De-O-benzylation of sterically hindered benzyl ethers

Article abstract of DOI:10.1081/CAR-100103955

Sterically hindered benzyl ethers that cannot be removed by hydrogenolysis with a variety of catalysts are removed readily by the reaction with N-bromo-succinimide and light in the presence of aqueous calcium carbonate, a reaction developed by Binkley and Hehemann. It was found that these conditions are compatible with the presence of phthalimides and glycosyl sulfides and fluorides, in addition to the groups previously shown to be inert.

Full text of DOI:10.1081/CAR-100103955

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DE-O-BENZYLATION OF STERICALLY HINDERED
BENZYL ETHERS
John G. Riley a & T. Bruce Grindley b
a Department of Chemistry , Dalhousie University , Halifax, NS, B3H 4J3, Canada
b Department of Chemistry , Dalhousie University , Halifax, NS, B3H 4J3, Canada
Published online: 16 Aug 2006.
To cite this article: John G. Riley & T. Bruce Grindley (2001) DE-O-BENZYLATION OF STERICALLY HINDERED BENZYL
ETHERS , Journal of Carbohydrate Chemistry, 20:2, 159-169, DOI: 10.1081/CAR-100103955
To link to this article: http://dx.doi.org/10.1081/CAR-100103955
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J. CARBOHYDRATE CHEMISTRY, 20(2), 159–169 (2001)
DE-O-BENZYLATION OF STERICALLY
HINDERED BENZYL ETHERS1
John G. Riley and T. Bruce Grindley*
Department of Chemistry, Dalhousie University, Halifax, NS,
Canada B3H 4J3
ABSTRACT
Sterically hindered benzyl ethers that cannot be removed by hydrogenolysis
with a variety of catalysts are removed readily by the reaction with N-bromo-
succinimide and light in the presence of aqueous calcium carbonate, a reaction
developed by Binkley and Hehemann. It was found that these conditions are
compatible with the presence of phthalimides and glycosyl sulfides and fluo-
rides, in addition to the groups previously shown to be inert.
INTRODUCTION
Benzyl ethers are probably the most commonly used protecting groups for al-
cohols. The normal technique for deprotection is hydrogenolysis, either catalytic
or by transfer of hydrogen.2–6 Palladium on charcoal is the most commonly used
catalyst but some benzyl groups resist hydrogenolysis with this catalyst and other
catalysts, such as Pearlman’s catalyst (Pd(OH)2), are often tried. Many other meth-
ods have been utilized, such as dissolving metal reductions,7–9 various oxidative
methods which convert benzyl ethers to benzoyl esters,10–15 or cleavage with
Lewis acids. However, few of these alternative methods are compatible with esters
and/or thioglycosides or other sensitive functional groups.
The method discovered by Binkley and Hehemann,16 which uses light-catal-
ysed ꢀ-bromination of benzyl ethers in the presence of aqueous base, has only been
*Corresponding author.
159
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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RILEY AND GRINDLEY
Scheme 1.
used preparatively three times in the ten years since the initial publication.17–19 We
now report that this method is very effective for the removal of hindered benzyl
ethers and also note that it is compatible with many sensitive functional groups,
such as thioglycosides and glycosyl fluorides.
RESULTS AND DISCUSSION
A key part of a synthetic sequence required the removal of a benzyl group on
an oxygen atom flanked by two pivaloyloxy groups, that is, the benzyl group in
compound 2a in Scheme 1. Despite repeated attempts, this benzyl group could not
be removed by hydrogenolysis at 4 atm using a variety of catalysts, including
Pd/C, Pd(OH)2 and Pd(OAc)2. Because most alternatives were not compatible
with ester protecting groups, we tried photochemical ꢀ-bromination,16,20 and this
method proved to be very effective.
Scheme 1 shows the de-O-benzylation of some substituted 3-O-benzyl-D-
galactopyranoside derivatives. Removal of the O-benzyl groups proceeds in short
times under mild conditions in excellent yields as summarized in the Table. The
conditions of Binkley and Hehemann were used,16 that is, irradiation with a 375 W
white light lamp of a vigorously magnetically stirred two-phase system consisting
Table 1. Reaction Times and Yields in
de-O-benzylation Reactions
Reaction Time
(min)
Yield
(%)
Substrate
2a
3a
4a
5a
6a
7a
15
15
15
30
45
15
95
87
95
76
83
72

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161
Scheme 2.
of the compound and N-bromosuccinimide in carbon tetrachloride and aqueous
calcium carbonate. It was necessary to purge the reaction mixtures thoroughly with
nitrogen before irradiation to avoid the conversion of the benzyl ethers to benzoate
esters, a process which has been noted as being a difficulty with this reaction.18 Re-
crystallization of the N-bromosuccinimide resulted in improved yields. The inex-
pensive 375 W lamps, usually called heat lamps, were originally used by Binkley
and Hehemann16,17 and are available in speciality lighting stores. The reactions
were monitored by TLC and stopped when the substrate had been consumed. Re-
action times for the benzyl ether to disappear completely ranged from 15 to 45 min.
Scheme 2 shows the application of the reaction to a di-O-benzyl derivative.
As can be seen from the Table, this procedure is remarkably effective for the
de-O-benzylation of sterically hindered benzyl ethers. Moreover, a number of pro-
tecting groups and reactive glycosidic groups that had not been studied by previ-
ous workers were shown to be unaffected; these include glycosyl thiophenyl
groups and fluorides, and phthalimide protecting groups.
EXPERIMENTAL
General Methods. 1H and 13C NMR spectra were run at 300 K on Bruker
AC-250 or AMX-400 NMR instruments operating at 250.13 and 62.9 MHz, and
400.16 and 100 MHz, respectively. The samples were made up in concentrations
between 10 and 15 mM in chloroform-d unless otherwise specified. Chemical
shifts are given in parts per million (ppm)(ꢁ/ꢂ0.01 ppm) relative to TMS
(tetramethylsilane) in the case of 1H NMR spectra, and to the central line of chlo-
roform-d (ꢃ 77.23) for the 13C NMR spectra. Spectral assignments were made by
first-order analysis and COSY and HETCOR experiments. Mass spectra were mea-
sured on a CEC 21-110B mass spectrometer using electron ionization (70.0 eV).
The probe and source temperature was 143°C. Pyridine was dried by refluxing over
calcium hydride before distillation. Dichloromethane was first dried with calcium
chloride, then refluxed over calcium hydride for one hour, fractionally distilled and
stored over molecular sieves (4 Å). N,N-Dimethylformamide was stored over acti-
vated molecular sieves (4 Å) for 72 h before distillation under reduced pressure
from freshly activated molecular sieves (4 Å). Toluene was stored over calcium hy-
dride for 3 h then distilled onto activated molecular sieves (4 Å). Benzyl chloride
was dried with MgSO4, refluxed over calcium hydride and then fractionally dis-
tilled under reduced pressure, collecting the middle fraction and then storing over
calcium hydride. N-Bromosuccinimide was recrystallized from water then dried
for 12 h at room temperature under vacuum (1 torr). Thin-layer chromatography

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RILEY AND GRINDLEY
(TLC) was performed on 0.25 mm thick Whatman G/UV silica gel on aluminum
plates. Components were visualized by spraying with a 2% ceric sulfate solution in
1 M H2SO4 followed by heating on a hot plate until discolouration occurred. Flash
chromatography was performed on silica gel TLC standard grade (230–400 mesh)
with mixed solvents of ethyl acetate: hexanes at volume ratios indicated. Irradia-
tion was performed with a Phillips 375 W reflector lamp.
Phenyl 3-O-Benzyl-1-thio-ꢄ-D-galactopyranoside (1a). Phenyl 1-thio-ꢄ-
D-galactopyranoside21 (20.13 g, 0.0740 mol) and dibutyltin oxide (19.57 g, 0.0786
mol, 1 equiv) were refluxed for 12 h in toluene (500 mL) with azeotropic removal
of water. The solvent was removed and the residue was dried at 0.1 torr for 1 h. Ce-
sium fluoride (16.60 g, 0.109 mol, 1.45 equiv) was added followed by a solution
of distilled benzyl bromide (15.82 g, 0.0925 mol, 1.0 equiv) in N,N-dimethylfor-
mamide (300 mL) and the reaction mixture was stirred until TLC (eluant, 4:1 ethyl
acetate: acetone) indicated that the starting material had been completely con-
sumed (3.5 h). Distilled water (2 mL) was added, the solvent evaporated and the
residue was dissolved in ethanol and filtered through celite. The filtrate was recon-
centrated to a dark brown syrup that was purified by flash chromatography using
1:1 ethyl acetate: hexanes as eluant. Crystallization (ethyl acetate) produced fine
white needles (15.9 g, 60 %): mp 156–160°C, lit22 161–163°C; [ꢀ]D ꢂ8.4° (c 2.0,
methanol), lit22 [ꢀ]D ꢂ8.5°; 1H NMR (acetone-d6): ꢃ 3.36 (dd, 1H, J3,4 ꢅ 3.36 Hz,
J
2,3 ꢅ 9.16 Hz, H-3), 3.64 (td, 1H, J4,5 ꢅ 0.92 Hz, J5,6 ꢅ J5,6ꢆ ꢅ 5.95 Hz, H -5),
3.76 (s, 1H, OH-4), 3.77 (d, 2H, J5,6 ꢅ 5.80 Hz, H-6,6ꢆ), 3.84 (t, 1H, J1,2 ꢅ J2,3
ꢅ 9.5 Hz, H-2), 4.22 (td, 1H, J4,5 ꢅ 1.0 Hz, J3,4 ꢅ 3.35 Hz, H-4), 4.42, 4.40 ( 2s,
2H, OH-2 and OH-3), 4.67 (d, 1H, J1,2 ꢅ 9.77 Hz, H-1), 4.69, 4.79 (2d, 2H, J
ꢅ ꢂ12.2 Hz, OCH2Ph), 7.22–7.60 (m, 10H, CH2Ph, SPh); 13C NMR (acetone-d6):
ꢃ 61.8 (C-6), 66.4 (C-4), 69.3 (C-2), 71.6 (CH2Ph) , 79.6 (C-5), 83.4 (C-3), 88.9
(C-1), 127.2–131.6 (Ph, SPh).
Phenyl 3-O-Benzyl-2,4,6-tri-O-pivaloyl-1-thio-ꢄ-D-galactopyranoside
(2a). Compound 1a (7.19 g, 0.0199 mol) was dissolved in dry pyridine (50 mL)
and pivaloyl chloride (8.81 g, 9.0 mL, 0.0731 mol, 3.7 equiv) was added dropwise.
The reaction was stirred at a bath temperature of 75°C for 12 h. The reaction mix-
ture was poured into ice water (150 mL) that was then extracted with
dichloromethane (150 mL). The organic layer was washed with 1 M hydrochloric
acid (3 ꢇ 150 mL), saturated sodium hydrogen carbonate solutions (3 ꢇ 150 mL),
and water (2 ꢇ 150 mL), then dried, and concentrated. The residue was applied to
a flash chromatography column and eluted with ethyl acetate:hexanes 1:4. The
title compound was obtained as colorless crystals (10.356 g, 0.0168 mol, 85 %),
recrystallized from methanol-water: mp 101–2°C; [ꢀ]D ꢁ21.3° (c 2.0, dichloro-
methane); 1H NMR: ꢃ 1.14, 1.21, 1.22 (3s, 3 ꢇ 9H, 3 C(CH3)3 ), 3.64 (dd, 1H, J3,4
ꢅ 3.3 Hz, J2,3 ꢅ 9.3 Hz, H-3), 3.93 ( br t, 1H, J5,6 ꢅ J5,6ꢆ ꢅ 6.7 Hz, H-5), 4.16 (m,
2H, H-6,6ꢆ), 4.36, 4.67 (2d, 2H, Jꢅ ꢂ11.29 Hz, OCH2Ph), 4.68 (d, 1H, J1,2
ꢅ 10.07 Hz, H-1), 5.16 (t, 1H, J1,2 ꢅ J2,3 ꢅ 9.8 Hz, H-2), 5.54 (br d, 1H, J3,4
ꢅ 3.21 Hz, H-4), 7.2–7.6 (m, 10H, CH2Ph, SPh); 13C NMR: ꢃ 26.8, 26.9, 27.0 (3

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163
C(CH3)3, 38.3,38.5, 38.8 (3 C(CH3)3), 62.0 (C-6), 65.5 (C-4), 67.9 (C-2), 71.2
(CH2Ph), 74.6 (C-5), 78.2 (C-3),86.1 (C-1), 127.4, 127.8, 127.9, 132.2, 132.8,
137.0 (Ph, SPh), 176.4, 177.2, 177.8 (3 OCO).
Anal. Calcd for C34H46O8S: C, 66.42; H, 7.54; S, 5.22. Found: C, 66.57; H,
7.52; S, 5.68.
3-O-Benzyl-2,4,6-tri-O-pivaloyl-ꢀ-D-galactopyranosyl Fluoride (3a).
Compound 2a (0.5215 g, 0.848 mmol) was dissolved in dry dichloromethane (20
mL) and cooled with a calcium chloride ice bath that maintained the temperature
at 0°C. Diethylaminosulfur trifluoride (0.155 mL, 1.27 mmol) was added dropwise
to the stirred solution followed by N-bromosuccinimide (NBS) (0.196 g, 1.10
mmol). After 40 min, the reaction mixture was poured into a saturated solution of
sodium hydrogen carbonate (50 mL). The aqueous mixture was extracted with
ether (4 ꢇ 25 mL) and the combined extracts were dried (MgSO4) and concen-
trated. The residue purified by flash chromatography on silica gel (eluant, ethyl ac-
etate: hexanes 1:5) to give the title compound (Rf, 0.94) as pure colorless crystals
(0.3675 g, 88%) that were recrystallized from ether-hexanes: mp 103–104°C; [ꢀ]D
ꢁ73.0° (c 0.9, dichloromethane); 1H NMR: ꢃ 1.21 (s, 3 ꢇ 9H, 3 C(CH3)3 ), 3.99
(dd, 1H, J3,4 ꢅ 3.20 Hz, J2,3 ꢅ 10.20 Hz, H-3), 4.13 (d, 2H, H-6,6ꢆ), 4.34 ( br t, 1H,
J
5,6 ꢅ J5,6ꢆ ꢅ 6.71 Hz, H-5), 4.46, 4.71 (2d, 2H, Jꢅ 11.14 Hz, OCH2Ph), 5.16 (ddd,
1H, J1,2 ꢅ 2.59 Hz, J2,3 ꢅ10.22 Hz, J2,F ꢅ 24.72 Hz, H-2), 5.64 (br d, 1 H, J3,4
ꢅ 2.51 Hz, H-4), 5.64, 5.86 (2d, 1H, J1,2 ꢅ 2.59, J1,F ꢅ 53.86 Hz, H-1), 7.2–7.6
(m, 5H, CH2Ph); 13C NMR: ꢃ 27.21, 27.24, 27.34 (3 C(CH3)3, 39.0, 39.3 (3
C(CH3)3), 61.6 (C-6), 66.0 (C-4), 69.4 (d, 2JC,F ꢅ 24.0 Hz, C-2), 69.4 (C-5), 71.9
(CH2Ph), 73.0 (C-3), 104.7 (d, 1JC,F ꢅ 226.7 Hz, C-1), 127.2, 127.5, 127.8, 128.3,
129.1, 137.3 (Ph), 177.3, 177.9, 177.9 (3 OCO); 19F NMR: ꢃ ꢂ150.52 (dd, JH1,F
ꢅ 53.4 Hz, JH2,F ꢅ 25.1 Hz,F); EIMS m/z: 524 (1.0%, Mꢁ), 489 (0.5%, Mꢁ - HF
-CH3), 439 (57%, Mꢁ - t-BuCꢅO).
Anal. Calcd for C28H41O8F: C, 64.10; H, 7.88. Found: C, 64.22; H, 7.71.
Ethyl 6-(3-O-Benzyl-2,4,6-tri-O-pivaloyl-ꢄ-D-galactopyranosyloxy)hex-
anoate (4a). Compound 2a (0.81 g, 1.317 mmol) was dissolved in dry
dichloromethane (40 mL) under nitrogen in a glove bag and ethyl 6-hydroxyhex-
anoate (0.428 mL, 2.635 mmol) was added, followed by N-iodosuccinimide (0.341
g, 1.515 mmol), silver triflate (0.677 g, 2.635 mmol), and powdered 4Å molecular
sieves. The reaction vessel was then stoppered with a rubber septum and covered
with aluminum foil. After 3 h, the mixture was filtered over celite and the filtrate
was washed with saturated sodium hydrogen carbonate solutions (3 ꢇ 30 mL) and
water (3 ꢇ 30 mL). The organic layer was dried and concentrated to a residue that
was applied to a flash chromatography column. Elution with ethyl acetate: hexanes
1:5 gave the title compound (Rf, 0.43) as a colorless syrup (0.739 g, 84.4%): [ꢀ]D
ꢁ18.0° (c 3.7, chloroform); 1H NMR: ꢃ 1.17, 1.20, 1.21 (3s, 3 ꢇ 9H, 3 C(CH3)3),
1.24 (t, 3H, J ꢅ 7.0 Hz, OCH2CH3), 1.29–1.41 (complex m, 2H, OCH2CH2CH2),
1.5–1.7 (complex m, 4H, OCH2CH2CH2CH2), 2.28 (t, 2H, J ꢅ 7.3 Hz, OCOCH2),
3.42 (complex m, 1H, one OCH2CH2), 3.58 (dd, 1H, J3,4 ꢅ 3.4 Hz, J2,3 ꢅ 9.9 Hz,

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H-3), 3.78–3.89 (complex m, 2H, one OCH2CH2, H-5), 4.05–4.22 (complex m,
4H, OCH2CH3, H-6,6ꢆ), 4.40 (d, 1H, J1,2 ꢅ 8.1 Hz, H-1), 4.37, 4.68 (2d, 2H, J
ꢅ ꢂ11.3 Hz, OCH2Ph), 5.13 (dd, 1H, J1,2 ꢅ 8.2 Hz, J2,3 ꢅ 10.1 Hz, H-2), 5.50 (br
d, 1H, J3,4 ꢅ 2.8 Hz, H-4), 7.2–7.4 (m, 5H, Ph); 13C NMR: ꢃ 14.4 (OCH2CH3),
24.8 (CH2CH2CO2Et), 25.7 (OCH2CH2CH2), 27.1–27.7 (9 C(CH3)3), 29.4
(OCH2CH2), 34.3 (CH2CO2Et), 38.9, 38.9, 39.2 (3 COC(CH3)3), 60.4,
(OCH2CH3), 61.9 (C-6), 65.6 (C-4), 69.6 (OCH2CH2), 70.3 (C-2), 71.1 (C-5), 71.6
(CH2Ph), 77.5 (C-3), 101.6 (C-1), 127.7, 127.8, 128.3, 128.3, 137.5 (Ph), 173.8
(COCH2), 176.9, 177.7, 178.1 (COC(CH3)3),; EIMS m/z: 664 (not observed, Mꢁ),
505 (2.4%, Mꢁ - O(CH2)5CO2Et); HRMS for C28H41O8: Calcd 505.2801. Found:
505.2806.
Phenyl 3-O-Benzyl-2,4,6-tri-O-acetyl-1-thio-ꢄ-D-galactopyranoside (5a).
Acetic anhydride (470 mL) was added slowly to a stirred solution of compound 1a
(15.67 g, 0.04353 mol) in pyridine (470 mL) at 0°C and the solution was left for 12
h, then poured into an ice-cold saturated solution of sodium hydrogen carbonate
(900 mL). The resulting mixture was extracted with dichloromethane (3 ꢇ 500
mL) and the combined extracts were washed with 0.8 M hydrochloric acid (3 ꢇ
250 mL), dried and concentrated to a dark yellow solid (25.69 g). Recrystallization
(ethyl acetate: hexanes 1:3) yielded the title compound as colourless needles (19.05
g, 90.2%): [ꢀ]D 63.4° (c 3.07, chloroform); mp 100–101°C; 1H NMR ꢃ: 2.06, 2.08,
2.16 (3s, 3 ꢇ 3H, 3 COCH3), 3.57 (dd, 1H, J3,4 ꢅ 3.36 Hz, J2,3 ꢅ 9.46 Hz, H-3),
3.83 (td, 1H, J4,5 ꢅ 1.7 Hz, J5,6 ꢅ J5,6ꢆ ꢅ 6.26 Hz, H -5), 4.17 (d, 2H, J5,6 ꢅ 6.41
Hz, H-6,6ꢆ), 4.62 (d, 1H, J1,2 ꢅ 10.07 Hz, H-1), 4.40, 4.68 (2d, 2H, J ꢅ ꢂ12.26
Hz, OCH2Ph), 5.16 (t, 1H, J1,2 ꢅ J2,3 ꢅ 9.8 Hz, H-2), 5.54 (dd, 1H, J4,5 ꢅ 1.07 Hz,
J
3,4 ꢅ 3.36 Hz, H-4), 7.23–7.55 (m, 10H, CH2Ph,SPh); 13C NMR ꢃ: 20.8,20.8,21.0
(3 COCH3), 62.3 (C-6), 66.0 (C-4), 68.8 (C-2), 71.3 (CH2Ph), 74.7 (C-5), 77.6 (C-
3), 86.6 (C-1), 127.9, 127.8, 128.4, 128.8, 132.3, 133.0, 137.3 (Ph, SPh), 169.4,
170.4, 170.5 (CO); EIMS m/z: 488 (not observed, Mꢁ), 379 (60.6%, Mꢁ - SPh);
HRMS for C19H23O8: Calcd 379.1393. Found: 379.1377.
Anal. Calcd for C25H28O8S: C, 61.46; H, 5.78. Found: C, 61.50; H, 5.62.
Ethyl 6-(2,4,6-Tri-O-acetyl-3-O-benzyl-ꢄ-D-galactopyranosyloxy)hex-
anoate (6a). Compound 5a (21.28 g, 0.0441 mol) was dissolved in distilled, dry
dichloromethane (200 mL) containing activated 3Å powdered molecular sieves in
a 2 necked round bottomed flask wrapped in aluminum foil. Ethyl 6-hydroxyhex-
anoate (14.78 g, 15.0 mL, 0.09222 mol, 2.0 equiv) was added, followed by N-io-
dosuccinimide (11.46 g, 0.0511 mol, 1.15 equiv), and then a solution of silver tri-
flate (12.76 g, 0.04966 mol, 1.10 equiv) in 100 mL of dry toluene. The reaction
mixture was stirred at room temperature under a stream of N2 (g) until starting ma-
terial was consumed (1.5 h). The reaction mixture was filtered through celite, and
the filtrate was washed with saturated sodium hydrogen carbonate solutions (2 ꢇ
250 mL), followed by water (2 ꢇ 250 mL). The combined aqueous layers were
washed with dichloromethane (2 ꢇ 250 mL). The organic fractions were com-
bined, dried and concentrated to a dark yellowish residue. Flash chromatography

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165
on silica gel using 1:2 ethyl acetate: hexanes as eluant gave the title compound as
a syrup (4.58 g, 19.5%): [ꢀ]D ꢁ36.6° (c 4.18, chloroform); 1H NMR 1.24 (t, 3H, J
ꢅ 7.0 Hz, OCH2CH3), 1.29–1.41 (complex m, 2H, OCH2CH2CH2), 1.5–1.7 (com-
plex m, 4H, OCH2CH2CH2CH2), 2.02, 2.06, 2.13 (3s, 3 ꢇ 3H, 3 COCH3), 2.27 (t,
2H, J ꢅ 7.3 Hz, OCOCH2), 3.45 (complex m, 1H, one OCH2CH2), 3.54(dd, 1H,
J3,4 ꢅ 3.5 Hz, J2,3 ꢅ 9.9 Hz, H-3), 3.79 (t, 1H, J5,6 ꢅ J5,6ꢆ ꢅ 6.76 Hz, H-5),
3.82–3.94 (m, 1H, one OCH2CH2), 4.11 (q, 2H, J ꢅ 7.0 Hz, OCH2CH3), 4.17 (AB
part of ABX, 2H, H-6,6ꢆ), 4.35 (d, 1H, J1,2 ꢅ 8.2 Hz, H-1), 4.40, 4.69 (2d, 2H, J
ꢅ ꢂ12.2 Hz, OCH2Ph), 5.11 (dd, 1H, J1,2 ꢅ 8.1 Hz, J2,3 ꢅ 10.0 Hz, H-2), 5.51 (br
d, 1H, J3,4 ꢅ 3.4 Hz, H-4), 7.2–7.4 (m, 5H, Ph); 13C NMR ꢃ: 14.3 (OCH2CH3),
20.7, 20.8, 20.8 (3 COCH3), 24.6 (CH2CH2CO2Et), 25.4 (OCH2CH2CH2), 29.1
(OCH2CH2), 34.2 (CH2CO2Et), 60.3 (OCH2CH3), 62.0 (C-6), 65.9 (C-4), 69.6
(OCH2CH2), 70.5 (C-2), 70.9 (C-5), 71.3 (OCH2Ph), 76.6 (C-3), 101.4 (C-1),
127.8, 127.9, 128.4, 137.6 (Ph), 169.4, 170.5, 170.6 (COCH3), 173.6 (COCH2);
EIMS m/z: 538 (not observed, Mꢁ), 379 (11.6%, Mꢁ - O(CH2)5CO2Et); HRMS for
C19H23O8: Calcd 379.1393. Found: 379.1369.
Phenyl 6-O-tert-Butyldimethylsilyl-2-deoxy-2-phthalimido-1-thio-ꢄ-D-
glucopyranoside (7b). Tert-butyldimethylsilyl chloride (0.903 g, 5.99 mmol) in
dry pyridine (15 mL) was added dropwise (3 mL / 20 min) via a syringe pipet to a
stirred solution of phenyl 2-deoxy-2-phthalimido-1-thio-ꢄ-D-glucopyranoside23
(2.004 g, 4.99 mmol) in dry pyridine (30 mL). The reaction mixture was stirred 12
h, then poured into water (200 mL). The mixture was extracted with diethyl ether
(5 ꢇ 40 mL). The combined extracts were dried (MgSO4), concentrated, and the
residue purified by flash chromatography on silica gel (eluant ethyl acetate: hex-
anes 2:1) to give the title compound (Rf, 0.66) as a colorless syrup (1.402 g,
70.0%), crystallized from ethanol-water to give very fine colorless needles: mp
1
68–70°C; [ꢀ]D ꢁ26.1° (c 2.1, dichloromethane); H NMR ꢃ 0.11 (d, 2 ꢇ 3H,
Si(CH3)2 ), 0.91 (d, 9H,SiC(CH3)3, 3.55–3.65 ( br m, 2H, H-4, H-5), 3.88, 3.97
(AB part of ABX pattern, 2H, J6,6ꢆ ꢅ ꢂ10.5 Hz, J5,6 ꢅ 5.1 Hz, J5,6ꢆ ꢅ 4.5 Hz, H-
6,6ꢆ), 4.18 (t, 1H, J1,2 ꢅ J2,3 ꢅ10.38 Hz, H-2), 4.35 (dd, 1H, J2,3 ꢅ 10.24 Hz, J3,4
ꢅ 7.94 Hz, H-3), 5.60 (d, 1H, J1,2 ꢅ 10.23 Hz, H-1), 7.2–7.6 (4m, 9H, SPh, Phth):
13C NMR: ꢃ ꢂ5.4 (SiC(CH3)3), 18.2 (SiC(CH3)3), 25.8 (SiC(CH3)3), 55.2 (C2),
64.7 (C6), 72.7, 74.3, 78.0 (C3, C4, C5), 83.6 (C1), 127.8, 128,9, 131.6, 132.3,
134.2 (SPh, Phth), 210.6 (2 CO, Phth). EIMS m/z: 515(Mꢁ, not observed, 406 (10
%, M - SPh), 388 (72 %, 406 - H2O).
Anal. Calcd for C26H33NO6SSi.H2O: C, 58.51; H, 6.61; N, 2.62. Found: C,
58.69; H, 6.54; N, 2.55.
Phenyl 6-O-tert-Butyldimethylsilyl-2-phthalimido-3,4-di-O-benzyl-2-de-
oxy-1-thio-ꢄ-D-glucopyranoside (7a). Compound 7b (0.100 g, 0.194 mmol)
was dissolved in dry benzyl chloride (10 mL, 71.8 mmol). Sodium hydride (60%
in mineral oil, 0.017 g, 0.423 mmol) was then added and the reaction was allowed
to proceed under nitrogen at 70°C for 12 h. The reaction mixture was then poured
into water (20 mL) and extracted with dichloromethane (3 ꢇ 30 mL). The com-

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RILEY AND GRINDLEY
bined organic extracts were dried (MgSO4), concentrated, and the residue purified
by flash chromatography on silica gel (eluant ethyl acetate: hexanes 1:2) to give the
title compound (Rf, 0.65) as a colorless syrup (0.068 g, 50 %): [ꢀ]D ꢁ22.3° (c 0.9,
1
dichloromethane); H NMR: ꢃ 0.11 (d, 2 ꢇ 3H, Si(CH3)2 ), 0.91 (d, 9H,
SiC(CH3)3), 3.52 ( broad dt, 1H, J4,5 ꢅ 10.38, J5,6 ꢅ J5,6ꢆ ꢅ 2.59 Hz, H-5), 3.78
(broad t, 1 H, J3,4 ꢅ J4,5 ꢅ 8.54 Hz, H-4), 3.92 (broad s, 2H, H-6,6ꢆ), 5.16 (t,1H,
J
1,2 ꢅ J2,3 ꢅ10.22 Hz, H-2) 4.35 (t, 1H, J3,4 ꢅ J2,3 ꢅ 8.85 Hz, H-3), 4.43, 4.78 (2d,
2H, Jꢅ 12.05 Hz, OCH2Ph), 4.77, 4.86 (2d, 2H, J ꢅ 10.99 Hz, OCH2Ph), 5.51 (d,
1H, J1,2 ꢅ 10.23 Hz, H-1), 7.2–7.6 (4m, 19H, 2CH2Ph, SPh, Npth): 13C NMR: ꢃ
ꢂ4.9 (SiC(CH3)3) 26.0 (SiC(CH3)3), 29.7 (SiC(CH3)3), 54.9 (C2), 61.5 (C3), 62.1
(C6), 72.1, 75.0 (2 OCH2Ph), 79.0 (C4), 80.2 (C5), 83.1 (C1), 127.4, 127.8, 128.0,
128.4, 128.5, 128.8, 132.7, (2 CH2Ph, SPh, Npth), 138.2, 138.4(2 CO, Npth).
General Method for De-O-benzylation: Phenyl 2,4,6-Tri-O-pivaloyl-1-
thio-ꢄ-D-galactopyranoside (2b). Compound 2a (0.100 g, 0.16 mmol) was dis-
solved in carbon tetrachloride (10 mL) and water (5 mL). NBS (2.5 equiv, 0.049 g,
0.276 mmol ) was then added, followed by calcium carbonate (4.4 equiv, 0.072 g,
0.716 mmol). The solution was then purged with nitrogen for one hour. Using a
375 W incandescent light, the reaction mixture was irradiated for 15 min while be-
ing monitored by TLC. The mixture was then poured into water (25 mL) and ex-
tracted with dichloromethane (3 ꢇ 30 mL). The combined organic extracts were
dried (MgSO4), concentrated, and the residue was purified by flash chromatogra-
phy on silica gel using ethyl acetate: hexanes 1:5 as eluant, to give the title com-
pound (0.081 g, 95%) as a colorless syrup (Rf, 0.23). The product was crystallized
from hexane to give fine colorless needles: mp 105–106°C; [ꢀ]D ꢂ5.0° (c 1.2,
chloroform); 1H NMR: ꢃ 1.27, 1.20 (2s, 3 ꢇ 9H, 3 C(CH3)3 ), 3.91 (m, 2H, H-3,
H5), 4.12 (m, 2H, H-6,6ꢆ), 4.70 (d, 1H, J1,2 ꢅ 10.07 Hz, H-1), 4.92 (t, 1H, J1,2
ꢅ J2,3 ꢅ 9.76 Hz, H-2), 5.32 (br dd, 1H, J3,4 ꢅ 3.35 Hz, J4,5 ꢅ 0.9, H-4), 7.2–7.6
(m, 5H, SPh); 13C NMR: ꢃ 27.1 (3 C(CH3)3), 38.7, 38.9, 39.2 (3 C(CH3)3), 62.1
(C-6), 69.5 (C-4), 70.2 (C-2), 73.0, 74.9 (C-3, C-5), 8.6 (C-1), 128.3, 128.9, 131.9,
133.2, (SPh), 178.0, 178.1, 178.6 (3 OCO); EIMS m/z: 524 (0.1%, Mꢁ), 509(0.1%,
M-Me), 415(100%, M-SPh); HRMS for C27H40O8S: Calcd 524.2444. Found:
524.2437.
2,4,6-Tri-O-pivaloyl-ꢄ-D-galactopyranosyl Fluoride (3b). Compound
3a (0.229 g, 0.56 mmol) was reacted as outlined for compound 2a to give the title
compound (0.187 g, 87%) as a colorless syrup: Rf, 0.50 (ethyl acetate: hexanes
1:5); [ꢀ]D ꢁ52.5° (c 3.9, dichloromethane); 1H NMR: ꢃ 1.20, 1.28, 1.29 (3s, 3 ꢇ
9H, 3 C(CH3)3 ), 4.11 (d, 2H, H-6,6ꢆ), 4.28 (dd, 1H, J3,4 ꢅ 3.36 Hz, J2,3 ꢅ 10.37
Hz, H-3), 4.37 (br t, 1H, J5,6 ꢅ J5,6ꢆ ꢅ 6.72 Hz, H-5), 4.98 (ddd, 1H, J1,2 ꢅ 2.60
Hz, J2,3 ꢅ10.38 Hz, J2,F ꢅ 24.42 Hz, H-2), 5.44 (br d, 1 H, J3,4 ꢅ 3.36 Hz, H-4),
5.63, 5.84 (2d, 1H, J1,2 ꢅ 2.89, J1,F ꢅ 53.86 Hz, H-1); 13C NMR: ꢃ 27.1, 27.2, 27.4
(3 C(CH3)3), 38.9, 39.2, 39.5 (3 C(CH3)3), 61.4 (C-6), 67.0 (C-3), 69.5 (2C, C-4,
C-5), 70.5 (d, 2JC,F ꢅ 23.8 Hz, C-2), 104.8 (d, 1JC,F ꢅ 227.7 Hz, C-1),178.1, 178.4,
178.9 (3 OCO); EIMS m/z: 434 (not observed, Mꢁ), 414 (7.6%, Mꢁ - HF), 399

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167
(1.5%, Mꢁ - HF - CH3), 333 (2.8 %, Mꢁ - OCOtBu); HRMS for C21H34O8: Calcd
414.2253. Found: 414.2245.
Ethyl 6-(2,4,6-Tri-O-pivaloyl-ꢄ-D-galactopyranosyloxy)hexanoate (4b).
Compound 4a (0.068 g, 0.10 mmol) was reacted as outlined for compound 2a to
give the title compound (0.057 g, 95%) as a colorless syrup: [ꢀ]D ꢁ3.2° (c 6.1,
dichloromethane); 1H NMR: ꢄ 1.20, 1.22, 1.27 (3s, 3 ꢇ 9H, 3 C(CH3)3), 1.25 (t,
3H, J ꢅ 6.8 Hz, OCH2CH3), 1.29–1.41 (complex m, 2H, OCH2CH2CH2), 1.5–1.8
(complex m, 4H,OCH2CH2CH2CH2), 2.30 (t, 2H, J ꢅ 7.3 Hz, OCOCH2),
3.41–3.50 (complex m, 1H, one OCH2CH2), 3.80–3.92 (m, 3H, one OCH2CH2, H-
3, H-5), 4.10 (q, 2H, J ꢅ 7.0 Hz, OCH2CH3), 4.12 (AB part of ABX, 2H, H-6,6ꢆ),
4.46 (d, 1H, J1,2 ꢅ 8.1 Hz, H-1), 4.90 (dd, 1H, J1,2 ꢅ 7.9 Hz, J2,3 ꢅ 10.1 Hz, H-2),,
5.30 (br d, 1H, J3,4 ꢅ 3.5 Hz, H-4); 13C NMR: ꢃ 14.3 (OCH2CH3), 21.1
(CH2CH2COOEt), 24.7 (OCH2CH2CH2), 25.6 (OCH2CH2),27.2–27.3 (9 C(CH3)3)
29.4 (CH2COOEt), 39.8, 39.0, 39.4 (3 C(CH3)3) 60.3 (OCH2CH3), 61.9 (C-6),
69.4, 69.7 (C-4, OCH2CH2), 71.1, 72.1 (C-3, C-5), 72.9 (C-2), 101.1 (C-1), 173.7
(COCH2), 178.0, 178.2, 179.2 (COC(CH3)3); EIMS m/z: 574 (not observed, Mꢁ),
415 (5.3%, Mꢁ - O(CH2)5CO2Et); HRMS for C21H35O8: Calcd 415.2332. Found:
415.2333.
Phenyl 2,4,6-Tri-O-acetyl-1-thio-ꢄ-D-galactopyranoside (5b). Com-
pound 5a (0.197 g, 0.404 mmol) was reacted as outlined for compound 2a to give
the title compound (0.122 g, 76%) as a colorless syrup, crystallized from hexanes:
ethyl acetate to give fine colorless needles: mp 120–121°C; Rf 0.21 (ethyl acetate:
hexanes 2:3); [ꢀ]D ꢁ14.6° (c 1.0, chloroform); 1H NMR: ꢃ 2.05, 2.15, 2.73 (3s, 3
ꢇ 3H, 3 COCH3), 3.89 (m, 2H, H-3, H-5), 4.13, 4.16 (AB part of ABX pattern, 2H,
J
5,6 ꢅ 7.4 Hz, J5,6ꢆ ꢅ 5.5 Hz, J6,6ꢆ ꢅ ꢂ11.5 Hz, H-6,6ꢆ), 4.68 (d, 1H, J1,2 ꢅ 9.92
Hz, H-1), 5.04 (t, 1H, J1,2 ꢅ J2,3 ꢅ 9.77 Hz, H-2), 5.36 (dd, 1 H, J3,4 ꢅ 3.53 Hz,
J4,5 ꢅ 0.94 Hz, H-4), 7.20–8.10 (3m, 6H, SPh); 13C NMR: ꢃ 20.8, 21.2, 29.7 (3
COCH3), 62.4 (C-6), 70.1 (C-4), 70.8 (C-2), 72.1, 74.9 (C-5, C-3), 86.3 (d, C-1),
128.1, 129.0, 129.0, 130.2, 132.4, 132.4 (SPh), 171.2, 171.2, 178.5 (3 OCO); EIMS
m/z: 398 (0.5%, Mꢁ), 289 (100, Mꢁ - SPh); HRMS for C18H22O8S: Calcd
398.1035. Found: 398.1054.
Ethyl 6-(2,4,6-Tri-O-acetyl-ꢄ-D-galactopyranosyloxy)hexanoate (6b).
Compound 6a (2.00 g, 3.43 mmol) was reacted as outlined for compound 2a to
give the title compound (1.26g, 83%) as a colorless syrup: [ꢀ]D ꢁ7.7° (c 1.3,
1
dichloromethane); H NMR: ꢃ 1.25 (t, 3H, J ꢅ 6.8 Hz, OCH2CH3), 1.29–1.41
(complex m, 2H, OCH2CH2CH2), 1.5–1.8 (complex m, 4H, OCH2CH2CH2CH2),
2.02, 2.04, 2.13 (3s, 3 ꢇ 3H, 3 COCH3), 2.29 (t, 2H, J ꢅ 7.3 Hz, OCOCH2), 3.48
(X of ABXY, 1H, OCH2CH2), 3.79–3.93 ( complex m, 3H, OCH2ꢆCH2, H-3, H-5),
4.12 (q, 2H, J ꢅ 7.2 Hz, OCH2CH3),4.15 (AB part of ABX, 2H, H-6,6ꢆ), 4.41(d,
1H, J1,2 ꢅ 7.9 Hz, H-1), 4.97 (dd, 1H, J1,2 ꢅ 8.4 Hz, J2,3 ꢅ 9.8 Hz, H-2), 5.33 (br
d, 1H, J3,4 ꢅ J4,5 ꢅ 3.2, H-4); 13C NMR: ꢃ 14.4 (OCH2CH3), 20.8, 20.9, 21.1 (3
COCH3), 24.7 (CH2CH2CO2Et), 25.5 (OCH2CH2CH2), 29.2 (OCH2CH2), 34.23

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(CH2CO2Et), 60.4 (OCH2CH3), 62.1 (C-6), 69.9 (C-4, OCH2CH2), 71.0, 71.4 (C-
3, C-5), 72.8 (C-2), 101.1 (C-1),170.7, 171.1, 171.1 (COCH3), 173.6 (COCH2);
EIMS m/z: 448 (not observed, Mꢁ), 403 (0.9%, Mꢁ - OEt), 289 (14.8%, Mꢁ
- O(CH2)5CO2Et); HRMS for C18H27O10 and C12H17O8: Calcd 403.1604 and
289.0923. Found: 403.1633 and 289.0987, respectively.
Phenyl 6-O-tert-Butyldimethylsilyl-2-deoxy-2-N-pthalimido-1-thio-ꢄ-D-
glucopyranoside (7b). Compound 7a (0.095 g, 0.137 mmol) was reacted as out-
lined for compound 2a to give the title compound (0.51 g, 72.4%) as a colorless
syrup, with Rf and spectral characteristics identical to 7b, prepared above.
ACKNOWLEDGMENTS
We thank Drs. L. R. Ramaley and J. S. Grossert for accurate mass determi-
nations and D. Johnston and M. Safatli for preparation of some starting materials.
We are grateful for financial support from NSERC.
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Accepted December 6, 2000

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