Asymmetric Mannich reactions catalyzed by proline and 4-hydroxyproline derived organocatalysts in the presence of water

Article abstract of DOI:10.1016/j.tetasy.2013.03.016

The ability of amphiphilic catalysts based on proline and 4-hydroxyproline to catalyze the Mannich reaction in aqueous media is reported. With a 4-tert-butyldimethylsiloxy-substituted organocatalyst derived from N-prolylsulfonamide, the reaction of cyclohexanone with iminoglyoxylate proceeds with high enantioselectivity (>99% ee for the syn-diastereomer). This catalyst was also successfully applied in a reaction of an iminoglyoxylate with an aqueous tetrahydro-2H-pyran-2,6-diol to give the corresponding 2,3-disubstituted tetrahydropyridine with up to 95:5 dr and 98% ee.

Full text of DOI:10.1016/j.tetasy.2013.03.016

Tetrahedron: Asymmetry 24 (2013) 548–552
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Tetrahedron: Asymmetry
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Asymmetric Mannich reactions catalyzed by proline and 4-hydroxyproline
derived organocatalysts in the presence of water
Eva Veverková a, Lucia Liptáková a, Miroslav Veverka b, Radovan Šebesta a,
⇑
a Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynska dolina CH-2, SK-84215 Bratislava, Slovakia
b Eurofins Bel/Novaman Ltd, Kollárovo nám. 9, SK-81107 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 February 2013
Accepted 21 March 2013
The ability of amphiphilic catalysts based on proline and 4-hydroxyproline to catalyze the Mannich reac-
tion in aqueous media is reported. With a 4-tert-butyldimethylsiloxy-substituted organocatalyst derived
from N-prolylsulfonamide, the reaction of cyclohexanone with iminoglyoxylate proceeds with high
enantioselectivity (>99% ee for the syn-diastereomer). This catalyst was also successfully applied in a
reaction of an iminoglyoxylate with an aqueous tetrahydro-2H-pyran-2,6-diol to give the corresponding
2,3-disubstituted tetrahydropyridine with up to 95:5 dr and 98% ee.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
line-catalyzed three-component Mannich reactions between a
ketone, glyoxylate, and p-methoxyaniline worked best in DMSO
Asymmetric organocatalytic Mannich reactions are a useful
strategy for the formation of chiral nitrogen containing com-
pounds.1–4 Mannich reaction products can be used in the synthesis
of b-amino acids,5 their derivatives,6 and other biologically relevant
compounds.7–11 Organocatalytic Mannich reactions are also fre-
quent components of cascade reactions, which lead to polyfunc-
tionalized molecules from simple starting materials.12,13 Various
concepts have been developed for performing organocatalytic Man-
nich reactions. These include the use of chiral Brönsted acids14–17
and thioureas,18–24 chiral bases, such as cinchona alkaloids,25,26
ammonium and phosphonium betains,27–29 or phase-transfer
catalysis.30–34 However, the enamine activation of a carbonyl donor
component is probably the most efficient strategy for transferring
stereogenic information from a catalyst to a product and activating
the reacting partner. This was reported by List in his seminal
paper,35 followed by a number of approaches, which used enamine
activation.36–42
containing 5 equiv of water.54 In pure water, more amphiphilic cat-
alysts have to be used, as reported by Lu. A silylated threonine
organocatalyst efficiently catalyzed a three-component Mannich
reaction in water.55 Silyloxy serine and 4-hydroxyproline also
served as catalysts in this reaction.56,57 Hayashi used a similar
approach with a silyloxy-tetrazole hybrid proline catalyst and
obtained excellent results in the reactions of ketones, aldehydes,
and anisidines.49 Another approach to amphiphilic proline derived
organocatalysts was demonstrated by Tao. Diterpene isosteviol
was attached to the hydroxy group of 4-hydroxyproline. The result-
ing catalyst was effective for three-component Mannich reactions.41
Asymmetric Mannich and nitro-Mannich reactions can also be per-
formed under phase-transfer conditions.58–60,30–33
In this context, we decided to investigate Mannich reactions
using proline derived sulfonamides, and O-protected 4-hydroxypr-
olines as catalysts in an aqueous media.
Proline sulfonamides were introduced as modifiable proline
analogues,43 which work well in the Mannich reactions of cyclic
ketones in organic solvents44,45 as well as in ionic liquids.46 Proline
sulfonamides are also useful catalysts for a Michael/Mannich cas-
cade.47 Hayashi showed that derivatives of 4-hydroxyproline are
useful catalysts for aldol reactions,48 and three-component Man-
nich reactions in the presence of water.49
2. Results and discussion
Recently, we have reported on the direct asymmetric Mannich
reaction of cyclohexanone with N-p-methoxyphenyl (PMP) pro-
tected a-iminoglyoxylate catalyzed by a proline-based N-arylsulfo-
nylcarboxamide in various organic solvents and ionic liquids.46 The
addition of a small amount of water often accelerates reactions and
improves enantioselectivities;61 as a result we were interested in
the influence of water on this reaction. In addition to praline itself,
its derivatives with large groups at the 2- and/or 4-position are
suitable also for the reaction in water. Therefore, we employed
proline-derived arylsulfonylcarboxamides 1a46 and 1b,62
4-hydroxyproline derivatives 2a48 and 2b63 with a hydrophobic
Water is an attractive medium for organocatalytic reactions.50–53
Various amounts of water have proven to be beneficial for
organocatalytic Mannich reactions. Cordova determined that pro-
⇑
Corresponding author. Tel.: +421 2 60296208; fax: +421 2 60296337.
E-mail address: radovan.sebesta@fns.uniba.sk (R. Šebesta).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.016

E. Veverková et al. / Tetrahedron: Asymmetry 24 (2013) 548–552
549
PMP
moiety at the 4-position. We also prepared catalyst 3 as a combi-
O
O
HN
nation of the two approaches (Fig. 1).
PMP
H
H
1a (10 mol%)
N
additive(10 mol%)
Firstly, we examined the reaction between N-PMP protected a-
iminoglyoxylate 4 and cyclohexanone 5 catalyzed by organocata-
lyst 1a in the presence of water (Scheme 1).
CO2Et
+
CO2Et
H2O, r.t., 1d
6
4
5
When the reaction was carried out using only a small amount of
water, no product 6 was detected in the reaction mixture after
24 h; only starting materials were present in the reaction mixture
(Table 1, entry 1). On the basis of our experiences with Michael
additions in water, a basic additive was necessary for a successful
reaction.64 Therefore, we repeated the reaction with 20 mol % of
NaHCO3 and the desired product 6 was obtained in 55% yield with
syn/anti 76:24 diastereoselectivity and high enantiomeric purity
for the syn-isomer (96% ee). We also used benzoic acid as an acidic
additive. The yield of product 6 increased to 67%, but no diastere-
oselectivity or enantioselectivity (syn/anti 1:1, 8% ee for syn-6)
(Table 1, entries 2–3) was observed. Similar results were also ob-
tained with organocatalyst 1b. The enantiomeric purity of product
6 was high using basic conditions (95% ee) but decreased dramat-
ically when benzoic acid was added to the reaction medium (14%
ee) (Table 1, entries 4–5).
Scheme 1.
Table 1
Mannich reaction of 4 with 5 in aqueous mediaa
Entry Catalyst Additive Yield of 6b (%) drc (syn/anti) eed (syn) (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
2a
2a
2b
2b
2b
3
—
—
—
—
NaHCO3
PhCO2H
NaHCO3
PhCO2H
NaHCO3
PhCO2H
NaHCO3
PhCO2H
NaHCO3
NaHCO3
55 76:24
67 47:53
51 77:23
47 41:59
49 75:25
61 50:50
58 76:24
61 44:56
39 52:48
70 87:13
96 (18)e
8
95
14
83
72
96
6
70
>99
9
10f
11
Organocatalyst 2a, which has an O-dodecanoyl substituent, was
selected because its long lipophilic chain can allow for the forma-
tion of micelles with hydrophobic cores as reaction environ-
ment.48,64 It also efficiently mediates the Mannich reaction
between imine 4 and cyclohexanone 5. In this case, both basic
and acidic additives have similar effects on the enantioselectivity
of the reaction and product 6 was obtained with 83% and 72% ee,
respectively. Although, compound 6 was isolated in higher yield
under acidic conditions, there was no diastereoselectivity (Table 1,
entries 6–7).
Catalyst 2b, with an O-benzoyl substituent instead of dodecan-
oyl, behaved differently. The enantiomeric purity of compound
syn-6 increased to 96% ee upon using NaHCO3 as an additive. On
the other hand, the addition of benzoic acid led to an almost race-
mic product. The yield was similarly moderate under acidic and
basic conditions (Table 1, entries 8–9). An attempt to improve
the yield of product 6 by using more water was unsuccessful. Com-
pound 6 was isolated in only 39% yield when 4 mL (222 equiv) of
water was used. More importantly, the diastereoselectivity and
enantioselectivity of the reaction also decreased (Table 1, entry
10).
The best results were obtained with organocatalyst 3, which
combines the characteristics of both catalysts 1 and 2. Product 6
was obtained in a synthetically useful yield (70%), with high syn-
selectivity (dr 87:13), and almost complete enantioselectivity
(more than 99% ee) (Table 1, entry 11). In all cases, the enantio-
meric purity of anti-6 was low (typically below 20% ee).
After evaluating the usefulness of organocatalysts 1–3 in a pro-
totypical Mannich reaction, we applied them to more complex
transformations based on the Mannich reaction. The organocata-
lytic reaction of aldimines with 5-hydroxypentanal, described by
Xu et al.65 attracted our attention. Part of our interest stemmed
from the fact that commercially available 5-hydroxypentanal is
an aqueous solution, which predominantly consists of the cyclic
a
Experimental conditions:
a
mixture of
4
(1 mmol),
5
(2 mmol), catalyst
(0.1 mmol), additive (0.1 mmol), and water (0.15 mL).
b
Yield of the pure product after flash chromatography.
c
Determined by 1H NMR spectroscopy of the crude products.
d
e
f
Determined by enantioselective HPLC on Chiralpak OD-H column.
In parentheses is enantiomeric purity of anti-6.
Reaction performed with 4 mL of water.
hemiacetal form of 5-hydroxypentanal, that is, tetrahydro-2H-pyr-
an-2,6-diol. Therefore, we argued that a cascade reaction initiated
by a Mannich reaction of imine 5 with aldehyde 8 can be per-
formed in the presence of water using organocatalysts 1–3. The
reaction led to 2,3-disubstituted tetrahydropyridines. Xu et al. re-
ported that the best reaction conditions for this reaction were
the combination of the simple (S)-proline as an organocatalyst
with DMSO as a solvent. Therefore, in an initial experiment, we
treated N-PMP aldimine 7 formed from p-nitrobenzaldehyde with
tetrahydro-2H-pyran-2,6-diol 8 in the presence of catalyst 2a in
DMSO (Scheme 2). After 18 h of stirring, the presence of product
9a was confirmed by 1H NMR analysis of the crude reaction mix-
ture. However, we were unable to isolate it in its pure form. Com-
plete decomposition of the crude material was observed using
column chromatography with both silica gel and aluminum oxide
as the stationary phase.
Since we were able to easily purify product 6 prepared using
iminoglyoxylate 4, we decided to continue in our studies with this
substrate. The reaction of tetrahydro-2H-pyran-2,6-diol 8 with
iminoglyoxylate 4 afforded after 18 h the desired tetrahydropyri-
dine 9b in a low 13% yield, but in high diastereomeric purity (dr
>95:5), and with medium enantiomeric purity (55% ee). (Table 2,
entry 1). The higher stability of product 9b allowed for its purifica-
tion by column chromatography. The addition of benzoic acid had
a negative effect both on the yield and the enantioselectivity of the
reaction (Table 2, entry 2). On the other hand, a basic medium
R
R
tBu
O
O
Bu
Si
H
Me
Me
H
N
H
O
H
N
S
N
H
CO2H
S
N
H
N
H
O
O
O
O
O
O
1a
, R = Bu
1b, R = NO2
2a, R = C11H23
2b, Ph
3
Figure 1.

550
PMP
E. Veverková et al. / Tetrahedron: Asymmetry 24 (2013) 548–552
RO
HO
O
OH
CHO
N
OR
2a (10 mol%)
DMSO, rt
+
O
H
R
N
R
N
N
HN SO2Ar
PMP
OHC
EtO2C
N
4, R = CO2Et
7, R = p-NO2C6H4
8
H
9a R = p-NO2C6H4
9b R = COOC2H5
O
O
N
PMP
O
N
CO2Et
S
O
Scheme 2.
PMP
Ar
(10 mol % NaHCO3) led to an increase in the enantiomeric purity of
compound 9b (96% ee) (Table 2, entry 3). Since isolated yields were
medium to low, we prolonged the reaction time to 5 days, but in
this experiment no product 9b was observed (TLC) in the reaction
mixture. It seems that the tetrahydropyridine product decom-
posed. Based on this observation, we attempted to improve the
yield by shortening the reaction time; product 9b was obtained
in 40% yield with high enantioselectivity after 4 h (Table 2, entry
4). To explore the solvent scope, some commonly used solvents
with differing polarities (MeOH, THF, CH2Cl2) were screened. In
comparison with DMSO, lower yields were obtained in MeOH
and THF (Table 2, entries 5–6). We found that dichloromethane
was not suitable at all. While we expected an enhancement of
the reaction in CH2Cl2 due to a possible dynamic extraction of
the product into the organic phase, no product was actually ob-
served. This is probably because the two reactants were not in suf-
ficient contact in the same phase (Table 2, entry 7).
We also attempted to perform the cascade reaction in an aque-
ous medium without any additional organic solvent (Table 2,
entries 8–11). The reaction in either acidic or basic medium was
not efficient and the yield of product 9b was between 11% and
20%. We also observed a reduction in the enantioselectivity under
basic conditions after prolonging the reaction time from 4 to 18 h
due to the stereochemical lability of the product under basic con-
ditions (Table 2, entries 8–9).
Finally, we performed a catalyst screen. Catalysts 1–3 mediated
the transformation with high diasteroselectivity (up to dr 95:5)
and high enantiomeric purity of syn-9b (98% ee). Synthetically use-
ful yields (around 50%) were obtained with proline-based catalyst
1a and catalyst 3 (Table 2, entries 13–14).
Proline, 4-hydroxyproline, and proline sulfonamide organocata-
lysts operate in the same stereochemical fashion;35,66,44,67 that is,
they all direct electrophiles through the hydrogen bond of the
COOH or CONH function. Therefore, we proposed a transition state
model similar to that of a proline catalyzed cyclization,65 in which
the imine approaches an (E)-anti-enamine, formed from aldehyde
CHO
N
CO2Et
PMP
9b
Scheme 3.
8 and catalyst 3, from the Re face. Thus the formed iminium salt
cyclizes to compound (S,S)-9b (Scheme 3).
3. Conclusion
In conclusion, we have demonstrated that the Mannich reaction
of cyclohexanone with ethyl-N-PMP-iminoglyoxylate can be effi-
ciently carried out in the aqueous medium. While better yields
were achieved using an acidic additive, basic additives led to high-
er enantioselectivities. The best results were obtained with catalyst
3 substituted both on the second and fourth positions of the pyr-
rolidine skeleton.
We also found that ethyl-N-PMP-iminoglyoxylate is more suit-
able for cascade Mannich type cyclization reactions in terms of the
stability of the product in comparison with N-PMP aldimines.
However, despite the high enantiomeric purities, the product of
the cascade was obtained in low yields in water without any addi-
tional organic solvent. The best result was obtained in DMSO by
using 2,4-disubstituted pyrrolidine 3 as the organocatalyst.
4. Experimental
4.1. General
The solvents were purified by standard methods.68 NMR spectra
were recorded on a Varian Mercury plus instrument (300 MHz for
Table 2
Cascade Mannich–type/intramolecular cyclization of 4 with an aqueous solution of 8a
Entry
Catalyst
Reaction medium
Additive
Time (h)
Yield of 9b (%)b
d.r.c
eed (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
1a
3
DMSO
DMSO
DMSO
DMSO
THF
MeOH
CH2Cl2
H2O
H2O
H2O
H2O
DMSO
DMSO
DMSO
—
18
18
18
4
4
4
4
18
4
18
4
4
13
8
7
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
—
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
55
31
96
98
98
96
—
49
61
97
96
98
98
98
PhCO2H
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
PhCO2H
PhCO2H
NaHCO3
NaHCO3
NaHCO3
40
24
18
—
15
15
11
20
38
51
56
9
10
11
12
13
14
4
4
a
Experimental conditions: a mixture of 7 (1 equiv), 8 (50% in water, 2 equiv), catalyst 2a (10 mol %), and additive (10 mol %) in organic solvent (4 mL) or water (4 mL) at
room temperature.
b
Yield of the pure product after flash chromatography.
c
Determined by 1H NMR spectroscopy of the crude products.
d
Determined by chiral-phase HPLC on a Chiralpak OD-H column.

E. Veverková et al. / Tetrahedron: Asymmetry 24 (2013) 548–552
551
1H, 75 MHz for 13C). Chemical shifts (d) are given in ppm relative to
tetramethylsilane. Optical rotations were measured on a JASCO
P2000 instrument and are given in deg cm3 gꢀ1 dmꢀ1. Column
chromatography was performed on Merck silica gel 60. Thin-layer
chromatography was performed on Merck TLC-plates silica gel 60,
F-254. Enantiomeric excesses were determined by HPLC using a
Chiralpak AD-H (Daicel Chemical Industries) column using n-hex-
Mp: 84–86 °C; ½a 2D0
ꢂ
¼ ꢀ50 (c 0.2, CHCl3); 1H NMR (CDCl3,
300 MHz) d: 7.81 (d, 2H, J = 8.1 Hz, Harom); 7.20 (d, 2H, J = 8.1 Hz,
H
arom), 4.43 (m, 2H, CHOTBS and NCHCO), 3.56 (dd, 1H, J = 12,0,
3.9 Hz, NCH), 3.25 (d, 1H, J = 12 Hz, NCH), 2.62 (t, 2H, J = 7.8,
CH2), 2.34–2.22 (m, 1H, CH), 2.09–1.97 (m, 1H, CH), 1.64–1.53
(m, 2H, CH2), 1.38–1.26 (m, 2H, CH2), 0.92 (t, 3H, J = 7.2 Hz, CH3),
0.83 (s. 9H, 3 ꢁ CH3), 0.03 (s, 6H, 2 ꢁ CH3); 13C NMR (CDCl3):
174.2, 146.8, 140.1, 128.4, 126.6, 71.3, 61.8, 54.3, 39.2, 38.7, 35.5,
33.3, 25.6, 22.3, 17.6, 13.9, ꢀ4.8. MS (ESI): 440.4 (M+).
ane/propan-2-ol as
254 nm and 269 nm.
a mobile phase and detected by UV at
Organocatalysts 1a,46 1b,62 2a,48 and 2b63 were synthesized
according to the literature. Catalyst 3 was synthesized in analogy
to literature procedures.69 The configuration of syn-6 was assigned
by comparison of the sign of the specific rotation with the litera-
ture.67 The relative configuration of 9b was established by the
NOESY NMR experiment. The absolute configuration of 9b was as-
signed by comparison of the sign of its specific rotation with sim-
ilar compounds in the literature.65
4.2.3. Procedure for the Mannich-type reaction of cyclohex-
anone imine 4 in an aqueous medium
To a solution of catalyst (0.1 mmol, 10 mol %) and additive
(10 mol %) was added cyclohexanone 5 (196 mg, 2 mmol), freshly
prepared N-(4-methoxyphenyl)-protected
a-imino ethyl glyoxy-
late 4 (207 mg, 1 mmol), and water (0.15 mL). The mixture was
stirred for 24 h. After this time, the mixture was quenched with
saturated aqueous ammonium chloride (10 mL) and extracted with
ethyl acetate (2 ꢁ 30 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by column chromatography (SiO2, EtOAc/hexane 1:5) to give prod-
uct 6 as a yellow oil.
4.2. Preparation of catalyst 3
4.2.1. trans-1-Benzyloxycarbonyl-4-(R)-tert-butyldimethylsilyl-
oxy-N-(p-butylbenzenesulfonyl)-2-(S)-pyrrolidinecarboxamide
Cbz-3
syn-6: ½a 2D0
ꢂ
¼ ꢀ33:4 (c 1.0, CHCl3) 98% ee. 1H NMR (300 MHz,
To 4-tert-butyldimethylsilyloxy-(S)-proline44 (981 mg, 4 mmol)
in THF (10 mL) was added to 16 mL of saturated NaHCO3 solution.
The mixture was brought to 0 °C in an ice bath, after which CbzCl
(1.15 mL, 8 mmol) was added dropwise. The mixture was allowed
to warm up to room temperature and stirred overnight. After this
time, the solution was acidified to pH 1 by 1 M HCl and extracted
by EtOAc (3 ꢁ 20 mL). The dried (Na2SO4) extract was concentrated
in vacuo and purified by chromatography over silica gel (eluent
AcOEt/hexanes from 1:4 to 1:2) to give 1.4 g (92%) of Cbz-protected
4-tert-butyldimethylsilyloxy-(S)-proline as an off-white wax [1H
NMR (CDCl3): 7.53–7.29 (m, 5H, Ph), 5.21–5.13 (m, 2H, OCH2Ph),
4.55–4.41 (m, 2H, CHOTBS and NCHCOOH), 3.66–3.42 (m, 2H,
NCH2), 2.24–2.02 (m, 2H, CH2), 0.85 (s, 9H, CH3), 0.66 (s, 6H, CH3)].
CDCl3) d: 6.77 (d, J = 9.3 Hz, 2H, Harom), 6.74 (d, J = 9.3 Hz, 2H, Har-
om), 4.23 (d, J = 5.4 Hz, 1H, CHNH), 4.15 (q, J = 7.2 Hz, 2H, CH2CH3),
3.88 (br s, 1H, NH), 3.74 (s, 3H, OCH3), 2.85–2.75 (m, 1H, CH), 2.49–
2.44 (m, 1H, CH), 2.39–2.28 (m, 1H, CH); 2.23–2.17 (m, 1H, CH);
2.038–2.05 (m, 1H, CH); 1.98–1.94 (m, 1H, CH), 1.84–1.64 (m,
3H; CH), 1.22 (t, J = 7.2 Hz, 3H, CH3).
anti-6: 1H NMR (300 MHz, CDCl3) d: 6.77 (d, J = 9.0 Hz, 2H, Harom);
6.63 (d, J = 9.0 Hz, 2H, Harom); 4.26 (br s, 1H, NH); 4.15 (q, J = 7.2 Hz,
2H, CH2CH3), 3.97 (d, J = 3.9 Hz, 1H, CHNH), 3.73 (s, 3H, OCH3), 3.15–
3.07 (m, 1H, CH), 2.46–2.32 (m, 2H, CH), 2.13–2.03 (m, 2H, CH), 1.98–
1.89 (m, 2H; CH); 1.77–1.67 (m, 2H, CH); 1.22 (t, J = 7.2 Hz, CH3).
HPLC (Daicel Chiralpak AD-H; hexane/iPrOH 90:10; 0.75 mL/min;
k = 254 nm) tR (minor-syn) = 26.3 min, tR (major-syn) = 28.1 min, tR
(major-anti) = 31.4 min, tR (minor-anti) = 33.0 min. Spectral data
are in agreement with the literature.46
To
1-Cbz-4-tert-butyldimethylsilyloxy-(S)-proline
(1.4 g,
3.7 mmol) in CH2Cl2 (36 mL) was added 4-butylbenzenesulfona-
mide (0.79 g, 3.7 mmol), DMAP (1.35 g, 11.1 mmol), and EDCl
(1.41 g, 7.4 mmol). The reaction mixture was stirred at room tem-
perature for 6 days, after which the solvent was evaporated in va-
cuo and the residue was diluted by 60 mL EtOAc. The mixture was
then washed with 1 M HCl (40 mL) and brine (2 ꢁ 50 mL).
4.2.4. Procedure for the cascade Mannich/cyclization reaction of
N-PMP-protected
hydro-2H-pyran-2,6-diol
To solution of catalyst (0.1 mmol, 10 mol %), additive
(10 mol %), and freshly prepared N-(4-methoxyphenyl)-protected
-imino ethyl glyoxylate 4 (207 mg, 1 mmol) was added glutaral-
a-imino ethyl glyoxalate with aqueous tetra-
a
After being dried over anhydrous Na2SO4, the solvent was evap-
orated under reduced pressure and the residue was subjected to
flash chromatography on silica gel (eluent AcOEt/hexanes 1:6) to
a
afford 0.96 g (42%) of Cbz-3 as a waxy solid. ½a D20
¼ ꢀ61 (c 0.2,
ꢂ
dehyde solution 8 (50% in water, 0.35 mL, 2 mmol). The reaction
mixture was stirred at room temperature for 4 h, after which the
mixture was quenched with saturated aqueous ammonium chlo-
ride (10 mL) and extracted with ethyl acetate (2 ꢁ 30 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. The residue was purified by column chromatography
(SiO2, EtOAc/hexane 1:3) to give ethyl-(2S,3S)-3-formyl-1-(4-
methoxyphenyl)-1,2,3,4-tetrahydropyridine-2-carboxylate 9b as a
CHCl3); 1H NMR (CDCl3, 300 MHz) d: 7.92 (d, 2H, J = 8.4 Hz, Harom);
7.37 (s, 5H, Harom), 7.31 (d, 2H, J = 8.4 Hz, Harom), 5.25–5.18 (2H, m,
OCH2Ph), 4.41–4.31 (m, 2H, CHOTBS and NCHCO), 3.41–3.37 (m,
2H, CH2NH) 2.67 (t, 2H, J = 7.8, CH2), 2.49–2.40 (m, 1H, CH), 1.92–
1.85 (m, 1H, CH), 1.61–1.57 (m, 2H, CH2), 1.36–1.30 (m, 2H, CH2),
0.92 (t, 3H, J = 7.5 Hz, CH3), 0.81 (s. 9H, 3 ꢁ CH3), 0.02 (s, 6H,
2 ꢁ CH3). 13C NMR (CDCl3): 168.5, 157.9, 149.7, 149.1, 135.8,
135.7, 128.9, 128.7, 128.3, 69.7, 68.4, 59.5, 54.7, 35.7, 33.1, 25.6,
22.3, 17.8, 13.9, ꢀ4.9. MS (ESI): 574.4 (M+).
yellow oil. ½a 2D0
¼ ꢀ131:8 (c 1.0, CHCl3) 98% ee. IR (ATR) 3434;
ꢂ
2927; 2853; 1722; 1644; 1509; 1241; 1179; 1028 cmꢀ1. UV
kmax = 269 nm. 1H NMR (CDCl3, 300 MHz) d: 9.52 (s, 1H, CHO);
6.86 (d, J = 9.3 Hz, 2H; Harom); 6.83 (d, J = 9.3 Hz, 2H; Harom); 6.46
(d, J = 8.1 Hz, 1H, @CH–N); 4.88 (d, J = 1.2 Hz, 1H, CHCOOC2H5);
4.59 (m, 1H, @CHCH2); 4.24 (q, J = 6.9 Hz, 2H, CH2CH3), 3.77 (s,
3H, OCH3), 3.22–3.18 (m, 1H, CHCH@O), 2.51 (dd, J = 5.4, 1.2 Hz,
1H, CHH); 2.32 (dd, J = 5.4, 1.2 Hz, 1H, CHH); 1.27 (t, J = 6.9 Hz,
3H, CH3). 13C NMR (CDCl3,75 MHz) d: 199.9; 170.9; 154.3; 140.1;
130.4; 118.8; 113.9; 94.4; 61.1; 57.6; 55.0; 45.7; 18.5; 13.7. HPLC
(AD-H, hexane/iPrOH 93:7, 0.75 mL/min, k = 269 nm): tR (ma-
jor) = 19.2 min, tR (minor) = 21.0 min. MS (ESI): 289.3 (M+).
4.2.2. trans-4-tert-(R)-Butyldimethylsilyloxy-N-(p-butylbenz-
enesulfonyl)-(S)-proline amide 3
To a solution of Cbz-3 (0.53 g, 0.93 mmol) in MeOH (20 mL) was
added Pd/C (54 mg). The mixture was stirred at rt under an atmo-
sphere of hydrogen. After 24 h, the methanol solution was filtered
through a short Celite column and the filtrate was concentrated in
vacuo to give a white solid. The crude product was purified by
chromatography over silica gel (eluent CHCl3/metanol 9:1) to give
catalyst 3 (0.39 g, 96%).

552
E. Veverková et al. / Tetrahedron: Asymmetry 24 (2013) 548–552
29. Zhang, W.-Q.; Cheng, L.-F.; Yu, J.; Gong, L.-Z. Angew. Chem., Int. Ed. 2012, 51,
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Financial support from Slovak Grant Agency VEGA, Grant no.
VEGA 1/0543/11 is acknowledged. This publication is the result
of the project implementation: 26240120025 supported by the Re-
search & Development Operational Programme funded by the
ERDF. This investigation was also supported by the Slovak Research
and Development Agency, Grant no. APVV-121-2009 and The
Agency of the Ministry of Education, Science, Research and Sport
of the Slovak Republic for the Structural Funds of EU, OP RaD of
ERDF, Grant ITMS 26240220040.
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