Glyoxylic acid versus ethyl glyoxylate for the aqueous enantio selective Synthesis of α-hydroxy-γ-keto acids and esters by the N-Tosyl-(S a)-binam-l-prolinamide-organocatalyzed aldol reaction

Article abstract of DOI:10.1055/s-0034-1379546

N-Tosyl-(S _a)-binam-l-prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo- and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.

Full text of DOI:10.1055/s-0034-1379546

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 549–561
paper
549
F. J. N. Moles et al.
Paper
Synthesis
Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio-
selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the
N-Tosyl-(Sa)-binam-L-prolinamide-Organocatalyzed Aldol Reaction
O
Fernando J. N. Molesa
OH
Gabriela Guillena*a
Carmen Nájera*a
Enrique Gómez-Bengoa*b
H
i.
O
OH
12 examples
17–90% yield
6–90% de
O
OMe
monohydrate
or aqueous solution
R1
R2
O
NH
O
33–97% ee
ii.
TMSCHN2
a Departamento de Química Orgánica and Instituto de Síntesis
Orgánica, Universidad de Alicante, Apdo. 99, 03080 Alicante,
O
catalyst
(10 mol%)
N
H
O
R1
NHTs
Spain
+
3
4
9
(
6
5
)
9
0
3
5
4
9
OEt
R2
0 ºC
gabriela.guillena@ua.es
cnajera@ua.es
b Departamento de Química Orgánica I, Universidad del País
Vasco, Apdo. 1072, 20080 San Sebastián, Spain
enrique.gomez@ehu.es
O
OH
H
8 examples
20–92% yield
10–96% de
50–97% ee
OEt
O
R1
( 50% toluene)
catalyst
R2
O
Received: 13.08.2014
Accepted after revision: 28.10.2014
Published online: 27.11.2014
benefits of the use of water as a reaction medium to per-
form the aldol reaction are not only environmental, but also
practical as the use of anhydrous solvents and substrates is
avoided.10 Despite this, the use of water as a reaction medi-
um to carry out this type of transformation remains a chal-
lenge, due to the fact that water can interfere with the for-
mation of hydrogen bonds and polar interactions between
the organocatalysts and substrates.11 However, there are
some privileged organocatalytic systems that have been
successfully used in the aldol reaction in water or aqueous
media. Generally, these systems are highly hydrophobic
molecules that diminish the contact with bulk water and
the transition states, and can concentrate the organocata-
lyst and reactants, with the aldol process taking place in a
highly concentrated organic phase.12 Included in these priv-
ileged hydrophobic organocatalysts are prolinamides13 114
and 215 derived from 1,1′-binaphthyl-2,2′-diamine (binam,
Figure 1), and their related supported binam derivatives
polymeric 316a,b and silica gel supported 4,16c,d which have
given excellent results in inter- and intramolecular aldol re-
actions under several reaction conditions, including aque-
ous13b,e,f and solvent-free conditions.14g,h,15,16
The possibility of using water as the solvent becomes
crucial when one of the reactants is only available as an
aqueous solution. This is the case with glyoxylic acid, which
is commercially available as the monohydrate form or as a
50% aqueous solution, due to its intrinsic instability. It is
known that glyoxylic acid and glyoxylates are prone to suf-
fer facile hydration and polymerization processes. Probably
due to this fact, there are only a few reports dealing with
the use of glyoxylic acid monohydrate as electrophile in the
direct aldol reaction with ketones, mediated by indium(III)
chloride, to afford racemic adducts.17 However, the use of
glyoxylates as electrophiles in the organocatalyzed asym-
metric aldol reaction has been reported for the synthesis of
α-hydroxy esters.18
DOI: 10.1055/s-0034-1379546; Art ID: ss-2014-f0509-op
Abstract N-Tosyl-(Sa)-binam-L-prolinamide is an efficient catalyst for
the aqueous aldol reaction between ketones and glyoxylic acid, as the
monohydrate or as an aqueous solution, or a 50% toluene solution of
ethyl glyoxylate. These reactions led to the formation of chiral α-hy-
droxy-γ-keto carboxylic acids and esters in high levels of diastereo- and
enantioselectivities (up to 97% ee), providing mainly anti aldol prod-
ucts. Only cyclopentanone and cyclohexane-1,4-dione afforded an al-
most 1:1 mixture of the syn/anti-diastereoisomers; however, the reac-
tion between 4-phenylcyclohexanone and ethyl glyoxylate gave the
corresponding syn,syn-product as the major diastereoisomer.
Key words aldol reaction, organocatalysis, glyoxylic acid, prolin-
amide, water
Optically active α-hydroxy carboxylic acids and their es-
ters1 are important structural frameworks that can be
found in several biologically active molecules. Due to their
synthetic interest, several methods have been developed for
the synthesis of such compounds.2 Among them, the asym-
metric aldol reaction3 is the most attractive and straightfor-
ward method to accomplish this synthetic goal. Although
the use of enantioselective catalytic methods to perform
this transformation would be desirable,4 the stereoselective
synthesis of natural products relies mostly on chiral auxilia-
ry based methods.5 Notwithstanding, the renaissance or
the use of organocatalyzed methodologies,6 which has been
closely related to the development of the direct aldol reac-
tion,7 has provided the chemical community with a power-
ful tool to perform these types of transformations. In this
sense, the use of enamine-catalyzed aldol processes8 has al-
lowed the efficient enantioselective synthesis of highly
functionalized carbonyl compounds in organic solvents.
Conversely, aldolases are able to promote the aldol reaction
in water with excellent efficiency and stereocontrol.9 The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 549–561

550
F. J. N. Moles et al.
Paper
Synthesis
uct 7a was converted in situ into the corresponding methyl
ester derivative 8a by further treatment with (trimethylsi-
lyl)diazomethane (TMSCHN2) to determine the obtained
enantiomeric excess and for purification purposes. Slightly
lower enantioselectivity was achieved with catalyst 1 than
with catalyst 2, and the results with both catalysts were su-
perior to the results achieved with L-proline. Also, the use
of glyoxylic acid in aqueous solution (AQ) afforded higher
diastereoselectivities than those when glyoxylic acid mono-
hydrate (MH) was employed (Table 1, entries 1–8). While
catalysts 1a and 2a afforded compound 8a, catalysts 1b and
2b gave its enantiomer (ent-8a), showing that the chirality
of the resulting aldol product is controlled by the chirality
of the proline moiety.21 On the other hand, the influence of
the stereochemical axis of the catalyst in the stereochemi-
cal outcome of the product is practically negligible. Under
aqueous conditions, catalyst ent-2b led, as expected, to
product 8a with similar results to those achieved using cat-
alyst 2b (Table 2, entries 8 and 9). The results obtained with
both catalysts 1 and 2 were superior in terms of yields and
diastereo- and enantioselectivities to the results achieved
with L-proline (Table 1, entries 10 and 11). Catalyst 2a was
chosen for the optimization of other reaction parameters,
such as temperature, effect of additives, catalyst loading,
and amount of nucleophile, with both glyoxylic acid sourc-
es. When the temperature was decreased to 0 °C, both gly-
oxylic acid sources led to better results in terms of yields
and diastereo- and enantioselectivities (Table 1, compare
entries 12 and 13 with 5 and 6, respectively). Using glyoxyl-
ic acid monohydrate, the acceleration of the reaction rate by
the addition of a small amount of water (10 equiv) was
evaluated, and product 8a was afforded in higher enantio-
selectivity and shorter reaction time (Table 1, entry 14).22
When the amount of ketone 5a was decreased to 2 equiva-
lents in the reaction with either monohydrated glyoxylic
acid or a 50% aqueous solution of glyoxylic acid, the results
were similar to those encountered when 5 equivalents of
nucleophile were used (Table 1, compare entries 13 with
16, and 14 with 15). The best reaction conditions were 0 °C,
10 equivalents of water, 10 mol% of catalyst 2a, and 2 equiv-
alents of nucleophile. Finally, the use of the supported bi-
nam derivatives 3 and 4 as catalysts in the reaction be-
tween cyclohexanone and glyoxylic acid monohydrate was
tested, but the reaction failed (Table 1, entries 17 and 18).
NH
NH
O
NH
NHR
O
NH
NHR
1b, R = D-Pro
2b, R = Ts
1a, R = L-Pro
2a, R = Ts
O
O
H
N
H
N
NH
NH
NH
NH
SO2
SO2
O
O
SiO2
O
Si
S
3
S
4
3
Figure 1 Binam-prolinamide derivatives used as catalysts in the aldol
reaction
We have recently reported the use of glyoxylic acid as
the monohydrate or as a 50% aqueous solution in the or-
ganocatalyzed direct aldol reaction with ketones, affording
enantioenriched α-hydroxy-γ-keto carboxylic acids.19
Based on this previous work, we thought it interesting to
extend this aldol reaction with glyoxylic acid to the de-
symmetrization of prochiral ketones,20 and to compare the
achieved results with those obtained using polymeric ethyl
glyoxylate as electrophile. With these two aldol processes,
enantioenriched α-hydroxy-γ-keto carboxylic acids and es-
ters can be afforded in a straightforward and efficient man-
ner.
In order to perform this study, the optimization of the
reaction parameters in the reaction between cyclohexa-
none (5a) and glyoxylic acid (6) in both forms, as the mono-
hydrate (MH) and as a 50% aqueous solution (AQ), was car-
ried out. The efficiency of the two different binam-prolin-
amide derivatives 1 and 2 was evaluated using glyoxylic
acid monohydrate under solvent-free conditions or as a 50%
aqueous solution at room temperature (Scheme 1 and Table
1). In all cases, the obtained α-hydroxyglyoxylic acid prod-
O
OH
O
O
OH
O
TMSCHN2
2a (10 mol%)
OH
OMe
OH
R1
R1
R1
+
R2
H
H2O, 0 °C
R2
O
R2
O
O
5
6
7
8
Scheme 1 Aldol reaction of glyoxylic acid (6) with ketones 5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 549–561

551
F. J. N. Moles et al.
Paper
Synthesis
Table 1 Optimization of the Conditions for the Reaction of Cyclohexa-
none (5a) with Glyoxylic Acid (6)a
Table 2 Aldol Reaction of Glyoxylic Acid (6) with Ketonesa
Entry 6c
Major product
Yieldb (%) drd
eee (%)
O
O
OH
OH
95:5
(93:7)
93:7
1f
2
MH
AQ
78 (71)
79
97 (97)
94
OMe
8a
O
OH
O
OH
O
OH
5a
+
TMSCHN2
catalyst
additive
OH
OMe
O
O
O
O
3
4
MH
AQ
84
77
47:53
43:57
64
80
OMe
OMe
8b
7a
H
8a
O
O
6
O
OH
OH
5
6
MH
AQ
86
76
89:11
84:16
86
84
Entry 6b
Cat.
Temp
(°C)
Time Conv.c Yieldd (%) anti/syne eef
8c
(h)
(%)
O
O
O
1
MH
1a
1a
1b
1b
2a
2a
2b
2b
25
25
25
25
25
25
25
25
6
5
6
5
6
6
6
6
6
100
100
100
100
100
100
100
100
100
60
–
74:26
85:15
79:21
83:17
78:22
78:22
81:19
84:16
85:15
60:40
55:45
92:8
92:8
96:4
95:5
92:8
–
81
2
AQ
MH
AQ
MH
AQ
MH
AQ
AQ
MH
AQ
MH
AQ
MH
MH
AQ
MH
MH
–
89
83g
83g
91
95
92g
84g
83
29
24
94
94
97
97
94
–
OMe
OMe
7
8
MH
AQ
53
49
93:7
93:7
91
90
3
76
51
46
42
–
8d
O
4
N
5
Boc
6
O
OH
7
9
10
MH
AQ
70
64
40:60
49:51
71
51
8e
8
–
O
O
9
ent-2b 25
46
21
18
79
79
76
78
–
O
O
10
11
12
13
14
15
16
17
18
L-Pro
L-Pro
2a
25
25
0
72
OH
72
7
70
OMe
OMe
100
100
100
100
100
–
11
12
MH
AQ
80
90
84:12:2:2 95
76:15:5:4 91
8f
2a
0
7
2ah
2ah,i
2ah,i
3
0
5
0
6
O
OH
0
6
13
14
MH
AQ
50
60
83:9:5:3
77:13:9:1 80
90
25
25
168
168
–
8g
O
4
–
–
–
–
a Reaction conditions: 5a (5 equiv), 6 (0.25 mmol), catalyst (10 mol%), un-
less otherwise stated.
Ph
O
OH
b MH: glyoxylic acid monohydrate; AQ: 50% aq solution of glyoxylic acid.
c Conversion based on the unreacted aldehyde.
d For the methyl ester 8a after purification by column chromatography.
e Determined from the 1H NMR spectrum of the crude product.
f Determined by chiral-phase HPLC analysis for the anti-isomer of the corre-
sponding methyl ester 8a.
OMe
15
16
MH
AQ
72
68
84:8:5:3
73:20:6:1 79
76
8h
O
g The product obtained was ent-8a.
h H2O (10 equiv) was added to the reaction mixture.
i Ketone 5a (2 equiv) was used.
O
OH
94:6
(89:11)
90:10
17f
18
MH
AQ
46 (26)
35
97 (97)
86
OMe
8i
Once the best reaction conditions were established us-
ing both glyoxylic acid sources, the scope of the reaction
was studied (Table 2).
O
OH
O
19
20
MH
AQ
32
35
76:24
68:32
80
62
OMe
8j
O
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F. J. N. Moles et al.
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Synthesis
Table 2 (continued)
precipitate the glyoxylic acid, with the pure product 7 being
soluble in the dioxane. Following this procedure, com-
pounds 7a, 7i, and 7k were isolated in moderate yields,
with slightly lower diastereoselectivities than the corre-
sponding methyl esters 8, and with the same enantioselec-
tivities (Table 2, entries 1, 17, and 21).
As the products of type 8 could be obtained directly by
reaction of ketones with glyoxylate derivatives, we decided
to carry out a study of the aldol reaction using ethyl glyox-
ylate as electrophile and binam-prolinamides as organocat-
alysts.
Ethyl glyoxylate is commercially available in polymeric
form in 50% toluene solution. This compound has been used
as an electrophile in enantioselective processes catalyzed
by transition-metal complexes23 or organocatalysts,19 either
freshly distilled or in its polymeric form.
Entry 6c
Major product
Yieldb (%) drd
eee (%)
O
OH
21f
22
MH
AQ
69 (30)
64
–
–
50 (50)
33
OMe
OMe
8k
8l
O
O
OH
23
24
MH
AQ
22
17
90:10
76:24
80
63
O
a Reactions conditions: glyoxylic acid monohydrate (MH, 0.25 mmol) and
H2O (10 equiv), or 50% aq glyoxylic acid solution (AQ, 0.25 mmol), ketone
(2 equiv), catalyst 2a (10 mol%), 0 °C.
b For the methyl ester 8 after purification by column chromatography;
yields for the corresponding acids 7 in parenthesis.
c MH: glyoxylic acid monohydrate; AQ: 50% aq solution of glyoxylic acid.
d Determined from the 1H NMR spectrum of the crude product.
e Determined by chiral-phase HPLC analysis for the anti-isomer of the corre-
sponding methyl ester 8.
Thus, the optimization of the reaction parameters was
carried out using cyclohexanone (5a) and ethyl glyoxylate
(9) as its polymeric form as the reaction model (Table 3).
As before, the performance of different binam-prolin-
amide derivatives was evaluated. Thus, the efficiency of the
binam-prolinamide derivatives 1 and 2 was tested using 20
mol% of catalyst and 10 equivalents of nucleophilic ketone
5a at room temperature (Table 3, entries 1–3). Best results
were achieved with catalyst 2a, with compound 10a being
mainly obtained as its anti-isomer (Table 3, entry 3).
Catalyst 1b gave the enantiomeric compound (ent-10a),
showing again that the chirality of the resulting aldol prod-
uct is controlled by the chirality of the proline moiety (Ta-
ble 3, compare entries 1 and 2). In this reaction, the use of
the supported binam derivatives 3 and 4 as catalysts under
similar reaction conditions afforded the expected product
10a in longer reaction time but increased diastereoselectiv-
ities (Table 3, entries 4 and 5). Catalyst 2a was chosen for
the optimization of other reaction parameters, such as cat-
alyst loading, temperature, water addition effect, and
amount of nucleophile. Decreasing the amount of catalyst
to 10 mol% did not invoke changes in the obtained results
(Table 3, entry 6). Lowering the temperature to 0 °C and
–20 °C led to better results in terms of diastereo- and
enantioselectivities, but a longer reaction time was re-
quired at –20 °C (Table 3, compare entry 6 with entries 7
and 8). The addition of a small amount of water (3 equiv)
accelerated the reaction rate at –20 °C, affording product
10a with similar results but in a shorter reaction time (Ta-
ble 3, entry 9). At this temperature and in the presence of a
small amount of water, the amount of ketone was de-
creased to 5 and 2 equivalents. In both cases, similar results
in terms of diastereo- and enantioselectivities were
achieved; however, there was a lower conversion when only
2 equivalents of 5a were used (Table 3, entries 10 and 11).
With 5 equivalents of ketone 5a, the addition of a small
amount of water was necessary in order to obtain full con-
version (Table 3, entries 10 and 12). Thus, using 5 equiva-
lents of ketone 5a and 3 equivalents of water, the reaction
f In parenthesis, results obtained for the corresponding acids 7.
With the exception of cyclopentanone and cyclohexane-
1,4-dione, that gave a poor diastereoselectivity and a mod-
erate enantioselectivity (Table 2, entries 3 and 4, and 9 and
10, respectively), in all cases the major isomer obtained was
the anti-isomer 8, even when an unsymmetrical ketone
such as butan-2-one was used (Table 2, entries 23 and 24).
Only product 8k, achieved by the reaction with acetone,
was obtained with low enantioselectivity (Table 2, entries
21 and 22).
In the case of the use of 4-substituted cyclohexanones
as nucleophiles, the major diastereoisomer formed was the
expected anti,anti aldol product, with the enantioselectivi-
ty being highly dependent on the substituent at the 4-posi-
tion (Table 2, entries 11–16). The anti relative stereochem-
istry between the protons at positions 2 and 3 was deter-
1
mined by a comparison of the H NMR chemical shifts and
coupling constants found in the literature for related aldol
products. On the other hand, the anti relative configuration
between protons 3 and 5 of product 8f was determined on
the basis of an NOE observed between the methyl group at
position 5 and the proton at position 3. Comparing the re-
sults obtained using glyoxylic acid in aqueous solution with
those achieved using glyoxylic acid monohydrate, generally,
the latter led to better diastereo- and enantioselectivities.
Attemps to extend the reaction to α-functionalized ketones,
such as α-alkoxy ketones and α-tetralone, or to aliphatic al-
dehydes failed.
Several products were isolated as the α-hydroxy-γ-keto
acids 7. Products 7 are soluble in organic solvent and water,
and prone to dehydration during purification through silica
gel. Thus, in order to isolate products 7 as pure compounds,
a small amount of ethyl acetate was added to the reaction
mixture. 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
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F. J. N. Moles et al.
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Synthesis
Table 3 Optimization of the Conditions for the Reaction of Cyclohexa-
none (5a) with Ethyl Glyoxylate (9)a
ed at 25 °C, which led to product 10a in moderate enantio-
meric excess but very low diastereomeric ratio (Table 3, en-
try 16).
O
O
OH
Under the best reaction conditions (Table 3, entry 13), a
study of the scope of this reaction was carried out (Table 4).
Several cyclic and acyclic ketones were used as nucleo-
philes, but only cyclic ketones led to the expected products.
Good yields were achieved for all substrates, with the ex-
ception of products 10b, 10d, and 10g (Table 4, entries 2, 5,
and 9, respectively). For these cases, the reaction was re-
peated with the addition of 1 mL of water, which afforded
the expected products in higher yields (Table 4, entries 3, 6,
and 10). With the exception of cyclopentanone, cyclohex-
ane-1,4-dione, and 4-phenylcyclohexanone (Table 4, en-
tries 2 and 3, 7, and 9 and 10, respectively), in all cases the
major isomer obtained was the anti-isomer 10 with up to
97% ee. When 4-methyl- and 4-tert-butylcyclohexanone
were used, the major diastereoisomer formed was the ex-
pected anti,anti aldol product, 10f and 10h, with good dia-
stereo- and enantioselectivities (Table 4, entries 8 and 11,
respectively). The anti relative stereochemistry between
the protons at positions 2 and 3 was determined by a com-
O
OEt
catalyst
additive
OEt
H
O
O
10a
5a
9
Entry Cat. (mol%) Temp Time Conv.b Yieldc
anti/synd
eee (%)
(°C)
(h)
24
(%)
1
1a (20)
1b (20)
2a (20)
3 (20)
25
25
25
25
25
25
0
100
100
100
100
100
100
100
100
100
100
80
–
–
63:37
56:44
76:24
83:17
84:16
77:23
86:14
94:6
72
60f
88
75
61
88
94
96
96
96
97
77
97
90
89f
75
2
24
24
72
72
24
24
48
24
48
48
48
24
24
24
24
3
85
4
57
65
–
5
4 (20)
6
2a (10)
2a (10)
2a (10)
2a (10)g
2a (10)g,h
2a (10)g,i
2a (10)h
2a (10)g,h
1a (10)g,h
2b (10)g,h
7
–
8
–20
81
–
9
–20
–20
–20
–20
0
97:3
10
11
12
13
14
15
16
–
95:5
1
parison of the H NMR chemical shifts and coupling con-
–
93:7
stants found for compounds 10f and 10h with those of
compounds 8f and 8h. On the other hand, the anti relative
configuration between protons 3 and 5 of product 10f was
determined on the basis of an NOE observed between the
methyl group at position 5 and the proton at position 3.
Surprisingly, the reaction with 4-phenylcyclohexanone af-
forded the syn,syn aldol product 10g as the major diastereo-
isomer. This relative configuration was determined based
40
–
77:23
98:2
100
100
100
100
90
92
94
–
0
98:2
0
91:9
L-Pro
25
56:44
(20)g,h
a Reaction conditions: 5a (10 equiv), 50% toluene solution of 9 (0.25
mmol), unless otherwise stated.
1
on the different H NMR chemical shifts and coupling con-
b Conversion based on the unreacted aldehyde.
c After purification by column chromatography.
d Determined from the 1H NMR spectrum of the crude product.
e Determined by chiral-phase HPLC analysis for the anti-isomer.
f The product obtained was ent-10a.
stants observed for the protons at positions 2 and 3 of com-
pound 10g relative to 8g, while the syn relationship be-
tween protons 3 and 5 was determined by a strong NOE ob-
served between these two protons. Diastereoisomer 10g
was isolated and crystallized, with its X-ray structure con-
firming the relative stereochemistry (Figure 2).24 This ste-
reochemical result is complementary to that obtained with
glyoxylic acid, which provided mainly anti-8g (Table 2, en-
tries 13 and 14). The erratic behavior of 4-phenylcyclohexa-
none has been observed previously; namely, in its aldol re-
action with 4-nitrobenzaldehyde.20d For this reported case,
changing from ball mill conditions to conventional stirring
led to the formation of the anti,anti-isomer and the
syn,syn-isomer, respectively, as the major isomers.
g H2O (3 equiv) was added to the reaction mixture.
h Ketone 5a (5 equiv) was used.
i Ketone 5a (2 equiv) was used.
was carried out at 0 °C with 10 mol% of catalysts 2a and 1a,
with the best results being obtained with catalyst 2a under
these reaction conditions (Table 3, compare entries 13 and
14 with 10). As expected, when catalyst 2b was used under
these reactions conditions, the enantiomeric product ent-
10a was obtained (Table 3, entry 15). Finally, the effective-
ness of L-proline as the catalyst in this process was evaluat-
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F. J. N. Moles et al.
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Table 4 Aldol Reaction of Ethyl Glyoxylate (9) with Ketonesa
O
O
OH
O
2a (10 mol%)
OEt
OEt
R1
R1
+
H
H2O, 0 °C
R2
R2
10
O
O
5
9
Entry Time (h) Major product
Yieldb drc
(%)
eed (%)
O
OH
OEt
1
24
10a
10b
92
98:2
97
O
Figure 2 X-ray crystal structure of compound 10g28
O
OH
2
24
6
44
60
25:75
27:73
75
50
OEt
3e
Finally, hydrolysis of the obtained α-hydroxy-γ-keto es-
ters 10 to the corresponding acids 7 was attempted using
lithium hydroxide in a water–N,N-dimethylformamide mix-
ture or lithium bromide in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene,25 but in both cases only the dehy-
drated product resulting from 10, among other subprod-
ucts, was obtained.
In order to establish if the anomalous results obtained
with ketone 5g in the reaction with ethyl glyoxylate (9)
were due to the reaction conditions or to the use of ethyl
glyoxylate as electrophile, the aldol reaction between 4-
phenylcyclohexanone (5g) and simple aromatic aldehydes
such as p-nitrobenzaldehyde or p-chlorobenzaldehyde was
performed in water (Scheme 2). Comparing these results
with those already reported for the synthesis of compounds
12,20d,f the anti,anti diastereoselection was obtained, high-
lighting that the reaction conditions used with ethyl glyox-
ylate are responsible for the results found in its reaction
with 4-phenylcyclohexanone.
To establish a plausible explanation for this unusual di-
astereoselection, some theoretical calculations were per-
formed; however, the results found from DFT calculations
for the formation of the syn,syn-product 10g were not con-
clusive. Meanwhile, the formation of the anti,anti-isomer
using 4-tert-butylcyclohexanone as nucleophile can be ex-
plained by a classical hydrogen-bond activation through the
two NH groups (Figure 3). In this case, the enamine has a
pseudochair conformation, with the tert-butyl group in a
pseudoequatorial position. The methyl glyoxylate attack oc-
curs via the rear face of the enamine due to the two hydro-
gen-bond interactions.
O
O
O
OH
OEt
4
24
10c
10d
83
82:18f
90
O
O
OH
OEt
5
24
8
20
38
83:17
67:33
82
50
6e
O
O
O
O
OH
OEt
7
8
24
24
10e
10f
84
92
45:55
56
93
O
O
O
OH
OEt
OEt
85:5:5:2
O
O
O
OH
9
24
6
20
90
10:86:3:1 74
6:90:3:1
10g
10e
89
Ph
O
OH
OEt
11
24
10h
89
90:5:4:1
85
O
We have demonstrated that N-tosyl-binam-prolinamide
is an efficient catalyst to promote the reaction of glyoxylic
acid as electrophile under aqueous conditions. This chiral
organocatalyst gave better results than L-proline in the syn-
thesis of enantioenriched α-hydroxy-γ-keto carboxylic es-
ters, being possible to obtain enantioenriched α-hydroxy-γ-
keto acids by aqueous extraction, without compromising
the achieved enantioselectivities. For cyclic ketones except
a Reactions conditions: 50% ethyl glyoxylate in toluene (0.25 mmol), ketone
5 (5 equiv), H2O (3 equiv), catalyst 2a (10 mol%), 0 °C.
b After purification by column chromatography.
c Determined from the 1H NMR spectrum of the crude product.
d Determined by chiral-phase HPLC analysis for the anti-isomer 10.
e In the presence of H2O (1 mL).
f Epimerization occurs during column chromatography purification; dr for
the pure product is 67:33.
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F. J. N. Moles et al.
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Synthesis
O
O
OH
2a (10 mol%)
H2O, 0 °C
+
ArCHO
11
Ar
Ph
5
Ph
12
12a, Ar = 4-O2NC6H4, 55%, dr 88:8:3:1, 92% ee .
12b, Ar = 4-ClC6H4, 16%, dr 65:26:7:2, 86% ee
Scheme 2 Binam-prolinamide desymmetrization of 4-phenylcyclohexanone
formed on an Agilent 1100 series system equipped with a chiral col-
umn and automatic injector, using mixtures of n-hexane–isopropyl
alcohol as mobile phase, at 25 °C. Analytical TLC was performed on
Schleicher & Schuell F1400/LS silica gel plates and the spots were vi-
sualized with a KMnO4 solution. Silica gel 60 (0.040–0.063 mm) was
employed for flash chromatography. High-resolution mass spectra
(HRMS-ESI) were carried out by the Research Technical Services of
the University of Alicante on a Waters LCT Premier XE apparatus
equipped with a time-of-flight analyzer; the samples were ionized by
ESI techniques and introduced by ultrahigh-pressure liquid chroma-
tography (UPLC) using a Waters Acquity H-Class system.
Aldehyde–Ketone Aldol Reaction Using Glyoxylic Acid Monohy-
drate; General Procedure
To a mixture of glyoxylic acid monohydrate (0.023 g, 0.25 mmol), cat-
alyst (10 mol%), and water (0.045 mL, 2.5 mmol) at the indicated tem-
perature was added the corresponding ketone (0.5 mmol). The reac-
tion mixture was stirred until the glyoxylic acid was consumed (mon-
itored by TLC). Then, 2 M TMSCHN2 in Et2O (0.5 mL, 1 mmol) was
added to the crude product. The corresponding mixture was stirred
for 1 h, and the solvents were evaporated in vacuo. The resulting resi-
due was purified by chromatography (hexanes–EtOAc) to yield the
pure aldol product.
Figure 3 NH activation mode affording anti,anti-isomers
Aldehyde–Ketone Aldol Reaction Using a 50% Aqueous Solution of
Glyoxylic Acid; General Procedure
To a mixture of 50% aq glyoxylic acid solution (0.027 mL, 0.25 mmol)
and catalyst (10 mol%) at the indicated temperature was added the
corresponding ketone (0.5 mmol). The reaction mixture was stirred
until the glyoxylic acid was consumed (monitored by TLC). Then, 2 M
TMSCHN2 in Et2O (0.5 mL, 1 mmol) was added to the crude product.
The corresponding mixture was stirred for 1 h, and the solvents were
evaporated in vacuo. The resulting residue was purified by chroma-
tography (hexanes–EtOAc) to yield the pure aldol product.
cyclopentanone and 4-substituted cyclohexanones, mainly
anti- and anti,anti-isomers were obtained as the major
product in moderate to high enantioselectivities (up to 97%
ee). Good results in terms of diastereo- and enantioselectiv-
ities were also accomplished by using polymeric ethyl gly-
oxylate as electrophile in the aldol reaction, but only with
cyclic ketones in the presence of water and N-tosyl-binam-
prolinamide as catalyst. Surprisingly, when 4-phenylcyclo-
hexanone was used as nucleophile, the syn,syn-product was
obtained as the major diastereoisomer.
Methyl (R)-2-Hydroxy-2-[(S)-2-oxocyclohexyl]acetate (8a)21
Data for the major isomer (2S,2′R).
26
Yellow oil; yield: 0.036 g (78%); [α]D –27 (c 1.3, CHCl3); Rf = 0.23
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3507.9 (OH), 1734.7 (C=O), 1707.7 (C=O), 1239.1 (OCH3) cm–1
.
Catalysts 1 and 2 were prepared according to literature proce-
dures.14h,15b All the reagents were commercially available and used
without further purification. Only the structurally most important
peaks of the IR spectra [recorded on a Jasco 4100 LE (Pike Miracle
ATR) spectrophotometer] are listed. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained on a Bruker AC-300 instrument us-
ing CDCl3 as solvent and TMS as internal standard, unless otherwise
stated. Optical rotations were measured on a Jasco P-1030 polarime-
ter with a 5-cm cell (c given in g/100 mL). HPLC analyses were per-
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.04 (d, J = 3.3 Hz, 1 H, CHOH),
3.78 (s, 3 H, OCH3), 2.97 (ddd, J = 12.8, 5.9, 3.3 Hz, 1 H, CHCHOH),
2.48–2.23 (m, 2 H, Hcyclo), 2.20–2.03 (m, 2 H, Hcyclo), 2.03–1.84 (m, 2 H,
H
cyclo), 1.80–1.62 (m, 2 H, Hcyclo).
13C NMR (75 MHz, CDCl3 + TMS): δ = 211.3 (C), 173.8 (C), 71.1 (CH),
53.6 (CH3), 52.5 (CH), 42.0 (CH2), 30.1 (CH2), 26.9 (CH2), 24.8 (CH2).
MS (EI): m/z (%) = 186 (16) [M+] (C9H14O4), 154 (19), 136 (17), 127
(100), 109 (20), 98 (36), 81 (81), 57 (30).
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GC (Cyclohexyl-β column, 130 °C, 13.4 psi): tR = 49.5 (minor anti),
50.7 (major anti), 68.2 (minor syn), 69.5 (major syn) min.
HRMS: m/z calcd for C13H21NO6: 287.1369; m/z [M+ + 1] calcd for
C
13H21NO6: 288.1447; found: 288.1446.
HPLC (Chiralpak IA column, hexane–EtOH, 90:10, 1 mL/min, 25 °C,
210 nm): tR = 15.5 (major anti), 18.2 (major syn), 20.1 (minor syn),
32.8 (minor anti) min.
Methyl (R)-2-Hydroxy-2-[(R)-2-oxocyclopentyl]acetate (8b)17b
Obtained as a diastereoisomeric mixture (47:53, anti/syn).
26
Yellow oil; yield: 0.036 g (84%); [α]D +20 (c 1.4, CHCl3); Rf = 0.25
(hexanes–EtOAc, 1:1; revealed with KMnO4).
Methyl (R)-2-[(R)-2,5-Dioxocyclohexyl]-2-hydroxyacetate (8e)
Obtained as a diastereoisomeric mixture (40:60, anti/syn).
IR (film): 3453.9 (OH), 1735.6 (C=O), 1722.1 (C=O), 1243.9 (OCH3) cm–1
.
26
Brown oil; yield: 0.035 g (70%); [α]D –15 (c 0.7, MeOH); Rf = 0.35
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.73 (d, J = 2.5 Hz, 1 H, syn), 4.34
(d, J = 3.4 Hz, 1 H, anti), 3.83 (s, 3 H, OCH3, anti), 3.81 (s, 3 H, OCH3,
syn), 2.76–2.66 (m, 1 H, OH, anti), 2.62–2.51 (m, 1 H, OH, syn), 2.41–
2.14 (m, 4 H, Hcyclo), 2.14–2.00 (m, 4 H, Hcyclo), 2.00–1.86 (m, 4 H, Hcyc-
lo), 1.86–1.72 (m, 2 H, Hcyclo).
13C NMR (75 MHz, CDCl3 + TMS): δ = 217.9 (C), 217.7 (C), 174.6 (C),
173.9 (C), 69.6 (CH), 68.8 (CH), 52.8 (2 × CH3), 51.9 (CH), 51.6 (CH),
38.5 (CH2), 38.4 (CH2), 25.9 (CH2), 22.4 (CH2), 20.7 (CH2), 20.5 (CH2).
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3503.1 (OH), 1730.8 (C=O), 1705.7 (C=O), 1267.9 (OCH3) cm–1
.
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.90 (dd, J = 3.9, 2.1 Hz, 1 H,
CHOH, syn), 4.15 (dd, J = 4.7, 2.6 Hz, 1 H, CHOH, anti), 3.85 (s, 3 H,
OCH3, anti), 3.83 (s, 3 H, OCH3, syn), 3.31 (ddd, J = 11.6, 6.2, 2.6 Hz, 1
H, CHCHOH, anti), 3.19–2.49 (m, 13 H, Hcyclo).
13C NMR (75 MHz, CDCl3 + TMS): δ = 207.4 (C), 207.3 (2 × C), 207.2
(C), 173.4 (C), 173.2 (C), 70.4 (CH), 69.8 (CH), 53.2 (CH3), 53.0 (CH3),
49.0 (CH), 48.8 (CH), 40.5 (2 × CH2), 37.5 (CH2), 37.0 (CH2), 36.3 (CH2),
36.1 (CH2).
MS (EI): m/z (%) = 172 (3) [M+] (C8H12O4), 154 (16), 140 (53), 122 (25),
113 (100), 95 (28), 85 (50), 67 (84), 57 (37).
GC (CP-Chirasil-Dex CB column, 120 °C, 13.4 psi): tR = 23.2 (major
anti), 25.2 (minor anti), 38.7 (major syn), 40.6 (minor syn) min.
HRMS: m/z calcd for C9H12O5: 200.0685; m/z [M+ + 1] calcd for
C9H12O5: 201.0763; found: 201.0753.
Methyl (R)-2-Hydroxy-2-[(S)-4-oxotetrahydro-2H-pyran-3-yl]ace-
tate (8c)
GC (CP-Chirasil-Dex CB column, 140 °C, 13.4 psi): tR = 68.4 (minor
syn), 70.7 (major syn), 80.5 (major anti), 84.3 (minor anti) min.
Obtained as a diastereoisomeric mixture (89:11, anti/syn).
Yellow oil; yield: 0.040 g (86%); [α]D26 –23 (c 1, MeOH); Rf = 0.28 (hex-
anes–EtOAc, 1:1; revealed with KMnO4).
Methyl (R)-2-Hydroxy-2-[(1S,5S)-5-methyl-2-oxocyclohexyl]ace-
tate (8f)26
Obtained as a diastereoisomeric mixture (84:12:2:2).
IR (film): 3471.2 (OH), 1737.5 (C=O), 1712.5 (C=O), 1121.4 (OCH3) cm–1
.
26
Yellow oil; yield: 0.040 g (80%); [α]D –38 (c 1.3, MeOH); Rf = 0.33
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.71 (d, J = 3.6 Hz, 1 H, CHOH,
syn), 4.36–4.09 (m, 4 H, Hcyclo), 4.07 (d, J = 3.1 Hz, 1 H, CHOH, anti),
3.95–3.67 (m, 10 H), 3.18 (ddd, J = 10.9, 6.7, 3.1 Hz, 1 H, CHCHOH,
anti), 3.00 (ddd, J = 9.8, 6.2, 3.6 Hz, 1 H, CHCHOH, syn), 2.72–2.31 (m,
4 H, Hcyclo).
13C NMR (75 MHz, CDCl3 + TMS): δ = 205.8 (C), 205.4 (C), 173.5 (C),
173.3 (C), 69.8 (CH2), 68.1 (CH2), 68.0 (CH2), 67.8 (CH), 67.7 (CH2),
67.3 (CH), 54.4 (CH3), 53.8 (CH3), 52.8 (2 × CH), 42.3 (2 × CH2).
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3489.6 (OH), 1736.6 (C=O), 1707.7 (C=O), 1127.2 (OCH3) cm–1
.
Data for the major isomer (1S,5S,2′R).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.04 (dd, J = 7.5, 3.6 Hz, 1 H,
CHOH), 3.79 (s, 3 H, OCH3), 3.12–3.02 (m, 2 H), 2.54–2.09 (m, 4 H,
H
cyclo), 2.09–1.68 (m, 3 H, Hcyclo), 1.20 (d, J = 7.0 Hz, 3 H, CHCH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 211.7 (C), 173.8 (C), 71.4 (CH),
52.6 (CH3), 49.3 (CH), 37.7 (CH2), 35.6 (CH2), 32.2 (CH2), 26.7 (CH),
18.2 (CH3).
HRMS: m/z calcd for C8H12O5: 188.0700; m/z [M+ + 1] calcd for
C8H12O5: 189.0763; found: 189.0763.
GC (CP-Chirasil-Dex CB column, 140 °C, 13.4 psi): tR = 17.3 (major
anti), 18.0 (minor anti), 22.5 (minor syn), 24.0 (major syn) min.
MS (EI): m/z (%) = 200 (12) [M+] (C10H16O4), 168 (9), 141 (100), 123
(24), 112 (29), 95 (62), 55 (28).
GC (CP-Chirasil-Dex CB column, 120 °C, 13.4 psi): tR = 53.9 (major an-
ti), 60.6 (minor anti) min.
tert-Butyl (S)-3-[(R)-1-Hydroxy-2-methoxy-2-oxoethyl]-4-oxo-
piperidine-1-carboxylate (8d)
Obtained as a diastereoisomeric mixture (93:7, anti/syn).
Methyl (R)-2-Hydroxy-2-[(1S,5S)-2-oxo-5-phenylcyclohexyl]ace-
tate (8g)
26
Yellow oil; yield: 0.038 g (53%); [α]D –64 (c 1.2, MeOH); Rf = 0.18
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3463.5 (OH), 1741.4 (C=O), 1687.4 (C=O), 1156.1 (OCH3) cm–1
Obtained as a diastereoisomeric mixture (83:9:5:3).
.
26
Yellow oil; yield: 0.032 g (50%); [α]D –17 (c 0.9, MeOH); Rf = 0.2
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.70 (dd, J = 4.5, 3.4 Hz, 1 H,
CHOH, syn), 4.11 (dd, J = 6.2, 2.8 Hz, 1 H, CHOH, anti), 3.82 (s, 3 H,
OCH3, syn), 3.80 (s, 3 H, OCH3, anti), 3.58–2.80 (m, 8 H, Hcyclo), 2.59–
2.21 (m, 4 H, Hcyclo), 1.50 (s, 9 H, C(CH3)3, anti), 1.49 (s, 9 H, C(CH3)3,
syn).
13C NMR (75 MHz, CDCl3 + TMS): δ = 206.9 (C), 206.5 (C), 173.4 (C),
173.3 (C), 154.5 (2 × C), 80.7 (2 × C), 68.7 (CH), 68.1 (CH), 52.8
(2 × CH), 52.5 (2 × CH3), 45.2 (2 × CH2), 43.0 (2 × CH2), 40.9 (CH2), 40.8
(CH2), 28.3 (6 × CH3).
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3493.4 (OH), 1736.6 (C=O), 1708.6 (C=O), 1108.9 (OCH3) cm–1
.
Data for the (1S,5S,2′R)-isomer.
1H NMR (300 MHz, CDCl3 + TMS): δ = 7.44–7.29 (m, 5 H, ArH), 4.23
(dd, J = 6.7, 4.1 Hz, 1 H, CHOH), 3.81 (s, 3 H, OCH3), 3.41–3.29 (m, 1 H,
H
cyclo), 3.12 (d, J = 6.7 Hz, 1 H, OH), 3.11–3.01 (m, 1 H, Hcyclo), 2.65–2.22
(m, 6 H, Hcyclo).
13C NMR (75 MHz, CDCl3 + TMS): δ = 211.0 (C), 173.7 (C), 143.3 (C),
128.8 (CH), 126.8 (CH), 126.7 (CH), 71.6 (CH), 52.7 (CH3), 50.4 (CH),
39.1 (CH2), 37.0 (CH), 34.3 (CH2), 30.6 (CH2).
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F. J. N. Moles et al.
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HRMS: m/z calcd for C15H18O4: 262.1200; m/z [M+ + 1] calcd for
15H18O4: 263.1283; found: 263.1283.
13C NMR (75 MHz, CDCl3 + TMS; 1:1 diastereoisomeric mixture):
δ = 207.7 (2 × C), 173.6 (C), 173.2 (C), 68.5 (CH), 67.6 (CH), 62.3
(2 × CH3), 53.0 (2 × CH), 46.4 (CH2), 46.0 (CH2), 13.5 (CH2), 11.0 (CH2).
C
HPLC (Chiralpak IA column, hexane–EtOH, 90:10, 1 mL/min, 25 °C,
210 nm): tR = 22.2 (minor anti), 25.4 (major anti) min.
HRMS: m/z calcd for C7H10O4: 158.0600; m/z [M+ + 1] calcd for
C7H10O4: 159.0657; found: 159.0654.
Methyl (R)-2-[(1S,5S)-5-tert-Butyl-2-oxocyclohexyl]-2-hydroxy-
acetate (8h)
GC (CP-Chirasil-Dex CB column, 120 °C, 13.4 psi): tR = 14.5 (major an-
ti), 15.5 (minor anti), 25.4 (syn) min.
Obtained as a diastereoisomeric mixture (84:8:5:3).
Yellow oil; yield: 0.043 g (72%); [α]D26 –42 (c 1, MeOH); Rf = 0.29 (hex-
anes–EtOAc, 1:1; revealed with KMnO4).
Methyl (R)-2-Hydroxy-4-oxopentanoate (8k)17b
26
Yellow oil; yield: 0.025 g (69%); [α]D –18 (c 0.8, CHCl3); Rf = 0.3
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3311.1 (OH), 1735.6 (C=O), 1717.3 (C=O), 1237.1 (OCH3) cm–1
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.49 (dd, J = 6.0, 4.0 Hz, 1 H,
CHOH), 3.80 (s, 3 H, OCH3), 3.00 (dd, J = 17.6, 4.0 Hz, 1 H, CHaHb-
CHOH), 2.91 (dd, J = 17.6, 6.1 Hz, 1 H, CHaHbCHOH), 2.21 (s, 3 H, CH3).
IR (film): 3473.2 (OH), 1736.6 (C=O), 1709.6 (C=O), 1236.1 (OCH3) cm–1
.
.
Data for the major isomer (1S,5S,2′R).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.22 (dd, J = 7.1, 4.7 Hz, 1 H,
CHOH), 3.80 (s, 3 H, OCH3), 3.05 (d, J = 7.2 Hz, 1 H, OH), 2.98–2.88 (m,
1 H, Hcyclo), 2.55–2.19 (m, 4 H, Hcyclo), 2.16–1.66 (m, 3 H, Hcyclo), 0.92 (s,
9 H, C(CH3)3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 206.2 (C), 174.0 (C), 66.9 (CH3),
52.7 (CH), 46.7 (CH2), 30.5 (CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 213.2 (C), 173.8 (C), 71.3 (CH),
69.3 (C), 52.6 (CH3), 50.6 (CH), 42.6 (CH), 39.5 (CH2), 27.1 (3 × CH3),
26.7 (CH2), 23.8 (CH2).
MS (EI): m/z (%) = 146 (6) (C6H10O4), 114 (13), 103 (12), 87 (100), 71
(15), 55 (12).
HRMS: m/z calcd for C13H22O4: 242.1500; m/z [M + H]+ calcd for
GC (CP-Chirasil-Dex CB column, 120 °C, 13.4 psi): tR = 15.1 (major),
C
13H22O4: 243.1596; found: 243.1585.
15.4 (minor) min.
GC (CP-Chirasil-Dex CB column, 160 °C, 13.4 psi): tR = 20.9 (major
anti), 22.5 (minor anti) min.
Methyl (2R,3S)-2-Hydroxy-3-methyl-4-oxopentanoate (8l)
Obtained as a diastereoisomeric mixture (90:10, anti/syn).
26
Methyl (R)-2-Hydroxy-2-[(S)-2-oxocycloheptyl]acetate (8i)
Obtained as a diastereoisomeric mixture (94:6, anti/syn).
Colorless oil; yield: 0.010 g (22%); [α]D –27 (c 1.2, MeOH); Rf = 0.4
(hexanes–EtOAc, 1:1; revealed with KMnO4).
Colorless oil; yield: 0.022 g (46%); [α]D26 –62.7 (c 1.2, MeOH); Rf = 0.26
IR (film): 3473.2 (OH), 1737.5 (C=O), 1711.5 (C=O), 1212.0 (OCH3) cm–1
.
(hexanes–EtOAc, 1:1; revealed with KMnO4).
1H NMR (300 MHz, CDCl3 + TMS; 40:60 diastereoisomeric mixture):
δ = 4.63 (dd, J = 3.6, 3.5 Hz, 1 H, CHOH, syn), 4.25 (dd, J = 6.7, 4.2 Hz, 1
H, CHOH, anti), 3.83 (s, 3 H, OCH3, anti), 3.80 (s, 3 H, OCH3, syn), 3.20
(d, J = 7.6 Hz, 1 H, OH, anti), 3.12–2.89 (m, 3 H), 2.26 (s, 3 H, COCH3,
anti), 2.21 (s, 3 H, COCH3, syn), 1.31 (d, J = 7.4 Hz, 3 H, CHCH3, syn),
1.18 (d, J = 7.2 Hz, 3 H, CHCH3, anti).
13C NMR (75 MHz, CDCl3 + TMS; 40:60 diastereoisomeric mixture):
δ = 210.5 (C), 209.2 (C), 174.1 (C), 173.7 (C), 72.6 (CH), 71.0 (CH), 52.8
(CH3), 52.7 (CH3), 52.6 (CH), 49.9 (CH), 28.8 (CH3), 28.3 (CH3), 13.0
(CH3), 10.5 (CH3).
IR (film): 3483.8 (OH), 1736.6 (C=O), 1697.05 (C=O), 1213.0 (OCH3)
cm–1
.
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.56 (dd, J = 4.5, 3.3 Hz, 1 H,
CHOH, syn), 4.23 (dd, J = 7.1, 3.4 Hz, 1 H, CHOH, anti), 3.81 (s, 3 H,
OCH3, syn), 3.80 (s, 3 H, OCH3, anti), 3.29 (d, J = 7.2 Hz, 1 H, OH, anti),
3.18 (d, J = 4.6 Hz, 1 H, OH, syn), 3.08 (dt, J = 10.8, 3.2 Hz, 1 H, CH-
CHOH, anti), 2.96 (dt, J = 10.6, 3.4 Hz, 1 H, CHCHOH, syn), 2.61–2.44
(m, 4 H, Hcyclo), 2.08–1.73 (m, 10 H, Hcyclo), 1.65–1.32 (m, 6 H, Hcyclo).
13C NMR (75 MHz, CDCl3 + TMS): δ = 215.1 (C), 214.5 (C), 174.0 (C),
173.9 (C), 73.7 (CH), 72.1 (CH), 55.2 (CH3), 55.0 (CH3), 52.6 (2 × CH),
44.1 (CH2), 43.8 (CH2), 29.8 (2 × CH2), 29.3 (CH2), 29.2 (CH2), 28.2
(CH2), 25.8 (CH2), 24.1 (CH2), 23.9 (CH2).
MS (EI): m/z (%) = 160 (4) [M+] (C7H12O4), 128 (7), 117 (18), 101 (78),
85 (43), 69 (100), 57 (36).
GC (CP-Chirasil-Dex CB column, 100 °C, 13.4 psi): tR = 27.1 (minor
anti), 28.8 (minor syn), 29.9 (major syn), 32.1 (major anti) min.
HRMS: m/z calcd for C10H16O4: 200.1049; m/z [M+ + 1] calcd for
C
10H16O4: 201.1127; found: 201.1126.
Aldehyde–Ketone Aldol Reaction Using a 50% Toluene Solution of
Ethyl Glyoxylate; General Procedure
GC (Cyclohexyl-β column, 150 °C, 13.4 psi): tR = 32.3 (minor anti),
32.9 (major anti), 38.9 (major syn), 40.5 (minor syn) min.
To a mixture of 50% ethyl glyoxylate in toluene (0.050 mL, 0.25
mmol), H2O (0.75 mmol), and catalyst (10 mol%) at the indicated tem-
perature was added the corresponding ketone (1.25 mmol). The reac-
tion mixture was stirred until the ethyl glyoxylate was consumed
(monitored by TLC). After concentration, the resulting residue was
purified by chromatography (hexanes–EtOAc) to yield the pure aldol
product.
Methyl (R)-2-Hydroxy-2-[(S)-2-oxocyclobutyl]acetate (8j)
Obtained as a diastereoisomeric mixture (68:32, anti/syn).
26
Colorless oil; yield: 0.014 g (35%); [α]D –16 (c 0.8, MeOH); Rf = 0.4
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3502.1 (OH), 1779.0 (C=O), 1731.8 (C=O), 1083.8 (OCH3) cm–1
.
1H NMR (300 MHz, CDCl3 + TMS; 1:1 diastereoisomeric mixture):
δ = 4.63 (dd, J = 4.5, 2.9 Hz, 1 H, CHOH, syn), 4.32 (dd, J = 4.4, 4.4 Hz, 1
H, CHOH, anti), 3.86 (s, 3 H, OCH3, syn), 3.83 (s, 3 H, OCH3, anti), 3.13–
2.93 (m, 6 H, Hcyclo), 2.32–1.97 (m, 4 H, Hcyclo).
Ethyl (R)-2-Hydroxy-2-[(S)-2-oxocyclohexyl]acetate (10a)27
Data for the (2S,2′R)-isomer.
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F. J. N. Moles et al.
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26
Yellow oil; yield: 0.046 g (92%); [α]D –45 (c 4.50, CHCl3); Rf = 0.20
Ethyl (R)-2-[(S)-2,2-Dimethyl-5-oxo-1,3-dioxan-4-yl]-2-hydroxy-
(hexanes–EtOAc, 7:3; revealed with KMnO4).
acetate (10d)27
IR (film): 3479.9 (OH), 1731.8 (C=O), 1693.2 (C=O), 1250.2 (OCH2) cm–1
.
Obtained as a diastereoisomeric mixture (83:17, anti/syn).
Yellow oil; yield: 0.012 g (20%); [α]D26 –13 (c 1, MeOH); Rf = 0.47 (hex-
anes–EtOAc, 1:1; revealed with KMnO4).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.25 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.02 (dd, J = 7.4, 3.2 Hz, 1 H, CHOH), 3.15 (d, J = 7.5 Hz, 1 H,
OH), 3.02–2.91 (m, 1 H, CHCHOH), 2.48–2.22 (m, 2 H, Hcyclo), 2.20–
2.08 (m, 2 H, Hcyclo), 2.04–1.85 (m, 2 H, Hcyclo), 1.80–1.65 (m, 2 H,
IR (film): 3488.6 (OH), 1752.3 (C=O), 1742.4 (C=O), 1251.6 (OCH2) cm–1
.
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.77 (dd, J = 1.9, 8.0 Hz, 0.2 H,
CHOH, syn), 4.65 (dd, J = 1.9, 8.0 Hz, 1 H, CHOH, anti), 4.40–4.20 (m,
4.5 H, OCH2CH3, anti and syn, 2 × Hcyclo, anti and syn), 4.07–3.98 (m,
1.2 H, 2 × OH anti and syn), 3.13 (d, J = 5.5 Hz, 1 H, Hcyclo anti), 3.01 (d,
J = 8.0 Hz, 0.2 H, Hcyclo syn), 1.49 [s, 3 H, C(CH3)2, anti], 1.46 [s, 3.5 H,
C(CH3)2, anti and syn], 1.42 [s, 0.5 H, C(CH3)2, syn], 1.31 (t, J = 7.1 Hz,
3.5 H, OCH2CH3, anti and syn).
H
cyclo), 1.28 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 211.2 (C), 173.3 (C), 71.1 (CH),
61.6 (CH2), 53.7 (CH), 41.9 (CH2), 30.2 (CH2), 26.9 (CH2), 24.8 (CH2),
14.1 (CH3).
MS (EI): m/z (%) = 200 (6) [M+] (C10H16O4), 136 (12), 127 (100), 99 (26),
81 (70), 57 (23).
13C NMR (75 MHz, CDCl3 + TMS): δ = 206.0 (C), 205.6 (C), 171.7 (C),
171.0 (C), 100.9 (2 × C), 77.5 (CH), 76.4 (CH), 70.4 (CH), 69.3 (CH), 67.0
(CH2), 66.8 (CH2), 62.3 (CH2), 62.1 (CH2), 24.4 (CH3), 23.9 (CH3), 23.5
(CH3), 23.2 (CH3), 14.2 (CH3), 14.1 (CH3).
HPLC (Chiralpak IA column, hexane–EtOH, 95:5, 0.5 mL/min, 25 °C,
280 nm): tR = 26.8 (major anti), 31.3 (major syn), 32.6 (minor syn),
35.5 (minor anti) min.
Ethyl (R)-2-Hydroxy-2-[(R)-2-oxocyclopentyl]acetate (10b)27
Obtained as a diastereoisomeric mixture (25:75, anti/syn).
HRMS: m/z [M + H]+ calcd for C10H16O6: 232.0947; found: 232.0959.
GC (HP-20 column, 130 °C, 13.4 psi): tR = 51.2 (major anti), 51.7
(minor anti), 61.2 (syn) min.
26
Yellow oil; yield: 0.020 g (44%); [α]D +18 (c 1.1, MeOH); Rf = 0.55
(hexanes–EtOAc, 7:3; revealed with KMnO4).
Ethyl (R)-2-[(R)-2,5-Dioxocyclohexyl]-2-hydroxyacetate (10e)
Obtained as a diastereoisomeric mixture (45:55, anti/syn).
IR (film): 3500.1 (OH), 1735.4 (C=O), 1728.7 (C=O), 1260.0 (OCH2) cm–1
.
Data for the major isomer (2R,2′R).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.72 (d, J = 2.4 Hz, 1 H, CHOH),
4.27 (q, J = 7.1 Hz, 2 H, OCH2CH3), 2.57 (ddd, J = 2.5, 1.9, 1.0 Hz, 1 H,
26
Brown oil; yield: 0.044 g (84%); [α]D +5 (c 1.2, MeOH); Rf = 0.20
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3458.7 (OH), 1726.7 (C=O), 1715.4 (C=O), 1296.9 (OCH2) cm–1
.
H
cyclo), 2.42–2.26 (m, 1 H, Hcyclo), 2.25–2.14 (m, 1 H, Hcyclo), 2.14–2.00
(m, 1 H, Hcyclo), 2.00–1.87 (m, 2 H, Hcyclo), 1.86–1.71 (m, 1 H, Hcyclo),
1.32 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 217.8 (C), 174.2 (C), 68.7 (CH),
62.1 (CH2), 51.6 (CH), 38.5 (CH2), 22.3 (CH2), 20.5 (CH2), 14.2 (CH3).
Data for the major isomer (2R,2′R).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.87 (d, J = 2.1 Hz, 1 H, CHOH),
4.31 (q, J = 7.3 Hz, 2 H, OCH2CH3), 3.12 (ddd, J = 10.5, 6.2, 2.1 Hz, 1 H,
H
cyclo), 3.06–2.68 (m, 5 H, Hcyclo), 2.55 (dd, J = 16.9, 6.2 Hz, 1 H, Hcyclo),
MS (EI): m/z (%) = 186 (5) [M+] (C9H14O4), 168 (7), 140 (36), 122 (10),
1.30 (t, J = 7.3 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 207.4 (C), 207.3 (C), 173.0 (C),
70.5 (CH), 62.6 (CH2), 49.0 (CH), 40.6 (CH2), 37.0 (CH2), 36.2 (CH2),
14.1 (CH3).
113 (100), 95 (21), 85 (50), 67 (78), 57 (27).
GC (Lipodex E column, 150 °C, 13.4 psi): tR = 25.1 (anti), 33.4 (major
syn), 34.4 (minor syn) min.
HRMS: m/z [M]+ calcd for C10H14O5: 214.0841; found: 214.0865.
Ethyl (R)-2-Hydroxy-2-[(S)-4-oxotetrahydro-2H-pyran-3-yl]ace-
GC (CP-Chirasil-Dex CB column, 160 °C, 13.4 psi): tR = 23.8 (minor
anti), 24.4 (major anti), tR = 26.8 (syn) min.
tate (10c)27
Obtained as a diastereoisomeric mixture (67:33, anti/syn).
Yellow oil; yield: 0.042 g (83%); [α]D26 –10 (c 1, MeOH); Rf = 0.31 (hex-
Ethyl (R)-2-Hydroxy-2-[(1S,5S)-5-methyl-2-oxocyclohexyl]acetate
anes–EtOAc, 1:1; revealed with KMnO4).
(10f)
IR (film): 3472.2 (OH), 1732.7 (C=O), 1717.3 (C=O), 1206.3 (OCH2) cm–1
.
Obtained as a diastereoisomeric mixture (88:5:5:2).
26
Yellow oil; yield: 0.053 g (92%); [α]D –35 (c 0.9, MeOH); Rf = 0.66
Data for the major isomer (2S,2′R).
(hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (film): 3488.6 (OH), 1731.8 (C=O), 1708.6 (C=O), 1255.4 (OCH2) cm–1
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.35–4.14 (m, 4 H, OCH2CH3,
2 × Hcyclo), 4.06 (d, J = 3.5 Hz, 1 H, CHOH), 4.03–3.72 (m, 2 H, Hcyclo),
3.18 (ddd, J = 6.3, 3.5, 1.1 Hz, 1 H, CHCHOH), 2.69–2.55 (m, 1 H, Hcyclo),
2.39 (ddd, J = 15.0, 3.0, 2.1 Hz, 1 H, Hcyclo), 1.29 (t, J = 7.2 Hz, 3 H,
OCH2CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 205.6 (C), 173.1 (C), 69.7 (CH2),
68.0 (CH2), 67.8 (CH), 62.1 (CH2), 54.4 (CH), 42.2 (CH2), 14.1 (CH3).
.
Data for the major isomer (1S,5S,2′R).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.26 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 4.04 (d, J = 3.8 Hz, 1 H, CHOH), 3.20 (s, 1 H, OH), 3.06 (ddd,
J = 11.8, 8.2, 5.1 Hz, 1 H, Hcyclo), 2.54–2.36 (m, 1 H, Hcyclo), 2.37–2.09
(m, 3 H, Hcyclo), 2.07–1.89 (m, 1 H, Hcyclo), 1.89–1.67 (m, 2 H, Hcyclo),
1.31 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.20 (d, J = 7.0 Hz, 3 H, CHCH3).
MS (EI): m/z (%) = 202 (6) [M+] (C9H14O5), 156 (9), 129 (56), 99 (66), 73
13C NMR (75 MHz, CDCl3 + TMS): δ = 211.5 (C), 173.6 (C), 71.4 (CH),
61.7 (CH2), 52.8 (CH), 41.1 (CH2), 35.6 (CH2), 34.7 (CH2), 31.4 (CH),
21.4 (CH3), 14.2 (CH3).
(100), 57 (94).
GC (Lipodex E column, 140 °C, 13.4 psi): tR = 67.2 (minor anti), 69.3
(major anti), 86.1 (minor syn), 88.1 (major syn) min.
HRMS: m/z [M]+ calcd for C11H18O4: 214.1205; found: 214.1190.
GC (CP-Chirasil-Dex CB column, 160 °C, 13.4 psi): tR = 64.1 (major anti
(C2–C3)), 70.1 (minor anti (C2–C3)) min.
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26
Ethyl (S)-2-Hydroxy-2-[(1S,5S)-2-oxo-5-phenylcyclohexyl]acetate
Colorless oil; yield: 0.030 g (71%); [α]D –10 (c 0.9, MeOH); Rf = 0.1
(10g)
(EtOAc, revealed with KMnO4).
IR (film): 3421 (CO2H), 1714 (C=O), 1702 (C=O) cm–1
.
Data for the (1S,5S,2′S)-isomer.
26
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.18 (d, J = 3.1 Hz, 1 H, CHOH),
3.12–2.98 (m, 1 H, CHCHOH), 2.56–2.31 (m, 2 H, Hcyclo), 2.31–2.06 (m,
2 H, Hcyclo), 2.05–1.90 (m, 1 H, Hcyclo), 1.88–1.58 (m, 3 H, Hcyclo).
White solid; yield: 0.062 g (90%); mp 85–86 °C; [α]D –21 (c 1.0,
MeOH); Rf = 0.60 (hexanes–EtOAc, 1:1; revealed with KMnO4).
IR (melt): 3483.8 (OH), 1716.5 (C=O), 1706.7 (C=O), 1254.5 (OCH2)
cm–1
.
13C NMR (75 MHz, CDCl3 + TMS): δ = 213.0 (C), 176.8 (C), 70.4 (CH),
1H NMR (300 MHz, CDCl3 + TMS): δ = 7.20–7.00 (m, 5 H, ArH), 4.78
(dd, J = 4.4, 2.3 Hz, 1 H, CHOH), 4.27 (q, J = 7.1 Hz, 2 H, OCH2CH3),
3.15–3.02 (m, 2 H, Hcyclo), 3.00 (d, J = 4.5 Hz, 1 H, OH), 2.66–2.55 (m, 2
H, Hcyclo), 2.34–2.17 (m, 2 H, Hcyclo), 2.07–1.96 (m, 2 H, Hcyclo), 1.32 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 209.3 (C), 173.5 (C), 144.3 (C),
128.6 (2 × CH), 126.8 (CH), 126.7 (2 × CH), 69.0 (CH), 61.9 (CH2), 53.2
(CH), 42.7 (CH), 41.4 (CH2), 34.0 (CH2), 33.8 (CH2), 14.2 (CH3).
53.7 (CH), 42.0 (CH2), 30.2 (CH2), 27.2 (CH2), 24.7 (CH2).
MS (EI): m/z (%) = 172 (2) [M+] (C8H12O4), 136 (10), 126 (100), 109
(95), 97 (18), 81 (51).
(R)-2-Hydroxy-2-[(S)-2-oxocycloheptyl]acetic Acid (7i)28
Data for the major isomer (2S,2′R).
26
Colorless oil; yield: 0.012 g (26%); [α]D –33 (c 1.1, MeOH); Rf = 0.1
(EtOAc, revealed with KMnO4).
IR (film): 3351.8 (CO2H), 1745.8 (C=O), 1701.9 (C=O) cm–1
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.31 (d, J = 2.5 Hz, 1 H, CHOH),
3.29 (d, J = 10.8 Hz, 1 H, CHCHOH), 2.79–2.46 (m, 2 H), 2.11–1.90 (m, 4
H), 1.74–1.71 (m, 1 H), 1.63–1.42 (m, 2 H), 1.36–1.19 (m, 1 H).
HRMS: m/z [M]+ calcd for C16H20O4: 276.1362; found: 276.1399.
.
HPLC (OD-H column, hexane–i-PrOH, 95:5, 0.5 mL/min, 25 °C, 210
nm): tR = 29.6 (minor), 36.8 (major) min.
GC (CP-Chirasil-Dex CB column, 160 °C, 13.4 psi): tR = 23.5 (major),
24.9 (minor) min.
13C NMR (75 MHz, CDCl3 + TMS): δ = 219.4 (C), 174.8 (C), 71.2 (CH),
54.5 (CH), 43.8 (CH2), 29.4 (CH2), 28.8 (CH2), 27.1 (CH2), 23.1 (CH2).
MS (EI): m/z (%) = 186 (3) [M+] (C9H14O4), 168 (20), 122 (100), 107
(74), 92 (18), 65 (48).
Ethyl (R)-2-[(1S,5S)-5-tert-Butyl-2-oxocyclohexyl]-2-hydroxyace-
tate (10h)
Obtained as a diastereoisomeric mixture (90:5:4:1).
Yellow oil; yield: 0.057 g (89%); [α]D26 –28 (c 1, MeOH); Rf = 0.71 (hex-
anes–EtOAc, 1:1; revealed with KMnO4).
(R)-2-Hydroxy-4-oxopentanoic Acid (7k)
26
Yellow oil; yield: 0.010 g (30%); [α]D –10 (c 0.5, CHCl3); Rf = 0.1
IR (film): 3483.8 (OH), 1720.5 (C=O), 1712.5 (C=O), 1259.3 (OCH2) cm–1
.
(EtOAc, revealed with KMnO4).
IR (film): 3359.1 (OH), 1742.6 (C=O), 1714.9 (C=O) cm–1
.
Data for the major isomer (1S,5S,2′R).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.28 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 4.26 (d, J = 5.1 Hz, 1 H, CHOH), 3.14 (d, J = 7.1 Hz, 1 H, OH),
2.89 (td, J = 7.5, 5.2 Hz, 1 H, Hcyclo), 2.53–2.20 (m, 2 H, Hcyclo), 2.14–1.88
(m, 2 H, Hcyclo), 1.79 (m, 1 H, Hcyclo), 1.66–1.48 (m, 2 H, Hcyclo), 1.30 (t,
J = 7.1 Hz, 3 H, OCH2CH3), 0.92 (s, 9 H, C(CH3)3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 210.7 (C), 173.6 (C), 69.3 (CH),
61.7 (CH2), 53.1 (CH), 46.6 (CH), 41.3 (CH2), 32.6 (C), 28.0 (CH2), 27.6
(CH2), 27.5 (3 × CH3), 14.2 (CH3).
1H NMR (300 MHz, CDCl3 + TMS): δ = 4.54 (dd, J = 6.5, 4.5 Hz, 1 H,
CHOH), 3.10 (dd, J = 18.2, 4.4 Hz, 1 H, CHaHbCHOH), 3.01 (dd, J = 18.3,
6.5 Hz, 1 H, CHaHbCHOH), 2.27 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3 + TMS): δ = 208.1 (C), 174.6 (C), 66.6 (CH),
46.2 (CH2), 30.4 (CH3).
MS (EI): m/z (%) = 132 (3) [M+] (C5H8O4), 114 (18), 103 (12), 96 (100),
68 (26), 55 (8).
HRMS: m/z [M]+ calcd for C14H24O4: 256.1675; found: 256.1687.
HPLC (OD-H column, hexane–i-PrOH, 95:5, 0.5 mL/min, 25 °C, 210
nm): tR = 29.6 (minor), 36.8 (major) min.
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. We also thank the
Basque Government (GV Grant IT-291-07) and SGI/IZO-SGIker UPV-
EHU for the allocation of computational resources. We thank O. C.
Townley for English polishing and corrections.
α-Hydroxy-γ-keto Acids 7; General Procedure
To a mixture of glyoxylic acid monohydrate (0.023 g, 0.25 mmol) and
catalyst 2a (0.013 g, 0.025 mmol) at 0 °C was added the correspond-
ing ketone (0.5 mmol). The reaction mixture was stirred until the gly-
oxylic acid was consumed (monitored by TLC). Then, EtOAc (10 mL)
was added, and the crude product was washed with H2O (3 × 10 mL);
the aqueous phase was concentrated to obtain the corresponding α-
hydroxy-γ-keto acid with glyoxylic acid traces. The glyoxylic acid was
precipitated using 1,4-dioxane and the corresponding α-hydroxy-γ-
keto acid was purified by passage through a small silica gel pad and
concentration in vacuo.
Supporting Information
Supporting information for this article is available online at
(R)-2-Hydroxy-2-[(S)-oxocyclohexyl]acetic Acid (7a)
Data for the major isomer (2S,2′R).
http://dx.doi.org/10.1055/s-0034-1379546.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 549–561

560
F. J. N. Moles et al.
Paper
Synthesis
References
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