Novel small organic molecules for a highly enantioselective direct aldol reaction

Article abstract of DOI:10.1021/ja034528q

Novel organic molecules containing an l-proline amide moiety and a terminal hydroxyl for catalyzing direct asymmetric aldol reactions of aldehydes in neat acetone are designed and prepared. Catalyst 3d, prepared from l-proline and (1S,2S)-diphenyl-2-amino

Full text of DOI:10.1021/ja034528q

Published on Web 04/11/2003
Novel Small Organic Molecules for a Highly Enantioselective Direct Aldol
Reaction
Zhuo Tang,†,‡ Fan Jiang,§ Luo-Ting Yu,‡ Xin Cui,† Liu-Zhu Gong,*,† Ai-Qiao Mi,†
Yao-Zhong Jiang,† and Yun-Dong Wu*,§
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, College of Chemical Engineering,
Sichuan UniVersity, Chengdu, 610065, China, and State Key Laboratory of Molecular Dynamics and
Stable Structures, College of Chemistry and Molecular Engineering, Peking UniVersity, Beijing, 100871, China
Received February 6, 2003; E-mail: gonglz@cioc.ac.cn
The great synthetic utility of the aldol reaction in organic
synthesis has powered the rapid evolution of numerous highly
enantioselective chiral catalysts.1 The direct aldol reaction is
atomically economic.2 Shibasaki has reported the first example of
a direct asymmetric aldol reaction catalyzed by heterobimetallic
complexes.3 Trost has designed a zinc complex for the direct
catalytic asymmetric aldol reaction with high enantioselectivities.4
Since the pioneering finding by List and Barbas III and their co-
workers that L-proline could work as a catalyst in the intermolecular
direct aldol reaction,5 the concept of small organic molecules as
catalysts has received great attention.6,7 However, efficient organic
Figure 1. The small organic molecules evaluated in this study.
Table 1. Direct Aldol Reaction of 4-Nitrobenzaldehyde with
Acetone Catalyzed by Organic Molecules 1-3a
catalysts other than chiral amino acids for asymmetric direct aldol
reactions are scarce.8 We seek to design small organic molecules
with structural diversity for catalyzing organic transformations with
high stereoselectivity and broad substrates. Here, we report on a
novel class of organic catalysts, (S)-pyrrolidine-2-carboxamide with
a terminal hydroxyl group, that efficiently catalyze the direct aldol
reactions of aromatic and aliphatic aldehydes in neat acetone with
high enantioselectiVities of up to >99% ee.
The acid proton of proline is critical for the reactivity and
stereoselectivity of the proline-catalyzed direct aldol reaction.
L-Prolinamide (2-pyrrolidine-carboxamide) has been shown to be
ineffective in catalyzing the direct aldol reaction.6b However, we
found that L-prolinamides with a terminal hydroxyl group exhibited
increased catalytic activity and enantioselectivity as compared with
the parent L-prolinamide. This observation prompted us to study
the direct aldol reaction catalyzed by L-prolinamides derived from
L-proline and R,â-hydroxyamines, 1-3 (Figure 1). Compounds 1-3
were readily prepared from L-proline and corresponding â-amino
alcohols by the known reaction sequences (see Supporting Informa-
tion).
In the presence of 20 mol % 1-3, the reaction of 4-nitroben-
zaldehyde with neat acetone was examined under different condi-
tions. Table 1 summarizes the results. This class of organic catalysts
exhibited high catalytic efficiency. Chiral catalyst 1a promoted the
reaction with a high yield of 84% but a moderate enantioselectivity
of 46% ee (entry 1), but it did not show an apparent difference in
catalytic efficiency from its isomer 2a (75% yield, 48% ee; entry
2). Compound 2b afforded a superior level of stereocontrol to its
diastereomer 1b (entries 3 and 4). This indicates that the (S)-
configuration of CR (see 1 for labeling) matched the L-proline to
enhance the stereochemical control. The catalysts 3c and 3d with
(S)-conformation of CR once again induced higher enantioselec-
tivities (entries 7 and 8, 64% ee with 3c; 69% ee with 3d) than
entry
catalyst
temp (
°
C)
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1a
2a
1b
2b
3a
3b
3c
3d
3d
3d
25
25
25
25
25
25
25
25
0
12
12
12
12
12
12
12
12
12
24
84
75
78
89
63
77
76
89
68
66
46
48
33
52
49
44
64
69
78
93
10
-25
a The reaction was carried out in neat acetone with a concentration of
0.5 M. b Isolated yield. c The ee values were determined by HPLC, and
the configuration was assigned as R by comparison of retention time.
their diastereomers 3a and 3b (entries 5 and 6, 49% ee with 3a;
44% ee with 3b) that contain (R)-CR. The (S)-configuration of Câ
also contributed to the selection. The highest enantioselectivity of
69% ee was observed with (S,S,S)-pyrolidine-2-carboxylic acid (2′-
hydroxyl-1′,2′-diphenyl-ethyl)-amine (3d) (entry 8). Upon the
decrease of the reaction temperature, the yield was somewhat
sacrificed, but the enantioselectivity increased significantly (entries
8-10). High enantioselectiVity of 93% ee was obtained for the
reaction of 4-nitrobenzaldehyde with acetone at -25 °C (entry 10).
The generality of catalyst 3d in catalyzing direct aldol reactions
with a variety of aldehydes including aromatic and aliphatic ones
was examined under optimal conditions. The results are shown in
Table 2. The aldol reactions of the aldehydes with acetone took
place smoothly and were catalyzed by 20 mol % 3d to give aldol
adducts in moderate to high yields with high enantioselectivities
of up to >99% ee. The observed enantioselectivities for both
aromatic and aliphatic aldehydes appear to be systematically higher
than those obtained with L-proline as the catalyst.6a,9 This is
attributed to the reduced temperature because of the high catalytic
activity of 3d. High enantioselectivities of up to 87% ee, but low
yields, were given for R-unbranched aldehydes (entries 13 and 14).10
† Chengdu Institute of Organic Chemistry.
‡ Sichuan University.
§ Peking University.
9
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J. AM. CHEM. SOC. 2003, 125, 5262-5263
10.1021/ja034528q CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Aldol Reactions of Acetone with Aldehydes by
Chiral Organic Catalyst 3da
A theoretical study of transition structures demonstrates the
important role of the terminal hydroxyl group in the catalyst in the
stereodiscrimination. Our results suggest a new strategy in the
design of new organic catalysts for direct asymmetric aldol reactions
and related transformations because plentiful chiral resources
containing multi-hydrogen bond donors, for example, peptides,
might be adopted in the design. Research on such a strategy is now
underway.15
entry
product
R
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4j
4-NO2Ph
4-BrPh
4-ClPh
2-ClPh
Ph
R-naphthyl
â-naphthyl
4-MePh
3-NO2Ph
c-C6H11
i-Pr
t-Bu
n-Pr
n-Bu
c-C6H11
c-C6H11
66
77
75
83
51
76
93
48
63
85
43
51
17
12
77
48
93
90
93
85
83
81
84
84
87
Acknowledgment. We are grateful for financial support from
the National Natural Science Foundation of China. We also thank
Prof. Benjamin List at the Scripps Research Institute for his
generosity in providing the HPLC conditions for determining the
enantiomeric excess of the aldol reaction.
Supporting Information Available: Experimental procedures,
NMR data for compounds 1-3, HPLC spectra of 4a-c and 4j-l, GC
spectra of 4m,n, and Cartesian coordinates of TS1 and TS2 (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
97
98
>99
87d
86d
98e
98f
4j
References
a The reaction was carried out in neat acetone with a concentration of
0.5 M at -25 °C for 24-48 h (see Supporting Information). b Isolated yields.
c Determined by HPLC. d Determined by GC. e Catalyzed by 10 mol % 3d.
f Catalyzed by 5 mol % 3d.
(1) For reviews, see: (a) Carreira, E. M.; Mukaiyama Aldol Reaction. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999; Vol. III, Chapter
29.1. (b) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (c) Gro¨ger, H.; Vogl,
E. M.; Shibasaki, M. Chem.-Eur. J. 1998, 4, 1137. (d) Johnson, J. S.;
Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (e) Machajewski, T. D.;
Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352.
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(3) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yamada, Y. M. A.; Shibasaki,
M. Tetrahedron Lett. 1998, 39, 5561. (c) Yoshikawa, N.; Yamada, Y. M.
A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.
(d) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki,
M. Org. Lett. 2001, 3, 1539.
(4) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (b) Trost,
B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (c)
Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497.
(5) For reviews, see: (a) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001,
40, 529. (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (c)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(6) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260. (c) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386.
Figure 2. The calculated transition structure of the aldol reaction of
benzaldehyde with acetone catalyzed by 3d. The geometries were optimized
with the HF/6-31G* method. The relative energies (kcal/mol) are with HF/
6-31G* in ( ) and B3LYP/6-31G** in [ ].
(7) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) Bui, T.; Barbas, C.
F., III. Tetrahedron Lett. 2000, 41, 6951. (c) Co`rdova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
124, 1842. (d) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (e) List, B. J. Am.
Chem. Soc. 2002, 124, 5656. (f) Bøgevig, A.; Juhl, K.; Kumaragurubaran,
N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790.
(g) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
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F., III. J. Am. Chem. Soc. 2002, 124, 1866. For reviews, see: (i) List, B.
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(8) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem., Int.
Ed. 2002, 41, 4542.
(9) A poor yield of 6% with 70% ee for 4a and a trace amount of 4j were
observed with aldol reactions catalyzed by 20 mol % L-proline under the
described reaction conditions (acetone, -25 °C) for 48 h.
(10) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
(11) All calculations were performed with the Gaussian 98 program.
(12) (a) Arno, M.; Domingo, L. R. Theor. Chem. Acc. 2002, 108, 232. (b)
Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106,
5155. (c) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273.
(d) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem.
Soc. 2003, 125, 2475. (e) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List,
B. J. Am. Chem. Soc. 2003, 125, 16.
(13) For studies on hydrogen bonds acting like Lewis acid, see: (a) Huang,
Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662. (b) Schreiner, P.
R.; Wittkopp, A. Org. Lett. 2002, 4, 217. (c) Vachal, P.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 10012.
(14) Poor enantioselectivity of 31% ee was observed with 3d when the reaction
of 4-nitrobenzaldehyde with acetone was carried out in the presence of
water (acetone:H2O ) 1:1) at room temperature, which demonstrates that
the hydrogen bond exists in the transition state (see ref 6b).
(15) Dipeptide Pro-Thr-Me catalyzes the direct asymmetric aldol reaction of
4-nitrobenzaldehyde with acetone in 69% ee at room temperature.
It is noteworthy that the enantioselectivity of 98% ee was still
provided for 4j even with 5 mol % 3d (entry 16).
Theoretical calculations have been carried out to understand the
high enantioselectivity.11 As shown in Figure 2, the best transition
structures for the reaction of benzaldehyde with acetone are similar
to those with proline as the catalyst,12 except that here both the
amide and the hydroxyl groups are hydrogen-bonded with the
aldehyde to serve as the Lewis acid.13,14 The hydroxyl group appears
to be the better hydrogen-bond donor as indicated by the shorter
hydrogen bond. The two phenyl groups of the hydroxylamine are
in equatorial positions. TS1, which leads to the formation of the
major product observed experimentally, is found to be much more
stable than TS2. The phenyl group of benzaldehyde in TS1 does
not have steric interactions with anything. On the other hand, the
phenyl group of benzaldehyde in TS2 has a severe steric interaction
with the hydroxyl group (H- - -H distance is only about 2.14 Å).
The CdO- - -H(O) angle must open up to reduce the steric
interaction.
In summary, we have presented the first successful example of
using L-proline amino alcohol amides as catalysts for highly
enantioselective direct aldol reactions of aldehydes with neat
acetone. Catalyst 3d, prepared from L-proline and (1S,2S)-diphenyl-
2-aminoethanol, exhibits high enantioselectivities of up to 93% ee
for aromatic aldehydes and up to >99% ee for aliphatic aldehydes.
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