hand, we next examined the
scope of this straightforward approach for enantioselective 2,3-bu-
tadienylation of α-imino carboxylates. To our delight, substrates
with commonly used R2 groups (tBu, Me, Et, and iPr, Table 2, entries
1-4) reacted smoothly, indicating that the steric hindrance in R2
group did not have remarkable influence on this enantioselective
catalytic process
Table 2 The effect of R2 groups in α-imino carboxylates 1a
O
O
0.5 mol%
1.0 mol%
[Pd(allyl)Cl]2
•
•
Ph
N
+
OR2
OCO2Me
OR2
Me N=CHPh
Cu(OTf)2
,
Me
L5
p)-
2.0 mol% R R
(
1.0
DCM,
Cs CO
1
2
equiv.
rt, 36
R 3'
( )-
2
3
N
h,
mmol
2
0.25
1.2
equiv.
R
3'
(
)-
R2
tBu 1a
Entry
ee
Yield
(%)
(%)
1
2
3
4
92
91
92
87
94((R 3'a
)- )
(
)
)
Me 1b
(
94((R 3'b
)-
)
Et
1c
96((
R 3'c
)-
(
)
)
iPr 1d
94((R 3'd
)-
(
)
)
,
,
mol%), Cu/(
R R L5
p)- (1.0
a
mmol),
mmol),
Pd/(
R R L5
1
2
Reaction conditions:
mol%),
(0.25
(0.3
p)- (1.0
and
ee was
Cs2CO
mmol),
DCM
mL)
at rt under N
for
36 h. Isolated
The
2 atmosphere
after column chromatographic
yield.
3 (0.25
determined
(0.5
on
chiral HPLC
silica
gel.
separation
by
analysis
Furthermore, we turned our attention to investigate the effects
of R1 in α-imino carboxylates (Table 3). The α-imino carboxylates
with a linear alkyl and branched alkyl substitution all reacted
smoothly with buta-2,3-dienyl methyl carbonate 2 to afford opti-
cally active amino derivatives with an allene unit 3 in high to excel-
lent yields with excellent ee, indicating that the protocol was ame-
nable to different carbon chain commonly existing in bioactive
amino acid derivatives (Table 3, (R)-3a to (R)-3g). When R1 = Bn, (S)-
3h was generated in 88% yield with 86% ee under 40 oC. In addition,
1i and 1k bearing allyl and but-2-ynyl groups worked well in this
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
Table 3 Substrate scope of acyclic α-imino carboxylates 1a
2-amino-4,5-hexadienoic acid. b Synthetic applications of (R)-3a and Estab-
lishment of stereochemistry
O
O
0.5 mol%
1M HCl
Et
rt, 0.5 h
•
•
[Pd(allyl)Cl]2
Ph
N
+
R2
R2
O
OCO2
Me
O
1.0 mol%
mol%
2.0
2O,
Cu(OTf)2
,
R1
R1
NH2
R R
L5
p)-
(
O
a
•
1.0
Cs CO
O
1
2
3
equiv.
2
3
•
0.5 mol%
1.0 mol%
COOH
NH2
OtBu
Ph
1)
2)
[Pd(allyl)Cl]
Cu(OTf)
2
1 M HCl, Et
r.t., 12 h
2O,
Ph
N
or
THF DCM, rt, 36
N
2
h,
OtBu
mmol
0.25
1.2
equiv.
N
TFA, DCM, r.t. 4 h
recrystallization
2
,
S S L5
( p)-
Ph
t
mol%
equiv.
equiv.
R2 Bu Me
2.0
1.2
1.0
=
or
Ph
2
4
5
)-
yield,
A
S
(
Cs2CO3
Alkyl substituted
mmol
ee
94%
1.0
87%
73%
yield
DCM, 40 o 72
N
2
O
O
O
O
C,
h,
•
•
•
•
TMSCHN2
THF:MeOH 3:2, rt, 2 h
1)
2)
(4.0 equiv.)
=
OtBu
Me NH2
OtBu
Et NH2
OtBu
nPr NH2
OtBu
iBu NH2
TsCl
(1.2 equiv.)
DMAP
(0.2 equiv.)
N
(1.2 equiv.)
R
3a
R
3e
R
3f
R 3g
( )-
(
)-
(
)-
(
)-
Et3
eeb,d
ee,b,e,g,h
eec,f
eec
eec
DCM, 0 oC to rt, Ar, 12 h
86%
90%
97%
96%
95%
95%
92%
96%
93% 91%
yield,
yield,
yield,
yield,
yield,
•
CO2Me
and
allyl
substituted
propargyl
NHTs
CCDC 1978399
S
6
)-
(
O
O
O
O
b
ee
62%
Br
92%
yield,
•
•
•
•
OtBu
OtBu
OtBu
NH2
OtBu
H
N
1.15
2.40
MsCl
Et3N
•
2-bromobenzoyl chloride
(1.15 equiv.)
equiv.
equiv.
•
Bn NH2
NH2
NH2
O
N
OH
Me NH2
Me
EtO2C
62%
Me
OH
3.0
DCM/H
Na2CO3
Br
80%
DCM, 0 oC to reflux
O
equiv.
S
3h
)-
86%
R
3i
R
3j
S
( )-
3k
(
(
)-
(
)-
rt, 2 h
2O,
Ar, 3 h
R
7
R 8
( )-
ee
97%
yield,
(
)-
•
eeb,e,g
eec
eeb
eec
88%
94%
92%
91%
91%
94%
ee
yield,
yield,
yield,
yield,
78%
97%
yield,
R
9
(
)-
yield,
ee
98%
95%
LiBH4
equiv)
(1.5
MeOH
equiv)
Other useful functional
(1.5
r.t., 17 h
groups
Et
2O,
O
O
O
O
•
•
•
•
O
O
O
OtBu
NH2
OtBu
OtBu
OtBu
•
•
•
TMSCH2N
2 (2
equiv)
1)
2)
TFA
tBuO2C
NH2
OtBu
3o
NH2
NH2
OtBu
Me NH2
ee
3a 96%
,
=
THF/MeOH 3:2, 1 h
OMe
Me NHTs
11
OH
Me NH2
tBuO2C
93%
NC
DCM, r.t., 3 Ar
h,
TsCl
(1.2 equiv)
DMAP
R
R
80%
10
equiv)
R
( )-
yield,
(0.2
equiv)
(
)-
(
)-
S
3l
R
3m
R
3n
S
( )-
(
)-
(
)-
(
)-
Et3
DCM,
N
ee
60%
95%
(1.2
r.t. 12 Ar
yield
eec
eec,f
eec
eec
93%
94%
O
95%
90%
91%
84% 93%
h,
yield,
yield,
yield,
yield,
TsCl
(1.2 equiv.)
DMAP
(0.2 equiv.)
Et3
N
Me
R1 Ph
•
(1.2 equiv.)
=
tBuO2C
54%
5 mol%
Cl]2
[Rh(CO)2
O
O
O
DCM, 0 o
C
to rt, Ar, 12 h
O
•
•
•
TsN
CO balloon
OtBu
NH2
OtBu
OtBu
Me
ee
toluene, 90 o 10
min
OMe
R
14
( )-
C,
O
Me
tBuO2C
TsN
•
O
NH2
NH2
NH2
•
96%
Ph
3s
yield,
OtBu
Me NHTs
12
S
O
K
2CO3
Me
(3.0
equiv.)
BocHN
S
3p
R
3q
R 3r
( )-
94%
(
)-
(
)-
R
(
1-bromo-2-butyne
R
13
)-
)-
yield,
(
Me
tBuO2C
TsN
H
eec
eec
eec
4%
b,f,g
ee
93%
>99%
91%
90%
89%
87%
ee
93%
95%
ee
97%
yield,
yield,
yield,
yield,
yield,
mol%), Cs CO
3 (0.25
79%
Mo(CO
(3.0 equiv.)
)
6 (1.2 equiv.)
acetone, 60 o 12 h
C,
O
O
DMSO
(10.0 equiv.)
,
,
a
mmol),
mmol),
Pd/(
1
2
R R L5
R R L5
Reaction conditions:
mol%), Cu/(
Toluene, 100 o Ar, 10 min
(0.25
(0.3
p)- (1.0
p)- (1.0
2
C,
Me
ee
R,4aS 15
(3 )-
and
ee were
mmol),
solvent
mL) at rt under N
for 36 h. Isolated
The
determined
solvent. d 24 h. 48 h. f 60
chiral HPLC
was
also
34%
2 atmosphere
yield.
as
DCM
by
of
R
14
1H NMR
(0.5
(17% yield
detected
(
)-
97%
yield,
c
e
b
on
as
analysis after column chromatographic
silica
solvent. THF
mmol
separation
mmol
gel.
by
analysis
+
.
o
crude
h. g 40 C. h The reaction
conducted with 8.0
of 1a
of 2 to afford 1.4206
R 3a
g
( )-
of the
product)
was
and
9.6
,
H
Me
tBuO2C
TsN
Me
ee
R,4aR 15
(3 )-
yield,
(R)-12 easily reacted with 1-bromo-2-butyne to afford alkyne-allene
(R)-13 in 79% yield with 97% ee. With [Rh(CO)2Cl]2 as catalyst,
[5.3.0]bicyclopentenone compound (R)-14 was formed by the Pau-
son-Khand reaction of (R)-13 in 54% yield with 96% ee. (R)-13 could
also be converted to [4.3.0]bicyclic products 15 with 1.2 equiv. of
Mo(CO)6 as the source of carbonyl group. These bicyclic structures
are important common skeletons in natural products. [17]
20% 96%
Based on these studies, a bimetallic catalytic cycle is proposed
as shown in Figure 2. In the presence of acyclic α-imino carboxylates
1a and base, the catalytically active species L*Pd(0) would be gen-
erated in situ from pre-catalyst Pd-1. This chiral palladium complex
L*Pd(0) would react with buta-2,3-dienyl methyl carbonate 2 via
SN2’-type oxidative addition to generate η1-1,3-dienyl Pd(II) inter-
mediate II. Subsequent σ-π rearrangement would yield the delocal-
ized methylene-π-allyl palladium(II) intermediate III. With the chiral
To unveil the nature of this Pd/Cu dual catalytic process, the
reaction of [Pd(allyl)Cl]2 and (R,Rp)-L5 was conducted in the mixture
of DCM/C6D6 (v/v = 8:1) at rt for 40 min and (R,Rp)- iPr-FOXAP-η1-
allyl palladium chloride Pd-1 has been isolated with its structure de-
termined by X-ray diffraction study (Figure 1a). Control experiments
were then conducted to probe the reaction mechanism: The reac-
tion performed with 1 mol% of Cu(OTf)2 and 1 mol% of (R,Rp)-L5
failed to afford (R)-3a, indicating the critical role of palladium for
this 2,3-butadienylation process (Figure 1b, Entry 1). When the re-
action was conducted in the absence of Cu(OTf)2 with only 0.5 mol%
of [Pd(allyl)Cl]2 and 1 mol% of (R,Rp)-L5, the conversion of 1a was
only 16% and the yield for (R)-3a was 9% with an enantioselectivity
as low as 14% (Figure 1b, Entry 2). When the reaction was per-
formed with 0.5 mol% of [Pd(allyl)Cl]2, 1 mol% of Cu(OTf)2, and 2
mol% of (R,Rp)-L5, (R)-3a was yielded in 86% yield with 97% ee (Fig-
ure 1b, Entry 3). Meanwhile, the combination of 1 mol% of Pd-1, 1
mol% Cu(OTf)2, and 1 mol% of (R,Rp)-L5 reacted smoothly to afford
(R)-3a in 87% yield with 97% ee (Figure 1b, Entry 4). These data in-
dicate that Pd-1 served as the pre-catalyst in the catalytic cycle.
When the reaction was performed with 1 mol% of Pd-1 and 1 mol%
of Cu(OTf)2 in the absence of extra chiral ligand, (R)-3a was yielded
in only 13% yield with 68% ee and 85% of 1a was recovered as de-
termined by 1H NMR analysis. These data indicate that coordination
of (R,Rp)-L5 to Cu(OTf)2 must have resulted in the formation of a
highly reactive chiral nucleophile for the improved reactivity and
enantioselective control (Figure 1b, compare Entry 4 with Entry 5).
copper(II) complex and base, α-imino carboxylate 1a would be
[11i]
readily converted to N-metalated azomethine ylide IV.
The
highly reactive nucleophile IV would attack the methylene-π-allyl
palladium(II) III in a highly enantioselective manner to afford the 2-
(N-imino)-4,5-allenoates and regenerate both chiral Pd and Cu cat-
alysts.
Cyclic α-imino carboxylates are privileged building blocks[18] in
organic chemistry and have been widely applied in the construction
[19]
of bioactive nitrogen-containing heterocyclic molecules.
Fur-
thermore, such products could be reduced to non-natural proline
derivatives with α-quaternary stereogenic center. It is interesting to
see that the current mono-chiral ligand based Pd/Cu dual catalytic
process is also amenable to the enantioselective 2,3-butadienyla-
tion of cyclic α-imino carboxylates. Different R3 in the ester groups
(Table 4, (R)-17a to (R)-17c) and aryl or heteroaryl substitutions (R4)
(Table 4, (R)-17d to (R)-17l) all worked well, resulting in excellent
yields with ee (85-96% yield, 92-97% ee), providing a reliable strat-
egy for the synthesis of extra optically active non-natural proline
derivatives containing allenic structures. The absolute configura-
tions of the chiral centers in 17 is tentatively assigned to be R based
on the analogy to (R)-3a.
Scheme 2 a Catalytic enantioselective synthesis of naturally occurring (S)-
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
a
In summary, we have developed a highly enantioselective 2,3-
butadienylation of acyclic and cyclic α-imino carboxylates via a syn-
ergistic Pd/Cu dual catalysis with (R,Rp)-iPr-FOXAP as the ligand for
both metals. A series of chiral 2,3-butadienyl α-amino acid deriva-
tives bearing versatile functionalities were easily synthesized in high
to excellent yields with enantioselectivities. This reaction was easily
scaled up and successful applied in the catalytic enantioselective
synthesis of naturally occurring (S)-2-amino-4,5-hexadienoic acid A.
In addition, the prepared 2-amino-4,5-allenoates could be easily
transformed to synthetically versatile materials such as optically ac-
tive 2,3-butadienyl α-amino acids, β-amino alcohols, oxazolines
bearing allenic moiety, and bicyclic ketone compounds. Further ap-
plications of this bimetallic catalysis strategy in stereocontrol on
both axial chirality of allene and central chirality of α-imino carbox-
ylates, applications in ligand-based asymmetric catalysis/natural
products, and study on biological activity are actively pursued in
both laboratories of Ma and Zhang.
Ph2
Pd
P
Cl
=
DCM: C6D6 8:1
N
H
,
+
R R L5
p)-
[Pd(allyl)Cl]2
(
r.t., 40 min, N2
Fe
O
2.0
equiv.
Pd-1
CCDC
1978402
O
b
O
x
mol% Pd
1M HCl
Et O r.t., 0.5 h
complex
•
•
Ph
N
+
OtBu
O
tBu
OCO2Me
mol%
mol% R R
1.0
DCM,
,
y
z
Cu(OTf)2
2
,
Me NH2
Me
1a
L5
(
p)-
Cs CO
2
equiv.
R -3a
)
2
3
(
rt, N time
,
2
(h)
mmol
0.25
1.2
equiv.
,
of
)- (%)
of
Entry
Pd mol%)
(x
R R L5
Time
(h)
Ee
Conv. of
Yield
Cu(OTf)2
mol%)
(y
(
(z
p)-
a
1
R
3a
R 3a
)- (%)
mol%)
(%)
(
-
(
-
-
<
1
2
3
4
5
1
0
1
1
1
1
24
24
24
36
36
1
1
16
9
14
[Pd(allyl)Cl]2 (0.5)
[Pd(allyl)Cl]2 (0.5)
2
1
0
>99
>99
15
86
87
13
97
97
68
Pd-1
Pd-1
(1)
(1)
Experimental
Figure 1 The studies on reaction mechanism. a Preparation of (R,Rp)-iPr-
FOXAP-η1-allylpalladium chloride Pd-1. b Control experiments.
The preparation of chiral Pd catalyst: To an oven-dried 4 mL vial
were added [Pd(allyl)Cl]2 (1.8 mg, 0.005 mmol), (R,Rp)-iPr-FOXAP
(4.8 mg, 0.01 mmol), and freshly distilled solvent (1 mL) in a glove
box. The resulting mixture was stirred at room temperature for 40
min.
Base•HX
L*
Cu
N
O
(II)
Pd+
(II)
O
L*
Ph
OtBu
Ph
N
III
OtBu
Pd+
II
3
η
Me
L*
IV
η1
(II)
to
Me
1a
N-metalated azomethine
σ−π
rearrangement
ylide
The preparation of chiral Cu catalyst: To an oven-dried 4 mL vial
were added Cu(OTf)2 (3.6 mg, 0.01 mmol), (R,Rp)-iPr-FOXAP (4.8 mg,
0.01 mmol), and freshly distilled solvent (1 mL) in a glove box. The
resulting mixture was stirred at room temperature for 40 min.
Typical procedure for the synthesis of (R)-3a: To an oven-dried
Schlenk flask were added Cs2CO3 (81.5 mg, 0.25 mmol), 1a (58.6 mg,
0.25 mmol), chiral Pd catalyst (0.25 mL), chiral Cu catalyst (0.25 mL),
and 2 (38.6 mg, 0.3 mmol) sequentially in a glove box. After being
stirred vigorously at room temperature for 24 h, the reaction was
complete as monitored by TLC. 2.0 mL of Et2O were added and the
resulting mixture was then filtered through a short pad of silica gel
eluted with Et2O (50 mL). After removal of the solvent under vac-
uum, 2 mL of Et2O and 2 mL of 1M HCl were added sequentially.
After the resulting mixture was stirred at room temperature for 0.5
h, 4 mL of Et2O were added. The pH value of the mixture was regu-
lated to 8-9 with solid K2CO3 (ca. 450 mg). The organic layer was
separated and the aqueous layer was extracted with Et2O (4 mL x 4).
The combined organic layer was dried over anhydrous Na2SO4, de-
canting into a round-bottom flask, and concentrated. After removal
of the solvent under vacuum, the residue was purified by flash chro-
matography on silica gel to afford (R)-3a (42.8 mg, 86% yield, 97%
ee) [eluent: petroleum ether: acetone = 20:1 (168 mL), petroleum
ether: acetone = 2:1 (225 mL)]: oil; HPLC conditions: AD-H column,
hexane/iPrOH = 100/1, 1.0 mL/min, λ = 214 nm, tR (minor) = 10.9
min, tR (major) = 11.9 min; [α]D28 = + 28.2 (c = 0.54, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 5.03 (quintet, J = 7.3 Hz, 1 H, =CH), 4.68 (dt,
J1 = 6.8 Hz, J2 = 2.8 Hz, 2 H, =CH2), 2.50-2.40 (m, 1 H, one proton of
CH2), 2.25-2.16 (m, 1 H, one proton of CH2), 1.81-1.67 (brs, 2 H, NH2),
1.46 (s, 9 H, OC(CH3)3), 1.30 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3):
δ = 209.9, 176.2, 84.9, 80.9, 74.5, 58.0, 40.1, 27.9, 26.3; IR (neat): ν
= 3379, 2977, 1956, 1722, 1368, 1157, 1112 cm-1; MS (ESI) m/z (%):
198 (M+H+); HRMS Calcd. for C11H20 NO2+ (M+H+): 198.1489, found
198.1487
+
oxidative
addition
Base
Pd
Catalytic
Cu(II)
OCO2Me
Pd(0)
Catalytic
Cycle
Cycle
•
L*
I
coordination
2
L*
L*
Cu(II)
Pd(0)
O
+
1a
Base
•
OtBu
Me N=CHPh
R -3'a
allyl
byproduct
Pd-1
(
)
Figure 2 Proposed bimetallic catalytic cycles.
Table 4 Substrate scope of cyclic α-imino carboxylates 16a
•
•
0.5 mol%
N
R3O2C
[Pd(allyl)Cl]
2
R4
N
+
R4
OCO2Me
Cu(OTf)
2
R3
O2C
1.0 mol%
mol%
2.0
,
R R
L5
(
p)-
16
2
R
17
( )-
1.0
Cs CO
equiv.
THF, rt, time, N2
2
3
mmol
0.25
1.2
equiv.
•
•
•
N
,
N
,
N
,
MeO2C
EtO2C
tBuO2C
R
93%
17a 36 h
R
(
17b 36 h
R
17c 36 h
97%
(
)-
)-
(
)-
ee
ee
ee
ee
95%
92%
92%
85%
yield,
yield,
yield,
•
•
•
N
N
N
Me
F
tBuO2C
tBuO2C
tBuO2C
Me
,
,
,
R
96%
17d 96 h
R
(
17e 48 h
R
17f 48 h
96%
(
)-
)-
(
)-
ee
ee
ee
ee
ee
93%
85%
97%
93%
yield,
yield,
yield,
•
•
•
N
N
N
Cl
OMe
O
tBuO2C
tBuO2C
tBuO2C
O
,
,
,
R
95%
17g 48 h
R
(
17h 84 h
R
17i 48 h
( )-
(
)-
)-
eeb
97%
91%
95%
yield,
89%
96%
yield,
yield,
•
•
•
O
N
N
,
N
OMe
tBuO2C
tBuO2C
tBuO2C
N
,
,
R
94%
17j 48 h
97%
R
(
17k 72 h
R
17l 96 h
( )-
(
)-
)-
eeb
ee
92% 95%
yield,
yield,
89%
94%
yield,
,
,
R R L5
mol%), Cu/(
p)- (1.0
a Reaction conditions: 16
mmol),
mmol), Pd/(
R R L5
mol%), Cs2CO
3 (0.25
2
(0.25
at rt
(0.3
p)- (1.0
The
Supporting Information
mmol), and
ee were
THF
mL)
under N
Isolated
b 40 oC.
determined by chiral HPLC analysis
2 atmosphere.
yield.
(0.5
on
after column chromatographic
silica
separation
gel.
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Conclusions
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
1984, 1284-1285; (c) Hatanaka, S.-I.; Niimura, Y.; Takishima, K.;
Sugiyama, J. (2R)-2-Amino-6-hydroxy-4-hexynoic Acid, and Related
Amino Acids in the Fruiting Bodies of Amanita miculifera. Phytochem-
istry, 1998, 49, 573-578.
Lachance, B.; Salvador, R. L.; Simon, D. Z. Synthesis and Evaluation of
Potential Glutamine Antagonists. Eur. J. Med. Chem. 1987, 22, 179-186.
Casara, P.; Jund, K.; Bey, P. General Synthetic Access to α-Allenyl
Amines and α-Allenyl-α-Aminoacids as Potential Enzyme Activated Ir-
reversible Inhibitors of PLP Dependent Enzymes. Tetrahedron Lett.
1984, 25, 1891-1894.
Acknowledgement
Financial support from the National Natural Science Foundation
of China (grant no. 21690063 to S.M., and grant no. 21901158 to
W.Z.) are greatly appreciated. We thank Mr. Huanan Wang in this
group for reproducing the results of (R)-3’d, (R)-3m and (R)-17k,
presented in Table 2, Table 3, and Table 4, respectively
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
Chin. J. Chem. 2021, 39, XXX－XXX
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Entry for the Table of Contents
One Stone Two Birds – Enantioselective Bimetalic Catalysis for α-Amino Acid Derivatives with An Allene Unit
Junzhe Xiao, Haibo Xu, Xiaohong Huo, Wanbin Zhang* and Shengming Ma*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
O
PPh2
Fe
N
•
N
R2
•
Ar
N
O2C
+
Cu
Pd
Me
OCO2
Ar
R2
R1
O2C
R1
examples
28
excellent enantioselectivity
under mild conditions
a
chiral
single
ligand
working for two metals
A highly enantioselective synergistic bimetallic Pd/Cu catalysis with a single chiral ligand affording optically active 2,3-butadienyl α-amino acids deriva-
tives is described. The product can be converted to useful basic chemicals, such as α-amino acid and β-amino alcohol bearing an allenic moiety, and
bicyclic skeleton.
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim