Rhodium-catalyzed asymmetric arylation of β,γ-unsaturated α-ketoamides for the construction of nonracemic γ,γ- diarylcarbonyl compounds

Article abstract of DOI:10.1002/anie.201403325

A highly regio- and enantioselective rhodium-catalyzed 1,4-addition of arylboronic acids to β,γ-unsaturated α-ketoamides using a simple new chiral sulfinylphosphine ligand is described. This transformation provides an attractive approach to construct chiral nonracemic γ,γ-diarylsubstituted carbonyl compounds, as exemplified in the concise syntheses of sertraline and tetrahydroquinoline-2-carboxylamide. Constructing chiral carbonyls: A simple new chiral sulfinylphosphine ligand L was developed, which promoted excellent 1,4-selectivities and enantioselectivities in the rhodium-catalyzed conjugate addition of arylboronic acids to β,γ-unsaturated α-ketoamides. The desired γ,γ-diaryl-α-ketocarbonyl compounds were afforded with high yields and high optical purities.

Full text of DOI:10.1002/anie.201403325

Angewandte
Chemie
DOI: 10.1002/anie.201403325
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric Arylation of b,g-Unsaturated a-
Ketoamides for the Construction of Nonracemic g,g-Diarylcarbonyl
Compounds**
Juanjuan Wang, Min Wang, Peng Cao, Liyin Jiang, Guihua Chen, and Jian Liao*
Abstract: A highly regio- and enantioselective rhodium-
catalyzed 1,4-addition of arylboronic acids to b,g-unsaturated
a-ketoamides using a simple new chiral sulfinylphosphine
ligand is described. This transformation provides an attractive
approach to construct chiral nonracemic g,g-diarylsubstituted
carbonyl compounds, as exemplified in the concise syntheses of
sertraline and tetrahydroquinoline-2-carboxylamide.
more versatile catalytic systems. The rhodium-catalyzed
asymmetric conjugate addition of electron-deficient olefins
with arylboronic acids, pioneered by Hayashi, Miyaura, and
co-workers,[4] is one straightforward method to construct
chiral gem-diaryl alkanes.[5] Nevertheless, the asymmetric
route to access enantioenriched g,g-diarylsubstituted carbon-
yl compounds remains a significant challenge.[6] Herein, we
report the first enantioselective Rh-catalyzed 1,4-selective
conjugate addition of arylboronic acids to b,g-unsaturated a-
ketoamides (Scheme 1), and demonstrate the synthetic utility
of the method with a concise formal synthesis of sertraline.
Chiral nonracemic g,g-diarylsubstituted carbonyl units and
their derivatives are typical scaffolds present in a number of
natural products, pharmaceuticals, and bioactive compounds
(Figure 1).[1] Many synthetic methods for the construction of
Figure 1. Selected bioactive compounds containing chiral g,g-
diarylsubstituted carbonyl compounds and derivatives.
Scheme 1. Rhodium-catalyzed asymmetric arylation of b,g-unsaturated
a-ketocarbonyl compounds. ShiP=aryl(1,1’-spirobiindane-7,7’-diyl)-
phosphite.
enantioenriched g,g-diarylsubstituted carbonyl compounds
have been developed; however, these compounds are gen-
erally prepared through the transformation of optically pure
precursors.[2] Although routes involving asymmetric catalysis
provide an attractive alternative, the current methods tend to
be limited in scope[3] and thus require the development of
Although b,g-unsaturated a-ketocarbonyl compounds are
widely used in aldol, Diels–Alder, Friedel–Crafts, and other
reactions,[7] they have seldom served as Michael acceptors in
transition-metal-catalyzed additions[8] of organometallic
reagents. Alexakis et al. used the highly reactive AlMe3 as
the Michael donor to achieve a remarkable Cu-catalyzed
asymmetric 1,4-addition to b,g-unsaturated a-ketoesters,[8a] as
well as b,g-unsaturated a-ketoamides.[8b] However, these
substrates are particularly challenging for rhodium-catalyzed
asymmetric conjugate additions, owing to the high reactivity
of the a-keto moiety, which promotes 1,2-addition.[9] For
instance, Zhou and co-workers demonstrated a rhodium-
catalyzed asymmetric addition of arylboronic acids to (E)-
benzyl-2-oxo-4-phenylbut-3-enoate using a spirophosphine
ligand, to furnish the 1,2-addition products with excellent
yields and enantioselectivities (Scheme 1, Equation 1).[9c]
Another challenge with these substrates is their ability to
undergo sequential 1,4- and 1,2-addition, which might com-
plicate the reaction system. To this end, we report a new
sulfinylphosphine ligand, which controls the 1,4-selectivity in
[*] Dr. J. J. Wang, Prof. Dr. J. Liao
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences, Chengdu 610041 (China)
and
University of Chinese Academy of Sciences, Beijing 100049 (China)
Dr. J. J. Wang, Dr. M. Wang, Prof. Dr. P. Cao, L. Y. Jiang,
Dr. G. H. Chen, Prof. Dr. J. Liao
Natural Products Research Center, Chengdu Institute of Biology,
Chinese Academy of Sciences, Chengdu, 610041 (China)
E-mail: jliao@cib.ac.cn
Prof. Dr. J. Liao
College of Chemical Engineering, Sichuan University (China)
[**] We thank the NSFC (No. 21272226, 21202160 and 21072186),
Chengdu Institute of Biology of CAS (Y0B1051100) and the Major
State Basic Research Development Program (973 program,
2010CB833300).
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403325.
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the rhodium-catalyzed arylation of b,g-unsaturated a-ketoa-
mides with excellent chemo-, regio- and enantioselectivities.
We have previously demonstrated that chiral sulfinyl-
phosphine ligands effectively promoted Rh-catalyzed aryla-
tion of arylboronic acids to nitro-styrenes and chalcones, and
provide chiral gem-diarylalkanes in high yield and enantio-
meric excess.[10] To examine the feasibility of this strategy,
phenylboronic acid 2a was added to the b,g-unsaturated a-
ketoamides (1a–c)[8b] and ligand L1[11] with [{Rh(C2H4)2Cl}2]
as catalyst, in the presence of aqueous KOH in dichloro-
methane (DCM) at 408C (Table 1, entries 1–3). Amides (1a–
c) provide the 1,4-adduct 3 as product in more than 86% yield
with excellent 1,4-selectivity (93/7 to 94/6) and enantioselec-
tivities (92–93% ee). The reaction also demonstrated excel-
lent chemoselectivity, in which no double arylation products
were detected.[12] In addition, the nature of the amide (tert-
butyl-, cyclohexyl-, and benzyl-) does not influence the regio-
and enantioselectivity of the reaction (entries 1–3).
moiety in L3. Importantly, L3 can be readily prepared by
a concise two-step synthetic route via a key intermediate, 1,3-
bis(tert-butylsulfinyl)benzene 6, starting from 1,3-dibromo-
benzene 5 (see Supporting Information). After a systematic
screening of the other reaction conditions, such as solvent,
base, and the ligand/Rh ratio, a mixture of dichloromethane/
potassium hydroxide with a 2:1 ligand/metal ratio proved
optimal (see Supporting Information). The best regio- and
enantioselectivity and the highest yield of isolated product
were achieved for the reaction at 208C for 12 hours (entry 6).
Having established the optimal reaction conditions, we
examined the scope of potential substrates. Table 2 shows
a range of 1,4-adducts 3aa–3ao, isolated in 75–91% yield and
with excellent enantioselectivities (96–99% ee). These
Table 2: Substrate scope for Rh-catalyzed asymmetric 1,4-addition of
various arylboronic acids 2 to b,g-unsaturated a-ketoamide 1a.[a]
Encouraged by the preliminary studies with the sulfinyl-
phosphine ligand L1, we tested other ligands (Table 1).[13]
Interestingly, the bifunctional sulfinylphosphine ligand L2,
which was recently introduced by our group,[14] did not afford
any of the desired product (entry 4). However, the sulfinyl-
phosphine L3 proved an efficient ligand for this reaction,
providing the desired 1,4-adduct 3 in 91% yield and with 98%
enantiomeric excess (entry 5). The increase of ee value from
L1 to L3 might be attributed to the more appropriate chiral
environment provided by the additional tert-butylsulfinyl
Table 1: Conditions screening for Rh-catalyzed asymmetric 1,4-addition
of phenylboronic acid 2a to b,g-unsaturated a-ketoamides (1a–c).[a]
entry
L
1
Ratio[b] of
3/4
Yield[c] of 3 [%]
ee[d] of
3 [%]
1
2
3
4
L1
L1
L1
L2
L3
L3
1a
1b
1c
1a
1a
1a
94/6
93/7
93/7
n.d.[e]
94/6
96/4
90
90
86
trace
91
93
92
92
n.d.[e]
98
5
6[f]
91
98(R)[15]
[a] Conditions: 1 (0.2 mmol), 2a (0.4 mmol), [{Rh(C2H4)2Cl}2]
(1.5 mol%), ligand (6.0 mol%), and KOH (50 mol%; 1.0m in H2O) in
1
DCM (1.0 mL), 408C, 4 h. [b] Determined by crude H NMR spectro-
scopic analysis. [c] Yield of isolated product. [d] Determined by chiral
HPLC analysis. [e] n.d.: not determined. [f] At 208C for 12 h. MOM=
methoxymethyl.
[a] Conditions: 1a (0.2 mmol), 2 (0.4 mmol), [{Rh(C2H4)2Cl}2]
(1.5 mol%), L3 (6.0 mol%), and KOH (50 mol%; 1.0m in H2O) in DCM
(1.0 mL), 208C, 12 h. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis. TBS=tert-butyldimethylsilyl.
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adducts were prepared from reactions between a-ketoamide
1a and a variety of arylboronic acids with different stereo-
electronic properties (electron-rich and electron-poor). Note,
in addition to monosubstituted derivatives, 3,4-disubstituted
phenylboronic acids 2m and 2n react efficiently with 1a to
furnish 3am and 3an. For ortho-substituted derivatives, ortho-
methoxyphenylboronic acid was unreactive, however the
reaction with 2-naphthylboronic acid proceeded efficiently
to yield 3ao (91% yield, 96% ee).
Having established the scope of the arylboronic acid
reagent, we turned our attention to the a-ketoamide. The
products from the reactions between various b,g-unsaturated
a-ketoamides 1e–1r (see the Supporting Information for
structures) and arylboronic acids (2a or 2q) are shown in
Table 3. Interestingly, the stereoelectronic properties of the g-
aryl groups in 1e–1n do not affect the overall efficiency and
selectivity of this transformation. Gratifyingly, bulky g-aryl
groups with ortho-substituents readily undergo reaction to
form products 3ha–3ka with good yields and excellent
enantioselectivities (up to 99% ee), in contrast to the
arylboronic acid substrate limitation. The g-dichlorophenyl-
and g-furyl-substituted 3na and 3oa were also readily
prepared by this method. Using the conjugated diene 1p as
substrate, functional crotyl-substituted 1,4-adduct 3pa was
obtained in 90% yield and more than 99% ee. In this
reaction, no 1,6-addition product was observed. Note, this
methodology also provided a general route for the synthesis
of enantiomerically enriched g-alkyl-g-aryl (particularly, g-
methyl-g-aryl) carbonyl compounds from g-alkyl-b,g-unsatu-
rated a-ketoamides.[8a,b,16] For example, the reaction between
phenylboronic acid 2a and g-methyl- and g-propyl-b,g-
unsaturated a-ketoamides (1q and 1r) proceeded smoothly
in the rhodium-catalyzed 1,4-arylation to provide 3qa and 3ra
in good yields and in enantiomeric excess. In addition, b,g-
unsaturated a-ketoesters were employed in the catalytic
system (using L1 as the ligand) and were readily transformed
to their corresponding products 3sa, 3sc, and 3sd with 46–
68% yields and 67–80% ee. In this case, lower yields were
observed because of the partial decomposition of substrates
and products under the basic reaction conditions.
Table 3: Substrate scope for Rh-catalyzed asymmetric 1,4-addition of
phenylboronic acid 2a to various b,g-unsaturated a-ketoamides.[a]
The performance of the new rhodium/sulfinylphosphine
catalyst in the enantioselective 1,4-addition reaction was also
undertaken on a gram scale, using 0.5 mol% of [{Rh-
(C2H4)2Cl}2] and the b,g-unsaturated a-ketoamide 1a
(1.04 g, 3.84 mmol), with 2 equivalents of phenylboronic
acid 2a at 408C for 12 hours. This reaction afforded the 1,4-
adduct 3aa in excellent yield (1.22 g, 90%) and without loss of
enantioselectivity (97% ee, Scheme 2).
Scheme 2. Gram scale experiment.
The utility of this methodology is demonstrated in
a concise formal synthesis[2a–c] of sertraline (Scheme 3), an
important pharmaceutical agent for the treatment of depres-
sion. The 1,4-adduct 3na (98% ee) was converted into 1,3-
dithiolane 7 and then reduced[8b,17] to form g,g-diarylamide 8,
without the loss of enantiomeric excess.[18] The amide 8 was
hydrolyzed by heating under reflux in concentrated HCl for
20 hours to afford 9. Product 9 was then subjected to an acid-
catalyzed cyclization[2b] to provide the tetralone 10 in 60%
yield and 92% enantiomeric excess for 2 steps (overall yield
22%). The tetralone 10 can be readily converted into
sertraline by a known procedure.[19] Furthermore, to exploit
the carbonyl group of the a-ketoamide product (Scheme 4),
the adduct N-tert-butyl-4-(2-nitrophenyl)-2-oxo-4-phenylbu-
tanamide (3ja) was exposed to an atmosphere of hydrogen
(1 atm) in the presence of Pd/C as catalyst (5 %).[20] Product
[a] Conditions: 1 (0.2 mmol), 2a/2q (0.4 mmol), [{Rh(C2H4)2Cl}2]
(1.5 mol%), L3 (6.0 mol%), and KOH (50 mol%; 1.0m in H2O) in DCM
(1.0 mL), 208C, 12 h. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis. [d] L1 as ligand, Cy=cyclohexyl.
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hydroquinoline-2-carboxylamide.
11, one of a new class of tetrahydroquinoline-2-carboxyl
derivatives, was isolated in 93% yield and 96% ee.[21]
In summary, we have developed a new chiral sulfinyl-
phosphine ligand L3, which promotes, for the first time, the
rhodium-catalyzed 1,4-addition of arylboronic acids to b,g-
unsaturated a-ketoamides. This methodology proceeds with
excellent chemo-, regio- and enantioselectivities in high yield
(up to 93%) and high enantiomeric excess (up to 99% ee).
The procedure provides a convenient approach to access
important chiral g,g-diarylsubstituted carbonyl compounds.
Additionally, the synthetic utility of this methodology was
demonstrated in a concise formal synthesis of sertraline and
the synthesis of a tetrahydroquinoline-2-carboxyl derivative.
Studies to apply enantioenriched g,g-diarylsubstituted car-
bonyl compounds in useful organic syntheses are underway in
our laboratory.
Received: March 14, 2014
Published online: && &&, &&&&
[6] Recently, a Rh-catalyzed 1,4-addition of arylboronic acid to b,g-
unsaturated a-ketoester was observed to obtain b,b-diaryl-a-
ketoester as product in 43% yield and 5% ee. See: T. S. Zhu,
M. H. Xu, Chin. J. Chem. 2013, 31, 321.
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Keywords: asymmetric synthesis · enantioselectivity ·
.
homogeneous catalysis · rhodium · S,P ligands
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[12] Control experiment: 1,4-adduct 3aa was added to phenylboronic
acid 2a under standard reaction conditions (see Table 1). No
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[15] The absolute configuration of 3aa was determined by single-
crystal X-ray crystallography, displacement ellipsoids set at 50%
probability. CCDC 995001 (3aa) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[18] 40% of starting material 3na was recovered from the first step.
Wolf–Kishner reduction was used to reduce the ketone and 8
was obtained in high yield (87% yield for two steps). However,
the ee of 8 decreased to 26% (see Supporting Information for
details).
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2011, 111, 7157.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
J. J. Wang, M. Wang, P. Cao, L. Y. Jiang,
G. H. Chen, J. Liao*
&&&& — &&&&
Rhodium-Catalyzed Asymmetric Arylation
of b,g-Unsaturated a-Ketoamides for the
Construction of Nonracemic g,g-
Diarylcarbonyl Compounds
Constructing chiral carbonyls: A simple
new chiral sulfinylphosphine ligand L was
developed, which promoted excellent 1,4-
selectivities and enantioselectivities in
the rhodium-catalyzed conjugate addition
of arylboronic acids to b,g-unsaturated a-
ketoamides. The desired g,g-diaryl-a-
ketocarbonyl compounds were afforded
with high yields and high optical purities.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!