Copper-Catalyzed Enantioselective Arylative Desymmetrization of Prochiral Cyclopentenes with Diaryliodonium Salts

Article abstract of DOI:10.1002/anie.201713329

A copper-catalyzed enantioselective arylative desymmetrization of prochiral cyclopentenes with diaryliodonium salts was developed. In the presence of a catalytic amount of a chiral copper–bisoxazoline complex, which was generated in situ, the reaction of 4-substituted or 4,4-disubstituted cyclopent-1-enes with diaryliodonium hexafluoroarsenates afforded the chiral arylated products in good yields with excellent enantioselectivity. A cyclohexyl-containing Box ligand was essential for the high enantioselectivity. Transformation of the enantiomerically enriched adducts into other chiral building blocks is also documented.

Full text of DOI:10.1002/anie.201713329

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Accepted Article
Title: Copper-Catalyzed Enantioselective Arylative Desymmetrization
of Prochiral Cyclopentenes with Diaryliodonium Salts
Authors: Hua Wu, Qian Wang, and Jieping Zhu
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10.1002/anie.201713329
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Enantioselective Arylative Desymmetrization of
Prochiral Cyclopentenes with Diaryliodonium Salts
Hua Wu, Qian Wang, Jieping Zhu*
Abstract:
A
copper-catalyzed enantioselective arylative
rearrangement.[18] All these examples involved the use of
highly electron-rich alkenes or strained ring systems bearing a
neighboring heteroatom or an internal nucleophiles to
stabilize/trap the incipient carbenium intermediates.
desymmetrization of prochiral cyclopentenes with diaryliodonium
salts was developed. In the presence of a catalytic amount of the
in situ generated chiral copper-bisoxazoline complex, reaction of
4-substituted or 4,4-disubstituted cyclopent-1-enes with the
diaryliodonium hexafluoroarsenate afforded the chiral arylated
products in good yields with excellent enantioselectivities. Use of
the cyclohexyl-containing Box ligand was essential for the high
enantioselectivity. Transformation of the enantioenriched adducts
to other chiral building blocks was also documented.
In connection with our ongoing research interests dealing
with the transition metal catalyzed enantioselective
carbofunctionalization of alkenes,[19] we became interested in
the enantioselective copper-catalyzed arylation of alkenes and
documented recently an enantioselective arylative semipinacol
rearrangement.[18b] We report herein the first examples of
copper catalyzed enantioselective arylative desymmetrization
of prochiral 4-substituted and 4,4-disubstituted cyclopentenes
with diaryliodonium salts for the synthesis of enantioenriched
cyclopentenyl carboxamides, cyclopentenyl alcohols and N-
cyclopentenyl pivalamides in high to excellent enantiomeric
excesses (Scheme 1c).[20] To the best of our knowledge, this
work represents the first examples of Cu-catalyzed
enantioselective arylation of simple isolated double bonds.
Since the seminal work of Shibasaki[1] and Overman[2] on
the enantioselective intramolecular Heck reaction for the
creation of chiral quaternary carbon centers,[3] significant
efforts have been dedicated to the enantioselective arylation of
alkenes by intermolecular Heck-type reactions.[4] The first
report came from Hayashi and co-workers who disclosed in
1991
a Pd-catalyzed enantioselective arylation of 2,3-
dihydrofuran with aryl triflates.[5] Conditions allowing the use of
aryl diazonium salts[6] and arylhalides[7] have been
subsequently developed for the enantioselective arylation of
cycloalkenes and asymmetric arylation of acyclic alkenyl
alcohols using a redox-relay strategy has been documented.[8]
Intrinsic to the mechanism of the Heck reaction, arylation of
small ring cycloalkenes afforded generally products with a
double bond shifted away from the newly formed C(sp2)-C(sp3)
bond, creating therefore the chiral stereocenter (Scheme 1a).
To the best of our knowledge, Lee’s work on Pd(II)-catalyzed
oxidative desymmetrization of 2,2-disubstituted cyclopentene-
1,3-diones with arylboroxine is an only example in which
carbon-carbon double bond was not shifted.[9-10] In this case,
the Pd-bearing stereocenter formed after cis-carbopalladation
can be epimerized via the Pd-enolate intermediate, rendering
therefore the subsequent cis b-H elimination possible.
a) Palladium-catalyzed enantioselective intermolecular Heck-type reaction
H
Pd
Pd(0), L*
FG
+
ArX
O
FG
*
FG
O
*
Ar
Ar
H
N
H
O
O
Ar
Ar
L* =
R’
B
B
Pd(OAc)2, L*
Me
Me
R
O
O
O
+
B
R
DMA, O2, 95 h
N
Ar
Ar
tBu
O
9 examples, ee from 30% to 88%
b) Copper-catalyzed enantioselective α-arylation of silyl enol ether
SiO
O
SiO
Y
X
Mes
Y
Y
[Cu], L*
Ar
I
+
Ar
Ar
c) This work: Copper-catalyzed enantioselective arylative desymmetrization
of prochiral cyclopentenes
R
Y
AsF6
Mes
R
R
Y
[Cu], L*
+
Ar
I
Y
Ar
Ar
2
3
1 R = H, aryl, alkyl
Y = Weinreb amide, OH, NHCOtBu
Parallel to palladium-catalyzed transformations, copper-
catalyzed arylation of alkenes[11] and arenes[12] with
diaryliodonium salts[13] has attracted much recent attention.
However, its enantioselective variants remain rare in spite of
the great synthetic significance of such processes. In 2011,
Gaunt[14] and MacMillan[15] reported independently the first
examples of Cu-catalyzed enantioselective a-arylation of silyl
enol ethers with diaryliodonium salts (Scheme 1b). This was
followed by enantioselective arylative cyclization of
tryptamines[16] and allylic amides,[17] and arylative semipinacol
Scheme 1. Enantioselective arylation of alkenes.
To realize the planned asymmetric transformation, we
need to identify a chiral catalyst that can differentiate not only
the two faces of the double bond, but also the sterically
unbiased two C(sp2) carbons. We started our investigation
using 1a and 2a as the model substrates (Table 1). The
arylative desymmetrization was carried out in DCM (80 oC,
sealed tube) in the presence of 2,6-di-tert-butylpyridine (DTBP,
1.2 equiv), Cu(OTf)2 (0.1 equiv) and a chiral ligand (0.2 equiv).
Only a trace amount of product 3a was formed using L1 or L2
(Figure 1) as ligand (entries 1-2), whereas the desired
cyclopentenyl carboxamide 3a was isolated in a reasonable
yield and ee in the presence of L3 (entry 3) or L4 (entry 4).
Using L5 as ligand afforded the desired product in 56% yield
with poor enantioselectivity (entry 5), whereas Pybox L6 was
inefficient in catalyzing the transformation (entry 6). Gem-
dibenzyl substituted (S,S)-diphenylbisoxazoline L7 failed to
catalyze the desired transformation indicating the importance
[*]
Dr. H. Wu, 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
Homepage: http://lspn.epfl.ch
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.201713329
Angewandte Chemie International Edition
COMMUNICATION
of the alkyl substituents on the catalytic activity of the Cu-
bisoxazoline complex (entries 7 vs 3). Therefore, further ligand
screening was focused on different bisoxazolines derived from
(S)-phenylglycinol (L8-L11). While the reaction with ligand L8
afforded 3a with low ee (entry 8), the same reaction in the
presence of ligands L9 or L10 having a cyclopentyl and a
cyclohexyl group, respectively, gave 3a with significantly
corresponding triflate salts. The absolute configuration of 3d
was determined to be R by single crystal X-ray diffraction
analysis.[22] Consequently, that of the other cyclopentenyl
carboxamides was assigned accordingly.
O
O
O
O
O
O
L1: R = Bn
L2: R = tBu
L3: R = Ph
Ph
Ph
N
N
N
N
N
N
Ph
Bn Bn
Ph
higher ee (93 and 95%, entries
9 and 10) than gem-
R
R
L4
L5
dimethylated ligand L3. Further increasing the ring size (L11)
afforded the product with diminished ee (entry 11). Using L10
as ligand, the effect of the counteranion of the diaryliodonium
salts on the reaction outcome was examined (X = OTf, PF6,
SbF6, entries 12-14). As it is seen, a significant counteranion
effect was observed and AsF6– remained optimal among those
examined in terms of both yield and ee. Subsequent survey of
reaction conditions varying the solvents and the copper
sources did not improve the reaction efficiency (entries 15-17).
Overall, the optimum conditions found consisted of performing
the arylative desymmetrization of 1a in DCM (c 0.1 M) at 80 oC
in the presence of Cu(OTf)2 (0.1 equiv), chiral bisoxazoline
L10 (0.2 equiv) and DTBP (1.2 equiv). Under these conditions
(entry 10), 3a was obtained in 76% yield with 95% ee.[21]
n
O
O
L8: n = 1
L9: n = 3
L10: n = 4
L11: n = 5
O
O
O
O
N
N
N
N
N
N
N
Ph
Ph
L6
L7
Ph
Ph
Ph
Ph
Figure 1. Structures of the representative chiral ligands.
Cu(OTf)2 (0.1 equiv)
L10 (0.2 equiv)
AsF6
N
N
+
OMe
OMe
Ar
I
Mes
Ar
DTBP (1.2 equiv)
O
O
N
1a
2
3
DCM, 80 o
C
N
OMe
OMe
R
O
O
R
3i R = Me, 68%, 95% ee
3j R = F, 55%, 92% ee
3a R = H, 76%, 95% ee
3b R = F, 76%, 92% ee
Table 1. Optimization of the reaction conditions.[a]
3k R = Cl, 81%, 88% ee
3l R = CF3, 58%, 89% ee
3m R = CO2Et, 78%, 88% ee[b]
3c R = Cl, 72%, 91% ee
3d R = Br, 77%, 88% ee
3e R = CF3O, 70%, 87% ee
3f R = CF3, 71%, 81% ee[a]
3g R = CO2Et, 66%, 91% ee
3h R = OMe, 34%, 94% ee
Cu(OTf)2 (0.1 equiv)
X
Ligand (0.2 equiv)
N
N
+
Ph
I
Mes
OMe
OMe
DTBP (1.2 equiv), DCM
Ph
O
O
1a
3a
2a
entry
1
2
3
4
5
6
7
8
Ligand
L1
L2
L3
L4
L5
L6
L7
L8
X
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
yield (%)[b]
trace
trace
65
48
56
trace
trace
61
ee (%)[c]
AsF6
AsF6
AsF6
AsF6
AsF6
AsF6
AsF6
AsF6
AsF6
AsF6
AsF6
OTf
-
-
N
3d
OMe
N
OMe
63
70
-12
-
N
OMe
O
O
O
S
3p 24%, 90% ee[c]
3n 53%, 93% ee
3o 57%, 90% ee
-
10
93
95
51
30
81
94
93
12
-
9
L9
71
76
65
77
51
70
52
53
Scheme 2. Scope of the diaryliodonium salts 2. The reaction was performed
on 0.2 mmol scale. Enantiomeric excess was determined by SFC analysis
on a chiral stationary phase. [a] At 70 oC. [b] The reaction performed at 1.0
mmol scale afforded 3m in 71% yield with 87% ee. [c] At 60 oC.
10
11
12
13
14
15
16
17[d]
L10
L11
L10
L10
L10
L10
L10
L10
PF6
SbF6
AsF6
AsF6
AsF6
Toluene
DCM
Cu(OTf)2 (0.1 equiv)
L10 (0.2 equiv)
R
R
AsF6
trace
N
N
Ph
I
Mes
+
OMe
OMe
N
DTBP (1.2 equiv)
Ph
O
DCM, 80 o
C
O
3
1
2a
[a] 1a (0.2 mmol), 2a (0.24 mmol), Cu(OTf)2 (0.02 mmol), Ligand (0.04
mmol), DTBP (0.24 mmol), DCM (2.0 mL), 80 oC, 12 h in a sealed tube. [b]
Isolated yield. [c] Determined by SFC analysis on a chiral stationary phase.
[d] CuCl (0.1 equiv) was used. DTBP = 2,6-di-tert-butylpyridine.
Cl
Ar
R
N
OMe
OMe
Ph
Ph
N
O
O
OMe
3u Ar = Ph, 71%, 94% ee
3q R = H, 68%, 93% ee[a]
3r R = nBu, 70%, 84% ee
3s R = Bn, 56%, 93% ee
Ph
A number of diaryliodonium salts with various electronic
properties were successfully converted into the corresponding
arylated cyclopentenyl carboxamides in moderate to high
yields with high to excellent ees (Scheme 2). Substituents at
para, meta positions were well-tolerated (3a-3m). The 4-
methoxyphenyl, an electron-rich aromatic group, was
transferred selectively at the expense of the mesityl group to
O
3v Ar = 4-BrC6H4, 65%, 94% ee
3w Ar = 4-MeOC6H4, 66%, 94% ee
3x Ar = 3-ClC6H4, 63%, 94% ee
3t 41%, 96% ee
Scheme 3. Scope of the cyclopentenes 1. The reaction was performed on
0.2 mmol scale (c 0.1 M). Enantiomeric excess was determined by SFC
analysis on a chiral stationary phase. [a] c 0.2 M.
afford
the
corresponding
product
with
excellent
enantioselectivity (3h). 3,5-Dimethylphenyl and 2-naphthyl
groups were transferred to cyclopentene without event (3n-3o).
Thiophenylated cyclopentene 3p can also be prepared, albeit
with low yield. Unfortunately, the reaction involving vinyl,
alkynyl and 3-indolyl aryliodonium hexafluoroarsenates
afforded a complex mixture mainly due to the instability of the
reagent at the reaction temperature. We noted that the
aryliodonium hexafluoroarsenates were less stable than their
Various substituted cyclopentenes were next examined as
reaction partners (Scheme 3). The α-unsubstituted amide was
phenylated to afford the desired product (3q) in good yield with
excellent enantiomeric excess. Different aliphatic (butyl, benzyl,
3-chloropropyl) and aromatic substituents with different
electronic properties at the α-position of the Weinreb amide
were compatible with this arylative desymmetrization process
affording the desired products (3r-3x) in good yields with
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10.1002/anie.201713329
Angewandte Chemie International Edition
COMMUNICATION
excellent ees. We note that arylation of cyclopent-3-ene-1-
carboxylic acid, its secondary and tertiary amide derivatives
under standard conditions afforded the arylated products in
only low to moderate yields. On the other hand, the methyl
ester was converted to the phenylated product in 66% yield
with 70% ee (see SI for details).
faces of the double bond as well as the otherwise sterically
unbiased C(sp2) carbons. Electrophilic arylation of the double
bond would generate the carbenium intermediate D with
concurrent generation of the chiral center. Removal of the
most acidic benzylic proton would then allow the regeneration
of the double bond leading to the observed product 3.
PhMgBr
THF, RT
Cu(OTf)2 (0.1 equiv), L10 (0.2 equiv)
MgBr
THF, RT
AsF6
Y
Y
Ph
+
Ar
I Mes
DTBP (1.2 equiv), DCM, 80 o
C
Ar
Ph
Ph
Ph
Ph
O
O
1
2
4
O
O
N
OMe
5 87%
6 74%
7 92%
O
Ph
OH
OH
O
OH
3a
OH
LiAlH4
THF, RT
NaOH/EtOH
50 oC, 12 h
Br
Me
8 83%
4a 47%, 97% ee
NH
4b 43%, 98% ee
4c 51%, 91% ee
NH
O
O
I2/KI, NaHCO3
OH
NH
I
THF/H2O, 50 o
C
Ph
tBu
tBu
tBu
O
EtO2C
O
Ph
H
O
O
9 73%
8
H
Cl
CH2I2, ZnEt2
DCM, RT
4d 77%, 97% ee
4e 71%, 94% ee
4f 75%, 95% ee
OH
OH
11 (+)-α-thujone
Ph
Ph
4a
10 81%
4a
4e
Scheme 6. Synthetic transformations of 3a and 4a.
Scheme 4. Desymmetrization of cyclopent-3-en-1-ol and N-(cyclopent-3-en-
1-yl)pivalamide. The reaction was performed on 0.2 mmol scale.
Enantiomeric excess was determined by SFC analysis on a chiral stationary
phase.
Further transformations of these chiral cyclopentenes were
performed to illustrate their synthetic potential (Scheme 6).
Nucleophilic addition of Grignard reagents to 3a at room
temperature afforded the corresponding ketones 5 and 6 in
high yields. Reduction of 3a with LiAlH4 delivered aldehyde 7
in 92% yield. Saponification of 3a (NaOH in ethanol, 50 oC)
furnished carboxylic acid 8 (83%), which was subsequently
converted to the bridged bicycle 9 (73%) under standard
iodolactonization conditions. Finally, the hydroxyl group-
directed Simmons-Smith cyclopropanation of 4a under
Furukawa conditions.[26] afforded bicycle 10 in 81% yield as a
single diastereomer. This represented an efficient access to
the analogues of thujone (11), an inhibitor of the
g-aminobutyric acid A (GABAA) receptor.[27]
Phenols and alcohols are known to react with
diaryliodonium salts to afford aryl ethers.[23] Therefore, we
were delighted to find that submitting the cyclopent-3-en-1-ols
to our standard reaction conditions led selectively to the
corresponding arylated cyclopentenyl alcohols (4a-4c) with
excellent ees, albeit in moderate yields (Scheme 4). Pleasantly,
N-(cyclopent-3-en-1-yl)pivalamide
underwent
arylative
desymmetrization smoothly to afford the corresponding
products 4d-4f in good yields with excellent ees. The absolute
configuration of 4a and 4e was determined to be R by single
crystal X-ray diffraction analysis and that of the others in these
series was assigned accordingly.[22]
In summary, we have presented the first example of
copper-catalyzed enantioselective arylative desymmetrization
of prochiral 4-substituted or 4,4-disubstituted cyclopent-1-enes
with diaryliodonium salts and documented that an achiral
counteranion of iodonium salts had an important effect on the
enantioselectivity of the reaction. Weinreb amide, hydroxyl
group and pivalamide were all effective directing groups in this
CuX2
R
L*
NMeOMe
AsF6
Cu+L* X–
Ar
Ar
I
Mes
O
3
A
2
X = AsF6 or OTf
Cu+L*
MeOMeN
R
–
X
2X
transformation.
The
reaction
provided
a
practical,
O
Ar-Cu2+L*
Ar
straightforward access to a wide range of structurally diverse
enantioenriched arylated cyclopentenes, difficultly accessible
otherwise. This Cu-catalyzed arylative desymmetrization
process complemented well the classic Heck reaction.
B
H
X
D
R
Ph
2X–
O
MeOMeN
R
Ar
NMeOMe
O
2+
N
N
Cu
1
O
O
C
Ph
Acknowledgements
We thank EPFL (Switzerland), Swiss National Science
Foundation (SNSF) for financial supports. We thank Dr. F.-T
Farzaneh and Dr. R. Scopelliti for X-ray crystallographic
analysis of 3d, 4a and 4e.
Scheme 5. Possible reaction pathway.
A possible reaction pathway is depicted in Scheme 5.
Oxidative addition of diaryliodonium salt 2 to the in situ formed
Cu(I) species A[24] would generate an Ar-Cu(III) intermediate
B.[25] which, upon coordination to both the carbonyl group of
the Weinreb amide and the double bond would generate
complex C. The formation of this chelate and the nature of the
C2-symmetric ligand allowed effective differentiation of the two
Keywords: desymmetrization • asymmetric synthesis •
diaryliodonium salt • homogeneous catalyst • Heck reaction
[1]
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10.1002/anie.201713329
Angewandte Chemie International Edition
COMMUNICATION
[2]
[3]
N. E. Carpenter, D. J. Kucera, L. E. Overman, J. Org. Chem. 1989,
54, 5846.
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[20] One single example of racemic reaction was described in the
Scheme 1 of ref 11a.
[6]
[21] The ratio of ligand/Cu salt influenced significantly the reaction
outcome (See SI for details). While the copper salt chelated to one
bidentate ligand might be the active catalyst, the presence of a
second equivalent of ligand might accelerate the dissociation of the
product from the metal salt, hence the turnover of the catalyst, and at
the same time stabilize the copper salt in the form of CuXL2.
[22] CCDC 1569766 (3d), CCDC 1568887 (4a) and CCDC 1572522 (4e)
contain the supplementary crystallographic data for this paper. These
data are provided free of charge by The Cambridge Crystallographic
Data Centre.
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10.1002/anie.201713329
Angewandte Chemie International Edition
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Asymmetric Synthesis
L* =
O
R
Y
AsF6
Mes
R
[Cu], L*
Hua Wu, Qian Wang, and Jieping
Zhu*__________ Page – Page
O
+
Ar
I
Y
Ar
N
N
R = H, aryl, alkyl
Y = Weinreb amide, OH, NHCOtBu
Ph
Ph
Copper-Catalyzed Enantioselective
Arylative Desymmetrization of Prochiral
Cyclopentenes with Diaryliodonium
Salts
No shift: In the presence of a catalytic amount of the in situ generated chiral copper-bisoxazoline
complex, reaction of 4-substituted or 4,4-disubstituted cyclopent-1-enes with the diaryliodonium
hexafluoroarsenate afforded the chiral arylated products in good yields with excellent
enantioselectivities. Double bond was not migrated in this transformation.
This article is protected by copyright. All rights reserved.