Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides

Article abstract of DOI:10.1002/chem.200501639

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of poly-peptides and proteins with different functions. Here we report that α-amino acids, β-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantio-selectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corre sponding aldol products with up to > 99% ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.

Full text of DOI:10.1002/chem.200501639

FULL PAPER
DOI: 10.1002/chem.200501639
Direct Asymmetric Intermolecular Aldol Reactions Catalyzed by Amino
Acids and Small Peptides
Armando Córdova,* Weibiao Zou, Pawel Dziedzic, Ismail Ibrahem, Efraim Reyes, and
Yongmei Xu[a]
Abstract: In nature there are at least
nineteen different acyclic amino acids
that act as the building blocks of poly-
peptides and proteins with different
functions. Here we report that a-amino
acids, b-amino acids, and chiral amines
containing primary amine functions
catalyze direct asymmetric intermolec-
ular aldol reactions with high enantio-
selectivities. Moreover, the amino acids
can be combined into highly modular
natural and unusual small peptides that
also catalyze direct asymmetric inter-
molecular aldol reactions with high
stereoselectivities, to furnish the corre-
sponding aldol products with up to
>99% ee. Simple amino acids and
small peptides can thus catalyze asym-
metric aldol reactions with stereoselec-
tivities matching those of natural en-
zymes that have evolved over billions
of years. A small amount of water ac-
celerates the asymmetric aldol reac-
tions catalyzed by amino acids and
small peptides, and also increases their
stereoselectivities. Notably, small pep-
tides and amino acid tetrazoles were
AHCTREUNG
able to catalyze direct asymmetric
aldol reactions with high enantioselec-
tivities in water, while the parent
amino acids, in starkcontrast, furnish-
ed nearly racemic products. These re-
sults suggest that the prebiotic oligo-
merization of amino acids to peptides
may plausibly have been a linkin the
evolution of the homochirality of
sugars. The mechanism and stereo-
chemistry of the reactions are also dis-
cussed.
Keywords: aldol reaction · amino
acids
·
asymmetric catalysis
·
ketones · organocatalysis · peptides
Introduction
ful in asymmetric Mukaiyama-type aldol reactions between
activated silyl enol ethers and aldehydes,[6] whilst further-
more, enantioselective aldol reactions between unmodified
ketones and aldehydes are catalyzed with excellent stereose-
lectivities by chiral organometallic complexes.[7] Another ap-
proach to the catalysis of direct asymmetric aldol reactions
is the use of aldolase enzymes.[1,8]
Asymmetric organocatalysis is a fast-moving research
field.[9] In this context, proline and its derivatives have
proven to be efficient catalysts for direct intermolecular
asymmetric aldol reactions.[10,11] In starkcontrast with pro-
line, linear amino acids are considered to be poor or no cat-
alysts for intermolecular enantioselective aldol reactions be-
tween unmodified ketones and aldehydes,[11a–d] though intra-
molecular aldol condensations have been mediated by the
utilization of stoichiometric equivalents of acyclic amino
acids together with HClO4 or camphorsulfonic acid.[10]
Moreover, N-terminal prolyl peptides have been used as
asymmetric catalysts for direct enantioselective intermolecu-
lar aldol reactions.[12] Oligopeptides and their derivatives
have the advantage of allowing the generation of structural
diversity and functionality and the employment of combina-
torial techniques.[13,14] However, small peptides with acyclic
The direct asymmetric aldol reaction is one of the most im-
portant C C bond-forming reactions in nature, and is cata-
À
lyzed by aldolase enzymes with excellent stereocontrol.[1]
The reaction is also believed to have been the key transfor-
mation for the prebiotic asymmetric formation of sugars.[2]
The goal of controlling the stereochemistry of the asymmet-
ric aldol reaction has inspired chemists and raised this trans-
formation to prominence in the asymmetric assembly of
complex natural products.[3,4] In particular, the development
of catalytic stereoselective methods for asymmetric directed
aldol reactions has recently been the subject of intense re-
search:[5] the utilization of, for example, organometallic com-
plexes and Lewis bases as catalysts has been highly success-
[a] Prof. Dr. A. Córdova, Dr. W. Zou, P. Dziedzic, I. Ibrahem, E. Reyes,
Dr. Y. Xu
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
Chem. Eur. J. 2006, 12, 5383 – 5397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5383

amino acid residues at their N-termini are not believed to
catalyze asymmetric aldol reactions. A dramatic increase in
potential catalyst structures would thus occur if acyclic
amino acids and small modular peptides N-terminated with
acyclic amino acids were indeed found to be able to catalyze
direct intermolecular asymmetric aldol reactions between
ketones and aldehydes. For example, there are 19 natural
amino acids containing a primary amine function that can
be combined to produce 192 (>361) and 193 (>6859) differ-
ent di- and tripeptides, respectively. Moreover, proteinogen-
ic acids, b-amino acids, and acyclic chiral amines could also
be used to expand the structural variety further. Intrigued
by this tremendous potential structural diversity and moti-
vated by our interest in stereoselective organocatalysis,[15]
we most recently found that acyclic amino acids and small
modular peptides can catalyze direct intermolecular asym-
metric aldol reactions with excellent stereoselectivities.[16] In
addition, we also found that ancient oligopeptides catalyze
the asymmetric formation of sugars under prebiotic condi-
tions.[16b] Here we describe: 1) structure–activity relation-
ships of acyclic amino acids, acyclic amino acid N-terminat-
ed peptides, and their derivatives, 2) the synthetic scope of
catalysis by acyclic amino acids, acyclic chiral amines, and
small modular peptides in direct asymmetric aldol reactions,
3) catalysis in aqueous media and water, and 4) studies con-
cerning the reaction mechanism.
Results and Discussion
During our studies of amino acid catalyzed de novo synthe-
sis of ketoses we most recently found that (S)-proline-medi-
ated aldol reactions with dimethyl-1,3-dioxan-5-one (1a)
were significantly accelerated by water,[11o] and so we decid-
ed to investigate asymmetric aldol reactions catalyzed by
acyclic amino acids and modular small peptides in wet or-
ganic solvents. In an initial experiment, we investigated the
reaction between the dihydroxyacetone phosphate mimetic
1a (1.5 mmol) and p-nitrobenzaldehyde (0.5 mmol) in wet
DMSO (2.0 mL+90 mL H2O) [Eq (1)].
Remarkably, the desired aldol adduct 2a was isolated in
84% yield with 6:1 d.r. and >99% ee. Inspired by the excel-
lent stereoselectivity of this reaction, we decided to screen
several acyclic amino acids and chiral amines for their abili-
ty to catalyze the direct aldol reaction between cyclohexa-
none (1b) and p-nitrobenzaldehyde in wet DMSO (Table 1).
Table 1. Asymmetric aldol reactions catalyzed by acyclic amino acids and chiral amines.
Entry Catalyst
Time [h] Yield[a] [%] d.r.[b] ee [%][c] Entry Catalyst
Time [h] Yield[a] (%) d.r.[b] ee[c] (%)
1
2
3
4
5
6
7
(S)-alanine
(S)-a-aminobutyric acid 72
(S)-valine
(S)-norvaline
(S)-alaninol
(S)-arginine
(S)-aspartate
72
95
88
98
79
91
62
75
15:1
6:1
37:1
6:1
1:2
1:1
92 14
92 15
>99 16
90 17
N-methyl-(S)-valine
(S)-histidine
(S)-phenylalanine
b-alanine
(S)-threonine
(S)-tyrosine
(S)-a-methylvaline
92
72
48
48
53
trace
60
70
35
80
1:1
4:1
3:1
3:1
8:1
3:1
1:1
À14
71
73
–
98
31
À4
72
72
72
72
72
46 18
4
19
53
310
45
62
6:1
63 20
8
72
72
72
94
82
88
1:15
24 21
23
48
68
70
87
80
16:1
7:1
98
88
63
9
(S)-isoleucine
(S)-serine
10:1
7:1
>99 22
80 23
(S)-methionine
10
4:1
11
12
13
8
51
48
60
60
74
10:1
10:1
1:1
92 24
92 25
84 26
((S)-cysteine)2
16
72
72
95
90
23
2:1
10:1
2:1
32
–
(S)-leucine
(S)-lysine
glycine
12
1
[a] Yield of isolated product yield after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn) was determined by H NMR analysis
of the crude product. [c] The ee of 2b was determined by chiral-phase HPLC analyses.
5384
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Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
FULL PAPER
To our delight, we found that several simple natural and
nonproteinogenic amino acids catalyzed the reaction with
excellent enantioselectivities, with alanine, valine, isoleucine,
leucine, and threonine, for example, catalyzing the asymmet-
ric assembly of b-hydroxyketone 2b with >90% ee. The ar-
omatic amino acids phenylalanine and histidine also mediat-
ed the asymmetric aldol reaction with good enantioselectivi-
ty, whereas tyrosine catalyzed the asymmetric formation of
2b with low stereoselectivity. In starkcontrast with the cys-
teine dimer, the sulfide-containing amino acid methionine
mediated the asymmetric assembly of 2b in high yield and
with high enantioselectivity (Table 1, entries 22 and 24). The
basic amino acid arginine catalyzed the formation of nearly
racemic 2b, whilst the acid-functionalized amino acid aspar-
tate catalyzed the asymmetric formation of 2b with good
enantioselectivity (Table 1, entries 6 and 7). In addition, the
asymmetric aldol reaction with lysine and serine as the cata-
lysts furnished 2b in high yields and with good ees (En-
tries 10 and 13). The trend from our studies is that employ-
ment of small aliphatic a-amino acids as asymmetric cata-
lysts gives high asymmetric induction. In addition, amino
acids containing an acid functionality or a b-hydroxy group
are good catalysts. Aromatic amino acids can also catalyze
the stereoselective aldol reaction with high enantioselectivi-
ty and should therefore be considered as catalysts, whilst N-
methylated valine was a poor catalyst under our reaction
conditions, giving ent-2b with low enantioselectivity
(Table 1, entry 14). The significant difference in reactivity
and stereoselectivity between valine and N-methylated
valine is plausibly due to steric effects in the enamine for-
mation between the N-methylated amino acid and cyclohex-
anone 1b and in the transition states.
Moreover, the intermolecular aldol reaction was also
mediated by linear amino alcohols and chiral amines, al-
though the enantioselectivities were low. The simple chiral
amine 3 mediated the stereoselective aldol reaction with ex-
cellent syn diastereoselectivity (Table 1, entry 8), indicating
that simple acyclic chiral amines might be excellent catalysts
for the development of syn-selective intermolecular aldol re-
actions. Notably, the strategy of converting the acid moieties
of the amino acids into tetrazoles increased the reactivities
and solubilities of the amino acids:[17] the primary amine tet-
razoles 4 and 5, for example, catalyzed the asymmetric for-
mation of aldol product 2b in 84% and 70% yields with
>99% and 98% ee, respectively (Table 1, entries 11 and
21). b-Amino acids also catalyzed the direct intermolecular
aldol reaction. Moreover, TBS-protected serine 6 also medi-
ated the asymmetric aldol reaction with good stereoselectiv-
ity (Table 1, entry 23).
We also screened several simple small peptides and their
analogues for their abilities to catalyze the direct aldol reac-
tion between cyclohexanone (1b) and p-nitrobenzaldehyde
in wet DMSO (Table 2).
Table 2. Direct asymmetric aldol reactions catalyzed by small peptides, dendritic peptides, urea peptides, pseudo peptides, and albumin.
Entry Catalyst
Time [h] Yield[a] [%] d.r.[b] ee [%][c] Entry Catalyst
Time [h] Yield[a] [%] d.r.[b] ee[c] [%]
1
2
3
4
5
6
7
8
(S)-ala-(S)-ala
(S)-ala-(S)-phe
(S)-ala-gly
(S)-ala-(S)-val
(S)-val-(S)-ala
(S)-val-(S)-val
(S)-ser-(S)-ala
(S)-val-(S)-phe
24
24
48
41
48
24
24
24
73
70
46
87
92
75
55[e]
72
8:1
2:1
4:1
1:1
1:1
1:1
2:1
2:1
91
93
81
87
98
94
92
96
12
13
14
15
16
17
18
19
((S)-ala)4
((S)-ala)5
(S)-ala-(S)-phenylalaninol 51
(S)-ala-(S)- alaninol 19
(S)-val-(S)- phenylglycinol 51
(S)-val-(R)- phenylglycinol 26
(S)-phe-(S)-phenylalaninol 19
72
72
trace
trace
45
20
30
35
19
65
1:1
1:1
1:1
1:2
67
6
25 (52)[d]
9
1:12 34 (65)[d]
1:1
1:2
2:1
33 (55)[d]
0 (52)[d]
10
albumin
48
9
gly-(S)-ala
48
65
2:1
11
20
54
32
62
1:1
2:1
76
62
10
11
b-ala-b-ala
48
45
90
1:2
1:2
–
21
57
(S)-ala-(S)-ala-(S)-ala 72
81
1
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn) was determined by H NMR analysis of the
crude product. [c] The ee of 2b was determined by chiral-phase HPLC analyses. [d] The ee of the syn diastereomer as determined by chiral HPLC analy-
ses. [e] 20 equivalents of H2O were used.
Chem. Eur. J. 2006, 12, 5383 – 5397
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5385

A. Córdova et al.
To our delight the efficiencies of the asymmetric aldol re-
actions improved (relative to those of those catalyzed by the
parent acyclic amino acids) when simple dipeptides were
used as the catalysts. Simple alanine- and valine-terminated
dipeptides, for example, catalyzed the asymmetric formation
of 2b in high yields and with up to 98% ee. Peptides con-
taining N-terminal glycine moieties also catalyzed the asym-
metric aldol reaction, but with lower stereoselectivities than
the corresponding peptides with N-terminal alanines. We
also found that small peptides based on b-amino acids also
catalyzed the direct intermolecular aldol reaction. The sizes
of the small peptides were important, since the efficiency
and stereoselectivity of the aldol reaction decreased with in-
creased number of amino acid residues in the oligopeptide:
the enantioselectivities of the asymmetric aldol reactions
mediated by oligoalanine catalysts, for instance, were in the
order ala-ala>ala-ala-ala>(ala)4 >(ala)5. Notably, the ste-
Asymmetric aldol reactions in different solvents: We next
decided to employ the simple amino acids valine and ala-
nine as catalysts for the asymmetric assembly of 2b in differ-
ent solvents (Table 3).
We found that valine catalyzed the asymmetric intermo-
lecular aldol reaction with high enantioselectivity in all the
wet organic solvents tested. The highest reaction rates were
achieved in DMSO, NMP, and DMF. Notably, performing
the valine- and alanine-mediated reactions in water gave the
aldol product 2b in low yield with less than 6% ee (Table 3,
entry 12).[18] Sodium dodecylsulfate (SDS) was used as sur-
factant since it improves the solubilities of the organic sub-
strates in water. However, a change of catalyst to the corre-
sponding valine tetrazole 5 gave 2b in moderate yield and
with 67% ee in water (Table 3, entry 21). Notably, increasing
the concentration accelerated the reaction and gave 2b with
99% ee (Table 3, entry 22). Moreover, the amino acid-de-
rived tetrazoles were more efficient than the parent amino
acids in all the organic solvents tested. We also investigated
simple alanine- and valine-derived dipeptides in different
solvents (Table 4).
A
dramatically when going from tetraalanine to pentaalanine,
which catalytically assembled 2b with 67% ee and 6% ee,
respectively (Table 2, entries 12 and 13). Interestingly, albu-
min, a protein available off the shelf, was also able to cata-
lyze the asymmetric aldol reaction and furnished 2b in high
yield and with 10% ee (Table 2, entry 19). Pseudo-dipeptides
containing alcohol moieties also catalyzed the asymmetric
formation of 2b, though with lower efficiencies and stereo-
selectivities than the corre-
We found that ala-ala catalyzed the asymmetric aldol re-
action with high enantioselectivities (89–94% ee) in wet
polar solvents such as DMSO, MeOH, EtOH, NMP, and
DMF. Notably, the dipeptide-mediated aldol reactions in
dry DMSO gave 2b with moderate enantioselectivities: ala-
sponding dipeptides. Notably,
Table 3. Solvent screen for aldol reactions catalyzed by acyclic amino acids and amino acid tetrazoles.
(S)-val-(S)-phenylglycinol cata-
lyzed the reaction with high syn
diastereoselectivity to give 2b
in moderate yield with 12:1 d.r.
and 65% ee (Table 2, entry 16).
Moreover, the urea-based pep-
tide analogue 8 catalyzed the
asymmetric formation of 2b
with high enantioselectivity but
in low yield (Table 2, entry 20).
Nevertheless, chiral urea deriv-
atives containing catalytic pri-
mary amine residues deserve
consideration in the design of
novel organocatalysts for asym-
Entry
Catalyst
Solvent
Temp [8C]
Time [h]
Yield [%][a]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-valine
(S)-alanine
(S)-alanine
(S)-alanine
(S)-alanine
(S)-alanine
(S)-4
DMSO[d]
DMSO
CHCl3
dioxane
MeOH
EtOH
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
4
47
72
147
124
28
52
51
69
195
144
240
41
92
72
97
24
163
8
96
70
98
20
16
25
30
65
60
10
25
5
20
50
95
55
21
12
84
15
70
40
30
5:1
37:1
6:1
4:1
6:1
4:1
9:1
8:1
4:1
8:1
2:1
1:1
3:1
15:1
8:1
15:1
1:1
14:1
6:1
16:1
1:1
94
>99
95
92
95
92
95
95
92
95
33
-6
83
92
92
95
67
NMP
DMF
9
EtOAc
CH3CN
H2O[e]
10
11
12
13
14
15
16
17
18
19
20
21
22
À
metric C C bond-forming reac-
H2O[f]
tions that proceed by a catalytic
enamine mechanism. The den-
dritic peptide 9 catalyzed the
asymmetric formation of 2b in
good yield and with good enan-
DMSO[d]
DMSO
DMSO
DMSO
H2O[f]
4
RT
RT
RT
RT
RT
RT
tioselectivity
(Table 2,
DMSO
CHCl3
DMSO
H2O[f]
>99
95
98
67
99
(S)-4
(S)-5
(S)-5
(S)-5
entry 21), so amino acid derived
dendrimers should be employ-
able in the design of new inter-
esting catalysts with multiple
catalytic sites.
23
96
7
H2O[g]
11:1
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn)
was determined by 1H NMR analysis of the crude product. [c] The ee of 2b was determined by chiral-phase
HPLC analyses. [d] No water was added. [e] DMSO (10 vol%) no SDS added. [f] Sodium dodecylsulfate
(SDS, 72 mg) added. [g] 5 equivalents of 1b and 130 mL H2O.
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Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
Table 4. Solvent screen for the simple peptide-catalyzed aldol reactions.
FULL PAPER
for instance, catalyzed the
asymmetric assembly of 2a with
3:1 d.r. and 86% ee under these
reaction conditions (Table 4,
entry 21).
Prebiotic significance: The re-
markably large differences in
enantioselectivity between the
dipeptides and their corre-
sponding parent acyclic amino
acids in aqueous media could
be important from a prebiotic
perspective. In this context, we
found that the simple peptides
(S)-ala-(S)-ala and (S)-val-(S)-
val furnished d-erythrose with
48 and 82% ee, respectively,
Entry
Catalyst
Solvent
DMSO[d]
DMSO
MeOH
EtOH
Time [h]
Yield [%][a]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-phe
(S)-ala-(S)-phe
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-val-(S)-val
(S)-val-(S)-phe
(S)-val-(S)-ala
((S)-alanine)3
((S)-alanine)4
((S)-alanine)5
(S)-val-(S)-phe
(S)-val-(S)-phe
(S)-val-(S)-phe
albumin
72
24
51
51
52
48
23
67
116
70
48
68
22
68
76
52
96
120
72
72
52
120
120
67
51
73
77
72
84
74
80
67
25
70
90
67
56
22
40
47
30
42
trace
trace
48
27
27
27
1:3
8:1
3:1
4:1
3:1
3:1
3:1
3:1
2:1
2:1
2:1
3:1
3:1
2:1
2:1
3:1
2:1
2:1
2:1
2:1
3:1
2:1
2:1
1:1
55
91
89
92
93
94
86
93
70
83
81
83
87
70
67
83
70
75
71
58
86
85
85
9
NMP
DMF
DMSO/H2O 1:1
DMF/H2O 1:1
DMF/H2O 1:5
DMF/H2O 1:5
MeOH/H2O 1:1
EtOH/H2O 1:1
NMP/H2O 1:1
H2O[e]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
under
prebiotic
conditions
H2O[e]
[Eq. (2)]. In comparison, (S)-
ala and (S)-val furnished d-er-
ythrose with 5 and 12% ee, re-
spectively.[2c]
Oligopeptide formation may
thus have played a role in the
evolution of homochirality of
sugars. For instance, we found
that ancient amino acids that
are oligomerized to peptides
with the help of volcanic gas[20]
catalyze the asymmetric aldol
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[f]
phosphate buffer[g]
phosphate buffer[h]
H2O[e]
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn)
was determined by 1H NMR of the crude product. [c] The ee of 2b was determined by chiral-phase HPLC
analyses. [d] No water added. [e] Sodium dodecylsulfate (SDS, 72 mg) added. [f] 1 equivalent of a-cyclodextrin
added. [g] Phosphate buffer, 40 mm, pH 7.2, SDS. [h] NaOAc buffer, 0.1m, pH 4.2, SDS.
ala catalyzed the formation of 2b, for example, with 55% ee
(Table 4, entry 1), so a small amount of water is important
for achieving high enantioselectivity in the dipeptide-cata-
lyzed asymmetric intermolecular aldol reaction. Interesting-
ly, the enantioselectivity of the dipeptide-catalyzed aldol re-
action was not affected by performing the reactions in buf-
fered aqueous media, product 2b being formed with high
ees. However, the efficiencies of the peptide-catalyzed asym-
metric aldol reactions decreased at low pH.
reaction with excellent stereoselectivity under these prebiot-
ic conditions.[21] In a plausible scenario, extraterrestrial
amino acids may perhaps have oligomerized to form oligo-
peptides that enabled the asymmetric formation of sugars
with high optical activity.[22]
The simple dipeptide val-phe catalyzed the asymmetric
aqueous aldol reaction with the highest enantioselectivity of
all the dipeptides tested. The enantioselectivities of the
tetra- and pentaalanine-catalyzed aqueous asymmetric aldol
reactions were also significantly improved (Table 4, en-
tries 19 and 20): penta-(S)-alanine, for example, catalyzed
the asymmetric formation of 2b with 58% ee in water, in
comparison with 6% ee in wet DMSO. The enantioselectivi-
ty of the albumin-catalyzed asymmetric aldol reaction was
almost the same either in DMSO or in water (2b, 9–
10% ee). Inspired by the pioneering workby Breslow and
co-workers,[19] we also investigated whether the addition of
a-cyclodextrin to the peptide-catalyzed asymmetric aldol re-
action in water (no SDS) would improve the enantioselectiv-
ity by creating a hydrophobic environment: (S)-val-(S)-phe,
Substrate scope: We next investigated the substrate scope of
asymmetric intermolecular aldol reactions catalyzed by acy-
clic amino acids and dipeptides in wet DMSO. We found
that the (S)- and (R)-amino acids and their derivatives
mediated the enantioselective aldol reactions with cyclohex-
anones as donors with excellent enantioselectivities, giving
the corresponding aldol products 2a, 2b, and 2e with 92–
99% ee (Table 5).
Moreover, unsymmetrical ketones were good donors and
the corresponding aldol products were furnished with excel-
Chem. Eur. J. 2006, 12, 5383 – 5397
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5387

A. Córdova et al.
Table 5. Asymmetric aldol reactions with different ketones, catalyzed by acyclic amino acids.
Entry
1
Catalyst
Ketone
Prod.
Time [h]
72
Yield [%][a]
84
d.r.[b]
ee [%][c]
>99
(S)-alanine
1a
6:1
2
3
4
(S)-valine
(S)-4
(S)-5
1a
1a
1a
2a
2a
2a
72
72
72
86
70
87
5:1
3.1
4:1
>99
>99
>99
5
(S)-valine
1b
1b
72
98
37:1
16:1
>99
6
7
8
9
(R)-valine
(S)-alanine
(S)-valine
(S)-alanine
ent-2b
72
120
120
72
89
99
56
54
75
30[d]
41[d]
56
1c
2c
3:1
10
(S)-alanine
71
80
16:1
92
1
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn) was determined by H NMR analysis of the
crude product. [c] The ee of 2 was determined by chiral-phase HPLC analyses. [d] 5 equivalents of acetone were used. In all other cases 3 equivalents of
donors 1 were used.
lent regioselectivities in moderate yields and with high enan-
tioselectivities. (S)-Alanine, for example, catalyzed the
asymmetric formation of 2d as a single regioisomer in 56%
tively (Table 6, entries 10 and 11). Notably, the acyclic
amino acids only furnished trace amounts of the dihydroxy-
A
À
yield with 3:1 d.r. and 75% ee (Table 5, entry 9), C C bond-
ty gives higher reactivity and stereoselectivity both in organ-
ic solvents and in aqueous media. This was also observed in
the case of the aldol reactions with acetone, in which the
corresponding product 2c had been formed with high enan-
tioselectivity but in low yield after 48 h. Moreover, small
modular peptides catalyze the formation of aldol products 2
with high enantioselectivity in aqueous media under envi-
ronmentally benign reaction conditions.[23]
formation thus having occurred on the methylene carbon of
the ketone. Reactions with acetone were slow, giving the
corresponding aldol products in low yields but with good
enantioselectivities after a reaction time of four days.
Hence, cyclohexanones and substituted acyclic ketones are
excellent and good donors, respectively, in asymmetric aldol
reactions mediated by acyclic amino acids. Similar substrate
specificities of the catalysts were observed in the dipeptide-
and pseudo-peptide-catalyzed direct asymmetric aldol reac-
tions (Table 6).
We also investigated direct intermolecular aldol reactions
between ketones and different acceptor aldehydes catalyzed
by alanine and by alanine tetrazole 4 (Table 7).
In particular, the dihydroxyacetone mimic 1a was an ex-
cellent donor and all the tested di- and pseudo-peptides
mediated the asymmetric formation of 2a with excellent
enantioselectivity. Moreover, the dipeptide-mediated asym-
metric aldol reactions with hydroxyacetone and dihydroxy-
The aldol reactions mediated by alanine and by the tetra-
zole 4 proceeded smoothly, and the aldol products 2h–2n—
derived from the dihydroxyacetone mimic 1a and cyclohex-
anone (1b)—were furnished with excellent enantioselectivi-
ties. Remarkably, a simple chiral methyl group is enough to
reach the stereoselectivity of aldolase enzymes. The acyclic
amino acid-catalyzed aldol reactions with acetone as the
ACHTREUNG
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Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
FULL PAPER
Table 6. Dipeptide- and pseudo-peptide-catalyzed asymmetric aldol reactions with different ketones.
The dipeptide-catalyzed reac-
tions were more efficient than
the alanine- and valine-cata-
lyzed asymmetric aldol reac-
tions, and the corresponding
aldol products 2h–2p were
asymmetrically assembled with
high enantioselectivity (71–
99% ee). The peptides comple-
ment each other, suggesting
that an ideal peptide catalyst
for a given pair of substrates
might be producible. Interest-
ingly, the dipeptides were more
soluble in wet DMSO than the
acyclic amino acids.
Entry Catalyst
Ketone Prod.
Time [h] Yield [%][a] d.r.[b] ee [%][c]
1
2
3
4
5
6
7
8
9
(S)-ala-(S)-ala
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2b
2c
2c
48
48
48
48
48
48
24
24
48
73
88
89
83
80
82
72
3:1
5:1
6:1
2:1
4:1
4:1
2:1
99
99
99
99
99
99
96
65
71
(S)-ala-(S)-phe
(S)-val-(S)-phe
(S)-val-(S)-val
(S)-val-(R)-phealaninol 1a
(S)-val-(R)-pheglycinol 1a
(S)-val-(S)-phe
(S)-val-(S)-phe
(S)-val-(S)-phe
1b
1c
1c
25[d]
20[d, e]
Aldol reactions mediated by
acyclic amino acids and by
small peptides were also per-
formed with substituted glyoxy-
late acceptors, generating aldol
products containing tetrasubsti-
tuted carbon centers. We found,
for example, that valine and
valine tetrazole 5 catalyzed the
reaction between cyclohexa-
none 1b and phenylglyoxylate
with excellent stereoselectivity
(Table 9).
10
(S)-val-(S)-phe
48
93
1:1
75
11
12
(S)-val-(S)-phe
(S)-val-(S)-val
72
72
53[f]
67[f]
1:1[f]
1:1[f]
70[f]
51[f]
1g
2g
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn)
was determined by 1H NMR analysis of the crude product. [c] The ee of 2 was determined by chiral-phase
HPLC analyses. [d] 5 equivalents of acetone were used. [e] Reaction run in H2O with SDS. [f] Reaction per-
formed in DMSO/H2O 1:1.
Table 7. Asymmetric aldol reactions catalyzed by alanine and by alanine tetrazole 4.
In particular, valine tetrazole
5 was an excellent catalyst, fur-
nishing the corresponding terti-
ary aldol product 2q in 78%
yield with >19:1 d.r. and
98% ee (Table 9, entry 3). Inter-
estingly, the diastereomer fur-
nished—with excellent diaste-
Entry
Catalyst
Ketone
R
Prod.
Yield [%][a]
d.r.[b]
6:1
6:1
5:1
>19:1
1:1
12:1
13:1
9:1
ee [%][c]
1
2
3
4
5
6
7
8
(S)-alanine
(S)-alanine
(S)-alanine
(S)-alanine
(S)-alanine
(S)-4
(S)-4
(S)-4
(S)-alanine
(S)-alanine
(S)-5
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
4-CNC6H4
4-BrC6H4
4-ClC6H4
CH2OBn
Ph
4-CNC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
Ph
2h
2i
2j
2k
2l
2h
2i
84
>99
97
98
77[d]
75[d]
41
AHCTREUNG
99
68
68
55
50
94 that obtained when (S)-proline
is used as the catalyst.[24] The
99
96
95
>99
>99
90[e]
50
acyclic amino acids and small
peptides are also able to cata-
lyze asymmetric self-aldol reac-
tions with aldehydes to furnish
the corresponding b-hydroxyal-
dehydes with moderate to high
2j
9
2m
2n
2n
2o
44
17:1
18:1
10
11
12
42
50[e]
39
13:1[e]
(S)-alanine
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn)
was determined by 1H NMR analysis of the crude product. [c] The ee of 2 was determined by chiral-phase
HPLC analyses. [d] 5 equivalents of H2O were used. [e] Reaction performed in water (130 mL) with 5 equiva-
lents of 1b.
enantioselectivities
[Eq. (2)].
Acyclic amino acids and highly
modular peptides and their de-
rivatives can also be employed
as catalysts for other asymmet-
À
donor were slow and furnished the corresponding aldol
products in low yields but with good enantioselectivities.
The dipeptide-catalyzed asymmetric aldol reactions between
ketones 1a and 1b and different acceptor aldehydes were
also investigated (Table 8).
ric C C bond-forming reactions such as the one-pot three-
component Mannich[25] [Eq. (3)] and nitro-Michael [Eq. (4)]
reactions[26]
.
Mechanism: A plausible acid-mediated enamine mecha-
nism of the acyclic acid- and dipeptide-catalyzed asymmetric
Chem. Eur. J. 2006, 12, 5383 – 5397
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5389

A. Córdova et al.
water in the acyclic amino acid
catalyzed and small peptide-cat-
alyzed asymmetric aldol reac-
tion is plausibly due to im-
proved catalyst turnover due to
faster hydrolysis of the inter-
mediates of the enamine cata-
lytic cycle, as well as to the sup-
pression of catalyst inhibi-
tion.[27]
We did not observe signifi-
cant nonlinear effects in the
alanine- and valine-catalyzed
reactions (Figure 1).[28] Howev-
er, the reactions display
a
Table 8. Dipeptide-catalyzed asymmetric aldol reactions.
slightly positive effect at low ee
of the catalyst and a slightly
negative effect at higher ee,
crossing the straight line. In
fact, if a stoichiometric amount
of amino acid was employed
(100 mol%) the effect would
become even higher and the
curves would display a signifi-
cant positive effect crossing the
straight line of no linear effect
(eutectic point)[29] to become
negative again. This phenomen-
on is the result of the different
solubility of the two-enantio-
Entry
Catalyst
Ketone
R
Prod.
Yield [%][a]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
9
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-ala
(S)-val-(S)-ala
(S)-ala-(S)-ala
(S)-ala-(S)-phe
(S)-ala-(S)-ala
(S)-ala-(S)-ala
1a
1a
1a
1a
1a
1a
1b
1b
1b
4-CNC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
iPr
4-BrC6H4
4-BrC6H4
4-ClC6H4
2h
2i
2i
2j
2j
2p
2n
2n
2m
64
55
48
43
30
50
88
86
57
13:1
2:1
2:1
1:1
1:1
2:1
2:1
2:1
2:1
99
92
78
80
71
97
99
96
98
[a] Yield of isolated product after silica gel column chromatography. [b] Diastereoselectivity (d.r. = anti:syn)
was determined by 1H NMR analysis of the crude product. [c] The ee of 2 was determined by chiral-phase
HPLC analyses.
mer crystals of the scalemic
Table 9. Organocatalytic asymmetric aldol reaction between cyclohexa-
none (1b) and phenylglyoxylate.
Entry
Catalyst
Time [h]
Yield [%][a]
d.r.[b]
ee[c]
1
2
3
(S)-valine
(S)-val-(S)-phe
(S)-5
120
120
78
51
60
78
6:1
2:1
>19:1
96
68
98
[a] Yield of isolated product after silica gel column chromatography.
[b] Diastereoselectivity (d.r.
anti:syn) was determined by 1H NMR
=
analysis of the crude product. [c] The ee of 2p was determined by chiral-
phase HPLC analyses.
intermolecular aldol reaction is depicted in Scheme 1. The
ketone donor reacts with the amino acid or dipeptide, result-
ing in a plausible enamine. Next, the acceptor aldehyde
reacts with the chiral enamine to give (after hydrolysis) the
enantiomerically enriched aldol product and the catalytic
cycle can be repeated. Furthermore, the beneficial effect of
Scheme 1. Mechanism of the acyclic amino acid- and dipeptide-catalyzed
direct asymmetric aldol reaction.
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Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
FULL PAPER
Figure 1. The enantiomeric excess of aldol product 2b as a function of
Figure 3. The enantiomeric excess of aldol product 2b as a function of
^
the enantiomeric excess of the direct asymmetric aldol reaction catalyzed
the enantiomeric excess of the (S)-ala-(S)-ala-catalyzed ( ) direct asym-
by (S)-alanine ( ) and by (S)-valine ( ).
metric aldol reaction (y = 0.93xÀ0.71, R2 = 0.992).
&
^
amino acid catalyst mixture in wet DMSO. We thus believe
that a single alanine and valine molecule is involved in the
transition state and mechanism, acting as a molecular
enzyme. Remarkably, in the case of (S)-serine we observed
a significant positive nonlinear effect, caused by the differ-
ent solubility of the two-enantiomer crystals of the scalemic
serine catalyst mixture in wet DMSO (Figure 2).[30]
The stereochemistry of the aldol products 2 obtained
through acyclic amino acid, primary amine, and peptide cat-
alysis was R as determined by chiral-phase HPLC analyses,
optical rotation, and comparison with the litera-
ture.[11–12,16,23,24] The relative stereochemistry of the cyclic
aldol products 2 was anti, as determined by NMR analyses
and comparison with the literature. From the relative and
absolute stereochemistries of the aldol products 2, we pro-
pose the six-membered chair-like transition states I and II to
account for the stereochemical outcomes of the reactions
catalyzed by the acyclic amino acids and the tetrazoles 4
and 5, respectively.
Thus, the Re face of the acceptor aldehyde is attacked by
the Si face of the chiral enamine to give the anti-aldol prod-
uct 2. In addition, density functional theory (DFT) calcula-
tions for the alanine-catalyzed aldol reactions are in accord-
ance with our suggested carboxylic acid catalyzed enamine
mechanism and transition state I for the acyclic amino acid-
mediated aldol reaction.[27,31] From the absolute and relative
stereochemistries of the b-hydroxy ketones 2, we propose
transition state III to account for the stereochemical out-
come of the dipeptide catalyzed reaction.
Figure 2. The enantiomeric excess of aldol product 2b as a function of
^
the enantiomeric excess of the (S)-serine-catalyzed ( ) direct asymmetric
aldol reaction.
We did not observe any significant nonlinear effect in the
(S)-ala-(S)-ala-catalyzed
asymmetric
aldol
reaction
(Figure 3). A single ala-ala molecule is thus involved in the
transition state and reaction mechanism, acting as a small
enzyme mimic. The higher solubility of the dipeptide rela-
tive to alanine and valine may explain the absence of signifi-
cant nonlinear effects in Figure 2.
Transition state III, in which the Re face of the chiral en-
amine is approached by the Si
face of the acceptor aldehyde,
is also
a plausible six-mem-
We also found that the aldol reaction can be reversible,
depending on the catalyst and substrate: the enantioselectiv-
ity of the aldol product 2b obtained with ala-ala catalysis,
for example, decreased from 91% ee after 48 h to 83% ee
after 120 h.
bered cyclic transition state in
which the stabilization of the
generated alkoxide of the prod-
uct is accomplished by hydro-
gen bonding by the peptide
Chem. Eur. J. 2006, 12, 5383 – 5397
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5391

A. Córdova et al.
backbone and the formation of a charge relay system that
increases the Brønsted acidity of the dipeptides. In fact, a
charge relay system is very important in the enamine cataly-
sis of aldolase enzymes.[32] In addition, we showed that
proton transfer from the carboxy group and hydrogen bond
activation, which is facilitated by the presence of a small
amount of water, were important to achieve high asymmet-
ric induction (Table 10, Figure 4). The higher enantioselec-
clic amino acid influences and directs most of the stereo-
chemistry. Nevertheless, the remote stereocenter of the C-
terminal amino acid of the dipeptide can provide asymmet-
ric induction in transition state III, which consequently gives
optically active aldol products. Moreover, the change from
(S)-ala-(S)-ala to (S)-ala-(R)-ala decreased the ee of 2b
from 91 to 77%, whilst the absence of an alkyl group at the
second stereocenter also decreased the ee by 10%. The ex-
cellent enantioselectivity observed for reactions with cyclic
ketones catalyzed by amino acids and small peptides can be
explained by stabilization of transition states I, II, and III,
respectively, by the rigidity of the cyclohexane ring. Thus,
the reactions with cyclic ketones showed higher enantiose-
lectivity than those with acyclic ketones.
Table 10. Peptide-catalyzed direct asymmetric aldol reactions.
The effect of water on the enantioselectivity of aldol
product 2b obtained through (S)-ala and (S)-ala-(S)-ala cat-
alysis was also investigated (Figure 4).
Entry Catalyst
Time [h] Yield [%][a] d.r.[b] ee [%][c]
In the case of the alanine-catalyzed reaction, the enantio-
selectivity is improved by a small amount of water (4.3–
15 vol%). We believe that the small amount of water in-
creases the enantioselectivity by increasing the Brønsted
acidity of the acyclic amino acid catalyst. Increasing the
amount of water (>15 vol%) decreases the enantioselectivi-
ty of the aldol reaction, which gives support for hydrogen
bonding as an essential feature of the transition state I. This
is further supported by the finding that valine tetrazole 4,
which has a more acidic proton then alanine or valine, cata-
lyzed the assembly of 2b in an asymmetric fashion with
good to excellent enantioselectivity in water, thus maintain-
ing an ordered transition state II in aqueous media. The ee
of aldol product 2b obtained through (S)-ala-(S)-ala cataly-
sis is also significantly improved by the addition of a small
amount of water: the addition of 10 equivalents of H2O, for
instance, increased the ee of 2b from 55% to 91%. In addi-
tion, the (S)-ala-(S)-ala-mediated asymmetric aldol reaction
tolerates up to 40 and 50 vol% of water in DMSO and
DMF, respectively, without the enantioselectivity of the re-
action being affected. Notably, the dipeptide-mediated aldol
reaction exhibited a high enantioselectivity in water. All
these results provide precedent that hydrogen bonding from
the acid moiety and the backbone of the peptide is very im-
portant in the transition state III, which allows a highly or-
dered transition state under aqueous conditions. The dra-
matic increase in the enantioselectivity of the asymmetric
aldol reaction mediated by pentapeptide (ala)5, which in-
creases with a magnitude of 9.2 when organic solvent is
changed to water may be explained in terms of a combina-
tion of improved hydrogen bonding and a more favored
conformation (folding) of the pentapeptide.
1
2
3
4
5
(S)-ala-(S)-ala
(S)-ala-(R)-ala
(S)-ala-gly
gly-(S)-ala
(S)-ala-(S)-ala-OEt 73
24
48
48
48
73
88
46
65
55
8:1
4:1
4:1
2:1
2:1
91
77
81
11
80
6
73
55
2:1
80
[a] Yield of isolated product after silica gel column chromatography.
[b] Diastereoselectivity (d.r.
anti:syn) was determined by 1H NMR
analysis of the crude product. [c] The ee of 2b was determined by chiral-
=
phase HPLC analyses.
Figure 4. The dependence of the enantiomeric excess (ee) of 2b derived
from the asymmetric aldol reactions between cyclohexanone (1b) and p-
nitrobenzaldehyde—catalyzed by (S)-alanine ( ) and by (S)-ala-(S)-ala
^
&
( )—as a function of the vol% H2O in DMSO.
tivities observed for the dipeptide-catalyzed reactions with
acyclic ketones, relative to those seen with the parent amino
acids, may be explained in terms of assistance by the peptide
backbone in the stabilization of transition state III. More-
over, the stereochemistry of the dipeptideꢁs two stereocen-
ters affects the enantioselectivity of the reaction: gly-(S)-ala-
nine, for example, catalyzed the asymmetric formation of 2b
with 11% ee. Thus, the stereocenter of the N-terminal acy-
Conclusion
In summary, we have shown that several natural and non-
proteinogenic acyclic amino acids, and also chiral amines,
can catalyze the asymmetric aldol reaction. Excellent enan-
tioselectivities were achieved in several cases: the amino
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Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
FULL PAPER
Typical experimental procedure for direct asymmetric aldol reactions cat-
alyzed by alanine and acyclic amino acids: A catalytic amount of (S)-
amino acid or chiral amine (0.15 mmol, 30 mol%) was added to a vial
containing acceptor aldehyde (0.5 mmol), donor ketone 2 (1.5 mmol),
and H2O (5 mmol, 90 mL) in DMSO (2 mL). After vigorous stirring at
room temperature for the times shown in the tables the reaction mixture
was poured into an extraction funnel containing brine (5.0 mL), diluted
with distilled H2O (5.0 mL), and EtOAc (15 mL). The reaction vial was
also washed with EtOAc (2 mL), which was poured into the extraction
funnel. The aqueous phase was extracted with EtOAc (2”15.0 mL). The
combined organic phases were dried with Na2SO4 and the solvent was re-
moved under reduced pressure. The crude aldol product was purified by
silica gel column chromatography (EtOAc/pentane mixtures) to furnish
the desired aldol product 2. The ee values of the aldol products 2 were
determined by chiral-phase HPLC analysis or chiral-phase GC analyses.
acid-derived tetrazole catalysts 4 and 5, for example, cata-
lyzed the formation of aldol products
>99% ee. We also showed that small highly modular pep-
tides, pseudo-peptides, peptide-based dendrimers, and urea
2 with up to
ACHTREUNG
derivatives can also catalyze the direct asymmetric intermo-
lecular aldol reaction with high enantioselectivities. Remark-
ably, simple amino acids and small peptides can catalyze the
asymmetric aldol reaction with enzyme-like stereoselectivity
to yield the corresponding aldol products with up to
>99% ee. In addition, phenylglyoxylate can be utilized as
an acceptor for the acyclic amino acid mediated asymmetric
aldol reaction to yield the corresponding tertiary aldol prod-
uct with high diastereo- and enantioselectivity. In addition,
acyclic amino acids and dipeptides are able to catalyze other
Typical experimental procedure for the direct asymmetric aldol reactions
catalyzed by peptides, pseudo-peptides, dendrimer 9, and urea 8: A cata-
lytic amount of di- or tripeptide (0.15 mmol, 30 mol%) was added to a
À
C C bond-forming reactions with excellent stereoselectivi-
vial containing acceptor aldehyde (0.5 mmol), donor ketone
2
ties. Notably, the presence of a small amount of water both
accelerated the reaction and improved the enantioselectivity,
which suggests hydrogen bonding is of significant impor-
tance in the transition state. Unlike the acyclic amino acids,
the small peptides catalyzed the asymmetric aqueous aldol
reaction with high stereoselectivity: the di- and tripeptides,
for instance, catalyzed the asymmetric formation of eryth-
rose with high enantioselectivity in water. These results may
be important for the evolution of homochirality of sugars
and evolution of aldolase enzymes. The mechanism and the
transition-state model have been discussed on the bases of
the stereochemistry of the aldol products, structure, and ac-
tivity, as well as enantiomeric excess relationships. In addi-
tion, our study shows that there is a plethora of readily
available amino acids and their derivatives that can be utiliz-
ed as highly selective organocatalysts for direct asymmetric
aldol reactions. Natureꢁs full structural variety can thus be
employed in the design and combinatorial synthesis of non-
toxic and simple organic catalysts.
(1.5 mmol), and H2O (5 mmol, 90 mL) in DMSO (2 mL). After vigorous
stirring at room temperature for the times shown in the tables the reac-
tion mixture was poured into an extraction funnel containing brine (5.
0 mL), diluted with distilled H2O (5.0 mL), and EtOAc (15 mL). The re-
action vial was also washed with EtOAc (2 mL), which was poured into
the extraction funnel. The aqueous phase was extracted with EtOAc (2”
15.0 mL). The combined organic phases were dried with Na2SO4 and the
solvent was removed under reduced pressure. The crude aldol product
was purified by silica gel column chromatography (EtOAc/pentane mix-
tures) to furnish the desired aldol product 2. The ees of the aldol prod-
ucts 2 were determined by chiral-phase HPLC analysis or chiral-phase
GC analyses.
Compound 2a:[16] [a]D25 = À131.1 (c = 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 1.30 (s, 3H; CH3), 1.40 (s, 3H; CH3), 3.9 (m, 1H), 4.13–4.50
(m, 3H), 5.01 (d, J = 7.8 Hz, 1H; CHOH), 7.70 (d, J = 8.4 Hz, 2H;
ArH), 8.22 (d, J = 8.4 Hz, 2H; ArH) ppm; 13C NMR (100 MHz, CDCl3):
d
= 23.3, 23.4, 66.6, 71.7, 75.8, 101.4, 123.2, 127.9, 138.3, 146.5,
210.6 ppm; HPLC (Daicel ChiralpakAD, iso-hexanes/i-PrOH 96:4, flow
rate 0.5 mLminÀ1, l = 254 nm): major isomer: tR = 52.12 min; minor
isomer: tR = 57.02 min.
Compound 2b:[11m] [a]D = +12.8 (c = 1.1, CHCl3); 1H NMR (CDCl3,
400 MHz): d = 1.52–2.14 (m, 6H), 2.33–2.52 (m, 2H), 2.59 (m, 1H), 3.15
(brs, 1H), 4.90 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 8.20 (d, J
= 8.7 Hz, 2H) ppm; 13C NMR (100 MHz): d = 24.6, 27.6, 30.7, 42.6,
57.1, 73.9, 123.5, 127.8, 147.5. 148.4, 214.7 ppm; HPLC (Daicel Chiralpak
A
AS, i-hexanes/iPrOH 90:10, flow rate 0.5 mLminÀ1, l = 254 nm): major
isomer: tR = 53.57 min; minor isomer: tR = 65.52 min; MALDI-TOF
MS: 272.0897; calcd for C13H15NO4 [M+Na]+ 272.0899.
Experimental Section
General methods: Chemicals and solvents were either purchased puriss
p. A. from commercial suppliers or were purified by standard techniques.
Silica gel plates (Merck60 F254) were used for thin-layer chromatogra-
phy (TLC), and compounds were visualized by irradiation with UV light
and/or by treatment with a solution of phosphomolybdic acid (25 g), Ce-
Compound 2c:[11m] [a]D25 = +41.2 (c = 1.7, CHCl3); 1H NMR (CDCl3,
400 MHz): d = 2.23 (s, 3H; CH3), 2.83–2.87 (m, 2H; CHOHCH2CO),
3.61 (s, 1H; OH), 5.26 (m, 1H; CHOH), 7.54 (d, J = 8.7 Hz, 2H), 8.21
(d, J = 8.7 Hz, 2H) ppm; HPLC (Daicel ChiralpakAS, i-hexanes/iPrOH
90:10, flow rate 0.5 mLminÀ1
22.41 min; minor isomer: tR = 30.31 min.
, l = 254 nm): major isomer: tR =
(SO4)2·H2O (10 g), conc. H2SO4 (60 mL), and H2O (940 mL), followed by
heating, or by treatment with a solution of p-anisaldehyde (23 mL), conc.
H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL), followed by
heating. Flash chromatography was performed with silica gel (Merck60,
particle size 0.040–0.063 mm), 1H NMR and 13C NMR spectra were re-
corded on a Varian AS 400 instrument. Chemical shifts are given in d rel-
ative to tetramethylsilane (TMS), the coupling constants (J) are given in
Hz. The spectra were recorded in CDCl3 as solvent at room temperature,
with TMS as internal standard (d = 0 ppm) for 1H NMR and CDCl3 as
internal standard (d = 77.0 ppm) for 13C NMR. GC was carried out with
a Varian 3800 GC instrument. Chiral GC-column used: CP-Chirasil-Dex
CB 25 m”0.32 mm. HPLC was carried out with a Waters 2690 Millenni-
um with photodiode array detector. Optical rotations were recorded with
a Perkin–Elmer 241 polarimeter (d = 589 nm, 1 dm cell). High-resolu-
tion mass spectra were recorded on an IonSpec FTMS mass spectrometer
with a DHB-matrix. The spectral data of chiral products 2a–2q are
known.[11,12,16,23,24]
Compound 2e:[11m] 1H NMR (400 MHz, CDCl3): d = 1.46–1.53 (m, 1H),
1.69–1.76 (m, 2H), 1.97–2.05 (m, 1H), 2.42–2.48 (m, 1H), 2.66–2.75 (m,
1H), 2.94–3.01 (m, 1H), 3.86–3.89 (m, 2H), 3.92–3.95 (m, 2H), 4.04 (m,
1H), 4.92 (m, 1H), 7.49 (d, J
= 8.6 Hz, 2H), 8.19 (d, J = 8.7 Hz,
2H) ppm; 13C NMR (100 MHz, CDCl3): d = 34.50, 37.9, 38.9, 53.4, 64.9,
65.2, 74.0, 107.2, 123.9, 128.0, 128.8, 148.4, 214.0 ppm; HPLC (Daicel
ChiralpakAD, iso-hexanes/i-PrOH 80:20, flow rate 0.5 mLminÀ1, l
=
254 nm): major isomer: tR = 35.71 min; minor isomer: tR = 44.03 min.
Compound 2 f:[16] 1H NMR (400 MHz, CDCl3) (anti:syn = 1:1 mixture):
d = 2.01 (s, 3H), 2.35 (s, 3H), 3.10 (brs, 1H; OH), 3.78 (brs, 1H; OH),
4.39 (m, 1H), 4.45 (d, J = 4.6 Hz, 1H), 5.07 (d, J = 4.5 Hz, 1H), 5.20
(m, 1H), 7.59 (d, J
= 8.8 Hz, 4H), 8.20 (d, J = 8.8 Hz, 4H) ppm;
13C NMR (100 MHz, CDCl3): d = 26.2, 28.0, 73.1, 74.6, 80.3, 80.9, 123.8,
123.9, 127.3, 127.5, 146.8, 147.7, 207.4, 208.0 ppm; HPLC (Daicel Chiral-
pakAD, i-hexanes/iPrOH 90:10, flow rate 0.5 mLminÀ1, l = 254 nm):
Chem. Eur. J. 2006, 12, 5383 – 5397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5393

A. Córdova et al.
major isomer: tRanti = 38.5 min; minor isomer: tRanti = 36.1 min;): major
isomer: tRsyn = 32.1 min; minor isomer: tRsyn = 34.0 min.
Compound 2g:[18c] 1H NMR (CDCl3, 400 MHz, 1:1 mixture of diaste-
J = 8.3 Hz, 2H), 8.45 (d, J = 8.3 Hz, 2H) ppm; 13C NMR (100 MHz): d
= 25.0, 28.0, 30.9, 42.8, 57.5, 74.3, 121.9, 128.9, 131.6, 140.3, 215.4 ppm;
HPLC (Daicel ChiralpakAS, i-hexanes/iPrOH 90:10, flow rate
1.0 mLminÀ1, l = 254 nm): major isomer: tR = 23.04 min; minor isomer:
tR = 21.22 min.
A
4.30 (d, J = 2.6 Hz, 1H), 4.44 (d, J = 19.4 Hz, 1H), 4.48 (d, J = 4.0 Hz,
2H), 4.86 (d, J = 5.9 Hz, 1H), 5.15 (d, J = 2.2 Hz, 1H), 7.54 (d, J =
1
Compound 2o:[11m] [a]D25 = +59.2 (c = 0.9, CHCl3); H NMR (400 MHz,
8.4 Hz, 2H; ArH), 7.60 (d, J
= 8.4 Hz, 2H; ArH), 8.12 (m, 4H;
CDCl3): d = 2.21 (s, 3H), 2.87 (m, 2H), 3.32 (d, J = 3.0 Hz, 1H), 5.17
(m, 1H), 7.27–7.38 (m, 5H) ppm; 13C NMR: d = 28.8, 30.1, 36.1, 38.7,
41.4, 45.8, 47.6, 58.0, 112.0, 121.2, 129.4, 147.0, 213.1 ppm; the enantio-
meric excess of the aldol was determined on the acetylated compound
ArH) ppm; 13C NMR (100 MHz): d = 68.2, 68.3, 74.7, 75.4, 79.7, 80.7,
124.0, 124.1, 128.7, 129.3, 148.7, 148.9, 150.2, 150.9, 212.1, 212.6 ppm;
HPLC (Daicel ChiralpakAD, i-hexanes/iPrOH 90:10, flow rate
0.5 mLminÀ1, l = 254 nm): major isomer: tR = 77.52 min; minor isomer:
tR = 80.23; major isomer: tR = 88.52 min; minor isomer: tR = 83.23 min.
MALDI-TOF MS: 264.0491; calcd for C10H11NO6 [M+Na]+: 264.0484.
(CP-Chirasil-Dex CB); Tinj
1.8 mLminÀ1
ti 1008C (35 min), tf
isomer: tR = 43.00 min; minor isomer: tR = 42.80 min.
Compound 2p:[11m] [a]D25 1.1, CHCl3); 1H NMR
À27.74 (c
=
2508C, Tdet
=
2758C, flow
=
,
=
=
2008C (58CminÀ1): major
Compound 2h:[16a] [a]D25 = À101.3 (c = 1.0, CHCl3); H NMR (400 MHz,
1
=
=
CDCl3): d = 1.20 (s, 3H; CH3), 1.37 (s, 3H; CH3) 3.78 (brs, 1H), 4.06 (d,
J = 17.3, 1H), 4.19–4.29 (m, 2H), 4.93 (d, J = 7.8 Hz, 1H; CHOH), 7.51
(400 MHz, CDCl3): d = 0.88 (d, J = 6.8 Hz, 3H; CH3), 0.96 (d, J =
6.8 Hz, 3H; CH3), 1.38 (s, 3H; CH3), 1.43 (s, 3H; CH3), 1.92–2.01 (m,
1H), 3.07 (d, J = 2.3 Hz, 1H), 3.64–3.67 (m, 1H), 3.97 (d, J = 17.3 Hz,
1H), 4.22 (dd, J = 1.5, 17.3 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3):
d = 15.5, 19.4, 23.8, 24.0, 28.7, 66.7, 74.1, 74.3, 101.1, 212.4 ppm; HPLC
(Daicel ChiralpakAD, i-hexanes/iPrOH 95:5, flow rate 0.5 mLminÀ1, l
= 254 nm): major isomer: tR = 15.21 min; minor isomer: tR = 12.81 min.
(d,
J = 8.4 Hz, 2H; ArH), 7.63 (d, J = 8.4 Hz, 2H; ArH) ppm;
13C NMR (100 MHz, CDCl3): d = 23.2, 23.5, 66.6, 72.0, 76.0, 101.2, 128.2,
128.4, 133.7, 137.8, 210.9 ppm; HPLC (Daicel ChiralpakOJ, i-hexanes/
iPrOH 90:10, flow rate 0.5 mLminÀ1, l = 254 nm): major isomer: tR
=
34.50 min; minor isomer: tR = 36.52 min.
Compound 2i:[16a] [a]D25 = À110.9 (c = 1.0, CHCl3); H NMR (400 MHz,
1
Typical experimental procedure for the peptide- and amino acid-cata-
lyzed direct asymmetric aldol reactions in water: A catalytic amount of
(S)-amino acid, dipeptide, or oligopeptide (0.075 mmol, 30 mol%) was
added to a vial containing acceptor aldehyde (0.25 mmol, 38 mg), cyclo-
hexanone (1b) (0.75 mmol, 80 mL), and SDS (72 mg, 0.25 mmol) in H2O
(1 mL). After vigorous stirring of the reaction mixture for the time
shown in the tables at room temperature it was directly loaded on a silica
gel column. The crude aldol product was purified by silica gel column
chromatography (EtOAc/pentane mixtures) to furnish the desired aldol
product 2b. The ees of the aldol product 2b were determined by chiral-
phase HPLC analyses.
CDCl3): d = 1.20 (s, 3H; CH3), 1.37 (s, 3H; CH3), 3.78 (brs, 1H), 4.03
(d, J
=
17.3 Hz, 1H), 4.19–4.29 (m, 2H), 4.93 (d, J
=
=
7.8 Hz, 1H;
8.4 Hz, 2H;
CHOH), 7.52 (d, J
=
8.4 Hz, 2H; ArH), 7.63 (d, J
ArH) ppm; 13C NMR (100 MHz, CDCl3): d = 23.2, 23.5, 66.6, 72.0, 76.0,
101.2, 128.2, 128.4, 133.7, 137.8, 210.9 ppm; HPLC (Daicel ChiralpakAS,
i-hexanes/iPrOH 97:3, flow rate 0.5 mLminÀ1
, l = 254 nm): major
isomer: tR = 24.10 min; minor isomer: tR = 30.32 min.
Compound 2j: [a]2D5 = À178.8 (c = 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 1.26 (s, 3H; CH3), 1.36 (s, 3H; CH3), 3.62 (brs, 1H), 4.03
(d, J
= 17.4 Hz, 1H), 4.19–4.29 (m, 2H), 4.86 (d, J = 7.8 Hz, 1H;
CHOH), 7.21–7.42 (4H; ArH) ppm; 13C NMR (100 MHz, CDCl3): d =
23.4, 23.7, 66.8, 72.1, 76.0, 101.6, 112.0, 119.0, 128.0, 132.0, 144.8,
210.8 ppm; HPLC (Daicel ChiralpakAS, i-hexanes/iPrOH 97:3, flow rate
0.5 mLminÀ1, l = 254 nm): major isomer: tR = 23.41 min; minor isomer:
tR = 28.9 min.
Typical experimental procedure for the peptide- and amino acid-cata-
lyzed direct asymmetric aldol reactions in water and aqueous buffer: A
catalytic amount of (S)-amino acid, dipeptide, or oligopeptide
(0.075 mmol, 30 mol%) was added to a vial containing acceptor aldehyde
(0.25 mmol) and cyclohexanone (1b, 0.75 mmol, 80 mL) in H2O
(0.25 mmol a-cyclodextrin, 1 mL) or aqueous buffer (1 equiv SDS, 1 mL).
After 1–4 days of vigorous stirring at room temperature the reaction mix-
ture was quenched by extraction with EtOAc (3”15 mL). In the latter
case the combined organic phases were dried with Na2SO4, filtered, and
concentrated under reduced pressure. The crude aldol product was puri-
fied by silica gel column chromatography (EtOAc/pentane mixtures) to
furnish the desired aldol product 2b. The ees of the aldol products 2b
were determined by chiral-phase HPLC analyses.
Compound 2k:[16a] [a]D23 = À129.7 (c = 3.3, CHCl3) [literature: [a]D25
=
À106.7 (c = 1.0, CHCl3)];[33] 1H NMR (400 MHz, CDCl3): d = 1.45 (s,
3H), 1.48 (s, 3H), 3.16 (d, J = 4.2 Hz, 1H), 3.70–3.67 (m, 2H), 4.03 (d, J
= 17.2 Hz, 1H), 4.21 (m, 1H), 4.27 (d, J = 17.2 Hz, 1H), 4.45 (d, J =
6.2 Hz, 1H), 4.56–4.63 (m, 2H), 7.27–7.37 (m, 5H) ppm; 13C NMR
(100 MHz, CDCl3): d = 23.5, 24.2, 66.9, 69.9, 70.2, 73.7, 74.04, 101.1,
127.9, 128.5, 129.2, 138.1, 210.0 ppm; HPLC (Daicel ChiralpakAD, hex-
anes/iPrOH 96:4, flow rate 0.5 mLminÀ1, l = 254 nm): major isomer: tR
= 46.02 min; minor isomer: tR = 40.73 min; MALDI-TOF MS: 303.1211;
calcd for C15H20O5 [M+Na]+: 303.1208.
Typical experimental procedure for the peptide- and amino acid-cata-
lyzed direct asymmetric aldol reactions in aqueous media: A catalytic
amount of (S)-amino acid, dipeptide, or tripeptide (0.075 mmol,
30 mol%) was added to a vial containing acceptor aldehyde (0.25 mmol,
38 mg) and donor ketone 1 (0.75 mmol), 1c (1.36 mmol, 100 mL), or 1g
(dimeric form, 500 mg) in H2O (1 equiv. SDS, 1 mL) or aqueous media
(1 mL). After vigorous stirring at room temperature for the times shown
in the tables the reaction mixture was quenched by extraction with
EtOAc (3”15 mL). The combined organics were dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude aldol prod-
ucts were purified by silica gel column chromatography (EtOAc/pentane
mixtures) to furnish the desired aldol products 2. The ee values of the
aldol products 2 were determined by chiral-phase HPLC analyses.
1
Compound 2l:[11o] [a]D25 = À95.69 (c = 2.6, CHCl3); H NMR (400 MHz,
CDCl3): d = 1.06 (s, 3H), 1.36 (s, 3H), 3.63 (brs, 1H), 4.03 (d, J =
16.5 Hz, 1H), 4.22 (d, J = 16.5 Hz, 1H), 4.33 (d, J = 7.1 Hz, 1H), 4.90
(d, J = 7.9 Hz, 1H), 7.29–7.40 (m, 5H) ppm; 13C NMR: d = 23.3, 24.0,
66.9, 73.0, 76.5, 101.4, 127.3, 128.0, 128.3, 139.5, 211.1 ppm; HPLC
(Diacel ChiralpakAD, i-isohexane/iPrOH 88:2, flow rate 0.5 mLminÀ1, l
= 254 nm): major isomer: tr = 36.05 min, minor isomer: tr = 40.77 min.
Compound 2m: [a]D
= +21.6 (c =
1.0, CHCl3); 1H NMR (CDCl3,
400 MHz): d = 1.23–1.32 (m, 1H), 1.50–1.58 (m, 2H), 1.60–1.66 (m, 1H),
1.73–1.81 (m, 1H), 2.03–2.10 (m, 1H), 2.29–2.37 (m, 1H), 2.43–2.48 (m,
1H), 2.51–2.57 (m, 1H), 3.99 (d, J = 2.9 Hz, 1H), 4.74 (dd, J = 8.8,
2.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H) ppm;
13C NMR (100 MHz): d = 24.9, 27.9, 31.0, 42.8, 57.5, 74.2, 128.6, 128.7,
133.7, 139.8, 215.4 ppm; HPLC (Daicel ChiralpakAS, i-hexanes/iPrOH
Synthesis of alanine-tetrazole 4: NH4HCO3 (0.89 g, 1.26 equiv) was
added to a solution of Boc2O (2.5 g, 1.3 equiv) and Cbz-Ala (2.0 g) in
MeCN (14 mL) and Py (2.2 mL, 3 equiv.) and the reaction mixture was
stirred overnight at room temperature. The solvents were removed by
evaporation and the residue was dissolved in EtOAc and washed with 2”
15 mL water. The water was reextracted with EtOAc and the combined
volume of EtOAc was dried over MgSO4, filtered, and concentrated. The
crude product was weakly UV active and had an Rf = 0.42 (MeOH/
CH2Cl2 1:9). 1H NMR (400 MHz, CDCl3) of the crude Cbz-Alanine
90:10, flow rate 1.0 mLminÀ1
22.04 min; minor isomer: tR = 20.36 min.
Compound 2n: [a]D +20.5 (c
1.7, CHCl3); 1H NMR (CDCl3,
, l = 254 nm): major isomer: tR =
=
=
400 MHz): d = 1.23–1.32 (m, 1H), 1.49–1.58 (m, 2H), 1.61–1.69 (m, 1H),
1.75–1.81 (m, 1H), 2.03–2.10 (m, 1H), 2.30–2.41 (m, 1H), 2.43–2.48 (m,
1H), 2.50–2.59 (m, 1H), 3.99 (brs, 1H), 4.74 (d, J = 8.6 Hz, 1H), 7.18 (d,
5394
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
FULL PAPER
amide: d = 1.41 (d, J = 7.1 Hz, 3H), 4.29 (m, 1H), 5.17 (m, 2H), 5.39
(400 MHz, D2O): d = 0.70 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz,
(brs, 1H), 6.11 (brs, 1H), 7.27 ppm (m, 5H).
3H), 2.25(m, 1H), 4.38 (d, J = 7.6 Hz, 1H).
A
Next, POCl3 (0.55 mL, 1.2 equiv in CH2Cl2 (5 mL)) was added dropwise
at À108C to a solution of Cbz-alanine amide (1.1 g) in Py (10 mL), and
the resulting mixture was stirred for 3 h. When the starting material was
“depleted” by TLC (MeOH/CH2Cl2 1:9) the mixture was poured onto ice
(ꢀ30 g). The organic phase was separated and pyridine was removed by
repeated washing with a not concentrated CuSO4 solution. The organic
phase was then pre-dried with brine and later dried over MgSO4. Filtra-
General procedure for the preparation of dipeptides: A stirred solution
of Cbz-protected a-amino acid (10 mmol) in dichloromethane (30 mL)
was cooled to À158C and neutralized with NMM (N-methyl morpholine,
10 mmol). Next, isobutyl chlorocarbonate (10 mmol) was added. After
the mixture had been stirred for 20 minutes a solution of the salt of
amino acid ester (10 mmol) and NMM (10 mmol) in dichloromethane
(30 mL) was added. The mixture was stirred at À158C for 1 h and was
next allowed to warm up to room temperature. The progress of the reac-
tion was monitored by TLC (AMC stain). At completion, the reaction
mixture was extracted with HCl (1n, 3”20 mL), Na2CO3 (1n, 3”20 mL),
and brine (30 mL). The organic layer was dried with sodium sulfate. The
dipeptide product was checked by TLC and NMR; in most cases it was
pure enough for the next step. If not, the product was purified by silica
gel column chromatography. Next, palladium on activated carbon
(100 mg, 10 wt%) was added under argon to a solution of protected di-
peptide (1 g) in methanol (20 mL). The reaction mixture was stirred
under hydrogen (90 psi) for one day. The reaction was checked by TLC
and NMR analyses. At the completion of hydrogenolysis, the Pd/C cata-
lyst was removed by filtration on celite and washed with methanol and
water. The combined filtrates were evaporated under reduced pressure.
The dipeptide product was checked by NMR analyses and, if necessary,
recrystallization was preformed in an appropriate solvent.
tion and concentration afforded the crude product as an oil, TLC Rf
=
0.51 (MeOH/CH2Cl2 1:9). 1H NMR (400 MHz, CDCl3) of the crude Cbz-
alanine nitrile: d = 1.41 (d, J = 6.8 Hz, 3H), 4.65 (m, 1H), 5.17 (m,
2H), 5.39 (brs, 1H), 7.28 (m, 5H).
NaN3 (300 mg, 1.1 equiv) and NH4Cl (256 mg, 1.15 equiv.) were added si-
multaneously to a solution of crude Cbz-alanine nitrile (850 mg) in DMF
(13 mL). The reaction was heated to 90–958C and kept at that tempera-
ture (3 h) until the TLC (HOAc/EtOA 1:99) spot at Rf = 0.63 did not in-
crease in strength. The reaction mixture was poured onto ice (30 g),
acidified to pH close to 2 with HCl (2m), and extracted with CHCl3 (3”
20 mL). The organic phase was washed with water (20 mL), then pre-
dried with brine (20 mL), and finally dried over MgSO4 before filtration
and removal of solvent by evaporation. Traces of DMF were removed
under reduced pressure. The crude product is a yellowish solid. 1H NMR
(400 MHz, CDCl3) of the crude Cbz-alanine tetrazole: d = 1.59 (d, J =
6.9 Hz, 3H), 5.07 (m, 2H), 5.22 (m, 1H), 6.19 (brs, 1H), 7.28 (m,
5H) ppm.[34]
Typical experimental procedure for the direct asymmetric synthesis of
tertiary aldol 2q catalyzed by valine tetrazole 5, valine, and dipeptide: A
catalytic amount of catalyst (0.20 mmol, 40 mol%) was added to a vial
containing acceptor aldehyde (0.5 mmol), donor ketone 2b (5 mmol),
and H2O (5 mmol, 90 mL) in DMSO (2 mL). After vigorous stirring at
room temperature for the time shown in Table 9 the reaction mixture
was poured into an extraction funnel containing brine (5.0 mL), diluted
with distilled H2O (5.0 mL), and EtOAc (15 mL). The reaction vial was
also washed with EtOAc (2 mL), which was poured into the extraction
funnel. The aqueous phase was extracted with EtOAc (2”15.0 mL). The
combined organic phases were dried with Na2SO4 and the solvent was re-
moved under reduced pressure. The crude aldol product was purified by
silica gel column chromatography (EtOAc/pentane mixtures) to furnish
the desired aldol product 2q.
The Cbz-alanine tetrazole (825 mg) was dissolved in MeOH (10 mL) and
a catalytic amount of Pd/C was added. After 17 h the catalyst was filtered
off with celite and the solvent was removed under reduced pressure to
give alanine tetrazole
3 quantitatively as a
white solid. 1H NMR
(400 MHz, D6-DMSO): d = 1.41 (d, J = 6.8 Hz, 3H), 4.51 (m, 1H) ppm;
13C NMR (100 MHz, [D6]DMSO): d = 20.2, 44.4, 161.0 ppm.
Synthesis of valine-tetrazole 5: NH4HCO3 (0.89 g, 1.26 equiv) was added
to a solution of Boc2O (2.5 g, 1.3 equiv) and Cbz-l-valine (2.0 g) in
MeCN (14 mL) and Py (2.2 mL, 3 equiv) and the reaction mixture was
stirred overnight at room temperature. The solvents were removed by
evaporation and the residue was dissolved in EtOAc and washed with
water (2”15 mL). The water was reextracted with EtOAc and the com-
bined volume of EtOAc was dried over MgSO4, filtered, and concentrat-
ed. The crude product was weakly UV active and had an Rf = 0.42
(MeOH/CH2Cl2 1:9). 1H NMR (400 MHz, CDCl3) of the crude Cbz-
valine amide: d = 0.99 (dd, J = 6.8 Hz, 6H), 2.15 (m, 1H), 4.02 (m,
1H), 5.12 (s, 2H), 5.29 (brs, 1H), 5.39 (brs, 1H) 5.78 (brs, 1H), 7.30 ppm
(m, 5H).
Compound 2q: Major diastereomer: [a]2D5 = À28.0 (c = 1.0, CHCl3,
98% ee); 1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 3H;
CH3), 1,55–1.88 (m, 5H), 1.90 (m, 1H), 2.06 (m, 1H), 2.29–2.44 (m, 2H),
3.18 (dd, J = 5.5, 12.7 Hz, 1H), 4.16 (s, 1H), 4.25 (q, J = 7.14, 7.12 Hz,
2H), 7.26–7.36 (m, 3H; ArH), 7.50 (d, J
= 7.2 Hz, 2H; ArH) ppm;
13C NMR (100 MHz, CDCl3): d = 14.3, 25.6, 28.0, 30.8, 30.8, 43.2, 53.9,
62.1, 73.4, 125.8, 128.1, 128.5, 128.7, 140.6, 173.2, 212.7 Hz ppm; HPLC
(Daicel ChiralpakAD, i-hexanes/iPrOH 95:5, flow rate 0.5 mLminÀ1, l
= 254 nm): major isomer: tR = 25.60 min; minor isomer: tR = 32.50 min.
POCl3 (0.55 mL, 1.2 equiv in CH2Cl2 (5 mL)) was added dropwise at
À108C to a solution of Cbz-l-valine amide (1.1 g) in Py (10 mL) and the
resulting mixture was stirred for 3 h. When the starting material was “de-
pleted” by TLC (MeOH/CH2Cl2 1:9) the mixture was poured onto ice
Minor diastereomer: [a]2D5 = +37.0 (c = 1.0, CHCl3, 26% ee) [literature:
[a]2D5
=
À139.6 (c
=
1.0, CHCl3, 96% ee)];[24] 1H NMR (400 MHz,
A
CDCl3): d = 1.23 (t, J = 7.2 Hz, 3H; CH3), 1,52–1.75 (m, 5H) 1.87 (m,
2H), 2.07 (m, 1H), 2.31–2.45 (m, 2H), 3.40 (dd, J = 6.1, 12.9 Hz, 1H),
3.87 (s, 1H), 4.11–4.25 (m, 2H), 7.27–7.37 (m, 3H; ArH), 7.58 (d, J =
7.9 Hz, 2H; ArH) ppm; 13C NMR (100 MHz, CDCl3): d = 14.2, 25.1,
27.5, 27.8, 42.6, 59.0, 62.2, 77.8, 125.5, 127.9, 128.5, 139.2, 174.8,
213.0 Hz ppm; HPLC (Daicel ChiralpakAD, i-hexanes/iPrOH 90:10,
repeated washing with a not concentrated CuSO4 solution. The organic
phase was then pre-dried with brine and later dried over MgSO4. Filtra-
tion and concentration afforded the crude product as an oil, TLC Rf
=
0.51 (MeOH/CH2Cl2 1:9).
NaN3 (300 mg, 1.1 equiv) and NH4Cl (256 mg, 1.15 equiv) were added si-
multaneously to a solution of crude Cbz-valine nitrile (850 mg) in DMF
(13 mL). The reaction was heated to 90–958C and kept at that tempera-
ture (3 h) until the TLC (HOAc/EtOAc 1:99) spot at Rf = 0.63 did not
increase in strength. The reaction mixture was poured onto ice (30 g),
acidified to pH close to 2 with HCl (2m), and extracted with CHCl3 (3”
20 mL). The organic phase was washed with water (20 mL), then pre-
dried with brine (20 mL), and finally dried over MgSO4 before filtration
and removal of solvent by evaporation. Traces of DMF were removed
under reduced pressure. The crude product is a yellowish solid.
flow rate 0.5 mLminÀ1, l
minor isomer: tR = 30.60 min
= 254 nm): major isomer: tR = 22.80 min;
Procedure for the ala-ala-catalyzed conjugate addition of ketone 1b to a
nitroolefin: The relevant ketone (0.75 mmol) and nitroolefin (0.25 mmol)
were added to a suspension of catalyst (30 mol%) in DMSO (0.5 mL),
NMP (0.5 mL), and H2O (45 mL, 10 equiv). The resulting mixture was
stirred for 72 h, quenched with brine, and extracted with ethyl acetate
(3”10 mL), and the combined organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography (silica gel, pentane/ethyl
acetate 10:1–4:1) to give the Michael products. The ees of the products
were determined by chiral HPLC analysis.
The Cbz-valine tetrazole (825 mg) was dissolved in MeOH (10 mL) and a
catalytic amount of Pd/C was added. After 17 h the catalyst was filtered
off with celite and the solvent was removed under reduced pressure to
give valine tetrazole
5 quantitatively as a
white solid. 1H NMR
Chem. Eur. J. 2006, 12, 5383 – 5397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5395

A. Córdova et al.
Compound 11: a white solid (96.6% ee): [a]2D5 = +27.4 (c=0.5, CHCl3);
1H NMR (CDCl3, TMS, 400 MHz): d = 7.40–7.10 (5H; m), 4.93 (dd, J =
12.4, 4.4 Hz; 1H), 4.64 (dd, J = 12.4, 9.6 Hz; 1H), 3.76 (dt, J = 9.6,
4.4 Hz; 1H), 2.78–2.72 (1H; m), 2.52–2.32 (2H; m), 2.15–2.05 (1H; m),
1.84–1.48 (4H; m), 1.30–1.18 (1H; m) ppm; 13C NMR (CDCl3, TMS,
100 MHz): d = 211.90, 137.74, 128.93, 128.16, 127.77, 78.88, 52.53, 43.93,
42.73, 33.19, 28.51, 25.02 ppm. The ee of the product was determined by
chiral HPLC analysis (ChiralpakAD column, i-hexane/iPrOH = 90/10,
0.5 mLminÀ1, tR (major) = 19.45 min, tR (minor) = 22.82 min). MALDI-
TOF MS: 270.1108; C14H17NO3 calcd for [M+Na]+ 270.1106.
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Acknowledgements
Support by Stockholm University is gratefully acknowledged. We thank
the Swedish National Research council, the Swedish Research Council
for Environment, Agricultural Sciences, and Spatial Planning, and the
Lars Hierta Foundation for financial support.
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www.chemeurj.org
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Chem. Eur. J. 2006, 12, 5383 – 5397

Asymmetric Catalysis by Amino Acids and Small Peptides
FULL PAPER
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Received: December 30, 2005
Published online: April 25, 2006
Chem. Eur. J. 2006, 12, 5383 – 5397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5397