Acyclic amino acid-catalyzed direct asymmetric aldol reactions: Alanine, the simplest stereoselective organocatalyst

Article abstract of DOI:10.1039/b507968n

The linear amino acid-catalyzed direct asymmetric intermolecular aldol reaction is presented; simple amino acids such as alanine, valine, isoleucine, aspartate, alanine tetrazole 3 and serine catalyzed the direct catalytic asymmetric intermolecular aldol

Full text of DOI:10.1039/b507968n

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Acyclic amino acid-catalyzed direct asymmetric aldol reactions:
alanine, the simplest stereoselective organocatalyst{
Armando Co´rdova,* Weibiao Zou, Ismail Ibrahem, Efraim Reyes, Magnus Engqvist and Wei-Wei Liao
Received (in Cambridge, UK) 6th June 2005, Accepted 8th June 2005
First published as an Advance Article on the web 21st June 2005
DOI: 10.1039/b507968n
enamine-catalyzed asymmetric transformations, thus allowing the
full exploration of nature’s diverse array of amino acids.
Herein, we show that linear amino acids catalyze the direct
asymmetric aldol reaction between cyclic ketones and aldehydes
with up to . 99% ee. Remarkably, nature’s smallest and oldest
chiral amino acid catalyzed the aldol reaction with a stereo-
selectivity that can match the ones of enzymes.11
The linear amino acid-catalyzed direct asymmetric inter-
molecular aldol reaction is presented; simple amino acids such
as alanine, valine, isoleucine, aspartate, alanine tetrazole 3 and
serine catalyzed the direct catalytic asymmetric intermolecular
aldol reactions between unmodified ketones and aldehydes with
excellent stereocontrol and furnished the corresponding aldol
products in up to 98% yield and with up to . 99% ee.
In an initial experiment, we investigated the L-alanine-catalyzed
reaction between dihydroxyacetone phosphate mimetic 1a and
p-nitrobenzaldehyde in wet DMSO (10 equiv. of water).
(Equation 1).12
The direct asymmetric aldol reaction is one of the most important
C–C bond-forming reactions in nature, and it is catalyzed by
aldolase enzymes with excellent stereocontrol.1 The enzyme’s
ability to control the enantioselectivity of the direct aldol reaction
has inspired chemists and raised this transformation to prominence
in the asymmetric assembly of complex natural products.2,3 In
particular, the development of catalytic stereoselective methods for
the asymmetric directed aldol reaction has recently been the subject
of intense research.4 For example, the utilization of organometallic
complexes and Lewis bases as catalysts has been highly successful
for the asymmetric Mukaiyama-type aldol reaction between
activated silyl enol ethers and aldehydes.5a–g Furthermore, the
enantioselective aldol reaction between unmodified ketones and
aldehydes is catalyzed by chiral organometallic complexes.5h–k
Another approach to the catalysis of the direct asymmetric aldol
reaction is the use of aldolase enzymes.1,6
ð1Þ
To our delight, the desired aldol adduct 2a was isolated in 84%
yield with 6 : 1 dr and . 99% ee. Having achieved this
extraordinary result, we decided to screen several natural amino
acids for their ability to catalyze the direct aldol reactions in wet
DMSO. Thus, cyclohexanone 1b was allowed to react with
p-nitrobenzaldehyde in the presence of a catalytic amount of
different natural and unnatural linear amino acids (Table 1).
Notably, all the amino acids tested mediated the formation of
the desired aldol products under the set reaction conditions and
several of the amino acids exhibited excellent stereoselectivity for
the transformation. For example, employing L-serine or L-valine
as the catalysts for the aldol reactions with cyclohexanone 1b
enabled the isolation of aldol product 2b in 80% yield with 6 : 1 dr
and . 99% ee and 98% yield with 37 : 1 dr and . 99% ee,
respectively. In comparison, L-proline furnishes aldol product 2b
with a dr of 2 : 1 and 89% ee.9c Importantly, tetrazole 3 derived
from L-alanine was an excellent catalyst for the direct asymmetric
aldol reaction and enabled the asymmetric formation of 2b in high
yield within 8 h with 14 : 1 dr and . 99% ee. Thus, the efficiency
and solubility of the primary amino acids in organic solvents can
be significantly improved by converting them to the corresponding
tetrazoles.9m Moreover, simple chiral primary amino alcohols and
amines did also catalyze the direct asymmetric aldol reaction with
high syn-selectivity. Intrigued by the small size and simplicity of
alanine, we decided to further investigate the L-alanine-catalyzed
direct intermolecular aldol reaction between a set of different
Recently, organocatalysis has experienced a renaissance in
asymmetric synthesis.7 In this context, proline and its derivatives
have proved to be the best catalysts for the direct intermolecular
asymmetric aldol reaction.8,9 In stark contrast to proline, linear
amino acids are considered to be poor or no catalysts for the
intermolecular enantioselective aldol reaction between unmodified
ketones and aldehydes.9a–d However, intramolecular aldol con-
densations have been mediated by employment of stoichiometric
equivalents of phenylalanine together with HClO4 or camphor-
sulfonic acid.8 Intrigued by these results and our interest in
stereoselective enamine-catalysis,10 we decided to investigate the
possibility of employing linear amino acids as catalysts for the
asymmetric aldol reaction between unmodified ketones and
aldehydes. Moreover, most natural amino acids and their
derivatives are acyclic, and therefore it would be of paramount
interest as well as a conceptual advance to enable their use in
{ Electronic supplementary information (ESI) available: experimental
procedures. See http://dx.doi.org/10.1039/b507968n
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Sweden. E-mail: acordova1a@netscape.net;
acordova@organ.su.se; Fax: + 46 8 15 49 08; Tel: +46 8 162479
*acordova1a@netscape.net; acordova@organ.su.se
donor ketones
1 and p-nitrobenzaldehyde (Table 2). The
L-alanine-catalyzed reactions proceeded smoothly and furnished
3586 | Chem. Commun., 2005, 3586–3588
This journal is ß The Royal Society of Chemistry 2005

View Article Online
the desired aldol products 2a–d in good yield with up to . 99% ee.
In particular, the L-alanine mediated aldol reactions with
cyclic ketones 1a–b and 1d as donors proceeded with high
chemo-, diastereo- and enantioselectivity. Moreover, the L-alanine-
catalyzed direct asymmetric aldol reactions with acyclic nonsym-
metric ketone 1c exclusively furnished regioisomer 2c in 56% yield
with 75% ee. The opposite enantiomer of the aldol products 2 was
obtained by employing the acyclic D-amino acid as the catalyst.
Furthermore, the reaction proceeded with excellent chemoselec-
tivity and no elimination product was observed. The L-alanine-
catalyzed asymmetric aldol reaction between different ketones and
acceptor aldehydes was also investigated (Table 3).
Table 1 Examples of screened catalysts for the direct asymmetric
intermolecular aldol reaction between 1b and p-nitrobenzaldehyde
Entry Catalyst
Yield (%)a Drb
Ee (%)c
1
2
3
4
5
6
7
95
88
98
79
91d
62
75
15 : 1
99
92
L-Alanine
6 : 1
37 : 1
6 : 1
1 : 2
1 : 1
5 : 1
L-Aminobutyric acid
L-Valine
The L-alanine-catalyzed asymmetric aldol reaction between
unmodified ketones 1a or 1b and different aromatic aldehydes
proceeded smoothly furnishing the desired aldol adducts 2 with up
to . 19 : 1 dr and . 99% ee. For instance, ketone products 2e and
carbohydrate 2h were isolated in 75% yield with 6 : 1 dr and .
99% ee and 41% yield with . 19 : 1 dr and 99% ee, respectively.
These results demonstrate that a cyclic five-membered structural
motif of the amino acid derivative is not essential to catalyze the
direct asymmetric aldol reaction between ketones and aldehydes
with high stereoselectivity.
. 99
90
L-Norvaline
L-Alaninol
46
4
L-Arginine
. 99
L-Aspartate
(R)-Methylbenzylamine 94d
8
9
1 : 15
10 : 1
24
. 99
82
L-Isoleucine
10
11
a
80
84e
6 : 1
. 99
. 99
L-Serine
14 : 1
L-Alanine tetrazoles
b
Isolated yield after silica-gel column chromatography. anti : syn
c
ratio as determined by NMR analyses. Determined by chiral-phase
d
HPLC analyses. Reaction time was 48 h. Reaction time was 8 h.
e
The stereochemistry of the b-hydroxy group of the aldol adducts
2 derived by linear L-amino acid catalysis was R as determined by
chiral-phase HPLC analysis, optical rotation and comparison with
the literature.9 The relative stereochemistry of the cyclic aldol
products 2 was anti as determined by NMR spectroscopy and
comparison with the literature.9 Based on the absolute and relative
configuration of aldol products 2, we propose that the L-alanine
and linear amino acid-catalyzed direct asymmetric aldol reactions
between ketones and aldehydes occurred via a plausible six-
membered chair-like transition-state I, where the Re-face of the
catalytically generated chiral enamine is approached by the Si-face
of the acceptor aldehyde (Fig. 1).13
Table 2 The alanine catalyzed direct intermolecular aldol reactions
with different ketones
Yield (%)a Drb
Ee (%)c
Furthermore, the beneficial effect of water in the L-alanine and
linear amino acid-catalyzed asymmetric aldol reaction is due to
improved catalyst turnover via faster hydrolysis of the intermedi-
ates of the enamine catalytic cycle, as well as the suppression of
catalyst inhibition.14
Entry Ketone Product
1
84
6 : 1 . 99
Table 3 Examples of different alanine-catalyzed direct asymmetric
aldol reactions
2
95
15 : 1
99
3
4
56
80
3 : 1
75
92
Yield
Product (%)a Drb
Entry Ketone
R
Ee (%)c
16 : 1
1
2
3
4
5
6
a
1a
1a
1a
1a
1b
1b
4-CNC6H4 2e
4-BrC6H4 2f
75
6 : 1 . 99
77d
75d
41
6 : 1d
5 : 1d
97d
98d
99
4-ClC6H4
CH2OBn
2g
2h
. 19 : 1
4-BrC6H4 2i
4-ClC6H4 2j
44
42
17 : 1 . 99
18 : 1 . 99
b
a
b
Isolated yield after silica-gel column chromatography. anti : syn
Isolated yield after silica-gel column chromatography Anti : syn
c
ratio as determined by NMR analyses Determined by chiral-phase
c
ratio as determined by NMR analyses. Determined by chiral-phase
HPLC analyses.
d
HPLC analyses 5 equiv. water was used
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3586–3588 | 3587

View Article Online
T. Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi and
M. Shibasaki, J. Am. Chem. Soc., 2003, 125, 2169; (i) B. M. Trost, H. Ito
and E. R. Silcoff, J. Am. Chem. Soc., 2001, 123, 3367; (j) Y. M. A.
Yamada, N. Yoshikawa, H. Sasai and M. Shibasaki, Angew. Chem.,
Int. Ed., 1997, 36, 1871; (k) D. A. Evans, C. W. Downey and
J. L. Hubbs, J. Am. Chem. Soc., 2003, 125, 8706.
6 R. Schoevaart, F. Van Rantwijk and R. A. Sheldon, J. Org. Chem.,
2000, 65, 6940; H. J. M. Gijsen, L. Qiao, W. Fitz and C.-H Wong,
Chem. Rev., 1996, 96, 443.
Fig. 1 Plausible transition state I for the primary amino acid-catalyzed
asymmetric aldol reactions between ketones and aldehydes.
7 Reviews see: P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004,
43, 5138; B. List, Tetrahedron, 2002, 58, 5573.
In summary, we have demonstrated that linear amino acids and
their derivatives can be of synthetic use as catalysts for the direct
asymmetric intermolecular aldol reaction. For example, alanine,
valine, aspartate, isoleucine, alanine tetrazole 3 and serine
catalyzed the direct asymmetric aldol reactions with excellent
stereoselectivity, and furnished the corresponding b-hydroxy
ketones in high yield and up to . 99% ee. The linear amino
acid- and amine-catalyzed reactions are accelerated by water, and
are inexpensive, operationally simple and environmentally benign.
Importantly, our study demonstrates that a cyclic five-membered
ring motif in the amino acid catalyst is not essential for achieving
high asymmetric induction of the aldol products. Thus, several
simple linear natural and nonproteogenic amino acids and their
derivatives can be used as catalysts for this important asymmetric
reaction, which will dramatically expand the structural diversity
that can be utilized in the design of novel organocatalysts. In fact,
a simple a-methyl group of an amino acid is enough to reach the
excellent stereoselectivity of natural aldolase enzymes. Further
expansion of the use of linear amino acids and their derivatives in
organocatalytic asymmetric C–C bond-forming reactions, mecha-
nistic studies and density functional theory calculations is ongoing.
We gratefully acknowledge the Swedish National Research
Council, Carl-Trygger Foundation, Lars-Hierta Foundation and
Wenner-Gren Foundation for financial support.
8 For the proline-catalyzed intermolecular aldol reaction see: (a)
Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615; (b)
U. Eder, R. Sauer and R. Wiechert, Angew. Chem., Int. Ed., 1971, 10,
496; (c) C. Pidathala, L. Hoang, N. Vignola and B. List, Angew. Chem.,
Int. Ed., 2003, 42, 2785. For the stoichiometric use of phenylalanine and
tyrosine to mediate asymmetric intermolecular aldol condensations see:
(d) S. Danishefsky and P. Cain, J. Am. Chem. Soc., 1975, 97, 5282; (e)
I. Shimizu, Y. Naito and J. Tsuji, Tetrahedron Lett., 1980, 21, 4975; (f)
H. Hagiwara and H. Uda, J. Org. Chem., 1988, 53, 2308; (g) E. J. Corey
and S. C. Virgil, J. Am. Chem. Soc., 1990, 112, 6429.
9 (a) B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc., 2000,
122, 2395; (b) W. Notz and B. List, J. Am. Chem. Soc., 2000, 122, 7386;
(c) K. S. Sakthivel, W. Notz, T. Bui and C. F. Barbas, III, J. Am. Chem.
Soc., 2001, 123, 5260; (d) B. List, P. Porjarliev and C. Castello, Org.
Lett., 2001, 3, 573; (e) A. Co´rdova, W. Notz and C. F. Barbas, III,
Chem. Commun., 2002, 3024; (f) A. Co´rdova, W. Notz and C. F. Barbas,
III, J. Org. Chem., 2002, 67, 301; (g) A. B. Northrup and D. W. C.
MacMillan, J. Am. Chem. Soc., 2002, 124, 6798; (h) A. Bøgevig,
N. Kumaragurubaran and K. A. Jørgensen, Chem. Commun., 2002,
620; S. Saito, M. Nakadai and H. Yamamoto, Tetrahedron, 2002, 58,
8167; (i) Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi,
Y.-Z. Jiang and Y.-D. Wu, J. Am. Chem. Soc., 2003, 125, 5262; (j)
H. Torii, M. Nakadai, K. Ishihara, S. Saito and H. Yamamoto, Angew.
Chem., Int. Ed., 2004, 43, 1983; (k) A. Hartikaa and P. I. Arvidsson,
Tetrahedron: Asymmetry, 2004, 15, 1831; (l) A. Berkessel, B. Koch and
J. Lex, Adv. Synth. Catal., 2004, 346, 1141; (m) A. J. A. Cobb,
D. M. Shaw, D. A. Longbottom, J. B. Gold and S. V. Ley, Org. Biomol.
Chem., 2005, 3, 84.
10 J. Casas, M. Engqvist, I. Ibrahem, B. Kaynak and A. Co´rdova, Angew.
Chem., Int. Ed., 2005, 44, 1343; A. Co´rdova, H. Sunde´n, M. Engqvist,
I. Ibrahem and J. Casas, J. Am. Chem. Soc., 2004, 126, 8914;
A. Co´rdova, Acc. Chem. Res., 2004, 37, 102; H. Sunde´n, M. Engqvist,
J. Casas, I. Ibrahem and A. Co´rdova, Angew. Chem., Int. Ed., 2004, 43,
6532; A. Co´rdova, I. Ibrahem, J. Casas, H. Sunde´n, M. Engqvist and
E. Reyes, Chem. Eur. J., 2005, 11, 4772; A. Co´rdova, M. Engqvist,
I. Ibrahem, J. Casas and H. Sunde´n, Chem. Commun., 2005, 2047.
11 Alanine is also the oldest chiral amino acid incorporated in the protein
evolution, see: I. K. Jordan, F. A. Kondrashov, I. A. Adzhubei,
Y. I. Wolf, E. V. Koonin, A. S. Kondrashov and S. Sunyaev, Nature,
2005, 433, 633. And it is also of extraterrestrial origin, see: J. R. Cronin
and S. Pizzarello, Science, 1997, 275, 951.
12 For examples of the use of dihydroxyacetone mimetic 2a in proline-
catalyzed reactions see: (a) D. Enders and C. Grondal, Angew. Chem.,
Int. Ed., 2005, 44, 1210; (b) I. Ibrahem and A. Co´rdova, Tetrahedron
Lett., 2005, 46, 3363. Performing the L-alanine-catalyzed reaction
without addition of water enabled the isolation of 2a in 55% yield with
2 : 1 dr and . 99% ee after 20 days.
Notes and references
1 (a) W.-D. Fessner, in Stereoselective Biocatalysis; R. N. Patel, Ed.;
Marcel Dekker, New York, 2000, p. 239; (b) T. D. Machajewski and
C.-H. Wong, Angew. Chem., Int. Ed., 2000, 39, 1352.
2 Comprehensive Organic Synthesis, Vol. 2, B. M. Trost, I. Fleming, C.-H.
Heathcock, Eds.; Pergamon, Oxford, 1991.
3 For examples of application in total synthesis see: (a) T. Mukaiyama,
Angew. Chem., Int. Ed., 2004, 43, 5590; (b) K. C. Nicolaou,
D. Vourloumis, N. Winssinger and P. S. Baran, Angew. Chem., Int.
Ed., 2000, 39, 44.
4 Modern Aldol Reactions, Vol. 1 & 2, R. Mahrwald, Ed.; Wiley-VCH,
Weinheim, 2004; E. M. Carreira, in Comprehensive Asymmetric
Catalysis; E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer,
Heidelberg, 1999; J. S. Johnson and D. A. Evans, Acc. Chem. Res.,
2000, 33, 325.
13 The stereochemical outcome of the acyclic L-amino acid-catalyzed
asymmetric aldol reactions between ketones and aldehydes was the same
as when L-proline was used as the catalyst, see: L. Hoang, S. Bahmanyar,
K. N. Houk and B. List, J. Am. Chem. Soc., 2003, 125, 16.
14 This beneficial effect of water has also been observed in proline and its
derivatives-catalyzed aldol reactions. See: reference 12b and (a) B. List,
L. Hoang and H. J. Martin, Proc. Natl. Acad. Sci. USA, 2004, 101,
5839; (b) A. I. Nyberg, A. Usano and P. Pihko, Synlett, 2004, 1891; (c)
D. E. Ward and V. Jheengut, Tetrahedron Lett., 2004, 45, 8347.
5 (a) K. Mikami and S. Matsukawa, J. Am. Chem. Soc., 1994, 116, 4077;
(b) G. E. Keck, X.-Y. Li and D. Krishnamurthy, J. Org. Chem., 1995,
60, 5998; (c) D. A. Evans, D. M. Fitch, T. E. Smith and V. J. Cee,
J. Am. Chem. Soc., 2000, 122, 10033; (d) K. Juhl, N. Gathergood and
K. A. Jørgensen, Chem. Commun., 2000, 2211; (e) E. M. Carreira,
R. A. Singer and W. S. Lee, J. Am. Chem. Soc., 1994, 116, 8837; (f)
H. Ishita, Y. Yamashita, H. Shimizu and S. Kobayashi, J. Am. Chem.
Soc., 2000, 122, 5403; (g) S. E. Denmark and R. A. Stavanger, J. Am.
Chem. Soc., 2000, 122, 8837; (h) N. Kumagai, S. Matsunaga,
3588 | Chem. Commun., 2005, 3586–3588
This journal is ß The Royal Society of Chemistry 2005