Readily tunable and bifunctional L-prolinamide derivatives: Design and application in the direct enantioselective aldol reactions

Article abstract of DOI:10.1021/ol0520323

(Chemical Equation Presented) Readily tunable and bifunctional L-prolinamides as novel organocatalysts have been developed, and their catalytic activities were evaluated in the direct asymmetric Aldol reactions of various aromatic aldehydes and cyclohexan

Full text of DOI:10.1021/ol0520323

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4543-4545
Readily Tunable and Bifunctional
-Prolinamide Derivatives: Design and
L
Application in the Direct
Enantioselective Aldol Reactions
Jia-Rong Chen, Hai-Hua Lu, Xin-Yong Li, Lin Cheng, Jian Wan, and
Wen-Jing Xiao*
The Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal UniVersity, 152 Luoyu Road,
Wuhan, Hubei 430079, China
wxiao@mail.ccnu.edu.cn
Received August 23, 2005
ABSTRACT
Readily tunable and bifunctional L-prolinamides as novel organocatalysts have been developed, and their catalytic activities were evaluated
in the direct asymmetric Aldol reactions of various aromatic aldehydes and cyclohexanone. High isolated yields (up to 94%), enantioselectivities
(up to 99% ee), and anti-diastereoselectivities (up to 99:1) were obtained under the optimal conditions.
Enantioselective organocatalysis has recently provided a
research avenue in which to explore the fundamental
chemical parameters such as reactivity, selectivity, and
mechanism and in doing so has led to the discovery of many
valuable reactions and catalysts.1 In this endeavor, the design
and the development of multifunctional chiral organocatalysts
are of great importance: one catalyst molecule possesses two
or more reaction-promoting functionalities such that activity
and selectivity can be tuned by a simple modification of the
structural motif of the catalyst. Thus, an elegant alignment
of the steric and electronic properties of the catalyst would
determine the reaction efficiency.
The aldol reaction ranks among the most important
carbon-carbon bond-forming reactions in organic synthesis.2
Several efficient asymmetric methodologies for this reaction
using organocatalysts have been developed, of which the
most remarkable advances in the domain of proline and its
derivative catalysts were made by List and Barbas,3 Mac-
Millan,4 Jørgensen,5 Gong,6 and Yamamoto.7 According to
the Houk-List model,8 the catalysts are believed to stabilize
the transition state through hydrogen bonding in proline and
(3) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Notz. W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (c)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001,
123, 5260. (d) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
(e) Cordova, A.; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67, 301.
(f) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun. 2002, 3024.
(g) List, B. Acc. Chem. Res. 2004, 37, 548. (h) List, B.; Hoang, L.; Martin,
H. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5839. (i) Notz, W.; Tanaka,
F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (j) Steiner, D. D.;
Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2005, 44, 3706
(4) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 32. (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152. (c) Storer,
R. I.; MacMillan, D. W. C. Tetrahedron 2004, 60, 7705. (d) Northrup, A.
B.; MacMillan, D. W. C. Science 2004, 305, 1752.
(5) (a) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjoerdgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (b) Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794. (c) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (d) Kumaragurubaran,
N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem.
Soc. 2002, 124, 6254. (e) Bøgevig, A,; Kumaragurubaran, N.; Jørgensen,
K. A. Chem. Commun. 2002, 620.
(1) The significance of organocatalysis is outlined in special issues of
Acc. Chem. Res. 2004, 37 (8) and AdV. Synth. Catal. 2004, 346 (9-10).
(2) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, 1991; Vol. 2, p 229.
10.1021/ol0520323 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/09/2005

its derivative-catalyzed Aldol reactions. Therefore, a subtle
change in catalyst structure may change the pKa value of
the catalyst to affect the strength of hydrogen bondings, such
that a dramatic enhancement of the catalytic activity and
selectivity may be anticipated.9 However it is a significant
challenge to realize this goal. Herein, we describe a new
series of tunable and bifunctional organocatalysts in attaining
the direct asymmetric aldol reaction with high efficiency.
diaminocyclo-hexane. The structures of 1 were confirmed
by X-ray crystallographic analysis (see the Supporting
Information). The pKa of the diamide can be readily tuned
by varying the R group (Scheme 1).10 The catalytic activity
of these new catalysts were then evaluated in a direct
asymmetric aldol reaction of 4-nitrobenzaldehyde 3a with
cyclohexanone 2.
Table 1. Enantioselective Direct Aldol Reaction of
4-Nitrobenzaldehyde (3a) and Cyclohexanone (2) under Various
Conditions
Scheme 1. Tunable and Bifunctional Organocatalysts
entry catalyst time (h) yieldb (%) dr (anti/syn)c eed (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1b
1b
1b
1b
2
5
8
12
7
24
24
120
5
73
81
89
63
79
89
89
74
83
90
84/16
75/25
76/24
77/23
73/27
79/21
96/4
79/21
91/9
85/15
54
86
80
73
73
69
92e
65f
57g
55h
10
5
aThe reactions were conducted with 1 (20 mol %), AcOH (20 mol %),
3a (0.5 mmol), and 2/CHCl3 (1:1) (2 mL) for 6-24 h. b Isolated yield of
mixture of anti/syn. c Determined by chiral HPLC analysis of the mixture
of anti/syn product. d Determined by chiral HPLC. e At -25 °C. f Without
AcOH, 120 h. g In the presence of 20 mol % of 1b and 10 mol % of AcOH.
h In the presence of 20 mol % of 1b and 40 mol % of AcOH.
A variety of bifunctional L-prolinamide derivatives 1, as
shown in Scheme 1, were prepared from commercially
available L-proline and enantiopure (R,R)- or (S,S)-1,2-
(6) (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.;
Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5755. (c) Tang, Z.; Yang, Z.-H.; Chen,
X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc.
2005, 127, 9285.
(7) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983. (b) Saito, S.; Yamamoto, H. Acc.
Chem. Res. 2004, 37, 570.
(8) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911.
(b) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc.
2003, 125, 16. (c) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J.
Am. Chem. Soc. 2003, 125, 2475.
(9) For selected literature, see: (a) Berkessel, A.; Koch, B.; Lex, J. AdV.
Synth. Catal. 2004, 346, 1141. (b) Cobb, A. J. A.; Shaw, D. M.; Longbottom,
D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
(10) The pKa values of 1a-f were estimated by evaluating the free energy
change ∆Ga (pKa ) ∆Ga/2.303RT). The geometries of 1a-f optimized at
the HF/6-31G* level were employed to perform self-consistent reaction field
(SCRF) calculations at the B3LYP/6-31+G* level, for calculating free
energies of solvation in the chloroform. All calculations were performed
by using the Gaussian 03 program. Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,
Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and
Pople, J. A. Gaussian, Inc., Wallingford CT, 2004.
As can be seen from the results summarized in Table 1,
the catalytic activities and the steroselectivities of 1a-f were
significantly influenced by the tuning of the amide moiety.
Among the catalytic systems examined, 1b with 20 mol %
of acetic acid (AcOH) exhibited excellent catalytic efficiency,
affording 4a in 81% yield and good stereoselectivity (anti/
syn 75:25; 86% ee) (Table 1, entry 2).11 Note that 1b showed
a superior level of enantiocontrol to its diastereomer 1f (Table
1, entry 2 vs entry 6). This indicates that (1R,2R)-diami-
nocyclohexanes can be superior to L-prolines in enhancing
stereochemical control. As solubility is not an issue for our
tunable bifunctional catalysts of L-prolinamide derivatives,
as compared to that of the proline catalyst, excellent
selectivity (anti/syn 96:4; 92% ee) was achieved by decreas-
ing the reaction temperature to -25 °C (Table 1, entry 7).
Significantly, we found that the concentration of AcOH
has a remarkable effect on the catalytic activity and selectiv-
ity. Without adding AcOH, the reaction proceeded slowly
in low selectivity (Table 1, entry 8 vs entry 2). A ratio of
AcOH to 1b of 1:2 enhanced the activity by 24 times with
an improved yield and increased diastereoselectivity, but
decreased enantioselectivity (Table 1, entry 9 vs entry 8),
whereas use of a ratio of AcOH to 1b of 2:1 led to similar
(11) Mase, N.; Tanaka, F.; Barbas III, C. F. Org. Lett. 2003, 5, 4369.
Org. Lett., Vol. 7, No. 20, 2005
4544

results in better yield but poorer selectivity (Table 1, entry
10 vs entry 9). We concluded that the 1:1 ratio of AcOH to
1b gave the optimal performance, where the ee value was
the most satisfactory (Table 1, entry 2 vs entries 8-10).
A representative selection of aldehydes was evaluated
under the optimized conditions and the results obtained are
summarized in Table 2. The reactions of various substituted
organocatalyst for the same reaction as entries 1 and 2. They
achieved a 83% yield with a diasteomeric ratio of anti/syn
) 95:5 and an ee (anti) of 79%.6
The reaction of 4-nitrobenzaldehyde with butanone was
also investigated (eq 1) to examine the scope of the Aldol
donors. Significantly, the reaction preferentially occurred at
the C-3 position to afford the Aldol product 6 as the major
product in remarkably high diastereoselectivity (95:5) and
enantioselectivity (99% ee). Interestingly, we noticed that
with Gong’s catalyst yields of 56% for 5 and 42% for 6
were obtained.6
Table 2. Scope of the Aldehydes 3 for the Direct Aldol
Reaction with Cyclohexanone 2 under Optimal Conditionsa
yieldb
(%)
dr
ee
entry
R
product
(anti/syn)c (%, anti)d
1
2
3
4
5
6
7
8
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
4-CNC6H4
4-CLC6H4
2-CLC6H4
4-BrC6H4
Ph
4a
4ae
4af
4b
4c
4d
4e
4f
4g
4h
4l
4jf
4k
89
83
81
94
78
89
88
83
76
73
41
53
53
96/4
97/3
98/2
99/1
96/4
97/3
96/4
97/3
98/2
83/17
97/3
87/13
80/20
92
87
97
96
94
92
94
92
97
87
90
93
77
Based on the L-proline catalysis model,8 we believe that
the two N-H groups of the diamide group play a key role
in stabilizing the transition state, where these two tunable
functionalities not only activate the aldol acceptor but also
locate the re-face of the acceptor proximate to the attack by
the enamine. AcOH also plays an important role, as it may
provide a proton to accelerate the formation of enamine;
whereas the excessive AcOH may have a negative effect on
the hydrogen bonding of diamide, which in turn depresses
the catalytic efficacy.
9
10
11
12
13
1-naphthyl
2-furfuryl
4-MeC6H4
In conclusion, we have developed a series of novel
L-prolinamide organocatalysts with readily tunable bifunc-
tionalities. Their catalytic activities were evaluated for the
direct asymmetric Aldol reactions of various aromatic
aldehydes and cyclohexanone. High isolated yields (up to
94%), enantioselectivities (up to 99% ee), and anti-diaste-
reoselectivities (up to 99:1) were obtained using our catalytic
system. Studies directed to the extension of this tunable
hydrogen bonding-Lewis base dual-activation strategy to
other reactions as well as the mechanistic aspects are
currently underway.
a The reactions were conducted with 1b (20 mol %), AcOH (20 mol
%), 3 (0.5 mmol), and 2/CHCl3 (1:1) (2 mL) for 24-72 h (see the
Supporting Information) at -25 °C. b Isolated yield of the mixture of anti/
syn. c Determined by analysis of the mixture of anti/syn product. d Deter-
mined by HPLC. e In the presence of 2 mol % of 1b and 2 mol % of AcOH.
f In the presence of 20 mol % of 1d and 20 mol % of AcOH at -40 °C.
benzaldehydes, which bear an electron-withdrawing group
on the benzene ring, proceeded smoothly in excellent
diastereoselectivities (up to 99:1) and enantioselectivities (up
to 97%) to furnish the Aldol adducts 4a-g (Table 2, entries
1 and 3-9), while the stereoselectivities of the reactions with
benzaldehyde and p-tolualdehyde were somewhat lower
possibly due to their electron-rich character (Table 2, entries
10 and 13). Similarly, other aromatic aldehydes, such as
1-naphthaldehyde and 2-furaldehyde, underwent clean reac-
tions as well, and gave the corresponding adducts in 90 and
93% ee, respectively (Table 2, entries 11 and 12). Further-
more, it is noteworthy that even with as little as 2 mol %
catalyst loading of 1b and 2 mol % AcOH, the reaction took
place in high diastereoselectivity, although there was a slight
decrease in enantioselectivity (Table 2, entry 1 vs entry 2).
Very recently, Gong et al. reported a highly efficient
Acknowledgment. We are grateful to the National
Science Foundation of China (200472021), the National
Basic Research Program of China (2004CCA00100), and the
Hubei Province Science Found for Distinguished Young
Scholar (2004ABBC011) for support of this research. We
thank Professor Xin Xu for fruitful discussions.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0520323
Org. Lett., Vol. 7, No. 20, 2005
4545