Direct asymmetric aldol reactions inspired by two types of natural aldolases: Water-compatible organocatalysts and ZnII complexes

Article abstract of DOI:10.1021/jo201584w

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C₂-symmetrical proline- and valine-based

Full text of DOI:10.1021/jo201584w

Article
pubs.acs.org/joc
Direct Asymmetric Aldol Reactions Inspired by Two Types of Natural
Aldolases: Water-Compatible Organocatalysts and ZnII Complexes
Joanna Paradowska,† Monika Pasternak,‡ Bartosz Gut,‡ Beata Gryzło,‡ and Jacek Mlynarski*,†,‡
†Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
‡Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
S
* Supporting Information
ABSTRACT: In this article the utility of water-compatible
amino-acid-based catalysts was explored in the development of
diastereo- and enantioselective direct aldol reactions of a broad
range of substrates. Chiral C2-symmetrical proline- and valine-
based amides and their ZnII complexes were designed for use
as efficient and flexible chiral catalysts for enantioselective
aldol reactions in water, on water, and in the presence of water.
The presence of 5 mol % of the prolinamide-based catalyst
affords asymmetric intermolecular aldol reactions between
unmodified ketones and various aldehydes to give anti
products with excellent enantioselectivities. We also demon-
strate aldol reactions of more demanding substrates with high
affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of
hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making
the elaborated methodology interesting from a green chemistry perspectives.
Scheme 1. Mechanism of Type I and II Aldolases
1. INTRODUCTION
The aldol reaction is a key carbon−carbon bond-forming tool
for organic synthesis and bio-organic transformations in
nature.1 The ability to control the enantioselectivity of the
newly generated stereogenic centers has established this reac-
tion as the principal chemical transformation for the stereo-
selective construction of simple β-hydroxy carbonyl building
blocks and more complex polyol architectures.2 The aldol
reaction is also crucial for the biosynthesis of carbohydrates,
keto acids, and some amino acids.3 The reaction is originally
catalyzed by enzymes using either the enamine (type I
aldolases) or metal enolate (type II aldolases) mechanisms
(Scheme 1).
Type I aldolases function via an enamine mechanism, in
which an enzyme lysine residue reacts with the donor
component (at the Scheme 1 dihydroxyacetone phosphate,
DAHP) to generate an enamine in the active site. In the latter, a
metal cofactor is bound in the enzyme active site (usually Zn),
which acts as a Lewis acid to activate substrate. This acidifies
the α-proton, allowing for facile generation of zinc enolate in
the active site.
These biological processes have provided a template for the
development of small molecule catalysts activating substrates
using direct aldol reaction strategy.4 While virtually all the
biochemical aldol reactions use unmodified donors and
acceptors and take place in an aqueous environment, the
chemical domain of the aldol addition has mostly relied on
prior transformation of carbonyl substrates, and the whole
process traditionally is carried out in anhydrous solvents.
Application of catalytic amounts of various nonenzymatic
chiral promoter to control the aldol reactions is undoubtedly a
big achievement of modern organic chemistry.5 Another
challenge is to find a catalyst capable of activating the donor
and the acceptor carbonyls simultaneously in water environ-
ment.6 Two obvious biomimetic strategies have been employed
to follow the aldolases’ mode of action in aqueous media: (1)
organocatalysts,7 including modified amino acids and small
Received: August 9, 2011
Published: December 2, 2011
© 2011 American Chemical Society
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peptides, acting as type I aldolases, and (2) metal-catalyzed
aldol reactions8 generally based on zinc complexes. Although
small organic molecules and metal-catalyzed direct aldol
reactions in organic solvents have been developed with a
great deal of success, their catalytic efficiency and substrate
scope in aqueous media have so far been limited.
interest in the search for organic catalysts that can promote
effectively not only biphasic reaction of cyclic ketones but also
reactions in homogeneous water solution for a broad range of
substrates.27 Better understanding of such a process is an
important issue in the context of general asymmetric synthesis.
The parallel field of metal-catalyzed enantioselective direct
aldol reaction mimicking type II aldolases in water has afforded
less satisfactory results. The first application of an in situ
generated zinc complex with amino acid ester ligands (TyrOEt)
was presented in 1985.28 The readily available catalyst, although
reactive, was unselective and led to racemic products by direct
condensation of acetone with aromatic aldehydes. First example
of an asymmetric direct aldol reaction of acetone in water was
described by Darbre et al.29 Zinc complexes of a range of amino
acids were tested in the aldol reaction of acetone and 4-
nitrobenzaldehyde with the best results observed for proline,
lysine, and arginine. Enantiomeric excesses of up to 56% could
be obtained with only 5 mol % of Zn(Pro)2 at room tempera-
ture. This reaction was conducted in homogeneous acetone/
water solution (1:2), making ketone not only the reactant but
also the solvent. Again, the aldol reaction catalyzed by zinc
complexes is regio- and stereoselective with hydroxy- and
dihydroxyacetone but leads unfortunately to racemic hydroxy-
aldols. The authors suggested that the applied catalyst forms
enamine species with acetone, but with dihydroxyacetone Zn-
enolate formation is preferred.30 More recently, Aoki reported
interesting mechanistic studies of catalysts consisting of chiral
amino acids and Zn−cyclene complex.31 Aldol reactions of
acetone and unprotected α-hydroxyketones such as hydroxy-
and dihydroxyacetone were catalyzed to give adducts with only
moderate ee values (up to 45%).
Continuous development of asymmetric aldol reaction in/on
water seems to be rational, as aqueous homogeneous and
biphasic catalysis is one of the most promising strategies toward
more economical and green processes.32 Undoubtedly, more
promising application of naturally occurring hydrophilic sub-
strates would be a great achievement in the field. In 2007 we
presented our preliminary studies on application of bispro-
linamide zinc complex for direct asymmetric aldol reaction in
aqueous media.33 The presented catalyst, although active for
cyclic and acyclic ketones, lost some selectivity for reactions
performed with equimolar ratios of carbonyl partners in pure
water. Herein we report a comprehensive overview on the use
of simple α-amino acids derivatives as practical, highly efficient,
and substrate-flexible catalysts for direct asymmetric aldol
reaction on/in water. The presented amino-acid-equipped
ligands are tunable catalysts for direct aldol addition in the
presence of a large amount of water without any additives
(organocatalyst) and also as a zinc complexes.
Proline catalyzes direct aldol reactions with high enantiose-
lectivity in polar organic solvents such as DMSO and DMF, but
in the presence of water9 or a buffer solution, nearly racemic
products were obtained.10 After initial application of catalytic
antibodies,11 nornicotine12 and some other organocatalysts
have been tested in water environment.13 It has been also
demonstrated by Janda’s12 and Barbas’9 groups that the
enamine, which had been considered to be easily hydrolyzed
in the presence of water, is in fact generated and reacts with an
electrophile to afford the aldol under aqueous conditions.
In 2004, Pihko recorded significantly higher yields on
addition of water to an intramolecular aldol reaction catalyzed
by proline in homogeneous water/DMF solution.14 Further
efforts have been made to develop efficient organocatalysts for
asymmetric intermolecular aldol reaction in water: proline,15
various proline derivatives,16 and some other amino acids17
were used as catalysts in aqueous−organic solvents with some
success. For the catalysts operating in water without organic
cosolvents, only moderate enantioselectivities were initially
observed.18
In 2006 Barbas et al. carried out a highly enantioselective
direct aldol reaction catalyzed by a proline-based hydrophobic
diamine in water.19 This enantioselective methodology was prom-
ising only for cyclic ketones while acyclic substrates gave only
moderate enantioselectivities. Simultaneously, Hayashi and co-
workers reported that a siloxyproline catalyzed highly
enantioselective aldol reaction in water by using only 1 mol %
of the organocatalyst.20 The presented catalyst works in
biphasic medium and failed to provide any product if one of
the partners was water miscible. More recently, Barbas III hypo-
thesized that a small organic catalysts with appropriate
hydrophobic groups assembled with the hydrophobic reactants
in water and sequestered the transition state from water. As a
result, the outcome of the reaction should be similar to that
performed in organic solvents.21 Further examples of highly
enantioselective aldol recations in water are known; the
efficient and nearly quantitative reaction of cyclohexanone in
a presence of large amount of water was also described.22
The above-mentioned catalysts have the limitation of giving
moderate enantioselectivity with a water-miscible ketone such
as acetone or hydroxyacetone (HA), a highly desirable substrate
from a conceptual and synthetic point of view. Therefore, there
was a great need for a chiral organocatalysts that could over-
come these drawbacks. To solve this problem Singh et al.
developed prolinamide catalyst bearing a nonpolar gem-
diphenyl group that works very efficiently for acetone in
water.23 Nevertheless, application of water-soluble substrates
still remains unsolved while most published examples of
organocatalysts activate only cyclic ketones in the presence of a
small amount of water. More flexible catalytic systems in the
field are still elusive.
2. RESULTS AND DISCUSSION
2.1. Asymmetric Aldol Reaction Catalyzed by Zn
Complexes. Scope and Limitations. It was shown in our
previous work that direct aldol reaction between acetone and
4-nitrobenzaldehyde can be efficiently promoted in an aqueous
media using C2-symmetric Zn-bisprolinamide 2a.33 Catalyst
design was based on an analogy to type II aldolases in which
the zinc ion is tightly coordinated by three histidine residues in
the reaction active site.34 In our search for the best catalysts, we
introduced C2-symmetry based on chiral (2, 3) and achiral
scaffolds (1). Thus, based on literature protocols35 we
synthesized bisprolinamides 1−3, expanding the family by
diastereo- and enantiomers of known compounds (Scheme 2).
Recent progress in the area24 has initiated constructive
discussion on the role and practical merits of water as a
solvent.25 Water and water-based reactions were debated with
regard to terminology (i.e., whether a reaction is carried out “in
water”, “in the presence of water”, or “in the presence of a large
excess of water”).26 This discussion showed also increased
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catalyst’s part component than its prolinamide analogues 4 and
5 (Table 1, entries 2 vs 6, 7).
Scheme 2. Bisprolinamide Catalysts Used at the Initial Stage
of the Study
We next checked the solvent effect on this aldol reaction
employing zinc complex with ligand 2a as a catalyst; the results
are summarized in a previous paper.33 In water alone the zinc
complex gave the (R) enantiomer in 36% ee. We were
delighted to find that the reaction without any organic
cosolvents proceeded well when 5 mol % of the catalyst was
applied (Table 1, entry 8). In this case desired aldol was
isolated in high yield with 86% enantiomeric excess, after
reaction at room temperature.
The scope of this aldol reaction using diamide 2a/Zn(OTf)2
catalyst in the presence of large amount of water was examined,
and the results are summarized in Table 2. Aldehyde acceptors
with electron-withdrawing substituents show higher reactivity.
In all cases, however, the reaction proceed smoothly at room
temperature, and enantioselectivity was good to high (entries
1−6). Both excellent enantioselectivity and anti-selectivity were
obtained when cyclohexanone was employed (entries 8−14).
The aldol reactions of o- and m-substituted aldehydes show
higher selectivity than that of p-substituted donors.
On the basis of presented findings it should be noted that the
large excess of water does not influence on the reaction results.
The developed zinc-based chiral catalyst seems efficient and
enantioselective system for aqueous aldol reaction, maintaining
high selectivity for noncyclic ketones without any organic
cosolvents.
2.2. Enantioselective Synthesis of (R)-Lipoic Acid
Precursor. Previously presented aldol methodology can be
also efficiently applied for the crucial step in enantioselective
synthesis of biologically relevant molecules. (R)-α-Lipoic acid
(7) plays an important role as a protein-bound transacylating
cofactor of several multienzymatic α-keto acid dehydrogenase
complexes.36 Since its isolation, (R)-α-lipoic acid has attracted
great attention because of its diverse biological functions. It is
an important growth factor, acting as a coenzyme in many bio-
logical processes found in animal tissues, plants, and micro-
organisms.37 In addition, it serves as an effective scavenger for
reactive oxygen species (ROS),38 which have been implicated in
a number of pathological conditions such as carcinogenesis,
inflammation, ischemia-reperfusion injury, and aging. It has
been reported that naturally occurring (+)-(R)-α-lipoic acid (7)
and its derivatives possess more potent anti-HIV and antitumor
activities than its (S)-enantiomer.39 Few asymmetric synthesis
of this molecule have been presented40 including organo-
catalytic approach by using an L-proline-catalyzed cross-aldol
reaction as the key step. It was shown that the target molecule
could be attained from lactone 8 (Scheme 3.) This dis-
connection raised a synthetic challenge related to the installa-
tion of the stereogenic centers in precursor lactone 9. This, in
turn resulted from L-proline-promoted cross-aldol reaction
between cyclohexanone and benzyloxyacetaldehyde.40b
We found it interesting to examine the generality of
previously elaborated zinc catalyst, as organocatalytic cross-
aldol reactions between cyclohexanone and desired aldehyde
created a significant challenge since the highly active aldehydes
readily undergoes self-aldol reaction. The results of aldol
reaction are summarized in Table 3.
We tested also zinc complexes of monoprolinamides 4 and 5 in
order to compare efficiency of catalysts with C1- and C2-
symmetry.
The reaction of acetone with 4-nitrobenzaldehyde was
explored as a catalyst test. The same reaction has been
explored in previous papers on the same subject leading to
desired aldol 6a with enantiomeric excesses of up to 56%.29
Application of all tested ligands as organocatalysts to the aldol
reaction led to promising results, and the condensation
proceeded efficiently in aqueous medium in all cases, yet
observed ee's were poor.33 However, addition of zinc
trifluoromethanesulfonate increased the selectivity as reflected
in higher enantioselectivities (Table 1). The best results with
Table 1. Screening of Efficient Catalysts in the Direct
Asymmetric Aldol Reaction of Acetone with 4-
Nitrobenzaldehyde
a
b
entry
catalyst
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1/Zn(OTf)2
2a/Zn(OTf)2
2b/Zn(OTf)2
2c/Zn(OTf)2
3/Zn(OTf)2
4/Zn(OTf)2
5/Zn(OTf)2
2a/Zn(OTf)2
90
92
0
24
60
0
98
75
93
27
39
16
86
c
87
a
Isolated yield. Conditions: catalyst (10 mol %), Zn(OTf)2 (10 mol %),
4-nitrobenzaldehyde (0.50 mmol) in acetone/water (1/1, 2 mL) at rt for
b
20 h. Enantiomeric excess was determined by HPLC analysis on a
c
chiral phase column (Chiralpak AS-H). Conditions: 2a (5 mol %),
Zn(OTf)2 (5 mol %), 4-nitrobenzaldehyde (0.50 mmol) in acetone/
water (9/1, 1 mL) at rt for 20 h
respect to yield and ee were observed with catalyst 2a and
Zn(OTf)2 as additive (Table 1, entry 2). The addition of Zn-
salt increased the enantioselectivity from 6% to 60%.33 We did
not observe the formation of aldol 6 in the presence of
Zn(OTf)2 and (S)-proline (1:2) under similar reaction
conditions. Interestingly, a C2-symmetric bisprolinamide with
two prolinamide moieties has been proved to be a better
With 20 mol % of proline, the reaction of cyclohexanone and
aldehyde 10 finished in 16−20 h with perfect ee and (95:5)
diastereoisomers ratio (Table 3, entry 1). The use of ketone as
a reaction medium led to a dramatic improvement in the yield
of the cross-aldol reaction.40b Application of 2a/Zn(OTf)2 in
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Table 2. Direct Catalytic Asymmetric Aldol Reaction in the Presence of Water Catalyzed by 2a/Zn(OTf)2 (5 mol %): Substrate
Scope
a
Yield refers to combined yield of isolated diastereomers. Conditions: prolinamide catalyst 2a (0.025 mmol, 5 mol %), Zn(OTf)2 (0.025 mmol),
b
aldehyde (0.50 mmol) in ketone/water mixture (9/1, 1 mL) at rt for 20 h. Diastereoselectivity was determined by HPLC and 1H NMR analysis of
the isolated diastereomers. Enantiomeric excess was determined by HPLC analysis on a chiral phase (Chiralpak AD-H and AS-H). This system
seems to be selective for the formation of the (R) configuration. All isolated aldol adducts were found in the (R)- (entries 1−7) and (2S,1′R)-
stereochemistry (entries 8−15).
c
d
the presence of water delivered essentially the same results,
while only 5 mol % of catalyst loading was necessary. An
obvious advantage of this strategy was much less ketone loading
being necessary for obtaining the same yield of aldol 11.
Interestingly, the same catalyst failed to react without water
additive. Thus obtained compound 11 was transformed into
key intermediate 9 in 65% yield using a literature protocol.40b
2.3. Effect of the Amount of Ketones and Water. Pre-
viously presented methodology, although highly substrate
flexible, suffers from a large excess of ketone that should be
used for obtaining reasonable yield. When an expensive ketone
is used in large excess, it is not reassuring for the direct aldol
reaction with atom-economical aqueous green chemistry.
The use of less volatile ketones in large excess, for example
cyclohexanone, complicates the reaction workup and final
product purification. On the other hand, ideal water-compatible
catalyst should operate in high excess of water, even used as a
solvent. The essential role of water was observed when the
reaction promoted by 2a/Zn-salt was carried out in pure
cyclohexanone. In this case only a trace of product was isolated
(Table 4, entry 1). Addition of water (10 vol %) resulted in
essential increasing of reactivity and selectivity. In a reaction
conducted at 0 °C the ee reached smoothly 98% with perfect
diastereoselectivity and reasonable reactivity of the catalytic
system with only 5 mol % catalyst loading (Table 4, entry 2).
Application of zinc trifluoroacetate as an additive showed
similar selectivity in the presence of 10 vol % of water (entries 2
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economically attractive reaction conditions. Whereas asym-
metric aqueous hydroxymethylation of an enolate component
with formaldehyde is known,44 the direct use of ketones instead
of silicon enolates in water still needs further investigations.
Recently, two examples of organocatalytic asymmetric hydroxy-
methylation using formalin in the presence of a small amount of
water were reported.45 In both cases, the chemical yields were
moderate, and the substrate scope was limited to a single
example, cyclohexanone, which is insoluble in pure water.
To improve the flexibility of the elaborated catalytic system
we focused on the direct aldol reaction of formaldehyde
promoted by a Zn complex of prolinamide 2a. Optimization
studies using cyclohexanone and formalin are summarized in
Table 5. To start from an organocatalytic protocol, cyclo-
hexanone (1.5 mmol), aqueous formaldehyde (0.75 mmol),
and 10 mol % of catalyst 2a were mixed in DMSO (Table 5,
entry 1). α-Hydroxymethyl ketone 13 was isolated in 10% yield
and 42% ee. Unfortunately, the use of a homogeneous aqueous
solution affected the enantioselectivity. Although the reaction
proceeded sluggishly under organocatalytic protocols (entries
1−4), the use of a catalytic amount of zinc triflate resulted in an
improved yield and enantioselectivity (entries 5, 6). The use of
an ethanol/water solution instead of THF/water mixtures
improved further the reaction. As far as we are aware, there are
no other examples in which this reaction proceeds with high
enantioselectivity in aqueous solution, with all of the reagents
and catalyst dissolved homogeneously in the reaction mixture.
The reaction in brine or in water is less efficient (entries 7, 8),
but the yield of hydroxymethylation in pure water can be
further improved by the use of an ultrasound bath (entry 9).
The reaction of cyclohexanone and formaldehyde was carried
out in pure water (1 mL) to generate the desired aldol in 74%
yield and 95% ee. Sonication enables the rapid dispersion of
ketone substrate on the water surface, allowing better contact
between water and reactants. The use of ultrasound as a means
of accelerating reactions is an important technique and one that
is rapidly developing for green processes.46
Scheme 3. Crucial Aldol Step in the Synthesis of (R)-Lipoic
Acid
vs 4), while both catalysts lost selectivity in huge amounts of
water (entries 5 and 6).
Thus, the reaction selectivity was greatly affected with
increasing amount of water in the reaction mixture. This
unwelcome tendency can be overcome by application of
ytterbium salt33 or by application of improved zinc complex
with more water-tolerant ligand 12. Whereas in the natural
enzyme the enamine is formed at the lysine residue in the active
site,3 most presented catalysts contain a cyclic proline motif for
this purpose. Studies of enantioselective organocatalytic
reactions promoted by primary amino acids and their deriva-
tives41 provided interesting and fresh results.42 The most
promising applications of siloxythreonine and siloxyserine must
be seen, however, as reactions “in the presence of water” rather
than “in water”.22b,c Nevertheless, we applied newly designed
bisvalinamide ligand 12, which turned out to be more water-
compatible when compared to the proline derivative. The
reaction proceeds smoothly in a large excess of water to provide
excellent selectivity with various aldehydes (Table 4, entries
7−11). Organic cosolvent additive was not necessary for
obtaining good yield and high enantioselectivities under
presented conditions.
Comparison of the HPLC analysis, on a chiral stationary
phase, of the benzoyl derivative of the product with that
reported in the literature44a revealed that applied proline-based
catalyst provided (S)-2-hydroxymethyl cyclohexanone.
The presented methodology is acceptable for other cyclic
ketones (cyclopentanone: 58%, 98% ee, cycloheptanone: 59%,
93% ee, in homogeneous solution of EtOH/water, 9/1).47
Recently, an excellent example of a metal-assisted direct hydroxy-
methylation in water was presented by Kobayashi,48 but the
2.4. Direct Asymmetric Hydroxymethylation of
Ketones in Aqueous Systems. Hydroxymethylation reac-
tions represent one of the most useful one-carbon extension
methods,43 but the use of formaldehyde as a C1-unit in direct
catalytic asymmetric aldol reactions is surprisingly rare, possibly
due to its high reactivity, high affinity to water, and symmetrical
structure. The direct use of commercially available aqueous
formaldehyde (formalin) solution gives the safest and most
Table 3. Cross Aldol Reaction between Cyclohexanone and Benzyloxyacetaldehyde
a
b
entry
1
catalyst
substrates
water
yield (%)
65
ee (%)
L-proline (20 mol %)
ketone (10 mL)
10 (3.3 mmol)
ketone (0.9 mL)
10 (3.3 mmol)
ketone (0.9 mL)
10 (3.3 mmol)
95 (de 90)
2
3
2a/Zn(OTf)2 (5 mol %)
2a/Zn(OTf)2 (5 mol %)
nd
66
0.1 mL
95 (de 94)
a
b
Isolated yield. Enantiomeric excess was determined by HPLC analysis on a chiral phase column (Chiralpak AS-H).
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Table 4. Direct Catalytic Asymmetric Aldol Reaction in the Presence of Larger Excess of Water without Organic Cosolvents
a
b
c
entry
R-C6H4CHO, R =
catalyst
ketone/water
cyclohexanone
temp (°C)
yield (%)
anti/syn
ee anti (%)
1
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
m-NO2
o-NO2
p-Cl
2a/Zn(OTf)2
2a/Zn(OTf)2
2a/Zn(OTf)2
2a/Zn(OTFA)2
2a/Zn(OTf)2
2a/Zn(OTFA)2
12/Zn(OTf)2
12/Zn(OTf)2
12/Zn(OTf)2
12/Zn(OTf)2
12/Zn(OTf)2
rt
0
tr
93
86
99
86
85
74
85
45
41
27
2
cyclohexanone/water (9/1)
98/2
87/13
98/2
8/2
98
80
94
57
66
97
98
99
99
98
3
cyclohexanone/water (1/1)
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
cyclohexanone/water (9/1)
5
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
6
82/18
9/1
7
8
88/12
99/1
8/2
9
10
11
H
9/1
a
Yield refers to combined yield of isolated diastereomers. Conditions: catalyst 2a/12 (0.025 mmol, 5 mol %), metal salt (0.025 mmol, 5 mol %),
aldehyde (0.50 mmol) in cyclohexanone/water (1 mL) or catalyst 2a/12 (0.025 mmol, 5 mol %), metal salt (0.025 mmol. Five mol %), aldehyde
b
1
(0.50 mmol), cyclohexanone (260 μL, 2.50 mmol) in water (1 mL). Diastereoselectivity was determined by HPLC and H NMR analysis of the
isolated diastereomers. Enantiomeric excess was determined by HPLC analysis on a chiral phase (Chiralpak AD-H and AS-H).
c
than its monoprolinamide counterpart.35b Molecules of amides
Table 5. Direct Catalytic Aldol Reaction of Cyclohexanone
with Formaldehyde
2a and 12 are insoluble in water and, according to Hayashi, can
support reactions “in the presence of water”. Nevertheless, we
decided to test activity of organocatalyts 2a and 12 in the
presence of larger amount of water assuming their high selec-
tivity. To test this hypothesis we focused only on reactions of
5-fold excess of ketone to aldehyde in the presence of large
excess of water. First, we compared results of the reaction
between cyclohexanone (5 equiv) and 4-nitrobenzaldehyde in
water (1 mL) catalyzed by both prolinamide 2a and valinamide
12 with various acid-type additives (TFA, TfOH, AcOH).
Acetic acid showed a little worse selectivity, while triflic acid
decreased the high reactivity of bisprolinamide. The best results
observed for trifluoroacetic acid additive are summarized in
Table 6.
While only valinamide zinc complex was highly selective
under similar conditions in water (Table 4), both prolinamide
and valinamide promoted diastereo- and enantioselective aldol
reaction when protonated by trifluoroacetic acid (entries 2
and 4). High enantioselectivity was observed for valinamide 12
without any additives yet observed diastereoselectivity was dis-
appointing (entry 3). Better balance between yield and
selectivity was achieved by using protonated prolinamide, and
this catalyst was used for further testing of reactions’ scope. The
best results with respect to yield, diastereoselectivity, and
enantioselectivity were observed with 2a and TFA as additive.
Good levels of ee and excellent diastereoselectivities were
maintained in water at around 0 °C (entry 5). For practical
reasons the catalyst loading was raised to 10 mol % and longer
reaction times were needed (entries 6−8). The same good yield
and selectivity were observed for far less reactive benzaldehyde
(entry 9) when more ketone was used. Protonated organo-
catalyst 2a and 12 seem to be less selective for acyclic ketones,
leading to a good level of ee only for acetone (entry 10).
a
b
entry
catalyst
solvent
DMSO
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
2a
2a
10
25
23
tr
42
20
THF/H2O (9/1)
THF/H2O (9/1)
THF/H2O (9/1)
THF/H2O (9/1)
EtOH/H2O (9/1)
brine
2a/TFA
rac
2a/TfOH
2a/Zn(OTf)2
2a/Zn(OTf)2
2a/Zn(OTf)2
2a/Zn(OTf)2
2a/Zn(OTf)2
39
55
25
25
74
92
94
90
95
95
H2O
c
H2O
a
Isolated yield. The reaction was performed by employing formalin
(0.75 mmol, 37% in water), cyclohexanone (1.5 mmol), catalyst 2a
(10 mol %), and solvent (1 mL). Additives: Zn(OTf)2 (10 mol %),
b
TFA (20 mol %). Determined by HPLC analysis of the benzoate
c
ester on a chiral phase (Daicel OD-H column). The reaction was
performed in 0.5 mL of water at rt for 10 h in an ultrasound bath.
applied catalytic system seems to be also limited to cyclic
ketones.
2.5. Mimicking Type I Aldolases by Organocatalytic
Aldol Reactions in Water. In the previous paragraph we
showed that direct hydroxymethylation of cyclic ketones needs
prolinamide ligand supported by Zn-salt, while a protonated
ligand failed to react under the same aqueous conditions
(Table 5). However, a C2-symmetric bisprolinamide with two
L-amino acid moieties has been found previously to be a pro-
mising catalyst for direct aldol reaction of/in dry acetone with
more than doubled reactivity and better asymmetric induction
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Table 6. Organocatalytic Asymmetric Aldol Reaction in the Presence of Larger Excess of Water
a
b
c
entry
R-C6H4CHO, R =
catalyst
ketone/water
temp (°C)
yield (%)
anti/syn
ee anti (%)
1
2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-CN
p-Cl
2a/-
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone (5 equiv) in water
cyclohexanone/water (9/1)
rt
rt
rt
rt
0
99
89
86
65
20
89
94
45
76
90
85/15
93/7
75/25
93/7
99/1
96/4
96/4
98/2
98/2
72
91
95
92
95
95
93
95
94
90
2a/TFA
12/-
3
4
12/TFA
2a/TFA
2a/TFA
2a/TFA
2a/TFA
2a/TFA
2a/TFA
5
d
6
0
d
7
0
d
8
0
e
9
H
rt
10
p-NO2
acetone/water (9/1)
rt
a
Yield refers to combined yield of isolated diastereomers. Conditions: catalyst 2a/12 (0.025 mmol, 5 mol %), additive (if used, 0.050 mmol, 10 mol %),
b
aldehyde (0.50 mmol), cyclohexanone (260 μL, 2.50 mmol) in water (1 mL). Diastereoselectivity was determined by HPLC and 1H NMR analysis
of the isolated diastereomers. Determined by HPLC analysis on a chiral phase (Chiralpak AD-H and AS-H). Reaction time 70 h, catalyst loading
10 mol %. Reaction time 40 h.
c
d
e
Scheme 4. NMR Studies of Ligand 2a
2.6. Insight into Zn-Based Catalyst Structures. To
shed light on the possible structure of the catalysts and the
catalytic action of species formed in situ, we gained insight into
the NMR spectra of H+ salt and ZnII complexes with
representative examples of both classes of tested ligands. We
first examined the 1H NMR spectra of proline-based catalyst 2a
(Scheme 4). After addition of 2 equiv of trifluoroacetic acid,
NMR spectra clearly changed. The most interesting signals
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Scheme 5. NMR Studies of Ligand 2a
were those of two diastereotopic protons at the pyrrolidine
nitrogen (δ 8.41 and 9.32 ppm). Addition of 1 equiv of
Zn(OTFA)2 resulted in the broadening of most signals. Such a
change must have resulted from a restrained rotation in the
ligand core and arms. It is noteworthy that amide protons still
appeared in spectra as broad signals, suggesting coordination of
Zn to the carbonyl group rather than to the amide nitrogen
(with possible deprotonation). Addition of TFA to previously
formed complex (iii) resulted in the formation of protonated
structure (iv), almost identical in NMR experiment to that
formed by direct protonation (ii). This suggests an essential
role of pyrrolidine nitrogen coordination to zinc at the initially
formed complex.
Further, we tested ligand structure by using better soluble
zinc trifluoacetate in CD3OD solution (Scheme 5). Interest-
ingly, strong change in spectra was observed with only 0.1 equiv
of Zn-salt. This suggest rather fast metal−ligand exchange in
the dynamic system at on the NMR experiment time scale.
Saturation, if any, was observed when 2.0 equiv of Zn(OTFA)2
was added, indicating a (2:1) stoichiometric complexation of
metal salt to ligand.
complex with (1:1) ligand−metal ratio as an aldol reaction
catalyst, but we could not neglect such a result suggesting a
possible (1:2) ratio of ligand−zinc complex. Thus the loading
amount of Zn(OTf)2 in the reaction was also investigated
(Table 7).
The use of 5 mol % of zinc salt (1:1 with 2a) seemed best for
the reaction (Table 7, entry 2). Although lower loading of
Zn(OTf)2 decreased both yield and selectivity, no improve-
ment was detected when more than 5 mol % of additive was
used (entry 5).
To gain insight into the sense of the asymmetric induction of
the aldol reaction resulting from the elaborated procedure, we
compared the optical rotation and results from HPLC analysis
of the obtained aldol with published data. The absolute con-
figuration of aldol 6a was determined as (4R) by a comparison
of the optical rotation of 6a with those of compounds prepared
in our laboratory using (S)-proline-organocatalyst and the pro-
tocol initially described by List. Comparison of optical rotation
and HPLC analysis unambiguously showed the same absolute
configuration of both aldols prepared using proline and proline-
based 2a.49
The 1H NMR spectra of a valine-composed complex showed
features similar to those observed for the proline-based
complex (Scheme 6). In the titration experiment, saturation
was observed for a (2:1) stoichiometric complexation of metal
salt to ligand 12. For this ligand, however, symmetrical
structure was observed, indicating a better-defined complex at
room temperature.
For both ligands 2a and 12, the complexation of zinc to
carbonyl oxygen and nitrogen of amine rings is expected on the
basis of presented NMR experiments. So far we have used a
The new catalyst incorporates a metal center that can act as a
Lewis acid in water and mimics the mode of action of type II
aldolases (Scheme 7). On the other hand, the complex could also
form an enamine intermediate (II), in analogy to type I aldolases.
The fact that proline alone is not an efficient catalyst supports only
the expectation that enamine formation is unfavorable under
the aqueous reaction conditions. The zinc complex gave the
(R) enantiomer of the aldol product in excess, and with proline
alone, the same (R) enantiomer was also predominant. Thus,
we postulate similar mechanism involving organocatalytic
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Scheme 6. NMR Studies of Ligand 12
a
Table 7. Dependence of Aldol Reaction on 2a/Zn Ratio
with protein catalysts such as aldolases and catalytic antibodies.3
Since 2000, several reports have addressed the aldol addition
using both organometallic and proline catalysis.51 Of the
diastereo- and enantioselective direct aldol reactions, anti-
selective variants have been available using proline-catalyzed
reactions.6 Recently, a number of syn-selective direct asym-
metric aldol additions catalyzed by primary52 and secondary53
amines have been reported, but they are mostly limited to
protected hydroxy- and dihydroxyacetones. Although some of
these catalysts gave good results in organic medium,54 they are
limited to protected donors and failed to give promising results
in the presence of water with unprotected hydroxyacetone.55 In
2009, Singh presented chiral cyclohexyldiamine-based catalyst
that efficiently catalyzes the syn-selective addition to hydroxy-
acetone donor in DMF/water (9:1) solution with high
enantioselectivity.56 The presented catalyst contained aromatic
substituents forming a hydrophobic cavity with the reactants in
aqueous medium. Thus, the catalyst successfully mimic
enzymes’ mode of action, and the reaction take place in this
cavity, resulting in high stereoselectivity. The idea behind this
design is that water-soluble substrate (i.e., natural dihydroxy-
acetone phosphate) can be efficiently activated in hydrophobic
pockets of water-unsoluble catalyst (i.e., natural aldolases). This
reverse-solubility concept is far more acceptable for water-
soluble hydroxyacetone than that presented by Barbas III, who
used silyl-protected ketones.21 Apart from the more economical
merits of application of unprotected hydroxyacetone, this
attempt constitutes a rare example of aqueous direct aldol
reaction in homogeneous solution.
b
c
entry
x mol %
yield (%)
ee (%)
1
2
3
4
5
0
0.5
1
61
83
56
85
88
13
19
25
85
85
5
10
a
Conditions: acetone (0.9 mL) and 4-nitrobenzaldehyde (0.50 mmol)
and water (0.1 mL) at rt for 20 h. Isolated yield. Enantiomeric excess
was determined by HPLC analysis on a chiral phase (Chiralpak AS-H).
b
c
enamine formation (I), where zinc complexation only stabilizes
the formation of an enamine intermediate in water as depicted
at Scheme 7, transition state II. Formation of the anti-product
observed in the reaction of cyclic substrates resulted from the
(E)-enolate of cyclohexanone (IV). By the same rules, aldol
reaction of enamine with formaldehyde (V) results in formation
of (S)-aldol.
2.7. Direct Aldol Reaction of Hydroxyacetone. Hydro-
xyacetone (HA) and dihydroxyacetone-based aldol reactions
are of considerable importance because they provide expedient
access to both natural carbohydrates and unnatural polyhy-
droxylated molecules of significance in medicine.50 Most of the
available knowledge on aldolases’ mode of action is based on
transformation of dihydroxyacetone phosphate (DHA). For a
long time, the direct catalytic asymmetric aldol reaction of
α-hydroxylated ketones with aldehydes had been achieved only
To verify this hypothesis, we decided to compare the
reactivity of previously prepared bisprolinamide 2a and
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Scheme 7. Possible Structures of Transition States
bisvalinamide 12 but also to design a more hindered and
lipophilic family member. We assumed that more bulky
substituents can effectively protect reaction-active site and
also shield one of the sites of nucleophilic attack, resulting in
the higher enantioselectivity. On the other hand, recent
findings suggest that selective hydrophobic acceleration can
play an interesting and important part in organic synthesis in
water.57 Thus, we decided to use O-tert-butyldiphenylsilyl-
protected bisserinamide 14.
Such a conclusion is in a full agreement with previously
observed sense of stereochemical induction observed for the
reaction of hydroxyacetone in the presence of primary amino-
acid-based organocatalysts.52
The organocatalytic reaction of hydroxyacetone presented
above took place in homogeneous aqueous solution, while the
formation of enamine intermediate in water is still a subject of
interesting discussion.26 To get deeper insight into the mecha-
nism of hydroxyacetone activation by primary amine catalyst
14, we used ESI-MS technique. Results of the analysis of the
sample containing HA and 14 (1/1) in water/methanol
solution are shown in Scheme 9. The presented MS spectra
confirm formation of tautomeric imine/enamine in the aqueous
phase: the signal at m/z 919 matches the expected molecular
weight. The isotopic pattern of this signal corresponds with the
calculated pattern of the expected structure.
Indeed, newly designed catalyst 14 shows better reactivity
when compared with 2a and 12. First tests have been made in
organic solvents using activated 4-nitrobenzaldehyde to asses
reactivity and selectivity of all three organocatalysts without
additional hydrogen bond interactions. The observations
collated in Table 8 revealed that the reaction of aromatic
aldehyde and 5 equiv of hydroxyacetone (HA) led to syn-diol
with good diastereoselectivity and 82% ee when THF was used
as a solvent (entry 4). Interestingly, monovalinamides 15−17
induced worse level of enantioselectivity (entries 5−7).
Catalyst 14 is even more selective for aliphatic isobutyr-
aldehyde, yet the isolated yield was less satisfactory (entries 10,
11). To test the substrate generality the reaction of various
aldehydes with HA was studied in homogeneous aqueous
solution, under optimized conditions. As shown in Table 8
(entries 10−15), aromatic aldehydes with a nitro group gave
very good results with only 2 equiv of ketone. For the
unreactive aromatic and aliphatic aldehydes, we kept an excess
of hydroxyketone and small addition of THF to maintain a
homogeneous reaction mixture. Aliphatic aldehydes, although
not highly reactive, delivered aldols with excellent diastereo-
and enantioselectivity at room temperature (entries 13−15).
For hydroxyacetone donor additives of Lewis and Brønsted acid
natures did not improved the yield or selectivity of tested
catalysts.58
3. CONCLUSIONS
In summary, we have developed a new family of amino-acid-
based ligands for direct aldol reactions in the presence of water.
In the designed systems the Lewis base (amine) activates the
ketone chelating also the Lewis acid (zinc salt). In this way, the
base and the Lewis acid can activate simultaneously both donor
and acceptor in the chiral environment of the backbone ligand.
Such a system mimic enzymes’ mode of action in their natural
water environment. The presented bifunctional catalysts
displayed exceptionally high reactivity in the direct asymmetric
aldol reactions of cyclic/acyclic ketones and aromatic and
aliphatic aldehydes. The presented family of tunable catalysts
showed high reactivity in the organic phase in the presence of
water, in water, or even in aqueous homogeneous solvents. Bis-
prolinamide ligands with zinc can be efficient catalysts for direct
activation of formaldehyde, while lipophilic bis-siloxyserinamide
acts as enantioselective organocatalyst for direct aldol reaction
of unprotected hydroxyacetone. We proved also that even in
the presence of a large amount of water the enamine is
generated and reacts with the aldehyde in the organic or water
phase, affording the aldol products in high enantioselectivity.
Since these Zn-complexes and organocatalysts gave good
results with a variety of donors and acceptors, they are in
We anticipated that hydroxyacetone may give the syn-aldol
product through an (Z)-enamine intermediate additionally
controlled by hydrogen bond formation to hydroxyl function
(Scheme 8). The stereochemistry of (3R,4S)-syn-configured
product can be explained by transition state VI because of the
(Z)-enamine reacts with Re face of aldehyde. Aldehyde
substituent is always placed away from catalyst’s bulky parts.
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Table 8. Direct Catalytic Asymmetric Aldol Reaction in the Presence of Larger Excess of Water: Metal Complexes versus
Organocatalysis
a
c
entry
RCHO
catalyst
solvent/conditions
temp (°C)
yield (%)
syn/anti
ee syn (%)
1
p-NO2-C6H4 (18a)
p-NO2-C6H4 (18a)
p-NO2-C6H4 (18a)
p-NO2-C6H4 (18a)
p-NO2-C6H4 (18a)
p-NO2-C6H4 (18a)
p-NO2-C6H4 (18a)
iPr (18b)
2a (5 mol %)
12 (5 mol %)
14 (5 mol %)
14 (5 mol %)
15 (5 mol %)
16 (5 mol %)
17 (5 mol %)
2a (5 mol %)
12 (5 mol %)
14 (5 mol %)
14 (5 mol %)
DCM (1 mL), HA (5 equiv)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
72
80
86
79
56
58
45
7
1/1
rac
64
2
DCM (1 mL), HA (5 equiv)
78/22
74/26
8/2
3
DCM (1 mL), HA (5 equiv)
70
4
THF (1 mL), HA (5 equiv)
82
5
THF (1 mL), HA (5 equiv)
72/28
66/34
66/34
28/72
95/5
64
6
THF (1 mL), HA (5 equiv)
64
7
THF (1 mL), HA (5 equiv)
60
8
DCM (1 mL), HA (5 equiv)
70 (anti)
80
9
iPr (18b)
DCM (1 mL), HA (5 equiv)
8
10
11
iPr (18b)
DCM (1 mL), HA (5 equiv)
21
33
95/5
90
iPr (18b)
PhMe (1 mL), HA (5 equiv)
95/5
92
Reactions in the Presence of Water
THF (0.9 mL), H2O (0.1 mL), HA (2 equiv)
THF (0.1 mL), H2O (0.1 mL), HA (0.9 mL)
THF (0.1 mL), H2O (0.1 mL), HA (0.9 mL)
THF (0.1 mL), H2O (0.1 mL), HA (0.9 mL)
THF (0.1 mL), H2O (0.1 mL), HA (0.9 mL)
THF (0.1 mL), H2O (0.1 mL), HA (0.9 mL)
10
11
12
13
14
15
p-NO2-C6H4 (18a)
o-Cl-C6H4 (18c)
C6H5 (18d)
14 (5 mol %)
14 (10 mol %)
14 (10 mol %)
14 (10 mol %)
14 (10 mol %)
14 (10 mol %)
rt
rt
rt
rt
rt
rt
95
88
44
59
42
35
8/2
9/1
86
96
82
91
99
97
75/25
99/1
99/1
99/1
iPr (18b)
cHex (18e)
Ph2CH (18f)
a
Yield refers to combined yield of isolated diastereomers. Conditions: catalyst (5 mol %), aldehyde (0.50 mmol), ketone (2.5 mmol) in organic
b
solvent (1 mL) or catalyst 14 (10 mol %), aldehyde (0.50 mmol), THF (0.9 mL), H2O (0.1 mL), HA (0.9 mL). Diastereoselectivity was
c
determined by HPLC and 1H NMR analysis of the isolated diastereomers. Enantiomeric excess was determined by HPLC analysis on a chiral phase
(Chiralpak AD-H and AS-H).
(s = singlet, d = doublet, t = triplet, q = quartet, dd = double-doublet,
m = multiplet, br = broad), coupling constants (in Hz), and
assignment. 13C NMR spectra were measured at 50 and 100 MHz with
complete proton decoupling. Chemical shifts were reported in ppm
from the residual solvent as an internal standard. High resolution mass
spectra (HRMS) were performed on an electrospray ionization time-
of-flight (ESI-TOF) mass spectrometer. Optical rotations were
measured on a digital polarimeter at room temperature. Reactions
were controlled using TLC on silica [alu-plates (0.2 mm)]. All
reagents and solvents were purified and dried according to common
methods. All organic solutions were dried over anhydrous sodium
sulfate. Reaction products were purified by flash chromatography using
silica gel 60 (240−400 mesh). HPLC analysis were performed on
HPLC system equipped with chiral stationary phase columns,
detection at 254 nm.
Scheme 8. Possible Structures of Transition States
contrast with the type II and type I aldolases that are limited to
the use of selected donors only. Thus, these catalysts not only
mimic but function better than aldolases.
4. EXPERIMENTAL SECTION
Synthesis and spectral data for compounds 1 and 2a−c,33,35 3,35 4,
and 559 were reported previously. Synthesis and NMR data of catalyst
2a and 3, being important for this study, are also provided below.
(1S,2S)-N,N′-Bis[(S)-prolyl]-1,2-diphenylethane-1,2-diamine
(2a).35 The reaction was performed under argon. Boc-L-proline
(2 mmol, 430.5 mg) was dissolved in freshly distilled dichloromethane
General Information. Infrared (IR) spectra were recorded on a
1
Fourier transform infrared (FT-IR) spectrometer. H NMR spectra
were measured at 200 and 400 MHz in CDCl3. Data were reported as
follows: chemical shifts in parts per million (ppm) from
tetramethylsilane as an internal standard, integration, multiplicity
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Scheme 9. (i) ESI-MS Spectra of HA and Catalyst 14 Mixture in Aqueous MeOH Solution. (ii) Measured and Calculated
Isotope Pattern for Enamine Intermediate.
(5 mL). The mixture was cooled to 0 °C, and triethylamine
(2.2 mmol, 222.6 mg, 307 μL) was added, followed by ethyl
chloroformate (2 mmol, 217.1 mg, 191 μL). After 15 min of stirring,
the precipitation of a white solid was observed and (1S,2S)-(−)-1,2-
diphenylethylenediamine (1 mmol, 212 mg) dissolved in dichloro-
methane was added. The resulting mixture was stirred at room
temperature and monitored by TLC. The reaction was complete
within 2 h. The reaction mixture was diluted with methyl tert-butyl
ether and washed with saturated solution of sodium hydrogen carbo-
nate and brine. The organic layer was dried over anhydrous mag-
nesium sulfate and concentrated. The crude product (2c) was used for
the next step without any purification. Crude (2c) was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added.
The resulting mixture was stirred at room temperature and monitored
by TLC (methanol/ethyl acetate = 1:2). After the consumption of
starting material, a 1 M solution of NaOH was added to pH 12. The
mixture was diluted with ethyl acetate, and the phases were separated.
The organic phase was washed with a small volume of water and brine.
It was dried over anhydrous sodium sulfate and concentrated. The
crude product was submitted to column chromatography on silica gel
(methanol/ethyl acetate = 1:2) to give the corresponding product with
80% yield. 1H NMR (200 MHz, CDCl3) δ 1.52−1.85 (m, 6H), 1.98−
2.16 (m, 2H), 2.27 (brs, 2H), 2.78−3.03 (m, 4H), 3.67−3.74 (dd, J =
5.2, 9 Hz, 2H), 5.12−5.24 (dd, J = 2.6, 6.4 Hz, 2H), 7.03−7.21 (m,
10H), 8.46−8.49 (brd, J 6.4 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ
(1R,2R)-N,N′-Bis[(S)-prolyl]-1,2-diphenylethane-1,-2-diamine
(3).35 The procedure was similar to the one described for 2a with
(1R,2R)-(+)-1,2-diphenylethylenediamine and Boc-L-proline. 1H
NMR (200 MHz, CDCl3) δ 1.62−1.89 (m, 6H), 2.06−2.19 (m,
2H), 2.24 (brs, 2H), 2.85−3.04 (m, 2H), 3.64 (dd, J = 8.8, 5 Hz, 2H),
5.20 (brs, 2H), 7.05−7.29 (m, 10H), 8.43 (br s, 2H); 13C NMR (50
MHz, CDCl3) δ 26.2, 30.7, 47.1, 57.9, 58.0, 60.4, 127.2, 127.4, 128.2,
138.7, 175.5; [α]21 = −71.4 (c 1.0, CH2Cl2).
D
General Method for Aldol Reactions of Cyclohexanone and
Acetone with Aldehydes (Table 2). Ketone (0.9 mL) and water
(0.1 mL) were added to a vial containing a catalytic amount of catalyst
(0.025 mmol) and zinc triflate (0.025 mmol). After vigorous stirring at
room temperature for 15 min an aldehyde (0.5 mmol) was added. The
resulting mixture was stirred at room temperature and monitored by
TLC. The reaction mixture was poured directly on the silica gel. The
aldol product (anti/syn mixture) was purified by flash column
chromatography (hexane/ethyl acetate).
Spectroscopic data of 4a−o9,19,60 are in agreement with the
published data.
(S)-2-((R)-2-(Benzyloxy)-1-hydroxyethyl)cyclohexanone
(11).40b Cyclohexanone (2.7 mL) and water (0.3 mL) were added to
a vial containing a catalytic amount of catalyst 2a (0.15 mmol, 61 mg)
and zinc triflate (0.15 mmol, 54.5 mg). After vigorous stirring at room
temperature for 15 min, aldehyde 10 (3 mmol, 450.5 mg, 0.421 mL)
was added. The resulting mixture was stirred at room temperature and
monitored by TLC (hexane/ethyl acetate = 9:1). The reaction mixture
was poured directly on the silica gel. The aldol product (anti/syn
mixture) was purified by flash column chromatography (hexanes/ethyl
26.2, 30.8, 47.4, 58.9, 60.9, 127.6, 127.7, 128.6, 139.2, 175.3; [α]21
−4.5 (c 1.0, CH2Cl2).
=
D
1
acetate = 9:1) to give desired product (66%). H NMR (300 MHz,
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CDCl3) δ 1.35−2.44 (m, 8H), 2.64−2.76 (m, 1H), 3.47−3.65 (m,
3H), 3.88−3.98 (m 1H), 4.47−4.69 (m, 2H), 7.30−7.35 (m, 5H) ppm;
13C NMR (75 MHz, CDCl3) δ 24.7, 27.7,30.3, 42.7, 52.5, 71,0, 71.2,
observed, and (1S,2S)-(−)-1,2-diphenylethylenediamine (2.0 mmol,
433 mg) dissolved in dichloromethane (1 mL) was added. The
reaction was stirred overnight at room temperature. The reaction
mixture was diluted with methyl tert-butyl ether and washed with
saturated solution of sodium hydrogen carbonate and brine. The
organic layer was dried over anhydrous magnesium sulfate, con-
centrated, and submitted to the deprotection step. The deprotection of
amino groups was performed by the hydrogenation in the presence of
palladium on charcoal. The protected bis(amide) (1 equiv, ca. 2 mmol,
2.2 g) was dissolved in methanol (40 mL). Ammonia solution in
methanol (0.5 equiv, 0.97 mmol, 16.52 mg, 139 μL, 7 M solution of
ammonia) was added, followed by 170 mg of palladium on charcoal
(moistened with water, 10% Pd basis), and the reaction was stirred
overnight under hydrogen atmosphere. The mixture was filtred
through a Celite plug and concentrated. The crude product was
submitted to column chromatography on silica gel (dichloromethane/
methanol = 95:5) to give the corresponding product with 90% yield.
1H NMR (500 MHz, CDCl3) δ 0.95 (s, 18H), 1.74 (bs, 4H), 3.41−
3.44 (m, 2H), 3.78−3.84 (m, 4H), 5.24 (dd, J = 6 Hz, 2H, 2.5 Hz),
7.06−7.12 (m, 10H), 7.30−7.39 (m, 10H), 7.54−7.57 (m, 10H),
8.30−8.32 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 19.1, 26.7, 56.7,
58.7, 65.9, 127.4, 127.4, 127.6, 127.7, 128.3, 129.6, 129.7, 132.9, 133.1,
135.4, 135.5, 138.6, 172.7; IR (KBr) 3304, 2929, 2856, 1638, 1526,
1112, 700 cm−1; HRMS (ESI) exact mass calcd for C25H62N4O4Si2
73.4, 127.6, 127.7, 128.8, 138.0, 215.0 ppm.
(1S,2S)-N,N′-Bis[(S)-valinyl]-1,2-diphenylethane-1,2-diamine
(12). The reaction was performed under argon. Boc-L-valine (2 mmol,
455 mg) was dissolved in freshly distilled dichloromethane (5 mL).
The mixture was cooled to 0 °C, and triethylamine (2.2 mmol, 222.6 mg,
307 μL) and ethyl chloroformate (2 mmol, 217.1 mg, 191 μL)
were added. After 15 min of stirring, the precipitation of a white solide
was observed, and (1S,2S)-(−)-1,2-diphenylethylenediamine (1 mmol,
212 mg) dissolved in dichloromethane (1 mL) was added. The
resulting mixture was stirred at room temperature and monitored by
TLC. The reaction was complete within 2 h. The reaction mixture was
diluted with dichloromethane and washed with saturated solution of
sodium hydrogen carbonate and brine. The organic phase was dried
over anhydrous magnesium sulfate and concentrated. The crude pro-
duct was used for the next step without purification; it was dissolved in
dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added.
The resulting mixture was stirred at room temperature and monitored
by TLC (methanol/ethyl acetate = 1:4). After reaction complition a
1 M solution of NaOH was added to pH 12. The mixture was diluted
with ethyl acetate, and the aqueous phase was separated. The organic
phase was washed with a small volume of water and brine. The organic
layer was dried over anhydrous sodium sulfate and concentrated. The
crude product was submitted to column chromatography on silica gel
(methanol/ethyl acetate = 1:9) to give the corresponding product with
78% yield. 1H NMR (400 MHz, CD3OD) δ 0.70 (d, J = 6.7 Hz, 6H),
0.86 (d, J = 6.8 Hz, 6H), 1.85−1.93 (m, 2H), 3.10 (d, J = 4.9 Hz, 2H),
5.38 (s, 2H), 7.18−7.23 (m, 10H); 13C NMR (50 MHz, CDCl3) δ
16.3, 20.01, 31.2, 59.1, 60.6, 127.7, 127.8, 128.6, 139.2, 175.0; IR
(KBr) 3318, 2961, 1635, 1526, 700 cm−1; HRMS (ESI) exact mass
calcd for C24H34N4O2 m/z 411.2755 ([M + H]+), found m/z 411.2752
m/z 863.4382 ([M + H]+), found m/z 863.4397 ([M + H]+); [α]21
+21.3, (c 0.91, MeOH).
=
D
General Method for Aldol Reactions of Hydroxyacetone
with Aldehydes. Hydroxyacetone (2.5 mmol) was added to a vial
containing a catalytic amount of catalyst (0.025 mmol) dissolved in
tetrahydrofuran (1 mL), followed by addition of an aldehyde
(0.5 mmol). The resulting mixture was stirred at room temperature
and monitored by TLC. The reaction mixture was diluted with ethyl
acetate and washed twice with water and brine. The organic layer was
dried over anhydrous sodium sulfate and concentrated. The pure aldol
product (syn/anti mixture) was obtained by flash chromatography on a
silica gel column (hexane/ethyl acetate).
([M + H]+); [α]21 = −25.9, (c 0.99, CH2Cl2).
D
(S)-2-(Hydroxymethyl)cyclohexanone (13).44b Prolinamide
2a (30.5 mg, 0.075 mmol, 10 mol %) and Zn(OTf)2 (27.3 mg,
0.075 mmol, 10 mol %) were stirred for 5 min in EtOH/H2O (9/1,
0.5 mL). To the resulting solution were added cyclohexanone
(1.5 mmol, or the same amount of another ketone) and formaldehyde
(0.75 mmol, 37% in water) at room temperature, and the mixture was
stirred for 20 h. The mixture was extracted with CH2Cl2, and the
combined organic layer was dried over anhydrous MgSO4. The
solvents were evaporated, and the residue was purified by flash
chromatography (hexane/EtOAc, = 1:1) to give desired product
(55%). The reaction can be performed in 0.5 mL water instead of
EtOH/water mixture, at rt for 10 h in ultrasound bath leading to aldol
Spectroscopic data of 18a,c,d52a,e and 18b,e,f55f are in agreement
with the published data.
ASSOCIATED CONTENT
■
S
* Supporting Information
Investigation of absolute configuration of compound 6a; HPLC
1
data of aldols 6, 11, 13, 18; H and 13C NMR for catalysts 2a,
3, 12, and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
13 with 75% yield. H NMR (300 MHz, CDCl3) δ 1.50−2.10 (m,
6H), 2.22−2.52 (m, 3H), 2.56 (s, 1H), 3.50−3.60 (m, 1H), 3.62−3.72
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 25.4, 28.2, 30.7, 42.9, 52.9,
63.5, 215.4.
AUTHOR INFORMATION
■
Corresponding Author
(1S,2S)-N,N′-Bis[(S)-tert-butyldiphenylsiloxyserinyl]-1,2-di-
phenylethane-1,2-diamine (14). N,N-Dimethylformamide (1 mL)
was added to a vial containing Cbz-L-serine (4.2 mmol, 1000 mg) and
imidazole (10.8 mmol, 739.9 mg). The mixture was cooled to 0 °C,
and tert-butyl(chloro)diphenylsilane (4.6 mmol, 1263.8 mg, 1196 μL)
was added slowly followed by a few crystals of 4-(dimethylamino)-
pyridine. The reaction was stirred overnight at room temperature. The
reaction mixture was diluted with methyl tert-butyl ether, and the
organic phase was separated and washed with water. The aqueous
phase was extracted three times with methyl tert-butyl ether. The
combined organic phase was washed with a small volume of water and
brine and then dried over anhydrous sodium sulfate and concentrated.
The desired siloxyserine was purified by column chromatography
(hexane/ethyl acetate = 85/15 + 1% HCOOH) and submitted to the
next step (yield 97%). Reaction with amine was performed under
argon. Previously obtained protected serine (4.1 mmol, 1953 mg) was
dissolved in freshly distilled dichloromethane (5 mL). The mixture was
cooled to 0 °C, and triethylamine (4.5 mmol, 454.6 mg, 626 μL) was
added, followed by ethyl chloroformate (4.1 mmol, 443.5 mg,
390.7 μL). After 15 min of stirring, the precipitation of a white solid was
*E-mail: jacek.mlynarski@gmail.com.
ACKNOWLEDGMENTS
■
We thank Ms. Maria Rogozin
́
ska (Institute of Organic
Chemistry Polish Academy of Sciences) for providing samples
of compounds 15, 16, and 17. Financial support from the
Ministry of Science and Higher Education (former Polish State
Committee for Scientific Research KBN Grants N N204 093
135 and N N204 124 037) is gratefully acknowledged. Project
operated also within the Foundation for Polish Science TEAM
Programme cofinanced by the EU European Regional
Development Fund.
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