Highly enantioselective conjugate addition of malonate and β-ketoester to nitroalkenes: Asymmetric C-C bond formation with new bifunctional organic catalysts based on cinchona alkaloids

Article abstract of DOI:10.1021/ja047281l

The development of readily accessible bifunctional chiral catalysts is a desirable yet challenging goal in catalytic asymmetric synthesis. In this communication, we describe the development of a new class of readily accessible chiral bifunctional organic catalysts that could be derived in one or two steps in high yield from either quinidine or quinine. These catalysts have been shown to catalyze a highly enantioselective conjugate addition of methyl and ethyl malonates and β-ketoesters to a broad range of β-substituted nitroalkenes, an synthetically important C-C bond-forming reaction utilizing readily available starting materials. This new catalytic asymmetric reaction proceeds in 91-98% ee and 71-99% yield. Copyright

Full text of DOI:10.1021/ja047281l

Published on Web 07/27/2004
Highly Enantioselective Conjugate Addition of Malonate and â-Ketoester to
Nitroalkenes: Asymmetric C-C Bond Formation with New Bifunctional
Organic Catalysts Based on Cinchona Alkaloids
Hongming Li, Yi Wang, Liang Tang, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received May 10, 2004; E-mail: deng@brandeis.edu
Chiral metallic and organic catalysts that possess both an acidic
and a basic/nucleophilic structural moiety constitute an increasingly
powerful platform for the development of asymmetric catalysis.1,2
The design and development of such bifunctional chiral catalysts
that are efficient, yet easily accessible, continues to be a major
challenge. Wynberg and co-workers demonstrated that natural
cinchona alkaloids such as quinidine (QD-1) and quinine (Q-1),
with a C-9 alcohol and a quinuclidine, serve as bifunctional chiral
organic catalysts by activating the nucleophile and electrophile,
respectively (Figure 1).3 However, the enantioselectivity of various
reactions catalyzed by natural cinchona alkaloids as chiral organic
catalysts is usually modest. Hatakeyama and co-workers reported
that the rigid modified cinchona alkaloid 2, which is readily
accessible from quinidine, efficiently catalyzes an enantioselective
Figure 1. Mode of activation of nucleophile and electrophile by cinchona
alkaloids.
Morita-Baylis-Hillman reaction.4 Both the quinoline phenol (C6′-
OH) and the quinuclidine of 2 were postulated to be involved in
stabilization of the transition state.4 With a cagelike structure that
prevents rotation of the C8-C9 bond, catalyst 2 is conformationally
Table 1. Asymmetric 1,4-Addition of Malonates to trans-Phenyl
Nitroalkene (5a)a
rigid, a common feature of many efficient chiral catalysts or ligands.
However, an enantiomer or pseudoenantiomer of 2 is not yet
accessible.
c
entry
catalystb
R
T (°C)
% conversion
%eed
Recent extensive studies using C-9 alcohol-modified cinchona
alkaloids 3 demonstrated that cinchona alkaloids with rotational
freedom around C8-C9 and C4′-C9 bonds are broadly effective
chiral organic catalysts.5,6 With an interest in developing efficient
bifunctional chiral organic catalysts, we became interested in the
asymmetric catalysis of cinchona alkaloids 4, which bear a
6′-hydroxyquinoline in place of a 6′-methoxyquinoline or quinoline
ring.7 Although previously not shown to be effective catalyst for
any asymmetric reaction,7 cinchona alkaloids QD-4 and Q-4 are
attractive to us due to their easy accessibility from quinine and
quinidine, respectively. Importantly, they could therefore serve as
bifunctional chiral catalysts that provide straightforward access to
either enantiomer of a given chiral product. Furthermore, with an
easily modified C9-OR group, 4 are more amenable than 1 or 2
toward structural variation for optimization of catalyst activity and
selectivity. In this communication, we report the first successful
use of cinchona alkaloids 4 as a catalyst for a highly enantioselective
reaction.
Our investigations began with the preparation of catalysts QD-
4a-c from quinidine (QD-1) via high-yielding and experimentally
simple one- or two-step protocols in 60-92% overall yield.8 These
catalysts and other readily accessible natural and modified cinchona
alkaloids were then examined for their ability to mediate enantio-
selective 1,4-addition of malonates to nitroalkenes, a synthetically
important C-C bond-forming reaction employing readily available
starting materials.9 Although high enantioselectivity for this 1,4-
addition is achieved with chiral Mg-bis(oxazoline) complexes10a,b
and bifunctional organic catalysts derived from chiral 1,2-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
QD
Et
Et
Et
Et
Et
Et
Et
Et
23
23
23
23
23
23
23
23
23
78
28
10
38
46
18
90
>98
91
84
75
86
90
16
6
DHQD-PHN
DHQD-CLB
(DHQD)2AQN
(DHQD)2PYR
(DHQD)2PHAL
2
QD-4a
QD-4b
QD-4c
2
QD-4a
QD-4b
QD-4c
QD-4a
Q-4a
QD-4a
Q-4a
12
18
24
13
75
79
78
82
86
90
88
91
93
96
97
99
Et
Et
23
Ete
Ete
Ete
Ete
Mef
Mef
Meg
Meg
-20
-20
-20
-20
-20
-20
-55
-55
73
>98
>98
81
93
a Unless noted, reactions were run with 0.1 mmol of 5 for 12 h. b See
Supporting Information for the structure of the catalysts. c Determined by
1H NMR analysis. d Determined by HPLC analysis (see Supporting
Information). e Reaction was run for 36 h. f Reaction was run for 36 h using
3.0 equiv of CH2(CO2Me)2. g Reaction was run for 108 h.
diaminocyclohexane,10c there is substantial room for improvement
in terms of both enantioselectivity and substrate scope.
Additions of dimethyl and diethyl malonate to nitroalkene 5a
mediated by various cinchona alkaloids were investigated in THF
(Table 1). Cinchona alkaloids bearing a 6′-hydroxyquinoline ring
(2 and 4) were found to afford significantly higher enantioselectivity
and a faster rate than those bearing a 6′-methoxyquinoline ring
(entries 7-10, 75-82% ee vs entries 1-6, 6-24% ee). Catalysts
9
9906
J. AM. CHEM. SOC. 2004, 126, 9906-9907
10.1021/ja047281l CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. 1,4-Addition of Dimethyl Malonate to Nitroalkenes
Catalyzed by Q-4a and QD-4aa,b
Scheme 1. Asymmetric 1,4-Addition of â-Ketoester to
trans-Phenyl Nitroalkene (5a)
a Isolated yield as a mixture of around 1/1 diasteromer. bDetermined by
HPLC analysis (see Supporting Information).
entry
R
time (h)
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
Ph
4-F-Ph
36 (36)
36 (36)
36 (36)
36 (36)
36 (44)
36 (39)
44 (47)
36 (36)
36 (36)
36 (36)
69 (72)
36 (36)
36 (44)
36 (36)
36 (36)
72 (72)
72 (72)
108 (108)
97 (99)
97 (97)
97 (97)
99 (98)
97 (97)
95 (96)
90 (94)
97 (99)
95 (97)
97 (94)
90 (88)
99 (99)
99 (96)
97 (95)
98 (99)
81 (82)
86 (84)
71 (80)
96g (93)
97 (94)
97 (94)
96 (94)
98 (94)
97 (93)
97 (95)
97 (93)
98 (96)
97 (95)
97 (92)
98 (92)
98 (95)
98 (96)
96 (92)
94 (91)
94 (92)
94 (91)
diastereomeric mixture, but both diastereomers were formed in 91%
ee. (Scheme 1). The 1:1 diastereomeric mixture is probably due to
racemization at the γ-stereogenic center under the reaction condi-
tions.
In summary, we have developed a new class of chiral bifunctional
organic catalysts based on cinchona alkaloids. These catalysts are
easily accessible from either quinine or quinidine and are shown
to be highly efficient for a synthetically important C-C bond-
forming asymmetric conjugate addition. We are now developing
these new bifunctional chiral organic catalysts for a wide range of
asymmetric reactions.
4-Cl-Ph
4-Br-Ph
4-Me-Ph
4-iPr-Ph
4-MeO-Ph
3-Me-Ph
2-Me-Ph
2-F-Ph
2-NO2-Phe
1-naphthyl
2-thienyl
2-furyl
3-pyridinyl
pentyl
Acknowledgment. We are grateful for the generous financial
support from NIH (GM-61591) and an Alfred P. Sloan research
fellowship (L.D.).
iBu
cyclohexylf
Supporting Information Available: Experimental procedures and
characterization of the products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
a Unless noted, reactions were run at -20 °C. b Results in parentheses
were obtained with QD-4a. c Isolated yield. d Determined by HPLC analysis
(see Supporting Information). e Reaction was performed at -55 °C. f Using
20 mol % catalyst. g Absolute configuration was determined to be S; for
details, see Supporting Information.
References
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Yoshikawa, N. Chem. ReV. 2002, 102, 2187-2210. (b) Gro¨ger, H. Chem.
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QD-4a-c, although conformationally mobile, afforded higher
enantioselectivity than 2 (entries 8-10 vs 7). The simplest and most
accessible member of cinchona alkaloids 4, QD-4a, was found to
be a highly efficient catalyst despite possessing two hydrogen-bond
donors. Better conversion and enantioselectivity can be achieved
with dimethyl rather than diethyl malonate (entries 15 vs 12).
Importantly, Q-4a afforded even higher enantioselectivity with an
opposite sense of asymmetric induction (entry 16) and up to 99%
ee can be attained with Q-4a at -55 °C (entry 18).
Preliminary kinetic studies established that the addition of
dimethyl malonate to 5a with Q-4a followed a first-order depend-
ence on the catalyst, the dimethyl malonate, and nitroalkene 5a.8
Phenol itself was found to be unable to catalyze the conjugate
addition. These results and the significantly higher enantioselectivity
and faster rates by QD-4a-c vs those by quinidine (QD-1) are
consistent with the notion that 4 serves as a bifunctional catalyst
that utilizes both the phenolic-OH and the quinuclidine function-
alities for the stabilization and organization of the transition state
assembly of the enantioselective 1,4-addition.
A wide range of nitroalkenes (5) bearing aryl, heteroaryl, and
alkyl groups were treated with dimethyl malonate in THF at -20
°C in the presence of either QD-4a or Q-4a (Table 2). Aryl and
heteroaryl nitroalkenes (5a-o) were found to be cleanly converted
into the corresponding 1,4-adducts in 92-98% ee and 88-99%
yield. High enantioselectivity and yield were also obtained with
nitroalkenes (5p-r) bearing a wide variety of alkyl groups. The
consistently excellent enantioselectivity obtained with various
heteroaryl and alkyl nitroalkenes (5m-r) is noteworthy, as such
nitroalkenes were shown to be relatively challenging substrates in
previous studies involving chiral Mg-bis(oxazoline) complexes10a,b
and organic catalysts.10c The results obtained with 5r represent the
first highly enantioselective addition of a malonate ester to a
sterically hindered γ-branched nitroalkene (entry 18).
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The addition of ethyl acetoacetate to 5a catalyzed by Q-4a
proceeded to completion in 6 h to afford 1,4-adduct 8 as a 1:1
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