Aluminium triflate catalysed O-glycosidation: Temperature-switched selective Ferrier rearrangement or direct addition with alcohols

Article abstract of DOI:10.1039/c2ob25540e

A temperature-controlled mechanism switch between the Al(OTf) ₃-catalysed direct addition of alcohols or the Ferrier rearrangement reactions in some glycals is presented. The scope and limitations are investigated as are the influence of the st

Full text of DOI:10.1039/c2ob25540e

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PAPER
Aluminium triflate catalysed O-glycosidation: temperature-switched selective
Ferrier rearrangement or direct addition with alcohols†
D. Bradley G. Williams,*a,b Sandile B. Simelanea and Henok H. Kinfea
Received 13th March 2012, Accepted 6th June 2012
DOI: 10.1039/c2ob25540e
A temperature-controlled mechanism switch between the Al(OTf)3-catalysed direct addition of alcohols
or the Ferrier rearrangement reactions in some glycals is presented. The scope and limitations are
investigated as are the influence of the stereochemistry and nature of the protecting groups on the glycal
substrate.
pseudoglycals, both reactions being mediated by Al(OTf)3. We
expand the protocol to other substrates, discussing the appli-
Introduction
The rapid assembly of complex materials requires powerful
approaches to bond-forming reactions. An ability to form carbon
and oxygen bonds to carbohydrate derivatives is a key feature in
the synthesis of many natural and physiologically active sub-
stances, and glycals are frequently-used starting materials for the
synthesis of important chiral compounds.1 The alkene function
in these substrates lends itself to a variety of transformations,
including addition reactions,2 Ferrier rearrangement reactions,3
etc. Glycals have accordingly been utilised in a variety of partial
and total syntheses of chiral natural products, many of which are
O-glycosides.1,4
O-Glycosides can be generated from glycals by the catalysed
addition of alcohols of various descriptions to the alkene.4,5 In
this way, a range of O-glycosides has been prepared making use
of, for example, BF3·Et2O, BCl3, Ph3P-HBr, p-TsOH, CSA and
Pd(OAc)2 as catalysts.5 Otherwise, the Ferrier rearrangement is a
powerful approach to the synthesis of pseudoglycals and their
derivatives, starting from glycals.3,6 This rearrangement reaction
is usually performed by reacting the glycal with a Lewis acid cat-
alyst or with redox reagents, such as InCl3, ceric ammonium
nitrate, HClO4–SiO2, SnCl4, Sc(OTf)3 and Fe2(SO4)3·xH2O.7
We herein disclose a simple temperature-controlled selection
between the direct addition of alcohols to the alkene of tri-O-
benzyl-D-glucal to generate 2-deoxy-O-glycoside sugars or the
Ferrier rearrangement reaction to produce the corresponding
cation of the technology to systems with better leaving groups
and, ultimately, to the facile synthesis of disaccharide sugars and
highly desirable bolaform-type structures.8
Results and discussion
We recently detailed the efficient tetrahydropyranylation and
tetrahydrofuranylation reactions of various alcohols making use
of Al(OTf)3 as catalyst.9 As an extension of that study,
Al(OTf)3-catalysed reactions of tri-O-benzyl-D-glucal 1 with
various alcohols were investigated.
To our delight, substrate 1 readily generated the 2-deoxyglyco-
sides 2 in acceptable to good yields within one hour when the
substrate was allowed to react with 1.5 equivalents of the alcohol
reagent in the presence of 5 mol% Al(OTf)3 as catalyst in 1,2-
dichloroethane as solvent at 60 °C (Scheme 1, Table 1, entries
1–5). The O-glycoside formation favoured the α-anomer, as
expected for systems absent of protecting groups at the C-2
aResearch Centre for Synthesis and Catalysis, Department of Chemistry,
University of Johannesburg, P.O. Box 524, Auckland Park, 2006,
South Africa. E-mail: bwilliams@uj.ac.za; Fax: +2711 559 2819;
Tel: +2711 559 3431
bIndustrial Research Limited, 69 Gracefield Road, Lower Hutt,
5040 Wellington, New Zealand. E-mail: b.williams@irl.cri.nz;
Fax: +644 566 6004; Tel: +644 931 3421
†Electronic supplementary information (ESI) available. CCDC 834632.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob25540e
Scheme 1 Temperature-controlled selective addition or Ferrier
rearrangement reactions.
5636 | Org. Biomol. Chem., 2012, 10, 5636–5642
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Table 1 Al(OTf)3-catalysed addition of alcohols to glucal 1a
T (°C) Product α : β ratiob Yieldc (%)
Entry Alcohol R =
1
2
3
4
5
6
7
8
CH3
60
60
60
60
60
0
0
0
0
0
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
1 : 1
3 : 2
7 : 3
2 : 3
4 : 1
7 : 1
7 : 1
8 : 1
3 : 1
4 : 1
9 : 1
8 : 1
4 : 1
56
69
74
72
67
74
69
74
83
63
76
86
67
Benzyl
Propargyl
Allyl
4-C6H4Br
CH3
Benzyl
Propargyl
Allyl
4-C6H4Br
4-C6H4OCH3
Cyclohexyl
—
9
10
11
12
13
0
0
0
3g
3b
Scheme 2 Ferrier-exclusive products from acetate-protected glycals.
Table 2 Al(OTf)3-catalysed Ferrier rearrangement addition productsa
a 5 mol% Al(OTf)3, 0.48 mmol substrate, 0.72 mmol alcohol (1.5 eq.),
2.0 mL DCE. b Determined using 1H NMR spectroscopy. c Isolated
yield.
Entry
R =
Product
α : β ratiob
Yieldc (%)
1
2
3
4
5
CH3
Benzyl
Propargyl
Cyclohexyl
5a
5b
5c
5d
5e
5 : 1
7 : 1
8 : 1
8 : 1
9 : 1
81
84
78
86
68
position of the sugar capable of participating in anchimeric
assistance.10
Most surprisingly, when the reaction temperature was lowered
to 0 °C, the mechanism of the reaction changed altogether to
produce, instead of the 2-deoxy-1-O-glycoside, the Ferrier
rearranged pseudoglycal products 3 (Scheme 1, Table 1, entries
6–12). This outcome was obtained without fail for each of the
alcohols employed in the first round of experiments. Here too,
the products were obtained predominantly as the α-anomers, in
good yields. While the yields overall remain modest to good, the
switch between the mechanisms in simple consequence of temp-
erature changes is attractive. The use of THF or acetonitrile as
solvent failed to show this switch in mechanism which was
observed only with DCM and 1,2-dichloroethane. In both
instances (i.e. for THF or acetonitrile as solvent), only the Ferrier
rearranged products were obtained for reactions that mimicked
Table 1, entries 6–12, regardless of the reaction temperature.
Treatment of the substrate 1 in 1,2-dichloroethane with Al(OTf)3
without any added alcohol (Table 1, entry 13) led to the gener-
ation of the pseudoglycal 3b in 67% yield, indicating that the
glycal substrate may be directly activated toward Ferrier
rearrangement chemistry without an added nucleophile. Some
measure of competition was noted in all of these reactions where
the C-3 benzyloxy leaving group also acted as nucleophile to
yield 3b as an unwanted by-product (≤5% in all cases). A poss-
ible rationalisation for this mechanistic outcome may lie in the
ability of Al(OTf)3 to behave as a Lewis acid11 or, by virtue of
its ability to bind to and polarise ROH compounds, as a Lewis-
assisted Brønsted acid.12 We propose that Al(OTf)3 interacts
with the OBn group as a Lewis acid, at low temperature, activat-
ing it as a leaving group in a mechanism akin to an assisted SN2′
(borderline, or SN1′) nucleophilic displacement. At higher temp-
erature, the enol ether is rather protonated by the Lewis-assisted
Brønsted acid, leading to the 2-deoxy product via the oxocarbe-
nium intermediate so common in sugar chemistry. The latter
would not be dissimilar to the supported HBr catalyst applied
previously in the synthesis of 2-deoxy sugars.13
6
7
8
Propargyl
Allyl
7a
7b
7c
>19 : 1
>19 : 1
9 : 1
75
71
63
a 5 mol% Al(OTf)3, 0.74 mmol substrate, 1.10 mmol alcohol (1.5 eq.),
3.0 mL DCE. b Determined using 1H NMR spectroscopy. c Isolated
yield.
competition reaction was altogether suppressed. The Ferrier-
rearranged O-glycoside could be obtained in excellent yields for
a variety of alcohol nucleophiles, including a D-ribose derivative
which led to disaccharide formation in good yield. In contrast to
the benzyl-protected substrate, no manipulation of the reaction
temperature could induce direct addition of the alcohol to gener-
ate the 2-deoxy sugars, presumably due to strong activation of
the acetate leaving group by its complexation to the Al(OTf)3
catalyst.
When making use of phenols as nucleophiles a different
picture emerged. The tri-O-acetyl-D-glucal and -galactal sub-
strates shuttled between the two mechanisms (Scheme 3,
Table 3) as a function of their stereochemistry. Accordingly, reac-
tions performed at temperatures as low as −20 °C allowed the
preparation of the Ferrier rearrangement O-glycosides as domi-
nant products from tri-O-acetyl-D-glucal while reactions per-
formed at 0 °C gave C-arylation products, an aspect we are
currently investigating in more detail. This observation is likely
an O–C rearrangement to the thermodynamically more stable
product, a process that has been used to prepare natural and
physiologically active compounds.14 Reaction of tri-O-acetyl-D-
When moving to the tri-O-acetyl-D-glucal and -galactal sub-
strates (Scheme 2, Table 2), which should produce the less com-
petitive acetate nucleophile from the C-3 leaving group, the
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Scheme 4 Formation of symmetrical bolaform-type compounds.
Scheme 3 Temperature switching mechanism with phenolic
nucleophiles.
corresponding 2-deoxy-D-glucoside derivatives or their pseudo-
glycal counterparts at will, from common starting materials.
With the tri-O-acetyl substrates, the reaction was limited to the
Ferrier rearrangement when making use of aliphatic alcohols.
However, with phenols the situation was different, once again
allowing access to both mechanisms. This methodology allowed
symmetrical dimer formation when making use of diols. We are
currently investigating this chemistry with the view to its appli-
cation to other materials with interesting characteristics, such as
bolaforms.8,11 In this context, the work holds promise, based on
the successes with the diols already shown here, to allow the
ready synthesis of unsymmetrical bolaform-type structures,
which are highly sought after compounds.
Table 3 Al(OTf)3-catalysed reactions with phenolic nucleophilesa
Entry
Ar =
Product
α : β ratiob
Yieldc (%)
1
2
3
C6H5
4-C6H4Br
4-C6H4I
5f
>19 : 1
>19 : 1
9 : 1
73
86
81
76
88
91
68
68
76
73
66
64
71
53
5g
5h
5i
5j
5k
5l
8a
8b
8c
8d
8e
8f
4
5
6
7
2-C6H4I
9 : 1
4-C6H4OCH3
4-C6H4CH3
2-Naphthyl
C6H5
>19 : 1
>19 : 1
9 : 1
>19 : 1
18 : 1
8
9
4-C6H4Br
4-C6H4I
2-C6H4I
4-C6H4OCH3
4-C6H4CH3
2-Naphthyl
10
11
12
13
14
11 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
8g
General methods
a 5 mol% Al(OTf)3, 0.74 mmol substrate, 1.10 mmol alcohol (1.5 eq.),
3.0 mL DCE. b Determined using 1H NMR spectroscopy. c Isolated
yield.
All reactions were performed under an atmosphere of either
nitrogen or argon. Reagents were used as received from commer-
cial sources without further purification. Unless otherwise stated,
dry solvents16 were used in oven dried, flamed out glass appar-
atus. Qualitative thin layer chromatography (TLC) was con-
ducted on “Merck GF254 precoated silica plates” (0.25 mm
layer). The chromatograms were eluted using an appropriate
solvent system as indicated for column chromatography. Com-
pounds were visualised by their fluorescence under UV light
(254 nm), as well as by spraying the plate with anisaldehyde
spray followed by heating with a heat gun or over a Bunsen
burner. “Flash chromatography” refers to column chromato-
graphy under nitrogen pressure using “Merck Kieselgel 60
(230–400 mesh), with eluents mixed in a volume per volume
ratio. Room temperature refers to ca. 20–23 °C. NMR spectra
were recorded by means of a Varian Gemini 2000, 300 MHz and
a Bruker Ultrashield 400 MHz spectrometer in CDCl3 unless
otherwise indicated. J values are given in Hz. Fractional
numbers of protons given in the 1H NMR data, below, reflect the
relative ratio of the isomers. Mass spectrometry was performed
on Thermo Double Focusing Sector high resolution mass spec-
trometer. Ionisation techniques include EIMS and CIMS. A
Tensor 27 spectrophotometer was used to record IR spectra
using an ATR fitting. The data are listed with the characteristic
peaks indicated in wavenumber (cm−1). Melting points were
determined using a Gallencamp oil immersion apparatus and are
uncorrected.
galactal at 0 °C provided the corresponding direct addition
2-deoxy derivatives but was unreactive at lower temperatures
thereby preventing the possibility of Ferrier rearrangement under
our conditions. In all cases the α-O-glycoside dominated.
Quite usefully, the employment of alkyl terminal diols
allowed symmetrical dimer formation of the pseudoglycals 9 or
10 from 4 (Scheme 4). This was achieved when reacting the
glucal with 1,4-butynediol or 1,6-hexanediol at low temperature,
to produce so-called bolaform-type compounds.8 In both cases,
the α,α′ ratio to α,β′ product was 8 : 1 (determined from the
respective 1H NMR spectra). Such materials show rather remark-
able physical characteristics and allow self-assembly of supra-
molecular structures.15
Conclusions
We have shown an ability to switch between Al(OTf)3-catalysed
direct addition of alcohols to the alkene functional group of
glycals and Ferrier rearrangement reactions by simply manipulat-
ing the temperature under which the reaction is performed, when
tri-O-benzyl-D-glucal is used as substrate with alkyl alcohols as
nucleophiles. This allows the ready synthesis either of the
5638 | Org. Biomol. Chem., 2012, 10, 5636–5642
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O-Glucoside 2e. Glycosidation of 3,4,6-tri-O-benzyl-D-glucal
(200 mg, 0.48 mmol) with p-bromobenzyl alcohol (134 mg,
0.72 mmol, 1.5 eq.) at 60 °C for 1 hour afforded glucoside 2e as
an inseparable α/β (4 : 1) mixture in a combined yield of 194 mg
(67%) as a light yellow oil. Found C, 67.7; H, 5.7%.
C34H35BrO5 requires C, 67.7; H, 5.9%; Rf = 0.53 (4 : 1, hexane–
Experimental section
General procedure for glycosylation reactions
To a solution of the specific glycal in DCE or DCM (2 mL),
were added a glycosyl acceptor alcohol (1.5 eq) and 5 mol% Al
(OTf)3 and the resulting mixture was stirred at the temperature
indicated (0 °C, room temperature or heated at 60 °C) until TLC
analysis showed completion of the reaction. Thereafter, the reac-
tion was quenched by addition of a saturated aqueous NaHCO3
solution (0.5 mL). The reaction mixture was extracted twice with
DCM (5 mL) and the organic layer washed with H2O (2 mL).
The organic layer was dried over anhydrous MgSO4 and the
solvent removed in vacuo. The crude product was purified by
column chromatography on silica gel using a mixture of ethyl
acetate and hexane as eluent.
Many of the compounds reported here have been previously
prepared and fully characterised. In all cases, the analytical data
produced for the products here compared favourably with litera-
ture data. A list of the known compounds follows in the Refer-
ences, which are listed by product number.17–27,29–32 The data
for only new or incompletely characterised compounds are given
here.
1
EtOAc); H NMR (400 MHz, CDCl3): δ 7.38–7.08 (m, 19H),
4.95 (s, 1H), 4.74 (d, 1H, J 10.5 Hz), 4.61–4.40 (m, 6H), 4.31
(d, 1H, J 12.0 Hz), 3.94–3.85 (m, 1H), 3.69 (d, 2H, J 9.0 Hz),
3.58–3.50 (m, 2H), 2.20 (dd, 1H, J 13.1, 4.3 Hz), 1.67 (dd, 1H,
J 16.6, 7.9 Hz); 13C NMR (75 MHz, CDCl3): δ 138.3, 138.0,
137.6, 136.6, 131.5, 131.4, 129.5, 129.2, 128.5, 128.4, 128.0,
127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.5, 126.9, 121.6,
121.3, 96.7, 78.2, 77.6, 75.0, 73.5, 71.0, 70.9, 68.9, 68.1, 35.3;
IR νmax/cm−1 3088, 3030, 2864, 1493, 1362, 1096, 803, 734,
696; MS: No useful peaks were identified from the CIMS spec-
trum apart from those arising from the bromobenzyl fragment.
O-Glucoside 3e. Glycosidation of 3,4,6-tri-O-benzyl-D-glucal
(200 mg, 0.48 mmol) with p-bromobenzyl alcohol (134 mg,
0.72 mmol, 1.5 eq.) at 0 °C for 7 hours afforded 3e as an in-
separable α/β (4 : 1) mixture in a combined yield of 150 mg
(63%) as a light yellow oil. Found C, 65.7; H, 5.9%.
C27H27BrO4 requires C, 65.5; H, 5.5%; Rf = 0.49 (5 : 1, hexane–
O-Glycoside 2b.18 This product has been previously
reported18 but no data are presented. Glycosidation of 3,4,6-tri-
O-benzyl-D-glucal (200 mg, 0.48 mmol) with benzyl alcohol
(78 mg, 0.72 mmol, 1.5 eq.) at 60 °C for 1 hour afforded gluco-
side 2b as an inseparable α/β (3 : 2) mixture in a combined yield
of 174 mg (69%) as a light yellow oil. Found C, 77.9; H, 6.7%.
C34H36O5 requires C, 77.8; H, 6.9%; Rf = 0.43 (7 : 1, Hexane–
1
EtOAc); H NMR (300 MHz, CDCl3): δ 7.38–7.09 (m, 14H),
6.00 (d, 1H, J 10.2 Hz), 5.69 (dt, 1H, J 10.3, 2.3 Hz), 5.10
(d, 0.2H, J 1.2 Hz), 5.01 (d, 0.8H, J 2.1 Hz), 4.73–4.33 (m, 6H),
4.09 (dt, 1H, J 9.3, 1.5 Hz), 3.91–3.89 (m, 1H), 3.60–3.58
(m, 2H); 13C NMR (75 MHz, CDCl3): δ 138.0, 137.9, 137.1,
131.4, 130.9, 129.6, 128.3, 127.9, 127.8, 127.7, 127.6, 126.2,
121.4, 94.0, 73.3, 71.0, 70.2, 69.3, 69.2, 68.6; IR νmax/cm−1
3063, 2865, 1453, 1362, 1096, 803, 734, 696; MS: No useful
peaks were identified from the CIMS spectrum.
1
EtOAc); H NMR (400 MHz, CDCl3): δ 7.40–7.05 (m, 20H),
4.97 (s, 0.7H), 4.89 (d, 0.3H, J 8.0 Hz), 4.85 (s, 0.3H), 4.81 (d,
0.7H, J 8.0 Hz), 4.65–4.30 (m, 8H), 4.09–3.85 (m, 1H),
3.80–3.49 (m, 3H), 2.25 (dd, 0.7H, J 16.0, 4.0 Hz), 2.12 (d,
0.3H, J 12.0 Hz), 1.67 (t, 0.7H, J 12.0 Hz), 1.58 (t, 0.3H, J 10.0
Hz); 13C NMR (75 MHz, CDCl3): δ 138.6, 138.5, 138.4, 138.1,
137.9, 137.6, 128.8, 128.5, 128.3, 128.2, 128.1, 127.9, 127.8,
127.7, 127.6, 127.5, 127.4, 126.9, 97.6, 96.7, 78.2, 77.7, 77.3,
75.4, 75.0, 73.4, 73.0, 71.8, 71.5, 71.4, 71.3, 70.9, 70.5, 69.8,
68.8, 35.4, 35.0; IR νmax 1698, 1492, 1454, 1070, 1011, 732,
694 cm−1; HR-CIMS calc for C27H30O5 434.2093 [M–C7H6]+,
found 434.2063.
O-Glucoside 3f. Glycosidation of 3,4,6-tri-O-benzyl-D-glucal
(200 mg, 0.48 mmol) with p-methoxybenzyl alcohol (90 μL,
0.72 mmol, 1.5 eq.) at 0 °C for 7 hours afforded 3f as an insepar-
able α/β (9 : 1) mixture in a combined yield of 146 mg (76%) as
a light yellow oil. Found C, 75.3; H, 7.1%. C28H30O5 requires
1
C, 75.3; H, 6.8%; Rf = 0.46 (5 : 1, hexane–EtOAc); H NMR
(300 MHz, CDCl3): δ 7.26–7.11 (m, 12H), 6.78–6.76 (m, 2H),
5.98 (d, 1H, J 10.2 Hz), 5.68 (d, 1H, J 10.2 Hz), 5.10 (s, 0.1H),
5.02 (s, 0.9H), 4.68–4.33 (m, 6H), 4.10 (d, 1H, J 9.3 Hz), 3.93
(m, 1H), 3.72–3.56 (m, 5H); 13C NMR (75 MHz, CDCl3): δ
159.1, 138.1, 138.0, 130.6, 130.0, 129.7, 129.8, 128.4, 128.3,
127.9, 127.8, 127.7, 127.6, 126.6, 113.7, 93.6, 73.3, 70.9, 70.3,
69.6, 69.2, 68.8, 55.2; IR νmax/cm−1 3031, 2865, 1513, 1247,
1027, 820, 733, 697; MS: No useful peaks were identified from
the CIMS spectrum.
O-Glycoside 2c. Glycosidation of 3,4,6-tri-O-benzyl-D-glucal
(200 mg, 0.48 mmol) with propargyl alcohol (40 mg,
0.72 mmol, 1.5 eq.) at 60 °C for 1 hour afforded glucoside 2c as
an inseparable α/β (7 : 3) mixture in a combined yield of 167 mg
(74%) as a light yellow oil. Rf = 0.39 (7 : 1, hexane–EtOAc);
1H NMR (400 MHz, CDCl3): δ 7.31–7.06 (m, 15H), 5.05
(s, 0.7H), 4.95 (s, 0.3H), 4.80 (t, 1H, J 10.2 Hz), 4.61–4.35
(m, 6H), 4.18 (s, 0.6H, OCH2), 4.09 (1.4H, OCH2), 3.95–3.86
(m, 1H), 3.69 (d, 1H, J 10.8 Hz), 3.62–3.49 (m, 2H), 2.33
(s, 0.3H), 2.31 (s, 0.7H), 2.26–2.19 (m, 1H), 1.71–1.56 (m, 1H);
13C NMR (75 MHz, CDCl3): δ 138.4, 138.3, 138.0), 137.5,
128.4, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 96.6,
96.1, 80.2, 79.2, 78.0, 77.9, 77.4, 74.9, 74.3, 74.1, 73.4, 71.7,
71.1, 70.8, 68.8, 68.6, 57.2, 53.9, 35.3, 35.0; IR νmax/cm−1
2860, 1501, 1456, 1301, 1070, 736, 698; MS: No useful peaks
were identified from the CIMS spectrum.
Disaccharide 5e. Glycosidation of 3,4,6-tri-O-acetyl-D-glucal
(200 mg, 0.735 mmol) with methyl 2,3-O-isopropylidine-β-D-
ribofuranoside (224 mg, 1.1 mmol, 1.5 eq.) for 1 hour at room
temperature afforded glycoside 5e as an inseparable α/β (9 : 1)
mixture in a combined yield of 208 mg (68%) as a clear oil.
Found C, 55.0; H, 7.2%. C19H28O10 requires C, 54.8; H, 6.8%;
1
Rf = 0.31 (3 : 1, hexane–EtOAc); H NMR (300 MHz, CDCl3):
δ 5.87–5.71 (m, 2H), 5.21 (dd, 1H, J 9.9, 1.2 Hz), 5.07 (s,
0.1H), 4.95 (s, 0.9H), 4.9 (s, 1H), 4.61 (d, 1H, J 5.7 Hz), 4.48
(d, 1H, J 5.7 Hz), 4.29–4.26 (m, 1H), 4.19–4.07 (m, 2H),
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4.02–3.97 (m, 1H), 3.71–3.68 (m, 1H), 3.46–3.43 (m, 1H), 3.21
(s, 3H), 2.00–1.98 (m, 6H), 1.38 (s, 3H), 1.22 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 170.8, 170.2, 129.3, 127.4, 112.3, 109.3,
95.0, 85.1, 85.0, 82.0, 69.6, 67.0, 65.0, 62.7, 54.8, 26.4, 24.9,
20.9, 20.7; IR νmax/cm−1 2987, 2939, 2836, 1741, 1371, 1224,
1015, 869, 736; HR-CIMS calc for C18H25O10 401.1448
[M–CH3]+, found 401.1363.
Mp 72–74 °C; Rf = 0.58 (3 : 1, hexane–EtOAc); 1H NMR
(300 MHz, CDCl3) δH δ 7.73–7.69 (m, 3H), 7.46 (d, 1H, J 2.4
Hz), 7.39 (ddd, 1H, J 9.3, 7.2, 1.2 Hz), 7.30 (ddd, 1H, J 9.3,
6.9, 1.2 Hz), 7.18 (dd, 1H, J 9.9, 3.9 Hz), 6.00 (unresolved fine
ABXY system, 2H), 5.79 (d, 1H, J 1.5 Hz), 5.37 (d, 1H, J 9.6
Hz), 4.32–4.20 (m, 2H), 4.06 (d, 1H, J 10.5 Hz), 2.05 (s, 3H),
1.83 (s, 3H); 13C NMR (75 MHz, CDCl3): δC 170.8, 170.3,
154.7, 134.4, 130.1, 129.7, 129.3, 127.6, 127.1, 127.0, 126.4,
O-Glucoside 5h. Glycosidation of 3,4,6-tri-O-acetyl-D-glucal
(200 mg, 0.735 mmol) with 4-iodophenol (194 mg, 1.2 equiva-
lents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in DCM
(2.0 mL) at −20 °C for 3 hours afforded glycoside 5h as an inse-
parable α/β (9 : 1) mixture in a combined yield of 257 mg (81%)
as a cream solid. Found C, 44.6; H, 4.3%. C16H17IO6 requires C,
44.5; H, 4.0%; Mp 56–58 °C; Rf = 0.55 (3 : 1, hexane–EtOAc);
1H NMR (300 MHz, CDCl3) δH 7.55 (d, 2H, J 9.0 Hz), 6.85 (d,
2H, J 8.7 Hz), 6.01(d, 1H, J 10.2 Hz), 5.94 (dt, 1H, J 10.3, 2.3
Hz), 5.62 (s, 1H), 5.34 (dd, 1H, J 9.5, 1.4 Hz), 4.27–4.12 (m,
2H), 4.09 (dd, 1H, J 11.6, 1.6 Hz), 2.07 (s, 3H), 1.95 (s, 3H);
13C NMR (75 MHz, CDCl3): δC 170.6, 170.2, 156.8, 138.2,
130.3, 126.6, 119.3, 92.8, 85.0, 67.8, 64.8, 62.5, 20.9, 20.6; IR
νmax/cm−1 2952, 2360, 1735, 1483, 1368, 1219, 978, 816;
HR-CIMS calc for C14H14IO6 372.9937 [M–C2H3O2]+, found
327.9980.
124.3, 119.1, 111.2, 92.9, 67.9, 65.0, 62.6, 20.9, 20.6; IR νmax/
cm−1 3296, 1631, 1602, 1513, 1468, 1218, 843; HR-CIMS calc
for C18H17O4 297.1127 [M–C2H3O2]+, found 297.1098.
Disaccharide 7c. Glycosidation of 3,4,6-tri-O-acetyl-D-galac-
tal (200 mg, 0.735 mmol) with methyl 2,3-O-isopropylidine-
β-D-ribofuranoside (224 mg, 1.1 mmol, 1.5 eq.) for 3 hours at
room temperature afforded 7c as an inseparable α/β (9 : 1)
mixture a combined yield of 193 mg (63%). Found C, 54.7; H,
6.8%. C19H28O10 requires C, 54.8; H, 6.8%; Rf = 0.33 (2 : 1,
1
hexane–EtOAc); H NMR (300 MHz, CDCl3): δ 6.08 (dd, 1H,
J 10.0, 5.1 Hz), 6.00 (dd, 1H, J 10.0, 2.6 Hz), 5.12 (s, 0.1H),
5.04 (s, 0.9H), 4.98–4.96 (m, 1H), 4.92 (s, 1H), 4.63 (d, 1H,
J 6.0 Hz), 4.54 (d, 1H, J 3.9 Hz), 4.39–4.18 (m, 1H), 4.19 (d,
2H, J 6.0 Hz), 3.77 (dd, 1H, J 10.0, 5.6 Hz), 3.49 (t, 1H, J 9.6
Hz), 2.05 (s, 3H), 2.04 (s, 3H), 1.44 (s, 3H), 1.28 (s, 3H); 13C
NMR (75 MHz, CDCl3): 170.6, 170.3, 130.2, 125.2, 112.3,
109.3, 94.5, 85.1, 84.9, 82.0, 69.2, 66.9, 63.9, 62.6, 54.9, 26.4,
24.9, 20.8, 20.7; IR νmax/cm−1 2941, 2834, 2364, 1742, 1371,
1224, 1036, 869, 733; HR-CIMS C18H25O10 401.1448
[M–CH3]+, found 401.1358.
O-Glucoside 5i. Glycosidation of 3,4,6-tri-O-acetyl-D-glucal
(200 mg, 0.735 mmol) with 2-iodophenol (194 mg, 1.2 equiva-
lents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in DCM
(2.0 mL) at −20 °C for 7 hours afforded glycoside 5i as an inse-
parable α/β (9 : 1) mixture in a combined yield of 241 mg (76%)
as a cream solid. Found C, 44.8; H, 3.9%. C16H17IO6 requires
C, 44.5; H, 4.0%; Mp 47–49 °C; Rf = 0.59 (3 : 1, hexane–EtOAc);
1H NMR (300 MHz, CDCl3) δH 7.71 (dd, 1H, J 8.1, 1.5 Hz),
7.23 (ddd, 1H, J 8.4, 7.5, 1.5 Hz), 7.14 (dd, 1H, J 8.2, 1.6 Hz),
6.74 (ddd, 1H, J 9.0, 7.2 1.5 Hz), 6.02–5.89 (unresolved fine
ABX system, 2H), 5.58 (d, 1H, J 1.8 Hz), 5.33 (dd, 1H, J 9.3,
1.2 Hz), 4.27–4.19 (m, 2H), 4.10 (d, 1H, J 9.9 Hz), 2.05 (s, 3H),
1.95 (s, 3H); 13C NMR (75 MHz, CDCl3): δC 170.7, 170.2,
156.2, 139.3, 130.5, 129.5, 126.6, 124.6, 117.4, 94.4, 88.5, 68.0,
64.9, 62.5, 21.0, 20.7; IR νmax/cm−1 2931, 2360, 1739, 1438,
1367, 1225, 1042, 958, 750; HR-CIMS calc for C14H14IO4
372.9937 [M–C2H3O2]+, found 372.9983.
General procedure for O-glycosylation of tri-O-acetyl-D-galactal
with phenolic nucleophiles
Tri-O-acetyl-D-galactal (200 mg, 0.735 mmol) was stirred in
DCM (2 mL) with the phenol (1.2 equivalents, 0.882 mmol) and
Al(OTf)3 (5 mol%, 17 mg) at 0 °C. After completion of the reac-
tion as traced by TLC, the reaction was quenched at 0 °C by
adding concentrated sodium bicarbonate (2 mL) solution and the
mixture extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were dried over anhydrous magnesium sulfate.
The volatile component was removed under vacuum leaving the
crude product that was subjected to column chromatography on
flash silica for purification, and a solution of hexane and ethyl
acetate (hexane–EtOAc, 3 : 1) was used as eluent.
O-Glucoside 5l. Glycosidation of 3,4,6-tri-O-acetyl-D-glucal
(200 mg, 0.735 mmol) with 2-naphthol (127 mg, 1.2 equiva-
lents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in DCM
(2.0 mL) at −20 °C for 7 hours afforded glycoside 5l as an inse-
parable α/β (9 : 1) mixture in a combined yield of 178 mg (68%)
as a cream solid. This compound has been previously reported,26
but the structure apparently incorrectly assigned. We are able to
obtain both the O- and C-glycosides, depending on the reaction
conditions and we report the analytical data for the O-glycoside
here. The reported data26 concur with the C-glycoside in our
hands, not the O-glycoside. (See main text discussing Scheme 3,
relating to C-glycoside formation. We also obtained a single
crystal X-ray structure of the C-glycoside.29 For this compound,
H-1 resonates as a doublet of doublets at 6.29 ppm (J 4.2 and
2.7 Hz) while in the O-glycoside H-1 resonates as a fine doublet
at 5.79 ppm with J 1.5 Hz.)
O-Galactoside 8a.29 This compound has been previously pre-
pared but no data are given.13 Glycosidation of 3,4,6-tri-O-
acetyl-D-galactal (200 mg, 0.735 mmol) with phenol (83 mg, 1.2
equivalents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in
DCM (2.0 mL) at 0 °C for 4 hours afforded glycoside 8a as an
inseparable α/β (>19 : 1) mixture in a combined yield of 183 mg
(68%) as a cream solid. Found C, 59.1; H, 5.8%. C18H22O8
requires C, 59.0; H, 6.1%; Mp 120–122 °C; Rf = 0.41 (3 : 1,
1
hexane–EtOAc); H NMR (400 MHz, CDCl3): δH 7.21 (t, 2H,
J 7.4 Hz), 6.66–6.92 (m, 3H), 5.67 (br s, 1H), 5.43 (dd, 1H,
J 9.2, 2.6 Hz), 5.33 (br s, 1H), 4.19 (t, 1H, J 6.4 Hz), 4.02–3.98
(m, 2H), 2.18 (br t, 1H, J 12.6 Hz), 2.09 (s, 3H), 2.03 (dd, 1H,
J 9.6 and 5.2 Hz), 1.95 (s, 3H), 1.84 (s, 3H); 13C NMR
(75 MHz, CDCl3): δC 170.3, 170.2, 170.0, 156.2, 129.4, 122.3,
5640 | Org. Biomol. Chem., 2012, 10, 5636–5642
This journal is © The Royal Society of Chemistry 2012

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O-Galactoside 8e.30 This compound has been previously
reported30 but no analytical data were given. Glycosidation of
3,4,6-tri-O-acetyl-D-galactal (200 mg, 0.735 mmol) with 4-meth-
oxyphenol (109 mg, 1.2 equivalents, 0.882 mmol) and Al(OTf)3
(20 mol%, 69 mg) in DCM (2.0 mL) at 0 °C for 4 hours afforded
glycoside 8e as an inseparable α/β (>19 : 1) mixture in a com-
bined yield of 186 mg (64%) as a cream solid. Found C, 57.9;
H, 6.3%. C19H24O9 requires C, 57.6; H, 6.1%; Mp 60–62 °C;
116.4, 95.7, 67.4, 66.4, 65.9, 62.0, 30.1, 20.8, 20.6, 20.5; IR
νmax/cm−1 2962, 1740, 1490, 1226, 1016, 798; HR-CIMS calc
for C18H23O8 367.1393 [M + H]+, found 367.1374, calc for
C16H20O6 [M–C2H3O2]+ 307.1182, found 307.1129.
O-Galactoside 8b. Glycosidation of 3,4,6-tri-O-acetyl-D-galac-
tal (200 mg, 0.735 mmol) with 4-bromophenol (152 mg, 1.2
equivalents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in
DCM (2.0 mL) at 0 °C for 6 hours afforded glycoside 8b as an
inseparable α/β (18 : 1) mixture in a combined yield of 249 mg
(76%) as a cream solid. Found C, 48.2; H, 5.0%. C18H21BrO8
requires C, 48.6; H, 4.8%; Rf = 0.44 (3 : 1, hexane–EtOAc);
1H NMR (400 MHz, CDCl3): δH 7.35 (d, 2H, J 8.4 Hz), 6.92 (d,
2H, J 8.4 Hz), 5.66 (br s, 1H), 5.43 (d, 1H, J 12.0 Hz), 5.35 (br
s, 1H), 4.17 (t, 1H, J 6.4 Hz), 4.04–4.00 (m, 2H), 2.22 (br t, 1H,
J 12.4 Hz), 2.12 (s, 3H), 2.06 (dd, 1H, J 12.8, 5.2 Hz), 1.98
(s, 3H), 1.89 (s, 3H); 13C NMR (75 MHz, CDCl3): δC 170.3,
170.1, 170.0, 155.3, 132.3, 118.2, 114.7, 95.9, 67.6, 66.3, 65.8,
62.0, 30.0, 20.8, 20.6, 20.5; IR νmax/cm−1 2960, 1743, 1487,
1367, 1221, 1198, 1115, 1018, 823; HR-CIMS calc for
C18H21BrO8 444.0420, 446.0399 [M]+, found 444.0418,
446.0292, calc for C16H18BrO6 [M–C2H3O2]+ 385.0287,
387.0266, found 385.0284, 387, 0269.
1
Rf = 0.40 (3 : 1, hexane–EtOAc); H NMR (400 MHz, CDCl3):
δH 6.96 (d, 2H, J 9.2 Hz), 6.78 (d, 2H, J 8.8 Hz), 5.59 (d, 1H,
J 2.8 Hz), 5.48–5.43 (m, 1H), 5.36 (d, 1H, J 2.8 Hz), 4.26 (t,
1H, J 6.6 Hz), 4.07–4.03 (m, 2H), 3.73 (s, 3H), 2.20 (td, 1H,
J 9.5, 2.7 Hz), 2.12 (s, 3H), 2.06 (dd, 1H, J 9.6, 5.2 Hz), 1.98 (s,
3H), 1.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δC 170.4, 170.2,
170.0, 154.9, 150.2, 117.7, 114.4, 96.5, 67.3, 66.4, 66.0, 62.1,
55.5, 30.2, 20.8, 20.7, 20.6; IR νmax/cm−1 2944, 1730, 1497,
1245, 1204, 1011, 975; HR-CIMS calc for C19H24O9
[M–C2H3O2]+ 337, 1287, found 337.1315.
O-Galactoside 8f.30 This compound has been previously
reported30 but no analytical data were given. Glycosidation of
3,4,6-tri-O-acetyl-D-galactal (200 mg, 0.735 mmol) with p-cresol
(95 mg, 1.2 equivalents, 0.882 mmol) and Al(OTf)3 (20 mol%,
69 mg) in DCM (2.0 mL) at 0 °C for 4 hours afforded glycoside
8f as an inseparable α/β (>19 : 1) mixture in a combined yield of
198 mg (71%) as a light yellow oil. Found C, 59.8; H, 6.2%.
C19H24O8 requires C, 60.0; H, 6.4%; Rf = 0.46 (3 : 1, hexane–
O-Galactoside 8c. Glycosidation of 3,4,6-tri-O-acetyl-D-galac-
tal (200 mg, 0.735 mmol) with 4-iodophenol (194 mg, 1.2
equivalents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in
DCM (2.0 mL) at 0 °C for 6 hours afforded glycoside 8c as an
inseparable α/β (11 : 1) mixture in a combined yield of 264 mg
(73%) as a cream solid. Found C, 43.7; H, 4.1%. C18H21IO8
requires C, 43.9; H, 4.3%; Mp 62–64 °C; Rf = 0.45 (3 : 1,
1
EtOAc); H NMR (400 MHz, CDCl3): δH 7.05 (d, 2H, J 8.0
Hz), 6.92 (d, 2H, J 7.6 Hz), 5.65 (s, 1H), 5.46 (m, 1H), 5.36 (s,
1H), 4.24 (t, 1H, J 6.6 Hz), 4.08–4.01 (m, 2H), 2.26 (s, 3H),
2.19 (d, 1H, J 12.4 Hz), 2.12 (s, 3H), 2.06 (dd, 1H, J 9.4, 4.6
Hz), 1.99 (s, 3H), 1.90 (s, 3H); 13C NMR (75 MHz, CDCl3):
δC 170.3, 170.2, 170.0, 154.1, 131.6, 129.8, 116.4, 96.0, 67.3,
66.4, 66.0, 62.0, 30.2, 20.8, 20.6, 20.5, 20.4; IR νmax/cm−1
2961, 1742, 1509, 1220, 1037, 1018, 785; HR-CIMS calc for
C17H21O6 [M–C2H3O2]+ 321.1338, found 321.1271.
1
hexane–EtOAc); H NMR (400 MHz, CDCl3): δH 7.52 (d, 2H,
J 7.6 Hz), 6.80 (d, 2H, J 8.0 Hz), 5.66 (br s, 1H), 5.42 (d, 1H,
J 12.4 Hz), 5.34 (s, 1H), 4.16 (t, 1H, J 6.4 Hz), 4.06–3.96 (m,
2H), 2.21 (br t, 1H, J 12.0 Hz), 2.11 (s, 3H), 2.05 (dd, 1H, J 9.8,
5.0 Hz), 1.98 (s, 3H), 1.89 (s, 3H); 13C NMR (75 MHz, CDCl3):
δC 170.2, 170.1, 169.9, 156.0, 138.2, 118.7, 95.8, 84.9, 67.6,
66.2, 65.7, 61.9, 30.0, 20.8, 20.6, 20.5; IR νmax/cm−1 2955,
1744, 1483, 1369, 1221, 1114, 1021, 820, 731; HR-CIMS calc
for C16H18IO6 [M–C2H3O2]+ 433.0148, found 433.0251.
Synthesis of symmetrical glucoside bolaform 10
Tri-O-acetyl-D-glucal (400 mg, 1.470 mmol) was stirred in DCM
(5 mL) with the diol (0.5 equivalents, 0.735 mmol) and Al
(OTf)3 (5 mol%, 17 mg) at room temperature. After completion
of the reaction as traced by TLC (2 h), the reaction was quenched
by adding concentrated sodium bicarbonate (4 mL) solution and
the mixture extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were dried over anhydrous magnesium sulfate.
The volatile component was removed under vacuum leaving the
crude product that was subjected to column chromatography on
flash silica for purification, using neat ethyl acetate as eluent.
The pure product was obtained in a yield of 87% (444 mg).
Found C, 56.2; H, 6.2%. C24H30O12 requires C, 56.5;
H, 5.9%; Mp: 90–92 °C; Rf = 0.67 (ethyl acetate); 1H NMR
(300 MHz, CDCl3): δH 5.83 (d, 2H, J 10.4 Hz), 5.77 (dt, 2H,
J 10.2, 2.4 Hz), 5.29–5.22 (m, 2H), 5.14 (s, 2H), 4.36–3.96
(m, 10H), 2.03 (d, 12H, J 4.5 Hz); 13C NMR (75 MHz, CDCl3):
δC 170.6, 170.1, 129.6, 127.1, 92.5, 81.9, 67.0, 65.0, 62.6, 55.1,
20.8, 20.6; IR νmax/cm−1 2923, 1727, 1374, 1230, 1187, 1031,
957; MS: No useful peaks were identified from the CIMS
O-Galactoside 8d. Glycosidation of 3,4,6-tri-O-acetyl-D-galac-
tal (200 mg, 0.735 mmol) with 2-iodophenol (194 mg, 1.2
equivalents, 0.882 mmol) and Al(OTf)3 (20 mol%, 69 mg) in
DCM (2.0 mL) at 0 °C for 7 hours afforded glycoside 8d as an
inseparable α/β (>19 : 1) mixture in a combined yield of 239 mg
(66%) as a cream solid. Found C, 43.9; H, 4.4%. C18H21IO8
requires C, 43.9; H, 4.3%; Mp 80–82 °C; Rf = 0.44 (3 : 1,
1
hexane–EtOAc); H NMR (400 MHz, CDCl3): δH 7.70 (d, 1H,
J 8.0 Hz), 7.20 (t, 1H, J 7.6 Hz), 7.03 (d, 1H, J 8.4 Hz), 6.71
(t, 1H, J 7.6 Hz), 5.70 (br s, 1H), 5.55–5.50 (m, 1H), 5.37 (br s,
1H), 4.18 (t, 1H, J 6.6 Hz), 3.99 (d, 2H, J 6.6 Hz), 2.24–2.14
(m, 2H), 2.08 (s, 3H), 1.95 (s, 3H), 1.85 (s, 3H); 13C NMR
(75 MHz, CDCl3): δC 170.2, 170.0, 169.8, 154.8, 139.3, 129.2,
124.1, 115.3, 96.4, 87.5, 68.0, 66.3, 65.9, 61.9, 30.0, 20.7, 20.6,
20.5; IR νmax/cm−1 2963, 1730, 1472, 1224, 1197, 1018, 799;
HR-CIMS calc for C16H18IO6 [M–C2H3O2]+ 433.0148, found
433.0060.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5636–5642 | 5641

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11 D. B. G. Williams and M. Lawton, Org. Biomol. Chem., 2005, 3, 3269–
3272; D. B. G. Williams and M. Lawton, Green Chem., 2008, 10, 914–
917.
12 D. B. G. Williams, M. S. Sibiya and P. S. van Heerden, Fuel Process.
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Catal. A: Chem., 2010, 317, 68–71; D. B. G. Williams, M. Shaw,
C. W. Holzapfel and M. J. Green, Angew. Chem., Int. Ed., 2008, 47, 560–
563.
spectrum. However,
observed at HR-CIMS calc for C10H13O5 213.0763, found
213.0750.
a carbohydrate-derived fragment was
Acknowledgements
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We thank the University of Johannesburg for financial support.
We also thank Ms Megan Shaw of the UJ Analytical Facility for
NMR and MS data and Dr Bernard Owaga of the UJ Department
of Chemistry for X-ray data and structures.
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