Preparation of new type of organocatalysts having a carbohydrate scaffold

Article abstract of DOI:10.1016/j.carres.2013.12.026

The synthesis of nine new, bifunctional organocatalysts having carbohydrate scaffolds has been accomplished. In these catalysts both of the catalytic amino and thiourea functions are directly attached to a carbohydrate core. The activities of the newly prepared catalysts were tested in a Michael addition.

Full text of DOI:10.1016/j.carres.2013.12.026

Carbohydrate Research 389 (2014) 50–56
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Preparation of new type of organocatalysts having a carbohydrate
scaffold q
⇑
Károly Ágoston , Péter Fügedi
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of nine new, bifunctional organocatalysts having carbohydrate scaffolds has been accom-
plished. In these catalysts both of the catalytic amino and thiourea functions are directly attached to a
carbohydrate core. The activities of the newly prepared catalysts were tested in a Michael addition.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 18 September 2013
Received in revised form 5 December 2013
Accepted 6 December 2013
Available online 31 January 2014
Keywords:
Bifunctional organocatalysts
Thiourea–amine type catalysts
Carbohydrate scaffold
Michael addition
1. Introduction
To date only a limited number of scaffolds have been used to
synthesize bifunctional organocatalysts. Monosaccharides as com-
In recent years, organocatalysis, the acceleration of various
chemical reactions by catalytic amounts of organic molecules,
emerged as one of the rapidly developing areas of organic chemis-
try.1 With the aid of organocatalysis a large number of chemical
reactions could then be performed in stereoselective manner. Par-
ticularly great attention has been paid to the development of new,
efficient catalysts. A special class of these catalysts is the so called
bifunctional organocatalysts in which H-bond donor and Lewis
base functionalities are combined in a single asymmetric molecu-
lar scaffold. Several different bifunctional catalysts have been de-
signed, synthesized, and tested. Most of these molecules have a
combination of thiourea and amine groups as catalytic functional-
ities which are presented on a single chemical entity. The very first
example of these catalysts has been described by Takemoto2 in this
molecule the catalytic centers are connected to a cyclohexane scaf-
fold (compound A, Fig. 1). Later some different chiral scaffolds such
as binaphtyl3 or cinchona alkaloids4 (compounds B and C, Fig. 1)
were investigated and the catalysts based on these scaffolds
showed promising results in asymmetric synthesis, particularly,
in catalyzing Michael and aza-Henry reactions.
mercially available, inexpensive molecules of diverse chirality can
be considered as obvious candidates for chiral scaffolds. Organo-
catalysts based on a
D-glucosamine scaffold carrying urea and
imine as catalytic functionalities were described by Kunz in
2007.5 Enantioselective Strecker and Mannich reactions were per-
formed using these catalysts.5
Thiourea–amine type bifunctional organocatalysts containing a
monosaccharide unit were prepared and their catalytic activities
were investigated recently.6 In these cases, the carbohydrate moi-
ety was located on the periphery of the catalyst molecule and not
in-between the two catalytic centers (compounds D and E, Fig. 2).
To our knowledge there is only one example in the literature where
a monosaccharide residue was used as a scaffold to connect thio-
urea and amine functionalities thereby defining the selectivity of
the catalyzed reaction (compound F, Fig. 2).7 In this study the
use of urea derivatives, however, provided higher yields and selec-
tivity than the corresponding thiourea derivative.7 Up to now,
there are no examples of bifunctional thiourea-amine organocata-
lysts where the core scaffold is a monosaccharide unit and the use
of the catalyst results in high yield and high enantioselectivity cat-
alyzing a chemical reaction.
We have initiated the preparation of new—bifunctional—thio-
urea–amine catalysts starting from D-glucose. In these molecules
q
Presented at the 17th European Carbohydrate Symposium, Tel-Aviv, Israel, July
the two catalytic centers are connected with a carbohydrate
residue. Using these catalysts the enantioselectivity of the
catalyzed reaction will be influenced only by the carbohydrate
moiety. The possible effect arising from carbohydrate chirality
7–11, 2013, as poster July 7th P1.
⇑
Corresponding author. Tel.: +36 1 438 1100 372; fax: +36 1 438 1168.
E-mail addresses: agoston.karoly@ttk.mta.hu (K. Ágoston), fugedi.peter@
ttk.mta.hu (P. Fügedi).
http://dx.doi.org/10.1016/j.carres.2013.12.026
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

K. Ágoston, P. Fügedi / Carbohydrate Research 389 (2014) 50–56
51
CF3
Ar
HN
S
NR'R"
O
R
R
CF3
F3C
HN
Ar
HN
S
O
O
F3C
R
S
N"RR'
R
HN
R
HN
S
S
NH
NR'R"
HN
Me2N
R
R
HN
R
R
Ar NH
HN
H2N
G
I
H
B
Figure 3. General structures of the targeted organocatalysts.
A
Takemoto's catalyst
binaphtyl based catalyst
N
Br
N3
N3
CF3
O
O
O
a
b
c
BzO
OMe
HO
OMe
S
OMe
BzO
OMe
H
F3C
N
H
N
H
MeO
OMe
MeO
OMe
MeO
OMe
N
1
2
3
C
S
cinchona based catalyst
HN
R'
N3
HN
Figure 1. Representative examples of bifunctional organocatalysts.
O
d
O
RHN
OMe
RHN
MeO
OMe
MeO
OMe
OMe
was taken into consideration in the design, by placing the catalytic
groups at various positions of the carbohydrate scaffold. Thus the
synthesis of molecules having the amino and thioureido groups
in positions 4 and 6 (G and H, Fig. 3), or in positions 2 and 3 (I,
Fig. 3), respectively, was planned. The catalytic groups are dis-
tanced by three carbon–carbon bonds in the first case, whereas
they are separated by two C–C bonds in the latter. In the case of
G and H, the synthetic route was designed to afford both the 4-
amino-6-thioureido (G) and the 6-amino-4-thioureido (H) deriva-
tives from the same starting material.
4
R = cHexyl
6 R = cHexyl, R' = Ph
5 R = Benzyl
7 R = cHexyl, R' = 3,5-CF3Ph
8 R = Benzyl, R' = Ph
9
R = Benzyl, R' = 3,5-CF3Ph
Scheme 1. Reagents and conditions: (a) NaN3, DMF, 70 °C, 6 h, 94%; (b) NaOMe,
MeOH, rt, 1 h, 80%; (c) (i) Tf2O, pyridine, CH2Cl2, 0 °C, 2 h, (ii) amine, DMF, 45 °C,
10 h, 50–70%; (d) (i) propanedithiol, MeOH, rt, 48 h (6 and 7), or PPh3, H2O, THF,
80 °C, (8 and 9), (ii) isothiocyanate, MeOH, rt, 4 h, 30–50%.
azido function of compound 4 was reduced to amine with
propanedithiol in methanol9 and the 6-amino derivative was re-
acted with phenyl isothiocyanate (4 ? 6) or 3,5-bis(trifluoro-
methyl)phenyl isothiocyanate (4 ? 7) affording the bifunctional
organocatalyst candidates.
For the reduction of azido function of compound 5, the use of
triphenylphosphine was found more advantageous, as reduction
with propanedithiol resulted in impurities which were difficult to
separate from the amino derivative. The amino derivative of com-
pound 5 was reacted with phenyl isothiocyanate or 3,5-bis(trifluo-
romethyl)phenyl isothiocyanate affording derivatives 8 and 9,
respectively.
For the preparation of the 6-amino-4-thioureido type target
molecule nucleophilic substitution of the bromo function of com-
pound 1 with piperidine was performed to afford 10 in high yield
(Scheme 2). This reaction was significantly slower than the substi-
tution of 1 with sodium azide. The removal of the benzoate pro-
tecting group from 10 by Zemplén’s method required elevated
temperature, but afforded compound 11 in good yield. The azido
function was introduced at position 4 by SN2 reaction via a triflate
intermediate. Treatment of 11 with Tf2O, as described for 4,
followed by reaction of the crude with sodium azide in DMF
2. Results and discussion
For the preparation of the targeted catalysts having the catalytic
groups in the 4 and 6 positions, methyl 4-O-benzoyl-6-bromo-
6-deoxy-2,3-di-O-methyl-
a
-D
-glucopyranoside8 (1, Scheme 1) was
selected as starting material which is easily available from
commercial methyl
yields.
a-D-glucopyranoside in a few steps in high
The synthesis of the 4-amino-6-thioureido type compounds
started with the preparation of the 6-azido derivative (2). Reaction
of compound 1 with sodium azide in DMF at elevated temperature
resulted in the formation of the 6-azido derivative (?2, Scheme 1)
in almost quantitative yield. The benzoate protecting group from
compound 2 was removed with NaOMe in MeOH affording deriv-
ative 3 in high yield. 4-Amino derivatives were prepared by SN2
replacement with primary amines via the 4-O-triflate in a one-
pot manner. Treatment of 3 with triflic anhydride in CH2Cl2 in
the presence of pyridine at 0 °C afforded the crude 4-O-triflate,
which was reacted directly with cyclohexylamine or benzylamine
in the solvent mixture of CH2Cl2/DMF to yield the 4-cyclohexyl-
amino (4) and 4-benzylamino (5) derivatives, respectively. The
CF3
Ph
F3C
Ph
CH2OR
OR
R'
CH2OR
R'
CH2OR
H2N
R'
HN
Me2N
HN
H2N
O
HN
O
HN
O
HN
OR
OR
HN
OR
OR
RO
OR
RO
F
D
E
Figure 2. Monosaccharide-containing bifunctional organocatalysts.

52
K. Ágoston, P. Fügedi / Carbohydrate Research 389 (2014) 50–56
isothiocyanate or 3,5-bis(trifluoromethyl)phenyl isothiocyanate
affording the target compounds (17 ? 19, 17 ? 20, 18 ? 21, and
18 ? 22).
N
N
c
O
b
O
a
1
BzO
MeO
OMe
HO
OMe
The catalytic activity of the prepared new, monosaccharide-
based bifunctional organocatalysts was tested on the Michael addi-
tion of acetylacetone to b-nitrostyrene (?23, Scheme 4). This reac-
tion is commonly used as test in evaluating newly developed
organocatalysts.13 Based on preliminary experiments dichloro-
methane was selected as solvent for the reaction. The use of other
solvents such as toluene, THF, MeCN, or diethyl ether resulted in
much longer reaction times (data not shown). The stereochemistry
of the products was determined by comparison of their optical
rotation values (Table 1) with literature references13b together
with the comparison of the chiral HPLC retention times with liter-
ature references.13c,d The enantiomeric excess was determined by
chiral HPLC.
The catalytic activity of the synthesized compounds is summa-
rized in Table 1. Only those compounds which have secondary
amine groups were able to promote the reaction to give good
yields (Table 1, entries 1, 2, and 3). Tertiary amine-containing
derivatives afforded very low yield or no reaction at all (entries
4, 5, and 6). The active catalysts favored the formation of the prod-
uct having the S configuration, the enantioselectivity, however,
was low. Further examination of the catalytic activity of prepared
compounds on different reactions is in progress, and will be re-
ported in due course.
OMe
MeO
OMe
10
11
N
N
d
S
O
HN
Ph
O
N3
MeO
OMe
HN
OMe
OMe
MeO
OMe
12
13
Scheme 2. Reagents and conditions: (a) piperidine, DMF, 70 °C, 50 h, 90%; (b)
NaOMe, MeOH, reflux, 2 h, 85%; (c) (i) Tf2O, pyridine, DCM, 0 °C, 2 h, (ii) NaN3, DMF,
45 °C, 72 h, 40%; (d) (i) propanedithiol, MeOH, rt, 48 h, (ii) phenyl isothiocyanate,
MeOH, rt, 8 h, 69%.
afforded the 4-azido galacto epimer (11 ? 12). The stereochemis-
try was proven by the two small coupling constants of the H-4 in
the 1H NMR spectrum (J3,4 2.3 Hz J4,5 <1 Hz,) while the presence
on the azido group was indicated by the upfield shift of the C-4 sig-
nal in the 13C NMR spectrum. The transformation of the azido func-
tion into thiourea derivative was performed as in the case of
compound 6. Treatment of 12 with propanedithiol resulted in the
formation of the 4-amino intermediate which was reacted with phe-
nyl isothiocyanate to form compound 13 as a catalyst candidate.
The preparation of the 2-amino-3-thioureido derivatives started
from the allo-epoxide 1410 (Scheme 3) as starting material which is
In conclusion, the synthesis of a new family of monosaccharide-
based bifunctional organocatalysts has been achieved. Thiourea and
amine functionalities were used as catalytic centers connected by a
monosaccharide unit thereby replacing the commonly employed
cyclohexane unit. The activities of the newly prepared catalysts
were tested on a model reaction, where some of the compounds
afforded high yields, although with low enantioselectivity.
easily available from commercial methyl a-D-glucopyranoside in a
few steps in high yields. The epoxide was opened with piperidine
or with morpholine according to a literature procedure11 affording
the altro derivatives 15 and 16 in high yields. The preparation of
the 3-azido derivatives was accomplished by using Mistunobu con-
ditions as only low yields were obtained in preliminary trials to
introduce the azide by the displacement of the 3-O-triflate inter-
mediate (data not shown). Compounds 15 and 16 were treated
with diisopropyl azodicarboxylate and triphenylphosphine then
with diphenylphosphoryl azide12 to form the 3-azido derivatives
17 and 18, respectively. The azido functions of compounds 17
and 18 were reduced with triphenylphosphine, the resulting
3-amino derivatives were subsequently treated with phenyl
3. Experimental
3.1. General
Commercially available starting materials were used without
further purification. Solvents were dried according to standard
O
NO2
NO2
O
O
10% cat.
DCM, rt.
O
O
O
O
O
+
Ph
O
Ph
O
b
a
OMe
OMe
R
HO
N
O
23
14
15 R = CH2
Scheme 4. Reagents and conditions: b-nitrostyrene, 1.1 equiv acetylacetone,
10 mol % catalyst, CH2Cl2, rt, 24 h.
16
R = O
O
O
Ph
O
N
Ph
O
c
Table 1
O
S
OMe
R
O
OMe
R
Summary of the catalytic activity of selected catalyst candidates
Yielda
ee%
½ ꢀ Values
a 2D5
NH
N3
N
Entry
Catalyst
R' NH
1
2
3
4
5
6
6
7
9
19
20
21
70%
78%
50%
<5%
None
None
18.7%
14.1%
12.9%
n.d.
—
—
13.9 (c 0.5, CHCl3)
8.0 (c 0.5, CHCl3)
7.8 (c 0.65, CHCl3)
n.d.
—
19 R = CH2, R' = Ph
17 R = CH2
18
20
R = O
R = CH2, R' = 3,5-CF3Ph
21 R = O, R' = Ph
22 R = O, R' = 3,5-CF3Ph
—
n.d.: not determined.
Reaction times were 24 h in all cases. Without the use of catalyst no product
formation was observed.
Scheme 3. Reagents and conditions: (a) piperidine or morpholine, LiClO4, MeCN,
90 °C, 24 h, 80–90%; (b) (i) PPh3, DIAD, THF, 0 °C, (ii) DPPA, THF, rt, 24 h, 60–80%; (c)
(i) PPh3, THF, H2O, 80 °C, (ii) isothiocyanate, MeOH, rt, 8 h, 60–80%.
a

K. Ágoston, P. Fügedi / Carbohydrate Research 389 (2014) 50–56
53
procedures. Melting points (uncorrected) were determined on a
Griffin apparatus. Optical rotations were measured with a Jasco-
Optical activity AA-10R polarimeter. NMR spectra were recorded
on a Varian Gemini 2000 (200 MHz for 1H and 50 MHz for 13C)
and on a Varian Unity-Inova (300 MHz for 1H and 75 MHz for
13C) spectrometer in CDCl3 as solvent. All chemical shifts are
quoted in ppm downfield from the characteristic signals (1H:
0.00 ppm (TMS), 13C: 77.00 ppm (CDCl3)). Kieselgel 60 (E. Merck,
Darmstadt, Germany) was used for column chromatography and
DC-Alufolien Kieselgel 60 F256 plates were used for TLC. MS spectra
were recorded on an Applied Biosystems 3200 QTRap spectrome-
ter. Enantiomeric excesses were determined on a Waters 600 HPLC
instrument. (Diacel Chiralpack AD column, hexane/i-propanol
80:20, flow rate: 1 mL/min, k = 210 nm).
provide 4 (1.1 g, 51%) as a pale yellow syrup. ½a D25
ꢀ
136.4 (c 0.64,
CHCl3); 1H NMR: d 4.86 (d, 1H, J1,2 3.5 Hz, H-1), 3.78 (m, 1H, H-
5), 3.60 (dd, 1H, Jgem 12.2 Hz, H-6a), 3.51 (dd, 1H, J2,3 9.5 Hz, J3,4
3.6 Hz, H-3), 3.44, 3.42, and 3.41 (each s, each 3H, 3 OMe), 3.35
(dd, 1H, H-2), 3.16 (dd, 1H, H-6b) 3.08 (dd, 1H, J4,5 ꢂ1 Hz, H-4),
2.25 (m, 1H, cyclohexyl CH), 1.80–1.50 and 1.20–0.70 (m, 10 H,
cyclohexyl CH2); 13C NMR: d 97.3 (C-1), 79.1 (C-3), 77.1 (C-2),
70.3 (C-5), 58.6, 57.8 and 55.2 (3 OMe), 56.8 (cyclohexyl CH) 53.7
(C-4), 52.2 (C-6), 34.5, 33.6, 25.8, 25.2, 25.0 (5 cyclohexyl CH2);
MS: Calcd for: C15H28N4O4 328, found: 329 [M+H]+; HRMS:
[M+H]+ calcd for 329.2189, found: 329.2191.
3.5. Methyl 6-azido-4-benzylamino-4,6-dideoxy-2,3-di-O-
methyl-a-D-galactopyranoside (5)
3.2. Methyl 6-azido-4-O-benzoyl-6-deoxy-2,3-di-O-methyl-
glucopyranoside (2)
a
-
D
-
Compound 3 (1.61 g, 6.7 mmol) was converted into the 4-O-tri-
flate intermediate as described for compound 4. A solution of ben-
zylamine (6 mL) in DMF (20 mL) was added to the triflate
intermediate and the mixture was stirred for 10 h at 45 °C. Then
the mixture was concentrated and the residue was purified by col-
umn chromatography (hexane–EtOAc; 1:1) to give 5 (1.67 g, 76%)
NaN3 (260 mg, 4.0 mmol) was added to a solution of 1 (780 mg,
2.0 mmol) in dry DMF (10 mL) and the mixture was stirred for 6 h
at 70 °C. The mixture was allowed to cool to rt then it was diluted
with EtOAc (100 mL) and washed with water (3 ꢁ 50 mL). The or-
ganic layer was dried over MgSO4, filtered, concentrated, and the
product was obtained after column chromatography (toluene–ace-
as a pale yellow syrup: ½a D25
ꢀ
117.2 (c 0.8, CHCl3); 1H NMR: d
7.40–7.20 (m, 5H, aromatic), 4.95 (d, 1H, J1,2 3.7 Hz, H-1), 3.85
(m, 3H, H-5 and benzyl CH2), 3.70 and 3.22 (each dd, 2H, J5,6 8.8
and 4.2 Hz, Jgem 12.5 Hz, H-6a), 3.60 (dd, 1H, J2,3 9.9 Hz, J3,4
4.2 Hz, H-3), 3.48, 3.44 and 3.28 (each s, each 3H, 3 OMe), 3.43
(dd, 1H, H-2), 3.10 (dd, 1H, J4,5 1.3 Hz, H-4); 13C NMR: d 140.1,
128.3, and 127.1 (aromatic), 97.5 (C-1), 79.4 (C-3), 77.1 (C-2),
70.2 (C-5), 58.6, 57.4 and 55.2 (3 OMe), 55.4 (C-4), 54.4 (benzyl
CH2), 52.3 (C-6); MS: Calcd for: C16H24N4O4 336, found: 337
[M+H]+. Anal. Calcd for C16H24N4O4: C, 57.13; H, 7.19. Found: C,
57.07; H, 7.18.
tone; 95:5) as a syrup (660 mg, 94%). ½a D25
ꢀ
52.5 (c 0.69, CHCl3); 1H
NMR: d 8.06, 7.60, and 7.46 (m, 5H, aromatic), 5.09 (dd, 1H, J3,4
9.4 Hz, J4,5 9.9 Hz, H-4), 4.93 (d, 1H, J1,2 3.5 Hz, H-1), 3.99 (ddd,
1H, J5,6 5.4 and 2.6 Hz, H-5), 3.74 (dd, 1H, J2,3 9.2 Hz, H-3), 3.56,
3.52 and 3.48 (each s, each 3H, 3 OMe), 3.38 (m, 2H, H-2 and H-
6a), 3.27 (dd, 1H, Jgem 13.3 Hz, H-6b); 13C NMR: d 165.4 (C@O),
133.4, 129.8, 129.3, and 128.5 (aromatic), 97.6 (C-1), 81.3 (C-2),
80.7 (C-3), 71.8 (C-4), 69.2 (C-5), 61.0, 59.3 and 55.5 (3 OMe),
51.3 (C-6); MS: Calcd for: C16H21N3O6 351, found: 352 [M+H]+,
374 [M+Na]+, 725 [2M+Na]+. Anal. Calcd for C16H21N3O6: C,
54.69; H, 6.02. Found: C, 54.82; H, 6.05.
3.6. Methyl 4-cyclohexylamino-4,6-dideoxy-2,3-di-O-methyl-6-
(N0-phenyl)thioureido-
a-D-galactopyranoside (6)
3.3. Methyl 6-azido-6-deoxy-2,3-di-O-methyl-
glucopyranoside (3)
a
-
D
-
Propanedithiol (2.0 mL) was added to a solution of 4 (0.8 g,
2.4 mmol) in MeOH (20 mL) at rt and the mixture was stirred for
48 h at rt. When TLC (hexane–EtOAc, 1:1) showed the formation
of the 6-amino derivative the mixture was filtered, the filtrate was
evaporated, and the residue was purified by column chromatogra-
phy (CH2Cl2–MeOH–water; 8:5:1) to afford the amino derivative
NaOMe (50 mg) was added to
a solution of 2 (660 mg,
1.88 mmol) in dry MeOH (20 mL). The mixture was stirred for
1 h at rt. Then the mixture was neutralized with Amberlite IR-
120 (H+). The resin was filtered off and washed with MeOH. The fil-
trate was concentrated and the product was isolated by column
chromatography (toluene–acetone; 4:1). 3 (370 mg, 80%) was ob-
(0.65 g). Phenyl isothiocyanate (400 lL) was added to a solution of
the amino derivative (650 mg) in MeOH (10 mL) at rt. The mixture
was stirred for 4 h then concentrated. After column chromatography
(CH2Cl2–MeOH–water; 8:5:1) of the residue a white solid was ob-
tained, which was recrystallized from EtOAc to yield 6 (450 mg,
tained as a colorless syrup: ½a D25
ꢀ
117.0 (c 0.58, CHCl3);1H NMR: d
4.81 (d, 1H, J1,2 3.5 Hz, H-1), 3.70 (m, 1H, H-5), 3.60, 3.46 and
3.41 (each s, each 3H, 3 OMe), 3.50 (dd, 1H, Jgem 13.2 Hz, H-6a),
3.44–3.30 (m, 3H, H-3, H-4 and H-6b) 3.20 (dd, 1H, J2,3 9.2 Hz, H-
2) 2.18 (br s, 1H, 4-OH); 13C NMR: d 97.3 (C-1), 82.6 (C-3), 81.7
(C-2), 70.4 and 70.3 (C-4 and C-5), 61.1, 58.4 and 55.3 (3 OMe),
51.4 (C-6); MS: Calcd for: C9H17N3O5 247, found: 270 [M+Na]+,
517 [2M+Na]+. Anal. Calcd for C9H17N3O5: C, 43.72; H, 6.93. Found:
C, 43.67; H, 6.95.
42%, over two steps): mp 160–162 °C; ½a D25
ꢀ
84.7 (c 0.54, CHCl3);
1H NMR: d 8.36 (br s, 1H, NH), 7.42–7.20 (m, 5H, aromatic), 4.80
(d, 1H, J1,2 3.7 Hz, H-1), 4.32 (br s, 1H, H-6a), 3.86 (m, 1H, H-5),
3.57 (dd, 1H, J2,3 10.2 Hz, J3,4 4.7 Hz, H-3), 3.48 (m, 1H, H-6b), 3.46,
3.42, and 3.20 (each s, each 3H, 3 OMe), 3.30 (dd, 1H, H-2), 3.14
(dd, 1H, H-4), 2.28 (m, 1H, cyclohexyl CH), 1.80–1.50 and 1.20–
0.70 (m, 10H, cyclohexyl CH2); 13C NMR: d 180.0 (C@S), 136.3,
129.8, 126.8, and 125.0 (aromatic), 97.4 (C-1), 79.0 (C-3), 77.1 (C-
2), 68.0 (C-5), 58.5, 58.0 and 54.9 (3 OMe), 56.9 (cyclohexyl CH)
54.5 (C-4), 47.2 (C-6), 34.0, 33.3, 25.7, 25.0, 24.9 (5 cyclohexyl
CH2); MS: Calcd for: C22H35N3O4S 437, found: 438 [M+H]+. Anal.
Calcd for C22H35N3O4S: C, 60.38; H, 8.06. Found: C, 60.42; H, 8.04.
3.4. Methyl 6-azido-4-cyclohexylamino-4,6-dideoxy-2,3-di-O-
methyl-a-D-galactopyranoside (4)
A solution of Tf2O (1.63 mL, 9.7 mmol) in CH2Cl2 (5 mL) was
added to a solution of 3 (1.61 g, 6.7 mmol) in a mixture of pyridine
(3.2 mL) and CH2Cl2 (20 mL) at 0 °C, then the mixture was stirred
for 2 h at 0 °C. TLC (hexane–EtOAc; 1:1) showed the formation of
a new apolar derivative. Cyclohexylamine (6 mL) in DMF (20 mL)
was added to the mixture and stirring was continued for 10 h at
45 °C. Then the mixture was concentrated and the residue was
purified by column chromatography (hexane–EtOAc; 1:1) to
3.7. Methyl 4-cyclohexylamino-4,6-dideoxy-2,3-di-O-methyl-6-
(N0-3,5-bis(trifluoromethyl)phenyl)thioureido-
a-D-
galactopyranoside (7)
Compound 4 (0.8 g, 2.4 mmol) was converted into the 6-amino
derivative as described for compound 6. 3,5-Bis(trifluoromethyl)phenyl

54
K. Ágoston, P. Fügedi / Carbohydrate Research 389 (2014) 50–56
isothiocyanate (400
l
L) was added to a solution of the 6-amino deriva-
132.8 (C-300 and C-500), 129.2, 128.8, 128.1, and 127.6 (aromatic),
1
tive (0.65 g) in MeOH (10 mL) at rt. The mixture was stirred for 4 h then
concentrated and the product was isolated after column chromatogra-
phy (hexane–EtOAc; 1:2) as a white solid. The solid was recrystallized
from EtOAc to yield 7 (530 mg, 35%, over two steps): mp 189–191 °C;
123.2 (q, 2C, JC,F 271 Hz, 2CF3), 121.4 (m, 2C, C-200 and C-600),
114.9 (m, 1 C, C-400), 98.0 (C-1), 79.1 (C-3), 77.9 (C-2), 66.1 (C-5),
59.4 (C-4), 59.0, 58.4 and 55.8 (3 OMe), 55.7 (benzyl CH2), 49.1
(C-6); MS: Calcd for: C25H29F6N3O4S 581, found: 582 [M+H]+. Anal.
Calcd for C25H29F6N3O4S: C, 51.63; H, 5.03. Found: C, 51.51; H, 5.00.
½
a 2D5 39.7 (c 0.51, CHCl3); 1H NMR: d 10.18 (br s, 1H, 6-NH), 8.95 (br s,
ꢀ
1H, NH), 7.84 (s, 2H, aromatic) 7.68 (s, 1H, aromatic), 4.95 (d, 1H, J1,2
3.5 Hz, H-1), 4.40 (m, 1H, H-6a), 3.96 (m, 1H, H-5), 3.65 (dd, 1H, J2,3
10.4 Hz, J3,4 4.7 Hz, H-3), 3.55, 3.46 and 3.44 (each s, each 3H, 3 OMe),
3.45 (m, 1H, H-6b), 3.28 (dd, 1H, H-2), 3.22 (dd, 1H, H-4), 2.37 (m, 1H,
3.10. Methyl 4-O-benzoyl-6-deoxy-2,3-di-O-methyl-6-
piperidino-
a-
D-glucopyranoside (10)
cyclohexyl CH), 1.60–1.44 and 1.20–0.50 (m, 10H, cyclohexyl CH2); 13
C
Piperidine (720 lL, 7.3 mmol) was added to a solution of 1
NMR: d 178.8 (C@S), 139.5 (aromatic quaterner), 132.8 (q, 2C, 2JC,F 33
Hz, C-300 and C-500), 122.9 (q, 2C, 1JC,F 271 Hz, 2CF3), 122.8 (m, 2C, C-200
and C-600), 118.4 (m, 1 C, C-400), 97.7 (C-1), 79.4 (C-3), 77.2 (C-2), 65.5
(C-5), 58.7, 58.6 and 55.5 (3 OMe), 57.0 (cyclohexyl CH) 54.3 (C-4),
49.3 (C-6), 33.2, 32.8, 25.5, 24.8, 24.6 (5 cyclohexyl CH2); MS: Calcd
for: C24H33F6N3O4S 573, found: 574 [M+H]+. Anal. Calcd for C24H33F6N3-
O4S: C, 50.25; H, 5.80. Found: C, 50.31; H, 5.82.
(1.12 g, 2.88 mmol) in dry DMF (5 mL) and the mixture was stirred
for 50 h at 70 °C. Then the mixture was allowed to cool to rt, it was
diluted with toluene (100 mL) and washed with water (2 ꢁ 30 mL),
the organic layer was dried over MgSO4, filtered, and concentrated.
Column chromatography (toluene–acetone; 3:1) of the residue
afforded 10 (1.01 g, 90%) as a syrup: ½a D25
ꢀ
80.2 (c 0.63, CHCl3); 1H
NMR: d 8.05, 7.55 and 7.42 (m, 5H, aromatic), 5.00 (dd, 1H, J3,4
9.4 Hz, J4,5 9.9 Hz, H-4), 4.86 (d, 1H, J1,2 3.5 Hz, H-1), 4.03 (m, 1H,
H-5), 3.66 (dd, 1H, J2,3 9.4 Hz, H-3), 3.51, 3.46 and 3.43 (each s, each
3H, 3 OMe), 3.31 (dd, 1H, H-2), 2.50 and 2.36 (each dd, 2H, Jgem
13.4 Hz, H-6), 2.33, 1.46 and 1.30 (each m, 10H, 5 piperidine
CH2); 13C NMR: d 165.5 (C@O), 133.1, 129.7 and 128.3 (aromatic),
97.5 (C-1), 81.4 (C-2), 81.0 (C-3), 73.2 (C-4), 66.9 (C-5), 60.8, 59.2
and 55.5 (3 OMe), 60.1 (C-6), 55.1, 25.7 and 24.1 (5 piperidine
CH2); MS: Calcd for: C21H31NO6 393, found: 394 [M+H]+. Anal.
Calcd for C21H31NO6: C, 64.10; H, 7.94. Found: C, 64.03; H, 7.92.
3.8. Methyl 4-benzylamino-4,6-dideoxy-2,3-di-O-methyl-6-(N0-
phenyl)thioureido-a-D-galactopyranoside (8)
Triphenylphosphine (1.2 g, 4.6 mmol) was added to a solution
of 5 (1.0 g, 3.0 mmol) in THF (20 mL) at rt and the mixture was stir-
red for 2 h at 80 °C. When TLC (hexane–EtOAc; 1:1) showed the ab-
sence of the starting material water (2 mL) was added to the
mixture and the stirring was continued for 4 h at 80 °C. The mix-
ture was concentrated, the residue was purified by column chro-
matography (CH2Cl2–MeOH–water 8:5:1) affording the 6-amino
3.11. Methyl 6-deoxy-2,3-di-O-methyl-6-piperidino-a-D-
derivative (0.7 g). Phenyl isothiocyanate (225
l
L) was added to a
glucopyranoside (11)
solution the 6-amino-derivative (485 mg) in MeOH (10 mL) at rt.
The mixture was stirred for 24 h then concentrated and the prod-
uct was obtained after column chromatography (CH2Cl2–MeOH–
water 8:5:1) as a white solid. The solid was recrystallized from
CH2Cl2/hexane to yield 8 (281 mg, 31%, over two steps) as white
NaOMe (50 mg) was added to
a solution of 10 (1.0 g,
2.54 mmol) in dry MeOH (20 mL) at rt, then the mixture was stir-
red for 2 h at reflux. The mixture was concentrated and the residue
was purified by column chromatography (CH2Cl2–MeOH;
crystals: mp 100–102 °C; ½a D25
ꢀ
116.9 (c 0.65, CHCl3); 1H NMR: d
95:5 ? 8:2) to give 11 (618 mg, 85%) as a colorless syrup: ½a D25
ꢀ
8.18 (s, 1H, NHPh), 7.40–7.18 (m, 10H, aromatic), 6.92 (d, 1H, 6-
NH), 4.78 (d, 1H, J1,2 3.5 Hz, H-1), 4.34 (br s, 1H, H-6a), 3.89 (m,
1H, H-5), 3.80 (ABq, 2H, benzyl CH2), 3.68 (m, 1H, H-6b), 3.59
(dd, 1H, J2,3 10.3 Hz, J3,4 3.6 Hz, H-3), 3.44, 3.25 and 3.17 (each s,
each 3H, 3 OMe), 3.35 (dd, 1H, H-2), 3.13 (dd, 1H, H-4), 1.66 (br
s, 1H, 4-NH); 13C NMR: d 180.4 (C@S), 139.7, 136.1, 129.9, 128.4,
127.1 and 125.2 (aromatic), 97.6 (C-1), 79.0 (C-3), 77.0 (C-2),
68.6 (C-5), 58.7, 57.4 and 55.0 (3 OMe), 56.2 (C-4), 54.9 (benzyl
CH2), 47.1 (C-6); MS: Calcd for: C23H31N3O4S 445, found: 446
[M+H]+. Anal. Calcd for C23H31N3O4S: C, 62.00; H, 7.01. Found: C,
62.07; H, 7.02.
73.4 (c 0.63, CHCl3); 1H NMR: d 4.68 (d, 1H, J1,2 3.5 Hz, H-1), 3.60
(m, 1H, H-5), 3.56, 3.42 and 3.32 (each s, each 3H, 3 OMe), 3.40
(m, 2H, H-3 and H-4), 3.10 (dd, 1H, H-2), 2.60 (m, 2H, Jgem
12.3 Hz, H-6), 2.55, 2.30, 1.50 and 1.33 (each m, 10 H, 5 piperidine
CH2); 13C NMR: d 97.5 (C-1), 82.0 (C-3), 81.0 (C-2), 71.1 (C-4), 64.4
(C-5), 63.1 (C-6), 60.8, 58.6 and 55.0 (3 OMe), 55.4, 25.7 and 23.3 (5
piperidine CH2); MS: Calcd for: C14H27NO5 289, found: 290 [M+H]+,
312 [M+Na]+. Anal. Calcd for C14H27NO5: C, 58.11; H, 9.40. Found:
C, 58.10; H, 9.37.
3.12. Methyl 4-azido-4,6-dideoxy-2,3-di-O-methyl-6-
piperidino-a-D-galactopyranoside (12)
3.9. Methyl 4-benzylamino-4,6-dideoxy-2,3-di-O-methyl-6-(N0-
3,5-bis(trifluoromethyl)phenyl)thioureido-
galactopyranoside (9)
a
-
D
-
A solution of Tf2O (1.89 mL, 11.3 mmol) in CH2Cl2 (5 mL) was
added to a solution of 11 (2.16 g 7.5 mmol) in a mixture of pyridine
(3.6 mL) and CH2Cl2 (50 mL) at 0 °C and the mixture was stirred for
2 h at 0 °C. Sodium azide (980 mg) in DMF (50 mL) was added to
the mixture and stirring was continued for 72 h at 45 °C. Then
the mixture was concentrated and the residue was purified by col-
umn chromatography (CH2Cl2–MeOH, 95:5) to yield 12 (700 mg,
Compound 5 (1.0 g 3.0 mmol) was converted into the 6-amino
derivative as described for 8. 3,5-Bis(trifluoromethyl)phenyl isothi-
ocyanate (350 lL) was added to a solution of the 6-amino deriva-
tive (497 mg) in MeOH (10 mL) at rt. The mixture was stirred for
10 min, during this time a light brown precipitate was formed.
The solid was filtered and was purified by recrystallization from
EtOAc/hexane to afford 9 (868 mg, 70%, over two steps) as white
30%) as a pale yellow syrup: ½a D25
ꢀ
104.8 (c 0.65, CHCl3); 1H NMR
d: 4.72 (d, 1H, J1,2 3.4 Hz, H-1), 4.10 (dd, 1H, J3,4 2.3 Hz J4,5 <1 Hz,
H-4), 3.90 (m, 1H, H-5), 3.69 (dd, 1H, J2,3 9.8 Hz, H-3), 3.58, 3.56
and 3.40 (each s, each 3H, 3 OMe), 3.50 (m, 1H, H-2), 2.50 (m,
6H, H-6 and 2 piperidine CH2), 1.60 and 1.40 (each m, 6H, 3 piper-
idine CH2); 13C NMR: d 98.2 (C-1), 79.8 (C-3), 78.1 (C-2), 66.3 (C-5),
61.7 (C-4), 59.7 (C-6), 59.4, 58.4 and 55.8 (3 OMe), 55.6, 26.2 and
24.4 (5 piperidine CH2); MS: Calcd for: C14H26N4O4 314, found:
315 [M+H]+, 332 [M+NH4]+. Anal. Calcd for C14H26N4O4: C, 53.49;
H, 8.34. Found: C, 53.42; H, 8.32.
crystals: mp 180–182 °C; ½a D25
ꢀ
69.9 (c 0.89, CHCl3); 1H NMR: d
9.28 (br s, 1H, NH), 8.66 (br s, 1H, NH), 7.50–7.40 (m, 8H, aromatic)
4.90 (d, 1H, J1,2 3.5 Hz, H-1), 4.40 (m, 1H, H-6a), 4.00 (m, 1H, H-5),
3.84 and 3.55 (each m, 2H, benzyl CH2), 3.70 (dd, 1H, J2,3 10.2 Hz,
J3,4 4.7 Hz, H-3), 3.65 (m, 1H, H-6b), 3.51, 3.41 and 3.40 (each s,
each 3H, 3 OMe), 3.34 (dd, 1H, H-2), 3.22 (dd, 1H, H-4), 2.00 (br
s, 1H, 4-NH); 13C NMR: d 179.6 (C@S), 139.5 (aromatic quaterner),

K. Ágoston, P. Fügedi / Carbohydrate Research 389 (2014) 50–56
55
3.13. Methyl 4,6-dideoxy-2,3-di-O-methyl-6-piperidino-4-(N0-
phenyl)thioureido- -galactopyranoside (13)
57.8 (C-3 and C-5), 55.4 (OMe), 51.1 (2 ꢁ –CH2); MS: Calcd for:
a-
D
C18H25NO6 351, found: 352 [M+H]+.
Propanedithiol (200
lL) was added to a solution of 12 (300 mg,
3.16. Methyl 3-azido-4,6-O-benzylidene-2,3-dideoxy-2-
0.95 mmol) in MeOH (5 mL) at rt and the mixture was stirred for
72 h at 50 °C. When TLC (CH2Cl2–MeOH, 95:5) showed the forma-
tion of the 4-amino derivative, the mixture was filtered and the fil-
trate was concentrated. The residue was dissolved in MeOH
piperidino-a-D-mannopyranoside (17)
Diisopropyl azodicarboxylate (1.33 mL, 6.8 mmol) was added to
a solution of 15 (2.0 g, 5.73 mmol) and PPh3 (1.79 g, 6.87 mmol) in
THF (50 mL) at 0 °C and the mixture was stirred for 20 min at 0 °C.
Then diphenylphosphoryl azide (1.48 mL, 6.86 mmol) in THF
(12 mL) was added and the mixture was stirred for 24 h at rt. Then
the mixture was concentrated, the residue was taken up in EtOAc
(300 mL), and washed with sat. NaHCO3 solution (150 mL), the or-
ganic layer was dried, filtered, and concentrated. Column chroma-
tography (CH2Cl2–EtOAc; 95:5) of the residue followed by
recrystallization from hexane/EtOAc afforded 17 (1.27 g, 60%) as
(10 mL) and phenyl isothiocyanate (200 lL) was added to the solu-
tion. The mixture was stirred for 8 h at rt, then it was concentrated
and the residue was purified by column chromatography (CH2Cl2–
MeOH; 95:5) to afford 13 (280 mg, 69% over two steps) as a syrup:
½
a 2D5 122.5 (c 0.59, CHCl3); 1H NMR: d 8.78 (br s, 1H, NH), 7.45–7.20
ꢀ
(m, 5H, aromatic), 6.51 (br s, 1H, NH), 5.30 (br s, 1H, H-4), 4.80 (d,
1H, J1,2 3.0 Hz, H-1), 4.10 (m, 1H, H-5), 3.67 (dd, 1H, J2,3 10.3 Hz, J3,4
4.4 Hz, H-3), 3.53, 3.50 and 3.38 (each s, each 3H, 3 OMe), 3.11 (m,
1H, H-2), 2.66 (dd, 1H, H-6a), 2.46 (m, 5H, H-6b and 2 piperidine
CH2), 1.58 and 1.42 (each m, 6H, 3 piperidine CH2); 13C NMR: d
181.5 (C@S), 136.7, 129.6, 126.5 and 126.6 (aromatic), 97.6 (C-1),
78.2 (C-3), 77.6 (C-2), 65.9 (C-5), 59.1 (C-6), 58.9, 58.1 and 55.6
(3 OMe), 54.5 (C-4), 54.9, 25.3 and 23.7 (5 piperidine CH2); MS:
Calcd for: C21H33N3O4S 423, found: 424 [M+H]+. Anal. Calcd for C21-
H33N3O4S: C, 59.55; H, 7.85. Found: C, 59.58; H, 7.89.
white crystals: mp 161–163 °C; ½a D25
ꢀ
17.8 (c 0.89, CHCl3); 1H
NMR: d 7.55–7.33 (m, 5H, aromatic), 5.60 (s, 1H, –CHPh), 4.70 (s,
1H, H-1), 4.32 (dd, 1H, Jgem 9.9 Hz, H-6a), 4.20 (m, 1H, H-5), 4.13
(m, 1H, H-3), 4.01 (dd, 1H, J3,4 3.8 Hz, J4,5 9.8 Hz, H-4), 3.74 (dd,
1H, H-6b), 3.38 (s, 3H, OMe), 2.86 (d, 1H, J2,3 1.2 Hz, H-2), 2.72
and 2.55 (each m, each 2H, 2 –CH2–), 1.60 and 1.45 (m, 6H, –
CH2–); 13C NMR: d 137.1, 129.1, 128.3 and 126.1 (aromatic),
102.2 (–CHPh), 101.3 (C-1), 77.7 (C-4), 69.4 (C-6), 67.4 (C-2), 58.0
(C-5), 56.0 (C-3), 55.2 (OMe), 51.7, 26.5 and 24.2 (5 –CH2); MS:
Calcd for: C19H26N4O4 374, found: 375 [M+H]+. Anal. Calcd for
3.14. Methyl 4,6-O-benzylidene-2-deoxy-2-piperidino-a-D-
altropyranoside (15)
C19H26N4O4: C, 60.95; H, 7.00. Found: C, 60.99; H, 7.01.
Piperidine (6.73 mL) and LiClO4 (3.62 g) were added to a solu-
tion of 14 (4.5 g, 17.0 mmol) in MeCN (50 mL) at rt and the mixture
was stirred for 24 h at 90 °C. Then the mixture was concentrated,
the residue was redissolved in EtOAc (300 mL), and washed with
water (3 ꢁ 150 mL), the organic layer was dried, filtered, and con-
centrated. After column chromatography (CH2Cl2–MeOH; 95:5) 15
(5.7 g, 95%) was obtained as white crystals:. mp 83–85 °C (hexane/
3.17. Methyl 3-azido-4,6-O-benzylidene-2,3-dideoxy-2-
morpholino- -mannopyranoside (18)
a-D
Compound 16 (2.0 g, 5.73 mmol) was converted into the azido
derivative as described for 17. Column chromatography (CH2Cl2–
EtOAc, 95:5) followed by crystallization from hexane/EtOAc affor-
ded 18 (1.49 g, 69%) as white crystals: mp 164–166 °C; ½a D25
ꢀ
26.2 (c
EtOAc), lit.11 mp 117–118 °C; ½a 2D5
ꢀ
74.3 (c 0.64, CHCl3); lit.11
½ ꢀ
a 2D5
0.62, CHCl3); 1H NMR: d 7.54–7.34 (m, 5H, aromatic), 5.61 (s, 1H, –
CHPh), 4.72 (s, 1H, H-1), 4.30 (dd, 1H, Jgem 10.0 Hz, H-6a), 4.21 (m,
1H, H-5), 4.11 (m, 1H, H-3), 4.04 (dd, 1H, J3,4 3.6 Hz, J4,5 9.2 Hz, H-
4), 3.73 (dd, 1H, H-6b), 3.70 (t, 4 H, –CH2OCH2–), 3.38 (s, 3H, OMe),
2.81 (d, 1H, J2,3 1.3 Hz, H-2), 2.75 and 2.64 (each m, each 2H, 2 –
CH2–); 13C NMR: d 137.0, 129.2, 128.3 and 126.1 (aromatic),
102.3 (–CHPh), 100.0 (C-1), 77.4 (C-4), 69.2 (C-6), 67.3 (–CH2OCH2–
), 66.5 (C-2), 58.1 (C-5), 56.5 (C-3), 55.4 (OMe), 50.9 (2 –CH2); MS:
Calcd for: C18H24N4O5 376, found: 377 [M+H]+. Anal. Calcd for
90.8 (c 1.3, CH2Cl2); 1H NMR: d 7.54–7.32 (m, 5 H, aromatic),
5.64 (s, 1H, –CHPh), 4.80 (s, 1H, H-1), 4.32 (dd, 1H, Jgem 10.1 Hz,
H-6a), 4.13 (m, 2H, H-3 and H-5), 3.90 (dd, 1H, J3,4 2.9 Hz, J4,5
9.8 Hz, H-4), 3.80 (dd, 1H, H-6b), 3.40 (s, 3H, OMe), 3.18 (d, 1H,
J3,OH 4.7 Hz, 3-OH), 2.84 (d, 1H, J2,3 2.1 Hz, H-2), 2.70 and 2.55 (each
m, each 2 H, 2 –CH2–), 1.60 and 1.45 (m, 6H, –CH2–); 13C NMR: d
137.4, 129.1, 128.2 and 126.2 (aromatic), 102.1 (–CHPh), 101.2
(C-1), 77.8 (C-4), 69.4 (C-6), 67.8 (C-2), 65.6 and 57.7 (C-3 and C-
5), 55.3 (OMe), 51.8, 26.5 and 24.2 (5 –CH2); MS: Calcd for:
C18H24N4O5: C, 57.44; H, 6.43. Found: C, 57.57; H, 6.44.
C
19H27NO5 349, found: 350 [M+H]+.
3.18. Methyl 4,6-O-benzylidene-2,3-dideoxy-2-piperidino-3-(N0-
phenyl)thioureido- -mannopyranoside (19)
3.15. Methyl 4,6-O-benzylidene-2-deoxy-2-morpholino-a-D-
altropyranoside (16)
a-D
Triphenylphosphine (1.51 g, 5.7 mmol) was added to a solution
of 17 (1.2 g, 3.2 mmol) in THF (15 mL) at rt and the mixture was
stirred for 2 h at 80 °C. When TLC (hexane:EtOAc; 1:1) showed
the absence of the starting material water (0.75 mL) was added
to the mixture and the stirring was continued for 4 h at 80 °C.
Evaporation of the solvent and column chromatography (CH2Cl2–
MeOH; 98:2) of the residue afforded the 3-amino derivative
Morpholine (5.9 mL) and LiClO4 (3.62 g) were added to a solu-
tion of 14 (4.5 g, 17.0 mmol) in MeCN (50 mL) at rt and the mixture
was stirred for 24 h at 90 °C. Then the mixture was concentrated
and the residue was taken up in EtOAc (300 mL) and washed with
water (3 ꢁ 150 mL), the organic layer was dried, filtered, and con-
centrated. Purification of the residue by column chromatography
(CH2Cl2–MeOH; 95:5) afforded 16 (5.0 g, 84%) as white crystals:.
(900 mg). Phenyl isothiocyanate (300 lL) was added to a solution
mp 117–119 °C (hexane), lit.11 mp 118–119 °C; ½a 2D5
ꢀ
73.2 (c 0.71,
of the amino derivative (600 mg) in MeOH (10 mL) at rt. The mix-
ture was stirred for 30 min, then concentrated, and the product
was isolated by column chromatography (CH2Cl2–MeOH; 98:2).
CHCl3); lit.11
½
a 2D5 71.7 (c 1.2, CH2Cl2); 1H NMR: d 7.54–7.32 (m,
ꢀ
5H, aromatic), 5.64 (s, 1H, –CHPh), 4.83 (s, 1H, H-1), 4.32 (dd, 1H,
Jgem 10.1 Hz, H-6a), 4.16 (m, 2H, H-3 and H-5), 3.92 (dd, 1H, J3,4
3.1 Hz, J4,5 9.8 Hz, H-4), 3.79 (dd, 1H, H-6b), 3.70 (t, 4H, –CH2OCH2–
), 3.42 (s, 3H, OMe), 3.17 (d, 1H, J3,OH 6.6 Hz, 3-OH), 2.79 (d, 1H, J2,3
1.9 Hz, H-2), 2.70 and 2.60 (each m, each 2H, 2 –CH2–); 13C NMR: d
137.2, 129.0, 128.2 and 126.2 (aromatic), 102.2 (–CHPh), 100.0 (C-
1), 77.4 (C-4), 69.2 (C-6), 67.2 (–CH2OCH2–), 67.0 (C-2), 65.9 and
Compound 19 (733 mg, 71%) was obtained as a syrup: ½a D25
ꢀ
18.7
(c 0.82, CHCl3); 1H NMR: d 8.2 (br s, 1H, NH), 7.80–7.00 (m, 10H,
aromatic), 5.65 (s, 1H, –CHPh), 4.76 (s, 1H, H-1), 4.20 (m, 2H, H-4
and H-6a), 3.79 (dd, 1H, H-6b), 3.65 (br s, 1H, H-5), 3.33 (br s,
3H, OMe), 2.80–2.50 (m, 4H, H-2, H-3 and 2 –CH2–), 1.58 and
1.45 (m, 6 H, –CH2–); 13C NMR: d 181.0 (C@S), 137.6, 137.1,

56
K. Ágoston, P. Fügedi / Carbohydrate Research 389 (2014) 50–56
131.9, 131.8, 131.7, 128.4, and 126.0 (aromatic), 101.6 (–CHPh),
99.4 (C-1), 76.0 (C-4), 69.2 (C-6), 66.2 (C-2), 59.4 (C-5), 55.6
(OMe), 52.0 (2 -CH2), 51.8 (C-3), 26.3 and 24.1 (3 –CH2); MS: Calcd
for: C26H33N3O4S 483, found: 484 [M+H]+. Anal. Calcd for C26H33N3-
O4S: C, 64.57; H, 6.88. Found: C, 64.37; H, 6.91.
3H, OMe), 2.80–2.60 (m, 6H, H-2, H-3 and 2 –CH2–); 13C NMR: d
183.1 (C@S), 136.2 (aromatic), 130.2 (C-300 and C-500), 128.9, 128.6
1
and 128.3 (aromatic), 122.8 (q, 2C, JC,F 270 Hz, 2CF3), 123.1 (m,
2C, C-200 and C-600), 102.8 (–CHPh), 98.5 (C-1), 77.4 (C-4), 69.0 (C-
6), 67.2 (–CH2OCH2–), 65.8 (C-2), 59.1 (C-5), 55.6 (OMe), 52.8 (C-
3), 51.2 (2 –CH2); MS: Calcd for: C27H29F6N3O5S 621, found: 622
[M+H]+; HRMS: [M+Na]+ calcd for 644.1624, found: 644.1629.
3.19. Methyl 4,6-O-benzylidene-2,3-dideoxy-2-piperidino-3-(N0-
3,5-bis(trifluoromethyl)phenyl)thioureido-
a-D-
mannopyranoside (20)
3.22. General procedure for the Michael addition
Compound 17 was converted into the 3-amino derivative as de-
scribed for compound 19. 3,5-Bis(trifluoromethyl)phenyl isothio-
cyanate (470 lL) was added to a solution of the 3-amino
Organocatalyst (0.02 mmol) was added to a solution of b-nitro-
styrene (0.2 mmol) in CH2Cl2 (0.5 mL) under Ar at rt. The mixture
was stirred for 5 min, then acetylacetone (0.22 mmol) was added,
and stirring was continued for 24 h at rt. The mixture was concen-
trated and the product was isolated by column chromatography
(Hexane–EtOAc; 7:3). The ratio of the formed enantiomers was
determined by chiral HPLC method: tmajor: 9.3 min tminor: 12.5 min.
derivative (600 mg) in MeOH (10 mL) at rt. The mixture was stirred
for 30 min then concentrated. Column chromatography (CH2Cl2–
EtOAc; 98:2) of the residue provided 20 (900 mg, 81%) as a syrup:
½
a 2D5
ꢀ
ꢃ41.7 (c 0.69, CHCl3); 1H NMR: d 8.76 (br s, 1H, NH), 7.70–7.30
(m, 8H, aromatic), 5.70 (s, 1H, –CHPh), 4.86 (s, 1H, H-1), 4.30 (m,
2H, H-4 and H-6a), 4.10 (m, 1H, H-5), 3.82 (dd, 1H, H-6b), 3.40
(br s, 3H, OMe), 2.80–2.55 (m, 4H, H-2, H-3 and 2 –CH2–), 1.58
and 1.45 (m, 6H, –CH2–); 13C NMR: d 183.2 (C@S), 136.5 (aromatic),
131.0 (C-300 and C-500), 128.5, 128.3 and 128.1 (aromatic), 122.8 (q,
2C, 1JC,F 271 Hz, 2CF3), 123.1 (m, 2C, C-200 and C-600), 102.8 (–CHPh),
99.3 (C-1), 77.5 (C-4), 69.1 (C-6), 66.4 (C-2), 59.8 (C-5), 55.5 (OMe),
53.1 (C-3), 52.0 (2 –CH2), 26.4 and 24.1 (3 –CH2); MS: Calcd for:
3.23. (S)-3-(2-Nitro-1-phenylethyl)-pentane-2,4-dione (23)
1H NMR: d 7.35–7.15 (m, 5H, aromatic), 4.62–4.58 (m, 2H), 4.36
(d, J = 10.8 Hz, 1H), 4.28–4.20 (m, 1H), 2.30 (s, 3H), 1.95 (s, 3H); 13
C
NMR: d 201.7, 201.0, 136.0, 129.3, 128.5, 128.0, 78.1, 70.7, 42.8,
30.4, 29.5.
C
28H31F6N3O4S 619, found: 620 [M+H]+. Anal. Calcd for C28H31F6N3-
Acknowledgements
O4S: C, 54.28; H, 5.04. Found: C, 54.16; H, 5.04.
The authors thank Mrs. Roczkov Ivánné for performing combus-
tion analysis, Dr. Palkó Roberta for helpful support with chiral
HPLC measurements, Dr. Szilárd Varga for supporting us with b-
nitrostyrene and for Dr. Tibor Soós for fruitful discussions.
3.20. Methyl 4,6-O-benzylidene-2,3-dideoxy-2-morpholino-3-
(N0-phenyl)thioureido-
a-D-mannopyranoside (21)
Compound 18 (2.46 g, 6.5 mmol) was converted into the 3-ami-
no derivative (1.34 g) as described for 19. Phenyl isothiocyanate
(130 lL) was added to a solution of the crude amino derivative
Supplementary data
(251 mg) in MeOH (8 mL) at rt. The mixture was stirred for
30 min, the product, which formed as a precipitate, was filtered
and was recrystallized from EtOAc/hexane to afford 21 (167 mg,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2013.12.
026.
29% over two steps) as white crystals: mp 192–193 °C; ½a D25
ꢀ
45.9
(c 0.84, CHCl3); 1H NMR: d 8.40 (br s, 1H, NH), 7.50–7.20 (m,
10H, aromatic), 5.65 (s, 1H, –CHPh), 4.67 (s, 1H, H-1), 4.20 (m,
2H, H-4 and H-6a), 3.78 (t, 1H, H-6b), 3.70 (t, 4H, –CH2OCH2–),
3.60 (br s, 1H, H-5), 3.10 (s, 3H, OMe), 2.80 and 2.60 (m, 6H, H-2,
H-3 and 2 –CH2–); 13C NMR: d 180.6 (C@S), 137.0, 129.4, 128.7,
128.0, 125.9, and 125.1 (aromatic), 101.6 (–CHPh), 98.2 (C-1),
75.2 (C-4), 69.0 (C-6), 67.2 (–CH2OCH2–), 65.4 (C-2), 59.5 (C-5),
55.7 (OMe), 51.4 (C-3), 51.2 (2 –CH2); MS: Calcd for: C25H31N3O5S
485, found: 486 [M+H]+, 508 [M+Na]+. Anal. Calcd for C25H31N3O5S:
C, 61.83; H, 6.43. Found: C, 61.87; H, 6.54.
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3.21. Methyl 4,6-O-benzylidene-2,3-dideoxy-2-morpholino-3-
(N0-3,5-bis(trifluoromethyl)phenyl)thioureido-
a-D-
mannopyranoside (22)
Compound 18 (2.46 g, 6.5 mmol) was converted into the 3-ami-
no derivative (1.34 g) as described for 19. 3,5-Bis(trifluoro-
methyl)phenyl isothiocyanate (720 lL) was added to a solution
of the crude amino derivative (920 mg) in MeOH (10 mL) at rt.
The mixture was stirred for 30 min then concentrated. Column
chromatography (CH2Cl2–EtOAc; 98:2 ? 95:5) of the residue
afforded 22 (733 mg, 27%) as a syrup: ½a D25
ꢃ23.4 (c 0.74, CHCl3);
ꢀ
1H NMR: d 8.70 (br s, 1H, NH), 7.50–7.10 (m, 8H, aromatic), 5.70
(s, 1H, –CHPh), 4.78 (s, 1H, H-1), 4.35 (m, 2H, H-4 and H-6a),
3.81 (dd, 1H, H-6b), 3.70 (m, 5H, H-5 and 2 ꢁ –CH2–), 3.40 (br s,