Stereodivergent Synthesis of α,α-Disubstituted α-Amino Acids via Synergistic Cu/Ir Catalysis

Article abstract of DOI:10.1021/jacs.7b12174

Cu/Ir dual catalysis has been developed for the stereodivergent α-allylation of aldimine esters. The method enables the preparation of a series of nonproteinogenic α-amino acids (α-AAs) bearing two contiguous stereogenic centers in high yield with excellent stereoselectivity. All four product stereoisomers could be obtained from the same set of starting materials via pairwise combination of two chiral catalysts. Notably, one-pot protocol could be successfully applied for the preparation of the bimetallic Cu/Ir complexes to simplify the manipulation of Cu/Ir dual catalysis. This method could be further utilized for the construction of the key intermediate of a bioactive pyrrolidine derivative and the concise synthesis of a plant growth regulator (2S,3S)-2-amino-3-cyclopropylbutanoic acid.

Full text of DOI:10.1021/jacs.7b12174

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Article
Stereodivergent Synthesis of #,#-Disubstituted
#-Amino Acids via Synergistic Cu/Ir Catalysis
Liang Wei, Qiao Zhu, Shi-Ming Xu, Xin Chang, and Chun-Jiang Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12174 • Publication Date (Web): 05 Jan 2018
Downloaded from http://pubs.acs.org on January 5, 2018
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Journal of the American Chemical Society
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Stereodivergent Synthesis of α,α-Disubstituted α-Amino Acids via
Synergistic Cu/Ir Catalysis
Liang Wei,† Qiao Zhu,† ShiꢀMing Xu,† Xin Chang,† ChunꢀJiang Wang*†,‡
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†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China ‡State Key Laboratory of Eleꢀ
mentoꢀorganic Chemistry, Nankai University, Tianjin, 300071, China
ABSTRACT: A Cu/Ir dual catalysis has been developed for the stereodivergent αꢀallylation of aldimine esters. The method enaꢀ
bles the preparation of a series of nonproteinogenic αꢀAAs bearing two contiguous stereogenic centers in high yield with excellent
stereoselectivity. All of the four product stereoisomers could be obtained from the same set of starting materials via pairwise comꢀ
bination of two chiral catalysts. Notably, oneꢀpot protocol could be successfully applied for the preparation of the bimetallic Cu/Ir
complexes to simplify the manipulation of Cu/Ir dual catalysis. This method could be further utilized for the construction of the key
intermediate of a bioactive pyrrolidine derivative and the concise synthesis of a plant growth regulator (2S,3S)ꢀ2ꢀaminoꢀ3ꢀ
cyclopropylbutanoic acid.
INTRODUCTION
four available catalyst permutations. Herein, we report our
investigation on the stereodivergent allylic alkylation of alꢀ
dimine esters with synergistic Cu/Ir catalysis. The synthetic
utility of this method is exemplified by the synthesis of a bioꢀ
active pyrrolidine derivative and the natural product (2S,3S)ꢀ2ꢀ
aminoꢀ3ꢀcyclopropylbutanoic acid. Notably, oneꢀpot protocol
could be successfully applied for the preparation of the bimeꢀ
tallic catalysts to simplify the manipulation process.
Stereochemically rigid α,αꢀdisubstituted αꢀamino acids (αꢀ
AAs) have been widely used in the design of novel nonꢀ
natural peptides and proteins with enhanced biological properꢀ
ties1 due to its stability towards racemization and restricted
conformational flexibility.2 Furthermore, α,αꢀdisubstituted αꢀ
AAs are also found in a series of natural product antibiotics
such as altemicidin.3 Accordingly, development of efficient
methods for the construction of α,αꢀdisubstituted αꢀAAs, esꢀ
pecially in a catalytic asymmetric way, has become of great
importance.4 With great efforts have been paid, chemists now
are able to synthesize different types of enantioenriched α,αꢀ
disubstituted αꢀAAs, for example through catalytic asymmetꢀ
ric Strecker reaction, Mannichꢀtype reaction and alkylation of
amino acids derived nucleophiles.5 In those methodologies,
both enantiomers of the αꢀAAs can be obtained by switching
a pair of enantiomeric catalysts. In contrast, construction of αꢀ
AAs bearing multiple stereocenters with full control of the
absolute and relative configuration is still an elusive goal.6 In
consideration of the stereoscopic configurations of αꢀAAs are
often crucial for the design of peptides,7 chiral ligꢀ
ands/catalysts,8 and the expression of biological activities,9
developing an efficient method for the stereodivergent syntheꢀ
sis of αꢀAAs is of great significance.
Scheme 1. Synergistic Catalysis for Stereoselective Con-
struction of Nonproteinogenic α-Amino Acids (α-AAs)
Previous work: dual Cu/Pd catalysis
R
Ar
N
+
R'
OPG
Cu Pd
R'
MeO2C
N
Ar
MeO2C
R
This design: stereodivergent dual Cu/Ir catalysis
Ar
[Ir*]
[*Cu]
N
nucleophile
electrophile
R
R'
O
OMe
Copper
Iridium
Catalytic Cycle
Catalytic Cycle
Synergistic catalysis has emerged as a powerful synthetic
strategy to enantioselective bond forming process.10 Recently,
Carreira and coworkers further advanced this concept to the
use of two distinct chiral catalyst and each is capable of exerꢀ
cising full control over the configuration of its corresponding
stereogenic center independently.11a Inspired by the elegant
work on stereodivergent dual catalysis11 and our continuous
interest in the construction of unnatural αꢀamino acids with
metallated azomethine ylides,12,13 we envisioned a synergistic
Cu/Ir catalyzed asymmetric allylic alkylation14 of aldimine
esters would furnish the branched α,αꢀdisubstituted αꢀAAs
bearing two adjacent stereogenic centers, in which full comꢀ
plement of stereoisomers could be readily prepared by using
R
[Cu*]
[Ir*]
MeO2C
N
Ar
GPO
R'
R
R
R
R
CO2Me
CO2Me
CO2Me
3
CO2Me
3
3
3
or
or
or
2
2
2
2
Ar
N
Ar
N
Ar
N
Ar
N
R'
R'
R'
R'
H
H
H
H
RESULTS AND DISCUSSION
Initial trials were carried out using cinnamyl methyl carꢀ
bonate 1a and alanine derived aldimine ester 2a as model subꢀ
strates, Cs2CO3 as the base and Ir(I)/(S,S,S)ꢀL5 complex15,16 as
the allylation catalyst at room temperature. To our delight,
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when Cu(I)/(R,Rp)ꢀPhosferrox(L1)17 complex was employed to
The results suggested that the two distinct metal catalysts exꢀ
erts almost absolute control over the corresponding stereogenꢀ
ic centers, respectively.
1
2
3
4
5
6
7
8
activate aldimine ester, the desired product 3a was isolated in
67% yield with exclusively branched selectivity, high diaꢀ
stereoselectivity and 97% ee via an allylation/reduction proꢀ
cess (Table 1, entry 1). After examination of different Phosferꢀ
rox ligands, we found that Cu(I)/L1-L4 all show high catalytic
activity with excellent asymmetric introduction, and the comꢀ
bination of [Cu(I)/(R,Rp)ꢀL4 + Ir/(S,S,S)ꢀL5] were the superior
synergistic catalysts, affording 3a in 82% yield with 15:1 dr
and 97% ee (entries 2ꢀ4). With optimized catalysts in hand, we
then evaluated the leaving groups of the πꢀallyl precursors.
The yield was slightly decreased when tertꢀbutyl carbonate 1b
was used, and acyl protected cinnamyl alcohol 1c gave no
better results than 1a either (entries 5 and 6). Reducing the
Scheme 2. Synthesis of All Stereoisomers of 3aa
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o
reaction temperature to 15 C with increasing the concentraꢀ
tion of 1a to 0.2 M further improved the stereoselectivity with
maintained yield (entries 7 and 8). The control experiments
suggested that both copper and iridium catalysts were indisꢀ
pensable for this transformation (entries 9 and 10). Additionalꢀ
ly, the combined copper and iridium complexes with the idenꢀ
tical chiral ligand L4 or L5 cannot promoted this allylic alkylꢀ
ation reaction either (entries 11 and 12).
a Conditions see Table 1, entry 8.
The scope of the αꢀallylation with regard to πꢀallyl precurꢀ
sors was then explored (Table 2). First, we assessed cinnamyl
methyl carbonate with different functional groups. The current
method shows good tolerance towards both electronic properꢀ
ties (electronꢀ deficient, ꢀneutral or ꢀrich) and substitution
positions (orthoꢀ, metaꢀ or paraꢀ), and the corresponding
products 3a-3g, 3i and 3j were achieved in good yield with
excellent enantioselectivity and exclusive diastereoselectivity
(Table 2, entries 1ꢀ7, 9 and 10). A slightly lower diastereoseꢀ
lectivity (14:1 dr) was observed when metaꢀchloro substituted
cinnamyl methyl carbonate 1h was employed as πꢀallyl preꢀ
cursor (entry 8). Fused arylꢀ and various heteroarylꢀsubstituted
1k-1m and 1oꢀ1q were then subjected to αꢀallylation leading
to the desired products in 62ꢀ96% yield with excellent diaꢀ
stereoselectivity and >99% ee (entries 11ꢀ13 and 15ꢀ17). For
2ꢀthiazolylꢀsubstituted allylic ester 1n, the corresponding
product could be achieved in good yield with 98% ee and 7:1
dr (entry 14). Furthermore, styrenylꢀ and methylꢀsubstituted
allylic esters 1r and 1s also reacted smoothly with 2a affordꢀ
ing the desired products 3r and 3s with satisfied results (enꢀ
tries 18 and 19). The absolute configuration of compound 3o
was determined as (2R,3S) by the Xꢀray analysis (CCDC
1578014) (Figure 1).
Table 1. Optimization of Reaction Conditionsa
entry L for Cu
PG
T (oC) yield (%)b
drc
15:1
14:1
15:1
15:1
16:1
12:1
>20:1
>20:1
n.d.
ꢀ
ee (%)d
97
91
95
97
97
91
99
99
1
2
3
4
5
L1
L2
L3
L4
L4
L4
L4
L4
-
CO2Me
CO2Me
CO2Me
CO2Me
Boc
25
25
25
25
25
25
15
15
25
25
25
25
67
78
75
82
58
71
65
84
trace
0
6
Ac
7
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
8e
9f
Table 2. Substrate Scope of Allyl Carbonatesa
n.d.
ꢀ
ꢀ
10g
11h
12
L4
L4
L5
0
trace
ꢀ
n.d.
n.d.
a All reactions were carried out with 0.20 mmol of 1 and 0.30 mmol of 2a in 2
b
c
mL of CH2Cl2 for 12 h. Cu(I) = Cu(MeCN)4BF4. Isolated yield. Dr was
determined by the crude 1H NMR. d Ee was determined by HPLC analysis. e 1
mL of DCM was used. Without Cu(I)/(R,Rp)ꢀL4. g Without Ir(I)/(S,S,S)ꢀL5.
f
h
entry
1
2
3
4
R
Ph
3
yield (%)b
drc
ee (%)d
99
>99
>99
98
>99
98
>99
98
With Ir(I)/(R,Rp)ꢀL4.
3a
3b
3c
3d
3e
3f
3g
3h
3i
84
95
73
71
67
69
81
79
89
78
79
71
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
14:1
>20:1
>20:1
>20:1
>20:1
pꢀMeꢀC6H4
mꢀMeꢀC6H4
oꢀMeꢀC6H4
pꢀMeOꢀC6H4
pꢀFꢀC6H4
pꢀClꢀC6H4
mꢀClꢀC6H4
3,4ꢀCl2ꢀC6H3
pꢀBrꢀC6H4
2ꢀnaphthyl
2ꢀfuryl
With optimized reaction conditions in hand, we then set out
to test whether all four stereoisomers could be prepared with
the current dual Cu/Ir catalysis. By simply selecting from the
complete set of catalyst permutations Cu(I)/(R,Rp)ꢀL4 or
Cu(I)/(S,Sp)ꢀL4 along with Ir(I)/(R,R,R)ꢀL5 or Ir(I)/(S,S,S)ꢀL5,
full array of stereoisomers of α,αꢀdisubstituted αꢀAAs 3a
were produced in good yield (81ꢀ87%) with excellent enantiꢀ
oselectivity (98ꢀ>99% ee) and exclusive diastereoselectivity
(>20:1 dr) from the same set of starting materials (Scheme 2).
5
6
7
8
9e
10
11
12
99
3j
3k
3l
>99
>99
>99
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Journal of the American Chemical Society
13
14f,g
15
2ꢀthienyl
2ꢀthiazolyl
3ꢀpyridinyl
3m
3n'
3o
62
86
73
90
96
71
69
>20:1
7:1
>99
98
>99
>99
>99
99
After examining the substrate scope of both electrophile and
nucleophile precursors, we further explored the stereodiverꢀ
gence of the current method with cinnamyl methyl carbonate
1a under the standard reaction conditions. Aldimine esters 2e,
2j and 2k were selected as the representative substrates. As
shown in Table 4, in each case, with the pairwise combination
of Cu/Ir catalysts, all of the four stereoisomeric products were
readilyꢀobtained in good yields with 91ꢀ>99% ee and >20:1 dr.
1
2
3
4
5
6
7
8
>20:1
>20:1
>20:1
>20:1
>20:1
16 4ꢀMeOꢀ3ꢀpyridinyl 3p
17f
18
19
6ꢀquinolinyl
styrenyl
CH3
3q'
3r
3s
99
a Conditions see Table 1, entry 8. Isolated yield. Dr was determined by the
b
c
1
d
e
crude H NMR. Ee was determined by HPLC analysis. Catalysts combinaꢀ
f
tion: [Cu(I)/(S,Sp)ꢀL4 + Ir(I)/(R,R,R)ꢀL5], work up with citric acid. Without
reduction. g Yield of the mixture of two diastereoisomers, and ee referred to
that of the major isomer.
Table 4. Representative Examples of Stereodivergencea
9
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11
12
13
14
15
16
17
18
19
20
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22
23
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R
Cu/Ir
dual catalyst
entry
1
PhCH2ꢀ
(2R,3S)ꢀ3w
72% yield
>20:1 dr
PhCH=CHꢀ MeSCH2CH2ꢀ
(2R,3S)ꢀ3ab (2R,3S)ꢀ3ac
88% yield
>20:1 dr
>99% ee
Cu/(R,Rp)ꢀL4
Ir/(S,S,S)ꢀL5
88% yield
>20:1 dr
98% ee
Figure 1. XꢀRay structure of (2R,3S)ꢀ3o
.
99% ee
(2R,3R)ꢀ3w (2R,3R)ꢀ3ab (2R,3R)ꢀ3ac
Subsequently, the scope with respect to the αꢀsubstituted alꢀ
dimine esters was also evaluated. As shown in Table 3, we
were pleased to find that both natural and nonꢀnatural αꢀAAs
derived aldimine esters are suitable azomethine ylide precurꢀ
sors for the current asymmetric allylic alkylation. Diverse
substituents including alkyl (2b-d), (substituted)benzyl (2e-g),
(substituted)allyl (2h-j), thioether (2k) and ester (2l) were all
wellꢀtolerated giving α,αꢀdisubstituted αꢀAAs derivatives in
high yield with excellent stereoselectivity (Table 3, entries 1ꢀ
11). In addition, aldimine esters 2m derived from 2ꢀaminoꢀγꢀ
Cu/(R,Rp)ꢀL4
Ir/(R,R,R)ꢀL5
71% yield
>20:1 dr
>99% ee
(2S,3R)ꢀ3w
81% yield
>20:1 dr
98% ee
(2S,3R)ꢀ3w
77% yield
>20:1 dr
99% ee
88% yield
>20:1 dr
99% ee
90% yield
>20:1 dr
>99% ee
2
3
4
(2S,3R)ꢀ3ab (2S,3R)ꢀ3ac
Cu/(S,Sp)ꢀL4
Ir/(R,R,R)ꢀL5
84% yield
>20:1 dr
99% ee
82% yield
>20:1 dr
91% ee
(2S,3R)ꢀ3ab (2S,3R)ꢀ3ac
Cu/(S,Sp)ꢀL4
Ir/(S,S,S)ꢀL5
89% yield
>20:1 dr
>99% ee
86% yield
>20:1 dr
>99% ee
a Conditions see Table 1, entry 8.
butyrolactone also worked well in this protocol and 3ae' was
isolated in 89% yield with 98% ee and 8:1 dr (entry 12).
With a variety of α,αꢀdisubstituted αꢀAAs have been obꢀ
tained from αꢀsubstituted aldimine ester, we determined to
investigate the compatibility of glycine derived aldimine ester
in this αꢀallylation protocol to synthesize αꢀmonosubstituted
αꢀAAs bearing two contiguous tertiary/tertiary stereogenic
centers. A notable challenge associated with this process is
that the products contain a racemizable proton at the αꢀ
position of carbonyl group, rendering them prone to epimeriꢀ
zation which was further enhanced by the coordination of the
carbonyl and imine moieties to copper center under basic conꢀ
dition. Indeed, preliminary experiment indicated that desired
product with 1:1 dr was isolated under the standard reaction
condition. Fortunately, after switching the inorganic base
Cs2CO3 to a weaker organic base Et3N under otherwise similar
reaction conditions, we successfully realized the stereodiverꢀ
gent αꢀallylation of glycinate derived aldimine ester 4. All
four stereoisomers of αꢀAAs 5 bearing vicinal tertiary/tertiary
stereogenic centers were readily constructed in high yield with
94ꢀ99% ee and 15:1ꢀ>20:1 dr (Scheme 3).
Table 3. Substrate Scope of Aldimine Estersa
entry
1
2
3
4
5
6
7
8
R
Et
nꢀPr
nꢀBu
PhCH2
3
3t
3u
3v
3w
3x
3y
yield (%)b
drc
ee (%)d
>99
>99
>99
99
97
>99
98
85
84
75
72
62
60
71
89
88
88
78
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
pꢀMeC6H4CH2
pꢀBrC6H4CH2
allyl
3z
crotyl
3aa
3ab
3ac
3ad
94
>99
98
9
10
11
cinnamyl
MeSCH2CH2
MeO2CCH2CH2
>99
12e,f
89
8:1
98
Scheme 3. Synthesis of All Stereoisomers of 5 Containing
Contiguous Tertiary/Tertiary Stereogenic Centersa,b
b
c
a Conditions see Table 1, entry 8. Isolated yield. Dr was determined by the
crude 1H NMR. Ee was determined by HPLC analysis. Without further
reduction. f Yield of the mixture of two diastereoisomers, and ee referred to that
of the major isomer.
d
e
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Ph
Ph
Cl
Cu/(R,Rp)-L4
Ir/(S,S,S)-L5
Cu/(S,Sp)-L4
Ir/(R,R,R)-L5
Ar
2a
N
CO2Me
H
H
2
2
Cu(I)/(S,Sp)-L4 (5 mol %)
L5
1
2
3
3
3
(Ar = -Cl-C6H4)
p
+
Ir(I)/(R,R,R)- (3 mol %)
Cl
NH2
MeO2C N=CHAr
MeO2C N=CHAr
Cs2CO3, CH2Cl2, 15 o
then citric acid
86% yield
C
Cl
Cl
CO2Me
OCO2Me
(2R,3S)-5, 95% yield
16:1 dr, 95% ee
(2S,3R)-5, 94% yield
15:1 dr, 99% ee
1a +
(2S,3R)-3i
1i
4
5
6
7
Ar
N
CO2Me
0.74 g, >20:1 dr, 99% ee
4 (Ar = p-Cl-C6H4)
Cl
Ph
Ph
BzCl, TEA
NBz
Cl
Cl
Cl
Ir/(S,S,S)-L5
Cu/(S,Sp)-L4
Ir/(R,R,R)-L5
Cu/(R,Rp)-L4
H
H
NHBz
2
2
CH2Cl2
95% yield
3
3
ref. 18
CO2Me
CO2Me
8
MeO2C N=CHAr
MeO2C N=CHAr
6
7
9
(2S,3S)-5, 94% yield
19:1 dr, 94% ee
(2R,3R)-5, 97% yield
0.96 g, >20:1 dr, 99% ee
>20:1 dr, 98% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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60
b
a Conditions see Table 1, entry 8 except with Et3N as the base. Without furꢀ
ther reduction.
Ar
N
CO2Bn
Cu(I)/(S,Sp)-L4 (3 mol %)
H
8 (Ar = p-Cl-C6H4)
L5
Ir(I)/(R,R,R)-
(2 mol %)
+
Et3N, CH2Cl2, 15 o
96% yield
C
BnO2C
N CHAr
OCO2Me
9
To showcase the utility of this methodology, further transꢀ
formation were conducted as shown in Scheme 4. (2S,3R)ꢀ3i
was obtained through allylation/hydrolysis in 3 mmol scale
catalyzed by [Cu(I)/(S,Sp)ꢀL4 + Ir(I)/(R,R,R)ꢀL5)] without loss
of stereoselectivity. By a simple benzoylation 3i was then
transformed to compound 6, which was the key intermediate
for the synthesis of pyrrolidine 7 possessing monoamineꢀ
reuptakeꢀblocking activity.18 Furthermore, starting from glyꢀ
cine derived aldimine ester 8 and crotyl carbonate 1s, an effiꢀ
cient asymmetric total synthesis of natural product (2S,3S)ꢀ2ꢀ
aminoꢀ3ꢀcyclopropylbutanoic acid19 was carried out. Under
the standard reaction conditions with Cu(I)/(S,Sp)ꢀL4 and
Ir(I)/(R,R,R)ꢀL5 as the catalysts combination, compound 9 was
isolated in 96% yield with 10:1 dr and 99% ee (without further
optimization). Pd(II)ꢀCatalyzed cyclopropanation of comꢀ
pound 9 with diazomethane provided compound 10 in quantiꢀ
tative yield and with maintained stereoselectivity. Hydrogenaꢀ
tion/debenzoylation of compound 10 under mild condition
delivered the target compound (2S,3S)ꢀ11 in 99% yield. It is
noteworthy that both compound 10 and 11 were separated
without column chromatography, and filtering the catalysts
followed by removing the solvents afforded the corresponding
products in high purity. Compared with previous 6ꢀ8 steps
synthetic protocols from the optically active starting materiꢀ
als,20 the current method shows its convenience and high effiꢀ
ciency.
1s
0.98 g, 10:1 dr, 99% ee
Pd(OAc)2 (0.5 mol%)
H2 (balloon)
H
H
CH2N2/Et2O, -5 o
99% yield
C
Pd/C, rt
BnO2C
N
CHAr
HO2C
NH2
99% yield
10
(2S,3S)-11
0.41 g, 10:1 dr
lit:20 6-8 steps
1.01 g, 10:1 dr, 99% ee
When testing the substrate scope, we realized one drawback
of the bimetallic dual catalysis is the complicated operation.
Unlike Carreria’s amine/Ir dual catalysis,11aꢀc the two distinct
metal/ligand complexes were usually prepared in separated
tubes to avoid the potential ligand scrambling and then merged
together, which obviously enlarged the manipulation complexꢀ
ity compared with traditional monoꢀtransitionꢀmetal catalysis.
The mechanistic studies on the Feringaꢀtype ligand L5 conꢀ
ducted by Hartwig15 revealed that the active catalytic species
of the chiral iridium complex was formed via an insertion of
the Ir center into the C(sp3)ꢀH bond in the methyl group of the
ligand with the aid of base. The preferential formation of the
cyclometalated iridium complex reminds us that the two deꢀ
sired Cu(I) and Ir(I) complexes could be readilyꢀformed
through directly mixing two metal sources and two chiral ligꢀ
ands in one pot. It is believed that the dynamic equilibrium of
coordination and dissociation of the mixtures of metal/ligand
complexes was broken by the event of C(sp3)ꢀH insertion unꢀ
der basic condition between iridium and phosphoramidite ligꢀ
and. With Ir/L5 complex formed completely, the coordination
of the remaining Cu(I) cation and chiral P,Nꢀligand would lead
to the desired copper complex.
Scheme 4. Formal Synthesis of Bioactive Pyrrolidine 7 and
Total Synthesis of Plant Growth Regulator 11 in 3 Steps
Table 5. Stereodivergent Synthesis of α,α-Disubstituted α-
AAs with Bimetallic Cu/Ir Catalysts Prepared in One-Pot
Protocola
entry
R
Ph
pꢀMeC6H4
2ꢀfuryl
2ꢀthienyl
Ph
R'
Me
Me
Me
Me
nꢀPr
3
yield (%)c ee (%)c
1
2
3
4
5
6
(2S,3R)ꢀ3a
(2S,3R)ꢀ3b
(2S,3S)ꢀ3l
(2S,3S)ꢀ3m
(2S,3R)ꢀ3u
75
88
72
65
78
75
99
>99
99
99
>99
98
Ph
cinnamyl (2S,3R)ꢀ3ab
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detti, E.; Gavuzzo, E.; Santini, A.; Kent, D. R.; Zhu, Y.ꢀF.; Zhu, Q.;
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Conditions see Table 1, entry
[Cu(I)/(S,Sp)ꢀL4 + Ir(I)/(R,R,R)ꢀL5].
8 except with catalyst combination
1
2
3
4
5
6
7
8
To verify this hypothesis, the bimetallic catalysts were preꢀ
pared from a mixture of Cu(MeCN)4BF4, [Ir(cod)Cl]2, (S,Sp)ꢀ
L4 and (R,R,R)ꢀL5 in one pot protocol (see Supporting Inforꢀ
mation for details) and then applied to the αꢀallylation of alꢀ
dimine esters to examine the catalytic efficiency. All the tested
substrates reacted smoothly, giving a set of (2S,3R)ꢀ or
(2S,3S)ꢀconfigured α,αꢀdisubstituted αꢀAAs with comparable
levels of yield and stereoselectivity (Table 5, entries 1ꢀ6). The
oneꢀpot protocol for the preparation of the bimetallic catalysts
clearly demonstrated that the practicability of the current dual
catalysis process. The 31P NMR and control experiments furꢀ
ther confirmed that the ligand scrambling was negligible in the
catalytic system (See Supporting Information for details).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSIONS
In summary, we have developed a stereodivergent synergisꢀ
tic Cu/Ir catalyzed αꢀallylation of aldimine esters. The method
enables the preparation of a series of nonproteinogenic αꢀAAs
bearing vicinal quaternary/tertiary or tertiary/tertiary stereoꢀ
genic centers with high yield and excellent stereoselectivity.
The pairwise combination of two chiral catalyst provide access
to all possible stereoisomers under identical conditions from
the same set of starting materials. Furthermore, the utility of
the method was proven in the construction of the key intermeꢀ
diate of a bioactive pyrrolidine derivative and the concise
asymmetric synthesis of a natural product (2S,3S)ꢀ2ꢀaminoꢀ3ꢀ
cyclopropylbutanoic acid.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all reacꢀ
tions and products, including H and 13C NMR spectra, HPLC
1
spectra, crystal data (3o). The Supporting Information is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
cjwang@whu.edu.cn
(10) (a) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3,
633. (b) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 1337. (c) Butt, N.
A.; Zhang, W. Chem. Soc. Rev. 2015, 44, 7929. (d) Inamdar, S. M.;
Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116.
(11) (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E.
M. Science 2013, 340, 1065. (b) Krautwald, S.; Sarlah, D.; Schafroth,
M. A.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020. (c)
Sandmeier, T.; Krautwald, S.; Zipfel, H. F.; Carreira, E. M. Angew.
Chem., Int. Ed. 2015, 54, 14363. (d) Nӕsborg, L.; Halskov, K. S.;
Tur, F.; Mønsted, S. M. N.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2015, 54, 10193. (e); Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am.
Chem. Soc. 2016, 138, 11093. (f) Cruz, F. A.; Dong, V. M. J. Am.
Chem. Soc. 2017, 139, 1029. (g) Jiang, X.; Beiger, J. J.; Hartwig, J. F.
J. Am. Chem. Soc. 2017, 139, 87.
(12) (a) Wei, L.; Xu, S.ꢀM.; Zhu, Q.; Che, C.; Wang, C.ꢀJ. Angew.
Chem. Inter. Ed., 2017, 56, 12312. (b) Xue, Z.ꢀY.; Li, Q.ꢀH.; Tao, H.ꢀ
Y.; Wang, C.ꢀJ. J. Am. Chem. Soc. 2011, 133, 11757. (c) Teng, H.ꢀL.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by NSFC (21372180, 21525207,
21772147), China Postdoctoral Science Foundation funded
project (2017M620331), and the Fundamental Research Funds for
the Central Universities. The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also
appreciated. The authors also thank the anonymous referees in the
first and second round review for valuable comments and suggesꢀ
tions.
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