Aqueous enantioselective aldol reaction of methyl- and phenylglyoxal organocatalyzed by N -tosyl-(S a)-binam- l -prolinamide

Article abstract of DOI:10.1055/s-0034-1379969

The direct aldol reaction between methylglyoxal (40% aqueous solution) or phenylglyoxal monohydrate and ketones or aldehydes is catalyzed by N-tosyl-(S _a)-binam-l-prolinamide to afford the corresponding chiral γ-oxo-β-hydroxy carbonyl compounds

Full text of DOI:10.1055/s-0034-1379969

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 656–660
letter
656
F. J. N. Moles et al.
Letter
Synlett
Aqueous Enantioselective Aldol Reaction of Methyl- and Phenyl-
glyoxal Organocatalyzed by N-Tosyl-(Sa)-binam-L-prolinamide
O
Fernando J. N. Moles
O
OH
Gabriela Guillena*
Carmen Nájera*
R2
R1
R3
R1
R2
O
NH
O
Dpto. Química Orgánica and Instituto de Síntesis Orgánica,
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
gabriela.guillena@ua.es
11 examples, 42–92% yield,
20–86% de, 34–97% ee
O
catalyst
(10 mol%)
R1
N
O
H
cnajera@ua.es
25 °C
NHTs
O
OH
H
R1
CO2Et
i.
R2
O
R2
ii.
Ph3PCHCO2Et
catalyst
6 examples, 40–65% yield,
10–98% de, 77–97% ee
Received: 10.11.2014
Accepted after revision: 12.12.2014
Published online: 20.01.2015
amides derived from 1,1′-binaphthyl-2,2′-diamine (binam)
29 and 310 (Figure 1) and their related supported binam de-
rivatives (4 and 5; Figure 1),11 led to excellent results in in-
ter- and intramolecular aldol reactions under several reac-
tion conditions, even using challenging aqueous electro-
philes such as glyoxylic acid12 and 2,2-dimethoxy-
acetaldehyde.13
DOI: 10.1055/s-0034-1379969; Art ID: st-2014-d0933-l
Abstract The direct aldol reaction between methylglyoxal (40% aque-
ous solution) or phenylglyoxal monohydrate and ketones or aldehydes
is catalyzed by N-tosyl-(Sa)-binam-L-prolinamide to afford the corre-
sponding chiral γ-oxo-β-hydroxy carbonyl compounds, mainly as anti
isomers with enantioselectivities up to 97%.
NH
O
NH
O
Key words methylglyoxal, organocatalysis, aldol, prolinamide, aque-
ous conditions
NH
NHR
NH
NHR
Methylglyoxal (1a), an endogenous α-oxoaldehyde that
is a potent protein modifier,1 is a versatile reagent for the
synthesis of heterocyclic compounds2 using organocata-
lyzed methodologies.3 However, its use as electrophile in
related organocatalyzed enantioselective aldol processes4
has been infrequently described,5 although it would afford
synthetically important chiral γ-oxo-β-hydroxycarbonyl
compounds. Probably, the reluctance to use this type of α-
alkyl-α-oxoaldehyde as an electrophile is a consequence of
their facile hydratation and polymerization. On the other
hand, methylglyoxal is only commercially available as an
aqueous solution (40%) and the use of water as a reaction
medium to carry out organocatalytic processes remains a
challenge, due to the fact that water can interfere with the
formation of hydrogen bonds and polar interactions be-
tween the organocatalysts and substrates.6 Only certain
privileged organocatalytic systems such as prolinamide and
diaryl prolinol derivatives, have shown their efficiency as
organocatalysts in water or aqueous media.7 Most of these
systems are highly hydrophobic molecules that show di-
minished contact with bulk water in the transition states,
with the process actually taking place in a highly concen-
trated organic phase.8 Recently, we have shown that prolin-
2b, R = D-Pro
3b, R = Ts
2a, R = L-Pro
3a, R = Ts
O
O
H
N
H
N
NH
NH
NH
NH
SO2
SO2
O
O
SiO2
O
Si
S
S
3
5
4
Figure 1 Binam prolinamide derivatives as catalyst in the aldol reac-
tion
Based on these previous results, we thought it of inter-
est to study the efficiency of binam prolinamide derivatives
as organocatalysts in the reaction between methyl- and
phenylglyoxal with ketones5a and with aldehydes.5b,c
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 656–660

657
F. J. N. Moles et al.
Letter
Synlett
First, the optimization of the reaction parameters in the
reaction between acetone (6a) and methylglyoxal (1a, 40%
aqueous solution) was studied. This reaction gave Henze’s
ketol14 (7a) as product, a compound that is involved in plant
metabolism.15
Table 1 Optimization of Reaction Conditions for the Reaction be-
tween Acetone (6a) and Methylglyoxal (1)a
O
OH
O
O
catalyst
additive
H
+
The efficiency of the two different binam prolinamide
derivatives 2 and 3 (20 mol%) was evaluated using 10 equiv-
alents of acetone as nucleophile (Table 1). Better enantiose-
lectivity was achieved with catalysts 3 than with catalysts 2
(Table 1, entries 1–4). While catalysts 2a and 3a afforded
compound 7a, catalysts 2b and 3b gave its enantiomer (ent-
7a) with lower enantioselectivity, showing that the config-
uration of the resultant aldol product was controlled by the
chirality of the proline,16 and that the match combination
was (Sa)-binam and L-Pro. The results obtained with both
catalysts were superior in terms of conversion, yields and
enantioselectivities to the results achieved with L-proline
(Table 1, compare entries 1–4 with entry 5), that gave prod-
uct 7a as a racemic mixture. As the best enantioselectivity
for this process was achieved with the (Sa)-binamsulfo-
L-Pro derivative (3a) as catalyst, the rest of the reaction pa-
rameter optimizations were carried out using this catalyst
(Table 1, entry 3).
The effect of the amount of nucleophile was evaluated.
While decreasing the amount of acetone (6a) from 10
equivalents to 5 equivalents gave similar results, using only
2 equivalents of acetone provoked a decrease in the reac-
tion rate and enantioselectivity (Table 1, compare entry 3
with entries 6 and 7). Changing the catalyst loading to 10
mol% and 5 mol%, led to similar results in terms of conver-
sion but with slightly lower selectivity being found when
only 5 mol% of 3a was used (Table 1, entries 8 and 9). De-
creasing the temperature to 0 °C in the presence of 10 mol%
of 3a and 5 equivalents of acetone, gave an 88% ee but lower
conversion and yield (Table 1, compare entries 3 and 10).
Therefore, the effect of the addition of benzoic acid as co-
catalyst was evaluated under these reaction conditions, but
hardly any acceleration of the reaction was observed (Table
1, entry 12). Thus, under the best reaction conditions (10
mol% of 3a, 5 equiv of 6a and 25 °C), the time required for
reaction completion was re-evaluated, finding that, after 12
hours product 7a was achieved in almost quantitative yield
and 90% ee (Table 1, entry 12). These results are superior to
those previously reported using simple L-prolinamide or
the dipeptide L-Pro-L-Leu under neat conditions.5a Finally,
the use of the supported binam derivatives 4 and 5 as cata-
lysts in the reaction between acetone and methylglyoxal
was tested, but the reaction failed (Table 1, entries 13 and
14).
O
O
7a
1a
6a
Entry Cat.
(mol%)
6a
Temp
Time
(h)
Conv.b
Yield ee
(equiv) (°C)
(%)c
(%)d
1
2
2a (20)
2b (20)
3a (20)
3b (20)
10
10
10
10
10
5
25
25
25
25
25
25
25
25
25
0
24
24
24
24
72
24
24
24
24
24
24
12
72
168
100
100
100
100
80
–
–
80
–66
88
–68
0
3
82
65
66
–
4
5
L-Pro (20)
3a (20)
3a (20)
3a (10)
3a (5)
6
100
95
87
80
87
80
88
88
90
–
7
2
–
8
5
100
100
90
–
9
5
–
10
11e
12
13
14
3a (10)
3a (10)
3a (10)
4 (20)
5
75
84
94
–
5
0
93
5
25
25
25
100
–
5
5 (20)
5
–
–
–
a Reaction conditions: 1a (0.25 mmol, 40% aq solution), 6a, and catalyst,
unless otherwise stated.
b Conversion based on unreacted aldehyde.
c After purification by column chromatography.
d Determined by chiral-phase HPLC.
e Benzoic acid (5 mol%) was added.
O
O
OH
O
3a (10 mol%)
R1
H
R1
+
R2
25 °C
R2
O
O
6
7
1a
Scheme 1 Aldol reaction of methylglyoxal with ketones
In all cases, with the exception of cyclopentanone and
1,4-cyclohexanedione (Table 2, entries 3 and 7, respective-
ly), the major isomer obtained was the anti-isomer 7. The
diastereoselectivities were rather moderate with the excep-
tion of cyclohexanone derivatives functionalized at the 4-
position (products 7d–f, entries 4–6). Only product 7g,
achieved by reaction with 1,4-cyclohexadione, was ob-
tained with low enantioselectivity (Table 2, entry 7), the
enantiomeric excesses for the rest of the examples being
consistently higher than 82%. In the case of 4-substituted
cyclohexanones, the major diastereoisomer formed was the
expected anti,anti-aldol, the diastereoselectivities being
highly dependent on the substituent at the 4-position (Ta-
ble 2, entries 8–10). The anti relative stereochemistry be-
Once the best reaction conditions were established (Ta-
ble 1, entry 12), the scope of the aldol reaction of methyl-
glyoxal (40% aqueous solution) with different ketones was
studied (Scheme 1 and Table 2).17
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 656–660

658
F. J. N. Moles et al.
Letter
Synlett
Table 2 (continued)
Entry Major product
O
tween protons at the 2- and 3-positions for compounds 7h–
j was demonstrated by comparing the chemical shifts and
coupling constants to those previously reported for the re-
lated glyoxylic acid and ethyl glyoxylate derivatives,12 and
confirmed by NOESY experiments. From these experi-
ments, the anti relative configuration between protons 3
and 5 was determined on the basis of an NOE effect ob-
served between the methyl group at the position 5 and the
proton at position 3 for compound 7h. The reaction with
cyclobutanone led to the expected anti product 7k in good
enantioselectivity but with low yield and diastereoselectiv-
ity (Table 2, entry 11). Attempts to extend the reaction to
other ketones such as butanone or α-alkoxy ketones failed.
Yield (%)b drc
ee (%)d
OH
OH
9
7i
67
68:29:2:1
87
O
O
Ph
O
10
11
7j
74
42
54:32:10:4
91
90
Table 2 Aldol Reaction of Methylglyoxal with Ketonesa
OH
O
OMe
7k
63:37
Entry Major product
Yield (%)b drc
ee (%)d
90
O
O
OH
OH
a Reaction conditions: methylglyoxal (0.25 mmol, 40% aq solution), ketone
(5 equiv), catalyst 3a (10 mol%) at 25 °C for 24 h, unless otherwise stated.
b After purification by column chromatography.
1e
7a
7b
7c
92
80
79
–
O
O
c Determined by 1H NMR spectroscopic analysis of the crude product.
d Determined by chiral-phase HPLC analysis for the major isomer.
e Only 12 h were required for the reaction completion.
O
f Time required for the reaction completion was 30 h.
2
62:38
22:78
86
86
97
Once the scope of the reaction of aqueous methylglyoxal
with ketones was established, the cross aldol between
methylglyoxal with enolizable aldehydes was studied under
the same reaction conditions. This cross aldol reaction has
been previously reported,5b,c showing that the correspond-
ing γ-oxo-β-hydroxyaldehydes isomerize easily during pu-
rification. Therefore, these aldol products were allowed to
react in situ with Ph3PCHCO2Et to give the corresponding
Wittig adducts. Following this one-pot two-step procedure,
products 10 were obtained (Scheme 2,Table 3).18 As before,
in all cases the anti-isomer was the major isomer, the ste-
reochemistry of the product being assigned based on previ-
ously reported results.5b The reaction of methylglyoxal (1a)
with propanal led to product 10a in moderate yield and di-
astereoselectivity but excellent enantioselectivity, compa-
rable to the enantioselectivity achieved using diarylprolinol
as catalyst (10 mol%) in THF5b (Table 3, entry 1). Better re-
sults were achieved in the reaction with octanal and hep-
tanal and phenylpropanal, giving products 10b, 10c and
10d in excellent diastereo- and enantioselectivity, respec-
tively (Table 3, entries 2–4). The reaction between phenyl-
glyoxal19 (1b) and several aldehydes was also tested.
When propanal was used as nucleophile, moderate yield,
diastereo- and enantioselectivity were obtained (Table 3,
entry 5). Meanwhile, phenylpropanal led to lower diastereo-
selectivity but better enantioselectivity (Table 3, entry 6).
O
OH
3
O
O
OH
OH
4
5
7d
7e
81
72
89:11
86:14
O
O
O
82
95
O
S
O
OH
6f
7f
77
70
78
93:7
O
O
N
Boc
O
OH
7
7g
7h
40:60
34
92
O
O
OH
8
87:7:4:2
O
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659
F. J. N. Moles et al.
Letter
Synlett
OH
O
OH
O
O
Ph3P=CHCO2Et
25 °C, 2 h
3a (10 mol%)
R1
CO2Et
R1
H
+
R1
H
H
25 °C
R2
R2
O
R2
O
O
1
8
9
10
Scheme 2 Aldol reaction of glyoxals with aldehydes
In conclusion, N-tosyl-(Sa)-binam-L-prolinamide has
been demonstrated to be an efficient catalyst to promote
the aldol reaction between methylglyoxal under aqueous
conditions or phenylglyoxal monohydrate with ketones or
aldehydes, affording chiral γ-oxo-β-hydroxycarbonyl com-
pounds and ε-oxo-δ-hydroxy-α,β-unsaturated esters, re-
spectively in good yields, diastereo- and enantioselectivi-
ties.
Acknowledgment
This work was financially supported by the Ministerio de Economia y
Competitividad (MINECO: Projects: CTQ2010-20387 and Consolider
INGENIO CSD2007-0006), FEDER, the Generalitat Valenciana (Prome-
teo/2009/039), the University of Alicante and the EU (ORCA action
CM0905). We thank Dr. Rosa M. Ortiz for the synthesis of both enan-
tiomers of (1,1′-binaphthalene)-2,2′-diamine.
Supporting Information
Table 3 Aldol Reaction of Glyoxals 1 with Aldehydes Followed by Wit-
Supporting information for this article is available online at
tig Olefinationa
http://dx.doi.org/10.1055/s-0034-1379969.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Entry Major product
Yield
(%)b
drc
ee
(%)d
References and Notes
OH
OH
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1
2
10a
10b
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57
76:24
92
95
O
O
98:2
(CH2)7Me
OH
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CO2Et
CO2Et
3
4
5
6
10c
10d
10e
10f
65
48
55
48
99:1
96
97
77
86
O
(CH2)6Me
OH
99:1
O
Bn
OH
Ph
CO2Et
62:38
55:45
O
O
OH
Ph
CO2Et
Bn
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D
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.
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To a mixture of methylglyoxal (40% aqueous solution, 0.25
mmol, 0.038 mL) and catalyst (10 mol%) at the indicated tem-
perature was added the corresponding aldehyde (0.5 mmol).
The reaction was stirred until the methylglyoxal was consumed
(monitored by TLC). Ph3PCHCO2Et (0.178 g, 0.5 mmol) was
added and the reaction mixture was stirred for 2 h. Upon com-
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EtOAc) to yield the α,β-unsaturated ester. Analytical data of
compound 10e are given as a representative compound (see the
Supporting Information for the rest of the compound data):
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(hexane–EtOAc, 70:30; revealed with KMnO4). IR: 3439.4 (OH),
1708.6 (C=O), 11692.2 (C=O), 1269.9 (MeC=O) cm–1 1H NMR
.
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(b) Fang, J.-M.; Wang, K.-C.; Cheng, Y.-S. J. Chin. Chem. Soc. 1991,
38, 297. (c) Li, Y.; Shi, Y.-P. Pharmazie 2007, 62, 714.
(300 MHz, CDCl3): δ = 7.88–7.98 (m, 2 H, ArH), 7.50–7.73 (m, 3
H, ArH), 7.15 (dd, J = 15.7, 7.4 Hz, 1 H, CH=CH), 5.94 (dd, J = 15.7,
1.4 Hz, 1 H, CH=CH), 5.20 (dd, J = 6.4, 2.4 Hz, 1 H, CHOH), 4.22 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 3.78 (d, J = 6.4 Hz, 1 H, OH), 2.78–2.91
(m, 1 H), 1.32 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.87 (d, J = 6.8 Hz, 3
H, CHMe).13C NMR (75 MHz, CDCl3): δ = 200.6 (C), 166.3 (C),
149.8 (CH), 134.3 (CH), 133.5 (C), 129.1 (2 × CH), 128.5 (2 × CH),
121.7 (CH), 75.0 (CH), 60.4 (CH2), 40.7 (CH), 14.3 (Me), 11.5
(Me). HRMS: m/z [M+ + Na] calcd for C15H18O4: 285.1103; found:
285.1111.
(18) Arylglyoxals are important reagents for the synthesis of hetero-
cyclic compounds. See, for instance: Eftekhari-Sis, B.; Zirak, M.;
Akbari, A. Chem. Rev. 2013, 113, 2953.
(16) Stereochemistry was assigned by comparison of the optical
rotation values given in the literature, in reference 5a.
(19) To a mixture of the phenylglyoxal monohydrate (0.25 mmol,
0.028 g) and catalyst (10 mol%) at the indicated temperature
was added the corresponding aldehyde (0.5 mmol). The reac-
tion was stirred until the phenylglyoxal was consumed (moni-
tored by TLC). Ph3PCHCO2Et (0.178 g, 0.5 mmol) was added and
the reaction mixture was stirred for 2 h. Upon completion, the
reaction was quenched by passing the reaction mixture through
a silica gel pad, and the filtrate concentrated in vacuo. The
resulting residue was purified by chromatography (hexanes–
EtOAc) to yield the α,β-unsaturated ester.
(17) To a mixture of the methylglyoxal (40% aqueous solution, 0.25
mmol, 0.038 mL) and catalyst (10 mol%) at the indicated tem-
perature was added the corresponding ketone (1.25 mmol). The
reaction was stirred until the methylglyoxal was consumed
(monitored by TLC). The resulting residue was purified by chro-
matography (hexanes–EtOAc) to yield the pure aldol product.
During purification aldols 7d–f underwent a slight epimeriza-
tion. Analytical data of compound 7b are given as a representa-
tive compound (see the Supporting Information for the rest of
the compound data): (2S,1′R)-isomer; yellow oil (yield: 0.034 g,
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