Synthesis of ribo-hexopyranoside- and altrose-based azacrown ethers and their application in an asymmetric Michael addition

Article abstract of DOI:10.1016/j.carres.2012.10.020

The synthesis of four new ribo-hexopyranoside-based chiral lariat ethers of monoaza-15-crown-5 type and two altropyranoside-based crown ethers were elaborated. Our syntheses utilized the regioselective ring opening of the oxiran moiety of the 2,3-anhydro sugars by nucleophilic reagents to afford the key intermediates. The reaction of methyl-2,3-anhydro-4,6-O-benzylidene-α-d- mannopyranoside with ethanolamine is especially of interest to afford a 3-substituted altropyranoside. One of the ribo-hexopyranoside-based lariat ethers with a 4-methoxyphenyl substituent induced an enantioselectivity of 80% when used as catalyst in the Michael addition of diethyl acetamidomalonate to trans-β-nitrostyrene under phase transfer catalytic conditions.

Full text of DOI:10.1016/j.carres.2012.10.020

Carbohydrate Research 365 (2013) 61–68
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of ribo-hexopyranoside- and altrose-based azacrown ethers
and their application in an asymmetric Michael addition
Zsolt Rapi a, Péter Bakó a, , György Keglevich , Áron Szöllosy , László Drahos , László Hegedus
⇑
a
b
c
d
}
}
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, 1521 Budapest, Hungary
b Department of Inorganic and Analytical Chemistry, H-1525 Budapest, Hungary
c Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1525 Budapest, Hungary
d MTA-BME Organic Chemical Technology Research Group, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 August 2012
Received in revised form 26 October 2012
Accepted 29 October 2012
Available online 8 November 2012
The synthesis of four new ribo-hexopyranoside-based chiral lariat ethers of monoaza-15-crown-5 type
and two altropyranoside-based crown ethers were elaborated. Our syntheses utilized the regioselective
ring opening of the oxiran moiety of the 2,3-anhydro sugars by nucleophilic reagents to afford the key
intermediates. The reaction of methyl-2,3-anhydro-4,6-O-benzylidene-a-D-mannopyranoside with
ethanolamine is especially of interest to afford a 3-substituted altropyranoside. One of the ribo-
hexopyranoside-based lariat ethers with a 4-methoxyphenyl substituent induced an enantioselectivity of
80% when used as catalyst in the Michael addition of diethyl acetamidomalonate to trans-b-nitrostyrene
under phase transfer catalytic conditions.
Dedicated to Professor Gábor Tóth on the
occasion of his 70th birthday
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sugar-based chiral crown ethers
Anhydro sugars
Asymmetric Michael addition
Enantioselectivity
1. Introduction
Thus, a broad scale of macrocycles based on carbohydrates with
different chirality are available. These macrocycles may signifi-
The enantiomer differentiation ability of the chiral crown ethers
can be used in two main fields: one is the separation of racemic
ammonium salts, the other is the application as chiral phase trans-
fer catalysts in asymmetric syntheses. Crown ethers with carbohy-
drate moieties form a special group of optically active macrocycles.
The incorporation of carbohydrates is advantageous in the synthe-
sis of chiral macromolecules because the starting carbohydrate
moieties are inexpensive and readily available as commercial prod-
ucts and they are biocompatible and can be obtained in enantio-
merically pure form with known chiroptical properties. The basic
chemistry of these compounds is well-explored. Carbohydrates
have functionalities which can be used to establish secondary
binding sites, as well as catalytic sites. This may be achieved most
easily by building the macrocycle around the ‘chiral ethylene gly-
col’ unit of the carbohydrate making use of the hydroxyl groups
on the vicinal C-atoms.1–4
cantly differ from each other by the number of sugar units, the size
of macrocyclic ring and the number and nature of the heteroatoms
incorporated in the crown ring. However, until now, only a limited
number of asymmetric reactions have been explored in which a
sugar-based crown catalyst induced the enantioselectivity. The
authors of this paper showed that the molecules of type monoaza-
15-crown-5 are efficient catalysts in a few asymmetric reactions.3,4
In this study the syntheses of ribo-hexopyranoside-based chiral
lariat ethers and macrocycles containing an altropyranoside unit
are described. Both syntheses have the common feature that for-
mation of the intermediates involves the regioselective ring open-
ing of 2,3-anhydro-hexopyranosides. The application of the crown
ethers prepared as chiral phase transfer catalysts in an asymmetric
Michael addition is also discussed.
Crown ethers containing a sugar unit in anellation with the
macrocyclic ring have been built from various carbohydrates: from
2. Results and discussion
D
-glucose,5,6
D
-galactose,7,8
D
-mannose,9,10
D
-altrose,11
D- or
2.1. Synthesis of ribo-hexopyranoside-based lariat ethers
L
-xylose,12,13 -arabinose14 and sugaralcohol -mannitol).15,16
L
(
D
The key intermediates for chiral macrocycles are ribo-hexopy-
ranoside derivatives (4 and 7) that are suitable for the construction
of the crown ring due to its vicinal hydroxyl groups. The synthesis
of sugar 4 is shown in Scheme 1.
⇑
Corresponding author. Tel.: +36 1 463 5883; fax: +36 1 463 3648.
E-mail address: pbako@mail.bme.hu (P. Bakó).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.10.020

62
Z. Rapi et al. / Carbohydrate Research 365 (2013) 61–68
OCH3
OCH3
OCH3
OCH3
NBS, CCl4
1.)
2.)
H2
O
O
LiAlH4
CaCO3, reflux
Pd/C
O
O
O
O
O
CH3OH
60 °C
10 bar
THF
reflux
NaOCH3
CH3OH
H3C
H3C
OH
O
O
Br
OH
OH
OH
Ph
1
2
3
4
Scheme 1. Preparation of methyl 2,6-dideoxy-a-D-ribo-hexopyranoside (4).
The opening of the benzylidene acetal ring of methyl-2,3-
anhydro-4,6-O-benzylidene-
-allopyranoside (1)17 was performed
The reductive ring opening of the 2,3-anhydro derivative 1 pre-
pared above was carried out with tetrabutylammonium tetrahydro-
borate (Bu4NBH4)21 leading to diaxial ring opening product, methyl
a-D
with N-bromosuccinimide (NBS),18 the following reaction with
sodium methylate resulted in the bromo sugar 2.19 The bromo func-
tion of intermediate 2 was removed by hydrogenolysis carried out
in methanol, in the presence of Pd/C at 60°C. Debrominated species
3 was obtained in 65% yield after chromatography. The regioselec-
tive reductive ring opening was accomplished by LiAlH4 in THF on
the basis of an analogy described in the literature to afford methyl
4,6-O-benzylidene-2-deoxy-a-D-ribo-hexopyranoside (5) in a yield
of 59%.22 Removal of the benzylidene acetal moiety in compound 5
was done by catalytic hydrogenation (Pd/C, MeOH, 10 bar) to furnish
methyl-2-deoxy-a-D
-ribo-hexopyranoside (6)23 in an almost quan-
titative yield. Selective protection of the C-6 hydroxyl group was
achieved by the Mitsunobu reaction using 4-methoxyphenol, diiso-
propyl-azodicarboxylate and triphenyl phosphine. Ether 7 was ob-
tained in 60% yield after chromatography. The structure of
compound 7 was proved by NMR spectrometry (DEPT-135, COSY,
HMQC and HMBC spectra). The coupling of the p-methoxyphenyl
moiety to the 6-CH2O unit was clearly proven by the HMBC spectra,
where both 6-CH2 proton signals show characteristic crosspeaks
with the C-10 carbon signal. This correlation also made possible the
2,6-dideoxy-a-D
-ribo-hexopyranoside (4)20 in a yield of 46%. Our
attempts to prepare sugar 4 by the reductive ring opening of spe-
cies 1 (LiAlH4), followed by the opening of the acetal ring by NBS
were unsuccessful. Although the individual steps of the synthesis
have been described as analogies, our method for the preparation
of methyl 2,6-dideoxy-
thesis of the another basic intermediate 7 can be seen in Scheme 2.
a-D
-ribo-hexopyranoside (4)20 is novel. Syn-
OCH3
OCH3
OCH3
OCH3
O
p-methoxy-phenol
2
3
H2
O
O
O
(n-C4H9)4N[BH4]
DIAD
Pd/C
O
OH
6
OH
benzene
reflux
CH2Cl2
CH3OH
PPh3
THF
reflux
O
OH
OH
O
O
O
O
1'
OH
OH
Ph
Ph
4'
H3CO
1
5
6
7
Scheme 2. Synthesis of methyl-2-deoxy-6-O-(4-methoxyphenyl)-a-D-ribo-hexopyranoside (7).
OCH3
H3CO
O
O
O
Cl
Cl
(ClCH2CH2)2O
O
NaI
O
acetone
reflux
50 % aq. NaOH
R1
OH
O
Bu4NHSO4
R1
OH
: R1 = CH3
7: R1 = CH2OC6H4OCH3
: R1 = CH3
8
9: R1 = CH2OC6H4OCH3
4
O
N
O
H3CO
O
O
O
I
I
O
O
H3CO
H2N(CH2)3OR2
(CH2)3OR2
O
O
CH3CN
Na2CO3
reflux
O
R1
R1
: R1 = CH3
: R1 = CH3, R2 = H
13: R1 = CH3, R2 = CH3
10
12
11: R1 = CH2OC6H4OCH3
14: R1 = CH2OC6H4OCH3, R2 = H
15: R1 = CH2OC6H4OCH3, R2 = CH3
Scheme 3. Preparation of ribo-hexopyranoside-based lariat ethers 12–15.

Z. Rapi et al. / Carbohydrate Research 365 (2013) 61–68
63
assignment of the C-10 and C-40 quaternary carbon signals, which are
close to each other (153.08 and 154.03 ppm). Anellation of the
The structure of compound 18 was proved by 1H and 13C NMR
and on the basis of DEPT-135, COSY, HMQC, HMBC and H2BC spec-
tra. The J1,2 60.6 Hz coupling constant of the H-1 (anomeric) pro-
ton shows that the methoxy group is in axial position in the
dominant conformation of the molecule. However, the assignment
of the crucial H-2 and H-3 signals and the corresponding carbon
signals could not be done in the usual conventional way. The
deduction of the coupling network cannot be started from H-1 be-
cause this signal practically has no coupling, and, furthermore, the
H-2 proton also has a relatively weak coupling The C-2 and C-6 sig-
nals are isochronous and no signal separation could be detected at
11.47 T. Additionally, the C-3 and C-5 signals are also very close to
each other. The structural determination was possible by applying
the H2BC experiment28,29 which is prominently useful in carbohy-
drate chemistry.30 Correlation from H-2 and H-4 signals made it
possible to assign the C-3 signal at 58.76 ppm and this chemical
shift value indicates that C-3 has the nitrogen substituent. The
analysis of the coupling constants shows that both H-2 and H-3
protons are equatorial and the 2-hydroxy and 3-hydroxyethyl-
amino substituents occupy trans-diaxial positions. A further con-
clusion is that both H-4 and H-6ax protons should be in axial
position in the 1,3-dioxane ring and both of them have steric prox-
imity with the H-7 signal, which was proven by the NOESY spec-
trum. The NOESY crosspeaks between H-4, H-6ax and H-7 signals
also serve as a proof for the axial position of the H-7 proton (and
consequently, the equatorial position of the phenyl group) in the
dominant conformation.
crown ring to positions 2 and 3 of the
a-D-ribo-hexopyranoside
derivatives (4 and 7) was accomplished in three steps, in a similar
way described earlier (Scheme 3).24
The vicinal hydroxyl groups of compounds 4 and 7 were alkylated
with bis(2-chloroethyl) ether in the presence of tetrabutylammo-
nium hydrogensulfate as the catalyst and 50% aq NaOH as the base
in a liquid–liquid two-phase system by the Gross method25 to give
intermediates 8 and 9 in 45% and 52% yields respectively after chro-
matography. The exchange of chlorine to iodine in intermediates 8
and 9 was accomplished by the reaction with NaI in boiling acetone
to afford bisiodo derivatives 10 and 11, respectively. These com-
pounds were then cyclized with two kinds of primary amines, such
as 3-aminopropanol and 3-methoxypropylamine, in boiling acetoni-
trile, in the presence of dry Na2CO3 to afford azacrown ethers 12–15
after purification by column chromatography. It is interesting to
note that the yields of 2,6-dideoxy-ribo-hexopyranoside-based lariat
ethers (12 and 13) were relatively low (46% and 30%, respectively),
while those of macrocycles having p-methoxyphenyl substituents
(14 and 15) were much higher (79% and 84%, respectively). The dif-
ference in yields may be the consequence of the efficiency of the
template effect within both reagents in the intramolecular ring clo-
sure reaction. The p-methoxyphenyl substituent may enhance the
formation of the template effect (Scheme 3). The ring-closing step
is facilitated by the sodium ion, which, by ion–dipole interaction
‘wraps’ the polyether-arms of the starting compound around itself
in an intermediate complex and disposes the chain-ends to ring-clo-
sure. The p-methoxyphenyl substituent of the sugar is able to bend
in the direction of the sodium cation and to stabilize this complex by
the interaction of CH3O group and Na+.
The amino sugar 18 was a suitable starting material for a few
sugar-based azacrown ethers using ethylene glycol bistosylates
as the ring forming reagents (Scheme 5).
Using triethylene glycol ditosylate and tetraethylene glycol
ditosylate in the presence of NaH in DMF, the 15-membered (19)
and 18-membered (20) amino crown ethers were formed, respec-
tively, in ca. 22% yield. The yields of the ring closure reactions are
unusually low which may be due to the significant difference in the
reactivity of the primary and secondary hydroxyl groups and
therefore a lot of by-products may be also formed.
In addition, the reactions to form macrocyclic compounds were
performed under high dilution conditions. The low concentrations
of reactants (3–4%) suppress the formation of acyclic oligomers
with respect to cyclic products.
2.2. Synthesis of altropyranoside-based crown ethers
Methyl-2,3-anhydro-4,6-O-benzylidene-
a-
D-mannopyranoside
2.3. Application of the macrocycles in asymmetric synthesis
(17) was synthesised from sugar 16 by the method of Hicks and
Fraser-Reid in one step (Scheme 4).26 Using N-p-tosyl-imidazol
and NaH in DMF, the yield of intermediate 17 was 44%. It is known
that the oxirane ring of the anhydro sugars may be opened by reac-
tion with nucleophilic agents (e.g., amines) when the amino sugar
may be formed as a mixture of two isomers. The resulting new
functionalities occupy the trans position and the ratio of the regioi-
somers depends on the structure and configuration of the starting
epoxy sugar. The epoxides of rigid six-membered rings open up to
place the new functionalities into a diaxial position according to
the Fürst–Plattner rule.27 Anhydro sugar 17 was reacted with
ethanolamine at 140°C for 6 h to result in the formation of
The crown compounds synthesized were tested as chiral phase
transfer catalysts in a few asymmetric reactions. One of these reac-
tions is the conjugate addition of diethyl acetamidomalonate (22)
to trans-b-nitrostyrene (21) in the presence of chiral crown ethers
12–15 and 19–20 (Scheme 6).31
The Michael addition was carried out in a solid–liquid two-
phase system employing 10 mol % of crown ether as the catalyst.
The organic phase comprised of the starting materials and the cat-
alyst in THF, while Na2CO3 used in twofold excess formed the solid
phase. Product 23 was obtained by preparative TLC, while the opti-
cal purity was measured by chiral HPLC. The results are summa-
rized in Table 1
methyl 4,6-O-benzylidene-3-deoxy-3-(N-hydroxyethyl)amino-a-D-
altropyranoside (18) by a regioselective ring opening (Scheme 4).
The yield of product 18 was 79% after recrystallization.
As can be seen from Table 1, using catalysts 12–15, 19 and 20,
the adduct 23 was formed in yields of 54–67%, but the ee values
OCH3
OH
OCH3
OCH3
OH
1
O
O
O
5
2
3
N
N
O
Ts
HO
NH2
140 °C
4
OH
OH
NH
NaH
DMF
6
O
O
O
O
O
O
7
Ph
Ph
Ph
16
17
18
Scheme 4. Regioselective ring opening of the anhydrosugar 18 with ethanolamine.

64
Z. Rapi et al. / Carbohydrate Research 365 (2013) 61–68
OCH3
OCH3
O
O
OH
NH
O
O
O
TsO
O
OTs
n
O
OH
NH
NaH
DMF
80 °C
O
O
O
O
n
Ph
Ph
18
19 n=1
20 n=2
Scheme 5. Synthesis of altrose-based crown-amines 19–20.
O
O
O
Ph
NO2
NO2
crown cat.
C2H5O
CH3
OC2H5
C2H5O
+
NH
CH3CONH COOC2H5
THF
Na2CO3
O
21
22
23
Scheme 6. Addition of diethyl acetamidomalonate (22) to trans-b-nitrostyrene (21).
group of ribo-hexopyranoside 6 was successfully protected by the
Mitsunobu reaction to afford compound 7.
The opening of the epoxy ring of methyl-2,3-anhydro-4,6-O-
benzylidene-a-D-mannopyranoside (17) by ethanolamine took
Table 1
Michael addition of diethyl acetamidomalonate (22) to trans-b-nitrostyrene (21) in
the presence of catalyst 12–15 and 19–20
Yield of 25a (%)
eec (%)
½ ꢀ
a 2D2
b
Entry
Catalyst
Time (h)
place in a regioselective manner to provide the 3-substituted altro-
pyranoside derivative 18.
1
2
3
4
5
6
12
13
14
15
19
20
28
24
20
21
27
21
56
67
59
56
54
41
+7
20
21
80
34
26
0
ꢁ7.6
ꢁ35
ꢁ2
From among the ribo-hexopyranoside-based lariat ethers, spe-
cies 14 used as the catalyst induced an ee of 80% in the Michael
addition of trans-b-nitrostyrene to diethyl acetamidomalonate.
Altropyranoside-based crown ethers 19 and 20 were not found to
be efficient enantioselective phase transfer catalysts.
The activity of the novel chiral macrocycles will be studied as
catalysts in different asymmetric reactions.
+11.7
0
a
b
c
Based on isolation by preparative TLC.
In CHCl3, c = 1.
Enantiomeric excesses were determined by chiral HPLC analysis in comparison
with authentic racemic material.
3. Experimental
were quite different. The macrocycles based on methyl-ribo-hexo-
pyranoside (12 and 13) induced modest enantioselectivities of 20–
21%. As the same time, there is a significant difference between the
effect of the p-methoxyphenyl derivatives: lariat ether 15 with a
methoxypropyl side arm induced an ee of 34%, while lariat ether
14 with a hydroxypropyl side arm brought about an ee of 80%. It
seems that the substituent of the sugar moiety plays also a role
in the discrimination of enantiomers. It is also possible that the
heteroatom at the end of the substituent (e.g., O in the case of –
CH2OC6H4–OCH3) takes also place in the formation of a transition
complex. Overall, the properties of the side arm on the crown ring
are of decisive importance.
The altrose-based monoaza-crown 19 induced only a modest
enantioselectivity of ca. 26% and derivative 20 having a larger ring
resulted in a racemic mixture. It is noteworthy that while catalysts
13–15 brought about the formation of the enantiomer with nega-
tive optical rotation (S), catalyst 12 with a hydroxypropyl side
arm and the altropyranoside-based crown 19 induced the forma-
tion of the enantiomer with positive optical rotation (R).
3.1. General procedures
Melting points were taken on using a Büchi 510 apparatus and
are uncorrected. Optical rotations were measured with a Perkin–
Elmer 241 polarimeter at 20°C. NMR spectra were recorded on
Bruker AV-300, DRX-500, and Varian Inova 500 instruments in
CDC13 solution with TMS as the internal standard. The exact mass
measurements were performed using Q-TOF Premier mass spec-
trometer (Waters Corporation, 34 Maple St, Milford, MA, USA) in
positive electrospray ionization mode. Analytical and preparative
thin layer chromatography was performed on silica gel plates (60
GF-254, Merck), while column chromatography was carried out
using 70–230 mesh silica gel (Merck). Chemicals and the shift
reagent Eu(hfc)3 were purchased from Aldrich Chem. Co.
3.2. Synthesis of chiral lariat ethers 12–15
Compound 1 was prepared acc. to lit.,17 compound 2 to lit.18,19
2.4. Conclusion
3.2.1. Methyl-6-deoxy-2,3-anhydro-a-D-allopyranoside (3)
A solution of compound 2 (16.4 g, 68.4 mmol) in methanol
(400 mL) containing triethyl amine (9.6 mL, 68.4 mmol) was stir-
red under an atmosphere of H2 (10 bar) in the presence of Pd/C
(4.9 g) at 60°C for 6 h. After cooling, the catalyst was filtered, and
the filtrate concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel using CHCl3 as an eluent to give
The ribo-hexopyranosides with vicinal hydroxy groups (4 and 7)
are key-intermediates in the synthesis of ribo-hexopyranoside-
based macrocycles. Methyl 2,6-dideoxy-a-D-ribo-hexo-pyranoside
(4) was prepared by the regio- and stereoselective opening of the
2,3-anhydro ring of compound 3 by LiAlH4. The primary hydroxyl

Z. Rapi et al. / Carbohydrate Research 365 (2013) 61–68
65
3 (7.11 g, 65%). ½a D22
ꢀ
+173.1 (c 1, CHCl3). Lit.32
½
a 2D2
ꢀ
+165 (c 1, CHCl3);
(ppm): 100.93, 74.88, 73.83, 70.86, 63.41, 57.30, 39.32. Anal. Calcd
for C7H14O5: C, 47.18; H, 7.92. Found C, 47.20; H, 7.90.
mp: 98–99 °C; lit.32 Mp: 99–100 °C; 1H NMR (CDCl3, 300 MHz), d
(ppm) 4.84 (d, J = 3 Hz, 1H), 3.68 (ddd, J = 15 Hz, 9 Hz, 6 Hz, 1H),
3.60–3.55 (m, 2H), 3.45 (s, 3H), 3.45–3.43 (m, 1H), 1.81 (br s,
OH), 1.27 (d, J = 6 Hz, 3H). 13C NMR (CDCl3, 75 MHz), d (ppm):
94.68, 72.05, 66.14, 56.10, 54.90, 51.35, 17.65. Anal. Calcd for
C7H12O4: C, 52.49; H, 7.55. Found C, 52.46; H, 7.60.
3.2.6. Methyl-2-deoxy-6-O-(4-methoxyphenyl)-a-D-ribo-
hexopyranoside (7)
A mixture of 6 (4.4 g, 24.8 mmol), PPh3 (16.26 g, 62 mmol), 4-
methoxyphenol (15.4 g, 124 mmol) and diisopropyl-azodicarboxyl-
ate (12.21 mL, 62 mmol) in dry THF (200 mL), was stirred and
refluxed under Ar atmosphere for 28 h. Then PPh3 (6.51 g,
24.8 mmol) and diisopropyl-azodicarboxylate (4.88 mL, 24.8 mmol)
were added and the mixture was refluxed for an additional 14 h.
After cooling the solvent was evaporated, and the residue was puri-
fied by flash chromatography on silica gel using CHCl3 as an eluent,
then the pure product was isolated by repeated column chromatog-
raphy on silica gel (hexane/EtOAc = 10:5) to give the product 7
3.2.2. Methyl-2,6-dideoxy-a-D-ribo-hexopyranoside (4)
To a well-stirred solution of 3 (8.6 g, 53.7 mmol) in dry THF
(100 mL) LiAlH4 (4.10 g, 107.4 mmol) was added, then the mixture
was refluxed for 16 h. After cooling, water (4 mL) was added drop-
wise with vigorous stirring. The mixture was filtered through Cel-
ite, and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography on silica gel using CHCl3/
CH3OH = 100:3 as an eluent to afford 4 (3.98 g, 46%); ½a D22
ꢀ
+134.3
(4.22 g, 60%) as a solid; mp: 44–48°C; ½a D22
ꢀ
+113,7 (c 1, CHCl3); 1H
(c 1, CH3OH). Lit.20
½
a 2D2 +126.5 (c 1, CH3OH); 1H NMR (CDCl3,
ꢀ
NMR (CDCl3, 500 MHz), d (ppm): 6.91 (d, J = 8.8 Hz, 2H), 6.88 (d,
J = 8.8 Hz, 2H), 4.88 (d, J = 3 Hz, 1H), 4.34 (dd, J = 9.1 Hz, 5.6 Hz,
1H), 4.17 (dd, J = 9.1 Hz, 5.6 Hz, 1H), 4.03 (m, 1H), 3.94 (m, 1H),
3.76 (s, 3H), 3.58 (ddd, J = 10.7 Hz, 10.7 Hz, 3 Hz, 1H), 3.45 (d,
J = 9.4 Hz, OH), 3.41 (s, 3H), 2.71 (d, J = 10 Hz, OH), 2.20 (dd,
J = 15.1 Hz, 3 Hz, 1H), 1.98 (ddd, J = 15.1 Hz, 3 Hz, 3 Hz, 1H); 13C
NMR (CDCl3, 75 MHz), d (ppm): 154.03, 153.08, 115.88, 114.59,
96.46, 68.68, 67.57, 67.32, 66.94, 55.72, 55.33, 34.74. HRMS calcd
for C14H20O6 284.1260 found 284.1257.
500 MHz), d (ppm) 4.59 (d, J = 3.5 Hz, 1H), 3.71 (ddd, J = 11.5 Hz,
5 Hz, 3.5 Hz, 1H), 3.50 (dq, J = 9 Hz, 6.5 Hz, 1H), 3.44 (s, 3H), 3.29
(ddd, J = 11 Hz, 9.5 Hz, 4.5 Hz, 1H), 2.19 (dt, J = 11,5 Hz, 5 Hz, 1H),
1.76 (br s, 2 OH), 1.64 (q, J = 11.5 Hz, 1H), 1.26 (d, J = 6 Hz, 3H).
13C NMR (CDCl3, 75 MHz), d (ppm): 97.30, 72.40, 66.40, 64.17,
55.28, 35.07, 17.62. Anal. Calcd for C7H14O4: C, 51.84; H, 8.70.
Found C, 51.80; H, 8.73.
3.2.3. Tetrabutylammonium borohydride21
Tetrabutylammonium hydrogensulphate (13.58 g, 40.0 mmol)
was dissolved in water (12 mL) and 5 M aqueous NaOH solution
(10 mL) was added, then the mixture was cooled to rt and NaBH4
(1.66 g, 44 mmol) was added during vigorous shaking. After all of
the NaBH4 was dissolved, the mixture was extracted with CH2Cl2
(2 ꢂ 10 mL). The organic layer was dried over K2CO3, then evapo-
rated. The residue was crystallized from ethyl-acetate to give the
product (10.39 g, 91%). Mp: 125–127 °C, Lit.21 Mp: 125–127 °C.
3.2.7. General method for the preparation of compounds 8 and
9
A solution of compound 4 (3.98 g, 24.6 mmol) or 7 (6.99 g,
24.6 mmol) and tetrabutylammonium hydrogensulphate (8.34 g,
24.6 mmol) in bis(2-chloroethyl)ether (81 mL, 0.69 mol) was vig-
orously stirred with 50% aqueous NaOH solution (81 mL) at rt for
14 h. Then the mixture was poured into a mixture of CH2Cl2
(200 mL) and water (200 mL) and the phases were separated. The
water layer was extracted with CH2Cl2 (2 ꢂ 100 mL), the combined
organic layer was washed with water (80 mL), dried (MgSO4) and
the solvent was evaporated. The remaining bis(2-chloroethyl)ether
was removed by vacuum distillation. The crude product was puri-
fied by column chromatography on silica gel (in the case of 8
CHCl3, in the case of 9 hexane/EtOAc = 1:1 were eluents) to give
product 8 and 9 as yellow syrups.
3.2.4. Methyl-2-deoxy-4,6-O-benzilidene-a-D-ribo-
hexopyranoside (5)22
A mixture of compound 1 (29.76 g, 0.113 mol) and tetrabutyl-
ammonium borohydride (87 g, 0.34 mol) in dry benzene (700 mL)
was stirred and refluxed for 12 h. After cooling, the mixture was
washed with water (3 ꢂ 150 mL), the organic phase was dried,
then concentrated under reduced pressure. The residue was recrys-
tallized from EtOAc to give 5 (17.64 g, 59%) as a solid. ½a D22
ꢀ
+140 (c
3.2.7.1. Methyl-2,6-dideoxy-3,4-bis[(2-chloroethoxy)ethyl]-a-
2, CHCl3); Lit.33
½
a 2D2 +141 (c 2.2, CHCl3); Mp: 130–132 °C Lit.33
ꢀ
D
-ribo-hexopyranoside (8). Yield: 4.16 g, (45%); ½a D22
ꢀ
+142 (c 1,
Mp:130–131 °C; 1H NMR (CDCl3, 500 MHz), d (ppm) 7.53–7.49
(m, 2H), 7.38–7.33 (m, 3H), 5.63 (s, 1H), 4.79 (d, J = 4 Hz, 1H),
4.33 (dd, J = 10 Hz, 5 Hz, 1H), 4.24 (td, J = 10 Hz, 5 Hz, 1H), 4.2–
.17 (m, 1H), 3.76 (t, J = 10 Hz, 1H), 3.61 (dd, J = 10 Hz, 3 Hz, 1H),
3.41 (s, 3H), 3.01 (br s, OH), 2.20 (dd, J = 15 Hz, 2.5 Hz, 1H), 2.01
(dt, J = 15 Hz, 3.5 Hz, 1H). 13C NMR (CDCl3, 75 MHz), d (ppm):
137.90, 128.83, 128.19, 126.25, 101.99, 98.38, 78.81, 68.93, 64.31,
58.15, 55.30, 35.26. Anal. Calcd for C14H18O5: C, 63.15; H, 6.81.
Found C, 63.11; H, 6.83.
CHCl3); 1H NMR (CDCl3, 500 MHz), d (ppm) 4.69 (d, J = 3 Hz, 1H),
3.77–3.72 (m, 5H), 3.70–3.64 (m, 5H), 3.64–3.60 (m, 6H), 3.59–
3.54 (m, 1H), 3.50 (ddd, J = 12 Hz, 4.5 Hz, 3.5 Hz, 1H), 3.41 (s,
3H), 3.02 (ddd, J = 11 Hz, 9.5 Hz, 4.5 Hz, 1H), 2.30 (dt, J = 11.5 Hz,
4.5 Hz, 1H), 1.72 (q, J = 11.5 Hz, 1H), 1.24 (d, J = 6 Hz, 3H). 13C
NMR (CDCl3, 75 MHz), d (ppm): 97.35, 72.42, 71.73, 71.27, 71.18,
71.10, 70.71, 70.35, 66.31, 64.10, 55.30, 42.82, 42.71, 35.03,
17.66. HRMS calcd for C15H28Cl2O6 374.1263 found 374.1260.
3.2.7.2.
Methyl-2-deoxy-6-O-(4-methoxyphenyl)-3,4-bis[(2-
-ribo-hexopyranoside (9). Yield: 6.36 g
+93,3 (c 1, CHCl3); 1H NMR (CDCl3, 500 MHz), d
3.2.5. Methyl-2-deoxy-a-D-ribo-hexopyranoside (6)
chloroethoxy)ethyl]-a-D
A solution of 5 (14.66 g, 55 mmol) in a mixture of CH2Cl2
(80 mL) and CH3OH (40 mL) was stirred under H2 (10 bar) in the
presence of Pd/C (2.2 g) at rt for 3.5 h. The catalyst was filtered,
and the filtrate was concentrated in vacuo to give 6 (9.78 g, 99%)
(52%); ½a 2D2
ꢀ
(ppm) 6.90 (d, J = 9 Hz, 2H), 6.82 (d, J = 9 Hz, 2H), 4.76 (d,
J = 4.5 Hz, 1H), 4.31–4.26 (m, 1H), 4.20 (dd, J = 10 Hz, 3.5 Hz, 1H),
4.16 (dd, J = 10 Hz, 2 Hz, 1H), 4.05 (dd, J = 6.5 Hz, 3 Hz, 1H), 3.83–
3.77 (m, 4H), 3.76 (s, 3H), 3.74–3.76 (m, 11H), 3.50 (t, J = 6 Hz,
2H), 3.34 (s, 3H), 2.23 (dd, J = 15 Hz, 2.5 Hz, 1H), 1.83 (dt,
J = 15 Hz, 3.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz), d (ppm): 154.06,
153.12, 115.85, 114.50, 96.51, 71.80, 71.33, 71.24, 71.18, 70.72,
70.31, 68.62, 67.55, 67.30, 66.88, 55.70, 55.35, 42.85, 42.74,
34.78. HRMS calcd for C22H34Cl2O8 496.1631 found 469.1634.
as a white solid; ½a D22
ꢀ
+143 (c 1, CHCl3); Lit.23
½
a 2D2
+143.1 (c 1,
ꢀ
CHCl3); Mp: 97–98 °C; Lit.23 98–99 °C. 1H NMR (CDCl3, 500 MHz),
d (ppm) 4.83 (d, J = 3 Hz, 1H), 4.02–3.98 (m, 1H), 3.93 (dd,
J = 11.5 Hz, 3.5 Hz, 1H), 3.86 (dd, J = 11.5 Hz, 5 Hz, 1H), 3.72–3.67
(m, 1H), 3.50 (dd, J = 10.5 Hz, 3.5 Hz, 1H), 3.39 (s, 3H), 2.75 (br s,
OH), 2.26 (br s, OH), 2.19 (dd, J = 14.5 Hz, 2.5 Hz, 1H), 2.10 (br s,
OH), 1.91 (dt, J = 14.5 Hz, 3.5 Hz, 1H). 13C NMR (D2O, 75 MHz), d

66
Z. Rapi et al. / Carbohydrate Research 365 (2013) 61–68
3.2.8. General method for the preparation of compounds 10 and
11
cane (13).
Yield: 0.63 g (30%). ½a D22
ꢀ
+128.7 (c 1, CHCl3); 1H NMR
(CDCl3, 500 MHz), d (ppm): 4.60 (d, J = 3 Hz, 1H), 3.90 (td, J = 12 Hz,
4 Hz, 2H), 3.66–3.50 (m, 12H), 3.43–3.41 (m, 1H), 3.41 (s, 3H), 3.33
(s, 3H), 3.18 (td, J = 10.5 Hz, 4 Hz, 1H), 2.87–2.80 (m, 2H), 2.79–2.71
(m, 2H), 2.59–2.53 (m, 3H), 1.77–1.67 (m, 4H), 1.24 (d, J = 6 Hz,
3H); 13C NMR (75 MHz, CDCl3) d ppm: 97.50, 79.95, 73.00, 72.63,
70.94, 70.39, 70.27, 69.86, 69.69, 69.33, 67.66, 58.60, 54.70,
54.43, 54.38, 52.04, 31.55, 27.42, 17.65; MS (EI): 392.2 [M+H]+,
414.2 [M+Na]+.
A mixture of bis-chloro derivative 8 or 9 (11 mmol) and NaI
(6.60 g, 44 mmol) in dry acetone (120 mL) was stirred under reflux
for 40 h. After cooling, the precipitate was filtered and washed
with acetone. The combined acetone solutions were evaporated
in vacuum. The residue was dissolved in a mixture of CHCl3
(80 mL) and water (80 mL), the layers were separated and the or-
ganic phase was washed with water and dried (MgSO4). Evapora-
tion of the solvent afforded the products 10 and 11 as yellow
oils, which were used without further purification.
HRMS calcd for C19H37NO7 391.2570 found 391.2573. Anal.
Calcd for C19H37NO7: C, 58.29; H, 9.53. Found C, 58.34; H, 9.47.
3.2.8.1. Methyl-2,6-dideoxy-3,4-bis[(2-iodoethoxy)ethyl]-
a
-
D
-
3.2.9.3.
Methyl-6-O-(4-methoxyphenyl)-2,3,4-trideoxy-a-D-
ribo-hexopyranoside (10). Yield: 6.08 g (99%); ½a D22
ꢀ
+59.6 (c 1,
ribo-hexopyranosido-[3,4-h]-N-(3-hydroxy)propyl-1,4,7,10-tet-
raoxa-13-azacyclopentadecane (14). Chromatography on silica
gel using CHCl3:CH3OH = 100:7 as an eluent to afford 14 (2.13 g,
CH3OH); 1H NMR (CDCl3, 300 MHz), d (ppm) 4.70 (d, J = 3 Hz,
1H), 3.79–3.72 (m, 5H), 3.70–3.61 (m, 7H), 3.58–3.49 (m, 2H),
3.42 (s, 3H), 3.26 (td, J = 6.6 Hz, 2.1 Hz, 4H), 3.04 (ddd, J = 10.8 Hz,
9.4 Hz, 4.2 Hz, 1H), 2.30 (dt, J = 11.4 Hz, 4.5 Hz, 1H), 1.73 (q,
J = 11.7 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz),
d (ppm): 97.38, 72.40, 71.76, 71.29, 71.20, 71.11, 70.72, 70.33,
66.32, 64.09, 55.31, 35.07, 17.68, 3.17, 3.11. HRMS calcd for
79%). ½a 2D2
ꢀ
+137.3 (c 1, CHCl3); 1H NMR (CDCl3, 500 MHz), d
(ppm): 6.89 (d, J = 9 Hz, 2H), 6.81 (d, J = 9 Hz, 2H), 4.95 (br s, OH),
4.74 (d, J = 4 Hz, 1H), 4.34 (d, J = 9.5 Hz, 1H), 4.21 (dd, J = 10 Hz,
4 Hz, 1H), 4.16–4.11 (m, 2H), 3.91–3.83 (m, 2H), 3.81–3.74 (m,
6H), 3.72–3.45 (m, 12H), 3.33 (s, 3H), 2.87–2.56 (m, 5H), 2.24
(dd, J = 15 Hz, 2 Hz, 2H), 1.76 (dt, J = 15 Hz, 4 Hz, 1H).
C15H28I2O6 557.9975 found 557.9971.
13C NMR (75 MHz, CDCl3) d ppm: 153.84, 153.28, 115.78,
114.52, 97.97, 75.49, 71.22, 70.46, 70.29, 69.29, 68.96, 68.61,
68.51, 68.14, 65.79, 63.79, 56.52, 55.70, 55.17, 54.27, 54.20,
31.74, 28.41; MS (EI): 500.2 [M+H]+, 522.0 [M+Na]+
3.2.8.2.
Methyl-2-deoxy-6-O-(4-methoxyphenyl)-3,4-bis[(2-
-ribo-hexopyranoside (11). Yield: 7.41 g
+64.3 (c 1, CHCl3); 1H NMR (CDCl3, 300 MHz), d
iodoethoxy)ethyl]-a-D
(99%); ½a 2D2
ꢀ
(ppm) 6.90 (d, J = 9 Hz, 2H), 6.83 (d, J = 9 Hz, 2H), 4.76 (d,
J = 4.2 Hz, 1H), 4.33–4.26 (m, 1H), 4.21 (dd, J = 10.2 Hz, 3.6 Hz,
1H), 4.16 (dd, J = 10.2 Hz, 2.1 Hz, 1H), 4.07 (dd, J = 6 Hz, 3.1 Hz,
1H), 3.84–3.77 (m, 4H), 3.77 (s, 3H), 3.75–3.54 (m, 9H), 3.35 (s,
3H), 3.27 (t, J = 6.9 Hz, 2H), 3.12 (t, J = 6.9 Hz, 2H), 2.23 (dd,
J = 15 Hz, 3 Hz, 1H), 1.84 (dt, J = 15 Hz, 3.6 Hz, 1H). 13C NMR (CDCl3,
75 MHz), d (ppm): 154.02, 153.16, 115.88, 114.47, 96.52, 71.78,
71.30, 71.26, 71.15, 70.74, 70.27, 68.63, 67.59, 67.28, 66.86,
55.71, 55.32, 34.77, 3.16, 3.10.
HRMS calcd for C25H41NO9 499.2781 found 499.2785. Anal.
Calcd for C25H41NO9: C, 60.10; H, 8.27. Found C, 60.06; H, 8.21.
3.2.9.4. Methyl-6-O-(4-methoxyphenyl)-2,3,4-trideoxy-a-D-ribo-
hexopyranosido-[3,4-h]-N-(3-methoxy)propyl-1,4,7,10-tetraox-
a-13-azacyclopentadecane (15).
Yield: 2.32 g (84%); ½a D22
ꢀ
+120
(c 1, CHCl3); 1H NMR (CDCl3, 500 MHz), d (ppm): 6.93 (d, J = 8.5 Hz,
2H), 6.82 (d, J = 8.5 Hz, 2H), 4.75 (d, J = 3.5 Hz, 1H), 4.49 (dd,
J = 18 Hz, 10.5 Hz, 1H), 4.33–4.08 (m, 3H), 3.95–3.78 (m, 6H),
3.76 (s, 3H), 3.72–3.45 (m, 11H), 3.37 (s, 3H), 3.33 (s, 3H), 2.83–
2.75 (m, 2H), 2.71–2.64 (m, 2H), 2.59–2.52 (m, 1H), 2.36–2.22
(m, 1H), 1.91–1.72 (m, 2H); 13C NMR (75 MHz, CDCl3) d ppm:
153.88, 153.16, 115.72, 114.55, 97.96, 75.85, 71.27, 70.78, 70.74,
70.22, 69.58, 69.39, 68.30, 68.26, 68.05, 65.78, 58.65, 55.70,
55.27, 54.70, 53.75, 53.70, 31.89, 27.18; MS (EI): 514.3 [M+H]+,
536.2 [M+Na]+; HRMS calcd for C26H43NO9 513.2938 found
513.2935. Anal. Calcd for C26H43NO9: C, 60.80; H 8.44. Found C,
60.84; H 8.50.
HRMS calcd for C22H34I2O8 680.0343 found 680.0338.
3.2.9. General method for the preparation of lariat ethers 12–15
A mixture of anhydrous Na2CO3 (3.43 g, 32.4 mmol), the corre-
sponding primary amine: 3-hydroxypropylamine (0.41 mL,
5.4 mmol) or 3-methoxypropylamine (0.44 mL, 5.4 mmol) and
bis-iodo compound 10 or 11 (5.4 mmol) in dry acetonitrile
(90 mL) was stirred and refluxed for 30–40 h, under argon. After
cooling, the precipitate was filtered and washed with acetonitrile.
The combined organic solutions were concentrated in vacuo. The
residual oil was dissolved in CHCl3, washed with water and dried
(MgSO4), and the solvent was evaporated. The crude monoaza-lar-
iat ethers (12–15) were purified by column chromatography on sil-
ica gel using CHCl3/CH3OH (100:5–100:10) as an eluent.
3.3. Synthesis of altrose-based monoaza-15-crown-5
compounds (19–20)
3.3.1. Methyl-2,3-anhydro-4,6-O-benzilidene-a-D-
mannopyranoside (17)26
3.2.9.1. Metyl-2,3,4,6-tetradeoxy-
a
-
D
-ribo-hexopyranosido-[3,
Suspension of 60% NaH (4.2 g, 0.105 mol) was washed with dry
hexane to remove the paraffin, and then was added to dry DMF
(400 mL). To this suspension 16 (14.1 g, 0.05 mol) was added and
the mixture was stirred for 1 h, then N-p-toluenesulfonyl imidaz-
ole (11.91 g, 0.054 mol) was added. After stirring for 2 h at rt the
mixture was poured into ice-water (2000 mL). The precipitate
was filtered and washed with water until the filtrate remained col-
ourless. The crude product was purified by flash chromatography
on silica gel using hexane/EtOAc = 2:1 as an eluent to afford 17
4-h]-N-(3-hydroxy)propyl-1,4,7,10-tetraoxa-13-azacyclopenta-
decane (12). Yield: 0.93 g (46%); ½a D22
ꢀ
+78.5 (c 1, CHCl3); 1H NMR
(CDCl3, 500 MHz), d (ppm) 4.90 (br s, OH), 4.60 (d, J = 3 Hz, 1H),
3.91 (td, J = 12 Hz, 4 Hz, 2H), 3.79 (t, J = 5 Hz, 2H), 3.67–3.56 (m,
9H), 3.55–3.49 (m, 3H), 3.41 (s, 3H), 3.16 (td, J = 10 Hz, 4 Hz, 1H),
2.84–2.73 (m, 4H), 2.67 (t, J = 5.5 Hz, 2H), 2.58–2.53 (m, 1H),
1.73–1.64 (m, 3H), 1.23 (d, J = 6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d ppm: 97.59, 80.07, 73.01, 72.70, 70.05, 69.91, 69.32, 69.30, 69.27,
67.61, 63.88, 56.52, 54.75, 54.68, 54.26, 31.40, 28.29, 17.63; MS
(EI): 378.3 [M+H]+ 400.3 [M+Na]+; HRMS calcd for C18H35NO7
377.2414 found 377.2410. Anal. Calcd for C18H35NO7: C, 57.27; H,
9.35. Found C, 57.32; H 9.41.
(5.76 g, 44%); ½a D22
ꢀ
+104 (c 1, CHCl3); Lit.35
½
a 2D2
+103 (c 1, CHCl3);
ꢀ
Mp: 148 °C
1H NMR (CDCl3, 500 MHz), d (ppm) 7.51–7.48 (m, 2H), 7.41–
7.36 (m, 3H), 5.57 (s, 1H), 4.90 (s, 1H), 4.26 (d, J = 5.5 Hz, 1H),
3.76–3.66 (m, 3H), 3.49–3.47 (m, 1H), 3.47 (s, 3H), 3.17
(d, J = 3.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d ppm: 137.80,
129.21, 128.30, 126.29, 102.02, 98.29, 78.80, 68.95, 66.98, 55.85,
3.2.9.2. Metyl-2,3,4,6-tetradeoxy-a-D-ribo-hexopyranosido-[3,4-
h]-N-(3-methoxy)propyl-1,4,7,10-tetraoxa-13-azacyclopentade-

Z. Rapi et al. / Carbohydrate Research 365 (2013) 61–68
67
54.81, 51.69. Anal. Calcd for C14H16O5: C, 63.63; H 6.10. Found C,
63.62; H 6.11.
1, CHCl3); 1H NMR (CDCl3, 500 MHz), d (ppm): 7.48 (dd, J = 7.5 Hz,
2 Hz, 2H), 7.36–7.32 (m, 3H), 5.57 (s, 1H), 4.67 (d, J = 3.5 Hz, 1H),
4.28 (dd, J = 10 Hz, 5 Hz, 1H), 4.21–4.15 (m, 1H), 3.98 (dd,
J = 10 Hz, 4 Hz, 1H), 3.87–3.56 (m, 20H), 3.46–3.44 (m, 1H), 3.40
(s, 3H), 2.99 (t, J = 5 Hz, 2H), 1.90 (br s, NH); 13C NMR (75 MHz,
CDCl3) d ppm: 137.94, 128.87, 128.16, 126.29, 102.08, 100.80,
78.30, 77.39, 71.44, 71.02, 70.94, 70.88, 70.82, 70.67, 70.46,
69.53, 69.46, 58.65, 55.56, 48.33; MS (EI): 484.2 [M+H]+ 506.1
[M+Na]+; HRMS calcd for C24H37NO9 483.2468 found 483.2470.
Anal. Calcd for C24H37NO9: C, 59.61; H 7.71. Found C, 59.63; H, 7.68.
3.3.2. Methyl-4,6-O-benzilidene-3-deoxy-3-(N-
hydroxyethyl)amino-a-D-altropyranoside (18)
The mixture of freshly distillated ethanolamine (2.95 mL,
49.0 mmol) and 17 (1 g, 3.8 mmol) was stirred at 140°C under Ar
for 5 h. After cooling, water (8 mL) was added, than the mixture
was extracted with CHCl3 (3 ꢂ 10 mL), the combined organic layer
was washed with brine (5 mL), dried and concentrated in vacuo.
The crude product was crystallized from diisopropylether–ethanol
6:1 to provide 18 (0.98 g, 79%); ½a D22
ꢀ
+137 (c 1, CHCl3);
3.4. General procedure for the Michael addition31
1H NMR (CDCl3, 500 MHz), d (ppm): 7.48 (m, 2H), 7.38 (m, 1H),
7.36 (m, 2H), 5.61 (s, 1H), 4.63 (s, 1H), 4.31 (dd, J = 10 Hz, 5 Hz, 1H),
4.24 (ddd, J = 10 Hz, 9.4 Hz, 5 Hz, 1H), 4.08 (dd, J = 9.4 Hz, 3.8 Hz,
1H), 4.00 (d, J = 3.1 Hz, 1H), 3.79 (dd, J = 10 Hz, 10 Hz, 1H), 3.51
(m, 2H), 3.42 (s, 3H), 3.20 (dd, J = 3.8 Hz, 3.1 Hz, 1H), 2.99 (ddd,
J = 13.2 Hz, 8,5 Hz, 4 Hz, 1H), 2.77 (ddd, J = 13.2 Hz, 8,5 Hz, 4 Hz,
1H), 2.32 (br s, NH), 1.74 (br s, 2 OH);
trans-b-Nitrostyrene 21 (0.15 g, 1 mmol), diethyl acetamido-
malonate 22 (0.33 g, 1.5 mmol) and the appropriate crown
(0.1 mmol) were dissolved in anhydrous THF (3 mL) and dry
Na2CO3 (2.08 mmol) was added. The reaction mixture was stirred
at room temperature. After completion of the reaction (20 h), the
organic phase was concentrated in vacuo and the residue was dis-
solved in toluene (10 mL) and washed with cold 10% HCl
(3 ꢂ 10 mL) and water (20 mL), dried (Na2CO3) and concentrated.
The crude product was purified on silica gel by preparative TLC
with hexane–EtOAc (3:1) as an eluent. Enantiomeric excesses were
determined by chiral HPLC analysis using a Chiralpack AD column
(hexane/isopropanol 85:15, 0.8 mL/min, 220 nm) tR = 17.8 min
13C NMR (CDCl3, 75 MHz), d (ppm): 137.58, 129.42, 128.57,
126.38, 102.49, 102.45, 76.69, 69.63, 61.58, 59.11, 58.76, 55.89,
49.36.
MS (EI): 326.3 [M+H]+, 348.4 [M+Na]+; HRMS calcd for
C16H23NO6 325.1525 found 325.1526. Anal. Calcd for C16H23NO6:
C, 59.06; H 7.13. Found C, 59.12; H, 7.18.
(major), tR = 27.7 min (minor). Yield of 23 59%; ½a D22
ꢁ35.9 (c 1,
ꢀ
3.3.3. Methyl-4,6-O-benzilydene-2,3-dideoxy-
altropyranosido-[2,3-k]-1,4,7,10-tetraoxa-13-
azacyclopentadecane (19)
a
-D
-
CHCl3, 80% ee). M.p. 135–136 °C; 1H NMR (300 MHz, CDCl3) d
7.28 (d, J = 8.7 Hz, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.69 (br s, NH),
5.50 (dd, J = 21.7, 12.2 Hz, 1H), 4.71–4.59 (m, 2H), 4.29 (dq,
J = 10.7, 7.2 Hz, 1H), 4.24 (dq, J = 10.7, 7.2 Hz, 1H), 4.15 (dq,
J = 10.7, 7.2 Hz, 1H), 4.03 (dq, J = 10.7, 7.2 Hz, 1H), 2.12 (s, 3H),
1.25 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H).31
Toa solutionof 18 (1.30 g, 4 mmol)in dryDMF (40 mL)wasadded
60% NaH (0.96 g, 24 mmol) (previously washed with dry hexane to
remove the paraffin) under Ar and the mixture was stirred at 80°C
for 4 h. Then triethylene glycol ditosylate34 (1.83 g, 4 mmol) was
added, and the mixture was stirred at 80°C for 50 h. The solvent
was removed by vacuum distillation, the residue was dissolved in a
mixture of CHCl3 and water, the water layer was extracted with
CHCl3 (3 ꢂ 20 mL), the combined organic phase was dried and con-
centrated under reduced pressure. The crude product was purified
by column chromatography on silica gel using CHCl3/CH3OH = 100:2
Acknowledgments
Financial support by the Hungarian Scientific Research Funds
(OTKA No. K 75098 and K 81127) is gratefully acknowledged. This
work is connected to the scientific program of the Development of
quality-oriented and harmonized R+D+I strategy and functional
model at BME project. This project is supported by the New
Hungary Development Plan (Project ID:TÁMOP-4.2.1/B-09/1/
KMR-2010–0002). The authors thank Professor Péter Fügedi for
helpful discussion in nomenclature. One of us (ZsR) is grateful for
the Gedeon Richter Plc for the fellowship.
as an eluent to give 19 (0.37 g, 21%); ½a D22
ꢀ
+53.8 (c 1, CHCl3); 1H NMR
(CDCl3, 500 MHz), d (ppm) 7.48 (dd, J = 7.5 Hz, 2 Hz, 2H), 7.37–7.32
(m, 3H), 5.57 (s, 1H), 4.64 (s, 1H), 4.28 (dd, J = 10 Hz, 5 Hz, 1H), 4.17
(td, J = 10 Hz, 5 Hz, 1H), 3.99 (dd, J = 9.5 Hz, 4 Hz, 1H), 3.92–3.84
(m, 1H), 3.86–3.83 (m, 1H), 3.79 (t, J = 10 Hz, 1H), 3.73–3.69 (m,
2H), 3.69–3.65 (m, 4H), 3.65–3.59 (m, 8H), 3.40 (s, 3H), 3.03 (t,
J = 10 Hz, 2H), 1.87 (br s, NH); 13C NMR (75 MHz, CDCl3) d ppm:
137.99, 128.81, 128.15, 126.23, 101.98, 100.29, 78.86, 77.73, 72.16,
71.71, 71.20, 70.98, 70.87, 70.14, 69.64, 69.45, 58.54, 55.58, 48.03;
MS (EI): 440.1 [M+H]+ 462.0 [M+Na]+.
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