A Highly Enantioselective Copper/Phosphoramidite-Thioether-Catalyzed Diastereodivergent 1,3-Dipolar Cycloaddition of Azomethine Ylides and Nitroalkenes

Article abstract of DOI:10.1002/chem.201705301

In contrast to the plethora of catalytic systems that enable access to any enantiomers of the chiral products by simply choosing between a pair of enantiomeric or pseudoenantiomeric chiral catalysts, few analogously effective protocols exist for the synth

Full text of DOI:10.1002/chem.201705301

A Journal of
Accepted Article
Title: Biologically Inspired Ligand Design for Asymmetric Dia-
stereodivergent 1,3-Dipolar Cycloaddition
Authors: Wen-Jing Xiao, Bin Feng, Jia-Rong Chen, Yun-Fang Yang,
and Bin Lu
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To be cited as: Chem. Eur. J. 10.1002/chem.201705301
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A Highly Enantioselective Copper/Phosphoramidite-Thioether-
Catalyzed Diastereodivergent 1,3-Dipolar Cycloaddition of
Azomethine Ylides and Nitroalkenes
Bin Feng,[a] Jia-Rong Chen,[a] Yun-Fang Yang,[b] Bin Lu,[a] and Wen-Jing Xiao*[a,c]
Abstract: In contrast to the plethora of catalytic systems that enable
a single type of metal or ligand-based catalytic strategy
represents an ideal approach for diastereodivergent
synthesis,[8,9] which eliminates the compatibility issue that always
needs to be considered in dual catalysis.[10] In biological system,
minor structural change of functional proteins and enzymes by
noncovalent interaction or covalent modification can result in a
distinct three-dimensional architecture, leading to modulation of
the timely intra- or extracellular events to proceed with precise
synergy (Figure 1a).[12] Inspired by this intriguing biological
process, we hypothesized that exploration of conformationally
flexible chiral ligands would allow to dictate the
diastereodivergency in asymmetric catalysis even when using a
single metal. Shibasaki and Kumagai in 2009 disclosed that
complexation of L-valine-derived amide with Sc(OiPr)3 or
Er(OiPr)3 resulted in two conformational distinct chiral catalysts
with different chiroptical properties, enabling diastereodivergent
direct asymmetric catalytic Mannich-type reactions of α-
cyanoketones and N-Boc imines.[8a,b] On the basis of this
pioneering work and our long standing interest in asymmetric
catalysis,[13] we conceived that our previously developed chiral
P,S-type ligands might enable diastereodivergent asymmetric
catalysis (Figure 1b). This ligand architecture exhibit a number
of features: (1) the coordination of P and S atoms with metal
might provide highly enantioselective chiral environment, and (2)
in analogy to the functional proteins and enzymes, modification
of the N substitution would result in a distinct conformation of the
catalyst.
access to any enantiomers of the chiral products by simply choosing
between
a pair of enantiomeric or pseudoenantiomeric chiral
catalysts, few analogously effective protocols exist for the synthesis
of compounds bearing multiple stereogenic centers with full control
of the absolute and relative stereochemical configurations. Here, we
report the application of our previously developed modular
phosphoramidite-thioether ligands for the copper-catalyzed
diastereodivergent asymmetric 1,3-dipolar cycloaddition of
azomethine ylides and nitroalkenes. Our catalytic system enables
wide substrate scope, great stereochemical control, and high
reaction efficiency.
Drug chirality is now a prominent theme in the drug discovery
and library design, as such fundamental property is of immense
significance to biological recognition in many pharmacologically
relevant events.[1] In particular, both the absolute and relative
configurations usually have distinct effects on the physiological
or pharmacological activities of
a given chiral bioactive
compound.[2] Over the past several decades, asymmetric
catalysis has proven to be a powerful and attractive tool to
produce enantioenriched molecules for its maximum efficiency.[3]
A variety of broadly useful reactions for the synthesis of chiral
compounds have been invented by ligand-controlled transition
metal catalysis and covalent or noncovalent activation-based
organocatalysis. Despite extensive efforts, however, developing
efficient catalytic systems that allow at will to access any
diastereomer of a chiral molecule with multiple stereogenic
centers remains a challenge. This is largely due to the fact that
the formation of certain diastereomers is usually inherently
favored when using conformationally rigid ligands or catalysts.[4]
In recent years, diastereodivergent asymmetric catalysis has
established its unwavering position in the synthesis of full
complement of diastereomers from the same set of starting
materials.[5] Representative methods include the ad hoc
adjustment of the reaction parameters (e.g., solvents, additives,
and temperature),[6] adapting organocatalysts,[7] metals,[8] or
ligands,[9] and two chiral catalysts-based dual catalysis.[10,11]
From the viewpoint of atom-economy and operational simplicity,
[a]
B. Feng, Prof. Dr. J.-R. Chen, B. Lu, Prof. Dr. W.-J. Xiao
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide
& Chemical Biology, Ministry of Education, College of Chemistry
Central China Normal University
Figure 1. (a) Functional diversification in functional proteins and enzymes and
(b) biologically inspired ligand design for the diastereodivergent asymmetric
catalysis.
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: chem-xiao.ccnu.edu.cn/
Dr. Y.-F. Yang
Catalytic asymmetric 1,3-dipolar cycloaddition reaction of
azomethine ylides with activated alkenes is an important type of
transformation for assembly of structurally diverse pyrrolidines
from conveniently prepared starting materials.[14] Despite the
significant advances in this field, however, the catalytic
asymmetric diastereodivergent variants are still rare. Recently,
[b]
[c]
[+]
Department of Chemistry and Biochemistry, University of California
Los Angeles, California 90095, United States
Prof. Dr. W.-J. Xiao
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, China
Supporting information for this article is available on the WWW under
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Figure 2. X-Ray crystal structures derived from the [Cu(CH3CN)2]BF4/1d and
[Cu(CH3CN)2]BF4/1f complexes. Counter sanion has been omitted for clarity.
Hou disclosed an elegant and creative strategy for the switch of
diastereoselectivity in the asymmetric Cu(I)/P,N-ferrocene-
catalyzed 1,3-dipolar cycloaddition by simply adjusting the
electronic properties of aryl substituent in the ligands.[9a] The
development of novel ligands showing highly efficient control of
diastereodivergency remains a great challenge. Herein, we
describe the application of our previously developed chiral P,S-
ligands bearing privileged (R)-BINOL-derived phosphoramidite
scaffold (Scheme 1),[15] to copper-catalyzed asymmetric
diastereodivergent 1,3-dipolar cycloaddition of azomethine
ylides and nitroalkenes. Notably, the modular structure of such
type of ligands facilitates their rapid synthesis, readily tuning,
and screening of a small library ligands.[16] Figure 2 shows the X-
ray crystal structures derived from [Cu(CH3CN)2]BF4/1d and
[Cu(CH3CN)2]BF4/1f with 1:1 or 1:2 ratios.[17] As expected, the P
and S atoms coordinate with Cu to form a chiral environment
that is essential for the enantioselective induction; and both
cyclohexyl and benzyl groups lie away from the copper atom,
which might serve as a potentially flexible handle.
With the phosphoramidite-thioether ligands 1a-i (Scheme 1),
we initially explored the ligand effect on the Lewis acid copper-
catalyzed 1,3-dipolar cycloaddition of azomethine ylide 4a and
nitroalkene 5a.[14] Representative results of the optimization
study are highlighted in Table 1, demonstrating that these
ligands showed high catalytic activity but with variable
stereoselectivity.[18] For example, the catalyst system consisting
of ligand 1a with Cu(CH3CN)4OTf in toluene at 0 oC could
efficiently catalyze the reaction in the presence of LiOAc as the
base; and the corresponding endo-6aa was formed as the major
product in excellent yield though with only 16% ee (entry 1). To
improve the enantioselectivity, we proceeded to modify the
substituents on the N atom and binaphthyl scaffold according to
our design plan. When introducing a cyclohexyl methyl group on
the N atom, incorporating the more sterically encumbered R
group resulted in higher enantioselectivity (entries 2-5). Finally,
ligand 1e was identified to be the best choice, and afforded
endo-6aa in 85% isolated yield with >19:1 dr and 94% ee, when
o
the reaction temperature was lowered to -5 C (entry 6). To our
delight, replacement of the cyclohexyl methyl group on N atom
with a benzyl group resulted in a complete diastereochemical
switch. For instance, the use of ligand 1f and (CuOTf)2•Tol as
the catalyst and catalytic amount of Et3N as the base in CHCl3
gave the exo-6aa as the major product with 88% ee (entry 7).
Though variation in the steric properties of the substituents on
the binaphthyl moiety did not result in any further improvement
of stereoselectivity (entries 8-9), H8-BINOL derived ligand 1i
gave rise to a significant increase of enantioselectivity (entry 10).
Further optimization study revealed that the exo-6aa could be
formed exclusively with 93% ee, when the reaction was
o
performed in a 5:1 mixture of CHCl3/toluene at 0 C (entry 11).
To prove the concept of our ligand design, we performed the
control experiments with ligands 2 and 3 without the binaphthyl
scaffold (entries 12-13). The moderate stereoselectivity
suggested that this privileged scaffold is critical to the chiral
induction.
Scheme 1. Modularly designed phosphoramidite-thioether ligands.
Table 1: Optimization of asymmetric diastereodivergent 1,3-dipolar
cycloaddition[a]
t
Entry
L
Cond.
Yield [%][b]
Endo/exo[c]
ee [%][d]
X-ray structure of [Cu]/1d
[h]
1
1a
1b
1c
1d
1e
1e
1f
A
A
A
A
A
A
A
B
B
B
B
A
3
3
3
3
6
14
3
3
3
3
3
3
77
10:1
8:1
16
24
82
82
86
94
88
37
51
92
93
20
2
96
3
99
>19:1
>19:1
>19:1
>19:1
1:10
4
93
5
6[e]
84
95(85)[f]
7
92
9
1g
1h
1i
90
1:1
9
85
1:1
10
11[g]
12
81
94(90)[f]
1:10
1i
<1:19
>19:1
X-ray structure of [Cu]/1f
2
92
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such as 5l, condition A still enabled excellent endo-selectivity
and enantioselectivity in cycloadduct product 6al, while
moderate diastereoselectivity was observed in the formation of
the exo-6al. These results indicate that the heteroaromatic and
aromatic rings of the nitroolefins might be beneficial for the
control of diastereoselectivity switch. Remarkably, our
diastereodivergent asymmetric catalyst systems also proved to
be suitable for the sterically hindered trisubsituted nitroalkenes,
such as 5m with a methyl group at the α-position, affording
products endo- and exo-6fm bearing a chiral quaternary carbon
center at 4-position with high enantioselectivity. To the best of
our knowledge, there is no precedent about the
diastereoselective synthesis of these challenging pyrrolidines.
13
3
B
3
95
1:1
17
[a] Condition A: 4a (0.3 mmol), 5a (0.2 mmol), Cu(CH3CN)4OTf (5 mmol %)
and ligand (5 mmol %) in mesitylene (2.0 mL) at 0 oC. Condition B: 4a (0.4
mmol), 5a (0.2 mmol), (CuOTf)2·Tol (2.5 mmol %) and ligand (5 mmol %) in
CHCl3 (2.0 mL) at r.t.. [b] Determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as an internal standard. [c] Determined by 1H NMR
analysis of the crude reaction mixtures. [d] The ee values of the major
diastereomers were determined by chiral HPLC analysis. [e] Performed at -5
oC. [f] Isolated yield in parentheses. [g] Performed in CHCl3/toluene (5:1, 2.0
mL) at 0 oC.
Table 2: Scope of the nitroalkenes.[a, b]
O2N
Ph
R
cond. A
Cu(CH3CN)4OTf (5 mol%)
1e (5 mol %), LiOAc (15 mol%)
mesitylene, -5 oC, 12-36 h
Ph
N
CO2Me
NO2
CO2Me
CO2Me
N
4a
H
endo-6
+
cond. B
(CuOTf)2•Tol (2.5 mol%)
O2N
Ph
R
R
5
Table 3: Scope of the azomethine ylides.[a, b]
1i (
5 mol%), Et3N (15 mol%)
N
H
O2N
R
Ph
CO2Me
CHCl3/toluene, 0 oC, 12-24 h
cond. A
exo-6
Cu(CH3CN)4OTf (5 mol%)
1e (5 mol %), LiOAc (15 mol%)
mesitylene, -5 oC, 12-36 h
R
N
CO2Me
NO2
N
4
H
endo-6
+
Cl
cond. B
(CuOTf)2•Tol (2.5 mol%)
O2N
R
Ph
cond. A: endo-6aa
cond. A: endo-6ab
cond. A: endo-6ac
94%, >19:1dr, 90% ee
cond. B: exo-6ac
Ph
85%, >19:1dr, 94% ee 97%, >19:1dr, 91% ee
cond. B: exo-6aa cond. B: exo-6ab
90%, >19:1 dr, 93% ee 93%, >19:1 dr, 91% ee
5a
1i (5 mol%), Et3N (15 mol%)
CHCl3/toluene, 0 oC, 12-24 h
CO2Me
N
H
92%, >19:1 dr, 94% ee
exo-6
OMe
Br
cond. A: endo-6ad
85%, >19:1dr, 90% ee
cond. B: exo-6ad
cond. A: endo-6ae
91%, >19:1dr, 90% ee
cond. B: exo-6ae
cond. A: endo-6af
92%, >19:1dr, 90% ee
cond. B: exo-6af
MeO
cond. A: endo-6aa
80%, >19:1dr, 93% ee
cond. B: exo-6aa
cond. A: endo-6ba
70%, >19:1dr, 90% ee
cond. B: exo-6ba
cond. A: endo-6ca
77%, >19:1 dr, 85% eec
cond. B: exo-6ca
85%, >19:1 dr, 92% ee
95%, >19:1 dr, 97% ee
81%, >19:1 dr, 90% ee
90%, >19:1 dr, 93% ee
91%, >19:1 dr, 94% ee
97%, >19:1 dr, 94% ee
Cl
Cl
Cl
cond. A: endo-6ag
cond. A: endo-6ah
cond. A: endo-6ai
90%, >19:1dr, 94% ee
cond. B: exo-6ai
F3C
Cl
Br
88%, >19:1dr, 88% ee 85%, >19:1dr, 94% ee
cond. B: exo-6ag cond. B: exo-6ah
92%, >19:1 dr, 98% ee 93%, >19:1 dr, 93% ee
cond. A: endo-6da
cond. A: endo-6ea
cond. A: endo-6fa
90%, >19:1dr, 91% ee
cond. B: exo-6fa
98%, >19:1 dr, 95% ee
84%, >19:1dr, 93% ee
cond. B: exo-6da
85%, >19:1 dr, 94% ee
84%, >19:1dr, 92% ee
(1.58 g, 97%, >19:1 dr, 90% ee)
cond. B: exo-6ea
94%, >19:1 dr, 93% ee
94%, >19:1 dr, 94% ee
O
S
(1.52 g, 95%, >19:1 dr, 94% ee)
cond. A: endo-6aj
83%, >19:1dr, 94% ee
cond. B: exo-6aj
cond. A: endo-6ak
71%, >19:1 dr, 91% ee
cond. B: exo-6ak
Cl
Br
cond. A: endo-6al
79%, >19:1 dr, 91% ee
cond. B: exo-6al
F
94%, >19:1 dr, 94% ee
74%, >19:1 dr, 93% ee
cond. A: endo-6ga
89%, >19:1 dr, 92% ee
cond. B: exo-6ga
93%, >19:1 dr, 95% ee
74%, 6:1 dr, 95% ee
cond. A: endo-6ha
98%, >19:1 dr, 93% ee
cond. B: exo-6ha
cond. A: endo-6ia
99%, >19:1 dr, 92% ee
cond. B: exo-6ia
O2N
O2N
R
Ph
Ph
CO2Me
94%, >19:1 dr, 98% ee
94%, >19:1 dr, 98% ee
R =
R
CO2Me
Cl
N
N
F3C
H
H
cond. A: endo-6fmc
cond. B: exo-6fm
F
Cl
98%, >19:1 dr, 95% ee
90%, >19:1 dr, 84% ee
cond. A: endo-6ja
90%, >19:1 dr, 90% ee
cond. B: exo-6ja
cond. A: endo-6ka
92%, >19:1 dr, 90% ee
cond. B: exo-6ka
97%, >19:1 dr, 97% ee
cond. A: endo-6la
96%, 12:1 dr, 88% ee
cond. B: exo-6la
[a] Reaction conditions A are the same as in entry 6 of Table 1. Reaction
conditions B are the same as in entry 11 of Table 1. [b] Isolated yields. The dr
values were determined by 1H NMR analysis of the crude reaction mixtures.
The ee values were determined by chiral HPLC analysis. [c] CsOAc (15 mol%)
was used as the base instead of LiOAc.
86%, 4:1 dr, 91% ee
97%, >19:1 dr, 94% ee
S
With the two sets of optimal conditions established, we first
explored the substrate scope of nitroolefins by reacting with
imino ester 4a (Table 2). In addition to 5a, a range of differently
substituted nitroolefins 5b-h bearing an electron-donating (e.g.,
Me, OMe) and electron-withdrawing (e.g., Cl, Br) substituent at
the ortho-, meta- and para-positions were all well tolerated. The
corresponding products endo-6ab-ah and exo-6ab-ah were
obtained exclusively in generally high yields with excellent
diastereoselectivity (>19:1) and enantioselectivity (88-98% ee).
Moreover, as demonstrated in the synthesis of 6ai, the steric
property or substitution pattern of the phenyl ring has no obvious
effect on the reaction efficiency or stereoselectivity. The reaction
of heteroaryl-substituted (e.g., 2-furyl and 2-thiophenyl)
nitroolefins 5j and 5k also proceeded smoothly, leading to the
diastereodivergent synthesis of 6aj and 6ak in good yields with
91-94% ee values. In the case of β-alkyl-substituted nitroolefins,
cond. A: endo-6na[d]
83%, >19:1dr, 94% ee
cond. B: exo-6na
NR
cond. A: endo-6ma
75%, >19:1 dr, 56% ee[c]
cond. B: exo-6ma
68%, >19:1 dr, 98% ee
[a] Reaction conditions A are the same as in entry 6 of Table 1. Reaction
conditions B are the same as in entry 11 of Table 1. [b] Isolated yields. The dr
values were determined by 1H NMR analysis of the crude reaction mixtures.
The ee values were determined by chiral HPLC analysis. [c] Performed with
KOAc (15 mol%) as the base. [d] CsOAc (15 mol%) was used as the base
instead of LiOAc. NR = No Reaction.
Then, we proceeded to examine the substrate generality of
the diastereodivergent 1,3-dipolar cycloaddition regarding the
azomethine ylides (Table 3). As expected, either the substitution
patterns or the electronic characteristics of the phenyl ring within
azomethine ylides show no apparent effect on the reaction
efficiency and stereoselectivity. For instance, a range of mono-
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substituted azomethine ylides 4b-g with electron-donating (e.g.,
Me, MeO) and electron-withdrawing (e.g., Cl, Br, CF3, F) groups
at the para-position of the benzene ring all reacted with
nitroolefin 5a nicely, furnishing the cycloaddition adducts endo-
and exo-6ba-ga in consistently high yields with excellent
enantioselectivities (85-95% ee). Notably, synthetically useful
halogen groups such as Cl, Br and F, could also be incorporated
into the meta- and ortho-positions of the phenyl ring. The
corresponding products endo-6ha-ja and exo-6ha-ia can be
obtained in satisfactory yields and high dr and ee values. In the
case of exo-6ja, the moderate exo-selectivity was probably due
to the steric hindrance in their transition states. Again, the
reactions with imino ester 4k bearing multiple chlorides on the
phenyl ring proceeded smoothly to give both of the endo- and
exo-6ka with excellent yields and stereoselectivity. Moreover,
the fused aromatic group substituted substrate 4l also reacted
well with 5a to produce both of the endo- and exo-6la in good
yield with 88% and 94% ee, respectively. However, 2-thiophene-
substituted imino ester 4m proved to be only suitable as 1,3-
dipole for the exo-selective reaction. And the aliphatic imino
ester 4n only readily participated in the endo-selective reaction
to give endo-6na with excellent ee values. To demonstrate the
synthetic applicability of our catalytic systems, we performed a
gram-scale reaction between imino ester 4e and 5a under the
standard conditions. Pleasingly, the reactions still proceeded
smoothly with almost no influence on the yields and
stereoselectivity (90-94% ee), indicating that this catalytic
system should be potential for large-scale chemical production
of densely tetrasubstituted pyrrolidines.[18]
With this hypothesis in mind, we also synthesized ligands 7
and 8 bearing 3-phenemyl and 3-hydrocinnamyl at the N-atom
respectively to confirm the importance of the N-benzyl unit within
ligand 1i. With 1i as the reference ligand, we examined the
catalytic ability of these structurally analogous ligands 7 and 8 in
the model reaction (Scheme 2). In contrast to 1i, while still
moderate to good enantioselectivities were obtained in the
reactions using ligands 7 and 8, the exo-selectivity decreased
significantly from >19:1 (exo-/endo-) to 3:1 and 1.5:1,
respectively under the identical conditions. These results clearly
demonstrate that the presence of a phenyl ring and its
appropriate position is critical to the complete switch of the
diastereoselectivity, namely from the endo- to exo-selectivity, as
well as enantioselective induction. Specifically, there might be a
π-π interaction of the N-benzyl with the aromatic ring of
azomethine ylide. Moreover, the formation of exo-products
should proceed through a stepwise pathway based on the fact
that we could also successfully isolate the conjugate addition
intermediate of exo-6ag in good yields with excellent
stereoselectivity when performing the reaction at -30 oC.[18]
The absolute configurations of enantiomerically pure endo-
6ea and exo-6ea were clearly determined to be (2R, 3S, 4R, 5R)
and (2R, 3R, 4S, 5R), respectively, by X-ray crystallography
(Figure 3).17 Stereochemistry of the other cycloaddition products
was assigned based on analogy to these compounds. Notably,
the same absolute configuration (2R, 5R) at the C-2 and C-5
positions of 6ea suggests that a preferred attack from the same
face of Cu(I)-bound imino ester to the nitroalkene occurs in both
cases of the ligands 1e and 1i. It means that both of the chiral
ligands shield the same prochiral faces of the azomethine ylide-
derived copper complexes. Thus, the diastereoselectivity switch
might originate from the different interactions between the
catalyst and nitroalkene.
Scheme 2. Control experiments.
Then, we carried out the study of nonlinear effect to gain
more insight into the mode of catalyst activation. We prepared
ligand 1i in six different levels of enantiopurity and evaluated
their catalytic activity in the reaction of azomethine ylide 9 and
nitroalkene 5a (Scheme 3). It was found that the enantiopurity of
the exclusively formed product exo-10 displays
a linear
relationship with that of the chiral ligand 1i, suggesting that the
active catalyst species for the reaction was consistent with a 1:1
ratio of the Cu(I) catalyst and ligand.[18]
Ph
N
CO2tBu
Cond. B
(CuOTf)2•Tol (2.5 mol%)
O2N
Ph
Ph
CO2tBu
exo-10
9
+
1i (5 mol%), Et3N (15 mol%)
NO2
N
Ph
CHCl3/toluene, r.t.
H
5a
Figure 3. X-Ray crystal structures of endo-6ea and exo-6ea.
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Scheme 3. Study of the nonlinear relationship between the optical activity of
ligand 1i and products.
Dong, Y.-C. Chen, J. Am. Chem. Soc. 2012, 134, 19942-19947; d) C.
Verrier, P. Melchiorre, Chem. Sci. 2015, 6, 4242-4246; e) G. Zhan, M.-L.
Shi, Q. He, W.-J. Lin, Q. Ouyang, W. Du, Y.-C. Chen, Angew. Chem.
Int. Ed. 2016, 55, 2147-2151; Angew. Chem. 2016, 128, 2187-2191.
a) A. Nojiri, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
3779-3784; b) G. Lu, T. Yoshino, H. Morimoto, S. Matsunaga, M.
Shibasaki, Angew. Chem. Int. Ed. 2011, 50, 4382-4385; Angew. Chem.,
2011, 123, 4474-4477; c) J. Lv, L. Zhang, S. Luo, J.-P. Cheng, Angew.
Chem. Int. Ed. 2013, 52, 9786-9790; Angew. Chem., 2013, 125, 9968-
9972.
In summary, we have described the application of our
previously developed modular phosphoramidite-thioether ligands
for highly enantioselective Cu(I)-catalyzed diastereodivergent
1,3-dipolar cycloaddition of azomethine ylides and nitroalkenes.
Both of the densely functionalized endo- and exo-pyrrolidines
can be obtained at will in good yields with excellent diastereo-
and enantioselectivity. Mechanistic investigation suggests that
the key to successful modulating the enforced sense of
diastereoselectivity was presumably due to the tuning of the
conformation and chiral environment of the catalyst by minor
ligand modification. Ongoing efforts are directed toward the
substrate scope of asymmetric diastereoselective 1,3-dipolar
cycloaddition induced by these P,S-ligands, and elucidating the
basis of the subtle ligand structural properties that control the
diastereoswitching.
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We are grateful to the NNSFC (No. 21472058, 21472057,
21622201 and 21232003), the Distinguished Youth Foundation
of Hubei Province (No. 2016CFA050), and CCNU (No.
CCNU16JCZX02 and CCNU17TS0011) for support of this
research. The support from the Program of Introducing Talents
of Discipline to Universities of China (111 Program, B17019) is
also appreciated. We also thank Prof. Dr. Fang−Fang Pan in
CCNU for the single-crystal X-ray diffraction analysis.
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Keywords: diastereodivergent catalysis • phosphoramidite-
thioether ligand • 1,3-dipolar cycloaddition • enantioselectivity
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[17] CCDC 1558965 ([Cu(CH3CN)2]BF4/1d), 1584930 ([Cu(CH3CN)2]BF4/1f),
1558993 (endo-6ea) and 1558982 (exo-6ea) contain the supplementary
crystallographic data.
[18] Please see the Supporting Information for more details.
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Entry for the Table of Contents (Please choose one layout)
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Heterocycles
Bin Feng, Jia-Rong Chen, Yun-Fang
Yang, Bin Lu, and Wen-Jing Xiao*
Page No. – Page No.
A Highly Enantioselective
Copper/Phosphoramidite-Thioether-
Catalyzed Diastereodivergent 1,3-
Dipolar Cycloaddition of Azomethine
Ylides and Nitroalkenes
In contrast to the plethora of catalytic systems that enable access to any
enantiomers of the chiral products by simply choosing between a pair of
enantiomeric or pseudoenantiomeric chiral catalysts, few analogously
effective protocols exist for the synthesis of compounds bearing multiple
stereogenic centers with full control of the absolute and relative
stereochemical configurations. Here, we report the application of our
previously developed modular phosphoramidite-thioether ligands for the
copper-catalyzed diastereodivergent asymmetric 1,3-dipolar cycloaddition of
azomethine ylides and nitroalkenes. Our catalytic system enables wide
substrate scope, great stereochemical control, and high reaction efficiency.
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