Asymmetric direct aldol reaction of functionalized ketones catalyzed by amine organocatalysts based on bispidine

Article abstract of DOI:10.1021/ja800839w

Organocatalysts containing primary-secondary amine based on bispidine and amino acid have been designed to catalyze the asymmetric direct aldol reaction of functionalized ketones including α-keto phosphonates, α-keto esters, as well as α,α-dialkoxy ketones as aldol reaction acceptors. The corresponding products with chiral tertiary alcohols were obtained in moderate to high yields (up to 97%) and high enantioselectivities (up to 98% ee). A theoretical study of transition structures demonstrated that protonated piperidine was important for the reactivity and enantioselectivity of this reaction. Copyright

Full text of DOI:10.1021/ja800839w

Published on Web 04/02/2008
Asymmetric Direct Aldol Reaction of Functionalized Ketones
Catalyzed by Amine Organocatalysts Based on Bispidine
Jie Liu,† Zhigang Yang,† Zhen Wang,† Fei Wang,† Xiaohong Chen,† Xiaohua Liu,†
Xiaoming Feng,*,†,‡ Zhishan Su,† and Changwei Hu*,†
Key Laboratory of Green Chemistry & Technology (Sichuan UniVersity), Ministry of Education,
College of Chemistry, (Sichuan UniVersity), Chengdu 610064, PR China, and State Key Laboratory
of Oral Diseases, Sichuan UniVersity, Chengdu 610041, PR China
Received February 11, 2008; E-mail: xmfeng@scu.edu.cn
Aldol condensation is one of the basic reactions for creating a
C-C bond in nature.1 Since the pioneering work of List, Barbas,
and co-workers in 2000,2 organocatalyst as a simple chemical
mimic for enzymes has received much attention in the direct aldol
reaction.3 Among these successful examples, the organocatalysts
utilized in the direct aldol reaction mainly employed secondary
amine of the proline moiety3a,b or primary amine of the chiral
diamine moiety (diaminocyclohexanes)3p to form the enamine
intermediate. Despite these successes, the development of the
efficient organocatalysts for the direct aldol reactions of syntheti-
cally important functionalized ketones is still a challenge and has
become a much attempted research endeavor.4 Bispidine as the
structural core of sparteine opened up the opportunity to develop
a new catalyst by introduction of an appropriate chiral group.5
Herein, we report a novel organocatalyst by introducing facile
amino acids into the bicyclic bispidine framework for the direct
aldol reaction of functionalized ketones (Figure 1). High enanti-
oselectivities (up to 98% ee) were obtained for a broad range of
substrates including R-keto phosphonates, R-keto esters, as well
as R,R-dialkoxy ketones as aldol reaction acceptors under mild
conditions.
In our initial studies, the direct aldol reaction between diethyl
benzoyl phosphonate and acetone was selected as a benchmark
for catalyst evaluation. Some screening results are listed in Table
1. Twenty mol % of catalyst 1a derived from L-phenylalanine
promoted this reaction with 80% yield and 78% ee (Table 1, entry
1). Other catalysts derived from L-phenylglycine, L-leucine, L-
proline, L-valine, and L-4-nitrophenylalanine were also screened,
but no superior result was obtained (Table 1, entries 2-6). To
obtain higher enantioselectivity, some acids were employed as
additives (Table 1, entries 7-11). The weak acidic additives such
as HCOOH were shown to be suitable for this reaction, affording
the product with 95% yield and 96% ee (Table 1, entry 7), while
stronger acids, such as TFA and TsOH, made the reaction sluggish
with only trace product (Table 1, entries 10 and 11). Other
conditions were also optimized for further improving reactivity and
enantioselectivity (see Supporting Information). To our delight, the
loading of catalyst could be reduced to 5 mol % with the same
enantioselectivity and reactivity (Table 1, entry 12). Extensive
screening showed that the optimized conditions were 1a/HCOOH
) 1/1, 0.1 mmol diethyl benzoyl phosphonate and 0.5 mL of
acetone at 0 °C.
Figure 1. Structures of the catalysts studied.
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
yield %b
ee %c
1
1a
1b
1c
1d
1e
1f
80
78
69
2
95
3
60
67
4
98
-38
5
NR
34
6
27
96
88
88
7d
8d
9d
10d
11d
12d,e
1a/HCOOH
1a/CH3COOH
1a/PhCOOH
1a/TsOH
95
92
74
trace
trace
94
1a/TFA
1a/HCOOH
96
a Unless otherwise noted, the reaction was carried out with 0.1 mmol
diethyl benzoyl phosphonate, 0.5 mL of acetone, and 20 mol % catalyst
loading at 0 °C for 24 h. b Isolated yield. c Determined by chiral HPLC.
d 1a/acid ) 1/1. e With 5 mol % catalyst loading, reaction time is 48 h.
phosphonate had no effect on both yield and enantioselectivity
(Table 2, entries 1-3). With benzoyl phosphonate, the methyl,
ethyl, and isopropyl esters performed the corresponding products
with nearly the same yields and enantioselectivities. Different
substituted benzoyl phosphonates were also good substrates for
this reaction. The electronic nature of the para- and meta-
substituents did not influence the enantioselectivity. Either electron-
rich methyl and methoxyl substituents or electron-deficient halogen
substituents all underwent smoothly the reaction with acetone in
moderate to high yields and 94-96% ee (Table 2, entries 4-9).
Moreover, thiophene-2-carbonyl phosphonate was tested with 80%
yield and 89% ee (Table 2, entry 10).
Further substrate exploration indicated that aldol reaction of
acetone with R-keto esters could also be achieved to produce
ꢀ-hydroxycarboxylic esters under optimal conditions. As shown
in Table 2, the reactions with a variety of aromatic R-keto esters
proceeded smoothly to generate aldol adducts with a tertiary alcohol
in high enantioselectivities of up to 94% ee regardless of the
electronic and sterical nature of the substituted keto esters (Table
2, entries 11-18). Heteroaromatic R-keto esters also succeed with
Application scope of the catalytic system was then examined
under the optimal conditions. As summarized in Table 2, optically
active tertiary R-hydroxyphosphonates were obtained with up to
97% isolated yield and 97% ee. It appeared that the size of
† College of Chemistry.
‡ State Key Laboratory of Oral Diseases.
9
5654 J. AM. CHEM. SOC. 2008, 130, 5654–5655
10.1021/ja800839w CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for the Asymmetric Direct Aldol
Reactiona
entry
R
X
t
cat mol %
yield %b
ee %c
1
Ph
Ph
Ph
X1
X2
X3
X1
X2
X1
X1
X2
X1
X1
X4
X4
X4
X4
X4
X4
X4
X4
X5
X5
X6
X6
X7
X7
X1
X4
X5
X7
48 h
5
10
10
5
94
97
93
72
75
94
90
91
85
80
91
52
56
96
83
92
85
90
90
83
35
92
70
97
65
41
40
35
96
2
22 h
96
97
96
94
96
95
94
93
89
94(R)h
94
94
93
93
91
91
91
98
98
82
86
91
96
93
90
96
90
3
33 h
4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-MeC6H4
3-BrC6H4
3-BrC6H4
2-thiophenyl
Ph
48 h
Figure 2. The calculated transition state of aldol reaction of keto ester with
acetone catalyzed by 1a-HCOOH. The geometries were optimized at the HF/
6-31G* level. The relative energies (kcal/mol) are with HF/6-31G* in () and
B3LYP/6-311G** and IEFPCM (acetone) in [ ].
5
96 h
5
6
22 h
10
5
7
38 h
8
17 h
20
10
10
30
30
30
30
30
30
30
30
30
30
30
30
30
30
20
30
30
30
9
48 h
10
11
12
13
14
15
16
17
18
19
20
21d
22d
23e
24e,f
25g
26g
27g
28e,g
96 h
mol. Thus, TS2 was found to be the favorable transition state and
led to the formation of the major R-product in accordance with
the experimental results.
6 days
6 days
6 days
4 days
6 days
3 days
5 days
6 days
4 days
4 days
4 days
10 days
2 days
2 days
3 days
6 days
4.5 days
3 days
4-MeC6H4
4-MeOC6H4
4-FC6H4
3-MeC6H4
3-FC6H4
2-thiophenyl
2-naphthyl
4-NO2C6H4
3-NO2C6H4
Ph
In conclusion, we have presented the example of introducing
the amino acids into the bispidine framework as catalysts for
highly enantioselective direct aldol reactions of functionalized
ketones. Catalyst 1a demonstrated high enantioselectivity and
yield (up to 97% yield and 98% ee) for a wide substrate scope
including R-keto phosphonates, R-keto esters, and R,R-dialkoxy
ketones under mild conditions. A theoretical study of transition
structures revealed that protonated piperidine was important for
the reactivity and enantioselectivity of this reaction. Further
exploration of this catalyst in other important reactions is
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
Ph
Ph
4-NO2C6H4
4-NO2C6H4
underway in our laboratory.
a Unless otherwise noted, all reactions were carried out with 0.1 mmol
functionalized ketone, 0.5 mL of acetone, and 1a/HCOOH (1/1) at 0 °C.
b Isolated yield. c Determined by chiral HPLC. d With 30 mol % catalyst
system 1a/2,4-dinitrophenol (1/1). e The reaction was carried out with 0.1
Acknowledgment. We appreciate the National Natural Science
Foundation of China (No. 20732003) for financial support. We
also thank Sichuan University Analytical & Testing Center for
NMR analysis.
Supporting Information Available: Experimental procedures,
spectral and analytical data for the reaction products. This material is
available free of charge via the Internet at http://pubs.acs.org.
mmol
4-NO2C6H4CHO,
0.5
mL
of
acetone,
and
1a/
3,3′,5,5′-tetrabromobiphenol (1/1) at 0 °C. f Cyclohexanone as donor, dr
4:1. g 2-Butanone (0.5 mL) was used instead of acetone. h See refs4d, e.
References
85% yield and 91% ee (Table 2, entry 17). Another kind of
important functional substrate, R,R-dialkoxy ketones, was also
examined for the first time in the presence of catalyst 1a and
different additives (Table 2, entries 19-22). The relative lower
reaction rate could be compensated by prolonging reaction time,
and up to 98% ee was obtained for electron-deficient aromatic
acetal ketones. When 4-nitrobenzaldehyde was used as an aldol
reaction acceptor, both acetone and cyclohexanone could react
smoothly with high yields and 91 and 96% ee, respectively (Table
2, entries 23 and 24). The reactions between 2-butanone and
different functional ketones furnished linear aldol adducts with up
to 96% ee and moderate yields (entries 25-27), while 4-nitroben-
zaldehyde provided a mixture aldol adducts with high ee (Table
2, entry 28, see Supporting Information).
(1) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, Germany,
2004; Vols. 1–2.
(2) (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.
(3) (a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Notz, W.; Tanaka, F.; Barbas,
C. F., III Acc. Chem. Res. 2004, 37, 580. (c) Northrup, A. B.; MacMillan,
D. W. C. Science 2004, 305, 1752. (d) Torii, H.; Nakadai, M.; Ishihara, K.;
Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (e) 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. (f) 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. (g) Raj, M.; Vishnumaya; Ginotra, S. K.; Singh,
V. K. Org. Lett. 2006, 8, 4097. (h) Kano, T.; Takai, J.; Tokuda, O.; Maruoka,
K. Angew. Chem., Int. Ed. 2005, 44, 3055. (i) Samanta, S.; Liu, J.; Dodda,
R.; Zhao, C. G. Org. Lett. 2005, 7, 5321. (j) Mase, N.; Nakai, Y.; Ohara,
N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc.
2006, 128, 734. (k) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (l) Cheng,
C.; Sun, J.; Wang, C.; Zhang, Y.; Wei, S.; Jiang, F.; Wu, Y. D. Chem.
Commun. 2006, 215. (m) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;
Barbas, C. F., III J. Am. Chem. Soc. 2007, 129, 288. (n) Kano, T.;
Yamaguchi, Y.; Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46,
1738. (o) Co´rdova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu,
Y. Chem.—Eur. J. 2006, 12, 5383. (p) Luo, S. Z.; Xu, H.; Li, J. Y; Zhang,
L.; Cheng, J. P. J. Am. Chem. Soc. 2007, 129, 3074. (q) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (r) Casas,
J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Co´rdova, A. Angew. Chem., Int.
Ed. 2005, 44, 1343.
The mechanism of direct aldol reaction between R-keto ester
and acetone catalyzed by the primary-secondary diamine catalyst
1a has been investigated by theoretical simulation as shown in
Figure 2. Simillar to the diamine catalyst,3p in the enamine complex
from the primary amine of 1a and acetone, the phenyl group was
positioned equatorially with the enamine and shielded one face of
the enamine, while the protonated piperidine could interact with
the keto group by hydrogen bond3l,6 and position the attachment
to the unshielded face of the enamine. The H-bond between the
substrate and catalyst 1a in TS2 was shorter than that in TS1, which
indicated stronger interaction to keto in TS2. On the other hand,
TS2 was also energetically more stable than TS1 by ∼3.7 kcal/
(4) (a) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun.
2002, 620. (b) Tokuda, O.; Kano, T.; Gao, W. G.; Ikemoto, T.; Maruoka,
K. Org. Lett. 2005, 7, 5103. (c) Samanta, S.; Zhao, C. G. J. Am. Chem. Soc.
2006, 128, 7442. (d) Tang, Z.; Cun, L. F.; Cui, X.; Mi, A. Q.; Jiang, Y. Z.;
Gong, L. Z. Org. Lett. 2006, 8, 1263. (e) Wang, F.; Xiong, Y.; Liu, X. H.;
Feng, X. M. AdV. Synth. Catal. 2007, 349, 2665.
(5) Spieler, J.; Huttenloch, O.; Waldmann, H. Eur. J. Org. Chem. 2000, 391.
(6) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624.
JA800839W
9
J. AM. CHEM. SOC. VOL. 130, NO. 17, 2008 5655