Tuneable regioselectivity during the mono-etherification of the 2,3-diol of a mannose derivative This paper is dedicated to the memory of the late Dr. John M. Webber, distinguished carbohydrate chemist and founding editor of Carbohydrate Research

Article abstract of DOI:10.1016/j.carres.2014.02.016

The paper reports selective mono-etherification of the 2-, and 3-hydroxyl groups of methyl 4,6-O-isopropylidene-α-d-mannopyranoside using tin(II) chloride catalysed reactions of diaryldiazomethanes. By the use of different diazo compounds and the variatio

Full text of DOI:10.1016/j.carres.2014.02.016

Carbohydrate Research 388 (2014) 37–43
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Tuneable regioselectivity during the mono-etherification
of the 2,3-diol of a mannose derivative
a
b
Sigthor Petursson a, , Sean M. Scully , Sigridur Jonsdottir
⇑
a Faculty of Natural Resourse Sciences, University of Akureyri, 600 Akureyri, Iceland
b Science Institute, University of Iceland, Dunhagi 3, 107 Reykjavík, Iceland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2014
Received in revised form 9 February 2014
Accepted 10 February 2014
Available online 20 February 2014
The paper reports selective mono-etherification of the 2-, and 3-hydroxyl groups of methyl 4,6-O-isopro-
pylidene- -mannopyranoside using tin(II) chloride catalysed reactions of diaryldiazomethanes. By the
use of different diazo compounds and the variation of the tin(II) chloride concentration the ether forma-
tion can be shifted from over 90% 3-selectivity to over 90% 2-selectivity.
Ó 2014 Elsevier Ltd. All rights reserved.
a
-D
This paper is dedicated to the memory of the
late Dr. John M. Webber, distinguished
carbohydrate chemist and founding editor
of Carbohydrate Research
Keywords:
Protection
Diol
Catalysis
Tin(II) chloride
Regioselectivity
1. Introduction
These compounds contain a cis 2-axial-3-equatorial diol, whereas
the equivalent gluco compounds are trans eq–eq. Preferential reac-
Many synthetic operations, both in oligosaccharide and general
synthetic chemistry, require the selective protection of hydroxyl
groups. This is particularly true for carbohydrate chemistry and
general synthetic chemistry which uses carbohydrates and related
compounds as chiral starting materials. Traditional acetel/ketal
groups can give effective protection of hexoses and other monosac-
charides, leaving from one to three free hydroxyl groups. These
unprotected sites are then available for manipulations.1,2
Compounds that are examples of this are the well-known 1,2:5,
tion of the sterically more accessible equatorial 3-OH for the manno
compound is generally observed, although this varies greatly with
reaction conditions. Thus, alkylations done under strongly basic
conditions may prefer the more acidic 2-OH. The difference in reac-
tivity is generally not so great as to be useful for either isomer on a
preparative scale.4 Very good regioselectivities of vicinal diols have,
however, been achieved by forming stannylene acetals of these
diols followed by alkylations or acylations.5–8 Aritomi and Kawasa-
ki’s results during methylations of C- and O glycosides, that tin(II)
chloride catalysed methylations with diazomethane gave a 3-OH
methylation on the glucose moiety as well as a reaction of a pheno-
lic OH present in the aglycone were of great interest. Other workers
expanded this to include the use of tin(II) chloride to catalyse the
reactions of aryl- or diaryldiazomethanes resulting in considerable
regioselectivety.9–16 The diaryldiazomethane methodology has the
advantage over the stannylene acetal method that it is direct and
does not require the separate step for the formation of the cyclic
stannylene acetal.
6-di-O-isopropyliden- -glucofuranose or diacetoneglucose and
a-D
1,2-O-isopropyliden- -D-glucofuranose or monocetoneglucose.
a
Another well-established protection strategy starts from the easily
available simple glycosides, methyl glycosides most commonly,
followed by the 4,6-protection as an acetal or a ketal. This leaves
the 2- and 3-hydroxyl groups free. Much work has been aimed at
the selective protection of either of those two groups.3 Interesting
examples of this system are the methyl 4,6-O-benzylidene-a-D-
mannopyranoside and the corresponding 4,6-O-isopropylidene.
Tin(II) chloride catalysed reactions of diaryldiazomethanes with
methyl 4,6-O-benzylidene-
vicinal 2-axial-3-equatorial diol gave almost exclusively 3-ether.
a-D-mannopyranoside containing a cis
⇑
Corresponding author. Tel.: +354 4627316, mobile: +354 8987316.
E-mail addresses: sigthor@unak.is, sigthorp@simnet.is (S. Petursson).
http://dx.doi.org/10.1016/j.carres.2014.02.016
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

38
S. Petursson et al. / Carbohydrate Research 388 (2014) 37–43
are summarized in Table 1 and, although isomers were not com-
Ph
Ph
O
O
pletely resolved, the results show a clear trend from a 3-O-selectiv-
ity in the case of diazo[bis(4-methoxyphenyl)]methane to an
overriding 2-O-selectivity for diazofluorene.19
O
O
OH
O
HO
O
HO
These reactions in the non-protic 1,2-dimethoxyethane solvent
are different from the stannous chloride catalysed reactions of
diazomethane with polyols in methanol which Shugar and
co-workers claim to happen via the formation of 2-stanna-1,3-
dioxolane involving the reaction of the methanol solvent with tin
chloride.18,20 Toman and collaborators have published a series of
papers on tin(II) chloride catalysis of reactions of diazomethane
and alkyl halides with polyols.21–24 Their diazomethane reactions
are also performed in methanol but the results are clearly consis-
tent with cyclic complex formation involving the diol and tin chlo-
ride.25 Anhydrous tin chloride is known to exist as a polymer chain
where the tin atoms are linked through chlorine atoms by a cova-
lent and a co-ordinate bond. With a donor solvent like methanol or
1,2-dimethoxyethane, used in the present work, the chain is
dismantled forming co-ordinate bonds to the solvent.25,26 For
1,2-dimethoxyethane as a solvent this could happen as illustrated
in Figure 2.
Based on these observations and on general chemical principles
a partial mechanism was proposed for the tin(II) chloride catalysed
reactions of diaryldiazomethanes with diols. This is reproduced
with minor modifications in Figure 3 with additional steps show-
ing how an ether could be formed on one of the hydroxyl groups.27
Tin(II) chloride dihydrate, which is normally formulated as SnCl2.
2H2O has been shown to be [SnCl2(H2O)]ÁH2O containing the pyra-
midal SnCl2(H2O) structure (SnACl, 259, Sn-AO, 216 pm; mean
bond angle 85°) and a separate more loosely bound H2O mole-
cule.28 A pyramidal structure such as 1 in Figure 3 must therefore
be considered possible on mixing the tin(II) chloride with a diol in
a non-protic solvent. Here a co-ordinate bond formed by a hydroxyl
group’s lone pair has replaced the ether co-ordinate bond.29
OH
OCH3
OCH3
Methyl 4,6-O-benzylidene-
Methyl 4,6-O-benzylidene-
α-D-mannopyranoside
α-D-glucopyranoside
Figure 1. Methyl 4,6-O-benzylidene-a-D-mannopyranoside and the gluco equiva-
lent contain vicinal diol systems, ax–eq and eq–eq respectively.
This was explained by the greater steric accessibility of the equato-
rial OH (Fig. 1).17
The dihedral angle between the 2-CAO and the 3-CAO bonds is
60° for both mannopyranose and glucopyranose. It was therefore
expected that the tin(II) chloride would catalyse reactions of the
diazo compounds with methyl 4,6-O-benzylidene-a-D-glucopyran-
oside in a similar manner. Initially, this seemed not to be the case,
but it was later found that the catalytic system was unstable at rel-
atively high reagent concentrations with the eq–eq diol of the gluco
compound. Tin(II) chloride catalysed reactions of dia-
zodiphenylmethane with methyl 4,6-O-benzylidene-a-D-glucopy-
ranoside at lower concentration were later performed and both
the 2- and the 3-ether isolated in a ratio of 2:7 in about 90% overall
yield.18
The 4,6-isopropylidene protection in combination with the dia-
zodiarylmethyl ether protection is of interest since the isopropyli-
dene is stable to hydrogenolysis, whereas both the diphenylmethyl
ether and the 4,6-O-benzylidene groups can be removed with
hydrogenolysis over palladium catalyst. It was therefore decided
to repeat the benzhydrylation reactions on methyl 4,6-O-isopro-
pylidene-a-D-mannopyranoside. The results from these reactions
Table 1
Results from the etherification of methyl 4,6-O-isopropylidene-a-D-mannopyranoside with diaryldiazomethanes/SnCl2
3-Ether (%)
Unresolved (%)
2-Ether (%)
Total yield (%)
(p-CH3OC6H4)2CN2
(p-CH3C6H4)2CN2
(p-ClC6H4)2CN2
(C6H5)2CN2
61
60
40
39
—
—
8
42
38
61
92
94
97
24
12
20
N2
5
13
70
88
Me
O
Sn
Cl
O
Cl
MeO
OMe
Sn
Cl
Sn
Me
Sn
Cl
Cl
Me
O
Cl
Cl
O
Sn
Cl
Cl
Me
Figure 2. Depolymerisation of SnCl2 chains by donor solvent.

S. Petursson et al. / Carbohydrate Research 388 (2014) 37–43
39
R
R
R
R'
R'
O
R
R
H
R
O
O
O
C
H
H
R
O
H
H
C
C
R
R
N
N
R'
N
N
O
R'
H
H
Sn
Sn
R
O
Cl
Cl
O
+ N2 + SnCl2
4
Cl
Cl
H
Distorted tetrahedral complex
Cl
Sn
(trigonal bipyramidal arrangement)
Cl
H
R
R
1
R
C
N
N
R
+
R'
C
N
N
3
R
O
O
H
Sn
Cl
Cl
O
Cl
Sn
Cl
H
H
2
O
5
R
R'
Square pyramidal complex
Lone electron pairs on oxygen are not shown
(octahedral arrangement)
Figure 3. Suggested partial mechanism for the tin(II) chloride catalysed reaction.
It is proposed that a diol would be more likely to form a sec-
ond coordinate bond to the tin atom than another H2O, which
does not happen in the case of [SnCl2(H2O)]ÁH2O. If that were
to happen the distorted tetrahedral structure 2 in Figure 3 would
be formed, with the lone pair on tin in the equatorial position.
The diazo compound’s terminal nitrogen is a powerful ligand.30
Complex formation of this ligand with 1 or 2 gives complexes
4 and 5. The free OH in complex 4 is well positioned to react
with the diazo carbon giving an ether with release of molecular
nitrogen happening before or concurrently. Since the 4,6-O-beny-
lidene gives an overwhelming 3-selectivity the 2-OH must be the
hydroxyl group, which complexes first with the tin(II) chloride
leaving the 3-OH to react with the diazo carbon in 4. This could
explain the almost exclusive 3-O-regioselectity in reactions with
were very different, giving a much higher 3-selectivity than ob-
served previously. A plausible explanation for this seemed to be
that the lower reaction rate observed earlier was due to a deterio-
rated sample of the catalyst and only a fraction of the material
added was in fact tin(II) chloride. To test this hypothesis experi-
ments were therefore conducted to ascertain whether lowering
of the catalyst concentration resulted in a shift from high 3-OH
selectivity to a significant or even overwhelming 2-OH reaction.
The diazo compounds selected for this investigation were
diazo[bis(4-methylphenyl)]methane, diazo[bis(4-chlorophenyl)]
methane, diazodiphenylmethane, and diazofluorene. Experiments
were conducted for each diazo compound using at least two differ-
ent catalyst concentrations, 1.7 mM SnCl2 (3.4 molar %) and 1/10 of
this amount or 0.17 mM SnCl2 (0.34 molar %). Up to four different
catalyst concentrations were used. The results are shown in Table 2
and Figure 4. For convenience this series of reactions were done on
a 0.5 millimolar scale, but the scaling up of these reactions to mul-
tigram amounts is easily done as was demonstrated in our original
work.17,19
The results in Table 2 and Figure 4 show clearly a shift from
3-selectivity to 2-selectivity for this series of diazo compounds.
This shift has been observed before and seems to follow the reac-
tivity of the diazo compounds, that is to say that the most reactive,
diazo[bis(4-methylphenyl)]methane, goes overwhelmingly for the
3-OH and the least reactive, diazofluorene, reacts preferentially
with the 2-OH. Diazo[bis(4-chlorophenyl)]methane and diazo-
methane are intermediate in reactivity and also in selectivity.
The 3-selectivity is rather higher for the dichloro compound even
if its rate of reaction is only about a quarter of that for the parent
diazodiphenylmethane pointing to a non-electronic component
affecting selectivity as well. More interestingly and in accordance
with the hypothesis, the results show a shift towards increased
2-selectivity on reduction of the tin(II) chloride concentration from
1.7 mM to 0.042 mM. This happens for all the diazo compounds.
This agrees with the earlier proposed mechanism that is, with
lower tin(II) chloride concentration the intramolecular shift from
1 to 2 in Figure 3 is expected to be relatively more likely to happen
before the complexation with the diazo compound.
methyl 4,6-O-benzylidene-a-D-mannopyranoside. The formation
of the square pyramidal complex 5 seems more likely to give a
reaction of either hydroxyl group and a trend towards the more
acidic hydroxyl group as the acid stability of the diazo com-
pound increases would also result since increased reactivity with
the diazo carbon by the more acidic OH results. This could
explain what is happening during the reactions of the five diazo
compounds with methyl 4,6-O-isopropylidene-a-D-mannopyran-
oside. It seems reasonable to assume that the two mannose
derivatives could show different ligand arrangements around
the divalent tin but firm evidence showing that only the
4,6-O-isopropylidene forms the square pyramidal complex is
not available.
2. Results and discussion
Following recent use of tin(II) bromide, instead of the chloride,
as a catalyst in mono-etherification of diols a re-examination of
some of these reactions has been undertaken.31 It was observed
that the tin(II) chloride catalyst used during this work was an order
of magnitude more active than the sample used in the original
study as observed by shorter reaction times.17 More importantly,
the relative amounts of the 3- and the 2-ethers formed from reac-
tions with methyl 4,6-O-isopropylidene-a-D-mannopyranoside

40
S. Petursson et al. / Carbohydrate Research 388 (2014) 37–43
Table 2
Yields and 3-ether/2-ether ratios from reactions of selected diazo compounds with methyl 4,6-O-isopropylidene-a-D-mannopyranoside using different concentrations of the
tin(II) chloride catalyst
Diazo compound
[SnCl2] = 1.7 mM
3-Ether (%)
[SnCl2] = 0.85 mM
3-Ether (%)
[SnCl2] = 0.17 mM
3-Ether (%)
[SnCl2] = 0.085 mM
3-Ether (%) 2-Ether (%)
2-Ether (%)
1.9
2-Ether (%)
48
2-Ether (%)
24
(p-CH3C6H4)2CN2
Total yield (%)
(p-ClC6H4)2CN2
Total yield (%)
(C6H5)2CN2
98
87
81
62
72
86
76
60
40
62
28
76
19
28
52
60
72
53
Total yield (%)
N2
40
60
14
86
10
90
6.0
94
Total yield (%)
75
85
91
84
diazofluorene, and a low catalyst concentration (0.084 mM) re-
sulted in a similar over-all yield of 87% but with a 6.0% 3-selectivity
and 94% 2-selectivity. Investigation of other similar systems awaits
future research.
4. Experimental section
The reactions of the diazo compounds with methyl 4,6-O-iso-
propylidene-a-D-mannopyranoside were done on a half millimolar
scale in dry 1,2-dimethoxyethane (10 mL). The products were
identified by proton and carbon-13 NMR by comparison with pre-
viously characterized compounds.15 Compounds were separated
on columns of silica gel and weight. Where separations were not
complete, amounts of 2- and 3-ethers in overlapping fractions
were estimated by NMR integration of suitable peaks, usually the
Ar2-CHO– or the isopropylidene methyl peaks or from HPLC peak
integrations.
4.1. General methods
Thin layer chromatography (TLC) was carried out on aluminium
sheets coated with silica gel 60-F254 and detected using a spray of
0.2% w/v cerium(IV) sulphate and 5% ammonium molybdate in 2 M
sulphuric acid with heating. 1H and 13C NMR spectra were run at
298 K on a Bruker AV400 instrument with Me4Si as the external
standard. Diaryldiazomethanes were prepared using published
methods.32 General reagents and the catalyst were from chemical
suppliers and usually used without further purification. 1,2-Dime-
thoxyethane was distilled from and stored over sodium. Ethyl ace-
tate and hexane were of HPLC grade and used as received. The
HPLC instrument was Shimadzu Prominence with a reversed phase
150 Â 4.6 mm SS Wakosil C18RS 3 mm column. The elution was
isocratic with methanol/water 4:1 and detection was done with a
UV detector at 254 nm.
Figure 4. The relative yields of the 3- and the 2-ethers from the etherification
reactions of methyl 4,6-O-isopropylidene- -mannopyranoside with diazo[bis(4-
methylphenyl)]methane (1), diazo[bis(4-chlorophenyl)]methane (2), diazomethane
a-D
(3) and diazofluorene (4) for varying concentrations of the SnCl2 catalyst.
4.2. Reaction of diazo[bis(4-methylphenyl)]methane with
methyl 4,6-O-isopropylidene-a-D-mannopyranoside
3. Conclusions
([SnCl2] = 1.7 mM)
In conclusion it can be stated that these results as a whole in
terms of regioselective 2-OH/3-OH protection using the two
variables, that is the different diazo compounds and secondly the
varying catalyst concentrations that the methodology represents
a tuneable regioselectivity for the methyl 4,6-O-isopropylidene-
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME)/
1.7 mM SnCl2, 10 mL. The reaction mixture was cooled on an ice
bath and diazo[bis(4-methylphenyl)]methane, 167 mg, 0.750 mmol,
and the reaction allowed to go to completion in 45 min. The
solvent was evaporated to dryness and the products purified
on a column of silica gel eluting with hexane/ethyl acetate
9:1, 4:1 and finally 3:2. Methyl 4,6-O-isopropylidene-2-O-[di(4-
a-D-mannopyranoside system. Thus diazo[bis(4-methylphenyl)]
methane with high concentration of catalyst (1.7 mM) gives 98%
selectivity for the 3-OH. The most reactive diazo compound,
diazo[bis(4-methoxyphenyl)]methane, was not included in this
series, but earlier reactions for this compound gave no
2-ether.15 Alternatively using the least reactive diazo compound,
methylphenyl)methyl]-a-D-mannopyranoside, 3.6 mg (H1-NMR:
SP291012A), was isolated from the early fractions followed by an

S. Petursson et al. / Carbohydrate Research 388 (2014) 37–43
41
unresolved mixture of the 2- and 3-ether, 80.8 mg (SP291012B; the
faster 2-ether was in an insignificant amount according to NMR),
and finally methyl 4,6-O-isopropylidene-3-O-[di(4-methylphenyl)
giving a total yield of 86%. NMR showed fractions 30–32 to repre-
sent a 62% yield of the 3-ether and 8% yield of the 2-ether, based on
the Ph2CH– integration. The 3-ether/2-ether ratio is therefore
72%:28%.
methyl]-a-D-mannopyranoside, 101.1 mg (SP291012D). The total
yield was 186 mg, 86.6%. The 3-ether/2-ether ratio is 98:2.0.
4.5. Reaction of diazodiphenylmethane with methyl 4,6-O-
4.3. Reaction of diazo[bis(4-methylphenyl)]methane with
isopropylidene-a-D-mannopyranoside ([SnCl2] = 0.17 M)
methyl 4,6-O-isopropylidene-a-D-mannopyranoside
([SnCl2] = 0.17 mM)
Tin(II) chloride solution: The tin(II) chloride solution was pre-
pared by dissolving 3.2 mg, 0.017 mmol, of tin(II) chloride in
10 mL of 1,2-dimethoxyethane (DME); a 10Â dilution was pre-
pared by diluting 1.0 mL to a total volume of 10 mL.
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME)/
0.17 mMSnCl2, 10 mL. The reaction mixturewascooled on an ice bath
and diazo[bis(4-methylphenyl)]methane, 167 mg, 0.750 mmol, and
the reaction allowed to go to completion in 75 min. The solvent was
evaporated to dryness and the products were purified on a column
of silica gel eluting with hexane/ethyl acetate 9:1, 4:1 and finally
3:2. Methyl 4,6-O-isopropylidene-2-O-[di(4-methylphenyl)methyl]-
a-D-mannopyranoside, 23.8 mg (SP291012A), was isolated from
the early fractions followed by an unresolved mixture of the
2- and 3-ether, 33.4 mg (SP291012C), and finally methyl 4,6-O-iso-
propylidene-3-O-[di(4-methylphenyl)methyl]-a-D-mannopyran-
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in DME, 9 mL and 1.0 mL of the tin(II)
chloride solution, 0.32 mg, 0.0017 mmol, was added followed by
diazodiphenylmethane, 145 mg, 0.750 mmol. After 4.5 h reaction
time the solution had a pink colour showing that it was close to
completion. The reaction was allowed to go to completion over-
night. Some dry silica gel was added and the solvent evaporated
to dryness and the products purified on a column of silica gel elut-
ing with hexane/ethyl acetate 9:1 to 3:2. Fractions 12–13 con-
tained the major component, methyl 2-O-diphenylmethyl-4,6-O-
oside, 69.3 mg (SP291012D). The total yield was 127 mg, 59.0%.
NMR analysis gave a 3-ether/2-ether ratio 76:24.
isopropylidene-
Fractions 14–17 contained the minor component, methyl 3-O-
diphenylmethyl-4,6-O-isopropylidene- -mannopyranoside and
a-D-mannopyranoside, 110 mg, 55% (SP030812B).
Methyl 4,6-O-isopropylidene-2-O-[di(4-methylphenyl)methyl]-
a-D
a
-
D
-mannopyranoside:
a trace of the minor component, 42 mg, 21%, giving a total yield
of 76%. The 3-ether/2-ether ratio is therefore 28%:72%.
1H NMR (CDCl3): d 1.37 & 1.48 (2 Â 3H s, C(CH3)2), 2.02 (1H s, –
OH), 2.25 & 2.26 (2 Â 3H s, 2xAr-CH3), 3.17 (3H, s, –OCH3), 3.50
(1H m, H-6A), 3.78 (4H m, H-2, H-3, H-5 & H-6B), 3.93 (1 H,
t(apparent), JH4–H3 & H4–H5 9.4 Hz, H-4), 4.49 (1H s, H-1), 5.46 (1H
s, Ar2-CH), 7.05–7.18 (8 H, m, aromatic protons). 13C NMR (CDCl3):
d 19.35 & 29.27 (C(CH3)2), 20.96 (2xAr2-CH3), 54.83 (–OCH3), 62.44
(C-6), 64.03 (C-2), 69.22 (C-5), 72.32 (C-4), 72.42 (C-3) 84.20 (C-1),
99.80 (Ar2-CHO–), 100.0 (C(CH3)2), 127.2, 129.1, 129.3, 137.4,
137.6, 138.8, 139.0 (aromatic C).
Methyl 4,6-O-isopropylidene-2-O-diphenylmethyl-a-D-manno-
pyranoside:
1H NMR (CDCl3): d 1.50 & 1.62 (2 Â 3H s, C(CH3)2), 2.25 (1H d,
JOH–H3 6.9 Hz, –OH), 3.29 (3H,s, –OCH3), 3.65 (1H m, H-6A), 3.94
(4H m, H-2, H-3, H-5 & H-6B), 4.09 (1H, t(apparent), JH4–H3 & H4–
9.5 Hz, H-4), 4.61 (1H s, H-1), 5.71 (1H s, Ph2-CH), 7.31–7.438
H5
(10H, m, aromatic protons). 13C NMR (CDCl3): d 19.38 & 29.36
(C(CH3)2), 54.92 (–OCH3), 62.45(C-6), 64.33 (C-2), 69.34 (C-5),
72.29 (C-4), 77.46 (C-3) 84.49 (C-1), 99.97 (C(CH3)2), 100.0 (Ph2-
CHO–), 127.2–128.5 & 141.7 (aromatic C).
Methyl 4,6-O-isopropylidene-3-O-[di(4-methylphenyl)methyl]-
a-D-mannopyranoside:
1H NMR (CDCl3): d 1.49 & 1.55 (2 Â 3H s, C(CH3)2), 2.37 & 2.39
Methyl 4,6-O-isopropylidene-3-O-diphenylmethyl-a-D-manno-
(2 Â 3H s, 2 Â Ar-CH3), 2.76 (1H s, –OH), 3.39 (3H, s, –OCH3), 3.64
(1H m, H-6A), 3.83 (1H dd, JH3–H2 3.53 Hz, JH3–H4 9.4 Hz, H-3), 3.89
(1H, m, H-5 & H-6B), 3.98 (1H dd, JH2–H1 1.26 Hz, JH2–H3 3.54 Hz, H-
2), 4.20 (1H t(apparent), JH4–H3 & JH4–H5 9.58 Hz, H-4), 4.74 (1H d,
JH1–H2 1.26 Hz, H1), 5.34 (1H s, Ar2-CH), 7.14–7.30 (8H, m, aromatic
protons). 13C NMR (CDCl3): d 19.57 & 29.40 (C(CH3)2), 21.22
(2 Â Ar2-CH3), 54.81 (–OCH3), 62.54 (C-6), 64.06 (C-2), 70.32 (C-
5), 71.68 (C-4), 74.49 (C-3), 82.88 (C-1), 99.68 (C(CH3)2), 101.0
(Ar2-C HO–) 127.2, 129.1, 129.3, 137.4, 137.6, 138.8, 139.0 (aro-
matic C).
pyranoside:
1H NMR (CDCl3): d 1.35 & 1.48 (2 Â 3H s, C(CH3)2), 2.62 (1H s,
–OH), 3.24 (3H,s, –OCH3), 3.51 (1H m, H-6A), 3.71–3.79 (3H m,
H-3, H-5 & H-6B), 3.87 (1H d, JH2–H3, 2.65 Hz, H-2), 4.07 (1H,
t(apparent), JH4–H3
9.6 Hz, H-4), 4.62 (1H d, JH1–H2 1.0 Hz,
&
H4–H5
H-1), 5.74 (1H s, Ph2-CH), 7.16–7.27 (10H, m, aromatic protons).
13C NMR (CDCl3): d 19.27 & 29.39 (C(CH3)2), 54.83 (–OCH3),
62.52 (C-6), 64.04 (C-2), 70.39 (C-4), 71.44 (C-5), 74.94 (C-3)
83.24 (C-1), 99.69 (C(CH3)2), 101.0 (Ph2CHO–), 127.2–128.7 &
142.1, 142.4 (aromatic C).
4.4. Reaction of diazodiphenylmethane with methyl 4,6-O-
4.6. Reaction of diazo[bis(4-chlorophenyl)]methane with
isopropylidene-
a
-D
-mannopyranoside ([SnCl2] = 1.7 M)
methyl 4,6-O-isopropylidene-a-D-mannopyranoside
([SnCl2] = 1.7 mM)
Methyl 4,6-O-isopropylidene-
a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME),
10 mL, and tin(II) chloride, 3.2 mg, 0.017 mmol, was added fol-
lowed by diazodiphenylmethane, 145 mg, 0.750 mmol. After 1 h
reaction time the solution had a faint pink colour showing that it
has gone virtually to completion. After complete disappearance
of the pink colour some dry silica gel was added and the solvent
evaporated to dryness and the products purified on a column of sil-
ica gel eluting with hexane/ethyl acetate 9:1, 4:1 and finally 3:2.
Fractions 27–29 contained the minor component, methyl 2-O-
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME), 10 mL,
and tin(II) chloride, 3.2 mg, 0.017 mmol, was added followed by
diazo[bis(4-chlorophenyl)]methane, 144 mg, 0.547 mmol. The reac-
tion had gone to completion in less than 2 h. Some dry silica gel was
added and the solvent evaporated to dryness and the products
purified on a column of silica gel eluting with hexane/ethyl acetate
4:1–3:2. Fractions 13–14 contained the minor component, methyl
2-O-[di(4-chlorophenyl)methyl]-4,6-O-isopropylidene-a-D-man-
diphenylmethyl-4,6-O-isopropylidene-
33 mg, 16% (SP030812B). Fractions 30–32 contained the major
component, methyl 3-O-diphenylmethyl-4,6-O-isopropylidene-
-mannopyranoside and some minor component, 141 mg, 70%,
a
-
D
-mannopyranoside,
nopyranoside, 28 mg, 12%. Found: 491.1017 g/mol; C23H26Cl2O6Á
Na+ requires 491.0999 g/mol. Fractions 15–18 contained the major
component, methyl 3-O-[di(4-chlorophenyl)methyl]-4,6-O-isopro-
a
-
D
pylidene-a-D-mannopyranoside, 120 mg, 50% (SP030812C), giving

42
S. Petursson et al. / Carbohydrate Research 388 (2014) 37–43
a total yield of 62%. Found: 491.0992 g/mol; C23H26Cl2O6ÁNa+
3.47 JH3–H4 9.20 Hz, H-3), 3.84–3.90 (2H m, H-5 & H-6B), 3.97 (1H,
d(apparent), JH2–H3 3.31 Hz, H-2), 4.19 (1H, t(apparent),
requires 491.0999 g/mol. The 3-ether/2-ether ratio is 81:19.
JH4–H3
9.6 Hz, H-4), 4.74 (1H s, H-1), 5.80 (1H s, Ar2-CH),
&
H4–H5
7.27–7.68 (8H, m, aromatic protons). 13C NMR (CDCl3): d 18.92 &
29.329 (C(CH3)2), 54.87 (–OCH3), 62.44 (C-6), 64.01 (C-2), 70.17
(C-4), 71.54 (C-5), 75.08 (C-3), 81.93 (C-1), 99.78 (C(CH3)2), 100.92
(Ar2CHO–), 128.7–128.9 (Ar C2/6 & C3/5), 133.5, 133.8 (Ar C4),
140.0, 140.4 (Ar C1).
4.7. Reaction of diazo[bis(4-chlorophenyl)]methane with
methyl 4,6-O-isopropylidene-a-D-mannopyranoside
([SnCl2] = 0.85 mM)
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME), 10 mL,
and tin(II) chloride, 1.6 mg, 0.0085 mmol, was added followed by
diazo[bis(4-chlorophenyl)]methane, 196 mg, 0.745 mmol, and the
reaction was allowed to go to completion overnight. Some dry silica
gel was added and the solvent evaporated to dryness and the prod-
ucts purified on a column of silica gel eluting with hexane/ethyl
acetate 9:1, then 4:1 and finally 3:1. Fractions 13–17 contained
the minor component, methyl 2-O-[di(4-chlorophenyl)methyl]-
4.9. Reaction of diazofluorene with methyl 4,6-O-
isopropylidene-
a-
D-mannopyranoside ([SnCl2] = 1.7 mM)
Methyl 4,6-O-isopropylidene-
a
-D
-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME),
10 mL, and tin(II) chloride, 3.2 mg, 0.017 mmol, was added fol-
lowed by diazofluorene, 144 mg, 0.750 mmol. The reaction was left
to go to completion overnight and then the products were sepa-
rated on a column of silica gel eluting with hexane/ethyl acetate
9:1 to 7:3. Methyl 2-O-(9H-fluoren-9-yl)-4,6-O-isopropylidene-
4,6-O-isopropylidene-
(SP291112A-2). Fractions 18-21 contained the major component,
methyl 3-O-[di(4-chlorophenyl)methyl]-4,6-O-isopropylidene-
a-D-mannopyranoside,
54 mg
contamin
a-D-
a
-
D
-mannopyranoside was isolated from fractions 14–15, 72 mg,
36% (SP170812A_H1) and fractions 16–19 contained methyl 3-O-
(9H-fluoren-9-yl)-4,6-O-isopropylidene- -mannopyranoside and
mannopyranoside, and 6% of the minor component as judged by
isopropylidene methyl proton integration, 70 mg (SP291112B-2).
The 2-ether formed is therefore 54 + 4 = 58 mg, 25% and the 3-ether
formed is 70À4 = 66 mg, 28%, giving a total yield of 53%. The
3-ether/2-ether ratio is 52:48.
a-D
some of the 2-ether, 77 mg, 39%. NMR showed fractions 16–19 to
be 30% 3-ether and 9% the 2-ether (SP170812B_H1). This gives a
total yield of 75% and the 2-ether/3/ether ratio as 60:40.
4.8. Reaction of diazo[bis(4-chlorophenyl)]methane with
4.10. Reaction of diazofluorene with methyl 4,6-O-
methyl 4,6-O-isopropylidene-a-D-mannopyranoside
([SnCl2] = 0.17 M)
isopropylidene-
a-
D-mannopyranoside ([SnCl2] = 0.85 mM)
Methyl 4,6-O-isopropylidene-
a
-D
-mannopyranoside, 117 mg,
Tin(II) chloride solution: The tin(II) chloride solution was pre-
pared by dissolving 3.2 mg, 0.017 mmol, of tin(II) chloride in
10 mL of 1,2-dimethoxyethane (DME) and making a 10Â dilution
by diluting 1.0 mL to a total volume of 10 mL.
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME), 10 mL,
and tin(II) chloride, 1.6 mg, 0.0085 mmol, was added followed by
diazofluorene, 144 mg, 0.750 mmol. The reaction was left to go to
completion for two days and then the products were passed
through a column of silica gel eluting with hexane/ethyl acetate
9:1–3:2. The unresolved mixture of methyl 2-O-(9H-fluoren-9-
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
0.500 mmol, was dissolved in DME, 9 mL and 1.0 mL of the tin(II)
chloride solution (0.32 mg, 0.0017 mmol, of tin(II) chloride) was
added followed by diazo[bis(4-chlorophenyl)]methane, 144 mg,
0.550 mmol. The reaction was left to go to completion overnight.
Some dry silica gel was added and the solvent evaporated to dryness
and the products purified on a column of silica gel eluting with
hexane/ethyl acetate 4:1–3:2. Fractions 11–13 contained 95 mg of
mono-ether consisting of 79 mg of the major component,
yl)-4,6-O-isopropylidene-
a-
D-mannopyranoside and methyl 3-O-
(9H-fluoren-9-yl)-4,6-O-isopropylidene-a-D-mannopyranoside was
isolated from fractions 17–26, 170 mg, 85% (SP301112B_2_H1).
NMR (Fl = CH– peak) analysis showed this to be a 2-ether/3-ether
mixture of 86:14.
4.11. Reaction of diazofluorene with methyl 4,6-O-
methyl 2-O-[di(4-chlorophenyl)methyl]-4,6-O-isopropylidene-
-mannopyranoside, and 16 mg of the 3-ether, methyl 3-O-[di
(4-chlorophenyl)methyl]-4,6-O-isopropylidene- -mannopy-
ranoside, as determined by the benzhydryl proton integration
(SP030812D). Fractions 14–15 contained the minor 3-ether,
37 + 16 = 53 mg. Total yield is 132 mg, 62% and the 3-ether/2-ether
ratio is 40:60.
a-
isopropylidene-a-D-mannopyranoside ([SnCl2] = 0.17 mM)
D
a
-D
Tin(II) chloride solution: The tin(II) chloride solution was pre-
pared by dissolving 3.2 mg, 0.017 mmol, of tin(II) chloride in
10 mL of 1,2-dimethoxyethane (DME); a 10Â dilution was pre-
pared by diluting 1.0 mL to a total volume of 10 mL.
Methyl 4,6-O-isopropylidene-a-D-mannopyranoside, 117 mg,
Methyl 4,6-O-isopropylidene-2-O-[di(4-chlorophenyl)methyl]-
0.500 mmol, was dissolved in 1,2-dimethoxyethane (DME), 9.0 mL,
and 1.0 mL of the diluted tin(II) chloride solution, 0.32 mg,
0.00017 mmol, was added followed by diazofluorene, 144 mg,
0.750 mmol. The reaction was left for three days to go to completion
and then the products were passed through a column of silica gel
eluting with hexane/ethyl acetate 9:1–7:3. Methyl 2-O-(9H-fluo-
ren-9-yl)-4,6-O-isopropylidene-a-D-mannopyranoside was isolated
from fractions 22-24, 153 mg, 77% (SP160812A_H1) and fractions
25-27 contained methyl 3-O-(9H-fluoren-9-yl)-4,6-O-isopropyli-
dene-a-D-mannopyranoside and some of the 2-ether, 28 mg
a-D-mannopyranoside:
1H NMR (CDCl3): d 1.36 & 1.47 (2 Â 3H s, C(CH3)2), 2.06 (1H s,
–OH), 3.18 (3H, s, –OCH3), 3.65 (1H m, H-6A), 3.7–3.9 (4H m,
H-2, H-3, H-5 & H-6B), 3.93 (1H, t(apparent), JH4–H3
&
H4–H5
9.6 Hz, H-4), 4.45 (1H d, JH1–H2 1.26 Hz, H-1), 5.57 (1H s, Ar2-CH),
7.15–7.27 (8H, m, aromatic protons). 13C NMR (CDCl3): d 19.14 &
29.29 (C(CH3)2), 54.87 (–OCH3), 62.36 (C-6), 64.34 (C-2), 69.58
(C-5), 71.68 (C-4), 77.34 (C-3), 82.89 (C-1), 100.0 (C(CH3)2), 100.8
(Ar2CHO–), 127.9–139.9 (aromatic C).
Methyl 4,6-O-isopropylidene-3-O-[di(4-chlorophenyl)methyl]-
(SP160812B_H1). NMR (Fl = CH– peak) showed this to be 9% yield
of the 3-ether and 5% yield of the 2-ether, giving a total yield of
the 2-ether as 82% and the combined yield of 91%. The 2-ether/
3-ether ratio is 90:10
a-D-mannopyranoside:
1H NMR (CDCl3): d 1.48 & 1.52 (2 Â 3H s, C(CH3)2), 2.67 (1H s,
–OH), 3.34 (3H, s, –OCH3), 3.62 (1H m, H-6A), 3.80 (1H dd, JH3–H2

S. Petursson et al. / Carbohydrate Research 388 (2014) 37–43
43
4.12. Reaction of diazofluorene with methyl 4,6-O-
isopropylidene- -mannopyranoside ([SnCl2] = 0.085 mM)
References
a
-D
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was added followed by diazofluorene, 144 mg, 0.750 mmol, was
then added. The reaction was left to go to completion over 24 h.
The products were isolated off a column of silica gel, eluting with
hexane/ethyl acetate 9:1–7:3. The early fractions contained pure
methyl 2-O-(9H-fluoren-9-yl)-4,6-O-isopropylidene-a-D-manno-
pyranoside, 161.1 mg, followed by mixed fractions containing
18.5 mg. Reversed phase HPLC analysis (see Supplements) gave
product 2, 3-ether, at 5.670 min, relative integration area:
12,472,228 or 72% and product 1,2-ether, at 7.701 min, relative
integration area: 4,799,611 or 28%. Pure methyl 3-O-(9H-fluoren-
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9-yl)-4,6-O-isopropylidene-a-D-mannopyranoside, 6.9 mg was
then obtained from the later fractions. Found: 421.1639 g/mol; C23-
H26O6ÁNa+ requires 421.1622 g/mol. Total 2-ether produced was
therefore: 161.1 + 13.4 = 174.5 mg and 3-ether: 5.1 + 6.9 = 12 mg,
giving a total yield of mono-ethers as 186.5 mg, 93.6% and a 2-
ether and 3-ether ratio of 94:6.
ˇ
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ˇ
´
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Acknowledgements
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The University of Akureyri Science Fund is thanked for financial
support and the Science Institute, University of Iceland, is thanked
for the provision of spectroscopic facilities.
30. Discussions with Dr. Vernon Box are acknowledged 2010/11.
31. Petursson, S. Tetrahedron: Asymmetry 2009, 20, 887–891.
32. Jackson, G.; Jones, H. F.; Petursson, S.; Webber, J. M. Carbohydr. Res. 1982, 102,
147–157.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.02.
016.