Regioselective acetolysis of highly O-benzylated carbohydrates promoted by iodine or an iodine/silane combined reagent: Use of isopropenyl acetate as an alternative to acetic anhydride

Article abstract of DOI:10.1002/ejoc.201300064

Regioselective acetolytic de-O-benzylation of poly-O-benzylated sugars can be triggered by the activation of isopropenyl acetate (IPA) with either an iodine/silane combined reagent or iodine alone. Unlike other known acetolysis procedures, the protocols p

Full text of DOI:10.1002/ejoc.201300064

FULL PAPER
DOI: 10.1002/ejoc.201300064
Regioselective Acetolysis of Highly O-Benzylated Carbohydrates Promoted by
Iodine or an Iodine/Silane Combined Reagent: Use of Isopropenyl Acetate as
an Alternative to Acetic Anhydride
Maddalena Giordano,[a] Alfonso Iadonisi,*[a] and Antonello Pastore[a]
Keywords: Synthetic methods / Ether cleavage / Regioselectivity / Protecting groups / Carbohydrates
Regioselective acetolytic de-O-benzylation of poly-O-benz-
ylated sugars can be triggered by the activation of isoprop-
enyl acetate (IPA) with either an iodine/silane combined
reagent or iodine alone. Unlike other known acetolysis pro-
cedures, the protocols presented here do not suffer from the
use of harsh acidic reagents and excess amounts of high-boil-
ing acetic anhydride. The activation of IPA with iodine and
triethylsilane (or the cheaper polymethylhydrosiloxane,
PMHS) usually results in shorter reaction times, with the ace-
tolysis occurring preferentially (with some exceptions) at pri-
mary benzyloxy groups. With anomerically armed sugars,
anomeric iodination can be a concomitant process to give
highly reactive intermediates which can be converted in situ
into workable and useful building blocks upon suitable
quenching conditions. On the other hand, IPA activation with
iodine alone allows the reactions to occur under milder con-
ditions, albeit over longer times. In almost all reported exam-
ples, IPA can be used in moderate excess (5 equiv.), but its
employment as the solvent is crucial with an amino sugar
model compound otherwise recalcitrant to any acetolytic
modification. An additional advantage of these conditions
lies in the unprecedented possibility of incorporating the
acetolysis step into one-pot synthetic sequences leading to
multiple functional modifications of saccharidic substrates.
As to the regioselectivity, most reactions seem to be con-
trolled by steric factors, as the most accessible primary benz-
yloxy groups are commonly acetolyzed. However, a couple
of disclosed examples display that under suitable structural
conditions, strain relief effects might be a ruling factor for the
regiocontrol of the processes. Overall, the reported protocols
offer complementary options for experimentally easy access
to a wide range of useful saccharide building blocks featur-
ing a varied profile of protecting groups.
generation of glycosyl iodide intermediates.[2] Very recently
we also reported that polymethylhydrosiloxane (PMHS)
can be an effective, cheaper alternative to triethylsilane in
many of these transformations.[3] In addition, the iodine/
triethylsilane system also proved effective in the regioselec-
tive removal of especially hindered benzyl protecting groups
from highly O-benzylated sugars.[4] In all these applications,
the reagents were used in anhydrous solvents but without
resorting to inert atmosphere.[5] The low price and the ease
of handling of these reagents prompted us to search further
for practical, convenient applications in carbohydrate chem-
istry, and we wish herein to report their effective use in the
highly regioselective acetolytic de-O-benzylation of sac-
charide derivatives and in unprecedented one-pot sequences
including an acetolytic deprotection step.
Acetolysis is a very useful transformation in carbo-
hydrate chemistry adopted for both the selective scission
of oligosaccharides[6] and the selective de-O-benzylation of
saccharide primary positions (with concomitant acetylation
thereof).[7–16] Depending on the substrate and the condi-
tions, this process can be accompanied by the acetolytic re-
moval of the aglycon. The selective change of protecting
groups in highly O-benzylated substrates is a widely investi-
gated option for introducing functional differentiation on
Introduction
Synthetic elaboration of carbohydrates is often based on
lengthy procedures due to the multifunctional nature of
sugars. Due to the relevance of carbohydrates in several
fields of synthetic organic chemistry, there is still a great
demand for ever-more-efficient protocols for the rapid dis-
crimination of their numerous reactive sites. Recently, effec-
tive sequential procedures have been proposed for that pur-
pose,[1] but use of experimentally demanding conditions is
still a frequent issue, where the reactions are mostly per-
formed under inert atmosphere and in the presence of
highly sensitive acidic reagents.
Over the last decade, we have demonstrated that a com-
bination of I2 and triethylsilane readily generates HI in situ
and can be conveniently used in a broad set of synthetic
elaborations of carbohydrates passing through a very quick
[a] Dipartimento di Scienze Chimiche, Università “Federico II” di
Napoli,
Via Cinthia 4, 80126 Naples, Italy
Fax: +39-081-674393
E-mail: iadonisi@unina.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300064.
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sugars, as also shown by recent examples of silylative de-O- Table 1. Acetolysis of 1 mediated by I2 and a silane.
benzylation at O-6 of hexopyranosides.[17]
Entry Acetylating agent Silane
Temp. [°C] % Yield (conv.)
Acetolytic de-O-benzylation is commonly carried out in
the presence of excess amounts of strong protic or Lewis
acids, such as TFA,[7] H2SO4,[8] p-toluensulfonic acid,[9]
ZnCl2,[10] ZnI2,[11] BF3·OEt2,[12] FeCl3,[13] and TMSOTf,[14]
together with a large excess of high-boiling acetic anhy-
dride, which often serves as a solvent or a cosolvent. More
recently, In(OTf)3 and I2 were also found effective for
the analogous purpose in neat acetic anhydride. Due to
these typical conditions, the experimental execution of these
reactions often entails use of sensitive reagents as well as
laborious and lengthy workup procedures. The goal of this
paper is thus focused on addressing these issues.
1
2
3
4
Ac2O
IPA
IPA
Et3SiH
Et3SiH
PMHS
none
–60 to 0
–60 to 0
–60 to 0
0 to r.t.
58
68 (78)
80
IPA
74
an acetylating agent (IPA or acetic anhydride), points to
the preferential interaction of HI with the acetylating agent
rather than with the benzyloxy groups of the substrate.
[15]
[16]
Results and Discussion
Spurred by our long-term interest towards the develop-
ment of practical procedures for regioselective modifica-
tions of carbohydrates,[4,18] we have explored the possible
development of experimentally less-demanding protocols
for acetolytic de-O-benzylation of sugars. In an initial test
reaction, model mannose derivative 1 was treated in DCM
with a slight excess of both I2 and triethylsilane (1.25 equiv.)
in the presence of a limited excess (5 equiv.) of acetic anhy-
dride (Table 1, entry 1). Starting from a very low tempera-
ture (–60 °C), the mixture was allowed to gradually warm,
and TLC analysis showed that the acetolytic de-O-benz-
ylation began at about –20 °C. After further warming to
0 °C, the 6-O-acetylated product 2 was obtained in a satis-
factory yield (55–60%). Interestingly, the use of isopropenyl
acetate (IPA) as the acetylating agent in an analogous trial
resulted in a cleaner reaction mixture and a higher yield of
2 (ca 70%) (Table 1, entry 2), although a higher tempera-
ture was required for detecting the beginning of the process.
A very good result was similarly obtained with IPA and
polymethylhydrosiloxane (PMHS) as a cheaper alternative
to triethylsilane[3] (Table 1, entry 3). Another relevant result
of this preliminary screen was the possible use of iodine
alone as an activator, although higher temperatures were
needed under these milder conditions (Table 1, entry 4).
Scheme 1. Dependence of the iodine/silane reactivity on the pres-
ence of isopropenyl acetate.
Experiments in Table 1 highlight the viable use of isopro-
penyl acetate as an effective alternative to acetic anhydride.
This is a rather interesting observation in that, to the best
of our knowledge, isopropenyl acetate has never been em-
ployed for inducing the cleavage of benzyl ethers via an ace-
tolysis pathway. Adoption of this reagent in place of acetic
anhydride looks advantageous for both the possible use of
a reduced stoichiometric excess and the much lower boiling
point (95 vs. 140 °C).
Isopropenyl acetate is instead known for its use in acetyl-
ation of free alcohols catalyzed by enzymes,[19] and its use
is less common for the analogous purpose under nonenzy-
matic conditions.[20] In particular, combination of iodine
and enol acetates was described for the acetylation of
alcohols,[21–23] phenols,[21] amines,[21] and other nucleophilic
functionalities.[24]
After the preliminary screening of conditions reported in
Table 1, the scope of iodine/silane activation of IPA was
examined with the set of saccharide building blocks shown
in Table 2.
When the gluco-configured substrate 5 was submitted to
It should be recalled at this stage that a previous investi- IPA in the presence of equimolar amounts of I2 and trieth-
gation demonstrated that under similar conditions to en- ylsilane, acetolysis at the primary position was partly ac-
tries 1–2, but in the absence of any acetylating reagent, de- companied by HI-promoted anomeric iodination to gener-
benzylation at O-4 occurs predominantly, as a consequence ate 7 together with the expected product 6 [Scheme 2, Equa-
of an HI-promoted benzyl ether cleavage (see comparison tion (1)]. Anomeric iodination was also observed previously
of results in Scheme 1).[4] The different regioselective out- on applying the HI-promoted de-O-benzylation to some
come of these reactions, only dependent on the presence of sugars specially armed at the anomeric position,[4] and the
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Regioselective Acetolysis of O-Benzylated Carbohydrates
Table 2. Acetolytic de-O-benzylation of saccharide substrates promoted by I2/silane. General conditions: premixed solution of I2
(1.25 equiv.) and silane (1.25 equiv. SiH units) in DCM at room temp., cooling to –60 °C and addition of isopropenyl acetate (5 equiv.)
and the saccharide substrate.
[a] 1.6 equiv. of I2 and Et3SiH. [b] 1.8 equiv. of I2 and –SiH units. [c] 2.0 equiv. of I2 and –SiH units. [d] Premixed solution of I2 (1.25 equiv.)
and the saccharide substrate in DCM at room temp., cooling to –60 °C and sequential addition of Et3SiH (1.25 equiv.) and isopropenyl
acetate (5 equiv.). Quenching conditions: A) addition of pyridine (5–10 equiv.); B) addition of MeOH (5 equiv.), lutidine (5 equiv.), TBAB
(0.3 equiv.), overnight stirring at room temp.; C) addition of acetic acid (4 equiv.), lutidine (7 equiv.); D) addition of MeOH (12 equiv.),
lutidine (6 equiv.), TBAB (0.4 equiv.), overnight stirring at room temp.
experience earned in that investigation provided useful Yet, the aglycon reattachment was generally found to occur
suggestions for optimizing the yield of 6. In particular, it with anomerization,[4] and a different quenching procedure
was found that: a) since part of the HI is consumed in the was therefore designed to achieve a full retention of the
anomeric iodination rather than in the de-O-benzylation, a initial α-configuration in the in situ regeneration of a
higher yielding de-O-benzylation process can be achieved methyl glucoside from iodide 7. For this purpose we at-
by increasing the I2 and triethylsilane amounts (up to tempted a halide-promoted glycosidation, performed by
1.6 equiv. after optimization in this case); and b) the diffi- adding substoichiometric amounts of tetrabutylammonium
cult isolation of highly sensitive glycosyl iodide intermedi- bromide (TBAB) and an excess of methanol and lutidine
ates (like 7) can be avoided with the reattachment of the [Scheme 2, Equation (1)]. According to a well known strat-
initial aglycon under suitable quenching conditions (ad- egy developed by Lemieux,[25] the α-iodinated intermediate
dition of the requisite alcohol and an appropriate base). can be converted in situ into a reactive β-glycosyl bromide
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(by addition of TBAB) which is more reactive towards a anomeric iodination of the starting galactoside.[26] On the
direct substitution by methanol in the presence of added other hand, when PMHS was used in place of triethylsilane,
lutidine. As a matter of fact, application of this quenching 2 equiv. of iodine and PMHS were needed to carry out both
protocol afforded the desired 6-O-acetylated product 6 es- processes (Table 2, Entry 6).
sentially as the α-anomer in high overall yield, and very
The assessment of the scope of the procedure on further
similar results were obtained by using either triethylsilane substrates resulted in other interesting observations. With
or PMHS (Table 2, entries 3 and 4). It should be noted that manno-configured precursors, a slightly decreased yield was
the analogous protocol described in Scheme 2 [Equation obtained by replacing the methyl aglycon with an allyl one
(1)] was instead much less effective on adopting acetic anhy- (compare entries 1 and 2 of Table 2 with entries 7 and 8 of
dride as the acetolysis reagent: in this case the quenching Table 2), whereas an especially good result was recorded
conditions, applied to a mixture preponderantly composed from the 2-O-Fmoc allyl mannoside 14 (Table 2, entry 9).
of 6 and 7, led to the prevalent conversion of intermediate With gluco derivatives, surprisingly, no relevant anomeric
iodide 7 into the corresponding 1-O-acetylated sugar so iodination was recorded on applying the procedure to the
that an almost equimolar mixture of this latter and the allyl β-glucoside 16Ϫthe acetolysis at O-6 was the only sig-
methyl glycoside 6 was obtained. This outcome is easily ra- nificantly detected process with both triethyilsilane and
tionalized by considering that such quenching conditions PMHS (Table 2, entries 10 and 11). On the other hand, ap-
generate an acetate anion in situ (from acetic anhydride, plication of this procedure to the 1,2-di-O-acetylated gluco
methanol and lutidine) which is especially competitive with derivative 18 proceeded with the expected anomeric iodin-
methanol for the displacement of the anomeric iodide.
ation[2a], and higher amounts of the reagents were again
necessary for the concomitant acetolysis at O-6 to occur
(Table 2, entry 12 and Scheme 3). Interestingly, the presence
of the participating group at O-2 was advantageously ex-
ploited to convert the glucosyl iodide intermediate 25 into
the corresponding 1,2-orthoester upon quenching the reac-
tion with methanol, lutidine and TBAB (Scheme 3).[2a]
Thus, the developed one-pot protocol allowed simultaneous
refunctionalization of three different positions of the start-
ing compound.
Scheme 3. One-pot 6-O-acetylation and 1,2-orthoesterification of
16.
Scheme 2. Acetolytic de-O-benzylation of gluco- and galacto pre-
cursors.
As expected, the galactose precursor 8 [Scheme 2, Equa-
Application of the procedure to the tri-O-benzylated
tion (2)] displayed increased anomeric reactivity during the glucofuranoside 20 (Table 2, entry 13) afforded an insepa-
acetolysis induced by iodine/triethyilsilane. Indeed, the allyl rable mixture composed of the corresponding 6-O-acetyl-
glycoside was quantitatively iodinated during the course of ated product 22 (minor component) and the bicyclic pyr-
the reaction to give intermediate 9, and the final quenching anoside 21. Preponderant generation of this latter product
with acetic acid and lutidine[4] allowed the high yielding highlights the propensity of the starting furanoside ring to
generation of the 1,6-di-O-acetylated derivative 10 (62%) undergo an acetolysis-induced endocyclic cleavage, followed
and the corresponding hemiacetal 11 (22%), whose genera- by the reclosure of a pyranoside ring and de-O-benzylation
tion was probably due to adventitious moisture in the reac- at O-5 (Scheme 4). The higher propensity of fused bicyclic
tion medium[26] [Scheme 2, Equation (2) and Table 2, entry systems to modifications passing through an endocyclic
5]. Notably, in this case a slight excess of I2 and triethyl- cleavage is documented by numerous recent examples in the
silane (1.25 equiv.) was sufficient to promote both acetolysis literature.[27] Interestingly, minor amounts of pure 23, which
at O-6 and anomeric iodination, to suggest that Et3SiI (gen- arises from acetolytic 6-de-O-benzylation of 21, could also
erated together with HI) is reactive enough to promote the be isolated from the reaction mixture (Table 2, entry 13).
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Regioselective Acetolysis of O-Benzylated Carbohydrates
Table 3. Acetolytic de-O-benzylation of saccharide substrates pro-
moted by I2 in DCM. General conditions: addition of I2
(1.25 equiv.) at 0 °C to a solution in DCM of the saccharide sub-
strate and isopropenyl acetate (5 equiv.). Spontaneous warming to
room temp., 3–20 h.
Scheme 4. Possible mechanism for the conversion of furanoside 20
into pyranoside 21.
In an initial attempt to expand the scope of the method-
ology to amino sugars, model compound 24, N-protected
with a phthalimido group, was also exposed to the I2/Et3-
SiH system in the presence of IPA (5 equiv.). Under these
conditions, no appreciable amounts of acetolysis products
could be isolated, and the starting substrate was almost
quantitatively recovered (Table 2, entry 14). In this regard,
it should be noted that some examples in the literature indi-
cate that N-protected amino sugars are less reactive towards
acetolysis conditions, as shown by the especially prolonged
times (16–48 h) needed by procedures that are otherwise ef-
fective in a few hours.[28]
Having established the scope of the acetolysis procedure
based on iodine/silane activation, the scope of iodine as the
sole promoter was next investigated. The results are re-
ported in Table 3.
Consistent with the trend observed in the preliminary
screening on compound 1 (Table 1), acetolysis reactions
conducted by exposing the saccharide substrates to a slight
excess of iodine and IPA (5 equiv.) in DCM required higher
temperatures and longer times than in presence of a silane
coreagent. However, in most cases, synthetically useful re-
sults were achieved. Interestingly, under these milder condi-
tions, the gluco derivative 5 (Table 3, entry 2) was also par-
tially acetolyzed at the anomeric position to produce an in-
separable mixture of 6-O-acetylated products 6 and 26. It
is worth recalling at this stage that with the iodine/silane
promoter, the analogous substrate underwent a different
anomeric modification [1-iodination rather than aglycon
acetolysis, Scheme 2, Equation (1)].
On the other hand, iodine activation resulted in the ex-
clusive acetolysis at the primary position of the β-glucoside
16 (Table 3, entry 5). Likewise, the same compound gave no
anomeric modification even with the more reactive iodine/
[a] 2.1 equiv. of I2 instead of 1.25.
silane promoter (Table 2, entries 10 and 11). Galactoside 8 the iodine activation was especially highlighted in its appli-
was instead highly prone to the acetolytic removal of both cation to compound 18, which was exclusively acetolyzed
the aglycon and the primary benzyl group, and use of at its primary position to give the 1,2,6-tri-O-acetylated
2.1 equiv. of iodine allowed access to the 1,6-di-O-acet- compound 27 (Table 3, entry 6), whereas the corresponding
ylated product 10 in a satisfactory yield (Table 3, entry 3). glycosyl iodide intermediate 25 (Scheme 3) was formed on
An especially good result was recorded once again with the using the combined I2/Et3SIH activation (Scheme 3 and
manno-configured 2-O-Fmoc derivative 14 (Table 3, entry Table 2, entry 12). Finally, the iodine-promoted acetolysis
4, see for comparison Table 2, entry 9). The usefulness of of 20 provided a set of products similar to that obtained
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with the iodine/silane reagent (compare entry 7 of Table 3 Table 4. Acetolytic de-O-benzylation of saccharide substrates pro-
moted by I2 in neat IPA. General conditions: Addition at 0 °C of
with entry 13 of Table 2).
I2 (1.7–1.8 equiv.) to a solution of sugar in isopropenyl acetate (ca.
100 mg/mL), and then spontaneous warming to room temp.
After having established two effective activation condi-
tions of IPA for achieving high-yielding regioselective acet-
olysis reactions, the effort was refocused on extending the
scope of the methodology to amino sugars. Due to the poor
reactivity exhibited by 24 when treated with a limited excess
of isopropenyl acetate in the presence of iodine and trieth-
ylsilane (Table 2, entry 14) in dichloromethane, it was antic-
ipated that use of isopropenyl acetate as a solvent might
result in an effective strategy to accelerate acetolytic depro-
tections. Due to the low cost of isopropenyl acetate and its
relative volatility (ca 95 °C), this procedure was deemed to
be of practical value, especially in view of the routine use
of the higher-boiling acetic anhydride as the solvent in al-
ternative protocols. As a matter of fact, exposure of 24 to
iodine in isopropenyl acetate eventually provided, after
overnight stirring at room temp., the desired acetolysis
product 28 in appreciable yield (49%) and conversion
(61%) (Table 4, entry 1).
The optimization of this protocol on several substrates
(Table 4) showed that iodine was partly consumed by pro-
cesses exclusively involving isopropenyl acetate molecules,
as also evidenced by the complex mixture of products ob- cally useful results were achieved. Exposure of cellobiose
tained by an experiment in the absence of any saccharidic disaccharide 29 to acetolysis promoted either by iodine
substrate. On this basis, an optimization of the acetolysis [Scheme 5, Equation (2)] or the iodine/triethylsilane reagent
yields was achieved by slightly increasing the stoichiometric [Scheme 5, Equation (1)] resulted in the unique result in
amount of iodine to 1.7–1.8 equiv. and by adopting highly which the debenzylation/acetylation process engaged exclu-
concentrated conditions (100 mg of sugars/mL isopropenyl sively a non-primary position (the O-3 position of the re-
acetate). Besides the feasible application to amino sugar 24, ducing gluco terminus). Interestingly, disaccharide 29 exhib-
these conditions gave especially good results on substrates ited the same kind of regioselectivity when submitted to
with poor anomeric reactivity (Table 4, entries 2 and 4). It the HI-induced de-O-benzylation procedure (namely, under
is also worth noting that these reactions were generally analogous conditions but in absence of isopropenyl acet-
shorter (a few hours) than when iodine was used in di- ate).[4] This analogy seemed to suggest that with this sub-
chloromethane with a limited excess of isopropenyl acetate strate, the acetolysis regiocontrol was mainly governed by
(5 equiv., see conditions of Table 3). On the other hand, iso- steric strain relief effects, because an especially encumbered
propenyl acetate side products were occasionally coeluted secondary benzyl ether was acetolyzed (see below for fur-
with the desired saccharide products, which were then ob- ther mechanistic considerations).
tained in slightly contaminated form.
Another interesting result was recorded with per-O-
The scope of our acetolysis protocols was next extended benzylated trehalose 31 [Scheme 5, Equation (3)]. Wide
to disaccharide model compounds, and further syntheti- interest is devoted to selective modifications of the primary
Scheme 5. Application of the acetolysis protocol to model disaccharides.
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Regioselective Acetolysis of O-Benzylated Carbohydrates
positions of this disaccharide, as shown by several examples of acids or acetic anhydride; namely, under the typical con-
of multistep sequences aimed at the selective deprotection ditions of numerous acetolysis protocols.
of one or both of the primary positions.[29] Indeed, unlike
the cellobiose disaccharide 29, acetolysis of per-O-benzyl-
ated trehalose 31 provided a mixture of separable mono-
and di-O-acetylated products, with the primary position(s)
being exclusively committed in the process [Scheme 5,
Equation (3)].
Mechanistic Considerations
As previously shown, the acetolysis rate was found to be
dependent on the presence of a silane co-promoter along
with iodine. This difference suggests that HI might be the
actual promoter upon use of both iodine and silane,
whereas iodine should play the corresponding role in the
absence of silane. Thus, the acetolysis in the presence of
IPA is likely triggered by the initial electrophilic iodination
(in the presence of iodine) or protonation (with iodine and
triethylsilane) of the electron-rich double bond (Scheme 7).
The resulting cationic intermediate should be reactive
enough to effect the acetylation of an accessible benzyl
ether oxygen with concomitant generation of iodoacetone
(or acetone). Nucleophilic attack of the iodide anion gener-
ated in situ on the benzyl oxonium intermediate brings
about the final release of the benzyl group as benzyl iodide,
which was detected in the crude reaction mixtures.
Besides its multiple practical advantages, our acetolysis
strategy offers an original opportunity for the possible in-
corporation of the reaction into one-pot synthetic se-
quences, which would allow the straightforward refunction-
alization of multiple saccharide positions. Inspired by a re-
cently reported one-pot sequence of glycosidation/Fmoc re-
moval,[30] we have probed on compound 14 the sequence of
acetolysis/Fmoc deprotection by simply adding excess TEA
to the corresponding acetolysis mixture. The overall pro-
cedure turned out to be very fast and provided compound
34 in an excellent overall yield (93%) (Scheme 6).
Consistent with the typical regioselectivity observed in
other acetolysis approaches, primary benzyl groups were
preferentially cleaved, thus highlighting the main role
played by the steric effects (in particular, the accessibility of
the substrate to the reactive reagent) in the regiocontrol of
the processes. However, this general trend was eluded in the
case of the bicyclic furanoside 20 (Table 2, entry 13 and
Scheme 6. One-pot acetolysis/Fmoc removal sequence.
It is pertinent to point out that an analogous sequence Table 3, entry 7) and the cellobioside disaccharide 29
would not be applicable in the presence of excess amounts [Scheme 5, Equation (1) and Equation (2)]. In order to as-
Scheme 7. Hypothesized mechanism of the acetolytic de-O-benzylation with IPA.
Scheme 8. Variable regioselectivity in acetolytic de-O-benzylation of disaccharide 29.
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M. Giordano, A. Iadonisi, A. Pastore
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sess the reproducibility of this unusual selectivity under dif- accordance with the trend displayed by other known ace-
ferent acetolysis conditions, 20 and 29 were submitted to tolysis protocols, with steric effects playing a prominent role
the acetolysis conditions reported by Kong and coworkers in the regioselectivity control. On the other hand, in a cou-
(8 eq of ZnCl2 in acetic anhydride/acetic acid),[10] which are ple of our examples strain relief effects emerged as the main
of frequent use according to recent literature.[28,31] Expo- factors ruling the regioselectivity. Overall, the set of re-
sure of 20 to such conditions afforded a very complex mix- ported protocols provide complementary options for exper-
ture containing furanoside and pyranoside structures as imentally easy access to a wide range of useful saccharide
well as products resulting from partial acetolytic cleavage. building blocks featuring a varied profile of protecting
In contrast, exposure of 29 to analogous conditions resulted groups.
in only a partial conversion of the starting compound to
the 6Ј-O-acetylated derivative 35 after 4 h at room temp.
[Scheme 8, Equation (2)], a result that is more consistent
Experimental Section
with the general preference of these reactions for an acet-
General Remarks: Spectroscopic data of known compounds 2,[7]
olytic cleavage of the most accessible O-benzylated sites.
6,[7] 10,[16] 11,[32] 26,[33] 27,[9] 34,[34] 35,[35] were in accordance with
those reported in the literature.
Interestingly, upon exposure of the same substrate to stoi-
chiometric iodine in isopropenyl acetate as the solvent, a
2:1 mixture of inseparable isomers 35 and 30 was obtained
in ca 60% overall yield as estimated by NMR due to the
contamination of isopropenyl acetate side products
[Scheme 8, Equation (3)]. It is worth recalling that 30 was
instead the main product when the I2-promoted acetolysis
General Procedure for Acetolysis Promoted by the Iodine/Silane
Combined System: To a solution of I2 (107 mg, 0.42 mmol) in
dichloromethane (7.0 mL) was added triethylsilane (67 μL,
0.42 mmol) or polymethylhydrosiloxane (25 μL, 0.42 mmol). The
solution was stirred for 5 min.at room temp., and then the vessel
was cooled to –60 °C. Isopropenyl acetate (165 μL, 1.5 mmol) and
reaction was performed in dichloromethane and in the pres-
ence of a limited excess of isopropenyl acetate [Scheme 8,
Equation (1)]. Comparison of these results points to the
influence of the concentration of the acetylating reagent in
determining the selectivity of the process, although at this
stage it is not clear how this effect might be exerted.
a solution of the saccharide substrate (0.3 mmol) in DCM (ca
1 mL) were sequentially added, and the temperature was left to
gradually rise. Upon completion (monitored by TLC analysis) the
reaction was quenched as indicated in the entries of Table 2. The
mixture was diluted with DCM, and the organic phase was washed
with aq. hydrogen carbonate containing sodium thiosulfate. The
aqueous phase was re-extracted with DCM, and the collected or-
ganic phases were dried and concentrated in vacuo. The resulting
crude product was purified by silica gel flash chromatography,
eluted by hexane/ethyl acetate mixtures.
Conclusions
General Procedure for Acetolysis Promoted by Iodine in Dichloro-
methane: A solution of I2 (107 mg, 0.42 mmol) in dichloromethane
(7.5 mL) was cooled to 0 °C, and then isopropenyl acetate (165 μL,
1.5 mmol) and a solution of the saccharide substrate (0.3 mmol) in
DCM (ca 1 mL) were sequentially added. The mixture was warmed
to room temp. Upon completion of the reaction, the mixture was
then diluted with DCM, and the organic phase was washed with
aq. hydrogen carbonate containing sodium thiosulfate. The aque-
ous phase was re-extracted with DCM, and the collected organic
phases were dried and concentrated in vacuo. The resulting crude
product was purified by silica gel flash chromatography, eluted by
hexane/ethyl acetate mixtures.
In this paper we have introduced a set of protocols for
the regioselective acetolytic de-O-benzylation of highly O-
benzylated substrates that are practically advantageous for
both the use of isopropenyl acetate (a very convenient alter-
native to acetic anhydride) and the avoidance of strong and
sensitive acidic reagents. When the reaction was activated
by a combination of iodine and triethylsilane (or the
cheaper polymethylhydrosiloxane polymer), faster aceto-
lysis reactions were generally observed, and a concomitant
anomeric iodination occurred on especially reactive gluco
and galacto derivatives. Intermediate glycosyl iodides thus
generated could be easily converted in situ into useful build-
ing blocks upon suitable quenching conditions. The use of
iodine as the sole stoichiometric promoter of the process
allowed acetolysis to occur under essentially neutral condi-
tions at room temperature with the avoidance of anomeric
iodination for 1-O-acetylated precursors. Application of
these conditions in isopropenyl acetate as the solvent
proved useful for extending the scope of the acetolysis to
the otherwise unreactive amino sugar building block 24.
An unprecedented application of the reported acetolysis
conditions within a one-pot sequence of acetolytic de-O-
benzylation/Fmoc removal was also demonstrated with the
multiple refunctionalization of a saccharidic precursor. The
reported acetolysis conditions led frequently to the regiose-
lective modification of primary saccharide positions and, in
General Procedure for Acetolysis Promoted by Iodine in Isopropenyl
Acetate as the Solvent: To a solution of the saccharide substrate in
isopropenyl acetate (100 mg/mL) was added iodine (1.7–1.8 eq/
mmol sugar) at 0 °C. The mixture was warmed spontaneously to
room temp. Upon completion (see Table 4 for the times), the mix-
ture was diluted with DCM, and the organic phase was washed
with aq. hydrogen carbonate containing sodium thiosulfate. The
aqueous phase was re-extracted with DCM, and the collected or-
ganic phases were dried and concentrated in vacuo. The resulting
crude product was purified by silica gel flash chromatography,
eluted by hexane/ethyl acetate mixtures.
One-Pot Acetolysis/Fmoc Removal. Synthesis of 34: To a solution
of I2 (57 mg, 0.22 mmol) in dichloromethane (4.0 mL) was added
PMHS (13.5 μL, 0.22 mmol). The solution was stirred for 5 min.
at room temp., and then the vessel was cooled to –60 °C. Isopro-
penyl acetate (120 μL, 1.1 mmol) and a solution of 14 (130 mg,
some cases, of the anomeric position. These results were in 0.18 mmol) in DCM (1.5 mL) were sequentially added, and the
3144 Eur. J. Org. Chem. 2013, 3137–3147
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Regioselective Acetolysis of O-Benzylated Carbohydrates
temperature was left to gradually rise to room temp. over 2 h. The
mixture was then cooled to 0 °C, excess TEA (0.4 mL) was added,
and the vessel was left to spontaneously warm. About 1.5 h after
the addition of the base, the mixture was diluted with DCM, and
the organic phase was washed with aq. thiosulfate. The aqueous
phase was re-extracted with DCM, and the collected organic
phases were dried and concentrated in vacuo. The resulting crude
product was purified by silica gel flash chromatography, eluted by
hexane/ethyl acetate, 1:1 to yield 34 as an oil (74 mg, 93% yield).
2.5, 12.5 Hz, 1 H, 6a-H), 4.19 (dd, J = 5.5, 12.5 Hz, 1 H, 6b-H),
3.93 (t, J = 3.5 Hz, 1 H, 3-H), 3.85 (m, 1 H, 5-H), 3.55 (t, J = 3.5
and 9.5 Hz, 1 H, 4-H), 3.30 (s, 3 H, -OCH3), 2.02 (s, 3 H, -COCH3),
1.67 (s, 3 H, orthoester CH3) ppm. 13C NMR (125 MHz, CDCl3): δ
= 170.8, (-COCH3); 137.4 (ϫ2, aromatic C), 128.5–128.1 (aromatic
CH), 121.3 (orthoester C), 97.5 (1-C), 77.7, 74.9, 74.8, 72.4, 71.8,
68.4, 63.6, 50.7 and 20.8 ppm. MALDI-TOF MS: m/z = 481.35 [M
+ Na]+. C25H30O8 (458.19): calcd. C 65.49, H 6.60; found C 65.35,
H 6.75.
Allyl 6-O-Acetyl-2,3,4-tri-O-benzyl-α-
D-mannopyranoside (13): 4-O-Acetyl-3,6-di-O-benzyl-1,2-isopropylidene-α-
D
-glucopyranose
[α]2D8 = +30.2 (c = 1.20, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
7.50–7.20 (aromatic H), 6.00–5.90 (m, 1 H, -OCH2CH=CH2), 5.27
(qd, J = 1.6, 17.2 Hz, 1 H, -OCH2CH=CHcisHtrans), 5.20 (qd, J =
1.6, 10.4 Hz, 1 H, -OCH2CH=CHcisHtrans), 4.94 (d, J = 1.6 Hz, 1
H, 1-H), 5.00–4.60 (2ϫ AB and s, 6 H, 3ϫ -CH2Ph), 4.38 (d, J =
(21) and 6-O-Acetyl-3,5-di-O-benzyl-1,2-isopropylidene-α-D-gluco-
furanose (22): 1H NMR (500 MHz, CDCl3): signals of 19 at δ =
7.40–7.20 (m, aromatic H), 5.65 (d, J = 5.0 Hz, 1 H, 1-H), 5.12
(dd, J = 1.5, 9.0 Hz, 1 H, 4-H), 4.84–4.54 (2 ϫ AB, 4 H, 2 ϫ
-CH2Ph), 4.23 (dd, J = 3.0, 5.0 Hz, 1 H, 2-H), 4.04 (m, 1 H, 5-H),
3.6 Hz, 2 H, 6-H2), 4.20–4.15 (m, 1 H, -OCHa HbCH=CH2), 4.05– 3.77 (t, J = 3.0 Hz, 1 H, 3-H), 3.62–3.55 (m, 2 H, 6-H2), 1.99 (s, 3
3.93 (overlapped signals, 3 H; 3-H, 5-H and -OCHaHbCH=CH2), H, -COCH3), 1.58 and 1.34 (2ϫ s, 6 H, 2 ϫ acetonide CH3) ppm.
3.90–3.80 (overlapped signals, 2 H, 2-H and 4-H), 2.10 (s, 3 H,
-COCH3) ppm. 13C NMR (100 MHz, CDCl3):
170.8 (m, 1 H, 2-H), 4.30 (dd, J = 3.0, 9.0 Hz, 1 H), 4.15 (dd, J = 5.0,
(-COCH3), 138.2, 138.1, 138.0 (aromatic C), 133.5 (-CH=CH2), 12.5 Hz, 1 H), 2.06 (s, 3 H, -COCH3), 1.49 and 1.32 (2ϫ s, 6 H,
Significant signals of 20 at δ = 5.90 (d, J = 3.5 Hz, 1 H, 1-H), 4.68
δ
=
128.5–127.5 (aromatic CH), 97.0 (1-C), 80.1, 75.2, 74.5 (ϫ2), 72.6,
72.1, 70.1, 67.9, 63.4; 20.8 (-COCH3) ppm. MALDI-TOF MS: m/z
= 555.35 [M + Na]+. C32H36O7 (522.25): calcd. C 72.16, H 6.81;
found C 72.30, H 6.75.
2ϫ acetonide CH3) ppm. 13C NMR (125 MHz, CDCl3) signals of
21 at δ = 170.1 (-COCH3), 138.0 and 137.7 (aromatic C), 128.4–
127.5 (aromatic CH), 109.4 (acetonide C), 96.9 (1-C), 75.7, 74.3,
73.4, 69.8, 68.4 (ϫ2); 26.3 and 25.4 (acetonide methyl groups), 21.0
(-COCH3) ppm. Significant signals of 22 at δ = 170.8 (-COCH3),
138.0 and 137.4 (aromatic C), 111.8 (acetonide C), 105.1 (1-C),
81.7, 81.6, 78.7, 74.2, 72.4, 71.9, 63.7; 26.8 and 26.3 (acetonide
methyl groups), 20.9 (-COCH3) ppm. MALDI-TOF MS: m/z =
465.50 [M + Na]+. C25H30O7 (442.51): calcd. C 67.86, H 6.83;
found C 67.70, H 6.85.
Allyl 6-O-Acetyl-3,4-di-O-benzyl-2-O-fluorenylmethoxycarbonyl-α-
D
-mannopyranoside (15): [α]2D8 = +13.3 (c = 1.47, CHCl3). 1H NMR
(400 MHz, CDCl3):
δ = 7.85–7.20 (aromatic H), 6.00–5.90
(m, 1 H, -OCH2CH=CH2), 5.32 (qd, J = 1.6, 17.2 Hz, 1 H,
-OCH2CH=CHcisHtrans), 5.30–5.24 (overlapped signals, 2 H, 2-H
and -OCH2CH=CHcisHtrans), 5.02 (d, J = 1.6 Hz, 1 H, 1-H), 5.00–
4.60 (2ϫ AB, 4 H, 2ϫ -CH2Ph), 4.49 (dd, J = 7.2, 10.0 Hz, 1 H,
4,6-Di-O-acetyl-3-O-benzyl-1,2-O-isopropylidene-α-D-glucopyranose
-OCHaHbCH-), 4.41 (d, J = 3.2 Hz, 2 H, 6-H2), 4.36 (dd, J = 7.6, (23): [α]2D4 = +17.4 (c = 1.15, CHCl3). 1H NMR (400 MHz, CDCl3):
10.0 Hz, 1 H, -OCHaHbCH-), 4.29 (bt, J = 7.2 Hz, 1 H, -OCH2CH- δ = –7.35–7.25 (m, aromatic H), 5.60 (d, J = 4.8 Hz, 1 H, 1-H), 4.99
), 4.25–4.20 (m, 1 H, -OCHaHbCH=CH2), 4.10 (dd, J = 3.2, 8.8 Hz,
1 H, 3-H), 4.04 (m, 1 H, -OCHaHbCH=CH2), 3.95–3.80 (over-
lapped signals, 2 H, 4-H and 5-H), 2.11 (s, 3 H, -COCH3) ppm.
δ = 170.8 (-COCH3), 154.6 and 2.05 (2ϫ s, 6 H, -COCH3), 1.56 and 1.30 (2ϫ s, 6 H, 2ϫ
(-OCO2-); 143.4, 143.1, 137.8 and 137.7 (aromatic C), 133.1, 128.5–
(dd, J = 2.0, 9.6 Hz, 1 H, 4-H), 4.80 and 4.68 (AB, J = 12.0 Hz, 2
H, -CH2Ph), 4.24 (dd, J = 3.2,4.8 Hz, 1 H, 2-H), 4.25–4.15 (m, 2
H, 6-H2), 4.06 (m, 1 H, 5-H), 3.77 (t, J = 3.0 Hz, 1 H, 3-H), 2.08
13C NMR (100 MHz, CDCl3):
acetonide CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.9,
170.1 (-COCH3), 137.5 (aromatic C), 128.4 and 127.9 (aromatic
127.6, 125.2, 125.0, 120.0 and 118.1 (aromatic CH), 96.5 (C-1),
78.1, 75.3, 73.8, 72.3, 71.7, 70.1, 69.7, 68.2, 63.2, 46.5; 20.8 CH), 109.5 (acetonide C), 96.8 (1-C), 75.8, 74.3, 71.7, 68.2, 67.1,
(-COCH3) ppm. MALDI-TOF MS: m/z = 687.10 [M + Na]+.
C40H40O9 (664.27): calcd. C 72.27, H 6.07; found C 72.40, H 6.05.
63.6; 26.4 and 25.4 (acetonide methyl groups), 21.0 and 20.9
(-COCH3) ppm. MALDI-TOF MS: m/z = 417.35 [M + Na]+.
C20H26O8 (394.36): calcd. C 60.90, H 6.64; found C 60.75, H 6.75.
Allyl 6-O-Acetyl-2,3,4-tri-O-benzyl-β-D
-glucopyranoside (17): [α]2D5
= +14.5 (c = 1.40, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.35–
7.20 (m, aromatic H), 6.00–5.90 (m, 1 H, -OCH2CH=CH2), 5.32
(qd, J = 1.6, 17.2 Hz, 1 H, -OCH2CH=CHcisHtrans), 5.23 (qd, J =
Allyl 6-O-Acetyl-3,4-di-O-benzyl-2-deoxy-2-phthalimido-β-D-gluco-
pyranoside (28): [α]2D8 = +46.3 (c = 0.67, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.70–6.80 (m, aromatic H), 5.60–5.70 (m,
1.6, 10.0 Hz, 1 H, -OCH2CH=CHcisHtrans), 5.00–4.55 (3ϫ AB, 12 1 H, -OCH2CH=CH2), 5.18 (d, J = 8.0 Hz, 1 H, 1-H), 5.11 (qd, J
H, 6ϫ -CH2Ph), 4.47 (d, J = 8.0 Hz, 1 H, 1-H), 4.45–4.35 (m, 1 = 1.5, 18.0 Hz, 1 H, -OCH2CH=CHcisHtrans), 5.23 (qd, J = 1.5,
H, -OCHa HbCH=CH2), 4.36 (dd, J = 2.0, 12.0 Hz, 2 H, 6a-H), 10.5 Hz, 1 H, -OCH2CH=CHcisHtrans), 4.90–4.40 (2ϫ AB, 4 H,
4.24 (dd, J = 4.8, 12.5 Hz, 2 H, 6b-H), 4.20–4.15 (m, 1 H, -OCHa-
HbCH=CH2), 3.69 (t, J = 9.6 Hz, 1 H, 3-H), 3.60–3.45 (overlapped
signals, 2 H, 2-H and 4-H), 2.02 (s, 3 H, COCH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.7 (-COCH3), 138.4, 138.3, 137.8 (aro-
matic C), 133.8 (CH=CH2), 128.5–127.4 (aromatic CH), 117.5
(CH=CH2), 101.9 (1-C), 84.6, 82.2, 77.4, 75.7, 75.0, 74.8, 72.8,
2ϫ -CH2Ph), 4.44 (t, J = 8.0, 10.5 Hz, 1 H, 3-H), 4.39 (dd, J =
7.5, 12.0 Hz, 1 H, 6a-H), 4.28 (dd, J = 3.5, 12.0 Hz, 1 H, 6b-H),
4.26–4.18 (overlapped signals, 2 H, 2-H and -OCHaHbCH=CH2),
4.00–3.97 (m, 1 H, -OCHaHbCH=CH2), 3.74–3.66 (overlapped sig-
nals, 2 H, 4-H and 5-H), 2.09 (s, 3 H, COCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.8 (-COCH3), 137.8, 137.6, 131.6 (aro-
70.4, 63.1; 20.8 (-COCH3) ppm. MALDI-TOF MS: m/z = 555.20 matic C), 133.6 (CH=CH2), 133.7, 128.6–127.3 (aromatic CH),
[M + Na]+. C32H36O7 (532.25): calcd. C 72.16, H 6.81; found C
72.35, H 6.70.
117.4 (CH=CH2), 97.3 (1-C), 79.5, 79.4, 75.0, 74.9, 73.0, 69.9, 62.9,
55.8; 20.9 (-COCH3) ppm. MALDI-TOF MS: m/z = 594.40 [M +
Na]+. C33H33NO8 (571.22): calcd. C 69.34, H 5.82; found C 60.20,
H 5.90.
6-O-Acetyl-3,4-di-O-benzyl-1,2-O-(1-methoxy)ethylidene-α-
D-gluco-
pyranose (19): 1H NMR (500 MHz, CDCl3): δ = 7.40–7.20 (m, aro-
matic H), 5.73 (d, J = 5.0 Hz, 1 H, 1-H), 4.75–4.38 (3ϫ AB, 6 H, Allyl 2,3,4,6-Tetra-O-benzyl-β-
D-glucopyranosyl-(1Ǟ4)-3-O-acetyl-
3ϫ -CH2Ph), 4.58 (dd, J = 3.0, 5.0 Hz, 1 H, 2-H), 4.26 (dd, J = 2,6-di-O-benzyl-β-
D
-glucopyranoside (30): [α]2D4 = +28.8 (c = 1.00,
Eur. J. Org. Chem. 2013, 3137–3147
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3145

M. Giordano, A. Iadonisi, A. Pastore
FULL PAPER
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.40–7.15 (m, aromatic
1
Nature Protocols 2008, 3, 97–113; d) A. A. Joseph, V. P. Verma,
X.-Y. Liu, C.-H. Wu, V. M. Dhurandhare, C.-C. Wang, Eur.
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The Polysaccharides (Ed.: G. O. Aspinall), Academic Press,
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H), 6.00–5.90 (m, 1 H, -OCH2CH=CH2), 5.33 (qd, J = 1.6,
17.2 Hz, 1 H, -OCH2CH=CHcisHtrans), 5.20 (qd, J = 1.6, 10.4 Hz,
1 H, -OCH2CH=CHcisHtrans), 5.15 (t, J = 9.6 Hz, 1 H, 3-H), 4.89–
4.43 (3ϫ AB, 12 H, 6ϫ -CH2Ph), 4.48 (d, J = 8.0 Hz, 1 H, 1-H),
4.45–4.35 (m, 1 H, -OCHaHbCH=CH2), 4.31 (d, J = 8.0 Hz, 1 H,
1Ј-H), 4.16–4.08 (m, 1 H, -OCHaHbCH=CH2), 3.86 (t, J = 9.6 Hz,
1 H, 4-H), 3.77 (dd, J = 4.0, 10.8 Hz, 1 H, 6-H), 3.72 (dd, J = 1.6,
10.8 Hz, 1 H, 6Ј-H), 3.68–3.62 (overlapped signals, 2 H, 6-H and
6Ј-H), 3.59 (t, J = 9.6 Hz, 1 H, 3Ј-H), 3.49 (t, J = 9.6 Hz, 1 H, 4Ј-
H), 3.43–3.35 (overlapped signals, 2 H, 2Ј-H-and 5Ј-H), 3.33–3.35
(overlapped signals, 2 H, 2-H and 5-H), 1.93 (s, 6 H, COCH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 170.5 (-COCH3), 138.6, 138.5
(ϫ2), 138.2, 138.0, 137.8 (aromatic C), 133.9 (-CH=CH2), 128.3–
127.5 (aromatic CH), 117.2 (-CH=CH2), 102.6 (1-C and 1Ј-C),
84.7, 82.3, 79.0, 77.6, 75.4, 74.9, 74.8, 74.4, 74.1, 73.7, 73.2, 73.1,
70.2, 68.9, 67.6, 20.8 ppm. MALDI-TOF MS: m/z = 988.40 [M +
Na]+. C59H64O12 (965.13): calcd. C 73.42, H 6.48; found C 73.25,
H 6.55.
[2]
[3]
[4]
6-O-Acetyl-2,3,4-tri-O-benzyl-α-
D-glucopyranosyl-(1Ǟ1)-2,3,4,6-
tetra-O-benzyl-α-
D
-glucopyranoside (32): [α]2D4 = +94.8 (c = 0.95,
[5]
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.45–7.10 (m, aromatic
H), 5.21 and 5.20 (2ϫ d, J = 3.5 Hz, 2 H, 1-H and 1Ј-H), 5.05–
4.35 (7ϫ AB, 14 H, 7ϫ -CH2Ph), 4.26 (m, 1 H, 5-H), 4.17–4.12
(overlapped signals, 2 H, 6a-H and 5Ј-H), 4.10–4.00 (overlapped
signals, 3 H, 3-H, 3Ј-H, 6b-H), 3.68 (t, J = 9.0 Hz, 1 H, 4Ј-HЈ),
3.61 (dd, J = 3.5, 10.0 Hz, 1 H, 2-H), 3.57 (dd, J = 3.5, 10.0 Hz, 1
H, 2Ј-H), 3.55–3.50 (overlapped signals, 2 H, 4-H and 6Јa-H), 3.38
(bd, J = 10.0 Hz, 1 H, 6Јb-H), 1.98 (s, 3 H, COCH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 170.6 (-COCH3), 138.8, 138.6, 138.3,
138.0, 137.9 (ϫ2), 137.8 (aromatic C), 128.3–127.3 (aromatic CH),
94.4 and 94.0 (1-C and 1Ј-C), 81.7, 81.6, 79.4, 79.2, 77.6, 75.5, 75.5,
75.0 (ϫ2), 73.5, 72.9, 72.6, 70.7, 68.9, 68.1, 62.8; 20.8 (-COCH3)
ppm. MALDI-TOF MS: m/z = 1037.65 [M + Na]+. C63H66O12
(1014.46): calcd. C 74.54, H 6.55; found C 74.75, H 6.45.
[6]
[7]
a) D. Prosperi, S. Ronchi, L. Lay, A. Rencurosi, G. Russo, Eur.
J. Org. Chem. 2004, 395–405; b) A. Fekete, K. Gyergyói, K.
Kövér, I. Bajza, A. Lipták, Carbohydr. Res. 2006, 341, 1312–
1321.
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27, 1907–1917; b) R. J. Tennant-Eyles, B. G. Davis, A. J. Fair-
banks, Tetrahedron: Asymmetry 2000, 11, 231–243; c) S. N.
Lam, J. Gervay-Hague, J. Org. Chem. 2005, 70, 2387–2390; d)
Y. Cao, H. Yamada, Carbohydr. Res. 2006, 341, 909–911.
[8]
[9]
Y. Cao, Y. Okada, H. Yamada, Carbohydr. Res. 2006, 341,
2219–2223.
6-O-Acetyl-2,3,4-tri-O-benzyl-α-
acetyl-2,3,4-tri-O-benzyl-α-
D-glucopyranosyl-(1Ǟ1)-6-O-
[10]
[11]
G. Yang, X. Ding, F. Kong, Tetrahedron Lett. 1997, 38, 6725–
D
-glucopyranoside (33): [α]2D4 = +89.2 (c
6728.
= 0.95, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.40–7.20 (m,
aromatic H), 5.18 (d, J = 3.0 Hz, 2 H, 1-H), 5.04–4.53 (3ϫ AB, 12
H, 6ϫ -CH2Ph), 4.24 (m, 2 H, 5-H), 4.15 (dd, J = 3.5, 12.5 Hz, 2
H, 6a- H), 4.07 (t, J = 9.5 Hz, 2 H, 3-H), 4.04 (dd, J = 2.0, 12.5 Hz,
2 H, 6b-H), 3.58 (dd, J = 3.5, 10.0 Hz, 2 H, 2-H), 3.54 (t, J =
10.0 Hz, 2 H, 4-H), 1.98 (s, 6 H, COCH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.5 (-COCH3), 138.6, 137.9, 137.8 (aro-
matic C), 128.5–127.4 (aromatic CH), 94.0 (C-1 and C-1Ј), 81.6,
79.3, 77.4, 75.6, 75.1, 74.2, 72.9, 69.1, 63.8; 20.2 (-COCH3) ppm.
MALDI-TOF MS: m/z = 989.55 [M + Na]+. C58H62O13 (966.56):
calcd. C 72.03, H 6.46; found C 72.15, H 6.40.
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Acknowledgments
MS and NMR facilities of CIMCF (Centro Interdipartimentale di
Metodologie Chimico-Fisiche dell’Università di Napoli) are ac-
knowledged for support.
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Received: January 14, 2013
Published Online: April 3, 2013
Eur. J. Org. Chem. 2013, 3137–3147
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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