Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids

Article abstract of DOI:10.1039/c3ra46800c

N-Tosyl-(S_a)-binam-l-prolinamide is an efficient catalyst for the aqueous aldol reaction, between glyoxylic acid, as monohydrate or aqueous solution, and ketones. This reaction led to the formation of chiral α-hydroxy-γ-keto carboxylic acids in

Full text of DOI:10.1039/c3ra46800c

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Aqueous organocatalyzed aldol reaction of
glyoxylic acid for the enantioselective synthesis of
Cite this: RSC Adv., 2014, 4, 9963
a-hydroxy-g-keto acids†
Received 18th November 2013
Accepted 18th December 2013
*
*
Fernando J. N. Moles, Gabriela Guillena and Carmen Najera
´
DOI: 10.1039/c3ra46800c
www.rsc.org/advances
N-Tosyl-(Sa)-binam-L-prolinamide is an efficient catalyst for the powerful tool for the enantioselective synthesis of valuable
aqueous aldol reaction, between glyoxylic acid, as monohydrate or chiral compounds,5 with the growth of this research area being
aqueous solution, and ketones. This reaction led to the formation of closely related to the development of the direct aldol reaction
chiral a-hydroxy-g-keto carboxylic acids in high levels of diastereo- using simple chiral organic molecules.6 Although the use of
and enantioselectivities achieving mainly anti aldol products.
some substrates in this type of transformation remain a chal-
lenge,7 the use of the enamine catalyzed processes has allowed
the synthesis of highly functionalized carbonyl compounds that
are useful building blocks for the synthesis of natural products.8
However, these amine type catalysts typically require the use of
an excess of reacting ketone or polar organic solvent as reaction
media, with several derivatives leading to good results using
water as the solvent.9 Some of these privileged organocatalysts
are prolinamides derived from 1,10-binaphthyl-2,20-diamine
(binam) 110 and 211 (Fig. 1), which led to excellent results in the
inter- and intramolecular aldol reactions under several reaction
Solvents play a major role, making up generally the major
source of the waste mass in any chemical process. Actually, the
use of solvent accounts for more than 80% of the mass of any
pharmaceutical batch processes, consuming about 60% of the
overall energy used and accounting for 50% of the post treat-
ment green house gas emissions.1 Therefore, the appropriate
solvent selection is a denitive factor in order to increase the
greenness of a given process,2 with the best option being the use
of one of the reactants as the solvent (neat conditions) or the
total absence of them (solvent-free conditions). However, this
becomes difficult when labile reactants are used. This is the
case for glyoxylic acid and glyoxylates, which are prone to suffer
a facile hydration and polymerization processes. In fact, glyox-
ylic acid is commercially available as a monohydrate form or as
a 50% aqueous solution due to its intrinsic instability. Although
its aldol reaction with a carbonylic compound can lead to a
direct entry to secondary a-hydroxycarboxylic acids, which are
important intermediates for the synthesis of relevant and
bioactive molecules,3 its use as an electrophile in this reaction
has been scarcely reported. Only a few reports dealing with the
use of glyoxylic acid monohydrate as an electrophile in a direct
aldol reaction with ketones mediated by InCl3 are found to
afford racemic adducts.4
conditions,
including
aqueous9b,e,f
and
solvent-free
conditions.10g,h,11,12
We envisaged that this type of organocatalyst would be effi-
cient in an asymmetric aldol reaction using challenging elec-
trophiles such as glyoxylic acid, in its two commercially
available forms, monohydrate and 50% aqueous solution, in
order to prepare enantioenriched a-hydroxy-g-keto carboxylic
acids.
First, optimization of the reaction parameters was carried
out in the reaction between cyclohexanone (3a) and glyoxylic
On the other hand, the use of asymmetric organocatalyzed
methodologies has provided the chemical community with a
´
´
´
´
Departamento de Quımica Organica e Instituto de Sıntesis Organica, Facultad de
Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain. E-mail:
gabriela.guillena@ua.es; cnajera@ua.es
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, HPLC charts and NMR spectra of all compounds. See DOI:
10.1039/c3ra46800c
Fig. 1 Binam-prolinamide derivatives that have been used as catalysts
in the aldol reaction.
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acid (4), in both forms, as monohydrate (MH) and as 50% (Table 1, entry 10 and 11). The optimization of the rest of the
aqueous solution (AQ). The performance of the two different reaction parameters such as temperature, effect of the additives,
binam-prolinamide derivatives 1 and 2 and the inuence of the catalyst loading and amount of nucleophile were done with
stereochemical axis in the stereochemical outcome of the catalyst 2a and both glyoxylic acid sources. Thus, decreasing the
reaction was evaluated using glyoxylic acid monohydrate under temperature to 0 ꢀC, better results in terms of yields, diastereo-
solvent-free conditions or 50% aqueous solution at room and enantioselectivities were achieved with both catalysts and
temperature (Table 1 and Scheme 1). In order to determine the glyoxylic acid sources (Table 1, compare entries 12 and 13 with 5
enantiomeric excess, the a-hydroxy glyoxylic acid product 5a and 6, respectively). When, glyoxylic acid was used as mono-
was converted in situ into the corresponding methyl ester hydrate, the effect of the addition of a small amount of water (10
derivative 6a, by further treatment with Me3SiCHN2. The results equiv.) in order to accelerate the reaction was evaluated,14
achieved with catalyst 1 were slightly lower in terms of enan- leading to a better enantioselectivity (Table 1, entry 14) in a
tioselectivities than those achieved with catalyst 2. For this shorter reaction time.
process, the chirality of the achieved aldol product was
Finally, using this catalyst 2a, the effect of the reduction of
controlled by the chirality of the proline, affording compound the amount of ketone to 2 equiv. in the reaction with either
6a using catalysts 1a and 2a,13 and by using catalysts 1b and 2b, monohydrated or 50% aqueous solution glyoxylic acid was
its enantiomer (ent-6a). Meanwhile, the inuence of the tested. In both cases, the obtained results were similar to those
stereochemical axis in the stereochemical outcome of the encountered using 5 equiv. of nucleophile (Table 1, compare
products was practically negligible, in contrast to what happens entries 13 with 16, and 14 with 15).
in the intermolecular aldol reaction between ketones and
Under the best reaction conditions and using both glyox-
aromatic aldehydes using these catalysts under similar reaction ylic acid sources, the scope of the reaction was studied
conditions.10h,i,11a Generally, the diastereoselectivities obtained (Scheme 1, Table 2). In all cases, with the exception of
with the glyoxylic acid in aqueous solution were higher than cyclopentanone and 1,4-cyclohexanedione (Table 2, entries 3
using the glyoxylic acid as monohydrate (Table 1, entries 1–8). and 4, 9 and 10, respectively) that gave poor diaster-
Under these later conditions, the reaction catalyzed by the ent- eoselectivity and moderate enantioselectivity, the major
2b, led, as expected, to product 6a with similar results to those isomer achieved was the anti isomer 6, even using unsym-
achieved using catalyst 2b (Table 1, entry 9). Anyhow, both metrical ketones such as 2-butanone (Table 2, entries 17 and
catalysts 1 and 2 were superior in terms of yields, diastereo- and 18). Only product 6h achieved by the reaction with acetone
enantioselectivities to those results obtained with L-proline was obtained with low enantioselectivity (Table 2, entries 15
Table 1 Optimization of reaction conditions between cyclohexanone (3a) and glyoxylic acid (4)a
T
(ꢀC)
t
(h)
Entry
Cat. (mol%)
4b
Conv.c
Yieldd (%)
Anti/syne
eef (%)
1
2
3
4
5
6
7
8
1a (10)
1a (10)
1b (10)
1b (10)
2a (10)
2a (10)
2b (10)
2b (10)
ent-2b (10)
L-Pro
25
25
25
25
25
25
25
25
25
25
25
0
MH
AQ
MH
AQ
MH
AQ
MH
AQ
AQ
MH
AQ
MH
AQ
MH
MH
AQ
6
5
6
5
6
6
6
6
6
72
72
7
7
5
100
100
100
100
100
100
100
100
100
60
—
—
76
51
46
42
—
—
46
21
18
79
79
76
78
—
74/26
85/15
79/21
83/17
78/22
78/22
81/19
84/16
85/15
60/40
55/45
92/8
81
89
83g
83g
91
95
92g
84g
83
29
24
94
94
97
97
94
9
10
11
12
13
14
15
16
L-Pro
70
2a (10)
2a (10)
2a (10)h
2a (10)h,i
2a (10)i
100
100
100
100
100
0
0
0
0
92/8
96/4
95/5
92/8
6
6
a
b
Reaction conditions: 3a (5 equiv.), 4 (0.25 mmol), unless otherwise stated. MH: glyoxylic acid monohydrate; AQ: 50% aqueous solution of
c
d
glyoxylic acid. Conversion based on the unreacted aldehyde. For the methyl ester 6a aer purication by column chromatography.
e
f
Determined by 1H NMR of the crude product. Determined by chiral-phase HPLC analysis of the anti isomer of the corresponding methyl
ester 6a. g The product achieved was ent-6a. h 10 equiv. of H2O were added to the reaction mixture. i 2 equiv. of ketone 3a were used.
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Scheme 1 Aldol reaction of glyoxylic acid with ketones catalyzed by binam prolinamides.
Table 2 Aldol reaction of glyoxylic acid with ketonesa
Several products were isolated as a-hydroxy-g-keto acids 5.
Products 5 were soluble either in organic solvent or water and
were prone to dehydration during purication with silica-gel.
Thus, in order to isolate products 5, as pure compounds, a small
amount of ethyl acetate was added to the reaction. This organic
layer was thoroughly washed with water in order to displace the
product to the aqueous layer. Then, the water was removed and
1,4-dioxane was added to precipitate the glyoxylic acid, leaving
the pure products 5 soluble in dioxane. Following this proce-
dure, compounds 5a, 5f and 5h were isolated in moderate
yields, with slightly lower diastereoselectivities than the corre-
sponding methyl ester 6 and with the same enantioselectivities
(Table 2, entries 1, 12 and 16). In the case of using 4-methyl-
cyclohexanone as the nucleophile, the major diastereoisomer
formed (based on NOESY experiments) was the expected anti,-
anti-aldol with high enantioselectivity (Table 2, entries 19–20).
Attempts to extend the reaction to other a-functionalized
ketones such as a-alkoxy ketones,10h a,b-unsaturated ketones
such as tetralone,15 or aliphatic aldehydes failed.
Entry Major product Yieldb (%) 4c
Drd
eee (%)
1f
2
78 (71)
79
MH 95 : 5 (93:7)
AQ 93 : 7
97 (97)
94
3
4
84
77
MH 47 : 53
AQ 43 : 57
64
80
5
6
86
76
MH 89 : 11
AQ 84 : 16
86
84
7
8
53
49
MH 93 : 7
AQ 93 : 7
91
90
9
10
70
64
MH 40 : 60
AQ 49 : 51
71
51
11f
12
46 (26)
35
MH 94 : 6 (89 : 11) 97 (97)
AQ
90 : 10
86
13
14
32
35
MH 76 : 24
80
62
Conclusions
AQ
68 : 32
We have demonstrated that glyoxylic acid can be used as the
electrophile in aqueous organocatalyzed aldol reactions cata-
lyzed by N-tosyl-binam-prolinamide. This chiral organocatalyst
gave better results than L-proline in the synthesis of enan-
tioenriched a-hydroxy-g-keto carboxylic esters. For cyclic
ketones, mainly anti-isomers were obtained as the major
products in moderate to high enantioselectivities (up to 97%).
The enantioenriched a-hydroxy-g-keto acids can be isolated by
aqueous extraction, without compromising the achieved
enantioselectivities.
15f
16
69 (30)
64
MH
AQ
50 (50)
33
—
17
18
22
17
MH 90 : 10
AQ 76 : 24
80
63
19
20
80
90
MH 84 : 12 : 2 : 2
AQ 76 : 15 : 5 : 4
95
91
a
Reactions conditions: glyoxylic acid monohydrate (0.25 mmol, MH)
and 10 equiv. of H2O or 50% aqueous solution of glyoxylic acid
(0.25 mmol; AQ), ketone (2 equiv.), catalyst 2a (10 mol%) at 0 ꢀC.
Acknowledgements
b
For methyl ester 6 aer purication by column chromatography. In
c
This work was nancially supported by the Ministerio de
Economia y Competitividad (MINECO: Projects: CTQ2010-
20387 and Consolider INGENIO CSD2007-0006), the Generalitat
Valenciana Prometeo/2009/039, the University of Alicante and
the EU (ORCA action CM0905). We thank to Rosa M. Ortiz for
the synthesis of both enantiomers of [1,10-binaphthalene]-2,20-
diamine.
parenthesis, yields for the corresponding acid 5. MH: glyoxylic acid
monohydrate; AQ: 50% aqueous solution of glyoxylic acid.
d
e
Determined by 1H NMR of the crude product. Determined by
chiral-phase HPLC analysis of the anti isomer of the corresponding
methyl ester 6.
corresponding product 5.
f
In parenthesis, results achieved for the
and 16). It seems that the achieved enantioselectivities are
related to the steric hindrance of the nucleophilic ketones.
Comparing the results obtained using glyoxylic acid in
aqueous solution with those achieved using glyoxylic acid as
monohydrate, generally, the later led to better diastereo- and
enantioselectivities.
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