Highly diastereoselective nitroaldol reactions with chiral derivatives of glyoxylic acid

Article abstract of DOI:10.1016/j.tetlet.2003.09.152

N-Glyoxyloyl-(2R)-bornane-10,2-sultam (1a) and (1R)-8-phenylmenthyl glyoxylate (1b) react stereoselectively with simple nitroalkanes giving diastereomeric nitroalcohols with high asymmetric induction. The glyoximide 1a is proved to be a highly efficient chiral inducer, superior to glyoxylate 1b. In all cases, the absolute configuration (2S) and relative configuration, syn for the major diastereoisomers, were confirmed.

Full text of DOI:10.1016/j.tetlet.2003.09.152

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8681–8683
Highly diastereoselective nitroaldol reactions with chiral
derivatives of glyoxylic acid
Iwona Kudyba,a Jerzy Raczkoa,b and Janusz Jurczaka,c,
*
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
bZD CHEMIPAN, Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
cDepartment of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Received 8 July 2003; revised 8 September 2003; accepted 18 September 2003
Abstract—N-Glyoxyloyl-(2R)-bornane-10,2-sultam (1a) and (1R)-8-phenylmenthyl glyoxylate (1b) react stereoselectively with
simple nitroalkanes giving diastereomeric nitroalcohols with high asymmetric induction. The glyoximide 1a is proved to be a
highly efficient chiral inducer, superior to glyoxylate 1b. In all cases, the absolute configuration (2S) and relative configuration,
syn for the major diastereoisomers, were confirmed.
© 2003 Published by Elsevier Ltd.
The nitroaldol addition (Henry reaction) is one of the
basic methods for the construction of carbonꢀcarbon
bonds.1 The nitroalcohols formed in this process offer
an easy access to a variety of numerous intermediates
(2-aminoalcohols, 2-nitroketones, nitroalkenes etc.),2–4
useful in the synthesis of biologically important com-
pounds.5,6 Currently, there is a substantial interest in
development of a stereocontrolled version of the Henry
reaction. The chiral-pool approach has been widely
investigated,7,8 however, particular attention was paid
to application of chiral catalysts, providing nitroalco-
hols in good yield and with high enantioselectivity.9–11
On the other hand, there are in the literature only two
examples of the stereoselective Henry reaction using
with that of the glyoxylic ester of (1R)-8-phenylmenthol
(1b) (Scheme 1). The latter chiral auxiliary has been
proved to be very effective in many other processes,
especially in the aldol condensation which is similar to
the Henry reaction.15
substrates containing
a
chiral auxiliary, (1R)-8-
phenylmenthol.12
In the course of our search for the synthetic applica-
tions of chiral derivatives of a-oxoacids, we have syn-
thesized N-glyoxyloyl-(2R)-bornane-10,2-sultam (1a)13
and examined its applicability in
a number of
diastereoselective reactions.14 High asymmetric induc-
tion obtained during these studies prompted us to
extend our investigations on addition of 1a to
nitromethane (2) and two other simple nitro com-
pounds of type 3, and to compare the efficiency of 1a
Keywords: nitroalcohols; nitroaldol reaction; asymmetric induction;
chiral auxiliary.
* Corresponding author. Tel.: +48-22-8230944; fax: +48-22-8230944;
e-mail: jjurczak@chem.uw.edu.pl
Scheme 1.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.152

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I. Kudyba et al. / Tetrahedron Letters 44 (2003) 8681–8683
vacuum (Method B%). Indeed, we obtained much better
yields for the reactions under investigation (entries 2
and 4). Similar results were observed for the reactions
of 1b (entries 5–8). As far as the diastereoselectivity is
concerned, we found that the (2R)-bornane-10,2-sultam
is a more efficient chiral auxiliary compared to (1R)-8-
phenylmenthol; the best asymmetric induction was
obtained with TBAF as the reaction promoter (entries 3
and 4).
Initial investigations on the reaction of 1a with
nitromethane, carried out under conditions described
by Solladie´-Cavallo et al.12 for glyoxalate 1b completely
failed giving only products of splitting of the bornane-
10,2-sultam. Owing to this result we excluded potas-
sium fluoride—a common mediator of the nitroaldol
reaction. To overcome this problem, we resolved to
check two other procedures using neutral Al2O3
(method A) or tetrabutylammonium fluoride trihydrate
(TBAF·3H2O, method B). The results of these prelimin-
ary studies are summarized in Table 1.
At the next stage of our studies, we decided to use two
other nitro compounds, namely 1-nitrohexane (3a) and
2-nitroacetaldehyde diethyl acetal (3b), which in the
reactions with 1a and 1b formed four diastereoisomeric
nitroalcohols (Scheme 1, Table 2).
Only moderate yields were obtained for the reactions of
1a with 2, promoted by both Al2O3 and TBAF·3H2O
(Table 1, entry 1, Method A, and entry 3, Method B,
respectively); substantial amounts of the sultam auxil-
iary were found in the reaction mixtures. In order to
improve the reaction yields we decided to use Al2O3
activated by heating at 120°C under reduced pressure
(Method A%) and anhydrous TBAF dried at 80°C in
Similarly to the reactions of 1a or 1b with 2 (Table 1),
the yields of reactions of 3a and 3b were higher when
activated catalysts were applied (Table 2, Methods A%
and B%). As regards stereoselectivity, we often observed
Table 1. Reactions of chiral aldehydes 1a and 1b with nitromethane (2)
Entry
Aldehyde
Methoda
Time (h)
Yieldb,c (%)
Diastereoisomeric ratiod 4:5
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
A
A%
B
B%
A
A%
B
48
4
2
30
80
38
50
78
90
43
86
83:17
77:23
97:3
8
98:2
17
24
5.5
2.5
85:15
73:27
53:47
75:25
B%
a Method A: 3 equiv. of neutral Al2O3, 1.5 equiv. of nitromethane, THF, rt; Method A%: 3 equiv. of activated Al2O3 used; Method B: 0.5 equiv.
of TBAF·3H2O, 1.5 equiv. of nitromethane, THF, −78°C; Method B%: 0.5 equiv. of anhydrous TBAF used.
b Yields are given for isolated products.
c All new products were fully characterized.
d Calculated by HPLC analysis and 1H NMR.
Table 2. Reactions of chiral aldehydes 1a and 1b with nitro compounds 3a and 3b
Entry
Aldehyde
Nitro compound
Methoda used
Time (h)
Yieldb,c (%)
Diastereoisomeric ratiod 6:7:8:9
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1a
1a
1b
1b
1b
1b
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
A
A%
B
B%
A
A%
B
B%
A
A%
B
B%
A
A%
B
26
8
2
2.5
17
24
22
1
26
1
5
2.5
17
6
5
93
29
58
60
85
43
90
0
78
45
80
39
96
47
64
74:26:0:0
68:14:12:6
90:10:0:0
51:35:7:7
62:22:10:6
58:24:12:6
34:30:24:12
33:28:23:16
–
64:16:15:5
100:0:0:0
100:0:0:0
88:7:5:0
9
10
11
12
13
14
15
16
68:21:8:3
62:17:15:6
66:24:10:0
2
1
B%
a Method A: 3 equiv. of neutral Al2O3, 1.5 equiv. of nitro compound, THF, rt; Method A%: 3 equiv. of activated Al2O3 used; Method B: 0.5 equiv.
of TBAF·3H2O, 1.5 equiv. of nitro compound, THF, −78°C; Method B%: 0.5 equiv. of anhydrous TBAF used.
b Yields are given for isolated products.
c All new products were fully characterized by 1H, 13C NMR, IR, ESI MS, and elemental analysis.
d Calculated by HPLC analysis and 1H NMR.

I. Kudyba et al. / Tetrahedron Letters 44 (2003) 8681–8683
8683
formation of the four possible diastereoisomers; in most
Scientific Research (Project PBZ 605/T09/1999).
cases, we were able to separate them, isolate them in a
chromatographically pure form and characterize them.
The best results were obtained for the reaction of
glyoximide 1a with 3b, when a single diastereoisomer
was formed (Table 2, entry 11, Method B, and entry 12,
Method B%, respectively). In general, the use of 1a, as
compared with 1b, led to better stereochemical results,
however, in both cases, the use of activated Al2O3 and
anhydrous TBAF decreased slightly the sterereoselec-
tivity (e.g. entries 3, 4, 13, and 14).
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Acknowledgements
This work was supported by the State Committee for