Synthesis of 2,3,4,5-tetra-O-methyl-D-glucono-1,6-lactone as a monomer for the preparation of copolyesters

Article abstract of DOI:10.1016/S0008-6215(02)00528-1

2,3,4,5-Tetra-O-methyl-D-glucono-1,6-lactone has been prepared as a crystalline compound in acceptable yield by two different routes. An initial assay of copolymerization with L-lactide by ring-opening polymerization was carried out. The incorporation of the carbohydrate monomer into the polymer chain was about 2%.

Full text of DOI:10.1016/S0008-6215(02)00528-1

Carbohydrate Research 338 (2003) 549–555
www.elsevier.com/locate/carres
Note
Synthesis of 2,3,4,5-tetra-O-methyl- -glucono-1,6-lactone as a
D
monomer for the preparation of copolyesters
Inmaculada Molina Pinilla, Manuel Bueno Mart´ınez, Juan A. Galbis*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia Qu´ımica Orga´nica y Farmace´utica, Uni6ersidad de Se6illa, 41071
Se6illa, Spain
Received 13 November 2002; accepted 13 December 2002
Abstract
2,3,4,5-Tetra-O-methyl-
routes. An initial assay of copolymerization with
the carbohydrate monomer into the polymer chain was about 2%. © 2003 Elsevier Science Ltd. All rights reserved.
D
-glucono-1,6-lactone has been prepared as a crystalline compound in acceptable yield by two different
L
-lactide by ring-opening polymerization was carried out. The incorporation of
Keywords:
D-Gluconic acid, protected; D-Glucono-1,6-lactone, protected; L-Lactide; Ring-opening polymerization; Copolyesters
1. Introduction
L-lactide seemed promising. A preliminary copolymer-
ization experiment is reported in this paper.
We have previously described several carbohydrate-
based-monomers which have been used for the synthe-
sis of various polyamides1 and poly(ester amide)s2
2. Results and discussion
derived from sugars such as
-glucose. In this paper we prepared, by two different
routes, the 2,3,4,5-tetra-O-methyl- -glucono-1,6-lac-
tone (11), which can be used as a monomer in the
preparation of copolyesters.
L-arabinose, D-xylose or
First, the synthesis of 10 was achieved (Scheme 1) by
protection of the primary alcohol group of methyl
D
D
a- -glucopyranoside as its triphenylmethyl derivative 2
D
followed by treatment with methyl iodide–potassium
hydroxide in dimethyl sulfoxide to give the tetra-O-
methyl derivative 3. Removal of the 6-O-triphenyl-
methyl group in 3 by acid hydrolysis led to 4 which was
then treated with sodium hydride and benzyl bromide
in THF, giving 5 in good yield (about 70% from 3).
Acid hydrolysis of 5 followed by oxidation8 with acetic
anhydride and dimethyl sulfoxide gave 6-O-benzyl-
Ring-opening polymerization (ROP) of lactones, us-
ing different types of catalyst, has been used for the
preparation of aliphatic polyesters,3 a type of degrad-
able polymers most widely used in the biomedical field,4
as drug delivery systems, biodegradable sutures, re-
sorbable prostheses, etc. Homopolymerization and co-
polymerization of o-caprolactone,5 some functionalized
o-caprolactone,6 and other cyclic ester7—functionalized
or not—are well known. However, as substitution of
the lactone ring increases, homopolymerization of the
monomer becomes more difficult. In our hands, at-
tempts at homopolymerization of the tetra-substituted
o-caprolactone 11 failed, but its copolymerization with
2,3,4-tri-O-methyl- -glucono-1,5-lactone (7). Opening
D
of the lactone ring in 7 and methylation of HO-5 was
performed with methyl iodide and potassium hydroxide
in THF to give 6-O-benzyl-2,3,4,5-tetra-O-methyl-D-
gluconic acid (8, 75%), the methyl ester of which 9 can
be isolated from the reaction mixture (see Section 3) or
converted into 8 by hydrolysis. Removal of the 6-O-
benzyl group was achieved by acid hydrolysis or by
hydrogenation with Pd–10% C in ethyl acetate to give
10 in about 90% yield.
* Corresponding author. Tel.: +34-954556736; fax: +34-
954556737
Compound 10 was also prepared by a different route
E-mail address: jgalbis@us.es (J.A. Galbis).
(Scheme 2) starting with D-glucose diethylmercaptal
0008-6215/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00528-1

550
I.M. Pinilla et al. / Carbohydrate Research 338 (2003) 549–555
Scheme 1.
(12).9 Thus, protection of the primary hydroxyl group
as the triphenylmethyl derivative 13, followed by
methylation of the secondary hydroxyl groups by treat-
ment with methyl iodide and sodium hydride in dry
DMF, gave 14 in good yield. Removal of the di-
ethylmercaptal protecting group10 and oxidation11 of
the resulting aldehyde led to 6-O-triphenylmethyl-
are various methods to achieve this purpose, such as
those of Corey,12 Mukaiyamam,13 Masamune,14 or Mit-
sunobu.15 In our case, 10 was converted to the corre-
sponding 1,6-lactone by treatment16 of the
v-hydroxyacid with DCC and DMAP in the presence
of 4-(dimethylamino)pyridine hydrochloride. By this
procedure, 11 was obtained in good yield as a crys-
talline compound whose analytical and spectroscopic
data were in agreement with the assigned structure.
2,3,4,5-tetra-O-methyl- -gluconic acid (16), which was
D
easily transformed into 10 by deprotection of the
triphenylmethyl group under acid conditions. This
route is shorter, and enabled us to obtain the v-hydrox-
yacid 10 in a higher yield. We could not obtain elemen-
tal analyses within the accepted limits for some of these
oily and highly hygroscopic compounds. However, the
obtained analyses could be adjusted by addition to the
formulae of small proportions of water. These com-
pounds were characterized by NMR and HRMS.
Both routes include a final lactonization step of the
Copolymerization of
L-lactide 17 with hydrophilic
cyclic monomers offers the possibility of modulating
the crystallinity of the copolymer and thereby con-
trolling its degradability. We have carried out a prelim-
inary experiment of copolymerization by bulk ROP of
a mixture of -lactide and 11, in a ratio of 5:1, using tin
L
(II) 2-ethylhexanoate (SnOct2) as initiator (Scheme 3).
From the copolymerization reaction mixture, we ob-
tained two copolymers containing different amounts of
the carbohydrate monomer, as was determined by
v-hydroxyacid into the 1,6- -gluconolactone 11. There
D
Scheme 2.

I.M. Pinilla et al. / Carbohydrate Research 338 (2003) 549–555
551
Scheme 3.
Table 1
Some physical characteristics of copolymers 18a and 18b
b
b
b
c
c
Copolymer
Yield (%)
12
Sugar a monomer (%)
1.3
Mw
Mn
Mw/Mn
Tg (°C)
Tm c (°C)
DH (J g−1
)
18a
23,700
18,500
20,100
14,900
1.2
57.4
55.9
155.3
149.8
33.1
18b
29
2.2
1.2
144.4
136.0
12.5
1
a Determined by H NMR.
b Determined by GPC, using THF as solvent.
c Measured by DSC, second heating.
NMR studies. The first fraction (copolymer 18a) was
insoluble in acetone and had the higher molecular
weight and the lower content in sugar monomer (Table
1). The second fraction (copolymer 18b) was soluble in
(230–400 mesh). IR spectra (films or KBr discs) were
recorded with a JASCO FT/IR-410 spectrometer. H
1
and 13C NMR spectra were recorded with a Bruker
AMX-500 or a Bruker 200 AC-P spectrometers. Chem-
ical shifts are reported as parts per million downfield
from Me4Si. Two-dimensional 1H–1H homonuclear
and 13C–1H heteronuclear shift correlation spectra were
recorded with COSY, HETCOR pulse sequences. The
assignments showing an asterisk may be reversed. Ele-
mental analyses were determined in the Microanalysis
Laboratories at the Universidad Complutense (Madrid)
and in the CSIC, Isla de la Cartuja (Sevilla). Optical
rotations were measured at 2095 °C with a Belling-
ham and Standley Inc., P20 polarimeter. FABMS
analyses were performed on a double-focusing Kratos
MS 80RFA mass spectrometer equipped with the stan-
dard FAB source. Argon was used as the bombarding
gas. Spectra were obtained using nitrobenzene–NaI as
a matrix. Melting points were determined by DSC
using a Perkin–Elmer DSC series 6, calibrated with
indium. Samples of about 2–3 mg were heated at a rate
of 10 °C min−1 and cooled to room temperature (rt).
The peak temperatures were taken as melting points.
GPC was performed at rt with a Waters apparatus
equipped with a Waters 410 differential refractometer
and a 60 cm PL gel 5 mm MIXED-C column, using
1
acetone. Both copolymers had similar infrared and H
NMR spectra. IR spectra contained the typical ester
1
absorption band at 1753 cm−1. In the H NMR spec-
tra, the characteristic signals of the lactic monomer
were detected at 5.14 (CH, quartet) and 1.55 (CH3,
doublet). Besides these signals, those corresponding to
the carbohydrate monomer appeared between 4.5 and
3.3 ppm (see Section 3 for a more detailed assignment).
Thermal properties of the two copolymers were similar,
as determined by differential scanning calorimetry
(DSC). In both cases, thermograms corresponding to
the second heating run displayed an exothermic crystal-
lization peak at 117 °C and two close endothermic
melting peaks. Copolymer 18b showed lower Tg and
Tm values than 18a (Table 1), which can be related
with its higher carbohydrate monomer content. Gel
permeation chromatography (GPC) of the copolymers
displayed unimodal chromatograms. The results of the
GPC study are also presented in Table 1.
3. Experimental
THF as solvent. The flow rate was 1 mL min−1
.
Calibration was based on polystyrene standards.
3.1. General methods
3.2. Methyl 2,3,4-tri-O-methyl-6-O-triphenylmethyl-a-D-
glucopyranoside (3)
Thin layer chromatography (TLC) was performed on
Silica Gel 60 F254 (E. Merck) with detection by UV
light or charring with H2SO4. Flash column chromatog-
raphy was performed using E. Merck Silica Gel 60
To a solution of 2 (10 g, 223 mmol) in dry Me2SO (40
mL) was added KOH (15.4 g, 0.274 mmol) and IMe

552
I.M. Pinilla et al. / Carbohydrate Research 338 (2003) 549–555
(6.0 mL, 91.5 mmol). The reaction mixture was stirred
at rt for 4 h, poured into an ice-water mixture and
extracted with CH2Cl2 (4×30 mL). The organic phase
was concentrated under diminished pressure to a
residue that was dissolved in EtOH to give 3 as a solid
(8 g, 73%): mp 104–106 °C; [h]D +84° (c 0.9, CHCl3);
IR (KBr): w 3061, 3032, 1597 cm−1 (Arom.); NMR
3.30–3.20 (m, 2H, H-2,4), 3.61, 3.50, 3.47, 3.40 (4s,
12H, OMe); 13C l 137.48, 127.65, 127.04, 126.94
(Arom.), 96.83 (C-1), 83.0, 81.10, 78.72, 69.43 (C-
2,3,4,5), 72.74 (CH2Ph), 67.97 (C-6), 60.11, 59.69,
58.20, 54.39 (OMe). Anal. Calcd for C17H26O6: C,
62.56; H, 8.03. Found: C, 62.59; H, 8.10.
1
data (CDCl3): H l 7.55–7.20 (m, 15H, Arom.), 4.90
3.5. 6-O-Benzyl-2,3,4-tri-O-methyl-D-glucopyranose (6)
(d, 1H, J1,2 3.5 Hz, H-1), 3.66–3.05 (m, 6H, H-
2,3,4,5,6a,6b), 3.61, 3.55, 3.44, 3.27 (4s, 12H, OMe); 13
C
A solution of 5 (2 g, 6.13 mmol) in a mixture of AcOH
(50.73 mL) and 4 N H2SO4 (28.44 mL) was heated at
80 °C for 1 day. After this time, the acids were neutral-
ized with NaHCO3 and the solution extracted with
CH2Cl2 (6×40 mL). The organic phase was concen-
trated and the residue chromatographed on a silica gel
column (eluent 2:1–1:1 C6H14–EtOAc) to give 6 (mix-
ture of anomers) as an oil (1.8 g, 94%); IR: w 3414
(OH), 3088, 3030 cm−1 (Arom.); NMR data (CDCl3):
1H l 7.35–7.15 (m, 5H, Arom.), 5.28 (d, 1H, J1,2 3.5
Hz, H-1a), 4.61 (d, 1H, J 12.2 Hz, CH2Pha), 4.59 (d,
1H, J 12.1 Hz, CH2Phb), 4.54 (d, 1H, J1,2 7.7 Hz,
H-1b), 4.49 (d, 1H, J 12.2 Hz, CH2Pha), 4.50 (d, 1H, J
12.1 Hz, CH2Phb), 4.00–2.90 (m, 6H, H-2,3,4,5,6),
3.60, 3.47, 3.45 (3s, 9H, 3 OMeb), 3.59, 3.58, 3.44 (3s,
9H, OMea); 13C l 137.69, 128.14, 127.66, 127.46
(Arom.), 96.80 (C-1b), 90.21 (C-1a), 86.24, 84.44, 79.46,
74.13, (C-2,3,4,5b), 82.99, 81.72, 79.46, 69.60 (C-
2,3,4,5a), 73.18 (CH2Pha,b), 68.84 (C-6b), 68.58 (C-6a),
60.63, 60.54, 60.27, 60.17, 58.53 (OMea,b). HRMS: m/z
294.146154 (calcd for [M−H2O]+: 294.146724).
l 143.99, 128.71, 127.67, 126.88 (Arom.), 97.26 (C-1),
86.19 (CPh3), 83.67, 81.84, 79.92, 70.04 (C-2,3,4,5),
62.37 (C-6), 60.89, 60.31, 58.96, 54.88 (OMe). Anal.
Calcd for C29H34O6: C, 72.78; H, 7.16. Found: C, 72.79;
H, 7.02.
3.3. Methyl 2,3,4-tri-O-methyl-a-D-glucopyranoside (4)
A solution of 3 (10 g, 21 mmol) in AcOH–water (4:1,
80 mL) was heated at 70 °C for 2 h. After this time, the
solid precipitate was filtered out, and the filtrate con-
centrated under diminished pressure to give an oil that
was chromatographed on a silica gel column (eluent
1:0–40:1 CH2Cl2–MeOH) to give 4 as an oil (4.34 g,
88%); [h]D +162° (c 1.4, CHCl3); IR: w 3480 cm−1
1
(OH); NMR data (CDCl3): H l 4.75 (d, 1H, J1,2 3.5
Hz, H-1), 3.76 (dd, 1H, J5,6a 2.7, J6a,6b 11.8 Hz, H-6a),
3.67 (dd, 1H, J5,6b 4.2 Hz, H-6b), 3.52–3.43 (m, 2H,
H-3*,5), 3.12 (dd, 1H, J2.3 9.5 Hz, H-2), 3.11 (t, 1H, J3.4
9.5 Hz, H-4*), 3.57, 3.51, 3.47, 3.35 (4s, 12H, OMe),
2.22 (bs, 1H, OH); 13C l 97.40 (C-1), 83.29 (C-3*),
81.73 (C-2), 79.48 (C-4*), 70.56 (C-5), 61.70 (C-6),
60.71, 60.40, 58.89, 55.01 (OMe). Anal. Calcd for
C10H20O6: C, 50.83; H, 8.53. Found: C, 50.85; H, 8.53.
3.6. 6-O-Benzyl-2,3,4-tri-O-methyl-D-glucono-1,5-lac-
tone (7)
3.4. Methyl 6-O-benzyl-2,3,4-tri-O-methyl-a-
ranoside (5)
D
-glucopy-
Acetic anhydride (7.9 mL) was added to a solution of 6
(1.2 g, 3.84 mmol) in dry Me2SO (11.8 mL). After
standing at rt for 24 h, the reaction mixture was poured
into ice-water (40 mL), the oil formed was separated
and the aqueous phase extracted with CH2Cl2 (4×50
mL). The oil and the organic phase were combined,
concentrated under diminished pressure and finally,
Me2SO was evaporated under high vacuum. The
residue was chromatographed on a silica gel column
(eluent 4:1 C6H14–EtOAc) to give 7 as an oil (1.0 g,
84%); [h]D +42° (c 1.1, CHCl3); IR: w 1757 cm−1
To a solution of 4 (1 g, 4.23 mmol) in dry THF (40 mL)
was added NaH (oil suspension 60%, 0.22 g, 5 mmol) at
0 °C. After stirring at rt for 30 min, the mixture was
cooled to 0 °C and benzyl bromide (0.6 mL) was added.
The reaction mixture was allowed to warm to rt and the
stirring was kept until the reaction finished (TLC 20:1
CH2Cl2–MeOH). At this point, the mixture was again
cooled to 0 °C and EtOH (10 mL) was added. After
stirring at rt for 30 min, the reaction mixture was
diluted with EtOAc (40 mL) and washed with brine.
The organic phase was dried (MgSO4) and concentrated
to dryness giving an oil that was chromatographed on a
silica gel column (eluent 2:1–1:1 C6H14–EtOAc) to give
5 as an oil (1.2 g, 86%); [h]D +124° (c 1.6, CHCl3); IR:
w 3030 cm−1 (Arom.); NMR data (CDCl3): 1H l
7.40–7.20 (m, 5H, Arom.), 4.83 (d, 1H, J1,2 3.0 Hz,
H-1), 4.65 (d, 1H, J 12.1 Hz, CH2Ph), 4.53 (d, 1H, J
12.1 Hz, CH2Ph), 3.80–3.40 (m, 4H, H-3,5,6a,6b),
1
(ester); NMR data (CDCl3): H l 7.40–7.25 (m, 5H,
Arom.), 4.62 (d, 1H, J 12.1 Hz, CH2Ph), 4.55 (d, 1H, J
12.1 Hz, CH2Ph), 4.40 (m, 1H, H-5), 3.82 (d, 1H, J2,3
5.9 Hz, H-2), 3.74 (dd, 1H, J5,6 1.8, J6,6% 11.0 Hz, H-6),
3.70 (dd, 1H, J5,6% 3.2 Hz, H-6%), 3.60–3.50 (m, 2H,
H-3,4), 3.56, 3.52, 3.46 (3s, 12H, OMe); 13C l 168.91
(CO), 137.67, 128.34, 127.72, 127.67 (Arom.), 82.51
(C-3), 79.51 (C-2), 77.85, 77.82 (C-4,5), 73.55 (CH2Ph),
68.53 (C-6), 59.33, 58.98, 58.77 (OMe). HRMS: m/z
310.142849 (calcd for [M]+: 310.141639).

I.M. Pinilla et al. / Carbohydrate Research 338 (2003) 549–555
553
1
3.7. 6-O-Benzyl-2,3,4,5-tetra-O-methyl-
(8)
D
-gluconic acid
(Arom.); NMR data (CDCl3): H l 7.60–7.20 (m, 15H,
Arom.), 4.27 (bs, 1H, H-3), 4.06 (d, 1H, J1,2 8.6 Hz,
H-1), 3.89 (m, 1H, H-5), 3.80 (dd, 1H, J4,5 7.0, J3,4 1.4
Hz, H-4), 3.65 (dd, 1H, J2,3 1.9 Hz, H-2), 3.36 (m, 2H,
H-6a,6b), 2.68 (m, 4H, SCH2CH3), 1.27 (t, 6H,
SCH2CH3); 13C l 143.70, 128.60, 127.89, 127.12
(Arom.), 86.97 (CPh3), 75.09 (C-2), 74.11 (C-4), 70.99
(C-5), 68.26 (C-3), 64.71 (C-6), 55.26 (C-1), 25.87, 23.71
(SCH2CH3), 14.58, 14.41 (SCH2CH3). Anal. Calcd for
C28H36O5S2: C, 65.09; H, 7.02. Found: C, 65.31; H,
6.74.
Freshly crushed KOH (1.96 g, 35.09 mmol) and MeI
(1.4 mL, 21.83 mmol) were added to a solution of 7 (2.0
g, 6.4 mmol) in dry THF (8.0 mL). After stirring,
protected from the light, at rt for 24 h, the reaction
mixture was poured into water (20 mL) and the stirring
was kept for 5 h more. The aqueous solution was
washed with CH2Cl2 (4×20 mL), acidified (pH 4–5,
HCl), and extracted with CH2Cl2 (4×20 mL). The
organic phases were combined and concentrated under
diminished pressure to give 8 as an oil (0.6 g, 75%); [h]D
+1° (c 1.3, CHCl3); IR: w 3430–2600 (COOH), 1744
3.9. 2,3,4,5-Tetra-O-methyl-6-O-triphenylmethyl-D-glu-
cose diethyl dithioacetal (14)
1
cm−1 (CO); NMR data (CDCl3): H l 9.18 (bs, 1H,
COOH), 7.40–7.15 (m, 5H, Arom.), 4.58 (d, 1H, J 12.1
Hz, CH2Ph), 4.55 (d, 1H, J 12.1 Hz, CH2Ph), 3.98 (d,
1H, J2,3 5.0 Hz, H-2), 3.78 (t, 1H, H-3), 3.77 (dd, 1H,
J5,6a 3.9 Hz, H-6a), 3.66 (dd, 1H, J3,4 4.7 Hz, J4,5 6.5
Hz, H-4), 3.56 (dd, 1H, J5,6b 4.1, J6a,6b 10.6 Hz, H-6b),
3.43–3.39 (m, 1H, H-5), 3.53, 3.49, 3.42, 3.41 (4s, 12H,
OMe); 13C l 173.39 (C-1), 137.98, 128.31, 127.73,
127.60 (Arom.), 81.59 (C-3), 80.00 (C-5), 79.27 (C-2*),
79.17 (C-4*), 73.37 (CH2Ph), 67.59 (C-6), 60.72, 60.60,
59.28, 57.36 (OMe). Mass spectrum: m/z 294.146845
To NaH (60% oil suspension, 0.32 g, 8.08 mmol)
washed with C6H14, was added dropwise, under stir-
ring, a solution of 13 (1.0 g, 1.9 mmol) in anhyd DMF
(25 mL). The stirring was continued for 1 h at rt, and
then cooled at 0 °C. Methyl iodide (1.1 mL, 17.67
mmol) was added, and the reaction mixture stirred at
0 °C until the reaction was almost completed (about 2
h, TLC eluent 2:1 C6H14–EtOAc). The reaction was
quenched by adding an excess of MeOH at 0 °C, di-
luted with water (50 mL) and extracted with CH2Cl2
(3×30 mL). The combined organic extract was washed
with water (30 mL), dried (MgSO4), and evaporated
under diminished pressure. The residue was chro-
matographed on a silica gel column (eluent 6:1 C6H14–
EtOAc) to give 14 as an oil (0.8 g, 80%); [h]D −7° (c
1.2, CHCl3); IR: w 3058, 3023, 1597 cm−1 (Arom.);
(calcd
for
[M−H2O−CH2O]+:
294.146724);
235.118279 (calcd for [M−OCH2Ph]+: 235.118164).
The methyl ester 9 could be isolated as an oil (30%)
from the reaction mixture, by pouring it into water, and
immediate extraction of the resulting solution with
1
CH2Cl2. NMR data (CDCl3): H l 7.20–7.10 (m, 5H,
1
Arom.), 4.30 (s, 2H, CH2Ph), 3.78 (d, 1H, J2,3 4.7 Hz,
H-2), 3.65–3.07 (m, 5H, H-3,4,5,6), 3.53, 3.28, 3.24,
3.21, 3.20 (5s, 15H, OMe); 13C l 169.92 (C-1), 137.31,
127.37, 126.74, 126.63 (Arom.), 81.17, 79.68, 79.47,
79.10 (C-2,3,4,5), 72.40 (CH2Ph), 67.30 (C-6), 59.74,
59.62, 57.82, 56.62, 50.79 (OMe). HRMS: m/z
356.184486 (calcd for [M]+: 356.183504); 249.134113
(calcd for [M−OCH2Ph]+: 249.133814).
NMR data (CDCl3): H l 7.50–7.15 (m, 15H, Arom.),
3.93 (d, 1H, J1,2 1.6 Hz, H-1), 3.79 (dd, 1H, J2,3 7.0, J3,4
3.1 Hz, H-3), 3.69 (dd, 1H, H-2), 3.61, 3.52, 3.46, 3.22
(s, 3H, OMe), 3.53 (dd, 1H, J4,5 3.6 Hz, H-4), 3.47 (m,
1H, H-6), 3.45–3.35 (m, 1H, H-5), 3.08 (dd, 1H, J5,6%
4.1, J6,6% 10.2 Hz, H-6%), 2.90–2.55 (m, 4H, SCH2CH3),
1.30, 1.26 (t, 6H, SCH2CH3); 13C l 143.99, 128.72,
127.70, 126.90 (Arom.), 86.38 (CPh3), 85.84 (C-2),
82.71 (C-3), 80.77 (C-5), 79.66 (C-4), 61.57 (C-6), 61.51,
61.10, 60.20, 58.08 (4 OMe), 53.17 (C-1), 25.44, 25.07
(SCH2CH3), 14.54 (SCH2CH3). Anal. Calcd for
C33H44O5S2: C, 67.81; H, 7.53; S, 10.97. Found: C,
67.92; H, 7.75; S, 10.91.
3.8. 6-O-Triphenylmethyl-D-glucose diethyl dithioacetal
(13)
To a solution of -glucose diethyl dithioacetal (12, 2.25
D
g, 7.85 mmol) in dry DMF (10 mL) were added Et3N
(1.96 mL, 14 mmol) and 4-DMAP (cat.). After 10 min,
chlorotriphenylmethane (2.4 g, 8.6 mmol) was added
and the reaction mixture was stirred at rt overnight.
The reaction mixture was quenched by adding ice-wa-
ter, and the aqueous phase was extracted with CH2Cl2
(3×25 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated under diminished
pressure. The residue was chromatographed on a silica
gel column (eluent 2:1 C6H14–EtOAc) to give 21 as a
solid (3.5 g, 95%): mp 65–66 °C; [h]D +25° (c 1.2,
CHCl3); IR: w 3441 (OH), 3057, 3031, 1597 cm−1
3.10. 2,3,4,5-Tetra-O-methyl-6-O-triphenylmethyl-D-glu-
cose (15)
To a solution of 14 (2.35 g, 4 mmol) and CaCO3 (7.21
g, 72.1 mmol) in THF (150 mL) and water (35 mL) was
added dropwise a 2 M aq soln of Hg(ClO4)2 (4.06 mL,
8.1 mmol). After 5 h of stirring at rt, the reaction
mixture was diluted with ether (60 mL) and filtered
through a plug of neutral alumina. The filtrate was
washed with water (100 mL) and extracted with EtOAc
(3×90 mL). The combined organic extract was dried,

554
I.M. Pinilla et al. / Carbohydrate Research 338 (2003) 549–555
filtered and evaporated. Flash chromatography (eluent
6:1–2:1 C6H14–EtOAc) gave 15 as an oil (1.7 g, 89%);
[h]D −24° (c 1.2, CHCl3); IR: w 3058, 3024, 1597
(d, 1H, J2,3 5.3 Hz, H-2), 3.89 (dd, 1H, J5,6a 3.3, J6a,6b
12.1 Hz, H-6a), 3.69 (dd, 1H, J5,6b 3.3 Hz, H-6b), 3.68
(m, 1H, H-3), 3.58 (dd, 1H, J3,4 4.3, J4,5 6.3 Hz, H-4),
3.53, 3.48, 3.47, 3.41 (s, 12H, OMe), 3.34 (ddd, 1H,
H-5); 13C l 173.28 (C-1), 81.64 (C-3), 80.91 (C-5), 79.97
(C-2), 79.93 (C-4), 59.37 (C-6), 60.72, 60.70, 59.10,
57.12 (OMe). HRMS: m/z 253.129554 (calcd for [M]+:
253.128728).
1
(Arom.), 1730 cm−1 (CO); NMR data (CDCl3): H l
9.67 (s, 1H, H-1), 7.55–7.15 (m, 15H, Arom.), 3.91 (dd,
1H, J2,3 5.7, J3,4 2.1 Hz, H-3), 3.82 (d, 1H, H-2),
3.60–3.35 (m, 3H, H-4,5,6), 3.53, 3.52, 3.45, 2.96 (s,
12H, OMe), 3.03 (dd, 1H, J5,6% 3.7, J6,6% 10.3 Hz, H-6%);
13C l 199.46 (C-1), 143.83, 128.71, 127.71, 126.94
(Arom.), 86.51 (CPh3), 82.29, 81.46, 79.51, 77.89 (C-
2,3,4,5), 61.40 (C-6), 59.50, 59.43, 59.24, 58.16 (OMe).
Anal. Calcd for C29H34O6: C, 72.78; H, 7.16. Found: C,
72.54; H, 6.83.
3.13. 2,3,4,5-Tetra-O-methyl-D-glucono-1,6-lactone (11)
To a mixture of dicyclohexylcarbodiimide (0.327 g, 1.58
mmol), 4-(dimethylamino)pyridine (0.290 g, 2.38
mmol), and 4-(dimethylamino)pyridine hydrochloride17
(0.250 g, 1.58 mmol) in EtOH-free CHCl3 (20.0 mL)
was added dropwise, under Ar atmosphere, a solution
of 10 (0.2 g, 0.793 mmol) in EtOH-free CHCl3 (5.0
mL). After the addition was complete, the reaction
mixture was stirred for 24 h at rt. Methanol (0.95 mL)
and AcOH (0.18 mL, 4.0 equiv) were added to the
reaction flask and the stirring was continued for 30
min. The reaction mixture was concentrated to 5 mL,
diluted with ether (25 mL), filtered, and concentrated to
dryness. The residue was taken up in a minimal amount
of ether and purified by flash column chromatography
(eluent ether) to give 11 as a crystalline compound
(0.148 g, 80%): mp 62–63 °C; [h]D −12° (c 1.2,
CHCl3); IR: w 1750 cm−1 (CO); NMR data (CDCl3):
1H l 4.61 (dd, 1H, J5,6 4.4, J6,6 13.5 Hz, H-6), 4.20 (dd,
1H, J5,6% 2.4 Hz, H-6%), 4.05 (d, 1H, J2,3 5.2 Hz, H-2),
3.69 (m, 2H, H-3,4), 3.60 (ddd, 1H, J4,5 3.3 Hz, H-5),
3.50, 3.48, 3.45, 3.40 (s, 12H, OMe); 13C l 169.25 (C-1),
82.71 (C-2), 80.24 (C-3*), 79.62 (C-4*), 76.57 (C-5),
65.00 (C-6), 59.58, 59.29, 58.75, 57.16 (OMe). Anal.
Calcd for C10H18O6: C, 51.27; H, 7.74. Found: C, 51.51;
H, 7.77.
3.11. 2,3,4,5-Tetra-O-methyl-6-O-triphenylmethyl-D-glu-
conic acid (16)
A mixture of 15 (0.524 g, 1.09 mmol) and pyridinium
dichromate (3 equiv 1.236 g, 3.28 mmol) in dry DMF (2
mg mL−1 DMF, 1.04 mL) was stirred at rt for 20 h.
After this time, the reaction mixture was diluted with
water (7 mL), extracted with ether (3×25 mL), and the
combined organic extract dried (MgSO4). Removal of
the solvent under diminished pressure gave 16 as a
syrup (0.42 g, 77%); [h]D −2° (c 1.2, CHCl3); IR: w
3500–2500 (acid), 3058, 3030, 1597 (Arom.), 1753
1
cm−1 (CO); NMR data (CDCl3): H l 7.60–7.10 (m,
15H, Arom.), 3.99 (d, 1H, J2,3 4.6 Hz, H-2), 3.83 (t, 1H,
J3,4 4.6 Hz, H-3), 3.73 (dd, 1H, J4,5 6.9 Hz, H-4), 3.52,
3.48, 3.43, 3.23 (s, 12H, OMe), 3.60–3.50 (m, 1H,
H-6a), 3.39 (m, 1H, H-5), 3.14 (dd, 1H, J5,6% 3.9, J6,6%
10.3 Hz, H-6b); 13C l 173.38 (C-1), 143.86, 128.69,
127.69, 126.92 (Arom.), 86.63 (CPh3), 81.51 (C-3),
80.61 (C-5), 79.27 (C-2), 79.13 (C-4), 61.63 (C-6), 60.61,
60.45, 59.28, 58.01 (OMe). HRMS: m/z 517.222041
(calcd for [M+Na]+: 517.220224).
3.12. 2,3,4,5-Tetra-O-methyl-D-gluconic acid (10)
3.14. Copolymerization of 11 with L-lactide
3.12.1. From 16. A solution of 16 (0.417 g, 0.843 mmol)
in a mixture of AcOH–water (4/1, 2.5 mL) was stirred
at 70 °C for 7 h. The reaction mixture was diluted with
water (3 mL) and the resulting yellow precipitate
filtered out. The resulting solution was concentrated
under diminished pressure affording 10 (0.19 g, 90%).
An homogeneous mixture of
mmol) and 2,3,4,5-tetra-O-methyl-
L
-lactide (17, 154 mg, 1.07
D-glucono-1,6-lac-
tone (11, 100 mg, 0.43 mmol) was introduced into a
round-bottomed flask with 1.5% Sn(Oct)2 as initiator.
After degassing, the flask was sealed under vacuum and
allowed to rotate continuously at 110 °C for 15 days.
The resulting crude polymer was treated with C3H6O
and the insoluble solid was filtered and washed several
times with more C3H6O giving copolymer 18a (12%).
The filtrate was concentrated to dryness, redissolved in
the minimum amount of C3H6O and precipitated in
EtOH. The process of dissolution/precipitation was re-
peated twice. Finally, the copolymer was filtrated and
washed with EtOH (5×2 mL) to obtain copolymer 18b
3.12.2. From 8. A solution of 8 (1.47 g, 4.29 mmol) in
dry EtOAc (30 mL) was hydrogenated (35 psi) at rt in
the presence of 10% Pd–C (30 wt.%, 0.441 g). The
suspension was stirred for 24 h at rt, filtered and the
filtrate evaporated under diminished pressure to give an
oil which was dissolved in water (5 mL). The aqueous
solution was washed once with CH2Cl2 (0.5 mL), and
concentrated again to give the title compound as a
colorless oil (0.89 g, 82%); [h]D +25° (c 1.2, CHCl3);
(29%). IR: w 1753 cm−1 (CO); NMR data (CDCl3): H
l 5.14 (q, 1H, J 7.1 Hz, CH), 4.48 (dd, 1H, J5,6 2.6, J6,6
12.0 Hz, H-6), 4.17 (dd, 1H, J5,6% 5.8 Hz, H-6%), 4.07 (d,
1
1
IR: w 1734 cm−1 (CO); NMR data (CDCl3): H l 3.96

I.M. Pinilla et al. / Carbohydrate Research 338 (2003) 549–555
555
5. (a) Kricheldorf, H. R.; Jonte´, J. M.; Berl, M. Makromol.
Chem., Suppl. 1985, 12, 25;
(b) Nomura, N.; Taira, A.; Tomioka, T.; Okada, M.
Macromolecules 2000, 33, 1497.
6. (a) Detrembleur, C.; Mazza, M.; Halleux, O.; Lecomte,
Ph.; Mecerreyes, D.; Hedrick, J. L.; Je´roˆme, R. Macro-
molecules 2000, 33, 14;
1H, J2,3 5.0 Hz, H-2), 3.65 (bt, 1H, J3,4 4.9 Hz, H-3),
3.55 (bt, 1H, J4,5 5.1 Hz, H-4), 3.52–3.46 (m, 1H, H-5),
3.50, 3.42, 3.40, 3.37 (s, 12H, OMe), 1.56 (d, 3H, CH3).
Some other physical characteristics of these copolymers
are collected in Table 1.
(b) Lecomte, Ph.; D’aloia, V.; Mazza, M.; Halleux, O.;
Gautier, S.; Detrembleur, C.; Je´roˆme, R. Polym.
Preprints 2000, 41, 1534;
Acknowledgements
(c) Detrembleur, C.; Mazza, M.; Lou, X.; Halleux, O.;
Lecomte, Ph.; Mecerreyes, D.; Hedrick, J. L.; Je´roˆme, R.
Macromolecules 2000, 33, 7751.
We thank the C.I.C.Y.T. (Comisio´n Interministerial
de Ciencia y Tecnolog´ıa) of Spain for financial support
(Grants MAT99-0578-C02-01 and MAT2002-04600-
C02-01).
7. (a) Hiki, S.; Taniguchi, I.; Miyamoto, M.; Kimura, Y.
Macromolecules 2002, 35, 2423;
(b) Edlund, U.; Albertsson, A.-C. J. Bioact. Compat.
Polym. 2000, 15 (3), 214.
8. Kuzuhara, H.; Fletcher, H. G., Jr. J. Org. Chem. 1967,
32, 2531.
References
9. Wolfrom, M. L.; Thompson, A. Methods Carbohydr.
Chem. 1963, 2, 427.
10. Berkowitz, D.; Bose, M.; Pfannenstiel, T. J.; Doukov, T.
J. Org. Chem. 2000, 65, 4498.
11. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
12. (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974,
96, 5614;
1. (a) Bueno, M.; Galbis, J. A.; Garc´ıa-Mart´ın, M. G.; de
Paz, M. V.; Zamora, F.; Mun˜oz-Guerra, S. J. Polym.
Sci., Part A: Polym. Chem. 1995, 33, 299;
(b) Bueno, M.; Zamora, F.; Molina, I.; Orgueira, H. A.;
Varela, O.; Galbis, J. A. J. Polym. Sci., Part A: Polym.
Chem. 1997, 35, 3645;
(c) Zamora, F.; Bueno, M.; Molina, I.; Iribarren, J. I.;
Mun˜oz-Guerra, S.; Galbis, J. A. Macromolecules 2000,
33, 2030;
(d) Garc´ıa Mart´ın, M. G.; Ruiz Pe´rez, R.; Benito Her-
na´ndez, E.; Galbis, J. A. Carbohydr. Res. 2001, 333, 95;
(e) Mancera, M.; Roffe´, I.; Rivas, M.; Silva, C.; Galbis, J.
A. Carbohydr. Res. 2002, 337, 607.
(b) Corey, E.J.; Nicolaou, K.C.; Melvin, L.S., Jr. J. Am.
Chem. Soc. 1975, 97, 653 and 654;
(c) Corey, E. J.; Brunelle, D. J. Tetrahedron Lett. 1976,
3409.
13. (a) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett.
1976, 49;
(b) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979,
18, 707.
14. (a) Masamune, S.; Kamata, S.; Schilling, W. J. Am.
Chem. Soc. 1975, 97, 3315;
2. (a) Molina, I.; Bueno, M.; Galbis, J. A. Macromolecules
1995, 28, 3766;
(b) Molina, I.; Bueno, M.; Zamora, F.; Galbis, J. A. J.
Polym. Sci., Part A: Polym. Chem. 1998, 36, 67;
(c) Molina, I.; Bueno, M.; Zamora, F.; Galbis, J. A.
Macromolecules 2002, 35, 2977.
(b) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W.
K.; Bates, G. S. J. Am. Chem. Soc. 1977, 99, 6756;
(c) Masamune, S. Aldrichim. Acta 1978, 11, 23.
15. (a) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetra-
hedron Lett. 1976, 2455;
3. (a) Webster, O. W. Science 1991, 251, 887;
(b) Aida, T. Prog. Polym. Sci. 1994, 19, 469.
4. (a) Vert, M.; Feijen, J.; Albertsson, A.-C.; Scott, G.;
Chiellini, E. In Biodegradable Polymers and Plastics;
Royal Society, 1992;
(b) Mitsunobu, O. Synthesis 1981, 1;
(c) Tsutsui, H.; Mitsunobu, O. Tetrahedron Lett. 1984,
(b) Chiellini, E.; Solaro, R. Ad6. Mater. 1996, 8, 305;
(c) Ni, Q.; Yu, L. J. Am. Chem. Soc. 1998, 120, 1645.
2163.
16. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.