Synthesis and complexation properties towards the ammonium cation of aza-coronand analogues containing sucrose

Article abstract of DOI:10.1016/j.carres.2008.01.016

1′,2,3,3′,4,4′-Hexa-O-benzyl-sucrose was converted in good yields into the macrocyclic receptors containing two and three nitrogen atoms in the ring. Their complexation properties towards the ammonium cation were significantly higher than for receptors wi

Full text of DOI:10.1016/j.carres.2008.01.016

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 965–969
Note
Synthesis and complexation properties towards the ammonium
cation of aza-coronand analogues containing sucrose
Slawomir Jarosz* and Bartosz Lewandowski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 5 November 2007; received in revised form 9 January 2008; accepted 14 January 2008
Available online 26 January 2008
Abstract—10,2,3,30,4,40-Hexa-O-benzyl-sucrose was converted in good yields into the macrocyclic receptors containing two and three
nitrogen atoms in the ring. Their complexation properties towards the ammonium cation were significantly higher than for receptors
without any nitrogen atoms in the ring.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Sucrose; Aza-coronands; Receptors; Complexation
Sucrose, the most abundant disaccharide occurring in
nature, is produced on the scale 150 million tons per
year. Most of it is used in the food industry, but its
application in other fields as a cheap organic raw mate-
rial has also attracted considerable interest. Consider-
able effort has been applied to promote this saccharide
as a scaffold for surfactants, pharmaceuticals or bio-
degradable polymers.1 Although sucrose is, by far, the
cheapest enantiomerically pure derivative and conse-
quently, it might be regarded as a convenient chiron,
its application in stereoselective organic synthesis is
rather limited due to the fact that it has eight hydroxyl
groups not much differing in reactivity, is not stable
under acidic conditions and is almost insoluble in
organic solvents.1 However, examples of the synthesis
of azasugars2 or other heterocycles3 have been
described, but this was connected with the destruction
of the disaccharide skeleton.
mary hydroxyl groups in the penta-O-benzyl analogue
1, which allowed the modification of each terminal posi-
tion.4,6 The sucrose amines, uronic acids and derivatives
with an elongated side chain (2–7 carbon atoms) were
conveniently obtained (e.g., 3 in Fig. 1).4
In free sucrose C-6 and C-60 are close to each other,
which results from the relatively strong hydrogen bond-
ing between 10-OH–2-OH and weaker hydrogen bond-
ing between the 60-OH and the oxygen atom from the
glucopyranose ring.7 We have found that C-6 and C-60
are also close to each other in selectively protected
sucroses: 1 and 2 (despite lacking the strong hydrogen
bond between 10-OH and 2-OH), since they could be
connected either via a carbon or polyethylene glycol
bridge.4 The ring closing metathesis reaction performed
for the diallyl derivative of 2 afforded the cyclic olefin 4.8
Alternatively, the reaction of 2 with polyethylene glycol
ditosylates provided crown ether analogues (such as 5
and 6).4,9 The aza-crown derivative 7 was also prepared
(Fig. 1).9 The benzyl groups blocking the oxygen
functions could be removed by simple hydrogenation
providing the corresponding unprotected derivatives of
sucrose.4,9
As a part of an on-going programme on the applica-
tion of sucrose in the synthesis of useful analogues (with
the preservation of the sugar skeleton) we have devel-
oped a convenient route to partially blocked derivatives:
2,3,30,4,40-penta- (1)4 and 10,2,3,30,4,40-hexa-O-benzyl-
sucroses (2).5 It was possible to differentiate all the pri-
The complexation abilities of simple sucrose ‘crowns’
towards Group I metal cations and ammonium cation
were moderate and low, respectively (see Table 1), as
indicated by the association constants (what was
*
Corresponding author. Tel.: +48 22 343 23 22; fax: +48 22 632 66
81; e-mail: sljar@icho.edu.pl
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.01.016

966
S. Jarosz, B. Lewandowski / Carbohydrate Research 343 (2008) 965–969
R
OH
O
6
OBOM
OSiR3
6
OR
1'
1'
O
5
6'
BnO
BnO
OH
O
2' 5'
from 1
1
6'
BnO
BnO
5
O
5'
1
O
2'
O
BnO
OBn
BnO
BnO
OBn
BnO
example of the functionalization at the C-6
3. R = CH2NH2, COOH, CH=CH-CO(R')
1. R = H; 2. R = Bn
Similar modifications were performed
also at the C1' and C6' positions
1. All-Br
2. Grubbs'-I
Bn
from 2
O
O
N
O
protecting
groups (Bn)
can be
removed
affording
the free
O
6
O
or
O
6
O
6'
O
6
O
6'
O
6'
O
6
6'
or
hexa-O-benzyl
sucrose
hexa-O-benzyl
sucrose
hexa-O-benzyl
sucrose
hexa-O-benzyl
sucrose
analogues
E / Z mixture
7
4
6
5
Figure 1. Synthesis of sucrose analogue from benzylated disaccharide.
Table 1. Complexation properties towards K+ and the ammonium
cation of aza-coronands analogues containing sucrose (in acetone-d6)
R
R
NBn
6
BnN
i.
6'
Ka (mol/dm3) (acetone-d6)
2
Compound
hexa-O-benzyl
sucrose
78%
v.
ðþÞ
NH4
K(+)
8. R = H
9. R = CH2CO2 Bu
10. R = CH2CH2OH
5
6
17
25
125
560a
230a
258
66
234
ND
88a
ii.
t
iii.
N
Bn
7
Bn
Bn
N
N
6'
11
14
6
iv.
OBn
60%
O
11
R
O
BnO
The data for compounds 5–7 are taken from Ref. 9
ND = not determined.
a This work.
OBn
O
Bn
Bn
BnO
OBn
N
N
OBn
R
O
6'
O
6
determined for the isothiocyanates (M-SCN)9). Change
of the size of the cavity (from 5 to 6) had almost no
influence on the association constant for ammonium
cation (in acetone-d6), however replacing one oxygen
atom with nitrogen significantly increased this constant
(Kas = 17 mol/dm3 for 5 and 125 mol/dm3 for 7).9 We
decided, therefore, to elaborate a general methodology
for the preparation of aza-macrocycles with the sucrose
scaffold; the results are shown in Scheme 1.
The synthesis of triaza-coronand 11 was initiated
from hexa-O-benzyl sucrose (2). Both free hydroxyl
groups in 2 were activated as mesyl esters, and this inter-
mediate was further converted into diamine 8 by reac-
tion with benzyl amine. Elongation by CH2CH2OH
units was performed by the reaction of 8 with tert-butyl
bromoacetate (to 9), followed by the reduction of the es-
ter functions with lithium aluminum hydride, which pro-
vided compound 10. Activation of the hydroxyl groups
(as mesyl esters) followed by reaction with benzylamine
produced aza-coronand 11 in 60% yield.
OBn
O
6
O
6'
O
O
BnO
BnO
OBn
O
hexa-O-benzyl
sucrose
14
OBn
OBn
12. R = OH
13. R = NHBn
vi.
i.
Scheme 1. Reagents and conditions: (i) (1) MsCl, Et3N, CH2Cl2; (2)
t
BnNH2, CH3CN, Na2CO3; (ii) BrCH2CO2 Bu; toluene, K2CO3, reflux,
48 h, 79%; (iii) LAH, THF; (iv) (1) MsCl, Et3N, CH2Cl2; (2) substrate
concentration (c = 3.85 ꢀ 10ꢁ3 mol/L), BnNH2 (1.2 equiv), CH3CN,
Na2CO3, 60%; (v) Ref. 11; (vi) substrate concentration (c =
3.45 ꢀ 10ꢁ3 mol/L), TsO(CH2CH2)OTs (1.2 equiv), CH3CN, Na2CO3,
55%.
diamine 13, which reacted with ethylene glycol ditosy-
late under standard conditions to afford receptor 14 in
55% yield (Scheme 1).
The association constants of the complexes with
ammonium cation (determined from the NMR titration
experiments10 in acetone-d6 with NH4SCN) were signifi-
cantly higher than for those already studied by us. For
receptor 14 with two nitrogen atoms in the ring it was
230 mol/dm3, while for that with smaller ring, but con-
taining three nitrogen atoms (11) it was found to be
560 mol/dm3. The association constants of the complex
of 6 and 14 with potassium cation were similar, while
Synthesis of compound 14 was performed from diol
12 with the elongated side chains at terminal positions
(easily obtained from the parent 2 acc. to Ref. 9) in a
similar sequence of reactions. Activation of the hydroxyl
groups followed by reaction with BnNH2 afforded

S. Jarosz, B. Lewandowski / Carbohydrate Research 343 (2008) 965–969
967
compound 11 showed almost no affinity towards potas-
sium ion. These results are in agreement with the litera-
ture data showing that the aza-coronands have higher
affinity than crown ethers towards ammonium cation
and lower (or much lower) towards potassium ion.11
Further work on the preparation of aza-coronands
with various cavity sizes and different number of N
atoms as well as the study on their complexation prop-
erties is in progress.
In conclusion, we have developed an efficient synthetic
strategy towards the aza-coronand analogues containing
sucrose. Such receptors show enhanced ability for
complexing ammonium cations which may allow their
application for the recognition of chiral amines or
aminoacids.
one extracted with ethyl acetate (2 ꢀ 15 mL), the com-
bined solutions were dried and concentrated, and the
product was purified by column chromatography
(hexane–EtOAc, 1:1 to 1:2) to afford 6,60-di(benzyloami-
no)-6,60-dideoxy-10,2,3,30, 4,40-hexa-O-benzylsucrose (8)
1
as a yellowish oil (210 mg, 82%). H NMR d: 5.51 (d,
1H, J1,2 = 3.5 Hz, H-1). 13C NMR d: 138.9, 138.8,
138.6, 138.5, 138.45, 138.34 138.2, 137.9 (Cquat
,
OCH2Ph, HNCH2Ph), 90.3 (C-1), 84.0, 81.9, 80.9,
79.8, 79.1, 77.5 and 70.7 (C-2,3,30,4,40,5,50), 75.4, 74.9,
73.4, 72.78, 72.6, 72.4, 70.3 (6 ꢀ OCH2Ph, C-10), 53.9,
53.5, 51.8, 49.3 (C-6,60, 2 ꢀ NCH2Ph). MS m/z: 1061.9
[M(C68H72N2O9)+H+], 1083.0 [M(C68H72N2O9)+Na+].
To a stirred solution of diamine 8 (200 mg, 0.19 mmol)
in toluene (10 mL) anh. K2CO3 (100 mg, 0.7 mmol) was
added followed by tert-butyl bromoacetate (0.2 mL).
The mixture was stirred for 8 h and partitioned between
water (10 mL) and toluene (30 mL). The organic layer
was separated, the aqueous one extracted with EtOAc
(2 ꢀ 10 mL), and the combined organic layers were
washed with water and dried. Purification of the crude
product by column chromatography (hexane–EtOAc,
5:1) afforded diester 9 (190 mg, 79%) as a yellowish oil.
1H NMR d: 5.56 (d, 1H, J1,2 = 3.4 Hz, H-1), 1.46 (s,
9H, C(CH3)3). 13C NMR d: 171.0, 170.7 (2 ꢀ CO2tBu),
139.1, 139.0, 138.9, 138.6, 138.5, 138.4, 138.3 and 138.1
(Cquat OCH2Ph, HNCH2Ph), 104.9 (C-20), 89.9 (C-1),
84.3, 83.8, 82.0, 80.3, 79.7, 79.0 and 71.9 (C-
2,3,30,4,40,5,50), 75.45, 74.47, 73.3, 72.8, 72.38, 72.36,
71.2 (6 ꢀ OCH2Ph, C-10), 59.0, 58.3, 57.6, 55.43, 55.37,
54.5 (C-6,60, 2 ꢀ NCH2Ph, 2 ꢀ CH2CO2tBu), 28.2
[2 ꢀ C(CH3)3], 25.6 [2 ꢀ C(CH3)3]. MS m/z: 1290.3
[M(C80H92N2O13)+H+], 1312.4 [M(C80H92N2O13)+
Na+].
1. Experimental
NMR spectra were recorded with a Bruker AM 500
spectrometer for solutions in CDCl3 (internal Me4Si)
unless otherwise stated. The resonances of the secondary
carbon atoms were assigned by DEPT experiments. The
1H- and 13C-aromatic resonances occurring at the typi-
1
cal d values (ꢂ7.2–7.3 and ꢂ128 ppm in H and 13C
NMR, respectively) were omitted for simplicity. In the
1H NMR spectra only signals not overlapping with
others were cited. Mass spectra were recorded with an
ESI/MS Mariner (PerSeptive Biosystem) mass spec-
trometer. Column chromatography was performed on
silica gel (Merck, 70–230 or 230–400 mesh). Organic
solutions were dried over anhydrous magnesium sulfate.
1.1. Synthesis of macrocycle 11
A solution of diester 9 (100 mg, 0.078 mmol) in dry
THF (5 mL) was added dropwise to a suspension of
LiAlH4 (15 mg, 0.39 mmol) in dry THF (5 mL) and
the mixture was stirred at room temperature for 6 h.
Saturated aqueous sodium sulfate (5 mL) and ethyl
acetate (10 mL) were added to decompose the excess
of hydride and product 10 was isolated in usual way
10,2,3,30,4,40-Hexa-O-benzylsucrose (2; 380 mg, 0.4
mmol) was dissolved in dichloromethane (12 mL) to
which triethyl amine (3 mL) and DMAP (2 mg) were
added. Mesyl chloride (0.15 mL, 1.75 mmol) was then
added dropwise, the mixture was stirred at rt for 5 h
and partitioned between water (15 mL) and dichloro-
methane (20 mL). The organic layer was separated, the
aqueous one extracted with CH2Cl2 (2 ꢀ 15 mL), and
the combined organic layers were washed with water,
and dried. Evaporation of the solvent under reduced
pressure left an oily residue, which was purified by
column chromatography (hexane–EtOAc 3:1) to afford
the corresponding dimesylate (420 mg, 95%) as colour-
less oil. MS m/z: 1039.3 [M(C56H62O15S2)+H+].
The above obtained dimesylate (250 mg, 0.24 mmol)
was dissolved in acetonitrile (10 mL) to which anh.
Na2CO3 (100 mg) and benzylamine (0.15 mL,
1.37 mmol) were added and the solution was boiled
under reflux for 48 h. Then it was cooled to rt and par-
titioned between water (10 mL) and ethyl acetate
(20 mL). The organic layer was separated, the aqueous
1
(72 mg, 80%). H NMR d: 5.64 (d, 1H, J1,2 = 3.5 Hz,
H-1). 13C NMR d: 138.8, 138.6, 138.5, 138.3, 138.21,
138.17, 138.1 and 138.0 (Cquat OCH2Ph, NCH2Ph),
105.4 (C-20), 90.4 (C-1), 84.2, 83.8, 81.5, 80.2, 79.8,
79.2 and 70.4 (C-2,3,30,4,40,5,50), 75.3, 74.4, 73.4, 73.0,
72.5, 72.1, 70.7 (6 ꢀ OCH2Ph, C-10), 59.22, 59.16,
59.05, 58.98, 57.4, 56.2, 56.0, 54.1 (C-6,60, 6 ꢀ OCH2Ph,
2 ꢀ NCH2Ph, 2 ꢀ CH2CH2OH). MS m/z: 1149.4
[M(C72H80N2O11)+H+]. The crude product 10 was used
in the next step without further purification.
Compound 10 was converted in 97% yield into the
dimesylate {MS m/z: 1327.5 [M(C72H84N2O15S2)+
Na+]} according to the procedure described for the
mesylation of 2. A solution of this dimesylate (100 mg,
0.0767 mmol) in CH3CN (20 mL) containing anh.

968
S. Jarosz, B. Lewandowski / Carbohydrate Research 343 (2008) 965–969
Na2CO3 (75 mg, 0.7 mmol) and benzylamine (0.014 mL,
0.099 mmol) was stirred at 70 °C for 48 h and
partitioned between (10 mL) and ethyl acetate
(25 mL). Organic layers were separated, the aqueous
one extracted with EtOAc (2 ꢀ 20 mL), the combined
organic layers were dried and concentrated, and the
crude product was purified by column chromatography
(hexane–EtOAc, 1:1 then 1:2) to afford the desired
tography (hexane–EtOAc, 1:2). 1H NMR d: 5.92 (d,
1H, J1,2 = 3.4 Hz, H-1). 13C NMR d: 139.7, 139.1,
138.83, 138.43, 138.39, 138.2, 138.06 and 138.03 (Cquat
OCH2Ph, HNCH2Ph), 103.9 (C-20), 88.3 (C-1), 83.3,
82.1, 80.6, 79.9, 79.1, 77.8 and 71.3 (C-2,3,30,4,40,5,50),
75.5, 74.8, 73.3, 72.9, 72.5, 72.4, 72.2, 707, 70.4, 70.3,
70.0, 69.0, 59.8, 59.4, 53.4, 52.6, 52.0 (C-10,6,60,
6 ꢀ OCH2Ph, 2 ꢀ NCH2Ph, 2 ꢀ OCH2CH2NBn+
NCH2CH2N). MS m/z: 1175.9 [M(C74H82N2O11)+H+]
1197.9 [M(C74H82N2O11)+Na+]. Anal. Calcd for
C72H80N2O11+2H2O: C, 72.97; H, 6.76; N, 2.36. Found:
C, 72.85; H, 6.71; N, 2.40.
1
macrocycle 11 as yellowish oil (54 mg, 60%). H NMR
d: 5.57 (d, 1H, J1,2 = 3.3 Hz, H-1). 13C NMR d: 138.8,
138.73, 138.68, 138.62, 138.57, 138.4, 138.3, 138.2 and
137.8 (Cquat OCH2Ph, NCH2Ph), 104.5 (C-20), 90.0
(C-1), 84.8, 83.7, 82.0, 80.3, 80.0, 78.2 and 71.0
(C-2,3,30,4,40,5,50), 75.5, 74.7, 73.3, 73.1, 72.43, 72.36,
70.1 (6 ꢀ OCH2Ph, C-10), 60.1, 59.0, 58.3, 57.5, 54.5,
52.5, 51.6, 50.7, 50.0 (C-6,60, 6 ꢀ O CH2Ph, 3 ꢀ
NCH2Ph, 2 ꢀ CH2CH2NBn). MS m/z: 1220.9
[M(C79H85N3O9)+H+]. Anal. Calcd for C79H85N3O9+
H2O: C, 76.64; H, 7.02; N, 3.40. Found: C, 76.58; H,
6.95; N, 3.40.
1.3. Determination of the association constants of the
complexes by NMR titration10
Determination of the association constant(s) was based
on the change of the chemical shift of the H-1 signal
of the receptor (11 or 14) after the addition of guest.
Thus, the macrocyclic compound 11 or 14 (0.02 mmol)
1
was dissolved in acetone-d6 (1 mL) and its H NMR
1.2. Synthesis of macrocycle 14
spectrum was recorded. Then a solution of the isothio-
cyanate in acetone-d6 (c = 0.5 mmol/L) was added in
5 lL portions. A 1H NMR spectrum was recorded after
the addition of each portion of guest solution. The shift
of the signal of H-1 proton was determined in each case.
The spectra were recorded until the shift of the signal
was no longer observed (which corresponded to the
saturation of the host–guest complex). The association
constant was calculated with Origin MicroCal pro-
gramme using the empirical equation determined by
Fielding.10
To a solution of the dimesylate (obtained by standard
mesylation of known9 12, 170 mg, 0.15 mmol) in aceto-
nitrile (10 mL) anh. Na2CO3 (100 mg, 0.9 mmol) and
benzylamine (0.1 mL, 0.917 mmol) were added and the
solution was stirred under reflux for 72 h. Then it was
cooled to rt and partitioned between water (10 mL)
and ethyl acetate (15 mL). The layers were separated,
the aqueous one extracted with ethyl acetate (2 ꢀ
10 mL) and the combined solutions were dried and con-
centrated. The product was purified by column chroma-
tography (hexane–EtOAc, 1:1, then 1:4, then EtOAc/
MeOH = 8:1) to afford 13 as yellow oil (125 mg, 72%).
1H NMR d: 5.63 (d, 1H, J1,2 = 3.4 Hz, H-1). 13C
NMR d: 138.93, 138.9, 138.7, 138.31, 138.28, 138.22,
138.18 and 137.9 (Cquat OCH2Ph, HNCH2Ph), 104.5
(C-20), 89.8 (C-1), 83.8, 82.1, 81.9, 79.9, 79.6, 77.5 and
70.6 (C-2,3,30,4,40,5,50), 75.4, 74.8, 73.4, 72.8, 72.4,
72.3, 72.0, 71.4, 70.0, 69.5, 53.7, 53.5, 53.2, 48.5, 48.4
(C-10,6,60, 6 ꢀ OCH2Ph, 2 ꢀ NCH2Ph, 2 ꢀ OCH2CH2-
NHBn). MS m/z: 575.6 [M(C72H80N2O11)+2H+]
1149.7 [M(C72H80N2O11)+H+]. Anal. Calcd for
C72H80N2O11+2H2O: C, 72.97; H, 6.76; N, 2.36. Found:
C, 72.85; H, 6.71; N, 2.40.
Acknowledgement
This work was financed by the Grant No. PBZ-KBN-
126/T09/07 from the Ministry of Science and Higher
Education.
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