D-Glucosamine in a chimeric prolinamide organocatalyst for direct asymmetric aldol addition

Article abstract of DOI:10.1016/j.carres.2012.03.041

O-TBDPS d-glucosamine coupled with l-proline is reported to act as an efficient organocatalyst in the accomplishment of direct aldol reactions. Excellent results, in terms of chemical yields, as well as diastereomeric and enantiomeric ratios, are reported

Full text of DOI:10.1016/j.carres.2012.03.041

Carbohydrate Research 356 (2012) 273–277
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Note
D-Glucosamine in a chimeric prolinamide organocatalyst for direct
asymmetric aldol addition
a,
Mauro De Nisco a, Silvana Pedatella a, , Semiha Bektasß , Ada Nucci b, Romualdo Caputo a
⇑
a Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Napoli, Italy
b Istituto di Scienze degli Alimenti e della Nutrizione, Università Cattolica del S. C., Piacenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
O-TBDPS D-glucosamine coupled with L-proline is reported to act as an efficient organocatalyst in the
Received 29 January 2012
Received in revised form 28 March 2012
Accepted 30 March 2012
Available online 18 April 2012
accomplishment of direct aldol reactions. Excellent results, in terms of chemical yields, as well as diaste-
reomeric and enantiomeric ratios, are reported for the catalyzed additions of cyclohexanone and acetone
to variously substituted benzaldehydes.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Asymmetric synthesis
D
-Glucosamine
Organocatalysis
-Proline catalyst
L
L
-Proline, among the simple natural molecules from the ‘chiral
groups (thus designed with the purpose of matching the hydro-
phobic nature of the active site in antibodies) were used to cata-
lyze the asymmetric aldol addition.
Under such circumstances we were stimulated to design a new
catalyst that, in our opinion, should have overcome the above men-
tioned limits of other reported proline-based catalysts. It consists
pool’, is well recognized to function as an asymmetric organocata-
lyst leading to appreciable levels of enantioselectivity in a range of
synthetic transformations.1 Most importantly, it works like an en-
zyme mimic of the class I aldolase,2 catalyzing an important organ-
ic asymmetric transformation, the aldol reaction.3,4
However, the simple proline molecule has not been demon-
strated to be an efficient catalyst in aqueous medium,2(e),5 likely
due to the fact that water itself alters enantioselectivities6 by inter-
rupting the hydrogen bonds that are crucial for stabilizing the tran-
sition states of the asymmetric catalytic reactions.7 Either the use
of cosolvents or, vice versa, attempts to enhance the hydrophilic
nature of proline by grafting on it polyhydroxylated auxiliaries,8
did not lead to significantly improved results.
Indeed, having in mind the catalytic mechanism of proline, an-
other non secondary aspect is that the reactions occurring in the
aldolase antibodies are considered to be accomplished in a hydro-
phobic active site,9 where the amino functionality of lysine and
the hydroxyl group of tyrosine seem to be also involved in the
catalytic cycle. This is corroborated by the encouraging results1a,10
obtained when small organic molecules bearing hydrophobic
of
and
L
-prolinamide 1 obtained from both commercial
D-glucosamine
L-proline (as shown in Scheme 1) and displays, as highlighted
in Figure 1, three different domains, namely a hydrophobic one,
represented by the cumbersome TBDPS protecting group at the
anomeric hydroxyl of b-glucosamine, a hydrophilic one, consisting
of the sugar moiety with its three free hydroxyl groups, and finally
the functional domain represented by
Simple
L-proline nucleus.
D
-glucosamine, indeed, had been already demon-
strated11 to exert a catalytic role on direct aldol reaction of ke-
tones and aromatic aldehydes, although affording moderate
yields and poor enantiomeric excess of the aldol product. As poor,
and even worse, results were reported8b for the use of unpro-
tected D-glucosamine-L-prolinamide as catalyst for the same kind
of reactions in water. Considering, on the other hand, that small
proline-based molecules bearing hydrophobic groups,10c as al-
ready mentioned above, had been reported to exhibit good cata-
lytic activity for aldol reactions, we combined all the information
in the same molecule that, as expected, turned out to be an excel-
lent organocatalyst to accomplish direct aldol reaction of cyclo-
hexanone and aromatic aldehydes.
⇑
Corresponding author. Tel.: +39 081674118; fax: +39 081674393.
E-mail address: pedatell@unina.it (S. Pedatella).
The new catalyst was extensively tested in the direct aldol addi-
tion of cyclohexanone to variously substituted benzaldehydes,
_
Present address: Department of Chemistry, Istanbul Technical University, ITÜ
Ayazag˘a Kampüsü, 34469 Maslak-Istanbul, Turkey.
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.03.041

274
M. De Nisco et al. / Carbohydrate Research 356 (2012) 273–277
OH
OAc
OAc
i
ii
O
O
O
HO
HO
AcO
AcO
AcO
AcO
75%
84%
OH
OAc
OH
NH2
TrocHN
TrocHN
2
3
4
iii
83%
OH
OAc
OAc
O
O
OTBDPS
OTBDPS
HO
HO
AcO
AcO
O
v
vi
OTBDPS
AcO
AcO
NH
NH
75%
90%
O
O
RHN
a R=Troc
b R=H
HN
FmocN
5
iv
82%
1
6
Scheme 1. Synthesis of 1 from commercial D-glucosamine and L-proline. Reagents and conditions: (i) (a) Cl3CH2OCOCl, NaHCO3; (b) (Ac)2O, Py; (ii) BnNH2; (iii) (a) ImH,
TBDPSiCl; (iv) Zn, glacial AcOH; (v) Fmoc-Pro-OH, HOBt, EDC; (vi) NH3, MeOH.
Table 1
OH
Cyclohexanone/miscellaneous benzaldehydes aldol additions in brine, 4 °C, 48 h,
catalyzed by 1 (2 mol %)
hydrophobic
domain
hydrophilic
domain
O
HO
OTBDPS
CHO
OH
O
O
HO
NH
(2 mol%)
1
+
functional
domain
brine, 4°C, 48 h
N
R
R
2
O
H
R
Yielda (%)
dr (anti:syn)b
eec (%)
Figure 1. (2R)-Pyrrolidine-2-carboxamide, 1.
3-Chloro
4-Chloro
3-Cyano
4-Cyano
3-Fluoro
4-Fluoro
2-Methoxyl
3-Methoxyl
4-Methoxyl
3-Methyl
4-Methyl
2-Nitro
99
99
86
>99
98
99
95
>99
96
99
98
96:4
97:3
98:2
97:3
96:4
96:4
88:12
92:8
87:13
95:5
92:8
98:2
97:3
97:3
91:9
96
98
96
96
96
98
83
94
82
94
87
>99
98
96
92
under standardized conditions (2 mol % loading in brine, 4 °C, 48 h)
obtaining rather impressive results (Table 1).
Some other miscellaneous experiments, carried out using differ-
ent catalyst loadings/solvents/temperatures/reaction times, are re-
ported in Table 2.
All the results show unambiguously that 1 is an efficient cata-
lyst working in aqueous medium (see the poor results of the reac-
tions carried out in THF, Table 2) at low temperature. The very low
catalyst loading (down to 0.1 mol %, Table 2) that can be utilized, as
well as the significant catalyst recovery (72–89%) and its reuse are
noteworthy (Table 3).
Compound 1 was also tested by the addition of acetone and 4-
nitrobenzaldehyde (Table 4). The reaction with acetone was car-
ried out both in the presence and in the absence of water. In the
first case (entries 1–3) the aldol product was obtained in rather
acceptable yields (42–54%), significantly higher than the yields
(10–12%) obtained in THF (entries 4 and 5). The enantioselectivi-
ties in both cases were substantially similar. In our opinion the aro-
matic aldehyde, that is scarcely soluble in hydrophilic medium
(brine), tends to position itself in the hydrophobic pocket of the
catalyst, thus being more available for the enamine nucleophilic at-
tack. Otherwise, in the absence of water (THF), acetone and aro-
matic aldehyde are both well dissolved in the organic solvent
and this may cause a slower reaction. No reversed configuration
of the aldol product was observed.12 Our results, however, are
96
>99
98
3-Nitro
4-Nitro
4-Isopropyl
98
a
b
c
After chromatography.
Determined by 1H NMR.
Determined by HPLC on chiral column.
mostly paralleling those reported by various authors for the aldol
addition of acetone and aromatic aldehydes in the presence of
water.2e,4d,10a,12,13
The performances of the catalyst 1 can be accounted for by con-
sidering that in water (even more in brine, due to salting-out ef-
fect14) catalyst’s molecules may undergo molecular aggregation,
much like surfactants, creating a local hydrophobic microenviron-
ment in which reactions can take place. In other words, in the tran-
sition state the organic nonpolar reactants would be buried in the

M. De Nisco et al. / Carbohydrate Research 356 (2012) 273–277
275
Table 2
Aldol additions as in Table 1, catalyzed by 1, carried out under various reaction
conditions
OTBDPS
H
O
R
Mol (%) °C
Time Yielda (%) dr (anti:syn)b eec (%)
O
O
N
HO
4-Cyano
4-Cyano
4-Cyano
4-Cyano
4-Cyano (THF)
4-Nitro
4-Nitro
4-Nitro
4-Nitro
4-Nitro
2
25 48 h
99
99
92
82
57
94
98
96
90
84
52
95:5
99:1
90:10
99:1
82:18
97:3
93:7
96:4
89:11
99:1
90:10
87
98
85
99
62
98
89
98
82
96
70
2
ꢁ16 48 h
N
hydrophobic
environment
0.1
0.1
2
25
ꢁ16
4
4 d
4 d
48 h
water
H
solvent
H
HO O
O
H
O
10
2
ꢁ16 48 h
OH
25 48 h
2
ꢁ16 48 h
R
0.1
0.1
2
25
ꢁ16
4
4 d
4 d
48 h
4-Nitro (THF)
a
b
c
After chromatography.
Determined by 1H NMR.
Determined by HPLC on chiral column.
Figure 2. Proposed transition state for aldol reactions catalyzed by 1.
1. Experimental
1.1. General
Table 3
Recycle of catalyst 1. Cyclohexanone/4-nitrobenzaldehyde aldol addition in brine,
2 mol % loading, 4 °C, 48 h.
Yield (%)
dr (anti:syn)
ee (%)
Inorganics, organic reagents, and solvents were commercial
pure compounds (Aldrich, Carlo Erba) and used without further
purification. TLC analyses were performed using silica gel plates
(Merck, Silica Gel 60 F-254) visualized by UV light, iodine, and nin-
hydrin spray. Column chromatography was carried out on silica gel
(Davisil 40–63 mesh).
1st run (as in Table 1)
2nd run
3rd run
98
99
82
66
97:3
95:5
94:6
90:10
96
94
92
83
4th run
1H and 13C NMR spectra were recorded on Varian Inova
500 MHz spectrometer (unless otherwise specified): chemical
shifts in ppm (d) and J coupling constants in Hz, solvent CDCl3.
The following abbreviations indicate the multiplicity: s, singlet;
d, doublet; m, multiplet; br, broad signal. Chiral HPLC analyses
were performed by Agilent 1100 chromatograph using Daicel Chir-
alPak IC column (250 ꢀ 4.6 mm) and DAD UV detector. Eluent, hex-
ane (+TFA 0.1%)/EtOH/CH2Cl2 85:4:11. Flow, 1.2 mL minꢁ1. The
wavelengths at which the areas of both anti enantiomers were read
are reported in Supplementary data Table S1. Optical rotations
were measured at k = 589 nm (1.0 dm cell).
Table 4
Acetone/4-nitrobenzaldehyde aldol additions, catalyzed by 1 (2 mol %), carried out
under various reaction conditions
CHO
OH
O
O
(2 mol%)
1
+
O2N
NO2
Solvent
T (°C)
Time
Yielda (%)
eeb (%)
1.2. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycar
bonylamino)-
Brine
Brine
Brine
THF
25
4
ꢁ16
25
4
48 h
48 h
4 d
48 h
48 h
42
54
21
10
12
66
70
75
72
82
a,b-D
-glucopyranoside (3)18
To a vigorously stirred suspension of commercial
D-glucosamine
THF
(4.0 g, 22 mmol) and NaHCO3 (3.2 g, 38 mmol) in water (47 mL), at
room temperature, trichloroethoxycarbonyl chloride (3.5 mL,
26 mmol) was added dropwise. After 2 h, the reaction mixture
was treated with aq 1 M HCl until neutral and water was removed
from the mixture by freeze-drying. The resulting solid residue was
then diluted with pyridine (66 mL) and acetic anhydride (33 mL),
the mixture being stirred overnight at room temperature. After re-
moval of the solvents by co-evaporation with toluene under re-
duced pressure, the oily residue was diluted with CHCl3 and aq
0.1 M HCl and shaken several times with CHCl3. The combined or-
ganic extracts were washed with brine until neutral, dried
(Na2SO4), and the solvents evaporated under reduced pressure. Sil-
ica-gel chromatography (petr. ether/AcOEt, 1:1) of the crude prod-
uct gave pure 3 (8.6 g, 16.5 mmol; yield 75%). One analytical
sample: oil. Calcd for C17H22Cl3NO11 (521.03): C, 39.06; H, 4.24;
N, 2.68. Found: C, 39.09; H, 4.20; N, 2.62.
a
After chromatography.
Determined by HPLC on chiral column.
b
hydrophobic environment15 whereas the entire system would be
kept in water by a hydrophilic surface. After the reaction accom-
plishment, the moderately polar aldol molecules would be
squeezed out of the hydrophobic environment and locate them-
selves closer to the polar surface of the catalyst.16
As a matter of fact, the only significant variable in the use of cat-
alyst 1 in aqueous medium seems to be the temperature: in our
opinion this is in line with the proposed transition state (Fig. 2)
insofar as low temperature could reduce the molecular freedom
and, consequently, contribute to the aggregation that creates a
hydrophobic environment to hold the nonpolar reactants.
The results show that the synthetic catalyst 1 works ‘in the
presence of water’10c,17 without organic solvent, accomplishing al-
dol reactions with very high enantioselectivity in most cases. It can
be regarded as an interesting example of a new family of organo-
catalysts carrying different sugars and/or hydrophobic moieties
worthy to be investigated for other C–C bond forming reactions.
1H NMR: d 2.04, 2.06, 2.10, 2.20 (s, 12H, 4 ꢀ CH3), 3.83 (m, 1H,
H-5 ), 3.95 (m, 1H, H-2b), 4.02 (m, 1H, H-5b), 4.07 (m, 2H, Ha-6),
a
4.22 (m, 1H, H-2 ), 4.28 (dd, J 3.8, J 12.3, 2H, Hb-6), 4.63 (d, J
a
11.8, 1H, Ha-Troc), 4.82 (d, J 11.8, 1H, Hb-Troc), 5.13 (br d, J 9.0,
1H, NH), 5.20 (t, J 9.9, 1H, H-4), 5.28 (t, J 10.8, 1H, H-3), 5.74 (d, J
8.9, 1H, H-1b), 6.24 (d, J 3.3, 1H, H-1 ).
a

276
M. De Nisco et al. / Carbohydrate Research 356 (2012) 273–277
13C NMR: d 20.7 (CH3-Ac), 53.3 (C-2), 61.8 (C-6), 69.8 (C-4), 70.5
(C-3), 72.8 (C-5), 74.8 (C-Troc), 90.6 (C-1), 92.4 (CCl3-Troc), 154.3
(CO-Troc), 168.8, 169.3, 170.8, 171.3.
rated under reduced pressure and the crude residue was purified
on silica gel (CH2Cl2/CH3OH, 99:1) to afford the pure product 5b
(2.5 g, 4.7 mmol; 82% yield). One analytical sample: oil. Calcd for
C28H37NO8Si (543.23): C, 61.86; H, 6.86; N, 2.58. Found: C, 61.82;
1.3. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-
H, 6.88; N, 2.60.
trichloroethoxycarbonylamino)-
a
,b-D
-glucopyranose (4)
1H NMR (400 MHz): d 1.09 (s, 9H, 3 ꢀ CH3-t-butyl), 1.95 (s, 6H,
CH3-Ac), 2.04 (s, 3H, CH3-Ac), 2.34 (br s, 2H, NH2), 2.98 (dd, J 10.2, J
7.8, 1H, H-2), 3.35 (m, 1H, H-5), 3.89 (dd, J 12.0, J 2.2, 1H, Ha-6),
4.04 (dd, J 12.0, J 5.7, 1H, Hb-6), 4.39 (d, J 7.8, 1H, H-1), 4.84 (t, J
9.8, 1H, H-3), 4.95 (t, J 9.7, 1H, H-4), 7.25–7.44 (m, 6H, H-arom),
7.65–7.69 (m, 4H, H-arom).
To a magnetically stirred solution of compound 3 (8.6 g,
16.5 mmol) in anhydrous THF (50 mL) at room temperature ben-
zylamine (2.2 mL, 19.8 mmol) was added dropwise. Within 12 h
the starting protected sugar was completely consumed (TLC mon-
itoring). After removal of the solvent under reduced pressure, an
excess of aq 1 M HCl was added to the residue and the suspension
was extracted with CHCl3. The organic layers were shaken with sat-
urated aq NaHCO3, washed with brine until neutral, dried
(Na2SO4), and the solvents were evaporated under reduced pres-
sure. Silica-gel chromatography (hexane/AcOEt, 8:2) of the crude
product gave pure 4 (6.6 g, 13.8 mmol; yield 84%). One analytical
sample: oil. Calcd for C15H20Cl3NO10 (479.02): C, 37.48; H, 4.19;
N, 2.91. Found: C, 37.51; H, 4.22; N, 2.98.
13C NMR (100 MHz): d 19.0 (C-t-butyl), 20.4 (CH3-Ac), 26.6
(CH3-t-butyl), 57.7 (C-2), 62.2 (C-6), 68.9 (C-4), 71.4 (C-3), 74.6
(C-5), 98.5 (C-1), 127.14–135.7 (C-arom), 169.6–170.6–171.5
(CO-Ac).
1.6. 1-O-tert-Butyldiphenylsilyl-3,4,6-tri-O-acetyl-2-deoxy-
2-[(((9H-fluoren-9-yl)methoxy)carbonyl) pyrrolidin-2-
carboxyamido]-b-
D-glucopyranoside (6)
1H NMR: d 1.99 (s, 3H, CH3), 2.02 (s, 3H, CH3), 2.08 (s, 3H, CH3),
3.24 (br s, 1H, OH), 4.03 (ddd, J 10.3, J 3.5, 1H, H-2), 4.12–4.32 (m,
3H, H-5, Ha-6, Hb-6), 4.65 (d, J 12.0, 1H, Ha-Troc), 4.82 (d, J 12.0, 1H,
Hb-Troc), 5.13 (t, J 9.4, 1H, H-4), 5.26–5.44 (m, 3H, H-1b, H-3, NH).
13C NMR: d 20.5 (CH3-Ac), 54.0 (C-2), 61.8 (C-6), 67.5 (C-5), 68.1
(C-4), 70.6 (C-3), 74.4 (CH2), 91.6 (C-1), 154.0 (CO-Troc), 169.3–
171.2 (CO-Ac).
To a magnetically stirred solution of commercial Fmoc-
L
-Pro-
OH (3.7 g, 11.1 mmol) in anhydrous CH2Cl2 (59 mL) in an ice bath,
HOBT (3.0 g, 22.2 mmol) was added in one portion. After 30 min, a
solution of compound 5b (5.0 g, 9.3 mmol) and EDC (18.1 mL,
10.2 mmol) in the same solvent (55 mL) was added dropwise over
5 min at the same temperature. The mixture was stirred for 12 h in
an ice bath and then allowed to warm slowly to room temperature.
As soon as the starting compound 5b was completely consumed
(TLC monitoring), most of the solvent was evaporated under re-
duced pressure and replaced by EtOAc. A precipitate was filtered
off and the solution was washed with saturated aq NaHCO3, brine
until neutral, and then dried (Na2SO4). The evaporation of the sol-
vents under reduced pressure gave a crude residue that was chro-
matographed on silica gel (CH2Cl2/Et2O, 95:5) to afford the oily
coupling product 6 (7.2 g, 8.4 mmol; 90% yield). One analytical
sample: oil. Calcd for C48H54N2O11Si (862.35): C, 66.80; H, 6.31;
N, 3.25. Found: C, 66.83; H, 6.32; N, 3.29.
1.4. 1-O-tert-Butyldiphenylsilyl-3,4,6-tri-O-acetyl-2-deoxy-2-
(2,2,2-trichloroethoxycarbonylamino)-b-D-glucopyranoside (5a)
To a magnetically stirred solution of 4 (6.6 g, 13.8 mmol) in
anhydrous CH3CN (72 mL) at room temperature, solid imidazole
(1.4 g, 20.7 mmol) was added in one portion, followed by tert-buty-
ldiphenylchlorosilane (TBDPSCl) (5.4 mL, 20.7 mmol), added drop-
wise. After 12 h the solvent was removed under reduced pressure.
The crude residue was dissolved in CHCl3 and the solution was
washed with brine until neutral, dried (Na2SO4), and the solvents
evaporated under vacuum. The final product (5a) was eventually
isolated by chromatography (hexane/AcOEt, 8:2) as an oil (8.3 g,
11.4 mmol; 83% yield). One analytical sample: oil. Calcd for
1H NMR: d 1.03 (s, 9H, 3 ꢀ CH3-t-butyl), 1.80–1.85 (m, 3H, H-40,
Ha-30), 1.93 (s, 9H, CH3-Ac), 2.29 (m, 1H, Hb-30), 3.29–3.44 (m, 3H,
H-5, H-50), 3.83–3.87 (m, 2H, Ha-6, H-2), 4.00 (dd, 1H, J 12.0, J 5.5,
Hb-6), 4.17–4.34 (m, 3H, H-20, H-Fmoc, CHa-Fmoc), 4.46 (m, 1H,
CHb-Fmoc), 4.81 (d, 1H, J 6.8, H-1), 4.97 (t, 1H, J 9.6, H-4), 5.17 (t,
1H, J 9.6, H-3), 6.92 (d, 1H, J 8.0, NH), 7.30–7.80 (m, 18H, H-arom).
13C NMR: d 18.7 (C-t-butyl), 20.1 (CH3-Ac), 24.1 (C-40), 26.3
(CH3-t-butyl), 27.4 (C-30), 46.7 (CH-Fmoc), 46.7 (C-50), 56.2 (C-2),
60.2 (C-20), 61.8 (C-6), 67.3 (CH2-Fmoc), 68.5 (C-4), 71.0 (C-5),
71.3 (C-3), 95.2 (C-1), 119.6–140.9 (C-arom), 143.4 (C-Fmoc),
168.9–170.0 (CO-Ac), 172.6 (CONH).
C31H38Cl3NO10Si (717.13): C, 51.78; H, 5.33; N, 1.95. Found: C,
51.82; H, 5.31; N, 2.00.
1H NMR: d 1.10 (s, 9H, 3 ꢀ CH3-t-butyl), 1.96 (s, 3H, CH3-Ac),
1.99 (s, 3H, CH3-Ac), 2.00 (s, 3H, CH3-Ac), 3.38 (m, 1H, H-5), 3.89
(m, 1H, H-2), 3.96 (dd, J 2.1, J 11.9, 1H, Ha-6), 4.09 (dd, J 5.2, J
11.9, 1H, Hb-6), 4.50–4.58 (m, 2H, H-1, Ha-Troc), 4.76 (d, J 11.9,
1H, Hb-Troc), 4.80 (d, J 9.8, 1H, NH), 4.98 (t, J 9.8, 1H, H-3), 5.40
(t, J 9.8, 1H, H-4), 7.30–7.80 (m, 10H, H-arom).
13C NMR: d 19.3 (C-t-butyl), 20.8 (CH3-Ac), 26.9 (CH3-t-butyl),
58.1 (C-2), 62.4 (C-6), 68.9 (C-4), 71.8 (C-3), 72.6 (CH2), 74.8 (C-
5), 93.9 (C-Cl3), 96.2 (C-1), 127.7–136.2 (C-arom), 154.2 (CO-Troc),
169.6–171.0 (CO-Ac).
1.7. (2S)-N-((2S,3S,4R,5S)-2-(tert-Butyldiphenylsilyloxy)-4,5-
dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)pyrrolidine-2-carboxamide (1)
Compound 6 was dissolved by a saturated solution of NH3 in
dry MeOH (43 mL), in ice bath and under magnetic stirring. After
12 h, 6 was completely consumed (TLC monitoring). The solvent
was co-evaporated with Et2O under reduced pressure to afford a
residue that was eventually chromatographed on silica gel
(CHCl3/CH3OH, 95:5) to obtain the final product 1. The latter was
purified by HPLC (FlowLab Semipreparative HPLC System) on Phe-
1.5. 1-O-tert-Butyldiphenylsilyl-3,4,6-tri-O-acetyl-2-deoxy-2-
amino-b-D-glucopyranoside (5b)
To a solution of compound 5a (4.2 g, 5.9 mmol) in glacial acetic
acid (0.8 L), activated Zn dust (76 g, 1.15 mmol) [washed with aq
2 M HCl, water, acetone, diethyl ether, and then dried under vac-
uum] was added in one portion and the mixture was vigorously
stirred for 12 h (TLC monitoring) at room temperature. The solid
was then filtered off and most of acetic acid was evaporated under
reduced pressure. The residue was diluted with AcOEt and the
resulting solution was shaken with saturated aq NaHCO3, washed
with brine until neutral, dried (Na2SO4). The solvents were evapo-
nomenex Axia Packed Luna C18(2) column: 50 ꢀ 21.20 mm, 5
lm,
100 Å, using H2O/MeCN/TFA (97:3:0.1) [eluent A] and MeCN/H2O/
TFA (80:20:0.1) [eluent B] gradient system with a flow rate of
12 mL minꢁ1. Final yield: 2.7 g, 5.3 mmol; 75%. One analytical sam-
ple: mp 71.8–72.0 °C; ½a D25
ꢁ12.6 (c 2.5 in MeOH). Calcd for
ꢂ

M. De Nisco et al. / Carbohydrate Research 356 (2012) 273–277
277
C27H38N2O6Si (514.25): C, 63.01; H, 7.44; N, 5.44. Found: C, 62.98;
H, 7.41; N, 5.43.
Università di Napoli Federico II. Varian Inova 500 MHz NMR instru-
ment is property of Consorzio INCA.
1H NMR (CD3OD): d 1.05 (s, 9H, CH3-t-butyl), 1.93–2.05 (m, 2H,
H-40), 2.11 (m, 1H, Ha-30), 2.36 (m, 1H, Hb-30), 2.98 (m, 1H, H-5),
3.34–3.42 (m, 4H, H-3, H-4, H-50), 3.61 (dd, J 11.6, J 4.7 Hz, 1H,
Ha-6), 3.70 (dd, J 11.6, J 2.8 Hz, 1H, Hb-6), 3.81 (dt, J 7.9, J 1.9 Hz,
1H, H-2), 3.99 (m, 1H. H-20), 4.67 (d, J 8.4 Hz, 1H, H-1), 7.28–7.50
(m, 6H, H-arom), 7.61–7.77 (m, 4H, H-arom).
Supplementary data
Supplementary data (1H and 13C spectra, HPLC conditions and
area graphs) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.carres.2012.03.041.
13C NMR (CD3OD): d 24.9 (C-40), 27.4 (C-t-butyl), 31.3 (C-30),
47.6 (C-50), 59.8 (C-2), 61.2 (C-20), 62.6 (C-6), 72.2 (C-4), 75.7 (C-
3), 77.8 (C-5), 97.4 (C-1), 128.6, 131.1, 134.7, 137.2 (C-arom),
169.8 (CO).
References
1. (a) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812–816;
(b) Córdova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J.
2006, 12, 5383–5397; (c) Ender, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496–497.
HRMS-TOF Calcd for C27H38N2O6Si [M+Na+]: 537.6742. Found:
537.6744.
2. (a) Mase, N.; Barbas, C. F., III Org. Biomol. Chem. 2010, 8, 4043–4050; (b)
Takayama, S.; McGarvey, G. J.; Wong, C.-H. Chem. Soc. Rev. 1997, 26, 407–415;
(c) Fessner, W.-D. In Stereoselective Biocatalysis; Patel, R. N., editor. New York:
Marcel Dekker Inc., 2000; pp 239–265.; (d) Rankin, K. N.; Gauld, J. W.; Boyd, R.
J. J. Phys. Chem. A 2002, 106, 5155–5159; (e) Córdova, A.; Notz, W.; Barbas, C. F.,
III Chem. Commun. 2002, 3024–3025.
3. (a) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904–1905; (b) List, B.;
Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396; (c) Notz,
W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387.
4. (a) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem., Int. Ed. 2010, 49,
4997–5003; (b) Zhu, X.; Tanaka, F.; Lerner, R. A.; Barbas, C. F., III; Wilson, I. A. J.
Am. Chem. Soc. 2009, 131, 18206–18207; (c) Wang, B.; Chen, G.-H.; Liu, L.-Y.;
Chang, W.-X.; Li, J. Adv. Synth. Catal. 2009, 351, 2441–2448; (d) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569; (e) Seebach,
D.; Beck, A. K.; Badine, D. M.; Limbach, M.; Eschenmoser, A.; Treasurywala, A.
M.; Hobi, R.; Prikoszovich, W.; Linder, B. Helv. Chim. Acta 2007, 90, 425–471; (f)
Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 5527–5529; (g) Saito, S.; Yamamoto, H. Acc. Chem. Res.
2004, 37, 570–579; (h) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res.
2004, 37, 580–591.
5. (a) Singh Chimni, S.; Mahajana, D.; Babub, V. V. S. Tetrahedron Lett. 2005, 46,
5617–5619; (b) Wu, Y.-S.; Shao, W.-Y.; Zheng, C.-Q.; Huang, Z.-L.; Cai, J.; Deng,
Q.-Y. Helv. Chim. Acta 2004, 87, 1377–1384; (c) Yi-Yuan Peng, Y.-Y.; Ding, O.-P.;
Li, Z.; Wang, P. G.; Cheng, J.-P. Tetrahedron Lett. 2003, 44, 3871–3875.
6. (a) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302–6337; (b) Lindström,
U. M. Chem. Rev. 2002, 102, 2751–2772.
1.8. General procedure for cyclohexanone/miscellaneous
benzaldehydes aldol reactions catalyzed by 1
Into an 8 mL Wheaton clear glass/screw cap vial, solid 1 (7.7 mg,
1.5 ꢀ 10ꢁ2 mmol) suspended in brine (or THF) (1 mL), cyclohexa-
none (3.0 mmol), and the aldehyde under investigation (0.75 mmol)
were poured in sequence. The mixture was vigorously stirred in the
stoppered vial at the chosen temperature/time (cf. Tables 1 and 2).
After quenching by 20% aq NH4Cl (4 mL) and extraction with Et2O
(3 ꢀ 5 mL), the organic layers were washed with brine and dried
(Na2SO4). The combined water extracts containing salts and most
of the recovered catalyst were freeze-dried and put aside. Evapora-
tion of the solvents under reduced pressure gave a crude residue
that was adsorbed on a preparative layer plate eluting twice with
hexane/EtOAc (7:3) to get residual starting aldehyde and anti plus
syn couples. The anti:syn ratio was determined by 500 MHz 1H
NMR. The anti ee was determined by HPLC on chiral column (Daicel,
Chiralpak, IC).
All the experiments were duplicated.
7. (a) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33–57;
(b) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed.
2008, 47, 6138–6171.
8. (a) Lu, A.; Gao, P.; Wu, Y.; Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem. 2009, 7,
3141–3147; (b) Tsutsui, A.; Takeda, H.; Kimura, M.; Fujimoto, T.; Machinami, T.
Tetrahedron Lett. 2007, 48, 5213–5217.
9. Zhu, X.; Tanaka, F.; Hu, Y.; Heine, A.; Fuller, R.; Zhong, G.; Olson, A. J.; Lerner, R.
A., ; Barbas, C. F., III; Wilson, I. A. J. Mol. Biol. 2004, 343, 1269–1280. and
references cited therein.
10. (a) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595; (b) Aratake, S.;
Itoh, T.; Okano, T.; Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem. Eur. J.
2007, 13, 10246–10256; (c) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958–961; (d) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am.
Chem. Soc. 2006, 128, 734–735.
11. Singh, N.; Pandey, J.; Tripathi, R. P. Catal. Commun. 2008, 9, 743–746.
12. Giacalone, F.; Gruttadauria, M.; Lo Meo, P.; Riela, S.; Noto, R. Adv. Synth. Catal.
2008, 350, 2747–2760.
13. (a) Raja, M.; Singh, V. K. Chem. Commun. 2009, 6687–6703; (b) Almaßsi, D.;
Alonso, D. A.; Balaguer, A.-N.; Nájera, C. Adv. Synth. Catal. 2009, 351,
1123–1131.
14. (a) Ni, N.; El-Sayed, M. M.; Sanghvi, T.; Yalkowsky, S. H. J. Pharm. Sci. 2000, 89,
1620–1625; (b) Breslow, R. Acc. Chem. Res. 2004, 37, 471–478.
15. (a) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2008,
10, 337–340; (b) Font, D.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2006, 8,
4653–4655.
16. In our opinion, this might explain the absolute lack of racemization of the aldol
species even under critical reaction conditions (e.g., 48 h, 2 mol %, 25°) (see
Supplementary data).
The solid coming from freeze-dried water extracts was poured
onto a short silica gel column and eluted with CHCl3/MeOH (8:2).
The crude organic product thus obtained was then purified by pre-
parative HPLC, as reported for the isolation of 1. Recovery range:
72–89% (when 2 mol % used, cf. Table 3).
1.9. Racemization assessment of the enantiomeric anti aldols 2
Into an 8 mL Wheaton clear glass/screw cap vial, solid 1 (2.6 mg,
5 ꢀ 10ꢁ3 mmol) and an authentic mixture (98:2; 2.5 mmol) of the
anti enantiomeric aldols, coming from the reaction of cyclohexa-
none and 4-nitrobenzaldehyde, were suspended in brine (1 mL).
The mixture was vigorously stirred in the stoppered vial at 25 °C
for 48 h. After extraction with Et2O (3 ꢀ 5 mL) of the crude reaction
mixture, the organic layers were washed with brine and dried
(Na2SO4). The combined water extracts containing salts and most
of the recovered catalyst were freeze-dried and put aside. Evapora-
tion of the solvents under reduced pressure gave a crude residue
that was analyzed by HPLC on chiral column (Daicel, Chiralpak,
IC). The mixture turned out to be unchanged (98:2).
Acknowledgments
17. (a) Paradowska, J.; Stodulski, M.; Jacek, M. Angew. Chem., Int. Ed. 2009, 48,
4288–4297; (b) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed.
2006, 45, 8100–8102; (c) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103–
8104.
18. (a) Schultz, M.; Kunz, H. Tetrahedron: Asymmetry 1993, 4, 1205–1220; (b)
Boulanger, P.; Jouineau, M.; Bouammali, B.; Lafont, D.; Descotes, G. Carbohydr.
Res. 1990, 202, 151–164.
The authors are gratefully indebted to Professor S. Hanessian for his
advice and the helpful discussions. They also thank Professor Y. Hay-
ashi for his precious hints. 1H and 13C NMR spectra were performed
at Centro Interdipartimentale di Metodologie Chimico-Fisiche,