Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to five-, six-, and seven-membered β-substituted cyclic enones: enantioselective construction of all-carbon quaternary stereocenters

Article abstract of DOI:10.1021/ja200664x

The first enantioselective Pd-catalyzed construction of all-carbon quaternary stereocenters via 1,4-addition of arylboronic acids to β-substituted cyclic enones is reported. Reaction of a wide range of arylboronic acids and cyclic enones using a catalyst

Full text of DOI:10.1021/ja200664x

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Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic
Acids to Five-, Six-, and Seven-Membered β-Substituted Cyclic Enones:
Enantioselective Construction of All-Carbon Quaternary
Stereocenters
Kotaro Kikushima, Jeffrey C. Holder, Michele Gatti, and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S Supporting Information
b
ketones.13 In 2010, Lu reported the use of a dicationic bipyridine-
ABSTRACT: The first enantioselective Pd-catalyzed con-
struction of all-carbon quaternary stereocenters via 1,4-addi-
tion of arylboronic acids to β-substituted cyclic enones is
reported. Reaction of a wide range of arylboronic acids and
cyclic enones using a catalyst prepared from Pd(OCOCF3)2
and a chiral pyridinooxazoline ligand yields enantioenriched
products bearing benzylic stereocenters. Notably, this trans-
formation is tolerant to air and moisture, providing a practical
and operationally simple method of synthesizing enantioen-
riched all-carbon quaternary stereocenters.
derived palladium catalyst for additions to β-substituted enones
that deliver racemic products containing the quaternary center in
high yield.14 Notably absent from the Lu report and from the
work of others in the area are examples of Pd-catalyzed enantio-
selective conjugate addition reactions that forge a quaternary
center.13 Herein, we report the first palladium-catalyzed asym-
metric conjugate addition of arylboronic acids to β-substituted
cyclic enones employing an easily accessible chiral pyridinoox-
azoline (PyOX) ligand.15 These reactions generate a wide array
of benzylic all-carbon quaternary stereocenters while exhibiting
extraordinary tolerance to both air and water.
To achieve the desired enantioselective conjugate addition,
the reaction of 3-methylcyclohexen-2-one (1) with phenylboronic
acid (2) was investigated in the presence of various palladium
catalysts and chiral ligands (Table 1). After a preliminary ligand
search that included an array of standard chiral ligand frame-
works,16 we discovered that t-BuPyOX (4)15 provided high levels
of enantioselection. In the presence of ligand 4, a range of Pd(II)
sources were capable of catalyzing the desired reaction (entries
1ꢀ5), with carboxylate counterions leading to the highest levels of
asymmetric induction and chemical yield. A catalyst derived from
Pd(OCOCF3)2 and pyridinooxazoline 4 produced the desired
ketone product 317 in 87% yield and 91% ee (entry 5).18 By using
1,2-dichloroethane in place of dichloromethane as solvent and
increasing the reaction temperature from 40 to 60 °C, ketone 3
was isolated in 99% yield and 93% ee (entry 6).19,20 Remarkably,
the high yield and enantioselectivity were maintained even upon
addition of 10 equiv of water (entry 7). Furthermore, the amount
of phenylboronic acid was reduced to 1.1 equiv with no detri-
mental effects (entry 8). Finally, we have performed the reaction
on a multigram scale without complication (entry 9). It should be
noted that (S)-t-BuPyOX (4) can be easily prepared in only two
synthetic steps from commercially available materials.15,18,21
To investigate the reaction scope, we explored various aryl-
boronic acids as nucleophiles for this process (Table 2). Gen-
erally, para-substituted arylboronic acids are well tolerated
(entries 1ꢀ9). Reactions with 4-methyl- and 4-ethylphenylboro-
nic acid proceeded well to give high yields of the desired products
with good asymmetric induction (entries 1 and 2). While
electron-rich nucleophiles tend to be reliable reaction partners,
he catalytic enantioselective construction of all-carbon qua-
T
ternary stereocenters remains a difficult problem in synthetic
chemistry.1 A reliable approach toward this challenge has been
the asymmetric conjugate addition of carbon-based nucleophiles
to suitable R,β-unsaturated carbonyl acceptors.2 Pioneered by
the groups of Feringa, Alexakis, and Hoveyda, the majority of
asymmetric conjugate additions for the synthesis of quaternary
centers involve the use of highly reactive organometallic reagents
(e.g., diorganozinc,3 triorganoaluminum,4j and organomagne-
sium reagents5) to a variety of unsaturated electrophiles with
copper catalysts.6 These reactions uniformly involve air and
moisture sensitive organometallic reagents that require rigor-
ously anhydrous reaction conditions. Alternatively, Hayashi has
championed the use of chiral rhodium catalysts in combination
with air stable, easily handled nucleophilic organoboron reagents to
produce a wide array of conjugate addition adducts in exceptional
yield and ee.7,8 In contrast to the copper systems, relatively few
examples in the rhodium series lead to the formation of products
containing quaternary centers.9 Notably, Hayashi and Shintani
have recently developed a rhodium•diene-catalyzed conjugate
addition of sodium tetraaryl borates (Ar4BNa) and arylboroxines
((ArBO)3) toβ,β-disubstituted enones to provide ketone products
bearing β-chiral all-carbon quarternary stereocenters.10,11 Unfortu-
nately, in these examples commercially available arylboronic acids
(ArB(OH)2) are not competent nucleophiles.10ꢀ12
The conjugate addition of arylboronic acids and their deriva-
tives to enones with palladium catalysis has been investigated for
some time and has resulted in the development of addition
reactions that produce enantioenriched tertiary β-substituted
Received: January 23, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Table 1. Optimization of Reaction Conditionsa
Table 2. Addition of Arylboronic Acids to 3-Methylcyclo-
hexen-2-onea
temp
time
(h)
yield
(%)b
ee
(%)c
Pd
temp
yield
(%)b
ee
(%)c
entry
R =
(°C)
entry
source
solvent
CH2CI2
(°C)
1
4-Meꢀ
4-Etꢀ
4-MeOꢀ
4-BnOꢀ
4-TBSOꢀ
4-Acꢀ
4-CIꢀ
4-Fꢀ
4-F3Cꢀ
3-Meꢀ
3-CIꢀ
3-Brꢀ
3-MeO2Cꢀ
3-O2Nꢀ
60
60
40
60
40
60
60
80
60
60
60
60
60
60
12
12
24
18
24
18
12
12
12
24
18
24
24
18
99
90
58
96
52
99
94
84
99
99
55
44
91
40
87
85
69
74
82
96
95
92
96
91
96
85
95
92
1
PdCI2
40
40
40
ꢀ
ꢀ
69
ꢀ
ꢀ
17
2
2
3d
Pd(MeCN)2CI2
Pd(MeCN)2CI2,
AgOTf
CH2CI2
CH2CI2
3
4
5
4
Pd(OAc)2
CH2CI2
40
40
60
60
60
60
65
87
99
99
99
97
92
91
93
91
93
91
6
5
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
CH2CI2
7
6
CICH2CH2CI
CICH2CH2CI
CICH2CH2CI
CICH2CH2CI
8
7e
8f
9g
9
10
11
12
13
14
a Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), 3-methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (5
mol %), and ligand 4 (6 mol %) in solvent (1 mL) for 12 h, unless
otherwise noted. b Isolated yield. c Ee was determined by chiral HPLC;
see Supporting Information. d 12 mol % AgOTf. e Reaction performed in
the presence of added H2O (2.5 mmol, 10 equiv). f Phenylboronic acid
loading reduced to 1.1 equiv. g Multigram scale-up reaction performed
with 3-methylcyclohexen-2-one (2.42 g, 22.0 mmol), phenylboronic
acid (44.0 mmol), H2O (5 equiv), Pd(OCOCF3)2 (5 mol %), and ligand
4 (6 mol %) in solvent (88 mL) for 12 h.
a Conditions: Reactions were performed with phenylboronic acid
(0.50 mmol), 3-methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2
(5 mol %), and ligand 4 (6 mol %) in (ClCH2)2 (1 mL) at 40ꢀ80 °C for
12ꢀ24 h. b Isolated yield. c Ee was determined by chiral HPLC; see
Supporting Information.
Table 3. Asymmetric Synthesis of β,β-Disubstituted Cyclic
they often furnish products in moderate enantioselectivity (entries
3ꢀ5). Electron-deficient nucleophiles fared particularly well,
producing ketone products in excellent ee (entries 6ꢀ9). Speci-
fically, these electron-poor nucleophiles can possess a wide range
of functional groups, such as a ketone (entry 6), halide (entries 7
and 8), and trifluoromethyl group (entry 9). Reactions involving
meta-substituted arylboronic acids were also broadly successful
with alkyl (entry 10), halide (entries 11 and 12), ester (entry 13)
and even nitro (entry 14) groups on the nucleophile.22ꢀ24
We sought to further examine the scope of the reaction by
exploring cyclic enones of different ring sizes and with a range of
β-substitution (Table 3). Importantly, altering the ring size to the
five- or seven-membered ring series had no deleterious effect on
the transformation and fashioned ketones 5 and 6 in high yield
and ee. To the best of our knowledge this represents the first time
that quaternary centers have been constructed by asymmetric
conjugate addition of boronic acids to these differing ring sized
enones using a single catalyst.2 Cyclohexenones bearing other
β-alkyl substituents, such as ethyl, n-butyl, and benzyl, furnished
ketone products (i.e., 7ꢀ9) in good yield and excellent ee as well.
In addition to linear alkyl substitution, ketones with branched
β-alkyl substituents such as isopropyl (10), cyclopropyl (11),
and cyclohexyl (12) are produced in good yield and enantios-
electivity. Finally, products containing functionalized side chains,
such as benzyl ether 13, are readily obtained, providing a useful
chemical handle for further transformations.25
Ketonesa
a Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), cycloalkenone (0.25 mmol), Pd(OCOCF3)2 (5 mol %), and
ligand 4 (6 mol %) in (ClCH2)2 (1 mL) at 60 °C for 12 h.
stereocenter. Critically, five-, six-, and seven-membered ring
enones function well in the process, delivering products of
uniformly high ee using a single catalyst. A wide variety of
commercially available arylboronic acids and substituted enones
In summary, we report the first palladium-catalyzed enantiose-
lective conjugate addition of arylboronic acids to β-substituted cyclic
enones to deliver products containing an all-carbon quaternary
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can be employed in the asymmetric transformation, while exhi-
biting broad functional group tolerance. Furthermore, the
reaction displays a remarkable tolerance to water and oxygen,
and reactions are typically performed under an atmosphere of
air in screw-top vials and without the need for purification or
distillation of any commercially obtained materials. Finally, the
optimal chiral ligand, (S)-t-BuPyOX (4), is expediently pre-
pared, rendering this process an experimentally simple, prac-
tical method for enantioselective construction of all-carbon
quaternary stereocenters. Continuing investigations of this
method and application of this chemistry in the context of
natural product synthesis are currently underway and will be
reported in due course.
2008, 47, 8211. (h) Ladjel, C.; Fuchs, N.; Zhao, J.; Bernardinelli, G.; Alexakis,
A. Eur. J. Org. Chem. 2009, 4949. (i) Palais, L.; Alexakis, A. Chem.—Eur. J.
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Synlett 2010, 1694. (k) Hawner, C.; M€uller, D.; Gremaud, L.; Felouat, A.;
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D.; Rix, D.; Mauduit, M.; Alexakis, A. Chem.—Eur. J. 2010, 16, 9890. (c)
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47, 9122. (d) Matsumoto, Y.; Yamada, K.-I.; Tomioka, K. J. Org. Chem.
2008, 73, 4578.
(6) Recently, an asymmetric conjugate addition of cyanide in the
presence of a catalyst derived from Sr(Oi-Pr)3 has been reported; see:
Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 8862.
(7) (a) For the seminal report in this area, see: Takaya, Y.;
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(8) For selected recent examples, see: (a) Hayashi, T.; Ueyama, K.;
Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (b)
Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
2004, 126, 1628. (c) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T.
Org. Lett. 2004, 6, 3425. (d) Otomaru, Y.; Okamoto, K.; Shintani, R.;
Hayashi, T. J. Org. Chem. 2005, 70, 2503. (e) Paquin, J.-F.; Defieber, C.;
Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850.
(9) (a) Mauleoꢀn, P.; Carretero, J. C. Chem. Commun. 2005, 4961.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details. This ma-
b
terial is available free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Corresponding Author
stoltz@caltech.edu
(10) (a) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588. (b) Shintani, R.; Takeda,
M.; Nishimura, T.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3969.
(11) The same group also reported additions to β,β-disubstituted
R,β-unsaturated esters; see: Shintani, R.; Hayashi, T. Org. Lett. 2011, 13,
350.
(12) A recent paper describing the use of a Rh•OlefOX (olefin-
oxazoline) complex provided a single example of a phenylboronic acid
addition to 3-methylcyclohexen-2-one (i.e., 1 þ 2 f 3). Unfortunately,
ketone 3 was isolated in only 36% yield and 85% ee; see: Hahn, B. T.;
Tewes, F.; Fr€ohlich, R.; Glorius, F. Angew Chem., Int. Ed. 2010, 49, 1143.
(13) For excellent review articles, see: (a) Gutnov, A. Eur. J. Org.
Chem. 2008, 4547. (b) Christoffers, J.; Koripelly, G.; Rosiak, A.; R€ossle,
M. Synthesis 2007, 1279. (c) For a recent example, see: Xu, Q.; Zhang,
R.; Zhang, T.; Shi, M. J. Org. Chem. 2010, 75, 3935.
’ ACKNOWLEDGMENT
This publication is based on work supported by Award No.
KUS-11-006-02, made by KingAbdullah University of Scienceand
Technology (KAUST). The authors wish to thank NIH-NIGMS
(R01GM080269-01), Amgen, Abbott, Boehringer Ingelheim, and
Caltech for financial support. K.K. acknowledges the Japan Society
for the Promotion of Science for a postdoctoral fellowship. M.G. is
grateful to the Swiss National Science Foundation for financial
support through a postdoctoral fellowship.
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but 52% and 40% ee, respectively.
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(R)-t-leucine, a relatively expensive commercial compound that is now
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detrimental to the yields and stereoselectivity of the reaction with enone
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to provide a product in 32% yield and 77% ee.18
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(23) Although the reactions are generally high yielding, the impurity
profile is dominated by homocoupling of the arylboronic acid to the
corresponding biaryl.
(24) To date, reactions involving either heteroarylboronic acids or
β-aryl substituted enones have been unsuccessful.
(25) We have conducted the Pd-catalyzed reaction of PhB(OH)2
with racemic bicyclic enone (()-i, under our standard conditions
(PhꢀB(OH)2 (2 equiv), 4 (6 mol %), Pd(OCOCF3)2 (5 mol %),
ClCH2CH2Cl, 60 °C, 12 h). This process results in a modest kinetic
resolution of the starting enone (krel(fast/slow) = 3.4, (ꢀ)-i isolated in 95%
ee at 89% conversion).
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