Highly enantioselective conjugate addition of ketones to alkylidene malonates catalyzed by a pyrrolidinyl-camphor-derived organocatalyst

Article abstract of DOI:10.1002/ejoc.201000072

Pyrrolidinyl-camphor derivatives have been proven to be efficient organocatalysts for enantioselective conjugate addition of ketones to alkylidene malonates, affording high chemical yields (up to 95 %) of the corresponding products with high to excellent levels of diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to 96%ee) under solvent-free reaction conditions at ambient temperature.

Full text of DOI:10.1002/ejoc.201000072

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000072
Highly Enantioselective Conjugate Addition of Ketones to Alkylidene
Malonates Catalyzed by a Pyrrolidinyl–Camphor-Derived Organocatalyst
Dhananjay R. Magar,[a] Chihliang Chang,[a] Ying-Fang Ting,[a] and Kwunmin Chen*[a]
Keywords: Michael addition / Lactones / Diesters / Organocatalysis / Enantioselectivity / Ketones
Pyrrolidinyl–camphor derivatives have been proven to be ef-
ficient organocatalysts for enantioselective conjugate ad-
dition of ketones to alkylidene malonates, affording high
chemical yields (up to 95%) of the corresponding products
with high to excellent levels of diastereoselectivity (up to
Ͼ99:1dr) and enantioselectivity (up to 96%ee) under sol-
vent-free reaction conditions at ambient temperature.
based diamine and trifluoromethanesulfonamide, respec-
tively.[14a–14c] Recently Feng and co-workers reported the
use of bispidine-derived organocatalysts for the Michael ad-
dition of ketones to alkylidene malonates and nitro-
styrene.[15] In these processes, although the Michael adducts
were obtained with high to excellent stereoselectivities, a
large excess of ketones as donors (20 equiv.) and prolonged
reaction times (weeks) were required to complete the reac-
tion. For example, the reaction of cyclohexanone and di-
ethyl 2-benzylidenemalonate catalyzed with N-(pyrrolidin-
2-ylmethyl)trifluoromethanesulfonamide takes 14 d to give
the desired product (36% yield, 90:10dr, and 88%ee).[14b]
The development of efficient catalytic systems for the
Michael addition of ketones to alkylidene malonates re-
mains a challenging goal in asymmetric synthesis. Herein,
we present a highly enantioselective organocatalytic conju-
gate addition of ketones to alkylidene malonates by using
novel pyrrolidinyl–camphor-based organocatalysts to afford
Michael adducts in high chemical yields (up to 95%) with
high to excellent levels of stereoselectivity (up to 99:1dr and
96%ee). Moreover the reactions were carried out under op-
erationally simple, solvent-free conditions in the absence of
an additive.
Introduction
The development of organocatalysts in asymmetric reac-
tions has attracted much attention, as catalytic systems are
generally nontoxic, highly efficient and selective, environ-
mentally friendly, and stable under aerobic and aqueous re-
action conditions.[1] Asymmetric conjugate addition of car-
bon-centered nucleophiles to electron-deficient olefins is
generally recognized as one of the most powerful, atom-
economical, C–C bond-forming reactions in modern syn-
thetic chemistry.[2] Remarkable advances have been realized
in the development of asymmetric variants of this reaction,
providing enantioenriched Michael adducts.[3] The organo-
catalytic conjugate addition of aldehydes and ketones to
Michael acceptors is among the most elegant methods de-
veloped. Electron-deficient alkenes, such as nitrostyrenes,[4]
α,β-unsaturated aldehydes,[5] enones,[6] vinyl sulfones,[7]
maleimides,[8] benzoquinones,[9] and vinyl phosphonates,[10]
have been successfully employed. On the other hand, alk-
ylidene malonates represent alternative Michael acceptors
because the functionalities are useful in the synthesis of im-
portant pharmaceutical molecules. For example, biolo-
gically active chiral substituted lactones and lactams are
easily accessible from malonate-containing aldehydes.[11,12a]
Enantioselective Friedel–Crafts alkylations of indole
with benzylidene malonates in the presence of chiral cop-
per(II) complexes have been reported.[13] The organocata-
lytic reaction of carbonyl compounds with alkylidene
malonates as efficient Michael acceptors has also been
achieved.[12] Of these, the groups of Barbas and Tang have
independently reported the efficient Michael addition of
ketones to alkylidene malonates catalyzed by pyrrolidine-
Results and Discussion
We envisioned that the assembly of a rigid stereocon-
trolling camphor structure with a pyrrolidinyl group may
constitute a well-defined scaffold. The motifs were linked
with appropriate functional groups, such as amides (1a–c),
sulfonamide (1d), sulfides (1e and 1f), and thiourea (1g) to
tune the intrinsic organocatalytic behaviors (Figure 1). For
this, various pyrrolidinyl–camphor-based organocatalysts
were designed and synthesized, and they have proven to be
effective in catalyzing asymmetric transformations.[16] As a
model reaction, we studied the Michael addition of cyclo-
hexanone 2a to dimethyl 2-(4-nitrobenzylidene)malonate
[a] Department of Chemistry, National Taiwan Normal University,
Taipei, Taiwan 116, ROC
Fax: +011-886-2-29324249
E-mail: kchen@ntnu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000072.
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Eur. J. Org. Chem. 2010, 2062–2066

Enantioselective Conjugate Addition of Ketones to Alkylidene Malonates
(3a) catalyzed by pyrrolidinyl–camphor derivative 1a Table 1. Optimization of the asymmetric Michael addition of cyclo-
hexanone (2a) to dimethyl 2-(4-nitrobenzylidene)malonate (3a).[a]
(20 mol-%). The results are shown in Table 1. Resulting
Michael adduct 4a was obtained with moderate chemical
yield, good diastereoselectivity, and good enantioselectivity
when the reaction was carried out in polar solvents such as
THF, CH3CN, and CHCl3 (Table 1, Entries 1–3). A slight
improvement was observed when toluene was used as the
reaction medium (Table 1, Entry 4). The reactivity was fur-
ther improved and the stereoselectivity was retained under
solvent-free reaction conditions (Table 1, Entry 5). Various
acidic additives (20 mol-%) were then screened to further
optimize the reaction. Comparable results were obtained
when the reaction was carried out in the presence of citric
acid, ketopinic acid, camphorsulfonic acid (CSA), prop-
ionic acid, and dodecylbenzenesulfonic acid (DBSA)
(Table 1, Entries 6–10). In contrast, the diastereoselectivi-
ties and the chemical yields were marginally improved when
the reaction was performed in the presence of PhCOOH,
acetic acid, or TsOH (Table 1, Entries 11–13). Surprisingly,
the reactivity dropped when trifluoroacetic acid (TFA) was
used as an acidic additive (Table 1, Entry 14). This may due
to the protonation of the secondary amine of the organoca-
talyst, which hampers enamine formation.
Entry
Solvent Cat.
THF 1a
CH3CN 1a
Additive
% Yield[b]
dr[c]
% ee[d]
1
2
3
4
5
6
7
8
–
–
–
–
–
70
64
62
71
85
76
80
70
74
75
90
89
90
20
15
nr
56
21
26
95
10
81
nr
92:8
91:9
90:10
92:8
88:12
91:9
85:15
93:7
87:13
94:6
91:9
90:10
93:7
95:5
–
84
84
84
88
88
88
88
90
90
90
88
88
89
88
–
CHCl3
toluene
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
1f
citric acid
ketopinic acid
CSA
propionic acid
DBSA
benzoic acid
AcOH
TsOH
TFA
9
10
11
12
13
14
15
16
17
18
19[e]
20[f]
21
22
23
TsOH
TsOH
TsOH
TsOH
TsOH
–
TsOH
–
TsOH
–
–
95:5
95:5
95:5
95:5
–
92
96
96
96
–
1f
1g
91:9
–
92
–
[a] Unless otherwise noted, all reactions were carried out with the
use of 2a (1.9 mmol, 10 equiv.) and 3a (0.19 mmol) in the presence
of the catalyst (20 mol-%) under neat conditions with the additive
(20 mol-%) at ambient temperature. [b] Isolated yield. [c] Deter-
1
mined by H NMR spectroscopy. [d] Determined by chiral HPLC
analysis. [e] 20 equiv. of 2a was used (3.8 mmol). [f] Reaction was
carried out in the absence of TsOH.
Figure 1. Structures of pyrrolidinyl–camphor-based organocata-
lysts.
prisingly, the reaction failed to proceed when C2-hydroxy
Encouraged by these results, we further optimized the (camphor numbering) analogue catalyst 1f was used
catalysis conditions by screening other catalysts that were (Table 1, Entry 21). In contrast, catalyst 1f worked well in
synthesized from our laboratory. Only trace amounts of the the absence of an acidic additive (Table 1, Entry 22). Thio-
Michael adducts were formed when amide-linked 1b was urea catalyst 1g also failed to catalyze the reaction under
used, whereas the use of silyl ether analogue 1c failed to the present catalysis conditions (Table 1, Entry 23).
catalyze the reaction (Table 1, Entries 15 and 16). The use
With the optimal reaction conditions realized, a broad
of sulfonamide 1d yielded the desired product with high range of alkylidene malonates were investigated to establish
diastereoselectivity and enantioselectivity, with a modest the general utility of this asymmetric transformation. As
chemical yield (Table 1, Entry 17). When sulfide-linked or- illustrated in Table 2, various alkylidene malonates reacted
ganocatalyst 1e was used under the optimized conditions, smoothly to produce the corresponding Michael adducts
desired addition product 4a was generated with poor chemi- with high chemical yields (up to 95%) and high to excellent
cal yield but high enantioselectivity (96%ee) and diastereo- levels of diastereoselectivity (up to 99:1dr) and enantio-
selectivity (95:5dr; Table 1, Entry 18). Surprisingly, increas- selectivity (up to 96%ee). The steric or electronic nature of
ing the ketone quantity (up to 20 equiv.) did not increase 3- and 4-substituents of the aryl substituents seemed to
the chemical yield of the reaction (Table 1, Entry 19). For- have no significant effect on the stereoselectivities (Table 2,
tuitously, in the absence of TsOH the Michael adduct was Entries 1–5). However, the chemical yields decreased when
obtained with excellent chemical yield with high levels of dimethyl 2-(2-nitrobenzylidene)malonate and dimethyl 2-(4-
diastereo- and enantioselectivity (Table 1, Entry 20). Sur- methoxybenzylidene)malonate were used (Table 2, Entries 6
Eur. J. Org. Chem. 2010, 2062–2066
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. R. Magar, C. Chang, Y.-F. Ting, K. Chen
SHORT COMMUNICATION
and 7). The former may be due to steric hindrance, whereas (Table 3, Entry 3). Moderate results were obtained when cy-
the latter was influenced by the presence of an electron- clopentanone, acetone, and acetophenone were employed
donating substituent in the phenyl ring. High enantio- (Table 3, Entries 4–6).
selectivities and diastereoselectivities were achieved with
phenyl and 1-naphthyl groups (Table 2, Entries 8 and 9).
Diethyl alkylidene malonates also reacted smoothly under
Table 3. Michael addition reaction of various ketones 2b–g to alk-
ylidene malonate 3a.[a]
the optimal conditions to afford the corresponding adducts
with excellent yields and high selectivities (Table 2, En-
tries 10 and 11). High to excellent diastereoselectivities were
observed at the expense of enantioselectivities when het-
eroarylidene malonates were used as Michael acceptors
(Table 2, Entries 12 and 13). However, the desired product
was not obtained when isopropylidene malonate was em-
ployed as the Michael acceptor (Table 2, Entry 14). The rel-
ative and absolute configurations of the Michael adducts
1
were determined by comparing the H and 13C NMR spec-
troscopic data and the optical rotations of the products
with those found in previous reports.[14b,15]
Entry
2
Product (% Yield)[b]
dr[c]
% ee[d]
1
2b
2c
2d
2e
2f
5b (87)
5c (88)
5d (84)
5e (73)
5f (76)
5g (75)
80:20
86:14
90:10
75:25
–
92
94
60
50
61
20
2[e]
3[e]
4[e]
5
Table 2. Michael addition of cyclohexanone to the alkylidene mal-
onates catalyzed by organocatalyst 1e.[a]
6
2g
–
[a] Unless otherwise stated, all reactions were carried out with the
use of 2 (1.9 mmol, 10 equiv.) and 3a (0.19 mmol) in the presence
of the catalyst (20 mol-%) under neat condition at room tempera-
ture, for 2–5 d. [b] Isolated yield. [c] Determined by 1H NMR spec-
troscopy. [d] Determined by chiral HPLC analysis. [e] Reaction was
carried out in toluene (0.5 mL).
Entry
R1
R2
4
% Yield[b]
dr[c]
% ee[d]
1
2
3
4
5
6
7
8
4-O2NC6H4
3-O2NC6H4
4-NCC6H4
4-ClC6H4
4-BrC6H4
2-O2NC6H4
4-MeOC6H4
Ph
1-naphthyl
4-O2NC6H4
4-BrC6H4
2-pyridyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
95
87
84
84
88
61
64
86
80
95
90
87
88
15
95:5
96
90
92
86
94
96
92
90
86
92
94
54
82
–
To rationalize the high stereoselectivities of the Michael
adducts obtained in the catalytic system, a plausible transi-
tion-state model was proposed (Figure 2). The reaction of
cyclohexanone and the organocatalyst to form a nucleo-
philic enamine under solvent-free conditions was con-
ducted. The rigid and bulky bicyclic camphor moiety selec-
tively shielded the approach of the Michael acceptor from
the enamine Si face. This was assisted by the hydrogen-
bond interactions between the trans-4-hydroxy group of the
pyrrolidine and the alkylidene malonates, which projected
the aromatic group away from the camphor scaffold.[14b,16b]
Thus, the alkylidene malonates would approach from the
less-hindered Re face of the enamine to give the observed
stereochemistry of the Michael adducts.
86:14
88:12
89:11
91:9
Ͼ99
91:9
91:9
91:9
90:10
90:10
Ͼ99
9
10
11
12
13
14
Et
Me
Me
Me
2-thiophene
iPr
90:10
–
[a] Unless otherwise stated, all reactions were carried out with the
use of 2a (1.9 mmol, 10 equiv.) and 3 (0.19 mmol) in the presence
of the catalyst (20 mol-%) under neat conditions at ambient tem-
1
perature for 2–12 d. [b] Isolated yield. [c] Determined by H NMR
spectroscopy. [d] Determined by chiral HPLC analysis.
Furthermore, the asymmetric Michael addition of vari-
ous ketones to dimethyl 2-(4-nitrobenzylidene)malonate
(3a) was studied (Table 3). Various cyclic and acyclic
ketones were subject to the optimal reaction conditions to
give the desired Michael adducts with good to high chemi-
cal yields. However, only good diastereoselectivities and
high enantioselectivities were obtained when tetrahydro-
Figure 2. Plausible transition-state model.
The utility of the catalytic process is illustrated by the
pyran-4-one (2b) and tetrahydrothiopyran-4-one (2c) were easy scale-up of the reaction and further chemical transfor-
used (Table 3, Entries 1 and 2). The use of acetal-protected mations that can be performed to prepare highly substi-
cyclohexanone 2d afforded the desired product with good tuted lactones. As shown in Scheme 1, under the optimized
diastereoselectivity and reasonable enantioselectivity conditions, we carried out the Michael addition of 2a with
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Eur. J. Org. Chem. 2010, 2062–2066

Enantioselective Conjugate Addition of Ketones to Alkylidene Malonates
Scheme 1. Synthesis of chiral lactone 6a.
3a on a 10-mmol scale, affording desired product 4a with
Acknowledgments
excellent chemical yield and high stereoselectivities. Michael
adduct 4a was converted into chiral lactone 6a by following
a reductive cyclization process without incident (85% chem-
ical yield, 92:8dr, and 98%ee). The structural characteriza-
tion of lactone 6a was confirmed by 1H and 13C NMR spec-
troscopy and NOESY experiments (see Supporting Infor-
mation).
We thank the National Science Council of the Republic of China
(NSC 96-2113-M-003-005-MY3 and NSC 98-2119-M-003-003) for
financial support of this work. Our gratitude goes to the Academic
Paper Editing Clinic at NTNU and to the National Center for
High-Performance Computing for providing us with computer time
and facilities.
[1] a) P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH,
Weinheim, 2007; b) A. Berkessel, H. Gröger, Asymmetric Or-
ganocatalysis: From Biomimetic Concepts to Applications in
Asymmetric Synthesis, Wiley-VCH, Weinheim, 2005; for re-
views on asymmetric organocatalysis, see: c) A. Dondoni, A.
Massi, Angew. Chem. Int. Ed. 2008, 47, 4638–4660; d) H. Pel-
lissier, Tetrahedron 2007, 63, 9267–9331.
Conclusions
In summary, we have presented an efficient asymmetric
Michael addition of ketones with various alkylidene malon-
ates catalyzed by novel pyrrolidinyl–camphor organocata-
lysts. The structurally well-defined organocatalysts were
easily accessible from inexpensive natural materials. The re-
action proceeded smoothly under neat conditions, and the
corresponding Michael products were generally obtained
with high chemical yields (up to 95%) and high to excellent
levels of diastereoselectivity (up to Ͼ99:1dr) and enantio-
selectivity (up to 96%ee). A reasonable mechanistic model
was proposed to explain the stereochemical outcome. The
exploration of these novel organocatalysts in organocata-
lytic transformations is under active investigation.
[2] P. Perlmutter, Conjugate Addition Reactions in Organic Synthe-
sis, Pergamon, Oxford, 1992.
[3] For reviews on organocatalytic asymmetric conjugate addition
reactions, see: a) K. Tomioka, Y. Nagaoka, M. Yamaguchi in
Comprehensive Asymmetric Catalysis (Eds: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, New York, 1999, vol. III, pp.
1105–1139; b) S. Sulzer-Mossé, A. Alexakis, Chem. Commun.
2007, 3123–3135; c) J. L. Vicario, D. Badia, L. Carrillo, Synthe-
sis 2007, 2065–2092; d) S. B. Tsogoeva, Eur. J. Org. Chem. 2007,
1701–1716; e) J. Christoffers, A. Baro, Angew. Chem. 2003, 115,
1726; Angew. Chem. Int. Ed. 2003, 42, 1688–1690; f) O. M.
Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem. 2002, 1877–
1894; g) N. Krause, A. Hoffmann-Roder, Synthesis 2001, 171–
196; h) D. Almasi, D. A. Alonso, C. Nájera, Tetrahedron:
Asymmetry 2007, 18, 299–365.
Experimental Section
[4] For asymmetric Michael additions of aldehydes and ketones to
nitroolefins, see: a) B. List, P. Pojarliev, H. J. Martin, Org. Lett.
2001, 3, 2423–2425; b) J. M. Betancort, C. F. Barbas III, Org.
Lett. 2001, 3, 3737–3740; c) A. Alexakis, O. Andrey, Org. Lett.
2002, 4, 3611–3614; d) T. Ishii, S. Fujioka, Y. Sekiguchi, H.
Kotsuki, J. Am. Chem. Soc. 2004, 126, 9558–9559; e) Y. Haya-
shi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. Int. Ed.
2005, 44, 4212–4215; f) Y. Xu, W. Zou, H. Sundén, I. Ibrahem,
A. Cordóva, Adv. Synth. Catal. 2006, 348, 418–424; g) S. Luo,
X. Mi, L. Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew. Chem.
Int. Ed. 2006, 45, 3093–3097; h) C. Palomo, S. Vera, A. Mielgo,
E. Gómez-Bengoa, Angew. Chem. Int. Ed. 2006, 45, 5984–5987;
i) S. Mossé, M. Laars, K. Kriis, T. Kanger, A. Alexakis, Org.
Lett. 2006, 8, 2559–2562; j) S. V. Pansare, K. Pandya, J. Am.
Chem. Soc. 2006, 128, 9624–9625; k) C.-L. Cao, M.-C. Ye, X.-
L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901–2904; l) E. Reyes,
J. L. Vicario, D. Badía, L. Carrillo, Org. Lett. 2006, 8, 6135–
6138; m) Y. Xu, A. Cordóva, Chem. Commun. 2006, 460–462;
n) T. Mandal, C.-G. Zhao, Tetrahedron Lett. 2007, 48, 5803–
5806; o) L.-q. Gu, G. Zhao, Adv. Synth. Catal. 2007, 349, 1629–
1632; p) B. Ni, Q. Zhang, A. D. Headley, Green Chem. 2007,
9, 737–739; q) Y. Chi, L. Guo, N. A. Kopf, S. H. Gellman, J.
Am. Chem. Soc. 2008, 130, 5608–5609; r) M. Wiesner, J. D.
Revell, H. Wennemers, Angew. Chem. Int. Ed. 2008, 47, 1871–
General Procedure for the Michael Addition of Ketones to Alkylidene
Malonates: To cyclohexanone (184.5 mg, 1.90 mmol) and alkylid-
ene malonate 3a (50 mg, 0.19 mmol) was added organocatalyst 1e
(10.77 mg, 0.038 mmol, 20 mol-%) in one portion at ambient tem-
perature. The resulting mixture was allowed to stir at ambient tem-
perature and monitored by thin-layer chromatography. After the
disappearance of the alkylidene malonate, the reaction mixture was
purified through flash column chromatography on silica gel (petro-
leum ether/ethyl acetate, 10:1 to 5:1) to give desired product 4a
(95% yield, 96%ee). The stereoselectivity was determined by
HPLC analysis. HPLC (Chiralcel AS-H; iPrOH/hexanes, 6:94;
1.0 mLmin–1): tR = 26.16 (minor), 31.20 (major) min. syn/anti =
95/5. [α]2D0 = –49.5 (c = 0.393, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.14 (d, J = 8.7 Hz, 2 H), 7.47 (d, J = 8.7 Hz, 2 H),
4.16–4.04 (m, 2 H), 3.68 (s, 3 H), 3.51 (s, 3 H), 2.99–2.95 (m, 1 H),
2.43–2.37 (m, 2 H), 2.03–2.02 (m, 1 H), 1.78–1.75 (m, 2 H), 1.61–
1.55 (m, 2 H), 1.12–1.09 (m, 1 H) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures; spectral and analytical data for the
Michael adducts and lactone.
Eur. J. Org. Chem. 2010, 2062–2066
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D. R. Magar, C. Chang, Y.-F. Ting, K. Chen
SHORT COMMUNICATION
1874; s) P. García-García, A. Ladépêche, R. Halder, B. List,
Angew. Chem. Int. Ed. 2008, 47, 4719–4721; t) D. Enders, C.
Wang, J. W. Bats, Angew. Chem. Int. Ed. 2008, 47, 7539–7542;
u) M. Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers, J. Am.
Chem. Soc. 2008, 130, 5610–5611; v) B. Tan, X. Zeng, Y. Lu,
P. J. Chua, G. Zhong, Org. Lett. 2009, 11, 1927–1930.
[5] a) B.-C. Hong, M.-F. Wu, H.-C. Tseng, J.-H. Liao, Org. Lett.
2006, 8, 2217–2220; b) M. Marigo, S. Bertelsen, A. Landa,
K. A. Jørgensen, J. Am. Chem. Soc. 2006, 128, 5475–5479.
[6] a) P. Melchiorre, K. A. Jørgensen, J. Org. Chem. 2003, 68,
4151–4157; b) M. T. H. Fonseca, B. List, Angew. Chem. Int.
Ed. 2004, 43, 3958–3960; c) T. J. Peelen, Y. G. Chi, S. H. Gell-
man, J. Am. Chem. Soc. 2005, 127, 11598–11599; d) J. Wang,
H. Li, L. Zu, W. Wang, Adv. Synth. Catal. 2006, 348, 425–428.
[7] a) S. Mossé, A. Alexakis, Org. Lett. 2005, 7, 4361–4364; b) S.
Sulzer-Mossé, A. Alexakis, J. Mareda, G. Bollot, G. Bernardi-
nelli, Y. Filinchuk, Chem. Eur. J. 2009, 15, 3204–3220.
[8] G.-L. Zhao, Y. Xu, H. Sundén, L. Eriksson, M. Sayah, A.
Córdova, Chem. Commun. 2007, 734–735.
[13] a) D. A. Evans, T. Rovis, M. C. Kozlowski, C. W. Downey, J. S.
Tedrow, J. Am. Chem. Soc. 2000, 122, 9134–9142; b) D. A. Ev-
ans, T. Rovis, M. C. Kozlowski, J. S. Tedrow, J. Am. Chem. Soc.
1999, 121, 1994–1995; c) A. Bernardi, G. Colombo, C. Scolas-
tico, Tetrahedron Lett. 1996, 37, 8921–8924; d) A. Alexakis, C.
Benhaim, Tetrahedron: Asymmetry 2001, 12, 1151–1157; e) A.
Alexakis, J. Vastra, P. Mangeney, Tetrahedron Lett. 1997, 38,
7745–7748; f) W. Zhuang, T. Hansen, K. A. Jørgensen, Chem.
Commun. 2001, 347–348; g) J. Zhou, Y. Tang, Chem. Commun.
2004, 432–433; h) J. Zhou, Y. Tang, J. Am. Chem. Soc. 2002,
124, 9030–9031; i) R. Rasappan, M. Hager, A. Gissibl, O. Re-
iser, Org. Lett. 2006, 8, 6099–6102; j) S. Yamazaki, Y. Iwata, J.
Org. Chem. 2006, 71, 739–743.
[14] a) J. M. Betancort, K. Sakthivel, R. Thayumanavan, C. F.
Barbas III, Tetrahedron Lett. 2001, 42, 4441–4444; b) C.-L.
Cao, X.-L. Sun, J.-L. Zhou, Y. Tang, J. Org. Chem. 2007, 72,
4073–4076; c) J. M. Betancort, K. Sakthivel, R. Thayumana-
van, F. Tanaka, C. F. Barbas III, Synthesis 2004, 1509–1521.
[15] J. Liu, Z. Yang, X. Liu, Z. Wang, Y. Liu, S. Bai, L. Lin, X.
Feng, Org. Biomol. Chem. 2009, 7, 4120–4127.
[16] a) C. Chang, S.-H. Li, R. J. Reddy, K. Chen, Adv. Synth. Catal.
2009, 351, 1273–1278; b) R. J. Reddy, H.-H. Kuan, T.-Y. Chou,
K. Chen, Chem. Eur. J. 2009, 15, 9294–9298; c) Z.-H. Tzeng,
H.-Y. Chen, R. J. Reddy, C.-T. Huang, K. Chen, Tetrahedron
2009, 65, 2879–2888; d) Z.-H. Tzeng, H.-Y. Chen, C.-T. Huang,
K. Chen, Tetrahedron Lett. 2008, 49, 4134–4137; e) P.-M. Liu,
C. Chang, R. J. Reddy, Y.-F. Ting, H.-H. Kuan, K. Chen, Eur.
J. Org. Chem. 2010, 42–46.
[9] J. Alemán, S. Cabrera, E. Maerten, J. Overgaard, K. A.
Jørgensen, Angew. Chem. 2007, 119, 5616; Angew. Chem. Int.
Ed. 2007, 46, 5520–5523.
[10] S. Sulzer-Mossé, M. Tissot, A. Alexakis, Org. Lett. 2007, 9,
3749–3752.
[11] S. Brandau, A. Landa, J. Franzén, M. Marigo, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2006, 45, 4305–4309.
[12] a) G.-L. Zhao, J. Vesely, J. Sun, K. E. Christensen, C. Bonneau,
A. Córdova, Adv. Synth. Catal. 2008, 350, 657–661; b) for or-
ganocatalytic reactions of aldehydes to α-keto-α,β-unsaturated
esters, see: J. Wang, F. Yu, X. Zhang, D. Ma, Org. Lett. 2008,
10, 2561–2564.
Received: January 20, 2010
Published Online: March 2, 2010
2066
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