Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3-Arylpyrroles

Article abstract of DOI:10.1002/anie.201812654

We report herein the first examples of catalytic enantioselective synthesis of axially chiral 3-arylpyrroles. Reaction of α-isocyanoacetates with β-aryl-α,β-alkynic ketones in the presence of silver oxide and a phosphine ligand derived from Cinchona alkal

Full text of DOI:10.1002/anie.201812654

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Accepted Article
Title: Catalytic Atropenantioselective Heteroannulation between
Isocyanoacetates and Alkynyl Ketones: Synthesis of
Enantioenriched Axially Chiral 3-Arylpyrroles
Authors: Sheng-Cai Zheng, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812654
Angew. Chem. 10.1002/ange.201812654
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10.1002/anie.201812654
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Atropenantioselective Heteroannulation between
Isocyanoacetates and Alkynyl Ketones: Synthesis of
Enantioenriched Axially Chiral 3-Arylpyrroles
Sheng-Cai Zheng, Qian Wang, and Jieping Zhu*
Abstract: We report herein the first examples of catalytic
enantioselective synthesis of axially chiral 3-arylpyrroles. Reaction of
a-isocyanoacetates with b-aryl-a,b-alkynic ketones in the presence of
silver oxide and a phosphine ligand derived from Cinchona alkaloid
occurred chemoselectively to afford enantioenriched 3-arylpyrroles in
high yields with excellent enantiomeric excesses. The pyrrole ring was
de novo constructed in this process.
developing a catalytic enantioselective version of Yamamoto-de
Meijere pyrrole synthesis. We report herein that the reaction of 1
and alkynyl ketones 2 (EWG = COR2) in the presence of Ag2O
and
a
Dixon-type amino phosphine ligand 4[15] is highly
atropenantioselective to afford axially chiral 3-arylpyrroles 3 in
good yields with excellent enantiomeric excesses (Scheme 1c).
a) Tan’s enantioselective synthesis of arylpyrroles with a chiral C-N axis
COOMe
O
COOMe
NH2
CPA (10 mol%)
The axially chiral biaryl motif is found in many important natural
products[1] and drugs,[2] and is a privileged structure in ligand and
catalyst design.[3] Not surprisingly, the development of catalytic
enantioselective synthesis of chiral biaryls has attracted attention
of chemists for many years.[4] While significant progress has been
recorded recently on the asymmetric synthesis of axial chiral six-
membered aryl-aryl or aryl-heteroaryl compounds,[5,6] catalytic
Fe(OTf)3 (10 mol%)
N
+
(a)
(b)
O
CCl4/cyclohexane
Br
Br
b) Yamamoto and de Meijere’s synthesis of 2,3,4-substituted pyrroles
EWG
COOR1
CN
Cu2O ( 5 mol%), 1,10-Phen (10 mol%)
dioxane, 80 °C or 100 °C
NH
COOR1
CuLn
+
1
R2
R2
EWG
3
2
enantioselective synthesis of atropisomers bearing
membered heterocycles remained scarce. [7]
a five-
EWG
R2
2
LnCu
EWG
NC
COOR1
Pyrrole is one of the most prominent five membered
heterocycles which is found in bioactive natural products and
pharmaceuticals.[8] Many synthetic methodologies have been
developed over a century for the synthesis of diversely substituted
pyrroles.[9] Very recently, Tan and coworkers developed an
LnCu
N
N
COOR1
R2
COOR1
A
B
C
c) This work: Atropenantioselective synthesis of arylpyrrols with a chiral C-C axis.
L* =
elegant
Fe(OTf)3/chiral
phosphoric
acid-catalyzed
COOR1
CN
HN
OMe
enantioselective Paal-Knorr reaction for the synthesis of
enantioenriched N-aryl substituted pyrroles bearing a chiral C-N
axis (Scheme 1a).[7d]
Ag2O (10 mol%)
4 (20 mol%)
+
1
R1OOC
COR2
R3
N
(c)
NH PPh2
K3PO4, CHCl3, RT
N
COR2
In 2005, Yamamoto[10] and de Meijere[11] reported
O
3
4
R3
2
independently
a
metal catalyzed heteroannulation of
isocyanoacetates 1 with activated alkynoates 2 for the synthesis
of 2,3,4-trisubstituted pyrroles 3 (EWG = COOR, CN, Scheme 1b).
This chemistry has subsequently been extended to terminal
Scheme 1. Atropenantioselective synthesis of arylpyrroles. CPA = chiral
phosphoric acid
alkynes[12]
and
a-substituted
a-isocyanoacetates.[13]
Mechanistically, it was proposed that the reaction was initiated by
the Michael addition of metallated species A to the alkynoate 2 to
afford B which, upon cyclization, provided intermediate C. The
protodemetallation and 1,5-H shift of C would then furnish the
polysubstituted pyrrole 3. We hypothesized that If R2 was an aryl
bearing ortho-substituents that could hinder the free rotation of
the newly formed aryl-pyrrole bond, the resulting C3 aryl
substituted pyrrole would be axially chiral. In connection with our
interest in the isocyanide chemistry, [14] we became interested in
Catalytic enantioselective addition of isocyanoacetate 1 to
carbonyls,
[15-16]
imines,[17] electron-deficient alkenes[18] and
allenes[19] are well documented in the literature. It is therefore
interesting to note that enantioselective addition of
isocyanoacetate 1 to alkynoates which constitutes the key step in
our planned asymmetric synthesis of 3-arylpyrroles remains
unknown at the outset of this work. Using Dixon’s conditions
developed for the aldol reaction of isocyanoacetate 1,[15] we
began our studies by examining the reaction between ethyl a-
isocyanoacetate 1a and ethyl 3-(2-methoxynaphthyl-1-
yl)propiolate 5a (Scheme 2). Performing the reaction of 1a and
5a at room temperature in the presence of Ag2O (10 mol%) and
the chiral phosphine 4 (20 mol%), the reaction went indeed
cleanly to afford the desired arylpyrrole 6a, albeit in moderate
conversion (< 20%) and low enantioselectivity. Using phenyl ester
5b as reaction partner, oxazole 7b, resulting from the Claisen
condensation between 1a and 5b followed by cyclization, was
isolated as the only product. These results suggested that the
[a]
Dr. S.-C. Zheng, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
École Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201812654
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COMMUNICATION
chemoselectivity of the addition reaction (1,4- vs 1,2-addition) is
very sensitive to the subtle electronic effect of the conjugated
carbonyl unit. While the results were disappointing at the first
glance, the fact that 6a was formed even at room temperature
Adding K3PO4 accelerated the reaction without having significant
impact on the enantioselectivity (entry 5 vs 9, Table 1). After
further survey of reaction conditions varying the additives, the
solvents, and the reaction temperature (for details, see SI), the
optimum conditions found consisted of performing the reaction of
1a (0.12 mmol) and 2a (0.10 mmol) in a mixed solvent
(THF/TBME = 1:4, c 0.1 M) in the presence of Ag2O (10 mol%),
ligand 4 (20 mol%), K3PO4 (2.0 equiv) and 5Å MS (100 mg) at 0 °C
for 48 hours. Under these conditions, 3-naphthylpyrrole (3a) was
encouraged us to pursue this study.
N
HN
CN
COOEt
O
COOEt
OMe
Conditions[a]
EtOOC
COOR
OMe
1a
+
+
O
OR
isolated in 52% yield with 91% ee (entry 16).
OMe
HN
6a 19% (99%)[b], 34% ee
6b 0%
5a R = Et
5b R = Ph
7a 0%
7b 25%
R1OOC
COR2
R3
Conditions[a]
COOR1
CN
COR2
Scheme 2. Reaction of a-isocyanoacetate with b-naphthyl substituted
propiolate. [a] Ag2O (10 mol%), 4 (20 mol%), K3PO4 (2.0 equiv), CHCl3, RT; [b]
yield based on the conversion.
R3
R
1
2
3
3a R = H, 52%, 91% ee
HN
HN
OMe
3b R = 4-Br, 46%, 92% ee
3c R = 4-Cl, 50%, 91% ee
3d R = 4-OMe, 91%, 91% ee
3e R = 4-Me, 76%, 90% ee
3f R = 4-tBu, 57%, 88% ee
EtO2C
EtO2C
O
O
OMe
OMe
Table 1. Conditions for enantioselective heteroannulation of 1a with 2a
3g 47%, 82% ee
HN
OMe
OMe
OMe
EtOOC
COPh
OMe
Conditions[a]
HN
HN
HN
CN
COOEt
+
COPh
EtO2C
EtO2C
EtO2C
O
OR
O
O
OMe
Br
Br
1a
2a
3a
Entry
1
2
3
4
Solvent
CHCl3
DCM
Toluene
EtOAc
THF
Dioxane
Et2O
TBME
THF
THF
THF
TBME
THF/TBME(1:1)
THF/TBME (1:4)
THF/TBME (1:4)
THF/TBME (1:4)
Additive
-
-
-
-
-
-
-
3a yield[b]
67
57
45
46
46
35
37
42
55
76
64
14
53
45
50
ee[c]
65
63
79
77
80
79
85
87
78
80
87
91
89
92
90
91
T (℃)
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
3h R = Et, 89%, 94% ee
3i R = iPr, 98%, 96% ee
3j R = OAc, 73%, 85% ee
Br
3l 83%, 85% ee
3k 74%, 85% ee
OMe
OMe
HN
5
6
7
8
HN
EtO2C
EtO2C
Me
O
OMe
O
Br
-
-
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
NC
N
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
3Å MS
5Å MS
3m 43%, 91% ee
3n 93%, 90% ee
0
0
0
0
OMe
OMe
HN
HN
EtO2C
Me
3p R = Me, 61%, 85% ee
3q R = Bn, 95%, 89% ee
3r R = tBu, 95%, 96% ee
RO2C
O
O
OMe
0
52
OMe
[a] General conditions: 1a (0.12 mmol), 2a (0.10 mmol), Ag2O (10 mol%), ligand
4 (20 mol%), solvent (c 0,1 M), RT, 24 h (or 0 °C, 48 h). [b] Isolated yield. [c]
Determined by SFC analysis on a chiral stationary phase. [d] K3PO4 (2.0 equiv)
was added. Abbreviation: TBME = tert-Butyl methyl ether.
3o 88%, 85% ee
OMe
HN
tBuO2C
O
Br
O
3s (1.23 g, 89% yield, 92% ee)
COOEt
N
Ph
Ph
COOEt
OMe
OMe
8
9
Scheme 3. [a] General conditions: 1a (0.12 mmol), 2a (0.10 mmol), Ag2O (10
mol%), ligand 4 (20 mol%), K3PO4 (2.0 equiv), THF/TBME = 1:4 (c 0,1 M), 5Å
MS (100 mg), 48 h. Yields refer to Isolated pure compounds. The ee was
determined by SFC analysis on a chiral stationary phase.
Figure 1. Side products isolated from the heteroannulation of 1a with 2a.
The substrate scope was next examined (Scheme 3). For the
carbonyl part of the α,β-alkynic ketones 2, the presence of both
electron-donating and -withdrawing groups on the phenyl ring
were well tolerated furnishing the products in excellent ees. With
an electron rich aromatic ring, the yield of the 3-arylpyrroles was
excellent (e.g. 3d, 3h, 3i). The acetate group was tolerated to
afford 3j and the presence of a bromide was also compatible
providing compounds 3k and 3l with a handle for the post-
functionalization. The alkynic ketone containing a quinoline
system participated in the reaction to furnish 3m in moderate yield
with an excellent ee. Axially chiral 3-phenylpyrroles 3n and 3o
We next set out to examine the reaction of 1a with α,β-alkynic
ketone 2a (R3 = OMe, R2 = Ph) in spite of the potential
chemoselectivity issue (1,2- vs 1,4-addition). To our delight, the
reaction between 1a and 2a in chloroform in the presence of Ag2O
(10 mol%) and the phosphine 4 (20 mol%) proceeded smoothly
to afford the axially chiral 3-arylpyrrole 3a (67% yield, 65% ee,
entry 1, Table 1) together with two side products 8 and 9 (Figure
1) resulting from the aldol reaction.[15] The solvent has a dramatic
effect on the outcome of the reaction (entries 1-8) and the higher
enantioselectivity was observed in etheric solvents (entries 5-8).
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10.1002/anie.201812654
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were similarly prepared in high yields and ees. Different alkyl a-
isocyanoacetates were examined and best results were obtained
with bulky tert-butyl group (3r, 95% yield, 96% ee). Finally, a gram
scale experiment was carried out to evaluate the practicality of the
protocol. The reaction between tert-butyl a-isocyanoacetate 1d
and 2k under standard conditions provided 3s (1.23 g) in 89%
yield with 92% ee. The absolute configuration of 3n and 3s was
determined to be (aR) by X-ray diffraction analysis[20] and that of
the other products were assigned by analogy. Finally, using
quinidine-derived phosphine ligand, a pseudoenantiomer of 4,
(aS)-3d was obtained in 81% yield with a slightly reduced ee (80%,
see SI). The enantiomerization barrier of 3d was determined to
be 123.7 KJ/mol at 70 °C corresponding to a half-life of 4.8 days
at this temperature (See SI).
HN
N
PMP
O
OH
PMP
N
PMP
b
tBuO2C
a
tBuO2C
O
O
NH
O
Br
Br
Br
10 98% yield, 92 % ee
PMP
11 85 % yield, 92 % ee
PMP
3s 92 % ee
N
N
O
O
d
c
OMe
O
N
O
N
Br
12 93% yield, 92 % ee
13 95% yield, 92% ee
Scheme 5. Transformations of 3s. [a] MeI, K2CO3, DMF, RT, 98%, 92% ee; [b]
DCM/TFA = 4:1, 0 °C, RT, then 2-aminoethan-1-ol, EDCI, HOBt, Et3N, DCM,
RT, 85%, 92% ee; [c] MeSO2Cl, Et3N, DCM, 0 °C, then NaOH, MeOH, 93%,
92% ee; [d] Pd(OTf)2 (10 mol%), Bu4NOAc (4.0 equiv), dioxane, 70-75 °C, 95%,
92% ee. Abbreviation: PMP = p-methoxyphenyl.
‡
Ph P
S
2
NC
O
H
CO2R1
L
Ag
N
H
N
S
N
In summary, we developed an efficient Ag/chiral ligand-
catalyzed asymmetric heteroannulation of a-isocyanoacetates
with a-aryl-a,b-alkynic ketones providing 3-arylpyrroles in good to
high yields with excellent enantioselectivities. The reaction
displayed high chemoselectivity since alkynyl substituted
oxazoline resulting from 1,2-addition of 1 to 2 was minimized
under optimized conditions. To the best of knowledge, this
represented the first examples of enantioselective synthesis of 3-
arylpyrroles bearing a chiral C-C axis.
1 + 2
O
.
O-
OAgL
L
R1O
Ag
R2
N
R2
MeO
D
E
HN
N
COR2
L
COR2
N
COR
R1O2C
R1O2C
L
R1O2C
L
S
S
S
F
G
3
Scheme 4. Atropenantioselective process: A possible stereochemical course.
Acknowledgements
A stereochemical model implicating a (Z)-enolate of a-
isocyanoacetate was proposed (Scheme 4).[15-18] The
coordination of amide nitrogen, phosphorous, carbonyl oxygen
and the divalent isocyanide carbon atoms to silver anion would
define the positioning of the two reactants. The additional
hydrogen bond between the protonated quinuclidine and ketone
oxygen could further refine the stereochemical environment of the
transition structure D. To minimize the steric interactions, the
alkyne unit would approach the enolate from the backside to
afford enantioselectively the intermediate E. Intramolecular
addition of silver allenolate to the isocyano carbon would afford F
which, upon protonation, provided G. 1,5-H shift afforded then the
axially chiral 3-arylpyrroles 3 as the major enantiomer. It is worth
noting that the reaction is highly chemoselective when R2 is an
electron-rich aromatic ring as the oxazoline resulting from the 1,2-
additon of enolate to ketone was not observed.
We thank EPFL (Switzerland), the Swiss National Science
Foundation (SNSF, N° 20021-178846/1) for financial support. We
are grateful to Dr. Farzaneh Fadaei Tirani and Dr. Rosario
Scopelliti for X-ray crystallographic analysis of compounds 3n, 3s.
Conflict of Interest
The authors declare no conflict of interest
Keywords: asymmetry synthesis • axial chirality • homogenous
catalysis • isocyanide • arylpyrrole
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10.1002/anie.201812654
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
Asymmetric Synthesis
L* =
COOR1
CN
HN
OMe
Ag2O (10 mol%)
L* (20 mol%)
+
R1OOC
COR2
R3
Sheng-Cai Zheng, Qian Wang, and
Jieping Zhu*__________ Page – Page
N
NH PPh2
K3PO4, CHCl3, RT
N
COR2
Catalytic Atropenantioselective
Heteroannulation between
O
R3
Isocyanoacetates and Alkynyl Ketones:
Synthesis of Enantioenriched Axially
Chiral 3-Arylpyrroles
de novo construction of pyrrole: In the presence of a catalytic amount of Ag2O and chiral
phosphine ligand, the heteroannulation between isocyanoacetates and alkynyl ketones afforded
the axially chiral 3- arylpyrroles in good yields with excellent enantioselectivities.
This article is protected by copyright. All rights reserved.