Catalytic asymmetric synthesis of 2,5-dihydrofurans using synergistic bifunctional Ag catalysis

Article abstract of DOI:10.1039/c9ob01903k

We report a bifunctional Ag catalyst promoted intramolecular capture of oxonium ylides with alkynes for the enantioselective synthesis of 2,5-dihydrofurans. This represents unprecedented synergistic catalysis of a bifunctional Ag catalyst. Mechanistic studies revealed that [(R)-3,5-DM-BINAP](AgSbF₆)₂ (9) is likely to be the active catalytic species and that the reaction involves second order kinetics with respect to 9, suggesting that two molecules of 9 are involved in the intramolecular trapping of a Ag-associated oxonium ylide with a Ag-activated alkyne. Based on our mechanistic hypothesis, we further optimized the reaction, rendering a facile approach to 2,5-dihydrofurans in good to excellent yields in a highly chemo- and enantioselective fashion.

Full text of DOI:10.1039/c9ob01903k

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Biomol. Chem., 2019, DOI: 10.1039/C9OB01903K.
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DOI: 10.1039/C9OB01903K
ARTICLE
Catalytic Asymmetric Synthesis of 2,5-Dihydrofurans Using
Synergistic Bifunctional Ag Catalysis
Taoda Shi,a,b Shenghan Teng,a Alavala Gopi Krishna Reddy,d Xin Guo,c Yueteng Zhang,b Kohlson T.
Received 00th January 20xx,
Accepted 00th January 20xx
Moore,b Thomas Buckley,b Damian J. Mason,b Wei Wang,b Eli Chapman,b* and Wenhao Hud*
DOI: 10.1039/x0xx00000x
We report a bifuctional Ag catalyst promoted intramolecular capture of oxonium ylides with alkynes for the enantioselective
synthesis of 2,5-dihydrofurans. This represents unprecedented synergistic catalysis of a bifunctional Ag catalyst. Mechanistic
studies revealed that [(R)-3,5-DM-BINAP](AgSbF6)2 (9) is likely to be the active catalytic species and that the reaction involves
second order kinetics with respect to 9, suggesting that two molecules of 9 are involved in the intramolecular trapping of a
Ag-associated oxonium ylide with a Ag-activated alkyne. Based on our mechanistic hypothesis, we further optimized the
reaction, rendering a facile approach to 2,5-dihydrofurans in good to excellent yields in a highly chemo- and enantioselective
fashion.
enantiocontrol is generally challenging for Ag complexes
because the linear or trigonal coordination geometry places the
chiral ligand far from the substrate (Scheme 1A).15 Second, the
Introduction
In recent years, the development of Ag catalysis in organic
synthesis has been well documented.1-6 The superior
alkynophilicity due to π-coordination with the carbon-carbon
triple bond makes Ag salts one of the best activators of
alkynes.7-10 Despite success in asymmetric Ag catalysis,
successful examples of enantioselective Ag-carbenoid transfer
(ACT) are rare. The Jørgensen group reported a Ag/BINAP-
distance problem is exacerbated if the reaction goes through a
Lewis acid pathway where the chiral ligand and the stereogenic
center are further separated by two more nitrogen atoms
(Scheme 1B).12 Last, enantioselectivity can be deteriorated by a
free carbene pathway even if the ACT proceeds through the
carbene pathway (Scheme 1C). It is a formidable task for the Ag-
associated carbene to compete against the highly active free
carbene for efficient stereoselective control.16 A successful
strategy for a catalytic enantioselective ACT would have to
contend with the aforementioned challenges. We hypothesized
that two molecules of bifunctional chiral Ag complex could
potentially solve these problems, increasing reactivity and
enantioselectivity by coordinating the carbene and the alkyne
independently (Scheme 1D).
catalyzed
aziridination
of
iminoesters
with
trimethylsilyldiazomethane.11 The same group also disclosed a
Ag/BOX-catalyzed N-H insertion.12 The Davies group
documented Ag(I)/PHOX-catalyzed cyclopropenation of
internal alkynes and donor/acceptor carbenoids.13 The Nemoto
group recently realized a chiral silver phosphate-catalyzed
intramolecular de-aromatization of phenols with excellent
enatioselectivities.14 Motivated by the pioneering work of these
researchers, we sought to develop a highly enantioselective ACT
via synergistic catalysis of a bifunctional chiral Ag(I)/neutral
ligand complex.
We previously reported a Pd(II)-catalyzed auto-tandem formal
[4+1] cycloaddition reaction of aryl diazoacetates and
arylpropargyl alcohols to generate 2,5-dihydrofurans, in which
the generation of the oxonium ylide and activation of the alkyne
were both catalyzed by [PdCl(η3-C3H5)]2.17 We evaluated the
The challenges associated with achieving high enantioselectivity
in ACT can be attributed to several factors (Scheme 1A-C). First,
biological activities of 2,5-dihydrofurans and identified them as
19
protein tyrosine phosphatase (PTP) inhibitors.18,
This
observation sparked our interest in an asymmetric synthesis of
2,5-dihydrofurans, to determine the relationship between the
stereochemistry of 2,5-dihydrofurans and the inhibitory activity
against PTPs. In addition to our own biological interests, 2,5-
dihydrofurans are an important class of heterocycles that are
pharmacophores of FDA approved
a. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, School of Chemistry and Chemical Engineering, East China Normal
University, Shanghai, China, 200062.
b. College of Pharmacy, Department of Pharmacology and Toxicology, the University
of Arizona, Tucson, Arizona 85721.
c. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou,
Zhejiang Province, China, 325035.
d. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China,
510006.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
A) linear or trigonal coordination of silver complex makes enantiocontrol challenging
View Article Online
DOI: 10.1039/C9OB01903K
S: substrate
L: ligand
Ag
S
L
distant
B) Lewis acid pathway gives poor enantioselectivity
R2
R1
N2
R2
R1
AgLn
AgLn
Nu
N
N
Nu Poor enantioselectivity
R1
R2
-N2
distant
C) free carbene deteriorates enatiocontrol
R2
R2
R1
R2
R1
N2
AgLn
AgLn
Nu
Nu No enantioselectivity
R1
R2
-N2
R1
D) this work: bifunctional silver complex
H
R3
R2
R1
OH
R3
R2
R1
R2
R1
O
N2
AgLn
R3
AgLn
AgLn
R1
R2
AgLn
O
Scheme 1. Challenges for enantioselective control in ACT and the strategy envisioned in this work.
OH
Results and discussion
Bu
N
In an attempt to directly adapt our Pd(II)-catalyzed reaction, we
tested traditional chiral ligands of palladium catalysts, such as
oxazolines, diimines, or BINAP, but these attempts resulted in
minimal enantioselectivity (for details of substrate preparation
and condition screening see supporting Information, Schemes
S1-S3, and Table S1). Therefore, we decided to try other
transition metal catalysts. Cu(OTf)2, Cu(CH3CN)4PF6, AgOTf, and
AgSbF6 are all known to catalyze this reaction.18 We used Zhou’s
chiral spirol-based diphosphine, L1,30 as a standard ligand to
test each of these catalysts and found AgSbF6 afforded 2,5-
dihydrofuran 3a with 15% ee, while the other catalysts had
minimal catalytic activities (Table 1, entries 1-4).
CN
S
Bu
2
NC
NC
CH2OH
Me
O
O
CF3
HO
CF3-TCF-based NLO chromophore
Cryptoresinol
N
NH2
N
O
N
N
CO2H
HO2C
Me
O
HO2C
H
NH2
O
OH
OH
(+)-Furanomycin
Grisenolic acid
Figure 1. Molecules containing the 2,5-dihydrofuran motif.
drugs, core motifs in many natural products, and components
of materials.20 2,5-Dihydrofuran containing molecules include
the CF3-TCF based nonlinear optical (NLO) chromophore,21
cryptoresinol,22 (+)-furanomycin,23 and grisenolic acid24 (Figure
1). These compounds possess intriguing properties such as
electro-optical, antifungal, antibiotic, and anticancer activities.
Given the therapeutic potential of 2,5-dihydrofurans,
understanding the relationship between biological activity and
stereochemistry is of interest. However, facile asymmetric
syntheses of 2,5-dihydrofurans are not well developed.25
Enantioselective construction of quaternary stereocenters in
2,5-dihydrofurnans is quite challenging,26-28 with few
documented examples.29 Therefore, a new methodology for the
catalytic, enantioselective synthesis of this important class of
compounds would open new lines of pharmacological
investigation. Herein, we report an enantioselective synthesis
of 2,5-dihydrofurans with a quaternary center via Ag(I)-
catalyzed formal [4+1] cycloaddition of diazoacetates and
propargyl alcohols.
After discovering a functional catalyst, we turned our attention
to enhancing the enantioselectivity through optimization of the
chiral ligand. We explored oxazolines, diamines, amino alcohols,
and diphosphines. Oxazolines L2, L3, L4,31, 32 diamines L5, L6,33,
34
and amino alcohol L735 afforded [1,2]-proton shift or [2,3]-
sigmatropic rearrangement as the major products and showed
no enantiomeric enrichment (Table 1, entries 5-10). However,
BINAP L8 gave 3a as the major product with 54% ee. Further
screening with other chiral phosphorous ligands including
substituted BINAP derivatives L9, L10, L11, spirophosphines L12
and fluorophos L14, indicated 3,5-DM-BINAP L10 was the
optimal ligand, giving 3a as the major product with 76% ee
(Table 1, entries 11-16). The enantioselectivity could be further
improved to 78% by performing the reaction in the dark (Table
1, entry 17). The synergistic catalysis of the bifunctional Ag-
complex, in combination with the proper BINAP-derived ligand,
is likely to contribute to the observed chemo- and
enatioselectivity.36-38
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB01903K
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Table 1. Catalyst and chiral ligand screening for formal [4+1] cycloaddition of diazoacetates and propargyl alcohols
Ph
Ph
MeO2C
Ph
OH
Ph
CO2Me
Ph
Ph
N2
O
Ph
Chiral catalyst (10 mol%)
DCM, 4Å MS, 25°C
Ph
+
+
Ph
CO2Me
MeO2C
Ph
MeO2C
O
HO
HO
S
1a
2a
3a
4a
5a
6a
PPh2
CF3
NH2
NH2
O
O
O
N
O
O
PPh2
N
N
H
PPh2
N
N
N
N
N
H
CF3
N
Ph
tBu
tBu
Ph
Ph
L1
L2
L3
L4
L5
L6
O
F
O
O
L8 Ar= phenyl
F
PPh2
PPh2
Ph
PAr2
PAr2
L9 Ar= 4-methylphenyl
L10 Ar= 3,5-dimethylphenyl
L11 Ar= 3,5-dimethyl-t-butylphenyl
O
O
Ph
OH
N
H
F
PPh2 Ph2P
F
O
L7
L12
L13
Entry
1
M
L
M:L
1:1
2:1
2:1
2:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
con.b (%)
<5
3a:4a:5a:6ab
-
eec (%)
-
Cu(OTf)2
L1
2
Cu(CH3CN)4PF6
AgOTf
L1
<5
-
-
3
L1
30
40:28:22:10
44:24:21:11
17:44:17:12
25:42:23:10
30:12:47:11
32:52:12:4
22:34:34:10
25:45:14:15
57:12:16:15
62:13:13:12
65:10:15:10
49:21:18:12
46:22:21:11
37:23:24:16
68:12:10:10
10
15
0
4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
L1
>90
>90
>90
>90
45
5
L2
6
L3
0
7
L4
0
8
L5
0
9
L6
65
0
10
11
12
13
14
15
16
17d
L7
68
0
L8
>90
>90
>90
68
54
60
76
53
32
20
78
L9
L10
L11
L12
L13
L10
>90
>90
>90
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ARTICLE
aReaction conditions: 1a (0.15 mmol) in DCM (1.0 mL) was added to a solution of 2a (0.15 mmol, 1.0 equiv), 150 mg 4Å MS, M (0.01 mmol, 0.1 equiv) and L (0.01 or 0.005
mmol, 0.1 or 0.05 equiv) in 1.0 mL of DCM, at 25°C. bDetermined by 1H NMR of the reaction mixture. cDetermined by chiral HPLC analysis. dReaction was performed in
the dark.
We next investigated the substrate scope of the Ag(I)-catalyzed
asymmetric formal [4+1] cycloaddition of diazoacetates 1 and
propargyl alcohols 2 (Table 2 and Scheme S4). Aryldiazoesters
with halo substituents on the aromatic ring increased the
enantioselectivity (Table 2, 3b-c), while ones with electron-
donating substituents on the aromatic ring showed similar
enantioselectivities as those obtained in the case of the
phenyldiazoester (Table 2, 3d-h). Alkyldiazoacetates such as
ethyl methyldiazoacetate and ethyl benzyldiazoacetate were
tested as well, resulting in dimers of alkyldiazoacetates as the
major product (Table 2, 3i-j). The meta-halo diazo substrates
also gave higher enantioselectivity than phenyldiazoester
(Table 2, 3k-l). The enhancement of enantiocontrol of halogen-
bearing substrates was possibly due to the weak interactions
between halogen and Ag catalyst. The yields and
enantioselectivities dropped sharply in the cases of tert-butyl
aReaction conditions: 1 (0.2 mmol) in DCM (4 mL) was added to a solution of 2 (0.4
mmol, 2.0 equiv), 200 mg 4Å MS, AgbF6 (0.04 mmol, 0.2 equiv) and (R)-3,5-DM-
BINAP (0.02 mmol, 0.1equiv) in 2.0 mL of DCM at 25°C in the dark. bIsolated yield.
cDetermined by chiral HPLC analysis.
Then, methyl meta-chlorophenyldiazoacetate was used as a
standard substrate to explore the scope of aryl propargyl
alcohols. By testing the effect of halo groups and methoxy on
the aromatic ring of propargyl alcohols (Table 2, 3m-o), all
substitutions gave high ees (80-82%). But the methoxy group
was better than the bromo group in terms of yield. Notably, 3-
methyl propargyl alcohol was compatible in the reaction with
53% yield and 49% ee (Table 2, 3p). Interestingly, the
combination of para-bromophenyldiazoacetate and para-
methylphenylpropargyl alcohol could generate 3q in 62% yield
and 92% ee. Overall, with these initial conditions, the reaction
could produce 2,5-dihydrofurans with moderate yields and
good to excellent enantioselectivities.
In an effort to improve the yield and stereoselectivity of the
Ag(I)-catalyzed [4+1] cycloaddition, we sought to understand
the reaction mechanism. Although we postulated this reaction
proceeded via a formal cycloaddition, we could not rule out
another pathway. It was reasoned that the formation of 3a may
proceed through one of the other three reaction products: the
[1,2]-proton shift product 4a, the [2,3]-sigmatropic
rearrangement product 5a, or cyclopropene 6a. To test this
possibility, we isolated each of these products and subjected
them to the optimized conditions for the formation of 3a
(Scheme 2). In no case did we observe the formation of 3a,
ruling out 4a, 5a, or 6a as intermediates, and offering support
to our mechanistic hypothesis.
meta-chlorophenyldiazoacetate
and
benzyl
meta-
chlorophenyldiazoacetate, indicating the size of the ester group
has a direct effect on the reactivity and enantioselectivity of the
reaction (Table 2, 3l’ and 3l’’).
Table 2. Initial substrate scope of the Ag-catalyzed [4+1] cycloaddition reaction.a
R'
(R)-3,5-DM-BINAP (10 mol%)
N2
O
(AgSbF6
)2 (20 mol%)
CO2R
Ar
+
DCM, 4Å MS, 25 oC, dark
Ar
CO2R
HO
R'
1
2
3
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2R
Ph
Ph
Ph
Ph
Me
Br
Cl
3a,
3c
3d
3b
54%b, 78% eec
42%, 88% ee
36%, 76% ee
46%, 87% ee
O
O
O
O
CO2Me
CO2Me
Ph
CO2Me
CO2Me
CO2Me
OH
Ph
Ph
AgSbF6 (20 mol%)
(R)-3,5-DM-BINAP (10 mol%)
Ph
Ph
MeO
Ph
Ph
OMe
OMe
OBn
OBn
Ph
or
O
CO2Me
Ph
OMe
OMe
Ph
or
MeO2C
OMe
BnO
O
DCM, 4Å MS, 25°C, dark
3e
3f
3g
Ph
3a
3h
MeO2C
Ph
42%,71% ee
36%, 69% ee
50%, 79% ee
55%, 68% ee
HO
4a
5a
6a
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
Me
Bn
Ph
Scheme 2. Product 3a does not derive from by-products 4a, 5a or 6a.
Ph
Ph
Br
Cl
Ph
3i
3j
3k
3l
0%
0%
46%, 87% ee
47%, 91% ee
We next sought to characterize the structure of the reactive
catalytic species. The coordination model of AgOTf and BINAP is
known to be related to the ratio of AgOTf and ligand and the
counter-ion of the complex.39 However, the coordination model
of AgSbF6 and (R)-3,5-DM-BINAP has not been reported. To
explore the structure of the active catalytic species, we titrated
AgSbF6 into (R)-3,5-DM-BINAP and measured the proton
O
O
O
CO2Me
CO2Me
CO2R
R'
p-Me-C6H4
Cl
Ph
Cl
R' =
Br
m-Br-C6H4, 3m, 44%, 81% ee
p-Br-C6H4, 3n, 49%, 80% ee
p-MeO-C6H4, 3o, 62%, 82% ee
Me, 3p, 53%, 49% ee
R=
But, 3l', 31%, 55% ee
3q
64%, 92% ee
Bn, 3l'', 28%, 81% ee
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ARTICLE
nuclear magnetic resonance (1H NMR) spectra. At a AgSbF6:(R)- BINAP](AgSbF6)2 (9), and not [(R)-3,5-DM-BINAPV]i(eAwgASrtbicFle6O) n(li8ne)
1
DOI: 10.1039/C9OB01903K
3,5-DM-BINAP ratio of 2:1, the H NMR spectra no longer (Scheme 3).
changed (Supporting Information, Figure S1). In addition, we We next asked how many molecules of 9 are needed for each
monitored 31P NMR spectra while carrying out the same catalytic cycle. To answer this question, we performed the
titration. Matching the 1H NMR data, we observed reaction using 9 with varied ee values, resulting in a positive
disappearance of the sharp free phosphine peak at the same 2:1 nonlinear relationship between the ee values of product 3l and
ratio of catalyst to ligand (Supporting Information, Figure S2). 9 (Figure 2a and Scheme S5). The result implicates more than
High resolution mass spectrometry analysis of the 2:1 molar one molecule of 9 involved in the key transition state, since a
ratio complex of AgSbF6 and (R)-3,5-DM-BINAP showed the positive nonlinear effect is usually caused by enantioselectivity
predicted signal for {[(R)-3,5-DM-BINAP]Ag2}2+ (Supporting enrichment during the formation of a multimeric active catalytic
Information, Figure S3).
species or a synergistic catalytic system.40-45 When the
To confirm the functional significance of these data, we varied combination of 5 mol% Rh2(OAc)4 and 10 mol% 9 was used as
the ratio of ligand to catalyst and carried out the reaction. When catalyst, both chemoselectivity and enantioselectivity of 3l
the molar ratio of AgSbF6 and (R)-3,5-DM-BINAP was lower than were decreased (Scheme S6). This indicates that the formation
2:1, both chemoselectivity and enantioselectivity decreased of the Ag-carbenoid and the synergy between the two
(Table 3, entries 1-5), while only reduction of the loading of the molecules of 9 is critical to the stereoselective cyclization step
complex of AgSbF6 and (R)-3,5-DM-BINAP without changing the because the presence of Rh2(OAc)4 likely generates the more
2:1 molar ratio did not influence enantioselectivity (Table 3, reactive Rh-carbenoid and disrupts the synergy of the two
entry 1 vs entry 5). Taken together, these data indicate the molecules of 9. Then we questioned whether two molecules of
reactive catalytic species of this formal [4+1] cycloaddtion of 9 functioned on one molecule of substrate
diazoacetates and propargyl alcohols is [(R)-3,5-DM-
Table 3. The effect of loading and ratio of (R)-3,5-DM-BINAP and AgSbF6 on chemo- and enantioselectivity.a
Ar
Ph
Ph
CO2Me
Ph
CO2Me
Ar
AgSbF6 (x mol%),
(R)-3,5-DM-BINAP (y mol%)
O
Ph
Ar
OH
+
N2
+
+
+
Ar
DCM, 4Å MS, 25°C, dark
Ar = m-Cl-C6H4-
MeO2C
Ar
CO2Me
Ph
3l
HO
MeO2C
O
HO
1l
2a
4l
5l
6l
Entry
x
y
con.a (%)
>90
>90
>90
>90
3l:4l:5l:6lb
47:33:9:11
40:14:11:35
30:10:10:50
22:10:6:62
47:25:6:22
3l, eec (%)
1
2
3
4
5
20
16
14
10
10
10
10
10
10
5
91
82
85
85
91
>90
aReaction conditions: 1l (0.1 mmol) in DCM (1 mL) was added to a solution of 2a (0.1 mmol, 1.0 equiv), 100 mg 4Å MS, AgSbF6 (0.001x mmol, 0.01x equiv) and (R)-3,5-
DM-BINAP (0.001y mmol, 0.01y equiv) in 2.0 mL of DCM at 25°C in the dark. bDetermined by 1H NMR of the reaction mixture. cDetermined by chiral HPLC analysis
+
2+
Ar
P
Ar
P
Ar
Ar
Ag
Ar
Ag
-
-
2SbF6
SbF6
P
Ag
Ar
P
Ar
Ar
9
8
Ar = 3,5-dimethylphenyl
Scheme 3. Possible structures of the reactive catalyst.
Figure 2. Mechanistic investigations. (a) Positive nonlinear effect of 9. (b) Possible interaction models of substrate (S) and catalyst 9. (c) Second order kinetics of 9.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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remove protons from the reaction, which might cut the side
(Figure 2b, model 1) or 9 and its substrate form a polymeric products 4a and 5a and stabilize the transition state. The
chain with a 1:1 ratio (Figure 2b, model 2). To clarify this, the Brønsted base must fulfill two requirements: 1) it must be basic
kinetic profile of 9 was investigated. A linear relationship enough to deprotonate propargyl alcohol to prevent the
between the initial reaction rates and the square of the catalyst formation of side products; and 2) its coordination ability should
concentration was revealed, representing second order kinetics not be strong enough to poison 9. We also reasoned a di-base
of 9 (Figure 2c, Scheme S7, Figure S4, and Table S2). This could potentially function as a linker between two molecules of
indicated a second molecule of 9 must engage the substrate-9 9. With these requirements in mind, we screened a panel of
complex in the rate-limiting step, to generate one molecule of Brønsted bases as additives (Table 4). First, a series of disodium
product 3l. Hence, model 1 is likely to be the interaction fashion carboxylates with varied linkers were evaluated. The reaction
of catalyst 9 and its substrate.
proceeded smoothly but with no improvement in chemo- or
Taking all of these data together, we propose the mechanism enantioselectivity (Table 4, entry 1-5). Second, a series of
for the Ag(I)-catalyzed formal [4+1] cycloaddition of aryl inorganic bases Na2HPO4, Na2CO3, NaH, and LiH were tested,
diazoacetates and aryl propargyl alcohols shown in Scheme 4. resulting in no reaction due to the inhibition of 9 by their
Diazoacetate 1a is decomposed by 9, forming Ag-carbenoid A. counter-ions that strongly coordinated the Ag. Finally, divalent
The Ag-enolate B1, which is in equilibrium with Ag-associated metal bases including CaH2, ZnEt2, and MeMgBr were screened.
oxonium ylide B2, is formed in situ from A and propargyl alcohol CaH2 improved chemoselectivity by suppressing generation of
2a. B1 or B2 utilize another molecule of 9 in the alkyne 5a and slightly increased enantioselectivity from 78% to 81%
coordinating site, thus generating a synergistic bi-catalyst (Table 4, entry 10). Both ZnEt2 and MeMgBr poisoned 9 (Table
species C, which undergoes a 5-endo-dig cyclization to form the 4, entry 11-12). The chemoselectivity was further improved if 2
final product 3a through intermediate D. Side products 4a and equiv of 2a or 2 equiv of both 2a and CaH2 were used (Table 4,
5a can be formed from B1 or B2 via a [2,3]-sigmatropic entry 13-14). In short, by adding CaH2, the chemoselectivity of
rearrangement and a [1,2]-proton shift, respectively.46, 47 Side this reaction could be increased by 17%.
product 6a can be formed from A through cyclopropenation.
Next, we used these new conditions and revisited the substrate
Based on our mechanistic hypothesis, we reasoned we might scope. First, phenyl propargyl alcohol was set as the
further optimize the reaction by using a Brønsted base to
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Organic & Biomolecular Chemistry
Page 7 of 11
View Article Online
DOI: 10.1039/C9OB01903K
ARTICLE
N2
CO2Me
Ph
O
Ph
CO2Me
1a
Ph
3a
AgX
AgX
P
P
*
AgX
AgX
[(R)-3,5-DM-BINAP](AgSbF6)2 (9)
H
P
P
O
CO2Me
Ph
Ph
*
AgX
P
AgX
OH
Ph
CO2Me
P
Ph
A
cyclopro
D
CO2Me
Ph
2a
AgX
Ph OH
P
P
[2,3]-s-rearrang
penation
4a
*
5-endo-dig
cyclization
AgX
ement
AgX
Ph
MeO2C
P
Ph
OH
O
*
AgX
P
P
Ph
Ph
CO2Me
shift
1,2-H
*
6a
H
AgX
5a
P
O
CO2Me
Ph
Ph
AgX
Ph
O
AgX
P
H
AgX
MeO2C
AgX
B2
Ph
P
P
C
*
P
Ph
AgO
MeO
X
HO
AgX
AgX
P
B1
*
P
Ph
Scheme 4 Proposed mechanism of the [4+1] cycloaddition
Table 4. Additive screening for formal [4+1] cycloaddition of diazoacetates and propargyl alcohols.a
Ph
Ph
MeO2C
Ph
Ph
OH
Ph
9
(10 mol%)
CO2Me
Ph
O
N2
Additive (1.0 equiv)
Ph
Ph
Ph
3a
Na2HPO4
+
+
Ph
1a
CO2Me
DCM, 4Å MS, 25°C, dark
MeO2C
MeO2C
4a
O
HO
HO
6a
2a
5a
A10
n=1:A1
A6
CaH2
n=2:A2
n=3:A3
n=4:A4
O
O
A7
Na
Na2CO3
A8
A11
ZnEt2,
Na
n
O
NaH
A9
A12
MeMgBr,
O
LiH
n=5:A5
Entry
Additives
con.b (%)
3a:4a:5a:6ab
eec (%)
1
2
3
A1
A2
A3
>90
>90
>90
68:11:16:5
65:10:20:5
66:12:17:5
78
78
78
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Page 8 of 11
ARTICLE
Journal Name
4
5
A4
A5
>90
>90
<5
65:13:17:5
78 View Article Online
63:12:20:5
DOI: 107.18039/C9OB01903K
6
A6
-
-
-
7
A7
<5
-
8
A8
<5
-
-
9
A9
<5
-
-
10
11
12d
13e
14e,f
A10
A11
A12
A10
A10
>90
<5
75:10:10:5
81
-
-
<5
-
-
>90
>90
80:5:10:5
85:5:5:5
81
81
aReaction conditions: 1a (0.1 mmol) in DCM (1 mL) was added to a solution of 2a (0.1 mmol, 1 equiv), 200 mg 4Å MS, AgSbF6 (0.02 mmol, 0.2 equiv) and (R)-3,5-DM-
BINAP (0.01 mmol, 0.1 quiv) in 2 mL of DCM at 25°C in the dark. bDetermined by crude 1H NMR of the reaction mixture. cDetermined by chiral HPLC analysis. d1 equiv
f
AgSbF6 was added. e2 equiv 2a was used. 2 equiv A10 was used.
standard substrate to evaluate a panel of aryldiazoacetates CaH2 as an additive, the reaction gave higher yields and ees and
(Table 5). With the new conditions, 3a could be isolated in 71% had much broader substrate scope for diazoacetates and
yield (Table 5, 3a) and 81% ee. Halogens, electron-donating propargyl alcohols. The result supports the hypothesis that a
groups (EDG), and electron-withdrawing groups (EWG) at the suitable Brønsted base additive could suppress the formation of
para position are all compatible with these reaction conditions, side products and benefit enantioselectivities. We currently do
giving high yields (67-80%), with the exception of not have a precise model for the effects of CaH2 on the reaction.
trifluoromethyl group, which gave only 40% yield, and 67-87%
Table 5. Aryldiazoacetate scope of the Ag-catalyzed [4+1] cycloaddition reaction with
ee. (Table 5, 3b, 3c, 3d, 3e, 3r, and 3s). Notably, this is the first
optimized conditions.a
time EWG-containing diazoacetates show good reactivity in this
cycloaddition
reaction.18,19
The
m-halo-substituted
Ph
9 (10 mol%)
N2
O
CaH2 (2.0 equiv)
diazoacetates showed a significant increase in yield (73-75%
yield vs 46-47% yield for the previous conditions) with no
significant loss in enantio-induction (83-90% ee; Table 5, 3f and
3l). Diazoacetates with multiple chloro or methoxy substitutions
were evaluated as well. Both afforded comparably high yields,
but the 3,4-chloro-substituted diazoacetate had higher
enantioselectivity than the 3,4,5-methoxy-substituted
diazoacetate (Table 5, 3t and 3g).
CO2Me
Ar
+
DCM,4Å MS, 25oC, dark
Ar
CO2Me
HO
Ph
1
2a
3
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2R
Ph
Ph
Ph
Ph
Br
Cl
F
3a
3r
3b
3c
71%,b 81% eec
71%, 71% ee
80%, 87% ee
75%, 83% ee
O
O
O
O
CO2Me
CO2Me
Then p-I and m-Cl substituted diazo, which had excellent
enantio-induction were used as standard substrates to test a
series of aryl propargyl alcohols. Generally, these two
diazoacetates could offer comparable yields, but methyl para-
iodophenyldiazoacetate gave higher ee except 3ac and 3ai. p-
Br, p-CF3, p-CO2Me, p-Ph and m-Br substituted aryl propargyl
alcohols showed excellent ees (Table 6, 3xI, 3zI, 3aaI, 3agI, 3ahI)
with yields in the range of 58-80%. Their m-Cl counterparts had
76-86% ees and 43-77% yields (Table 6, 3xCl, 3zCl, 3aaCl, 3agCl,
3m). p-F, p-Cl, p-I, p-Me, m-Me, and 3,4-methyl-substituted
propargyl alcohols gave 61-75% yields and 85-88% ees (Table 6,
3vI, 3wI, 3yI, 3abI, 3aiI, 3afI). And their m-Cl analogues gave 59-
CO2Me
CO2Me
Ph
Ph
Cl
Ph
Ph
F
Cl
I
Cl
3t
3s
3f
3l
70%, 92% ee
75%, 83% ee
73%, 90% ee
78%, 88% ee
O
O
O
CO2Me
CO2Me
CO2Me
O
CO2Me
Ph
Ph
Ph
OMe
OMe
Ph
MeO
Me
OMe
CF3
40%, 76% ee
3d
3e
73%, 82% ee
3g
79%, 70% ee
3u
75%, 67% ee
aReaction conditions: 1 (0.2 mmol) in DCM (2 mL) was added to a solution of 2a
(0.4 mmol, 2 equiv), CaH2 (0.4 mmol, 2 equiv), 200 mg 4Å MS, AgSbF6 (0.04 mmol,
0.2 equiv) and (R)-3,5-DM-BINAP (0.02 mmol, 0.1 equiv) in 2 mL of DCM at 25°C in
the dark. bIsolated yield. cDetermined by chiral HPLC analysis.
76% yields and 78-85% ees (Table 6, 3vCl, 3wCl, 3yCl, 3abCl, 3aiCl
,
3afCl). p-Et, p-tert-Bu, and p-MeO substituted-phenyl propargyl
alcohols generated 2,5-dihydrofurans with 71-82% yields and
70-82% ees (Table 6, 3acI, 3adI, 3aeI), with their m-Cl parallels
giving 72-78% yields and 67-87% ees (Table 6, 3acCl, 3adCl, 3aeCl).
Interestingly, the heteroaromatic group, thiophene, is also
compatible with the reaction, furnishing 3aj with 40-80% yields
and 72-77% ees (Table 6, 3ajCl 3ajI). Generally speaking, with
,
8 | J. Name., 2012, 00, 1-3
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Page 9 of 11
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
and excellent enantioselectivities. Based on theViemweAcrthicalenOinsltinice
studies, basic additives were explored, and it was found CaH2 as
Table 6. Aryl propargyl alcohol scope of the Ag-catalyzed [4+1] cycloaddition reaction
with optimized conditions.a
DOI: 10.1039/C9OB01903K
an additive increased the chemo- and enantioselectivity.
Synthetic application showed product 3k could be readily
transformed to lactone 7k. The application of the synergistic
catalysis of a bifunctional Ag catalyst in other ACT or Ag-
nitrenoid transfer (ANT) is still ongoing in our lab.
R
9 (10 mol%)
O
N2
CO2Me
CaH2 (2.0 equiv)
+
DCM, 4Å MS, 25oC, dark
Ar
Ar
CO2Me
R
Ar = p-I-C6H4 1s
Ar = m-Cl-C6H41l
Ar = p-I-C6H4, 3I
HO
Ar = m-Cl-C6H4, 3Cl
2
O
O
O
O
CO2Me
Ar
CO2Me
CO2Me
Ar
CO2Me
Ar
Ar
Cl
Br
F
3l, 73%b, 90% eec
3s, 70%, 92% ee
3vCl, 64%, 80% ee
3vI, 68%, 88% ee
3wCl, 59%, 80% ee
3wI, 67%, 88% ee
3n, 64%, 79% ee
3xI, 72%, 91% ee
Conflicts of interest
“There are no conflicts to declare”.
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
Ar
Ar
Ar
Ar
F3
C
MeO2
C
I
Acknowledgements
Me
3yCl, 56%, 78% ee
3yI, 61%, 87% ee
3zCl, 53%, 78% ee
3zI, 58%, 90% ee
3aaCl, 43%, 76% ee
3aaI, 50%,90% ee
3abCl, 76%, 80% ee
3abI, 72%, 86% ee
We are grateful for the financial support from NSFC 21332003
(WH), the Program for Guangdong Introducing Innovative and
Enterpreneurial Teams 2016ZT06Y337 (WH), the University of
Arizona (EC), and the China Scholarship Council (TS). We also
thank members of the Chapman and Hu labs for helpful
discussions.
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
Ar
Ar
Ar
Ar
Me
tBu
MeO
Et
Me
3acCl, 78%, 87% ee
3acI, 76%, 82% ee
3adCl, 78%, 67% ee
3adI, 70%, 71% ee
3aeCl, 72%, 70% ee
3aeI, 81%, 82% ee
3afCl, 61%, 80% ee
3afI, 74%, 85% ee
O
O
CO2Me
O
O
CO2Me
CO2Me
CO2Me
Ar
Ar
Ar
Ar
S
Notes and references
Me
Br
Ph
3agCl, 71%, 86% ee
3agI, 73%, 92% ee
3m, 77%, 83% ee
3ahI, 80%, 93% ee
3aiCl, 73%, 85% ee
3aiI, 75%, 85% ee
3ajCl, 40%, 72% ee
3ajI, 48%, 77% ee
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the matter
under discussion, limited experimental and spectral data, and
crystallographic data.
aReaction conditions: 1 (0.2 mmol) in DCM (2 mL) was added to a solution of 2a
(0.4 mmol, 2 equiv), CaH2 (0.4 mmol, 2 equiv), 200 mg 4Å MS, AgSbF6 (0.04 mmol,
0.2 equiv) and (R)-3,5-DM-BINAP (0.02 mmol, 0.1 equiv) in 2 mL of DCM at 25°C in
the dark. bIsolated yield. cDetermined by chiral HPLC analysis.
1.
2.
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Finally, to unambiguously assign the absolute stereochemistry
of the 2,5-dihydrofurans, the heavy atom-containing product 3k
was selected to transform into the corresponding lactone 7k
through PCC oxidation in 67% yield and 91% ee. The absolute
configuration of 7k was unambiguously confirmed as S by X-ray
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O
O
O
PCC
Ph
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1,2-dichloroethane, reflux
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O
Me
O
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7k
Br
67%, 91% ee
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of its product 7k. (CCDC number: 1432486)
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Conclusions
We have developed an asymmetric Ag(I)/(R)-3,5-DM-BINAP-
catalyzed ACT method for the enantioselective synthesis of 2,5-
dihydrofurans from aryl diazoacetates and propargyl alcohols.
The synergistic catalysis of the bifunctional Ag(I)/(R)-3,5-DM-
BINAP allows for high chemo- and enantioselectivities.
Mechanistic investigations implied that the reaction involved
two molecules of bifunctional catalyst 9 in the key transition
state, which is the likely reason for the high chemoselectivities
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB01903K
Catalytic Asymmetric Synthesis of 2,5-Dihydrofurans Using Synergistic
Bifunctional Ag Catalysis
Taoda Shi,a,b Shenghan Teng,a Alavala Gopi Krishna Reddy,d Xin Guo,c Yueteng Zhang,b Kohlson T. Moore,b Thomas
Buckley,b Damian J. Mason,b Wei Wang,b Eli Chapman,b* and Wenhao Hud*
Enantioselective
Ag-carbenoid transfer
N2
O
CO2R
Ar
R'
+
Ar
CO2R
OH
[1,4]-formal cycloaddition
1
2
3
R'
50 expamples
up to 81% yield, 93% ee




Synergistic catalysis of a bifunctional Ag catalyst
Mechanistic study on the reaction and catalyst
Mechanism-guided discovery of CaH2 as an additive
High chemo- and enantioselectivities and broad substrate scope