Synthesis of β-Cyclodextin, Per-O-glycosylated through an Ethylene Glycol Spacer Arm

Article abstract of DOI:10.1055/s-2001-14574

The synthesis of cyclodextrin-based O-α-manno, O-β-galactopyranoside and O-β-galactofuranoside clusters, having seven sugar residues attached to the core, through ethylene, ethyleneoxyethylene and ethylene-(dioxyethylene)-ethylene spacer arms is described. The synthesis involves the glycosylation of the oxyethylene arm and the attachment of the O-glycosides onto the heptakis(6-deoxy-6-iodo)-β-cyclodextrin derivative by means of nucleophilic displacement reaction using cesium carbonate in dimethylformamide.

Full text of DOI:10.1055/s-2001-14574

PAPER
1057
Synthesis of -Cyclodextrin, Per-O-glycosylated through an Ethylene Glycol
Spacer Arm
S
ynthesis of -Cyc
f
lodextri
r
n
ica García-Barrientos,a Juan J. García-López,b Joaquín Isac-García,a Fernando Ortega-Caballero,b Clara Uriel,a
Antonio Vargas-Berenguel,*b Francisco Santoyo-González*a
a
Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
b
Área de Química Orgánica, Universidad de Almería, 04120 Almería, Spain
Fax +34-958243186; +34-950015481; E-mail: fsantoyo@ugr.es; avargas@ual.es
Received 26 January 2001; revised 14 March 2001
as the preparation of a hepta-antennated C-6-branched
Abstract: The synthesis of cyclodextrin-based O- -manno, O- -
galactopyranoside and O- -galactofuranoside clusters, having sev-
en sugar residues attached to the core, through ethylene, ethylenox-
yethylene and ethylene-(dioxyethylene)-ethylene spacer arms is
glucosylthioureido-cyclomaltoheptaose derivative14 and,
more recently, perthioglucopyranosylated -CD carrying
the attached glycopyranosides on both the primary and the
described. The synthesis involves the glycosylation of the oxyethyl- secondary faces simultaneously.15
ene arm and the attachment of the O–glycosides onto the hep-
In line with this research, we have described16,17 the syn-
takis(6-deoxy-6-iodo)- -cyclodextrin derivative by means of
nucleophilic displacement reaction using cesium carbonate in dim-
ethylformamide.
thesis of perglycosylated CDs having a variety of
monosaccharide units, mainly as S-glycosides and glyco-
pyranosylamines, grafted onto the primary face of a -CD
core by means of different spacer arms. We also have
demonstrated the ability of some of these compounds to
interact with plant lectins, developing their lectin-binding
properties dependent on the length of the spacer arm be-
tween the CD and the appended sugar. These results were
in accordance with previous observations made by Kassab
and co-workers.6
Key words: carbohydrates, cyclodextrins, glycosylation, macrocy-
cles, oligosaccharides
Cyclodextrins (CDs) are cyclomalto–oligosaccharides
containing six ( -CD), seven ( -CD) and eight ( -CD)
-(1 4)-D-glucopyranosyl units, respectively.1,2 These
compounds and their derivatives are of great importance
due to their well-known ability to incorporate hydropho-
bic molecules yielding inclusion complexes. One of their
potential applications is the use of these host/guest com-
plexes as drug delivery systems although most drug-CD
complexes exhibit very little site-specificity as they lack
biologically recognizable sites.2 In order to develop sys-
tems that can selectively deliver drugs to their sites of ac-
tion within the organism, the grafting of bio-recognizable
carbohydrate structures onto CDs has been addressed as a
targeting method.3–6 In addition, the particular structural
features of CDs make these compounds adequate candi-
dates to function as scaffolds of multivalent systems of
those bioactive molecules. Thus, the combination of both
abilities, to include guest molecules and to function as
cores of cluster glycosides could allow us to use the so-
called glycoside cluster effect7 to improve the site-speci-
ficity of the drug carrier system. The majority of the sac-
charide-branched CDs synthesized chemically or
chemoenzymatically are monosubstituted derivatives at
the primary position of the CDs, in which simple sugars as
well as disaccharides or oligosaccharides have been
bound either directly3,8–10or via a spacer arm.3,6,11–13 Since
In this paper, we describe the synthesis of a series of new
-CD-based cluster O-glycosides 16-18 (Scheme), with
different spacer arms for which ethylene glycol has been
used as spacing unit.
2-Bromoethanol (3), 2-(2-chloroethoxy)ethanol (4) and
2-[2-(2-chloroethoxy)ethoxy]ethanol (5) were chosen as
spacers because they are readily available starting materi-
als and they can be directly glycosylated leading to func-
tionalized glycosides that can be further transformed into
thiolate derivatives. Nucleophilic displacement of per-6-
halo-6-deoxy- -CDs by sugar-containing thiol deriva-
tives has been probed to be a very useful strategy for the
attachment of sugar units onto CDs.4,16–18 Thus, the syn-
thesis started with the glycosylation of the spacers 3-5
with D-mannose and D-galactose, the latter one in both,
pyranoside and furanoside, forms. The galactofuranoside
glycosyl donor 2c was prepared by treatment of D-galac-
tose with pivaloyl imidazole19 in DMF at 80 ºC, obtaining
the mixture of anomers in 92% yield. The galactopyrano-
syl and mannopyranosyl donors were used as bromide
derivatives20 1a and 2a, and imidate derivatives21 1b and
2b. Both manno- and galactosylations of acceptors 3 and
4 were promoted, either with mercury(II) cyanide when
the reactions were performed using 1a and 2a or with bo-
ron trifluoride etherate when performed with the imidates
1b and 2b, respectively. For the preparation of the ga-
lactofuranoside derivatives 7c and 8c, compound 2c was
used as glycosyl donor and the glycosylation reactions
were performed with 4 and 5 as glycosyl acceptors and
the
first
reports
on
the
syntheses
of
perthiogalactosylated3,6and perthioglucosylated -CD,4
several other syntheses have been reported recently, such
Synthesis 2001, No. 7, 01 06 2001. Article Identifier:
1437-210X,E;2001,0,07,1057,1064,ftx,en;Z01201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1058
A. García-Barrientos et al.
PAPER
Scheme Reagents and conditions: i) F3BOEt2 , CH2Cl2; ii) Hg(CN)2, CH2Cl2; iii) SnCl4, CH2Cl2; iv) KSCN, DMF; v) KSAc, DMF, 80 ºC;
vi) Zn, AcOH, vii) NH3, MeOH; viii) Cs2CO3, DMF; ix) Cs2CO3, DMF, 60 ºC then NaOMe, MeOH; x) NaOMe, MeOH
stannous(IV) chloride as promoter. The haloglycosides 6- 95% yield), which were de-O-acetylated applying the
8 were obtained in 30-68% (Table 1). The thiol function Zemplen method yielding the desired glyco-CDs 19a,b
required for the coupling of the O-glycosides with -CD and 20a,b in almost quantitative yields. When the reaction
was introduced in two steps. Glycopyranosides 6a,b and was performed with the thiols 13c and 14c and the CD
7a,b were treated with KSCN in DMF at 90 ºC to displace 15b, the crude product obtained from the nucleophilic
the halogen by a thiocyanate group followed by reduction substitution reaction was subsequently treated with
of the thiocyanate function with Zn/AcOH. The thiol de- NaOMe in methanol to afford the seven-fold symmetrical
rivatives 12a,b and 13a,b were obtained in moderate to galactofuranyl-CDs 17c and 18c in 63% and 36% yield,
good yields (36-88% overall yield from 6a,b and 7a,b). A respectively.
similar sequence of reactions with galactofuranosides 7c
In conclusion, we have prepared cyclodextrin-based O- -
and 8c failed to afford the corresponding thiol derivatives.
manno and O- -galactopyranoside clusters having seven
Alternatively, compounds 7c and 8c were treated with
sugar residues attached to the core through ethylene and
ethylenoxyethylene spacer arms. In addition, we reported
the first synthesis of O- -galactofuranoside clusters based
on a -cyclodextrin core and consisting of seven branches
of sugar residues using ethylenoxyethylene and ethylene-
(dioxyethylene)-ethylene as spacer arms. We are current-
ly investigating both the binding abilities of these com-
pounds with lectins and their abilities to form inclusion
KSAc in DMF at 80 ºC yielding the thioacetate deriva-
tives 10c and 11c in 92% and 89% yield, respectively.
Subsequent treatment of compounds 10c and 11c with
ammonia in methanol afforded thiol derivatives 13c and
14c in 87% and 89% yield, respectively. Reaction of thi-
ols 12-14 with per-(6-deoxy-6-iodo)-cyclomaltoheptaos-
es 15a,b was carried out using Cs2CO3 and DMF as
solvent. With compounds 12a,b and 13a,b, the reaction
complexes with guest molecules.
led to the peracetylated glyco-CDs 16a,b and 17a,b (33-
Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Cyclodextrin
1059
Table 1 Yield and Significant Physical Data for Compounds 6–20
25
Compound Starting Solvent for Chromatography Mp
[ ]D
MS
-
Yield (%) Material
(ºC)
6a (44)
6a (30)
1a
1b
Et2O-hexane 2:1
Et2O-hexane 2:1
Et2O-hexane 4:1
Et2O-hexane 4:1
Et2O
104-108a
+45 (c 0.1)b
6b (52)
2a
117-119c
+3 (c 1.2) b
-
6b (41)
2b
7a (68)
1b
syrup
syrup
syrup
syrup
71-75
67-69
syrup
syrup
syrup
syrup
86-89
72-75
syrup
syrup
syrup
syrup
97-102
110-114
81-86
+34 (c 1.8)b
–3 (c 1.0) b
–24 (c 1.0)b
–23 (c 0.5)b
+52 (c 0.5)b
+19 (c 0.4)b
+26 (c 0.1)b
+30 (c 0.1)b
–14 (c 0.5)b
–13 (c 1.0)b
+31 (c 0.4)b
–3 (c 1.6) b
+29 (c 1.0)b
+29 (c 1.0) b
–25 (c 1.0)b
–30 (c 0.5)b
+76 (c 1.0)b
+39 (c 1.0)b
+97 (c 1.6)b
–3 (c 1.6) b
Calcd for C18H27ClO11 + Na 477.11.39. Found: 477.1123
Calcd for C18H27ClO11 + Na 477.1139. Found: 477.1129
Calcd for C30H51ClO11 + Na 645.3018. Found: 645.3019
Calcd for C32H55ClO12 + Na 689.3280. Found: 689.3282
Calcd for C17H23O10NS + Na 456.0940. Found: 456.0943
Calcd for C17H23O10NS + Na 456.0940. Found: 456.0935
Calcd for C19H27O11NS + Na 500.1202. Found: 500.1205
Calcd for C19H27O11NS + Na 500.1202. Found: 500.1208
Calcd for C32H54O12S + Na 685.3234. Found: 685.3234
Calcd for C34H58O13S + Na 729.3496. Found: 729.3494
Calcd for C16H24O10S + Na 431.0988. Found: 431.0987
Calcd for C16H24O10S + Na 431.0988. Found: 431.0987
Calcd for C18H28O11S + Na 475.1250. Found: 475.1260
Calcd for C18H28O11S + Na 475.1250. Found: 475.1249
Calcd for C30H52O11S + Na 643.3129. Found: 643.3129
Calcd for C32H56O12S + Na 687.3391. Found: 687.3394
Calcd for C182H252O112S7 + Na 4478.20. Found: 4478.30
Calcd for C182H252O112S7 + Na 4478.20. Found: 4479.30
Calcd for C196H280O119S7 + Na 4787.38. Found: 4787.37
Calcd for C196H280O119S7 + Na 4787.38. Found: 4787.40
7b (68)
2b
Et2O-hexane 5:1
Et2O-hexane 1:7
Et2O-hexane 1:5
EtOAc-hexane 1:1
EtOAc-hexane 1:1
EtOAc-hexane 1:1
EtOAc-hexane 1:1
tBuOMe-hexane 1:7
tBuOMe-hexane 1:5
EtOAc-hexane 1:2
EtOAc-hexane 1:2
EtOAc-hexane 1:1
EtOAc-hexane 1:1
tBuOMe-hexane 1:5
Et2O-hexane 1:3
MeOH-EtOAc 0:1 1:15
MeOH-EtOAc 0:1 1:15
MeOH-EtOAc 0:1 1:15
MeOH-EtOAc 0:1 1:15
CH3CN-H2O 10:1
CH3CN-H2O 10:1
-
7c (60)
2c
8c (36)
2c
9a (90)
6a
9b (98)
6b
10a (84)
10b (67)
10c (92)
11c (89)
12a (80)
12b (90)
13a (54)
13b (44)
13c (89)
14c (89)
16a (33)
16b (48)
17a (95)
17b (85)
17c (63)
18c (35)
19a (100)
7a
7b
7c
8c
9a
9b
10a
10b
10c
11c
12a
12b
13a
13b
13c
14c
16a
81-86
d
+14 (c 0.25)e Calcd for C112H196O77S7 + Na 3022.2. Found: 3022.6f
d
d
d
d
d
–4 (c 0.25)e
+83 (c 0.8)e
+27 (c 0.5)e
+29 (c 0.5)e
+9 (c 0.5) e
Calcd for C126H224O84S7 – 2H + Na 3328.6. Found: 3328.9f
Calcd for C98H168O70S7 + Na 2713.78 Found: 2713.7
19b (100) 16b
20a (100) 17a
20b (100) 17b
-
Calcd for C98H168O70S7 + Na 2713.78 Found: 2713.8
-
-
-
-
a Lit.22 mp 118-119 °C; [ ]D23 +45 (c 0.6, CHCl3); 1H NMR and J1,2 values for H-1 are in agreement with those reported.
b CHCl3 as solvent.
c Lit.22 mp 119-120 °C; [ ]D23 –11 (c 1.2, CHCl3); 1H NMR and J1,2 values for H-1 are in agreement with those reported.
d Highly hygroscopic product.
e H2O as solvent.
f MALDI-TOF.
Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

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A. García-Barrientos et al.
PAPER
Table 2 Spectroscopic Data for Compounds 7–20
Entry
1
Com-
pound
IR (cm-1)
1H NMR (300 MHz) , J (Hz)
13C NMR (75 MHz)
7a
(nujol) 1750,
1250,
1136, 1089
(CDCl3) 1.97, 2.02, 2.08, 2.13 (4 s, 12 H, 4 MeCO), 3.59-3.82 (CDCl3) 20.4, 20.5, 20.6 (4 MeCO),
(m, 8 H, 3 CH2O, CH2Cl), 4.04-4.10 (m, 2 H, H-5,6’), 4.27
(dd, 1 H, J = 5.6 and 12.6, H-6), 4.87 (d, 1 H, J = 1.6, H-1),
5.24 (dd, 1 H, J = 1.8 and 3.3, H-2), 5.26 (t, 1 H, J = 9.8, H-
4), 5.34 (dd, 1 H, J = 3.3 and 10.0, H-3)
42.7 (CH2Cl), 62.3 (C-6), 66.0 (C-2),
68.2, 68.9, 69.3 (C-3,4,5), 69.9, 71.2
(CH2O), 97.4 (C-1), 169.6, 169.7,
169.8, 170.5 (4 CO)
2
3
4
7b
(film) 1749,
1226, 1175,
1132
(CDCl3) 1.95, 2.02, 2.04, 2.12, (4 s, 12 H, 4 MeCO), 3.56-3.76 (CDCl3) 20.6, 20.7, 20.8 (4 MeCO),
(m, 8 H, 4 CH2), 3.94 (ddd, 1 H, J = 1.0, 5.6 and 6.6, H-5), 4.10 42.8 (CH2Cl), 61.4 (C-6), 67.1 (C-4),
(dd, 1 H, J = 5.6 and 11.0, H-6’), 4.15 (dd, 1 H, J = 6.5 and
11.0, H-6), 4.56 (d, 1 H, J = 7.9, H-1), 4.99 (dd, 1 H, J = 3.4
68.8 (C-2), 70.4 (CH2O), 70.7, 70.9
(C-3,5), 71.4 (CH2O), 101.4 (C-1),
and 10.5, H-3), 5.18 (dd, 1 H, J = 7.9 and 10.5, H-2), 5.36 (dd, 169.5, 170.1, 170.2, 170.4 (4 CO)
1 H, J = 0.8 and 3.4, H-4)
7c
8c
(film) 2972,
1737, 1140
(CDCl3) 1.14, 1.16, 1.18, 1.19 (4 s, 36 H, 12 Me), 3.56-3.80
(CDCl3) 26.8, 26.9, 27.0 (12 MeC),
(m, 8 H, 3 CH2O, CH2Cl), 4.11 (dd, 1 H, J = 7.7 and 11.7, H- 38.2, 38.8 (4 MeC) 42.7 (CH2Cl),
6’), 4.27 (dd, 1 H, J = 5.0 and 6.0, H-4), 4.36 (dd, 1 H, J = 3.8 62.5 (C-6), 66.6 (CH2O), 68.8 (C-5),
and 11.7, H-6), 4.96-5.00 (m, 2 H, H-1,3), 4.99 (ddt, 1 H, J = 70.2 (CH2O), 71.3 (CH2O), 75.6 (C-
2.75 and 6.2, H-2), 5.29 (ddd, 1 H, J = 3.8 and 4.3, H-5)
2), 79.4 (C-4), 81.3 (C-3), 105.5 (C-
1), 177.1, 177.2, 177.8 (4 CO)
(film) 2973,
1737, 1140
(CDCl3) 1.13, 1.15, 1.17, 1.19 (4 s, 36 H, 12 Me), 3.67 (m, 12 (CDCl3) 27.0 (12 MeC), 38.4, 39.0 (4
H, 5 CH2O, CH2Cl), 4.11 (dd, 1 H, J = 7.8 and 11.8, H-6’), MeC), 42.6 (CH2Cl), 62.5 (C-6), 66.7
4.24 (t, 1 H, J = 5.3, H-4), 4.35 (dd, 1 H, J = 3.6 and 11.8, H- (CH2O), 68.7 (C-5), 70.1 (CH2O),
6), 4.97 (m, 2 H, H-1,3), 4.98 (dd, 1 H, J = 2.4 and 5.3, H-2), 70.5 (2 CH2O), 71.2 (CH2O), 75.5 (C-
5.29 (ddd, 1 H, J = 3.6 and 7.8, H-5)
2), 79.3 (C-4), 81.3 (C-3), 105.5 (C-
1), 177.1, 177.7 (4 CO)
5
6
9a
9b
(nujol) 2150,
1735, 1247,
722
(CDCl3) 2.00, 2.06, 2.12, 2.17 (4 s, 12 H, 4 MeCO), 3.17-3.23 (CDCl3) 20.7, 20.8, 20.9 (4 MeCO),
(m, 2 H, CH2S), 3.90 (dt, 1 H, J = 5.4 and 10.9, CH2O), 4.00- 33.4 (CH2S), 62.5 (C-6), 65.9 (C-4),
4.10 (m, 2 H, H-5, CH2O), 4.15 (dd, 1 H, J = 2.3 and 12.2, H- 66.0 (CH2O), 68.8, 69.3 (C-2,3,5),
6’), 4.31 (dd, 1 H, J = 5.7 and 12.2, H-6), 4.90 (br s, 1 H, H-
1), 5.24-5.38 (m, 3 H, H-2,3,4)
97.8 (C-1), 112.0 (SCN), 169.7,
169.9, 170.0, 170.7 (4 CO)
(nujol) 2156,
1749, 1222,
1134
(CDCl3) 1.99, 2.06, 2.09, 2.17 (4 s, 12 H, 4 MeCO), 3.12 (ddd, (CDCl3) 20.6, 20.7, 20.8 (4 MeCO),
1 H, J = 5.5, 8.2 and 13.6, CH2S), 3.23 (dt, 1 H, J = 4.8 and
13.6, CH2S), 3.85 (ddd, 1 H, J = 5.2, 8.3 and 10.8, CH2O),
33.7 (CH2S), 61.3 (C-6), 67.0 (C-4),
67.2 (CH2O), 68.5 (C-2), 70.7, 71.0
3.96 (t, 1 H, J = 6.6, H-5), 4.15-4.30 (m, 3 H, H-6,6’, CH2O), (C-3,5), 101.4 (C-1), 111.6 (SCN),
4.57 (d, 1 H, J = 7.9, H-1), 5.04 (dd, 1 H, J = 3.4 and 10.5, H- 169.5, 170.1, 170.2, 170.4 (4 CO)
3), 5.23 (dd, 1 H, J = 7.9 and 10.5, H-2), 5.41 (d, 1 H, J = 3.2,
H-4)
7
8
10a
10b
(film) 2156,
1749, 1227,
1136
(CDCl3) 2.00, 2.05, 2.10, 2.16 (4 s, 12 H, 4 MeCO), 3.17 (t, 2 (CDCl3) 20.6, 20.7, 20.8 (4 MeCO),
H, J = 5.7, CH2S), 3.62-3.88 (m, 6 H, 3 CH2O), 4.06 (m, 1 H, 33.8 (CH2S), 62.5 (C-6), 66.2 (C-4),
H-5), 4.12 (dd, 1 H, J = 2.5 and 12.1, H-6’), 4.29 (dd, 1 H, J = 67.0 (CH2O), 68.5 (C-2), 68.9
5.1 and 12.1, H-6), 4.89 (d, 1 H, J = 1.8, H-1), 5.27 (dd, 1 H, (CH2O), 69.0 (C-3), 69.5 (C-5), 70.1
J = 1.8 and 3.3, H-2), 5.29 (t, 1 H, J = 10.0, H-4), 5.37 (dd, 1 (CH2O), 97.6 (C-1), 112.0 (SCN),
H, J = 3.3 and 10.0, H-3)
169.7, 169.9, 170.0, 170.6 (4 CO)
(film) 2156,
1749, 1226,
1127
(CDCl3) 1.98, 2.05, 2.07, 2.15 (4 s, 12 H, 4 MeCO), 3.17 (t, 2 (CDCl3) 20.6, 20.7, 20.9 (4 MeCO),
H, J = 5.7, CH2S), 3.67-3.83 (m, 5 H, 3 CH2O), 3.93 (dt, 1 H, 34.0 (CH2S), 61.3 (C-6), 67.1 (C-4),
J = 1.1 and 6.7, H-5), 3.96 (m, 1 H, CH2O), 4.13 (dd, 1 H, J = 68.8 (CH2O), 68.9 (C-2), 69.1, 70.6,
6.6 and 11.3, H-6’), 4.19 (dd, 1 H, J = 6.6 and 11.3, H-6), 4.58 (2 CH2O), 70.8, 70.9 (C-3,5), 101.4
(d, 1 H, J = 7.9, H-1), 5.03 (dd, 1 H, J = 3.4 and 10.5, H-3),
5.21 (dd, 1 H, J = 7.9 and 10.5, H-2), 5.40 (dd, 1 H, J = 1.1
and 3.4, H-4)
(C-1), 111.9 (SCN), 169.4, 170.1,
170.2, 170.4 (4 CO)
9
10c
(film) 2974,
1737, 1695,
1282, 1139
(CDCl3) 1.15, 1.17, 1.19, 1.20 (4 s, 36 H, 12 MeC), 2.31 (s, 3 (CDCl3) 26.8, 26.9, 27.0 (12 MeC),
H, MeCOS), 3.05 (t, 2 H, J = 6.4, CH2S), 3.44-3.83 (m, 6 H, 28.8 (CH2S), 30.5 (MeCOS), 37.9,
3 CH2O), 4.12 (dd, 1 H, J = 7.7 and 11.8, H-6’), 4.26 (t, 1 H, 38.7 (4 MeC), 62.6 (C-6), 66.5
J = 5.4, H-4), 4.36 (dd, 1 H, J = 3.7 and 11.8, H-6), 4.98 (m, 2 (CH2O), 68.8 (C-5), 69.7 (CH2O),
H, H-1,3), 5.00 (dd, 1 H, J = 2.2 and 5.4, H-2), 5.30 (ddd, 1 H, 69.8 (CH2O), 75.6 (C-2), 79.5 (C-4),
J = 3.7 and 7.7, H-5)
81.4 (C-3), 105.6 (C-1), 177.1, 177.8
(4 CO), 195.4 (COS)
Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Cyclodextrin
13C NMR (75 MHz)
1061
Table 2 Spectroscopic Data for Compounds 7–20 (continued)
Entry
10
Com-
pound
IR (cm-1)
1H NMR (300 MHz) , J (Hz)
11c
(film) 2972,
1737, 1694,
1281, 1139
(CDCl3) 1.13, 1.15, 1.17, 1.18 (4 s, 36 H, 12 MeC), 2.29 (s, 3 (CDCl3) 26.8, 26.9, 27.0 (12 MeC),
H, MeCOS), 3.05 (t, 2 H, J = 6.4, CH2S), 3.58 (m, 9 H, 5 28.6 (CH2S), 30.4 (MeCOS), 38.2,
CH2O), 3.75 (m, 1 H, CH2O), 4.11 (dd, 1 H, J = 7.7 and 11.8, 38.9 (4 MeC), 62.6 (C-6), 66.7
H-6’), 4.24 (t, 1 H, J = 5.3, H-4), 4.35 (dd, 1 H, J = 3.6 and (CH2O), 68.7 (C-5), 69.6 (CH2O),
11.8, H-6), 4.97 (m, 3 H, H-1,2,3), 5.29 (ddd, 1 H, J = 3.6 and 70.1 (CH2O), 70.2 (CH2O), 70.5
7.7, H-5)
(CH2O), 75.6 (C-2), 79.4 (C-4), 81.3
(C-3), 105.5 (C-1), 177.1, 177.7 (4
CO), 195.2 (COS)
11
12
13
14
12a
12b
13a
13b
(nujol) 1735,
1237, 1138
(CDCl3) 1.56 (t, 1 H, J = 8.5, SH), 2.00, 2.05, 2.11, 2.15 (4 s, (CDCl3) 20.7, 20.8, 20.9 (4 MeCO),
12 H, 4 MeCO), 2.74 (dt, 2 H, J = 6.5 and 8.0, CH2S), 3.65 (dt, 24.1 (CH2S), 62.5 (C-6), 66.2 (C-4),
1 H, J = 6.2 and 10.1, CH2O), 3.81 (dt, 1 H, J = 6.2 and 10.1, 68.9, 69.1, 69.5 (C-2,3,5), 70.2
CH2O), 4.08 (m, 1 H, H-5), 4.13 (dd, 1 H, J = 2.4 and 12.3, H- (CH2O), 97.7 (C-1), 169.8, 169.9,
6’), 4.29 (dd, 1 H, J = 5.4 and 12.3, H-6), 4.86 (d, 1 H, J = 1.4, 170.1, 170.7 (4 CO)
H-1), 5.27 (dd, 1 H, J = 1.4 and 3.1, H-2), 5.29 (t, 1 H, J = 9.7,
H-4), 5.35 (dd, 1 H, J = 3.1 and 10.0, H-3)
(nujol) 1747,
1254, 1154
(CDCl3) 1.56 (t, 1 H, J = 8.0, SH), 1.99, 2.06, 2.08, 2.16 (4 s, (CDCl3) 20.6, 20.7, 20.9 (4 MeCO),
12 H, 4 MeCO), 2.60-2.82 (m, 2 H, CH2S), 3.63 (ddd, 1 H, J 24.3 (CH2S), 61.3 (C-6), 67.0 (C-4),
= 6.4, 7.4 and 10.0, CH2O), 3.92 (t, 1 H, J = 6.7, H-5), 4.04
(dt, 1 H, J = 5.0 and 10.0, CH2O), 4.13 (dd, 1 H, J = 6.8 and
11.3, H-6’), 4.19 (dd, 1 H, J = 6.7 and 11.3, H-6), 4.51 (d, 1
H, J = 7.9, H-1), 5.03 (dd, 1 H, J = 3.3 and 10.5, H-3), 5.23
(dd, 1 H, J = 7.9 and 10.5, H-2), 5.40 (d, 1 H, J = 3.3, H-4)
68.8 (C-2), 70.8, 70.9 (C-3,5), 71.7
(CH2O), 101.4 (C-1), 170.0, 170.7,
171.9 (4 CO)
(film) 1749,
1373, 1226,
1051
(CDCl3) 1.58 (t, 1 H, J = 8.2, SH), 1.99, 2.03, 2.10, 2.15 (4 s, (CDCl3) 20.6, 20.7, 20.9 (4 MeCO),
12 H, 4 MeCO), 2.69 (dt, 2 H, J = 6.3 and 8.2, CH2S), 3.62 (t, 24.3 (CH2S), 62.5 (C-6), 66.2 (C-4),
2 H, J = 6.4, CH2CH2S), 3.65-3.85 (m, 4 H, 2 CH2O), 4.06-
4.13 (m, 2 H, H-5,6’), 4.26 (dd, 1 H, J = 5.0 and 12.1, H-6),
67.2 (CH2O), 68.4, 69.1, 69.6 (C-
2,3,5), 69.7, 72.6 (2 CH2O), 97.6 (C-
4.88 (d, 1 H, J = 1.7, H-1), 5.27 (dd, 1 H, J = 1.7 and 3.4, H- 1), 169.7, 169.9, 170.0, 170.7 (4 CO)
2), 5.28 (t, 1 H, J = 10.0, H-4), 5.36 (dd, 1 H, J = 3.4 and 10.0,
H-3)
(film) 1748
(CDCl3) 1.59 (t, 1 H, J = 8.1, SH), 1.99, 2.05, 2.07, 2.15 (4 s, (CDCl3) 20.6, 20.7, 20.8 (4 MeCO),
12 H, 4 MeCO), 2.66 (dt, 2 H, J = 6.3 and 8.1 CH2S), 3.61 (t, 24.4 (CH2S), 61.3 (C-6), 67.1 (C-4),
2 H, J = 6.3, CH2CH2S), 3.64 (m, 2 H, CH2O), 3.75 (dt, 1 H, 68.9 (C-2), 68.9, 70.0 (2 CH2O), 70.8,
J = 5.3 and 11.0, CH2O), 3.92 (dt, 1 H, J = 1.2 and 6.7, H-5), 71.0 (C-3,5), 72.9 (CH2O), 101.3 (C-
3.97 (dt, 1 H, J = 4.1 and 11.0, CH2O), 4.13 (dd, 1 H, J = 6.8 1), 169.4, 170.1, 170.2, 170.3 (4 CO)
and 11.2, H-6’), 4.19 (dd, 1 H, J = 6.6 and 11.2, H-6), 4.58 (d,
1 H, J = 7.9, H-1), 5.02 (dd, 1 H, J = 3.4 and 10.4, H-3), 5.22
(dd, 1 H, J = 7.9 and 10.5, H-2), 5.40 (dd, 1 H, J = 1.1 and 3.4
H-4)
15
16
17
13c
14c
16a
(film) 2972,
1738, 1480,
1281, 1137
(CDCl3) 1.12, 1.13, 1.16, 1.17 (4 s, 36 H, 12 Me), 1.54 (t, 1 H, (Cl3CD) 24.2 (CH2S), 26.9 (12 MeC),
J = 8.2, SH), 2.61 (dd, 1 H, J = 6.4 and 8.2, CH2S), 2.63 (dd, 38.8, 38.9 (4 MeC), 62.5 (C-6), 66.5
1 H, J = 6.3 and 8.2, CH2S), 3.56 (m, 5 H, 3 CH2O), 3.74 (m, (CH2O), 68.8 (C-5), 69.7 (CH2O),
1 H, CH2O), 4.09 (dd, 1 H, J = 7.8 and 11.9, H-6’), 4.24 (t, 1 72.7 (CH2O), 75.5 (C-2), 79.4 (C-4),
H, J = 5.5, H-4), 4.34 (dd, 1 H, J = 3.6 and 11.8, H-6), 4.95
(m, 3 H, H-1,2,3), 5.27 (ddd, 1 H, J = 3.6, 5.5 and 7.7, H-5)
81.3 (C-3), 105.5 (C-1), 177.0, 177.7
(4 CO)
(film) 2973,
1737, 1480,
1281, 1138
(CDCl3) 1.15, 1.16, 1.19, 1.20 (4 s, 36 H, 12 Me), 1.56 (t, 1 H, (CDCl3) 24.2 (CH2S), 27.0 (12 MeC),
J = 8.3, SH), 2.66 (dd, 1 H, J = 6.3 and 8.1, CH’S), 2.68 (dd, 38.7, 38.8 (MeC), 62.6 (C-6), 66.7
1 H, J = 6.3 and 8.4, CHS) 3.61 (m, 9 H, 5 CH2O), 3.78 (m, 1 (CH2O), 68.8 (C-5), 70.2 (2 CH2O),
H, CH2O), 4.12 (dd, 1 H, J = 7.8 and 12.0, H-6’), 4.26 (t, 1 H, 70.5 (CH2O), 72.8 (CH2O), 75.6 (C-
J = 5.3, H-4), 4.37 (dd, 1 H, J = 3.5 and 12.0, H-6), 4.99 (m, 3 2), 79.4 (C-4), 81.3 (C-3), 105.6 (C-
H, H-1,2,3), 5.30 (ddd, 1 H, J = 3.5, 5.3 and 7.8, H-5)
1), 177.1, 177.9 (4 CO)
(nujol) 1749,
1226, 1086
(CDCl3) 1.97, 2.06, 2.08, 2.09, 2.11, 2.15 (6 s, 126 H, 42
MeCO), 2.82-3.00 (m, 14 H, CH2S), 3.04-3.26 (m, 14 H, H-
(CDCl3) 20.7, 20.8, 20.9 (42 MeCO),
29.8 (CH2S), 32.9 (C-6), 62.3 (C-6’),
6,6’), 3.70-3.90 (m, 21 H, H-4, CH2O), 4.03-4.20 (m, 21 H, H- 66.0 (C-4’), 68.7 (CH2O), 68.7, 69.1,
5,5’6’), 4.32 (dd, 7 H, J = 6.1 and 12.5, H-6’), 4.85 (dd, 7 H, 69.5 (C-2’,3’,5’), 70.5, 71.1, 72.3 (C-
J = 3.3 and 9.8, H-2), 4.88 (br s, 7 H, H-1’), 5.12 (d, 7 H, J = 2,3,5), 79.3 (C-4), 97.1 (C-1), 97.7
3.7, H-1), 5.20-5.40 (m, 28 H, H-2,3,3’,4’)
(C-1’), 169.5, 169.8, 169.9, 170.0,
170.7 (42 CO)
Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

1062
A. García-Barrientos et al.
PAPER
Table 2 Spectroscopic Data for Compounds 7–20 (continued)
Entry
18
Com-
pound
IR (cm-1)
1H NMR (300 MHz) , J (Hz)
13C NMR (75 MHz)
16b
17a
17b
(nujol) 1749,
1222, 1043
(CDCl3) 1.99, 2.05, 2.09, 2.16 (5 s, 126 H, 42 MeCO), 2.76-
(CDCl3) 20.6, 20.7, 20.9 (42 MeCO),
2.98 (m, 14 H, CH2S), 3.04 (m, 14 H, H-6,6), 3.61-4.22 (sev- 29.7 (CH2S), 36.5 (C-6), 60.9 (C-6’),
eral m, 49 H, H-4,5,5’,6’,6’, CH2O), 4.57 (d, 7 H, J = 7.6, H- 65.6, 67.0 (C-2,2’,3,3’,4’,5,5’), 68.8,
1’), 4.81 (dd, 7 H, J = 3.6 and 9.5, H-2), 5.08 (dd, 7 H, J = 3.6 68.9, 69.7, 70.6, 70.8, 72.1 (CH2O),
and 10.5, H-3’), 5.11 (d, 7 H, J = 3.7, H-1), 5.18 (dd, 7 H, J = 78.9 (C-4), 96.9 (C-1), 101.3 (C-1’),
7.7 and 10.5, H-2’), 5.26 (t, 7 H, J = 8.8, H-3), 5.41 (dd, 7 H, 169.5, 170.1, 170.3, 170.7 (42 CO)
J = 2.9, H-4’)
19
20
(nujol) 1749,
1229, 1043
(CDCl3) 1.98, 2.05, 2.08, 2.11, 2.15 (5 s, 126 H, 42 MeCO),
2.84, 3.07 ( 2 m, 28 H, CH2S), 3.60-3.86 (several m, 42 H, 7
OCH2CH2OCH2), 3.93 (t, 7 H, J = 8.9, H-4), 4.10 (dd, 7 H, J 66.2 (C-4’), 67.3 (CH2O), 68.5, 69.2,
= 2.3 and 12.3, H-6’), 4.00-4.18 (m, 14 H, H-5,5’), 4.30 (dd, 69.6 (C-2’,3’,5’), 69.7, 70.9 (CH2O),
7 H, J = 4.7 and 12.3, H-6’), 4.81 (dd, 7 H, J = 3.6 and 9.8, H- 70.6, 71.1, 71.9 (C-2,3,5), 78.6 (C-4),
2), 4.89 (br s, 7 H, H-1’), 5.12 (d, 7 H, J = 3.3, H-1), 5.22-5.37 96.1 (C-1), 97.8 (C-1’), 169.5, 169.8,
(m, 28 H, H-2,3,3’,4’)
(CDCl3) 20.7, 20.8, 20.9 (6 MeCO),
33.4, 34.2 (C-6, CH2S), 62.4 (C-6’),
170.0, 170.6, 170.7 (42 CO)
(nujol) 1749,
1249, 1160
(CDCl3) 1.98, 2.05, 2.07, 2.08, 2.16 (5 s, 126 H, 42 MeCO),
(CDCl3) 20.5, 20.6, 20.7, 20.9 (42
2.77-3.04 (m, 28 H, 2 CH2S), 3.56-4.22 (several m, 77 H, H- MeCO), 29.7 (CH2S), 33.6 (C-6), 61.2
4,5,5’,6’,6’, 21 CH2O), 4.57 (d, 7 H, J = 7.9, H-1’), 4.78 (dd, (C-6’), 67.4 (C-4’), 68.9 (C-2’), 69.1,
7 H, J = 3.6 and 9.6, H-2), 5.04 (dd, 7 H, J = 3.1 and 10.5, H- 69.9, 70.8 (CH2O), 70.7, 70.9 (C-
3’), 5.09 (d, 7 H, J = 3.5, H-1), 5.18 (dd, 7 H, J = 7.9 and 10.5, 2,3,3’,5’), 71.8 (C-5), 78.6 (C-4), 96.8
H-2’), 5.39 (d, 7 H, J = 3.1, H-4)
(C-1), 101.4 (C-1’), 169.4, 170.1,
170.2, 170.3, 170.7 (42 CO)
21
22
17c
18c
(D2O) 31.9 (CH2S), 33.4 (C-6), 62.8
(C-6’), 66.6, 69.5, 70.2 (CH2O), 70.7
(C-2’ or 4’ or 5’), 72.0, 72.1 (C-2,3),
72.9 (C-5), 76.8, 81.0 (C-2’ or 4’ or
5’), 83.0 (C-3’), 84.6 (C-4), 101.6 (C-
1), 107.4 (C-1’)
(D2O) 32.0 (CH2S), 33.4 (C-6), 62.7
(C-6’), 66.7, 69.5, 69.7, 70.1 (CH2O),
70.7 (C-2’ or 4’ or 5’), 71.9, 72.3 (C-
2,3), 72.9 (C-5), 76.6, 81.0 (C-2’ or 4’
or 5’), 82.7 (C-3’), 84.6 (C-4), 101.7
(C-1), 107.4 (C-1’)
23
24
25
26
19a
19b
20a
20b
(D2O) 32.7 (CH2S), 34.0 (C-6), 61.2
(C-6’), 66.9 (C-4’), 67.3 (CH2O),
70.5, 71.1 (C-2’,3’), 72.3, 72.8 (C-
2,3), 73.2 (C-5,5’), 84.9 (C-4), 100.2
(C-1), 101.8 (C-1’)
(D2O) 32.4 (CH2S), 33.3 (C-6), 61.1
(C-6’), 68.8, 71.0, 73.0, 75.3 (C-
2’,3’,4’,5’), 69.1 (CH2O), 72.3, 72.4
(C-2,3,5), 85.0 (C-4), 102.1 (C-1),
103.2 (C-1’)
(DMSO-d6) 32.2, 33.3 (C-6, CH2S),
61.2 (C-6’), 65.7, 66.9, 69.2, 70.1,
70.9, 72.0, 72.3, 72.5, 73.8 (C-
2,2’,3,3’,4’,5,5’, CH2O), 84.5 (C-4),
100.0, 102,1 (C-1,1’)
(D2O) 33.4 (CH2S), 33.4 (C-6), 62.5
(C-6’), 70.2, 71.2, 71.6 (CH2O), 70.1,
72.3, 73.1, 73.5, 74.3, 74.5, 76.6 (C-
2,2’,3,3’,4’,5,5’), 85.9 (C-4), 103.1
(C-1), 104.5 (C-1’)
TLC was performed on Merck Silica Gel 60 F254 aluminium sheets
with detection by charring with sulfuric acid, and by UV light when
applicable. Flash and column chromatography was performed on
Silica Gel Scharlau (230-400 mesh, ASTM) and Merck (70-230
mesh, ASTM). Melting points were measured on a Büchi melting
point apparatus and a Reichter hotplate microscope and are uncor-
Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Cyclodextrin
1063
rected. Optical rotations were recorded on a Perkin-Elmer 141 po-
larimeter at room temperature. IR spectra were recorded on a
Perkin-Elmer 983G and Mattson Genesis II FTIR. 1H and 13C NMR
spectra were recorded on Bruker AM 300, Avance DPX 300, AMX
300 MHz and AMX 400 MHz spectrometers. Chemical shifts are
Synthesis of 12a,b and 13a,b; General Procedure
To a solution of 9a,b or 10a,b (3.46 mmol) in glacial AcOH (45
mL) was added Zn dust (2.75 g). The reaction mixture was kept un-
der reflux for 3 h. After cooling, CH2Cl2 (100 mL) was added and
the solution filtered through celite. The filtrate was washed with
H2O (50 mL) and with sat. aq NaHCO3 solution (2 50 mL). The
organic layer was dried (Na2SO4) and the solvent evaporated under
vacuum. The residue was purified by column chromatography.
given in ppm and referenced to internal SiMe4 (
, C 0.00). J values
H
are given in Hz. Mass spectra were recorded on a Micromass Au-
tospec-Q spectrometer. MALDI-TOF mass spectra were recorded
on a Voyager-DE-RP Perspective Biosystems using a 2,5-dihydrox-
ybenzoic acid matrix.
Synthesis of 10c and 11c; General Procedure
A mixture of the halosugar 7c or 8c (1.44 mmol), and KSAc (14.4
mmol) in anhyd DMF (10 mL) was stirred at 80 ºC for 14 h. After
cooling to r.t., CH2Cl2 (150 mL) was added and the mixture was fil-
tered. The filtrate was washed with H2O (100 mL) and the organic
layer was dried (Na2SO4) and evaporated. The residue was purified
by column chromatography.
Synthesis of 1,2,3,5,6-Penta-O-pivaloyl- , -D-galactofuranose
(2c)
Pivaloyl imidazol (18.9 g, 124 mmol) was added to a stirred solu-
tion of D-galactose (2.5 g, 14 mmol) in anhyd DMF (40 mL). The
mixture was kept at 80 ºC for 72 h and then concentrated to approx-
imately 20 mL under reduce pressure. The solution was diluted with
Et2O (250 mL) and toluene (100 mL) and then washed with 5% HCl
solution (2 200 mL), H2O (200 mL), sat. aq NaHCO3 (2 100 mL)
and H2O (200 mL). The organic layer was dried (MgSO4), filtered
and evaporated, and the crude product chromatographed on silica
gel (Et2O-hexane, 1:10) to give 2c (7.7 g, 92%).19
Synthesis of 13c and 14c; General Procedure
The thioacetyl derivative 10c or 11c (1.2 mmol) was treated with
7 N methanolic NH3 solution (40 mL) at r.t. for 15-30 min. Then the
solvent was evaporated and the residue was purified by column
chromatography.
Synthesis of Compounds 6a,b and 7a,b; General Procedure for
Imidate Glycosylations
Synthesis of Per-glycosylated -CDs 16a,b, and 17a,b; General
Procedure
To a solution of the acceptor 3 or 4 (12 mmol) and the trichloroac-
etamidate 1b or 2b (10 mmol) in anhyd CH2Cl2 (10 mL) was added
BF3 OEt2 (1 mL) at –30 ºC under nitrogen atmosphere. After stir-
ring for 10 min, the mixture was poured into ice-cold sat. aq
NaHCO3 with vigorous stirring. The aqueous layer was extracted
with CH2Cl2 (70 mL) and the organic layer was washed with H2O,
dried (Na2SO4), and evaporated. The crude product was purified by
column chromatography.
A mixture of the thiols 12a,b or 13a,b (14 mmol), 15a23 (1 mmol)
and Cs2CO3 (14 mmol) in anhyd DMF (6 mL) was stirred at r.t. un-
der Ar atmosphere for 72 h. Aq HCl (5%, 50 mL) was then added
and the aqueous layer was extracted with CH2Cl2 (100 mL). The or-
ganic phase was washed with H2O (4 50 mL), dried (Na2SO4) and
evaporated. The crude product was purified by column chromatog-
raphy.
Synthesis of Per-glycosylated -CDs 19a,b and 20a,b; General
Procedure
Synthesis of Compounds 6a,b and 7a,b; General Procedure for
Bromide Glycosylations
A solution of compound 16a,b or 17a,b in anhyd MeOH (5 mL) was
treated with a methanolic solution of NaOMe (1 M) until pH 10 was
reached. The reaction mixture was stirred for 30 min at r.t. followed
by evaporation of the solvent. The residue was dissolved in H2O (25
mL) and the solution was neutralized with Dowex-50 resin, filtered
and concentrated by lyophilization.
To a solution of the acceptor 3 (100 mmol) and the bromide 1a or
2a (22 mmol) in anhyd CH2Cl2 (60 mL) was added Hg(CN)2 (25
mmol) and 4 Å MS (10 g) under nitrogen atmosphere. After stirring
for 4 h, the mixture was diluted with CH2Cl2 (200 mL) and filtered
through celite. The filtrate was washed with sat. aq NaHCO3 solu-
tion (50 mL) and H2O (50 mL), and dried over Na2SO4. Evaporation
of the solvent was followed by purification by column chromatog-
raphy.
Synthesis of Per-glycosylated -CDs 17c and 18c; General
Procedure
A mixture of the thiols 13c or 14c (1.8 mmol), 15b23(0.9 mmol) and
Cs2CO3 (1.8 mmol) in anhyd DMF (8 mL) was stirred at 60 ºC un-
der an Ar atmosphere for 72 h. After this time, the mixture was fil-
tered, H2O (15 mL) was added and the solvent was evaporated by
lyophilization. The crude product was treated with a methanolic so-
lution of NaOMe (1 M) until pH 10 was reached. The reaction mix-
ture was stirred for 24 h at r.t. and then filtered. The solid residue
was purified by column chromatography on silica gel.
Synthesis of Compounds 7c and 8c; General Procedure for
Galactofuranosyl Glycosylations
To a mixture of the galactofuranose 2c (1.67 mmol), activated 4 Å
MS (3 g) and anhyd CH2Cl2 (50 mL) was added SnCl4 (5.01 mmol)
at 0 ºC under Ar atmosphere. After 15 min of stirring, the acceptor
4 or 5 (5.01 mmol) was added and the suspension was stirred for 17
h at 0 ºC. The mixture was neutralized with Et3N, filtered through
celite and the filtrate was concentrated. The residue was suspended
in Et2O (150 mL) and the mixture was filtered. Evaporation of the
solvent was followed by purification by column chromatography.
Acknowledgement
We thank the Dirección General de Enseñanza Superior for financi-
al support (Grants PB98-1320 and PB96-1505) and for a scholar-
ship (F. O. C.).
Synthesis of 9a,b and 10a,b; General Procedure
A solution of the halosugar 6a,b or 7a,b (6.6 mmol), KSCN (10
mmol) in DMF (12 mL), n-Bu4NI (50 mg) and dibenzo-18-crown-
6-ether (10 mg) was stirred at 80-90 ºC for 3-4 h. After cooling,
Et2O-toluene (1:3, 100 mL) was added and the mixture was extract-
ed with H2O (2 50 mL). The organic phase was dried (Na2SO4)
and evaporated. The residue was purified by column chromatogra-
phy.
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Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

1064
A. García-Barrientos et al.
PAPER
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Synthesis 2001, No. 7, 1057–1064 ISSN 0039-7881 © Thieme Stuttgart · New York