Inverse-Electron-Demand Palladium-Catalyzed Asymmetric [4+2] Cycloadditions Enabled by Chiral P,S-Ligand and Hydrogen Bonding

Article abstract of DOI:10.1002/anie.201905993

Catalytic asymmetric cycloadditions of ambident Pd-containing dipolar species with nucleophilic dipolarophiles, namely, inverse-electron-demand cycloadditions, are challenging and underdeveloped. Possibly, the inherent linear selectivity of Pd-catalyzed intermolecular allylations and the lack of efficient chiral ligands are responsible for this limitation. Herein, two cycloadditions of such intermediates with deconjugated butenolides and azlactones were accomplished by using a novel chiral hybrid P,S-ligand and hydrogen bonding. By doing so, highly functionalized, optically active dihydroquinol-2-ones were produced with generally high reaction efficiencies and selectivities. Preliminary DFT calculations were performed to explain the high enantio- and diastereoselectivities.

Full text of DOI:10.1002/anie.201905993

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Inverse Electron-Demand, Pd-Catalyzed Asymmetric [4+2] Cyclo-
additions Enabled by Chiral P,S-Ligand and Hydrogen Bonding
Authors: Wen-Jing Xiao, Ya-Ni Wang, Qin Xiong, Liang-Qiu Lu, Qun-
Liang Zhang, Ying Wang, and Yu Lan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905993
Angew. Chem. 10.1002/ange.201905993
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10.1002/anie.201905993
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Inverse Electron-Demand, Pd-Catalyzed Asymmetric [4+2] Cyclo-
additions Enabled by Chiral P,S-Ligand and Hydrogen Bonding
Ya-Ni Wang,[a] Qin Xiong,[b] Liang-Qiu Lu,*,[a] Qun-Liang Zhang,[a] Ying Wang,[a] Yu Lan*,[b] and Wen-Jing
Xiao*,[a,c]
Abstract: Catalytic asymmetric cycloadditions of ambident Pd-
containing dipolar species with nucleophilic dipolarophiles, namely,
inverse electron-demand cycloadditions, are challenging and under-
developed. Possibly, the inherent linear selectivity of Pd-catalyzed
intermolecular allylations and the lack of efficient chiral ligands are
responsible for this limitation. Herein, two cycloadditions of such
intermediates with deconjugated butenolides and azlactones were
firstly accomplished by using a novel chiral hybrid P,S-ligand and H-
bonding direction. By doing so, highly functionalized, optically active
dihydroquinol-2-ones were produced with generally high reaction
efficiency and selectivity (35 examples, 54->99% yields with up to
95% ee and >95:5 dr). Preliminary DFT calculations were performed
to explain the high enantio- and diastereoselectivities.
highly desirable (Scheme 1a, right).
In our efforts towards transition metal-catalyzed dipolar
cycloaddition,[9,11] we have developed a kind of chiral hybrid P,S-
ligands[9b,d][10] for the asymmetric [4+2] cycloaddition of vinyl
carbamates with electrophilic dipolarophiles (EDs), namely,
normal electron-demand cycloadditions (Scheme 1b).[12] In this
work, we further exploited the potential of these ligands in the
Pd-catalyzed asymmetric [4+2] cycloaddition of vinyl carbamates
and
a nucleophilic dipolarophile (NuD), namely, inverse
electron-demand cycloadditions (Scheme 1c).[13] As depicted in
Scheme 1d, we envisioned that, the chiral Pd(0) catalyst formed
from a Pd(0) precursor and a chiral P,S-ligand would undergo an
oxidative addition to the vinyl carbamate substrate 1. The
resulting Pd-containing 1,4-dipolar species A would react with
deconjugated butenolide substrate 2 through an asymmetric
The development of efficient methods to elaborate naturally
ubiquitous structural units is an important task in modern
synthetic chemistry due to its biological and pharmaceutical
significance.[1] In this context, butenolides have received
increasing research interest from the synthetic community
because of the popularity of buteolides and their derivatives in
bioactive molecules.[2] In the past decade, many protocols,
particularly the catalytic asymmetric protocols, have been
exploited for modifying deconjugated butenolides.[3-6] Among
them, asymmetric organocatalysis (AOC) stood out as the most
reliable strategy (Scheme 1a, left), being widely used for
enantioselective vinylogous Michael additions[3] and allylic
substitutions.[4] Notably, most of these impressive investigations
were performed to introduce a molecular fragment at the γ-
position of butenolides. Recently, however,
a significant
breakthrough was achieved independently by the group of
Johnson and a cooperation between Zhou and Lan, who applied
cinchona alkaloids or their derivatives to realize the α-addition of
deconjugated butenolides to β-halo-α-ketoesters[6a] and ortho-
quinone methides,[6b] respectively. In contrast, though transition
metal catalysis is a powerful tool in forging chemical bonds,[7] the
strategy has received much limited attention in the field of
butenolide modification. To our knowledge, only one racemic
example of Pd-catalyzed γ-arylations was reported in 2009.[8]
Thus, the exploitation of asymmetric transition metal catalysis
(ATMC) to achieve different and interesting chemistry is still
Scheme 1. Reaction development of Pd-containing dipoles with butenolides.
allylic substitution and intermediate C would be delivered in a
regio- and stereo-controlled manner, together with the
regeneration of the chiral Pd(0) catalyst. In this step, inspired by
research on AOC where the hydrogen bonding between Lewis
base catalysts and substrates was responsible for the unusual
α-selectivity,[6] we plan to use the similar non-bonding interaction
between the Pd-containing dipoles and enolates (see B in
Scheme 1d) to control both the branched selectivity of allylic
substitution[14] and the α-selectivity of the deconjugated
butenolide. Finally, significant dihydroquinol-2-one products 3
would be obtained after the subsequent intramolecular
aminolysis process.[15]
[a]
Y.-N. Wang, Prof. L.-Q. Lu, Q.-L. Zhang, Y. Wang, Prof. W.-J. Xiao
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide
& Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, 152 Luoyu Road, Wuhan, Hubei
430079, China
E-mail: luliangqiu@mail.ccnu.edu.cn; wxiao@mail.ccnu.edu.cn
Q. Xiong, Prof. Y. Lan
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001, China
[b]
[c]
Email: lanyu@cqu.edu.cn
Prof. W.-J. Xiao
Key Lab of Functional Molecular Engineering of Guangdong
Province, South China University of Technology, Guangdong
510006, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Given the importance of chiral ligands for the reaction
efficiency and enantioselectivity, this study began with the
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10.1002/anie.201905993
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evaluation of our chiral hybrid P,S-ligands for cycloaddition
between the vinyl carbamate 1a and deconjugated butenolides
2a.[16] Initially, the combination of Pd2(dba)3·CHCl3 and chiral
P,S-ligand L1 or L2, two catalyst systems that showed good
catalytic efficiency and high stereoinduction in our previous Pd-
catalyzed NEDC reactions,[9b,d] was chosen to check the
designed cycloaddition. To our delight, the desired products 3aa
were indeed afforded in good yields and with moderate
enantioselectivities (Table 1, entries 1 and 2). Encouraged by
these results, we modified the chiral P,S-ligand by replacing the
Bn group on the N-atom with a CyCH2 group (L3) and replacing
the (PhO)2P group with an R-BINOL-derived phosphanyl group
(L4). Both of these ligands provided a slight improvement in the
enantioselectivity (Table 1, entries 3 and 4). To further increase
the enantio-induction, steric groups such as Ph (L5) and β-Np
(L6) were introduced to the 3,3’-position of the BINOL scaffold,
which resulted in much higher ee values (Table 1, entries 5 and
6). Control experiments indicated that the chirality of the BINOL
backbone clearly affected the enantioselectivity of the reaction,
and the chiral diphenylethane unit was also necessary for the
entries 7-11). We are pleased that the reaction with ligand L6
performed at 0 °C can afford the chiral product 3aa with a further
improved enantioselectivity (Table 1, entry 12).[17]
With the optimal conditions in hand, we sought to probe the
scope of vinyl carbamates for this cycloaddition. As shown in
Table 2, the electronically varied substituents on the 6-position
of the benzene ring, such as H-, Br-, Cl-, Me- and MeO-, were
found to have no obvious influence on the enantioselectivity.
Structurally varied chiral dihydroquinol-2-ones were produced in
64-92 yields and with 88-93% ee (Table 2, entries 1-5). In
addition, varying the substitution pattern was proven feasible for
the present transformation. Vinyl carbamates that have a
substituent at the 7-position (i.e., CF3 and Cl) can participate
very well in cycloaddition, affording the corresponding products
in good results (Table 2, entry 6: 75% yield and 91% ee; entry 7:
97% yield and 92% ee). Moreover, the presence of ortho-
substituents on the vinyl group or the N-atom has varied
influence on the enantio-induction. The reaction performed with
substrates having electron-donating groups (1h and 1k) gave
slightly better enantioselectivity than the electron-deficient
good enantio-induction (See Table S1 in Supporting Information). reaction (1j), albeit all of them provided satisfactory results (71-
Meanwhile, other ligands that have been successfully applied in
Pd-catalyzed NEDC reactions,[9,12,13] such as chiral hybrid P,N-
ligand L7, chiral diphosphine ligand L8 and chiral monodentate
P-ligands L9-L11, were also examined for this cycloaddition. As
summarized in Table 1, compared to those obtained with the
above chiral P,S-ligands, no better yield and enantioselectivity
were observed under similar reaction conditions (Table 1,
99% yields and 87-94% ee). The steric effect of the substituent
at the 8-position (Table 2, entry 10: 71% yield and 87% ee)
seems to influence the enantioselectivity less than that at the 5-
position (Table 2, entry 9: 61% yield and 82% ee). In addition, n-
propenyl carbamate 1l can successfully participate in this
cycloaddition well, giving the desired product 3la in 70% yield
and 91% ee (Table 2, entry 12).[18]
Table 1. Condition optimization: the effect of chiral ligands on the Pd-catalyzed
IEDC reaction.[a]
Table 2. Scope of vinyl carbamates in the Pd-catalyzed asymmetric [4+2]
cycloaddition.[a]
Entry
1
L
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L6
Time/h
Yield/[%][b]
91
Ee/%[c]
35
47
56
69
82
85
-
Dr[c]
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
-
Entry
1
1 (R, R’)
3
Yield/[%][b]
Ee/[%][c]
93
8
8
1a: H, H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
92
68
65
86
64
75
97
91
61
71
99
70
2
85
2
1b: 6-Br, H
1c: 6-Cl, H
1d: 6-Me, H
1e: 6-MeO, H
1f: 7-CF3, H
1g: 7-Cl, H
1h: 7,8-2Me, H
1i: 5-F, H
91
3
8
70
92
3
4
8
87
88
4
5[d]
5
8
99
89
6
8
99
91
6
7
24
8
<5
92
7
8
58
48
21
-
87:13
>95:5
-
93
8
9
8
60
9
82
10
11
12[d]
24
24
20
N.R.
N.R.
92%
10
11
12
1j: 8-F, H
3ja
87
-
-
1k: 8-Me, H
1l: H, Me
3ka
3la
94
93
>95:5
91
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd2(dba)3·CHCl3 (5
mol%) and chiral ligand (12 mol%) in 2 mL of solvent at 30 °C for 5 h. [b]
Isolated yield. [c] Determined by chiral HPLC analysis. [d] 0 °C for 20 h then
warm to 30 °C . dba: dibenzylideneacetone, DCE: 1,2-dichloroethane.
[a-c] See entry 12 in Table 1; all dr are >95:5. [d] Ratio of 1e/2a = 2:1 (0.2
mmol scale).
Next, we examined the scope of deconjugated butenolides.
As revealed in Table 3, a range of γ-aryl substituted substrates 2
were suitable for this asymmetric [4+2] cycloaddition. The
electronic proprieties of the substituents have no obvious
influence on the enantiocontrol, generally providing high
enantioselectivities (Table 3, entries 1-5: 76-99% yields and 92-
95% ee). Additionally, the variation of substituent position on the
benzene ring did not affect the reaction efficiency and
enantioselectivity,
affording
the
corresponding
chiral
dihydroquinol-2-ones in 86-96% yields with 88-93% ee (Table 3,
entries 6-8). To our delight, the success of Pd-catalyzed
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10.1002/anie.201905993
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asymmetric [4+2] cycloadditions can be extended to
deconjugated butenolides with heteroaryl substituent and other
groups. For example, the reaction performed with 2-thiophenyl-
(2j) or benzyl-containing butenolide (2k) under the standard
conditions provided the desired products 3ja and 3ka with 92%
ee and 88% ee, respectively (Table 3, entries 9 and 10).
Deconjugated butenolides with additional substituents at α- and
β-positions proved to be tolerated, thus providing multi-
substituted dihydroquinol-2-one products in good results (Table
3, entries 11 and 12). Moreover,
a
convenient aldol
condensation of 3aa with benzaldehyde performed under basic
conditions can deliver a new dihydroquinol-2-one 7 in 89% yield
and with the same enantioselectivity (See Eq. S1 in Supporting
Information).
Scheme 2. Stereochemical analysis via DFT calculations.
Table 3. Scope of deconjugated butenolides in the Pd-catalysed asymmetric
[4+2] cycloaddition.[a]
azlactones, and 3-amido- and 4-vinyl- substituted dihydroquinol-
2-ones were produced in high yields with excellent
5
enantioselectivities (Table 4, entries1-6, 86->99% yields and 82-
92% ee). Note that the reaction of n-propenyl carbamate 1l with
azlactone 4a also proceeded well, affording the corresponding
product in 83% yield and with 88% ee (Table 4, entry 7).
Importantly, this protocol tolerates the azlactone partner well.
Variation of electronic characters and positions of substituents
on the benzene ring are compatible, achieving structurally
various products in 80-93% yields and 82-92% ee (Table 4,
entries 8-11).[18]
Entry
1
2 (R1, R2, R3)
3
Yield/[%][b]
Ee/[%][c]
93
2b: Ph, H, H
3ab
3ac
3ad
3ae
3af
92
88
94
99
76
96
86
86
94
79
83
54
2
2c: 4-Me-C6H4, H, H
2d: 4-F-C6H4, H, H
2e: 4-Br-C6H4, H, H
2f: 4-Ph-C6H4, H, H
2g: 2-Me-C6H4, H, H
2h: 3-Me-C6H4, H, H
2i: 2-Naphthyl, H, H
2j: 2-Thiophenyl, H, H
2k: Bn, H, H
92
3
93
4
95
5
93
6
3ag
3ag
3ai
92
Table 4. Representative results of Pd-catalysed asymmetric [4+2]
cycloaddition of azlactones with vinyl carbamates.[a]
7
93
8
88
9
3aj
92
10
11[d]
12
3ak
3al
88
2l: Me, Ac, H
86
2m: Me, H, Me
3am
73
[a-c] See entry 12 in Table 1; otherwise noted, dr are >95:5. [d] Performed at
30 oC; 93:7 dr. Ac, acetyl.
Entry
1[d]
2[d]
3
1 (R1, R2); 4 (R3)
5
Yield/[%][b]
Ee/[%][c]
92
1a: H, H; 4a: Ph
5aa
5ba
5da
5ga
5ha
5ka
5la
99
86
93
99
>99
96
83
93
93
88
80
To understand the origin of the high levels of enantio- and
diastereo-control obtained by using chiral P,S-ligand L6,
preliminary density functional theory (DFT) calculations were
carried out.[19] As shown in Scheme 2, we proposed four
possible diastereomeric transition states for the regio- and
stereoselectivity-determined step on the basis of different anti-
effects of P and S atoms, together with chiral transfer from the
chiral backbone to the sulfur center.[9b] In this key step, TS-Si-Si
is 2.6 kcal/mol lower in energy than TS-Re-Re, and also 3.7/3.4
kcal/mol lower than other two transition states. These calculated
results were in good accordance with the high enantio- and
diastereoselectivity observed experimentally. Analyzing the 3D
structure of transition state TS-Si-Si (See Figure S2 in
Supporting Information) shows that β-naphthyl group in chiral
P,S-ligand L6 seems to significantly influence the orientation of
hydrogen-bonding-bound enolate species, which might be
responsible for the high enantioselectivity.
Encouraged by the above success, we questioned the
possibility whether glycine-derived azlactones could be applied
as efficient nucleophilic dipolarophiles for this Pd-catalyzed
asymmetric IEDC reaction.[20] Indeed, we are delighted to find
that the same catalyst system and H-bonding direction strategy
are indeed efficient for this cycloaddition. As shown in Table 4,
vinyl carbamates 1 bearing substituents at C6-C8 positions were
accommodated in the Pd-catalyzed [4+2] cycloaddition with
1b: 6-Br, H; 4a: Ph
90
1d: 6-Me, H; 4a: Ph
1g: 7-Cl, H; 4a: Ph
82
4[e]
90
5
1h: 7,8-2Me, H; 4a: Ph
1k: 8-Me, H; 4a: Ph
1l: H, Me; 4a: Ph
88
6
7[e]
90
88
8
1a: H, H; 4b: 2-Me-C6H4
1a: H, H; 4c: 3-MeO-C6H4
1a: H, H; 4d: 4-Br-C6H4
1a: H, H; 4e: 4-MeO-C6H4
5ab
5ac
5ad
5ae
85
9[f]
10[d,g]
11
82
90
92
[a-c] See entry 12 in Table 1; performed at 30 oC; otherwise noted, dr
are >95:5. [d] 0 oC for 20 h, then warm to rt 30 oC. [e] 93:7 dr. [f] 81:19 dr. [g]
94:6 dr.
In conclusion, we have developed
a
Pd-catalyzed
asymmetric [4+2] cycloaddition of deconjugated butenolides with
vinyl carbamates. This unprecedented transformation provides a
new approach towards highly functionalized chiral dihydroquinol-
2-ones featuring high yields, high enantio- and diastereo-
selectivities. The keys of this success are attributed to the
application of a newly exploited chiral P,S-ligand and the
utilization of hydrogen bonding to control the regioselectivity.
Preliminary theoretical investigations through DFT calculations
were performed to illustrate the observed high level of enantio-
and diastereo-control. Furthermore, this catalyst system and H-
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10.1002/anie.201905993
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COMMUNICATION
bonding direction strategy can be successfully extended to the
Pd-catalyzed asymmetric [4+2] cycloaddition of azlactones with
vinyl carbamates.
Li, Y. Wei, J. Liu, H-W. Chen, L.-Q. Lu, W.-J. Xiao, J. Am. Chem. Soc.
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Acknowledgements
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We are grateful to the National Science Foundation of China (No.
21822103, 21820102003, 21822303, 21772052, 21772053,
21572074 and 21472057), the Program of Introducing Talents of
Discipline to Universities of China (111 Program, B17019), the
Natural Science Foundation of Hubei Province (2017AHB047),
the Open Fund of the Key Laboratory of Functional Molecular
Engineering of Guangdong Province (2016kf03) and the
International Joint Research Center for Intelligent Biosensing
Technology and Health for support of this research.
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Keywords: palladium catalysis • hydrogen bonding • chiral P,S
ligand • asymmetric cycloaddition • butenolide
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10.1002/anie.201905993
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
With the help of chiral P,S-ligands and
H-bonding interaction, two kinds of Pd-
catalyzed, inverse electron-demand
asymmetric [4+2] cycloadditions were
accomplished for the first time. A
variety of optically active, highly
functionalized hydroquinolin-2-ones
were produced in good yields with
excellent stereo-control.
Ya-Ni Wang, Qin Xiong, Liang-Qiu Lu,* Qun-
Liang Zhang, Ying Wang, Yu Lan* and Wen-
Jing Xiao*
Page No. – Page No.
Inverse Electron-Demand, Pd-Catalyzed
Asymmetric [4+2] Cycloadditions Enabled
by Chiral P,S-Ligand and Hydrogen
Bonding
This article is protected by copyright. All rights reserved.