Application of 1',2,3,3',4,4'-hexa-obenzylsucrose in the preparation of sucrose macrocycles via a click chemistry route: Regioselectivity study

Article abstract of DOI:10.1080/00397911.2010.499489

1',2,3,3',4,4'-Hexa-O-benzyl-sucrose was applied in the preparation of sucrosebased macrocycles via a click chemistry route. This was realized by protection of the 6'-OH with silyl block followed by elongation of the glucose end with the -CH₂CH

Full text of DOI:10.1080/00397911.2010.499489

Synthetic Communications1, 41: 2161–2168, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.499489
APPLICATION OF 1’,2,3,3’,4,4’-HEXA-O-
BENZYLSUCROSE IN THE PREPARATION OF
SUCROSE MACROCYCLES VIA A CLICK CHEMISTRY
ROUTE: REGIOSELECTIVITY STUDY
Bartosz Lewandowski and Sławomir Jarosz
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka, Warsaw, Poland
GRAPHICAL ABSTRACT
Abstract 10,2,3,30,4,40-Hexa-O-benzyl-sucrose was applied in the preparation of sucrose-
based macrocycles via a click chemistry route. This was realized by protection of the
60ꢀOH with silyl block followed by elongation of the glucose end with the ꢀCH2CH2N3
unit. Removal of the silyl block and subsequent propargylation of the released C60ꢀOH
afforded the corresponding synthon, cyclization of which under the click condition provided
the desired macrocycle with the expected 1,4-pattern of substituents at the triazole ring.
Keywords Click chemistry; cyclization; macrocycles; sucrose
Sucrose, available in more than 150 million tons per year, is a subject of interest not
only at the food market but also as a cheap raw material. Although this chemical is
very demanding to work with (because of a presence of eight hydroxyl groups diffi-
cult to differentiate, the high sensitivity of the glycosidic bond in acidic media, and
finally very poor solubility in organic solvents), many laboratories are currently try-
ing to apply this disaccharide as a starting material for the preparation of optically
pure fine chemicals, biodegradable polymers, or surfactants.[1]
We have succeeded in the preparation of several useful sucrose derivatives:
2,3,30,4,40-penta-O-benzylsucrose (1), having all three primary hydroxyl groups
free,[2] and 10,2,3,30,4,40-hexa-O-benzylsucrose (2), with only two hydroxyl groups
at the glucose and fructose ends unprotected.[3] Connection of these terminal
(6 and 60) positions was possible; thus a number of crown and aza-crown ether
Received May 7, 2010.
Address correspondence to Sławomir Jarosz, Institute of Organic Chemistry, Polish Academy of
Sciences, Kasprzaka 44=52, 01-224 Warsaw, Poland. E-mail: sljar@icho.edu.pl
2161

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B. LEWANDOWSKI AND S. JAROSZ
Figure 1. Partially protected sucroses (1,2) and their applications in the preparation of macrocyclic sucrose
receptors 3.
analogs of sucrose were prepared (Fig. 1).[4] One of them (3; X Y ¼ Z NBn)
displayed very high enantioselectivity in complexation of a-phenylethylamine.[5]
We have explored also another field of the sweet sucrose macrocycles.
Recently, we have reported that compound 4 (readily prepared from the diol 2) pro-
vided, under the Cu(I)-catalyzed azide-alkyne cycloaddition[6,7] conditions, the
sucrose-based macrocycles. Depending on the concentration of the starting material
and Cu(I) source, products with either the C1- or C2-symmetry were formed (Fig. 2;
5=6, or 7).[8]
=
=
The C2-symmetrical product 7 had the expected (1,4) pattern of substitution[6]
at the triazole rings. However, the reaction conducted in dilution afforded two
regioisomeric products to which structures 5 and 6 were assigned.[8] Formation of
Figure 2. Transformation of hexa-O-benzylsucrose into macrocycles via click chemistry.[8]

SUCROSE MACROCYCLES VIA A CLICK CHEMISTRY
2163
the (unexpected) 1,5-triazole 5 might be explained by steric factors. In the normal
product 6, the carbon atom from the triazole ring is located in the sucrose cavity;
thus steric repulsion makes this structure less favorable than the alternative
derivative 5, which, on the other hand, is not favored by the mechanism of the click
cyclization.[6]
To determine if the steric hindrance caused formation of the unfavorable (on
the mechanistic base) 1,5-regioisomer, we have prepared the longer analog of 4
(compound 14), which was elongated by two carbon atoms at the glucose terminal
position.
The synthesis (shown in Scheme 1) was initiated from the monoprotected
sucrose 8,[9] which was alkylated with tert-butyl bromoacetate to afford the ester
9. Reduction of the ester function with LiAlH4 provided the alcohol 10, which
was transformed in a few steps into the azide 12 and next into the target 14, ready
for cyclization.
Treatment of an acetonitrile solution of this compound with copper(I) iodide
and diisopropyl-ethylamine (DIPEA) furnished only one isomer of the product,
the structure of which was determined by spectral analysis. Mass spectrometry
Scheme 1. (i) BrCH2CO2tBu, NaH, DMF, 90%; (ii) LiAlH4, THF, 90%; (iii) MsCl, DMAP, NEt3,
CH2Cl2, 95%; (iv) NaN3, DMF, 120 ꢁC, 85%; (v) Bu4NF, THF, 95%; and (vi) propargyl bromide,
NaH, DMF, 85%.

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B. LEWANDOWSKI AND S. JAROSZ
Scheme 2. (i) CuI, DIPEA, MeCN, 55%.
indicated formation of a monomer [m=z ¼ 1012.5 (M þ Hþ)], and NMR data pointed
at the structure of 1,4-triazole 15 (Scheme 2). The assignment was based on the
empirical rules provided by Dondoni and Marra, which connect the chemical shifts
of the proton and carbon resonances of the atoms engaged in the triazole ring with
the structure of triazole.[10] The signals of the heterocyclic ring in the normal (1,4)
derivative and its 1,5-regioiosomer differ significantly (see Fig. 3 for compounds
16 and 17), which us allow to assign safely the substitution pattern 1,4 vs. 1,5.
The triazole resonances in compound 15 prepared by us were very close to
those observed for derivative 17, 1,4-disubstituted triazole, obtained by Dondoni
and Marra.[10]
Figure 3. The 1H and 13C NMR data for sugar derived 1,5- (16) and 1,4-triazoles (16).

SUCROSE MACROCYCLES VIA A CLICK CHEMISTRY
2165
EXPERIMENTAL
NMR spectra were recorded with a Bruker AM 500 spectrometer for solu-
1
tions in CDCl3 (internal Me4Si). The H and 13C aromatic resonances occurring
1
at the typical d values were omitted for simplicity. In the H NMR spectra only
diagnostic signals are shown. Mass spectra were recorded with an electrospray
ionization=mass spectrometry (ESI=MS) Mariner (PerSeptive Biosystem) mass
spectrometer. Column chromatography was performed on silica gel (Merck,
70–230 or 230–400 mesh). Organic solutions were dried over anhydrous magnes-
ium sulfate.
6-O-(tert-Butoxycarbonyl-methylene)-6’-O-tert-butyl-diphenylsilyl-
1’,2,3,3’,4,4’-hexa-O-benzylosucrose (9)
To a solution of 60-O-tert-butyl-diphenylsilyl-10,2,3,30,4,40-hexa-O-benzylosu-
crose[9] (8; 380 mg, 0.33 mmol) in DMF (10 mL), NaH (60% dispersion in mineral
oil; 27 mg, 0.68 mmol) was added, followed by tert-butyl bromoacetate (0.4 mL,
2.6 mmol). The mixture was stirred at room temperature for 24 h and partitioned
between water (15 mL) and ether (15 mL). The layers were separated, the aqueous
one was extracted with ether (3 ꢂ 10 mL), and the combined organic solutions were
washed with water (15 mL), dried, and concentrated. The product was purified by
column chromatography (hexane–ethyl acetate, 6:1) to afford pure 9 as an oil
(340 mg, 0.275 mmol, 85%).
1H NMR d: 5.74 (d, 1H, J1,2 ¼ 3.8 Hz, H-1), 1.42 [s, 9H, CO2C(CH3)3], 1.06 [s,
9H, SiC(CH3)3]. 13C NMR d: 169.04 (CO2tBu), 139.1, 139.0, 138.5, 138.3, 138.2,
138.0 (Cquat, 6 ꢂ OCH2Ph), 135.7, 135.5 (Cquat, Ph2tBuSi-), 104.7 (C-20), 89.8
(C-1), 84.2, 82.6, 82.0, 81.3, 79.9, 77.3 and 70.8 (C-2,3,30,4,40,5,50), 81.8 (CO2CMe3),
75.5, 74.7, 73.5, 73.2, 72.5, 72.1, 71.3, 69.3, 68.5, 65.0 (C-10,6,60, 6 ꢂ OCH2Ph, OCH2-
CO2tBu), 28.1 (CO2CMe3), 26.9 (SiCMe3), 19.3 (SiCMe3). MS m=z: 1257.8
[M(C76H86O13Si) þ Naþ].
6-O-(2-Hydroxyethyl)-6’-O-tert-butyl-diphenylosilyl-1’,2,3,3’,4,4’-
hexa-O-benzylsucrose (10)
A solution of the ester 9 (310 mg, 0.25 mmol) in tetrahydrofuran (THF)
(10 mL) was added slowly to a suspension of LiAlH4 (30 mg) in THF (10 mL),
and the mixture was stirred for 2 h at rt. Then water (2 mL) was carefully added,
and the mixture was partitioned between ethyl acetate (20 mL) and water (10 mL).
Standard workup followed by column chromatography (hexane–ethyl acetate, 4:1)
afforded alcohol the 10 as an oil (262 mg, 0.225 mmol; 90%).
1H NMR d: 5.75 (d, 1H, J1,2 ¼ 3.5 Hz, H-1), 1.04 [s, 9H, SiC(CH3)3]. 13C NMR
d: 138.9, 138.7, 138.4, 138.25, 138.20, 138.0 (Cquat, 6 ꢂ OCH2Ph), 135.6, 135.5 (Cquat
,
Ph2tBuSi-), 104.7 (C-20), 89.7 (C-1), 84.1, 82.5, 81.9, 81.3, 80.0, 77.5 i and 70.7
(C-2,3,30,4,40,5,50), 75.5, 74.7, 73.5, 73.1, 72.5, 72.4, 72.2, 71.4, 69.4, 64.8, 61.7
(C-10,6,60, 6 ꢂ OCH2Ph, OCH2CH2OH), 26.9 (SiCMe3), 19.2 (SiCMe3). MS m=z:
1187.8 [M(C72H80O12Si) þ Naþ].

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B. LEWANDOWSKI AND S. JAROSZ
6-O-(2-Mesyloxyethyl)-6’-O-tert-butyl-diphenylosilyl-1’,2,3,3’,4,4’-
hexa-O-benzylsucrose (11)
Compound 10 (250 mg, 0.215 mmol) was dissolved in dichloromethane (10 mL)
containing triethylamine (2 mL) and dimethylaminopyridine (DMAP) (30 mg).
Mesyl chloride (0.2 mL) was added dropwise during 10 min, and the mixture was stir-
red at rt for 4 h and partitioned between water (10 mL) and dichloromethane
(10 mL). The layers were separated, and the aqueous one was extracted with dichlor-
omethane (10 mL). Combined organic solutions were dried and concentrated, and
the product was purified by column chromatography (hexane–ethyl acetate, 4:1)
to afford mesylate 11 as a colorless oil (253 mg, 0. 204 mmol, 95%).
1H NMR d: 5.70 (d, 1H, J1,2 ¼ 3.6 Hz, H-1), 2.83 (s, 3H, SO2CH3), 1.05 (s, 9H,
SiC(CH3)3). 13C NMR d: 138.9, 138.8, 138.3, 138.22, 138.19, 138.0 (Cquat
,
6 ꢂ OCH2Ph), 135.6, 135.5 (Cquat, Ph2tBuSi-), 104.7 (C-20), 89.7 (C-1), 84.8, 82.4,
81.9, 81.3, 80.0, 77.7 i and 71.4 (C-2,3,30,4,40,5,50), 75.5, 74.6, 73.5, 73.1, 72.3, 72.2,
70.6, 69.6, 68.7, 64.8, 54.0 (C-10,6,60, 6 ꢂ OCH2Ph, OCH2CH2OMs), 38.1 (OSO2CH3),
26.9 (SiCMe3), 19.2 (SiCMe3). MS m=z: 1265.5 [M(C73H82O14SSi) þ Naþ].
6-O-(2-Azidoethyl)-6’-O-tert-butyl-diphenylsilyl-1’,2,3,3’,4,4’-hexa-O-
benzylsucrose (12)
Solid NaN3 (100 mg, 1.5 mmol) was added to a solution of compound 11
(150 mg, 0.12 mmol) in DMF (10 mL), and the mixture was stirred for 24 h at
100 ꢁC. After cooling, it was partitioned between water (15 mL) and ether (15 mL),
the organic layer was separated, and the aqueous one was extracted with ether
(3 ꢂ 15 mL). Combined organic solutions were washed with water (15 mL), dried,
and concentrated, and the crude product 12 (120 mg) was used in the next step
without further purification. MS m=z: 1212.8 [M(C72H79N3O11Si) þ Naþ].
6-O-(2-Azidoethyl)-1’,2,3,3’,4,4’-hexa-O-benzylsucrose (13)
Compound 12 (120 mg) was dissolved in THF (10 mL) to which
tetrabutyl-ammonium fluoride trihydrate (80 mg, 0.26 mmol) was added, and the
mixture was stirred at room temperature for 15 h. Solvent was removed in vacuum,
and the product was purified by column chromatography (hexane–ethyl acetate, 2:1)
to afford 13 as an oil (96 mg, 0.101 mmol, 84% overall from 11).
1H NMR d: 5.50 (d, 1H, J1,2 ¼ 3.4 Hz, H-1). 13C NMR d: 138.7, 138.6, 138.3,
138.14, 138.13, 137.8 (Cquat, 6 ꢂ OCH2Ph), 103.8 (C-20), 91.1 (C-1), 83.5, 81.7, 81.2,
79.43, 79.41, 77.3 and 71.4 (C-2,3,30,4,40,5,50), 75.5, 74.9, 73.6, 73.30, 73.26, 72.8,
72.5, 70.3, 68.9, 61.1, 50.7 (C-10,6,60, 6 ꢂ OCH2Ph, OCH2CH2N3). MS m=z: 974.7
[M(C56H61N3O11) þ Naþ].
6-O-(2-Azidoethyl)-6’-O-propargyl-1’,2,3,3’,4,4’-hexa-O-
benzylsucrose (14)
Sodium hydride (60% susp. in mineral oil; 14 mg, 0.35 mmol) was added to a
solution of compound 13 (80 mg, 0.084 mmol) in DMF (5 mL), and the mixture

SUCROSE MACROCYCLES VIA A CLICK CHEMISTRY
2167
was stirred at rt for 10 min. Propargyl bromide (80% solution in toluene, 0.1 mL) was
added, and stirring was prolonged for 5 h. The mixture was partitioned between
water (10 mL) and ether (10 mL), the organic phase was separated, and the aqueous
one was extracted with ether (3 ꢂ 10 mL). The combined organic solutions were
washed with water (10 mL), dried, and concentrated, and the product was purified
by column chromatography (hexane–ethyl acetate, 3:1) to afford 14 as an oil
(70 mg, 0.071 mmol, 85%).
1H NMR d: 5.67 (d, 1H, J1,2 ¼ 3.6 Hz, H-1), 2.38 (t, 1H, J1,2 ¼ 2.2 Hz,
CH2CCH). 13C NMR d: 139.0, 138.8, 138.4, 138.3, 138.2, 137.9 (Cquat
,
6 ꢂ OCH2Ph), 104.8 (C-20), 90.3 (C-1), 83.9, 82.4, 81.8, 81.3, 79.9, 79.5, 77.4 i and
70.6 (C-2,3,30,4,40,5,50 þ OCH2CCH), 79.7 (CCH), 75.4, 74.8, 73.5, 73. 0, 72.48,
72.36, 71.1, 71.0, 70.2, 69.7, 58.4, 50.7 (C-10,6,60, 6 ꢂ OCH2Ph, OCH2CH2N3,
OCH2CCH). MS m=z: 1012.5 [M(C59H63N3O11) þ Naþ].
Click Reaction of Compound 14: Synthesis of the Macrocycle 15
CuI (3.5 mg, 0.018 mmol) and diisopropylethyl amine (DIPEA) (20 mL) were
added to a solution of 14 (60 mg, 0.061 mmol) in acetonitrile (15 mL), and the
mixture was stirred at room temperature for 72 h. The mixture was filtered, the fil-
trate was concentrated, and the product was isolated by column chromatography
1
(hexane–ethyl acetate, 2:1) to afford 15 as an oil (33 mg, 0.033 mmol, 55%). H
NMR d: 8.06 (s, 1H, H-triazole), 5.61 (d, 1H, J1,2 ¼ 3.6 Hz, H-1). 13C NMR d:
145.1 (Cquat, triazole), 138.9, 138.6, 138.3, 138.2, 138.1 (double intensity) (Cquat
,
6 ꢂ OCH2Ph), 124.6 (C-H, triazole), 103.7 (C-20), 89.1 (C-1), 83.2, 81.9, 80.6, 79.6,
79.1, 76.8 and 70.4 (C-2,3,30,4,40,5,50), 75.4, 74.7, 73.3, 72.9, 72.4, 72.3, 70.2, 70.0,
69.7, 69.2, 66.0, 51.2 (C-10,6,60, 6 ꢂ OCH2Ph, OCH2CH2triazol, OCH2triazole).
MS m=z: 1012.6 [M(C59H63N3O11) þ Naþ].
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.
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