The small peptide-catalyzed direct asymmetric aldol reaction in water

Article abstract of DOI:10.1039/b515880j

The asymmetric aldol reaction is a powerful method for forming carbon-carbon bonds. Small peptides with a primary amine as the catalytic residue catalyze asymmetric aqueous aldol reactions between unmodified ketones and aldehydes to furnish the corresponding aldol products with high ees. The high momodularity of the small peptides should enable the construction of several novel catalysts by combinatorial techniques for the aqueous asymmetric aldol reaction. The remarkably high difference in stereoselectivity between the peptide bond-formation was an important step towards the evaluation of asymmetric catalysis and homochilarity.

Full text of DOI:10.1039/b515880j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
The small peptide-catalyzed direct asymmetric aldol reaction in water†
Pawel Dziedzic,a Weibiao Zou,a Jonas Ha´frenb and Armando Co´rdova*a
Received 28th September 2005, Accepted 8th November 2005
First published as an Advance Article on the web 22nd November 2005
DOI: 10.1039/b515880j
Simple modular di- and tripeptides with a primary amine at
the N-terminus catalyze the aqueous asymmetric aldol reac-
tion between unmodified ketones and aldehydes to furnish
the corresponding b-hydroxy ketones with up to 86% ee in
water and 99% ee in aqueos media.
to furnish the corresponding aldol products with high ees (up to
86% in H2O, up to 99% in aqueous media). In stark contrast,
natural amino acids catalyzed the formation of nearly racemic
aldol products, which implies that peptide bond-formation is
important for the evolution of high asymmetry in water.
In initial experiments, we screened a variety of natural amino
acids, di- and tripeptides for their ability to catalyze the asymmetric
aldol reaction between cyclohexanone 1a (0.75 mmol) and p-
nitrobenzaldehyde (0.25 mmol) in water (1 mL) and sodium
dodecyl sulfate (SDS, 0.25 mmol) (Table 1).
We found a remarkable high difference in stereoselectivity
between the small peptide- and amino acid-catalyzed direct
aldol reactions: All the peptides tested catalyzed the asymmetric
formation of the desired aldol product 2a with 39–83% ee whereas
the simple amino acids catalyzed the formation of small amounts
of 2a with <5% ee. For example, L-vaL–L-phe and (L-ala)3 mediated
the asymmetric assembly of product 2a in 47% yield with 3 :
1 dr and 83% ee and 42% yield with 2 : 1 dr and 75% ee, respec-
tively. Moreover, the tripeptide (L-ala)3 catalyzed the asymmetric
assembly of 2a with a higher ee as compared to the dipeptide (L-
ala)2 showing the beneficial effect of structural complexity in water.
In addition, valine tetrazole 3 catalyzed the asymmetric formation
of 2a with 1 : 1 dr and 67% ee. Hence, converting amino acids to
tetrazole derivatives can have a beneficial effect in water as well
The asymmetric aldol reaction is a powerful method for forming
carbon–carbon bonds.1,2 In Nature, there are two types of aldolase
enzymes that catalyze the direct aldol reaction with excellent
stereocontrol: class I aldolases employ chiral enamines whereas
class II aldolases utilizes chiral Zn enolates as nucleophiles for the
stereoselective addition of dihydroxyacetone phosphate (DHAP)
to aldehydes.1 Water is the reaction media for most enzymatic
reactions in living systems. Thus, the stereoselective aldol reaction
plausibly evolved in aqueous media along with the evolution of
aldolase enzymes. In organic synthesis, there are several methods
for achieving directed catalytic stereoselective aldol reactions.2,3
However, methods for catalyzing enantioselective aldol reactions
in water are rare.4 For example, chiral organometallic complexes
have been developed that catalyze the asymmetric Mukaiyama-
type aldol reaction between activated silyl enol ethers and aldehy-
des in aqueous media.5 Moreover, biocatalysts mediate the direct
asymmetric aldol reaction with high stereoselectivity in aqueous
buffers.1,6,7 Organocatalysis is an active research area.8 In this
context, proline and its derivatives are excellent catalysts for the
direct asymmetric aldol reaction in organic solvent.9 However,
proline and other chiral pyrrolidine derivatives furnish nearly
racemic products in water.10 Moreover, amino acids catalyze the
asymmetric dimerization of glycol aldehyde to furnish tetroses
with low ees in water.11 This has led to speculation that amino acid
catalysis is a plausible mechanism for the origins of homochirality.
We recently found that acyclic amino acids12a and small linear
peptides12b catalyze the direct intermolecular asymmetric aldol
reaction with high stereoselectivity in organic solvents. We there-
fore wanted to expand this concept to water or aqueous media
providing for the asymmetric assembly of aldol products under
environmentally benign reaction conditions. Moreover, the lessons
learnt from these studies would give important information on a
molecular level about the evolution of homochirality and catalysis
of aldolase enzymes. Herein, we report that small peptides with
a primary amine as the catalytic residue, catalyze the asymmetric
aqueous aldol reaction between unmodified ketones and aldehydes
Table 1 Examples of screened catalysts for the direct asymmetric inter-
molecular aldol reaction between 1a and p-nitrobenzaldehyde in water
Entry Catalyst
Time/h Yield (%)a Drb Ee (%)c
1
2
3
4
5
6
7
L-val–L-val
76
52
40
47
70
30
22
45
42
2 : 1
3 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
67
83
83
71
70
56
75
L-val–L-phe
L-val–L-phe
L-val–L-ala
L-val–L-ala
L-val–L-val
L-ala–L-
70d
96
68
68
120
ala–L-ala
8
9
L-ser–L-ala
73
96
80
40
2 : 1
1 : 1
39
67
10
11
12
L-valine
L-proline
L-alanine
41
42
163
20
10
12
1 : 1 <5
1 : 1 <5
aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm Uni-
versity, Sweden. E-mail: acordova1a@netscape.net, acordova@organ.su.se;
Fax: + 46 8 15 49 08; Tel: +46 8 162479
1 : 1
0
bSwedish University of Agricultural Sciences, Department of Wood Science,
Box 7008, SE-750 07, Uppsala, Sweden
a Isolated yield after silica-gel column chromatography. b anti : syn ratio
as determined by NMR analyses of the crude product. c Determined by
chiral-phase HPLC analyses. d 20 vol% DMF and no SDS.
† Electronic supplementary information (ESI) available: Experimental
details, NMR data and amino acid analyses. See DOI: 10.1039/b515880j
3 8 | Org. Biomol. Chem., 2006, 4, 38–40
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Table 2 The peptide-catalyzed direct intermolecular aldol reaction in
a hydrophobic environment (entry 4). In fact, L-val–L-phe–L-ala
catalyzed the asymmetric assembly of 2a with 3 : 1 dr and 86%
ee under these reaction conditions. The dipetide-catalyzed direct
asymmetric aldol reaction proceeded smoothly in aqueous media
and product 2a was isolated in high yield with 3 : 1 dr and up
to 93% ee. Encouraged by these results we also investigated the
peptide-catalyzed aqueous asymmetric aldol reaction for a set of
different ketones and aldehydes in aqueous media (Table 3).
To our delight, the simple linear peptides catalyzed the asym-
metric aldol reactions with DHAP mimetic 1b and ketones 1
as the donors with high enantioselectivity and furnished the
corresponding aldol products 2b–e in 51–83% yield with up to 99%
ee. Notably, the small peptides catalyzed the first enantioselective
aldol reactions with dihydroxy acetone (DHA) as the donor.
For instance, L-val–L-phe catalyzed the asymmetric assembly of
aldol product 2e in 53% yield with 1 : 1 dr and 70% ee (entry
6). In comparison, proline and valine catalyzed the formation
of trace amounts of 2e (<10% ee). Thus, small peptides should
be considered for the development of direct asymmetric aldol
reactions with DHA as the donor.
different aqueous media
Entry Catalyst
Solvent
Yield (%)a Drb
Ee (%)c
1
2
3
4
5
6
7
8
9
L-val–L-phe Phosphate bufferd
L-val–L-phe NaOAc buffere
L-val–L-phe H2Of
48
27
47
48
70
67
72
2 : 1 83
2 : 1 85
3 : 1 83
3 : 1 86
2 : 1 83
3 : 1 93
3 : 1 83
2 : 1 81
3 : 1 87
3 : 1 86
L-val–L-phe H2Og
L-val–L-phe H2O–DMF, 5 : 1
L-val–L-ala
L-ala–L-ala
H2O–DMF, 1 : 1
H2O–EtOH, 1 : 1
L-ser–L-phe H2O–MeOH, 1 : 1 90
L-ala–L-ala
L-ala–L-ala
H2O–NMP, 1 : 1
H2O–DMSO, 1 : 1 80
56
10
a Isolated yield after silica-gel column chromatography. b anti : syn ratio
as determined by NMR analyses of the crude product. c Determined by
chiral-phase HPLC analyses. d Phosphate buffer, 40 mM, pH 7.2, SDS.
e NaOAc buffer, 0.1M, pH 4.2, SDS. f 1 equiv. SDS. g 1 equiv. a-cyclodextrin
added.
Our recent density functional theory (DFT) calculations have
shown that the primary amino acids utilize a carboxylic acid-
catalyzed enamine mechanism (Fig. 1, I).14
as in organic solvent.9o The addition of a small amount of DMF
(20 vol%) instead of SDS increased the yields and ees of 2a. Thus,
we also investigated the peptide-catalyzed direct asymmetric aldol
reaction in different aqueous buffer and media (Table 2).
The enantioselectivity of the dipeptide-catalyzed aldol reaction
was not affected by performing the reactions in buffered aqueous
media and product 2a was formed with high ees. However, the
efficiency of the peptide-catalyzed asymmetric aldol reactions
decreased at low pH. Inspired by the pioneering studies of Breslow
and co-workers,13 we also investigated whether the addition of a-
cyclodextrin to the peptide-catalyzed asymmetric aldol reaction in
water (no SDS) would improve the enantioselectivity by creating
Fig. 1 Plausible transition states I and II for the primary amino
acid–dipeptide-catalyzed asymmetric aldol reactions.
The generation of nearly racemic aldol products 2 by amino
acid catalysis in water indicates that the H2O molecules prevent
Table 3 Examples of dipeptide-catalyzed direct intermolecular aldol reactions between different ketones aldehydes in aqueous media
Entry
1
Dipeptide
Ketone
R
Product
Conditions
Yield (%)a
51
Drb
Ee (%)c
99
L-val–L-phe
4-NO2C6H4
H2O–DMSO, 1 : 1
15 : 1
2
3
4
L-val–L-phe
L-val–L-val
L-val–L-phe
1b
1b
1a
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
2b
2b
H2O–MeOH, 1 : 1
H2O–DMSO, 1 : 1
H2O–MeOH, 1 : 1
83
52
65
2 : 1
1 : 1
1 : 1
99
99
86
5
6
L-val–L-phe
L-val–L-phe
1a
4-BrC6H4
4-NO2C6H4
2d
H2O–MeOH, 1 : 1
H2O–DMSO, 1 : 1
66
53
1 : 1
1 : 1
63
70
7
L-val–L-val
1c
4-NO2C6H4
2e
H2O–DMSO, 1 : 1
67
1 : 1
51
a Isolated yield after silica-gel column chromatography. b anti : syn ratio as determined by NMR analyses of the crude product. c Determined by chiral-phase
HPLC analyses.
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efficient stabilization of the six-membered transition state by the
chiral enamine, which lowers the energy difference between the
possible transition states. In contrast, the high enantioselectivity of
the small peptide-catalyzed aldol reactions in water suggests that
the peptide bond of the natural catalyst is crucial in preserving a
stabilized transition state structure, were the Re-face of the chiral
enamine is approached by the Si-face of the acceptor aldehyde
(Fig. 1, II). This is plausibly accomplished by stabilization of the
generated alkoxide of the product by hydrogen bonding by the
peptide backbone and the formation of a charge relay system that
increases the Brønstedt acidity of the di- and tri-peptides. In fact,
a charge relay system is very important in the enamine catalysis of
aldolase enzymes.15
In summary, we present that small peptides with a catalytic
primary amino acid residue at the N-terminus catalyze the
asymmetric intermolecular aldol reaction between unmodified
ketones and aldehydes with high stereoselectivity in water. For
example, simple di- and tripeptides catalyzed the asymmetric
assembly of the corresponding b-hydroxy ketones in up to 86%
ee in water and 99% ee in aqueous media. The high modularity of
the small peptides should enable the construction of several novel
catalysts by combinatorial techniques for the aqueous asymmetric
aldol reaction. The remarkably high difference in stereoselectivity
between the peptide and amino acid-catalyzed aqueous aldol reac-
tions suggest that peptide bond-formation was an important step
towards the evolution of asymmetric catalysis and homochirality.
Moreover, the small peptide-catalyzed aqueous aldol reaction
may be of biological significance.16,17 Further development of
environmentally benign asymmetric C–C bond-forming reactions,
mechanistic studies and DFT calculations are ongoing.
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We gratefully acknowledge the Swedish National Research
Council, Carl-Trygger, Lars-Hierta and Wenner-Gren Founda-
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The Royal Society of Chemistry 2006
©