Three Solvent-Free Catalytic Approaches to the Acetal Functionalization of Carbohydrates and Their Applicability to One-Pot Generation of Orthogonally Protected Building Blocks

Article abstract of DOI:10.1002/adsc.201500745

Three alternative protocols were developed to carry out the selective installation of acetal groups on carbohydrates and polyols under mildly acidic, solvent-free conditions. One protocol is based on a diol/aldehyde condensation at room temperature, with an acetolysis process serving for the activation of the carbonyl component. A second approach is based on an orthoester-mediated activation of the carbonyl component at high temperature. The third protocol is instead entailing a transacetalation mechanism. Combination of these methods allows a wide set of acetal-protected building blocks to be accessed in short times under very simple experimental conditions working under air. The scope of the latter two approaches was also extended to unusual one-pot synthetic sequences leading to concomitant Fischer glycosidation/acetal protection of reducing sugars.

Full text of DOI:10.1002/adsc.201500745

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DOI: 10.1002/adsc.201500745
Three Solvent-Free Catalytic Approaches to the Acetal Function-
alization of Carbohydrates and Their Applicability to One-Pot
Generation of Orthogonally Protected Building Blocks
Serena Traboni,a Emiliano Bedini,a Maddalena Giordano,a,b
and Alfonso Iadonisia,*
a
Department of Chemical Sciences, University of Naples Federico II, Via Cinthia 4, I-80126 Naples, Italy
Fax: (+39)-(0)81-674-393; phone: (+39)-(0)81-674-154; e-mail: iadonisi@unina.it
Consiglio Nazionale delle Ricerche, Istituto per i Polimeri, Compositi e Biomateriali, IPCB UOS Mostra d’Oltremare
b
pad. 20, Viale J.F. Kennedy 54, I-80125 Naples, Italy
Received: August 9, 2015; Revised: September 10, 2015; Published online: November 17, 2015
Dedicated to the memory of Prof. Matteo Adinolfi.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500745.
Abstract: Three alternative protocols were devel- anism. Combination of these methods allows a wide
oped to carry out the selective installation of acetal set of acetal-protected building blocks to be accessed
groups on carbohydrates and polyols under mildly in short times under very simple experimental condi-
acidic, solvent-free conditions. One protocol is based tions working under air. The scope of the latter two
on a diol/aldehyde condensation at room tempera- approaches was also extended to unusual one-pot
ture, with an acetolysis process serving for the activa- synthetic sequences leading to concomitant Fischer
tion of the carbonyl component. A second approach glycosidation/acetal protection of reducing sugars.
is based on an orthoester-mediated activation of the
carbonyl component at high temperature. The third Keywords: acetals; benzylidenes; carbohydrates;
protocol is instead entailing a transacetalation mech- polyols; solvent-free reactions
Introduction
HClO4-SiO2, tetrabutylammonium tribromide, FeCl3,
I2, In(OTf)3, Cu(OTf)2 have also been reported.[3,4]
Generation of acetal or ketal functionalities is an Very recently, the feasible use of organic catalysts has
almost ubiquitous step in organic synthesis when been described, too.[5]
polyol substrates, such as carbohydrates, have to be
A more straightforward and atom-economical strat-
chemically manipulated. The reaction allows protec- egy for acetal/ketal synthesis entails an acid-catalyzed
tion of either 1,2- or 1,3-diol motifs, and the selectivi- condensation of the polyol with the requisite alde-
ty is dependent on several factors such as nature of hyde/ketone, but especially demanding experimental
the polyol substrate, nature of the acetalating agent conditions are needed for the removal of water in
and experimental conditions applied.[1] Besides the order to shift the equilibrium towards the desired
broad application in the synthesis of highly function- products, and much slower reactions are generally ob-
alized targets, the usefulness of this reaction is further served than with the transacetalation approaches.[2,6]
demonstrated by the increasing number of examples Collectively, the reported protocols for polyol acetali-
of sugar acetals employed as key building blocks in zation are suffering from one or more practical issues
materials science.[2]
such as the use of sensitive or commercially unavaila-
The acetal/ketal functionalization of polyols is ble promoters, use of sub-stoichiometric or stoichio-
more commonly performed through an acid-catalyzed metric amounts of acidic agents, adoption of strictly
transacetalation process committing the polyol sub- anhydrous conditions with the application of drying
strate and the requisite dimethyl acetal/ketal. For this agents and inert atmosphere, need for an apparatus
purpose, sulfonic acids in polar solvents are routinely aimed at water removal, use of high-boiling solvents,
employed,[1] but a large set of alternative acid cata- application of vacuum conditions, use of ultrasonica-
lysts such as HBF4, NaHSO4-SiO2, H2SO4-SiO2, tion, prolonged reaction times.
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Three Solvent-Free Catalytic Approaches to the Acetal Functionalization
On pursuing our recent interest towards the devel-
In this preliminary screening, Yb(OTf)3,[9]
opment of experimentally simple solvent-free proto- Cu(OTf)2, and triflic acid proved effective at room
cols for the regioselective manipulation of carbohy- temperature within 4 h, with a loading as low as 1%,
drates,[7] an effort was targeted to practical acetalation to afford benzylidene 2 as the main product (Table 1,
approaches employing experimentally simple proce- entries 1, 2 and 4), whereas per-O-acetylation largely
dures in the absence of solvents and under air. Herein prevailed with Bi(OTf)3 (Table 1, entry 3). Interest-
we wish to report three alternative strategies aimed at ingly, a typical acetalation catalyst such as camphor-
the practical acetal functionalization of saccharide sulfonic acid (CSA) led to a much slower reaction
precursors and polyols.
albeit in a high yield (Table 1, entry 5). A remarkable
yield improvement was achieved through the portion-
wise addition of acetic anhydride, that minimized the
undesired competitive acetylation at O-4 and O-6
(compare entries 6 and 7, with entries 1 and 4, respec-
Results and Discussion
Initially, we examined the potential of a sugar/alde- tively). The reaction was instead unproductive when
hyde condensation triggered by the O-acetylation of 1 was added to a premixed mixture of all the other re-
the carbonyl component,[8] a mechanism which would agents. In addition, the reaction was very sluggish also
prevent generation of water as the side product when performed in the absence of acetic anhydride,
(acetic acid should be formed instead). In the first thus evidencing the key role played by this latter re-
trials, the activation under air of a moderate excess of agent.
acetic anhydride (3 equiv.) with a catalytic amount of
This acetalation approach is mechanistically inter-
several acid promoters, in the presence of methyl a- esting because the benzaldehyde carbonyl is appa-
glucopyranoside 1 and a moderate excess of benzalde- rently O-acetylated faster than saccharide carbinols
hyde (3 equiv.), afforded in some cases 4,6-O-benzyli- with most acid catalysts (Table 1).[10] A critical role
dene products in interesting yields (significant exam- for this selectivity might be played by the insolubility
ples in Table 1). Since the 4,6-O-benzylidenation was of the sugar in the liquid medium, as suggested by the
often accompanied by partial and unselective acetyla- yield decrease observed on applying the Yb(OTf)3-
tion of saccharide carbinols, a short per-O-acetylation catalyzed procedure in the benzylidenation of gluco-
step was performed in situ so as to simplify the com- sides less polar than 1 (Table 2, entries 2 and 3). The
position of the final mixtures, invariably containing scope of this really simple procedure was then exam-
benzylidene 2 and per-O-acetylated 3.
ined on 1 with alternative aldehydes and ketones
(Table 2), and satisfying results were achieved in the
synthesis of glucosides 6–8 (Table 2, entries 4–6). The
isopropylidenated compound 9 was also prepared in
a very good yield (Table 2, entry 7), but in this case
the reaction was effective only on using 2,2-dimethox-
ypropane rather than acetone. On the other hand, the
method failed in the attempted condensation with
anisaldehyde and nonanal, or when assessed on alter-
native sugar substrates. For example, attempted pro-
tection of a b-thioglucoside tetraol afforded the corre-
sponding benzylidene 10 in a low yield (Table 2,
entry 8), whereas galacto-configured substrates exhib-
ited a very poor reactivity (data not shown). In all
these latter cases per-O-acetylation of the tetraol was
the prevailing route. With methyl a-mannopyranoside
(Table 2, entry 9), the method gave an approximately
equimolar mixture of 4,6-O-benzylidene 11 (acetylat-
ed at O-2 and O-3) and dibenzylidene 12 (diastereo-
isomeric mixture).
Table 1. Optimization of the acetolysis-induced synthesis of
benzylidenes[a]
Entry
Catalyst
Time [h]
Yield [%] of 2
1
2
3
4
Yb(OTf)3
Cu(OTf)2
Bi(OTf)3
CF3SO3H
CSA
4
4
4
4
36
2.5
2.5
60
50
10
55
70
77
71
5
6[b]
7[b]
Yb(OTf)3
CF3SO3H
In an attempt to extend the scope of the solvent-
free strategies for acetal protection, alternative syn-
thetic pathways were surveyed. The combination of
orthoesters with carbonyl compounds under acid cat-
alysis is occasionally employed under solvent-free
conditions for the acetalation of diols,[11] but it is not
applied to regioselective functionalization of polyols.
This is likely due to the poor solubility of polar polyol
[a]
General conditions: benzaldehyde (3 equiv.), Ac2O
(3 equiv.), catalyst (0.01 equiv.), room temperature; addi-
tion of pyridine (1.2 mLmmolÀ1) and Ac2O (3 equiv.).
Benzaldehyde (3 equiv.), Ac2O (1.5 equiv.), catalyst
(0.01 equiv.), room temperature; after 1.5 h, addition of
further Ac2O (1.5 equiv.); after total 2.5 h, per-O-acetyla-
tion as described above.
[b]
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Table 2. Synthesis of sugar acetals/ketals via an acetolytic activation of the aldehyde/ketone[a]
Entry
1
Product
Yield [%][b]
77
Entry
6[c]
Product
Yield [%][b]
82
2
8
2
3
4
5
41
53
7[d]
9
85
24
8
10
11 R3 =Ac
40[e]
40[e]
4
6
7
78
71
9
12 R3 =CHPh
5
[a]
General conditions: aldehyde or ketone (3 equiv.), Ac2O (1.5 equiv.), Yb(OTf)3 (0.01 equiv.), room temperature; after
1.5 h, addition of further Ac2O (1.5 equiv.); after total 2–4 h, addition of pyridine (1.2 mLmmolÀ1) and Ac2O (3 equiv.).
Isolated yield unless otherwise stated.
A third aliquot of Ac2O (1.5 equiv.) was added prior to the O-acetylation step.
2,2-Dimethoxypropane was used as the reagent.
[b]
[c]
[d]
[e]
Yield estimated by NMR analysis of the crude reaction mixture.
substrates in the reaction medium and the possible precursors. In most cases 1% catalyst was sufficient
occurrence of competitive processes arising from for a fast reaction; when necessary, the in situ addi-
direct interaction of the orthoester reagent with tion of a further aliquot was performed to shorten re-
sugars (i.e., generation of sugar orthoesters).[5b,12] Not- action times. The method was found applicable at
withstanding, an extensive screening of conditions evi- a 10-g scale (entry 4) and effective even in the pres-
denced that the aldehyde-orthoester strategy can lead ence of purportedly added water (entry 3). Notably,
to especially good results in the absence of solvents the best performing methods described in the litera-
(Table 3), adopting methyl orthoformate or orthoben- ture for the generation of 13 via a condensation with
zoate as the orthoesters, and a very low catalytic load- benzaldehyde[2b,3f,5b,6b] gave comparable or slightly
ing of CSA or Yb(OTf)3 (0.01–0.03 equiv. in most lower yields than under the solvent-free conditions
cases). Due to the much lower cost of methyl ortho- herein reported (Table 3, entry 2), but required
formate than the orthobenzoate counterpart, the a higher catalyst loading and often much more pro-
former was preferentially assessed in the following longed reaction times.
applications. As to the acid, CSA was the preferred
A preliminary exposure of the aldehyde and or-
choice in most cases, although Yb(OTf)3 was found to thoester to the catalyst in the absence of the polyol
be the best serving catalyst with thioglycoside sub- was occasionally found critical for yield improvement,
strates (Table 3, entries 11–13, 15, 17, 21) and in the owing to the minimized generation of undesired sugar
synthesis of nonylidene 16 (entries 8 and 9); on the orthoesters; this beneficial effect was especially evi-
other hand, its application in the benzylidenation of dent in the synthesis of the galacto-products 21 and
O-glycoside substrates caused partial anomerization 22 (Table 3, entries 16 and 17). Application to manno-
(Table 3, entry 5). As shown in Table 3, high yields sides once again was affected by the competitive
were generally achieved within a few hours at 70– double acetalation (data not shown), whereas the
908C, with a wide range of aldehydes and saccharide method served well with a 3-O-protected mannoside
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Three Solvent-Free Catalytic Approaches to the Acetal Functionalization
Table 3. Solvent-free synthesis of sugar acetals mediated by orthoesters[a]
Entry Catalyst (equiv.), Additional remarks
time
Product
Isolated yield [%]
79
1
CSA (0.01), 0.5 h
13
2[b]
3[b]
4[b]
CSA (0.02), 1.5 h
13
13
13
13
92
90
85
CSA (0.02), 1.5 h 0.1 equiv. H2O added
CSA (0.02), 1.5 h 10-g scale
5[b],[c] Yb(OTf)3 (0.02),
1.5 h
79 (anomeric mix-
ture)
6
CSA (0.01), 1 h
14
15
84
7
CSA (0.01), 2.5 h
44
Yb(OTf)3 (0.02),
1 h
8[d]
9
16
16
59
91
Yb(OTf)3 (0.01), PhC(OMe)3 in place of
1.5 h
HC(OMe)3
10
CSA (0.01), 1.5 h
17
91
Yb(OTf)3 (0.02),
4 h
12[d] Yb(OTf)3 (0.02), under argon
4 h
11[b]
18
18
75
82
Yb(OTf)3 (0.01),
2 h
13
19
90
gram-scale, 3 equiv. of
HC(OMe)3,
14[e] CSA (0.01), 4.5 h
20
20
69
15
Yb(OTf)3 (0.01),
3.5 h
73
16[f]
CSA (0.05), 3 h
3 equiv. of HC(OMe)3
3 equiv. of HC(OMe)3
21
81
Yb(OTf)3 (0.03),
2 h
17 [g]
22
23
89
74
18
CSA (0.01), 3 h
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Table 3. (Continued)
Entry Catalyst (equiv.), Additional remarks
time
Product
Isolated yield [%]
80
19
CSA (0.01), 1 h
24
20[b] CSA (0.02), 1.5 h
25
26
67
67
Yb(OTf)3 (0.02),
21[b]
2.5 h
27 R3 =i-Pr
28 R3 =i-Pr and/
or Me
diisopropyl tartrate as the
substrate
67
20
22
CSA (0.01), 3 h
[a]
General conditions: aldehyde (3 equiv.), HC(OMe)3 (2 equiv.), CSA or Yb(OTf)3 (0.01 equiv.), 908C. Further catalyst was
added in some cases up to the final amount indicated in the Scheme (see footnotes below for details). Times are referred
to the overall process (including the eventual pre-activation step, see below).
The second aliquot of the catalyst was added after 1 hour.
Product obtained as an anomeric mixture (a:b ca. 8).
The overall amount of the catalyst added from the start.
Aldehyde, orthoester and the catalyst kept at 908C for 1 h, then addition of the sugar.
Aldehyde, orthoester and Yb(OTf)3 (0.03 equiv.) kept at 908C for 1.5 h, then addition of the sugar and the second aliquot
of the catalyst.
Aldehyde, orthoester and the catalyst kept at 708C for 1.5 h, then addition of the sugar and the second aliquot of the cat-
alyst.
[b]
[c]
[d]
[e]
[f]
[g]
precursor (Table 3, entries 18 and 19), easily obtained out the benzylidene functionalization of carbohy-
in a single regioselective step from a mannoside pre- drates; indeed, exposure of the polyol to just a moder-
cursor.[7b,13] Besides the effective installation of ben- ate excess of benzylidene dimethyl acetal and a very
zylidene protecting groups, the strategy worked re- low loading of CSA (0.01–0.02 equiv.) at 908C proved
markably well with alternative alkyl or aromatic alde- effective within short times (0.5–3.5 h) on a variety of
hydes (Table 3, entries 6-10, 13, 14, and 19), even substrates (Table 4). Also in this case, the best per-
when applied to a sterically hindered di-substitued forming methods described in the literature for the
benzaldehyde such as o-vanillin (Table 3, entry 10). In generation of 13 via a trans-acetalation mechan-
a test experiment, the synthesis of 18 (Table 3, ism[3e,h,5b,c,14] gave comparable or slightly lower yields
entry 11) was also performed under argon, and just
a slight increase of yield was recorded (Table 3,
entry 12) to confirm the tolerance of the method to-
wards adventitious moisture. For a comparison pur-
pose, the synthesis of (2-naphthyl)methylidene 20 (en-
tries 14 and 15) was attempted through a standard
protocol by exposing ethyl b-thioglucoside to 2-naph-
thaldehyde in DMF and in the presence of CSA (0.3–
0.5 equiv.); under these conditions compound 20 was
never obtained in yields exceeding 40% even after
prolonged reaction times (48 h) at high temperature.
Unlike the method in Table 2, this orthoster-based ap-
proach was unfruitful for the isopropylidene protec-
tion; indeed, neither acetone nor 2,2-dimethoxypro-
pane were successfully activated by this reagent
system.
Another result of this investigation lies in the ex-
tension of the solvent-free strategy to the transaceta-
lation approach that is prevalently exploited to carry sugars under solvent-free conditions.
Scheme 1. One-pot Fischer glycosidation/acetalation of
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Three Solvent-Free Catalytic Approaches to the Acetal Functionalization
Table 4. Solvent-free synthesis of sugar acetals via a transacetalation process.[a]
Entry
Catalyst (equiv.)
Time [h]
Product
Isolated yield [%]
1
2
3
CSA (0.01)
1
1
1
13
13
14
95
65
80
Yb(OTf)3 (0.01)
CSA (0.01)
4
5
CSA (0.01)
CSA (0.01)
3
1
18
19
76
85
6
CSA (0.03)
1
21
78
7
8
CSA (0.01)
CSA (0.01)
0.5
1.5
25
26
78
83
27 R2 =i-Pr
65
20
9
CSA (0.01)
CSA (0.02)
3.5
3.5
28 R2 =i-Pr and/or Me
10
29
58 (73)[b]
[a]
General conditions: dimethyl acetal (2 equiv.), CSA or Yb(OTf)3 (0.01–0.03 equiv.), 908C.
Conversion.
[b]
than under the solvent-free conditions herein report- stallation of the allyl aglycone (synthetically more ver-
ed (Table 4, entry 1), requiring a higher catalyst load- satile than the methyl one) by simply performing the
ing.
transacetalation reaction in the presence of excess
The scope of some of the developed approaches allyl alcohol (Scheme 1, reactions 2 and 3). It is also
was further extended to an unprecedented one-pot worth noting that such conditions also allowed the O-
process leading to concomitant Fischer glycosidation 1 methyl to be replaced with an allyl group along with
and acetal protection of glucose and galactose in the the benzylidene installation (Scheme 1, reaction 4).
reducing form, where Yb(OTf)3 (0.05–0.07 equiv.)
proved to be the best performing catalyst (Scheme 1);
for example, 4,6-O-benzylidenated methyl glucoside Conclusions
13 was directly accessed as an anomeric mixture upon
a short exposure at 908C of glucose to benzaldehyde, In conclusion, three alternative approaches were de-
trimethyl orthoformate and the catalyst (Scheme 1, veloped for the selective acetal functionalization of
reaction 1). Even more remarkable is the feasible in- polyols. These procedures are differentiated by the
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of the benzylidene with 0.1M aqueous NaOH, and water.
The resulting organic phase was dried with sodium sulfate
and concentrated under vacuum to yield the desired product
in a pure form.
In the synthesis of galacto-benzylidenes 21 and 22, best re-
sults were obtained by premixing the aldehyde (3 mmol),
the orthoester (3 mmol) and ytterbium(III) triflate or cam-
phorsulfonic acid (0.01 mmol) at 908C. The sugar was then
added with the second aliquot of catalyst (see Table 3 for
times and amounts)
acetalation mechanism, but are endowed with multi-
ple advantages such as a remarkable experimental
simplicity, the avoided use of high-boiling solvents,
the feasible applicability to a wide range of carbonyl
precursors, reduced reaction times, very low catalyst
loadings. Some of the protocols were also found com-
patible with an unprecedented Fischer glycosidation/
acetal formation one-pot elaboration. Owing to these
practical advantages, it is expected that such protocols
will find wide application in synthetic organic chemis-
try.
Large-Scale Synthesis of 13 Mediated by Methyl
Orthoformate
To a mixture of methyl glucoside 1 (10.0 g, 51.5 mmol),
methyl orthoformate (11.3 mL. 103 mmol) and benzalde-
hyde (15.6 mL), camphorsulfonic acid (120 mg, 0.51 mmol)
was added. The mixture was kept at 908C (oil bath) for 1 h
allowing distillation of volatiles, then another aliquot of
camphorsulfonic acid (120 mg, 0.51 mmol) was added. Upon
completion of the reaction (TLC, approx. 90 min), the mix-
ture was diluted with dichloromethane and washed with
0.1M aqueous NaOH (to remove benzoic acid). The residue
of the organic phase was then crystallized with ethyl ace-
tate/hexane mixtures to obtain 8.20 g of 13. The supernatant
was concentrated and submitted to flash chromatography
(eluent: dichloromethane and then dichloromethane/metha-
nol 95:5) to obtain further 4.16 g of 13; overall yield: 85%.
Experimental Section
General Remarks
All acidic catalysts adopted in this investigation are com-
mercially available and were used as supplied without any
pre-treatment. The progress of reactions was monitored by
TLC; after elution in the suitable eluent, the plates were
soaked in 5% concentrated H2SO4 in ethanol and heated at
2308C. NMR spectra were recorded in a 400 MHz device.
Synthesis of Sugar Acetals/Ketals Mediated by Acetic
Anhydride
To a mixture of the polyol sugar (1 mmol), the aldehyde (or
ketone) (3 mmol) and acetic anhydride (140 mL, 1.5 mmol),
ytterbium(III) triflate (6.2 mg, 0.01 mmol) was added under
air. The mixture was kept under stirring for 90 min at room
temperature, after which a further aliquot of acetic anhy-
dride (140 mL, 1.5 mmol) was added. When the starting
sugar was totally consumed, pyridine (0.9 mL) and acetic an-
hydride (190 mL, 2.0 mmol) were added. On completion of
the acetylation step (approx. one hour), the mixture was
treated with methanol, and diluted with DCM. The organic
phase was washed with water, and the aqueous phase was
re-extracted with DCM. Combined organic phases were
dried with anhydrous sodium sulfate, and concentrated
under vacuum. The residue was purified by silica-gel flash
chromatography to afford acetal derivatives in the yields in-
dicated in Table 2.
Synthesis of Sugar Acetals Based on
a Transacetalation Mechanism
To a mixture of the polyol sugar (1 mmol) and dimethyl
acetal (2 mmol), camphorsulfonic acid (0.01 mmol) was
added under air (see Table 4). The mixture was kept under
stirring at 908C, allowing distillation of the volatiles. The re-
action was quenched with a few drops of pyridine and the
mixture was concentrated under vacuum. The mixture was
submitted to silica-gel flash chromatography (eluents: di-
chloromethane/methanol or hexane/ethyl acetate mixtures)
for purification of the acetal products.
One-Pot Fischer Glycosidation/Benzylidenation of
Free Sugars
For the relative amounts of reagents and the reaction tem-
peratures see entries in Scheme 1. To a mixture of the free
sugar, the acetalating agent, methyl orthoformate (when
necessary), and allyl alcohol (when necessary), ytterbiu-
m(III) triflate was added under air. The mixture was heated
to the reaction temperature and kept under stirring allowing
distillation of the volatiles. Upon completion (TLC analysis)
the reaction was quenched with a few drops of pyridine and
the mixture was concentrated under vacuo. The mixture was
submitted to silica-gel flash chromatography (eluents: di-
chloromethane/methanol or hexane/ethyl acetate mixtures)
for purification of the acetal products.
Methyl 2,3-di-O-acetyl-4,6-O-benzylidene-a-d-glucopyra-
noside (2):[15] Eluted with hexane/ethyl acetate from 7:3 to
1:1; white solid; mp 107–1098C; 1H NMR (400 MHz,
CDCl3): d=7.45–7.30 (aromatic H, 5H), 5.59 (H-3, t, J=
9.6 Hz, 1H), 5.50 (benzylidene acetal CH, s, 1H), 4.94 (H-1,
d, J=3.2 Hz, 1H), 4.91 (H-2, dd, J=3.6, 9.6 Hz, 1H), 4.29
Synthesis of Sugar Acetals Mediated by an
Orthoester
To a mixture of the polyol sugar (1 mmol), the aldehyde (or
ketone) (3 mmol) and the orthoester (220 mL, 2 mmol),
ytterbium(III) triflate or camphorsulfonic acid (0.01 mmol)
was added under air. The mixture was kept under stirring at
908C allowing distillation of the volatiles. When necessary
a further aliquot of the catalyst was added (see Table 3 for
times and amounts). The reaction was quenched with a few
drops of pyridine and the mixture was concentrated under
vacuum. The mixture was submitted to silica-gel flash chro-
matography (eluents: dichloromethane/methanol or hexane/
ethyl acetate mixtures) for purification of acetal products.
Unsubstituted benzylidene products obtained by this proce-
dure were generally contaminated with variable amounts of
benzoic acid which was removed washing a DCM solution
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FULL PAPERS
Three Solvent-Free Catalytic Approaches to the Acetal Functionalization
(H-6eq, dd, J=4.8, 10.0 Hz, 1H), 3.92 (H-5, m, 1H), 3.77 (t,
J=10.0 Hz, 1H), 3.65 (t, J=10.0 Hz, 1H), 3.40 (1-OCH3, s,
3H), 2.09 and 2.05 (2”COCH3, 2”6H); 13C NMR
(100 MHz, CDCl3): d=170.3 and 169.7 (-COCH3), 136.8 (ar-
omatic C), 129.1, 128.4, 126.0 (aromatic CH), 101.4 and 97.4
(acetal CH), 79.1, 71.5, 68.9, 68.7, 62.1, 55.2, 20.7, 20.6;
MALDI-MS: m/z=389.35 [M+Na]+, calcd. for (C18H22O8):
389.12; anal. calcd. for C13H16O4: C 59.01, H 6.05; found: C
58.94, H 6.10.
Methyl 2,3-di-O-benzoyl-4,6-O-benzylidene-a-d-glucopyr-
anoside (4):[16] Eluted with hexane/ethyl acetate from 8:2 to
7:3; white solid; mp 152–1548C; 1H NMR (400 MHz,
CDCl3): d=8.00–7.30 (aromatic H, 15H), 6.11 (H-3, t, J=
9.6 Hz, 1H), 5.60 (s, 1H), 5.31 (H-2, dd, J=3.6, 9.6 Hz, 1H),
5.21 (H-1, d, J=3.6 Hz, 1H), 4.40 (H-6eq, dd, J=4.8,
10.0 Hz, 1H), 4.11 (H-5, m, 1H), 3.95 (H-4, t, J=10.0 Hz,
1H), 3.89 (H-6ax, t, J=10.0 Hz, 1H), 3.45 (3H, s, -OCH3);
13C NMR (100 MHz, CDCl3): d=165.9, 165.5 (2”-COPh);
136.8, 133.3, and 132.9 (aromatic C); 130.0–126.1 (aromatic
CH); 101.5 and 97.7 (acetal CH), 79.3, 72.5, 69.4, 68.8, 62.5,
55.4; MALDI-MS: m/z=513.20 [M+Na]+, calcd. for
(C28H26O8); 513.15; anal. calcd. for C28H26O8: C 68.56, H
5.34; found: C 68.40, H 5.40.
71.3, 68.6, 68.5, 61.9, 55.1, 20.6 and 20.5; MALDI-MS: m/z=
389.30 [M+Na]+, calcd. for (C16H20O9): 389.11; anal. calcd.
for C16H20O9: C 56.97, H 7.31; found: C 53.93, H 5.66.
Methyl 2,3-di-O-acetyl-4,6-O-(2-naphtyl)methylene-a-d-
glucopyranoside (8):[6a] Eluted with dichloromethane/hexane
1
from 80:20 to 100:0; foam; H NMR (400 MHz, CDCl3): d=
7.95–7.45 (aromatic H, 7H), 5.67 (s, 1H), 5.64 (H-3, t, J=
9.6 Hz, 1H), 4.98 (H-1, d, J=4.0 Hz, 1H), 4.95 (H-2, dd, J=
4.0 and 9.6 Hz, 1H), 4.37 (H-6eq, dd, J=4.8 and 10.0 Hz,
1H), 4.00 (H-5, m, 1H), 3.84 (t, J=10.0 Hz, 1H), 3.72 (t, J=
10.0 Hz, 1H), 3.44 (1-OCH3, s, 3H), 2.12 and 2.07 (2”-
COCH3, 2”s, 6H); 13C NMR (100 MHz, CDCl3): d=170.4
and 169.7 (-COCH3), 134.2, 133.5, 132.7 (aromatic C); 128.3,
128.0, 127.6, 126.4, 126.0, 125.6, 123.6 (aromatic CH); 101.7
and 97.5 (acetal CH), 79.2, 71.5, 68.9, 62.3, 55.3, 20.7;
MALDI-MS: m/z=439.05 [M+Na]+, calcd. for (C22H24O8):
439.14; anal. calcd. for C22H24O8: C 63.45, H 5.81; found: C
63.65, H 5.75.
Methyl
2,3-di-O-acetyl-4,6-O-isopropylidene-a-d-gluco-
pyranoside (9): Eluted with hexane/acetone 8:2; oil; [a]2D3:
1
+85.1 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3): d=5.43
(H-3, t, J=9.6 Hz, 1H), 4.96 (H-1, d, J=3.6 Hz, 1H), 4.90
(H-2, dd, J=3.6 and 9.6 Hz, 1H), 3.95 (m, 1H), 3.87–3.65
(overlapped signals, 3H), 3.46 (1-OCH3, s, 3H), 2.12 and
2.09 (2”-COCH3, 2”s, 6H), 1.53 and 1.44 (2”isopropyli-
dene methyls, 2”s, 6H); 13C NMR (100 MHz, CDCl3): d=
170.2 and 169.7 (-COCH3), 99.6 [-C(CH3)2] and 97.4 (C-1),
71.8, 71.5, 69.2, 63.0, 62.0, 55.0, 28.8, 20.6, 20.5, 18.8;
MALDI-MS: m/z=341.10 [M+Na]+, calcd. for (C14H22O8):
341.31, anal. calcd. for C14H22O4: C 52.82, H 6.97; found: C
53.03, H 6.90.
p-Methoxyphenyl 2,3-di-O-acetyl-4,6-O-benzylidene-b-d-
glucopyranoside (5):[17] Eluted with hexane/ethyl acetate
from 8:2 to 3:7ꢁ; white solid; mp 211–2128C; 1H NMR
(400 MHz, CDCl3): d=7.45–6.80 (aromatic H, 9H), 5.52 (s,
1H), 5.39 (H-3, t, J=9.6 Hz, 1H), 5.25 (H-2, dd, J=8.0,
9.6 Hz, 1H), 5.06 (H-1, d, J=7.6 Hz, 1H), 4.38 (H-6eq, dd,
J=4.8, 10.0 Hz, 1H), 3.84 (H-4, t, J=10.0 Hz, 1H), 3.81 (H-
6ax, t, J=10.0 Hz, 1H), 3.77 (3H, s, -OCH3), 3.60 (1H, m,
H-5), 2.08 and 2.07 (2”-COCH3, 2”s, 6H); 13C NMR
(100 MHz, CDCl3): d=170.1, 169.5 (2”-COCH3); 155.8,
150.8, 136.7 (aromatic C); 130.1, 129.1, 128.4, 126.1, 118.7,
114.7 (aromatic CH); 101.5 and 100.8 (acetal CH), 78.0,
72.2, 71.7, 68.5, 66.4, 55.6, 20.7, 20.6; MALDI-MS: m/z=
481.20 [M+Na]+, calcd. for (C24H26O9): 481.15; anal. calcd.
for C24H26O9: C 62.88, H 5.72; found: C 62.70, H 5.75.
Methyl 2,3-di-O-acetyl-4,6-O-cyclohexylidene-a-d-gluco-
pyranoside (6): Eluted with hexane/ethyl acetate from 7:3 to
6:4; oil; [a]2D3: +87.8 (c 1.8, CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.25 (H-3, t, J=9.6 Hz, 1H), 4.80–4.70 (H-1 and
H-2, overlapped signals, 2H), 3.75 (H-6eq, dd, J=4.0,
10.0 Hz, 1H), 3.66 (t, J=9.6 Hz, 1H), 3.61 (H-5, m, 1H),
3.54 (t, J=9.6 Hz, 1H), 3.25 (1-OCH3, s, 3H), 2.25–2.00 (m,
3H), 1.95 and 1.92 (2”-COCH3, 2”s, 6H), 1.80–1.20 (m,
7H); 13C NMR (100 MHz, CDCl3): d=170.0 and 169.4
(-COCH3), 99.4 and 97.3 (acetal CH), 71.2, 71.1, 69.1, 63.0,
61.3, 54.8, 37.4, 27.2, 25.2, 22.4, 22.3, 20.4; MALDI-MS:
m/z=381.35 [M+Na]+, calcd. for (C17H26O8): 381.15; anal.
calcd. for C17H26O8: C 56.97, H 7.31; found: C 56.84, H 6.35.
Methyl 2,3-di-O-acetyl-4,6-O-(2-furyl)methylene-a-d-glu-
copyranoside (7):[18] Eluted with hexane/ethyl acetate 6:4;
Ethyl 2,3-di-O-acetyl-4,6-O-benzylidene-1-thio-b-d-gluco-
pyranoside (10):[19] Eluted with hexane/ethyl acetate from
1
8:2 to 7:3; foam; H NMR (400 MHz, CDCl3): d=7.50–7.30
(aromatic H, 5H), 5.50 (s, 1H), 5.34 (H-3, t, J=10.0 Hz,
1H), 5.04 (H-2, t, J=10.0 Hz, 1H), 4.59 (H-1, d, J=10.0 Hz,
1H), 4.37 (H-6eq, dd, J=4.8 and 10.4 Hz, 1H), 3.78 (t, J=
10.4 Hz, 1H), 3.66 (t, J=10.4 Hz, 1H), 3.52 (H-5, m, 1H),
2.69 (m, -SCH2CH3, 2H), 2.07 and 2.04 (2”-COCH3, 2”s,
6H), 1.26 (-SCH2CH3, t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=170.0 and 169.6 (-COCH3), 136.6 (ar-
omatic C); 129.0, 128.2, 126.6 (aromatic CH); 101.4 (acetal
CH), 84.0 (C-1), 79.1, 72.6, 71.3, 70.6, 70.5, 68.4, 24.2, 20.7
and 14.8; MALDI-MS: m/z=419.20 [M+Na]+, calcd. for
(C19H24O7S): 419.11; anal. calcd. for C19H24O7S: C 57.56, H
6.10; found: C 57.70, H 6.05.
Methyl 4,6-O-benzylidene-a-d-glucopyranoside (13):[20]
Eluted with dichloromethane/methanol from 100:0 to 95:5;
white solid; mp 165–1678C; 1H NMR (400 MHz, CDCl3):
d=7.60–7.40 (aromatic H, 5H), 5.65 (s, 1H), 4.92 (H-1, d,
J=3.6 Hz, 1H), 4.41 (H-6eq, dd, J=4.4 and 10.0 Hz, 1H),
4.04 (t, J=9.6 Hz, 1H), 3.93 (H-5, m, 1H), 3.87 (t, J=
9.6 Hz, 1H), 3.76 (H-2, dd, J=3.6, 9.6 Hz, 1H), 3.60 (t, J=
9.6 Hz, 1H), 3.58 (1-OCH3, s, 3H), 2.82 (-OH, 1H), 2.36
(-OH, d, J=9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
137.0 (aromatic C), 129.1, 128.2, and 126.3 (aromatic CH);
101.7 and 99.8 (acetal CH), 80.8, 72.5, 71.0, 68.8, 62.3, 55.3;
MALDI-MS: m/z=305.00 [M+Na]+, calcd. for (C14H18O6):
305.10; anal. calcd. for C14H18O6: C 59.57, H 6.43; found: C
59.55, H 6.40.
1
foam; H NMR (400 MHz, CDCl3): d=7.34 (bs, 1H), 6.40
(bs, 1H), 6.31 (bs, 1H), 5.51 (s, 1H), 5.50 (H-3, t, J=
10.0 Hz, 1H), 4.88 (H-1, d, J=3.2 Hz, 1H), 4.84 (H-2, dd,
J=3.2, 10.0 Hz, 1H), 4.24 (H-6eq, dd, J=4.8, 10.4 Hz, 1H),
3.88 (H-5, m, 1H), 3.69 (t, J=10.4 Hz, 1H), 3.57 (t, J=
10.4 Hz, 1H), 3.35 (1-OCH3, s, 3H), 2.08 and 2.03
(2”-COCH3, 2”s, 6H); 13C NMR (100 MHz, CDCl3): d=
170.2 and 169.6 (-COCH3), 149.2 (aromatic C); 142.5, 110.0,
and 107.9 (aromatic CH); 97.3 and 96.0 (acetal CH), 78.9,
Methyl 4,6-O-(p-methoxy)benzylidene-a-d-glucopyrano-
side (14):[21] Eluted with dichloromethane/methanol from
Adv. Synth. Catal. 2015, 357, 3562 – 3572
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Serena Traboni et al.
1
100:0 to 90:10; solid; mp 193–1958C; H NMR (400 MHz,
335.37 [M+Na]+, calcd. for (C15H20O5S): 335.09; anal. calcd.
for C15H20O5S: C 57.67, H 6.45; found: C 57.45, H 6.50.
Ethyl 4,6-O-(p-methoxy)benzylidene-1-thio-b-d-glucopyr-
anoside (19):[24] Eluted with dichloromethane/methanol
CDCl3): d=7.42 and 6.90 (2”d, J=8.4 Hz, aromatic H,
4H), 5.50 (s, 1H), 4.82 (H-1, d, J=3.2 Hz, 1H), 4.29 (H-6eq,
dd, J=4.4, 10.0 Hz, 1H), 3.96 (t, J=9.6 Hz, 1H), 3.81 (aro-
matic-OCH3, s, 3H), 3.80 (H-2, dd, J=3.6, 9.6 Hz, 1H), 3.78
(t, J=9.6 Hz, 1H), 3.77 (H-5, m, 1H), 3.50 (t, J=9.6 Hz,
1H), 3.48 (1-OCH3, s, 3H), 2.63 and 2.23 (2”bs, 2”OH);
13C NMR (100 MHz, CDCl3): d=160.2 and 129.4 (aromatic
C); 127.5, 113.6 (aromatic CH), 101.8 and 99.6 (acetal CH),
80.7, 72.7, 71.7, 68.8, 62.2, 55.4, 55.2; MALDI-MS: m/z=
335.25 [M+Na]+, calcd. for (C15H20O7): 335.12; anal. calcd.
for C15H20O7: C 57.69, H 6.45; found: C 57.80, H 6.35.
1
from 100:0 to 90:10; foam; H NMR (400 MHz, CDCl3): d=
7.40 and 6.84 (2”d, J=8.4 Hz, aromatic H, 4H), 5.42 (s,
1H), 4.36 (H-1, d, J=10.0 Hz, 1H), 4.24 (H-6eq, dd, J=4.8,
10.4 Hz, 1H), 3.75 (-OCH3, s, 3H), 3.75–3.60 (overlapped
signals, 2H), 3.50–3.30 (overlapped signals, 3H), 2.68 (m,
-SCH2CH3, 2H), 1.26 (-SCH2CH3, t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=160.0, 129.3 (aromatic C),
127.8, 113.7 (aromatic CH); 101.6 (acetal CH), 86.2 (C-1),
80.1, 74.3, 73.1, 70.3, 68.4, 55.2, 24.5, 15.1; MALDI-MS:
m/z=365.30 [M+Na]+, calcd. for (C16H22O6S): 365.40; anal.
calcd. for C16H22O6S: C 56.12, H 6.48; found: C 56.35, H
6.40.
Methyl
4,6-O-(2-furyl)methylene-a-d-glucopyranoside
(15):[18] Eluted with ethyl acetate/methanol from 100:0 to
1
80:20; foam; H NMR (400 MHz, CDCl3): d=7.37 (bs, 1H),
6.45 (d, J=2.8 Hz, 1H), 6.32 (bd, J=2.8 Hz, 1H), 5.54 (s,
1H), 4.69 (H-1, d, J=3.6 Hz, 1H), 4.19 (H-6eq, dd, J=4.8,
10.0 Hz, 1H), 3.87 (t, J=9.6 Hz, 1H), 3.75 (H-5, m, 1H),
3.65 (t, J=9.6 Hz, 1H), 3.55 (H-2, dd, J=3.6, 10.0 Hz, 1H),
3.39 (t, J=9.6 Hz, 1H), 3.36 (1-OCH3, s, 3H); 13C NMR
(100 MHz, CDCl3): d=149.4 (aromatic C), 142.6, 110.1,
108.2 (aromatic CH), 99.8 and 95.6 (acetal CH), 80.8, 72.4,
70.7, 68.7, 62.0, 55.2; MALDI-MS: m/z=295.30 [M+Na]+,
calcd. for (C12H16O7): 295.08; anal. calcd. for C12H16O7: C
52.94, H 5.92; found: C 52.75, H 5.80.
Ethyl 4,6-O-(2-naphthyl)methylene-1-thio-b-d-glucopyra-
noside (20): Eluted with dichloromethane/methanol from
1
100:0 to 95:5; foam; [a]2D3: À18.0 (c 1.1, CHCl3); H NMR
(400 MHz, CDCl3): d=7.96–7.40 (aromatic H, 7H), 5.62 (s,
1H), 4.37 (H-1, d, J=9.6 Hz, 1H), 4.34 (H-6eq, dd, J=4.8,
10.4 Hz, 1H), 3.80 (t, J=10.0 Hz, 1H), 3.74 (t, J=10.0 Hz,
1H), 3.60–3.40 (overlapped signals, 3H), 2.70 (m,
-SCH2CH3, 2H), 1.27 (-SCH2CH3, t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=134.2, 133.6, 132.8 (aro-
matic C), 128.3, 128.2, 127.6, 16.5, 126.2, 125.9, 123.7 (aro-
matic CH); 101.8 (acetal CH), 86.3, 80.3, 74.4, 73.2, 70.3,
68.5, 24.5, 15.1; MALDI-MS: m/z=385.05 [M+Na]+, calcd.
for (C19H22O5S): 385.11; anal. calcd. for C19H22O5S: C 62.96,
H 6.12; found: C 62.75, H 6.25.
Methyl 4,6-O-nonylidene-a-d-glucopyranoside (16):[22]
Eluted with ethyl acetate/hexane 7:3; oil; 1H NMR
(400 MHz, CDCl3): d=4.78 (H-1, d, J=3.6 Hz, 1H), 4.59
(nonylidene acetal CH, t, J=5.2 Hz, 1H), 4.15 (H-6eq, dd,
J=4.8, 10.0 Hz, 1H), 3.90 (t, J=9.6 Hz, 1H), 3.67 (H-5, m,
1H), 3.62 (H-2, dd, J=3.6 and 9.6 Hz, 1H), 3.52 (t, J=
9.6 Hz, 1H), 3.46 (1-OCH3, s, 3H), 3.30 (t, J=9.6 Hz, 1H),
2.15–2.10 (m, 2H), 1.80–1.65 (m, 2H), 1.40–1.20 (m, 10H),
0.93 (nonylidene -CH3, s, 3H); 13C NMR (100 MHz, CDCl3):
d=102.6 and 99.9 (acetal CH), 80.4, 72.7, 71.1, 68.4, 62.5,
55.2, 34.1, 31.7, 29.4 (”2), 29.1, 24.0, 22.5, 14.0: MALDI-
MS: m/z=341.10 [M+Na]+, calcd. for (C16H30O6): 341.20;
anal. calcd. for C16H30O6: C 60.35, H 9.50; found: C 60.40, H
9.40.
Allyl 4,6-O-benzylidene-a-d-galactopyranoside (21):[25]
Eluted with ethyl acetate/methanol from 100:0 to 90:10;
1
foam; H NMR (400 MHz, CDCl3): d=7.60–7.30 (aromatic
H, 5H), 6.02 (CH2 =CHCH2-, m, 1H), 5.63 (s, 1H), 5.42
(CHcisHtrans =CHCH2-,
bd,
J=17.2 Hz,
1H),
5.33
(CHcisHtrans =CHCH2-, bd, J=10.4 Hz, 1H), 5.17 (H-1, bs,
1H), 4.40–4.30 (CH2 =CHCHaHb-, H-4, H-6a; overlapped
signals, 3H), 4.20–4.10 (CH2 =CHCHaHb-, H-6b; overlapped
signals, 2H), 4.04 (H-2 and H-3, overlapped signals, 2H),
3.80 (H-5, s, 1H), 3.02, 2.78 (2”OH, 2H); 13C NMR
(100 MHz, CDCl3): d=137.5 (aromatic C), 133.5 (CH2=
CHCH2-), 129.1, 128.1, 126.2 (aromatic CH), 117.9 (CH2=
CHCH2-), 101.1, 98.2 (acetal CH), 75.9, 69.6, 69.4, 69.2, 68.7,
62.9; MALDI-MS: m/z=331.35 [M+Na]+, calcd. for
(C16H20O6): 331.12; anal. calcd. for C16H20O6: C 62.33, H
6.54; found: C 62.20, H 6.45.
Methyl
4,6-O-(o-hydroxy-m-methoxy)benzylidene-a-d-
glucopyranoside (17): Eluted with ethyl acetate/methanol
from 100:0 to 90:10; foam; [a]2D3: +80.8 (c 1, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.10–6.80 (aromatic H,
3H), 6.44 (phenol OH), 5.83 (s, 1H), 4.73 (H-1, bs, 1H),
4.26 (H-6eq, dd, J=3.6, 9.6 Hz, 1H), 3.90–3.60 (overlapped
signals, 3H), 3.77 (aromatic -OCH3, s, 3H), 3.52 (m, 1H),
3.43 (t, J=9.6 Hz, 1H), 3.42 (1-OCH3, s, 3H); 13C NMR
(100 MHz, CDCl3): d=147.0, 143.4, 122.8 (aromatic C);
119.6, 118.9, 111.6 (aromatic CH), 99.9 and 98.4 (acetal
CH), 81.0, 72.5, 70.9, 68.9, 62.2, 56.0, 55.4; MALDI-MS:
m/z=351.00 [M+Na]+ calcd. for (C15H20O8): 351.11; anal.
calcd. for C15H20O8: C 54.87, H 6.14; found: C 54.70, H 6.25.
Ethyl
4,6-O-benzylidene-1-thio-b-d-galactopyranoside
(22):[26] Eluted with hexane/acetone 1:1; foam; 1H NMR
(400 MHz, CDCl3): d=7.50–7.30 (aromatic H, 5H), 5.47 (s,
1H), 4.30 (H-1, d, J=9.6 Hz, 1H), 4.26 (H-6a, bd, J=
12.0 Hz, 1H), 4.13 (H-4, J=2.4 Hz, 1H), 3.94 (H-6b, bd, J=
12.0 Hz, 1H), 3.78 (H-2, t, J=9.6 Hz, 1H), 3.62 (H-3, dd,
J=2.4, 9.6 Hz, 1H), 3.37 (H-5, bs, 1H), 2.80 (m, -SCH2CH3,
2H), 1.31 (t, J=7.2 Hz, -SCH2CH3, 3H); 13C NMR
(100 MHz, CDCl3): d=137.4 (aromatic C), 128.9, 128.0,
126.2 (aromatic CH), 101.0 (acetal CH), 84.9 (C-1), 75.4,
73.4, 69.6, 69.2, 68.9, 23.2, 14.9; MALDI-MS: m/z=335.20
[M+Na]+, calcd. for (C15H20O5S): 335.09; anal. calcd. for
C15H20O5S: C 57.67, H 6.45; found: C 57.55, H 6.40.
Ethyl
4,6-O-benzylidene-1-thio-b-d-glucopyranoside
(18):[23] Eluted with dichloromethane/methanol from 100:0
1
to 90:10; foam; H NMR (400 MHz, CDCl3): d=7.50–7.30
(aromatic H, 5H), 5.48 (s, 1H), 4.38 (H-1, d, J=9.6 Hz,
1H), 4.29 (H-6eq, dd, J=4.0, 10.0 Hz, 1H), 3.75–3.60 (over-
lapped signals, 3H), 3.50–3.35 (overlapped signals, 2H), 2.71
(m, -SCH2CH3, 2H), 1.29 (-SCH2CH3, t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=136.8 (aromatic C), 129.2,
128.2, 126.2 (aromatic CH); 101.7 (acetal CH), 86.2 (C-1),
80.2, 74.3, 73.0, 70.3, 68.4, 24.5, 15.1; MALDI-MS: m/z=
Methyl 3-O-benzyl-4,6-O-benzylidene-a-d-mannopyrano-
side (23):[27] Eluted with hexane/ethyl acetate from 7:3 to
1:1; oil; 1H NMR (400 MHz, CDCl3): d=7.60–7.30 (aromatic
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Three Solvent-Free Catalytic Approaches to the Acetal Functionalization
H, 10H), 5.63 (s, 1H), 4.86 and 4.72 (-CH2Ph, AB, J=
12.0 Hz, 2H), 4.76 (H-1, s, 1H), 4.29 (H-3, dd, J=3.6 and
9.6 Hz, 1H), 4.12 (H-4, t, J=9.6 Hz, 1H), 4.05 (H-2, bs,
1H), 3.95–3.80 (H-5 and H2-6, overlapped signals, 3H), 3.38
(1-OCH3, s, 3H), 2.79 (OH-2, s, 1H); 13C NMR (100 MHz,
CDCl3): d=137.8, 137.4 (aromatic C), 133.3–126.0 (aromatic
CH), 101.5, 101.0 (acetal CH), 78.7, 75.5, 72.9, 69.7, 68.7,
63.1, 54.8; MALDI-MS: m/z=395.20 [M+Na]+, calcd. for
(C21H24O6): 395.15; anal. calcd. for C21H24O6: C 67.73, H
6.50; found: C 67.50, H 6.60.
1.26 (CH3, d, J=6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=169.1 and 168.4 (2”-CO), 135.6 (aromatic C), 129.8,
128.2, 127.1 (aromatic CH), 106.6 (-CHPh), 77.6, 77.5, 69.7,
21.6 (”2), 21.5, 21.4; MALDI-MS: m/z=345.30 [M+Na]+,
calcd. for (C17H22O6): 345.13; anal. calcd. for C17H22O6: C
63.34, H 6.88; found: C 63.55, H 6.75.
3,4,6-Tri-O-benzyl-1,2-O-benzylidene-d-sorbitol
(29):
Eluted with hexane/ethyl acetate from 8:2 to 6:4; foam;
1
[a]2D3: À1.0 (c 1.8, CHCl3); H NMR (400 MHz, CDCl3): d=
7.48–7.29 (aromatic H, 20H), 5.63 (s, 1H), 4.90–4.33 (3”-
CH2Ph, 3”AB, J=11.2 Hz, 6H), 4.15 (d, J=9.6 Hz, 1H),
4.06 (bd, J=8.0 Hz, 1H), 4.00 (bd, J=6.4 Hz, 1H), 3.95 (d,
J=11.2 Hz, 1H), 3.90–3.75 (ovelapped signals, 3H), 3.58
(dd, J=4.8, 11.2 Hz, 1H), 1.90 (bs, OH); 13C NMR
(100 MHz, CDCl3): d =138.2 (”3), 137.8 (aromatic C);
128.3–126.2 (aromatic CH); 100.9 (acetal CH), 80.5, 78.1,
76.0, 73.9, 73.3, 71.0, 69.9, 67.4, 62.5; MALDI-MS: m/z=
563.35 [M+Na]+, calcd. for (C34H36O6): 563.24, anal. calcd.
for C34H36O6: C 75.53, H 6.71; found: C 75.40, H 6.75.
Methyl
3-O-benzyl-4,6-O-(p-methoxy)benzylidene-a-d-
mannopyranoside (24): Eluted with hexane/ethyl acetate
from 7:3 to 1:1; oil; [a]2D3: +35.3 (c 2, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.60–7.00 (aromatic H, 9H), 5.71 (s,
1H), 4.97 and 4.82 (-CH2Ph, AB, J=12.0 Hz, 2H), 4.86 (H-
1, d, J=1.2 Hz, 1H), 4.40 (H-6eq, dd, J=3.6 and 9.6 Hz,
1H), 4.25 (t, J=9.6 Hz, 1H), 4.13 (H-2, dd, J=1.2, 9.6 Hz,
1H), 4.02 (H-3, dd, J=3.6, 9.6 Hz, 1H), 4.01 (t, J=9.6 Hz,
1H), 3.97 (H-5, m, 1H), 3.95 (aromatic -OCH3, s, 3H), 3.49
(1-OCH3, s, 3H); 13C NMR (100 MHz, CDCl3): d=159.8,
137.9, 128.3 (aromatic C), 128.3, 127.7, 127.2, 113.4 (aromat-
ic CH), 101.4, 101.0 (acetal CH), 78.6, 75.5, 72.8, 69.6, 68.6,
63.1, 55.1, 54.7; MALDI-MS: m/z=425.00 [M+Na]+, calcd.
for (C22H26O7): 425.16; anal. calcd. for C22H26O7: C 65.66, H
6.51; found: C 65.40, H 6.45.
Allyl
4,6-O-benzylidene-a/b-d-glucopyranoside
(30):
Eluted with dichloromethane/methanol from 100:0 to 95:5;
1
foam; H NMR (400 MHz, CDCl3; significant signals at): d=
7.60–7.30 (aromatic H), 6.00 (CH2=CHCH2-, m, 1H), 5.52
(s, 1H), 5.34 (CHcisHtrans=CHCH2-, bd, J=17.2 Hz, 1H), 5.17
(CHcisHtrans=CHCH2-, bd, J=9.6 Hz, 1H), 4.91 (H-1a, d, J=
3.6 Hz, 1H), 4.43 (H-1b, d, J=7.6 Hz, 1H), 3.95 (t, J=
9.6 Hz, 1H), 3.85 (m, 1H), 3.75 (t, J=9.6 Hz, 1H), 3.72 (H-
2a, dd, J=3.6, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3;
significant signals at): d=137.1 (aromatic C), 133.2 (CH2=
CHCH2-), 129.2, 128.3, 126.3 (aromatic signals); 118.2
(CH2=CHCH2-), 101.8, 97.9 (acetal CH), 80.9, 72.7, 71.4,
68.8, 62.5; MALDI-MS: m/z=331.20 [M+Na]+, calcd. for
(C16H20O6): 331.12; anal. calcd. for C16H20O6: C 62.33, H
6.54; found: C 62.40, H 6.50.
Allyl 4,6-O-benzylidene-2-deoxy-2-acetamido-a-d-gluco-
pyranoside (25):[28] Eluted with dichloromethane/methanol
from 100:0 to 95:5; solid; mp 207–2098C; 1H NMR
(400 MHz, CDCl3): d=7.50–7.30 (aromatic H, 5H), 6.00–
5.80 (CH2 =CHCH2- and NH-2, overlapped signals, 2H),
5.57 (s, 1H), 5.31 (CHcisHtrans=CHCH2-, bd, J=17.2 Hz, 1H),
5.25 (CHcisHtrans=CHCH2-, bd, J=10.8 Hz, 1H), 4.87 (H-1, d,
J=3.6 Hz, 1H), 4.30–4.20 (CH2 =CHCHaHb-, H-6eq and
H-2; overlapped signals, 3H), 3.98 (CH2=CHCHaHb-, m,
1H), 3.94 (t, J=10.0 Hz, 1H), 3.85 (m, H-5, 1H), 3.76 (t, J=
10.0 Hz, 1H), 3.58 (t, J=10.0 Hz, 1H), 2.07 (-NHCOCH3, s,
3H); 13C NMR (100 MHz, CDCl3) d 171.4 (CO), 137.0 (aro- Acknowledgements
matic C), 133.2 (CH2=CHCH2-), 129.1, 128.2, 126.2 (aromat-
ic CH), 118.1 (CH2=CHCH2-), 101.7, 96.9 (acetal CH), 81.9,
71.7, 70.3, 70.1, 62.6, 53.9; MALDI-MS: m/z=372.30 [M+
Na]+, calcd. for (C18H23NO6): 372.14; anal. calcd. for
C18H23NO6: C 61.88, H 6.64; found: C 61.70, H 6.70.
Financial support from Ministero dell’Istruzione, dell’Univer-
istà e della Ricerca (MIUR) (Progetto PON 00117: “Antigeni
ed adiuvanti per vaccini ed immunoterapie”) and Regione
Campania (“Progetto di Ricerca POR-BIP BioIndustrial
Processes”) is acknowledged.
Ethyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-b-
d-glucopyranoside (26):[29] Eluted with hexane/ethyl acetate
from 7:3 to 6:4; foam; 1H NMR (400 MHz, CDCl3): d=
7.85–7.30 (aromatic H, 9H), 5.59 (s, 1H), 5.42 (H-1, d, J=
10.4 Hz, 1H), 4.68 (t, J=9.6 Hz, 1H), 4.41 (H-6eq, dd, J=
4.8, 10.4 Hz, 1H), 4.35 (t, J=9.6 Hz, 1H), 3.83 (t, J=9.6 Hz,
1H), 3.71 (H-5, m, 1H), 3.62 (t, J=9.6 Hz, 1H), 2.71
(-SCH2CH3, m, 2H), 1.22 (-SCH2CH3, t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=168.1 and 167.6 (-CO),
136.9, 134.0, 131.2, 128.2, 126.2, 123.6, 123.2 (aromatic sig-
nals); 101.7 (acetal CH), 81.9, 81.7, 70.2, 69.2, 68.4, 55.4,
24.0,14.7. MALDI-MS: m/z=463.20 [M+Na]+; calcd. for
(C23H23NO6S): 463.11; anal. calcd. for C23H23NO6S: C 62.57,
H 5.25; found: C 62.75, H 5.10.
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asc.wiley-vch.de
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3572
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3562 – 3572