Novel approach to selectively functionalized derivatives of sucrose

Article abstract of DOI:10.1055/s-0033-1340180

New synthetic routes to complex sucrose derivatives are presented. They are based on a highly selective silylation of the hydroxyl group at the C6′ position ('fructose end') in 2,3,3′,4,4′-penta-O-benzylsucrose followed by functionalization of the remaining (C-1′,6) positions. One of these synthons was used as a chiral platform for the construction of aza-macrocyclic systems. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0033-1340180

LETTER
▌641
lNettoervel Approach to Selectively Functionalized Derivatives of Sucrose
Selectively Functionalized Derivatives of Sucrose
Michał Kowalski, Piotr Cmoch, Sławomir Jarosz*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: slawomir.jarosz@icho.edu.pl
Received: 09.12.2013; Accepted after revision: 10.01.2014
Abstract: New synthetic routes to complex sucrose derivatives are
presented. They are based on a highly selective silylation of the hy-
droxyl group at the C6′ position (‘fructose end’) in 2,3,3′,4,4′-penta-
O-benzylsucrose followed by functionalization of the remaining (C-
1′,6) positions. One of these synthons was used as a chiral platform
for the construction of aza-macrocyclic systems.
OH
O
n
6
OBn
1'
O
O
OH
O
BnO
O
6
6'
Glu
6'
Fruc
O
Glu Fruc
OBn OBn
BnO
BnO
OBn
BnO
2
Key words: sucrose, protecting groups, regioselectivity, phase-
1
transfer catalysis, macrocycles
N
R
N
N
N
O
6
O
Bn
Chiral crown ethers and their analogues play an important
role in molecular recognition; they are able to differentiate
chiral guests and may be used as catalysts in enantioselec-
tive reactions.1 Enantioselective recognition of chiral am-
monium cations (derived from amines or amino acids)
represents especially interesting case, particularly impor-
tant in analytical chemistry. Among a variety of optically
pure scaffolds, sugars are probably the most promising,
due to their availability and biocompatibility. Up to date,
only mono-sugars have found a wide application in the
synthesis of crown ether analogues.2 The disaccharide
scaffold is much less pronounced.3
Bn Bn
N
N
Bn
Bn
6'
O
6
O
6
6'
6'
5a R = H
5b R = substituent
4
3
N
N
Bn
Bn
Bn N
O
N
Bn
O
6
6'
6
6'
7
6
Figure 1 Crown and aza-crown ethers with sucrose scaffold
Since more than a decade we are engaged in the synthesis
of macrocyclic derivatives with sucrose scaffold, as well
as, their applications in enantioselective complexation of
chiral ammonium cations.4 These receptors are built on
the skeleton of 1′,2,3,3′,4,4′-hexa-O-benzylsucrose 1
(Figure 1).
Glu Fruc
OBn OBn
N
6
6'
N
N
N
HN
O
O
We have succeeded in the preparation of a series of
crown5 and aza-crown derivatives (e.g. 2–7, Figure 1)
from this diol and applied them as receptors in complex-
ation of chiral ammonium salts; as expected the aza-
crown analogues have much better complexing properties
than simple sucrose-based crown ethers.6–9
N
HN
6'
N
6
N
Fruc Glu
OBn OBn
Glu Fruc
OBn OBn
8
6'
6
A series of differentially arranged sucrose-macrocycles
such as 4 or ‘unsymmetrical’ 6 and 7 were prepared (Fig-
ure 1). All these compounds had the benzyl protection at
the nitrogen atom. We have also obtained macrocycle 5a
with the NH functionality which allowed us to install var-
ious substituents at this center (5b).
O
N
N
N
O
O
X
N
N
NH
HN
N
O
6
6'
X = CH, N
More complex derivatives such as 810 or 911, as well as,
macrocyclic amides (10; Figure 2) with sucrose scaffold
are also available.12
Glu Fruc
OBn OBn
O
O
6
9
6'
Glu
OMe
Fruc
OMe
10 (o-, m-, p-)
SYNLETT 2014, 25, 0641–0644
Advanced online publication: 11.02.2014
DOI: 10.1055/s-0033-1340180; Art ID: ST-2013-B1122-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Figure 2 Examples of more sophisticated sucrose macrocycles

642
M. Kowalski et al.
LETTER
Macrocycles built on penta-O-benzylsucrose13 (11) offer
more flexibility in planning the synthesis. It is possible to
install the proper pendant at the 1′-OH and then close the
ring. Properties of the macrocyclic derivative, therefore,
will be governed by both the size and the nature of the
ring, as well as, the substituent at the primary 1′-OH group
(Figure 3).
OH
6
OH
OTBDPS
1'
TPSCl
O
6'
BnO
O
11
O
BnO
BnO
OBn
BnO
12
I2, Im
Ph3P
ArCO2H
Ph3P, DEAD
OH
I
OTBDPS
OTBDPS
6'
I
I
6
introduction of the
closure of the ring
substituent at 1"-OH
1'
6
1'
6'
between C6 and C6'
OH
+
5 x OBn
14
5 x OBn
6
OH
1'
OH
15
O
6'
BnO
O
NaN3, DMF, 60 °C
O
Ar
O
BnO
BnO
OBn
BnO
OH
1'
OTBDPS
6'
O
6
11
O-R
OTBDPS
N3
6
1'
6'
Figure 3 Application of penta-O-benzylsucrose for the preparation
of macrocyclic derivatives
5 x OBn
13
5 x OBn
14a R = H
14b R = All
AllBr, PTC
The convenient methodology of the synthesis of selective-
ly blocked penta-O-benzylsucrose 11 is, therefore, desir-
able.
Scheme 1 Selective transformations of penta-O-benzylsucrose
In the preliminary studies (summarized in our recent re-
view)14 we have proposed a few methods for differentia-
tion of the primary positions in 11.
dialkylated derivatives, 16a–18a, easily separated by col-
umn chromatography were, however, also formed.
In this communication another useful route to selectively
protected sucrose derivatives will be presented.
Table 1 Alkylation of Diol 12 with Different Agents
It is known that the free sucrose is selectively silylated at
the C-6′ position;15 this is also true for partially protected
derivatives.16 Selective silylation of triol 11 at the C-6′ po-
sition with tert-butyldiphenylsilyl chloride (TBDPS-Cl)
was possible and provided diol 12 with the 6- and 1′-hy-
droxyl groups free.17
.
R3
O
1'
R2
OTBDPS
O
R1Br
PTC
6
6'
12
5 x OBn
16–18
This reaction proceeded well only in highly concentrated
solutions (ca. 1 g of substrate in 1–2 mL of dichlorometh-
ane); at lower concentrations (e.g. 1 g/10 mL) we did not
observe any progress of the reaction. Also, the rate of ad-
dition of silylating agent is crucial; too fast addition of
R3SiCl results in an inseparable mixture of disilylated re-
gioisomers.
R1
R1 = R2 = R3 R1 = R2; R3 = H R1 = R3; R2 = H
CH2CO2t-Bu
CH2CH=CH2
CH2C≡CH
23% (16a)
13% (17a)
13% (18a)
51% (16b)
63% (17b)
65% (18b)
21% (16c)
15% (17c)
15% (18c)
Differentiation of the remaining primary hydroxyl groups
in 12 was done with the Mitsunobu (Ph3P–DEAD–p-ni-
trobenzoic acid)18 or Garegg reagents (Ph3P–imidazole–
iodine).19 The former afforded highly selectively monoes-
ter 13 in good yield (81%). The latter was less selective
and furnished monoiodide 14 in 72% yield together with
small amounts (8%) of diiodide 15 (Scheme 1). These
compounds were used for the preparation of more ad-
vanced derivatives, 14a or 14b, potential synthons for
macrocycles.
When such alkylation was conducted under strongly basic
conditions (e.g., NaH in DMF), removal of the TBDPS
protection from 6′-OH was noted.
We have also found that reaction of 12 with an excess (ca.
4 equiv) of tert-butyl bromoacetate affords dialkylated de-
rivative 16a in high yield (87%). Thus, we were able to
control this process and to prepare either mono- or dial-
kylated derivatives in good yield.
Further work was concentrated on the application of these
synthons in the preparation of macrocyclic derivatives. As
an example, macrocycle 21 was chosen as a target (Figure
4). This compound offers a possibility of modification of
the properties of the (potential) receptor by changing the
substituent placed at the C-1′ position. Such modification
Regioselective alkylation of diol 12 was also possible. Re-
action of 12 with various alkylating agents such as, tert-
butyl bromoacetate, allyl bromide, and propargyl bro-
mide, performed under classical PTC conditions,20,21 af-
forded compounds 16b–18b in decent yields (Table 1).
Small amounts of regioisomers at the C-1′, 16c–18c, and
Synlett 2014, 25, 641–644
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selectively Functionalized Derivatives of Sucrose
643
may have an effect on the complexation of ammonium volatile allylamine) furnished the corresponding macro-
cations.
cycles 21–23 in very good yields (67–96%; Scheme 3).
Bn
N
RNH2, KI, Na2CO3, MeCN, 80 °C
R
R
N
8
8'
7'
7
RO
OR
O
O
O
O
8
8'
OBn
N
7'
7
6
6
6'
1'
6'
O
O
O
BnO
O
2'
6
6'
5
5'
4'
O
O
1
O
O
4
1'
5b
Ka complexation of
(S)-α-phenylethylamine
R = Bn Ka = 70 M/L
R = MeOCH2CH2 Ka = 730 M/L
OAll
OBn
3'
3
6
1'
6'
BnO
BnO
O
2'
5
5'
4'
2
O
1
O
4
1'
BnO
OBn
3'
3
OBn
2
21
5 x OBn
20 R = H
20a R = Ms
OBn
O
LiAlH4
OBn
possibility of
placing various
substituents
OBn
MsCl, Et3N
DMAP, CH2Cl2
21 R = Bn, 96%
22 R = All, 86%
19
Figure 4 Influence of the nature of substituent in 5b on the complex-
80% (over two steps)
23 R = MeOCH2CH2, 67%
ation of chiral amines
Scheme 3 Synthesis of macrocycles 21–23
For example, we have noticed that changing the substitu-
ent (located at the ring nitrogen atom in 5b) from benzyl
to hydroxyethyl increases significantly the association
constant of the complex with (S)-α-phenylethylamine9
(Figure 4).
We have found that addition of potassium iodide to the re-
action mixture highly accelerates the cyclization process.
Without KI only 20–30% of dimesylate is consumed after
48 hours of refluxing (for details see the Supporting Infor-
mation).
Synthesis of 21 was initiated from diester 19 which was
prepared from 16b. Alkylation of 16b with allyl bromide
followed by deprotection of the 6′-position with TBAF
and its subsequent alkylation with tert-butyl bromoacetate
afforded the title derivative 19 in good overall yield
(Scheme 2). Alternative, shorter route involving selective
dialkylation of triol 11 was not effective; a mixture of sev-
eral products was obtained from which the desired diester
could not be isolated.
In conclusion, we have elaborated a convenient way to
differentiate the primary hydroxyl groups in 2,3,3′,4,4′-
penta-O-benzylsucrose. A number of suitable derivatives
with selectively blocked positions are available. One of
these synthons was used for the preparation of the macro-
cycles with sucrose scaffold.
Acknowledgment
The support from Grant POIG.01.01.02-14-102/09 (part-financed
by the European Union within the European Regional Development
Fund) is acknowledged.
t-Bu2OC
O
6
TPDPSO
OH
6'
BnO
BnO
O
5
5'
4'
O
4
3
1'
2'
OBn
1
3'
2
O
Supporting Information for this article is available online at
triol 11
OBn
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
OBn
16b
selective
alkylation
1. AllBr, PTC, 71%
2. TBAF, 90%
3. BrCH2CO2t-Bu
PTC, 80%
References and Notes
(1) Review: (a) Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M.
Chem. Rev. 1997, 97, 3313. (b) Roca-Lopez, D.; Sadaba, D.;
Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron:
Asymmetry 2010, 21, 2561. (c) Shirakawa, S.; Maruoka, K.
Angew. Chem. Int. Ed. 2013, 52, 4312.
(2) See reviews: (a) Jarosz, S.; Listkowski, A. Curr. Org. Chem.
2006, 10, 643. (b) Bakó, P.; Keglevich, G.; Rapi, Z.; Tőke,
L. Curr. Org. Chem. 2012, 16, 297.
t-BuO
Ot-Bu
t-BuO
Ot-Bu
O
O
OH
O
O
O
O
O
?
O
O
1'
6
6'
1'
6
6'
(3) (a) Alonso-Lopez, M.; Bernabe, M.; Fernandez-Mayoralas,
A.; Jimenez-Barbero, M.; Martin-Lomas, M.; Penades, S.
Carbohydr. Res. 1986, 150, 103. (b) Alonso-Lopez, M. M.;
Martin-Lomas, M.; Penades, S. Tetrahedron Lett. 1986, 27,
3551. (c) Alonso-Lopez, M.; Barbat, J.; Fanton, E.;
Fernandez-Mayoralas, A.; Gelas, J.; Horton, D.; Martin-
Lomas, M.; Penades, S. Tetrahedron 1987, 43, 1169.
(d) Alonso-Lopez, M.; Jimenez-Barbero, M.; Martin-
Lomas, M.; Penades, S. Tetrahedron 1988, 44, 1535.
(e) Dumont-Hornebeck, B.; Joly, J.-P.; Coulol, J.; Chapleur,
Y. Carbohydr. Res. 1999, 320, 147.
5 x OBn
19a
5 x OBn
19
Scheme 2 Synthesis of homologated diester 19
Compound 19 was converted into dialcohol 20 by reduc-
tion with LiAlH4, activation of which with MsCl–Et3N–
DMAP afforded dimesylate 20a. Reaction of this active
intermediate with a primary amine (1.3 equiv of
benzylamine22 or 2-methoxyethylamine and 2.6 equiv of
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 641–644

644
M. Kowalski et al.
LETTER
(19) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem.
(4) Jarosz, S.; Listkowski, A. J. Carbohydr. Chem. 2003, 22,
753.
Commun. 1979, 978.
(5) Brzuszkiewicz, A.; Ciunik, Z.; Jarosz, S.; Lewandowski, B.;
Listkowski, A. Tetrahedron 2005, 61, 8485.
(6) Jarosz, S.; Lewandowski, B. Chem. Commun. 2008, 6399.
(7) Jarosz, S.; Lewandowski, B. Carbohydr. Res. 2008, 343,
965.
(8) Potopnyk, M. A.; Jarosz, S. Eur. J. Org. Chem. 2013, 5117.
(9) Potopnyk, M. A.; Lewandowski, B.; Jarosz, S. Tetrahedron:
Asymmetry 2012, 23, 1474.
(10) Jarosz, S.; Lewandowski, B.; Listkowski, A. Synthesis 2008,
913.
(11) Lewandowski, B.; Jarosz, S. Org. Lett. 2010, 12, 2532.
(12) Potopnyk, M. A.; Cmoch, P.; Jarosz, S. Org. Lett. 2012, 14,
4258.
(20) Mąkosza, M.; Fedoryński, M. Curr. Catal. 2012, 1, 79.
(21) Alkylation of 12 with tert-Butyl bromoacetate: To a
solution of diol 12 (1030 mg, 0.999 mmol) in toluene (15
mL), TBAB (32 mg, 0.099 mmol, 0.1 equiv) was added
followed by 50% NaOH (10 mL). A solution of tert-butyl
bromoacetate (0.16 mL, 1.1 mmol, 1.1 equiv) in toluene
(0.84 mL) was added dropwise via syringe pump (for 1 h)
and the mixture was vigorously stirred at r.t. for 165 min.
H2O (50 mL) was added, the phases were separated, and the
aqueous one was extracted with Et2O (2 × 50 mL).
Combined organic solutions were washed with H2O (25 mL)
and brine (25 mL), dried, concentrated, and the oily residue
was purified by flash chromatography (hexanes–EtOAc,
100:1 → 83:17) to yield the main product 16b (588 mg,
0.513 mmol, 51%), its regioisomer 16c (236 mg, 0.206
mmol, 21%), and diester 16a (298 mg, 0.236 mmol, 23%) as
oils.
(13) Mach, M.; Zawisza, A.; Lewandowski, B.; Jarosz, S. Proven
Carbohydrate Methods; Vol. I; Kovac, P., Ed.; Chap. 43;
CRC Press, Taylor & Francis Group: Boca Raton, FL, 2011,
387–411; and references therein.
(14) See review: Queneau, Y.; Jarosz, S.; Lewandowski, B.;
Fitremann, J. Adv. Carbohydr. Chem. Biochem. 2007, 61,
217.
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P.; Petrova, K.; Potewar, T. M. Green Chem. 2011, 13, 1897.
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(17) Burdyńska, J.; Lewandowski, B.; Jarosz, S. J. Carbohydr.
Chem. 2011, 29, 403.
(22) Synthesis of Macrocycle 21: To a solution of 20 (113 mg,
0.105 mmol) in MeCN (10 mL) anhyd Na2CO3 (330 mg, 3.1
mmol, 30 equiv) was added followed by anhyd KI (52 mg,
0.314 mmol, 3 equiv), and benzylamine (15 μL, 14.6 mg,
0.136 mmol, 1.3 equiv). The mixture was stirred at 80 °C in
septum sealed flask for 48 h. Toluene (20 mL) was added
and MeCN was removed under reduced pressure. The
mixture was filtered through celite pad which was washed
with EtOAc (40 mL), the filtrate was concentrated, and the
residue was purified by flash chromatography (CH2Cl2–
MeOH, 100:0 → 99:1) to afford a macrocycle 21 as an
orange oil (100 mg, 0.101 mmol, 96%).
(18) (a) Mitsunobu, O. Synthesis 1981, 1. (b) For the application
of p-nitrobenzoic acid, see: Jarosz, S.; Głodek, J.; Zamojski,
A. Carbohydr. Res. 1987, 163, 289.
Synlett 2014, 25, 641–644
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