Simple and practical direct asymmetric aldol reaction of hydroxyacetone catalyzed by 9-amino Cinchona alkaloid tartrates

Article abstract of DOI:10.1039/c1gc15064b

A novel organocatalytic procedure for the direct aldol reaction of unprotected acetol and activated aromatic aldehydes catalyzed by 9-amino-9-epi-Cinchona ditartrates is presented. The protocol presented avoids the use of problematic solvents and toxic re

Full text of DOI:10.1039/c1gc15064b

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PAPER
Simple and practical direct asymmetric aldol reaction of hydroxyacetone
catalyzed by 9-amino Cinchona alkaloid tartrates†‡
Paweł Czarnecki, Agnieszka Plutecka, Jacek Gawron´ski and Karol Kacprzak*
Received 17th January 2011, Accepted 25th February 2011
DOI: 10.1039/c1gc15064b
A novel organocatalytic procedure for the direct aldol reaction of unprotected acetol and activated
aromatic aldehydes catalyzed by 9-amino-9-epi-Cinchona ditartrates is presented. The protocol
presented avoids the use of problematic solvents and toxic reagents as well as chromatographic
purification of the products – instead a simple extraction has been applied for the isolation of pure
aldols from the reaction mixture. This catalytic system provides exclusively linear aldols with
quantitative yields and good syn-diastereoselectivity and enantioselectvitiy up to 90% ee. Further
upgrading of the enantiomeric excess of syn-aldols up to 99% ee is easily accomplished by a single
and reliable crystallization. The use of cinchonine or quinine-derived catalysts gives access to both
enantiomers of syn-aldols for which the absolute configuration has been determined by X-ray
diffraction. The operationally convenient and scalable organocatalytic procedure using cheap and
renewable chemicals – both acetol and the catalysts, offers a sustainable and green way for the
synthesis of a number of a-keto-syn-diols.
to the presence of the primary amino group of Lys in the active
Introduction
cavity of the enzyme.5 Class II aldolases are metaloenzymes in
Catalytic enantioselective synthesis mediated by metal com-
which the zinc-histidine complex activates the donor molecule
plexes, organocatalysts or enzymes contributed to a revolution-
by coordination.6 For a long time the high efficiency of
ary progress in synthetic methodology, providing access to a
aldolases, regarding the selectivity and activity as well as the
broad range of enantiopure products from almost all types of
reactions.1
operating parameters (room temperature, water as a medium)
has not been reached by their synthetic low-molecular weight
The aldol addition leading to non-racemic b-hydroxyketones,
b-hydroxyaldehydes, keto-1,2-diols and related products de-
serves special attention as one of the most important and
straightforward methods of carbon–carbon bond formation in
a stereoselective fashion.2 The aldol addition occurring in water
and at ambient temperature apparently has been selected by
Nature for the extremely efficient synthesis of a wide array
of sugars, ketoacids and other derivatives from very simple
achiral building blocks like hydroxyacetone, dihydroxyacetone3
and other simple carbonyl compounds.4 Aldol additions in living
organisms are catalyzed by aldolases which can be divided into
two classes: aldolase I and II, depending on the mechanism of
activation of the reactants and the reaction pathway. Class I
aldolases work according to an imine-enamine mechanism, due
mimics (“microaldolases”) designed in the laboratory.2 Another
problem associated with early attempts to develop competitive
aldol promoting systems was the necessity of preactivation of
at least one of the reacting partners by formation of an enolate
from the carbonyl donor, thus lowering the overall economy of
such processes.2e–d The problems of selectivity and activity have
partially been solved upon the recent introduction of catalytic
systems mimicking aldolases I or II workingbydualactivation of
substrates (bifunctional catalysis).7 The most exciting examples
of such catalytic systems were demonstrated by Shibasaki,8
Trost,2a,9 List,10,24 Barbas10,11 and others.12,13
Unfortunately, in the process of developing efficient and direct
stereoselective aldol addition methodologies the practical and
environmental aspects were largely overlooked. For this reason
many catalytic aldol addition protocols were demonstrated
only in mmol scale and appear impractical for large scale
synthesis. For example, in order to obtain a high yield and a
high level of asymmetric induction, a substantial amount of
catalyst (often 20–30 mol%) is required. With the exception of
natural proline and Cinchona alkaloids, most of the catalysts are
non-commercial products of multi-step syntheses. In addition,
many protocols use large amounts of co-catalysts or additives,
Department of Chemistry, Adam Mickiewicz University, ul.
Grunwaldzka 6, 60–780, Poznan´, Poland
† Electronic supplementary information (ESI) available: Experimental
details, procedures and product characterization. CCDC reference
number 783759. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1gc15064b
‡ Dedicated to Professor Janusz Jurczak on the occasion of his 70th
birthday.
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Scheme 1 Different activation pathways of hydroxyacetone (acetol) as a donor in the aldol addition.
such as toxic and corrosive trifluoroacetic acid,18,23 1H-1,2,3- has been reported by Wu.16 Non-peptide catalysts, such as
triazole or other rare heterocycles,11a 2,4-dinitrophenol15 or
metal salts.2a,10,18 This increases the cost of the reaction and
causes environmental problems associated with product sepa-
ration and waste disposal on a large scale. Another drawback
of many stereoselective aldol reactions is the use of anhydrous
or environmentally problematic solvents, such as chlorinated
hydrocarbons, DMSO, DMF or N-methylpyrolidone (NMP)26
as well as column chromatography for products purification.
We took these limitations into consideration when we started
the project on the green organocatalytic aldol reaction27 of
acetol (hydroxyacetone). Acetol is an important substrate for the
aldol reaction which, depending on the catalytic system or the
conditions, may generate two diastereomeric types of branched
ketodiols or one type of a linear ketodiol. Thus potentially up
to three pairs of distinct enantiomeric aldols can be obtained in
one step (Scheme 1).
Moreover hydroxyacetone is a cheap product of partial
hydrogenolysis of glycerol and is currently available in large
quantities from the oleochemical/biofuel industry.14 For this
reason its conversion into high value chiral products offers
a source of intermediates for asymmetric synthesis. Acetol
also meets the green chemistry requirements – it is non-toxic,
biodegradable and as a liquid it may serve simultaneously as a
polar solvent in the reaction.
Unprotected hydroxyacetone has already been explored as
a donor in the stereoselective aldol reaction although due to
the need of simultaneous control of chemo-, enantio- and
diastereoselectivity its use created problems and therefore it
was less explored than other simple carbonyl donors.2a Most
of the catalysts used for the aldol reaction of acetol have
so far been based on the structures of aminoacids (proline)
and their derivatives or on peptides. These catalysts often
show insufficient control of reaction selectivity.2 However List
and Barbas reported examples of more efficient highly anti-
selective reactions of hydroxyacetone with either aromatic or
aliphatic aldehydes, catalyzed either by proline or by 5,5-
dimethyl thiazolidinium-4-carboxylate (DMTC).10,11f Another
exampleof an anti-selective reaction has been published byWu et
al. and it involves the use of a tetrapeptide – (S)-BINOL complex
as a catalytic system.15 Efficient syn-selective aldol reactions of
acetol and aliphatic aldehydes catalyzed by modified dipeptides
a monoprotected trans-(1S,2S)-diaminocyclohexane derivative
designed by Singh,17 primary-tertiary amine salts derived form
aminoacids by Cheng18 or pyrrolidinecarboxylic acid by Wu19
showed high enantio- and syn-diastereoselectivity in the aldol
or Mannich reaction of acetol and activated aromatic aldehydes.
Linear products of the aldol reaction of acetol due to activation
of the methyl group have been selectively obtained by using a
tetrapeptide (Pro-Phe-Phe-Phe-OMe) or prolinamide catalysts,
as reported by Gong et al.20
Interestingly, Cinchona alkaloids which belong to the group
of “privileged catalysts” and promote a wide array of reactions,
were not studied intensively in stereoselective aldol additions.21
Only recently Młynarski et al. reported that quinine or quinidine
catalyze the aldol reaction of acetol and aromatic aldehydes,
albeit with modest yield and an asymmetric induction level.22
Better results were obtained by Marhwald who used cincho-
nine as a catalyst for the stereoselective aldol reaction of
protected (R)-glyceraldehyde with dihydroxyacetone leading to
D-fructopyranose with >98% ee.23
Despite many successful applications in other stereoselective
syntheses, 9-amino derivatives of Cinchona alkaloids which
form a primary-tertiary amine catalytic system, have not been
systematically tested in the area of aldol addition. Recently Liu et
al. have shown that in situ generated 9-amino-9-epicinchoninium
trifluoroacetate catalyzes anti-selective addition of aromatic
aldehydes to cyclohexanone with high yield and enantiomeric
excess (up to 99%).24 Analogous primary amines derived from
quinine and quinidine have been used by List in an intramolec-
ular aldolization of substituted 1,5-diketone in the asymmetric
synthesis of both enantiomers of the fragrant celery ketone.25
Recently, Xiao has shown that the cinchonine-prolinamide
hybrid is able to promote an aldol reaction of activated aldehydes
with acetone with high enantioselectivity up to 98% ee.26
In the present work we describe the use of 9-amino-9-epi-
Cinchona alkaloid ditartrates as new organocatalysts, designed
for the direct aldol reaction of acetol and aromatic aldehydes
without the use of solvent. The focus of this methodology is
on providing an efficient, scalable, operationally simple and
environmentally friendly aldol protocol, utilizing the renewable
feedstock – acetol – and Cinchona alkaloid derivatives as
organocatalysts.
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aldols 6a, slightly favoring syn-6a (dr syn/anti 1.4 : 1). The use
of the same catalyst in a 1 : 1 water–methanol mixture led to a
slightly higher yield (33%) and a raise in enantioselectivity of
syn-6a, up to 66% (dr syn/anti 1.8 : 1) (Table 1, runs 1, 2). These
disappointing results shifted our interest to the organic salts of
Cinchona amines. We tested a large number of combinations of
9-amino-9-epiquinine or 9-amino-9-epicinchonine and organic
acids as additives. The respective salts having different ratios
of amine and acid have been generated in situ by addition of
an acid to the amine followed by addition of the substrates.
The results are presented in Table 1. We have found that the
most promising results were obtained for the combination of
10 mol% of Cinchona amines and trifluoroacetic acid in a ratio
1 : 2, giving quantitative conversion of p-nitrobenzaldehyde after
24 h at room temperature and providing the corresponding
aldol syn-6a having 78% ee (dr syn/anti 2.5 : 1). Interestingly,
nearly identical results were obtained when the same amine
was combined with natural (R,R)-tartaric acid (TA) as an
additive.29 For example, the addition of 10 mol% of 9-amino-
9-epicinchonine ditartrate as a catalyst gave quantitative yield
of the aldols after 48 h at room temperature and syn-6a was
formed with the same (78% ee) enantiomeric excess and only
slightly lower dr 2.4 : 1 (syn/anti). It is worth noting that this
catalyst also gave the highest induction level of diastereoisomeric
anti-6a (51% ee). As expected, the use of pseudoenantiomeric
9-amino-9-epiquinine (R,R)-ditartrate salt gave predominantly
the opposite enantiomer of syn-6a having 70% ee and dr 1.9 : 1
(syn/anti) with quantitative yield. In contrast to trifluoroacetic
acid which is volatile, toxic, highly corrosive and expensive,
natural tartaric acid is cheap, available from renewable sources
and non-toxic. For this reason we have chosen natural tartaric
acid as an acidic additive for further work. To make the protocol
more practical, solid ditartrates of 9-amino Cinchona alkaloids
have been obtained by dissolving the respective amines and two
equivalents of tartaric acid in methanol and evaporation of the
solvent. These solid salts are stable and easy to handle and
they have been used in further experiments with exactly the
same results as obtained with the salts generated in situ.30 Other
acidic additives, such as benzoic, succinic and (S)-malic acids
have also been tested and although similarly high conversion of
the aldehyde (about 100%) has been observed, the asymmetric
Results and discussion
For initial screening experiments a model system comprising
of technical hydroxyacetone (1 mL) and p-nitrobenzaldehyde
(0.5 mmol) leading to syn- and anti-aldols 6a has been selected
(Scheme 2). 9-Amino-9-epi-Cinchona derivatives which have
been used as organocatalysts 1–4 (Fig. 1) were obtained in the
form of trihydrochlorides in the Mitsunobu/Staudinger one-
pot sequence of reactions from the corresponding Cinchona
alkaloids.28
Scheme 2 Model aldol reaction of acetol and p-nitrobenzaldehyde.
Fig. 1 Structures of 9-amino-9-epi-Cinchona alkaloids used as catalysts
1–4.
A simple salt such as 9-amino-9-epiquininium trihydrochlo-
ride 1a ¥ 3HCl (10% mol) used in a model reaction with acetol
serving as the solvent produced only a low level of conversion
(29%) of the aldehyde and gave a nearly racemic mixture of
Table 1 Screening the acidic additives in the model reaction
Product
Run
Cat.a
Acid (eq.)b
Solvent
Time (h)
Yield 6a (%)
ee (%) anti-6a
ee (%) syn-6a
dr (anti/syn)
1
2
3
4
5
6
7
8
1a
1a
4a
4a
4a
4a
4a
1a
1a
1a
1a
1a
HCl (3)
HCl (3)
TFA (2)
(R,R)-TA (1)
(R,R)-TA (2)
(R,R)-TA (5)
(R,R)-TA (10)
(R,R)-TA (2)
BA (2)
HAC
MeOH/H2O (1 : 1)
HCA
HAC
HAC
HAC
HAC
HCA
HCA
48
48
24
48
48
48
48
48
48
48
48
48
29
33
100
100
100
93
5
6
6
1 : 1.4
1 : 1.8
1 : 2.5
1 : 2.1
1 : 2.4
1 : 2.0
1 : 1.8
1 : 1.9
1 : 2.1
1 : 2.3
1 : 2.1
1 : 2.6
66
78
72
78
76
75
70
52
71
65
73
43
51
51
44
36
36
17
34
26
28
94
100
100
100
100
93
9
10
11
12
(S)-MA (2)
SA (2)
DNP (2)
HCA
HCA
HCA
a 0.1 eq. of catalysts was used; cat 1a and 4a give products of opposite configuration. b Equivalents relative to catalyst used; abbreviations: HCA =
hydroxyacetone, (R,R)-TA = (R,R)-tartaric acid, BA = benzoic acid, (S)-MA = (S)-malic acid, SA = succinic acid, DNP = 2,4-dinitrophenol.
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Table 2 Effect of water addition in the model reaction catalyzed by 10 mol% 4a ¥ 2 (R,R)-TAa
Product
Run
Solvent
Yield 6a (%)
ee (%) anti-6a
ee (%) syn-6a
dr (anti/syn)
1b
2c
3c
4c
5d
HAC
100
100
100
94
51
51
51
38
52
78
76
78
67
83
1 : 2.4
1 : 2.2
1 : 2.3
1 : 1.8
1 : 3.1
HAC + 2% H2O
HAC + 10% H2O
HAC + 50% H2O
HAC dried
100
a Reaction time 48 h at rt. b Technical acetol containing 1.8% water. c Technical acetol with water additive specified. d Technical acetol dried with
anhydrous Na2SO4, water content ca. 0.5%.
induction level was lower, compared to TFA or TA salts. The
use of 2,4-dinitrophenol as an acid led to aldols with slightly
better diastereoselectivity (dr 2.6 : 1 syn/anti) but with lower
conversion (93%). We also checked the effect of the molar ratio of
the amine and tartaric acid on the yield and the stereoselectivity
of the model aldol reaction (Table 1, runs 4–7). Best results were
observed with two equivalents of (R,R)-TA per one equivalent
of the amine, although the monotartrate salt gave a very similar
result with only a slightly lower asymmetric induction level (run
4). The use of a large excess of (R,R)-TA (5 or 10 eq.) did not
result in a further increase of stereoselectivity.
Next step in the optimization of experimental procedure
involved the investigation of the role of water as an additive
or a co-solvent. The water content in technical acetol was found
by the Karl-Fisher titration at the level 1.8%. In these set of
experiments we added increasing amounts of water, up to 50%
v/v. As can be seen in Table 2 water content in the range from
1.8% (technical acetol) up to 10% v/v had a moderate effect
on the yield and the level of asymmetric induction in the model
reaction. Continuous increase of the water content up to 50%
v/v resulted in lowering both the conversion and the level of
asymmetric induction. Thus, low water concentration seems to
be optimal in order to obtain the highest level of asymmetric
induction and the yield. To check this hypothesis we dried
chemically acetol (by the use of anhydrous Na2SO4 for 12 h,
<0.5% H2O) and under similar reaction conditions we observed
only a slight increase of enantioselectivity of the reaction,
providing syn-6a with 83% ee and reaction diastereoselectivity
of 3.1 : 1 (syn/anti).
the data, none of the solvents screened offered a better reaction
selectivity as compared to acetol itself. The only comparable
results regarding asymmetric induction level were obtained for
methanol but this solvent significantly compromised the overall
yield. Less polar solvents, such as dichloromethane or THF,
showed very low reagent conversion and lower selectivity.
The subsequent optimization of our protocol has been carried
out by screening the catalytic performance of all four major
members of Cinchona amines (1–4) as well as by subtle tuning of
their structures involving the replacement of the pendant vinyl
group by the ethynyl (catalyst 1b) or the ethyl group (catalyst
4b). The results of these experiments are presented in Table
4. As expected, two pseudoenantiomeric pairs of amines (1, 2
vs. 3, 4) gave the corresponding main diastereoisomers of the
aldols having opposite absolute configuration. We have also
found that the best catalysts are those lacking the methoxy
group in the quinoline ring (derived from cinchonine or cin-
chonidine). For example, quinidine derived amine 3 and its
demetoxylated analogue 4a (cinchonine) led to syn-6a with
Table 4 Catalysts screening in model reactiona
Product
Run Cat.b Yield 6a (%) ee (%) anti-6a ee (%) syn-6a dr (anti/syn)
1
2
3
4
5
6
1a
1b
2
100
100
100
92
100
100
36
30
40
23
51
53
70
72
76
66
78
75
1 : 1.9
1 : 2.4
1 : 2.0
1 : 2.2
1.2.4
3
4a
4b
Although acetol served both as a donor and as a solvent in the
model reaction with good efficiency, we also tested other solvents
to possibly identify a better reaction medium. The results of
these experiments are shown in Table 3. As it can be seen from
1 : 2.2
a Reaction in HAC, 48 h at rt. b 0.1 eq. of catalysts was used in the form
of (R,R)-ditartrate salt.
Table 3 Solvent effect on model reaction catalyzed by 10 mol% 4a ¥ 2 (R,R)-TAa
Product
Run
Solvent
Yield 6a (%)
ee (%) anti-6a
ee (%) syn-6a
dr (anti/syn)
1
2
3
4
5
6
HAC
MeOH
MeOH–H2O (1 : 1)
H2O–MeOH (95 : 5)
THF
100
75
57
43
31
21
51
22
32
16
3
78
75
68
61
57
56
1 : 2.4
1 : 2.8
1 : 1.9
1 : 1.6
1 : 2.1
1 : 2.0
DCM
19
a Reaction time 48 h at rt.
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Table 5 Temperature effect on the model reaction catalyzed by 10 mol% 4a ¥ 2 (R,R)-TA
Product
Run
Temp. (◦C)
Solvent
Time (d)
Yield 6a (%)
ee (%) anti-6a
ee (%) syn-6a
dr (anti/syn)
1
2
3
25
0
-20
HAC
HAC
HAC/MeOH (2 : 1)
2
5
7
100
100
74
51
61
61
78
82
90
1 : 2.4
1 : 2.1
1 : 2.5
66 and 78% ee, respectively. Interestingly, the use of a more
basic 10,11-dehydroquinine amine 1b masks the unfavorable
effect of the methoxy substituent leading eventually to a higher
asymmetric induction level in the formation of syn-6a (run 1 vs.
2, Table 4). The ethyl analogue 4b of cinchonine derived amine
showed comparable catalytic efficiency in the model reaction.
Attempts to reduce the catalyst load from 10 to 5 and to 2
mol% showed that at lower catalyst concentration the raction
rate was considerably lower giving 6a with only 50 and 30%
yield, respectively. However the enantioselectivity remained at a
comparable level 66–71% ee.31
Having at hand the optimized protocol giving quantitative
yield of the aldol products 6a we attempted to upgrade the
asymmetric induction level by lowering the reaction temper-
ature. Two reactions catalyzed by 10 mol% of 4a ditartrate
salt have been conducted at 0 and -20 ◦C. In the latter case
30% (v/v) of methanol was added as antifreezing co-solvent. In
both cases, enhancement of the enantioselectivity was observed
with respect to either syn-6a or anti-6a aldols, which was
more substantial in the reaction carried out at -20 ◦C (Table
5). In this case syn-6a and anti-6a have been obtained with
90% and 61% ee, respectively. Unfortunately, the rate of the
reaction at -20 ◦C was significantly lower, resulting in a 74%
yield of the isolated product after seven days of continuous
process.
Finally, we investigated the scope of the aldol reaction
catalyzed by Cinchona amine ditartrate with respect to the
aldehyde acceptors. As it is evidenced in Table 6 the reaction
proceeded well with activated aromatic aldehydes bearing an
electron-withdrawing substituent such as the nitro group or the
halogen atom (5b–e). The halogen substituted aldehydes are less
active and require significantly longer reaction times. The aldol
addition is not affected by any substitution pattern as either
ortho-, meta- or para-nitroaldehydes underwent the reaction
with comparable efficiency. However, a notable exception was
observed for 2-nitrobenzaldehyde which gave the corresponding
aldol 6b with substantially higher diastereoselectivity 8.7 : 1
(syn/anti). This behavior can be explained on the basis of
an additional stabilization of the transition state by hydrogen
bond formation between the 2-nitro group of the aldehyde and
the hydroxy groups of acetol, leading to the syn-product (vide
infra). Unfortunately, benzaldehyde reacted sluggishly giving
only traces of the corresponding aldols 6f.
Having at hand the catalysts providing aldol product with
nearly quantitative yield, reasonable enantioselectivity and
rather poor diastereselectivity we tried to develop a proto-
col allowing easy isolation and to upgrade the enantiomeric
excess of the desired syn-aldols in a simple (preferably non-
chromatographic) way. The first goal has been easily achieved
by simple extraction of the reaction mixture with ethyl acetate–
water which separates the aldols from the excess of acetol and the
catalyst. We found that triple extraction of the reaction mixture
led to the quantitative separation of aldol products 6a–e, which
were obtained as a crystalline mass after evaporation of the
solvent. They showed usually >95% purity (TLC, NMR). The
enantiomeric excess upgrade of the predominant syn-6a aldol
as well as its separation from the anti-diastereomer has been
successfully completed by crystallization. We were pleased to
find that single crystallization of crude syn/anti-aldols 6a from
the mixture of ethyl acetate–hexane gave practically enantiopure
syn-6a with 99% ee, which contained only a very minor amount
of one of anti-6a enantiomer (dr ~50 : 1 syn/anti, Fig. 2).
Similarly, opposite enantiomer ent,syn-6a could also be obtained
by crystallization of the crude products of the reaction catalyzed
by quinine derived catalyst (ent,syn-6a 99% ee, 40 : 1 dr). This
methodology has also been tested on a larger scale with the use
of 1–5 g of p-nitrobenzaldehyde giving a similar level of the ee
and dr upgrade and with a typical isolated yield of 35–55%.
Similar favorable results have been obtained for syn-aldols 6b
and 6c which had 99.5% and 97% ee, respectively, after single
crystallization of the products from a mixture EtOAc–hexane
with the yield 40–50%.
Table 6 Other activated aldehydes as substratesa
Run
Aldehyde
Time (d)
Yield (%)
ee (%) anti
ee (%) syn
dr (anti/syn)
1
2
3
4
5
2-NO2C6H4CHO (5b)
3-NO2C6H4CHO (5c)
4-FC6H4CHO (5d)
4-BrC6H4CHO (5e)
PhCHO (5f)
2
2
2
7
7
100
97
89
87
Trace
11
54
39
33
nd
87
73
72
82
nd
1 : 8.7
1 : 2.3
1 : 1.9
1 : 1
nd
a Reaction catalyzed by 10 mol% 4a ¥ 2 (R,R)-TA, at rt; nd = not determined.
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Fig. 2 HPLC data for crude aldols-6a obtained by extraction of the reaction mixture (upper panel, left - catalyst 4a, right - catalyst 1a) and syn-6a
product obtained after single crystallization from ethyl acetate–hexane.
Proposed model for the stereoselectivity of the reaction
In a number of published papers it is suggested that primary
amine organocatalysts work by an iminium-enamine activation
of the donor with subsequent attack of an electrophile. In
the reaction of acetol (dihydroxyacetone) syn- selectivity is
usually attributed to the additional stabilization of Z-enamine
in the transition state by an intramolecular N–H ◊ ◊ ◊ O hydrogen
bond.11a The proposed mechanism and the tentative transition
state model based on the molecular modeling data are shown
in Fig. 3. It is assumed that the primary amino group of the
Cinchona amine activates the acetol by the formation of Z-
enamine which has one face hindered by a bulky quinoline
ring. On the other hand, the aldehyde group is activated by a
hydrogen bond formation with the protonated nitrogen atom of
the quinuclidine. The mutual orientation of these two partners
force the syn-addition direction. Nevertheless, flexibility of the
system is responsible for the observed non-perfect enantio- and
diastereoselectivity of the reaction.
Absolute configuration of the aldols
In order to confirm the relative32 and to determine the absolute
configuration of the crystalline syn-6a product, X-ray diffraction
method has been applied. Thus, the absolute structure of the
crystal of syn-6a was investigated on the basis of the anomalous
signal originating mostly from the O atoms at the Cu-Ka
wavelength. For the examined enantiomerically pure crystal, the
refined value of Flack x was sufficiently small (0.09) to indicate
that the assumed absolute structure was correct. However, a
slightly greater standard uncertainty (0.16) than the upper limit
(0.10) for the enantiopure compounds needed to be confronted
by an independent method.33 Therefore, apart from the conven-
tional Flack parameter, the absolute structure of the crystal was
Fig. 3 Proposed stereoselectivity in the aldol reaction.
further investigated by the Hooft method34 implemented within
PLATON.35 From the analysis of 5964 Bijvoet pairs, the Hooft y
parameter 0.059(23) was found with the probability p2 = 1.000,
showing that the correct enantiomer has been chosen. Hence,
based on the Hooft parameter the absolute configuration of
syn-6a obtained with the use of cinchonine derived catalysts 4a
could be unambiguously determined as 3S,4R (Fig. 4).
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the products were separated by flash chromatography using
a mixture hexane–EtOAc (10 : 1, aldehyde removal) and then
hexane–EtOAc (1 : 1, products). Yields 6a–f see Table 5.
Large scale procedure (syn-6a)
In a 150 mL round-bottom flask equipped with a stirring bar
9-amino-9-(deoxy)epiquinine ditartrate 1a (2.0 g, 10 mol%)
was placed followed by 4-nitrobenzaldehyde (5a, 5 g, 1 eq.).
The solids were then mixed with acetol (35 mL) resulting in
the formation of a homogenous solution within approximately
30 min. The reaction mixture was stirred for 48 h at room
temperature after which time quantitative consumption of
the aldehyde was observed (TLC). The reaction mixture was
transferred to a large separatory funnel, diluted with water (500
mL) and extracted with EtOAc (3 ¥ 50 mL). Combined organic
phases were separated and the aqueous phase was additionally
extracted twice with EtOAc (2 ¥ 50 mL). The organic phases
were combined, dried over anhydrous MgSO4 and filtered.
After removal of the solvent under reduced pressure, the crude
product was obtained as yellowish crystals. Yield 7.47 g, 100%.
Crystallization of the crude product from EtOAc–hexane (see
supporting material†) afforded 2.51 g (3R,4S)-syn-6a (35%), ee
99%, dr 1 : 50.
Fig. 4 ORTEP diagram of the molecular structure of syn-(3S,4R)-
3,4-dihydroxy-4-(4-nitrophenyl)butan-2-one (syn-6a) showing the atom-
numbering scheme. Displacement ellipsoids for non-H atoms are drawn
at the 40% probability level.
Conclusion
The transformation of inexpensive hydroxyacetone derived from
glycerin (available currently in large quantities from the biodiesel
industry) into more complex chiral chemicals constitutes a
timely and attractive area of current research. Such methodolo-
gies, when properly focused on economical and environmental
issues, may result in the development of new sustainable organic
technologies. Presented here is our attempt to make a more
green, practical and scalable direct aldol reaction of acetol
and activated aromatic aldehydes catalyzed by 9-amino-9-epi-
Cinchona ditartrates as novel organocatalysts. This organocat-
alytic system combined with a single crystallization step provides
exclusively branched enantiopure (>98% ee) aldols 6a–c with
good yield. Additional benefits of the presented protocol include
no need for the use of chromatographic purification of the
product, instead simple extraction has been applied for the
isolation of pure aldols from the reaction mixture. We believe
that this organocatalytic procedure which uses inexpensive and
renewable chemicals, both the acetol and the catalysts, and
meets the modern criteria of sustainable chemical processes and
provides a competitive way to syn-aldols.
Similarly, the use catalyst 4a afforded the aldols in 100%
yield; after crystallization from EtOAc–hexane ent,syn-6a was
obtained with the yield 40–55%, ee 99%, dr 1 : 42.
Acknowledgements
Research support from Ministry of Science and Higher Educa-
tion (Grant No. N N204 178340) is gratefully acknowledged.
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