Catalytic Enantioselective Double Carbopalladation/C?H Functionalization with Statistical Amplification of Product Enantiopurity: A Convertible Linker Approach

Article abstract of DOI:10.1002/anie.201709133

Combining a catalytic enantioselective reaction with dimerization in a single operation is an efficient way to upgrade the enantiomeric excesses (ee) of the product. Palladium-catalyzed reaction of N-(2-iodophenyl)-N-methyl methacrylamide derivatives with

Full text of DOI:10.1002/anie.201709133

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Catalytic Enantioselective Carbopalladation/C-H Functionalization
with Statistical Amplification of Product Enantiopurity: A
Convertible Linker Approach
Authors: Shuo Tong, Aurore Limouni, Qian Wang, Mei-Xiang Wang,
and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709133
Angew. Chem. 10.1002/ange.201709133
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10.1002/anie.201709133
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Enantioselective Double Carbopalladation/C-H
Functionalization with Statistical Amplification of Product
Enantiopurity: A Convertible Linker Approach
Shuo Tong, Aurore Limouni, Qian Wang, Mei-Xiang Wang and Jieping Zhu*
Abstract: We demonstrated that combining
a
catalytic
to the reaction sequence. Enantioselective reaction on achiral
substrates having multiple prochiral functions have also been
exploited to increase the ee of the desired products.[11-12]
enantioselective reaction with dimerization in a single operation is an
efficient way to upgrade the enantiomeric excesses (ee) of the
product. Palladium-catalyzed reaction of N-(2-iodophenyl)-N-methyl
methacrylamide derivatives with oxadiazole afforded, via a double
enantioselective carbopalladation/intermolecular direct heteroarene
C-H alkylation cascade, homodimers in good yields with excellent ee.
The dimer was subsequently elaborated to the monomer in which
the linker (oxadiazole) was incorporated into the target product.
a) Horeau duplication principle: Enantiomeric enrichment via dimerization
FG1
R
FG
FG
R
R
(R)-1
mole fraction a
FG1
(S)-1
(R,R)-3
mole fraction a2
FG2
FG2
FG
FG
2
R
S
(R,S)-3
mole fraction 2a(1-a)
S
FG
FG
mole fraction 1-a
S
S
(S,S)-3
e.r. = a/(1-a)
mole fraction (1-a)2
Enantioenriched compounds are routinely prepared by
resolution of racemates, enantioselective reactions or from chiral
pool. Many enantioselective transformations leading to the
products with high ee have been developed during the past 50
years. However, there were still some reactions whose
enantioselective versions provided products with less than
satisfactory ee and additional purification or synthetic
manipulations were therefore needed in order to upgrade the
enantiopurity of the target.[1] Among those ee amplification
methods without recurring chiral catalyst or reagent was the
statistical enantiomeric enrichment via dimerization pioneered by
Langenback[2] and Horeau.[3-5] It consists of reaction of a chiral
non-racemic compound 1 with an achiral bifunctional linker 2 to
afford a mixture of (R,R)-3/(S,S)-3 and (R,S)-3 dimers. Isolation
of the (R,R)-3/(S,S)-3 pair followed by removal of the linker
FG1
FG1
R
S
a) separation
1
mole fraction
a2
(1-a)2
b) cleavage of linker
e.r. = a2/(1-a)2
b) This work: Generation of stereocenters with concurrent dimerization
S
R
FG1
R
(R)-C
(S)-C
Cat*
B
(R,S)-D
A
FG1
S
B
S
R
S
R
100
90
80
70
60
50
40
30
20
10
0
ee(dimer)
(S,S)-D
94.3%
70.7%
(R,R)-D
ee(monomer)
regenerates compound
1
with increased enantiopurity.
Assuming that there was no kinetic resolution in the dimerization
process and the e.r. of the initial compound was a/(1-a) (a
represents the mole fraction of the major enantiomer in its initial
composition), then the e.r. of the recovered compound 1 after
dimerization and removal of the linker will be upgraded to a2/(1-
a)2. The price to be paid is the partial loss of the materials in the
form of meso diastereomer (Scheme 1a). The so-called Horeau
duplication principle[6-8] has since been successfully used for the
ee amplification of non-racemic compounds[9] and the ee
determination via the in situ dimerization with an achiral
bifunctional linker.[10] A prerequisite to apply such a strategy is
that the prochiral substrate must contain an additional functional
group that can be used for the dimerization and two extra steps,
i.e. introducing and cleaving the linker, would have to be added
ee(dimer) = (1-1/dr2)1/2
ee(monomer) = [(dr-1)/(dr+1)]1/2
R
FG
R
E
F
ee(dimer) = (1 + 1/dr)ee(monomer)
1
2
3
4
5
d.r.
6
7
8
9
10
c) Reaction design
R2
R2
O
R2
Ar
Ar
O
H
H
Pd/L*
N
N
Ar
+
N
R1
N
N
N
O
O
N
O
R1
R1
6
X
4
5
Me
R
R2
N
Me
N
H
Me
N
Ar
H
H
N
8 R = OCONHMe, (-)-physostigmine
9 R = OMe, (-)-esermethole
R1
7
Scheme 1. Horeau Duplication Principle: Concept and Reaction Design
[*]
Dr. S. Tong, A. Limouni, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
We propose herein
enantioselective reaction with the dimerization in
a
novel approach combining the
single
a
operation. As illustrated in Scheme 1b, reaction of substrate A
with a bifunctional substrate B under catalytic enantioselective
conditions would produce firstly the monomer C in which two
chemical bonds were formed, one for generating a stereocenter
from the prochiral function (FG1) while the other for connecting
with the linker. Reaction of C with another molecule of B
following the same domino sequence would afford a mixture of
diastereomers (R,R)-D/(S,S)-D and (R,S)-D. Separation of the
Homepage: http://lspn.epfl.ch
Prof. Dr. M.-X. Wang
Laboratory of Bioorganic Phosphorous Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084 (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201709133
Angewandte Chemie International Edition
COMMUNICATION
Me
Me
O
(R,R)-D/(S,S)-D pair from the (R,S)-D diastereomer followed by
removal of the linker would afford two molecules of monomer
with an ee higher than that obtained by a single enantioselective
process. Two options exist for this last step: a) simple cleavage
of the linker to reveal the target monomer E and b) the linker
contains latent functions that could be elaborated into a more
complex monomeric structure F. Assuming that substrate control
in the second asymmetric reaction (from C to D) was minimum,
one could then calculate the ee of the dimer and the monomer
from the d.r. value of the dimers according to the following
N
N
N
N
O
O
Me
N
Me Me
(S,S)-6a and its enantiomer
O
Conditions
H
H
+
O
+
N
N
I
Me
Me
Me
O
4a
5
N
N
N
N
O
O
Me
Me
(S,R)-10a
a) initial screening (conditions i)
O
PPh2
R
N
PPh2
PPh2
PTol2
equations: ee(dimer) = (1-1/dr2)1/2, ee(monomer) = [(dr-1)/(dr+1)]1/2
,
PTol2
PAr2
PPh2
ee(dimer) = (1 + 1/dr)ee(monomer) (see SI for algebraic solution). The
d.r. value, measurable by 1H NMR spectroscopy or by HPLC
without recurring the chiral stationary phase, could therefore be
used as an indicator of the enantioselectivity of the reaction. A
moderate d.r. of 3/1 would indicate that the ee of the compound
D could reach 94.3%, while that of C would be only 70.7% ee
(Scheme 1b). As a proof of concept, we report herein a Pd-
L2 R = H, Ar = Ph, 1:1 d.r.
L3 R = CF3, Ar = 4-CF3C6H4
no reaction
L11:1 d.r.
L4 1:1 d.r.
L5 1:1 d.r.
O
Cl
O
O
PAr2
MeO
PPh2
PPh2
MeO
PPh2
PPh2
O
O
PPh2
PAr2
MeO
O
MeO
PPh2
O
Cl
O
L7 Ar = 3,5-dimethyl
phenyl, 1.7:1 d.r.
L6 1.3:1 d.r.
OMe
L8 1.9:1 d.r.
L9 1.2:1 d.r.
catalyzed
enantioselective
double
carbopalladation/C-H
functionalization of acetanilide 4 with oxadiazole (5) for the
synthesis of bis-oxindoles 6 and its subsequent conversion to
two molecules of pyrroloindolines 7, important structural motif
found in natural products and medicinally relevant compounds.
For example, (-)-physostigmine (8), isolated from calabar bean,
and (-)-esermethole (9) are reversible cholinesterase inhibitors
with proving medicinal application.[13]
PPh2
N
P
P
PPh2
PPh2
O
O
H3C
H3C
MeO
MeO
PPh2
PPh2
N
PPh2
OMe
L10 1.2:1 d.r.
L11 1:1 d.r.
L12 no reaction
L13 1.2:1 d.r.
b) optimization of conditions (conditions ii and iii)
O
The domino carbopalladation/nucleophilic capture is
a
O
F
F
powerful strategy for the synthesis of medicinally relevant
heterocycles.[14] However, the development of enantioselective
version is highly challenging.[15-18] N-(2-Iodophenyl)-N-methyl
methacrylamide (4a) and oxadiazole (5) were chosen as our test
substrates (Scheme 2). After initial survey of reaction conditions,
we were pleased to find that the racemic products 6a and 10a
can be produced in 84% overall yield by heating a THF solution
of 4a and 5 in the presence of Pd(OAc)2 (10 mol %), dppp (L1,
20 mol %), and Cs2CO3 (3.0 equiv) at 80 °C. Chiral ligands were
next screened under these conditions utilizing the d.r. value of
the dimers as an indicator of the enantioselectivity. The ligands
producing the dimers with d.r. < 2 were not considered further
since it implied that the eedimer of 6a would be lower than 86.6%.
Of note, the PHOX ligand L2,[19] the best performer in our
previous studies involving aryltriflates as electrophilic
partners,[17a] was completely ineffective. Three ligands, (S)-
O
O
O
O
O
O
PTol2
PTol2
PPh2
PPh2
PPh2
PPh2
F
F
O
O
L14 (S)-SEGPHOS
ii) 58%, 2:1 d.r., 89% ee
L15 (R)-C3-TUNEPHOS
ii) 100%, 3:1 d.r., 95% ee ii) 86%, 2.8:1 d.r., 95% ee
iii) 100%, 3:1 d.r., 96% ee iii) 100%, 3.2:1 d.r., 94% ee iii) 100%, 4.4:1 d.r., 99% ee
L16 (S)-DIFLUORPHOS
Scheme 2. Catalytic double enantioselective carbopalladation/direct
intermolecular C-H functionalization. Reaction conditions: i) 4a (0.25 mmol), 5
(0.1 mmol), Pd(OAc)2 (0.01 mmol), ligand (0.02 mmol), Cs2CO3 (0.3 mmol),
THF, 80 °C. ii) 4a (0.25 mmol), 5 (0.1 mmol), PdCl2(MeCN)2 (0.005 mmol),
ligand (0.01 mmol), Cs2CO3 (0.3 mmol), THF, 80 °C. iii) conditions ii) + Ag3PO4
(0.1 mmol). Yields correspond to the purified products. The d.r. was
determined by 1H NMR spectrum of the crude product. The ee was determined
by SFC using chiral stationary phase (see SI for details).
and ee enhancement via dimerization in one-pot was applicable
to a wide range of substrates (Table 1). On the aniline part,
SEGPHOS
L14,
(R)-C3-TUNEPHOS
L15
and
(S)-
DIFLUORPHOS L16,[20] stood out from this screening. Further
fine-tuning of the reaction conditions using these ligands
indicated that PdCl2(MeCN)2 was a better palladium source than
Pd(OAc)2 at a lower catalyst loading (5 mol%) and that adding
Ag3PO4 increased significantly the diastereoselectivity, hence
the enantioselectivity, of this reaction. The role of the silver salt
is likely due to its ability to abstract iodide from the palladium(II)
intermediate leading to the 16-electron cationic Pd(II) species.
This would allow the coordination of the tethered alkene to the
metal center without interrupting the chelating property of the
bidentate ligand, hence the higher intrinsic ee of the reaction.[21]
Under optimized conditions (conditions iii with L16, Scheme 2),
the reaction of 4a with 5 afforded (S,S)-6a (99% ee) and (S,R)-
10a in the isolated yields of 82% and 18% (4.4:1 d.r.),
respectively.
electron-donating
(6b)
or
electron-withdrawing
(6c-6f)
substituents located at different positions of the phenyl ring were
tolerated affording homodimers in excellent yields and ee. High
efficiency and selectivity was also observed with acetanilides
bearing an alkyl group (linear, branched and functionalized) on
the a-position of the double bond (6a-6k). For the substrates
with the aryl substituent on the same position, the reaction has
to be performed in MeCN under otherwise identical conditions.
Bis-oxindoles 6l-6r bearing an aromatic substituent with different
electronic properties at C3 position were prepared with high
efficiency and excellent enantioselectivities. The aryl chloride
and aryl bromide were compatible to the present conditions
providing therefore oxindoles with
a
handle for further
functionalization. The absolute configuration of 6l (R,R) was
determined by X-ray crystallographic analysis and that of the
other homodimers was assigned accordingly.[23]
This domino process involving generation of the
stereocenter, attachment of linker via C-H functionalization[22]
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10.1002/anie.201709133
Angewandte Chemie International Edition
COMMUNICATION
the stereochemical integrity. Cleavage of the N-N bond of the
hydrazine (Raney Ni, H2) afforded two molecules of
pyrroloindolines 7. It is worth noting that only three molecules of
water were formed as by-product per generation of two
molecules of the target 7 from the dimer 11. Compound (R,R)-7a
has previously been converted to physostigmine (8) and
esermethole (9)[17a]
Table 1. Scope of the double enantioselective carbopalladation/C-H
functionalization
5
R2
6
R2
R1
H
ҴaҶ
O
N
O
R2
R1
H
+
5
R1
N
N
N
O
N
N
O
Me
6
I
Me
O
N
4
5
6
Me
Me
Me
O
O
H
Entry
R1
R2
Product
Yield [%]
ee [%]
d.r.
ҴbҶ
H
H
ҴaҶ
+
N
N
N
O
1
2
3
5-OMe
5-Cl
Me
Me
Me
6b
6c
6d
84
75
82
99
98
99
5.7:1
3.8:1
4.5:1
N N
N
O
Me
4a
I
5
Me
(S)-14a eemeasured 79%; eecalculated 78%
5-Br
Me
Me
O
4
5-CN
6-Cl
H
Me
Me
Bn
iPr
6e
6f
80
76
79
79
74
73
70
69
74
72
77
70
79
52
95
99
98
98
95
97
98
96
96
96
98
97
96
96
4.5:1
4.9:1
4.0:1
6.5:1
3.1:1
3.0:1
5.0:1
3.6:1
4.0:1
4.5:1
4.5:1
4.1:1
4.5:1
5.0:1
+
(S,R)-10a
N
N
5
N
N
O
O
6
6g
6h
6i
Me
(S,S)-6a eemeasured 99%; eecalculated 98%
Me
7
H
8
H
nC8H17
CH2OMe
CH2OAc
Ph
9
H
6j
Scheme 4 [a] 4a (0.1 mmol), 5 (0.1 mmol), PdCl2(MeCN)2 (0.005 mmol), (S)-
L16 (0.01 mmol), Ag3PO4 (0.1 mmol), Cs2CO3 (0.15 mmol), THF (c 0.05 M),
80 oC, 2 h. [b] 14a (0.1 mmol), 4a (0.1 mmol), standard conditions.
10
H
6k
6l
11[b]
12[b]
13[b]
14[b]
15[b]
16[b]
17[b]
H
H
4-MeC6H4
6m
6n
6o
6p
6q
6r
H
4-MeOC6H4
4-FC6H4
The above domino process raised an interesting question
regarding the second stereocenter-generating step: Was it
substrate- or catalyst-controlled? If both were operating, was it a
matched or a mismatched case?[24] To understand the reaction
course, following control experiments were performed. Firstly,
the monomer 14a was prepared by reaction of 4a with
oxadiazole (5, 1.0 equiv) in the presence of (S)-L16 under
optimized conditions. The isolated monomer (S)-14a was
allowed to react again with 4a to produce the dimers (S,S)-6a
and (S,R)-10a. The measured ee of monomer (S)-14a (78%)
and dimer (S,S)-6a (ee 99%) matched well with the ee
calculated from the d.r. (4.4/1) of the (S,S)-6a vs (S,R)-10a.
Monitoring the formation of 6b-c and 6f bearing substituents with
different electronic natures led to the same observation (see SI
for data). Secondly, monitoring the reaction progress indicated
that the ee of 6a and 14a remained constant as the reaction
progressed (Table 2). Most importantly, reaction of the monomer
(S)-14a (ee 78%) with 4a in the presence of (R)-L16 under
standard conditions afforded racemic 6a and 10a with a d.r. of
1:4.1, which, within experimental error, was in agreement with
our algebraic expression.[25] The results of these control
experiments indicated clearly that the conversion of monomer 14
to dimer 6 was likely catalyst-controlled and that the easily
measurable d.r. was indeed an excellent indicator for the
enantioselectivity of the reaction.
H
H
4-PhC6H4
3-ClC6H4
H
H
2-Naphthyl
[a] Standard conditions: 4a (0.25 mmol), 5 (0.1 mmo), PdCl2(MeCN)2 (0.005
mmol), (S)-L16 (0.01 mmol), Cs2CO3 (0.3 mmol), Ag3PO4 (0.1 mmol), THF (c
0.05 M), 80 oC, 24-72 h. [b] in MeCN at 120 °C under otherwise standard
conditions. The d.r. was determined by 1H NMR spectrum of the crude
product. The ee was determined by SFC using chiral stationary phase (see SI
for details).
R
R
R
O
b
a
N
N
N
O
N
N
O
O
I
Me
4
Me
Me
+
(R,R)-11a R = Me, 80%, -97% ee, 4.1:1 d.r.
(R,R)-11g R = CH2Ph, 69%, -95% ee, 3.0:1 d.r.
(R,R)-11i R = nC8H17, 74%, -98% ee, 3.1:1 d.r.
(S,S)-11l R = Ph, 72%, -96% ee, 3.2:1 d.r.
O
H
H
N
N
5
Me
N
Me
N
R
R
H
H
d
c
N
N
N
N
N
H
N
Me
H
R
R
Me
O
13a R = Me, 52%, 98% ee
13g R = CH2Ph, 52%, 93% ee
13i R = nC8H17, 75%, 97% ee
13l R = Ph, 38%, 98% ee
12
R
7a R = Me, 58%
N
7g R = CH2Ph, 55%
7i R = nC8H17, 60%
7l R = Ph, 50%
R = Me
ref 17a
H
8 and 9
N
Me
H
Scheme 3. [a] 4 (0.25 mmol), 5 (0.1 mmol), PdCl2(MeCN)2 (0.005 mmol), (R)-
L16 (0.01 mmol), Ag3PO4 (0.1 mmol), Cs2CO3 (0.3 mmol), THF or MeCN (c
0.05 M), 80 oC, 24-72 h. [b] LiAlH4, THF, 0 °C to reflux. [c] BH3•Me2S, Et2O,
0 °C to RT. [d] Raney Ni, EtOH, H2, 1 atm, 90 °C.
Table 2. Evolution of ee of monomer 14a and dimer 6a vs reaction time
Entry
Time (h)
d.r.
14a (yield, ee)
69%, 78.5%
79%, 78.5%
77%, 78.0%
30%, 78.0%
0%, ––
6a (yield, ee)
8.5%, 99.2%
16%, 99.0%
22%, 98.7%
69%, 99.0%
100%, 98.9%
1
2
3
4
5
1
3
4.2:1
4.2:1
4.2:1
4.2:1
4.2:1
6
The same reaction between 4 and 5 using (R)-L16 as ligand
under otherwise identical conditions afforded (R,R)-11, an
antipode of 6, in high yields with excellent enantioselectivities
(Scheme 3). Having demonstrated the validity of our approach,
the transformation of these homodimers was investigated. The
symmetric nature of oxadiazole and its vicinity with the amide
function of the oxindole prompted us to examine the possibility
of transforming 11 into a monomer with increased molecular
complexity. It was found that reduction of bis-oxindoles 11 with
LiAlH4 afforded 12 which, without purification, was further
reduced to C2-symmetric bis-pyrroloindolines 13 without loss of
10
22
In summary, we demonstrated that combining an
enantioselective reaction with a dimerization is an efficient way
to create chiral molecules with high enantiopurity. The salient
features of the present work included: a) the linker was
connected to the prochiral function via C-H functionalization; b)
part of the linker was permanently incorporated into the structure
of the monomeric target product rendering the introduction of the
linker non-redundant; c) the ee of the product was uniformly
high; d) the enantiopurity of the product can be estimated with
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COMMUNICATION
[11] T. R. Hoye, M. J. Mayer, T. J. Vos, Z. Ye, J. Org. Chem. 1998, 63, 8554.
[12] a) J.-C. Poulin, H. B. Kagan, J. Chem. Soc. Chem. Soc. 1982, 1261; b)
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L. Schreiber, T. S. Schreiber, D. B. Smith, J. Am. Chem. Soc. 1987,
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A. Stearns, J. Am. Chem. Soc. 2002, 124, 9008; h) J. A. Enquist Jr, B.
M. Stoltz, Nature 2008, 453, 1228.
precision from the diastereomeric ratio (d.r.) of the dimers. Since
the d.r. value is easily determined from the 1H NMR spectrum of
the crude product, it greatly accelerates the process of the
condition optimization, especially in the initial stage of the ligand
screening.[26] Further application of this approach to the reactions
whose enantioselective versions are still difficultly achievable is
underway.
Acknowledgements
[13] P. Ruiz-Sanchis, S. A. Savina, F. Albericio, M. AIvarez, Chem. Eur. J.
2011, 17, 1388.
Financial supports from Swiss State Secretariat for Education,
Research and Innovation (C16.0030), EPFL (Switzerland) and
National Natural Science Foundation of China (21320102002,
21502202) are gratefully acknowledged. We thank Dr. F.-T.
Farzaneh and Dr. R. Scopelliti for X-ray crystallographic analysis
of 6l.
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Keywords: Asymmetric synthesis • homogeneous catalyst • C-H
activation • Horeau duplication principle • oxindole
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10.1002/anie.201709133
Angewandte Chemie International Edition
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Synthetic Method
Shuo Tong, Aurore Limouni, Qian Wang,
Mei-Xiang Wang, Jieping
Zhu*__________ Page – Page
Catalytic Enantioselective Double
Carbopalladation/C-H Functionalization
with Statistical Amplification of Product
Enantiopurity: A Convertible Linker
Approach
A new dimension of Horeau duplication principle Palladium-catalyzed reaction of N-(2-iodophenyl)-
N-methyl methacrylamide derivatives with oxadiazole afforded homodimers in good yields with
excellent enantiomeric excesses (ee). The dimer was subsequently converted to structurally elaborated
monomer in which the linker (oxadiazole) was incorporated into the target product.
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