Design of highly enantioselective organocatalysts based on molecular recognition

Article abstract of DOI:10.1021/ol0529391

Various organocatalysts have been designed based on molecular recognition to catalyze the asymmetric direct aldol reaction of ketones with aryl and alkyl α-keto acids, affording β-hydroxyl carboxylic acids with a tertiary stereogenic center with excellent

Full text of DOI:10.1021/ol0529391

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1263-1266
Design of Highly Enantioselective
Organocatalysts Based on Molecular
Recognition
Zhuo Tang, Lin-Feng Cun, Xin Cui, Ai-Qiao Mi, Yao-Zhong Jiang, and
Liu-Zhu Gong*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince
and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, and Graduate
School of the Chinese Academy of Sciences, Beijing, China
gonglz@cioc.ac.cn
Received December 4, 2005
ABSTRACT
Various organocatalysts have been designed based on molecular recognition to catalyze the asymmetric direct aldol reaction of ketones with
aryl and alkyl -keto acids, affording -hydroxyl carboxylic acids with a tertiary stereogenic center with excellent enantioselectivities of up
to 98% ee. A linear effect was observed for the reaction, demonstrating a single molecule of the catalyst involved in the catalysis.
r
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The aldol reaction is one of the most important carbon-
carbon bond-forming reactions in organic synthesis and has
been studied extensively.1 Since the seminal findings that
L-proline could catalyze the direct aldol reaction,2,3 many
chiral organocatalysts have been discovered for the direct
aldol reaction.4-10 In contrast to organocatalyzed direct
aldolizations with aldehydes as acceptors, however, those
related with ketones as acceptors were rarely reported and
thus are even more challenging. Recently, a L-proline-
catalyzed direct aldol reaction of R-keto esters with aldehydes
was reported.11 In this case, only two specific R-keto esters,
which contain two highly electron-withdrawing groups to
(4) For reviews, see: (a) List, B. Tetrahedron 2002, 58, 5573. (b) List,
B. Synlett 2001, 1675. (c) Alcaide, B.; Almendros, P. Angew. Chem., Int.
Ed. 2003, 42, 858. (d) List, B. Acc. Chem. Res. 2004, 37, 548. (e) Notz,
W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. For leading
literature, see: (f) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798. (g) Co´rdova, A.; Notz, W.; Barbas, C. F., III J. Org.
Chem. 2002, 67, 301. (h) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen,
K. A. Chem. Commun. 2002, 620. (i) Pidathala, C.; Hoang, L.; Vignola,
N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (j) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152. (k) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 1343.
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Int. Ed. 2002, 41, 4542.
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1831. (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983. For review, see: (c) Saito, S.;
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
* Address correspondence to this author at the Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences.
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Eur. J. 1998, 4, 1137. (b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9,
357. (c) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg,
Germany, 1999; Vol. III, Chapter 29.1. (d) Mahrwald, R. Chem. ReV. 1999,
99, 1095. (e) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed.
2000, 39, 1352. (f) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33,
325. (g) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
(h) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Soc. ReV. 2004, 33, 65.
(i) Modern Aldol Reaction; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004; Vols. 1 and 2.
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J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445.
10.1021/ol0529391 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/09/2006

activate the keto function, were investigated as aldol accep-
tors.11 Most recently, the proline-catalyzed asymmetric aldol
reaction between cyclohexanone and phenylglyoxylate was
discovered.12 However, the organocatalyzed asymmetric aldol
reaction of ketone with keto acids has not been reported yet.
We report here the direct aldol reaction of ketones with
R-keto acids catalyzed by an organic molecule to directly
form â-hydroxy carboxylic acids with a tertiary stereogenic
center with high enantioselectivities of up to 98% ee.
Molecular recognition phenomena are critically important
in the actions of enzymes on substrates. A large number of
enzyme-mimetic systems such as crown ethers,13 cryptands,14
cyclodextrins,15 and capsules16 have been designed as
artificial receptor sites to bind appropriate guest molecules
or ions. Since the pioneering finding by Hamilton and co-
workers that aminopyridine is a good site for the formation
of hydrogen bonds specifically with a carboxyl group (1,
Figure 1),17 aminopyridine has been widely used in the self-
search for structurally diverse organocatalysts, we recently
found that L-prolinamide derivatives catalyzed the direct aldol
reaction via enamine catalysis.9 Stimulated by these findings
and Hamilton’s molecular recognition model 1 of carboxylic
acid with aminopyrodine (Figure 1), we reasoned that the
combination of pyrrolidine-2-carboxylic acid amide and
aminopyrodine in a single molecule could lead to a kind of
chiral organocatalysts 3a-g, and they would catalyze the
direct aldol reaction of ketone with R-keto acids via a
possible transition state 2a or 2b (Figure 1). Principally, 2a
would be more stable than 2b.17 But 2b would more easily
occur with the aldol reaction than 2a because the keto group
in 2b is activated by a hydrogen bond.9
It was found that prolinamides 3a-g were highly catalyti-
cally active for the direct aldol reaction of acetone with
benzoylformic acid (4a) to generate an aldol product 5a that
directly reacted with CH2N2 to give 6a for the conVenient
HPLC analysis (Table 1). In the presence of 20 mol % of
Table 1. Direct Aldol Reaction of Acetone and Benzoylformic
Acid Catalyzed by Organocatalyst 3a-ga
entry
catalysta
4
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3e
4a
4a
4a
4a
4a
4a
4a
4a
4a
98
86
86
87
79
87
90
92
90
74
-9
93d
90
>99
>99
30
22
>99
Figure 1. General strategy for the design of new organocatalysts
3.
assembly18 and molecular recognition of carboxylic acids.19
Molecular recognition has also been found as one of the
factors to design organocatalysts for other reactions.20 In our
a A mixture of benzoylformic acid (0.5 mmol), catalyst (0.1 mmol), and
acetone (1.0 mL) in toluene (2.0 mL) was stirred for 48 h. b Isolated yield
of 6a. c The ee value of 6a and was determined by chiral HPLC. d The
reaction was performed in toluene (3.0 mL)
(9) (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.; Cun,
L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285. (d)
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.
(10) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem., Int.
Ed. 2005, 44, 3055.
(11) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem.
Commun. 2002, 620.
(12) Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.; Maruoka, K. Org.
Lett. 2005, 7, 5107.
(13) For recent reviews: (a) Gokel, G. W.; Leevy, W. M.; Weber, M.
E. Chem. ReV. 2004, 104, 2723. (b) Bradshaw, J. S.; Izatt, R. M. Acc. Chem.
Res. 1997, 30, 338.
(14) (a) Lehn, J.-M. Science 1985, 227, 849. (b) Chao, Y.; Weisman, G.
R.; Sogan, G. D. Y.; Cram, P. J. J. Am. Chem. Soc. 1979, 101, 4948.
(15) For recent reviews: (a) Breslow, R.; Dong, S. D. Chem. ReV. 1998,
98, 1997. (b) Takahashi, K. Chem. ReV. 1998, 98, 2013.
(16) Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647.
(17) Garcia-Tellado, F.; Goswami, S.; Chang, S. K.; Geib, S. J.; Hamilton,
A. D. J. Am. Chem. Soc. 1990, 112, 7393.
3a, the reaction conditions were optimized and the best
results were obtained when the reaction was performed in
toluene at 0 °C. Compared with 3a, organocatalysts 3b-e,
which contain an additional methyl group on the pyridine
ring, catalyzed the direct aldol reaction in high yield with
varying enantioselectivities that depended on the position of
the methyl group (Table 1, entries 1-5). The best result was
obtained with catalyst 3e (entry 5). One more methyl group
was introduced to the pyridine, as shown in 3f, and this
resulted in a decrease in enantioselectivity (entry 6). Orga-
nocatalyst 3g, which was modified by replacing the methyl
group with an acetylamino group, gave a dramatically
deteriorated yield and enantioselectivity, indicating that the
introduction of an additional hydrogen bond donor negatively
(18) (a) Yang, J.; Fan, E.; Geib, S.; Hamilton, A. D. J. Am. Chem. Soc.
1993, 115, 5314. (b) Geib, S. J.; Vicent, G.; Fan, E.; Hamilton, A. D. Angew.
Chem., Int. Ed. Engl. 1993, 32, 119.
(19) (a) Goodman, M. S.; Hamilton, A. D.; Weiss, J. J. Am. Chem. Soc.
1995, 117, 8447. (b) Moriuchi, T.; Yoshida, K.; Hirao, T. Org. Lett. 2003,
5, 4285.
(20) (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. (c) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 6576. (d) Dove, A. P.; Pratt, R. C.; Lohmeijer,
B. C. G.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2005, 127,
13798.
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Org. Lett., Vol. 8, No. 7, 2006

affected the catalytic performance (entry 7). However,
catalyst 3h derived from 3-aminopyridine, which is princi-
pally unable to form double hydrogen bonds with the
substrate, catalyzed the direct aldol reaction of acetone with
benzoylformic acid in very low yield (22%) and enantiose-
lectivity (-9% ee) with a reversed configuration (Table 1,
entry 8), which demonstrates the importance of the double
hydrogen bonds and that the reaction very likely proceeds
via the transition state 2. Fine-tuning the ratio of toluene to
acetone resulted in the highest level of enantioselectivity
(93% ee) and a nearly quantitative yield for the reaction of
acetone and benzoylformic acid catalyzed by 3e (entry 9).
The aldolization of methyl benzoylformic ester (4b) with
acetone in the presence of 3e, however, yielded 6a in a 28%
yield with poor enantioselectivity (eq 1), implying that the
interaction between carboxylic acid and pyridinyl group is
important for the reaction and a single hydrogen bond is not
efficient enough to activate the keto group. The use of
L-proline amide 3i, which is unable to provide a proton to
form the hydrogen bond, to catalyze the aldol reaction of
4a with acetone gave 5a in a trace amount (eq 2), indicating
that the hydrogen bond formed between the keto and amide
exists and plays a crucial role in promoting the reaction.
Thus, this organocatalyzed reaction proceeds more likely via
2b rather than 2a.
Figure 2. 1HNMR spectra of mixtures of racemic mandelic acid
with different host molecules: (a) racemic mandelic acid and
receptor 3e; (b) racemic mandelic acid and receptor Cbz-3e; and
(c) racemic mandelic acid and receptor 3h.
also observed with Cbz-3e as a receptor (peak b). On the
contrary, two enantiomers could not be distinguished by
1HNMR spectroscopy with 3h as a host peak c). The racemic
aldol product 5a was also recognized by 3e based on 1HNMR
spectroscopy of the mixture of 3e and 2a (see the Supporting
Information). These facts also implied that the R-keto group
of the acceptor was interacting with the proline amide, and
the transition structure 2b is therefore more possible than
2a.
A linear effect was observed for the reaction of benzoyl-
formic acid (4a) with acetone with 20 mol % of 3e in toluene
(Figure 3). This result is consistent with the proposed
Despite the preceding positive evidence to support our
proposed transition structure 2b for the aldol reaction, more
evidence is still required. Recently, chiral molecules either
bearing multiple hydrogen-bond donors21 or containing
pyrrolidinyl22 and pyridinyl groups,23 which are similar to
the building blocks of organocatalysts 3, have been designed
for the enantiomeric recognition of mandelic acid. The mul-
tiple hydrogen bonds between the carboxylic acid and the
host are considered to be responsible for chiral recognition.21
We studied the bonding properties of 3e with racemic man-
delic acid in CDCl3 by 1HNMR spectroscopy to further prove
the existence of hydrogen bonds between the keto acid and
the aminopyrodine of 3e (Figure 2, see the Supporting Infor-
mation for details).22,23 The chemical shift of the proton on
the stereogenic centers of two enantiomers of mandelic acid
is obviously different in the presence of stoichiometric
amounts of 3e (peak a). Enantioselective recognition was
Figure 3. Linear effect in the 3e catalyzed direct aldol reaction of
benzoylformic acid (4a) with acetone in toluene.
transition state 2b (Figure 1), and thus, a single molecule of
3e participates in the reaction.
The generality of catalyst 3e at catalyzing direct aldol
reactions of ketones with a variety of R-keto acids including
both aromatic and aliphatic acids was examined under
optimal conditions (Table 2). The aldol reactions proceeded
smoothly to generate aldol adducts with a tertiary center in
high yields of up to >99% and with high enantioselectivities
of up to 98% ee regardless of the electronic and sterical
nature of the substituent of the keto acids. Cyclopentanone
can also react with benzoylformic acid in a moderate yield
with a diastereomeric ratio of 2:1 in favor of the syn-isomer
and 81% ee for anti-product. The absolute configuration of
6c was determined to be R by X-ray crystallography (see
the Supporting Information). However, the â-keto acid does
(21) (a) Pu, L. Chem. ReV. 2004, 104, 1687. (b) Lin, J.; Hu, Q.-S.; Xu,
M.-H.; Pu, L. J. Am. Chem. Soc. 2002, 124, 2088. (c) Xu, M.-H.; Lin, J.;
Hu, Q.-S.; Pu, L. J. Am. Chem. Soc. 2002, 124, 14239.
(22) Yang, X.-M.; Wu, X.-J.; Fang, M.-H.; Yuan, Q.; Fu, E.-Q.
Tetrahedron: Asymmetry 2004, 15, 2491.
(23) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am. Chem. Soc. 2005,
127, 7996.
Org. Lett., Vol. 8, No. 7, 2006
1265

Table 2. Direct Aldol Reactions of Ketone and Keto Acida
Scheme 1. Diagram of the Catalyst Recycling
a A mixture of keto acid (0.5 mmol), catalyst 3e (0.1 mmol), and acetone
(1.0 mL) in toluene (3.0 mL) was stirred for 48 h at 0 °C. b Isolated yield.
c The ee values were determined by chiral HPLC. d Determined by X-ray
crystallography of a single crystal (see the Supporting Information).
the transition state stabilized by the double hydrogen bonds
formed between 2-aminopyridine and both the keto and
carboxyl groups of the organocatalyst 3e. A linear effect was
not react with acetone catalyzed by 3h under the optimal
conditions.24
Since the aldol product is a â-hydroxy carboxylic acid and
the catalyst is an organic base, it is very convenient to
separate the product and the catalyst by an acid-base
conversion strategy, as illustrated in Scheme 1. Recycling
of the catalyst is therefore allowed. After the aldol reaction
of benzoylformic acid with acetone is quenched with aqueous
Na2CO3, the product exists in the basic aqueous layer,
whereas organocatalyst 3e remains in the organic layer.
Evaporation of the organic solution to dryness recovers the
organocatalyst 3e, which can be reused to catalyze the aldol
reaction. The aldol product in the aqueous layer was obtained
by extraction after the pH was adjusted to 6. After two
recyclings, catalyst 3e is still active enough to catalyze the
direct aldol reaction of acetone and benzylformic acid in
moderate yield and a slightly decreased enantioselectivity
(Table 3).
Table 3. Catalyst Recyclinga
entry
recycle
yield (%)b
ee (%)c
1
2
3
1st
2nd
3rd
99
90
62
93
93
89
a The procedure for catalyst recycling is presented in the Supporting
Information. b Isolated yield. c The ee values ware determined by chiral
HPLC.
observed for the reaction, demonstrating a single molecule
of the catalyst involved in the catalysis. On the basis of their
different chemical properties, the aldol product and organo-
catalyst 3e were conveniently separated to allow for easy
recycling of the organocatalyst.
In conclusion, we have designed a family of organocata-
lysts based on molecular recognition to catalyze the asym-
metric direct aldol reaction of ketone with R-keto acids to
afford â-hydroxyl carboxylic acids with a tertiary stereogenic
center with excellent enantioselectivities of up to 98% ee.
The high enantioselectivity of the organocatalyst comes from
Acknowledgment. We are grateful for financial support
from NSFC (20472082, 203900505 and 20325211).
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) The aldolization of 3-oxo-3-phenylpropionic acid with acetone
catalyzed by 3h was examined to result in no reaction.
OL0529391
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